WO2022089463A1 - Agent induisant l'apoptose de protéine bcl-2 et son utilisation - Google Patents

Agent induisant l'apoptose de protéine bcl-2 et son utilisation Download PDF

Info

Publication number
WO2022089463A1
WO2022089463A1 PCT/CN2021/126588 CN2021126588W WO2022089463A1 WO 2022089463 A1 WO2022089463 A1 WO 2022089463A1 CN 2021126588 W CN2021126588 W CN 2021126588W WO 2022089463 A1 WO2022089463 A1 WO 2022089463A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
oxy
pyridin
amino
pyrrolo
Prior art date
Application number
PCT/CN2021/126588
Other languages
English (en)
Chinese (zh)
Inventor
刘兴国
苏明波
吴一哲
高安慧
周星露
钟利
胡苗
黄景来
景杭辉
金欣欣
朱建荣
Original Assignee
杭州和正医药有限公司
百极弘烨(南通)医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州和正医药有限公司, 百极弘烨(南通)医药科技有限公司 filed Critical 杭州和正医药有限公司
Publication of WO2022089463A1 publication Critical patent/WO2022089463A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a class of compounds or pharmaceutically acceptable salts that inhibit anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins, and as drugs for the treatment of hyperproliferative diseases such as cancer and inflammation, as well as immune and autologous immune disease.
  • Bcl-2 anti-apoptotic B-cell lymphoma-2
  • Bcl-2 family proteins include anti-apoptotic proteins such as BCL-2, BCL-XL and MCL-1, etc., and pro-apoptotic proteins such as Bid, Bim, Bad, Bak and Bax, etc.
  • Bcl-2 proteins have been investigated as potential drug therapy targets, including Bcl-2 and Bcl-XL.
  • Bcl-2 protein expression can be used as an independent indicator of poor prognosis in tumors such as chronic lymphocytic leukemia (CLL), prostate cancer and small cell lung cancer (SCLC).
  • CLL chronic lymphocytic leukemia
  • SCLC small cell lung cancer
  • Bcl-XL expression correlates with disease severity and stage, and in hepatocellular carcinoma, Bcl-XL expression can be an independent indicator of prognosis.
  • Bcl-2 inhibitors have been reported in the literature, such as WO 2011149492A/CN110546151A/WO2020140005A2/WO2019210828A1, etc., which disclose an apoptosis inducer, but many have problems such as short half-life or high toxicity.
  • the present invention relates to a new class of compounds, their pharmaceutically acceptable salts and their pharmaceutical compositions, and their use as medicines.
  • n 0, 1, 2, 3;
  • Z When forming a ring, Z is substituted by two substituents to form a ring; when not forming a ring, Z is replaced by one substituent;
  • R a , R b , R c and R d can each be independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxyl , amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, Heterocyclyl, spirocyclyl, aryl or heteroaryl, said alkyl, cycloalkenyl, cycloalkyl, bridged, spiro, heterocyclyl, aryl or heteroaryl may be further one or more R e substitutions;
  • Re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino , haloalkoxy, haloalkamino, cycloalkyl;
  • X is NR 8 , CR 8 R 8 ′, O, C(O), S, S(O), S(O) 2 ;
  • X and Z may form a ring B or not form a ring; when the B ring is formed, the dashed line connected to X is represented as a chemical bond; when B is an open ring, the dashed line connected to X is represented as absent; when the B ring is formed, R 2 can be substituted on Z, and can also be substituted on any atom between Z and X; when B is an open ring, R 2 is substituted on X;
  • Y 1 , Y 2 , Y 3 are each independently selected from CR 9 , N; and:
  • n is 0, 1, 2, 3, or 4;
  • X and Z form a ring B, and n is 2, 3, or 4;
  • n 1, 2, 3, 4;
  • o is selected from 0, 1, 2, 3, 4;
  • p is selected from 0, 1, 2;
  • q is selected from 0, 1, 2, 3;
  • r is selected from 0, 1, 2, 3, 4, 5;
  • s is selected from 0, 1, 2, 3, 4, 5;
  • t is selected from 0, 1, 2, 3, 4;
  • u is selected from 0, 1, 2, 3, 4;
  • Ring A is selected from cycloalkane, cycloalkenyl, bridged ring, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 ′, R 9 are each independently selected from hydrogen, deuterium, alkyl, bridged cyclyl, spirocyclyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR g , SR g , alkyl-R g , NH ( CH 2 )R g , C(O)R g , S(O)R g , SO 2 R g , C(O)OR g , OC(O)R g , NR h R i , C(O)N ( R h )R i , N(R h )C(O)R i , -P(O)R h R i
  • R 2 , R 3 , R 5 , R 6 or R 7 groups can form a ring to form cycloalkyl, heterocycloalkyl, and can be further substituted by one or more R k ;
  • R f , R g , R h , R i , R j and R k may each be independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl , bridged ring group, heterocyclic group, aryl group or heteroaryl group, said alkyl group, spirocyclic group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, aminoalkyl group, alkanecarbonyl group, alkoxycarbonyl group , alkylamino,
  • R m is selected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkcarbonyl, alkoxycarbonyl, alkylamino, halo Substituted hydroxyalkyl, haloalkylamino, cycloalkyl.
  • n 0, 1, 2, 3;
  • Z is selected from ( CH2 ) u , NH, O, S, C(O), S( O2 ), OC(O), N(H)C(O), S( O2 )N(H), N(H)S(O 2 ), OC(O)N(H), N(H)C(O)S, or hydrogen, deuterium, alkyl, spirocyclyl, bridged ring, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR a , SR a , alkyl-R a , NH(CH 2 )R a , C(O)R a , S(O)R a , SO 2 R a , C(O)OR a , OC(O)R a , NR b R c , C(O)N(R
  • R a , R b , R c and R d are each independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, Amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, hetero Cyclic, spiro, aryl or heteroaryl, the alkyl, cycloalkenyl, cycloalkyl, bridged, spiro, heterocyclyl, aryl or heteroaryl may be further replaced by a or multiple R e substitutions;
  • Re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino , haloalkoxy, haloalkamino, cycloalkyl;
  • X is NR 8 or CR 8 R 8 ′;
  • X and Z may form a ring B or not form a ring; when the B ring is formed, the dashed line connected to X is represented as a chemical bond; when B is an open ring, the dashed line connected to X is represented as absent; when the B ring is formed, R 2 can be substituted on Z, and can also be substituted on any atom between Z and X; when B is an open ring, R 2 is substituted on X;
  • Y 1 , Y 2 , Y 3 are each independently selected from CR 9 , N; and:
  • n is 0, 1, 2, 3, or 4;
  • X and Z form a ring B, and n is 2, 3, or 4;
  • o is selected from 0, 1, 2, 3, 4;
  • p is selected from 0, 1, 2;
  • q is selected from 0, 1, 2, 3;
  • r is selected from 0, 1, 2, 3, 4, 5;
  • s is selected from 0, 1, 2, 3, 4, 5;
  • t is selected from 0, 1, 2, 3, 4;
  • u is selected from 0, 1, 2, 3, 4;
  • Ring A is selected from cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl or heteroaryl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 ′, R 9 are each independently selected from hydrogen, deuterium, alkyl, bridged cyclyl, spirocyclyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl, halogen, nitro, oxo, cyano, OR g , SR g , alkyl-R g , NH ( CH)R g , C(O)R g , S(O)R g , SO 2 R g , C(O)OR g , OC(O)R g , NR h R i , C(O)N(R h ) R i , N(R h )C(O)R i , -P(O)R h R i , the
  • R 2 , R 3 , R 5 , R 6 or R 7 groups can form a ring to form cycloalkyl, heterocycloalkyl, and can be further substituted by one or more R k ;
  • R f , R g , Rh , R i , R j and R k are each independently selected from hydrogen, deuterium, alkyl, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl , oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, Bridged cyclyl, heterocyclyl, aryl or heteroaryl, said alkyl, spirocyclyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, alkoxycarbonyl, Alkylamino, cycloalkyl, cycloalken
  • R m is selected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkcarbonyl, alkoxycarbonyl, alkylamino, halo Substituted hydroxyalkyl, haloalkylamino, cycloalkyl.
  • C marked with * in formula (I) is R configuration or S configuration.
  • a compound has the structure shown in general formula (II-A) or (II-B):
  • the preferred compound of the present invention has the structure of general formula (III-A) or (III-B):
  • Y 1 , Y 2 , Y 3 , Z, R 2 , R 5 , R 6 , R 7 , n, r, q, s are defined as in the general formula (I).
  • preferred compounds of the present invention have the structure of general formula (IV-A) or (IV-B):
  • Y 1 , Y 2 , Y 3 , Z, R 2 , R 5 , R 6 , n, r, and q are defined as in general formulae (III-A) and (III-B).
  • preferred compounds of the present invention have the structure of general formula (V-A):
  • Y 1 , Y 2 , Y 3 , R 2 , R 5 , R 6 , n, r, q are as defined in general formula IV-A.
