WO2023186058A1 - Indazole compound, preparation method therefor, and use thereof in medicine - Google Patents

Indazole compound, preparation method therefor, and use thereof in medicine Download PDF

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Publication number
WO2023186058A1
WO2023186058A1 PCT/CN2023/085315 CN2023085315W WO2023186058A1 WO 2023186058 A1 WO2023186058 A1 WO 2023186058A1 CN 2023085315 W CN2023085315 W CN 2023085315W WO 2023186058 A1 WO2023186058 A1 WO 2023186058A1
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group
alkyl
general formula
cycloalkyl
cancer
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PCT/CN2023/085315
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French (fr)
Chinese (zh)
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张志高
陈露
***
李心
贺峰
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2023186058A1 publication Critical patent/WO2023186058A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

Definitions

  • the present disclosure belongs to the field of medicine and relates to an indazole compound, its preparation method and its application in medicine. Specifically, the present disclosure relates to an indazole compound represented by general formula (I), its preparation method, pharmaceutical compositions containing such compounds, and its use as a TEAD inhibitor, especially in the preparation of compounds for the treatment of and/or use in cancer prevention drugs.
  • the Hippo signaling pathway was discovered in Drosophila and is a conserved signaling pathway in mammals. It regulates the growth and development of the body or organs, cell homeostasis, cell proliferation and differentiation, etc.
  • the Hippo signaling pathway is a cascade signaling network composed of a series of kinases that regulate the downstream transcription co-activator YAP/TAZ into and out of the nucleus through phosphorylation.
  • YAP/TAZ enters the cell nucleus, binds to TEAD family transcription factors TEAD1-4, regulates target gene transcription, and then exerts a variety of biological behaviors.
  • TEAD proteins are generally considered to be the main effector molecules mediating the growth-promoting and carcinogenic effects of YAP/TAZ.
  • YAP and/or TAZ are expressed or entered into the nucleus in some tumors, such as breast cancer, non-small cell lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, and osteosarcoma. Elevated leading to overactivation. Hippo pathway gene mutations account for about 10% of tumors.
  • tumors such as cervical cancer, ovarian cancer, head and neck cancer, lung cancer, liver cancer, breast cancer, and prostate cancer with YAP and/or TAZ amplification , YAP, TAZ gene fusion epithelioid hemangioendothelioma, ependymoma and other tumors.
  • YAP/TAZ activation also plays a role in resistance to chemotherapy or inhibitors of the MAPK pathway such as EGFR, ALK, RAF/MEK. Studies have shown that YAP/TAZ mediates primary or secondary resistance to the above drugs by inhibiting apoptotic protein levels and upregulating spindle assembly checkpoints.
  • inhibiting the tumor-promoting transcriptional activity of YAP/TAZ-TEAD by inhibiting palmitoylation of TEAD protein or inhibiting YAP/TAZ-TEAD protein interaction is expected to become an effective treatment for the above-mentioned tumors.
  • Z is O or NH
  • Ring A is aryl or heteroaryl
  • R is an alkyl group or R w R x N, and the alkyl group is optionally selected from one of deuterium atoms, halogen, alkoxy, deuterated alkoxy, haloalkoxy, cyano, amino and hydroxyl or Substituted with multiple substituents;
  • R 1 is selected from hydrogen atom, deuterium atom, halogen, alkyl group, R v O and R y R z N, and the alkyl group is optionally selected from deuterium atom, halogen, alkoxy group, deuterated alkoxy group, Substituted with one or more substituents among haloalkoxy, cyano, amino and hydroxyl;
  • R w , R x , Ry and R z are the same or different, and are each independently selected from hydrogen atoms, deuterium atoms and alkyl groups.
  • the alkyl groups are optionally selected from deuterium atoms, halogens, alkoxy groups, deuterium atoms. Substituted with one or more substituents from alkoxy, haloalkoxy, cyano, amino and hydroxy;
  • Rv is selected from alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently selected from Deuterium atom, halogen, oxo group, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, deuterated alkoxy group, haloalkoxy group, nitro group, cyano group, amino group, hydroxyl group, hydroxyalkyl group, cycloalkyl group Substituted with one or more substituents among base, heterocyclyl, aryl and heteroaryl;
  • R a and R b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a haloalkyl group and a hydroxyalkyl group;
  • R 2 , R 3 and R 4 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, -NR n1 R n2 , -C( O)NR n3 R n4 , -C(O)R a1 , -C(O)OR a2 , -OR a3 , -S(O) t1 R a4 , cycloalkyl, heterocyclyl, aryl and heteroaryl ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of deuterium atoms, halogens, oxo groups, alkyl groups, deuterated groups In alkyl, halo
  • Each R 5 is the same or different, and each is independently selected from deuterium atom, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, -NR n5 R n6 , -C(O)NR n7 R n8 , - C(O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from deuterium, halogen, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy Substituted with one or more substituents of base, deuterated alkoxy, haloalkoxy, nitro, cyan
  • R n1 , R n2 , R n3 , R n4 , R n5 , R n6 , R n7 and R n8 are the same or different each time they appear, and are each independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups base, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R n1 and R n2 together with the connected nitrogen atom form a heterocyclic group
  • R n3 and R n4 together with the connected nitrogen atom form a heterocyclic group
  • R n5 and R n6 together with the connected nitrogen atom form a heterocyclic group
  • R n7 and R n8 together with the attached nitrogen atom form a heterocyclic group, each of which is independently selected from the group consisting of deuterium atoms, halogens, and oxo groups.
  • R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 are the same or different each time they appear, and are each independently selected from hydrogen atoms, deuterium atoms, alkyl groups, and hydroxyalkyl groups.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of deuterium atoms, halogens, Oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl , substituted by one or more substituents in aryl and heteroaryl;
  • t1 0, 1 or 2;
  • t2 is 0, 1 or 2;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1 or 2;
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably , Ring A is phenyl or 6-membered heteroaryl; further preferably, ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl; more preferably, ring A is phenyl or pyridyl ; Most preferably, Ring A is phenyl.
  • each R 5 is the same or different, and each is independently selected from halogen, C 1-6 alkane group, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N, C 1- 6 alkoxy, C 1-6 haloalkoxy and 3 to 8-membered cycloalkyl; preferably, each R 5 is the same or different, and each is independently selected from halogen, C 1-6 alkyl and C 1-6 Haloalkyl; further preferably, R 5 is C 1-6 haloalkyl; more preferably, R 5 is trifluoromethyl.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein m is 0 or 1; preferably, m is 1.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein R is a C 1-6 alkyl group, and the C 1-6 alkyl group is optionally Selected from deuterium, halogen, C 1-6 alkoxy and C 1-6 Substituted with one or more substituents in the haloalkoxy group; preferably, R is C 1-6 alkyl or C 1-6 deuterated alkyl; further preferably, R is C 1-6 alkyl; more preferably Ground, R is methyl.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:
  • G 0 is a nitrogen atom or CR 5a ;
  • G 1 is a nitrogen atom or CR 5b ;
  • G 2 is a nitrogen atom or CR 5d ;
  • G 3 is a nitrogen atom or CR 5e ;
  • R 5a is selected from hydrogen atom, deuterium atom, F, Br, I, alkyl group, alkenyl group, alkynyl group, nitro group, cyano group, -NR n5 R n6 , -C(O)NR n7 R n8 , -C( O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl and alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of deuterium atoms, halogens, oxo groups, alkyl groups, deuterated alkyl groups, haloalkyl groups, alkoxy groups, Substituted with one or more substituents from deuterated alk
  • R 5c is selected from hydrogen atom, deuterium atom, Cl, Br, I, alkyl group, alkenyl group, alkynyl group, nitro group, cyano group, -NR n5 R n6 , -C(O)NR n7 R n8 , -C( O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl and alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of deuterium atoms, halogens, oxo groups, alkyl groups, deuterated alkyl groups, haloalkyl groups, alkoxy groups, Substituted with one or more substituents from deuterated alk
  • R 5b , R 5d and R 5e are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, -NR n5 R n6 , -C( O)NR n7 R n8 , -C(O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of deuterium atoms, halogens, oxo groups, alkyl groups, deuterated groups In alkyl,
  • Z, R w , R x , R 1 , R 2 , R 3 , R 4 , R a , R b , R n5 , R n6 , R n7 , R n8 , R a5 , R a6 , R a7 , R a8 , t2 and n are as defined in general formula (I).
  • the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable compound thereof Salts used wherein R 2 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano group, amino, C 1- 6 alkyl NH, (C 1-6 alkyl) 2 N, C 1-6 alkoxy, C 1-6 haloalkoxy and 3 to 8-membered cycloalkyl; preferably, R 2 is selected from hydrogen atom, Halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, R 2 is a hydrogen atom.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein R 3 is selected from hydrogen atom, halogen, C 1-6 alkane group, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N, C 1- 6 alkoxy, C 1-6 haloalkoxy and 3 to 8-membered cycloalkyl; preferably, R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably , R 3 is a hydrogen atom.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein R 4 is selected from hydrogen atom, halogen, C 1-6 alkane group, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N, C 1- 6 alkoxy, C 1-6 haloalkoxy and 3 to 8-membered cycloalkyl; preferably, R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably , R 4 is a hydrogen atom.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein R a is selected from hydrogen atoms, halogens and C 1-6 alkane group; preferably, R a is a hydrogen atom.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein R b is selected from hydrogen atoms, halogens and C 1-6 alkane group; preferably, R b is a hydrogen atom.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein G 0 is CR 5a and R 5a is selected from hydrogen atoms, F, Br, I, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N , C 1-6 alkoxy group, C 1-6 haloalkoxy group and 3 to 8-membered cycloalkyl group; preferably, G 0 is CR 5a , R 5a is selected from hydrogen atom, F, Br, I, C 1- 6 alkyl and C 1-6 haloalkyl; more preferably, G 0 is CH.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein G 2 is CR 5d and R 5d is selected from hydrogen atoms, halogens, C 1-6 alkane group, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N, C 1- 6 alkoxy, C 1-6 haloalkoxy and 3 to 8-membered cycloalkyl; preferably, G 2 is CR 5d , R 5d is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 Haloalkyl; more preferably, G 2 is CH.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof. Salt used:
  • the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein R 1 is selected from a hydrogen atom, C 1-6 alkyl, R v O and R y R z N, the C 1-6 alkyl is optionally selected from deuterium atom, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy , substituted by one or more substituents among cyano group, amino group and hydroxyl group, R v , R y and R z are as defined in the general formula (I); preferably, R 1 is selected from hydrogen atom, C 1-6 Alkyl, R v O and R y R z N, Ry and R z are as defined in the general formula (I); further preferably, R 1 is selected from a hydrogen atom, C 1-6 alkyl, R v O and R y R z N, R y and R z are the same or different, and are each
  • the C 1-6 alkyl group is optionally selected from the group consisting of deuterium atom, halogen, C 1-6 alkoxy group and C 1-6 haloalkoxy group.
  • R y and R z are the same or different, and each is independently selected from a hydrogen atom, a C 1-6 alkyl group and a C 1-6 deuterated alkyl group; further preferably Specifically, R y and R z are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; further preferably, R y and R z are the same or different, and each is independently a hydrogen atom or a methyl group.
  • the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein R v is a C 1-6 alkane group or a 3- to 6-membered cycloalkyl group, and each of the C 1-6 alkyl or 3 to 6-membered cycloalkyl groups is independently selected from the group consisting of deuterium atom, halogen, C 1-6 alkyl, C 1- Substituted with one or more substituents in 6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, amino, hydroxyl and C 1-6 hydroxyalkyl; preferably, R v It is a C 1-6 alkyl group or a 3- to 6-membered cycloalkyl group.
  • the C 1-6 alkyl group or a 3- to 6-membered cycloalkyl group is each independently selected from the group consisting of deuterium atoms, halogens and C 1-6 Substituted with one or more substituents in the alkyl group; further preferably, R v is selected from C 1-6 alkyl, C 1-6 deuterated alkyl and 3 to 6-membered cycloalkyl; more preferably, R v is C 1-6 alkyl or C 1-6 deuterated alkyl; more preferably, R v is C 1-6 alkyl; most preferably, R v is methyl or isopropyl.
  • the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein G 1 is CR 5b and R 5b is selected from hydrogen atom, halogen , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano group, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N, C 1-6 alkoxy group, C 1-6 haloalkoxy group and 3 to 8-membered cycloalkyl group; preferably, G 1 is CR 5b , R 5b is selected from hydrogen atom, halogen, C 1-6 alkane and C 1-6 haloalkyl; more preferably, G 1 is CH.
  • the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein G 3 is CR 5e and R 5e is selected from hydrogen atom, halogen , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N, C 1-6 alkoxy, C 1-6 haloalkoxy and 3 to 8-membered cycloalkyl; preferably, G 3 is CR 5e , and R 5e is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, G 3 is CH.
  • the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein R 5e is selected from hydrogen atoms, F, Br, I, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N , C 1-6 alkoxy group, C 1-6 haloalkoxy group and 3 to 8-membered cycloalkyl group; preferably, R 5e is selected from hydrogen atom, F, Br, I, C 1-6 alkyl group and C 1 -6 haloalkyl; more preferably, R 5e is H.
  • the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein R 5c is selected from hydrogen atom, Cl, Br, I, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N , C 1-6 alkoxy group, C 1-6 haloalkoxy group and 3 to 8-membered cycloalkyl group; preferably, R 5c is selected from hydrogen atom, Cl, Br, I, C 1-6 alkyl group and C 1 -6 haloalkyl; further preferably, R 5c is a hydrogen atom or C 1-6 haloalkyl; more preferably, R 5c is a hydrogen atom or trifluoromethyl.
  • the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein R w is a hydrogen atom or C 1 -6 alkyl, the C 1-6 alkyl is optionally substituted with one or more substituents selected from deuterium atoms, halogens, C 1-6 alkoxy and C 1-6 haloalkoxy;
  • R w is selected from hydrogen atom, C 1-6 alkyl group and C 1-6 deuterated alkyl group; further preferably, R w is a hydrogen atom or C 1-6 alkyl group; more preferably, R w is Hydrogen atom or methyl group.
  • the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein R x is a hydrogen atom or C 1 -6 alkyl, the C 1-6 alkyl is optionally substituted with one or more substituents selected from deuterium atoms, halogens, C 1-6 alkoxy and C 1-6 haloalkoxy;
  • Rx is selected from a hydrogen atom , a C 1-6 alkyl group and a C 1-6 deuterated alkyl group; further preferably, R C 1-6 alkyl; more preferably, R x is methyl.
  • the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein R n1 , R n2 , R n3 , R n4 , R n5 , R n6 , R n7 and R n8 are the same or different each time they appear, and are each independently selected from hydrogen atoms, C 1-6 alkyl and C 1-6 haloalkyl; preferably, R n1 , R n2 , R n3 , R n4 , R n5 , R n6 , R n7 and R n8 are the same or different each time they appear, and are each independently a hydrogen atom or a C 1-6 alkyl group.
  • the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 are the same or different each time they appear, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group and a C 1-6 haloalkyl group; preferably, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 are the same or different on each occurrence, and are each independently a C 1-6 alkyl group or a C 1-6 haloalkyl group.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein Z is O or NH; Rw is selected from hydrogen atoms, C 1-6 alkyl and C 1-6 deuterated alkyl; R x is selected from hydrogen atom, C 1-6 alkyl and C 1-6 deuterated alkyl; R 1 is selected from hydrogen atom, C 1-6 alkyl, R v O and R y R z N, R y and R z are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group and a C 1-6 deuterated alkyl group, and R v is a C 1-6 alkyl group or C 1-6 deuterated alkyl; R 2 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1 -6 haloalkyl;
  • Typical compounds of the present disclosure include, but are not limited to:
  • R L is an amino protecting group; preferably, R L is PMB;
  • R x , Z, R 1 , R 2 , R 3 , R 4 , R 5c , Ra , R b , G 0 , G 1 , G 2 , G 3 and n are as defined in general formula (II).
  • R L is an amino protecting group; preferably, R L is PMB;
  • Rx , Z, R1 , R5c , G1 , G3 and n are as defined in general formula (III).
  • R N is halogen; preferably, R N is Cl;
  • R 5c is selected from deuterium atom, Cl, Br, I, alkyl group, alkenyl group, alkynyl group, nitro group, cyano group, -NR n5 R n6 , -C(O)NR n7 R n8 , -C(O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of deuterium, halogen, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkyl Substituted with one or more substituents from oxygen, haloalkoxy,
  • R 1 , R 2 , R 3 , R 4 , R a , R b , G 0 , G 1 , G 2 , G 3 , R n5 , R n6 , R n7 , R n8 , R a5 , R a6 , R a7 , R a8 , t2 and n are as defined in general formula (II).
  • R N is halogen; preferably, R N is Cl;
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (IIa) or a salt thereof is subjected to a deprotection reaction to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
  • R L is an amino protecting group; preferably, R L is PMB;
  • R w is a hydrogen atom
  • R x , Z, R 1 , R 2 , R 3 , R 4 , R 5c , Ra , R b , G 0 , G 1 , G 2 , G 3 and n are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (IIIa) or a salt thereof is subjected to a deprotection reaction to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
  • R L is an amino protecting group; preferably, R L is PMB;
  • R w is a hydrogen atom
  • Rx , Z, R1 , R5c , G1 , G3 and n are as defined in general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • a sulfonylation reaction occurs between a compound represented by general formula (IIA) or a salt thereof and a compound represented by general formula (IIB) or a salt thereof, to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;
  • R N is halogen; preferably, R N is Cl;
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, which method includes the following steps:
  • the compound represented by the general formula (IIIA) or a salt thereof undergoes a sulfonylation reaction with the compound represented by the general formula (IIB) or a salt thereof, to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
  • R N is halogen; preferably, R N is Cl;
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing a compound represented by the general formula (I), general formula (II), general formula (III) or table A of the present disclosure or a pharmaceutically acceptable compound thereof salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to the use of compounds represented by general formula (I), general formula (II), general formula (III) or table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them in the preparation of TEAD inhibitor drugs. use.
  • the present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III) or table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same for the preparation of compounds that inhibit YAP/TAZ-TEAD. Use in transcriptionally active drugs.
  • the present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III) or table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same for the preparation of treatments and/or Use in drugs to prevent diseases or conditions mediated by YAP/TAZ-TEAD interactions.
  • the present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III) or table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same for the preparation of treatments and/or Use in medicines to prevent cancer, fibrosis, polycystic kidney disease and cardiovascular disease;
  • the fibrosis is preferably liver fibrosis;
  • the cancer is preferably selected from mesothelioma, Schwann cell tumor, leukemia, lymphoma , macroglobulinemia, heavy chain disease, sarcoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer , cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer,
  • the present disclosure further relates to a method for inhibiting YAP/TAZ-TEAD transcriptional activity, which includes administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (III) or Table A.
  • a method for inhibiting YAP/TAZ-TEAD transcriptional activity which includes administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (III) or Table A.
  • the present disclosure further relates to a method of inhibiting TEAD, comprising administering to a patient in need thereof a therapeutically effective amount
  • a method of inhibiting TEAD comprising administering to a patient in need thereof a therapeutically effective amount
  • the present disclosure further relates to a method of treating and/or preventing diseases or conditions mediated by YAP/TAZ-TEAD interactions, comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (II), A compound represented by general formula (III) or Table A, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same.
  • the present disclosure further relates to a method of treating and/or preventing cancer, fibrosis, polycystic kidney disease and cardiovascular disease; which includes administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (II), Formula (III) Or the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same;
  • the fibrosis is preferably liver fibrosis;
  • the cancer is preferably selected from mesothelioma, Schwann Cytoma, leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, myeloid carcinoma carcinoma, bronchial carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wil
  • the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III) or table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used as a medicine .
  • the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III) or table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used as a TEAD Inhibitors.
  • the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III) or table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used to inhibit YAP/TAZ-TEAD transcriptional activity.
  • the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III) or table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used for treatment and/or prevent diseases or conditions mediated by YAP/TAZ-TEAD interactions.
  • the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III) or table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used for treatment And/or prevent cancer, fibrosis, polycystic kidney disease and cardiovascular disease;
  • the fibrosis is preferably liver fibrosis;
  • the cancer is preferably selected from the group consisting of mesothelioma, Schwann cell tumor, leukemia, lymphoma, giant cell carcinoma, Globulinemia, heavy chain disease, sarcoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, bile duct Carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial
  • the disease or disorder mediated by YAP/TAZ-TEAD interaction described in the present disclosure is preferably selected from cancer, fibrosis, polycystic kidney disease and cardiovascular disease; the fibrosis is preferably liver fibrosis; the The cancer is preferably selected from mesothelioma, Schwann cell tumor, leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma , papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, Lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, epend
  • the mesothelioma described in the present disclosure is preferably pleural mesothelioma; the sarcoma is preferably soft tissue sarcoma or osteosarcoma; the ovarian cancer is preferably ovarian serous adenocarcinoma; the liver cancer is preferably hepatocellular carcinoma; the endometrial cancer is preferably endometrial gland Squamous carcinoma; lung cancer is preferably non-small cell lung cancer; glioma is preferably glioblastoma; hemangioma is preferably hemangioblastoma or epithelioid hemangioendothelioma; schwannoma is preferably malignant peripheral nerve sheath tumor;
  • the gastric cancer is preferably gastric adenocarcinoma; the esophageal cancer is preferably esophageal adenocarcinoma; the brain tumor is preferably meningioma.
  • the active compounds may be prepared in a form suitable for administration by any appropriate route and the compositions of the present disclosure may be formulated by conventional means using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.
  • the active compounds are preferably in unit dosage form, or in such form that the patient may self-administer a single dose.
  • the unit dosage form of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder or liquid preparation.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients wait.
  • auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations may also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or in which the active ingredient is mixed with a water-soluble carrier or oil vehicle.
  • Aqueous suspensions contain the active substances and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oil suspensions can be formulated by suspending the active ingredient in vegetable oil, or mineral oil. Oil suspensions may contain thickening agents. Sweetening and flavoring agents as described above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oil phase can be vegetable oil, or mineral oil or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Such preparations may also contain demulcents, preservatives, coloring agents and antioxidants.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • Acceptable vehicles or solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution.
  • Sterile injectable preparations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oily phase.
  • injectable solutions or microemulsions may be injected into the patient's bloodstream by local mass injection.
  • solutions and microemulsions are preferably administered in a manner that maintains constant circulating concentrations of the compounds of the present disclosure.
  • continuous intravenous drug delivery devices can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents such as those mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent.
  • sterile fixed oil can be conveniently used as the solvent or suspending medium. For this purpose, any blend of fixed oils can be used.
  • fatty acids are also prepared as injectables.
  • the compounds of the present disclosure may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore dissolve in the rectum to release the drug.
  • compositions of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules.
  • These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.
  • the dosage of a drug depends on a variety of factors, including, but not limited to, the activity of the specific compound used, the patient's age, the patient's weight, the patient's health, and the patient's behavior. , patient's diet, administration time, administration method, excretion rate, combination of drugs, severity of disease, etc.; in addition, the best treatment method such as treatment mode, daily dosage of compounds or pharmaceutically acceptable salts Types can be verified based on traditional treatment regimens.
  • alkyl refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e. C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e. C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (ie, C 1-6 alkyl).
  • 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
  • the alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein the alkyl group is as defined above and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 alkylene group).
  • the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene group), and more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 alkylene group ).
  • Non-limiting examples include: -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 2 CH 3 )-, -CH 2 CH (CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, etc.
  • the alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituent is preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, where the alkyl group is as defined above and has 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C 2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably selected from the group consisting of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where the alkyl group is as defined above and has 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, C 2-6 alkynyl group). No Limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment.
  • the substituents are preferably selected from the group consisting of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkoxy refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituent is preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 3 to 20 membered cycloalkyl).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group), and more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group). ) or preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6 membered cycloalkyl group).
  • Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.
  • the polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic system in which one carbon atom (called a spiro atom) is shared between the rings.
  • the ring may contain one or more double bonds, or the ring may contain one or more atoms selected from nitrogen, Heteroatoms of oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxoated, that is, to form sulfoxide or sulfone, but does not include -O-O-, -O-S - or -S-S-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, which has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e.
  • the spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spirocycloalkyl group), and more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spirocycloalkyl group). membered spirocycloalkyl).
  • the spirocycloalkyl group includes a single spirocycloalkyl group and a multi-spirocycloalkyl group (such as a double spirocycloalkyl group, etc.), preferably a single spirocycloalkyl group or a double spirocycloalkyl group, and more preferably a 3-membered/4-membered, 3-membered or 3-membered spirocycloalkyl group.
  • Non-limiting examples include:
  • connection point can be at any position
  • fused cycloalkyl refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with a heterocyclic cycloalkyl group.
  • One or more of the cyclic groups, aryl groups or heteroaryl groups are condensed, wherein the point of attachment is on a single-ring cycloalkyl group, which may contain one or more double bonds in the ring, and has 5 to 20 (for example, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e.
  • the fused ring alkyl group is preferably a fused ring alkyl group having 6 to 14 ring atoms (ie, a 6 to 14-membered fused ring alkyl group), and more preferably a fused ring alkyl group having 7 to 10 ring atoms (ie, a 7 to 10 membered ring alkyl group). fused ring alkyl group).
  • the fused cycloalkyl group includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl , more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan , 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6
  • bridged cycloalkyl refers to an all-carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings.
  • the ring may contain one or more double bonds and has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie, 5 to 20 membered bridged cycloalkyl).
  • the bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6- to 14-membered bridged cycloalkyl group), and more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl group). bridged cycloalkyl).
  • the bridged cycloalkyl group includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl .
  • Non-limiting examples include:
  • a cycloalkyl group may be substituted or unsubstituted, and when substituted it may be used in any available linkage
  • the points are substituted, and the substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, One or more of cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or a polycyclic heterocyclic system (i.e., polycyclic heterocyclyl), which contains at least one ring (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxogenated, that is, to form sulfoxide or sulfone, but not including -O-O-, -O-S- or -S-S-), and having 3 to 20 (e.g.
  • the heterocyclyl group is preferably a heterocyclyl group having 3 to 12 ring atoms (i.e. a 3 to 12 membered heterocyclyl group); further preferably a heterocyclyl group having 3 to 8 ring atoms (i.e. a 3 to 8 membered heterocyclyl group) ); more preferably a heterocyclyl group having 3 to 6 ring atoms (i.e. a 3 to 6 membered heterocyclyl group) or preferably a heterocyclyl group having 5 or 6 ring atoms (i.e. a 5 or 6 membered heterocyclyl group).
  • Non-limiting examples of the monocyclic heterocyclyl include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , thiomorpholinyl and homopiperazinyl, etc.
  • the polycyclic heterocyclyl group includes spiroheterocyclyl group, fused heterocyclyl group and bridged heterocyclyl group.
  • spiroheterocyclyl refers to a polycyclic heterocyclic system in which the rings share one atom (called a spiro atom).
  • the ring may contain one or more double bonds, and the ring contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, But does not include -O-O-, -O-S- or -S-S-), provided that it contains at least one monocyclic heterocyclyl group and the point of attachment is on the monocyclic heterocyclyl group, which has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie, 5 to 20 membered spiroheterocyclyl).
  • the spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroheterocyclyl group), and more preferably a spiroheterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclyl group).
  • 1-membered spiroheterocyclyl 1-membered spiroheterocyclyl
  • the spiroheterocyclyl group includes a single spiroheterocyclyl group and a polyspiroheterocyclyl group (such as a double spiroheterocyclyl group, etc.), preferably a single spiroheterocyclyl group or a double spiroheterocyclyl group, more preferably 3-membered/4-membered, 3-membered or 3-membered spiroheterocyclyl.
  • Non-limiting examples include:
  • fused heterocyclyl refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between the rings.
  • the ring may contain one or more double bonds, and the ring may contain at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, but not including -OO-, -OS- or -SS-), which is a monocyclic heterocyclyl group with one Or multiple monocyclic heterocyclyl groups are fused, or the monocyclic heterocyclyl group is condensed with one or more of cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl group, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20
  • the fused heterocyclyl group is preferably a fused heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused heterocyclyl group), and more preferably a fused heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclyl group). fused heterocyclic group).
  • the fused heterocyclyl group includes bicyclic and polycyclic fused heterocyclyl groups (such as tricyclic fused heterocyclyl group, tetracyclic fused heterocyclyl group, etc.), preferably bicyclic fused heterocyclyl group or tricyclic fused heterocyclyl group, more preferably 3 Yuan/4 Yuan, 3 Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/ 5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan Or 7-membered/6-membered bicyclic fused heterocyclyl
  • bridged heterocyclyl refers to a polycyclic heterocyclic system that shares two atoms that are not directly connected between the rings.
  • the ring may contain one or more double bonds, and the ring contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, but not including -OO-, -OS- or -SS-), which have 5 to 20 (e.g. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e.
  • the bridged heterocyclyl group is preferably a bridged heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclyl group), and more preferably a bridged heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered bridged heterocyclyl group). Yuan-bridged heterocyclyl).
  • bicyclic bridged heterocyclyl and polycyclic bridged heterocyclyl such as tricyclic bridged heterocyclyl, tetracyclic bridged heterocyclyl, etc.
  • bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl preferably bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl.
  • base preferably bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl.
  • Non-limiting examples include: wait.
  • Heterocyclyl may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment.
  • the substituent is preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkyl. oxygen or Multiple.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated ⁇ electron system, having 6 to 14 (e.g., 6 , 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e. 6 to 14 membered aryl group).
  • the aryl group is preferably an aryl group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aryl group), and more preferably an aryl group having 8 to 10 ring atoms (i.e., an 8- to 10-membered polycyclic aryl group).
  • the monocyclic aryl group is, for example, phenyl.
  • Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc.
  • the polycyclic aryl group also includes phenyl fused with one or more of heterocyclyl or cycloalkyl, or naphthyl fused with one or more of heterocyclyl or cycloalkyl, where the point of attachment on phenyl or naphthyl, and in this case, the number of ring atoms continues to mean the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:
  • Aryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment.
  • the substituents are preferably selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups. or Multiple.
  • heteroaryl refers to a monocyclic heteroaromatic ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) with a conjugated ⁇ electron system, which contains at least one (For example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo-substituted, i.e.
  • the heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group), and more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered monocyclic heteroaryl group).
  • aryl or preferably a heteroaryl group having 8 to 10 ring atoms (ie, 8 to 10 membered polycyclic heteroaryl).
  • Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, furazyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (such as etc.), pyrazinyl, pyridazinyl, etc.
  • Non-limiting examples of the polycyclic heteroaryl include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene base, benzofuranyl, quinazolinyl, carbazolyl, pyrrolotriazinyl, 5,6,7,8-tetrahydro-triazolopyrazinyl, imidazopyridazinyl and [1,2 ,4]triazolo[1,5-a]pyridyl, etc.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent a polycyclic heteroaryl ring The number of ring atoms in the system.
  • the polycyclic heteroaryl also includes one of monocyclic heteroaryl and cycloalkyl or heterocyclyl. or multiple fusions, where the point of attachment is on a monocyclic heteroaromatic ring, and in this case the number of ring atoms continues to mean the number of ring atoms in a polycyclic heteroaromatic ring system.
  • Non-limiting examples include:
  • Heteroaryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment.
  • the substituents are preferably selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkyl groups.
  • amino protecting group refers to an easily removable group introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule react.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), watmethoxycarbonyl (Fmoc), allyl Oxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthalyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), Trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, 4-methoxybenzyl (PMB), etc., preferably PMB.
  • hydroxyl protecting group refers to an easily removable group introduced on a hydroxyl group to block or protect the hydroxyl group for reactions on other functional groups of the compound.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Diphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), methyl Acyl, acetyl, benzoyl, p-nitrobenzoyl, etc.
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, where aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, where heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, where alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • mercapto refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, where alkyl and cycloalkyl are as defined above.
  • stereoisomer refers to isomers that have the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformational isomers and their mixtures (e.g. racemates, mixtures of diastereomers) . Additional asymmetric atoms may be present for substituents in the compounds of the present disclosure.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer.
  • An isomer of a certain compound of the present disclosure can be prepared through asymmetric synthesis or chiral auxiliaries, or when the molecule contains basic functional groups (such as amino) or acidic functional groups (such as carboxyl), and appropriate optical Reactive acids or bases form diastereomeric salts, and then the diastereoisomers are resolved by conventional methods known in the art to obtain pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates that the configuration is not specified, i.e. if there are chiral isomers in the chemical structure, the bond can be or or both and Two configurations.
  • tautomer or tautomeric form refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, either as single isomers or as mixtures of said tautomers in any proportion. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like. An example of lactam-lactam equilibrium is shown below:
  • the compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof.
  • isotopic derivative refers to a compound in which at least one atom is replaced by an atom with the same atomic number but a different atomic mass.
  • isotopes that may be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, such as 2 H (deuterium, D), respectively.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of the drug. All variations in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, where the replacement of deuterium can be partial or complete.
  • the replacement of partial deuterium means that at least one hydrogen is replaced by at least one deuterium.
  • a position when a position is specifically designated as "deuterium” or “D", that position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e. , at least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, The abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).
  • alkyl optionally substituted by halogen or cyano includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen or cyano.
  • Substituted or “substituted” means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents.
  • a person skilled in the art will be able to determine possible or impossible substitutions without undue effort (either experimentally or theoretically).
  • an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond, such as an alkene.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, as well as other ingredients such as pharmaceutically acceptable carriers and excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of compounds of the present disclosure, which may be selected from inorganic salts or organic salts. This type of salt is safe and effective when used in mammals, and has due biological activity. They can be prepared individually during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • therapeutically effective amount refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect.
  • the determination of the therapeutically effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance.
  • the appropriate therapeutically effective amount in an individual case can be determined by those skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to compounds, materials, compositions and/or dosage forms which, within the scope of reasonable medical judgment, are suitable for contact with patient tissue without undue toxicity, irritation, allergic reaction or other problems or complications, has a reasonable benefit/risk ratio, and is effective for the intended use.
  • the preparation method of the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof of the present disclosure includes the following steps:
  • the compound represented by the general formula (IIa) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
  • R L is an amino protecting group; preferably, R L is PMB;
  • R w is a hydrogen atom
  • R x , Z, R 1 , R 2 , R 3 , R 4 , R 5c , Ra , R b , G 0 , G 1 , G 2 , G 3 and n are as defined in general formula (II).
  • the preparation method of the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof of the present disclosure includes the following steps:
  • the compound represented by the general formula (IIIa) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
  • R L is an amino protecting group; preferably, R L is PMB;
  • R w is a hydrogen atom
  • Rx , Z, R1 , R5c , G1 , G3 and n are as defined in general formula (III).
  • the preparation method of the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof of the present disclosure includes the following steps:
  • a sulfonylation reaction occurs between a compound represented by general formula (IIA) or a salt thereof and a compound represented by general formula (IIB) or a salt thereof, to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;
  • R N is halogen; preferably, R N is Cl;
  • the preparation method of the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof of the present disclosure includes the following steps:
  • the compound represented by the general formula (IIIA) or a salt thereof undergoes a sulfonylation reaction with the compound represented by the general formula (IIB) or a salt thereof, to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
  • R N is halogen; preferably, R N is Cl;
  • reagents that provide acidic conditions include but are not limited to hydrogen chloride, hydrogen chloride solution in 1,4-dioxane, hydrochloric acid solution in 1,4-dioxane, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, Concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzenesulfonic acid, Me 3 SiCl and TMSOTf and mixtures thereof, preferably trifluoroacetic acid.
  • the reaction of the above steps is preferably carried out in a solvent.
  • the solvents used include but are not limited to: pyridine, glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, Ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromo Ethane and its mixtures.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR is measured using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M.
  • the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD).
  • the internal standard is tetramethylsilane (TMS).
  • MS was measured using Agilent 1200/1290DAD-6110/6120Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS). waters ACQuity UPLC-QD/SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector). THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • High-performance liquid phase preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm ⁇ 0.2mm.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200 ⁇ 300 mesh silica gel as the carrier.
  • the average kinase inhibition rate and IC 50 value were measured using NovoStar microplate reader (BMG Company, Germany).
  • the known starting materials of the present invention can be synthesized by 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.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenator and Clear Blue QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the microwave reaction uses CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • the reaction temperature is room temperature, which is 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developing agent used in the reaction, the column chromatography eluent system and the thin layer chromatography developing agent system used to purify the compound include: A: n-hexane/ethyl acetate system, B: methylene chloride/methanol system, the volume ratio of the solvent varies according to the polarity of the compound
  • Dissolve compound 2a 500 mg, 2.29 mmol in water (10 mL), add sodium hydroxide (105 mg, 2.58 mmol, Shaoyuan), stir at 40°C for 10 minutes, add 1-(chloromethyl)-4-(tris Fluoromethyl)benzene (460 mg, 2.41 mmol, Shaoyuan), the reaction solution was heated to 70°C and stirred for 12 hours. Cool to room temperature, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain the crude title compound 3a (720 mg, yield: 82.7%). The product is directly used in the next reaction without purification.
  • Test Example 1 Test of the inhibitory effect of the disclosed compounds on YAP-TEAD-mediated reporter gene Luc2P luciferase activity
  • the 8 ⁇ GTIIC-Luc2P (Jinweizhi) plasmid was transferred into HEK293 (ATCC, CRL-1573) cells, and antibiotics were used to screen and select single clones to obtain the HEK293-8 ⁇ GTIIC-Luc2P cell line.
  • HEK293-8 ⁇ GTIIC-Luc2P cells were seeded into a 96-well plate (Beyotime, FCP968) at a density of 2 ⁇ 10 4 cells/90 ⁇ L/well using DMEM complete medium containing 10% FBS and cultured for 24 h. Prepare the compound with DMSO and carry out gradient dilution.
  • the first concentration is 10mM, and the compound is diluted 5 times in a 5-fold gradient, with a total of 9 concentration points.
  • the blank control and vehicle control are 100% DMSO. Then take 5 ⁇ L of the compound diluted in the gradient from each well and add it to 95 ⁇ L of complete culture medium in each well. After shaking and mixing, take 10 ⁇ L of the compound diluted in the medium from each well and add it to the 96-well plate containing cells. The final initial concentration of the compound is 10 ⁇ M.
  • the wells with only culture medium and no cells are the blank control.
  • the wells with cells and no compound are the vehicle control.
  • the DMSO content in the compound wells, blank control and vehicle control is all 0.5%.
  • the disclosed compound has a significant inhibitory effect on the YAP/TAZ-TEAD-mediated reporter gene Luc2P luciferase activity.
  • Test Example 2 Proliferation inhibitory effect of the disclosed compound on NCI-H226 cells
  • NCI-H226 ATCC, CRL-5826 cells that grew well and reached 70%-80% confluence were digested and resuspended in RPMI (Hyclone, SH30809.01) medium containing 10% FBS. , and adjust to the desired cell density. Add 135 ⁇ L of cell suspension to each well of a 96-well plate (Corning, 3903), and the cell density is 1000 cells/well. Place the cell plate in a 37°C, 5% CO2 incubator for 24 hours.
  • RPMI Hyclone, SH30809.01
  • Duplicate wells were set for each compound concentration and control well, and the final DMSO concentration in each well was 0.5%. Place the cell plate in a 37°C, 5% CO2 incubator for 6 days. On the eighth day, take out the 96-well cell culture plate and add 50 ⁇ L of luminescent cell activity detection reagent ( Luminescent Cell Viability Assay) (Promega, G7573), place it at room temperature in the dark for 10 minutes, and place it on a microplate reader VICTOR3 to read the luminescence signal value.
  • luminescent cell activity detection reagent Luminescent Cell Viability Assay
  • Inhibition rate [RLU (vehicle control well) - RLU (test compound)] / [RLU (vehicle control well) - RLU (blank control well)] ⁇ 100%, using Graphpad Prism software according to Draw an inhibition curve for each concentration of the compound and the corresponding inhibition rate, and calculate the IC 50 value of the compound.
  • Rats were used as test animals, and the concentration of the compound of Example 1 in the plasma of rats at different times after intragastric administration of the compound of Example 1 was measured using the LC/MS/MS method. Study the pharmacokinetic behavior of the disclosed compound in rats and evaluate its pharmacokinetic characteristics.
  • Example 1 Weigh a certain amount of the compound of Example 1 and add 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HPMCK100LV) to form a clear solution of 0.5 mg/mL.
  • the dosage of the compound of Example 1 was 5 mg/kg, and the administration volume was 10 mL/kg.
  • Rats were administered the compound of Example 1 by gavage, and 0.1 mL of blood was collected from the orbit at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 11h, and 24h after administration, placed in an EDTA-K2 anticoagulant test tube, and centrifuged at 10,000 rpm. 1 minute (4°C), separate plasma within 1 hour, and store at -20°C. The process from blood collection to centrifugation is operated under ice bath conditions.
  • Example 1 compound in rat plasma after administration of Example 1 compound Take 25 ⁇ L of rat plasma at each time after administration, add 200 ⁇ L ACN (containing tolbutamide 100 ng/mL), and vortex for 5 min. , centrifuge for 15 minutes (3700 rpm), take 100 ⁇ L of the supernatant, add 50 ⁇ L of water, mix for 5 minutes, and take 2 ⁇ L for LC/MS/MS analysis.
  • ACN containing tolbutamide 100 ng/mL
  • centrifuge for 15 minutes 3700 rpm
  • the disclosed compound has good pharmacological absorption activity in rats.
  • Test Example 4 Pharmacokinetic evaluation of the disclosed compounds in Beagle dogs
  • the LC/MS/MS method was used to determine the concentration of the compound of Example 1 in the plasma of the Beagle dogs at different times after intragastric administration of the compound of Example 1. Study the pharmacokinetic behavior of the disclosed compound in Beagle dogs and evaluate its pharmacokinetic characteristics.
  • the dosage of the compound of Example 1 was 2 mg/kg, and the administration volume was 5 mL/kg.
  • Beagle dogs were fasted overnight and administered the compound of Example 1 by gavage.
  • 0.5 mL of blood was collected from the forelimb vein at 0 h before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 11 h, and 24 h after administration.
  • the disclosed compound has good pharmacological absorption activity in Beagle dogs.

Abstract

Disclosed are an indazole compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition comprising said compound, and use of said compound as a TEAD inhibitor, particularly use thereof in the preparation of a drug for treating and/or preventing cancer.

Description

吲唑类化合物、其制备方法及其在医药上的应用Indazole compounds, their preparation methods and their applications in medicine 技术领域Technical field
本公开属于医药领域，涉及一种吲唑类化合物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(I)所示的吲唑类化合物、其制备方法及含有该类化合物的药物组合物以及其作为TEAD抑制剂的用途，特别是在制备用于治疗和/或预防癌症的药物中的用途。The present disclosure belongs to the field of medicine and relates to an indazole compound, its preparation method and its application in medicine. Specifically, the present disclosure relates to an indazole compound represented by general formula (I), its preparation method, pharmaceutical compositions containing such compounds, and its use as a TEAD inhibitor, especially in the preparation of compounds for the treatment of and/or use in cancer prevention drugs.
背景技术Background technique
Hippo信号通路是在果蝇中发现，在哺乳动物中保守的信号通路，调控机体或器官的生长发育、细胞稳态、细胞增殖和分化等。Hippo信号通路由一系列激酶组成的级联信号网络，通过磷酸化作用调控下游转录共激活因子YAP/TAZ进出细胞核。当Hippo通路失活时，YAP/TAZ进入细胞核，结合TEAD家族的转录因子TEAD1-4，调控靶基因转录，进而发挥多种生物学行为。TEAD蛋白通常被认为是介导YAP/TAZ促生长和致癌作用的主要效应分子。The Hippo signaling pathway was discovered in Drosophila and is a conserved signaling pathway in mammals. It regulates the growth and development of the body or organs, cell homeostasis, cell proliferation and differentiation, etc. The Hippo signaling pathway is a cascade signaling network composed of a series of kinases that regulate the downstream transcription co-activator YAP/TAZ into and out of the nucleus through phosphorylation. When the Hippo pathway is inactivated, YAP/TAZ enters the cell nucleus, binds to TEAD family transcription factors TEAD1-4, regulates target gene transcription, and then exerts a variety of biological behaviors. TEAD proteins are generally considered to be the main effector molecules mediating the growth-promoting and carcinogenic effects of YAP/TAZ.
研究表明，YAP和/或TAZ在一些肿瘤如乳腺癌、非小细胞肺癌、卵巢癌、结直肠癌、胰腺癌、***癌、胃癌、食管癌、肝癌和骨肉瘤等中表达水平或入核水平升高导致过度激活。Hippo通路基因变异在各肿瘤中占10％左右。主要包括上游NF2或LATS1/2失活导致YAP/TEAD过度激活的胸膜间皮瘤，YAP和/或TAZ扩增的***、卵巢癌、头颈癌、肺癌、肝癌、乳腺癌、***癌等肿瘤，YAP、TAZ基因融合的上皮样血管内皮瘤、室管膜瘤等肿瘤。Studies have shown that YAP and/or TAZ are expressed or entered into the nucleus in some tumors, such as breast cancer, non-small cell lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, and osteosarcoma. Elevated leading to overactivation. Hippo pathway gene mutations account for about 10% of tumors. Mainly include pleural mesothelioma in which inactivation of upstream NF2 or LATS1/2 leads to overactivation of YAP/TEAD, and tumors such as cervical cancer, ovarian cancer, head and neck cancer, lung cancer, liver cancer, breast cancer, and prostate cancer with YAP and/or TAZ amplification , YAP, TAZ gene fusion epithelioid hemangioendothelioma, ependymoma and other tumors.
YAP/TAZ激活在化疗或针对MAPK通路的EGFR、ALK、RAF/MEK等抑制剂的耐药中也发挥作用。有研究表明，YAP/TAZ通过抑制凋亡蛋白水平、上调纺锤体组装检查点等机制介导上述药物的原发性或继发性耐药。YAP/TAZ activation also plays a role in resistance to chemotherapy or inhibitors of the MAPK pathway such as EGFR, ALK, RAF/MEK. Studies have shown that YAP/TAZ mediates primary or secondary resistance to the above drugs by inhibiting apoptotic protein levels and upregulating spindle assembly checkpoints.
因此，通过抑制TEAD蛋白棕榈酰化或者抑制YAP/TAZ-TEAD蛋白相互作用抑制YAP/TAZ-TEAD的促癌转录活性，有望成为上述肿瘤的有效治疗手段。Therefore, inhibiting the tumor-promoting transcriptional activity of YAP/TAZ-TEAD by inhibiting palmitoylation of TEAD protein or inhibiting YAP/TAZ-TEAD protein interaction is expected to become an effective treatment for the above-mentioned tumors.
公开的相关专利申请包括WO2020097389A1、WO2020081572A1、WO2006052190A1、WO2019040380A1和WO2020243415A2等。The relevant published patent applications include WO2020097389A1, WO2020081572A1, WO2006052190A1, WO2019040380A1 and WO2020243415A2, etc.
发明内容Contents of the invention
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
其中：in:
Z为O或NH；Z is O or NH;
环A为芳基或杂芳基；Ring A is aryl or heteroaryl;
R为烷基或RwRxN，所述的烷基任选被选自氘原子、卤素、烷氧基、氘代烷氧基、卤代烷氧基、氰基、氨基和羟基中的一个或多个取代基所取代；R is an alkyl group or R w R x N, and the alkyl group is optionally selected from one of deuterium atoms, halogen, alkoxy, deuterated alkoxy, haloalkoxy, cyano, amino and hydroxyl or Substituted with multiple substituents;
R1选自氢原子、氘原子、卤素、烷基、RvO和RyRzN，所述的烷基任选被选自氘原子、卤素、烷氧基、氘代烷氧基、卤代烷氧基、氰基、氨基和羟基中的一个或多个取代基所取代；R 1 is selected from hydrogen atom, deuterium atom, halogen, alkyl group, R v O and R y R z N, and the alkyl group is optionally selected from deuterium atom, halogen, alkoxy group, deuterated alkoxy group, Substituted with one or more substituents among haloalkoxy, cyano, amino and hydroxyl;
Rw、Rx、Ry和Rz相同或不同，且各自独立地选自氢原子、氘原子和烷基，所述的烷基任选被选自氘原子、卤素、烷氧基、氘代烷氧基、卤代烷氧基、氰基、氨基和羟基中的一个或多个取代基所取代；R w , R x , Ry and R z are the same or different, and are each independently selected from hydrogen atoms, deuterium atoms and alkyl groups. The alkyl groups are optionally selected from deuterium atoms, halogens, alkoxy groups, deuterium atoms. Substituted with one or more substituents from alkoxy, haloalkoxy, cyano, amino and hydroxy;
Rv选自烷基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Rv is selected from alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently selected from Deuterium atom, halogen, oxo group, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, deuterated alkoxy group, haloalkoxy group, nitro group, cyano group, amino group, hydroxyl group, hydroxyalkyl group, cycloalkyl group Substituted with one or more substituents among base, heterocyclyl, aryl and heteroaryl;
Ra和Rb相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基和羟烷基；R a and R b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a haloalkyl group and a hydroxyalkyl group;
R2、R3和R4相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烯基、炔基、硝基、氰基、-NRn1Rn2、-C(O)NRn3Rn4、-C(O)Ra1、-C(O)ORa2、-ORa3、-S(O)t1Ra4、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R 2 , R 3 and R 4 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, -NR n1 R n2 , -C( O)NR n3 R n4 , -C(O)R a1 , -C(O)OR a2 , -OR a3 , -S(O) t1 R a4 , cycloalkyl, heterocyclyl, aryl and heteroaryl ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of deuterium atoms, halogens, oxo groups, alkyl groups, deuterated groups In alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;
各个R5相同或不同，且各自独立地选自氘原子、卤素、烷基、烯基、炔基、硝基、氰基、-NRn5Rn6、-C(O)NRn7Rn8、-C(O)Ra5、-C(O)ORa6、-ORa7、-S(O)t2Ra8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Each R 5 is the same or different, and each is independently selected from deuterium atom, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, -NR n5 R n6 , -C(O)NR n7 R n8 , - C(O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from deuterium, halogen, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy Substituted with one or more substituents of base, deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl ;
Rn1、Rn2、Rn3、Rn4、Rn5、Rn6、Rn7和Rn8在每次出现时相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；R n1 , R n2 , R n3 , R n4 , R n5 , R n6 , R n7 and R n8 are the same or different each time they appear, and are each independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups base, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
或者Rn1和Rn2与相连的氮原子一起形成杂环基、Rn3和Rn4与相连的氮原子一起形成杂环基、Rn5和Rn6与相连的氮原子一起形成杂环基或Rn7和Rn8与相连的氮原子一起形成杂环基，所述的杂环基各自独立地任选被选自氘原子、卤素、氧代 基、烷基、烷氧基、氘代烷基、卤代烷基、氘代烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Or R n1 and R n2 together with the connected nitrogen atom form a heterocyclic group, R n3 and R n4 together with the connected nitrogen atom form a heterocyclic group, R n5 and R n6 together with the connected nitrogen atom form a heterocyclic group or R n7 and R n8 together with the attached nitrogen atom form a heterocyclic group, each of which is independently selected from the group consisting of deuterium atoms, halogens, and oxo groups. Base, alkyl, alkoxy, deuterated alkyl, haloalkyl, deuterated alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aromatic Substituted with one or more substituents in the radical and heteroaryl;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7和Ra8在每次出现时相同或不同，且各自独立地选自氢原子、氘原子、烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 are the same or different each time they appear, and are each independently selected from hydrogen atoms, deuterium atoms, alkyl groups, and hydroxyalkyl groups. , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of deuterium atoms, halogens, Oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl , substituted by one or more substituents in aryl and heteroaryl;
t1为0、1或2；t1 is 0, 1 or 2;
t2为0、1或2；t2 is 0, 1 or 2;
m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
n为0、1或2；n is 0, 1 or 2;
条件是，requirement is,
i)当R为RwRxN且n为1时，不为 i) When R is R w R x N and n is 1, Not for
ii)当R为甲基且n为0时，R1不为 ii) When R is methyl and n is 0, R 1 is not
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中R为RwRxN，Rw和Rx如通式(I)中所定义。In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R is R w R x N, R w and R x are as in the general formula (I) defined.
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A为6至10元芳基或5至10元杂芳基；优选地，环A为苯基或6元杂芳基；进一步优选地，环A选自苯基、吡啶基、哒嗪基、嘧啶基和吡嗪基；更优选地，环A为苯基或吡啶基；最优选地，环A为苯基。In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably , Ring A is phenyl or 6-membered heteroaryl; further preferably, ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl; more preferably, ring A is phenyl or pyridyl ; Most preferably, Ring A is phenyl.
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中各个R5相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、氰基、氨基、C1-6烷基NH、(C1-6烷基)2N、C1-6烷氧基、C1-6卤代烷氧基和3至8元环烷基；优选地，各个R5相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；进一步优选地，R5为C1-6卤代烷基；更优选地，R5为三氟甲基。In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 5 is the same or different, and each is independently selected from halogen, C 1-6 alkane group, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N, C 1- 6 alkoxy, C 1-6 haloalkoxy and 3 to 8-membered cycloalkyl; preferably, each R 5 is the same or different, and each is independently selected from halogen, C 1-6 alkyl and C 1-6 Haloalkyl; further preferably, R 5 is C 1-6 haloalkyl; more preferably, R 5 is trifluoromethyl.
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中m为0或1；优选地，m为1。In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; preferably, m is 1.
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中R为C1-6烷基，所述的C1-6烷基任选被选自氘原子、卤素、C1-6烷氧基和C1-6 卤代烷氧基中的一个或多个取代基所取代；优选地，R为C1-6烷基或C1-6氘代烷基；进一步优选地，R为C1-6烷基；更优选地，R为甲基。In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R is a C 1-6 alkyl group, and the C 1-6 alkyl group is optionally Selected from deuterium, halogen, C 1-6 alkoxy and C 1-6 Substituted with one or more substituents in the haloalkoxy group; preferably, R is C 1-6 alkyl or C 1-6 deuterated alkyl; further preferably, R is C 1-6 alkyl; more preferably Ground, R is methyl.
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:
其中：in:
G0为氮原子或CR5a；G 0 is a nitrogen atom or CR 5a ;
G1为氮原子或CR5b；G 1 is a nitrogen atom or CR 5b ;
G2为氮原子或CR5d；G 2 is a nitrogen atom or CR 5d ;
G3为氮原子或CR5e；G 3 is a nitrogen atom or CR 5e ;
R5a选自氢原子、氘原子、F、Br、I、烷基、烯基、炔基、硝基、氰基、-NRn5Rn6、-C(O)NRn7Rn8、-C(O)Ra5、-C(O)ORa6、-ORa7、-S(O)t2Ra8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R 5a is selected from hydrogen atom, deuterium atom, F, Br, I, alkyl group, alkenyl group, alkynyl group, nitro group, cyano group, -NR n5 R n6 , -C(O)NR n7 R n8 , -C( O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl and alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of deuterium atoms, halogens, oxo groups, alkyl groups, deuterated alkyl groups, haloalkyl groups, alkoxy groups, Substituted with one or more substituents from deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R5c选自氢原子、氘原子、Cl、Br、I、烷基、烯基、炔基、硝基、氰基、-NRn5Rn6、-C(O)NRn7Rn8、-C(O)Ra5、-C(O)ORa6、-ORa7、-S(O)t2Ra8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R 5c is selected from hydrogen atom, deuterium atom, Cl, Br, I, alkyl group, alkenyl group, alkynyl group, nitro group, cyano group, -NR n5 R n6 , -C(O)NR n7 R n8 , -C( O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl and alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of deuterium atoms, halogens, oxo groups, alkyl groups, deuterated alkyl groups, haloalkyl groups, alkoxy groups, Substituted with one or more substituents from deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R5b、R5d和R5e相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烯基、炔基、硝基、氰基、-NRn5Rn6、-C(O)NRn7Rn8、-C(O)Ra5、-C(O)ORa6、-ORa7、-S(O)t2Ra8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R 5b , R 5d and R 5e are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, -NR n5 R n6 , -C( O)NR n7 R n8 , -C(O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of deuterium atoms, halogens, oxo groups, alkyl groups, deuterated groups In alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;
其中Z、Rw、Rx、R1、R2、R3、R4、Ra、Rb、Rn5、Rn6、Rn7、Rn8、Ra5、Ra6、Ra7、Ra8、t2和n如通式(I)中所定义。Among them, Z, R w , R x , R 1 , R 2 , R 3 , R 4 , R a , R b , R n5 , R n6 , R n7 , R n8 , R a5 , R a6 , R a7 , R a8 , t2 and n are as defined in general formula (I).
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药 用的盐，其中R2选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、氰基、氨基、C1-6烷基NH、(C1-6烷基)2N、C1-6烷氧基、C1-6卤代烷氧基和3至8元环烷基；优选地，R2选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；更优选地，R2为氢原子。In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable compound thereof Salts used, wherein R 2 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano group, amino, C 1- 6 alkyl NH, (C 1-6 alkyl) 2 N, C 1-6 alkoxy, C 1-6 haloalkoxy and 3 to 8-membered cycloalkyl; preferably, R 2 is selected from hydrogen atom, Halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, R 2 is a hydrogen atom.
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中R3选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、氰基、氨基、C1-6烷基NH、(C1-6烷基)2N、C1-6烷氧基、C1-6卤代烷氧基和3至8元环烷基；优选地，R3选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；更优选地，R3为氢原子。In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen atom, halogen, C 1-6 alkane group, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N, C 1- 6 alkoxy, C 1-6 haloalkoxy and 3 to 8-membered cycloalkyl; preferably, R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably , R 3 is a hydrogen atom.
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中R4选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、氰基、氨基、C1-6烷基NH、(C1-6烷基)2N、C1-6烷氧基、C1-6卤代烷氧基和3至8元环烷基；优选地，R4选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；更优选地，R4为氢原子。In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen atom, halogen, C 1-6 alkane group, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N, C 1- 6 alkoxy, C 1-6 haloalkoxy and 3 to 8-membered cycloalkyl; preferably, R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably , R 4 is a hydrogen atom.
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中Ra选自氢原子、卤素和C1-6烷基；优选地，Ra为氢原子。In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein R a is selected from hydrogen atoms, halogens and C 1-6 alkane group; preferably, R a is a hydrogen atom.
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中Rb选自氢原子、卤素和C1-6烷基；优选地，Rb为氢原子。In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein R b is selected from hydrogen atoms, halogens and C 1-6 alkane group; preferably, R b is a hydrogen atom.
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中G0为CR5a，R5a选自氢原子、F、Br、I、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、氰基、氨基、C1-6烷基NH、(C1-6烷基)2N、C1-6烷氧基、C1-6卤代烷氧基和3至8元环烷基；优选地，G0为CR5a，R5a选自氢原子、F、Br、I、C1-6烷基和C1-6卤代烷基；更优选地，G0为CH。In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G 0 is CR 5a and R 5a is selected from hydrogen atoms, F, Br, I, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N , C 1-6 alkoxy group, C 1-6 haloalkoxy group and 3 to 8-membered cycloalkyl group; preferably, G 0 is CR 5a , R 5a is selected from hydrogen atom, F, Br, I, C 1- 6 alkyl and C 1-6 haloalkyl; more preferably, G 0 is CH.
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中G2为CR5d，R5d选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、氰基、氨基、C1-6烷基NH、(C1-6烷基)2N、C1-6烷氧基、C1-6卤代烷氧基和3至8元环烷基；优选地，G2为CR5d，R5d选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；更优选地，G2为CH。In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G 2 is CR 5d and R 5d is selected from hydrogen atoms, halogens, C 1-6 alkane group, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N, C 1- 6 alkoxy, C 1-6 haloalkoxy and 3 to 8-membered cycloalkyl; preferably, G 2 is CR 5d , R 5d is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 Haloalkyl; more preferably, G 2 is CH.
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof. Salt used:
其中Z、Rw、Rx、R1、G1、G3、R5c和n如通式(II)中所定义。 Wherein Z, R w , R x , R 1 , G 1 , G 3 , R 5c and n are as defined in general formula (II).
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中Z为O。In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein Z is O.
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中R1选自氢原子、C1-6烷基、RvO和RyRzN，所述的C1-6烷基任选被选自氘原子、卤素、C1-6烷氧基、C1-6卤代烷氧基、氰基、氨基和羟基中的一个或多个取代基所取代，Rv、Ry和Rz如通式(I)中所定义；优选地，R1选自氢原子、C1-6烷基、RvO和RyRzN，Ry和Rz如通式(I)中所定义；进一步优选地，R1选自氢原子、C1-6烷基、RvO和RyRzN，Ry和Rz相同或不同，且各自独立地选自氢原子、C1-6烷基和C1-6氘代烷基，Rv为C1-6烷基或C1-6氘代烷基；更优选地，R1选自氢原子、异丙基、甲氧基、异丙基氧基、氨基、甲基NH(即甲氨基)和二甲基N(即二甲氨基)；最优选地，R1为甲氧基。In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from a hydrogen atom, C 1-6 alkyl, R v O and R y R z N, the C 1-6 alkyl is optionally selected from deuterium atom, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy , substituted by one or more substituents among cyano group, amino group and hydroxyl group, R v , R y and R z are as defined in the general formula (I); preferably, R 1 is selected from hydrogen atom, C 1-6 Alkyl, R v O and R y R z N, Ry and R z are as defined in the general formula (I); further preferably, R 1 is selected from a hydrogen atom, C 1-6 alkyl, R v O and R y R z N, R y and R z are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group and a C 1-6 deuterated alkyl group, and R v is a C 1-6 alkyl group or C 1-6 deuterated alkyl; more preferably, R 1 is selected from hydrogen atom, isopropyl, methoxy, isopropyloxy, amino, methyl NH (i.e. methylamino) and dimethyl N ( i.e. dimethylamino); most preferably, R 1 is methoxy.
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中Ry和Rz相同或不同，且各自独立地为氢原子或C1-6烷基，所述的C1-6烷基任选被选自氘原子、卤素、C1-6烷氧基和C1-6卤代烷氧基中的一个或多个取代基所取代；优选地，Ry和Rz相同或不同，且各自独立地选自氢原子、C1-6烷基和C1-6氘代烷基；进一步优选地，Ry和Rz相同或不同，且各自独立地为氢原子或C1-6烷基；进一步优选地，Ry和Rz相同或不同，且各自独立地为氢原子或甲基。In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R y and R z are the same or different , and each is independently a hydrogen atom or a C 1-6 alkyl group. The C 1-6 alkyl group is optionally selected from the group consisting of deuterium atom, halogen, C 1-6 alkoxy group and C 1-6 haloalkoxy group. Substituted with one or more substituents in; preferably, R y and R z are the same or different, and each is independently selected from a hydrogen atom, a C 1-6 alkyl group and a C 1-6 deuterated alkyl group; further preferably Specifically, R y and R z are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; further preferably, R y and R z are the same or different, and each is independently a hydrogen atom or a methyl group.
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中Rv为C1-6烷基或3至6元环烷基，所述的C1-6烷基或3至6元环烷基各自独立地任选被选自氘原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、氰基、氨基、羟基和C1-6羟烷基中的一个或多个取代基所取代；优选地，Rv为C1-6烷基或3至6元环烷基，所述的C1-6烷基或3至6元环烷基各自独立地任选被选自氘原子、卤素和C1-6烷基中的一个或多个取代基所取代；进一步优选地，Rv选自C1-6烷基、C1-6氘代烷基和3至6元环烷基；更优选地，Rv为C1-6烷基或C1-6氘代烷基；再优选地，Rv为C1-6烷基；最优选地，Rv为甲基或异丙基。In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R v is a C 1-6 alkane group or a 3- to 6-membered cycloalkyl group, and each of the C 1-6 alkyl or 3 to 6-membered cycloalkyl groups is independently selected from the group consisting of deuterium atom, halogen, C 1-6 alkyl, C 1- Substituted with one or more substituents in 6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, amino, hydroxyl and C 1-6 hydroxyalkyl; preferably, R v It is a C 1-6 alkyl group or a 3- to 6-membered cycloalkyl group. The C 1-6 alkyl group or a 3- to 6-membered cycloalkyl group is each independently selected from the group consisting of deuterium atoms, halogens and C 1-6 Substituted with one or more substituents in the alkyl group; further preferably, R v is selected from C 1-6 alkyl, C 1-6 deuterated alkyl and 3 to 6-membered cycloalkyl; more preferably, R v is C 1-6 alkyl or C 1-6 deuterated alkyl; more preferably, R v is C 1-6 alkyl; most preferably, R v is methyl or isopropyl.
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中n为0或1；优选地，n为0。In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; preferably , n is 0.
在本公开的一些实施方案中，所述的通式(II)或通式(III)所示的化合物或其可药用的盐，其中G1为CR5b，R5b选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、氰基、氨基、C1-6烷基NH、(C1-6烷基)2N、C1-6烷氧基、C1-6卤代烷氧基和3至8元环烷基；优选地，G1为CR5b，R5b选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；更优选地，G1为CH。In some embodiments of the present disclosure, the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein G 1 is CR 5b and R 5b is selected from hydrogen atom, halogen , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano group, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N, C 1-6 alkoxy group, C 1-6 haloalkoxy group and 3 to 8-membered cycloalkyl group; preferably, G 1 is CR 5b , R 5b is selected from hydrogen atom, halogen, C 1-6 alkane and C 1-6 haloalkyl; more preferably, G 1 is CH.
在本公开的一些实施方案中，所述的通式(II)或通式(III)所示的化合物或其可药用的盐，其中G3为CR5e，R5e选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C2-6 烯基、C2-6炔基、氰基、氨基、C1-6烷基NH、(C1-6烷基)2N、C1-6烷氧基、C1-6卤代烷氧基和3至8元环烷基；优选地，G3为CR5e，R5e选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；更优选地，G3为CH。In some embodiments of the present disclosure, the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein G 3 is CR 5e and R 5e is selected from hydrogen atom, halogen , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N, C 1-6 alkoxy, C 1-6 haloalkoxy and 3 to 8-membered cycloalkyl; preferably, G 3 is CR 5e , and R 5e is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, G 3 is CH.
在本公开的一些实施方案中，所述的通式(II)或通式(III)所示的化合物或其可药用的盐，其中R5e选自氢原子、F、Br、I、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、氰基、氨基、C1-6烷基NH、(C1-6烷基)2N、C1-6烷氧基、C1-6卤代烷氧基和3至8元环烷基；优选地，R5e选自氢原子、F、Br、I、C1-6烷基和C1-6卤代烷基；更优选地，R5e为H。In some embodiments of the present disclosure, the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 5e is selected from hydrogen atoms, F, Br, I, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N , C 1-6 alkoxy group, C 1-6 haloalkoxy group and 3 to 8-membered cycloalkyl group; preferably, R 5e is selected from hydrogen atom, F, Br, I, C 1-6 alkyl group and C 1 -6 haloalkyl; more preferably, R 5e is H.
在本公开的一些实施方案中，所述的通式(II)或通式(III)所示的化合物或其可药用的盐，其中G1和G3均为CH。In some embodiments of the present disclosure, the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein G 1 and G 3 are both CH.
在本公开的一些实施方案中，所述的通式(II)或通式(III)所示的化合物或其可药用的盐，其中R5c选自氢原子、Cl、Br、I、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、氰基、氨基、C1-6烷基NH、(C1-6烷基)2N、C1-6烷氧基、C1-6卤代烷氧基和3至8元环烷基；优选地，R5c选自氢原子、Cl、Br、I、C1-6烷基和C1-6卤代烷基；进一步优选地，R5c为氢原子或C1-6卤代烷基；更优选地，R5c为氢原子或三氟甲基。In some embodiments of the present disclosure, the compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 5c is selected from hydrogen atom, Cl, Br, I, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl NH, (C 1-6 alkyl) 2 N , C 1-6 alkoxy group, C 1-6 haloalkoxy group and 3 to 8-membered cycloalkyl group; preferably, R 5c is selected from hydrogen atom, Cl, Br, I, C 1-6 alkyl group and C 1 -6 haloalkyl; further preferably, R 5c is a hydrogen atom or C 1-6 haloalkyl; more preferably, R 5c is a hydrogen atom or trifluoromethyl.
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中Rw为氢原子或C1-6烷基，所述的C1-6烷基任选被选自氘原子、卤素、C1-6烷氧基和C1-6卤代烷氧基中的一个或多个取代基所取代；优选地，Rw选自氢原子、C1-6烷基和C1-6氘代烷基；进一步优选地，Rw为氢原子或C1-6烷基；更优选地，Rw为氢原子或甲基。In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R w is a hydrogen atom or C 1 -6 alkyl, the C 1-6 alkyl is optionally substituted with one or more substituents selected from deuterium atoms, halogens, C 1-6 alkoxy and C 1-6 haloalkoxy; Preferably, R w is selected from hydrogen atom, C 1-6 alkyl group and C 1-6 deuterated alkyl group; further preferably, R w is a hydrogen atom or C 1-6 alkyl group; more preferably, R w is Hydrogen atom or methyl group.
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中Rx为氢原子或C1-6烷基，所述的C1-6烷基任选被选自氘原子、卤素、C1-6烷氧基和C1-6卤代烷氧基中的一个或多个取代基所取代；优选地，Rx选自氢原子、C1-6烷基和C1-6氘代烷基；进一步优选地，Rx为氢原子或C1-6烷基；进一步优选地，Rx为C1-6烷基；更优选地，Rx为甲基。In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R x is a hydrogen atom or C 1 -6 alkyl, the C 1-6 alkyl is optionally substituted with one or more substituents selected from deuterium atoms, halogens, C 1-6 alkoxy and C 1-6 haloalkoxy; Preferably, Rx is selected from a hydrogen atom , a C 1-6 alkyl group and a C 1-6 deuterated alkyl group; further preferably, R C 1-6 alkyl; more preferably, R x is methyl.
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中Rx为氢原子。In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R x is a hydrogen atom.
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中Rn1、Rn2、Rn3、Rn4、Rn5、Rn6、Rn7和Rn8在每次出现时相同或不同，且各自独立地选自氢原子、C1-6烷基和C1-6卤代烷基；优选地，Rn1、Rn2、Rn3、Rn4、Rn5、Rn6、Rn7和Rn8在每次出现时相同或不同，且各自独立地为氢原子或C1-6烷基。In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R n1 , R n2 , R n3 , R n4 , R n5 , R n6 , R n7 and R n8 are the same or different each time they appear, and are each independently selected from hydrogen atoms, C 1-6 alkyl and C 1-6 haloalkyl; preferably, R n1 , R n2 , R n3 , R n4 , R n5 , R n6 , R n7 and R n8 are the same or different each time they appear, and are each independently a hydrogen atom or a C 1-6 alkyl group.
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7和Ra8在每次出现时相同或不同，且各自独立地选自氢原子、C1-6烷基和C1-6卤代烷基；优选地，Ra1、 Ra2、Ra3、Ra4、Ra5、Ra6、Ra7和Ra8在每次出现时相同或不同，且各自独立地为C1-6烷基或C1-6卤代烷基。In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 are the same or different each time they appear, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group and a C 1-6 haloalkyl group; preferably, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 are the same or different on each occurrence, and are each independently a C 1-6 alkyl group or a C 1-6 haloalkyl group.
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中t1为0或2；优选地，t1为2。In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein t1 is 0 or 2; preferably , t1 is 2.
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中t2为0或2；优选地，t2为2。In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein t2 is 0 or 2; preferably , t2 is 2.
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中Z为O或NH；Rw选自氢原子、C1-6烷基和C1-6氘代烷基；Rx选自氢原子、C1-6烷基和C1-6氘代烷基；R1选自氢原子、C1-6烷基、RvO和RyRzN，Ry和Rz相同或不同，且各自独立地选自氢原子、C1-6烷基和C1-6氘代烷基，Rv为C1-6烷基或C1-6氘代烷基；R2选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；R3选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；R4选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；Ra选自氢原子、卤素和C1-6烷基；Rb选自氢原子、卤素和C1-6烷基；n为0或1；G0为CR5a，R5a选自氢原子、F、Br、I、C1-6烷基和C1-6卤代烷基；G2为CR5d，R5d选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；G1为CR5b，R5b选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；，G3为CR5e，R5e选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；且R5c选自氢原子、Cl、Br、I、C1-6烷基和C1-6卤代烷基。In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein Z is O or NH; Rw is selected from hydrogen atoms, C 1-6 alkyl and C 1-6 deuterated alkyl; R x is selected from hydrogen atom, C 1-6 alkyl and C 1-6 deuterated alkyl; R 1 is selected from hydrogen atom, C 1-6 alkyl, R v O and R y R z N, R y and R z are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group and a C 1-6 deuterated alkyl group, and R v is a C 1-6 alkyl group or C 1-6 deuterated alkyl; R 2 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1 -6 haloalkyl; R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R a is selected from hydrogen atom, halogen and C 1-6 alkyl; R b is selected from hydrogen atom , halogen and C 1-6 alkyl; n is 0 or 1; G 0 is CR 5a , R 5a is selected from hydrogen atom, F, Br, I, C 1-6 alkyl and C 1-6 haloalkyl; G 2 is CR 5d , R 5d is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; G 1 is CR 5b , R 5b is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl;, G 3 is CR 5e , R 5e is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; and R 5c is selected from hydrogen atom, Cl, Br, I , C 1-6 alkyl and C 1-6 haloalkyl.
在本公开的一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中Z为O；Rw为氢原子或C1-6烷基；Rx为C1-6烷基；R1选自氢原子、C1-6烷基、C1-6烷氧基和RyRzN，Ry和Rz相同或不同，且各自独立地为氢原子或C1-6烷基；G1为CR5b，R5b选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；G3为CR5e，R5e选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；R5c为氢原子或C1-6卤代烷基；且n为0或1。In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein Z is O; R w is a hydrogen atom or a C 1-6 alkyl group; R x is C 1-6 alkyl; R 1 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy and R y R z N, R y and R z are the same or different, and each is independently hydrogen atom or C 1-6 alkyl; G 1 is CR 5b , R 5b is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; G 3 is CR 5e , R 5e is selected from hydrogen atom , halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 5c is a hydrogen atom or C 1-6 haloalkyl; and n is 0 or 1.
在本公开的一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中Z为O；Rw为氢原子或C1-6烷基；Rx为氢原子或C1-6烷基；R1选自氢原子、C1-6烷基、C1-6烷氧基和RyRzN，Ry和Rz相同或不同，且各自独立地为氢原子或C1-6烷基；G1为CR5b，R5b选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；G3为CR5e，R5e选自氢原子、卤素、C1-6烷基和C1-6卤代烷基；R5c为氢原子或C1-6卤代烷基；且n为0或1。In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein Z is O; R w is a hydrogen atom or a C 1-6 alkyl group; R x is Hydrogen atom or C 1-6 alkyl group; R 1 is selected from hydrogen atom, C 1-6 alkyl group, C 1-6 alkoxy group and R y R z N, R y and R z are the same or different, and each is independent Ground is a hydrogen atom or C 1-6 alkyl group; G 1 is CR 5b , R 5b is selected from hydrogen atom, halogen, C 1-6 alkyl group and C 1-6 haloalkyl group; G 3 is CR 5e , R 5e is selected from From hydrogen atom, halogen, C 1-6 alkyl group and C 1-6 haloalkyl group; R 5c is a hydrogen atom or C 1-6 haloalkyl group; and n is 0 or 1.
表A本公开的典型化合物包括但不限于：


Table A Typical compounds of the present disclosure include, but are not limited to:


本公开的另一方面涉及通式(IIa)所示的化合物或其盐：
Another aspect of the present disclosure relates to compounds represented by general formula (IIa) or salts thereof:
其中：in:
RL为氨基保护基；优选地，RL为PMB；R L is an amino protecting group; preferably, R L is PMB;
Rx、Z、R1、R2、R3、R4、R5c、Ra、Rb、G0、G1、G2、G3和n如通式(II)中所定义。R x , Z, R 1 , R 2 , R 3 , R 4 , R 5c , Ra , R b , G 0 , G 1 , G 2 , G 3 and n are as defined in general formula (II).
本公开的另一方面涉及通式(IIIa)所示的化合物或其盐：
Another aspect of the present disclosure relates to compounds represented by general formula (IIIa) or salts thereof:
其中：in:
RL为氨基保护基；优选地，RL为PMB；R L is an amino protecting group; preferably, R L is PMB;
Rx、Z、R1、R5c、G1、G3和n如通式(III)中所定义。 Rx , Z, R1 , R5c , G1 , G3 and n are as defined in general formula (III).
本公开的另一方面涉及通式(IIA)所示的化合物或其盐：
Another aspect of the present disclosure relates to compounds represented by general formula (IIA) or salts thereof:
其中：in:
RN为卤素；优选地，RN为Cl；R N is halogen; preferably, R N is Cl;
R5c选自氘原子、Cl、Br、I、烷基、烯基、炔基、硝基、氰基、-NRn5Rn6、-C(O)NRn7Rn8、-C(O)Ra5、-C(O)ORa6、-ORa7、-S(O)t2Ra8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R 5c is selected from deuterium atom, Cl, Br, I, alkyl group, alkenyl group, alkynyl group, nitro group, cyano group, -NR n5 R n6 , -C(O)NR n7 R n8 , -C(O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of deuterium, halogen, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkyl Substituted with one or more substituents from oxygen, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Z、R1、R2、R3、R4、Ra、Rb、G0、G1、G2、G3、Rn5、Rn6、Rn7、Rn8、Ra5、Ra6、Ra7、Ra8、t2和n如通式(II)中所定义。Z, R 1 , R 2 , R 3 , R 4 , R a , R b , G 0 , G 1 , G 2 , G 3 , R n5 , R n6 , R n7 , R n8 , R a5 , R a6 , R a7 , R a8 , t2 and n are as defined in general formula (II).
本公开的另一方面涉及通式(IIIA)所示的化合物或其盐：
Another aspect of the present disclosure relates to compounds represented by general formula (IIIA) or salts thereof:
其中：in:
RN为卤素；优选地，RN为Cl；R N is halogen; preferably, R N is Cl;
Z、R1、R5c、G1、G3和n如通式(IIA)中所定义。Z, R 1 , R 5c , G 1 , G 3 and n are as defined in general formula (IIA).
表B本公开的典型中间体化合物包括但不限于：


Table B Typical intermediate compounds of the present disclosure include, but are not limited to:


本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
通式(IIa)所示的化合物或其盐经脱保护反应，得到通式(II)所示的化合物或其可药用的盐；The compound represented by the general formula (IIa) or a salt thereof is subjected to a deprotection reaction to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
其中： in:
RL为氨基保护基；优选地，RL为PMB；R L is an amino protecting group; preferably, R L is PMB;
Rw为氢原子；R w is a hydrogen atom;
Rx、Z、R1、R2、R3、R4、R5c、Ra、Rb、G0、G1、G2、G3和n如通式(II)中所定义。R x , Z, R 1 , R 2 , R 3 , R 4 , R 5c , Ra , R b , G 0 , G 1 , G 2 , G 3 and n are as defined in general formula (II).
本公开的另一方面涉及一种制备通式(III)所示的化合物或其盐的方法，该方法包括以下步骤：
Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a salt thereof, the method comprising the following steps:
通式(IIIa)所示的化合物或其盐经脱保护反应，得到通式(III)所示的化合物或其可药用的盐；The compound represented by the general formula (IIIa) or a salt thereof is subjected to a deprotection reaction to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
其中：in:
RL为氨基保护基；优选地，RL为PMB；R L is an amino protecting group; preferably, R L is PMB;
Rw为氢原子；R w is a hydrogen atom;
Rx、Z、R1、R5c、G1、G3和n如通式(III)中所定义。 Rx , Z, R1 , R5c , G1 , G3 and n are as defined in general formula (III).
本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
通式(IIA)所示的化合物或其盐与通式(IIB)所示的化合物或其盐发生磺酰化反应，得到通式(II)所示的化合物或其可药用的盐；A sulfonylation reaction occurs between a compound represented by general formula (IIA) or a salt thereof and a compound represented by general formula (IIB) or a salt thereof, to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;
其中：in:
RN为卤素；优选地，RN为Cl；R N is halogen; preferably, R N is Cl;
Z、Rx、Rw、R1、R2、R3、R4、R5c、Ra、Rb、G0、G1、G2、G3和n如通式(II)中所定义。Z, Rx , Rw , R1 , R2 , R3, R4, R5c , Ra , Rb , G0 , G1 , G2 , G3 and n are as in the general formula (II) definition.
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, which method includes the following steps:
通式(IIIA)所示的化合物或其盐与通式(IIB)所示的化合物或其盐发生磺酰化反应，得到通式(III)所示的化合物或其可药用的盐；The compound represented by the general formula (IIIA) or a salt thereof undergoes a sulfonylation reaction with the compound represented by the general formula (IIB) or a salt thereof, to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
其中：in:
RN为卤素；优选地，RN为Cl；R N is halogen; preferably, R N is Cl;
Z、Rx、Rw、R1、R5c、G1、G3和n如通式(III)中所定义。Z, Rx , Rw , R1 , R5c , G1 , G3 and n are as defined in general formula (III).
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。Another aspect of the present disclosure relates to a pharmaceutical composition containing a compound represented by the general formula (I), general formula (II), general formula (III) or table A of the present disclosure or a pharmaceutically acceptable compound thereof salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
本公开进一步涉及通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用盐，或包含其的药物组合物在制备TEAD抑制剂药物中的用途。The present disclosure further relates to the use of compounds represented by general formula (I), general formula (II), general formula (III) or table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them in the preparation of TEAD inhibitor drugs. use.
本公开进一步涉及通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用盐，或包含其的药物组合物在制备抑制YAP/TAZ-TEAD转录活性的药物中的用途。The present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III) or table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same for the preparation of compounds that inhibit YAP/TAZ-TEAD. Use in transcriptionally active drugs.
本公开进一步涉及通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用盐，或包含其的药物组合物在制备用于治疗和/或预防由YAP/TAZ-TEAD相互作用介导的疾病或病症的药物中的用途。The present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III) or table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same for the preparation of treatments and/or Use in drugs to prevent diseases or conditions mediated by YAP/TAZ-TEAD interactions.
本公开进一步涉及通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用盐，或包含其的药物组合物在制备用于治疗和/或预防癌症、纤维化、多囊肾病和心血管疾病的药物中的用途；所述的纤维化优选为肝纤维化；所述的癌症优选选自间皮瘤、许旺细胞瘤、白血病、淋巴瘤、巨球蛋白血症、重链病、肉瘤、胰腺癌、乳腺癌、卵巢癌、***癌、鳞癌、汗腺癌、皮脂腺癌、***状癌、囊腺癌、髓样癌、支气管癌、肝癌、胆管癌、绒毛膜癌、***瘤、胚胎癌、威尔姆氏肿瘤、***、子宫内膜癌、睾丸癌、肺癌、膀胱癌、神经胶质瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管瘤、听神经瘤、神经鞘瘤、神经纤维瘤、视网膜母细胞瘤、黑色素瘤、皮肤癌、肾癌、鼻咽癌、胃癌、食管癌、头颈癌、结直肠癌、小肠癌、胆囊癌、儿科肿瘤、尿路上皮癌、输尿管肿瘤、甲状腺癌、骨瘤、成神经细胞瘤、脑瘤、室管膜瘤和骨髓瘤。The present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III) or table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same for the preparation of treatments and/or Use in medicines to prevent cancer, fibrosis, polycystic kidney disease and cardiovascular disease; the fibrosis is preferably liver fibrosis; the cancer is preferably selected from mesothelioma, Schwann cell tumor, leukemia, lymphoma , macroglobulinemia, heavy chain disease, sarcoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer , cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharynx Angiomas, ependymomas, pineal tumors, hemangioma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, Head and neck cancer, colorectal cancer, small bowel cancer, gallbladder cancer, pediatric cancer, urothelial cancer, ureteral cancer, thyroid cancer, osteoma, neuroblastoma, brain tumors, ependymoma, and myeloma.
本公开进一步涉及一种抑制YAP/TAZ-TEAD转录活性的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物。The present disclosure further relates to a method for inhibiting YAP/TAZ-TEAD transcriptional activity, which includes administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (III) or Table A. The compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
本公开进一步涉及一种抑制TEAD的方法，其包括给予所需患者治疗有效量 的通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物。The present disclosure further relates to a method of inhibiting TEAD, comprising administering to a patient in need thereof a therapeutically effective amount The compound represented by the general formula (I), the general formula (II), the general formula (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same.
本公开进一步涉及一种治疗和/或预防由YAP/TAZ-TEAD相互作用介导的疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物。The present disclosure further relates to a method of treating and/or preventing diseases or conditions mediated by YAP/TAZ-TEAD interactions, comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (II), A compound represented by general formula (III) or Table A, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same.
本公开进一步涉及一种治疗和/或预防癌症、纤维化、多囊肾病和心血管疾病的方法；其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物；所述的纤维化优选为肝纤维化；所述的癌症优选选自间皮瘤、许旺细胞瘤、白血病、淋巴瘤、巨球蛋白血症、重链病、肉瘤、胰腺癌、乳腺癌、卵巢癌、***癌、鳞癌、汗腺癌、皮脂腺癌、***状癌、囊腺癌、髓样癌、支气管癌、肝癌、胆管癌、绒毛膜癌、***瘤、胚胎癌、威尔姆氏肿瘤、***、子宫内膜癌、睾丸癌、肺癌、膀胱癌、神经胶质瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管瘤、听神经瘤、神经鞘瘤、神经纤维瘤、视网膜母细胞瘤、黑色素瘤、皮肤癌、肾癌、鼻咽癌、胃癌、食管癌、头颈癌、结直肠癌、小肠癌、胆囊癌、儿科肿瘤、尿路上皮癌、输尿管肿瘤、甲状腺癌、骨瘤、成神经细胞瘤、脑瘤、室管膜瘤和骨髓瘤。The present disclosure further relates to a method of treating and/or preventing cancer, fibrosis, polycystic kidney disease and cardiovascular disease; which includes administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (II), Formula (III) Or the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same; the fibrosis is preferably liver fibrosis; the cancer is preferably selected from mesothelioma, Schwann Cytoma, leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, myeloid carcinoma carcinoma, bronchial carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, Medulloblastoma, craniopharyngioma, ependymoma, pineal gland tumor, hemangioma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharynx Cancer, stomach cancer, esophageal cancer, head and neck cancer, colorectal cancer, small bowel cancer, gallbladder cancer, pediatric cancer, urothelial cancer, ureteral cancer, thyroid cancer, osteoma, neuroblastoma, brain tumor, ependymoma and Myeloma.
本公开进一步涉及一种通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作药物。The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III) or table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used as a medicine .
本公开进一步涉及一种通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作TEAD抑制剂。The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III) or table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used as a TEAD Inhibitors.
本公开进一步涉及一种通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于抑制YAP/TAZ-TEAD转录活性。The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III) or table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used to inhibit YAP/TAZ-TEAD transcriptional activity.
本公开进一步涉及一种通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防由YAP/TAZ-TEAD相互作用介导的疾病或病症。The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III) or table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used for treatment and/or prevent diseases or conditions mediated by YAP/TAZ-TEAD interactions.
本公开进一步涉及一种通式(I)、通式(II)、通式(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防癌症、纤维化、多囊肾病和心血管疾病；所述的纤维化优选为肝纤维化；所述的癌症优选选自间皮瘤、许旺细胞瘤、白血病、淋巴瘤、巨球蛋白血症、重链病、肉瘤、胰腺癌、乳腺癌、卵巢癌、***癌、鳞癌、汗腺癌、皮脂腺癌、***状癌、囊腺癌、髓样癌、支气管癌、肝癌、胆管癌、绒毛膜癌、***瘤、胚胎癌、威尔姆氏肿瘤、***、子宫内膜癌、睾丸癌、肺癌、膀胱癌、神经胶质瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管瘤、听神经瘤、神经鞘瘤、神经纤维瘤、视网膜母细胞瘤、黑色素瘤、皮肤癌、肾癌、鼻咽癌、胃癌、食管癌、头颈癌、结直肠癌、小肠癌、胆囊癌、儿科肿瘤、尿路上皮癌、输尿管肿瘤、甲状腺癌、骨瘤、成神经细胞瘤、脑瘤、室管膜瘤和骨髓瘤。 The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III) or table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used for treatment And/or prevent cancer, fibrosis, polycystic kidney disease and cardiovascular disease; the fibrosis is preferably liver fibrosis; the cancer is preferably selected from the group consisting of mesothelioma, Schwann cell tumor, leukemia, lymphoma, giant cell carcinoma, Globulinemia, heavy chain disease, sarcoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, bile duct Carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma , ependymoma, pineal tumor, hemangioma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer , colorectal cancer, small bowel cancer, gallbladder cancer, pediatric tumors, urothelial cancer, ureteral tumors, thyroid cancer, osteoma, neuroblastoma, brain tumors, ependymoma, and myeloma.
本公开中所述的由YAP/TAZ-TEAD相互作用介导的疾病或病症优选选自癌症、纤维化、多囊肾病和心血管疾病；所述的纤维化优选为肝纤维化；所述的癌症优选选自间皮瘤、许旺细胞瘤、白血病、淋巴瘤、巨球蛋白血症、重链病、肉瘤、胰腺癌、乳腺癌、卵巢癌、***癌、鳞癌、汗腺癌、皮脂腺癌、***状癌、囊腺癌、髓样癌、支气管癌、肝癌、胆管癌、绒毛膜癌、***瘤、胚胎癌、威尔姆氏肿瘤、***、子宫内膜癌、睾丸癌、肺癌、膀胱癌、神经胶质瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管瘤、听神经瘤、神经鞘瘤、神经纤维瘤、视网膜母细胞瘤、黑色素瘤、皮肤癌、肾癌、鼻咽癌、胃癌、食管癌、头颈癌、结直肠癌、小肠癌、胆囊癌、儿科肿瘤、尿路上皮癌、输尿管肿瘤、甲状腺癌、骨瘤、成神经细胞瘤、脑瘤、室管膜瘤和骨髓瘤。The disease or disorder mediated by YAP/TAZ-TEAD interaction described in the present disclosure is preferably selected from cancer, fibrosis, polycystic kidney disease and cardiovascular disease; the fibrosis is preferably liver fibrosis; the The cancer is preferably selected from mesothelioma, Schwann cell tumor, leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma , papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, Lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma Cancer, skin cancer, kidney cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, pediatric cancer, urothelial cancer, ureteral cancer, thyroid cancer, osteoma, neuroblast tumours, brain tumors, ependymoma and myeloma.
本公开所述的间皮瘤优选为胸膜间皮瘤；肉瘤优选为软组织肉瘤或骨肉瘤；卵巢癌优选为卵巢浆液性腺癌；肝癌优选为肝细胞癌；子宫内膜癌优选为子宫内膜腺鳞状癌；肺癌优选为非小细胞肺癌；神经胶质瘤优选为胶质母细胞瘤；血管瘤优选为血管母细胞瘤或上皮样血管内皮瘤；神经鞘瘤优选为恶性周围神经鞘瘤；胃癌优选为胃腺癌；食管癌优选为食管腺癌；脑瘤优选为脑膜瘤。The mesothelioma described in the present disclosure is preferably pleural mesothelioma; the sarcoma is preferably soft tissue sarcoma or osteosarcoma; the ovarian cancer is preferably ovarian serous adenocarcinoma; the liver cancer is preferably hepatocellular carcinoma; the endometrial cancer is preferably endometrial gland Squamous carcinoma; lung cancer is preferably non-small cell lung cancer; glioma is preferably glioblastoma; hemangioma is preferably hemangioblastoma or epithelioid hemangioendothelioma; schwannoma is preferably malignant peripheral nerve sheath tumor; The gastric cancer is preferably gastric adenocarcinoma; the esophageal cancer is preferably esophageal adenocarcinoma; the brain tumor is preferably meningioma.
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药、吸入或吹入给药的各种剂型。本公开的化合物也可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。The active compounds may be prepared in a form suitable for administration by any appropriate route and the compositions of the present disclosure may be formulated by conventional means using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.
作为一般性指导，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。As a general guide, the active compounds are preferably in unit dosage form, or in such form that the patient may self-administer a single dose. The unit dosage form of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder or liquid preparation. A suitable unit dose may be 0.1 to 1000 mg.
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients wait. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。 Oral formulations may also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or in which the active ingredient is mixed with a water-soluble carrier or oil vehicle.
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。Aqueous suspensions contain the active substances and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。Oil suspensions can be formulated by suspending the active ingredient in vegetable oil, or mineral oil. Oil suspensions may contain thickening agents. Sweetening and flavoring agents as described above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase can be vegetable oil, or mineral oil or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may also contain demulcents, preservatives, coloring agents and antioxidants.
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。Pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. Sterile injectable preparations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oily phase. Injectable solutions or microemulsions may be injected into the patient's bloodstream by local mass injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains constant circulating concentrations of the compounds of the present disclosure. To maintain this constant concentration, continuous intravenous drug delivery devices can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。Pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents such as those mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent. In addition, sterile fixed oil can be conveniently used as the solvent or suspending medium. For this purpose, any blend of fixed oils can be used. In addition, fatty acids are also prepared as injectables.
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore dissolve in the rectum to release the drug.
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。Compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including, but not limited to, the activity of the specific compound used, the patient's age, the patient's weight, the patient's health, and the patient's behavior. , patient's diet, administration time, administration method, excretion rate, combination of drugs, severity of disease, etc.; in addition, the best treatment method such as treatment mode, daily dosage of compounds or pharmaceutically acceptable salts Types can be verified based on traditional treatment regimens.
术语说明Terminology
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”指饱和的直链或带有支链的脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即 C1-12烷基)，更优选具有1至6个碳原子的烷基(即C1-6烷基)。非限制性的实例包括：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。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "alkyl" refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e. C 1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e. C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (ie, C 1-6 alkyl). 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-di Methylpentyl, 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, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20亚烷基)。所述亚烷基优选具有1至12个碳原子的亚烷基(即C1-12亚烷基)，更优选具有1至6个碳原子的亚烷基(即C1-6亚烷基)。非限制性的实例包括：-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH(CH2CH3)-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH2-等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group is as defined above and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 alkylene group). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene group), and more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 alkylene group ). Non-limiting examples include: -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 2 CH 3 )-, -CH 2 CH (CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment. The substituent is preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, where the alkyl group is as defined above and has 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C 2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 alkenyl group). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from the group consisting of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C2-6炔基)。非 限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where the alkyl group is as defined above and has 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C 2-12 alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, C 2-6 alkynyl group). No Limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment. The substituents are preferably selected from the group consisting of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment. The substituent is preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“环烷基”指饱和或部分不饱和的单环全碳环(即单环环烷基)或多环***(即多环环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元环烷基)。所述环烷基优选具有3至12个环原子的环烷基(即3至12元环烷基)，更优选具有3至8个环原子的环烷基(即3至8元环烷基)或优选具有3至6个环原子的环烷基(即3至6元环烷基)。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 3 to 20 membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group), and more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group). ) or preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6 membered cycloalkyl group).
所述的单环环烷基，非限制性的实例包括：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、环庚三烯基和环辛基等。Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.
所述的多环环烷基包括：螺环烷基、稠环烷基和桥环烷基。The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.
术语“螺环烷基”指环之间共用一个碳原子(称螺原子)的多环***，其环内可以含有一个或多个双键，或其环内可以含有一个或多个选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个全碳环且连接点在该全碳环上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺环烷基)。所述螺环烷基优选具有6至14个环原子的螺环烷基(即6至14元螺环烷基)，更优选具有7至10个环原子的螺环烷基(即7至10元螺环烷基)。所述螺环烷基包括单螺环烷基和多螺环烷基(如双螺环烷基等)，优选单螺环烷基或双螺环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。非限制性的实例包括：The term "spirocycloalkyl" refers to a polycyclic system in which one carbon atom (called a spiro atom) is shared between the rings. The ring may contain one or more double bonds, or the ring may contain one or more atoms selected from nitrogen, Heteroatoms of oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxoated, that is, to form sulfoxide or sulfone, but does not include -O-O-, -O-S - or -S-S-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, which has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 5 to 20 membered spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spirocycloalkyl group), and more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spirocycloalkyl group). membered spirocycloalkyl). The spirocycloalkyl group includes a single spirocycloalkyl group and a multi-spirocycloalkyl group (such as a double spirocycloalkyl group, etc.), preferably a single spirocycloalkyl group or a double spirocycloalkyl group, and more preferably a 3-membered/4-membered, 3-membered or 3-membered spirocycloalkyl group. Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/5 Yuan, 5 Yuan/ 6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan Single spirocycloalkyl. Non-limiting examples include:
其连接点可在任意位置； Its connection point can be at any position;
等。 wait.
术语“稠环烷基”指环之间共享毗邻的两个碳原子的多环***，其为单环环烷基与一个或多个单环环烷基稠合，或者单环环烷基与杂环基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环环烷基上，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠环烷基)。所述稠环烷基优选具有6至14个环原子的稠环烷基(即6至14元稠环烷基)，更优选具有7至10个环原子的稠环烷基(即7至10元稠环烷基)。所述稠环烷基包括双环稠环烷基和多环稠环烷基(如三环稠环烷基、四环稠环烷基等)，优选双环稠环烷基或三环稠环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。非限制性的实例包括：其连接点可在任意位置；等。The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with a heterocyclic cycloalkyl group. One or more of the cyclic groups, aryl groups or heteroaryl groups are condensed, wherein the point of attachment is on a single-ring cycloalkyl group, which may contain one or more double bonds in the ring, and has 5 to 20 (for example, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 5 to 20 membered fused ring alkyl group). The fused ring alkyl group is preferably a fused ring alkyl group having 6 to 14 ring atoms (ie, a 6 to 14-membered fused ring alkyl group), and more preferably a fused ring alkyl group having 7 to 10 ring atoms (ie, a 7 to 10 membered ring alkyl group). fused ring alkyl group). The fused cycloalkyl group includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl , more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan , 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 One-membered/5-membered or 7-membered/6-membered bicyclic fused cycloalkyl group. Non-limiting examples include: Its connection point can be at any position; wait.
术语“桥环烷基”指环之间共用两个不直接连接的碳原子的全碳多环***，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即5至20元桥环烷基)。所述桥环烷基优选具有6至14个碳原子的桥环烷基(即6至14元桥环烷基)，更优选具有7至10个碳原子的桥环烷基(即7至10元桥环烷基)。所述桥环烷基包括双环桥环烷基和多环桥环烷基(如三环桥环烷基、四环桥环烷基等)，优选双环桥环烷基或三环桥环烷基。非限制性的实例包括：The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings. The ring may contain one or more double bonds and has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie, 5 to 20 membered bridged cycloalkyl). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6- to 14-membered bridged cycloalkyl group), and more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl group). bridged cycloalkyl). The bridged cycloalkyl group includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl . Non-limiting examples include:
其连接点可在任意位置。 Its connection point can be anywhere.
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接 点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。A cycloalkyl group may be substituted or unsubstituted, and when substituted it may be used in any available linkage The points are substituted, and the substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, One or more of cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“杂环基”指饱和或部分不饱和的单环杂环(即单环杂环基)或多环杂环***(即多环杂环基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，且具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元杂环基)。所述杂环基优选具有3至12个环原子的杂环基(即3至12元杂环基)；进一步优选具有3至8个环原子的杂环基(即3至8元杂环基)；更优选具有3至6个环原子的杂环基(即3至6元杂环基)或优选具有5或6个环原子的杂环基(即5或6元杂环基)。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or a polycyclic heterocyclic system (i.e., polycyclic heterocyclyl), which contains at least one ring (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxogenated, that is, to form sulfoxide or sulfone, but not including -O-O-, -O-S- or -S-S-), and having 3 to 20 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 3 to 20 membered heterocyclyl). The heterocyclyl group is preferably a heterocyclyl group having 3 to 12 ring atoms (i.e. a 3 to 12 membered heterocyclyl group); further preferably a heterocyclyl group having 3 to 8 ring atoms (i.e. a 3 to 8 membered heterocyclyl group) ); more preferably a heterocyclyl group having 3 to 6 ring atoms (i.e. a 3 to 6 membered heterocyclyl group) or preferably a heterocyclyl group having 5 or 6 ring atoms (i.e. a 5 or 6 membered heterocyclyl group).
所述的单环杂环基，非限制性的实例包括：吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基和高哌嗪基等。Non-limiting examples of the monocyclic heterocyclyl include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , thiomorpholinyl and homopiperazinyl, etc.
所述的多环杂环基包括螺杂环基、稠杂环基和桥杂环基。The polycyclic heterocyclyl group includes spiroheterocyclyl group, fused heterocyclyl group and bridged heterocyclyl group.
术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环***，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个单环杂环基且连接点在该单环杂环基上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺杂环基)。所述螺杂环基优选具有6至14个环原子的螺杂环基(即6至14元螺杂环基)，更优选具有7至10个环原子的螺杂环基(即7至10元螺杂环基)。所述螺杂环基包括单螺杂环基和多螺杂环基(如双螺杂环基等)，优选单螺杂环基或双螺杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环基。非限制性的实例包括：The term "spiroheterocyclyl" refers to a polycyclic heterocyclic system in which the rings share one atom (called a spiro atom). The ring may contain one or more double bonds, and the ring contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, But does not include -O-O-, -O-S- or -S-S-), provided that it contains at least one monocyclic heterocyclyl group and the point of attachment is on the monocyclic heterocyclyl group, which has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie, 5 to 20 membered spiroheterocyclyl). The spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroheterocyclyl group), and more preferably a spiroheterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclyl group). 1-membered spiroheterocyclyl). The spiroheterocyclyl group includes a single spiroheterocyclyl group and a polyspiroheterocyclyl group (such as a double spiroheterocyclyl group, etc.), preferably a single spiroheterocyclyl group or a double spiroheterocyclyl group, more preferably 3-membered/4-membered, 3-membered or 3-membered spiroheterocyclyl. Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/5 Yuan, 5 Yuan/ 6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan Single spiroheterocyclyl. Non-limiting examples include:
等。 wait.
术语“稠杂环基”指环之间共享毗邻的两个原子的多环杂环***，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其为单环杂环基与一个 或多个单环杂环基稠合，或者单环杂环基与环烷基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环杂环基上，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠杂环基)。所述稠杂环基优选具有6至14个环原子的稠杂环基(即6至14元稠杂环基)，更优选具有7至10个环原子的稠杂环基(即7至10元稠杂环基)。所述稠杂环基包括双环和多环稠杂环基(如三环稠杂环基、四环稠杂环基等)，优选双环稠杂环基或三环稠杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。非限制性的实例包括：The term "fused heterocyclyl" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between the rings. The ring may contain one or more double bonds, and the ring may contain at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, but not including -OO-, -OS- or -SS-), which is a monocyclic heterocyclyl group with one Or multiple monocyclic heterocyclyl groups are fused, or the monocyclic heterocyclyl group is condensed with one or more of cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl group, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic rings base). The fused heterocyclyl group is preferably a fused heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused heterocyclyl group), and more preferably a fused heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclyl group). fused heterocyclic group). The fused heterocyclyl group includes bicyclic and polycyclic fused heterocyclyl groups (such as tricyclic fused heterocyclyl group, tetracyclic fused heterocyclyl group, etc.), preferably bicyclic fused heterocyclyl group or tricyclic fused heterocyclyl group, more preferably 3 Yuan/4 Yuan, 3 Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/ 5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan Or 7-membered/6-membered bicyclic fused heterocyclyl. Non-limiting examples include:
等。 wait.
术语“桥杂环基”指环之间共用两个不直接连接的原子的多环杂环***，其环内可以含有一个或多个双键，并且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元桥杂环基)。所述桥杂环基优选具有6至14个环原子的桥杂环基(即6至14元桥杂环基)，更优选具有7至10个环原子的桥杂环基(即7至10元桥杂环基)。根据组成环的数目可以分为双环桥杂环基和多环桥杂环基(如三环桥杂环基、四环桥杂环基等)，优选双环桥杂环基或三环桥杂环基。非限制性的实例包括：等。The term "bridged heterocyclyl" refers to a polycyclic heterocyclic system that shares two atoms that are not directly connected between the rings. The ring may contain one or more double bonds, and the ring contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, but not including -OO-, -OS- or -SS-), which have 5 to 20 (e.g. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 5 to 20 membered bridged heterocyclyl). The bridged heterocyclyl group is preferably a bridged heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclyl group), and more preferably a bridged heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered bridged heterocyclyl group). Yuan-bridged heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclyl and polycyclic bridged heterocyclyl (such as tricyclic bridged heterocyclyl, tetracyclic bridged heterocyclyl, etc.), preferably bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl. base. Non-limiting examples include: wait.
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧 基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。Heterocyclyl may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituent is preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkyl. oxygen or Multiple.
术语“芳基”指具有共轭的π电子体系的单环全碳芳环(即单环芳基)或多环芳环***(即多环芳基)，其具有6至14个(例如6、7、8、9、10、11、12、13或14个)环原子(即6至14元芳基)。所述芳基优选具有6至10个环原子的芳基(即6至10元芳基)，更优选为8至10个环原子的芳基(即8至10元多环芳基)。所述的单环芳基，例如苯基。所述的多环芳基，非限制性的实例包括：萘基、蒽基、菲基等。所述多环芳基还包括苯基与杂环基或环烷基中的一个或多个稠合，或萘基与杂环基或环烷基中的一个或多个稠合，其中连接点在苯基或萘基上，并且在这种情况下，环原子个数继续表示多环芳环***中的环原子个数，非限制性的实例包括：The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated π electron system, having 6 to 14 (e.g., 6 , 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e. 6 to 14 membered aryl group). The aryl group is preferably an aryl group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aryl group), and more preferably an aryl group having 8 to 10 ring atoms (i.e., an 8- to 10-membered polycyclic aryl group). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aryl group also includes phenyl fused with one or more of heterocyclyl or cycloalkyl, or naphthyl fused with one or more of heterocyclyl or cycloalkyl, where the point of attachment on phenyl or naphthyl, and in this case, the number of ring atoms continues to mean the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:
等。 wait.
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。Aryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment. The substituents are preferably selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups. or Multiple.
术语“杂芳基”指具有共轭的π电子体系的单环杂芳环(即单环杂芳基)或多环杂芳环***(即多环杂芳基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至14个(例如5、6、7、8、9、10、11、12、13或14个)环原子(即5至14元杂芳基)。所述杂芳基优选具有5至10个环原子的杂芳基(即5至10元杂芳基)，更优选具有5或6个环原子的杂芳基(即5或6元单环杂芳基)或者优选具有8至10个环原子的杂芳基(即8至10元多环杂芳基)。The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) with a conjugated π electron system, which contains at least one (For example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo-substituted, i.e. Forms sulfoxides or sulfones, but not -O-O-, -O-S-, or -S-S-), which have 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ) ring atoms (i.e. 5 to 14 membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group), and more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered monocyclic heteroaryl group). aryl) or preferably a heteroaryl group having 8 to 10 ring atoms (ie, 8 to 10 membered polycyclic heteroaryl).
所述的单环杂芳基，非限制性的实例包括：呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、***基、四唑基、呋咱基、吡咯基、N-烷基吡咯基、吡啶基、嘧啶基、吡啶酮基、N-烷基吡啶酮(如等)、吡嗪基、哒嗪基等。Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, furazyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (such as etc.), pyrazinyl, pyridazinyl, etc.
所述的多环杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、苯并呋喃基、喹唑啉基、咔唑基、吡咯并三嗪基、5,6,7,8-四氢-***并吡嗪基、咪唑并哒嗪基和[1,2,4]***并[1,5-a]吡啶基等。所述多环杂芳基还包括单环杂芳基与一个或多个芳基稠合，其中连接点在芳香环上，并且在这种情况下，环原子个数继续表示多环杂芳环***中的环原子个数。所述多环杂芳基还包括单环杂芳基与环烷基或杂环基中的一个 或多个稠合，其中连接点在单环杂芳环上，并且在这种情况下，环原子个数继续表示多环杂芳环***中的环原子个数。非限制性的实例包括：Non-limiting examples of the polycyclic heteroaryl include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene base, benzofuranyl, quinazolinyl, carbazolyl, pyrrolotriazinyl, 5,6,7,8-tetrahydro-triazolopyrazinyl, imidazopyridazinyl and [1,2 ,4]triazolo[1,5-a]pyridyl, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent a polycyclic heteroaryl ring The number of ring atoms in the system. The polycyclic heteroaryl also includes one of monocyclic heteroaryl and cycloalkyl or heterocyclyl. or multiple fusions, where the point of attachment is on a monocyclic heteroaromatic ring, and in this case the number of ring atoms continues to mean the number of ring atoms in a polycyclic heteroaromatic ring system. Non-limiting examples include:
等。 wait.
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。Heteroaryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment. The substituents are preferably selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkyl groups. One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“氨基保护基”是指为了使分子其它部位进行反应时氨基保持不变，在氨基上引入的易于脱去的基团。非限制性的实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲氧羰基、乙氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、三苯甲基(Trt)、2,4-二甲氧基苄基(DMB)、乙酰基、苄基、烯丙基、4-甲氧基苄基(PMB)等，优选为PMB。The term "amino protecting group" refers to an easily removable group introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), watmethoxycarbonyl (Fmoc), allyl Oxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthalyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), Trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, 4-methoxybenzyl (PMB), etc., preferably PMB.
术语“羟基保护基”是指在羟基上引入的易于脱去的基团，用于阻断或保护羟基而在化合物的其它官能团上进行反应。非限制性的实例包括：三甲基硅基(TMS)、三乙基硅基(TES)、三异丙基硅基(TIPS)、叔丁基二甲基硅基(TBS)、叔丁基二苯基硅基(TBDPS)、甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氢吡喃基(THP)、甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等。The term "hydroxyl protecting group" refers to an easily removable group introduced on a hydroxyl group to block or protect the hydroxyl group for reactions on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Diphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), methyl Acyl, acetyl, benzoyl, p-nitrobenzoyl, etc.
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。The term "cycloalkyloxy" refers to cycloalkyl-O-, where cycloalkyl is as defined above.
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。The term "aryloxy" refers to aryl-O-, where aryl is as defined above.
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。The term "heteroaryloxy" refers to heteroaryl-O-, where heteroaryl is as defined above.
术语“烷硫基”指烷基-S-，其中烷基如上所定义。The term "alkylthio" refers to alkyl-S-, where alkyl is as defined above.
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined above.
术语“甲叉基”指＝CH2。 The term "methylene" refers to = CH2 .
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“羟基”指-OH。The term "hydroxy" refers to -OH.
术语“巯基”指-SH。The term "mercapto" refers to -SH.
术语“氨基”指-NH2。The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO2。The term "nitro" refers to -NO2 .
术语“氧代”或“氧代基”指“＝O”。The term "oxo" or "oxo" refers to "=O".
术语“羰基”指C＝O。The term "carbonyl" refers to C=O.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
Ms指甲磺酰基。Ms Methylsulfonyl.
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, where alkyl and cycloalkyl are as defined above.
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。Compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that have the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformational isomers and their mixtures (e.g. racemates, mixtures of diastereomers) . Additional asymmetric atoms may be present for substituents in the compounds of the present disclosure. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer. An isomer of a certain compound of the present disclosure can be prepared through asymmetric synthesis or chiral auxiliaries, or when the molecule contains basic functional groups (such as amino) or acidic functional groups (such as carboxyl), and appropriate optical Reactive acids or bases form diastereomeric salts, and then the diastereoisomers are resolved by conventional methods known in the art to obtain pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.
本公开所述化合物的化学结构中，键表示未指定构型，即如果化学结构中存在手性异构体，键可以为或或者同时包含和两种构型。In the chemical structure of the compounds described in this disclosure, the bond Indicates that the configuration is not specified, i.e. if there are chiral isomers in the chemical structure, the bond can be or or both and Two configurations.
本公开的化合物可以以不同的互变异构体形式存在，并且所有这样的形式包含在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺平衡实例如下所示：
The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, either as single isomers or as mixtures of said tautomers in any proportion. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like. An example of lactam-lactam equilibrium is shown below:
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：
When referring to pyrazolyl, it should be understood to include either one of the following two structures or a mixture of two tautomers:
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。All tautomeric forms are within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form.
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为2H(氘，D)、3H(氚，T)、11C、13C、14C、15N、17O、18O、32p、33p、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I等，优选氘。The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom with the same atomic number but a different atomic mass. Examples of isotopes that may be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, such as 2 H (deuterium, D), respectively. 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N , 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., preferably deuterium.
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of the drug. All variations in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, where the replacement of deuterium can be partial or complete. The replacement of partial deuterium means that at least one hydrogen is replaced by at least one deuterium.
在本公开化合物中，当一个位置被特别地指定为“氘”或“D”时，该位置应理解为氘的丰度比氘的天然丰度(其为0.015％)大至少1000倍(即，至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少1000倍(即，至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少2000倍(即，至少30％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3000倍(即，至少45％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3340倍(即，至少50.1％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3500倍(即，至少52.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4000倍(即，至少60％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4500倍(即，至少67.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5000倍(即，至少75％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5500倍(即，至少82.5％的氘掺入)。在一些实施方案中， 每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6000倍(即，至少90％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6333.3倍(即，至少95％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6466.7倍(即，至少97％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6600倍(即，至少99％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6633.3倍(即，至少99.5％的氘掺入)。In a compound of the present disclosure, when a position is specifically designated as "deuterium" or "D", that position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e. , at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, The abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).
“任选的”或“任选”是指随后所描述的事件或环境可以但不必然发生，其包括该事件或环境发生或不发生两种情形。例如“任选被卤素或者氰基取代的烷基”包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。"Optional" or "optional" means that the subsequently described event or circumstance may, but does not necessarily, occur, including the occurrence or non-occurrence of the event or circumstance. For example, "alkyl optionally substituted by halogen or cyano" includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen or cyano.
“取代”或“取代的”指基团中的一个或多个氢原子，优选1～6个，更优选1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定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键的碳原子(如烯)结合时可能是不稳定的。"Substituted" or "substituted" means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. A person skilled in the art will be able to determine possible or impossible substitutions without undue effort (either experimentally or theoretically). For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond, such as an alkene.
“药物组合物”表示含有一种或多种本文所述化合物或其可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。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 pharmaceutically acceptable salt thereof, and other chemical components, as well as other ingredients such as pharmaceutically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。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。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。"Pharmaceutically acceptable salts" refer to salts of compounds of the present disclosure, which may be selected from inorganic salts or organic salts. This type of salt is safe and effective when used in mammals, and has due biological activity. They can be prepared individually during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
针对药物或药理学活性剂而言，术语“治疗有效量”是指足以达到或至少部分达到预期效果的药物或药剂的用量。治疗有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的治疗有效量可以由本领域技术人员根据常规试验确定。The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of the therapeutically effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate therapeutically effective amount in an individual case can be determined by those skilled in the art based on routine experiments.
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and/or dosage forms which, within the scope of reasonable medical judgment, are suitable for contact with patient tissue without undue toxicity, irritation, allergic reaction or other problems or complications, has a reasonable benefit/risk ratio, and is effective for the intended use.
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。 When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is intended that the parameter may vary by ±10%, and is sometimes more preferably within ±5%. As those skilled in the art will appreciate, when a parameter is not critical, numbers are generally given for purposes of illustration only and not limitation.
本公开化合物的合成方法Synthetic methods of compounds of the present disclosure
为了完成本公开的目的，本公开采用如下技术方案：In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:
方案一Option One
本公开通式(II)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
The preparation method of the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof of the present disclosure includes the following steps:
通式(IIa)所示的化合物或其盐在酸性条件下经脱保护反应，得到通式(II)所示的化合物或其可药用的盐；The compound represented by the general formula (IIa) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
其中：in:
RL为氨基保护基；优选地，RL为PMB；R L is an amino protecting group; preferably, R L is PMB;
Rw为氢原子；R w is a hydrogen atom;
Rx、Z、R1、R2、R3、R4、R5c、Ra、Rb、G0、G1、G2、G3和n如通式(II)中所定义。R x , Z, R 1 , R 2 , R 3 , R 4 , R 5c , Ra , R b , G 0 , G 1 , G 2 , G 3 and n are as defined in general formula (II).
方案二Option II
本公开通式(III)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
The preparation method of the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof of the present disclosure includes the following steps:
通式(IIIa)所示的化合物或其盐在酸性条件下经脱保护反应，得到通式(III)所示的化合物或其可药用的盐；The compound represented by the general formula (IIIa) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
其中：in:
RL为氨基保护基；优选地，RL为PMB；R L is an amino protecting group; preferably, R L is PMB;
Rw为氢原子；R w is a hydrogen atom;
Rx、Z、R1、R5c、G1、G3和n如通式(III)中所定义。 Rx , Z, R1 , R5c , G1 , G3 and n are as defined in general formula (III).
方案三third solution
本公开通式(II)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
The preparation method of the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof of the present disclosure includes the following steps:
通式(IIA)所示的化合物或其盐与通式(IIB)所示的化合物或其盐发生磺酰化反应，得到通式(II)所示的化合物或其可药用的盐；A sulfonylation reaction occurs between a compound represented by general formula (IIA) or a salt thereof and a compound represented by general formula (IIB) or a salt thereof, to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;
其中：in:
RN为卤素；优选地，RN为Cl；R N is halogen; preferably, R N is Cl;
Z、Rx、Rw、R1、R2、R3、R4、R5c、Ra、Rb、G0、G1、G2、G3和n如通式(II)中所定义。Z, Rx , Rw , R1 , R2 , R3, R4, R5c , Ra , Rb , G0 , G1 , G2 , G3 and n are as in the general formula (II) definition.
方案四Option 4
本公开通式(III)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
The preparation method of the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof of the present disclosure includes the following steps:
通式(IIIA)所示的化合物或其盐与通式(IIB)所示的化合物或其盐发生磺酰化反应，得到通式(III)所示的化合物或其可药用的盐；The compound represented by the general formula (IIIA) or a salt thereof undergoes a sulfonylation reaction with the compound represented by the general formula (IIB) or a salt thereof, to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
其中：in:
RN为卤素；优选地，RN为Cl；R N is halogen; preferably, R N is Cl;
Z、Rx、Rw、R1、R5c、G1、G3和n如通式(III)中所定义。Z, Rx , Rw , R1 , R5c , G1 , G3 and n are as defined in general formula (III).
上述合成方案中，提供酸性条件的试剂包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、盐酸的1,4-二氧六环溶液、三氟乙酸、甲酸、乙酸、盐酸、浓硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸、Me3SiCl和TMSOTf及其混合物，优选为三氟乙酸。In the above synthesis scheme, reagents that provide acidic conditions include but are not limited to hydrogen chloride, hydrogen chloride solution in 1,4-dioxane, hydrochloric acid solution in 1,4-dioxane, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, Concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzenesulfonic acid, Me 3 SiCl and TMSOTf and mixtures thereof, preferably trifluoroacetic acid.
上述步骤的反应优选在溶剂中进行，所用的溶剂包括但不限于：吡啶、乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。The reaction of the above steps is preferably carried out in a solvent. The solvents used include but are not limited to: pyridine, glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, Ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromo Ethane and its mixtures.
具体实施方式Detailed ways
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.
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核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR is measured using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M. The measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). , the internal standard is tetramethylsilane (TMS).
MS的测定用Agilent 1200/1290DAD-6110/6120Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)。waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)。THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。MS was measured using Agilent 1200/1290DAD-6110/6120Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS). waters ACQuity UPLC-QD/SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector). THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive).
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC1200VWD和Waters HPLC e2695-2489高效液相色谱仪。High performance liquid chromatography (HPLC) analysis used Agilent HPLC 1200DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489 high performance liquid chromatography.
手性HPLC分析测定使用Agilent 1260DAD高效液相色谱仪。Chiral HPLC analysis was performed using Agilent 1260DAD high performance liquid chromatography.
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。High-performance liquid phase preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
手性制备使用Shimadzu LC-20AP制备型色谱仪。Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
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。Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm~0.2mm. The specifications used for thin layer chromatography separation and purification products are 0.4mm. ~0.5mm.
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200~300 mesh silica gel as the carrier.
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。The average kinase inhibition rate and IC 50 value were measured using NovoStar microplate reader (BMG Company, Germany).
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 synthesized by 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。There are no special instructions in the examples, and 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 1L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume 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 hydrogenator and Clear Blue QL-500 hydrogen generator or HC2-SS hydrogenator.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
微波反应使用CEM Discover-S 908860型微波反应器。The microwave reaction uses CEM Discover-S 908860 microwave reactor.
实施例中无特殊说明，溶液是指水溶液。There is no special explanation in the examples, and 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℃。There are no special instructions 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，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：正己烷/乙酸乙酯体系，B：二氯甲烷/甲醇体系，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 reaction progress in the embodiment is monitored by thin layer chromatography (TLC). The developing agent used in the reaction, the column chromatography eluent system and the thin layer chromatography developing agent system used to purify the compound include: A: n-hexane/ethyl acetate system, B: methylene chloride/methanol system, the volume ratio of the solvent varies according to the polarity of the compound For adjustment, you can also add a small amount of alkaline or acidic reagents such as triethylamine and acetic acid for adjustment.
实施例1Example 1
3-甲氧基-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺1
3-Methoxy-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 1
第一步first step
5-(氯磺酰基)-2-碘苯甲酸1b5-(chlorosulfonyl)-2-iodobenzoic acid 1b
将氯磺酸(23.50g，201.70mmol，阿达玛斯)滴加至2-碘苯甲酸1a(5g，20.10mmol，韶远)中，反应液升温至120℃搅拌反应1小时。反应冷却至室温，随后滴加至碎冰中淬灭，用二氯甲烷(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，即得粗品标题化合物1b(5.20g，产率：74.6％)，产物不经纯化，直接用于下一步反应。Chlorosulfonic acid (23.50g, 201.70mmol, Adamas) was added dropwise to 2-iodobenzoic acid 1a (5g, 20.10mmol, Shaoyuan), and the reaction solution was heated to 120°C and stirred for 1 hour. The reaction was cooled to room temperature, then added dropwise to crushed ice to quench, extracted with dichloromethane (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain the crude product The title compound 1b (5.20 g, yield: 74.6%) was used directly in the next reaction without purification.
第二步Step 2
2-碘-5-(N-(4-甲氧基苄基)-N-甲基氨磺酰基)苯甲酸1c2-Iodo-5-(N-(4-methoxybenzyl)-N-methylsulfamoyl)benzoic acid 1c
将化合物1b(5.20g，15mmol)溶解于50mL二氯甲烷，溶液冷却至0℃，随后依次加入三乙胺(6.10g，60.30mmol，国药)与N-甲基-4-甲氧基苄胺(3.40g，22.50mmol，阿达玛斯)，反应于室温搅拌1小时。加入50mL饱和氯化铵溶液淬灭，分液，水相用二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，即得粗品标题化合物1c(9g，产率：130.2％)，产物不经纯化，直接用于下一步反应。Compound 1b (5.20g, 15mmol) was dissolved in 50mL dichloromethane, the solution was cooled to 0°C, and then triethylamine (6.10g, 60.30mmol, Sinopharm) and N-methyl-4-methoxybenzylamine were added in sequence (3.40g, 22.50mmol, Adamas) and the reaction was stirred at room temperature for 1 hour. Add 50 mL saturated ammonium chloride solution to quench, separate the layers, extract the aqueous phase with dichloromethane (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title compound 1c ( 9g, yield: 130.2%), the product was directly used in the next step of reaction without purification.
MS m/z(ESI)：460.1[M-1]。MS m/z(ESI): 460.1[M-1].
第三步third step
4-碘-N-(4-甲氧基苄基)-N-甲基-3-(2-(4-(三氟甲基)苯基)肼-1-羰基)苯磺酰胺1d4-iodo-N-(4-methoxybenzyl)-N-methyl-3-(2-(4-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)benzenesulfonamide 1d
将化合物1c(2g，4.30mmol)、4-(三氟甲基)苯肼(840mg，4.80mmol，阿达玛斯)与吡啶(1.10g，13.90mmol，国药)溶解于45mL二氯甲烷中，反应液冷却至0℃， 缓慢滴加三氯氧磷(665mg，4.30mmol，阿达玛斯)，0℃搅拌反应30分钟。加入50mL饱和碳酸氢钠溶液淬灭反应，分液，水相用二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物1d(960mg，产率：35.7％)。Compound 1c (2g, 4.30mmol), 4-(trifluoromethyl)phenylhydrazine (840mg, 4.80mmol, Adamas) and pyridine (1.10g, 13.90mmol, Sinopharm) were dissolved in 45mL dichloromethane and reacted The liquid is cooled to 0℃, Phosphorus oxychloride (665 mg, 4.30 mmol, Adamas) was slowly added dropwise, and the reaction was stirred at 0°C for 30 minutes. Add 50 mL of saturated sodium bicarbonate solution to quench the reaction, separate the layers, extract the aqueous phase with dichloromethane (50 mL Purification with eluent system A gave the target compound 1d (960 mg, yield: 35.7%).
MS m/z(ESI)：618.0[M-1]。MS m/z(ESI): 618.0[M-1].
第四步the fourth step
3-羟基-N-(4-甲氧基苄基)-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺1e3-Hydroxy-N-(4-methoxybenzyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 1e
在氮气氛围下，将化合物1d(200mg，0.32mmol)、碘化亚铜(7mg，0.04mmol，Alfa)、L-脯氨酸(8mg，0.07mmol，阿达玛斯)与碳酸钾(90mg，0.65mmol，国药)溶于2mL二甲亚砜中，室温搅拌1小时。加入30mL二氯甲烷溶解，有机相经水(30mL×2)洗涤、饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，即得粗品标题化合物1e(147mg，产率：93.7％)，产物不经纯化，直接用于下一步反应。Under a nitrogen atmosphere, compound 1d (200 mg, 0.32 mmol), copper iodide (7 mg, 0.04 mmol, Alfa), L-proline (8 mg, 0.07 mmol, Adamas) and potassium carbonate (90 mg, 0.65 mmol, Sinopharm) was dissolved in 2 mL of dimethyl sulfoxide and stirred at room temperature for 1 hour. Add 30 mL of methylene chloride to dissolve, wash the organic phase with water (30 mL × 2), wash with saturated sodium chloride solution (30 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title compound 1e ( 147mg, yield: 93.7%), the product was directly used in the next reaction without purification.
MS m/z(ESI)：492.1[M+1]。MS m/z(ESI): 492.1[M+1].
第五步the fifth step
3-甲氧基-N-(4-甲氧基苄基)-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺1f3-Methoxy-N-(4-methoxybenzyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 1f
将化合物1e(147mg，0.3mmol)溶解于5mL丙酮中，依次加入碳酸铯(100mg，0.31mmol，阿达玛斯)与碘甲烷(35mg，0.25mmol，阿达玛斯)，60℃加热搅拌30分钟。冷却至室温，反应液过滤，滤液减压浓缩，即得粗品标题化合物1f(150mg，产率：98.6％)，产物不经纯化，直接用于下一步反应。Compound 1e (147 mg, 0.3 mmol) was dissolved in 5 mL acetone, cesium carbonate (100 mg, 0.31 mmol, Adamas) and methyl iodide (35 mg, 0.25 mmol, Adamas) were added successively, and the mixture was heated and stirred at 60°C for 30 minutes. Cool to room temperature, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain the crude title compound 1f (150 mg, yield: 98.6%). The product is directly used in the next reaction without purification.
MS m/z(ESI)：506.1[M+1]。MS m/z(ESI): 506.1[M+1].
第六步Step 6
3-甲氧基-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺13-Methoxy-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 1
将化合物1f(150mg，0.29mmol)溶解于5mL二氯甲烷中，加入0.5mL三氟乙酸，反应于室温下搅拌12小时。反应液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系B纯化，得到目标化合物1(100mg，产率：87.4％)。Compound 1f (150 mg, 0.29 mmol) was dissolved in 5 mL of methylene chloride, 0.5 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain target compound 1 (100 mg, yield: 87.4%).
MS m/z(ESI)：386.2[M+1]。MS m/z(ESI): 386.2[M+1].
1H NMR(500MHz,CDCl3):δ8.36(s,1H),7.94-7.92(d,1H),7.86-7.79(m,5H),4.22(s,3H),2.72-2.71(d,3H)。 1 H NMR (500MHz, CDCl 3 ): δ8.36(s,1H),7.94-7.92(d,1H),7.86-7.79(m,5H),4.22(s,3H),2.72-2.71(d, 3H).
实施例2Example 2
3-异丙氧基-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺2
3-Isopropoxy-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 2
第一步first step
5-溴-3-异丙氧基-1H-吲唑2b5-bromo-3-isopropoxy-1H-indazole 2b
将5-溴-1H-吲唑-3-醇2a(200mg，0.94mmol，阿达玛斯)溶于甲苯(10mL)中，加入异丙醇(85mg，1.38mmol，韶远)、(三苯基膦)乙腈(566mg，1.89mmol，韶远)中，反应液升温至100℃搅拌反应12小时。反应冷却至室温，随后滴加至碎冰中淬灭，用二氯甲烷(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物2b(95mg，产率：39.7％)。Dissolve 5-bromo-1H-indazol-3-ol 2a (200 mg, 0.94 mmol, Adamas) in toluene (10 mL), add isopropyl alcohol (85 mg, 1.38 mmol, Shaoyuan), (triphenyl Phosphine) acetonitrile (566 mg, 1.89 mmol, Shaoyuan), the reaction solution was heated to 100°C and stirred for 12 hours. The reaction was cooled to room temperature, then added dropwise to crushed ice to quench, extracted with dichloromethane (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, the filtrate was concentrated under reduced pressure, and the residue was Silica gel column chromatography was used for purification with eluent system A to obtain target compound 2b (95 mg, yield: 39.7%).
MS m/z(ESI)：256.0[M+1]。MS m/z(ESI): 256.0[M+1].
第二步Step 2
5-溴-3-异丙氧基-1-(4-(三氟甲基)苯基)-1H-吲唑2c5-Bromo-3-isopropoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazole 2c
在氧气氛围下，将化合物2b(95mg，0.37mmol)、4-(三氟甲基)苯硼酸(212mg，1.11mmol)、醋酸铜(102mg，0.56mmol)、联吡啶(88mg，0.56mmol)与碳酸钠(119mg，1.11mmol，国药)溶于1,2-二氯乙烷(10mL)中，反应60℃搅拌12小时。冷却至室温，加入30mL二氯甲烷进行溶解，有机相经水(20mL×2)洗涤、饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物2c(30mg，产率：20.2％)。Under an oxygen atmosphere, compound 2b (95 mg, 0.37 mmol), 4-(trifluoromethyl)phenylboronic acid (212 mg, 1.11 mmol), copper acetate (102 mg, 0.56 mmol), bipyridine (88 mg, 0.56 mmol) and Sodium carbonate (119 mg, 1.11 mmol, Sinopharm) was dissolved in 1,2-dichloroethane (10 mL), and the reaction was stirred at 60°C for 12 hours. Cool to room temperature, add 30 mL of methylene chloride to dissolve, wash the organic phase with water (20 mL × 2), wash with saturated sodium chloride solution (20 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purification using silica gel column chromatography with eluent system A gave the target compound 2c (30 mg, yield: 20.2%).
MS m/z(ESI)：401.0[M+1]。 MS m/z(ESI): 401.0[M+1].
第三步third step
3-异丙氧基-5-((4-甲氧基苄基)硫基)-1-(4-(三氟甲基)苯基)-1H-吲唑2d3-Isopropoxy-5-((4-methoxybenzyl)thio)-1-(4-(trifluoromethyl)phenyl)-1H-indazole 2d
将化合物2c(30mg，0.08mmol)、(4-甲氧基苯基)甲硫醇(18mg，0.12mmol，国药)、三(二亚苄基丙酮)二钯(7mg，0.01mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(9mg，0.02mmol)、二异丙基乙基胺(30mg，0.23mmol)，溶解于二氧六环(5mL)中，氮气氛下，加热至120℃，搅拌反应5小时。冷却至室温，反应液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物2d(30mg，产率：84.5％)。Compound 2c (30 mg, 0.08 mmol), (4-methoxyphenyl) methyl mercaptan (18 mg, 0.12 mmol, Sinopharm), tris(dibenzylideneacetone) dipalladium (7 mg, 0.01 mmol), 4, 5-bisdiphenylphosphine-9,9-dimethylxanthene (9mg, 0.02mmol), diisopropylethylamine (30mg, 0.23mmol), dissolved in dioxane (5mL), Under nitrogen atmosphere, heat to 120°C and stir for 5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain target compound 2d (30 mg, yield: 84.5%).
MS m/z(ESI)：473.3[M+1]。MS m/z(ESI): 473.3[M+1].
第四步the fourth step
3-异丙氧基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰氯2e3-Isopropoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonyl chloride 2e
将化合物2d(40mg，0.09mmol)溶于8mL冰乙酸和水的混合溶液中(V/V＝3:1)，0℃加入N-氯代丁二酰亚胺(68mg，0.51mmol)，升至室温，搅拌4小时。加入30mL二氯甲烷进行溶解，有机相经水(20mL×2)洗涤、饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，即得粗品标题化合物2e(35mg，产率：98.7％)，产物不经纯化，直接用于下一步反应。Compound 2d (40 mg, 0.09 mmol) was dissolved in 8 mL of a mixed solution of glacial acetic acid and water (V/V = 3:1), and N-chlorosuccinimide (68 mg, 0.51 mmol) was added at 0°C. to room temperature and stir for 4 hours. Add 30 mL of dichloromethane for dissolution. The organic phase was washed with water (20 mL × 2) and saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2e. (35 mg, yield: 98.7%), the product was directly used in the next step of reaction without purification.
第五步the fifth step
3-异丙氧基-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺23-Isopropoxy-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 2
将化合物2e(35mg，0.08mmol)溶解于二氯甲烷(5mL)中，加入甲胺乙醇溶液(48mg，0.52mmol，在乙醇中含量为30-35％)，室温搅拌30分钟。滤液浓缩，残余物用硅胶柱色谱以洗脱剂体系B纯化，得到目标化合物2(10mg，产率：28.9％)。Compound 2e (35 mg, 0.08 mmol) was dissolved in dichloromethane (5 mL), methylamine ethanol solution (48 mg, 0.52 mmol, content in ethanol was 30-35%) was added, and the mixture was stirred at room temperature for 30 minutes. The filtrate was concentrated, and the residue was purified by silica gel column chromatography using eluent system B to obtain target compound 2 (10 mg, yield: 28.9%).
MS m/z(ESI)：414.3[M+1]。MS m/z(ESI): 414.3[M+1].
1H NMR(500MHz,CDCl3)：δ8.37(s,1H),7.92-7.90(d,1H),7.85-7.83(d,1H),7.81-7.78(m,4H),5.29-5.26(m,1H),2.72-2.71(d,3H),1.54-1.53(m,6H)。 1 H NMR (500MHz, CDCl3): δ8.37(s,1H),7.92-7.90(d,1H),7.85-7.83(d,1H),7.81-7.78(m,4H),5.29-5.26(m ,1H),2.72-2.71(d,3H),1.54-1.53(m,6H).
实施例3Example 3
3-甲氧基-N-甲基-1-(4-(三氟甲基)苄基)-1H-吲唑-5-磺酰胺3

3-Methoxy-N-methyl-1-(4-(trifluoromethyl)benzyl)-1H-indazole-5-sulfonamide 3

第一步first step
5-溴-1-(4-(三氟甲基)苄基)-1H-吲唑-3-醇3a5-Bromo-1-(4-(trifluoromethyl)benzyl)-1H-indazole-3-ol 3a
将化合物2a(500mg，2.29mmol)溶于水(10mL)中，加入氢氧化钠(105mg，2.58mmol，韶远)，40℃搅拌10分钟，加1-(氯甲基)-4-(三氟甲基)苯(460mg，2.41mmol，韶远)，反应液升温至70℃搅拌反应12小时。冷却至室温，反应液过滤，滤液减压浓缩，即得粗品标题化合物3a(720mg，产率：82.7％)，产物不经纯化，直接用于下一步反应。Dissolve compound 2a (500 mg, 2.29 mmol) in water (10 mL), add sodium hydroxide (105 mg, 2.58 mmol, Shaoyuan), stir at 40°C for 10 minutes, add 1-(chloromethyl)-4-(tris Fluoromethyl)benzene (460 mg, 2.41 mmol, Shaoyuan), the reaction solution was heated to 70°C and stirred for 12 hours. Cool to room temperature, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain the crude title compound 3a (720 mg, yield: 82.7%). The product is directly used in the next reaction without purification.
MS m/z(ESI)：372.9[M+1]。MS m/z(ESI): 372.9[M+1].
第二步Step 2
5-溴-3-甲氧基-1-(4-(三氟甲基)苄基)-1H吲唑3b5-Bromo-3-methoxy-1-(4-(trifluoromethyl)benzyl)-1H indazole 3b
将化合物3a(200mg，0.54mmol)溶于丙酮(10mL)中，加碘甲烷(114mg，0.80mmol)、碳酸铯(176mg，0.54mmol)，60℃搅拌30分钟。冷却至室温，加入30mL二氯甲烷进行溶解，有机相经水(20mL×2)洗涤、饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物3b(134mg，产率：64.6％)。Compound 3a (200 mg, 0.54 mmol) was dissolved in acetone (10 mL), methyl iodide (114 mg, 0.80 mmol) and cesium carbonate (176 mg, 0.54 mmol) were added, and the mixture was stirred at 60°C for 30 minutes. Cool to room temperature, add 30 mL of methylene chloride to dissolve, wash the organic phase with water (20 mL × 2), wash with saturated sodium chloride solution (20 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purification using silica gel column chromatography with eluent system A gave target compound 3b (134 mg, yield: 64.6%).
MS m/z(ESI)：387.0[M+1]。MS m/z(ESI): 387.0[M+1].
第三步third step
3-甲氧基-5-((4-甲氧基苄基)硫基)-1-(4-(三氟甲基)苄基)-1H-吲唑3c3-Methoxy-5-((4-methoxybenzyl)thio)-1-(4-(trifluoromethyl)benzyl)-1H-indazole 3c
将化合物3b(134mg，0.35mmol)、(4-甲氧基苯基)甲硫醇(81mg，0.53mmol，国药)、三(二亚苄基丙酮)二钯(32mg，0.035mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(41mg，0.071mmol)、二异丙基乙基胺(135mg，1.1mmol)溶解于二氧六环(5mL)中，氮气氛下，加热至120℃，搅拌反应5小时。冷却至室温，反应液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物3c(150mg，产率：94.1％)。Compound 3b (134 mg, 0.35 mmol), (4-methoxyphenyl) methyl mercaptan (81 mg, 0.53 mmol, Sinopharm), tris(dibenzylideneacetone) dipalladium (32 mg, 0.035 mmol), 4, 5-bisdiphenylphosphine-9,9-dimethylxanthene (41mg, 0.071mmol) and diisopropylethylamine (135mg, 1.1mmol) were dissolved in dioxane (5mL), nitrogen Under the atmosphere, heat to 120°C and stir for 5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain target compound 3c (150 mg, yield: 94.1%).
MS m/z(ESI)：459.4[M+1]。MS m/z(ESI): 459.4[M+1].
第四步the fourth step
3-甲氧基-1-(4-(三氟甲基)苄基)-1H-吲唑-5-磺酰氯3d3-Methoxy-1-(4-(trifluoromethyl)benzyl)-1H-indazole-5-sulfonyl chloride 3d
将化合物3c(80mg，0.17mmol)溶于8mL冰乙酸和水的混合溶液中 (V/V＝3:1)，0℃加N-氯代丁二酰亚胺(140mg，0.98mmol)，反应于室温搅拌4小时。加入30mL二氯甲烷进行溶解，有机相经水(20mL×2)洗涤、饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，即得粗品标题化合物3d(70mg，产率：99.1％)，产物不经纯化，直接用于下一步反应。Compound 3c (80 mg, 0.17 mmol) was dissolved in a mixed solution of 8 mL glacial acetic acid and water. (V/V=3:1), add N-chlorosuccinimide (140 mg, 0.98 mmol) at 0°C, and stir the reaction at room temperature for 4 hours. Add 30 mL of methylene chloride for dissolution. The organic phase was washed with water (20 mL × 2) and saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 3d. (70 mg, yield: 99.1%), the product was directly used in the next reaction without purification.
MS m/z(ESI)：405.1[M+1]。MS m/z(ESI): 405.1[M+1].
第五步the fifth step
3-甲氧基-N-甲基-1-(4-(三氟甲基)苄基)-1H-吲唑-5-磺酰胺33-Methoxy-N-methyl-1-(4-(trifluoromethyl)benzyl)-1H-indazole-5-sulfonamide 3
将化合物3d(70mg，0.17mmol)溶解于二氯甲烷(5mL)中，加入甲胺乙醇溶液(162mg，1.67mmol，在乙醇中含量为30-35％)，室温搅拌30分钟。滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系B纯化，得到目标化合物3(20mg，产率：29.0％)。Compound 3d (70 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), methylamine ethanol solution (162 mg, 1.67 mmol, content in ethanol was 30-35%) was added, and the mixture was stirred at room temperature for 30 minutes. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain target compound 3 (20 mg, yield: 29.0%).
MS m/z(ESI)：400.3[M+1]。MS m/z(ESI): 400.3[M+1].
1H NMR(500MHz,CDCl3)：δ8.30(s,1H),7.81-7.78(m,1H),7.60-7.59(m,2H),7.32-7.26(m,3H),5.49(s,2H),4.13(s,3H),2.68-2.67(d,3H)。 1 H NMR (500MHz, CDCl 3 ): δ8.30(s,1H),7.81-7.78(m,1H),7.60-7.59(m,2H),7.32-7.26(m,3H),5.49(s, 2H),4.13(s,3H),2.68-2.67(d,3H).
实施例4Example 4
3-甲氧基-N,N-二甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺4
3-Methoxy-N,N-dimethyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 4
第一步first step
2-碘-5-(N-甲基氨磺酰基)苯甲酸4a2-iodo-5-(N-methylsulfamoyl)benzoic acid 4a
将化合物1b(2.8g，8.1mmol)溶解于30mL二氯甲烷，溶液冷却至0℃，随后依次加入三乙胺(4.1g，40.5mmol，国药)与甲胺盐酸盐(820mg，12.1mmol，国药)，升至室温，反应于室温搅拌1小时。加入50mL饱和氯化铵溶液淬灭，分液，水相用二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压 浓缩，即得粗品标题化合物4a(980mg，产率：35.5％)，产物不经纯化，直接用于下一步反应。Compound 1b (2.8g, 8.1mmol) was dissolved in 30mL dichloromethane, the solution was cooled to 0°C, and then triethylamine (4.1g, 40.5mmol, Sinopharm) and methylamine hydrochloride (820mg, 12.1mmol, were added successively, Sinopharm), raised to room temperature, and the reaction was stirred at room temperature for 1 hour. Add 50 mL saturated ammonium chloride solution to quench, separate the layers, extract the aqueous phase with dichloromethane (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and decompress the filtrate. After concentration, the crude title compound 4a (980 mg, yield: 35.5%) was obtained. The product was directly used in the next reaction without purification.
MS m/z(ESI)：340.1[M-1]。MS m/z(ESI): 340.1[M-1].
第二步Step 2
4-碘-N-甲基-3-(2-(4-(三氟甲基)苯基)肼-1-羰基)苯磺酰胺4b4-iodo-N-methyl-3-(2-(4-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)benzenesulfonamide 4b
将化合物4a(200mg，0.59mmol)、4-(三氟甲基)苯肼(115mg，0.65mmol)与吡啶(140mg，1.77mmol，国药)溶解于4mL二氯甲烷中，冷却至0℃，缓慢滴加三氯氧磷(90mg，0.59mmol)，0℃搅拌反应30分钟。加入10mL饱和碳酸氢钠溶液淬灭反应，分液，水相用二氯甲烷萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物4b(230mg，产率：78.6％)。Compound 4a (200 mg, 0.59 mmol), 4-(trifluoromethyl)phenylhydrazine (115 mg, 0.65 mmol) and pyridine (140 mg, 1.77 mmol, Sinopharm) were dissolved in 4 mL of methylene chloride, cooled to 0°C, and slowly Phosphorus oxychloride (90 mg, 0.59 mmol) was added dropwise, and the reaction was stirred at 0°C for 30 minutes. Add 10 mL saturated sodium bicarbonate solution to quench the reaction, separate the layers, extract the aqueous phase with dichloromethane (20 mL Purification with eluent system A gave target compound 4b (230 mg, yield: 78.6%).
MS m/z(ESI)：498.0[M-1]。MS m/z(ESI): 498.0[M-1].
第三步third step
3-羟基-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺4c3-Hydroxy-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 4c
在氮气氛围下，将化合物4b(230mg，0.46mmol)、碘化亚铜(9mg，0.05mmol，Alfa)、L-脯氨酸(11mg，0.09mmol)与碳酸钾(130mg，0.94mmol，国药)溶于3mL二甲亚砜中，反应于室温搅拌1小时。加入30mL二氯甲烷溶解，有机相经水(30mL×2)洗涤、饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，即得粗品标题化合物4c(185mg，产率：108.0％)，产物不经纯化，直接用于下一步反应。Under a nitrogen atmosphere, compound 4b (230 mg, 0.46 mmol), copper iodide (9 mg, 0.05 mmol, Alfa), L-proline (11 mg, 0.09 mmol) and potassium carbonate (130 mg, 0.94 mmol, Sinopharm) were mixed. Dissolve in 3 mL dimethyl sulfoxide and stir the reaction at room temperature for 1 hour. Add 30 mL of methylene chloride to dissolve, wash the organic phase with water (30 mL × 2) and saturated sodium chloride solution (30 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title compound 4c ( 185 mg, yield: 108.0%), the product was directly used in the next reaction without purification.
MS m/z(ESI)：370.1[M-1]。MS m/z(ESI): 370.1[M-1].
第四步the fourth step
3-甲氧基-N,N-二甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺43-Methoxy-N,N-dimethyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 4
将化合物4c(185mg，0.49mmol)溶解于5mL丙酮中，依次加入碳酸铯(325mg，1.0mmol)与碘甲烷(142mg，1.0mmol)，反应于60℃加热搅拌30分钟。冷却至室温，反应液过滤，滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系B纯化，得到目标化合物4(25mg，产率：12.5％)。Compound 4c (185 mg, 0.49 mmol) was dissolved in 5 mL of acetone, cesium carbonate (325 mg, 1.0 mmol) and methyl iodide (142 mg, 1.0 mmol) were added in sequence, and the reaction was heated and stirred at 60°C for 30 minutes. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain target compound 4 (25 mg, yield: 12.5%).
MS m/z(ESI)：400.3[M+1]。MS m/z(ESI): 400.3[M+1].
1H NMR(500MHz,CDCl3)：δ8.27(s,1H),7.87-7.80(m,6H),4.23(s,3H),2.77(s,6H)。 1 H NMR (500MHz, CDCl 3 ): δ 8.27 (s, 1H), 7.87-7.80 (m, 6H), 4.23 (s, 3H), 2.77 (s, 6H).
实施例5Example 5
1-苄基-3-甲氧基-N-甲基-1H-吲唑-5-磺酰胺5
1-Benzyl-3-methoxy-N-methyl-1H-indazole-5-sulfonamide 5
第一步first step
1-苄基-5-溴-1H-吲唑-3-醇5a1-Benzyl-5-bromo-1H-indazol-3-ol 5a
将化合物2a(500mg，2.31mmol)溶于水(10mL)中，加入氢氧化钠(105mg，2.59mmol，韶远)，40℃搅拌10分钟，加苄氯(298mg，2.39mmol，韶远)，反应液升温至70℃搅拌反应12小时。冷却至室温，过滤，滤液减压浓缩，即得粗品标题化合物5a(600mg，产率：84.3％)，产物不经纯化，直接用于下一步反应。Dissolve compound 2a (500 mg, 2.31 mmol) in water (10 mL), add sodium hydroxide (105 mg, 2.59 mmol, Shaoyuan), stir at 40°C for 10 minutes, add benzyl chloride (298 mg, 2.39 mmol, Shaoyuan), The reaction solution was heated to 70°C and stirred for 12 hours. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure to obtain crude title compound 5a (600 mg, yield: 84.3%). The product is directly used in the next reaction without purification.
MS m/z(ESI)：305.1[M+1]。MS m/z(ESI): 305.1[M+1].
第二步Step 2
1-苄基-5-溴-3-甲氧基-1H-吲唑5b1-benzyl-5-bromo-3-methoxy-1H-indazole 5b
将化合物5a(200mg，0.66mmol)溶于丙酮(10mL)中，加碘甲烷(131mg，0.92mmol)、碳酸铯(215mg，0.66mmol)，反应60℃搅拌30分钟。冷却至室温，加入30mL二氯甲烷进行溶解，有机相经水(20mL×2)洗涤、饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物5b(105mg，产率：50.2％)。Compound 5a (200 mg, 0.66 mmol) was dissolved in acetone (10 mL), methyl iodide (131 mg, 0.92 mmol) and cesium carbonate (215 mg, 0.66 mmol) were added, and the reaction was stirred at 60°C for 30 minutes. Cool to room temperature, add 30 mL of methylene chloride to dissolve, wash the organic phase with water (20 mL × 2), wash with saturated sodium chloride solution (20 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purification using silica gel column chromatography with eluent system A gave target compound 5b (105 mg, yield: 50.2%).
MS m/z(ESI)：319.1[M+1]。MS m/z(ESI): 319.1[M+1].
第三步third step
1-苄基-3-甲氧基-5-((4-甲氧基苄基)硫代)-1H-吲唑5c1-benzyl-3-methoxy-5-((4-methoxybenzyl)thio)-1H-indazole 5c
将化合物5b(105mg，0.33mmol)、(4-甲氧基苯基)甲硫醇(77mg，0.50mmol，国药)、三(二亚苄基丙酮)二钯(31mg，0.034mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(39mg，0.067mmol)、二异丙基乙基胺(129mg，1.0mmol)溶解于二氧六环(5mL)中，氮气氛下，加热至120℃，搅拌反应5小时。反应液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物5c(125mg，产率：96.7％)。Compound 5b (105 mg, 0.33 mmol), (4-methoxyphenyl) methyl mercaptan (77 mg, 0.50 mmol, Sinopharm), tris(dibenzylideneacetone) dipalladium (31 mg, 0.034 mmol), 4, 5-Bisdiphenylphosphine-9,9-dimethylxanthene (39mg, 0.067mmol) and diisopropylethylamine (129mg, 1.0mmol) were dissolved in dioxane (5mL), nitrogen Under the atmosphere, heat to 120°C and stir for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain target compound 5c (125 mg, yield: 96.7%).
MS m/z(ESI)：391.4[M-1]。 MS m/z(ESI): 391.4[M-1].
第四步the fourth step
1-苄基-3-甲氧基-1H-吲唑-5-磺酰氯5d1-Benzyl-3-methoxy-1H-indazole-5-sulfonyl chloride 5d
将化合物5c(50mg，0.13mmol)溶于8mL冰乙酸和水的混合溶液中(V/V＝3:1)，0℃加N-氯代丁二酰亚胺(102mg，0.76mmol)，反应于室温搅拌4小时。加入30mL二氯甲烷进行溶解，有机相经水(20mL×2)洗涤、饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，即得粗品标题化合物5d(40mg，产率：92.8％)，产物不经纯化，直接用于下一步反应。Compound 5c (50 mg, 0.13 mmol) was dissolved in 8 mL of a mixed solution of glacial acetic acid and water (V/V = 3:1), and N-chlorosuccinimide (102 mg, 0.76 mmol) was added at 0°C to react. Stir at room temperature for 4 hours. Add 30 mL of methylene chloride for dissolution. The organic phase was washed with water (20 mL × 2) and saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5d. (40 mg, yield: 92.8%), the product was directly used in the next reaction without purification.
第五步the fifth step
1-苄基-3-甲氧基-N-甲基-1H-吲唑-5-磺酰胺51-Benzyl-3-methoxy-N-methyl-1H-indazole-5-sulfonamide 5
将化合物5d(40mg，0.12mmol)溶解于二氯甲烷(5mL)中，加入甲胺乙醇溶液(111mg，1.21mmol，在乙醇中含量为30-35％)，室温搅拌30分钟。滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系B纯化，得到目标化合物5(10mg，产率：25.4％)。Compound 5d (40 mg, 0.12 mmol) was dissolved in dichloromethane (5 mL), methylamine ethanol solution (111 mg, 1.21 mmol, content in ethanol was 30-35%) was added, and the mixture was stirred at room temperature for 30 minutes. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain target compound 5 (10 mg, yield: 25.4%).
MS m/z(ESI)：332.3[M+1]。MS m/z(ESI): 332.3[M+1].
1H NMR(500MHz,CDCl3)：δ8.31(s,1H),7.78-7.76(m,1H),7.30-7.20(m,6H),5.49(s,2H),4.13(s,3H),2.68-2.67(d,3H)。 1 H NMR (500MHz, CDCl 3 ): δ8.31(s,1H),7.78-7.76(m,1H),7.30-7.20(m,6H),5.49(s,2H),4.13(s,3H) ,2.68-2.67(d,3H).
实施例6Example 6
3-异丙基-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺6
3-Isopropyl-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 6
第一步 first step
5-溴-3-异丙基-1-(4-(三氟甲基)苯基)-1H-吲唑6b5-Bromo-3-isopropyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole 6b
在氧气氛围下，将5-溴-3-异丙基-1H-吲唑6a(300mg，1.31mmol，韶远)、4-(三氟甲基)苯硼酸(715mg，3.81mmol)、醋酸铜(342mg，1.9mmol)、联吡啶(294mg，1.88mmol)与碳酸钠(399mg，3.8mmol，国药)溶于1,2-二氯乙烷(10mL)中，反应60℃搅拌12小时。加入30mL二氯甲烷进行溶解，有机相经水(20mL×2)洗涤、饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物6b(361mg，产率：75.1％)。Under an oxygen atmosphere, 5-bromo-3-isopropyl-1H-indazole 6a (300 mg, 1.31 mmol, Shaoyuan), 4-(trifluoromethyl)phenylboronic acid (715 mg, 3.81 mmol), copper acetate (342 mg, 1.9 mmol), bipyridine (294 mg, 1.88 mmol) and sodium carbonate (399 mg, 3.8 mmol, Sinopharm) were dissolved in 1,2-dichloroethane (10 mL), and the reaction was stirred at 60°C for 12 hours. Add 30 mL of dichloromethane for dissolution. The organic phase was washed with water (20 mL × 2) and saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. Purification with eluent system A gave target compound 6b (361 mg, yield: 75.1%).
MS m/z(ESI)：383.1[M+1]。MS m/z(ESI): 383.1[M+1].
第二步Step 2
3-异丙基-5-((4-甲氧基苄基)硫基)-1-(4-(三氟甲基)苯基)-1H-吲唑6c3-Isopropyl-5-((4-methoxybenzyl)thio)-1-(4-(trifluoromethyl)phenyl)-1H-indazole 6c
将化合物6b(361mg，0.94mmol)、(4-甲氧基苯基)甲硫醇(218mg，1.42mmol，国药)、三(二亚苄基丙酮)二钯(87mg，0.095mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(110mg，0.19mmol)、二异丙基乙基胺(366mg，2.79mmol)溶解于二氧六环(10mL)中，氮气氛下，加热至120℃搅拌反应5小时。冷却至室温，反应液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物6c(430mg，产率：99.9％)。Compound 6b (361 mg, 0.94 mmol), (4-methoxyphenyl) methyl mercaptan (218 mg, 1.42 mmol, Sinopharm), tris(dibenzylideneacetone) dipalladium (87 mg, 0.095 mmol), 4, 5-bisdiphenylphosphine-9,9-dimethylxanthene (110mg, 0.19mmol) and diisopropylethylamine (366mg, 2.79mmol) were dissolved in dioxane (10mL), nitrogen Under the atmosphere, heat to 120°C and stir for 5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain target compound 6c (430 mg, yield: 99.9%).
MS m/z(ESI)：457.5[M+1]。MS m/z(ESI): 457.5[M+1].
第三步third step
3-异丙基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰氯6d3-Isopropyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonyl chloride 6d
将化合物6c(100mg，0.22mmol)溶于8mL冰乙酸和水的混合溶液中(V/V＝3:1)，0℃加N-氯代丁二酰亚胺(176mg，1.31mmol)，室温搅拌4小时。加入30mL二氯甲烷进行溶解，有机相经水(20mL×2)洗涤、饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，即得粗品标题化合物6d(80mg，产率：90.1％)，产物不经纯化，直接用于下一步反应。Compound 6c (100 mg, 0.22 mmol) was dissolved in 8 mL of a mixed solution of glacial acetic acid and water (V/V = 3:1), and N-chlorosuccinimide (176 mg, 1.31 mmol) was added at 0°C and kept at room temperature. Stir for 4 hours. Add 30 mL of methylene chloride for dissolution. The organic phase was washed with water (20 mL × 2) and saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 6d. (80 mg, yield: 90.1%), the product was directly used in the next reaction without purification.
MS m/z(ESI)：403.1[M+1]。MS m/z(ESI): 403.1[M+1].
第四步the fourth step
3-异丙基-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺63-Isopropyl-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 6
将化合物6d(80mg，0.20mmol)溶解于二氯甲烷(5mL)中，加入甲胺乙醇溶液(186mg，2.01mmol，在乙醇中含量为30-35％)，室温搅拌30分钟。滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系B纯化，得到目标化合物6(15mg，产率：19.0％)。Compound 6d (80 mg, 0.20 mmol) was dissolved in dichloromethane (5 mL), methylamine ethanol solution (186 mg, 2.01 mmol, content in ethanol was 30-35%) was added, and the mixture was stirred at room temperature for 30 minutes. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain target compound 6 (15 mg, yield: 19.0%).
MS m/z(ESI)：398.4[M+1]。MS m/z(ESI): 398.4[M+1].
1H NMR(500MHz,CDCl3)：δ8.43(s,1H),7.91-7.83(m,6H),3.55-3.52(m,1H),2.73-2.72(d,3H),1.59-1.54(m,6H)。1H NMR (500MHz, CDCl 3 ): δ8.43(s,1H),7.91-7.83(m,6H),3.55-3.52(m,1H),2.73-2.72(d,3H),1.59-1.54(m ,6H).
实施例7 Example 7
N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺7
N-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 7
第一步first step
5-溴-1-(4-(三氟甲基)苯基)-1H-吲唑7b5-Bromo-1-(4-(trifluoromethyl)phenyl)-1H-indazole 7b
将5-溴-2-氟苯甲醛7a(1g，4.88mmol)、4-(三氟甲基)苯肼(867mg，4.88mmol)、碳酸铯(3.2g，9.87mmol)溶于N,N-二甲基甲酰胺(30mL)中，反应120℃搅拌2小时。冷却至室温，加入30mL乙酸乙酯进行溶解，有机相经水(20mL×2)洗涤、饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品目标化合物7b(200mg，产率：11.9％)，产物不经纯化，直接用于下一步反应。Dissolve 5-bromo-2-fluorobenzaldehyde 7a (1g, 4.88mmol), 4-(trifluoromethyl)phenylhydrazine (867mg, 4.88mmol), and cesium carbonate (3.2g, 9.87mmol) in N,N- dimethylformamide (30 mL), and the reaction was stirred at 120°C for 2 hours. Cool to room temperature, add 30 mL of ethyl acetate to dissolve, wash the organic phase with water (20 mL × 2), wash with saturated sodium chloride solution (20 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product The target compound 7b (200 mg, yield: 11.9%) was used directly in the next reaction without purification.
MS m/z(ESI)：343.1[M+1]。MS m/z(ESI): 343.1[M+1].
第二步Step 2
5-((4-甲氧基苄基)硫基)-1-(4-(三氟甲基)苯基)-1H-吲唑7c5-((4-methoxybenzyl)thio)-1-(4-(trifluoromethyl)phenyl)-1H-indazole 7c
将化合物7b(100mg，0.29mmol)、(4-甲氧基苯基)甲硫醇(59mg，0.38mmol，国药)、三(二亚苄基丙酮)二钯(27mg，0.029mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(34mg，0.059mmol)、二异丙基乙基胺(76mg，0.59mmol)溶解于二氧六环(5mL)中，氮气氛下，加热至120℃，搅拌反应5小时。冷却至室温，反应液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物7c(100mg，产率：82.3％)。Compound 7b (100 mg, 0.29 mmol), (4-methoxyphenyl) methyl mercaptan (59 mg, 0.38 mmol, Sinopharm), tris(dibenzylideneacetone) dipalladium (27 mg, 0.029 mmol), 4, 5-Bisdiphenylphosphine-9,9-dimethylxanthene (34mg, 0.059mmol) and diisopropylethylamine (76mg, 0.59mmol) were dissolved in dioxane (5mL), nitrogen Under the atmosphere, heat to 120°C and stir for 5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain target compound 7c (100 mg, yield: 82.3%).
MS m/z(ESI)：415.1[M+1]。MS m/z(ESI): 415.1[M+1].
第三步third step
1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰氯7d1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonyl chloride 7d
将化合物7c(100mg，0.24mmol)溶于8mL冰乙酸和水的混合溶液中 (V/V＝3:1)，0℃加N-氯代丁二酰亚胺(129mg，1.01mmol)，升至室温，反应于室温搅拌4小时。加入30mL二氯甲烷进行溶解，有机相经水(20mL×2)洗涤、饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，即得粗品标题化合物7d(80mg，产率：91.9％)，产物不经纯化，直接用于下一步反应。Compound 7c (100 mg, 0.24 mmol) was dissolved in 8 mL of a mixed solution of glacial acetic acid and water. (V/V=3:1), add N-chlorosuccinimide (129 mg, 1.01 mmol) at 0°C, raise to room temperature, and stir the reaction at room temperature for 4 hours. Add 30 mL of dichloromethane for dissolution. The organic phase was washed with water (20 mL × 2) and saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 7d. (80 mg, yield: 91.9%), the product was directly used in the next reaction without purification.
MS m/z(ESI)：361.1[M+1]。MS m/z(ESI): 361.1[M+1].
第四步the fourth step
N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺7N-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 7
将化合物7d(80mg，0.22mmol)溶解于二氯甲烷(5mL)中，加入甲胺乙醇溶液(207mg，2.22mmol，在乙醇中含量为30-35％)，室温搅拌30分钟。滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系B纯化，得到目标化合物7(25mg，产率：31.7％)。Compound 7d (80 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL), methylamine ethanol solution (207 mg, 2.22 mmol, content in ethanol was 30-35%) was added, and the mixture was stirred at room temperature for 30 minutes. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain target compound 7 (25 mg, yield: 31.7%).
MS m/z(ESI)：356.1[M+1]。MS m/z(ESI): 356.1[M+1].
1H NMR(500MHz,CD3OD)：δ8.53-8.52(d,1H),δ8.46(s,1H),δ8.10-7.94(m,6H),2.57-2.56(d,3H)。 1 H NMR (500MHz, CD 3 OD): δ8.53-8.52(d,1H), δ8.46(s,1H), δ8.10-7.94(m,6H), 2.57-2.56(d,3H) .
实施例8Example 8
3-(二甲氨基)-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺8
3-(Dimethylamino)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 8
第一步first step
3-氰基-4-氟-N-(4-甲氧基苄基)-N-甲基苯磺酰胺8b3-cyano-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide 8b
将3-氰基-4-氟苯磺酰氯8a(1g，4.5mmol，毕得)溶解于15mL二氯甲烷，溶液冷却至0℃，随后依次加入N,N-二异丙基乙胺(1.20g，9.10mmol，阿达玛斯)与N-甲基-4-甲氧基苄胺(690mg，4.50mmol)，反应于室温搅拌1小时。加入50mL 饱和氯化铵溶液淬灭，分液，水相用二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，即得粗品标题化合物8b(1.20g，产率：78.9％)，产物不经纯化，直接用于下一步反应。Dissolve 3-cyano-4-fluorobenzenesulfonyl chloride 8a (1g, 4.5mmol, Bid) in 15mL dichloromethane, cool the solution to 0°C, and then add N,N-diisopropylethylamine (1.20 g, 9.10 mmol, Adamas) and N-methyl-4-methoxybenzylamine (690 mg, 4.50 mmol), the reaction was stirred at room temperature for 1 hour. Add 50mL The saturated ammonium chloride solution was quenched and separated. The aqueous phase was extracted with dichloromethane (50mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 8b (1.20g , yield: 78.9%), the product was directly used in the next reaction without purification.
MS m/z(ESI)：333.2[M-1]。MS m/z(ESI): 333.2[M-1].
第二步Step 2
3-氨基-N-(4-甲氧基苄基)-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺8c3-Amino-N-(4-methoxybenzyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 8c
在氮气氛围下，将4-(三氟甲基)苯肼(475mg，2.70mmol)溶于1mL二乙二醇二甲醚中，加入叔丁醇钾(135mg，1.20mmol，韶远)，室温搅拌5分钟后加入化合物8b(300mg，0.90mmol)，封管加热至130℃搅拌反应1小时。冷却至室温，加入50mL二氯甲烷溶解，有机相经水(50mL×2)洗涤、饱和氯化钠溶液(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到目标化合物8c(214mg，产率：48.2％)。Under a nitrogen atmosphere, dissolve 4-(trifluoromethyl)phenylhydrazine (475 mg, 2.70 mmol) in 1 mL of diethylene glycol dimethyl ether, add potassium tert-butoxide (135 mg, 1.20 mmol, Shaoyuan), and mix at room temperature. After stirring for 5 minutes, compound 8b (300 mg, 0.90 mmol) was added, the tube was sealed and heated to 130°C, and the reaction was stirred for 1 hour. Cool to room temperature, add 50 mL of methylene chloride to dissolve, wash the organic phase with water (50 mL × 2) and saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Silica gel column chromatography was used for purification with eluent system A to obtain target compound 8c (214 mg, yield: 48.2%).
MS m/z(ESI)：491.1[M+1]。MS m/z(ESI): 491.1[M+1].
第三步third step
3-(二甲氨基)-N-(4-甲氧基苄基)-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺8d3-(Dimethylamino)-N-(4-methoxybenzyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 8d
将化合物8c(100mg，0.20mmol)溶于2mL N,N-二甲基甲酰胺中，冷却至0℃，加入氢化钠(7mg，0.18mmol，国药)，搅拌反应10分钟，加入碘甲烷(43mg，0.30mmol)，反应升温至室温，搅拌12小时。加入10mL饱和氯化铵溶液淬灭，分液，水相用二氯甲烷萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，即得粗品标题化合物8d(102mg，产率：98.3％)，产物不经纯化，直接用于下一步反应。Dissolve compound 8c (100 mg, 0.20 mmol) in 2 mL N, N-dimethylformamide, cool to 0°C, add sodium hydride (7 mg, 0.18 mmol, Sinopharm), stir and react for 10 minutes, add methyl iodide (43 mg , 0.30 mmol), the reaction was warmed to room temperature and stirred for 12 hours. Add 10 mL saturated ammonium chloride solution to quench, separate the layers, extract the aqueous phase with dichloromethane (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title compound 8d ( 102 mg, yield: 98.3%), the product was directly used in the next reaction without purification.
MS m/z(ESI)：519.3[M+1]。MS m/z(ESI): 519.3[M+1].
第四步the fourth step
3-(二甲氨基)-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺83-(Dimethylamino)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 8
将化合物8d(102mg，0.2mmol)溶解于5mL二氯甲烷中，加入0.5mL三氟乙酸，反应于室温下搅拌12小时。反应液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系B纯化，得到目标化合物8(5mg，产率：6.4％)。Compound 8d (102 mg, 0.2 mmol) was dissolved in 5 mL of methylene chloride, 0.5 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain target compound 8 (5 mg, yield: 6.4%).
MS m/z(ESI)：399.0[M+1]。MS m/z(ESI): 399.0[M+1].
1H NMR(500MHz,CDCl3)：δ8.48(s,1H),8.01-7.99(d,2H),7.83-7.82(d,2H),7.67-7.65(d,2H),7.58-7.56(d,2H),3.04(m,6H),2.72-2.71(d,3H)。 1 H NMR (500MHz, CDCl 3 ): δ8.48(s,1H),8.01-7.99(d,2H),7.83-7.82(d,2H),7.67-7.65(d,2H),7.58-7.56( d,2H),3.04(m,6H),2.72-2.71(d,3H).
实施例9Example 9
N-甲基-3-(甲氨基)-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺9
N-methyl-3-(methylamino)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 9
第一步first step
3-氨基-N-(4-甲氧基苄基)-N-甲基-1H-吲唑-5-磺酰胺9a3-amino-N-(4-methoxybenzyl)-N-methyl-1H-indazole-5-sulfonamide 9a
将化合物8b(690mg，2.06mmol)溶于10mL乙醇中，加入水合肼(516mg，10.30mmol，国药)，反应加热至100℃搅拌12小时。冷却至室温，反应液减压浓缩，即得粗品标题化合物9a(780mg，产率：109.2％)，产物不经纯化，直接用于下一步反应。Compound 8b (690 mg, 2.06 mmol) was dissolved in 10 mL of ethanol, hydrazine hydrate (516 mg, 10.30 mmol, Sinopharm) was added, and the reaction was heated to 100°C and stirred for 12 hours. Cool to room temperature, and the reaction solution is concentrated under reduced pressure to obtain the crude title compound 9a (780 mg, yield: 109.2%). The product is directly used in the next reaction without purification.
MS m/z(ESI)：347.1[M+1]。MS m/z(ESI): 347.1[M+1].
第二步Step 2
3-氨基-N-(4-甲氧基苄基)-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺8c3-Amino-N-(4-methoxybenzyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 8c
将化合物9a(780mg，2.25mmol)溶于8mL甲醇中，加入醋酸铜(82mg，0.45mmol，国药)与4-(三氟甲基)苯硼酸(470mg，2.48mmol，韶远)，反应于空气氛围下搅拌12小时。反应液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系A纯化，得到标题化合物8c(310mg，产率：28.1％)。Compound 9a (780 mg, 2.25 mmol) was dissolved in 8 mL of methanol, copper acetate (82 mg, 0.45 mmol, Sinopharm) and 4-(trifluoromethyl)phenylboronic acid (470 mg, 2.48 mmol, Shaoyuan) were added, and reacted in air Stir under air for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 8c (310 mg, yield: 28.1%).
MS m/z(ESI)：491.1[M+1]。MS m/z(ESI): 491.1[M+1].
第三步third step
N-(4-甲氧基苄基)-N-甲基-3-(甲氨基)-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺9bN-(4-methoxybenzyl)-N-methyl-3-(methylamino)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 9b
将化合物8c(100mg，0.2mmol)溶于1mL甲醇中，依次加入多聚甲醛(25mg，0.82mmol，国药)与甲醇钠(110mg，2.0mmol，阿达玛斯)，反应加热至70℃搅拌1小时。反应液冷却至室温，加入硼氢化钠(16mg，0.41mmol，国药)，反应加热至70℃搅拌2小时。反应液冷却至室温，加入5mL冰水淬灭，水相用二氯甲烷萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，即得粗品标 题化合物9b(100mg，产率：99.0％)，产物不经纯化，直接用于下一步反应。Compound 8c (100 mg, 0.2 mmol) was dissolved in 1 mL of methanol, paraformaldehyde (25 mg, 0.82 mmol, Sinopharm) and sodium methoxide (110 mg, 2.0 mmol, Adamas) were added in sequence, and the reaction was heated to 70°C and stirred for 1 hour. . The reaction solution was cooled to room temperature, sodium borohydride (16 mg, 0.41 mmol, Sinopharm) was added, and the reaction was heated to 70°C and stirred for 2 hours. The reaction solution was cooled to room temperature, quenched by adding 5 mL of ice water, and the aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude standard product. The title compound 9b (100 mg, yield: 99.0%) was used directly in the next reaction without purification.
MS m/z(ESI)：505.1[M+1]。MS m/z(ESI): 505.1[M+1].
第四步the fourth step
N-甲基-3-(甲氨基)-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺9N-methyl-3-(methylamino)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 9
将化合物9b(100mg，0.2mmol)溶于5mL二氯甲烷中，加入0.5mL三氟乙酸，反应于室温搅拌12小时。反应液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系B纯化，得到目标化合物9(10mg，产率：13.0％)。Compound 9b (100 mg, 0.2 mmol) was dissolved in 5 mL of methylene chloride, 0.5 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain target compound 9 (10 mg, yield: 13.0%).
MS m/z(ESI)：385.1[M+1]。MS m/z(ESI): 385.1[M+1].
1H NMR(500MHz,DMSO-d6)：δ8.45(s,1H),8.05-7.99(m,3H),7.87-7.81(m,3H),7.40(s,1H),7.08(s,1H),2.98-2.96(d,3H),2.42(s,3H)。 1 H NMR (500MHz, DMSO-d6): δ8.45(s,1H),8.05-7.99(m,3H),7.87-7.81(m,3H),7.40(s,1H),7.08(s,1H ),2.98-2.96(d,3H),2.42(s,3H).
实施例10Example 10
3-氨基-N-甲基-1-(4-(三氟甲基)苯基)-1H-吲唑-5-磺酰胺10
3-Amino-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole-5-sulfonamide 10
将化合物8c(100mg，0.2mmol)溶解于5mL二氯甲烷中，加入0.5mL三氟乙酸，反应于室温搅拌12小时。反应液减压浓缩，残余物用硅胶柱色谱以洗脱剂体系B纯化，得到目标化合物10(10mg，产率：13.2％)。Compound 8c (100 mg, 0.2 mmol) was dissolved in 5 mL of methylene chloride, 0.5 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain target compound 10 (10 mg, yield: 13.2%).
MS m/z(ESI)：371.0[M+1]。MS m/z(ESI): 371.0[M+1].
1H NMR(500MHz,DMSO-d6)：δ8.49(s,1H),8.04-8.03(d,1H),7.96-7.95(d,2H),7.87-7.85(d,2H),7.82-7.80(d,1H),7.40(s,1H),6.43(s,2H),2.43(s,3H)。 1 H NMR (500MHz, DMSO-d6): δ8.49(s,1H),8.04-8.03(d,1H),7.96-7.95(d,2H),7.87-7.85(d,2H),7.82-7.80 (d,1H),7.40(s,1H),6.43(s,2H),2.43(s,3H).
实施例11Example 11
3-甲氧基-1-[4-(三氟甲基)苯基]-1H-吲唑-5-磺酰胺11
3-Methoxy-1-[4-(trifluoromethyl)phenyl]-1H-indazole-5-sulfonamide 11
第一步first step
2-碘-N'-[4-(三氟甲基)苯基]苯甲酰肼11c2-iodo-N'-[4-(trifluoromethyl)phenyl]benzoylhydrazide 11c
将2-碘苯甲酸11a(50.0g，201.60mmol，Adamas)溶于二氯甲烷(1000mL)中，加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(84.3g，221.71mmol)，搅拌均匀后加入(4-(三氟甲基)苯基)肼盐酸盐11b(45.0g，211.67mmol，江苏艾康)，水浴冷却，滴加入N,N-二异丙基乙基胺(57.3g，443.35mmol，75.9mL)，内温维持约25℃，反应浑浊液逐渐澄清，约15分钟快加完时突然析出大量固体，内温变化不明显，补加500mL二氯甲烷使搅拌顺畅，室温搅拌反应30分钟，反应液中加入500mL二氯甲烷稀释，再加入1000mL柠檬酸水溶液(10％)搅拌10分钟，过滤收集固体，固体用1200mL乙酸乙酯溶清后分液除水，无水硫酸钠干燥，滤液分液后有机相依次用柠檬酸水溶液(10％)(1×200mL)、碳酸钠水溶液(10％)洗涤(1×500mL)，无水硫酸钠干燥，合并有机相得黄色固体，即为标题化合物11c(120g，产率：146.6％)，产物不经纯化，直接用于下一步反应。 Dissolve 2-iodobenzoic acid 11a (50.0g, 201.60mmol, Adamas) in dichloromethane (1000mL), and add O-(7-azabenzotriazol-1-yl)-N,N,N ',N'-tetramethylurea hexafluorophosphate (HATU) (84.3g, 221.71mmol), stir well and then add (4-(trifluoromethyl)phenyl)hydrazine hydrochloride 11b (45.0g, 211.67 mmol, Jiangsu Aikang), cool in a water bath, add N,N-diisopropylethylamine (57.3g, 443.35mmol, 75.9mL) dropwise, maintain the internal temperature at about 25°C, and the reaction turbid liquid gradually becomes clear, about 15 minutes When the addition is almost complete, a large amount of solid suddenly precipitates, and the internal temperature does not change significantly. Add 500 mL of dichloromethane to make the stirring smooth. Stir and react at room temperature for 30 minutes. Add 500 mL of dichloromethane to the reaction solution to dilute it, and then add 1000 mL of citric acid aqueous solution (10% ) Stir for 10 minutes, collect the solid by filtration, dissolve the solid with 1200 mL of ethyl acetate, separate and remove the water, and dry with anhydrous sodium sulfate. After the filtrate is separated, the organic phase is sequentially treated with citric acid aqueous solution (10%) (1 × 200 mL), Wash with sodium carbonate aqueous solution (10%) (1×500mL), dry over anhydrous sodium sulfate, and combine the organic phases to obtain a yellow solid, which is the title compound 11c (120g, yield: 146.6%). The product is used directly without purification. Next reaction.
MS m/z(ESI)：406.9[M+1]。MS m/z(ESI): 406.9[M+1].
第二步Step 2
1-[4-(三氟甲基)苯基]-1H-吲唑-3-醇11d1-[4-(Trifluoromethyl)phenyl]-1H-indazole-3-ol 11d
化合物11c(81.8g，210.41mmol)、L-脯氨酸(4.67g，40.56mmol)、碘化亚铜(38.4g，201.62mmol)和无水碳酸钾(55.7g，403.02mmol)中加入二甲亚砜(600mL)，氮气置换三次后室温反应1小时，反应液缓慢倒入3000mL冰水混合物中淬灭反应，搅拌10分钟，用乙酸乙酯(3×1000mL)萃取，合并有机相，用氯化钠水溶液(10％)洗涤(1×500mL)，无水硫酸钠干燥，过滤浓缩得23g粗品。水相用浓盐酸调节至pH＝4～5，再次用乙酸乙酯(2×500mL)萃取，有机相用氯化钠水溶液(10％)洗涤(1×300mL)，无水硫酸钠干燥，过滤浓缩并合并23g粗品，用硅胶柱色谱以洗脱剂体系A纯化，得标题产物11d(9.6g，产率：17.1％)。Dimethyl was added to compound 11c (81.8g, 210.41mmol), L-proline (4.67g, 40.56mmol), copper iodide (38.4g, 201.62mmol) and anhydrous potassium carbonate (55.7g, 403.02mmol). Sulfoxide (600 mL), replaced with nitrogen three times and reacted at room temperature for 1 hour. The reaction solution was slowly poured into 3000 mL of ice-water mixture to quench the reaction. Stir for 10 minutes. Extract with ethyl acetate (3×1000 mL). Combine the organic phases and use chlorine. Wash with sodium chloride aqueous solution (10%) (1×500mL), dry with anhydrous sodium sulfate, filter and concentrate to obtain 23g of crude product. The aqueous phase was adjusted to pH=4~5 with concentrated hydrochloric acid, extracted again with ethyl acetate (2×500mL), the organic phase was washed with sodium chloride aqueous solution (10%) (1×300mL), dried over anhydrous sodium sulfate, and filtered Concentrate and combine 23 g of crude product, and purify by silica gel column chromatography with eluent system A to obtain the title product 11d (9.6 g, yield: 17.1%).
MS m/z(ESI)：278.9[M+1]。MS m/z(ESI): 278.9[M+1].
第三步third step
3-羟基-1-[4-(三氟甲基)苯基]-1H-吲唑-5-磺酰氯11e3-Hydroxy-1-[4-(trifluoromethyl)phenyl]-1H-indazole-5-sulfonyl chloride 11e
将化合物11d(6.0g，21.56mmol)溶于氯仿(60mL)中，室温下滴加入磺酰氯(14.6g，108.17mmol，8.3mL)，加完后60℃反应1小时。冷却至室温，反应液浓缩除去溶剂，残余物滴加入80mL冰水混合物中，析出大量固体，搅拌10分钟后过滤收集固体，用水(2×5mL)洗涤。固体过滤后用150mL乙酸乙酯溶解完全，再加入无水硫酸钠干燥，干燥后很快析出固体，加入150mL四氢呋喃助溶，基本溶清(有小部分悬浊固体不溶)后用滤纸过滤，用四氢呋喃(2×5mL)洗涤，浓缩滤液，干燥得标题产物11e(7.47g，产率：91.9％)。Compound 11d (6.0g, 21.56mmol) was dissolved in chloroform (60mL), and sulfonyl chloride (14.6g, 108.17mmol, 8.3mL) was added dropwise at room temperature. After the addition was completed, the reaction was carried out at 60°C for 1 hour. After cooling to room temperature, the reaction solution was concentrated to remove the solvent. The residue was added dropwise to 80 mL of ice-water mixture to precipitate a large amount of solid. After stirring for 10 minutes, the solid was collected by filtration and washed with water (2×5 mL). After filtering the solid, dissolve it completely with 150 mL of ethyl acetate, then add anhydrous sodium sulfate and dry it. After drying, the solid will precipitate out quickly. Add 150 mL of tetrahydrofuran to help dissolve it. After it is basically dissolved (a small part of the suspended solid is insoluble), filter it with filter paper. Wash with tetrahydrofuran (2×5 mL), concentrate the filtrate, and dry to obtain the title product 11e (7.47 g, yield: 91.9%).
MS m/z(ESI)：376.9[M+1]。MS m/z(ESI): 376.9[M+1].
第四步the fourth step
3-羟基-N,N-双[(4-甲氧基苄基]-1-[4-(三氟甲基)苯基]-1H-吲唑-5-磺酰胺11f3-Hydroxy-N,N-bis[(4-methoxybenzyl]-1-[4-(trifluoromethyl)phenyl]-1H-indazole-5-sulfonamide 11f
将双-(4-甲氧基苄基)-胺(1.75g，6.80mmol，韶远)溶于四氢呋喃(15mL)中，搅拌均匀。将化合物11e(513mg，1.3617mmol)溶于四氢呋喃(15mL)中，然后滴加入反应液中，加完后反应10分钟，过滤除去不溶物，加入10mL氢氧化锂水溶液(1M)和5mL甲醇，搅拌1小时，用柠檬酸水溶液(10％)酸化至pH＝5～6，浓缩除去有机相，过滤收集析出的固体，固体用四氢呋喃溶清后无水硫酸钠干燥，过滤浓缩，用硅胶柱色谱以洗脱剂体系A纯化，得标题产物11f(234m g，产率：28.8％)。Dissolve bis-(4-methoxybenzyl)-amine (1.75g, 6.80mmol, Shaoyuan) in tetrahydrofuran (15mL) and stir evenly. Dissolve compound 11e (513 mg, 1.3617 mmol) in tetrahydrofuran (15 mL), and then add it dropwise to the reaction solution. After the addition, react for 10 minutes, filter to remove insoluble matter, add 10 mL of lithium hydroxide aqueous solution (1M) and 5 mL of methanol, and stir 1 hour, acidify with citric acid aqueous solution (10%) to pH=5~6, concentrate to remove the organic phase, collect the precipitated solid by filtration, dissolve the solid with tetrahydrofuran, dry it over anhydrous sodium sulfate, filter and concentrate, and use silica gel column chromatography to Purification with eluent system A gave the title product 11f (234 mg, yield: 28.8%).
MS m/z(ESI)：598.1[M+1]。MS m/z(ESI): 598.1[M+1].
第五步the fifth step
3-甲氧基-N,N-双[(4-甲氧基苄基]-1-[4-(三氟甲基)苯基]-1H-吲唑-5-磺酰胺11h3-Methoxy-N,N-bis[(4-methoxybenzyl]-1-[4-(trifluoromethyl)phenyl]-1H-indazole-5-sulfonamide 11h
将化合物11f(500mg，0.8367mmol)溶于丙酮(15mL)中，搅拌均匀，加入碳酸铯(818mg，2.511mmol)和碘甲烷(357mg，2.515mmol，0.157mL)，加完后室温反应1小时，反应液浓缩除去溶剂，再加入50mL水，用混合液(20mL乙酸乙 酯+4mL四氢呋喃)×3萃取，无水硫酸钠干燥，过滤浓缩，用硅胶柱色谱以洗脱剂体系A纯化，得标题产物11h(287mg，产率：56.1％)。Dissolve compound 11f (500 mg, 0.8367 mmol) in acetone (15 mL), stir evenly, add cesium carbonate (818 mg, 2.511 mmol) and methyl iodide (357 mg, 2.515 mmol, 0.157 mL), and react at room temperature for 1 hour after addition. The reaction solution was concentrated to remove the solvent, then 50 mL of water was added, and the mixture (20 mL of ethyl acetate Esters + 4 mL of tetrahydrofuran)
第六步Step 6
3-甲氧基-1-[4-(三氟甲基)苯基]-1H-吲唑-5-磺酰胺113-Methoxy-1-[4-(trifluoromethyl)phenyl]-1H-indazole-5-sulfonamide 11
将三氟乙酸(1.34g，11.7520mmol，0.873mL)溶于二氯甲烷(2mL)中，再加入到化合物11h(287mg，0.4692mmol)中，加完后室温反应3小时，反应液浓缩后，再加入20mL饱和碳酸氢钠水溶液中和至pH＝7～8，再加入20mL水稀释，用混合溶剂(20ml二氯甲烷+2ml甲醇)×3萃取，无水硫酸钠干燥，过滤浓缩，用硅胶柱色谱以洗脱剂体系A纯化，得标题产物11(103m g，产率：59.4％)。Dissolve trifluoroacetic acid (1.34g, 11.7520mmol, 0.873mL) in dichloromethane (2mL), and then add it to compound 11h (287mg, 0.4692mmol). After the addition is completed, react at room temperature for 3 hours. After the reaction solution is concentrated, Then add 20 mL saturated sodium bicarbonate aqueous solution to neutralize to pH=7~8, then add 20 mL water to dilute, extract with mixed solvent (20 ml methylene chloride + 2 ml methanol) × 3, dry over anhydrous sodium sulfate, filter and concentrate, and use silica gel Column chromatography was purified with eluent system A to obtain the title product 11 (103 mg, yield: 59.4%).
MS m/z(ESI)：372.0[M+1]。MS m/z(ESI): 372.0[M+1].
1H NMR(500MHz,DMSO-d6)δ8.18(s,1H),8.10(d,J＝9.0Hz,1H),8.02(d,J＝8.4Hz,2H),7.97(d,J＝9.1Hz,1H),7.92(d,J＝8.4Hz,2H),7.43(s,2H),4.17(s,3H)。 1 H NMR (500MHz, DMSO-d 6 ) δ8.18 (s, 1H), 8.10 (d, J = 9.0Hz, 1H), 8.02 (d, J = 8.4Hz, 2H), 7.97 (d, J = 9.1Hz, 1H), 7.92 (d, J = 8.4Hz, 2H), 7.43 (s, 2H), 4.17 (s, 3H).
生物学评价biological evaluation
测试例1本公开化合物对YAP-TEAD介导的报告基因Luc2P荧光素酶活性的抑制作用的测试Test Example 1 Test of the inhibitory effect of the disclosed compounds on YAP-TEAD-mediated reporter gene Luc2P luciferase activity
将8×GTIIC-Luc2P(金唯智)质粒转入HEK293(ATCC，CRL-1573)细胞中，用抗生素筛选并挑选单克隆得到HEK293-8×GTIIC-Luc2P细胞株。用含有10％FBS的DMEM完全培养基将HEK293-8×GTIIC-Luc2P细胞以2×104个/90μL/孔的密度接种于96孔板(Beyotime，FCP968)中，培养24h。用DMSO配制化合物并进行梯度稀释，首浓度为10mM，以5倍梯度稀释，共9个浓度点，空白对照和溶媒对照为100％DMSO。再分别每孔取5μL梯度稀释的化合物添加至每孔95μL完全培养基中，震荡混匀后每孔分别取10μL培养基稀释的化合物添加至含细胞的96孔板中。最终化合物首浓度为10μM，只有培养基无细胞的孔为空白对照，有细胞无化合物的孔为溶媒对照，化合物孔、空白对照和溶媒对照中DMSO含量均为0.5％。细胞继续于培养箱中孵育24h后，取出96孔板，每孔加入50μL One GloTMLuciferase(Promega，E6120)，室温下震荡5min后用酶标仪(PerkinElmer Victor3)读取发光信号值，使用下列公式计算化合物各浓度的抑制率，用Graphpad Prism软件根据抑制率计算化合物抑制活性的IC50值，化合物各浓度对应抑制率的最大值为最大抑制率。
抑制率(％)＝(RLU溶媒对照-RLU化合物孔)/(RLU溶媒对照-RLU空白对照)×100％The 8×GTIIC-Luc2P (Jinweizhi) plasmid was transferred into HEK293 (ATCC, CRL-1573) cells, and antibiotics were used to screen and select single clones to obtain the HEK293-8×GTIIC-Luc2P cell line. HEK293-8×GTIIC-Luc2P cells were seeded into a 96-well plate (Beyotime, FCP968) at a density of 2×10 4 cells/90 μL/well using DMEM complete medium containing 10% FBS and cultured for 24 h. Prepare the compound with DMSO and carry out gradient dilution. The first concentration is 10mM, and the compound is diluted 5 times in a 5-fold gradient, with a total of 9 concentration points. The blank control and vehicle control are 100% DMSO. Then take 5 μL of the compound diluted in the gradient from each well and add it to 95 μL of complete culture medium in each well. After shaking and mixing, take 10 μL of the compound diluted in the medium from each well and add it to the 96-well plate containing cells. The final initial concentration of the compound is 10 μM. The wells with only culture medium and no cells are the blank control. The wells with cells and no compound are the vehicle control. The DMSO content in the compound wells, blank control and vehicle control is all 0.5%. After the cells continued to incubate in the incubator for 24 hours, take out the 96-well plate, add 50 μL One Glo TM Luciferase (Promega, E6120) to each well, shake at room temperature for 5 minutes, and then use a microplate reader (PerkinElmer Victor3) to read the luminescence signal value. Use the following The inhibition rate of each concentration of the compound was calculated using the formula, and the IC 50 value of the inhibitory activity of the compound was calculated based on the inhibition rate using Graphpad Prism software. The maximum value of the inhibition rate corresponding to each concentration of the compound was the maximum inhibition rate.
Inhibition rate (%) = (RLU vehicle control - RLU compound well ) / (RLU vehicle control - RLU blank control ) × 100%
表1本公开化合物对YAP/TAZ-TEAD介导的报告基因Luc2P荧光素酶活性的抑制作用

