WO2022166810A1 - Fused azatricyclic derivative, preparation method therefor, and application thereof in medicine - Google Patents

Fused azatricyclic derivative, preparation method therefor, and application thereof in medicine Download PDF

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Publication number
WO2022166810A1
WO2022166810A1 PCT/CN2022/074588 CN2022074588W WO2022166810A1 WO 2022166810 A1 WO2022166810 A1 WO 2022166810A1 CN 2022074588 W CN2022074588 W CN 2022074588W WO 2022166810 A1 WO2022166810 A1 WO 2022166810A1
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Prior art keywords
general formula
ring
group
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/074588
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French (fr)
Chinese (zh)
Inventor
李心
钟家鑫
蔡国栋
贺峰
陶维康
Original Assignee
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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Priority to CN202280012570.5A priority Critical patent/CN116829556A/en
Publication of WO2022166810A1 publication Critical patent/WO2022166810A1/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
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a fused azatricyclic derivative, a preparation method thereof and its application in medicine.
  • the present disclosure relates to the fused azatricyclic derivatives represented by the general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, as well as their use as a GR regulator and in the preparation of Use in medicines for the treatment and/or prevention of tumors.
  • Glucocorticoid Receptor is a member of the nuclear receptor family, and is associated with the mineralocorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR), and estrogen receptor. (ER) together, belong to the class of steroid hormone receptors in the nuclear receptor family.
  • Glucocorticoids regulate gene expression by activating GR, and regulate a variety of cellular functions, such as metabolism, inflammation, cell growth and differentiation. Physiologically, glucocorticoids regulate glucose, protein, and lipid metabolism in humans.
  • glucocorticoid levels caused by pathological factors can lead to metabolic disorders, developmental delay, etc., which is clinically called Cushing Syndrome (CS); and low glucocorticoid levels caused by pathological trauma or other factors, It will lead to Addison's disease, mainly manifested as anxiety, fatigue, muscle and joint pain and depression, and some patients will show severe depression.
  • CS Cushing Syndrome
  • GR receptor agonists such as steroid glucocorticoids are widely used in the clinical treatment of autoimmune diseases or allergies. In hematological tumors with malignant proliferation of immune cells, steroid glucocorticoids are also one of the combination therapy.
  • GR signaling pathway is directly related to the progression, metastasis, drug resistance and poor prognosis of various solid tumors.
  • GR gene knockout or GR antagonist can significantly inhibit the growth of tumor models in vivo.
  • GR triple negative breast cancer
  • Activation of GR signaling pathway is associated with cancer cell metastasis and resistance to paclitaxel.
  • Paclitaxel-based chemotherapy is currently the main method for the treatment of TNBC.
  • the use of GR antagonists can enhance chemosensitivity and reduce metastasis.
  • targeting GR and interfering its signal transduction with antagonistic means is a new tumor treatment method.
  • its mechanism of action has been effectively confirmed by a large number of literature data.
  • Patent applications that have disclosed GR modulators include WO2005087769A1, WO2012027702A1, WO2013177559A2, and WO2015077530A1, among others.
  • Ring A is selected from heterocyclyl, aryl and heteroaryl
  • Each R 1 is the same or different, and is independently selected from a hydrogen atom, halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 4 R 5 , hydroxy , -C(O)R 6 , -C(O)OR 6 , -C(O)NR 4 R 5 , -S(O) p R 6 , cycloalkyl, heterocyclyl, aryl and heteroaryl , wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, Substituted with one or more substituents of cyano, -NR 7 R 8 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, ary
  • heterocyclyl group is optionally selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy substituted with one or more substituents in group, cyano group, -NR 7 R 8 , nitro group, hydroxy group and hydroxyalkyl group;
  • Ring B is aryl or heteroaryl
  • Each R 2 is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 4 R 5 , hydroxy, cycloalkyl , heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, One or more substitutions of alkoxy, haloalkyl, haloalkoxy , cyano, -NR7R8 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl base substituted;
  • Ring C is aryl or heteroaryl
  • each R 3 is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 4 R 5 and hydroxy;
  • R 6 is the same or different at each occurrence, and is each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein said alkyl, cycloalkyl, and heterocyclyl groups are each independently optionally substituted with one or more substituents selected from halo, alkyl, alkoxy, haloalkyl, and haloalkoxy;
  • R 4 , R 5 , R 7 and R 8 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group, wherein said alkyl group, cycloalkyl group and The heterocyclyl groups are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy;
  • R4 and R5 together with the attached nitrogen atom form a heterocyclyl group optionally selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, Substituted with one or more substituents of amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R7 and R8 together with the attached nitrogen atom form a heterocyclyl group optionally selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, Substituted with one or more substituents of amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • p 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3, or 4;
  • t 0, 1, 2, 3 or 4.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:
  • Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (I).
  • the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is the general formula (II-1) or the general formula (II-2) ) or a pharmaceutically acceptable salt thereof:
  • Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (I).
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:
  • Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (I).
  • the compound represented by the general formula (I) or the general formula (III) or a pharmaceutically acceptable salt thereof is the general formula (III-1) or the general formula (III- 2) The compound shown or a pharmaceutically acceptable salt thereof:
  • Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (I).
  • the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof of salt:
  • Rings A, R 1 to R 3 , m, n and t are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (II), general formula (II-1) or general formula (IV) or a pharmaceutically acceptable salt thereof is The compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof:
  • Rings A, R 1 to R 3 , m, n and t are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (II), general formula (II-2) or general formula (IV) or a pharmaceutically acceptable salt thereof is The compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof:
  • Rings A, R 1 to R 3 , m, n and t are as defined in general formula (I).
  • the compound represented by the general formula (I) or the general formula (III) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof of salt:
  • Rings A, R 1 to R 3 , m, n and t are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (III), general formula (III-1) or general formula (V) or a pharmaceutically acceptable salt thereof is The compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof:
  • Rings A, R 1 to R 3 , m, n and t are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (III), general formula (III-2) or general formula (V) or a pharmaceutically acceptable salt thereof is The compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof:
  • Rings A, R 1 to R 3 , m, n and t are as defined in general formula (I).
  • two adjacent R 1 are fused with ring A to form a 5- or 6-membered heterocyclic group, wherein the 5 or 6-membered heterocyclic group is optionally selected
  • the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) or general formula (V) or its pharmaceutically acceptable salt of which selected wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -NR 7 R 8 , nitro, hydroxy and C 1-6 hydroxyalkyl, s is 0, 1, 2, 3 or 4, R 1 , R 7 and R 8 are as defined in general formula (I); preferably, selected More preferably, for
  • the compound represented by the general formula (II-1), the general formula (III-1), the general formula (IV-1) or the general formula (V-1) or its pharmaceutically acceptable salt used of which selected wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -NR 7 R 8 , nitro, hydroxy and C 1-6 hydroxyalkyl, s is 0, 1, 2, 3 or 4, R 1 , R 7 and R 8 are as defined in general formula (I); preferably, selected from More preferably, for
  • the compound represented by the general formula (II-2), the general formula (III-2), the general formula (IV-2) or the general formula (V-2) or its pharmaceutically acceptable salt used of which selected from wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -NR 7 R 8 , nitro, hydroxy and C 1-6 hydroxyalkyl, s is 0, 1, 2, 3 or 4, R 1 , R 7 and R 8 are as defined in general formula (I); preferably, selected from More preferably, for
  • the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) or general formula (V) or its pharmaceutically acceptable salt of which selected from wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -NR 7 R 8 , nitro, hydroxy and C 1-6 hydroxyalkyl, s is 0, 1, 2, 3 or 4, R 1 , R 7 and R 8 are as defined in general formula (I); preferably, selected from More preferably, for
  • the compound represented by the general formula (II-1), the general formula (III-1), the general formula (IV-1) or the general formula (V-1) or its pharmaceutically acceptable salt used of which selected wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -NR 7 R 8 , nitro, hydroxy and C 1-6 hydroxyalkyl, s is 0, 1, 2, 3 or 4, R 1 , R 7 and R 8 are as defined in general formula (I); preferably, selected More preferably, for
  • the compound represented by the general formula (II-2), the general formula (III-2), the general formula (IV-2) or the general formula (V-2) or its pharmaceutically acceptable salt used of which selected wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -NR 7 R 8 , nitro, hydroxy and C 1-6 hydroxyalkyl, s is 0, 1, 2, 3 or 4, R 1 , R 7 and R 8 are as defined in general formula (I); preferably, selected from More preferably, for
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Ring A is selected from 3- to 12-membered heterocyclic group, 6- to 10-membered aryl group, and 5- to 10-membered aryl group 10-membered heteroaryl; Ring B is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; Ring C is 6- to 10-membered aryl or 5- to 10 -membered heteroaryl; each R is the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclic group, wherein said 3- to 12-membered cycloalkyl group and 3- to 12-membered heterocyclic group are each independently optionally selected from halogen, C 1-6 alkyl, C 1-6 alkoxy,
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Ring A is selected from 3- to 12-membered heterocyclic group, 6- to 10-membered aryl group, and 5- to 10-membered aryl group 10-membered heteroaryl; Ring B is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; Ring C is 6- to 10-membered aryl or 5- to 10 -membered heteroaryl; each R is the same or different, and Each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; or two adjacent R 1 and ring A is fused to form a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is optionally selected from halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, substituted by one or
  • the compound represented by general formula (II), general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof wherein ring A is selected from pyridine azolyl, imidazolyl, 1,2,3 - triazolyl and tetrazolyl; ring B is pyridyl; ring C is phenyl; each R is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally selected from one of halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl or Replaced by multiple substituents;
  • the compound represented by general formula (II), general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof wherein ring A is selected from pyridine azolyl, imidazolyl and 1,2,3-triazolyl; ring B is pyridyl; ring C is phenyl; each R 1 is the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; Or two adjacent R 1 are fused with ring A to form a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally selected from halogen, C 1-6 alkyl, oxo is substituted with one or more substituents in group, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; each R 2 is the same or different, and each is independently selected from hydrogen atoms , halogen, C 1-6 alkyl and
  • the compound represented by general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof wherein ring A is selected from pyridine azolyl, imidazolyl, 1,2,3 - triazolyl and tetrazolyl; ring B is pyridyl; ring C is phenyl; each R is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl; or two adjacent R 1 fused with Ring A to form a 5- or 6-membered heterocycle group, wherein said 5- or 6-membered heterocyclic group is optionally selected from halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl and C 1- 6 substituted with one or more substituents in haloal
  • the compound represented by general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof wherein ring A is selected from pyridine azolyl, imidazolyl and 1,2,3-triazolyl; ring B is pyridyl; ring C is phenyl; each R 1 is the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; Or two adjacent R 1 are fused with ring A to form a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally selected from halogen, C 1-6 alkyl, oxo is substituted with one or more substituents in group, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; each R 2 is the same or different, and each is independently selected from hydrogen atoms , halogen, C 1-6 alkyl and C 1-6
  • the compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein ring A is 5 or 6-membered heteroaryl; each R 1 is the same or different, and each is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and 3- to 6-membered cycloalkyl, or two adjacent R 1 Condensed with ring A to form a 5- or 6-membered heterocyclic group; R 2 is C 1-6 haloalkyl; R 3 is halogen; m is 1 or 2; n is 1;
  • the compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein ring A is 5 membered nitrogen-containing heteroaryl; each R 1 is the same or different, and each is independently selected from C 1-6 alkyl, C 1-6 haloalkyl and 3- to 6-membered cycloalkyl; R 2 is C 1-6 haloalkane R 3 is halogen; m is 1; n is 1; t is 1.
  • the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein selected R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
  • the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof wherein selected R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
  • the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein selected from R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
  • the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein selected from R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
  • the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof wherein selected R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
  • the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein selected from R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
  • the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof wherein selected from R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
  • the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof wherein selected from R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
  • the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof wherein selected from R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
  • the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof wherein selected R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a compound of formula (IA) or a salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, Ring B, Ring C, R1 to R3 , m, n and t are as defined for compounds of general formula (I).
  • Another aspect of the present disclosure relates to a compound of general formula (IIA) or a salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a compound of general formula (II-1A) or a salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (II-1).
  • Another aspect of the present disclosure relates to a compound of general formula (II-2A) or a salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (II-2).
  • Another aspect of the present disclosure relates to a compound of general formula (IIIA) or a salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (III).
  • Another aspect of the present disclosure relates to a compound of general formula (III-1A) or a salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (III-1).
  • Another aspect of the present disclosure relates to a compound of general formula (III-2A) or a salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (III-2).
  • Another aspect of the present disclosure relates to a compound of general formula (IVA) or a salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Rings A , R1 to R3 , m, n and t are as defined in general formula (IV).
  • Another aspect of the present disclosure relates to a compound of general formula (IV-1A) or a salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, R 1 to R 3 , m, n and t are as defined in the general formula (IV-1).
  • Another aspect of the present disclosure relates to a compound of general formula (IV-2A) or a salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, R 1 to R 3 , m, n and t are as defined in general formula (IV-2).
  • Another aspect of the present disclosure relates to a compound of general formula (VA) or a salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Rings A, R 1 to R 3 , m, n and t are as defined in general formula (V).
  • Another aspect of the present disclosure relates to a compound of general formula (V-1A) or a salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, R 1 to R 3 , m, n and t are as defined in the general formula (V-1).
  • Another aspect of the present disclosure relates to a compound of general formula (V-2A) or a salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, R 1 to R 3 , m, n and t are as defined in general formula (V-2).
  • 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 (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (I).
  • 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 compound represented by the general formula (IIA) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t 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 (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (II-1A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (II-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (II-2A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (II-2).
  • 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, the method comprising:
  • the compound represented by the general formula (IIIA) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t 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 (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (III-1A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (III-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (III-2A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (III-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IVA) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Rings A , R1 to R3 , m, n and t are as defined in general formula (IV).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IV-1A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, R 1 to R 3 , m, n and t are as defined in the general formula (IV-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IV-2A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, R 1 to R 3 , m, n and t are as defined in general formula (IV-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (VA) or its salt is removed from the amino protecting group R w to obtain the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Rings A, R 1 to R 3 , m, n and t are as defined in general formula (V).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, R 1 to R 3 , m, n and t are as defined in the general formula (V-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (V-2A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, R 1 to R 3 , m, n and t are as defined in general formula (V-2).
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (II-2), general formula Formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula Compounds of formula (V-1), general formula (V-2) and Table A or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III) -2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A
  • the present disclosure further relates to general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III) -2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A
  • Use of the indicated compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder by antagonizing GR.
  • the present disclosure further relates to general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III) -2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A
  • the compound shown or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same is used in the preparation of drugs for the treatment and/or prevention of tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, eye diseases and neurodegenerative diseases.
  • the present disclosure also relates to a method of treating and/or preventing a disease or disorder by modulating GR, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II), formula (II-1), General formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2 ), general formula (V), general formula (V-1), general formula (V-2) and the compounds shown in Table A or their pharmaceutically acceptable salts, or a pharmaceutical composition comprising them.
  • the present disclosure also relates to a method of treating and/or preventing a disease or disorder by antagonizing GR, comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (II), Formula (II-1), General formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2 ), general formula (V), general formula (V-1), general formula (V-2) and the compounds shown in Table A or their pharmaceutically acceptable salts, or a pharmaceutical composition comprising them.
  • the present disclosure also relates to a method of treating and/or preventing tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, ocular diseases and neurodegenerative diseases, comprising administering to a patient in need thereof a therapeutically effective amount of the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), the general formula (IV-1), the general formula (IV-2), the general formula (V), the general formula (V-1), the general formula (V-2) and the compounds shown in Table A or their compounds A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and A compound shown in Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, for use as a medicament.
  • the present disclosure further relates to general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III) -2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A
  • the present disclosure further relates to general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III) -2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A
  • the present disclosure further relates to general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III) -2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A
  • the compound shown or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, is used for the treatment and/or prevention of tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, eye diseases and neurological diseases Degenerative diseases.
  • the disease or disorder described in the present disclosure is selected from cancer, obesity, diabetes, hypertension, syndrome X, depression (eg, psychotic depression, postpartum depression), allergies, anxiety, glaucoma, Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive enhancement, Cushing's syndrome, Addison's disease, osteoporosis, frailty, muscle weakness, osteoarthritis, rheumatoid arthritis, asthma, rhinitis, adrenal-related disorders, Viral infection (eg, human immunodeficiency virus (HIV)), immunodeficiency (eg, acquired immunodeficiency syndrome (AIDS)), immune modulation, allergies, wound healing, compulsive behavior, addiction, psychosis (eg, postpartum psychosis), Anorexia, cachexia, mild cognitive impairment, dementia, hyperglycemia, central serous chorioretinopathy, alcohol dependence, stress disorders (eg, posttraumatic stress disorder), delirium, chronic pain, neurological disorders of prematurity and migraine
  • Example 1-P1 of the present disclosure Compared with the positive control compound Relacorilant (CORT-125134, WO2013177559A2 Example 18), the compound of Example 1-P1 of the present disclosure has better safety than Relacorilant, and has obvious pharmacokinetic advantages.
  • the structural formula of Relacorilant is as follows:
  • the active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation.
  • the compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound is preferably presented in a unit dose or in a form that the patient can self-administer in a single dose.
  • a unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients 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 they 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 can 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 or oily vehicle.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents.
  • the 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.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils.
  • the oily suspensions may contain thickening agents. Sweetening and flavoring agents 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 oily phase can be vegetable oil, or mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids.
  • the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used.
  • fatty acids are also available in the preparation of injectables.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension.
  • These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.
  • the optimal treatment modality such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to conventional treatment regimens.
  • alkyl refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C 1-12 alkyl group), and more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 alkyl group).
  • 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
  • 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 base, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-Dimethylbutyl, etc.
  • the alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein the alkyl group is as defined above, having from 1 to 20 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkylene).
  • the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (ie, a C 1-12 alkylene group), and more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C 1-6 alkylene group).
  • Non-limiting examples of alkylene groups include, but are not limited to: methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene base (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like.
  • the alkylene 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 alkenyl, alkynyl, alkoxy, haloalkoxy, cyclic Alkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy , one or more of heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, which is 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms alkenyl (ie C2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
  • Alkenyl can be substituted or unsubstituted, when substituted, the substituent is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl one or more of , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkynyl refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above, which is 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (ie C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkynyl group).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl one or more of , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy can be optionally substituted or unsubstituted, when substituted, the substituent is preferably selected from D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, hetero One or more of cyclooxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 20 cycloalkyl rings (eg 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably 3 to 12 carbon atoms (ie 3 to 12 membered ring alkyl), more preferably 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl), most preferably 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl).
  • 3 to 20 cycloalkyl rings eg 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20
  • carbon atoms ie 3 to 20 membered cycloalkyl
  • preferably 3 to 12 carbon atoms ie 3 to 12 membered ring alkyl
  • Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5 to 20 membered (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 membered) monocyclic ring A polycyclic group with one carbon atom (called a spiro atom) shared between them, which may contain one or more double bonds.
  • a 6- to 14-membered spirocycloalkyl group is preferred, and a 7- to 10-membered spirocycloalkyl group is more preferred.
  • spirocycloalkyl groups are divided into mono-spirocycloalkyl groups or multi-spirocycloalkyl groups (such as bis-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups or double-spirocycloalkyl groups .
  • spirocycloalkyl More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5-membered/6-membered, 6-membered/4-membered, 6-membered/5-membered or 6-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to a ring of 5 to 20 membered (eg, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 membered).
  • a 6- to 14-membered fused cycloalkyl group is preferred, and a 7- to 10-membered fused cycloalkyl group is more preferred.
  • bicyclic, tricyclic, tetracyclic and other polycyclic fused cycloalkyl groups preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered RMB, RMB 4/RMB 4, RMB 4/RMB 5, RMB 4/RMB 6, RMB 5/RMB 4, RMB 5/RMB 5, RMB 5/RMB 6, RMB 6/RMB 3, RMB 6/RMB 4, 6-membered/5-membered and 6-membered/6-membered bicyclic fused cycloalkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to any two of 5 to 20 membered (eg, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 membered) An all-carbon polycyclic group in which each ring shares two non-directly attached carbon atoms, which may contain one or more double bonds.
  • a 6- to 14-membered bridged cycloalkyl group is preferred, and a 7- to 10-membered bridged cycloalkyl group is more preferred.
  • bridged cycloalkyl preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include etc.; preferred
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having 3 to 20 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, and sulfur, optionally oxo ( i.e. forming a sulfoxide or sulfone), but excluding ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms are carbon.
  • 3 to 12 ring atoms of which 1 to 4 (eg 1, 2, 3 or 4) are heteroatoms (ie 3 to 12 membered heterocyclyl); it is further preferred to have 3 to 8 ring atoms, wherein 1 to 3 are heteroatoms (eg 1, 2 or 3) (ie 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (ie 3 to 6 membered) heterocyclyl); most preferably having 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (ie, 5 or 6 membered heterocyclyl).
  • 1 to 4 eg 1, 2, 3 or 4
  • 3 to 8 ring atoms wherein 1 to 3 are heteroatoms (eg 1, 2 or 3) (ie 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (ie 3 to 6 membered) heterocyclyl); most preferably having 5
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine base, homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5 to 20 membered (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 membered) monocyclic ring
  • a 6- to 14-membered spiroheterocyclic group is preferable, and a 7- to 10-membered spiroheterocyclic group is more preferable.
  • spiroheterocyclyl groups are classified into mono-spiroheterocyclyl groups or poly-spiroheterocyclyl groups (such as bis-spiroheterocyclyl groups), preferably mono-spiroheterocyclyl groups and bis-spiro-heterocyclyl groups .
  • spiroheterocyclyl More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan or 6 yuan/6 yuan unit Spiroheterocyclyl.
  • spiroheterocyclyl include:
  • fused heterocyclyl refers to a ring of 5 to 20 membered (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 membered)
  • a polycyclic heterocyclic group sharing an adjacent pair of atoms, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, said The sulphur can optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • a 6- to 14-membered condensed heterocyclic group is preferable, and a 7- to 10-membered condensed heterocyclic group is more preferable.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/ 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-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic
  • bridged heterocyclyl refers to a polycyclic group in which any two rings of 5 to 14 membered (eg, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 membered) share two atoms that are not directly connected.
  • a cyclic heterocyclic group which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, the sulfur optionally being oxo (i.e. to form a sulfoxide) or sulfone), the remaining ring atoms are carbon.
  • a 6- to 14-membered bridged heterocyclic group is preferable, and a 7- to 10-membered bridged heterocyclic group is more preferable.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be substituted or unsubstituted, when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • aryl refers to a 6- to 14-membered (eg, 6, 7, 8, 9, 10, 11, 12, 13, or 14 membered) all-carbon monocyclic or fused polycyclic (fused Polycycles are cyclic) groups that share adjacent pairs of carbon atoms, preferably 6 to 10 membered aryl groups such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
  • Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heteroaryl refers to containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms, 5 to 14 (eg 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14-membered) heteroaromatic system of ring atoms, wherein the heteroatom is selected from oxygen, sulfur and nitrogen.
  • 5- to 10-membered heteroaryl groups are preferred; 5- or 6-membered heteroaryl groups are more preferred, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl , imidazolyl, pyrazolyl, triazolyl (such as 1,2,3-triazolyl and 1,2,4-triazolyl), tetrazolyl, etc.; most preferably 5-membered nitrogen-containing heteroaryl, such as Pyrazolyl, imidazolyl, 1,2,3-triazolyl and tetrazolyl.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent Residues derived from atoms are "cycloalkylene", “heterocyclylene”, “arylene”, “heteroarylene”.
  • amino protecting group refers to a group introduced on an amino group that is easily removed in order to keep the amino group unchanged when other parts of the molecule are reacted.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, p-toluenesulfonyl (Ts), benzyl, allyl, p-methoxybenzyl, tert-butyldimethylsilyl (TBS), etc.
  • These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • hydroxyl protecting group refers to an easily removed group introduced on a hydroxy group, which is usually used to block or protect the hydroxy group while reacting on other functional groups of the compound.
  • Non-limiting examples include: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, tert-butyl, C 1-6 alkoxy C 1-6 alkyl substituted with phenyl or C 1-6 alkyl substituted by phenyl (such as methoxymethyl (MOM) and ethoxyethyl, etc.), (C 1-10 alkyl or aryl) Acyl (such as: formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.), (C 1-6 alkyl or 6- to 10-membered aryl) sulfonyl, (C 1-6 alkoxy or 6- to 10-membered
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein 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 hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol 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-, wherein alkyl and cycloalkyl are as defined above.
  • stereoisomer refers to isomers that are structurally identical but differ in the arrangement of the 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, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in the compounds of the present disclosure may have additional asymmetric atoms.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (D)- and (+)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques (L)-isomer.
  • An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, when the molecule contains basic functional groups (such as amino groups) or acidic functional groups (such as carboxyl groups), with appropriate optical Active acids or bases form diastereomeric salts, which are then resolved by conventional methods known in the art to yield the pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both 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, ie as a single isomer or as a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. An example of a 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 having the same atomic number but a different atomic mass.
  • isotopes that can be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, 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.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All transformations of 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 attached to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and a partial replacement of 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 be at least 1000 times more abundant (i.e., deuterium) than the natural abundance of deuterium, which is 0.015%. 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 (i.e., 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).
  • C 1-6 alkyl optionally (optionally) substituted by halogen or cyano means that halogen or cyano may, but need not, be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the alkane The case where the group is not substituted by halogen and 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, independently of one another, are substituted by the corresponding number of substituents.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, in admixture with other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have due biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, 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.
  • the term "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, depending on the age and general condition of the subject, and also on the specific active substance.
  • the appropriate therapeutically effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
  • the preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • the compound represented by the general formula (IA) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (I).
  • the preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • the compound represented by the general formula (IIA) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (II).
  • the preparation method of the compound represented by the general formula (II-1) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • the compound represented by the general formula (II-1A) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (II-1).
  • the preparation method of the compound represented by the general formula (II-2) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • the compound represented by the general formula (II-2A) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (II-2).
  • the preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (III).
  • the preparation method of the compound represented by the general formula (III-1) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (III-1).
  • the preparation method of the compound represented by the general formula (III-2) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (III-2).
  • the preparation method of the compound represented by the general formula (IV) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • the compound represented by the general formula (IVA) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Rings A, R 1 to R 3 , m, n and t are as defined in general formula (IV).
  • the preparation method of the compound represented by the general formula (IV-1) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • the compound represented by the general formula (IV-1A) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, R 1 to R 3 , m, n and t are as defined in the general formula (IV-1).
  • the preparation method of the compound represented by the general formula (IV-2) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, R 1 to R 3 , m, n and t are as defined in general formula (IV-2).
  • the preparation method of the compound represented by the general formula (V) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • the compound represented by the general formula (VA) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Rings A, R 1 to R 3 , m, n and t are as defined in general formula (V).
  • the preparation method of the compound represented by the general formula (V-1) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, R 1 to R 3 , m, n and t are as defined in the general formula (V-1).
  • the preparation method of the compound represented by the general formula (V-2) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
  • Ring A, R 1 to R 3 , m, n and t are as defined in general formula (V-2).
  • the acid in the acidic condition includes organic acid and inorganic acid
  • the organic acid includes but is not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me 3 SiCl and TMSOTf, preferably trifluoroacetic acid
  • the inorganic acids include but are not limited to hydrogen chloride, hydrogen chloride solution in 1,4-dioxane, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, preferably hydrochloric acid.
  • the above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane Alkane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide and mixtures thereof.
  • the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane Alkane, dimethyl sulfoxide, 1,4-
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • Mass spectrometry was measured with Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC (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
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and Adjust with alkaline or acidic reagents such as acetic acid.
  • TLC thin layer chromatography
  • HPLC analysis retention time 1.45 minutes, purity: 96% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.47 minutes, purity: 97% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • Dichlorotriphenylphosphine 120 mg, 360.15 ⁇ mol was dissolved in 3 mL of trichloromethane, triethylamine (91 mg, 820 ⁇ mol) was added at 0°C, 2c (75 mg, 272.28 ⁇ mol) was added after stirring for 5 minutes, and the stirring was continued for ten minutes Then, 1d (80 mg, 180.82 ⁇ mol) was added, and the reaction was naturally raised to room temperature and stirred for 2 hours.
  • reaction solution was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL ⁇ 3), the organic phase was concentrated under reduced pressure and then subjected to high performance liquid chromatography (chromatographic column: SharpSil-T, 30*150 mm, 5 ⁇ m; mobile phase: Aqueous phase (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: aqueous phase 25%-42%) was purified to give the title compounds 2-P1 (5 mg, yield: 11.9%) and 2-P2 (20 mg, yield: 47.8 %).
  • HPLC analysis retention time 2.68 minutes, purity: 99% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 2.74 minutes, purity: 99% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • Dichlorotriphenylphosphine (57 mg, 717.0 ⁇ mol) was dissolved in 3 mL of trichloromethane, triethylamine (60 mg, 592.9 mmol) was added at 0°C, 3f (40 mg, 132.6 ⁇ mol) was added after stirring for 5 minutes, and the stirring was continued. Ten minutes later, 1d (150 mg, 113.0 ⁇ mol) was added, and the mixture was naturally raised to room temperature and stirred for 16 hours.
  • HPLC analysis retention time 1.40 minutes, purity: 99% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.43 minutes, purity: 99% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.48 minutes, purity: 99% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.51 minutes, purity: 99% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.82 minutes, purity: 98% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.84 minutes, purity: 98% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.40 minutes, purity: 90% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.42 minutes, purity: 99% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.42 minutes, purity: 97% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.45 minutes, purity: 99% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • the reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride solution and saturated sodium chloride solution in turn, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title
  • the product 8c (1.2 g, yield: 33%) was directly used in the next step without purification.
  • HPLC analysis retention time 1.54 minutes, purity: 98.5% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.56 minutes, purity: 98.9% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 3.11 minutes, purity: 96% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 3.16 minutes, purity: 97% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.45 minutes, purity: 99% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.47 minutes, purity: 97% (column: ACQUITY C18, 1.7 ⁇ m, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • Test Example 1 GR receptor reporter gene assay
  • MDA-kb2 cells (ATCC, CRL-2713) were cultured in complete medium (ie Leibovitz's L-15 medium (Gibco, 11415114) containing 10% fetal bovine serum (Gibco, 10099-141)).
  • complete medium ie Leibovitz's L-15 medium (Gibco, 11415114) containing 10% fetal bovine serum (Gibco, 10099-141).
  • MDA-kb2 cells were cultured at 30,000 cells/cell using an incomplete medium, namely Leibovitz's L-15 medium (Gibco, 11415114) containing 5% charcoal-treated serum (Biosun, S-FBS-AU-045).
  • the density of the wells was seeded in a 96-well plate, with 80 ⁇ L of cell suspension per well, and the plate was placed at 37°C in a CO2 -free cell incubator overnight. The next day, 10 ⁇ L of the compound to be tested in a serial dilution prepared in incomplete medium was added to each well, and the final concentration of the compound was 8 concentration points of 5-fold serial dilution starting from 10 ⁇ M, and the final concentration of DMSO was 0.5% DMSO. Continue to add 10 ⁇ L of dexamethasone (MCE, HY-14648) in incomplete medium to each well at a final concentration of 10 nM.
  • MCE dexamethasone
  • the disclosed compounds have good inhibitory activity on GR receptor transcription in MDA-kb2 cells.
  • This experiment uses GR Receptor Competitive Binding Assay Kit (Invitrogen, A15901).
  • the Nuclear Receptor Buffer F Invitrogen, PV4547
  • GR Stabilizing Peptide (10 ⁇ ) Invitrogen, P2815
  • DTT Invitrogen, P2325) in the kit were mixed into an experimental buffer in a ratio of 179:20:1.
  • the compounds to be tested were diluted with DMSO, and the first concentration was 1 mM for 4-fold serial dilution, with a total of 9 concentration points.
  • the compound DMSO solution was then diluted with experimental buffer, and 10 ⁇ L of compound dilution was added to each well of a black 384-well plate (Corning, 4514).
  • the buffer well containing 1% DMSO was set as a negative control, and the well added with a final concentration of 20 ⁇ M dexamethasone (MCE, HY-14648) was set as a positive control.
  • Fluormone TM GS1 Green (Invitrogen, PV6044) was prepared in buffer to a final concentration of 5 nM and added to a 384-well plate at 5 ⁇ L per well.
  • GR-LBD (Invitrogen, A15668) was prepared in buffer and A mixture of Tb-anti-GST antibody (Invitrogen, PV3550), the final concentration of Tb anti-GST antibody was 2nM, and the final concentration of GR-LBD (GST) was as indicated in the instructions of each batch, and the mixture was 5 ⁇ L per well. Add to 384-well plate. After the well plate was placed at room temperature for 2 hours, the fluorescence values of excitation light wavelength of 340 nm and emission light wavelength of 520 nm and 490 nm were read with a PHERAstar microplate reader (BMG LABTECH).
  • the ratio of the fluorescence values at 520 nm and 490 nm was used to calculate the inhibition rate. According to each concentration of the compound and the corresponding inhibition rate, the IC 50 value of the compound's competitive binding activity with the GR receptor was calculated by GraphPad Prism software.
  • the compounds of the present disclosure have good inhibitory activity for competitive binding with GR receptor.
  • MDA-MB-231 cells (ATCC, HTB-26) were cultured in complete medium (ie Leibovitz's L-15 medium (ThermoFisher, 11415-114) containing 10% fetal bovine serum (Gibco, 10099-141)). On the first day of the experiment, MDA-MB-231 cells were seeded at a density of 1000 cells/well using Leibovitz's L-15 incomplete medium containing 10% activated charcoal-treated fetal bovine serum (BioSun, S-FBS-AU-045).
  • the inhibition rate was calculated using the luminescence values of each concentration of the compound and the negative and positive control wells. According to each concentration of the compound and the corresponding inhibition rate, the IC 50 value of the compound to inhibit the proliferation of MDA-MB-231 cells was calculated by GraphPad Prism software.
  • Test Example 4 Enzymatic activity of the compounds of the present disclosure on the CYP3A4 midazolam metabolic site in human liver microsomes inhibition
  • the enzymatic activity of the compounds of the present disclosure on the CYP3A4 midazolam metabolic site in human liver microsomes was determined by the following experimental method.
  • CYP probe substrate (midazolam, TRC, M343000/3 ⁇ M)
  • Example 1-P1 of the present disclosure has a weak inhibitory effect on the midazolam metabolic site of CYP3A4 in human liver microsomes, and the risk of metabolic drug interactions based on the CYP3A4 metabolism of the midazolam metabolic site is less, and the risk of metabolic drug interactions is relatively low.
  • the positive control compound Relacorilant showed better safety profile.
  • Test Example 5 Inhibition of the enzymatic activity of the CYP3A4 testosterone metabolic site of human liver microsomes by the compounds of the present disclosure effect
  • the enzymatic activity of the compounds of the present disclosure on the CYP3A4 testosterone metabolic site in human liver microsomes was determined by the following experimental method.
  • CYP probe substrate testosterone, Wokai, CAS No.[58-22-0]/75 ⁇ M
  • Example 1-P1 of the present disclosure has weak inhibition on the testosterone metabolic site of human liver microsomes CYP3A4, and shows better safety than the positive control compound Relacorilant.
  • Test Example 6 Enzymatic Activity of Compounds of the Present Disclosure on CYP2C9 Diclofenac Metabolic Site in Human Liver Microsomes inhibition
  • the enzymatic activity of the compounds of the present disclosure on the metabolic site of CYP2C9 diclofenac in human liver microsomes was determined by the following experimental method.
  • CYP probe substrate (diclofenac, SIGMA, Cat No.D6899-10G/4 ⁇ M)
  • Example 1-P1 of the present disclosure does not have a metabolic drug interaction based on the CYP2C9 diclofenac metabolic site in the concentration range of 30 ⁇ M, and shows better safety than the positive control compound Relacorilant.
  • Test Example 7 Enzymatic Activity of the Compounds of the Present Disclosure on CYP2C19(S)-Mephenytoin Metabolic Site in Human Liver Microsomes sexual inhibition
  • the enzymatic activity of the compounds of the present disclosure on the CYP2C19(S)-mephenytoin metabolic site of human liver microsomes was determined by the following experimental method.
  • CYP probe substrate ((S)-Mephenytoin/20 ⁇ M, powder purchased from Bailingwei Technology Co., Ltd., Cat No.303768)
  • the series of solutions I were diluted 200 times to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 ⁇ M).
  • (S)-Mephentoin working solution diluted with PBS to a concentration of 100 ⁇ M.
  • Example 1-P1 of the present disclosure will not have metabolic drug interactions based on the CYP2C19(S)-mephenytoin metabolic site in the concentration range of 30 ⁇ M, and it has better safety than the positive control compound Relacorilant .
  • Test Example 8 Enzymatic activity of the compounds of the present disclosure on the CYP1A2 phenacetin metabolic site in human liver microsomes inhibition
  • the enzymatic activity of the compounds of the present disclosure on the CYP1A2 phenacetin metabolic site in human liver microsomes was determined by the following experimental method.
  • CYP probe substrate phenacetin/12 ⁇ M, China Institute for the Control of Pharmaceutical and Biological Products, Cat No.100095-200204
  • the series of solutions I were diluted 200 times to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 ⁇ M). Dilute with PBS to a working solution of phenacetin at a concentration of 60 ⁇ M.
  • Example 1-P1 of the present disclosure does not have a metabolic drug interaction based on the CYP1A2 phenacetin metabolic site in the concentration range of 30 ⁇ M.
  • Test Example 9 Enzyme activity of the compounds of the present disclosure on the metabolic site of CYP2D6 dextromethorphan in human liver microsomes inhibition
  • the enzymatic activity of the compounds of the present disclosure on the CYP2D6 dextromethorphan metabolic site of human liver microsomes was determined by the following experimental method.
  • CYP probe substrate (dextromethorphan/4 ⁇ M, Sigma, Cat No.D9684-5G)
  • the series of solutions I were diluted 200 times to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 ⁇ M).
  • Dextromethorphan working solution diluted with PBS to a concentration of 20 ⁇ M.
  • Example 1-P1 of the present disclosure does not have a metabolic drug interaction based on the CYP2D6 dextromethorphan metabolic site within the concentration range of 30 ⁇ M, and shows better safety than the positive control compound Relacorilant.
  • nude mice Taking nude mice as test animals, the drug concentration in plasma at different times after oral administration of the test compounds to nude mice was determined by LC/MS/MS method. The pharmacokinetic behavior of the disclosed compounds in nude mice was studied, and their pharmacokinetic characteristics were evaluated.
  • Example 1 P1 compound, Relacorilant.
  • mice were fasted overnight and then intragastrically administered.
  • the doses were 10 mg/kg and 30 mg/kg, respectively, and the administration volume was 0.2 mL/10 g.
  • Nude mice were administered the test compound by gavage, and 0.1 mL of blood was collected before and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, and placed in an EDTA-K2 anticoagulation test tube, 10000 Centrifuge at rpm for 1 minute (4°C), separate plasma within 1 hour, and store at -20°C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions.
  • Determination of the content of the test compound in the plasma of nude mice after oral administration of different concentrations of drugs take 20 ⁇ L of nude mouse plasma at each time after administration, add 50 ⁇ L of internal standard solution (camptothecin 100 ng/mL), 200 ⁇ L of acetonitrile, and vortex. Spin and mix for 5 minutes, centrifuge for 10 minutes (3700 rpm), and take 1 ⁇ L of the supernatant from plasma samples for LC/MS/MS analysis.
  • internal standard solution camptothecin 100 ng/mL
  • acetonitrile 200 ⁇ L
  • vortex Spin and mix for 5 minutes, centrifuge for 10 minutes (3700 rpm), and take 1 ⁇ L of the supernatant from plasma samples for LC/MS/MS analysis.
  • Example 1-P1 of the present disclosure have good pharmacokinetic absorption, and have obvious pharmacokinetic advantages over the positive control compound Relacorilant.

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Abstract

The present disclosure relates to a fused azatricyclic derivative, a preparation method therefor, and an application thereof in medicine. In particular, the present disclosure relates to a fused azatricyclic derivative represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing said derivative, and a use thereof as a therapeutic agent, in particular a use as a GR modulator and a use in the preparation of a drug for the treatment and/or prevention of tumors.

Description

稠合的氮杂三环类衍生物、其制备方法及其在医药上的应用Condensed azatricyclic derivatives, their preparation method and their application in medicine 技术领域technical field
本公开属于医药领域，涉及一种稠合的氮杂三环类衍生物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的稠合的氮杂三环类衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为GR调节剂的用途和在制备用于治疗和/或预防肿瘤的药物中的用途。The present disclosure belongs to the field of medicine, and relates to a fused azatricyclic derivative, a preparation method thereof and its application in medicine. In particular, the present disclosure relates to the fused azatricyclic derivatives represented by the general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, as well as their use as a GR regulator and in the preparation of Use in medicines for the treatment and/or prevention of tumors.
背景技术Background technique
糖皮质激素受体(Glucocorticoid Receptor，简称GR)是细胞核受体家族的成员，与盐皮质激素受体(MR)、孕激素受体(PR)、雄激素受体(AR)、雌激素受体(ER)一起，属于细胞核受体家族中的类固醇激素受体一类。糖皮质激素通过激活GR来调控基因表达，调节多种细胞功能，如代谢、炎症、细胞生长和分化等。在生理上，糖皮质激素调节人类的糖代谢、蛋白质代谢和脂类代谢。病理因素导致的糖皮质激素过高会导致代谢紊乱，发育迟缓等，临床上称为库欣综合征(Cushing Syndrome，简称CS)；而因病理创伤或其他因素引起的糖皮质激素水平过低，则会导致阿狄森病，主要表现为焦虑、疲劳、肌肉关节疼痛和抑郁，有的病人会表现为严重抑郁。The Glucocorticoid Receptor (GR) is a member of the nuclear receptor family, and is associated with the mineralocorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR), and estrogen receptor. (ER) together, belong to the class of steroid hormone receptors in the nuclear receptor family. Glucocorticoids regulate gene expression by activating GR, and regulate a variety of cellular functions, such as metabolism, inflammation, cell growth and differentiation. Physiologically, glucocorticoids regulate glucose, protein, and lipid metabolism in humans. Excessive glucocorticoid levels caused by pathological factors can lead to metabolic disorders, developmental delay, etc., which is clinically called Cushing Syndrome (CS); and low glucocorticoid levels caused by pathological trauma or other factors, It will lead to Addison's disease, mainly manifested as anxiety, fatigue, muscle and joint pain and depression, and some patients will show severe depression.
由于对免疫反应的有效抑制作用，GR受体激动剂如类固醇类糖皮质激素在临床上被广泛用于自身免疫类疾病或者过敏的治疗。在免疫细胞恶性增殖的血液肿瘤中，类固醇类糖皮质激素也是组合疗法之一。Due to their effective inhibitory effects on immune responses, GR receptor agonists such as steroid glucocorticoids are widely used in the clinical treatment of autoimmune diseases or allergies. In hematological tumors with malignant proliferation of immune cells, steroid glucocorticoids are also one of the combination therapy.
在实体瘤的治疗中，类固醇类糖皮质激素被批准治疗作为辅助治疗以减轻病人过敏，呕吐等症状，增强对化疗或者靶向治疗的耐受。但近几年来，越来越多的临床及学术研究表明，GR信号通路激活与多种实体瘤的进展、转移、耐药以及预后不良直接相关。In the treatment of solid tumors, steroids and glucocorticoids are approved as adjuvant therapy to relieve symptoms of allergies, vomiting, and enhance tolerance to chemotherapy or targeted therapy. However, in recent years, more and more clinical and academic studies have shown that the activation of GR signaling pathway is directly related to the progression, metastasis, drug resistance and poor prognosis of various solid tumors.
在去势抵抗性前列腺癌(castration-resistant prostate cancer，简称CRPC)中，GR信号通路活化与恩杂鲁胺耐药直接相关。患者使用恩杂鲁胺后(>8周)，肿瘤组织内GR水平上调，并且对恩杂鲁胺响应较差。GR和AR在前列腺癌细胞中可共同调节一系列与前列腺癌进展相关基因，GR通路激活是前列腺癌细胞对AR抑制形成代偿作用。在体内药效模型上，GR基因敲除或者GR拮抗剂均可显著抑制体内肿瘤模型生长。In castration-resistant prostate cancer (CRPC), activation of the GR signaling pathway is directly associated with enzalutamide resistance. After patients were treated with enzalutamide (>8 weeks), the level of GR in tumor tissue was up-regulated, and the response to enzalutamide was poor. GR and AR can co-regulate a series of genes related to prostate cancer progression in prostate cancer cells, and GR pathway activation is a compensatory effect of prostate cancer cells on AR inhibition. In the in vivo pharmacodynamic model, GR gene knockout or GR antagonist can significantly inhibit the growth of tumor models in vivo.
在三阴性乳腺癌(triple negative breast cancer，简称TNBC)患者中，GR的表达水平和TNBC以及卵巢癌中生存率不佳有统计学显著相关性。GR信号通路活化与癌细胞转移以及对紫杉醇耐药相关。而以紫杉醇为主的化疗目前是治疗TNBC的主要手段。研究发现GR激动剂地塞米松介导的GR活化，导致了与化疗耐受以 及肿瘤转移相关基因高表达，进而促进化疗耐受，以及TNBC肿瘤细胞的转移。使用GR拮抗剂可以增强化疗的敏感性，减少转移。In triple negative breast cancer (TNBC) patients, the expression level of GR was statistically significantly associated with poor survival in TNBC and ovarian cancer. Activation of GR signaling pathway is associated with cancer cell metastasis and resistance to paclitaxel. Paclitaxel-based chemotherapy is currently the main method for the treatment of TNBC. The study found that the GR activation mediated by the GR agonist dexamethasone leads to the high expression of genes related to chemotherapy resistance and tumor metastasis, which in turn promotes chemotherapy resistance and metastasis of TNBC tumor cells. The use of GR antagonists can enhance chemosensitivity and reduce metastasis.
因此，靶向GR，用拮抗手段干扰其信号转导是一个新的肿瘤治疗手段。尤其在前列腺癌和乳腺癌中，其作用机制已被大量文献数据有效证实。Therefore, targeting GR and interfering its signal transduction with antagonistic means is a new tumor treatment method. Especially in prostate cancer and breast cancer, its mechanism of action has been effectively confirmed by a large number of literature data.
现已公开GR调节剂的专利申请包括WO2005087769A1、WO2012027702A1、WO2013177559A2和WO2015077530A1等。Patent applications that have disclosed GR modulators include WO2005087769A1, WO2012027702A1, WO2013177559A2, and WO2015077530A1, among others.
发明内容SUMMARY 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 of general formula (I) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074588-appb-000001
Figure PCTCN2022074588-appb-000001
其中：in:
Figure PCTCN2022074588-appb-000002
为不存在或化学键；
Figure PCTCN2022074588-appb-000002
for absence or chemical bond;
环A选自杂环基、芳基和杂芳基；Ring A is selected from heterocyclyl, aryl and heteroaryl;
各个R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、氧代基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、-NR 4R 5、羟基、-C(O)R 6、-C(O)OR 6、-C(O)NR 4R 5、-S(O) pR 6、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR 7R 8、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； Each R 1 is the same or different, and is independently selected from a hydrogen atom, halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 4 R 5 , hydroxy , -C(O)R 6 , -C(O)OR 6 , -C(O)NR 4 R 5 , -S(O) p R 6 , cycloalkyl, heterocyclyl, aryl and heteroaryl , wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, Substituted with one or more substituents of cyano, -NR 7 R 8 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
或者，两个相邻的R 1与环A稠合形成杂环基，其中所述的杂环基任选地被选自卤素、烷基、氧代基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR 7R 8、硝基、羟基和羟烷基中的一个或多个取代基所取代； Alternatively, two adjacent R1's are fused to ring A to form a heterocyclyl group, wherein said heterocyclyl group is optionally selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy substituted with one or more substituents in group, cyano group, -NR 7 R 8 , nitro group, hydroxy group and hydroxyalkyl group;
环B为芳基或杂芳基；Ring B is aryl or heteroaryl;
各个R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、-NR 4R 5、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR 7R 8、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； Each R 2 is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 4 R 5 , hydroxy, cycloalkyl , heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, One or more substitutions of alkoxy, haloalkyl, haloalkoxy , cyano, -NR7R8 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl base substituted;
环C为芳基或杂芳基；Ring C is aryl or heteroaryl;
各个R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代 烷基、卤代烷氧基、羟烷基、氰基、-NR 4R 5和羟基； each R 3 is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 4 R 5 and hydroxy;
R 6在每次出现时相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代； R 6 is the same or different at each occurrence, and is each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein said alkyl, cycloalkyl, and heterocyclyl groups are each independently optionally substituted with one or more substituents selected from halo, alkyl, alkoxy, haloalkyl, and haloalkoxy;
R 4、R 5、R 7和R 8相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代； R 4 , R 5 , R 7 and R 8 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group, wherein said alkyl group, cycloalkyl group and The heterocyclyl groups are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy;
或者R 4和R 5与相连的氮原子一起形成杂环基，所述杂环基任选被选自卤素、烷基、氧代基、烷氧基、卤代烷基、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 R4 and R5 together with the attached nitrogen atom form a heterocyclyl group optionally selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, Substituted with one or more substituents of amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
或者R 7和R 8与相连的氮原子一起形成杂环基，所述杂环基任选被选自卤素、烷基、氧代基、烷氧基、卤代烷基、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 R7 and R8 together with the attached nitrogen atom form a heterocyclyl group optionally selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, Substituted with one or more substituents of amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
p为0、1或2；p is 0, 1 or 2;
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
n为0、1、2、3或4；且n is 0, 1, 2, 3, or 4; and
t为0、1、2、3或4。t is 0, 1, 2, 3 or 4.
在本公开一些实施方案中，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 the general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074588-appb-000003
Figure PCTCN2022074588-appb-000003
其中：in:
环A、环B、环C、R 1至R 3、m、n和t如通式(I)中所定义。 Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (I).
在本公开一些实施方案中，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(II-1)或通式(II-2)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is the general formula (II-1) or the general formula (II-2) ) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074588-appb-000004
Figure PCTCN2022074588-appb-000004
其中：in:
环A、环B、环C、R 1至R 3、m、n和t如通式(I)中所定义。 Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t 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)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 the general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074588-appb-000005
Figure PCTCN2022074588-appb-000005
其中：in:
环A、环B、环C、R 1至R 3、m、n和t如通式(I)中所定义。 Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t 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(III)所示的化合物或其可药用的盐，其为通式(III-1)或通式(III-2)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (III) or a pharmaceutically acceptable salt thereof is the general formula (III-1) or the general formula (III- 2) The compound shown or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074588-appb-000006
Figure PCTCN2022074588-appb-000006
其中：in:
环A、环B、环C、R 1至R 3、m、n和t如通式(I)中所定义。 Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t 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)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)或通式(III-2)所示的化合物或其可药用的盐，其中环B为6至10元芳基或5至10元杂芳基；优选地，环B为吡啶基。In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III) -1) or a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein ring B is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, ring B is a pyridyl group .
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)或通式(III-2)所示的化合物或其可药用的盐，其中环C为6至10元芳基或5至10元杂芳基；优选地，环C为苯基。In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III) -1) or a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein ring C is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, ring C is a phenyl group .
在本公开一些实施方案中，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(IV)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof of salt:
Figure PCTCN2022074588-appb-000007
Figure PCTCN2022074588-appb-000007
其中：in:
环A、R 1至R 3、m、n和t如通式(I)中所定义。 Rings A, R 1 to R 3 , m, n and t are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)或通式(IV)所示的化合物或其可药用的盐，其为通式(IV-1)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), general formula (II), general formula (II-1) or general formula (IV) or a pharmaceutically acceptable salt thereof is The compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074588-appb-000008
Figure PCTCN2022074588-appb-000008
其中：in:
环A、R 1至R 3、m、n和t如通式(I)中所定义。 Rings A, R 1 to R 3 , m, n and t are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-2)或通式(IV)所示的化合物或其可药用的盐，其为通式(IV-2)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), general formula (II), general formula (II-2) or general formula (IV) or a pharmaceutically acceptable salt thereof is The compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074588-appb-000009
Figure PCTCN2022074588-appb-000009
其中：in:
环A、R 1至R 3、m、n和t如通式(I)中所定义。 Rings A, R 1 to R 3 , m, n and t are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(I)或通式(III)所示的化合物或其可药用的盐，其为通式(V)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (III) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof of salt:
Figure PCTCN2022074588-appb-000010
Figure PCTCN2022074588-appb-000010
其中：in:
环A、R 1至R 3、m、n和t如通式(I)中所定义。 Rings A, R 1 to R 3 , m, n and t are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(I)、通式(III)、通式(III-1)或通式(V)所示的化合物或其可药用的盐，其为通式(V-1)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), general formula (III), general formula (III-1) or general formula (V) or a pharmaceutically acceptable salt thereof is The compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074588-appb-000011
Figure PCTCN2022074588-appb-000011
其中：in:
环A、R 1至R 3、m、n和t如通式(I)中所定义。 Rings A, R 1 to R 3 , m, n and t are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(I)、通式(III)、通式(III-2)或通式(V)所示的化合物或其可药用的盐，其为通式(V-2)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), general formula (III), general formula (III-2) or general formula (V) or a pharmaceutically acceptable salt thereof is The compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074588-appb-000012
Figure PCTCN2022074588-appb-000012
其中：in:
环A、R 1至R 3、m、n和t如通式(I)中所定义。 Rings A, R 1 to R 3 , m, n and t are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中环A选自3至12元杂环基、6至10元芳基和5至10元杂芳基；优选地，环A为5或6元杂芳基；进一步优选地，环A为5元含氮杂芳基；更优选地，环A选自吡唑基、咪唑基、1,2,3-三唑基和四唑基；最优选地，环A为1,2,3-三唑基。In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III- 1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula ( The compound represented by V-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 3- to 12-membered heterocyclic group, 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group; preferably, ring A is 5- or 6-membered heteroaryl; further preferably, ring A is a 5-membered nitrogen-containing heteroaryl; more preferably, ring A is selected from pyrazolyl, imidazolyl, 1,2,3-triazolyl and tetrazole group; most preferably, Ring A is 1,2,3-triazolyl.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中环A选自吡唑基、咪唑基和1,2,3-三唑基。In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III- 1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula ( The compound represented by V-2) or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyrazolyl, imidazolyl and 1,2,3-triazolyl.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、3至12元环烷基和3至12元杂环基，其中所述的3至12元环烷基和3至12元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、羟基和C 1-6羟烷基中的一个或多个取代基所取代；优选地，各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、3至6元环烷基和3至6元杂环基，其中所述的3至6元环烷基和3至6元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基中的一个或多个取代基所取代；更优选地，各个R 1相同或不同，且各自独立地选自C 1-6烷基、C 1-6卤代烷基和3至6元环烷基。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III- 1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula ( The compound represented by V-2) or a pharmaceutically acceptable salt thereof, wherein each R 1 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclyl, wherein said 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclyl each independently optionally selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, cyano, hydroxy, and C1-6 hydroxy One or more substituents in the alkyl group are substituted; preferably, each R 1 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, 3 to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl, wherein said 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally selected from halogen, C 1-6 alkyl, substituted by one or more substituents among C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; more preferably, each R 1 is the same or different, and each is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and 3- to 6-membered cycloalkyl.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基和C 1-6卤代烷氧基；优选地，R 1为氢原子或C 1-6烷基。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III- 1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula ( The compound represented by V-2) or a pharmaceutically acceptable salt thereof, wherein each R 1 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; preferably, R 1 is a hydrogen atom or a C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中两个相邻的R 1与环A稠合形成3至8元杂环基，其中所述的3至8元杂环基任选地被选自卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基中的一个或多个取代基所取代；优选地，两个相邻的R 1与环A稠合形成5或6元杂环基，其中所述的5或6元杂环基任选地被选自卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基中的一个或多个取代基所取代；更优选地，两个相邻的R 1与环A稠合形成5或6元杂环基。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III- 1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula ( The compound shown in V-2) or a pharmaceutically acceptable salt thereof, wherein two adjacent R 1 are fused with ring A to form a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is any optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy ; Preferably, two adjacent R 1 are fused with ring A to form a 5- or 6-membered heterocyclic group, wherein the 5 or 6-membered heterocyclic group is optionally selected from halogen, C 1-6 alkyl , oxo, C 1-6 alkoxy, C 1-6 haloalkyl and one or more substituents in C 1-6 haloalkoxy; more preferably, two adjacent R 1 and Ring A is fused to form a 5 or 6 membered heterocyclyl.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、3至12元环烷基和3至12元杂环基，其中所述的3至12元环烷基和3至12元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6 卤代烷基、C 1-6卤代烷氧基、氰基、羟基和C 1-6羟烷基中的一个或多个取代基所取代；或者两个相邻的R 1与环A稠合形成3至8元杂环基，其中所述的3至8元杂环基任选地被选自卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基中的一个或多个取代基所取代。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III- 1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula ( The compound represented by V-2) or a pharmaceutically acceptable salt thereof, wherein each R 1 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclyl, wherein said 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclyl each independently optionally selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, cyano, hydroxy, and C1-6 hydroxy substituted by one or more substituents in the alkyl group; or two adjacent R 1 are fused with ring A to form a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is optionally Substituted with one or more substituents selected from halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中各个R 1相同或不同，且各自独立地选自C 1-6烷基、C 1-6卤代烷基和3至6元环烷基；或者两个相邻的R 1与环A稠合形成5或6元杂环基。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III- 1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula ( The compound represented by V-2) or a pharmaceutically acceptable salt thereof, wherein each R 1 is the same or different, and each is independently selected from C 1-6 alkyl, C 1-6 haloalkyl and 3- to 6-membered cycloalkane group; or two adjacent R 1 are fused with ring A to form a 5- or 6-membered heterocyclic group.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)或通式(V)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000013
选自
Figure PCTCN2022074588-appb-000014
Figure PCTCN2022074588-appb-000015
其中R 0选自氢原子、卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-NR 7R 8、硝基、羟基和C 1-6羟烷基，s为0、1、2、3或4，R 1、R 7和R 8如通式(I)中所定义；优选地，
Figure PCTCN2022074588-appb-000016
选自
Figure PCTCN2022074588-appb-000017
Figure PCTCN2022074588-appb-000018
更优选地，
Figure PCTCN2022074588-appb-000019
为
Figure PCTCN2022074588-appb-000020
In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) or general formula (V) or its pharmaceutically acceptable salt, of which
Figure PCTCN2022074588-appb-000013
selected
Figure PCTCN2022074588-appb-000014
Figure PCTCN2022074588-appb-000015
wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -NR 7 R 8 , nitro, hydroxy and C 1-6 hydroxyalkyl, s is 0, 1, 2, 3 or 4, R 1 , R 7 and R 8 are as defined in general formula (I); preferably,
Figure PCTCN2022074588-appb-000016
selected
Figure PCTCN2022074588-appb-000017
Figure PCTCN2022074588-appb-000018
More preferably,
Figure PCTCN2022074588-appb-000019
for
Figure PCTCN2022074588-appb-000020
在本公开一些实施方案中，所述的通式(II-1)、通式(III-1)、通式(IV-1)或通式(V-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000021
选自
Figure PCTCN2022074588-appb-000022
Figure PCTCN2022074588-appb-000023
其中R 0选自氢原子、卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-NR 7R 8、硝基、羟基和C 1-6羟烷基，s为0、1、2、3或4，R 1、R 7和R 8如通式(I) 中所定义；优选地，
Figure PCTCN2022074588-appb-000024
选自
Figure PCTCN2022074588-appb-000025
Figure PCTCN2022074588-appb-000026
更优选地，
Figure PCTCN2022074588-appb-000027
为
Figure PCTCN2022074588-appb-000028
In some embodiments of the present disclosure, the compound represented by the general formula (II-1), the general formula (III-1), the general formula (IV-1) or the general formula (V-1) or its pharmaceutically acceptable salt used, of which
Figure PCTCN2022074588-appb-000021
selected
Figure PCTCN2022074588-appb-000022
Figure PCTCN2022074588-appb-000023
wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -NR 7 R 8 , nitro, hydroxy and C 1-6 hydroxyalkyl, s is 0, 1, 2, 3 or 4, R 1 , R 7 and R 8 are as defined in general formula (I); preferably,
Figure PCTCN2022074588-appb-000024
selected from
Figure PCTCN2022074588-appb-000025
Figure PCTCN2022074588-appb-000026
More preferably,
Figure PCTCN2022074588-appb-000027
for
Figure PCTCN2022074588-appb-000028
在本公开一些实施方案中，所述的通式(II-2)、通式(III-2)、通式(IV-2)或通式(V-2)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000029
选自
Figure PCTCN2022074588-appb-000030
Figure PCTCN2022074588-appb-000031
其中R 0选自氢原子、卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-NR 7R 8、硝基、羟基和C 1-6羟烷基，s为0、1、2、3或4，R 1、R 7和R 8如通式(I)中所定义；优选地，
Figure PCTCN2022074588-appb-000032
选自
Figure PCTCN2022074588-appb-000033
Figure PCTCN2022074588-appb-000034
更优选地，
Figure PCTCN2022074588-appb-000035
为
Figure PCTCN2022074588-appb-000036
In some embodiments of the present disclosure, the compound represented by the general formula (II-2), the general formula (III-2), the general formula (IV-2) or the general formula (V-2) or its pharmaceutically acceptable salt used, of which
Figure PCTCN2022074588-appb-000029
selected from
Figure PCTCN2022074588-appb-000030
Figure PCTCN2022074588-appb-000031
wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -NR 7 R 8 , nitro, hydroxy and C 1-6 hydroxyalkyl, s is 0, 1, 2, 3 or 4, R 1 , R 7 and R 8 are as defined in general formula (I); preferably,
Figure PCTCN2022074588-appb-000032
selected from
Figure PCTCN2022074588-appb-000033
Figure PCTCN2022074588-appb-000034
More preferably,
Figure PCTCN2022074588-appb-000035
for
Figure PCTCN2022074588-appb-000036
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)或通式(V)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000037
选自
Figure PCTCN2022074588-appb-000038
Figure PCTCN2022074588-appb-000039
其中R 0选自氢原子、卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-NR 7R 8、硝基、羟基和C 1-6羟烷基，s为0、1、2、3或4，R 1、R 7和R 8如通式(I)中所定义；优选地，
Figure PCTCN2022074588-appb-000040
选自
Figure PCTCN2022074588-appb-000041
更优选地，
Figure PCTCN2022074588-appb-000042
为
Figure PCTCN2022074588-appb-000043
In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) or general formula (V) or its pharmaceutically acceptable salt, of which
Figure PCTCN2022074588-appb-000037
selected from
Figure PCTCN2022074588-appb-000038
Figure PCTCN2022074588-appb-000039
wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -NR 7 R 8 , nitro, hydroxy and C 1-6 hydroxyalkyl, s is 0, 1, 2, 3 or 4, R 1 , R 7 and R 8 are as defined in general formula (I); preferably,
Figure PCTCN2022074588-appb-000040
selected from
Figure PCTCN2022074588-appb-000041
More preferably,
Figure PCTCN2022074588-appb-000042
for
Figure PCTCN2022074588-appb-000043
在本公开一些实施方案中，所述的通式(II-1)、通式(III-1)、通式(IV-1)或通式(V-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000044
选自
Figure PCTCN2022074588-appb-000045
Figure PCTCN2022074588-appb-000046
其中R 0选自氢原子、卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-NR 7R 8、硝基、羟基和C 1-6羟烷基，s为0、1、2、3或4，R 1、R 7和R 8如通式(I)中所定义；优选地，
Figure PCTCN2022074588-appb-000047
选自
Figure PCTCN2022074588-appb-000048
更优选地，
Figure PCTCN2022074588-appb-000049
为
Figure PCTCN2022074588-appb-000050
In some embodiments of the present disclosure, the compound represented by the general formula (II-1), the general formula (III-1), the general formula (IV-1) or the general formula (V-1) or its pharmaceutically acceptable salt used, of which
Figure PCTCN2022074588-appb-000044
selected
Figure PCTCN2022074588-appb-000045
Figure PCTCN2022074588-appb-000046
wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -NR 7 R 8 , nitro, hydroxy and C 1-6 hydroxyalkyl, s is 0, 1, 2, 3 or 4, R 1 , R 7 and R 8 are as defined in general formula (I); preferably,
Figure PCTCN2022074588-appb-000047
selected
Figure PCTCN2022074588-appb-000048
More preferably,
Figure PCTCN2022074588-appb-000049
for
Figure PCTCN2022074588-appb-000050
在本公开一些实施方案中，所述的通式(II-2)、通式(III-2)、通式(IV-2)或通式(V-2)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000051
选自
Figure PCTCN2022074588-appb-000052
Figure PCTCN2022074588-appb-000053
其中R 0选自氢原子、卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-NR 7R 8、硝基、羟基和C 1-6羟烷基，s为0、1、2、3或4，R 1、R 7和R 8如通式(I)中所定义；优选地，
Figure PCTCN2022074588-appb-000054
选自
Figure PCTCN2022074588-appb-000055
更优选地，
Figure PCTCN2022074588-appb-000056
为
Figure PCTCN2022074588-appb-000057
In some embodiments of the present disclosure, the compound represented by the general formula (II-2), the general formula (III-2), the general formula (IV-2) or the general formula (V-2) or its pharmaceutically acceptable salt used, of which
Figure PCTCN2022074588-appb-000051
selected
Figure PCTCN2022074588-appb-000052
Figure PCTCN2022074588-appb-000053
wherein R 0 is selected from hydrogen atom, halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -NR 7 R 8 , nitro, hydroxy and C 1-6 hydroxyalkyl, s is 0, 1, 2, 3 or 4, R 1 , R 7 and R 8 are as defined in general formula (I); preferably,
Figure PCTCN2022074588-appb-000054
selected from
Figure PCTCN2022074588-appb-000055
More preferably,
Figure PCTCN2022074588-appb-000056
for
Figure PCTCN2022074588-appb-000057
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基和C 1-6卤代烷氧基；优选地，各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，R 2为C 1-6卤代烷基；最优选地，R 2为三氟甲基。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III- 1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula ( The compound represented by V-2) or a pharmaceutically acceptable salt thereof, wherein each R 2 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; preferably, each R 2 is the same or different, and each is independently selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; More preferably, R 2 is C 1-6 haloalkyl; most preferably, R 2 is trifluoromethyl.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中各个R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；优选地，各个R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，R 3为卤素；最优选地，R 3为氟原子。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III- 1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula ( The compound represented by V-2) or a pharmaceutically acceptable salt thereof, wherein each R 3 is the same or different, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, C 1-6 haloalkyl and C 1-6 haloalkoxy; preferably, each R 3 is the same or different, and each is independently selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; More preferably, R3 is halogen; most preferably, R3 is a fluorine atom.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中m为0、1或2；优选地，m为1或2；更优选地，m为1。In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III- 1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula ( The compound represented by V-2) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; preferably, m is 1 or 2; more preferably, m is 1.
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中n为0、1或2；优选地，n为1。In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III) -1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula The compound represented by (V-2) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; preferably, n is 1.
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中t为0、1或2；优选地，t为1。In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III- 1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula ( The compound represented by V-2) or a pharmaceutically acceptable salt thereof, wherein t is 0, 1 or 2; preferably, t is 1.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A选自3至12元杂环基、6至10元芳基和5至10元杂芳基；环B为6至10元芳基或5至10元杂芳基；环C为6至10元芳基或5至10元杂芳基；各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、3至12元环烷基和3至12元杂环基，其中所述的3至12元环烷基和3至12元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、羟基和C 1-6羟烷基中的一个或多个取代基所取代；或者两个相邻的R 1与环A稠合形成3至8元杂环基，其中所述的3至8元杂环基任选地被选自卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基中的一个或多个取代基所取代；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基和C 1-6卤代烷氧基；各个R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；m为0、1或2；n为0、1或2；t为0、1或2。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 3- to 12-membered heterocyclic group, 6- to 10-membered aryl group, and 5- to 10-membered aryl group 10-membered heteroaryl; Ring B is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; Ring C is 6- to 10-membered aryl or 5- to 10 -membered heteroaryl; each R is the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclic group, wherein said 3- to 12-membered cycloalkyl group and 3- to 12-membered heterocyclic group are each independently optionally selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, substituted by one or more substituents in C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, hydroxyl and C 1-6 hydroxyalkyl; or two adjacent R 1 are fused with ring A synthesized to form a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is optionally selected from halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1 substituted with one or more substituents in -6 haloalkyl and C 1-6 haloalkoxy; each R 2 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; each R 3 is the same or different, and each is independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; m is 0, 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A选自3至12元杂环基、6至10元芳基和5至10元杂芳基；环B为6至10元芳基或5至10元杂芳基；环C为6至10元芳基或5至10元杂芳基；各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基和C 1-6卤代烷氧基；或者两个相邻的R 1与环A稠合形成3至8元杂环基，其中所述的3至8元杂环基任选地被选自卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基中的一个或多个取代基所取代；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基和C 1-6卤代烷氧基；各个R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；m为0、1或2；n为0、1或2；t为0、1或2。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 3- to 12-membered heterocyclic group, 6- to 10-membered aryl group, and 5- to 10-membered aryl group 10-membered heteroaryl; Ring B is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; Ring C is 6- to 10-membered aryl or 5- to 10 -membered heteroaryl; each R is the same or different, and Each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; or two adjacent R 1 and ring A is fused to form a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is optionally selected from halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, substituted by one or more substituents in C 1-6 haloalkyl and C 1-6 haloalkoxy; each R 2 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; each R 3 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1 -6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; m is 0, 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.
在本公开一些实施方案中，所述的通式(II)、通式(II-1)或通式(II-2)所示的化合物或其可药用的盐，其中环A选自吡唑基、咪唑基、1,2,3-三唑基和四唑基；环B为吡啶基；环C为苯基；各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、3至6元环烷基和3至6元杂环基，其中所述的3至6元环烷基和3至6元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基中的一个或多个取代基所取代；或者两个相邻的R 1与环A稠合形成5或6元杂环基，其中所述的5或6元杂环基任选地被选自卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基中的一个或多个取代基所取代；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；各个R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；m为1或2；n为0、1或2；t为0、1或2。 In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyridine azolyl, imidazolyl, 1,2,3 - triazolyl and tetrazolyl; ring B is pyridyl; ring C is phenyl; each R is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl, wherein the 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally selected from one of halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl or Replaced by multiple substituents; or two adjacent R 1 are fused with ring A to form a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally selected from halogen, C 1 -6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy one or more substituents; each R 2 is the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; each R is the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; m is 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.
在本公开一些实施方案中，所述的通式(II)、通式(II-1)或通式(II-2)所示的化合物或其可药用的盐，其中环A选自吡唑基、咪唑基和1,2,3-三唑基；环B为吡啶基；环C为苯基；各个R 1相同或不同，且各自独立地为氢原子或C 1-6烷基；或者两个相邻的R 1与环A稠合形成5或6元杂环基，其中所述的5或6元杂环基任选地被选自卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基中的一个或多个取代基所取代；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；各个R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；m为1或2；n为0、1或2；t为0、1或2。 In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyridine azolyl, imidazolyl and 1,2,3-triazolyl; ring B is pyridyl; ring C is phenyl; each R 1 is the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; Or two adjacent R 1 are fused with ring A to form a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally selected from halogen, C 1-6 alkyl, oxo is substituted with one or more substituents in group, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; each R 2 is the same or different, and each is independently selected from hydrogen atoms , halogen, C 1-6 alkyl and C 1-6 haloalkyl; each R 3 is the same or different, and each is independently selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; m is 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.
在本公开一些实施方案中，所述的通式(III)、通式(III-1)或通式(III-2)所示的化合物或其可药用的盐，其中环A选自吡唑基、咪唑基、1,2,3-三唑基和四唑基；环B为吡啶基；环C为苯基；各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、3至6元环烷基和3至6元杂环基；或者两个相邻的R 1与环A稠合形成5或6元杂环基，其中所述的5或6元杂环基任选地被选自卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基中的一个或多个取代基所取代；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；各个R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；m为1或2；n为0、1或2；t为0、1或2。 In some embodiments of the present disclosure, the compound represented by general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyridine azolyl, imidazolyl, 1,2,3 - triazolyl and tetrazolyl; ring B is pyridyl; ring C is phenyl; each R is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl; or two adjacent R 1 fused with Ring A to form a 5- or 6-membered heterocycle group, wherein said 5- or 6-membered heterocyclic group is optionally selected from halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl and C 1- 6 substituted with one or more substituents in haloalkoxy; each R 2 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; each R 3 same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; m is 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2 .
在本公开一些实施方案中，所述的通式(III)、通式(III-1)或通式(III-2)所示的化合物或其可药用的盐，其中环A选自吡唑基、咪唑基和1,2,3-三唑基；环B为吡啶基；环C为苯基；各个R 1相同或不同，且各自独立地为氢原子或C 1-6烷基；或者两个相邻的R 1与环A稠合形成5或6元杂环基，其中所述的5或6元杂环基任选地被选自卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基中的一个或多个取代基所取代；各个R 2相同或不同，且各自独立地选自氢原 子、卤素、C 1-6烷基和C 1-6卤代烷基；各个R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；m为1或2；n为0、1或2；t为0、1或2。 In some embodiments of the present disclosure, the compound represented by general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyridine azolyl, imidazolyl and 1,2,3-triazolyl; ring B is pyridyl; ring C is phenyl; each R 1 is the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; Or two adjacent R 1 are fused with ring A to form a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally selected from halogen, C 1-6 alkyl, oxo is substituted with one or more substituents in group, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; each R 2 is the same or different, and each is independently selected from hydrogen atoms , halogen, C 1-6 alkyl and C 1-6 haloalkyl; each R 3 is the same or different, and each is independently selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; m is 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.
在本公开的一些实施方案中，所述的通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中环A为5或6元杂芳基；各个R 1相同或不同，且各自独立地选自C 1-6烷基、C 1-6卤代烷基和3至6元环烷基，或者两个相邻的R 1与环A稠合形成5或6元杂环基；R 2为C 1-6卤代烷基；R 3为卤素；m为1或2；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein ring A is 5 or 6-membered heteroaryl; each R 1 is the same or different, and each is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and 3- to 6-membered cycloalkyl, or two adjacent R 1 Condensed with ring A to form a 5- or 6-membered heterocyclic group; R 2 is C 1-6 haloalkyl; R 3 is halogen; m is 1 or 2; n is 1;
在本公开的一些实施方案中，所述的通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中环A为5元含氮杂芳基；各个R 1相同或不同，且各自独立地选自C 1-6烷基、C 1-6卤代烷基和3至6元环烷基；R 2为C 1-6卤代烷基；R 3为卤素；m为1；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein ring A is 5 membered nitrogen-containing heteroaryl; each R 1 is the same or different, and each is independently selected from C 1-6 alkyl, C 1-6 haloalkyl and 3- to 6-membered cycloalkyl; R 2 is C 1-6 haloalkane R 3 is halogen; m is 1; n is 1; t is 1.
在本公开的一些实施方案中，所述的通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中环A为5或6元杂芳基；各个R 1相同或不同，且各自独立地选自C 1-6烷基、C 1-6卤代烷基和3至6元环烷基；或者两个相邻的R 1与环A稠合形成5或6元杂环基；R 2为C 1-6卤代烷基；R 3为卤素；m为1或2；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by general formula (V), general formula (V-1) or general formula (V-2) or a pharmaceutically acceptable salt thereof, wherein ring A is 5 or 6-membered heteroaryl; each R 1 is the same or different, and each is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and 3- to 6-membered cycloalkyl; or two adjacent R 1 Condensed with ring A to form a 5- or 6-membered heterocyclic group; R 2 is C 1-6 haloalkyl; R 3 is halogen; m is 1 or 2; n is 1;
在本公开的一些实施方案中，所述的通式(IV)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000058
选自
Figure PCTCN2022074588-appb-000059
Figure PCTCN2022074588-appb-000060
R 2为C 1-6卤代烷基；R 3为卤素；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022074588-appb-000058
selected
Figure PCTCN2022074588-appb-000059
Figure PCTCN2022074588-appb-000060
R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
在本公开的一些实施方案中，所述的通式(IV-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000061
选自
Figure PCTCN2022074588-appb-000062
Figure PCTCN2022074588-appb-000063
R 2为C 1-6卤代烷基；R 3为卤素；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022074588-appb-000061
selected
Figure PCTCN2022074588-appb-000062
Figure PCTCN2022074588-appb-000063
R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
在本公开的一些实施方案中，所述的通式(IV-2)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000064
选自
Figure PCTCN2022074588-appb-000065
Figure PCTCN2022074588-appb-000066
R 2为C 1-6卤代烷基；R 3为卤素；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022074588-appb-000064
selected from
Figure PCTCN2022074588-appb-000065
Figure PCTCN2022074588-appb-000066
R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
在本公开的一些实施方案中，所述的通式(IV)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000067
选自
Figure PCTCN2022074588-appb-000068
R 2为C 1-6卤代烷基；R 3为卤素；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022074588-appb-000067
selected from
Figure PCTCN2022074588-appb-000068
R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
在本公开的一些实施方案中，所述的通式(IV-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000069
选自
Figure PCTCN2022074588-appb-000070
R 2为C 1-6卤代烷基；R 3为卤素；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022074588-appb-000069
selected
Figure PCTCN2022074588-appb-000070
R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
在本公开的一些实施方案中，所述的通式(IV-2)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000071
选自
Figure PCTCN2022074588-appb-000072
R 2为C 1-6卤代烷基；R 3为卤素；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022074588-appb-000071
selected from
Figure PCTCN2022074588-appb-000072
R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
在本公开的一些实施方案中，所述的通式(V)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000073
选自
Figure PCTCN2022074588-appb-000074
Figure PCTCN2022074588-appb-000075
R 2为C 1-6卤代烷基；R 3为卤素；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022074588-appb-000073
selected from
Figure PCTCN2022074588-appb-000074
Figure PCTCN2022074588-appb-000075
R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
在本公开的一些实施方案中，所述的通式(V-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000076
选自
Figure PCTCN2022074588-appb-000077
Figure PCTCN2022074588-appb-000078
R 2为C 1-6卤代烷基；R 3为卤素；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022074588-appb-000076
selected
Figure PCTCN2022074588-appb-000077
Figure PCTCN2022074588-appb-000078
R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
在本公开的一些实施方案中，所述的通式(V-2)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000079
选自
Figure PCTCN2022074588-appb-000080
Figure PCTCN2022074588-appb-000081
R 2为C 1-6卤代烷基；R 3为卤素；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022074588-appb-000079
selected from
Figure PCTCN2022074588-appb-000080
Figure PCTCN2022074588-appb-000081
R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
在本公开的一些实施方案中，所述的通式(V)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000082
选自
Figure PCTCN2022074588-appb-000083
R 2为C 1-6 卤代烷基；R 3为卤素；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022074588-appb-000082
selected from
Figure PCTCN2022074588-appb-000083
R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
在本公开的一些实施方案中，所述的通式(V-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000084
选自
Figure PCTCN2022074588-appb-000085
R 2为C 1-6卤代烷基；R 3为卤素；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022074588-appb-000084
selected from
Figure PCTCN2022074588-appb-000085
R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 1.
在本公开的一些实施方案中，所述的通式(V-2)所示的化合物或其可药用的盐，其中
Figure PCTCN2022074588-appb-000086
选自
Figure PCTCN2022074588-appb-000087
R 2为C 1-6卤代烷基；R 3为卤素；n为1；t为1。 In some embodiments of the present disclosure, the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022074588-appb-000086
selected
Figure PCTCN2022074588-appb-000087
R 2 is C 1-6 haloalkyl; R 3 is halogen; n is 1; t is 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:
Figure PCTCN2022074588-appb-000088
Figure PCTCN2022074588-appb-000088
Figure PCTCN2022074588-appb-000089
Figure PCTCN2022074588-appb-000089
Figure PCTCN2022074588-appb-000090
Figure PCTCN2022074588-appb-000090
Figure PCTCN2022074588-appb-000091
Figure PCTCN2022074588-appb-000091
Figure PCTCN2022074588-appb-000092
Figure PCTCN2022074588-appb-000092
Figure PCTCN2022074588-appb-000093
Figure PCTCN2022074588-appb-000093
Figure PCTCN2022074588-appb-000094
Figure PCTCN2022074588-appb-000094
Figure PCTCN2022074588-appb-000095
Figure PCTCN2022074588-appb-000095
Figure PCTCN2022074588-appb-000096
Figure PCTCN2022074588-appb-000096
本公开的另一方面涉及通式(IA)所示的化合物或其盐，Another aspect of the present disclosure relates to a compound of formula (IA) or a salt thereof,
Figure PCTCN2022074588-appb-000097
Figure PCTCN2022074588-appb-000097
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
Figure PCTCN2022074588-appb-000098
环A、环B、环C、R 1至R 3、m、n和t如通式(I)化合物所定义。
Figure PCTCN2022074588-appb-000098
Ring A, Ring B, Ring C, R1 to R3 , m, n and t are as defined for compounds of general formula (I).
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 a compound of general formula (IIA) or a salt thereof:
Figure PCTCN2022074588-appb-000099
Figure PCTCN2022074588-appb-000099
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(II)中所定义。 Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (II).
本公开的另一方面涉及通式(II-1A)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (II-1A) or a salt thereof:
Figure PCTCN2022074588-appb-000100
Figure PCTCN2022074588-appb-000100
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(II-1)中所定义。 Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (II-1).
本公开的另一方面涉及通式(II-2A)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (II-2A) or a salt thereof:
Figure PCTCN2022074588-appb-000101
Figure PCTCN2022074588-appb-000101
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(II-2)中所定义。 Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (II-2).
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 a compound of general formula (IIIA) or a salt thereof:
Figure PCTCN2022074588-appb-000102
Figure PCTCN2022074588-appb-000102
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(III)中所定义。 Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (III).
本公开的另一方面涉及通式(III-1A)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (III-1A) or a salt thereof:
Figure PCTCN2022074588-appb-000103
Figure PCTCN2022074588-appb-000103
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(III-1)中所定义。 Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (III-1).
本公开的另一方面涉及通式(III-2A)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (III-2A) or a salt thereof:
Figure PCTCN2022074588-appb-000104
Figure PCTCN2022074588-appb-000104
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(III-2)中所定义。 Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (III-2).
本公开的另一方面涉及通式(IVA)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (IVA) or a salt thereof:
Figure PCTCN2022074588-appb-000105
Figure PCTCN2022074588-appb-000105
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(IV)中所定义。 Rings A , R1 to R3 , m, n and t are as defined in general formula (IV).
本公开的另一方面涉及通式(IV-1A)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (IV-1A) or a salt thereof:
Figure PCTCN2022074588-appb-000106
Figure PCTCN2022074588-appb-000106
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(IV-1)中所定义。 Ring A, R 1 to R 3 , m, n and t are as defined in the general formula (IV-1).
本公开的另一方面涉及通式(IV-2A)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (IV-2A) or a salt thereof:
Figure PCTCN2022074588-appb-000107
Figure PCTCN2022074588-appb-000107
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(IV-2)中所定义。 Ring A, R 1 to R 3 , m, n and t are as defined in general formula (IV-2).
本公开的另一方面涉及通式(VA)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (VA) or a salt thereof:
Figure PCTCN2022074588-appb-000108
Figure PCTCN2022074588-appb-000108
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(V)中所定义。 Rings A, R 1 to R 3 , m, n and t are as defined in general formula (V).
本公开的另一方面涉及通式(V-1A)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (V-1A) or a salt thereof:
Figure PCTCN2022074588-appb-000109
Figure PCTCN2022074588-appb-000109
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(V-1)中所定义。 Ring A, R 1 to R 3 , m, n and t are as defined in the general formula (V-1).
本公开的另一方面涉及通式(V-2A)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound of general formula (V-2A) or a salt thereof:
Figure PCTCN2022074588-appb-000110
Figure PCTCN2022074588-appb-000110
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(V-2)中所定义。 Ring A, R 1 to R 3 , m, n and t are as defined in general formula (V-2).
表B本公开的典型中间体化合物包括但不限于：Typical intermediate compounds of the present disclosure include, but are not limited to:
Figure PCTCN2022074588-appb-000111
Figure PCTCN2022074588-appb-000111
Figure PCTCN2022074588-appb-000112
Figure PCTCN2022074588-appb-000112
Figure PCTCN2022074588-appb-000113
Figure PCTCN2022074588-appb-000113
Figure PCTCN2022074588-appb-000114
Figure PCTCN2022074588-appb-000114
Figure PCTCN2022074588-appb-000115
Figure PCTCN2022074588-appb-000115
Figure PCTCN2022074588-appb-000116
Figure PCTCN2022074588-appb-000116
Figure PCTCN2022074588-appb-000117
Figure PCTCN2022074588-appb-000117
Figure PCTCN2022074588-appb-000118
Figure PCTCN2022074588-appb-000118
Figure PCTCN2022074588-appb-000119
Figure PCTCN2022074588-appb-000119
本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2022074588-appb-000120
Figure PCTCN2022074588-appb-000120
通式(IA)所示的化合物或其盐脱去氨基保护基R w，得到通式(I)所示的化合物或其可药用的盐， The compound represented by the general formula (IA) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
Figure PCTCN2022074588-appb-000121
环A、环B、环C、R 1至R 3、m、n和t如通式(I)中所定义。
Figure PCTCN2022074588-appb-000121
Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (I).
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：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:
Figure PCTCN2022074588-appb-000122
Figure PCTCN2022074588-appb-000122
通式(IIA)所示的化合物或其盐脱去氨基保护基R w，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 removes the amino protecting group R w to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(II)中所定义。 Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (II).
本公开的另一方面涉及一种制备通式(II-1)所示的化合物或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2022074588-appb-000123
Figure PCTCN2022074588-appb-000123
通式(II-1A)所示的化合物或其盐脱去氨基保护基R w，得到通式(II-1)所示的化合物或其可药用的盐， The compound represented by the general formula (II-1A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(II-1)中所定义。 Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (II-1).
本公开的另一方面涉及一种制备通式(II-2)所示的化合物或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2022074588-appb-000124
Figure PCTCN2022074588-appb-000124
通式(II-2A)所示的化合物或其盐脱去氨基保护基R w，得到通式(II-2)所示的化合物或其可药用的盐， The compound represented by the general formula (II-2A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(II-2)中所定义。 Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (II-2).
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：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, the method comprising:
Figure PCTCN2022074588-appb-000125
Figure PCTCN2022074588-appb-000125
通式(IIIA)所示的化合物或其盐脱去氨基保护基R w，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 removes the amino protecting group R w to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(III)中所定义。 Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (III).
本公开的另一方面涉及一种制备通式(III-1)所示的化合物或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2022074588-appb-000126
Figure PCTCN2022074588-appb-000126
通式(III-1A)所示的化合物或其盐脱去氨基保护基R w，得到通式(III-1)所示的化合物或其可药用的盐， The compound represented by the general formula (III-1A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(III-1)中所定义。 Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (III-1).
本公开的另一方面涉及一种制备通式(III-2)所示的化合物或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2022074588-appb-000127
Figure PCTCN2022074588-appb-000127
通式(III-2A)所示的化合物或其盐脱去氨基保护基R w，得到通式(III-2)所示的化合物或其可药用的盐， The compound represented by the general formula (III-2A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(III-2)中所定义。 Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (III-2).
本公开的另一方面涉及一种制备通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2022074588-appb-000128
Figure PCTCN2022074588-appb-000128
通式(IVA)所示的化合物或其盐脱去氨基保护基R w，得到通式(IV)所示的化合物或其可药用的盐， The compound represented by the general formula (IVA) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(IV)中所定义。 Rings A , R1 to R3 , m, n and t are as defined in general formula (IV).
本公开的另一方面涉及一种制备通式(IV-1)所示的化合物或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2022074588-appb-000129
Figure PCTCN2022074588-appb-000129
通式(IV-1A)所示的化合物或其盐脱去氨基保护基R w，得到通式(IV-1)所示的化合物或其可药用的盐， The compound represented by the general formula (IV-1A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(IV-1)中所定义。 Ring A, R 1 to R 3 , m, n and t are as defined in the general formula (IV-1).
本公开的另一方面涉及一种制备通式(IV-2)所示的化合物或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2022074588-appb-000130
Figure PCTCN2022074588-appb-000130
通式(IV-2A)所示的化合物或其盐脱去氨基保护基R w，得到通式(IV-2)所示的化合物或其可药用的盐， The compound represented by the general formula (IV-2A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(IV-2)中所定义。 Ring A, R 1 to R 3 , m, n and t are as defined in general formula (IV-2).
本公开的另一方面涉及一种制备通式(V)所示的化合物或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2022074588-appb-000131
Figure PCTCN2022074588-appb-000131
通式(VA)所示的化合物或其盐脱去氨基保护基R w，得到通式(V)所示的化合物或其可药用的盐， The compound represented by the general formula (VA) or its salt is removed from the amino protecting group R w to obtain the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(V)中所定义。 Rings A, R 1 to R 3 , m, n and t are as defined in general formula (V).
本公开的另一方面涉及一种制备通式(V-1)所示的化合物或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2022074588-appb-000132
Figure PCTCN2022074588-appb-000132
通式(V-1A)所示的化合物或其盐脱去氨基保护基R w，得到通式(V-1)所示的化合物或其可药用的盐， The compound represented by the general formula (V-1A) or a salt thereof is removed from the amino protecting group R w to obtain the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(V-1)中所定义。 Ring A, R 1 to R 3 , m, n and t are as defined in the general formula (V-1).
本公开的另一方面涉及一种制备通式(V-2)所示的化合物或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V-2) or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2022074588-appb-000133
Figure PCTCN2022074588-appb-000133
通式(V-2A)所示的化合物或其盐脱去氨基保护基R w，得到通式(V-2)所示的化合物或其可药用的盐， The compound represented by the general formula (V-2A) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(V-2)中所定义。 Ring A, R 1 to R 3 , m, n and t are as defined in general formula (V-2).
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(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A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。Another aspect of the present disclosure relates to a pharmaceutical composition comprising the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (II-2), general formula Formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula Compounds of formula (V-1), general formula (V-2) and Table A or pharmaceutically acceptable salts thereof, 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(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物在制备通过调节GR治疗和/或预防疾病或病症的药物中的用途。The present disclosure further relates to general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III) -2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A Use of a compound shown, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder by modulating GR.
本公开进一步涉及通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通 式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物在制备通过拮抗GR治疗和/或预防疾病或病症的药物中的用途。The present disclosure further relates to general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III) -2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A Use of the indicated compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder by antagonizing GR.
本公开进一步涉及通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物在制备治疗和/或预防肿瘤、心血管疾病、炎性疾病、自身免疫性疾病、代谢类疾病、眼疾和神经变性疾病的药物中的用途；优选在制备治疗和/或预防选自癌症、肥胖、糖尿病、高血压、X综合征、抑郁症(如精神病型抑郁症、产后抑郁症)、过敏、焦虑、青光眼、阿尔茨海默病、帕金森病、亨廷顿病、认知增强、库欣综合征(又称皮质醇增多症(hypercortisolism))、阿狄森病、骨质疏松症、虚弱、肌肉虚弱、骨关节炎、类风湿关节炎、哮喘、鼻炎、肾上腺功能相关的疾病、病毒感染(如人类免疫缺陷病毒(HIV))、免疫缺陷(如获得性免疫缺陷综合症(AIDS))、免疫调节、过敏症、伤口愈合、强迫行为、成瘾、精神病(如产后精神病)、厌食、恶病质、轻度认知障碍、痴呆症、高血糖症、中心性浆液性脉络膜视网膜病变、酒精依赖症、应激障碍(如创伤后应激障碍)、谵妄、慢性疼痛、早产儿神经障碍和偏头痛的药物中的用途；更优选在制备治疗和/或预防选自乳腺癌、前列腺癌、肾上腺皮质癌、输卵管癌(如复发性输卵管癌)、胰腺癌(如转移性胰腺导管腺癌)、腹膜癌(如复发性原发性腹膜癌)、皮肤癌、脑癌、膀胱癌、宫颈癌、肝癌、肺癌(如非小细胞肺癌和小细胞肺癌)、白血病、骨癌、黑色素瘤、淋巴瘤、神经母细胞瘤、肾细胞癌和卵巢癌(如复发性卵巢癌)的药物中的用途；最优选在制备治疗和/或预防选自乳腺癌、前列腺癌、库欣综合征、肾上腺皮质癌、输卵管癌(如复发性输卵管癌)、胰腺癌(如转移性胰腺导管腺癌)、腹膜癌(如复发性原发性腹膜癌)和卵巢癌(如复发性卵巢癌)的药物中的用途。The present disclosure further relates to general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III) -2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A The compound shown or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same is used in the preparation of drugs for the treatment and/or prevention of tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, eye diseases and neurodegenerative diseases. Use in medicine; preferably in the preparation of treatment and/or prevention selected from the group consisting of cancer, obesity, diabetes, hypertension, Syndrome X, depression (eg psychotic depression, postpartum depression), allergy, anxiety, glaucoma, Alzheimer's Haimer's disease, Parkinson's disease, Huntington's disease, cognitive enhancement, Cushing's syndrome (also known as hypercortisolism), Addison's disease, osteoporosis, frailty, muscle weakness, osteoarthritis, Rheumatoid arthritis, asthma, rhinitis, diseases related to adrenal function, viral infections (eg, human immunodeficiency virus (HIV)), immune deficiencies (eg, acquired immunodeficiency syndrome (AIDS)), immune modulation, allergies, wounds Healing, obsessive-compulsive behavior, addiction, psychosis (eg, postpartum psychosis), anorexia, cachexia, mild cognitive impairment, dementia, hyperglycemia, central serous chorioretinopathy, alcohol dependence, stress disorder (eg, trauma post-stress disorder), delirium, chronic pain, neurological disorders of premature infants and migraine use; more preferably in the preparation of treatment and/or prevention selected from breast cancer, prostate cancer, adrenal cortical cancer, fallopian tube cancer (such as recurrence fallopian tube cancer), pancreatic cancer (eg, metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (eg, recurrent primary peritoneal cancer), skin cancer, brain cancer, bladder cancer, cervical cancer, liver cancer, lung cancer (eg, non-small cell cancer) Use in medicaments for lung cancer and small cell lung cancer), leukemia, bone cancer, melanoma, lymphoma, neuroblastoma, renal cell carcinoma and ovarian cancer (eg, recurrent ovarian cancer); most preferably in the manufacture of therapeutic and/or Prevention is selected from breast cancer, prostate cancer, Cushing's syndrome, adrenocortical cancer, fallopian tube cancer (eg, recurrent fallopian tube cancer), pancreatic cancer (eg, metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (eg, recurrent primary peritoneal cancer) cancer) and ovarian cancer (eg, recurrent ovarian cancer).
本公开还涉及一种通过调节GR治疗和/或预防疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物。The present disclosure also relates to a method of treating and/or preventing a disease or disorder by modulating GR, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II), formula (II-1), General formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2 ), general formula (V), general formula (V-1), general formula (V-2) and the compounds shown in Table A or their pharmaceutically acceptable salts, or a pharmaceutical composition comprising them.
本公开还涉及一种通过拮抗GR治疗和/或预防疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物。The present disclosure also relates to a method of treating and/or preventing a disease or disorder by antagonizing GR, comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (II), Formula (II-1), General formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2 ), general formula (V), general formula (V-1), general formula (V-2) and the compounds shown in Table A or their pharmaceutically acceptable salts, or a pharmaceutical composition comprising them.
本公开还涉及一种治疗和/或预防肿瘤、心血管疾病、炎性疾病、自身免疫性疾病、代谢类疾病、眼疾和神经变性疾病的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式 (III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物。The present disclosure also relates to a method of treating and/or preventing tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, ocular diseases and neurodegenerative diseases, comprising administering to a patient in need thereof a therapeutically effective amount of the general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), the general formula (IV-1), the general formula (IV-2), the general formula (V), the general formula (V-1), the general formula (V-2) and the compounds shown in Table A or their compounds A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same.
本公开进一步涉及一种通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐或包含其的药物组合物，其用作药物。The present disclosure further relates to a general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and A compound shown in Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, for use as a medicament.
本公开进一步涉及通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于通过调节GR治疗和/或预防疾病或病症。The present disclosure further relates to general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III) -2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A The compound shown, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of a disease or disorder by modulating GR.
本公开进一步涉及通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于通过拮抗GR治疗和/或预防疾病或病症。The present disclosure further relates to general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III) -2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A The indicated compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of a disease or disorder by antagonizing GR.
本公开进一步涉及通式(I)、通式(II)、通式(II-1)、通式(II-2)、通式(III)、通式(III-1)、通式(III-2)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于治疗和/或预防肿瘤、心血管疾病、炎性疾病、自身免疫性疾病、代谢类疾病、眼疾和神经变性疾病。The present disclosure further relates to general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III) -2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A The compound shown or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, is used for the treatment and/or prevention of tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, eye diseases and neurological diseases Degenerative diseases.
本公开中所述的疾病或病症选自癌症、肥胖、糖尿病、高血压、X综合征、抑郁症(如精神病型抑郁症、产后抑郁症)、过敏、焦虑、青光眼、阿尔茨海默病、帕金森病、亨廷顿病、认知增强、库欣综合征、阿狄森病、骨质疏松症、虚弱、肌肉虚弱、骨关节炎、类风湿关节炎、哮喘、鼻炎、肾上腺功能相关的疾病、病毒感染(如人类免疫缺陷病毒(HIV))、免疫缺陷(如获得性免疫缺陷综合症(AIDS))、免疫调节、过敏症、伤口愈合、强迫行为、成瘾、精神病(如产后精神病)、厌食、恶病质、轻度认知障碍、痴呆症、高血糖症、中心性浆液性脉络膜视网膜病变、酒精依赖症、应激障碍(如创伤后应激障碍)、谵妄、慢性疼痛、早产儿神经障碍和偏头痛；优选地，所述的癌症选自乳腺癌、前列腺癌、肾上腺皮质癌、输卵管癌(如复发性输卵管癌)、胰腺癌(如转移性胰腺导管腺癌)、腹膜癌(如复发性原发性腹膜癌)、皮肤癌、脑癌、膀胱癌、宫颈癌、肝癌、肺癌(如非小细胞肺癌和小细胞肺癌)、白血病、骨癌、黑色素瘤、淋巴瘤、神经母细胞瘤、肾细胞癌和卵巢癌(如复发性卵巢癌)；更优选地，所述的疾病或病症选自乳腺癌、前列腺癌、库欣综合征、肾上腺皮质癌、输卵管癌(如复发性输卵管癌)、胰腺癌(如转移性胰腺导管腺癌)、腹膜癌(如复发性原发性腹膜癌)和卵巢癌(如复发性卵巢癌)。The disease or disorder described in the present disclosure is selected from cancer, obesity, diabetes, hypertension, syndrome X, depression (eg, psychotic depression, postpartum depression), allergies, anxiety, glaucoma, Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive enhancement, Cushing's syndrome, Addison's disease, osteoporosis, frailty, muscle weakness, osteoarthritis, rheumatoid arthritis, asthma, rhinitis, adrenal-related disorders, Viral infection (eg, human immunodeficiency virus (HIV)), immunodeficiency (eg, acquired immunodeficiency syndrome (AIDS)), immune modulation, allergies, wound healing, compulsive behavior, addiction, psychosis (eg, postpartum psychosis), Anorexia, cachexia, mild cognitive impairment, dementia, hyperglycemia, central serous chorioretinopathy, alcohol dependence, stress disorders (eg, posttraumatic stress disorder), delirium, chronic pain, neurological disorders of prematurity and migraine; preferably, the cancer is selected from breast cancer, prostate cancer, adrenocortical cancer, fallopian tube cancer (such as recurrent fallopian tube cancer), pancreatic cancer (such as metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (such as recurrent primary peritoneal cancer), skin cancer, brain cancer, bladder cancer, cervical cancer, liver cancer, lung cancer (eg, non-small cell lung cancer and small cell lung cancer), leukemia, bone cancer, melanoma, lymphoma, neuroblastoma , renal cell carcinoma and ovarian cancer (such as recurrent ovarian cancer); more preferably, the disease or condition is selected from breast cancer, prostate cancer, Cushing's syndrome, adrenocortical cancer, fallopian tube cancer (such as recurrent fallopian tube cancer) ), pancreatic cancer (eg, metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (eg, recurrent primary peritoneal cancer), and ovarian cancer (eg, recurrent ovarian cancer).
与阳性对照化合物Relacorilant(CORT-125134，WO2013177559A2实施例18) 相比，本公开实施例1-P1化合物较Relacorilant具有更好的安全性，且具有明显的药代动力学优势，具体数据见生物学评价部分，Relacorilant的结构式如下：Compared with the positive control compound Relacorilant (CORT-125134, WO2013177559A2 Example 18), the compound of Example 1-P1 of the present disclosure has better safety than Relacorilant, and has obvious pharmacokinetic advantages. For specific data, see Biology In the evaluation part, the structural formula of Relacorilant is as follows:
Figure PCTCN2022074588-appb-000134
Figure PCTCN2022074588-appb-000134
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持续释放剂型，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。The active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, 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 compound is preferably presented in a unit dose or in a form that the patient can self-administer in a single dose. A unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid. 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 excipients 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 they 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 can 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 or oily 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 in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The 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。Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents. Sweetening and flavoring agents 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。The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, or mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
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。The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 IV 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。The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used. In addition, fatty acids are also available in the preparation of 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 can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt 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。The compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension. These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, 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、排泄的速率、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 to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc. In addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to conventional treatment regimens.
术语说明Glossary
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, terms used in the specification and claims have the following meanings.
术语“烷基”指饱和的直链或支链的脂肪族烃基，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C 1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C 1-12烷基)，更优选具有1至6个碳原子的烷基(即C 1-6烷基)。非限制性实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己 基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。最优选具有1至6个碳原子的低级烷基，非限制性实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。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上被取代，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 straight or branched chain aliphatic hydrocarbon group having 1 to 20 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C 1-12 alkyl group), and more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 alkyl group). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4- Ethylhexyl, 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 chain isomers thereof, etc. Most preferably lower alkyl having 1 to 6 carbon atoms, non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3- Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl base, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-Dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, 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C 1-20亚烷基)。所述亚烷基优选具有1至12个碳原子的亚烷基(即C 1-12亚烷基)，更优选具有1至6个碳原子的亚烷基(即C 1-6亚烷基)。亚烷基的非限制性实例包括但不限于：亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)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上被取代，取代基优选选自烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个。 The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group is as defined above, having from 1 to 20 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkylene). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (ie, a C 1-12 alkylene group), and more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C 1-6 alkylene group). ). Non-limiting examples of alkylene groups include, but are not limited to: methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene base (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like. The alkylene 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 alkenyl, alkynyl, alkoxy, haloalkoxy, cyclic Alkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy , one or more of heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
术语“烯基”指分子中含有至少一个碳碳双键的烷基化合物，其中烷基的定义如上所述，其为具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的烯基(即C 2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C 2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、丁烯基、戊烯基、己烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选选自烷氧基、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 compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, which is 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms alkenyl (ie C2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkenyl group). Non-limiting examples include: vinyl, propenyl, butenyl, pentenyl, hexenyl, and the like. Alkenyl can be substituted or unsubstituted, when substituted, the substituent is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl one or more of , 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化合物，其中烷基的定义如上所述，其为具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基(即C 2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C 2-6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，取代基优选选自烷氧基、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 compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above, which is 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (ie C 2-12 alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl one or more of , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
术语“烷氧基”指-O-(烷基)，其中烷基定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选选自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。The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. Alkoxy can be optionally substituted or unsubstituted, when substituted, the substituent is preferably selected from D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, hetero One or more of cyclooxy, hydroxy, 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或多环环状烃取代基，环烷基环具有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)碳原子(即3至20元环烷基)，优选具有3至12个碳原子(即3至12元环烷基)，更优选具有3至8个碳原子(即3至8元环烷基)，最优选具有3至6个碳原子(即3至6元环烷基)。单环环烷基的非限制性实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环烷基、稠环烷基和桥环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 20 cycloalkyl rings (eg 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably 3 to 12 carbon atoms (ie 3 to 12 membered ring alkyl), more preferably 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl), most preferably 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups.
术语“螺环烷基”指5至20元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20元)的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选6至14元螺环烷基，更优选7至10元螺环烷基。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基或多螺环烷基(如双螺环烷基)，优选单螺环烷基或双螺环烷基。更优选3元/5元、3元/6元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元、6元/4元、6元/5元或6元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a 5 to 20 membered (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 membered) monocyclic ring A polycyclic group with one carbon atom (called a spiro atom) shared between them, which may contain one or more double bonds. A 6- to 14-membered spirocycloalkyl group is preferred, and a 7- to 10-membered spirocycloalkyl group is more preferred. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl groups or multi-spirocycloalkyl groups (such as bis-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups or double-spirocycloalkyl groups . More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5-membered/6-membered, 6-membered/4-membered, 6-membered/5-membered or 6-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:
Figure PCTCN2022074588-appb-000135
Figure PCTCN2022074588-appb-000135
术语“稠环烷基”指5至20元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20元)的环之间共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选6至14元稠环烷基，更优选7至10元稠环烷基。根据组成环的数目可以分双环、三环、四环等多环稠环烷基，优选双环或三环稠环烷基，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/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元双环稠环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to a ring of 5 to 20 membered (eg, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 membered). An all-carbon polycyclic group sharing an adjacent pair of carbon atoms, wherein one or more rings may contain one or more double bonds. A 6- to 14-membered fused cycloalkyl group is preferred, and a 7- to 10-membered fused cycloalkyl group is more preferred. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered RMB, RMB 4/RMB 4, RMB 4/RMB 5, RMB 4/RMB 6, RMB 5/RMB 4, RMB 5/RMB 5, RMB 5/RMB 6, RMB 6/RMB 3, RMB 6/RMB 4, 6-membered/5-membered and 6-membered/6-membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2022074588-appb-000136
Figure PCTCN2022074588-appb-000136
术语“桥环烷基”指5至20元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20元)的任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选6至14元桥环烷基，更优选7至10元桥环烷基。根据组成环的数目可以分双环、三环、四环等多环桥环烷基，优选双环、三环或四环桥环烷基，更优选双环或三环桥环烷基。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to any two of 5 to 20 membered (eg, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 membered) An all-carbon polycyclic group in which each ring shares two non-directly attached carbon atoms, which may contain one or more double bonds. A 6- to 14-membered bridged cycloalkyl group is preferred, and a 7- to 10-membered bridged cycloalkyl group is more preferred. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl include:
Figure PCTCN2022074588-appb-000137
Figure PCTCN2022074588-appb-000137
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括
Figure PCTCN2022074588-appb-000138
等；优选
Figure PCTCN2022074588-appb-000139
Figure PCTCN2022074588-appb-000140
The cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include
Figure PCTCN2022074588-appb-000138
etc.; preferred
Figure PCTCN2022074588-appb-000139
Figure PCTCN2022074588-appb-000140
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上被取代，取代基优选选自卤素、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。Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，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，其中一个或多个环原子为选自氮、氧和硫的杂原子，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-的环部分，其余环原子为碳。优选具有3至12个环原子，其中1至4个(例如1、2、3或4个)是杂原子(即3至12元杂环基)；进一步优选具有3至8个环原子，其中1至3是杂原子(例如1、2或3个)(即3至8元杂环基)；更优选具有3至6个环原子，其中1至3个是杂原子(即3至6元杂环基)；最优选具有5或6个环原子，其中1至3个是杂原子(即5或6元杂环基)。单环杂环基的非限制性实例包括吡咯烷基、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、高哌嗪基等。多环杂环基包括螺杂环基、稠杂环基和桥杂环基。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having 3 to 20 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, and sulfur, optionally oxo ( i.e. forming a sulfoxide or sulfone), but excluding ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms are carbon. It is preferred to have 3 to 12 ring atoms, of which 1 to 4 (eg 1, 2, 3 or 4) are heteroatoms (ie 3 to 12 membered heterocyclyl); it is further preferred to have 3 to 8 ring atoms, wherein 1 to 3 are heteroatoms (eg 1, 2 or 3) (ie 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (ie 3 to 6 membered) heterocyclyl); most preferably having 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (ie, 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine base, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.
术语“螺杂环基”指5至20元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20元)的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选6至14元螺杂环基，更优选7至10元螺杂环基。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基或多螺杂环基(如双螺杂环基)，优选单螺杂环基和双螺 杂环基。更优选3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元或6元/6元单螺杂环基。螺杂环基的非限制性实例包括：The term "spiroheterocyclyl" refers to a 5 to 20 membered (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 membered) monocyclic ring A polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxo (that is, to form a sulfoxide or sulfone), the remaining ring atoms are carbon. It may contain one or more double bonds. A 6- to 14-membered spiroheterocyclic group is preferable, and a 7- to 10-membered spiroheterocyclic group is more preferable. According to the number of spiro atoms shared between the rings, spiroheterocyclyl groups are classified into mono-spiroheterocyclyl groups or poly-spiroheterocyclyl groups (such as bis-spiroheterocyclyl groups), preferably mono-spiroheterocyclyl groups and bis-spiro-heterocyclyl groups . More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan or 6 yuan/6 yuan unit Spiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:
Figure PCTCN2022074588-appb-000141
Figure PCTCN2022074588-appb-000141
术语“稠杂环基”指5至20元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20元)的环之间共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选6至14元稠杂环基，更优选7至10元稠杂环基。根据组成环的数目可以分为双环、三环、四环等多环稠杂环基，优选双环或三环稠杂环基，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。稠杂环基的非限制性实例包括：The term "fused heterocyclyl" refers to a ring of 5 to 20 membered (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 membered) A polycyclic heterocyclic group sharing an adjacent pair of atoms, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, said The sulphur can optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. A 6- to 14-membered condensed heterocyclic group is preferable, and a 7- to 10-membered condensed heterocyclic group is more preferable. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/ 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-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
Figure PCTCN2022074588-appb-000142
Figure PCTCN2022074588-appb-000142
术语“桥杂环基”指5至14元(例如5、6、7、8、9、10、11、12、13或14元)的任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选6至14元桥杂环基，更优选7至10元桥杂环基。根据组成环的数目可以分为双环、三环、四环等多环桥杂环基，优选双环、三环或四环桥杂环基，更优选双环或三环桥杂环基。桥杂环基的非限制性实例包括：The term "bridged heterocyclyl" refers to a polycyclic group in which any two rings of 5 to 14 membered (eg, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 membered) share two atoms that are not directly connected. A cyclic heterocyclic group, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, the sulfur optionally being oxo (i.e. to form a sulfoxide) or sulfone), the remaining ring atoms are carbon. A 6- to 14-membered bridged heterocyclic group is preferable, and a 7- to 10-membered bridged heterocyclic group is more preferable. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclyl groups include:
Figure PCTCN2022074588-appb-000143
Figure PCTCN2022074588-appb-000143
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the The rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
Figure PCTCN2022074588-appb-000144
等。
Figure PCTCN2022074588-appb-000144
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上被取代，取代基优选选自卤素、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。Heterocyclyl may be substituted or unsubstituted, when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
术语“芳基”指具有共轭的π电子体系的6至14元(例如6、7、8、9、10、11、12、13或14元)全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选6至10元芳基，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6- to 14-membered (eg, 6, 7, 8, 9, 10, 11, 12, 13, or 14 membered) all-carbon monocyclic or fused polycyclic (fused Polycycles are cyclic) groups that share adjacent pairs of carbon atoms, preferably 6 to 10 membered aryl groups such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
Figure PCTCN2022074588-appb-000145
Figure PCTCN2022074588-appb-000145
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上被取代，取代基优选选自卤素、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。Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
术语“杂芳基”指包含1至4个(例如1、2、3或4个)杂原子、5至14个(例如5、6、7、8、9、10、11、12、13或14元)环原子的杂芳族体系，其中杂原子选自氧、硫和氮。优选5至10元杂芳基；更优选5元或6元杂芳基，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基(如1,2,3-三唑基和1,2,4-三唑基)、四唑基等；最优选5元含氮杂芳基，例如吡唑基、咪唑基、1,2,3-三唑基和四唑基。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms, 5 to 14 (eg 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14-membered) heteroaromatic system of ring atoms, wherein the heteroatom is selected from oxygen, sulfur and nitrogen. 5- to 10-membered heteroaryl groups are preferred; 5- or 6-membered heteroaryl groups are more preferred, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl , imidazolyl, pyrazolyl, triazolyl (such as 1,2,3-triazolyl and 1,2,4-triazolyl), tetrazolyl, etc.; most preferably 5-membered nitrogen-containing heteroaryl, such as Pyrazolyl, imidazolyl, 1,2,3-triazolyl and tetrazolyl. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
Figure PCTCN2022074588-appb-000146
Figure PCTCN2022074588-appb-000146
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上被取代，取代基优选选自卤素、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 may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同环原子或两个不同的环原子上除去两个氢原子所衍生的残基即“亚环烷基”、“亚杂环基”、“亚芳基”、“亚杂芳基”。The aforementioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent Residues derived from atoms are "cycloalkylene", "heterocyclylene", "arylene", "heteroarylene".
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。非限制性实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、乙酰基、对甲苯磺酰基(Ts)、苄基、烯丙基、对甲氧苄基、叔丁基二甲基硅基(TBS)等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。The term "amino protecting group" refers to a group introduced on an amino group that is easily removed in order to keep the amino group unchanged when other parts of the molecule are reacted. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, p-toluenesulfonyl (Ts), benzyl, allyl, p-methoxybenzyl, tert-butyldimethylsilyl (TBS), etc. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
术语“羟基保护基”是指在羟基上引入的易于脱去的基团，通常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。非限制性实例包括：三乙基硅基、三异丙基硅基、叔丁基二甲基硅烷基(TBS)、叔丁基二苯基硅基、叔丁基、C 1-6烷氧基取代的C 1-6烷基或苯基取代的C 1-6烷基(如甲氧基甲基(MOM)和乙氧基乙基等)、(C 1-10烷基或芳香基)酰基(如：甲酰基，乙酰基，苯甲酰基、对硝基苯甲酰基等)、(C 1-6烷基或6至10元芳基)磺酰基、(C 1-6烷氧基或6至10元芳基氧基)羰基、烯丙基、2-四氢吡喃基(THP)等。 The term "hydroxyl protecting group" refers to an easily removed group introduced on a hydroxy group, which is usually used to block or protect the hydroxy group while reacting on other functional groups of the compound. Non-limiting examples include: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, tert-butyl, C 1-6 alkoxy C 1-6 alkyl substituted with phenyl or C 1-6 alkyl substituted by phenyl (such as methoxymethyl (MOM) and ethoxyethyl, etc.), (C 1-10 alkyl or aryl) Acyl (such as: formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.), (C 1-6 alkyl or 6- to 10-membered aryl) sulfonyl, (C 1-6 alkoxy or 6- to 10-membered aryloxy)carbonyl, allyl, 2-tetrahydropyranyl (THP) and the like.
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-, wherein 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-, wherein 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-, wherein 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-, wherein 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, wherein 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, wherein 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 hydroxy groups, wherein alkyl is as defined above.
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 "thiol" refers to -SH.
术语“氨基”指-NH 2。 The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2。 The term "nitro" refers to -NO2 .
术语“氧代基”或“氧代”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.
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-, wherein 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。The compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that are structurally identical but differ in the arrangement of the 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, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in the compounds of the present disclosure may have additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are included within the scope of this disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (D)- and (+)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques (L)-isomer. An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, when the molecule contains basic functional groups (such as amino groups) or acidic functional groups (such as carboxyl groups), with appropriate optical Active acids or bases form diastereomeric salts, which are then resolved by conventional methods known in the art to yield the 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
Figure PCTCN2022074588-appb-000147
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022074588-appb-000148
可以为
Figure PCTCN2022074588-appb-000149
或者同时包含
Figure PCTCN2022074588-appb-000150
Figure PCTCN2022074588-appb-000151
两种构型。 In the chemical structure of the compound described in the present disclosure, the bond
Figure PCTCN2022074588-appb-000147
Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond
Figure PCTCN2022074588-appb-000148
can be
Figure PCTCN2022074588-appb-000149
or both
Figure PCTCN2022074588-appb-000150
Figure PCTCN2022074588-appb-000151
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, ie as a single isomer or as a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. An example of a lactam-lactam equilibrium is shown below:
Figure PCTCN2022074588-appb-000152
Figure PCTCN2022074588-appb-000152
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:
Figure PCTCN2022074588-appb-000153
Figure PCTCN2022074588-appb-000153
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 this disclosure and the naming of compounds does not exclude any tautomers.
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 having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, 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 toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All transformations of 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 attached to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and a partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.
本公开的化合物，当其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 the compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D", that position is understood to be at least 1000 times more abundant (i.e., deuterium) than the natural abundance of deuterium, which is 0.015%. 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 (i.e., 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).
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选地(任选)被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明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。 "Optionally" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "C 1-6 alkyl optionally (optionally) substituted by halogen or cyano" means that halogen or cyano may, but need not, be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the alkane The case where the group is not substituted by halogen and cyano.
“取代”或“取代的”指基团中的一个或多个氢原子，优选为1至6个，更优选为1至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(如烯属)键的碳原子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, independently of one another, are substituted by the corresponding number of substituents. A person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
“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 of the compounds described herein, or a pharmaceutically acceptable salt thereof, in admixture with other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
“可药用的盐”或“药学上可接受的盐”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盐。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 salt" or "pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have due biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, 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，取决于受试者的年龄和一般情况，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实验确定。With respect to a drug or pharmacologically active agent, the term "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, depending on the age and general condition of the subject, and also on the specific active substance. The appropriate therapeutically effective amount in individual cases 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 those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are 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 parameters such as pH, concentration, temperature, etc., it is indicated that the parameter can vary by ±10%, and is sometimes more preferably within ±5%. As will be understood by those skilled in the art, when parameters are not critical, numbers are generally given for illustrative purposes only, rather than limitations.
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 accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:
方案一Option One
本公开通式(I)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000154
Figure PCTCN2022074588-appb-000154
通式(IA)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，得到通式(I)所示的化合物或其可药用的盐， The compound represented by the general formula (IA) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
Figure PCTCN2022074588-appb-000155
环A、环B、环C、R 1至R 3、m、n和t如通式(I)中所定义。
Figure PCTCN2022074588-appb-000155
Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (I).
方案二Option II
本公开通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000156
Figure PCTCN2022074588-appb-000156
通式(IIA)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，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 its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(II)中所定义。 Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (II).
方案三third solution
本公开通式(II-1)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (II-1) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000157
Figure PCTCN2022074588-appb-000157
通式(II-1A)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，得到通式(II-1)所示的化合物或其可药用的盐， The compound represented by the general formula (II-1A) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(II-1)中所定义。 Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (II-1).
方案四Option 4
本公开通式(II-2)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (II-2) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000158
Figure PCTCN2022074588-appb-000158
通式(II-2A)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，得到通式(II-2)所示的化合物或其可药用的盐， The compound represented by the general formula (II-2A) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(II-2)中所定义。 Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (II-2).
方案五Option five
本公开通式(III)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000159
Figure PCTCN2022074588-appb-000159
通式(IIIA)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，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 its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(III)中所定义。 Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in general formula (III).
方案六Option 6
本公开通式(III-1)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (III-1) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000160
Figure PCTCN2022074588-appb-000160
通式(III-1A)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，得到通式(III-1)所示的化合物或其可药用的盐， The compound represented by the general formula (III-1A) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(III-1)中所定义。 Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (III-1).
方案七Option 7
本公开通式(III-2)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (III-2) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000161
Figure PCTCN2022074588-appb-000161
通式(III-2A)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，得到通式(III-2)所示的化合物或其可药用的盐， The compound represented by the general formula (III-2A) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、环B、环C、R 1至R 3、m、n和t如通式(III-2)中所定义。 Ring A, ring B, ring C, R 1 to R 3 , m, n and t are as defined in general formula (III-2).
方案八Option 8
本公开通式(IV)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (IV) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000162
Figure PCTCN2022074588-appb-000162
通式(IVA)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，得到通式(IV)所示的化合物或其可药用的盐， The compound represented by the general formula (IVA) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(IV)中所定义。 Rings A, R 1 to R 3 , m, n and t are as defined in general formula (IV).
方案九Option Nine
本公开通式(IV-1)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (IV-1) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000163
Figure PCTCN2022074588-appb-000163
通式(IV-1A)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，得到通式(IV-1)所示的化合物或其可药用的盐， The compound represented by the general formula (IV-1A) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(IV-1)中所定义。 Ring A, R 1 to R 3 , m, n and t are as defined in the general formula (IV-1).
方案十Option ten
本公开通式(IV-2)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (IV-2) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000164
Figure PCTCN2022074588-appb-000164
通式(IV-2A)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，得到通式(IV-2)所示的化合物或其可药用的盐， The compound represented by the general formula (IV-2A) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(IV-2)中所定义。 Ring A, R 1 to R 3 , m, n and t are as defined in general formula (IV-2).
方案十一Plan Eleven
本公开通式(V)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (V) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000165
Figure PCTCN2022074588-appb-000165
通式(VA)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，得到通式(V)所示的化合物或其可药用的盐， The compound represented by the general formula (VA) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(V)中所定义。 Rings A, R 1 to R 3 , m, n and t are as defined in general formula (V).
方案十二Option 12
本公开通式(V-1)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (V-1) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000166
Figure PCTCN2022074588-appb-000166
通式(V-1A)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，得到通式(V-1)所示的化合物或其可药用的盐， The compound represented by the general formula (V-1A) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(V-1)中所定义。 Ring A, R 1 to R 3 , m, n and t are as defined in the general formula (V-1).
方案十三Plan Thirteen
本公开通式(V-2)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (V-2) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
Figure PCTCN2022074588-appb-000167
Figure PCTCN2022074588-appb-000167
通式(V-2A)所示的化合物或其盐在酸性条件下脱去氨基保护基R w，得到通式(V-2)所示的化合物或其可药用的盐， The compound represented by the general formula (V-2A) or its salt is removed from the amino protecting group R w under acidic conditions to obtain the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof,
其中：in:
R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
环A、R 1至R 3、m、n和t如通式(V-2)中所定义。 Ring A, R 1 to R 3 , m, n and t are as defined in general formula (V-2).
上述脱保护反应中，所述的酸性条件中的酸包括有机酸和无机酸，所述的有机酸包括但不限于三氟乙酸、甲酸、乙酸、甲磺酸、对甲苯磺酸、Me 3SiCl和TMSOTf，优选三氟乙酸；所述的无机酸包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、盐酸、硫酸、硝酸和磷酸，优选盐酸。 In the above deprotection reaction, the acid in the acidic condition includes organic acid and inorganic acid, and the organic acid includes but is not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me 3 SiCl and TMSOTf, preferably trifluoroacetic acid; the inorganic acids include but are not limited to hydrogen chloride, hydrogen chloride solution in 1,4-dioxane, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, preferably hydrochloric acid.
上述反应优选在溶剂中进行，所用溶剂包括但不限于：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-二甲基乙酰胺及其混合物。The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane Alkane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide and mixtures thereof.
具体实施方式Detailed ways
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。The present disclosure is further described below in conjunction with the examples, 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(d)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE NEO 500M核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (d) are given in units of 10-6 (ppm). NMR was measured by Bruker AVANCE NEO 500M nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
质谱(MS)的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC(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)。Mass spectrometry (MS) was measured with Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC (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 HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。High performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD and a Waters HPLC e2695-2489 high performance liquid chromatograph.
手性HPLC分析测定使用Agilent 1260 DAD液相色谱仪。Chiral HPLC analysis was determined using an Agilent 1260 DAD liquid chromatograph.
高效液相制备色谱法使用Waters 2545-2767、Waters 2767-SQD2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。High performance liquid preparative chromatography used Waters 2545-2767, Waters 2767-SQD2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
手性制备色谱法使用Shimadzu LC-20AP制备型色谱仪。Chiral preparative chromatography used a Shimadzu LC-20AP preparative chromatograph.
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。The 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。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ~ 0.2mm, and the size of the TLC separation and purification products is 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IC 50值的测定用NovoStar酶标仪(德国BMG公司)。 The average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
本公开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 disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。There is no special description in the examples, and the reaction can be carried out in 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 or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或 HC2-SS型氢化仪。The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
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 and filled with hydrogen, and the operation is repeated 3 times.
微波反应使用CEM Discover-S 908860型微波反应器。The microwave reaction used a 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 description 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 is no special description in the examples, and 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：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and Adjust with alkaline or acidic reagents such as acetic acid.
实施例1-P1，1-P2Example 1-P1, 1-P2
((R)-1-(4-氟苯基)-6-((S)-2-甲基-2H-1,2,3-三唑-4-磺酰亚胺基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮1-P1((R)-1-(4-Fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazole-4-sulfonimido)-1,4 ,5,6,7,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 1 -P1
((R)-1-(4-氟苯基)-6-((R)-2-甲基-2H-1,2,3-三唑-4-磺酰亚胺基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮1-P2((R)-1-(4-Fluorophenyl)-6-((R)-2-methyl-2H-1,2,3-triazole-4-sulfonimido)-1,4 ,5,6,7,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 1 -P2
Figure PCTCN2022074588-appb-000168
Figure PCTCN2022074588-appb-000168
第一步first step
2-甲基-2H-1,2,3-三唑-4-磺酰胺1b2-Methyl-2H-1,2,3-triazole-4-sulfonamide 1b
将化合物2-甲基-2H-1,2,3-三唑-4-磺酰氯1a(4g，11.07mmol，采用公知的方法“Journal of Medicinal Chemistry,2017,60(8),3405-3421”制备而得)溶于氨的甲醇溶液(7M，30mL)中，搅拌反应3小时后，反应液减压浓缩后用柱层析色谱法以洗脱剂体系A纯化，得到标题化合物1b(1.9g，产率：53.2％)。Compound 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride 1a (4 g, 11.07 mmol, using a known method "Journal of Medicinal Chemistry, 2017, 60(8), 3405-3421" prepared) was dissolved in methanol solution of ammonia (7M, 30 mL), and after stirring for 3 hours, the reaction solution was concentrated under reduced pressure and purified by column chromatography with eluent system A to obtain the title compound 1b (1.9 g). , yield: 53.2%).
MS m/z(ESI):163.1[M+1]。MS m/z (ESI): 163.1 [M+1].
第二步second step
N-(叔丁基二甲基硅基)-2-甲基-2H-1,2,3-三唑-4-磺酰胺1cN-(tert-Butyldimethylsilyl)-2-methyl-2H-1,2,3-triazole-4-sulfonamide 1c
将1b(5g，30.83mmol)、叔丁基二甲基氯硅烷(7g，46.64mmol)溶于N,N-二甲基甲酰胺中，0℃加入三乙胺(10g，98.8mol)、4-二甲氨基吡啶(760mg，6.22mmol)，自然升至室温搅拌反应16小时，反应液减压浓缩后加入100mL水，乙酸乙酯萃取(50mL×3)后，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产物1c(2.6g，收率：30.5％))，产物不经纯化直接进行下一步反应。1b (5g, 30.83mmol) and tert-butyldimethylsilyl chloride (7g, 46.64mmol) were dissolved in N,N-dimethylformamide, and triethylamine (10g, 98.8mol), 4 was added at 0°C. - Dimethylaminopyridine (760mg, 6.22mmol), naturally warmed to room temperature and stirred for 16 hours, the reaction solution was concentrated under reduced pressure, added 100mL of water, extracted with ethyl acetate (50mL×3), combined the organic phases, anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to obtain the crude title product 1c (2.6 g, yield: 30.5%)). The product is directly subjected to the next step without purification.
MS m/z(ESI)：277.1[M+1]。MS m/z (ESI): 277.1 [M+1].
第三步third step
((R)-6-((R)-N-(叔丁基二甲基硅基)-2-甲基-2H-1,2,3-三唑-4-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮1e((R)-6-((R)-N-(tert-butyldimethylsilyl)-2-methyl-2H-1,2,3-triazole-4-sulfonimide)- 1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(tri Fluoromethyl)pyridin-2-yl)methanone 1e
((R)-6-((S)-N-(叔丁基二甲基硅基)-2-甲基-2H-1,2,3-三唑-4-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮1f((R)-6-((S)-N-(tert-butyldimethylsilyl)-2-methyl-2H-1,2,3-triazole-4-sulfonimide)- 1-(4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(tri Fluoromethyl)pyridin-2-yl)methanone 1f
将二氯三苯基膦(2.85g，8.55mmol)溶于20mL三氯甲烷中，0℃加入三乙胺(2.2g，21.74mmol)，搅拌5分钟后加入1c(1.43g，5.17mmol)，继续搅拌十分钟后加入1d(1.9g，4.29mol，采用专利申请“WO2013177559A2”中说明书第101页的中间体78公开的方法制备而得)，搅拌反应2小时后，反应液减压浓缩，残余物用柱层析色谱法以洗脱剂体系B纯化，得到标题化合物1e和1f的混合物(1.5g，产率：49.8％)。Dichlorotriphenylphosphine (2.85g, 8.55mmol) was dissolved in 20mL of trichloromethane, triethylamine (2.2g, 21.74mmol) was added at 0°C, and 1c (1.43g, 5.17mmol) was added after stirring for 5 minutes, After continuing to stir for ten minutes, 1d (1.9 g, 4.29 mol, prepared by the method disclosed in Intermediate 78 on page 101 of the specification in the patent application "WO2013177559A2") was added, and after stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the residual The material was purified by column chromatography with eluent system B to give a mixture of title compounds 1e and 1f (1.5 g, yield: 49.8%).
MS m/z(ESI)：701.1[M+1]。MS m/z (ESI): 701.1 [M+1].
第四步the fourth step
((R)-1-(4-氟苯基)-6-((S)-2-甲基-2H-1,2,3-三唑-4-磺酰亚胺基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮1-P1((R)-1-(4-Fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazole-4-sulfonimido)-1,4 ,5,6,7,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 1 -P1
((R)-1-(4-氟苯基)-6-((R)-2-甲基-2H-1,2,3-三唑-4-磺酰亚胺基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮1-P2((R)-1-(4-Fluorophenyl)-6-((R)-2-methyl-2H-1,2,3-triazole-4-sulfonimido)-1,4 ,5,6,7,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 1 -P2
将1e和1f的混合物(60mg，85.6μmol)溶于3mL四氢呋喃中，加入2mL 1M的盐酸，搅拌反应0.5小时。反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取(10 mL×3)，有机相减压浓缩后用高效液相色谱法(色谱柱：SharpSil-T，30*150mm，5μm；流动相：水相(10mM碳酸氢铵)和乙腈，梯度配比：水相25％-42％)纯化得到标题化合物1-P1(6mg，产率：11.9％)和1-P2(8mg，产率：15.9％)。The mixture of 1e and 1f (60 mg, 85.6 μmol) was dissolved in 3 mL of tetrahydrofuran, 2 mL of 1 M hydrochloric acid was added, and the reaction was stirred for 0.5 h. The reaction solution was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL×3), the organic phase was concentrated under reduced pressure and then subjected to high performance liquid chromatography (chromatographic column: SharpSil-T, 30*150 mm, 5 μm; mobile phase : aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 25%-42%) was purified to give the title compounds 1-P1 (6 mg, yield: 11.9%) and 1-P2 (8 mg, yield: 15.9%).
化合物1-P1(较短保留时间)：Compound 1-P1 (shorter retention time):
MS m/z(ESI)：587.2[M+1]。MS m/z (ESI): 587.2 [M+1].
HPLC分析：保留时间1.45分钟，纯度：96％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000169
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.45 minutes, purity: 96% (column: ACQUITY
Figure PCTCN2022074588-appb-000169
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3):δ8.93(d,1H),8.16(s,1H),7.88(s,1H),7.72(d,1H),7.47(dd,2H),7.33(s,1H),7.20(t,2H),6.55(s,1H),5.73(d,1H),4.28(d,4H),4.07-3.95(m,1H),2.96(dd,2H),2.83(d,1H),2.63-2.51(m,3H)。 1 H NMR (1500MHz, CDCl 3 ): δ 8.93(d,1H), 8.16(s,1H), 7.88(s,1H), 7.72(d,1H), 7.47(dd,2H), 7.33(s ,1H),7.20(t,2H),6.55(s,1H),5.73(d,1H),4.28(d,4H),4.07-3.95(m,1H),2.96(dd,2H),2.83( d, 1H), 2.63-2.51 (m, 3H).
化合物1-P2(较长保留时间)：Compound 1-P2 (longer retention time):
MS m/z(ESI)：587.2[M+1]。MS m/z (ESI): 587.2 [M+1].
HPLC分析：保留时间1.47分钟，纯度：97％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000170
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.47 minutes, purity: 97% (column: ACQUITY
Figure PCTCN2022074588-appb-000170
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3):δ8.91(d,1H),8.18(s,1H),7.91(s,1H),7.76-7.72(m,1H),7.47(dd,2H),7.33(s,1H),7.20(t,2H),6.52(s,1H),5.59-5.53(m,1H),4.28(s,3H),4.02(d,2H),2.92(d,1H),2.85(d,1H),2.79-2.64(m,2H),2.51(d,1H),2.19(s,1H)。 1 H NMR (1500 MHz, CDCl 3 ): δ 8.91 (d, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.76-7.72 (m, 1H), 7.47 (dd, 2H), 7.33 (s, 1H), 7.20(t, 2H), 6.52(s, 1H), 5.59-5.53(m, 1H), 4.28(s, 3H), 4.02(d, 2H), 2.92(d, 1H), 2.85(d,1H), 2.79-2.64(m,2H), 2.51(d,1H), 2.19(s,1H).
实施例2-P1，2-P2Example 2-P1, 2-P2
((R)-1-(4-氟苯基)-6-((S)-1-甲基-1H-吡唑-4-磺酰亚胺基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮2-P1((R)-1-(4-Fluorophenyl)-6-((S)-1-methyl-1H-pyrazole-4-sulfonimido)-1,4,5,6,7 ,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 2-P1
((R)-1-(4-氟苯基)-6-((R)-1-甲基-1H-吡唑-4-磺酰亚胺基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮2-P2((R)-1-(4-Fluorophenyl)-6-((R)-1-methyl-1H-pyrazole-4-sulfonimido)-1,4,5,6,7 ,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 2-P2
Figure PCTCN2022074588-appb-000171
Figure PCTCN2022074588-appb-000171
Figure PCTCN2022074588-appb-000172
Figure PCTCN2022074588-appb-000172
第一步first step
1-甲基-1H-吡唑-4-磺酰胺2b1-Methyl-1H-pyrazole-4-sulfonamide 2b
将化合物1-甲基-1H-吡唑-4-磺酰氯2a(2g，11.07mmol)溶于150mL二氯甲烷中，加入氨的甲醇溶液(7M，3mL)，搅拌反应14小时后，反应液减压浓缩得到粗品标题产物2b(1.8g，产率：98.6％)，不经纯化直接用于下一步。Compound 1-methyl-1H-pyrazole-4-sulfonyl chloride 2a (2 g, 11.07 mmol) was dissolved in 150 mL of dichloromethane, methanol solution of ammonia (7 M, 3 mL) was added, and after stirring for 14 hours, the reaction solution was Concentration under reduced pressure gave the crude title product 2b (1.8 g, yield: 98.6%), which was used in the next step without purification.
MS m/z(ESI)：161.8[M+1]。MS m/z (ESI): 161.8 [M+1].
第二步second step
N-(叔丁基二甲基硅基)-1-甲基-1H-吡唑-4-磺酰胺2cN-(tert-Butyldimethylsilyl)-1-methyl-1H-pyrazole-4-sulfonamide 2c
将2b(1.8g，11.16mmol)、叔丁基二甲基氯硅烷(1.1g，13.35mmol)溶于N,N-二甲基甲酰胺中，0℃加入三乙胺(1.7g，16.8mol)，自然升至室温搅拌反应16小时。反应液减压浓缩后加入150mL水，用乙酸乙酯萃取(30mL×3)后，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩即得标题化合物2c(1g，收率：32.5％))。2b (1.8g, 11.16mmol) and tert-butyldimethylsilyl chloride (1.1g, 13.35mmol) were dissolved in N,N-dimethylformamide, and triethylamine (1.7g, 16.8mol) was added at 0°C ), the reaction was naturally raised to room temperature and stirred for 16 hours. After the reaction solution was concentrated under reduced pressure, 150 mL of water was added, extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 2c (1 g, yield: 32.5%)).
MS m/z(ESI)：276.1[M+1]。MS m/z (ESI): 276.1 [M+1].
第三步third step
((R)-6-((R)-N-(叔丁基二甲基硅基)-1-甲基-1H-吡唑-4-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮2d((R)-6-((R)-N-(tert-butyldimethylsilyl)-1-methyl-1H-pyrazole-4-sulfonimide)-1-(4-fluoro Phenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridine- 2-yl)methanone 2d
((R)-6-((S)-N-(叔丁基二甲基硅基)-1-甲基-1H-吡唑-4-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮2e((R)-6-((S)-N-(tert-butyldimethylsilyl)-1-methyl-1H-pyrazole-4-sulfonimido)-1-(4-fluoro Phenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridine- 2-yl)methanone 2e
将二氯三苯基膦(120mg，360.15μmol)溶于3mL三氯甲烷中，0℃加入三乙胺(91mg，820μmol)，搅拌5分钟后加入2c(75mg，272.28μmol)，继续搅拌十分钟后加入1d(80mg，180.82μmol)，自然升至室温搅拌反应2小时。反应液中加入5 mL水，用二氯甲烷萃取(10mL×3)，合并有机相，减压浓缩，残余物经柱层析色谱法以洗脱剂体系B纯化，得到标题化合物2d和2e的混合物(100mg，产率：79.0％)。Dichlorotriphenylphosphine (120 mg, 360.15 μmol) was dissolved in 3 mL of trichloromethane, triethylamine (91 mg, 820 μmol) was added at 0°C, 2c (75 mg, 272.28 μmol) was added after stirring for 5 minutes, and the stirring was continued for ten minutes Then, 1d (80 mg, 180.82 μmol) was added, and the reaction was naturally raised to room temperature and stirred for 2 hours. 5 mL of water was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to obtain the title compounds 2d and 2e. mixture (100 mg, yield: 79.0%).
MS m/z(ESI)：700.1[M+1]。MS m/z (ESI): 700.1 [M+1].
第四步the fourth step
((R)-1-(4-氟苯基)-6-((S)-1-甲基-1H-吡唑-4-磺酰亚胺基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮2-P1((R)-1-(4-Fluorophenyl)-6-((S)-1-methyl-1H-pyrazole-4-sulfonimido)-1,4,5,6,7 ,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 2-P1
((R)-1-(4-氟苯基)-6-((R)-1-甲基-1H-吡唑-4-磺酰亚胺基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮2-P2((R)-1-(4-Fluorophenyl)-6-((R)-1-methyl-1H-pyrazole-4-sulfonimido)-1,4,5,6,7 ,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 2-P2
将2d和2e的混合物(150mg，71.44μmol)溶于3mL四氢呋喃中，加入2mL 1M的盐酸，搅拌反应0.5小时。反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取(10mL×3)，有机相减压浓缩后用高效液相色谱法(色谱柱：SharpSil-T，30*150mm，5μm；流动相：水相(10mM碳酸氢铵)，乙腈，梯度配比：水相25％-42％)纯化得到标题化合物2-P1(5mg，产率：11.9％)和2-P2(20mg，产率：47.8％)。The mixture of 2d and 2e (150 mg, 71.44 μmol) was dissolved in 3 mL of tetrahydrofuran, 2 mL of 1M hydrochloric acid was added, and the reaction was stirred for 0.5 h. The reaction solution was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL×3), the organic phase was concentrated under reduced pressure and then subjected to high performance liquid chromatography (chromatographic column: SharpSil-T, 30*150 mm, 5 μm; mobile phase: Aqueous phase (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: aqueous phase 25%-42%) was purified to give the title compounds 2-P1 (5 mg, yield: 11.9%) and 2-P2 (20 mg, yield: 47.8 %).
化合物2-P1(较短保留时间)：Compound 2-P1 (shorter retention time):
MS m/z(ESI)：586.2[M+1]。MS m/z (ESI): 586.2 [M+1].
HPLC分析：保留时间2.68分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022074588-appb-000173
C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 2.68 minutes, purity: 99% (column: ACQUITY
Figure PCTCN2022074588-appb-000173
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3):δ8.92(d,1H),8.18-8.15(m,1H),7.75(s,1H),7.74-7.70(m,2H),7.150-7.44(m,2H),7.31(s,1H),7.24-7.17(m,2H),6.53(d,1H),5.56(dd,1H),4.26(d,1H),3.95(s,3H),3.94-3.88(m,1H),2.94(d,1H),2.88-2.80(m,1H),2.62(d,1H),2.54(d,1H),2.43-2.29(m,2H)。 1 H NMR (1500MHz, CDCl 3 ): δ 8.92 (d, 1H), 8.18-8.15 (m, 1H), 7.75 (s, 1H), 7.74-7.70 (m, 2H), 7.150-7.44 (m, 2H), 7.31(s, 1H), 7.24-7.17(m, 2H), 6.53(d, 1H), 5.56(dd, 1H), 4.26(d, 1H), 3.95(s, 3H), 3.94-3.88 (m, 1H), 2.94 (d, 1H), 2.88-2.80 (m, 1H), 2.62 (d, 1H), 2.54 (d, 1H), 2.43-2.29 (m, 2H).
化合物2-P2(较长保留时间)：Compound 2-P2 (longer retention time):
MS m/z(ESI)：586.2[M+1]。MS m/z (ESI): 586.2 [M+1].
HPLC分析：保留时间2.74分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022074588-appb-000174
C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 2.74 minutes, purity: 99% (column: ACQUITY
Figure PCTCN2022074588-appb-000174
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3):δ8.92(d,1H),8.20(s,1H),7.78(s,1H),7.75(d,2H),7.49-7.43(m,2H),7.32(s,1H),7.23-7.16(m,2H),6.150(d,1H),5.150(dd,1H),4.05(d,1H),3.97-4.10(m,5H),2.92(d,1H),2.82-2.72(m,1H),2.57(d,1H),2.52-2.45(m,1H),2.36(ddd,1H)。 1 H NMR (1500MHz, CDCl 3 ): δ 8.92(d,1H), 8.20(s,1H), 7.78(s,1H), 7.75(d,2H), 7.49-7.43(m,2H), 7.32 (s,1H),7.23-7.16(m,2H),6.150(d,1H),5.150(dd,1H),4.05(d,1H),3.97-4.10(m,5H),2.92(d,1H) ), 2.82-2.72 (m, 1H), 2.57 (d, 1H), 2.52-2.45 (m, 1H), 2.36 (ddd, 1H).
实施例3-P1，3-P2Example 3-P1, 3-P2
((R)-6-((S)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮3-P1((R)-6-((S)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonimido)-1-(4-fluorophenyl )-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridine-2- base) ketone 3-P1
((R)-6-((R)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮3-P2((R)-6-((R)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonimido)-1-(4-fluorophenyl )-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridine-2- base) ketone 3-P2
Figure PCTCN2022074588-appb-000175
Figure PCTCN2022074588-appb-000175
第一步first step
3-溴-5,6-二氢-4H-吡咯并[1,2-b]吡唑3b3-Bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 3b
将化合物3a(200mg，1.84mmol，上海乐研)溶于乙腈(5mL)，加入N-溴代丁二酰亚胺(3150mg，1.97mmol)，搅拌反应14小时。反应液减压浓缩后加入15mL水，用乙酸乙酯(10mL×3)萃取，收集有机相，用饱和氯化钠溶液洗涤(10mL×3)后，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用柱层析色谱法以洗脱剂体系C纯化得到标题化合物3b(340mg，产率：98.2％)。Compound 3a (200 mg, 1.84 mmol, Shanghai Leyan) was dissolved in acetonitrile (5 mL), N-bromosuccinimide (3150 mg, 1.97 mmol) was added, and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, added with 15 mL of water, extracted with ethyl acetate (10 mL×3), the organic phase was collected, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced It was concentrated under pressure, and the residue was purified by column chromatography with eluent system C to give the title compound 3b (340 mg, yield: 98.2%).
MS m/z(ESI)：188.2[M+1]。MS m/z (ESI): 188.2 [M+1].
第二步second step
3-((4-甲氧基苄基)硫代)-5,6-二氢-4H-吡咯并[1,2-b]吡唑3c3-((4-Methoxybenzyl)thio)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 3c
将化合物3b(2150mg，1.33mmol)、化合物4-甲氧基苄硫醇(2150mg，1.62mmol)溶于5mL 1,4-二氧六环中，加入三(二亚苄基丙酮)二钯(123mg，0.134mmol)、 4,5-双二苯基膦-9,9-二甲基氧杂蒽(155mg，0.268mmol)、N,N-二异丙基乙胺(3150mg，2.70mmol)。氮气氛下，120℃微波反应1.5小时。冷却至室温，反应液减压浓缩后残余物用柱层析色谱法以洗脱剂体系B纯化得到标题产物3c(340mg，产率：97.7％)。Compound 3b (2150 mg, 1.33 mmol), compound 4-methoxybenzylthiol (2150 mg, 1.62 mmol) were dissolved in 5 mL of 1,4-dioxane, and tris(dibenzylideneacetone)dipalladium ( 123 mg, 0.134 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (155 mg, 0.268 mmol), N,N-diisopropylethylamine (3150 mg, 2.70 mmol). Under nitrogen atmosphere, microwave reaction at 120°C for 1.5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to obtain the title product 3c (340 mg, yield: 97.7%).
MS m/z(ESI)：261.1[M+1]。MS m/z (ESI): 261.1 [M+1].
第三步third step
5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-磺酰氯3d5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonyl chloride 3d
将化合物3c(340mg，1.30mmol)溶于6mL乙酸和水(V/V＝2:1)的混合溶液中，加入N-氯代丁二酰亚胺(700mg，5.24mmol)，搅拌反应2小时。反应液中加入15mL水，用乙酸乙酯(10mL×3)萃取，收集有机相，依次用饱和碳酸氢钠溶液(10mL)、饱和氯化钠溶液(10mL)洗涤后，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用柱层析色谱法以洗脱剂体系C纯化得到标题化合物3d(200mg，产率：74.1％)。Compound 3c (340 mg, 1.30 mmol) was dissolved in a mixed solution of 6 mL of acetic acid and water (V/V=2:1), N-chlorosuccinimide (700 mg, 5.24 mmol) was added, and the reaction was stirred for 2 hours . 15 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phase was collected, washed with saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL) in turn, and dried with anhydrous sodium sulfate , filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system C to give the title compound 3d (200 mg, yield: 74.1%).
MS m/z(ESI)：207.1[M+1]。MS m/z (ESI): 207.1 [M+1].
第四步the fourth step
5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-磺酰胺3e5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonamide 3e
将化合物3d(370mg，1.79mmol)溶于氨的甲醇溶液(7M，5mL)中，搅拌反应1小时后，反应液减压浓缩得到粗品标题产物3e(200mg，产率：59.66％)，不经纯化直接用于下一步。Compound 3d (370 mg, 1.79 mmol) was dissolved in methanolic ammonia solution (7 M, 5 mL), and after stirring for 1 hour, the reaction solution was concentrated under reduced pressure to obtain the crude title product 3e (200 mg, yield: 59.66%), which was not purified without further purification. Purification was used directly in the next step.
MS m/z(ESI)：188.2[M+1]。MS m/z (ESI): 188.2 [M+1].
第五步the fifth step
N-(叔丁基二甲基硅基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-磺酰胺3fN-(tert-Butyldimethylsilyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonamide 3f
将3e(300mg，1.62mmol)、叔丁基二甲基氯硅烷(200mg，2.42mmol，上海毕得)溶于N,N-二甲基甲酰胺中，0℃加入三乙胺(811mg，8.01mmol)、4-二甲氨基吡啶(10mg，324.7μmol)，自然升至室温搅拌反应16小时。反应液减压浓缩后加入15mL水，用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩即得粗品标题产物3f(200mg，收率：41.4％)，产物不经纯化直接用于下一步反应。3e (300 mg, 1.62 mmol), tert-butyldimethylsilyl chloride (200 mg, 2.42 mmol, Shanghai Bide) were dissolved in N,N-dimethylformamide, and triethylamine (811 mg, 8.01 mmol) was added at 0°C. mmol), 4-dimethylaminopyridine (10 mg, 324.7 μmol), and the reaction was naturally warmed to room temperature and stirred for 16 hours. After the reaction solution was concentrated under reduced pressure, 15 mL of water was added, extracted with ethyl acetate (10 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 title product 3f (200 mg, yield: 41.4%), the product was used directly in the next reaction without purification.
MS m/z(ESI)：302.2[M+1]。MS m/z (ESI): 302.2 [M+1].
第六步Step 6
((R)-6-((R)-N-(叔丁基二甲基硅基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-磺酰亚胺基基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮3g((R)-6-((R)-N-(tert-butyldimethylsilyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonyl imino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl )(4-(trifluoromethyl)pyridin-2-yl)methanone 3g
((R)-6-((S)-N-(叔丁基二甲基硅基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-磺酰亚胺基基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮3h((R)-6-((S)-N-(tert-butyldimethylsilyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonyl imino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl )(4-(trifluoromethyl)pyridin-2-yl)methanone 3h
将二氯三苯基膦(57mg，717.0μmol)溶于3mL三氯甲烷中，0℃加入三乙胺(60 mg，592.9mmol)，搅拌5分钟后加入3f(40mg，132.6μmol)，继续搅拌十分钟后加入1d(150mg，113.0μmol)，自然升至室温搅拌反应16小时。反应液中加入5mL水，用二氯甲烷萃取(10mL×3)，合并有机相，减压浓缩，残余物用柱层析色谱法以洗脱剂体系B纯化，得到标题化合物3g和3h的混合物(150mg，产率：60.9％)。Dichlorotriphenylphosphine (57 mg, 717.0 μmol) was dissolved in 3 mL of trichloromethane, triethylamine (60 mg, 592.9 mmol) was added at 0°C, 3f (40 mg, 132.6 μmol) was added after stirring for 5 minutes, and the stirring was continued. Ten minutes later, 1d (150 mg, 113.0 μmol) was added, and the mixture was naturally raised to room temperature and stirred for 16 hours. 5 mL of water was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to obtain a mixture of the title compounds 3g and 3h (150 mg, yield: 60.9%).
MS m/z(ESI)：726.2[M+1]。MS m/z (ESI): 726.2 [M+1].
第七步Step 7
((R)-6-((S)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮3-P1((R)-6-((S)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonimido)-1-(4-fluorophenyl )-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridine-2- base) ketone 3-P1
((R)-6-((R)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮3-P2((R)-6-((R)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonimido)-1-(4-fluorophenyl )-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridine-2- base) ketone 3-P2
将3g和3h的混合物(150mg，60.88μmol)溶于3mL四氢呋喃中，加入2mL 1M的盐酸，搅拌反应0.5小时。反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取(10mL×3)，合并有机相，减压浓缩。残余物用高效液相色谱法(色谱柱：SharpSil-T，30*150mm，5μm；流动相：水相(10mM碳酸氢铵)，乙腈，梯度配比：水相25％-42％)纯化，得到标题化合物3-P1(6mg，产率：14.2％)和3-P2(6mg，产率：14.2％)。The mixture of 3 g and 3 h (150 mg, 60.88 μmol) was dissolved in 3 mL of tetrahydrofuran, 2 mL of 1 M hydrochloric acid was added, and the reaction was stirred for 0.5 h. The reaction solution was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL×3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: SharpSil-T, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: aqueous phase 25%-42%), The title compounds 3-P1 (6 mg, yield: 14.2%) and 3-P2 (6 mg, yield: 14.2%) were obtained.
化合物3-P1(较短保留时间)：Compound 3-P1 (shorter retention time):
MS m/z(ESI)：612.2[M+1]。MS m/z (ESI): 612.2 [M+1].
HPLC分析：保留时间1.40分钟，纯度：99％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000176
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.40 minutes, purity: 99% (column: ACQUITY
Figure PCTCN2022074588-appb-000176
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3):δ8.91(d,1H),8.16(s,1H),7.72(d,2H),7.150-7.44(m,2H),7.31(s,1H),7.20(t,2H),6.52(d,1H),5.58-5.52(m,1H),4.24(d,1H),4.18(q,2H),3.90(d,1H),3.09(tt,3H),2.94(d,1H),2.88-2.79(m,1H),2.72-2.62(m,3H),2.54(d,1H),2.48-2.40(m,1H)。 1 H NMR (1500MHz, CDCl 3 ): δ 8.91(d,1H), 8.16(s,1H), 7.72(d,2H), 7.150-7.44(m,2H), 7.31(s,1H), 7.20 (t, 2H), 6.52(d, 1H), 5.58-5.52(m, 1H), 4.24(d, 1H), 4.18(q, 2H), 3.90(d, 1H), 3.09(tt, 3H), 2.94(d,1H), 2.88-2.79(m,1H), 2.72-2.62(m,3H), 2.54(d,1H), 2.48-2.40(m,1H).
化合物3-P2(较长保留时间)：Compound 3-P2 (longer retention time):
MS m/z(ESI)：612.2[M+1]。MS m/z (ESI): 612.2 [M+1].
HPLC分析：保留时间1.43分钟，纯度：99％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000177
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.43 minutes, purity: 99% (column: ACQUITY
Figure PCTCN2022074588-appb-000177
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3):δ8.89(d,1H),8.17(s,1H),7.72(s,2H),7.47-7.41(m,2H),7.29(s,1H),7.18(t,2H),6.47(s,1H),5.48(d,1H),4.18(t,2H),4.04(d,1H),3.91(s,1H),3.09(q,2H),2.90(d,1H),2.79-2.57(m,5H),2.47(d,1H),2.38(t,1H)。 1 H NMR (1500MHz, CDCl 3 ): δ 8.89(d,1H), 8.17(s,1H), 7.72(s,2H), 7.47-7.41(m,2H), 7.29(s,1H), 7.18 (t, 2H), 6.47(s, 1H), 5.48(d, 1H), 4.18(t, 2H), 4.04(d, 1H), 3.91(s, 1H), 3.09(q, 2H), 2.90( d, 1H), 2.79-2.57 (m, 5H), 2.47 (d, 1H), 2.38 (t, 1H).
实施例4-P1，4-P2Example 4-P1, 4-P2
((4aR,8aS)-1-(4-氟苯基)-6-((S)-2-甲基-2H-1,2,3-三唑-4-磺酰亚胺 基)-1,4,5,6,7,8,8a,9-八氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮4-P1((4aR,8aS)-1-(4-Fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazole-4-sulfonimide)-1 ,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridine-2 -yl)methanone 4-P1
((4aR,8aS)-1-(4-氟苯基)-6-((R)-2-甲基-2H-1,2,3-三唑-4-磺酰亚胺基)-1,4,5,6,7,8,8a,9-八氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮4-P2((4aR,8aS)-1-(4-Fluorophenyl)-6-((R)-2-methyl-2H-1,2,3-triazole-4-sulfonimide)-1 ,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridine-2 -yl)methanone 4-P2
Figure PCTCN2022074588-appb-000178
Figure PCTCN2022074588-appb-000178
第一步first step
(4aR,8aS)-1-(4-氟苯基)-4a-(4-(三氟甲基)吡啶酰基)-1,4,4a,5,7,8,8a,9-八氢-6H-吡唑并[3,4-g]异喹啉-6-羧酸叔丁基酯4b(4aR,8aS)-1-(4-Fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-1,4,4a,5,7,8,8a,9-octahydro- 6H-Pyrazolo[3,4-g]isoquinoline-6-carboxylate tert-butyl ester 4b
将化合物4a(400mg，737.3μmol，采用专利申请“WO2013177559A2”中说明书第104页的中间体82公开的方法制备而得)溶于甲醇(10mL)，加入10％钯碳催化剂(湿)(200mg)，氢气氛下搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩得到粗品标题产物4b(400mg，产率：99.6％)，产物不经纯化直接进行下一步反应。Compound 4a (400 mg, 737.3 μmol, prepared by the method disclosed in intermediate 82 on page 104 of the specification in patent application “WO2013177559A2”) was dissolved in methanol (10 mL), and 10% palladium-carbon catalyst (wet) (200 mg) was added. , and the reaction was stirred under a hydrogen atmosphere for 12 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude title product 4b (400 mg, yield: 99.6%). The product was directly subjected to the next reaction without purification.
MS m/z(ESI)：545.0[M+1]。MS m/z (ESI): 545.0 [M+1].
第二步second step
((4aR,8aS)-1-(4-氟苯基)-1,4,5,6,7,8,8a,9-八氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮4c((4aR,8aS)-1-(4-Fluorophenyl)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquine Linn-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 4c
化合物4b(1g，1.84mmol)溶解于5mL二氯甲烷中，滴加三氟乙酸(2g，17.5 mmol)，搅拌1小时。用饱和碳酸氢钠溶液中和体系至弱碱性，用乙酸乙酯萃取(150mL×3)，合并有机相，减压浓缩，得到粗品标题产物粗品4c(0.5g，产率：61.3％)，产物不经纯化直接进行下一步反应。Compound 4b (1 g, 1.84 mmol) was dissolved in 5 mL of dichloromethane, trifluoroacetic acid (2 g, 17.5 mmol) was added dropwise, and the mixture was stirred for 1 hour. The system was neutralized to weakly basic with saturated sodium bicarbonate solution, extracted with ethyl acetate (150 mL×3), the organic phases were combined and concentrated under reduced pressure to obtain the crude title product crude 4c (0.5 g, yield: 61.3%), The product was directly carried to the next step without purification.
MS m/z(ESI)：445.0[M+1]。MS m/z (ESI): 445.0 [M+1].
第三步third step
((4aR)-6-((R)-N-(叔丁基二甲基硅基)-2-甲基-2H-1,2,3-三唑-4-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8,8a,9-八氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮4d((4aR)-6-((R)-N-(tert-butyldimethylsilyl)-2-methyl-2H-1,2,3-triazole-4-sulfonimide)- 1-(4-Fluorophenyl)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)( 4-(Trifluoromethyl)pyridin-2-yl)methanone 4d
((4aR)-6-((S)-N-(叔丁基二甲基硅基)-2-甲基-2H-1,2,3-三唑-4磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8,8a,9-八氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮4e((4aR)-6-((S)-N-(tert-butyldimethylsilyl)-2-methyl-2H-1,2,3-triazole-4sulfonimide)-1 -(4-Fluorophenyl)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4 -(Trifluoromethyl)pyridin-2-yl)methanone 4e
将二氯三苯基膦(203mg，609.26μmol)溶于5mL三氯甲烷中，0℃加入三乙胺(210mg，2.07mmol)，搅拌5分钟后加入1c(40mg，132.6μmol)，继续搅拌十分钟后加入4c(150mg，113.0μmol)，自然升至室温，搅拌反应16小时。向反应液中加入5mL水，用二氯甲烷萃取(10mL×3)，合并有机相，减压浓缩，残余物用柱层析色谱法以洗脱剂体系B纯化，得到标题化合物4d和4e的混合物(180mg，产率：70.3％)。Dichlorotriphenylphosphine (203 mg, 609.26 μmol) was dissolved in 5 mL of trichloromethane, triethylamine (210 mg, 2.07 mmol) was added at 0°C, 1c (40 mg, 132.6 μmol) was added after stirring for 5 minutes, and the stirring was continued for ten After minutes, 4c (150 mg, 113.0 μmol) was added, and the mixture was naturally warmed to room temperature, and the reaction was stirred for 16 hours. 5 mL of water was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to obtain the title compounds 4d and 4e. mixture (180 mg, yield: 70.3%).
MS m/z(ESI)：703.0[M+1]。MS m/z (ESI): 703.0 [M+1].
第四步the fourth step
((4aR,8aS)-1-(4-氟苯基)-6-((S)-2-甲基-2H-1,2,3-三唑-4-磺酰亚胺基)-1,4,5,6,7,8,8a,9-八氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮4-P1((4aR,8aS)-1-(4-Fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazole-4-sulfonimide)-1 ,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridine-2 -yl)methanone 4-P1
((4aR,8aS)-1-(4-氟苯基)-6-((R)-2-甲基-2H-1,2,3-三唑-4-磺酰亚胺基)-1,4,5,6,7,8,8a,9-八氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮4-P2((4aR,8aS)-1-(4-Fluorophenyl)-6-((R)-2-methyl-2H-1,2,3-triazole-4-sulfonimide)-1 ,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridine-2 -yl)methanone 4-P2
将化合物4d和4e的混合物(200mg，284.56μmol)溶于3mL四氢呋喃中，加入2mL 1M的盐酸，搅拌反应0.5小时，反应液用饱和碳酸氢钠溶液中和，用乙酸乙酯萃取(15mL×3)，合并有机相，减压浓缩后用高效液相色谱法(色谱柱：SharpSil-T，30*150mm，5μm；流动相：水相(10mM碳酸氢铵)，乙腈，梯度配比：水相25％-42％)纯化，得到标题化合物4-P1(20mg，产率：11.9％)和4-P2(20mg，产率：11.9％)。The mixture of compounds 4d and 4e (200 mg, 284.56 μmol) was dissolved in 3 mL of tetrahydrofuran, 2 mL of 1M hydrochloric acid was added, the reaction was stirred for 0.5 hour, the reaction solution was neutralized with saturated sodium bicarbonate solution, and extracted with ethyl acetate (15 mL×3 ), combined the organic phases, concentrated under reduced pressure and used high performance liquid chromatography (chromatographic column: SharpSil-T, 30*150mm, 5μm; mobile phase: water phase (10mM ammonium bicarbonate), acetonitrile, gradient ratio: water phase 25%-42%) to obtain the title compounds 4-P1 (20 mg, yield: 11.9%) and 4-P2 (20 mg, yield: 11.9%).
化合物4-P1(较短保留时间)：Compound 4-P1 (shorter retention time):
MS m/z(ESI):589.0[M+1]。MS m/z (ESI): 589.0 [M+1].
HPLC分析：保留时间1.48分钟，纯度：99％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000179
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.48 minutes, purity: 99% (column: ACQUITY
Figure PCTCN2022074588-appb-000179
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3):δ8.91(d,1H),8.11(d,1H),7.88(s,1H),7.68(d,1H),7.53-7.47(m,2H),7.35(s,1H),7.17(dd,2H),5.78(dd,1H),4.31-4.25(m,4H),4.06(d,1H),3.43(dd,1H),2.75(dd,1H),2.63(d,1H),2.53(d,3H),2.43(tt,1H),1.86-1.74(m,2H)。 1 H NMR (1500MHz, CDCl 3 ): δ 8.91(d,1H), 8.11(d,1H), 7.88(s,1H), 7.68(d,1H), 7.53-7.47(m,2H), 7.35 (s,1H),7.17(dd,2H),5.78(dd,1H),4.31-4.25(m,4H),4.06(d,1H),3.43(dd,1H),2.75(dd,1H), 2.63(d,1H), 2.53(d,3H), 2.43(tt,1H), 1.86-1.74(m,2H).
化合物4-P2(较长保留时间)：Compound 4-P2 (longer retention time):
MS m/z(ESI)：589.0[M+1]。MS m/z (ESI): 589.0 [M+1].
HPLC分析：保留时间1.51分钟，纯度：99％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000180
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.51 minutes, purity: 99% (column: ACQUITY
Figure PCTCN2022074588-appb-000180
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3):δ8.94(d,1H),8.12(s,1H),7.91(s,1H),7.72(d,1H),7.150(dd,2H),7.34(s,1H),7.18(t,2H),5.77(d,1H),4.30(s,3H),4.13-4.06(m,2H),3.43(dd,1H),2.75(dd,1H),2.60(t,2H),2.52-2.42(m,2H),1.87-1.73(m,3H)。 1 H NMR (1500MHz, CDCl 3 ): δ 8.94(d,1H), 8.12(s,1H), 7.91(s,1H), 7.72(d,1H), 7.150(dd,2H), 7.34(s ,1H),7.18(t,2H),5.77(d,1H),4.30(s,3H),4.13-4.06(m,2H),3.43(dd,1H),2.75(dd,1H),2.60( t, 2H), 2.52-2.42 (m, 2H), 1.87-1.73 (m, 3H).
实施例5-P1，5-P2Example 5-P1, 5-P2
((R)-6-(S)-(5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-3-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮5-P1((R)-6-(S)-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazine-3-sulfonimido)-1-( 4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl) )pyridin-2-yl)methanone 5-P1
((R)-6-(R)-(5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-3-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮5-P2((R)-6-(R)-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazine-3-sulfonimido)-1-( 4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl) )pyridin-2-yl)methanone 5-P2
Figure PCTCN2022074588-appb-000181
Figure PCTCN2022074588-appb-000181
Figure PCTCN2022074588-appb-000182
Figure PCTCN2022074588-appb-000182
第一步first step
3-((4-甲氧基苄基)硫基)-5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪5b3-((4-Methoxybenzyl)thio)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine 5b
将化合物3-溴-5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪5a(300mg，1.47mmmol，药明康德)、化合物4-甲氧基苄硫醇(341mg，2.21mmol，上海毕得)溶于6mL 1,4-二氧六环中，加入三(二亚苄基丙酮)二钯(135mg，0.147mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(170mg，0.293mmol)、N,N-二异丙基乙胺(432mg，3.34mmol)，氮气氛下，120℃微波反应1.5小时。冷却至室温，反应液减压浓缩后用柱层析色谱法以洗脱剂体系B纯化得到标题化合物5b(300mg，产率：73.4％)。Compound 3-bromo-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine 5a (300mg, 1.47mmmol, WuXi AppTec), compound 4-methoxybenzyl Thiol (341mg, 2.21mmol, Shanghai Bide) was dissolved in 6mL of 1,4-dioxane, tris(dibenzylideneacetone)dipalladium (135mg, 0.147mmol), 4,5-bisdiphenyl were added phosphine-9,9-dimethylxanthene (170 mg, 0.293 mmol), N,N-diisopropylethylamine (432 mg, 3.34 mmol), microwave reaction at 120° C. for 1.5 hours under nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by column chromatography with eluent system B to obtain the title compound 5b (300 mg, yield: 73.4%).
MS m/z(ESI)：277.1[M+1]。MS m/z (ESI): 277.1 [M+1].
第二步second step
5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-3-磺酰氯5c5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazine-3-sulfonyl chloride 5c
将化合物5b(400mg，1.44mmol)溶于13.5mL乙酸和水(V/V＝2:1)的混合溶液中，加入N-氯代丁二酰亚胺(773mg，5.78mmol)，搅拌反应2小时。反应液中加入15mL水，用乙酸乙酯(10mL×3)萃取，收集有机相，依次用饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用柱层析色谱法以洗脱剂体系C纯化得到标题化合物5c(100mg，产率：31.0％)。Compound 5b (400 mg, 1.44 mmol) was dissolved in 13.5 mL of a mixed solution of acetic acid and water (V/V=2:1), N-chlorosuccinimide (773 mg, 5.78 mmol) was added, and the reaction was stirred for 2 Hour. 15 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phase was collected, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was purified by column chromatography with eluent system C to give the title compound 5c (100 mg, yield: 31.0%).
MS m/z(ESI)：223.2[M+1]。MS m/z (ESI): 223.2 [M+1].
第三步third step
5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-3-磺酰胺5d5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazine-3-sulfonamide 5d
将化合物5c(100mg，449.1μmol)溶于氨的甲醇溶液(7M，2mL)中，搅拌反应1小时后，反应液减压浓缩，得到粗品标题产物5d(90mg，产率：98.6％)，不经纯化直接用于下一步。Compound 5c (100 mg, 449.1 μmol) was dissolved in methanol solution of ammonia (7 M, 2 mL), and after stirring for 1 hour, the reaction solution was concentrated under reduced pressure to obtain the crude title product 5d (90 mg, yield: 98.6%), which was not Purified and used directly in the next step.
MS m/z(ESI)：203.9[M+1]。MS m/z (ESI): 203.9 [M+1].
第四步the fourth step
N-(叔丁基二甲基硅基)-5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-3-磺酰胺5eN-(tert-Butyldimethylsilyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine-3-sulfonamide 5e
将5d(150mg，246.0μmol)、叔丁基二甲基氯硅烷(40mg，485.7μmol，上海毕得)溶于N,N-二甲基甲酰胺中，0℃加入三乙胺(74mg，731.3μmol)、4-二甲氨基吡啶(5mg，40.59μmol)，自然升至室温搅拌反应16小时。反应液减压浓缩后加入5mL水，乙酸乙酯萃取(5mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩即得粗品标题化合物5e(20mg，收率：25.6％)，产物不经纯化直接进行下一步反应。5d (150 mg, 246.0 μmol), tert-butyldimethylsilyl chloride (40 mg, 485.7 μmol, Shanghai Biide) were dissolved in N,N-dimethylformamide, and triethylamine (74 mg, 731.3 μmol), 4-dimethylaminopyridine (5 mg, 40.59 μmol), and the reaction was naturally raised to room temperature and stirred for 16 hours. After the reaction solution was concentrated under reduced pressure, 5 mL of water was added, extracted with ethyl acetate (5 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 title compound 5e (20 mg, yield: 25.6 %), the product was directly subjected to the next step without purification.
MS m/z(ESI)：318.1[M+1]。MS m/z (ESI): 318.1 [M+1].
第五步the fifth step
((R)-6-((R)-N-(叔丁基二甲基硅基)-5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-3-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮5f((R)-6-((R)-N-(tert-butyldimethylsilyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine -3-Sulfonimido)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline -4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 5f
((R)-6-((S)-N-(叔丁基二甲基硅基)-5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-3-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮5g((R)-6-((S)-N-(tert-butyldimethylsilyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine -3-Sulfonimido)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline -4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 5g
将二氯三苯基膦(60mg，180.1μmol)溶于3mL三氯甲烷中，0℃加入三乙胺(144mg，1.42mmol)，搅拌5分钟后加入5e(28mg，88.2μmol)，继续搅拌10分钟后加入1d(40mg，90.4μmol)，自然升至室温搅拌反应2小时。反应液中加入5mL水，用二氯甲烷萃取(10mL×3)，合并有机相，减压浓缩，残余物用柱层析色谱法以洗脱剂体系B纯化残余物，得到标题化合物5f和5g的混合物(30mg，产率：44.7％)。Dichlorotriphenylphosphine (60 mg, 180.1 μmol) was dissolved in 3 mL of trichloromethane, triethylamine (144 mg, 1.42 mmol) was added at 0°C, 5e (28 mg, 88.2 μmol) was added after stirring for 5 minutes, and stirring was continued for 10 After 1 minute, 1d (40 mg, 90.4 μmol) was added, and the reaction was stirred at room temperature for 2 hours. 5 mL of water was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to obtain the title compounds 5f and 5g A mixture of (30 mg, yield: 44.7%).
MS m/z(ESI)：742.2[M+1]。MS m/z (ESI): 742.2 [M+1].
第六步Step 6
((R)-6-(S)-(5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-3-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮5-P1((R)-6-(S)-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazine-3-sulfonimido)-1-( 4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl) )pyridin-2-yl)methanone 5-P1
((R)-6-(R)-(5,6-二氢-8H-咪唑并[5,1-c][1,4]噁嗪-3-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮5-P2((R)-6-(R)-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazine-3-sulfonimido)-1-( 4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl) )pyridin-2-yl)methanone 5-P2
将5f和5g的混合物(30mg，40.4μmol)溶于1mL四氢呋喃中，加入0.5mL 1M的盐酸，搅拌反应0.5小时。反应液用饱和碳酸氢钠淬灭后，减压浓缩，残余物 用高效液相色谱法(色谱柱：SharpSil-T，30*150mm，5μm；流动相：水相(10mM碳酸氢铵)，乙腈，梯度配比：水相25％-42％)纯化，得到标题化合物5-P1(3mg，产率：11.8％)和5-P2(2mg，产率：7.88％)。The mixture of 5f and 5g (30 mg, 40.4 μmol) was dissolved in 1 mL of tetrahydrofuran, 0.5 mL of 1 M hydrochloric acid was added, and the reaction was stirred for 0.5 h. The reaction solution was quenched with saturated sodium bicarbonate, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (chromatographic column: SharpSil-T, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate), acetonitrile , gradient ratio: aqueous phase 25%-42%) and purified to obtain the title compounds 5-P1 (3 mg, yield: 11.8%) and 5-P2 (2 mg, yield: 7.88%).
化合物5-P1(较短保留时间)：Compound 5-P1 (shorter retention time):
MS m/z(ESI)：628.2[M+1]。MS m/z (ESI): 628.2 [M+1].
HPLC分析：保留时间1.82分钟，纯度：98％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000183
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.82 minutes, purity: 98% (column: ACQUITY
Figure PCTCN2022074588-appb-000183
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3):δ8.84(d,1H),8.11(s,1H),7.74-7.64(m,1H),7.49-7.43(m,2H),7.28(s,1H),7.18(t,2H),6.75(s,1H),6.56(d,1H),5.76-5.63(m,1H),4.87-4.68(m,2H),4.35(dt,1H),4.24(d,1H),4.17(dd,1H),4.09-4.00(m,1H),3.94(t,2H),3.53(d,1H),3.19(td,1H),2.98(d,1H),2.83(dt,1H),2.59(d,1H),2.01(d,1H)。 1 H NMR (1500MHz, CDCl 3 ): δ 8.84(d,1H), 8.11(s,1H), 7.74-7.64(m,1H), 7.49-7.43(m,2H), 7.28(s,1H) ,7.18(t,2H),6.75(s,1H),6.56(d,1H),5.76-5.63(m,1H),4.87-4.68(m,2H),4.35(dt,1H),4.24(d ,1H),4.17(dd,1H),4.09-4.00(m,1H),3.94(t,2H),3.53(d,1H),3.19(td,1H),2.98(d,1H),2.83( dt, 1H), 2.59 (d, 1H), 2.01 (d, 1H).
化合物5-P2(较长保留时间)：Compound 5-P2 (longer retention time):
MS m/z(ESI)：628.2[M+1]。MS m/z (ESI): 628.2 [M+1].
HPLC分析：保留时间1.84分钟，纯度：98％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000184
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.84 minutes, purity: 98% (column: ACQUITY
Figure PCTCN2022074588-appb-000184
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3):δ8.84(d,1H),8.14(s,1H),7.71-7.66(m,1H),7.47-7.43(m,2H),7.30(s,1H),7.19(d,2H),6.79(s,1H),6.53(s,1H),5.66-5.54(m,1H),4.82(d,2H),4.41-4.31(m,1H),4.26(dt,1H),4.05(d,1H),3.97(t,2H),3.53(d,1H),3.21(t,1H),2.96(d,1H),2.82-2.67(m,1H),2.52(d,1H),2.25-2.13(m,1H),2.01(s,1H)。 1 H NMR (1500MHz, CDCl 3 ): δ 8.84(d,1H), 8.14(s,1H), 7.71-7.66(m,1H), 7.47-7.43(m,2H), 7.30(s,1H) ,7.19(d,2H),6.79(s,1H),6.53(s,1H),5.66-5.54(m,1H),4.82(d,2H),4.41-4.31(m,1H),4.26(dt ,1H),4.05(d,1H),3.97(t,2H),3.53(d,1H),3.21(t,1H),2.96(d,1H),2.82-2.67(m,1H),2.52( d, 1H), 2.25-2.13 (m, 1H), 2.01 (s, 1H).
实施例6-P1，6-P2Example 6-P1, 6-P2
((R)-6-((S)-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-2-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮6-P1((R)-6-((S)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonimido)-1- (4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl) yl)pyridin-2-yl)methanone 6-P1
((R)-6-((R)-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-2-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮6-P2((R)-6-((R)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonimido)-1- (4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl) yl)pyridin-2-yl)methanone 6-P2
Figure PCTCN2022074588-appb-000185
Figure PCTCN2022074588-appb-000185
Figure PCTCN2022074588-appb-000186
Figure PCTCN2022074588-appb-000186
第一步first step
3-溴-1-(2-溴乙基)-1H-吡唑-5-羧酸甲酯6b3-Bromo-1-(2-bromoethyl)-1H-pyrazole-5-carboxylate methyl ester 6b
将化合物3-溴-1H-吡唑-5-羧酸甲酯6a(10g，48.77mmol，上海毕得)和二溴乙烷(45.8g，45.8mmol)溶于乙腈(1150mL)中，加入无水碳酸钾(33.7g，243.9mmol)，80℃反应3小时。冷却至室温，将反应液过滤，滤液减压浓缩，残余物用柱层析色谱法以洗脱剂体系B纯化残余物，得到标题化合物6b(10g，产率：65.7％)。Compound 3-bromo-1H-pyrazole-5-carboxylate methyl ester 6a (10 g, 48.77 mmol, Shanghai Bide) and dibromoethane (45.8 g, 45.8 mmol) were dissolved in acetonitrile (1150 mL), added without Water potassium carbonate (33.7 g, 243.9 mmol) was reacted at 80°C for 3 hours. After cooling to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to give the title compound 6b (10 g, yield: 65.7%).
MS m/z(ESI)：312.8[M+1]。MS m/z (ESI): 312.8 [M+1].
第二步second step
(3-溴-1-(2-溴乙基)-1H-吡唑-5-基)甲醇6c(3-Bromo-1-(2-bromoethyl)-1H-pyrazol-5-yl)methanol 6c
将化合物6b(9.2g，29.5mmol)溶于四氢呋喃(100mL)，冰浴下加入硼氢化锂的四氢呋喃溶液(2M，40mL)，自然升温反应5小时。加入饱和氯化铵淬灭，用乙酸乙酯(150mL×3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩即得标题化合物6c(8g，收率：95.5％)，产物不经纯化，直接用于下一步反应。Compound 6b (9.2 g, 29.5 mmol) was dissolved in tetrahydrofuran (100 mL), a solution of lithium borohydride in tetrahydrofuran (2 M, 40 mL) was added under ice bath, and the reaction was carried out at natural temperature for 5 hours. Saturated ammonium chloride was added to quench, extracted with ethyl acetate (150 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 6c (8 g, yield: 95.5%). purified and used directly in the next reaction.
MS m/z(ESI)：284.8[M+1]。MS m/z (ESI): 284.8 [M+1].
第三步third step
2-溴-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪6d2-Bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine 6d
将化合物6c(8g，28.17mmol)和三乙胺(5.78g，57.1mmol)溶于N,N-二甲基甲酰胺(80mL)，100℃反应3小时。将反应液减压浓缩，残余物用柱层析色谱法以洗脱剂体系B纯化，得到标题化合物6d(1g，产率：17.48％)。Compound 6c (8 g, 28.17 mmol) and triethylamine (5.78 g, 57.1 mmol) were dissolved in N,N-dimethylformamide (80 mL) and reacted at 100° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to obtain the title compound 6d (1 g, yield: 17.48%).
MS m/z(ESI)：204.2[M+1]。MS m/z (ESI): 204.2 [M+1].
后续采用实施例5-P1和5-P2中的合成路线，将第一步原料化合物5a替换为化合物6d，制得标题化合物6-P1(2mg，产率：4.22％)和6-P2(2mg，产率：4.22％)。化合物6-P1(较短保留时间)：Subsequent use of the synthetic routes in Examples 5-P1 and 5-P2, the first step starting compound 5a was replaced with compound 6d to obtain the title compounds 6-P1 (2 mg, yield: 4.22%) and 6-P2 (2 mg , yield: 4.22%). Compound 6-P1 (shorter retention time):
MS m/z(ESI)：628.0[M+1]。MS m/z (ESI): 628.0 [M+1].
HPLC分析：保留时间1.40分钟，纯度：90％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000187
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.40 minutes, purity: 90% (column: ACQUITY
Figure PCTCN2022074588-appb-000187
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3)：δ8.91(d,1H),8.19(s,1H),7.75-7.70(m,1H),7.150-7.46(m,2H),7.33(s,1H),7.21(d,2H),6.98(s,1H),6.51(s,1H),6.43(s,1H),5.61-5.56(m,1H),4.85(s,2H),4.71(s,2H),4.27-4.23(m,1H),4.16(dt,2H),4.02(t,1H),2.95(d,1H),2.87(d,1H),2.77(m,1H),2.51(td,1H),2.40-2.31(m,1H)。 1 H NMR (1500 MHz, CDCl 3 ): δ 8.91 (d, 1H), 8.19 (s, 1H), 7.75-7.70 (m, 1H), 7.150-7.46 (m, 2H), 7.33 (s, 1H) ,7.21(d,2H),6.98(s,1H),6.51(s,1H),6.43(s,1H),5.61-5.56(m,1H),4.85(s,2H),4.71(s,2H ), 4.27-4.23(m, 1H), 4.16(dt, 2H), 4.02(t, 1H), 2.95(d, 1H), 2.87(d, 1H), 2.77(m, 1H), 2.51(td, 1H), 2.40-2.31 (m, 1H).
化合物6-P2(较长保留时间)：Compound 6-P2 (longer retention time):
MS m/z(ESI)：628.0[M+1]。MS m/z (ESI): 628.0 [M+1].
HPLC分析：保留时间1.42分钟，纯度：99％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000188
C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.42 minutes, purity: 99% (column: ACQUITY
Figure PCTCN2022074588-appb-000188
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3)：δ8.92(d,1H),8.16(d,1H),7.74-7.69(m,1H),7.49-7.45(m,2H),7.33(s,1H),7.21(d,2H),6.98(s,1H),6.54(d,1H),6.41(s,1H),5.70(dd,1H),4.84(s,2H),4.71(s,2H),4.27-4.25(m,1H),4.14(t,2H),3.98(td,1H),2.95(d,1H),2.86-2.79(m,1H),2.64-2.56(m,1H),2.53(dd,1H),2.39-2.35(m,1H)。 1 H NMR (1500 MHz, CDCl 3 ): δ 8.92(d,1H), 8.16(d,1H), 7.74-7.69(m,1H), 7.49-7.45(m,2H), 7.33(s,1H) ,7.21(d,2H),6.98(s,1H),6.54(d,1H),6.41(s,1H),5.70(dd,1H),4.84(s,2H),4.71(s,2H), 4.27-4.25(m,1H), 4.14(t,2H), 3.98(td,1H), 2.95(d,1H), 2.86-2.79(m,1H), 2.64-2.56(m,1H), 2.53( dd, 1H), 2.39-2.35 (m, 1H).
实施例7-P1，7-P2Example 7-P1, 7-P2
((4aR,8aS)-6-((S)-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-2-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8,8a,9-八氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮7-P1((4aR,8aS)-6-((S)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonimido)- 1-(4-Fluorophenyl)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)( 4-(Trifluoromethyl)pyridin-2-yl)methanone 7-P1
((4aR,8aS)-6-((R)-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-2-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8,8a,9-八氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮7-P2((4aR,8aS)-6-((R)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonimido)- 1-(4-Fluorophenyl)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)( 4-(Trifluoromethyl)pyridin-2-yl)methanone 7-P2
Figure PCTCN2022074588-appb-000189
Figure PCTCN2022074588-appb-000189
采用实施例4-P1和4-P2中的合成路线，将第三步原料化合物1c替换为化合物6d，制得标题化合物7-P1(10mg，产率：23.6％)和7-P2(5mg，产率：11.8％)。Using the synthetic routes in Examples 4-P1 and 4-P2, the third step starting compound 1c was replaced with compound 6d to obtain the title compounds 7-P1 (10 mg, yield: 23.6%) and 7-P2 (5 mg, Yield: 11.8%).
化合物7-P1(较短保留时间)：Compound 7-P1 (shorter retention time):
MS m/z(ESI)：630.0[M+1]。MS m/z (ESI): 630.0 [M+1].
HPLC分析：保留时间1.42分钟，纯度：97％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000190
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.42 minutes, purity: 97% (column: ACQUITY
Figure PCTCN2022074588-appb-000190
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3):δ8.86(d,1H),8.20-8.04(m,1H),7.68-7.61(m,1H),7.52-7.43(m,2H),7.32(s,1H),7.15(dd,2H),6.37(s,1H),5.67(dd,1H),4.82(s,2H),4.32-4.20(m,3H),4.12(t,2H),4.02(dd,1H),3.42(dd,1H),2.72(dd,1H),2.66-2.150(m,3H),2.38(d,2H),1.85-1.73(m,2H)。 1 H NMR (1500MHz, CDCl 3 ): δ 8.86(d,1H), 8.20-8.04(m,1H), 7.68-7.61(m,1H), 7.52-7.43(m,2H), 7.32(s, 1H), 7.15(dd, 2H), 6.37(s, 1H), 5.67(dd, 1H), 4.82(s, 2H), 4.32-4.20(m, 3H), 4.12(t, 2H), 4.02(dd , 1H), 3.42 (dd, 1H), 2.72 (dd, 1H), 2.66-2.150 (m, 3H), 2.38 (d, 2H), 1.85-1.73 (m, 2H).
化合物7-P2(较长保留时间)：Compound 7-P2 (longer retention time):
MS m/z(ESI):630.0[M+1]。MS m/z (ESI): 630.0 [M+1].
HPLC分析：保留时间1.45分钟，纯度：99％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000191
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.45 minutes, purity: 99% (column: ACQUITY
Figure PCTCN2022074588-appb-000191
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(1500MHz,CDCl 3):δ8.89(d,1H),8.11-8.01(m,1H),7.72-7.60(m,1H),7.58-7.43(m,2H),7.32(s,1H),7.15(dd,2H),6.39(d,1H),5.69(dd,1H),4.83(s,2H),4.26(t,2H),4.17-4.00(m,4H),3.42(dd,1H),2.72(dd,1H),2.59(td,2H),2.51(d,1H),2.47-2.32(m,2H),1.84-1.73(m,2H)。 1 H NMR (1500MHz, CDCl 3 ): δ8.89(d,1H), 8.11-8.01(m,1H), 7.72-7.60(m,1H), 7.58-7.43(m,2H), 7.32(s, 1H), 7.15(dd, 2H), 6.39(d, 1H), 5.69(dd, 1H), 4.83(s, 2H), 4.26(t, 2H), 4.17-4.00(m, 4H), 3.42(dd , 1H), 2.72 (dd, 1H), 2.59 (td, 2H), 2.51 (d, 1H), 2.47-2.32 (m, 2H), 1.84-1.73 (m, 2H).
实施例8-P1，8-P2Example 8-P1, 8-P2
((R)-6-((S)-2-环丙基-2H-1,2,3-三唑-4-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮8-P1((R)-6-((S)-2-cyclopropyl-2H-1,2,3-triazole-4-sulfonimido)-1-(4-fluorophenyl)-1, 4,5,6,7,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 8-P1
((R)-6-((R)-2-环丙基-2H-1,2,3-三唑-4-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮8-P2((R)-6-((R)-2-Cyclopropyl-2H-1,2,3-triazole-4-sulfonimido)-1-(4-fluorophenyl)-1, 4,5,6,7,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 8-P2
Figure PCTCN2022074588-appb-000192
Figure PCTCN2022074588-appb-000192
第一步first step
4-(苄基硫基)-1H-1,2,3-三唑8b4-(Benzylthio)-1H-1,2,3-triazole 8b
将化合物5-巯基-1,2,3-三氮唑钠盐8a(10g，81.22mmol，上海毕得)溶于100 mL乙醇中，滴加溴化苄(15.3g，89.45mmol)，搅拌反应1小时。反应液减压浓缩后即得粗品标题产物8b(11g，产率：70.8％)，产物不经纯化直接进行下一步反应。Compound 5-mercapto-1,2,3-triazole sodium salt 8a (10 g, 81.22 mmol, Shanghai Bide) was dissolved in 100 mL of ethanol, benzyl bromide (15.3 g, 89.45 mmol) was added dropwise, and the reaction was stirred. 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 8b (11 g, yield: 70.8%). The product was directly subjected to the next reaction without purification.
MS m/z(ESI)：191.9[M+1]。MS m/z (ESI): 191.9 [M+1].
第二步second step
4-(苄基硫基)-2-环丙基-2H-1,2,3-三唑8c4-(Benzylthio)-2-cyclopropyl-2H-1,2,3-triazole 8c
将化合物8b(3g，15.68mmol)、环丙基硼酸(2.7g，31.43mmol)溶于1,2-二氯乙烷(100mL)，加入碳酸钠(5g，47.17mmol)、醋酸铜(3.13g，15.67mmol)和2,2'-联吡啶(3.7g，23.69mmol)，加热至70℃搅拌反应4小时。反应液冷却至室温，用乙酸乙酯(50mL)稀释后，依次用饱和氯化铵溶液、饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩即得粗品标题产物8c(1.2g，产率：33％)，产物不经纯化直接进行下一步反应。Compound 8b (3 g, 15.68 mmol) and cyclopropylboronic acid (2.7 g, 31.43 mmol) were dissolved in 1,2-dichloroethane (100 mL), and sodium carbonate (5 g, 47.17 mmol), copper acetate (3.13 g) were added. , 15.67 mmol) and 2,2'-bipyridine (3.7 g, 23.69 mmol), heated to 70 °C and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride solution and saturated sodium chloride solution in turn, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title The product 8c (1.2 g, yield: 33%) was directly used in the next step without purification.
MS m/z(ESI)：232.1[M+1]。MS m/z (ESI): 232.1 [M+1].
第三步third step
2-环丙基-2H-1,2,3-三唑-4-磺酰氯8d2-Cyclopropyl-2H-1,2,3-triazole-4-sulfonyl chloride 8d
将化合物8c(0.54g，2.33mmol)溶于9mL醋酸和水(V:V＝2:1)的混合溶液中，加入N-氯代丁二酰亚胺(1.25g，9.36mmol)，搅拌反应1小时，反应液中加入水(10mL)，用乙酸乙酯(5mL×3)萃取，合并有机相，依次用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤，然后用无水硫酸钠干燥，过滤，滤液减压浓缩即得粗品标题产物8d(0.4g，产率：82.5％)，产物不经纯化直接进行下一步反应。Compound 8c (0.54 g, 2.33 mmol) was dissolved in a mixed solution of 9 mL of acetic acid and water (V:V=2:1), N-chlorosuccinimide (1.25 g, 9.36 mmol) was added, and the reaction was stirred. After 1 hour, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL×3), the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, and then dried with anhydrous sodium sulfate, After filtration, the filtrate was concentrated under reduced pressure to obtain the crude title product 8d (0.4 g, yield: 82.5%). The product was directly subjected to the next reaction without purification.
MS m/z(ESI)：207.9[M+1]。MS m/z (ESI): 207.9 [M+1].
第四步the fourth step
2-环丙基-2H-1,2,3-三唑-4-磺酰胺8e2-Cyclopropyl-2H-1,2,3-triazole-4-sulfonamide 8e
0℃，向化合物8d(0.885g，4.26mmol)中加入7M氨甲醇溶液(3mL)，自然升至室温搅拌反应2小时，反应液减压浓缩即得粗品标题产物8e(0.4g，产率：82.5％)，产物不经纯化直接进行下一步反应。0°C, 7M ammonia methanol solution (3 mL) was added to compound 8d (0.885 g, 4.26 mmol), the reaction was naturally raised to room temperature and stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title product 8e (0.4 g, yield: 82.5%), the product was directly carried to the next step without purification.
MS m/z(ESI)：189.1[M+1]。MS m/z (ESI): 189.1 [M+1].
第五步the fifth step
N-(叔丁基二甲基硅基)-2-环丙基-2H-1,2,3-三唑-4-磺酰胺8fN-(tert-Butyldimethylsilyl)-2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide 8f
化合物8e(0.8g，4.25mmol)、4-二甲氨基吡啶(0.1g，811.84μmol)溶于二氯甲烷(50mL)中，0℃加入叔丁基二甲基氯硅烷(528mg，6.4mmol)，升至室温搅拌反应16小时后，反应液减压浓缩，残余物用柱层析色谱法以洗脱剂体系A纯化，得到标题化合物8f(0.5g，产率：38.8％)。Compound 8e (0.8 g, 4.25 mmol), 4-dimethylaminopyridine (0.1 g, 811.84 μmol) were dissolved in dichloromethane (50 mL), and tert-butyldimethylsilyl chloride (528 mg, 6.4 mmol) was added at 0°C , the reaction was stirred at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to obtain the title compound 8f (0.5 g, yield: 38.8%).
MS m/z(ESI)：303.1[M+1]。MS m/z (ESI): 303.1 [M+1].
后续采用实施例1-P1和1-P2中的合成路线，将第三步原料化合物1c替换为化合物8f，制得标题化合物8-P1(2mg，产率：9.49％)和8-P2(2mg，产率：3.56％)。Subsequently, the synthetic routes in Examples 1-P1 and 1-P2 were adopted, and the starting compound 1c of the third step was replaced with compound 8f to obtain the title compounds 8-P1 (2 mg, yield: 9.49%) and 8-P2 (2 mg , yield: 3.56%).
化合物8-P1(较短保留时间)：Compound 8-P1 (shorter retention time):
MS m/z(ESI)：613.0[M+1]。MS m/z (ESI): 613.0 [M+1].
HPLC分析：保留时间1.54分钟，纯度：98.5％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000193
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.54 minutes, purity: 98.5% (column: ACQUITY
Figure PCTCN2022074588-appb-000193
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(500MHz,CDCl 3):δ8.93(s,1H),8.15(d,1H),7.83(s,1H),7.74-7.70(m,1H),7.53-7.42(m,2H),7.32(s,1H),7.24-7.17(m,1H),7.07(s,1H),6.55(d,1H),5.72(dd,1H),4.28(d,1H),4.10(tt,2H),4.03-3.95(m,1H),3.01-2.91(m,2H),2.88-2.78(m,1H),2.64-2.51(m,2H),1.47-1.38(m,2H),1.22-1.14(m,2H)。 1 H NMR (500MHz, CDCl 3 ): δ 8.93(s,1H), 8.15(d,1H), 7.83(s,1H), 7.74-7.70(m,1H), 7.53-7.42(m,2H) ,7.32(s,1H),7.24-7.17(m,1H),7.07(s,1H),6.55(d,1H),5.72(dd,1H),4.28(d,1H),4.10(tt,2H ),4.03-3.95(m,1H),3.01-2.91(m,2H),2.88-2.78(m,1H),2.64-2.51(m,2H),1.47-1.38(m,2H),1.22-1.14 (m, 2H).
化合物8-P2(较长保留时间)：Compound 8-P2 (longer retention time):
MS m/z(ESI)：613.0[M+1]。MS m/z (ESI): 613.0 [M+1].
HPLC分析：保留时间1.56分钟，纯度：98.9％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000194
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.56 minutes, purity: 98.9% (column: ACQUITY
Figure PCTCN2022074588-appb-000194
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(500MHz,CDCl 3):δ8.90(d,1H),8.17(s,1H),7.86(s,1H),7.73(dd,1H),7.47(dd,2H),7.32(s,1H),7.20(t,2H),6.52(d,1H),5.55(dd,1H),4.03(d,3H),2.92(d,1H),2.84(d,1H),2.79-2.63(m,3H),2.54-2.48(m,1H),1.42(dd,2H),1.18(dd,2H)。 1 H NMR (500MHz, CDCl 3 ): δ 8.90(d,1H), 8.17(s,1H), 7.86(s,1H), 7.73(dd,1H), 7.47(dd,2H), 7.32(s ,1H),7.20(t,2H),6.52(d,1H),5.55(dd,1H),4.03(d,3H),2.92(d,1H),2.84(d,1H),2.79-2.63( m, 3H), 2.54-2.48 (m, 1H), 1.42 (dd, 2H), 1.18 (dd, 2H).
实施例9-P1，9-P2Example 9-P1, 9-P2
((R)-6-((S)-2-(二氟甲基)-2H-1,2,3-三唑-4-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮9-P1((R)-6-((S)-2-(difluoromethyl)-2H-1,2,3-triazole-4-sulfonimido)-1-(4-fluorophenyl) -1,4,5,6,7,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl ) ketone 9-P1
((R)-6-((R)-2-(二氟甲基)-2H-1,2,3-三唑-4-磺酰亚胺基)-1-(4-氟苯基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮9-P2((R)-6-((R)-2-(difluoromethyl)-2H-1,2,3-triazole-4-sulfonimido)-1-(4-fluorophenyl) -1,4,5,6,7,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl ) ketone 9-P2
Figure PCTCN2022074588-appb-000195
Figure PCTCN2022074588-appb-000195
第一步first step
4-(苄基硫基)-2-(二氟甲基)-2H-1,2,3-三唑9a4-(Benzylthio)-2-(difluoromethyl)-2H-1,2,3-triazole 9a
将化合物8b(10g，52.28mmol)溶于N,N-二甲基甲酰胺(80mL)，加入碳酸铯(34g，104.35mmol)、二氟氯乙酸钠(16g，104.94mmol)，加热至100℃反应5小时。冷却至室温，反应液减压浓缩后用柱层析色谱法以洗脱剂体系A纯化，得到标题化合物9a(2.92g，产率：23.1％)Compound 8b (10 g, 52.28 mmol) was dissolved in N,N-dimethylformamide (80 mL), cesium carbonate (34 g, 104.35 mmol) and sodium difluorochloroacetate (16 g, 104.94 mmol) were added, and heated to 100 °C The reaction was carried out for 5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by column chromatography with eluent system A to obtain the title compound 9a (2.92 g, yield: 23.1%)
MS m/z(ESI)：242.2[M+1]。MS m/z (ESI): 242.2 [M+1].
后续采用实施例8-P1和8-P2中的合成路线，将第三步原料化合物8c替换为化合物9a，制得标题化合物9-P1(45mg，产率：26.6％)和9-P2(32mg，产率：18.9％)。Subsequently, the synthetic routes in Examples 8-P1 and 8-P2 were adopted, and the starting compound 8c in the third step was replaced with compound 9a to obtain the title compounds 9-P1 (45 mg, yield: 26.6%) and 9-P2 (32 mg) , yield: 18.9%).
化合物9-P1(较短保留时间)：Compound 9-P1 (shorter retention time):
MS m/z(ESI)：623.1[M+1]。MS m/z (ESI): 623.1 [M+1].
HPLC分析：保留时间3.11分钟，纯度：96％(色谱柱:ACQUITY
Figure PCTCN2022074588-appb-000196
C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 3.11 minutes, purity: 96% (column: ACQUITY
Figure PCTCN2022074588-appb-000196
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(500MHz,CDCl 3):δ8.90(d,1H),8.12(s,1H),8.06(s,1H),7.71(dd,1H),7.48-7.42(m,2H),7.33(t,1H),7.18(t,2H),6.54(d,1H),5.77(dd,1H),4.25(d,1H),4.10-3.91(m,1H),3.08(d,1H),2.95(d,1H),2.90-2.78(m,1H),2.69(td,2H),2.62-2.47(m,1H)。 1 H NMR (500MHz, CDCl 3 ): δ 8.90(d,1H), 8.12(s,1H), 8.06(s,1H), 7.71(dd,1H), 7.48-7.42(m,2H), 7.33 (t, 1H), 7.18(t, 2H), 6.54(d, 1H), 5.77(dd, 1H), 4.25(d, 1H), 4.10-3.91(m, 1H), 3.08(d, 1H), 2.95(d,1H), 2.90-2.78(m,1H), 2.69(td,2H), 2.62-2.47(m,1H).
化合物9-P2(较长保留时间)：Compound 9-P2 (longer retention time):
MS m/z(ESI)：623.1[M+1]。MS m/z (ESI): 623.1 [M+1].
HPLC分析：保留时间3.16分钟，纯度：97％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000197
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 3.16 minutes, purity: 97% (column: ACQUITY
Figure PCTCN2022074588-appb-000197
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(500MHz,CDCl 3):δ8.86(d,1H),8.15(s,1H),8.10(d,1H),7.75-7.70(m,1H),7.48-7.42(m,2H),7.35(d,1H),7.18(dd,2H),6.50(d,1H),5.52(dd,1H),4.15-4.05(m,1H),3.96(d,1H),2.99-2.85(m,2H),2.81(td,1H),2.71(td,1H),2.56-2.48(m,1H),2.40(s,1H)。 1 H NMR (500MHz, CDCl 3 ): δ 8.86(d,1H), 8.15(s,1H), 8.10(d,1H), 7.75-7.70(m,1H), 7.48-7.42(m,2H) ,7.35(d,1H),7.18(dd,2H),6.50(d,1H),5.52(dd,1H),4.15-4.05(m,1H),3.96(d,1H),2.99-2.85(m , 2H), 2.81(td, 1H), 2.71(td, 1H), 2.56-2.48(m, 1H), 2.40(s, 1H).
