WO2023143354A1 - Composé tricyclique et son application - Google Patents

Composé tricyclique et son application Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
ring
alkyl
substituted
cancer
optionally substituted
Prior art date
Application number
PCT/CN2023/073087
Other languages
English (en)
Chinese (zh)
Inventor
张海生
卓鉥
胡亚兵
代长贵
陈洁
程辉敏
陈誉
王雯莉
潘伟
Original Assignee
希格生科（深圳）有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 希格生科（深圳）有限公司 filed Critical 希格生科（深圳）有限公司
Priority to CN202380019299.2A priority Critical patent/CN118715221A/zh
Publication of WO2023143354A1 publication Critical patent/WO2023143354A1/fr

Links

Classifications

    • 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).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un composé tricyclique représenté par la formule (O), une composition pharmaceutique comprenant le composé en tant que principe actif, et une application de celui-ci. Le composé est un excellent inhibiteur de TEAD et peut être utilisé pour traiter des tumeurs.
PCT/CN2023/073087 2022-01-30 2023-01-19 Composé tricyclique et son application WO2023143354A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202380019299.2A CN118715221A (zh) 2022-01-30 2023-01-19 三环化合物及其应用

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202210113616.4 2022-01-30
CN202210113616 2022-01-30
CN202211572946 2022-12-08
CN202211572946.6 2022-12-08

Publications (1)

Publication Number Publication Date
WO2023143354A1 true WO2023143354A1 (fr) 2023-08-03

Family

ID=87470770

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/073087 WO2023143354A1 (fr) 2022-01-30 2023-01-19 Composé tricyclique et son application

Country Status (3)

Country Link
CN (1) CN118715221A (fr)
TW (1) TW202340180A (fr)
WO (1) WO2023143354A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020081572A1 (fr) * 2018-10-15 2020-04-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs du facteur de transcription à domaine associé transcriptionnel amélioré (tead) et leurs utilisations
CN111132673A (zh) * 2017-05-03 2020-05-08 维瓦斯治疗公司 非稠合三环化合物
CN111542315A (zh) * 2017-08-21 2020-08-14 维瓦斯治疗公司 苯并磺酰基化合物
WO2020243415A2 (fr) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2020243423A1 (fr) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111132673A (zh) * 2017-05-03 2020-05-08 维瓦斯治疗公司 非稠合三环化合物
CN111542315A (zh) * 2017-08-21 2020-08-14 维瓦斯治疗公司 苯并磺酰基化合物
WO2020081572A1 (fr) * 2018-10-15 2020-04-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs du facteur de transcription à domaine associé transcriptionnel amélioré (tead) et leurs utilisations
WO2020243415A2 (fr) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2020243423A1 (fr) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations

Also Published As

Publication number Publication date
TW202340180A (zh) 2023-10-16
CN118715221A (zh) 2024-09-27

Similar Documents

Publication Publication Date Title
CN109879859B (zh) Cot调节剂及其使用方法
TWI423962B (zh) 有效作為黃嘌呤氧化酶抑制劑之新穎化合物、其製備方法及含該化合物之醫藥組成物
CN103420977B (zh) 具有抗肿瘤活性的乙炔衍生物
WO2016026445A1 (fr) Composés indazole utilisés comme inhibiteurs de la fgfr kinase, préparation et utilisation associées
WO2018113584A1 (fr) Inhibiteur de fgfr4, son procédé de préparation et son utilisation pharmaceutique
CN103124730A (zh) 杂环炔苯类化合物及其药用组合物和应用
CN113454085A (zh) Mat2a的aza杂双环抑制剂和用于治疗癌症的方法
CN108026067A (zh) 作为cot调节剂的6-氨基-喹啉-3-腈
WO2023098439A1 (fr) Dérivé de pyrazole, son procédé de préparation et son utilisation en médecine
WO2018010514A1 (fr) Composé hétérocyclique utilisé en tant qu'inhibiteur de fgfr
CN104109166B (zh) 喹啉类化合物、其制备方法、中间体、药物组合物和应用
WO2021175283A1 (fr) Synthèse d'un nouvel antagoniste d'ep4 et utilisation dans des cancers et des inflammations
WO2020143763A1 (fr) Composés d'halogénoallylamine et leur utilisation
WO2023280237A1 (fr) Synthèse et utilisation d'agent de dégradation de phosphatase
TW201917129A (zh) 含吡唑基的三并環類衍生物、其製備方法和應用
CN114437074A (zh) 一种化合物、含该化合物的药物组合物及其用途
WO2022127199A1 (fr) Composés polycycliques pour inhiber l'arn hélicase dhx33 et leur utilisation
TW202313048A (zh) 組合療法
TW202214615A (zh) 一種ｅｇｆｒ抑制劑及其製備方法和應用
WO2023142641A1 (fr) Dérivé de pyridine, son procédé de préparation et son utilisation
WO2023036252A1 (fr) Dérivé de pyrrolopyrimidine ou de pyrrolopyridine et son utilisation médicale
TW202043209A (zh) Mek抑制劑及其在醫藥上的應用
WO2023169573A1 (fr) Inhibiteur de polθ
WO2023143354A1 (fr) Composé tricyclique et son application
WO2023125841A1 (fr) COMPOSÉ HÉTÉROCYCLIQUE EN TANT QU'INHIBITEUR DE POLθ, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23746235

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE