WO2023143354A1 - Tricyclic compound and application thereof - Google Patents

Tricyclic compound and application thereof Download PDF

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WO2023143354A1
WO2023143354A1 PCT/CN2023/073087 CN2023073087W WO2023143354A1 WO 2023143354 A1 WO2023143354 A1 WO 2023143354A1 CN 2023073087 W CN2023073087 W CN 2023073087W WO 2023143354 A1 WO2023143354 A1 WO 2023143354A1
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ring
alkyl
substituted
cancer
optionally substituted
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PCT/CN2023/073087
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Chinese (zh)
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张海生
卓鉥
胡亚兵
代长贵
陈洁
程辉敏
陈誉
王雯莉
潘伟
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希格生科（深圳）有限公司
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Publication of WO2023143354A1 publication Critical patent/WO2023143354A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to tricyclic compounds and applications thereof.
  • the Hippo signaling pathway regulates many biological processes, including cell proliferation, survival, differentiation, organ size, and tissue homeostasis.
  • This pathway consists of a complex cascade of serine/threonine protein kinases, including serine-threonine kinase 3 (STK3) and STK4.
  • SAV1 adapter protein salvador homolog 1
  • LATS1/2 Upon activation, LATS1/2 binds to MOB kinase activator 1A/B (MOB1A/B) and represses the transcriptional cofactor yes-associated protein (YAP1) and transcriptional coactivators with PDZ-binding motifs (TAZ or WWTR1).
  • Hippo pathway When the Hippo pathway is "off,” phosphorylated YAP/TAZ remains cytoplasmic and proteolytic degradation may occur. When the Hippo pathway is "on,” unphosphorylated YAP/TAZ enters the nucleus and binds the transcription factors TEADNA-binding proteins (TEAD1-4). Dysregulation of the Hippo pathway leads to increased activity of YAP/TAZ, which is associated with tumors, hyperproliferation, cell invasion, metastasis, and chemoresistance.
  • TEADNA-binding proteins TEAD1-4
  • the TEAD transcription factor family is the final effector of the Hippo pathway, which regulates the expression of target genes (Kras, Braf, Ctgf, Cyr6, Axl, Myc, etc.) ), which in turn mediate tumor growth, metastasis, and tissue homeostasis.
  • target genes Kras, Braf, Ctgf, Cyr6, Axl, Myc, etc.
  • TEAD is highly expressed in a variety of solid tumors, including prostate cancer, gastric cancer, breast cancer, germ cell tumors, squamous cell carcinoma of the head and neck, and renal cell carcinoma. Due to its high correlation with clinicopathological parameters of human malignancies, TEAD can be used as a prognostic biomarker in solid tumors.
  • the Hippo pathway is an important anti-tumor target discovered in the past decade. Compared with regulators targeting the upstream of the Hippo signaling pathway, inhibitors targeting TEAD-YAP may be more effective and directly correct the dysregulated Hippo signaling pathway,
  • One aspect of the present application relates to a class of compounds capable of binding to TEAD and acting as TEAD inhibitors. Another aspect of the application relates to processes for the preparation of the compounds described herein. Still another aspect of the present application relates to a pharmaceutical composition comprising the compound of the present invention as an active ingredient, and the clinical application of the compound or the pharmaceutical composition of the present invention for tumor treatment.
  • the Ao ring is selected from 5-6 membered heteroaryl groups, 5-6 membered heterocyclic groups, and phenyl groups, and the Ao ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, Rm; preferably Preferably, the Ao ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, pyridyl, and the Ao ring is optionally replaced by 1-3 members selected from Rx, Ry, Substituents of Rz and Rm are substituted; more preferably, the Ao ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, pyridyl, and the 5-membered heteroaryl
  • the group contains 2-4 heteroatoms selected from N, O, S, and the Ao ring is optionally substituted by 1-3 substitu
  • the Ao ring is selected from a 5-membered heteroaryl group, the Ao ring is optionally substituted by Rx,
  • the Ao ring is optionally substituted by Ry, Rz and Rm;
  • the Ao ring is optionally substituted by Ry and Rm;
  • the Ao ring is optionally substituted by Rz;
  • the Ao ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the Ao ring is optionally substituted by 1-2 substituents selected from Rz and Rm ;
  • the Ao ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group,
  • the 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any of the following conditions (1)-(3):
  • the Ao ring is selected from a 5-membered heteroaryl group, the Ao ring is optionally substituted by Rx,
  • the Ao ring is optionally substituted by Ry, Rz and Rm;
  • the Ao ring is optionally substituted by Ry and Rm;
  • the Ao ring is optionally substituted by Rz;
  • the Ao ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the Ao ring is optionally substituted by 1-2 substituents selected from Rz and Rm ;
  • Ra, Rb, and Rc are each independently selected from H, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, or Ra, Rb and the carbon atoms connected to them together form azetidine, and
  • the azetidine is optionally substituted by a hydroxyl group; preferably, Ra, Rb, and Rc are each independently selected from H, methyl, cyano, cyclopropyl, or Ra, Rb and their joint
  • the carbon atoms are taken together to form an azetidine, and the azetidine is optionally substituted with a hydroxyl group;
  • Rx is selected from hydroxyl, methyl,
  • Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by 1-6 deuterium, C3- C1-C6 alkyl substituted by C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, C1-C6 alkyl substituted by C6-C10 aryl, Substituted C1-C6 alkyl, 4-6 membered saturated heterocyclic group; preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 substituted by 1-6 halogen Alkyl, C1-C6 alkyl substituted by 1-6 deuterium, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10
  • Rz is selected from C1-C6 alkyl, halogen, Preferably, Rz is selected from methyl, Br, Or, Ry, Rz and their common carbon atoms together form a 4-6 membered saturated carbocyclic ring, a 4-6 membered saturated heterocyclic ring; or preferably, Ry, Rz and their common connected carbon atoms form a 4-6 membered saturated carbocyclic ring, 4-6 membered saturated heterocyclic ring, the 4-6 membered saturated heterocyclic ring contains 1 heteroatom; or more preferably, Ry, Rz and their common carbon atoms together form Cyclobutane, cyclopentane, cyclohexane, piperidine, tetrahydropyran; or most preferably, Ry, Rz and together with the carbon atoms to which they are commonly attached, form Wherein, the 1' carbon atom is a carbon atom connected to Ry and Rz; Rm is an oxo group;
  • the Ao ring and its optional substituents, taken as a whole, are selected from the following:
  • Bo rings are selected from: It is optionally substituted with 1-3 substituents selected from: thiopentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1 -6 halogen substituted C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkoxy, halogen, nitro, cyano, amino;
  • the above It is optionally substituted with 1-2 substituents selected from the group consisting of: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkane Base, 1-6 halogen substituted C1-C6 alkoxy, halogen; more preferably, the above Optionally substituted with 1-2 substituents selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl , 1-6 halogen substituted C1-C6 alkoxy, halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl, halogen;
  • substitution positions of the substituents on it are: 2-position mono-substitution, 3-position mono-substitution, 5-position mono-substitution, 4-, 5-position double substitution, 5-, 6-position double substitution, 2-, 5-position - double substitution, 3-, 5-position double substitution;
  • the substitution positions of the substituents on it are 3-position mono-substitution and 5-position mono-substitution;
  • the substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 6-position monosubstituted;
  • the substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution;
  • substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 5-position monosubsti
  • Bo ring is selected from:
  • the Co ring is selected from 5-membered heteroaryl ring, 6-membered partially unsaturated heterocyclic ring; preferably, the 5-membered heteroaryl ring is selected from Preferably, the 6-membered partially unsaturated heterocycle is
  • a 10 , A 20 , A 30 , A 40 are independently selected from: N, CH, wherein at most 3 are N;
  • L is selected from direct bonds, NH, O, S; preferably, L is selected from direct bonds, NH;
  • Ro is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C5 heteroaryl, C1-C6 Alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 Heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen Substituted C1-C6 alkyl, C1-C6 alkyl substituted by cyano, C1-C6 alkoxy substituted by 1-6 halogen, halogen, cyano, nitro, oxo, C2-C6 alkene C1-C6 alkyl group, C1-C6 alky
  • Ro is selected from: oxo, -OCH 3 , -CH 3 , -F, -Cl, -CN, -OH, -NH 2 , -COOH, -COOCH 3 , -CH 2 CH 3 , -CF 3 , -CHF 2 , or two Ro together with the atoms to which they are attached:
  • the Ao ring and its optional substituents as a whole are selected from Preferably, the Ao ring and its optional substituents as a whole are selected from Most preferably, the Ao ring and its optional substituents, taken as a whole, are
  • the Aoc ring and its optional substituents as a whole are selected from Preferably, the Aoc ring and its optional substituents as a whole are selected from Most preferably, the Aoc ring and its optional substituents as a whole are
  • the definition of the Co ring is the same as that of the Co ring in the above formula O; the definition of Ro is the same as the definition of Ro in the above formula O.
  • the definition of the Aoc ring and its optional substituents as a whole is the same as the definition of the Aoc ring and its optional substituents in the above formula Oc; the definitions of A 10 , A 20 , A 30 , and A 40 are the same as those in the above formula The definitions of A 10 , A 20 , A 30 , and A 40 in O are the same; the definition of Ro is the same as that of Ro in the above formula O.
  • the above-mentioned compound of formula O is the following formula O-1:
  • the definition of Ao ring is the same as the definition of Ao ring in the above-mentioned formula O;
  • the definition of Bo ring is the same as the definition of Bo ring in the above-mentioned formula O;
  • the definition of Co ring is the same as the definition of Co ring in the above-mentioned formula O;
  • the definition is the same as the definition of L 0 in the above formula O;
  • Ro 11 , Ro 12 and the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or 5-6 membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, partially unsaturated 5-6 membered heterocyclic ring or 5-6 membered heteroaromatic ring is optionally replaced by 1-6 members selected from halogen and deuterium group; preferably, Ro 11 ,
  • Ro 11 , Ro 12 and the atoms attached to them together form:
  • A1 ring is the same as the definition of Ao ring in the above formula O;
  • B1 ring is the same as the definition of Bo ring in the above formula O;
  • L 1 is the same as the definition of L 0 in the above formula O;
  • a 1 , A 2 , A 3 and A 4 are independently selected from: N, CH, and at most 3 of them are N;
  • R 1 is the same as the definition of Ro in the above formula O.
  • a 1c ring and its optional substituents as a whole have the same definition as the Aoc ring and its optional substituents in the above formula Oc as a whole;
  • a 1 , A 2 , A 3 , and A 4 are independently selected from : N, CH, wherein at most 3 are N;
  • the definition of R1 is the same as the definition of R1 in the above formula I.
  • the A11 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group,
  • the 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
  • the A11 ring is selected from a 5-membered heteroaryl group, the A11 ring is optionally substituted by Rx,
  • the A11 ring is selected from a 5-membered unsaturated heterocyclic group, the A11 ring is optionally substituted by Rm or Rz, or optionally substituted by Ry and Rm;
  • Rx is selected from methyl
  • Ry is a methyl group; Rz is selected from halogen (preferably Br); Rm is an oxo group;
  • ring A11 and its optional substituents taken as a whole, are selected from the following:
  • Ring B11 is selected from: It is optionally substituted with 1-3 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 Alkyl, 1-6 halogen substituted C1-C6 alkoxy, halogen, amino;
  • the above Optionally substituted with 1-2 substituents selected from: 1-6 halogen substituted C1-C6 alkyl, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 alkane Oxygen, amino;
  • the B11 ring is selected from:
  • R 11 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, halogen, cyano, nitro;
  • R 11 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl , halogen, cyano; further preferably, R 11 is selected from: -CH 3 , -F, -Cl, -CN; more preferably, R 11 is located in ring The position on is selected from: 1-position, 2-position, 3-position, 4-position.
  • the above-mentioned compound of formula I-1 is the following formula I-1c:
  • a 11c ring and its optional substituents as a whole are selected from Preferably, the A 11c ring and its optional substituents as a whole are selected from More preferably, the A 11c ring and its optional substituents, taken as a whole, are
  • the definition of R 11 is the same as the definition of R 11 in the above formula I-1.
  • the A12 ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group,
  • the 5-membered heteroaryl is selected from
  • the 5-membered unsaturated heterocyclic group is selected from And meet any of the following conditions (1)-(3):
  • the A12 ring is selected from a 5-membered heteroaryl group, the A12 ring is optionally substituted by Rx,
  • Ring A12 is selected from When, the A12 ring is optionally substituted by 1-2 substituents selected from Rz and Rm;
  • Rx is selected from hydroxyl
  • Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3
  • Rz is selected from methyl, Alternatively, Ry, Rz, and the carbon atoms connected to them together form Wherein, the 1' carbon atom is a carbon atom connected to Ry and Rz; Rm is an oxo group;
  • ring A12 and its optional substituents taken as a whole, are selected from the following:
  • the B12 ring is selected from: It is optionally substituted with 1-3 substituents selected from: thiopentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1 -6 halogen substituted C1-C6 alkyl, halogen, nitro, cyano, amino;
  • substituents are selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen;
  • substitution positions of the substituents on it are: 2-position mono-substitution, 3-position mono-substitution, 5-position mono-substitution, 4-, 5-position double substitution, 5-, 6-position double substitution, 2-, 5-position - double substitution, 3-, 5-position double substitution;
  • the substitution positions of the substituents on it are 3-position mono-substitution and 5-position mono-substitution;
  • substitution position is 5-position monosubstitution;
  • substitution position of the substituent on it is 6-position monosubstituted;
  • substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution;
  • substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution;
  • substitution position of the substituent on it is 5-position monosubstituted;
  • substitution position of the substituent on it is 5-position monosubstituted;
  • the B12 ring is selected from:
  • R 12 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by amino, C1-C6 alkoxy substituted by 1-6 halogen, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester Group (-CO-O-C1-C6 alkyl), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered heterocycl
  • the above-mentioned compound of formula I-2 is the following formula I-2c:
  • a 12c ring and its optional substituents as a whole are selected from:
  • the A 12c ring and its optional substituents, taken as a whole, are selected from:
  • the A 12c ring and its optional substituents, taken as a whole, are selected from:
  • the definition of A 12 , A 22 , A 32 , A 42 is the same as the definition of A 12 , A 22 , A 32 , A 42 in the above formula I-2;
  • the definition of R 12 is the same as the definition of R 12 in the above formula I-2 same.
  • the above-mentioned compound of formula I is the following formula I-3:
  • A13 ring is selected from 5-6 membered heteroaryl, 5-6 membered heterocyclic group, phenyl, and A13 ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, Rm ;
  • the A13 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, pyridine group, and A13 ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, Rm; more preferably, A13 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, pyridyl, the 5-membered heteroaryl group contains 2-4 heteroatoms selected from N, O, S, and the A13 ring is optionally replaced by 1-3 selected from Rx , Ry, Rz, Rm are substituted by substituents;
  • the A13 ring is selected from a 5-membered heteroaryl group, the A13 ring is optionally substituted by Rx,
  • the A13 ring is optionally substituted by Ry and Rm;
  • the A13 ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the A13 ring is optionally substituted by 1-2 substituents selected from Rz and Rm ;
  • the A13 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group,
  • the 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any of the following conditions (1)-(3):
  • the A13 ring is selected from a 5-membered heteroaryl group, the A13 ring is optionally substituted by Rx,
  • the A13 ring is optionally substituted by Ry and Rm;
  • the A13 ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the A13 ring is optionally substituted by 1-2 substituents selected from Rz and Rm ;
  • Ra, Rb, and Rc are each independently selected from H, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, or Ra, Rb and the carbon atoms connected to them together form azetidine, and The azetidine is optionally substituted by a hydroxyl group; preferably, Ra, Rb, and Rc are each independently selected from H, methyl, cyano, cyclopropyl, or Ra, Rb and their joint carbon atoms together to form azetidine, and said azetidine is optionally substituted by hydroxyl;
  • Rx is selected from hydroxyl, methyl,
  • Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by 1-6 deuterium, C3- C1-C6 alkyl substituted by C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, C1-C6 alkyl substituted by C6-C10 aryl, Substituted C1-C6 alkyl, 4-6 membered saturated heterocyclic group; preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 substituted by 1-6 halogen Alkyl, C1-C6 alkyl substituted by 1-6 deuterium, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10
  • Rz is selected from C1-C6 alkyl, halogen, Preferably, Rz is selected from methyl, Br,
  • Ry, Rz and their common carbon atoms together form a 4-6 membered saturated carbocyclic ring, a 4-6 membered saturated heterocyclic ring; or preferably, Ry, Rz and their common connected carbon atoms form a 4-6 membered saturated carbocyclic ring, 4-6 membered saturated heterocyclic ring, the 4-6 membered saturated heterocyclic ring contains 1 heteroatom; or more preferably, Ry, Rz and their common carbon atoms together form Cyclobutane, cyclopentane, cyclohexane, piperidine, tetrahydropyran;
  • Ry, Rz and together with their common carbon atoms form Wherein, the 1' carbon atom is the carbon atom connected with Ry and Rz;
  • Rm is an oxo group
  • the A13 ring and its optional substituents as a whole are selected from the following:
  • the A13 ring is selected from: and said optionally by Rm Substituted, or optionally substituted by Ry and Rm; wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 ; Rm is an oxo group;
  • ring A13 and its optional substituents taken as a whole, are selected from the following:
  • Ring B13 is selected from: It is optionally substituted with 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 substituted with 1-6 halogen Alkyl, halogen, amino;
  • the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl;
  • the B13 ring is selected from:
  • L is selected from direct bond, NH, O, S; preferably, L is selected from direct bond, NH;
  • R 13 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkoxy substituted by 1-6 halogen, cyano Substituted C1-C6 alkyl, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, 5-6 membered saturated heterocyclic group substituted by C1-C3 alkyl (preferably C1-C3 alkyl substituted 6-membered saturated heterocyclic group); or two R 13 , the atoms connected to them together form a C6-C10 aromatic ring, partially unsaturated C5-C6 carbocyclic ring, partially unsaturated 5-6-membered Heterocyclic ring or 5-6 membered heteroaryl ring, wherein the partially unsaturated C5-C6 carbocyclic ring, partially unsaturated 5-6 membered heterocyclic ring
  • R 13 is selected from: -OCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CF 3 , -CHF 2 , -NH 2 , or two R 13 together with the atoms they are attached to form: More preferably, the position of R 13 on the ring is selected from: A 23 position, A 33 position;
  • a 13 , A 23 , A 33 , and A 43 are independently selected from: N, CH, and only 2 of them are N, and the rest are CH;
  • a 13 , A 23 , A 33 , A 43 are selected from the following combinations:
  • Both A 13 and A 43 are N, and both A 23 and A 33 are CH;
  • Both A 33 and A 43 are N, and both A 13 and A 23 are CH;
  • Both A 23 and A 43 are N, and both A 13 and A 33 are CH.
  • the above-mentioned compound of formula I-3 is the following formula I-3c:
  • a 13c ring and its optional substituents as a whole are selected from:
  • the A 13c ring and its optional substituents, taken as a whole, are selected from:
  • the A 13c ring and its optional substituents, taken as a whole, are selected from:
  • a 13 , A 23 , A 33 , A 43 is the same as the definition of A 13 , A 23 , A 33 , A 43 in the above formula I-3; the definition of R 13 is the same as the definition of R 13 in the above formula I-3 same.
  • Y 14 is selected from N, CH;
  • A14 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, and the 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
  • the A14 ring is selected from a 5-membered heteroaryl group, the A14 ring is optionally substituted by Rx,
  • Rx is selected from hydroxyl
  • Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rz is selected from methyl,
  • Ry, Rz, and the carbon atoms connected to them together form Wherein, the 1' carbon atom is the carbon atom connected with Ry and Rz;
  • Rm is an oxo group
  • ring A14 and its optional substituents, taken as a whole, are selected from the following:
  • Ring B14 is selected from: It is optionally substituted with 1-3 substituents selected from: thiopentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1 -C6 alkyl, halogen, nitro, cyano, amino, C3-C4 cycloalkyl,;
  • the above It is optionally substituted with 1-2 substituents selected from the group consisting of: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkane base, halogen;
  • the substitution positions of the substituents on it are: 2-position mono-substitution, 3-position mono-substitution, 5-position mono-substitution, 4-, 5-position double substitution, 5-, 6-position double substitution, 2-, 5-position - double substitution, 3-, 5-position double substitution;
  • the substitution positions of the substituents on it are 3-position mono-substitution and 5-position mono-substitution;
  • the substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 6-position monosubstituted,
  • the substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution;
  • the substitution position of the substituent on it is 5-position monosub
  • the B14 ring is selected from:
  • R 14 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by amino, C1-C6 alkyl substituted by cyano, C1-C6 substituted by 1-6 halogen Alkoxy, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 heterocycle Oxygen group, carboxyl group (-COOH), ester group (-CO-O-C1-C6 alkane base), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substitute
  • R is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyls on N, carbamoyl substituted by 1-2 C1-C6 alkyls on N, pyridyl C1-C6 Alkoxy, hydroxyl substituted C1-C6 alkoxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkane Oxygen, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogen, C1-C6 alkyl substituted by amino, C1-C6 alkyl substituted by cyano, halogen, cyano, C2 -C6 alkenyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclic group is optionally substituted by
  • R 14 is selected from: -OH, -NH 2 , -COOH, -COOCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CHF 2 , -CF 3 , or two R14 together with the atoms they are attached to form:
  • the A111 ring is selected from 5-membered heteroaryl groups and 5-membered unsaturated heterocyclic groups
  • the 5-membered heteroaryl groups are selected from
  • the 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
  • the A111 ring is selected from a 5-membered heteroaryl group, the A111 ring is optionally substituted by Rx,
  • the A111 ring is selected from a 5-membered unsaturated heterocyclic group, the A111 ring is optionally substituted by Rm or Rz, or optionally substituted by Rm and Ry;
  • Rx is selected from methyl
  • Ry is selected from methyl
  • Rz is selected from halogen (preferably Br);
  • Rm is an oxo group;
  • ring A111 and its optional substituents, taken as a whole are selected from the following: More preferably, ring A111 and its optional substituents as a whole are selected from Further preferably, ring A111 and its optional substituents as a whole are selected from Most preferably, the A111 ring and its optional substituents, taken as a whole, are
  • the B111 ring is selected from: It is optionally substituted with 1-3 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, 1-6 Halogen substituted C1-C6 alkoxy, halogen; preferably, the above Optionally substituted by 1-2 substituents selected from: 1-6 halogen substituted C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkoxy; more preferably, the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -OCF 3 ;
  • the B111 ring is selected from: preferably
  • the A112 ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group,
  • the 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
  • the A112 ring is selected from a 5-membered heteroaryl group, the A112 ring is optionally substituted by Rx,
  • the A112 ring is selected from a 5-membered unsaturated heterocyclic group, the A112 ring is optionally substituted by Rm or Rz, or optionally substituted by Ry and Rm;
  • Rx is selected from methyl
  • Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rz is selected from halogen (preferably Br), Rm is an oxo group;
  • the A112 ring and its optional substituents, taken as a whole, are selected from the following:
  • B112 rings are selected from: It is optionally substituted with 1-3 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, 1-6 Halogen substituted C1-C6 alkoxy, halogen; preferably, the above Optionally substituted by 1-2 substituents selected from: 1-6 halogen substituted C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkoxy; more preferably, the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -OCF 3 ; most preferably, ring B112 is:
  • R 112 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, halogen, cyano, nitro, amino; more preferably, R 112 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyls on N, 1-2 C1- on N C6 alkyl substituted carbamoyl, C1-C6 alkyl, halogen, cyano; further preferably, R is selected from: -CH 3 , -CH 2 CH 3 , CF 3 , -F, -Cl, -CN;
  • R 112 is located in ring
  • the position on is selected from: 1-position, 2-position, 3-position, 4-position.
  • the A 112c ring and its optional substituents as a whole are selected from Preferably, the A 112c ring and its optional substituents as a whole are selected from
  • R 112 is the same as the definition of R 112 in the above formula I-1-2.
  • the A121 ring is selected from 5-membered heteroaryl groups and 5-membered unsaturated heterocyclic groups
  • the 5-membered heteroaryl groups are selected from
  • the 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
  • the A121 ring is selected from a 5-membered heteroaryl group, the A121 ring is optionally substituted by Rx,
  • the A121 ring is optionally substituted by Ry, Rz and Rm;
  • the A121 ring is optionally substituted by Ry and Rm;
  • the A121 ring is optionally substituted by Rz;
  • Rx is selected from hydroxyl
  • Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rz is selected from methyl,
  • Ry, Rz, and the carbon atoms connected to them together form Wherein, the 1' carbon atom is the carbon atom connected with Ry and Rz;
  • Rm is an oxo group
  • ring A121 and its optional substituents taken as a whole, are selected from the following:
  • the B121 ring is selected from: It is optionally substituted with 1-3 substituents selected from: thiopentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1 -C6 alkyl, halogen, nitro, cyano, amino;
  • the above It is optionally substituted with 1-2 substituents selected from the group consisting of: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkane base, halogen;
  • substitution positions of the substituents on it are: 2-position mono-substitution, 3-position mono-substitution, 5-position mono-substitution, 4-, 5-position double substitution, 5-, 6-position double substitution, 2-, 5-position - double substitution, 3-, 5-position double substitution;
  • the substitution positions of the substituents on it are 3-position mono-substitution and 5-position mono-substitution;
  • the substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 6-position monosubstituted,
  • the substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution;
  • the substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 5-position monosubstituted;
  • the substitution position of the substituent on it is 5-position monosub
  • the B121 ring is selected from:
  • R 121 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by amino, C1-C6 alkoxy substituted by 1-6 halogen, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester Group (-CO-O-C1-C6 alkyl), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered hetero
  • R 121 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyls on N, carbamoyl substituted by 1-2 C1-C6 alkyls on N, pyridyl C1-C6 Alkoxy, hydroxyl substituted C1-C6 alkoxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkane Oxygen, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogen, C1-C6 alkyl substituted by amino, halogen, cyano, C2-C6 alkenyl, C1 substituted by phenyl -C6 alkyl, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclyl is optionally substituted by C1-C3 alkyl, tetrahydr
  • R 121 is selected from: -OH, -NH 2 , -COOH, -COOCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CHF 2 , -CF 3 , or two R 121 together with the atoms they are attached to form:
  • the position of R 121 on the ring is selected from: 1-position, 3-position, 2-position, preferably 3-position, 2-position.
  • the A 121c ring and its optional substituents as a whole are selected from:
  • the A 121c ring and its optional substituents, taken as a whole are selected from:
  • the A 121c ring and its optional substituents, taken as a whole are:
  • R 121 is the same as the definition of R 121 in the above formula I-2-1.
  • the A122 ring is selected from Preferably, the A122 ring is selected from
  • B122 rings are selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are selected from -CF 3 ; further more preferably, the B122 ring is
  • the A123 ring is selected from Preferably, the A123 ring is selected from
  • B123 rings are selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; More preferably, the substituent is selected from -CF 3 ; further more preferably, the B123 ring is
  • the A124 ring is selected from: and said optionally substituted by Rm or optionally substituted by Ry and Rm, the optionally substituted with 1-2 substituents selected from Rz and Rm;
  • Ry is a methyl group
  • Rz is selected from Rm is an oxo group
  • ring A124 and its optional substituents taken as a whole, are selected from the following: More preferably, ring A124 and its optional substituents as a whole are selected from
  • B124 rings are selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; More preferably, the substituent is selected from -CF 3 ; further more preferably, the B124 ring is
  • ring A125 is the same as the definition of ring A12 in the above formula I-2;
  • a 125 , A 225 , A 325 , and A 425 are independently selected from: N, CH, and only one of them is N, and the rest are CH ;
  • a 125 , A 225 , and A 325 are CH, and A 425 is N;
  • the definition of R 125 is the same as the definition of R 12 in the above formula I-2;
  • B125 rings are selected from: It is optionally substituted with 1 substituent selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; and the above The substitution position of the substituent on it is: 5-position monosubstituted;
  • the B125 ring is selected from: which is optionally substituted with 1 substituent selected from: -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 ; and the above
  • the substitution position of the substituent on it is: 5-position monosubstituted;
  • the B125 ring is selected from: Most preferably, the B125 ring is
  • the A131 ring is selected from: and said optionally substituted by Rm, or optionally substituted by Ry and Rm;
  • Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3, -CH 2 CH 2 OH;
  • Rm is an oxo group;
  • ring A131 and its optional substituents, taken as a whole, are selected from the following:
  • ring A131 and its optional substituents, taken as a whole are selected from the following: Most preferably, the A131 ring and its optional substituents, taken as a whole, are selected from:
  • the B131 ring is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituent is selected from: C1-C6 alkyl, C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituent is selected from -CF 3 , Further more preferably, the B131 ring is
  • L 131 is selected from direct bond, NH, O, S; preferably, L 131 is selected from direct bond, NH; A 131 , A 231 , A 331 , A 431 are independently selected from: N, CH, and only 2 of them is N, and the rest are CH; preferably, A 131 , A 231 , A 331 , and A 431 are selected from the following combinations:
  • Both A 131 and A 431 are N, and both A 231 and A 331 are CH;
  • Both A 331 and A 431 are N, and both A 131 and A 231 are CH;
  • Both A 231 and A 431 are N, and both A 131 and A 331 are CH.
  • ring A131c is the same as that of ring A131 in the above formula I-3-1;
  • a 131 , A 231 , A 331 , and A 431 are the same as the definitions of A 131 , A 231 , A 331 , and A 431 in the above formula I-3-1.
  • the A132 ring is selected from: and said Optionally substituted by Rm, or optionally substituted by Ry and Rm; wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3, -CH 2 CH 2 OH; Rm is an oxo group;
  • the A132 ring and its optional substituents, taken as a whole, are selected from the following:
  • ring A132 and its optional substituents taken as a whole, are selected from the following: Most preferably, the A132 ring and its optional substituents act as Overall, selected from:
  • B132 rings are selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are selected from -CF 3 ; further more preferably, the B132 ring is
  • R 132 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkoxy substituted by 1-6 halogen, cyano Substituted C1-C6 alkyl, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, 6-membered saturated heterocyclic group substituted by C1-C3 alkyl; or two R 132 , and the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, in which a partially unsaturated C5-C6 carbon Ring, partially unsaturated 5-6 membered heterocycle or 5-6 membered heteroaromatic ring are each optionally substituted with 1-6
  • R 132 is selected from: -OCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CF 3 , -CHF 2 , -NH 2 , or two R 132 together with the atoms they are attached to form:
  • the position of R 132 on the ring is selected from: A 232 position, A 332 position; A 132 , A 232 , A 332 , A 432 are independently selected from: N, CH, and only 2 of them are N , and the rest are CH; preferably, A 132 , A 232 , A 332 , and A 432 are selected from the following combinations: both A 132 and A 432 are N, and both A 232 and A 332 are CH.
  • A132c ring is the same as the definition of A132 ring in the above formula I-3-2;
  • R 132 is the same as the definition of R 132 in the above formula I-3-2;
  • the definition of 432 is the same as that of A 132 , A 232 , A 332 , and A 432 in the above formula I-3-2.
  • the definition of the A133 ring is the same as the definition of the A13 ring in the above-mentioned formula I-3; the definition of the B133 ring is the same as the definition of the B13 ring in the above-mentioned formula I- 3 ; Same definition.
  • ring A134 is the same as the definition of ring A13 in the above formula I-3; preferably, ring A134 and its optional substituents as a whole are selected from More preferably, the A134 ring and its optional substituents as a whole are selected from:
  • the definition of the B134 ring is the same as the definition of the B13 ring in the above formula I-3; preferably, the B134 ring is selected from: It is optionally substituted with 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 substituted with 1-6 halogen Alkyl, halogen, amino; more preferably, the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl; more preferably, the above optionally substituted with 1 substituent,
  • the substituent is selected from: -CF 3 , Still further preferably, the B134 ring is selected from: Most preferably, the B134 ring is
  • R 134 is the same as the definition of R 13 in the above formula I-3; preferably, two R 134 , and the atoms connected to them together form a 5-membered heteroaromatic ring; more preferably, or two R 134 connected to them The atoms of together form:
  • ring A135 is the same as the definition of ring A13 in the above formula I-3;
  • B135 rings are selected from: It is optionally substituted with 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 alkyl , halogen, amino; and the above The substitution position of the substituent on it is: 5-position monosubstituted;
  • R 135 is the same as the definition of R 13 in the above formula I-3;
  • a 135 , A 235 , A 335 , and A 435 are independently selected from: N, CH, and only 2 of them are N, and the rest are CH; preferably Specifically, A 135 , A 235 , A 335 , A 435 are selected from the following combinations:
  • Both A 135 and A 435 are N, and both A 235 and A 335 are CH;
  • Both A 335 and A 435 are N, and both A 135 and A 235 are CH;
  • Both A 235 and A 435 are N, and both A 135 and A 335 are CH.
  • Ring A2 is selected from: Preferably, the A2 ring is selected from More preferably, ring A2 is selected from
  • R 2 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 alkyl, halogen, amino; preferably, R 2 is selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, R 2 is -CF 3 ; further more preferably, the position of R 2 is: 5-position monosubstitution.
  • the A3 ring is selected from: Preferably, the A3 ring is selected from More preferably, the A3 ring is selected from
  • R is selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 alkyl, halogen, amino; preferably, R is selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, R 3 is -CF 3 ; further more preferably, the position of R 3 is: 5-position monosubstitution.
  • the A4 ring is selected from: and said optionally substituted by Rm, or optionally substituted by Ry and Rm;
  • Ry is selected from methyl, -CHF 2 , -CF 3 , CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rm is an oxo group;
  • ring A4 and its optional substituents, taken as a whole are selected from:
  • ring A4 and its optional substituents, taken as a whole are selected from:
  • ring A4 and its optional substituents, taken as a whole are selected from:
  • Ring B4 is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B4 ring is
  • the C4 ring is selected from
  • R is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkoxy substituted by 1-6 halogen, halogen, cyano group, amino group; or two R 4 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; preferably, R 4 is selected from: C1-C6 alkyl; or two R 4 , the atoms connected to them form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; more preferably, two R 4 , and the atoms connected to them form a 5-6-membered heterocyclic ring; most preferably , two R 4 , together with the atoms they are connected to form:
  • the above-mentioned compound of formula IV is the following formula IV-1:
  • ring A41 is the same as the definition of ring A4 in the above formula IV;
  • Ring B41 is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B41 ring is A 41 is selected from: O, S.
  • the above-mentioned compound of formula IV is the following formula IV-2,
  • ring A42 is the same as the definition of ring A4 in the above formula IV;
  • the B42 ring is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B42 ring is
  • R 421 and R 422 are each independently selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkane substituted by 1-6 halogens Oxygen, halogen, cyano, amino; or R 421 and R 422 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; preferably, R 421 and R 422 are independently Selected from: C1-C6 alkyl; or R 421 and R 422 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; more preferably, R 421 and R 422 , together with them The connected atoms together form a 5-6 membered heterocyclic ring; most preferably, R 421 and R 422 , together with their connected atom
  • the above-mentioned compound of formula IV is the following formula IV-3,
  • ring A43 is the same as the definition of ring A4 in the above formula IV;
  • Ring B43 is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B43 ring is R 431 and R 432 are each independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1- C6 alkoxy, halogen, cyano, amino; or R 431 and R 432 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; preferably, R 431 and R 432 are each independently selected from: hydrogen, C1-C6
  • the A5 ring is selected from: and said Optionally substituted by Rm, or optionally substituted by Ry and Rm; wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rm is an oxo group; preferably, the A5 ring and its optional substituents as a whole are selected from: Preferably, ring A5 and its optional substituents as a whole are selected from: Most preferably, ring A5 and its optional substituents, taken as a whole, are selected from:
  • Ring B5 is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B5 ring is R is selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkoxy substituted by 1-6 halogen, halogen , cyano, amino; preferably, R 5 is selected from C1-C6 alkyl; more preferably, R 5 is -CH 3 .
  • R 6' is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by 1-6 deuterium , C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, substituted by Substituted C1-C6 alkyl; preferably, R 6' is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 C1-C6 alkyl substituted by deuterium, C1-C6 alkyl substituted by cyclopropyl, C1-C6 substituted by phenyl alkyl, More preferably, R 6' is selected from methyl, -C6
  • the definition of the B6 ring is the same as the definition of the Bo ring in the above-mentioned formula O; or, the definition of the B6 ring is the same as the definition of the B11 ring in the above-mentioned formula I-1; or, the definition of the B6 ring is the same as that of the B12 ring in the above-mentioned formula I-2
  • the definition is the same; or, the definition of the B6 ring is the same as the definition of the B13 ring in the above formula I-3; or, the definition of the B6 ring is the same as the definition of the B14 ring in the above formula I-4; or, the definition of the B6 ring is the same as the above formula
  • the definition of the B4 ring in sub-IV is the same;
  • the definition of the C6 ring is the same as the definition of the Co ring in the above formula O; or, the definition of the C6 ring is the same as the definition of the C4 ring in the above formula IV;
  • R6 is the same as the definition of Ro in the above formula O; or, the definition of R6 is the same as the definition of R11 in the above formula I-1; or, the definition of R6 is the same as the definition of R12 in the above formula I-2 Or, the definition of R6 is the same as the definition of R13 in the above formula I-3; or, the definition of R6 is the same as the definition of R14 in the above formula I-4; or, the definition of R6 is the same as that of the above formula
  • the definition of R4 in IV is the same.
  • the above-mentioned compound of formula O is the following formula Ox:
  • the Aox ring is selected from:
  • the Aox ring is Y is selected from CH, N;
  • the definition of Rx is the same as the definition of R 121 in the above formula I-2-1; or, the definition of Rx is the same as the definition of R 132 in the above formula I-3-2; preferably, Rx is located at The position on the ring is selected from: 2-position mono-substitution, 3-position mono-substitution, or 2-, 3-position double substitution.
  • the above-mentioned compound is selected from the following:
  • the present application relates to the preparation of the above-mentioned compounds, or tautomers of the compounds, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereomers thereof, or tautomers thereof
  • a method for a racemate, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof comprising:
  • Co ring is the same as the definition of Co ring in the above formula O
  • Ro is the same as the definition of Ro in the above formula O
  • X is selected from halogen, preferably -F, -Cl.
  • step a 1) carry out nucleophilic substitution under basic conditions (such as cesium carbonate, sodium tert-butoxide, sodium hydrogen, potassium tert-butoxide, etc.); 2) Buchwald can also be used Coupling (such as Pd2(dba)3 or Pd G3, Pd G2 and other palladium catalysts, BINAP, Xantphos as phosphorus ligand, Cs2CO3, or sodium tert-butoxide as basic) conditions for the reaction.
  • basic conditions such as cesium carbonate, sodium tert-butoxide, sodium hydrogen, potassium tert-butoxide, etc.
  • Buchwald can also be used Coupling (such as Pd2(dba)3 or Pd G3, Pd G2 and other palladium catalysts, BINAP, Xantphos as phosphorus ligand, Cs2CO3, or sodium tert-butoxide as basic) conditions for the reaction.
  • the solvent in step a is N,N-dimethylformamide or dimethyl sulfoxide, 1,4-dioxane, toluene and the like.
  • step b is in carried out in the presence of molecular sieves.
  • the solvent of step b is methanol. In some embodiments of the present application, the solvent in step c is tetrahydrofuran.
  • the present application relates to the preparation of the aforementioned compounds, or tautomers of said compounds, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereomers thereof isomers, racemates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, hydrates thereof, esters thereof, isotopes thereof, or metabolites thereof, comprising :
  • R 1' is the same as the definition of Ro in the above formula O;
  • R 2' is selected from -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 , -OCF 3 ;
  • R 3' is selected from H, -CH 3 ; R 4' is selected from -CN, LG 1 is a leaving group, preferably halogen, more preferably -F, -Cl; A 1 , A 2 , A 3 , A 4 are each independently selected from N, CH.
  • step m can be designed and synthesized in three different ways.
  • Scheme (1) under basic conditions such as cesium carbonate, sodium tert-butoxide, sodium hydrogen, potassium tert-butoxide, etc., use DMF or MeCN as a solvent, and under the condition of heating reaction temperature, the substituted indole will carry out affinity to the C ring Nuclear substitution, introducing a substituted indole ring structure;
  • Scheme (2) can be coupled with Buchwald, such as Pd 2 (dba) 3 or Pd G 3 , Pd G 2 , Pd G 4 and other palladium catalysts, in the BINAP phosphorus ligand, In the presence of phosphorus ligands such as Xantphos, use Cs 2 CO 3 , or sodium tert-butoxide as a base, use toluene or 1,4-dioxane as a solvent, and heat to the reaction temperature to carry out the coupling reaction.
  • phosphorus ligands such as X
  • Scheme (3) can use the ullmann reaction, under CuI catalyzed conditions, L-poline, or trans-N, N'-dimethyl-1,2-cyclohexanediamine, etc. as ligands, with potassium phosphate Alkali, toluene as solvent, heating to a certain temperature for coupling reaction indole substituted indole ring.
  • step n can use hydroxylamine hydrochloride, under the conditions of organic bases such as N,N-diethylisopropylamine, triethylamine, etc., methanol is used as a solvent, adding The bar with molecular sieves is heated to 80 degrees, reacted for a certain period of time to obtain the addition of hydroxylamine to the cyano functional group to obtain an amidine structure, and then under the condition of dicarbonylimidazole reagent, DBU is used as an organic base, THF is used as a solvent, and the reaction is detected by TLC. This completes the formation of dioxazolones.
  • This structure can be further subjected to an electrophilic substitution reaction by an electrophilic alkyl halide structure to introduce an alkyl side chain, for example
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound, or a tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereomer isomers, racemates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, hydrates thereof, esters thereof, isotopes thereof, or metabolites thereof; optionally, Also contains pharmaceutically acceptable excipients.
  • the present application relates to a method for treating cancer in a patient, comprising administering the above-mentioned compound, or the compound to the patient tautomers, stereoisomers, geometric isomers, enantiomers, diastereomers, racemates, prodrugs, pharmaceutically acceptable A salt, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the above pharmaceutical composition.
  • the cancer is associated with TEAD overexpression.
  • the cancer is associated with increased TEAD activity.
  • the present application relates to a method for inhibiting cancer progression in a patient, which comprises administering to the patient the above-mentioned compound, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, Its enantiomers, its diastereoisomers, its racemates, its prodrugs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its hydrates, its esters, its Isotopes, or their metabolites; or the aforementioned pharmaceutical compositions.
  • the cancer is associated with TEAD overexpression.
  • the cancer is associated with increased TEAD activity.
  • the present application relates to a method of treating a patient suffering from a disease or condition associated with increased expression of TEAD, comprising administering to the patient the above-mentioned compound, or a tautomer of the compound, Stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereomers thereof, racemates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts thereof A solvate, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the above pharmaceutical composition.
  • the present application relates to a method of treating a patient suffering from a disease or condition associated with increased TEAD activity, comprising administering to the patient the above compound, or a tautomer of the compound, its Stereoisomers, geometric isomers thereof, enantiomers thereof, diastereomers thereof, racemates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvents thereof compounds, hydrates thereof, esters thereof, isotopes thereof, or metabolites thereof; or the aforementioned pharmaceutical compositions.
  • the present application relates to a method of treating a disease or disorder, wherein inhibition of TEAD activity will be beneficial to the disease or disorder, comprising administering the above-mentioned compound, or a tautomer of the compound to the patient , its stereoisomers, its geometric isomers, its enantiomers, its diastereomers, its racemates, its prodrugs, its pharmaceutically acceptable salts, its pharmaceutically acceptable
  • the present application relates to a method of treating a disease or disorder for which inhibition of the Hippo pathway will be beneficial for the disease or disorder, comprising administering the above compound, or a tautomer of the compound to the patient , its stereoisomers, its geometric isomers, its enantiomers, its diastereoisomers, its racemates, its prodrugs, its pharmaceutically acceptable salts, its pharmaceutically acceptable
  • the disease or disorder is a cell proliferative disorder.
  • the cell proliferative disease is cancer.
  • the cancer is one in which YAP is localized in the nucleus of the cancer.
  • the TEAD overexpression or TEAD activity increase is TEAD1 overexpression or TEAD1 activity increase.
  • the TEAD overexpression or TEAD activity increase is TEAD2 overexpression or TEAD2 activity increase.
  • the TEAD overexpression or TEAD activity increase is TEAD3 overexpression or TEAD3 activity increase.
  • the TEAD overexpression or TEAD activity increase is TEAD4 overexpression or TEAD4 activity increase.
  • the TEAD overexpression or TEAD activity increase is TEAD1 overexpression or TEAD1 activity increase; TEAD2 overexpression or TEAD2 activity increase; TEAD3 overexpression or TEAD3 activity increase; or TEAD4 overexpression or TEAD4 activity increase; or any combination thereof.
  • the present application relates to the above-mentioned compound, or a tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereoisomer, Its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above pharmaceutical composition in the preparation of therapeutic Use in medicine for cancer.
  • the cancer is associated with TEAD overexpression.
  • the cancer is associated with increased TEAD activity.
  • the present application relates to the above-mentioned compound, or a tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereoisomer, Its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above-mentioned pharmaceutical composition Use in a medicament to inhibit the progression of cancer.
  • the cancer is associated with TEAD overexpression.
  • the cancer is associated with increased TEAD activity.
  • the present application relates to one of the aforementioned compounds, or tautomers of said compounds, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereoisomers thereof body, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above pharmaceutical composition
  • Use in the preparation of a medicament for treating diseases or conditions associated with increased expression of TEAD Use in the preparation of a medicament for treating diseases or conditions associated with increased expression of TEAD.
  • the present application relates to a compound as described above, or a tautomer of said compound, a stereoisomer thereof, a Geometric isomers, their enantiomers, their diastereoisomers, their racemates, their prodrugs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and their hydrates , its ester, its isotope, or its metabolite; or the use of the above pharmaceutical composition in the preparation of a medicament for the treatment of diseases or disorders associated with increased TEAD activity.
  • the present application relates to one of the aforementioned compounds, or tautomers of said compounds, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereoisomers thereof body, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above pharmaceutical composition
  • the present application relates to one of the aforementioned compounds, or tautomers of said compounds, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereoisomers thereof body, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above pharmaceutical composition in Use in the manufacture of a medicament for treating a disease or disorder associated with the Hippo pathway; wherein inhibition of the Hippo pathway would benefit the disease or disorder.
  • the disease or disorder is a cell proliferative disorder.
  • the cell proliferative disease is cancer.
  • the cancer is one in which YAP is localized in the nucleus of the cancer.
  • the TEAD overexpression or TEAD activity increase is TEAD1 overexpression or TEAD1 activity increase.
  • the TEAD overexpression or TEAD activity increase is TEAD2 overexpression or TEAD2 activity increase.
  • the TEAD overexpression or TEAD activity increase is TEAD3 overexpression or TEAD3 activity increase.
  • the TEAD overexpression or TEAD activity increase is TEAD4 overexpression or TEAD4 activity increase.
  • the TEAD overexpression or TEAD activity increase is TEAD1 overexpression or TEAD1 activity increase; TEAD2 overexpression or TEAD2 activity increase; TEAD3 overexpression or TEAD3 activity increase; or TEAD4 overexpression or TEAD4 activity increase; or any combination thereof.
  • the present application relates to the above-mentioned compound, or a tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereoisomer, Its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, or the above pharmaceutical composition has Use in a medicament for the activity of binding to TEAD and blocking the interaction between YAP/TEAD.
  • the present application relates to a method for treating a disease or disorder in a patient, which comprises administering the above-mentioned compound, or a tautomer, a stereoisomer, or a geometric isomer of the compound to the patient , its enantiomers, its diastereoisomers, its racemates, its prodrugs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its hydrates, its esters, Its isotope, or its metabolite; or the above-mentioned pharmaceutical composition; said disease or disease is related to the protein that TEAD interacts with.
  • the disease or disorder associated with the TEAD-interacting protein includes, but is not limited to, cancer, metabolic disease, inflammatory disease, or neurodegenerative disease.
  • the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer , mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the Said cancer is selected from brain cancer, esophageal cancer, renal cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma , mixed adenosquamous carcinoma, undifferentiated carcinoma; further preferably, the brain cancer includes but not limited to glioma; head and neck
  • the present application relates to the above-mentioned compound, or a tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereoisomer, Its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above pharmaceutical composition in the preparation of therapeutic Use in medicine for a disease or disorder; said disease or disorder is associated with a TEAD-interacting protein.
  • the disease or disorder associated with the TEAD-interacting protein includes, but is not limited to, cancer, metabolic disease, inflammatory disease, or neurodegenerative disease.
  • the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer , mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the Said cancer is selected from brain cancer, esophageal cancer, renal cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma , mixed adenosquamous carcinoma, undifferentiated carcinoma; further preferably, the brain cancer includes but not limited to glioma; head and neck
  • the present application relates to the above-mentioned compound, or a tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereoisomer , its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above pharmaceutical composition in Use in the treatment of a disease or disorder; said disease or disorder is associated with a TEAD-interacting protein.
  • the disease or disorder associated with the TEAD-interacting protein includes, but is not limited to, cancer, metabolic disease, inflammatory disease, or neurodegenerative disease.
  • the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer , mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the Said cancer is selected from brain cancer, esophageal cancer, renal cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma , mixed adenosquamous carcinoma, undifferentiated carcinoma; further preferably, the brain cancer includes but not limited to glioma; head and neck
  • C1-C6 alkyl specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.
  • alkyl is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms.
  • C1-C6 alkyl refers to C1, C2, C3, C4, C5 and C6.
  • C1-C6 alkyl means an alkyl group having 1 to 6 carbon atoms, preferably “C1-C4 alkyl", more preferably "C1-C3 alkyl”.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n- Pentyl, isopentyl, neopentyl) etc.
  • alkoxy refers to an oxygen atom substituted with an alkyl group as defined herein.
  • C1-C6 alkoxy includes groups -O-C1-C6 alkyl, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy , tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, etc.
  • cycloalkyl refers to a cyclized alkyl group, including monocyclic, bicyclic or polycyclic ring systems, which does not contain unsaturated bonds such as double bonds, and does not contain any heteroatoms, such as C3-C8 cycloalkyl, C3- C7 cycloalkyl or C3-C6 cycloalkyl.
  • C3-C6 cycloalkyl refers to include C3, C4, C5 and C6 cycloalkyl.
  • "3-6 membered cycloalkyl” and “C3-C6 cycloalkyl” can be used interchangeably. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Ra, Rb and the carbon atoms connected to them together form azetidine
  • azetidine is optionally substituted by hydroxyl, for example, can be Other similar definitions can be understood with reference to the foregoing.
  • the wavy line in the aforementioned structure The two sites shown represent the sites where the ring formed by the two Ros and the atoms respectively attached to them is fused with the Co ring.
  • the structure formed after the two rings are fused can be, for example,
  • the structure formed after the fusion of two rings can be, for example,
  • the structure formed after the fusion of two rings can be, for example,
  • the structure formed after the fusion of two rings can be, for example, for another example, if the ring formed by two Ro and the atoms connected to them is And the Co ring is Then the structure formed after the fusion of two rings can be, for example, for another example, if the ring formed by two Ro and the atoms connected to them is And the Co ring is Then the structure formed after the fusion of two rings can be, for example, For another example, if the ring formed by two Ro and the atoms connected to them is And the Co ring is Then the structure formed after the fusion of two rings can be, for example
  • C1-C6 alkyl substituted by hydroxy means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by hydroxy, for example Wherein, the definition of alkyl is as described above.
  • C1-C6 alkyl substituted by C6-C10 aryl means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by C6-C10 aryl, such as benzyl or
  • C1-C6 alkyl substituted by amino means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by an amino group, for example Similarly, “C1-C6 alkyl substituted by cyano” It means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by a cyano group, for example Similarly, "C1-C6 alkyl substituted by C3-C6 cycloalkyl” means that one hydrogen atom in the aforementioned C
  • a partially unsaturated C5-C6 carbocyclic ring and a partially unsaturated 5-6 membered heterocyclic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium
  • a partially unsaturated Saturated C5-C6 carbocycle and “partially unsaturated 5-6 membered heterocycle” may be unsubstituted, or may be substituted by 1-6 groups selected from halogen and deuterium, and "partially unsaturated C5-C6
  • the substituents of the "carbocycle” and the substituents of the "partially unsaturated 5-6 membered heterocycle” do not affect each other, and may be the same or different.
  • substituted means that any one or more hydrogens on the designated atom or group are replaced by a selection of the designated group, provided that the designated atom's normal valence is not exceeded.
  • the "heteroatom” in the present invention is N, O or S.
  • the "halogen” in the present invention is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine or bromine.
  • the "(by) 1-6 halogen substituted C1-C6 alkyl" and "(by) 1-6 halogen substituted C1 - C6 alkoxy" in the present invention refer to the said alkyl and a group formed by replacing one or more hydrogen atoms in an alkoxy group with 1-6 halogen atoms, especially fluorine or chlorine atoms.
  • fluorination is preferred, eg -CF3 , -CHF2 , -CH2F , -CH2CH2F , -CH2CHF2 , -CH2CF3 , -OCF3 , -OCHF2 , -OCH 2 F, -OCH 2 CH 2 F, -OCH 2 CHF 2 or -OCH 2 CF 3 .
  • C1-C6 alkyl substituted by 1-6 deuterium refers to a group formed after one or more hydrogen atoms in the alkyl group are replaced by 1-6 deuterium atoms, for example -CD3 .
  • alkenyl refers to a group formed by one or more double bonds in the above-mentioned “alkyl”, preferably “C2-C6 alkenyl”. Preferred examples are
  • heteroaryl refers to substituted and unsubstituted aromatic 5-membered or 6-membered monocyclic groups having at least one heteroatom (O, N or S) in at least one ring, 8- Yuan, 9-membered or 10-membered bicyclic groups and 11-membered to 14-membered tricyclic groups, the heteroatom-containing ring optionally also has 1, 2 or 3 members selected from O, N or S of heteroatoms.
  • the heteroaryl is preferably a 5-membered or 6-membered monocyclic group (ie "5-6 membered heteroaryl").
  • a heteroaryl group can be attached at any available nitrogen or carbon atom of either ring.
  • heteroaryl group is limited by the number of carbon atoms, such as "C1-C5 heteroaryl", it means that the heteroaryl group contains carbon atoms of the limited number of carbon atoms, and in addition to carbon atoms also contains 1-5 heteroatoms; for example, "C1-C5 heteroaryl” means that the heteroaryl group contains 1-5 carbon atoms, and contains 1-5 heteroatoms in addition to carbon atoms, such as pyrrole Base, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl , pyridazinyl, triazinyl, triazolyl, etc.
  • Exemplary 5-6 membered heteroaryl groups include, but are not limited to: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thiophene Base, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, etc.
  • heterocycle refers to substituted and unsubstituted 3-membered to 7-membered monocyclic groups, 7-membered to 11-membered Membered bicyclic groups and 10- to 15-membered tricyclic groups, which may contain one or more double bonds, but do not constitute aromatic rings; wherein at least one ring has at least one heteroatom (O, S or N) .
  • the heterocyclic group is preferably a 5- to 6-membered monocyclic group (ie, "5-6-membered heterocyclic group”).
  • a heterocyclic group can be attached at any available nitrogen or carbon atom.
  • heterocyclic group does not contain one or more double bonds, it is called “saturated heterocyclic group”. Similarly, if the heterocyclic group contains one or more double bonds and does not constitute an aromatic ring, it is called “unsaturated heterocyclic group”.
  • the heterocyclic group is limited by carbon atoms, such as “C3-C5 heterocyclic group", it means that the heterocyclic group contains carbon atoms with the limited number of carbon atoms, and in addition to carbon atoms, it also contains 1 -2 heteroatoms; for example, "C3-C5 heterocyclic group” means that the heterocyclic group contains 3-5 carbon atoms, and contains 1-2 heteroatoms in addition to carbon atoms, for example
  • Exemplary 5-6 membered heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidine Pyridyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepine, 1-pyridonyl, 4 -piperidinonyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolyl, etc.
  • a 5-membered unsaturated heterocycle be oxo or be oxo Substituted by the substituent, the substituted structural formula is Similarly, if thiomorpholino When it is substituted by two oxo groups, and the substitution site is S, the substituted structural formula
  • Other similar definitions can be understood with reference to the foregoing.
  • a direct bond means that the groups on both sides are directly connected, for example, the formula O In , if L 0 is a direct bond, the structural formula of formula O will become Other similar definitions can be understood with reference to the foregoing.
  • the dotted line bond------ refers to the existence or non-existence of the bond.
  • Formula O Among them, if Ro is 0, it means that Ro does not exist, that is, the structural formula of formula O becomes If Ro is 1, the structural formula of formula O becomes If Ro is 2, the structural formula of formula O becomes In addition, the two definitions of Ro are independent of each other, and may be the same or different. Other similar structural formulas or definitions can be understood with reference to the foregoing.
  • treatment generally refers to obtaining desired pharmacological and/or physiological effects.
  • the effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms; and/or therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a disease in a patient, including: (a) prophylaxis of a disease or condition in a patient susceptible to the disease or condition but not yet diagnosed; (b) suppressing the symptoms of the disease, ie arresting its development; or (c) alleviating the symptoms of the disease, ie causing regression of the disease or symptoms.
  • a vertebrate refers to a vertebrate.
  • a vertebrate is a mammal.
  • Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats.
  • a mammal is a human.
  • an effective amount refers to the amount effective to achieve the desired therapeutic or preventive effect at the necessary dose and time.
  • a “therapeutically effective amount” of a molecule can vary depending on factors such as the disease state, age, sex and weight of the individual and the ability of the substance/molecule to elicit a desired response in the individual.
  • a therapeutically effective amount also encompasses an amount in which any toxic or detrimental consequences are outweighed by the therapeutically beneficial effects of the substance/molecule.
  • a “prophylactically effective amount” refers to an amount effective at dosages and for periods of time necessary to achieve the desired prophylactic effect.
  • the prophylactically effective amount will be lower than the therapeutically effective amount because the prophylactic dose is administered to the subject before the onset of the disease or at an early stage of the disease.
  • the therapeutically effective amount of the drug reduces the number of cancer cells; reduces tumor volume; inhibits (i.e. slows down to some extent, preferably stops) the infiltration of cancer cells into surrounding organs; inhibits (i.e. slows down to some extent, preferably stops) ) tumor metastasis; inhibition of tumor growth to a certain extent; and/or alleviation of one or more symptoms associated with cancer to a certain extent.
  • auxiliary materials include but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate , glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal oxidation Silicon, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, macrogol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin, etc.
  • ion exchangers aluminum oxide, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphate , glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts
  • the pharmaceutical composition of the present invention can be prepared in various forms according to different administration routes.
  • the pharmaceutical composition can be administered in any of the following ways: oral, inhalation spray, rectal, nasal, buccal, vaginal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, peritoneal Intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • prodrug refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction only under biological conditions to become active compounds, or they are active in their unreacted form. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed.).
  • Tautomers in the compounds described herein refer to two isomers containing heteroatoms (such as nitrogen, oxygen or sulfur atoms) whose structures differ only in the migration of protons and corresponding double bonds , and these two isomers coexist in an equilibrium system, and they are transformed into each other at a very high rate.
  • Typical examples, such as the group in this paper Can be transformed by tautomerism into Furthermore, both coexist. Therefore, if the structural formula of the compound described herein is Those skilled in the art can understand that its representation structure and structure simultaneously exist. If there are similar groups in other compounds, it should be understood with reference to the aforementioned content.
  • geometric isomers the isomers caused by double bonds or single bonds of ring carbon atoms that cannot rotate freely are called geometric isomers, also known as cis-trans isomers.
  • enantiomer stereoisomers that are real and mirror images of each other but not superimposable are called enantiomers.
  • diastereoisomers refer to stereoisomers whose molecules have two or more chiral centers and which are not mirror images.
  • racemate refers to an equimolar mixture of an optically active chiral molecule and its enantiomer.
  • the meso form refers to a molecule with two or more asymmetric centers, but there are other symmetry factors, such as symmetry planes, so that the entire molecule does not have optical activity and no enantiomers exist, usually in the form of meso or i said.
  • hydrate refers to a compound that exists in combination with water molecules.
  • the combination may include water in stoichiometric amounts, such as the monohydrate or dihydrate, or may include any amount of water.
  • esters refers to an ester of -COOH present in the compounds provided by the invention with a suitable alcohol, or an -OH present in the compounds provided by the present invention with a suitable acid (e.g., carboxylic acid or oxygen-containing inorganic acids) to form esters.
  • suitable ester groups include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, ethylsuccinate, stearate, or palmitate. In the presence of acid or base, esters can be hydrolyzed to produce corresponding acids or alcohols.
  • isotopes Different atoms of the same element with the same number of protons but different numbers of neutrons are called isotopes.
  • isotope of a compound refers to the structure formed after one or more atoms in the compound provided by the present invention are replaced by its isotope.
  • the "metabolite” mentioned herein refers to the intermediate metabolite or the final metabolite of the compound provided by the present invention under certain metabolic conditions.
  • the "pharmaceutically acceptable salt” in the present invention refers to the acid addition salt prepared by reacting the compound of the present invention with a pharmaceutically acceptable acid, or the salt formed by the reaction of a compound with an acidic group and a basic compound .
  • the acid is preferably selected from inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, etc.), and organic acids (such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, lysine , histidine, citric acid or benzoic acid, etc.); said basic compound is preferably selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate or potassium bicarbonate and the like.
  • the above pharmaceutically acceptable salts are easy to separate and can be purified by conventional separation methods, such as solvent extraction, dilution, recrystallization, column chromatography and preparative thin-layer chromatography.
  • Solvate is a compound that exists in combination with certain solvent molecules.
  • the combination may include stoichiometric amounts of certain solvents, such as monohydrate or dihydrate, or may include any amount of water; as another example, methanol or ethanol may form “alcoholates,” which may also be stoichiometric or non-stoichiometric.
  • solvate refers to a solid form, ie, a compound in solution in a solvent, although it may be solvated, it is not a solvate as the term is used herein.
  • the compounds described in the present invention can optionally be used in combination with one or more other active ingredients, and their respective dosages and ratios can be adjusted by those skilled in the art according to specific diseases, specific conditions of patients, and clinical needs.
  • Step 1 Add 5-(trifluoromethyl)-1H-indole (1.53g, 8.26mmol) to 3-fluoro-2-benzonitrile (1.0g, 8.26mmol), cesium carbonate (5.38g, 16.52 mmol) and N,N-dimethylformamide (8 mL). The reaction mixture was stirred at 80°C for 3 hours, diluted with water (15 mL), and extracted with ethyl acetate (45 mL).
  • Step 1 To a solution of 3-chloropyrazine-2-carbonitrile (250 mg, 1.79 mmol) and sodium tert-butoxide (172.17 mg, 1.79 mmol) in N,N-dimethylformamide (8 mL) was added 5- (Trifluoromethyl)-1H-indole (331.71 mg, 1.79 mmol). After the reaction mixture was stirred at 120° C. for 3 hours, it was diluted with water (15 mL), and then extracted with ethyl acetate (45 mL).
  • Step 2 To a mixture of compound 2-1 (100 mg, 3.05 mmol), triethylamine (0.97 mL, 7.00 mmol) and molecular sieves (100 mg), and methanol (4 mL) was added hydroxylamine hydrochloride (121.61 mg, 1.75 mmol). After stirring the reaction mixture at 80° C. for 2 hours, it was filtered, and the resulting filtrate was concentrated. Water (10 mL) was added to the obtained concentrate, followed by extraction with ethyl acetate (30 mL).
  • Step 3 Add CDI (69.40mg, 0.43mmol) to compound 2-2 (110mg, 0.34mmol) in tetrahydrofuran (3mL) at 0°C, stir at room temperature for 0.5 hours, then add DBU (76.66 ⁇ L, 0.51 mmol). The reaction mixture was stirred at room temperature for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL).
  • Step 4 CDI (0.03 mL, 0.25 mmol) was added to N-hydroxy-5-methyl-3-(5-(trifluoromethyl)-1H-indol-1-yl)pyridine at 0 °C A solution of oxazine-2-carboxamidine (66 mg, 0.20 mmol) in tetrahydrofuran (1 mL) was stirred at 0°C for 0.5 hour, and DBU (0.04 mL, 0.30 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour, diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3).
  • Step 1 To a solution of 3,5-dichloropyrazine-2-carbonitrile (1.0 g, 5.75 mmol) in methanol (25 mL) was added sodium methoxide (117.19 mg, 2.17 mmol) at 0°C. The reaction mixture was stirred at room temperature for 12 hours and then concentrated. Water (15 mL) was added to the obtained concentrate, followed by extraction with ethyl acetate (45 mL).
  • Step 2 To compound 5-1 (100 mg, 22.99 mmol) and sodium tert-butoxide (56.67 mg, 0.59 mmol) in N,N-dimethylformamide (5 mL) was added 5-(trifluoromethyl) -1H-indole (109.19mg, 0.59mmol). The reaction mixture was stirred at 120°C for 12 hours, diluted with water (10 mL), and extracted with ethyl acetate (30 mL).
  • Step 4 Add N,N'-carbonyldiimidazole (11.54 mg, 0.07 mmol) to compound 5-3 (20 mg, 0.06 mmol) in tetrahydrofuran (2 mL) at 0°C, and stir at room temperature for 0.5 hours, 1,8-Diazabicyclo[5.4.0]-7-undecene (12.75 ⁇ L, 0.09 mmol) was added. After stirring the reaction mixture for 1 hour, it was diluted with water (15 mL), and extracted with ethyl acetate (45 mL).
  • Step 1 To a solution of 3,6-dichloropyrazine-2-carbonitrile (4.0 g, 22.99 mmol) and sodium tert-butoxide (2.65 g, 27.59 mmol) in N,N-dimethylformamide (45 mL) 5-(Trifluoromethyl)-1H-indole (4.26 g, 22.99 mmol) was added. The reaction mixture was stirred at 120°C for 12 hours, diluted with water (60 mL), and extracted with ethyl acetate (180 mL).
  • Step 3 To compound 6-2 (100mg, 0.29mmol), triethylamine (0.40mL, 2.85mmol) and To a solution (4 mL) of molecular sieves (100 mg) in ethanol was added hydroxylamine hydrochloride (99.19 mg, 1.43 mmol). The reaction mixture was stirred and refluxed at 80°C for 3 hours, concentrated, then added with water (15 mL), and extracted with ethyl acetate (45 mL).
  • Step 4 Add N,N'-carbonyldiimidazole (155.78mg, 0.96mmol) to compound 6-3 (273mg, crude product, 0.77mmol) in tetrahydrofuran (10mL) at 0°C, and stir the mixture at room temperature for 0.5 After hours, 1,8-diazabicyclo[5.4.0]-7-undecene (172.08 ⁇ L, 1.15 mmol) was added. The reaction mixture was stirred for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL).
  • Step 1 Trimethylboroxane (0.14mL, 0.50mmol, 3.5M in THF), potassium carbonate (513.95mg, 3.72mmol) and pd(dppf)Cl 2 (45.35mg, 0.06mmol) were added to In a solution of compound 6-1 (400mg, 1.24mmol) in dioxane (4mL) and water (0.5mL). The reaction mixture was warmed up to 100° C. and stirred overnight under nitrogen protection, filtered, and the resulting concentrate was diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3).
  • Step 3 At 0°C, CDI (0.03mL, 0.23mmol) was added to a solution of the crude product of compound 7-2 (60mg) in tetrahydrofuran (1mL), stirred at 0°C for 0.5h, then at 0°C DBU (0.04 mL, 0.28 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 h, diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated, and the resulting residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 7 (19.69 mg, 0.05 mmol, yield 29.12%, purity 98.79%).
  • HPLC preparative high-performance liquid chromatography
  • Step 1 To a solution of compound 2-chloro-4-methoxynicotinonitrile (300 mg, 1.78 mmol) in DMF (6 mL) was added 5-trifluoromethylindole (330 mg, 1.78 mmol) and sodium tert-butoxide ( 171 mg, 1.78 mmol). The reaction mixture was stirred at 120°C for 2 hours, cooled to 25°C, quenched by adding saturated ammonium chloride solution (10 mL) and extracted with EA (50 mL). The combined organic phases were washed with brine (3 times), dried and concentrated.
  • Step 2 Add hydroxylamine hydrochloride (440mg, 6.3mmol) successively to compound 8-1 (200mg, 0.63mmol) in methanol (10mL) solution, Molecular sieves (200 mg) and triethylamine (5.0 mL, 37.8 mmol). The reaction mixture was stirred overnight at 75°C, cooled to 25°C and filtered. Sat ammonium chloride solution (15 mL) was added to the filtrate to quench and extracted with EA (100 mL). The combined organic phases were washed with saturated brine (3 times), dried and concentrated.
  • Step 3 Add CDI (82.5mg, 0.505mmol) to compound 8-2 (101mg, 0.29mmol) in THF (3mL) at 0°C, warm to room temperature and stir for 30 minutes overnight, then cool to 0 °C, DBU (63 ⁇ L, 0.42 mmol) was added, warmed to room temperature and stirred for 1 hour, then concentrated. To the concentrate was added saturated ammonium chloride solution (2 mL) to quench the reaction, and extracted with EA (20 mL). The combined organic phases were washed with saturated brine (3 times), dried and concentrated.
  • Step 1 Disperse tert-butoxycarbonyl sarcosine (143.04mg, 0.76mmol) and HATU (359.33mg, 0.95mmol) in dichloromethane (5mL), stir at room temperature for 3mins, then add compound 9-1 (200mg, 0.63mmol) and N,N-diisopropylethylamine (0.21mL, 1.26mmol). After the reaction mixture was stirred at room temperature for 3 hours, it was quenched by adding saturated sodium bicarbonate (2 mL), and extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated.
  • Step 4 Under stirring at room temperature, cyanogen bromide (49.00mg, 0.46mmol) was added to dissolved compound 9-4 (150mg, 0.31mmol) and N,N-diisopropylethylamine (0.15mL, 0.93mmol ) in tetrahydrofuran (2 mL). After the reaction mixture was stirred at room temperature for 10 minutes, it was quenched with water (1 ml), and extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phases were washed successively with saturated ammonium chloride solution (5 ml) and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated.
  • Step 1 According to the similar synthesis method of step 1 in Example 2, compound 10-1 was prepared by using ethyl 2-chloronicotinate and 5-(trifluoromethyl)-indole as reactants.
  • LCMS: m/z 335 [M+H] + .
  • Step 2 Compound 10-2 was prepared according to the similar synthesis method of Step 2 in Example 2, using compound 10-1 as a reactant.
  • LCMS: m/z 321 [M+H] + .
  • Step 1 Compound 11-1 was prepared according to the similar synthesis method of Step 1 in Example 9, using compound 10-2 as a reactant.
  • LCMS: m/z 506 [M+H] + .
  • Step 2 Compound 11-2 was prepared according to the similar synthesis method of Step 2 in Example 9, using compound 11-1 as a reactant.
  • LCMS: m/z 488 [M+H] + .
  • Step 3 According to the similar synthesis method of Step 3 in Example 9, Compound 11-3 was prepared using Compound 11-2 as a reactant.
  • LCMS: m/z 388 [M+H] + .
  • Step 1 Mix 5-trifluoromethylindole (5.00g, 27.01mmol), DMF (20mL), ethyl 2-chloronicotinate (7.52g, 40.51mmol) and Cs 2 CO 3 (17.60g, 17.60mmol ) was purged three times with N 2 , stirred at 120° C. for 3 h, diluted with H 2 O (200 mL), and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (20 mL ⁇ 3), dried over anhydrous Na 2 SO 4 , and concentrated to obtain The residue.
  • Step 1 Slowly add LDA/THF (2M, 4.8mL, 4.78mmol) dropwise to a solution of compound 12-3 (2.14g, 8.32mmol) in THF (20mL) under ice bath and nitrogen atmosphere, and stir for 1 hour Then MeI (1.36 g, 9.57 mmol) was added dropwise. The reaction mixture was stirred for an additional 2 h in the ice bath and then quenched with saturated NH4Cl (20 mL) and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (20 mL ⁇ 3), dried over anhydrous Na 2 SO 4 , and concentrated to obtain a residue.
  • LDA/THF 2M, 4.8mL, 4.78mmol
  • Step 4 Under stirring conditions, T3P/EA (50%, 5.44g, 8.55mmol) was added dropwise to the crude product of compound 12-6 obtained in the above step 3, DMF (15mL), compound 12-2 (0.68g , 2.14mmol) and DIPEA (1.42mL, 8.55mmol) in a mixture. The reaction mixture was stirred at room temperature for 10 min, quenched by adding saturated NaHCO 3 (20 mL), and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (50 mL ⁇ 3), dried over anhydrous Na 2 SO 4 , and concentrated to obtain a residue.
  • Step 1 The crude product of compound 14-2 obtained in the above step (1.87g, 5.40mmol) (45.4% by content), 5mL DMF, HATU (2.26g, 5.94mmol) and DIPEA (1.34mL, 8.10mmol) After the mixture was stirred at room temperature for 10 min, compound 14-3 (1.73 g, 5.40 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, concentrated, added saturated NaHCO 3 (aq) (50 mL), extracted with EA (30 mL). The combined organic phases were concentrated to give a residue.
  • Step 3 Under the condition of 0 °C and N 2 atmosphere, compound 16-3 (200mg, 0.63mmol) was slowly added to the dissolved monoethyl oxalyl chloride (0.07mL, 0.63mmol) and triethylamine (0.26mL, 1.88 mmol) in dichloromethane (5 mL). Maintaining the N2 atmosphere, the reaction mixture was stirred overnight at room temperature, p-toluenesulfonyl chloride (0.12mL, 0.63mmol) was added, and then the reaction was continued at room temperature for 5 hours, quenched by adding a saturated solution of sodium bicarbonate, and washed with ethyl acetate (50 mL ⁇ 2) extraction.
  • Step 4 Tosyl chloride (83mg, 0.44mmol) and triethylamine (0.12mL, 0.87mmol) were sequentially added to compound 16-4 dissolved in dichloromethane (2mL) at room temperature under N2 atmosphere ( 183mg, 0.44mmol) solution. Maintaining the N 2 atmosphere, the reaction mixture was stirred at room temperature for 5 hours, concentrated, added water, and extracted with ethyl acetate (50 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 5 Aqueous ammonia (0.4 mL, 10.39 mmol) was added into methanol (2 mL) dissolved with compound 16-5 (173 mg, 0.43 mmol) in a dry 25 mL sealed tube at room temperature under N 2 atmosphere. After the reaction mixture was quickly sealed, the temperature was slowly raised to 60° C. and stirred for 4 hours, concentrated, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 16 (136 mg, yield: 84.74%).
  • Step 1 A solution of compound 16 (30 mg, 0.08 mmol) dissolved in DMF (2 mL) was purged with N 2 at room temperature and maintained under N 2 atmosphere, cooled to 0° C., and at this temperature, sodium hydride ( 9.67mg, 0.24mmol), and after stirring for 30 minutes, methyl iodide (11.04uL, 0.18mmol) was added. After the reaction mixture was slowly warmed to room temperature, it was stirred for 30 minutes, quenched by adding saturated sodium thiosulfate solution, added water, and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 1 Compound 21-1 was prepared according to the similar synthesis method of Step 1 in Example 9, using compound 12-2 as a reactant.
  • LCMS: m/z 421 [M+H] + .
  • Step 2 Compound 21 (10 mg, 0.024 mmol, yield: 35.33%, purity: 97.10%) was prepared according to the similar synthesis method of step 4 in Example 9, using compound 21-1 as a reactant.
  • MS (ESI): m/z 433 [M+H] + .
  • Step 1 5-Trifluoromethylindole (212 mg, 1.14 mmol) and Cs 2 CO 3 (745 mg, 2.28 mmol) were added to 1-bromo-2-fluorobenzene (200 mg, 1.14 mmol) in DMSO (5 mL) in solution.
  • the reaction mixture was stirred under microwave conditions at 130° C. for 2 h, cooled to room temperature, diluted with H 2 O and extracted with EA. The combined organic phases were dried and concentrated to give a residue.
  • the obtained residue was purified by silica gel column chromatography to obtain compound 24-1 (350 mg, 1.04 mmol).
  • MS (ESI): m/z 340 [M+H] + .
  • Step 2 Add compound 2-methyl-5-(tributyltin)-2H tetrazole (442 mg, 1.18 mmol), Pd( PPh 3 ) 4 (68 mg, 0.06 mmol) and Cul (12 mg, 0.06 mmol). The reaction mixture was stirred overnight at 120 °C, cooled to room temperature, diluted with potassium fluoride solution (2M) and extracted with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography to obtain compound 24 (68 mg, 0.20 mmol, yield: 33.9%).
  • Step 1 To compound 26-1 (200mg, 0.59mmol), potassium carbonate (162.52mg, 1.18mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (48.02mg, 0.06mmol) to a mixture of dioxane (2.5mL) and water (0.5mL) was added 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxane Pentaboran-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (443.69 mg, 1.18 mmol). The reaction mixture was purged with nitrogen and maintained under nitrogen atmosphere.
  • Step 1 To a solution of compound 26-1 (150 mg, 0.44 mmol) in 1,4-dioxane/water (4 mL/0.8 mL) was sequentially added compound 29-1 (203 mg, 0.66 mmol), Pd(dppf) Cl2 (36mg, 0.044mmol) and sodium carbonate (93mg, 0.8mmol). The reaction mixture was reacted under nitrogen atmosphere at 105°C for 16 hours, quenched by adding saturated ammonium chloride solution (4 mL), and extracted with EA (40 mL). The combined organic phases were washed with saturated brine, dried, and concentrated to obtain a residue.
  • Step 1 To a solution of compound 26-1 (150 mg, 0.44 mmol) in 1,4-dioxane/water (4 mL/0.8 mL) was sequentially added compound 31-1 (166 mg, 0.66 mmol), Pd(dppf) Cl2 (36mg, 0.044mmol) and sodium carbonate (93mg, 0.8mmol). The reaction mixture was stirred under N 2 atmosphere at 105 °C for 16 h, cooled to room temperature, quenched by adding saturated ammonium chloride solution (4 mL), and extracted with EA (40 mL). The combined organic phases were washed with saturated brine, dried and concentrated to obtain a residue.
  • Step 1 Mix DMSO (10 mL), 5-trifluoromethylindole (1.50 g, 8.10 mmol), 3-fluorobenzocyanide (0.98 g, 8.10 mmol) and Cs 2 CO 3 (5.28 g, 16.20 mmol) The mixture was purged with N 2 and maintained under N 2 atmosphere, the reaction mixture was stirred at 90° C. for 4 h, diluted with H 2 O (30 mL), and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (10 mL ⁇ 3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue.
  • Step 2 Add MeOH (50mL), compound 39-1 (1.00g, 3.49mmol), NH 2 OH ⁇ HCl (2.43g, 34.93mmol), TEA (29mL) and Molecular sieves (1.00 g).
  • the reaction mixture was purged with N2 and maintained at N2 atmosphere, stirred at 80 °C After stirring for 4 hours, the filtrate was concentrated after suction filtration.
  • H2O (20 mL), and extracted with EA (30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated to obtain a crude product (1.23 g) of compound 39-2 (MS (ESI): m/z 320 [M+H] + ).
  • Step 3 Add CDI (380.9 mg, 2.35 mmol) to the crude product of compound 39-2 (500.0 mg) in THF (10 mL) under ice-bath conditions, stir at room temperature for 30 minutes, and again in the ice-bath Under conditions, DBU (357.6 mg, 2.35 mmol) was added dropwise. The reaction mixture was stirred under ice bath for 1 h, H 2 O (20 mL) was added, and extracted with EA (30 mL). The combined organic phases were concentrated to obtain a residue, and the obtained residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 39 (360 mg, 1.04 mmol, yield: 66.58%).
  • HPLC preparative high-performance liquid chromatography
  • Step 2 Add hydroxylamine hydrochloride (490 mg, 7.0 mmol) successively to compound 40-1 (200 mg, 0.70 mmol) in methanol (10 mL), Molecular sieves (200 mg) and triethylamine (5.4 mL, 47 mmol). The reaction mixture was stirred at 75°C for 3 hours, cooled to 25°C, and filtered. To the resulting filtrate was added saturated ammonium chloride solution (15 mL) to quench the reaction, and extracted with EA (100 mL). The combined organic phases were washed with saturated brine (3 times), dried and concentrated to obtain a residue.
  • Step 3 Add CDI (57mg, 0.35mmol) to a solution of compound 40-2 (90mg, 0.28mmol) in THF (2mL) at 0°C, warm to room temperature, stir at room temperature for 30 minutes and then cool to 0°C , DBU (63 ⁇ L, 0.42 mmol) was added at 0° C., warmed to room temperature again, stirred at room temperature for 1 hour and then concentrated. Saturated ammonium chloride solution (2 mL) was added to the concentrate to quench the reaction, and extracted with EA (20 mL). The combined organic phases were washed with saturated brine (3 times), dried and concentrated to obtain a residue.
  • Step 1 Dissolve 2-fluorobenzonitrile (0.27mL, 2.48mmol), 5-trifluoromethoxyindole (498.27mg, 2.48mmol) and cesium carbonate (1614.17mg, 4.95mmol) in succession at room temperature in DMSO (10 mL).
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 120° C., stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated.
  • Step 2 At room temperature, successively add hydroxylamine hydrochloride (1551.83mg, 22.33mmol), Molecular sieves (675 mg, 2.23 mmol) and TEA (18.57 mL, 133.99 mmol) were added to a solution of compound 41-1 (675 mg, 2.23 mmol) in methanol (30 mL).
  • the reaction mixture was used N 2 purged and maintained N 2 atmosphere, slowly warmed up to 75 °C and stirred overnight, quenched by adding saturated ammonium chloride solution, and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated.
  • Step 3 N,N'-carbonyldiimidazole (199.49 mg, 1.23 mmol) was added to a solution of compound 41-2 (330 mg, 0.98 mmol) in THF (5 mL) at 0°C.
  • the reaction mixture was warmed up to room temperature, stirred at room temperature for 30 minutes, cooled to 0°C, added DBU (0.22mL, 1.48mmol), warmed up to room temperature again, stirred at room temperature for 1 hour, quenched with saturated ammonium chloride solution and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated.
  • Step 1 Add 5-trifluoromethylindole (359mg, 1.90mmol) and cesium carbonate (1.23g, 3.8mmol) to 3-bromo-4-fluoro-N-toluenesulfonamide (510mg, 1.90mmol) DMSO (14mL) solution.
  • the reaction mixture was reacted under microwave conditions (130W, 120°C) for 40min, cooled to 25°C, quenched with saturated ammonium chloride solution, and extracted with EA (100mL). The combined organic phases were washed with saturated brine (3 times), dried and concentrated.
  • Step 2 To compound 42-1 (494mg, 1.14mmol) in 1.4-dioxane/water (10mL/2ml) solution, add 1-methyl-4-(4,4,5,5-tetramethyl 1,3,2-Dioxybenzaldehyde-2-yl)-1H imidazole (474mg, 2.28mmol), Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (114mg, 0.14mmol), sodium carbonate (242mg, 2.28 mmol). The reaction mixture was purged with N2 and maintained under N2 atmosphere, stirred at 80 °C for 7 h, quenched with saturated ammonium chloride solution (10 mL), and extracted with EA (60 mL).
  • Step 1 Mix 2-chloro-3-fluoropyridine (0.76mL, 7.60mmol), 5-(trifluoromethyl)indole (1.41g, 7.60mmol) and cesium carbonate (4.95g, 15.21mmol) at room temperature ) was dispersed in N,N-dimethylformamide (12 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed up to 120°C and stirred for 1 hour, then diluted with water and extracted with ethyl acetate (100 mL ⁇ 3).
  • Step 2 In a dry 50mL single-necked bottle, dissolve methylamine hydrochloride (6.34g, 93.93mmol) in H 2 O (20mL) at 0°C and add sodium bicarbonate (10.52 g, 125.24mmol) (aq), and finally 3-bromobenzenesulfonyl chloride (4.52mL, 31.31mmol) dissolved in tetrahydrofuran (60mL) was added to the reaction system to replace N 2 . The reaction system was slowly raised to room temperature and stirred for 2 hours.
  • Step 3 In a dry 50mL single-necked bottle, compound 47-1 (1.1g, 4.40mmol), pinacol diborate (1.12g, 4.40mmol), potassium acetate (1.08g, 11.00mmol) were sequentially mixed at room temperature ) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.36g, 0.44mmol) were dissolved in dimethyl sulfoxide (13mL) and replaced with nitrogen , the reaction system was slowly warmed up to 80°C and stirred for 6 hours.
  • Step 4 At room temperature, compound 47-3 (100mg, 0.34mmol), compound 47-2 (100.17mg, 0.34mmol), sodium carbonate (392.16mg, 3.70mmol) and [1,1'-bis(di Phenylphosphino)ferrocene]palladium dichloride (392.16 mg, 3.70 mmol) was dispersed in 1,4-dioxane (5 mL)/water (1 mL). The reaction mixture was purged with N2 and maintained at N2 atmosphere, slowly warmed up to 105°C and stirred overnight, then diluted with water, Extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 1 To a solution of 3,5-dichloropyridine-2-carbonitrile (1.0 g, 5.75 mmol) in methanol (25 mL) was added sodium methoxide (117.19 mg, 2.17 mmol) at 0°C. The reaction mixture was stirred at room temperature for 12 hours, concentrated, and water (15 mL) was added to the obtained concentrate, followed by extraction with ethyl acetate (45 mL).
  • Step 3 According to the similar synthesis method of Step 2 in Example 2, Compound 50-3 was prepared using Compound 50-2 as a reactant.
  • LCMS: m/z 351 [M+H] + .
  • Step 4 Compound 50 (50 mg, 0.13 mmol, yield: 58%, purity: 98.29%) was prepared according to the similar synthesis method of step 3 in Example 2, using compound 50-3 as a reactant.
  • MS (ESI): m/z 377 [M+H] + .
  • Step 1 Compound 51-1 (46.42mg, 0.38mmol), pyridin-2-ylboronic acid (46.42mg, 0.38mmol), tetrakis(triphenylphosphine) palladium (29.09mg, 0.03mmol), Sodium bicarbonate (53.37 mg, 0.50 mmol) was dispersed in a mixed solvent of dimethyl sulfoxide (5 mL)/water (1 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 105° C., stirred overnight, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 2 Lithium hydroxide (0.47 g, 11.30 mmol) was added to a solution of compound 52-1 (1.5 g, 3.77 mmol) in THF (8 mL), water (4 mL), and methanol (2 mL) at room temperature .
  • the reaction mixture was slowly heated to 60°C, stirred for 2 hours, concentrated, diluted with water, adjusted to pH below 4 with dilute hydrochloric acid (2N), and extracted with ethyl acetate (100 mL ⁇ 3).
  • the combined organic phases were dried over anhydrous sodium sulfate and concentrated.
  • Step 3 Add N,N-diisopropylethylamine (1.10 mL, 6.64 mmol) to compound 52-2 (850 mg, 2.21 mmol), methylamine hydrochloride (224.10 mg, 3.32 mmol) at room temperature and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1262.02mg, 3.32mmol) in N,N-dimethylformamide (15mL) solution. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 4 Add compound 52-3 (200mg, 0.50mmol), 1-methyl-4-(tributylstannyl)-1H-imidazole (279.75mg, 0.75mmol), tetrakis(triphenylphosphine) at room temperature ) palladium (57.78 mg, 0.05 mmol) and cuprous iodide (10 mg, 0.05 mmol) were dispersed in N,N-dimethylformamide (4 mL).
  • Step 2 To compound 53-1 (400mg, 1.58mmol), triethylamine (2.19mL, 15.77mmol) and To a solution (25 mL) of molecular sieves (200 mg) in ethanol was added hydroxylamine hydrochloride (547.83 mg, 7.88 mmol). The mixture was stirred and refluxed at 80°C for 12 hours. The mixture was concentrated, then water (15 mL) was added, extracted with ethyl acetate (45 mL), and washed with saturated sodium chloride solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product.
  • Step 3 Dissolve compound 53-2 (420mg, 1.46mmol), N,N'-carbonyldiimidazole (285mg, 1.76mmol) in tetrahydrofuran (10mL), react at 0°C for 30 minutes, then add 1,8 - Diazabicyclo[5.4.0]-7-undecene (0.33 mL, 2.20 mmol) was reacted at room temperature for 30 minutes.
  • Step 1 Add N-iodosuccinimide (5.28g, 23.45mmol) to 3-fluoro-4-(trifluoromethyl)aniline (2.8g, 15.63mmol) at 0°C methane (40mL) solution.
  • the reaction mixture was warmed to room temperature and stirred for 1 hour, diluted with water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were concentrated.
  • Step 2 Ethynyltrimethylsilane (1.62 mL, 11.41 mmol), triethylamine (1.32 mL, 9.51 mmol), cuprous iodide (0.09 mg, 0.68 mmol) and bis(triphenylphosphine) were chlorinated Palladium (0.33 g, 0,48 mml) was added to compound 56-1 (2.9 g, 9.51 mmol) in tetrahydrofuran (15 mL). The reaction mixture was purged with N2 and maintained under N2 atmosphere, stirred at room temperature for 3 hours, diluted with water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were concentrated to give crude product.
  • Step 5 To a methanol solution (10 mL) of compound 56-4 (150 mg, 0.49 mmol), triethylamine (0.68 mL, 4.91 mmol) and molecular sieves (100 mg) was added hydroxylamine hydrochloride (170.74 mg, 2.46 mmol). The reaction mixture was stirred at 80°C for 12 hours, concentrated, then added with water (15 mL), and extracted with ethyl acetate (45 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • Step 6 To a solution of compound 56-5 (136 mg, 0.40 mmol) in THF (5 mL) was added N,N'-carbonyldiimidazole (81.49 mg, 0.50 mmol) at 0°C. After the reaction mixture was stirred at room temperature for 30 minutes, 1,8-diazabicyclo[5.4.0]-7-undecene (90.01 ⁇ L, 0.60 mmol) was added and stirred for 1 hour, diluted with water (15 mL), Extract with ethyl acetate (45 mL). The combined organic phases were washed with saturated sodium chloride solution, dried and concentrated to obtain a crude product.
  • N,N'-carbonyldiimidazole 81.49 mg, 0.50 mmol
  • Step 2 Compound 59-1 (500mg, 1.6mmol), trimethylethynylsilane (240mg, 2.4mmol), Pd(PPh 3 ) 4 (184mg, 0.16mmol), CuI (30mg, 0.16mmol), DIPEA (412 mg, 3.2 mmol), and DMF (10 mL) were purged with N 2 and maintained under N 2 atmosphere, then stirred at 80° C. for 12 hours, added H 2 O (20 mL), and extracted with EA (30 mL). The combined organic phases were washed with saturated brine (10 mL ⁇ 3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue.
  • Step 6 Compound 59-5 (300mg, 0.9mmol), NH 2 OH ⁇ HCl (630mg, 9mmol), 10mL MeOH, TEA (3mL) and The mixture of molecular sieves (300 mg) was purged with N 2 and maintained under N 2 atmosphere, and after stirring at 80° C. for 3 hours, it was filtered under reduced pressure. After the filtrate was concentrated, H 2 O (20 mL) was added and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL ⁇ 3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue.
  • Step 7 CDI (57.3 mg, 0.35 mmol) was added to a solution of compound 59-6 (100 mg, 0.29 mmol) in THF (10 mL) under ice bath.
  • the organic phase was washed with saturated brine (10 mL ⁇ 3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue.
  • Step 1 N-iodosuccinimide (2.59 g, 11.50 mmol) was added to 3-chloro-4-(trifluoromethyl)aniline (1.5 g, 7.67 mmol) in acetic acid ( 20mL) solution.
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to room temperature, stirred for one hour, quenched with saturated sodium bicarbonate, and extracted with ethyl acetate (100 mL ⁇ 3).
  • the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 2 Add DIPEA (2.01 mL, 12.13 mmol) and ethynyltrimethylsilane (1.30 mL, 9.10 mmol) to compound 60-1 (1.95 g, 6.07 mmol), tetrakis(triphenylphosphine) at room temperature ) in a mixture of palladium (0.70g, 0.61mmol), cuprous iodide (0.12g, 0.61mmol) and DMF (25mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 80 °C and stirred overnight, then diluted with water, and extracted with ethyl acetate (100 mL ⁇ 3).
  • Step 3 Tetrabutylammonium fluoride (3.77 mL, 3.77 mmol) was added to a solution of compound 60-2 (1.0 g, 3.43 mmol) in THF (10 mL) at room temperature.
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at room temperature for 30 min, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2).
  • the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • MS (ESI): m/z 218 [MH] - .
  • Step 4 Sodium tert-butoxide (1.02 g, 9.11 mmol) was added to a solution of compound 60-3 (1.0 g, 4.55 mmol) in NMP (10 mL) under ice-bath conditions. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80° C., stirred for 2 hours, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 5 2-Chloronicotinonitrile (350 mg, 1.59 mmol) and Cs 2 CO 3 (1038.64 mg, 3.19 mmol) were sequentially added to a solution of compound 60-4 (350 mg, 1.59 mmol) in DMF (7 mL) at room temperature middle.
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 120° C., stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2).
  • the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 6 At room temperature, successively add hydroxylamine hydrochloride (907.26mg, 13.06mmol), Molecular sieves (420mg, 1.31mmol) and triethylamine (10.86mL, 78.34mmol) were added to a solution of compound 60-5 (420mg, 1.31mmol) in methanol (15mL), and the reaction mixture was purged with N2 and maintained under N2 Atmosphere, the temperature was slowly raised to 80° C., stirred for 3 hours, quenched with saturated ammonium chloride, filtered and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • hydroxylamine hydrochloride 907.26mg, 13.06mmol
  • Molecular sieves 420mg, 1.31mmol
  • triethylamine 10.86mL, 78.34mmol
  • Step 7 Add CDI (257.13mg, 1.59mmol) to a solution of compound 60-6 (450mg, 1.27mmol) in tetrahydrofuran (5mL) under ice-bath conditions, stir at room temperature for 30 minutes, and again in ice-bath DBU (284.02 ⁇ L, 1.90 mmol) was added under conditions.
  • the reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 1 According to the similar synthesis method of Step 1 in Example 3, compound 66-1 was prepared using 2-fluoro-3-methylbenzonitrile and 5-(trifluoromethyl)-1H-indole as reactants .
  • LCMS: m/z 301 [M+H] + .
  • Step 1 To a solution of 2,3-difluorobenzene-1-carbonitrile (0.4 mL, 3.59 mmol) and sodium tert-butoxide (414 mg, 4.31 mmol) in N,N-dimethylformamide (10 mL) was added 5-(Trifluoromethyl)-1H-indole (664.69 mg, 3.59 mmol). The reaction mixture was stirred at 120°C for 12 hours, diluted with water, and extracted with ethyl acetate (60 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to obtain a crude product.
  • Step 2 Hydroxylamine hydrochloride (342.60 mg, 4.93 mmol) was added to a mixture of compound 67-1 (300 mg, 0.99 mmol), triethylamine (1.37 mL, 9.86 mmol), molecular sieves (200 mg) and methanol (4 mL). The reaction mixture was stirred at 80°C for 12 hours and then concentrated. Water (15 mL) was added to the concentrate, followed by extraction with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product.
  • Step 3 Add N,N'-carbonyldiimidazole (70.66mg, 0.44mmol) to a tetrahydrofuran solution (5mL) of compound 67-2 (112mg, 0.35mmol) at 0°C, and stir at room temperature for 30 , 1,8-Diazabicyclo[5.4.0]-7-undecene (78.05 ⁇ L, 0.52 mmol) was added. The reaction mixture was stirred for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to obtain a residue.
  • Step 2 According to the similar synthesis method of Step 2 in Example 67, Compound 68-2 was prepared using Compound 68-1 as a reactant.
  • LCMS: m/z 354 [M+H] + .
  • Step 3 Compound 70 (86.17 mg, 0.25 mmol, yield 8.54%, purity: 99.6%) was prepared according to the similar synthesis method of Step 3 in Example 2, using compound 70-2 as a reactant.
  • MS (ESI): m/z 348 [M+H] + .
  • Step 1 To a solution of 4-chloropyrimidine-5-carbonitrile (1.0 g, 7.17 mmol) and sodium tert-butoxide (0.83 g, 8.60 mmol) in N,N-dimethylformamide (20 mL) was added 5- (Trifluoromethyl)-1H-indole (1.33 g, 7.17 mmol), and the reaction was stirred at 120° C. for 12 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (90 mL), and washed with saturated sodium chloride solution. The combined organic layers were dried, filtered and concentrated to give crude product.
  • Step 2 To compound 71-1 (380mg, 1.32mmol), triethylamine (1.83mL, 13.18mmol) and To a methanol solution (15 mL) of molecular sieves (380 mg) was added hydroxylamine hydrochloride (458.08 mg, 6.59 mmol). The mixture was stirred and refluxed at 80°C for 12 hours. After returning to room temperature, it was filtered, and the filtrate was concentrated, then water (15 mL) was added, extracted with ethyl acetate (45 mL), and washed with saturated sodium chloride solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product.
  • hydroxylamine hydrochloride 458.08 mg, 6.59 mmol
  • Step 3 Add N,N'-carbonyldiimidazole (70.66mg, 0.44mmol) to compound 71-2 (112mg, 0.35mmol) in tetrahydrofuran (5mL) at 0°C, and the mixture was stirred at room temperature for 30 minutes . Further 1,8-diazabicyclo[5.4.0]-7-undecene (78.05 ⁇ L, 0.52 mmol) was added to the mixture and stirred for 1 hour. The mixture was diluted with water (15 mL), extracted with ethyl acetate (45 mL), and washed with saturated ammonium chloride solution and saturated sodium chloride solution. The combined organic layers were dried, filtered and concentrated to give crude product.
  • Step 3 Compound 72 (76.46 mg, 0.22 mmol, yield: 22.24%, purity 99.7%) was prepared according to the similar synthesis method of Step 3 in Example 2, using compound 72-2 as a reactant.
  • MS (ESI): m/z 347 [M+H] + .
  • Step 1 Add 5-(trifluoromethyl)indole (2.55g, 13.80mmol) and potassium tert-butoxide (3.10g, 27.59mmol) to 5-bromo-2-chloronicotinonitrile (3.00g, 13.80mmol ) in DMF (30 mL) solution.
  • the reaction mixture was warmed up to 120° C. and stirred for 2 h, diluted with water (50 mL), and extracted with ethyl acetate (50 mL*3).
  • Step 2 Trimethylboroxine (0.12mL, 0.44mmol, 3.5M in THF), potassium carbonate (452.94mg, 3.28mmol) and pd(dppf)Cl 2 (39.97mg, 0.05mmol) were added to Compound 75-1 (400mg, 1.09mmol) in dioxane (4mL) and water (0.5mL) mixed solution. The reaction mixture was heated to 100°C under nitrogen protection and stirred overnight, then filtered, and the resulting filtrate was diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3).
  • Step 4 At 0°C, CDI (0.03mL, 0.22mmol) was added to a solution of the crude product of compound 75-3 (60mg) in tetrahydrofuran (1mL), stirred at 0°C for 0.5h, then at 0°C DBU (0.04 mL, 0.27 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 h, diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated, and the resulting residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 75 (13.47 mg, 0.04 mmol, yield 20.44%).
  • HPLC preparative high-performance liquid chromatography
  • Step 1 Add 5-(trifluoromethyl)indoline (810.55mg, 4.33mmol) and sodium tert-butoxide (416.17mg, 4.33mmol) to 2-chloronicotinonitrile (0.45mL, 4.33mmol) DMF (10mL) solution.
  • the reaction mixture was warmed up to 80°C and stirred for 2 hours, diluted with water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were concentrated to obtain a residue.
  • Step 1 5-trifluoromethylindole (5.00g, 27.01mmol), compound 2-chloronicotinic acid ethyl ester (7.52g, 40.51mmol), Cs 2 CO 3 (17.60g, 17.60mmol) and DMF ( 20 mL) of the mixture was purged with N2 and maintained at N2 atmosphere, stirred at 120 °C for 3 h Afterwards, it was diluted with water (200 mL) and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL ⁇ 3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue.
  • Step 1 Methyl 2-amino-2-methylpropanoate hydrochloride (226mg, 1.47mmol), HATU (647mg, 1.96mmol), DIPEA (759mg, 5.88mmol) and DMAP (12g, 0.10mmol) were added To a solution of compound 2-(5-trifluoromethyl)-1H-indol-1-ylnicotinic acid (300 mg, 0.98 mmol) in DMF (5 mL). The reaction mixture was stirred overnight at room temperature, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 1 According to the similar synthesis method of Step 1 in Example 80, the compound 2-(5-trifluoromethyl)-1H-indol-1-ylnicotinic acid and 1-aminocyclopentane-1-carboxylic acid Methyl ester hydrochloride was used as a reactant to prepare compound 81-1.
  • MS (ESI): m/z 432 [M+H] + .
  • Step 1 To a solution of 2,5-dichloronicotinonitrile (1.0 g, 5.78 mmol) and sodium tert-butoxide (666.59 mg, 6.94 mmol) in N,N-dimethylformamide (15 mL) was added 5-( Trifluoromethyl)-1H-indole (1.07 g, 5.78 mmol). After the reaction mixture was stirred at 120°C for 12 hours, it was diluted with water (30 mL), and extracted with ethyl acetate (90 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to obtain the crude product.
  • Step 2 Hydroxylamine hydrochloride (540.04 mg, 7.77 mmol) was added to a mixture of compound 94-1 (500 mg, 1.55 mmol), triethylamine (2.15 mL, 15.54 mmol), molecular sieves (300 mg) and methanol (15 mL). The reaction mixture was stirred at 80 °C for 12 hours and then concentrated. Water (15 mL) was added to the concentrate, which was extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product.
  • Step 3 Add N,N'-carbonyldiimidazole (142.85mg, 0.88mmol) to a solution of compound 94-2 (250mg, 0.70mmol) in tetrahydrofuran (8mL) at 0°C, and stir at room temperature for 30 minutes Afterwards, 1,8-diazabicyclo[5.4.0]-7-undecene (157.79 ⁇ L, 1.06 mmol) was added. The reaction mixture was stirred for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to obtain the crude product.
  • Step 1 To a mixture of compound 2-chloroquinoline-3-carbonitrile (1.88 g, 10 mmol) in 1-4 dioxane (20 mL) was added 5-trifluoromethylindole (2.2 g, 12 mmol), CuI (92mg, 0.5mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (284mg, 2mmol), potassium phosphate (4.2g, 20mmol) the reaction mixture with N 2 purged and maintained N 2 atmosphere, after stirring at 110°C for 12 hours, diluted with H 2 O (200 mL), and extracted with EA (50 mL).
  • Step 2 Compound 95-1 (1.3g, 4.26mmol), 20mL MeOH, NH 2 OH ⁇ HCl (2.9g, 42.6mmol), TEA (10mL) and The mixture of molecular sieves (1.3 g) was purged with N2 and maintained under N2 atmosphere, stirred at 80 °C for 3 hours, filtered under reduced pressure, and the filtrate was concentrated. The phase concentrate was added with H2O (20 mL) and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL ⁇ 3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue.
  • Step 1 To a mixture of compound 3-chloro-6,7-dihydro-5H-cyclopentane[c]pyridine-4-carbonitrile (1.78 g, 10 mmol) in 1-4Dioxane (20 mL) was added 5-trifluoroform Indole (2.2g, 12mmol), CuI (92mg, 0.5mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (284mg, 2mmol), phosphoric acid Potassium (4.2 g, 20 mmol).
  • Step 2 Compound 97-1 (1.3g, 4.26mmol), 20mL MeOH, NH 2 OH ⁇ HCl (2.9g, 42.6mmol), TEA (10mL) and The mixture of molecular sieves (1.3 g) was purged with N2 and maintained under N2 atmosphere, stirred at 80 °C for 3 hours, filtered under reduced pressure, and the filtrate was concentrated. After adding H2O (20 mL) to the concentrate, it was extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL ⁇ 3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue.
  • Step 1 Disperse 2-aminonicotinonitrile (500mg, 4.20mmol), 1-chloro-2-nitro-4-trifluoromethylbenzene (0.63mL, 4.20mmol) and cesium carbonate (2735.00mg, 8.39mmol) in DMF (10 mL).
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 100°C and stirred for one hour, diluted with water, and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 2 Add iron powder (956.57mg, 17.13mmol) and ammonium chloride (916.32mg, 17.13mmol) to compound 108-1 (880mg, 2.86mmol) in ethanol (12mL) and water (3mL) at room temperature in the solution.
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80 °C and stirred for 2 hours, then filtered while hot.
  • MS (ESI): m/z 279 [M+H] + .
  • Step 4 At room temperature, successively add hydroxylamine hydrochloride (1205.46mg, 17.35mmol), Molecular sieves (500 mg, 2.23 mmol) and TEA (14.43 mL, 104.08 mmol) were added to a solution of compound 108-3 (500 mg, 1.73 mmol) in methanol (15 mL).
  • the reaction mixture was purged with N2 and maintained under N2 atmosphere, slowly warmed up to 75 °C and stirred overnight, then quenched by adding saturated aqueous ammonium chloride solution, filtered and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 5 At room temperature, the crude product of compound 108-4 was dispersed in tetrahydrofuran (8 mL), and CDI (365.30 mg, 2.25 mmol) was added under ice-bath conditions, slowly raised to room temperature and stirred for 30 minutes, and then placed on ice DBU (403.50 ⁇ L, 2.70 mmol) was added under bath conditions, and the reaction system was slowly raised to room temperature and stirred for 1 hour. After the reaction was complete, the reaction system was diluted with water, and then extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • CDI 365.30 mg, 2.25 mmol
  • Step 1 5-(Trifluoromethyl)-1H-pyrrole[2,3-b]pyridine (806 mg, 4.33 mmol) and sodium tert-butoxide (416.17 mg, 4.33 mmol) were added to 2-chloronicotinonitrile ( 0.45 mL, 4.33 mmol) in DMF (10 mL). The reaction mixture was warmed up to 80°C and stirred for 2 hours, diluted with water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were concentrated to give a residue.
  • Step 2 Hydroxylamine hydrochloride (807.66mg, 11.62mmol), TEA (6.44mL, 46.49mmol) and Molecular sieve (100mg) plus into a solution of compound 111-1 (670 mg, 2.32 mmol) in methanol (10 mL). The reaction mixture was warmed up to 80°C and stirred for 2 hours, then filtered. The resulting filtrate was concentrated, diluted with water (30 mL), and extracted with ethyl acetate (30 mL*3). The combined organic phases were concentrated to obtain a residue.
  • Step 3 Add CDI (0.13mL, 1.05mmol) to a solution of compound 111-2 (270mg, 0.84mmol) in tetrahydrofuran (2mL) at 0°C, stir at 0°C for 0.5 hours, then add DBU (0.19mL, 1.26 mmol), warmed to room temperature and stirred for 1 hour, diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated to obtain a residue. The obtained residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 111 (15.47 mg, 0.04 mmol, yield: 5.29%).
  • HPLC high-performance liquid chromatography
  • Step 1 At room temperature, successively dissolve 2-iodo-4-trifluoromethylaniline (1.0g, 3.48mmol) in propyne (8mL) and DMF (1mL) and add cuprous iodide (0.07g, 0.35mmol), bistriphenylphosphinepalladium dichloride (0.12g, 0.17mmol) and triethylamine (3mL, 21.64mmol).
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80 °C and stirred for 16 hours, diluted with water, and extracted with ethyl acetate (100 mL ⁇ 3).
  • the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • the resulting residue was purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 113-1 (677 mg, yield: 97.56%).
  • MS (ESI): m/z 200 [M+H
  • Step 2 Potassium tert-butoxide (381.39 mg, 3.40 mmol) was added to a solution of compound 113-1 (677 mg, 3.40 mmol) in NMP (8 mL) at room temperature. The reaction mixture was slowly warmed to 80°C and stirred for 2 hours, diluted with water, and extracted with ethyl acetate (100 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 113-2 (380 mg, yield: 56.13%).
  • Step 4 At room temperature, hydroxylamine hydrochloride (359.82mg, 5.18mmol), Molecular sieves (160 mg, 2.23 mmol), and triethylamine (4.31 mL, 31.07 mmol) were sequentially added to a solution of compound 113-3 (156 mg, 0.52 mmol) in methanol (5 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 75 °C, stirred overnight, quenched with saturated ammonium chloride, and filtered. The resulting filtrate was extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 5 Add CDI (101.86mg, 0.63mmol) to a solution of compound 113-4 (168mg, 0.50mmol) in tetrahydrofuran (3mL) under ice bath conditions, slowly rise to room temperature and stir for 30min, then again in ice bath DBU (112.51 ⁇ L, 0.75 mmol) was added under conditions. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 1 According to the similar synthesis method of step 1 in Example 67, compound 114-1 was prepared using 2-chloro-4-methylbenzonitrile and 5-(trifluoromethyl)-1H-indole as reactants .
  • MS (ESI): m/z 301 [M+H] + .
  • Step 1 At room temperature, mix 2-chloro-4-methylnicotinonitrile (200mg, 1.31mmol), 5-(trifluoromethyl)-1H-indole (242.69mg, 1.31mmol) and cesium carbonate (854.16 mg, 2.62mmol) was dispersed in DMF (5mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 100° C., stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 2 At room temperature, successively add hydroxylamine hydrochloride (369.05mg, 5.31mmol), Molecular sieves (160 mg, 2.23 mmol) and triethylamine (4.42 mL, 31.87 mmol) were added to a solution of compound 116-1 (160 mg, 0.53 mmol) in methanol (8 mL).
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, the temperature was slowly raised to 75 °C, stirred overnight, quenched by adding saturated ammonium chloride, and filtered.
  • Step 3 Add CDI (75.79mg, 0.47mmol) to a solution of compound 116-2 (125mg, 0.37mmol) in tetrahydrofuran (3mL) under ice bath conditions, stir at room temperature for 30min, and again under ice bath conditions DBU (83.71 ⁇ L, 0.56 mmol) was added at the bottom.
  • the reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 1 According to the similar synthesis method of Step 1 in Example 116, compound 117-1 was prepared using 2-chloro-5-methoxynicotinonitrile and 5-(trifluoromethyl)-1H-indole as reactants .
  • MS (ESI): m/z 318 [M+H] + .
  • Step 3 Compound 117 (50 mg, 0.13 mmol, yield: 58%, purity: 98.29%) was prepared according to the similar synthesis method of step 3 in Example 116, using compound 117-2 as a reactant.
  • MS (ESI): m/z 377 [M+H] + .
  • Step 1 2-Chloro-5-fluoronicotinonitrile (250mg, 1.60mmol), 5-(trifluoromethyl)-1H-indole (296.24mg, 1.60mmol) and cesium carbonate (1042.62mg , 3.20mmol) was dispersed in DMF (5mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 120° C., stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 2 At room temperature, successively add hydroxylamine hydrochloride (182.13mg, 2.62mmol), Molecular sieves (80 mg, 0.26 mmol) and triethylamine (2.18 mL, 15.73 mmol) were added to a solution of compound 118-2 (80 mg, 0.26 mmol) in methanol (3 mL).
  • the reaction mixture was purged with N 2 and the N 2 atmosphere was maintained, the temperature was slowly raised to 80°C and stirred for 3 hours, the reaction solution was quenched with saturated ammonium chloride and filtered.
  • Step 3 Add CDI (100.06mg, 0.62mmol) to a solution of compound 118-2 (167mg, 0.49mmol) in tetrahydrofuran (3mL) under ice-bath conditions, stir at room temperature for 30 minutes, and again in ice-bath DBU (110.53 ⁇ L, 0.74 mmol) was added under conditions.
  • the reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 1 To 5-bromo-2-[5-(trifluoromethyl)indol-1-yl]pyridine-3-carbonitrile (400mg, 1.09mmol), potassium carbonate (301.96mg, 2.18mmol) and bis [5-(Diphenylphosphino)cyclopent-1,3-dienyl]- ⁇ 2-iron(II)palladium chloride (79.94 mg, 0.11 mmol) in 1,4-dioxane (10 mL) Ethylboronic acid (80.72mg, 1.09mmol) was added to the mixed solution with water (2mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at 90° C.
  • Step 2 Hydroxylamine hydrochloride (104.69 mg, 2.14 mmol) was added to a mixture of compound 119-1 (135 mg, 0.43 mmol), triethylamine (0.42 mL, 4.28 mmol), molecular sieves (100 mg), and methanol (10 mL) .
  • the reaction mixture was stirred at 80 °C for 3 hours and then concentrated.
  • Water (15 mL) was added to the obtained concentrate, and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 3 Disperse the crude product of compound 119-2 (123mg) and N,N'-carbonyldiimidazole (71.57mg, 0.44mmol) in tetrahydrofuran (5mL), react at 0°C for 30 minutes, then add 1, 8-Diazabicyclo[5.4.0]-7-undecene (79.06 ⁇ L, 0.53 mmol). After reacting the reaction mixture at room temperature for 1 hour, it was quenched with water (15 mL), and extracted with ethyl acetate (15 mL ⁇ 3). The combined organic phases were washed with water and concentrated to obtain a residue.
  • Step 1 Mix 5-bromo-2-chloronicotinonitrile (3.00g, 13.80mmol), sodium tert-butoxide (1.59g, 16.56mmol), 5-(trifluoromethyl)-1H-indole (2.55g, 13.80 mmol), and N,N-dimethylformamide (30 mL) were stirred at 120° C. for 3 hours, diluted with water (40 mL), and extracted with ethyl acetate (120 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to obtain a crude product.
  • Step 2 Hydroxylamine hydrochloride (759.16 mg, 10.92 mmol) was added to a mixture of compound 121-1 (800 mg, 2.18 mmol), triethylamine (3.03 mL, 21.85 mmol), molecular sieves (500 mg), and methanol (30 mL) .
  • the reaction mixture was stirred at 80 °C for 12 hours and then concentrated.
  • Water (20 mL) was added to the obtained concentrate, and extracted with ethyl acetate (60 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product.
  • Step 4 Zinc cyanide (181.17 mg, 1.54 mmol) was added to compound 121-3 (164 mg, 0.39 mmol) and tetrakis(triphenylphosphine) palladium (89.15 mg, 0.08 mmol), and N,N-dimethyl in a mixture of methyl formamide solution (1.9 mL).
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, then stirred at 120° C. for 12 hours, water (10 mL) was added, and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 2 5-(trifluoromethyl)-1H-indole (1.19g, 6.42mmol) was added to the crude product of compound 122-1 (1.07g, 6.42mmol), sodium tert-butoxide (0.8g, 7.06 mmol) and N,N-dimethylformamide (15 mL). After the reaction mixture was stirred at 120°C for 1.5 hours, it was diluted with water (30 mL), and extracted with ethyl acetate (90 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to obtain a crude product.
  • Step 3 Hydroxylamine hydrochloride (550.98 mg, 7.93 mmol) was added to a mixture of compound 122-2 (500 mg, 1.59 mmol), triethylamine (2.2 mL, 15.86 mmol), molecular sieves (300 mg) and methanol (15 mL). After the reaction mixture was stirred at 80°C for 12 hours, water (15 mL) was added, and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product.
  • Step 4 Add N,N'-carbonyldiimidazole (200.17mg, 1.23mmol) to a solution of compound 122-3 (344mg, 0.99mmol) in tetrahydrofuran (10mL) under ice bath conditions, and react at 0°C After 30 minutes 1,8-diazabicyclo[5.4.0]-7-undecene (221.1 ⁇ L, 1.48 mmol) was added. After reacting the reaction mixture at room temperature for 1 hour, it was quenched with water (15 mL), and extracted with ethyl acetate (15 mL ⁇ 3). The combined organic phases were washed with water, dried and concentrated to obtain a residue.
  • Step 3 Add CDI (36.5mg, 0.22mmol) to a THF (2mL) solution of compound 123-2 (83mg, 0.28mmol) at 0°C, warm to room temperature and stir for 30 minutes, then add DBU (41 ⁇ L, 0.27 mmol). The reaction mixture was warmed to room temperature, stirred for 1 hour and then concentrated. Saturated ammonium chloride solution (2 mL) was added to the resulting concentrate to quench the reaction, and extracted with EA (20 mL). The organic phase was washed with saturated brine (3 times), dried and concentrated to obtain a residue.
  • Step 1 At room temperature, 2-chloro-6-methylnicotinonitrile (300mg, 1.97mmol), 5-(trifluoromethyl)-1H-indole (364.04mg, 1.97mmol) and cesium carbonate ( 1281.24 mg, 3.93 mmol) was dispersed in DMF (8 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed slowly to 120° C. and stirred for 1 h, diluted with water, and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 2 At room temperature, successively add hydroxylamine hydrochloride (1314.74mg, 18.92mmol), Molecular sieves (675 mg, 2.23 mmol) and TEA (15.74 mL, 113.52 mmol) were added to a solution of compound 124-1 (570 mg, 1.89 mmol) in methanol (20 mL).
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 75 °C, stirred overnight, quenched with saturated ammonium chloride, and filtered.
  • the resulting filtrate was extracted with ethyl acetate (50 mL ⁇ 2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated.
  • Step 3 Add CDI (121.26mg, 0.75mmol) to a solution of compound 124-2 (200mg, 0.60mmol) in tetrahydrofuran (5mL) under ice bath conditions, stir at room temperature for 30min, and again under ice bath conditions DBU (0.13 mL, 0.90 mmol) was added at the same time.
  • the reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 1 Disperse 5-bromo-2-chloronicotinonitrile (500mg, 2.30mmol), 5-trifluoromethylindole (425.73mg, 2.30mmol) and cesium carbonate (1498.37mg, 4.60mmol) in DMF (10mL )middle.
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed up to 120 °C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL ⁇ 3).
  • the combined organic phases were dried over anhydrous sodium sulfate and concentrated.
  • Step 2 Compound 126-1 (1130mg, 3.09mmol), pinacol diboronate (1175.58mg, 4.63mmol), potassium acetate (605.77mg, 6.17mmol) and Pd(dppf)Cl 2 were sequentially mixed at room temperature (225.82 mg, 0.31 mmol) was dispersed in 1,4-dioxane (20 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 95 °C, stirred overnight, diluted with water, and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated.
  • Step 3 Compound 126-2 (1.1 g, 2.66 mmol), 2-fluorobromomethylbenzene (0.38 mL, 3.19 mmol), potassium carbonate (0.74 g, 5.32 mmol) and Pd(dppf)Cl were mixed at room temperature 2 (0.19g, 0.27mmol) was dispersed in a mixed solvent of acetonitrile (20mL) and water (4mL). mix the reaction The mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed up to 80 °C and stirred overnight, diluted with water, and extracted with ethyl acetate (100 mL ⁇ 3).
  • Step 4 At room temperature, successively add hydroxylamine hydrochloride (790.94mg, 11.38mmol), Molecular sieves (450 mg, 2.23 mmol), and TEA (9.47 mL, 68.29 mmol) were added to a solution of compound 126-3 (450 mg, 1.14 mmol) in methanol (15 mL).
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 75 °C and stirred overnight, quenched with saturated ammonium chloride, filtered and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 5 Add CDI (149.51mg, 0.92mmol) to a solution of compound 126-4 (316mg, 0.74mmol) in tetrahydrofuran (3mL) under ice-bath conditions, slowly rise to room temperature and stir for 30min. DBU (165.15 ⁇ L, 1.11 mmol, 1 mL) was added under conditions. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 1 To a mixture of compound 5-bromo-2-chloronicotinonitrile (2.14 g, 10 mmol) in DMF (20 mL) was added 5-trifluoromethylindole (2.2 g, 12 mmol) and sodium tert-butoxide (1.9 g ,20mmol). The reaction mixture was stirred at 80 °C for 3 h, diluted with H2O (200 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL ⁇ 3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue.
  • Step 2 Compound 127-1 (1.8g, 5mmol), 3-hydroxypyrrolidine (560mg, 6.5mmol) Pd 2 (dba) 3 (450mg, 0.5mmol), XantPhos (570mg, 1mmol), and 1-4
  • the mixture of dioxane (20 mL) was stirred at 80°C for 12 hours and then concentrated.
  • MS (ESI): m/z 373 [M+H] + .
  • Step 3 Compound 127-2 (1 g, 2.7 mmol), MeOH (20 mL), NH 2 OH ⁇ HCl (1.8 g, 27 mmol), TEA (10 mL) and The mixture was purged with N2 and maintained under N2 atmosphere, after stirring at 80 °C for 3 h, it was filtered under reduced pressure. The resulting filtrate was concentrated, added H 2 O (20 mL), and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL ⁇ 3), dried over anhydrous Na 2 SO 4 and concentrated.
  • Step 5 Compound 128-4 (315 mg, 0.96 mmol), MeOH (20 mL), NH 2 OH ⁇ HCl (672 mg, 9.6 mmol), TEA (15 mL) and The mixture was purged with N2 and maintained under N2 atmosphere, stirred at 80 °C for 3 h and then filtered under reduced pressure. H2O (20 mL) was added to the resulting filtrate and extracted with EA (30 mL).
  • Step 4 Compound 129-3 (570 mg, 2.93 mmol), 5-trifluoromethylindole (542.26 mg, 2.93 mmol) and cesium carbonate (1908.51 mg, 5.86 mmol) were dispersed in DMF (10 mL) at room temperature middle. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80° C., stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL ⁇ 2).
  • Step 5 At room temperature, hydroxylamine hydrochloride (1522.14mg, 21.90mmol), Molecular sieves (760 mg, mmol), and triethylamine (18.22 mL, 131.43 mmol) were added to a solution of compound 129-4 (752 mg, 2.19 mmol) in methanol (20 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80 °C and stirred for 3 hours, quenched with saturated ammonium chloride and filtered. The resulting filtrate was extracted with ethyl acetate (50 mL ⁇ 2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue.
  • Step 6 Add CDI (262.82mg, 1.62mmol) to a solution of compound 129-5 (488mg, 1.30mmol) in tetrahydrofuran (8mL) under ice-bath conditions, slowly rise to room temperature and stir for 30min. DBU (290.31 ⁇ L, 1.95 mmol) was added at the same time. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 129 (15 mg, yield: 2.87%).
  • Step 3 At room temperature, di-tert-butyl dicarbonate (0.41 mL, 1.94 mmol) was added dropwise to a solution of compound 130-2 (375 mg, 1.94 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL), followed by Sodium carbonate (205.27 mg, 1.94 mmol) was added.
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at 28 °C for 12 h, concentrated, and extracted with dichloromethane (20 mL ⁇ 2).
  • Step 4 5-Trifluoromethylindole (94.54 mg, 0.51 mmol) and cesium carbonate (166.38 mg, 0.51 mmol) were added to compound 130-3 (150 mg, 0.51 mmol) in DMF (2 mL) at room temperature in solution.
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80 °C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (20 mL ⁇ 2).
  • Step 5 At room temperature, hydroxylamine hydrochloride (133.50mg, 1.92mmol), Molecular sieves (90 mg, mmol) and triethylamine (1.60 mL, 11.53 mmol) were added to a solution of compound 130-4 (85 mg, 0.19 mmol) in methanol (2 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 75 °C and stirred for 3 hours, quenched by adding saturated ammonium chloride, filtered, and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 6 Add CDI (23.87mg, 0.15mmol) to compound 130-5 (56mg, 0.12mmol) in tetrahydrofuran (1mL) under ice-bath conditions, slowly warm up to room temperature and stir for 30min, then under ice-bath conditions DBU (26.37 ⁇ L, 0.18 mmol) was added. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 1 Add 5-trifluoromethylindole (2, 159mg, 0.86mmol) and t- Sodium butoxide (83 mg, 0.86 mmol).
  • the reaction mixture was purged with N2 and maintained under N2 atmosphere, after stirring at 80 °C for 3 h, cooled to 25 °C, quenched with saturated ammonium chloride solution (5 mL), and extracted with EA (40 mL).
  • Step 3 Add CDI (31mg, 0.19mmol) to compound 131-2 (55mg, 0.15mmol) in THF (2mL) at 0°C, warm to room temperature and stir for 30 minutes, then add DBU at 0°C (34 ⁇ L, 0.22 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour, then concentrated, the mixture was quenched by adding saturated ammonium chloride solution (2 mL), and extracted with EA (20 mL).
  • Step 2 Compound 133-1 (461.7 mg, 1.43 mmol), MeOH (21 mL), NH 2 OH ⁇ HCl (994.3 mg, 14.31 mmol), TEA (13 mL) and The mixture was purged with N2 and maintained under N2 atmosphere, stirred at 80 °C for 2 h, filtered under reduced pressure, and the resulting filtrate was concentrated. H 2 O (20 mL) was added to the obtained concentrate, followed by extraction with EA (30 mL). The organic phase was washed with saturated brine (10 mL ⁇ 3), dried over anhydrous Na 2 SO 4 and concentrated.
  • Step 4 Aqueous solution (0.2 mL) of Na 2 CO 3 (41.7 mg, 323.40 mmol) was added to compound 133-3 (75.0 mg, 0.20 mmol), 1,4-dioxane (1.2 mL), vinyl In a mixture of pinacol borate (45.4mg, 0.29mmol) and Pd(dppf)Cl 2 (14.3mg, 0.02mmol). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at 100° C. for 12 h, diluted with H 2 O (2 mL), and extracted with EA (5 mL).
  • Step 1 Na 2 CO 3 (38.3 mg, 0.36 mmol) in water (0.2 mL H 2 O) was added to compound 133-3 (70.0 mg, 0.18 mmol), 1,4-dioxane (1.2 mL), 4,4,5,5-Tetramethyl-2-propen-2-yl-1,3,2-dioxaborinane (60.7mg, 0.36mmol) and Pd(dppf)Cl 2 (13.2mg, 0.02 mmol) in the mixture.
  • the reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at 100° C. for 12 h, diluted with H 2 O (2 mL), and extracted with EA (5 mL).
  • Step 2 A mixture of compound 134-1 (15.0 mg, 0.04 mmol), THF (0.2 mL), MeOH (0.5 mL) and Pd/C (5%) (3.0 mg) was purged with H2 and maintained under H2 Atmosphere, after stirring at room temperature for 4 hours, purged with N2 and maintained N2 atmosphere, filtered under reduced pressure. The filtrate obtained by filtration and the filtrate obtained by washing the filter cake with DCM, EA, and MeOH successively were combined, dried over anhydrous Na 2 SO 4 , and concentrated to obtain a residue.
  • Step 3 Slowly add NaH (48 mg, 1.2 mmol) to a solution of compound 136-2 (100 mg, 0.59 mmol) in DMF (5 mL), react at room temperature for 1 hour, add 5-trifluoromethylindole (130 mg , 0.7 mmol). The reaction mixture was stirred at 120 °C for 3 h, diluted with H2O (200 mL), and extracted with EA (50 mL).
  • Step 4 Compound 136-3 (176 mg, 0.55 mmol), MeOH (20 mL), NH 2 OH ⁇ HCl (388 mg, 5.5 mmol), TEA (10 mL) and The mixture was purged with N2 and maintained under N2 atmosphere, after stirring at 80 °C for 3 h, it was filtered under reduced pressure. The obtained filtrate was concentrated, and H 2 O (20 mL) was added to the obtained concentrate, extracted with EA (30 mL).
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 8.12(s, 2H), 7.87(s, 1H).
  • Step 2 5-(Trifluoromethyl)-indole (4.14 g, 4.33 mmol) and sodium tert-butoxide (2.15 g, 22.39 mmol) were added to compound 137-1 (3.46 g, 22.39 mmol) in DMF ( 40mL) solution.
  • the reaction mixture was stirred at 80°C for 2 hours, diluted with water (100 mL), and extracted with ethyl acetate (100 mL*3).
  • Step 4 Add CDI (114.52mg, 0.71mmol) to a solution of compound 137-3 (190mg, 0.57mmol) in tetrahydrofuran (2mL) at 0°C, stir at room temperature for 0.5 hours, then add DBU (0.13 mL, 0.85 mmol). After the reaction mixture was stirred at room temperature for 1 hr, it was diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated and the resulting residue was purified by preparative high performance liquid chromatography (HPLC) to afford compound 137-4. (45.47 mg, 0.12 mmol, yield: 21.31%, purity: 96.04%).
  • HPLC preparative high performance liquid chromatography
  • Step 5 Add copper chloride (38.97 mg, 0.29 mmol) and tert-butyl nitrite (0.03 mL, 0.29 mmol) to a solution of compound 137-4 (70 mg, 0.19 mmol) in acetonitrile (1 mL) at 0 °C middle. After the reaction mixture was stirred at 50°C for 16 hours, it was diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated, and the obtained crude product was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 137 (2.88 mg, 0.01 mmol, yield: 3.89%, purity: 99.65%).
  • HPLC preparative high-performance liquid chromatography
  • Step 1 According to the similar synthesis method of Step 1 in Example 118, 3-chloro-5-trifluoromethylpyrazine-2-carbonitrile and 5-trifluoromethyl-1H- Indole was used as a reactant to prepare compound 138-1.
  • MS (ESI): m/z 357 [M+H] + .
  • Step 1 At room temperature, mix 5-bromo-3-(5-(trifluoromethyl)-1H-indol-1-yl)pyrazine-2-carbonitrile (50mg, 0.14mmol), ethylboronic acid (50 mg, 0.68 mmol), potassium carbonate (56 mg, 0.41 mmol) and Pd(dppf)Cl 2 (28 mg, 0.07 mmol) were dispersed in 1,4-dioxane (1 mL)/water (0.1 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80 °C and stirred overnight, diluted with water, and extracted with ethyl acetate (10 mL ⁇ 3).
  • Step 6 Under nitrogen atmosphere, to compound 144-5 (100mg, 0.56mmol), 5-trifluoromethyl-1H-indole (123.32mg, 0.67mmol), trans-N-dimethylcyclohexane - To a solution of 1,2-diamine (165mg, 1.16mmol) and potassium phosphate (117.82mg, 0.56mmol) in toluene (6mL) was added cuprous iodide (100mg, 0.53mmol). The reaction mixture was stirred overnight at 110 °C, diluted with H2O , and extracted with EA.
  • Step 8 Add CDI (58.92mg, 0.36mmol) to a THF (4mL) solution of compound 144-7 (72mg, 0.18mmol) at 0°C, stir at room temperature for 1 hour, then add DBU (54.23 ⁇ L, 0.36 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, cooled to 0 °C, adjusted to pH 6 with hydrochloric acid (2M), diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 144 (16 mg, 0.04 mmol, yield: 20.86%).
  • Step 3 Add 5-(trifluoromethyl)-1H-indole (132.36mg, 0.71mmol) to a solution of compound 146-2 (107mg, 0.60mmol) in toluene (2mL), BrettPhos Pd G3 (54.01mg, 0.06mmol) and sodium tert-butoxide (85.88mg, 0.89mmol). After stirring the reaction mixture at 100 °C for 18 hours. Poured into water (3 mL), and extracted with ethyl acetate (5 mLx3).
  • Step 5 At 0° C., CDI (11.23 mg, 0.07 mmol) was added to a solution of the crude product (35 mg) of compound 146-4 in THF (6 mL), and after stirring at 0° C. for 1 hour, DBU ( 14.11 ⁇ L, 0.09 mmol). After the reaction mixture was stirred at 0° C. for 1 hour, it was poured into water (6 mL), and extracted with ethyl acetate (6 mL ⁇ 3). The combined organic phases were washed with hydrochloric acid (1M), dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by high performance liquid chromatography to obtain compound 146 (3.16 mg, yield: 11.93%).
  • Step 9 Compound 147-8 (1g, 5.16mmol), 5-(trifluoromethyl)-1H-indole (1.15g, 6.20mmol), and Breetphos G3 (468.17mg, 0.52mmol) were dispersed in toluene ( 20mL).
  • the reaction mixture was purged with N2 and maintained under N2 atmosphere, after stirring at 100 °C for 12 h, water was added and extracted with ethyl acetate.
  • the combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 147-9 (389 mg, yield: 22%).
  • MS (ESI): m/z 343 [M+H] + .
  • Step 5 Add 5-trifluoromethyl-1H-indole (344.98 mg, 1.86 mmol), cuprous iodide (202.83 mg, 1.06mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (66.85mg, 0.47mmol) and potassium phosphate (329.58mg, 1.55mmol).
  • the reaction mixture was stirred overnight at 110 °C, cooled to room temperature, diluted with H2O , and extracted with EA. The organic phase was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 150-5 (280 mg, 0.74 mmol, yield: 47.79%).
  • MS (ESI): m/z 378 [M+H] + .
  • Step 7 Add CDI (148.18 mg, 0.91 mmol) to a THF (8 mL) solution of compound 150-6 (230 mg, 0.61 mmol) at 0°C, stir at room temperature for 0.5 hours, then add DBU (163.68 ⁇ L, 1.10 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, cooled to 0 °C and adjusted to pH 6 with hydrochloric acid (2M), diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 150 (57 mg, 0.13 mmol, yield: 21.44%).
  • Step 1 At room temperature, tert-butyl carbamate (740.69mg, 6.32mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (Xantphos) (997.75mg, 1.72mmol ), cesium carbonate (3745.49mg, 11.50mmol) and palladium acetate (129.04mg, 0.57mmol) were added to 3,6-dichloropyrazine-2-carbonitrile (0.63mL, 5.75mmol) in 1,4 dioxane ring (25 mL).
  • Xantphos 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
  • Step 2 Compound 155-1 (600mg, 2.36mmol), 5-trifluoromethyl-1H-indole (436.21mg, 2.36mmol), cesium carbonate (1535.26mg, 4.71mmol) were dispersed in DMF at room temperature (10mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 120 °C and stirred for 8 hours, diluted with water, and extracted with ethyl acetate (50 mL ⁇ 2).

Abstract

The present invention relates to a tricyclic compound represented by formula (O), a pharmaceutical composition comprising the compound as an active ingredient, and an application thereof. The compound is an excellent TEAD inhibitor and can be used for treating tumors.

Description

三环化合物及其应用Tricyclic compounds and their applications
相关申请的引用References to related applications
本申请要求享有2022年1月30日提交的申请号为202210113616.4、发明名称为“TEAD抑制剂”的中国专利申请以及2022年12月8日提交的申请号为202211572946.6发明名称为“三环化合物及其应用”的中国专利申请的优先权，其全部内容通过引用整体并入本文。This application claims to be entitled to the Chinese patent application with the application number 202210113616.4 submitted on January 30, 2022, and the invention name is "TEAD inhibitor" and the application number 202211572946.6 submitted on December 8, 2022, the invention name is "Tricyclic compounds and The priority of the Chinese patent application for its application”, the entire content of which is incorporated herein by reference in its entirety.
技术领域technical field
本发明属于药物化学领域，具体涉及三环化合物及其应用。The invention belongs to the field of medicinal chemistry, and specifically relates to tricyclic compounds and applications thereof.
背景技术Background technique
Hippo信号通路调控着许多生物进程，包括细胞增殖、存活、分化、器官大小和组织稳态。该通路由丝氨酸/苏氨酸蛋白激酶的复杂级联反应组成，包括丝氨酸苏氨酸激酶3(STK3)和STK4。这些激酶与衔接蛋白salvador同系物1(SAV1)形成的复合物可以磷酸化并激活效应蛋白LATS1/2。LATS1/2活化后会与MOB激酶激活因子1A/B(MOB1A/B)结合，并抑制转录辅助因子yes相关蛋白(YAP1)以及带有PDZ结合基序的转录共激活因子(TAZ或WWTR1)。Hippo通路“关闭”时，磷酸化的YAP/TAZ会滞留在细胞质中，并且可能发生蛋白降解。Hippo通路“开启”时，未磷酸化的YAP/TAZ会进入细胞核，并与转录因子TEADNA结合蛋白(TEAD1-4)结合。Hippo通路失调会导致YAP/TAZ的活性增加，从而与肿瘤、过度增殖、细胞侵袭、转移和化学抗性有关。The Hippo signaling pathway regulates many biological processes, including cell proliferation, survival, differentiation, organ size, and tissue homeostasis. This pathway consists of a complex cascade of serine/threonine protein kinases, including serine-threonine kinase 3 (STK3) and STK4. These kinases form a complex with the adapter protein salvador homolog 1 (SAV1) to phosphorylate and activate the effector proteins LATS1/2. Upon activation, LATS1/2 binds to MOB kinase activator 1A/B (MOB1A/B) and represses the transcriptional cofactor yes-associated protein (YAP1) and transcriptional coactivators with PDZ-binding motifs (TAZ or WWTR1). When the Hippo pathway is "off," phosphorylated YAP/TAZ remains cytoplasmic and proteolytic degradation may occur. When the Hippo pathway is "on," unphosphorylated YAP/TAZ enters the nucleus and binds the transcription factors TEADNA-binding proteins (TEAD1-4). Dysregulation of the Hippo pathway leads to increased activity of YAP/TAZ, which is associated with tumors, hyperproliferation, cell invasion, metastasis, and chemoresistance.
TEAD转录因子家族是Hippo通路的最终效应因子，其通过整合协调多种信号转导通路(包括Hippo，Wnt，TGFβ和EGFR)调控靶基因的表达(Kras，Braf，Ctgf，Cyr6，Axl，Myc等)，进而介导肿瘤生长、转移、组织稳态。众多临床研究发现，TEAD在多种实体瘤高水平表达，包括前列腺癌、胃癌、乳腺癌、生殖细胞肿瘤、头颈鳞状细胞癌、肾细胞癌等。由于与人类恶性肿瘤的临床病理参数高度相关，TEAD可作为实体瘤预后生物标志物。Hippo通路作为近十年发现的重要抗肿瘤靶点，相对于针对Hippo信号通路上游的调节子，靶向TEAD-YAP的抑制剂可能会更有效和直接地纠正失调的Hippo信号通路，从而达到肿瘤治疗目的。The TEAD transcription factor family is the final effector of the Hippo pathway, which regulates the expression of target genes (Kras, Braf, Ctgf, Cyr6, Axl, Myc, etc.) ), which in turn mediate tumor growth, metastasis, and tissue homeostasis. Many clinical studies have found that TEAD is highly expressed in a variety of solid tumors, including prostate cancer, gastric cancer, breast cancer, germ cell tumors, squamous cell carcinoma of the head and neck, and renal cell carcinoma. Due to its high correlation with clinicopathological parameters of human malignancies, TEAD can be used as a prognostic biomarker in solid tumors. The Hippo pathway is an important anti-tumor target discovered in the past decade. Compared with regulators targeting the upstream of the Hippo signaling pathway, inhibitors targeting TEAD-YAP may be more effective and directly correct the dysregulated Hippo signaling pathway, thereby reaching the tumor therapeutic purposes.
目前对于作为TEAD抑制剂新的化合物存在持续的需求。There is currently a continuing need for new compounds that are TEAD inhibitors.
发明内容Contents of the invention
本申请的一个方面，涉及一类能够与TEAD结合并作为TEAD抑制剂的化合物。本申请另一方面涉及本文所述化合物的制备方法。本申请的又一方面涉及包括本发明化合物作为活性成分的药物组合物，以及本发明化合物或药物组合物用于肿瘤治疗中的临床应用。One aspect of the present application relates to a class of compounds capable of binding to TEAD and acting as TEAD inhibitors. Another aspect of the application relates to processes for the preparation of the compounds described herein. Still another aspect of the present application relates to a pharmaceutical composition comprising the compound of the present invention as an active ingredient, and the clinical application of the compound or the pharmaceutical composition of the present invention for tumor treatment.
第一方面，本申请涉及以下通式O所示化合物：
In the first aspect, the present application relates to compounds represented by the following general formula O:
或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中：or tautomers of said compounds, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereomers thereof, racemates thereof, prodrugs thereof, pharmaceutically Acceptable salts, pharmaceutically acceptable solvates thereof, hydrates thereof, esters thereof, isotopes thereof, or metabolites thereof, wherein:
Ao环选自5-6元杂芳基、5-6元杂环基、苯基，且Ao环任选地被1-3个选自Rx、Ry、Rz、Rm的取代基所取代；优选地，Ao环选自5元杂芳基、5元不饱和杂环基、6元饱和杂环基、苯基、吡啶基，且Ao环任选地被1-3个选自Rx、Ry、Rz、Rm的取代基所取代；更优选地，Ao环选自5元杂芳基、5元不饱和杂环基、6元饱和杂环基、苯基、吡啶基，所述5元杂芳基包含2-4个选自N、O、S的杂原子，且Ao环任选地被1-3个选自Rx、Ry、Rz、Rm的取代基所取代；进一步优选地，Ao环选自5元杂芳基、5元不饱和杂环基、硫代吗啉基、四氢硫代吡喃基、苯基、吡啶基，所述5元杂芳基包含2-4个选自N、O、S的杂原子，且满足以下条件(1)-(3)中任意一项：The Ao ring is selected from 5-6 membered heteroaryl groups, 5-6 membered heterocyclic groups, and phenyl groups, and the Ao ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, Rm; preferably Preferably, the Ao ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, pyridyl, and the Ao ring is optionally replaced by 1-3 members selected from Rx, Ry, Substituents of Rz and Rm are substituted; more preferably, the Ao ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, pyridyl, and the 5-membered heteroaryl The group contains 2-4 heteroatoms selected from N, O, S, and the Ao ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, Rm; further preferably, the Ao ring is selected from From 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, thiomorpholinyl, tetrahydrothiopyranyl, phenyl, pyridyl, the 5-membered heteroaryl group contains 2-4 selected from N , O, S heteroatoms, and satisfy any one of the following conditions (1)-(3):
(1)Ao环选自5元杂芳基时，所述Ao环任选地被Rx所取代，(1) When the Ao ring is selected from a 5-membered heteroaryl group, the Ao ring is optionally substituted by Rx,
(2)Ao环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the Ao ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
(2-1)所述Ao环任选地被Rm所取代； (2-1) The Ao ring is optionally substituted by Rm;
(2-2)所述Ao环任选地被Ry、Rz和Rm所取代；(2-2) The Ao ring is optionally substituted by Ry, Rz and Rm;
(2-3)所述Ao环任选地被Ry和Rm所取代；(2-3) The Ao ring is optionally substituted by Ry and Rm;
(2-4)所述Ao环任选地被2个Rm所取代；(2-4) The Ao ring is optionally substituted by 2 Rm;
(2-5)所述Ao环任选地被Rz所取代；(2-5) The Ao ring is optionally substituted by Rz;
(3)Ao环选自硫代吗啉基、四氢硫代吡喃基、苯基、吡啶基时，所述Ao环任选地被1-2个选自Rz和Rm的取代基所取代；(3) When the Ao ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the Ao ring is optionally substituted by 1-2 substituents selected from Rz and Rm ;
最优选地，Ao环选自5元杂芳基、5元不饱和杂环基、 Most preferably, the Ao ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group,
所述5元杂芳基选自 所述5元不饱和杂环基选自 且满足以下条件(1)-(3)中任意一项：The 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any of the following conditions (1)-(3):
(1)Ao环选自5元杂芳基时，所述Ao环任选地被Rx所取代，(1) When the Ao ring is selected from a 5-membered heteroaryl group, the Ao ring is optionally substituted by Rx,
(2)Ao环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the Ao ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
(2-1)所述Ao环任选地被Rm所取代；(2-1) The Ao ring is optionally substituted by Rm;
(2-2)所述Ao环任选地被Ry、Rz和Rm所取代；(2-2) The Ao ring is optionally substituted by Ry, Rz and Rm;
(2-3)所述Ao环任选地被Ry和Rm所取代；(2-3) The Ao ring is optionally substituted by Ry and Rm;
(2-4)所述Ao环任选地被2个Rm所取代；(2-4) The Ao ring is optionally substituted by 2 Rm;
(2-5)所述Ao环任选地被Rz所取代；(2-5) The Ao ring is optionally substituted by Rz;
(3)Ao环选自硫代吗啉基、四氢硫代吡喃基、苯基、吡啶基时，所述Ao环任选地被1-2个选自Rz和Rm的取代基所取代；(3) When the Ao ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the Ao ring is optionally substituted by 1-2 substituents selected from Rz and Rm ;
其中，Rx选自C1-C6烷基、4-6元饱和杂环基(优选地，所述4-6元饱和杂环基包含1个选自N、O、S的杂原子)、-C(＝O)NRaRb、-S(＝O)2NRaRb、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、-NRaC(＝O)Rc，所述Rx任选地被1-2个选自Rn的取代基所取代；优选地，Rx选自甲基、乙基、氧杂环丁烷基、四氢吡咯基、四氢吡喃基、哌啶基、-C(＝O)NRaRb、-NRaC(＝O)Rc、-S(＝O)2NRaRb、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基；Wherein, Rx is selected from C1-C6 alkyl, 4-6 membered saturated heterocyclic group (preferably, the 4-6 membered saturated heterocyclic group contains 1 heteroatom selected from N, O, S), -C (=O)NRaRb, -S(=O) 2 NRaRb, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, -NRaC(=O)Rc, the Rx is any is optionally substituted by 1-2 substituents selected from Rn; preferably, Rx is selected from methyl, ethyl, oxetanyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, -C(=O)NRaRb, -NRaC(=O)Rc, -S(=O) 2 NRaRb, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl;
Rn选自C1-C6烷基、-NRaRb、-C(＝O)NRaRb、氧代、5-6元饱和杂环基(优选地，所述5-6元饱和杂环基包含2个选自N、O、S的杂原子)、C1-C6烷氧基、羧基、羟基；优选地，Rn选自甲基、乙基、-NRaRb、-C(＝O)NRaRb、氧代基、吗啉基、甲氧基、羟基、羧基；Rn is selected from C1-C6 alkyl, -NRaRb, -C(=O)NRaRb, oxo, 5-6 membered saturated heterocyclic group (preferably, the 5-6 membered saturated heterocyclic group contains 2 selected from Heteroatoms of N, O, S), C1-C6 alkoxy, carboxyl, hydroxyl; preferably, Rn is selected from methyl, ethyl, -NRaRb, -C(=O)NRaRb, oxo, morpholine group, methoxy group, hydroxyl group, carboxyl group;
Ra、Rb、Rc各自独立地选自H、C1-C6烷基、氰基、C3-C6环烷基，或者Ra、Rb和与它们共同相连的碳原子一起，形成氮杂环丁烷，且所述氮杂环丁烷任选地被羟基所取代；优选地，Ra、Rb、Rc各自独立地选自H、甲基、氰基、环丙基，或者Ra、Rb和与它们共同相连的碳原子一起，形成氮杂环丁烷，且所述氮杂环丁烷任选地被羟基所取代；Ra, Rb, and Rc are each independently selected from H, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, or Ra, Rb and the carbon atoms connected to them together form azetidine, and The azetidine is optionally substituted by a hydroxyl group; preferably, Ra, Rb, and Rc are each independently selected from H, methyl, cyano, cyclopropyl, or Ra, Rb and their joint The carbon atoms are taken together to form an azetidine, and the azetidine is optionally substituted with a hydroxyl group;
最优选地，Rx选自羟基、甲基、 Most preferably, Rx is selected from hydroxyl, methyl,
Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷基、被1-6个氘取代的C1-C6烷基、被C3-C6环烷基取代的C1-C6烷基、被C6-C10芳基取代的C1-C6烷基、被取代的C1-C6烷基、4-6元饱和杂环基；优选地，Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷基、被1-6个氘取代的C1-C6烷基、被C3-C6环烷基取代的C1-C6烷基、被C6-C10芳基取代的C1-C6烷基、被取代的C1-C6烷基、5-6元饱和杂环基；更优选地，Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被1-3个氘取代的C1-C6烷基、被环丙基取代的C1-C6烷基、被苯基取代的C1-C6烷基、5-6元饱和杂环基，所述5-6元饱和杂环基含有1个杂原子；进一步优选地，Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被1-3个氘取代的C1-C6烷基、被环丙基取代的C1-C6烷基、被苯基取代的C1-C6烷基、四氢吡咯基、哌啶基；最优选地，Ry选自甲基、-CHF2、-CF3、-CD3、-CH2CH3、-CH2CHF2、-CH2CF3、 Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by 1-6 deuterium, C3- C1-C6 alkyl substituted by C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, C1-C6 alkyl substituted by C6-C10 aryl, Substituted C1-C6 alkyl, 4-6 membered saturated heterocyclic group; preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 substituted by 1-6 halogen Alkyl, C1-C6 alkyl substituted by 1-6 deuterium, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, Substituted C1-C6 alkyl, 5-6 membered saturated heterocyclic group; more preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1- C6 alkyl, C1-C6 alkyl substituted by 1-3 deuterium, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, 5-6 membered saturated heterocyclic group, the 5-6 membered saturated heterocyclic group contains 1 heteroatom; more preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, substituted by 1 - C1-C6 alkyl substituted by 3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, Tetrahydropyrrolyl, piperidinyl; most preferably, Ry is selected from methyl, -CHF 2 , -CF 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 ,
Rz选自C1-C6烷基、卤素、优选地，Rz选自甲基、Br、或者，Ry、Rz以及和它们共同相连的碳原子一起，形成4-6元饱和碳环、4-6元饱和杂环；或者优选地，Ry、Rz以及和它们共同相连的碳原子一起，形成4-6元饱和碳环、4-6元饱和杂环，所述4-6元饱和杂环含有1个杂原子；或者更优选地，Ry、Rz以及和它们共同相连的碳原子一起，形成环丁烷、环戊烷、环己烷、哌啶、四氢吡喃；或者最优选地，Ry、Rz以及和它们共同相连的碳原子一起，形成其中，1’号碳原子为与Ry和Rz共同相连的碳原子；Rm为氧代基；Rz is selected from C1-C6 alkyl, halogen, Preferably, Rz is selected from methyl, Br, Or, Ry, Rz and their common carbon atoms together form a 4-6 membered saturated carbocyclic ring, a 4-6 membered saturated heterocyclic ring; or preferably, Ry, Rz and their common connected carbon atoms form a 4-6 membered saturated carbocyclic ring, 4-6 membered saturated heterocyclic ring, the 4-6 membered saturated heterocyclic ring contains 1 heteroatom; or more preferably, Ry, Rz and their common carbon atoms together form Cyclobutane, cyclopentane, cyclohexane, piperidine, tetrahydropyran; or most preferably, Ry, Rz and together with the carbon atoms to which they are commonly attached, form Wherein, the 1' carbon atom is a carbon atom connected to Ry and Rz; Rm is an oxo group;
最优选地，Ao环及其任选的取代基作为整体，选自以下：

Most preferably, the Ao ring and its optional substituents, taken as a whole, are selected from the following:

Bo环选自： 其任选地被1-3个取代基取代，所述取代基选自：五氟化硫基、-OH、C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基、卤素、硝基、氰基、氨基；Bo rings are selected from: It is optionally substituted with 1-3 substituents selected from: thiopentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1 -6 halogen substituted C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkoxy, halogen, nitro, cyano, amino;
优选地，上述 其任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基、卤素；更优选地，上述任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基、卤素；或者上述 任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基、卤素； Preferably, the above It is optionally substituted with 1-2 substituents selected from the group consisting of: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkane Base, 1-6 halogen substituted C1-C6 alkoxy, halogen; more preferably, the above Optionally substituted with 1-2 substituents selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl , 1-6 halogen substituted C1-C6 alkoxy, halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl, halogen;
更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-Cl、-SF5、-CH3、-F、-OCH3、-OCF3；或者上述 任选地被1-2个取代基取代，所述取代基选自：-CF3、-CH3、-F、 More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 , -OCF 3 ; or the above optionally substituted with 1-2 substituents selected from: -CF 3 , -CH 3 , -F,
进一步优选地，上述其上的取代基的取代位置为：2-位单取代、3-位单取代、5-位单取代、4-、5-位双取代、5-、6-位双取代、2-、5-位双取代、3-、5-位双取代；其上的取代基的取代位置为3-位单取代、5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为6-位单取代；其上的取代基的取代位置为5-位或6位单取代或双取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代； 其上的取代基的取代位置为4-位单取代、5-位单取代；其上的取代基的取代位置为3-位单取代；Further preferably, the above The substitution positions of the substituents on it are: 2-position mono-substitution, 3-position mono-substitution, 5-position mono-substitution, 4-, 5-position double substitution, 5-, 6-position double substitution, 2-, 5-position - double substitution, 3-, 5-position double substitution; The substitution positions of the substituents on it are 3-position mono-substitution and 5-position mono-substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 6-position monosubstituted; The substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 4-position mono-substitution, 5-position mono-substitution; The substitution position of the substituent on it is 3-position monosubstituted;
最优选地，Bo环选自： Most preferably, the Bo ring is selected from:
Co环选自5元杂芳环、6元部分不饱和杂环；优选地，所述5元杂芳环选自 优选地，所述6元部分不饱和杂环为 The Co ring is selected from 5-membered heteroaryl ring, 6-membered partially unsaturated heterocyclic ring; preferably, the 5-membered heteroaryl ring is selected from Preferably, the 6-membered partially unsaturated heterocycle is
A10、A20、A30、A40独立地选自：N、CH，其中最多3个为N；A 10 , A 20 , A 30 , A 40 are independently selected from: N, CH, wherein at most 3 are N;
L0选自直接键、NH、O、S；优选地，L0选自直接键、NH； L is selected from direct bonds, NH, O, S; preferably, L is selected from direct bonds, NH;
Ro选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C5杂芳基、C1-C6烷氧基、羟基取代的C1-C6烷氧基、被5-6元杂芳基取代的C1-C6烷氧基、C3-C5 杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被氰基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、卤素、氰基、硝基、氧代基、C2-C6烯基、被C6-C10芳基取代的C1-C6烷基、5-6元杂环基、被氨基取代的C1-C6烷基；其中C3-C5杂环基被C1-C3烷基任意取代，C6-C10芳基被1-6个卤素任意取代，5-6元杂环基被C1-C3烷基或羟基任意取代；或两个Ro，与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；更优选地，Ro选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、吡啶基C1-C6烷氧基、羟基取代的C1-C6烷氧基、C3杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、C1-C6烷氧基、C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被氰基取代的C1-C6烷基、卤素、氰基、氧代基、C2-C6烯基、被苯基取代的C1-C6烷基、被氨基取代的C1-C6烷基、四氢吡咯基、哌嗪基，其中C3杂环基被C1-C3烷基任意取代，四氢吡咯基被羟基任意取代，哌嗪基被C1-C3烷基任意取代；或两个Ro，与它们相连的原子共同形成苯环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素(优选-F)和氘的基团所取代；Ro is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C5 heteroaryl, C1-C6 Alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 Heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen Substituted C1-C6 alkyl, C1-C6 alkyl substituted by cyano, C1-C6 alkoxy substituted by 1-6 halogen, halogen, cyano, nitro, oxo, C2-C6 alkene C1-C6 alkyl group, C1-C6 alkyl group substituted by C6-C10 aryl group, 5-6 membered heterocyclic group, C1-C6 alkyl group substituted by amino group; where C3-C5 heterocyclic group is optionally substituted by C1-C3 alkyl group, C6-C10 aryl is optionally substituted by 1-6 halogens, 5-6 membered heterocyclic group is optionally substituted by C1-C3 alkyl or hydroxyl; or two Ro, and the atoms connected to them together form a C6-C10 aromatic ring, Partially unsaturated C5-C6 carbocycle, partly unsaturated 5-6 membered heterocycle or 5-6 membered heteroaromatic ring, of which partially unsaturated C5-C6 carbocycle, partly unsaturated 5-6 membered heterocycle or 5-6 Each membered heteroaromatic ring is optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, Ro is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, Carbamoyl, pyridyl C1-C6 alkoxy, hydroxyl substituted C1-C6 alkoxy, C3 heterocyclyloxy, carboxyl (-COOH), Ester group (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogen, substituted by cyano C1-C6 alkyl, halogen, cyano, oxo, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, C1-C6 alkyl substituted by amino, tetrahydropyrrolyl, piperazine A group, wherein the C3 heterocyclic group is optionally substituted by a C1-C3 alkyl group, the tetrahydropyrrolyl group is optionally substituted by a hydroxyl group, and the piperazinyl group is optionally substituted by a C1-C3 alkyl group; Ring, partially unsaturated C5-C6 carbocyclic ring, partially unsaturated 5-6 membered heterocyclic ring or 5-membered heteroaryl ring, wherein the partially unsaturated C5-C6 carbocyclic ring and the partially unsaturated 5-6 membered heterocyclic ring are each optionally Substituted by 1-6 groups selected from halogen (preferably -F) and deuterium;
最优选地，Ro选自：氧代基、 -OCH3、-CH3、-F、-Cl、-CN、-OH、-NH2、-COOH、-COOCH3、-CH2CH3、-CF3、-CHF2、 或两个Ro与它们相连的原子共同形成： Most preferably, Ro is selected from: oxo, -OCH 3 , -CH 3 , -F, -Cl, -CN, -OH, -NH 2 , -COOH, -COOCH 3 , -CH 2 CH 3 , -CF 3 , -CHF 2 , or two Ro together with the atoms to which they are attached:
在本申请的一些实施方案中，Ao环及其任选的取代基作为整体，选自 优选地，Ao环及其任选的取代基作为整体，选自最优选地，Ao环及其任选的取代基作为整体，为 In some embodiments of the present application, the Ao ring and its optional substituents as a whole are selected from Preferably, the Ao ring and its optional substituents as a whole are selected from Most preferably, the Ao ring and its optional substituents, taken as a whole, are
在本申请的一些实施方案中，上述式O化合物为以下式Oc：
In some embodiments of the present application, the above-mentioned compound of formula O is the following formula Oc:
Aoc环及其任选的取代基作为整体，选自 优选地，Aoc环及其任选的取代基作为整体，选自最优选地，Aoc环及其任选的取代基作为整体，为 The Aoc ring and its optional substituents as a whole are selected from Preferably, the Aoc ring and its optional substituents as a whole are selected from Most preferably, the Aoc ring and its optional substituents as a whole are
Co环的定义与上述式O中Co环的定义相同；Ro的定义与上述式O中Ro的定义相同。The definition of the Co ring is the same as that of the Co ring in the above formula O; the definition of Ro is the same as the definition of Ro in the above formula O.
在本申请的一些实施方案中，上述式Oc化合物为以下式Occ：
In some embodiments of the present application, the above-mentioned compound of formula Oc is the following formula Occ:
Aocc环及其任选的取代基作为整体，其定义与上述式Oc中Aoc环及其任选的取代基作为整体的定义相同；A10、A20、A30、A40的定义与上述式O中A10、A20、A30、A40的定义相同；Ro的定义与上述式O中Ro的定义相同。The definition of the Aoc ring and its optional substituents as a whole is the same as the definition of the Aoc ring and its optional substituents in the above formula Oc; the definitions of A 10 , A 20 , A 30 , and A 40 are the same as those in the above formula The definitions of A 10 , A 20 , A 30 , and A 40 in O are the same; the definition of Ro is the same as that of Ro in the above formula O.
在本申请的一些实施方案中，上述式O化合物为以下式O-1：
In some embodiments of the present application, the above-mentioned compound of formula O is the following formula O-1:
或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，or tautomers of said compounds, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereomers thereof, racemates thereof, prodrugs thereof, pharmaceutically Acceptable salts, pharmaceutically acceptable solvates thereof, hydrates thereof, esters thereof, isotopes thereof, or metabolites thereof,
其中：Ao环的定义与上述式O中Ao环的定义相同；Bo环的定义与上述式O中Bo环的定义相同；Co环的定义与上述式O中Co环的定义相同；L0的定义与上述式O中L0的定义相同；Ro11、Ro12和与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；优选地，Ro11、Ro12和与它们相连的原子共同形成苯环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素和氘的基团所取代；或者优选地，Ro11、Ro12和与它们相连的原子共同形成部分不饱和C5-C6碳环或部分不饱和5-6元杂环，其中部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素和氘的基团所取代；更优选地，Ro11、Ro12和与它们相连的原子共同形成： Wherein: the definition of Ao ring is the same as the definition of Ao ring in the above-mentioned formula O; the definition of Bo ring is the same as the definition of Bo ring in the above-mentioned formula O; the definition of Co ring is the same as the definition of Co ring in the above-mentioned formula O; The definition is the same as the definition of L 0 in the above formula O; Ro 11 , Ro 12 and the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or 5-6 membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, partially unsaturated 5-6 membered heterocyclic ring or 5-6 membered heteroaromatic ring is optionally replaced by 1-6 members selected from halogen and deuterium group; preferably, Ro 11 , Ro 12 and the atoms connected to them together form a benzene ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-membered heteroaromatic ring, wherein Partially unsaturated C5-C6 carbocycle and partially unsaturated 5-6 membered heterocycle are each optionally substituted by 1-6 groups selected from halogen and deuterium; or preferably, Ro 11 , Ro 12 and their The connected atoms together form a partially unsaturated C5-C6 carbocyclic ring or a partially unsaturated 5-6 membered heterocyclic ring, wherein the partially unsaturated C5-C6 carbon ring and the partially unsaturated 5-6 membered heterocyclic ring are each optionally replaced by 1- 6 groups selected from halogen and deuterium are substituted; more preferably, Ro 11 , Ro 12 and the atoms connected to them together form:
最优选地，Ro11、Ro12和与它们相连的原子共同形成： Most preferably, Ro 11 , Ro 12 and the atoms attached to them together form:
在本申请的一些实施方案中，上述式O化合物为以下式I：
In some embodiments of the present application, the above-mentioned compound of formula O is the following formula I:
A1环的定义与上述式O中Ao环的定义相同；B1环的定义同上述式O中Bo环的定义；L1的定义与上述式O中L0的定义相同；A1、A2、A3、A4独立地选自：N、CH，其中最多3个为N；R1的定义与上述式O中Ro的定义相同。The definition of A1 ring is the same as the definition of Ao ring in the above formula O; the definition of B1 ring is the same as the definition of Bo ring in the above formula O; the definition of L 1 is the same as the definition of L 0 in the above formula O; A 1 , A 2 , A 3 and A 4 are independently selected from: N, CH, and at most 3 of them are N; the definition of R 1 is the same as the definition of Ro in the above formula O.
在本申请的一些实施方案中，上述式I化合物为以下式Ic:
In some embodiments of the present application, the above-mentioned compound of formula I is the following formula Ic:
A1c环及其任选的取代基作为整体，其定义与上述式Oc中Aoc环及其任选的取代基作为整体的定义相同；A1、A2、A3、A4独立地选自：N、CH，其中最多3个为N；R1的定义与上述式I中R1的定义相同。A 1c ring and its optional substituents as a whole have the same definition as the Aoc ring and its optional substituents in the above formula Oc as a whole; A 1 , A 2 , A 3 , and A 4 are independently selected from : N, CH, wherein at most 3 are N; the definition of R1 is the same as the definition of R1 in the above formula I.
在本申请的一些实施方案中，上述式I化合物为以下式I-1：
In some embodiments of the present application, the above-mentioned compound of formula I is the following formula I-1:
A11环选自5元杂芳基、5元不饱和杂环基、所述5元杂芳基选自 所述5元不饱和杂环基选自 且满足以下条件(1)-(2)中任意一项：The A11 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
(1)A11环选自5元杂芳基时，所述A11环任选地被Rx所取代，(1) When the A11 ring is selected from a 5-membered heteroaryl group, the A11 ring is optionally substituted by Rx,
(2)A11环选自5元不饱和杂环基时，所述A11环任选地被Rm或Rz所取代，或者任选地被Ry和Rm所取代；(2) When the A11 ring is selected from a 5-membered unsaturated heterocyclic group, the A11 ring is optionally substituted by Rm or Rz, or optionally substituted by Ry and Rm;
其中，Rx选自甲基、 Wherein, Rx is selected from methyl,
Ry为甲基；Rz选自卤素(优选Br)；Rm为氧代基；Ry is a methyl group; Rz is selected from halogen (preferably Br); Rm is an oxo group;
优选地，A11环及其任选的取代基作为整体，选自以下：

Preferably, ring A11 and its optional substituents, taken as a whole, are selected from the following:

B11环选自：其任选地被1-3个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、C3-C4环烷基，1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基、卤素、氨基；Ring B11 is selected from: It is optionally substituted with 1-3 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 Alkyl, 1-6 halogen substituted C1-C6 alkoxy, halogen, amino;
优选地，上述任选地被1-2个取代基取代，所述取代基选自：1-6个卤素取代的C1-C6烷基、C3-C4环烷基，1-6个卤素取代的C1-C6烷氧基、氨基；Preferably, the above Optionally substituted with 1-2 substituents selected from: 1-6 halogen substituted C1-C6 alkyl, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 alkane Oxygen, amino;
更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-OCF3；More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -OCF 3 ;
最优选地，B11环选自： Most preferably, the B11 ring is selected from:
R11选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、C1-C6烷氧基、卤素、氰基、硝基；R 11 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, halogen, cyano, nitro;
更优选地，R11选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、卤素、氰基；进一步优选地，R11选自：-CH3、-F、 -Cl、-CN；更进一步优选地，R11位于环上的位置选自：1-位、2-位、3位、4-位。More preferably, R 11 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl , halogen, cyano; further preferably, R 11 is selected from: -CH 3 , -F, -Cl, -CN; more preferably, R 11 is located in ring The position on is selected from: 1-position, 2-position, 3-position, 4-position.
在本申请的一些实施方案中，上述式I-1化合物为以下式I-1c：
In some embodiments of the present application, the above-mentioned compound of formula I-1 is the following formula I-1c:
A11c环及其任选的取代基作为整体，选自 优选地，A11c环及其任选的取代基作为整体，选自 更优选地，A11c环及其任选的取代基作为整体，为 R11的定义与上述式I-1中R11的定义相同。A 11c ring and its optional substituents as a whole are selected from Preferably, the A 11c ring and its optional substituents as a whole are selected from More preferably, the A 11c ring and its optional substituents, taken as a whole, are The definition of R 11 is the same as the definition of R 11 in the above formula I-1.
在本申请的一些实施方案中，上述式I化合物为以下式I-2：
In some embodiments of the present application, the above-mentioned compound of formula I is the following formula I-2:
A12环选自5元杂芳基、5元不饱和杂环基、所述5元杂芳基选自 所述5元不饱和杂环基选自 且满足以下条件(1)-(3)中任意一项：The A12 ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any of the following conditions (1)-(3):
(1)A12环选自5元杂芳基时，所述A12环任选地被Rx所取代，(1) When the A12 ring is selected from a 5-membered heteroaryl group, the A12 ring is optionally substituted by Rx,
(2)A12环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the A12 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
(2-1)所述A12环任选地被Rm所取代；(2-1) The A12 ring is optionally substituted by Rm;
(2-2)所述A12环任选地被Ry、Rz和Rm所取代；(2-2) The A12 ring is optionally substituted by Ry, Rz and Rm;
(2-3)所述A12环任选地被Ry和Rm所取代；(2-3) the A12 ring is optionally substituted by Ry and Rm;
(2-4)所述A12环任选地被2个Rm所取代；(2-4) The A12 ring is optionally substituted by 2 Rm;
(2-5)所述A12环任选地被Rz所取代；(2-5) the A12 ring is optionally substituted by Rz;
(3)A12环选自时，所述A12环任选地被1-2个选自Rz和Rm的取代基所取代；(3) Ring A12 is selected from When, the A12 ring is optionally substituted by 1-2 substituents selected from Rz and Rm;
其中，Rx选自羟基、 Ry选自甲基、-CHF2、-CF3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rz选自甲基、 或者，Ry、Rz以及和它们共同相连的碳原子一起，形成其中，1’号碳原子为与Ry和Rz共同相连的碳原子；Rm为氧代基；Wherein, Rx is selected from hydroxyl, Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rz is selected from methyl, Alternatively, Ry, Rz, and the carbon atoms connected to them together form Wherein, the 1' carbon atom is a carbon atom connected to Ry and Rz; Rm is an oxo group;
最优选地，A12环及其任选的取代基作为整体，选自以下：

Most preferably, ring A12 and its optional substituents, taken as a whole, are selected from the following:

B12环选自： 其任选地被1-3个取代基取代，所述取代基选自：五氟化硫基、-OH、C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、卤素、硝基、氰基、氨基；The B12 ring is selected from: It is optionally substituted with 1-3 substituents selected from: thiopentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1 -6 halogen substituted C1-C6 alkyl, halogen, nitro, cyano, amino;
优选地，上述 其任选地被 1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；Preferably, the above which is optionally 1-2 substituents are substituted, and the substituents are selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen;
更优选地，上述任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；或者上述 任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；More preferably, the above Optionally substituted with 1-2 substituents selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl , halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl;
更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-Cl、-SF5、-CH3、-F、-OCH3；或者上述 任选地被1-2个取代基取代，所述取代基选自：-CF3、-CH3；进一步优选地，上述其上的取代基的取代位置为：2-位单取代、3-位单取代、5-位单取代、4-、5-位双取代、5-、6-位双取代、2-、5-位双取代、3-、5-位双取代；其上的取代基的取代位置为3-位单取代、5-位单取代；其上的取代基 的取代位置为5-位单取代；其上的取代基的取代位置为6-位单取代；其上的取代基的取代位置为5-位或6位单取代或双取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 ; or the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -CH 3 ; more preferably, the above The substitution positions of the substituents on it are: 2-position mono-substitution, 3-position mono-substitution, 5-position mono-substitution, 4-, 5-position double substitution, 5-, 6-position double substitution, 2-, 5-position - double substitution, 3-, 5-position double substitution; The substitution positions of the substituents on it are 3-position mono-substitution and 5-position mono-substitution; Substituents on it The substitution position is 5-position monosubstitution; The substitution position of the substituent on it is 6-position monosubstituted; The substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted;
最优选地，B12环选自： Most preferably, the B12 ring is selected from:
R12选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被氨基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、C1-C5杂芳基、C1-C6烷氧基、羟基取代的C1-C6烷氧基、被5-6元杂芳基取代的C1-C6烷氧基、C3-C5杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、卤素、氰基、C2-C6烯基、被C6-C10芳基取代的C1-C6烷基、5-6元杂环基；其中C3-C5杂环基被C1-C3烷基任意取代，C6-C10芳基被1-6个卤素任意取代，5-6元杂环基被C1-C3烷基或羟基任意取代；或两个R12，与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；更优选地，R12选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、吡啶基C1-C6烷氧基、羟基取代的C1-C6烷氧基、C3杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、C1-C6烷氧基、C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被氨基取代的C1-C6烷基、卤素、氰基、C2-C6烯基、被苯基取代的C1-C6烷基、四氢吡咯基、哌嗪基，其中C3杂环基被C1-C3烷基任意取代，四氢吡咯基被羟基任意取代，哌嗪基被C1-C3烷基任意取代；或两个R12，与它们相连的原子共同形成苯环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素(优选-F)和氘的基团所取代；进一步优选地，R12选自： -OH、-NH2、-COOH、-COOCH3、-CH3、-CH2CH3、-F、-Cl、-CN、-CHF2、-CF3、或两个R12与它们相连的原子共同形成： 更进一步优选地，R12位于环上的位置选自：A12-位、A32-位、A22-位；A12、A22、A32、A42独立地选自：N、CH，且其中只有1个为N，其余为CH。R 12 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by amino, C1-C6 alkoxy substituted by 1-6 halogen, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester Group (-CO-O-C1-C6 alkyl), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered heterocyclic group ; wherein the C3-C5 heterocyclic group is optionally substituted by a C1-C3 alkyl group, the C6-C10 aryl group is optionally substituted by 1-6 halogens, and the 5-6 membered heterocyclic group is optionally substituted by a C1-C3 alkyl or hydroxyl group; or Two R 12 , the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, in which the partially unsaturated C5 Each of -C6 carbocycle, partially unsaturated 5-6 membered heterocycle or 5-6 membered heteroaryl ring is optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, R is selected from : Aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, pyridyl C1-C6 alkoxy, C1 substituted by hydroxyl -C6 alkoxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkyl , C1-C6 alkyl substituted by 1-3 halogen, C1-C6 alkyl substituted by amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrole Base, piperazinyl, wherein C3 heterocyclic group is optionally substituted by C1-C3 alkyl, tetrahydropyrrolyl is optionally substituted by hydroxyl, piperazinyl is optionally substituted by C1-C3 alkyl; or two R 12 are connected to them The atoms together form a benzene ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-membered heteroaryl ring, wherein a partially unsaturated C5-C6 carbocyclic ring and a partially unsaturated 5-6 membered heterocyclic ring Each ring is optionally substituted by 1-6 groups selected from halogen (preferably -F) and deuterium; further preferably, R is selected from: -OH, -NH 2 , -COOH, -COOCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CHF 2 , -CF 3 , or two R 12 together with the atoms to which they are attached: More preferably, the position of R 12 on the ring is selected from: A 12 -position, A 32 -position, A 22 -position; A 12 , A 22 , A 32 , A 42 are independently selected from: N, CH, And only one of them is N, and the rest are CH.
在本申请的一些实施方案中，上述式I-2化合物为以下式I-2c：
In some embodiments of the present application, the above-mentioned compound of formula I-2 is the following formula I-2c:
A12c环及其任选的取代基作为整体，选自： A 12c ring and its optional substituents as a whole are selected from:
优选地，A12c环及其任选的取代基作为整体，选自： Preferably, the A 12c ring and its optional substituents, taken as a whole, are selected from:
最优选地，A12c环及其任选的取代基作为整体，选自： A12、A22、A32、A42的定义与上述式I-2中A12、A22、A32、A42的定义相同；R12的定义与上述式I-2中R12的定义相同。Most preferably, the A 12c ring and its optional substituents, taken as a whole, are selected from: The definition of A 12 , A 22 , A 32 , A 42 is the same as the definition of A 12 , A 22 , A 32 , A 42 in the above formula I-2; the definition of R 12 is the same as the definition of R 12 in the above formula I-2 same.
在本申请的一些实施方案中，上述式I化合物为以下式I-3：
In some embodiments of the present application, the above-mentioned compound of formula I is the following formula I-3:
其中，A13环选自5-6元杂芳基、5-6元杂环基、苯基，且A13环任选地被1-3个选自Rx、Ry、Rz、Rm的取代基所取代；优选地，A13环选自5元杂芳基、5元不饱和杂环基、6元饱和杂环基、苯基、吡啶 基，且A13环任选地被1-3个选自Rx、Ry、Rz、Rm的取代基所取代；更优选地，A13环选自5元杂芳基、5元不饱和杂环基、6元饱和杂环基、苯基、吡啶基，所述5元杂芳基包含2-4个选自N、O、S的杂原子，且A13环任选地被1-3个选自Rx、Ry、Rz、Rm的取代基所取代；进一步优选地，A13环选自5元杂芳基、5元不饱和杂环基、硫代吗啉基、四氢硫代吡喃基、苯基、吡啶基，所述5元杂芳基包含2-4个选自N、O、S的杂原子，且满足以下条件(1)-(3)中任意一项：Wherein, A13 ring is selected from 5-6 membered heteroaryl, 5-6 membered heterocyclic group, phenyl, and A13 ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, Rm ; Preferably, the A13 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, pyridine group, and A13 ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, Rm; more preferably, A13 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, pyridyl, the 5-membered heteroaryl group contains 2-4 heteroatoms selected from N, O, S, and the A13 ring is optionally replaced by 1-3 selected from Rx , Ry, Rz, Rm are substituted by substituents; further preferably, ring A13 is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, thiomorpholinyl, tetrahydrothiopyranyl, phenyl , pyridyl, the 5-membered heteroaryl group contains 2-4 heteroatoms selected from N, O, S, and satisfies any one of the following conditions (1)-(3):
(1)A13环选自5元杂芳基时，所述A13环任选地被Rx所取代，(1) When the A13 ring is selected from a 5-membered heteroaryl group, the A13 ring is optionally substituted by Rx,
(2)A13环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the A13 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
(2-1)所述A13环任选地被Rm所取代；(2-1) the A13 ring is optionally substituted by Rm;
(2-2)所述A13环任选地被Ry、Rz和Rm所取代；(2-2) The A13 ring is optionally substituted by Ry, Rz and Rm;
(2-3)所述A13环任选地被Ry和Rm所取代；(2-3) The A13 ring is optionally substituted by Ry and Rm;
(2-4)所述A13环任选地被2个Rm所取代；(2-4) The A13 ring is optionally substituted by 2 Rm;
(2-5)所述A13环任选地被Rz所取代；(2-5) the A13 ring is optionally substituted by Rz;
(3)A13环选自硫代吗啉基、四氢硫代吡喃基、苯基、吡啶基时，所述A13环任选地被1-2个选自Rz和Rm的取代基所取代；(3) When the A13 ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the A13 ring is optionally substituted by 1-2 substituents selected from Rz and Rm ;
更进一步优选地，A13环选自5元杂芳基、5元不饱和杂环基、 More preferably, the A13 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group,
所述5元杂芳基选自 所述5元不饱和杂环基选自 且满足以下条件(1)-(3)中任意一项：The 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any of the following conditions (1)-(3):
(1)A13环选自5元杂芳基时，所述A13环任选地被Rx所取代，(1) When the A13 ring is selected from a 5-membered heteroaryl group, the A13 ring is optionally substituted by Rx,
(2)A13环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the A13 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
(2-1)所述A13环任选地被Rm所取代；(2-1) the A13 ring is optionally substituted by Rm;
(2-2)所述A13环任选地被Ry、Rz和Rm所取代；(2-2) The A13 ring is optionally substituted by Ry, Rz and Rm;
(2-3)所述A13环任选地被Ry和Rm所取代；(2-3) The A13 ring is optionally substituted by Ry and Rm;
(2-4)所述A13环任选地被2个Rm所取代；(2-4) The A13 ring is optionally substituted by 2 Rm;
(2-5)所述A13环任选地被Rz所取代；(2-5) the A13 ring is optionally substituted by Rz;
(3)A13环选自硫代吗啉基、四氢硫代吡喃基、苯基、吡啶基时，所述A13环任选地被1-2个选自Rz和Rm的取代基所取代；(3) When the A13 ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the A13 ring is optionally substituted by 1-2 substituents selected from Rz and Rm ;
其中，Rx选自C1-C6烷基、4-6元饱和杂环基(优选地，所述4-6元饱和杂环基包含1个选自N、O、S的杂原子)、-C(＝O)NRaRb、-S(＝O)2NRaRb、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、-NRaC(＝O)Rc，所述Rx任选地被1-2个选自Rn的取代基所取代；优选地，Rx选自甲基、乙基、氧杂环丁烷基、四氢吡咯基、四氢吡喃基、哌啶基、-C(＝O)NRaRb、-NRaC(＝O)Rc、-S(＝O)2NRaRb、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基；Wherein, Rx is selected from C1-C6 alkyl, 4-6 membered saturated heterocyclic group (preferably, the 4-6 membered saturated heterocyclic group contains 1 heteroatom selected from N, O, S), -C (=O)NRaRb, -S(=O) 2 NRaRb, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, -NRaC(=O)Rc, the Rx is any is optionally substituted by 1-2 substituents selected from Rn; preferably, Rx is selected from methyl, ethyl, oxetanyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, -C(=O)NRaRb, -NRaC(=O)Rc, -S(=O) 2 NRaRb, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl;
Rn选自C1-C6烷基、-NRaRb、-C(＝O)NRaRb、氧代、5-6元饱和杂环基(优选地，所述5-6元饱和杂环基包含2个选自N、O、S的杂原子)、C1-C6烷氧基、羧基、羟基；优选地，Rn选自甲基、乙基、-NRaRb、-C(＝O)NRaRb、氧代基、吗啉基、甲氧基、羟基、羧基；Rn is selected from C1-C6 alkyl, -NRaRb, -C(=O)NRaRb, oxo, 5-6 membered saturated heterocyclic group (preferably, the 5-6 membered saturated heterocyclic group contains 2 selected from Heteroatoms of N, O, S), C1-C6 alkoxy, carboxyl, hydroxyl; preferably, Rn is selected from methyl, ethyl, -NRaRb, -C(=O)NRaRb, oxo, morpholine group, methoxy group, hydroxyl group, carboxyl group;
Ra、Rb、Rc各自独立地选自H、C1-C6烷基、氰基、C3-C6环烷基，或者Ra、Rb和与它们共同相连的碳原子一起，形成氮杂环丁烷，且所述氮杂环丁烷任选地被羟基所取代；优选地，Ra、Rb、Rc各自独立地选自H、甲基、氰基、环丙基，或者Ra、Rb和与它们共同相连的碳原子一起，形成氮杂环丁烷， 且所述氮杂环丁烷任选地被羟基所取代；Ra, Rb, and Rc are each independently selected from H, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, or Ra, Rb and the carbon atoms connected to them together form azetidine, and The azetidine is optionally substituted by a hydroxyl group; preferably, Ra, Rb, and Rc are each independently selected from H, methyl, cyano, cyclopropyl, or Ra, Rb and their joint carbon atoms together to form azetidine, and said azetidine is optionally substituted by hydroxyl;
最优选地，Rx选自羟基、甲基、 Most preferably, Rx is selected from hydroxyl, methyl,
Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷基、被1-6个氘取代的C1-C6烷基、被C3-C6环烷基取代的C1-C6烷基、被C6-C10芳基取代的C1-C6烷基、被取代的C1-C6烷基、4-6元饱和杂环基；优选地，Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷基、被1-6个氘取代的C1-C6烷基、被C3-C6环烷基取代的C1-C6烷基、被C6-C10芳基取代的C1-C6烷基、被取代的C1-C6烷基、5-6元饱和杂环基；更优选地，Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被1-3个氘取代的C1-C6烷基、被环丙基取代的C1-C6烷基、被苯基取代的C1-C6烷基、5-6元饱和杂环基，所述5-6元饱和杂环基含有1个杂原子；进一步优选地，Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被1-3个氘取代的C1-C6烷基、被环丙基取代的C1-C6烷基、被苯基取代的C1-C6烷基、四氢吡咯基、哌啶基；最优选地，Ry选自甲基、-CHF2、-CF3、-CH2CH3、-CH2CHF2、-CH2CF3、 Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by 1-6 deuterium, C3- C1-C6 alkyl substituted by C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, C1-C6 alkyl substituted by C6-C10 aryl, Substituted C1-C6 alkyl, 4-6 membered saturated heterocyclic group; preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 substituted by 1-6 halogen Alkyl, C1-C6 alkyl substituted by 1-6 deuterium, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, Substituted C1-C6 alkyl, 5-6 membered saturated heterocyclic group; more preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1- C6 alkyl, C1-C6 alkyl substituted by 1-3 deuterium, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, 5-6 membered saturated heterocyclic group, the 5-6 membered saturated heterocyclic group contains 1 heteroatom; more preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, substituted by 1 - C1-C6 alkyl substituted by 3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, Tetrahydropyrrolyl, piperidinyl; most preferably, Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 ,
Rz选自C1-C6烷基、卤素、优选地，Rz选自甲基、Br、 Rz is selected from C1-C6 alkyl, halogen, Preferably, Rz is selected from methyl, Br,
或者，Ry、Rz以及和它们共同相连的碳原子一起，形成4-6元饱和碳环、4-6元饱和杂环；或者优选地，Ry、Rz以及和它们共同相连的碳原子一起，形成4-6元饱和碳环、4-6元饱和杂环，所述4-6元饱和杂环含有1个杂原子；或者更优选地，Ry、Rz以及和它们共同相连的碳原子一起，形成环丁烷、环戊烷、环己烷、哌啶、四氢吡喃；Or, Ry, Rz and their common carbon atoms together form a 4-6 membered saturated carbocyclic ring, a 4-6 membered saturated heterocyclic ring; or preferably, Ry, Rz and their common connected carbon atoms form a 4-6 membered saturated carbocyclic ring, 4-6 membered saturated heterocyclic ring, the 4-6 membered saturated heterocyclic ring contains 1 heteroatom; or more preferably, Ry, Rz and their common carbon atoms together form Cyclobutane, cyclopentane, cyclohexane, piperidine, tetrahydropyran;
或者最优选地，Ry、Rz以及和它们共同相连的碳原子一起，形成其中，1’号碳原子为与Ry和Rz共同相连的碳原子；Or most preferably, Ry, Rz and together with their common carbon atoms, form Wherein, the 1' carbon atom is the carbon atom connected with Ry and Rz;
Rm为氧代基；Rm is an oxo group;
再进一步优选地，A13环及其任选的取代基作为整体，选自以下：

Still further preferably, the A13 ring and its optional substituents as a whole are selected from the following:

再更进一步优选地，A13环选自：且所述任选地被Rm 所取代，或任选地被Ry和Rm所取代；其中，Ry选自甲基、-CHF2、-CF3、-CH2CH3、-CH2CHF2、-CH2CF3；Rm为氧代基；Still further preferably, the A13 ring is selected from: and said optionally by Rm Substituted, or optionally substituted by Ry and Rm; wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 ; Rm is an oxo group;
最优选地，A13环及其任选的取代基作为整体，选自以下：
Most preferably, ring A13 and its optional substituents, taken as a whole, are selected from the following:
B13环选自：其任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、卤素、氨基；Ring B13 is selected from: It is optionally substituted with 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 substituted with 1-6 halogen Alkyl, halogen, amino;
优选地，上述任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；Preferably, the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl;
更优选地，上述任选地被1个取代基取代，所述取代基选自：-CF3、 More preferably, the above optionally substituted with 1 substituent selected from: -CF 3 ,
最优选地，B13环选自： Most preferably, the B13 ring is selected from:
L13选自直接键、NH、O、S；优选地，L13选自直接键、NH；L is selected from direct bond, NH, O, S; preferably, L is selected from direct bond, NH;
R13选自：C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、被氰基取代的C1-C6烷基、卤素、氰基、氨基、被氨基取代的C1-C6烷基、C2-C6烯基、被C1-C3烷基取代的5-6元饱和杂环基(优选被C1-C3烷基取代的6元饱和杂环基)；或两个R13，与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；更优选地，R13选自：C1-C6烷基、C1-C6烷氧基、被1-3个卤素取代的C1-C6烷基、被氰基取代的C1-C6烷基、卤素、氰基、氨基、被氨基取代的C1-C6烷基、C2-C6烯基、被C1-C3烷基取代的哌嗪基；或两个R13，与它们相连的原子共同形成苯环、部分不饱和C5碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素(优选-F)和氘的基团所取代；R 13 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkoxy substituted by 1-6 halogen, cyano Substituted C1-C6 alkyl, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, 5-6 membered saturated heterocyclic group substituted by C1-C3 alkyl (preferably C1-C3 alkyl substituted 6-membered saturated heterocyclic group); or two R 13 , the atoms connected to them together form a C6-C10 aromatic ring, partially unsaturated C5-C6 carbocyclic ring, partially unsaturated 5-6-membered Heterocyclic ring or 5-6 membered heteroaryl ring, wherein the partially unsaturated C5-C6 carbocyclic ring, partially unsaturated 5-6 membered heterocyclic ring or 5-6 membered heteroaryl ring are each optionally replaced by 1-6 members selected from halogen and deuterium; more preferably, R 13 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-3 halogen, C1 substituted by cyano -C6 alkyl, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, piperazinyl substituted by C1-C3 alkyl; or two R 13 , connected to them The atoms together form a benzene ring, a partially unsaturated C5 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5 carbocyclic ring and the partially unsaturated 5-6 membered heterocyclic ring are each optionally Substituted by 1-6 groups selected from halogen (preferably -F) and deuterium;
进一步优选地，R13选自：-OCH3、-CH3、-CH2CH3、-F、-Cl、-CN、-CF3、-CHF2、-NH2、 或两个R13与它们相连的原子共同形成： 更进一步优选地，R13位于环上的位置选自：A23位、A33位；Further preferably, R 13 is selected from: -OCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CF 3 , -CHF 2 , -NH 2 , or two R 13 together with the atoms they are attached to form: More preferably, the position of R 13 on the ring is selected from: A 23 position, A 33 position;
A13、A23、A33、A43独立地选自：N、CH，且其中只有2个为N，其余为CH；A 13 , A 23 , A 33 , and A 43 are independently selected from: N, CH, and only 2 of them are N, and the rest are CH;
优选地，A13、A23、A33、A43选自以下组合：Preferably, A 13 , A 23 , A 33 , A 43 are selected from the following combinations:
1)A13、A43都为N，A23、A33都为CH；1) Both A 13 and A 43 are N, and both A 23 and A 33 are CH;
2)A33、A43都为N，A13、A23都为CH；2) Both A 33 and A 43 are N, and both A 13 and A 23 are CH;
3)A23、A43都为N，A13、A33都为CH。3) Both A 23 and A 43 are N, and both A 13 and A 33 are CH.
在本申请的一些实施方案中，上述式I-3化合物为以下式I-3c：
In some embodiments of the present application, the above-mentioned compound of formula I-3 is the following formula I-3c:
A13c环及其任选的取代基作为整体，选自： A 13c ring and its optional substituents as a whole are selected from:
优选地，A13c环及其任选的取代基作为整体，选自： Preferably, the A 13c ring and its optional substituents, taken as a whole, are selected from:
最优选地，A13c环及其任选的取代基作为整体，选自： Most preferably, the A 13c ring and its optional substituents, taken as a whole, are selected from:
A13、A23、A33、A43的定义与上述式I-3中A13、A23、A33、A43的定义相同；R13的定义与上述式I-3中R13的定义相同。The definition of A 13 , A 23 , A 33 , A 43 is the same as the definition of A 13 , A 23 , A 33 , A 43 in the above formula I-3; the definition of R 13 is the same as the definition of R 13 in the above formula I-3 same.
在本申请的一些实施方案中，上述式I化合物为以下式I-4：
In some embodiments of the present application, the above-mentioned compound of formula I is the following formula I-4:
其中：in:
Y14选自N、CH；A14环选自5元杂芳基、5元不饱和杂环基，所述5元杂芳基选自所述5元不饱和杂环基选自 且满足以下条件(1)-(2)中任意一项：Y 14 is selected from N, CH; A14 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, and the 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
(1)A14环选自5元杂芳基时，所述A14环任选地被Rx所取代，(1) When the A14 ring is selected from a 5-membered heteroaryl group, the A14 ring is optionally substituted by Rx,
(2)A14环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the A14 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
(2-1)所述A14环任选地被Rm所取代；(2-1) the A14 ring is optionally substituted by Rm;
(2-2)所述A14环任选地被Ry、Rz和Rm所取代；(2-2) The A14 ring is optionally substituted by Ry, Rz and Rm;
(2-3)所述A14环任选地被Ry和Rm所取代；(2-3) the A14 ring is optionally substituted by Ry and Rm;
(2-4)所述A14环任选地被2个Rm所取代；(2-4) The A14 ring is optionally substituted by 2 Rm;
(2-5)所述A14环任选地被Rz所取代；(2-5) the A14 ring is optionally substituted by Rz;
其中，in,
Rx选自羟基、 Rx is selected from hydroxyl,
Ry选自甲基、-CHF2、-CF3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rz选自甲基、 Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rz is selected from methyl,
或者，Ry、Rz以及和它们共同相连的碳原子一起，形成其中，1’号碳原子为与Ry和Rz共同相连的碳原子；Alternatively, Ry, Rz, and the carbon atoms connected to them together form Wherein, the 1' carbon atom is the carbon atom connected with Ry and Rz;
Rm为氧代基；Rm is an oxo group;
最优选地，A14环及其任选的取代基作为整体，选自以下：

Most preferably, ring A14 and its optional substituents, taken as a whole, are selected from the following:

B14环选自： 其任选地被1-3个取代基取代，所述取代基选自：五氟化硫基、-OH、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素、硝基、氰基、氨基、C3-C4环烷基、；Ring B14 is selected from: It is optionally substituted with 1-3 substituents selected from: thiopentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1 -C6 alkyl, halogen, nitro, cyano, amino, C3-C4 cycloalkyl,;
优选地，上述 其任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；Preferably, the above It is optionally substituted with 1-2 substituents selected from the group consisting of: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkane base, halogen;
更优选地，上述任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；或者上述 任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基； More preferably, the above Optionally substituted with 1-2 substituents selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl , halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl;
更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-Cl、-SF5、-CH3、-F、-OCH3、或者上述 任选地被1-2个取代基取代，所述取代基选自：-CF3、-CH3；进一步优选地，上述其上的取代基的取代位置为：2-位单取代、3-位单取代、5-位单取代、4-、5-位双取代、5-、6-位双取代、2-、5-位双取代、3-、5-位双取代；其上的取代基的取代位置为3-位单取代、5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为6-位单取代，其上的取代基的取代位置为5-位或6位单取代或双取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位 置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；More preferably, the above Optionally substituted with 1-2 substituents selected from: -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 , or above Optionally substituted by 1-2 substituents selected from: -CF 3 , -CH 3 ; more preferably, the above The substitution positions of the substituents on it are: 2-position mono-substitution, 3-position mono-substitution, 5-position mono-substitution, 4-, 5-position double substitution, 5-, 6-position double substitution, 2-, 5-position - double substitution, 3-, 5-position double substitution; The substitution positions of the substituents on it are 3-position mono-substitution and 5-position mono-substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 6-position monosubstituted, The substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substituent position of the substituent on it Set to 5-position single substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted;
最优选地，B14环选自：
Most preferably, the B14 ring is selected from:
R14选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被氨基取代的C1-C6烷基、被氰基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、C1-C5杂芳基、C1-C6烷氧基、羟基取代的C1-C6烷氧基、被5-6元杂芳基取代的C1-C6烷氧基、C3-C5杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷 基)、羟基、氨基、卤素、氰基、C2-C6烯基、被C6-C10芳基取代的C1-C6烷基、5-6元杂环基；其中C3-C5杂环基被C1-C3烷基任意取代，C6-C10芳基被1-6个卤素任意取代，5-6元杂环基被C1-C3烷基或羟基任意取代；或两个R14，与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；R 14 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by amino, C1-C6 alkyl substituted by cyano, C1-C6 substituted by 1-6 halogen Alkoxy, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 heterocycle Oxygen group, carboxyl group (-COOH), ester group (-CO-O-C1-C6 alkane base), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered heterocyclic group; where C3-C5 heterocyclic group is replaced by C1- C3 alkyl is optionally substituted, C6-C10 aryl is optionally substituted by 1-6 halogens, 5-6 membered heterocyclic group is optionally substituted by C1-C3 alkyl or hydroxyl; or two R 14 , together with the atoms connected to them Form C6-C10 aromatic ring, partially unsaturated C5-C6 carbocyclic ring, partially unsaturated 5-6 membered heterocyclic ring or 5-6 membered heteroaromatic ring, in which partially unsaturated C5-C6 carbocyclic ring, partially unsaturated 5-6 Each membered heterocycle or 5-6 membered heteroaromatic ring is optionally substituted with 1-6 groups selected from halogen and deuterium;
更优选地，R14选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、吡啶基C1-C6烷氧基、羟基取代的C1-C6烷氧基、C3杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、C1-C6烷氧基、C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被氨基取代的C1-C6烷基、被氰基取代的C1-C6烷基、卤素、氰基、C2-C6烯基、被苯基取代的C1-C6烷基、四氢吡咯基、哌嗪基，其中C3杂环基被C1-C3烷基任意取代，四氢吡咯基被羟基任意取代，哌嗪基被C1-C3烷基任意取代；或两个R14，与它们相连的原子共同形成苯环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素(优选-F)和氘的基团所取代；More preferably, R is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyls on N, carbamoyl substituted by 1-2 C1-C6 alkyls on N, pyridyl C1-C6 Alkoxy, hydroxyl substituted C1-C6 alkoxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkane Oxygen, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogen, C1-C6 alkyl substituted by amino, C1-C6 alkyl substituted by cyano, halogen, cyano, C2 -C6 alkenyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclic group is optionally substituted by C1-C3 alkyl, tetrahydropyrrolyl is optionally substituted by hydroxyl, piperazine The group is optionally substituted by a C1-C3 alkyl group; or two R 14 , the atoms connected to them together form a benzene ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6-membered heterocyclic ring or a 5-membered heteroaromatic ring , wherein the partially unsaturated C5-C6 carbocycle and the partially unsaturated 5-6 membered heterocyclic ring are each optionally substituted by 1-6 groups selected from halogen (preferably -F) and deuterium;
进一步优选地，R14选自： -OH、-NH2、-COOH、-COOCH3、-CH3、-CH2CH3、-F、-Cl、-CN、-CHF2、-CF3、 或两个R14与它们相连的原子共同形成： Further preferably, R 14 is selected from: -OH, -NH 2 , -COOH, -COOCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CHF 2 , -CF 3 , or two R14 together with the atoms they are attached to form:
在本申请的某些实施方案中，上述式I为 In some embodiments of the present application, the above formula I is
其中，A111环选自5元杂芳基、5元不饱和杂环基，所述5元杂芳基选自所述5元不饱和杂环基选自且满足以下条件(1)-(2)中任意一项：Among them, the A111 ring is selected from 5-membered heteroaryl groups and 5-membered unsaturated heterocyclic groups, and the 5-membered heteroaryl groups are selected from The 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
(1)A111环选自5元杂芳基时，所述A111环任选地被Rx所取代，(1) When the A111 ring is selected from a 5-membered heteroaryl group, the A111 ring is optionally substituted by Rx,
(2)A111环选自5元不饱和杂环基时，所述A111环任选地被Rm或Rz所取代，或者任选地被Rm和Ry所取代；(2) When the A111 ring is selected from a 5-membered unsaturated heterocyclic group, the A111 ring is optionally substituted by Rm or Rz, or optionally substituted by Rm and Ry;
其中，in,
Rx选自甲基、 Ry选自甲基、-CHF2、-CF3、、-CH2CH3、-CH2CHF2、-CH2CF3、 Rz选自卤素(优选Br)；Rm为氧代基；Rx is selected from methyl, Ry is selected from methyl, -CHF2, -CF3, -CH2CH3, -CH2CHF2, -CH2CF3, Rz is selected from halogen (preferably Br); Rm is an oxo group;
优选地，A111环及其任选的取代基作为整体，选自以下：

更优选地，A111环及其任选的取代基作为整体，选自 进一步优选地，A111环及其任选的取代基作为整体，选自最优选地，A111环及其任选的取代基作为整体，为 Preferably, ring A111 and its optional substituents, taken as a whole, are selected from the following:

More preferably, ring A111 and its optional substituents as a whole are selected from Further preferably, ring A111 and its optional substituents as a whole are selected from Most preferably, the A111 ring and its optional substituents, taken as a whole, are
B111环选自：其任选地被1-3个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基、卤素；优选地，上述任选地被1-2个取代基取代，所述取代基选自：1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基；更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-OCF3； The B111 ring is selected from: It is optionally substituted with 1-3 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, 1-6 Halogen substituted C1-C6 alkoxy, halogen; preferably, the above Optionally substituted by 1-2 substituents selected from: 1-6 halogen substituted C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkoxy; more preferably, the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -OCF 3 ;
最优选地，B111环选自：优选为 Most preferably, the B111 ring is selected from: preferably
在本申请的某些实施方案中，上述式I为 In some embodiments of the present application, the above formula I is
其中，A112环选自5元杂芳基、5元不饱和杂环基、所述5元杂芳基选自 所述5元不饱和杂环基选自且满足以下条件(1)-(2)中任意一项：Wherein, the A112 ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
(1)A112环选自5元杂芳基时，所述A112环任选地被Rx所取代，(1) When the A112 ring is selected from a 5-membered heteroaryl group, the A112 ring is optionally substituted by Rx,
(2)A112环选自5元不饱和杂环基时，所述A112环任选地被Rm或Rz所取代，或者任选地被Ry和Rm所取代；(2) When the A112 ring is selected from a 5-membered unsaturated heterocyclic group, the A112 ring is optionally substituted by Rm or Rz, or optionally substituted by Ry and Rm;
其中，Rx选自甲基、 Wherein, Rx is selected from methyl,
Ry选自甲基、-CHF2、-CF3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rz选自卤素(优选Br)，Rm为氧代基；Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rz is selected from halogen (preferably Br), Rm is an oxo group;
优选地，A112环及其任选的取代基作为整体，选自以下：
Preferably, the A112 ring and its optional substituents, taken as a whole, are selected from the following:
B112环选自：其任选地被1-3个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基、卤素；优选地，上述 任选地被1-2个取代基取代，所述取代基选自：1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基；更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-OCF3；最优选地，B112环为： B112 rings are selected from: It is optionally substituted with 1-3 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, 1-6 Halogen substituted C1-C6 alkoxy, halogen; preferably, the above Optionally substituted by 1-2 substituents selected from: 1-6 halogen substituted C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkoxy; more preferably, the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -OCF 3 ; most preferably, ring B112 is:
R112选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、C1-C6烷氧基、卤素、氰基、硝基、氨基；更优选地，R112选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、卤素、氰基；进一步优选地，R112选自：-CH3、-CH2CH3、CF3、-F、-Cl、-CN；R 112 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, halogen, cyano, nitro, amino; more preferably, R 112 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyls on N, 1-2 C1- on N C6 alkyl substituted carbamoyl, C1-C6 alkyl, halogen, cyano; further preferably, R is selected from: -CH 3 , -CH 2 CH 3 , CF 3 , -F, -Cl, -CN;
更进一步优选地，R112位于环上的位置选自：1-位、2-位、3-位、4-位。Even more preferably, R 112 is located in ring The position on is selected from: 1-position, 2-position, 3-position, 4-position.
在本申请的某些实施方案中，上述式I-1-2为 In certain embodiments of the present application, the above-mentioned formula I-1-2 is
其中，A112c环及其任选的取代基作为整体，选自 优选地，A112c环及其任选的取代基作为整体，选自 Wherein, the A 112c ring and its optional substituents as a whole are selected from Preferably, the A 112c ring and its optional substituents as a whole are selected from
更优选地，A112c环及其任选的取代基作为整体，为 R112的定义与上述式I-1-2中R112的定义相同。More preferably, the A 112c ring and its optional substituents, taken as a whole, are The definition of R 112 is the same as the definition of R 112 in the above formula I-1-2.
在本申请的某些实施方案中，上述式I为 In some embodiments of the present application, the above formula I is
其中，A121环选自5元杂芳基、5元不饱和杂环基，所述5元杂芳基选自所述5元不饱和杂环基选自 且满足以下条件(1)-(2)中任意一项：Among them, the A121 ring is selected from 5-membered heteroaryl groups and 5-membered unsaturated heterocyclic groups, and the 5-membered heteroaryl groups are selected from The 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
(1)A121环选自5元杂芳基时，所述A121环任选地被Rx所取代，(1) When the A121 ring is selected from a 5-membered heteroaryl group, the A121 ring is optionally substituted by Rx,
(2)A121环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the A121 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
(2-1)所述A121环任选地被Rm所取代；(2-1) the A121 ring is optionally substituted by Rm;
(2-2)所述A121环任选地被Ry、Rz和Rm所取代；(2-2) The A121 ring is optionally substituted by Ry, Rz and Rm;
(2-3)所述A121环任选地被Ry和Rm所取代；(2-3) The A121 ring is optionally substituted by Ry and Rm;
(2-4)所述A121环任选地被2个Rm所取代；(2-4) The A121 ring is optionally substituted by 2 Rm;
(2-5)所述A121环任选地被Rz所取代；(2-5) The A121 ring is optionally substituted by Rz;
其中，in,
Rx选自羟基、 Rx is selected from hydroxyl,
Ry选自甲基、-CHF2、-CF3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rz选自甲基、 Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rz is selected from methyl,
或者，Ry、Rz以及和它们共同相连的碳原子一起，形成其中，1’号碳原子为与Ry和Rz共同相连的碳原子；Alternatively, Ry, Rz, and the carbon atoms connected to them together form Wherein, the 1' carbon atom is the carbon atom connected with Ry and Rz;
Rm为氧代基； Rm is an oxo group;
最优选地，A121环及其任选的取代基作为整体，选自以下：
Most preferably, ring A121 and its optional substituents, taken as a whole, are selected from the following:
B121环选自： 其任选地被1-3个取代基取代，所述取代基选自：五氟化硫基、-OH、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素、硝基、氰基、氨基；The B121 ring is selected from: It is optionally substituted with 1-3 substituents selected from: thiopentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1 -C6 alkyl, halogen, nitro, cyano, amino;
优选地，上述 其任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；Preferably, the above It is optionally substituted with 1-2 substituents selected from the group consisting of: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkane base, halogen;
更优选地，上述任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；或者上述 任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；More preferably, the above Optionally substituted with 1-2 substituents selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl , halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl;
更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-Cl、-SF5、-CH3、-F、-OCH3；或者上述 任选地被1-2个取代基取代，所述取代基选自：-CF3、-CH3；More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 ; or the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -CH 3 ;
进一步优选地，上述其上的取代基的取代位置为：2-位单取代、3-位单取代、5-位单取代、4-、5-位双取代、5-、6-位双取代、2-、5-位双取代、3-、5-位双取代；其上的取代基的取代位置为3-位单取代、5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为6-位单取代，其上的取代基的取代位置为5-位或6位单取代或双取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代； Further preferably, the above The substitution positions of the substituents on it are: 2-position mono-substitution, 3-position mono-substitution, 5-position mono-substitution, 4-, 5-position double substitution, 5-, 6-position double substitution, 2-, 5-position - double substitution, 3-, 5-position double substitution; The substitution positions of the substituents on it are 3-position mono-substitution and 5-position mono-substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 6-position monosubstituted, The substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted;
最优选地，B121环选自： Most preferably, the B121 ring is selected from:
R121选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被氨基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、C1-C5杂芳基、C1-C6烷氧基、羟基取代的C1-C6烷氧基、被5-6元杂芳基取代的C1-C6烷氧基、C3-C5杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、卤素、氰基、C2-C6烯基、被C6-C10芳基取代的C1-C6烷基、5-6元杂环基；其中C3-C5杂环基被C1-C3烷基任意取代，C6-C10芳基被1-6个卤素任意取代，5-6元杂环基被C1-C3烷基或羟基任意取代；或两个R121，与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；R 121 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by amino, C1-C6 alkoxy substituted by 1-6 halogen, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester Group (-CO-O-C1-C6 alkyl), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered heterocyclic group ; wherein the C3-C5 heterocyclic group is optionally substituted by a C1-C3 alkyl group, the C6-C10 aryl group is optionally substituted by 1-6 halogens, and the 5-6 membered heterocyclic group is optionally substituted by a C1-C3 alkyl or hydroxyl group; or Two R 121 , the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, in which the partially unsaturated C5 -C6 carbocycle, partially unsaturated 5-6 membered heterocyclic ring or 5-6 membered heteroaromatic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium;
更优选地，R121选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、吡啶基C1-C6烷氧基、羟基取代的C1-C6烷氧基、C3杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、C1-C6烷氧基、C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被氨基取代的C1-C6烷基、卤素、氰基、C2-C6烯基、被苯基取代的C1-C6烷基、四氢吡咯基、哌嗪基，其中C3杂环基被C1-C3烷基任意取代，四氢吡咯基被羟基任意取代，哌嗪基被C1-C3烷基任意取代；或两个R121，与它们相连的原子共同形成苯环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素(优选-F)和氘的基团所取代；More preferably, R 121 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyls on N, carbamoyl substituted by 1-2 C1-C6 alkyls on N, pyridyl C1-C6 Alkoxy, hydroxyl substituted C1-C6 alkoxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkane Oxygen, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogen, C1-C6 alkyl substituted by amino, halogen, cyano, C2-C6 alkenyl, C1 substituted by phenyl -C6 alkyl, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclyl is optionally substituted by C1-C3 alkyl, tetrahydropyrrolyl is optionally substituted by hydroxyl, and piperazinyl is optionally substituted by C1-C3 alkyl; or Two R 121 , the atoms connected to them jointly form a benzene ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-membered heteroaryl ring, wherein a partially unsaturated C5-C6 carbocyclic ring and Each partially unsaturated 5-6 membered heterocycle is optionally substituted with 1-6 groups selected from halogen (preferably -F) and deuterium;
进一步优选地，R121选自： -OH、-NH2、-COOH、-COOCH3、-CH3、-CH2CH3、-F、 -Cl、-CN、-CHF2、-CF3、或两个R121与它们相连的原子共同形成： Further preferably, R 121 is selected from: -OH, -NH 2 , -COOH, -COOCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CHF 2 , -CF 3 , or two R 121 together with the atoms they are attached to form:
更进一步优选地，R121位于环上的位置选自：1-位、3-位、2-位，优选3-位、2-位。More preferably, the position of R 121 on the ring is selected from: 1-position, 3-position, 2-position, preferably 3-position, 2-position.
在本申请的某些实施方案中，上述式I-2-1为 In some embodiments of the present application, the above-mentioned formula I-2-1 is
其中，A121c环及其任选的取代基作为整体，选自： 优选地，A121c环及其任选的取代基作为整体，选自：最优选地，A121c环及其任选的取代基作为整体，为： Wherein, the A 121c ring and its optional substituents as a whole are selected from: Preferably, the A 121c ring and its optional substituents, taken as a whole, are selected from: Most preferably, the A 121c ring and its optional substituents, taken as a whole, are:
R121的定义与上述式I-2-1中R121的定义相同。 The definition of R 121 is the same as the definition of R 121 in the above formula I-2-1.
在本申请的某些实施方案中，上述式I为 In some embodiments of the present application, the above formula I is
其中，A122环选自优选地，A122环选自 Among them, the A122 ring is selected from Preferably, the A122 ring is selected from
B122环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基选自为-CF3；进一步更优选地，B122环为 B122 rings are selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are selected from -CF 3 ; further more preferably, the B122 ring is
在本申请的某些实施方案中，上述式I为 In some embodiments of the present application, the above formula I is
A123环选自优选地，A123环选自 The A123 ring is selected from Preferably, the A123 ring is selected from
B123环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基； 更优选地，所述取代基选自为-CF3；进一步更优选地，B123环为 B123 rings are selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; More preferably, the substituent is selected from -CF 3 ; further more preferably, the B123 ring is
在本申请的某些实施方案中，上述式I为 In some embodiments of the present application, the above formula I is
其中，A124环选自：且所述任选地被Rm所取代或者任选地被Ry和Rm所取代，所述任选地被1-2个选自Rz和Rm的取代基所取代；Wherein, the A124 ring is selected from: and said optionally substituted by Rm or optionally substituted by Ry and Rm, the optionally substituted with 1-2 substituents selected from Rz and Rm;
其中，Ry为甲基；Rz选自Rm为氧代基；Wherein, Ry is a methyl group; Rz is selected from Rm is an oxo group;
优选地，A124环及其任选的取代基作为整体，选自以下： 更优选地，A124环及其任选的取代基作为整体，选自 Preferably, ring A124 and its optional substituents, taken as a whole, are selected from the following: More preferably, ring A124 and its optional substituents as a whole are selected from
B124环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基； 更优选地，所述取代基选自为-CF3；进一步更优选地，B124环为 B124 rings are selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; More preferably, the substituent is selected from -CF 3 ; further more preferably, the B124 ring is
在本申请的某些实施方案中，上述式I为 In some embodiments of the present application, the above formula I is
其中，A125环的定义与上述式I-2中A12环的定义相同；A125、A225、A325、A425独立地选自：N、CH，且其中只有1个为N，其余为CH；优选地，A125、A225、A325为CH，A425为N；R125的定义与上述式I-2中R12的定义相同；Among them, the definition of ring A125 is the same as the definition of ring A12 in the above formula I-2; A 125 , A 225 , A 325 , and A 425 are independently selected from: N, CH, and only one of them is N, and the rest are CH ; Preferably, A 125 , A 225 , and A 325 are CH, and A 425 is N; the definition of R 125 is the same as the definition of R 12 in the above formula I-2;
B125环选自：其任选地被1个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；且上述其上的取代基的取代位置为：5-位单取代；B125 rings are selected from: It is optionally substituted with 1 substituent selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; and the above The substitution position of the substituent on it is: 5-position monosubstituted;
优选地，B125环选自：其任选地被1个取代基取代，所述取代基选自：-CF3、-Cl、-SF5、-CH3、-F、-OCH3；且上述其上的取代基的取代位置为：5-位单取代；Preferably, the B125 ring is selected from: which is optionally substituted with 1 substituent selected from: -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 ; and the above The substitution position of the substituent on it is: 5-position monosubstituted;
更优选地，B125环选自：最优选地，B125环为 More preferably, the B125 ring is selected from: Most preferably, the B125 ring is
在本申请的某些实施方案中，上述式I为 In some embodiments of the present application, the above formula I is
其中，A131环选自：且所述任选地被Rm所取代，或任选地被Ry和Rm所取代；Wherein, the A131 ring is selected from: and said optionally substituted by Rm, or optionally substituted by Ry and Rm;
其中，Ry选自甲基、-CHF2、-CF3、-CH2CH3、-CH2CHF2、-CH2CF3、-CH2CH2OH；Rm为氧代基；Wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3, -CH 2 CH 2 OH; Rm is an oxo group;
优选地，A131环及其任选的取代基作为整体，选自以下：Preferably, ring A131 and its optional substituents, taken as a whole, are selected from the following:
更优选地，A131环及其任选的取代基作为整体，选自以下： 最优选地，A131环及其任选的取代基作为整体，选自： More preferably, ring A131 and its optional substituents, taken as a whole, are selected from the following: Most preferably, the A131 ring and its optional substituents, taken as a whole, are selected from:
B131环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；更优选地，所述取代基选自为-CF3、进一步更优选地，B131环为 The B131 ring is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituent is selected from: C1-C6 alkyl, C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituent is selected from -CF 3 , Further more preferably, the B131 ring is
L131选自直接键、NH、O、S；优选地，L131选自直接键、NH；A131、A231、A331、A431独立地选自：N、CH，且其中只有2个为N，其余为CH；优选地，A131、A231、A331、A431选自以下组合：L 131 is selected from direct bond, NH, O, S; preferably, L 131 is selected from direct bond, NH; A 131 , A 231 , A 331 , A 431 are independently selected from: N, CH, and only 2 of them is N, and the rest are CH; preferably, A 131 , A 231 , A 331 , and A 431 are selected from the following combinations:
1)A131、A431都为N，A231、A331都为CH；1) Both A 131 and A 431 are N, and both A 231 and A 331 are CH;
2)A331、A431都为N，A131、A231都为CH；2) Both A 331 and A 431 are N, and both A 131 and A 231 are CH;
3)A231、A431都为N，A131、A331都为CH。3) Both A 231 and A 431 are N, and both A 131 and A 331 are CH.
在本申请的某些实施方案中，上述式I-3-1为 In some embodiments of the present application, the above-mentioned formula I-3-1 is
其中，A131c环定义与上述式I-3-1中A131环定义相同；Wherein, the definition of ring A131c is the same as that of ring A131 in the above formula I-3-1;
A131、A231、A331、A431定义与上述式I-3-1中A131、A231、A331、A431的定义相同。The definitions of A 131 , A 231 , A 331 , and A 431 are the same as the definitions of A 131 , A 231 , A 331 , and A 431 in the above formula I-3-1.
在本申请的某些实施方案中，上述式I为 In some embodiments of the present application, the above formula I is
其中，A132环选自：且所述任选地被Rm所取代，或任选地被Ry和Rm所取代；其中，Ry选自甲基、-CHF2、-CF3、-CD3、-CH2CH3、-CH2CHF2、-CH2CF3、-CH2CH2OH；Rm为氧代基；Wherein, the A132 ring is selected from: and said Optionally substituted by Rm, or optionally substituted by Ry and Rm; wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3, -CH 2 CH 2 OH; Rm is an oxo group;
优选地，A132环及其任选的取代基作为整体，选自以下：Preferably, the A132 ring and its optional substituents, taken as a whole, are selected from the following:
更优选地，A132环及其任选的取代基作为整体，选自以下： 最优选地，A132环及其任选的取代基作为 整体，选自： More preferably, ring A132 and its optional substituents, taken as a whole, are selected from the following: Most preferably, the A132 ring and its optional substituents act as Overall, selected from:
B132环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基选自为-CF3；进一步更优选地，B132环为 B132 rings are selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are selected from -CF 3 ; further more preferably, the B132 ring is
R132选自：C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、被氰基取代的C1-C6烷基、卤素、氰基、氨基、被氨基取代的C1-C6烷基、C2-C6烯基、被C1-C3烷基取代的6元饱和杂环基；或两个R132，与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；更优选地，R132选自：C1-C6烷基、C1-C6烷氧基、被1-3个卤素取代的C1-C6烷基、被氰基取代的C1-C6烷基、卤素、氰基、氨基、被氨基取代的C1-C6烷基、C2-C6烯基、被C1-C3烷基取代的哌嗪基；或两个R132，与它们相连的原子共同形成苯环、部分不饱和C5碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素(优选-F)和氘的基团所取代；R 132 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkoxy substituted by 1-6 halogen, cyano Substituted C1-C6 alkyl, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, 6-membered saturated heterocyclic group substituted by C1-C3 alkyl; or two R 132 , and the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, in which a partially unsaturated C5-C6 carbon Ring, partially unsaturated 5-6 membered heterocycle or 5-6 membered heteroaromatic ring are each optionally substituted with 1-6 groups selected from halogen and deuterium; more preferably , R is selected from: C1- C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-3 halogen, C1-C6 alkyl substituted by cyano, halogen, cyano, amino, C1-C6 substituted by amino Alkyl, C2-C6 alkenyl, piperazinyl substituted by C1-C3 alkyl; or two R 132 , the atoms connected to them together form a benzene ring, a partially unsaturated C5 carbocycle, and a partially unsaturated 5-6 A membered heterocyclic ring or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5 carbocyclic ring and the partially unsaturated 5-6 membered heterocyclic ring are each optionally replaced by 1-6 groups selected from halogen (preferably -F) and deuterium replace;
进一步优选地，R132选自：-OCH3、-CH3、-CH2CH3、-F、-Cl、-CN、-CF3、-CHF2、-NH2、或两个R132与它们相连的原子共同形成： Further preferably, R 132 is selected from: -OCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CF 3 , -CHF 2 , -NH 2 , or two R 132 together with the atoms they are attached to form:
更进一步优选地，R132位于环上的位置选自：A232位、A332位；A132、A232、A332、A432独立地选自：N、CH，且其中只有2个为N，其余为CH；优选地，A132、A232、A332、A432选自以下组合：A132、A432都为N，A232、A332都为CH。More preferably, the position of R 132 on the ring is selected from: A 232 position, A 332 position; A 132 , A 232 , A 332 , A 432 are independently selected from: N, CH, and only 2 of them are N , and the rest are CH; preferably, A 132 , A 232 , A 332 , and A 432 are selected from the following combinations: both A 132 and A 432 are N, and both A 232 and A 332 are CH.
在本申请的某些实施方案中，上述式I-3-2为 In some embodiments of the present application, the above-mentioned formula I-3-2 is
其中，A132c环的定义与上述式I-3-2中A132环的定义相同；R132的定义与上述式I-3-2中R132的定义相同；A132、A232、A332、A432的定义与上述式I-3-2中A132、A232、A332、A432的定义相同。Among them, the definition of A132c ring is the same as the definition of A132 ring in the above formula I-3-2; the definition of R 132 is the same as the definition of R 132 in the above formula I-3-2; A 132 , A 232 , A 332 , A The definition of 432 is the same as that of A 132 , A 232 , A 332 , and A 432 in the above formula I-3-2.
在本申请的某些实施方案中，上述式I为 In some embodiments of the present application, the above formula I is
其中，A133环的定义与上述式I-3中A13环的定义相同；B133环的定义与上述式I-3中B13环的定义相同；R133的定义与上述式I-3中R13的定义相同。Wherein, the definition of the A133 ring is the same as the definition of the A13 ring in the above-mentioned formula I-3; the definition of the B133 ring is the same as the definition of the B13 ring in the above-mentioned formula I- 3 ; Same definition.
在本申请的某些实施方案中，上述式I为 In some embodiments of the present application, the above formula I is
其中，A134环的定义与上述式I-3中A13环的定义相同；优选地，A134环及其任选的取代基作为整体，选自更优选地，A134环及其任选的取代基作为整体，选自： Wherein, the definition of ring A134 is the same as the definition of ring A13 in the above formula I-3; preferably, ring A134 and its optional substituents as a whole are selected from More preferably, the A134 ring and its optional substituents as a whole are selected from:
B134环的定义与上述式I-3中B13环的定义相同；优选地，B134环选自：其任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、卤素、氨基；更优选地，上述任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；进一步优选地，上述任选地被1个取代基取代， 所述取代基选自：-CF3、更进一步优选地，B134环选自： 最优选地，B134环为 The definition of the B134 ring is the same as the definition of the B13 ring in the above formula I-3; preferably, the B134 ring is selected from: It is optionally substituted with 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 substituted with 1-6 halogen Alkyl, halogen, amino; more preferably, the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl; more preferably, the above optionally substituted with 1 substituent, The substituent is selected from: -CF 3 , Still further preferably, the B134 ring is selected from: Most preferably, the B134 ring is
R134的定义与上述式I-3中R13的定义相同；优选地，两个R134，与它们相连的原子共同形成5元杂芳环；更优选地，或两个R134与它们相连的原子共同形成： The definition of R 134 is the same as the definition of R 13 in the above formula I-3; preferably, two R 134 , and the atoms connected to them together form a 5-membered heteroaromatic ring; more preferably, or two R 134 connected to them The atoms of together form:
在本申请的某些实施方案中，上述式I为 In some embodiments of the present application, the above formula I is
其中，A135环的定义与上述式I-3中A13环的定义相同；Wherein, the definition of ring A135 is the same as the definition of ring A13 in the above formula I-3;
B135环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、卤素、氨基；且上述其上的取代基的取代位置为：5-位单取代；B135 rings are selected from: It is optionally substituted with 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 alkyl , halogen, amino; and the above The substitution position of the substituent on it is: 5-position monosubstituted;
优选地，上述任选地被1个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；且上述其上的取代基的取代位置为：5-位单取代；更优选地，B135 环选自：最优选地，B135环为 Preferably, the above optionally substituted with 1 substituent selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl; and the above The substitution position of the substituent on it is: 5-position monosubstituted; more preferably, B135 ring selected from: Most preferably, the B135 ring is
R135的定义与上述式I-3中R13的定义相同；A135、A235、A335、A435独立地选自：N、CH，且其中只有2个为N，其余为CH；优选地，A135、A235、A335、A435选自以下组合：The definition of R 135 is the same as the definition of R 13 in the above formula I-3; A 135 , A 235 , A 335 , and A 435 are independently selected from: N, CH, and only 2 of them are N, and the rest are CH; preferably Specifically, A 135 , A 235 , A 335 , A 435 are selected from the following combinations:
1)A135、A435都为N，A235、A335都为CH；1) Both A 135 and A 435 are N, and both A 235 and A 335 are CH;
2)A335、A435都为N，A135、A235都为CH；2) Both A 335 and A 435 are N, and both A 135 and A 235 are CH;
3)A235、A435都为N，A135、A335都为CH。3) Both A 235 and A 435 are N, and both A 135 and A 335 are CH.
在本申请的一些实施方案中，上述式O化合物为以下式II：
In some embodiments of the present application, the above-mentioned compound of formula O is the following formula II:
A2环选自： 优选地，A2环选自 更优选地，A2环选自 Ring A2 is selected from: Preferably, the A2 ring is selected from More preferably, ring A2 is selected from
R2选自：C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、卤素、氨基；优选地，R2选自：1-6个卤素取代的C1-C6烷基；更优选地，R2为-CF3；进一步更优选地，R2所在位置为：5-位单取代。R 2 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 alkyl, halogen, amino; preferably, R 2 is selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, R 2 is -CF 3 ; further more preferably, the position of R 2 is: 5-position monosubstitution.
在本申请的一些实施方案中，上述式O化合物为以下式III：
In some embodiments of the present application, the above-mentioned compound of formula O is the following formula III:
A3环选自： 优选地，A3环选自 更优选地，A3环选自 The A3 ring is selected from: Preferably, the A3 ring is selected from More preferably, the A3 ring is selected from
R3选自：C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、卤素、氨基；优选地，R3选自：1-6个卤素取代的C1-C6烷基；更优选地，R3为-CF3；进一步更优选地，R3所在位置为：5-位单取代。R is selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 alkyl, halogen, amino; preferably, R is selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, R 3 is -CF 3 ; further more preferably, the position of R 3 is: 5-position monosubstitution.
在本申请的一些实施方案中，上述式O化合物为以下式IV：
In some embodiments of the present application, the above-mentioned compound of formula O is the following formula IV:
A4环选自：且所述任选地被Rm所取代，或任选地被Ry和Rm所取代；The A4 ring is selected from: and said optionally substituted by Rm, or optionally substituted by Ry and Rm;
其中，Ry选自甲基、-CHF2、-CF3、CD3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rm为氧代基；Wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rm is an oxo group;
优选地，A4环及其任选的取代基作为整体，选自： 优选地，A4环及其任选的取代基作为整体，选自： 最优选地，A4环及其任选的取代基作为整体，选自： Preferably, ring A4 and its optional substituents, taken as a whole, are selected from: Preferably, ring A4 and its optional substituents, taken as a whole, are selected from: Most preferably, ring A4 and its optional substituents, taken as a whole, are selected from:
B4环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基为-CF3；进一步更优选地，B4环为 Ring B4 is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B4 ring is
C4环选自 The C4 ring is selected from
R4选自：C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、卤素、氰基、氨基；或两个R4，与它们相连的原子共同形成5-6元杂环或5-6元杂芳环；优选地，R4选自：C1-C6烷基；或两个R4，与它们相连的原子共同形成5-6元杂环或5-6元杂芳环；更优选地，两个R4，与它们相连的原子共同形成5-6元杂环；最优选地，两个R4，与它们相连的原子共同形成： R is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkoxy substituted by 1-6 halogen, halogen, cyano group, amino group; or two R 4 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; preferably, R 4 is selected from: C1-C6 alkyl; or two R 4 , the atoms connected to them form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; more preferably, two R 4 , and the atoms connected to them form a 5-6-membered heterocyclic ring; most preferably , two R 4 , together with the atoms they are connected to form:
在本申请的一些实施方案中，上述式IV化合物为以下式IV-1：
In some embodiments of the present application, the above-mentioned compound of formula IV is the following formula IV-1:
A41环的定义与上述式IV中A4环定义相同；The definition of ring A41 is the same as the definition of ring A4 in the above formula IV;
B41环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基为-CF3；进一步更优选地，B41环为A41选自：O、S。Ring B41 is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B41 ring is A 41 is selected from: O, S.
在本申请的一些实施方案中，上述式IV化合物为以下式IV-2，
In some embodiments of the present application, the above-mentioned compound of formula IV is the following formula IV-2,
A42环的定义与上述式IV中A4环定义相同；The definition of ring A42 is the same as the definition of ring A4 in the above formula IV;
B42环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基为-CF3；进一步更优选地，B42环为 The B42 ring is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B42 ring is
R421、R422各自独立地选自：C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、卤素、氰基、氨基；或R421和R422，与它们相连的原子共同形成5-6元杂环或5-6元杂芳环；优选地，R421、R422各自独立地选自：C1-C6烷基；或R421和R422，与它们相连的原子共同形成5-6元杂环或5-6元杂芳环；更优选地，R421和R422，与它们相连的原子共同形成5-6元杂环；最优选地，R421和R422，与它们相连的原子共同形成： R 421 and R 422 are each independently selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkane substituted by 1-6 halogens Oxygen, halogen, cyano, amino; or R 421 and R 422 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; preferably, R 421 and R 422 are independently Selected from: C1-C6 alkyl; or R 421 and R 422 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; more preferably, R 421 and R 422 , together with them The connected atoms together form a 5-6 membered heterocyclic ring; most preferably, R 421 and R 422 , together with their connected atoms form:
在本申请的一些实施方案中，上述式IV化合物为以下式IV-3，
In some embodiments of the present application, the above-mentioned compound of formula IV is the following formula IV-3,
A43环的定义与上述式IV中A4环定义相同；The definition of ring A43 is the same as the definition of ring A4 in the above formula IV;
B43环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基为-CF3；进一步更优选地，B43环为R431、R432各自独立地选自：氢、C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、卤素、氰基、氨基；或R431和R432，与它们相连的原子共同形成5-6元杂环或5-6元杂芳环；优选地，R431、R432各自独立地选自：氢、C1-C6烷基；或R431和R432，与它们相连的原子共同形成5-6元杂环或5-6元杂芳环；更优选地，R431、R432为氢；或R431和R432，与它们相连的原子共同形成5-6元杂环；最优选地，R431、R432为氢；或R431和R432，与它们相连的原子共同形成： Ring B43 is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B43 ring is R 431 and R 432 are each independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1- C6 alkoxy, halogen, cyano, amino; or R 431 and R 432 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; preferably, R 431 and R 432 are each independently selected from: hydrogen, C1-C6 alkyl; or R 431 and R 432 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; more preferably, R 431 , R 432 is hydrogen; or R 431 and R 432 , together form a 5-6-membered heterocyclic ring with their connected atoms; most preferably, R 431 and R 432 are hydrogen; or R 431 and R 432 , together with their connected atoms form:
在本申请的一些实施方案中，上述式O化合物为以下式V：
In some embodiments of the present application, the above-mentioned compound of formula O is the following formula V:
A5环选自：且所述任选地被Rm所取代，或任选地被Ry和Rm所取代；其中，Ry选自甲基、-CHF2、-CF3、CD3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rm为氧代基；优选地，A5环及其任选的取代基作为整体，选自： 优选地，A5环及其任选的取代基作为整体，选自：最优选地，A5环及其任选的取代基作为整体，选自： The A5 ring is selected from: and said Optionally substituted by Rm, or optionally substituted by Ry and Rm; wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rm is an oxo group; preferably, the A5 ring and its optional substituents as a whole are selected from: Preferably, ring A5 and its optional substituents as a whole are selected from: Most preferably, ring A5 and its optional substituents, taken as a whole, are selected from:
B5环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基为-CF3；进一步更优选地，B5环为R5选自：氢、C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、卤素、氰基、氨基；优选地，R5选自C1-C6烷基；更优选地，R5为-CH3。Ring B5 is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B5 ring is R is selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkoxy substituted by 1-6 halogen, halogen , cyano, amino; preferably, R 5 is selected from C1-C6 alkyl; more preferably, R 5 is -CH 3 .
在本申请的一些实施方案中，上述式O化合物为以下式VI：
In some embodiments of the present application, the above-mentioned compound of formula O is the following formula VI:
其中：R6’选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷基、被1-6个氘取代的C1-C6烷基、被C3-C6环烷基取代的C1-C6烷基、被C6-C10芳基取代的C1-C6烷基、被取代的C1-C6烷基；优选地，R6’选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被1-3个氘取代的C1-C6烷基、被环丙基取代的C1-C6烷基、被苯基取代的C1-C6 烷基、更优选地，R6’选自甲基、-CHF2、-CF3、-CH2CH3、-CH2CHF2、-CH2CF3、最优选地，R6’为甲基；Wherein: R 6' is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by 1-6 deuterium , C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, substituted by Substituted C1-C6 alkyl; preferably, R 6' is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 C1-C6 alkyl substituted by deuterium, C1-C6 alkyl substituted by cyclopropyl, C1-C6 substituted by phenyl alkyl, More preferably, R 6' is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Most preferably, R 6' is methyl;
B6环的定义与上述式O中Bo环的定义相同；或者，B6环的定义与上述式I-1中B11环的定义相同；或者，B6环的定义与上述式I-2中B12环的定义相同；或者，B6环的定义与上述式I-3中B13环的定义相同；或者，B6环的定义与上述式I-4中B14环的定义相同；或者，B6环的定义与上述式子IV中B4环的定义相同；The definition of the B6 ring is the same as the definition of the Bo ring in the above-mentioned formula O; or, the definition of the B6 ring is the same as the definition of the B11 ring in the above-mentioned formula I-1; or, the definition of the B6 ring is the same as that of the B12 ring in the above-mentioned formula I-2 The definition is the same; or, the definition of the B6 ring is the same as the definition of the B13 ring in the above formula I-3; or, the definition of the B6 ring is the same as the definition of the B14 ring in the above formula I-4; or, the definition of the B6 ring is the same as the above formula The definition of the B4 ring in sub-IV is the same;
C6环的定义与上述式O中Co环的定义相同；或者，C6环的定义与上述式子IV中C4环的定义相同；The definition of the C6 ring is the same as the definition of the Co ring in the above formula O; or, the definition of the C6 ring is the same as the definition of the C4 ring in the above formula IV;
R6的定义与上述式O中Ro的定义相同；或者，R6的定义与上述式I-1中R11的定义相同；或者，R6的定义与上述式I-2中R12的定义相同；或者，R6的定义与上述式I-3中R13的定义相同；或者，R6的定义与上述式I-4中R14的定义相同；或者，R6的定义与上述式子IV中R4的定义相同。The definition of R6 is the same as the definition of Ro in the above formula O; or, the definition of R6 is the same as the definition of R11 in the above formula I-1; or, the definition of R6 is the same as the definition of R12 in the above formula I-2 Or, the definition of R6 is the same as the definition of R13 in the above formula I-3; or, the definition of R6 is the same as the definition of R14 in the above formula I-4; or, the definition of R6 is the same as that of the above formula The definition of R4 in IV is the same.
在本申请的一些实施方案中，上述式O化合物为以下式Ox：
In some embodiments of the present application, the above-mentioned compound of formula O is the following formula Ox:
其中：in:
Aox环选自： 优选地，Aox环选自： 最优选地，Aox环为 Y选自CH、N；Rx的定义与上述式I-2-1中R121的定义相同；或者，Rx的定义与上述式I-3-2中R132的定义相同；优选地，Rx位于环上的位置选自：2-位单取代，3-位单取代，或2-、3-位双取代。Aox rings selected from: Preferably, the Aox ring is selected from: Most preferably, the Aox ring is Y is selected from CH, N; the definition of Rx is the same as the definition of R 121 in the above formula I-2-1; or, the definition of Rx is the same as the definition of R 132 in the above formula I-3-2; preferably, Rx is located at The position on the ring is selected from: 2-position mono-substitution, 3-position mono-substitution, or 2-, 3-position double substitution.
在本申请的一些实施方案中，上述化合物选自以下：















In some embodiments of the present application, the above-mentioned compound is selected from the following:















