WO2023098880A1 - Fused ring derivative, preparation method therefor, and application thereof - Google Patents

Fused ring derivative, preparation method therefor, and application thereof Download PDF

Info

Publication number
WO2023098880A1
WO2023098880A1 PCT/CN2022/136232 CN2022136232W WO2023098880A1 WO 2023098880 A1 WO2023098880 A1 WO 2023098880A1 CN 2022136232 W CN2022136232 W CN 2022136232W WO 2023098880 A1 WO2023098880 A1 WO 2023098880A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
halogen
aryl
amino
Prior art date
Application number
PCT/CN2022/136232
Other languages
French (fr)
Chinese (zh)
Inventor
肖华玲
苏熠东
邓海宁
邢静
俞文胜
Original Assignee
上海翰森生物医药科技有限公司
江苏豪森药业集团有限公司
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 上海翰森生物医药科技有限公司, 江苏豪森药业集团有限公司 filed Critical 上海翰森生物医药科技有限公司
Publication of WO2023098880A1 publication Critical patent/WO2023098880A1/en

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
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C07D519/06—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 containing at least one condensed beta-lactam ring system, provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00, e.g. a penem or a cepham system

Definitions

  • the invention belongs to the field of biomedicine, and in particular relates to a regulator of condensed ring derivatives and its preparation method and application.
  • the phosphatidylinositol 3-kinase (PI3K) protein family is divided into four categories: I, II, III, and IV, and is involved in the regulation of various cellular functions such as cell growth, proliferation, differentiation, survival, and energy metabolism.
  • the four classes of PI3K proteins have different structures and functions.
  • the most widely studied class I PI3Ks are divided into four subtypes: PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and PI3K ⁇ . Among them, PI3K ⁇ undergoes activation mutation and amplification in various tumors. , is closely related to the occurrence and development of tumors.
  • PI3K ⁇ can activate platelets and play an important role in the occurrence and development of thrombosis and other diseases.
  • PI3K ⁇ and PI3K ⁇ are mainly expressed in the blood system and are closely related to the immune system and inflammation.
  • PI3K ⁇ is also closely related to blood pressure stability and smooth muscle contraction.
  • PI3K ⁇ is composed of p110 ⁇ catalytic subunit and p85 regulatory subunit.
  • the p110 ⁇ subunit is encoded by the PIK3CA gene.
  • PI3K ⁇ When PI3K ⁇ is regulated by upstream receptor tyrosine kinases (such as insulin receptor, platelet-derived growth factor receptor, etc.) and Ras protein, After activation, it catalyzes phosphatidylinositol 2 phosphate (PIP2) to generate phosphatidylinositol 3 phosphate (PIP3).
  • PIP3 can further activate protein kinase B (also known as AKT) and its downstream signaling pathways, thereby regulating cell differentiation, migration, and metabolic stability. state.
  • AKT protein kinase B
  • PI3K ⁇ is also a key protein in the insulin/insulin receptor pathway, which can regulate the balance of glucose metabolism in tissues such as liver and skeletal muscle. Inhibition of PI3K ⁇ can lead to decreased glycogen synthesis in the liver, increased blood sugar, and increased insulin levels in the body.
  • PI3K ⁇ is one of the kinases with the highest mutation rate in cancer. The total mutation rate in all cancers reaches 14%. It is widely distributed, such as breast cancer, head and neck cancer, ovarian cancer, gastric cancer, head and neck cancer and other cancers. There are various types of PIK3CA gene mutations, among which the three most common hotspot mutations are H1047R mutation (kinase region), E542K (helix region) and E545K (helix region).
  • PI3K ⁇ inhibitors have strong inhibitory activity against PI3K ⁇ mutants, PI3K ⁇ wild-type inhibition is non-selective, and there is a certain inhibition of PI3K ⁇ / ⁇ / ⁇ , resulting in severe hyperglycemic side effects mediated by PI3K ⁇ wild-type and PI3K in clinical trials.
  • the /AKT pathway is involved in side effects such as rash and diarrhea, and due to the increase of insulin in the body, the insulin receptor pathway is activated, resulting in enhanced activation of the PI3K pathway, which in turn affects the efficacy of PI3K ⁇ inhibitors.
  • Novartis' Alpelisib (BYL-719) is currently the fastest-growing PI3K ⁇ inhibitor.
  • PI3K ⁇ inhibitors have remarkable therapeutic effects in breast cancer and other indications, and have good market prospects.
  • Existing PI3K ⁇ inhibitors have no selectivity for wild-type PI3K ⁇ , leading to serious side effects of hyperglycemia, which limits the dosage and efficacy of clinical medication. Therefore, it is of great significance to develop PI3K ⁇ mutation-specific allosteric inhibitors.
  • PI3K ⁇ mutant allosteric inhibitors in the preclinical development stage abroad, namely Relay’s RLY-2608 and Eli Lilly’s LOXO-783. These two inhibitors have improved the selection of PI3K ⁇ wild type It has high selectivity to PI3K ⁇ / ⁇ / ⁇ , which is expected to reduce toxicity and improve efficacy. It will start clinical trials in 2022 and has a good development prospect.
  • the object of the present invention is to provide a compound shown in general formula (I), its stereoisomer or its pharmaceutically acceptable salt:
  • Ring A, ring B and ring C are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further substituted;
  • Ring A is present or absent
  • Ring C is present or absent
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, Alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR 33 , -(CH 2 ) n NR 22 C(O)(CH 2
  • R 11 to R 33 are selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, Haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterium Alkenyloxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
  • n 0, 1 or 2;
  • x, y, z, n and n1 are each independently 0, 1, 2, 3 or 4.
  • Ring A and Ring B are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further substituted;
  • Ring A and Ring B form a 6-20 membered condensed heterocyclic ring containing 1-3 heteroatoms selected from O, S or N or contain 1-3 heteroatoms selected from O, S or N 6-20 membered fused heteroaromatic ring; more preferably, ring A and ring B form an 8-10 membered fused heteroaromatic ring containing 1-3 N, S or O; further preferably, ring A and ring B form Any of the following fused heteroaromatic rings:
  • ring A does not exist
  • ring B is selected from 6-12 membered aryls or 5-14 membered heteroaryls containing 1-4 heteroatoms; more preferably, ring A does not exist, and ring B is selected from A 5-membered heteroaryl group containing 1-2 heteroatoms; further preferably, ring A does not exist, and ring B is selected from
  • R 1 are each independently selected from cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably aryl; more preferably 6-12 membered aryl; further preferably phenyl; Can be substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl;
  • R 2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optional substituted by one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino and C 1-6 alkyl, preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, -(CH 2 ) n NR 22 C
  • R 3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3- 12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, optionally replaced by hydrogen, hydroxyl, halogen, cyano, amino, C 1-6 alkyl, One or more substituents of C 1-6 haloalkyl or C 1-6 deuterated alkyl, preferably C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5 -12-membered heteroaryl, optionally substituted by one or more of hydrogen,
  • R2 and R3 are not H at the same time;
  • R 22 is selected from hydrogen, deuterium, halogen
  • R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally can be further replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl , haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;
  • y and z are each independently 1, 2, 3 or 4;
  • n, n1 and m1 are each independently 0, 1, 2, 3 or 4.
  • M2 is selected from N or C
  • Ring D and ring E are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably 3-10 membered heterocyclic groups containing 1-3 selected from nitrogen, oxygen or sulfur atoms or containing 1 -3 5-10 membered heteroaryl groups selected from nitrogen, oxygen or sulfur atoms, more preferably 1-3 3-6 membered heterocyclic groups selected from nitrogen, oxygen or sulfur atoms or 1-3 members selected from Nitrogen, oxygen or sulfur atom 5-8 membered heteroaryl, more preferably
  • Ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally can be further substituted; preferably, ring C is selected from heterocyclyl or heteroaryl, optionally can be further substituted; More preferably, ring C is selected from 3-12 membered heterocyclic groups or 5-12 membered heteroaryl groups, which may be further substituted; further preferably, ring C is selected from
  • Each R is independently selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl, heteroaryl; preferably alkyl or aryl; more preferably C 1-6 alkyl or 6-12 yuan aryl; further preferably methyl or phenyl; wherein at least one R 1 is substituted phenyl; said R can optionally be replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl , alkoxy, alkenyl, alkynyl substitution;
  • R 2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optional substituted by one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino and C 1-6 alkyl, preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, -(CH 2 ) n NR 22 C
  • R 22 is selected from hydrogen, deuterium, halogen
  • R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally can be further replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl , haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;
  • x and y are each independently 1, 2, 3 or 4;
  • n and n1 are each independently 0, 1, 2, 3 or 4.
  • R 2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optional substituted by one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino and C 1-6 alkyl, preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, -(CH 2 ) n NR 22 C
  • R 22 is selected from hydrogen, deuterium, halogen
  • R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally can be further replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl , haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;
  • R is selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycle Base, aryl, heteroaryl; preferably aryl; more preferably 6-12 yuan aryl; further preferably phenyl; said R optionally can be hydrogen, deuterium, halogen, nitro, hydroxyl, Mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl substitution;
  • R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy , haloalkoxy, alkenyl, alkynyl; preferably amino or hydroxyl;
  • y is 1, 2, 3 or 4;
  • n and n1 are each independently 0, 1, 2, 3 or 4.
  • M or M are each independently selected from S, NR a or CR b ;
  • R and R are each independently selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl;
  • Each R is independently selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl, heteroaryl; preferably aryl; more preferably 6-12 yuan aryl; further preferably phenyl; said R optionally can be hydrogen, deuterium, halogen, nitro , hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl substitution;
  • R 2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optional substituted by one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino and C 1-6 alkyl, preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, -(CH 2 ) n NR 22 C
  • R 22 is selected from hydrogen, deuterium, halogen
  • R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally can be further replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl , haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;
  • x or y are each independently 1, 2, 3 or 4;
  • n or n1 are each independently 0, 1, 2, 3 or 4;
  • n2 0, 1 or 2.
  • Ring A and ring B or ring B and ring C each independently form a fused ring, and each of the fused rings is independently selected from
  • ring A, ring B and ring C together form a fused ring, the fused ring is selected from
  • Each R is independently selected from hydrogen, deuterium,
  • R and R are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, cyano, ethoxy, propoxy, methylamino, dimethylamino, formamido, difluoromethyl, trifluoro methyl, cyanomethyl,
  • R 1 are each independently selected from phenyl substituted by halogen; preferably phenyl substituted by 1 to 3 atoms selected from fluorine, chlorine and bromine, more preferably is further preferably
  • R 2 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, -NHC(O)R 33 ; preferably, each of R 2 independently selected from hydrogen, methyl, And when ring A is absent, wherein at least one R 2 is selected from
  • R 3 are each independently selected from hydrogen, deuterium, C 6-10 aryl or 5-10 membered heteroaryl, and the C 6-10 aryl or 5-10 membered heteroaryl is replaced by hydrogen, hydroxyl, halogen, cyano
  • One or more substituents of radical, amino, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuterated alkyl preferably hydrogen, deuterium, phenyl or 5-10 membered heteroaryl base, the phenyl or 5-10 membered heteroaryl is substituted by one or more substituents of hydrogen, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl; more preferably hydrogen, deuterium,
  • the present invention provides a compound selected from Table 1, a pharmaceutically acceptable salt or stereoisomer thereof.
  • R 2 are each independently:
  • R 3 are each independently:
  • the present invention further relates to a pharmaceutical composition, which comprises a therapeutically effective dose of any compound of the general formula shown, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers , diluent or excipient.
  • the present invention further relates to the application of any one of the compounds shown in the general formula, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in the preparation of drugs for treating diseases related to PI3K ⁇ .
  • the present invention further relates to the compound represented by the general formula, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of treatment of cancer, PROS (PIK3CA-related overgrowth spectrum, PIK3CA-related overgrowth spectrum),
  • PROS PIK3CA-related overgrowth spectrum, PIK3CA-related overgrowth spectrum
  • the application in the medicine of immune disorder or inflammatory disorder wherein said PROS is selected from vascular malformation, lymphatic malformation and megalencephaly, and said cancer is selected from gastric cancer, breast cancer, prostate cancer, lung cancer, liver cancer, bone cancer, brain cancer cancer, head and neck cancer, bowel cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer, endometrial cancer, or multiple myeloma.
  • the present invention further relates to the compound represented by the general formula, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of medicines for treating PI3K ⁇ -related and related diseases.
  • the present invention also relates to a method for treating, preventing and/or treating diseases related to PI3K ⁇ , which comprises administering to the patient a therapeutically effective dose of the compound represented by the general formula, its stereoisomer or a pharmaceutically acceptable salt thereof, or its pharmaceutical composition.
  • the invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions, including but not limited to conditions associated with PI3K ⁇ .
  • the present invention also relates to a method for treating a PI3K ⁇ -related disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrated substances or derivatives.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms An alkyl group, most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, “propylene” refers to -(CH 2 ) 3 -, “butylene” refers to -(CH 2 ) 4 -, and the like.
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene group, cyclooctyl group, etc.; polycyclic cycloalkyl group includes spiro ring, fused ring and bridged ring cycloalkyl group, preferably cyclopropyl group, cyclobutyl group, cyclohexyl group, cyclopentyl group and cycloheptyl group.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include:
  • spirocycloalkyls in which a single spirocycloalkyl shares a spiro atom with a heterocycloalkyl, non-limiting examples include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • the membered heterocyclic group is optionally substituted by 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiroheterocyclic groups or nitrogen-containing condensed heterocyclic groups.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azeptyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, Piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl.
  • Polycyclic heterocyclic groups include spiro rings, fused rings and bridged ring heterocyclic groups; the spiro rings, condensed rings and bridged ring heterocyclic groups involved are optionally connected to other groups through single bonds, or through rings Any two or more atoms on the ring are further linked with other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclic group.
  • spiroheterocyclyls include:
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 12 membered, having a conjugated ⁇ -electron system, such as benzene base and naphthyl. Phenyl is more preferred.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group with a sulfur atom; or a three-membered nitrogen-containing condensed ring containing a benzene ring.
  • ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 12 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrole group and oxazolyl group.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cyclo
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • Haloalkyl means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy means an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • Hydroalkyl means an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • alkenyl refers to alkenyl, also known as alkenyl, wherein said alkenyl can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio group, carboxyl group or carboxylate group.
  • Alkynyl refers to (CH ⁇ C-), wherein said alkynyl can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • alkenylcarbonyl refers to -C(O)-(alkenyl), wherein alkenyl is as defined above.
  • alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl.
  • Alkenylcarbonyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • Haldroxy means an -OH group.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Carbonyl refers to -C(O)-.
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc means ethyl acetate
  • MeOH means methanol
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • MeCN refers to acetonitrile
  • DMA refers to N,N-dimethylacetamide.
  • Et2O means diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • the hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by a deuterium atom.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” and “pharmaceutically acceptable salt” refer to the salts of the compounds of the present invention, which are safe and effective when used in mammals, and have proper biological activity.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui chemical companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin-layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • TLC thin-layer chromatography
  • the eluent system of column chromatography and the developer system of thin-layer chromatography used for purifying compounds include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • 6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-7-methyl-4-nitroisoindol-1-one 1e (8.60 g, 16mmol) was dissolved in 100mL 1,4-dioxane, and ammonium chloride (4.42g, 83mmol), tris(diphenylbenzylideneacetone) dipalladium (1.52g, 1.6mmol) were added successively in the reaction system , 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (2.06 g, 3.3 mmol) and sodium tert-butoxide (4.77 g, 96 mmol).
  • 6-amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-7-methyl-4-nitroisoindol-1-one 1f (5.20 g, 11 mmol) was dissolved in 60 mL of glacial acetic acid, sodium nitrite (0.86 g, 12 mmol) and 3 mL of water were added, and the reaction was stirred at 25°C for 2 hours.
  • reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl) -5-nitro-6,7-dihydropyrrole[3,4-e]indazol-8(3H)-one 1 g (3.52 g), yield: 67.7%.
  • reaction solution was concentrated under reduced pressure, 100 mL of water was added to the obtained residue, extracted with ethyl acetate (50 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5-amino-6-(2-chloro-5-fluorophenyl)-7-(4-methoxy Benzyl)-6,7-dihydropyrrole[3,4-e]indazol-8(3H)-one 1h (0.91 g), yield: 27.6%.
  • N-(6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-8-oxo-3,6,7,8-tetrahydropyrrole[3,4 -e] Indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide 1i (0.29g, 0.46mmol) was dissolved in 5mL methanesulfonic acid, and stirred at 60°C for 15 hours.
  • Add saturated sodium bicarbonate solution to the reaction solution to adjust the pH to greater than 7 extract with ethyl acetate (10 mL ⁇ 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL ⁇ 2), and dry over anhydrous sodium sulfate.
  • Example 1 for the preparation of the compounds of Examples 2-4, and the corresponding mass spectrometry data are listed in Table 1.
  • Example 5 for the preparation of the compounds of Examples 6-8, and the corresponding mass spectrometry data are listed in Table 1.
  • the reaction was stirred at 25°C for 2 hours. Add 30 mL of water to the reaction solution, extract with ethyl acetate (30 mL ⁇ 3), combine the organic phases, wash with saturated sodium chloride solution (20 mL ⁇ 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Example 9 for the preparation of the compounds of Examples 10-12, and the corresponding mass spectrometry data are listed in Table 1.
  • 7-nitroquinoline-5-carboxylic acid 13a (5.0 g, 23 mmol) was dissolved in 80 mL of dichloromethane, N, N'-carbonyldiimidazole (5.61 g, 34 mmol) and 4-dimethylaminopyridine ( 0.28g, 2.3mmol). The reaction was stirred at 25°C for 2 hours. 4-Methoxybenzylamine (3.14 g, 23 mmol) was added to the above reaction solution, and after the addition was completed, the reaction was continued to stir at 25° C. for 1 hour.
  • N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide 13b (6.30 g, 19 mmol) was dissolved in 80 mL of tetrahydrofuran, and sodium hydrogen (1.49 g, 37 mmol) was added. The reaction was stirred at 25°C for 2 hours. A solution of 2-chloro-5-fluorobenzoyl chloride (5.39g, 28mmol) in tetrahydrofuran (10mL) was added to the above reaction solution, and after the addition was completed, the reaction was continued at 25°C for 2 hours.
  • N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide 13c (6.80g, 14mmol) was dissolved in 80mL tetrahydrofuran, and LiHMDS (1.0M, 20.9mL, 21mmol) was added. The reaction was stirred at -50°C for 3 hours. Add 100 mL of water to the reaction solution, extract with ethyl acetate (50 mL ⁇ 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL ⁇ 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • reaction solution was slowly poured into 50 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (20 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL ⁇ 2), anhydrous Drying over sodium sulfate, filtration, and concentration of the filtrate under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 3-(2-chloro-5-fluorophenyl)-4-nitro- 2,3-Dihydro-1H-pyrrolo[3,4]quinolin-1-one 13f (0.43 g), yield: 60.6%.
  • reaction solution was concentrated under reduced pressure, 30 mL of water was added to the resulting residue, extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 4-amino-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H -Pyrrolo[3,4]quinolin-1-one 13g (0.21g), yield: 53.8%.
  • Embodiment 13-P1 MSm/z (ESI): 518.1[M+1]
  • Example 13 for the preparation of the compounds of Examples 14-16, and the corresponding mass spectrometry data are listed in Table 1.
  • reaction solution was washed with water (50 mL) and saturated sodium chloride solution (50 mL) successively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product tert-butyl((2-chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)carbamate 17c (3.4 g), yield: 91.2%.
  • reaction solution was cooled to room temperature, poured into 100mL water, and extracted with ethyl acetate (100mL*2). Combined organic phases, Washed with water (100mL) and saturated sodium chloride solution (100mL) successively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product tert-butyl Base ((2-chloro-5-fluorophenyl)(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-8-yl)methyl)carbamate 17d( 2.4 g), yield: 52.1%.
  • reaction solution was poured into 50 mL of water and extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain tert-butyl((2-chloro-5-fluorophenyl)(7-(3-fluoro-5-(trifluoromethyl)benzamido)imidazo[1,2-a]pyridin-8-yl) Methyl)carbamate 17f (65 mg), yield: 21.9%.
  • Example 17 The preparation of the compounds of Examples 18-20 refers to Example 17, and the corresponding mass spectrum data are listed in Table 1.
  • reaction solution was cooled to room temperature, poured into 100 mL of water, and extracted with ethyl acetate (100 mL*2). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain The title product (2-chloro-5-fluorophenyl)(7-((diphenylmethylene)amino)imidazol[1,2-a]pyridin-8-yl)methanol 21c (3.1 g), yield : 58.6%.
  • Example 21 for the preparation of the compounds of Examples 22-24, and the corresponding mass spectrum data are listed in Table 1.
  • 2-Amino-6-bromobenzoic acid (5 g, 23.1 mmol) was dissolved in 50 mL of tetrahydrofuran, and lithium aluminum tetrahydrogen (1.76 g, 46.2 mmol) was slowly added in batches under an ice bath, and reacted at room temperature for 1 hour. Cooled to 0°C, slowly added 2mL of water, 2mL of 15% sodium hydroxide solution, and 2mL of water successively, stirred for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain (2-amino-6-bromophenyl)methanol 25a (3.6g ), yield: 77.3%.
  • Example 25 The synthesis method of Example 25 was referred to the synthesis method of the sixth step in Example 17, and Example 25f (160 mg, yield: 47.6%) was obtained from Example 25e.
  • Example 25 for the preparation of the compounds of Examples 26-28, and the corresponding mass spectrum data are listed in Table 1.
  • reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title product 2-chloro-5-fluoro-N-(4-methoxybenzyl)-N-((3-nitrobenzene (yl)sulfonyl)benzamide 29b (2 g), yield: 72%.
  • reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title product 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl) -4-Nitro-2,3-dihydrobenzo[d]isothiazole-1,1-dioxide 29c (1 g), yield: 50%.
  • Example 29 for the preparation of the compounds of Examples 30-32, and the corresponding mass spectrometry data are listed in Table 1.
  • N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-5-nitrothiophene-3-carboxamide 33b (2 g, 4.50 mmol) was dissolved in LiHMDS (9 mL, 1M) was added to 40 mL of tetrahydrofuran, and the reaction was stirred for 3 hours.
  • reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title product 6-(2-chloro-5-fluorophenyl)-6-hydroxy-5-(4-methoxybenzyl) -1-nitro-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one 33c (1 g), yield: 50%.
  • 6-(2-Chloro-5-fluorophenyl)-5-(4-methoxybenzyl)-1-nitro-5,6-dihydro-4H-thieno[3,4-c] Pyrrol-4-one 33d (700 mg, 1.62 mol) was dissolved in 10 mL of trifluoroacetic acid, refluxed for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the title product 6-(2-chloro-5-fluorophenyl)-1- Nitro-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one 33e (500 mg), yield: 99%.
  • 6-(2-Chloro-5-fluorophenyl)-1-nitro-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one 33e (500mg, 1.6mmol) Dissolve in 20 mL of ethanol, add 10 mL of water and iron powder (1.70 g, 3.20 mol), and react at 60°C for 4 hours. Filtration and concentration of the filtrate under reduced pressure gave the title product 1-amino-6-(2-chloro-5-fluorophenyl)-5,6-dihydro-4H-thieno[3,4-c]pyrrole-4- Ketone 33f (300 mg), yield: 66%.
  • reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title product N-(6-(2-chloro-5-fluorophenyl)-4-oxo-5,6-dihydro- 4H-thieno[3,4-c]pyrrol-1-yl)-3-fluoro-5-(trifluoromethyl)benzamide 33 (100 mg), yield: 60%.
  • Example 33 for the preparation of the compounds of Examples 34-36, and the corresponding mass spectrometry data are listed in Table 1.
  • 5-Nitrothiazole-3-carboxylic acid 37a (1 g, 5.78 mmol), 2-chloro-5-fluoro-N-(4-methoxybenzyl) benzamide (1.70 g, 5.78 mmol) were dissolved in In 10mL of DMF, add diisopropylethylamine (8mL, 11.6mmol) and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.85g, 8.7mmol), React at room temperature for 3 hours.
  • reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title product N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-5- Nitrothiazole-3-carboxamide 37b (2 g), yield: 77%.
  • N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-5-nitrothiazole-3-carboxamide 37b (2 g, 4.5 mmol) was dissolved in LiHMDS (9 mL, 1M) was added to 40 mL of tetrahydrofuran, and the reaction was stirred for 3 hours.
  • 6-(2-Chloro-5-fluorophenyl)-1-nitro-5,6-dihydro-4H-thiazolo[3,4-c]pyrrol-4-one 37e (0.5g, 1.6mmol ) was dissolved in 20 mL of ethanol, 10 mL of water and iron powder (1.7 g, 3.2 mol) were added, and reacted at 60° C. for 4 hours. Filtration, and the filtrate was concentrated under reduced pressure to obtain the title product 1-amino-6-(2-chloro-5-fluorophenyl)-5,6-dihydro-4H-thiazolo[3,4-c]pyrrole-4- Ketone 37f (0.3 g), yield: 66%.
  • reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title product N-(6-(2-chloro-5-fluorophenyl)-4-oxo-5,6-dihydro- 4H-Thiazolo[3,4-c]pyrrol-1-yl)-3-fluoro-5-(trifluoromethyl)benzamide 37 (100 mg), yield: 60%.
  • Example 37 for the preparation of the compounds of Examples 38-40, and the corresponding mass spectrometry data are listed in Table 1.
  • Example 41 for the preparation of the compounds of Examples 42-44, and the corresponding mass spectrometry data are listed in Table 1.
  • Example 45 for the preparation of the compounds of Examples 46-48, and the corresponding mass spectrometry data are listed in Table 1.
  • methylhydrazine (10 g, 217 mmol) was dissolved in 20 mL of methanol and 10 mL of water, and stirred at 0° C. for 1 hour.
  • compound 49a (12 g, 84.5 mmol) was added to the reaction solution, and the reaction was stirred at room temperature for 16 hours.
  • compound 56a (5g, 22mmol) and (2-chloro-5-fluorophenyl) boronic acid (4.59g, 26.4mmol) were dissolved in 25mL tetrahydrofuran, and 2,2′-bipyridine (3.4g, 22mmol ), potassium fluoride (1.3g, 22mmol), palladium acetate (0.5g, 2.2mmol) and acetic acid (1mL), stirred at 80°C for 48 hours.
  • Example 56 for the preparation of the compounds of Examples 53-55, and the corresponding mass spectrometry data are listed in Table 1.
  • reaction solution was cooled to room temperature, concentrated under reduced pressure, added 100 mL of ethyl acetate, washed with water (100 mL*2) and saturated sodium chloride solution (100 mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product title Product 5-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxyl-2-(4-methoxybenzyl)-4-nitroisoindol-1-one 57b (16.3g ), used directly in the next reaction.
  • Example 57 The synthesis method of Example 57 was referred to the synthesis method of the ninth step in Example 1, and Example 57 (23 mg) was obtained by using Example 57h as a raw material, and the yield was 36.0%.
  • Example 58 The synthesis method of Example 58 was referred to the synthesis method of the ninth step in Example 1, and Example 58 (17 mg) was obtained from Example 58a with a yield of 23.8%.
  • Example 59 The preparation of the compound of Example 59 refers to Example 58, and the corresponding mass spectrometry data are listed in Table 1.
  • synthesis method of compound 60d refer to the synthesis method of compound 49h, and use compound 60c as a raw material to obtain N-(2-(tert-butylamino)-1-(2-chloro-5-fluorophenyl)-2-oxoethane yl)-6-fluoro-2-(3-fluoro-5-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-7-carboxamide 60d (7.8g), yield: 86.6% .
  • synthesis method of compound 60 refer to the synthesis method of compound 49i, and use compound 60d as a raw material to obtain 8-(2-chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)benzene yl)-7,8-dihydroimidazo[4,5-e]isoindol-6(1H)-one 60 (0.2 g), yield: 36.2%.
  • synthesis method of compound 61f refer to the synthesis method of compound 60d, using compound 61e as a raw material to obtain (N-(2-(tert-butylamine)-1-(2-chloro-5-fluorophenyl)-2-oxyethyl) -6-fluoro-2-((S)-5-fluoro-3-oxindol-1-yl)-1H-benzo[d]imidazole-7-carboxamide 60f (1.8g), yield: 76.2 %.
  • the synthetic method of compound 61 referring to the synthetic method of compound 60, using compound 61f as raw material, obtains 8-(2-chloro-5-fluorophenyl)-2-((S)-5-fluoro-3-oxindole -1-yl)-7,8-dihydroimidazo[4,5-e]isoindol-6(1H)-one 61 (0.2 g), yield: 36.2%.
  • Example 62 The preparation of the compound of Example 62 refers to Example 61, and the corresponding mass spectrum data are listed in Table 1.
  • Examples 64 and 65 were prepared with reference to Example 63, and the corresponding mass spectrometry data are listed in Table 1.
  • 2-Bromobenzo[d]thiazole-5-carboxylic acid 66a (3.1 g, 12 mmol) was dissolved in 40 mL of dichloromethane, N,N'-carbonyldiimidazole (3.02 g, 18 mmol) and 4-dimethyl Aminopyridine (0.15 g, 1.2 mmol). The reaction was stirred at 25°C for 2 hours. 4-Methoxybenzylamine (1.70 g, 12 mmol) was added to the above reaction solution, and after the addition was completed, the reaction was continued to stir at 25° C. for 1 hour.
  • Examples 67 and 68 were prepared with reference to Example 66, and the corresponding mass spectrometry data are listed in Table 1.
  • Indole-2,3-dione 69a (1.0 g, 6.80 mmol) was dissolved in 20 mL of tetrahydrofuran, cesium fluoride (1.04 g, 20.39 mmol) and trimethyltrifluoromethylsilane (1.93 g, 13.59 mmol) were added ). React at 25°C for 2 hours. Add 30 mL of water to the reaction solution, extract with ethyl acetate (20 mL ⁇ 3), combine the organic phases, wash with saturated sodium chloride solution (20 mL ⁇ 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 3-hydroxy-3-(trifluoromethyl)indol-2-one 69b (0.70 g, yield: 47.4%).
  • Example 70 The preparation of the compound of Example 70 refers to Example 69, MS m/z (ESI): 499.1[M+1].
  • Example 71 The preparation of the compound of Example 71 refers to Example 69, MS m/z (ESI): 499.1[M+1].
  • Example 72 The preparation of the compound of Example 72 refers to Example 69, MS m/z (ESI): 513.1[M+1].
  • Example 73 The preparation of the compound of Example 73 refers to Example 69, MS m/z (ESI): 521.1[M+1].
  • Example 74 The preparation of the compound of Example 74 refers to Example 69, MS m/z (ESI): 515.1[M+1].
  • Example 75 compound refers to Example 69, MS m/z (ESI): 487.1[M+1].
  • Test Example 1 Experiment of the inhibitory activity of the compounds of the present invention on PI3K ⁇ mutant and wild-type kinases.
  • the purpose of this test example is to test the inhibitory activity of the compound on PI3K ⁇ mutant and wild-type kinases.
  • PI3K(p110 ⁇ /p85 ⁇ ) was purchased from Promega, catalog number V1721
  • PI3K (p110 ⁇ [H1047R]/p85 ⁇ ) was purchased from Promega, Cat. No. V1741
  • PI3K (p110 ⁇ [E545K]/p85 ⁇ ) was purchased from Promega, Cat. No. V1731
  • PIK3CA[E542K]/PIK3R1 was purchased from Carna, Cat. No. 11-413-20N
  • PIP2:3PS Lipid Kinase Substrate was purchased from Promega, the article number is V1701
  • Bovine Serum Albumin was purchased from Sigma, item number B2064-100G
  • HEPES (1M) was purchased from Gibco, Cat. No. 15630-080
  • DMSO was purchased from Sigma, Cat. No. D8418-100ML
  • ADP-Glo TM Kinase Assay was purchased from Promega, the article number is V9102
  • the ADP-Glo lipid kinase assay method of Promega Company was used.
  • the lipid kinase PI3K ⁇ catalyzed the reaction in the presence of the substrate PIP2:3PS and ATP, ATP generated ADP, and the lipid was characterized by measuring the content of ADP in the reaction.
  • Kinase activity, and the half inhibitory concentration IC 50 of the compound against PI3K ⁇ kinase activity was obtained.
  • the kinase reaction was carried out in a white 384-well plate, and 2 ⁇ L of different concentrations of compounds diluted with ddH 2 O containing 1% DMSO were added to each well, and 2 ⁇ L of ddH 2 O containing 1% DMSO was added to the positive control wells, and then 2 ⁇ L of ddH 2 O containing 1% DMSO was added to each well.
  • PI3K ⁇ mutant H1047R, E545K, E542K
  • wild-type kinase solutions diluted in 5 ⁇ kinase buffer (HEPES 250mM, MgCl 2 15mM, NaCl 250mM, BSA 0.05%)
  • 2 ⁇ L of 5 ⁇ Kinase buffer placed at room temperature for pre-incubation for 30 minutes, add 4 ⁇ L of 50 ⁇ M substrate PIP2:3PS prepared with 10 ⁇ Dilution buffer and ddH 2 O to all wells, and finally add 2 ⁇ L of 50-100 ⁇ M ATP solution diluted with water to start the reaction, room temperature After reacting for 60-120 minutes, add 10 ⁇ L ADP-Glo Reagent (containing 10 mM MgCl 2 ) to each well and react at room temperature for 60 minutes to remove excess ATP in the reaction, then add 20 ⁇ L Kinase Detection Reagent to each well, and
  • Enzyme name enzyme reaction concentration Enzyme reaction time ATP concentration PI3K ⁇ 0.025 ⁇ 0.1 ⁇ g/mL 60 ⁇ 120min 50 ⁇ M PI3K ⁇ H1047R 0.025 ⁇ 0.1 ⁇ g/mL 60 ⁇ 120min 50 ⁇ M PI3K ⁇ E545K 0.025 ⁇ 0.1 ⁇ g/mL 60 ⁇ 120min 50 ⁇ M PI3K ⁇ E542K 0.1 ⁇ 1 ⁇ g/mL 60 ⁇ 120min 50 ⁇ 100 ⁇ M
  • IC 50 values were calculated by fitting different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula using GraphPad prism.
  • Example (H1047R)IC50(nM) Example 13 116
  • Test Example 2 Determination of the inhibitory activity of the compounds of the present invention on PI3K ⁇ / ⁇ / ⁇ kinases
  • the purpose of this test example is to test the inhibitory activity of the compound on PI3K ⁇ / ⁇ / ⁇ kinase.
  • PI3K ⁇ was purchased from Carna, Cat. No. 11-102
  • PI3K ⁇ was purchased from Thermofisher, item number PV4786
  • PI3K ⁇ was purchased from Carna, Cat. No. 11-103
  • PIP2:3PS Lipid Kinase Substrate was purchased from Promega, the article number is V1701
  • Bovine Serum Albumin was purchased from Sigma, item number B2064-100G
  • HEPES (1M) was purchased from Gibco, Cat. No. 15630-080
  • DMSO was purchased from Sigma, Cat. No. D8418-100ML
  • ADP-Glo TM Kinase Assay was purchased from Promega, the article number is V9102
  • Lipid kinase PI3K ⁇ / ⁇ / ⁇ catalyzes the reaction in the presence of substrate PIP2:3PS and ATP, and ATP generates ADP.
  • ATP phospholipase
  • measuring the content of ADP in the reaction To characterize the activity of lipid kinases, and obtain the half inhibitory concentration IC 50 of the compound on PI3K ⁇ / ⁇ / ⁇ kinase activity.
  • the kinase reaction was carried out in a white 384-well plate, and 2 ⁇ L of different concentrations of compounds diluted with ddH 2 O containing 1% DMSO were added to each well, and 2 ⁇ L of ddH 2 O containing 1% DMSO was added to the positive control wells, and then 2 ⁇ L of ddH 2 O containing 1% DMSO was added to each well.
  • PI3K ⁇ / ⁇ / ⁇ kinase solution diluted in 5 ⁇ kinase buffer (HEPES 250mM, MgCl 2 15mM, NaCl 250mM, BSA 0.05%), add 2 ⁇ L of 5 ⁇ kinase buffer to negative control wells, and add to all wells 4 ⁇ L of 50 ⁇ M substrate PIP2:3PS prepared with 10 ⁇ Dilution buffer and ddH 2 O, and finally 2 ⁇ L of 50-100 ⁇ M ATP solution diluted with water was added to start the reaction.
  • Enzyme name enzyme reaction concentration Enzyme reaction time ATP concentration PI3K ⁇ 1 ⁇ g/mL 90min 100 ⁇ M PI3K ⁇ 0.5 ⁇ g/mL 120min 50 ⁇ M PI3K ⁇ 0.25 ⁇ g/mL 90min 100 ⁇ M
  • IC 50 values were calculated by fitting different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula using GraphPad prism.
  • the compounds shown in the present invention exhibit biological activity of about 1 nM to 10000 nM (IC 50 ) in the PI3K ⁇ / ⁇ / ⁇ kinase activity assay.
  • the compounds of the present invention have an IC50 of greater than about 10 nM for PI3K ⁇ / ⁇ / ⁇ kinase activity, preferably greater than about 100 nM, more preferably greater than about 1000 nM, and more preferably greater than about 10000 nM. Still further preferred compounds of the listed compounds inhibit activity with IC50 values greater than 1000 nM or even greater than about 10000 nM.
  • Test Example 3 Determination of the Proliferation Inhibitory Activity of Compounds of the Present Invention on PI3K ⁇ Mutant and Wild Type Tumor Cell Lines
  • the purpose of this test example is to test the effect of compounds on different PI3K ⁇ mutant tumor cell lines HCC1954 (PIK3CA H1047R), HGC-27 (PIK3CA E542K), MCF-7 (PIK3CA E545K) and PI3K ⁇ wild-type tumor cell line SK-BR Proliferation inhibitory activity of -3.

Abstract

A fused ring derivative having a structure shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing a compound, and a use of the pharmaceutical composition as a regulator in treating cancer-related diseases.