  • Preferred compounds of the present invention have the structures of general formula (V-B1), (V-B2), (V-B3), (V-B4), (V-B5):
  • Y 1 , Y 2 , Y 3 , R 2 , R 5 , R 6 , r, q are as defined in general formula (IV-B).
  • the compound of the present invention has the structure of general formula VI-A1, VI-A2:
  • Y 1 , Y 2 , Y 3 , R 5 , R 6 , r, and q are as defined in the general formula VA;
  • T is selected from absent, NRn , O, S;
  • R k , R n are independently selected from hydrogen, deuterium, alkane, spirocyclyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, alkoxy, haloalkyl , hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged, heterocyclyl, aryl or heteroaryl , the alkyl group, cycloalkyl group, cycloalkenyl group, bridged ring group, heterocyclic group, spirocyclic group, aryl group or heteroaryl group can be further substituted by 1 or more R o ;
  • R is selected from hydrogen, deuterium , alkyl, halogen, cyano, amino, nitro, hydroxyl, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkane Amino, halogenated hydroxyalkyl, halogenated alkylamino, cycloalkyl;
  • n 1 is selected from 0, 1, 2, 3.
  • Z is selected from O, NH, CH 2 , CO; when not forming a ring, Z is selected from H;
  • Y 1 , Y 2 , Y 3 are independently selected from CR 9 , N;
  • R 1 is H, nitro
  • R7 is H.
  • the compound of the present invention has the structure of general formula (VII):
  • Y 1 , Y 2 , Y 3 , R 2 , R 5 , R 6 , R 7 , r, q, s are as defined in general formula (I);
  • the compound of the present invention has the structure of general formula (VIII-A1), (VIII-A2), (VIII-A3), (VIII-A4), (VIII-A5):
  • Y 1 , Y 2 , Y 3 , R 2 , R 5 , R 6 , r, q are as defined in general formula VII;
  • the compound of the present invention has the structure shown by the general formula (IX):
  • X is selected from NR 11 , O;
  • L 1 is selected from a chemical bond, an alkyl group, a cycloalkyl group, a heterocyclic group, a bridged ring group, and a spirocyclic group;
  • Ring C is selected from cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl, heteroaryl;
  • R 10 and R 11 are each independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxyl, alkoxycarbonyl, spirocyclyl, alkenyl, alkynyl, Carboxyl, amide, cycloalkenyl, bridged ring, aryl or heteroaryl;
  • f is selected from 0, 1, 2, 3, 4;
  • R m may be further substituted by one or more R r ;
  • R r is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, hydroxy, oxo, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, heterocyclyl, alkylamino, alkylcarbonyl, alkane Oxycarbonyl, halohydroxyalkyl, haloalkylamino, haloalkyl, cycloalkyl, spiro, alkenyl, alkynyl, nitro, carboxyl, amide, cycloalkenyl, bridged, aryl or heteroaryl;
  • the C marked with * is preferably the S configuration
  • R 2 is methyl, methoxycarbonyl, 4-hydroxycyclohexyloxymethyl, a spiro ring structure formed by sharing a C atom with ring B (including cyclopropanyl, cyclobutanyl , cyclopentyl, N-methyl substituted azacyclopentanyl, N-methyl substituted azacyclohexyl), (4-methylpiperazin-1-yl) methyl, 2-(two Methylamino)ethyl, morpholinemethyl, (4-(oxetan-3-yl)piperazin-1-yl)methyl, (1,1-dioxythiomorpholine)methyl base, (4-acetylpiperazin-1-yl)methyl, (4-hydroxycyclohexyl)methyl, (2-(4-methylpiperazin-1-yl)ethyl, (4-(methyl) Sulfonamido)piperidin-1-yl)methyl, (4-
  • two substituents that occur in X can form a ring structure with X, including monocyclic, polycyclic (spiro-ring structure), such as R2 and X can form 6-(oxygen Etetan-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl, 6-(oxetan-3-yl)-2,6-diazaspiro [3.4]Octan-2-yl, 7-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl).
  • Parts are preferably the following structural segments:
  • the Bcl-2 inhibitor is preferably the following specific compound:
  • the compound is the following compound:
  • Substituted means that a hydrogen atom is replaced by a substituent. It should be noted that the substituents on a particular atom are restricted by their valence. In the Definitions section, " Cij " refers to a range including a starting point and an ending point, where i and j are both integers and represent the number of carbon atoms. For example, C 1-4 , C 1-10 , C 3-10 and the like.