第二方面，本申请涉及制备上述化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物的方法，其包括：
In a second aspect, the present application relates to the preparation of the above-mentioned compounds, or tautomers of the compounds, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereomers thereof, or tautomers thereof A method for a racemate, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof comprising:
其中：Co环的定义与上述式O中Co环的定义相同；Ro的定义与上述式O中Ro的定义相同；X选自卤素，优选为-F、-Cl。Wherein: the definition of Co ring is the same as the definition of Co ring in the above formula O; the definition of Ro is the same as the definition of Ro in the above formula O; X is selected from halogen, preferably -F, -Cl.
在本申请的一些实施方案中，步骤a：1)在碱性(如碳酸铯、叔丁醇钠，钠氢，叔丁醇钾等)的条件下进行亲核取代；2)也可以用Buchwald偶联(如Pd2(dba)3或者Pd G3，Pd G2等钯催化剂，BINAP，Xantphos做磷配体，Cs2CO3,或者叔丁醇钠做碱性)条件下进行反应。In some embodiments of the present application, step a: 1) carry out nucleophilic substitution under basic conditions (such as cesium carbonate, sodium tert-butoxide, sodium hydrogen, potassium tert-butoxide, etc.); 2) Buchwald can also be used Coupling (such as Pd2(dba)3 or Pd G3, Pd G2 and other palladium catalysts, BINAP, Xantphos as phosphorus ligand, Cs2CO3, or sodium tert-butoxide as basic) conditions for the reaction.
在本申请的一些实施方案中，步骤a的溶剂为N,N-二甲基甲酰胺或二甲亚砜，1,4-二氧六环，甲苯等。In some embodiments of the present application, the solvent in step a is N,N-dimethylformamide or dimethyl sulfoxide, 1,4-dioxane, toluene and the like.
在本申请的一些实施方案中，步骤b是在分子筛存在的条件下进行的。In some embodiments of the present application, step b is in carried out in the presence of molecular sieves.
在本申请的一些实施方案中，步骤b的溶剂为甲醇。在本申请的一些实施方案中，步骤c的溶剂为四氢呋喃。In some embodiments of the present application, the solvent of step b is methanol. In some embodiments of the present application, the solvent in step c is tetrahydrofuran.
在本申请的一些实施方案中，本申请涉及制备上述化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物的方法，其包括：
In some embodiments of the present application, the present application relates to the preparation of the aforementioned compounds, or tautomers of said compounds, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereomers thereof isomers, racemates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, hydrates thereof, esters thereof, isotopes thereof, or metabolites thereof, comprising :
其中：R1’的定义与上述式O中Ro的定义相同；R2’选自-CF3、-Cl、-SF5、-CH3、-F、-OCH3、-OCF3； Wherein: the definition of R 1' is the same as the definition of Ro in the above formula O; R 2' is selected from -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 , -OCF 3 ;
R3’选自H、-CH3；R4’选自-CN、LG1为离去基团，优选为卤素，更优选为-F、-Cl；A1、A2、A3、A4各自独立地选自N、CH。R 3' is selected from H, -CH 3 ; R 4' is selected from -CN, LG 1 is a leaving group, preferably halogen, more preferably -F, -Cl; A 1 , A 2 , A 3 , A 4 are each independently selected from N, CH.
在本申请的一些实施方案中，作为整体，选自：
In some embodiments of the present application, As a whole, selected from:
在本申请的一些实施方案中，步骤m可以选用三种不同的思路方案设计合成。方案(1)在碱性如碳酸铯、叔丁醇钠，钠氢，叔丁醇钾等的条件下，以DMF或者MeCN作溶剂，加热反应温度条件下，取代的吲哚对C环进行亲核取代，引入取代吲哚环系结构；方案(2)可以用Buchwald偶联，如Pd2(dba)3或者Pd G3，Pd G2，Pd G4等钯催化剂，在BINAP磷配体，Xantphos等磷配体存在下，以Cs2CO3,或者叔丁醇钠等做碱，以甲苯或者1,4-二氧六环做溶剂，加热至反应温度条件下进行偶联反应，能够以相对较高的产率引入取代吲哚环系结构。方案(3)可以使用ullmann反应，在CuI催化条件下，L-poline，或者反式N,N'-二甲基-1,2-环己二胺等作为配体条件下，以磷酸钾做碱，甲苯作溶剂，加热至一定温度发生的偶联反应吲哚取代的吲哚环。In some embodiments of the present application, step m can be designed and synthesized in three different ways. Scheme (1) under basic conditions such as cesium carbonate, sodium tert-butoxide, sodium hydrogen, potassium tert-butoxide, etc., use DMF or MeCN as a solvent, and under the condition of heating reaction temperature, the substituted indole will carry out affinity to the C ring Nuclear substitution, introducing a substituted indole ring structure; Scheme (2) can be coupled with Buchwald, such as Pd 2 (dba) 3 or Pd G 3 , Pd G 2 , Pd G 4 and other palladium catalysts, in the BINAP phosphorus ligand, In the presence of phosphorus ligands such as Xantphos, use Cs 2 CO 3 , or sodium tert-butoxide as a base, use toluene or 1,4-dioxane as a solvent, and heat to the reaction temperature to carry out the coupling reaction. Relatively high yields of substituted indole ring-system structures were introduced. Scheme (3) can use the ullmann reaction, under CuI catalyzed conditions, L-poline, or trans-N, N'-dimethyl-1,2-cyclohexanediamine, etc. as ligands, with potassium phosphate Alkali, toluene as solvent, heating to a certain temperature for coupling reaction indole substituted indole ring.
在本申请的一些实施方案中，步骤n可以选用盐酸羟胺，在有机碱如N,N-二乙基异丙基胺，三乙胺等条件下，甲醇做溶剂，加入分子筛存在的条加热至80度，反应一定时间得到羟胺加成到氰基官能团上得到脒类结构，然后在二羰基咪唑试剂条件下，DBU做为有机碱，THF做溶剂，反应TLC检测，反应完成得到二噁唑酮类结构。该结构可以进一步被亲电类的烷基卤代物结构发生亲电取代反应，引入烷基侧链，例如 In some embodiments of the present application, step n can use hydroxylamine hydrochloride, under the conditions of organic bases such as N,N-diethylisopropylamine, triethylamine, etc., methanol is used as a solvent, adding The bar with molecular sieves is heated to 80 degrees, reacted for a certain period of time to obtain the addition of hydroxylamine to the cyano functional group to obtain an amidine structure, and then under the condition of dicarbonylimidazole reagent, DBU is used as an organic base, THF is used as a solvent, and the reaction is detected by TLC. This completes the formation of dioxazolones. This structure can be further subjected to an electrophilic substitution reaction by an electrophilic alkyl halide structure to introduce an alkyl side chain, for example
第三方面，本申请涉及药物组合物，其包含上述化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；任选地，还包含药学上可接受的辅料。In a third aspect, the present application relates to a pharmaceutical composition comprising the above-mentioned compound, or a tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereomer isomers, racemates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, hydrates thereof, esters thereof, isotopes thereof, or metabolites thereof; optionally, Also contains pharmaceutically acceptable excipients.
第四方面，本申请涉及一种治疗患者中癌症的方法，其包含向所述患者给予上述化合物、或所述化合 物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述药物组合物。In a fourth aspect, the present application relates to a method for treating cancer in a patient, comprising administering the above-mentioned compound, or the compound to the patient tautomers, stereoisomers, geometric isomers, enantiomers, diastereomers, racemates, prodrugs, pharmaceutically acceptable A salt, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the above pharmaceutical composition.
在一些实施方案中，所述癌症与TEAD过表达相关。In some embodiments, the cancer is associated with TEAD overexpression.
在一些实施方案中，所述癌症与TEAD活性增加相关。In some embodiments, the cancer is associated with increased TEAD activity.
第五方面，本申请涉及一种抑制患者中癌症进展的方法，其包含向所述患者给予上述化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述药物组合物。In the fifth aspect, the present application relates to a method for inhibiting cancer progression in a patient, which comprises administering to the patient the above-mentioned compound, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, Its enantiomers, its diastereoisomers, its racemates, its prodrugs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its hydrates, its esters, its Isotopes, or their metabolites; or the aforementioned pharmaceutical compositions.
在一些实施方案中，所述癌症与TEAD过表达相关。In some embodiments, the cancer is associated with TEAD overexpression.
在一些实施方案中，所述癌症与TEAD活性增加相关。In some embodiments, the cancer is associated with increased TEAD activity.
在一些实施方案中，本申请涉及一种治疗患有与TEAD表达增加相关的疾病或病症的患者的方法，其包含向所述患者给予上述的化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述药物组合物。In some embodiments, the present application relates to a method of treating a patient suffering from a disease or condition associated with increased expression of TEAD, comprising administering to the patient the above-mentioned compound, or a tautomer of the compound, Stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereomers thereof, racemates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts thereof A solvate, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the above pharmaceutical composition.
在一些实施方案中，本申请涉及一种治疗患有与TEAD活性增加相关的疾病或病症的患者的方法，其包含向所述患者给予上述化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述药物组合物。In some embodiments, the present application relates to a method of treating a patient suffering from a disease or condition associated with increased TEAD activity, comprising administering to the patient the above compound, or a tautomer of the compound, its Stereoisomers, geometric isomers thereof, enantiomers thereof, diastereomers thereof, racemates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvents thereof compounds, hydrates thereof, esters thereof, isotopes thereof, or metabolites thereof; or the aforementioned pharmaceutical compositions.
在一些实施方案中，本申请涉及一种治疗疾病或病症的方法，其抑制TEAD活性将有益于所述疾病或病症，包含向所述患者给予上述化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述药物组合物。In some embodiments, the present application relates to a method of treating a disease or disorder, wherein inhibition of TEAD activity will be beneficial to the disease or disorder, comprising administering the above-mentioned compound, or a tautomer of the compound to the patient , its stereoisomers, its geometric isomers, its enantiomers, its diastereomers, its racemates, its prodrugs, its pharmaceutically acceptable salts, its pharmaceutically acceptable The solvate, its hydrate, its ester, its isotope, or its metabolite; or the above-mentioned pharmaceutical composition.
在一些实施方案中，本申请涉及一种治疗疾病或病症的方法，其抑制Hippo通路将有益于所述疾病或病症，包含向所述患者给予上述化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述药物组合物。In some embodiments, the present application relates to a method of treating a disease or disorder for which inhibition of the Hippo pathway will be beneficial for the disease or disorder, comprising administering the above compound, or a tautomer of the compound to the patient , its stereoisomers, its geometric isomers, its enantiomers, its diastereoisomers, its racemates, its prodrugs, its pharmaceutically acceptable salts, its pharmaceutically acceptable The solvate, its hydrate, its ester, its isotope, or its metabolite; or the above-mentioned pharmaceutical composition.
在一些实施方案中，所述疾病或病症是细胞增殖性病症。In some embodiments, the disease or disorder is a cell proliferative disorder.
在一些实施方案中，所述细胞增殖性疾病是癌症。In some embodiments, the cell proliferative disease is cancer.
在一些实施方案中，所述癌症是YAP局限于癌症的细胞核中的癌症。In some embodiments, the cancer is one in which YAP is localized in the nucleus of the cancer.
在一些实施方案中，所述TEAD过表达或TEAD活性增加是TEAD1过表达或TEAD1活性增加。In some embodiments, the TEAD overexpression or TEAD activity increase is TEAD1 overexpression or TEAD1 activity increase.
在一些实施方案中，所述TEAD过表达或TEAD活性增加是TEAD2过表达或TEAD2活性增加。In some embodiments, the TEAD overexpression or TEAD activity increase is TEAD2 overexpression or TEAD2 activity increase.
在一些实施方案中，所述TEAD过表达或TEAD活性增加是TEAD3过表达或TEAD3活性增加。In some embodiments, the TEAD overexpression or TEAD activity increase is TEAD3 overexpression or TEAD3 activity increase.
在一些实施方案中，所述TEAD过表达或TEAD活性增加是TEAD4过表达或TEAD4活性增加。In some embodiments, the TEAD overexpression or TEAD activity increase is TEAD4 overexpression or TEAD4 activity increase.
在一些实施方案中，所述TEAD过表达或TEAD活性增加是TEAD1过表达或TEAD1活性增加；TEAD2过表达或TEAD2活性增加；TEAD3过表达或TEAD3活性增加；或TEAD4过表达或TEAD4活性增加；或其任意组合。In some embodiments, the TEAD overexpression or TEAD activity increase is TEAD1 overexpression or TEAD1 activity increase; TEAD2 overexpression or TEAD2 activity increase; TEAD3 overexpression or TEAD3 activity increase; or TEAD4 overexpression or TEAD4 activity increase; or any combination thereof.
第六方面，本申请涉及一种上述化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述药物组合物在制备治疗癌症的药物中的用途。In a sixth aspect, the present application relates to the above-mentioned compound, or a tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereoisomer, Its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above pharmaceutical composition in the preparation of therapeutic Use in medicine for cancer.
在一些实施方案中，所述癌症与TEAD过表达相关。In some embodiments, the cancer is associated with TEAD overexpression.
在一些实施方案中，所述癌症与TEAD活性增加相关。In some embodiments, the cancer is associated with increased TEAD activity.
第七方面，本申请涉及一种上述化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述的药物组合物在制备抑制癌症进展的药物中的用途。In a seventh aspect, the present application relates to the above-mentioned compound, or a tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereoisomer, Its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above-mentioned pharmaceutical composition Use in a medicament to inhibit the progression of cancer.
在一些实施方案中，所述癌症与TEAD过表达相关。In some embodiments, the cancer is associated with TEAD overexpression.
在一些实施方案中，所述癌症与TEAD活性增加相关。In some embodiments, the cancer is associated with increased TEAD activity.
在一些实施方案中，本申请涉及一种上述化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述的药物组合物在制备治疗与TEAD表达增加相关的疾病或病症的药物中的用途。In some embodiments, the present application relates to one of the aforementioned compounds, or tautomers of said compounds, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereoisomers thereof body, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above pharmaceutical composition Use in the preparation of a medicament for treating diseases or conditions associated with increased expression of TEAD.
在一些实施方案中，本申请涉及一种上述的化合物、或所述化合物的互变异构体、其立体异构体、其 几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述药物组合物在制备治疗与TEAD活性增加相关的疾病或病症的药物中的用途。In some embodiments, the present application relates to a compound as described above, or a tautomer of said compound, a stereoisomer thereof, a Geometric isomers, their enantiomers, their diastereoisomers, their racemates, their prodrugs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and their hydrates , its ester, its isotope, or its metabolite; or the use of the above pharmaceutical composition in the preparation of a medicament for the treatment of diseases or disorders associated with increased TEAD activity.
在一些实施方案中，本申请涉及一种上述化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述的药物组合物在制备治疗与TEAD活性有关的疾病或病症的药物中的用途；其中，抑制TEAD活性将有益于所述疾病或病症。In some embodiments, the present application relates to one of the aforementioned compounds, or tautomers of said compounds, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereoisomers thereof body, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above pharmaceutical composition Use in the manufacture of a medicament for the treatment of a disease or condition associated with TEAD activity; wherein inhibition of TEAD activity would be beneficial to said disease or condition.
在一些实施方案中，本申请涉及一种上述化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述药物组合物在制备治疗与Hippo通路相关的疾病或病症的药物中的用途；其中，所述Hippo通路被抑制将有益于所述疾病或病症。In some embodiments, the present application relates to one of the aforementioned compounds, or tautomers of said compounds, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereoisomers thereof body, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above pharmaceutical composition in Use in the manufacture of a medicament for treating a disease or disorder associated with the Hippo pathway; wherein inhibition of the Hippo pathway would benefit the disease or disorder.
在一些实施方案中，所述疾病或病症是细胞增殖性病症。In some embodiments, the disease or disorder is a cell proliferative disorder.
在一些实施方案中，所述细胞增殖性疾病是癌症。In some embodiments, the cell proliferative disease is cancer.
在一些实施方案中，所述癌症是YAP局限于癌症的细胞核中的癌症。In some embodiments, the cancer is one in which YAP is localized in the nucleus of the cancer.
在一些实施方案中，所述TEAD过表达或TEAD活性增加是TEAD1过表达或TEAD1活性增加。In some embodiments, the TEAD overexpression or TEAD activity increase is TEAD1 overexpression or TEAD1 activity increase.
在一些实施方案中，所述TEAD过表达或TEAD活性增加是TEAD2过表达或TEAD2活性增加。In some embodiments, the TEAD overexpression or TEAD activity increase is TEAD2 overexpression or TEAD2 activity increase.
在一些实施方案中，所述TEAD过表达或TEAD活性增加是TEAD3过表达或TEAD3活性增加。In some embodiments, the TEAD overexpression or TEAD activity increase is TEAD3 overexpression or TEAD3 activity increase.
在一些实施方案中，所述TEAD过表达或TEAD活性增加是TEAD4过表达或TEAD4活性增加。In some embodiments, the TEAD overexpression or TEAD activity increase is TEAD4 overexpression or TEAD4 activity increase.
在一些实施方案中，所述TEAD过表达或TEAD活性增加是TEAD1过表达或TEAD1活性增加；TEAD2过表达或TEAD2活性增加；TEAD3过表达或TEAD3活性增加；或TEAD4过表达或TEAD4活性增加；或其任意组合。In some embodiments, the TEAD overexpression or TEAD activity increase is TEAD1 overexpression or TEAD1 activity increase; TEAD2 overexpression or TEAD2 activity increase; TEAD3 overexpression or TEAD3 activity increase; or TEAD4 overexpression or TEAD4 activity increase; or any combination thereof.
第八方面，本申请涉及一种上述化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，或者上述药物组合物在制备具有与TEAD结合并阻断YAP/TEAD之间的相互作用的活性的药物中的用途。In an eighth aspect, the present application relates to the above-mentioned compound, or a tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereoisomer, Its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, or the above pharmaceutical composition has Use in a medicament for the activity of binding to TEAD and blocking the interaction between YAP/TEAD.
第九方面，本申请涉及一种治疗患者中疾病或病症的方法，其包含向所述患者给予上述化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述药物组合物；所述疾病或病症与TEAD发生相互作用的蛋白相关。In the ninth aspect, the present application relates to a method for treating a disease or disorder in a patient, which comprises administering the above-mentioned compound, or a tautomer, a stereoisomer, or a geometric isomer of the compound to the patient , its enantiomers, its diastereoisomers, its racemates, its prodrugs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its hydrates, its esters, Its isotope, or its metabolite; or the above-mentioned pharmaceutical composition; said disease or disease is related to the protein that TEAD interacts with.
在一些实施方案中，所述与TEAD发生相互作用的蛋白相关的疾病或病症包括但不限于癌症、代谢性疾病、炎症性疾病、或神经退行性疾病。In some embodiments, the disease or disorder associated with the TEAD-interacting protein includes, but is not limited to, cancer, metabolic disease, inflammatory disease, or neurodegenerative disease.
在一些实施方案中，所述癌症选自乳腺癌、中枢神经系统癌、子宫内膜癌、肝癌、肾癌、大肠癌、肺癌、食管癌、舌癌、卵巢癌、胰腺癌、前列腺癌、胃癌、间皮瘤、黑色素瘤、纤维肉瘤、膀胱癌、直肠癌、淋巴瘤、宫颈癌、头颈癌、脑癌、上呼吸消化道癌、结直肠癌、尿路癌或结肠癌；优选地，所述癌症选自脑癌、食管癌、肾癌、间皮瘤、肝癌、头颈癌、肺癌、胃癌、乳腺癌或前列腺癌；更优选地，每种癌症独立地选自腺癌、鳞状细胞癌、混合腺鳞癌、未分化癌；进一步优选地，所述脑癌包括但不限于脑胶质瘤；头颈癌包括但不限于头颈鳞状细胞癌；肺癌包括但不限于肺腺癌、肺腺鳞癌、鳞状细胞肺癌、大细胞肺癌、小细胞肺癌、肺乳头状腺癌或非小细胞肺癌；胃癌包括但不限于胃腺癌；乳腺癌包括但不限于导管乳腺癌、乳腺癌或HR+乳腺癌；前列腺癌包括但不限于前列腺腺癌、前列腺鳞状细胞癌、或前列腺腺鳞癌。In some embodiments, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer , mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the Said cancer is selected from brain cancer, esophageal cancer, renal cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma , mixed adenosquamous carcinoma, undifferentiated carcinoma; further preferably, the brain cancer includes but not limited to glioma; head and neck cancer includes but not limited to head and neck squamous cell carcinoma; lung cancer includes but not limited to lung adenocarcinoma, lung adenocarcinoma Squamous cell carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, papillary adenocarcinoma or non-small cell lung cancer; gastric cancer including but not limited to gastric adenocarcinoma; breast cancer including but not limited to ductal breast cancer, breast cancer or HR+ breast cancer Cancer; Prostate cancer includes, but is not limited to, adenocarcinoma of the prostate, squamous cell carcinoma of the prostate, or adenosquamous carcinoma of the prostate.
第十方面，本申请涉及一种上述化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述药物组合物在制备治疗疾病或病症的药物中的用途；所述疾病或病症与TEAD发生相互作用的蛋白相关。In a tenth aspect, the present application relates to the above-mentioned compound, or a tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereoisomer, Its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above pharmaceutical composition in the preparation of therapeutic Use in medicine for a disease or disorder; said disease or disorder is associated with a TEAD-interacting protein.
在一些实施方案中，所述与TEAD发生相互作用的蛋白相关的疾病或病症包括但不限于癌症、代谢性疾病、炎症性疾病、或神经退行性疾病。In some embodiments, the disease or disorder associated with the TEAD-interacting protein includes, but is not limited to, cancer, metabolic disease, inflammatory disease, or neurodegenerative disease.
在一些实施方案中，所述癌症选自乳腺癌、中枢神经系统癌、子宫内膜癌、肝癌、肾癌、大肠癌、肺癌、食管癌、舌癌、卵巢癌、胰腺癌、前列腺癌、胃癌、间皮瘤、黑色素瘤、纤维肉瘤、膀胱癌、直肠癌、淋巴瘤、宫颈癌、头颈癌、脑癌、上呼吸消化道癌、结直肠癌、尿路癌或结肠癌；优选地，所述癌症选自脑癌、食管癌、肾癌、间皮瘤、肝癌、头颈癌、肺癌、胃癌、乳腺癌或前列腺癌；更优选地，每种癌症独立地选自腺癌、鳞状细胞癌、混合腺鳞癌、未分化癌；进一步优选地，所述脑癌包括但不限于脑胶质瘤；头颈癌包括但不限于头颈鳞状细胞癌；肺癌包括但不限于肺腺癌、肺腺鳞癌、鳞状细胞肺癌、大细胞肺癌、小细胞肺癌、肺乳头状腺癌或非小细胞肺癌；胃癌包括但不限于胃腺癌；乳腺癌包括但不限于导管乳腺癌、 乳腺癌或HR+乳腺癌；前列腺癌包括但不限于前列腺腺癌、前列腺鳞状细胞癌、或前列腺腺鳞癌。In some embodiments, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer , mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the Said cancer is selected from brain cancer, esophageal cancer, renal cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma , mixed adenosquamous carcinoma, undifferentiated carcinoma; further preferably, the brain cancer includes but not limited to glioma; head and neck cancer includes but not limited to head and neck squamous cell carcinoma; lung cancer includes but not limited to lung adenocarcinoma, lung adenocarcinoma Squamous cell carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, papillary adenocarcinoma or non-small cell lung cancer; gastric cancer including but not limited to gastric adenocarcinoma; breast cancer including but not limited to ductal breast cancer, Breast cancer or HR+ breast cancer; prostate cancer includes but is not limited to prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma.
第十一方面，本申请涉及一种上述化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或上述的药物组合物在治疗疾病或病症中的用途；所述疾病或病症与TEAD发生相互作用的蛋白相关。In the eleventh aspect, the present application relates to the above-mentioned compound, or a tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereoisomer , its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the above pharmaceutical composition in Use in the treatment of a disease or disorder; said disease or disorder is associated with a TEAD-interacting protein.
在一些实施方案中，所述与TEAD发生相互作用的蛋白相关的疾病或病症包括但不限于癌症、代谢性疾病、炎症性疾病、或神经退行性疾病。In some embodiments, the disease or disorder associated with the TEAD-interacting protein includes, but is not limited to, cancer, metabolic disease, inflammatory disease, or neurodegenerative disease.
在一些实施方案中，所述癌症选自乳腺癌、中枢神经系统癌、子宫内膜癌、肝癌、肾癌、大肠癌、肺癌、食管癌、舌癌、卵巢癌、胰腺癌、前列腺癌、胃癌、间皮瘤、黑色素瘤、纤维肉瘤、膀胱癌、直肠癌、淋巴瘤、宫颈癌、头颈癌、脑癌、上呼吸消化道癌、结直肠癌、尿路癌或结肠癌；优选地，所述癌症选自脑癌、食管癌、肾癌、间皮瘤、肝癌、头颈癌、肺癌、胃癌、乳腺癌或前列腺癌；更优选地，每种癌症独立地选自腺癌、鳞状细胞癌、混合腺鳞癌、未分化癌；进一步优选地，所述脑癌包括但不限于脑胶质瘤；头颈癌包括但不限于头颈鳞状细胞癌；肺癌包括但不限于肺腺癌、肺腺鳞癌、鳞状细胞肺癌、大细胞肺癌、小细胞肺癌、肺乳头状腺癌或非小细胞肺癌；胃癌包括但不限于胃腺癌；乳腺癌包括但不限于导管乳腺癌、乳腺癌或HR+乳腺癌；前列腺癌包括但不限于前列腺腺癌、前列腺鳞状细胞癌、或前列腺腺鳞癌。In some embodiments, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer , mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the Said cancer is selected from brain cancer, esophageal cancer, renal cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma , mixed adenosquamous carcinoma, undifferentiated carcinoma; further preferably, the brain cancer includes but not limited to glioma; head and neck cancer includes but not limited to head and neck squamous cell carcinoma; lung cancer includes but not limited to lung adenocarcinoma, lung adenocarcinoma Squamous cell carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, papillary adenocarcinoma or non-small cell lung cancer; gastric cancer including but not limited to gastric adenocarcinoma; breast cancer including but not limited to ductal breast cancer, breast cancer or HR+ breast cancer Cancer; Prostate cancer includes, but is not limited to, adenocarcinoma of the prostate, squamous cell carcinoma of the prostate, or adenosquamous carcinoma of the prostate.
术语定义Definition of Terms
本发明中，除非以其他方式明确指出，在本文中通篇采用的描述方式“…各自独立地选自”既可以是指在不同基团中，相同或不同的符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同或不同的符号之间所表达的具体选项之间互相不影响。In the present invention, unless otherwise clearly stated, the description method "...independently selected from" used throughout this article may refer to the specific options expressed between the same or different symbols in different groups They do not affect each other, and it can also mean that in the same group, the specific options expressed by the same or different symbols do not affect each other.
本发明化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-C6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。The substituents of the compounds of the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C1-C6 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.
术语“烷基”是指包括具有指定碳原子数的支链和直链饱和脂肪族烃基。例如，“C1-C6烷基”是指C1、C2、C3、C4、C5和C6。另外，例如“C1-C6烷基”是指具有1至6个碳原子的烷基，优选“C1-C4烷基”，更优选“C1-C3烷基”。烷基的实例包括但不限于甲基、乙基、丙基(例如正丙基和异丙基)、丁基(例如，正丁基、异丁基、叔丁基)、戊基(例如正戊基、异戊基、新戊基)等。The term "alkyl" is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C1-C6 alkyl" refers to C1, C2, C3, C4, C5 and C6. In addition, for example, "C1-C6 alkyl" means an alkyl group having 1 to 6 carbon atoms, preferably "C1-C4 alkyl", more preferably "C1-C3 alkyl". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n- Pentyl, isopentyl, neopentyl) etc.
术语“烷氧基”是指被如本文所定义的烷基取代的氧原子。例如，术语“C1-C6烷氧基”包括基团-O-C1-C6烷基，例如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、戊氧基、2-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基等。The term "alkoxy" refers to an oxygen atom substituted with an alkyl group as defined herein. For example, the term "C1-C6 alkoxy" includes groups -O-C1-C6 alkyl, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy , tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, etc.
术语“环烷基”是指环化的烷基，包括单环、双环或多环体系，其中不含有双键等不饱和键，且不含有任何杂原子，例如C3-C8环烷基、C3-C7环烷基或C3-C6环烷基。C3-C6环烷基是指包括C3、C4、C5和C6环烷基。“3-6元环烷基”与“C3-C6环烷基”可以互换使用。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基等。The term "cycloalkyl" refers to a cyclized alkyl group, including monocyclic, bicyclic or polycyclic ring systems, which does not contain unsaturated bonds such as double bonds, and does not contain any heteroatoms, such as C3-C8 cycloalkyl, C3- C7 cycloalkyl or C3-C6 cycloalkyl. C3-C6 cycloalkyl refers to include C3, C4, C5 and C6 cycloalkyl. "3-6 membered cycloalkyl" and "C3-C6 cycloalkyl" can be used interchangeably. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
本发明中，“Ra、Rb和与它们共同相连的碳原子一起，形成氮杂环丁烷”，其指的是，Ra、Rb和与它们共同相连的碳原子一起，形成所述氮杂环丁烷任选地被羟基所取代，例如，可以为其余类似的定义可以参照前述内容进行理解。In the present invention, "Ra, Rb and the carbon atoms connected to them together form azetidine", which means that Ra, Rb and the carbon atoms connected to them together form azetidine The azetidine is optionally substituted by hydroxyl, for example, can be Other similar definitions can be understood with reference to the foregoing.
本发明中，“两个Ro，与它们相连的原子共同形成苯环”，其指的是，两个Ro和与它们分别相连的原子共同形成的环为苯环，如等所示的环状结构。类似地，“两个Ro，与它们相连的原子共同形成部分不饱和C5-C6碳环”，其指的是，两个Ro和与它们分别相连的原子共同形成的环为部分不饱和C5-C6碳环，如等所示的环状结构。类似地，“两个Ro，与它们相连的原子共同形成部分不饱 和5-6元杂环”，其指的是两个Ro和与它们分别相连的原子共同形成的环为部分不饱和5-6元杂环，如

等所示的环状结构。类似地，“两个Ro，与它们相连的原子共同形成5元杂芳环”，其指的是两个Ro和与它们分别相连的原子共同形成的环为5元杂芳环，如等所示的环状结构。其中，前述结构中的波浪线所示的两个位点表示两个Ro和与它们分别相连的原子共同形成的环与Co环进行稠合的位点。例如，若两个Ro和与它们分别相连的原子共同形成的环为且Co环为(本领域技术人员可以理解，Co环上波浪线所示的两个位点为分别与Ao环、L0/Bo环进行连接的连接位点)，则两个环稠合后形成的结构例如可以为再例如，若两个Ro和与它们分别相连的原子共同形成的环为且Co环为则两个环稠合后形成的结构例如可以为再例如，若两个Ro和与它们分别相连的原子共同形成的环为且Co环为则两个环稠合后形成的结构例如可以为再例如，若两个Ro和与它们分别相连的原子共同形成的环为且Co环为且两个环稠合后形成的结构例如可以为其余类似的定义可以参照前述内容进行理解。In the present invention, "two Ro, and the atoms connected to them jointly form a benzene ring", which means that the ring formed by two Ro and the atoms connected to them is a benzene ring, such as The ring structure shown in et al. Similarly, "two Ro, and the atoms connected to them form a partially unsaturated C5-C6 carbocyclic ring", which means that the ring formed by two Ro and the atoms connected to them is partially unsaturated C5- C6 carbon ring, such as The ring structure shown in et al. Similarly, "Two Ro, together with the atoms attached to them form a partially unsaturated and 5-6-membered heterocyclic ring", which means that the ring formed by two Ro and the atoms connected to them is a partially unsaturated 5-6-membered heterocyclic ring, such as

The ring structure shown in et al. Similarly, "two Ro, and the atoms connected to them together form a 5-membered heteroaromatic ring" means that the ring formed by two Ro and the atoms connected to them is a 5-membered heteroaromatic ring, such as The ring structure shown in et al. Among them, the wavy line in the aforementioned structure The two sites shown represent the sites where the ring formed by the two Ros and the atoms respectively attached to them is fused with the Co ring. For example, if the ring formed by two Ro and the atoms connected to them is And the Co ring is (those skilled in the art can understand that the wavy line on the Co ring The two sites shown are the connection sites connected to the Ao ring and the L 0 /Bo ring respectively), then the structure formed after the two rings are fused can be, for example, For another example, if the ring formed by two Ro and the atoms connected to them is And the Co ring is Then the structure formed after the fusion of two rings can be, for example, For another example, if the ring formed by two Ro and the atoms connected to them is And the Co ring is Then the structure formed after the fusion of two rings can be, for example, For another example, if the ring formed by two Ro and the atoms connected to them is And the Co ring is And the structure formed after the fusion of two rings can be, for example, Other similar definitions can be understood with reference to the foregoing.
术语“被羟基取代的C1-C6烷基”，是指前述C1-C6烷基中1个氢原子被羟基替代，实例如 其中，烷基的定义如前所述。类似地，“被C6-C10芳基取代的C1-C6烷基”是指前述C1-C6烷基中1个氢原子被C6-C10芳基替代，实例如苄基或类似地，“被氨基取代的C1-C6烷基”是指前述C1-C6烷基中1个氢原子被氨基替代，实例如类似地，“被氰基取代的C1-C6烷基” 是指前述C1-C6烷基中1个氢原子被氰基替代，实例如类似地，“被C3-C6环烷基取代的C1-C6烷基”是指前述C1-C6烷基中1个氢原子被C3-C6环烷基替代，实例如其余类似的定义可参照前述内容进行理解。The term "C1-C6 alkyl substituted by hydroxy" means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by hydroxy, for example Wherein, the definition of alkyl is as described above. Similarly, "C1-C6 alkyl substituted by C6-C10 aryl" means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by C6-C10 aryl, such as benzyl or Similarly, "C1-C6 alkyl substituted by amino" means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by an amino group, for example Similarly, "C1-C6 alkyl substituted by cyano" It means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by a cyano group, for example Similarly, "C1-C6 alkyl substituted by C3-C6 cycloalkyl" means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by a C3-C6 cycloalkyl, for example Other similar definitions can be understood with reference to the foregoing.
本发明中，“部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素和氘的基团所取代”，其表示，“部分不饱和C5-C6碳环”和“部分不饱和5-6元杂环”可以不被取代，也可以被1-6个选自卤素和氘的基团所取代，且“部分不饱和C5-C6碳环”的取代基和“部分不饱和5-6元杂环”的取代基互不影响，可以相同，也可以不同。同时，若“部分不饱和C5-C6碳环”或“部分不饱和5-6元杂环”被2-6个选自卤素和氘的基团所取代时，2-6个取代基相互之间可以相同，也可以不同。其余类似的定义可参照前述内容进行理解。In the present invention, "a partially unsaturated C5-C6 carbocyclic ring and a partially unsaturated 5-6 membered heterocyclic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium", which means, "a partially unsaturated Saturated C5-C6 carbocycle" and "partially unsaturated 5-6 membered heterocycle" may be unsubstituted, or may be substituted by 1-6 groups selected from halogen and deuterium, and "partially unsaturated C5-C6 The substituents of the "carbocycle" and the substituents of the "partially unsaturated 5-6 membered heterocycle" do not affect each other, and may be the same or different. At the same time, if the "partially unsaturated C5-C6 carbocycle" or "partially unsaturated 5-6 membered heterocyclic ring" is substituted by 2-6 groups selected from halogen and deuterium, the 2-6 substituents are mutually can be the same or different. Other similar definitions can be understood with reference to the foregoing.
术语“被取代的”是指指定原子或基团上的任一或多个氢被指定基团的选择替代，条件为不超过指定原子的正常价态。The term "substituted" means that any one or more hydrogens on the designated atom or group are replaced by a selection of the designated group, provided that the designated atom's normal valence is not exceeded.
本发明所述的”杂原子”为N、O或S。本发明所述的“卤素”为氟、氯、溴或碘，优先为氟或氯或溴。The "heteroatom" in the present invention is N, O or S. The "halogen" in the present invention is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine or bromine.
本发明所述的“(被)1-6个卤素取代的C1-C6烷基”和“(被)1-6个卤素取代的C1-C6烷氧基”，是指所述烷基和烷氧基中一个或多个氢原子被1-6个卤素原子，特别是氟或氯原子替代后形成的基团。在一些实施方案中，优选氟代，例如-CF3、-CHF2、-CH2F、-CH2CH2F、-CH2CHF2、-CH2CF3、-OCF3、-OCHF2、-OCH2F、-OCH2CH2F、-OCH2CHF2或者-OCH2CF3。类似地，“被1-6个氘取代的C1-C6烷基”是指所述烷基中一个或多个氢原子被1-6个氘原子替代后形成的基团，实例如-CD3。The "(by) 1-6 halogen substituted C1-C6 alkyl" and "(by) 1-6 halogen substituted C1 - C6 alkoxy" in the present invention refer to the said alkyl and a group formed by replacing one or more hydrogen atoms in an alkoxy group with 1-6 halogen atoms, especially fluorine or chlorine atoms. In some embodiments, fluorination is preferred, eg -CF3 , -CHF2 , -CH2F , -CH2CH2F , -CH2CHF2 , -CH2CF3 , -OCF3 , -OCHF2 , -OCH 2 F, -OCH 2 CH 2 F, -OCH 2 CHF 2 or -OCH 2 CF 3 . Similarly, "C1-C6 alkyl substituted by 1-6 deuterium" refers to a group formed after one or more hydrogen atoms in the alkyl group are replaced by 1-6 deuterium atoms, for example -CD3 .
术语“烯基”是指上述“烷基”中具有一个或多个双键所形成的基团，优选“C2-C6烯基”，优选的实例如 The term "alkenyl" refers to a group formed by one or more double bonds in the above-mentioned "alkyl", preferably "C2-C6 alkenyl". Preferred examples are
术语“杂芳基”是指在至少一个环中具有至少一个杂原子(O、N或S)的被取代的和未被取代的芳香族5-元或6-元单环基团、8-元、9-元或10-元二环基团和11-元至14-元三环基团，该含杂原子环任选还具有1个、2个或3个选自O、N或S的杂原子。所述杂芳基优选5-元或6-元单环基团(即“5-6元杂芳基”)。杂芳基可在任一环的任一可用氮或碳原子上连接。若所述杂芳基以碳原子数进行限定，如“C1-C5杂芳基”，其指的是所述杂芳基含有所限定的碳原子数的碳原子，且除碳原子外还含有1-5个杂原子；例如，“C1-C5杂芳基”指的是所述杂芳基含有1-5个碳原子，且除碳原子外还含有1-5个杂原子，实例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、噻吩基、噁二唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基、三氮唑基等。示例性的5-6元杂芳基包括但不限于：吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、噻吩基、噁二唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基、三氮唑基等。The term "heteroaryl" refers to substituted and unsubstituted aromatic 5-membered or 6-membered monocyclic groups having at least one heteroatom (O, N or S) in at least one ring, 8- Yuan, 9-membered or 10-membered bicyclic groups and 11-membered to 14-membered tricyclic groups, the heteroatom-containing ring optionally also has 1, 2 or 3 members selected from O, N or S of heteroatoms. The heteroaryl is preferably a 5-membered or 6-membered monocyclic group (ie "5-6 membered heteroaryl"). A heteroaryl group can be attached at any available nitrogen or carbon atom of either ring. If the heteroaryl group is limited by the number of carbon atoms, such as "C1-C5 heteroaryl", it means that the heteroaryl group contains carbon atoms of the limited number of carbon atoms, and in addition to carbon atoms also contains 1-5 heteroatoms; for example, "C1-C5 heteroaryl" means that the heteroaryl group contains 1-5 carbon atoms, and contains 1-5 heteroatoms in addition to carbon atoms, such as pyrrole Base, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl , pyridazinyl, triazinyl, triazolyl, etc. Exemplary 5-6 membered heteroaryl groups include, but are not limited to: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thiophene Base, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, etc.
术语“杂环”、“杂环的”或“杂环基”可互换使用并且是指被取代的和未被取代的3-元至7-元单环基团、7-元至11-元二环基团和10-元至15-元三环基团，其中可以包含一个或多个双键，但不构成芳香环；其中至少一个环具有至少一个杂原子(O、S或N)。所述杂环基优选5-元至6-元单环基团(即“5-6元杂环基”)。杂环基团可在任何可用氮或碳原子上连接。其中，若所述杂环基不包含一个或多个双键，则称为“饱和杂环基”。类似地，若所述杂环基包含一个或多个双键，且不构成芳香环，则称为“不饱和杂环基”。若所述杂环基以碳原子进行限定，如“C3-C5杂环基”，其指的是所述杂环基含有所限定的碳原子数的碳原子，且除碳原子外还含有1-2个杂原子；例如，“C3-C5杂环基”指的是所述杂环基含有3-5个碳原子，且除碳原子外还含有1-2个杂原子，实例如 The terms "heterocycle", "heterocyclic" or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 3-membered to 7-membered monocyclic groups, 7-membered to 11-membered Membered bicyclic groups and 10- to 15-membered tricyclic groups, which may contain one or more double bonds, but do not constitute aromatic rings; wherein at least one ring has at least one heteroatom (O, S or N) . The heterocyclic group is preferably a 5- to 6-membered monocyclic group (ie, "5-6-membered heterocyclic group"). A heterocyclic group can be attached at any available nitrogen or carbon atom. Wherein, if the heterocyclic group does not contain one or more double bonds, it is called "saturated heterocyclic group". Similarly, if the heterocyclic group contains one or more double bonds and does not constitute an aromatic ring, it is called "unsaturated heterocyclic group". If the heterocyclic group is limited by carbon atoms, such as "C3-C5 heterocyclic group", it means that the heterocyclic group contains carbon atoms with the limited number of carbon atoms, and in addition to carbon atoms, it also contains 1 -2 heteroatoms; for example, "C3-C5 heterocyclic group" means that the heterocyclic group contains 3-5 carbon atoms, and contains 1-2 heteroatoms in addition to carbon atoms, for example
示例性的5-6元杂环基包括氮杂环丁基、氧杂环丁基、吡咯烷基、咪唑啉基、噁唑烷基、异噁唑啉基、噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂环庚三烯基、1-吡啶酮基、4-哌啶酮基、四氢吡喃基、吗啉基、1,3-二氧杂环戊烷基等。Exemplary 5-6 membered heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidine Pyridyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepine, 1-pyridonyl, 4 -piperidinonyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolyl, etc.
术语“氧代”或“氧代基”可互换使用并且指的是“＝O”。例如，5元不饱和杂环被氧代或被氧代 基取代，则被取代后的结构式为类似地，若硫代吗啉基被2个氧代基取代，且取代位点为S时，则被取代后的结构式其余类似的定义可以参照前述内容进行理解。The terms "oxo" or "oxo" are used interchangeably and refer to "=O". For example, a 5-membered unsaturated heterocycle be oxo or be oxo Substituted by the substituent, the substituted structural formula is Similarly, if thiomorpholino When it is substituted by two oxo groups, and the substitution site is S, the substituted structural formula Other similar definitions can be understood with reference to the foregoing.
本发明中，直接键指的是其两边的基团直接相连，例如，式O中，若L0为直接键，则式O的结构式将变为其余类似的定义可参照前述内容进行理解。In the present invention, a direct bond means that the groups on both sides are directly connected, for example, the formula O In , if L 0 is a direct bond, the structural formula of formula O will become Other similar definitions can be understood with reference to the foregoing.
本发明中，虚线键------指的是该键存在或不存在。In the present invention, the dotted line bond------refers to the existence or non-existence of the bond.
式O中，若Ro为0个时，其表示Ro不存在，即式O的结构式变为若Ro为1个时，式O的结构式变为若Ro为2个时，式O的结构式变为且两个Ro的定义相互独立，可以相同，也可以不同。其余类似的结构式或定义可以参照前述内容进行理解。Formula O Among them, if Ro is 0, it means that Ro does not exist, that is, the structural formula of formula O becomes If Ro is 1, the structural formula of formula O becomes If Ro is 2, the structural formula of formula O becomes In addition, the two definitions of Ro are independent of each other, and may be the same or different. Other similar structural formulas or definitions can be understood with reference to the foregoing.
本发明中，“治疗”一般是指获得需要的药理和/或生理效应。该效应根据完全或部分地预防疾病或其症状，可以是预防性的；和/或根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)预防易感染疾病或症状但还没诊断出患病的患者所发生的疾病或症状；(b)抑制疾病的症状，即阻止其发展；或(c)缓解疾病的症状，即，导致疾病或症状退化。In the present invention, "treatment" generally refers to obtaining desired pharmacological and/or physiological effects. The effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms; and/or therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. "Treatment" as used herein encompasses any treatment of a disease in a patient, including: (a) prophylaxis of a disease or condition in a patient susceptible to the disease or condition but not yet diagnosed; (b) suppressing the symptoms of the disease, ie arresting its development; or (c) alleviating the symptoms of the disease, ie causing regression of the disease or symptoms.
本发明中，“受试者”指脊椎动物。在某些实施方案中，脊椎动物指哺乳动物。哺乳动物包括，但不限于，牲畜(诸如牛)、宠物(诸如猫、犬、和马)、灵长类动物、小鼠和大鼠。在某些实施方案中，哺乳动物指人。In the present invention, "subject" refers to a vertebrate. In certain embodiments, a vertebrate is a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, a mammal is a human.
本发明中，“有效量”指在必需的剂量和时间上有效实现期望的治疗或预防效果的量。本发明的物质/ 分子的“治疗有效量”可根据诸如个体的疾病状态、年龄、性别和体重及该物质/分子在个体中引发期望应答的能力等因素而变化。治疗有效量还涵盖该物质/分子的治疗有益效果胜过任何有毒或有害后果的量。“预防有效量”指在必需的剂量和时间上有效实现期望的预防效果的量。通常而非必然，由于预防剂量是在疾病发作之前或在疾病的早期用于受试者的，因此预防有效量会低于治疗有效量。在癌症的情况中，药物的治疗有效量可减少癌细胞数；缩小肿瘤体积；抑制(即一定程度的减缓，优选停止)癌细胞浸润到周围器官中；抑制(即一定程度的减缓，优选停止)肿瘤转移；一定程度的抑制肿瘤生长；和/或一定程度的减轻与癌症有关的一种或多种症状。In the present invention, "effective amount" refers to the amount effective to achieve the desired therapeutic or preventive effect at the necessary dose and time. Substances of the present invention/ A "therapeutically effective amount" of a molecule can vary depending on factors such as the disease state, age, sex and weight of the individual and the ability of the substance/molecule to elicit a desired response in the individual. A therapeutically effective amount also encompasses an amount in which any toxic or detrimental consequences are outweighed by the therapeutically beneficial effects of the substance/molecule. A "prophylactically effective amount" refers to an amount effective at dosages and for periods of time necessary to achieve the desired prophylactic effect. Usually, but not necessarily, the prophylactically effective amount will be lower than the therapeutically effective amount because the prophylactic dose is administered to the subject before the onset of the disease or at an early stage of the disease. In the case of cancer, the therapeutically effective amount of the drug reduces the number of cancer cells; reduces tumor volume; inhibits (i.e. slows down to some extent, preferably stops) the infiltration of cancer cells into surrounding organs; inhibits (i.e. slows down to some extent, preferably stops) ) tumor metastasis; inhibition of tumor growth to a certain extent; and/or alleviation of one or more symptoms associated with cancer to a certain extent.
本发明涉及的药物组合物可以包含药学上可接受的辅料，辅料包括但不限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血白蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛脂等等。The pharmaceutical composition involved in the present invention may contain pharmaceutically acceptable auxiliary materials, and auxiliary materials include but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate , glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal oxidation Silicon, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, macrogol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin, etc.
本发明所述药物组合物可以根据不同给药途径而制备成各种形式。例如，所述的药物组合物可以以下面的任意方式施用：口服、喷雾吸入、直肠用药、鼻腔用药、颊部用药、阴道用药、局部用药、非肠道用药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输入、或借助一种外植储器用药。其中优选口服、腹膜内或静脉内用药方式。The pharmaceutical composition of the present invention can be prepared in various forms according to different administration routes. For example, the pharmaceutical composition can be administered in any of the following ways: oral, inhalation spray, rectal, nasal, buccal, vaginal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, peritoneal Intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir. Of these, oral, intraperitoneal or intravenous administration is preferred.
如本文所使用，除非另外说明，术语“前药”是指可以在生物学条件(体外或体内)下水解、氧化或进行其他反应以提供本发明的化合物的衍生物。前药仅在生物学条件下经过该反应成为活性化合物，或者它们在它们不反应的形式中具有活性。通常可以使用公知的方法制备前药，例如Burger's Medicinal Chemistry and Drug Discovery(1995)172-178,949-982(Manfred E.Wolff编,第5版)中描述的那些方法。As used herein, unless otherwise stated, the term "prodrug" refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction only under biological conditions to become active compounds, or they are active in their unreacted form. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed.).
本文所述的化合物中的立体异构体，当以化学名称特别指定为(R)-或(S)-异构体时，应分别理解为主要构型为(R)-异构体或(S)-异构体。任何不对称碳原子可以存在于(R)-、(S)-或(R、S)-构型中，优选以(R)-或(S)-构型存在。Stereoisomers in the compounds described herein, when specifically designated as (R)- or (S)-isomers by chemical names, should be understood as the predominant configuration being the (R)-isomer or ( S)-isomer. Any asymmetric carbon atom may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration.
本文所述的化合物中的互变异构体，指的是含有杂原子(如氮、氧或硫原子)的两个同分异构体，其结构差异仅在于质子和相应的双键的迁移，且这两个异构体共存于一个平衡体系中，以相当高的速率互相变换着，典型的实例如，本文中的基团可以通过互变异构转化为进而，两者共存。因此，若本文所述的化合物的结构式为则本领域技术人员可以理解，其表示结构和结构同时存在。其余化合物中若存在类似的基团，则参照前述内容进行理解。Tautomers in the compounds described herein refer to two isomers containing heteroatoms (such as nitrogen, oxygen or sulfur atoms) whose structures differ only in the migration of protons and corresponding double bonds , and these two isomers coexist in an equilibrium system, and they are transformed into each other at a very high rate. Typical examples, such as the group in this paper Can be transformed by tautomerism into Furthermore, both coexist. Therefore, if the structural formula of the compound described herein is Those skilled in the art can understand that its representation structure and structure simultaneously exist. If there are similar groups in other compounds, it should be understood with reference to the aforementioned content.
本文所述的“几何异构体”的定义为，因双键或环碳原子的单键不能自由旋转而引起的异构体称为几何异构体，又称顺反异构体。The definition of "geometric isomers" mentioned in this article is that the isomers caused by double bonds or single bonds of ring carbon atoms that cannot rotate freely are called geometric isomers, also known as cis-trans isomers.
本文所述的“对映异构体”的定义为，互为实物与镜像而不可重叠的立体异构体，称为对映异构体。The definition of "enantiomer" described herein is that stereoisomers that are real and mirror images of each other but not superimposable are called enantiomers.
本文所述的“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。As used herein, "diastereoisomers" refer to stereoisomers whose molecules have two or more chiral centers and which are not mirror images.
本文所述的“消旋体”包括外消旋体和内消旋体。外消旋体指的是一种具有旋光性的手性分子与其对映体的等摩尔混合物。内消旋体指的是分子内具有2个或多个非对称中心，但又有其他对称因素，如对称面存在，因而使整个分子不具有旋光性，没有对映体存在，通常以meso或i表示。The "racemate" described herein includes racemate and mesoform. A racemate refers to an equimolar mixture of an optically active chiral molecule and its enantiomer. The meso form refers to a molecule with two or more asymmetric centers, but there are other symmetry factors, such as symmetry planes, so that the entire molecule does not have optical activity and no enantiomers exist, usually in the form of meso or i said.
本文所述的“水合物”是指以与水分子的组合存在的化合物。该组合可以包括化学计量的量的水，例如一水合物或二水合物，或者可以包括任意量的水。 As used herein, "hydrate" refers to a compound that exists in combination with water molecules. The combination may include water in stoichiometric amounts, such as the monohydrate or dihydrate, or may include any amount of water.
本文所述的“酯”是指，本发明所提供的化合物中存在的-COOH与适当的醇形成的酯，或者本发明所提供的化合物中存在的-OH与适当的酸(例如，羧酸或含氧无机酸)形成的酯。适宜的酯基团包括但不限于，甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯、乙基琥珀酸酯、硬脂肪酸酯或棕榈酸酯。酯在酸或者碱存在的条件下，可以发生水解反应生成相应的酸或醇。As used herein, "ester" refers to an ester of -COOH present in the compounds provided by the invention with a suitable alcohol, or an -OH present in the compounds provided by the present invention with a suitable acid (e.g., carboxylic acid or oxygen-containing inorganic acids) to form esters. Suitable ester groups include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, ethylsuccinate, stearate, or palmitate. In the presence of acid or base, esters can be hydrolyzed to produce corresponding acids or alcohols.
质子数相同而中子数不同的同一元素的不同原子互称为同位素。本文所述的“化合物的同位素”是指，本发明所提供的化合物中的某一个或多个原子被其同位素替换后形成的结构。Different atoms of the same element with the same number of protons but different numbers of neutrons are called isotopes. The "isotope of a compound" mentioned herein refers to the structure formed after one or more atoms in the compound provided by the present invention are replaced by its isotope.
本文所述的“代谢产物”是指，本发明所提供的化合物在一定的代谢条件下的中间代谢产物或最终代谢产物。The "metabolite" mentioned herein refers to the intermediate metabolite or the final metabolite of the compound provided by the present invention under certain metabolic conditions.
本发明所述的“药学可接受的盐”是指本发明化合物与药学上可接受的酸进行反应制得的酸加成盐，或者其中具有酸性基团的化合物和碱性化合物反应生成的盐。其中，所述的酸较佳的选自无机酸(如盐酸、硫酸、磷酸或氢溴酸等)，和有机酸(如草酸、马来酸、富马酸、苹果酸、酒石酸、赖氨酸、组氨酸、柠檬酸或苯甲酸等)；所述的碱性化合物较佳的选自氢氧化钠、氢氧化钾、氢氧化钙、碳酸钠或碳酸氢钾等。上述药学上可接受的盐容易分离，可采用常规分离方法提纯，如溶剂萃取、稀释、重结晶、柱色谱和制备薄层色谱等。The "pharmaceutically acceptable salt" in the present invention refers to the acid addition salt prepared by reacting the compound of the present invention with a pharmaceutically acceptable acid, or the salt formed by the reaction of a compound with an acidic group and a basic compound . Wherein, the acid is preferably selected from inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, etc.), and organic acids (such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, lysine , histidine, citric acid or benzoic acid, etc.); said basic compound is preferably selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate or potassium bicarbonate and the like. The above pharmaceutically acceptable salts are easy to separate and can be purified by conventional separation methods, such as solvent extraction, dilution, recrystallization, column chromatography and preparative thin-layer chromatography.
“溶剂化物”是以与某种溶剂分子的组合存在的化合物。该组合可以包括化学计量的量的某种溶剂，例如一水合物或二水合物，或者可以包括任意量的水；又如，甲醇或乙醇可以形成“醇化物”，其也可以为化学计量的或非化学计量的。在本文中使用的术语“溶剂化物”指的是固体形式，即，在溶剂的溶液中的化合物虽然其可以为溶剂化的，但是它不是如本文中使用的术语的溶剂化物。"Solvate" is a compound that exists in combination with certain solvent molecules. The combination may include stoichiometric amounts of certain solvents, such as monohydrate or dihydrate, or may include any amount of water; as another example, methanol or ethanol may form "alcoholates," which may also be stoichiometric or non-stoichiometric. The term "solvate" as used herein refers to a solid form, ie, a compound in solution in a solvent, although it may be solvated, it is not a solvate as the term is used herein.
本发明所述的化合物任选地可与其它一种或多种活性成分联合使用，其各自用量和比例可由本领域技术人员根据具体病症和患者具体情况以及临床需要等而进行调整。The compounds described in the present invention can optionally be used in combination with one or more other active ingredients, and their respective dosages and ratios can be adjusted by those skilled in the art according to specific diseases, specific conditions of patients, and clinical needs.
本发明中所提供的实施例和制备例进一步阐明并举例说明了本发明所述化合物及其制备方法。应当理解，下述制备例和实施例不以任何方式限制本发明的范围。The examples and preparation examples provided in the present invention further illustrate and illustrate the compounds of the present invention and their preparation methods. It should be understood that the following Preparations and Examples do not limit the scope of the present invention in any way.
具体实施方式Detailed ways
可以使用本文所述的合成方法和反应方案由市售试剂合成本发明的化合物。概述具体合成路线的实施例和以下通用方案旨在为普通合成化学家提供指导，他们将很容易理解溶剂、浓度、试剂、保护基团、合成步骤的顺序、时间、温度等可以根据需要在普通技术人员的技能和判断范围内进行修改。Compounds of the invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples outlining specific synthetic routes and the following general schemes are intended to provide guidance to ordinary synthetic chemists who will readily understand that solvents, concentrations, reagents, protecting groups, sequence of synthetic steps, time, temperature, etc. Modifications are within the skill and judgment of the technician.
实施例Example
以下提供的实施例将更好地说明本发明。除非另有明确说明，所有份数和百分比均以重量计，并且所有的温度均为摄氏度。实施例中如下缩写：分子筛；CDI：N,N'-羰基二咪唑；DBU：1,8-二氮杂双环[5.4.0]-7-十一碳烯；HATU：2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯；Pd/C：钯碳；Pd(dppf)Cl2：1,1'-二(二苯膦基)二茂铁二氯化钯(II)；Pd(PPh3)4：四(三苯基膦)钯；DMF：N,N-二甲基甲酰胺；EA：乙酸乙酯；CH3CN/ACN：乙腈；DCM：二氯甲烷；NMP：N-甲基吡咯烷酮；THF：四氢呋喃；TEA：三乙胺；DIPEA：N,N-二异丙基乙基胺；h/hrs：小时；min/mins：分钟；NCS：N-氯代丁二酰亚胺；rt/r.t/r.t./室温：温度范围为20～30℃；MW：微波；Pd2(dba)3：三(二亚苄基丙酮)二钯；XantPhos：4,5-双二苯基膦-9,9-二甲基氧杂蒽；Deoxo fluor：双(2-甲氧基乙基)氨基三氟化硫；BrettPhos Pd G3：甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)；XPhos Pd G2：氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)；t-Buxphos Pd G4：(甲磺酸(2-二叔丁基膦-2',4',6'-三异丙基-1,1'-联苯基)(2'-甲氨基-1,1'-联苯-2-基)钯(II)；The examples provided below will better illustrate the invention. All parts and percentages are by weight and all temperatures are in degrees Celsius unless expressly stated otherwise. The following abbreviations in the embodiments: Molecular sieves; CDI: N,N'-carbonyldiimidazole; DBU: 1,8-diazabicyclo[5.4.0]-7-undecene; HATU: 2-(7-azobenzotriazole )-N,N,N',N'-Tetramethylurea hexafluorophosphate; Pd/C: Palladium on carbon; Pd(dppf)Cl 2 : 1,1'-bis(diphenylphosphino)ferrocene Palladium(II) dichloride; Pd(PPh 3 ) 4 : tetrakis(triphenylphosphine)palladium; DMF: N,N-dimethylformamide; EA: ethyl acetate; CH 3 CN/ACN: acetonitrile; DCM: dichloromethane; NMP: N-methylpyrrolidone; THF: tetrahydrofuran; TEA: triethylamine; DIPEA: N,N-diisopropylethylamine; h/hrs: hours; min/mins: minutes; NCS: N-chlorosuccinimide; rt/rt/rt/room temperature: temperature range 20-30°C; MW: microwave; Pd 2 (dba) 3 : tris(dibenzylideneacetone) dipalladium; XantPhos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene; Deoxo fluor: bis(2-methoxyethyl)aminosulfur trifluoride; BrettPhos Pd G3: methanesulfonic acid ( 2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'- Biphenyl-2-yl)palladium(II); XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[ 2-(2'-amino-1,1'-biphenyl)]palladium(II); t-Buxphos Pd G4: ((2-di-tert-butylphosphine-2',4',6'- Triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II);
实施例1
Example 1
步骤1：将5-(三氟甲基)-1H-吲哚(1.53g，8.26mmol)加入到3-氟-2-苯甲腈(1.0g，8.26mmol)、碳酸铯(5.38g，16.52mmol)和N,N-二甲基甲酰胺(8mL)的混合物中。将反应混合物在80℃下搅拌3小时，加水(15mL)稀释后，用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，干燥后浓缩，并将所得残余物用硅胶柱层析(洗脱剂梯度从石油醚:EtOAc＝20:1过渡到4:1)纯化，得到化合物1-1(2.10g，6.99mmol，产率：84.6％)。 Step 1: Add 5-(trifluoromethyl)-1H-indole (1.53g, 8.26mmol) to 3-fluoro-2-benzonitrile (1.0g, 8.26mmol), cesium carbonate (5.38g, 16.52 mmol) and N,N-dimethylformamide (8 mL). The reaction mixture was stirred at 80°C for 3 hours, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from petroleum ether:EtOAc=20:1 to 4:1) to obtain compound 1 -1 (2.10 g, 6.99 mmol, yield: 84.6%).
步骤2：向化合物1-1(389mg,1.36mmol)的MeOH(17mL)溶液中加入盐酸羟胺(1.89g,27.20mmol)、三乙胺(5.5mL,39.68mmol)和分子筛(400mg)。将反应混合物在78℃下搅拌过夜后，过滤，并将所得滤液浓缩。向所得浓缩物中加H2O稀释，并用EA萃取。将有机层干燥后浓缩，并将所得残余物通过柱层析纯化，得到化合物1-2(110mg，0.34mmol，产率：25.0％)。MS(ESI)：m/z＝320[M+H]+。 Step 2: Add hydroxylamine hydrochloride (1.89 g, 27.20 mmol), triethylamine (5.5 mL, 39.68 mmol) and Molecular sieves (400 mg). After stirring the reaction mixture at 78 °C overnight, it was filtered and the resulting filtrate was concentrated. The resulting concentrate was diluted with H2O and extracted with EA. The organic layer was dried and concentrated, and the resulting residue was purified by column chromatography to obtain Compound 1-2 (110 mg, 0.34 mmol, yield: 25.0%). MS (ESI): m/z = 320 [M+H] + .
步骤3：在0℃下，将CDI(135mg,0.83mmol)加入到化合物1-2(90mg,0.28mmol)的THF(4mL)溶液中，室温搅拌过夜后加入DBU(0.13mL,0.89mmol)。将反应混合物在室温下搅拌3小时后浓缩。向所得浓缩物中加入EA以稀释浓缩物，并用盐酸(1M)将pH调至中性。将有机层干燥后浓缩，并将所得残余物通过硅胶柱层析纯化，得到化合物1(60mg，0.17mmol，产率：60.7％)。MS(ESI)：m/z＝346[M+H]+。 Step 3: CDI (135mg, 0.83mmol) was added to compound 1-2 (90mg, 0.28mmol) in THF (4mL) at 0°C, stirred overnight at room temperature and then DBU (0.13mL, 0.89mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. To the obtained concentrate was added EA to dilute the concentrate, and the pH was adjusted to neutral with hydrochloric acid (1M). The organic layer was dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 1 (60 mg, 0.17 mmol, yield: 60.7%). MS (ESI): m/z = 346 [M+H] + .
1HNMR(400MHz,DMSO-d6)δ8.05(d,J＝1.8Hz,1H),7.90(dd,J＝7.7,1.6Hz,1H),7.86(td,J＝7.7,1.6Hz,1H),7.76(td,J＝7.6,1.3Hz,1H),7.70(dd,J＝7.9,1.2Hz,1H),7.59(d,J＝3.3Hz,1H),7.44(dd,J＝8.8,1.8Hz,1H),7.24(d,J＝8.6Hz,1H),6.85(d,J＝3.3Hz,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.05 (d, J = 1.8Hz, 1H), 7.90 (dd, J = 7.7, 1.6Hz, 1H), 7.86 (td, J = 7.7, 1.6Hz, 1H ),7.76(td,J=7.6,1.3Hz,1H),7.70(dd,J=7.9,1.2Hz,1H),7.59(d,J=3.3Hz,1H),7.44(dd,J=8.8, 1.8Hz, 1H), 7.24(d, J=8.6Hz, 1H), 6.85(d, J=3.3Hz, 1H).
实施例2
Example 2
步骤1：向3-氯吡嗪-2-甲腈(250mg，1.79mmol)和叔丁醇钠(172.17mg，1.79mmol)的N,N-二甲基甲酰胺溶液(8mL)中加入5-(三氟甲基)-1H-吲哚(331.71mg，1.79mmol)。将反应混合物在120℃下搅拌3个小时后，加水(15mL)稀释，然后用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，干燥后浓缩，并将所得残余物用硅胶柱层析(洗脱剂梯度从石油醚:EtOAc＝20:1过渡到4:1)纯化，得到化合物2-1(303mg，1.05mmol，产率：58.68％)。MS(ESI)：m/z＝289[M+H]+。 Step 1: To a solution of 3-chloropyrazine-2-carbonitrile (250 mg, 1.79 mmol) and sodium tert-butoxide (172.17 mg, 1.79 mmol) in N,N-dimethylformamide (8 mL) was added 5- (Trifluoromethyl)-1H-indole (331.71 mg, 1.79 mmol). After the reaction mixture was stirred at 120° C. for 3 hours, it was diluted with water (15 mL), and then extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from petroleum ether:EtOAc=20:1 to 4:1) to obtain compound 2 -1 (303 mg, 1.05 mmol, yield: 58.68%). MS (ESI): m/z = 289 [M+H] + .
步骤2：向化合物2-1(100mg，3.05mmol)、三乙胺(0.97mL，7.00mmol)和分子筛(100mg)、和甲醇(4mL)的混合物中加入盐酸羟胺(121.61mg，1.75mmol)。将反应混合物在80℃下搅拌2小时后，过滤，并将所得滤液浓缩。向所得浓缩物中加入水(10mL)然后用乙酸乙酯(30mL)萃取。将所得有机相用饱和氯化钠溶液洗涤，干燥后浓缩，并将所得残余物用硅胶柱层析(洗脱剂梯度从石油醚:EtOAc＝20:1过渡到4:1)纯化，得到化合物2-2(110mg，0.34mmol，产率：98.69％)。MS(ESI)：m/z＝322[M+H]+。 Step 2: To a mixture of compound 2-1 (100 mg, 3.05 mmol), triethylamine (0.97 mL, 7.00 mmol) and molecular sieves (100 mg), and methanol (4 mL) was added hydroxylamine hydrochloride (121.61 mg, 1.75 mmol). After stirring the reaction mixture at 80° C. for 2 hours, it was filtered, and the resulting filtrate was concentrated. Water (10 mL) was added to the obtained concentrate, followed by extraction with ethyl acetate (30 mL). The obtained organic phase was washed with saturated sodium chloride solution, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from petroleum ether:EtOAc=20:1 to 4:1) to obtain compound 2-2 (110 mg, 0.34 mmol, yield: 98.69%). MS (ESI): m/z = 322 [M+H] + .
步骤3：在0℃下，将CDI(69.40mg，0.43mmol)加入到化合物2-2(110mg，0.34mmol)的四氢呋喃(3mL)溶液中，在室温下搅拌0.5小时后加入DBU(76.66μL，0.51mmol)。将反应混合物在室温下搅拌1小时，用水(15mL)稀释，用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，干燥后浓缩，并将所得残余物用硅胶柱层析(洗脱剂梯度从二氯甲烷：甲醇＝1:0过渡到10:1)纯化，得到化合物2(47mg，0.14mmol，产率：39.53％)。MS(ESI)：m/z＝348[M+H]+。 Step 3: Add CDI (69.40mg, 0.43mmol) to compound 2-2 (110mg, 0.34mmol) in tetrahydrofuran (3mL) at 0°C, stir at room temperature for 0.5 hours, then add DBU (76.66μL, 0.51 mmol). The reaction mixture was stirred at room temperature for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from dichloromethane:methanol=1:0 to 10:1) to obtain compound 2 (47 mg, 0.14 mmol, yield: 39.53%). MS (ESI): m/z = 348 [M+H] + .
1H NMR(CHLOROFORM-d)δ:9.75(br s,1H),8.80(d,J＝2.3Hz,1H),8.75(d,J＝2.3Hz,1H),7.99(s,1H),7.49-7.54(m,3H),6.88(d,J＝3.5Hz,1H)。 1 H NMR (CHLOROFORM-d) δ: 9.75 (br s, 1H), 8.80 (d, J = 2.3Hz, 1H), 8.75 (d, J = 2.3Hz, 1H), 7.99 (s, 1H), 7.49 -7.54 (m, 3H), 6.88 (d, J=3.5Hz, 1H).
实施例3
Example 3
步骤1:在0℃下，将叔丁醇钠(69mg,0.72mmol)加入到2-氯-3-氰基吡啶(100mg,0.72mmol)和5-(三氟甲基)吲哚(134mg,0.72mmol)的N，N-二甲基甲酰胺(3mL)溶液中。将反应混合物升温至120℃后搅拌18小时。加水(10mL)淬灭，然后用乙酸乙酯(20mL×3)萃取。将合并所得有机相用水洗涤，干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物3-1(155mg)。MS(ESI)：m/z＝288[M+H]+。 Step 1: Add sodium tert-butoxide (69mg, 0.72mmol) to 2-chloro-3-cyanopyridine (100mg, 0.72mmol) and 5-(trifluoromethyl)indole (134mg, 0.72mmol) in N,N-dimethylformamide (3mL) solution. The reaction mixture was warmed to 120°C and stirred for 18 hours. Water (10 mL) was added to quench, then extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with water, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 3-1 (155 mg). MS (ESI): m/z = 288 [M+H] + .
步骤2:将化合物3-1(85mg,0.30mmol)，盐酸羟胺(206mg,2.96mmol)，三乙胺(0.82mL,5.92mmol)和分子筛(100mg)加入到甲醇(5mL)中。将反应混合物在室温下搅拌15分钟后，升温至75℃并在此温度下搅拌5小时，加水(10mL)淬灭反应，用乙酸乙酯(20mL×3)萃取。将合并所得有机相用水洗涤，干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物3-2(70mg)。MS(ESI)：m/z＝321[M+H]+。 Step 2: Compound 3-1 (85mg, 0.30mmol), hydroxylamine hydrochloride (206mg, 2.96mmol), triethylamine (0.82mL, 5.92mmol) and Molecular sieves (100 mg) were added to methanol (5 mL). After the reaction mixture was stirred at room temperature for 15 minutes, it was warmed up to 75° C. and stirred at this temperature for 5 hours, quenched by adding water (10 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with water, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 3-2 (70 mg). MS (ESI): m/z = 321 [M+H] + .
步骤3:在0℃下，将CDI(111mg,0.68mmol)加入到化合物3-2(182mg,0.57mmol)的四氢呋喃(10mL)溶液中，在0℃下反应30分钟后加入DBU(0.13mL,0.85mmol)。将反应混合物在室温下反应30分钟后,加水(10mL)淬灭，并用EA(20mL×3)萃取。将合并所得有机相用水洗涤，干燥后浓缩，并将所得残余物用高效液相色谱(HPLC)纯化，得到化合物3(86.15mg,0.25mmol,产率：43.6％)。MS(ESI)：m/z＝347[M+H]+。 Step 3: Add CDI (111mg, 0.68mmol) to a solution of compound 3-2 (182mg, 0.57mmol) in THF (10mL) at 0°C, react at 0°C for 30 minutes, then add DBU (0.13mL, 0.85 mmol). The reaction mixture was reacted at room temperature for 30 minutes, quenched with water (10 mL), and extracted with EA (20 mL×3). The combined organic phases were washed with water, dried and concentrated, and the resulting residue was purified by high performance liquid chromatography (HPLC) to obtain compound 3 (86.15 mg, 0.25 mmol, yield: 43.6%). MS (ESI): m/z = 347 [M+H] + .
1H NMR(DMSO-d6)δ:12.79(br s,1H),8.87(dd,J＝4.8,1.7Hz,1H),8.36(dd,J＝7.8,1.8Hz,1H),8.07(s,1H),7.75(dd,J＝7.8,4.8Hz,1H),7.70(d,J＝8.8Hz,1H),7.63(d,J＝3.4Hz,1H),7.51(dd,J＝8.8,1.3Hz,1H),6.88(d,J＝3.4Hz,1H)。 1 H NMR (DMSO-d 6 )δ: 12.79(br s, 1H), 8.87(dd, J=4.8, 1.7Hz, 1H), 8.36(dd, J=7.8, 1.8Hz, 1H), 8.07(s ,1H),7.75(dd,J=7.8,4.8Hz,1H),7.70(d,J=8.8Hz,1H),7.63(d,J=3.4Hz,1H),7.51(dd,J=8.8, 1.3Hz, 1H), 6.88 (d, J = 3.4Hz, 1H).
实施例4
Example 4
步骤1：将三甲基环三硼氧烷(1.31mL,4.6mmol,3.5M in THF)，氟化铯(5.24g,34.39mmol)，pd(dppf)Cl2(0.42g,0.57mmol)加入到3,5-二氯吡嗪-2-甲腈(2.00g,11.50mmol)的甲苯(10mL)溶液中。将反应混合物在氮气保护下升温到90℃搅拌过夜后，过滤。将所得滤液用水(50mL)稀释，并用乙酸乙酯(50mL*3)萃取。将合并所得有机相浓缩，并将所得残余物通过快速柱层析(石油醚/乙酸乙酯＝3/1)纯化得化合物4-1(200mg)。 Step 1: Add trimethylboroxine (1.31 mL, 4.6 mmol, 3.5M in THF), cesium fluoride (5.24 g, 34.39 mmol), pd(dppf)Cl 2 (0.42 g, 0.57 mmol) To a solution of 3,5-dichloropyrazine-2-carbonitrile (2.00 g, 11.50 mmol) in toluene (10 mL). The reaction mixture was heated to 90° C. under nitrogen protection, stirred overnight, and then filtered. The resulting filtrate was diluted with water (50 mL), and extracted with ethyl acetate (50 mL*3). The combined organic phases were concentrated, and the resulting residue was purified by flash column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 4-1 (200 mg).
步骤2：将叔丁醇钾(336.35mg,3.50mmol)加入到5-(三氟甲基)-吲哚(432.02mg,2.33mmol)的DMF(5mL)的溶液中，室温搅拌0.5h后，加入化合物4-1(430mg,2.80mmol)。将反应混合物升温到120℃搅拌5h后，加水(10mL)稀释，并用乙酸乙酯(5mL*3)萃取。将合并所得有机相浓缩得残余物，并将所得残余物经快速柱层析(石油醚/乙酸乙酯＝3/1)纯化，得化合物4-2(60mg)。LCMS：m/z＝ 303.08[M+H]+。 Step 2: Potassium tert-butoxide (336.35 mg, 3.50 mmol) was added to a solution of 5-(trifluoromethyl)-indole (432.02 mg, 2.33 mmol) in DMF (5 mL), and stirred at room temperature for 0.5 h, Compound 4-1 (430 mg, 2.80 mmol) was added. The reaction mixture was warmed up to 120° C. and stirred for 5 h, diluted with water (10 mL), and extracted with ethyl acetate (5 mL*3). The combined organic phases were concentrated to obtain a residue, which was purified by flash column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 4-2 (60 mg). LCMS: m/z = 303.08[M+H] + .
步骤3：将盐酸羟胺(68.97mg,0.99mmol)，TEA(0.55mL,3.97mmol)和4A分子筛(10mg)加入到化合物4-2(60mg,0.20mmol)的甲醇(1mL)溶液中。将反应混合物升温到80℃搅拌2小时后，过滤，并将滤液浓缩。将浓缩物用水(3mL)稀释，并用乙酸乙酯(3mL*3)萃取。将合并所得有机相浓缩得化合物4-3的粗产物(66mg)。LCMS：m/z＝336.10[M+H]+。 Step 3: Hydroxylamine hydrochloride (68.97 mg, 0.99 mmol), TEA (0.55 mL, 3.97 mmol) and 4A molecular sieves (10 mg) were added to a solution of compound 4-2 (60 mg, 0.20 mmol) in methanol (1 mL). The reaction mixture was warmed up to 80°C and stirred for 2 hours, then filtered, and the filtrate was concentrated. The concentrate was diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated to obtain a crude product of compound 4-3 (66 mg). LCMS: m/z = 336.10 [M+H] + .
步骤4：在0℃下，将CDI(0.03mL,0.25mmol)加入到N-羟基-5-甲基-3-(5-(三氟甲基)-1H-吲哚-1-基)吡嗪-2-甲脒(66mg,0.20mmol)的四氢呋喃(1mL)溶液中，在0℃下搅拌0.5小时后，在0℃下加入DBU(0.04mL,0.30mmol)。将反应混合物升温到室温搅拌1小时后，加水(3mL)稀释，并用乙酸乙酯(3mL*3)萃取。将合并所得有机相浓缩，并将所得残余物通过制备高效液相色谱HPLC纯化，得到化合物4(5.92mg，0.02mmol，产率7.80％，纯度93.69％)。MS(ESI)：m/z＝362[M+H]+。1H NMR(400MHz,MeOH-d4)δ8.76(d,J＝0.6Hz,1H),7.98(s,1H),7.64(d,J＝2.9Hz,1H),7.55(d,J＝8.6Hz,1H),7.44(d,J＝8.4Hz,1H),6.85(d,J＝2.9Hz,1H),2.71(s,3H)。 Step 4: CDI (0.03 mL, 0.25 mmol) was added to N-hydroxy-5-methyl-3-(5-(trifluoromethyl)-1H-indol-1-yl)pyridine at 0 °C A solution of oxazine-2-carboxamidine (66 mg, 0.20 mmol) in tetrahydrofuran (1 mL) was stirred at 0°C for 0.5 hour, and DBU (0.04 mL, 0.30 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour, diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated, and the resulting residue was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 4 (5.92 mg, 0.02 mmol, yield 7.80%, purity 93.69%). MS (ESI): m/z = 362 [M+H] + . 1 H NMR (400MHz, MeOH-d4) δ8.76(d, J=0.6Hz, 1H), 7.98(s, 1H), 7.64(d, J=2.9Hz, 1H), 7.55(d, J=8.6 Hz, 1H), 7.44 (d, J = 8.4Hz, 1H), 6.85 (d, J = 2.9Hz, 1H), 2.71 (s, 3H).
实施例5
Example 5
步骤1：在0℃下，向3,5-二氯吡嗪-2-甲腈(1.0g，5.75mmol)的甲醇溶液(25mL)中加入甲醇钠(117.19mg，2.17mmol)。将反应混合物在常温下搅拌12小时后浓缩，向所得浓缩物中加入水(15mL)，用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，并将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡到8:1)纯化，得到化合物5-1(856mg，5.05mmol，87.79％)。MS(ESI)：m/z＝170[M+H]+。 Step 1: To a solution of 3,5-dichloropyrazine-2-carbonitrile (1.0 g, 5.75 mmol) in methanol (25 mL) was added sodium methoxide (117.19 mg, 2.17 mmol) at 0°C. The reaction mixture was stirred at room temperature for 12 hours and then concentrated. Water (15 mL) was added to the obtained concentrate, followed by extraction with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=20:1 to 8:1) , to obtain compound 5-1 (856 mg, 5.05 mmol, 87.79%). MS (ESI): m/z = 170 [M+H] + .
步骤2：向化合物5-1(100mg，22.99mmol)和叔丁醇钠(56.67mg，0.59mmol)的N,N-二甲基甲酰胺溶液(5mL)中加入5-(三氟甲基)-1H-吲哚(109.19mg，0.59mmol)。将反应混合物在120℃下搅拌12个小时，用水(10mL)进行稀释，然后用乙酸乙酯(30mL)萃取。将有机相用饱和氯化钠溶液洗涤，干燥后浓缩，并将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡到8:1)纯化，得到化合物5-2(20mg，0.06mmol，产率：10.66％)。MS(ESI)：m/z＝319[M+H]+。 Step 2: To compound 5-1 (100 mg, 22.99 mmol) and sodium tert-butoxide (56.67 mg, 0.59 mmol) in N,N-dimethylformamide (5 mL) was added 5-(trifluoromethyl) -1H-indole (109.19mg, 0.59mmol). The reaction mixture was stirred at 120°C for 12 hours, diluted with water (10 mL), and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=20:1 to 8:1) to obtain compound 5- 2 (20 mg, 0.06 mmol, yield: 10.66%). MS (ESI): m/z = 319 [M+H] + .
步骤3：向化合物5-2(20mg，0.06mmol)、三乙胺(0.17mL，1.26mmol)和分子筛(20mg)的甲醇溶液(2mL)中加入盐酸羟胺(21.83mg，0.31mmol)。将反应混合物在80℃下搅拌并回流3小时后浓缩，得到化合物5-3的粗产物(20mg)，该粗产物无需纯化可直接用于下一步反应。MS(ESI)：m/z＝352[M+H]+。 Step 3: To compound 5-2 (20mg, 0.06mmol), triethylamine (0.17mL, 1.26mmol) and To a methanol solution (2 mL) of molecular sieves (20 mg) was added hydroxylamine hydrochloride (21.83 mg, 0.31 mmol). The reaction mixture was stirred at 80°C and refluxed for 3 hours, then concentrated to obtain the crude product of compound 5-3 (20 mg), which was directly used in the next reaction without purification. MS (ESI): m/z = 352 [M+H] + .
步骤4：在0℃下向化合物5-3(20mg，0.06mmol)的四氢呋喃溶液(2mL)中加入N,N'-羰基二咪唑(11.54mg，0.07mmol)，在室温下搅拌0.5小时后，加入1,8-二氮杂双环[5.4.0]-7-十一碳烯(12.75μL，0.09mmol)。将反应混合物搅拌1小时后，用水(15mL)稀释，并用乙酸乙酯(45mL)萃取。将有机相依次用饱和氯化铵溶液和饱和氯化钠溶液洗涤，干燥后浓缩，并将所得残余物通过硅胶柱层析(洗脱剂梯度从DCM:MeOH＝99:1过渡到10:1)纯化，得到化合物5(21mg，0.06mmol，产率：97.77％，纯度：94.55％)。MS(ESI)：m/z＝378[M+H]+。1H NMR(DMSO-d6)δ:13.07(br s,1H),8.60(s,1H),8.06(s,1H),7.78-7.87(m,2H),7.51(dd,J＝8.6,1.4Hz,1H),6.87(d,J＝3.3Hz,1H),4.02-4.05(m,3H)。 Step 4: Add N,N'-carbonyldiimidazole (11.54 mg, 0.07 mmol) to compound 5-3 (20 mg, 0.06 mmol) in tetrahydrofuran (2 mL) at 0°C, and stir at room temperature for 0.5 hours, 1,8-Diazabicyclo[5.4.0]-7-undecene (12.75 μL, 0.09 mmol) was added. After stirring the reaction mixture for 1 hour, it was diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed successively with saturated ammonium chloride solution and saturated sodium chloride solution, dried and concentrated, and the resulting residue was subjected to silica gel column chromatography (eluent gradient transitioned from DCM:MeOH=99:1 to 10:1 ) was purified to obtain compound 5 (21 mg, 0.06 mmol, yield: 97.77%, purity: 94.55%). MS (ESI): m/z = 378 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 13.07 (br s, 1H), 8.60 (s, 1H), 8.06 (s, 1H), 7.78-7.87 (m, 2H), 7.51 (dd, J=8.6, 1.4Hz, 1H), 6.87(d, J=3.3Hz, 1H), 4.02-4.05(m, 3H).
实施例6
Example 6
步骤1：向3,6-二氯吡嗪-2-甲腈(4.0g，22.99mmol)和叔丁醇钠(2.65g，27.59mmol)的N,N-二甲基甲酰胺溶液(45mL)中加入5-(三氟甲基)-1H-吲哚(4.26g，22.99mmol)。将反应混合物在120℃下搅拌12个小时，用水(60mL)稀释，然后用乙酸乙酯(180mL)萃取。将有机相用饱和氯化钠溶液洗涤，干燥后浓缩，并将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡到4:1)纯化，得到化合物6-1(2.9g，8.99mmol，产率：39.09％)。MS(ESI)：m/z＝323[M+H]+。 Step 1: To a solution of 3,6-dichloropyrazine-2-carbonitrile (4.0 g, 22.99 mmol) and sodium tert-butoxide (2.65 g, 27.59 mmol) in N,N-dimethylformamide (45 mL) 5-(Trifluoromethyl)-1H-indole (4.26 g, 22.99 mmol) was added. The reaction mixture was stirred at 120°C for 12 hours, diluted with water (60 mL), and extracted with ethyl acetate (180 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=20:1 to 4:1) to obtain compound 6- 1 (2.9 g, 8.99 mmol, yield: 39.09%). MS (ESI): m/z = 323 [M+H] + .
步骤2：在0℃下，向化合物6-1(700mg，2.17mmol)的甲醇溶液(25mL)中加入甲醇钠(117.19mg，2.17mmol)。将反应混合物在常温下搅拌反应12小时后浓缩，然后加入水(15mL)稀释，并用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，并将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡到4:1)纯化，得到化合物6-2(373mg，1.06mmol，产率：49.07％)。MS(ESI)：m/z＝351[M+H]+。 Step 2: To a methanol solution (25 mL) of compound 6-1 (700 mg, 2.17 mmol) was added sodium methoxide (117.19 mg, 2.17 mmol) at 0°C. The reaction mixture was stirred at room temperature for 12 hours, concentrated, then diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=20:1 to 4:1) , to obtain compound 6-2 (373 mg, 1.06 mmol, yield: 49.07%). MS (ESI): m/z = 351 [M+H] + .
步骤3：向化合物6-2(100mg，0.29mmol)、三乙胺(0.40mL，2.85mmol)和分子筛(100mg)的乙醇溶液(4mL)中加入盐酸羟胺(99.19mg，1.43mmol)。反应混合物在80℃下搅拌并回流3小时后浓缩，然后加入水(15mL)，用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，并将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡到0:1)纯化，得到化合物6-3(273mg，粗品)。MS(ESI)：m/z＝352[M+H]+。 Step 3: To compound 6-2 (100mg, 0.29mmol), triethylamine (0.40mL, 2.85mmol) and To a solution (4 mL) of molecular sieves (100 mg) in ethanol was added hydroxylamine hydrochloride (99.19 mg, 1.43 mmol). The reaction mixture was stirred and refluxed at 80°C for 3 hours, concentrated, then added with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=20:1 to 0:1) , to obtain compound 6-3 (273 mg, crude product). MS (ESI): m/z = 352 [M+H] + .
步骤4：在0℃下向化合物6-3(273mg，粗品，0.77mmol)的四氢呋喃溶液(10mL)中加入N,N'-羰基二咪唑(155.78mg，0.96mmol)，混合物在室温下搅拌0.5小时后，加入1,8-二氮杂双环[5.4.0]-7-十一碳烯(172.08μL，1.15mmol)。将反应混合物搅拌1小时，加水(15mL)稀释，并用乙酸乙酯(45mL)萃取。将有机相依次用饱和氯化铵溶液和饱和氯化钠溶液洗涤，干燥后浓缩，并将所得残余物通过硅胶柱层析(洗脱剂梯度从DCM:MeOH＝99:1过渡到10:1)纯化，得到化合物6(66mg,0.17mmol,产率：22.76％，纯度：99.14％)。MS(ESI)：m/z＝378[M+H]+。1H NMR(甲醇-d4)δ:8.43(s,1H),7.96(s,1H),7.52(d,J＝3.4Hz,1H),7.38-7.42(m,1H),7.32-7.37(m,1H),6.81(d,J＝3.4Hz,1H),4.17(s,3H)。 Step 4: Add N,N'-carbonyldiimidazole (155.78mg, 0.96mmol) to compound 6-3 (273mg, crude product, 0.77mmol) in tetrahydrofuran (10mL) at 0°C, and stir the mixture at room temperature for 0.5 After hours, 1,8-diazabicyclo[5.4.0]-7-undecene (172.08 μL, 1.15 mmol) was added. The reaction mixture was stirred for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed successively with saturated ammonium chloride solution and saturated sodium chloride solution, dried and concentrated, and the resulting residue was subjected to silica gel column chromatography (eluent gradient transitioned from DCM:MeOH=99:1 to 10:1 ) to obtain compound 6 (66mg, 0.17mmol, yield: 22.76%, purity: 99.14%). MS (ESI): m/z = 378 [M+H] + . 1 H NMR (methanol-d 4 )δ: 8.43(s, 1H), 7.96(s, 1H), 7.52(d, J=3.4Hz, 1H), 7.38-7.42(m, 1H), 7.32-7.37( m, 1H), 6.81 (d, J=3.4Hz, 1H), 4.17 (s, 3H).
实施例7
Example 7
步骤1：将三甲基环三硼氧烷(0.14mL,0.50mmol,3.5M in THF)，碳酸钾(513.95mg,3.72mmol)和pd(dppf)Cl2(45.35mg,0.06mmol)加入到化合物6-1(400mg,1.24mmol)的二氧六环(4mL)和水(0.5mL)的溶液中。将反应混合物在氮气保护下升温到100℃搅拌过夜，过滤，将所得浓缩物用水(10mL)稀释，并用乙酸乙酯(10mL*3)萃取。将合并所得有机相浓缩，并将所得残余物通过快速柱层析(石油醚/乙酸 乙酯＝3/1)纯化，得到化合物7-1(190mg)。1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),8.12(d,J＝3.6Hz,2H),7.93(d,J＝8.6Hz,1H),7.59(d,J＝8.8,1.5Hz,1H),7.02(d,J＝3.5Hz,1H),2.68(s,3H). Step 1: Trimethylboroxane (0.14mL, 0.50mmol, 3.5M in THF), potassium carbonate (513.95mg, 3.72mmol) and pd(dppf)Cl 2 (45.35mg, 0.06mmol) were added to In a solution of compound 6-1 (400mg, 1.24mmol) in dioxane (4mL) and water (0.5mL). The reaction mixture was warmed up to 100° C. and stirred overnight under nitrogen protection, filtered, and the resulting concentrate was diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The combined organic phases were concentrated, and the resulting residue was subjected to flash column chromatography (petroleum ether/acetic acid ethyl ester=3/1) to obtain compound 7-1 (190 mg). 1 H NMR (400MHz, DMSO-d 6 )δ8.92(s, 1H), 8.12(d, J=3.6Hz, 2H), 7.93(d, J=8.6Hz, 1H), 7.59(d, J= 8.8,1.5Hz,1H),7.02(d,J=3.5Hz,1H),2.68(s,3H).
步骤2：将盐酸羟胺(80.47mg,1.16mmol)，TEA(0.64mL,4.63mmol)和4A分子筛(10mg)加入到化合物7-1(70mg,0.23mmol)的甲醇(1mL)溶液中。将反应混合物升温到80℃搅拌2小时后，过滤，并将滤液浓缩。向所得浓缩物中加水(3mL)稀释，并用乙酸乙酯(3mL*3)萃取。将合并所得有机相浓缩得化合物7-2的粗产物(60mg)。LCMS：m/z＝336[M+H]+。 Step 2: Hydroxylamine hydrochloride (80.47 mg, 1.16 mmol), TEA (0.64 mL, 4.63 mmol) and 4A molecular sieves (10 mg) were added to a solution of compound 7-1 (70 mg, 0.23 mmol) in methanol (1 mL). The reaction mixture was warmed up to 80°C and stirred for 2 hours, then filtered, and the filtrate was concentrated. To the obtained concentrate was diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated to obtain a crude product of compound 7-2 (60 mg). LCMS: m/z = 336 [M+H] + .
步骤3：在0℃下，将CDI(0.03mL,0.23mmol)加入到化合物7-2的粗产物(60mg)的四氢呋喃(1mL)溶液中，在0℃下搅拌0.5h后，在0℃下加入DBU(0.04mL,0.28mmol)。将反应混合物升温到室温搅拌1h后，加水(3mL)稀释，并用乙酸乙酯(3mL*3)萃取。将合并所得有机相浓缩，并将所得残余物通过制备高效液相色谱(HPLC)纯化，得到化合物7(19.69mg,0.05mmol,产率29.12％，纯度98.79％)。MS(ESI)：m/z＝362[M+H]+。1HNMR(400MHz,DMSO-d6)δ13.03–13.28(m,1H),8.84(s,1H),8.06(s,1H),7.80(d,J＝3.4Hz,1H),7.55–7.60(m,1H),7.47(dd,J＝8.8,1.6Hz,1H),6.86(d,J＝3.0Hz,1H),2.72(s,3H)。 Step 3: At 0°C, CDI (0.03mL, 0.23mmol) was added to a solution of the crude product of compound 7-2 (60mg) in tetrahydrofuran (1mL), stirred at 0°C for 0.5h, then at 0°C DBU (0.04 mL, 0.28 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 h, diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated, and the resulting residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 7 (19.69 mg, 0.05 mmol, yield 29.12%, purity 98.79%). MS (ESI): m/z = 362 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.03–13.28 (m, 1H), 8.84 (s, 1H), 8.06 (s, 1H), 7.80 (d, J=3.4Hz, 1H), 7.55–7.60 ( m, 1H), 7.47 (dd, J=8.8, 1.6Hz, 1H), 6.86 (d, J=3.0Hz, 1H), 2.72 (s, 3H).
实施例8
Example 8
步骤1：向化合物2-氯-4-甲氧基烟腈(300mg，1.78mmol)的DMF(6mL)溶液中加入5-三氟甲基吲哚(330mg，1.78mmol)和叔丁醇钠(171mg,1.78mmol)。将反应混合物在120℃下搅拌2小时后，冷却至25℃，并加入饱和氯化铵溶液(10mL)淬灭后用EA(50mL)萃取。将合并所得的有机相用饱和食盐水(3次)洗涤后，干燥并浓缩。将所得残余物通过硅胶柱层析(用PE：EA＝20/1至5/1洗脱)纯化得到化合物8-1(413mg,1.30mmol)。MS(ESI)：m/z＝318[M+H]+。 Step 1: To a solution of compound 2-chloro-4-methoxynicotinonitrile (300 mg, 1.78 mmol) in DMF (6 mL) was added 5-trifluoromethylindole (330 mg, 1.78 mmol) and sodium tert-butoxide ( 171 mg, 1.78 mmol). The reaction mixture was stirred at 120°C for 2 hours, cooled to 25°C, quenched by adding saturated ammonium chloride solution (10 mL) and extracted with EA (50 mL). The combined organic phases were washed with brine (3 times), dried and concentrated. The obtained residue was purified by silica gel column chromatography (eluted with PE:EA=20/1 to 5/1) to obtain compound 8-1 (413 mg, 1.30 mmol). MS (ESI): m/z = 318 [M+H] + .
步骤2：向化合物8-1(200mg，0.63mmol)的甲醇(10mL)溶液中依次加入盐酸羟胺(440mg，6.3mmol),分子筛(200mg)和三乙胺(5.0mL,37.8mmol)。将反应混合物在75℃下搅拌过夜，冷却至25℃后过滤。将饱和氯化铵溶液(15mL)加到滤液中淬灭，并用EA(100mL)萃取。将合并所得的有机相用饱和食盐水洗涤(3次)，干燥后浓缩。将所得残余物通过硅胶柱层析(用PE：EA＝5/1至1/1洗脱)纯化得到化合物8-2(101mg，0.29mmol)。MS(ESI)：m/z＝351[M+H]+。Step 2: Add hydroxylamine hydrochloride (440mg, 6.3mmol) successively to compound 8-1 (200mg, 0.63mmol) in methanol (10mL) solution, Molecular sieves (200 mg) and triethylamine (5.0 mL, 37.8 mmol). The reaction mixture was stirred overnight at 75°C, cooled to 25°C and filtered. Sat ammonium chloride solution (15 mL) was added to the filtrate to quench and extracted with EA (100 mL). The combined organic phases were washed with saturated brine (3 times), dried and concentrated. The obtained residue was purified by silica gel column chromatography (eluted with PE:EA=5/1 to 1/1) to obtain compound 8-2 (101 mg, 0.29 mmol). MS (ESI): m/z = 351 [M+H] + .
步骤3：在0℃下，将CDI(82.5mg,0.505mmol)加入到化合物8-2(101mg,0.29mmol)的THF(3mL)溶液中，升温至室温并搅拌30分钟后过夜，冷却至0℃，加入DBU(63μL，0.42mmol)，升温至室温搅拌1小时后浓缩。向浓缩物中加入饱和氯化铵溶液(2mL)以淬灭反应，并用EA(20mL)萃取。将合并所得的有机相用饱和食盐水洗涤(3次)，干燥后浓缩。将所得残余物分别通过硅胶柱层析(用PE：EA＝5/1至1/1洗脱)和制备高效液相色谱(HPLC)纯化，得到化合物8(29mg,0.21mmol,产率：72.4％，纯度99.54％)。MS(ESI)：m/z＝377[M+H]+。1HNMR(DMSO-d6)δ:12.79(br s,1H),8.76(d,J＝5.9Hz,1H),8.06(s,1H),7.69(d,J＝8.8Hz,1H),7.47-7.52(m,3H),6.85(d,J＝3.4Hz,1H),4.05(s,3H)。Step 3: Add CDI (82.5mg, 0.505mmol) to compound 8-2 (101mg, 0.29mmol) in THF (3mL) at 0°C, warm to room temperature and stir for 30 minutes overnight, then cool to 0 °C, DBU (63 μL, 0.42 mmol) was added, warmed to room temperature and stirred for 1 hour, then concentrated. To the concentrate was added saturated ammonium chloride solution (2 mL) to quench the reaction, and extracted with EA (20 mL). The combined organic phases were washed with saturated brine (3 times), dried and concentrated. The resulting residue was purified by silica gel column chromatography (eluted with PE:EA=5/1 to 1/1) and preparative high-performance liquid chromatography (HPLC) to obtain compound 8 (29mg, 0.21mmol, yield: 72.4 %, purity 99.54%). MS (ESI): m/z = 377 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.79 (br s, 1H), 8.76 (d, J = 5.9Hz, 1H), 8.06 (s, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.47 -7.52 (m, 3H), 6.85 (d, J=3.4Hz, 1H), 4.05 (s, 3H).
实施例9
Example 9
步骤1：将叔丁氧羰酰基肌氨酸(143.04mg,0.76mmol)和HATU(359.33mg,0.95mmol)分散于二氯甲烷(5mL)中，在室温下搅拌3mins后，加入化合物9-1(200mg,0.63mmol)和N,N-二异丙基乙胺(0.21mL,1.26mmol)。将反应混合物在室温下搅拌3小时后，加入饱和碳酸氢钠(2mL)淬灭，用乙酸乙酯(30mL×3)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩。将所得残余物用硅胶柱层析(用乙酸乙酯洗脱)纯化，得到化合物9-2(216mg，产率：69.9％)。MS(ESI)：m/z＝391[M-100+H]+。 Step 1: Disperse tert-butoxycarbonyl sarcosine (143.04mg, 0.76mmol) and HATU (359.33mg, 0.95mmol) in dichloromethane (5mL), stir at room temperature for 3mins, then add compound 9-1 (200mg, 0.63mmol) and N,N-diisopropylethylamine (0.21mL, 1.26mmol). After the reaction mixture was stirred at room temperature for 3 hours, it was quenched by adding saturated sodium bicarbonate (2 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 9-2 (216 mg, yield: 69.9%). MS (ESI): m/z = 391 [M-100+H] + .
步骤2：将化合物9-2溶于二氯甲烷(4mL)中，并在室温搅拌下依次加入对甲苯磺酰氯(77.74mg,0.41mmol)和三乙胺。反应混合物在室温下搅拌5小时后浓缩，加水(10ml)稀释，并用乙酸乙酯(30mL×3)萃取。将合并所得有机相，用无水硫酸钠干燥后浓缩。将所得残余物用硅胶柱层析(用石油醚:乙酸乙酯＝1:1)纯化得到化合物9-3(139mg，产率：72.15％)。MS(ESI)：m/z＝471[M-H]-。 Step 2: Compound 9-2 was dissolved in dichloromethane (4 mL), and p-toluenesulfonyl chloride (77.74 mg, 0.41 mmol) and triethylamine were added sequentially under stirring at room temperature. The reaction mixture was stirred at room temperature for 5 hours, concentrated, diluted with water (10 ml), and extracted with ethyl acetate (30 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 9-3 (139 mg, yield: 72.15%). MS (ESI): m/z = 471 [MH] - .
步骤3：在0℃下，将三氟乙酸(0.4mL,5.37mmol)加入到溶解有化合物9-3(130mg,0.28mmol)的二氯甲烷(2mL)溶液中。将反应混合物在室温下搅拌过夜后浓缩，得到化合物9-4的粗产物(150mg)。MS(ESI)：m/z＝373[M+H]+。 Step 3: Trifluoroacetic acid (0.4 mL, 5.37 mmol) was added to a solution of compound 9-3 (130 mg, 0.28 mmol) in dichloromethane (2 mL) at 0°C. The reaction mixture was stirred overnight at room temperature and then concentrated to obtain a crude product of compound 9-4 (150 mg). MS (ESI): m/z = 373 [M+H] + .
步骤4：在室温搅拌下，将溴化氰(49.00mg,0.46mmol)加入到溶解有化合物9-4(150mg,0.31mmol)和N,N-二异丙基乙胺(0.15mL,0.93mmol)的四氢呋喃(2mL)溶液中。将反应混合物在室温下搅拌10分钟后，加水(1ml)淬灭，并用乙酸乙酯(30mL×3)萃取。将合并所得的有机相依次用饱和氯化铵溶液(5ml)和饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩。将所得残余物用硅胶柱层析(用石油醚：乙酸乙酯＝1:1洗脱)纯化，得到化合物9(50mg，产率：40.80％)。MS(ESI)：m/z＝398[M-56+H]+。1H NMR(CHLOROFORM-d)δ:8.28(dd,J＝7.8,1.5Hz,1H),8.02(s,1H),7.79-7.84(m,1H),7.69-7.75(m,1H),7.61(dd,J＝7.8,1.1Hz,1H),7.32-7.38(m,2H),7.06(d,J＝8.6Hz,1H),6.88(dd,J＝3.3,0.6Hz,1H),4.06(s,2H),2.38(s,3H)。 Step 4: Under stirring at room temperature, cyanogen bromide (49.00mg, 0.46mmol) was added to dissolved compound 9-4 (150mg, 0.31mmol) and N,N-diisopropylethylamine (0.15mL, 0.93mmol ) in tetrahydrofuran (2 mL). After the reaction mixture was stirred at room temperature for 10 minutes, it was quenched with water (1 ml), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed successively with saturated ammonium chloride solution (5 ml) and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=1:1) to obtain compound 9 (50 mg, yield: 40.80%). MS (ESI): m/z = 398 [M-56+H] + . 1 H NMR (CHLOROFORM-d) δ: 8.28 (dd, J=7.8, 1.5Hz, 1H), 8.02 (s, 1H), 7.79-7.84 (m, 1H), 7.69-7.75 (m, 1H), 7.61 (dd, J=7.8,1.1Hz,1H),7.32-7.38(m,2H),7.06(d,J=8.6Hz,1H),6.88(dd,J=3.3,0.6Hz,1H),4.06( s,2H), 2.38(s,3H).
实施例10
Example 10
步骤1：按照实施例2中步骤1的类似合成方法，以2-氯烟酸乙酯以及5-(三氟甲基)-吲哚作为反应物制备得到化合物10-1。LCMS：m/z＝335[M+H]+。 Step 1: According to the similar synthesis method of step 1 in Example 2, compound 10-1 was prepared by using ethyl 2-chloronicotinate and 5-(trifluoromethyl)-indole as reactants. LCMS: m/z = 335 [M+H] + .
步骤2：按照实施例2中步骤2的类似合成方法，以化合物10-1作为反应物制备得到化合物10-2。LCMS：m/z＝321[M+H]+。 Step 2: Compound 10-2 was prepared according to the similar synthesis method of Step 2 in Example 2, using compound 10-1 as a reactant. LCMS: m/z = 321 [M+H] + .
步骤3-步骤6：以化合物10-2作为起始反应物，依次按照实施例9的步骤1、步骤2、步骤3和步骤 4的类似合成方法，经依次得到中间产物化合物10-3、化合物10-4、化合物10-5、最终得到化合物10(9mg,0.022mmol,产率42.25％，纯度96.65％)。MS(ESI)：m/z＝399[M-56+H]+。1H NMR(DMSO-d6)δ:8.91(dd,J＝4.8,1.8Hz,1H),8.62(dd,J＝7.8,1.8Hz,1H),8.06(s,1H),7.82(dd,J＝7.9,4.8Hz,1H),7.70-7.77(m,1H),7.36-7.53(m,2H),6.86(d,J＝3.3Hz,1H),4.47(s,2H),2.60(s,3H)。 Step 3-step 6 : with compound 10-2 as the starting reactant, follow step 1, step 2, step 3 and step of embodiment 9 successively Similar to the synthesis method of 4, the intermediate products Compound 10-3, Compound 10-4, Compound 10-5 were sequentially obtained, and finally Compound 10 (9mg, 0.022mmol, yield 42.25%, purity 96.65%) was obtained. MS (ESI): m/z = 399 [M-56+H] + . 1 H NMR (DMSO-d6) δ: 8.91 (dd, J=4.8, 1.8Hz, 1H), 8.62 (dd, J=7.8, 1.8Hz, 1H), 8.06 (s, 1H), 7.82 (dd, J =7.9,4.8Hz,1H),7.70-7.77(m,1H),7.36-7.53(m,2H),6.86(d,J=3.3Hz,1H),4.47(s,2H),2.60(s, 3H).
实施例11
Example 11
步骤1：按照实施例9中步骤1的类似合成方法，以化合物10-2作为反应物制备得到化合物11-1。LCMS：m/z＝506[M+H]+。 Step 1: Compound 11-1 was prepared according to the similar synthesis method of Step 1 in Example 9, using compound 10-2 as a reactant. LCMS: m/z = 506 [M+H] + .
步骤2：按照实施例9中步骤2的类似合成方法，以化合物11-1作为反应物制备得到化合物11-2。LCMS：m/z＝488[M+H]+。 Step 2: Compound 11-2 was prepared according to the similar synthesis method of Step 2 in Example 9, using compound 11-1 as a reactant. LCMS: m/z = 488 [M+H] + .
步骤3：按照实施例9中步骤3的类似合成方法，以化合物11-2作为反应物制备得到化合物11-3。LCMS：m/z＝388[M+H]+。 Step 3: According to the similar synthesis method of Step 3 in Example 9, Compound 11-3 was prepared using Compound 11-2 as a reactant. LCMS: m/z = 388 [M+H] + .
步骤4：按照实施例9中步骤4的类似合成方法，以化合物11-3作为反应物制备得到化合物11(123mg，0.29mmol，产率68.33％，纯度97.87％)。MS(ESI)：m/z＝413[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝8.91-8.88(m,1H),8.65-8.61(m,1H),8.10-8.06(m,1H),7.84-7.78(m,1H),7.68(d,J＝3.4Hz,1H),7.51-7.41(m,2H),6.90-6.84(m,1H),3.20-3.13(m,2H),3.08-3.00(m,2H),2.72(s,3H)。 Step 4: Compound 11 (123 mg, 0.29 mmol, 68.33% yield, 97.87% purity) was prepared according to the similar synthesis method of Step 4 in Example 9, using compound 11-3 as a reactant. MS (ESI): m/z = 413 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ=8.91-8.88(m,1H),8.65-8.61(m,1H),8.10-8.06(m,1H),7.84-7.78(m,1H),7.68 (d,J=3.4Hz,1H),7.51-7.41(m,2H),6.90-6.84(m,1H),3.20-3.13(m,2H),3.08-3.00(m,2H),2.72(s ,3H).
实施例12
Example 12
化合物12-2的制备：Preparation of Compound 12-2:
步骤1：将5-三氟甲基吲哚(5.00g,27.01mmol)、DMF(20mL)、2-氯烟酸乙酯(7.52g,40.51mmol)和Cs2CO3(17.60g,17.60mmol)的混合物用N2吹扫三次后，在120℃下搅拌3小时，加H2O(200mL)稀释，并用EA(50mL)萃取。将合并所得的有机相用饱和食盐水(20mL×3)洗涤，无水Na2SO4干燥后，浓缩得到 残余物。将所得残余物经硅胶柱层析(用DCM:PE＝1/1洗脱)纯化得到化合物12-1(7.86g,23.51mmol,产率：87.06％)。MS(ESI)：m/z＝335[M+H]+。Step 1: Mix 5-trifluoromethylindole (5.00g, 27.01mmol), DMF (20mL), ethyl 2-chloronicotinate (7.52g, 40.51mmol) and Cs 2 CO 3 (17.60g, 17.60mmol ) was purged three times with N 2 , stirred at 120° C. for 3 h, diluted with H 2 O (200 mL), and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 , and concentrated to obtain The residue. The obtained residue was purified by silica gel column chromatography (eluted with DCM:PE=1/1) to obtain compound 12-1 (7.86 g, 23.51 mmol, yield: 87.06%). MS (ESI): m/z = 335 [M+H] + .
步骤2：将化合物12-1(7.86g,23.51mmol)、MeOH(165mL)和N2H4·H2O(18mL,370.36mmol)的混合物在80℃下搅拌18小时后浓缩，加H2O(50mL)，并用EA(50mL)萃取。将合并后的有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥后浓缩得化合物12-2(6.57g)的粗产品。MS(ESI)：m/z＝321[M+H]+。Step 2: Stir the mixture of compound 12-1 (7.86g, 23.51mmol), MeOH (165mL) and N 2 H 4 ·H 2 O (18mL, 370.36mmol) at 80°C for 18 hours, concentrate, add H 2 O (50 mL), and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a crude product of compound 12-2 (6.57 g). MS (ESI): m/z = 321 [M+H] + .
化合物12的制备：Preparation of compound 12:
步骤1：在冰浴和氮气氛围下，将LDA/THF(2M，4.8mL,4.78mmol)缓慢滴加到化合物12-3(2.14g,8.32mmol)的THF(20mL)溶液中，搅拌1小时后滴入MeI(1.36g,9.57mmol)。将反应混合物在冰浴下继续搅拌2小时后用饱和NH4Cl(20mL)淬灭，并用EA(50mL)萃取。将合并后的有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥，浓缩得到残余物。将所得残余物经硅胶柱层析(用EA:PE＝1/2洗脱)纯化得到化合物12-4(1.42g，5.23mmol，产率：62.93％)。MS(ESI)：m/z＝272[M+H]+。Step 1: Slowly add LDA/THF (2M, 4.8mL, 4.78mmol) dropwise to a solution of compound 12-3 (2.14g, 8.32mmol) in THF (20mL) under ice bath and nitrogen atmosphere, and stir for 1 hour Then MeI (1.36 g, 9.57 mmol) was added dropwise. The reaction mixture was stirred for an additional 2 h in the ice bath and then quenched with saturated NH4Cl (20 mL) and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 , and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1/2) to obtain compound 12-4 (1.42 g, 5.23 mmol, yield: 62.93%). MS (ESI): m/z = 272 [M+H] + .
步骤2：在搅拌条件下，将溶解于H2O(4mL)的LiOH(0.25g,10.47mmol)的水溶液加入化合物12-4(1.42g,5.23mmol)的THF(10mL)溶液中。反应混合物在室温下搅拌1小时，得到无需纯化直接用于下一步反应的含有化合物12-5(MS(ESI)：m/z＝244[M+H]+)的混合物。Step 2: An aqueous solution of LiOH (0.25 g, 10.47 mmol) dissolved in H 2 O (4 mL) was added to a solution of compound 12-4 (1.42 g, 5.23 mmol) in THF (10 mL) under stirring condition. The reaction mixture was stirred at room temperature for 1 hour to obtain a mixture containing compound 12-5 (MS(ESI): m/z=244[M+H] + ) which was directly used in the next reaction without purification.
步骤3：将HCl/1,4-Dioxane(4M，13.05mL，52.21mmol)加入到上述步骤2得到的含有化合物12-5的混合物中。将反应混合物在室温下搅拌3小时后浓缩，得到化合物12-6(MS(ESI)：m/z＝144[M+H]+)的粗产物(1.53g)。Step 3: HCl/1,4-Dioxane (4M, 13.05 mL, 52.21 mmol) was added to the mixture containing compound 12-5 obtained in the above step 2. The reaction mixture was stirred at room temperature for 3 hours and then concentrated to obtain a crude product (1.53 g) of compound 12-6 (MS(ESI): m/z=144[M+H] + ).
步骤4：在搅拌条件下，将T3P/EA(50％，5.44g，8.55mmol)滴入到上述步骤3得到的化合物12-6的粗产物、DMF(15mL)、化合物12-2(0.68g,2.14mmol)和DIPEA(1.42mL,8.55mmol)的混合物中。将反应混合物在室温下搅拌10分钟，加入饱和NaHCO3(20mL)淬灭，并用EA(50mL)萃取。将合并得到的有机相用饱和食盐水(50mL×3)洗涤，用无水Na2SO4干燥后，浓缩得到残余物。将所得残余物在DCM中打浆12小时后，抽滤得到化合物12-7(346.6mg,0.78mmol,产率：36.45％)。MS(ESI)：m/z＝446[M+H]+。Step 4: Under stirring conditions, T3P/EA (50%, 5.44g, 8.55mmol) was added dropwise to the crude product of compound 12-6 obtained in the above step 3, DMF (15mL), compound 12-2 (0.68g , 2.14mmol) and DIPEA (1.42mL, 8.55mmol) in a mixture. The reaction mixture was stirred at room temperature for 10 min, quenched by adding saturated NaHCO 3 (20 mL), and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (50 mL×3), dried over anhydrous Na 2 SO 4 , and concentrated to obtain a residue. After the obtained residue was slurried in DCM for 12 hours, the compound 12-7 was obtained by suction filtration (346.6 mg, 0.78 mmol, yield: 36.45%). MS (ESI): m/z = 446 [M+H] + .
步骤5:将化合物12-7(296.6mg,0.67mmol)、3mL DMF、TsCl(127.73mg,0.67mmol)和TEA(0.19mL,1.34mmol)的混合物在室温下搅拌6小时，加入饱和NaHCO3(aq)(10mL)，并用EA(20mL)萃取。将合并所得有机相用饱和食盐水(50mL×3)洗涤，用无水Na2SO4干燥后，浓缩得到残余物。将所得残余物经硅胶柱层析(用MeOH:DCM＝1/30洗脱)纯化得到化合物12(140.0mg,0.33mmol,产率：48.05％)。MS(ESI)：m/z＝428[M+H]+。1HNMR(400MHz,DMSO-d6)δppm 1.18(s,3H)1.81-1.88(m,2H)2.83(dt,J＝9.63,6.88Hz,1H)3.09(dt,J＝9.60,6.64Hz,1H)6.88(d,J＝3.38Hz,1H)7.30-7.36(m,1H)7.38-7.42(m,1H)7.76(d,J＝3.38Hz,1H)7.80(dd,J＝7.88,4.75Hz,1H)7.96(s,1H)8.08(s,1H)8.64(dd,J＝7.88,1.75Hz,1H)8.90(dd,J＝4.75,1.75Hz,1H)。Step 5: A mixture of compound 12-7 (296.6 mg, 0.67 mmol), 3 mL of DMF, TsCl (127.73 mg, 0.67 mmol) and TEA (0.19 mL, 1.34 mmol) was stirred at room temperature for 6 hours, and saturated NaHCO 3 ( aq) (10 mL), and extracted with EA (20 mL). The combined organic phases were washed with saturated brine (50 mL×3), dried over anhydrous Na 2 SO 4 , and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1/30) to obtain compound 12 (140.0 mg, 0.33 mmol, yield: 48.05%). MS (ESI): m/z = 428 [M+H] + . 1 HNMR (400MHz,DMSO-d 6 )δppm 1.18(s,3H)1.81-1.88(m,2H)2.83(dt,J＝9.63,6.88Hz,1H)3.09(dt,J＝9.60,6.64Hz,1H )6.88(d, J=3.38Hz,1H)7.30-7.36(m,1H)7.38-7.42(m,1H)7.76(d,J=3.38Hz,1H)7.80(dd,J=7.88,4.75Hz, 1H) 7.96 (s, 1H) 8.08 (s, 1H) 8.64 (dd, J=7.88, 1.75Hz, 1H) 8.90 (dd, J=4.75, 1.75Hz, 1H).
实施例14
Example 14
化合物14-2的制备：Preparation of Compound 14-2:
在搅拌条件下，将溶解于H2O(4mL)的LiOH(0.26g,10.80mmol)的水溶液滴入溶解于THF(10mL)的化合物14-1(1.00g,5.40mmol)的溶液中。在室温下搅拌0.5小时后，用1M HCl(aq)将反应混合物的pH调至2，然后浓缩得到化合物14-2(MS(ESI)：m/z＝158[M+H]+)的粗产物(1.87g)。An aqueous solution of LiOH (0.26 g, 10.80 mmol) dissolved in H 2 O (4 mL) was dropped into a solution of compound 14-1 (1.00 g, 5.40 mmol) dissolved in THF (10 mL) under stirring condition. After stirring at room temperature for 0.5 hours, the pH of the reaction mixture was adjusted to 2 with 1M HCl(aq), and then concentrated to obtain the crude Product (1.87g).
化合物14的制备：Preparation of Compound 14:
步骤1：将上述步骤中得到的化合物14-2的粗产物(1.87g,5.40mmol)(按含量45.4％)、5mL DMF、HATU(2.26g,5.94mmol)和DIPEA(1.34mL,8.10mmol)的混合物在室温下搅拌10min后，加入化合物14-3(1.73g,5.40mmol)。将反应混合物在室温下搅拌3小时后浓缩，加入饱和NaHCO3(aq)(50mL)，用EA(30mL)萃取。将合并得到的有机相浓缩得到残余物。将所得残余物经硅胶柱层析(DCM:MeOH＝20/1)纯化得到化合物14-4(292.6mg,0.64mmol,产率：11.79％)。MS(ESI)：m/z＝460[M+H]+。 Step 1: The crude product of compound 14-2 obtained in the above step (1.87g, 5.40mmol) (45.4% by content), 5mL DMF, HATU (2.26g, 5.94mmol) and DIPEA (1.34mL, 8.10mmol) After the mixture was stirred at room temperature for 10 min, compound 14-3 (1.73 g, 5.40 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, concentrated, added saturated NaHCO 3 (aq) (50 mL), extracted with EA (30 mL). The combined organic phases were concentrated to give a residue. The obtained residue was purified by silica gel column chromatography (DCM:MeOH=20/1) to obtain compound 14-4 (292.6 mg, 0.64 mmol, yield: 11.79%). MS (ESI): m/z = 460 [M+H] + .
步骤2：向25mL烧瓶中依次加入化合物14-4(292.6mg,1.27mmol)、2mL THF、2mL DCM、TsCl(242.8mg,1.27mmol)和TEA(0.35mL,2.55mmol)。将反应混合物在室温下搅拌2小时后浓缩，加入饱和NaHCO3(aq)(10mL)，并用EA(20mL)萃取，浓缩得到残余物。将所得残余物经制备高效液相色谱纯化得到化合物14(31.1mg，0.07mmol，产率：11.06％)。MS(ESI)：m/z＝442[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 1.13-1.21(m,1H)1.24(s,3H)1.26-1.32(m,1H)1.39-1.46(m,1H)1.47-1.53(m,1H)2.85-2.93(m,1H)3.07(br dd,J＝7.07,4.94Hz,1H)6.90(d,J＝3.38Hz,1H)7.26(d,J＝8.63Hz,1H)7.38(dd,J＝8.76,1.38Hz,1H)7.69(br s,1H)7.78-7.80(m,1H)7.80-7.83(m,1H)8.08(s,1H)8.66(dd,J＝7.88,1.75Hz,1H)8.90(dd,J＝4.75,1.75Hz,1H)。Step 2: Compound 14-4 (292.6 mg, 1.27 mmol), 2 mL THF, 2 mL DCM, TsCl (242.8 mg, 1.27 mmol) and TEA (0.35 mL, 2.55 mmol) were sequentially added to a 25 mL flask. The reaction mixture was stirred at room temperature for 2 hours, concentrated, added saturated NaHCO 3 (aq) (10 mL), extracted with EA (20 mL), and concentrated to give a residue. The obtained residue was purified by preparative high performance liquid chromatography to obtain compound 14 (31.1 mg, 0.07 mmol, yield: 11.06%). MS (ESI): m/z = 442 [M+H] + . 1 H NMR (400MHz,DMSO-d 6 )δppm 1.13-1.21(m,1H)1.24(s,3H)1.26-1.32(m,1H)1.39-1.46(m,1H)1.47-1.53(m,1H) 2.85-2.93(m,1H)3.07(br dd,J＝7.07,4.94Hz,1H)6.90(d,J＝3.38Hz,1H)7.26(d,J＝8.63Hz,1H)7.38(dd,J＝ 8.76,1.38Hz,1H)7.69(br s,1H)7.78-7.80(m,1H)7.80-7.83(m,1H)8.08(s,1H)8.66(dd,J＝7.88,1.75Hz,1H)8.90 (dd, J=4.75, 1.75Hz, 1H).
实施例16
Example 16
步骤1：在室温下，将化合物16-1溶于醋酸(25mL)中，用N2吹扫并维持N2氛围。反应混合物在70℃下搅拌过夜，加入饱和碳酸氢钠溶液淬灭，并用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥，并浓缩得到残余物。将所得残余物用硅胶柱层析(用石油醚洗脱)纯化得到化合物16-2(1.142g，产率：65.34％)。MS(ESI)：m/z＝320[M+H]+。Step 1: Compound 16-1 was dissolved in acetic acid (25 mL) at room temperature, purged with N 2 and maintained under N 2 atmosphere. The reaction mixture was stirred overnight at 70 °C, quenched by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 16-2 (1.142 g, yield: 65.34%). MS (ESI): m/z = 320 [M+H] + .
步骤2：在室温且N2氛围条件下，将水合肼(5.8mL,119.57mmol)缓慢滴入化合物16-2(1.0g,3.28mmol)的甲醇(30mL)溶液中。将反应混合物在80℃下搅拌4小时后浓缩得到残余物。将所得残余物用硅胶柱层析(用石油醚：乙酸乙酯＝2：1洗脱)纯化得到化合物16-3(916mg，产率：91.60％)。MS(ESI)：m/z＝320[M+H]+。Step 2: Hydrazine hydrate (5.8 mL, 119.57 mmol) was slowly dropped into a solution of compound 16-2 (1.0 g, 3.28 mmol) in methanol (30 mL) at room temperature under N 2 atmosphere. The reaction mixture was stirred at 80°C for 4 hours and then concentrated to a residue. The resulting residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=2:1) to obtain compound 16-3 (916 mg, yield: 91.60%). MS (ESI): m/z = 320 [M+H] + .
步骤3：在0℃且N2氛围条件下，将化合物16-3(200mg,0.63mmol)缓慢加入到溶解有草酰氯单乙酯(0.07mL,0.63mmol)和三乙胺(0.26mL,1.88mmol)的二氯甲烷(5mL)溶液中。维持N2氛围，将反应混合物在室温下搅拌过夜后，加入对甲苯磺酰氯(0.12mL,0.63mmol)，随后在室温下继续反应5小时，加入碳酸氢钠饱和溶液淬灭，用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥并浓缩得到残余物。将所得残余物用制备硅胶板(用石油醚：乙酸乙酯＝1:1洗脱)纯化，得到化合物16-4(183mg，产率：69.67％)。MS(ESI)：m/z＝420[M+H]+。Step 3: Under the condition of 0 ℃ and N 2 atmosphere, compound 16-3 (200mg, 0.63mmol) was slowly added to the dissolved monoethyl oxalyl chloride (0.07mL, 0.63mmol) and triethylamine (0.26mL, 1.88 mmol) in dichloromethane (5 mL). Maintaining the N2 atmosphere, the reaction mixture was stirred overnight at room temperature, p-toluenesulfonyl chloride (0.12mL, 0.63mmol) was added, and then the reaction was continued at room temperature for 5 hours, quenched by adding a saturated solution of sodium bicarbonate, and washed with ethyl acetate (50 mL×2) extraction. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified with a preparative silica gel plate (eluted with petroleum ether:ethyl acetate=1:1) to obtain compound 16-4 (183 mg, yield: 69.67%). MS (ESI): m/z = 420 [M+H] + .
步骤4：在室温且N2氛围条件下，将甲苯磺酰氯(83mg,0.44mmol)和三乙胺(0.12mL,0.87mmol)依次加入到溶解于二氯甲烷(2mL)的化合物16-4(183mg,0.44mmol)的溶液中。维持N2氛围，将反应混合物在室温下搅拌5小时后浓缩，加入水，并用乙酸乙酯(50mL×3)萃取。将合并得到的有机相用无水硫酸钠干燥并浓缩得到残余物。将所得残余物用硅胶柱层析(用石油醚：乙酸乙酯＝1：1洗脱)纯化，得到化合物16-5(169mg，产率：96.49％)。MS(ESI)：m/z＝402[M+H]+。Step 4: Tosyl chloride (83mg, 0.44mmol) and triethylamine (0.12mL, 0.87mmol) were sequentially added to compound 16-4 dissolved in dichloromethane (2mL) at room temperature under N2 atmosphere ( 183mg, 0.44mmol) solution. Maintaining the N 2 atmosphere, the reaction mixture was stirred at room temperature for 5 hours, concentrated, added water, and extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=1:1) to obtain compound 16-5 (169 mg, yield: 96.49%). MS (ESI): m/z = 402 [M+H] + .
步骤5:在室温且N2氛围条件下，在干燥的25mL封管中，将氨水(0.4mL,10.39mmol)加入溶解有化合物16-5(173mg,0.43mmol)的甲醇(2mL)中。将反应混合物快速密封后，缓慢升温至60℃搅拌4小时，浓缩后加水稀释，并用乙酸乙酯(50mL×3)萃取。将合并得到的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物经硅胶柱层析(用乙酸乙酯洗脱)纯化，得到化合物16(136mg，产率：84.74％)。MS(ESI)：m/z＝373[M+H]+。1H NMR(DMSO-d6)δ:8.46(s,1H),8.24(dd,J＝7.8,1.5Hz,1H),8.17(s,1H),8.05(s,1H),7.88-7.93(m,1H),7.79-7.84(m,1H),7.74(dd,J＝7.9,0.9Hz,1H),7.65(d,J＝3.4Hz,1H),7.37(dd,J＝8.8,1.5Hz,1H),7.18(d,J＝8.6Hz,1H),6.83(d,J＝3.3Hz,1H)。Step 5: Aqueous ammonia (0.4 mL, 10.39 mmol) was added into methanol (2 mL) dissolved with compound 16-5 (173 mg, 0.43 mmol) in a dry 25 mL sealed tube at room temperature under N 2 atmosphere. After the reaction mixture was quickly sealed, the temperature was slowly raised to 60° C. and stirred for 4 hours, concentrated, diluted with water, and extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 16 (136 mg, yield: 84.74%). MS (ESI): m/z = 373 [M+H] + . 1 H NMR (DMSO-d 6 ) δ: 8.46(s, 1H), 8.24(dd, J=7.8, 1.5Hz, 1H), 8.17(s, 1H), 8.05(s, 1H), 7.88-7.93( m,1H),7.79-7.84(m,1H),7.74(dd,J=7.9,0.9Hz,1H),7.65(d,J=3.4Hz,1H),7.37(dd,J=8.8,1.5Hz , 1H), 7.18 (d, J=8.6Hz, 1H), 6.83 (d, J=3.3Hz, 1H).
实施例17
Example 17
步骤1：将溶解于DMF(2mL)的化合物16(30mg,0.08mmol)的溶液在室温下用N2吹扫并维持N2氛围，冷却至0℃，并在此温度下，加入氢化钠(9.67mg,0.24mmol)，搅拌30分钟后加入碘甲烷(11.04uL,0.18mmol)。将反应混合物缓慢升至室温后，搅拌30分钟，加入饱和硫代硫酸钠溶液淬灭，加水、并用乙酸乙酯(100mL×3)萃取。将合并后的有机相用无水硫酸钠干燥，浓缩得到残余物。将所得残余物用硅胶柱层析(用乙酸乙酯洗脱)纯化，得到化合物17(27mg，产率：83.69％)。MS(ESI)：m/z＝401[M+H]+。1H NMR(METHANOL-d4)δ:8.24(dd,J＝7.8,1.5Hz,1H),7.96(s,1H),7.86-7.91(m,1H),7.77(td,J＝7.7,1.3Hz,1H),7.68(dd,J＝7.9,0.9Hz,1H),7.48(d,J＝3.4Hz,1H),7.32(dd,J＝8.6,1.5Hz,1H),7.09(d,J＝8.6Hz,1H),6.83(d,J＝3.4Hz,1H),3.01(s,3H),2.95(s,3H)。Step 1: A solution of compound 16 (30 mg, 0.08 mmol) dissolved in DMF (2 mL) was purged with N 2 at room temperature and maintained under N 2 atmosphere, cooled to 0° C., and at this temperature, sodium hydride ( 9.67mg, 0.24mmol), and after stirring for 30 minutes, methyl iodide (11.04uL, 0.18mmol) was added. After the reaction mixture was slowly warmed to room temperature, it was stirred for 30 minutes, quenched by adding saturated sodium thiosulfate solution, added water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 17 (27 mg, yield: 83.69%). MS (ESI): m/z = 401 [M+H] + . 1 H NMR (METHANOL-d 4 )δ: 8.24(dd, J=7.8,1.5Hz,1H),7.96(s,1H),7.86-7.91(m,1H),7.77(td,J=7.7,1.3 Hz,1H),7.68(dd,J=7.9,0.9Hz,1H),7.48(d,J=3.4Hz,1H),7.32(dd,J=8.6,1.5Hz,1H),7.09(d,J =8.6Hz, 1H), 6.83(d, J=3.4Hz, 1H), 3.01(s, 3H), 2.95(s, 3H).
实施例21
Example 21
步骤1：按照实施例9中步骤1的类似合成方法，以化合物12-2作为反应物制备得到化合物21-1。LCMS：m/z＝421[M+H]+。Step 1: Compound 21-1 was prepared according to the similar synthesis method of Step 1 in Example 9, using compound 12-2 as a reactant. LCMS: m/z = 421 [M+H] + .
步骤2：按照实施例9中步骤4的类似合成方法，以化合物21-1作为反应物制备得到化合物21(10mg，0.024mmol，产率：35.33％，纯度：97.10％)。MS(ESI)：m/z＝433[M+H]+。Step 2: Compound 21 (10 mg, 0.024 mmol, yield: 35.33%, purity: 97.10%) was prepared according to the similar synthesis method of step 4 in Example 9, using compound 21-1 as a reactant. MS (ESI): m/z = 433 [M+H] + .
1H NMR(DMSO-d6)δ:8.91(dd,J＝4.8,1.7Hz,1H),8.65(dd,J＝7.9,1.8Hz,1H),8.07(s,1H),7.81(dd,J＝7.9,4.9Hz,1H),7.74(d,J＝3.5Hz,1H),7.39-7.50(m,2H),7.03(s,1H),6.87(d,J＝3.4Hz,1H),4.52(q,J＝7.0Hz,4H)。 1 H NMR (DMSO-d6) δ: 8.91(dd, J=4.8, 1.7Hz, 1H), 8.65(dd, J=7.9, 1.8Hz, 1H), 8.07(s, 1H), 7.81(dd, J =7.9,4.9Hz,1H),7.74(d,J=3.5Hz,1H),7.39-7.50(m,2H),7.03(s,1H),6.87(d,J=3.4Hz,1H),4.52 (q, J = 7.0 Hz, 4H).
实施例24
Example 24
步骤1：将5-三氟甲基吲哚(212mg,1.14mmol)和Cs2CO3(745mg,2.28mmol)加入到1-溴-2-氟苯(200mg,1.14mmol)的DMSO(5mL)溶液中。将反应混合物在微波条件下以及130℃下搅拌2小时，冷却至室温，加H2O稀释并用EA萃取。将合并得到的有机相干燥并浓缩，得到残余物。将所得残余物通过硅胶柱层析纯化得到化合物24-1(350mg，1.04mmol)。MS(ESI)：m/z＝340[M+H]+。Step 1: 5-Trifluoromethylindole (212 mg, 1.14 mmol) and Cs 2 CO 3 (745 mg, 2.28 mmol) were added to 1-bromo-2-fluorobenzene (200 mg, 1.14 mmol) in DMSO (5 mL) in solution. The reaction mixture was stirred under microwave conditions at 130° C. for 2 h, cooled to room temperature, diluted with H 2 O and extracted with EA. The combined organic phases were dried and concentrated to give a residue. The obtained residue was purified by silica gel column chromatography to obtain compound 24-1 (350 mg, 1.04 mmol). MS (ESI): m/z = 340 [M+H] + .
步骤2：向化合物24-1(200mg,0.59mmol)的DMF(6mL)溶液中加入化合物2-甲基-5-(三丁烷基锡)-2H四唑(442mg,1.18mmol)、Pd(PPh3)4(68mg,0.06mmol)和CuI(12mg,0.06mmol)。将反应混合物在120℃下搅拌过夜，冷却至室温，加入氟化钾溶液(2M)稀释并用EA萃取。将合并得到的有机相用饱和食盐水洗涤，无水硫酸钠干燥，并浓缩得到残余物。将所得残余物通过硅胶柱层析纯化得到化合物24(68mg，0.20mmol，产率：33.9％)。MS(ESI)：m/z＝344[M+H]+。1H NMR(DMSO-d6)δ:8.11(dd,J＝7.5,1.6Hz,1H),8.02(s,1H),7.77(ddd,J＝10.3,7.5,1.6Hz,2H),7.66(dd,J＝7.6,1.3Hz,1H),7.50(d,J＝3.3Hz,1H),7.33(dd,J＝8.7,1.3Hz,1H),7.08(d,J＝8.6Hz,1H),6.77(d,J＝3.1Hz,1H),4.17(s,3H)。Step 2: Add compound 2-methyl-5-(tributyltin)-2H tetrazole (442 mg, 1.18 mmol), Pd( PPh 3 ) 4 (68 mg, 0.06 mmol) and Cul (12 mg, 0.06 mmol). The reaction mixture was stirred overnight at 120 °C, cooled to room temperature, diluted with potassium fluoride solution (2M) and extracted with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography to obtain compound 24 (68 mg, 0.20 mmol, yield: 33.9%). MS (ESI): m/z = 344 [M+H] + . 1 H NMR (DMSO-d 6 ) δ: 8.11 (dd, J=7.5, 1.6Hz, 1H), 8.02(s, 1H), 7.77 (ddd, J=10.3, 7.5, 1.6Hz, 2H), 7.66( dd,J=7.6,1.3Hz,1H),7.50(d,J=3.3Hz,1H),7.33(dd,J=8.7,1.3Hz,1H),7.08(d,J=8.6Hz,1H), 6.77 (d, J = 3.1 Hz, 1H), 4.17 (s, 3H).
实施例26
Example 26
步骤1：往化合物26-1(200mg，0.59mmol)，碳酸钾(162.52mg，1.18mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(48.02mg，0.06mmol)在二氧六环(2.5mL)和水(0.5mL)的混合物中加入4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯(443.69mg，1.18mmol)。将反应混合物用氮气吹扫并维持氮气氛围，在100℃下搅拌反应3个小时后，加入水(10mL)，用乙酸乙酯(30mL)萃取。将有机相并用饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，并将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡到5:1)得到化合物26-2(374mg，粗品)。MS(ESI)：m/z＝511[M+H]+。Step 1: To compound 26-1 (200mg, 0.59mmol), potassium carbonate (162.52mg, 1.18mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (48.02mg, 0.06mmol) to a mixture of dioxane (2.5mL) and water (0.5mL) was added 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxane Pentaboran-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (443.69 mg, 1.18 mmol). The reaction mixture was purged with nitrogen and maintained under nitrogen atmosphere. After stirring the reaction at 100° C. for 3 hours, water (10 mL) was added and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was subjected to silica gel column chromatography (eluent gradient from PE:EA=20:1 to 5:1) to obtain Compound 26-2 (374 mg, crude product). MS (ESI): m/z = 511 [M+H] + .
步骤2：在0℃下，向化合物26-2(168mg，0.33mmol)的二氧六环溶液(1.5mL)中加入盐酸的二氧六环溶液(1mL，4.0mol/L)。将反应混合物在室温下搅拌1个小时后浓缩，并将所得浓缩物通过制备高效液相色谱(HPLC)进行纯化，，得到化合物26的盐酸盐(39.28mg，0.10mmol，产率：30.16％，纯度：99.57％)。MS(ESI)：m/z＝411[M+H]+。1H NMR(DMSO-d6)δ:8.55-8.79(m,1H),8.42(br s,1H),8.07(s,1H),7.85(d,J＝7.5Hz,1H),7.57-7.63(m,2H),7.44-7.51(m,2H),7.33(dd,J＝8.7,1.6Hz,1H),7.10(s,1H),7.00(d,J＝8.6Hz,1H),6.88(d,J＝2.9Hz,1H),6.81(s,1H),4.18-4.32(m,1H),3.27(br d,J＝12.0Hz,2H),2.97(br t,J＝11.1Hz,2H),1.77-1.96(m,4H)。Step 2: To a solution of compound 26-2 (168 mg, 0.33 mmol) in dioxane (1.5 mL) was added a solution of hydrochloric acid in dioxane (1 mL, 4.0 mol/L) at 0°C. The reaction mixture was stirred at room temperature for 1 hour and concentrated, and the obtained concentrate was purified by preparative high-performance liquid chromatography (HPLC) to obtain the hydrochloride salt of compound 26 (39.28mg, 0.10mmol, yield: 30.16% , purity: 99.57%). MS (ESI): m/z = 411 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.55-8.79 (m, 1H), 8.42 (br s, 1H), 8.07 (s, 1H), 7.85 (d, J=7.5Hz, 1H), 7.57-7.63 (m,2H),7.44-7.51(m,2H),7.33(dd,J=8.7,1.6Hz,1H),7.10(s,1H),7.00(d,J=8.6Hz,1H),6.88( d,J=2.9Hz,1H),6.81(s,1H),4.18-4.32(m,1H),3.27(br d,J=12.0Hz,2H),2.97(br t,J=11.1Hz,2H ), 1.77-1.96 (m, 4H).
实施例27
Example 27
按照实施例26中步骤1的类似合成方法，以化合物26-1作为反应物制备得到化合物27(45.85mg，0.11mmol，产率：37.84％，纯度：99.82％)。MS(ESI)：m/z＝412[M+H]+。1H NMR(400MHz,CDCl3-d)δ7.99(s,1H),7.71(d,J＝6.9Hz,1H),7.50–7.61(m,1H),7.44(d,J＝3.8Hz,3H),7.30(d,J＝8.9Hz,1H),7.22(d,J＝2.9Hz,1H),7.00(d,J＝8.4Hz,1H),6.79(d,J＝2.6Hz,1H),6.12(s,1H),4.07–4.23(m,1H),3.94(d,J＝10.1Hz,2H),3.40(t,J＝11.4Hz,2H),1.40–1.77(m,4H).Compound 27 (45.85 mg, 0.11 mmol, yield: 37.84%, purity: 99.82%) was prepared according to the similar synthesis method of step 1 in Example 26, using compound 26-1 as a reactant. MS (ESI): m/z = 412 [M+H] + . 1 H NMR (400MHz, CDCl 3 -d) δ7.99(s, 1H), 7.71(d, J=6.9Hz, 1H), 7.50–7.61(m, 1H), 7.44(d, J=3.8Hz, 3H), 7.30(d, J=8.9Hz, 1H), 7.22(d, J=2.9Hz, 1H), 7.00(d, J=8.4Hz, 1H), 6.79(d, J=2.6Hz, 1H) ,6.12(s,1H),4.07–4.23(m,1H),3.94(d,J=10.1Hz,2H),3.40(t,J=11.4Hz,2H),1.40–1.77(m,4H).
实施例29
Example 29
步骤1：向化合物26-1(150mg，0.44mmol)的1，4-二氧六环/水(4mL/0.8mL)溶液中依次加入化合物29-1(203mg，0.66mmol)，Pd(dppf)Cl2(36mg,0.044mmol)和碳酸钠(93mg,0.8mmol)。将反应混合物在氮气氛围中及105℃下反应16小时，加入饱和氯化铵溶液(4mL)淬灭，并用EA(40mL)萃取。将合并所得的有机相用饱和食盐水洗涤，干燥，并浓缩得到残余物。将所得残余物依次经硅胶柱层析(洗脱液梯度从PE:EA＝1/1过渡至纯EA)和制备高效液相色谱(HPLC)纯化，得到化合物29(60.5mg,0.14mmol,纯度96.26％)。MS(ESI)：m/z＝441[M+H]+。1H NMR(CHLOROFORM-d)δ:7.90(s,1H),7.63(d,J＝7.6Hz,1H),7.45(t,J＝7.4Hz,1H),7.33(q,J＝8.0Hz,2H),7.24(d,J＝8.6Hz,1H),7.20(s,1H),7.12(d,J＝3.1Hz,1H),6.98(d,J＝8.6Hz,1H),6.68(d,J＝3.1Hz,1H),6.35(s,1H),3.98(br s,2H),3.49-3.61(m,4H),2.50(br d,J＝17.8 Hz,2H),2.23-2.38(m,4H)。Step 1: To a solution of compound 26-1 (150 mg, 0.44 mmol) in 1,4-dioxane/water (4 mL/0.8 mL) was sequentially added compound 29-1 (203 mg, 0.66 mmol), Pd(dppf) Cl2 (36mg, 0.044mmol) and sodium carbonate (93mg, 0.8mmol). The reaction mixture was reacted under nitrogen atmosphere at 105°C for 16 hours, quenched by adding saturated ammonium chloride solution (4 mL), and extracted with EA (40 mL). The combined organic phases were washed with saturated brine, dried, and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=1/1 to pure EA) and preparative high performance liquid chromatography (HPLC) to obtain compound 29 (60.5mg, 0.14mmol, purity 96.26%). MS (ESI): m/z = 441 [M+H] + . 1 H NMR (CHLOROFORM-d) δ: 7.90(s, 1H), 7.63(d, J=7.6Hz, 1H), 7.45(t, J=7.4Hz, 1H), 7.33(q, J=8.0Hz, 2H), 7.24(d, J=8.6Hz, 1H), 7.20(s, 1H), 7.12(d, J=3.1Hz, 1H), 6.98(d, J=8.6Hz, 1H), 6.68(d, J=3.1Hz,1H),6.35(s,1H),3.98(br s,2H),3.49-3.61(m,4H),2.50(br d,J=17.8 Hz, 2H), 2.23-2.38 (m, 4H).
实施例30
Example 30
按照实施例26中步骤1的类似合成方法，以化合物26-1和化合物30-1作为反应物制备得到化合物30(21mg，0.05mmol，产率16.67％，纯度99.55％)。MS(ESI)：m/z＝399[M+H]+。1H NMR(CHLOROFORM-d)δ:7.89(s,1H),7.57(d,J＝7.3Hz,1H),7.47(td,J＝7.5,1.4Hz,1H),7.38(td,J＝7.5,1.3Hz,1H),7.32-7.35(m,1H),7.20-7.23(m,1H),7.15(d,J＝8.7Hz,1H),7.01(s,1H),6.85(d,J＝8.6Hz,1H),6.70-6.74(m,2H),4.22-4.39(m,2H),3.24(br s,2H),2.41(s,6H)。Compound 30 (21 mg, 0.05 mmol, yield 16.67%, purity 99.55%) was prepared according to the similar synthesis method in step 1 in Example 26, using compound 26-1 and compound 30-1 as reactants. MS (ESI): m/z = 399 [M+H] + . 1 H NMR (CHLOROFORM-d) δ: 7.89(s, 1H), 7.57(d, J=7.3Hz, 1H), 7.47(td, J=7.5, 1.4Hz, 1H), 7.38(td, J=7.5 ,1.3Hz,1H),7.32-7.35(m,1H),7.20-7.23(m,1H),7.15(d,J＝8.7Hz,1H),7.01(s,1H),6.85(d,J＝ 8.6Hz, 1H), 6.70-6.74(m, 2H), 4.22-4.39(m, 2H), 3.24(br s, 2H), 2.41(s, 6H).
实施例31
Example 31
步骤1：向化合物26-1(150mg，0.44mmol)的1，4-二氧六环/水(4mL/0.8mL)溶液中依次加入化合物31-1(166mg，0.66mmol)，Pd(dppf)Cl2(36mg,0.044mmol)和碳酸钠(93mg,0.8mmol)。将反应混合物在N2氛围中及105℃下搅拌16小时，冷却至室温后，加入饱和氯化铵溶液(4mL)淬灭，并用EA(40mL)萃取。将合并所得的有机相用饱和食盐水洗涤，干燥并浓缩得到残余物。将所得残余物依次经硅胶柱层析(洗脱液梯度从PE:EA＝5/1过渡至1/1)和制备高效液相色谱(HPLC)纯化，得到化合物31(114.2mg,0.30mmol,纯度：99.39％)。MS(ESI)：m/z＝386[M+H]+。1H NMR(CHLOROFORM-d)δ:7.90(s,1H),7.61-7.66(m,1H),7.44(td,J＝7.3,2.1Hz,1H),7.23-7.34(m,3H),7.19(d,J＝1.8Hz,1H),7.11(d,J＝3.3Hz,1H),6.99(d,J＝8.6Hz,1H),6.68(d,J＝3.1Hz,1H),6.36(s,1H),3.94(br t,J＝4.7Hz,2H),3.37(br s,2H),3.05(s,3H)。Step 1: To a solution of compound 26-1 (150 mg, 0.44 mmol) in 1,4-dioxane/water (4 mL/0.8 mL) was sequentially added compound 31-1 (166 mg, 0.66 mmol), Pd(dppf) Cl2 (36mg, 0.044mmol) and sodium carbonate (93mg, 0.8mmol). The reaction mixture was stirred under N 2 atmosphere at 105 °C for 16 h, cooled to room temperature, quenched by adding saturated ammonium chloride solution (4 mL), and extracted with EA (40 mL). The combined organic phases were washed with saturated brine, dried and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=5/1 to 1/1) and preparative high performance liquid chromatography (HPLC) to obtain compound 31 (114.2mg, 0.30mmol, Purity: 99.39%). MS (ESI): m/z = 386 [M+H] + . 1 H NMR (CHLOROFORM-d) δ: 7.90 (s, 1H), 7.61-7.66 (m, 1H), 7.44 (td, J=7.3, 2.1Hz, 1H), 7.23-7.34 (m, 3H), 7.19 (d, J=1.8Hz, 1H), 7.11(d, J=3.3Hz, 1H), 6.99(d, J=8.6Hz, 1H), 6.68(d, J=3.1Hz, 1H), 6.36(s , 1H), 3.94 (br t, J=4.7Hz, 2H), 3.37 (br s, 2H), 3.05 (s, 3H).
实施例39
Example 39
步骤1：将DMSO(10mL)、5-三氟甲基吲哚(1.50g,8.10mmol)、3-氟苯甲氰(0.98g,8.10mmol)和Cs2CO3(5.28g,16.20mmol)的混合物用N2吹扫并维持N2氛围，将反应混合物在90℃下搅拌4小时，加H2O(30mL)稀释，并用EA(50mL)萃取。将合并后得到的有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将所得残余物通过硅胶柱层析(PE:EA＝2/1)纯化，得到化合物39-1(1.88g，6.57mmol，产率：81.06％)。MS(ESI)：m/z＝287[M+H]+。Step 1: Mix DMSO (10 mL), 5-trifluoromethylindole (1.50 g, 8.10 mmol), 3-fluorobenzocyanide (0.98 g, 8.10 mmol) and Cs 2 CO 3 (5.28 g, 16.20 mmol) The mixture was purged with N 2 and maintained under N 2 atmosphere, the reaction mixture was stirred at 90° C. for 4 h, diluted with H 2 O (30 mL), and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (PE:EA=2/1) to obtain compound 39-1 (1.88 g, 6.57 mmol, yield: 81.06%). MS (ESI): m/z = 287 [M+H] + .
步骤2：向100mL烧瓶中依次加入MeOH(50mL)、化合物39-1(1.00g,3.49mmol)、NH2OH·HCl(2.43g,34.93mmol)、TEA(29mL)和分子筛(1.00g)。将反应混合物用N2吹扫并维持N2氛围，在80℃下搅 拌4小时，抽滤后将滤液浓缩。向所得浓缩物中加入H2O(20mL)，并用EA(30mL)萃取。将合并得到的有机相用无水Na2SO4干燥后浓缩得到化合物39-2(MS(ESI)：m/z＝320[M+H]+)的粗产物(1.23g)。Step 2: Add MeOH (50mL), compound 39-1 (1.00g, 3.49mmol), NH 2 OH·HCl (2.43g, 34.93mmol), TEA (29mL) and Molecular sieves (1.00 g). The reaction mixture was purged with N2 and maintained at N2 atmosphere, stirred at 80 °C After stirring for 4 hours, the filtrate was concentrated after suction filtration. To the resulting concentrate was added H2O (20 mL), and extracted with EA (30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated to obtain a crude product (1.23 g) of compound 39-2 (MS (ESI): m/z=320 [M+H] + ).
步骤3：在冰浴条件下，向化合物39-2的粗产物(500.0mg)的THF(10mL)溶液中加入CDI(380.9mg,2.35mmol)，在室温下搅拌30分钟后，再次在冰浴条件下，滴入DBU(357.6mg,2.35mmol)。将反应混合物在冰浴条件下搅拌1h，加入H2O(20mL)，并用EA(30mL)萃取。将合并得到的有机相浓缩得到残余物，并将所得残余物经制备高效液相色谱(HPLC)纯化，得到化合物39(360mg,1.04mmol,产率：66.58％)。MS(ESI)：m/z＝346[M+H]+。1HNMR(400MHz,DMSO-d6)δ6.94(d,J＝3.25Hz,1H)7.53(dd,J＝8.75,1.63Hz,1H)7.82(t,J＝7.94Hz,2H)7.87–7.94(m,3H)8.03(t,J＝1.75Hz,1H)8.11(s,1H)13.09(br s,1H)。Step 3: Add CDI (380.9 mg, 2.35 mmol) to the crude product of compound 39-2 (500.0 mg) in THF (10 mL) under ice-bath conditions, stir at room temperature for 30 minutes, and again in the ice-bath Under conditions, DBU (357.6 mg, 2.35 mmol) was added dropwise. The reaction mixture was stirred under ice bath for 1 h, H 2 O (20 mL) was added, and extracted with EA (30 mL). The combined organic phases were concentrated to obtain a residue, and the obtained residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 39 (360 mg, 1.04 mmol, yield: 66.58%). MS (ESI): m/z = 346 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ6.94 (d, J = 3.25Hz, 1H) 7.53 (dd, J = 8.75, 1.63Hz, 1H) 7.82 (t, J = 7.94Hz, 2H) 7.87–7.94 (m,3H)8.03(t,J=1.75Hz,1H)8.11(s,1H)13.09(br s,1H).
实施例40
Example 40
步骤1：向化合物4-氟-氰基苯(1.0g，8.26mmol)的DMSO(21mL)溶液中加入5-三氟甲基吲哚(1.5g，8.26mmol)和碳酸铯(5.4g,16.52mmol)。将反应混合物在氮气氛围中及在120℃下搅拌2.5小时，冷却至25℃，加入饱和氯化铵溶液(20mL)淬灭，并用EA(100mL)萃取。将合并得到的有机相用饱和食盐水洗涤(3次)，干燥，并浓缩得到残余物。将所得残余物经硅胶柱层析(洗脱液梯度从PE：EA＝20/1过渡至5/1)纯化，得到化合物40-1(1.09g,3.84mmol)。Step 1: To a solution of compound 4-fluoro-cyanobenzene (1.0 g, 8.26 mmol) in DMSO (21 mL) was added 5-trifluoromethylindole (1.5 g, 8.26 mmol) and cesium carbonate (5.4 g, 16.52 mmol). The reaction mixture was stirred at 120 °C under nitrogen atmosphere for 2.5 h, cooled to 25 °C, quenched by adding saturated ammonium chloride solution (20 mL), and extracted with EA (100 mL). The combined organic phases were washed with saturated brine (3 times), dried, and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=20/1 to 5/1) to obtain compound 40-1 (1.09 g, 3.84 mmol).
步骤2：向化合物40-1(200mg，0.70mmol)的甲醇(10mL)溶液中依次加入盐酸羟胺(490mg，7.0mmol),分子筛(200mg)和三乙胺(5.4mL,47mmol)。将反应混合物在75℃下搅拌3小时，冷却至25℃后，过滤。向所得滤液中加入饱和氯化铵溶液(15mL)以淬灭反应，并用EA(100mL)萃取。将合并所得的有机相用饱和食盐水洗涤(3次)，干燥后浓缩得到残余物。将所得残余物经硅胶柱层析(洗脱液梯度从PE：EA＝5/1过渡至1/1)纯化，得到化合物40-2(181mg，0.57mmol)。MS(ESI)：m/z＝320[M+H]+。Step 2: Add hydroxylamine hydrochloride (490 mg, 7.0 mmol) successively to compound 40-1 (200 mg, 0.70 mmol) in methanol (10 mL), Molecular sieves (200 mg) and triethylamine (5.4 mL, 47 mmol). The reaction mixture was stirred at 75°C for 3 hours, cooled to 25°C, and filtered. To the resulting filtrate was added saturated ammonium chloride solution (15 mL) to quench the reaction, and extracted with EA (100 mL). The combined organic phases were washed with saturated brine (3 times), dried and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=5/1 to 1/1) to obtain compound 40-2 (181 mg, 0.57 mmol). MS (ESI): m/z = 320 [M+H] + .
步骤3：将CDI(57mg,0.35mmol)在0℃下加入到化合物40-2(90mg,0.28mmol)的THF(2mL)溶液中,升温至室温，在室温下搅拌30分钟后冷却至0℃，在0℃下加入DBU(63μL，0.42mmol),再次升温至室温，并在室温下搅拌1小时后浓缩。将饱和氯化铵溶液(2mL)加入到浓缩物中以淬灭反应，并用EA(20mL)萃取。将合并所得的有机相用饱和食盐水洗涤(3次)，干燥后浓缩以得到残余物。将所得残余物经硅胶柱层析(洗脱液梯度从PE：EA＝5/1过渡至1/1)和制备高效液相色谱(HPLC)纯化，得到化合物40(72mg,0.21mmol,纯度99.3％)。MS(ESI)：m/z＝344[M-H]-。1H NMR(DMSO-d6)δ:8.10(s,1H),8.02(d,J＝7.9Hz,2H),7.95(d,J＝3.3Hz,1H),7.88(d,J＝8.8Hz,2H),7.82(d,J＝8.8Hz,1H),7.52(d,J＝8.2Hz,1H),6.94(d,J＝3.3Hz,1H))。Step 3: Add CDI (57mg, 0.35mmol) to a solution of compound 40-2 (90mg, 0.28mmol) in THF (2mL) at 0°C, warm to room temperature, stir at room temperature for 30 minutes and then cool to 0°C , DBU (63 μL, 0.42 mmol) was added at 0° C., warmed to room temperature again, stirred at room temperature for 1 hour and then concentrated. Saturated ammonium chloride solution (2 mL) was added to the concentrate to quench the reaction, and extracted with EA (20 mL). The combined organic phases were washed with saturated brine (3 times), dried and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=5/1 to 1/1) and preparative high-performance liquid chromatography (HPLC) to obtain compound 40 (72mg, 0.21mmol, purity 99.3 %). MS (ESI): m/z = 344 [MH] - . 1 H NMR (DMSO-d 6 )δ: 8.10(s, 1H), 8.02(d, J=7.9Hz, 2H), 7.95(d, J=3.3Hz, 1H), 7.88(d, J=8.8Hz , 2H), 7.82 (d, J=8.8Hz, 1H), 7.52 (d, J=8.2Hz, 1H), 6.94 (d, J=3.3Hz, 1H)).
实施例41
Example 41
步骤1：在室温下，依次将2-氟苯腈(0.27mL,2.48mmol)、5-三氟甲氧基吲哚(498.27mg,2.48mmol)和碳酸铯(1614.17mg,4.95mmol)溶于DMSO(10mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至120℃后搅拌1小时，加水稀释，并用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩。将所得残余物用硅胶柱层析(用乙酸乙酯：石油醚＝1：5洗脱)纯化，得到化合物41-1(675mg，产率：90.15％)。MS(ESI)：m/z＝303[M+H]+。Step 1: Dissolve 2-fluorobenzonitrile (0.27mL, 2.48mmol), 5-trifluoromethoxyindole (498.27mg, 2.48mmol) and cesium carbonate (1614.17mg, 4.95mmol) in succession at room temperature in DMSO (10 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 120° C., stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 41-1 (675 mg, yield: 90.15%). MS (ESI): m/z = 303 [M+H] + .
步骤2：在室温下，依次将盐酸羟胺(1551.83mg,22.33mmol)、分子筛(675mg,2.23mmol)和TEA(18.57mL,133.99mmol)加入到化合物41-1(675mg,2.23mmol)的甲醇(30mL)溶液中。将反应混合物用 N2吹扫并维持N2氛围，缓慢升温至75℃并搅拌过夜，加入氯化铵饱和溶液淬灭，并用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩。将所得残余物用硅胶柱层析(用石油醚：乙酸乙酯＝1：1洗脱)纯化，得到化合物41-2(644mg，产率：86.01％)。MS(ESI)：m/z＝336[M+H]+。Step 2: At room temperature, successively add hydroxylamine hydrochloride (1551.83mg, 22.33mmol), Molecular sieves (675 mg, 2.23 mmol) and TEA (18.57 mL, 133.99 mmol) were added to a solution of compound 41-1 (675 mg, 2.23 mmol) in methanol (30 mL). The reaction mixture was used N 2 purged and maintained N 2 atmosphere, slowly warmed up to 75 °C and stirred overnight, quenched by adding saturated ammonium chloride solution, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=1:1) to obtain compound 41-2 (644 mg, yield: 86.01%). MS (ESI): m/z = 336 [M+H] + .
步骤3：在0℃下，将N,N’-羰基二咪唑(199.49mg,1.23mmol)加入到化合物41-2(330mg,0.98mmol)的四氢呋喃(5mL)溶液中。将反应混合物升温至室温，在室温下搅拌30分钟后，冷却至0℃，加入DBU(0.22mL,1.48mmol)，再次升温至室温，在室温下搅拌1小时后，用氯化铵饱和溶液淬灭，并用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩。所得残余物经制备硅胶板(用乙酸乙酯洗脱)纯化，得到化合物41(153mg，产率：43.03％)。MS(ESI)：m/z＝362[M+H]+。1H NMR(DMSO-d6)δ:12.66(br s,1H),7.82-7.92(m,2H),7.68-7.77(m,2H),7.65(s,1H),7.53(d,J＝3.3Hz,1H),7.09-7.21(m,2H),6.76(d,J＝2.8Hz,1H)。Step 3: N,N'-carbonyldiimidazole (199.49 mg, 1.23 mmol) was added to a solution of compound 41-2 (330 mg, 0.98 mmol) in THF (5 mL) at 0°C. The reaction mixture was warmed up to room temperature, stirred at room temperature for 30 minutes, cooled to 0°C, added DBU (0.22mL, 1.48mmol), warmed up to room temperature again, stirred at room temperature for 1 hour, quenched with saturated ammonium chloride solution and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by preparative silica gel plate (eluted with ethyl acetate) to obtain compound 41 (153 mg, yield: 43.03%). MS (ESI): m/z = 362 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.66 (br s, 1H), 7.82-7.92 (m, 2H), 7.68-7.77 (m, 2H), 7.65 (s, 1H), 7.53 (d, J= 3.3Hz, 1H), 7.09-7.21 (m, 2H), 6.76 (d, J = 2.8Hz, 1H).
实施例42
Example 42
步骤1：将5-三氟甲基吲哚(359mg，1.90mmol)和碳酸铯(1.23g，3.8mmol)加入到3-溴-4-氟-N-甲苯磺酰胺(510mg，1.90mmol)的DMSO(14mL)溶液中。将反应混合物在微波条件(130W，120℃)下反应40min后，冷却至25℃，用饱和氯化铵溶液淬灭，并用EA(100mL)萃取。将合并得到的有机相用饱和食盐水洗涤(3次)，干燥后浓缩。将所得残余物经硅胶柱层析(洗脱液梯度从PE:EA＝10:1过渡至2:1)纯化，得到化合物42-1(594mg，1.37mmol)。MS(ESI)：m/z＝433[M+H]+。Step 1: Add 5-trifluoromethylindole (359mg, 1.90mmol) and cesium carbonate (1.23g, 3.8mmol) to 3-bromo-4-fluoro-N-toluenesulfonamide (510mg, 1.90mmol) DMSO (14mL) solution. The reaction mixture was reacted under microwave conditions (130W, 120°C) for 40min, cooled to 25°C, quenched with saturated ammonium chloride solution, and extracted with EA (100mL). The combined organic phases were washed with saturated brine (3 times), dried and concentrated. The obtained residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=10:1 to 2:1) to obtain compound 42-1 (594 mg, 1.37 mmol). MS (ESI): m/z = 433 [M+H] + .
步骤2：向化合物42-1(494mg，1.14mmol)的1.4-二氧六环/水(10mL/2ml)溶液中依次加入1-甲基-4-(4，4，5，5-四甲基-1，3，2-二氧苯甲醛-2-基)-1H咪唑(474mg，2.28mmol)，Pd(dppf)Cl2·CH2Cl2(114mg，0.14mmol)，碳酸钠(242mg，2.28mmol)。将反应混合物用N2吹扫并维持N2氛围，在80℃下搅拌7小时，用饱和氯化铵溶液(10mL)淬灭，并用EA(60mL)萃取。将合并所得的有机相用饱和食盐水洗涤(2次)，干燥后浓缩。将所得残余物经硅胶柱层析(洗脱液梯度从PE:EA＝5:1过渡至1:1)和制备高效液相色谱(HPLC)纯化，得到化合物42(53mg，0.12mmol，纯度98.50％)。MS(ESI)：m/z＝435[M+H]+。1HNMR(CHLOROFORM-d)δ:8.82(d,J＝1.8Hz,1H),8.02(s,1H),7.89(dd,J＝8.1,2.0Hz,1H),7.47(d,J＝7.9Hz,1H),7.36-7.40(m,2H),7.20(d,J＝3.1Hz,1H),7.10(d,J＝8.5Hz,1H),6.84(d,J＝2.7Hz,1H),5.38(s,1H),4.69(br d,J＝5.2Hz,1H),3.40(s,3H),2.80(d,J＝5.2Hz,3H)。Step 2: To compound 42-1 (494mg, 1.14mmol) in 1.4-dioxane/water (10mL/2ml) solution, add 1-methyl-4-(4,4,5,5-tetramethyl 1,3,2-Dioxybenzaldehyde-2-yl)-1H imidazole (474mg, 2.28mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (114mg, 0.14mmol), sodium carbonate (242mg, 2.28 mmol). The reaction mixture was purged with N2 and maintained under N2 atmosphere, stirred at 80 °C for 7 h, quenched with saturated ammonium chloride solution (10 mL), and extracted with EA (60 mL). The combined organic phases were washed with saturated brine (twice), dried and concentrated. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=5:1 to 1:1) and preparative high-performance liquid chromatography (HPLC) to obtain compound 42 (53 mg, 0.12 mmol, purity 98.50 %). MS (ESI): m/z = 435 [M+H] + . 1 H NMR (CHLOROFORM-d) δ: 8.82 (d, J = 1.8Hz, 1H), 8.02 (s, 1H), 7.89 (dd, J = 8.1, 2.0Hz, 1H), 7.47 (d, J = 7.9Hz ,1H),7.36-7.40(m,2H),7.20(d,J=3.1Hz,1H),7.10(d,J=8.5Hz,1H),6.84(d,J=2.7Hz,1H),5.38 (s, 1H), 4.69 (br d, J = 5.2Hz, 1H), 3.40 (s, 3H), 2.80 (d, J = 5.2Hz, 3H).
实施例43
Example 43
步骤1：在0℃下，将化合物43-1(5.0g，18.28mmol)的四氢呋喃(15mL)溶液加入到甲氨盐酸盐(2.5g，37.03mmol)、碳酸氢钠(4.6g，54.70mmol)和水(15mL)的混合物中。将反应混合物在常温下搅拌3小时后用乙酸乙酯萃取。将合并得到的有机层用无水硫酸钠干燥并浓缩。将所得残余物用石油醚打浆，得到化合物43-2(4.5g，16.78mmol)。MS(ESI)：m/z＝268,270[M+H]+。Step 1: A solution of compound 43-1 (5.0 g, 18.28 mmol) in THF (15 mL) was added to methylammonium hydrochloride (2.5 g, 37.03 mmol), sodium bicarbonate (4.6 g, 54.70 mmol) at 0° C. ) and water (15 mL). The reaction mixture was stirred at room temperature for 3 hours and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The obtained residue was slurried with petroleum ether to obtain compound 43-2 (4.5 g, 16.78 mmol). MS (ESI): m/z = 268,270 [M+H] + .
步骤2：将5-三氟甲基吲哚(898mg,4.85mmol)和Cs2CO3(3.2g,9.70mmol)加入到化合物43-2(1.3g,4.85mmol)的DMSO(15mL)溶液中。将反应混合物在120℃下微波40分钟后，冷却至室温，用H2O稀释，并用EA萃取。将合并所得的有机相干燥后浓缩。将所得残余物经硅胶柱层析纯化，得到化合物43-3(1.4g，3.24mmol)。MS(ESI)：m/z＝433,435[M+H]+。Step 2: Add 5-trifluoromethylindole (898 mg, 4.85 mmol) and Cs 2 CO 3 (3.2 g, 9.70 mmol) to a solution of compound 43-2 (1.3 g, 4.85 mmol) in DMSO (15 mL) . After the reaction mixture was microwaved at 120 °C for 40 min, cooled to room temperature, diluted with H2O , and extracted with EA. The combined organic phases were dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain compound 43-3 (1.4 g, 3.24 mmol). MS (ESI): m/z = 433,435 [M+H] + .
步骤3：向化合物43-3(100mg,0.2315mmol)的DMF(4mL)溶液中加入化合物2-甲基-5-(三丁烷基锡)-2H四唑(174mg,0.4630mmol)、Pd(PPh3)4(27mg,0.0231mmol)和CuI(5mg,0.0231mmol)。将反应混 合物在120℃下搅拌过夜，冷却至室温，加H2O稀释，并用EA萃取。将合并得到的有机相干燥后浓缩。将所得的残余物依次通过硅胶柱层析以及制备高效液相色谱(Prep-HPLC)纯化，得到化合物43(24mg，0.0531mmol)。MS(ESI)：m/z＝437[M+H]+。1H NMR(DMSO-d6)δ:8.50(s,1H),8.14(br d,J＝8.0Hz,1H),8.05(s,1H),7.94(br d,J＝8.3Hz,1H),7.85(br s,1H),7.57(br d,J＝2.5Hz,1H),7.36(br d,J＝8.6Hz,1H),7.20(br d,J＝8.5Hz,1H),6.83(br d,J＝2.3Hz,1H),4.22(s,3H),2.53-2.59(m,3H)。Step 3: Add compound 2-methyl-5-(tributyltin)-2H tetrazole (174 mg, 0.4630 mmol), Pd( PPh 3 ) 4 (27 mg, 0.0231 mmol) and Cul (5 mg, 0.0231 mmol). mix the reaction The mixture was stirred overnight at 120 °C, cooled to room temperature, diluted with H2O , and extracted with EA. The combined organic phases were dried and concentrated. The obtained residue was purified by silica gel column chromatography and preparative high-performance liquid chromatography (Prep-HPLC) successively to obtain compound 43 (24 mg, 0.0531 mmol). MS (ESI): m/z = 437 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.50(s, 1H), 8.14(br d, J=8.0Hz, 1H), 8.05(s, 1H), 7.94(br d, J=8.3Hz, 1H) ,7.85(br s,1H),7.57(br d,J=2.5Hz,1H),7.36(br d,J=8.6Hz,1H),7.20(br d,J=8.5Hz,1H),6.83( br d, J=2.3Hz, 1H), 4.22(s, 3H), 2.53-2.59(m, 3H).
实施例44
Example 44
步骤1：向化合物43-3(600mg,1.38mmol)的DMF(9mL)和MeOH(3mL)的混合溶液中加入Pd(dppf)Cl2·CH2Cl2(120mg,0.15mmol)和三乙胺(1.40g,13.84mmol)。反应混合物在CO氛围下及90℃下搅拌过夜，冷却至室温，加H2O稀释，并用EA萃取。将合并所得的有机相用饱和食盐水洗涤，无水硫酸钠干燥并浓缩。将所得的残余物通过硅胶柱层析纯化，得到化合物44-1(160mg，0.39mmol)。MS(ESI)：m/z＝413[M+H]+。Step 1: To a mixed solution of compound 43-3 (600 mg, 1.38 mmol) in DMF (9 mL) and MeOH (3 mL) was added Pd(dppf)Cl 2 ·CH 2 Cl 2 (120 mg, 0.15 mmol) and triethylamine (1.40 g, 13.84 mmol). The reaction mixture was stirred overnight at 90 °C under CO atmosphere, cooled to room temperature, diluted with H2O , and extracted with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography to obtain compound 44-1 (160 mg, 0.39 mmol). MS (ESI): m/z = 413 [M+H] + .
步骤2：将40％水合肼(1mL,8.23mmol)加入到化合物44-1(100mg,0.39mmol)的MeOH(6mL)溶液中。反应混合物在80℃下搅拌过夜，冷却至室温后浓缩。将所得残余物分散至DCM中后过滤。将所得滤液旋干得到粗产物。将所得粗产物用PE/DCM(10/1)打浆得到化合物44-2(125mg，0.30mmol)。MS(ESI)：m/z＝413[M+H]+。Step 2: 40% hydrazine hydrate (1 mL, 8.23 mmol) was added to a solution of compound 44-1 (100 mg, 0.39 mmol) in MeOH (6 mL). The reaction mixture was stirred overnight at 80 °C, cooled to room temperature and concentrated. The resulting residue was dispersed in DCM and filtered. The resulting filtrate was spin-dried to obtain a crude product. The obtained crude product was slurried with PE/DCM (10/1) to obtain compound 44-2 (125 mg, 0.30 mmol). MS (ESI): m/z = 413 [M+H] + .
步骤3：将化合物44-2(110mg,0.27mmol)和原甲酸三甲酯(6mg,54.84mmol)的混合物在150℃下搅拌过夜，冷却至室温后，浓缩得到残余物。将残余物依次通过硅胶柱层析及制备高效液相色谱(Prep-HPLC)纯化，得到化合物44(9mg，0.02mmol)。MS(ESI)：m/z＝423[M+H]+。1H NMR(DMSO-d6)δ:9.17(s,1H),8.53(d,J＝2.1Hz,1H),8.19(dd,J＝8.3,2.2Hz,1H),8.08(s,1H),7.97(d,J＝8.4Hz,1H),7.88(br d,J＝4.1Hz,1H),7.70(d,J＝3.3Hz,1H),7.40(dd,J＝8.7,1.6Hz,1H),7.28(d,J＝8.6Hz,1H),6.89(d,J＝3.3Hz,1H),2.56(d,J＝3.5Hz,3H)。Step 3: A mixture of compound 44-2 (110 mg, 0.27 mmol) and trimethyl orthoformate (6 mg, 54.84 mmol) was stirred overnight at 150° C., cooled to room temperature, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography and preparative high-performance liquid chromatography (Prep-HPLC) successively to obtain compound 44 (9 mg, 0.02 mmol). MS (ESI): m/z = 423 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 9.17(s, 1H), 8.53(d, J=2.1Hz, 1H), 8.19(dd, J=8.3, 2.2Hz, 1H), 8.08(s, 1H) ,7.97(d,J=8.4Hz,1H),7.88(br d,J=4.1Hz,1H),7.70(d,J=3.3Hz,1H),7.40(dd,J=8.7,1.6Hz,1H ), 7.28 (d, J=8.6Hz, 1H), 6.89 (d, J=3.3Hz, 1H), 2.56 (d, J=3.5Hz, 3H).
实施例45
Example 45
将化合物2-(三丁烷基锡)噁唑(267mg,0.69mmol)、Pd(PPh3)4(54mg,0.05mmol)和CuI(9mg,0.05mmol)加入到化合物43-3(200mg,0.46mmol)的DMF(5mL)溶液中。反应混合物在120℃下搅拌过夜，冷却至室温，用氟化钾溶液(2M)稀释，并用EA萃取。将合并得到的有机相用饱和食盐水洗涤(3×5ml)，用无水硫酸钠干燥并浓缩。将所得残余物依次通过硅胶柱层析及制备高效液相色谱(Prep-HPLC)纯化，得到化合物45(70mg，0.17mmol)。MS(ESI)：m/z＝422[M+H]+。Compound 2-(tributyltin)oxazole (267mg, 0.69mmol), Pd(PPh 3 ) 4 (54mg, 0.05mmol) and CuI (9mg, 0.05mmol) were added to compound 43-3 (200mg, 0.46 mmol) in DMF (5 mL). The reaction mixture was stirred overnight at 120 °C, cooled to room temperature, diluted with potassium fluoride solution (2M), and extracted with EA. The combined organic phases were washed with saturated brine (3×5 ml), dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography and preparative high-performance liquid chromatography (Prep-HPLC) successively to obtain compound 45 (70 mg, 0.17 mmol). MS (ESI): m/z = 422 [M+H] + .
1H NMR(DMSO-d6)δ:8.51(d,J＝2.1Hz,1H),8.08(dd,J＝8.4,2.1Hz,1H),8.06(s,1H),7.99(s,1H),7.87(d,J＝8.3Hz,1H),7.82(q,J＝4.9Hz,1H),7.68(d,J＝3.4Hz,1H),7.36(d,J＝8.8Hz,1H),7.26(s,1H),7.21(d,J＝8.6Hz,1H),6.87(d,J＝3.4Hz,1H),2.55(d,J＝4.9Hz,3H). 1 H NMR (DMSO-d 6 )δ: 8.51(d, J=2.1Hz, 1H), 8.08(dd, J=8.4, 2.1Hz, 1H), 8.06(s, 1H), 7.99(s, 1H) ,7.87(d,J=8.3Hz,1H),7.82(q,J=4.9Hz,1H),7.68(d,J=3.4Hz,1H),7.36(d,J=8.8Hz,1H),7.26 (s,1H),7.21(d,J=8.6Hz,1H),6.87(d,J=3.4Hz,1H),2.55(d,J=4.9Hz,3H).
实施例46
Example 46
步骤1：将化合物46-1(180mg,0.9259mmol)、Pd(dppf)Cl2·CH2Cl2(40mg,0.0463mmol)和Na2CO3(100mg,0.9259mmol)加入到化合物43-3(200mg,0.4630mmol)的DMSO(5mL)和H2O(1mL)的溶液中。将反应混合物在100℃下搅拌过夜，用H2O稀释，并用EA萃取。将合并所得的有机相干燥后浓缩，得到残余物。将所得残余物通过硅胶柱层析纯化，得到化合物46(40mg，0.0952mmol)。MS(ESI)：m/z＝421[M+H]+。1H NMR(DMSO-d6)δ:12.87(br s,1H),8.17(d,J＝1.9Hz,1H),8.09(s,1H),7.81(dd,J＝8.2,1.9Hz,1H),7.71(d,J＝8.1Hz,1H),7.66(br d,J＝5.0Hz,1H),7.65(d,J＝3.3Hz,1H),7.35(d,J＝8.8Hz,1H),7.19(br s,1H),7.09(d,J＝8.5Hz,1H),6.92(d,J＝3.1Hz,1H),6.89(br s,1H),2.55(d,J＝4.9Hz,3H)。Step 1: Compound 46-1 (180 mg, 0.9259 mmol), Pd(dppf)Cl 2 · CH 2 Cl 2 (40 mg, 0.0463 mmol) and Na 2 CO 3 (100 mg, 0.9259 mmol) were added to compound 43-3 ( 200mg, 0.4630mmol) in a solution of DMSO (5mL) and H 2 O (1mL). The reaction mixture was stirred overnight at 100 °C, diluted with H2O , and extracted with EA. The combined organic phases were dried and concentrated to give a residue. The obtained residue was purified by silica gel column chromatography to obtain compound 46 (40 mg, 0.0952 mmol). MS (ESI): m/z = 421 [M+H] + . 1 H NMR (DMSO-d6)δ:12.87(br s,1H),8.17(d,J=1.9Hz,1H),8.09(s,1H),7.81(dd,J=8.2,1.9Hz,1H) ,7.71(d,J=8.1Hz,1H),7.66(br d,J=5.0Hz,1H),7.65(d,J=3.3Hz,1H),7.35(d,J=8.8Hz,1H), 7.19(br s,1H),7.09(d,J=8.5Hz,1H),6.92(d,J=3.1Hz,1H),6.89(br s,1H),2.55(d,J=4.9Hz,3H ).
实施例47
Example 47
步骤1：在室温下，将2-氯-3-氟吡啶(0.76mL,7.60mmol)、5-(三氟甲基)吲哚(1.41g,7.60mmol)和碳酸铯(4.95g,15.21mmol)分散于N,N-二甲基甲酰胺(12mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至120℃搅拌1小时后，加水将反应液稀释，并用乙酸乙酯(100mL×3)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将残余物用硅胶柱层析(乙酸乙酯：石油醚＝1：5)纯化，得到化合物47-3(2.0781g)。MS(ESI)：m/z＝297[M+H]+。Step 1: Mix 2-chloro-3-fluoropyridine (0.76mL, 7.60mmol), 5-(trifluoromethyl)indole (1.41g, 7.60mmol) and cesium carbonate (4.95g, 15.21mmol) at room temperature ) was dispersed in N,N-dimethylformamide (12 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed up to 120°C and stirred for 1 hour, then diluted with water and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:5) to obtain compound 47-3 (2.0781 g). MS (ESI): m/z = 297 [M+H] + .
步骤2：在干燥的50mL单口瓶中，在0℃下将甲氨盐酸盐(6.34g,93.93mmol)溶于H2O(20mL)再加入用水(30ml)溶好的碳酸氢钠(10.52g,125.24mmol)(aq)，最后将3-溴苯磺酰氯(4.52mL,31.31mmol)溶于四氢呋喃(60mL)加入到反应体系中，置换N2。反应体系缓慢升至室温搅拌2小时。反应完成后用乙酸乙酯(150mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，残余物用硅胶柱层析(乙酸乙酯：石油醚＝1：5)纯化，得到中间体化合物47-1(7.7681g)。MS(ESI)：m/z＝250、252[M+H]+。Step 2: In a dry 50mL single-necked bottle, dissolve methylamine hydrochloride (6.34g, 93.93mmol) in H 2 O (20mL) at 0°C and add sodium bicarbonate (10.52 g, 125.24mmol) (aq), and finally 3-bromobenzenesulfonyl chloride (4.52mL, 31.31mmol) dissolved in tetrahydrofuran (60mL) was added to the reaction system to replace N 2 . The reaction system was slowly raised to room temperature and stirred for 2 hours. After the reaction was completed, it was extracted with ethyl acetate (150mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:5). Intermediate compound 47-1 (7.7681 g) was obtained. MS (ESI): m/z = 250, 252 [M+H] + .
步骤3：在干燥的50mL单口瓶中，在室温下依次将化合物47-1(1.1g,4.40mmol)、联硼酸频那醇酯(1.12g,4.40mmol)，醋酸钾(1.08g,11.00mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.36g,0.44mmol)溶于二甲基亚砜(13mL)中，置换氮气，反应体系缓慢升温至80℃搅拌6小时。反应完成后用水稀释，再用乙酸乙酯(150mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，残余物用硅胶柱层析(石油醚：乙酸乙酯＝2：1)纯化，得到中间体化合物47-2(1.36g)。Step 3: In a dry 50mL single-necked bottle, compound 47-1 (1.1g, 4.40mmol), pinacol diborate (1.12g, 4.40mmol), potassium acetate (1.08g, 11.00mmol) were sequentially mixed at room temperature ) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.36g, 0.44mmol) were dissolved in dimethyl sulfoxide (13mL) and replaced with nitrogen , the reaction system was slowly warmed up to 80°C and stirred for 6 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate (150mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) Purification to obtain intermediate compound 47-2 (1.36 g).
1H NMR(DMSO-d6)δ:8.07(s,1H),7.63(t,J＝7.6Hz,1H),7.49(q,J＝5.0Hz,1H),3.93(s,1H),2.39(d,J＝5.0Hz,3H),1.32(s,12H) 1 H NMR (DMSO-d 6 )δ: 8.07(s, 1H), 7.63(t, J=7.6Hz, 1H), 7.49(q, J=5.0Hz, 1H), 3.93(s, 1H), 2.39 (d,J=5.0Hz,3H),1.32(s,12H)
步骤4：在室温下，将化合物47-3(100mg,0.34mmol)、化合物47-2(100.17mg,0.34mmol)、碳酸钠(392.16mg,3.70mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(392.16mg,3.70mmol)分散于1，4二氧六环(5mL)/水(1mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至105℃搅拌过夜后，用水稀释， 用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用制备硅胶板(乙酸乙酯：石油醚＝1：1)纯化，得到化合物47(64mg，产率：8.02％，纯度96.04％)。MS m/z(ESI):432[M+H]+.1HNMR(DMSO-d6)δ:8.90(dd,J＝4.8,1.5Hz,1H),8.11(dd,J＝8.0,1.5Hz,1H),7.98(s,1H),7.72(dd,J＝8.0,4.8Hz,1H),7.69(t,J＝1.6Hz,1H),7.68(d,J＝3.3Hz,1H),7.60(dt,J＝7.9,1.3Hz,1H),7.40(d,J＝15.5Hz,1H),7.32(dt,J＝7.8,1.4Hz,1H),7.26-7.31(m,2H),7.12(d,J＝8.6Hz,1H),6.83(d,J＝3.3Hz,1H),2.03(d,J＝5.1Hz,3H).Step 4: At room temperature, compound 47-3 (100mg, 0.34mmol), compound 47-2 (100.17mg, 0.34mmol), sodium carbonate (392.16mg, 3.70mmol) and [1,1'-bis(di Phenylphosphino)ferrocene]palladium dichloride (392.16 mg, 3.70 mmol) was dispersed in 1,4-dioxane (5 mL)/water (1 mL). The reaction mixture was purged with N2 and maintained at N2 atmosphere, slowly warmed up to 105°C and stirred overnight, then diluted with water, Extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified on a preparative silica gel plate (ethyl acetate:petroleum ether=1:1) to obtain compound 47 (64 mg, yield: 8.02%, purity 96.04%). MS m/z (ESI): 432[M+H] + . 1 H NMR (DMSO-d 6 ) δ: 8.90 (dd, J = 4.8, 1.5 Hz, 1H), 8.11 (dd, J = 8.0, 1.5 Hz ,1H),7.98(s,1H),7.72(dd,J=8.0,4.8Hz,1H),7.69(t,J=1.6Hz,1H),7.68(d,J=3.3Hz,1H),7.60 (dt, J=7.9,1.3Hz,1H),7.40(d,J=15.5Hz,1H),7.32(dt,J=7.8,1.4Hz,1H),7.26-7.31(m,2H),7.12( d,J=8.6Hz,1H),6.83(d,J=3.3Hz,1H),2.03(d,J=5.1Hz,3H).
实施例50
Example 50
步骤1：在0℃下，向3,5-二氯吡啶-2-甲腈(1.0g，5.75mmol)的甲醇溶液(25mL)中加入甲醇钠(117.19mg，2.17mmol)。将反应混合物在室温下搅拌反应12小时后浓缩，并向所得浓缩物中加水(15mL)，用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，并将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡到8:1)纯化，得到化合物50-1(856mg)。MS(ESI)：m/z＝169[M+H]+。Step 1: To a solution of 3,5-dichloropyridine-2-carbonitrile (1.0 g, 5.75 mmol) in methanol (25 mL) was added sodium methoxide (117.19 mg, 2.17 mmol) at 0°C. The reaction mixture was stirred at room temperature for 12 hours, concentrated, and water (15 mL) was added to the obtained concentrate, followed by extraction with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=20:1 to 8:1) , Compound 50-1 (856 mg) was obtained. MS (ESI): m/z = 169 [M+H] + .
步骤2：按照实施例2中步骤1的类似合成方法，以化合物50-1和5-(三氟甲基)-1H-吲哚作为反应物制备得到化合物50-2。LCMS：m/z＝318[M+H]+。Step 2: According to the similar synthesis method of Step 1 in Example 2, Compound 50-2 was prepared using Compound 50-1 and 5-(trifluoromethyl)-1H-indole as reactants. LCMS: m/z = 318 [M+H] + .
步骤3：按照实施例2中步骤2的类似合成方法，以化合物50-2作为反应物制备得到化合物50-3。LCMS：m/z＝351[M+H]+。Step 3: According to the similar synthesis method of Step 2 in Example 2, Compound 50-3 was prepared using Compound 50-2 as a reactant. LCMS: m/z = 351 [M+H] + .
步骤4：按照实施例2中步骤3的类似合成方法，以化合物50-3作为反应物制备得到化合物50(50mg，0.13mmol，产率：58％，纯度：98.29％)。MS(ESI)：m/z＝377[M+H]+。去1H NMR(DMSO-d6)δ:8.55(d,J＝2.9Hz,1H),8.04(s,1H),7.95(d,J＝2.9Hz,1H),7.59(d,J＝3.3Hz,1H),7.41-7.50(m,2H),6.81(d,J＝3.3Hz,1H),3.99(s,3H),3.35(br s,1H)。Step 4: Compound 50 (50 mg, 0.13 mmol, yield: 58%, purity: 98.29%) was prepared according to the similar synthesis method of step 3 in Example 2, using compound 50-3 as a reactant. MS (ESI): m/z = 377 [M+H] + . De1 H NMR (DMSO-d 6 )δ: 8.55(d, J=2.9Hz, 1H), 8.04(s, 1H), 7.95(d, J=2.9Hz, 1H), 7.59(d, J=3.3 Hz, 1H), 7.41-7.50 (m, 2H), 6.81 (d, J=3.3Hz, 1H), 3.99 (s, 3H), 3.35 (br s, 1H).
实施例51
Example 51
步骤1：在室温下，将化合物51-1(46.42mg,0.38mmol)、吡啶-2-基硼酸(46.42mg,0.38mmol)、四(三苯基膦)钯(29.09mg,0.03mmol)、碳酸氢钠(53.37mg,0.50mmol)分散于二甲基亚砜(5mL)/水(1mL)的混合溶剂中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至105℃后搅拌过夜，加水稀释，随后用乙酸乙酯(50mL×2)萃取。将合并后的有机相用无水硫酸钠干燥后，浓缩得到残余物。将残余物用制备硅胶板(用乙酸乙酯：石油醚＝1：1洗脱)纯化，得到化合物51(10mg，产率：10.05％)。MS(ESI)：m/z＝396[M+H]+。1H NMR(CHLOROFORM-d)δ:8.58(br d,J＝3.6Hz,1H),8.23(s,1H),8.03(br d,J＝6.6Hz,1H),7.84(s,1H),7.53(d,J＝8.3Hz,1H),7.23-7.31(m,2H),7.13(br d,J＝8.4Hz,2H),6.99(d,J＝3.1Hz,1H),6.59(br d,J＝2.9Hz,1H),6.52(br s,1H),6.46(br d,J＝7.6Hz,1H),3.00(d,J＝4.8Hz,3H)。Step 1: Compound 51-1 (46.42mg, 0.38mmol), pyridin-2-ylboronic acid (46.42mg, 0.38mmol), tetrakis(triphenylphosphine) palladium (29.09mg, 0.03mmol), Sodium bicarbonate (53.37 mg, 0.50 mmol) was dispersed in a mixed solvent of dimethyl sulfoxide (5 mL)/water (1 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 105° C., stirred overnight, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified on a preparative silica gel plate (eluted with ethyl acetate:petroleum ether=1:1) to obtain compound 51 (10 mg, yield: 10.05%). MS (ESI): m/z = 396 [M+H] + . 1 H NMR (CHLOROFORM-d) δ: 8.58 (br d, J = 3.6Hz, 1H), 8.23 (s, 1H), 8.03 (br d, J = 6.6Hz, 1H), 7.84 (s, 1H), 7.53(d, J=8.3Hz, 1H), 7.23-7.31(m, 2H), 7.13(br d, J=8.4Hz, 2H), 6.99(d, J=3.1Hz, 1H), 6.59(br d , J=2.9Hz, 1H), 6.52 (br s, 1H), 6.46 (br d, J=7.6Hz, 1H), 3.00 (d, J=4.8Hz, 3H).
实施例52
Example 52
步骤1：在室温下，将3-溴-4-氟苯甲酸甲酯(1.5g,6.44mmol)、5-(三氟甲基)吲哚(1.19g,6.44mmol)和碳酸铯(4.19g,12.87mmol)分散于N,N-二甲基甲酰胺(20mL)中。将反应混合物用N2吹扫并维持氛围N2，缓慢升温至120℃后搅拌1小时，加水稀释，用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用硅胶柱层析(用乙酸乙酯：石油醚＝1：5洗脱)纯化，得到化合物52-1(1.5g，产率：58.53％)。Step 1: Methyl 3-bromo-4-fluorobenzoate (1.5g, 6.44mmol), 5-(trifluoromethyl)indole (1.19g, 6.44mmol) and cesium carbonate (4.19g , 12.87mmol) was dispersed in N,N-dimethylformamide (20mL). The reaction mixture was purged with N 2 and maintained under N 2 , the temperature was slowly raised to 120° C., stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 52-1 (1.5 g, yield: 58.53%).
步骤2：在室温下，将氢氧化锂(0.47g,11.30mmol)加入到化合物52-1(1.5g,3.77mmol)的四氢呋喃(8mL)、水(4mL)、和甲醇(2mL)的溶液中。将反应混合物缓慢升温至60℃，搅拌2小时后浓缩，加水稀释，用稀盐酸(2N)将pH调至4以下，并用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩。将所得残余物用硅胶柱层析(用石油醚：乙酸乙酯＝1：1洗脱)纯化，得到化合物52-2(850mg，产率：58.69％)。Step 2: Lithium hydroxide (0.47 g, 11.30 mmol) was added to a solution of compound 52-1 (1.5 g, 3.77 mmol) in THF (8 mL), water (4 mL), and methanol (2 mL) at room temperature . The reaction mixture was slowly heated to 60°C, stirred for 2 hours, concentrated, diluted with water, adjusted to pH below 4 with dilute hydrochloric acid (2N), and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=1:1) to obtain compound 52-2 (850 mg, yield: 58.69%).
步骤3：在室温下，将N,N-二异丙基乙胺(1.10mL,6.64mmol)加入到化合物52-2(850mg,2.21mmol)、甲氨盐酸盐(224.10mg,3.32mmol)和2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(1262.02mg,3.32mmol)的N,N-二甲基甲酰胺(15mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，在室温下搅拌过夜，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并得到的有机相用无水硫酸钠干燥后浓缩。将所得残余物用制备硅胶板(用乙酸乙酯洗脱)纯化，得到化合物52-3(861mg，产率：97.97％)。MS(ESI)：m/z＝397，399[M+H]+。Step 3: Add N,N-diisopropylethylamine (1.10 mL, 6.64 mmol) to compound 52-2 (850 mg, 2.21 mmol), methylamine hydrochloride (224.10 mg, 3.32 mmol) at room temperature and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1262.02mg, 3.32mmol) in N,N-dimethylformamide (15mL) solution. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified with a preparative silica gel plate (eluted with ethyl acetate) to obtain compound 52-3 (861 mg, yield: 97.97%). MS (ESI): m/z = 397, 399 [M+H] + .
步骤4：在室温下将化合物52-3(200mg,0.50mmol)、1-甲基-4-(三丁基甲锡烷基)-1H-咪唑(279.75mg,0.75mmol)、四(三苯基膦)钯(57.78mg,0.05mmol)和碘化亚铜(10mg,0.05mmol)分散于N,N-二甲基甲酰胺(4mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至120℃搅拌过夜，加入氟化钾溶液(2N)并在室温下搅拌2小时将反应液淬灭后，用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩。将所得残余物用硅胶柱层析(用乙酸乙酯：石油醚＝1:1洗脱)纯化，得到化合物52(97mg，产率：48.35％)。MS(ESI)：m/z＝399[M+H]+。1H NMR(DMSO-d6)δ:8.69(d,J＝1.4Hz,1H),8.66(br d,J＝4.4Hz,1H),8.11(s,1H),7.85(dd,J＝8.1,1.7Hz,1H),7.56-7.61(m,2H),7.46(d,J＝8.1Hz,1H),7.37(br d,J＝8.6Hz,1H),7.06(br d,J＝8.6Hz,1H),6.92(d,J＝2.9Hz,1H),5.50(s,1H),3.35(s,3H),2.84(br d,J＝4.3Hz,3H)。Step 4: Add compound 52-3 (200mg, 0.50mmol), 1-methyl-4-(tributylstannyl)-1H-imidazole (279.75mg, 0.75mmol), tetrakis(triphenylphosphine) at room temperature ) palladium (57.78 mg, 0.05 mmol) and cuprous iodide (10 mg, 0.05 mmol) were dispersed in N,N-dimethylformamide (4 mL). The reaction mixture was purged with N 2 and maintained in N 2 atmosphere, slowly warmed up to 120°C and stirred overnight, and potassium fluoride solution (2N) was added and stirred at room temperature for 2 hours to quench the reaction solution, then ethyl acetate (100 mL ×3) Extraction. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:1) to obtain compound 52 (97 mg, yield: 48.35%). MS (ESI): m/z = 399 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.69(d, J=1.4Hz, 1H), 8.66(br d, J=4.4Hz, 1H), 8.11(s, 1H), 7.85(dd, J=8.1 ,1.7Hz,1H),7.56-7.61(m,2H),7.46(d,J=8.1Hz,1H),7.37(br d,J=8.6Hz,1H),7.06(br d,J=8.6Hz , 1H), 6.92 (d, J = 2.9Hz, 1H), 5.50 (s, 1H), 3.35 (s, 3H), 2.84 (br d, J = 4.3Hz, 3H).
实施例53
Example 53
步骤1：向2-氯烟腈(1.0g，7.22mmol)和叔丁醇钠(0.83g，8.66mmol)的N,N-二甲基甲酰胺溶液(20mL)中加入5-氯-1H-吲哚(1.09g，7.22mmol)，然后反应在120℃下搅拌12个小时。将混合物用水(30mL)进行稀释，然后用乙酸乙酯(90mL)萃取，并用饱和氯化钠溶液洗涤。将合并后的有机层经干燥、过滤和浓缩，得到粗产物。将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡到4:1)纯化得到化合物53-1(1.34g)。MS(ESI)：m/z＝254[M+H]+。Step 1: Add 5-chloro-1H- Indole (1.09 g, 7.22 mmol), and the reaction was stirred at 120°C for 12 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (90 mL), and washed with saturated sodium chloride solution. The combined organic layers were dried, filtered and concentrated to give crude product. The obtained residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=20:1 to 4:1) to obtain compound 53-1 (1.34 g). MS (ESI): m/z = 254 [M+H] + .
步骤2：向化合物53-1(400mg，1.58mmol)、三乙胺(2.19mL，15.77mmol)和分子筛(200mg)的乙醇溶液(25mL)中加入盐酸羟胺(547.83mg，7.88mmol)。混合物在80℃下搅拌并回流12个小时。将混合物进行浓缩，然后加入水(15mL)，用乙酸乙酯(45mL)萃取，并用饱和氯化钠溶液洗涤。将合并后的有机层用无水硫酸钠干燥，过滤浓缩，得到粗产物。将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡到0:1)纯化得到化合物53-2(粗品，422mg)。MS(ESI)：m/z＝287[M+H]+。 Step 2: To compound 53-1 (400mg, 1.58mmol), triethylamine (2.19mL, 15.77mmol) and To a solution (25 mL) of molecular sieves (200 mg) in ethanol was added hydroxylamine hydrochloride (547.83 mg, 7.88 mmol). The mixture was stirred and refluxed at 80°C for 12 hours. The mixture was concentrated, then water (15 mL) was added, extracted with ethyl acetate (45 mL), and washed with saturated sodium chloride solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=20:1 to 0:1) to obtain compound 53-2 (crude product, 422 mg). MS (ESI): m/z = 287 [M+H] + .
步骤3:将化合物53-2(420mg,1.46mmol),N,N'-羰基二咪唑(285mg,1.76mmol)溶于四氢呋喃(10mL)中，在0℃下反应30分钟，然后加入1,8-二氮杂双环[5.4.0]-7-十一碳烯(0.33mL,2.20mmol)在室温下反应30分钟。用水(10mL)淬灭反应，乙酸乙酯(20mL×3)萃取，有机相水洗，干燥浓缩，柱层析纯化得到化合物53(26.54mg，0.08mmol，产率：5.79％，纯度：99.33％)。MS(ESI)：m/z＝313[M+H]+。1H NMR(DMSO-d6)δ:12.76(br s,1H),8.84(dd,J＝4.8,1.8Hz,1H),8.32(dd,J＝7.8,1.9Hz,1H),7.69-7.72(m,2H),7.53-7.57(m,1H),7.49-7.53(m,1H),7.22(dd,J＝8.9,2.1Hz,1H),6.71(d,J＝3.5Hz,1H)。Step 3: Dissolve compound 53-2 (420mg, 1.46mmol), N,N'-carbonyldiimidazole (285mg, 1.76mmol) in tetrahydrofuran (10mL), react at 0°C for 30 minutes, then add 1,8 - Diazabicyclo[5.4.0]-7-undecene (0.33 mL, 2.20 mmol) was reacted at room temperature for 30 minutes. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL×3), the organic phase was washed with water, dried and concentrated, and purified by column chromatography to obtain compound 53 (26.54 mg, 0.08 mmol, yield: 5.79%, purity: 99.33%) . MS (ESI): m/z = 313 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.76 (br s, 1H), 8.84 (dd, J=4.8, 1.8Hz, 1H), 8.32 (dd, J=7.8, 1.9Hz, 1H), 7.69-7.72 (m, 2H), 7.53-7.57 (m, 1H), 7.49-7.53 (m, 1H), 7.22 (dd, J=8.9, 2.1Hz, 1H), 6.71 (d, J=3.5Hz, 1H).
实施例56
Example 56
步骤1：在0℃下，将N-碘代丁二酰亚胺(5.28g,23.45mmol)加入到3-氟-4-(三氟甲基)苯胺(2.8g,15.63mmol)的二氯甲烷(40mL)溶液中。将反应混合物升温到室温并搅拌1小时，加水(30mL)稀释，并用乙酸乙酯(20mL*3)萃取。将合并所得的有机相浓缩。将所得的残余物经快速柱层析(用石油醚/乙酸乙酯＝4/1洗脱)纯化，得到化合物56-1(2.9g，9.51mmol，产率：60.82％)。1H NMR(400MHz,DMSO-d6)δ7.77(d,J＝8.1Hz,1H),6.63(d,J＝13.6Hz,1H),6.24(s,2H)。Step 1: Add N-iodosuccinimide (5.28g, 23.45mmol) to 3-fluoro-4-(trifluoromethyl)aniline (2.8g, 15.63mmol) at 0°C methane (40mL) solution. The reaction mixture was warmed to room temperature and stirred for 1 hour, diluted with water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were concentrated. The resulting residue was purified by flash column chromatography (eluted with petroleum ether/ethyl acetate=4/1) to obtain compound 56-1 (2.9 g, 9.51 mmol, yield: 60.82%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.77 (d, J=8.1 Hz, 1H), 6.63 (d, J=13.6 Hz, 1H), 6.24 (s, 2H).
步骤2：将乙炔基三甲基硅烷(1.62mL,11.41mmol)，三乙胺(1.32mL,9.51mmol)，碘化亚铜(0.09mg,0.68mmol)和双(三苯基膦)氯化钯(0.33g,0,48mml)加入到化合物56-1(2.9g,9.51mmol)的四氢呋喃(15mL)中。将反应混合物用N2吹扫并维持N2氛围，在室温搅拌3小时，用水(30mL)稀释，并用乙酸乙酯(20mL*3)萃取。将合并所得的有机相浓缩得到粗产物。将粗产物经快速柱层析(用石油醚/乙酸乙酯＝4/1洗脱)纯化，得到化合物56-2(2.45g,8.90mmol,产率：93.59％)。1H NMR(400MHz,DMSO-d6)δ7.43(d,J＝8.3,1H),6.64(d,J＝13.5Hz,1H),6.32(s,2H),0.24(s,9H)。Step 2: Ethynyltrimethylsilane (1.62 mL, 11.41 mmol), triethylamine (1.32 mL, 9.51 mmol), cuprous iodide (0.09 mg, 0.68 mmol) and bis(triphenylphosphine) were chlorinated Palladium (0.33 g, 0,48 mml) was added to compound 56-1 (2.9 g, 9.51 mmol) in tetrahydrofuran (15 mL). The reaction mixture was purged with N2 and maintained under N2 atmosphere, stirred at room temperature for 3 hours, diluted with water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were concentrated to give crude product. The crude product was purified by flash column chromatography (eluted with petroleum ether/ethyl acetate=4/1) to obtain compound 56-2 (2.45 g, 8.90 mmol, yield: 93.59%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.43 (d, J=8.3, 1H), 6.64 (d, J=13.5 Hz, 1H), 6.32 (s, 2H), 0.24 (s, 9H).
步骤3：将碘化亚铜(1.42g,7.45mmol)加入到化合物56-2(2.405g,7.45mmol)的DMF(20mL)中。将反应混合物升温至100℃后搅拌1.5小时，加水(30mL)稀释，并用乙酸乙酯(20mL*3)萃取。将合并所得的有机相浓缩得到粗产物。将粗产物经快速柱层析(用石油醚/乙酸乙酯＝4/1洗脱)纯化，得到化合物56-3(830mg,4.09mmol,产率：54.87％)。1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),7.95(d,J＝7.1Hz,1H),7.48–7.56(m,1H),7.43(d,J＝12.0Hz,1H),6.61(t,J＝2.1Hz,1H)。Step 3: Add cuprous iodide (1.42 g, 7.45 mmol) to compound 56-2 (2.405 g, 7.45 mmol) in DMF (20 mL). The reaction mixture was warmed up to 100° C., stirred for 1.5 hours, diluted with water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were concentrated to give crude product. The crude product was purified by flash column chromatography (eluted with petroleum ether/ethyl acetate=4/1) to obtain compound 56-3 (830 mg, 4.09 mmol, yield: 54.87%). 1 H NMR (400MHz, DMSO-d 6 )δ11.59(s, 1H), 7.95(d, J=7.1Hz, 1H), 7.48–7.56(m, 1H), 7.43(d, J=12.0Hz, 1H), 6.61 (t, J = 2.1 Hz, 1H).
步骤4：将化合物56-3(700mg,3.45mmol)和叔丁醇钠(331.15mg,3.45mmol)加入到2-氯烟腈(0.24mL,2.30mmol)的DMF(10mL)溶液中。将反应混合物升温至100℃后搅拌2小时，用水(30mL)稀释，并用乙酸乙酯(20mL*3)萃取。将合并所得的有机相浓缩得到粗产物。将粗产物经快速柱层析(石油醚/乙酸乙酯＝3/1)纯化，得到化合物56-4(730mg,2.39mmol)。1H NMR(400MHz,DMSO-d6)δ8.91(d,J＝4.9,1.8Hz,1H),8.62(d,J＝7.9,1.8Hz,1H),8.15(d,J＝7.1Hz,1H),8.10(d,J＝3.5Hz,1H),7.85(d,J＝12.1Hz,1H),7.71(d,J＝7.9,4.9Hz,1H),6.99(d,J＝3.5Hz,1H)。Step 4: Compound 56-3 (700 mg, 3.45 mmol) and sodium tert-butoxide (331.15 mg, 3.45 mmol) were added to a solution of 2-chloronicotinonitrile (0.24 mL, 2.30 mmol) in DMF (10 mL). The reaction mixture was warmed up to 100° C., stirred for 2 hours, diluted with water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were concentrated to give crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 56-4 (730 mg, 2.39 mmol). 1 H NMR (400MHz, DMSO-d 6 ) δ8.91(d, J=4.9, 1.8Hz, 1H), 8.62(d, J=7.9, 1.8Hz, 1H), 8.15(d, J=7.1Hz, 1H), 8.10(d, J=3.5Hz, 1H), 7.85(d, J=12.1Hz, 1H), 7.71(d, J=7.9, 4.9Hz, 1H), 6.99(d, J=3.5Hz, 1H).
步骤5：向化合物56-4(150mg，0.49mmol)、三乙胺(0.68mL，4.91mmol)和分子筛(100mg)的甲醇溶液(10mL)中加入盐酸羟胺(170.74mg，2.46mmol)。反应混合物在80℃下搅拌12小时后浓缩，然后加水(15mL)，用乙酸乙酯(45mL)萃取。将合并所得的有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥，浓缩得到粗产物。将粗产物用硅胶柱层析(洗脱液梯度从石油醚:乙酸乙酯＝20:1过渡到1:1)纯化，得到化合物56-5(136mg，0.40mmol，产率：81.81％)。MS(ESI)：m/z＝339[M+H]+。Step 5: To a methanol solution (10 mL) of compound 56-4 (150 mg, 0.49 mmol), triethylamine (0.68 mL, 4.91 mmol) and molecular sieves (100 mg) was added hydroxylamine hydrochloride (170.74 mg, 2.46 mmol). The reaction mixture was stirred at 80°C for 12 hours, concentrated, then added with water (15 mL), and extracted with ethyl acetate (45 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether: ethyl acetate = 20:1 to 1:1) to obtain compound 56-5 (136 mg, 0.40 mmol, yield: 81.81%). MS (ESI): m/z = 339 [M+H] + .
步骤6：在0℃下，向化合物56-5(136mg，0.40mmol)的四氢呋喃溶液(5mL)中加入N,N’-羰基二咪唑(81.49mg，0.50mmol)。反应混合物在室温下搅拌30分钟后，加入1,8-二氮杂双环[5.4.0]-7-十一碳烯(90.01μL，0.60mmol)并搅拌1个小时，加水(15mL)稀释，用乙酸乙酯(45mL)萃取。将合并所得的有机相用饱和氯化钠溶液洗涤，干燥后浓缩得到粗产物。将粗产物用硅胶柱层析(洗脱液梯度从二氯甲烷:甲醇＝1:0～过渡到10:1)纯化，得到化合物56(26mg,0.07mmol,产率：17.75％,纯度：98.74％)。MS(ESI)：m/z＝365[M+H]+。1HNMR(DMSO-d6)δ:8.84(br d,J＝3.5Hz,1H),8.34(br d,J＝7.5Hz,1H),8.09(d,J＝7.1Hz,1H),7.73(dd,J＝7.6,4.9Hz,1H),7.57-7.65(m,2H),6.86(d,J＝3.3Hz,1H)。Step 6: To a solution of compound 56-5 (136 mg, 0.40 mmol) in THF (5 mL) was added N,N'-carbonyldiimidazole (81.49 mg, 0.50 mmol) at 0°C. After the reaction mixture was stirred at room temperature for 30 minutes, 1,8-diazabicyclo[5.4.0]-7-undecene (90.01 μL, 0.60 mmol) was added and stirred for 1 hour, diluted with water (15 mL), Extract with ethyl acetate (45 mL). The combined organic phases were washed with saturated sodium chloride solution, dried and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient from dichloromethane:methanol=1:0 to transition to 10:1) to obtain compound 56 (26mg, 0.07mmol, yield: 17.75%, purity: 98.74 %). MS (ESI): m/z = 365 [M+H] + . 1 H NMR (DMSO-d 6 ) δ: 8.84 (br d, J = 3.5Hz, 1H), 8.34 (br d, J = 7.5Hz, 1H), 8.09 (d, J = 7.1Hz, 1H), 7.73 ( dd, J = 7.6, 4.9 Hz, 1H), 7.57-7.65 (m, 2H), 6.86 (d, J = 3.3 Hz, 1H).
实施例59
Example 59