实施例10-P1，10-P2Example 10-P1, 10-P2
((R)-1-(4-氟苯基)-6-((S)-1-甲基-1H-四唑-5-磺酰亚胺基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮10-P1((R)-1-(4-Fluorophenyl)-6-((S)-1-methyl-1H-tetrazole-5-sulfonimido)-1,4,5,6,7 ,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 10-P1
((R)-1-(4-氟苯基)-6-((R)-1-甲基-1H-四唑-5-磺酰亚胺基)-1,4,5,6,7,8-六氢-4aH-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮10-P2((R)-1-(4-Fluorophenyl)-6-((R)-1-methyl-1H-tetrazole-5-sulfonimido)-1,4,5,6,7 ,8-Hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone 10-P2
Figure PCTCN2022074588-appb-000198
Figure PCTCN2022074588-appb-000198
第一步first step
5-(苄基硫基)-1-甲基-1H-四唑10b5-(Benzylthio)-1-methyl-1H-tetrazole 10b
将化合物5-(苄硫基)-1H-四唑10a(2g，10.4mmol，上海毕得)溶于四氢呋喃(20mL)，滴加三甲基硅基重氮甲烷(2.39g，20.9mmol)，搅拌反应2小时后，反应液减压浓缩即得粗品标题产物10b(2g，产率：93.1％)，产物不经纯化直接进行下一步反应。Compound 5-(benzylthio)-1H-tetrazole 10a (2g, 10.4mmol, Shanghai Bide) was dissolved in tetrahydrofuran (20mL), and trimethylsilyldiazomethane (2.39g, 20.9mmol) was added dropwise, After stirring and reacting for 2 hours, the reaction solution was concentrated under reduced pressure to obtain the crude title product 10b (2 g, yield: 93.1%). The product was directly subjected to the next reaction without purification.
MS m/z(ESI)：207.2[M+1]。MS m/z (ESI): 207.2 [M+1].
后续采用实施例8-P1和8-P2中的合成路线，将第三步原料化合物8c替换为化合物10b，制得标题化合物10-P1(4mg，产率：15.6％)和10-P2(4mg，产率：15.6％)。Subsequently, the synthetic routes in Examples 8-P1 and 8-P2 were adopted, and the starting material compound 8c in the third step was replaced with compound 10b to obtain the title compounds 10-P1 (4 mg, yield: 15.6%) and 10-P2 (4 mg , yield: 15.6%).
化合物10-P1(较短保留时间)：Compound 10-P1 (shorter retention time):
MS m/z(ESI)：588.2[M+1]。MS m/z (ESI): 588.2 [M+1].
HPLC分析：保留时间1.45分钟，纯度：99％(色谱柱：ACQUITY
Figure PCTCN2022074588-appb-000199
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.45 minutes, purity: 99% (column: ACQUITY
Figure PCTCN2022074588-appb-000199
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(500MHz,CDCl 3):δ8.91(d,1H),8.15(s,1H),7.72(dd,1H),7.51-7.44(m,2H),7.32(s,1H),7.20(t,2H),6.57(d,1H),5.81(dd,1H),4.44(s,3H),4.28(d,1H),4.14(dq,1H),3.27(d,1H),3.09-2.82(m,4H),2.58(dd,1H)。 1 H NMR (500 MHz, CDCl 3 ): δ 8.91 (d, 1H), 8.15 (s, 1H), 7.72 (dd, 1H), 7.51-7.44 (m, 2H), 7.32 (s, 1H), 7.20 (t, 2H), 6.57(d, 1H), 5.81(dd, 1H), 4.44(s, 3H), 4.28(d, 1H), 4.14(dq, 1H), 3.27(d, 1H), 3.09- 2.82 (m, 4H), 2.58 (dd, 1H).
化合物10-P1(较长保留时间)：Compound 10-P1 (longer retention time):
MS m/z(ESI)：588.2[M+1]。MS m/z (ESI): 588.2 [M+1].
HPLC分析：保留时间1.47分钟，纯度：97％(色谱柱:ACQUITY
Figure PCTCN2022074588-appb-000200
C18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 1.47 minutes, purity: 97% (column: ACQUITY
Figure PCTCN2022074588-appb-000200
C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(500MHz,CDCl 3):δ8.88(d,1H),8.17(s,1H),7.72(d,1H),7.47(dd, 2H),7.33(s,1H),7.21(t,2H),6.54(s,1H),5.63(d,1H),4.45(s,3H),4.15(dd,1H),4.04(d,1H),3.20(d,1H),3.03-2.89(m,2H),2.80-2.68(m,2H),2.55(d,1H)。 1 H NMR (500MHz, CDCl 3 ): δ 8.88(d,1H), 8.17(s,1H), 7.72(d,1H), 7.47(dd, 2H), 7.33(s,1H), 7.21(t ,2H),6.54(s,1H),5.63(d,1H),4.45(s,3H),4.15(dd,1H),4.04(d,1H),3.20(d,1H),3.03-2.89( m, 2H), 2.80-2.68 (m, 2H), 2.55 (d, 1H).
生物学评价Biological evaluation
以下结合测试例进一步描述解释本公开，但这些测试例并非意味着限制本公开的范围。The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not meant to limit the scope of the present disclosure.
测试例1：GR受体报告基因实验Test Example 1: GR receptor reporter gene assay
以下方法用来测定本公开化合物对MDA-kb2细胞中GR受体转录活性的影响，实验方法简述如下。The following methods were used to determine the effects of the disclosed compounds on the transcriptional activity of GR receptors in MDA-kb2 cells. The experimental methods are briefly described below.
MDA-kb2细胞(ATCC，CRL-2713)用完全培养基(即含有10％胎牛血清(Gibco，10099-141)的Leibovitz's L-15培养基(Gibco，11415114))进行培养。实验第一天，使用不完全培养基即含有5％活性炭处理血清(Biosun，S-FBS-AU-045)的Leibovitz's L-15培养基(Gibco，11415114)将MDA-kb2细胞以30000个细胞/孔的密度种于96孔板，每孔80μL细胞悬液，孔板放置37℃，无CO 2细胞培养箱培养过夜。第二天，每孔加入10μL用不完全培养基配制的梯度稀释的待测化合物，化合物的终浓度是从10μM开始进行5倍梯度稀释的8个浓度点，DMSO终浓度为0.5％DMSO。每孔继续加入10μL用不完全培养基配制的地塞米松(MCE，HY-14648)，终浓度为10nM。设置只含有0.5％DMSO孔为阴性对照，含有10nM地塞米松孔为阳性对照。孔板放置37℃，无CO 2细胞培养箱培养18小时。第三天，取出96孔细胞培养板，每孔加入90μL配制后的ONE-Glo荧光素酶检测试剂(Promega，E6120)，室温放置10分钟后，在酶标仪EnVision(PerkinElmer)中读取发光信号值。利用化合物各浓度和阴性对照以及阳性对照孔的发光值计算抑制率。根据化合物各浓度和相应的抑制率用GraphPad Prism软件计算化合物抑制GR转录活性的IC 50值。 MDA-kb2 cells (ATCC, CRL-2713) were cultured in complete medium (ie Leibovitz's L-15 medium (Gibco, 11415114) containing 10% fetal bovine serum (Gibco, 10099-141)). On the first day of the experiment, MDA-kb2 cells were cultured at 30,000 cells/cell using an incomplete medium, namely Leibovitz's L-15 medium (Gibco, 11415114) containing 5% charcoal-treated serum (Biosun, S-FBS-AU-045). The density of the wells was seeded in a 96-well plate, with 80 μL of cell suspension per well, and the plate was placed at 37°C in a CO2 -free cell incubator overnight. The next day, 10 μL of the compound to be tested in a serial dilution prepared in incomplete medium was added to each well, and the final concentration of the compound was 8 concentration points of 5-fold serial dilution starting from 10 μM, and the final concentration of DMSO was 0.5% DMSO. Continue to add 10 μL of dexamethasone (MCE, HY-14648) in incomplete medium to each well at a final concentration of 10 nM. Set wells containing only 0.5% DMSO as negative controls, and wells containing 10 nM dexamethasone as positive controls. The plate was placed at 37°C in a CO2 -free cell incubator for 18 hours. On the third day, the 96-well cell culture plate was taken out, and 90 μL of the prepared ONE-Glo luciferase detection reagent (Promega, E6120) was added to each well. After 10 minutes at room temperature, the luminescence was read in a microplate reader EnVision (PerkinElmer). signal value. The inhibition rate was calculated using the luminescence values of each concentration of the compound and the negative and positive control wells. The IC 50 value of compound inhibiting GR transcriptional activity was calculated by GraphPad Prism software according to each concentration of compound and the corresponding inhibition rate.
表1本公开化合物对MDA-kb2细胞中GR受体转录活性的影响Table 1 Effects of the disclosed compounds on GR receptor transcriptional activity in MDA-kb2 cells
实施例编号Example number IC 50(nM) IC50 (nM)
1-P11-P1 1010
1-P21-P2 4949
2-P12-P1 270270
2-P22-P2 129129
3-P13-P1 153153
4-P14-P1 6565
4-P24-P2 159159
5-P15-P1 9797
7-P17-P1 157157
8-P18-P1 77
8-P28-P2 1616
9-P19-P1 66
9-P29-P2 3535
10-P110-P1 2020
10-P210-P2 103103
结论：本公开化合物对MDA-kb2细胞中GR受体转录具有较好的抑制活性。Conclusion: The disclosed compounds have good inhibitory activity on GR receptor transcription in MDA-kb2 cells.
测试例2：GR受体结合实验Test Example 2: GR Receptor Binding Experiment
以下方法用来测定本公开化合物与GR受体竞争性结合活性，实验方法简述如下。The following method was used to determine the competitive binding activity of the disclosed compounds to the GR receptor, and the experimental method is briefly described as follows.
本实验使用
Figure PCTCN2022074588-appb-000201
GR受体竞争性结合检测试剂盒(Invitrogen，A15901)。首先将试剂盒中的Nuclear Receptor Buffer F(Invitrogen，PV4547)，GR Stabilizing Peptide(10×)(Invitrogen，P2815)和DTT(Invitrogen，P2325)按照179:20:1的比例混合成实验缓冲液。用DMSO稀释待测化合物，以1mM为首浓度进行4倍梯度稀释，共9个浓度点。再用实验缓冲液稀释化合物DMSO溶液，在黑色384孔板(Corning，4514)中每孔加入10μL化合物稀释液，化合物终浓度为10μM起始4倍梯度稀释的9个浓度。设置含有1％DMSO的缓冲液孔为阴性对照，加入终浓度为20μM地塞米松(MCE，HY-14648)的孔为阳性对照。用缓冲液配制Fluormone TMGS1Green(Invitrogen，PV6044)，使其终浓度为5nM，以每孔5μL加入384孔板。用缓冲液配制GR-LBD(GST)(Invitrogen，A15668)和
Figure PCTCN2022074588-appb-000202
Tb-anti-GST antibody(Invitrogen，PV3550)的混合物，使Tb anti-GST antibody的终浓度为2nM，GR-LBD(GST)的终浓度为各批次说明书所示，将该混合物以每孔5μL加入384孔板。将孔板在室温放置2小时后用PHERAstar酶标仪(BMG LABTECH)读取激发光波长为340nm，发射光波长分别为520nm和490nm的荧光值，利用化合物各浓度和阴性对照以及阳性对照孔的520nm和490nm荧光值的比值计算抑制率。根据化合物各浓度和相应的抑制率用GraphPad Prism软件计算化合物与GR受体竞争性结合活性的IC 50值。 This experiment uses
Figure PCTCN2022074588-appb-000201
GR Receptor Competitive Binding Assay Kit (Invitrogen, A15901). First, the Nuclear Receptor Buffer F (Invitrogen, PV4547), GR Stabilizing Peptide (10×) (Invitrogen, P2815) and DTT (Invitrogen, P2325) in the kit were mixed into an experimental buffer in a ratio of 179:20:1. The compounds to be tested were diluted with DMSO, and the first concentration was 1 mM for 4-fold serial dilution, with a total of 9 concentration points. The compound DMSO solution was then diluted with experimental buffer, and 10 μL of compound dilution was added to each well of a black 384-well plate (Corning, 4514). The buffer well containing 1% DMSO was set as a negative control, and the well added with a final concentration of 20 μM dexamethasone (MCE, HY-14648) was set as a positive control. Fluormone ™ GS1 Green (Invitrogen, PV6044) was prepared in buffer to a final concentration of 5 nM and added to a 384-well plate at 5 μL per well. GR-LBD (GST) (Invitrogen, A15668) was prepared in buffer and
Figure PCTCN2022074588-appb-000202
A mixture of Tb-anti-GST antibody (Invitrogen, PV3550), the final concentration of Tb anti-GST antibody was 2nM, and the final concentration of GR-LBD (GST) was as indicated in the instructions of each batch, and the mixture was 5 μL per well. Add to 384-well plate. After the well plate was placed at room temperature for 2 hours, the fluorescence values of excitation light wavelength of 340 nm and emission light wavelength of 520 nm and 490 nm were read with a PHERAstar microplate reader (BMG LABTECH). The ratio of the fluorescence values at 520 nm and 490 nm was used to calculate the inhibition rate. According to each concentration of the compound and the corresponding inhibition rate, the IC 50 value of the compound's competitive binding activity with the GR receptor was calculated by GraphPad Prism software.
表2本公开化合物与GR受体竞争性结合活性Table 2 Competitive binding activity of compounds of the present disclosure with GR receptor
实施例编号Example number IC 50(nM) IC50 (nM)
1-P11-P1 1515
1-P21-P2 22twenty two
2-P22-P2 4141
4-P14-P1 4343
5-P15-P1 5858
结论：本公开化合物与GR受体竞争性结合具有较好的抑制活性。Conclusion: The compounds of the present disclosure have good inhibitory activity for competitive binding with GR receptor.
测试例3：MDA-MB-231细胞增殖实验Test Example 3: MDA-MB-231 Cell Proliferation Experiment
以下方法用来测定本公开化合物在体外对MDA-MB-231细胞增殖的抑制作用，实验方法简述如下。The following method is used to determine the inhibitory effect of the disclosed compounds on the proliferation of MDA-MB-231 cells in vitro, and the experimental method is briefly described as follows.
MDA-MB-231细胞(ATCC，HTB-26)用完全培养基(即含有10％胎牛血清(Gibco，10099-141)的Leibovitz's L-15培养基(ThermoFisher，11415-114))进行培养。实验第一天，使用含10％活性炭处理胎牛血清(BioSun，S-FBS-AU-045)的Leibovitz's L-15不完全培养基将MDA-MB-231细胞以1000个细胞/孔的密度种于96孔3D细胞培养板(Corning，CLS7007-24EA)，每孔120μL细胞悬液，在离心机中以2000转离心3分钟后将孔板放置37℃，无CO 2细胞培养箱培养过夜。第二天，每孔加入15μL用不完全培养基配制的梯度稀释的待测化合物，化合物的终浓度是从10μM起始进行3倍梯度稀释的9个浓度点。之后每孔再加入15μL地塞米松(MCE，HY-14648)，终浓度为0.1μM。设置只含有0.5％DMSO孔为阴性对照，含有0.1μM地塞米松孔为阳性对照。孔板放置37℃，无CO 2细胞培养箱培养8天。8天后，取出96孔3D细胞培养板，每孔加入50μL
Figure PCTCN2022074588-appb-000203
3D Cell Viability Assay(Promega，G9683)，振荡器避光震荡25分钟后，每孔转移100μL溶液至96孔不透明白底板中(PerkinElmer，6005290)，使用多功能微孔板酶标仪VICTOR 3(PerkinElmer)读取发光信号值。利用化合物各浓度和阴性对照以及阳性对照孔的发光值计算抑制率。根据化合物各浓度和相应的抑制率用GraphPad Prism软件计算化合物抑制MDA-MB-231细胞增殖活性的IC 50值。 MDA-MB-231 cells (ATCC, HTB-26) were cultured in complete medium (ie Leibovitz's L-15 medium (ThermoFisher, 11415-114) containing 10% fetal bovine serum (Gibco, 10099-141)). On the first day of the experiment, MDA-MB-231 cells were seeded at a density of 1000 cells/well using Leibovitz's L-15 incomplete medium containing 10% activated charcoal-treated fetal bovine serum (BioSun, S-FBS-AU-045). In a 96-well 3D cell culture plate (Corning, CLS7007-24EA), 120 μL of cell suspension per well was centrifuged at 2000 rpm in a centrifuge for 3 minutes, and then the plate was placed at 37°C and cultured overnight in a CO2 -free cell incubator. The next day, 15 μL of serially diluted test compound prepared in incomplete medium was added to each well, and the final concentration of the compound was 9 concentration points of 3-fold serial dilution starting from 10 μM. After that, 15 μL of dexamethasone (MCE, HY-14648) was added to each well at a final concentration of 0.1 μM. Set wells containing only 0.5% DMSO as negative controls, and wells containing 0.1 μM dexamethasone as positive controls. Plates were placed at 37°C in a CO2 -free cell incubator for 8 days. After 8 days, remove the 96-well 3D cell culture plate and add 50 μL to each well
Figure PCTCN2022074588-appb-000203
3D Cell Viability Assay (Promega, G9683), after 25 minutes of shaking in the dark on a shaker, transfer 100 μL of the solution per well to a 96-well opaque white bottom plate (PerkinElmer, 6005290), using a multi-function microplate reader VICTOR 3 (PerkinElmer ) to read the luminescence signal value. The inhibition rate was calculated using the luminescence values of each concentration of the compound and the negative and positive control wells. According to each concentration of the compound and the corresponding inhibition rate, the IC 50 value of the compound to inhibit the proliferation of MDA-MB-231 cells was calculated by GraphPad Prism software.
表3本公开化合物在体外对MDA-MB-231细胞增殖的抑制作用Table 3 Inhibitory effect of the disclosed compounds on the proliferation of MDA-MB-231 cells in vitro
实施例编号Example number IC 50(nM) IC50 (nM)
1-P11-P1 205205
1-P21-P2 405405
8-P18-P1 5353
8-P28-P2 380380
9-P19-P1 4747
9-P29-P2 259259
结论：本公开化合物在体外对MDA-MB-231细胞增殖具有较好的抑制作用。Conclusion: The disclosed compounds have a good inhibitory effect on the proliferation of MDA-MB-231 cells in vitro.
测试例4：本公开化合物对人肝微粒体CYP3A4咪达唑仑代谢位点的酶活性的Test Example 4: Enzymatic activity of the compounds of the present disclosure on the CYP3A4 midazolam metabolic site in human liver microsomes 抑制作用inhibition
本公开化合物对人肝微粒体CYP3A4咪达唑仑代谢位点的酶活性采用如下实验方法测定。The enzymatic activity of the compounds of the present disclosure on the CYP3A4 midazolam metabolic site in human liver microsomes was determined by the following experimental method.
一、实验材料及仪器1. Experimental materials and instruments
1、磷酸缓冲液(20×PBS，购买自生工)1. Phosphate buffered saline (20×PBS, purchased from the manufacturer)
2、还原型辅酶II(以下简称NADPH，ACROS，A2646-71-1)2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)
3、人肝微粒体(Corning Gentest，Cat No，452161，Lot No.9050002，Donor， 35)3. Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 9050002, Donor, 35)
4、ABI QTrap 4000液质两用仪(AB Sciex)4. ABI QTrap 4000 Liquid/Mass Spectrometer (AB Sciex)
5、ZORBAX Extend-C18，3×50mm，3.5μm(美国安捷伦公司)5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent, USA)
6、CYP探针底物(咪达唑仑，TRC，M343000/3μM)6. CYP probe substrate (midazolam, TRC, M343000/3μM)
7、质控对照抑制剂(酮康唑，SIGMA，Cat No.K1003-100MG)7. Quality control inhibitor (ketoconazole, SIGMA, Cat No.K1003-100MG)
8、阳性对照化合物Relacorilant(CORT-125134，参考WO2013177559A2实施例18合成)8. Positive control compound Relacorilant (CORT-125134, synthesized with reference to Example 18 of WO2013177559A2)
二、实验步骤2. Experimental steps
配制100mM的PBS缓冲液，用该缓冲液配制7.5mM的MgCl 2和5mM的NADPH溶液，然后用该7.5mM的MgCl 2配制0.25mg/mL的微粒体溶液，用DMSO将浓度为30mM的实施例1-P1化合物或者阳性对照化合物Relacorilant的储备液稀释成浓度为30mM、10mM、3mM、1mM、0.3mM、0.03mM、0.003mM、0mM的系列溶液I，再用磷酸缓冲液(PBS)，将上述系列溶液I稀释200倍得到系列待测溶液II(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS稀释至15μM浓度的咪达唑仑工作液。 Prepare 100 mM PBS buffer, use this buffer to make 7.5 mM MgCl and 5 mM NADPH solution, then use this 7.5 mM MgCl to make 0.25 mg /mL microsome solution, use DMSO to make a concentration of 30 mM Example The stock solution of the 1-P1 compound or the positive control compound Relacorilant was diluted into a series of solutions I with a concentration of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM, and then phosphate buffered saline (PBS) was used. The series of solutions I were diluted 200 times to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM). Dilute to 15 μM concentration of midazolam working solution with PBS.
取配制在7.5mM MgCl 2中的0.25mg/mL的微粒体溶液40μL，再分别取15μM的咪达唑仑工作液和化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM)各20μL，混合均匀。质控对照组用相同浓度的酮康唑代替化合物。同时将5mM的NADPH溶液一起在37℃预孵育5分钟。5分钟之后每个孔中加入20μL NADPH，启动反应，孵育30分钟。所有孵育样品设双样本。30分钟后向所有样本中加入250μL含内标的乙腈，混匀，800rpm摇10分钟，然后3700rpm离心10分钟。取100μL的上清液与80μL的超纯水混匀，转移至LC-MS/MS分析。 Take 40 μL of 0.25 mg/mL microsomal solution prepared in 7.5 mM MgCl 2 , and then take 15 μM midazolam working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM, respectively). ) 20 μL each, mix well. The quality control control group replaced the compound with the same concentration of ketoconazole. Simultaneously, 5 mM NADPH solution was pre-incubated together at 37°C for 5 minutes. After 5 minutes, 20 [mu]L of NADPH was added to each well to initiate the reaction and incubated for 30 minutes. All incubation samples were double-sampled. After 30 minutes, 250 μL of acetonitrile containing internal standard was added to all samples, mixed well, shaken at 800 rpm for 10 minutes, and then centrifuged at 3700 rpm for 10 minutes. 100 μL of the supernatant was mixed with 80 μL of ultrapure water, and then transferred to LC-MS/MS analysis.
数值经Graphpad Prism计算得到药物对CYP3A4咪达唑仑代谢位点的IC 50值见表4。 The values were calculated by Graphpad Prism, and the IC 50 values of the drugs on the CYP3A4 midazolam metabolic site are shown in Table 4.
表4本公开化合物对人肝微粒体CYP3A4的咪达唑仑代谢位点的IC 50值 Table 4 IC50 values of compounds of the present disclosure for the midazolam metabolic site of human liver microsomes CYP3A4
化合物compound IC 50(μM) IC50 (μM)
实施例1-P1Example 1-P1 10.410.4
RelacorilantRelacorilant 2.42.4
结论：本公开实施例1-P1化合物对人肝微粒体CYP3A4的咪达唑仑代谢位点抑制作用弱，基于CYP3A4代谢咪达唑仑代谢位点发生代谢性药物相互作用的风险较小，较阳性对照化合物Relacorilant表现出更好的安全性。Conclusion: The compound of Example 1-P1 of the present disclosure has a weak inhibitory effect on the midazolam metabolic site of CYP3A4 in human liver microsomes, and the risk of metabolic drug interactions based on the CYP3A4 metabolism of the midazolam metabolic site is less, and the risk of metabolic drug interactions is relatively low. The positive control compound Relacorilant showed better safety profile.
测试例5：本公开化合物对人肝微粒体CYP3A4睾酮代谢位点的酶活性的抑制Test Example 5: Inhibition of the enzymatic activity of the CYP3A4 testosterone metabolic site of human liver microsomes by the compounds of the present disclosure 作用effect
本公开化合物对人肝微粒体CYP3A4睾酮代谢位点的酶活性采用如下实验方法测定。The enzymatic activity of the compounds of the present disclosure on the CYP3A4 testosterone metabolic site in human liver microsomes was determined by the following experimental method.
一、实验材料及仪器1. Experimental materials and instruments
1、磷酸缓冲液(20×PBS，购买自生工)1. Phosphate buffered saline (20×PBS, purchased from the manufacturer)
2、还原型辅酶II(以下简称NADPH，ACROS，A2646-71-1)2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)
3、人肝微粒体(Corning Gentest，Cat No，452161，Lot No.905002，Donor35)3. Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 905002, Donor35)
4、ABI QTrap 4000液质两用仪(AB Sciex)4. ABI QTrap 4000 Liquid/Mass Spectrometer (AB Sciex)
5、ZORBAX Extend-C18，3×50mm，3.5μm(美国安捷伦公司)5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent, USA)
6、CYP探针底物(睾酮，沃凯，CAS No.[58-22-0]/75μM)6. CYP probe substrate (testosterone, Wokai, CAS No.[58-22-0]/75μM)
7、质控对照抑制剂(酮康唑，SIGMA，Cat No.K1003-100MG)7. Quality control inhibitor (ketoconazole, SIGMA, Cat No.K1003-100MG)
8、阳性对照化合物Relacorilant(CORT-125134，参考WO2013177559A2实施例18合成)8. Positive control compound Relacorilant (CORT-125134, synthesized with reference to Example 18 of WO2013177559A2)
二、实验步骤2. Experimental steps
配制100mM的PBS缓冲液，用该缓冲液配制7.5mM的MgCl 2和5mM的NADPH溶液，然后用该7.5mM的MgCl 2配制0.25mg/mL的微粒体溶液，用DMSO将浓度为30mM的实施例1-P1化合物或者阳性对照化合物Relacorilant的储备液稀释成浓度为30mM、10mM、3mM、1mM、0.3mM、0.03mM、0.003mM、0mM的系列溶液I，再用磷酸缓冲液(PBS)，将上述系列溶液I稀释200倍得到系列待测溶液II(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS稀释至375μM浓度的睾酮工作液。 Prepare 100 mM PBS buffer, use this buffer to make 7.5 mM MgCl and 5 mM NADPH solution, then use this 7.5 mM MgCl to make 0.25 mg /mL microsome solution, use DMSO to make a concentration of 30 mM Example The stock solution of the 1-P1 compound or the positive control compound Relacorilant was diluted into a series of solutions I with a concentration of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM, and then phosphate buffered saline (PBS) was used. The series of solutions I were diluted 200 times to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM). Testosterone working solution diluted with PBS to a concentration of 375 μM.
取配制在7.5mM MgCl 2中的0.25mg/mL的微粒体溶液40μL，再分别取375μM的睾酮工作液和化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM)各20μL，混合均匀。质控对照组用相同浓度的酮康唑代替化合物。同时将5mM的NADPH溶液一起在37℃预孵育5分钟。5分钟之后每个孔中加入20μL NADPH，启动反应，孵育30分钟。30分钟后向所有样本中加入250μL含内标的乙腈，混匀，800rpm摇10分钟，然后3700rpm离心10分钟。取100μL的上清液与80μL的超纯水混匀，转移至LC-MS/MS分析。 Take 40 μL of 0.25 mg/mL microsomal solution prepared in 7.5 mM MgCl 2 , and then take 20 μL each of 375 μM testosterone working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM) ,well mixed. The quality control control group replaced the compound with the same concentration of ketoconazole. Simultaneously, 5 mM NADPH solution was pre-incubated together at 37°C for 5 minutes. After 5 minutes, 20 [mu]L of NADPH was added to each well to initiate the reaction and incubated for 30 minutes. After 30 minutes, 250 μL of acetonitrile containing internal standard was added to all samples, mixed well, shaken at 800 rpm for 10 minutes, and then centrifuged at 3700 rpm for 10 minutes. 100 μL of the supernatant was mixed with 80 μL of ultrapure water, and then transferred to LC-MS/MS analysis.
数值经Graphpad Prism计算得到药物对CYP3A4睾酮代谢位点的IC 50值见表5。 The values were calculated by Graphpad Prism, and the IC 50 values of the drugs on the CYP3A4 testosterone metabolic site are shown in Table 5.
表5本公开化合物对人肝微粒体CYP3A4的睾酮代谢位点的IC 50值 Table 5 IC50 values of compounds of the present disclosure for testosterone metabolism sites of human liver microsomes CYP3A4
化合物compound IC 50(μM) IC50 (μM)
实施例1-P1Example 1-P1 25.225.2
RelacorilantRelacorilant 2.52.5
结论：本公开实施例1-P1化合物对人肝微粒体CYP3A4的睾酮代谢位点的抑制较弱，较阳性对照化合物Relacorilant表现出更好的安全性。Conclusion: The compound of Example 1-P1 of the present disclosure has weak inhibition on the testosterone metabolic site of human liver microsomes CYP3A4, and shows better safety than the positive control compound Relacorilant.
测试例6：本公开化合物对人肝微粒体CYP2C9双氯芬酸代谢位点的酶活性的Test Example 6: Enzymatic Activity of Compounds of the Present Disclosure on CYP2C9 Diclofenac Metabolic Site in Human Liver Microsomes 抑制作用inhibition
本公开化合物对人肝微粒体CYP2C9双氯芬酸代谢位点的酶活性采用如下实验方法测定。The enzymatic activity of the compounds of the present disclosure on the metabolic site of CYP2C9 diclofenac in human liver microsomes was determined by the following experimental method.
一、实验材料及仪器1. Experimental materials and instruments
1、磷酸缓冲液(20×PBS，购买自生工)1. Phosphate buffered saline (20×PBS, purchased from the manufacturer)
2、还原型辅酶II(以下简称NADPH，ACROS，A2646-71-1)2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)
3、人肝微粒体(Corning Gentest，Cat No，452161，Lot No.9050002，Donor，35)3. Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 9050002, Donor, 35)
4、ABI QTrap 4000液质两用仪(AB Sciex)4. ABI QTrap 4000 Liquid/Mass Spectrometer (AB Sciex)
5、ZORBAX Extend-C18,3×50mm,3.5μm(美国安捷伦公司)5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent, USA)
6、CYP探针底物(双氯芬酸，SIGMA，Cat No.D6899-10G/4μM)6. CYP probe substrate (diclofenac, SIGMA, Cat No.D6899-10G/4μM)
7、质控对照抑制剂(磺胺苯吡唑，SIGMA，Cat No.526-08-9)7. Quality control inhibitor (Sulfaphenazole, SIGMA, Cat No.526-08-9)
8、阳性对照化合物Relacorilant(CORT-125134，参考WO2013177559A2实施例18合成)8. Positive control compound Relacorilant (CORT-125134, synthesized with reference to Example 18 of WO2013177559A2)
二、实验步骤2. Experimental steps
配制100mM的PBS缓冲液，用该缓冲液配制7.5mM的MgCl 2和5mM的NADPH溶液，然后用该7.5mM的MgCl 2配制0.25mg/mL的微粒体溶液，用DMSO将浓度为30mM的实施例1-P1化合物或者阳性对照化合物Relacorilant的储备液稀释成浓度为30mM、10mM、3mM、1mM、0.3mM、0.03mM、0.003mM、0mM的系列溶液I，再用磷酸缓冲液(PBS)，将上述系列溶液I稀释200倍得到系列待测溶液II(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS稀释至20μM浓度的双氯芬酸工作液。 Prepare 100 mM PBS buffer, use this buffer to make 7.5 mM MgCl and 5 mM NADPH solution, then use this 7.5 mM MgCl to make 0.25 mg /mL microsome solution, use DMSO to make a concentration of 30 mM Example The stock solution of the 1-P1 compound or the positive control compound Relacorilant was diluted into a series of solutions I with a concentration of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM, and then phosphate buffered saline (PBS) was used. The series of solutions I were diluted 200 times to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM). Diclofenac working solution diluted with PBS to a concentration of 20 μM.
取配制在7.5mM MgCl 2中的0.25mg/mL的微粒体溶液40μL，再分别取15μM的双氯芬酸工作液和化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM)各20μL，混合均匀。质控对照组用相同浓度的磺胺苯吡唑代替化合物。同时将5mM的NADPH溶液一起在37℃预孵育5分钟。5分钟之后每个孔中加入20μL NADPH，启动反应，孵育30分钟。所有孵育样品设双样本。30分钟后向所有样本中加入250μL含内标的乙腈，混匀，800rpm摇10分钟，然后3700rpm离心10分钟。取100μL的上清液与80μL的超纯水混匀，转移至LC-MS/MS分析。 Take 40 μL of 0.25 mg/mL microsomal solution prepared in 7.5 mM MgCl 2 , and then take 20 μL each of 15 μM diclofenac working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM) ,well mixed. In the quality control control group, the compound was replaced with the same concentration of sulfapyrazole. Simultaneously, 5 mM NADPH solution was pre-incubated together at 37°C for 5 minutes. After 5 minutes, 20 [mu]L of NADPH was added to each well to initiate the reaction and incubated for 30 minutes. All incubation samples were double-sampled. After 30 minutes, 250 μL of acetonitrile containing internal standard was added to all samples, mixed well, shaken at 800 rpm for 10 minutes, and then centrifuged at 3700 rpm for 10 minutes. 100 μL of the supernatant was mixed with 80 μL of ultrapure water, and then transferred to LC-MS/MS analysis.
数值经Graphpad Prism计算得到药物对CYP2C9双氯芬酸代谢位点的IC 50值见表6。 The values were calculated by Graphpad Prism, and the IC 50 values of the drug on the CYP2C9 diclofenac metabolic site are shown in Table 6.
表6本公开化合物对人肝微粒体CYP2C9双氯芬酸代谢位点的IC 50值 Table 6 IC 50 values of compounds of the present disclosure on human liver microsomal CYP2C9 diclofenac metabolic site
化合物compound IC 50(μM) IC50 (μM)
实施例1-P1Example 1-P1 >30>30
RelacorilantRelacorilant 4.24.2
结论：本公开实施例1-P1化合物在30μM浓度范围内不会发生基于CYP2C9双氯芬酸代谢位点的代谢性药物相互作用，较阳性对照化合物Relacorilant表现出 更好的安全性。Conclusion: The compound of Example 1-P1 of the present disclosure does not have a metabolic drug interaction based on the CYP2C9 diclofenac metabolic site in the concentration range of 30 μM, and shows better safety than the positive control compound Relacorilant.
测试例7：本公开化合物对人肝微粒体CYP2C19(S)-美芬妥英代谢位点的酶活Test Example 7: Enzymatic Activity of the Compounds of the Present Disclosure on CYP2C19(S)-Mephenytoin Metabolic Site in Human Liver Microsomes 性的抑制作用sexual inhibition
本公开化合物对人肝微粒体CYP2C19(S)-美芬妥英代谢位点的酶活性采用如下实验方法测定。The enzymatic activity of the compounds of the present disclosure on the CYP2C19(S)-mephenytoin metabolic site of human liver microsomes was determined by the following experimental method.
一、实验材料及仪器1. Experimental materials and instruments
1、磷酸缓冲液(20×PBS，购买自生工)1. Phosphate buffered saline (20×PBS, purchased from the manufacturer)
2、还原型辅酶II(以下简称NADPH，ACROS，A2646-71-1)2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)
3、人肝微粒体(Corning Gentest，Cat No，452161，Lot No.9050002，Donor，35)3. Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 9050002, Donor, 35)
4、ABI QTrap 4000液质两用仪(AB Sciex)4. ABI QTrap 4000 Liquid/Mass Spectrometer (AB Sciex)
5、ZORBAX Extend-C18,3×50mm，3.5μm(美国安捷伦公司)5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent, USA)
6、CYP探针底物((S)-美芬妥英/20μM，粉末购自百灵威科技有限公司，Cat No.303768)6. CYP probe substrate ((S)-Mephenytoin/20μM, powder purchased from Bailingwei Technology Co., Ltd., Cat No.303768)
7、质控对照抑制剂(噻氯匹定，粉末购自SIGMA，Cat No.T6654-1G)7. Quality control inhibitor (ticlopidine, powder purchased from SIGMA, Cat No.T6654-1G)
8、阳性对照化合物Relacorilant(CORT-125134，参考WO2013177559A2实施例18合成)8. Positive control compound Relacorilant (CORT-125134, synthesized with reference to Example 18 of WO2013177559A2)
二、实验步骤2. Experimental steps
配制100mM的PBS缓冲液，用该缓冲液配制7.5mM的MgCl 2和5mM的NADPH溶液，然后用该7.5mM的MgCl 2配制0.25mg/mL的微粒体溶液，用DMSO将浓度为30mM的实施例1-P1化合物或者阳性对照化合物Relacorilant的储备液稀释成浓度为30mM、10mM、3mM、1mM、0.3mM、0.03mM、0.003mM、0mM的系列溶液I，再用磷酸缓冲液(PBS)，将上述系列溶液I稀释200倍得到系列待测溶液II(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS稀释至100μM浓度的(S)-美芬妥英工作液。 Prepare 100 mM PBS buffer, use this buffer to make 7.5 mM MgCl and 5 mM NADPH solution, then use this 7.5 mM MgCl to make 0.25 mg /mL microsome solution, use DMSO to make a concentration of 30 mM Example The stock solution of the 1-P1 compound or the positive control compound Relacorilant was diluted into a series of solutions I with a concentration of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM, and then phosphate buffered saline (PBS) was used. The series of solutions I were diluted 200 times to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM). (S)-Mephentoin working solution diluted with PBS to a concentration of 100 μM.
取配制在7.5mM MgCl 2中的0.25mg/mL的微粒体溶液40μL，再分别取15μM的(S)-美芬妥英工作液和化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM)各20μL，混合均匀。质控对照组用相同浓度的噻氯匹定代替化合物。同时将5mM的NADPH溶液一起在37℃预孵育5分钟。5分钟之后每个孔中加入20μL NADPH，启动反应，孵育30分钟。所有孵育样品设双样本。30分钟后向所有样本中加入250μL含内标的乙腈，混匀，800rpm摇10分钟，然后3700rpm离心10分钟。取100μL的上清液与80μL的超纯水混匀，转移至LC-MS/MS分析。 Take 40 μL of 0.25 mg/mL microsomal solution prepared in 7.5 mM MgCl 2 , and then take 15 μM (S)-mephenytoin working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15 , 0.015, 0 μM) 20 μL each, and mix well. The quality control control group was replaced with the compound with the same concentration of ticlopidine. Simultaneously, 5 mM NADPH solution was pre-incubated together at 37°C for 5 minutes. After 5 minutes, 20 [mu]L of NADPH was added to each well to initiate the reaction and incubated for 30 minutes. All incubation samples were double-sampled. After 30 minutes, 250 μL of acetonitrile containing internal standard was added to all samples, mixed well, shaken at 800 rpm for 10 minutes, and then centrifuged at 3700 rpm for 10 minutes. 100 μL of the supernatant was mixed with 80 μL of ultrapure water, and then transferred to LC-MS/MS analysis.
数值经Graphpad Prism计算得到药物对CYP2C19(S)-美芬妥英代谢位点的IC 50值见表7。 The values were calculated by Graphpad Prism, and the IC 50 values of the drug on the CYP2C19(S)-mephenytoin metabolic site were shown in Table 7.
表7本公开化合物对人肝微粒体CYP2C19(S)-美芬妥英代谢位点的IC 50值 Table 7 IC 50 values of the compounds of the present disclosure on the CYP2C19(S)-mephenytoin metabolic site in human liver microsomes
化合物compound IC 50(μM) IC50 (μM)
实施例1-P1Example 1-P1 >30>30
RelacorilantRelacorilant 6.96.9
结论：本公开实施例1-P1化合物在30μM浓度范围内不会发生基于CYP2C19(S)-美芬妥英代谢位点的代谢性药物相互作用，较阳性对照化合物Relacorilant表现出更好的安全性。Conclusion: The compound of Example 1-P1 of the present disclosure will not have metabolic drug interactions based on the CYP2C19(S)-mephenytoin metabolic site in the concentration range of 30 μM, and it has better safety than the positive control compound Relacorilant .
测试例8：本公开化合物对人肝微粒体CYP1A2非那西丁代谢位点的酶活性的Test Example 8: Enzymatic activity of the compounds of the present disclosure on the CYP1A2 phenacetin metabolic site in human liver microsomes 抑制作用inhibition
本公开化合物对人肝微粒体CYP1A2非那西丁代谢位点的酶活性采用如下实验方法测定。The enzymatic activity of the compounds of the present disclosure on the CYP1A2 phenacetin metabolic site in human liver microsomes was determined by the following experimental method.
一、实验材料及仪器1. Experimental materials and instruments
1、磷酸缓冲液(20×PBS，购买自生工)1. Phosphate buffered saline (20×PBS, purchased from the manufacturer)
2、还原型辅酶II(以下简称NADPH，ACROS，A2646-71-1)2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)
3、人肝微粒体(Corning Gentest，Cat No，452161，Lot No.9050002，Donor，35)3. Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 9050002, Donor, 35)
4、ABI QTrap 4000液质两用仪(AB Sciex)4. ABI QTrap 4000 Liquid/Mass Spectrometer (AB Sciex)
5、ZORBAX Extend-C18，3×50mm，3.5μm(美国安捷伦公司)5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent, USA)
6、CYP探针底物(非那西丁/12μM，中国药品生物制品检定所，Cat No.100095-200204)6. CYP probe substrate (phenacetin/12μM, China Institute for the Control of Pharmaceutical and Biological Products, Cat No.100095-200204)
7、质控对照抑制剂(α-萘黄酮，SIGMA，Cat No.N5757-1G)7. Quality control inhibitor (α-naphthoflavone, SIGMA, Cat No.N5757-1G)
8、阳性对照化合物Relacorilant(CORT-125134，参考WO2013177559A2实施例18合成)8. Positive control compound Relacorilant (CORT-125134, synthesized with reference to Example 18 of WO2013177559A2)
二、实验步骤2. Experimental steps
配制100mM的PBS缓冲液，用该缓冲液配制7.5mM的MgCl 2和5mM的NADPH溶液，然后用该7.5mM的MgCl 2配制0.25mg/mL的微粒体溶液，用DMSO将浓度为30mM的实施例1-P1化合物或者阳性对照化合物Relacorilant的储备液稀释成浓度为30mM、10mM、3mM、1mM、0.3mM、0.03mM、0.003mM、0mM的系列溶液I，再用磷酸缓冲液(PBS)，将上述系列溶液I稀释200倍得到系列待测溶液II(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS稀释至60μM浓度的非那西丁工作液。 Prepare 100 mM PBS buffer, use this buffer to make 7.5 mM MgCl and 5 mM NADPH solution, then use this 7.5 mM MgCl to make 0.25 mg /mL microsome solution, use DMSO to make a concentration of 30 mM Example The stock solution of the 1-P1 compound or the positive control compound Relacorilant was diluted into a series of solutions I with a concentration of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM, and then phosphate buffered saline (PBS) was used. The series of solutions I were diluted 200 times to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM). Dilute with PBS to a working solution of phenacetin at a concentration of 60 μM.
取配制在7.5mM MgCl 2中的0.25mg/mL的微粒体溶液40μL，再分别取15μM的非那西丁工作液和化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM)各20μL，混合均匀。质控对照组用相同浓度的α-萘黄酮代替化合物。同时将5mM的NADPH溶液一起在37℃预孵育5分钟。5分钟之后每个孔中加入20μL NADPH，启动反应，孵育30分钟。所有孵育样品设双样本。30分钟后向所有样本中加入 250μL含内标的乙腈，混匀，800rpm摇10分钟，然后3700rpm离心10分钟。取100μL的上清液与80μL的超纯水混匀，转移至LC-MS/MS分析。 Take 40 μL of 0.25 mg/mL microsomal solution prepared in 7.5 mM MgCl 2 , and then take 15 μM phenacetin working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM, respectively). ) 20 μL each, mix well. The quality control control group replaced the compound with the same concentration of α-naphthoflavone. Simultaneously, 5 mM NADPH solution was pre-incubated together at 37°C for 5 minutes. After 5 minutes, 20 [mu]L of NADPH was added to each well to initiate the reaction and incubated for 30 minutes. All incubation samples were double-sampled. After 30 minutes, 250 μL of acetonitrile containing internal standard was added to all samples, mixed well, shaken at 800 rpm for 10 minutes, and then centrifuged at 3700 rpm for 10 minutes. 100 μL of the supernatant was mixed with 80 μL of ultrapure water, and then transferred to LC-MS/MS analysis.
数值经Graphpad Prism计算得到药物对CYP1A2非那西丁代谢位点的IC 50值见表8。 The values were calculated by Graphpad Prism, and the IC 50 values of the drugs on the CYP1A2 phenacetin metabolic site were shown in Table 8.
表8本公开化合物对人肝微粒体CYP1A2非那西丁代谢位点的IC 50值 Table 8 IC 50 values of the compounds of the present disclosure on the CYP1A2 phenacetin metabolic site in human liver microsomes
化合物compound IC 50(μM) IC50 (μM)
实施例1-P1Example 1-P1 >30>30
结论：本公开实施例1-P1化合物在30μM浓度范围内不会发生基于CYP1A2非那西丁代谢位点的代谢性药物相互作用。Conclusion: The compound of Example 1-P1 of the present disclosure does not have a metabolic drug interaction based on the CYP1A2 phenacetin metabolic site in the concentration range of 30 μM.
测试例9：本公开化合物对人肝微粒体CYP2D6右美沙芬代谢位点的酶活性的Test Example 9: Enzyme activity of the compounds of the present disclosure on the metabolic site of CYP2D6 dextromethorphan in human liver microsomes 抑制作用inhibition
本公开化合物对人肝微粒体CYP2D6右美沙芬代谢位点的酶活性采用如下实验方法测定。The enzymatic activity of the compounds of the present disclosure on the CYP2D6 dextromethorphan metabolic site of human liver microsomes was determined by the following experimental method.
一、实验材料及仪器1. Experimental materials and instruments
1、磷酸缓冲液(20×PBS，购买自生工)1. Phosphate buffered saline (20×PBS, purchased from the manufacturer)
2、还原型辅酶II(以下简称NADPH，ACROS，A2646-71-1)2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)
3、人肝微粒体(Corning Gentest，Cat No，452161，Lot No.9050002，Donor，35)3. Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 9050002, Donor, 35)
4、ABI QTrap 4000液质两用仪(AB Sciex)4. ABI QTrap 4000 Liquid/Mass Spectrometer (AB Sciex)
5、ZORBAX Extend-C18，3×50mm，3.5μm(美国安捷伦公司)5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent, USA)
6、CYP探针底物(右美沙芬/4μM，Sigma，Cat No.D9684-5G)6. CYP probe substrate (dextromethorphan/4μM, Sigma, Cat No.D9684-5G)
7、质控对照抑制剂(奎尼丁，SIGMA，Q0750-5G)7. Quality control inhibitor (quinidine, SIGMA, Q0750-5G)
8、阳性对照化合物Relacorilant(CORT-125134，参考WO2013177559A2实施例18合成)8. Positive control compound Relacorilant (CORT-125134, synthesized with reference to Example 18 of WO2013177559A2)
二、实验步骤2. Experimental steps
配制100mM的PBS缓冲液，用该缓冲液配制7.5mM的MgCl 2和5mM的NADPH溶液，然后用该7.5mM的MgCl 2配制0.25mg/mL的微粒体溶液，用DMSO将浓度为30mM的实施例1-P1化合物或者阳性对照化合物Relacorilant的储备液稀释成浓度为30mM、10mM、3mM、1mM、0.3mM、0.03mM、0.003mM、0mM的系列溶液I，再用磷酸缓冲液(PBS)，将上述系列溶液I稀释200倍得到系列待测溶液II(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS稀释至20μM浓度的右美沙芬工作液。 Prepare 100 mM PBS buffer, use this buffer to make 7.5 mM MgCl and 5 mM NADPH solution, then use this 7.5 mM MgCl to make 0.25 mg /mL microsome solution, use DMSO to make a concentration of 30 mM Example The stock solution of the 1-P1 compound or the positive control compound Relacorilant was diluted into a series of solutions I with a concentration of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM, and then phosphate buffered saline (PBS) was used. The series of solutions I were diluted 200 times to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM). Dextromethorphan working solution diluted with PBS to a concentration of 20 μM.
取配制在7.5mM MgCl 2中的0.25mg/mL的微粒体溶液40μL，再分别取15μM的右美沙芬工作液和化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM)各20μL，混合均匀。质控对照组用相同浓度的奎尼丁代替化合物。同时将5mM的 NADPH溶液一起在37℃预孵育5分钟。5分钟之后每个孔中加入20μL NADPH，启动反应，孵育30分钟。所有孵育样品设双样本。30分钟后向所有样本中加入250μL含内标的乙腈，混匀，800rpm摇10分钟，然后3700rpm离心10分钟。取100μL的上清液与80μL的超纯水混匀，转移至LC-MS/MS分析。 Take 40 μL of 0.25 mg/mL microsomal solution prepared in 7.5 mM MgCl 2 , and then take 15 μM dextromethorphan working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM) 20 μL each, mix well. The QC control group replaced the compound with the same concentration of quinidine. Simultaneously, 5 mM NADPH solution was pre-incubated together at 37°C for 5 minutes. After 5 minutes, 20 [mu]L of NADPH was added to each well to initiate the reaction and incubated for 30 minutes. All incubation samples were double-sampled. After 30 minutes, 250 μL of acetonitrile containing internal standard was added to all samples, mixed well, shaken at 800 rpm for 10 minutes, and then centrifuged at 3700 rpm for 10 minutes. 100 μL of the supernatant was mixed with 80 μL of ultrapure water, and then transferred to LC-MS/MS analysis.
数值经Graphpad Prism计算得到药物对CYP2D6右美沙芬代谢位点的IC 50值见表9。 The values were calculated by Graphpad Prism, and the IC 50 values of the drug on the CYP2D6 dextromethorphan metabolic site are shown in Table 9.
表9本公开化合物对人肝微粒体CYP2D6右美沙芬代谢位点的IC 50值 Table 9 IC 50 values of the compounds of the present disclosure on the CYP2D6 dextromethorphan metabolic site in human liver microsomes
化合物compound IC 50(μM) IC50 (μM)
实施例1-P1Example 1-P1 >30>30
RelacorilantRelacorilant 9.09.0
结论：本公开实施例1-P1化合物在30μM浓度范围内不会发生基于CYP2D6右美沙芬代谢位点的代谢性药物相互作用，较阳性对照化合物Relacorilant表现出更好的安全性。Conclusion: The compound of Example 1-P1 of the present disclosure does not have a metabolic drug interaction based on the CYP2D6 dextromethorphan metabolic site within the concentration range of 30 μM, and shows better safety than the positive control compound Relacorilant.
b试例10：本公开化合物的药代动力学测试b Test Example 10: Pharmacokinetic testing of the disclosed compounds
1、摘要1. Abstract
以裸鼠为受试动物，应用LC/MS/MS法测定了裸鼠灌胃给予待测化合物后不同时刻血浆中的药物浓度。研究本公开化合物在裸鼠体内的药代动力学行为，评价其药动学特征。Taking nude mice as test animals, the drug concentration in plasma at different times after oral administration of the test compounds to nude mice was determined by LC/MS/MS method. The pharmacokinetic behavior of the disclosed compounds in nude mice was studied, and their pharmacokinetic characteristics were evaluated.
2、实验方案2. Experimental scheme
2.1实验药品2.1 Experimental drugs
实施例1-P1化合物、Relacorilant。Example 1 - P1 compound, Relacorilant.
2.2实验动物2.2 Experimental animals
裸鼠27只，雌性，分为3组，购自维通利华实验动物有限公司。27 nude mice, female, divided into 3 groups, were purchased from Weitong Lihua Laboratory Animal Co., Ltd.
2.3药物配制2.3 Drug preparation
称取一定量药物，加入10％DMSO、0.1％吐温80和89.9％HPMC(0.5％)配制成澄明溶液。A certain amount of medicine was weighed, and 10% DMSO, 0.1% Tween 80 and 89.9% HPMC (0.5%) were added to prepare a clear solution.
2.4给药2.4 Administration
裸鼠禁食过夜后灌胃给药，给药剂量分别为10mg/kg、30mg/kg，给药体积均为0.2mL/10g。Nude mice were fasted overnight and then intragastrically administered. The doses were 10 mg/kg and 30 mg/kg, respectively, and the administration volume was 0.2 mL/10 g.
3、操作3. Operation
裸鼠灌胃给药待测化合物，于给药前及给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小时采血0.1mL，置EDTA-K2抗凝试管中，10000转/分钟离心1分钟(4℃)，1小时内分离血浆，-20℃保存待测。采血至离心过程在冰浴条件下操作。Nude mice were administered the test compound by gavage, and 0.1 mL of blood was collected before and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, and placed in an EDTA-K2 anticoagulation test tube, 10000 Centrifuge at rpm for 1 minute (4°C), separate plasma within 1 hour, and store at -20°C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions.
测定不同浓度的药物灌胃给药后裸鼠血浆中的待测化合物含量：取给药后各 时刻的裸鼠血浆20μL，加入内标溶液(喜树碱100ng/mL)50μL，乙腈200μL，涡旋混合5分钟，离心10分钟(3700转/分钟)，血浆样品取上清液1μL进行LC/MS/MS分析。Determination of the content of the test compound in the plasma of nude mice after oral administration of different concentrations of drugs: take 20 μL of nude mouse plasma at each time after administration, add 50 μL of internal standard solution (camptothecin 100 ng/mL), 200 μL of acetonitrile, and vortex. Spin and mix for 5 minutes, centrifuge for 10 minutes (3700 rpm), and take 1 μL of the supernatant from plasma samples for LC/MS/MS analysis.
4、药代动力学参数结果4. Pharmacokinetic parameter results
表10本公开化合物的药代动力学参数Table 10 Pharmacokinetic parameters of compounds of the present disclosure
Figure PCTCN2022074588-appb-000204
Figure PCTCN2022074588-appb-000204
结论：本公开实施例1-P1化合物的药代吸收良好，较阳性对照化合物Relacorilant具有明显的药代动力学优势。Conclusion: The compounds of Example 1-P1 of the present disclosure have good pharmacokinetic absorption, and have obvious pharmacokinetic advantages over the positive control compound Relacorilant.

Claims (18)

  1. 一种通式(I)所示的化合物或其可药用的盐：A compound of general formula (I) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022074588-appb-100001
    Figure PCTCN2022074588-appb-100001
    其中：in:
    Figure PCTCN2022074588-appb-100002
    为不存在或化学键；
    Figure PCTCN2022074588-appb-100002
    for absence or chemical bond;
    环A选自杂环基、芳基和杂芳基；Ring A is selected from heterocyclyl, aryl and heteroaryl;
    各个R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、氧代基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、-NR 4R 5、羟基、-C(O)R 6、-C(O)OR 6、-C(O)NR 4R 5、-S(O) pR 6、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR 7R 8、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； Each R 1 is the same or different, and is independently selected from a hydrogen atom, halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 4 R 5 , hydroxy , -C(O)R 6 , -C(O)OR 6 , -C(O)NR 4 R 5 , -S(O) p R 6 , cycloalkyl, heterocyclyl, aryl and heteroaryl , wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, Substituted with one or more substituents of cyano, -NR 7 R 8 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    或者，两个相邻的R 1与环A稠合形成杂环基，其中所述的杂环基任选地被选自卤素、烷基、氧代基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR 7R 8、硝基、羟基和羟烷基中的一个或多个取代基所取代； Alternatively, two adjacent R1's are fused to ring A to form a heterocyclyl group, wherein said heterocyclyl group is optionally selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy substituted with one or more substituents in group, cyano group, -NR 7 R 8 , nitro group, hydroxy group and hydroxyalkyl group;
    环B为芳基或杂芳基；Ring B is aryl or heteroaryl;
    各个R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、-NR 4R 5、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-NR 7R 8、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； Each R 2 is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 4 R 5 , hydroxy, cycloalkyl , heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, One or more substitutions of alkoxy, haloalkyl, haloalkoxy , cyano, -NR7R8 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl base substituted;
    环C为芳基或杂芳基；Ring C is aryl or heteroaryl;
    各个R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、-NR 4R 5和羟基； each R 3 is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 4 R 5 and hydroxy;
    R 6在每次出现时相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代； R 6 is the same or different at each occurrence, and each is independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein said alkyl group, cycloalkyl group, and heterocyclyl group are each independently optionally substituted with one or more substituents selected from halo, alkyl, alkoxy, haloalkyl, and haloalkoxy;
    R 4、R 5、R 7和R 8相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基和杂环基，其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代； R 4 , R 5 , R 7 and R 8 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group, wherein said alkyl group, cycloalkyl group and The heterocyclyl groups are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy;
    或者R 4和R 5与相连的氮原子一起形成杂环基，所述杂环基任选被选自卤素、烷基、氧代基、烷氧基、卤代烷基、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 R4 and R5 together with the attached nitrogen atom form a heterocyclyl group optionally selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, Substituted with one or more substituents of amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    或者R 7和R 8与相连的氮原子一起形成杂环基，所述杂环基任选被选自卤素、烷基、氧代基、烷氧基、卤代烷基、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 R7 and R8 together with the attached nitrogen atom form a heterocyclyl group optionally selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, Substituted with one or more substituents of amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    p为0、1或2；p is 0, 1 or 2;
    m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    n为0、1、2、3或4；且n is 0, 1, 2, 3, or 4; and
    t为0、1、2、3或4。t is 0, 1, 2, 3 or 4.
  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，其为通式(II)、通式(II-1)或通式(II-2)所示的化合物或其可药用的盐：The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is represented by general formula (II), general formula (II-1) or general formula (II-2) A compound or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022074588-appb-100003
    Figure PCTCN2022074588-appb-100003
    其中：in:
    环A、环B、环C、R 1至R 3、m、n和t如权利要求1中所定义。 Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in claim 1 .
  3. 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，其为通式(III)、通式(III-1)或通式(III-2)所示的化合物或其可药用的盐：The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is represented by general formula (III), general formula (III-1) or general formula (III-2) A compound or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022074588-appb-100004
    Figure PCTCN2022074588-appb-100004
    Figure PCTCN2022074588-appb-100005
    Figure PCTCN2022074588-appb-100005
    其中：in:
    环A、环B、环C、R 1至R 3、m、n和t如权利要求1中所定义。 Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in claim 1 .
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其可药用的盐，其中环B为6至10元芳基或5至10元杂芳基；优选地，环B为吡啶基。The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring B is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably Typically, Ring B is pyridyl.
  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，其中环C为6至10元芳基或5至10元杂芳基；优选地，环C为苯基。The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein ring C is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably Typically, Ring C is phenyl.
  6. 根据权利要求1至2、4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，其为通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐：The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 4 to 5, which is general formula (IV), general formula (IV-1) or The compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022074588-appb-100006
    Figure PCTCN2022074588-appb-100006
    其中：in:
    环A、R 1至R 3、m、n和t如权利要求1中所定义。 Rings A, R 1 to R 3 , m, n and t are as defined in claim 1 .
  7. 根据权利要求1、3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，其为通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐：The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 3 to 5, which is general formula (V), general formula (V-1) or general formula The compound represented by (V-2) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022074588-appb-100007
    Figure PCTCN2022074588-appb-100007
    其中：in:
    环A、R 1至R 3、m、n和t如权利要求1中所定义。 Rings A, R 1 to R 3 , m, n and t are as defined in claim 1 .
  8. 根据权利要求1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，其中环A选自3至12元杂环基、6至10元芳基和5至10元杂芳基；优选地，环A为5或6元杂芳基；进一步优选地，环A为5元含氮杂芳基；更优选地，环A选自吡唑基、咪唑基、1,2,3-三唑基和四唑基；最优选地，环A为1,2,3-三唑基。The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein ring A is selected from a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group and 5 to 10-membered heteroaryl; preferably, ring A is a 5- or 6-membered heteroaryl; further preferably, ring A is a 5-membered nitrogen-containing heteroaryl; more preferably, ring A is selected from pyrazolyl, imidazole 1,2,3-triazolyl and tetrazolyl; most preferably, Ring A is 1,2,3-triazolyl.
  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，其中各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、3至12元环烷基和3至12元杂环基，其中所述的3至12元环烷基和3至12元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、羟基和C 1-6羟烷基中的一个或多个取代基所取代；或者两个相邻的R 1与环A稠合形成3至8元杂环基，其中所述的3至8元杂环基任选地被选自卤素、C 1-6烷基、氧代基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基中的一个或多个取代基所取代。 The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein each R 1 is the same or different, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclyl, wherein the 3 to 12 membered cycloalkyl and 3 to 12 membered heterocyclyl are each independently optionally selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 substituted by one or more substituents in haloalkoxy, cyano, hydroxyl and C 1-6 hydroxyalkyl; or two adjacent R 1 are fused with ring A to form a 3- to 8-membered heterocyclic group, wherein The 3- to 8-membered heterocyclic group is optionally selected from halogen, C 1-6 alkyl, oxo, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy substituted with one or more substituents in the 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，其中各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基和C 1-6卤代烷氧基。 The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein each R 2 is the same or different, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy.
  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，其中各个R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基。 The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each R 3 is the same or different, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy.
  12. 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，其选自以下化合物：The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, which is selected from the following compounds:
    Figure PCTCN2022074588-appb-100008
    Figure PCTCN2022074588-appb-100008
    Figure PCTCN2022074588-appb-100009
    Figure PCTCN2022074588-appb-100009
    Figure PCTCN2022074588-appb-100010
    Figure PCTCN2022074588-appb-100010
  13. 一种通式(IA)所示的化合物或其盐，A compound of general formula (IA) or its salt,
    Figure PCTCN2022074588-appb-100011
    Figure PCTCN2022074588-appb-100011
    其中：in:
    R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
    Figure PCTCN2022074588-appb-100012
    环A、环B、环C、R 1至R 3、m、n和t如权利要求1中所定义。
    Figure PCTCN2022074588-appb-100012
    Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in claim 1 .
  14. 根据权利要求13所述的通式(IA)所示的化合物或其盐，其选自以下化合物：The compound represented by the general formula (IA) according to claim 13 or a salt thereof, which is selected from the following compounds:
    Figure PCTCN2022074588-appb-100013
    Figure PCTCN2022074588-appb-100013
    Figure PCTCN2022074588-appb-100014
    Figure PCTCN2022074588-appb-100014
    Figure PCTCN2022074588-appb-100015
    Figure PCTCN2022074588-appb-100015
  15. 一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
    Figure PCTCN2022074588-appb-100016
    Figure PCTCN2022074588-appb-100016
    通式(IA)所示的化合物或其盐脱去氨基保护基R w，得到通式(I)所示的化合物或其可药用的盐， The compound represented by the general formula (IA) or a salt thereof removes the amino protecting group R w to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,
    其中：in:
    R w为氨基保护基；优选地，R w为叔丁基二甲基硅基(TBS)； R w is an amino protecting group; preferably, R w is tert-butyldimethylsilyl (TBS);
    Figure PCTCN2022074588-appb-100017
    环A、环B、环C、R 1至R 3、m、n和t如权利要求1中所定义。
    Figure PCTCN2022074588-appb-100017
    Ring A, Ring B, Ring C, R 1 to R 3 , m, n and t are as defined in claim 1 .
  16. 一种药物组合物，所述药物组合物含有根据权利要求1至12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, the pharmaceutical composition contains a compound of the general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable salts thereof. acceptable carrier, diluent or excipient.
  17. 根据权利要求1至12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16所述的药物组合物在制备通过调节GR治疗和/或预防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 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 16 is prepared for treating and/or preventing GR by regulating Use in medicine for a disease or disorder.
  18. 根据权利要求1至12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16所述的药物组合物在制备用于治疗和/或预防肿瘤、心血管疾病、炎性疾病、自身免疫性疾病、代谢类疾病、眼疾和神经变性疾病的药物中的 用途；优选在制备用于治疗和/或预防选自癌症、肥胖、糖尿病、高血压、X综合征、抑郁症、过敏、焦虑、青光眼、阿尔茨海默病、帕金森病、亨廷顿病、认知增强、库欣综合征、阿狄森病、骨质疏松症、虚弱、肌肉虚弱、骨关节炎、类风湿关节炎、哮喘、鼻炎、肾上腺功能相关的疾病、人类免疫缺陷病毒、获得性免疫缺陷综合症、免疫调节、过敏症、伤口愈合、强迫行为、成瘾、精神病、厌食、恶病质、轻度认知障碍、痴呆症、高血糖症、中心性浆液性脉络膜视网膜病变、酒精依赖症、应激障碍、谵妄、慢性疼痛、早产儿神经障碍和偏头痛的药物中的用途；更优选在制备用于治疗和/或预防选自乳腺癌、前列腺癌、肾上腺皮质癌、输卵管癌、胰腺癌、腹膜癌、皮肤癌、脑癌、膀胱癌、宫颈癌、肝癌、肺癌、白血病、骨癌、黑色素瘤、淋巴瘤、神经母细胞瘤、肾细胞癌和卵巢癌的药物中的用途；最优选在制备用于治疗和/或预防选自乳腺癌、前列腺癌、库欣综合征、肾上腺皮质癌、输卵管癌、胰腺癌、腹膜癌和卵巢癌的药物中的用途。The compound represented by the general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 16 is prepared for the treatment and/or prevention of tumors , cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, eye diseases and neurodegenerative diseases; preferably in the preparation of drugs for the treatment and/or prevention selected from cancer, obesity, diabetes, hypertension, Syndrome X, depression, allergies, anxiety, glaucoma, Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive enhancement, Cushing's syndrome, Addison's disease, osteoporosis, frailty, muscle weakness, Osteoarthritis, Rheumatoid Arthritis, Asthma, Rhinitis, Adrenal-related disorders, Human Immunodeficiency Virus, Acquired Immune Deficiency Syndrome, Immunomodulation, Allergies, Wound Healing, Obsessive-Compulsive Behavior, Addiction, Psychosis, Anorexia, Use in drugs for cachexia, mild cognitive impairment, dementia, hyperglycemia, central serous chorioretinopathy, alcohol dependence, stress disorder, delirium, chronic pain, neurological disorders of prematurity, and migraine; more Preferably in preparation for the treatment and/or prophylaxis of a cancer selected from the group consisting of breast cancer, prostate cancer, adrenocortical cancer, fallopian tube cancer, pancreatic cancer, peritoneal cancer, skin cancer, brain cancer, bladder cancer, cervical cancer, liver cancer, lung cancer, leukemia, bone cancer Use in medicaments for cancer, melanoma, lymphoma, neuroblastoma, renal cell carcinoma and ovarian cancer; most preferably in the manufacture of a medicament for the treatment and/or prevention selected from the group consisting of breast cancer, prostate cancer, Cushing's syndrome, adrenal gland cancer Use in the medicament of cortical, fallopian tube, pancreatic, peritoneal and ovarian cancers.
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