Description

稠环类衍生物调节剂、其制备方法和应用Fused ring derivative regulator, its preparation method and application 技术领域technical field
本发明属于生物医药领域，具体涉及一种稠环类衍生物调节剂及其制备方法和应用。The invention belongs to the field of biomedicine, and in particular relates to a regulator of condensed ring derivatives and its preparation method and application.
背景技术Background technique
磷脂酰肌醇3激酶(PI3K)蛋白家族分为I、II、III、IV四个大类，参与细胞生长、增殖、分化、生存和能量代谢等多种细胞功能的调节。PI3K四类蛋白结构与功能各异，研究最为广泛的是I类PI3K，该类PI3K又分为PI3Kα、PI3Kβ、PI3Kδ和PI3Kγ四个亚型，其中PI3Kα在多种肿瘤中发生激活突变和扩增，与肿瘤的发生发展密切相关。有报道证明PI3Kβ能激活血小板，在血栓形成等疾病的发生发展中起重要作用。PI3Kδ和PI3Kγ主要在血液***中表达，与免疫***和炎症的发生密切相关，另外PI3Kγ还与血压稳定和平滑肌收缩密切相关。The phosphatidylinositol 3-kinase (PI3K) protein family is divided into four categories: I, II, III, and IV, and is involved in the regulation of various cellular functions such as cell growth, proliferation, differentiation, survival, and energy metabolism. The four classes of PI3K proteins have different structures and functions. The most widely studied class I PI3Ks are divided into four subtypes: PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ. Among them, PI3Kα undergoes activation mutation and amplification in various tumors. , is closely related to the occurrence and development of tumors. It has been reported that PI3Kβ can activate platelets and play an important role in the occurrence and development of thrombosis and other diseases. PI3Kδ and PI3Kγ are mainly expressed in the blood system and are closely related to the immune system and inflammation. In addition, PI3Kγ is also closely related to blood pressure stability and smooth muscle contraction.
PI3Kα由p110α催化亚基以及p85调节亚基组成，p110α亚基由PIK3CA基因编码，当PI3Kα受到上游受体酪氨酸激酶(如胰岛素受体，血小板衍生生长因子受体等)以及Ras蛋白调控，激活后催化磷脂酰肌醇2磷酸(PIP2)生成磷脂酰肌醇3磷酸(PIP3)，PIP3能进一步激活蛋白激酶B(又称AKT)及其下游信号通路，从而调节细胞分化、迁移、代谢稳态。PI3Kα突变或扩增后可导致AKT通路持续激活，细胞快速增殖从而引起肿瘤的发生。PI3Kα也是胰岛素/胰岛素受体通路中的关键蛋白，可调节肝脏、骨骼肌等组织中的糖代谢平衡，抑制PI3Kα可导致肝脏糖原合成减少，血糖上升，体内胰岛素水平增加。PI3Kα is composed of p110α catalytic subunit and p85 regulatory subunit. The p110α subunit is encoded by the PIK3CA gene. When PI3Kα is regulated by upstream receptor tyrosine kinases (such as insulin receptor, platelet-derived growth factor receptor, etc.) and Ras protein, After activation, it catalyzes phosphatidylinositol 2 phosphate (PIP2) to generate phosphatidylinositol 3 phosphate (PIP3). PIP3 can further activate protein kinase B (also known as AKT) and its downstream signaling pathways, thereby regulating cell differentiation, migration, and metabolic stability. state. Mutation or amplification of PI3Kα can lead to continuous activation of the AKT pathway, rapid cell proliferation and tumorigenesis. PI3Kα is also a key protein in the insulin/insulin receptor pathway, which can regulate the balance of glucose metabolism in tissues such as liver and skeletal muscle. Inhibition of PI3Kα can lead to decreased glycogen synthesis in the liver, increased blood sugar, and increased insulin levels in the body.
PI3Kα是癌症中突变率最高的激酶之一，所有癌症中的总突变率达到14％，分布广泛，如乳腺癌、头颈癌、卵巢癌、胃癌、头颈癌等癌症中分布较多。PIK3CA基因突变类型多样，其中最常见的3种热点突变是H1047R突变(激酶区)，E542K(螺旋区)和E545K(螺旋区)。目前临床PI3Kα抑制剂对于PI3Kα突变型抑制活性强，PI3Kα野生型抑制无选择性，对PI3Kβ/γ/δ存在一定的抑制，导致临床试验中出现了PI3Kα野生型介导的严重高血糖副作用以及PI3K/AKT通路参与的皮疹、腹泻等副作用，并且由于体内胰岛素的增加，胰岛素受体通路激活，导致PI3K通路的激活增强，进而影响PI3Kα抑制剂的疗效。诺华公司的Alpelisib(BYL-719)是目前进展最快的PI3Kα抑制剂，已获批联合氟维斯群治疗PIK3CA突变的ER +HER2 -乳腺癌，疗效较好，但临床高血糖副作用较为严重，此外仍在开展HER2 +乳腺癌、三阴性乳腺癌、卵巢癌等适应症的临床试验。罗氏公司的PI3Kα抑制剂GDC-0077处于临床三期，适应症为联用治疗PIK3CA突变的ER +HER2 -乳腺癌，早期临床效果较好，但也出现较为严重的高血糖副作用。 PI3Kα is one of the kinases with the highest mutation rate in cancer. The total mutation rate in all cancers reaches 14%. It is widely distributed, such as breast cancer, head and neck cancer, ovarian cancer, gastric cancer, head and neck cancer and other cancers. There are various types of PIK3CA gene mutations, among which the three most common hotspot mutations are H1047R mutation (kinase region), E542K (helix region) and E545K (helix region). At present, clinical PI3Kα inhibitors have strong inhibitory activity against PI3Kα mutants, PI3Kα wild-type inhibition is non-selective, and there is a certain inhibition of PI3Kβ/γ/δ, resulting in severe hyperglycemic side effects mediated by PI3Kα wild-type and PI3K in clinical trials. The /AKT pathway is involved in side effects such as rash and diarrhea, and due to the increase of insulin in the body, the insulin receptor pathway is activated, resulting in enhanced activation of the PI3K pathway, which in turn affects the efficacy of PI3Kα inhibitors. Novartis' Alpelisib (BYL-719) is currently the fastest-growing PI3Kα inhibitor. It has been approved in combination with fulvestrant for the treatment of PIK3CA-mutated ER + HER2- breast cancer. In addition, clinical trials for indications such as HER2 + breast cancer, triple-negative breast cancer, and ovarian cancer are still underway. Roche's PI3Kα inhibitor GDC-0077 is in the third phase of clinical trials. It is indicated for combined use in the treatment of PIK3CA-mutated ER + HER2- breast cancer. The early clinical effect is good, but there are also serious hyperglycemic side effects.
综上所述，PI3Kα抑制剂在乳腺癌等适应症中治疗效果显著，具有较好的市场前景。现有PI3Kα抑制剂由于对PI3Kα野生型无选择性，导致了严重的高血糖副作用，限制了临床用药剂量和疗效，因此开发PI3Kα突变特异型变构抑制剂意义重大。目前国外已有两款PI3Kα突变型变构抑制剂在临床前开发阶段，分别是Relay公司的RLY-2608以及礼来公司的LOXO-783，这两个抑制剂均提高了对PI3Kα野生型的选择性，且对PI3Kβ/γ/δ的选择性非常高，有望降低毒性，提高疗效，将于2022年开启临床试验，具有较好的开发前景。In summary, PI3Kα inhibitors have remarkable therapeutic effects in breast cancer and other indications, and have good market prospects. Existing PI3Kα inhibitors have no selectivity for wild-type PI3Kα, leading to serious side effects of hyperglycemia, which limits the dosage and efficacy of clinical medication. Therefore, it is of great significance to develop PI3Kα mutation-specific allosteric inhibitors. At present, there are two PI3Kα mutant allosteric inhibitors in the preclinical development stage abroad, namely Relay’s RLY-2608 and Eli Lilly’s LOXO-783. These two inhibitors have improved the selection of PI3Kα wild type It has high selectivity to PI3Kβ/γ/δ, which is expected to reduce toxicity and improve efficacy. It will start clinical trials in 2022 and has a good development prospect.
发明内容Contents of the invention
本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐：The object of the present invention is to provide a compound shown in general formula (I), its stereoisomer or its pharmaceutically acceptable salt:
Figure PCTCN2022136232-appb-000001
Figure PCTCN2022136232-appb-000001
其中：in:
环A，环B和环C各自独立地选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被取代；Ring A, ring B and ring C are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further substituted;
环A存在或不存在；Ring A is present or absent;
环C存在或不存在；Ring C is present or absent;
R 1、R 2和R 3各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nR 11、-(CH 2) nOR 11、-(CH 2) nC(O)R 11、-(CH 2) nC(O)OR 11、-(CH 2) nS(O) mR 11、-(CH 2) nNR 22R 33、-(CH 2) nNR 22C(O)OR 33、-(CH 2) nNR 22C(O)(CH 2) n1R 33、-(CH 2) nNR 22C(O)NR 22R 33、-(CH 2) nC(O)NR 22(CH 2) n1R 33、-OC(R 11R 22) n(CH 2) n1R 33、-(CH 2) nNR 22S(O) mR 33，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代； R 1 , R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, Alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR 33 , -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , -(CH 2 ) n NR 22 C(O )NR 22 R 33 , -(CH 2 ) n C(O)NR 22 (CH 2 ) n1 R 33 , -OC(R 11 R 22 ) n (CH 2 ) n1 R 33 , -(CH 2 ) n NR 22 S(O) m R 33 , the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl, optionally can be further substituted;
R 11～R 33选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代； R 11 to R 33 are selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, Haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterium Alkenyloxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
m为0、1或2；m is 0, 1 or 2;
x、y、z、n和n1各自独立地为0、1、2、3或4。x, y, z, n and n1 are each independently 0, 1, 2, 3 or 4.
在本发明进一步优选的实施方式中，所述化合物进一步如通式(I-A)所示：In a further preferred embodiment of the present invention, the compound is further shown in general formula (I-A):
Figure PCTCN2022136232-appb-000002
Figure PCTCN2022136232-appb-000002
M选自S＝O、N或C＝O；M 1选自N或C； M is selected from S=O, N or C=O; M is selected from N or C;
Figure PCTCN2022136232-appb-000003
为单键或双键；
Figure PCTCN2022136232-appb-000003
is a single or double bond;
环A和环B各自独立地选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被取代；Ring A and Ring B are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further substituted;
或，优选地，环A和环B形成含1-3个选自O，S或N的杂原子的6-20元稠杂环或含1-3个选自O，S或N的杂原子的6-20元稠杂芳环；更优选地，环A和环B形成含1-3个N，S或O的8-10元稠杂芳环；进一步优选地，环A和环B形成如下任一稠杂芳环：
Figure PCTCN2022136232-appb-000004
Figure PCTCN2022136232-appb-000005
Or, preferably, Ring A and Ring B form a 6-20 membered condensed heterocyclic ring containing 1-3 heteroatoms selected from O, S or N or contain 1-3 heteroatoms selected from O, S or N 6-20 membered fused heteroaromatic ring; more preferably, ring A and ring B form an 8-10 membered fused heteroaromatic ring containing 1-3 N, S or O; further preferably, ring A and ring B form Any of the following fused heteroaromatic rings:
Figure PCTCN2022136232-appb-000004
Figure PCTCN2022136232-appb-000005
或，优选地，环A不存在，环B选自6-12元芳基或含1-4个杂原子的5-14元杂芳基；更优选地，环A不存在，环B选自含1-2个杂原子的5元杂芳基；进一步优选地，环A不存在，环B选自
Figure PCTCN2022136232-appb-000006
Or, preferably, ring A does not exist, and ring B is selected from 6-12 membered aryls or 5-14 membered heteroaryls containing 1-4 heteroatoms; more preferably, ring A does not exist, and ring B is selected from A 5-membered heteroaryl group containing 1-2 heteroatoms; further preferably, ring A does not exist, and ring B is selected from
Figure PCTCN2022136232-appb-000006
R 1各自独立地选自环烷基、杂环基、芳基、杂芳基；优选为芳基；更优选为6-12元芳基；进一步优选为苯基；所述R 1任选地可以被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基取代； R 1 are each independently selected from cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably aryl; more preferably 6-12 membered aryl; further preferably phenyl; Can be substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl;
R 2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基和C 1-6烷基的一个或多个取代基所取代，优选氢、氘、卤素、烷基、卤代烷基、氘代烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33； R 2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optional substituted by one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino and C 1-6 alkyl, preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 ;
R 3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷 基或C 1-6氘代烷基的一个或多个取代基所取代，优选C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷基或C 1-6氘代烷基的一个或多个取代基所取代； R 3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3- 12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, optionally replaced by hydrogen, hydroxyl, halogen, cyano, amino, C 1-6 alkyl, One or more substituents of C 1-6 haloalkyl or C 1-6 deuterated alkyl, preferably C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5 -12-membered heteroaryl, optionally substituted by one or more of hydrogen, hydroxyl, halogen, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuterated alkyl base replaced;
条件是，当环A存在时，R 2和R 3不同时为H； Provided that, when ring A exists, R2 and R3 are not H at the same time;
R 22选自氢、氘、卤素； R 22 is selected from hydrogen, deuterium, halogen;
R 33选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基取代； R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally can be further replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl , haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;
y和z各自独立地为1、2、3或4；y and z are each independently 1, 2, 3 or 4;
n、n1和m1各自独立地为0、1、2、3或4。n, n1 and m1 are each independently 0, 1, 2, 3 or 4.
在本发明进一步优选的实施方式中，所述化合物进一步如通式(I-A-1)所示：In a further preferred embodiment of the present invention, the compound is further shown in general formula (I-A-1):
Figure PCTCN2022136232-appb-000007
Figure PCTCN2022136232-appb-000007
其中：in:
M 2选自N或C； M2 is selected from N or C;
环D存在或不存在；环E存在或不存在；且环D和环E不存在的情况不能同时发生；The presence or absence of ring D; the presence or absence of ring E; and the absence of ring D and ring E cannot occur simultaneously;
环D和环E各自独立地选自环烷基、杂环基、芳基或杂芳基，优选含1-3个选自氮、氧或硫原子的3-10元杂环基或含1-3个选自氮、氧或硫原子5-10元杂芳基，更优选含1-3个选自氮、氧或硫原子的3-6元杂环基或含1-3个选自氮、氧或硫原子5-8元杂芳基，进一步优选
Figure PCTCN2022136232-appb-000008
Figure PCTCN2022136232-appb-000009
Ring D and ring E are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably 3-10 membered heterocyclic groups containing 1-3 selected from nitrogen, oxygen or sulfur atoms or containing 1 -3 5-10 membered heteroaryl groups selected from nitrogen, oxygen or sulfur atoms, more preferably 1-3 3-6 membered heterocyclic groups selected from nitrogen, oxygen or sulfur atoms or 1-3 members selected from Nitrogen, oxygen or sulfur atom 5-8 membered heteroaryl, more preferably
Figure PCTCN2022136232-appb-000008
Figure PCTCN2022136232-appb-000009
在本发明进一步优选的实施方式中，所述化合物进一步如通式(I-A-2)所示：In a further preferred embodiment of the present invention, the compound is further shown in general formula (I-A-2):
Figure PCTCN2022136232-appb-000010
Figure PCTCN2022136232-appb-000010
M选自S＝O或C＝O。M is selected from S=O or C=O.
在本发明进一步优选的实施方式中，所述化合物进一步如通式(I-B)所示：In a further preferred embodiment of the present invention, the compound is further shown in general formula (I-B):
Figure PCTCN2022136232-appb-000011
Figure PCTCN2022136232-appb-000011
环C选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被取代；优选地，环C选自杂环基或杂芳基，任选地可以进一步被取代；更优选地，环C选自3-12元杂环基或5-12元杂芳基，任选地可以进一步被取代；进一步优选地，环C选自
Figure PCTCN2022136232-appb-000012
Ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally can be further substituted; preferably, ring C is selected from heterocyclyl or heteroaryl, optionally can be further substituted; More preferably, ring C is selected from 3-12 membered heterocyclic groups or 5-12 membered heteroaryl groups, which may be further substituted; further preferably, ring C is selected from
Figure PCTCN2022136232-appb-000012
R 1各自独立地选自氢、氘、卤素、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基；优选为烷基或芳基；更优选为C 1-6烷基或6-12元芳基；进一步优选为甲基或苯基；其中至少一个R 1为取代的苯基；所述R 1任选地可以被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基取代； Each R is independently selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl, heteroaryl; preferably alkyl or aryl; more preferably C 1-6 alkyl or 6-12 yuan aryl; further preferably methyl or phenyl; wherein at least one R 1 is substituted phenyl; said R can optionally be replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl , alkoxy, alkenyl, alkynyl substitution;
R 2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基和C 1-6烷基的一个或多个取代基所取代，优选氢、氘、卤素、烷基、卤代烷基、氘代烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33，且其中至少一个R 2选自-(CH 2) nNR 22C(O)(CH 2) n1R 33； R 2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optional substituted by one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino and C 1-6 alkyl, preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , and wherein at least one R 2 is selected from -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 ;
R 22选自氢、氘、卤素； R 22 is selected from hydrogen, deuterium, halogen;
R 33选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基取代； R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally can be further replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl , haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;
x和y各自独立地为1、2、3或4；x and y are each independently 1, 2, 3 or 4;
n和n1各自独立地为0、1、2、3或4。n and n1 are each independently 0, 1, 2, 3 or 4.
在本发明进一步优选的实施方式中，所述化合物进一步如通式(I-C)所示：In a further preferred embodiment of the present invention, the compound is further shown in general formula (I-C):
Figure PCTCN2022136232-appb-000013
Figure PCTCN2022136232-appb-000013
R 2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基和C 1-6烷基的一个或多个取代基所取代，优选氢、氘、卤素、烷基、卤代烷基、氘代烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33，且其中至少一个R 2选自-(CH 2) nNR 22C(O)(CH 2) n1R 33； R 2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optional substituted by one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino and C 1-6 alkyl, preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , and wherein at least one R 2 is selected from -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 ;
R 22选自氢、氘、卤素； R 22 is selected from hydrogen, deuterium, halogen;
R 33选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基取代； R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally can be further replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl , haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;
R 4选自氢、氘、卤素、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基；优选为芳基；更优选为6-12元芳基；进一步优选为苯基；所述R 4任选地可以被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基取代； R is selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycle Base, aryl, heteroaryl; preferably aryl; more preferably 6-12 yuan aryl; further preferably phenyl; said R optionally can be hydrogen, deuterium, halogen, nitro, hydroxyl, Mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl substitution;
R 5选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基；优选为氨基或羟基； R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy , haloalkoxy, alkenyl, alkynyl; preferably amino or hydroxyl;
y为1、2、3或4；y is 1, 2, 3 or 4;
n和n1各自独立地为0、1、2、3或4。n and n1 are each independently 0, 1, 2, 3 or 4.
在本发明进一步优选的实施方式中，所述化合物进一步如通式(I-D)所示：In a further preferred embodiment of the present invention, the compound is further shown in general formula (I-D):
Figure PCTCN2022136232-appb-000014
Figure PCTCN2022136232-appb-000014
Figure PCTCN2022136232-appb-000015
代表双键或单键；
Figure PCTCN2022136232-appb-000015
Represents a double bond or a single bond;
M 1或M 2各自独立地选自S、NR a或CR b； M or M are each independently selected from S, NR a or CR b ;
R a和R b各自独立地选自氢、氘、卤素、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基； R and R are each independently selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl;
R 1各自独立地选自氢、氘、卤素、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基；优选为芳基；更优选为6-12元芳基；进一步优选为苯基；所述R 1任选地可以被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基取代； Each R is independently selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl, heteroaryl; preferably aryl; more preferably 6-12 yuan aryl; further preferably phenyl; said R optionally can be hydrogen, deuterium, halogen, nitro , hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl substitution;
R 2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基和C 1-6烷基的一个或多个取代基所取代，优选氢、氘、卤素、烷基、卤代烷基、氘代烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33，且其中至少一个R 2选自-(CH 2) nNR 22C(O)(CH 2) n1R 33； R 2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optional substituted by one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino and C 1-6 alkyl, preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , and wherein at least one R 2 is selected from -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 ;
R 22选自氢、氘、卤素； R 22 is selected from hydrogen, deuterium, halogen;
R 33选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基取代； R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally can be further replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl , haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;
x或y各自独立地为1、2、3或4；x or y are each independently 1, 2, 3 or 4;
n或n1各自独立地为0、1、2、3或4；n or n1 are each independently 0, 1, 2, 3 or 4;
n2为0、1或2。n2 is 0, 1 or 2.
在本发明的某些实施方式中，所述各通式中，In some embodiments of the present invention, in each of the general formulas,
环A和环B或环B和环C各自独立地组成稠环，所述稠环各自独立地选自
Figure PCTCN2022136232-appb-000016
Ring A and ring B or ring B and ring C each independently form a fused ring, and each of the fused rings is independently selected from
Figure PCTCN2022136232-appb-000016
或，环A，环B和环C共同组成稠环，所述稠环选自
Figure PCTCN2022136232-appb-000017
Figure PCTCN2022136232-appb-000018
Or, ring A, ring B and ring C together form a fused ring, the fused ring is selected from
Figure PCTCN2022136232-appb-000017
Figure PCTCN2022136232-appb-000018
R 1各自独立地选自氢，氘，
Figure PCTCN2022136232-appb-000019
Figure PCTCN2022136232-appb-000020
 Each R is independently selected from hydrogen, deuterium,
Figure PCTCN2022136232-appb-000019
Figure PCTCN2022136232-appb-000020
R 2和R 3各自独立地选自氢、氘、氟、氯、氨基、氰基、乙氧基、丙氧基、甲基氨基、二甲氨基、甲酰胺基、二氟甲基、三氟甲基、氰基甲基、
Figure PCTCN2022136232-appb-000021
Figure PCTCN2022136232-appb-000022
R and R are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, cyano, ethoxy, propoxy, methylamino, dimethylamino, formamido, difluoromethyl, trifluoro methyl, cyanomethyl,
Figure PCTCN2022136232-appb-000021
Figure PCTCN2022136232-appb-000022
Figure PCTCN2022136232-appb-000023
Figure PCTCN2022136232-appb-000023
Figure PCTCN2022136232-appb-000024
Figure PCTCN2022136232-appb-000024
在本发明的某些实施方式中，所述各通式中，In some embodiments of the present invention, in each of the general formulas,
R 1各自独立地选自被卤素取代的苯基；优选为被1～3个选自氟、氯和溴原子取代的苯基，更优选
Figure PCTCN2022136232-appb-000025
进一步优选为
Figure PCTCN2022136232-appb-000026
R 1 are each independently selected from phenyl substituted by halogen; preferably phenyl substituted by 1 to 3 atoms selected from fluorine, chlorine and bromine, more preferably
Figure PCTCN2022136232-appb-000025
is further preferably
Figure PCTCN2022136232-appb-000026
R 2各自独立地选自氢、氘、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6氘代烷基、 -NHC(O)R 33；优选地，R 2各自独立地选自氢、甲基、
Figure PCTCN2022136232-appb-000027
Figure PCTCN2022136232-appb-000028
且当环A不存在时，其中至少一个R 2选自
Figure PCTCN2022136232-appb-000029
Figure PCTCN2022136232-appb-000030
R 2 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, -NHC(O)R 33 ; preferably, each of R 2 independently selected from hydrogen, methyl,
Figure PCTCN2022136232-appb-000027
Figure PCTCN2022136232-appb-000028
And when ring A is absent, wherein at least one R 2 is selected from
Figure PCTCN2022136232-appb-000029
Figure PCTCN2022136232-appb-000030
R 3各自独立地选自氢、氘、C 6-10芳基或5-10元杂芳基，所述C 6-10芳基或5-10元杂芳基被氢、羟基、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷基或C 1-6氘代烷基的一个或多个取代基所取代；优选氢、氘、苯基或5-10元杂芳基，所述苯基或5-10元杂芳基被氢、羟基、氟、氯、溴、三氟甲基的一个或多个取代基所取代；更优选氢、氘、
Figure PCTCN2022136232-appb-000031
R 3 are each independently selected from hydrogen, deuterium, C 6-10 aryl or 5-10 membered heteroaryl, and the C 6-10 aryl or 5-10 membered heteroaryl is replaced by hydrogen, hydroxyl, halogen, cyano One or more substituents of radical, amino, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuterated alkyl; preferably hydrogen, deuterium, phenyl or 5-10 membered heteroaryl base, the phenyl or 5-10 membered heteroaryl is substituted by one or more substituents of hydrogen, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl; more preferably hydrogen, deuterium,
Figure PCTCN2022136232-appb-000031
“*”代表连接位点。"*" represents a ligation site.
本发明的代表性化合物列于表1中。在某些实施方式中，本发明提供一个选自表1的化合物，其药学上可接受的盐或立体异构体。Representative compounds of the invention are listed in Table 1. In certain embodiments, the present invention provides a compound selected from Table 1, a pharmaceutically acceptable salt or stereoisomer thereof.
表1Table 1
Figure PCTCN2022136232-appb-000032
Figure PCTCN2022136232-appb-000032
Figure PCTCN2022136232-appb-000033
Figure PCTCN2022136232-appb-000033
Figure PCTCN2022136232-appb-000034
Figure PCTCN2022136232-appb-000034
R 2各自独立地为： R 2 are each independently:
Figure PCTCN2022136232-appb-000035
Figure PCTCN2022136232-appb-000035
R 3各自独立地为： R 3 are each independently:
Figure PCTCN2022136232-appb-000036
Figure PCTCN2022136232-appb-000036
“*”代表连接位点。"*" represents a ligation site.
本发明进一步涉及一种药物组合物，其包括治疗有效剂量的任一所示的通式化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。The present invention further relates to a pharmaceutical composition, which comprises a therapeutically effective dose of any compound of the general formula shown, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers , diluent or excipient.
本发明进一步涉及任一所示的通式化合物、其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备治疗与PI3Kα相关疾病药物中的应用。The present invention further relates to the application of any one of the compounds shown in the general formula, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in the preparation of drugs for treating diseases related to PI3Kα.
本发明进一步涉及通式所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗癌症、PROS(PIK3CA-related overgrowth spectrum，PIK3CA相关过度生长谱)、免疫病症或炎性病症的药物中的应用，其中所述PROS选自血管畸形、***畸形及巨脑症，所述癌症选自胃癌、乳腺癌、***癌、肺癌、肝癌、骨癌、脑癌、头颈癌、肠癌、胰腺癌、膀胱癌、睾丸癌、卵巢癌、子宫内膜癌或多发性骨髓瘤。The present invention further relates to the compound represented by the general formula, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of treatment of cancer, PROS (PIK3CA-related overgrowth spectrum, PIK3CA-related overgrowth spectrum), The application in the medicine of immune disorder or inflammatory disorder, wherein said PROS is selected from vascular malformation, lymphatic malformation and megalencephaly, and said cancer is selected from gastric cancer, breast cancer, prostate cancer, lung cancer, liver cancer, bone cancer, brain cancer cancer, head and neck cancer, bowel cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer, endometrial cancer, or multiple myeloma.
本发明进一步涉及通式所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗与PI3Kα相关及相关疾病的药物中的方法。The present invention further relates to the compound represented by the general formula, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of medicines for treating PI3Kα-related and related diseases.
本发明还涉及一种治疗预防和/或治疗治疗与PI3Kα相关疾病的方法，其包括向患者施用治疗有效剂量的通式所示的化合物其立体异构体或其药学上可接受的盐，或其药物组合物。The present invention also relates to a method for treating, preventing and/or treating diseases related to PI3Kα, which comprises administering to the patient a therapeutically effective dose of the compound represented by the general formula, its stereoisomer or a pharmaceutically acceptable salt thereof, or its pharmaceutical composition.
本发明还提供了使用本发明的化合物或药物组合物治疗疾病状况的方法，该疾病状况包括但不限于与PI3Kα相关的状况。The invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions, including but not limited to conditions associated with PI3Kα.
本发明还涉及治疗哺乳动物中的与PI3Kα相关疾病的方法，其包括向所述哺乳动物施用治疗有效量的本发明的化合物或其药学上可接受的盐、酯、前药、溶剂化物、水合物或衍生物。The present invention also relates to a method for treating a PI3Kα-related disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrated substances or derivatives.
发明的详细说明Detailed Description of the Invention
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至8个碳原子的烷基，更优选1至6个碳原子的烷基，最优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁 基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms An alkyl group, most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl ylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl 2,2-diethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH 2-、“亚乙基”指-(CH 2) 2-、“亚丙基”指-(CH 2) 3-、“亚丁基”指-(CH 2) 4-等。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。 The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means -CH 2 -, "ethylene" means -(CH 2 ) 2 -, "propylene" refers to -(CH 2 ) 3 -, "butylene" refers to -(CH 2 ) 4 -, and the like. The term "alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene group, cyclooctyl group, etc.; polycyclic cycloalkyl group includes spiro ring, fused ring and bridged ring cycloalkyl group, preferably cyclopropyl group, cyclobutyl group, cyclohexyl group, cyclopentyl group and cycloheptyl group.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基 团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为3元/6元、3元/5元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The π-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl. More preferably, it is a 3-membered/6-membered, 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2022136232-appb-000037
等；
Figure PCTCN2022136232-appb-000037
wait;
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：Also included are spirocycloalkyls in which a single spirocycloalkyl shares a spiro atom with a heterocycloalkyl, non-limiting examples include:
Figure PCTCN2022136232-appb-000038
等。
Figure PCTCN2022136232-appb-000038
wait.
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2022136232-appb-000039
等。
Figure PCTCN2022136232-appb-000039
wait.
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated π-electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2022136232-appb-000040
Figure PCTCN2022136232-appb-000040
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以 下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；最优选包含3至8个环原子；进一步优选包含1-3氮原子的3-8元杂环基，任选地，被1-2个氧原子、硫原子、氧代基取代，包括含氮单环杂环基、含氮螺杂环基或含氮稠杂环基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contain 3 to 8 ring atoms; most preferably contain 3 to 8 ring atoms; further preferably contain 1-3 nitrogen atoms 3-8 The membered heterocyclic group is optionally substituted by 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiroheterocyclic groups or nitrogen-containing condensed heterocyclic groups.
单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吖庚基、1,4-二氮杂环庚基、吡喃基等，优选吡咯烷基、吗啉基、哌啶基、吖庚基、1,4-二氮杂环庚基和哌嗪基。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azeptyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, Piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl. Polycyclic heterocyclic groups include spiro rings, fused rings and bridged ring heterocyclic groups; the spiro rings, condensed rings and bridged ring heterocyclic groups involved are optionally connected to other groups through single bonds, or through rings Any two or more atoms on the ring are further linked with other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括： The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclic group. Non-limiting examples of spiroheterocyclyls include:
Figure PCTCN2022136232-appb-000041
Figure PCTCN2022136232-appb-000042
等。
Figure PCTCN2022136232-appb-000041
Figure PCTCN2022136232-appb-000042
wait.
术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或 S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括： The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated π-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring The atom is carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2022136232-appb-000043
Figure PCTCN2022136232-appb-000044
等。
Figure PCTCN2022136232-appb-000043
Figure PCTCN2022136232-appb-000044
wait.
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括： The term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond. A pi-electron system of a yoke wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
Figure PCTCN2022136232-appb-000045
Figure PCTCN2022136232-appb-000046
等。
Figure PCTCN2022136232-appb-000045
Figure PCTCN2022136232-appb-000046
wait.
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
Figure PCTCN2022136232-appb-000047
等。
Figure PCTCN2022136232-appb-000047
wait.
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤 素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，包括苯并5-10元杂芳基、苯并3-8元环烷基和苯并3-8元杂烷基，优选苯并5-6元杂芳基、苯并3-6元环烷基和苯并3-6元杂烷基，其中杂环基为含1-3氮原子、氧原子、硫原子的杂环基；或者还包含含苯环的三元含氮稠环。The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 12 membered, having a conjugated π-electron system, such as benzene base and naphthyl. Phenyl is more preferred. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group with a sulfur atom; or a three-membered nitrogen-containing condensed ring containing a benzene ring.
其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：Where the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure PCTCN2022136232-appb-000048
Figure PCTCN2022136232-appb-000049
等。
Figure PCTCN2022136232-appb-000048
Figure PCTCN2022136232-appb-000049
wait.
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至12元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为***基、噻吩基、咪唑基、吡唑基、噁唑基、嘧啶基或噻唑基；更有选吡唑基、吡咯基和噁唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrole group and oxazolyl group. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2022136232-appb-000050
等。
Figure PCTCN2022136232-appb-000050
wait.
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。"Haloalkyl" means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。"Haloalkoxy" means an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。"Hydroxyalkyl" means an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
“烯基”指链烯基，又称烯烃基，其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkenyl" refers to alkenyl, also known as alkenyl, wherein said alkenyl can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio group, carboxyl group or carboxylate group.
“炔基”指(CH≡C-)，其中所述的炔基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkynyl" refers to (CH≡C-), wherein said alkynyl can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
术语“烯基羰基”指-C(O)-(烯基)，其中烯基的定义如上所述。烯基羰基的非限制性实例包括：乙烯基羰基、丙烯基羰基、丁烯基羰基。烯基羰基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
“羟基”指-OH基团。"Hydroxy" means an -OH group.
“卤素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.
“氨基”指-NH 2。 "Amino" refers to -NH2 .
“氰基”指-CN。"Cyano" refers to -CN.
“硝基”指-NO 2。 "Nitro" refers to -NO2 .
“羰基”指-C(O)-。"Carbonyl" refers to -C(O)-.
“羧基”指-C(O)OH。"Carboxy" refers to -C(O)OH.
“THF”指四氢呋喃。"THF" means tetrahydrofuran.
“EtOAc”指乙酸乙酯。"EtOAc" means ethyl acetate.
“MeOH”指甲醇。"MeOH" means methanol.
“DMF”指N,N-二甲基甲酰胺。"DMF" refers to N,N-dimethylformamide.
“DIPEA”指二异丙基乙胺。"DIPEA" means diisopropylethylamine.
“TFA”指三氟乙酸。"TFA" means trifluoroacetic acid.
“MeCN”指乙晴。"MeCN" refers to acetonitrile.
“DMA”指N,N-二甲基乙酰胺。"DMA" refers to N,N-dimethylacetamide.
“Et 2O”指***。 " Et2O " means diethyl ether.
“DCE”指1,2二氯乙烷。"DCE" means 1,2 dichloroethane.
“DIPEA”指N,N-二异丙基乙胺。"DIPEA" refers to N,N-diisopropylethylamine.
“NBS”指N-溴代琥珀酰亚胺。"NBS" refers to N-bromosuccinimide.
“NIS”指N-碘代丁二酰亚胺。"NIS" refers to N-iodosuccinimide.
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。Different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", "X is A, B, and C" all express the same The meaning means that X can be any one or several of A, B, and C.
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。The hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by a deuterium atom.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, a "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
“药学上可接受的盐”“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salt" and "pharmaceutically acceptable salt" refer to the salts of the compounds of the present invention, which are safe and effective when used in mammals, and have proper biological activity.
具体实施方式Detailed ways
实施例Example
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD),内标为四甲基硅烷(TMS)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). The determination of NMR is to use Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is four Methylsilane (TMS).
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号：Finnigan LCQ advantage MAX)。MS was determined with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。The determination of HPLC used Agilent 1200DAD high pressure liquid chromatography (Sunfire C18 150×4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150×4.6mm column).
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。 Kinase average inhibition rate and IC 50 value were measured with NovoStar microplate reader (BMG Company, Germany).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ~0.5mm.
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。The known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui chemical companies.
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
微波反应使用CEM Discover-S 908860型微波反应器。For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.
实施例中无特殊说明，溶液是指水溶液。Unless otherwise specified in the examples, the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：二氯甲烷和丙酮体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The monitoring of the reaction progress in the embodiment adopts thin-layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound. The eluent system of column chromatography and the developer system of thin-layer chromatography used for purifying compounds include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
实施例1Example 1
N-(6-(2-氯-5-氟苯基)-8-氧代-3,6,7,8-四氢吡咯[3,4-e]吲唑-5-基)-3-氟-5-(三氟 甲基)苯甲酰胺N-(6-(2-Chloro-5-fluorophenyl)-8-oxo-3,6,7,8-tetrahydropyrrole[3,4-e]indazol-5-yl)-3- Fluoro-5-(trifluoromethyl)benzamide
Figure PCTCN2022136232-appb-000051
Figure PCTCN2022136232-appb-000051
第一步first step
3-溴-6-氟-2-甲基-5-硝基苯甲酸3-Bromo-6-fluoro-2-methyl-5-nitrobenzoic acid
25℃下，将2-氟-6-甲基-3-硝基苯甲酸1a(5g,25mmol)溶解于60mL浓硫酸中，加入1,3-二溴-5，5-二甲基己内酰脲(7.18g,25mmol)。85℃加热反应2小时。将反应液冷却到室温后，倒入300mL冰水中，有浅黄色固体析出。过滤，滤饼用水洗涤(20mL×2)，烘干，得到标题产物3-溴-6-氟-2-甲基-5-硝基苯甲酸1b(6.98g)，直接用于下步反应。At 25°C, dissolve 2-fluoro-6-methyl-3-nitrobenzoic acid 1a (5g, 25mmol) in 60mL of concentrated sulfuric acid, add 1,3-dibromo-5,5-dimethylhexyl Urea (7.18 g, 25 mmol). The reaction was heated at 85°C for 2 hours. After the reaction solution was cooled to room temperature, it was poured into 300 mL of ice water, and a light yellow solid precipitated out. After filtration, the filter cake was washed with water (20 mL×2) and dried to obtain the title product 3-bromo-6-fluoro-2-methyl-5-nitrobenzoic acid 1b (6.98 g), which was directly used in the next reaction.
第二步second step
3-溴-N-(2-(叔丁胺)-1-(2-氯-5-氟苯基)-2-氧乙基)-6-氟-N-(4-甲氧基苄基)-2-甲基-5-硝基苯甲酰胺3-Bromo-N-(2-(tert-butylamine)-1-(2-chloro-5-fluorophenyl)-2-oxyethyl)-6-fluoro-N-(4-methoxybenzyl)- 2-Methyl-5-nitrobenzamide
将2-氯-5-氟苯甲醛(3.98g，25mmol)溶解于100mL甲醇中，依次加入4-甲氧基苄胺(3.44g，25mmol)，3-溴-6-氟-2-甲基-5-硝基苯甲酸1b(6.98g，25mmol)和叔丁基异氰(2.09g，25mmol)，20℃搅拌反应2小时。将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-溴 -N-(2-(叔丁胺)-1-(2-氯-5-氟苯基)-2-氧乙基)-6-氟-N-(4-甲氧基苄基)-2-甲基-5-硝基苯甲酰胺1c(13.50g)，产率：84.2％。Dissolve 2-chloro-5-fluorobenzaldehyde (3.98g, 25mmol) in 100mL of methanol, add 4-methoxybenzylamine (3.44g, 25mmol), 3-bromo-6-fluoro-2-methyl - 5-Nitrobenzoic acid 1b (6.98g, 25mmol) and tert-butyl isocyanide (2.09g, 25mmol), stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3-bromo-N-(2-(tert-butylamine)-1-(2-chloro-5-fluorobenzene yl)-2-oxyethyl)-6-fluoro-N-(4-methoxybenzyl)-2-methyl-5-nitrobenzamide 1c (13.50 g), yield: 84.2%.
MS m/z(ESI):638.2[M+1]MS m/z(ESI):638.2[M+1]
第三步third step
6-溴-3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧基苄基)-7-甲基-4-硝基异吲哚-1-酮6-Bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-7-methyl-4-nitroisoindol-1-one
将3-溴-N-(2-(叔丁胺)-1-(2-氯-5-氟苯基)-2-氧乙基)-6-氟-N-(4-甲氧基苄基)-2-甲基-5-硝基苯甲酰胺1c(13.50g，21mmol)溶解于150mL乙腈中，加入2-叔丁基-1,1,3,3-四甲基胍(5.43g，32mmol)，50℃搅拌反应2小时。将反应液减压浓缩，得到标题产物6-溴-3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧基苄基)-7-甲基-4-硝基异吲哚-1-酮1d(11.32g)，直接用于下步反应。3-Bromo-N-(2-(tert-butylamine)-1-(2-chloro-5-fluorophenyl)-2-oxoethyl)-6-fluoro-N-(4-methoxybenzyl) -2-Methyl-5-nitrobenzamide 1c (13.50g, 21mmol) was dissolved in 150mL acetonitrile, and 2-tert-butyl-1,1,3,3-tetramethylguanidine (5.43g, 32mmol ), stirred and reacted at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title product 6-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxyl-2-(4-methoxybenzyl)-7-methyl-4 -Nitroisoindol-1-one 1d (11.32g), directly used in the next reaction.
MS m/z(ESI):535.1[M+1]MS m/z(ESI):535.1[M+1]
第四步the fourth step
6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-7-甲基-4-硝基异吲哚-1-酮6-Bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-7-methyl-4-nitroisoindol-1-one
将6-溴-3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧基苄基)-7-甲基-4-硝基异吲哚-1-酮1d(11.32g，21mmol)溶解于150mL三氟乙酸中，加入三乙基硅烷(12.60g，0.11mol)，90℃加热反应5小时。将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-7-甲基-4-硝基异吲哚-1-酮1e(8.60g)，产率：78.3％。6-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-7-methyl-4-nitroisoindole-1- Ketone 1d (11.32g, 21mmol) was dissolved in 150mL of trifluoroacetic acid, triethylsilane (12.60g, 0.11mol) was added, and the reaction was heated at 90°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methyl Oxybenzyl)-7-methyl-4-nitroisoindol-1-one 1e (8.60 g), yield: 78.3%.
MS m/z(ESI):519.2[M+1]MS m/z(ESI):519.2[M+1]
第五步the fifth step
6-氨基-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-7-甲基-4-硝基异吲哚-1-酮6-amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-7-methyl-4-nitroisoindol-1-one
将6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-7-甲基-4-硝基异吲哚-1-酮1e(8.60g，16mmol)溶解于100mL 1,4-二氧六环，在反应体系中依次加入氯化铵(4.42g,83mmol)，三(二苯亚苄基丙酮)二钯(1.52g，1.6mmol),1,1’-联萘-2，2’-双二苯膦(2.06g，3.3mmol)和叔丁醇钠(4.77g，96mmol)。90℃加热反应5小时。冷却到室温后，向反应液中加入500mL水，用乙酸乙酯萃取(200mL×3)，合并有机相，用饱和氯化钠溶液洗涤(100mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物6-氨基-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-7-甲基-4-硝基异吲哚-1-酮1f(5.20g)，产率：69.0％。6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-7-methyl-4-nitroisoindol-1-one 1e (8.60 g, 16mmol) was dissolved in 100mL 1,4-dioxane, and ammonium chloride (4.42g, 83mmol), tris(diphenylbenzylideneacetone) dipalladium (1.52g, 1.6mmol) were added successively in the reaction system , 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (2.06 g, 3.3 mmol) and sodium tert-butoxide (4.77 g, 96 mmol). The reaction was heated at 90°C for 5 hours. After cooling to room temperature, 500 mL of water was added to the reaction solution, extracted with ethyl acetate (200 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography with eluent system B to give the title product 6-amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl yl)-7-methyl-4-nitroisoindol-1-one 1f (5.20 g), yield: 69.0%.
MS m/z(ESI):456.1[M+1]MS m/z(ESI):456.1[M+1]
第六步step six
6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-5-硝基-6,7-二氢吡咯[3,4-e]吲唑-8(3H)-酮6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-5-nitro-6,7-dihydropyrrole[3,4-e]indazole-8( 3H)-ketone
将6-氨基-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-7-甲基-4-硝基异吲哚-1-酮1f(5.20g，11mmol)溶解于60mL冰醋酸中，加入亚硝酸钠(0.86g，12mmol)和3mL 水，25℃搅拌反应2小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-5-硝基-6,7-二氢吡咯[3,4-e]吲唑-8(3H)-酮1g(3.52g)，产率：67.7％。6-amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-7-methyl-4-nitroisoindol-1-one 1f (5.20 g, 11 mmol) was dissolved in 60 mL of glacial acetic acid, sodium nitrite (0.86 g, 12 mmol) and 3 mL of water were added, and the reaction was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl) -5-nitro-6,7-dihydropyrrole[3,4-e]indazol-8(3H)-one 1 g (3.52 g), yield: 67.7%.
MS m/z(ESI):467.2[M+1]MS m/z(ESI):467.2[M+1]
第七步step seven
5-氨基-6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-6,7-二氢吡咯[3,4-e]吲唑-8(3H)-酮5-amino-6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-6,7-dihydropyrrole[3,4-e]indazole-8(3H )-ketone
将6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-5-硝基-6,7-二氢吡咯[3,4-e]吲唑-8(3H)-酮1g(3.52g，7.5mmol)溶解于50mL乙醇和5mL冰醋酸的混合溶液中，加入氯化铵(2.79g,52mmol)。升温到50℃，在此温度下分批加入还原铁粉(2.91g,52mmol)。80℃加热反应1小时。反应液减压浓缩，所得残余物中加入100mL水，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(30mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物5-氨基-6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-6,7-二氢吡咯[3,4-e]吲唑-8(3H)-酮1h(0.91g)，产率：27.6％。6-(2-Chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-5-nitro-6,7-dihydropyrrole[3,4-e]indazole-8 (3H)-Kone 1g (3.52g, 7.5mmol) was dissolved in a mixed solution of 50mL ethanol and 5mL glacial acetic acid, and ammonium chloride (2.79g, 52mmol) was added. The temperature was raised to 50° C., and reduced iron powder (2.91 g, 52 mmol) was added in batches at this temperature. The reaction was heated at 80°C for 1 hour. The reaction solution was concentrated under reduced pressure, 100 mL of water was added to the obtained residue, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5-amino-6-(2-chloro-5-fluorophenyl)-7-(4-methoxy Benzyl)-6,7-dihydropyrrole[3,4-e]indazol-8(3H)-one 1h (0.91 g), yield: 27.6%.
MS m/z(ESI):437.3[M+1]MS m/z(ESI):437.3[M+1]
第八步eighth step
N-(6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-8-氧代-3,6,7,8-四氢吡咯[3,4-e]吲唑-5-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-8-oxo-3,6,7,8-tetrahydropyrrole[3,4- e] Indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide
将5-氨基-6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-6,7-二氢吡咯[3,4-e]吲唑-8(3H)-酮1h(200mg，0.46mmol)溶解于5.0mL乙腈中，加入吡啶(72mg，0.92mmol)和3-氟-5-(三氟甲基)苯甲酰氯(104mg，0.46mmol)，25℃下搅拌反应24小时。在反应液中加入20mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和氯化钠溶液洗涤(10mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物N-(6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-8-氧代-3,6,7,8-四氢吡咯[3,4-e]吲唑-5-基)-3-氟-5-(三氟甲基)苯甲酰胺1i(0.29g)，直接用于下步反应。5-amino-6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-6,7-dihydropyrrole[3,4-e]indazole-8( 3H)-ketone 1h (200 mg, 0.46 mmol) was dissolved in 5.0 mL of acetonitrile, pyridine (72 mg, 0.92 mmol) and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (104 mg, 0.46 mmol) were added, 25 The reaction was stirred at °C for 24 hours. Add 20 mL of water to the reaction solution, extract with ethyl acetate (10 mL×3), combine the organic phases, wash with saturated sodium chloride solution (10 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The title product N-(6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-8-oxo-3,6,7,8-tetrahydropyrrole[3, 4-e] Indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide 1i (0.29g), used directly in the next reaction.
MS m/z(ESI):627.2[M+1]MS m/z(ESI):627.2[M+1]
第九步Ninth step
N-(6-(2-氯-5-氟苯基)-8-氧代-3,6,7,8-四氢吡咯[3,4-e]吲唑-5-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(6-(2-Chloro-5-fluorophenyl)-8-oxo-3,6,7,8-tetrahydropyrrole[3,4-e]indazol-5-yl)-3- Fluoro-5-(trifluoromethyl)benzamide
将N-(6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-8-氧代-3,6,7,8-四氢吡咯[3,4-e]吲唑-5-基)-3-氟-5-(三氟甲基)苯甲酰胺1i(0.29g，0.46mmol)溶解于5mL甲烷磺酸中，60℃下搅拌反应15小时。向反应液中加入饱和碳酸氢钠溶液调节pH大于7，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和氯化钠溶液洗涤(10mL×2)，用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用制备HPLC纯化，得到标题产物N-(6-(2-氯-5-氟苯基)-8-氧代-3,6,7,8-四氢吡咯[3,4-e]吲唑-5- 基)-3-氟-5-(三氟甲基)苯甲酰胺1(58mg)，产率：25.2％。N-(6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-8-oxo-3,6,7,8-tetrahydropyrrole[3,4 -e] Indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide 1i (0.29g, 0.46mmol) was dissolved in 5mL methanesulfonic acid, and stirred at 60°C for 15 hours. Add saturated sodium bicarbonate solution to the reaction solution to adjust the pH to greater than 7, extract with ethyl acetate (10 mL×3), combine the organic phases, wash with saturated sodium chloride solution (10 mL×2), and dry over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give the title product N-(6-(2-chloro-5-fluorophenyl)-8-oxo-3,6,7,8-tetrahydro Pyrrolo[3,4-e]indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide 1 (58 mg), yield: 25.2%.
MS m/z(ESI):507.2[M+1]MS m/z(ESI):507.2[M+1]
实施例2-4化合物的制备参照实施例1，相应的质谱数据列于表1中。Refer to Example 1 for the preparation of the compounds of Examples 2-4, and the corresponding mass spectrometry data are listed in Table 1.
实施例5Example 5
N-(3-(2-氯-5-氟苯基)-1-氧代-2,3,6,9a-四氢-1H-咪唑并[1,2-a]吡咯[3,4-e]吡啶-4-N-(3-(2-Chloro-5-fluorophenyl)-1-oxo-2,3,6,9a-tetrahydro-1H-imidazo[1,2-a]pyrrole[3,4- e] pyridine-4- 基)-3-氟-5-(三氟甲基)苯甲酰胺base)-3-fluoro-5-(trifluoromethyl)benzamide
Figure PCTCN2022136232-appb-000052
Figure PCTCN2022136232-appb-000052
第一步first step
4-氯-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-2,3,6,9a-四氢-1H-咪唑并[1,2-a]吡咯[3,4-e]吡啶-1-酮4-Chloro-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2,3,6,9a-tetrahydro-1H-imidazo[1,2- a]pyrrole[3,4-e]pyridin-1-one
将2-氨基-4-氯-5-(2-氯-5-氟苯基)-6-(4-甲氧基苄基)-5,6-二氢-7H-吡咯[3,4-b]吡啶-7-酮5a(2.0g，4.6mmol)溶解于30mL异丙醇中，加入50％2-氯乙醛溶液(1.50g，9.2mmol)和碳酸氢钠(0.97g，11mmol)，80℃下加热反应24小时。冷却到室温后，在反应液中加入30mL水，用二氯甲烷萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4-氯-3-(2- 氯-5-氟苯基)-2-(4-甲氧基苄基)-2,3,6,9a-四氢-1H-咪唑并[1,2-a]吡咯[3,4-e]吡啶-1-酮5b(1.43g)，产率：67.4％。2-Amino-4-chloro-5-(2-chloro-5-fluorophenyl)-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrole[3,4- b] Pyridin-7-one 5a (2.0 g, 4.6 mmol) was dissolved in 30 mL of isopropanol, 50% 2-chloroacetaldehyde solution (1.50 g, 9.2 mmol) and sodium bicarbonate (0.97 g, 11 mmol) were added, The reaction was heated at 80°C for 24 hours. After cooling to room temperature, add 30 mL of water to the reaction solution, extract with dichloromethane (20 mL×3), combine the organic phases, wash with saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, filter, and the filtrate After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 4-chloro-3-(2-chloro-5-fluorophenyl)-2-(4-methoxy Benzyl)-2,3,6,9a-tetrahydro-1H-imidazo[1,2-a]pyrrole[3,4-e]pyridin-1-one 5b (1.43g), yield: 67.4% .
MS m/z(ESI):458.2[M+1]MS m/z(ESI):458.2[M+1]
第二步second step
3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-((4-甲氧基苄基)氨基)-2,3,6,9a-四氢-1H-咪唑并[1,2-a]吡咯[3,4-e]吡啶-1-酮3-(2-Chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-((4-methoxybenzyl)amino)-2,3,6,9a-tetra Hydrogen-1H-imidazo[1,2-a]pyrrole[3,4-e]pyridin-1-one
将4-氯-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-2,3,6,9a-四氢-1H-咪唑并[1,2-a]吡咯[3,4-e]吡啶-1-酮5b(1.43g，3.1mmol)溶解于20mL4-甲氧基苄胺中，120℃下加热反应12小时。冷却到室温后，在反应液中加入50mL 1M稀盐酸，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-((4-甲氧基苄基)氨基)-2,3,6,9a-四氢-1H-咪唑并[1,2-a]吡咯[3,4-e]吡啶-1-酮5c(1.35g)，产率：77.4％。4-chloro-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2,3,6,9a-tetrahydro-1H-imidazo[1,2 -a]pyrrole[3,4-e]pyridin-1-one 5b (1.43g, 3.1mmol) was dissolved in 20mL of 4-methoxybenzylamine, and heated at 120°C for 12 hours. After cooling to room temperature, add 50mL of 1M dilute hydrochloric acid to the reaction solution, extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated sodium chloride solution (20mL×2), dry over anhydrous sodium sulfate, and filter , after the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl )-4-((4-methoxybenzyl)amino)-2,3,6,9a-tetrahydro-1H-imidazo[1,2-a]pyrrole[3,4-e]pyridine-1 - Ketone 5c (1.35 g), yield: 77.4%.
MS m/z(ESI):559.3[M+1]MS m/z(ESI):559.3[M+1]
第三步third step
4-氨基-3-(2-氯-5-氟苯基)-2,3,6,9a-四氢-1H-咪唑并[1,2-a]吡咯[3,4-e]吡啶-1-酮4-Amino-3-(2-chloro-5-fluorophenyl)-2,3,6,9a-tetrahydro-1H-imidazo[1,2-a]pyrrole[3,4-e]pyridine- 1-keto
将3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-((4-甲氧基苄基)氨基)-2,3,6,9a-四氢-1H-咪唑并[1,2-a]吡咯[3,4-e]吡啶-1-酮5c(1.35g，2.4mmol)溶解于15mL三氟乙酸和三氟甲磺酸(V/V＝9:1)混合溶剂中，80℃下加热反应5小时。冷却到室温后，将反应液慢慢倒入100mL饱和碳酸氢钠溶液中，用二氯甲烷萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4-氨基-3-(2-氯-5-氟苯基)-2,3,6,9a-四氢-1H-咪唑并[1,2-a]吡咯[3,4-e]吡啶-1-酮5d(0.42g)，产率：54.5％。3-(2-Chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-((4-methoxybenzyl)amino)-2,3,6,9a- Tetrahydro-1H-imidazo[1,2-a]pyrrole[3,4-e]pyridin-1-one 5c (1.35 g, 2.4 mmol) was dissolved in 15 mL of trifluoroacetic acid and trifluoromethanesulfonic acid (V/ V=9:1) in a mixed solvent, heated at 80°C for 5 hours. After cooling to room temperature, the reaction solution was slowly poured into 100mL saturated sodium bicarbonate solution, extracted with dichloromethane (30mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20mL×2), anhydrous Drying over sodium sulfate, filtration, and concentration of the filtrate under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 4-amino-3-(2-chloro-5-fluorophenyl)-2 , 3,6,9a-tetrahydro-1H-imidazo[1,2-a]pyrrole[3,4-e]pyridin-1-one 5d (0.42 g), yield: 54.5%.
MS m/z(ESI):319.2[M+1]MS m/z(ESI):319.2[M+1]
第四步the fourth step
N-(3-(2-氯-5-氟苯基)-1-氧代-2,3,6,9a-四氢-1H-咪唑并[1,2-a]吡咯[3,4-e]吡啶-4-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(3-(2-Chloro-5-fluorophenyl)-1-oxo-2,3,6,9a-tetrahydro-1H-imidazo[1,2-a]pyrrole[3,4- e] pyridin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
将4-氨基-3-(2-氯-5-氟苯基)-2,3,6,9a-四氢-1H-咪唑并[1,2-a]吡咯[3,4-e]吡啶-1-酮5d(50mg，0.15mmol)溶解于5mL二氯甲烷中，加入3-氟-5-(三氟甲基)苯甲酸(39mg，0.19mmol)，1-甲基咪唑(38mg，0.47mmol)和四甲基氯代脲六氟磷酸酯(66mg，0.24mmol)，25℃搅拌反应1小时。在反应液中加入10mL水，用二氯甲烷萃取(10mL×2)，合并有机相，用饱和氯化钠溶液洗涤(10mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，所得残余物用制备HPLC纯化，得到 标题产物N-(3-(2-氯-5-氟苯基)-1-氧代-2,3,6,9a-四氢-1H-咪唑并[1,2-a]吡咯[3,4-e]吡啶-4-基)-3-氟-5-(三氟甲基)苯甲酰胺5(15mg)，产率：18.8％。4-Amino-3-(2-chloro-5-fluorophenyl)-2,3,6,9a-tetrahydro-1H-imidazo[1,2-a]pyrrole[3,4-e]pyridine -1-ketone 5d (50 mg, 0.15 mmol) was dissolved in 5 mL of dichloromethane, 3-fluoro-5-(trifluoromethyl) benzoic acid (39 mg, 0.19 mmol), 1-methylimidazole (38 mg, 0.47 mmol) and tetramethylchlorourea hexafluorophosphate (66mg, 0.24mmol), stirred at 25°C for 1 hour. Add 10 mL of water to the reaction solution, extract with dichloromethane (10 mL×2), combine the organic phases, wash with saturated sodium chloride solution (10 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by preparative HPLC to give the title product N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3,6,9a-tetrahydro-1H-imidazo[1 ,2-a]pyrrole[3,4-e]pyridin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide 5 (15 mg), yield: 18.8%.
MS m/z(ESI):509.1[M+1]MS m/z(ESI):509.1[M+1]
实施例6-8化合物的制备参照实施例5，相应的质谱数据列于表1中。Refer to Example 5 for the preparation of the compounds of Examples 6-8, and the corresponding mass spectrometry data are listed in Table 1.
实施例9Example 9
N-(6-(2-氯-5-氟苯基)-8-氧代-7,8-二氢-6H-吡咯[3,4-e][1,2,4]***基[1,5-a]吡啶-5-N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-pyrrole[3,4-e][1,2,4]triazolyl[ 1,5-a]pyridine-5- 基)-3-氟-5-(三氟甲基)苯甲酰胺base)-3-fluoro-5-(trifluoromethyl)benzamide
Figure PCTCN2022136232-appb-000053
Figure PCTCN2022136232-appb-000053
第一步first step
5-氯-6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-3,3a,6,7-四氢-8H-吡咯[3,4-e][1,2,4]***基[1,5-a]吡啶-8-酮5-chloro-6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-3,3a,6,7-tetrahydro-8H-pyrrole[3,4-e ][1,2,4]triazolyl[1,5-a]pyridin-8-one
将2-氨基-4-氯-5-(2-氯-5-氟苯基)-6-(4-甲氧基苄基)-5,6-二氢-7H-吡咯[3,4-b]吡啶-7-酮9a(2.0g，4.6mmol)溶解于30mL DMF中，加入1,1-二甲氧基-N，N-二甲基甲胺(1.10g，9.2mmol)，130℃下加热反应6小时。减压浓缩除去溶剂。将所得残余物溶解于30mL甲醇和吡啶(V/V＝9:1)混合溶剂中加入盐酸羟胺 (0.38g，5.5mmol)。25℃搅拌反应2小时。在反应液中加入30mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物5-氯-6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-3,3a,6,7-四氢-8H-吡咯[3,4-e][1,2,4]***基[1,5-a]吡啶-8-酮9b(1.10g)，产率：51.9％。2-Amino-4-chloro-5-(2-chloro-5-fluorophenyl)-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrole[3,4- b] pyridin-7-one 9a (2.0g, 4.6mmol) was dissolved in 30mL DMF, added 1,1-dimethoxy-N, N-dimethylmethylamine (1.10g, 9.2mmol), 130°C The reaction was heated for 6 hours. Concentrate under reduced pressure to remove the solvent. The resulting residue was dissolved in 30 mL of a mixed solvent of methanol and pyridine (V/V=9:1) and hydroxylamine hydrochloride (0.38 g, 5.5 mmol) was added. The reaction was stirred at 25°C for 2 hours. Add 30 mL of water to the reaction solution, extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel with eluent system B to give the title product 5-chloro-6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-3 , 3a,6,7-Tetrahydro-8H-pyrrole[3,4-e][1,2,4]triazolyl[1,5-a]pyridin-8-one 9b (1.10 g), yield : 51.9%.
MS m/z(ESI):457.1[M+1]MS m/z(ESI):457.1[M+1]
第二步second step
6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-5-(4-甲氧基苄基)氨基)-3,3a,6,7-四氢-8H-吡咯[3,4-e][1,2,4]***[1,5-a]吡啶-8-酮6-(2-Chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-5-(4-methoxybenzyl)amino)-3,3a,6,7-tetrahydro -8H-Pyrrole[3,4-e][1,2,4]triazol[1,5-a]pyridin-8-one
将5-氯-6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-3,3a,6,7-四氢-8H-吡咯[3,4-e][1,2,4]***基[1,5-a]吡啶-8-酮9b(1.10g，2.4mmol)溶解于15mL4-甲氧基苄胺中，120℃下加热反应12小时。冷却到室温后，在反应液中加入50mL 1M稀盐酸，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-5-(4-甲氧基苄基)氨基)-3,3a,6,7-四氢-8H-吡咯[3,4-e][1,2,4]***[1,5-a]吡啶-8-酮9c(0.98g)，产率：73.1％。5-chloro-6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-3,3a,6,7-tetrahydro-8H-pyrrole[3,4- e][1,2,4]Triazolyl[1,5-a]pyridin-8-one 9b (1.10g, 2.4mmol) was dissolved in 15mL of 4-methoxybenzylamine, heated at 120°C for 12 hours . After cooling to room temperature, add 50mL of 1M dilute hydrochloric acid to the reaction solution, extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated sodium chloride solution (20mL×2), dry over anhydrous sodium sulfate, and filter , after the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 6-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl )-5-(4-methoxybenzyl)amino)-3,3a,6,7-tetrahydro-8H-pyrrole[3,4-e][1,2,4]triazole[1,5 -a] Pyridin-8-one 9c (0.98 g), yield: 73.1%.
MS m/z(ESI):558.2[M+1]MS m/z(ESI):558.2[M+1]
第三步third step
5-氨基-6-(2-氯-5-氟苯基)-3,3a,6,7-四氢-8H-吡咯[3,4-e][1,2,4]***基[1,5-a]吡啶-8-酮5-amino-6-(2-chloro-5-fluorophenyl)-3,3a,6,7-tetrahydro-8H-pyrrole[3,4-e][1,2,4]triazolyl[ 1,5-a]pyridin-8-one
将6-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-5-(4-甲氧基苄基)氨基)-3,3a,6,7-四氢-8H-吡咯[3,4-e][1,2,4]***[1,5-a]吡啶-8-酮9c(0.98g，1.7mmol)溶解于15mL三氟乙酸和三氟甲磺酸(V/V＝9:1)混合溶剂中，80℃下加热反应5小时。冷却到室温后，将反应液慢慢倒入100mL饱和碳酸氢钠溶液中，用二氯甲烷萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物5-氨基-6-(2-氯-5-氟苯基)-3,3a,6,7-四氢-8H-吡咯[3,4-e][1,2,4]***基[1,5-a]吡啶-8-酮9d(0.32g)，产率：57.2％。6-(2-Chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-5-(4-methoxybenzyl)amino)-3,3a,6,7-tetra Hydrogen-8H-pyrrole[3,4-e][1,2,4]triazol[1,5-a]pyridin-8-one 9c (0.98 g, 1.7 mmol) was dissolved in 15 mL of trifluoroacetic acid and trifluoroacetic acid In a mixed solvent of methanesulfonic acid (V/V=9:1), the reaction was heated at 80° C. for 5 hours. After cooling to room temperature, the reaction solution was slowly poured into 100mL saturated sodium bicarbonate solution, extracted with dichloromethane (30mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20mL×2), anhydrous Drying over sodium sulfate, filtration, and concentration of the filtrate under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5-amino-6-(2-chloro-5-fluorophenyl)-3 ,3a,6,7-Tetrahydro-8H-pyrrole[3,4-e][1,2,4]triazolyl[1,5-a]pyridin-8-one 9d (0.32 g), yield : 57.2%.
MS m/z(ESI):318.0[M+1]MS m/z(ESI):318.0[M+1]
第四步the fourth step
N-(6-(2-氯-5-氟苯基)-8-氧代-7,8-二氢-6H-吡咯[3,4-e][1,2,4]***基[1,5-a]吡啶-5-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-pyrrole[3,4-e][1,2,4]triazolyl[ 1,5-a]pyridin-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide
将5-氨基-6-(2-氯-5-氟苯基)-3,3a,6,7-四氢-8H-吡咯[3,4-e][1,2,4]***基[1,5-a]吡啶-8-酮9d(50mg，0.16mmol)溶解于5mL二氯甲烷中，加入3-氟-5-(三氟 甲基)苯甲酸(39mg，0.19mmol)，1-甲基咪唑(39mg，0.47mmol)和四甲基氯代脲六氟磷酸酯(66mg，0.23mmol)，25℃搅拌反应1小时。在反应液中加入10mL水，用二氯甲烷萃取(10mL×2)，合并有机相，用饱和氯化钠溶液洗涤(10mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，所得残余物用制备HPLC纯化，得到标题产物N-(6-(2-氯-5-氟苯基)-8-氧代-7,8-二氢-6H-吡咯[3,4-e][1,2,4]***基[1,5-a]吡啶-5-基)-3-氟-5-(三氟甲基)苯甲酰胺9(18mg)，产率：22.6％。5-amino-6-(2-chloro-5-fluorophenyl)-3,3a,6,7-tetrahydro-8H-pyrrole[3,4-e][1,2,4]triazolyl [1,5-a]pyridin-8-one 9d (50 mg, 0.16 mmol) was dissolved in 5 mL of dichloromethane, 3-fluoro-5-(trifluoromethyl)benzoic acid (39 mg, 0.19 mmol) was added, 1 -Methylimidazole (39mg, 0.47mmol) and tetramethylchlorourea hexafluorophosphate (66mg, 0.23mmol), stirred at 25°C for 1 hour. Add 10 mL of water to the reaction solution, extract with dichloromethane (10 mL×2), combine the organic phases, wash with saturated sodium chloride solution (10 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by preparative HPLC to give the title product N-(6-(2-chloro-5-fluorophenyl)-8-oxo-7,8-dihydro-6H-pyrrole[3,4-e] [1,2,4]Triazolyl[1,5-a]pyridin-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide 9 (18 mg), yield: 22.6%.
MS m/z(ESI):508.0[M+1]MS m/z(ESI):508.0[M+1]
实施例10-12化合物的制备参照实施例9，相应的质谱数据列于表1中。Refer to Example 9 for the preparation of the compounds of Examples 10-12, and the corresponding mass spectrometry data are listed in Table 1.
实施例13Example 13
N-(3-(2-氯-5-氟苯基)-1-氧代-2,3-二氢-1H-吡咯[3,4]喹啉-4-基)-3-氟-5-(三氟甲基)N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4]quinolin-4-yl)-3-fluoro-5 -(trifluoromethyl) 苯甲酰胺benzamide
Figure PCTCN2022136232-appb-000054
Figure PCTCN2022136232-appb-000054
方法1：method 1:
Figure PCTCN2022136232-appb-000055
Figure PCTCN2022136232-appb-000055
第一步first step
N-(4-甲氧基苄基)-7-硝基喹啉-5-甲酰胺N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide
将7-硝基喹啉-5-羧酸13a(5.0g,23mmol)溶解于80mL二氯甲烷中，加入N,N’-羰基二咪唑(5.61g,34mmol)和4-二甲氨基吡啶(0.28g,2.3mmol)。25℃搅拌反应2小时。将4-甲氧基苄胺(3.14g，23mmol)加入上述反应液中，加完后继续25℃搅拌反应1小时。在反应液中加入50mL水，用二氯甲烷萃取(30mL×2)，合并有机相，用饱和氯化钠溶液洗涤(30mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物N-(4-甲氧基苄基)-7-硝基喹啉-5-甲酰胺13b(6.30g)，产率：81.5％。7-nitroquinoline-5-carboxylic acid 13a (5.0 g, 23 mmol) was dissolved in 80 mL of dichloromethane, N, N'-carbonyldiimidazole (5.61 g, 34 mmol) and 4-dimethylaminopyridine ( 0.28g, 2.3mmol). The reaction was stirred at 25°C for 2 hours. 4-Methoxybenzylamine (3.14 g, 23 mmol) was added to the above reaction solution, and after the addition was completed, the reaction was continued to stir at 25° C. for 1 hour. Add 50 mL of water to the reaction solution, extract with dichloromethane (30 mL×2), combine the organic phases, wash with saturated sodium chloride solution (30 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to afford the title product N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide 13b (6.30 g), yield : 81.5%.
MS m/z(ESI):338.2[M+1]MS m/z(ESI):338.2[M+1]
第二步second step
N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)-7-硝基喹啉-5-甲酰胺N-(2-Chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide
将N-(4-甲氧基苄基)-7-硝基喹啉-5-甲酰胺13b(6.30g,19mmol)溶解于80mL四氢呋喃中，加入钠氢(1.49g,37mmol)。25℃搅拌反应2小时。将2-氯-5-氟苯甲酰氯(5.39g，28mmol)的四氢呋喃(10mL)溶液加入到上述反应液中，加完后继续25℃搅拌反应2小时。在反应液中加入100mL水，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)-7-硝基喹啉-5-甲酰胺13c(6.80g)，产率：73.8％。N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide 13b (6.30 g, 19 mmol) was dissolved in 80 mL of tetrahydrofuran, and sodium hydrogen (1.49 g, 37 mmol) was added. The reaction was stirred at 25°C for 2 hours. A solution of 2-chloro-5-fluorobenzoyl chloride (5.39g, 28mmol) in tetrahydrofuran (10mL) was added to the above reaction solution, and after the addition was completed, the reaction was continued at 25°C for 2 hours. Add 100 mL of water to the reaction solution, extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated sodium chloride solution (50 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel with eluent system B to give the title product N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-7-nitro Quinoline-5-carboxamide 13c (6.80 g), yield: 73.8%.
MS m/z(ESI):494.2[M+1]MS m/z(ESI):494.2[M+1]
第三步third step
3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧基苄基)-4-硝基-2,3-二氢-1H-吡咯[3,4]喹啉-1-酮3-(2-Chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitro-2,3-dihydro-1H-pyrrole[3,4] Quinolin-1-one
-50℃条件下，将N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)-7-硝基喹啉-5-甲酰胺13c(6.80g，14mmol)溶解于80mL四氢呋喃中，加入LiHMDS(1.0M,20.9mL,21mmol)。-50℃搅拌反应3小时。在反应液中加入100mL水，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧基苄基)-4-硝基-2,3-二氢-1H-吡咯[3,4]喹啉-1-酮13d(1.20g)，产率：17.6％。At -50°C, N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide 13c (6.80g, 14mmol) was dissolved in 80mL tetrahydrofuran, and LiHMDS (1.0M, 20.9mL, 21mmol) was added. The reaction was stirred at -50°C for 3 hours. Add 100 mL of water to the reaction solution, extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated sodium chloride solution (50 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4 -Nitro-2,3-dihydro-1H-pyrrole[3,4]quinolin-1-one 13d (1.20 g), yield: 17.6%.
MS m/z(ESI):494.2[M+1]MS m/z(ESI):494.2[M+1]
第四步the fourth step
3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基-2,3-二氢-1H-吡咯[3,4]喹啉-1-酮3-(2-Chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitro-2,3-dihydro-1H-pyrrole[3,4]quinoline-1 -ketone
将3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧基苄基)-4-硝基-2,3-二氢-1H-吡咯[3,4] 喹啉-1-酮13d(1.20g，2.4mmol)溶解于30mL二氯甲烷中，加入三乙基硅烷(2.79g，24mmol)和三氟化硼***(0.99g，7.3mmol)，40℃加热反应15小时。向反应液中加入饱和碳酸氢钠溶液调节pH大于7，用二氯甲烷萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基-2,3-二氢-1H-吡咯[3,4]喹啉-1-酮13e(0.95g)，产率：81.9％。3-(2-Chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitro-2,3-dihydro-1H-pyrrole[3,4 ] Quinolin-1-one 13d (1.20g, 2.4mmol) was dissolved in 30mL of dichloromethane, triethylsilane (2.79g, 24mmol) and boron trifluoride diethyl ether (0.99g, 7.3mmol) were added, 40°C The reaction was heated for 15 hours. Add saturated sodium bicarbonate solution to the reaction solution to adjust the pH to greater than 7, extract with dichloromethane (20mL×3), combine the organic phases, wash with saturated sodium chloride solution (20mL×2), dry over anhydrous sodium sulfate, and filter , after the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl )-4-nitro-2,3-dihydro-1H-pyrrole[3,4]quinolin-1-one 13e (0.95 g), yield: 81.9%.
MS m/z(ESI):478.2[M+1]MS m/z(ESI):478.2[M+1]
第五步the fifth step
3-(2-氯-5-氟苯基)-4-硝基-2,3-二氢-1H-吡咯并[3,4]喹啉-1-酮3-(2-Chloro-5-fluorophenyl)-4-nitro-2,3-dihydro-1H-pyrrolo[3,4]quinolin-1-one
将3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基-2,3-二氢-1H-吡咯[3,4]喹啉-1-酮13e(0.95g，2.0mmol)溶解于10mL三氟乙酸和三氟甲磺酸(V/V＝9:1)混合溶剂中，80℃下加热反应5小时。冷却到室温后，将反应液慢慢倒入50mL饱和碳酸氢钠溶液中，用二氯甲烷萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物3-(2-氯-5-氟苯基)-4-硝基-2,3-二氢-1H-吡咯并[3,4]喹啉-1-酮13f(0.43g)，产率：60.6％。3-(2-Chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitro-2,3-dihydro-1H-pyrrole[3,4]quinoline- 1-Kone 13e (0.95g, 2.0mmol) was dissolved in 10mL of a mixed solvent of trifluoroacetic acid and trifluoromethanesulfonic acid (V/V=9:1), and heated at 80°C for 5 hours. After cooling to room temperature, the reaction solution was slowly poured into 50 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), anhydrous Drying over sodium sulfate, filtration, and concentration of the filtrate under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 3-(2-chloro-5-fluorophenyl)-4-nitro- 2,3-Dihydro-1H-pyrrolo[3,4]quinolin-1-one 13f (0.43 g), yield: 60.6%.
MS m/z(ESI):358.2[M+1]MS m/z(ESI):358.2[M+1]
第六步step six
4-氨基-3-(2-氯-5-氟苯基)-2,3-二氢-1H-吡咯并[3,4]喹啉-1-酮4-amino-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-pyrrolo[3,4]quinolin-1-one
将3-(2-氯-5-氟苯基)-4-硝基-2,3-二氢-1H-吡咯并[3,4]喹啉-1-酮13f(0.43g，1.2mmol)溶解于10mL乙醇和1mL冰醋酸的混合溶液中，加入氯化铵(0.64g,12mmol)。升温到50℃，在此温度下加入还原铁粉(0.67g,52mmol)。80℃加热反应1小时。反应液减压浓缩，所得残余物中加入30mL水，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(10mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4-氨基-3-(2-氯-5-氟苯基)-2,3-二氢-1H-吡咯并[3,4]喹啉-1-酮13g(0.21g)，产率：53.8％。3-(2-Chloro-5-fluorophenyl)-4-nitro-2,3-dihydro-1H-pyrrolo[3,4]quinolin-1-one 13f (0.43g, 1.2mmol) Dissolve in a mixed solution of 10mL ethanol and 1mL glacial acetic acid, and add ammonium chloride (0.64g, 12mmol). The temperature was raised to 50° C., and reduced iron powder (0.67 g, 52 mmol) was added at this temperature. The reaction was heated at 80°C for 1 hour. The reaction solution was concentrated under reduced pressure, 30 mL of water was added to the resulting residue, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 4-amino-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H -Pyrrolo[3,4]quinolin-1-one 13g (0.21g), yield: 53.8%.
MS m/z(ESI):328.1[M+1]MS m/z(ESI):328.1[M+1]
第七步step seven
N-(3-(2-氯-5-氟苯基)-1-氧代-2,3-二氢-1H-吡咯[3,4]喹啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4]quinolin-4-yl)-3-fluoro-5 -(Trifluoromethyl)benzamide
将4-氨基-3-(2-氯-5-氟苯基)-2,3-二氢-1H-吡咯并[3,4]喹啉-1-酮13g(50mg，0.15mmol)溶解于5mL二氯甲烷中，加入3-氟-5-(三氟甲基)苯甲酸(38mg，0.18mmol)，1-甲基咪唑(38mg，0.46mmol)和四甲基氯代脲六氟磷酸酯(64mg， 0.23mmol)，25℃搅拌反应1小时。在反应液中加入10mL水，用二氯甲烷萃取(10mL×2)，合并有机相，用饱和氯化钠溶液洗涤(10mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，所得残余物用制备HPLC纯化，得到标题产物N-(3-(2-氯-5-氟苯基)-1-氧代-2,3-二氢-1H-吡咯[3,4]喹啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺13(11mg)，产率：13.9％。Dissolve 13g (50mg, 0.15mmol) of 4-amino-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-pyrrolo[3,4]quinolin-1-one in To 5 mL of dichloromethane, add 3-fluoro-5-(trifluoromethyl)benzoic acid (38 mg, 0.18 mmol), 1-methylimidazole (38 mg, 0.46 mmol) and tetramethylchlorourea hexafluorophosphate (64mg, 0.23mmol), stirred at 25°C for 1 hour. Add 10 mL of water to the reaction solution, extract with dichloromethane (10 mL×2), combine the organic phases, wash with saturated sodium chloride solution (10 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by preparative HPLC to give the title product N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4]quinoline -4-yl)-3-fluoro-5-(trifluoromethyl)benzamide 13 (11 mg), yield: 13.9%.
MS m/z(ESI):518.2[M+1]MS m/z(ESI):518.2[M+1]
方法2：Method 2:
Figure PCTCN2022136232-appb-000056
Figure PCTCN2022136232-appb-000056
第一步：first step:
3-溴-2-氟-5-硝基苯甲酸的制备Preparation of 3-bromo-2-fluoro-5-nitrobenzoic acid
将3-溴-2-氟苯甲酸(10g,45.66mmol)加入到浓硫酸(30mL)中，在冰浴下滴加浓硝酸(3.13g,49.73mmol)，室温下反应3小时。将反应液倒入冰水中，用乙酸乙酯(30mL×3)萃取。有机相用饱和氯化钠溶液(40mL)洗涤，无水硫酸钠干燥，减压浓缩得到13b’(8g,产率：66.4％)。3-Bromo-2-fluorobenzoic acid (10g, 45.66mmol) was added to concentrated sulfuric acid (30mL), concentrated nitric acid (3.13g, 49.73mmol) was added dropwise under ice-cooling, and reacted at room temperature for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (30 mL×3). The organic phase was washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 13b' (8 g, yield: 66.4%).
MS m/z(ESI):264.1[M+1]MS m/z(ESI):264.1[M+1]
第二步：Step two:
3-溴-2-氟-5-硝基苯甲酸甲酯的制备Preparation of 3-bromo-2-fluoro-5-nitrobenzoic acid methyl ester
将13b’(8g,30.30mmol)溶于甲醇(60mL)中，加入浓硫酸0.1mL，75℃下反应16小时。反应液减压浓缩得到粗品，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到产物13c’(8g，产率：90.4％)。Dissolve 13b' (8 g, 30.30 mmol) in methanol (60 mL), add 0.1 mL of concentrated sulfuric acid, and react at 75°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain product 13c' (8 g, yield: 90.4%).
1H NMR(400MHz,CDCl 3)δ8.88-8.77(d,1H),8.65-8.63(d,1H),4.01(s,3H)； 1 H NMR (400MHz, CDCl 3 ) δ8.88-8.77(d, 1H), 8.65-8.63(d, 1H), 4.01(s, 3H);
第三步：third step:
5-氨基-3-溴-2-氟苯甲酸甲酯的制备Preparation of methyl 5-amino-3-bromo-2-fluorobenzoate
将13c’(4.6g,16.54mmol)和铁粉(4.6g,82.72mmol)加入到乙醇(40mL)和饱和氯化铵溶液(10mL)中，在80℃下反应2小时。待反应液冷却至室温，过滤后用乙酸乙酯(30mL×2)萃取。有机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，减压浓缩得到产物13d’(4g,产率：97.5％)。13c' (4.6g, 16.54mmol) and iron powder (4.6g, 82.72mmol) were added to ethanol (40mL) and saturated ammonium chloride solution (10mL), and reacted at 80°C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered and extracted with ethyl acetate (30 mL×2). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain product 13d' (4 g, yield: 97.5%).
MS m/z(ESI):247.9[M+1]MS m/z(ESI):247.9[M+1]
第四步：the fourth step:
7-溴-6-氟喹啉-5-羧酸的制备Preparation of 7-bromo-6-fluoroquinoline-5-carboxylic acid
将13d’(4g,16.13mmol)和3-硝基苯磺酸钠(10.89g,48.38mmol)加入到75％硫酸(40mL)中，在100℃下加入甘油(6mL)，反应2小时，并将温度升至140℃继续反应3小时。待反应液冷却至室温，倒入冰水中，加入5M氢氧化钠溶液至反应液pH为5～6。将反应液过滤得到粗品黑色固体(2g)，水相用氯仿和异丙醇(V/V＝3:1,50mL×2)萃取。有机相用饱和食盐水洗涤(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化得到产物13e’(200mg)。13d' (4g, 16.13mmol) and sodium 3-nitrobenzenesulfonate (10.89g, 48.38mmol) were added to 75% sulfuric acid (40mL), glycerin (6mL) was added at 100°C, reacted for 2 hours, and The temperature was raised to 140°C to continue the reaction for 3 hours. After the reaction solution was cooled to room temperature, it was poured into ice water, and 5M sodium hydroxide solution was added until the pH of the reaction solution was 5-6. The reaction solution was filtered to obtain a crude black solid (2 g), and the aqueous phase was extracted with chloroform and isopropanol (V/V=3:1, 50 mL×2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the product 13e' (200 mg).
MS m/z(ESI):269.9[M+1]MS m/z(ESI):269.9[M+1]
第五步：the fifth step:
7-溴-N-(2-(叔-丁基氨基)-1-(2-氯-5-氟苯基)-2-羰基乙基)-6-氟-N-(4-甲氧苄基)喹啉-5-甲酰胺的制备7-Bromo-N-(2-(tert-butylamino)-1-(2-chloro-5-fluorophenyl)-2-carbonylethyl)-6-fluoro-N-(4-methoxybenzyl Base) the preparation of quinoline-5-carboxamide
将2-氯-4-氟苯甲醛(252.5mg,1.59mmol)溶于甲醇(10mL)，依次加入(4-甲氧苯基)甲胺(218.4mg,1.59mmol)，13e’(270mg,1mmol)和异氰酸叔丁酯(132.4mg,1.59mmol,180μL)，在室温下反应16小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到产物13f’(600mg,产率：95.2％)。2-Chloro-4-fluorobenzaldehyde (252.5mg, 1.59mmol) was dissolved in methanol (10mL), and (4-methoxyphenyl)methylamine (218.4mg, 1.59mmol), 13e' (270mg, 1mmol) were added successively ) and tert-butyl isocyanate (132.4 mg, 1.59 mmol, 180 μL) were reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain product 13f' (600 mg, yield: 95.2%).
MS m/z(ESI):630.0[M+1]MS m/z(ESI):630.0[M+1]
第六步：Step six:
4-溴-3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧苄基)-2,3-二氢-1H-吡咯并[3,4-f]喹啉-1-酮的制备4-Bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-f ] The preparation of quinolin-1-one
将13f’(1g,1.59mmol)溶于乙腈(10mL)，加入2-叔丁基-1,1,3,3-四甲基胍(407mg,2.38mmol)，在50℃下反应16小时。待反应液冷却至室温，减压浓缩，用反相制备纯化得到产物13g’(200mg,产率：23.9％)。13f' (1 g, 1.59 mmol) was dissolved in acetonitrile (10 mL), 2-tert-butyl-1,1,3,3-tetramethylguanidine (407 mg, 2.38 mmol) was added, and reacted at 50°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by reverse phase preparation to obtain product 13g' (200 mg, yield: 23.9%).
MS m/z(ESI):526.9[M+1]MS m/z(ESI):526.9[M+1]
1H NMR(400MHz,CDCl 3)δ9.08(s,1H),8.29-8.26(d,1H),8.10(s,1H),8.03(s,1H),7.40-7.33(m,1H),7.30-7.28(m,2H),7.00-6.97(m,2H),6.77-6.75(m,2H),6.36(brs,1H),4.52-4.49(d,1H),4.42-4.38(d,1H),3.76(s,3H). 1 H NMR (400MHz, CDCl 3 )δ9.08(s,1H),8.29-8.26(d,1H),8.10(s,1H),8.03(s,1H),7.40-7.33(m,1H), 7.30-7.28(m,2H),7.00-6.97(m,2H),6.77-6.75(m,2H),6.36(brs,1H),4.52-4.49(d,1H),4.42-4.38(d,1H ),3.76(s,3H).
第七步：Step seven:
4-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧苄基)-2,3-二氢-1H-吡咯并[3,4-f]喹啉-1-酮的制备4-Bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinoline- Preparation of 1-keto
将13g’(150mg,284.22μmol)溶于三氟乙酸(2mL)，加入三乙基硅氢(0.5mL)，在70℃下反应24小时。待反应液冷却至室温，减压浓缩，加入乙酸乙酯(20mL)溶解，依次用饱和碳酸氢钠溶液(5mL)，饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到产物13h’(55mg,产率：37.8％)。Dissolve 13g' (150mg, 284.22μmol) in trifluoroacetic acid (2mL), add triethylsilane hydrogen (0.5mL), and react at 70°C for 24 hours. After the reaction solution was cooled to room temperature, concentrated under reduced pressure, added ethyl acetate (20 mL) to dissolve, washed with saturated sodium bicarbonate solution (5 mL), saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure , the resulting residue was purified by silica gel column chromatography with eluent system B to give the product 13h' (55 mg, yield: 37.8%).
MS m/z(ESI):512.1[M+1]MS m/z(ESI):512.1[M+1]
第八步：Step Eight:
N-(3-(2-氯-5-氟苯基)-2-(4-甲氧苄基)-1-羰基-2,3-二氢-1H-吡咯并[3,4-f]喹啉-4-基)-3-氟-5-(三氟甲基)苯酰胺的制备N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f] Preparation of quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
将13h’(60mg,117.24μmol)和3-氟-5-(三氟甲基)苯甲酰胺(19.4mg,93.79μmol)溶于1,4-二氧六环(2mL)，加入碳酸铯(57.3mg,175.9μmol)，三(二亚苄基丙酮)二钯(10.7mg,11.7μmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(10.2mg,17.6μmol)，氮气置换三次，在微波上100℃反应1小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到产物13i’(50mg,产率：66.9％)13h' (60 mg, 117.24 μmol) and 3-fluoro-5-(trifluoromethyl)benzamide (19.4 mg, 93.79 μmol) were dissolved in 1,4-dioxane (2 mL), and cesium carbonate ( 57.3mg, 175.9μmol), tris(dibenzylideneacetone) dipalladium (10.7mg, 11.7μmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (10.2mg, 17.6 μmol), replaced with nitrogen three times, and reacted on a microwave oven at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain product 13i' (50 mg, yield: 66.9%)
MS m/z(ESI):638.1[M+1]MS m/z(ESI):638.1[M+1]
第九步：Step Nine:
N-(3-(2-氯-5-氟苯基)-1-羰基-2,3-二氢-1H-吡咯并[3,4-f]喹啉-4-基)-3-氟-5-(三氟甲基)苯酰胺的制备N-(3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro - Preparation of 5-(trifluoromethyl)benzamide
将13i’(50mg,78.4μmol)溶于三氟乙酸(2mL)，加入三氟甲磺酸(0.5mL)，在70℃下反应2小时。反应液减压浓缩，用乙酸乙酯(10mL)溶解，依次用饱和碳酸氢钠溶液(5mL)，饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，减压浓缩，用反相制备纯化得到实施例13(24.4mg,产率：58.9％)。Dissolve 13i' (50 mg, 78.4 μmol) in trifluoroacetic acid (2 mL), add trifluoromethanesulfonic acid (0.5 mL), and react at 70°C for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate (10 mL), washed successively with saturated sodium bicarbonate solution (5 mL), saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and prepared by reverse phase Purification gave Example 13 (24.4 mg, yield: 58.9%).
化合物13用手性柱拆分(色谱柱：CHIRALCEL AD-H4.6*250mm,5μm；检测波长(nm)：214；温度(℃)：35；流速(mL/min)：1；流动相：Hexane:IPA:DEA＝70:30:0.1％；运行时长(min):8；线性模式:等度)，得到标题产物13-P1，(10mg，RT(保留时间)＝3.770min，产率：24.7％)；标题产物13-P2(10mg，RT(保留时间)＝4.657min,产率：24.7％)。Compound 13 was resolved with a chiral column (column: CHIRALCEL AD-H4.6*250mm, 5μm; detection wavelength (nm): 214; temperature (°C): 35; flow rate (mL/min): 1; mobile phase: Hexane:IPA:DEA=70:30:0.1%; running time (min): 8; linear mode: isocratic), to obtain the title product 13-P1, (10mg, RT (retention time)=3.770min, yield: 24.7%); the title product 13-P2 (10 mg, RT (retention time) = 4.657 min, yield: 24.7%).
实施例13-P1，MSm/z(ESI):518.1[M+1]Embodiment 13-P1, MSm/z (ESI): 518.1[M+1]
1H NMR(400MHz,CDCl3)δ10.7(s,1H),9.47-9.41(m,2H),9.07-9.05(m,1H),8.15(s,1H),7.99-7.97(m,1H),7.78-7.70(m,3H),7.35-7.32(m,1H),7.14-7.10(m,1H),6.23(brs,1H).1H NMR (400MHz, CDCl3) δ10.7(s,1H),9.47-9.41(m,2H),9.07-9.05(m,1H),8.15(s,1H),7.99-7.97(m,1H), 7.78-7.70(m,3H),7.35-7.32(m,1H),7.14-7.10(m,1H),6.23(brs,1H).
实施例13-P2，MS m/z(ESI):518.1[M+1]Embodiment 13-P2, MS m/z (ESI): 518.1[M+1]
1H NMR(400MHz,CDCl3)δ10.7(s,1H),9.47-9.41(m,2H),9.07-9.05(m,1H),8.15(s,1H),7.99-7.97(m,1H),7.78-7.70(m,3H),7.35-7.32(m,1H),7.14-7.10(m,1H),6.23(br s,1H).1H NMR (400MHz, CDCl3) δ10.7(s,1H),9.47-9.41(m,2H),9.07-9.05(m,1H),8.15(s,1H),7.99-7.97(m,1H), 7.78-7.70(m,3H),7.35-7.32(m,1H),7.14-7.10(m,1H),6.23(br s,1H).
实施例14-16化合物的制备参照实施例13，相应的质谱数据列于表1中。Refer to Example 13 for the preparation of the compounds of Examples 14-16, and the corresponding mass spectrometry data are listed in Table 1.
实施例17Example 17
N-(8-(氨基(2-氯-5-氟苯基)甲基)咪唑[1,2-a]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(8-(amino(2-chloro-5-fluorophenyl)methyl)imidazo[1,2-a]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl)benzidine Amide
Figure PCTCN2022136232-appb-000057
Figure PCTCN2022136232-appb-000057
第一步first step
(2-氯-5-氟苯基)(7-氯咪唑并[1,2-a]吡啶-8-基)甲苯胺(2-Chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)toluidine
将7-氯-8-碘代咪唑[1,2-a]吡啶(3g，10.8mmol)溶解在50mL四氢呋喃中，氮气保护下冷却至-78℃，缓慢滴加正丁基锂的正己烷溶液(10.1mL，16.2mmol)，搅拌1小时。加入2-氯-5-氟苯腈(2.02g，13.0mmol)的四氢呋喃溶液，继续反应1小时。加入100mL饱和氯化铵溶液，升至室温后用乙酸乙酯萃取(100mL*2)。合并有机相，依次用水(100mL)、饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(2-氯-5-氟苯基)(7-氯咪唑并[1,2-a]吡啶-8-基)甲苯胺17a(3.3g)，直接用于下步反应。Dissolve 7-chloro-8-iodoimidazo[1,2-a]pyridine (3g, 10.8mmol) in 50mL tetrahydrofuran, cool to -78°C under nitrogen protection, and slowly add n-butyl lithium in n-hexane solution dropwise (10.1 mL, 16.2 mmol), stirred for 1 hour. A solution of 2-chloro-5-fluorobenzonitrile (2.02 g, 13.0 mmol) in tetrahydrofuran was added and the reaction was continued for 1 hour. Add 100 mL of saturated ammonium chloride solution, warm to room temperature and extract with ethyl acetate (100 mL*2). The organic phases were combined, washed successively with water (100 mL), saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product (2-chloro-5-fluorophenyl) (7 -Chlorimidazo[1,2-a]pyridin-8-yl)toluidine 17a (3.3g), directly used in the next reaction.
MS m/z(ESI):308.0[M+1]MS m/z(ESI):308.0[M+1]
第二步second step
(2-氯-5-氟苯基)(7-氯咪唑并[1,2-a]吡啶-8-基)甲胺(2-Chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)methanamine
将(2-氯-5-氟苯基)(7-氯咪唑并[1,2-a]吡啶-8-基)甲苯胺17a(3.3g，10.7mmol)溶解在50mL四氢呋喃中，缓慢分批加入硼氢化钠(814mg，21.4mmol)，室温反应3小时。加入100mL水，乙酸乙酯萃取(100mL*2)。合并有机相，依次用水(100mL)、饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(2-氯-5-氟苯基)(7-氯咪唑并[1,2-a]吡啶-8-基)甲胺17b(2.8g)，产率：85.0％。Dissolve (2-chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)toluidine 17a (3.3 g, 10.7 mmol) in 50 mL THF and slowly batch Add sodium borohydride (814mg, 21.4mmol) and react at room temperature for 3 hours. Add 100 mL of water, and extract with ethyl acetate (100 mL*2). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain The title product (2-chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)methanamine 17b (2.8 g), yield: 85.0%.
MS m/z(ESI):310.1[M+1]MS m/z(ESI):310.1[M+1]
第三步third step
叔丁基((2-氯-5-氟苯基)(7-氯咪唑[1,2-a]吡啶-8-基)氨基甲酸酯tert-butyl((2-chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)carbamate
将(2-氯-5-氟苯基)(7-氯咪唑并[1,2-a]吡啶-8-基)甲胺17b(2.8g，9.09mmol)溶解在50mL二氯甲烷中，加入二碳酸二叔丁酯(2.38g，10.9mmol)和三乙胺(2.75g，27.3mmol)，室温反应4小时。反应液依次用水(50mL)、饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物叔丁基((2-氯-5-氟苯基)(7-氯咪唑[1,2-a]吡啶-8-基)氨基甲酸酯17c(3.4g)，产率：91.2％。Dissolve (2-chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)methanamine 17b (2.8 g, 9.09 mmol) in 50 mL of dichloromethane and add Di-tert-butyl dicarbonate (2.38g, 10.9mmol) and triethylamine (2.75g, 27.3mmol) were reacted at room temperature for 4 hours. The reaction solution was washed with water (50 mL) and saturated sodium chloride solution (50 mL) successively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product tert-butyl((2-chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)carbamate 17c (3.4 g), yield: 91.2%.
MS m/z(ESI):410.1[M+1]MS m/z(ESI):410.1[M+1]
第四步the fourth step
叔丁基((2-氯-5-氟苯基)(7-((二苯基亚甲基)氨基)咪唑[1,2-a]吡啶-8-基)甲基)氨基甲酸酯tert-Butyl((2-chloro-5-fluorophenyl)(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-8-yl)methyl)carbamate
将叔丁基((2-氯-5-氟苯基)(7-氯咪唑[1,2-a]吡啶-8-基)氨基甲酸酯17c(3.4g，8.29mmol)溶解在30mL1，4-二氧六环中，加入二苯甲胺(1.82g，9.95mmol)、醋酸钯(93mg，0.415mmol)、1,1'-联萘-2,2'-双二苯膦(258mg，0.415mmol)和碳酸铯(8.11g，24.9mmol)，氮气保护下加热至110℃反应4小时。反应液冷却至室温，倒入100mL水中，乙酸乙酯萃取(100mL*2)。合并有机相，依次用水(100mL)、饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物叔丁基((2-氯-5-氟苯基)(7-((二苯基亚甲基)氨基)咪唑[1,2-a]吡啶-8-基)甲基)氨基甲酸酯17d(2.4g)，产率：52.1％。tert-Butyl((2-chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)carbamate 17c (3.4 g, 8.29 mmol) was dissolved in 30 mL of 1, To 4-dioxane, add benzhydrylamine (1.82g, 9.95mmol), palladium acetate (93mg, 0.415mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (258mg, 0.415mmol) and cesium carbonate (8.11g, 24.9mmol), heated to 110°C for 4 hours under nitrogen protection. The reaction solution was cooled to room temperature, poured into 100mL water, and extracted with ethyl acetate (100mL*2). Combined organic phases, Washed with water (100mL) and saturated sodium chloride solution (100mL) successively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product tert-butyl Base ((2-chloro-5-fluorophenyl)(7-((diphenylmethylene)amino)imidazo[1,2-a]pyridin-8-yl)methyl)carbamate 17d( 2.4 g), yield: 52.1%.
MS m/z(ESI):555.2[M+1]MS m/z(ESI):555.2[M+1]
第四步the fourth step
叔丁基((7-氨基咪唑[1,2-a]吡啶-8-基)(2-氯-5-氟苯基)甲基)氨基甲酸酯tert-Butyl ((7-aminoimidazo[1,2-a]pyridin-8-yl)(2-chloro-5-fluorophenyl)methyl)carbamate
将叔丁基((2-氯-5-氟苯基)(7-((二苯基亚甲基)氨基)咪唑[1,2-a]吡啶-8-基)甲基)氨基甲酸酯17d(2.4g，4.32mmol)溶解在30mL甲醇中，加入盐酸羟胺(447mg，6.49mmol)和乙酸钠(532mg，6.49mmol)，室温搅拌2小时。反应液倒入100mL水中，乙酸乙酯萃取(100mL*2)。合并有机相，用饱和氯化钠溶液(100 mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物叔丁基((7-氨基咪唑[1,2-a]吡啶-8-基)(2-氯-5-氟苯基)甲基)氨基甲酸酯17e(1.5g)，产率：88.9％。Tert-butyl ((2-chloro-5-fluorophenyl) (7-((diphenylmethylene)amino)imidazol[1,2-a]pyridin-8-yl)methyl)carbamate Ester 17d (2.4g, 4.32mmol) was dissolved in 30mL of methanol, hydroxylamine hydrochloride (447mg, 6.49mmol) and sodium acetate (532mg, 6.49mmol) were added, and stirred at room temperature for 2 hours. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (100 mL*2). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product tert-butyl Base ((7-aminoimidazo[1,2-a]pyridin-8-yl)(2-chloro-5-fluorophenyl)methyl)carbamate 17e (1.5 g), yield: 88.9%.
MS m/z(ESI):391.1[M+1]MS m/z(ESI):391.1[M+1]
第五步the fifth step
叔丁基((2-氯-5-氟苯基)(7-(3-氟-5-(三氟甲基)苯甲酰胺基)咪唑[1,2-a]吡啶-8-基)甲基)氨基甲酸酯tert-butyl((2-chloro-5-fluorophenyl)(7-(3-fluoro-5-(trifluoromethyl)benzamido)imidazo[1,2-a]pyridin-8-yl) Methyl) carbamate
将叔丁基((7-氨基咪唑[1,2-a]吡啶-8-基)(2-氯-5-氟苯基)甲基)氨基甲酸酯17e(200mg，0.511mmol)溶解在5mL乙腈中，加入3-氟-5-(三氟甲基)苯甲酸(128mg，0.614mmol)，N,N,N',N'-四甲基氯甲脒六氟磷酸盐(172mg，0.614mmol)和N-甲基吗啉(186mg，1.84mmol)，室温反应4小时。反应液倒入50mL水中，乙酸乙酯萃取(50mL*2)。合并有机相，依次用水(50mL)、饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到叔丁基((2-氯-5-氟苯基)(7-(3-氟-5-(三氟甲基)苯甲酰胺基)咪唑[1,2-a]吡啶-8-基)甲基)氨基甲酸酯17f(65mg)，产率：21.9％。tert-Butyl((7-aminoimidazo[1,2-a]pyridin-8-yl)(2-chloro-5-fluorophenyl)methyl)carbamate 17e (200 mg, 0.511 mmol) was dissolved in In 5mL of acetonitrile, add 3-fluoro-5-(trifluoromethyl)benzoic acid (128mg, 0.614mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (172mg, 0.614 mmol) and N-methylmorpholine (186mg, 1.84mmol), react at room temperature for 4 hours. The reaction solution was poured into 50 mL of water and extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain tert-butyl((2-chloro-5-fluorophenyl)(7-(3-fluoro-5-(trifluoromethyl)benzamido)imidazo[1,2-a]pyridin-8-yl) Methyl)carbamate 17f (65 mg), yield: 21.9%.
MS m/z(ESI):581.1[M+1]MS m/z(ESI):581.1[M+1]
第六步step six
N-(8-(氨基(2-氯-5-氟苯基)甲基)咪唑[1,2-a]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(8-(amino(2-chloro-5-fluorophenyl)methyl)imidazo[1,2-a]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl)benzidine Amide
将叔丁基((2-氯-5-氟苯基)(7-(3-氟-5-(三氟甲基)苯甲酰胺基)咪唑[1,2-a]吡啶-8-基)甲基)氨基甲酸酯17f(65mg，0.112mmol)溶解在5mL二氯甲烷中，加入2mL三氟乙酸，室温反应2小时。反应液倒入50mL饱和碳酸氢钠溶液中，乙酸乙酯萃取(50mL*2)。合并有机相，依次用水(50mL)、饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用C18反向色谱法以洗脱剂体系C纯化所得残余物，得到N-(8-(氨基(2-氯-5-氟苯基)甲基)咪唑[1,2-a]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲酰胺17(22mg)，产率：40.9％。Tert-butyl ((2-chloro-5-fluorophenyl) (7-(3-fluoro-5-(trifluoromethyl) benzamido) imidazol[1,2-a]pyridin-8-yl )methyl)carbamate 17f (65 mg, 0.112 mmol) was dissolved in 5 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and reacted at room temperature for 2 hours. The reaction solution was poured into 50 mL saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by C18 reverse chromatography with eluent system C, N-(8-(amino(2-chloro-5-fluorophenyl)methyl)imidazo[1,2-a]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl)benzene Formamide 17 (22 mg), yield: 40.9%.
MS m/z(ESI):481.1[M+1]MS m/z(ESI):481.1[M+1]
实施例18-20化合物的制备参照实施例17，相应的质谱数据列于表1中。The preparation of the compounds of Examples 18-20 refers to Example 17, and the corresponding mass spectrum data are listed in Table 1.
实施例21Example 21
N-(8-((2-氯-5-氟苯基)(羟基)甲基)咪唑[1,2-a]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(8-((2-chloro-5-fluorophenyl)(hydroxyl)methyl)imidazo[1,2-a]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl) benzamide
Figure PCTCN2022136232-appb-000058
Figure PCTCN2022136232-appb-000058
第一步first step
7-氯-8-碘代咪唑[1,2-a]吡啶7-Chloro-8-iodoimidazo[1,2-a]pyridine
将4-氯-3-碘吡啶-2-胺(5g，19.6mmol)溶解在50mL乙醇和水(2:1)的混合溶剂中，加入2-溴-1,1-二甲氧基乙烷(6.6g，39.2mmol)，加热至80℃反应16小时。反应液冷却至室温，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物7-氯-8-碘代咪唑[1,2-a]吡啶21a(4.2g)，产率：77.1％。Dissolve 4-chloro-3-iodopyridin-2-amine (5g, 19.6mmol) in a mixed solvent of 50mL ethanol and water (2:1), add 2-bromo-1,1-dimethoxyethane (6.6g, 39.2mmol), heated to 80°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 7-chloro-8-iodoimidazol[1,2-a]pyridine 21a (4.2 g ), yield: 77.1%.
MS m/z(ESI):278.9[M+1]MS m/z(ESI):278.9[M+1]
第二步second step
(2-氯-5-氟苯基)(7-氯咪唑并[1,2-a]吡啶-8-基)甲醇(2-Chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)methanol
将7-氯-8-碘代咪唑[1,2-a]吡啶21a(4.2g，15.1mmol)溶解在50mL四氢呋喃中，氮气保护下冷却至-78℃，缓慢滴加正丁基锂的正己烷溶液(14.2mL，22.7mmol)，搅拌反应1小时。加入2-氯-5-氟苯甲醛(3.59g，22.7mmol)的四氢呋喃溶液，继续反应1小时。加入100mL饱和氯化铵溶液，升至室温后用乙酸乙酯萃取(100mL*2)。合并有机相，依次用水(100mL)、饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(2-氯-5-氟苯基)(7-氯咪唑并[1,2-a]吡啶-8-基)甲醇21b(3.6g)，产率：76.9％。Dissolve 7-chloro-8-iodoimidazo[1,2-a]pyridine 21a (4.2g, 15.1mmol) in 50mL tetrahydrofuran, cool to -78°C under nitrogen protection, slowly add n-butyllithium in n-hexane Alkanes solution (14.2mL, 22.7mmol), stirred for 1 hour. A solution of 2-chloro-5-fluorobenzaldehyde (3.59 g, 22.7 mmol) in tetrahydrofuran was added and the reaction was continued for 1 hour. Add 100 mL of saturated ammonium chloride solution, warm to room temperature and extract with ethyl acetate (100 mL*2). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain The title product (2-chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)methanol 21b (3.6 g), yield: 76.9%.
MS m/z(ESI):311.0[M+1]MS m/z(ESI):311.0[M+1]
第三步third step
(2-氯-5-氟苯基)(7-((二苯基亚甲基)氨基)咪唑[1,2-a]吡啶-8-基)甲醇(2-Chloro-5-fluorophenyl)(7-((diphenylmethylene)amino)imidazol[1,2-a]pyridin-8-yl)methanol
将(2-氯-5-氟苯基)(7-氯咪唑并[1,2-a]吡啶-8-基)甲醇21b(3.6g，11.6mmol)溶解在40mL 1，4-二氧六环中，加入二苯甲胺(3.19g，17.4mmol)、醋酸钯(130mg，0.581mmol)、1,1'-联萘-2,2'-双二苯膦(362mg，0.581mmol)和碳酸铯(11.3g，34.8mmol)，氮气保护下加热至110℃反应4小时。反应液冷却至室温，倒入100mL水中，乙酸乙酯萃取(100mL*2)。合并有机相，依次用水(100mL)、饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(2-氯-5-氟苯基)(7-((二苯基亚甲基)氨基)咪唑[1,2-a]吡啶-8-基)甲醇21c(3.1g)，产率：58.6％。Dissolve (2-chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)methanol 21b (3.6 g, 11.6 mmol) in 40 mL 1,4-dioxane To the ring, add benzhydrylamine (3.19g, 17.4mmol), palladium acetate (130mg, 0.581mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (362mg, 0.581mmol) and carbonic acid Cesium (11.3 g, 34.8 mmol) was heated to 110° C. for 4 hours under the protection of nitrogen. The reaction solution was cooled to room temperature, poured into 100 mL of water, and extracted with ethyl acetate (100 mL*2). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain The title product (2-chloro-5-fluorophenyl)(7-((diphenylmethylene)amino)imidazol[1,2-a]pyridin-8-yl)methanol 21c (3.1 g), yield : 58.6%.
MS m/z(ESI):456.1[M+1]MS m/z(ESI):456.1[M+1]
第四步the fourth step
(7-氨基咪唑[1,2-a]吡啶-8-基)(2-氯-5-氟苯基)甲醇(7-aminoimidazol[1,2-a]pyridin-8-yl)(2-chloro-5-fluorophenyl)methanol
将(2-氯-5-氟苯基)(7-氯咪唑并[1,2-a]吡啶-8-基)甲醇21c(3.6g，7.91mmol)溶解在40mL四氢呋喃和水(2：1)的混合溶剂中，加入4mL 1M的稀盐酸，室温搅拌2小时。反应液倒入100mL饱和碳酸氢钠溶液中，乙酸乙酯萃取(100mL*2)。合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物(7-氨基咪唑[1,2-a]吡啶-8-基)(2-氯-5-氟苯基)甲醇21d(2.3g)，产率：99.6％。Dissolve (2-chloro-5-fluorophenyl)(7-chloroimidazo[1,2-a]pyridin-8-yl)methanol 21c (3.6 g, 7.91 mmol) in 40 mL THF and water (2:1 ), add 4 mL of 1M dilute hydrochloric acid, and stir at room temperature for 2 hours. The reaction solution was poured into 100 mL saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL*2). The organic phases were combined, washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product (7-aminoimidazol[1,2-a]pyridin-8-yl) ( 2-Chloro-5-fluorophenyl)methanol 21d (2.3 g), yield: 99.6%.
MS m/z(ESI):292.1[M+1]MS m/z(ESI):292.1[M+1]
第五步the fifth step
N-(8-((2-氯-5-氟苯基)(羟基)甲基)咪唑[1,2-a]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(8-((2-chloro-5-fluorophenyl)(hydroxyl)methyl)imidazo[1,2-a]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl) benzamide
将(7-氨基咪唑[1,2-a]吡啶-8-基)(2-氯-5-氟苯基)甲醇21d(200mg，0.687mmol)溶解在5mL乙腈中，加入3-氟-5-(三氟甲基)苯甲酸(172mg，0.825mmol)，N,N,N',N'-四甲基氯甲脒六氟磷酸盐(231mg，0.825mmol)和N-甲基吗啉(208mg，2.06mmol)，室温反应2小时。反应液倒入50mL水中，乙酸乙酯萃取(50mL*2)。合并有机相，依次用水(50mL)、饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用C18反向色谱法以洗脱剂体系C纯化所得残余物，得到N-(8-((2-氯-5-氟苯基)(羟基)甲基)咪唑[1,2-a]吡啶-7-基)-3-氟-5-(三氟甲基)苯甲酰胺21(43mg)，产率：13.0％。Dissolve (7-aminoimidazo[1,2-a]pyridin-8-yl)(2-chloro-5-fluorophenyl)methanol 21d (200 mg, 0.687 mmol) in 5 mL of acetonitrile and add 3-fluoro-5 -(trifluoromethyl)benzoic acid (172mg, 0.825mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (231mg, 0.825mmol) and N-methylmorpholine ( 208mg, 2.06mmol), react at room temperature for 2 hours. The reaction solution was poured into 50 mL of water and extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by C18 reverse chromatography with eluent system C, N-(8-((2-chloro-5-fluorophenyl)(hydroxy)methyl)imidazol[1,2-a]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl ) benzamide 21 (43 mg), yield: 13.0%.
MS m/z(ESI):482.1[M+1]MS m/z(ESI):482.1[M+1]
实施例22-24化合物的制备参照实施例21，相应的质谱数据列于表1中。Refer to Example 21 for the preparation of the compounds of Examples 22-24, and the corresponding mass spectrum data are listed in Table 1.
实施例25Example 25
N-(1-(2-氯-5-氟苯基)-2-亚氨基-2-氧化-2,3-二氢-1H-2l4-苯并[c]噻吩-4-基)-3-氟 -5-(三氟甲基)苯甲酰胺N-(1-(2-Chloro-5-fluorophenyl)-2-imino-2-oxide-2,3-dihydro-1H-2l4-benzo[c]thiophen-4-yl)-3 -Fluoro-5-(trifluoromethyl)benzamide
Figure PCTCN2022136232-appb-000059
Figure PCTCN2022136232-appb-000059
第一步first step
(2-氨基-6-溴苯基)甲醇(2-Amino-6-bromophenyl)methanol
将2-氨基-6-溴苯甲酸(5g，23.1mmol)溶解在50mL四氢呋喃中，冰浴下缓慢分批加入四氢锂铝(1.76g，46.2mmol)，室温反应1小时。冷却至0℃，依次缓慢滴加2mL水、2mL15％氢氧化钠溶液、2mL水，搅拌30分钟，过滤，滤液减压浓缩，得到(2-氨基-6-溴苯基)甲醇25a(3.6g)，产率：77.3％。2-Amino-6-bromobenzoic acid (5 g, 23.1 mmol) was dissolved in 50 mL of tetrahydrofuran, and lithium aluminum tetrahydrogen (1.76 g, 46.2 mmol) was slowly added in batches under an ice bath, and reacted at room temperature for 1 hour. Cooled to 0°C, slowly added 2mL of water, 2mL of 15% sodium hydroxide solution, and 2mL of water successively, stirred for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain (2-amino-6-bromophenyl)methanol 25a (3.6g ), yield: 77.3%.
MS m/z(ESI):202.0[M+1]MS m/z(ESI):202.0[M+1]
第二步second step
(3-溴-2-(羟甲基)苯基)氨基甲酸叔丁酯(3-Bromo-2-(hydroxymethyl)phenyl)carbamate tert-butyl ester
将(2-氨基-6-溴苯基)甲醇25a(3.6g，17.8mmol)溶解在50mL二氯甲烷中，加入4-二甲氨基吡啶(109mg，0.891mmol)和二碳酸二叔丁酯(4.66g，21.4mmol)，室温反应16小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(3-溴-2-(羟甲基)苯基)氨基甲酸叔丁酯25b(4.6g)，产率：85.5％。Dissolve (2-amino-6-bromophenyl)methanol 25a (3.6 g, 17.8 mmol) in 50 mL of dichloromethane, add 4-dimethylaminopyridine (109 mg, 0.891 mmol) and di-tert-butyl dicarbonate ( 4.66g, 21.4mmol), react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product (3-bromo-2-(hydroxymethyl)phenyl)carbamate tert-butyl ester 25b (4.6g) , Yield: 85.5%.
MS m/z(ESI):302.0[M+1]MS m/z(ESI):302.0[M+1]
第三步third step
叔丁基(3-((2-氯-5-氟苯基)(羟基)甲基)-2-(羟甲基)苯基)氨基甲酸酯tert-butyl(3-((2-chloro-5-fluorophenyl)(hydroxy)methyl)-2-(hydroxymethyl)phenyl)carbamate
将((3-溴-2-(羟甲基)苯基)氨基甲酸叔丁酯25b(4.6g，15.2mmol)溶解在50mL四氢呋喃中，氮气保护下冷却至-78℃，滴加正丁基锂的正己烷溶液(28.6mL，1.6M，45.7mmol)，搅拌1小时。加入2-氯-5-氟苯甲醛(2.89g，18.3mmol)的四氢呋喃溶液，搅拌1小时。加入100mL饱和氯化铵溶液，缓慢升至室温后用乙酸乙酯萃取(100mL*2)。合并有机相，依次用水(100mL)、饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物叔丁基(3-((2-氯-5-氟苯基)(羟基)甲基)-2-(羟甲基)苯基)氨基甲酸酯25c(3.6g)，产率：61.9％。Dissolve tert-butyl ((3-bromo-2-(hydroxymethyl)phenyl)carbamate 25b (4.6g, 15.2mmol) in 50mL tetrahydrofuran, cool to -78°C under nitrogen protection, and add n-butyl Lithium in n-hexane (28.6mL, 1.6M, 45.7mmol), stirred for 1 hour. Added 2-chloro-5-fluorobenzaldehyde (2.89g, 18.3mmol) in tetrahydrofuran, stirred for 1 hour. Added 100mL of saturated chloride Ammonium solution, after slowly rising to room temperature, extract with ethyl acetate (100mL*2). Combine the organic phases, wash with water (100mL) and saturated sodium chloride solution (100mL) successively, dry over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentrate and purify the resulting residue by column chromatography on silica gel with eluent system B to give the title product tert-butyl(3-((2-chloro-5-fluorophenyl)(hydroxy)methyl)-2-(hydroxyl Methyl)phenyl)carbamate 25c (3.6 g), yield: 61.9%.
MS m/z(ESI):382.1[M+1]MS m/z(ESI):382.1[M+1]
第四步the fourth step
(1-(2-氯-5-氟苯基)-1,3-二氢苯并[c]噻吩-4-基)氨基甲酸叔丁酯(1-(2-Chloro-5-fluorophenyl)-1,3-dihydrobenzo[c]thiophen-4-yl)carbamate tert-butyl ester
将叔丁基(3-((2-氯-5-氟苯基)(羟基)甲基)-2-(羟甲基)苯基)氨基甲酸酯25c(3.6g，9.42mmol)溶解在100mL甲苯中，加入劳森试剂(5.71g，14.1mmol)，加热至90℃反应30分钟。反应液冷却至室温，倒入100mL水中，乙酸乙酯萃取(100mL*2)。合并有机相，依次用水(100mL)、饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(1-(2-氯-5-氟苯基)-1,3-二氢苯并[c]噻吩-4-基)氨基甲酸叔丁酯25d(1.2g)，产率：33.5％。tert-Butyl(3-((2-chloro-5-fluorophenyl)(hydroxy)methyl)-2-(hydroxymethyl)phenyl)carbamate 25c (3.6 g, 9.42 mmol) was dissolved in Add Lawson's reagent (5.71 g, 14.1 mmol) to 100 mL of toluene, and heat to 90° C. for 30 minutes. The reaction solution was cooled to room temperature, poured into 100 mL of water, and extracted with ethyl acetate (100 mL*2). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain The title product (tert-butyl 1-(2-chloro-5-fluorophenyl)-1,3-dihydrobenzo[c]thiophen-4-yl)carbamate 25d (1.2 g), yield: 33.5% .
MS m/z(ESI):380.1[M+1]MS m/z(ESI):380.1[M+1]
第五步the fifth step
1-(2-氯-5-氟苯基)-1,3-二氢苯并[c]噻吩-4-胺盐酸盐1-(2-Chloro-5-fluorophenyl)-1,3-dihydrobenzo[c]thiophen-4-amine hydrochloride
将(1-(2-氯-5-氟苯基)-1,3-二氢苯并[c]噻吩-4-基)氨基甲酸叔丁酯25d(1.2g，3.16mmol)溶解在15mL二氯甲烷中，加入盐酸二氧六环溶液(5mL，4M)，室温反应2小时。反应液减压浓缩，得到标题产物1-(2-氯-5-氟苯基)-1,3-二氢苯并[c]噻吩-4-胺盐酸盐25e(990mg)，产率：99.3％。Dissolve tert-butyl (1-(2-chloro-5-fluorophenyl)-1,3-dihydrobenzo[c]thiophen-4-yl)carbamate 25d (1.2 g, 3.16 mmol) in 15 mL di Dioxane hydrochloride solution (5 mL, 4M) was added to methyl chloride, and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title product 1-(2-chloro-5-fluorophenyl)-1,3-dihydrobenzo[c]thiophen-4-amine hydrochloride 25e (990mg), yield: 99.3%.
MS m/z(ESI):280.0[M-HCl+H]MS m/z(ESI):280.0[M-HCl+H]
第六步step six
N-(1-(2-氯-5-氟苯基)-1,3-二氢苯并[c]噻吩-4-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(1-(2-chloro-5-fluorophenyl)-1,3-dihydrobenzo[c]thiophen-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
实施例25的合成方法参考实施例17中的第六步的合成方法，以实施例25e为原料得到实施例25f(160mg，产率：47.6％)。The synthesis method of Example 25 was referred to the synthesis method of the sixth step in Example 17, and Example 25f (160 mg, yield: 47.6%) was obtained from Example 25e.
MS m/z(ESI):470.0[M+1]MS m/z(ESI):470.0[M+1]
第七步step seven
N-(1-(2-氯-5-氟苯基)-2-亚氨基-2-氧化-2,3-二氢-1H-2l4-苯并[c]噻吩-4-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(1-(2-Chloro-5-fluorophenyl)-2-imino-2-oxide-2,3-dihydro-1H-2l4-benzo[c]thiophen-4-yl)-3 -Fluoro-5-(trifluoromethyl)benzamide
将N-(1-(2-氯-5-氟苯基)-1,3-二氢苯并[c]噻吩-4-基)-3-氟-5-(三氟甲基)苯甲酰 胺(160mg，0.340mmol)溶解在5mL甲醇中，加入碘苯二乙酸(164mg，0.511mmol)和碳酸铵(96mg，0.511mmol)，室温反应3小时。反应液倒入50mL水中，乙酸乙酯萃取(50mL*2)。合并有机相，依次用水(50mL)、饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用C18反向色谱法以洗脱剂体系C纯化所得残余物，得到N-(1-(2-氯-5-氟苯基)-2-亚氨基-2-氧化-2,3-二氢-1H-2l4-苯并[c]噻吩-4-基)-3-氟-5-(三氟甲基)苯甲酰胺25(24mg)，产率：14.1％。N-(1-(2-chloro-5-fluorophenyl)-1,3-dihydrobenzo[c]thiophen-4-yl)-3-fluoro-5-(trifluoromethyl)benzene The amide (160mg, 0.340mmol) was dissolved in 5mL of methanol, and iodobenzenediacetic acid (164mg, 0.511mmol) and ammonium carbonate (96mg, 0.511mmol) were added, and reacted at room temperature for 3 hours. The reaction solution was poured into 50 mL of water and extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by C18 reverse chromatography with eluent system C, N-(1-(2-Chloro-5-fluorophenyl)-2-imino-2-oxide-2,3-dihydro-1H-2l4-benzo[c]thiophen-4-yl)- 3-fluoro-5-(trifluoromethyl)benzamide 25 (24 mg), yield: 14.1%.
MS m/z(ESI):501.0[M+1]MS m/z(ESI):501.0[M+1]
实施例26-28化合物的制备参照实施例25，相应的质谱数据列于表1中。Refer to Example 25 for the preparation of the compounds of Examples 26-28, and the corresponding mass spectrum data are listed in Table 1.
实施例29Example 29
N-(3-(2-氯-5-氟苯基)-1-氧化-2,3-二氢苯并[d]异噻唑-4-基)-3-氟-5-(三氟甲基)苯甲N-(3-(2-chloro-5-fluorophenyl)-1-oxygen-2,3-dihydrobenzo[d]isothiazol-4-yl)-3-fluoro-5-(trifluoromethyl Base) Benzene 酰胺Amide
Figure PCTCN2022136232-appb-000060
Figure PCTCN2022136232-appb-000060
第一步first step
2-氯-5-氟-N-(4-甲氧基苄基)-N-((3-硝基苯基)磺酰基)苯甲酰胺2-Chloro-5-fluoro-N-(4-methoxybenzyl)-N-((3-nitrophenyl)sulfonyl)benzamide
将3-硝基苯磺酰氯29a(1.28g，5.78mmol),2-氯-5-氟-N-(4-甲氧基苄基)苯甲酰胺(1.70g，5.78mmol)溶解于10mL二氯甲烷中，加入二异丙基乙胺(8mL，11.60mmol)，室温反应3小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物2-氯-5-氟-N-(4-甲氧基苄基)-N-((3-硝基苯基)磺酰基)苯甲酰胺29b(2g)，产率：72％。Dissolve 3-nitrobenzenesulfonyl chloride 29a (1.28g, 5.78mmol), 2-chloro-5-fluoro-N-(4-methoxybenzyl)benzamide (1.70g, 5.78mmol) in 10mL di Diisopropylethylamine (8 mL, 11.60 mmol) was added to methyl chloride, and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title product 2-chloro-5-fluoro-N-(4-methoxybenzyl)-N-((3-nitrobenzene (yl)sulfonyl)benzamide 29b (2 g), yield: 72%.
MS m/z(ESI):479.1[M+1]MS m/z(ESI):479.1[M+1]
第二步second step
3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧基苄基)-4-硝基-2,3-二氢苯并[d]异噻唑-1,1-二氧化物3-(2-Chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitro-2,3-dihydrobenzo[d]isothiazole-1 ,1-dioxide
在0℃将2-氯-5-氟-N-(4-甲氧基苄基)-N-((3-硝基苯基)磺酰基)苯甲酰胺29b(2g，4.18mmol)溶解于40mL四氢呋喃中，加入LiHMDS(8.4mL，1M)，搅拌反应3小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧基苄基)-4-硝基-2,3-二氢苯并[d]异噻唑-1,1-二氧化物29c(1g)，产率：50％。2-Chloro-5-fluoro-N-(4-methoxybenzyl)-N-((3-nitrophenyl)sulfonyl)benzamide 29b (2 g, 4.18 mmol) was dissolved in LiHMDS (8.4 mL, 1M) was added to 40 mL of tetrahydrofuran, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title product 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl) -4-Nitro-2,3-dihydrobenzo[d]isothiazole-1,1-dioxide 29c (1 g), yield: 50%.
MS m/z(ESI):479.1[M+1]MS m/z(ESI):479.1[M+1]
第三步third step
3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基-2,3-二氢苯并[d]异噻唑-1,1-二氧化物3-(2-Chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitro-2,3-dihydrobenzo[d]isothiazole-1,1-di Oxide
将3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧基苄基)-4-硝基-2,3-二氢苯并[d]异噻唑-1,1-二氧化物29c(1g，2.09mmol)溶解于15mL乙腈中，加入三乙基硅氢(3g，20.90mmol),在70℃搅拌反应5小时。减压浓缩，用硅胶柱色谱法硅胶柱色谱法以洗脱剂体系C纯化所得残余物，得到标题产物3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基-2,3-二氢苯并[d]异噻唑-1,1-二氧化物29d(0.6g)，产率：62％。3-(2-Chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitro-2,3-dihydrobenzo[d]isothiazole- 1,1-Dioxide 29c (1 g, 2.09 mmol) was dissolved in 15 mL of acetonitrile, triethylsilane (3 g, 20.90 mmol) was added, and the reaction was stirred at 70°C for 5 hours. Concentrate under reduced pressure and purify the resulting residue by silica gel column chromatography with eluent system C to give the title product 3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl yl)-4-nitro-2,3-dihydrobenzo[d]isothiazole-1,1-dioxide 29d (0.6 g), yield: 62%.
MS m/z(ESI):463.1[M+1]MS m/z(ESI):463.1[M+1]
第四步the fourth step
3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基-2,3-二氢苯并[d]异噻唑1-氧化物3-(2-Chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitro-2,3-dihydrobenzo[d]isothiazole 1-oxide
将3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基-2,3-二氢苯并[d]异噻唑-1,1-二氧化物29d(0.60g，1.30mol)溶解于10mL甲醇中，加入亚硫酸钠(1.60g，1.30mmol)，室温反应2小时，反应液减压浓缩，用硅胶柱色谱法硅胶柱色谱法以洗脱剂体系C纯化得到标题产物3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基-2,3-二氢苯并[d]异噻唑1-氧化物29e(0.5g)，产率：86％。3-(2-Chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitro-2,3-dihydrobenzo[d]isothiazole-1,1- Dioxide 29d (0.60g, 1.30mol) was dissolved in 10mL of methanol, sodium sulfite (1.60g, 1.30mmol) was added, reacted at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and silica gel column chromatography was used to elute Purification of Reagent System C gave the title product 3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitro-2,3-dihydrobenzo[d]iso Thiazole 1-oxide 29e (0.5 g), yield: 86%.
MS m/z(ESI):447.2[M+1]MS m/z(ESI):447.2[M+1]
第五步the fifth step
3-(2-氯-5-氟苯基)-4-硝基-2,3-二氢苯并[d]异噻唑1-氧化物3-(2-Chloro-5-fluorophenyl)-4-nitro-2,3-dihydrobenzo[d]isothiazole 1-oxide
将3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基-2,3-二氢苯并[d]异噻唑1-氧化物29e(0.50g，1.12mol)溶解于10mL三氟乙酸中，回流反应2小时，反应液减压浓缩，得到标题产物3-(2-氯-5-氟苯基)-4-硝基-2,3-二氢苯并[d]异噻唑1-氧化物29f(0.35g)，产率：96％。3-(2-Chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitro-2,3-dihydrobenzo[d]isothiazole 1-oxide 29e (0.50g, 1.12mol) was dissolved in 10mL trifluoroacetic acid, refluxed for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the title product 3-(2-chloro-5-fluorophenyl)-4-nitro-2, 3-Dihydrobenzo[d]isothiazole 1-oxide 29f (0.35 g), yield: 96%.
MS m/z(ESI):327.2[M+1]MS m/z(ESI):327.2[M+1]
第六步step six
4-氨基-3-(2-氯-5-氟苯基)-2,3-二氢苯并[d]异噻唑1-氧化物4-Amino-3-(2-chloro-5-fluorophenyl)-2,3-dihydrobenzo[d]isothiazole 1-oxide
将3-(2-氯-5-氟苯基)-4-硝基-2,3-二氢苯并[d]异噻唑1-氧化物29f(0.35g，1.07mmol)溶解于20mL乙醇中，加入10mL水和铁粉(1.2g，2.14mol)，60℃下，反应4小时。过滤，滤液减压浓缩，得到标题产物4-氨基-3-(2-氯-5-氟苯基)-2,3-二氢苯并[d]异噻唑1-氧化物29g(0.2g)，产率：66％。Dissolve 3-(2-chloro-5-fluorophenyl)-4-nitro-2,3-dihydrobenzo[d]isothiazole 1-oxide 29f (0.35 g, 1.07 mmol) in 20 mL of ethanol , add 10mL of water and iron powder (1.2g, 2.14mol), and react at 60°C for 4 hours. Filtration, and the filtrate was concentrated under reduced pressure to obtain 29 g (0.2 g) of the title product 4-amino-3-(2-chloro-5-fluorophenyl)-2,3-dihydrobenzo[d]isothiazole 1-oxide , Yield: 66%.
MS m/z(ESI):297.1[M+1]MS m/z(ESI):297.1[M+1]
第七步step seven
N-(3-(2-氯-5-氟苯基)-1-氧化-2,3-二氢苯并[d]异噻唑-4-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(3-(2-chloro-5-fluorophenyl)-1-oxygen-2,3-dihydrobenzo[d]isothiazol-4-yl)-3-fluoro-5-(trifluoromethyl base) benzamide
将4-氨基-3-(2-氯-5-氟苯基)-2,3-二氢苯并[d]异噻唑1-氧化物29g(0.20g，0.67mmol),3-氟-5-(三氟甲基)苯甲酸(148mg，0.70mmol)溶解于6mL DMF中，加入二异丙基乙胺(2mL，1.40mmol)和苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(470mg，1.40mmol)，室温反应3小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化得到标题产物N-(3-(2-氯-5-氟苯基)-1-氧化-2,3-二氢苯并[d]异噻唑-4-基)-3-氟-5-(三氟甲基)苯甲酰胺29(100mg)，产率：30.5％。29g (0.20g, 0.67mmol) of 4-amino-3-(2-chloro-5-fluorophenyl)-2,3-dihydrobenzo[d]isothiazole 1-oxide, 3-fluoro-5 -(Trifluoromethyl)benzoic acid (148 mg, 0.70 mmol) was dissolved in 6 mL of DMF, diisopropylethylamine (2 mL, 1.40 mmol) and benzotriazole-N,N,N',N' were added -Tetramethylurea hexafluorophosphate (470mg, 1.40mmol), react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title product N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydrobenzo [d] Isothiazol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide 29 (100 mg), yield: 30.5%.
MS m/z(ESI):487.1[M+1]MS m/z(ESI):487.1[M+1]
实施例30-32化合物的制备参照实施例29，相应的质谱数据列于表1中。Refer to Example 29 for the preparation of the compounds of Examples 30-32, and the corresponding mass spectrometry data are listed in Table 1.
实施例33Example 33
N-(6-(2-氯-5-氟苯基)-4-氧代-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基)-3-氟-5-(三氟N-(6-(2-chloro-5-fluorophenyl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-3-fluoro -5-(trifluoro 甲基)苯甲酰胺Methyl)benzamide
Figure PCTCN2022136232-appb-000061
Figure PCTCN2022136232-appb-000061
第一步first step
N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)-5-硝基噻吩-3-甲酰胺N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-5-nitrothiophene-3-carboxamide
将5-硝基噻吩-3-羧酸33a(1g，5.78mmol),2-氯-5-氟-N-(4-甲氧基苄基)苯甲酰胺(1.70g，5.78mmol)溶解于10mL DMF中，加入二异丙基乙胺(8mL，11.6mmol)和苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(2.85g，8.7mmol)，室温反应3小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B得到标题产物N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)-5-硝基噻吩-3-甲酰胺33b(2g)，产率：77％。Dissolve 5-nitrothiophene-3-carboxylic acid 33a (1 g, 5.78 mmol), 2-chloro-5-fluoro-N-(4-methoxybenzyl) benzamide (1.70 g, 5.78 mmol) in In 10mL of DMF, add diisopropylethylamine (8mL, 11.6mmol) and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.85g, 8.7mmol), React at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the title product N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-5-nitrate was obtained by silica gel column chromatography with eluent system B Ethylthiophene-3-carboxamide 33b (2 g), Yield: 77%.
MS m/z(ESI):449.1[M+1]MS m/z(ESI):449.1[M+1]
第二步second step
6-(2-氯-5-氟苯基)-6-羟基-5-(4-甲氧基苄基)-1-硝基-5,6-二氢-4H-噻吩并[3,4-c]吡咯-4-酮6-(2-Chloro-5-fluorophenyl)-6-hydroxy-5-(4-methoxybenzyl)-1-nitro-5,6-dihydro-4H-thieno[3,4 -c]pyrrol-4-one
在0℃将N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)-5-硝基噻吩-3-甲酰胺33b(2g，4.50mmol)溶解于40mL四氢呋喃中，加入LiHMDS(9mL，1M)，搅拌反应3小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化得到标题产物6-(2-氯-5-氟苯基)-6-羟基-5-(4-甲氧基苄基)-1-硝基-5,6-二氢-4H-噻吩并[3,4-c]吡咯-4-酮33c(1g)，产率：50％。N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-5-nitrothiophene-3-carboxamide 33b (2 g, 4.50 mmol) was dissolved in LiHMDS (9 mL, 1M) was added to 40 mL of tetrahydrofuran, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title product 6-(2-chloro-5-fluorophenyl)-6-hydroxy-5-(4-methoxybenzyl) -1-nitro-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one 33c (1 g), yield: 50%.
MS m/z(ESI):449.1[M+1]MS m/z(ESI):449.1[M+1]
第三步third step
6-(2-氯-5-氟苯基)-5-(4-甲氧基苄基)-1-硝基-5,6-二氢-4H-噻吩并[3,4-c]吡咯-4-酮6-(2-Chloro-5-fluorophenyl)-5-(4-methoxybenzyl)-1-nitro-5,6-dihydro-4H-thieno[3,4-c]pyrrole -4-one
将6-(2-氯-5-氟苯基)-6-羟基-5-(4-甲氧基苄基)-1-硝基-5,6-二氢-4H-噻吩并[3,4-c]吡咯-4-酮33c(1g，2.23mmol)溶解于15mL乙腈中，加入三乙基硅氢(3.60g，22.3mol),在70℃搅拌反应5小时。减压浓缩，用硅胶柱色谱法硅胶柱色谱法以洗脱剂体系C纯化所得残余物，得到标题产物6-(2-氯-5-氟苯基)-5-(4-甲氧基苄基)-1-硝基-5,6-二氢-4H-噻吩并[3,4-c]吡咯-4-酮33d(700mg)，产率：72.6％。6-(2-Chloro-5-fluorophenyl)-6-hydroxy-5-(4-methoxybenzyl)-1-nitro-5,6-dihydro-4H-thieno[3, 4-c] Pyrrol-4-one 33c (1 g, 2.23 mmol) was dissolved in 15 mL of acetonitrile, triethylsilane (3.60 g, 22.3 mol) was added, and the reaction was stirred at 70°C for 5 hours. Concentrate under reduced pressure and purify the resulting residue by silica gel column chromatography with eluent system C to give the title product 6-(2-chloro-5-fluorophenyl)-5-(4-methoxybenzyl yl)-1-nitro-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one 33d (700 mg), yield: 72.6%.
MS m/z(ESI):433.1[M+1]MS m/z(ESI):433.1[M+1]
第四步the fourth step
6-(2-氯-5-氟苯基)-1-硝基-5,6-二氢-4H-噻吩并[3,4-c]吡咯-4-酮6-(2-Chloro-5-fluorophenyl)-1-nitro-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one
将6-(2-氯-5-氟苯基)-5-(4-甲氧基苄基)-1-硝基-5,6-二氢-4H-噻吩并[3,4-c]吡咯-4-酮33d(700mg，1.62mol)溶解于10mL三氟乙酸中，回流反应2小时，反应液减压浓缩，得到标题产物6-(2-氯-5-氟苯基)-1-硝基-5,6-二氢-4H-噻吩并[3,4-c]吡咯-4-酮33e(500mg)，产率：99％。6-(2-Chloro-5-fluorophenyl)-5-(4-methoxybenzyl)-1-nitro-5,6-dihydro-4H-thieno[3,4-c] Pyrrol-4-one 33d (700 mg, 1.62 mol) was dissolved in 10 mL of trifluoroacetic acid, refluxed for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the title product 6-(2-chloro-5-fluorophenyl)-1- Nitro-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one 33e (500 mg), yield: 99%.
MS m/z(ESI):313.2[M+1]MS m/z(ESI):313.2[M+1]
第五步the fifth step
1-氨基-6-(2-氯-5-氟苯基)-5,6-二氢-4H-噻吩并[3,4-c]吡咯-4-酮1-amino-6-(2-chloro-5-fluorophenyl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one
将6-(2-氯-5-氟苯基)-1-硝基-5,6-二氢-4H-噻吩并[3,4-c]吡咯-4-酮33e(500mg， 1.6mmol)溶解于20mL乙醇中，加入10mL水和铁粉(1.70g，3.20mol)，60℃下，反应4小时。过滤，滤液减压浓缩，得到标题产物1-氨基-6-(2-氯-5-氟苯基)-5,6-二氢-4H-噻吩并[3,4-c]吡咯-4-酮33f(300mg)，产率：66％。6-(2-Chloro-5-fluorophenyl)-1-nitro-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one 33e (500mg, 1.6mmol) Dissolve in 20 mL of ethanol, add 10 mL of water and iron powder (1.70 g, 3.20 mol), and react at 60°C for 4 hours. Filtration and concentration of the filtrate under reduced pressure gave the title product 1-amino-6-(2-chloro-5-fluorophenyl)-5,6-dihydro-4H-thieno[3,4-c]pyrrole-4- Ketone 33f (300 mg), yield: 66%.
MS m/z(ESI):283.3[M+1]MS m/z(ESI):283.3[M+1]
第六步step six
N-(6-(2-氯-5-氟苯基)-4-氧代-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(6-(2-chloro-5-fluorophenyl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-3-fluoro -5-(Trifluoromethyl)benzamide
将1-氨基-6-(2-氯-5-氟苯基)-5,6-二氢-4H-噻吩并[3,4-c]吡咯-4-酮33f(100mg，0.35mmol),3-氟-5-(三氟甲基)苯甲酸(74mg，0.35mmol)溶解于6mL DMF中，加入二异丙基乙胺(1mL，0.7mmol)和苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(235mg，0.7mmol)，室温反应3小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化得到标题产物N-(6-(2-氯-5-氟苯基)-4-氧代-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基)-3-氟-5-(三氟甲基)苯甲酰胺33(100mg)，产率：60％。1-Amino-6-(2-chloro-5-fluorophenyl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one 33f (100mg, 0.35mmol), 3-Fluoro-5-(trifluoromethyl)benzoic acid (74 mg, 0.35 mmol) was dissolved in 6 mL of DMF, diisopropylethylamine (1 mL, 0.7 mmol) and benzotriazole-N,N, N',N'-Tetramethyluronium hexafluorophosphate (235 mg, 0.7 mmol) was reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title product N-(6-(2-chloro-5-fluorophenyl)-4-oxo-5,6-dihydro- 4H-thieno[3,4-c]pyrrol-1-yl)-3-fluoro-5-(trifluoromethyl)benzamide 33 (100 mg), yield: 60%.
MS m/z(ESI):473.1[M+1]MS m/z(ESI):473.1[M+1]
实施例34-36化合物的制备参照实施例33，相应的质谱数据列于表1中。Refer to Example 33 for the preparation of the compounds of Examples 34-36, and the corresponding mass spectrometry data are listed in Table 1.
实施例37Example 37
N-(6-(2-氯-5-氟苯基)-4-氧代-5,6-二氢-4H-噻唑并[3,4-c]吡咯-1-基)-3-氟-5-(三氟N-(6-(2-chloro-5-fluorophenyl)-4-oxo-5,6-dihydro-4H-thiazolo[3,4-c]pyrrol-1-yl)-3-fluoro -5-(trifluoro 甲基)苯甲酰胺Methyl)benzamide
Figure PCTCN2022136232-appb-000062
Figure PCTCN2022136232-appb-000062
第一步first step
N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)-5-硝基噻唑-3-甲酰胺N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-5-nitrothiazole-3-carboxamide
将5-硝基噻唑-3-羧酸37a(1g，5.78mmol)，2-氯-5-氟-N-(4-甲氧基苄基)苯甲酰胺(1.70g，5.78mmol)溶解于10mL DMF中，加入二异丙基乙胺(8mL，11.6mmol)和苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(2.85g，8.7mmol)，室温反应3小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化得到标题产物N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)-5-硝基噻唑-3-甲酰胺37b(2g)，产率：77％。5-Nitrothiazole-3-carboxylic acid 37a (1 g, 5.78 mmol), 2-chloro-5-fluoro-N-(4-methoxybenzyl) benzamide (1.70 g, 5.78 mmol) were dissolved in In 10mL of DMF, add diisopropylethylamine (8mL, 11.6mmol) and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.85g, 8.7mmol), React at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title product N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-5- Nitrothiazole-3-carboxamide 37b (2 g), yield: 77%.
MS m/z(ESI):450.1[M+1]MS m/z(ESI):450.1[M+1]
第二步second step
6-(2-氯-5-氟苯基)-6-羟基-5-(4-甲氧基苄基)-1-硝基-5,6-二氢-4H-噻唑并[3,4-c]吡咯-4-酮6-(2-Chloro-5-fluorophenyl)-6-hydroxy-5-(4-methoxybenzyl)-1-nitro-5,6-dihydro-4H-thiazolo[3,4 -c]pyrrol-4-one
在0℃将N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)-5-硝基噻唑-3-甲酰胺37b(2g，4.5mmol)溶解于40mL四氢呋喃中，加入LiHMDS(9mL，1M)，搅拌反应3小时。反应液减压浓缩，用硅胶柱色谱法纯化所得残余物(洗脱剂：二氯甲烷：甲醇＝10：1)，得到标题产物6-(2-氯-5-氟苯基)-6-羟基-5-(4-甲氧基苄基)-1-硝基-5,6-二氢-4H-噻唑并[3,4-c]吡咯-4-酮37c(1g)，产率：50％。N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-5-nitrothiazole-3-carboxamide 37b (2 g, 4.5 mmol) was dissolved in LiHMDS (9 mL, 1M) was added to 40 mL of tetrahydrofuran, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=10:1) to obtain the title product 6-(2-chloro-5-fluorophenyl)-6- Hydroxy-5-(4-methoxybenzyl)-1-nitro-5,6-dihydro-4H-thiazolo[3,4-c]pyrrol-4-one 37c (1 g), yield: 50%.
MS m/z(ESI):450.1[M+1]MS m/z(ESI):450.1[M+1]
第三步third step
6-(2-氯-5-氟苯基)-5-(4-甲氧基苄基)-1-硝基-5,6-二氢-4H-噻唑并[3,4-c]吡咯-4-酮6-(2-Chloro-5-fluorophenyl)-5-(4-methoxybenzyl)-1-nitro-5,6-dihydro-4H-thiazolo[3,4-c]pyrrole -4-one
将6-(2-氯-5-氟苯基)-6-羟基-5-(4-甲氧基苄基)-1-硝基-5,6-二氢-4H-噻唑并[3,4-c]吡咯-4-酮37c(1g，2.23mmol)溶解于15mL乙腈中，加入三乙基硅氢(3.6g，22.3mol),在70℃搅拌反应5小时。减压浓缩，用硅胶柱色谱法硅胶柱色谱法以洗脱剂体系C纯化所得残余物，得到标题产物6-(2-氯-5-氟苯基)-5-(4-甲氧基苄基)-1-硝基-5,6-二氢-4H-噻唑并[3,4-c]吡咯-4-酮37d(700mg)，产率：72.6％。6-(2-Chloro-5-fluorophenyl)-6-hydroxy-5-(4-methoxybenzyl)-1-nitro-5,6-dihydro-4H-thiazolo[3, 4-c] Pyrrol-4-one 37c (1 g, 2.23 mmol) was dissolved in 15 mL of acetonitrile, triethylsilane (3.6 g, 22.3 mol) was added, and the reaction was stirred at 70°C for 5 hours. Concentrate under reduced pressure and purify the resulting residue by silica gel column chromatography with eluent system C to give the title product 6-(2-chloro-5-fluorophenyl)-5-(4-methoxybenzyl yl)-1-nitro-5,6-dihydro-4H-thiazolo[3,4-c]pyrrol-4-one 37d (700 mg), yield: 72.6%.
MS m/z(ESI):434.1[M+1]MS m/z(ESI):434.1[M+1]
第四步the fourth step
6-(2-氯-5-氟苯基)-1-硝基-5,6-二氢-4H-噻唑并[3,4-c]吡咯-4-酮6-(2-Chloro-5-fluorophenyl)-1-nitro-5,6-dihydro-4H-thiazolo[3,4-c]pyrrol-4-one
将6-(2-氯-5-氟苯基)-5-(4-甲氧基苄基)-1-硝基-5,6-二氢-4H-噻唑并[3,4-c]吡咯-4-酮37d(0.7g，1.62mol)溶解于10mL三氟乙酸中，回流反应2小时，反应液减压浓缩，得到标题产物6-(2-氯-5-氟苯基)-1-硝基-5,6-二氢-4H-噻唑并[3,4-c]吡咯-4-酮37e(0.5g)，产率：99％。6-(2-Chloro-5-fluorophenyl)-5-(4-methoxybenzyl)-1-nitro-5,6-dihydro-4H-thiazolo[3,4-c] Pyrrol-4-one 37d (0.7g, 1.62mol) was dissolved in 10mL of trifluoroacetic acid, refluxed for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the title product 6-(2-chloro-5-fluorophenyl)-1 -Nitro-5,6-dihydro-4H-thiazolo[3,4-c]pyrrol-4-one 37e (0.5 g), yield: 99%.
MS m/z(ESI):314.2[M+1]MS m/z(ESI):314.2[M+1]
第五步the fifth step
1-氨基-6-(2-氯-5-氟苯基)-5,6-二氢-4H-噻唑并[3,4-c]吡咯-4-酮1-amino-6-(2-chloro-5-fluorophenyl)-5,6-dihydro-4H-thiazolo[3,4-c]pyrrol-4-one
将6-(2-氯-5-氟苯基)-1-硝基-5,6-二氢-4H-噻唑并[3,4-c]吡咯-4-酮37e(0.5g，1.6mmol)溶解于20mL乙醇中，加入10mL水和铁粉(1.7g，3.2mol)，60℃下，反应4小时。过滤，滤液减压浓缩，得到标题产物1-氨基-6-(2-氯-5-氟苯基)-5,6-二氢-4H-噻唑并[3,4-c]吡咯-4-酮37f(0.3g)，产率：66％。6-(2-Chloro-5-fluorophenyl)-1-nitro-5,6-dihydro-4H-thiazolo[3,4-c]pyrrol-4-one 37e (0.5g, 1.6mmol ) was dissolved in 20 mL of ethanol, 10 mL of water and iron powder (1.7 g, 3.2 mol) were added, and reacted at 60° C. for 4 hours. Filtration, and the filtrate was concentrated under reduced pressure to obtain the title product 1-amino-6-(2-chloro-5-fluorophenyl)-5,6-dihydro-4H-thiazolo[3,4-c]pyrrole-4- Ketone 37f (0.3 g), yield: 66%.
MS m/z(ESI):284.3[M+1]MS m/z(ESI):284.3[M+1]
第六步step six
N-(6-(2-氯-5-氟苯基)-4-氧代-5,6-二氢-4H-噻唑并[3,4-c]吡咯-1-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(6-(2-chloro-5-fluorophenyl)-4-oxo-5,6-dihydro-4H-thiazolo[3,4-c]pyrrol-1-yl)-3-fluoro -5-(Trifluoromethyl)benzamide
将1-氨基-6-(2-氯-5-氟苯基)-5,6-二氢-4H-噻唑并[3,4-c]吡咯-4-酮37f(100mg，0.35mmol),3-氟-5-(三氟甲基)苯甲酸(74mg，0.35mmol)溶解于6mL DMF中，加入二异丙基乙胺(1mL，0.7mmol)和苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(235mg，0.7mmol)，室温反应3小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化得到标题产物N-(6-(2-氯-5-氟苯基)-4-氧代-5,6-二氢-4H-噻唑并[3,4-c]吡咯-1-基)-3-氟-5-(三氟甲基)苯甲酰胺37(100mg)，产率：60％。1-Amino-6-(2-chloro-5-fluorophenyl)-5,6-dihydro-4H-thiazolo[3,4-c]pyrrol-4-one 37f (100mg, 0.35mmol), 3-Fluoro-5-(trifluoromethyl)benzoic acid (74 mg, 0.35 mmol) was dissolved in 6 mL of DMF, diisopropylethylamine (1 mL, 0.7 mmol) and benzotriazole-N,N, N',N'-Tetramethyluronium hexafluorophosphate (235 mg, 0.7 mmol) was reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title product N-(6-(2-chloro-5-fluorophenyl)-4-oxo-5,6-dihydro- 4H-Thiazolo[3,4-c]pyrrol-1-yl)-3-fluoro-5-(trifluoromethyl)benzamide 37 (100 mg), yield: 60%.
MS m/z(ESI):474.1[M+1]MS m/z(ESI):474.1[M+1]
实施例38-40化合物的制备参照实施例37，相应的质谱数据列于表1中。Refer to Example 37 for the preparation of the compounds of Examples 38-40, and the corresponding mass spectrometry data are listed in Table 1.
实施例41Example 41
N-(3-(2-氯-5-氟苯基)-2H-吲唑-4-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(3-(2-Chloro-5-fluorophenyl)-2H-indazol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
Figure PCTCN2022136232-appb-000063
Figure PCTCN2022136232-appb-000063
第一步first step
3-溴-4-硝基-2H-吲唑3-Bromo-4-nitro-2H-indazole
冰浴下，将化合物41a(1.6g，9.82mmol)溶解于5mL乙腈中，加入N-溴代丁二酰亚胺(1.74g，9.82mmol)，80℃下搅拌反应3小时。向反应液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-溴-4-硝基-2H-吲唑41b(1.7g)，产率：72.1％。Under ice-cooling, compound 41a (1.6 g, 9.82 mmol) was dissolved in 5 mL of acetonitrile, N-bromosuccinimide (1.74 g, 9.82 mmol) was added, and the reaction was stirred at 80° C. for 3 hours. Add 20 mL of water to the reaction solution, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography with eluent system B to give the title product 3-bromo-4-nitro-2H-indazole 41b (1.7 g), yield: 72.1%.
MS：m/z(ESI):242.1[M+1]MS: m/z(ESI):242.1[M+1]
第二步second step
3-溴-2-(4-甲氧基苄基)-4-硝基-2H-吲唑3-Bromo-2-(4-methoxybenzyl)-4-nitro-2H-indazole
冰浴下，将化合物41b(1.7g，7.05mmol)和碳酸钾(1.95g，14.1mmol)溶解于5mL N,N-二甲基甲酰胺中，加入4-甲氧基氯苄(1.33g，8.46mmol)，室温下搅拌反应24小时。向反应液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-溴-4-硝基-2H-吲唑41c(1.96g)，产率：77.2％。Under ice-cooling, compound 41b (1.7g, 7.05mmol) and potassium carbonate (1.95g, 14.1mmol) were dissolved in 5mL N,N-dimethylformamide, and 4-methoxybenzyl chloride (1.33g, 8.46mmol), stirred at room temperature for 24 hours. Add 20 mL of water to the reaction solution, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography with eluent system B to give the title product 3-bromo-4-nitro-2H-indazole 41c (1.96 g), yield: 77.2%.
MS：m/z(ESI):362.1[M+1]MS: m/z(ESI):362.1[M+1]
第三步third step
3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基-2H-吲唑3-(2-Chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitro-2H-indazole
将化合物41c(1.9g，5.26mmol)，(2-氯-5-氟苯基)硼酸(1.1g，6.32mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.42g,0.53mmol)，碳酸铯(5.14g，15.78mmol)溶解于5mL1,4-二氧六环和2mL水中，100℃下搅拌反应3小时。向反应液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基-2H-吲唑41d(1.52g)，产率：70.3％。Compound 41c (1.9g, 5.26mmol), (2-chloro-5-fluorophenyl)boronic acid (1.1g, 6.32mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium dichloromethane complex (0.42g, 0.53mmol) and cesium carbonate (5.14g, 15.78mmol) were dissolved in 5mL of 1,4-dioxane and 2mL of water, and stirred at 100°C for 3 hours. Add 20 mL of water to the reaction solution, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography with eluent system B to give the title product 3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitro-2H- Indazole 41d (1.52 g), yield: 70.3%.
MS：m/z(ESI):412.1[M+1]MS: m/z(ESI):412.1[M+1]
第四步the fourth step
3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-2H-吲唑-4-胺3-(2-Chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2H-indazol-4-amine
将化合物41d(1.5g，3.65mmol)溶解于5mL甲醇和2mL水中，随后将还原铁粉(1.0g，18.25mmol)，氯化铵(0.98g，18.25mmol)加入反应液，100℃下搅拌反应3小时。反应液过滤，甲醇(5mL×3)洗涤滤饼，滤液浓缩。向滤液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-2H-吲唑-4-胺41e(1.52g)，产率：70.3％。Compound 41d (1.5g, 3.65mmol) was dissolved in 5mL of methanol and 2mL of water, then reduced iron powder (1.0g, 18.25mmol), ammonium chloride (0.98g, 18.25mmol) was added to the reaction solution, and the reaction was stirred at 100°C 3 hours. The reaction solution was filtered, the filter cake was washed with methanol (5 mL×3), and the filtrate was concentrated. Add 20 mL of water to the filtrate, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by chromatography with eluent system B to give the title product 3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2H-indazol-4-amine 41e (1.52g), yield: 70.3%.
MS：m/z(ESI):382.1[M+1]MS: m/z(ESI):382.1[M+1]
第五步the fifth step
N-(3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-2H-吲唑-4-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2H-indazol-4-yl)-3-fluoro-5-(trifluoromethyl ) benzamide
将化合物41e(1.5g，3.94mmol)，3-氟-5-(三氟甲基)苯甲酸(0.98g，4.73mmol)，N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(3.0g，7.88mmol)溶解于5mL二氯甲烷中，随后将三乙胺(1.22g，11.82mmol)加入反应液,室温下搅拌反应3小时。向滤液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物N-(3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-2H-吲唑-4-基)-3-氟-5-(三氟甲基)苯甲酰胺41f(1.26g)，产率：56.1％。Compound 41e (1.5g, 3.94mmol), 3-fluoro-5-(trifluoromethyl)benzoic acid (0.98g, 4.73mmol), N,N,N',N'-tetramethyl-O-( 7-Azabenzotriazol-1-yl) urea hexafluorophosphate (3.0g, 7.88mmol) was dissolved in 5mL of dichloromethane, then triethylamine (1.22g, 11.82mmol) was added to the reaction solution, at room temperature The reaction was stirred for 3 hours. Add 20 mL of water to the filtrate, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by chromatography with eluent system B to give the title product N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2H-indazole- 4-yl)-3-fluoro-5-(trifluoromethyl)benzamide 41f (1.26 g), yield: 56.1%.
MS：m/z(ESI):572.1[M+1]MS: m/z(ESI):572.1[M+1]
第六步step six
N-(3-(2-氯-5-氟苯基)-2H-吲唑-4-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(3-(2-Chloro-5-fluorophenyl)-2H-indazol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
将化合物1f(0.2，0.35mmol)溶解于5mL三氟乙酸中，室温下搅拌反应3小时。反应液浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物N-(3-(2-氯-5-氟苯基)-2H-吲唑-4-基)-3-氟-5-(三氟甲基)苯甲酰胺41(80mg)，产率：51.3％。Compound 1f (0.2, 0.35 mmol) was dissolved in 5 mL of trifluoroacetic acid, and stirred at room temperature for 3 hours. The reaction was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product N-(3-(2-chloro-5-fluorophenyl)-2H-indazol-4-yl)- 3-fluoro-5-(trifluoromethyl)benzamide 41 (80 mg), yield: 51.3%.
MS：m/z(ESI):452.1[M+1]MS: m/z(ESI):452.1[M+1]
实施例42-44化合物的制备参照实施例41，相应的质谱数据列于表1中。Refer to Example 41 for the preparation of the compounds of Examples 42-44, and the corresponding mass spectrometry data are listed in Table 1.
实施例45Example 45
N-(4-(2-氯-5-氟苯基)-6-氧代-4,5,6,7-四氢噻吩[3,4-c]吡啶-3-基)-3-氟-5-(三氟甲N-(4-(2-Chloro-5-fluorophenyl)-6-oxo-4,5,6,7-tetrahydrothiophene[3,4-c]pyridin-3-yl)-3-fluoro -5-(Trifluoroform 基)苯甲酰胺base) benzamide
Figure PCTCN2022136232-appb-000064
Figure PCTCN2022136232-appb-000064
Figure PCTCN2022136232-appb-000065
Figure PCTCN2022136232-appb-000065
第一步first step
2-(5-硝基噻吩-3-基)乙酸乙酯2-(5-Nitrothiophen-3-yl)ethyl acetate
冰浴下，将金属钠(1.3g，57mmol)放置于75mL无水乙醇中，50℃下搅拌反应1小时。0℃下，将乙酰乙酸乙酯(4.55ml，36mmol)加入反应液，随后将化合物45a(4.95g，24mmol)和铜粉(0.25g，3.9mmmol)加入反应液，90℃下搅拌反应16小时。向反应液中加入20mL水，过滤，滤液用浓盐酸调节pH至2～3，过滤得固体，固体干燥得到标题产物2-(5-硝基噻吩-3-基)乙酸乙酯4b(5.0g)，产率：99.1％。Under ice-cooling, sodium metal (1.3 g, 57 mmol) was placed in 75 mL of absolute ethanol, and stirred at 50° C. for 1 hour. At 0°C, ethyl acetoacetate (4.55ml, 36mmol) was added to the reaction solution, then compound 45a (4.95g, 24mmol) and copper powder (0.25g, 3.9mmmol) were added to the reaction solution, and the reaction was stirred at 90°C for 16 hours . Add 20 mL of water to the reaction solution, filter, adjust the pH of the filtrate to 2-3 with concentrated hydrochloric acid, filter to obtain a solid, and dry the solid to obtain the title product 2-(5-nitrothiophen-3-yl) ethyl acetate 4b (5.0 g ), yield: 99.1%.
MS：m/z(ESI):216.2[M+1]MS: m/z(ESI):216.2[M+1]
第二步second step
2-(5-硝基噻吩-3-基)乙酸2-(5-Nitrothiophen-3-yl)acetic acid
冰浴下，将化合物45b(5.0g，23.3mmol)溶解于5mL水中，加入氢氧化钾(5.2g，93.2mmol)，室温下搅拌反应16小时。向反应液中加入20mL水，用浓盐酸调节pH至2～3，过滤得固体，固体干燥得到标题产物2-(5-硝基噻吩-3-基)乙酸45c(3.5g)，产率：77.2％。Under ice-cooling, compound 45b (5.0 g, 23.3 mmol) was dissolved in 5 mL of water, potassium hydroxide (5.2 g, 93.2 mmol) was added, and the reaction was stirred at room temperature for 16 hours. Add 20 mL of water to the reaction solution, adjust the pH to 2-3 with concentrated hydrochloric acid, filter to obtain a solid, and dry the solid to obtain the title product 2-(5-nitrothiophen-3-yl)acetic acid 45c (3.5 g), the yield: 77.2%.
MS：m/z(ESI):188.2[M+1]MS: m/z(ESI):188.2[M+1]
第三步third step
N-(4-甲氧基苄基)-2-(5-硝基噻吩-3-基)乙酰胺N-(4-methoxybenzyl)-2-(5-nitrothiophen-3-yl)acetamide
将化合物45c(3.5g，18.7mmol)溶解于5mL二氯甲烷中，加入N,N'-羰基二咪唑(4.5g，28.1mmol)和4-二甲氨基吡啶(68mg，0.56mmol)，室温下搅拌反应16小时，对甲氧基苄胺(2.6g，18.7mmol)加入反应液，室温下搅拌反应2小时。向反应液中加入20mL水，用浓盐酸调节pH至2～3，过滤得固体，固体干燥得到标题产物N-(4-甲氧基苄基)-2-(5-硝基噻吩-3-基)乙酰胺45d(4.3g)，产率：75.2％。Compound 45c (3.5g, 18.7mmol) was dissolved in 5mL of dichloromethane, N,N'-carbonyldiimidazole (4.5g, 28.1mmol) and 4-dimethylaminopyridine (68mg, 0.56mmol) were added, at room temperature The reaction was stirred for 16 hours, p-methoxybenzylamine (2.6 g, 18.7 mmol) was added to the reaction solution, and the reaction was stirred at room temperature for 2 hours. Add 20 mL of water to the reaction solution, adjust the pH to 2-3 with concentrated hydrochloric acid, filter to obtain a solid, and dry the solid to obtain the title product N-(4-methoxybenzyl)-2-(5-nitrothiophene-3- base) Acetamide 45d (4.3 g), Yield: 75.2%.
MS：m/z(ESI):307.2[M+1]MS: m/z(ESI):307.2[M+1]
第四步the fourth step
2-氯-5-氟-N-(4-甲氧基苄基)-N-(2-(5-硝基噻吩-3-基)乙酰基)苯甲酰胺2-Chloro-5-fluoro-N-(4-methoxybenzyl)-N-(2-(5-nitrothiophen-3-yl)acetyl)benzamide
将化合物45d(4.0g，13.1mmol)溶解于10mL四氢呋喃中，加入氢化钠(0.63g，26.2mmol)，室温下搅拌反应2小时，2-氯-5-氟苯甲酰氯(3.8g，19.6mmol)加入反应液，室温下搅拌反应2小时。向反应液中加入20mL水，用浓盐酸调节pH至2～3，过滤得固体，固体干燥得到标题产物2-氯-5-氟-N-(4-甲氧基苄基)-N-(2-(5-硝基噻吩-3-基)乙酰基)苯甲酰胺45e(4.3g)，产率：75.2％。Compound 45d (4.0g, 13.1mmol) was dissolved in 10mL of tetrahydrofuran, sodium hydride (0.63g, 26.2mmol) was added, and the reaction was stirred at room temperature for 2 hours, 2-chloro-5-fluorobenzoyl chloride (3.8g, 19.6mmol ) was added to the reaction solution, and the reaction was stirred at room temperature for 2 hours. Add 20 mL of water to the reaction solution, adjust the pH to 2-3 with concentrated hydrochloric acid, filter to obtain a solid, and dry the solid to obtain the title product 2-chloro-5-fluoro-N-(4-methoxybenzyl)-N-( 2-(5-Nitrothiophen-3-yl)acetyl)benzamide 45e (4.3 g), yield: 75.2%.
MS：m/z(ESI):463.2[M+1]MS: m/z(ESI):463.2[M+1]
第五步the fifth step
4-(2-氯-5-氟苯基)-4-羟基-5-(4-甲氧基苄基)-3-硝基-4,5-二氢噻吩[3,4-c]吡啶-6(7H)-酮4-(2-Chloro-5-fluorophenyl)-4-hydroxy-5-(4-methoxybenzyl)-3-nitro-4,5-dihydrothiophene[3,4-c]pyridine -6(7H)-one
将化合物45e(4.0g，8.6mmol)溶解于10mL四氢呋喃中，反应液冷却至-50℃，加入双三甲基硅基胺基锂(1.0M,12.9mL)，-50℃下搅拌反应3小时。向反应液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4-(2-氯-5-氟苯基)-4-羟基-5-(4-甲氧基苄基)-3-硝基-4,5-二氢噻吩[3,4-c]吡啶-6(7H)-酮45f(1.0g)，产率：25.2％。Compound 45e (4.0 g, 8.6 mmol) was dissolved in 10 mL of tetrahydrofuran, the reaction solution was cooled to -50 °C, lithium bistrimethylsilylamide (1.0 M, 12.9 mL) was added, and the reaction was stirred at -50 °C for 3 hours . Add 20 mL of water to the reaction solution, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography with eluent system B to give the title product 4-(2-chloro-5-fluorophenyl)-4-hydroxy-5-(4-methoxybenzyl)-3-nitrate Dihydrothiophene[3,4-c]pyridin-6(7H)-one 45f (1.0 g), yield: 25.2%.
MS：m/z(ESI):463.2[M+1]MS: m/z(ESI):463.2[M+1]
第六步step six
4-(2-氯-5-氟苯基)-5-(4-甲氧基苄基)-3-硝基-4,5-二氢噻吩[3,4-c]吡啶-6(7H)-酮4-(2-Chloro-5-fluorophenyl)-5-(4-methoxybenzyl)-3-nitro-4,5-dihydrothiophene[3,4-c]pyridine-6(7H )-ketone
将化合物45f(1.0g，2.1mmol)溶解于5mL二氯甲烷中，加入三乙基硅烷(2.4g,21mL)和三氟化硼***(0.9g，6.3mmol)，40℃下搅拌反应16小时。向反应液中加入20mL水，用饱和碳酸氢钠调节pH至7～8，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4-(2-氯-5-氟苯基)-5-(4-甲氧基苄基)-3-硝基-4,5-二氢噻吩[3,4-c]吡啶-6(7H)-酮45g(0.9g)，产率：96.2％。Compound 45f (1.0g, 2.1mmol) was dissolved in 5mL of dichloromethane, triethylsilane (2.4g, 21mL) and boron trifluoride ether (0.9g, 6.3mmol) were added, and the reaction was stirred at 40°C for 16 hours . Add 20mL of water to the reaction solution, adjust the pH to 7-8 with saturated sodium bicarbonate, extract with dichloromethane (15mL×3), combine the organic phases, wash with saturated sodium chloride solution (50mL×2), anhydrous sulfuric acid Dry over sodium, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue by column chromatography on silica gel with eluent system B to give the title product 4-(2-chloro-5-fluorophenyl)-5-(4-methoxy benzyl)-3-nitro-4,5-dihydrothiophene[3,4-c]pyridin-6(7H)-one 45g (0.9g), yield: 96.2%.
MS：m/z(ESI):447.2[M+1]MS: m/z(ESI):447.2[M+1]
第七步step seven
3-氨基-4-(2-氯-5-氟苯基)-5-(4-甲氧基苄基)-4,5-二氢噻吩[3,4-c]吡啶-6(7H)-酮3-amino-4-(2-chloro-5-fluorophenyl)-5-(4-methoxybenzyl)-4,5-dihydrothiophene[3,4-c]pyridine-6(7H) -ketone
将化合物45g(0.9g，2.01mmol)溶解于5mL甲醇和2mL水中，随后将还原铁粉(0.56g，10.1mmol)，氯化铵(0.54g，10.1mmol)加入反应液，100℃下搅拌反应3小时。反应液过滤，甲醇(5mL×3)洗涤滤饼,滤液浓缩。向滤液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱 剂体系B纯化所得残余物，得到标题产物3-氨基-4-(2-氯-5-氟苯基)-5-(4-甲氧基苄基)-4,5-二氢噻吩[3,4-c]吡啶-6(7H)-酮45h(0.65g)，产率：78.3％。Compound 45g (0.9g, 2.01mmol) was dissolved in 5mL of methanol and 2mL of water, then reduced iron powder (0.56g, 10.1mmol), ammonium chloride (0.54g, 10.1mmol) was added to the reaction solution, and the reaction was stirred at 100°C 3 hours. The reaction solution was filtered, the filter cake was washed with methanol (5 mL×3), and the filtrate was concentrated. Add 20 mL of water to the filtrate, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by chromatography with eluent system B to give the title product 3-amino-4-(2-chloro-5-fluorophenyl)-5-(4-methoxybenzyl)-4,5- Dihydrothiophene[3,4-c]pyridin-6(7H)-one 45h (0.65g), yield: 78.3%.
MS：m/z(ESI):417.2[M+1]MS: m/z(ESI):417.2[M+1]
第八步eighth step
N-(4-(2-氯-5-氟苯基)-5-(4-甲氧基苄基)-6-氧基-4,5,6,7-四氢噻吩[3,4-c]吡啶-3-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(4-(2-chloro-5-fluorophenyl)-5-(4-methoxybenzyl)-6-oxyl-4,5,6,7-tetrahydrothiophene[3,4- c] pyridin-3-yl)-3-fluoro-5-(trifluoromethyl)benzamide
将化合物45h(0.65g，1.56mmol)，3-氟-5-(三氟甲基)苯甲酸(0.38g，1.87mmol)，N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(1.78g，4.68mmol)溶解于5mL二氯甲烷中，随后将三乙胺(0.48g，4.68mmol)加入反应液,室温下搅拌反应3小时。向滤液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物N-(4-(2-氯-5-氟苯基)-5-(4-甲氧基苄基)-6-氧基-4,5,6,7-四氢噻吩[3,4-c]吡啶-3-基)-3-氟-5-(三氟甲基)苯甲酰胺45i(0.53g)，产率：56.1％。Compound 45h (0.65g, 1.56mmol), 3-fluoro-5-(trifluoromethyl)benzoic acid (0.38g, 1.87mmol), N,N,N',N'-tetramethyl-O-( 7-Azabenzotriazol-1-yl) urea hexafluorophosphate (1.78g, 4.68mmol) was dissolved in 5mL of dichloromethane, then triethylamine (0.48g, 4.68mmol) was added to the reaction solution, at room temperature The reaction was stirred for 3 hours. Add 20 mL of water to the filtrate, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by chromatography with eluent system B to give the title product N-(4-(2-chloro-5-fluorophenyl)-5-(4-methoxybenzyl)-6-oxyl- 4,5,6,7-tetrahydrothiopheno[3,4-c]pyridin-3-yl)-3-fluoro-5-(trifluoromethyl)benzamide 45i (0.53 g), yield: 56.1 %.
MS：m/z(ESI):607.2[M+1]MS: m/z(ESI):607.2[M+1]
第九步Ninth step
N-(4-(2-氯-5-氟苯基)-6-氧代-4,5,6,7-四氢噻吩[3,4-c]吡啶-3-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(4-(2-Chloro-5-fluorophenyl)-6-oxo-4,5,6,7-tetrahydrothiophene[3,4-c]pyridin-3-yl)-3-fluoro -5-(Trifluoromethyl)benzamide
将化合物45i(0.2，0.33mmol)溶解于5mL三氟乙酸中，室温下搅拌反应3小时。反应液浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物N-(4-(2-氯-5-氟苯基)-6-氧代-4,5,6,7-四氢噻吩[3,4-c]吡啶-3-基)-3-氟-5-(三氟甲基)苯甲酰胺45(72mg)，产率：45.1％。Compound 45i (0.2, 0.33 mmol) was dissolved in 5 mL of trifluoroacetic acid, and stirred at room temperature for 3 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product N-(4-(2-chloro-5-fluorophenyl)-6-oxo-4,5,6 , 7-tetrahydrothiophene[3,4-c]pyridin-3-yl)-3-fluoro-5-(trifluoromethyl)benzamide 45 (72 mg), yield: 45.1%.
MS：m/z(ESI):487.2[M+1]MS: m/z(ESI):487.2[M+1]
实施例46-48化合物的制备参照实施例45，相应的质谱数据列于表1中。Refer to Example 45 for the preparation of the compounds of Examples 46-48, and the corresponding mass spectrometry data are listed in Table 1.
实施例49Example 49
N-(4-(2-氯-5-氟苯基)-1-甲基-6-氧代-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)-3-N-(4-(2-chloro-5-fluorophenyl)-1-methyl-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3 -base)-3- 氟-5-(三氟甲基)苯甲酰胺Fluoro-5-(trifluoromethyl)benzamide
Figure PCTCN2022136232-appb-000066
Figure PCTCN2022136232-appb-000066
Figure PCTCN2022136232-appb-000067
Figure PCTCN2022136232-appb-000067
第一步first step
3-羟基-1-甲基-1H-吡唑-5-羧酸甲酯3-Hydroxy-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester
冰浴下，将甲基肼(10g，217mmol)溶解于20mL甲醇和10mL水中，0℃下搅拌反应1小时。0℃下，将化合物49a(12g，84.5mmol)加入反应液，室温下搅拌反应16小时。向反应液中加入20mL水，过滤得固体，固体干燥得到标题产物3-羟基-1-甲基-1H-吡唑-5-羧酸甲酯49b(5.0g)，产率：37.8％。Under ice-cooling, methylhydrazine (10 g, 217 mmol) was dissolved in 20 mL of methanol and 10 mL of water, and stirred at 0° C. for 1 hour. At 0°C, compound 49a (12 g, 84.5 mmol) was added to the reaction solution, and the reaction was stirred at room temperature for 16 hours. Add 20 mL of water to the reaction solution, filter to obtain a solid, and dry the solid to obtain the title product 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester 49b (5.0 g), yield: 37.8%.
MS：m/z(ESI):157.1[M+1]MS: m/z(ESI):157.1[M+1]
第二步second step
3-氯-1-甲基-1H-吡唑-5-羧酸甲酯3-Chloro-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester
将化合物49b(5g，32.1mmol)溶解于10mLN,N-二甲基甲酰胺中。将三氯氧磷(10m)加入反应液，100℃下搅拌反应5小时。将反应液倒入20mL冰水中，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-氯-1-甲基-1H-吡唑-5-羧酸甲酯49c(2.1g)，产率：30.1％。Compound 49b (5 g, 32.1 mmol) was dissolved in 10 mL of N,N-dimethylformamide. Phosphorus oxychloride (10m) was added to the reaction solution, and the reaction was stirred at 100°C for 5 hours. The reaction solution was poured into 20 mL of ice water, extracted with dichloromethane (15 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester 49c (2.1 g), yield: 30.1%.
MS：m/z(ESI):175.0[M+1]MS: m/z(ESI):175.0[M+1]
第三步third step
4-溴-3-氯-1-甲基-1H-吡唑-5-羧酸甲酯4-Bromo-3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester
将化合物49c(2.1g，9.6mmol)溶解于10mL乙腈中，将N-溴代丁二酰亚胺(4.3g，24mmol)加入反应液，60℃下搅拌反应16小时。向反应液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4-溴-3-氯-1-甲基-1H-吡唑-5-羧酸甲酯49d(1.2g)，产率：49.6％。Compound 49c (2.1 g, 9.6 mmol) was dissolved in 10 mL of acetonitrile, N-bromosuccinimide (4.3 g, 24 mmol) was added to the reaction solution, and the reaction was stirred at 60° C. for 16 hours. Add 20 mL of water to the reaction solution, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography with eluent system B to give the title product 4-bromo-3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester 49d (1.2 g), yield: 49.6%.
MS：m/z(ESI):253.1[M+1]MS: m/z(ESI):253.1[M+1]
第四步the fourth step
3-氨基-4-溴-1-甲基-1H-吡唑-5-羧酸甲酯3-Amino-4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester
将化合物49d(1.2g，4.8mmol)溶解于10mL二氯甲烷中，将氨水(5mL)加入反应液，室温下搅拌反应5小时。向反应液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-氨基-4-溴-1-甲基-1H-吡唑-5-羧酸甲酯49e(0.8g)，产率：72.1％。Compound 49d (1.2 g, 4.8 mmol) was dissolved in 10 mL of dichloromethane, ammonia water (5 mL) was added to the reaction solution, and the reaction was stirred at room temperature for 5 hours. Add 20 mL of water to the reaction solution, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography with eluent system B to give the title product 3-amino-4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester 49e (0.8 g), yield: 72.1%.
MS：m/z(ESI):234.0[M+1]MS: m/z(ESI):234.0[M+1]
第五步the fifth step
3-乙酰氨基-4-溴-1-甲基-1H-吡唑-5-羧酸甲酯3-Acetamido-4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester
将化合物49e(0.8g，3.5mmol)溶解于5mL二氯甲烷中，将醋酸酐(1mL)加入反应液，室温下搅拌反应5小时。向反应液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-氨基-4-溴-1-甲基-1H-吡唑-5-羧酸甲酯49f(0.94g)，产率：96.9％。Compound 49e (0.8 g, 3.5 mmol) was dissolved in 5 mL of dichloromethane, acetic anhydride (1 mL) was added to the reaction solution, and the reaction was stirred at room temperature for 5 hours. Add 20 mL of water to the reaction solution, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography with eluent system B to give the title product 3-amino-4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester 49f (0.94 g), yield: 96.9%.
MS：m/z(ESI):276.1[M+1]MS: m/z(ESI):276.1[M+1]
第六步step six
3-乙酰氨基-4-溴-1-甲基-1H-吡唑-5-羧酸3-Acetamido-4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid
冰浴下，将化合物49f(0.94g，3.4mmol)溶解于5mL水中，加入氢氧化钾(0.57g，10.2mmol)，室温下搅拌反应16小时。向反应液中加入10mL水，用浓盐酸调节pH至2～3，过滤得固体，固体干燥得到标题产物3-乙酰氨基-4-溴-1-甲基-1H-吡唑-5-羧酸49g(0.86g)，产率：96.9％。Under ice-cooling, compound 49f (0.94 g, 3.4 mmol) was dissolved in 5 mL of water, potassium hydroxide (0.57 g, 10.2 mmol) was added, and the reaction was stirred at room temperature for 16 hours. Add 10 mL of water to the reaction solution, adjust the pH to 2-3 with concentrated hydrochloric acid, filter to obtain a solid, and dry the solid to obtain the title product 3-acetylamino-4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid 49g (0.86g), yield: 96.9%.
MS：m/z(ESI):262.1[M+1]MS: m/z(ESI):262.1[M+1]
第七步step seven
3-乙酰氨基-4-溴-N-(2-(叔丁胺)-1-(2-氯-5-氟苯基)-2-氧乙基)-1-甲基-1H-吡唑-5-甲酰胺3-Acetamido-4-bromo-N-(2-(tert-butylamine)-1-(2-chloro-5-fluorophenyl)-2-oxyethyl)-1-methyl-1H-pyrazole-5 -Formamide
将2-氯-5-氟苯甲醛(0.58g，3.3mmol)溶解于5mL甲醇中，依次将醋酸胺(0.2g，3.3mmol)，化合物49g(0.86g，3.3mmol)，叔丁基异氰(0.27g，3.3mmol)加入反应液，室温下搅拌反应2小时，反应液浓缩。向浓缩液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-乙酰氨基-4-溴-N-(2-(叔丁胺)-1-(2-氯-5-氟苯基)-2-氧乙基)-1-甲基-1H-吡唑-5-甲酰胺49h(1.46g)，产率：88.6％。2-Chloro-5-fluorobenzaldehyde (0.58g, 3.3mmol) was dissolved in 5mL methanol, followed by ammonium acetate (0.2g, 3.3mmol), compound 49g (0.86g, 3.3mmol), tert-butylisocyanate (0.27 g, 3.3 mmol) was added to the reaction solution, stirred and reacted at room temperature for 2 hours, and the reaction solution was concentrated. Add 20mL of water to the concentrated solution, extract with dichloromethane (15mL×3), combine the organic phases, wash with saturated sodium chloride solution (50mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography with eluent system B to give the title product 3-acetamido-4-bromo-N-(2-(tert-butylamine)-1-(2-chloro-5-fluorophenyl)-2 -Oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide 49h (1.46g), yield: 88.6%.
MS：m/z(ESI):502.1[M+1]MS: m/z(ESI):502.1[M+1]
第八步eighth step
N-(4-(2-氯-5-氟苯基)-1-甲基-6-氧代-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)乙酰胺N-(4-(2-chloro-5-fluorophenyl)-1-methyl-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3 -yl)acetamide
将化合物49h(1.46g，2.9mmol)溶解于5mL乙腈中，将2-叔丁基-1,1,3,3-四甲基胍(0.74g，4.35mmol)加入反应液，50℃下搅拌反应2小时，反应液浓缩。向浓缩液中加入10mL三氟乙酸和三乙基硅烷(1.68g，14.5mmol)，50℃下搅拌反应2小时。反应液浓缩，向浓缩液中加入20mL水用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物N-(4-(2-氯-5-氟苯基)-1-甲基-6-氧代-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)乙酰胺49i(0.45g)，产率：48.6％。Compound 49h (1.46g, 2.9mmol) was dissolved in 5mL of acetonitrile, 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.74g, 4.35mmol) was added to the reaction solution, stirred at 50°C After reacting for 2 hours, the reaction solution was concentrated. 10 mL of trifluoroacetic acid and triethylsilane (1.68 g, 14.5 mmol) were added to the concentrated solution, and the reaction was stirred at 50° C. for 2 hours. Concentrate the reaction solution, add 20 mL of water to the concentrated solution and extract with dichloromethane (15 mL×3), combine the organic phases, wash with saturated sodium chloride solution (50 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting residue was purified by silica gel column chromatography with eluent system B to afford the title product N-(4-(2-chloro-5-fluorophenyl)-1-methyl-6-oxo-1,4 , 5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)acetamide 49i (0.45 g), yield: 48.6%.
MS：m/z(ESI):323.1[M+1]MS: m/z(ESI):323.1[M+1]
第九步Ninth step
3-氨基-4-(2-氯-5-氟苯基)-1-甲基-4,5-二氢吡咯[3,4-c]吡唑-6(1H)-酮3-Amino-4-(2-chloro-5-fluorophenyl)-1-methyl-4,5-dihydropyrrole[3,4-c]pyrazol-6(1H)-one
将化合物49i(0.45g，1.4mmol)溶解于5mL盐酸/1，4-二氧六环中，90℃下搅拌反应2小时。反应液浓缩，向浓缩液中加入20mL水用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物N-(4-(2-氯-5-氟苯基)-1-甲基-6-氧代-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)乙酰胺49g(0.35g)，产率：88.6％。Compound 49i (0.45 g, 1.4 mmol) was dissolved in 5 mL of hydrochloric acid/1,4-dioxane, and stirred at 90° C. for 2 hours. Concentrate the reaction solution, add 20 mL of water to the concentrated solution and extract with dichloromethane (15 mL×3), combine the organic phases, wash with saturated sodium chloride solution (50 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting residue was purified by silica gel column chromatography with eluent system B to afford the title product N-(4-(2-chloro-5-fluorophenyl)-1-methyl-6-oxo-1,4 , 5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)acetamide 49g (0.35g), yield: 88.6%.
MS：m/z(ESI):281.1[M+1]MS: m/z(ESI):281.1[M+1]
第十步tenth step
N-(4-(2-氯-5-氟苯基)-1-甲基-6-氧代-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)-3-氟-5-(三氟甲基)苯甲酰胺N-(4-(2-chloro-5-fluorophenyl)-1-methyl-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3 -yl)-3-fluoro-5-(trifluoromethyl)benzamide
化合物49的合成方法，参考化合物41f的合成方法，以化合物49i和3-氟-5-(三氟甲基)苯甲酸为原料，得到N-(4-(2-氯-5-氟苯基)-1-甲基-6-氧代-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)-3-氟-5-(三氟甲基)苯甲酰胺49(80mg)，产率：36.2％。MS：m/z(ESI):471.1[M+1]For the synthetic method of compound 49, refer to the synthetic method of compound 41f, using compound 49i and 3-fluoro-5-(trifluoromethyl)benzoic acid as raw materials to obtain N-(4-(2-chloro-5-fluorophenyl )-1-methyl-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-3-fluoro-5-(trifluoromethyl ) benzamide 49 (80 mg), yield: 36.2%. MS: m/z(ESI):471.1[M+1]
实施例50-52化合物的制备参照实施例49，相应的质谱数据列于表1中。The compounds of Examples 50-52 were prepared with reference to Example 49, and the corresponding mass spectrum data are listed in Table 1.
实施例56Example 56
(S)-N-(6-溴-1-(2-氯-5-氟苯基)-3-氧-2,3-二氢咪唑[1,5-a]吡啶-8-基)-5-氟-3-羟基(S)-N-(6-bromo-1-(2-chloro-5-fluorophenyl)-3-oxo-2,3-dihydroimidazo[1,5-a]pyridin-8-yl)- 5-fluoro-3-hydroxyl -3-(三氟甲基)吲哚-1-甲酰胺-3-(Trifluoromethyl)indole-1-carboxamide
Figure PCTCN2022136232-appb-000068
Figure PCTCN2022136232-appb-000068
第一步first step
(5-溴-3-硝基吡啶-2-基)(2-氯-5-氟苯基)甲酮(5-Bromo-3-nitropyridin-2-yl)(2-chloro-5-fluorophenyl)methanone
冰浴下，将化合物56a(5g，22mmol)和(2-氯-5-氟苯基)硼酸(4.59g，26.4mmol)溶解于25mL四氢呋喃中，加入2,2ˊ-联吡啶(3.4g，22mmol)，氟化钾(1.3g，22mmol)，醋酸钯(0.5g，2.2mmol)和醋酸(1mL)，80℃下搅拌反应48小时。向反应液中加入20mL水，用二氯甲烷萃取(150mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(5-溴-3-硝基吡啶-2-基)(2-氯-5-氟苯基)甲酮56b(6.2g)，产率：78.2％。Under ice-cooling, compound 56a (5g, 22mmol) and (2-chloro-5-fluorophenyl) boronic acid (4.59g, 26.4mmol) were dissolved in 25mL tetrahydrofuran, and 2,2′-bipyridine (3.4g, 22mmol ), potassium fluoride (1.3g, 22mmol), palladium acetate (0.5g, 2.2mmol) and acetic acid (1mL), stirred at 80°C for 48 hours. Add 20mL of water to the reaction solution, extract with dichloromethane (150mL×3), combine the organic phases, wash with saturated sodium chloride solution (50mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography with eluent system B to give the title product (5-bromo-3-nitropyridin-2-yl)(2-chloro-5-fluorophenyl)methanone 56b (6.2 g) , Yield: 78.2%.
MS：m/z(ESI):359.0[M+1]MS: m/z(ESI):359.0[M+1]
第二步second step
(5-溴-3-硝基吡啶-2-基)(2-氯-5-氟苯基)甲胺(5-Bromo-3-nitropyridin-2-yl)(2-chloro-5-fluorophenyl)methanamine
将化合物56b(5g，13.9mmol)和盐酸羟胺(0.96g，13.9mmol)和乙酸钠(3.4g，41.7mmol)溶解于20mL四氢呋喃和20mL四氢呋喃水中，100℃下搅拌反应6小时。向反应液中加入20mL水，用二氯甲烷萃取(150mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩得残余物，残余物溶解于20mL三氟乙酸中,锌粉(2.6g，41.7mmol)加入反应液,室温下搅拌反应48小时,反应液过滤,滤液浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(5-溴-3-硝基吡啶-2-基)(2-氯-5-氟苯基)甲胺56c(2.9g)，产率：58.2％。Compound 56b (5g, 13.9mmol), hydroxylamine hydrochloride (0.96g, 13.9mmol) and sodium acetate (3.4g, 41.7mmol) were dissolved in 20mL THF and 20mL THF water, and stirred at 100°C for 6 hours. Add 20 mL of water to the reaction solution, extract with dichloromethane (150 mL×3), combine the organic phases, wash with saturated sodium chloride solution (50 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a residue , the residue was dissolved in 20 mL of trifluoroacetic acid, zinc powder (2.6 g, 41.7 mmol) was added to the reaction solution, stirred and reacted at room temperature for 48 hours, the reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography with eluent system B The resulting residue afforded the title product (5-bromo-3-nitropyridin-2-yl)(2-chloro-5-fluorophenyl)methanamine 56c (2.9 g), yield: 58.2%.
MS：m/z(ESI):360.0[M+1]MS: m/z(ESI):360.0[M+1]
第三步third step
6-溴-1-(2-氯-5-氟苯基)-8-硝基咪唑并[1,5-a]吡啶-3(2H)-酮6-Bromo-1-(2-chloro-5-fluorophenyl)-8-nitroimidazo[1,5-a]pyridin-3(2H)-one
冰浴下，将化合物56c(2.9g，8.1mmol)和三乙胺(2.6g，0.11mmol)溶解于15mL二氯甲烷中，加入三光气(0.8g，2.7mmol)，室温下搅拌反应1小时，。向反应液中加入20mL水，用二氯甲烷萃取(150mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物6-溴-1-(2-氯-5-氟苯基)-8-硝基咪唑并[1,5-a]吡啶-3(2H)-酮56d(2.4g)，产率：78.5％。Under ice-cooling, compound 56c (2.9g, 8.1mmol) and triethylamine (2.6g, 0.11mmol) were dissolved in 15mL of dichloromethane, triphosgene (0.8g, 2.7mmol) was added, and the reaction was stirred at room temperature for 1 hour ,. Add 20mL of water to the reaction solution, extract with dichloromethane (150mL×3), combine the organic phases, wash with saturated sodium chloride solution (50mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography with eluent system B to give the title product 6-bromo-1-(2-chloro-5-fluorophenyl)-8-nitroimidazo[1,5-a]pyridine- 3(2H)-Kone 56d (2.4 g), Yield: 78.5%.
MS：m/z(ESI):386.0[M+1]MS: m/z(ESI):386.0[M+1]
第四步the fourth step
8-氨基-6-溴-1-(2-氯-5-氟苯基)咪唑并[1,5-a]吡啶-3(2H)-酮8-Amino-6-bromo-1-(2-chloro-5-fluorophenyl)imidazo[1,5-a]pyridin-3(2H)-one
将化合物56d(2.0g，5.2mmol)溶解于10mL甲醇和4mL水中，随后将还原铁粉(1.5g，26mmol)，氯化铵(1.4g，18.25mmol)加入反应液，100℃下搅拌反应3小时。反应液过滤，甲醇(15mL×3)洗涤滤饼，滤液浓缩。向滤液中加入20mL水，用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-2H-吲唑-4-胺56e(1.12g)，产率：60.3％。Compound 56d (2.0g, 5.2mmol) was dissolved in 10mL of methanol and 4mL of water, then reduced iron powder (1.5g, 26mmol), ammonium chloride (1.4g, 18.25mmol) was added to the reaction solution, and the reaction was stirred at 100°C. Hour. The reaction solution was filtered, the filter cake was washed with methanol (15 mL×3), and the filtrate was concentrated. Add 20 mL of water to the filtrate, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by chromatography with eluent system B to give the title product 3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2H-indazol-4-amine 56e (1.12g), yield: 60.3%.
MS：m/z(ESI):356.0[M+1]MS: m/z(ESI):356.0[M+1]
第五步the fifth step
(S)-N-(6-溴-1-(2-氯-5-氟苯基)-3-氧-2,3-二氢咪唑[1,5-a]吡啶-8-基)-3-羟基-3-(三氟甲基)吲哚-1-甲酰胺(S)-N-(6-bromo-1-(2-chloro-5-fluorophenyl)-3-oxo-2,3-dihydroimidazo[1,5-a]pyridin-8-yl)- 3-Hydroxy-3-(trifluoromethyl)indole-1-carboxamide
冰浴下，将化合物56e(0.2g，0.56mmol)和三乙胺(1.2g，1.12mmol)溶解于5mL二氯甲烷中，加入三光气(56mg，0.19mmol)，室温下搅拌反应1小时，向反应液中加入((S)-5-氟-3-(三氟甲基)吲哚-3-醇(80mg，0.56mmol)，室温下搅拌反应2小时。向反应液中加入20mL水，用二氯甲烷萃取(150mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(S)-N-(6-溴-1-(2-氯-5-氟苯基)-3-氧-2,3-二氢咪唑[1,5-a]吡啶-8-基)-3-羟基-3-(三氟甲基)吲哚-1-甲酰胺56(0.18g)，产率：55.2％。Under ice-cooling, compound 56e (0.2g, 0.56mmol) and triethylamine (1.2g, 1.12mmol) were dissolved in 5mL of dichloromethane, triphosgene (56mg, 0.19mmol) was added, and the reaction was stirred at room temperature for 1 hour, ((S)-5-fluoro-3-(trifluoromethyl)indol-3-ol (80 mg, 0.56 mmol) was added to the reaction liquid, and the reaction was stirred at room temperature for 2 hours. 20 mL of water was added to the reaction liquid, Extract with dichloromethane (150mL×3), combine the organic phases, wash with saturated sodium chloride solution (50mL×2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography to eluent system Purification of the resulting residue in B afforded the title product (S)-N-(6-bromo-1-(2-chloro-5-fluorophenyl)-3-oxo-2,3-dihydroimidazol[1,5- a] Pyridin-8-yl)-3-hydroxy-3-(trifluoromethyl)indole-1-carboxamide 56 (0.18 g), yield: 55.2%.
MS：m/z(ESI):603.0[M+1]MS: m/z(ESI):603.0[M+1]
实施例53-55化合物的制备参照实施例56，相应的质谱数据列于表1中。Refer to Example 56 for the preparation of the compounds of Examples 53-55, and the corresponding mass spectrometry data are listed in Table 1.
实施例57Example 57
9-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-8,9-二氢-7H-吡咯[3,4-h]喹9-(2-Chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-8,9-dihydro-7H-pyrrole[3,4-h] Quinoa 唑啉-7-酮Azolin-7-one
Figure PCTCN2022136232-appb-000069
Figure PCTCN2022136232-appb-000069
第一步first step
4-溴-N-(2-(叔丁胺)-1-(2-氯-4-氟苯基)-2-氧乙基)-2-氟-N-(4-甲氧基苄基)-3-硝基苯甲酰胺4-bromo-N-(2-(tert-butylamine)-1-(2-chloro-4-fluorophenyl)-2-oxyethyl)-2-fluoro-N-(4-methoxybenzyl)- 3-nitrobenzamide
将2-氯-4-氟苯甲醛(6.0g，38.0mmol)和对甲氧基苄胺(5.2g，38.0mmol)溶解在150mL甲醇中，加入4-溴-2-氟-3-硝基苯甲酸(10g，38.0mmol)和叔丁基异氰(3.2g，38.0mmol)，氮气保护下室温反应3小时。反应液过滤，滤饼少量甲醇洗涤，干燥，得到标题产物4-溴-N-(2-(叔丁胺)-1-(2-氯-4-氟苯基)-2-氧乙基)-2-氟-N-(4-甲氧基苄基)-3-硝基苯甲酰胺57a(19.6g)，产率：82.7％。2-Chloro-4-fluorobenzaldehyde (6.0 g, 38.0 mmol) and p-methoxybenzylamine (5.2 g, 38.0 mmol) were dissolved in 150 mL of methanol, and 4-bromo-2-fluoro-3-nitro Benzoic acid (10 g, 38.0 mmol) and tert-butyl isocyanide (3.2 g, 38.0 mmol) were reacted at room temperature for 3 hours under nitrogen protection. The reaction solution was filtered, the filter cake was washed with a small amount of methanol, and dried to obtain the title product 4-bromo-N-(2-(tert-butylamine)-1-(2-chloro-4-fluorophenyl)-2-oxyethyl)-2 -Fluoro-N-(4-methoxybenzyl)-3-nitrobenzamide 57a (19.6 g), yield: 82.7%.
MS m/z(ESI):624.1[M+1]MS m/z(ESI):624.1[M+1]
第二步second step
5-溴-3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧基苄基)-4-硝基异吲哚-1-酮5-Bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitroisoindol-1-one
将4-溴-N-(2-(叔丁胺)-1-(2-氯-4-氟苯基)-2-氧乙基)-2-氟-N-(4-甲氧基苄基)-3-硝基苯甲酰胺(19.6g，31.4mmol)溶解在100mL乙腈中，加入2-叔丁基-1,1,3,3-四甲基胍(8.1g，47.1mmol)，50℃反应2小时。反应液冷却至室温，减压浓缩，加入100mL乙酸乙酯，依次用水(100mL*2)、饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物5-溴-3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧基苄基)-4-硝基异吲哚-1-酮57b(16.3g)，直接用于下步反应。4-bromo-N-(2-(tert-butylamine)-1-(2-chloro-4-fluorophenyl)-2-oxoethyl)-2-fluoro-N-(4-methoxybenzyl) -3-Nitrobenzamide (19.6g, 31.4mmol) was dissolved in 100mL of acetonitrile, added 2-tert-butyl-1,1,3,3-tetramethylguanidine (8.1g, 47.1mmol), 50°C React for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added 100 mL of ethyl acetate, washed with water (100 mL*2) and saturated sodium chloride solution (100 mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product title Product 5-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxyl-2-(4-methoxybenzyl)-4-nitroisoindol-1-one 57b (16.3g ), used directly in the next reaction.
MS m/z(ESI):521.0[M+1]MS m/z(ESI):521.0[M+1]
第三步third step
5-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基异吲哚-1-酮5-Bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitroisoindol-1-one
将5-溴-3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧基苄基)-4-硝基异吲哚-1-酮57b(16.3g，31.3mmol)溶解在100mL三氟甲酸中，加入三乙基硅烷(14.5g，125mmol)，90℃反应4小时。反应液冷却至室温，减压浓缩，得到粗品标题产物5-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基异吲哚-1-酮57c(15.8g)，直接用于下步反应。5-Bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitroisoindol-1-one 57b (16.3g , 31.3mmol) was dissolved in 100mL trifluoroformic acid, triethylsilane (14.5g, 125mmol) was added, and reacted at 90°C for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude title product 5-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitroisoind Indol-1-one 57c (15.8g) was directly used in the next reaction.
MS m/z(ESI):505.0[M+1]MS m/z(ESI):505.0[M+1]
第四步the fourth step
4-氨基-5-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)异吲哚-1-酮4-amino-5-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)isoindol-1-one
将5-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-4-硝基异吲哚-1-酮(15.8g，31.3mmol)和氯化铵(6.6g，125mmol)溶解在150mL乙醇和乙酸的混合溶液(20：1)中，加热至50℃，缓慢分批加入铁粉(7.0g，31.3mmol)，继续反应2小时。反应液冷却至室温，硅藻土过滤，滤液减压浓缩，加入100mL乙酸乙酯。依次用水(100mL)、饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4-氨基-5-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)异吲哚-1-酮57d(9.5g)，产率：63.9％。5-Bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitroisoindol-1-one (15.8g, 31.3mmol) and Ammonium chloride (6.6g, 125mmol) was dissolved in 150mL of a mixed solution of ethanol and acetic acid (20:1), heated to 50°C, iron powder (7.0g, 31.3mmol) was slowly added in batches, and the reaction was continued for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and 100 mL of ethyl acetate was added. Washed with water (100mL) and saturated sodium chloride solution (100mL) successively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 4- Amino-5-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)isoindol-1-one 57d (9.5 g), yield: 63.9%.
MS m/z(ESI):475.0[M+1]MS m/z(ESI):475.0[M+1]
第五步the fifth step
4-氨基-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-1-氧异喹啉-5-碳醛4-amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoquinoline-5-carbaldehyde
将4-氨基-5-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)异吲哚-1-酮57d(9.5g，20.0mmol)溶解在100mL四氢呋喃中，氮气保护下冷却至-78℃，滴加正丁基锂的正己烷溶液(20mL，2.5M，50.0mmol)，搅拌30分钟，加入N,N-二甲基甲酰胺(7.3g，100mmol)，搅拌1小时。反应液中加入100mL饱和氯化胺，缓慢升至室温后乙酸乙酯萃取(100mL*2)。合并有机相，依次用水(100mL)、饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4-氨基-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-1-氧异喹啉-5-碳醛57e(6.1g)，产率：71.8％。4-Amino-5-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)isoindol-1-one 57d (9.5 g, 20.0 mmol) was dissolved In 100mL of tetrahydrofuran, cooled to -78°C under the protection of nitrogen, a n-hexane solution of n-butyllithium (20mL, 2.5M, 50.0mmol) was added dropwise, stirred for 30 minutes, N,N-dimethylformamide (7.3 g, 100mmol), stirred for 1 hour. Add 100 mL of saturated ammonium chloride to the reaction solution, slowly warm to room temperature, and then extract with ethyl acetate (100 mL*2). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain The title product 4-amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoquinoline-5-carbaldehyde 57e (6.1 g), yielding Rate: 71.8%.
MS m/z(ESI):425.1[M+1]MS m/z(ESI):425.1[M+1]
第六步step six
9-(2-氯-5-氟苯基)-2-羟基-8-(4-甲氧基苄基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮9-(2-Chloro-5-fluorophenyl)-2-hydroxy-8-(4-methoxybenzyl)-8,9-dihydro-7H-pyrrolo[3,4-h]quinazoline -7-one
将4-氨基-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-1-氧异喹啉-5-碳醛57e(6.1g，14.4mmol)溶解在60mL四氢呋喃中，冰浴下加入三光气(1.33g，4.78mmol)，0℃反应4小时。加入氨气的甲醇溶液(20.6mL，144mmol)，缓慢升 至室温反应16小时。反应液减压浓缩，得到粗品标题产物9-(2-氯-5-氟苯基)-2-羟基-8-(4-甲氧基苄基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮57f(6.48g)，直接用于下步反应。4-Amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoquinoline-5-carbaldehyde 57e (6.1g, 14.4mmol) Dissolve in 60mL tetrahydrofuran, add triphosgene (1.33g, 4.78mmol) under ice-cooling, and react at 0°C for 4 hours. A methanol solution of ammonia gas (20.6 mL, 144 mmol) was added, and the reaction was slowly raised to room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title product 9-(2-chloro-5-fluorophenyl)-2-hydroxy-8-(4-methoxybenzyl)-8,9-dihydro-7H-pyrrole [3,4-h]quinazolin-7-one 57f (6.48g) was directly used in the next reaction.
MS m/z(ESI):450.1[M+1]MS m/z(ESI):450.1[M+1]
第七步step seven
2-氯-9-(2-氯-5-氟苯基)-8-(4-甲氧基苄基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮2-Chloro-9-(2-chloro-5-fluorophenyl)-8-(4-methoxybenzyl)-8,9-dihydro-7H-pyrrolo[3,4-h]quinazoline -7-one
将9-(2-氯-5-氟苯基)-2-羟基-8-(4-甲氧基苄基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮57f(6.48g，14.4mmol)溶解在30mL甲苯中，加入***(11.0g，72.0mmol)，100℃反应1小时。反应液倒入100mL饱和碳酸氢钠溶液中，乙酸乙酯萃取(100mL*2)。合并有机相，依次用水(100mL)、饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-氯-9-(2-氯-5-氟苯基)-8-(4-甲氧基苄基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮57g(2.6g)，产率：38.6％。9-(2-Chloro-5-fluorophenyl)-2-hydroxy-8-(4-methoxybenzyl)-8,9-dihydro-7H-pyrrole[3,4-h]quinazole Lin-7-one 57f (6.48g, 14.4mmol) was dissolved in 30mL of toluene, phosphorus oxychloride (11.0g, 72.0mmol) was added, and reacted at 100°C for 1 hour. The reaction solution was poured into 100 mL saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL*2). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain The title product 2-chloro-9-(2-chloro-5-fluorophenyl)-8-(4-methoxybenzyl)-8,9-dihydro-7H-pyrrolo[3,4-h]quinone Azolin-7-one 57g (2.6g), yield: 38.6%.
MS m/z(ESI):468.1[M+1]MS m/z(ESI):468.1[M+1]
第八步eighth step
9-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮9-(2-Chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-8,9-dihydro-7H-pyrrole[3,4-h] Quinazolin-7-one
将2-氯-9-(2-氯-5-氟苯基)-8-(4-甲氧基苄基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮57g(100mg，0.206mmol)溶解在3mL1，4-二氧六环和水(4：1)的混合溶剂中，加入3-氟-5-三氟甲基苯硼酸(86mg，0.412mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(17mg，0.0206mmol)和磷酸钾(131mg，0.617mmol)，氮气保护下100℃反应2小时。反应液冷却至室温，倒入30mL水中，乙酸乙酯萃取(30mL*2)。合并有机相，依次用水(30mL)、饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物9-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮57h(80mg)，产率：63.0％。2-chloro-9-(2-chloro-5-fluorophenyl)-8-(4-methoxybenzyl)-8,9-dihydro-7H-pyrrole[3,4-h]quinazole Lin-7-one 57g (100mg, 0.206mmol) was dissolved in 3mL of a mixed solvent of 1,4-dioxane and water (4:1), and 3-fluoro-5-trifluoromethylphenylboronic acid (86mg, 0.412mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (17mg, 0.0206mmol) and potassium phosphate (131mg, 0.617mmol), under nitrogen protection React at 100°C for 2 hours. The reaction solution was cooled to room temperature, poured into 30 mL of water, and extracted with ethyl acetate (30 mL*2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain The title product 9-(2-chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-8,9-dihydro-7H-pyrrole[3,4- h] Quinazolin-7-one 57h (80 mg), yield: 63.0%.
MS m/z(ESI):596.1[M+1]MS m/z(ESI):596.1[M+1]
第九步Ninth step
9-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮9-(2-Chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-8,9-dihydro-7H-pyrrole[3,4-h] Quinazolin-7-one
实施例57的合成方法参考实施例1中的第九步的合成方法，以实施例57h为原料得到实施例57(23mg)，产率：36.0％。The synthesis method of Example 57 was referred to the synthesis method of the ninth step in Example 1, and Example 57 (23 mg) was obtained by using Example 57h as a raw material, and the yield was 36.0%.
MS m/z(ESI):476.0[M+1]MS m/z(ESI):476.0[M+1]
实施例58Example 58
9-(2-氯-5-氟苯基)-2-((S)-5-氟-3-羟基吲哚-1-基)-8,9-二氢-7H-吡咯[3,4-h]9-(2-Chloro-5-fluorophenyl)-2-((S)-5-fluoro-3-oxindol-1-yl)-8,9-dihydro-7H-pyrrole[3,4 -h] 喹唑啉-7-酮Quinazolin-7-one
Figure PCTCN2022136232-appb-000070
Figure PCTCN2022136232-appb-000070
第一步first step
9-(2-氯-5-氟苯基)-2-((S)-5-氟-3-羟基吲哚-1-基)-8-(4-甲氧基苄基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮9-(2-Chloro-5-fluorophenyl)-2-((S)-5-fluoro-3-oxindol-1-yl)-8-(4-methoxybenzyl)-8, 9-Dihydro-7H-pyrrole[3,4-h]quinazolin-7-one
将2-氯-9-(2-氯-5-氟苯基)-8-(4-甲氧基苄基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮57g(100mg，0.214mmol)溶解在3mLN,N-二甲基甲酰胺中，加入(S)-5-氟吲哚-3-醇(39mg，0.256mmol)和碳酸铯(139mg，0.427mmol)，80℃反应2小时。反应液冷却至室温，倒入30mL水中，乙酸乙酯萃取(30mL*2)。合并有机相，依次用水(30mL)、饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物9-(2-氯-5-氟苯基)-2-((S)-5-氟-3-羟基吲哚-1-基)-8-(4-甲氧基苄基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮58a(90mg)，产率：72.0％。2-chloro-9-(2-chloro-5-fluorophenyl)-8-(4-methoxybenzyl)-8,9-dihydro-7H-pyrrole[3,4-h]quinazole Lin-7-one 57g (100mg, 0.214mmol) was dissolved in 3mL N,N-dimethylformamide, and (S)-5-fluoroindol-3-ol (39mg, 0.256mmol) and cesium carbonate (139mg , 0.427mmol), reacted at 80°C for 2 hours. The reaction solution was cooled to room temperature, poured into 30 mL of water, and extracted with ethyl acetate (30 mL*2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain The title product 9-(2-chloro-5-fluorophenyl)-2-((S)-5-fluoro-3-oxindol-1-yl)-8-(4-methoxybenzyl)- 8,9-Dihydro-7H-pyrrole[3,4-h]quinazolin-7-one 58a (90 mg), yield: 72.0%.
MS m/z(ESI):585.1[M+1]MS m/z(ESI):585.1[M+1]
第二步second step
9-(2-氯-5-氟苯基)-2-((S)-5-氟-3-羟基吲哚-1-基)-8,9-二氢-7H-吡咯[3,4-h]喹唑啉-7-酮9-(2-Chloro-5-fluorophenyl)-2-((S)-5-fluoro-3-oxindol-1-yl)-8,9-dihydro-7H-pyrrole[3,4 -h]quinazolin-7-one
实施例58的合成方法参考实施例1中的第九步的合成方法，以实施例58a为原料得到实施例58(17mg)，产率：23.8％。The synthesis method of Example 58 was referred to the synthesis method of the ninth step in Example 1, and Example 58 (17 mg) was obtained from Example 58a with a yield of 23.8%.
MS m/z(ESI):465.1[M+1]MS m/z(ESI):465.1[M+1]
实施例59化合物的制备参照实施例58，相应的质谱数据列于表1中。The preparation of the compound of Example 59 refers to Example 58, and the corresponding mass spectrometry data are listed in Table 1.
实施例60Example 60
8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7,8-二氢咪唑并[4,5-e]异吲8-(2-Chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-7,8-dihydroimidazo[4,5-e]isoindol 哚-6(1H)-酮Indol-6(1H)-one
Figure PCTCN2022136232-appb-000071
Figure PCTCN2022136232-appb-000071
第一步first step
6-氟-2-(3-氟-5-(三氟甲基)苯基)-1H-苯并[d]咪唑-7-羧酸乙酯6-Fluoro-2-(3-fluoro-5-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-7-carboxylic acid ethyl ester
将化合物60a(5.0g，25.3mmol)和3-氟-5-(三氟甲基)苯甲醛(4.8g，25.3mmol)溶解于15mL 1，4-二氧六环中，三氟甲磺酸钪(1.2g，2.5mmol)加入反应液,100℃下搅拌反应2小时。反应液浓缩，向浓缩液中加入20mL水用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物6-氟-2-(3-氟-5-(三氟甲基)苯基)-1H-苯并[d]咪唑-7-羧酸乙酯60b(7.4g)，产率：78.6％。Compound 60a (5.0 g, 25.3 mmol) and 3-fluoro-5-(trifluoromethyl)benzaldehyde (4.8 g, 25.3 mmol) were dissolved in 15 mL of 1,4-dioxane, trifluoromethanesulfonic acid Scandium (1.2 g, 2.5 mmol) was added to the reaction solution, and the reaction was stirred at 100° C. for 2 hours. Concentrate the reaction solution, add 20 mL of water to the concentrated solution and extract with dichloromethane (15 mL×3), combine the organic phases, wash with saturated sodium chloride solution (50 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting residue was purified by silica gel column chromatography with eluent system B to afford the title product 6-fluoro-2-(3-fluoro-5-(trifluoromethyl)phenyl)-1H-benzo[d] Ethyl imidazole-7-carboxylate 60b (7.4 g), yield: 78.6%.
MS：m/z(ESI):371.1[M+1]MS: m/z(ESI):371.1[M+1]
第二步second step
6-氟-2-(3-氟-5-(三氟甲基)苯基)-1H-苯并[d]咪唑-7-羧酸6-fluoro-2-(3-fluoro-5-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-7-carboxylic acid
冰浴下，将化合物60b(7.4g，20mmol)溶解于5mL水中，加入氢氧化钾(2.2g，40mmol)，室温下搅拌反应16小时。向反应液中加入20mL水，用浓盐酸调节pH至2～3，过滤得固体，固体干燥得到标题产物6-氟-2-(3-氟-5-(三氟甲基)苯基)-1H-苯并[d]咪唑-7-羧酸60c(5.3g)，产率：77.2％。Under ice-cooling, compound 60b (7.4 g, 20 mmol) was dissolved in 5 mL of water, potassium hydroxide (2.2 g, 40 mmol) was added, and the reaction was stirred at room temperature for 16 hours. Add 20 mL of water to the reaction solution, adjust the pH to 2-3 with concentrated hydrochloric acid, filter to obtain a solid, and dry the solid to obtain the title product 6-fluoro-2-(3-fluoro-5-(trifluoromethyl)phenyl)- 1H-Benzo[d]imidazole-7-carboxylic acid 60c (5.3 g), yield: 77.2%.
MS：m/z(ESI):343.0[M+1]MS: m/z(ESI):343.0[M+1]
第三步third step
N-(2-(叔丁基氨基)-1-(2-氯-5-氟苯基)-2-氧乙基)-6-氟-2-(3-氟-5-(三氟甲基)苯基)-1H-苯并[d]咪唑-7-甲酰胺N-(2-(tert-butylamino)-1-(2-chloro-5-fluorophenyl)-2-oxoethyl)-6-fluoro-2-(3-fluoro-5-(trifluoromethyl Base) phenyl) -1H-benzo [d] imidazole-7-carboxamide
化合物60d的合成方法，参考化合物49h的合成方法，以化合物60c为原料，得到N-(2-(叔丁基氨基)-1-(2-氯-5-氟苯基)-2-氧乙基)-6-氟-2-(3-氟-5-(三氟甲基)苯基)-1H-苯并[d]咪唑-7-甲酰胺60d(7.8g)，产率：86.6％。For the synthesis method of compound 60d, refer to the synthesis method of compound 49h, and use compound 60c as a raw material to obtain N-(2-(tert-butylamino)-1-(2-chloro-5-fluorophenyl)-2-oxoethane yl)-6-fluoro-2-(3-fluoro-5-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-7-carboxamide 60d (7.8g), yield: 86.6% .
MS：m/z(ESI):583.1[M+1]MS: m/z(ESI):583.1[M+1]
第四步the fourth step
8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7,8-二氢咪唑并[4,5-e]异吲哚-6(1H)-酮8-(2-Chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-7,8-dihydroimidazo[4,5-e]isoindol Indol-6(1H)-one
化合物60的合成方法，参考化合物49i的合成方法，以化合物60d为原料，得到8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7,8-二氢咪唑并[4,5-e]异吲哚-6(1H)-酮60(0.2g)，产率：36.2％。For the synthesis method of compound 60, refer to the synthesis method of compound 49i, and use compound 60d as a raw material to obtain 8-(2-chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)benzene yl)-7,8-dihydroimidazo[4,5-e]isoindol-6(1H)-one 60 (0.2 g), yield: 36.2%.
MS：m/z(ESI):464.0[M+1]MS: m/z(ESI):464.0[M+1]
实施例61Example 61
8-(2-氯-5-氟苯基)-2-((S)-5-氟-3-羟基吲哚-1-基)-7,8-二氢咪唑[4,5-e]异吲哚8-(2-Chloro-5-fluorophenyl)-2-((S)-5-fluoro-3-oxindol-1-yl)-7,8-dihydroimidazol[4,5-e] Isoindole -6(1H)-酮-6(1H)-one
Figure PCTCN2022136232-appb-000072
Figure PCTCN2022136232-appb-000072
第一步first step
5-氟-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-羧酸乙酯5-Fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylic acid ethyl ester
将化合物61a(5.0g，25.3mmol)和N,N'-羰基二咪唑(4.1g，25.3mmol)溶解于15mL四氢呋喃中,80℃下搅拌反应16小时。反应液浓缩，向浓缩液中加入20mL水用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物5-氟-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-羧酸乙酯61b(2.2g)，产率：38.6％。Compound 61a (5.0 g, 25.3 mmol) and N,N'-carbonyldiimidazole (4.1 g, 25.3 mmol) were dissolved in 15 mL of tetrahydrofuran, and stirred at 80° C. for 16 hours. Concentrate the reaction solution, add 20 mL of water to the concentrated solution and extract with dichloromethane (15 mL×3), combine the organic phases, wash with saturated sodium chloride solution (50 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting residue was purified by silica gel column chromatography with eluent system B to afford the title product ethyl 5-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate Ester 61b (2.2 g), yield: 38.6%.
MS：m/z(ESI):225.1[M+1]MS: m/z(ESI):225.1[M+1]
第二步second step
2-氯-6-氟-1H-苯并[d]咪唑-7-羧酸乙酯2-Chloro-6-fluoro-1H-benzo[d]imidazole-7-carboxylic acid ethyl ester
将化合物61b(2.0g，8.9mmol)溶解于15mL三氯氧磷中,100℃下搅拌反应16小时。反应液浓缩，向浓缩液中加入20mL水用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-氯-6-氟-1H-苯并[d]咪唑-7-羧酸乙酯61c(1.9g)，产率：88.6％。Compound 61b (2.0 g, 8.9 mmol) was dissolved in 15 mL of phosphorus oxychloride, and stirred at 100° C. for 16 hours. Concentrate the reaction solution, add 20 mL of water to the concentrated solution and extract with dichloromethane (15 mL×3), combine the organic phases, wash with saturated sodium chloride solution (50 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product ethyl 2-chloro-6-fluoro-1H-benzo[d]imidazole-7-carboxylate 61c (1.9 g), yielding Rate: 88.6%.
MS：m/z(ESI):243.0[M+1]MS: m/z(ESI):243.0[M+1]
第三步third step
(S)-6-氟-2-(5-氟-3-羟基吲哚-1-基)-1H-苯并[d]咪唑-7-羧酸乙酯(S)-Ethyl 6-fluoro-2-(5-fluoro-3-oxindol-1-yl)-1H-benzo[d]imidazole-7-carboxylate
将化合物61c(1.9g，7.8mmol)和(S)-5-氟吲哚-3-醇(1.2g，7.8mmol)溶解于15mL1，4-二氧六环中,随后将N,N-二异丙基乙胺(3.1g，23.4mmol)加入反应液,100℃下搅拌反应16小时。反应液浓缩，向浓缩液中加入20mL水用二氯甲烷萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-氯-6-氟-1H-苯并[d]咪唑-7-羧酸乙酯61d(1.9g)，产率：88.6％。Compound 61c (1.9 g, 7.8 mmol) and (S)-5-fluoroindol-3-ol (1.2 g, 7.8 mmol) were dissolved in 15 mL of 1,4-dioxane, followed by N,N-di Isopropylethylamine (3.1 g, 23.4 mmol) was added to the reaction liquid, and the reaction was stirred at 100° C. for 16 hours. Concentrate the reaction solution, add 20 mL of water to the concentrated solution and extract with dichloromethane (15 mL×3), combine the organic phases, wash with saturated sodium chloride solution (50 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting residue was purified by silica gel column chromatography with eluent system B to afford the title product ethyl 2-chloro-6-fluoro-1H-benzo[d]imidazole-7-carboxylate 61d (1.9 g), yielding Rate: 88.6%.
MS：m/z(ESI):360.1[M+1]MS: m/z(ESI):360.1[M+1]
第四步the fourth step
(S)-6-氟-2-(5-氟-3-羟基吲哚-1-基)-1H-苯并[d]咪唑-7-羧酸(S)-6-fluoro-2-(5-fluoro-3-oxindol-1-yl)-1H-benzo[d]imidazole-7-carboxylic acid
化合物61e的合成方法，参考化合物60c的合成方法，以化合物61d为原料，得到(S)-6-氟-2-(5-氟-3-羟基吲哚-1-基)-1H-苯并[d]咪唑-7-羧酸60e(1.1g)，产率：96.2％。The synthesis method of compound 61e, referring to the synthesis method of compound 60c, using compound 61d as a raw material to obtain (S)-6-fluoro-2-(5-fluoro-3-oxindol-1-yl)-1H-benzo [d] Imidazole-7-carboxylic acid 60e (1.1 g), yield: 96.2%.
MS：m/z(ESI):332.1[M+1]MS: m/z(ESI):332.1[M+1]
第五步the fifth step
N-(2-(叔丁胺)-1-(2-氯-5-氟苯基)-2-氧乙基)-6-氟-2-((S)-5-氟-3-羟基吲哚-1-基)-1H-苯并[d]咪唑-7-甲酰胺N-(2-(tert-butylamine)-1-(2-chloro-5-fluorophenyl)-2-oxoethyl)-6-fluoro-2-((S)-5-fluoro-3-oxindole -1-yl)-1H-benzo[d]imidazole-7-carboxamide
化合物61f的合成方法，参考化合物60d的合成方法，以化合物61e为原料， 得到(N-(2-(叔丁胺)-1-(2-氯-5-氟苯基)-2-氧乙基)-6-氟-2-((S)-5-氟-3-羟基吲哚-1-基)-1H-苯并[d]咪唑-7-甲酰胺60f(1.8g)，产率：76.2％。For the synthesis method of compound 61f, refer to the synthesis method of compound 60d, using compound 61e as a raw material to obtain (N-(2-(tert-butylamine)-1-(2-chloro-5-fluorophenyl)-2-oxyethyl) -6-fluoro-2-((S)-5-fluoro-3-oxindol-1-yl)-1H-benzo[d]imidazole-7-carboxamide 60f (1.8g), yield: 76.2 %.
MS：m/z(ESI):572.2[M+1]MS: m/z(ESI):572.2[M+1]
第六步step six
8-(2-氯-5-氟苯基)-2-((S)-5-氟-3-羟基吲哚-1-基)-7,8-二氢咪唑[4,5-e]异吲哚-6(1H)-酮8-(2-Chloro-5-fluorophenyl)-2-((S)-5-fluoro-3-oxindol-1-yl)-7,8-dihydroimidazol[4,5-e] Isoindol-6(1H)-one
化合物61的合成方法，参考化合物60的合成方法，以化合物61f为原料，得到8-(2-氯-5-氟苯基)-2-((S)-5-氟-3-羟基吲哚-1-基)-7,8-二氢咪唑[4,5-e]异吲哚-6(1H)-酮61(0.2g)，产率：36.2％。The synthetic method of compound 61, referring to the synthetic method of compound 60, using compound 61f as raw material, obtains 8-(2-chloro-5-fluorophenyl)-2-((S)-5-fluoro-3-oxindole -1-yl)-7,8-dihydroimidazo[4,5-e]isoindol-6(1H)-one 61 (0.2 g), yield: 36.2%.
MS：m/z(ESI):453.1[M+1]MS: m/z(ESI):453.1[M+1]
实施例62化合物的制备参照实施例61，相应的质谱数据列于表1中。The preparation of the compound of Example 62 refers to Example 61, and the corresponding mass spectrum data are listed in Table 1.
实施例63Example 63
8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7,8-二氢-6H-噁唑并[4,5-e]8-(2-Chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-7,8-dihydro-6H-oxazolo[4,5- e] 异吲哚-6-酮Isoindol-6-one
Figure PCTCN2022136232-appb-000073
Figure PCTCN2022136232-appb-000073
第一步first step
2-溴-N-(4-甲氧基苄基)苯并[d]噁唑-5-甲酰胺2-Bromo-N-(4-methoxybenzyl)benzo[d]oxazole-5-carboxamide
将2-溴苯并[d]噁唑-5-羧酸63a(3.0g,12mmol)溶解于40mL二氯甲烷中， 加入N,N ’-羰基二咪唑(3.02g,18mmol)和4-二甲氨基吡啶(0.15g,1.2mmol)。25℃搅拌反应2小时。将4-甲氧基苄胺(1.70g，12mmol)加入上述反应液中，加完后继续25℃搅拌反应1小时。在反应液中加入30mL水，用二氯甲烷萃取(20mL×2)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-溴-N-(4-甲氧基苄基)苯并[d]噁唑-5-甲酰胺63b(3.81g)，产率：85.1％。 Dissolve 2-bromobenzo[d]oxazole-5-carboxylic acid 63a (3.0g, 12mmol) in 40mL of dichloromethane, add N, N' -carbonyldiimidazole (3.02g, 18mmol) and 4-di Aminopyridine (0.15 g, 1.2 mmol). The reaction was stirred at 25°C for 2 hours. 4-Methoxybenzylamine (1.70 g, 12 mmol) was added to the above reaction solution, and after the addition was completed, the reaction was continued to stir at 25° C. for 1 hour. Add 30 mL of water to the reaction solution, extract with dichloromethane (20 mL×2), combine the organic phases, wash with saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2-bromo-N-(4-methoxybenzyl)benzo[d]oxazole-5-carboxamide 63b (3.81 g ), yield: 85.1%.
MS m/z(ESI):361.0[M+1]MS m/z(ESI):361.0[M+1]
第二步second step
2-溴-N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)苯并[d]噁唑-5-甲酰胺2-Bromo-N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)benzo[d]oxazole-5-carboxamide
将2-溴-N-(4-甲氧基苄基)苯并[d]噁唑-5-甲酰胺63b(3.81g,10mmol)溶解于50mL四氢呋喃中，加入钠氢(0.84g,21mmol)。25℃搅拌反应2小时。将2-氯-5-氟苯甲酰氯(3.05g，16mmol)的四氢呋喃(5mL)溶液加入到上述反应液中，加完后继续25℃搅拌反应2小时。在反应液中加入50mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(30mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-溴-N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)苯并[d]噁唑-5-甲酰胺63c(3.92g)，产率：71.8％。2-Bromo-N-(4-methoxybenzyl)benzo[d]oxazole-5-carboxamide 63b (3.81g, 10mmol) was dissolved in 50mL THF, sodium hydrogen (0.84g, 21mmol) was added . The reaction was stirred at 25°C for 2 hours. A solution of 2-chloro-5-fluorobenzoyl chloride (3.05g, 16mmol) in tetrahydrofuran (5mL) was added to the above reaction solution, and after the addition was completed, the reaction was continued with stirring at 25°C for 2 hours. Add 50 mL of water to the reaction solution, extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated sodium chloride solution (30 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2-bromo-N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)benzene Ac[d]oxazole-5-carboxamide 63c (3.92 g), yield: 71.8%.
MS m/z(ESI):517.0[M+1]MS m/z(ESI):517.0[M+1]
第三步third step
2-溴-8-(2-氯-5-氟苯基)-8-羟基-7-(4-甲氧基苄基)-7,8-二氢-6H-噁唑并[4,5-e]异吲哚-6-酮2-Bromo-8-(2-chloro-5-fluorophenyl)-8-hydroxy-7-(4-methoxybenzyl)-7,8-dihydro-6H-oxazolo[4,5 -e]isoindol-6-one
-50℃条件下，将2-溴-N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)苯并[d]噁唑-5-甲酰胺63c(3.92g,7.6mmol)溶解于50mL四氢呋喃中，加入LiHMDS(1.0M,11.3mL,11mmol)。-50℃搅拌反应3小时。在反应液中加入50mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(30mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-溴-8-(2-氯-5-氟苯基)-8-羟基-7-(4-甲氧基苄基)-7,8-二氢-6H-噁唑并[4,5-e]异吲哚-6-酮63d(1.04g)，产率：26.5％。At -50°C, 2-bromo-N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)benzo[d]oxazole-5-carboxamide 63c (3.92g, 7.6mmol) was dissolved in 50mL THF, and LiHMDS (1.0M, 11.3mL, 11mmol) was added. The reaction was stirred at -50°C for 3 hours. Add 50 mL of water to the reaction solution, extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated sodium chloride solution (30 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel with eluent system B to give the title product 2-bromo-8-(2-chloro-5-fluorophenyl)-8-hydroxy-7-(4-methoxybenzyl yl)-7,8-dihydro-6H-oxazolo[4,5-e]isoindol-6-one 63d (1.04 g), yield: 26.5%.
MS m/z(ESI):517.0[M+1]MS m/z(ESI):517.0[M+1]
第四步the fourth step