步骤1：将化合物3-氟-4-三氟甲基苯胺(1g,5.5mmol)、NIS(1.8g,8mmol)、和AcOH(5mL)的混合物在室温下搅拌2小时后浓缩。在冰浴条件，将NaHCO3(20mL)缓慢加入所得浓缩物中，并用EA(30mL)萃取。将合并所得有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥，浓缩得到残余物。将残余物经硅胶柱层析(用EA:PE＝1/10洗脱)纯化，得到化合物59-1(580mg,1.8mmol,产率：34.4％)。MS(ESI)：m/z＝306[M+H]+。Step 1: A mixture of compound 3-fluoro-4-trifluoromethylaniline (1 g, 5.5 mmol), NIS (1.8 g, 8 mmol), and AcOH (5 mL) was stirred at room temperature for 2 hours and concentrated. In ice bath condition, NaHCO 3 (20 mL) was slowly added to the obtained concentrate, and extracted with EA (30 mL). The combined organic phases were washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 , and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/10) to obtain compound 59-1 (580 mg, 1.8 mmol, yield: 34.4%). MS (ESI): m/z = 306 [M+H] + .
步骤2：将化合物59-1(500mg,1.6mmol)、三甲基乙炔基硅(240mg,2.4mmol)、Pd(PPh3)4(184mg,0.16mmol)、CuI(30mg,0.16mmol)，DIPEA(412mg,3.2mmol),和DMF(10mL)的混合物用N2吹扫并维持N2氛围，随后在80℃下搅拌12小时，加H2O(20mL)，并用EA(30mL)萃取。将合并所得的有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将残余物通过硅胶柱层析(用EA:PE＝1/5洗脱)纯化，得到化合物59-2(220mg,0.79mmol,产率：49.8％)。MS(ESI)：m/z＝276[M+H]+。Step 2: Compound 59-1 (500mg, 1.6mmol), trimethylethynylsilane (240mg, 2.4mmol), Pd(PPh 3 ) 4 (184mg, 0.16mmol), CuI (30mg, 0.16mmol), DIPEA (412 mg, 3.2 mmol), and DMF (10 mL) were purged with N 2 and maintained under N 2 atmosphere, then stirred at 80° C. for 12 hours, added H 2 O (20 mL), and extracted with EA (30 mL). The combined organic phases were washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/5) to obtain compound 59-2 (220 mg, 0.79 mmol, yield: 49.8%). MS (ESI): m/z = 276 [M+H] + .
步骤3：向化合物59-2(220mg，0.79mmol)的THF(10mL)溶液中缓慢加入TBAF(247mg,0.94mmol)。将反应混合物在室温下反应1小时后，用H2O(50mL)稀释，并用EA(20mL)萃取。将有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将残余物经硅胶柱层析(用EA:PE＝1/5洗脱)纯化，得到化合物59-3(90mg,0.45mmol,产率：57.5％)。MS(ESI)：m/z＝204[M+H]+。Step 3: To a solution of compound 59-2 (220 mg, 0.79 mmol) in THF (10 mL) was slowly added TBAF (247 mg, 0.94 mmol). After the reaction mixture was reacted at room temperature for 1 hour, it was diluted with H 2 O (50 mL), and extracted with EA (20 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/5) to obtain compound 59-3 (90 mg, 0.45 mmol, yield: 57.5%). MS (ESI): m/z = 204 [M+H] + .
步骤4：将化合物59-3(380mg,1.8mmol)、叔丁醇钾(403mg,3.6mmol)和NMP(5mL)的混合物用N2吹扫并维持N2氛围，在80℃下搅拌12小时后，用H2O(50mL)稀释，并用EA(20mL)萃取。将有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将残余物经硅胶柱层析(用EA:PE＝1/3洗脱)纯化，得到化合物59-4(270mg,1.32mmol,产率：73.5％)。MS(ESI)：m/z＝204[M+H]+。Step 4: The mixture of compound 59-3 (380mg, 1.8mmol), potassium tert-butoxide (403mg, 3.6mmol) and NMP (5mL) was purged with N 2 and maintained under N 2 atmosphere, stirred at 80°C for 12 hours Afterwards, it was diluted with H2O (50 mL) and extracted with EA (20 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/3) to obtain compound 59-4 (270 mg, 1.32 mmol, yield: 73.5%). MS (ESI): m/z = 204 [M+H] + .
步骤5：向化合物59-4(270mg，1.32mmol)的DMF(20mL)溶液中加入2-氯烟腈(293mg，1.58mmol)和碳酸铯(855mg,2.64mmol)。将反应混合物在120℃下搅拌3小时，用H2O(200mL)稀释，并用EA(50mL)萃取。将有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将残余物经硅胶柱层析(用EA:PE＝1/4洗脱)纯化，得到化合物59-5(300mg,0.98mmol,产率：74.2％)。MS(ESI)：m/z＝306[M+H]+。Step 5: To a solution of compound 59-4 (270 mg, 1.32 mmol) in DMF (20 mL) was added 2-chloronicotinonitrile (293 mg, 1.58 mmol) and cesium carbonate (855 mg, 2.64 mmol). The reaction mixture was stirred at 120 °C for 3 h, diluted with H2O (200 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/4) to obtain compound 59-5 (300 mg, 0.98 mmol, yield: 74.2%). MS (ESI): m/z = 306 [M+H] + .
步骤6：将化合物59-5(300mg,0.9mmol)、NH2OH·HCl(630mg,9mmol)、10mL MeOH、TEA(3mL)和分子筛(300mg)的混合物用N2吹扫并维持N2氛围，在80℃下搅拌3小时后，减压过滤。将滤液浓缩后加入H2O(20mL)，用EA(30mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将残余物经硅胶柱层析(用EA:PE＝1/2洗脱)纯化，得到化合物59-6(158mg,0.46mmol,产率51.7％)。MS(ESI)：m/z＝339[M+H]+。Step 6: Compound 59-5 (300mg, 0.9mmol), NH 2 OH·HCl (630mg, 9mmol), 10mL MeOH, TEA (3mL) and The mixture of molecular sieves (300 mg) was purged with N 2 and maintained under N 2 atmosphere, and after stirring at 80° C. for 3 hours, it was filtered under reduced pressure. After the filtrate was concentrated, H 2 O (20 mL) was added and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/2) to obtain compound 59-6 (158 mg, 0.46 mmol, yield 51.7%). MS (ESI): m/z = 339 [M+H] + .
步骤7：在冰浴下，将CDI(57.3mg,0.35mmol)加入至化合物59-6(100mg,0.29mmol)的THF(10mL)溶液中。将反应混合物在室温下搅拌30分钟，用冰浴冷却，滴入DBU(66mg,0.43mmol)后继续在冰浴下搅拌2h，加入HCl的水溶液(20mL，pH＝2)，用EA(20mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将残余物经制备高效液相色谱纯化，得到化合物59(63mg,0.17mmol,产率：59.5％)。MS(ESI)：m/z＝365[M+H]+。1H NMR(DMSO-d6)δ:8.87(dd,J＝4.9,1.8Hz,1H),8.36(dd,J＝7.8,1.8Hz,1H),8.11(d,J＝7.1Hz,1H),7.76(dd,J＝7.8,4.8Hz,1H),7.58-7.64(m,2H),6.88(d,J＝3.5Hz,1H)。Step 7: CDI (57.3 mg, 0.35 mmol) was added to a solution of compound 59-6 (100 mg, 0.29 mmol) in THF (10 mL) under ice bath. The reaction mixture was stirred at room temperature for 30 minutes, cooled in an ice bath, DBU (66mg, 0.43mmol) was added dropwise and stirred for 2h under an ice bath, aqueous HCl (20mL, pH=2) was added, and EA (20mL) extraction. The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The residue was purified by preparative high performance liquid chromatography to obtain compound 59 (63 mg, 0.17 mmol, yield: 59.5%). MS (ESI): m/z = 365 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.87 (dd, J=4.9, 1.8Hz, 1H), 8.36 (dd, J=7.8, 1.8Hz, 1H), 8.11 (d, J=7.1Hz, 1H) , 7.76 (dd, J=7.8, 4.8Hz, 1H), 7.58-7.64 (m, 2H), 6.88 (d, J=3.5Hz, 1H).
实施例60
Example 60
步骤1：在冰浴下，将N-碘代丁二酰亚胺(2.59g,11.50mmol)加入到3-氯-4-(三氟甲基)苯胺(1.5g,7.67mmol)的乙酸(20mL)溶液中。反应混合物用N2吹扫并维持N2氛围，缓慢升至室温后搅拌一个小时，用饱和碳酸氢钠淬灭，并用乙酸乙酯(100mL×3)萃取。将合并后的有机相用无水硫酸钠干燥后浓缩得到残余物。将残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物60-1(1.993g，产率：80.83％)。1HNMR(DMSO-d6)δ:7.84(s,1H),6.89(s,1H),6.22(br s,2H)。Step 1: N-iodosuccinimide (2.59 g, 11.50 mmol) was added to 3-chloro-4-(trifluoromethyl)aniline (1.5 g, 7.67 mmol) in acetic acid ( 20mL) solution. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to room temperature, stirred for one hour, quenched with saturated sodium bicarbonate, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 60-1 (1.993 g, yield: 80.83%). 1 H NMR (DMSO-d 6 ) δ: 7.84 (s, 1H), 6.89 (s, 1H), 6.22 (br s, 2H).
步骤2：在室温下，将DIPEA(2.01mL,12.13mmol)和乙炔基三甲基硅烷(1.30mL,9.10mmol)加入到化合物60-1(1.95g,6.07mmol)、四(三苯基膦)钯(0.70g,0.61mmol)、碘化亚铜(0.12g,0.61mmol)以及DMF(25mL)的混合物中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌过夜，后加水稀释，并用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将残余物用硅胶柱层析(用石油醚：乙酸乙酯＝5：1洗脱)纯化，得到化合物60-2(1.08g，产率：61.02％)。MS(ESI)：m/z＝292[M+H]+。Step 2: Add DIPEA (2.01 mL, 12.13 mmol) and ethynyltrimethylsilane (1.30 mL, 9.10 mmol) to compound 60-1 (1.95 g, 6.07 mmol), tetrakis(triphenylphosphine) at room temperature ) in a mixture of palladium (0.70g, 0.61mmol), cuprous iodide (0.12g, 0.61mmol) and DMF (25mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 80 °C and stirred overnight, then diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=5:1) to obtain compound 60-2 (1.08 g, yield: 61.02%). MS (ESI): m/z = 292 [M+H] + .
步骤3：在室温下，将四丁基氟化铵(3.77mL,3.77mmol)加入到化合物60-2(1.0g,3.43mmol)的四氢呋喃(10mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，在室温下搅拌30分钟后，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将残余物用制备硅胶板(用石油醚:乙酸乙酯＝5:1)纯化，得到化合物60-3(1.056g)。MS(ESI)：m/z＝218[M-H]-。Step 3: Tetrabutylammonium fluoride (3.77 mL, 3.77 mmol) was added to a solution of compound 60-2 (1.0 g, 3.43 mmol) in THF (10 mL) at room temperature. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at room temperature for 30 min, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified with a preparative silica gel plate (with petroleum ether:ethyl acetate=5:1) to obtain compound 60-3 (1.056 g). MS (ESI): m/z = 218 [MH] - .
步骤4：在冰浴条件下，将叔丁醇钠(1.02g,9.11mmol)加入到化合物60-3(1.0g,4.55mmol)的NMP(10mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃后搅拌2小时，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用制备硅胶板(用石油醚:乙酸乙酯＝5:1洗脱)纯化，得到化合物60-4(678mg，产率：67.80％)。MS(ESI)：m/z＝220[M+H]+。1H NMR(DMSO-d6)δ:11.64(br s,1H),8.09(s,1H),7.68(s,1H),7.57(t,J＝2.8Hz,1H),6.64(t,J＝2.1Hz,1H).Step 4: Sodium tert-butoxide (1.02 g, 9.11 mmol) was added to a solution of compound 60-3 (1.0 g, 4.55 mmol) in NMP (10 mL) under ice-bath conditions. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80° C., stirred for 2 hours, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified on a preparative silica gel plate (eluted with petroleum ether:ethyl acetate=5:1) to obtain compound 60-4 (678 mg, yield: 67.80%). MS (ESI): m/z = 220 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 11.64 (br s, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 7.57 (t, J=2.8Hz, 1H), 6.64 (t, J =2.1Hz,1H).
步骤5：在室温下，依次将2-氯烟腈(350mg,1.59mmol)和Cs2CO3(1038.64mg,3.19mmol)加入到化合物60-4(350mg,1.59mmol)的DMF(7mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至120℃后搅拌1小时，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将残余物用制备硅胶板(用石油醚:乙酸乙酯＝5:1洗脱)纯化，得到化合物60-5(429mg，产率：83.67％)。MS(ESI)：m/z＝322[M+H]+。Step 5: 2-Chloronicotinonitrile (350 mg, 1.59 mmol) and Cs 2 CO 3 (1038.64 mg, 3.19 mmol) were sequentially added to a solution of compound 60-4 (350 mg, 1.59 mmol) in DMF (7 mL) at room temperature middle. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 120° C., stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified on a preparative silica gel plate (eluted with petroleum ether:ethyl acetate=5:1) to obtain compound 60-5 (429 mg, yield: 83.67%). MS (ESI): m/z = 322 [M+H] + .
步骤6：在室温下，依次将盐酸羟胺(907.26mg,13.06mmol),分子筛(420mg,1.31mmol)和三乙胺(10.86mL,78.34mmol)加入到化合物60-5(420mg,1.31mmol)的甲醇(15mL)溶液中，将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃后搅拌3小时，用饱和氯化铵淬灭，过滤后用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将残余物用制备硅胶板(用乙酸乙酯洗脱)纯化，得到化合物60-6(459mg，产率：99.11％)。MS(ESI)：m/z＝355[M+H]+。Step 6: At room temperature, successively add hydroxylamine hydrochloride (907.26mg, 13.06mmol), Molecular sieves (420mg, 1.31mmol) and triethylamine (10.86mL, 78.34mmol) were added to a solution of compound 60-5 (420mg, 1.31mmol) in methanol (15mL), and the reaction mixture was purged with N2 and maintained under N2 Atmosphere, the temperature was slowly raised to 80° C., stirred for 3 hours, quenched with saturated ammonium chloride, filtered and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified with a preparative silica gel plate (eluted with ethyl acetate) to obtain compound 60-6 (459 mg, yield: 99.11%). MS (ESI): m/z = 355 [M+H] + .
步骤7：在冰浴条件下，将CDI(257.13mg,1.59mmol)加入到化合物60-6(450mg,1.27mmol)的四氢呋喃(5mL)溶液中，在室温下搅拌30分钟后，再次在冰浴条件下加入DBU(284.02μL,1.90mmol)。将反应混合物缓慢升至室温后搅拌1小时，用水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将残余物用制备硅胶板(用乙酸乙酯洗脱)纯化，得到化合物60(205mg，产率：42.45％)。MS(ESI)：m/z＝381[M+H]+。1H NMR(DMSO-d6)δ:8.80(dd,J＝4.8,1.8Hz,1H),8.37(dd,J＝7.8,1.7Hz,1H),8.19(s,1H),7.74(s,1H),7.71(dd,J＝7.8,4.8Hz,1H),7.64(d,J＝3.4Hz,1H),6.85(d,J＝3.3Hz,1H).Step 7: Add CDI (257.13mg, 1.59mmol) to a solution of compound 60-6 (450mg, 1.27mmol) in tetrahydrofuran (5mL) under ice-bath conditions, stir at room temperature for 30 minutes, and again in ice-bath DBU (284.02 μL, 1.90 mmol) was added under conditions. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified with a preparative silica gel plate (eluted with ethyl acetate) to obtain compound 60 (205 mg, yield: 42.45%). MS (ESI): m/z = 381 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.80(dd, J=4.8, 1.8Hz, 1H), 8.37(dd, J=7.8, 1.7Hz, 1H), 8.19(s, 1H), 7.74(s, 1H), 7.71(dd, J=7.8, 4.8Hz, 1H), 7.64(d, J=3.4Hz, 1H), 6.85(d, J=3.3Hz, 1H).
实施例66
Example 66
步骤1：按照实施例3中步骤1的类似合成方法，以2-氟-3-甲基苯甲腈和5-(三氟甲基)-1H-吲哚作为反应物制备得到化合物66-1。LCMS：m/z＝301[M+H]+。Step 1: According to the similar synthesis method of Step 1 in Example 3, compound 66-1 was prepared using 2-fluoro-3-methylbenzonitrile and 5-(trifluoromethyl)-1H-indole as reactants . LCMS: m/z = 301 [M+H] + .
步骤2：按照实施例3中步骤2的类似合成方法，以化合物66-1作为反应物制备得到化合物66-2。LCMS：m/z＝334[M+H]+。Step 2: According to the similar synthesis method of Step 2 in Example 3, Compound 66-2 was prepared using Compound 66-1 as a reactant. LCMS: m/z = 334 [M+H] + .
步骤3：按照实施例3中步骤3的类似合成方法，以化合物66-2作为反应物制备得到化合物66(58mg,纯度98.5％)。MS(ESI)：m/z＝360[M+H]+。1H NMR(DMSO-d6)δ:12.64(br s,1H),8.04(s,1H),7.65-7.76(m,3H),7.53(d,J＝3.3Hz,1H),7.39(dd,J＝8.7,1.6Hz,1H),6.96(d,J＝8.5Hz,1H),6.83(d,J＝3.1Hz,1H),1.90(s,3H)。Step 3: According to the similar synthesis method of Step 3 in Example 3, Compound 66 (58 mg, purity 98.5%) was prepared using Compound 66-2 as a reactant. MS (ESI): m/z = 360 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.64 (br s, 1H), 8.04 (s, 1H), 7.65-7.76 (m, 3H), 7.53 (d, J=3.3Hz, 1H), 7.39 (dd , J=8.7, 1.6Hz, 1H), 6.96(d, J=8.5Hz, 1H), 6.83(d, J=3.1Hz, 1H), 1.90(s, 3H).
实施例67
Example 67
步骤1：向2,3-二氟苯-1-甲腈(0.4mL，3.59mmol)和叔丁醇钠(414mg，4.31mmol)的N,N-二甲基甲酰胺溶液(10mL)中加入5-(三氟甲基)-1H-吲哚(664.69mg，3.59mmol)。反应混合物在120℃下搅拌12个小时后，加水稀释，然后用乙酸乙酯(60mL)萃取。将有机相用饱和氯化钠溶液洗涤，干燥后浓缩得到粗产物。将粗产物用硅胶柱层析(洗脱液梯度从石油醚：乙酸乙酯＝20:1过渡至4/1)纯化，得到化合物67-1(1.02g，3.36mmol，产率：93.57％)。MS(ESI)：m/z＝305[M+H]+。Step 1: To a solution of 2,3-difluorobenzene-1-carbonitrile (0.4 mL, 3.59 mmol) and sodium tert-butoxide (414 mg, 4.31 mmol) in N,N-dimethylformamide (10 mL) was added 5-(Trifluoromethyl)-1H-indole (664.69 mg, 3.59 mmol). The reaction mixture was stirred at 120°C for 12 hours, diluted with water, and extracted with ethyl acetate (60 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether: ethyl acetate = 20:1 to 4/1) to obtain compound 67-1 (1.02 g, 3.36 mmol, yield: 93.57%) . MS (ESI): m/z = 305 [M+H] + .
步骤2：将盐酸羟胺(342.60mg，4.93mmol)加入到化合物67-1(300mg，0.99mmol)、三乙胺(1.37mL，9.86mmol)、分子筛(200mg)和甲醇(4mL)的混合物中。反应混合物在80℃下搅拌12小时后浓缩。向浓缩液中加入水(15mL)，并用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，得到粗产物。将粗产物用硅胶柱层析(洗脱液梯度从石油醚:乙酸乙酯＝20:1过渡到0:1)纯化，得到化合物67-2(309mg，0.92mmol，产率：92.91％)。MS(ESI)：m/z＝338[M+H]+。Step 2: Hydroxylamine hydrochloride (342.60 mg, 4.93 mmol) was added to a mixture of compound 67-1 (300 mg, 0.99 mmol), triethylamine (1.37 mL, 9.86 mmol), molecular sieves (200 mg) and methanol (4 mL). The reaction mixture was stirred at 80°C for 12 hours and then concentrated. Water (15 mL) was added to the concentrate, followed by extraction with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether: ethyl acetate = 20:1 to 0:1) to obtain compound 67-2 (309 mg, 0.92 mmol, yield: 92.91%). MS (ESI): m/z = 338 [M+H] + .
步骤3：在0℃下,将N,N'-羰基二咪唑(70.66mg，0.44mmol)加入到化合物67-2(112mg，0.35mmol)的四氢呋喃溶液(5mL)中，在室温下搅拌30后，加入1,8-二氮杂双环[5.4.0]-7-十一碳烯(78.05μL，0.52mmol)。将反应混合物搅拌1个小时，加水(15mL)稀释，并用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，干燥后浓缩得到残余物。将残余物用硅胶柱层析(洗脱液梯度从二氯甲烷:甲醇＝1:0过渡至10:1)纯化，得到化合物67(151mg,0.42mmol,产率：45.37％,纯度：99.0％)。MS(ESI)：m/z＝364[M+H]+。1H NMR(DMSO-d6)δ:12.86(br s,1H),8.06(s,1H),7.82-7.90(m,2H),7.73-7.80(m,1H),7.59(d,J＝3.4Hz,1H),7.44(dd,J＝8.7,1.4Hz,1H),7.16(d,J＝8.5Hz,1H),6.87(d,J＝3.3Hz,1H)。Step 3: Add N,N'-carbonyldiimidazole (70.66mg, 0.44mmol) to a tetrahydrofuran solution (5mL) of compound 67-2 (112mg, 0.35mmol) at 0°C, and stir at room temperature for 30 , 1,8-Diazabicyclo[5.4.0]-7-undecene (78.05 μL, 0.52 mmol) was added. The reaction mixture was stirred for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluent gradient transition from dichloromethane:methanol=1:0 to 10:1) to obtain compound 67 (151mg, 0.42mmol, yield: 45.37%, purity: 99.0% ). MS (ESI): m/z = 364 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.86(br s,1H), 8.06(s,1H), 7.82-7.90(m,2H), 7.73-7.80(m,1H), 7.59(d,J= 3.4Hz, 1H), 7.44 (dd, J = 8.7, 1.4Hz, 1H), 7.16 (d, J = 8.5Hz, 1H), 6.87 (d, J = 3.3Hz, 1H).
实施例68
Example 68
步骤1：按照实施例67中步骤1的类似合成方法，以3-氯-2-氟苯甲腈和5-(三氟甲基)-1H-吲哚作为反应物制备得到化合物68-1。LCMS：m/z＝321[M+H]+。Step 1: According to the similar synthesis method of Step 1 in Example 67, Compound 68-1 was prepared using 3-chloro-2-fluorobenzonitrile and 5-(trifluoromethyl)-1H-indole as reactants. LCMS: m/z = 321 [M+H] + .
步骤2：按照实施例67中步骤2的类似合成方法，以化合物68-1作为反应物制备得到化合物68-2。LCMS：m/z＝354[M+H]+。Step 2: According to the similar synthesis method of Step 2 in Example 67, Compound 68-2 was prepared using Compound 68-1 as a reactant. LCMS: m/z = 354 [M+H] + .
步骤3：按照实施例67中步骤3的类似合成方法，以化合物68-2作为反应物制备得到化合物68(83mg， 纯度：98.9％)。MS(ESI)：m/z＝380[M+H]+。1H NMR(DMSO-d6)δ:12.83(br s,1H),8.02-8.09(m,2H),7.81-7.95(m,2H),7.55(d,J＝3.3Hz,1H),7.42(d,J＝8.4Hz,1H),7.04(d,J＝8.6Hz,1H),6.86(d,J＝3.3Hz,1H)。Step 3: Compound 68 (83 mg, Purity: 98.9%). MS (ESI): m/z = 380 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.83 (br s, 1H), 8.02-8.09 (m, 2H), 7.81-7.95 (m, 2H), 7.55 (d, J=3.3Hz, 1H), 7.42 (d, J=8.4Hz, 1H), 7.04 (d, J=8.6Hz, 1H), 6.86 (d, J=3.3Hz, 1H).
实施例69
Example 69
步骤1：按照实施例67中步骤1的类似合成方法，以3-氯-2-氟苯甲腈和5-(三氟甲基)-1H-吲哚作为反应物制备得到化合物69-1。MS(ESI)：m/z＝413[M+H]+。Step 1: According to the similar synthesis method of Step 1 in Example 67, compound 69-1 was prepared using 3-chloro-2-fluorobenzonitrile and 5-(trifluoromethyl)-1H-indole as reactants. MS (ESI): m/z = 413 [M+H] + .
步骤2：按照实施例67中步骤2的类似合成方法，以化合物69-1作为反应物制备得到化合物69-2。MS(ESI)：m/z＝446[M+H]+。Step 2: According to the similar synthesis method of Step 2 in Example 67, Compound 69-2 was prepared using Compound 69-1 as a reactant. MS (ESI): m/z = 446 [M+H] + .
步骤3：按照实施例67中步骤3的类似合成方法，以化合物69-2作为反应物制备得到化合物69-3(83mg，纯度：98.9％)。MS(ESI)：m/z＝472[M+H]+。Step 3: According to the similar synthesis method of Step 3 in Example 67, Compound 69-3 (83 mg, purity: 98.9%) was prepared using Compound 69-2 as a reactant. MS (ESI): m/z = 472 [M+H] + .
步骤4：向化合物69-3(100mg,0.98mmol)的DMF(5mL)溶液中加入Zn(CN)2(115mg,1.47mmol)和Pd(PPh3)4(60mg,1.96mmol)。反应混合物在120℃下搅拌过夜，加水，用乙酸乙酯萃取。将有机层用无水硫酸钠干燥并浓缩得到残余物。将残余物通过硅胶柱层析纯化，得到化合物69(43mg，0.65mmol)。MS(ESI)：m/z＝371[M+H]+。1H NMR(400MHz,DMSO-d6)δ6.91(d,J＝3.25Hz,1H)7.17(d,J＝8.50Hz,1H)7.45(d,J＝8.63Hz,1H)7.69(d,J＝3.25Hz,1H)8.00(t,J＝7.82Hz,1H)8.08(s,1H)8.23(dd,J＝7.94,1.19Hz,1H)8.37(dd,J＝7.82,1.19Hz,1H)。13C NMR(DMSO-d6)δ:156.0,139.0,138.5,137.5,135.5,132.3,131.0,128.4,125.4,122.0,121.7,119.4,119.0,115.6,114.4,111.2,105.5。Step 4: To a solution of compound 69-3 (100 mg, 0.98 mmol) in DMF (5 mL) was added Zn(CN) 2 (115 mg, 1.47 mmol) and Pd(PPh 3 ) 4 (60 mg, 1.96 mmol). The reaction mixture was stirred overnight at 120°C, added with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography to obtain compound 69 (43 mg, 0.65 mmol). MS (ESI): m/z = 371 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ6.91 (d, J = 3.25Hz, 1H) 7.17 (d, J = 8.50Hz, 1H) 7.45 (d, J = 8.63Hz, 1H) 7.69 (d, J=3.25Hz,1H)8.00(t,J=7.82Hz,1H)8.08(s,1H)8.23(dd,J=7.94,1.19Hz,1H)8.37(dd,J=7.82,1.19Hz,1H) . 13 C NMR (DMSO-d6) δ: 156.0, 139.0, 138.5, 137.5, 135.5, 132.3, 131.0, 128.4, 125.4, 122.0, 121.7, 119.4, 119.0, 115.6, 114.4, 111.2, 105.5.
实施例70
Example 70
步骤1：按照实施例2中步骤1的类似合成方法，以3-氯-4-腈-哒嗪和5-(三氟甲基)-1H-吲哚作为反应物制备得到化合物70-1。MS(ESI)：m/z＝289[M+H]+。Step 1: According to the similar synthesis method of Step 1 in Example 2, compound 70-1 was prepared using 3-chloro-4-carbonitrile-pyridazine and 5-(trifluoromethyl)-1H-indole as reactants. MS (ESI): m/z = 289 [M+H] + .
步骤2：按照实施例2中步骤2的类似合成方法，以化合物70-1作为反应物制备得到化合物70-2。MS(ESI)：m/z＝322[M+H]+。Step 2: According to the similar synthesis method of Step 2 in Example 2, Compound 70-2 was prepared using Compound 70-1 as a reactant. MS (ESI): m/z = 322 [M+H] + .
步骤3：按照实施例2中步骤3的类似合成方法，以化合物70-2作为反应物制备得到化合物70(86.17mg，0.25mmol，产率8.54％，纯度：99.6％)。MS(ESI)：m/z＝348[M+H]+。1H NMR(400MHz,DMSO-d6)δ:9.65(d,J＝5.1Hz,1H),8.25(d,J＝5.1Hz,1H),8.10(s,1H),7.73-7.79(m,1H),7.70(d,J＝8.5Hz,1H),7.54(dd,J＝8.8,1.5Hz,1H),6.95(d,J＝3.4Hz,1H)。Step 3: Compound 70 (86.17 mg, 0.25 mmol, yield 8.54%, purity: 99.6%) was prepared according to the similar synthesis method of Step 3 in Example 2, using compound 70-2 as a reactant. MS (ESI): m/z = 348 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ: 9.65(d, J=5.1Hz, 1H), 8.25(d, J=5.1Hz, 1H), 8.10(s, 1H), 7.73-7.79(m, 1H), 7.70 (d, J=8.5Hz, 1H), 7.54 (dd, J=8.8, 1.5Hz, 1H), 6.95 (d, J=3.4Hz, 1H).
实施例71
Example 71
步骤1：向4-氯嘧啶-5-甲腈(1.0g，7.17mmol)和叔丁醇钠(0.83g，8.60mmol)的N,N-二甲基甲酰胺溶液(20mL)中加入5-(三氟甲基)-1H-吲哚(1.33g，7.17mmol)，然后反应在120℃下搅拌12个小时。将混合物用水(30mL)进行稀释，然后用乙酸乙酯(90mL)萃取，并用饱和氯化钠溶液洗涤。将合并后的有机层经干燥、过滤和浓缩，得到粗产物。将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡到4:1)纯化得到化合物71-1(755mg，2.62mmol，36.55％)。MS(ESI)：m/z＝289[M+H]+。Step 1: To a solution of 4-chloropyrimidine-5-carbonitrile (1.0 g, 7.17 mmol) and sodium tert-butoxide (0.83 g, 8.60 mmol) in N,N-dimethylformamide (20 mL) was added 5- (Trifluoromethyl)-1H-indole (1.33 g, 7.17 mmol), and the reaction was stirred at 120° C. for 12 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (90 mL), and washed with saturated sodium chloride solution. The combined organic layers were dried, filtered and concentrated to give crude product. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=20:1 to 4:1) to obtain compound 71-1 (755 mg, 2.62 mmol, 36.55%). MS (ESI): m/z = 289 [M+H] + .
步骤2：向化合物71-1(380mg，1.32mmol)、三乙胺(1.83mL，13.18mmol)和分子筛(380mg)的甲醇溶液(15mL)中加入盐酸羟胺(458.08mg，6.59mmol)。混合物在80℃下搅拌并回流12小时。恢复到室温后过滤，滤液浓缩，然后加入水(15mL)，用乙酸乙酯(45mL)萃取，并用饱和氯化钠溶液洗涤。将合并后的有机层用无水硫酸钠干燥，过滤浓缩，得到粗产物。将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡到0:1)纯化得到化合物71-2(112mg，0.35mmol，26.44％)。MS(ESI)：m/z＝322[M+H]+。Step 2: To compound 71-1 (380mg, 1.32mmol), triethylamine (1.83mL, 13.18mmol) and To a methanol solution (15 mL) of molecular sieves (380 mg) was added hydroxylamine hydrochloride (458.08 mg, 6.59 mmol). The mixture was stirred and refluxed at 80°C for 12 hours. After returning to room temperature, it was filtered, and the filtrate was concentrated, then water (15 mL) was added, extracted with ethyl acetate (45 mL), and washed with saturated sodium chloride solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=20:1 to 0:1) to obtain compound 71-2 (112 mg, 0.35 mmol, 26.44%). MS (ESI): m/z = 322 [M+H] + .
步骤3：在0℃下，向化合物71-2(112mg，0.35mmol)的四氢呋喃溶液(5mL)中加入N,N'-羰基二咪唑(70.66mg，0.44mmol)，混合物在室温下搅拌30分钟。再向混合物中加入1,8-二氮杂双环[5.4.0]-7-十一碳烯(78.05μL，0.52mmol)并搅拌1个小时。将混合物用水(15mL)稀释，用乙酸乙酯(45mL)萃取，并用饱和氯化铵溶液和饱和氯化钠溶液洗涤。将合并后的有机层干燥、过滤和浓缩，得到粗产物。将所得残余物通过硅胶柱层析(洗脱剂梯度从DCM:MeOH＝99:1过渡到10:1)纯化得到化合物71(30mg，0.09mmol，产率：24.78％，纯度：98.17％)。MS(ESI)：m/z＝348[M+H]+。1H NMR(DMSO-d6)δ:9.26(s,1H),9.10(s,1H),8.06(s,1H),8.02-8.04(m,1H),7.65(d,J＝3.6Hz,1H),7.54(dd,J＝8.9,1.5Hz,1H),7.19(s,1H),6.85(d,J＝3.5Hz,1H)。Step 3: Add N,N'-carbonyldiimidazole (70.66mg, 0.44mmol) to compound 71-2 (112mg, 0.35mmol) in tetrahydrofuran (5mL) at 0°C, and the mixture was stirred at room temperature for 30 minutes . Further 1,8-diazabicyclo[5.4.0]-7-undecene (78.05 μL, 0.52 mmol) was added to the mixture and stirred for 1 hour. The mixture was diluted with water (15 mL), extracted with ethyl acetate (45 mL), and washed with saturated ammonium chloride solution and saturated sodium chloride solution. The combined organic layers were dried, filtered and concentrated to give crude product. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from DCM:MeOH=99:1 to 10:1) to obtain compound 71 (30 mg, 0.09 mmol, yield: 24.78%, purity: 98.17%). MS (ESI): m/z = 348 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 9.26(s, 1H), 9.10(s, 1H), 8.06(s, 1H), 8.02-8.04(m, 1H), 7.65(d, J=3.6Hz, 1H), 7.54 (dd, J=8.9, 1.5Hz, 1H), 7.19(s, 1H), 6.85 (d, J=3.5Hz, 1H).
实施例72
Example 72
步骤1：按照实施例2中步骤1的类似合成方法，以3-氯异烟腈和5-(三氟甲基)-1H-吲哚作为反应物制备得到化合物72-1。MS(ESI)：m/z＝288[M+H]+。Step 1: According to the similar synthesis method of Step 1 in Example 2, compound 72-1 was prepared using 3-chloroisonicotinonitrile and 5-(trifluoromethyl)-1H-indole as reactants. MS (ESI): m/z = 288 [M+H] + .
步骤2：按照实施例2中步骤2的类似合成方法，以化合物72-1作为反应物制备得到化合物72-2。MS(ESI)：m/z＝321[M+H]+。Step 2: According to the similar synthesis method of Step 2 in Example 2, Compound 72-2 was prepared using Compound 72-1 as a reactant. MS (ESI): m/z = 321 [M+H] + .
步骤3：按照实施例2中步骤3的类似合成方法，以化合物72-2作为反应物制备得到化合物72(76.46mg，0.22mmol，产率：22.24％，纯度99.7％)。MS(ESI)：m/z＝347[M+H]+。1H NMR(DMSO-d6)δ:8.99(d,J＝5.0Hz,1H),8.95(s,1H),8.07(s,1H),7.93(d,J＝5.0Hz,1H),7.69(d,J＝3.4Hz,1H),7.45(dd,J＝8.8,1.5Hz,1H),7.27(d,J＝8.6Hz,1H),6.89(d,J＝3.3Hz,1H)。Step 3: Compound 72 (76.46 mg, 0.22 mmol, yield: 22.24%, purity 99.7%) was prepared according to the similar synthesis method of Step 3 in Example 2, using compound 72-2 as a reactant. MS (ESI): m/z = 347 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.99(d, J=5.0Hz, 1H), 8.95(s, 1H), 8.07(s, 1H), 7.93(d, J=5.0Hz, 1H), 7.69 (d, J=3.4Hz, 1H), 7.45 (dd, J=8.8, 1.5Hz, 1H), 7.27 (d, J=8.6Hz, 1H), 6.89 (d, J=3.3Hz, 1H).
实施例75
Example 75
步骤1：将5-(三氟甲基)吲哚(2.55g,13.80mmol)和叔丁醇钾(3.10g,27.59mmol)加入到5-溴-2-氯烟腈(3.00g,13.80mmol)的DMF(30mL)溶液中。将反应混合物升温到120℃搅拌2h后，用水(50mL)稀释，并用乙酸乙酯(50mL*3)萃取。将合并所得有机相浓缩，并将所得残余物通过快速柱层析(石油醚/乙酸乙酯＝3/1)纯化得化合物75-1(3.20g)。1H NMR(400MHz,DMSO-d6)δ9.06(d,J＝2.5Hz,1H),9.01 (d,J＝2.5Hz,1H),8.11(s,1H),8.08(d,J＝3.5Hz,1H),7.94(d,J＝8.5Hz,1H),7.58(d,J＝8.8,1.6Hz,1H),6.99(d,J＝3.5Hz,1H).Step 1: Add 5-(trifluoromethyl)indole (2.55g, 13.80mmol) and potassium tert-butoxide (3.10g, 27.59mmol) to 5-bromo-2-chloronicotinonitrile (3.00g, 13.80mmol ) in DMF (30 mL) solution. The reaction mixture was warmed up to 120° C. and stirred for 2 h, diluted with water (50 mL), and extracted with ethyl acetate (50 mL*3). The combined organic phases were concentrated, and the resulting residue was purified by flash column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 75-1 (3.20 g). 1 H NMR (400MHz, DMSO-d 6 ) δ9.06 (d, J=2.5Hz, 1H), 9.01 (d,J=2.5Hz,1H),8.11(s,1H),8.08(d,J=3.5Hz,1H),7.94(d,J=8.5Hz,1H),7.58(d,J=8.8, 1.6Hz,1H),6.99(d,J＝3.5Hz,1H).
步骤2：将三甲基环三硼氧烷(0.12mL,0.44mmol,3.5M in THF)，碳酸钾(452.94mg,3.28mmol)和pd(dppf)Cl2(39.97mg,0.05mmol)加入到化合物75-1(400mg,1.09mmol)的二氧六环(4mL)和水(0.5mL)混合溶液中。将反应混合物在氮气保护下升温到100℃搅拌过夜后过滤，将所得滤液用水(10mL)稀释，并用乙酸乙酯(10mL*3)萃取。将合并所得有机相浓缩，并将所得残余物通过快速柱层析(石油醚/乙酸乙酯＝3/1)纯化得化合物75-2(140mg)。1H NMR(400MHz,DMSO-d6)δ8.77(d,J＝1.6Hz,1H),8.48(d,J＝1.5Hz,1H),8.11(s,1H),8.05(d,J＝3.5Hz,1H),7.85(d,J＝8.6Hz,1H),7.55(d,J＝8.8,1.4Hz,1H),6.96(d,J＝3.4Hz,1H),2.45(s,3H).Step 2: Trimethylboroxine (0.12mL, 0.44mmol, 3.5M in THF), potassium carbonate (452.94mg, 3.28mmol) and pd(dppf)Cl 2 (39.97mg, 0.05mmol) were added to Compound 75-1 (400mg, 1.09mmol) in dioxane (4mL) and water (0.5mL) mixed solution. The reaction mixture was heated to 100°C under nitrogen protection and stirred overnight, then filtered, and the resulting filtrate was diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The combined organic phases were concentrated, and the resulting residue was purified by flash column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 75-2 (140 mg). 1 H NMR (400MHz, DMSO-d6) δ8.77(d, J=1.6Hz, 1H), 8.48(d, J=1.5Hz, 1H), 8.11(s, 1H), 8.05(d, J=3.5 Hz,1H),7.85(d,J=8.6Hz,1H),7.55(d,J=8.8,1.4Hz,1H),6.96(d,J=3.4Hz,1H),2.45(s,3H).
步骤3：将盐酸羟胺(80.73mg,1.16mmol)，TEA(0.64mL,4.65mmol)和4A分子筛(10mg)加入到化合物75-2(70mg,0.23mmol)的甲醇(1mL)溶液中。将反应混合物升温到80℃搅拌2h后过滤，并将所得滤液浓缩。向所得浓缩物中加水(3mL)稀释，并用乙酸乙酯(3mL*3)萃取。将有机相浓缩得化合物75-3的粗产物(60mg)。MS m/z(ESI):＝335.1[M+H]+.Step 3: Hydroxylamine hydrochloride (80.73 mg, 1.16 mmol), TEA (0.64 mL, 4.65 mmol) and 4A molecular sieves (10 mg) were added to a solution of compound 75-2 (70 mg, 0.23 mmol) in methanol (1 mL). The reaction mixture was heated to 80 °C and stirred for 2 h, then filtered, and the obtained filtrate was concentrated. To the obtained concentrate was diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The organic phase was concentrated to obtain a crude product of compound 75-3 (60 mg). MS m/z(ESI):＝335.1[M+H] + .
步骤4：在0℃下，将CDI(0.03mL,0.22mmol)加入到化合物75-3的粗产物(60mg)的四氢呋喃(1mL)溶液中，在0℃下搅拌0.5h后，在0℃下加入DBU(0.04mL,0.27mmol)。将反应混合物升温到室温搅拌1h后，加水(3mL)稀释，并用乙酸乙酯(3mL*3)萃取。将合并所得有机相浓缩，并将所得残余物通过制备高效液相色谱(HPLC)纯化，得到化合物75(13.47mg,0.04mmol,产率20.44％)。MS m/z(ESI):m/z＝361.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.69(d,J＝1.6Hz,1H),8.19(d,J＝1.6Hz,1H),8.05(s,1H),7.58–7.64(m,2H),7.48(dd,J＝8.8,1.6Hz,1H),6.85(d,J＝3.4Hz,1H),2.45–2.48(m,3H).Step 4: At 0°C, CDI (0.03mL, 0.22mmol) was added to a solution of the crude product of compound 75-3 (60mg) in tetrahydrofuran (1mL), stirred at 0°C for 0.5h, then at 0°C DBU (0.04 mL, 0.27 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 h, diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated, and the resulting residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 75 (13.47 mg, 0.04 mmol, yield 20.44%). MS m/z (ESI): m/z=361.1[M+H] + .1 H NMR (400MHz, DMSO-d6) δ8.69(d, J=1.6Hz, 1H), 8.19(d, J= 1.6Hz, 1H), 8.05(s, 1H), 7.58–7.64(m, 2H), 7.48(dd, J＝8.8, 1.6Hz, 1H), 6.85(d, J＝3.4Hz, 1H), 2.45– 2.48(m,3H).
实施例76
Example 76
步骤1：将5-(三氟甲基)二氢吲哚(810.55mg,4.33mmol)和叔丁醇钠(416.17mg,4.33mmol)加入到2-氯烟腈(0.45mL,4.33mmol)的DMF(10mL)溶液中。将反应混合物升温到80℃搅拌2小时后，加水(30mL)稀释，并用乙酸乙酯(20mL*3)萃取。将合并所得的有机相浓缩得残余物。将残余物经快速柱层析(用石油醚:乙酸乙酯＝3:1洗脱)纯化，得到化合物76-1(1.00g,3.46mmol,产率：79.83％)。Step 1: Add 5-(trifluoromethyl)indoline (810.55mg, 4.33mmol) and sodium tert-butoxide (416.17mg, 4.33mmol) to 2-chloronicotinonitrile (0.45mL, 4.33mmol) DMF (10mL) solution. The reaction mixture was warmed up to 80°C and stirred for 2 hours, diluted with water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were concentrated to obtain a residue. The residue was purified by flash column chromatography (eluted with petroleum ether:ethyl acetate=3:1) to obtain compound 76-1 (1.00 g, 3.46 mmol, yield: 79.83%).
1H NMR(400MHz,DMSO-d6)δ8.57(d,J＝4.8,2.0Hz,1H),8.28(d,J＝7.8,1.9Hz,1H),7.73(d,J＝8.5Hz,1H),7.59(s,1H),7.49(d,J＝8.5Hz,1H),7.19(d,J＝7.8,4.8Hz,1H),4.42(t,J＝8.5Hz,2H),3.27(t,J＝8.4Hz,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ8.57(d, J=4.8, 2.0Hz, 1H), 8.28(d, J=7.8, 1.9Hz, 1H), 7.73(d, J=8.5Hz, 1H), 7.59(s, 1H), 7.49(d, J=8.5Hz, 1H), 7.19(d, J=7.8, 4.8Hz, 1H), 4.42(t, J=8.5Hz, 2H), 3.27( t, J=8.4Hz, 2H).
步骤2：将盐酸羟胺(1020.99mg,14.69mmol)，TEA(8.15mL,58.77mmol)和分子筛(100mg)加入到化合物76-1(850mg,2.94mmol)的甲醇(10mL)溶液中。将反应混合物升温到80℃搅拌2小时后浓缩。向浓缩物中加水(30mL)稀释并用乙酸乙酯(30mL*3)萃取。将合并所得的有机相浓缩得粗产物。将粗产物通过快速柱层析(用二氯甲烷:甲醇＝10:1洗脱)纯化，得到化合物76-2(190mg,0.59mmol,产率：20.06％)。MS(ESI)：m/z＝323[M+H]+。Step 2: Hydroxylamine hydrochloride (1020.99mg, 14.69mmol), TEA (8.15mL, 58.77mmol) and Molecular sieves (100 mg) were added to a solution of compound 76-1 (850 mg, 2.94 mmol) in methanol (10 mL). The reaction mixture was warmed up to 80°C and stirred for 2 hours, then concentrated. The concentrate was diluted with water (30 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were concentrated to obtain crude product. The crude product was purified by flash column chromatography (eluted with dichloromethane:methanol=10:1) to obtain compound 76-2 (190 mg, 0.59 mmol, yield: 20.06%). MS (ESI): m/z = 323 [M+H] + .
步骤3：在0℃并维持此温度，将CDI(0.09mL,0.74mmol)加入到化合物76-2(190mg,0.59mmol)的四氢呋喃(2mL)溶液中，搅拌0.5小时后，加入DBU(0.13mL,0.88mmol)。将反应混合物升温至室温，并搅拌1h后加水(3mL)稀释，并用乙酸乙酯(3mL*3)萃取。将合并所得的有机相浓缩得到粗产物。将粗产物通过制备高效液相色谱纯化，得到化合物76(5.23mg,产率：13.68％)。MS(ESI)：m/z＝349[M+H]+。1H NMR(400MHz,MeOH-d4)δ8.56(d,J＝4.8,1.9Hz,1H),8.08(d,J＝7.7,1.9Hz,1H),7.52(s,1H),7.26–7.41(m,2H),6.88(d,J＝8.3Hz,1H),4.06(t,J＝8.4Hz,2H),3.18(t,J＝8.3Hz,2H)。Step 3: At 0°C and maintaining this temperature, CDI (0.09mL, 0.74mmol) was added to a solution of compound 76-2 (190mg, 0.59mmol) in tetrahydrofuran (2mL), and after stirring for 0.5 hours, DBU (0.13mL ,0.88mmol). The reaction mixture was warmed to room temperature and stirred for 1 h, diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated to give crude product. The crude product was purified by preparative high performance liquid chromatography to obtain compound 76 (5.23 mg, yield: 13.68%). MS (ESI): m/z = 349 [M+H] + . 1 H NMR (400MHz, MeOH-d 4 )δ8.56(d, J=4.8,1.9Hz,1H),8.08(d,J=7.7,1.9Hz,1H),7.52(s,1H),7.26– 7.41 (m, 2H), 6.88 (d, J=8.3Hz, 1H), 4.06 (t, J=8.4Hz, 2H), 3.18 (t, J=8.3Hz, 2H).
实施例79
Example 79
步骤1：将5-三氟甲基吲哚(5.00g,27.01mmol)、化合物2-氯烟酸乙酯(7.52g,40.51mmol)、Cs2CO3(17.60g,17.60mmol)和DMF(20mL)的混合物用N2吹扫并维持N2氛围，在120℃下搅拌3小时 后，加水(200mL)稀释并用EA(50mL)萃取。将有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将残余物通过硅胶柱层析(用DCM:PE＝1:1洗脱)纯化，得到化合物79-1(7.86g,23.51mmol,产率：87.06％)。MS(ESI)：m/z＝335[M+H]+。Step 1: 5-trifluoromethylindole (5.00g, 27.01mmol), compound 2-chloronicotinic acid ethyl ester (7.52g, 40.51mmol), Cs 2 CO 3 (17.60g, 17.60mmol) and DMF ( 20 mL) of the mixture was purged with N2 and maintained at N2 atmosphere, stirred at 120 °C for 3 h Afterwards, it was diluted with water (200 mL) and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with DCM:PE=1:1) to obtain compound 79-1 (7.86 g, 23.51 mmol, yield: 87.06%). MS (ESI): m/z = 335 [M+H] + .
步骤2：将化合物79-1(7.86g,23.51mmol)、N2H4·H2O(18mL,370.36mmol)和MeOH(165mL)的混合物在80℃下搅拌18小时后浓缩。向浓缩物中加入H2O(50mL)，并用EA(50mL)萃取。将有机相用无水Na2SO4干燥后浓缩得到化合物79-2(MS(ESI)：m/z＝321[M+H]+)的粗产物(6.57g)。Step 2: A mixture of compound 79-1 (7.86 g, 23.51 mmol), N 2 H 4 ·H 2 O (18 mL, 370.36 mmol) and MeOH (165 mL) was stirred at 80° C. for 18 hours and concentrated. To the concentrate was added H2O (50 mL), and extracted with EA (50 mL). The organic phase was dried over anhydrous Na 2 SO 4 and concentrated to obtain the crude product (6.57 g) of compound 79-2 (MS (ESI): m/z=321 [M+H] + ).
步骤3：将化合物79-2的粗产物(200mg)、CDI(405.0mg,2.50mmol)和THF(20mL)的混合物用N2吹扫并维持N2氛围，在80℃下搅拌3小时后浓缩。向浓缩物中加入H2O(50mL)，并用EA(30mL)萃取。将有机相浓缩得到残余物。将所得残余物通过制备高效液相色谱纯化，得到化合物79(121.8mg,0.35mmol,产率：56.28％)。MS(ESI)：m/z＝347[M+H]+。1H NMR(400MHz,CHLOROFORM-d)δppm 6.80(d,J＝3.13Hz,1H)7.39(s,1H)7.42(d,J＝1.50Hz,1H)7.44(d,J＝3.38Hz,1H)7.54(dd,J＝7.88Hz,4.75Hz,1H)7.96(s,1H)8.32(dd,J＝7.88Hz,1.75Hz,1H)8.67(brd,J＝7.50Hz,1H)8.77(dd,J＝4.75Hz,1.75Hz,1H)。Step 3: The mixture of the crude product of compound 79-2 (200mg), CDI (405.0mg, 2.50mmol) and THF (20mL) was purged with N2 and maintained under N2 atmosphere, stirred at 80°C for 3 hours and then concentrated . To the concentrate was added H2O (50 mL), and extracted with EA (30 mL). The organic phase was concentrated to give a residue. The obtained residue was purified by preparative high performance liquid chromatography to obtain compound 79 (121.8 mg, 0.35 mmol, yield: 56.28%). MS (ESI): m/z = 347 [M+H] + . 1 H NMR (400MHz, CHLOROFORM-d) δppm 6.80 (d, J = 3.13Hz, 1H) 7.39 (s, 1H) 7.42 (d, J = 1.50Hz, 1H) 7.44 (d, J = 3.38Hz, 1H) 7.54(dd,J=7.88Hz,4.75Hz,1H)7.96(s,1H)8.32(dd,J=7.88Hz,1.75Hz,1H)8.67(brd,J=7.50Hz,1H)8.77(dd,J = 4.75Hz, 1.75Hz, 1H).
实施例80
Example 80
步骤1：将2-氨基-2-甲基丙酸甲酯盐酸盐(226mg,1.47mmol)、HATU(647mg,1.96mmol)、DIPEA(759mg,5.88mmol)和DMAP(12g,0.10mmol)加入到化合物2-(5-三氟甲基)-1H-吲哚-1-基烟酸(300mg,0.98mmol)的DMF(5mL)溶液中。将反应混合物在常温下搅拌过夜，用乙酸乙酯萃取。将有机相用无水硫酸钠干燥并浓缩得到残余物。将所得残余物经硅胶柱层析纯化，得到化合物80-1(263mg，0.65mmol)。MS(ESI)：m/z＝406[M+H]+。1H NMR(DMSO-d6)δ:8.97(s,1H),8.72(dd,J＝4.8,1.8Hz,1H),8.07(dd,J＝7.7,1.8Hz,1H),8.04(s,1H),7.83(d,J＝8.6Hz,1H),7.64(d,J＝3.5Hz,1H),7.59(dd,J＝7.7,4.8Hz,1H),7.49(dd,J＝8.8,1.5Hz,1H),6.85(d,J＝3.4Hz,1H),3.54(s,3H),1.25(s,6H)。Step 1: Methyl 2-amino-2-methylpropanoate hydrochloride (226mg, 1.47mmol), HATU (647mg, 1.96mmol), DIPEA (759mg, 5.88mmol) and DMAP (12g, 0.10mmol) were added To a solution of compound 2-(5-trifluoromethyl)-1H-indol-1-ylnicotinic acid (300 mg, 0.98 mmol) in DMF (5 mL). The reaction mixture was stirred overnight at room temperature, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography to obtain compound 80-1 (263 mg, 0.65 mmol). MS (ESI): m/z = 406 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.97(s, 1H), 8.72(dd, J=4.8, 1.8Hz, 1H), 8.07(dd, J=7.7, 1.8Hz, 1H), 8.04(s, 1H), 7.83(d, J=8.6Hz, 1H), 7.64(d, J=3.5Hz, 1H), 7.59(dd, J=7.7, 4.8Hz, 1H), 7.49(dd, J=8.8, 1.5 Hz, 1H), 6.85 (d, J=3.4Hz, 1H), 3.54 (s, 3H), 1.25 (s, 6H).
步骤2：将化合物80-1(210mg，0.50mmol)的胺甲醇(7M,5mL)溶液在80℃搅拌过夜，冷却至室温，加H2O稀释并用EA萃取。将有机相干燥并浓缩得到残余物。将残余物经柱层析纯化，得到化合物80-2(130mg，0.65mmol)。MS(ESI)：m/z＝391[M+H]+。1H NMR(DMSO-d6)δ:8.70(dd,J＝4.8,1.8Hz,1H),8.47(s,1H),8.27(dd,J＝7.6,1.9Hz,1H),8.03(s,1H),7.78(d,J＝8.8Hz,1H),7.72(d,J＝3.4Hz,1H),7.59(dd,J＝7.6,4.9Hz,1H),7.47(d,J＝8.8Hz,1H),7.09(br s,1H),6.90(br s,1H),6.81(d,J＝3.4Hz,1H),1.21(s,6H)。Step 2: A solution of compound 80-1 (210 mg, 0.50 mmol) in amine methanol (7M, 5 mL) was stirred at 80° C. overnight, cooled to room temperature, diluted with H 2 O and extracted with EA. The organic phase was dried and concentrated to a residue. The residue was purified by column chromatography to obtain compound 80-2 (130 mg, 0.65 mmol). MS (ESI): m/z = 391 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.70(dd, J=4.8, 1.8Hz, 1H), 8.47(s, 1H), 8.27(dd, J=7.6, 1.9Hz, 1H), 8.03(s, 1H), 7.78(d, J=8.8Hz, 1H), 7.72(d, J=3.4Hz, 1H), 7.59(dd, J=7.6, 4.9Hz, 1H), 7.47(d, J=8.8Hz, 1H), 7.09 (br s, 1H), 6.90 (br s, 1H), 6.81 (d, J=3.4Hz, 1H), 1.21 (s, 6H).
步骤3：向化合物80-2(120mg,0.31mmol)的MeOH(4mL)溶液中加入NaOH溶液(6N,0.26mL,1.56mmol)。将反应混合物加热回流并搅拌过夜，冷却至室温，用盐酸(2M)调节pH至中性，加H2O稀释并用EA萃取。将有机相干燥并浓缩得到残余物。将残余物依次经硅胶柱层析及制备高效液相色谱(Prep-HPLC)纯化，得到化合物80(26mg，0.069mmol，纯度：94.30％)。MS(ESI)：m/z＝373[M+H]+。1H NMR(DMSO-d6)δ:11.06(s,1H),8.80(br d,J＝3.4Hz,1H),8.21-8.35(m,1H),8.05(s,1H),7.69(dd,J＝7.8,4.9Hz,1H),7.66(d,J＝3.4Hz,1H),7.62(d,J＝8.8Hz,1H),7.47(br d,J＝8.8Hz,1H),6.85(d,J＝3.4Hz,1H),0.99(s,6H)。Step 3: To a solution of compound 80-2 (120 mg, 0.31 mmol) in MeOH (4 mL) was added NaOH solution (6N, 0.26 mL, 1.56 mmol). The reaction mixture was heated to reflux and stirred overnight, cooled to room temperature, adjusted to neutral pH with hydrochloric acid (2M), diluted with H2O and extracted with EA. The organic phase was dried and concentrated to a residue. The residue was purified by silica gel column chromatography and preparative high-performance liquid chromatography (Prep-HPLC) successively to obtain compound 80 (26 mg, 0.069 mmol, purity: 94.30%). MS (ESI): m/z = 373 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 11.06(s, 1H), 8.80(br d, J=3.4Hz, 1H), 8.21-8.35(m, 1H), 8.05(s, 1H), 7.69(dd ,J=7.8,4.9Hz,1H),7.66(d,J=3.4Hz,1H),7.62(d,J=8.8Hz,1H),7.47(br d,J=8.8Hz,1H),6.85( d, J=3.4Hz, 1H), 0.99(s, 6H).
实施例81
Example 81
步骤1：按照实施例80中步骤1的类似合成方法，以化合物2-(5-三氟甲基)-1H-吲哚-1-基烟酸和1-氨基环戊烷-1-羧酸甲酯盐酸盐作为反应物制备得到化合物81-1。MS(ESI)：m/z＝432[M+H]+。Step 1: According to the similar synthesis method of Step 1 in Example 80, the compound 2-(5-trifluoromethyl)-1H-indol-1-ylnicotinic acid and 1-aminocyclopentane-1-carboxylic acid Methyl ester hydrochloride was used as a reactant to prepare compound 81-1. MS (ESI): m/z = 432 [M+H] + .
步骤2：按照实施例80中步骤2的类似合成方法，以化合物81-1作为反应物制备得到化合物81-2。 MS(ESI)：m/z＝417[M+H]+。Step 2: According to the similar synthesis method of Step 2 in Example 80, Compound 81-2 was prepared using Compound 81-1 as a reactant. MS (ESI): m/z = 417 [M+H] + .
步骤3：按照实施例2中步骤3的类似合成方法，以化合物81-2作为反应物制备得到化合物81(15mg，0.037mmol，纯度：98.3％)。MS(ESI)：m/z＝399[M+H]+。1H NMR(DMSO-d6)δ:11.00(br s,1H),8.80(dd,J＝4.8,1.8Hz,1H),8.29(dd,J＝7.8,1.8Hz,1H),8.04(s,1H),7.63-7.70(m,2H),7.59(d,J＝8.6Hz,1H),7.46(dd,J＝8.8,1.5Hz,1H),6.85(d,J＝3.4Hz,1H),1.55-1.72(m,8H),1.31-1.44(m,2H)。Step 3: Compound 81 (15 mg, 0.037 mmol, purity: 98.3%) was prepared according to the similar synthesis method of Step 3 in Example 2, using compound 81-2 as a reactant. MS (ESI): m/z = 399 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 11.00 (br s, 1H), 8.80 (dd, J=4.8, 1.8Hz, 1H), 8.29 (dd, J=7.8, 1.8Hz, 1H), 8.04 (s ,1H),7.63-7.70(m,2H),7.59(d,J=8.6Hz,1H),7.46(dd,J=8.8,1.5Hz,1H),6.85(d,J=3.4Hz,1H) ,1.55-1.72(m,8H),1.31-1.44(m,2H).
实施例94
Example 94
步骤1：向2,5-二氯烟腈(1.0g，5.78mmol)和叔丁醇钠(666.59mg，6.94mmol)的N,N-二甲基甲酰胺溶液(15mL)中加入5-(三氟甲基)-1H-吲哚(1.07g，5.78mmol)。将反应混合物在120℃下搅拌12个小时后，加水(30mL)稀释，然后用乙酸乙酯(90mL)萃取。将有机相用饱和氯化钠溶液洗涤，干燥后浓缩，得到粗产物。将所得粗产物用硅胶柱层析(洗脱液梯度从石油醚:乙酸乙酯＝20:1过渡到4:1)纯化，得到化合物94-1(1.5g，4.66mmol，产率：80.67％)。Step 1: To a solution of 2,5-dichloronicotinonitrile (1.0 g, 5.78 mmol) and sodium tert-butoxide (666.59 mg, 6.94 mmol) in N,N-dimethylformamide (15 mL) was added 5-( Trifluoromethyl)-1H-indole (1.07 g, 5.78 mmol). After the reaction mixture was stirred at 120°C for 12 hours, it was diluted with water (30 mL), and extracted with ethyl acetate (90 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to obtain the crude product. The resulting crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether:ethyl acetate=20:1 to 4:1) to obtain compound 94-1 (1.5g, 4.66mmol, yield: 80.67% ).
步骤2：将盐酸羟胺(540.04mg，7.77mmol)加入到化合物94-1(500mg，1.55mmol)、三乙胺(2.15mL，15.54mmol)、分子筛(300mg)和甲醇(15mL)的混合物中。将反应混合物在80℃下搅拌12小时后浓缩。将水(15mL)加入到浓缩物中，用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，并用无水硫酸钠干燥后浓缩得到粗产物。将粗产物用硅胶柱层析(洗脱液梯度从石油醚:乙酸乙酯＝20:1过渡到2:1)纯化，得到化合物94-2(497mg，1.40mmol，产率：90.14％)。MS(ESI)：m/z＝355[M+H]+。Step 2: Hydroxylamine hydrochloride (540.04 mg, 7.77 mmol) was added to a mixture of compound 94-1 (500 mg, 1.55 mmol), triethylamine (2.15 mL, 15.54 mmol), molecular sieves (300 mg) and methanol (15 mL). The reaction mixture was stirred at 80 °C for 12 hours and then concentrated. Water (15 mL) was added to the concentrate, which was extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether:ethyl acetate=20:1 to 2:1) to obtain compound 94-2 (497 mg, 1.40 mmol, yield: 90.14%). MS (ESI): m/z = 355 [M+H] + .
步骤3：在0℃下，将N,N'-羰基二咪唑(142.85mg，0.88mmol)加入到化合物94-2(250mg，0.70mmol)的四氢呋喃(8mL)溶液中，在室温下搅拌30分钟后，加入1,8-二氮杂双环[5.4.0]-7-十一碳烯(157.79μL，1.06mmol)。将反应混合物搅拌1个小时后加水(15mL)稀释，用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，干燥后浓缩，得到粗产物。将粗产物用硅胶柱层析(洗脱液梯度从二氯甲烷:甲醇＝1:0过渡到10:1)纯化，得到化合物94(90mg,产率：33.54％)。MS(ESI)：m/z＝381[M+H]+。1H NMR(DMSO-d6)δ:8.92(d,J＝2.5Hz,1H),8.51(d,J＝2.5Hz,1H),8.06(s,1H),7.68(d,J＝8.6Hz,1H),7.62(d,J＝3.4Hz,1H),7.50(dd,J＝8.8,1.4Hz,1H),6.86(d,J＝3.4Hz,1H)。Step 3: Add N,N'-carbonyldiimidazole (142.85mg, 0.88mmol) to a solution of compound 94-2 (250mg, 0.70mmol) in tetrahydrofuran (8mL) at 0°C, and stir at room temperature for 30 minutes Afterwards, 1,8-diazabicyclo[5.4.0]-7-undecene (157.79 μL, 1.06 mmol) was added. The reaction mixture was stirred for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent gradient transition from dichloromethane:methanol=1:0 to 10:1) to obtain compound 94 (90 mg, yield: 33.54%). MS (ESI): m/z = 381 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.92(d, J=2.5Hz, 1H), 8.51(d, J=2.5Hz, 1H), 8.06(s, 1H), 7.68(d, J=8.6Hz , 1H), 7.62 (d, J=3.4Hz, 1H), 7.50 (dd, J=8.8, 1.4Hz, 1H), 6.86 (d, J=3.4Hz, 1H).
实施例95
Example 95
步骤1：向化合物2-氯喹啉-3-甲腈(1.88g，10mmol)的1-4二氧六环(20mL)混合物中加入5-三氟甲基吲哚(2.2g，12mmol)，CuI(92mg,0.5mmol)，反-(1R,2R)-N,N'-二甲基1,2-环己烷二胺(284mg，2mmol)，磷酸钾(4.2g，20mmol)将反应混合物用N2吹扫并维持N2氛围，在110℃下搅拌12小时后，加H2O(200mL)稀释，并用EA(50mL)萃取。将有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将所得残余物经硅胶柱层析(用EA:PE＝1:4洗脱)纯化，得到化合物95-1(1.3g,3.45mmol,产率：34.5％)。MS(ESI)：m/z＝338[M+H]+。Step 1: To a mixture of compound 2-chloroquinoline-3-carbonitrile (1.88 g, 10 mmol) in 1-4 dioxane (20 mL) was added 5-trifluoromethylindole (2.2 g, 12 mmol), CuI (92mg, 0.5mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (284mg, 2mmol), potassium phosphate (4.2g, 20mmol) the reaction mixture with N 2 purged and maintained N 2 atmosphere, after stirring at 110°C for 12 hours, diluted with H 2 O (200 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 95-1 (1.3 g, 3.45 mmol, yield: 34.5%). MS (ESI): m/z = 338 [M+H] + .
步骤2：将化合物95-1(1.3g,4.26mmol)、20mLMeOH、NH2OH·HCl(2.9g,42.6mmol)、TEA(10mL)和分子筛(1.3g)的混合物用N2吹扫并维持N2氛围，在80℃下搅拌3小时，减压过滤后，将滤液浓缩。相浓缩物中加入H2O(20mL)，并用EA(30mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将残余物经硅胶柱层析(用EA:PE＝1:2洗脱)纯化，得到化合物95-2(875mg,2.36mmol,产率：55.6％)。MS(ESI)：m/z＝371[M+H]+。Step 2: Compound 95-1 (1.3g, 4.26mmol), 20mL MeOH, NH 2 OH·HCl (2.9g, 42.6mmol), TEA (10mL) and The mixture of molecular sieves (1.3 g) was purged with N2 and maintained under N2 atmosphere, stirred at 80 °C for 3 hours, filtered under reduced pressure, and the filtrate was concentrated. The phase concentrate was added with H2O (20 mL) and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain compound 95-2 (875 mg, 2.36 mmol, yield: 55.6%). MS (ESI): m/z = 371 [M+H] + .
步骤3：将CDI(99.1mg,0.61mmol)在冰浴条件下加入到化合物95-2(200mg,0.51mmol)的THF(10mL)溶液中，在室温下搅拌30分钟后再次用冰浴冷却，滴入DBU(116mg,0.76mmol)后继续在冰浴条件下搅拌2h，加入HCl(aq，20mL，pH＝2)，并用EA(20mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用 无水Na2SO4干燥后浓缩得到残余物。将残余物经制备高效色谱纯化，得到化合物95(58mg,0.14mmol,产率：27％)。MS(ESI)：m/z＝397[M+H]+。1H NMR(DMSO-d6)δ＝9.06(s,1H),8.26(d,J＝7.6Hz,1H),8.15-8.07(m,2H),8.07-7.98(m,1H),7.92-7.76(m,2H),7.72(d,J＝3.5Hz,1H),7.55(dd,J＝1.5,8.8Hz,1H),6.92(d,J＝3.3Hz,1H)。Step 3: CDI (99.1 mg, 0.61 mmol) was added to a THF (10 mL) solution of compound 95-2 (200 mg, 0.51 mmol) in an ice bath, stirred at room temperature for 30 minutes and then cooled in an ice bath again, DBU (116mg, 0.76mmol) was added dropwise and stirred under ice bath for 2h, HCl (aq, 20mL, pH=2) was added, and extracted with EA (20mL). The organic phase was washed with saturated brine (10mL×3), washed with Drying over anhydrous Na2SO4 and concentration gave a residue. The residue was purified by preparative high performance chromatography to obtain compound 95 (58 mg, 0.14 mmol, yield: 27%). MS (ESI): m/z = 397 [M+H] + . 1 H NMR (DMSO-d 6 )δ=9.06(s,1H),8.26(d,J=7.6Hz,1H),8.15-8.07(m,2H),8.07-7.98(m,1H),7.92- 7.76 (m, 2H), 7.72 (d, J=3.5Hz, 1H), 7.55 (dd, J=1.5, 8.8Hz, 1H), 6.92 (d, J=3.3Hz, 1H).
实施例96
Example 96
在0℃下，将吡啶(54mg,0.69mmol)加入到化合物N-羟基-5-甲氧基-2-(5-三氟甲基)-1H-吲哚-1-基)烟酰胺(117-2)(120mg,0.34mmol)的DCM(4mL)溶液中，降温至-50℃后，加入SOCl2(49mg,0.41mmol)的DCM(0.5mL)溶液。将反应混合物在室温下搅拌3小时后浓缩。将浓缩物用DCM稀释，并用盐酸(1M)调节pH至中性。将有机相干燥并浓缩得到残余物。将残余物经硅胶柱层析纯化，得到化合物96(7mg，0.02mmol，产率：5％，纯度：93.18％)。MS(ESI)：m/z＝397[M+H]+。1H NMR(400MHz,DMSO-d6)δppm4.00(s,3H)6.78(d,J＝3.13Hz,1H)7.45(br d,J＝8.63Hz,1H)7.50(d,J＝3.25Hz,1H)7.55(d,J＝8.53Hz,1H)7.93(d,J＝2.75Hz,1H)8.02(s,1H)8.57(d,J＝2.75Hz,1H)。At 0°C, pyridine (54 mg, 0.69 mmol) was added to the compound N-hydroxy-5-methoxy-2-(5-trifluoromethyl)-1H-indol-1-yl)nicotinamide (117 -2) To a solution of (120 mg, 0.34 mmol) in DCM (4 mL), after cooling down to -50° C., a solution of SOCl 2 (49 mg, 0.41 mmol) in DCM (0.5 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The concentrate was diluted with DCM and the pH was adjusted to neutral with hydrochloric acid (1M). The organic phase was dried and concentrated to a residue. The residue was purified by silica gel column chromatography to obtain compound 96 (7 mg, 0.02 mmol, yield: 5%, purity: 93.18%). MS (ESI): m/z = 397 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δppm4.00(s,3H)6.78(d,J=3.13Hz,1H)7.45(br d,J=8.63Hz,1H)7.50(d,J=3.25Hz , 1H) 7.55 (d, J = 8.53Hz, 1H) 7.93 (d, J = 2.75Hz, 1H) 8.02 (s, 1H) 8.57 (d, J = 2.75Hz, 1H).
实施例97
Example 97
步骤1：向化合物3-氯-6,7-二氢-5H-环戊烷[c]吡啶-4-腈(1.78g，10mmol)的1-4Dioxane(20mL)混合物中加入5-三氟甲基吲哚(2.2g，12mmol)，CuI(92mg,0.5mmol)，反-(1R,2R)-N,N'-二甲基1,2-环己烷二胺(284mg，2mmol)，磷酸钾(4.2g，20mmol)。将反应混合物用N2吹扫并维持N2氛围，在110℃下搅拌12小时后，加水(200mL)稀释，并用EA(50mL)萃取。将有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将残余物经硅胶柱层析(用EA:PE＝1/4洗脱)纯化，得到化合物97-1(1.3g,4.26mmol,产率：42.6％)。MS(ESI)：m/z＝328[M+H]+。Step 1: To a mixture of compound 3-chloro-6,7-dihydro-5H-cyclopentane[c]pyridine-4-carbonitrile (1.78 g, 10 mmol) in 1-4Dioxane (20 mL) was added 5-trifluoroform Indole (2.2g, 12mmol), CuI (92mg, 0.5mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (284mg, 2mmol), phosphoric acid Potassium (4.2 g, 20 mmol). The reaction mixture was purged with N2 and maintained under N2 atmosphere, after stirring at 110 °C for 12 h, diluted with water (200 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/4) to obtain compound 97-1 (1.3 g, 4.26 mmol, yield: 42.6%). MS (ESI): m/z = 328 [M+H] + .
步骤2：将化合物97-1(1.3g,4.26mmol)、20mLMeOH、NH2OH·HCl(2.9g,42.6mmol)、TEA(10mL)和分子筛(1.3g)的混合物用N2吹扫并维持N2氛围，在80℃下搅拌3小时后减压过滤，并将滤液浓缩。将H2O(20mL)加入浓缩物中后，并用EA(30mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将残余物经硅胶柱层析(用EA:PE＝1:2洗脱)纯化，得到化合物97-2(855mg,2.36mmol,产率：55.6％)。MS(ESI)：m/z＝361[M+H]+。Step 2: Compound 97-1 (1.3g, 4.26mmol), 20mL MeOH, NH 2 OH·HCl (2.9g, 42.6mmol), TEA (10mL) and The mixture of molecular sieves (1.3 g) was purged with N2 and maintained under N2 atmosphere, stirred at 80 °C for 3 hours, filtered under reduced pressure, and the filtrate was concentrated. After adding H2O (20 mL) to the concentrate, it was extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain compound 97-2 (855 mg, 2.36 mmol, yield: 55.6%). MS (ESI): m/z = 361 [M+H] + .
步骤3：在冰浴条件下，将CDI(458mg,2.8mmol)加入到化合物97-2(855mg,2.36mmol)的THF(10mL)溶液中，在室温下搅拌30min后再次用冰浴冷却，滴入DBU(440mg,2.9mmol)后继续在冰浴条件下搅拌2h，加入20mL HCl(aq,pH＝2)，并用EA(20mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将所得残余物经制备高效液相色谱纯化，得到化合物97(58mg,0.14mmol,产率：6％)。MS(ESI)：m/z＝387[M+H]+。1H NMR(DMSO-d6)δ:8.65(s,1H),8.04(s,1H),7.66(d,J＝8.7Hz,1H),7.44-7.55(m,2H),6.84(d,J＝3.3Hz,1H),2.99-3.18(m,4H),2.10-2.21(m,2H)。Step 3: Add CDI (458mg, 2.8mmol) to a solution of compound 97-2 (855mg, 2.36mmol) in THF (10mL) under ice bath conditions, stir at room temperature for 30min, then cool with ice bath again, drop Added DBU (440mg, 2.9mmol) and continued to stir in ice bath for 2h, added 20mL HCl (aq, pH=2), and extracted with EA (20mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The resulting residue was purified by preparative high performance liquid chromatography to obtain compound 97 (58 mg, 0.14 mmol, yield: 6%). MS (ESI): m/z = 387 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.65(s, 1H), 8.04(s, 1H), 7.66(d, J=8.7Hz, 1H), 7.44-7.55(m, 2H), 6.84(d, J=3.3Hz, 1H), 2.99-3.18(m, 4H), 2.10-2.21(m, 2H).
实施例108
Example 108
步骤1：将2-氨基烟腈(500mg,4.20mmol)、1-氯-2-硝基-4-三氟甲基苯(0.63mL,4.20mmol)和碳酸铯(2735.00mg,8.39mmol)分散于DMF(10mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至100℃搅拌一个小时后，加水稀释，用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物108-1(880mg，产率：67.98％)。MS(ESI)：m/z＝309[M+H]+。Step 1: Disperse 2-aminonicotinonitrile (500mg, 4.20mmol), 1-chloro-2-nitro-4-trifluoromethylbenzene (0.63mL, 4.20mmol) and cesium carbonate (2735.00mg, 8.39mmol) in DMF (10 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 100°C and stirred for one hour, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 108-1 (880 mg, yield: 67.98%). MS (ESI): m/z = 309 [M+H] + .
步骤2：在室温下，依次将铁粉(956.57mg 17.13mmol)和氯化铵(916.32mg,17.13mmol)加入到化合物108-1(880mg,2.86mmol)的乙醇(12mL)和水(3mL)的溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃并搅拌2小时后趁热过滤。将滤液浓缩得到残余物，将残余物用硅胶柱层析(用石油醚:乙酸乙酯＝5:1洗脱)纯化，得到化合物108-2(562mg，产率：70.74％)。MS(ESI)：m/z＝279[M+H]+。Step 2: Add iron powder (956.57mg, 17.13mmol) and ammonium chloride (916.32mg, 17.13mmol) to compound 108-1 (880mg, 2.86mmol) in ethanol (12mL) and water (3mL) at room temperature in the solution. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80 °C and stirred for 2 hours, then filtered while hot. The filtrate was concentrated to obtain a residue, which was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=5:1) to obtain compound 108-2 (562 mg, yield: 70.74%). MS (ESI): m/z = 279 [M+H] + .
步骤3：将化合物108-2(560mg,2.01mmol)的原甲酸三甲酯(5mL)的溶液微波(150W，140℃)2.5小时，冷却至室温，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用制备硅胶板(用乙酸乙酯:石油醚＝1:2洗脱)纯化，得到化合物108-3(510mg，产率：87.91％)。MS(ESI)：m/z＝289[M+H]+。Step 3: A solution of compound 108-2 (560mg, 2.01mmol) in trimethyl orthoformate (5mL) was microwaved (150W, 140°C) for 2.5 hours, cooled to room temperature, diluted with water, and washed with ethyl acetate (50mL×2 )extraction. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified with a preparative silica gel plate (eluted with ethyl acetate:petroleum ether=1:2) to obtain compound 108-3 (510 mg, yield: 87.91%). MS (ESI): m/z = 289 [M+H] + .
步骤4：在室温下，依次将盐酸羟胺(1205.46mg,17.35mmol),分子筛(500mg,2.23mmol)和TEA(14.43mL,104.08mmol)加入到化合物108-3(500mg,1.73mmol)的甲醇(15mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至75℃后搅拌过夜，加入饱和氯化铵的水溶液将反应淬灭，过滤后用乙酸乙酯(50mL×2)萃取。将合并后的有机相用无水硫酸钠干燥后浓缩得到化合物108-4(MS(ESI)：m/z＝322[M+H]+)的粗产物(579mg)，所得粗产物无需进一步纯化而直接用于下一步反应。Step 4: At room temperature, successively add hydroxylamine hydrochloride (1205.46mg, 17.35mmol), Molecular sieves (500 mg, 2.23 mmol) and TEA (14.43 mL, 104.08 mmol) were added to a solution of compound 108-3 (500 mg, 1.73 mmol) in methanol (15 mL). The reaction mixture was purged with N2 and maintained under N2 atmosphere, slowly warmed up to 75 °C and stirred overnight, then quenched by adding saturated aqueous ammonium chloride solution, filtered and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain the crude product (579 mg) of compound 108-4 (MS (ESI): m/z=322[M+H] + ), which was obtained without further purification and directly used in the next reaction.
步骤5：在室温下，将化合物108-4的粗产物分散于四氢呋喃(8mL)中，并在冰浴条件下加入CDI(365.30mg,2.25mmol)，缓慢升至室温搅拌30分钟后又在冰浴条件下加入DBU(403.50μL,2.70mmol)，反应体系缓慢升至室温搅拌1小时。反应完全后用水将反应体系稀释，再用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用制备硅胶板(用乙酸乙酯洗脱)纯化，得到化合物108(130mg，产率：20.77％)。MS(ESI)：m/z＝348[M+H]+。1H NMR(DMSO-d6)δ:8.81(dd,J＝4.6,1.3Hz,1H),8.63(s,1H),8.42(dd,J＝7.9,1.4Hz,1H),8.13(s,1H),7.79(dd,J＝7.8,4.9Hz,1H),7.62(s,2H)。Step 5: At room temperature, the crude product of compound 108-4 was dispersed in tetrahydrofuran (8 mL), and CDI (365.30 mg, 2.25 mmol) was added under ice-bath conditions, slowly raised to room temperature and stirred for 30 minutes, and then placed on ice DBU (403.50 μL, 2.70 mmol) was added under bath conditions, and the reaction system was slowly raised to room temperature and stirred for 1 hour. After the reaction was complete, the reaction system was diluted with water, and then extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified with a preparative silica gel plate (eluted with ethyl acetate) to obtain compound 108 (130 mg, yield: 20.77%). MS (ESI): m/z = 348 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.81(dd, J=4.6, 1.3Hz, 1H), 8.63(s, 1H), 8.42(dd, J=7.9, 1.4Hz, 1H), 8.13(s, 1H), 7.79 (dd, J=7.8, 4.9 Hz, 1H), 7.62 (s, 2H).
实施例111
Example 111
步骤1：将5-(三氟甲基)-1H-吡咯[2,3-b]吡啶(806mg,4.33mmol)和叔丁醇钠(416.17mg,4.33mmol)加入到2-氯烟腈(0.45mL,4.33mmol)的DMF(10mL)中。将反应混合物升温到80℃搅拌2小时后，加水(30mL)稀释，并用乙酸乙酯(20mL*3)萃取。将合并所得的有机相浓缩得到残余物。将残余物经快速柱层析(用石油醚:乙酸乙酯＝3:1洗脱)纯化，得到化合物111-1(670mg，2.32mmol，产率：53.68％)。1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝4.9,1.8Hz,1H),8.57–8.73(m,3H),8.16(d,J＝3.8,1H),7.79(d,J＝7.9,4.9Hz,1H),7.01(d,J＝3.8Hz,1H)。Step 1: 5-(Trifluoromethyl)-1H-pyrrole[2,3-b]pyridine (806 mg, 4.33 mmol) and sodium tert-butoxide (416.17 mg, 4.33 mmol) were added to 2-chloronicotinonitrile ( 0.45 mL, 4.33 mmol) in DMF (10 mL). The reaction mixture was warmed up to 80°C and stirred for 2 hours, diluted with water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were concentrated to give a residue. The residue was purified by flash column chromatography (eluted with petroleum ether:ethyl acetate=3:1) to obtain compound 111-1 (670 mg, 2.32 mmol, yield: 53.68%). 1 H NMR (400MHz, DMSO-d 6 ) δ8.94(d, J=4.9, 1.8Hz, 1H), 8.57–8.73(m, 3H), 8.16(d, J=3.8, 1H), 7.79(d , J=7.9, 4.9Hz, 1H), 7.01 (d, J=3.8Hz, 1H).
步骤2：将盐酸羟胺(807.66mg,11.62mmol)，TEA(6.44mL,46.49mmol)和分子筛(100mg)加 入到化合物111-1(670mg,2.32mmol)的甲醇(10mL)溶液中。将反应混合物升温到80℃搅拌2小时后过滤。将所得滤液浓缩后用水(30mL)稀释，并用乙酸乙酯(30mL*3)萃取。将合并所得的有机相浓缩得残余物。将所得残余物经快速柱层析(用二氯甲烷:甲醇＝10:1洗脱)纯化，得到化合物111-2(270mg,0.84mmol,产率：36.16％)。MS(ESI)：m/z＝322[M+H]+。Step 2: Hydroxylamine hydrochloride (807.66mg, 11.62mmol), TEA (6.44mL, 46.49mmol) and Molecular sieve (100mg) plus into a solution of compound 111-1 (670 mg, 2.32 mmol) in methanol (10 mL). The reaction mixture was warmed up to 80°C and stirred for 2 hours, then filtered. The resulting filtrate was concentrated, diluted with water (30 mL), and extracted with ethyl acetate (30 mL*3). The combined organic phases were concentrated to obtain a residue. The resulting residue was purified by flash column chromatography (eluted with dichloromethane:methanol=10:1) to obtain compound 111-2 (270 mg, 0.84 mmol, yield: 36.16%). MS (ESI): m/z = 322 [M+H] + .
步骤3：在0℃下，将CDI(0.13mL,1.05mmol)加入化合物111-2(270mg,0.84mmol)的四氢呋喃(2mL)溶液中，在0℃下搅拌0.5小时后加入DBU(0.19mL,1.26mmol)，升温到室温搅拌1小时后，加水(3mL)稀释，并用乙酸乙酯(3mL*3)萃取。将合并所得的有机相浓缩得残余物。将所得残余物通过制备高效液相色谱(HPLC)纯化，得到化合物111(15.47mg,0.04mmol,产率：5.29％)。MS(ESI)：m/z＝348[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.25–13.58(m,1H),8.77–8.95(m,1H),8.43–8.59(m,2H),8.28–8.41(m,1H),8.12(d,J＝3.6Hz,1H),7.79(d,J＝7.7,4.8Hz,1H),6.93(d,J＝3.6Hz,1H)。Step 3: Add CDI (0.13mL, 1.05mmol) to a solution of compound 111-2 (270mg, 0.84mmol) in tetrahydrofuran (2mL) at 0°C, stir at 0°C for 0.5 hours, then add DBU (0.19mL, 1.26 mmol), warmed to room temperature and stirred for 1 hour, diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated to obtain a residue. The obtained residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 111 (15.47 mg, 0.04 mmol, yield: 5.29%). MS (ESI): m/z = 348 [M+H] + . 1 H NMR (400MHz,DMSO-d 6 )δ12.25–13.58(m,1H),8.77–8.95(m,1H),8.43–8.59(m,2H),8.28–8.41(m,1H),8.12 (d, J=3.6Hz, 1H), 7.79 (d, J=7.7, 4.8Hz, 1H), 6.93 (d, J=3.6Hz, 1H).
实施例113
Example 113
步骤1：在室温下，依次将2-碘-4-三氟甲基苯胺(1.0g,3.48mmol)溶于丙炔(8mL)和DMF(1mL)中依次加入碘化亚铜(0.07g,0.35mmol)、双三苯基磷二氯化钯(0.12g,0.17mmol)和三乙胺(3mL,21.64mmol)。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃后搅拌16个小时，加水稀释，并用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用硅胶柱层析(用石油醚洗脱)纯化，得到化合物113-1(677mg，产率：97.56％)。MS(ESI)：m/z＝200[M+H]+。Step 1: At room temperature, successively dissolve 2-iodo-4-trifluoromethylaniline (1.0g, 3.48mmol) in propyne (8mL) and DMF (1mL) and add cuprous iodide (0.07g, 0.35mmol), bistriphenylphosphinepalladium dichloride (0.12g, 0.17mmol) and triethylamine (3mL, 21.64mmol). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80 °C and stirred for 16 hours, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 113-1 (677 mg, yield: 97.56%). MS (ESI): m/z = 200 [M+H] + .
步骤2：在室温下，将叔丁醇钾(381.39mg,3.40mmol)加入到化合物113-1(677mg,3.40mmol)的NMP(8mL)溶液中。将反应混合物缓慢升温至80℃后搅拌2个小时，加水将稀释，并用乙酸乙酯(100mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用硅胶柱层析(用石油醚洗脱)纯化，得到化合物113-2(380mg,产率：56.13％)。Step 2: Potassium tert-butoxide (381.39 mg, 3.40 mmol) was added to a solution of compound 113-1 (677 mg, 3.40 mmol) in NMP (8 mL) at room temperature. The reaction mixture was slowly warmed to 80°C and stirred for 2 hours, diluted with water, and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 113-2 (380 mg, yield: 56.13%).
步骤3：将化合物113-2(320mg,1.61mmol)、2-氯烟腈(222.59mg,1.61mmol)、叔丁醇钾(360.55mg,3.21mmol)和DMF(8mL)的混合物缓慢升温至100℃后搅拌1个小时，加水稀释，并用乙酸乙酯(100mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物113-3(156mg,产率：32.23％)。MS(ESI)：m/z＝300[M+H]+。Step 3: The mixture of compound 113-2 (320mg, 1.61mmol), 2-chloronicotinonitrile (222.59mg, 1.61mmol), potassium tert-butoxide (360.55mg, 3.21mmol) and DMF (8mL) was slowly heated to 100 After stirring at ℃ for 1 hour, dilute with water, and extract with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 113-3 (156 mg, yield: 32.23%). MS (ESI): m/z = 300 [M+H] + .
步骤4：在室温下，将盐酸羟胺(359.82mg,5.18mmol),分子筛(160mg,2.23mmol),和三乙胺(4.31mL,31.07mmol)依次加入到化合物113-3(156mg,0.52mmol)的甲醇(5mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至75℃后搅拌过夜，用饱和氯化铵淬灭后过滤。将所得滤液用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:1洗脱)纯化，得到化合物113-4(168mg,产率：97.05％)。MS(ESI)：m/z＝335[M+H]+。Step 4: At room temperature, hydroxylamine hydrochloride (359.82mg, 5.18mmol), Molecular sieves (160 mg, 2.23 mmol), and triethylamine (4.31 mL, 31.07 mmol) were sequentially added to a solution of compound 113-3 (156 mg, 0.52 mmol) in methanol (5 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 75 °C, stirred overnight, quenched with saturated ammonium chloride, and filtered. The resulting filtrate was extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:1) to obtain compound 113-4 (168 mg, yield: 97.05%). MS (ESI): m/z = 335 [M+H] + .
步骤5：在冰浴条件下，将CDI(101.86mg,0.63mmol)加入到化合物113-4(168mg,0.50mmol)的四氢呋喃(3mL)溶液中，缓慢升至室温搅拌30min后，再次在冰浴条件下加入DBU(112.51μL,0.75mmol)。将反应混合物缓慢升至室温后搅拌1小时，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用硅胶柱层析(用乙酸乙酯洗脱)纯化，得到化合物113(19.7mg,产率：10.91％)。MS(ESI)：m/z＝361[M+H]+。1HNMR(DMSO-d6)δ:12.74-13.24(m,1H),8.93(dd,J＝4.9,1.8Hz,1H),8.45(dd,J＝7.9,1.8Hz,1H),7.92(s,1H),7.89(dd,J＝7.9,4.8Hz,1H),7.31(dd,J＝8.6,1.4Hz,1H),6.99(d,J＝8.5Hz,1H),6.62(s,1H),2.25(s,3H)。Step 5: Add CDI (101.86mg, 0.63mmol) to a solution of compound 113-4 (168mg, 0.50mmol) in tetrahydrofuran (3mL) under ice bath conditions, slowly rise to room temperature and stir for 30min, then again in ice bath DBU (112.51 μL, 0.75 mmol) was added under conditions. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 113 (19.7 mg, yield: 10.91%). MS (ESI): m/z = 361 [M+H] + . 1 H NMR (DMSO-d 6 ) δ: 12.74-13.24 (m, 1H), 8.93 (dd, J=4.9, 1.8Hz, 1H), 8.45 (dd, J=7.9, 1.8Hz, 1H), 7.92 (s ,1H),7.89(dd,J=7.9,4.8Hz,1H),7.31(dd,J=8.6,1.4Hz,1H),6.99(d,J=8.5Hz,1H),6.62(s,1H) ,2.25(s,3H).
实施例114
Example 114
步骤1：按照实施例67中步骤1的类似合成方法，以2-氯-4-甲基苯甲腈和5-(三氟甲基)-1H-吲哚作为反应物制备得到化合物114-1。MS(ESI)：m/z＝301[M+H]+。Step 1: According to the similar synthesis method of step 1 in Example 67, compound 114-1 was prepared using 2-chloro-4-methylbenzonitrile and 5-(trifluoromethyl)-1H-indole as reactants . MS (ESI): m/z = 301 [M+H] + .
步骤2：按照实施例67中步骤2的类似合成方法，以化合物114-1作为反应物制备得到化合物114-2。MS(ESI)：m/z＝334[M+H]+。Step 2: According to the similar synthesis method of Step 2 in Example 67, Compound 114-2 was prepared using Compound 114-1 as a reactant. MS (ESI): m/z = 334 [M+H] + .
步骤3：按照实施例67中步骤3的类似合成方法，以化合物114-2作为反应物制备得到化合物114(85mg,纯度：99.6％)。MS(ESI)：m/z＝358[M+H]+。1H NMR(DMSO-d6)δ＝12.61(br s,1H),8.05(s,1H),7.78(d,J＝7.9Hz,1H),7.59-7.54(m,2H),7.53(s,1H),7.43(d,J＝8.1Hz,1H),7.24(d,J＝8.6Hz,1H),6.83(d,J＝3.1Hz,1H),2.48-2.46(m,3H)。Step 3: According to the similar synthesis method of Step 3 in Example 67, Compound 114 (85 mg, purity: 99.6%) was prepared using Compound 114-2 as a reactant. MS (ESI): m/z = 358 [M+H] + . 1 H NMR (DMSO-d 6 )δ=12.61(br s,1H),8.05(s,1H),7.78(d,J=7.9Hz,1H),7.59-7.54(m,2H),7.53(s , 1H), 7.43 (d, J=8.1Hz, 1H), 7.24 (d, J=8.6Hz, 1H), 6.83 (d, J=3.1Hz, 1H), 2.48-2.46 (m, 3H).
实施例116
Example 116
步骤1：在室温下，将2-氯-4-甲基烟腈(200mg,1.31mmol)、5-(三氟甲基)-1H-吲哚(242.69mg,1.31mmol)和碳酸铯(854.16mg,2.62mmol)分散于DMF(5mL)。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至100℃后搅拌1小时，加水稀释，并用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物116-1(166mg，产率：42.04％)。MS(ESI)：m/z＝302[M+H]+。Step 1: At room temperature, mix 2-chloro-4-methylnicotinonitrile (200mg, 1.31mmol), 5-(trifluoromethyl)-1H-indole (242.69mg, 1.31mmol) and cesium carbonate (854.16 mg, 2.62mmol) was dispersed in DMF (5mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 100° C., stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 116-1 (166 mg, yield: 42.04%). MS (ESI): m/z = 302 [M+H] + .
步骤2：在室温下，依次将盐酸羟胺(369.05mg,5.31mmol)、分子筛(160mg,2.23mmol)和三乙胺(4.42mL,31.87mmol)加入到化合物116-1(160mg,0.53mmol)的甲醇(8mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至75℃后搅拌过夜，加入饱和氯化铵淬灭后过滤。将所得滤液用乙酸乙酯(50mL×2)萃取，并将合并所得有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用硅胶柱层析(用乙酸乙酯洗脱)纯化，得到化合物116-2(125mg，产率：70.41％)。MS(ESI)：m/z＝335[M+H]+。Step 2: At room temperature, successively add hydroxylamine hydrochloride (369.05mg, 5.31mmol), Molecular sieves (160 mg, 2.23 mmol) and triethylamine (4.42 mL, 31.87 mmol) were added to a solution of compound 116-1 (160 mg, 0.53 mmol) in methanol (8 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, the temperature was slowly raised to 75 °C, stirred overnight, quenched by adding saturated ammonium chloride, and filtered. The resulting filtrate was extracted with ethyl acetate (50 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 116-2 (125 mg, yield: 70.41%). MS (ESI): m/z = 335 [M+H] + .
步骤3：在冰浴条件下，将CDI(75.79mg,0.47mmol)加入到化合物116-2(125mg,0.37mmol)的四氢呋喃(3mL)溶液中，在室温下搅拌30min后，再次在冰浴条件下加入DBU(83.71μL,0.56mmol)。将反应混合物缓慢升温至室温后搅拌1小时，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用制备硅胶板(乙酸乙酯)纯化，得到化合物116(40mg，产率：29.69％)。MS(ESI)：m/z＝361[M+H]+。1H NMR(DMSO-d6)δ:12.59-12.87(m,1H),8.72(d,J＝5.0Hz,1H),8.06(s,1H),7.70(d,J＝8.8Hz,1H),7.64(d,J＝5.1Hz,1H),7.51-7.53(m,1H),7.49-7.51(m,1H),6.86(d,J＝3.3Hz,1H)。Step 3: Add CDI (75.79mg, 0.47mmol) to a solution of compound 116-2 (125mg, 0.37mmol) in tetrahydrofuran (3mL) under ice bath conditions, stir at room temperature for 30min, and again under ice bath conditions DBU (83.71 μL, 0.56 mmol) was added at the bottom. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified with a preparative silica gel plate (ethyl acetate) to obtain compound 116 (40 mg, yield: 29.69%). MS (ESI): m/z = 361 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.59-12.87 (m, 1H), 8.72 (d, J = 5.0Hz, 1H), 8.06 (s, 1H), 7.70 (d, J = 8.8Hz, 1H) , 7.64 (d, J=5.1Hz, 1H), 7.51-7.53 (m, 1H), 7.49-7.51 (m, 1H), 6.86 (d, J=3.3Hz, 1H).
实施例117
Example 117
步骤1：按照实施例116中步骤1的类似合成方法，以2-氯-5-甲氧基烟腈和5-(三氟甲基)-1H-吲哚作为反应物制备得到化合物117-1。MS(ESI)：m/z＝318[M+H]+。Step 1: According to the similar synthesis method of Step 1 in Example 116, compound 117-1 was prepared using 2-chloro-5-methoxynicotinonitrile and 5-(trifluoromethyl)-1H-indole as reactants . MS (ESI): m/z = 318 [M+H] + .
步骤2：按照实施例116中步骤2的类似合成方法，以化合物117-1作为反应物制备得到化合物117-2。MS(ESI)：m/z＝351[M+H]+。 Step 2: According to the similar synthesis method of Step 2 in Example 116, Compound 117-2 was prepared using Compound 117-1 as a reactant. MS (ESI): m/z = 351 [M+H] + .
步骤3：按照实施例116中步骤3的类似合成方法，以化合物117-2作为反应物制备得到化合物117(50mg，0.13mmol，产率：58％，纯度：98.29％)。MS(ESI)：m/z＝377[M+H]+。1H NMR(DMSO-d6)δ:8.55(d,J＝2.9Hz,1H),8.04(s,1H),7.95(d,J＝2.9Hz,1H),7.59(d,J＝3.3Hz,1H),7.41-7.50(m,2H),6.81(d,J＝3.3Hz,1H),3.99(s,3H),3.35(br s,1H)。Step 3: Compound 117 (50 mg, 0.13 mmol, yield: 58%, purity: 98.29%) was prepared according to the similar synthesis method of step 3 in Example 116, using compound 117-2 as a reactant. MS (ESI): m/z = 377 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.55(d, J=2.9Hz, 1H), 8.04(s, 1H), 7.95(d, J=2.9Hz, 1H), 7.59(d, J=3.3Hz , 1H), 7.41-7.50 (m, 2H), 6.81 (d, J=3.3Hz, 1H), 3.99 (s, 3H), 3.35 (br s, 1H).
实施例118
Example 118
步骤1：在室温下，将2-氯-5-氟烟腈(250mg,1.60mmol)、5-(三氟甲基)-1H-吲哚(296.24mg,1.60mmol)和碳酸铯(1042.62mg,3.20mmol)分散于DMF(5mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至120℃后搅拌1小时，加水稀释，并用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物118-1(90mg，产率：18.43％)。MS(ESI)：m/z＝306[M+H]+。Step 1: 2-Chloro-5-fluoronicotinonitrile (250mg, 1.60mmol), 5-(trifluoromethyl)-1H-indole (296.24mg, 1.60mmol) and cesium carbonate (1042.62mg , 3.20mmol) was dispersed in DMF (5mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 120° C., stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 118-1 (90 mg, yield: 18.43%). MS (ESI): m/z = 306 [M+H] + .
步骤2：在室温下，依次将盐酸羟胺(182.13mg,2.62mmol)、分子筛(80mg,0.26mmol)和三乙胺(2.18mL,15.73mmol)加入到化合物118-2(80mg,0.26mmol)的甲醇(3mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃后搅拌3个小时，用饱和氯化铵将反应液淬灭后过滤。将所得滤液用乙酸乙酯(50mL×2)萃取，并将合并所得有机相用无水硫酸钠干燥后浓缩得到参悟与。将所得残余物用硅胶柱层析(用石油醚:乙酸乙酯＝1:1洗脱)纯化，得到化合物118-2(87mg，产率：98.13％)。MS(ESI)：m/z＝339[M+H]+。Step 2: At room temperature, successively add hydroxylamine hydrochloride (182.13mg, 2.62mmol), Molecular sieves (80 mg, 0.26 mmol) and triethylamine (2.18 mL, 15.73 mmol) were added to a solution of compound 118-2 (80 mg, 0.26 mmol) in methanol (3 mL). The reaction mixture was purged with N 2 and the N 2 atmosphere was maintained, the temperature was slowly raised to 80°C and stirred for 3 hours, the reaction solution was quenched with saturated ammonium chloride and filtered. The resulting filtrate was extracted with ethyl acetate (50mL×2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain ginseng. The resulting residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=1:1) to obtain compound 118-2 (87 mg, yield: 98.13%). MS (ESI): m/z = 339 [M+H] + .
步骤3：在冰浴条件下，将CDI(100.06mg,0.62mmol)加入到化合物118-2(167mg,0.49mmol)的四氢呋喃(3mL)溶液中，在室温下搅拌30分钟后，再次在冰浴条件下加入DBU(110.53μL,0.74mmol)。将反应混合物缓慢升至室温后搅拌1小时，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用制备硅胶板(乙酸乙酯)纯化，得到化合物118(23mg，产率：12.79％)。MS(ESI)：m/z＝363[M-H]-。1H NMR(DMSO-d6)δ:8.80(dd,J＝4.8,1.8Hz,1H),8.37(dd,J＝7.8,1.7Hz,1H),8.19(s,1H),7.74(s,1H),7.71(dd,J＝7.8,4.8Hz,1H),7.64(d,J＝3.4Hz,1H),6.85(d,J＝3.3Hz,1H)。Step 3: Add CDI (100.06mg, 0.62mmol) to a solution of compound 118-2 (167mg, 0.49mmol) in tetrahydrofuran (3mL) under ice-bath conditions, stir at room temperature for 30 minutes, and again in ice-bath DBU (110.53 μL, 0.74 mmol) was added under conditions. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified with a preparative silica gel plate (ethyl acetate) to obtain compound 118 (23 mg, yield: 12.79%). MS (ESI): m/z = 363 [MH] - . 1 H NMR (DMSO-d 6 )δ: 8.80(dd, J=4.8, 1.8Hz, 1H), 8.37(dd, J=7.8, 1.7Hz, 1H), 8.19(s, 1H), 7.74(s, 1H), 7.71 (dd, J=7.8, 4.8Hz, 1H), 7.64 (d, J=3.4Hz, 1H), 6.85 (d, J=3.3Hz, 1H).
实施例119
Example 119
步骤1：向5-溴-2-[5-(三氟甲基)吲哚-1-基]吡啶-3-甲腈(400mg，1.09mmol)、碳酸钾(301.96mg,2.18mmol)和双[5-(二苯基膦基)环戊-1,3-二烯基]-λ2-铁(II)氯化钯(79.94mg,0.11mmol)的1,4-二氧六环(10mL)和水(2mL)的混合溶液中加入乙基硼酸(80.72mg,1.09mmol)。将反应混合物用N2吹扫并维持N2氛围，在90℃下搅拌12个小时，加水(15mL)后，用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，并用无水硫酸钠干燥后浓缩，得到粗产物。将所得粗产物用硅胶柱层析(洗脱剂梯度由石油醚:乙酸乙酯＝20:1过渡到5:1)纯化，得到化合物119-1(140mg，0.44mmol，产率：40.64％)。MS(ESI)：m/z＝316[M+H]+。Step 1: To 5-bromo-2-[5-(trifluoromethyl)indol-1-yl]pyridine-3-carbonitrile (400mg, 1.09mmol), potassium carbonate (301.96mg, 2.18mmol) and bis [5-(Diphenylphosphino)cyclopent-1,3-dienyl]-λ2-iron(II)palladium chloride (79.94 mg, 0.11 mmol) in 1,4-dioxane (10 mL) Ethylboronic acid (80.72mg, 1.09mmol) was added to the mixed solution with water (2mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at 90° C. for 12 hours, added water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether:ethyl acetate=20:1 to 5:1) to obtain compound 119-1 (140mg, 0.44mmol, yield: 40.64%) . MS (ESI): m/z = 316 [M+H] + .
步骤2：将盐酸羟胺(104.69mg，2.14mmol)加入到化合物119-1(135mg，0.43mmol)、三乙胺(0.42mL，4.28mmol)、分子筛(100mg)、和甲醇(10mL)的混合物中。将反应混合物在80℃下搅拌3个小时后浓缩。向所得浓缩物中加入水(15mL)，并用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用硅胶柱层析(洗脱液梯度从石油醚:乙酸乙酯＝20:1过渡到1:1)纯化，得到化合物119-2的粗产物(123mg)。MS(ESI)：m/z＝349[M+H]+。 Step 2: Hydroxylamine hydrochloride (104.69 mg, 2.14 mmol) was added to a mixture of compound 119-1 (135 mg, 0.43 mmol), triethylamine (0.42 mL, 4.28 mmol), molecular sieves (100 mg), and methanol (10 mL) . The reaction mixture was stirred at 80 °C for 3 hours and then concentrated. Water (15 mL) was added to the obtained concentrate, and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from petroleum ether:ethyl acetate=20:1 to 1:1) to obtain a crude product of compound 119-2 (123 mg). MS (ESI): m/z = 349 [M+H] + .
步骤3:将化合物119-2的粗产物(123mg)和N,N'-羰基二咪唑(71.57mg,0.44mmol)分散到四氢呋喃(5mL)中，在0℃下反应30分钟后，加入1,8-二氮杂双环[5.4.0]-7-十一碳烯(79.06μL,0.53mmol)。将反应混合物在室温下反应1个小时后，用水(15mL)淬灭，并用乙酸乙酯(15mL×3)萃取。将合并所得的有机相用水洗涤后浓缩得到残余物。将所得残余物用硅胶柱层析(洗脱液梯度从二氯甲烷:甲醇＝1:0过渡到10:1)纯化，得到化合物119(30.2mg，0.08mmol，纯度：99.87％)。MS(ESI)：m/z＝375[M+H]+。1H NMR(DMSO-d6)δ:12.77(br s,1H),8.74(d,J＝2.1Hz,1H),8.23(d,J＝2.3Hz,1H),8.06(s,1H),7.59-7.65(m,2H),7.49(dd,J＝8.7,1.4Hz,1H),6.85(d,J＝3.4Hz,1H),2.81(q,J＝7.5Hz,2H),1.30(t,J＝7.6Hz,3H)。Step 3: Disperse the crude product of compound 119-2 (123mg) and N,N'-carbonyldiimidazole (71.57mg, 0.44mmol) in tetrahydrofuran (5mL), react at 0°C for 30 minutes, then add 1, 8-Diazabicyclo[5.4.0]-7-undecene (79.06 μL, 0.53 mmol). After reacting the reaction mixture at room temperature for 1 hour, it was quenched with water (15 mL), and extracted with ethyl acetate (15 mL×3). The combined organic phases were washed with water and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from dichloromethane:methanol=1:0 to 10:1) to obtain compound 119 (30.2 mg, 0.08 mmol, purity: 99.87%). MS (ESI): m/z = 375 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.77(br s, 1H), 8.74(d, J=2.1Hz, 1H), 8.23(d, J=2.3Hz, 1H), 8.06(s, 1H), 7.59-7.65(m, 2H), 7.49(dd, J=8.7, 1.4Hz, 1H), 6.85(d, J=3.4Hz, 1H), 2.81(q, J=7.5Hz, 2H), 1.30(t , J=7.6Hz, 3H).
实施例121
Example 121
步骤1：将5-溴-2-氯烟腈(3.00g，13.80mmol)、叔丁醇钠(1.59g，16.56mmol)、5-(三氟甲基)-1H-吲哚(2.55g，13.80mmol)、以及N,N-二甲基甲酰胺(30mL)的混合物在120℃下搅拌3个小时，用水(40mL)稀释，然后用乙酸乙酯(120mL)萃取。将有机相用饱和氯化钠溶液洗涤，干燥后浓缩得到粗产物。将粗产物经硅胶色谱柱(洗脱剂梯度从石油醚:乙酸乙酯＝20:1过渡到5:1)纯化，得到化合物121-1(1.19g，3.25mmol，产率23.56％)。Step 1: Mix 5-bromo-2-chloronicotinonitrile (3.00g, 13.80mmol), sodium tert-butoxide (1.59g, 16.56mmol), 5-(trifluoromethyl)-1H-indole (2.55g, 13.80 mmol), and N,N-dimethylformamide (30 mL) were stirred at 120° C. for 3 hours, diluted with water (40 mL), and extracted with ethyl acetate (120 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (eluent gradient transition from petroleum ether:ethyl acetate=20:1 to 5:1) to obtain compound 121-1 (1.19 g, 3.25 mmol, yield 23.56%).
步骤2：将盐酸羟胺(759.16mg，10.92mmol)加入到化合物121-1(800mg，2.18mmol)、三乙胺(3.03mL，21.85mmol)、分子筛(500mg)、和甲醇(30mL)的混合物中。将反应混合物在80℃下搅拌12个小时后浓缩。将水(20mL)加入到所得浓缩物中，并用乙酸乙酯(60mL)萃取。将有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩得到粗产物。将所得粗产物用硅胶柱层析(洗脱剂梯度从石油醚:乙酸乙酯＝20:1过渡到1：1)纯化，得到化合物121-2的粗产物(820mg)。MS(ESI)：m/z＝399，401[M+H]+。Step 2: Hydroxylamine hydrochloride (759.16 mg, 10.92 mmol) was added to a mixture of compound 121-1 (800 mg, 2.18 mmol), triethylamine (3.03 mL, 21.85 mmol), molecular sieves (500 mg), and methanol (30 mL) . The reaction mixture was stirred at 80 °C for 12 hours and then concentrated. Water (20 mL) was added to the obtained concentrate, and extracted with ethyl acetate (60 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether:ethyl acetate=20:1 to 1:1) to obtain a crude product of compound 121-2 (820 mg). MS (ESI): m/z = 399, 401 [M+H] + .
步骤3:将化合物121-2(820mg,2.05mmol)和N,N'-羰基二咪唑(416.37mg,2.57mmol)分散到四氢呋喃(12mL)中，在0℃下反应30分钟后，加入1,8-二氮杂双环[5.4.0]-7-十一碳烯(459.91μL,3.08mmol)。将反应混合物在室温下反应1个小时后，用水(20mL)淬灭，并用乙酸乙酯(20mL×3)萃取。将合并所得的有机相用水洗涤后浓缩，得到残余物。将所得残余物用硅胶色谱法(洗脱液梯度从二氯甲烷:甲醇＝1:0过渡到10:1)纯化，得到化合物121-3(495mg,1.16mmol,产率：56.67％)。Step 3: Disperse compound 121-2 (820mg, 2.05mmol) and N,N'-carbonyldiimidazole (416.37mg, 2.57mmol) in tetrahydrofuran (12mL), react at 0°C for 30 minutes, add 1, 8-Diazabicyclo[5.4.0]-7-undecene (459.91 μL, 3.08 mmol). After reacting the reaction mixture at room temperature for 1 hour, it was quenched with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases are washed with water and concentrated to give a residue. The resulting residue was purified by silica gel chromatography (eluent gradient transition from dichloromethane:methanol=1:0 to 10:1) to obtain compound 121-3 (495 mg, 1.16 mmol, yield: 56.67%).
步骤4:将氰化锌(181.17mg,1.54mmol)加入到化合物121-3(164mg，0.39mmol)和四(三苯基膦)钯(89.15mg,0.08mmol)、和N,N-二甲基甲酰胺溶液(1.9mL)的混合物中。将反应混合物用N2吹扫并维持N2氛围，然后在120℃下搅拌12个小时后，加入水(10mL)，并用乙酸乙酯(30mL)萃取。将有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，得到残余物。将所得残余物使用硅胶柱层析(用石油醚：乙酸乙酯＝10/1)纯化，得到化合物121(18.56mg,产率：13.0％)。MS(ESI)：m/z＝372[M+H]+。Step 4: Zinc cyanide (181.17 mg, 1.54 mmol) was added to compound 121-3 (164 mg, 0.39 mmol) and tetrakis(triphenylphosphine) palladium (89.15 mg, 0.08 mmol), and N,N-dimethyl in a mixture of methyl formamide solution (1.9 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, then stirred at 120° C. for 12 hours, water (10 mL) was added, and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified using silica gel column chromatography (petroleum ether: ethyl acetate = 10/1) to obtain compound 121 (18.56 mg, yield: 13.0%). MS (ESI): m/z = 372 [M+H] + .
1H NMR(DMSO-d6)δ:9.23(d,J＝2.1Hz,1H),8.79(d,J＝2.1Hz,1H),8.06(s,1H),7.87(d,J＝8.6Hz,1H),7.61(d,J＝3.6Hz,1H),7.54(dd,J＝8.8,1.6Hz,1H),6.89(d,J＝3.5Hz,1H)。 1 H NMR (DMSO-d 6 )δ: 9.23(d, J=2.1Hz, 1H), 8.79(d, J=2.1Hz, 1H), 8.06(s, 1H), 7.87(d, J=8.6Hz , 1H), 7.61 (d, J=3.6Hz, 1H), 7.54 (dd, J=8.8, 1.6Hz, 1H), 6.89 (d, J=3.5Hz, 1H).
实施例122
Example 122
步骤1：将5,6-二甲基-2-氧代-1,2-二氢吡啶-3-甲腈(1.16g，7.83mmol)溶于三氯氧磷(15mL)中。将反应混合物加热到110℃，搅拌12小时后浓缩，加入饱和碳酸氢钠溶液稀释并淬灭所得浓缩物直至无气泡产生，并用乙酸乙酯(90mL)萃取。将有机相用饱和氯化钠溶液洗涤，干燥并浓缩得到化合物122-1的粗产物(1.12g)。所得粗产物无需纯化可直接用于下一步反应。MS(ESI)：m/z＝167[M+H]+。Step 1: 5,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1.16 g, 7.83 mmol) was dissolved in phosphorus oxychloride (15 mL). The reaction mixture was heated to 110° C., stirred for 12 hours, concentrated, diluted with saturated sodium bicarbonate solution and quenched until no bubbles occurred, and extracted with ethyl acetate (90 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to give a crude product of compound 122-1 (1.12 g). The obtained crude product was directly used in the next reaction without further purification. MS (ESI): m/z = 167 [M+H] + .
步骤2：将5-(三氟甲基)-1H-吲哚(1.19g，6.42mmol)加入到化合物122-1的粗产物(1.07g，6.42mmol)、叔丁醇钠(0.8g，7.06mmol)和N,N-二甲基甲酰胺(15mL)的混合物中。将反应混合物在120℃下搅拌1.5个小时后，加水(30mL)稀释，然后用乙酸乙酯(90mL)萃取。将有机相用饱和氯化钠溶液洗涤，干燥后浓缩得到粗产物。将所得粗产物用硅胶柱层析(洗脱剂梯度从石油醚:乙酸乙酯＝20:1过渡到5:1)纯化，得到化合物122-2(1.01g，3.21mmol，产率：49.98％)。Step 2: 5-(trifluoromethyl)-1H-indole (1.19g, 6.42mmol) was added to the crude product of compound 122-1 (1.07g, 6.42mmol), sodium tert-butoxide (0.8g, 7.06 mmol) and N,N-dimethylformamide (15 mL). After the reaction mixture was stirred at 120°C for 1.5 hours, it was diluted with water (30 mL), and extracted with ethyl acetate (90 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether:ethyl acetate=20:1 to 5:1) to obtain compound 122-2 (1.01g, 3.21mmol, yield: 49.98% ).
步骤3：将盐酸羟胺(550.98mg，7.93mmol)加入到化合物122-2(500mg，1.59mmol)、三乙胺(2.2mL，15.86mmol)、分子筛(300mg)和甲醇(15mL)的混合物中。将反应混合物在80℃下搅拌12个小时后，加入水(15mL)，并用乙酸乙酯(45mL)萃取。将有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，得到粗产物。将所得粗产物用硅胶柱层析(洗脱剂梯度从石油醚：乙酸乙酯＝20:1过渡到1:1)纯化，得到化合物122-3(344mg，0.99mmol，产率：62.28％)。MS(ESI)：m/z＝349[M+H]+。Step 3: Hydroxylamine hydrochloride (550.98 mg, 7.93 mmol) was added to a mixture of compound 122-2 (500 mg, 1.59 mmol), triethylamine (2.2 mL, 15.86 mmol), molecular sieves (300 mg) and methanol (15 mL). After the reaction mixture was stirred at 80°C for 12 hours, water (15 mL) was added, and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether: ethyl acetate = 20:1 to 1:1) to obtain compound 122-3 (344mg, 0.99mmol, yield: 62.28%) . MS (ESI): m/z = 349 [M+H] + .
步骤4：在冰浴条件下，将N,N'-羰基二咪唑(200.17mg,1.23mmol)加入到化合物122-3(344mg,0.99mmol)的四氢呋喃(10mL)溶液中，在0℃下反应30分钟后加入1,8-二氮杂双环[5.4.0]-7-十一碳烯(221.1μL,1.48mmol)。将反应混合物在室温下反应1个小时后，用水(15mL)淬灭，并用乙酸乙酯(15mL×3)萃取。将合并所得有机相水洗，干燥浓缩得到残余物。将所得残余物用硅胶柱层析(洗脱剂梯度从二氯甲烷:甲醇＝1/0过渡到10/1)纯化，得到化合物122-4(95mg,产率：25.70％)。MS(ESI)：m/z＝375[M+H]+。Step 4: Add N,N'-carbonyldiimidazole (200.17mg, 1.23mmol) to a solution of compound 122-3 (344mg, 0.99mmol) in tetrahydrofuran (10mL) under ice bath conditions, and react at 0°C After 30 minutes 1,8-diazabicyclo[5.4.0]-7-undecene (221.1 μL, 1.48 mmol) was added. After reacting the reaction mixture at room temperature for 1 hour, it was quenched with water (15 mL), and extracted with ethyl acetate (15 mL×3). The combined organic phases were washed with water, dried and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from dichloromethane:methanol=1/0 to 10/1) to obtain compound 122-4 (95 mg, yield: 25.70%). MS (ESI): m/z = 375 [M+H] + .
1H NMR(DMSO-d6)δ:12.70(br s,1H),8.09(s,1H),8.05(s,1H),7.56-7.64(m,2H),7.48(dd,J＝8.7,1.4Hz,1H),6.84(d,J＝3.4Hz,1H),2.57(s,3H),2.42(s,3H)。 1 H NMR (DMSO-d 6 )δ: 12.70 (br s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.56-7.64 (m, 2H), 7.48 (dd, J=8.7, 1.4Hz, 1H), 6.84(d, J=3.4Hz, 1H), 2.57(s, 3H), 2.42(s, 3H).
实施例123
Example 123
步骤1：将5-三氟甲基吲哚(2，88mg，0.48mmol)和叔丁醇钠(46mg,0.48mmol)加入到化合物2-氯-6-三氟甲基烟腈(100mg，0.48mmol)的DMF(2mL)溶液中。将反应混合物在氮气氛围及在80℃下搅拌3小时后，冷却至25℃，加入饱和氯化铵溶液(5mL)淬灭，并用EA(50mL)萃取。将有机相用饱和 食盐水洗涤(3次)，干燥后浓缩得到残余物。将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡到5:1)纯化，得到化合物123-1(83mg,0.23mmol)。Step 1: Add 5-trifluoromethylindole (2, 88 mg, 0.48 mmol) and sodium tert-butoxide (46 mg, 0.48 mmol) to compound 2-chloro-6-trifluoromethylnicotinonitrile (100 mg, 0.48 mmol) in DMF (2 mL). After stirring the reaction mixture at 80 °C under nitrogen atmosphere for 3 h, it was cooled to 25 °C, quenched by adding saturated ammonium chloride solution (5 mL), and extracted with EA (50 mL). Saturate the organic phase with Washed with brine (3 times), dried and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=20:1 to 5:1) to obtain compound 123-1 (83 mg, 0.23 mmol).
步骤2：向化合物123-1(83mg，0.23mmol)的甲醇(5mL)溶液中依次加入盐酸羟胺(162mg，2.3mmol),分子筛(83mg)和三乙胺(1.9mL,14mmol)。将反应混合物在75℃下搅拌8小时，冷却至25℃后过滤。将饱和氯化铵溶液(5mL)加到所得滤液中以淬灭反应，并用EA(50mL)萃取。将有机相用饱和食盐水洗涤(3次)，干燥后浓缩得到残余物。将所得残余物通过硅胶柱层析(洗脱剂梯度从PE:EA＝5:1过渡至1:1)纯化，得到化合物123-2(69mg，0.18mmol)。Step 2: Add hydroxylamine hydrochloride (162mg, 2.3mmol) successively to compound 123-1 (83mg, 0.23mmol) in methanol (5mL), Molecular sieves (83 mg) and triethylamine (1.9 mL, 14 mmol). The reaction mixture was stirred at 75°C for 8 hours, cooled to 25°C and filtered. Saturated ammonium chloride solution (5 mL) was added to the resulting filtrate to quench the reaction, and extracted with EA (50 mL). The organic phase was washed with saturated brine (3 times), dried and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=5:1 to 1:1) to obtain compound 123-2 (69 mg, 0.18 mmol).
步骤3：在0℃下，将CDI(36.5mg,0.22mmol)加入到化合物123-2(83mg,0.28mmol)的THF(2mL)溶液中，升温至室温后搅拌30分钟，在0℃下加入DBU(41μL，0.27mmol)。将反应混合物升温至室温，搅拌1小时后浓缩。将饱和氯化铵溶液(2mL)加入到所得浓缩物中以淬灭反应，并用EA(20mL)萃取。将有机相用饱和食盐水洗涤(3次)，干燥并浓缩得到残余物。将所得残余物依次经硅胶柱层析(先用PE：EA＝1/1，随后用DCM洗脱)和制备高效液相色谱(HPLC)纯化，得到化合物123(13mg,0.03mmol,产率：17％)。MS(ESI)：m/z＝413[M-H]-。Step 3: Add CDI (36.5mg, 0.22mmol) to a THF (2mL) solution of compound 123-2 (83mg, 0.28mmol) at 0°C, warm to room temperature and stir for 30 minutes, then add DBU (41 μL, 0.27 mmol). The reaction mixture was warmed to room temperature, stirred for 1 hour and then concentrated. Saturated ammonium chloride solution (2 mL) was added to the resulting concentrate to quench the reaction, and extracted with EA (20 mL). The organic phase was washed with saturated brine (3 times), dried and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (firstly eluted with PE:EA=1/1, then with DCM) and preparative high performance liquid chromatography (HPLC) to obtain compound 123 (13mg, 0.03mmol, yield: 17%). MS (ESI): m/z = 413 [MH] - .
1H NMR(DMSO-d6)δ:8.62(d,J＝7.9Hz,1H),8.22(d,J＝8.0Hz,1H),8.09(s,1H),7.76(d,J＝8.8Hz,1H),7.65(d,J＝3.5Hz,1H),7.55-7.63(m,1H),6.90(d,J＝3.5Hz,1H)。 1 H NMR (DMSO-d 6 )δ: 8.62(d, J=7.9Hz, 1H), 8.22(d, J=8.0Hz, 1H), 8.09(s, 1H), 7.76(d, J=8.8Hz , 1H), 7.65 (d, J=3.5Hz, 1H), 7.55-7.63 (m, 1H), 6.90 (d, J=3.5Hz, 1H).
实施例124
Example 124
步骤1：在室温下，依次将2-氯-6-甲基烟腈(300mg,1.97mmol)、5-(三氟甲基)-1H-吲哚(364.04mg,1.97mmol)和碳酸铯(1281.24mg,3.93mmol)分散于DMF(8mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至120℃并搅拌1小时，加水稀释，并用乙酸乙酯(100mL×3)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物124-1(570mg，产率：96.04％)。MS(ESI)：m/z＝302[M+H]+。Step 1: At room temperature, 2-chloro-6-methylnicotinonitrile (300mg, 1.97mmol), 5-(trifluoromethyl)-1H-indole (364.04mg, 1.97mmol) and cesium carbonate ( 1281.24 mg, 3.93 mmol) was dispersed in DMF (8 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed slowly to 120° C. and stirred for 1 h, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 124-1 (570 mg, yield: 96.04%). MS (ESI): m/z = 302 [M+H] + .
步骤2：在室温下，依次将盐酸羟胺(1314.74mg,18.92mmol)、分子筛(675mg,2.23mmol)和TEA(15.74mL,113.52mmol)加入到化合物124-1(570mg,1.89mmol)的甲醇(20mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至75℃后搅拌过夜，用饱和氯化铵淬灭后过滤。将所得滤液用乙酸乙酯(50mL×2)萃取，并将合并所得的有机相用无水硫酸钠干燥后浓缩。将浓缩所得残余物用硅胶柱层析(用石油醚:乙酸乙酯＝5:1洗脱)纯化，得到化合物124-2(504mg，产率：79.68％)。MS(ESI)：m/z＝335[M+H]+。Step 2: At room temperature, successively add hydroxylamine hydrochloride (1314.74mg, 18.92mmol), Molecular sieves (675 mg, 2.23 mmol) and TEA (15.74 mL, 113.52 mmol) were added to a solution of compound 124-1 (570 mg, 1.89 mmol) in methanol (20 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 75 °C, stirred overnight, quenched with saturated ammonium chloride, and filtered. The resulting filtrate was extracted with ethyl acetate (50 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=5:1) to obtain compound 124-2 (504 mg, yield: 79.68%). MS (ESI): m/z = 335 [M+H] + .
步骤3：在冰浴条件下，将CDI(121.26mg,0.75mmol)加入到化合物124-2(200mg,0.60mmol)的四氢呋喃(5mL)溶液中，在室温下搅拌30min后，再次在冰浴条件下加入DBU(0.13mL,0.90mmol)。将反应混合物缓慢升至室温后搅拌1小时，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将所得残余物经制备硅胶板(用乙酸乙酯洗脱)纯化，得到化合物124(91mg，产率：42.22％)。MS(ESI)：m/z＝361[M+H]+。1H NMR(DMSO-d6)δ:12.99(br d,J＝2.5Hz,1H),8.27(d,J＝8.0Hz,1H),8.06(s,1H),7.68(d,J＝8.6Hz,1H),7.63(d,J＝3.5Hz,1H),7.61(d,J＝8.1Hz,1H),7.49(dd,J＝8.8,1.3Hz,1H),6.86(d,J＝3.3Hz,1H),2.63(s,3H)。Step 3: Add CDI (121.26mg, 0.75mmol) to a solution of compound 124-2 (200mg, 0.60mmol) in tetrahydrofuran (5mL) under ice bath conditions, stir at room temperature for 30min, and again under ice bath conditions DBU (0.13 mL, 0.90 mmol) was added at the same time. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The resulting residue was purified on a preparative silica gel plate (eluted with ethyl acetate) to obtain compound 124 (91 mg, yield: 42.22%). MS (ESI): m/z = 361 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.99(br d, J=2.5Hz, 1H), 8.27(d, J=8.0Hz, 1H), 8.06(s, 1H), 7.68(d, J=8.6 Hz, 1H), 7.63(d, J=3.5Hz, 1H), 7.61(d, J=8.1Hz, 1H), 7.49(dd, J=8.8, 1.3Hz, 1H), 6.86(d, J=3.3 Hz,1H), 2.63(s,3H).
实施例125
Example 125
步骤1：向6-氯-5-碘吡啶-2-胺(5.0g,19.65mmol)的DMF(30mL)溶液中加入Zn(CN)2(2.31g,19.65mmol)和Pd(PPh3)4(2.27g,1.96mmol)。将反应混合物在65℃下搅拌过夜，冷却至室温后加水稀释，并用EA萃取。将有机相用饱和食盐水洗涤(3次)，干燥并浓缩，得到残余物。将所述残余物通过硅胶柱层析纯化，得到化合物125-1(2.56g，16.73mmol)。MS(ESI)：m/z＝154[M+H]+。Step 1: To a solution of 6-chloro-5-iodopyridin-2-amine (5.0 g, 19.65 mmol) in DMF (30 mL) was added Zn(CN) 2 (2.31 g, 19.65 mmol) and Pd(PPh 3 ) 4 (2.27g, 1.96mmol). The reaction mixture was stirred overnight at 65 °C, cooled to room temperature, diluted with water, and extracted with EA. The organic phase was washed with saturated brine (3 times), dried and concentrated to give a residue. The residue was purified by silica gel column chromatography to obtain compound 125-1 (2.56 g, 16.73 mmol). MS (ESI): m/z = 154 [M+H] + .
步骤2：按照实施例67中步骤1的类似合成方法，以化合物125-1作为反应物制备得到化合物125-2。MS(ESI)：m/z＝303[M+H]+。Step 2: According to the similar synthesis method of Step 1 in Example 67, Compound 125-2 was prepared using Compound 125-1 as a reactant. MS (ESI): m/z = 303 [M+H] + .
步骤3：按照实施例67中步骤2的类似合成方法，以化合物125-2作为反应物制备得到化合物125-3。MS(ESI)：m/z＝336[M+H]+。Step 3: According to the similar synthesis method of Step 2 in Example 67, Compound 125-3 was prepared using Compound 125-2 as a reactant. MS (ESI): m/z = 336 [M+H] + .
步骤4：按照实施例67中步骤3的类似合成方法，以化合物125-3作为反应物制备得到化合物125-4。MS(ESI)：m/z＝362[M+H]+。Step 4: According to the similar synthesis method of Step 3 in Example 67, Compound 125-4 was prepared using Compound 125-3 as a reactant. MS (ESI): m/z = 362 [M+H] + .
步骤5：向化合物125-4(200mg,0.55mmol)的乙腈(10mL)溶液中加入t-BuONO(90mg,0.87mmol)和CuCl2(140mg,1.04mmol)。将反应混合物在70℃下搅拌过夜，过滤，并将所得滤液用乙酸乙酯萃取。将有机相用无水硫酸钠干燥并浓缩得到残余物，将所得残余物经硅胶柱层析纯化，得到化合物125(30mg，0.08mmol)。MS(ESI)：m/z＝381[M+H]+。1H NMR(DMSO-d6)δ:12.85(br s,1H),8.36-8.40(m,J＝8.1Hz,1H),8.08(s,1H),7.87-7.91(m,J＝8.1Hz,1H),7.74(d,J＝8.8Hz,1H),7.63(d,J＝3.5Hz,1H),7.56(dd,J＝8.8,1.6Hz,1H),6.90(d,J＝3.3Hz,1H)。Step 5: To a solution of compound 125-4 (200 mg, 0.55 mmol) in acetonitrile (10 mL) was added t-BuONO (90 mg, 0.87 mmol) and CuCl 2 (140 mg, 1.04 mmol). The reaction mixture was stirred overnight at 70 °C, filtered, and the resulting filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue, which was purified by silica gel column chromatography to obtain compound 125 (30 mg, 0.08 mmol). MS (ESI): m/z = 381 [M+H] + . 1 H NMR (DMSO-d 6 ) δ: 12.85 (br s, 1H), 8.36-8.40 (m, J=8.1Hz, 1H), 8.08 (s, 1H), 7.87-7.91 (m, J=8.1Hz ,1H),7.74(d,J=8.8Hz,1H),7.63(d,J=3.5Hz,1H),7.56(dd,J=8.8,1.6Hz,1H),6.90(d,J=3.3Hz ,1H).
实施例126
Example 126
步骤1：将5-溴-2-氯烟腈(500mg,2.30mmol)、5-三氟甲基吲哚(425.73mg,2.30mmol)和碳酸铯(1498.37mg,4.60mmol)分散于DMF(10mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至120℃搅拌1小时，加水稀释后，用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩。将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物126-1(600mg，产率：71.27％)。Step 1: Disperse 5-bromo-2-chloronicotinonitrile (500mg, 2.30mmol), 5-trifluoromethylindole (425.73mg, 2.30mmol) and cesium carbonate (1498.37mg, 4.60mmol) in DMF (10mL )middle. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed up to 120 °C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 126-1 (600 mg, yield: 71.27%).
步骤2：在室温下，依次将化合物126-1(1130mg,3.09mmol)、联硼酸频那醇酯(1175.58mg,4.63mmol)、乙酸钾(605.77mg,6.17mmol)和Pd(dppf)Cl2(225.82mg,0.31mmol)分散于1，4-二氧六环(20mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至95℃后搅拌过夜，加水稀释，并用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩。将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物126-2(1100mg，产率：86.26％)。MS(ESI)：m/z＝414[M+H]+。Step 2: Compound 126-1 (1130mg, 3.09mmol), pinacol diboronate (1175.58mg, 4.63mmol), potassium acetate (605.77mg, 6.17mmol) and Pd(dppf)Cl 2 were sequentially mixed at room temperature (225.82 mg, 0.31 mmol) was dispersed in 1,4-dioxane (20 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 95 °C, stirred overnight, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 126-2 (1100 mg, yield: 86.26%). MS (ESI): m/z = 414 [M+H] + .
步骤3：在室温下，将化合物126-2(1.1g,2.66mmol)、2-氟溴甲基苯(0.38mL,3.19mmol)、碳酸钾(0.74g,5.32mmol)和Pd(dppf)Cl2(0.19g,0.27mmol)分散于乙腈(20mL)和水(4mL)的混合溶剂中。将反应混合 物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌过夜，加水稀释，并用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩，并将所得的残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5)纯化，得到化合物126-3(554mg，产率：52.64％)。MS(ESI)：m/z＝396[M+H]+。Step 3: Compound 126-2 (1.1 g, 2.66 mmol), 2-fluorobromomethylbenzene (0.38 mL, 3.19 mmol), potassium carbonate (0.74 g, 5.32 mmol) and Pd(dppf)Cl were mixed at room temperature 2 (0.19g, 0.27mmol) was dispersed in a mixed solvent of acetonitrile (20mL) and water (4mL). mix the reaction The mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed up to 80 °C and stirred overnight, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (with ethyl acetate:petroleum ether=1:5) to obtain compound 126-3 (554 mg, yield rate: 52.64%). MS (ESI): m/z = 396 [M+H] + .
步骤4：在室温下，依次将盐酸羟胺(790.94mg,11.38mmol)、分子筛(450mg,2.23mmol)、和TEA(9.47mL,68.29mmol)加入到化合物126-3(450mg,1.14mmol)的甲醇(15mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至75℃后搅拌过夜，用饱和氯化铵淬灭，过滤后用乙酸乙酯(50mL×2)萃取。将合并所得到的有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝2:1洗脱)纯化，得到化合物126-4(316mg，产率：64.81％)。MS(ESI)：m/z＝429[M+H]+。Step 4: At room temperature, successively add hydroxylamine hydrochloride (790.94mg, 11.38mmol), Molecular sieves (450 mg, 2.23 mmol), and TEA (9.47 mL, 68.29 mmol) were added to a solution of compound 126-3 (450 mg, 1.14 mmol) in methanol (15 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 75 °C and stirred overnight, quenched with saturated ammonium chloride, filtered and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=2:1) to obtain compound 126-4 (316mg , yield: 64.81%). MS (ESI): m/z = 429 [M+H] + .
步骤5：在冰浴条件下，将CDI(149.51mg,0.92mmol)加入到化合物126-4(316mg,0.74mmol)的四氢呋喃(3mL)溶液中，缓慢升至室温后搅拌30min，再次在冰浴条件下加入DBU(165.15μL，1.11mmol，1mL)。将反应混合物缓慢升至室温后搅拌1小时，用水稀释，再用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用制备硅胶板(用乙酸乙酯洗脱)纯化，得到化合物126(81mg，产率：24.17％)。MS(ESI)：m/z＝453[M-H]-。1H NMR(DMSO-d6)δ:10.86(br dd,J＝7.8,3.8Hz,1H),8.77(br s,1H),8.16(br s,1H),8.05(br s,1H),7.66(br d,J＝8.5Hz,1H),7.59(br d,J＝2.4Hz,1H),7.49(br d,J＝5.5Hz,2H),7.35(br d,J＝6.0Hz,1H),7.16-7.29(m,2H),6.85(br s,1H),4.20(br s,2H)。Step 5: Add CDI (149.51mg, 0.92mmol) to a solution of compound 126-4 (316mg, 0.74mmol) in tetrahydrofuran (3mL) under ice-bath conditions, slowly rise to room temperature and stir for 30min. DBU (165.15 μL, 1.11 mmol, 1 mL) was added under conditions. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified on a preparative silica gel plate (eluted with ethyl acetate) to obtain compound 126 (81 mg, yield: 24.17%). MS (ESI): m/z = 453 [MH] - . 1 H NMR (DMSO-d 6 )δ: 10.86 (br dd, J=7.8, 3.8Hz, 1H), 8.77 (br s, 1H), 8.16 (br s, 1H), 8.05 (br s, 1H), 7.66(br d,J=8.5Hz,1H),7.59(br d,J=2.4Hz,1H),7.49(br d,J=5.5Hz,2H),7.35(br d,J=6.0Hz,1H ), 7.16-7.29 (m, 2H), 6.85 (br s, 1H), 4.20 (br s, 2H).
实施例127
Example 127
步骤1：向化合物5-溴-2-氯烟腈(2.14g，10mmol)的DMF(20mL)混合物中加入5-三氟甲基吲哚(2.2g，12mmol)和叔丁醇钠(1.9g,20mmol)。将反应混合物在80℃下搅拌3小时，加H2O(200mL)稀释，并用EA(50mL)萃取。将有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将所得残余物经硅胶柱层析(EA:PE＝1/4)纯化，得到化合物127-1(3.09g,8.5mmol,产率：84.5％)。MS(ESI)：m/z＝366,368[M+H]+。Step 1: To a mixture of compound 5-bromo-2-chloronicotinonitrile (2.14 g, 10 mmol) in DMF (20 mL) was added 5-trifluoromethylindole (2.2 g, 12 mmol) and sodium tert-butoxide (1.9 g ,20mmol). The reaction mixture was stirred at 80 °C for 3 h, diluted with H2O (200 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (EA:PE=1/4) to obtain compound 127-1 (3.09 g, 8.5 mmol, yield: 84.5%). MS (ESI): m/z = 366,368 [M+H] + .
步骤2：将化合物127-1(1.8g,5mmol)、3-羟基吡咯烷(560mg，6.5mmol)Pd2(dba)3(450mg,0.5mmol)，XantPhos(570mg，1mmol)，和1-4二氧六环(20mL)的混合物在80℃下搅拌12小时后浓缩。向浓缩物中加H2O(100mL)，并用EA(50mL)萃取。将有机相用无水Na2SO4干燥后浓缩，并将所得残余物通过硅胶柱层析(用EA:PE＝1:4洗脱)纯化，得到化合物127-2(1.01g,2.7mmol,产率：54.6％)。MS(ESI)：m/z＝373[M+H]+。Step 2: Compound 127-1 (1.8g, 5mmol), 3-hydroxypyrrolidine (560mg, 6.5mmol) Pd 2 (dba) 3 (450mg, 0.5mmol), XantPhos (570mg, 1mmol), and 1-4 The mixture of dioxane (20 mL) was stirred at 80°C for 12 hours and then concentrated. To the concentrate was added H2O (100 mL), and extracted with EA (50 mL). The organic phase was dried over anhydrous Na 2 SO 4 and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 127-2 (1.01 g, 2.7 mmol, Yield: 54.6%). MS (ESI): m/z = 373 [M+H] + .
步骤3：将化合物127-2(1g,2.7mmol)、MeOH(20mL)、NH2OH·HCl(1.8g,27mmol)、TEA(10mL)和的混合物用N2吹扫并维持N2氛围，在80℃下搅拌3小时后，减压过滤。将所得滤液浓缩后加入H2O(20mL)，并用EA(30mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩。将所得残余物经硅胶柱层析(用EA:PE＝1:2洗脱)纯化，得到化合物127-3(595mg,1.47mmol,产率：54.5％)。MS(ESI)：m/z＝406[M+H]+。Step 3: Compound 127-2 (1 g, 2.7 mmol), MeOH (20 mL), NH 2 OH·HCl (1.8 g, 27 mmol), TEA (10 mL) and The mixture was purged with N2 and maintained under N2 atmosphere, after stirring at 80 °C for 3 h, it was filtered under reduced pressure. The resulting filtrate was concentrated, added H 2 O (20 mL), and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated. The resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain compound 127-3 (595 mg, 1.47 mmol, yield: 54.5%). MS (ESI): m/z = 406 [M+H] + .
步骤4：在冰浴条件下，将CDI(46mg,0.28mmol)加入到化合物127-3(100mg,0.24mmol)的THF(10mL)溶液中，室温下搅拌30min后，在冰浴条件下滴入DBU(54.7mg,0.36mmol)。将反应混合物在冰浴条件下搅拌2h后，加入HCl水溶液(pH＝2，20mL)，并用EA(20mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物通过硅胶柱层析(用MeOH:DCM＝1:20洗脱)纯化，得到化合物127(3mg,0.006mmol,产率：2.5％)。MS(ESI)：m/z＝432[M+H]+。Step 4: Add CDI (46mg, 0.28mmol) to a THF (10mL) solution of compound 127-3 (100mg, 0.24mmol) under ice-bath conditions, stir at room temperature for 30min, then drop into DBU (54.7 mg, 0.36 mmol). After the reaction mixture was stirred under ice bath for 2 h, aqueous HCl (pH=2, 20 mL) was added and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:20) to obtain Compound 127 (3 mg, 0.006 mmol, yield: 2.5%). MS (ESI): m/z = 432 [M+H] + .
1H NMR(DMSO-d6)δ:12.72-12.90(m,1H),8.12(d,J＝2.9Hz,1H),8.02(s,1H),7.52-7.56(m,1H),7.40-7.44(m,1H),7.32-7.38(m,2H),6.76-6.82(m,1H),4.48(br s,1H),3.52-3.62(m,1H),3.43-3.51(m,2H),3.22-3.30(m,2H),1.96-2.15(m,2H)。 1 H NMR (DMSO-d 6 )δ: 12.72-12.90 (m, 1H), 8.12 (d, J=2.9Hz, 1H), 8.02 (s, 1H), 7.52-7.56 (m, 1H), 7.40- 7.44(m,1H),7.32-7.38(m,2H),6.76-6.82(m,1H),4.48(br s,1H),3.52-3.62(m,1H),3.43-3.51(m,2H) ,3.22-3.30(m,2H),1.96-2.15(m,2H).
实施例128
Example 128
步骤1：向化合物4-(环戊-1-烯-1-基)吗啉(3g，20mmol)的MeOH(20mL)混合物中加入乙氧基亚甲基丙二腈(2.4g，20mmol)。将反应混合物在室温下搅拌过夜后过滤。将过滤所得固体用MeOH洗涤后，烘干得到化合物128-1(2.29g,11mmol,产率：55％)。MS(ESI)：m/z＝230[M+H]+。Step 1: To a mixture of compound 4-(cyclopent-1-en-1-yl)morpholine (3 g, 20 mmol) in MeOH (20 mL) was added ethoxymethylenemalononitrile (2.4 g, 20 mmol). The reaction mixture was stirred overnight at room temperature and then filtered. After the filtered solid was washed with MeOH, it was dried to obtain compound 128-1 (2.29 g, 11 mmol, yield: 55%). MS (ESI): m/z = 230 [M+H] + .
步骤2：将化合物128-1(229mg,1mmol)、和NH3的甲醇溶液(2mol/L，1mL，2mmol)的混合物在微波(120W,100℃)条件下1小时。将所得反应液冷却后浓缩，加入H2O(100mL)，并用EA(50mL)萃取。将有机相用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用EA:PE＝1:2洗脱)纯化，得到化合物128-2(92mg,0.58mmol,产率：58.6％)。MS(ESI)：m/z＝160[M+H]+。Step 2: The mixture of compound 128-1 (229mg, 1mmol) and NH 3 in methanol (2mol/L, 1mL, 2mmol) was subjected to microwave (120W, 100°C) for 1 hour. The resulting reaction solution was cooled, concentrated, added H 2 O (100 mL), and extracted with EA (50 mL). The organic phase was dried over anhydrous Na 2 SO 4 and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain compound 128-2 (92mg, 0.58mmol, product rate: 58.6%). MS (ESI): m/z = 160 [M+H] + .
步骤3：在冰浴条件下，将NaNO2(276mg,4mmol)缓慢加到化合物128-2(318mg,2mmol)、AcOH(5mL)和HCl(5mL)的混合物中。将反应混合物在室温下搅拌3小时后，缓慢加入饱和碳酸氢钠将pH调至7，随后用EA(30mL)萃取。所得有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用EA:PE＝1:4洗脱)纯化，得到化合物128-3(234mg,1.47mmol,产率：65.8％)。MS(ESI)：m/z＝179[M+H]+。Step 3: NaNO 2 (276 mg, 4 mmol) was slowly added to a mixture of compound 128-2 (318 mg, 2 mmol), AcOH (5 mL) and HCl (5 mL) under ice-bath conditions. After the reaction mixture was stirred at room temperature for 3 hours, the pH was adjusted to 7 by slowly adding saturated sodium bicarbonate, followed by extraction with EA (30 mL). The obtained organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated, and the obtained residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain Compound 128-3 (234 mg, 1.47 mmol, yield: 65.8%). MS (ESI): m/z = 179 [M+H] + .
步骤4：向化合物128-3(234mg，1.47mmol)的DMF(20mL)溶液中加入5-三氟甲基吲哚(407mg，2.20mmol)和碳酸铯(955mg,2.94mmol)。将反应混合物在120℃下搅拌3小时，加H2O(200mL)稀释，并用EA(50mL)萃取。将所得有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥后浓缩，将所得残余物经硅胶柱层析(用EA:PE＝1:4洗脱)纯化，得到化合物128-4(315mg,0.96mmol,产率：65.6％)。MS(ESI)：m/z＝328[M+H]+。Step 4: To a solution of compound 128-3 (234 mg, 1.47 mmol) in DMF (20 mL) was added 5-trifluoromethylindole (407 mg, 2.20 mmol) and cesium carbonate (955 mg, 2.94 mmol). The reaction mixture was stirred at 120 °C for 3 h, diluted with H2O (200 mL), and extracted with EA (50 mL). The obtained organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 and concentrated, and the obtained residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain Compound 128-4 (315 mg, 0.96 mmol, yield: 65.6%). MS (ESI): m/z = 328 [M+H] + .
步骤5：将化合物128-4(315mg,0.96mmol)、MeOH(20mL)、NH2OH·HCl(672mg,9.6mmol)、TEA(15mL)和的混合物用N2吹扫并维持N2氛围，在80℃下搅拌3小时后减压过滤。将H2O(20mL)加入所得滤液中，并用EA(30mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用EA:PE＝1:2洗脱)纯化，得到化合物128-5(158mg,0.43mmol,产率：45.8％)。MS(ESI)：m/z＝361[M+H]+。Step 5: Compound 128-4 (315 mg, 0.96 mmol), MeOH (20 mL), NH 2 OH·HCl (672 mg, 9.6 mmol), TEA (15 mL) and The mixture was purged with N2 and maintained under N2 atmosphere, stirred at 80 °C for 3 h and then filtered under reduced pressure. H2O (20 mL) was added to the resulting filtrate and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain Compound 128-5 (158 mg, 0.43 mmol, yield: 45.8%). MS (ESI): m/z = 361 [M+H] + .
步骤6：在冰浴条件下，将CDI(83mg,0.51mmol)加入化合物128-5(158mg,0.43mol)的THF(10mL)溶液中，室温下搅拌30min后，在冰浴条件下滴入DBU(98mg,0.64mmol)。将反应混合物在冰浴条件下搅拌2h后，加入HCl水溶液(2mL，pH＝2)，并用EA(20mL)萃取。将所得有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩。将所得残余物通过硅胶柱层析(用MeOH:DCM＝1:20洗脱)纯化，得到化合物128(110mg,0.28mmol,产率：66.2％)。MS(ESI)：m/z＝387[M+H]+。1H NMR(DMSO-d6)δ:12.61-12.82(m,1H),8.13(s,1H),8.06(s,1H),7.56-7.61(m,2H),7.48(dd,J＝8.8,1.7Hz,1H),6.85(d,J＝3.4Hz,1H),3.07(t,J＝7.6Hz,4H),2.13-2.27(m,2H)。Step 6: Add CDI (83mg, 0.51mmol) to a THF (10mL) solution of compound 128-5 (158mg, 0.43mol) under ice-bath conditions, stir at room temperature for 30min, then add DBU dropwise under ice-bath conditions (98 mg, 0.64 mmol). After the reaction mixture was stirred in ice bath for 2 h, aqueous HCl (2 mL, pH=2) was added and extracted with EA (20 mL). The obtained organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated. The obtained residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:20) to obtain compound 128 (110 mg, 0.28 mmol, yield: 66.2%). MS (ESI): m/z = 387 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.61-12.82 (m, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.56-7.61 (m, 2H), 7.48 (dd, J=8.8 , 1.7Hz, 1H), 6.85(d, J=3.4Hz, 1H), 3.07(t, J=7.6Hz, 4H), 2.13-2.27(m, 2H).
实施例129
Example 129
步骤1：在室温下，将四氢-4H-吡喃-4-酮(0.93mL,9.99mmol)的DMF-DMA(10mL)溶液用N2吹扫并维持N2氛围，缓慢升温至110℃后搅拌16个小时，浓缩得到无需纯化可直接用于下一步的化合物129-1 (MS(ESI)：m/z＝156[M+H]+)的粗产物(1.75g)。Step 1: At room temperature, a solution of tetrahydro-4H-pyran-4-one (0.93mL, 9.99mmol) in DMF-DMA (10mL) was purged with N2 and maintained under N2 atmosphere, and the temperature was slowly raised to 110°C After stirring for 16 hours, concentrate to obtain compound 129-1 which can be directly used in the next step without purification Crude product (1.75 g) of (MS (ESI): m/z = 156 [M+H] + ).
步骤2：在室温下，将丙二腈(0.49mL,7.73mmol)和醋酸铵(0.06g,0.77mmol)加入到化合物129-1(1.2g,7.73mmol)的乙腈(15mL)溶液中。将反应混合物缓慢升温至80℃，搅拌5个小时后浓缩得到残余物。将所得残余物用硅胶柱层析(用乙酸乙酯洗脱)纯化，得到化合物129-2(MS(ESI)：m/z＝177[M+H]+)的粗产物(2.5g)。Step 2: Malononitrile (0.49 mL, 7.73 mmol) and ammonium acetate (0.06 g, 0.77 mmol) were added to a solution of compound 129-1 (1.2 g, 7.73 mmol) in acetonitrile (15 mL) at room temperature. The reaction mixture was slowly warmed to 80 °C, stirred for 5 hours and then concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain a crude product (2.5 g) of compound 129-2 (MS (ESI): m/z=177 [M+H] + ).
步骤3：在室温下，将化合物129-2(1.5g,8.51mmol)溶于POCl3(10mL)中。将反应混合物缓慢升温至100℃，搅拌3个小时后浓缩除去大部分POCl3，随后加饱和碳酸氢钠淬灭反应，加水稀释，并用乙酸乙酯(100mL×2)萃取。将合并得到的有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物129-3(578mg,产率：34.88％)。MS(ESI)：m/z＝195[M+H]+。Step 3: Compound 129-2 (1.5 g, 8.51 mmol) was dissolved in POCl 3 (10 mL) at room temperature. The reaction mixture was slowly heated to 100°C, stirred for 3 hours, concentrated to remove most of POCl 3 , then quenched with saturated sodium bicarbonate, diluted with water, and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 129-3 (578mg, Yield: 34.88%). MS (ESI): m/z = 195 [M+H] + .
步骤4：在室温下，将化合物129-3(570mg,2.93mmol)、5-三氟甲基吲哚(542.26mg,2.93mmol)和碳酸铯(1908.51mg,5.86mmol)分散于DMF(10mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃后搅拌1个小时，加水稀释，并用乙酸乙酯(100mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物129-4(752.7mg,产率：74.86％)。MS(ESI)：m/z＝344[M+H]+。Step 4: Compound 129-3 (570 mg, 2.93 mmol), 5-trifluoromethylindole (542.26 mg, 2.93 mmol) and cesium carbonate (1908.51 mg, 5.86 mmol) were dispersed in DMF (10 mL) at room temperature middle. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80° C., stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 129-4 (752.7mg , Yield: 74.86%). MS (ESI): m/z = 344 [M+H] + .
步骤5：在室温下，将盐酸羟胺(1522.14mg,21.90mmol),分子筛(760mg,mmol),和三乙胺(18.22mL,131.43mmol)加入化合物129-4(752mg,2.19mmol)的甲醇(20mL)溶液。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃后搅拌3个小时，用饱和氯化铵淬灭后过滤。将所得滤液用乙酸乙酯(50mL×2)萃取，并将合并所得的有机相用无水硫酸钠干燥后浓缩得到残余物。将残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:1洗脱)纯化，得到化合物129-5(488mg,产率：59.20％)。MS(ESI)：m/z＝377[M+H]+。Step 5: At room temperature, hydroxylamine hydrochloride (1522.14mg, 21.90mmol), Molecular sieves (760 mg, mmol), and triethylamine (18.22 mL, 131.43 mmol) were added to a solution of compound 129-4 (752 mg, 2.19 mmol) in methanol (20 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80 °C and stirred for 3 hours, quenched with saturated ammonium chloride and filtered. The resulting filtrate was extracted with ethyl acetate (50 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:1) to obtain compound 129-5 (488 mg, yield: 59.20%). MS (ESI): m/z = 377 [M+H] + .
步骤6：在冰浴条件下，将CDI(262.82mg,1.62mmol)加入到化合物129-5(488mg,1.30mmol)的四氢呋喃(8mL)溶液中，缓慢升至室温搅拌30min后，在冰浴条件下加入DBU(290.31μL,1.95mmol)。将反应混合物缓慢升至室温后搅拌1小时，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(乙酸乙酯)纯化，得到化合物129(15mg,产率：2.87％)。MS(ESI)：m/z＝403[M+H]+。1H NMR(DMSO-d6)δ:8.08(br s,1H),8.07(br s,1H),7.69(d,J＝8.6Hz,1H),7.60(d,J＝3.4Hz,1H),7.49(d,J＝8.9Hz,1H),6.86(d,J＝3.4Hz,1H),4.87(s,2H),4.08(t,J＝5.7Hz,2H),3.03(brt,J＝5.6Hz,2H)。Step 6: Add CDI (262.82mg, 1.62mmol) to a solution of compound 129-5 (488mg, 1.30mmol) in tetrahydrofuran (8mL) under ice-bath conditions, slowly rise to room temperature and stir for 30min. DBU (290.31 μL, 1.95 mmol) was added at the same time. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 129 (15 mg, yield: 2.87%). MS (ESI): m/z = 403 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.08 (br s, 1H), 8.07 (br s, 1H), 7.69 (d, J=8.6Hz, 1H), 7.60 (d, J=3.4Hz, 1H) ,7.49(d,J=8.9Hz,1H),6.86(d,J=3.4Hz,1H),4.87(s,2H),4.08(t,J=5.7Hz,2H),3.03(brt,J= 5.6Hz, 2H).
实施例130
Example 130
步骤1：在室温下，将丙二腈(0.12mL,1.97mmol)和醋酸铵(15.15mg,0.20mmol)加入(E)-3-(二甲氨基)亚甲基)-4-氧代哌啶-1-羧酸叔丁酯(500mg,1.97mmol)的乙腈(6mL)溶液中。将反应混合物缓慢升温至80℃，搅拌5小时后浓缩，得到无需纯化可直接用于下一步反应的化合物130-1(MS(ESI)：m/z＝276[M+H]+)的粗产物(500mg)。Step 1: Add malononitrile (0.12 mL, 1.97 mmol) and ammonium acetate (15.15 mg, 0.20 mmol) to (E)-3-(dimethylamino)methylene)-4-oxopiperene at room temperature In a solution of tert-butyl pyridine-1-carboxylate (500mg, 1.97mmol) in acetonitrile (6mL). The reaction mixture was slowly heated to 80°C, stirred for 5 hours and then concentrated to obtain the crude compound 130-1 (MS(ESI): m/z=276[M+H] + ) which could be directly used in the next reaction without purification. Product (500 mg).
步骤2：在室温下，将化合物130-1的粗产物(500mg)溶于三氯氧磷(3mL)中。将反应混合物缓慢升温至110℃后搅拌3个小时，浓缩除去大部分POCl3，随后用饱和碳酸氢钠淬灭反应，加水稀释，并用二氯甲烷(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物130-2(375mg,产率：106.64％)。MS(ESI)：m/z＝194[M+H]+。Step 2: The crude product of compound 130-1 (500 mg) was dissolved in phosphorus oxychloride (3 mL) at room temperature. The reaction mixture was slowly warmed to 110°C, stirred for 3 hours, concentrated to remove most of POCl 3 , then quenched with saturated sodium bicarbonate, diluted with water, and extracted with dichloromethane (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 130-2 (375 mg, yield rate: 106.64%). MS (ESI): m/z = 194 [M+H] + .
步骤3：在室温下，将二碳酸二叔丁酯(0.41mL,1.94mmol)滴加到化合物130-2(375mg,1.94mmol)的四氢呋喃(5mL)和水(2.5mL)的溶液中，随后加入碳酸钠(205.27mg,1.94mmol)。将反应混合物用N2吹扫并维持N2氛围，在28℃下搅拌12小时后浓缩，并用二氯甲烷(20mL×2)萃取。将合并所得的有机相用无 水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物130-3(150mg,产率：26.37％)。MS(ESI)：m/z＝294[M+H]+。Step 3: At room temperature, di-tert-butyl dicarbonate (0.41 mL, 1.94 mmol) was added dropwise to a solution of compound 130-2 (375 mg, 1.94 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL), followed by Sodium carbonate (205.27 mg, 1.94 mmol) was added. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at 28 °C for 12 h, concentrated, and extracted with dichloromethane (20 mL×2). The combined organic phases were used without It was dried over sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 130-3 (150 mg, yield: 26.37%). MS (ESI): m/z = 294 [M+H] + .
步骤4：在室温下，将5-三氟甲基吲哚(94.54mg,0.51mmol)和碳酸铯(166.38mg,0.51mmol)加入到化合物130-3(150mg,0.51mmol)的DMF(2mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌1个小时，加水稀释，并用乙酸乙酯(20mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(用乙酸乙酯:石油醚＝1:10洗脱)纯化，得到化合物130-4(85mg,产率：37.62％)。MS(ESI)：m/z＝443[M+H]+。Step 4: 5-Trifluoromethylindole (94.54 mg, 0.51 mmol) and cesium carbonate (166.38 mg, 0.51 mmol) were added to compound 130-3 (150 mg, 0.51 mmol) in DMF (2 mL) at room temperature in solution. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80 °C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (20 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:10) to obtain compound 130-4 (85 mg, yield rate: 37.62%). MS (ESI): m/z = 443 [M+H] + .
步骤5：在室温下，将盐酸羟胺(133.50mg,1.92mmol)、分子筛(90mg,mmol)和三乙胺(1.60mL,11.53mmol)加入到化合物130-4(85mg,0.19mmol)的甲醇(2mL)的溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至75℃后搅拌3个小时，加入饱和氯化铵将反应淬灭后过滤，并用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯洗脱)纯化，得到化合物130-5(56mg,产率：61.31％)。MS(ESI)：m/z＝476[M+H]+。Step 5: At room temperature, hydroxylamine hydrochloride (133.50mg, 1.92mmol), Molecular sieves (90 mg, mmol) and triethylamine (1.60 mL, 11.53 mmol) were added to a solution of compound 130-4 (85 mg, 0.19 mmol) in methanol (2 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 75 °C and stirred for 3 hours, quenched by adding saturated ammonium chloride, filtered, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 130-5 (56 mg, yield: 61.31%). MS (ESI): m/z = 476 [M+H] + .
步骤6：在冰浴条件下，将CDI(23.87mg,0.15mmol)加入到化合物130-5(56mg,0.12mmol)的四氢呋喃(1mL)中，缓慢升温到室温搅拌30min后，在冰浴条件下加入DBU(26.37μL,0.18mmol)。将反应混合物缓慢升温至室温后搅拌1小时，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯洗脱)纯化，得到化合物130-6(33mg,产率：55.87％)。MS(ESI)：m/z＝[M+H]+。Step 6: Add CDI (23.87mg, 0.15mmol) to compound 130-5 (56mg, 0.12mmol) in tetrahydrofuran (1mL) under ice-bath conditions, slowly warm up to room temperature and stir for 30min, then under ice-bath conditions DBU (26.37 μL, 0.18 mmol) was added. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 130-6 (33 mg, yield: 55.87%). MS (ESI): m/z = [M+H] + .
步骤7：在0℃下，将盐酸二氧六环溶液(3mL,0.07mmol)滴加到化合物130-6(33mg,0.07mmol)的二氯甲烷(2mL)溶液中。将反应混合物缓慢升温至34℃后搅拌3小时，浓缩得到残余物，并将残余物经制备高效液相色谱(Pre-HPLC)(用TFA洗脱)纯化，得到化合物130(8mg,产率：30.15％)。MS(ESI)：m/z＝402[M+H]+。1HNMR(DMSO-d6)δ:8.19(s,1H),8.02(s,1H),7.54-7.59(m,2H),7.43(d,J＝8.6Hz,1H),6.77(d,J＝3.3Hz,1H),4.45(s,2H),3.55(br t,J＝6.3Hz,2H),3.15(brt,J＝6.0Hz,2H)。Step 7: Dioxane hydrochloride solution (3 mL, 0.07 mmol) was added dropwise to a solution of compound 130-6 (33 mg, 0.07 mmol) in dichloromethane (2 mL) at 0°C. The reaction mixture was slowly warmed to 34 ° C and stirred for 3 hours, concentrated to obtain a residue, and the residue was purified by preparative high-performance liquid chromatography (Pre-HPLC) (eluted with TFA) to obtain compound 130 (8 mg, yield: 30.15%). MS (ESI): m/z = 402 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.19 (s, 1H), 8.02 (s, 1H), 7.54-7.59 (m, 2H), 7.43 (d, J = 8.6Hz, 1H), 6.77 (d, J =3.3Hz, 1H), 4.45(s, 2H), 3.55(brt, J=6.3Hz, 2H), 3.15(brt, J=6.0Hz, 2H).
实施例131
Example 131
步骤1：向化合物3，6-二氯吡嗪-2-甲腈(150g，0.86mmol)的DMF(4mL)溶液中加入5-三氟甲基吲哚(2，159mg，0.86mmol)和叔丁醇钠(83mg,0.86mmol)。将反应混合物用N2吹扫并维持N2氛围，在80℃下搅拌3小时后，冷却至25℃，用饱和氯化铵溶液(5mL)淬灭，并用EA(40mL)萃取。将有机相用饱和食盐水洗涤(3次)后浓缩得到残余物，并将所得残余物经硅胶柱层析(洗脱剂梯度从PE:EA＝20:1过渡至5:1)纯化，得到化合物131-1(116.5mg,0.36mmol)。Step 1: Add 5-trifluoromethylindole (2, 159mg, 0.86mmol) and t- Sodium butoxide (83 mg, 0.86 mmol). The reaction mixture was purged with N2 and maintained under N2 atmosphere, after stirring at 80 °C for 3 h, cooled to 25 °C, quenched with saturated ammonium chloride solution (5 mL), and extracted with EA (40 mL). The organic phase was washed with saturated brine (3 times) and concentrated to obtain a residue, and the obtained residue was purified by silica gel column chromatography (eluent gradient transitioned from PE:EA=20:1 to 5:1) to obtain Compound 131-1 (116.5 mg, 0.36 mmol).
步骤2：将盐酸羟胺(236mg，3.4mmol),分子筛(110mg)和三乙胺(2.8mL,20.5mmol)加入到化合物131-1(110mg，0.34mmol)的甲醇(5mL)溶液中。将反应混合物在75℃下搅拌8小时，冷却至25℃后过滤。向滤液中加入饱和氯化铵溶液(5mL)以淬灭反应，并用EA(50mL)萃取。将有机相用饱和食盐水洗涤(3次)，干燥后浓缩。将所得残余物经硅胶柱层析(洗脱剂梯度从PE:EA＝5:1过渡至1:1)纯化，得到化合物131-2(55mg，0.15mmol)。Step 2: Hydroxylamine hydrochloride (236mg, 3.4mmol), Molecular sieves (110 mg) and triethylamine (2.8 mL, 20.5 mmol) were added to a solution of compound 131-1 (110 mg, 0.34 mmol) in methanol (5 mL). The reaction mixture was stirred at 75°C for 8 hours, cooled to 25°C and filtered. Saturated ammonium chloride solution (5 mL) was added to the filtrate to quench the reaction, and extracted with EA (50 mL). The organic phase was washed with saturated brine (3 times), dried and concentrated. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=5:1 to 1:1) to obtain compound 131-2 (55 mg, 0.15 mmol).
步骤3：在0℃下，将CDI(31mg,0.19mmol)加入到化合物131-2(55mg,0.15mmol)的THF(2mL)溶液中，升温至室温搅拌30分钟后，在0℃下加入DBU(34μL，0.22mmol)。将反应混合物升温至室温搅拌1小时后浓缩，加入饱和氯化铵溶液(2mL)将混合物淬灭，并用EA(20mL)萃取。将有机相用饱和食盐水洗涤(3次)，干燥后浓缩，并将所得残余物依次经硅胶柱层析(洗脱剂梯度从PE:EA＝5:1过渡至1:1)和制备高效液相色谱(HPLC)纯化，得到化合物131(25mg,0.06mmol,产率：40％)。MS(ESI)：m/z＝380[M+H]+。1H NMR(DMSO-d6)δ:12.86-13.95(s,1H),9.08(s,1H),8.07(s,1H),7.80(d,J＝3.5Hz,1H),7.69(d,J＝8.8Hz,1H),7.51(dd,J＝8.8,1.4Hz,1H),6.89(d,J＝3.5Hz,1H)。Step 3: Add CDI (31mg, 0.19mmol) to compound 131-2 (55mg, 0.15mmol) in THF (2mL) at 0°C, warm to room temperature and stir for 30 minutes, then add DBU at 0°C (34 μL, 0.22 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour, then concentrated, the mixture was quenched by adding saturated ammonium chloride solution (2 mL), and extracted with EA (20 mL). The organic phase was washed with saturated brine (3 times), dried and concentrated, and the obtained residue was successively subjected to silica gel column chromatography (eluent gradient transitioned from PE:EA=5:1 to 1:1) and prepared highly efficient Purification by liquid chromatography (HPLC) gave compound 131 (25 mg, 0.06 mmol, yield: 40%). MS (ESI): m/z = 380 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.86-13.95(s, 1H), 9.08(s, 1H), 8.07(s, 1H), 7.80(d, J=3.5Hz, 1H), 7.69(d, J=8.8Hz, 1H), 7.51 (dd, J=8.8, 1.4Hz, 1H), 6.89 (d, J=3.5Hz, 1H).
实施例133
Example 133
步骤1：将5-三氟甲基吲哚(1500mg,8.10mmol)、DMF(15mL)、和t-BuONa(778.6mg,8.10mmol)的混合物在室温下搅拌30min后，在冰浴条件下加入3，6-二氯吡嗪-2-甲腈(1423.6mg,8.18mmol)。将反应混合物缓慢升温至室温后搅拌30分钟，加入饱和NH4Cl(aq)(50mL)稀释，并用EA(50mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩得到残余物。将残余物经硅胶柱层析(用DCM:PE＝1:3洗脱)纯化，得到化合物133-1(872mg,2.70mmol,产率：33.36％)。Step 1: A mixture of 5-trifluoromethylindole (1500mg, 8.10mmol), DMF (15mL), and t-BuONa (778.6mg, 8.10mmol) was stirred at room temperature for 30min, and then added in an ice bath 3,6-Dichloropyrazine-2-carbonitrile (1423.6 mg, 8.18 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 30 min, diluted with saturated NH 4 Cl(aq) (50 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with DCM:PE=1:3) to obtain compound 133-1 (872 mg, 2.70 mmol, yield: 33.36%).
步骤2：将化合物133-1(461.7mg,1.43mmol)、MeOH(21mL)、NH2OH·HCl(994.3mg,14.31mmol)、TEA(13mL)和的混合物用N2吹扫并维持N2氛围，在80℃下搅拌2小时后减压过滤，并将所得滤液浓缩。向所得浓缩物中加入H2O(20mL)后用EA(30mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩。将所得残余物经硅胶柱层析(用EA:PE＝1:5洗脱)纯化，得到化合物133-2(358.5mg,1.01mmol,产率：70.44％)。MS(ESI)：m/z＝356[M+H]+。Step 2: Compound 133-1 (461.7 mg, 1.43 mmol), MeOH (21 mL), NH 2 OH·HCl (994.3 mg, 14.31 mmol), TEA (13 mL) and The mixture was purged with N2 and maintained under N2 atmosphere, stirred at 80 °C for 2 h, filtered under reduced pressure, and the resulting filtrate was concentrated. H 2 O (20 mL) was added to the obtained concentrate, followed by extraction with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated. The resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:5) to obtain compound 133-2 (358.5 mg, 1.01 mmol, yield: 70.44%). MS (ESI): m/z = 356 [M+H] + .
步骤3：在冰浴条件下，将二羰基咪唑(204.0mg,1.26mmol)加入到化合物133-2(358mg,0.17mmol)的THF(10mL)溶液中，在室温下搅拌30分钟后，在冰浴条件下滴加DBU(229.8mg,1.51mmol)。将反应混合物在冰浴条件下搅拌2小时后，加入HCl的水溶液(20mL，pH＝2)，并用EA(20mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用MeOH:DCM＝1:20洗脱)纯化，得到化合物133-3(239.4mg,0.63mmol,产率：62.32％)。MS(ESI)：m/z＝382[M+H]+。Step 3: Add dicarbonyl imidazole (204.0mg, 1.26mmol) to a THF (10mL) solution of compound 133-2 (358mg, 0.17mmol) under ice bath conditions, stir at room temperature for 30 minutes, and then DBU (229.8 mg, 1.51 mmol) was added dropwise under bath conditions. After the reaction mixture was stirred under ice bath for 2 hours, aqueous HCl (20 mL, pH=2) was added and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:20) to obtain Compound 133-3 (239.4 mg, 0.63 mmol, yield: 62.32%). MS (ESI): m/z = 382 [M+H] + .
步骤4：将Na2CO3(41.7mg,323.40mmol)的水溶液(0.2mL)加入到化合物133-3(75.0mg,0.20mmol)、1,4-二氧六环(1.2mL)、乙烯基频哪醇硼酸酯(45.4mg,0.29mmol)和Pd(dppf)Cl2(14.3mg,0.02mmol)的混合物中。将反应混合物用N2吹扫并维持N2氛围，在100℃下搅拌12小时，加H2O(2mL)稀释，并用EA(5mL)萃取。将有机相用饱和食盐水(2mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用MeOH:DCM＝1:20洗脱)纯化，得到化合物133-4(26.0mg,0.07mmol,产率：35.45％)。MS(ESI)：m/z＝372[M+H]+。Step 4: Aqueous solution (0.2 mL) of Na 2 CO 3 (41.7 mg, 323.40 mmol) was added to compound 133-3 (75.0 mg, 0.20 mmol), 1,4-dioxane (1.2 mL), vinyl In a mixture of pinacol borate (45.4mg, 0.29mmol) and Pd(dppf)Cl 2 (14.3mg, 0.02mmol). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at 100° C. for 12 h, diluted with H 2 O (2 mL), and extracted with EA (5 mL). The organic phase was washed with saturated brine (2 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:20) to obtain Compound 133-4 (26.0 mg, 0.07 mmol, yield: 35.45%). MS (ESI): m/z = 372 [M+H] + .
步骤5：将化合物133-4(26.0mg,0.07mmol)、MeOH(0.5mL)和Pd/C(5％)(5.0mg)的混合物用H2吹扫并维持H2氛围，在室温下搅拌18小时后，用N2吹扫并维持N2氛围，减压过滤。将过滤所得滤液及依次用DCM、EA、和MeOH洗涤滤饼所得的滤液合并后，用无水Na2SO4干燥，浓缩得到残余物。将所得残余物经硅胶柱层析(用MeOH:DCM＝1:20洗脱)纯化，得到化合物133(9.0mg,0.02mmol,产率：32.65％)。MS(ESI)：m/z＝376[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 1.40(t,J＝7.57Hz,3H)3.02(q,J＝7.55Hz,2H)6.86(d,J＝3.38Hz,1H)7.47(dd,J＝8.76,1.38Hz,1H)7.59(d,J＝8.63Hz,1H)7.81(d,J＝3.38Hz,1H)8.06(s,1H)8.86(s,1H)13.12(br s,1H)。Step 5: A mixture of compound 133-4 (26.0 mg, 0.07 mmol), MeOH (0.5 mL) and Pd/C (5%) (5.0 mg) was purged with H 2 and maintained under H 2 atmosphere, stirring at room temperature After 18 hours, purging with N2 and maintaining the N2 atmosphere, filtered under reduced pressure. The filtrate obtained by filtration and the filtrate obtained by washing the filter cake with DCM, EA, and MeOH successively were combined, dried over anhydrous Na 2 SO 4 , and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:20) to obtain compound 133 (9.0 mg, 0.02 mmol, yield: 32.65%). MS (ESI): m/z = 376 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δppm 1.40 (t, J = 7.57Hz, 3H) 3.02 (q, J = 7.55Hz, 2H) 6.86 (d, J = 3.38Hz, 1H) 7.47 (dd, J = 8.76, 1.38Hz, 1H) 7.59 (d, J = 8.63Hz, 1H) 7.81 (d, J = 3.38Hz, 1H) 8.06 (s, 1H) 8.86 (s, 1H) 13.12 (br s, 1H).
实施例134
Example 134
步骤1：将Na2CO3(38.3mg,0.36mmol)的水溶液(0.2mLH2O)加入到化合物133-3(70.0mg,0.18mmol)、1,4-二氧六环(1.2mL)、4,4,5,5-四甲基-2-丙烯-2-基-1,3,2-二氧杂硼烷(60.7mg,0.36mmol)和Pd(dppf)Cl2(13.2mg,0.02mmol)的混合物中。将反应混合物用N2吹扫并维持N2氛围，在100℃下搅拌12小时，加H2O(2mL)稀释，并用EA(5mL)萃取。将所得有机相用饱和食盐水(2mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用MeOH:DCM＝1:20洗脱)纯化，得到化合物134-1(15.0mg,0.04mmol,产率：21.43％)。MS(ESI)：m/z＝388[M+H]+。 Step 1: Na 2 CO 3 (38.3 mg, 0.36 mmol) in water (0.2 mL H 2 O) was added to compound 133-3 (70.0 mg, 0.18 mmol), 1,4-dioxane (1.2 mL), 4,4,5,5-Tetramethyl-2-propen-2-yl-1,3,2-dioxaborinane (60.7mg, 0.36mmol) and Pd(dppf)Cl 2 (13.2mg, 0.02 mmol) in the mixture. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at 100° C. for 12 h, diluted with H 2 O (2 mL), and extracted with EA (5 mL). The obtained organic phase was washed with saturated brine (2 mL×3), dried over anhydrous Na 2 SO 4 and concentrated, and the obtained residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:20), Compound 134-1 (15.0 mg, 0.04 mmol, yield: 21.43%) was obtained. MS (ESI): m/z = 388 [M+H] + .
步骤2：将化合物134-1(15.0mg,0.04mmol)、THF(0.2mL)、MeOH(0.5mL)和Pd/C(5％)(3.0mg)的混合物用H2吹扫并维持H2氛围，在室温下搅拌4小时后，用N2吹扫并维持N2氛围，减压过滤。将过滤所得滤液及依次用DCM、EA、和MeOH洗涤滤饼所得的滤液合并后，用无水Na2SO4干燥，浓缩得到残余物。将所得残余物经硅胶柱层析(用MeOH:DCM＝1:20洗脱)纯化，得到化合物134(3.5mg,0.01mmol,产率：22.76％)。MS(ESI)：m/z＝390[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 1.38(dd,J＝6.88,2.00Hz,6H)3.32(dt,J＝13.79,7.05Hz,1H)6.86(d,J＝3.50Hz,1H)7.46(d,J＝8.75Hz,1H)7.53-7.59(m,1H)7.78(t,J＝3.44Hz,1H)8.05(s,1H)8.85(d,J＝3.00Hz,1H)。Step 2: A mixture of compound 134-1 (15.0 mg, 0.04 mmol), THF (0.2 mL), MeOH (0.5 mL) and Pd/C (5%) (3.0 mg) was purged with H2 and maintained under H2 Atmosphere, after stirring at room temperature for 4 hours, purged with N2 and maintained N2 atmosphere, filtered under reduced pressure. The filtrate obtained by filtration and the filtrate obtained by washing the filter cake with DCM, EA, and MeOH successively were combined, dried over anhydrous Na 2 SO 4 , and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:20) to obtain compound 134 (3.5 mg, 0.01 mmol, yield: 22.76%). MS (ESI): m/z = 390 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δppm 1.38 (dd, J = 6.88, 2.00Hz, 6H) 3.32 (dt, J = 13.79, 7.05Hz, 1H) 6.86 (d, J = 3.50Hz, 1H) 7.46 (d, J = 8.75Hz, 1H) 7.53-7.59 (m, 1H) 7.78 (t, J = 3.44Hz, 1H) 8.05 (s, 1H) 8.85 (d, J = 3.00Hz, 1H).
实施例135
Example 135
将化合物133-3(100.0mg,0.26mmol)、DMAc(1.7mL)、P(t-Bu)3(10％甲苯溶液)(106.0mg,0.36mmol)、Pd2(dba)3(27.1mg,0.03mmol)和Zn(CN)2(21.5mg,0.18mmol)的混合物用N2吹扫并维持N2氛围，在95℃下搅拌12小时后，加H2O(5mL)稀释，并用EA(5mL)萃取。将有机相用饱和食盐水(2mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用MeOH:DCM＝1:100洗脱)纯化，得到化合物135(1.7mg,4.5μmol,产率：1.70％)。MS(ESI)：m/z＝371[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 6.93(d,J＝3.63Hz,1H)7.58(d,J＝8.63Hz,1H)7.83-7.86(m,1H)7.89(br d,J＝9.13Hz,1H)8.08(s,1H)9.38-9.42(m,1H)。Compound 133-3 (100.0mg, 0.26mmol), DMAc (1.7mL), P(t-Bu) 3 (10% toluene solution) (106.0mg, 0.36mmol), Pd 2 (dba) 3 (27.1mg, 0.03mmol) and Zn(CN) 2 (21.5mg, 0.18mmol) was purged with N 2 and maintained N 2 atmosphere, stirred at 95°C for 12 hours, diluted with H 2 O (5 mL), and washed with EA ( 5mL) extraction. The organic phase was washed with saturated brine (2 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:100) to obtain Compound 135 (1.7 mg, 4.5 μmol, yield: 1.70%). MS (ESI): m/z = 371 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δppm 6.93 (d, J = 3.63Hz, 1H) 7.58 (d, J = 8.63Hz, 1H) 7.83-7.86 (m, 1H) 7.89 (br d, J = 9.13 Hz, 1H) 8.08 (s, 1H) 9.38-9.42 (m, 1H).
实施例136
Example 136
步骤1：向2-氨基丙二酰胺盐酸盐(5g，32mmol)、NaOH水溶液(50％，20mL)和H2O(10mL)的混合物中加入2,3-丁二酮(2.7g，32mmol)。将反应混合物在室温下搅拌12小时，加H2O稀释，用HCl水溶液(2N)将pH调至6以析出固体。将所述固体真空干燥，得到无需进一步纯化的化合物136-1。(4.5g,26mmol,产率：83.7％)。MS(ESI)：m/z＝168[M+H]+。Step 1: To a mixture of 2-aminomalonamide hydrochloride (5 g, 32 mmol), aqueous NaOH (50%, 20 mL) and H 2 O (10 mL) was added 2,3-butanedione (2.7 g, 32 mmol ). The reaction mixture was stirred at room temperature for 12 hours, diluted with H2O , and the pH was adjusted to 6 with aqueous HCl (2N) to precipitate a solid. The solid was dried in vacuo to afford compound 136-1 without further purification. (4.5 g, 26 mmol, yield: 83.7%). MS (ESI): m/z = 168 [M+H] + .
步骤2：将化合物136-1(2g,11mmol)、三氯氧磷(40mL)和TEA(3.7mL)，的混合物用N2吹扫并维持N2氛围，在60℃下搅拌3小时后，在冰浴条件下缓慢加入H2O(20mL)，并用EA(30mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将残余物经硅胶柱层析(用EA:PE＝1:5洗脱)纯化，得到化合物136-2(1.2g,7.1mmol,产率：64.5％)。MS(ESI)：m/z＝168[M+H]+。Step 2: The mixture of compound 136-1 (2g, 11mmol), phosphorus oxychloride (40mL) and TEA (3.7mL), was purged with N2 and maintained under N2 atmosphere, after stirring at 60°C for 3 hours, H2O (20 mL) was added slowly under ice bath condition, and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the residue was purified by silica gel column chromatography (eluted with EA:PE=1:5) to obtain the compound 136-2 (1.2 g, 7.1 mmol, yield: 64.5%). MS (ESI): m/z = 168 [M+H] + .
步骤3：向化合物136-2(100mg，0.59mmol)的DMF(5mL)溶液中缓慢加入NaH(48mg,1.2mmol)，在室温下反应1小时后，加入5-三氟甲基吲哚(130mg，0.7mmol)。将反应混合物在120℃下搅拌3小时，加H2O(200mL)稀释，并用EA(50mL)萃取。将有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用EA:PE＝1:4洗脱)纯化，得到化合物136-3(76mg,0.23mmol,产率：43.5％)。MS(ESI)：m/z＝317[M+H]+。Step 3: Slowly add NaH (48 mg, 1.2 mmol) to a solution of compound 136-2 (100 mg, 0.59 mmol) in DMF (5 mL), react at room temperature for 1 hour, add 5-trifluoromethylindole (130 mg , 0.7 mmol). The reaction mixture was stirred at 120 °C for 3 h, diluted with H2O (200 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain Compound 136-3 (76 mg, 0.23 mmol, yield: 43.5%). MS (ESI): m/z = 317 [M+H] + .
步骤4：将化合物136-3(176mg,0.55mmol)、MeOH(20mL)、NH2OH·HCl(388mg,5.5mmol)、TEA(10mL)和的混合物用N2吹扫并维持N2氛围，在80℃下搅拌3小时后，减压过滤。将所得滤液浓缩，并将H2O(20mL)加入到所得浓缩物，用EA(30mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用EA:PE＝1:2洗脱)纯化，得到化合物136-4(150mg,0.42mmol,产率：78.1％)。MS(ESI)：m/z＝350[M+H]+。Step 4: Compound 136-3 (176 mg, 0.55 mmol), MeOH (20 mL), NH 2 OH·HCl (388 mg, 5.5 mmol), TEA (10 mL) and The mixture was purged with N2 and maintained under N2 atmosphere, after stirring at 80 °C for 3 h, it was filtered under reduced pressure. The obtained filtrate was concentrated, and H 2 O (20 mL) was added to the obtained concentrate, extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain Compound 136-4 (150 mg, 0.42 mmol, yield: 78.1%). MS (ESI): m/z = 350 [M+H] + .
步骤5：在冰浴条件下，将CDI(91.9mg,0.56mmol)加入到化合物136-4(150mg,0.47mmol)的THF (10mL)溶液中，在室温下搅拌30分钟后，在冰浴条件下滴入DBU(107mg,0.70mmol)。将反应混合物在冰浴条件下搅拌2小时后，加入HCl水溶液(20mL，pH＝2)，并用EA(20mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物经制备高效液相色谱纯化，得到化合物136(21mg,0.14mmol,产率：9.4％)。MS(ESI)：m/z＝376[M+H]+。1H NMR(DMSO-d6)δ:8.06(s,1H),7.77(d,J＝3.4Hz,1H),7.56(d,J＝8.8Hz,1H),7.43-7.51(m,1H),6.85(d,J＝3.4Hz,1H),2.69(s,3H),2.63-2.67(m,3H)。Step 5: Add CDI (91.9mg, 0.56mmol) to compound 136-4 (150mg, 0.47mmol) in THF under ice bath condition (10 mL) solution, after stirring at room temperature for 30 minutes, DBU (107 mg, 0.70 mmol) was added dropwise in ice bath. After the reaction mixture was stirred in ice bath for 2 hours, aqueous HCl (20 mL, pH=2) was added and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated, and the resulting residue was purified by preparative high performance liquid chromatography to obtain compound 136 (21 mg, 0.14 mmol, yield: 9.4%). MS (ESI): m/z = 376 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.06(s, 1H), 7.77(d, J=3.4Hz, 1H), 7.56(d, J=8.8Hz, 1H), 7.43-7.51(m, 1H) , 6.85 (d, J=3.4Hz, 1H), 2.69 (s, 3H), 2.63-2.67 (m, 3H).
实施例137
Example 137
步骤1：将3,5-二氯吡嗪-2-甲腈(3.13mL,28.74mmol)加入到NH3的二氧六环溶液(2.15.54mL,86.22mmol,0.4M)中。将反应混合物在室温下搅拌3小时后浓缩，并将水(100mL)加入到所得浓缩物中，用乙酸乙酯(100mL*3)萃取。将合并所得有机相浓缩，并将所得残余物经快速柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到化合物137-1(3.46g,22.39mmol,产率：77.89％)。1H NMR(400MHz,DMSO-d6)δ8.12(s,2H),7.87(s,1H).Step 1: 3,5-Dichloropyrazine-2-carbonitrile (3.13 mL, 28.74 mmol) was added to NH 3 in dioxane (2.15.54 mL, 86.22 mmol, 0.4 M). The reaction mixture was stirred at room temperature for 3 hours and concentrated, and water (100 mL) was added to the obtained concentrate, which was extracted with ethyl acetate (100 mL*3). The combined organic phases were concentrated, and the resulting residue was purified by flash column chromatography (petroleum ether/ethyl acetate=1/1) to obtain compound 137-1 (3.46 g, 22.39 mmol, yield: 77.89%). 1 H NMR (400MHz, DMSO-d6) δ8.12(s, 2H), 7.87(s, 1H).
步骤2：将5-(三氟甲基)-吲哚(4.14g,4.33mmol)和叔丁醇钠(2.15g,22.39mmol)加入到化合物137-1(3.46g,22.39mmol)的DMF(40mL)溶液中。将反应混合物在80℃下搅拌2小时，加水(100mL)稀释，并用乙酸乙酯(100mL*3)萃取。将合并所得的有机相浓缩，并将所得残余物经快速柱层析(用石油醚/乙酸乙酯＝1/1洗脱)纯化，得到化合物137-2(3.36g,11.08mmol,产率：49.49％)。1H NMR(400MHz,DMSO-d6)δ8.07–8.17(m,2H),8.04(s,2H),8.00(d,J＝3.5Hz,1H),7.97(s,1H),7.56(d,J＝8.8,1.6Hz,1H),6.95(d,J＝3.5Hz,1H).Step 2: 5-(Trifluoromethyl)-indole (4.14 g, 4.33 mmol) and sodium tert-butoxide (2.15 g, 22.39 mmol) were added to compound 137-1 (3.46 g, 22.39 mmol) in DMF ( 40mL) solution. The reaction mixture was stirred at 80°C for 2 hours, diluted with water (100 mL), and extracted with ethyl acetate (100 mL*3). The combined organic phases were concentrated, and the resulting residue was purified by flash column chromatography (eluted with petroleum ether/ethyl acetate=1/1) to obtain compound 137-2 (3.36g, 11.08mmol, yield: 49.49%). 1 H NMR (400MHz, DMSO-d6) δ8.07–8.17(m, 2H), 8.04(s, 2H), 8.00(d, J=3.5Hz, 1H), 7.97(s, 1H), 7.56(d ,J=8.8,1.6Hz,1H),6.95(d,J=3.5Hz,1H).
步骤3：将盐酸羟胺(229.15mg,3.30mmol)，TEA(1.83mL,13.19mmol)和分子筛(30mg)加入到化合物137-2(200mg,0.66mmol)的甲醇(2mL)溶液中。将反应混合物在80℃搅拌2小时，过滤，并向所得浓缩物中加水(5mL)稀释，用乙酸乙酯(5mL*3)萃取。将合并所得有机相浓缩，并将所得残余物经快速柱层析(用二氯甲烷:甲醇＝10:1洗脱)纯化，得到化合物137-3(190mg,0.57mmol,产率：85.67％)。MS(ESI)：m/z＝338[M+H]+。Step 3: Hydroxylamine hydrochloride (229.15mg, 3.30mmol), TEA (1.83mL, 13.19mmol) and Molecular sieves (30 mg) were added to a solution of compound 137-2 (200 mg, 0.66 mmol) in methanol (2 mL). The reaction mixture was stirred at 80° C. for 2 hours, filtered, and the resulting concentrate was diluted with water (5 mL), extracted with ethyl acetate (5 mL*3). The combined organic phase was concentrated, and the resulting residue was purified by flash column chromatography (eluted with dichloromethane:methanol=10:1) to obtain compound 137-3 (190mg, 0.57mmol, yield: 85.67%) . MS (ESI): m/z = 338 [M+H] + .
步骤4：在0℃下，将CDI(114.52mg,0.71mmol)加入到化合物137-3(190mg,0.57mmol)的四氢呋喃(2mL)溶液中，在室温下搅拌0.5小时后，在0℃下加入DBU(0.13mL,0.85mmol)。将反应混合物在室温下搅拌1小时后，加水(3mL)稀释，并用乙酸乙酯(3mL*3)萃取。将合并所得有机相浓缩，并将所得残余物通过制备高效液相色谱(HPLC)纯化，得到化合物137-4。(45.47mg,0.12mmol,产率：21.31％,纯度：96.04％)。1HNMR(400MHz,DMSO-d6)δ12.59–12.85(m,1H),8.07(s,1H),8.02(s,1H),7.71(d,J＝3.5Hz,1H),7.68(s,2H),7.53–7.59(m,1H),7.45(d,J＝8.7,1.6Hz,1H),6.80(d,J＝3.4Hz,1H)。Step 4: Add CDI (114.52mg, 0.71mmol) to a solution of compound 137-3 (190mg, 0.57mmol) in tetrahydrofuran (2mL) at 0°C, stir at room temperature for 0.5 hours, then add DBU (0.13 mL, 0.85 mmol). After the reaction mixture was stirred at room temperature for 1 hr, it was diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated and the resulting residue was purified by preparative high performance liquid chromatography (HPLC) to afford compound 137-4. (45.47 mg, 0.12 mmol, yield: 21.31%, purity: 96.04%). 1 HNMR(400MHz,DMSO-d6)δ12.59–12.85(m,1H),8.07(s,1H),8.02(s,1H),7.71(d,J＝3.5Hz,1H),7.68(s, 2H), 7.53–7.59 (m, 1H), 7.45 (d, J=8.7, 1.6Hz, 1H), 6.80 (d, J=3.4Hz, 1H).
步骤5：在0℃下，将氯化铜(38.97mg,0.29mmol)和亚硝酸叔丁酯(0.03mL,0.29mmol)加入到化合物137-4(70mg,0.19mmol)的乙腈(1mL)溶液中。将反应混合物在50℃下搅拌16小时后，加水(3mL)稀释，并用乙酸乙酯(3mL*3)萃取。将合并所得有机相浓缩，并将所得粗产物经制备高效液相色谱(HPLC)纯化，得到化合物137(2.88mg，0.01mmol，产率：3.89％，纯度：99.65％)。MS(ESI)：m/z＝380[M+H]+。1HNMR(400MHz,DMSO-d6)δ13.16–13.53(m,1H),9.09(s,1H),7.81(s,1H),7.75(d,J＝8.6Hz,1H),7.54(d,J＝8.3Hz,1H),6.89(d,J＝3.0Hz,1H)。Step 5: Add copper chloride (38.97 mg, 0.29 mmol) and tert-butyl nitrite (0.03 mL, 0.29 mmol) to a solution of compound 137-4 (70 mg, 0.19 mmol) in acetonitrile (1 mL) at 0 °C middle. After the reaction mixture was stirred at 50°C for 16 hours, it was diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated, and the obtained crude product was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 137 (2.88 mg, 0.01 mmol, yield: 3.89%, purity: 99.65%). MS (ESI): m/z = 380 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.16–13.53 (m, 1H), 9.09 (s, 1H), 7.81 (s, 1H), 7.75 (d, J=8.6Hz, 1H), 7.54 (d, J=8.3Hz, 1H), 6.89(d, J=3.0Hz, 1H).
实施例138
Example 138
步骤1：按照实施例118中步骤1的类似合成方法，以3-氯-5-三氟甲基吡嗪-2-甲腈和5-三氟甲基-1H- 吲哚作为反应物制备得到化合物138-1。MS(ESI)：m/z＝357[M+H]+。Step 1: According to the similar synthesis method of Step 1 in Example 118, 3-chloro-5-trifluoromethylpyrazine-2-carbonitrile and 5-trifluoromethyl-1H- Indole was used as a reactant to prepare compound 138-1. MS (ESI): m/z = 357 [M+H] + .
步骤2：按照实施例118中步骤2的类似合成方法，以化合物138-1作为反应物制备得到化合物138-2。MS(ESI)：m/z＝390[M+H]+。Step 2: According to the similar synthesis method of Step 2 in Example 118, Compound 138-2 was prepared using Compound 138-1 as a reactant. MS (ESI): m/z = 390 [M+H] + .
步骤3：按照实施例118中步骤3的类似合成方法，以化合物138-2作为反应物制备得到化合物138(17mg，纯度：97.7％)。MS(ESI)：m/z＝416[M+H]+。1H NMR(DMSO-d6)δ:9.43(s,1H),8.09(s,1H),7.88(d,J＝3.4Hz,1H),7.76(d,J＝8.6Hz,1H),7.57(d,J＝8.8Hz,1H),6.92(d,J＝3.4Hz,1H)。Step 3: According to the similar synthesis method of Step 3 in Example 118, Compound 138 (17 mg, purity: 97.7%) was prepared using Compound 138-2 as a reactant. MS (ESI): m/z = 416 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 9.43(s, 1H), 8.09(s, 1H), 7.88(d, J=3.4Hz, 1H), 7.76(d, J=8.6Hz, 1H), 7.57 (d, J=8.8Hz, 1H), 6.92 (d, J=3.4Hz, 1H).
实施例140
Example 140
步骤1：在室温下，将5-溴-3-(5-(三氟甲基)-1H-吲哚-1-基)吡嗪-2-甲腈(50mg,0.14mmol)、乙基硼酸(50mg,0.68mmol)、碳酸钾(56mg,0.41mmol)和Pd(dppf)Cl2(28mg,0.07mmol)分散于1,4-二氧六环(1mL)/水(0.1mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌过夜，加水稀释，并用乙酸乙酯(10mL×3)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物140-2(24mg，产率：57.1％)。MS(ESI)：m/z＝317[M+H]+。Step 1: At room temperature, mix 5-bromo-3-(5-(trifluoromethyl)-1H-indol-1-yl)pyrazine-2-carbonitrile (50mg, 0.14mmol), ethylboronic acid (50 mg, 0.68 mmol), potassium carbonate (56 mg, 0.41 mmol) and Pd(dppf)Cl 2 (28 mg, 0.07 mmol) were dispersed in 1,4-dioxane (1 mL)/water (0.1 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80 °C and stirred overnight, diluted with water, and extracted with ethyl acetate (10 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 140-2 (24 mg, yield rate: 57.1%). MS (ESI): m/z = 317 [M+H] + .
步骤2：在室温下，将盐酸羟胺(49mg,0.76mmol)、三乙胺(0.21mL,1.51mmol)和分子筛(50mg)加入到化合物140-2(24mg,0.07mmol)的MeOH(5mL)溶液中。将反应混合物升温至80℃搅拌过夜，用水淬灭，并用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，得到无需纯化可直接用于下一步反应的化合物140-3(26mg，产率：97.4％)。MS(ESI)：m/z＝350[M+H]+。Step 2: At room temperature, mix hydroxylamine hydrochloride (49mg, 0.76mmol), triethylamine (0.21mL, 1.51mmol) and Molecular sieves (50 mg) were added to a solution of compound 140-2 (24 mg, 0.07 mmol) in MeOH (5 mL). The reaction mixture was warmed to 80 °C and stirred overnight, quenched with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain compound 140-3 (26 mg, yield: 97.4%), which was directly used in the next reaction without purification. MS (ESI): m/z = 350 [M+H] + .
步骤3：在0℃下，将CDI(22mg,0.14mmol)加入到化合物140-3(26mg,0.07mmol)的THF(2mL)溶液中，缓慢升至室温搅拌1小时后，在0℃下滴加DBU(21mg,0.14mmol)。将反应体系缓慢升至室温搅拌1小时，加水淬灭，并用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:1洗脱)纯化，得到化合物140(11mg，产率：41.7％)。MS(ESI)：m/z＝376[M+H]+。1H NMR(DMSO-d6)δ:13.03-13.36(m,1H),8.78-9.04(m,1H),8.01-8.15(m,1H),7.78-7.92(m,1H),7.65-7.76(m,1H),7.44-7.56(m,1H),6.78-6.96(m,1H),2.85-3.15(m,2H),1.29-1.42(m,3H)。Step 3: Add CDI (22mg, 0.14mmol) to a THF (2mL) solution of compound 140-3 (26mg, 0.07mmol) at 0°C, slowly rise to room temperature and stir for 1 hour, then drop at 0°C Add DBU (21 mg, 0.14 mmol). The reaction system was slowly raised to room temperature and stirred for 1 hour, quenched with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:1) to obtain compound 140 (11 mg, yield: 41.7%). MS (ESI): m/z = 376 [M+H] + . 1 H NMR(DMSO-d6)δ:13.03-13.36(m,1H),8.78-9.04(m,1H),8.01-8.15(m,1H),7.78-7.92(m,1H),7.65-7.76( m, 1H), 7.44-7.56(m, 1H), 6.78-6.96(m, 1H), 2.85-3.15(m, 2H), 1.29-1.42(m, 3H).
实施例144
Example 144
步骤1：向化合物2-氯-6,7-二氢-5H-环戊烷[b]吡啶-3-腈(4.0g,24.54mmol)的DCE(40mL)溶液中加入m-CPBA(6.0g,3.71mmol)。将反应混合物在50℃下搅拌过夜，加H2O稀释，并用EA萃取。将有机层用饱和硫代硫酸钠溶液洗涤3次，干燥后浓缩，得到残余物。将残余物经硅胶柱层析纯化，得到化合物144-1(4.5g，18.60mmol)。MS(ESI)：m/z＝242[M+H]+。Step 1: To a solution of the compound 2-chloro-6,7-dihydro-5H-cyclopentane[b]pyridine-3-carbonitrile (4.0 g, 24.54 mmol) in DCE (40 mL) was added m-CPBA (6.0 g , 3.71mmol). The reaction mixture was stirred overnight at 50 °C, diluted with H2O , and extracted with EA. The organic layer was washed 3 times with saturated sodium thiosulfate solution, dried and concentrated to obtain a residue. The residue was purified by silica gel column chromatography to obtain compound 144-1 (4.5 g, 18.60 mmol). MS (ESI): m/z = 242 [M+H]+.
步骤2：将化合物144-1(2.5g,10.38mmol)的醋酸酐(30mL)溶液在110℃下搅拌过夜，冷却至室温，加H2O稀释，并用EA萃取。将有机层用饱和食盐水洗涤(3次)，干燥后浓缩，并将所得残余通过柱层析纯化，得到化合物144-2(429mg，2.28mmol)。MS(ESI)：m/z＝189[M+H]+。Step 2: A solution of compound 144-1 (2.5 g, 10.38 mmol) in acetic anhydride (30 mL) was stirred at 110° C. overnight, cooled to room temperature, diluted with H 2 O, and extracted with EA. The organic layer was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by column chromatography to obtain compound 144-2 (429 mg, 2.28 mmol). MS (ESI): m/z = 189 [M+H]+.
步骤3：向化合物144-2(570mg,2.41mmol)的甲醇(6mL)和水(1.5mL)的溶液中加入碳酸钾(832.14mg,6.02mmol)。将反应混合物在常温下搅拌2小时，加H2O稀释并用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，得到化合物144-3的粗产物(380mg)。MS(ESI)：m/z＝195[M+H]+。Step 3: To a solution of compound 144-2 (570 mg, 2.41 mmol) in methanol (6 mL) and water (1.5 mL) was added potassium carbonate (832.14 mg, 6.02 mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with H2O and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated to obtain a crude product of compound 144-3 (380 mg). MS (ESI): m/z = 195 [M+H]+.
步骤4：在0℃下，向化合物144-3的粗产物(380mg)的DCM(12mL)溶液中缓慢加入戴斯－马丁氧 化剂(1076.59mg,2.54mmol)。将反应混合物在常温下搅拌2小时，用饱和碳酸氢钠溶液淬灭，并用DCM萃取。将有机相用饱和碳酸氢钠溶液洗涤(2次)，用饱和食盐水洗涤(1次)，干燥后浓缩得到化合物144-4的粗产物(290mg)。MS(ESI)：m/z＝193[M+H]+。Step 4: To a solution of the crude product of compound 144-3 (380 mg) in DCM (12 mL) was slowly added Dess-Martin oxygen at 0 °C Compounding agent (1076.59mg, 2.54mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated sodium bicarbonate solution, and extracted with DCM. The organic phase was washed with saturated sodium bicarbonate solution (2 times), washed with saturated brine (1 time), dried and concentrated to obtain a crude product of compound 144-4 (290 mg). MS (ESI): m/z = 193 [M+H]+.
步骤5：在0℃下，向化合物144-4(100mg,0.53mmol)的DCM(6mL)溶液中缓慢加入双(2-甲氧基乙基)氨基三氟化硫(600μL,3.25mmol)。将反应混合物在室温下搅拌2天，加入饱和碳酸氢钠溶液淬灭，并用DCM萃取。将有机层用饱和碳酸氢钠溶液洗涤(2次)，用饱和食盐水洗涤(1次)，干燥后浓缩，得到化合物144-5(70mg，0.33mmol,产率：69.80％)。MS(ESI)：m/z＝215[M+H]+。Step 5: To a solution of compound 144-4 (100 mg, 0.53 mmol) in DCM (6 mL) was slowly added bis(2-methoxyethyl)aminosulfur trifluoride (600 μL, 3.25 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 days, quenched by adding saturated sodium bicarbonate solution, and extracted with DCM. The organic layer was washed with saturated sodium bicarbonate solution (2 times), washed with saturated brine (1 time), dried and concentrated to obtain compound 144-5 (70 mg, 0.33 mmol, yield: 69.80%). MS (ESI): m/z = 215 [M+H]+.
步骤6：在氮气氛围下，向化合物144-5(100mg,0.56mmol)，5-三氟甲基-1H-吲哚(123.32mg,0.67mmol)，反式-N-二甲基环己烷-1，2-二胺(165mg,1.16mmol)和磷酸钾(117.82mg,0.56mmol)的甲苯(6mL)溶液中加入碘化亚铜(100mg,0.53mmol)。将反应混合物在110℃下搅拌过夜，加H2O稀释，并用EA萃取。将有机层用饱和食盐水洗涤，干燥后浓缩，并将所得的残余物通过硅胶柱层析纯化，得到化合物144-6(78mg,0.21mmol,产率：38.68％)。MS(ESI)：m/z＝364[M+H]+。Step 6: Under nitrogen atmosphere, to compound 144-5 (100mg, 0.56mmol), 5-trifluoromethyl-1H-indole (123.32mg, 0.67mmol), trans-N-dimethylcyclohexane - To a solution of 1,2-diamine (165mg, 1.16mmol) and potassium phosphate (117.82mg, 0.56mmol) in toluene (6mL) was added cuprous iodide (100mg, 0.53mmol). The reaction mixture was stirred overnight at 110 °C, diluted with H2O , and extracted with EA. The organic layer was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 144-6 (78 mg, 0.21 mmol, yield: 38.68%). MS (ESI): m/z = 364 [M+H]+.
步骤7：向化合物144-6的甲醇(4mL)溶液中加入盐酸羟胺(137.72mg,1.98mmol)、三乙胺(549.44μL,3.96mmol)和分子筛(160mg)。将反应混合物在80℃下搅拌4小时后，冷却至室温，过滤。将所得滤液浓缩后，向浓缩物中加H2O稀释，并用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，得到化合物144-7的粗产物(80mg)。MS(ESI)：m/z＝397[M+H]+。Step 7: Add hydroxylamine hydrochloride (137.72 mg, 1.98 mmol), triethylamine (549.44 μL, 3.96 mmol) and Molecular sieves (160mg). After stirring the reaction mixture at 80° C. for 4 hours, it was cooled to room temperature and filtered. After the obtained filtrate was concentrated, the concentrate was diluted with H2O and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated to obtain a crude product of compound 144-7 (80 mg). MS (ESI): m/z = 397 [M+H]+.
步骤8：在0℃下，将CDI(58.92mg,0.36mmol)加入到化合物144-7(72mg,0.18mmol)的THF(4mL)溶液中，在室温下搅拌1小时后，在0℃下加入DBU(54.23μL,0.36mmol)。将反应混合物在室温下搅拌1.5小时，冷却至0℃，用盐酸(2M)将pH调至6，加水稀释，并用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物144(16mg,0.04mmol,产率：20.86％)。MS(ESI)：m/z＝423[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝12.85(br s,1H),8.48(s,1H),8.09(s,1H),7.66(d,J＝8.8Hz,1H),7.62(d,J＝3.5Hz,1H),7.56(dd,J＝1.3,8.8Hz,1H),6.90(d,J＝3.4Hz,1H),3.21(br s,2H),2.87-2.74(m,2H)。Step 8: Add CDI (58.92mg, 0.36mmol) to a THF (4mL) solution of compound 144-7 (72mg, 0.18mmol) at 0°C, stir at room temperature for 1 hour, then add DBU (54.23 μL, 0.36 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, cooled to 0 °C, adjusted to pH 6 with hydrochloric acid (2M), diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 144 (16 mg, 0.04 mmol, yield: 20.86%). MS (ESI): m/z = 423 [M+H]+. 1 H NMR (400MHz, DMSO-d 6 )δ=12.85(br s,1H),8.48(s,1H),8.09(s,1H),7.66(d,J=8.8Hz,1H),7.62(d ,J=3.5Hz,1H),7.56(dd,J=1.3,8.8Hz,1H),6.90(d,J=3.4Hz,1H),3.21(br s,2H),2.87-2.74(m,2H ).
实施例146
Example 146
步骤1：向6-溴-2,3-二氢-1H-吡咯并[3,2-b]吡啶(2g,10.05mmol)的乙腈(40mL)溶液中加入NCS(1.34g,10.05mmol)。将反应混合物在90℃下搅拌18小时后过滤。将所得滤液浓缩，并将残余物放置于硅树脂塔中(用PE:EA＝1:1洗脱)精馏，得到化合物146-1(1.14g,产率：48.59％)。MS(ESI)：m/z＝233[M+H]+。Step 1: To a solution of 6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (2 g, 10.05 mmol) in acetonitrile (40 mL) was added NCS (1.34 g, 10.05 mmol). The reaction mixture was stirred at 90°C for 18 hours and then filtered. The obtained filtrate was concentrated, and the residue was placed in a silicone resin column (eluted with PE:EA=1:1) for rectification to obtain compound 146-1 (1.14 g, yield: 48.59%). MS (ESI): m/z = 233 [M+H] + .
步骤2:向化合物146-1(800mg,3.42mmol)的NMP(16mL)溶液中加入氰化亚铜(3.07g,34.26mmol)。将反应混合物在180℃下搅拌2.5小时后，倒入水(12mL)中，并用乙酸乙酯(20mLx3)萃取。将合并所得有机相用饱和氯化钠溶液(20mL)洗涤，用无水硫酸钠干燥后浓缩，并将残余物放置于硅树脂塔中(用PE:EA＝2:1洗脱)精馏，得到化合物146-2。MS(ESI)：m/z＝180[M+H]+。Step 2: To a solution of compound 146-1 (800 mg, 3.42 mmol) in NMP (16 mL) was added cuprous cyanide (3.07 g, 34.26 mmol). After the reaction mixture was stirred at 180° C. for 2.5 hours, it was poured into water (12 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was placed in a silicone resin tower (eluted with PE:EA=2:1) for rectification, Compound 146-2 was obtained. MS (ESI): m/z = 180 [M+H] + .
步骤3:向化合物146-2(107mg,0.60mmol)的甲苯(2mL)溶液中加入5-(三氟甲基)-1H-吲哚(132.36mg,0.71mmol)，BrettPhos Pd G3(54.01mg,0.06mmol)和叔丁醇钠(85.88mg,0.89mmol)。将反应混合物在100℃下搅拌18小时后。倒入水(3mL)中，并用乙酸乙酯(5mLx3)萃取。将合并所得有机相用饱和氯化钠溶液(5mL)洗涤，用无水硫酸钠干燥后浓缩，并将残余物放置于硅树脂塔中(用PE:EA＝1:1洗脱)精馏，得到化合物146-3(34mg,产率：17.38％)。MS(ESI)：m/z＝329[M+H]+。Step 3: Add 5-(trifluoromethyl)-1H-indole (132.36mg, 0.71mmol) to a solution of compound 146-2 (107mg, 0.60mmol) in toluene (2mL), BrettPhos Pd G3 (54.01mg, 0.06mmol) and sodium tert-butoxide (85.88mg, 0.89mmol). After stirring the reaction mixture at 100 °C for 18 hours. Poured into water (3 mL), and extracted with ethyl acetate (5 mLx3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was placed in a silicone resin tower (eluted with PE:EA=1:1) for rectification, Compound 146-3 (34 mg, yield: 17.38%) was obtained. MS (ESI): m/z = 329 [M+H] + .
步骤4:向化合物146-3(28mg,0.09mmol)的甲醇(1mL)溶液中加入盐酸羟胺(59.27mg,0.85mmol)，三乙胺(0.36mL,2.56mmol)和分子筛(100mg)。将反应混合物在80℃下搅拌6小时后，倒入水(1mL)中，并用二氯甲烷(2mLx3)萃取。将合并所得有机相用饱和氯化钠溶液(2mL)洗涤，用无水硫酸钠干燥后浓缩，得到化合物146-4的粗产物(35mg)。MS(ESI)：m/z＝362[M+H]+。 Step 4: Add hydroxylamine hydrochloride (59.27mg, 0.85mmol), triethylamine (0.36mL, 2.56mmol) and Molecular sieves (100 mg). After the reaction mixture was stirred at 80° C. for 6 hours, it was poured into water (1 mL), and extracted with dichloromethane (2 mL×3). The combined organic phases were washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate and concentrated to obtain a crude product of compound 146-4 (35 mg). MS (ESI): m/z = 362 [M+H] + .
步骤5:在0℃下，将CDI(11.23mg,0.07mmol)加入到化合物146-4的粗产物(35mg)的四氢呋喃(6mL)的溶液中，在0℃下搅拌1小时后，加入DBU(14.11μL,0.09mmol)。将反应混合物在0℃下搅拌1小时后，倒入水(6mL)中，并用乙酸乙酯(6mLx3)萃取。将合并所得有机相用盐酸(1M)洗涤，用无水硫酸钠干燥后浓缩，并将所得残余物经高效液相色谱纯化，得到化合物146(3.16mg,产率：11.93％)。MS(ESI)：m/z＝388[M+H]+。1H NMR(DMSO-d6)δ:12.60(br s,1H),8.00(s,1H),7.50(d,J＝3.3Hz,1H),7.38-7.44(m,1H),7.31-7.38(m,1H),7.05(s,1H),6.76(d,J＝3.3Hz,1H),6.57(s,1H),3.68(t,J＝8.8Hz,2H),3.05-3.23(m,2H)。Step 5: At 0° C., CDI (11.23 mg, 0.07 mmol) was added to a solution of the crude product (35 mg) of compound 146-4 in THF (6 mL), and after stirring at 0° C. for 1 hour, DBU ( 14.11 μL, 0.09 mmol). After the reaction mixture was stirred at 0° C. for 1 hour, it was poured into water (6 mL), and extracted with ethyl acetate (6 mL×3). The combined organic phases were washed with hydrochloric acid (1M), dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by high performance liquid chromatography to obtain compound 146 (3.16 mg, yield: 11.93%). MS (ESI): m/z = 388 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.60 (br s, 1H), 8.00 (s, 1H), 7.50 (d, J=3.3Hz, 1H), 7.38-7.44 (m, 1H), 7.31-7.38 (m,1H),7.05(s,1H),6.76(d,J=3.3Hz,1H),6.57(s,1H),3.68(t,J=8.8Hz,2H),3.05-3.23(m, 2H).
实施例147
Example 147
步骤1:在冰浴条件下，将氢化钠(5.05g,126.35mmol)分批次加入到丙二酸二甲酯(13.91g,105.29mmol)的DMF(150mL)溶液中，在室温下反应半小时后，加入5-溴-2-氯-3-硝基吡啶(25g,105.29mmol)。将反应混合物在室温下搅拌12小时后，加水稀释，并用乙酸乙酯萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物147-1(22.7g,产率：64.73％)。MS(ESI)：m/z＝335[M+H]+。Step 1: Under ice-bath conditions, sodium hydride (5.05g, 126.35mmol) was added in batches to a DMF (150mL) solution of dimethyl malonate (13.91g, 105.29mmol), and the reaction was half-way at room temperature After hours, 5-bromo-2-chloro-3-nitropyridine (25 g, 105.29 mmol) was added. After stirring the reaction mixture at room temperature for 12 hours, it was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 147-1 (22.7 g, yield: 64.73%). MS (ESI): m/z = 335 [M+H] + .
步骤2:在冰浴条件下，将氢化钠(3.27g,81.78mmol)分批次加入到化合物147-1(22.7g,68.15mmol)的DMF(200mL)溶液中，在室温下反应半小时后，加入溴乙酸乙酯(11.38g,68.15mmol)。将反应混合物在室温下搅拌反应12小时后，加入水，并用乙酸乙酯萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物147-2(23g,产率：48.31％)。MS(ESI)：m/z＝420[M+H]+。Step 2: Under ice-bath conditions, sodium hydride (3.27g, 81.78mmol) was added in batches to a solution of compound 147-1 (22.7g, 68.15mmol) in DMF (200mL) and reacted at room temperature for half an hour , and ethyl bromoacetate (11.38 g, 68.15 mmol) was added. After the reaction mixture was stirred at room temperature for 12 hours, water was added and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 147-2 (23 g, yield: 48.31%). MS (ESI): m/z = 420 [M+H] + .
步骤3:将化合物147-2(21.8g,52.01mmol)的浓盐酸(150mL)溶液用N2吹扫并维持N2氛围，90℃搅拌反应12小时后，加水(50mL)稀释，过滤。将所得滤渣用水洗涤后干燥，得到化合物147-3(12g,产率：83.89％)。MS(ESI)：m/z＝277[M+H]+。Step 3: The solution of compound 147-2 (21.8g, 52.01mmol) in concentrated hydrochloric acid (150mL) was purged with N 2 and maintained under N 2 atmosphere, stirred and reacted at 90°C for 12 hours, diluted with water (50mL), and filtered. The resulting filter residue was washed with water and dried to obtain compound 147-3 (12 g, yield: 83.89%). MS (ESI): m/z = 277 [M+H] + .
步骤4:将化合物147-3(12.1g,43.99mmol)、铁粉(7.37g,131.97mmol)、氯化铵(7.06g,131.97mmol)分散于四氢呋喃(150mL)、甲醇(75mL)和水(75mL)的混合溶剂中。将反应混合物用N2吹扫并维持N2氛围，在60℃下搅拌12小时后浓缩，加入水，并用乙酸乙酯萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析，得到化合物147-4(8g,产率：74.20％)。MS(ESI)：m/z＝247[M+H]+。Step 4: Compound 147-3 (12.1g, 43.99mmol), iron powder (7.37g, 131.97mmol), ammonium chloride (7.06g, 131.97mmol) were dispersed in tetrahydrofuran (150mL), methanol (75mL) and water ( 75mL) in a mixed solvent. The reaction mixture was purged with N2 and maintained under N2 atmosphere, stirred at 60 °C for 12 h, concentrated, added water, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was subjected to silica gel column chromatography to obtain compound 147-4 (8 g, yield: 74.20%). MS (ESI): m/z = 247 [M+H] + .
步骤5:将T3P(20.77g,65.28mmol)和DIEA(16.88g,130.57mmol)加入到化合物147-4(8g,32.64mmol)的DMF(100mL)溶液中。将反应混合物在室温下搅拌12小时后，加入水，并用乙酸乙酯萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物147-5(7.4g,产率：99.84％)。MS(ESI)：m/z＝229[M+H]+。Step 5: T 3 P (20.77 g, 65.28 mmol) and DIEA (16.88 g, 130.57 mmol) were added to a solution of compound 147-4 (8 g, 32.64 mmol) in DMF (100 mL). After the reaction mixture was stirred at room temperature for 12 hours, water was added and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 147-5 (7.4 g, yield: 99.84%). MS (ESI): m/z = 229 [M+H] + .
步骤6:将化合物147-5(7.8g,34.35mmol)和NCS(9.17g,68.70mmol)的乙腈(80mL)溶液在90℃下搅拌反应12小时后，过滤。将所得滤饼用乙腈冲洗，得到化合物147-6(8.5g,产率：94.62％)。MS(ESI)：m/z＝262[M1]+。Step 6: A solution of compound 147-5 (7.8g, 34.35mmol) and NCS (9.17g, 68.70mmol) in acetonitrile (80mL) was stirred and reacted at 90°C for 12 hours, and then filtered. The resulting filter cake was washed with acetonitrile to obtain compound 147-6 (8.5 g, yield: 94.62%). MS (ESI): m/z=262[M1] + .
步骤7:将硼烷的四氢呋喃溶液(1M，53.54mL)加入到化合物147-6(4g,15.30mmol)的四氢呋喃(300mL)溶液。将反应混合物在70℃下搅拌反应2小时后，将水在冰浴条件下滴入以淬灭反应，加入水稀释，并用乙酸乙酯萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析得到化合物147-7(3.7g,产率：97.72％)。MS(ESI)：m/z＝249[M+H]+。Step 7: A solution of borane in THF (1M, 53.54 mL) was added to a solution of compound 147-6 (4 g, 15.30 mmol) in THF (300 mL). After the reaction mixture was stirred at 70° C. for 2 hours, water was added dropwise in an ice bath to quench the reaction, diluted with water, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was subjected to silica gel column chromatography to obtain compound 147-7 (3.7 g, yield: 97.72%). MS (ESI): m/z = 249 [M+H] + .
步骤8:将化合物147-7(3.6g,14.54mmol)和氰化亚铜分散于NMP(80mL)。将反应混合物用N2吹扫并维持N2氛围，在180℃下搅拌3小时后，加入水，并用乙酸乙酯萃取。将合并所得有机相用无水硫 酸钠干燥后浓缩，将所得残余物经硅胶柱层析纯化，得到化合物147-8(2.4g,产率：85.22％)。MS(ESI)：m/z＝194[M+H]+。Step 8: Compound 147-7 (3.6 g, 14.54 mmol) and cuprous cyanide were dispersed in NMP (80 mL). The reaction mixture was purged with N2 and maintained under N2 atmosphere, after stirring at 180 °C for 3 h, water was added and extracted with ethyl acetate. The combined organic phases were treated with anhydrous sulfur After drying over sodium chloride and concentrating, the resulting residue was purified by silica gel column chromatography to obtain compound 147-8 (2.4 g, yield: 85.22%). MS (ESI): m/z = 194 [M+H] + .
步骤9:将化合物147-8(1g,5.16mmol)、5-(三氟甲基)-1H-吲哚(1.15g,6.20mmol)、和Breetphos G3(468.17mg,0.52mmol)分散于甲苯(20mL)中。将反应混合物用N2吹扫并维持N2氛围，在100℃下搅拌12小时后，加入水，并用乙酸乙酯萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物147-9(389mg,产率：22％)。MS(ESI)：m/z＝343[M+H]+。Step 9: Compound 147-8 (1g, 5.16mmol), 5-(trifluoromethyl)-1H-indole (1.15g, 6.20mmol), and Breetphos G3 (468.17mg, 0.52mmol) were dispersed in toluene ( 20mL). The reaction mixture was purged with N2 and maintained under N2 atmosphere, after stirring at 100 °C for 12 h, water was added and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 147-9 (389 mg, yield: 22%). MS (ESI): m/z = 343 [M+H] + .
步骤10:将三乙胺(5.12g,50.65mmol)加入到化合物147-9(289mg,0.84mmol)、盐酸羟胺(586.64mg,8.44mmol)、和分子筛(289mg)、和甲醇(10mL)的混合物中。将反应混合物用N2吹扫并维持N2氛围，在75℃下搅拌12小时后，加入饱和氯化铵水溶液，并用乙酸乙酯萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，将所得残余物经硅胶柱层析纯化，得到化合物147-10(126mg,产率：39.76％)。MS(ESI)：m/z＝317[M+H]+。Step 10: Triethylamine (5.12g, 50.65mmol) was added to compound 147-9 (289mg, 0.84mmol), hydroxylamine hydrochloride (586.64mg, 8.44mmol), and In a mixture of molecular sieves (289mg) and methanol (10mL). The reaction mixture was purged with N2 and maintained under N2 atmosphere, after stirring at 75 °C for 12 h, saturated aqueous ammonium chloride was added, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 147-10 (126 mg, yield: 39.76%). MS (ESI): m/z = 317 [M+H] + .
步骤11:在冰浴条件下，将CDI(68.04mg,0.42mmol)加入到化合物147-10(126mg,0.34mmol)的THF(2mL)的溶液中，搅拌半小时后加入DBU(76.66mg,0.5mmol)。将反应混合物在室温下搅拌半小时后，加入水，并用乙酸乙酯萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩，将所得残余物经硅胶柱层析纯化，得到化合物147(19.8mg,产率：14.70％)。MS(ESI)：m/z＝402[M+H]+。1H NMR(DMSO-d6)δ:8.00(s,1H),7.50(d,J＝3.3Hz,1H),7.35-7.43(m,2H),7.20(s,1H),6.75(d,J＝3.3Hz,1H),6.64(s,1H),3.26-3.30(m,2H),2.86(t,J＝6.3Hz,2H),1.96(br d,J＝5.4Hz,2H)。Step 11: Add CDI (68.04mg, 0.42mmol) to a solution of compound 147-10 (126mg, 0.34mmol) in THF (2mL) under ice bath conditions, add DBU (76.66mg, 0.5mL) after stirring for half an hour mmol). After the reaction mixture was stirred at room temperature for half an hour, water was added and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 147 (19.8 mg, yield: 14.70%). MS (ESI): m/z = 402 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.00(s, 1H), 7.50(d, J=3.3Hz, 1H), 7.35-7.43(m, 2H), 7.20(s, 1H), 6.75(d, J=3.3Hz, 1H), 6.64(s, 1H), 3.26-3.30(m, 2H), 2.86(t, J=6.3Hz, 2H), 1.96(br d, J=5.4Hz, 2H).
实施例149
Example 149
步骤1：将2-(乙氧基亚甲基)丙二腈(2.19g,17.94mmol)加入4-(环己-1-烯-1-基)吗啉(3.0g,17.94mmol)的甲醇(35mL)溶液中。将反应混合物在28℃下搅拌4小时以析出固体，然后过滤。将所得滤饼用0℃的甲醇(3mL*3)洗涤后干燥,得到化合物149-1(1.86g,7.64mmol,产率：42.62％)。MS(ESI)：m/z＝243[M+H]+。Step 1: Add 2-(ethoxymethylene)malononitrile (2.19g, 17.94mmol) to 4-(cyclohex-1-en-1-yl)morpholine (3.0g, 17.94mmol) in methanol (35mL) solution. The reaction mixture was stirred at 28°C for 4 hours to precipitate a solid, then filtered. The resulting filter cake was washed with 0°C methanol (3 mL*3) and dried to obtain compound 149-1 (1.86 g, 7.64 mmol, yield: 42.62%). MS (ESI): m/z = 243 [M+H] + .
步骤2：将化合物149-1(1.86g,7.64mmol)和NH3的甲醇溶液(7M，20mL)的混合物在(130w,110℃)微波条件下反应40分钟，冷却至室温后析出固体，然后过滤。将所得滤饼用0℃的甲醇(3mL*3)洗涤，得到化合物149-2(1130mg,6.52mmol,产率：88％)。MS(ESI)：m/z＝174[M+H]+。Step 2: The mixture of compound 149-1 (1.86g, 7.64mmol) and NH 3 methanol solution (7M, 20mL) was reacted under microwave conditions (130w, 110°C) for 40 minutes, and a solid precipitated after cooling to room temperature, and then filter. The resulting filter cake was washed with methanol (3 mL*3) at 0° C. to obtain compound 149-2 (1130 mg, 6.52 mmol, yield: 88%). MS (ESI): m/z = 174 [M+H] + .
步骤3：在0℃下，将亚硝酸钠(1.55mL,28.99mmol)缓慢加入到化合物149-2(1.0g,5.77mmol)的醋酸(6mL)和浓盐酸(6mL)的溶液中。将反应混合物在0℃下搅拌1小时后，在0℃下缓慢加水淬灭，并析出固体，然后过滤。将所得滤饼依次用水(5mL*3)和0℃的甲醇(3mL*3)洗涤后干燥，得到化合物149-3(640mg,3.32mmol,产率：57.55％)。MS(ESI)：m/z＝193[M+H]+。Step 3: Sodium nitrite (1.55 mL, 28.99 mmol) was slowly added to a solution of compound 149-2 (1.0 g, 5.77 mmol) in acetic acid (6 mL) and concentrated hydrochloric acid (6 mL) at 0°C. After the reaction mixture was stirred at 0°C for 1 hour, it was quenched by slowly adding water at 0°C, and a solid precipitated out, which was then filtered. The obtained filter cake was washed successively with water (5 mL*3) and 0° C. methanol (3 mL*3) and dried to obtain compound 149-3 (640 mg, 3.32 mmol, yield: 57.55%). MS (ESI): m/z = 193 [M+H] + .
步骤4：将5-三氟甲基-1H-吲哚(563.47mg,3.04mmol)和碳酸铯(1352.16mg,4.15mmol)加入到化合物149-3(533mg,2.77mmol)的DMF(8mL)溶液中。将反应混合物在120℃下搅拌1小时后，冷却至室温，加H2O稀释，并用EA萃取。将所得有机相用饱和食盐水洗涤(3次)，干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物149-4(336mg,0.98mmol,产率：35.58％)。MS(ESI)：m/z＝342[M+H]+。Step 4: Add 5-trifluoromethyl-1H-indole (563.47 mg, 3.04 mmol) and cesium carbonate (1352.16 mg, 4.15 mmol) to a solution of compound 149-3 (533 mg, 2.77 mmol) in DMF (8 mL) middle. After stirring the reaction mixture at 120 °C for 1 hour, it was cooled to room temperature, diluted with H2O , and extracted with EA. The obtained organic phase was washed with saturated brine (3 times), dried and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain compound 149-4 (336 mg, 0.98 mmol, yield: 35.58%). MS (ESI): m/z = 342 [M+H] + .
步骤5：将盐酸羟胺(684.03mg,9.84mmol)、三乙胺(2.72mL,19.69mmol)和分子筛(600mg)加入到化合物149-4(336mg,0.98mmol)的甲醇(12mL)溶液中。将反应混合物在80℃下搅拌4小时，冷却至室温后过滤，并将所得滤液浓缩。向所得浓缩物中加H2O稀释，并用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，将所得残余物经硅胶柱层析纯化，得到化合物149-5(230mg,0.61mmol,产率：62.41％)。MS(ESI)：m/z＝375[M+H]+。Step 5: Hydroxylamine hydrochloride (684.03mg, 9.84mmol), triethylamine (2.72mL, 19.69mmol) and Molecular sieves (600 mg) were added to a solution of compound 149-4 (336 mg, 0.98 mmol) in methanol (12 mL). The reaction mixture was stirred at 80° C. for 4 hours, cooled to room temperature and filtered, and the resulting filtrate was concentrated. The resulting concentrate was diluted with H2O and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 149-5 (230 mg, 0.61 mmol, yield: 62.41%). MS (ESI): m/z = 375 [M+H] + .
步骤6：在0℃下向，将CDI(150mg,0.92mmol)加入到化合物149-5(230mg,0.61mmol)的THF(8mL)的溶液中，在室温下搅拌0.5小时后，在0℃下加入DBU(0.14mL,0.92mmol)。将反应混合物在室温下搅拌1.5小时，在0℃下用盐酸(2M)将pH调节至6，加入水稀释，并用EA萃取。将有机层用饱和食盐水洗涤，干燥后浓缩，并将所得残余物通过柱层析纯化，得到化合物149(160mg,0.40mmol,产率：65.51％)。 MS(ESI)：m/z＝401[M+H]+。1H NMR(DMSO-d6)δ:8.05(s,2H),7.63(d,J＝8.6Hz,1H),7.59(d,J＝3.4Hz,1H),7.48(dd,J＝8.8,1.3Hz,1H),6.84(d,J＝3.4Hz,1H),2.83-3.02(m,4H),1.76-1.96(m,4H)。Step 6: Add CDI (150mg, 0.92mmol) to a solution of compound 149-5 (230mg, 0.61mmol) in THF (8mL) at 0°C, and stir at room temperature for 0.5 hours. DBU (0.14 mL, 0.92 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours, adjusted to pH 6 with hydrochloric acid (2M) at 0 °C, diluted with water, and extracted with EA. The organic layer was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography to obtain compound 149 (160 mg, 0.40 mmol, yield: 65.51%). MS (ESI): m/z = 401 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.05 (s, 2H), 7.63 (d, J = 8.6Hz, 1H), 7.59 (d, J = 3.4Hz, 1H), 7.48 (dd, J = 8.8, 1.3Hz, 1H), 6.84(d, J=3.4Hz, 1H), 2.83-3.02(m, 4H), 1.76-1.96(m, 4H).
实施例150
Example 150
步骤1：将化合物1,4-二氧杂环[4.5]癸-8-酮(10.0g,62.75mmol)溶于DMF-DMA(100mL,724.49mmol)中。将反应混合物在110℃下搅拌过夜后浓缩，得到化合物150-1(14.02g,66.36mmol)。MS(ESI)：m/z＝207[M+H]+。Step 1: Compound 1,4-dioxacyclo[4.5]dec-8-one (10.0 g, 62.75 mmol) was dissolved in DMF-DMA (100 mL, 724.49 mmol). The reaction mixture was stirred overnight at 110° C. and then concentrated to obtain compound 150-1 (14.02 g, 66.36 mmol). MS (ESI): m/z = 207 [M+H] + .
步骤2：向化合物150-1(5000mg,23.67mmol)的乙腈(60mL)溶液中加入丙二腈(1804.01μL,28.40mmol)和醋酸铵(182.43mg,2.37mmol)。将反应混合物在70℃下搅拌过夜，冷却至室温，加H2O稀释，并用EA萃取。将有机相用饱和食盐水洗涤(3次)，干燥后浓缩，得到化合物150-2的粗产物(2.56g，16.73mmol)。MS(ESI)：m/z＝233[M+H]+。Step 2: To a solution of compound 150-1 (5000 mg, 23.67 mmol) in acetonitrile (60 mL) was added malononitrile (1804.01 μL, 28.40 mmol) and ammonium acetate (182.43 mg, 2.37 mmol). The reaction mixture was stirred overnight at 70 °C, cooled to room temperature, diluted with H2O , and extracted with EA. The organic phase was washed with saturated brine (3 times), dried and concentrated to obtain a crude product of compound 150-2 (2.56 g, 16.73 mmol). MS (ESI): m/z = 233 [M+H] + .
步骤3：将化合物150-2的粗产物(1.84g,7.92mmol)溶于三氯氧磷(25mL)中。将反应混合物在100℃下搅拌2小时后浓缩，并将浓缩物缓慢滴入饱和碳酸钠溶液中，用EA萃取。将有机相用饱和食盐水洗涤(3次)，干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物150-3(750mg,3.63mmol,产率：45.81％)。MS(ESI)：m/z＝207[M+H]+。Step 3: The crude product of compound 150-2 (1.84 g, 7.92 mmol) was dissolved in phosphorus oxychloride (25 mL). The reaction mixture was stirred at 100° C. for 2 hours and concentrated, and the concentrate was slowly dropped into a saturated sodium carbonate solution and extracted with EA. The organic phase was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 150-3 (750 mg, 3.63 mmol, yield: 45.81%). MS (ESI): m/z = 207 [M+H] + .
步骤4：在0℃下,向化合物150-3(720mg,3.48mmol)的DCM(12mL)溶液中缓慢加入双(2-甲氧基乙基)氨基三氟化硫(1381.14μL,10.45mmol)。将反应混合物在室温下搅拌2天，用饱和碳酸氢钠溶液淬灭，并用DCM萃取。将有机相用饱和碳酸氢钠溶液洗涤(2次)，用饱和食盐水洗涤(1次)，干燥后浓缩，得到化合物150-4(425mg,1.86mmol,产率：53.35％)。MS(ESI)：m/z＝229[M+H]+。Step 4: To a solution of compound 150-3 (720 mg, 3.48 mmol) in DCM (12 mL) was slowly added bis(2-methoxyethyl)aminosulfur trifluoride (1381.14 μL, 10.45 mmol) at 0 °C . The reaction mixture was stirred at room temperature for 2 days, quenched with saturated sodium bicarbonate solution, and extracted with DCM. The organic phase was washed with saturated sodium bicarbonate solution (2 times), washed with saturated brine (1 time), dried and concentrated to obtain compound 150-4 (425 mg, 1.86 mmol, yield: 53.35%). MS (ESI): m/z = 229 [M+H] + .
步骤5：向化合物150-4(355mg,1.55mmol)的甲苯(10mL)溶液中加入5-三氟甲基-1H-吲哚(344.98mg,1.86mmol),、碘化亚铜(202.83mg,1.06mmol)、反-N，N-二甲基环己烷-1,2-二胺(66.85mg,0.47mmol)和磷酸钾(329.58mg,1.55mmol)。将反应混合物在110℃下搅拌过夜，冷却至室温，加H2O稀释，并用EA萃取。将有机相用饱和食盐水洗涤(3次)，干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物150-5(280mg,0.74mmol,产率：47.79％)。MS(ESI)：m/z＝378[M+H]+。Step 5: Add 5-trifluoromethyl-1H-indole (344.98 mg, 1.86 mmol), cuprous iodide (202.83 mg, 1.06mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (66.85mg, 0.47mmol) and potassium phosphate (329.58mg, 1.55mmol). The reaction mixture was stirred overnight at 110 °C, cooled to room temperature, diluted with H2O , and extracted with EA. The organic phase was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 150-5 (280 mg, 0.74 mmol, yield: 47.79%). MS (ESI): m/z = 378 [M+H] + .
步骤6：向化合物150-5(250mg,0.66mmol)的甲醇(8mL)溶液中加入盐酸羟胺(460.42mg,6.63mmol)、三乙胺(1.84mL,13.25mmol)和分子筛(250mg)。将反应混合物在80℃下搅拌4小时，冷却至室温后过滤，并将所得滤液浓缩。向所得浓缩物中加H2O稀释，并用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物150-6(300mg,0.42mmol,产率：62.90％)。MS(ESI)：m/z＝411[M+H]+。Step 6: Add hydroxylamine hydrochloride (460.42 mg, 6.63 mmol), triethylamine (1.84 mL, 13.25 mmol) and Molecular sieves (250 mg). The reaction mixture was stirred at 80° C. for 4 hours, cooled to room temperature and filtered, and the resulting filtrate was concentrated. The resulting concentrate was diluted with H2O and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 150-6 (300 mg, 0.42 mmol, yield: 62.90%). MS (ESI): m/z = 411 [M+H] + .
步骤7：在0℃下，将CDI(148.18mg,0.91mmol)加入到化合物150-6(230mg,0.61mmol)的THF(8mL)溶液中，在常温下搅拌0.5小时后，在0℃下加入DBU(163.68μL,1.10mmol)。将反应混合物在常温下搅拌1.5小时，冷却至0℃后用盐酸(2M)调节pH至6，加水稀释，并用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，将所得残余物通过硅胶柱层析纯化，得到化合物150(57mg,0.13mmol,产率：21.44％)。MS(ESI)：m/z＝437[M+H]+。1HNMR(DMSO-d6)δ:8.17(s,1H),8.07(s,1H),7.72(d,J＝8.8Hz,1H),7.60(d,J＝3.5Hz,1H),7.51(d,J＝8.8Hz,1H),6.87(d,J＝3.5Hz,1H),3.48-3.60(m,2H),3.16-3.24(m,2H),2.38-2.49(m,2H)。Step 7: Add CDI (148.18 mg, 0.91 mmol) to a THF (8 mL) solution of compound 150-6 (230 mg, 0.61 mmol) at 0°C, stir at room temperature for 0.5 hours, then add DBU (163.68 μL, 1.10 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, cooled to 0 °C and adjusted to pH 6 with hydrochloric acid (2M), diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 150 (57 mg, 0.13 mmol, yield: 21.44%). MS (ESI): m/z = 437 [M+H] + . 1 H NMR (DMSO-d 6 ) δ: 8.17(s, 1H), 8.07(s, 1H), 7.72(d, J=8.8Hz, 1H), 7.60(d, J=3.5Hz, 1H), 7.51( d,J=8.8Hz,1H), 6.87(d,J=3.5Hz,1H), 3.48-3.60(m,2H), 3.16-3.24(m,2H), 2.38-2.49(m,2H).
实施例155
Example 155
步骤1：在室温下，将氨基甲酸叔丁酯(740.69mg,6.32mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)(997.75mg,1.72mmol),碳酸铯(3745.49mg,11.50mmol)和醋酸钯(129.04mg,0.57mmol)加入到3，6-二氯吡嗪-2-甲腈(0.63mL,5.75mmol)的1,4二氧六环(25mL)的溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌6个小时，加水稀释，再用乙酸乙酯(100mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，将所得残余物经硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物155-1(600mg,产率：40.99％)。MS(ESI)：m/z＝199[M-56+H]+。Step 1: At room temperature, tert-butyl carbamate (740.69mg, 6.32mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (Xantphos) (997.75mg, 1.72mmol ), cesium carbonate (3745.49mg, 11.50mmol) and palladium acetate (129.04mg, 0.57mmol) were added to 3,6-dichloropyrazine-2-carbonitrile (0.63mL, 5.75mmol) in 1,4 dioxane ring (25 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 80°C and stirred for 6 hours, diluted with water, and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 155-1 (600mg, yield : 40.99%). MS (ESI): m/z = 199 [M-56+H] + .
步骤2：在室温下，将化合物155-1(600mg,2.36mmol)、5-三氟甲基-1H-吲哚(436.21mg,2.36mmol)、碳酸铯(1535.26mg,4.71mmol)分散于DMF(10mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至120℃搅拌8个小时后，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(用乙酸乙酯：石油醚＝1：5洗脱)纯化，得到化合物155-2(390mg,产率：41.04％)。MS(ESI)：m/z＝348[M-56+H]+。Step 2: Compound 155-1 (600mg, 2.36mmol), 5-trifluoromethyl-1H-indole (436.21mg, 2.36mmol), cesium carbonate (1535.26mg, 4.71mmol) were dispersed in DMF at room temperature (10mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 120 °C and stirred for 8 hours, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 155-2 (390 mg, yield rate: 41.04%). MS (ESI): m/z = 348 [M-56+H] + .
步骤3：在0℃下，将盐酸二氧六环溶液(4mL)滴入化合物155-2(200mg,0.50mmol)的二氯甲烷(1mL)溶液中。将反应混合物缓慢升温至34℃搅拌8个小时后，用饱和碳酸氢钠淬灭，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(乙酸乙酯:石油醚＝1:2)纯化，得到化合物155-3(31mg,产率：20.62％)。MS(ESI)：m/z＝304[M+H]+。Step 3: Dioxane hydrochloride solution (4 mL) was added dropwise into a solution of compound 155-2 (200 mg, 0.50 mmol) in dichloromethane (1 mL) at 0°C. The reaction mixture was slowly warmed to 34 °C and stirred for 8 hours, then quenched with saturated sodium bicarbonate, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:2) to obtain compound 155-3 (31 mg, yield: 20.62 %). MS (ESI): m/z = 304 [M+H] + .
步骤4：在室温下，将盐酸羟胺(71.04mg,1.02mmol)、分子筛(270mg,0.66mmol)和三乙胺(0.85mL,6.13mmol)加入到化合物155-3(31mg,0.10mmol)的甲醇(2mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌3个小时，用饱和氯化铵淬灭，过滤。将所得滤液用乙酸乙酯(20mL×2)萃取，并将合并所得有机相用无水硫酸钠干燥后浓缩。将所得残余物用硅胶柱层析(用乙酸乙酯洗脱)纯化，得到化合物155-4(32mg,产率：93.09％)。MS(ESI)：m/z＝337[M+H]+。Step 4: At room temperature, hydroxylamine hydrochloride (71.04mg, 1.02mmol), Molecular sieves (270 mg, 0.66 mmol) and triethylamine (0.85 mL, 6.13 mmol) were added to a solution of compound 155-3 (31 mg, 0.10 mmol) in methanol (2 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 80 °C and stirred for 3 hours, quenched with saturated ammonium chloride, and filtered. The resulting filtrate was extracted with ethyl acetate (20 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 155-4 (32 mg, yield: 93.09%). MS (ESI): m/z = 337 [M+H] + .
步骤5：在冰浴条件下，将CDI(19.29mg,0.12mmol)加入到化合物155-4(32mg,0.10mmol)的四氢呋喃(1mL)中，缓慢升温至室温搅拌30分钟后，在冰浴条件下加入DBU(21.30μL,0.14mmol)。将反应混合物缓慢升温至室温搅拌1小时后，加水稀释，并用乙酸乙酯(20mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经制备硅胶板纯化，得到化合物155(20mg,产率：54.35％)。MS(ESI)：m/z＝363[M+H]+。1H NMR(DMSO-d6)δ:7.95(d,J＝9.6Hz,2H),7.48(d,J＝3.3Hz,1H),7.34(br d,J＝4.5Hz,2H),7.00(br s,2H),6.68(d,J＝3.3Hz,1H)。Step 5: Add CDI (19.29mg, 0.12mmol) to compound 155-4 (32mg, 0.10mmol) in tetrahydrofuran (1mL) under ice-bath conditions, slowly warm up to room temperature and stir for 30 minutes. Next, DBU (21.30 μL, 0.14 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (20 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified on a preparative silica gel plate to obtain compound 155 (20 mg, yield: 54.35%). MS (ESI): m/z = 363 [M+H] + . 1 H NMR (DMSO-d 6 ) δ: 7.95 (d, J = 9.6Hz, 2H), 7.48 (d, J = 3.3Hz, 1H), 7.34 (br d, J = 4.5Hz, 2H), 7.00 ( br s, 2H), 6.68 (d, J=3.3Hz, 1H).
实施例159
Example 159
步骤1：向化合物160-3(50mg,0.14mmol)的甲醇(4mL)溶液中加入甲醇钠的甲醇溶液(5.4M,125.22μL,0.68mmol)。将反应混合物在70℃下搅拌2小时后，加H2O稀释，并用EA萃取。将有机相用饱和食盐水洗涤(3次)，干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物159-2(48mg,0.13mmol,产率：97.16％)。MS(ESI)：m/z＝366[M+H]+。Step 1: To a solution of compound 160-3 (50 mg, 0.14 mmol) in methanol (4 mL) was added sodium methoxide in methanol (5.4 M, 125.22 μL, 0.68 mmol). After the reaction mixture was stirred at 70°C for 2 hours, it was diluted with H2O and extracted with EA. The organic phase was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 159-2 (48 mg, 0.13 mmol, yield: 97.16%). MS (ESI): m/z = 366 [M+H] + .
步骤2：在0℃下，将CDI(42.61mg,0.26mmol)加入到化合物159-2(48mg,0.13mmol)的THF(5mL)溶液中，常温下搅拌0.5小时后，在0℃下加入DBU(39.22μL,0.26mmol)。将反应混合物在常温下搅拌1.5小时，在0℃下用盐酸(2M)将pH调至6，加水稀释，并用EA萃取。将有机相用饱和食盐水洗涤，干 燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物159(34mg,0.09mmol,产率：66.13％)。MS(ESI)：m/z＝392[M+H]+。1H NMR(DMSO-d6)δ:13.03(br s,1H),8.04(s,1H),7.70(d,J＝3.4Hz,1H),7.44(s,2H),6.83(d,J＝3.4Hz,1H),4.16(s,3H),2.52-2.54(m,3H)。Step 2: Add CDI (42.61mg, 0.26mmol) to a THF (5mL) solution of compound 159-2 (48mg, 0.13mmol) at 0°C, stir at room temperature for 0.5 hours, then add DBU at 0°C (39.22 μL, 0.26 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, adjusted to pH 6 with hydrochloric acid (2M) at 0°C, diluted with water, and extracted with EA. The organic phase was washed with saturated brine and dried After drying, it was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain compound 159 (34 mg, 0.09 mmol, yield: 66.13%). MS (ESI): m/z = 392 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 13.03 (br s, 1H), 8.04 (s, 1H), 7.70 (d, J=3.4Hz, 1H), 7.44 (s, 2H), 6.83 (d, J =3.4Hz, 1H), 4.16(s, 3H), 2.52-2.54(m, 3H).
实施例160
Example 160
步骤1：在0℃下，向化合物5-三氟甲基-1H-吲哚(2149.69mg,11.61mmol)和叔丁醇钠(1115.77mg,11.61mmol)的DMF(30mL)溶液中加入3，6-二氯吡嗪-2-甲腈(2000mg,11.50mmol)。将反应混合物在室温下搅拌2小时后，在冰浴条件下加水(40mL)淬灭，并用EA(50mL)萃取。将有机相用饱和氯化钠溶液洗涤(30mL*3)，干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物160-1(1700mg,5.27mmol,产率：45.83％)。MS(ESI)：m/z＝323[M+H]+。Step 1: To a solution of compound 5-trifluoromethyl-1H-indole (2149.69 mg, 11.61 mmol) and sodium tert-butoxide (1115.77 mg, 11.61 mmol) in DMF (30 mL) was added 3 at 0 °C, 6-Dichloropyrazine-2-carbonitrile (2000 mg, 11.50 mmol). After the reaction mixture was stirred at room temperature for 2 hours, it was quenched with water (40 mL) under ice-bath condition, and extracted with EA (50 mL). The organic phase was washed with saturated sodium chloride solution (30 mL*3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 160-1 (1700 mg, 5.27 mmol, yield: 45.83%). MS (ESI): m/z = 323 [M+H] + .
步骤2：将化合物160-1(460mg,2.11mmol)和过硫酸铵(1300mg,5.70mmol)加入到乙腈(10mL)和水(5mL)的混合溶剂中形成溶液，在70℃下加入硝酸银(2421mg,14.26mmol)和乙酸(815.29μL,14.26mmol)的乙腈(4mL)和水(2mL)的溶液。将反应混合物在70℃下搅拌10分钟，冷却至室温，加入水(20mL)淬灭，并用EA(20mL)萃取。将有机相用水(10mL*2)洗涤，干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物160-2(91mg,0.27mmol,产率：18.96％)。MS(ESI)：m/z＝337[M+H]+。Step 2: Compound 160-1 (460mg, 2.11mmol) and ammonium persulfate (1300mg, 5.70mmol) were added to a mixed solvent of acetonitrile (10mL) and water (5mL) to form a solution, and silver nitrate ( 2421 mg, 14.26 mmol) and acetic acid (815.29 μL, 14.26 mmol) in acetonitrile (4 mL) and water (2 mL). The reaction mixture was stirred at 70 °C for 10 min, cooled to room temperature, quenched by adding water (20 mL), and extracted with EA (20 mL). The organic phase was washed with water (10 mL*2), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 160-2 (91 mg, 0.27 mmol, yield: 18.96%). MS (ESI): m/z = 337 [M+H] + .
步骤3：向化合物160-2(30mg,0.09mmol)的甲醇(4mL)溶液中加入盐酸羟胺(61.92mg,0.89mmol)、三乙胺(247.01μL,1.78mmol)和分子筛(60mg)。将反应混合物在80℃下搅拌3小时，冷却至室温后过滤，并将滤液浓缩。将所得浓缩物加H2O稀释后用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，将所得残余物通过硅胶柱层析纯化，得到化合物160-3(32mg,0.09mmol,产率：97.15％)。MS(ESI)：m/z＝370[M+H]+。Step 3: Add hydroxylamine hydrochloride (61.92 mg, 0.89 mmol), triethylamine (247.01 μL, 1.78 mmol) and Molecular sieves (60 mg). The reaction mixture was stirred at 80 °C for 3 hours, cooled to room temperature and filtered, and the filtrate was concentrated. The resulting concentrate was diluted with H2O and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 160-3 (32 mg, 0.09 mmol, yield: 97.15%). MS (ESI): m/z = 370 [M+H] + .
步骤4：在0℃下，将CDI(28.07mg,0.17mmol)加入到化合物160-3(32mg,0.09mmol)的THF(4mL)溶液中，在室温下搅拌1小时后，在0℃下加入DBU(25.84μL,0.17mmol)。将反应混合物在室温下搅拌1.5小时，冷却至0℃后用盐酸(2M)将pH调至6，加入水稀释，并用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物经柱层析纯化，得到化合物160(25mg,0.06mmol,产率：72.99％)。MS(ESI)：m/z＝396[M+H]+。1HNMR(DMSO-d6)δ:8.07(s,1H),7.80(d,J＝3.5Hz,1H),7.70(d,J＝8.6Hz,1H),7.51(d,J＝8.3Hz,1H),6.88(d,J＝3.4Hz,1H),2.74(s,3H)。Step 4: Add CDI (28.07mg, 0.17mmol) to a solution of compound 160-3 (32mg, 0.09mmol) in THF (4mL) at 0°C, stir at room temperature for 1 hour, then add DBU (25.84 μL, 0.17 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, cooled to 0 °C and adjusted to pH 6 with hydrochloric acid (2M), diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography to obtain compound 160 (25 mg, 0.06 mmol, yield: 72.99%). MS (ESI): m/z = 396 [M+H] + . 1 H NMR (DMSO-d 6 ) δ: 8.07(s, 1H), 7.80(d, J=3.5Hz, 1H), 7.70(d, J=8.6Hz, 1H), 7.51(d, J=8.3Hz, 1H), 6.88 (d, J=3.4Hz, 1H), 2.74 (s, 3H).
实施例161
Example 161
步骤1：将3,5-二氯吡嗪-2-甲腈(10g,58mmol)与NH3的1,4-二氧六环溶液(150mL，0.4mol/L)的混合物在室温下搅拌过夜后浓缩。向所得浓缩物中加入H2O(100mL)，并用EA(100mL)萃取。将有机相用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用EA:PE＝1:10洗脱)纯化，得到化合物161-1(5.5g,35mmol,产率：61.5％)。MS(ESI)：m/z＝155[M+H]+。Step 1: A mixture of 3,5-dichloropyrazine-2-carbonitrile (10 g, 58 mmol) and NH3 in 1,4-dioxane (150 mL, 0.4 mol/L) was stirred overnight at room temperature After concentration. To the resulting concentrate was added H2O (100 mL), and extracted with EA (100 mL). The organic phase was dried with anhydrous Na 2 SO 4 and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:10) to obtain compound 161-1 (5.5 g, 35 mmol, rate: 61.5%). MS (ESI): m/z = 155 [M+H] + .
步骤2：在冰浴条件下，将NBS(6.8g,38mmol)加入到化合物161-1(5.5g,35mmol)的DMF(30mL)溶液中，室温下搅拌过夜后，加入H2O(50mL)，并用EA(100mL)萃取。将有机相用无水Na2SO4干燥后浓缩，并将所得残余物通过硅胶柱层析(用EA:PE＝1:10洗脱)纯化，得到化合物161-2(5.4g,23mmol,产率：65.9％)。MS(ESI)：m/z＝234,235[M+H]+。Step 2: Add NBS (6.8g, 38mmol) to a solution of compound 161-1 (5.5g, 35mmol) in DMF (30mL) in an ice bath, stir overnight at room temperature, then add H 2 O (50mL) , and extracted with EA (100 mL). The organic phase was dried with anhydrous Na 2 SO 4 and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:10) to obtain compound 161-2 (5.4 g, 23 mmol, rate: 65.9%). MS (ESI): m/z = 234,235 [M+H] + .
步骤3：将化合物161-2(5.4g,23mmol)，三甲基环三硼氧烷(5.7g,46mmol)，Pd(dppf)Cl2(1.4g,2mmol)，碳酸钾(6.3g,46mmol),氟化铯(6.9g,46mmol)分散到1,4二氧六环(50mL)和H2O(10mL)的混合溶剂中。将反应混合物用N2吹扫并维持N2氛围，在100℃下搅拌过夜后浓缩，向所得浓缩物中加入H2O(50mL)，并用EA(100mL)萃取。将有机相用无水Na2SO4干燥后浓缩，并将所得残余物通过硅胶柱层析(用EA:PE＝1:4洗脱)纯化，得到化合物161-3(2.3g,13mmol,产率：39.1％)。MS(ESI)：m/z＝169[M+H]+。Step 3: Compound 161-2 (5.4g, 23mmol), trimethylboroxine (5.7g, 46mmol), Pd(dppf)Cl 2 (1.4g, 2mmol), potassium carbonate (6.3g, 46mmol) ), cesium fluoride (6.9 g, 46 mmol) were dispersed in a mixed solvent of 1,4 dioxane (50 mL) and H 2 O (10 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at 100° C. overnight and then concentrated. To the obtained concentrate was added H 2 O (50 mL), and extracted with EA (100 mL). The organic phase was dried with anhydrous Na 2 SO 4 and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 161-3 (2.3 g, 13 mmol, rate: 39.1%). MS (ESI): m/z = 169 [M+H] + .
步骤4：将化合物161-3(2.3g,13mmol)，5-三氟甲基吲哚(2.8g，15mmol)和碳酸铯(8.4g,26mmol)的混合物在120℃下搅拌3小时，加H2O(200mL)稀释，并用EA(50mL)萃取。将有机相用饱和食盐水洗涤(20mL×3)，用无水Na2SO4干燥后浓缩，并将所得残余物通过硅胶柱层析(用EA:PE＝1:4洗脱)纯化，得到化合物161-4(2.4g,7.5mmol,产率：58.2％)。MS(ESI)：m/z＝318[M+H]+。Step 4: A mixture of compound 161-3 (2.3g, 13mmol), 5-trifluoromethylindole (2.8g, 15mmol) and cesium carbonate (8.4g, 26mmol) was stirred at 120°C for 3 hours, and H Dilute with 2 O (200 mL) and extract with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain Compound 161-4 (2.4 g, 7.5 mmol, yield: 58.2%). MS (ESI): m/z = 318 [M+H] + .
步骤5：将化合物161-4(2.4g,7.5mmol)，碘化亚铜(118g，0.7mmol)，二碘甲烷(1.2mL,15mmol)，亚硝酸叔丁酯(1.7mL,15mmol)和THF(20mL)的混合物在60℃下搅拌过夜后浓缩，向所得浓缩物中加入H2O(50mL)，并用EA(30mL)萃取。将有机相用无水Na2SO4干燥后浓缩，并将所得残余物通过硅胶柱层析(用EA:PE＝1:4洗脱)纯化，得到化合物161-5(740mg,1.7mmol,产率：22.6％)。MS(ESI)：m/z＝429[M+H]+。Step 5: Compound 161-4 (2.4g, 7.5mmol), cuprous iodide (118g, 0.7mmol), diiodomethane (1.2mL, 15mmol), tert-butyl nitrite (1.7mL, 15mmol) and THF (20 mL) was stirred at 60°C overnight and then concentrated. To the resulting concentrate was added H 2 O (50 mL) and extracted with EA (30 mL). The organic phase was dried with anhydrous Na 2 SO 4 and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 161-5 (740 mg, 1.7 mmol, rate: 22.6%). MS (ESI): m/z = 429 [M+H] + .
步骤6：将化合物161-5(740mg,1.7mmol)，氟磺酰基二氟乙酸甲酯(489mg，2.5mmol)，碘化亚铜(19mg,0.1mmol)和DMF(10mL)的混合物在100℃下搅拌过夜后，加入H2O(20mL)，并用EA(30mL)萃取。将有机相用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用EA:PE＝1:4洗脱)纯化，得到化合物161-6(360mg,0.9mmol,产率：57.1％)。MS(ESI)：m/z＝371[M+H]+。Step 6: A mixture of compound 161-5 (740mg, 1.7mmol), methyl fluorosulfonyl difluoroacetate (489mg, 2.5mmol), cuprous iodide (19mg, 0.1mmol) and DMF (10mL) was incubated at 100°C After stirring overnight, H2O (20 mL) was added and extracted with EA (30 mL). The organic phase was dried with anhydrous Na 2 SO 4 and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 161-6 (360 mg, 0.9 mmol, product rate: 57.1%). MS (ESI): m/z = 371 [M+H] + .
步骤7：将化合物161-6(360mg,0.9mmol)，盐酸羟胺(672mg,9.0mmol)，三乙胺(15mL)、与20mLMeOH的混合物，用N2吹扫并维持N2氛围，在80℃下搅拌3小时后减压过滤，并将所得滤液浓缩。向所得浓缩物中加入20mLH2O，并用EA(30mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用EA:PE＝1:2洗脱)纯化，得到化合物161-7(240mg,0.59mmol,产率：66.1％)。MS(ESI)：m/z＝404[M+H]+。Step 7: Compound 161-6 (360mg, 0.9mmol), hydroxylamine hydrochloride (672mg, 9.0mmol), triethylamine (15mL), The mixture with 20 mL of MeOH was purged with N2 and maintained under N2 atmosphere, stirred at 80 °C for 3 h, filtered under reduced pressure, and the resulting filtrate was concentrated. To the resulting concentrate was added 20 mL of H 2 O and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain Compound 161-7 (240 mg, 0.59 mmol, yield: 66.1%). MS (ESI): m/z = 404 [M+H] + .
步骤8：在冰浴条件下，将CDI(115mg,0.71mmol)加入到化合物161-7(240mg,0.59mmol)的THF(10mL)溶液中，室温下搅拌30min后，在冰浴条件下滴入DBU(134mg,0.88mmol)。将反应混合物在冰浴条件下搅拌2小时后用盐酸(2M，2mL)将pH调至6，并用EA(20mL)萃取。将有机相用饱和食盐水洗涤(10mL×3)，用无水Na2SO4干燥后浓缩，并将所得残余物经高效液相色谱纯化，得到化合物161(14mg,0.03 mmol,产率：5.5％)。MS(ESI)：m/z＝430[M+H]+。1H NMR(DMSO-d6)δ:8.08(s,1H),7.85(d,J＝3.5Hz,1H),7.73(d,J＝8.6Hz,1H),7.51-7.59(m,1H),6.90(d,J＝3.4Hz,1H),2.86(d,J＝1.6Hz,3H)。Step 8: Add CDI (115mg, 0.71mmol) to a THF (10mL) solution of compound 161-7 (240mg, 0.59mmol) under ice-bath conditions, stir at room temperature for 30min, then drop into DBU (134 mg, 0.88 mmol). The reaction mixture was stirred under ice bath for 2 hours, then the pH was adjusted to 6 with hydrochloric acid (2M, 2 mL), and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated, and the resulting residue was purified by high performance liquid chromatography to obtain compound 161 (14 mg, 0.03 mmol, yield: 5.5%). MS (ESI): m/z = 430 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.08(s, 1H), 7.85(d, J=3.5Hz, 1H), 7.73(d, J=8.6Hz, 1H), 7.51-7.59(m, 1H) , 6.90 (d, J=3.4Hz, 1H), 2.86 (d, J=1.6Hz, 3H).
实施例162
Example 162
步骤1：将化合物161-2(1g,4.3mmol)，5-三氟甲基-1-H-吲哚(1.6g，8.6mmol)，碳酸铯(4.1g,12.9mmol)分散于DMF(30mL)中。将反应混合物在120℃下搅拌3小时，加H2O(50mL)稀释，并用EA(30mL)萃取。将有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物经硅胶柱层析(用EA:PE＝1:4洗脱)纯化，得到化合物162-1(250mg,0.6mmol,15.2％)。MS(ESI)：m/z＝382[M+H]+。Step 1: Compound 161-2 (1 g, 4.3 mmol), 5-trifluoromethyl-1-H-indole (1.6 g, 8.6 mmol), cesium carbonate (4.1 g, 12.9 mmol) were dispersed in DMF (30 mL )middle. The reaction mixture was stirred at 120 °C for 3 h, diluted with H2O (50 mL), and extracted with EA (30 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain Compound 162-1 (250 mg, 0.6 mmol, 15.2%). MS (ESI): m/z = 382 [M+H] + .
步骤2：将化合物162-1(250mg,0.6mmol)，三甲基环三硼氧烷(150mg,1.2mmol)，Pd(dppf)Cl2(43mg,0.06mmol)，碳酸钾(165mg,1.2mmol),氟化铯(181mg,1.2mmol)分散于1,4二氧六环(10mL)和H2O(2mL)的混合溶剂中。将反应混合物用N2吹扫并维持N2氛围，在100℃下搅拌过夜，浓缩，并向所得浓缩物中加入H2O(50mL)后用EA(100mL)萃取。将有机相用无水Na2SO4干燥，干燥后浓缩，并将所得残余物经硅胶柱层析(用EA:PE＝1:4)纯化，得到化合物162-2(50mg,0.15mmol,产率：13％)。MS(ESI)：m/z＝318[M+H]+。Step 2: Compound 162-1 (250mg, 0.6mmol), trimethylboroxine (150mg, 1.2mmol), Pd(dppf)Cl 2 (43mg, 0.06mmol), potassium carbonate (165mg, 1.2mmol ), cesium fluoride (181 mg, 1.2 mmol) were dispersed in a mixed solvent of 1,4 dioxane (10 mL) and H 2 O (2 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at 100° C. overnight, concentrated, and the resulting concentrate was extracted with EA (100 mL) after adding H 2 O (50 mL). The organic phase was dried with anhydrous Na 2 SO 4 , concentrated after drying, and the resulting residue was purified by silica gel column chromatography (with EA:PE=1:4) to obtain compound 162-2 (50 mg, 0.15 mmol, rate: 13%). MS (ESI): m/z = 318 [M+H] + .
步骤3：将化合物162-2(50mg,0.15mmol)，盐酸羟胺(15mg,1.5mmol)，三乙胺(2mL)、和MeOH(10mL)的混合物用N2吹扫并维持N2氛围，在80℃下搅拌3小时，减压过滤，并将所得滤液浓缩。向所得浓缩物中加入H2O(20mL)后，用EA(30mL)萃取。将有机相用饱和食盐水洗涤(10mL×3)，用无水Na2SO4干燥后浓缩，并将所得残余物通过硅胶柱层析(用EA:PE＝1:2洗脱)纯化，得到化合物162-3(45mg,0.12mmol,产率：85.7％)。MS(ESI)：m/z＝351[M+H]+。Step 3: Compound 162-2 (50mg, 0.15mmol), hydroxylamine hydrochloride (15mg, 1.5mmol), triethylamine (2mL), and MeOH (10 mL) was purged with N 2 and maintained under N 2 atmosphere, stirred at 80 °C for 3 h, filtered under reduced pressure, and the resulting filtrate was concentrated. After adding H 2 O (20 mL) to the obtained concentrate, it was extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain Compound 162-3 (45 mg, 0.12 mmol, yield: 85.7%). MS (ESI): m/z = 351 [M+H] + .
步骤4：在冰浴条件下，将CDI(22mg,0.14mmol)加入到化合物162-3(45mg,0.12mmol)的THF(10mL)溶液中，室温下搅拌30min后，在冰浴条件下滴入DBU(27mg,0.18mmol)。将反应混合物在冰浴条件下搅拌2小时后，加入HCl水溶液(1mL)将pH调至2，随后用EA(20mL)萃取。将有机相用饱和食盐水(10mL×3)洗涤，无水Na2SO4干燥后浓缩，并将所得残余物通过制备高效液相色谱纯化，得到化合物162(9mg,0.02mmol,产率：19.8％)。MS(ESI)：m/z＝377[M+H]+。1H NMR(DMSO-d6)δ:8.02(s,1H),7.67(d,J＝3.4Hz,1H),7.50(br d,J＝8.8Hz,2H),7.39-7.53(m,2H),6.79(d,J＝3.3Hz,1H),2.43(s,3H)。Step 4: Add CDI (22mg, 0.14mmol) to a solution of compound 162-3 (45mg, 0.12mmol) in THF (10mL) under ice-bath conditions, stir at room temperature for 30min, then drop into DBU (27 mg, 0.18 mmol). After the reaction mixture was stirred in ice bath for 2 hours, aqueous HCl (1 mL) was added to adjust the pH to 2, followed by extraction with EA (20 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated, and the resulting residue was purified by preparative high performance liquid chromatography to obtain compound 162 (9 mg, 0.02 mmol, yield: 19.8 %). MS (ESI): m/z = 377 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.02(s, 1H), 7.67(d, J=3.4Hz, 1H), 7.50(br d, J=8.8Hz, 2H), 7.39-7.53(m, 2H ), 6.79 (d, J=3.3Hz, 1H), 2.43 (s, 3H).
实施例163
Example 163
步骤1：将化合物133-1(400mg,1.24mmol)和过硫酸铵(848mg,3.72mmol)溶解于乙腈(10mL)和水(5mL)的混合溶剂中形成溶液A，将硝酸银(2105mg,12.40mmol)和丙酸(1785.35μL,9.92mmol)溶解于乙腈(4mL)和水(2mL)的混合溶剂中形成溶液B，在70℃下，将溶液B加入溶液A中。将反应混合物 在70℃下搅拌10分钟，冷却至室温，加入水(20mL)淬灭后用EA(20mL)萃取。将有机相用水洗涤(10mL*2)，干燥后浓缩，并将所得残余物通过硅胶柱层析纯化，得到化合物163-1(287mg,0.73mmol,产率：58.75％)。MS(ESI)：m/z＝351[M+H]+。Step 1: Compound 133-1 (400mg, 1.24mmol) and ammonium persulfate (848mg, 3.72mmol) were dissolved in a mixed solvent of acetonitrile (10mL) and water (5mL) to form solution A, silver nitrate (2105mg, 12.40 mmol) and propionic acid (1785.35 μL, 9.92 mmol) were dissolved in a mixed solvent of acetonitrile (4 mL) and water (2 mL) to form solution B, and solution B was added to solution A at 70°C. the reaction mixture Stir at 70°C for 10 minutes, cool to room temperature, quench with water (20 mL) and extract with EA (20 mL). The organic phase was washed with water (10 mL*2), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 163-1 (287 mg, 0.73 mmol, yield: 58.75%). MS (ESI): m/z = 351 [M+H] + .
步骤2：在氮气氛围下，向化合物163-1(100mg,0.29mmol)，2三甲基环三硼氧烷(244.39μL,0.86mmol)，碳酸钾(78.81mg,0.57mmol)、氟化铯(86.62mg,0.57mmol)、1,4-二氧六环(5mL)和水(0.5mL)的混合物中加入Pd(dppf)Cl2·CH2Cl2(46.57mg,0.06mmol)。将反应混合物在100℃下搅拌过夜，冷却至室温，干燥后浓缩，并将所得残余物通过硅胶柱层析纯化，得到化合物163-2(78mg,0.24mmol,产率：82.82％)。MS(ESI)：m/z＝331[M+H]+。Step 2: Add compound 163-1 (100 mg, 0.29 mmol), 2 trimethylboroxane (244.39 μL, 0.86 mmol), potassium carbonate (78.81 mg, 0.57 mmol), cesium fluoride to To a mixture of (86.62 mg, 0.57 mmol), 1,4-dioxane (5 mL) and water (0.5 mL) was added Pd(dppf)Cl 2 ·CH 2 Cl 2 (46.57 mg, 0.06 mmol). The reaction mixture was stirred overnight at 100° C., cooled to room temperature, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 163-2 (78 mg, 0.24 mmol, yield: 82.82%). MS (ESI): m/z = 331 [M+H] + .
步骤3：向化合物163-2(78mg,0.24mmol)的甲醇(4mL)溶液中加入盐酸羟胺(164.09mg,2.36mmol)、三乙胺(654.66μL,4.72mmol)和分子筛(60mg)。将反应混合物在80℃下搅拌3小时，冷却至室温后过滤，并将所得滤液浓缩。向所得浓缩液中加水稀释，并用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物通过硅胶柱层析纯化，得到化合物163-3(82mg,0.23mmol,产率：95.57％)。MS(ESI)：m/z＝364[M+H]+。Step 3: Add hydroxylamine hydrochloride (164.09 mg, 2.36 mmol), triethylamine (654.66 μL, 4.72 mmol) and Molecular sieves (60 mg). The reaction mixture was stirred at 80° C. for 3 hours, cooled to room temperature, filtered, and the resulting filtrate was concentrated. The resulting concentrate was diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 163-3 (82 mg, 0.23 mmol, yield: 95.57%). MS (ESI): m/z = 364 [M+H] + .
步骤4：在0℃下，将CDI(73.19mg,0.45mmol)加入到化合物163-3(82mg,0.23mmol)的THF(4mL)溶液中，室温下搅拌1小时后，在0℃下加入DBU(67.37μL,0.45mmol)。将反应混合物在室温下搅拌1.5小时后，在0℃下，用盐酸(2M)将pH调至6，加水稀释，并用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物通过柱层析纯化，得到化合物163(32mg,0.08mmol,产率：35.73％)。MS(ESI)：m/z＝390[M+H]+。1H NMR(DMSO-d6)δ:13.06(br s,1H),8.06(s,1H),7.79(d,J＝3.5Hz,1H),7.64(d,J＝8.5Hz,1H),7.49(d,J＝8.8Hz,1H),6.85(d,J＝3.4Hz,1H),2.99(q,J＝7.4Hz,2H),2.70(s,3H),1.28(t,J＝7.4Hz,3H)。Step 4: CDI (73.19mg, 0.45mmol) was added to a THF (4mL) solution of compound 163-3 (82mg, 0.23mmol) at 0°C, and after stirring at room temperature for 1 hour, DBU was added at 0°C (67.37 μL, 0.45 mmol). After the reaction mixture was stirred at room temperature for 1.5 hours, the pH was adjusted to 6 with hydrochloric acid (2M) at 0 °C, diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography to obtain compound 163 (32 mg, 0.08 mmol, yield: 35.73%). MS (ESI): m/z = 390 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 13.06 (br s, 1H), 8.06 (s, 1H), 7.79 (d, J=3.5Hz, 1H), 7.64 (d, J=8.5Hz, 1H), 7.49(d, J=8.8Hz, 1H), 6.85(d, J=3.4Hz, 1H), 2.99(q, J=7.4Hz, 2H), 2.70(s, 3H), 1.28(t, J=7.4 Hz, 3H).
实施例165
Example 165
步骤1:将氢氧化钠(2.05g,51.20mmol)水溶液(3mL)加入到2-氨基丙二酰胺(5g,42.69mmol)和己烷-3,4-二酮(4.87g,42.67mmol)的水(7mL)溶液中。将反应混合物在室温下搅拌过夜(12小时)后过滤。将所得滤饼干燥，得到化合物165-1(6.29g,产率：75.52％)。MS(ESI)：m/z＝196[M+H]+。Step 1: Sodium hydroxide (2.05g, 51.20mmol) in water (3mL) was added to 2-aminomalonamide (5g, 42.69mmol) and hexane-3,4-dione (4.87g, 42.67mmol) in water (7mL) solution. The reaction mixture was stirred overnight (12 hours) at room temperature and then filtered. The obtained filter cake was dried to obtain compound 165-1 (6.29 g, yield: 75.52%). MS (ESI): m/z = 196 [M+H] + .
步骤2:将三氯氧磷(18.85g,122.94mmol)加入到化合物165-1(6g,30.73mmol)的氯苯(40mL)溶液中，在60℃搅拌20分钟，滴加DIPEA(11.92g,92.20mmol)。将反应混合物升温至90℃，搅拌过夜(12h)后，加冰水淬灭，用乙酸乙酯萃取。将合并所得有机相用无水硫酸钠干燥，过滤后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物165-2(6g,产率：99.78％)。MS(ESI)：m/z＝196[M+H]+。Step 2: Phosphorus oxychloride (18.85g, 122.94mmol) was added to a solution of compound 165-1 (6g, 30.73mmol) in chlorobenzene (40mL), stirred at 60°C for 20 minutes, and DIPEA (11.92g, 92.20 mmol). The reaction mixture was warmed up to 90° C., stirred overnight (12 h), quenched with ice water, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 165-2 (6 g, yield: 99.78%). MS (ESI): m/z = 196 [M+H] + .
步骤3:在冰浴条件下，将NaH(53.16mg,1.33mmol)加入到化合物165-2(200mg,1.02mmol)和5-(三氟甲基)-1H-吲哚(189.27mg,1.02mmol)的DMF(3mL)溶液中。将反应混合物在室温下搅拌1.5小时后，加饱和氯化铵水溶液淬灭反应，用二氯甲烷萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物165-3(65mg,产率：18.47％)。MS(ESI)：m/z＝345[M+H]+。Step 3: Add NaH (53.16mg, 1.33mmol) to compound 165-2 (200mg, 1.02mmol) and 5-(trifluoromethyl)-1H-indole (189.27mg, 1.02mmol) under ice bath conditions ) in DMF (3mL) solution. After the reaction mixture was stirred at room temperature for 1.5 hours, the reaction was quenched by adding saturated aqueous ammonium chloride solution, and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 165-3 (65 mg, yield: 18.47%). MS (ESI): m/z = 345 [M+H] + .
步骤4:将化合物165-3(65mg,0.19mmol)、盐酸羟胺(131.17mg,1.89mmol)、分子筛(65mg)分散于甲醇(4mL)中，随后加入三乙胺(1.15g,11.33mmol)。将反应混合物升温至75℃搅拌过夜(12h)后，加饱和氯化铵水溶液淬灭，并用二氯甲烷萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物165-4(34mg,产率：47.73％)。MS(ESI)：m/z＝378[M+H]+。Step 4: Compound 165-3 (65mg, 0.19mmol), hydroxylamine hydrochloride (131.17mg, 1.89mmol), Molecular sieves (65 mg) were dispersed in methanol (4 mL), followed by the addition of triethylamine (1.15 g, 11.33 mmol). The reaction mixture was warmed to 75 °C and stirred overnight (12 h), quenched with saturated aqueous ammonium chloride, and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 165-4 (34 mg, yield: 47.73%). MS (ESI): m/z = 378 [M+H] + .
步骤5:在冰浴条件下，将CDI(18.26mg,0.11mmol)加入到化合物165-4(34mg,0.09mmol)的四氢呋喃(1mL)溶液中，在冰浴条件下搅拌30分钟后加入DBU(20.57mg,0.14mmol)。将反应混合物缓慢升温至室温，并在室温下继续搅拌30分钟，加入水，并用乙酸乙酯萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物165(10mg,产率：27.52％)。MS(ESI)： m/z＝404[M+H]+。1H NMR(CHLOROFORM-d)δ:7.98(s,1H),7.49(t,J＝3.9Hz,3H),6.84(d,J＝3.4Hz,1H),3.03(qd,J＝7.4,3.1Hz,4H),1.41(dt,J＝17.7,7.5Hz,6H)。Step 5: under ice-bath conditions, CDI (18.26mg, 0.11mmol) was added to compound 165-4 (34mg, 0.09mmol) in tetrahydrofuran (1mL) solution, stirred under ice-bath conditions for 30 minutes and then added DBU ( 20.57 mg, 0.14 mmol). The reaction mixture was slowly warmed to room temperature, and stirring was continued at room temperature for 30 minutes, water was added, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 165 (10 mg, yield: 27.52%). MS(ESI): m/z = 404 [M+H] + . 1 H NMR (CHLOROFORM-d) δ: 7.98(s, 1H), 7.49(t, J=3.9Hz, 3H), 6.84(d, J=3.4Hz, 1H), 3.03(qd, J=7.4, 3.1 Hz, 4H), 1.41 (dt, J = 17.7, 7.5Hz, 6H).
实施例167
Example 167
步骤1：向化合物163-1(80mg,0.23mmol)的甲醇(6mL)溶液中加入盐酸羟胺(158.50mg,2.28mmol)、三乙胺(632.36μL,4.56mmol)和分子筛(100mg)。将反应混合物在80℃下搅拌4小时，冷却至室温后过滤，并将所得滤液浓缩。向所得浓缩液中加H2O稀释，用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物通过硅胶柱层析纯化，得到化合物167-1(85mg,0.22mmol,产率：97.11％)。MS(ESI)：m/z＝384[M+H]+。Step 1: Add hydroxylamine hydrochloride (158.50 mg, 2.28 mmol), triethylamine (632.36 μL, 4.56 mmol) and Molecular sieves (100 mg). The reaction mixture was stirred at 80° C. for 4 hours, cooled to room temperature and filtered, and the resulting filtrate was concentrated. The resulting concentrate was diluted with H 2 O and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 167-1 (85 mg, 0.22 mmol, yield: 97.11%). MS (ESI): m/z = 384 [M+H]+.
步骤2：在0℃下，将CDI(84.51mg,0.52mmol)加入到化合物167-1(85mg,0.22mmol,97.11％)的THF(5mL)溶液中，在室温下搅拌0.5小时后，在0℃下加入DBU(77.79μL,0.52mmol)。将反应混合物在室温下搅拌1.5小时，冷却至0℃后，用盐酸(2M)将pH调至6，加水稀释，并用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物通过硅胶柱层析纯化，得到化合物167(56mg,0.13mmol,产率：62.68％)。MS(ESI)：m/z＝410[M+H]+。1H NMR(DMSO-d6)δ＝8.07(s,1H),7.81(d,J＝3.4Hz,1H),7.76(d,J＝8.6Hz,1H),7.53(d,J＝8.8Hz,1H),6.88(d,J＝3.4Hz,1H),3.07(q,J＝7.4Hz,2H),1.31(t,J＝7.4Hz,3H)。Step 2: At 0°C, CDI (84.51mg, 0.52mmol) was added to a THF (5mL) solution of compound 167-1 (85mg, 0.22mmol, 97.11%), and after stirring at room temperature for 0.5 hours, at 0 DBU (77.79 μL, 0.52 mmol) was added at °C. The reaction mixture was stirred at room temperature for 1.5 hours, after cooling to 0°C, the pH was adjusted to 6 with hydrochloric acid (2M), diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 167 (56 mg, 0.13 mmol, yield: 62.68%). MS (ESI): m/z = 410 [M+H]+. 1 H NMR (DMSO-d 6 )δ=8.07(s,1H),7.81(d,J=3.4Hz,1H),7.76(d,J=8.6Hz,1H),7.53(d,J=8.8Hz , 1H), 6.88 (d, J=3.4Hz, 1H), 3.07 (q, J=7.4Hz, 2H), 1.31 (t, J=7.4Hz, 3H).
实施例168
Example 168
步骤1：在0℃下，将N-溴代丁二酰亚胺(NBS)(2.98g,16.77mmol)加入3-氰基-6-甲基-吡啶酮(1.5g,11.18mmol)的N,N-二甲基甲酰胺(30mL)溶液中。将反应混合物用用N2吹扫并维持N2氛围，缓慢升温至30℃搅拌18小时，加水稀释，用乙酸乙酯(100mL×3)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:1)纯化，得到化合物168-1(2.24g，产率：94.03％)。MS(ESI)：m/z＝213,215[M+H]+。Step 1: Add N-bromosuccinimide (NBS) (2.98g, 16.77mmol) to 3-cyano-6-methyl-pyridone (1.5g, 11.18mmol) in N at 0°C , in N-dimethylformamide (30 mL) solution. The reaction mixture was purged with N2 and maintained under N2 atmosphere, slowly warmed to 30 °C and stirred for 18 hours, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (with ethyl acetate:petroleum ether=1:1) to obtain compound 168-1 (2.24g, yield rate: 94.03%). MS (ESI): m/z = 213,215 [M+H] + .
步骤2：在室温下，将化合物168-1(2.24g,10.51mmol)溶解于三氯氧磷(20mL)中。将反应混合物缓慢升温至80℃搅拌3个小时后，缓慢滴加冰水(50mL)将反应淬灭，用乙酸乙酯(100mL×3)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用石油醚:乙酸乙酯＝1:3洗脱)纯化，得到化合物168-2(1.0496g，产率：48.12％)。MS(ESI)：m/z＝231,233[M+H]+。Step 2: Compound 168-1 (2.24 g, 10.51 mmol) was dissolved in phosphorus oxychloride (20 mL) at room temperature. The reaction mixture was slowly warmed up to 80°C and stirred for 3 hours, then ice water (50 mL) was slowly added dropwise to quench the reaction, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=1:3) to obtain compound 168-2 (1.0496g, Yield: 48.12%). MS (ESI): m/z = 231,233 [M+H] + .
步骤3：在室温下，将化合物168-2(1g,4.32mmol)、5-(三氟甲基)-1H-吲哚(0.80g,4.32mmol)和碳酸铯(2.82g,8.64mmol)分散于N,N-二甲基甲酰胺(15mL)中。将反应混合物缓慢升温至100℃搅拌1个小时，加水稀释，并用乙酸乙酯(100mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩，并将所得残余物用制备硅胶板(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物168-3(358mg，产率：21.8％)。Step 3: Compound 168-2 (1 g, 4.32 mmol), 5-(trifluoromethyl)-1H-indole (0.80 g, 4.32 mmol) and cesium carbonate (2.82 g, 8.64 mmol) were dispersed at room temperature In N,N-dimethylformamide (15 mL). The reaction mixture was slowly warmed to 100° C. and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified on a preparative silica gel plate (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 168-3 (358 mg, yield rate: 21.8%).
步骤4：在室温下，将(甲磺酸(2-二叔丁基膦-2',4',6'-三异丙基-1,1'-联苯基)(2'-甲氨基-1,1'-联苯-2-基)钯(II)(55.29mg,0.07mmol)、叔丁醇钠(92.01mg,0.96mmol)和甲醇(0.14mL,3.42mmol)依次加入到化合物168-3(260mg,0.68mmol)的1，4-二氧六环(5mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至50℃搅拌16个小时，加水(5mL)稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5)纯化，得到化合物168-4(55mg，产率：25.27％)。MS(ESI)：m/z＝332[M+H]+。Step 4: At room temperature, (methanesulfonic acid (2-di-tert-butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino -1,1'-biphenyl-2-yl)palladium(II) (55.29mg, 0.07mmol), sodium tert-butoxide (92.01mg, 0.96mmol) and methanol (0.14mL, 3.42mmol) were sequentially added to compound 168 -3 (260mg, 0.68mmol) in 1,4-dioxane (5mL) solution. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warming up to 50°C and stirring for 16 hours, adding water (5mL ) was diluted, and extracted with ethyl acetate (50mL × 2).The combined organic phase was concentrated after drying with anhydrous sodium sulfate, and the resulting residue was subjected to silica gel column chromatography (with ethyl acetate:petroleum ether=1:5 ) to obtain compound 168-4 (55 mg, yield: 25.27%). MS (ESI): m/z=332[M+H] + .
步骤5：在室温下，将盐酸羟胺(83.90mg,1.21mmol)、分子筛(40mg,0.33mmol),和三乙胺(1.00mL,7.24mmol)依次加入到化合物168-4(40mg,0.12mmol)的甲醇(2mL)溶液中。将反应混合物用N2吹扫并 维持N2氛围，缓慢升温至75℃搅拌3个小时，用饱和氯化铵淬灭后过滤。将所得滤液用乙酸乙酯(50mL×2)萃取，用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯洗脱)纯化，得到化合物168-5(21mg，产率：47.74％)。MS(ESI)：m/z＝365[M+H]+。Step 5: At room temperature, hydroxylamine hydrochloride (83.90mg, 1.21mmol), Molecular sieves (40 mg, 0.33 mmol), and triethylamine (1.00 mL, 7.24 mmol) were sequentially added to a solution of compound 168-4 (40 mg, 0.12 mmol) in methanol (2 mL). The reaction mixture was purged with N and Maintain the N2 atmosphere, slowly raise the temperature to 75°C and stir for 3 hours, quench with saturated ammonium chloride and filter. The obtained filtrate was extracted with ethyl acetate (50mL×2), dried over anhydrous sodium sulfate and concentrated, and the obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 168-5 (21mg , yield: 47.74%). MS (ESI): m/z = 365 [M+H] + .
步骤6：在冰浴条件下，将N,N'-羰基二咪唑(11.68mg,0.07mmol)加入到化合物168-5(21mg,0.06mmol)的四氢呋喃(3mL)溶液中，缓慢升至室温搅拌30分钟后，在冰浴条件下加入DBU(12.90μL,0.09mmol)。将反应混合物缓慢升至30℃搅拌1小时，加水稀释，并用乙酸乙酯(20mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用高效液相色谱(HPLC)纯化，得到化合物168(3mg，产率：13.33％)。MS(ESI)：m/z＝391[M+H]+。1H NMR(DMSO-d6)δ:8.04(s,1H),7.88(s,1H),7.59(d,J＝3.4Hz,1H),7.46(s,2H),6.82(d,J＝3.3Hz,1H),3.99(s,3H),2.49-2.49(m,3H)。Step 6: Add N,N'-carbonyldiimidazole (11.68mg, 0.07mmol) to a solution of compound 168-5 (21mg, 0.06mmol) in tetrahydrofuran (3mL) under ice-bath conditions, slowly rise to room temperature and stir After 30 minutes, DBU (12.90 μL, 0.09 mmol) was added under ice bath conditions. The reaction mixture was slowly raised to 30 °C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (20 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by high performance liquid chromatography (HPLC) to obtain compound 168 (3 mg, yield: 13.33%). MS (ESI): m/z = 391 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.04(s, 1H), 7.88(s, 1H), 7.59(d, J=3.4Hz, 1H), 7.46(s, 2H), 6.82(d, J= 3.3Hz, 1H), 3.99(s, 3H), 2.49-2.49(m, 3H).
实施例174
Example 174
步骤1：在室温下，将乙烯三氟硼酸钾(0.45g,3.39mmol)、1,1'-双(二苯基膦)二茂铁]二氯化钯(0.25mg,0.34mmol)和碳酸钾(0.47mg,3.39mmol)加入到化合物176-3(1.45g,3.39mmol)的1，4-二氧六环(25mL)和水(5mL)的溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌16个小时，加水(5mL)稀释，并用乙酸乙酯(100mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:3洗脱)纯化，得到化合物174-2(712mg,产率：63.65％)。MS(ESI)：m/z＝329[M+H]+。Step 1: Potassium ethylene trifluoroborate (0.45 g, 3.39 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.25 mg, 0.34 mmol) and carbonic acid were mixed at room temperature Potassium (0.47 mg, 3.39 mmol) was added to a solution of compound 176-3 (1.45 g, 3.39 mmol) in 1,4-dioxane (25 mL) and water (5 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80°C and stirred for 16 hours, diluted with water (5 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:3) to obtain compound 174-2 (712 mg, yield rate: 63.65%). MS (ESI): m/z = 329 [M+H] + .
步骤2：在室温下，将化合物174-2(580mg,0.12mmol)的甲醇(25mL)溶液用N2吹扫并维持N2氛围，加入Pd/C 10％(60mg,0.56mmol)。将反应混合物用H2吹扫并维持H2氛围，在30℃下搅拌16个小时后过滤。将所得滤液浓缩，得到化合物174-3的粗产物(560.9mg,产率：96.12％)。MS(ESI)：m/z＝331[M+H]+。Step 2: At room temperature, a solution of compound 174-2 (580 mg, 0.12 mmol) in methanol (25 mL) was purged with N 2 and maintained under N 2 atmosphere, and Pd/C 10% (60 mg, 0.56 mmol) was added. The reaction mixture was purged with H2 and maintained under H2 atmosphere, stirred at 30 °C for 16 h and then filtered. The obtained filtrate was concentrated to obtain a crude product of compound 174-3 (560.9 mg, yield: 96.12%). MS (ESI): m/z = 331 [M+H] + .
步骤3：在室温下，将碘化亚铜(422.06mg,2.22mmol)、二碘甲烷(0.74mL,9.23mmol)和亚硝酸叔丁酯(0.80mL,6.65mmol)依次加入到化合物174-3的粗产物(610mg,1.85mmol)的四氢呋喃(10mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至68℃后搅拌1个小时，用碳酸氢钠饱和溶液将反应淬灭，加水(5mL)稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(用乙酸乙酯:石油醚＝1:3洗脱)纯化，得到化合物174-4(737mg,产率：90.45％)。Step 3: At room temperature, copper iodide (422.06 mg, 2.22 mmol), diiodomethane (0.74 mL, 9.23 mmol) and tert-butyl nitrite (0.80 mL, 6.65 mmol) were sequentially added to compound 174-3 A solution of the crude product (610mg, 1.85mmol) in tetrahydrofuran (10mL). The reaction mixture was purged with N2 and maintained under N2 atmosphere, slowly warmed up to 68°C and stirred for 1 hour, quenched with saturated sodium bicarbonate solution, diluted with water (5 mL), and washed with ethyl acetate (50 mL×2 )extraction. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:3) to obtain compound 174-4 (737 mg, yield rate: 90.45%).
步骤4：在室温下，将三甲基环三硼氧烷(0.29mL,1.02mmol)、1,1'-双(二苯基膦)二茂铁]二氯化钯(49.75mg,0.07mmol)、碳酸钾(187.94mg,1.36mmol)和氟化铯(206.57mg,1.36mmol)加入到化合物174-4(300mg,0.68mmol)的1，4-二氧六环(7.5mL)和水(1.5mL)的溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌16个小时，加水稀释(3mL)，用乙酸乙酯(100mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(用乙酸乙酯:石油醚＝1:5)纯化，得到化合物174-5(187mg,产率：83.91％)。MS(ESI)：m/z＝330[M+H]+。Step 4: At room temperature, trimethylboroxine (0.29mL, 1.02mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (49.75mg, 0.07mmol ), potassium carbonate (187.94mg, 1.36mmol) and cesium fluoride (206.57mg, 1.36mmol) were added to compound 174-4 (300mg, 0.68mmol) in 1,4-dioxane (7.5mL) and water ( 1.5mL) solution. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 80°C and stirred for 16 hours, diluted with water (3 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:5) to obtain compound 174-5 (187 mg, yield: 83.91%). MS (ESI): m/z = 330 [M+H] + .
步骤5：在室温下，将盐酸羟胺(394.58mg,5.68mmol)、分子筛(190mg,0.33mmol)和三乙胺(4.72mL,34.07mmol)加入化合物174-5(187mg,0.57mmol)的甲醇(5mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至75℃搅拌3个小时后，加饱和氯化铵将反应淬灭后，过滤，并将所得滤液用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(洗脱剂梯度从乙酸乙酯:石油醚＝1:3过渡至乙酸乙酯)纯化，得到化合物174-6(100mg,产率：69.38％)。MS(ESI)：m/z＝363[M+H]+。Step 5: At room temperature, hydroxylamine hydrochloride (394.58mg, 5.68mmol), Molecular sieves (190 mg, 0.33 mmol) and triethylamine (4.72 mL, 34.07 mmol) were added to a solution of compound 174-5 (187 mg, 0.57 mmol) in methanol (5 mL). The reaction mixture was purged with N2 while maintaining the N2 atmosphere, slowly warming up to 75°C and stirring for 3 hours, adding saturated ammonium chloride to quench the reaction, filtering, and the resulting filtrate was washed with ethyl acetate (50mL×2 )extraction. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from ethyl acetate:petroleum ether=1:3 to ethyl acetate) to obtain compound 174-6 (100 mg, yield: 69.38%). MS (ESI): m/z = 363 [M+H] + .
步骤6：在冰浴条件下，将CDI(77.75mg,0.48mmol)加入到化合物174-6(139mg,0.38mmol)的四氢呋喃(3mL)溶液中，缓慢升至30℃搅拌30分钟后，在冰浴条件下加入DBU(85.88μL,0.58mmol)。将反应混合物缓慢升至30℃后搅拌1小时，加水(2mL)稀释，随后用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物通过制备高效液相色谱(HPLC)纯化，得到化合物174(45mg,产率：28.86％)。MS(ESI)：m/z＝389[M+H]+。1H NMR(DMSO-d6)δ:12.65-12.93(m,1H),8.08(s,1H),8.05(s,1H),7.57-7.64(m,2H),7.48(d,J＝8.9Hz,1H),6.83(d,J＝3.4Hz,1H),2.78(q,J＝7.6Hz,2H),2.60(s, 3H),1.28(t,J＝7.5Hz,3H)。Step 6: Add CDI (77.75mg, 0.48mmol) to a solution of compound 174-6 (139mg, 0.38mmol) in tetrahydrofuran (3mL) under ice-bath conditions, slowly rise to 30°C and stir for 30 minutes. DBU (85.88 μL, 0.58 mmol) was added under bath conditions. The reaction mixture was slowly warmed to 30° C., stirred for 1 hour, diluted with water (2 mL), and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 174 (45 mg, yield: 28.86%). MS (ESI): m/z = 389 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 12.65-12.93 (m, 1H), 8.08 (s, 1H), 8.05 (s, 1H), 7.57-7.64 (m, 2H), 7.48 (d, J=8.9 Hz, 1H), 6.83(d, J=3.4Hz, 1H), 2.78(q, J=7.6Hz, 2H), 2.60(s, 3H), 1.28 (t, J=7.5Hz, 3H).
实施例175
Example 175
步骤1：在室温下，将三甲基环三硼氧烷(1.80mL,6.31mmol)、1,1'-双(二苯基膦)二茂铁]二氯化钯(0.31g,0.42mmol)、碳酸钾(1.16g,8.41mmol)和氟化铯(1.28g,8.41mmol)加入到化合物176-3(1.8g,4.20mmol)的1，4-二氧六环(30mL)和水(6mL)的溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌16个小时后，加水稀释(3mL)，用乙酸乙酯(100mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物175-1(590mg,产率：44.37％)。MS(ESI)：m/z＝315[M-H]-。Step 1: At room temperature, trimethylboroxane (1.80 mL, 6.31 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.31 g, 0.42 mmol ), potassium carbonate (1.16g, 8.41mmol) and cesium fluoride (1.28g, 8.41mmol) were added to compound 176-3 (1.8g, 4.20mmol) in 1,4-dioxane (30mL) and water ( 6mL) solution. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80°C and stirred for 16 hours, then diluted with water (3 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 175-1 (590 mg, yield : 44.37%). MS (ESI): m/z = 315 [MH] - .
步骤2：在室温下，将碘化亚铜(216.77mg,1.14mmol)、二碘甲烷(382.60μL,4.74mmol)和亚硝酸叔丁酯(409.43μL,3.41mmol)加入到化合物175-1(300mg,0.95mmol)的四氢呋喃(8mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至68℃搅拌1个小时，用碳酸氢钠饱和溶液将反应淬灭，加水(3mL)稀释，并乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，将所得残余物经硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物175-2(355mg,产率：87.62％)。MS(ESI)：m/z＝428[M+H]+。Step 2: At room temperature, copper iodide (216.77 mg, 1.14 mmol), diiodomethane (382.60 μL, 4.74 mmol) and tert-butyl nitrite (409.43 μL, 3.41 mmol) were added to compound 175-1 ( 300mg, 0.95mmol) in tetrahydrofuran (8mL) solution. The reaction mixture was purged with N2 and maintained at N2 atmosphere, slowly warmed to 68°C and stirred for 1 hour, quenched with saturated sodium bicarbonate solution, diluted with water (3 mL), and ethyl acetate (50 mL×2) extraction. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 175-2 (355 mg, yield : 87.62%). MS (ESI): m/z = 428 [M+H] + .
步骤3：在室温下，将乙烯三氟硼酸钾(31.29mg,0.23mmol)、1,1'-双(二苯基膦)二茂铁]二氯化钯(30.40mg,0.04mmol)和碳酸钾(114.85mg,0.83mmol)依次加入到化合物175-2(355mg,0.83mmol)的1，4-二氧六环(10mL)和水(2mL)的溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌16个小时，加水(5mL)稀释，并用乙酸乙酯(100mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:3)纯化，得到化合物175-3(136mg,产率：50.00％)。MS(ESI)：m/z＝328[M+H]+。Step 3: Potassium ethylene trifluoroborate (31.29 mg, 0.23 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (30.40 mg, 0.04 mmol) and carbonic acid were mixed at room temperature Potassium (114.85 mg, 0.83 mmol) was sequentially added to a solution of compound 175-2 (355 mg, 0.83 mmol) in 1,4-dioxane (10 mL) and water (2 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 80°C and stirred for 16 hours, diluted with water (5 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:3) to obtain compound 175-3 (136 mg, yield: 50.00 %). MS (ESI): m/z = 328 [M+H] + .
步骤4：在室温下，将化合物175-3(136mg,0.42mmol)的甲醇(10mL)溶液用N2吹扫并维持N2氛围，加入10％的钯碳(15mg,0.14mmol)。将反应混合物用H2吹扫并维持H2氛围，在30℃搅拌16个小时后，过滤。将所得滤液浓缩得到化合物175-4的粗产物(131mg)。MS(ESI)：m/z＝330[M+H]+。Step 4: At room temperature, a solution of compound 175-3 (136 mg, 0.42 mmol) in methanol (10 mL) was purged with N 2 and maintained under N 2 atmosphere, and 10% palladium on carbon (15 mg, 0.14 mmol) was added. The reaction mixture was purged with H2 and maintained under H2 atmosphere, and after stirring at 30 °C for 16 hours, it was filtered. The obtained filtrate was concentrated to obtain a crude product of Compound 175-4 (131 mg). MS (ESI): m/z = 330 [M+H] + .
步骤5：在室温下，将盐酸羟胺(276.42mg,3.98mmol)、分子筛(155mg,0.33mmol)和三乙胺(3.31mL,23.87mmol)依次加入到化合物175-4(131mg,0.40mmol)的甲醇(5mL)溶液。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至75℃搅拌3个小时，用饱和氯化铵将反应淬灭后过滤，并将所得滤液用乙酸乙酯(50mL×2)萃取。将有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(洗脱剂梯度从乙酸乙酯:石油醚＝1:1过渡到乙酸乙酯)纯化，得到化合物175-5(100mg,产率：69.38％)。MS(ESI)：m/z＝363[M+H]+。Step 5: At room temperature, hydroxylamine hydrochloride (276.42mg, 3.98mmol), Molecular sieves (155 mg, 0.33 mmol) and triethylamine (3.31 mL, 23.87 mmol) were sequentially added to a solution of compound 175-4 (131 mg, 0.40 mmol) in methanol (5 mL). The reaction mixture was purged with N2 and maintained at N2 atmosphere, slowly warmed up to 75°C and stirred for 3 hours, quenched with saturated ammonium chloride and filtered, and the obtained filtrate was extracted with ethyl acetate (50mL×2) . The organic phase was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from ethyl acetate:petroleum ether=1:1 to ethyl acetate) to obtain compound 175- 5 (100 mg, yield: 69.38%). MS (ESI): m/z = 363 [M+H] + .
步骤6：在冰浴条件下，将CDI(55.94mg,0.34mmol)加入到化合物175-5(100mg,0.28mmol)的四氢呋喃(5mL)溶液中，缓慢升至30℃搅拌30分钟后，在冰浴条件下加入DBU(61.78μL,0.41mmol)(1mL)。将反应混合物缓慢升温至30℃搅拌1小时，加水(2mL)稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得的有机相用无水硫酸钠干燥后浓缩，并将所得残余物通过制备高效液相色谱(HPLC)纯化，得到化合物175(22mg,产率：20.26％)。MS(ESI)：m/z＝389[M+H]+。Step 6: Add CDI (55.94mg, 0.34mmol) to a solution of compound 175-5 (100mg, 0.28mmol) in tetrahydrofuran (5mL) under ice-bath conditions, slowly rise to 30°C and stir for 30 minutes. DBU (61.78 μL, 0.41 mmol) (1 mL) was added under bath conditions. The reaction mixture was slowly warmed to 30°C and stirred for 1 hour, diluted with water (2 mL), and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 175 (22 mg, yield: 20.26%). MS (ESI): m/z = 389 [M+H] + .
1H NMR(DMSO-d6)δ:12.69(br s,1H),8.08-8.10(m,1H),8.06(s,1H),7.70(d,J＝8.8Hz,1H),7.58(d,J＝3.4Hz,1H),7.49-7.53(m,1H),6.85(d,J＝3.3Hz,1H),2.90(q,J＝7.5Hz,2H),2.44(s,3H),1.27(t,J＝7.5Hz,3H)。 1 H NMR (DMSO-d6) δ: 12.69 (br s, 1H), 8.08-8.10 (m, 1H), 8.06 (s, 1H), 7.70 (d, J=8.8Hz, 1H), 7.58 (d, J＝3.4Hz, 1H), 7.49-7.53(m, 1H), 6.85(d, J＝3.3Hz, 1H), 2.90(q, J＝7.5Hz, 2H), 2.44(s, 3H), 1.27( t, J=7.5Hz, 3H).
实施例176
Example 176
步骤1：在室温下，将6-氯-5-碘吡啶-2-胺(10g,39.30mmol)、Pd(PPh3)4(2.27g,1.96mmol)和二氰化锌(4.61g,39.30mmol)分散于DMF(100mL)中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌16小时后过滤。将所得滤液用水稀释(300mL)，并用乙酸乙酯(800mL×3)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物176-1(7g,产率：115.99％)。MS(ESI)：m/z＝154[M+H]+。Step 1: Mix 6-chloro-5-iodopyridin-2-amine (10g, 39.30mmol), Pd(PPh 3 ) 4 (2.27g, 1.96mmol) and zinc dicyanide (4.61g, 39.30mmol) at room temperature mmol) was dispersed in DMF (100 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, the temperature was slowly raised to 80° C., stirred for 16 hours, and then filtered. The resulting filtrate was diluted with water (300 mL), and extracted with ethyl acetate (800 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 176-1 (7 g, yield Rate: 115.99%). MS (ESI): m/z = 154 [M+H] + .
步骤2：在0℃下，将(N-碘代丁二酰亚胺)(5.49g,24.42mmol)和三氟乙酸(1.21mL,16.28mmol)加入到化合物176-1(2.5g,16.28mmol)的乙腈(40mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至室温后搅拌16个小时，用碳酸氢钠饱和溶液将反应淬灭，加水稀释，并用乙酸乙酯(250mL×3)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(用乙酸乙酯:石油醚＝1:3洗脱)纯化，得到化合物176-2(4.3g,产率：94.51％)。MS(ESI)：m/z＝280[M+H]+。Step 2: (N-iodosuccinimide) (5.49 g, 24.42 mmol) and trifluoroacetic acid (1.21 mL, 16.28 mmol) were added to compound 176-1 (2.5 g, 16.28 mmol) at 0 °C ) in acetonitrile (40 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to room temperature and stirred for 16 hours, quenched with saturated sodium bicarbonate solution, diluted with water, and extracted with ethyl acetate (250 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:3) to obtain compound 176-2 (4.3g, Yield: 94.51%). MS (ESI): m/z = 280 [M+H] + .
步骤3：在室温下，将化合物176-2(1.5g,5.37mmol)、5-(三氟甲基)-1H-吲哚(0.99g,5.37mmol)和碳酸铯(3.50g,10.73mmol)分散于DMF(30mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至120℃后搅拌1小时，加水(50mL)稀释，用乙酸乙酯(300mL×3)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(用乙酸乙酯:石油醚＝1:5)纯化，得到化合物176-3(1.95g,产率：84.85％)。MS(ESI)：m/z＝429[M+H]+。Step 3: Compound 176-2 (1.5g, 5.37mmol), 5-(trifluoromethyl)-1H-indole (0.99g, 5.37mmol) and cesium carbonate (3.50g, 10.73mmol) were mixed at room temperature Disperse in DMF (30 mL) solution. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, warmed up slowly to 120°C and stirred for 1 hour, diluted with water (50 mL), and extracted with ethyl acetate (300 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (with ethyl acetate:petroleum ether=1:5) to obtain compound 176-3 (1.95 g, yield : 84.85%). MS (ESI): m/z = 429 [M+H] + .
步骤4：在室温下，将乙基硼酸(245.92mg,3.33mmol)、1,1'-双(二苯基膦)二茂铁]二氯化钯(81.18mg,0.11mmol)、碳酸钾(306.80mg,2.22mmol)和氟化铯(674.07mg,4.44mmol)加入到化合物176-3(950mg,2.22mmol)的1，4-二氧六环(15mL)和水(3mL)的溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌16小时，加水(5mL)稀释，用乙酸乙酯(100mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:3洗脱)纯化，得到化合物176-4(109mg,产率：14.87％)。MS(ESI)：m/z＝331[M+H]+。Step 4: At room temperature, ethylboronic acid (245.92 mg, 3.33 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (81.18 mg, 0.11 mmol), potassium carbonate ( 306.80 mg, 2.22 mmol) and cesium fluoride (674.07 mg, 4.44 mmol) were added to a solution of compound 176-3 (950 mg, 2.22 mmol) in 1,4-dioxane (15 mL) and water (3 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 80°C and stirred for 16 hours, diluted with water (5 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:3) to obtain compound 176-4 (109 mg, yield rate: 14.87%). MS (ESI): m/z = 331 [M+H] + .
步骤5：在室温下，将盐酸羟胺(229.31mg,3.30mmol)、分子筛(110mg,0.33mmol)和三乙胺(2.74mL,19.80mmol)加入到化合物176-4(109mg,0.33mmol)的甲醇(5mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌3个小时，用饱和氯化铵将反应液淬灭后过滤。将所得滤液用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(洗脱液梯度从乙酸乙酯:石油醚＝1:1过渡到乙酸乙酯)纯化，得到化合物176-5(47mg,产率：39.20％)。MS(ESI)：m/z＝364[M+H]+。Step 5: At room temperature, hydroxylamine hydrochloride (229.31mg, 3.30mmol), Molecular sieves (110 mg, 0.33 mmol) and triethylamine (2.74 mL, 19.80 mmol) were added to a solution of compound 176-4 (109 mg, 0.33 mmol) in methanol (5 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, the temperature was slowly raised to 80° C. and stirred for 3 hours, the reaction solution was quenched with saturated ammonium chloride and filtered. The resulting filtrate was extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from ethyl acetate:petroleum ether=1:1 to ethyl acetate) to obtain compound 176-5 (47 mg, yield: 39.20%). MS (ESI): m/z = 364 [M+H] + .
步骤6：在冰浴条件下，将CDI(26.22mg,0.16mmol)加入到化合物176-5(47mg,0.13mmol)的四氢呋喃(1mL)溶液中，缓慢升温至30℃并搅拌30分钟后，在冰浴条件下加入DBU(28.96μL,0.19mmol)。将反应混合物缓慢升温至室温搅拌1小时后，加水(2mL)稀释，再用乙酸乙酯(20mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物通过制备高效液相色谱(HPLC)纯化，得到化合物176(7.6mg,产率:14.95％)。MS(ESI)：m/z＝390[M+H]+。1H NMR(DMSO-d6)δ:8.02(s,1H),7.68(s,1H),7.53-7.59(m,2H),7.44(dd,J＝8.8,1.6Hz,1H),6.89(s,2H),6.78(d,J＝3.4Hz,1H),2.52-2.57(m,2H),1.23(t,J＝7.4Hz,3H)。Step 6: Add CDI (26.22mg, 0.16mmol) to a solution of compound 176-5 (47mg, 0.13mmol) in tetrahydrofuran (1mL) under ice bath conditions, slowly warm up to 30°C and stir for 30 minutes, then DBU (28.96 μL, 0.19 mmol) was added under ice bath conditions. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour, diluted with water (2 mL), and extracted with ethyl acetate (20 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 176 (7.6 mg, yield: 14.95%). MS (ESI): m/z = 390 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.02(s, 1H), 7.68(s, 1H), 7.53-7.59(m, 2H), 7.44(dd, J=8.8, 1.6Hz, 1H), 6.89( s, 2H), 6.78 (d, J = 3.4Hz, 1H), 2.52-2.57 (m, 2H), 1.23 (t, J = 7.4Hz, 3H).
实施例187
Example 187
步骤1：在室温下，将碘甲烷(20μL,0.32mmol)和碳酸钾(79.59mg,0.58mmol)加入到化合物2(100mg,0.29mmol)的DMF(4mL)溶液中，将反应混合物在室温下搅拌2小时。加入水(5mL)稀释，并用EA(5mLx 3)萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物经柱层析及pre-HPLC纯化，得到化合物187(94mg,0.26mmol,产率89.72％)。MS(ESI)：m/z＝362.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝9.02(s,2H),8.10-8.04(m,1H),7.86(br d,J＝8.5Hz,1H),7.78(br d,J＝3.0Hz,1H),7.55(br d,J＝8.6Hz,1H),6.90(br d,J＝2.9Hz,1H),3.32(br s,3H)。Step 1: At room temperature, methyl iodide (20 μL, 0.32 mmol) and potassium carbonate (79.59 mg, 0.58 mmol) were added to a solution of compound 2 (100 mg, 0.29 mmol) in DMF (4 mL), and the reaction mixture was heated at room temperature Stir for 2 hours. Added water (5 mL) to dilute and extracted with EA (5 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography and pre-HPLC to obtain compound 187 (94 mg, 0.26 mmol, yield 89.72%). MS (ESI): m/z = 362.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ=9.02(s, 2H), 8.10-8.04(m, 1H), 7.86(br d, J=8.5Hz, 1H), 7.78(br d, J=3.0 Hz, 1H), 7.55 (br d, J = 8.6Hz, 1H), 6.90 (br d, J = 2.9Hz, 1H), 3.32 (br s, 3H).
实施例209
Example 209
步骤1：在室温下，将乙基硼酸(75.36mg,1.02mmol)、1,1'-双(二苯基膦)二茂铁]二氯化钯(49.75mg,0.07mmol)、碳酸钾(187.94mg,1.36mmol)和氟化铯(206.57mg,1.36mmol)加入到化合物209-1(300mg,0.68mmol)的1,4-二氧六环(7.5mL)和水(1.5mL)的溶液中。将反应混合物缓慢升温至80℃后搅拌16个小时，加水(5mL)稀释，用乙酸乙酯(100mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗涤)纯化，得到化合物209-2(193mg,产率：82.67％)。MS(ESI)：m/z＝344[M+H]+。Step 1: At room temperature, ethylboronic acid (75.36mg, 1.02mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (49.75mg, 0.07mmol), potassium carbonate ( 187.94 mg, 1.36 mmol) and cesium fluoride (206.57 mg, 1.36 mmol) were added to a solution of compound 209-1 (300 mg, 0.68 mmol) in 1,4-dioxane (7.5 mL) and water (1.5 mL) middle. The reaction mixture was slowly warmed to 80°C and stirred for 16 hours, diluted with water (5 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (washed with ethyl acetate:petroleum ether=1:5) to obtain compound 209-2 (193mg, yield : 82.67%). MS (ESI): m/z = 344 [M+H] + .
步骤2：将盐酸羟胺(390.61mg,5.62mmol)、分子筛(190mg,0.33mmol)和三乙胺(4.68mL,33.73mmol)加入到化合物209-2(193mg,0.56mmol)的甲醇(5mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至75℃搅拌3个小时，用饱和氯化铵将反应液淬灭后过滤。将过滤所得滤液用乙酸乙酯(50mL×2)萃取，用无水硫酸钠干燥后浓缩，将所得残余物用硅胶柱层析(洗脱剂梯度从乙酸乙酯:石油醚＝1:1过渡到乙酸乙酯)纯化，得到化合物209-3(135mg,产率：63.81％)。MS(ESI)：m/z＝377[M+H]+。Step 2: Add hydroxylamine hydrochloride (390.61mg, 5.62mmol), Molecular sieves (190 mg, 0.33 mmol) and triethylamine (4.68 mL, 33.73 mmol) were added to a solution of compound 209-2 (193 mg, 0.56 mmol) in methanol (5 mL). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, the temperature was slowly raised to 75° C. and stirred for 3 hours, the reaction solution was quenched with saturated ammonium chloride and filtered. The filtered filtrate was extracted with ethyl acetate (50mL×2), dried over anhydrous sodium sulfate and concentrated, and the resulting residue was subjected to silica gel column chromatography (eluent gradient from ethyl acetate:petroleum ether=1:1 transition to ethyl acetate) to obtain compound 209-3 (135 mg, yield: 63.81%). MS (ESI): m/z = 377 [M+H] + .
步骤3：在冰浴条件下，将CDI(72.70mg,0.45mmol)加入到化合物209-3(135mg,0.36mmol)的四氢呋喃(5mL)溶液中，缓慢升温至30℃搅拌30min后，在冰浴条件下加入DBU(80.30μL,0.54mmol)。将反应混合物缓慢升温至室温搅拌1小时，加水(2mL)稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物通过制备高效液相色谱(HPLC)纯化，得到化合物209(2mg,产率：1.38％)。MS(ESI)：m/z＝403[M+H]+。1H NMR(DMSO-d6)δ:8.03(s,2H),7.67(br d,J＝8.5Hz,1H),7.56(br s,1H),7.47(br d,J＝8.1Hz,1H),6.79(s,1H),2.90(d,J＝7.5Hz,2H),2.75-2.83(m,2H),1.28(br t,J＝7.4Hz,6H)。Step 3: Add CDI (72.70mg, 0.45mmol) to a solution of compound 209-3 (135mg, 0.36mmol) in tetrahydrofuran (5mL) under ice-bath conditions, slowly warm up to 30°C and stir for 30min. DBU (80.30 μL, 0.54 mmol) was added under conditions. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour, diluted with water (2 mL), and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain compound 209 (2 mg, yield: 1.38%). MS (ESI): m/z = 403 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.03(s, 2H), 7.67(br d, J=8.5Hz, 1H), 7.56(br s, 1H), 7.47(br d, J=8.1Hz, 1H ), 6.79 (s, 1H), 2.90 (d, J=7.5Hz, 2H), 2.75-2.83 (m, 2H), 1.28 (br t, J=7.4Hz, 6H).
实施例210
Example 210
步骤1：在0℃条件下，将NIS(3.35g,14.91mmol)加入到6-甲基-2-氧代-1，2-二氢吡啶-3-甲腈(2.0g,14.91mmol)的DMF(22mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至室温搅拌过夜，加水(5mL)稀释，并用乙酸乙酯(100mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯:石油醚＝1:1洗脱)纯化，得到化合物210-1(3.14g,产率：80.99％)。MS(ESI)：m/z＝261[M+H]+。Step 1: Add NIS (3.35g, 14.91mmol) to 6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (2.0g, 14.91mmol) at 0°C DMF (22mL) solution. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to room temperature and stirred overnight, diluted with water (5 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:1) to obtain compound 210-1 (3.14g, Yield: 80.99%). MS (ESI): m/z = 261 [M+H] + .
步骤2：在室温下，将化合物210-1(2.14g,8.23mmol)溶于三氯氧磷(15mL)。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至80℃搅拌5个小时后，加冰水缓慢将反应淬灭，并用乙酸乙酯(100mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(用乙酸乙酯:石油醚＝1:1洗脱)纯化，得到化合物210-2(1.4685g,产率：64.08％)。MS(ESI)：m/z＝279[M+H]+。Step 2: Compound 210-1 (2.14 g, 8.23 mmol) was dissolved in phosphorus oxychloride (15 mL) at room temperature. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed up to 80°C and stirred for 5 hours, then quenched slowly with ice water, and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:1) to obtain compound 210-2 (1.4685g, Yield: 64.08%). MS (ESI): m/z = 279 [M+H] + .
步骤3：在室温下，将碘化亚铜(410.33mg,2.15mmol)和2，2-二氟-2-(氟磺酰基)乙酸甲酯(0.46mL,3.59mmol)加入到化合物210-2(500mg,1.80mmol)的DMF(6mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至100℃搅拌3个小时，加水稀释，并用乙酸乙酯(100mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用石油醚洗脱)纯化，得到化合物210-3(300mg,产率：75.75％)。1H NMR(DMSO-d6)δ:8.88(s,1H),2.70(d,J＝1.5Hz,3H)。19F NMR(DMSO-d6)δ:-60.93(s,3F)。Step 3: Add cuprous iodide (410.33 mg, 2.15 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.46 mL, 3.59 mmol) to compound 210-2 at room temperature (500mg, 1.80mmol) in DMF (6mL) solution. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, slowly warmed to 100°C and stirred for 3 hours, diluted with water, and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 210-3 (300 mg, yield: 75.75%). 1 H NMR (DMSO-d6) δ: 8.88 (s, 1H), 2.70 (d, J = 1.5 Hz, 3H). 19 F NMR (DMSO-d6) δ: -60.93 (s, 3F).
步骤4：在室温下，将化合物210-3(140mg,0.63mmol)、5-三氟甲基吲哚(117.51mg,0.63mmol)和碳酸钾(104.48mg,0.76mmol)分散于DMF(3mL)中。将反应混合物用N2吹扫并维持N2氛围，在室温下搅拌1个小时，加水稀释，再用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(用乙酸乙酯:石油醚＝1:5洗脱)纯化，得到化合物210-4(30mg,产率：12.80％)。1H NMR(DMSO-d6)δ:9.01(s,1H),8.13(s,1H),8.11-8.18(m,2H),7.62(d,J＝8.9Hz,1H),7.04(d,J＝3.5Hz,1H),2.79(s,3H)。Step 4: Compound 210-3 (140 mg, 0.63 mmol), 5-trifluoromethylindole (117.51 mg, 0.63 mmol) and potassium carbonate (104.48 mg, 0.76 mmol) were dispersed in DMF (3 mL) at room temperature middle. The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, stirred at room temperature for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 210-4 (30 mg, yield rate: 12.80%). 1 H NMR (DMSO-d 6 )δ: 9.01(s, 1H), 8.13(s, 1H), 8.11-8.18(m, 2H), 7.62(d, J=8.9Hz, 1H), 7.04(d, J=3.5Hz, 1H), 2.79(s, 3H).
步骤5：在室温下，将盐酸羟胺(56.45mg,0.81mmol),分子筛(40mg,mmol)、和三乙胺(0.68mL,4.87mmol)加入到化合物210-4(30mg,0.08mmol)的甲醇(3mL)溶液中。将反应混合物用N2吹扫并维持N2氛围，缓慢升温至75℃搅拌3个小时后，加入饱和氯化铵水溶液将反应淬灭，过滤。将所得滤液用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物经硅胶柱层析(用乙酸乙酯洗脱)纯化，得到化合物210-5(15.7mg,产率：48.04％)。MS(ESI)：m/z＝403[M+H]+。Step 5: At room temperature, hydroxylamine hydrochloride (56.45mg, 0.81mmol), Molecular sieves (40 mg, mmol), and triethylamine (0.68 mL, 4.87 mmol) were added to a solution of compound 210-4 (30 mg, 0.08 mmol) in methanol (3 mL). The reaction mixture was purged with N 2 and the N 2 atmosphere was maintained, the temperature was slowly raised to 75° C. and stirred for 3 hours, the reaction was quenched by adding saturated aqueous ammonium chloride solution, and filtered. The resulting filtrate was extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 210-5 (15.7 mg, yield: 48.04%). MS (ESI): m/z = 403 [M+H] + .
步骤6：在冰浴条件下，将CDI(7.56mg,0.05mmol)加入到化合物210-5(15mg,0.04mmol)的四氢呋喃(1mL)溶液中，缓慢升温至室温搅拌30分钟后，在冰浴条件下加入DBU(8.35μL,0.06mmol)。将反应混合物缓慢升温至室温搅拌1小时，加水稀释，并用乙酸乙酯(50mL×2)萃取。将合并所得有机相用无水硫酸钠干燥后浓缩，并将所得残余物用硅胶柱层析(用乙酸乙酯洗脱)纯化，得到化合物210(6mg,产率：37.57％)。MS(ESI)：m/z＝429[M+H]+。1HNMR(DMSO-d6)δ:8.62(s,1H),8.08(s,1H),7.91(d,J＝8.6Hz,1H),7.66(d,J＝3.5Hz,1H),7.55(dd,J＝8.8,1.4Hz,1H),6.91(d,J＝3.4Hz,1H),2.78(d,J＝1.0Hz,3H)。Step 6: Add CDI (7.56mg, 0.05mmol) to a solution of compound 210-5 (15mg, 0.04mmol) in tetrahydrofuran (1mL) under ice-bath conditions, slowly warm up to room temperature and stir for 30 minutes. DBU (8.35 μL, 0.06 mmol) was added under conditions. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 210 (6 mg, yield: 37.57%). MS (ESI): m/z = 429 [M+H] + . 1 H NMR (DMSO-d 6 ) δ: 8.62(s, 1H), 8.08(s, 1H), 7.91(d, J=8.6Hz, 1H), 7.66(d, J=3.5Hz, 1H), 7.55( dd, J=8.8, 1.4Hz, 1H), 6.91 (d, J=3.4Hz, 1H), 2.78 (d, J=1.0Hz, 3H).
实施例211
Example 211
步骤1：向化合物3-溴-2-氯-5-甲基吡啶(1000mg,4.84mmol)的DMA(10mL)溶液中加入Na2CO3(513.34mg,4.84mmol),铁氰化钾(II)三水合物(0.24mL,1.07mmol)和Pd(OAc)2(54.37mg,0.24mmol)。将反应混合物在120℃下搅拌过夜，加H2O稀释，并用EA萃取。将有机层用饱和食盐水洗涤(3次)，干燥后浓缩，并将所得残余物经柱层析纯化，得到化合物211-1(265mg,1.74mmol,35.86％)。MS(ESI)：m/z＝153[M+H]+。Step 1: Add Na 2 CO 3 (513.34 mg, 4.84 mmol), potassium ferricyanide (II ) trihydrate (0.24 mL, 1.07 mmol) and Pd(OAc) 2 (54.37 mg, 0.24 mmol). The reaction mixture was stirred overnight at 120 °C, diluted with H2O , and extracted with EA. The organic layer was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by column chromatography to obtain compound 211-1 (265 mg, 1.74 mmol, 35.86%). MS (ESI): m/z = 153 [M+H] + .
步骤2：在室温下，向化合物211-1(240mg,1.57mmol)和(苄氧基)羰基)甘氨酸(510.17μL,3.15mmol)的水(5mL)溶液中加入硝酸银(184.27μL,4.72mmol和三氟乙酸(150μL,2.01mmol)，缓慢升温至70℃后，加入过硫酸铵(725.11μL,6.29mmol)的水(2mL)溶液。将反应混合物在70℃搅拌30分钟，冷却至室温，加入水(20mL)淬灭反应，并用EA(20mL)萃取。将有机相用水洗涤(10mL*2)，干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物211-2(145mg,0.46mmol,29.19％)。MS(ESI)：m/z＝316[M+H]+。Step 2: To a solution of compound 211-1 (240 mg, 1.57 mmol) and (benzyloxy)carbonyl)glycine (510.17 μL, 3.15 mmol) in water (5 mL) was added silver nitrate (184.27 μL, 4.72 mmol) at room temperature and trifluoroacetic acid (150 μL, 2.01 mmol), after slowly warming up to 70 ° C, a solution of ammonium persulfate (725.11 μ L, 6.29 mmol) in water (2 mL) was added. The reaction mixture was stirred at 70 ° C for 30 minutes, cooled to room temperature, Water (20mL) was added to quench the reaction, and extracted with EA (20mL).The organic phase was washed with water (10mL*2), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 211-2 (145mg , 0.46 mmol, 29.19%). MS (ESI): m/z = 316 [M+H] + .
步骤3：向化合物211-2(90mg,0.29mmol)的甲苯(5mL)溶液中加入5-三氟甲基吲哚(63.33mg,0.34mmol)、叔丁醇钠(32.87mg,0.34mmol)、XPhos Pd G2(49.34mg,0.06mmol)和分子筛(25mg)。将反应混合物在90℃下搅拌过夜，冷却至室温，加H2O稀释并用EA萃取。将有机层用饱和食盐水洗涤(3次)，干燥后浓缩，并将所得残余物经硅胶柱层析纯化，得到化合物211-3(76mg,0.16mmol,57.41％)。MS(ESI)：m/z＝465[M+H]+。Step 3: Add 5-trifluoromethylindole (63.33 mg, 0.34 mmol), sodium tert-butoxide (32.87 mg, 0.34 mmol) to a solution of compound 211-2 (90 mg, 0.29 mmol) in toluene (5 mL), XPhos Pd G2 (49.34mg, 0.06mmol) and Molecular sieves (25 mg). The reaction mixture was stirred overnight at 90 °C, cooled to room temperature, diluted with H2O and extracted with EA. The organic layer was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 211-3 (76 mg, 0.16 mmol, 57.41%). MS (ESI): m/z = 465 [M+H] + .
步骤4：向化合物211-3(70mg,0.16mmol)的甲醇(6mL)溶液中加入盐酸羟胺(104.73mg,1.51mmol)、三乙胺(417.83μL,3.01mmol)和分子筛(150mg)。将反应混合物在80℃下搅拌4小时，冷却至室温后过滤，并将滤液浓缩。将所得浓缩物用H2O稀释，用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物通过硅胶柱层析纯化，得到化合物211-4(70mg,0.14mmol,93.36％)。MS(ESI)：m/z＝498[M+H]+。Step 4: Add hydroxylamine hydrochloride (104.73 mg, 1.51 mmol), triethylamine (417.83 μL, 3.01 mmol) and Molecular sieves (150 mg). The reaction mixture was stirred at 80 °C for 4 hours, cooled to room temperature and filtered, and the filtrate was concentrated. The resulting concentrate was diluted with H2O and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 211-4 (70 mg, 0.14 mmol, 93.36%). MS (ESI): m/z = 498 [M+H] + .
步骤5：在0℃下，将CDI(45.63mg,0.28mmol)加入到化合物211-4(70mg,0.14mmol)的THF(4mL)溶液中，在室温下搅拌0.5小时，冷却至0℃后加入入DBU(42.00μL,0.28mmol)。将反应混合物在室温下搅拌1.5小时，冷却至0℃，用盐酸(2M)将pH调至6，加水稀释并用EA萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，得到化合物211-5(MS(ESI)：m/z＝524[M+H]+)的粗产物(72mg)。Step 5: Add CDI (45.63mg, 0.28mmol) to a THF (4mL) solution of compound 211-4 (70mg, 0.14mmol) at 0°C, stir at room temperature for 0.5 hours, cool to 0°C and add into DBU (42.00 μL, 0.28 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, cooled to 0°C, adjusted to pH 6 with hydrochloric acid (2M), diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated to obtain a crude product (72 mg) of compound 211-5 (MS(ESI): m/z=524[M+H] + ).
步骤6：在室温下，向化合物211-5(50mg,0.10mmol)的甲醇(4mL)溶液中加入10％Pd/C(22mg,0.21mmol)。将反应混合物在室温下搅拌2小时后过滤。将所得滤液浓缩，并将所得残余物通过制备高效液相色谱(HPLC)纯化，得到化合物211(1.33mg,3.58％)。MS(ESI)：m/z＝390[M+H]+。Step 6: To a solution of compound 211-5 (50 mg, 0.10 mmol) in methanol (4 mL) was added 10% Pd/C (22 mg, 0.21 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then filtered. The obtained filtrate was concentrated, and the obtained residue was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 211 (1.33 mg, 3.58%). MS (ESI): m/z = 390 [M+H] + .
实施例214
Example 214
步骤1：向化合物214-12-氯-3-氰基吡嗪(250mg,1.79mmol)的DMF(8mL)溶液中加入5-三氟甲基吲哚(331.71mg,1.79mmol)和叔丁醇钠(172.17mg,1.79mmol)。将反应混合物在120℃下搅拌3小时。冷却至室温后，加入饱和氯化铵溶液(10mL)淬灭，并用EA(8mL x 3)萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物经柱层析纯化，得到化合物214-2(429mg,1.49mmol,产率83.15％)。MS(ESI)： m/z＝289.3[M+H]+。Step 1: To a solution of compound 214-12-chloro-3-cyanopyrazine (250 mg, 1.79 mmol) in DMF (8 mL) was added 5-trifluoromethylindole (331.71 mg, 1.79 mmol) and tert-butanol Sodium (172.17 mg, 1.79 mmol). The reaction mixture was stirred at 120°C for 3 hours. After cooling to room temperature, it was quenched by adding saturated ammonium chloride solution (10 mL), and extracted with EA (8 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography to obtain compound 214-2 (429 mg, 1.49 mmol, yield 83.15%). MS(ESI): m/z = 289.3 [M+H] + .
步骤2：向化合物214-2(200mg,0.69mmol)的甲醇(5mL)溶液中加入N-甲基羟胺盐酸盐(579.54mg,6.94mmol)、三乙胺(5.77mL,41.63mmol)和分子筛(200mg)。将反应混合物在氮气氛围下80℃搅拌2小时。冷却至室温后，过滤，并将滤液浓缩。将所得浓缩物加入水(5mL)稀释，并用EA(5mL x 3)萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物经柱层析纯化，得到化合物214-3(65.3mg,0.19mmol,产率28.07％)。MS(ESI)：m/z＝336.0[M+H]+。Step 2: Add N-methylhydroxylamine hydrochloride (579.54 mg, 6.94 mmol), triethylamine (5.77 mL, 41.63 mmol) and Molecular sieves (200 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, it was filtered, and the filtrate was concentrated. The resulting concentrate was diluted with water (5 mL), and extracted with EA (5 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography to obtain compound 214-3 (65.3 mg, 0.19 mmol, yield 28.07%). MS (ESI): m/z = 336.0 [M+H] + .
步骤3：在0℃下，将CDI(39.47mg,0.24mmol)加入到化合物214-3(65.3mg,0.19mmol)的THF(3mL)溶液中，0℃下搅拌1小时。而后在0℃下加入DBU(0.04mL,0.29mmol)，将反应混合物在室温下搅拌1.5小时。加入饱和氯化铵溶液(5mL)淬灭，并用EA(5mL x 3)萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物经柱层析及pre-HPLC纯化，得到化合物214的三氟乙酸盐(28mg,0.08mmol,产率39.77％)。1H NMR(400MHz,DMSO-d6)δ＝10.50(br s,1H),8.79(br d,J＝4.5Hz,2H),8.22-7.90(m,2H),7.74-7.48(m,2H),6.95(br s,1H),3.17(br s,3H)。Step 3: CDI (39.47 mg, 0.24 mmol) was added to a THF (3 mL) solution of compound 214-3 (65.3 mg, 0.19 mmol) at 0° C. and stirred at 0° C. for 1 hour. Then DBU (0.04 mL, 0.29 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 1.5 hours. It was quenched by adding saturated ammonium chloride solution (5 mL), and extracted with EA (5 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography and pre-HPLC to obtain the trifluoroacetate salt of compound 214 (28 mg, 0.08 mmol, yield 39.77%). 1 H NMR (400MHz, DMSO-d 6 )δ=10.50(br s,1H),8.79(br d,J=4.5Hz,2H),8.22-7.90(m,2H),7.74-7.48(m,2H ), 6.95 (br s, 1H), 3.17 (br s, 3H).
实施例215
Example 215
步骤1：向化合物136(50mg,0.13mmol)的DMF(2mL)溶液中加入碳酸钾(36.82mg,0.27mmol)和碘甲烷(10.78μL,0.17mmol)。将反应混合物在25℃下搅拌1.5小时，冷却至0℃后加入水，固体析出，升至室温后过滤，滤饼用水洗涤并干燥后用二氯甲烷溶解并将滤液浓缩得到化合物215(47mg,0.12mmol,产率：90.61％)。MS(ESI)：m/z＝390.0[M+H]+。1H NMR(DMSO-d6)δ:8.07(s,1H),7.81-7.67(m,2H),7.52(d,J＝8.8Hz,1H),6.87(d,J＝3.4Hz,1H),3.28(s,3H),2.69(s,6H).Step 1: To a solution of compound 136 (50 mg, 0.13 mmol) in DMF (2 mL) was added potassium carbonate (36.82 mg, 0.27 mmol) and iodomethane (10.78 μL, 0.17 mmol). The reaction mixture was stirred at 25°C for 1.5 hours, cooled to 0°C and water was added, the solid precipitated out, raised to room temperature and filtered, the filter cake was washed with water and dried, dissolved in dichloromethane and the filtrate was concentrated to obtain compound 215 (47mg, 0.12 mmol, yield: 90.61%). MS (ESI): m/z = 390.0 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.07(s, 1H), 7.81-7.67(m, 2H), 7.52(d, J=8.8Hz, 1H), 6.87(d, J=3.4Hz, 1H) ,3.28(s,3H),2.69(s,6H).
实施例216
Example 216
步骤1：向化合物163(40mg,0.10mmol)的DMF(2mL)溶液中加入碳酸钾(28.40mg,0.21mmol)和碘甲烷(8.31μL,0.13mmol)。将反应混合物在25℃下搅拌1.5小时，冷却至0℃后加入水，固体析出，升至室温后过滤，滤饼用水洗涤并干燥后用二氯甲烷溶解并将滤液浓缩得到化合物216(35mg,0.09mmol,产率：84.46％)。MS(ESI)：m/z＝404.0[M+H]+。1H NMR(DMSO-d6)δ:8.07(s,1H),7.83(d,J＝8.6Hz,1H),7.74(d,J＝3.4Hz,1H),7.54(dd,J＝1.5,8.8Hz,1H),6.87(d,J＝3.4Hz,1H),3.28(s,3H),3.04(q,J＝7.3Hz,2H),2.71(s,3H),1.33(t,J＝7.4Hz,3H).Step 1: To a solution of compound 163 (40 mg, 0.10 mmol) in DMF (2 mL) was added potassium carbonate (28.40 mg, 0.21 mmol) and iodomethane (8.31 μL, 0.13 mmol). The reaction mixture was stirred at 25°C for 1.5 hours, cooled to 0°C and water was added, the solid precipitated out, rose to room temperature and filtered, the filter cake was washed with water and dried, dissolved in dichloromethane and the filtrate was concentrated to obtain compound 216 (35 mg, 0.09 mmol, yield: 84.46%). MS (ESI): m/z = 404.0 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.07(s, 1H), 7.83(d, J=8.6Hz, 1H), 7.74(d, J=3.4Hz, 1H), 7.54(dd, J=1.5, 8.8Hz, 1H), 6.87(d, J=3.4Hz, 1H), 3.28(s, 3H), 3.04(q, J=7.3Hz, 2H), 2.71(s, 3H), 1.33(t, J= 7.4Hz, 3H).
实施例217
Example 217
步骤1：向化合物160(40mg,0.10mmol)的DMF(2mL)溶液中加入碳酸钾(27.94mg,0.20mmol)和碘甲烷(8.18μL,0.13mmol)。将反应混合物在25℃下搅拌1.5小时，冷却至0℃后加入水，固体析出，升至室温后过滤，滤饼用水洗涤并干燥后用二氯甲烷溶解并将滤液浓缩得到化合物217(35mg,0.09mmol,产率：84.50％)。MS(ESI)：m/z＝409.9[M+H]+。1H NMR(DMSO-d6)δ:8.08(s,1H),7.87(d,1H,J＝8.6Hz),7.73(d,1H,J＝3.4Hz),7.56(d,1H,J＝8.9Hz),6.90(d,1H,J＝3.4Hz),3.23(s,3H),2.77(s,3H).Step 1: To a solution of compound 160 (40 mg, 0.10 mmol) in DMF (2 mL) was added potassium carbonate (27.94 mg, 0.20 mmol) and iodomethane (8.18 μL, 0.13 mmol). The reaction mixture was stirred at 25°C for 1.5 hours, cooled to 0°C and water was added, the solid precipitated out, rose to room temperature and filtered, the filter cake was washed with water and dried, dissolved in dichloromethane and the filtrate was concentrated to obtain compound 217 (35 mg, 0.09 mmol, yield: 84.50%). MS (ESI): m/z = 409.9 [M+H] + . 1 H NMR (DMSO-d 6 )δ: 8.08(s, 1H), 7.87(d, 1H, J=8.6Hz), 7.73(d, 1H, J=3.4Hz), 7.56(d, 1H, J= 8.9Hz), 6.90(d, 1H, J=3.4Hz), 3.23(s, 3H), 2.77(s, 3H).
实施例258
Example 258
步骤1：向化合物2(20mg,0.06mmol)的DMF(4mL)溶液中加入二氟氯乙酸钠(17.56mg,0.12mmol)和碳酸铯(37.53mg,0.12mmol)，将反应混合物在室温下搅拌3小时。加入饱和氯化铵溶液(5mL)淬灭，并用EA(5mLx 3)萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物经柱层析及pre-HPLC纯化，得到化合物258(8mg,0.02mmol,产率34.96％)。MS(ESI)：m/z＝398.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝9.02(dd,J＝2.1,19.0Hz,2H),8.09(s,1H),7.92-7.81(m,2H),7.55(br d,J＝8.9Hz,1H),6.92(d,J＝3.3Hz,1H)。Step 1: Add sodium difluorochloroacetate (17.56 mg, 0.12 mmol) and cesium carbonate (37.53 mg, 0.12 mmol) to a solution of compound 2 (20 mg, 0.06 mmol) in DMF (4 mL), and stir the reaction mixture at room temperature 3 hours. It was quenched by adding saturated ammonium chloride solution (5 mL), and extracted with EA (5 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography and pre-HPLC to obtain compound 258 (8 mg, 0.02 mmol, yield 34.96%). MS (ESI): m/z = 398.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 9.02 (dd, J = 2.1, 19.0Hz, 2H), 8.09 (s, 1H), 7.92-7.81 (m, 2H), 7.55 (br d, J = 8.9 Hz, 1H), 6.92 (d, J=3.3Hz, 1H).
实施例259
Example 259
步骤1：向化合物2(60mg,0.17mmol)的DMF(3mL)溶液中加入氘代碘甲烷(0.01mL,0.17mmol)和碳酸钾(47.76mg,0.35mmol)，将反应混合物在室温下搅拌2小时。加入饱和氯化铵溶液(5mL)淬灭，并用EA(5mLx 3)萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物经柱层析及pre-HPLC纯化，得到化合物259(31mg,0.08mmol,产率48.49％)。MS(ESI)：m/z＝365.1[M+H]+。Step 1: Add deuterated iodomethane (0.01 mL, 0.17 mmol) and potassium carbonate (47.76 mg, 0.35 mmol) to a solution of compound 2 (60 mg, 0.17 mmol) in DMF (3 mL), and stir the reaction mixture at room temperature for 2 Hour. It was quenched by adding saturated ammonium chloride solution (5 mL), and extracted with EA (5 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography and pre-HPLC to obtain compound 259 (31 mg, 0.08 mmol, yield 48.49%). MS (ESI): m/z = 365.1 [M+H] + .
1HNMR(400MHz,DMSO-d6)δ＝9.02(s,2H),8.08(s,1H),7.86(d,J＝8.8Hz,1H),7.78(d,J＝3.5Hz,1H),7.55(br d,J＝8.0Hz,1H),6.90(d,J＝3.4Hz,1H)。 1 HNMR (400MHz, DMSO-d6) δ=9.02(s,2H),8.08(s,1H),7.86(d,J=8.8Hz,1H),7.78(d,J=3.5Hz,1H),7.55 (br d, J=8.0Hz, 1H), 6.90 (d, J=3.4Hz, 1H).
实施例260
Example 260
步骤1：向化合物2(40mg,0.12mmol)的DMF(4mL)溶液中加入碘乙烷(0.01mL,0.12mmol)和碳酸钾(23.88mg,0.17mmol)，将反应混合物在室温下搅拌3小时。加入饱和氯化铵溶液(5mL)淬灭，并用EA(5mLx 3)萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物经柱层析及pre-HPLC纯化，得到化合物260(24.5mg,0.07mmol,产率56.67％)。MS(ESI)：m/z＝376.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝9.03(br s,2H),8.08(br s,1H),7.84(br d,J＝7.4Hz,1H),7.70(br s,1H),7.63-7.46(m,1H),6.90(br s,1H),3.92-3.74(m,2H),1.26(br s,4H)。Step 1: Add iodoethane (0.01 mL, 0.12 mmol) and potassium carbonate (23.88 mg, 0.17 mmol) to a solution of compound 2 (40 mg, 0.12 mmol) in DMF (4 mL), and stir the reaction mixture at room temperature for 3 hours . It was quenched by adding saturated ammonium chloride solution (5 mL), and extracted with EA (5 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography and pre-HPLC to obtain compound 260 (24.5 mg, 0.07 mmol, yield 56.67%). MS (ESI): m/z = 376.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ=9.03(br s,2H),8.08(br s,1H),7.84(br d,J=7.4Hz,1H),7.70(br s,1H), 7.63-7.46 (m, 1H), 6.90 (br s, 1H), 3.92-3.74 (m, 2H), 1.26 (br s, 4H).
实施例303
Example 303
步骤1：向化合物2(40mg,0.12mmol)的DMF(2mL)溶液中加入溴丙烷(0.01mL,0.12mmol)和碳酸钾 (31.84mg,0.23mmol)，将反应混合物在室温下搅拌3小时。加入饱和氯化铵溶液(3mL)淬灭，并用EA(3mLx 3)萃取。将有机相用饱和食盐水洗涤，干燥后浓缩，并将所得残余物经柱层析及pre-HPLC纯化，得到化合物303(1.8mg,0.005mmol,产率4.01％)。MS(ESI)：m/z＝390.0[M+H]+。11H NMR(400MHz,METHANOL-d4)δ＝8.94-8.87(m,2H),7.99(s,1H),7.77(d,J＝8.8Hz,1H),7.54(d,J＝3.5Hz,1H),7.49(d,J＝8.8Hz,1H),6.88(d,J＝3.5Hz,1H),3.72-3.66(m,2H),1.69-1.62(m,2H),0.84(t,J＝7.4Hz,3H)。Step 1: Add bromopropane (0.01 mL, 0.12 mmol) and potassium carbonate to a solution of compound 2 (40 mg, 0.12 mmol) in DMF (2 mL) (31.84 mg, 0.23 mmol), the reaction mixture was stirred at room temperature for 3 hours. It was quenched by adding saturated ammonium chloride solution (3 mL), and extracted with EA (3 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography and pre-HPLC to obtain compound 303 (1.8 mg, 0.005 mmol, yield 4.01%). MS (ESI): m/z = 390.0 [M+H] + . 1 1H NMR (400MHz, METHANOL-d 4 )δ=8.94-8.87(m,2H),7.99(s,1H),7.77(d,J=8.8Hz,1H),7.54(d,J=3.5Hz, 1H), 7.49(d, J=8.8Hz, 1H), 6.88(d, J=3.5Hz, 1H), 3.72-3.66(m, 2H), 1.69-1.62(m, 2H), 0.84(t,J =7.4Hz, 3H).
对照化合物制备过程Reference compound preparation process
合成3-(3-(4-(三氟甲基苯基)氨基吡嗪-2-基)-1,2,4-噁二唑-5(4H)酮
Synthesis of 3-(3-(4-(trifluoromethylphenyl)aminopyrazin-2-yl)-1,2,4-oxadiazol-5(4H)one
步骤1：3-((4-(三氟甲基)苯基)氨基)吡嗪-2-甲腈Step 1: 3-((4-(Trifluoromethyl)phenyl)amino)pyrazine-2-carbonitrile
将3-氯吡嗪-2-甲腈(1.3g,10mmol)、对三氟甲基苯胺(1.9g,12mmol)、Pd2(dba)3(91mg,1mmol)、XantPhos(121mg,2mmol)、和碳酸铯(8.1g，25mmol)分散于1,4-二氧六环(30ml)中。将反应混合物用N2吹扫并维持N2氛围,在80℃下搅拌过夜后，加H2O(100mL)稀释并用EA(50mL)萃取。将有机相用饱和食盐水(20mL×3)洗涤，用无水Na2SO4干燥后浓缩，并将所得残余物通过硅胶柱层析(用EA:PE＝1:4洗脱)纯化，得到化合物3-((4-(三氟甲基)苯基)氨基)吡嗪-2-甲腈(2.1g,7.9mmol,79.5％)。MS(ESI)：m/z＝265[M+H]+。3-chloropyrazine-2-carbonitrile (1.3g, 10mmol), p-trifluoromethylaniline (1.9g, 12mmol), Pd 2 (dba) 3 (91mg, 1mmol), XantPhos (121mg, 2mmol), and cesium carbonate (8.1 g, 25 mmol) were dispersed in 1,4-dioxane (30 ml). The reaction mixture was purged with N 2 and maintained under N 2 atmosphere, after stirring overnight at 80° C., diluted with H 2 O (100 mL) and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain Compound 3-((4-(trifluoromethyl)phenyl)amino)pyrazine-2-carbonitrile (2.1 g, 7.9 mmol, 79.5%). MS (ESI): m/z = 265 [M+H] + .
步骤2：N-羟基-3-((4-(三氟甲基)苯基)氨基)吡嗪-2-甲脒Step 2: N-Hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazine-2-carboxamidine
将3-((4-(三氟甲基)苯基)氨基)吡嗪-2-甲腈(2.1g,7.9mmol)、MeOH(20mL)、NH2OH·HCl(5.4g,79mmol)、TEA(15mL)和的混合物用N2吹扫并维持N2氛围，在80℃下搅拌3小时后过滤，并将滤液浓缩。向所得浓缩物中加入H2O(20mL)，用EA(30mL)萃取。将有机相用饱和食盐水洗涤(10mL×3)，用无水Na2SO4干燥后浓缩，并将所得残余物通过硅胶柱层析(用EA:PE＝1:2洗脱)纯化，得到化合物N-羟基-3-((4-(三氟甲基)苯基)氨基)吡嗪-2-甲脒(1.8g,6.1mmol,77.2％)。MS(ESI)：m/z＝298[M+H]+。3-((4-(Trifluoromethyl)phenyl)amino)pyrazine-2-carbonitrile (2.1 g, 7.9 mmol), MeOH (20 mL), NH 2 OH·HCl (5.4 g, 79 mmol), TEA (15mL) and The mixture was purged with N2 and maintained under N2 atmosphere, stirred at 80 °C for 3 h, filtered, and the filtrate was concentrated. To the obtained concentrate was added H 2 O (20 mL), extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 , concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain Compound N-hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazine-2-carboxamidine (1.8 g, 6.1 mmol, 77.2%). MS (ESI): m/z = 298 [M+H] + .
步骤3：3-(3-(4-(三氟甲基苯基)氨基吡嗪-2-基)-1，2，4-噁二唑-5(4H)酮Step 3: 3-(3-(4-(trifluoromethylphenyl)aminopyrazin-2-yl)-1,2,4-oxadiazol-5(4H)one
在冰浴条件下，将CDI(1.1g,7.3mmol)加入N-羟基-3-((4-(三氟甲基)苯基)氨基)吡嗪-2-甲脒(1.8g,6.1mmol,)的THF(20mL)的溶液中，在室温下搅拌30分钟在冰浴条件下滴入DBU(1.3g,9.1mmol)。将反应混合物在冰浴条件下搅拌1小时，加入HCl水溶液将pH调至2(2mL)，用EA(20mL)萃取。将有机相用饱和食盐水洗涤(10mL×3)，用无水Na2SO4干燥后浓缩，并将所得残余物通过制备高效液相色谱纯化，得到化合物3-(3-(4-(三氟甲基苯基)氨基吡嗪-2-基)-1,2,4-噁二唑-5(4H)酮(458mg，1.4mmol，23.2％)。MS(ESI)：m/z＝323[M+H]+。1H NMR(DMSO-d6,400MHz)δ13.40(br s,1H),9.20(s,1H),8.49(d,1H,J＝2.5Hz),8.31(d,1H,J＝2.3Hz),7.90(d,1H,J＝8.5Hz),7.70(d,1H,J＝8.5Hz)。Under ice bath conditions, CDI (1.1g, 7.3mmol) was added to N-hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazine-2-carboxamidine (1.8g, 6.1mmol ,) in THF (20 mL), stirred at room temperature for 30 minutes and added DBU (1.3 g, 9.1 mmol) dropwise under ice-cooling conditions. The reaction mixture was stirred under ice bath for 1 h, the pH was adjusted to 2 (2 mL) by adding aqueous HCl, and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 and concentrated, and the resulting residue was purified by preparative high performance liquid chromatography to obtain compound 3-(3-(4-(tri Fluoromethylphenyl)aminopyrazin-2-yl)-1,2,4-oxadiazol-5(4H)one (458 mg, 1.4 mmol, 23.2%). MS (ESI): m/z=323 [M+H] + .1 H NMR (DMSO-d 6 , 400MHz) δ13.40(br s, 1H), 9.20(s, 1H), 8.49(d, 1H, J=2.5Hz), 8.31(d , 1H, J = 2.3Hz), 7.90 (d, 1H, J = 8.5Hz), 7.70 (d, 1H, J = 8.5Hz).
本发明的其他化合物可以通过与以上实施例所述的方法类似的方法(必要时，进行适当的修改)制备。Other compounds of the present invention can be prepared by methods similar to those described in the examples above (with appropriate modifications, if necessary).
生物学评价biological evaluation
测试例1.TEAD报告基因实验-HEK293TTest example 1. TEAD reporter gene experiment-HEK293T
细胞：用8X GTIIC荧光素酶报告基因稳定转染的HEK293T细胞。Cells: HEK293T cells stably transfected with 8X GTIIC luciferase reporter gene.
细胞培养：所有的细胞均按照ATCC建议的指南进行培养。Cell Culture: All cells were cultured according to ATCC recommended guidelines.
细胞接种：除去所有培养基后，用PBS轻轻冲洗细胞，然后加入TrypLE，在室温下孵育一分钟，加入培养基并将细胞轻轻重悬于培养基中，直至团块完全消失。将细胞离心，用PBS冲洗两次，除去PBS后用培养基将细胞稀释，以10000个细胞/孔的密度接种到384孔板中。将细胞在培养箱(37℃，5％CO2)中孵育。Cell Seeding: After removing all medium, gently rinse cells with PBS, then add TrypLE, incubate at room temperature for one minute, add medium and gently resuspend cells in medium until clumps completely disappear. The cells were centrifuged, washed twice with PBS, diluted with culture medium after removing the PBS, and seeded into a 384-well plate at a density of 10,000 cells/well. Cells were incubated in an incubator (37°C, 5% CO 2 ).
化合物处理：以30μM为起始浓度，以1:3的稀释度，一式三份10个点，通过Echo加入384孔板中。将板置于培养箱(37℃，5％CO2)中孵育24小时。Compound treatment: starting at 30 μM, at a dilution of 1:3, 10 points in triplicate, added to a 384-well plate via Echo. Plates were incubated in an incubator (37°C, 5% CO 2 ) for 24 hours.
检测：每孔加入25μl荧光素酶检测试剂，通过Envision酶标仪检测发光值。Detection: add 25 μl of luciferase detection reagent to each well, and detect the luminescence value with an Envision microplate reader.
结果如下表1所示，且化合物的HEK293IC50值等级如下：The results are shown in Table 1 below, and the HEK293 IC50 values of the compounds were ranked as follows:
A：IC50≤100nMA: IC50≤100nM
B：100nM<IC50≤300n MB: 100nM<IC 50 ≤300nM
C：300nM<IC50≤3μMC: 300nM<IC 50 ≤3μM
D：IC50>3μMD: IC50 >3μM
表1

Table 1

实验结果显示，本申请的化合物具有TEAD抑制活性，大部分化合物的TEAD抑制活性IC50值小于3μM；很多化合物的IC50值小于300nM；甚至还有不少化合物的IC50值小于100nM。The experimental results show that the compounds of the present application have TEAD inhibitory activity, and the IC 50 values of most of the compounds are less than 3 μM; the IC 50 values of many compounds are less than 300 nM; and even the IC 50 values of many compounds are less than 100 nM.
测试例2.TEAD报告基因实验-MCF7Test example 2. TEAD reporter gene experiment-MCF7
细胞：Hippo Pathway/TEAD Luciferase Reporter MCF7细胞(BPS Bioscience，60618)。Cells: Hippo Pathway/TEAD Luciferase Reporter MCF7 cells (BPS Bioscience, 60618).
1.实验前，将生长培养基(BPS Bioscience，79531)在37℃水浴中预热。1. Before the experiment, preheat the growth medium (BPS Bioscience, 79531) in a 37°C water bath.
2.MCF7细胞(BPS Bioscience，60618)从37℃恒温培养箱中取出，PBS洗涤一次。2. MCF7 cells (BPS Bioscience, 60618) were taken out from the incubator at 37°C and washed once with PBS.
3.将2mL胰蛋白酶加入T75细胞培养瓶中，在37℃ CO2培养箱中消化3分钟。3. Add 2 mL of trypsin into a T75 cell culture flask and digest in a 37°C CO 2 incubator for 3 minutes.
加入4.5mL培养基终止消化，收集细胞于50mL离心管中，1000rpm离心5min，弃上清，用10mL新鲜培养基重悬细胞。 Add 4.5mL medium to stop the digestion, collect the cells in a 50mL centrifuge tube, centrifuge at 1000rpm for 5min, discard the supernatant, and resuspend the cells with 10mL fresh medium.
5.将30μL细胞悬液与30μL台盼蓝混合，用细胞计数器计数。5. Mix 30 μL of cell suspension with 30 μL of trypan blue and count with a cell counter.
6.将细胞密度调整为2.5x 105/mL，每孔40μL细胞接种到白色透明底384微孔板(Corning，3765)中。6. The cell density was adjusted to 2.5 x 10 5 /mL, and 40 μL of cells per well were seeded into a white transparent bottom 384 microwell plate (Corning, 3765).
7.将细胞在37℃，CO2培养箱中孵育过夜。7. Incubate the cells overnight in a 37°C, CO2 incubator.
8.使用Ehco650加入40nL化合物到384微孔板中。DMSO在测定培养基中的最终浓度为0.1％。8. Add 40 nL of compound to 384 microwell plate using Ehco650. The final concentration of DMSO in the assay medium was 0.1%.
9.在37℃，CO2培养箱中培养细胞24小时。9. Incubate the cells in a 37°C, CO2 incubator for 24 hours.
10.每孔加入20μL ONE-StepTMLuciferase Assay System(BPS，60690)试剂，室温稳定5分钟。使用EnVision Xcite Multilabel Reader(PerkinElmer，2105-0020)测量发光值。10. Add 20 μL of ONE-Step TM Luciferase Assay System (BPS, 60690) reagent to each well, and stabilize at room temperature for 5 minutes. Luminescence values were measured using EnVision Xcite Multilabel Reader (PerkinElmer, 2105-0020).
11.数据处理：11. Data processing:
％Inhibition＝100(Signalcompound-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)*100%Inhibition=100(Signalcompound-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)*100
IC50(nM)计算：curve fit(Prism 9,non-liner inhibitor,4parameter)IC 50 (nM) calculation: curve fit(Prism 9, non-liner inhibitor, 4parameter)
结果如下表2所示，且化合物的MCF7IC50值等级如下：The results are shown in Table 2 below, and the MCF7IC50 values of the compounds were ranked as follows:
A：IC50≤30nMA: IC 50 ≤30nM
B：30nM<IC50≤100nMB: 30nM<IC 50 ≤100nM
C：100nM<IC50≤300nMC: 100nM<IC 50 ≤300nM
D：IC50>300nMD: IC50 >300nM
表2

Table 2

实验结果显示，本申请的化合物具有抑制TEAD报告基因活性。大部分化合物IC50值小于300nM；很多化合物的IC50值满足30nM<IC50≤100nM；还有不少化合物的IC50值小于30nM。Experimental results show that the compound of the present application can inhibit the activity of TEAD reporter gene. The IC 50 values of most compounds are less than 300nM; the IC 50 values of many compounds satisfy 30nM<IC 50 ≤100nM; and the IC 50 values of many compounds are less than 30nM.
测试例3.化学发光法检测TEAD抑制剂对NCI-H226，NCI-H2452细胞活力的影响Test case 3. Effect of TEAD inhibitors on the viability of NCI-H226 and NCI-H2452 cells detected by chemiluminescence
1.实验前准备：康宁孔黑色透明底细胞板，Corning公司，货号：#3603；检测试剂盒：Promega公司，货号：G7570；型号酶标仪1. Preparation before experiment: Corning Well black transparent bottom cell plate, Corning Company, Cat. No.: #3603; Detection kit: Promega Company, article number: G7570; Model microplate reader
2.NCI-H226细胞培养：来源于ATCC货号:CRL-5826的NCI-H226培养于89％RPMI-1640+10％FBS+1％双抗，置于含5％CO2的37℃恒温培养箱。2. NCI-H226 cell culture: NCI-H226 derived from ATCC article number: CRL-5826 was cultured in 89% RPMI-1640+10% FBS+1% double antibody, placed in a 37°C constant temperature incubator containing 5% CO 2 .
NCI-H2452细胞培养：来源于ATCC货号:CRL-5946，培养方法同NCI-H226NCI-H2452 cell culture: derived from ATCC product number: CRL-5946, the culture method is the same as NCI-H226
第一天：待细胞汇合率达90％，吸走培养基，加入3mLPBS洗净残余培养基，加入1mL Trypsin置于培养箱孵育5min。大部分细胞脱落后，加入2mL培养基中止消化。将细胞浓度稀释到5X103个/mL，在康宁孔黑色透明底细胞板，铺500个细胞/孔，即每孔加入100μL。Day 1: When the cell confluency rate reaches 90%, remove the medium, add 3mL PBS to wash the residual medium, add 1mL Trypsin and incubate in the incubator for 5min. After most of the cells are detached, add 2 mL of culture medium to stop the digestion. Dilute the cell concentration to 5X10 cells /mL in Corning Well black transparent bottom cell plate, plate 500 cells/well, that is, add 100 μL to each well.
3.第二天给药：取出10mM的TEAD抑制剂储存液室温解冻，配置以下浓度的工作液：0.0015μM，0.0046μM，0.0137μM，0.0412μM，0.1235μM，0.3704μM，1.1111μM，3.3333μM，10μM。0.6mL完全培养基+1.2μL 10mM的储存液,配置成20μM的工作液；取0.2mL上述药液加到0.4mL完全培养基，配置成6.6666μM的工作液，依此3倍梯度稀释配置其他浓度。在已铺细胞的96孔板中加100μL工作液。3. Dosing on the next day: Take out the 10mM TEAD inhibitor stock solution and thaw it at room temperature, and prepare the following working solutions: 10 μM. 0.6mL of complete medium + 1.2μL of 10mM stock solution to make a 20μM working solution; add 0.2mL of the above drug solution to 0.4mL of complete medium to make a 6.6666μM working solution, and then 3-fold serial dilution to prepare other concentration. Add 100 μL of working solution to the 96-well plate where the cells have been plated.
4.加药后第3天更换新鲜的药液。4. Replace the fresh drug solution on the 3rd day after adding the drug.
5.给药第6天用试剂盒检测。在酶标仪上选择CellTiter-Glo的检测程序，读取发光值。5. Use on the 6th day of administration Kit testing. Select the detection program of CellTiter-Glo on the microplate reader, and read the luminescence value.
6.数据处理：细胞活力值＝100*(加药孔发光值-空白空发光值)/(溶剂孔发光值-空白空发光值)，IC50计算：将细胞活力值和对应的药物浓度值使用Prism 8软件Curve fit中的(log(inhibitor)vs.normalized  response--Variable slope算法计算。6. Data processing: cell viability value = 100*(luminescence value of drug-dosing well-luminescence value of blank space)/(luminescence value of solvent well-luminescence value of blank space), IC50 calculation: cell viability value and corresponding drug concentration value Use (log(inhibitor)vs.normalized in Curve fit in Prism 8 software response--Variable slope algorithm calculation.
选择性结果如下表3所示，且化合物的H226IC50值等级为：A：IC50≤300nM；B：300nM<IC50≤1000nM；C：IC50>1000nM；且化合物的H2452IC50值等级为：A：IC50≤1μM；B：1μM<IC50≤10μM；C：IC50>10μM。The selectivity results are shown in Table 3 below, and the H226 IC 50 value ranks of the compounds are: A: IC 50 ≤300nM; B: 300nM<IC 50 ≤1000nM; C: IC 50 >1000nM; and the H2452IC 50 value ranks of the compounds are: A: IC 50 ≤1 μM; B: 1 μM<IC 50 ≤10 μM; C: IC 50 >10 μM.
表3
table 3
实验结果显示，本申请的化合物能够有效抑制靶点敏感肿瘤细胞H226的增殖，但却不抑制靶点不敏感肿瘤细胞H2452的增殖，可见，本申请化合物具有良好的靶点选择性。然而，对照化合物却几乎没有选择性(对照化合物为WO2021018869A1中的化合物)。The experimental results show that the compound of the present application can effectively inhibit the proliferation of the target-sensitive tumor cell H226, but does not inhibit the proliferation of the target-insensitive tumor cell H2452. It can be seen that the compound of the present application has good target selectivity. However, the control compound has almost no selectivity (the control compound is the compound in WO2021018869A1 ).
测试例4.实时荧光定量核酸扩增检测系统(qPCR)检测TEAD抑制剂对NCI-H226细胞YAP/TEAD转录活性的影响Test Example 4. Real-time fluorescence quantitative nucleic acid amplification detection system (qPCR) detects the effect of TEAD inhibitors on NCI-H226 cell YAP/TEAD transcriptional activity
1.试剂及细胞1. Reagents and cells
NCI-H226细胞培养：来源于ATCC货号:CRL-5826的NCI-H226培养于89％RPMI-1640+10％FBS+1％双抗，置于含5％CO2的37℃恒温培养箱。RNA提取试剂盒(天根，DP430，常温放置)。SYBR染料(康为世纪,CW0957M，-20℃放置)。NCI-H226 cell culture: NCI-H226 derived from ATCC article number: CRL-5826 was cultured in 89% RPMI-1640+10% FBS+1% double antibody, and placed in a 37°C constant temperature incubator containing 5% CO 2 . RNA extraction kit (Tiangen, DP430, placed at room temperature). SYBR dye (Kangwei Century, CW0957M, placed at -20°C).
2.RNA提取操作步骤2. RNA extraction steps
2.1细胞在0.5μM或1μM药物处理24h后，收集细胞(细胞量不要超过1×107)，吸除细胞培养基上清，PBS洗一次，吸除PBS，立即进行第二步裂解步骤。2.1 After the cells were treated with 0.5 μM or 1 μM drug for 24 hours, the cells were collected (the cell volume should not exceed 1×10 7 ), the supernatant of the cell culture medium was aspirated, washed once with PBS, the PBS was aspirated, and the second lysis step was performed immediately.
2.2裂解细胞2.2 Cell Lysis
配裂解液：在RL中加入β-巯基乙醇至终浓度为1％，如1mL RL中加入10μLβ-巯基乙醇；裂解：加入适量裂解液RL，将细胞裂解液转移至离心管中，涡旋震荡混匀，条件参见表4。Prepare lysate: add β-mercaptoethanol to RL to a final concentration of 1%, for example, add 10 μL β-mercaptoethanol to 1 mL RL; lyse: add an appropriate amount of lysate RL, transfer the cell lysate to a centrifuge tube, and vortex Mix well, see Table 4 for conditions.
表4
Table 4
2.3将所有溶液转移至过滤柱CS上(过滤柱CS放在收集管中)，12000rpm(～13400×g)离心2min，收集滤液。2.3 Transfer all the solutions to the filter column CS (the filter column CS is placed in a collection tube), centrifuge at 12000 rpm (~13400×g) for 2 minutes, and collect the filtrate.
2.4向滤液中加入1倍体积70％乙醇(通常为350μL或600μL)，混匀，得到的溶液和沉淀一起转入吸附柱CR3中，12000rpm(～13400×g)离心30-60sec，倒掉收集管中的废液，将吸附柱CR3放回收集管中。2.4 Add 1 volume of 70% ethanol (usually 350 μL or 600 μL) to the filtrate, mix well, transfer the obtained solution and the precipitate into the adsorption column CR3, centrifuge at 12000 rpm (~13400 × g) for 30-60 sec, pour it out and collect For the waste liquid in the tube, put the adsorption column CR3 back into the collection tube.
2.5向吸附柱CR3中加入350μL去蛋白液RW1，12000rpm(13400×g)离心30-60sec，倒掉收集管中的废液，将吸附柱CR3放回收集管中。2.5 Add 350 μL protein-removing solution RW1 to the adsorption column CR3, centrifuge at 12000 rpm (13400×g) for 30-60 sec, discard the waste liquid in the collection tube, and put the adsorption column CR3 back into the collection tube.
2.6 DNase I工作液的配制：取10μL DNase I储存液放入新的RNase-Free离心管中，加入70μL RDD缓冲液，轻柔混匀。2.6 Preparation of DNase I working solution: Take 10 μL DNase I storage solution into a new RNase-Free centrifuge tube, add 70 μL RDD buffer, and mix gently.
2.7向吸附柱CR3中央加入80μL的DNase I工作液，室温放置15min。2.7 Add 80 μL of DNase I working solution to the center of the adsorption column CR3, and let it stand at room temperature for 15 minutes.
2.8向吸附柱CR3中加入350μL去蛋白液RW1，12000rpm(～13400×g)离心30-60sec，倒掉收集管中的废液，将吸附柱CR3放回收集管中。2.8 Add 350 μL protein-removing solution RW1 to the adsorption column CR3, centrifuge at 12000 rpm (~13400×g) for 30-60 sec, pour off the waste liquid in the collection tube, and put the adsorption column CR3 back into the collection tube.
2.9向吸附柱CR3中加入500μL漂洗液RW，室温静置2min，12000rpm(～13400×g)离心30-60sec，倒掉收集管中的废液，将吸附柱CR3放回收集管中。2.9 Add 500 μL of rinse solution RW to the adsorption column CR3, let it stand at room temperature for 2 minutes, centrifuge at 12000 rpm (~13400×g) for 30-60 sec, discard the waste liquid in the collection tube, and put the adsorption column CR3 back into the collection tube.
2.10重复步骤9。2.10 Repeat step 9.
2.11 12000rpm(～13400×g)离心2min，倒掉废液。将吸附柱CR3置于室温放置3-5分钟，以彻底晾干吸附材料中残余的漂洗液。2.11 Centrifuge at 12000rpm (~13400×g) for 2min, and discard the waste liquid. Place the adsorption column CR3 at room temperature for 3-5 minutes to completely dry the residual rinse solution in the adsorption material.
2.12将吸附柱CR3转入一个新的RNase-Free离心管中，加入30-100μL RNase-Free ddH2O室温放置2min，12000rpm(～13400×g)离心2min，得到RNA溶液。2.12 Transfer the adsorption column CR3 into a new RNase-Free centrifuge tube, add 30-100 μL RNase-Free ddH2O and leave it at room temperature for 2 minutes, then centrifuge at 12000 rpm (~13400 × g) for 2 minutes to obtain the RNA solution.
2.13用Nanodrop检测所提RNA的浓度。2.13 Use Nanodrop to detect the concentration of the extracted RNA.
3反转录操作步骤3 reverse transcription steps
3.1将准备反转录的RNA样品和反转录的试剂盒(thermo，4368814，-20℃放置)的试剂放在冰上完全溶解。3.1 Put the RNA sample prepared for reverse transcription and the reagents of the reverse transcription kit (thermo, 4368814, placed at -20°C) on ice to dissolve completely.
3.2按照试剂盒说明书配置2×RT master mix3.2 Configure 2×RT master mix according to the kit instructions
3.3将配好的2×RT mastermix轻弹管底混合均匀，用掌上离心机轻甩一下，置于冰上备用。 3.3 Mix the prepared 2×RT mastermix by flicking the bottom of the tube evenly, shake it with a hand centrifuge, and put it on ice for later use.
3.4先根据提取的RNA浓度计算出每个样品吸取500ng RNA所需要的的体积，然后按照10μL体系计算出需要补齐的RNase-free H2O的体积。将RNase的PCR8联管做好编号，先对应编号加入RNase-free H2O，再加入对应体积的500ngRNA，吹打数次混匀后，加入10uL的2×RT master mix，轻弹管底混合均匀，用掌上离心机轻甩一下，置于冰上。3.4 First calculate the volume required to absorb 500ng RNA for each sample based on the extracted RNA concentration, and then calculate the volume of RNase-free H 2 O that needs to be supplemented according to the 10 μL system. Number the PCR8 tubes of RNase, first add RNase-free H2O corresponding to the number, then add the corresponding volume of 500ngRNA, mix well by pipetting several times, add 10uL of 2×RT master mix, flick the bottom of the tube to mix evenly, and use Centrifuge briefly and place on ice.
3.5将PCR管放入PCR仪器中，拧好盖子按下面条件设置PCR程序，反应体积是20ul。3.5 Put the PCR tube into the PCR instrument, tighten the cap and set the PCR program according to the following conditions, the reaction volume is 20ul.
3.6将反转完的cDNA放-20℃保存备用。3.6 Store the reversed cDNA at -20°C for later use.
4 qPCR操作步骤4 qPCR operation steps
4.1将所检测基因36B4，CTGF和CYR61的正反向引物，样品cDNA和SYBR green放在冰上完全溶解，混合均匀。4.1 Dissolve the forward and reverse primers of the detected genes 36B4, CTGF and CYR61, sample cDNA and SYBR green on ice completely, and mix well.
4.2稀释引物4.2 Dilution of primers
将合成的forward primer和reverse primer按照管上体积用ddH2O溶解混匀(一般浓度为100μM)。分别取2.5μL100uM的引物stock，加到装有47.5μLddH2O的EP管中，便稀释成5μM。然后将5μM的forward primer和reverse primer等体积混合成2.5μM的F/Rprimer混合液。The synthesized forward primer and reverse primer were dissolved and mixed with ddH 2 O according to the volume on the tube (the general concentration was 100 μM). Take 2.5 μL of 100uM primer stock and add it to an EP tube filled with 47.5 μL ddH 2 O to dilute to 5 μM. Then mix equal volumes of 5 μM forward primer and reverse primer to form 2.5 μM F/Rprimer mixture.
4.3稀释cDNA4.3 Dilution of cDNA
反转录后的cDNA在冰上完全溶解后，混合均匀，根据每次实验，384QPCR板中每孔加入4μL cDNA，做3个重复，计算好所需样本体积，取出PCR8连管，将cDNA用ddH2O稀释20倍，轻弹管底混合均匀，在掌上离心机上甩一下，置于冰上备用。After the reverse-transcribed cDNA is completely dissolved on ice, mix it evenly. According to each experiment, add 4 μL cDNA to each well of the 384QPCR plate, do 3 repetitions, calculate the required sample volume, take out the PCR8 tube, and use the cDNA Dilute 20 times with ddH 2 O, flick the bottom of the tube to mix evenly, shake it on a hand centrifuge, and put it on ice for later use.
4.4在1.5mL离心管中配好SYBR和引物的混合液，轻弹管底混合均匀，在掌上离心机上甩一下，置于冰上备用。4.4 Prepare the mixture of SYBR and primers in a 1.5mL centrifuge tube, flick the bottom of the tube to mix evenly, shake it in a hand-held centrifuge, and put it on ice for later use.
4.5加样，加完所有孔后用排枪吸入6μL对应基因的SYBR和2.5μM的F/Rprimer混合液，加完后贴上封板膜，并四边压紧，在上机前先用离心机离心5min，保证液体都在板底。设置QPCR反应程序，康为世纪SYBR染料预变性反应必须在95℃10min下完成，反应体系20ul，40个循环。保存好数据进行分析。4.5 Add samples. After adding all the wells, inhale 6 μL of the corresponding gene SYBR and 2.5 μM F/Rprimer mixture with a row gun. After adding, paste the sealing film and press it tightly on the four sides. Centrifuge in a centrifuge before loading 5min, to ensure that the liquid is at the bottom of the plate. To set up the QPCR reaction program, the Kangwei Century SYBR dye pre-denaturation reaction must be completed at 95°C for 10 minutes, the reaction system is 20ul, and 40 cycles. Save the data for analysis.
实验结果显示，本申请化合物对NCI-H226细胞YAP/TEAD转录活性具有明显的抑制作用。The experimental results show that the compound of the present application has obvious inhibitory effect on the YAP/TEAD transcriptional activity of NCI-H226 cells.
测试例5.体内PK试验Test Example 5. In Vivo PK Test
1.实验动物1. Experimental animals
SD大鼠/ICR小鼠(雄性/雌性)6只，分为口服和静脉给药两组，每组各3只。给药前禁食10-14小时，自由饮水。Six SD rats/ICR mice (male/female) were divided into two groups of oral administration and intravenous administration, 3 in each group. Fast for 10-14 hours before administration, and drink water freely.
2.配制给药制剂2. Preparation of drug preparations
根据给药剂量称量待测化合物，以溶媒(常用5％DMSO+10％Solutol+85％生理盐水)配制成适量浓度的给药制剂(大、小鼠静脉和口服给药分别按5mL/kg和10mL/kg的体积给药)，静脉注射剂为澄清溶液，口服剂为澄清溶液或均一的混悬液。Weigh the compound to be tested according to the dosage, and prepare the drug preparation of appropriate concentration (vein and oral administration respectively by 5mL/kg) and 10mL/kg volume administration), the intravenous injection is a clear solution, and the oral dose is a clear solution or a homogeneous suspension.
3.动物给药及血样采集3. Animal administration and blood sample collection
通过静脉注射和口服灌胃进行动物给药，并于静脉注射给药后0.033h、0.083h、0.25h、0.5h、1h、2h、4h、8h和24h及口服给药后0.083h、0.25h、0.5h、1h、2h、4h、6h、8h和24h采集血样。全血4℃，6800g离心6min，取上层血浆保存于-80℃冰箱待分析。Animal administration by intravenous injection and oral gavage, and at 0.033h, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after intravenous administration and 0.083h, 0.25h after oral administration , 0.5h, 1h, 2h, 4h, 6h, 8h and 24h to collect blood samples. Whole blood was centrifuged at 6800g for 6min at 4°C, and the upper layer of plasma was collected and stored in a -80°C refrigerator for analysis.
4.血浆样本检测4. Plasma sample detection
取待测物DMSO储备液以甲醇或乙腈溶液稀释成系列工作溶液，加入空白血浆基质中，配制标准曲线及质控样品。取血浆样本适量体积，根据响应加入适量倍数含内标的甲醇或者乙腈进行蛋白沉淀。将所有样本4℃，18000g离心10min后，取上清适量待LC-MS/MS进样分析。The DMSO stock solution of the analyte was diluted with methanol or acetonitrile solution to form a series of working solutions, which were added to the blank plasma matrix to prepare the standard curve and quality control samples. Take an appropriate volume of plasma sample, and add appropriate multiples of methanol or acetonitrile containing internal standard according to the response for protein precipitation. After all the samples were centrifuged at 18,000 g for 10 min at 4°C, an appropriate amount of supernatant was taken for analysis by LC-MS/MS.
5.参数计算5. Parameter calculation
根据测试浓度绘制血药浓度-时间曲线，通过WinNonlin软件，按非房室模型计算，包括：半衰期(T1/2)、药时曲线下面积(AUC0-t)、清除率(CL)、稳态分布容积(Vss)、生物利用度(F)等药代动力学参数。结果参见表5。Draw the blood drug concentration-time curve according to the test concentration, and calculate it according to the non-compartmental model through WinNonlin software, including: half-life (T1/2), area under the drug-time curve (AUC0-t), clearance rate (CL), steady state Pharmacokinetic parameters such as volume of distribution (Vss) and bioavailability (F). See Table 5 for the results.
表5

table 5

实验结果显示，本申请的化合物具有优良的药代动力学性质Experimental results show that the compound of the present application has excellent pharmacokinetic properties
测试例6.NCI-H226裸鼠移植瘤模型检测TEAD抑制剂体内抑制YAP/TEAD转录活性Test example 6. NCI-H226 nude mouse xenograft tumor model detection of TEAD inhibitor inhibiting YAP/TEAD transcriptional activity in vivo
1.NCI-H226 CDX裸鼠模型的建立1. Establishment of NCI-H226 CDX nude mouse model
来源于ATCC货号:CRL-5826的NCI-H226培养于89％RPMI-1640+10％FBS+1％青-链霉素，置于含5％CO2的37℃恒温培养箱。在15cm培养皿，待细胞汇合率达90％，吸走培养基，加入5mL PBS洗净残余培养基，加入3mL Trypsin置于培养箱孵育5min。大部分细胞脱落后，加入6mL培养基中止消化。收集NCI-H226细胞，用50mL PBS洗2遍，将浓度用PBS稀释到2*108个/mL，加入1倍体积的Matrigel(Corning)混匀。在裸鼠的右前腋窝皮下注射100μL细胞悬液，即1*107个细胞。NCI-H226 derived from ATCC product number: CRL-5826 was cultured in 89% RPMI-1640+10% FBS+1% penicillin-streptomycin, and placed in a 37°C constant temperature incubator containing 5% CO 2 . In a 15 cm culture dish, when the cell confluency reaches 90%, the culture medium is aspirated, 5 mL of PBS is added to wash the remaining culture medium, and 3 mL of Trypsin is added to incubate in an incubator for 5 min. After most of the cells were detached, 6 mL of culture medium was added to stop the digestion. Collect NCI-H226 cells, wash them twice with 50 mL PBS, dilute the concentration to 2*10 8 cells/mL with PBS, add 1 volume of Matrigel (Corning) and mix well. Inject 100 μL of cell suspension subcutaneously in the right anterior axilla of nude mice, that is, 1*10 7 cells.
2.给药2. Administration
药物配置：溶剂：8.5mL生理盐水+1mL Solutol，药物用DMSO溶解成20mg/mL储存。药物工作液：35μL药物储存液加入665μL溶剂，即配成10mg/kg的TEAD抑制剂。Drug configuration: Solvent: 8.5mL normal saline + 1mL Solutol, the drug is dissolved in DMSO to 20mg/mL for storage. Drug working solution: Add 665 μL solvent to 35 μL drug storage solution to prepare 10 mg/kg TEAD inhibitor.
待移植瘤体积达100mm3，给予灌胃10mg/kg的TEAD抑制剂和对应的溶剂，每天给药一次，连续3天，第四天上午取出移植瘤，液氮速冻。When the volume of the transplanted tumor reached 100 mm 3 , 10 mg/kg of TEAD inhibitor and the corresponding solvent were given by intragastric administration once a day for 3 consecutive days. The transplanted tumor was taken out in the morning of the fourth day and quickly frozen in liquid nitrogen.
3.移植瘤总RNA提取3. Extraction of total RNA from transplanted tumors
3.1将组织研磨仪的模块，盖子，研磨管标记好先放-80冰箱预冷，用前将模块放液氮浸泡一下。将液氮速冻后的肿瘤组织放研磨仪中，60HZ,运行30s,中断30s，运行5次，每次都取出放液氮中浸泡30s确保低温；3.1 Mark the module, cover, and grinding tube of the tissue grinder and put it in a -80 refrigerator for pre-cooling, and soak the module in liquid nitrogen before use. Put the liquid nitrogen quick-frozen tumor tissue into the grinder, 60HZ, run for 30s, stop for 30s, run 5 times, take out each time and soak in liquid nitrogen for 30s to ensure low temperature;
3.2研磨完后放冰上，每管加入600μL裂解液(thermos,purelinkmini kit,12183025)，震荡溶解，放冰上静置5min，将上清转移到无酶EP管中，4℃12000rpm离心10min，转移上清至新的无酶EP管中，加入等体积的70％乙醇，votex震荡混匀。3.2 After grinding, put it on ice, add 600 μL lysate (thermos, purelink) to each tube mini kit, 12183025), shake to dissolve, put it on ice for 5min, transfer the supernatant to an enzyme-free EP tube, centrifuge at 12000rpm at 4°C for 10min, transfer the supernatant to a new enzyme-free EP tube, add an equal volume of 70 % ethanol, Votex shake and mix.
3.3将混匀的液体转移到吸附柱，室温条件下12000rpm离心1min，倒掉废液，最多可转移700ul，剩下的液体可重复加入离心。3.3 Transfer the mixed liquid to the adsorption column, centrifuge at 12,000 rpm for 1 min at room temperature, discard the waste liquid, transfer up to 700ul, and add the remaining liquid to the centrifuge again.
3.4在吸附柱中加入350μL wash buffer I，室温条件下12000rpm离心1min，倒掉废液。3.4 Add 350μL wash buffer I to the adsorption column, centrifuge at 12000rpm for 1min at room temperature, and discard the waste liquid.
3.5 DNase I消化：取10μL DNase I储存液放入新的RNase-Free离心管中，加入70μL RDD缓冲液，轻柔混匀。每个样品向吸附柱中央加入80μL的DNase I工作液，室温放置15min。3.5 DNase I digestion: Take 10 μL DNase I storage solution into a new RNase-Free centrifuge tube, add 70 μL RDD buffer, and mix gently. Add 80 μL of DNase I working solution to the center of the adsorption column for each sample, and place at room temperature for 15 min.
3.6消化后在吸附柱中加入350μL wash buffer I，室温条件下12000rpm离心1min，倒掉废液。3.6 After digestion, add 350 μL wash buffer I to the adsorption column, centrifuge at 12000 rpm for 1 min at room temperature, and discard the waste liquid.
3.7在吸附柱中加入500μL wash bufferⅡ，室温条件下12000rpm离心1min，倒掉废液。并重复一次。3.7 Add 500 μL wash buffer II to the adsorption column, centrifuge at 12000 rpm for 1 min at room temperature, and discard the waste liquid. and repeat.
3.8将吸附柱放入离心机，室温条件下12000rpm离心2min，将吸附柱置于室温放置5min，以彻底晾干吸附材料中残余的漂洗液3.8 Put the adsorption column into the centrifuge, centrifuge at 12,000 rpm for 2 minutes at room temperature, and place the adsorption column at room temperature for 5 minutes to completely dry the residual rinse solution in the adsorption material
3.9将吸附柱转入一个新的RNase-Free离心管中，加入30-100μL RNase-Free ddH2O室温放置2min，12000rpm(～13400×g)离心2min，得到RNA溶液。3.9 Transfer the adsorption column to a new RNase-Free centrifuge tube, add 30-100 μL RNase-Free ddH2O and place at room temperature for 2 minutes, then centrifuge at 12000 rpm (~13400 × g) for 2 minutes to obtain the RNA solution.
3.10用Nanodrop检测所提RNA的浓度。3.10 Use Nanodrop to detect the concentration of the extracted RNA.
4.反转录及QPCR步骤与测试例4的步骤4qPCR操作一致。4. The steps of reverse transcription and qPCR are the same as step 4 qPCR of test example 4.
实验结果显示，本申请化合物在NCI-H226裸鼠移植瘤模型中具有良好的TEAD/YAP转录活性抑制能力。The experimental results show that the compound of the present application has a good ability to inhibit TEAD/YAP transcriptional activity in the NCI-H226 nude mouse xenograft tumor model.
测试例7.裸鼠移植瘤长期药效实验Test Example 7. Long-term Drug Effect Experiment of Transplanted Tumor in Nude Mice
1.NCI-H226细胞培养：来源于ATCC货号:CRL-5826的NCI-H226培养于89％RPMI-1640+10％FBS+1％青-链霉素，置于含5％CO2的37℃恒温培养箱。在15cm培养皿，待细胞汇合率达90％，吸走培养基，加入5mL PBS洗净残余培养基，加入3mL Trypsin置于培养箱孵育5min。大部分细胞脱落后，加入6mL培养基中止消化。收集NCI-H226细胞，用50mL PBS洗2遍，将浓度用PBS稀释到2*108个/mL，加入1倍体积的Matrigel(Corning)混匀。在裸鼠的右前腋窝皮下注射100uL细胞悬液，即1*107个细胞。1. NCI-H226 cell culture: NCI-H226 derived from ATCC product number: CRL-5826 was cultured in 89% RPMI-1640+10% FBS+1% penicillin-streptomycin, placed at 37°C containing 5% CO 2 Constant temperature incubator. In a 15 cm culture dish, when the cell confluency reaches 90%, the culture medium is aspirated, 5 mL of PBS is added to wash the remaining culture medium, and 3 mL of Trypsin is added to incubate in an incubator for 5 min. After most of the cells were detached, 6 mL of culture medium was added to stop the digestion. Collect NCI-H226 cells, wash them twice with 50 mL PBS, dilute the concentration to 2*10 8 cells/mL with PBS, add 1 volume of Matrigel (Corning) and mix well. 100uL of cell suspension, that is, 1*10 7 cells, was subcutaneously injected into the right anterior axilla of nude mice.
2.约一个半月后，待移植瘤长至100mm3左右，分5只/组药物，记录体重、移植瘤长和宽。药物配置：85％生理盐水+10％Solutol+5％DMSO溶解的药物储存液，每只裸鼠每天灌胃200μL。每周记录体重、移植瘤长和宽。 2. About one and a half months later, when the transplanted tumor grows to about 100mm3, divide 5 mice into each group and record the body weight, length and width of the transplanted tumor. Drug configuration: 85% normal saline + 10% Solutol + 5% DMSO dissolved drug storage solution, each nude mouse was gavaged with 200 μL per day. Body weight, length and width of transplanted tumors were recorded weekly.
3.待移植瘤长至合适大小，4％水合氯醛麻醉裸鼠，心脏取血。CO2处死裸鼠后取材：移植瘤，肺，心，肾，胰腺，脾，胃，肝，十二指肠，空肠，盲肠，回肠，直肠，结肠。移植瘤液氮速冻，其余组织固定在4％多聚甲醛。3. After the transplanted tumor grows to a suitable size, nude mice are anesthetized with 4% chloral hydrate, and blood is collected from the heart. After killing nude mice with CO 2 , the following samples were collected: transplanted tumor, lung, heart, kidney, pancreas, spleen, stomach, liver, duodenum, jejunum, cecum, ileum, rectum, and colon. The transplanted tumors were quickly frozen in liquid nitrogen, and the remaining tissues were fixed in 4% paraformaldehyde.
实验结果显示，本申请化合物在NCI-H226移植瘤模型中能够有效抑制肿瘤生长。Experimental results show that the compound of the present application can effectively inhibit tumor growth in the NCI-H226 transplanted tumor model.
测试例8.TEAD抑制剂对细胞水平TEAD1/2/3/4棕榈酰化的影响Test Example 8. Effects of TEAD inhibitors on TEAD1/2/3/4 palmitoylation at the cellular level
1.细胞铺板：10cm细胞培养皿293T细胞铺板(1分5)，细胞密度第二天达到40％左右；1. Cell plating: 10cm cell culture dish 293T cell plating (1 minute 5), the cell density reaches about 40% the next day;
2.细胞转染：1皿细胞不做转染，当空白对照，4皿细胞转入TEAD-myc-flag质粒(1皿转入8μg质粒)，转染步骤参照lipo2000转染protocol，转染后6小时换液；2. Cell transfection: 1 dish of cells was not transfected, and as a blank control, 4 dishes of cells were transferred into TEAD-myc-flag plasmid (1 dish was transferred with 8 μg plasmid). The transfection steps refer to lipo2000 transfection protocol. 6 hours to change the liquid;
3.酰基化反应：转染后24小时，将Palmitic Acid Alkyne(工作浓度100μM)和TEAD抑制剂加入到细胞中，过夜，试验组别设置如下：空白对照；阴性组(DMSO+TEAD+PAA-)；对照组(DMSO+TEAD+PAA+)；阳性对照(阳参药物+TEAD+PAA+)；阴性对照组(阴参药物+TEAD+PAA+)；加药组(测试药物+TEAD+PAA+)；3. Acylation reaction: 24 hours after transfection, Palmitic Acid Alkyne (working concentration 100 μM) and TEAD inhibitor were added to the cells overnight, and the test groups were set as follows: blank control; negative group (DMSO+TEAD+PAA- ); Control group (DMSO+TEAD+PAA+); Positive control (Yangshen drug+TEAD+PAA+); Negative control group (Yin ginseng drug+TEAD+PAA+); Dosing group (Test drug+TEAD+PAA+);
4.收蛋白：转染后48h裂解细胞收蛋白(1皿细胞1mL RIPA裂解液)，超声(20％功率超4s停9s，5次)，最大转速离心10min，取其中90μL做Input样品，其余进行IP。4. Harvest protein: 48 hours after transfection, lyse cells to harvest protein (1 mL RIPA lysate for 1 plate of cells), sonicate (20% power over 4 s, stop 9 s, 5 times), centrifuge at maximum speed for 10 min, take 90 μL of it as input sample, and the rest for IP.
5.IP和洗脱蛋白：利用FLAG标签抗体磁珠进行IP，孵育前磁珠用RIPA清洗，细胞裂解液用琼脂糖beads预清洗孵育常温20min，磁珠用量40μL每管(参考说明书用量)，细胞裂解液与磁珠孵育时间为常温1h(thermo Beads)或2h(碧云天Beads)。IP完后，用200μL 3xFLAG肽段(150μg/ml)4℃洗脱磁珠2h；5. IP and eluted protein: use FLAG-labeled antibody magnetic beads for IP, wash the magnetic beads with RIPA before incubation, pre-wash the cell lysate with agarose beads and incubate at room temperature for 20 minutes, the amount of magnetic beads is 40 μL per tube (refer to the amount in the manual), The incubation time of cell lysate and magnetic beads is 1h (thermo Beads) or 2h (Biyuntian Beads) at room temperature. After IP, elute the magnetic beads with 200 μL 3xFLAG peptide (150 μg/ml) at 4 °C for 2 h;
6.Click chemistry：将步骤5中IP后洗脱的蛋白样品进行第二部反应，首先调整蛋白样品SDS浓度为1％，随后加入Tris-(benzyltriazolylmethyl)amine(100μM),CuSO4(1mM),Tris-carboxyethylphosphine(1mM),和azidobiotin(100μM)。37℃反应30min，随后加入10倍体积的丙酮进行终止反应，将样品放入-20℃中1h以上沉淀蛋白，加入40μL 2x loading buffer煮样。6. Click chemistry: The protein sample eluted after IP in step 5 is subjected to the second reaction, first adjust the SDS concentration of the protein sample to 1%, then add Tris-(benzyltriazolylmethyl)amine (100μM), CuSO4 (1mM), Tris - carboxyethylphosphine (1mM), and azidobiotin (100μM). React at 37°C for 30 minutes, then add 10 times the volume of acetone to terminate the reaction, put the sample at -20°C for more than 1 hour to precipitate protein, add 40 μL 2x loading buffer to cook the sample.
7.常规WesternBlot操作流程检测样品，最后用Streptavidin-HRP进行化学发光检测棕榈酰化水平。7. The routine Western Blot operation process was used to detect the samples, and finally the palmitoylation level was detected by chemiluminescence with Streptavidin-HRP.
实验结果显示，本申请的化合物对细胞水平TEAD1/2/3/4棕榈酰化具有抑制作用。Experimental results show that the compound of the present application has an inhibitory effect on TEAD1/2/3/4 palmitoylation at the cellular level.
测试例9.免疫共沉淀(IP)检测TEAD抑制剂对YAP/TEAD4互作的影响Test Example 9. Co-immunoprecipitation (IP) detection of the effect of TEAD inhibitors on YAP/TEAD4 interaction
1.1个10cm的293T，按1/3细胞铺4块6孔板的比例铺所需数量的6孔板，第二天做转染，以配制8个孔的转染液用量为例：在800μL无血清DMEM+4ug YAP-Flag+4μg TEAD4，另一管在800μL无血清DMEM+8μL Lipo 2000。将800μL无血清DMEM+4ug YAP-Flag+4μg TEAD4，加到800μL无血清DMEM+8μL Lipo 2000，立即混合，室温放置20分钟。取200μL混合后的Cocktail加入一个孔里。1. One 10cm 293T, spread the required number of 6-well plates according to the ratio of 1/3 cells to 4 6-well plates, and transfect the next day. Take the amount of transfection solution for preparing 8 wells as an example: at 800 μL Serum-free DMEM+4ug YAP-Flag+4μg TEAD4, another tube in 800μL serum-free DMEM+8μL Lipo 2000. Add 800 μL serum-free DMEM+4ug YAP-Flag+4 μg TEAD4 to 800 μL serum-free DMEM+8 μL Lipo 2000, mix immediately, and place at room temperature for 20 minutes. Take 200μL of the mixed cocktail and add it to one well.
2.转染后24小时，试验组别设置如下：空白对照；阴性组(DMSO)；对照组(DMSO+YAP-Flag/TEAD4)；阳性对照(阳参药物+YAP-Flag/TEAD4)；阴性对照组(阴参药物+YAP-Flag/TEAD4)；加药组(测试药物+YAP-Flag/TEAD4)；2. 24 hours after transfection, the test groups were set as follows: blank control; negative group (DMSO); control group (DMSO+YAP-Flag/TEAD4); positive control (yangshen drug+YAP-Flag/TEAD4); Control group (yin ginseng drug + YAP-Flag/TEAD4); drug-dosed group (test drug + YAP-Flag/TEAD4);
3.收蛋白：加药后24h裂解细胞收蛋白(1皿细胞1ml RIPA裂解液)，超声(20％功率超4s停9s，5次)，最大转速离心10min，取其中90μl做Input样品，其余进行IP。3. Collection of protein: 24 hours after adding the drug, the cells were lysed to collect the protein (1 ml of RIPA lysate for 1 plate of cells), ultrasonic (20% power over 4 seconds, stop for 9 seconds, 5 times), centrifuge at the maximum speed for 10 minutes, take 90 μl of it as the input sample, and the rest for IP.
4.IP和洗脱蛋白：利用FLAG标签抗体磁珠进行IP，孵育前磁珠用RIPA清洗，细胞裂解液用琼脂糖beads预清洗孵育常温20min，磁珠用量40μl每管(参考说明书用量)，细胞裂解液与磁珠孵育时间为常温1h(thermo Beads)或2h(碧云天Beads)。IP完后，用200μl 3xFLAG肽段(150μg/ml)4℃洗脱磁珠2h；离心得到洗脱后的蛋白上清，进行后续的蛋白印迹实验检测TEAD4蛋白相对量。4. IP and eluted protein: use FLAG-labeled antibody magnetic beads for IP, wash the magnetic beads with RIPA before incubation, pre-wash the cell lysate with agarose beads and incubate at room temperature for 20 minutes, the amount of magnetic beads is 40 μl per tube (refer to the amount in the manual), The incubation time of cell lysate and magnetic beads is 1h (thermo Beads) or 2h (Biyuntian Beads) at room temperature. After IP, the magnetic beads were eluted with 200 μl 3xFLAG peptide (150 μg/ml) at 4°C for 2 hours; the eluted protein supernatant was obtained by centrifugation, and the relative amount of TEAD4 protein was detected by subsequent Western blot experiments.
本发明所述的所有化合物，包括本发明化合物及对照分子均以化学结构式为准。 All the compounds described in the present invention, including the compounds of the present invention and reference molecules, are based on the chemical structural formula.

Claims (34)

  1. 以下通式O所示化合物或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物：
    The compound shown in the following general formula O or the tautomer of the compound, its stereoisomer, its geometric isomer, its enantiomer, its diastereoisomer, its racemate, Its prodrugs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its hydrates, its esters, its isotopes, or its metabolites:
    其中：in:
    Ao环选自5-6元杂芳基、5-6元杂环基、苯基，且Ao环任选地被1-3个选自Rx、Ry、Rz、Rm的取代基所取代；优选地，Ao环选自5元杂芳基、5元不饱和杂环基、6元饱和杂环基、苯基、吡啶基，且Ao环任选地被1-3个选自Rx、Ry、Rz、Rm的取代基所取代；更优选地，Ao环选自5元杂芳基、5元不饱和杂环基、6元饱和杂环基、苯基、吡啶基，所述5元杂芳基包含2-4个选自N、O、S的杂原子，且Ao环任选地被1-3个选自Rx、Ry、Rz、Rm的取代基所取代；进一步优选地，Ao环选自5元杂芳基、5元不饱和杂环基、硫代吗啉基、四氢硫代吡喃基、苯基、吡啶基，所述5元杂芳基包含2-4个选自N、O、S的杂原子，且满足以下条件(1)-(3)中任意一项：The Ao ring is selected from 5-6 membered heteroaryl groups, 5-6 membered heterocyclic groups, and phenyl groups, and the Ao ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, Rm; preferably Preferably, the Ao ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, pyridyl, and the Ao ring is optionally replaced by 1-3 members selected from Rx, Ry, Substituents of Rz and Rm are substituted; more preferably, the Ao ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, pyridyl, and the 5-membered heteroaryl The group contains 2-4 heteroatoms selected from N, O, S, and the Ao ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, Rm; further preferably, the Ao ring is selected from From 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, thiomorpholinyl, tetrahydrothiopyranyl, phenyl, pyridyl, the 5-membered heteroaryl group contains 2-4 selected from N , O, S heteroatoms, and satisfy any one of the following conditions (1)-(3):
    (1)Ao环选自5元杂芳基时，所述Ao环任选地被Rx所取代，(1) When the Ao ring is selected from a 5-membered heteroaryl group, the Ao ring is optionally substituted by Rx,
    (2)Ao环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the Ao ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
    (2-1)所述Ao环任选地被Rm所取代；(2-1) The Ao ring is optionally substituted by Rm;
    (2-2)所述Ao环任选地被Ry、Rz和Rm所取代；(2-2) The Ao ring is optionally substituted by Ry, Rz and Rm;
    (2-3)所述Ao环任选地被Ry和Rm所取代；(2-3) The Ao ring is optionally substituted by Ry and Rm;
    (2-4)所述Ao环任选地被2个Rm所取代；(2-4) The Ao ring is optionally substituted by 2 Rm;
    (2-5)所述Ao环任选地被Rz所取代；(2-5) The Ao ring is optionally substituted by Rz;
    (3)Ao环选自硫代吗啉基、四氢硫代吡喃基、苯基、吡啶基时，所述Ao环任选地被1-2个选自Rz和Rm的取代基所取代；(3) When the Ao ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the Ao ring is optionally substituted by 1-2 substituents selected from Rz and Rm ;
    最优选地，Ao环选自5元杂芳基、5元不饱和杂环基、 Most preferably, the Ao ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group,
    所述5元杂芳基选自 所述5元不饱和杂环基 且满足以下条件(1)-(3)中任意一项：The 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group And meet any of the following conditions (1)-(3):
    (1)Ao环选自5元杂芳基时，所述Ao环任选地被Rx所取代，(1) When the Ao ring is selected from a 5-membered heteroaryl group, the Ao ring is optionally substituted by Rx,
    (2)Ao环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项： (2) When the Ao ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
    (2-1)所述Ao环任选地被Rm所取代；(2-1) The Ao ring is optionally substituted by Rm;
    (2-2)所述Ao环任选地被Ry、Rz和Rm所取代；(2-2) The Ao ring is optionally substituted by Ry, Rz and Rm;
    (2-3)所述Ao环任选地被Ry和Rm所取代；(2-3) The Ao ring is optionally substituted by Ry and Rm;
    (2-4)所述Ao环任选地被2个Rm所取代；(2-4) The Ao ring is optionally substituted by 2 Rm;
    (2-5)所述Ao环任选地被Rz所取代；(2-5) The Ao ring is optionally substituted by Rz;
    (3)Ao环选自硫代吗啉基、四氢硫代吡喃基、苯基、吡啶基时，所述Ao环任选地被1-2个选自Rz和Rm的取代基所取代；(3) When the Ao ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the Ao ring is optionally substituted by 1-2 substituents selected from Rz and Rm ;
    其中，Rx选自C1-C6烷基、4-6元饱和杂环基(优选地，所述4-6元饱和杂环基包含1个选自N、O、S的杂原子)、-C(＝O)NRaRb、-S(＝O)2NRaRb、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、-NRaC(＝O)Rc，所述Rx任选地被1-2个选自Rn的取代基所取代；优选地，Rx选自甲基、乙基、氧杂环丁烷基、四氢吡咯基、四氢吡喃基、哌啶基、-C(＝O)NRaRb、-NRaC(＝O)Rc、-S(＝O)2NRaRb、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基；Wherein, Rx is selected from C1-C6 alkyl, 4-6 membered saturated heterocyclic group (preferably, the 4-6 membered saturated heterocyclic group contains 1 heteroatom selected from N, O, S), -C (=O)NRaRb, -S(=O) 2 NRaRb, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, -NRaC(=O)Rc, the Rx is any is optionally substituted by 1-2 substituents selected from Rn; preferably, Rx is selected from methyl, ethyl, oxetanyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, -C(=O)NRaRb, -NRaC(=O)Rc, -S(=O) 2 NRaRb, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl;
    Rn选自C1-C6烷基、-NRaRb、-C(＝O)NRaRb、氧代、5-6元饱和杂环基(优选地，所述5-6元饱和杂环基包含2个选自N、O、S的杂原子)、C1-C6烷氧基、羧基、羟基；优选地，Rn选自甲基、乙基、-NRaRb、-C(＝O)NRaRb、氧代基、吗啉基、甲氧基、羟基、羧基；Rn is selected from C1-C6 alkyl, -NRaRb, -C(=O)NRaRb, oxo, 5-6 membered saturated heterocyclic group (preferably, the 5-6 membered saturated heterocyclic group contains 2 selected from Heteroatoms of N, O, S), C1-C6 alkoxy, carboxyl, hydroxyl; preferably, Rn is selected from methyl, ethyl, -NRaRb, -C(=O)NRaRb, oxo, morpholine group, methoxy group, hydroxyl group, carboxyl group;
    Ra、Rb、Rc各自独立地选自H、C1-C6烷基、氰基、C3-C6环烷基，或者Ra、Rb和与它们共同相连的碳原子一起，形成氮杂环丁烷，且所述氮杂环丁烷任选地被羟基所取代；优选地，Ra、Rb、Rc各自独立地选自H、甲基、氰基、环丙基，或者Ra、Rb和与它们共同相连的碳原子一起，形成氮杂环丁烷，且所述氮杂环丁烷任选地被羟基所取代；Ra, Rb, and Rc are each independently selected from H, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, or Ra, Rb and the carbon atoms connected to them together form azetidine, and The azetidine is optionally substituted by a hydroxyl group; preferably, Ra, Rb, and Rc are each independently selected from H, methyl, cyano, cyclopropyl, or Ra, Rb and their joint The carbon atoms are taken together to form an azetidine, and the azetidine is optionally substituted with a hydroxyl group;
    最优选地，Rx选自羟基、甲基、 Most preferably, Rx is selected from hydroxyl, methyl,
    Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷基、被1-6个氘取代的C1-C6烷基、被C3-C6环烷基取代的C1-C6烷基、被C6-C10芳基取代的C1-C6烷基、被取代的C1-C6烷基、4-6元饱和杂环基；优选地，Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷基、被1-6个氘取代的C1-C6烷基、被C3-C6环烷基取代的C1-C6烷基、被C6-C10芳基取代的C1-C6烷基、被取代的C1-C6烷基、5-6元饱和杂环基；更优选地，Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被1-3个氘取代的C1-C6烷基、被环丙基取代的C1-C6烷基、被苯基取代的C1-C6烷基、5-6元饱和杂环基，所述5-6元饱和杂环基含有1个杂原子；进一步优选地，Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被1-3个氘取代的C1-C6烷基、被环丙基取代的C1-C6烷基、被苯基取代的 C1-C6烷基、四氢吡咯基、哌啶基；Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by 1-6 deuterium, C3- C1-C6 alkyl substituted by C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, C1-C6 alkyl substituted by C6-C10 aryl, Substituted C1-C6 alkyl, 4-6 membered saturated heterocyclic group; preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 substituted by 1-6 halogen Alkyl, C1-C6 alkyl substituted by 1-6 deuterium, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, Substituted C1-C6 alkyl, 5-6 membered saturated heterocyclic group; more preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1- C6 alkyl, C1-C6 alkyl substituted by 1-3 deuterium, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, 5-6 membered saturated heterocyclic group, the 5-6 membered saturated heterocyclic group contains 1 heteroatom; more preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, substituted by 1 -C1-C6 alkyl substituted by 3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, phenyl substituted C1-C6 alkyl, Tetrahydropyrrolyl, piperidinyl;
    最优选地，Ry选自甲基、-CHF2、-CF3、-CD3、-CH2CH3、-CH2CHF2、-CH2CF3、 Most preferably, Ry is selected from methyl, -CHF 2 , -CF 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 ,
    Rz选自C1-C6烷基、卤素、优选地，Rz选自甲基、Br、 Rz is selected from C1-C6 alkyl, halogen, Preferably, Rz is selected from methyl, Br,
    或者，Ry、Rz以及和它们共同相连的碳原子一起，形成4-6元饱和碳环、4-6元饱和杂环；或者优选地，Ry、Rz以及和它们共同相连的碳原子一起，形成4-6元饱和碳环、4-6元饱和杂环，所述4-6元饱和杂环含有1个杂原子；或者更优选地，Ry、Rz以及和它们共同相连的碳原子一起，形成环丁烷、环戊烷、环己烷、哌啶、四氢吡喃；或者最优选地，Ry、Rz以及和它们共同相连的碳原子一起，形成其中，1’号碳原子为与Ry和Rz共同相连的碳原子；Or, Ry, Rz and their common carbon atoms together form a 4-6 membered saturated carbocyclic ring, a 4-6 membered saturated heterocyclic ring; or preferably, Ry, Rz and their common connected carbon atoms form a 4-6 membered saturated carbocyclic ring, 4-6 membered saturated heterocyclic ring, the 4-6 membered saturated heterocyclic ring contains 1 heteroatom; or more preferably, Ry, Rz and their common carbon atoms together form Cyclobutane, cyclopentane, cyclohexane, piperidine, tetrahydropyran; or most preferably, Ry, Rz and together with the carbon atoms to which they are commonly attached, form Wherein, the 1' carbon atom is the carbon atom connected with Ry and Rz;
    Rm为氧代基；Rm is an oxo group;
    最优选地，Ao环及其任选的取代基作为整体，选自以下：

    Most preferably, the Ao ring and its optional substituents, taken as a whole, are selected from the following:

    Bo环选自： 其任选地被1-3个取代基取代，所述取代基选自：五氟化硫基、-OH、C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基、卤素、硝基、氰基、氨基；Bo rings are selected from: It is optionally substituted with 1-3 substituents selected from: thiopentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1 -6 halogen substituted C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkoxy, halogen, nitro, cyano, amino;
    优选地，上述 其任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基、卤素；Preferably, the above It is optionally substituted with 1-2 substituents selected from the group consisting of: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkane Base, 1-6 halogen substituted C1-C6 alkoxy, halogen;
    更优选地，上述任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基、卤素；或者上述 任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基、卤素； More preferably, the above Optionally substituted with 1-2 substituents selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl , 1-6 halogen substituted C1-C6 alkoxy, halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl, halogen;
    更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-Cl、-SF5、-CH3、-F、-OCH3、-OCF3；或者上述 任选地被1-2个取代基取代，所述取代基选自：-CF3、-CH3、-F、 More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 , -OCF 3 ; or the above optionally substituted with 1-2 substituents selected from: -CF 3 , -CH 3 , -F,
    进一步优选地，上述其上的取代基的取代位置为：2-位单取代、3-位单取代、5-位单取代、4-、5-位双取代、5-、6-位双取代、2-、5-位双取代、3-、5-位双取代；其上的取代基的取代位置为3-位单取代、5-位单取代；其上的取代基的取代位置为 5-位单取代；其上的取代基的取代位置为6-位单取代；其上的取代基的取代位置为5-位或6位单取代或双取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为4-位单取代、5-位单取代；其上的取代基的取代位置为3-位单取代；Further preferably, the above The substitution positions of the substituents on it are: 2-position mono-substitution, 3-position mono-substitution, 5-position mono-substitution, 4-, 5-position double substitution, 5-, 6-position double substitution, 2-, 5-position - double substitution, 3-, 5-position double substitution; The substitution positions of the substituents on it are 3-position mono-substitution and 5-position mono-substitution; The substitution position of the substituent on it is 5-position single substitution; The substitution position of the substituent on it is 6-position monosubstituted; The substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 4-position mono-substitution, 5-position mono-substitution; The substitution position of the substituent on it is 3-position monosubstituted;
    最优选地，Bo环选自：
    Most preferably, the Bo ring is selected from:
    Co环选自5元杂芳环、6元部分不饱和杂环；优选地，所述5元杂芳环选自 优选地，所述6元部分不饱和杂环为 The Co ring is selected from 5-membered heteroaryl ring, 6-membered partially unsaturated heterocyclic ring; preferably, the 5-membered heteroaryl ring is selected from Preferably, the 6-membered partially unsaturated heterocycle is
    A10、A20、A30、A40独立地选自：N、CH，其中最多3个为N；A 10 , A 20 , A 30 , A 40 are independently selected from: N, CH, wherein at most 3 are N;
    L0选自直接键、NH、O、S；优选地，L0选自直接键、NH； L is selected from direct bonds, NH, O, S; preferably, L is selected from direct bonds, NH;
    Ro选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C5杂芳基、C1-C6烷氧基、羟基取代的C1-C6烷氧基、被5-6元杂芳基取代的C1-C6烷氧基、C3-C5杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被氰基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、卤素、氰基、硝基、氧代基、C2-C6烯基、被C6-C10芳基取代的C1-C6烷基、5-6元杂环基、被氨基取代的C1-C6烷基；其中C3-C5杂环基被C1-C3烷基任意取代，C6-C10芳基被1-6个卤素任意取代，5-6元杂环基被 C1-C3烷基或羟基任意取代；或两个Ro，与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；更优选地，Ro选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、吡啶基C1-C6烷氧基、羟基取代的C1-C6烷氧基、C3杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、C1-C6烷氧基、C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被氰基取代的C1-C6烷基、卤素、氰基、氧代基、C2-C6烯基、被苯基取代的C1-C6烷基、被氨基取代的C1-C6烷基、四氢吡咯基、哌嗪基，其中C3杂环基被C1-C3烷基任意取代，四氢吡咯基被羟基任意取代，哌嗪基被C1-C3烷基任意取代；或两个Ro，与它们相连的原子共同形成苯环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素和氘的基团所取代；最优选地，Ro选自：氧代基、-OCH3、-CH3、-F、-Cl、-CN、-OH、-NH2、-COOH、-COOCH3、-CH2CH3、-CF3、-CHF2、或两个Ro与它们相连的原子共同形成： Ro is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C5 heteroaryl, C1-C6 Alkoxy, C1-C6 alkoxy substituted by hydroxyl, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester (- CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 substituted by cyano Alkyl, C1-C6 alkoxy substituted by 1-6 halogen, halogen, cyano, nitro, oxo, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered heterocyclic group, C1-C6 alkyl substituted by amino; wherein C3-C5 heterocyclic group is optionally substituted by C1-C3 alkyl, C6-C10 aryl is optionally substituted by 1-6 halogens, 5- 6-membered heterocyclyl C1-C3 alkyl or hydroxyl is optionally substituted; or two Ro, and the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 A membered heteroaryl ring, wherein a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaryl ring is optionally replaced by 1-6 groups selected from halogen and deuterium Substitution; more preferably, Ro is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, pyridyl C1- C6 alkoxy, hydroxyl substituted C1-C6 alkoxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 Alkoxy, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogen, C1-C6 alkyl substituted by cyano, halogen, cyano, oxo, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, C1-C6 alkyl substituted by amino, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclic group is optionally substituted by C1-C3 alkyl, tetrahydropyrrolyl is substituted by hydroxyl Any substitution, piperazinyl is optionally substituted by C1-C3 alkyl; or two Ro, the atoms connected to them together form a benzene ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5 membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring and the partially unsaturated 5-6 membered heterocyclic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium; most preferably, R is selected from From: Oxo, -OCH 3 , -CH 3 , -F, -Cl, -CN, -OH, -NH 2 , -COOH, -COOCH 3 , -CH 2 CH 3 , -CF 3 , -CHF 2 , or two Ro together with the atoms to which they are attached:
  2. 根据权利要求1所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为以下式O-1：

    The compound according to claim 1, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemization thereof body, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is the following formula O-1 :

    其中：in:
    Ao环的定义与权利要求1中Ao环的定义相同；Bo环的定义与权利要求1中Bo环的定义相同；Co环的定义与权利要求1中Co环的定义相同；L0的定义与权利要求1中L0的定义相同；The definition of Ao ring is the same as the definition of Ao ring in claim 1; the definition of Bo ring is the same as the definition of Bo ring in claim 1; the definition of Co ring is the same as the definition of Co ring in claim 1; the definition of L0 is the same as The definition of L0 in claim 1 is the same;
    Ro11、Ro12和与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；优选地，Ro11、Ro12和与它们相连的原子共同形成苯环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素和氘的基团所取代；或者优选地，Ro11、Ro12和与它们相连的原子共同形成部分不饱和C5-C6碳环或部分不饱和5-6元杂环，其中部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素和氘的基团所取代；更优选地，Ro11、Ro12和与它们相连的原子共同形成： 最优选地，Ro11、Ro12和与它们相连的原子共同形成： Ro 11 , Ro 12 and the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, in which some unsaturated Each of the C5-C6 carbocycle, partially unsaturated 5-6 membered heterocyclic ring or 5-6 membered heteroaromatic ring is optionally substituted by 1-6 groups selected from halogen and deuterium; preferably, Ro 11 , Ro 12 and the atoms connected to them together form a benzene ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-membered heteroaryl ring, wherein a partially unsaturated C5-C6 carbocyclic ring and a partially unsaturated Each of the 5-6 membered heterocyclic rings is optionally substituted by 1-6 groups selected from halogen and deuterium; or preferably, Ro 11 , Ro 12 and the atoms connected to them together form a partially unsaturated C5-C6 carbon Ring or partially unsaturated 5-6 membered heterocycle, wherein each of partially unsaturated C5-C6 carbocycle and partially unsaturated 5-6 membered heterocycle is optionally substituted by 1-6 groups selected from halogen and deuterium ; More preferably, Ro 11 , Ro 12 and the atoms connected to them jointly form: Most preferably, Ro 11 , Ro 12 and the atoms attached to them together form:
    或者所述式O化合物为以下式Oc：
    Or the compound of formula O is the following formula Oc:
    式Oc中，Aoc环及其任选的取代基作为整体，选自 优选地，Aoc环及其任选的取代基作为整体，选自最优选地，Aoc环及其任选的取代基作为整体，为 In formula Oc, the Aoc ring and its optional substituents as a whole are selected from Preferably, the Aoc ring and its optional substituents as a whole are selected from Most preferably, the Aoc ring and its optional substituents as a whole are
    Co环的定义与所述式O中Co环的定义相同；Ro的定义与所述式O中Ro的定义相同；The definition of Co ring is the same as the definition of Co ring in the formula O; the definition of Ro is the same as the definition of Ro in the formula O;
    优选地，所述式Oc化合物为以下式Occ：
    Preferably, the compound of formula Oc is the following formula Occ:
    Aocc环及其任选的取代基作为整体，其定义与所述式Oc中Aoc环及其任选的取代基作为整体的定义相同；A10、A20、A30、A40的定义与所述式O中A10、A20、A30、A40的定义相同；Ro的定义与所述式O中Ro的定义相同。The definition of the Aoc ring and its optional substituents as a whole is the same as the definition of the Aoc ring and its optional substituents in the formula Oc; the definitions of A 10 , A 20 , A 30 , and A 40 are the same The definitions of A 10 , A 20 , A 30 , and A 40 in the above formula O are the same; the definition of Ro is the same as that of Ro in the above formula O.
  3. 根据权利要求1所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为以下式I：
    The compound according to claim 1, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemization thereof body, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is the following formula I:
    A1环的定义与权利要求1中Ao环的定义相同；B1环的定义同权利要求1中Bo环的定义；L1的定义与权利要求1中L0的定义相同；A1、A2、A3、A4独立地选自：N、CH，其中最多3个为N；R1的定义与权利要求1中Ro的定义相同。The definition of ring A1 is the same as that of ring Ao in claim 1; the definition of ring B1 is the same as that of ring Bo in claim 1; the definition of L 1 is the same as that of L 0 in claim 1; A 1 , A 2 , A 3 and A 4 are independently selected from: N, CH, wherein at most 3 are N; the definition of R 1 is the same as the definition of Ro in claim 1.
  4. 根据权利要求3所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述式I化合物为以下式Ic：
    The compound according to claim 3, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemization thereof body, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound of formula I is the following formula Ic :
    A1c环及其任选的取代基作为整体，其定义与上述式Oc中Aoc环及其任选的取代基作为整体的定义相同；A1、A2、A3、A4独立地选自：N、CH，其中最多3个为N；R1的定义与所述式I中R1的定义相同；A 1c ring and its optional substituents as a whole have the same definition as the Aoc ring and its optional substituents in the above formula Oc as a whole; A 1 , A 2 , A 3 , and A 4 are independently selected from : N, CH, wherein at most 3 are N; the definition of R is the same as that of R in the formula I;
    或者，所述化合物为以下式I-1：
    Alternatively, the compound is the following formula I-1:
    A11环选自5元杂芳基、5元不饱和杂环基、所述5元杂芳基选自 所述5元不饱和杂环基选自且满足以下条件(1)-(2)中任意一项：The A11 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
    (1)A11环选自5元杂芳基时，所述A11环任选地被Rx所取代，(1) When the A11 ring is selected from a 5-membered heteroaryl group, the A11 ring is optionally substituted by Rx,
    (2)A11环选自5元不饱和杂环基时，所述A11环任选地被Rm或Rz所取代，或者任选地被Ry和Rm所取代； (2) When the A11 ring is selected from a 5-membered unsaturated heterocyclic group, the A11 ring is optionally substituted by Rm or Rz, or optionally substituted by Ry and Rm;
    其中，Rx选自甲基、 Wherein, Rx is selected from methyl,
    Ry为甲基；Rz选自卤素(优选Br)；Rm为氧代基；Ry is a methyl group; Rz is selected from halogen (preferably Br); Rm is an oxo group;
    优选地，A11环及其任选的取代基作为整体，选自以下：

    Preferably, ring A11 and its optional substituents, taken as a whole, are selected from the following:

    B11环选自：其任选地被1-3个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、C3-C4环烷基，1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基、卤素、氨基；Ring B11 is selected from: It is optionally substituted with 1-3 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 Alkyl, 1-6 halogen substituted C1-C6 alkoxy, halogen, amino;
    优选地，上述任选地被1-2个取代基取代，所述取代基选自：1-6个卤素取代的C1-C6烷基、C3-C4环烷基，1-6个卤素取代的C1-C6烷氧基、氨基；更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-OCF3；最优选地，B11环选自： Preferably, the above Optionally substituted with 1-2 substituents selected from: 1-6 halogen substituted C1-C6 alkyl, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 alkane Oxygen, amino; more preferably, the above Optionally substituted with 1-2 substituents selected from: -CF 3 , -OCF 3 ; most preferably, ring B11 is selected from:
    R11选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、C1-C6烷氧基、卤素、氰基、硝基；更优选地，R11选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、卤素、氰基；进一步优选地，R11选自：-CH3、-F、-Cl、-CN；更进一步优选地，R11位于环上的位置选自：1-位、2-位、3位、4-位；R 11 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, halogen, cyano, nitro; more preferably, R 11 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, 1-2 C1-C6 alkane on N Carbamoyl, C1-C6 alkyl, halogen, cyano group substituted by radical; More preferably, R 11 is selected from: -CH 3 , -F, -Cl, -CN; more preferably, R 11 is located at the ring The position on is selected from: 1-position, 2-position, 3-position, 4-position;
    优选地，所述式I-1化合物为以下式I-1c：
    Preferably, the compound of formula I-1 is the following formula I-1c:
    A11c环及其任选的取代基作为整体，选自 优选地，A11c环及其任选的取代基作为整体，选自 更优选地，A11c环及其任选的取代基作为整体，为 R11的定义与所述式I-1中R11的定义相同。A 11c ring and its optional substituents as a whole are selected from Preferably, the A 11c ring and its optional substituents as a whole are selected from More preferably, the A 11c ring and its optional substituents, taken as a whole, are The definition of R 11 is the same as the definition of R 11 in the formula I-1.
  5. 根据权利要求3所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为以下式I-2：
    The compound according to claim 3, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemization thereof body, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is the following formula I-2 :
    A12环选自5元杂芳基、5元不饱和杂环基、所述5元杂芳基选自 所述5元不饱和杂环基选自 且满足以下条件(1)-(3)中任意一项：The A12 ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any of the following conditions (1)-(3):
    (1)A12环选自5元杂芳基时，所述A12环任选地被Rx所取代，(1) When the A12 ring is selected from a 5-membered heteroaryl group, the A12 ring is optionally substituted by Rx,
    (2)A12环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the A12 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
    (2-1)所述A12环任选地被Rm所取代；(2-1) The A12 ring is optionally substituted by Rm;
    (2-2)所述A12环任选地被Ry、Rz和Rm所取代；(2-2) The A12 ring is optionally substituted by Ry, Rz and Rm;
    (2-3)所述A12环任选地被Ry和Rm所取代；(2-3) the A12 ring is optionally substituted by Ry and Rm;
    (2-4)所述A12环任选地被2个Rm所取代；(2-4) The A12 ring is optionally substituted by 2 Rm;
    (2-5)所述A12环任选地被Rz所取代； (2-5) the A12 ring is optionally substituted by Rz;
    (3)A12环选自时，所述A12环任选地被1-2个选自Rz和Rm的取代基所取代；(3) Ring A12 is selected from When, the A12 ring is optionally substituted by 1-2 substituents selected from Rz and Rm;
    其中，Rx选自羟基、 Ry选自甲基、-CHF2、-CF3、-CD3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rz选自甲基、 或者，Ry、Rz以及和它们共同相连的碳原子一起，形成其中，1’号碳原子为与Ry和Rz共同相连的碳原子；Rm为氧代基；最优选地，A12环及其任选的取代基作为整体，选自以下：

    Wherein, Rx is selected from hydroxyl, Ry is selected from methyl, -CHF 2 , -CF 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rz is selected from methyl, Alternatively, Ry, Rz, and the carbon atoms connected to them together form Wherein, the carbon atom No. 1' is the carbon atom connected to Ry and Rz; Rm is an oxo group; most preferably, the A12 ring and its optional substituents as a whole are selected from the following:

    B12环选自： 其任选地被1-3个取代基取代，所述取代基选自：五氟化硫基、-OH、C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、卤素、硝基、氰基、氨基；优选地，上述 其任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；The B12 ring is selected from: It is optionally substituted with 1-3 substituents selected from: thiopentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1 -6 halogen substituted C1-C6 alkyl, halogen, nitro, cyano, amino; preferably, the above It is optionally substituted with 1-2 substituents selected from the group consisting of: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkane base, halogen;
    更优选地，上述任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；或者上述 任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-Cl、-SF5、-CH3、-F、-OCH3；或者上述 任选地被1-2个取代基取代，所述取代基选自：-CF3、-CH3；进一步优选地，上述 其上的取代基的取代位置为：2-位单取代、3-位单取代、5-位单取代、4-、5-位双取代、5-、6-位双取代、2-、5-位双取代、3-、5-位双取代；其上的取代基的取代位置为3-位单取代、5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为6-位单取代；其上的取代基的取代位置为5-位或6位单取代或双取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代； 其上的取代基的取代位置为5-位单取代；最优选地，B12环选自： More preferably, the above Optionally substituted with 1-2 substituents selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl , halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl; more preferably, the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 ; or the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -CH 3 ; more preferably, the above The substitution positions of the substituents on it are: 2-position mono-substitution, 3-position mono-substitution, 5-position mono-substitution, 4-, 5-position double substitution, 5-, 6-position double substitution, 2-, 5-position - double substitution, 3-, 5-position double substitution; The substitution positions of the substituents on it are 3-position mono-substitution and 5-position mono-substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 6-position monosubstituted; The substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; most preferably, the B12 ring is selected from:
    R12选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被氨基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、C1-C5杂芳基、C1-C6烷氧基、羟基取代的C1-C6烷氧基、被5-6元杂芳基取代的C1-C6烷氧基、C3-C5杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、卤素、氰基、C2-C6烯基、被C6-C10芳基取代的C1-C6烷基、5-6元杂环基；其中C3-C5杂环基被C1-C3烷基任意取代，C6-C10芳基被1-6个卤素任意取代，5-6元杂环基被C1-C3烷基或羟基任意取代；或两个R12，与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；更优选地，R12选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、吡啶基C1-C6烷氧基、羟基取代的C1-C6烷氧基、C3杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、C1-C6烷氧基、C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被氨基取代的C1-C6烷基、卤素、氰基、C2-C6烯基、被苯基取代的C1-C6烷基、四氢吡咯基、哌嗪基，其中C3杂环基被C1-C3烷基任意取代，四氢吡咯基被羟基任意取代，哌嗪基被C1-C3烷基任意取代；或两个R12，与它们相连的原子共同形成苯环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素和氘的基团所取代；进一步优选地，R12选自： -OH、-NH2、-COOH、-COOCH3、-CH3、-CH2CH3、-F、-Cl、-CN、-CHF2、 或两个R12与它们相连的原子共同形成： R 12 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by amino, C1-C6 alkoxy substituted by 1-6 halogen, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester Group (-CO-O-C1-C6 alkyl), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered heterocyclic group ; wherein the C3-C5 heterocyclic group is optionally substituted by a C1-C3 alkyl group, the C6-C10 aryl group is optionally substituted by 1-6 halogens, and the 5-6 membered heterocyclic group is optionally substituted by a C1-C3 alkyl or hydroxyl group; or Two R 12 , the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, in which the partially unsaturated C5 Each of -C6 carbocycle, partially unsaturated 5-6 membered heterocycle or 5-6 membered heteroaryl ring is optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, R is selected from : Aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, pyridyl C1-C6 alkoxy, C1 substituted by hydroxyl -C6 alkoxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkyl , C1-C6 alkyl substituted by 1-3 halogen, C1-C6 alkyl substituted by amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrole Base, piperazinyl, wherein C3 heterocyclic group is optionally substituted by C1-C3 alkyl, tetrahydropyrrolyl is optionally substituted by hydroxyl, piperazinyl is optionally substituted by C1-C3 alkyl; or two R 12 are connected to them The atoms together form a benzene ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-membered heteroaryl ring, wherein a partially unsaturated C5-C6 carbocyclic ring and a partially unsaturated 5-6 membered heterocyclic ring Each ring is optionally substituted by 1-6 groups selected from halogen and deuterium; further preferably, R is selected from: -OH, -NH 2 , -COOH, -COOCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CHF2 , or two R 12 together with the atoms to which they are attached:
    更进一步优选地，R12位于环上的位置选自：A12-位、A32-位、A22-位；A12、A22、A32、A42独立地选自：N、CH，且其中只有1个为N，其余为CH；More preferably, the position of R 12 on the ring is selected from: A 12 -position, A 32 -position, A 22 -position; A 12 , A 22 , A 32 , A 42 are independently selected from: N, CH, And only one of them is N, and the rest are CH;
    优选地，所述式I-2化合物为以下式I-2c：
    Preferably, the compound of formula I-2 is the following formula I-2c:
    A12c环及其任选的取代基作为整体，选自： A 12c ring and its optional substituents as a whole are selected from:
    优选地，A12c环及其任选的取代基作为整体，选自： Preferably, the A 12c ring and its optional substituents, taken as a whole, are selected from:
    最优选地，A12c环及其任选的取代基作为整体，选自： A12、A22、A32、A42的定义与上述式I-2中A12、A22、A32、A42的定义相同；R12的定义与上述式I-2中R12的定义相同。Most preferably, the A 12c ring and its optional substituents, taken as a whole, are selected from: The definition of A 12 , A 22 , A 32 , A 42 is the same as the definition of A 12 , A 22 , A 32 , A 42 in the above formula I-2; the definition of R 12 is the same as the definition of R 12 in the above formula I-2 same.
  6. 根据权利要求1-5任一项所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为式I-1-1：
    The compound according to any one of claims 1-5, or tautomers of said compound, its stereoisomers, its geometric isomers, its enantiomers, its diastereoisomers body, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is Formula I-1-1:
    其中，A111环选自5元杂芳基、5元不饱和杂环基，所述5元杂芳基选自所述5元不饱和杂环基选自且满足以下条件(1)-(2)中任意一项：Among them, the A111 ring is selected from 5-membered heteroaryl groups and 5-membered unsaturated heterocyclic groups, and the 5-membered heteroaryl groups are selected from The 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
    (1)A111环选自5元杂芳基时，所述A111环任选地被Rx所取代，(1) When the A111 ring is selected from a 5-membered heteroaryl group, the A111 ring is optionally substituted by Rx,
    (2)A111环选自5元不饱和杂环基时，所述A111环任选地被Rm或Rz所取代，或者任选地被Rm和Ry所取代；(2) When the A111 ring is selected from a 5-membered unsaturated heterocyclic group, the A111 ring is optionally substituted by Rm or Rz, or optionally substituted by Rm and Ry;
    其中，in,
    Rx选自甲基、 Ry选自甲基、-CHF2、-CF3、、-CH2CH3、-CH2CHF2、-CH2CF3、 Rz选自卤素(优选Br)；Rm为氧代基；Rx is selected from methyl, Ry is selected from methyl, -CHF2, -CF3, -CH2CH3, -CH2CHF2, -CH2CF3, Rz is selected from halogen (preferably Br); Rm is an oxo group;
    优选地，A111环及其任选的取代基作为整体，选自以下：
    更优选地，A111环及其任选的取代基作为整体，选自 进一步优选地，A111环及其任选的取代基作为整体，选自最优选地，A111 环及其任选的取代基作为整体，为     Preferably, ring A111 and its optional substituents, taken as a whole, are selected from the following:
    More preferably, ring A111 and its optional substituents as a whole are selected from Further preferably, ring A111 and its optional substituents as a whole are selected from Most preferably, A111 The ring and its optional substituents as a whole are
    B111环选自：其任选地被1-3个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基、卤素；优选地，上述任选地被1-2个取代基取代，所述取代基选自：1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基；更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-OCF3；The B111 ring is selected from: It is optionally substituted with 1-3 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, 1-6 Halogen substituted C1-C6 alkoxy, halogen; preferably, the above Optionally substituted by 1-2 substituents selected from: 1-6 halogen substituted C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkoxy; more preferably, the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -OCF 3 ;
    最优选地，B111环选自：优选为 Most preferably, the B111 ring is selected from: preferably
  7. 根据权利要求1-6任一项所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为式I-1-2：
    The compound according to any one of claims 1-6, or tautomers of said compound, its stereoisomers, its geometric isomers, its enantiomers, its diastereoisomers body, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is Formula I-1-2:
    其中，A112环选自5元杂芳基、5元不饱和杂环基、所述5元杂芳基选自 所述5元不饱和杂环基选自且满足以下条 件(1)-(2)中任意一项：Wherein, the A112 ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from and meet the following conditions Any one of items (1)-(2):
    (1)A112环选自5元杂芳基时，所述A112环任选地被Rx所取代，(1) When the A112 ring is selected from a 5-membered heteroaryl group, the A112 ring is optionally substituted by Rx,
    (2)A112环选自5元不饱和杂环基时，所述A112环任选地被Rm或Rz所取代，或者任选地被Ry和Rm所取代；(2) When the A112 ring is selected from a 5-membered unsaturated heterocyclic group, the A112 ring is optionally substituted by Rm or Rz, or optionally substituted by Ry and Rm;
    其中，Rx选自甲基、 Wherein, Rx is selected from methyl,
    Ry选自甲基、-CHF2、-CF3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rz选自卤素(优选Br)，Rm为氧代基；Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rz is selected from halogen (preferably Br), Rm is an oxo group;
    优选地，A112环及其任选的取代基作为整体，选自以下：

    Preferably, the A112 ring and its optional substituents, taken as a whole, are selected from the following:

    B112环选自：其任选地被1-3个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基、卤素；优选地，上述任选地被1-2个取代基取代，所述取代基选自：1-6个卤素取代的C1-C6烷基、1-6个卤素取代的C1-C6烷氧基；更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-OCF3；最优选地，B112环为： B112 rings are selected from: It is optionally substituted with 1-3 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, 1-6 Halogen substituted C1-C6 alkoxy, halogen; preferably, the above Optionally substituted by 1-2 substituents selected from: 1-6 halogen substituted C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkoxy; more preferably, the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -OCF 3 ; most preferably, ring B112 is:
    R112选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、C1-C6烷氧基、卤素、氰基、硝基、氨基；更优选地，R112选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、卤素、氰基；进一步优选地，R112选自：-CH3、-CH2CH3、CF3、-F、-Cl、-CN；R 112 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, halogen, cyano, nitro, amino; more preferably, R 112 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyls on N, 1-2 C1- on N C6 alkyl substituted carbamoyl, C1-C6 alkyl, halogen, cyano; further preferably, R is selected from: -CH 3 , -CH 2 CH 3 , CF 3 , -F, -Cl, -CN;
    更进一步优选地，R112位于环上的位置选自：1-位、2-位、3-位、4-位； Even more preferably, R 112 is located in ring The position on is selected from: 1-position, 2-position, 3-position, 4-position;
    优选地，上述式I-1-2为 Preferably, the above formula I-1-2 is
    其中，A112c环及其任选的取代基作为整体，选自 优选地，A112c环及其任选的取代基作为整体，选自更优选地，A112c环及其任选的取代基作为整体，为R112的定义与上述式I-1-2中R112的定义相同；Wherein, the A 112c ring and its optional substituents as a whole are selected from Preferably, the A 112c ring and its optional substituents as a whole are selected from More preferably, the A 112c ring and its optional substituents, taken as a whole, are The definition of R 112 is the same as the definition of R 112 in the above formula I-1-2;
    或者，所述化合物为以下式I-2-1：
    Alternatively, the compound is the following formula I-2-1:
    其中：in:
    A121环选自5元杂芳基、5元不饱和杂环基，所述5元杂芳基选自所述5元不饱 和杂环基选自 且满足以下条件(1)-(2)中任意一项：The A121 ring is selected from 5-membered heteroaryl groups and 5-membered unsaturated heterocyclic groups, and the 5-membered heteroaryl groups are selected from The 5 yuan is not full and heterocyclyl selected from And meet any one of the following conditions (1)-(2):
    (1)A121环选自5元杂芳基时，所述A121环任选地被Rx所取代，(1) When the A121 ring is selected from a 5-membered heteroaryl group, the A121 ring is optionally substituted by Rx,
    (2)A121环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the A121 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
    (2-1)所述A121环任选地被Rm所取代；(2-1) the A121 ring is optionally substituted by Rm;
    (2-2)所述A121环任选地被Ry、Rz和Rm所取代；(2-2) The A121 ring is optionally substituted by Ry, Rz and Rm;
    (2-3)所述A121环任选地被Ry和Rm所取代；(2-3) The A121 ring is optionally substituted by Ry and Rm;
    (2-4)所述A121环任选地被2个Rm所取代；(2-4) The A121 ring is optionally substituted by 2 Rm;
    (2-5)所述A121环任选地被Rz所取代；(2-5) The A121 ring is optionally substituted by Rz;
    其中，in,
    Rx选自羟基、 Rx is selected from hydroxyl,
    Ry选自甲基、-CHF2、-CF3、-CD3、-CH2CH3、-CH2CHF2、-CH2CF3、 Ry is selected from methyl, -CHF 2 , -CF 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 ,
    Rz选自甲基、 Rz is selected from methyl,
    或者，Ry、Rz以及和它们共同相连的碳原子一起，形成其中，1’号碳原子为与Ry和Rz共同相连的碳原子；Rm为氧代基；Alternatively, Ry, Rz, and the carbon atoms connected to them together form Wherein, the 1' carbon atom is a carbon atom connected to Ry and Rz; Rm is an oxo group;
    最优选地，A121环及其任选的取代基作为整体，选自以下：

    Most preferably, ring A121 and its optional substituents, taken as a whole, are selected from the following:

    B121环选自： 其任选地被1-3个取代基取代，所述取代基选自：五氟化硫基、-OH、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素、硝基、氰基、氨基；优选地，上述 其任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；The B121 ring is selected from: It is optionally substituted with 1-3 substituents selected from: thiopentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1 -C6 alkyl, halogen, nitro, cyano, amino; preferably, the above It is optionally substituted with 1-2 substituents selected from the group consisting of: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkane base, halogen;
    更优选地，上述任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；或者上述 任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；更优选地，上述任选地被1-2个取代基取代，所述取代基选 自：-CF3、-Cl、-SF5、-CH3、-F、-OCH3；或者上述 任选地被1-2个取代基取代，所述取代基选自：-CF3、-CH3；进一步优选地，上述其上的取代基的取代位置为：2-位单取代、3-位单取代、5-位单取代、4-、5-位双取代、5-、6-位双取代、2-、5-位双取代、3-、5-位双取代；其上的取代基的取代位置为3-位单取代、5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为6-位单取代，其上的取代基的取代位置为5-位或6位单取代或双取代；其上的取代基的取代位置为5-位单取代；其上 的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；More preferably, the above Optionally substituted with 1-2 substituents selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl , halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl; more preferably, the above optionally substituted with 1-2 substituents selected from From: -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 ; or the above Optionally substituted by 1-2 substituents selected from: -CF 3 , -CH 3 ; more preferably, the above The substitution positions of the substituents on it are: 2-position mono-substitution, 3-position mono-substitution, 5-position mono-substitution, 4-, 5-position double substitution, 5-, 6-position double substitution, 2-, 5-position - double substitution, 3-, 5-position double substitution; The substitution positions of the substituents on it are 3-position mono-substitution and 5-position mono-substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 6-position monosubstituted, The substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution; The substitution position of the substituent on it is 5-position monosubstituted; on it The substitution position of the substituent is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted;
    最优选地，B121环选自： Most preferably, the B121 ring is selected from:
    R121选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被氨基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、C1-C5杂芳基、C1-C6烷氧基、羟基取代的C1-C6烷氧基、被5-6元杂芳基取代的C1-C6烷氧基、C3-C5杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、卤素、氰基、C2-C6烯基、被C6-C10芳基取代的C1-C6烷基、5-6元杂环基；其中C3-C5杂环基被C1-C3烷基任意取代，C6-C10芳基被1-6个卤素任意取代，5-6元杂环基被C1-C3烷基或羟基任意取代；或两个R121，与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；更优选地，R121选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、吡啶基C1-C6烷氧基、羟基取代的C1-C6烷氧基、C3杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、C1-C6烷氧基、C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被氨基取代的C1-C6烷基、卤素、氰基、C2-C6烯基、被苯基取代的C1-C6烷基、四氢吡咯基、哌嗪基，其中C3杂环基被C1-C3烷基任意取代，四氢吡咯基被羟基任意取代，哌嗪基被C1-C3烷基任意取代；或两个R121，与它们相连的原子共同形成苯环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素(优选-F)和氘的基团所取代；进一步优选地，R121选自： -OH、-NH2、-COOH、-COOCH3、-CH3、-CH2CH3、-F、-Cl、-CN、-CHF2、-CF3、或两个R121与它们相连的原子共同形成： 更进一步优选地，R121位于环上的位置选自：1-位、3-位、2-位，优选3-位、2-位；R 121 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by amino, C1-C6 alkoxy substituted by 1-6 halogen, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester Group (-CO-O-C1-C6 alkyl), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered heterocyclic group ; wherein the C3-C5 heterocyclic group is optionally substituted by a C1-C3 alkyl group, the C6-C10 aryl group is optionally substituted by 1-6 halogens, and the 5-6 membered heterocyclic group is optionally substituted by a C1-C3 alkyl or hydroxyl group; or Two R 121 , the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, in which the partially unsaturated C5 -C6 carbocycle, partially unsaturated 5-6 membered heterocycle or 5-6 membered heteroaromatic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, R is selected from : Aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, pyridyl C1-C6 alkoxy, C1 substituted by hydroxyl -C6 alkoxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkyl , C1-C6 alkyl substituted by 1-3 halogen, C1-C6 alkyl substituted by amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrole Base, piperazinyl, wherein C3 heterocyclic group is optionally substituted by C1-C3 alkyl, tetrahydropyrrolyl is optionally substituted by hydroxyl, piperazinyl is optionally substituted by C1-C3 alkyl; or two R 121 are connected to them The atoms together form a benzene ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-membered heteroaryl ring, wherein a partially unsaturated C5-C6 carbocyclic ring and a partially unsaturated 5-6 membered heterocyclic ring Each ring is optionally substituted by 1-6 groups selected from halogen (preferably -F) and deuterium; further preferably, R is selected from: -OH, -NH 2 , -COOH, -COOCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CHF 2 , -CF 3 , or two R 121 together with the atoms they are attached to form: Still further preferably, the position of R 121 on the ring is selected from: 1-position, 3-position, 2-position, preferably 3-position, 2-position;
    优选地，所述化合物为以下式I-1-2c：
    Preferably, the compound is the following formula I-1-2c:
    其中，A112c环及其任选的取代基作为整体，选自 优选地，A112c环及其任选的取代基作为整体，选自更优选地，A112c环及其任选的取代基作为整体，为 Wherein, the A 112c ring and its optional substituents as a whole are selected from Preferably, the A 112c ring and its optional substituents as a whole are selected from More preferably, the A 112c ring and its optional substituents, taken as a whole, are
    R112的定义与上述式I-1-2中R112的定义相同。The definition of R 112 is the same as the definition of R 112 in the above formula I-1-2.
  8. 根据权利要求1-7任一项所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为以下式I-2-2、式I-2-3、式I-2-4或式I-2-5：
    The compound according to any one of claims 1-7, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereoisomer thereof body, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is The following formula I-2-2, formula I-2-3, formula I-2-4 or formula I-2-5:
    其中，A122环选自优选 地，A122环选自 Among them, the A122 ring is selected from preferred Ground, the A122 ring is selected from
    B122环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基选自为-CF3；进一步更优选地，B122环为
    B122 rings are selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are selected from -CF 3 ; further more preferably, the B122 ring is
    A123环选自优选地，A123环选自 The A123 ring is selected from Preferably, the A123 ring is selected from
    B123环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基选自为-CF3；进一步更优选地，B123环为
    B123 rings are selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are selected from -CF 3 ; further more preferably, the B123 ring is
    其中，A124环选自：且所述任选地被Rm所取代或者任选地被Ry和Rm所取代，所述任选地被1-2个选自Rz和Rm的取代基所取代；Wherein, the A124 ring is selected from: and said optionally substituted by Rm or optionally substituted by Ry and Rm, the optionally substituted with 1-2 substituents selected from Rz and Rm;
    其中，Ry为甲基；Rz选自Rm为氧代基；Wherein, Ry is a methyl group; Rz is selected from Rm is an oxo group;
    优选地，A124环及其任选的取代基作为整体，选自以下： 更优选地，A124环及其任选的取代基作为整体，选自 Preferably, ring A124 and its optional substituents, taken as a whole, are selected from the following: More preferably, ring A124 and its optional substituents as a whole are selected from
    B124环选自其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；B124 ring selected from It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens;
    更优选地，所述取代基选自为-CF3；进一步更优选地，B124环为 More preferably, the substituent is selected from -CF 3 ; further more preferably, the B124 ring is
    其中：A125环的定义与权利要求5中A12环的定义相同；A125、A225、A325、A425独立地选自：N、CH，且其中只有1个为N，其余为CH；优选地，A125、A225、A325为CH，A425为N；R125的定义与权利要求5中R12的定义相同；Wherein: the definition of ring A125 is the same as that of ring A12 in claim 5; A 125 , A 225 , A 325 , and A 425 are independently selected from: N, CH, and only one of them is N, and the rest are CH; preferably Specifically, A 125 , A 225 , and A 325 are CH, and A 425 is N; the definition of R 125 is the same as that of R 12 in claim 5;
    B125环选自：其任选地被1个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；且上述其上的取代基的取代位置为：5-位单取代；优选地，B125环选自：其任选地被1个取代基取代，所述取代基选自：-CF3、-Cl、-SF5、-CH3、-F、-OCH3；且上述其上的取代基的取代位置为：5-位单取代；更优选地，B125环选自： 最优选地，B125环为 B125 rings are selected from: It is optionally substituted with 1 substituent selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; and the above The substitution position of the substituent on it is: 5-position monosubstitution; preferably, the B125 ring is selected from: which is optionally substituted with 1 substituent selected from: -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 ; and the above The substitution position of the substituent on it is: 5-position monosubstitution; more preferably, the B125 ring is selected from: Most preferably, the B125 ring is
  9. 根据权利要求1-8任一项所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为以下式I-3：
    The compound according to any one of claims 1-8, or tautomers of said compound, its stereoisomers, its geometric isomers, its enantiomers, its diastereoisomers body, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is Formula I-3 below:
    其中，in,
    A13环选自5-6元杂芳基、5-6元杂环基、苯基，且A13环任选地被1-3个选自Rx、Ry、Rz、Rm的取代基所取代；优选地，A13环选自5元杂芳基、5元不饱和杂环基、6元饱和杂环基、苯基、吡啶基，且A13环任选地被1-3个选自Rx、Ry、Rz、Rm的取代基所取代；更优选地，A13环选自5元杂芳基、5元不饱和杂环基、6元饱和杂环基、苯基、吡啶基，所述5元杂芳基包含2-4个选自N、O、S的杂原子，且A13环任选地被1-3个选自Rx、Ry、Rz、Rm的取代基所取代；进一步优选地，A13环选自5元杂芳基、5元不饱和杂环基、硫代吗啉基、四氢硫代吡喃基、苯基、吡啶基，所述5元杂芳基包含2-4个选自N、O、S的杂原子，且满足以下条件(1)-(3)中任意一项：A13 ring is selected from 5-6 membered heteroaryl, 5-6 membered heterocyclic group, phenyl, and A13 ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, Rm; preferably Preferably, the A13 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, pyridyl, and the A13 ring is optionally selected from 1-3 members selected from Rx, Ry, Substituents of Rz and Rm are substituted; more preferably, the A13 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, pyridyl, and the 5-membered heteroaryl The group contains 2-4 heteroatoms selected from N, O, S, and the A13 ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, Rm; further preferably, the A13 ring is selected from From 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, thiomorpholinyl, tetrahydrothiopyranyl, phenyl, pyridyl, the 5-membered heteroaryl group contains 2-4 selected from N , O, S heteroatoms, and satisfy any one of the following conditions (1)-(3):
    (1)A13环选自5元杂芳基时，所述A13环任选地被Rx所取代，(1) When the A13 ring is selected from a 5-membered heteroaryl group, the A13 ring is optionally substituted by Rx,
    (2)A13环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the A13 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
    (2-1)所述A13环任选地被Rm所取代；(2-1) the A13 ring is optionally substituted by Rm;
    (2-2)所述A13环任选地被Ry、Rz和Rm所取代；(2-2) The A13 ring is optionally substituted by Ry, Rz and Rm;
    (2-3)所述A13环任选地被Ry和Rm所取代；(2-3) The A13 ring is optionally substituted by Ry and Rm;
    (2-4)所述A13环任选地被2个Rm所取代；(2-4) The A13 ring is optionally substituted by 2 Rm;
    (2-5)所述A13环任选地被Rz所取代；(2-5) the A13 ring is optionally substituted by Rz;
    (3)A13环选自硫代吗啉基、四氢硫代吡喃基、苯基、吡啶基时，所述A13环任选地被1-2个选自Rz和Rm的取代基所取代；(3) When the A13 ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the A13 ring is optionally substituted by 1-2 substituents selected from Rz and Rm ;
    更进一步优选地，A13环选自5元杂芳基、5元不饱和杂环基、 More preferably, the A13 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group,
    所述5元杂芳基选自 所述5元不饱和杂环基选自 且满足以下条件(1)-(3)中任意一项：The 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And meet any of the following conditions (1)-(3):
    (1)A13环选自5元杂芳基时，所述A13环任选地被Rx所取代，(1) When the A13 ring is selected from a 5-membered heteroaryl group, the A13 ring is optionally substituted by Rx,
    (2)A13环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the A13 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
    (2-1)所述A13环任选地被Rm所取代；(2-1) the A13 ring is optionally substituted by Rm;
    (2-2)所述A13环任选地被Ry、Rz和Rm所取代；(2-2) The A13 ring is optionally substituted by Ry, Rz and Rm;
    (2-3)所述A13环任选地被Ry和Rm所取代；(2-3) The A13 ring is optionally substituted by Ry and Rm;
    (2-4)所述A13环任选地被2个Rm所取代；(2-4) The A13 ring is optionally substituted by 2 Rm;
    (2-5)所述A13环任选地被Rz所取代； (2-5) the A13 ring is optionally substituted by Rz;
    (3)A13环选自硫代吗啉基、四氢硫代吡喃基、苯基、吡啶基时，所述A13环任选地被1-2个选自Rz和Rm的取代基所取代；(3) When the A13 ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the A13 ring is optionally substituted by 1-2 substituents selected from Rz and Rm ;
    其中，Rx选自C1-C6烷基、4-6元饱和杂环基(优选地，所述4-6元饱和杂环基包含1个选自N、O、S的杂原子)、-C(＝O)NRaRb、-S(＝O)2NRaRb、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、-NRaC(＝O)Rc，所述Rx任选地被1-2个选自Rn的取代基所取代；优选地，Rx选自甲基、乙基、氧杂环丁烷基、四氢吡咯基、四氢吡喃基、哌啶基、-C(＝O)NRaRb、-NRaC(＝O)Rc、-S(＝O)2NRaRb、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基；Wherein, Rx is selected from C1-C6 alkyl, 4-6 membered saturated heterocyclic group (preferably, the 4-6 membered saturated heterocyclic group contains 1 heteroatom selected from N, O, S), -C (=O)NRaRb, -S(=O) 2 NRaRb, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, -NRaC(=O)Rc, the Rx is any is optionally substituted by 1-2 substituents selected from Rn; preferably, Rx is selected from methyl, ethyl, oxetanyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, -C(=O)NRaRb, -NRaC(=O)Rc, -S(=O) 2 NRaRb, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl;
    Rn选自C1-C6烷基、-NRaRb、-C(＝O)NRaRb、氧代、5-6元饱和杂环基(优选地，所述5-6元饱和杂环基包含2个选自N、O、S的杂原子)、C1-C6烷氧基、羧基、羟基；优选地，Rn选自甲基、乙基、-NRaRb、-C(＝O)NRaRb、氧代基、吗啉基、甲氧基、羟基、羧基；Rn is selected from C1-C6 alkyl, -NRaRb, -C(=O)NRaRb, oxo, 5-6 membered saturated heterocyclic group (preferably, the 5-6 membered saturated heterocyclic group contains 2 selected from Heteroatoms of N, O, S), C1-C6 alkoxy, carboxyl, hydroxyl; preferably, Rn is selected from methyl, ethyl, -NRaRb, -C(=O)NRaRb, oxo, morpholine group, methoxy group, hydroxyl group, carboxyl group;
    Ra、Rb、Rc各自独立地选自H、C1-C6烷基、氰基、C3-C6环烷基，或者Ra、Rb和与它们共同相连的碳原子一起，形成氮杂环丁烷，且所述氮杂环丁烷任选地被羟基所取代；优选地，Ra、Rb、Rc各自独立地选自H、甲基、氰基、环丙基，或者Ra、Rb和与它们共同相连的碳原子一起，形成氮杂环丁烷，且所述氮杂环丁烷任选地被羟基所取代；Ra, Rb, and Rc are each independently selected from H, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, or Ra, Rb and the carbon atoms connected to them together form azetidine, and The azetidine is optionally substituted by a hydroxyl group; preferably, Ra, Rb, and Rc are each independently selected from H, methyl, cyano, cyclopropyl, or Ra, Rb and their joint The carbon atoms are taken together to form an azetidine, and the azetidine is optionally substituted with a hydroxyl group;
    最优选地，Rx选自羟基、甲基、 Most preferably, Rx is selected from hydroxyl, methyl,
    Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷基、被1-6个氘取代的C1-C6烷基、被C3-C6环烷基取代的C1-C6烷基、被C6-C10芳基取代的C1-C6烷基、被取代的C1-C6烷基、4-6元饱和杂环基；优选地，Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷基、被1-6个氘取代的C1-C6烷基、被C3-C6环烷基取代的C1-C6烷基、被C6-C10芳基取代的C1-C6烷基、被取代的C1-C6烷基、5-6元饱和杂环基；更优选地，Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被1-3个氘取代的C1-C6烷基、被环丙基取代的C1-C6烷基、被苯基取代的C1-C6烷基、5-6元饱和杂环基，所述5-6元饱和杂环基含有1个杂原子；进一步优选地，Ry选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被1-3个氘取代的C1-C6烷基、被环丙基取代的C1-C6烷基、被苯基取代的C1-C6烷基、四氢吡咯基、哌啶基；最优选地，Ry选自甲基、-CHF2、-CF3、-CD3、-CH2CH3、 -CH2CHF2、-CH2CF3、 Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by 1-6 deuterium, C3- C1-C6 alkyl substituted by C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, C1-C6 alkyl substituted by C6-C10 aryl, Substituted C1-C6 alkyl, 4-6 membered saturated heterocyclic group; preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 substituted by 1-6 halogen Alkyl, C1-C6 alkyl substituted by 1-6 deuterium, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, Substituted C1-C6 alkyl, 5-6 membered saturated heterocyclic group; more preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1- C6 alkyl, C1-C6 alkyl substituted by 1-3 deuterium, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, 5-6 membered saturated heterocyclic group, the 5-6 membered saturated heterocyclic group contains 1 heteroatom; more preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, substituted by 1 - C1-C6 alkyl substituted by 3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, Tetrahydropyrrolyl, piperidinyl; most preferably, Ry is selected from methyl, -CHF 2 , -CF 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 ,
    Rz选自C1-C6烷基、卤素、优选地，Rz选自甲基、Br、 Rz is selected from C1-C6 alkyl, halogen, Preferably, Rz is selected from methyl, Br,
    或者，Ry、Rz以及和它们共同相连的碳原子一起，形成4-6元饱和碳环、4-6元饱和杂环；或者优选地，Ry、Rz以及和它们共同相连的碳原子一起，形成4-6元饱和碳环、4-6元饱和杂环，所述4-6元饱和杂环含有1个杂原子；或者更优选地，Ry、Rz以及和它们共同相连的碳原子一起，形成环丁烷、环戊烷、环己烷、哌啶、四氢吡喃；或者最优选地，Ry、Rz以及和它们共同相连的碳原子一起，形成其中，1’号碳原子为与Ry和Rz共同相连的碳原子；Or, Ry, Rz and their common carbon atoms together form a 4-6 membered saturated carbocyclic ring, a 4-6 membered saturated heterocyclic ring; or preferably, Ry, Rz and their common connected carbon atoms form a 4-6 membered saturated carbocyclic ring, 4-6 membered saturated heterocyclic ring, the 4-6 membered saturated heterocyclic ring contains 1 heteroatom; or more preferably, Ry, Rz and their common carbon atoms together form Cyclobutane, cyclopentane, cyclohexane, piperidine, tetrahydropyran; or most preferably, Ry, Rz and together with the carbon atoms to which they are commonly attached, form Wherein, the 1' carbon atom is the carbon atom connected with Ry and Rz;
    Rm为氧代基；Rm is an oxo group;
    再进一步优选地，A13环及其任选的取代基作为整体，选自以下：


    再更进一步优选地，A13环选自：且所述任选地被Rm所取代，或任选地被Ry和Rm所取代；其中，Ry选自甲基、-CHF2、-CF3、-CH2CH3、-CH2CHF2、-CH2CF3；Rm为氧代基；    Still further preferably, the A13 ring and its optional substituents as a whole are selected from the following:


    Still further preferably, the A13 ring is selected from: and said Optionally substituted by Rm, or optionally substituted by Ry and Rm; wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 ; Rm is an oxo group;
    最优选地，A13环及其任选的取代基作为整体，选自以下：Most preferably, ring A13 and its optional substituents, taken as a whole, are selected from the following:
    优选地，A13环及其任选的取代基作为整体，选自 更优选地，A13环及其任选的取代基作为整体，为B13环选自：其任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、卤素、氨 基；优选地，上述任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；更优选地，上述 任选地被1个取代基取代，所述取代基选自：-CF3、 Preferably, ring A and its optional substituents as a whole are selected from More preferably, ring A and its optional substituents, taken as a whole, are Ring B13 is selected from: It is optionally substituted with 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 substituted with 1-6 halogen Alkyl, halogen, ammonia base; preferably, the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl; more preferably, the above optionally substituted with 1 substituent selected from: -CF 3 ,
    最优选地，B13环选自： Most preferably, the B13 ring is selected from:
    L13选自直接键、NH、O、S；优选地，L13选自直接键、NH；L is selected from direct bond, NH, O, S; preferably, L is selected from direct bond, NH;
    R13选自：C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、被氰基取代的C1-C6烷基、卤素、氰基、氨基、被氨基取代的C1-C6烷基、C2-C6烯基、被C1-C3烷基取代的5-6元饱和杂环基(优选被C1-C3烷基取代的6元饱和杂环基)；或两个R13，与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；更优选地，R13选自：C1-C6烷基、C1-C6烷氧基、被1-3个卤素取代的C1-C6烷基、被氰基取代的C1-C6烷基、卤素、氰基、氨基、被氨基取代的C1-C6烷基、C2-C6烯基、被C1-C3烷基取代的哌嗪基；或两个R13，与它们相连的原子共同形成苯环、部分不饱和C5碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素和氘的基团所取代；R 13 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkoxy substituted by 1-6 halogen, cyano Substituted C1-C6 alkyl, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, 5-6 membered saturated heterocyclic group substituted by C1-C3 alkyl (preferably C1-C3 alkyl substituted 6-membered saturated heterocyclic group); or two R 13 , the atoms connected to them together form a C6-C10 aromatic ring, partially unsaturated C5-C6 carbocyclic ring, partially unsaturated 5-6-membered Heterocyclic ring or 5-6 membered heteroaryl ring, wherein the partially unsaturated C5-C6 carbocyclic ring, partially unsaturated 5-6 membered heterocyclic ring or 5-6 membered heteroaryl ring are each optionally replaced by 1-6 members selected from halogen and deuterium; more preferably, R 13 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-3 halogen, C1 substituted by cyano -C6 alkyl, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, piperazinyl substituted by C1-C3 alkyl; or two R 13 , connected to them The atoms together form a benzene ring, a partially unsaturated C5 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5 carbocyclic ring and the partially unsaturated 5-6 membered heterocyclic ring are each optionally Substituted by 1-6 groups selected from halogen and deuterium;
    进一步优选地，R13选自：-OCH3、-CH3、-CH2CH3、-F、-Cl、-CN、-CF3、-CHF2、-NH2、或两个R13与它们相连的原子共同形成： Further preferably, R 13 is selected from: -OCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CF 3 , -CHF 2 , -NH 2 , or two R 13 together with the atoms they are attached to form:
    更进一步优选地，R13位于环上的位置选自：A23位、A33位；More preferably, the position of R 13 on the ring is selected from: A 23 position, A 33 position;
    A13、A23、A33、A43独立地选自：N、CH，且其中只有2个为N，其余为CH；优选地，A13、A23、A33、A43选自以下组合：A 13 , A 23 , A 33 , A 43 are independently selected from: N, CH, and only 2 of them are N, and the rest are CH; preferably, A 13 , A 23 , A 33 , A 43 are selected from the following combinations :
    1)A13、A43都为N，A23、A33都为CH；1) Both A 13 and A 43 are N, and both A 23 and A 33 are CH;
    2)A33、A43都为N，A13、A23都为CH；2) Both A 33 and A 43 are N, and both A 13 and A 23 are CH;
    3)A23、A43都为N，A13、A33都为CH。3) Both A 23 and A 43 are N, and both A 13 and A 33 are CH.
  10. 根据权利要求1-9任一项所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为以下式I-3-1、式I-3-2或者式I-3-3：
    The compound according to any one of claims 1-9, or tautomers of said compound, its stereoisomers, its geometric isomers, its enantiomers, its diastereoisomers body, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is The following formula I-3-1, formula I-3-2 or formula I-3-3:
    其中，A131环选自：且所述任选地被Rm所取代，或任选地被Ry和Rm所取代；Wherein, the A131 ring is selected from: and said optionally substituted by Rm, or optionally substituted by Ry and Rm;
    其中，Ry选自甲基、-CHF2、-CF3、-CH2CH3、-CH2CHF2、-CH2CF3、-CH2CH2OH；Rm为氧代基；Wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3, -CH 2 CH 2 OH; Rm is an oxo group;
    优选地，A131环及其任选的取代基作为整体，选自以下：
    更优选地，A131环及其任选的取代基作为整体，选自以下： 最优选地，A131环及其任选的取代基作为整体，选自：     Preferably, ring A131 and its optional substituents, taken as a whole, are selected from the following:
    More preferably, ring A131 and its optional substituents, taken as a whole, are selected from the following: Most preferably, the A131 ring and its optional substituents, taken as a whole, are selected from:
    B131环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；更优选地，所述取代基选自为-CF3、进一步更优选地，B131环为 The B131 ring is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituent is selected from: C1-C6 alkyl, C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituent is selected from -CF 3 , Further more preferably, the B131 ring is
    L131选自直接键、NH、O、S；优选地，L131选自直接键、NH；A131、A231、A331、A431独立地选自：N、CH，且其中只有2个为N，其余为CH；优选地，A131、A231、A331、A431选自以下组合：L 131 is selected from direct bond, NH, O, S; preferably, L 131 is selected from direct bond, NH; A 131 , A 231 , A 331 , A 431 are independently selected from: N, CH, and only 2 of them is N, and the rest are CH; preferably, A 131 , A 231 , A 331 , and A 431 are selected from the following combinations:
    1)A131、A431都为N，A231、A331都为CH；1) Both A 131 and A 431 are N, and both A 231 and A 331 are CH;
    2)A331、A431都为N，A131、A231都为CH；2) Both A 331 and A 431 are N, and both A 131 and A 231 are CH;
    3)A231、A431都为N，A131、A331都为CH；
    3) Both A 231 and A 431 are N, and both A 131 and A 331 are CH;
    其中，A131c环定义与上述式I-3-1中A131环定义相同；Wherein, the definition of ring A131c is the same as that of ring A131 in the above formula I-3-1;
    A131、A231、A331、A431定义与上述式I-3-1中A131、A231、A331、A431的定义相同；
    The definitions of A 131 , A 231 , A 331 , and A 431 are the same as the definitions of A 131 , A 231 , A 331 , and A 431 in the above formula I-3-1;
    其中，A132环选自：且所述任选地被Rm所取代，或任选地被Ry和Rm所取代；其中，Ry选自甲基、-CHF2、-CF3、-CD3、-CH2CH3、-CH2CHF2、-CH2CF3、-CH2CH2OH；Rm为氧代基；Wherein, the A132 ring is selected from: and said Optionally substituted by Rm, or optionally substituted by Ry and Rm; wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3, -CH 2 CH 2 OH; Rm is an oxo group;
    优选地，A132环及其任选的取代基作为整体，选自以下：
    更优选地，A132环及其任选的取代基作为整体，选自以下： 最优选地，A132环及其任选的取代基作为整体，选自：     Preferably, the A132 ring and its optional substituents, taken as a whole, are selected from the following:
    More preferably, ring A132 and its optional substituents, taken as a whole, are selected from the following: Most preferably, the A132 ring and its optional substituents, taken as a whole, are selected from:
    B132环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基选自为-CF3；进一步更优选地，B132环为 B132 rings are selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are selected from -CF 3 ; further more preferably, the B132 ring is
    R132选自：C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、被氰基取代的C1-C6烷基、卤素、氰基、氨基、被氨基取代的C1-C6烷基、C2-C6烯基、被C1-C3烷基取代的6元饱和杂环基；或两个R132，与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各自任选地被1-6个选自卤素和氘的基团所取代；更优选地，R132选自：C1-C6烷基、C1-C6烷氧基、被1-3个卤素取代的C1-C6烷基、被氰基取代的C1-C6烷基、卤素、氰基、氨基、被氨基取代的C1-C6烷基、C2-C6烯基、被C1-C3烷基取代的哌嗪基；或两个R132，与它们相连的原子共同形成苯环、部分不饱和C5碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素(优选-F)和氘的基团所取代；R 132 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkoxy substituted by 1-6 halogen, cyano Substituted C1-C6 alkyl, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, 6-membered saturated heterocyclic group substituted by C1-C3 alkyl; or two R 132 , and the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, in which a partially unsaturated C5-C6 carbon Ring, partially unsaturated 5-6 membered heterocycle or 5-6 membered heteroaromatic ring are each optionally substituted with 1-6 groups selected from halogen and deuterium; more preferably , R is selected from: C1- C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-3 halogen, C1-C6 alkyl substituted by cyano, halogen, cyano, amino, C1-C6 substituted by amino Alkyl, C2-C6 alkenyl, piperazinyl substituted by C1-C3 alkyl; or two R 132 , the atoms connected to them together form a benzene ring, a partially unsaturated C5 carbocycle, and a partially unsaturated 5-6 A membered heterocyclic ring or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5 carbocyclic ring and the partially unsaturated 5-6 membered heterocyclic ring are each optionally replaced by 1-6 groups selected from halogen (preferably -F) and deuterium replace;
    进一步优选地，R132选自：-OCH3、-CH3、-CH2CH3、-F、-Cl、-CN、-CF3、-CHF2、-NH2、或两个R132与它们相连的原子共同形成： Further preferably, R 132 is selected from: -OCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CF 3 , -CHF 2 , -NH 2 , or two R 132 together with the atoms they are attached to form:
    更进一步优选地，R132位于环上的位置选自：A232位、A332位；A132、A232、A332、A432独立地选自：N、CH，且其中只有2个为N，其余为CH；优选地，A132、A232、A332、A432选自以下组合：A132、A432都为N，A232、A332都为CH；More preferably, the position of R 132 on the ring is selected from: A 232 position, A 332 position; A 132 , A 232 , A 332 , A 432 are independently selected from: N, CH, and only 2 of them are N , and the rest are CH; preferably, A 132 , A 232 , A 332 , and A 432 are selected from the following combinations: both A 132 and A 432 are N, and both A 232 and A 332 are CH;
    优选地，所述式I-3-2为式I-3-2c，Preferably, the formula I-3-2 is Formula I-3-2c,
    其中，A132c环的定义与上述式I-3-2中A132环的定义相同；R132的定义与上述式I-3-2中R132的定义相同；A132、A232、A332、A432的定义与上述式I-3-2中A132、A232、A332、A432的定义相同；
    Among them, the definition of A132c ring is the same as the definition of A132 ring in the above formula I-3-2; the definition of R 132 is the same as the definition of R 132 in the above formula I-3-2; A 132 , A 232 , A 332 , A The definition of 432 is the same as the definition of A 132 , A 232 , A 332 , A 432 in the above formula I-3-2;
    其中：A133环的定义与权利要求9中A13环的定义相同；B133环的定义与权利要求9中B13环的定义相同；R133的定义与权利要求9中R13的定义相同；或者，所述化合物为以下式I-3-4：
    Wherein: the definition of A133 ring is the same as the definition of A13 ring in claim 9; the definition of B133 ring is the same as the definition of B13 ring in claim 9; the definition of R 133 is the same as the definition of R 13 in claim 9; or, the Described compound is following formula I-3-4:
    其中：in:
    A134环的定义与权利要求9中A13环的定义相同；优选地，A134环及其任选的取代基作为整体，选自 The definition of ring A134 is the same as that of ring A13 in claim 9; preferably, ring A134 and its optional substituents as a whole are selected from
    更优选地，A134环及其任选的取代基作为整体，选自： More preferably, the A134 ring and its optional substituents as a whole are selected from:
    B134环的定义与权利要求9中B13环的定义相同；优选地，B134环选自：其任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、卤素、氨基；更优选地，上述任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；进一步优选地，上述任选地被1个取代基取代，所述取代基选自：-CF3、更进一步优选地，B134环选自： 最优选地，B134环为 The definition of ring B134 is the same as that of ring B13 in claim 9; preferably, ring B134 is selected from: It is optionally substituted with 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 substituted with 1-6 halogen Alkyl, halogen, amino; more preferably, the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl; more preferably, the above optionally substituted with 1 substituent selected from: -CF 3 , Still further preferably, the B134 ring is selected from: Most preferably, the B134 ring is
    R134的定义与权利要求9中R13的定义相同；优选地，两个R134，与它们相连的原子共同形成5元杂芳环；The definition of R 134 is the same as the definition of R 13 in claim 9; preferably, two R 134 and the atoms connected to them together form a 5-membered heteroaromatic ring;
    更优选地，或两个R134与它们相连的原子共同形成： More preferably, or two R 134 together with the atoms to which they are attached form:
    或者，所述化合物为以下式I-3-5：
    Alternatively, the compound is the following formula I-3-5:
    其中：in:
    A135环的定义与权利要求9中A13环的定义相同； The definition of ring A135 is the same as the definition of ring A13 in claim 9;
    B135环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、卤素、氨基；且上述其上的取代基的取代位置为：5-位单取代；优选地，上述任选地被1个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；且上述其上的取代基的取代位置为：5-位单取代；更优选地，B135环选自：最优选地，B135环为 B135 rings are selected from: It is optionally substituted with 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 alkyl , halogen, amino; and the above The substitution position of the substituent on it is: 5-position monosubstituted; preferably, the above-mentioned optionally substituted with 1 substituent selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl; and the above The substitution position of the substituent on it is: 5-position monosubstitution; more preferably, the B135 ring is selected from: Most preferably, the B135 ring is
    R135的定义与权利要求9中R13的定义相同；The definition of R 135 is the same as the definition of R 13 in claim 9;
    A135、A235、A335、A435独立地选自：N、CH，且其中只有2个为N，其余为CH；优选地，A135、A235、A335、A435选自以下组合：A 135 , A 235 , A 335 , and A 435 are independently selected from: N, CH, and only 2 of them are N, and the rest are CH; preferably, A 135 , A 235 , A 335 , and A 435 are selected from the following combinations :
    1)A135、A435都为N，A235、A335都为CH；1) Both A 135 and A 435 are N, and both A 235 and A 335 are CH;
    2)A335、A435都为N，A135、A235都为CH；2) Both A 335 and A 435 are N, and both A 135 and A 235 are CH;
    3)A235、A435都为N，A135、A335都为CH；3) Both A 235 and A 435 are N, and both A 135 and A 335 are CH;
    或者，所述化合物为以下式I-4：
    Alternatively, the compound is the following formula I-4:
    其中：in:
    Y14选自N、CH； Y 14 is selected from N, CH;
    A14环选自5元杂芳基、5元不饱和杂环基，所述5元杂芳基选自所述5元不饱和杂环基选自 且满足以下条件(1)-(2)中任意一项：The A14 ring is selected from 5-membered heteroaryl groups and 5-membered unsaturated heterocyclic groups, and the 5-membered heteroaryl groups are selected from The 5-membered unsaturated heterocyclic group is selected from And meet any one of the following conditions (1)-(2):
    (1)A14环选自5元杂芳基时，所述A14环任选地被Rx所取代，(1) When the A14 ring is selected from a 5-membered heteroaryl group, the A14 ring is optionally substituted by Rx,
    (2)A14环选自5元不饱和杂环基时，满足以下条件(2-1)～(2-5)中任意一项：(2) When the A14 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:
    (2-1)所述A14环任选地被Rm所取代；(2-1) the A14 ring is optionally substituted by Rm;
    (2-2)所述A14环任选地被Ry、Rz和Rm所取代；(2-2) The A14 ring is optionally substituted by Ry, Rz and Rm;
    (2-3)所述A14环任选地被Ry和Rm所取代；(2-3) the A14 ring is optionally substituted by Ry and Rm;
    (2-4)所述A14环任选地被2个Rm所取代；(2-4) The A14 ring is optionally substituted by 2 Rm;
    (2-5)所述A14环任选地被Rz所取代；(2-5) the A14 ring is optionally substituted by Rz;
    其中，in,
    Rx选自羟基、 Rx is selected from hydroxyl,
    Ry选自甲基、-CHF2、-CF3、D3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rz选自甲基、 Ry is selected from methyl, -CHF 2 , -CF 3 , D 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rz is selected from methyl,
    或者，Ry、Rz以及和它们共同相连的碳原子一起，形成其中，1’号碳原子为与Ry和Rz共同相连的碳原子；Rm为氧代基；Alternatively, Ry, Rz, and the carbon atoms connected to them together form Wherein, the 1' carbon atom is a carbon atom connected to Ry and Rz; Rm is an oxo group;
    最优选地，A14环及其任选的取代基作为整体，选自以下：

    Most preferably, ring A14 and its optional substituents, taken as a whole, are selected from the following:

    B14环选自： 其任选地被1-3个取代基取代，所述取代基选自：五氟化硫基、-OH、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素、硝基、氰基、氨基、C3-C4环烷基、；Ring B14 is selected from: It is optionally substituted with 1-3 substituents selected from: thiopentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1 -C6 alkyl, halogen, nitro, cyano, amino, C3-C4 cycloalkyl,;
    优选地，上述 其任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；Preferably, the above It is optionally substituted with 1-2 substituents selected from the group consisting of: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkane base, halogen;
    更优选地，上述任选地被1-2个取代基取代，所述取代基选自：五氟化硫基、C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；或者上述 任选地被1-2个取代基取代，所述取代基选自：C1-C6烷基、1-6个卤素取代的C1-C6烷基；More preferably, the above Optionally substituted with 1-2 substituents selected from: thiopentafluoride, C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl , halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, 1-6 halogen substituted C1-C6 alkyl;
    更优选地，上述任选地被1-2个取代基取代，所述取代基选自：-CF3、-Cl、-SF5、-CH3、 -F、-OCH3、或者上述 任选地被1-2个取代基取代，所述取代基选自：-CF3、-CH3；进一步优选地，上述其上的取代基的取代位置为：2-位单取代、3-位单取代、5-位单取代、4-、5-位双取代、5-、6-位双取代、2-、5-位双取代、3-、5-位双取代；其上的取代基的取代位置为3-位单取代、5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为6-位单取代，其上的取代基的取代位置为5-位或6位单取代或双取代；其上的取代基的取代位置为5-位单取代；其上 的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；其上的取代基的取代位置为5-位单取代；More preferably, the above Optionally substituted with 1-2 substituents selected from: -CF 3 , -Cl, -SF 5 , -CH 3 , -F, -OCH 3 , or above Optionally substituted by 1-2 substituents selected from: -CF 3 , -CH 3 ; more preferably, the above The substitution positions of the substituents on it are: 2-position mono-substitution, 3-position mono-substitution, 5-position mono-substitution, 4-, 5-position double substitution, 5-, 6-position double substitution, 2-, 5-position - double substitution, 3-, 5-position double substitution; The substitution positions of the substituents on it are 3-position mono-substitution and 5-position mono-substitution; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 6-position monosubstituted, The substitution position of the substituent on it is 5-position or 6-position single substitution or double substitution; The substitution position of the substituent on it is 5-position monosubstituted; on it The substitution position of the substituent is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted; The substitution position of the substituent on it is 5-position monosubstituted;
    最优选地，B14环选自： Most preferably, the B14 ring is selected from:
    R14选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被氨基取代的C1-C6烷基、被氰基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、C1-C5杂芳基、C1-C6烷氧基、羟基取代的C1-C6烷氧基、被5-6元杂芳基取代的C1-C6烷氧基、C3-C5杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、卤素、氰基、C2-C6烯基、被C6-C10芳基取代的C1-C6烷基、5-6元杂环基；其中C3-C5杂环基被C1-C3烷基任意取代，C6-C10芳基被1-6个卤素任意取代，5-6元杂环基被C1-C3烷基或羟基任意取代；或两个R14，与它们相连的原子共同形成C6-C10芳环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环，其中部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5-6元杂芳环各 自任选地被1-6个选自卤素和氘的基团所取代；更优选地，R14选自：N上被1-2个C1-C6烷基取代的氨基磺酰基、N上被1-2个C1-C6烷基取代的氨基甲酰基、吡啶基C1-C6烷氧基、羟基取代的C1-C6烷氧基、C3杂环基氧基、羧基(-COOH)、酯基(-CO-O-C1-C6烷基)、羟基、氨基、C1-C6烷氧基、C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被氨基取代的C1-C6烷基、被氰基取代的C1-C6烷基、卤素、氰基、C2-C6烯基、被苯基取代的C1-C6烷基、四氢吡咯基、哌嗪基，其中C3杂环基被C1-C3烷基任意取代，四氢吡咯基被羟基任意取代，哌嗪基被C1-C3烷基任意取代；或两个R14，与它们相连的原子共同形成苯环、部分不饱和C5-C6碳环、部分不饱和5-6元杂环或5元杂芳环，其中部分不饱和C5-C6碳环和部分不饱和5-6元杂环各自任选地被1-6个选自卤素(优选-F)和氘的基团所取代；进一步优选地，R14选自： -OH、-NH2、-COOH、-COOCH3、-CH3、-CH2CH3、-F、-Cl、-CN、-CHF2、-CF3、 或两个R14与它们相连的原子共同形成： R 14 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, C1-C6 alkyl, C1-C6 Alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by amino, C1-C6 alkyl substituted by cyano, C1-C6 substituted by 1-6 halogen Alkoxy, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 heterocycle Oxygen, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1- substituted by C6-C10 aryl C6 alkyl, 5-6 membered heterocyclic group; where C3-C5 heterocyclic group is optionally substituted by C1-C3 alkyl, C6-C10 aryl is optionally substituted by 1-6 halogens, 5-6 membered heterocyclic group is optionally substituted by C1-C3 alkyl or hydroxyl is optionally substituted; or two R 14 , and the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5- 6-membered heteroaromatic ring, wherein partially unsaturated C5-C6 carbocycle, partially unsaturated 5-6 membered heterocyclic ring or 5-6 membered heteroaryl ring each is optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, R 14 is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyls on N, substituted by 1-2 C1-C6 alkyl substituted carbamoyl, pyridyl C1-C6 alkoxy, hydroxyl substituted C1-C6 alkoxy, C3 heterocyclyloxy, carboxyl (-COOH), ester ( -CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogen, C1-C6 substituted by amino Alkyl, C1-C6 alkyl substituted by cyano, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrolyl, piperazinyl, of which C3 heterocyclyl It is optionally substituted by C1-C3 alkyl, tetrahydropyrrolyl is arbitrarily substituted by hydroxyl, piperazinyl is arbitrarily substituted by C1-C3 alkyl; or two R 14 , the atoms connected to them together form a benzene ring, partially unsaturated C5 -C6 carbocycle, partly unsaturated 5-6 membered heterocycle or 5 membered heteroaryl ring, wherein partly unsaturated C5-C6 carbocycle and partly unsaturated 5-6 membered heterocycle are each optionally selected from 1-6 Substituted from halogen (preferably -F) and deuterium; Further preferably, R 14 is selected from: -OH, -NH 2 , -COOH, -COOCH 3 , -CH 3 , -CH 2 CH 3 , -F, -Cl, -CN, -CHF 2 , -CF 3 , or two R14 together with the atoms they are attached to form:
  11. 根据权利要求1所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为以下式II：
    The compound according to claim 1, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemization thereof body, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is the following formula II:
    A2环选自： 优选地，A2环选自 更优选地，A2环选自R2选自：C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、卤素、氨基；优选地，R2选自：1-6个卤素取代的C1-C6烷基；更优选地，R2为-CF3；Ring A2 is selected from: Preferably, the A2 ring is selected from More preferably, ring A2 is selected from R 2 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 alkyl, halogen, amino; preferably, R 2 is selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, R 2 is -CF 3 ;
    进一步更优选地，R2所在位置为：5-位单取代；Further more preferably, the position of R2 is: 5-position single substitution;
    或者，所述化合物为以下式III：
    Alternatively, the compound is of formula III below:
    A3环选自： 优选地，A3环选自 更优选地，A3环选自 The A3 ring is selected from: Preferably, the A3 ring is selected from More preferably, the A3 ring is selected from
    R3选自：C1-C6烷基、C1-C6烷氧基、C3-C4环烷基、1-6个卤素取代的C1-C6烷基、卤素、氨基； 优选地，R3选自：1-6个卤素取代的C1-C6烷基；更优选地，R3为-CF3；进一步更优选地，R3所在位置为：5-位单取代。 R is selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, 1-6 halogen substituted C1-C6 alkyl, halogen, amino; Preferably, R 3 is selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, R 3 is -CF 3 ; still more preferably, the position of R 3 is: 5-position monosubstitution.
  12. 根据权利要求1所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为以下式IV：
    The compound according to claim 1, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemization thereof body, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is the following formula IV:
    A4环选自：且所述任选地被Rm所取代，或任选地被Ry和Rm所取代；The A4 ring is selected from: and said optionally substituted by Rm, or optionally substituted by Ry and Rm;
    其中，Ry选自甲基、-CHF2、-CF3、CD3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rm为氧代基；Wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rm is an oxo group;
    优选地，A4环及其任选的取代基作为整体，选自： 优选地，A4环及其任选的取代基作为整体，选自： 最优选地，A4环及其任选的取代基作为整体，选自：B4环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优 选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基为-CF3；进一步更优选地，B4环为 Preferably, ring A4 and its optional substituents, taken as a whole, are selected from: Preferably, ring A4 and its optional substituents, taken as a whole, are selected from: Most preferably, ring A4 and its optional substituents, taken as a whole, are selected from: Ring B4 is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably Optionally, the substituent is selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituent is -CF 3 ; further more preferably, the B4 ring is
    C4环选自 The C4 ring is selected from
    R4选自：C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、卤素、氰基、氨基；或两个R4，与它们相连的原子共同形成5-6元杂环或5-6元杂芳环；优选地，R4选自：C1-C6烷基；或两个R4，与它们相连的原子共同形成5-6元杂环或5-6元杂芳环；更优选地，两个R4，与它们相连的原子共同形成5-6元杂环；最优选地，两个R4，与它们相连的原子共同形成： R is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkoxy substituted by 1-6 halogen, halogen, cyano group, amino group; or two R 4 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; preferably, R 4 is selected from: C1-C6 alkyl; or two R 4 , the atoms connected to them form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; more preferably, two R 4 , and the atoms connected to them form a 5-6-membered heterocyclic ring; most preferably , two R 4 , together with the atoms they are connected to form:
  13. 根据权利要求10所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为以下式IV-1：
    The compound according to claim 10, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemization thereof body, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is the following formula IV-1 :
    A41环选自：且所述任选地被Rm所取代，或任选地被Ry和Rm所取代；The A41 ring is selected from: and said optionally substituted by Rm, or optionally substituted by Ry and Rm;
    其中，Ry选自甲基、-CHF2、-CF3、CD3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rm为氧代基；Wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rm is an oxo group;
    优选地，A41环及其任选的取代基作为整体，选自： 优选地，A41环及其任选的取代基作为整体，选自： 最优选地，A41环及其任选的取代基作为整体，选自： Preferably, ring A41 and its optional substituents as a whole are selected from: Preferably, ring A41 and its optional substituents as a whole are selected from: Most preferably, ring A41 and its optional substituents, taken as a whole, are selected from:
    B41环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基为-CF3；进一步更优选地，B41环为 Ring B41 is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B41 ring is
    A41选自：O、S；A 41 is selected from: O, S;
    或者，所述化合物为以下式IV-2，
    Alternatively, the compound is the following formula IV-2,
    A42环选自：且所述任选地被Rm所取代，或任选地被Ry和Rm所取代；A42 rings are selected from: and said optionally substituted by Rm, or optionally substituted by Ry and Rm;
    其中，Ry选自甲基、-CHF2、-CF3、CD3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rm为氧代基；Wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rm is an oxo group;
    优选地，A42环及其任选的取代基作为整体，选自： 优选地，A42环及其任选的取代基作为整体，选自： 最优选地，A42环及其任选的取代基作为整体，选自： Preferably, ring A42 and its optional substituents, taken as a whole, are selected from: Preferably, ring A42 and its optional substituents, taken as a whole, are selected from: Most preferably, ring A42 and its optional substituents, taken as a whole, are selected from:
    B42环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基为-CF3；进一步更优选地，B42环为 The B42 ring is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B42 ring is
    R421、R422各自独立地选自：C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、卤素、氰基、氨基；或R421和R422，与它们相连的原子共同形成5-6元杂环或5-6元杂芳环；优选地，R421、R422各自独立地选自：C1-C6烷基；或R421和R422，与它们相连的原子共同形成5-6元杂环或5-6元杂芳环；更优选地，R421和R422，与它们相连的原子共同形成5-6元杂环；最优选地，R421和R422，与它们相连的原子共同形成： R 421 and R 422 are each independently selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkane substituted by 1-6 halogens Oxygen, halogen, cyano, amino; or R 421 and R 422 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; preferably, R 421 and R 422 are independently Selected from: C1-C6 alkyl; or R 421 and R 422 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; more preferably, R 421 and R 422 , together with them The connected atoms together form a 5-6 membered heterocyclic ring; most preferably, R 421 and R 422 , together with their connected atoms form:
    或者，所述化合物为以下式IV-3，
    Alternatively, the compound is the following formula IV-3,
    A43环选自：且所述任选地被Rm所取代，或任选地被Ry和Rm所取代； The A43 ring is selected from: and said optionally substituted by Rm, or optionally substituted by Ry and Rm;
    其中，Ry选自甲基、-CHF2、-CF3、CD3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rm为氧代基；Wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rm is an oxo group;
    优选地，A43环及其任选的取代基作为整体，选自： 优选地，A43环及其任选的取代基作为整体，选自： 最优选地，A43环及其任选的取代基作为整体，选自： Preferably, ring A43 and its optional substituents, taken as a whole, are selected from: Preferably, ring A43 and its optional substituents, taken as a whole, are selected from: Most preferably, ring A43 and its optional substituents, taken as a whole, are selected from:
    B43环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基；更优选地，所述取代基为-CF3；进一步更优选地，B43环为 Ring B43 is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; more preferably, the substituents are -CF 3 ; further more preferably, the B43 ring is
    R431、R432各自独立地选自：氢、C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、卤素、氰基、氨基；或R431和R432，与它们相连的原子共同形成5-6元杂环或5-6元杂芳环；优选地，R431、R432各自独立地选自：氢、C1-C6烷基；或R431和R432，与它们相连的原子共同形成5-6元杂环或5-6元杂芳环；更优选地，R431、R432为氢；或R431和R432，与它们相连的原子共同形成5-6元杂环；最优选地，R431、R432为氢；或R431和R432，与它们相连的原子共同形成： R 431 and R 432 are each independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1- C6 alkoxy, halogen, cyano, amino; or R 431 and R 432 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; preferably, R 431 and R 432 are each independently selected from: hydrogen, C1-C6 alkyl; or R 431 and R 432 , and the atoms connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; more preferably, R 431 , R 432 is hydrogen; or R 431 and R 432 , together form a 5-6-membered heterocyclic ring with their connected atoms; most preferably, R 431 and R 432 are hydrogen; or R 431 and R 432 , together with their connected atoms form:
  14. 根据权利要求1所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为以下式V：
    The compound according to claim 1, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemization thereof body, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is the following formula V:
    A5环选自：且所述任选地被Rm所取代，或任选地被Ry和Rm所取代；The A5 ring is selected from: and said optionally substituted by Rm, or optionally substituted by Ry and Rm;
    其中，Ry选自甲基、-CHF2、-CF3、CD3、-CH2CH3、-CH2CHF2、-CH2CF3、 Rm为氧代基；Wherein, Ry is selected from methyl, -CHF 2 , -CF 3 , CD 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Rm is an oxo group;
    优选地，A5环及其任选的取代基作为整体，选自： 优选地，A5环及其任选的取代基作为整体，选自： 最优选地，A5环及其任选的取代基作为整体，选自： Preferably, ring A5 and its optional substituents as a whole are selected from: Preferably, ring A5 and its optional substituents as a whole are selected from: Most preferably, ring A5 and its optional substituents, taken as a whole, are selected from:
    B5环选自：其任选地被1个取代基取代，所述取代基选自：C1-C6烷基、C1-C6烷氧基、1-6个卤素取代的C1-C6烷基、卤素；优选地，所述取代基选自：1-6个卤素取代的C1-C6烷基； 更优选地，所述取代基为-CF3；进一步更优选地，B5环为R5选自：氢、C1-C6烷基、C1-C6烷氧基、被1-6个卤素取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷氧基、卤素、氰基、氨基；优选地，R5选自C1-C6烷基；更优选地，R5为-CH3。Ring B5 is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, 1-6 halogen substituted C1-C6 alkyl, halogen; preferably, the The substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens; More preferably, the substituent is -CF 3 ; further more preferably, the B5 ring is R is selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkoxy substituted by 1-6 halogen, halogen , cyano, amino; preferably, R 5 is selected from C1-C6 alkyl; more preferably, R 5 is -CH 3 .
  15. 根据权利要求1所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物为以下式VI：
    The compound according to claim 1, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemization thereof body, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is the following formula VI:
    其中：in:
    R6’选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-6个卤素取代的C1-C6烷基、被1-6个氘取代的C1-C6烷基、被C3-C6环烷基取代的C1-C6烷基、被C6-C10芳基取代的C1-C6烷基、被取代的C1-C6烷基；优选地，R6’选自C1-C6烷基、被羟基取代的C1-C6烷基、被1-3个卤素取代的C1-C6烷基、被1-3个氘取代的C1-C6烷基、被环丙基取代的C1-C6烷基、被苯基取代的C1-C6烷基、更优选地，R6’选自甲基、-CHF2、-CF3、-CH2CH3、-CH2CHF2、-CH2CF3、 最优选地，R6’为甲基；R 6' is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogen, C1-C6 alkyl substituted by 1-6 deuterium, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, Substituted C1-C6 alkyl; preferably, R 6' is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 C1-C6 alkyl substituted by deuterium, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, More preferably, R 6' is selected from methyl, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , Most preferably, R 6' is methyl;
    B6环的定义与权利要求1中Bo环的定义相同；或者，B6环的定义与权利要求4中B11环的定义相同；或者，B6环的定义与权利要求5中B12环的定义相同；或者，B6环的定义与权利要求9中B13环的定义相同；或者，B6环的定义与权利要求10中B14环的定义相同；或者，B6环的定义与权利要求12中B4环的定义相同；The definition of the B6 ring is the same as the definition of the Bo ring in claim 1; or, the definition of the B6 ring is the same as the definition of the B11 ring in claim 4; or, the definition of the B6 ring is the same as the definition of the B12 ring in claim 5; or , the definition of B6 ring is the same as the definition of B13 ring in claim 9; or, the definition of B6 ring is the same as the definition of B14 ring in claim 10; or, the definition of B6 ring is the same as the definition of B4 ring in claim 12;
    C6环的定义与权利要求1中Co环的定义相同；或者，C6环的定义与权利要求15中C4环的定义相同；The definition of C6 ring is the same as the definition of Co ring in claim 1; or, the definition of C6 ring is the same as the definition of C4 ring in claim 15;
    R6的定义与权利要求1中Ro的定义相同；或者，R6的定义与权利要求4中R11的定义相同；或者，R6的定义与权利要求5中R12的定义相同；或者，R6的定义与权利要求9中R13的定义相同；或者，R6的定义与权利要求10中R14的定义相同；或者，R6的定义与权利要求12中R4的定义相同；The definition of R6 is the same as the definition of Ro in claim 1; or, the definition of R6 is the same as the definition of R11 in claim 4; or, the definition of R6 is the same as the definition of R12 in claim 5; or , The definition of R 6 is the same as the definition of R 13 in claim 9; or, the definition of R 6 is the same as the definition of R 14 in claim 10; or, the definition of R 6 is the same as the definition of R 4 in claim 12;
    或者化合物为以下式Ox：
    Or the compound is the following formula Ox:
    其中：in:
    Aox环选自： 优选地，Aox环选自： 最优选地，Aox环为 Y选自CH、N；Rx的定义与上述式I-2-1中R121的定义相同；或者，Rx的定义与上述式I-3-2中R132的定义相同；优选地，Rx位于环上的位置选自：2-位单取代，3-位单取代，或2-、3-位双取代。Aox rings selected from: Preferably, the Aox ring is selected from: Most preferably, the Aox ring is Y is selected from CH, N; the definition of Rx is the same as the definition of R 121 in the above formula I-2-1; or, the definition of Rx is the same as the definition of R 132 in the above formula I-3-2; preferably, Rx is located at The position on the ring is selected from: 2-position mono-substitution, 3-position mono-substitution, or 2-, 3-position double substitution.
  16. 根据权利要求1-15任一项所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物，其中，所述化合物选自以下：















    The compound according to any one of claims 1-15, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereoisomer thereof body, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite, wherein, the compound is selected from from the following:















  17. 药物组合物，其包含权利要求1-16任一项所述的化合物，或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；任选地，还包含药学上可接受的辅料。A pharmaceutical composition comprising the compound of any one of claims 1-16, or a tautomer of said compound, its stereoisomer, its geometric isomer, its enantiomer, its Diastereomers, their racemates, their prodrugs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, their hydrates, their esters, their isotopes, or their metabolites; any Optionally, pharmaceutically acceptable auxiliary materials are also included.
  18. 一种治疗患者中癌症的方法，其包含向所述患者给予权利要求1至16中任一权利要求所述的化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或权利要求17所述的药物组合物。A method of treating cancer in a patient comprising administering to said patient a compound according to any one of claims 1 to 16, or a tautomer of said compound, a stereoisomer thereof, a geometric Isomers, enantiomers thereof, diastereomers thereof, racemates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, hydrates thereof, Its ester, its isotope, or its metabolite; or the pharmaceutical composition described in claim 17.
  19. 一种抑制患者中癌症进展的方法，其包含向所述患者给予权利要求1至16中任一权利要求所述的化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或权利要求17所述的药物组合物。A method of inhibiting cancer progression in a patient comprising administering to said patient a compound according to any one of claims 1 to 16, or a tautomer of said compound, a stereoisomer thereof, a Geometric isomers, their enantiomers, their diastereoisomers, their racemates, their prodrugs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and their hydrates , its ester, its isotope, or its metabolite; or the pharmaceutical composition of claim 17.
  20. 根据权利要求18或19所述的方法，其中，所述癌症与TEAD过表达相关；或与TEAD活性增加相关。The method of claim 18 or 19, wherein the cancer is associated with TEAD overexpression; or with increased TEAD activity.
  21. 一种治疗患有与TEAD表达增加相关的疾病或病症的患者的方法，其包含向所述患者给予权利要求1至16中任一权利要求所述的化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或权利要求17所述的药物组合物。A method of treating a patient suffering from a disease or disorder associated with increased expression of TEAD comprising administering to said patient a compound of any one of claims 1 to 16, or a tautomer of said compound its stereoisomers, its geometric isomers, its enantiomers, its diastereoisomers, its racemates, its prodrugs, its pharmaceutically acceptable salts, its pharmaceutically acceptable Accepted solvates, hydrates thereof, esters thereof, isotopes thereof, or metabolites thereof; or the pharmaceutical composition of claim 17.
  22. 一种治疗患有与TEAD活性增加相关的疾病或病症的患者的方法，其包含向所述患者给予权利要求1至16中任一权利要求所述的化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或权利要求17所述的药物组合物。A method of treating a patient suffering from a disease or disorder associated with increased TEAD activity, comprising administering to said patient a compound according to any one of claims 1 to 16, or a tautomer of said compound its stereoisomers, its geometric isomers, its enantiomers, its diastereoisomers, its racemates, its prodrugs, its pharmaceutically acceptable salts, its pharmaceutically acceptable Accepted solvates, hydrates thereof, esters thereof, isotopes thereof, or metabolites thereof; or the pharmaceutical composition of claim 17.
  23. 一种治疗疾病或病症的方法，其抑制TEAD活性将有益于所述疾病或病症，其包含向所述患者给予权利要求1至16中任一权利要求所述的化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或权利要求17所述的药物组合物。A method of treating a disease or disorder for which inhibition of TEAD activity would be beneficial, comprising administering to said patient a compound of any one of claims 1 to 16, or an interaction of said compound isomers, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereomers thereof, racemates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, A pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the pharmaceutical composition as claimed in claim 17.
  24. 一种治疗疾病或病症的方法，其抑制Hippo通路将有益于所述疾病或病症，其包含向所述患者给予权利要求1至16中任一权利要求所述的化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或权利要求17所述的药物组合物。A method of treating a disease or disorder for which inhibition of the Hippo pathway would be beneficial, comprising administering to said patient a compound according to any one of claims 1 to 16, or an interaction of said compound isomers, stereoisomers thereof, geometric isomers thereof, enantiomers thereof, diastereomers thereof, racemates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, A pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or the pharmaceutical composition as claimed in claim 17.
  25. 根据权利要求18-24中任一项所述的方法，其中，所述疾病或病症是细胞增殖性病症；优选地，所述细胞增殖性疾病是癌症；优选地，所述癌症是YAP局限于癌症的细胞核中的癌症。The method according to any one of claims 18-24, wherein the disease or disorder is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer; preferably, the cancer is YAP localized Cancer in the nucleus of a cancer cell.
  26. 根据权利要求18-25中任一项所述的方法，其中，所述TEAD过表达或TEAD活性增加是TEAD1过表达或TEAD1活性增加；TEAD2过表达或TEAD2活性增加；TEAD3过表达或TEAD3活性增加；或TEAD4过表达或TEAD4活性增加；或其任意组合。The method according to any one of claims 18-25, wherein the TEAD overexpression or TEAD activity increase is TEAD1 overexpression or TEAD1 activity increase; TEAD2 overexpression or TEAD2 activity increase; TEAD3 overexpression or TEAD3 activity increase ; or TEAD4 overexpression or TEAD4 activity increased; or any combination thereof.
  27. 一种权利要求1至16中任一权利要求所述的化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或权利要求17所述的药物组合物在制备治疗癌症、抑制癌症进展、治疗与TEAD表达增加相关的疾病或病症、治疗与TEAD活性增加相关的疾病或病症、治疗与Hippo通路相关的疾病或病症、具有与TEAD结合并阻断YAP/TEAD之间的相互作 用的活性的药物中的用途，所述Hippo通路被抑制将有益于所述疾病或病症。A compound according to any one of claims 1 to 16, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, an astereoisomer thereof An enantiomer, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or claim The pharmaceutical composition described in 17 is used in the preparation of treating cancer, inhibiting cancer progression, treating diseases or diseases related to increased expression of TEAD, treating diseases or diseases related to increased TEAD activity, treating diseases or diseases related to Hippo pathway, and having TEAD binds and blocks the YAP/TEAD interaction Inhibition of the Hippo pathway would be beneficial for the disease or condition for use in an active medicament.
  28. 根据权利要求27所述的用途，其中，所述癌症与TEAD过表达相关或TEAD活性增加相关，The use according to claim 27, wherein the cancer is associated with TEAD overexpression or increased TEAD activity,
    和/或所述疾病或病症是细胞增殖增殖性病症，优选地，所述细胞增殖性疾病是癌症，更优选地，所述癌症是YAP局限于癌症的细胞核中的癌症；优选地，所述癌症选自乳腺癌、中枢神经系统癌、子宫内膜癌、肝癌、肾癌、大肠癌、肺癌、食管癌、舌癌、卵巢癌、胰腺癌、前列腺癌、胃癌、间皮瘤、黑色素瘤、纤维肉瘤、膀胱癌、直肠癌、淋巴瘤、宫颈癌、头颈癌、脑癌、上呼吸消化道癌、结直肠癌、尿路癌或结肠癌；优选地，所述癌症选自脑癌、食管癌、肾癌、间皮瘤、肝癌、头颈癌、肺癌、胃癌、乳腺癌或前列腺癌；更优选地，每种癌症独立地选自腺癌、鳞状细胞癌、混合腺鳞癌、未分化癌；进一步优选地，所述脑癌包括但不限于脑胶质瘤；头颈癌包括但不限于头颈鳞状细胞癌；肺癌包括但不限于肺腺癌、肺腺鳞癌、鳞状细胞肺癌、大细胞肺癌、小细胞肺癌、肺乳头状腺癌或非小细胞肺癌；胃癌包括但不限于胃腺癌；乳腺癌包括但不限于导管乳腺癌、乳腺癌或HR+乳腺癌；前列腺癌包括但不限于前列腺腺癌、前列腺鳞状细胞癌、或前列腺腺鳞癌；and/or said disease or disorder is a cell proliferative disorder, preferably said cell proliferative disorder is cancer, more preferably said cancer is a cancer in which YAP is localized in the nucleus of the cancer; preferably said The cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, Fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the cancer is selected from brain cancer, esophageal cancer Carcinoma, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, undifferentiated Cancer; further preferably, the brain cancer includes but not limited to glioma; head and neck cancer includes but not limited to head and neck squamous cell carcinoma; lung cancer includes but not limited to lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, Large cell lung cancer, small cell lung cancer, papillary adenocarcinoma or non-small cell lung cancer; gastric cancer including but not limited to gastric adenocarcinoma; breast cancer including but not limited to ductal breast cancer, breast cancer or HR+ breast cancer; prostate cancer including but not limited to Adenocarcinoma of the prostate, squamous cell carcinoma of the prostate, or adenosquamous carcinoma of the prostate;
    和/或所述TEAD过表达或TEAD活性增加是TEAD1过表达或TEAD1活性增加；TEAD2过表达或TEAD2活性增加；TEAD3过表达或TEAD3活性增加；或TEAD4过表达或TEAD4活性增加；或其任意组合。And/or said TEAD overexpression or TEAD activity increase is TEAD1 overexpression or TEAD1 activity increase; TEAD2 overexpression or TEAD2 activity increase; TEAD3 overexpression or TEAD3 activity increase; or TEAD4 overexpression or TEAD4 activity increase; or any combination thereof .
  29. 一种治疗患者中疾病或病症的方法，其包含向所述患者给予权利要求1至16中任一权利要求所述的化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或权利要求17所述的药物组合物；所述疾病或病症与TEAD发生相互作用的蛋白相关。A method of treating a disease or condition in a patient comprising administering to said patient a compound according to any one of claims 1 to 16, or a tautomer of said compound, a stereoisomer thereof, Geometric isomers thereof, enantiomers thereof, diastereomers thereof, racemates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, hydrates thereof substance, its ester, its isotope, or its metabolite; or the pharmaceutical composition of claim 17; the disease or disease is related to the protein that TEAD interacts with.
  30. 根据权利要求29所述的方法，其中所述与TEAD发生相互作用的蛋白相关的疾病或病症包括但不限于癌症、代谢性疾病、炎症性疾病、或神经退行性疾病；The method according to claim 29, wherein the disease or disorder associated with the protein interacting with TEAD includes but is not limited to cancer, metabolic disease, inflammatory disease, or neurodegenerative disease;
    优选地，所述癌症选自乳腺癌、中枢神经系统癌、子宫内膜癌、肝癌、肾癌、大肠癌、肺癌、食管癌、舌癌、卵巢癌、胰腺癌、前列腺癌、胃癌、间皮瘤、黑色素瘤、纤维肉瘤、膀胱癌、直肠癌、淋巴瘤、宫颈癌、头颈癌、脑癌、上呼吸消化道癌、结直肠癌、尿路癌或结肠癌；优选地，所述癌症选自脑癌、食管癌、肾癌、间皮瘤、肝癌、头颈癌、肺癌、胃癌、乳腺癌或前列腺癌；更优选地，每种癌症独立地选自腺癌、鳞状细胞癌、混合腺鳞癌、未分化癌；进一步优选地，所述脑癌包括但不限于脑胶质瘤；头颈癌包括但不限于头颈鳞状细胞癌；肺癌包括但不限于肺腺癌、肺腺鳞癌、鳞状细胞肺癌、大细胞肺癌、小细胞肺癌、肺乳头状腺癌或非小细胞肺癌；胃癌包括但不限于胃腺癌；乳腺癌包括但不限于导管乳腺癌、乳腺癌或HR+乳腺癌；前列腺癌包括但不限于前列腺腺癌、前列腺鳞状细胞癌、或前列腺腺鳞癌。Preferably, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelial cancer tumor, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the cancer is selected from from brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed glandular carcinoma Squamous cell carcinoma, undifferentiated carcinoma; further preferably, the brain cancer includes but not limited to glioma; head and neck cancer includes but not limited to head and neck squamous cell carcinoma; lung cancer includes but not limited to lung adenocarcinoma, lung adenosquamous carcinoma, Squamous cell lung cancer, large cell lung cancer, small cell lung cancer, papillary adenocarcinoma, or non-small cell lung cancer; gastric cancer including but not limited to gastric adenocarcinoma; breast cancer including but not limited to ductal, breast or HR+ breast cancer; prostate Cancers include, but are not limited to, prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma.
  31. 一种权利要求1至16中任一权利要求所述的化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或权利要求17所述的药物组合物在制备治疗疾病或病症的药物中的用途；所述疾病或病症与TEAD发生相互作用的蛋白相关。A compound according to any one of claims 1 to 16, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, an astereoisomer thereof An enantiomer, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or claim Use of the pharmaceutical composition described in 17 in the preparation of a medicament for treating a disease or disorder; the disease or disorder is related to a protein that interacts with TEAD.
  32. 根据权利要求31所述的方法，其中所述与TEAD发生相互作用的蛋白相关的疾病或病症选自癌症、代谢性疾病、炎症性疾病、或神经退行性疾病；The method according to claim 31, wherein the disease or disorder associated with the protein interacting with TEAD is selected from cancer, metabolic disease, inflammatory disease, or neurodegenerative disease;
    优选地，所述癌症选自乳腺癌、中枢神经系统癌、子宫内膜癌、肝癌、肾癌、大肠癌、肺癌、食管癌、舌癌、卵巢癌、胰腺癌、前列腺癌、胃癌、间皮瘤、黑色素瘤、纤维肉瘤、膀胱癌、直肠癌、淋巴瘤、宫颈癌、头颈癌、脑癌、上呼吸消化道癌、结直肠癌、尿路癌或结肠癌；优选地，所述癌症选自脑癌、食管癌、肾癌、间皮瘤、肝癌、头颈癌、肺癌、胃癌、乳腺癌或前列腺癌；更优选地，每种癌症独立地选自腺癌、鳞状细胞癌、混合腺鳞癌、未分化癌；进一步优选地，所述脑癌包括但不限于脑胶质瘤；头颈癌包括但不限于头颈鳞状细胞癌；肺癌包括但不限于肺腺癌、肺腺鳞癌、鳞状细胞肺癌、大细胞肺癌、小细胞肺癌、肺乳头状腺癌或非小细胞肺癌；胃癌包括但不限于胃腺癌；乳腺癌包括但不限于导管乳腺癌、乳腺癌或HR+乳腺癌；前列腺癌包括但不限于前列腺腺癌、前列腺鳞状细胞癌、或前列腺腺鳞癌。Preferably, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelial cancer tumor, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the cancer is selected from from brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed glandular carcinoma Squamous cell carcinoma, undifferentiated carcinoma; further preferably, the brain cancer includes but not limited to glioma; head and neck cancer includes but not limited to head and neck squamous cell carcinoma; lung cancer includes but not limited to lung adenocarcinoma, lung adenosquamous carcinoma, Squamous cell lung cancer, large cell lung cancer, small cell lung cancer, papillary adenocarcinoma, or non-small cell lung cancer; gastric cancer including but not limited to gastric adenocarcinoma; breast cancer including but not limited to ductal, breast or HR+ breast cancer; prostate Cancers include, but are not limited to, prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma.
  33. 一种权利要求1至16中任一权利要求所述的化合物、或所述化合物的互变异构体、其立体异构体、其几何异构体、其对映异构体、其非对映异构体、其消旋体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物、其水合物、其酯、其同位素、或其代谢产物；或权利要求17所述的药物组合物在治疗疾病或病症中的用途；所述疾病或病症与TEAD发生相互作用的蛋白相关。A compound according to any one of claims 1 to 16, or a tautomer of said compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, an astereoisomer thereof An enantiomer, its racemate, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, its hydrate, its ester, its isotope, or its metabolite; or claim Use of the pharmaceutical composition described in 17 in the treatment of diseases or disorders; the diseases or disorders are related to TEAD-interacting proteins.
  34. 根据权利要求33所述的方法，其中所述与TEAD发生相互作用的蛋白相关的疾病或病症选自癌症、代谢性疾病、炎症性疾病、或神经退行性疾病；The method according to claim 33, wherein the disease or disorder associated with the protein interacting with TEAD is selected from cancer, metabolic disease, inflammatory disease, or neurodegenerative disease;
    优选地，所述癌症选自乳腺癌、中枢神经系统癌、子宫内膜癌、肝癌、肾癌、大肠癌、肺癌、食管癌、舌癌、卵巢癌、胰腺癌、前列腺癌、胃癌、间皮瘤、黑色素瘤、纤维肉瘤、膀胱癌、直肠癌、淋巴瘤、宫颈癌、头颈癌、脑癌、上呼吸消化道癌、结直肠癌、尿路癌或结肠癌；优选地，所述癌症选自脑癌、食管 癌、肾癌、间皮瘤、肝癌、头颈癌、肺癌、胃癌、乳腺癌或前列腺癌；更优选地，每种癌症独立地选自腺癌、鳞状细胞癌、混合腺鳞癌、未分化癌；进一步优选地，所述脑癌包括但不限于脑胶质瘤；头颈癌包括但不限于头颈鳞状细胞癌；肺癌包括但不限于肺腺癌、肺腺鳞癌、鳞状细胞肺癌、大细胞肺癌、小细胞肺癌、肺乳头状腺癌或非小细胞肺癌；胃癌包括但不限于胃腺癌；乳腺癌包括但不限于导管乳腺癌、乳腺癌或HR+乳腺癌；前列腺癌包括但不限于前列腺腺癌、前列腺鳞状细胞癌、或前列腺腺鳞癌。 Preferably, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelial cancer tumor, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the cancer is selected from from brain cancer, esophagus Carcinoma, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, undifferentiated Cancer; further preferably, the brain cancer includes but not limited to glioma; head and neck cancer includes but not limited to head and neck squamous cell carcinoma; lung cancer includes but not limited to lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, Large cell lung cancer, small cell lung cancer, papillary adenocarcinoma or non-small cell lung cancer; gastric cancer including but not limited to gastric adenocarcinoma; breast cancer including but not limited to ductal breast cancer, breast cancer or HR+ breast cancer; prostate cancer including but not limited to Adenocarcinoma of the prostate, squamous cell carcinoma of the prostate, or adenosquamous carcinoma of the prostate.
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WO2020081572A1 (en) * 2018-10-15 2020-04-23 Dana-Farber Cancer Institute, Inc. Transcriptional enhanced associate domain (tead) transcription factor inhibitors and uses thereof
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