Table 1 Inhibitory effects of the disclosed compounds on YAP/TAZ-TEAD-mediated reporter gene Luc2P luciferase activity

结论：本公开化合物对YAP/TAZ-TEAD介导的报告基因Luc2P荧光素酶活性具有明显的抑制作用。Conclusion: The disclosed compound has a significant inhibitory effect on the YAP/TAZ-TEAD-mediated reporter gene Luc2P luciferase activity.
测试例2本公开化合物对NCI-H226细胞的增殖抑制作用Test Example 2: Proliferation inhibitory effect of the disclosed compound on NCI-H226 cells
实验第一天，将生长良好、达70％-80％汇合度的NCI-H226(ATCC，CRL-5826)细胞消化后，用含有10％FBS的RPMI(Hyclone，SH30809.01)培养基重悬，并调整至所需细胞密度。在96孔板中(Corning，3903)每孔加入135μL细胞悬液，细胞密度为1000个/孔。将细胞板置于37℃，5％CO2培养箱中培养24小时。第二天，将溶于DMSO的20mM受试化合物用DMSO稀释至首浓度2mM，然后再以5倍梯度稀释，共9个浓度点，对照孔为DMSO。然后用培养基将梯度稀释的化合物进一步稀释20倍。在细胞板每孔加入15μL培养基稀释后的受试化合物，化合物终浓度为首浓度10μM，5倍梯度稀释的9个浓度点。设置含有0.5％DMSO的细胞孔为溶媒对照孔，仅有培养基和0.5％DMSO的孔为空白对照孔。化合物各浓度和对照孔均设置复孔，每孔DMSO终浓度为0.5％。将细胞板置于37℃，5％CO2培养箱中培养6天。第八天取出96孔细胞培养板，每孔加入50μL发光细胞活性检测试剂(Luminescent Cell Viability Assay)(Promega，G7573)，于室温避光放置10分钟，置于酶标仪VICTOR3上读取发光信号值。On the first day of the experiment, NCI-H226 (ATCC, CRL-5826) cells that grew well and reached 70%-80% confluence were digested and resuspended in RPMI (Hyclone, SH30809.01) medium containing 10% FBS. , and adjust to the desired cell density. Add 135 μL of cell suspension to each well of a 96-well plate (Corning, 3903), and the cell density is 1000 cells/well. Place the cell plate in a 37°C, 5% CO2 incubator for 24 hours. The next day, 20mM of the test compound dissolved in DMSO was diluted with DMSO to a first concentration of 2mM, and then diluted 5 times in a gradient for a total of 9 concentration points. The control wells were DMSO. The serially diluted compound was then further diluted 20-fold with culture medium. Add 15 μL of the test compound diluted in culture medium to each well of the cell plate. The final concentration of the compound is the first concentration of 10 μM and 9 concentration points of 5-fold gradient dilution. Set the cell wells containing 0.5% DMSO as vehicle control wells, and the wells containing only culture medium and 0.5% DMSO as blank control wells. Duplicate wells were set for each compound concentration and control well, and the final DMSO concentration in each well was 0.5%. Place the cell plate in a 37°C, 5% CO2 incubator for 6 days. On the eighth day, take out the 96-well cell culture plate and add 50 μL of luminescent cell activity detection reagent ( Luminescent Cell Viability Assay) (Promega, G7573), place it at room temperature in the dark for 10 minutes, and place it on a microplate reader VICTOR3 to read the luminescence signal value.
使用以下公式计算抑制率：抑制率＝[RLU(溶媒对照孔)-RLU(受试化合物)]/[RLU(溶媒对照孔)-RLU(空白对照孔)]×100％，用Graphpad Prism软件根据化合物各浓度与相应的抑制率绘出抑制曲线，并计算化合物的IC50值。Use the following formula to calculate the inhibition rate: Inhibition rate = [RLU (vehicle control well) - RLU (test compound)] / [RLU (vehicle control well) - RLU (blank control well)] × 100%, using Graphpad Prism software according to Draw an inhibition curve for each concentration of the compound and the corresponding inhibition rate, and calculate the IC 50 value of the compound.
表2本公开化合物对NCI-H226细胞的增殖抑制作用
Table 2 Inhibitory effects of compounds of the present disclosure on the proliferation of NCI-H226 cells
结论：本公开化合物对NCI-H226细胞具有好的抑制作用。Conclusion: The disclosed compounds have good inhibitory effects on NCI-H226 cells.
测试例3本公开化合物在大鼠体内的药代动力学评价Test Example 3 Pharmacokinetic evaluation of the disclosed compounds in rats
1、摘要1. Abstract
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予实施例1化合物后不同时刻血浆中实施例1化合物的浓度。研究本公开化合物在大鼠体内的药代动力学行为，评价其药动学特征。Rats were used as test animals, and the concentration of the compound of Example 1 in the plasma of rats at different times after intragastric administration of the compound of Example 1 was measured using the LC/MS/MS method. Study the pharmacokinetic behavior of the disclosed compound in rats and evaluate its pharmacokinetic characteristics.
2、实验方案2. Experimental plan
2.1、实验药品2.1. Experimental drugs
实施例1化合物。 Example 1 Compounds.
2.2、试验动物2.2. Experimental animals
SD大鼠4只，雌雄各半，由维通利华实验动物技术有限公司提供，动物生产许可证号：SCXK(浙)2019-0001。Four SD rats, half male and half female, were provided by Weitong Lihua Experimental Animal Technology Co., Ltd., animal production license number: SCXK (Zhejiang) 2019-0001.
2.3、药物配制2.3. Drug preparation
称取一定量的实施例1化合物，加入5％DMSO+20％PEG400+70％(10％TPGS)+5％(1％HPMCK100LV)使其成0.5mg/mL的澄明溶液。Weigh a certain amount of the compound of Example 1 and add 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HPMCK100LV) to form a clear solution of 0.5 mg/mL.
2.4、给药2.4. Administration
灌胃给药，实施例1化合物的给药剂量为5mg/kg，给药体积为10mL/kg。For intragastric administration, the dosage of the compound of Example 1 was 5 mg/kg, and the administration volume was 10 mL/kg.
3、操作3. Operation
大鼠灌胃给药实施例1化合物，于给药后0.25h、0.5h、1h、2h、4h、6h、8h、11h、24h眼眶采血0.1mL，置EDTA-K2抗凝试管中，10000rpm离心1分钟(4℃)，1h内分离血浆，-20℃保存。采血至离心过程在冰浴条件下操作。Rats were administered the compound of Example 1 by gavage, and 0.1 mL of blood was collected from the orbit at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 11h, and 24h after administration, placed in an EDTA-K2 anticoagulant test tube, and centrifuged at 10,000 rpm. 1 minute (4°C), separate plasma within 1 hour, and store at -20°C. The process from blood collection to centrifugation is operated under ice bath conditions.
测定实施例1化合物给药后大鼠血浆中的实施例1化合物的含量：取给药后各时刻的大鼠血浆25μL，加入200μL ACN(含甲苯磺丁脲100ng/mL)，涡旋混合5min，离心15min(3700rpm)，取上清液100μL加50μL水混匀5min，取2μL进行LC/MS/MS分析。Determine the content of Example 1 compound in rat plasma after administration of Example 1 compound: Take 25 μL of rat plasma at each time after administration, add 200 μL ACN (containing tolbutamide 100 ng/mL), and vortex for 5 min. , centrifuge for 15 minutes (3700 rpm), take 100 μL of the supernatant, add 50 μL of water, mix for 5 minutes, and take 2 μL for LC/MS/MS analysis.
4、药代动力学参数结果4. Pharmacokinetic parameter results
表3本公开化合物的药代动力学参数
Table 3 Pharmacokinetic parameters of the disclosed compounds
结论：本公开化合物在大鼠体内具有良好的药代吸收活性。Conclusion: The disclosed compound has good pharmacological absorption activity in rats.
测试例4本公开化合物在Beagle犬体内的药代动力学评价Test Example 4: Pharmacokinetic evaluation of the disclosed compounds in Beagle dogs
1、摘要1. Abstract
以Beagle犬为受试动物，应用LC/MS/MS法测定了Beagle犬灌胃给予实施例1化合物后不同时刻血浆中实施例1化合物的浓度。研究本公开化合物在Beagle犬体内的药代动力学行为，评价其药动学特征。Using Beagle dogs as the test animals, the LC/MS/MS method was used to determine the concentration of the compound of Example 1 in the plasma of the Beagle dogs at different times after intragastric administration of the compound of Example 1. Study the pharmacokinetic behavior of the disclosed compound in Beagle dogs and evaluate its pharmacokinetic characteristics.
2、实验方案2. Experimental plan
2.1、实验药品2.1. Experimental drugs
实施例1化合物。Example 1 Compounds.
2.2、试验动物2.2. Experimental animals
Beagle犬4只，雌雄各半，由天津康文斯生物科技有限公司提供。Four Beagle dogs, half male and half female, were provided by Tianjin Convance Biotechnology Co., Ltd.
2.3、药物配制 2.3. Drug preparation
称取一定量的实施例1化合物，加入5％DMSO+30％PG+30％PEG400+35％生理盐水使其成0.4mg/mL的澄明溶液。Weigh a certain amount of the compound of Example 1 and add 5% DMSO + 30% PG + 30% PEG400 + 35% physiological saline to make it a clear solution of 0.4 mg/mL.
2.4、给药2.4. Administration
灌胃给药，实施例1化合物的给药剂量为2mg/kg，给药体积为5mL/kg。For intragastric administration, the dosage of the compound of Example 1 was 2 mg/kg, and the administration volume was 5 mL/kg.
3、操作3. Operation
Beagle犬禁食过夜后灌胃给药实施例1化合物，于给药前0h及给药后0.25h、0.5h、1h、2h、4h、6h、8h、11h、24h由前肢静脉采血0.5mL，置EDTA-K2抗凝试管中，10000rpm离心2分钟(4℃)，1h内分离血浆，-80℃保存。给药后3h进食。Beagle dogs were fasted overnight and administered the compound of Example 1 by gavage. 0.5 mL of blood was collected from the forelimb vein at 0 h before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 11 h, and 24 h after administration. Place in an EDTA-K2 anticoagulant test tube, centrifuge at 10,000 rpm for 2 minutes (4°C), separate plasma within 1 hour, and store at -80°C. Eat 3 hours after administration.
测定实施例1化合物给药后Beagle犬血浆中的实施例1化合物的含量：取给药后各时刻的Beagle犬血浆50μL，加入25μL喜树碱(1μg/mL)和450μL乙腈，涡旋混合，离心10min(3700rpm)，取上清液0.5μL进行LC/MS/MS分析。Determine the content of the compound of Example 1 in the plasma of Beagle dogs after administration of the compound of Example 1: Take 50 μL of the plasma of Beagle dogs at each time after administration, add 25 μL of camptothecin (1 μg/mL) and 450 μL of acetonitrile, and vortex to mix. Centrifuge for 10 min (3700 rpm), and take 0.5 μL of the supernatant for LC/MS/MS analysis.
4、药代动力学参数结果4. Pharmacokinetic parameter results
表4本公开化合物的药代动力学参数
Table 4 Pharmacokinetic parameters of compounds of the present disclosure
结论：本公开化合物在Beagle犬体内具有良好的药代吸收活性。 Conclusion: The disclosed compound has good pharmacological absorption activity in Beagle dogs.

Claims (21)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
    其中：in:
    Z为O或NH；Z is O or NH;
    环A为芳基或杂芳基；Ring A is aryl or heteroaryl;
    R为烷基或RwRxN，所述的烷基任选被选自氘原子、卤素、烷氧基、氘代烷氧基、卤代烷氧基、氰基、氨基和羟基中的一个或多个取代基所取代；R is an alkyl group or R w R x N, and the alkyl group is optionally selected from one of deuterium atoms, halogen, alkoxy, deuterated alkoxy, haloalkoxy, cyano, amino and hydroxyl or Substituted with multiple substituents;
    R1选自氢原子、氘原子、卤素、烷基、RvO和RyRzN，所述的烷基任选被选自氘原子、卤素、烷氧基、氘代烷氧基、卤代烷氧基、氰基、氨基和羟基中的一个或多个取代基所取代；R 1 is selected from hydrogen atom, deuterium atom, halogen, alkyl group, R v O and R y R z N, and the alkyl group is optionally selected from deuterium atom, halogen, alkoxy group, deuterated alkoxy group, Substituted with one or more substituents among haloalkoxy, cyano, amino and hydroxyl;
    Rw、Rx、Ry和Rz相同或不同，且各自独立地选自氢原子、氘原子和烷基，所述的烷基任选被选自氘原子、卤素、烷氧基、氘代烷氧基、卤代烷氧基、氰基、氨基和羟基中的一个或多个取代基所取代；R w , R x , Ry and R z are the same or different, and are each independently selected from hydrogen atoms, deuterium atoms and alkyl groups. The alkyl groups are optionally selected from deuterium atoms, halogens, alkoxy groups, deuterium atoms. Substituted with one or more substituents from alkoxy, haloalkoxy, cyano, amino and hydroxy;
    Rv选自烷基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Rv is selected from alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently selected from Deuterium atom, halogen, oxo group, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, deuterated alkoxy group, haloalkoxy group, nitro group, cyano group, amino group, hydroxyl group, hydroxyalkyl group, cycloalkyl group Substituted with one or more substituents among base, heterocyclyl, aryl and heteroaryl;
    Ra和Rb相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基和羟烷基；R a and R b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a haloalkyl group and a hydroxyalkyl group;
    R2、R3和R4相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烯基、炔基、硝基、氰基、-NRn1Rn2、-C(O)NRn3Rn4、-C(O)Ra1、-C(O)ORa2、-ORa3、-S(O)t1Ra4、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R 2 , R 3 and R 4 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, -NR n1 R n2 , -C( O)NR n3 R n4 , -C(O)R a1 , -C(O)OR a2 , -OR a3 , -S(O) t1 R a4 , cycloalkyl, heterocyclyl, aryl and heteroaryl ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of deuterium atoms, halogens, oxo groups, alkyl groups, deuterated groups In alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;
    各个R5相同或不同，且各自独立地选自氘原子、卤素、烷基、烯基、炔基、硝基、氰基、-NRn5Rn6、-C(O)NRn7Rn8、-C(O)Ra5、-C(O)ORa6、-ORa7、-S(O)t2Ra8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷 基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Each R 5 is the same or different, and each is independently selected from deuterium atom, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, -NR n5 R n6 , -C(O)NR n7 R n8 , - C(O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from deuterium atoms, halogens, oxo groups, alkyl groups, deuterated alkyl groups One of alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or substituted by multiple substituents;
    Rn1、Rn2、Rn3、Rn4、Rn5、Rn6、Rn7和Rn8在每次出现时相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；R n1 , R n2 , R n3 , R n4 , R n5 , R n6 , R n7 and R n8 are the same or different each time they appear, and are each independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups base, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    或者Rn1和Rn2与相连的氮原子一起形成杂环基、Rn3和Rn4与相连的氮原子一起形成杂环基、Rn5和Rn6与相连的氮原子一起形成杂环基或Rn7和Rn8与相连的氮原子一起形成杂环基，所述的杂环基各自独立地任选被选自氘原子、卤素、氧代基、烷基、烷氧基、氘代烷基、卤代烷基、氘代烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Or R n1 and R n2 together with the connected nitrogen atom form a heterocyclic group, R n3 and R n4 together with the connected nitrogen atom form a heterocyclic group, R n5 and R n6 together with the connected nitrogen atom form a heterocyclic group or R n7 and R n8 together with the attached nitrogen atom form a heterocyclic group, each of which is independently selected from the group consisting of deuterium atom, halogen, oxo group, alkyl group, alkoxy group, deuterated alkyl group, One or more substituents of haloalkyl, deuterated alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replace;
    Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7和Ra8在每次出现时相同或不同，且各自独立地选自氢原子、氘原子、烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 are the same or different each time they appear, and are each independently selected from hydrogen atoms, deuterium atoms, alkyl groups, and hydroxyalkyl groups. , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of deuterium atoms, halogens, Oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl , substituted by one or more substituents in aryl and heteroaryl;
    t1为0、1或2；t1 is 0, 1 or 2;
    t2为0、1或2；t2 is 0, 1 or 2;
    m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
    n为0、1或2；n is 0, 1 or 2;
    条件是，requirement is,
    i)当R为RwRxN且n为1时，不为 i) When R is R w R x N and n is 1, Not for
    ii)当R为甲基且n为0时，R1不为 ii) When R is methyl and n is 0, R 1 is not
  2. 根据权利要求1所述的通式(I)所示的化合物或其可药用的盐，其中R为RwRxN，Rw和Rx如权利要求1中所定义。The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is R w R x N, and R w and R x are as defined in claim 1.
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
    The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:
    其中：in:
    G0为氮原子或CR5a；G 0 is a nitrogen atom or CR 5a ;
    G1为氮原子或CR5b；G 1 is a nitrogen atom or CR 5b ;
    G2为氮原子或CR5d；G 2 is a nitrogen atom or CR 5d ;
    G3为氮原子或CR5e；G 3 is a nitrogen atom or CR 5e ;
    R5a选自氢原子、氘原子、F、Br、I、烷基、烯基、炔基、硝基、氰基、-NRn5Rn6、-C(O)NRn7Rn8、-C(O)Ra5、-C(O)ORa6、-ORa7、-S(O)t2Ra8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R 5a is selected from hydrogen atom, deuterium atom, F, Br, I, alkyl group, alkenyl group, alkynyl group, nitro group, cyano group, -NR n5 R n6 , -C(O)NR n7 R n8 , -C( O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl and alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of deuterium atoms, halogens, oxo groups, alkyl groups, deuterated alkyl groups, haloalkyl groups, alkoxy groups, Substituted with one or more substituents from deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R5c选自氢原子、氘原子、Cl、Br、I、烷基、烯基、炔基、硝基、氰基、-NRn5Rn6、-C(O)NRn7Rn8、-C(O)Ra5、-C(O)ORa6、-ORa7、-S(O)t2Ra8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R 5c is selected from hydrogen atom, deuterium atom, Cl, Br, I, alkyl group, alkenyl group, alkynyl group, nitro group, cyano group, -NR n5 R n6 , -C(O)NR n7 R n8 , -C( O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl and alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of deuterium atoms, halogens, oxo groups, alkyl groups, deuterated alkyl groups, haloalkyl groups, alkoxy groups, Substituted with one or more substituents from deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R5b、R5d和R5e相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烯基、炔基、硝基、氰基、-NRn5Rn6、-C(O)NRn7Rn8、-C(O)Ra5、-C(O)ORa6、-ORa7、-S(O)t2Ra8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R 5b , R 5d and R 5e are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, -NR n5 R n6 , -C( O)NR n7 R n8 , -C(O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of deuterium atoms, halogens, oxo groups, alkyl groups, deuterated groups In alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;
    其中Z、Rw、Rx、R1、R2、R3、R4、Ra、Rb、Rn5、Rn6、Rn7、Rn8、Ra5、Ra6、Ra7、Ra8、t2和n如权利要求1中所定义。Among them, Z, R w , R x , R 1 , R 2 , R 3 , R 4 , R a , R b , R n5 , R n6 , R n7 , R n8 , R a5 , R a6 , R a7 , R a8 , t2 and n are as defined in claim 1.
  4. 根据权利要求3所述的通式(I)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
    The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, which is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:
    其中Z、Rw、Rx、R1、G1、G3、R5c和n如权利要求3中所定义；优选地，Z为O。Wherein Z, Rw , Rx , R1 , G1 , G3 , R5c and n are as defined in claim 3; preferably, Z is O.
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R1选自氢原子、C1-6烷基、C1-6烷氧基和RyRzN，Ry和Rz如权利要求1中所定义；优选地，Ry和Rz相同或不同，且各自独立地为氢原子或C1-6烷基。The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1 is selected from a hydrogen atom, C 1-6 alkyl, C 1-6 alkyl Oxygen and R y R z N, R y and R z are as defined in claim 1; preferably, R y and R z are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group.
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其可药用的盐，其中n为0或1。The compound represented by general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
  7. 根据权利要求3至6中任一项所述的通式(I)所示的化合物或其可药用的盐，其中G1和G3均为CH。The compound represented by general formula (I) according to any one of claims 3 to 6, or a pharmaceutically acceptable salt thereof, wherein G 1 and G 3 are both CH.
  8. 根据权利要求3至7中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R5c为氢原子或C1-6卤代烷基。The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 7, wherein R 5c is a hydrogen atom or a C 1-6 haloalkyl group.
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其可药用的盐，其中Rw为氢原子或C1-6烷基。The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R w is a hydrogen atom or a C 1-6 alkyl group.
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其可药用的盐，其中Rx为氢原子或C1-6烷基；优选地，Rx为C1-6烷基。The compound represented by general formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R x is a hydrogen atom or a C 1-6 alkyl group; preferably, R x is C 1-6 alkyl.
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自以下化合物：

    The compound represented by general formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

  12. 一种通式(IIa)所示的化合物或其盐：
    A compound represented by general formula (IIa) or a salt thereof:
    其中：in:
    RL为氨基保护基；优选地，RL为PMB；R L is an amino protecting group; preferably, R L is PMB;
    Rx、Z、R1、R2、R3、R4、R5c、Ra、Rb、G0、G1、G2、G3和n如权利要求3中所定义。 Rx , Z, R1 , R2, R3, R4, R5c , Ra , Rb , G0 , G1 , G2 , G3 and n are as defined in claim 3.
  13. 根据权利要求12所述的通式(IIa)所示的化合物或其盐，其选自以下化合物：
    The compound represented by the general formula (IIa) according to claim 12 or a salt thereof, which is selected from the following compounds:
  14. 一种通式(IIA)所示的化合物或其盐：
    A compound represented by general formula (IIA) or a salt thereof:
    其中：in:
    RN为卤素；优选地，RN为Cl；R N is halogen; preferably, R N is Cl;
    R5c选自氘原子、Cl、Br、I、烷基、烯基、炔基、硝基、氰基、-NRn5Rn6、-C(O)NRn7Rn8、-C(O)Ra5、-C(O)ORa6、-ORa7、-S(O)t2Ra8、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、硝基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R 5c is selected from deuterium atom, Cl, Br, I, alkyl group, alkenyl group, alkynyl group, nitro group, cyano group, -NR n5 R n6 , -C(O)NR n7 R n8 , -C(O)R a5 , -C(O)OR a6 , -OR a7 , -S(O) t2 R a8 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of deuterium, halogen, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkyl Substituted with one or more substituents from oxygen, haloalkoxy, nitro, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    Z、R1、R2、R3、R4、Ra、Rb、G0、G1、G2、G3、Rn5、Rn6、Rn7、Rn8、Ra5、Ra6、Ra7、Ra8、t2和n如权利要求3中所定义。Z, R 1 , R 2 , R 3 , R 4 , R a , R b , G 0 , G 1 , G 2 , G 3 , R n5 , R n6 , R n7 , R n8 , R a5 , R a6 , R a7 , R a8 , t2 and n are as defined in claim 3.
  15. 化合物，其选自以下结构：
    A compound selected from the following structures:
  16. 一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
    A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
    通式(IIa)所示的化合物或其盐经脱保护反应，得到通式(II)所示的化合物或其可药用的盐；The compound represented by the general formula (IIa) or a salt thereof is subjected to a deprotection reaction to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
    其中：in:
    RL为氨基保护基；优选地，RL为PMB；R L is an amino protecting group; preferably, R L is PMB;
    Rw为氢原子；R w is a hydrogen atom;
    Rx、Z、R1、R2、R3、R4、R5c、Ra、Rb、G0、G1、G2、G3和n如权利要求3中所定义。 Rx , Z, R1 , R2, R3, R4, R5c , Ra , Rb , G0 , G1 , G2 , G3 and n are as defined in claim 3.
  17. 一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
    A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
    通式(IIA)所示的化合物或其盐与通式(IIB)所示的化合物或其盐发生磺酰化反应，得到通式(II)所示的化合物或其可药用的盐；A sulfonylation reaction occurs between a compound represented by general formula (IIA) or a salt thereof and a compound represented by general formula (IIB) or a salt thereof, to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;
    其中：in:
    RN为卤素；优选地，RN为Cl；R N is halogen; preferably, R N is Cl;
    Z、Rx、Rw、R1、R2、R3、R4、R5c、Ra、Rb、G0、G1、G2、G3和n如权利要求3中所定义。Z, Rx , Rw , R1 , R2 , R3 , R4 , R5c , Ra, Rb , G0 , G1 , G2 , G3 and n are as defined in claim 3.
  18. 一种药物组合物，所述药物组合物含有根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐，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 containing a compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical Acceptable carriers, diluents or excipients.
  19. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备TEAD抑制剂药物中的用途。Use of the compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 in the preparation of TEAD inhibitor drugs.
  20. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于治疗和/或预防由YAP/TAZ-TEAD相互作用介导的疾病或病症的药物中的用途。The compound represented by the general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 is used for the treatment and/or prevention of Use in medicines for diseases or conditions mediated by YAP/TAZ-TEAD interactions.
  21. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于治疗和/或预防癌症、纤维化、多囊肾病和心血管疾病的药物中的用途；所述的纤维化优选为肝纤维化；所述的癌症优选选自间皮瘤、许旺细胞瘤、白血病、淋巴瘤、巨球蛋白血症、重链病、肉瘤、胰腺癌、乳腺癌、卵巢癌、***癌、鳞癌、汗腺癌、皮脂腺癌、***状癌、囊腺癌、髓样癌、支气管癌、肝癌、胆管癌、绒毛膜癌、***瘤、胚胎癌、威尔姆氏肿瘤、***、子宫内膜癌、睾丸癌、肺癌、膀胱癌、神经胶质瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管瘤、听神经瘤、神经鞘瘤、神经纤维瘤、视网膜母细胞瘤、黑色素瘤、皮肤癌、肾癌、鼻咽癌、胃癌、食管癌、头颈癌、结直肠癌、小肠癌、胆囊癌、儿科肿瘤、尿路上皮癌、输尿管肿瘤、甲状腺癌、骨瘤、成神经细胞瘤、脑瘤、室管膜瘤和骨髓瘤。 The compound represented by the general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 is used for the treatment and/or prevention of cancer. , use in medicines for fibrosis, polycystic kidney disease and cardiovascular disease; the fibrosis is preferably liver fibrosis; the cancer is preferably selected from mesothelioma, Schwann cell tumor, leukemia, lymphoma, giant cell carcinoma, Globulinemia, heavy chain disease, sarcoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, bile duct Carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma , ependymoma, pineal tumor, hemangioma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer , colorectal cancer, small bowel cancer, gallbladder cancer, pediatric tumors, urothelial cancer, ureteral tumors, thyroid cancer, osteoma, neuroblastoma, brain tumors, ependymoma, and myeloma.
PCT/CN2023/085315 2022-03-31 2023-03-31 Indazole compound, preparation method therefor, and use thereof in medicine WO2023186058A1 (en)

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Citations (5)

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CN101098858A (en) * 2004-11-11 2008-01-02 阿斯利康(瑞典)有限公司 Indazole sulphonamide derivatives
CN104869992A (en) * 2012-10-26 2015-08-26 默沙东公司 N-substituted indazole sulfonamide compounds with selective activity in voltage-gated sodium channels
WO2016097391A1 (en) * 2014-12-19 2016-06-23 Galderma Research & Development Indazole sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (ror gamma (t))
CN112805267A (en) * 2018-09-03 2021-05-14 豪夫迈·罗氏有限公司 Carboxamide and sulfonamide derivatives as TEAD modulators
WO2022120353A1 (en) * 2020-12-02 2022-06-09 Ikena Oncology, Inc. Tead inhibitors and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101098858A (en) * 2004-11-11 2008-01-02 阿斯利康(瑞典)有限公司 Indazole sulphonamide derivatives
CN104869992A (en) * 2012-10-26 2015-08-26 默沙东公司 N-substituted indazole sulfonamide compounds with selective activity in voltage-gated sodium channels
WO2016097391A1 (en) * 2014-12-19 2016-06-23 Galderma Research & Development Indazole sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (ror gamma (t))
CN112805267A (en) * 2018-09-03 2021-05-14 豪夫迈·罗氏有限公司 Carboxamide and sulfonamide derivatives as TEAD modulators
WO2022120353A1 (en) * 2020-12-02 2022-06-09 Ikena Oncology, Inc. Tead inhibitors and uses thereof

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