2-溴-8-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-7,8-二氢-6H-噁唑并[4,5-e]异吲哚-6-酮2-Bromo-8-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-7,8-dihydro-6H-oxazolo[4,5-e]iso Indol-6-one
将2-溴-8-(2-氯-5-氟苯基)-8-羟基-7-(4-甲氧基苄基)-7,8-二氢-6H-噁唑并[4,5-e]异吲哚-6-酮63d(1.04g，2.0mmol)溶解于15mL二氯甲烷中，加入三乙基硅烷(2.33g，20mmol)和三氟化硼***(1.01g，7.0mmol)，40℃加热反应15 小时。向反应液中加入饱和碳酸氢钠溶液调节pH大于7，用二氯甲烷萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-溴-8-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-7,8-二氢-6H-噁唑并[4,5-e]异吲哚-6-酮63e(0.85g)，产率：85.0％。2-bromo-8-(2-chloro-5-fluorophenyl)-8-hydroxyl-7-(4-methoxybenzyl)-7,8-dihydro-6H-oxazolo[4, 5-e] Isoindol-6-one 63d (1.04 g, 2.0 mmol) was dissolved in 15 mL of dichloromethane, triethylsilane (2.33 g, 20 mmol) and boron trifluoride diethyl ether (1.01 g, 7.0 mmol) were added ), heated at 40°C for 15 hours. Add saturated sodium bicarbonate solution to the reaction solution to adjust the pH to greater than 7, extract with dichloromethane (20mL×3), combine the organic phases, wash with saturated sodium chloride solution (20mL×2), dry over anhydrous sodium sulfate, and filter , after the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2-bromo-8-(2-chloro-5-fluorophenyl)-7-(4-methyl Oxybenzyl)-7,8-dihydro-6H-oxazolo[4,5-e]isoindol-6-one 63e (0.85 g), yield: 85.0%.
MS m/z(ESI):501.0[M+1]MS m/z(ESI):501.0[M+1]
第五步the fifth step
8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7-(4-甲氧基苄基)-7,8-二氢-6H-噁唑并[4,5-e]异吲哚-6-酮8-(2-Chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-7-(4-methoxybenzyl)-7,8-di Hydrogen-6H-oxazolo[4,5-e]isoindol-6-one
将2-溴-8-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-7,8-二氢-6H-噁唑并[4,5-e]异吲哚-6-酮63e(0.20g，0.40mmol)和(3-氟-5-(三氟甲基)苯基)硼酸(0.12g，0.60mmol)溶解于5mL 1,4-二氧六环中，加入1，1’-双(二苯基磷)二茂铁氯化钯(29mg，0.040mmol)和磷酸钾(0.25g，1.2mmol)，80℃下加热反应5小时。冷却到室温后，在反应液中加入10mL水，用乙酸乙酯萃取(10mL×2)，合并有机相，用饱和氯化钠溶液洗涤(10mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，所得残余物用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7-(4-甲氧基苄基)-7,8-二氢-6H-噁唑并[4,5-e]异吲哚-6-酮63f(52mg)，产率：22.3％。2-Bromo-8-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-7,8-dihydro-6H-oxazolo[4,5-e] Isoindol-6-one 63e (0.20 g, 0.40 mmol) and (3-fluoro-5-(trifluoromethyl)phenyl)boronic acid (0.12 g, 0.60 mmol) were dissolved in 5 mL of 1,4-dioxane 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (29mg, 0.040mmol) and potassium phosphate (0.25g, 1.2mmol) were added to the ring, and the reaction was heated at 80°C for 5 hours. After cooling to room temperature, add 10 mL of water to the reaction solution, extract with ethyl acetate (10 mL×2), combine the organic phases, wash with saturated sodium chloride solution (10 mL×2), dry over anhydrous sodium sulfate, filter, and the filtrate After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 8-(2-chloro-5-fluorophenyl)-2-(3-fluoro-5- (Trifluoromethyl)phenyl)-7-(4-methoxybenzyl)-7,8-dihydro-6H-oxazolo[4,5-e]isoindol-6-one 63f( 52 mg), yield: 22.3%.
MS m/z(ESI):585.1[M+1]MS m/z(ESI):585.1[M+1]
第六步step six
8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7,8-二氢-6H-噁唑并[4,5-e]异吲哚-6-酮8-(2-Chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-7,8-dihydro-6H-oxazolo[4,5- e] Isoindol-6-one
将8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7-(4-甲氧基苄基)-7,8-二氢-6H-噁唑并[4,5-e]异吲哚-6-酮63f(52mg，0.089mmol)溶解于2mL三氟乙酸和三氟甲磺酸(V/V＝9:1)混合溶剂中，80℃下加热反应5小时。冷却到室温后，将反应液慢慢倒入20mL饱和碳酸氢钠溶液中，用二氯甲烷萃取(10mL×3)，合并有机相，用饱和氯化钠溶液洗涤(10mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，所得残余物用制备HPLC纯化，得到标题产物8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7,8-二氢-6H-噁唑并[4,5-e]异吲哚-6-酮63(11mg)，产率：26.8％。8-(2-chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-7-(4-methoxybenzyl)-7,8- Dihydro-6H-oxazolo[4,5-e]isoindol-6-one 63f (52 mg, 0.089 mmol) was dissolved in 2 mL of trifluoroacetic acid and trifluoromethanesulfonic acid (V/V=9:1) In the mixed solvent, the reaction was heated at 80° C. for 5 hours. After cooling to room temperature, the reaction solution was slowly poured into 20 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL×2), anhydrous After drying over sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, the resulting residue was purified by preparative HPLC to give the title product 8-(2-chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethane yl)phenyl)-7,8-dihydro-6H-oxazolo[4,5-e]isoindol-6-one 63 (11 mg), yield: 26.8%.
MS m/z(ESI):465.0[M+1]MS m/z(ESI):465.0[M+1]
实施例64，65化合物的制备参照实施例63，相应的质谱数据列于表1中。Examples 64 and 65 were prepared with reference to Example 63, and the corresponding mass spectrometry data are listed in Table 1.
实施例66Example 66
8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7,8-二氢-6H-噻唑并[4,5-e]8-(2-Chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-7,8-dihydro-6H-thiazolo[4,5-e ] 异吲哚-6-酮Isoindol-6-one
Figure PCTCN2022136232-appb-000074
Figure PCTCN2022136232-appb-000074
第一步first step
2-溴-N-(4-甲氧基苄基)苯并[d]噻唑-5-甲酰胺2-Bromo-N-(4-methoxybenzyl)benzo[d]thiazole-5-carboxamide
将2-溴苯并[d]噻唑-5-羧酸66a(3.1g,12mmol)溶解于40mL二氯甲烷中，加入N,N’-羰基二咪唑(3.02g,18mmol)和4-二甲氨基吡啶(0.15g,1.2mmol)。25℃搅拌反应2小时。将4-甲氧基苄胺(1.70g，12mmol)加入上述反应液中，加完后继续25℃搅拌反应1小时。在反应液中加入30mL水，用二氯甲烷萃取(20mL×2)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-溴-N-(4-甲氧基苄基)苯并[d]噻唑-5-甲酰胺66b(3.8g)，产率：83％。2-Bromobenzo[d]thiazole-5-carboxylic acid 66a (3.1 g, 12 mmol) was dissolved in 40 mL of dichloromethane, N,N'-carbonyldiimidazole (3.02 g, 18 mmol) and 4-dimethyl Aminopyridine (0.15 g, 1.2 mmol). The reaction was stirred at 25°C for 2 hours. 4-Methoxybenzylamine (1.70 g, 12 mmol) was added to the above reaction solution, and after the addition was completed, the reaction was continued to stir at 25° C. for 1 hour. Add 30 mL of water to the reaction solution, extract with dichloromethane (20 mL×2), combine the organic phases, wash with saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2-bromo-N-(4-methoxybenzyl)benzo[d]thiazole-5-carboxamide 66b (3.8 g) , Yield: 83%.
MS m/z(ESI):377.0[M+1]MS m/z(ESI):377.0[M+1]
第二步second step
2-溴-N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)苯并[d]噻唑-5-甲酰胺2-Bromo-N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)benzo[d]thiazole-5-carboxamide
将2-溴-N-(4-甲氧基苄基)苯并[d]噻唑-5-甲酰胺66b(3.8g,10mmol)溶解于50mL四氢呋喃中，加入钠氢(0.84g,20mmol)。25℃搅拌反应2小时。将2-氯-5-氟苯甲酰氯(3.05g，16mmol)的四氢呋喃(5mL)溶液加入到上述反应液中，加完后继续25℃搅拌反应2小时。在反应液中加入50mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(30mL×2)，无水硫酸钠 干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-溴-N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)苯并[d]噻唑-5-甲酰胺66c(3.9g)，产率：71％。2-Bromo-N-(4-methoxybenzyl)benzo[d]thiazole-5-carboxamide 66b (3.8 g, 10 mmol) was dissolved in 50 mL of tetrahydrofuran, and sodium hydrogen (0.84 g, 20 mmol) was added. The reaction was stirred at 25°C for 2 hours. A solution of 2-chloro-5-fluorobenzoyl chloride (3.05g, 16mmol) in tetrahydrofuran (5mL) was added to the above reaction solution, and after the addition was completed, the reaction was continued with stirring at 25°C for 2 hours. Add 50 mL of water to the reaction solution, extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated sodium chloride solution (30 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2-bromo-N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)benzene And[d]thiazole-5-carboxamide 66c (3.9 g), yield: 71%.
MS m/z(ESI):533.0[M+1]MS m/z(ESI):533.0[M+1]
第三步third step
2-溴-8-(2-氯-5-氟苯基)-8-羟基-7-(4-甲氧基苄基)-7,8-二氢-6H-噻唑并[4,5-e]异吲哚-6-酮2-bromo-8-(2-chloro-5-fluorophenyl)-8-hydroxy-7-(4-methoxybenzyl)-7,8-dihydro-6H-thiazolo[4,5- e] Isoindol-6-one
-50℃条件下，将2-溴-N-(2-氯-5-氟苯甲酰基)-N-(4-甲氧基苄基)苯并[d]噻唑-5-甲酰胺63c(3.9g,7.5mmol)溶解于50mL四氢呋喃中，加入LiHMDS(1.0M,11.3mL,11mmol)。-50℃搅拌反应3小时。在反应液中加入50mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(30mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-溴-8-(2-氯-5-氟苯基)-8-羟基-7-(4-甲氧基苄基)-7,8-二氢-6H-噻唑并[4,5-e]异吲哚-6-酮66d(1.03g)，产率：25.5％。At -50°C, 2-bromo-N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)benzo[d]thiazole-5-carboxamide 63c( 3.9 g, 7.5 mmol) was dissolved in 50 mL of tetrahydrofuran, and LiHMDS (1.0 M, 11.3 mL, 11 mmol) was added. The reaction was stirred at -50°C for 3 hours. Add 50 mL of water to the reaction solution, extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated sodium chloride solution (30 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel with eluent system B to give the title product 2-bromo-8-(2-chloro-5-fluorophenyl)-8-hydroxy-7-(4-methoxybenzyl yl)-7,8-dihydro-6H-thiazolo[4,5-e]isoindol-6-one 66d (1.03 g), yield: 25.5%.
MS m/z(ESI):533.0[M+1]MS m/z(ESI):533.0[M+1]
第四步the fourth step
2-溴-8-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-7,8-二氢-6H-噻唑并[4,5-e]异吲哚-6-酮2-Bromo-8-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-7,8-dihydro-6H-thiazolo[4,5-e]isoindo Indol-6-one
将2-溴-8-(2-氯-5-氟苯基)-8-羟基-7-(4-甲氧基苄基)-7,8-二氢-6H-恶唑并[4,5-e]异吲哚-6-酮66d(1.03g，2mmol)溶解于15mL二氯甲烷中，加入三乙基硅烷(2.33g，20mmol)和三氟化硼***(1.01g，7.0mmol)，40℃加热反应15小时。向反应液中加入饱和碳酸氢钠溶液调节pH大于7，用二氯甲烷萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-溴-8-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-7,8-二氢-6H-噻唑并[4,5-e]异吲哚-6-酮66e(0.85g)，产率：84.0％。2-bromo-8-(2-chloro-5-fluorophenyl)-8-hydroxyl-7-(4-methoxybenzyl)-7,8-dihydro-6H-oxazolo[4, 5-e] Isoindol-6-one 66d (1.03 g, 2 mmol) was dissolved in 15 mL of dichloromethane, triethylsilane (2.33 g, 20 mmol) and boron trifluoride diethyl ether (1.01 g, 7.0 mmol) were added , heated at 40°C for 15 hours. Add saturated sodium bicarbonate solution to the reaction solution to adjust the pH to greater than 7, extract with dichloromethane (20mL×3), combine the organic phases, wash with saturated sodium chloride solution (20mL×2), dry over anhydrous sodium sulfate, and filter , after the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2-bromo-8-(2-chloro-5-fluorophenyl)-7-(4-methyl Oxybenzyl)-7,8-dihydro-6H-thiazolo[4,5-e]isoindol-6-one 66e (0.85 g), yield: 84.0%.
MS m/z(ESI):517.0[M+1]MS m/z(ESI):517.0[M+1]
第五步the fifth step
8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7-(4-甲氧基苄基)-7,8-二氢-6H-噻唑并[4,5-e]异吲哚-6-酮8-(2-Chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-7-(4-methoxybenzyl)-7,8-di Hydrogen-6H-thiazolo[4,5-e]isoindol-6-one
将2-溴-8-(2-氯-5-氟苯基)-7-(4-甲氧基苄基)-7,8-二氢-6H-噻唑并[4,5-e]异吲哚-6-酮66e(0.20g，0.39mmol)和(3-氟-5-(三氟甲基)苯基)硼酸(0.12g，0.60mmol)溶解于5mL1,4-二氧六环中，加入1，1’-双(二苯基磷)二茂铁氯化钯(29mg，0.04mmol)和磷酸钾(0.25g，1.2mmol)，80℃下加热反应5小时。冷却到室温后，在反应液中加入10mL水，用乙酸乙酯萃取(10mL×2)，合并有机 相，用饱和氯化钠溶液洗涤(10mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，所得残余物用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7-(4-甲氧基苄基)-7,8-二氢-6H-噻唑并[4,5-e]异吲哚-6-酮66f(52mg)，产率：23.3％。2-bromo-8-(2-chloro-5-fluorophenyl)-7-(4-methoxybenzyl)-7,8-dihydro-6H-thiazolo[4,5-e]iso Indol-6-one 66e (0.20 g, 0.39 mmol) and (3-fluoro-5-(trifluoromethyl)phenyl)boronic acid (0.12 g, 0.60 mmol) were dissolved in 5 mL of 1,4-dioxane , 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (29mg, 0.04mmol) and potassium phosphate (0.25g, 1.2mmol) were added, and the reaction was heated at 80°C for 5 hours. After cooling to room temperature, add 10 mL of water to the reaction solution, extract with ethyl acetate (10 mL×2), combine the organic phases, wash with saturated sodium chloride solution (10 mL×2), dry over anhydrous sodium sulfate, filter, and the filtrate After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 8-(2-chloro-5-fluorophenyl)-2-(3-fluoro-5- (Trifluoromethyl)phenyl)-7-(4-methoxybenzyl)-7,8-dihydro-6H-thiazolo[4,5-e]isoindol-6-one 66f (52mg ), yield: 23.3%.
MS m/z(ESI):601.1[M+1]MS m/z(ESI):601.1[M+1]
第六步step six
8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7,8-二氢-6H-噻唑并[4,5-e]异吲哚-6-酮8-(2-Chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-7,8-dihydro-6H-thiazolo[4,5-e ]isoindol-6-one
将8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7-(4-甲氧基苄基)-7,8-二氢-6H-噻唑并[4,5-e]异吲哚-6-酮66f(52mg，0.085mmol)溶解于2mL三氟乙酸和三氟甲磺酸(V/V＝9:1)混合溶剂中，80℃下加热反应5小时。冷却到室温后，将反应液慢慢倒入20mL饱和碳酸氢钠溶液中，用二氯甲烷萃取(10mL×3)，合并有机相，用饱和氯化钠溶液洗涤(10mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，所得残余物用制备HPLC纯化，得到标题产物8-(2-氯-5-氟苯基)-2-(3-氟-5-(三氟甲基)苯基)-7,8-二氢-6H-噻唑并[4,5-e]异吲哚-6-酮66(11mg)，产率：26.8％。8-(2-chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethyl)phenyl)-7-(4-methoxybenzyl)-7,8- Dihydro-6H-thiazolo[4,5-e]isoindol-6-one 66f (52 mg, 0.085 mmol) was dissolved in 2 mL of trifluoroacetic acid and mixed with trifluoromethanesulfonic acid (V/V=9:1) In a solvent, the reaction was heated at 80° C. for 5 hours. After cooling to room temperature, the reaction solution was slowly poured into 20 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL×2), anhydrous After drying over sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, the resulting residue was purified by preparative HPLC to give the title product 8-(2-chloro-5-fluorophenyl)-2-(3-fluoro-5-(trifluoromethane yl)phenyl)-7,8-dihydro-6H-thiazolo[4,5-e]isoindol-6-one 66 (11 mg), yield: 26.8%.
MS m/z(ESI):481.0[M+1]MS m/z(ESI):481.0[M+1]
实施例67，68化合物的制备参照实施例66，相应的质谱数据列于表1中。Examples 67 and 68 were prepared with reference to Example 66, and the corresponding mass spectrometry data are listed in Table 1.
实施例69Example 69
N-(3-(2-氯-5-氟苯基)-1-氧代-2,3-二氢-1H-吡咯并[3,4-f]喹啉-4-基)-3-羟基-3-N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3- Hydroxy-3- (三氟甲基)吲哚-2,2-d(Trifluoromethyl)indole-2,2-d 22 -1-甲酰胺-1-formamide
Figure PCTCN2022136232-appb-000075
Figure PCTCN2022136232-appb-000075
第一步first step
3-羟基-3-(三氟甲基)吲哚-2-酮3-Hydroxy-3-(trifluoromethyl)indol-2-one
将吲哚-2,3-二酮69a(1.0g,6.80mmol)溶于20mL四氢呋喃中，加入氟化铯(1.04g,20.39mmol)和三甲基三氟甲基硅烷(1.93g,13.59mmol)。25℃反应2小时。向反应液中加入30mL水，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-羟基-3-(三氟甲基)吲哚-2-酮69b(0.70g,产率：47.4％)。Indole-2,3-dione 69a (1.0 g, 6.80 mmol) was dissolved in 20 mL of tetrahydrofuran, cesium fluoride (1.04 g, 20.39 mmol) and trimethyltrifluoromethylsilane (1.93 g, 13.59 mmol) were added ). React at 25°C for 2 hours. Add 30 mL of water to the reaction solution, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 3-hydroxy-3-(trifluoromethyl)indol-2-one 69b (0.70 g, yield: 47.4%).
MS m/z(ESI):218.1[M+1]MS m/z(ESI):218.1[M+1]
第二步second step
3-(三氟甲基)吲哚-2,2-d 2-3-醇 3-(Trifluoromethyl)indole-2,2-d 2 -3-ol
将3-羟基-3-(三氟甲基)吲哚-2-酮69b(0.70g,3.22mmol)溶于5.0mL四氢呋喃中，加入氘代硼烷(6.4mL,6.44mmol)。60℃加热反应3小时。向反应液中加入2.0Ml氘代甲醇，减压浓缩后，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物3-(三氟甲基)吲哚-2,2-d 2-3-醇69c(0.46g,产率：69.7％)。 3-Hydroxy-3-(trifluoromethyl)indol-2-one 69b (0.70 g, 3.22 mmol) was dissolved in 5.0 mL of tetrahydrofuran, and deuterated borane (6.4 mL, 6.44 mmol) was added. The reaction was heated at 60°C for 3 hours. Add 2.0Ml deuterated methanol to the reaction solution, concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography with eluent system B to obtain the title product 3-(trifluoromethyl)indole-2,2- d 2 -3-ol 69c (0.46 g, yield: 69.7%).
MS m/z(ESI):218.1[M+1]MS m/z(ESI):218.1[M+1]
第三步third step
N-(3-(2-氯-5-氟苯基)-1-氧代-2,3-二氢-1H-吡咯并[3,4-f]喹啉-4-基)-3-羟基-3-(三氟甲基)吲哚-2,2-d 2-1-甲酰胺 N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3- Hydroxy-3-(trifluoromethyl)indole-2,2-d 2 -1-carboxamide
将4-氨基-3-(2-氯-5-氟苯基)-2,3-二氢-1H-吡咯并[3,4]喹啉-1-酮13g(60mg,0.18mmol)溶解于2.0mL无水二氯甲烷中，冷却至0℃，加入二异丙基乙基胺(118mg,0.92mmol)，再加入三光气(82mg,0.27mmol)的二氯甲烷溶液(1.0mL)，反应在25℃下搅拌1小时。溶剂旋干，加入3-(三氟甲基)吲哚-2,2-d 2-3-醇69c(57mg,0.27mmol)和二异丙基乙基胺(71mg,0.55mmol)，反应在25℃下搅拌1小时。加入10mL水，用二氯甲烷萃取(5mL×2)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用制备HPLC纯化，得到标题产物N-(3-(2-氯-5-氟苯基)-1-氧代-2,3-二氢-1H-吡咯并[3,4-f]喹啉-4-基)-3-羟基-3-(三氟甲基)吲哚-2,2-d 2-1-甲酰胺69(15mg,产率13.9％)。 Dissolve 13g (60mg, 0.18mmol) of 4-amino-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-pyrrolo[3,4]quinolin-1-one in 2.0mL of anhydrous dichloromethane, cooled to 0 ℃, added diisopropylethylamine (118mg, 0.92mmol), then added triphosgene (82mg, 0.27mmol) in dichloromethane solution (1.0mL), reacted Stir at 25°C for 1 hour. The solvent was spin-dried, and 3-(trifluoromethyl)indole-2,2-d 2 -3-ol 69c (57mg, 0.27mmol) and diisopropylethylamine (71mg, 0.55mmol) were added to react in Stir at 25°C for 1 hour. Add 10 mL of water, extract with dichloromethane (5 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, and the resulting residue is purified by preparative HPLC to obtain the title product N-(3-( 2-Chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(tri Fluoromethyl)indole-2,2- d2-1 -carboxamide 69 (15 mg, 13.9% yield).
MS m/z(ESI):559.2[M+1]MS m/z(ESI):559.2[M+1]
实施例70Example 70
N-(3-(2-氯-5-氟苯基)-1-氧代-2,3-二氢-1H-吡咯并[3,4-f]喹啉-4-基)螺[环N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)spiro[cyclo 丙烷-1,3'-吲哚啉]-1'-甲酰胺Propane-1,3'-indoline]-1'-carboxamide
Figure PCTCN2022136232-appb-000076
Figure PCTCN2022136232-appb-000076
实施例70化合物的制备参照实施例69，MS m/z(ESI):499.1[M+1].The preparation of the compound of Example 70 refers to Example 69, MS m/z (ESI): 499.1[M+1].
实施例71Example 71
N-(3-(2-氯-5-氟苯基)-1-氧代-2,3-二氢-1H-吡咯并[3,4-f]喹啉-4-基)螺[环丙烷N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)spiro[cyclo propane -1,2'-吲哚啉]-1'-甲酰胺-1,2'-indoline]-1'-carboxamide
Figure PCTCN2022136232-appb-000077
Figure PCTCN2022136232-appb-000077
实施例71化合物的制备参照实施例69，MS m/z(ESI):499.1[M+1].The preparation of the compound of Example 71 refers to Example 69, MS m/z (ESI): 499.1[M+1].
实施例72Example 72
N-(3-(2-氯-5-氟苯基)-1-氧代-2,3-二氢-1H-吡咯并[3,4-f]喹啉-4-基)螺[环N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)spiro[cyclo 丁烷-1,3'-吲哚啉]-1'-甲酰胺Butane-1,3'-indoline]-1'-carboxamide
Figure PCTCN2022136232-appb-000078
Figure PCTCN2022136232-appb-000078
实施例72化合物的制备参照实施例69，MS m/z(ESI):513.1[M+1].The preparation of the compound of Example 72 refers to Example 69, MS m/z (ESI): 513.1[M+1].
实施例73Example 73
N-(3-(2-氯-5-氟苯基)-1-氧代-2,3-二氢-1H-吡咯[3,4-f]喹啉-4-基)-9H-咔N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrole[3,4-f]quinolin-4-yl)-9H-carba 唑-9-甲酰胺Azole-9-carboxamide
Figure PCTCN2022136232-appb-000079
Figure PCTCN2022136232-appb-000079
实施例73化合物的制备参照实施例69，MS m/z(ESI):521.1[M+1].The preparation of the compound of Example 73 refers to Example 69, MS m/z (ESI): 521.1[M+1].
实施例74Example 74
N-(3-(2-氯-5-氟苯基)-1-氧代-2,3-二氢-1H-吡咯并[3,4-f]喹啉-4-基)螺[吲N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)spiro[ind 哚-3,2'-氧杂环丁烷]-1-甲酰胺Indole-3,2'-oxetane]-1-carboxamide
Figure PCTCN2022136232-appb-000080
Figure PCTCN2022136232-appb-000080
实施例74化合物的制备参照实施例69，MS m/z(ESI):515.1[M+1].The preparation of the compound of Example 74 refers to Example 69, MS m/z (ESI): 515.1[M+1].
实施例75Example 75
N-(3-(2-氯-5-氟苯基)-1-氧代-2,3-二氢-1H-吡咯并[3,4-f]喹啉-4-基)-3,4-N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3, 4- 二氢喹啉-1(2H)-甲酰胺Dihydroquinoline-1(2H)-carboxamide
Figure PCTCN2022136232-appb-000081
Figure PCTCN2022136232-appb-000081
实施例75化合物的制备参照实施例69，MS m/z(ESI):487.1[M+1].The preparation of Example 75 compound refers to Example 69, MS m/z (ESI): 487.1[M+1].
生物学测试评价Biology Test Evaluation
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。The following further describes and explains the present invention in combination with test examples, but these examples are not meant to limit the scope of the present invention.
测试例1、本发明化合物对PI3Kα突变型及野生型激酶的抑制活性实验。Test Example 1. Experiment of the inhibitory activity of the compounds of the present invention on PI3Kα mutant and wild-type kinases.
实验目的：该测试例的目的是测试化合物对PI3Kα突变型及野生型激酶的抑制活性。Purpose of the experiment: The purpose of this test example is to test the inhibitory activity of the compound on PI3Kα mutant and wild-type kinases.
实验仪器：laboratory apparatus:
离心机(Eppendorf 5810R)Centrifuge (Eppendorf 5810R)
酶标仪(BioTek Synergy H1)Microplate reader (BioTek Synergy H1)
移液器(Eppendorf或Rainin)Pipettes (Eppendorf or Rainin)
实验试剂耗材：Experimental reagent consumables:
PI3K(p110α/p85α)购自Promega，货号为V1721PI3K(p110α/p85α) was purchased from Promega, catalog number V1721
PI3K(p110α[H1047R]/p85α)购自Promega，货号为V1741PI3K (p110α[H1047R]/p85α) was purchased from Promega, Cat. No. V1741
PI3K(p110α[E545K]/p85α)购自Promega，货号为V1731PI3K (p110α[E545K]/p85α) was purchased from Promega, Cat. No. V1731
PIK3CA[E542K]/PIK3R1购自Carna，货号为11-413-20NPIK3CA[E542K]/PIK3R1 was purchased from Carna, Cat. No. 11-413-20N
PIP2:3PS Lipid Kinase Substrate购自Promega，货号为V1701PIP2:3PS Lipid Kinase Substrate was purchased from Promega, the article number is V1701
Bovine Serum Albumin购自Sigma，货号为B2064-100GBovine Serum Albumin was purchased from Sigma, item number B2064-100G
HEPES(1M)购自Gibco，货号为15630-080HEPES (1M) was purchased from Gibco, Cat. No. 15630-080
氯化钠购自Sigma，货号为S7653-250GSodium chloride was purchased from Sigma, item number S7653-250G
DMSO购自Sigma，货号为D8418-100MLDMSO was purchased from Sigma, Cat. No. D8418-100ML
ADP-Glo TMKinase Assay购自Promega，货号为V9102 ADP-Glo TM Kinase Assay was purchased from Promega, the article number is V9102
白色384孔板购自Perkin Elmer，货号为6007299White 384-well plates were purchased from Perkin Elmer, Cat. No. 6007299
实验方法：experimental method:
本实验采用Promega公司的ADP-Glo脂质激酶测定方法，脂质激酶PI3Kα在底物PIP2：3PS和ATP存在的条件下发生催化反应，ATP生成ADP，通过测定反应中ADP的含量来表征脂质激酶的活性，并得出化合物对PI3Kα激酶活性抑制的半数抑制浓度IC 50。 In this experiment, the ADP-Glo lipid kinase assay method of Promega Company was used. The lipid kinase PI3Kα catalyzed the reaction in the presence of the substrate PIP2:3PS and ATP, ATP generated ADP, and the lipid was characterized by measuring the content of ADP in the reaction. Kinase activity, and the half inhibitory concentration IC 50 of the compound against PI3Kα kinase activity was obtained.
激酶反应在白色384孔板中进行，每孔加入2μL用含1％DMSO的ddH 2O稀释的不同浓度的化合物，阳性对照孔加入2μL含1％DMSO的ddH 2O，然后每孔加入2μL用5×激酶缓冲液(HEPES 250mM，MgCl 2 15mM，NaCl 250mM,BSA 0.05％)稀释的0.01～1μg/mL PI3Kα突变型(H1047R,E545K,E542K)和野生型激酶溶液，阴性对照孔加入2μL的5×激酶缓冲液，放置于室温预孵育30分钟，所有孔加入4μL用10×Dilution buffer和ddH 2O配制的50μM底物PIP2:3PS，最后加入2μL用水稀释的50～100μM ATP溶液启动反应，室温反应60～120分钟后，每孔加入10μL ADP-Glo Reagent(含10mM MgCl 2)室温反应60分钟以去除反应中多余的ATP，后每孔加入20μL Kinase Detection Reagent，室温避光反应20分钟后用BioTek Synergy H1酶标仪检测化学发光值。 The kinase reaction was carried out in a white 384-well plate, and 2 μL of different concentrations of compounds diluted with ddH 2 O containing 1% DMSO were added to each well, and 2 μL of ddH 2 O containing 1% DMSO was added to the positive control wells, and then 2 μL of ddH 2 O containing 1% DMSO was added to each well. 0.01-1 μg/mL PI3Kα mutant (H1047R, E545K, E542K) and wild-type kinase solutions diluted in 5× kinase buffer (HEPES 250mM, MgCl 2 15mM, NaCl 250mM, BSA 0.05%), and 2 μL of 5 ×Kinase buffer, placed at room temperature for pre-incubation for 30 minutes, add 4 μL of 50 μM substrate PIP2:3PS prepared with 10×Dilution buffer and ddH 2 O to all wells, and finally add 2 μL of 50-100 μM ATP solution diluted with water to start the reaction, room temperature After reacting for 60-120 minutes, add 10 μL ADP-Glo Reagent (containing 10 mM MgCl 2 ) to each well and react at room temperature for 60 minutes to remove excess ATP in the reaction, then add 20 μL Kinase Detection Reagent to each well, and react in the dark at room temperature for 20 minutes before using BioTek Synergy H1 microplate reader was used to detect the chemiluminescence value.
酶名称Enzyme name 酶反应浓度enzyme reaction concentration 酶反应时间Enzyme reaction time ATP浓度ATP concentration
PI3KαPI3Kα 0.025～0.1μg/mL0.025～0.1μg/mL 60～120min60～120min 50μM50μM
PI3KαH1047RPI3KαH1047R 0.025～0.1μg/mL0.025～0.1μg/mL 60～120min60～120min 50μM50μM
PI3KαE545KPI3KαE545K 0.025～0.1μg/mL0.025～0.1μg/mL 60～120min60～120min 50μM50μM
PI3KαE542KPI3KαE542K 0.1～1μg/mL0.1～1μg/mL 60～120min60～120min 50～100μM50～100μM
实验数据处理方法：Experimental data processing method:
通过于板上阳性对照孔(DMSO对照孔)和阴性对照孔(不添加激酶)计算使用化合物处理的孔的百分比抑制数据{％抑制率＝100-[(测试化合物值-阴性对照值)]/(阳性对照值-阴性对照值)×100}。使用GraphPad prism拟合不同浓度和相应百分比抑制率数据至4参数非线性逻辑公式计算出IC 50值。 Percent inhibition data for wells treated with compounds were calculated by plate positive control wells (DMSO control wells) and negative control wells (no kinase added) {% inhibition = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. IC 50 values were calculated by fitting different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula using GraphPad prism.
实验结果：Experimental results:
实施例Example (H1047R)IC50(nM)(H1047R)IC50(nM)
实施例13Example 13 116116
实施例13-P1Example 13-P1 423423
实施例13-P2Example 13-P2 134134
实验结论：Experimental results:
通过以上方案得出本发明所示的化合物在PI3Kα激酶活性试验中显示出较高的生物活性。Through the above scheme, it can be concluded that the compounds shown in the present invention show higher biological activity in the PI3Kα kinase activity test.
测试例2、本发明化合物对PI3Kβ/γ/δ激酶的抑制活性测定Test Example 2, Determination of the inhibitory activity of the compounds of the present invention on PI3Kβ/γ/δ kinases
实验目的：该测试例的目的是测试化合物对PI3Kβ/γ/δ激酶的抑制活性。Experiment purpose: The purpose of this test example is to test the inhibitory activity of the compound on PI3Kβ/γ/δ kinase.
实验仪器：laboratory apparatus:
离心机(Eppendorf 5810R)Centrifuge (Eppendorf 5810R)
酶标仪(BioTek Synergy H1)Microplate reader (BioTek Synergy H1)
移液器(Eppendorf或Rainin)Pipettes (Eppendorf or Rainin)
实验试剂耗材：Experimental reagent consumables:
PI3Kβ购自Carna，货号为11-102PI3Kβ was purchased from Carna, Cat. No. 11-102
PI3Kγ购自Thermofisher，货号为PV4786PI3Kγ was purchased from Thermofisher, item number PV4786
PI3Kδ购自Carna，货号为11-103PI3Kδ was purchased from Carna, Cat. No. 11-103
PIP2:3PS Lipid Kinase Substrate购自Promega，货号为V1701PIP2:3PS Lipid Kinase Substrate was purchased from Promega, the article number is V1701
Bovine Serum Albumin购自Sigma，货号为B2064-100GBovine Serum Albumin was purchased from Sigma, item number B2064-100G
HEPES(1M)购自Gibco，货号为15630-080HEPES (1M) was purchased from Gibco, Cat. No. 15630-080
氯化钠购自Sigma，货号为S7653-250GSodium chloride was purchased from Sigma, item number S7653-250G
DMSO购自Sigma，货号为D8418-100MLDMSO was purchased from Sigma, Cat. No. D8418-100ML
ADP-Glo TMKinase Assay购自Promega，货号为V9102 ADP-Glo TM Kinase Assay was purchased from Promega, the article number is V9102
白色384孔板购自Perkin Elmer，货号为6007299White 384-well plates were purchased from Perkin Elmer, Cat. No. 6007299
实验方法：experimental method:
本实验采用Promega公司的ADP-Glo脂质激酶测定方法，脂质激酶PI3Kβ/γ/δ在底物PIP2:3PS和ATP存在的条件下发生催化反应，ATP生成ADP，通过测定反应中ADP的含量来表征脂质激酶的活性，并得出化合物对PI3Kβ/γ/δ激酶活性抑制的半数抑制浓度IC 50。 This experiment adopts the ADP-Glo lipid kinase assay method of Promega Company. Lipid kinase PI3Kβ/γ/δ catalyzes the reaction in the presence of substrate PIP2:3PS and ATP, and ATP generates ADP. By measuring the content of ADP in the reaction To characterize the activity of lipid kinases, and obtain the half inhibitory concentration IC 50 of the compound on PI3Kβ/γ/δ kinase activity.
具体实验操作如下：The specific experimental operation is as follows:
激酶反应在白色384孔板中进行，每孔加入2μL用含1％DMSO的ddH 2O稀释的不同浓度的化合物，阳性对照孔加入2μL含1％DMSO的ddH 2O，然后每孔加入2μL用5×激酶缓冲液(HEPES 250mM，MgCl 2 15mM，NaCl 250mM,BSA 0.05％)稀释的0.25～1μg/mL PI3Kβ/γ/δ激酶溶液，阴性对照孔加入2μL的 5×激酶缓冲液，所有孔加入4μL用10×Dilution buffer和ddH 2O配制的50μM底物PIP2:3PS，最后加入2μL用水稀释的50～100μM ATP溶液启动反应，室温反应90～120分钟后，每孔加入10μL ADP-Glo Reagent(含10mM MgCl 2)室温反应60分钟以去除反应中多余的ATP，后每孔加入20μL Kinase Detection Reagent，室温避光反应20分钟后用BioTek Synergy H1酶标仪检测化学发光值。 The kinase reaction was carried out in a white 384-well plate, and 2 μL of different concentrations of compounds diluted with ddH 2 O containing 1% DMSO were added to each well, and 2 μL of ddH 2 O containing 1% DMSO was added to the positive control wells, and then 2 μL of ddH 2 O containing 1% DMSO was added to each well. 0.25-1 μg/mL PI3Kβ/γ/δ kinase solution diluted in 5× kinase buffer (HEPES 250mM, MgCl 2 15mM, NaCl 250mM, BSA 0.05%), add 2 μL of 5× kinase buffer to negative control wells, and add to all wells 4 μL of 50 μM substrate PIP2:3PS prepared with 10×Dilution buffer and ddH 2 O, and finally 2 μL of 50-100 μM ATP solution diluted with water was added to start the reaction. After reacting at room temperature for 90-120 minutes, 10 μL of ADP-Glo Reagent was added to each well ( Containing 10mM MgCl 2 ) at room temperature for 60 minutes to remove excess ATP in the reaction, then add 20 μL Kinase Detection Reagent to each well, react at room temperature for 20 minutes in the dark, and then use a BioTek Synergy H1 microplate reader to detect the chemiluminescence value.
酶名称Enzyme name 酶反应浓度enzyme reaction concentration 酶反应时间Enzyme reaction time ATP浓度ATP concentration
PI3KβPI3Kβ 1μg/mL1μg/mL 90min90min 100μM100μM
PI3KγPI3Kγ 0.5μg/mL0.5μg/mL 120min120min 50μM50μM
PI3KδPI3Kδ 0.25μg/mL0.25μg/mL 90min90min 100μM100μM
实验数据处理方法：Experimental data processing method:
通过于板上阳性对照孔(DMSO对照孔)和阴性对照孔(不添加激酶)计算使用化合物处理的孔的百分比抑制数据{％抑制率＝100-[(测试化合物值-阴性对照值)]/(阳性对照值-阴性对照值)×100}。使用GraphPad prism拟合不同浓度和相应百分比抑制率数据至4参数非线性逻辑公式计算出IC 50值。 Percent inhibition data for wells treated with compounds were calculated by plate positive control wells (DMSO control wells) and negative control wells (no kinase added) {% inhibition = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. IC 50 values were calculated by fitting different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula using GraphPad prism.
实验结论：Experimental results:
通过以上方案得出本发明所示的化合物在PI3Kβ/γ/δ激酶活性试验中显示出约1nM至10000nM(IC 50)的生物活性。 Through the above protocol, it can be concluded that the compounds shown in the present invention exhibit biological activity of about 1 nM to 10000 nM (IC 50 ) in the PI3Kβ/γ/δ kinase activity assay.
在一些实施方案中，本发明的化合物对于PI3Kβ/γ/δ激酶活性的IC 50大于约10nM、优选的化合物大于约100nM、更优选的化合物大于约1000nM、进一步优选的化合物大于约10000nM、本发明所列示的化合物中更进一步优选的化合物大于1000nM或甚至大于约10000nM的IC 50值抑制活性。 In some embodiments, the compounds of the present invention have an IC50 of greater than about 10 nM for PI3K β/γ/δ kinase activity, preferably greater than about 100 nM, more preferably greater than about 1000 nM, and more preferably greater than about 10000 nM. Still further preferred compounds of the listed compounds inhibit activity with IC50 values greater than 1000 nM or even greater than about 10000 nM.
测试例3、本发明化合物对PI3Kα突变型和野生型肿瘤细胞株的增殖抑制活性的测定Test Example 3, Determination of the Proliferation Inhibitory Activity of Compounds of the Present Invention on PI3Kα Mutant and Wild Type Tumor Cell Lines
实验目的：该测试例的目的是测试化合物对不同PI3Kα突变型肿瘤细胞株HCC1954(PIK3CA H1047R)、HGC-27(PIK3CA E542K)、MCF-7(PIK3CA E545K)以及PI3Kα野生型肿瘤细胞株SK-BR-3的增殖抑制活性。Purpose of the experiment: The purpose of this test example is to test the effect of compounds on different PI3Kα mutant tumor cell lines HCC1954 (PIK3CA H1047R), HGC-27 (PIK3CA E542K), MCF-7 (PIK3CA E545K) and PI3Kα wild-type tumor cell line SK-BR Proliferation inhibitory activity of -3.
实验仪器：laboratory apparatus:
离心机(Eppendorf 5810R)Centrifuge (Eppendorf 5810R)
酶标仪(BioTek Synergy H1)Microplate reader (BioTek Synergy H1)
移液器(Eppendorf或Rainin)Pipettes (Eppendorf or Rainin)
二氧化碳培养箱(Thermo 311)CO2 Incubator (Thermo 311)
细胞计数仪(Life Countess Ⅱ)Cell Counter (Life Countess Ⅱ)
实验试剂耗材：Experimental reagent consumables:
HCC1954细胞购自南京科佰生物科技有限公司HCC1954 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.
HGC-27细胞购自中科院细胞所HGC-27 cells were purchased from the Institute of Cells, Chinese Academy of Sciences
MCF-7细胞购自中科院细胞所MCF-7 cells were purchased from the Institute of Cells, Chinese Academy of Sciences
SK-BR-3细胞购自南京科佰生物科技有限公司SK-BR-3 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.
Cell Titer-Glo购自Promega公司，货号为G7573Cell Titer-Glo was purchased from Promega Company, the article number is G7573
RPMI 1640购自Gibco，货号为22400089；RPMI 1640 was purchased from Gibco, the article number is 22400089;
McCoy's 5a购自Gibco，货号为12330-031；McCoy's 5a was purchased from Gibco, the article number is 12330-031;
FBS购自Gibco，货号为10091148；FBS was purchased from Gibco, the article number is 10091148;
PBS购自Gibco，货号为10010023；PBS was purchased from Gibco, the article number is 10010023;
胰酶购自Gibco，货号为25200056；Trypsin was purchased from Gibco, the product number is 25200056;
细胞培养板购自Corning公司，货号为3610The cell culture plate was purchased from Corning Company, the product number is 3610
实验方法：experimental method:
采用Cell Titer-Glo的方法检测了化合物对PI3Kα突变型肿瘤细胞株HCC1954(PIK3CA H1047R)、HGC-27(PIK3CA E542K)、MCF-7(PIK3CA E545K)以及PI3Kα野生型肿瘤细胞株SK-BR-3的增殖抑制活性。不同细胞株使用含10％FBS的RPMI 1640或者McCoy's 5a的完全培养基在37℃，5％CO 2的条件下培养，生长到一定融合度时收集细胞，计数后调整为合适的细胞密度，将细胞以每孔90μL铺于白色96孔板，放入37℃，5％CO 2培养箱培养过夜，加入配制好的不同浓度的化合物溶液，每孔10μL，同时设相应的溶媒对照，继续放入37℃，5％CO 2培养箱培养72小时后，每孔加入50μL CellTiter-Glo溶液，振荡混合均匀后，避光孵育10分钟，用BioTek Synergy H1酶标仪进行读数。。 Cell Titer-Glo method was used to detect the effect of compounds on PI3Kα mutant tumor cell lines HCC1954 (PIK3CA H1047R), HGC-27 (PIK3CA E542K), MCF-7 (PIK3CA E545K) and PI3Kα wild-type tumor cell line SK-BR-3 growth inhibitory activity. Different cell lines were cultured in RPMI 1640 or McCoy's 5a complete medium containing 10% FBS at 37°C and 5% CO 2 . Cells were collected when they grew to a certain degree of confluence, counted and adjusted to an appropriate cell density. Cells were spread on a white 96-well plate with 90 μL per well, cultured overnight in a 37°C, 5% CO 2 incubator, and the prepared compound solutions of different concentrations were added, 10 μL per well, and corresponding solvent controls were set at the same time, and continued to be placed in After culturing in a 5% CO2 incubator at 37°C for 72 hours, add 50 μL of CellTiter-Glo solution to each well, shake and mix evenly, incubate in the dark for 10 minutes, and read with a BioTek Synergy H1 microplate reader. .
实验数据处理方法：Experimental data processing method:
使用发光信号值计算抑制率，将浓度以及抑制率使用Graphpad Prism软件进行非线性回归曲线拟合，得到IC 50值。 The inhibition rate was calculated using the luminescent signal value, and the concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC 50 value.
实验结论：Experimental results:
通过以上方案得出本发明所示的化合物对PI3Kα突变型肿瘤细胞株HCC1954(PIK3CA H1047R)、HGC-27(PIK3CA E542K)、MCF-7(PIK3CA E545K)增殖抑制活性试验中显示出约10nM至10000nM(IC 50)的生物活性。 Through the above scheme, the compound shown in the present invention shows about 10nM to 10000nM in the growth inhibitory activity test of PI3Kα mutant tumor cell lines HCC1954 (PIK3CA H1047R), HGC-27 (PIK3CA E542K), MCF-7 (PIK3CA E545K) (IC 50 ) biological activity.
在一些实施方案中，本发明所制得的化合物对于测试化合物对PI3Kα突变型癌症细胞HCC1954(PIK3CA H1047R)、HGC-27(PIK3CA E542K)、MCF-7(PIK3CA E545K)的增殖抑制活性的IC 50小于约10000nM、优选的化合物小于约5000nM、更优选的化合物小于约1000nM、进一步优选的化合物小于约500nM、更进一步优选的化合物小于100nM的IC 50值抑制活性。 In some embodiments, the compound prepared by the present invention has an IC 50 for the growth inhibitory activity of the test compound on PI3Kα mutant cancer cells HCC1954 (PIK3CA H1047R), HGC-27 (PIK3CA E542K), MCF-7 (PIK3CA E545K) An IC50 value of less than about 10000 nM, preferably less than about 5000 nM, more preferably less than about 1000 nM, more preferably less than about 500 nM, and more preferably less than 100 nM inhibits activity.
测试例4、本发明化合物对PI3Kα突变型和野生型肿瘤细胞内AKT磷酸化水平的抑制活性的测定Test Example 4. Determination of the inhibitory activity of the compounds of the present invention on the phosphorylation level of AKT in PI3Kα mutant and wild-type tumor cells
实验目的：该测试例的目的是测量化合物对PI3Kα突变型及野生型肿瘤细 胞内AKT磷酸化水平的抑制活性。Purpose of the experiment: The purpose of this test example is to measure the inhibitory activity of the compound on the phosphorylation level of AKT in PI3Kα mutant and wild-type tumor cells.
实验仪器：laboratory apparatus:
离心机(5810R)购自Eppendorf公司The centrifuge (5810R) was purchased from Eppendorf Company
移液器购自Eppendorf或Rainin公司Pipettes were purchased from Eppendorf or Rainin
酶标仪购自美国BioTek公司,型号为SynergyH1全功能酶标仪The microplate reader was purchased from BioTek, USA, and the model was Synergy H1 full-function microplate reader.
生物安全柜购自上海***实业有限公司，型号为BSC-1300IIA2The biological safety cabinet was purchased from Shanghai Boxun Industrial Co., Ltd., model BSC-1300IIA2
二氧化碳培养箱购自Thermo公司，型号为311The carbon dioxide incubator was purchased from Thermo Company, model 311
细胞计数仪购自Life公司，型号为Countess IIThe cell counter was purchased from Life Company, model Countess II
实验试剂耗材：Experimental reagent consumables:
HCC1954细胞株购自南京科佰生物科技有限公司HCC1954 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd.
SK-BR-3细胞株购自南京科佰生物科技有限公司SK-BR-3 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd.
HTRF Phospho-AKT(SER473)Detection Kits购自Cisbio公司，货号为64AKSPEGHTRF Phospho-AKT(SER473) Detection Kits were purchased from Cisbio, the article number is 64AKSPEG
McCoy's 5a培养基购自Gibco，货号为12330-031McCoy's 5a medium was purchased from Gibco, catalog number 12330-031
RPMI1640培养基购自Gibco，货号为22400-089RPMI1640 medium was purchased from Gibco, the product number is 22400-089
FBS购自Gibco，货号为10091-148FBS was purchased from Gibco, Cat. No. 10091-148
胰酶购自Gibco，货号为25200-056Trypsin was purchased from Gibco, Cat. No. 25200-056
PBS购自Gibco，货号为10010-023PBS was purchased from Gibco, Cat. No. 10010-023
DMSO购自Sigma，货号为D8418-250mlDMSO was purchased from Sigma, Cat. No. D8418-250ml
细胞培养板购自Corning公司，货号为3610The cell culture plate was purchased from Corning Company, the product number is 3610
计数板购自Invitrogen，货号为C10283Counting plates were purchased from Invitrogen, Cat. No. C10283
白色384孔板购自PE，货号为6007299White 384-well plates were purchased from PE, Cat. No. 6007299
实验方法：experimental method:
本实验采用HTRF方法检测PI3Kα突变型细胞HCC1954(PIK3CA H1047R)、HGC-27(E542K)、MCF-7(E545K)以及PI3Kα野生型细胞SK-BR-3的胞内磷酸化AKT(SER473)水平。不同细胞株使用含10％FBS的RPMI 1640或者McCoy's 5a完全培养基在37℃，5％CO 2的条件下培养，生长到一定融合度时收集细胞，计数后使用完全培养基调整为合适的细胞密度，将细胞悬液铺于96孔板，每孔50μL，放入37℃，5％CO 2培养箱贴壁过夜。使用DMSO以及培养基配制不同浓度的化合物溶液，设置溶媒对照，将化合物溶液加入到96孔板中，每孔50μL，放入37℃，5％CO 2培养箱中继续培养2小时后，弃去上清，加入50μL含封闭液的细胞裂解液室温震荡30分钟至1小时使细胞充***解，吸取16μL上清至384孔板，再加入4μL预混的检测试剂(phospho-AKT Eu Cryptate antibody和phospho-AKT d2 antibody)，振荡混合均匀后，室温避光孵育过夜，用BioTek Synergy H1酶标仪进行读数。 In this experiment, the HTRF method was used to detect the intracellular phosphorylated AKT (SER473) level of PI3Kα mutant cells HCC1954 (PIK3CA H1047R), HGC-27 (E542K), MCF-7 (E545K) and PI3Kα wild-type cells SK-BR-3. Different cell lines were cultured in RPMI 1640 or McCoy's 5a complete medium containing 10% FBS at 37°C and 5% CO 2 , and the cells were collected when they grew to a certain degree of confluence, counted and adjusted to suitable cells using complete medium Density, the cell suspension was spread on a 96-well plate, 50 μL per well, and placed in a 37°C, 5% CO 2 incubator to adhere to the wall overnight. Use DMSO and culture medium to prepare compound solutions of different concentrations, set up the vehicle control, add the compound solution to a 96-well plate, 50 μL per well, put it in a 37°C, 5% CO 2 incubator for 2 hours, then discard For the supernatant, add 50 μL of cell lysate containing blocking solution and shake at room temperature for 30 minutes to 1 hour to fully lyse the cells, pipette 16 μL of the supernatant to a 384-well plate, and then add 4 μL of premixed detection reagents (phospho-AKT Eu Cryptate antibody and phospho -AKT d2 antibody), shake and mix well, incubate overnight at room temperature in the dark, and read with a BioTek Synergy H1 microplate reader.
实验数据处理方法：Experimental data processing method:
使用荧光比值计算抑制率，比值为(665nm信号值/620nm信号值)*10 4，抑制率％＝[(阳性对照孔平均值-样品孔值)/(阳性对照孔平均值-阴性对照孔平均值)]*100，其中阳性对照孔为含细胞裂解液孔，阴性对照孔为裂解液孔。将浓度以及抑制率使用Graphpad Prism软件进行非线性回归曲线拟合，得到IC 50值。 Use the fluorescence ratio to calculate the inhibition rate, the ratio is (665nm signal value/620nm signal value)*10 4 , inhibition rate%=[(positive control well average value-sample well value)/(positive control well average value-negative control well average value value)]*100, where the positive control wells are wells containing cell lysate, and the negative control wells are wells containing lysate. The concentration and inhibition rate were fitted with nonlinear regression curve using Graphpad Prism software to obtain the IC 50 value.
实验结果：Experimental results:
实施例Example HCC1954(H1047R)p-AKT IC50(nM)HCC1954(H1047R)p-AKT IC50(nM)
实施例13Example 13 648648
实施例69Example 69 279279
Figure PCTCN2022136232-appb-000082
Figure PCTCN2022136232-appb-000082
实验结论：Experimental results:
根据以上结果可知，本发明所示的化合物对PI3Kα突变型肿瘤细胞株HCC1954(PIK3CA H1047R)和HGC-27(E542K)的pAKT抑制活性试验中显示出较高的抑制能力。According to the above results, it can be seen that the compounds shown in the present invention have higher inhibitory ability in the pAKT inhibitory activity test of PI3Kα mutant tumor cell lines HCC1954 (PIK3CA H1047R) and HGC-27 (E542K).
测试例5、本发明化合物对Balb/C小鼠Cassette药代动力学的测定(PO)Test example 5, compound of the present invention is to the mensuration (PO) of Balb/C mouse Cassette pharmacokinetics
1.研究目的：1. Research purposes:
以Balb/C小鼠为受试动物，研究以下化合物实施例，在5mg/kg剂量下口服给药在小鼠体内血浆的药代动力学行为。Taking Balb/C mice as the experimental animals, the pharmacokinetics of the following compound examples were orally administered at a dose of 5 mg/kg in mice in vivo.
2.试验方案2. Test plan
2.1试验药品：2.1 Test drugs:
本发明实施例，自制。Embodiment of the present invention, self-made.
2.2试验动物：2.2 Test animals:
Balb/C Mouse 3只/实施例，雄性，上海市计划生育科学研究所实验动物经营部，动物许可证号(SCXK(沪)2018-0006 N0.20180006037467)。Balb/C Mouse 3/embodiment, male, Shanghai Institute of Family Planning Science Experimental Animal Management Department, animal license number (SCXK (Shanghai) 2018-0006 N0.20180006037467).
2.3药物配制：2.3 Drug preparation:
称取5g羟乙基纤维素(HEC，CMC-Na，粘度：800-1200Cps)，溶于1000mL纯净水，加入10g Tween80。混合均匀成澄清溶液。Weigh 5g of hydroxyethylcellulose (HEC, CMC-Na, viscosity: 800-1200Cps), dissolve it in 1000mL of purified water, and add 10g of Tween80. Mix well to form a clear solution.
称取受试化合物各1.6mg，一起溶于3.04mL该溶液中，摇匀，细胞破碎机打碎1min，超声15分钟，得到乳白色混悬溶液，浓度为0.5mg/mL。Weigh 1.6 mg of each test compound, dissolve them together in 3.04 mL of the solution, shake well, crush the cells for 1 min, and sonicate for 15 minutes to obtain a milky white suspension solution with a concentration of 0.5 mg/mL.
2.4给药：2.4 Administration:
Balb/C小鼠，雄性；禁食一夜后p.o.给药，剂量为5mg/kg，给药体积10mL/kg。Balb/C mice, male; administered p.o. after overnight fasting, the dose is 5mg/kg, and the administration volume is 10mL/kg.
2.5样品采集：2.5 Sample collection:
小鼠给药前和给药后，在0、0.5、1、2、4、6、8和24小时，采用眼眶采血0.04mL，置于EDTA-K 2试管中，4℃6000rpm离心6min分离血浆，于-80℃保存，给药后4h进食。 Before and after administration, at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours, 0.04 mL of orbital blood was collected from mice, placed in EDTA-K 2 test tubes, and centrifuged at 6000 rpm at 4°C for 6 minutes to separate plasma , stored at -80°C, and fed 4 hours after administration.
2.6样品处理：2.6 Sample handling:
1)血浆样品40uL加入160uL乙腈沉淀，混合后3500×g离心5～20分钟。1) Add 40uL of plasma sample to 160uL of acetonitrile for precipitation, after mixing, centrifuge at 3500×g for 5-20 minutes.
2)取处理后上清溶液100uL进行LC/MS/MS分析待测化合物的浓度。2) Take 100uL of the treated supernatant solution and analyze the concentration of the compound to be tested by LC/MS/MS.
2.7液相分析2.7 Liquid phase analysis
·液相条件：Shimadzu LC-20AD泵Liquid phase conditions: Shimadzu LC-20AD pump
·质谱条件:ABSciex API 4000质谱仪Mass Spectrometry Conditions: ABSciex API 4000 Mass Spectrometer
·色谱柱：phenomenex Gemiu 5um C18 50×4.6mmChromatographic column: phenomenonex Gemiu 5um C18 50×4.6mm
·移动相：A液为0.1％甲酸水溶液，B液为乙腈Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is acetonitrile
·流速：0.8mL/min·Flow rate: 0.8mL/min
·洗脱时间：0-4.0分钟，洗脱液如下：Elution time: 0-4.0 minutes, the eluent is as follows:
Figure PCTCN2022136232-appb-000083
Figure PCTCN2022136232-appb-000083
3.试验结果与分析3. Test results and analysis
药代动力学主要参数用WinNonlin8.2计算得到，小鼠药代实验结果见下表：The main parameters of pharmacokinetics are calculated by WinNonlin8.2, and the results of pharmacokinetic experiments in mice are shown in the table below:
小鼠药代实验结果(PO)Mouse Pharmacokinetic Experiment Results (PO)
Figure PCTCN2022136232-appb-000084
Figure PCTCN2022136232-appb-000084
注：0.5％CMC-Na(1％吐温80)Note: 0.5% CMC-Na (1% Tween 80)
实验结论：Experimental results:
从表中小鼠药代实验结果可以看出，本发明实施例化合物表现出良好的代谢性质，暴露量AUC和最大血药浓度C max都表现良好。 It can be seen from the results of pharmacokinetic experiments in mice in the table that the compounds of the examples of the present invention exhibit good metabolic properties, and both the exposure AUC and the maximum blood concentration C max are good.

Claims (12)

  1. 一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐：A compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt:
    Figure PCTCN2022136232-appb-100001
    Figure PCTCN2022136232-appb-100001
    其中：in:
    环A，环B和环C各自独立地选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被取代；Ring A, ring B and ring C are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further substituted;
    环A存在或不存在；Ring A is present or absent;
    环C存在或不存在；Ring C is present or absent;
    R 1、R 2和R 3各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nR 11、-(CH 2) nOR 11、-(CH 2) nC(O)R 11、-(CH 2) nC(O)OR 11、-(CH 2) nS(O) mR 11、-(CH 2) nNR 22R 33、-(CH 2) nNR 22C(O)OR 33、-(CH 2) nNR 22C(O)(CH 2) n1R 33、-(CH 2) nNR 22C(O)NR 22R 33、-(CH 2) nC(O)NR 22(CH 2) n1R 33、-OC(R 11R 22) n(CH 2) n1R 33、-(CH 2) nNR 22S(O) mR 33，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代； R 1 , R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, Alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR 33 , -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , -(CH 2 ) n NR 22 C(O )NR 22 R 33 , -(CH 2 ) n C(O)NR 22 (CH 2 ) n1 R 33 , -OC(R 11 R 22 ) n (CH 2 ) n1 R 33 , -(CH 2 ) n NR 22 S(O) m R 33 , the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl, optionally can be further substituted;
    R 11～R 33选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代； R 11 to R 33 are selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, Haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterium Alkenyloxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
    m为0、1或2；m is 0, 1 or 2;
    x、y、z、n和n1各自独立地为0、1、2、3或4。x, y, z, n and n1 are each independently 0, 1, 2, 3 or 4.
  2. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述化合物进一步如通式(I-A)所示：The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, said compound is further shown in general formula (I-A):
    Figure PCTCN2022136232-appb-100002
    Figure PCTCN2022136232-appb-100002
    M选自S＝O、N或C＝O；M is selected from S=O, N or C=O;
    M 1选自N或C； M1 is selected from N or C;
    Figure PCTCN2022136232-appb-100003
    为单键或双键；
    Figure PCTCN2022136232-appb-100003
    is a single or double bond;
    环A和环B各自独立地选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被取代；Ring A and Ring B are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further substituted;
    或，优选地，环A和环B形成含1-3个选自O，S或N的杂原子的6-20元稠杂环或含1-3个选自O，S或N的杂原子的6-20元稠杂芳环；更优选地，环A和环B形成含1-3个N，S或O的8-10元稠杂芳环；进一步优选地，环A和环B形成如下任一稠杂芳环：
    Figure PCTCN2022136232-appb-100004
    Figure PCTCN2022136232-appb-100005
    Or, preferably, Ring A and Ring B form a 6-20 membered condensed heterocyclic ring containing 1-3 heteroatoms selected from O, S or N or contain 1-3 heteroatoms selected from O, S or N 6-20 membered fused heteroaromatic ring; more preferably, ring A and ring B form an 8-10 membered fused heteroaromatic ring containing 1-3 N, S or O; further preferably, ring A and ring B form Any of the following fused heteroaromatic rings:
    Figure PCTCN2022136232-appb-100004
    Figure PCTCN2022136232-appb-100005
    或，优选地，环A不存在，环B选自6-12元芳基或含1-4个杂原子的5-14元杂芳基；更优选地，环A不存在，环B选自含1-2个杂原子的5元杂芳基；进一步优选地，环A不存在，环B选自
    Figure PCTCN2022136232-appb-100006
    Or, preferably, ring A does not exist, and ring B is selected from 6-12 membered aryls or 5-14 membered heteroaryls containing 1-4 heteroatoms; more preferably, ring A does not exist, and ring B is selected from A 5-membered heteroaryl group containing 1-2 heteroatoms; further preferably, ring A does not exist, and ring B is selected from
    Figure PCTCN2022136232-appb-100006
    R 1各自独立地选自环烷基、杂环基、芳基、杂芳基；优选为芳基；更优选为6-12元芳基；进一步优选为苯基；所述R 1任选地可以被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基取代； R 1 are each independently selected from cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably aryl; more preferably 6-12 membered aryl; further preferably phenyl; Can be substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl;
    R 2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷基或C 1-6氘代烷基的一个或多个取代基所取代，优选氢、氘、卤素、烷基、卤代烷基、氘代烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33； R 2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optional is substituted by one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuterated alkyl, preferably hydrogen, deuterium, Halogen, alkyl, haloalkyl, deuterated alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 ;
    R 3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷基或C 1-6氘代烷基的一个或多个取代基所取代，优选C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷基或C 1-6氘代烷基的一个或多个取代基所取代； R 3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3- 12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, optionally replaced by hydrogen, hydroxyl, halogen, cyano, amino, C 1-6 alkyl, One or more substituents of C 1-6 haloalkyl or C 1-6 deuterated alkyl, preferably C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5 -12-membered heteroaryl, optionally substituted by one or more of hydrogen, hydroxyl, halogen, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuterated alkyl base replaced;
    条件是，当环A存在时，R 2和R 3不同时为H； Provided that, when ring A exists, R2 and R3 are not H at the same time;
    R 22选自氢、氘、卤素； R 22 is selected from hydrogen, deuterium, halogen;
    R 33选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷 氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基取代，优选C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷基或C 1-6氘代烷基的一个或多个取代基所取代； R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally can be further replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl , haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution, preferably C 3-12 ring Alkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, optionally replaced by hydrogen, hydroxyl, halogen, cyano, amino, C 1-6 alkyl, C 1 One or more substituents of -6 haloalkyl or C 1-6 deuterated alkyl;
    y和z各自独立地为1、2、3或4；y and z are each independently 1, 2, 3 or 4;
    n、n1和m1各自独立地为0、1、2、3或4。n, n1 and m1 are each independently 0, 1, 2, 3 or 4.
  3. 根据权利要求2所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述化合物进一步如通式(I-A-1)所示：The compound according to claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is further shown in the general formula (I-A-1):
    Figure PCTCN2022136232-appb-100007
    Figure PCTCN2022136232-appb-100007
    其中：in:
    M 2选自N或C； M2 is selected from N or C;
    环D存在或不存在；环E存在或不存在；且环D和环E不存在的情况不能同时发生；The presence or absence of ring D; the presence or absence of ring E; and the absence of ring D and ring E cannot occur simultaneously;
    环D和环E各自独立地选自环烷基、杂环基、芳基或杂芳基，优选含1-3个选自氮、氧或硫原子的3-10元杂环基或含1-3个选自氮、氧或硫原子5-10元杂芳基，更优选含1-3个选自氮、氧或硫原子的3-6元杂环基或含1-3个选自氮、氧或硫原子5-8元杂芳基，进一步优选
    Figure PCTCN2022136232-appb-100008
    Figure PCTCN2022136232-appb-100009
    Ring D and ring E are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably 3-10 membered heterocyclic groups containing 1-3 selected from nitrogen, oxygen or sulfur atoms or containing 1 -3 5-10 membered heteroaryl groups selected from nitrogen, oxygen or sulfur atoms, more preferably 1-3 3-6 membered heterocyclic groups selected from nitrogen, oxygen or sulfur atoms or 1-3 members selected from Nitrogen, oxygen or sulfur atom 5-8 membered heteroaryl, more preferably
    Figure PCTCN2022136232-appb-100008
    Figure PCTCN2022136232-appb-100009
  4. 根据权利要求2所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述化合物进一步如通式(I-A-2)所示：The compound according to claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is further shown in the general formula (I-A-2):
    Figure PCTCN2022136232-appb-100010
    Figure PCTCN2022136232-appb-100010
    M选自S＝O或C＝O。M is selected from S=O or C=O.
  5. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述化合物进一步如通式(I-B)所示：The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, said compound is further shown in general formula (I-B):
    Figure PCTCN2022136232-appb-100011
    Figure PCTCN2022136232-appb-100011
    W 1和W 2各自独立地选自N或CR c； W 1 and W 2 are each independently selected from N or CR c ;
    R c选自氢、氘、卤素、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基或炔基； R is selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl or alkynyl;
    环C选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被取代；优选地，环C选自杂环基或杂芳基，任选地可以进一步被取代；更优选地，环C选自3-12元杂环基或5-12元杂芳基，任选地可以进一步被取代；进一步优选地，环C选自
    Figure PCTCN2022136232-appb-100012
    Ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally can be further substituted; preferably, ring C is selected from heterocyclyl or heteroaryl, optionally can be further substituted; More preferably, ring C is selected from 3-12 membered heterocyclic groups or 5-12 membered heteroaryl groups, which may be further substituted; further preferably, ring C is selected from
    Figure PCTCN2022136232-appb-100012
    R 1各自独立地选自氢、氘、卤素、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基；优选为烷基或芳基；更优选为C 1-6烷基或6-12元芳基；进一步优选为甲基或苯基；其中至少一个R 1为取代的苯基；所述R 1任选地可以被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基取代； Each R is independently selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl, heteroaryl; preferably alkyl or aryl; more preferably C 1-6 alkyl or 6-12 yuan aryl; further preferably methyl or phenyl; wherein at least one R 1 is substituted phenyl; said R can optionally be replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl , alkoxy, alkenyl, alkynyl substitution;
    R 2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基和C 1-6烷基的一个或多个取代基所取代，优选氢、氘、卤素、烷基、卤代烷基、氘代烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33，且其中至少一个R 2选自-(CH 2) nNR 22C(O)(CH 2) n1R 33； R 2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optional substituted by one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino and C 1-6 alkyl, preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , and wherein at least one R 2 is selected from -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 ;
    R 22选自氢、氘、卤素； R 22 is selected from hydrogen, deuterium, halogen;
    R 33选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基取代，优选C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷基或C 1-6氘代烷基的一个 或多个取代基所取代； R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally can be further replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl , haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution, preferably C 3-12 ring Alkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, optionally replaced by hydrogen, hydroxyl, halogen, cyano, amino, C 1-6 alkyl, C 1 One or more substituents of -6 haloalkyl or C 1-6 deuterated alkyl;
    x和y各自独立地为1、2、3或4；x and y are each independently 1, 2, 3 or 4;
    n和n1各自独立地为0、1、2、3或4。n and n1 are each independently 0, 1, 2, 3 or 4.
  6. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述化合物进一步如通式(I-C)所示：The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is further shown in general formula (I-C):
    Figure PCTCN2022136232-appb-100013
    Figure PCTCN2022136232-appb-100013
    R 2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基和C 1-6烷基的一个或多个取代基所取代，优选氢、氘、卤素、烷基、卤代烷基、氘代烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33，且其中至少一个R 2选自-(CH 2) nNR 22C(O)(CH 2) n1R 33； R 2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optional substituted by one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino and C 1-6 alkyl, preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , and wherein at least one R 2 is selected from -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 ;
    R 22选自氢、氘、卤素； R 22 is selected from hydrogen, deuterium, halogen;
    R 33选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基取代，优选C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷基或C 1-6氘代烷基的一个或多个取代基所取代； R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally can be further replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl , haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution, preferably C 3-12 ring Alkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, optionally replaced by hydrogen, hydroxyl, halogen, cyano, amino, C 1-6 alkyl, C 1 One or more substituents of -6 haloalkyl or C 1-6 deuterated alkyl;
    R 4选自氢、氘、卤素、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基；优选为芳基；更优选为6-12元芳基；进一步优选为苯基；所述R 4任选地可以被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基取代； R is selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycle Base, aryl, heteroaryl; preferably aryl; more preferably 6-12 yuan aryl; further preferably phenyl; said R optionally can be hydrogen, deuterium, halogen, nitro, hydroxyl, Mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl substitution;
    R 5选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基；优选为氨基或羟基； R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy , haloalkoxy, alkenyl, alkynyl; preferably amino or hydroxyl;
    y为1、2、3或4；y is 1, 2, 3 or 4;
    n和n1各自独立地为0、1、2、3或4。n and n1 are each independently 0, 1, 2, 3 or 4.
  7. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述化合物进一步如通式(I-D)所示：The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, said compound is further shown in general formula (I-D):
    Figure PCTCN2022136232-appb-100014
    Figure PCTCN2022136232-appb-100014
    Figure PCTCN2022136232-appb-100015
    代表双键或单键；
    Figure PCTCN2022136232-appb-100015
    represents a double bond or a single bond;
    M 1或M 2各自独立地选自S、NR a或CR b； M or M are each independently selected from S, NR a or CR b ;
    R a和R b各自独立地选自氢、氘、卤素、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基或炔基； R and R are each independently selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl or alkynyl;
    R 1各自独立地选自氢、氘、卤素、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基；优选为芳基；更优选为6-12元芳基；进一步优选为苯基；所述R 1任选地可以被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、烯基、炔基取代； Each R is independently selected from hydrogen, deuterium, halogen, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl, heteroaryl; preferably aryl; more preferably 6-12 yuan aryl; further preferably phenyl; said R optionally can be hydrogen, deuterium, halogen, nitro , hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl substitution;
    R 2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基和C 1-6烷基的一个或多个取代基所取代，优选氢、氘、卤素、烷基、卤代烷基、氘代烷基、-(CH 2) nNR 22C(O)(CH 2) n1R 33，且其中至少一个R 2选自-(CH 2) nNR 22C(O)(CH 2) n1R 33； R 2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optional substituted by one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino and C 1-6 alkyl, preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , and wherein at least one R 2 is selected from -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 ;
    R 22选自氢、氘、卤素； R 22 is selected from hydrogen, deuterium, halogen;
    R 33选自环烷基、杂环基、芳基或杂芳基，任选地可以进一步被氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基取代，优选C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，任选的被氢、羟基、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷基或C 1-6氘代烷基的一个或多个取代基所取代； R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally can be further replaced by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl , haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution, preferably C 3-12 ring Alkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, optionally replaced by hydrogen, hydroxyl, halogen, cyano, amino, C 1-6 alkyl, C 1 One or more substituents of -6 haloalkyl or C 1-6 deuterated alkyl;
    x或y各自独立地为1、2、3或4；x or y are each independently 1, 2, 3 or 4;
    n或n1各自独立地为0、1、2、3或4；n or n1 are each independently 0, 1, 2, 3 or 4;
    n2为0、1或2。n2 is 0, 1 or 2.
  8. 根据权利要求1-7任一项所述的化合物、其立体异构体或其药学上可接受 的盐，其特征在于，The compound according to any one of claims 1-7, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that,
    R 1各自独立地选自被卤素取代的苯基；优选为被1～3个选自氟、氯和溴原子取代的苯基，更优选为
    Figure PCTCN2022136232-appb-100016
    R 1 are each independently selected from phenyl substituted by halogen; preferably phenyl substituted by 1 to 3 atoms selected from fluorine, chlorine and bromine, more preferably
    Figure PCTCN2022136232-appb-100016
    R 2各自独立地选自氢、氘、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6氘代烷基、-NHC(O)R 33；优选地，R 2各自独立地选自氢、甲基、
    Figure PCTCN2022136232-appb-100017
    Figure PCTCN2022136232-appb-100018
    且当环A不存在时，其中至少一个R 2选自
    Figure PCTCN2022136232-appb-100019
    Figure PCTCN2022136232-appb-100020
    R 2 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, -NHC(O)R 33 ; preferably, each of R 2 independently selected from hydrogen, methyl,
    Figure PCTCN2022136232-appb-100017
    Figure PCTCN2022136232-appb-100018
    And when ring A is absent, wherein at least one R 2 is selected from
    Figure PCTCN2022136232-appb-100019
    Figure PCTCN2022136232-appb-100020
    R 3各自独立地选自氢、氘、C 6-10芳基或5-10元杂芳基，所述C 6-10芳基或5-10元杂芳基被氢、羟基、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷基或C 1-6氘代烷基的一个或多个取代基所取代；优选氢、氘、苯基或5-10元杂芳基，所述苯基或5-10元杂芳基被氢、羟基、氟、氯、溴、三氟甲基的一个或多个取代基所取代；更优选氢、氘、
    Figure PCTCN2022136232-appb-100021
    R 3 are each independently selected from hydrogen, deuterium, C 6-10 aryl or 5-10 membered heteroaryl, and the C 6-10 aryl or 5-10 membered heteroaryl is replaced by hydrogen, hydroxyl, halogen, cyano One or more substituents of radical, amino, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuterated alkyl; preferably hydrogen, deuterium, phenyl or 5-10 membered heteroaryl base, the phenyl or 5-10 membered heteroaryl is substituted by one or more substituents of hydrogen, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl; more preferably hydrogen, deuterium,
    Figure PCTCN2022136232-appb-100021
    “*”代表连接位点。"*" represents a ligation site.
  9. 根据权利要求1-8任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，选自如下化合物：The compound according to any one of claims 1-8, its stereoisomer or pharmaceutically acceptable salt thereof, is characterized in that it is selected from the following compounds:
    Figure PCTCN2022136232-appb-100022
    Figure PCTCN2022136232-appb-100022
    Figure PCTCN2022136232-appb-100023
    Figure PCTCN2022136232-appb-100023
    Figure PCTCN2022136232-appb-100024
    Figure PCTCN2022136232-appb-100024
    R 2各自独立地选自： R 2 are each independently selected from:
    Figure PCTCN2022136232-appb-100025
    Figure PCTCN2022136232-appb-100025
    R 3各自独立地为： R 3 are each independently:
    Figure PCTCN2022136232-appb-100026
    Figure PCTCN2022136232-appb-100026
  10. 一种药物组合物，其包括治疗有效剂量的权利要求1～9任一所示的通式化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective dose of the compound of the general formula shown in any one of claims 1 to 9, its stereoisomer or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier, diluent or excipient.
  11. 根据权利要求1～9任一所示的通式化合物、其立体异构体或其药学上可接受的盐，或权利要求10所述的药物组合物在制备治疗与PI3Kα相关疾病的 药物中的应用。According to the compound of the general formula shown in any one of claims 1 to 9, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 10 in the preparation of medicines for treating diseases related to PI3Kα application.
  12. 根据权利要求1～9任一所示的通式化合物、其立体异构体或其药学上可接受的盐，或权利要求10所述的药物组合物在制备治疗癌症、PROS、免疫病症或炎性病症中的应用；其中所述PROS选自血管畸形、***畸形及巨脑症，癌症选自胃癌、乳腺癌、***癌、肺癌、肝癌、骨癌、脑癌、头颈癌、肠癌、胰腺癌、膀胱癌、睾丸癌、卵巢癌、子宫内膜癌及多发性骨髓瘤。According to the compound of the general formula shown in any one of claims 1 to 9, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in claim 10 in the preparation and treatment of cancer, PROS, immune disorders or inflammation sexual diseases; wherein the PROS is selected from vascular malformation, lymphatic malformation and megalencephaly, and the cancer is selected from gastric cancer, breast cancer, prostate cancer, lung cancer, liver cancer, bone cancer, brain cancer, head and neck cancer, intestinal cancer, Pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer, endometrial cancer and multiple myeloma.
PCT/CN2022/136232 2021-12-02 2022-12-02 Fused ring derivative, preparation method therefor, and application thereof WO2023098880A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111458328 2021-12-02
CN202111458328.4 2021-12-02

Publications (1)

Publication Number Publication Date
WO2023098880A1 true WO2023098880A1 (en) 2023-06-08

Family

ID=86611560

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/136232 WO2023098880A1 (en) 2021-12-02 2022-12-02 Fused ring derivative, preparation method therefor, and application thereof

Country Status (1)

Country Link
WO (1) WO2023098880A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024051784A1 (en) * 2022-09-09 2024-03-14 上海璎黎药业有限公司 Nitrogen-containing heterocyclic compound, pharmaceutical composition thereof, and use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011087776A1 (en) * 2009-12-22 2011-07-21 Vertex Pharmaceuticals Incorporated Isoindolinone inhibitors of phosphatidylinositol 3-kinase
WO2015193765A1 (en) * 2014-06-17 2015-12-23 Pfizer Inc. Substituted dihydroisoquinolinone compounds
WO2017055860A1 (en) * 2015-09-29 2017-04-06 Astex Therapeutics Limited Isoindolinone inhibitors of the mdm2-p53 interaction having anticancer activity
WO2021222556A1 (en) * 2020-04-29 2021-11-04 Relay Therapeutics, Inc. PI3K-α INHIBITORS AND METHODS OF USE THEREOF

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011087776A1 (en) * 2009-12-22 2011-07-21 Vertex Pharmaceuticals Incorporated Isoindolinone inhibitors of phosphatidylinositol 3-kinase
WO2015193765A1 (en) * 2014-06-17 2015-12-23 Pfizer Inc. Substituted dihydroisoquinolinone compounds
WO2017055860A1 (en) * 2015-09-29 2017-04-06 Astex Therapeutics Limited Isoindolinone inhibitors of the mdm2-p53 interaction having anticancer activity
WO2021222556A1 (en) * 2020-04-29 2021-11-04 Relay Therapeutics, Inc. PI3K-α INHIBITORS AND METHODS OF USE THEREOF

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024051784A1 (en) * 2022-09-09 2024-03-14 上海璎黎药业有限公司 Nitrogen-containing heterocyclic compound, pharmaceutical composition thereof, and use thereof

Similar Documents

Publication Publication Date Title
CN111295384B (en) Bicyclic derivative inhibitor, preparation method and application thereof
WO2022223025A1 (en) Heterocyclic derivative inhibitor and preparation method therefor and application thereof
AU2017250448C1 (en) Heterocyclic compounds as RET kinase inhibitors
US20210008023A1 (en) N4-phenyl-quinazoline-4 -amine derivatives and related compounds as ErbB type I receptor tyrosine kinase inhibitors for the treatment of hyperproliferative diseases
AU2011288876B2 (en) Phthalazinone ketone derivative, preparation method thereof, and pharmaceutical use thereof
EP3356345B1 (en) Heteroaryl derivatives as sepiapterin reductase inhibitors
JP4718637B2 (en) Pyrido (2,3-D) pyrimidinone compounds and their use as PI3 inhibitors
TWI713952B (en) Compounds and compositions as inhibitors of bromodomain proteins
JP5591809B2 (en) Imidazo [1,5] naphthyridine compounds, their use in medicine and compositions
US9956220B2 (en) Imidazo-pyridazine derivatives as casein kinase 1 δ/ϵ inhibitors
JP2012514044A (en) Heteroaryl compounds useful as Raf kinase inhibitors
WO2020108613A1 (en) Heteroaromatic derivatives for use as regulator, preparation method therefor and use thereof
BR112013000275B1 (en) tetrahydro-pyrido-pyrimidine derivatives, their uses, pharmaceutical composition and composition
JP5722781B2 (en) Fused heterocyclic derivatives and uses thereof
KR20220061958A (en) Heterobicyclic amides as inhibitors of CD38
CN107207504B (en) Phthalazinone derivatives, preparation method and use thereof
JP2022517085A (en) Halogenated allylamine compounds and their applications
EP3313852B1 (en) Substituted pyrazolo/imidazolo bicyclic compounds as pde2 inhibitors
WO2023067546A1 (en) Novel bicyclic heteroaryl derivatives as sos1:kras proteinprotein interaction inhibitors
AU2019280356B2 (en) ERK inhibitor and use thereof
WO2023098880A1 (en) Fused ring derivative, preparation method therefor, and application thereof
CN114907358A (en) Pyridine-containing polycyclic derivative regulator, and preparation method and application thereof
JP2021011492A (en) 4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE COMPOUND
CN113150012B (en) Pyrazolo [1,5-a ] pyrazine derivative and preparation method and application thereof
WO2023185073A1 (en) Parp7 inhibitor and use thereof

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: 22900684

Country of ref document: EP

Kind code of ref document: A1