  • alkyl used in the present invention refers to a linear saturated monovalent hydrocarbon group having one to six carbon atoms or a branched saturated monovalent hydrocarbon group having three to six carbon atoms, preferably methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.
  • the alkyl group can be unsubstituted or mono-substituted or multi-substituted, and the substituents can be the same or different when multi-substituted; the substituents of the alkyl group are selected from D (deuterium), halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, Ethyl carboxylate, isopropyl ester, carbamoyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, alkoxycarbonyl, alkylthio, alkyl Sulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3- to 10-membered heterocyclic group, or amino or mono- or poly-substituted amino, wherein the amino substituents may be the same or different, and are selected from hydrogen , C 1 -C 6 alkyl, C 1 -C 6
  • cycloalkyl refers to a non-aromatic monovalent monocyclic or polycyclic (two monocyclic rings are linked by chemical bonds or bridged or spiro or fused) having three to ten carbon atoms. Hydrocarbyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., wherein one or two carbon atoms may be replaced by an oxygen.
  • the cycloalkyl can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3 - C6cycloalkyl, halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group can be the same
  • alkenyl refers to a straight or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, containing at least one double bond and having 2 to 10 carbon atoms (ie, C 2 -C 10 alkenyl) , including but not limited to vinyl, allyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
  • Alkenyl may be substituted with one or more substituents independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halo Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
  • alkynyl refers to a straight or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, containing at least one triple bond and having 2 to 10 carbon atoms (ie C 2 -C 10 alkynyl) , including but not limited to ethynyl, propynyl, butynyl, pentynyl and hexynyl and the like.
  • the alkynyl group may be substituted with one or more substituents independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halo Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • alkoxy refers to an -O-alkyl group, wherein alkyl is as defined above.
  • alkoxy as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
  • Alkoxy also includes substituted alkoxy, the substituents of which may be D, halogen, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy , C 1 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • alkylamino refers to alkyl-NH-, wherein alkyl is as defined above.
  • alkylamino used in the present invention include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, and the like.
  • Alkylamino also includes substituted alkylamino groups, the substituents of which may be D, halogen, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 cycloalkyl group, 3- to 10-membered heterocyclic group, C 6 -C 12 aryl group, C 5 -C 14 heteroaryl group, the substituents thereof may be substituted on alkyl or N.
  • aryl refers to an all-carbon monocyclic or fused polycyclic group of 6 to 12 carbon atoms (wherein one fused ring may be partially saturated).
  • aromatic rings are: benzene ring, naphthalene ring, anthracene ring, indene ring, dihydroindenyl (indanyl).
  • Aromatic rings can be unsubstituted or substituted.
  • the substituent of the aromatic ring is selected from D, halogen (preferably fluorine, chlorine, bromine, iodine), cyano, nitro, amino, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 - C6 alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.), C1 -C 6 hydroxyalkyl (preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, etc.), C 1 -C 6 alkoxy (preferably methoxy, ethoxy, propoxy , isopropyloxy, butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, etc.), halogenated C 1 -C
  • heteroaryl refers to a monocyclic or fused polycyclic group of 5 to 14 ring atoms (one of which may be partially saturated), corresponding to one or more carbons in the above-mentioned "aryl” Replaced by heteroatoms such as oxygen, nitrogen, sulfur, and the like.
  • the heteroaromatic ring can be monocyclic or bicyclic, that is, formed by the fusion of two rings.
  • heteroaryl groups can be: pyridyl, pyrimidinyl, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, indole, Indoline, benzimidazole, etc.
  • Heterocyclic aryl groups can be unsubstituted or substituted.
  • the substituent of the heterocyclic aryl group is selected from halogen, cyano, nitro, amino, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 - C6 alkyl, halogenated C1 - C6 hydroxyalkyl, halogenated C1 - C6 alkoxy, C3 - C6 cycloalkyl, halogenated C3- C6 cycloalkyl, 3 to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • heterocyclyl refers to a non-aromatic ring having three to ten ring atoms of a monocyclic or polycyclic ring (two monocyclic rings are linked by chemical bonds or bridged or spiro or fused) group, has one or more heteroatoms selected from N, O, S, and may have one or more chemical bonds that are double bonds or triple bonds.
  • the heterocyclic group can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, oxo, thio, C 1 - C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, halo C 1 -C 6 hydroxyalkyl, halo C 1 -C 6alkoxy , C3 - C6cycloalkyl , halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, Sulfonamide group, 3- to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group
  • spirocyclyl used in the present invention refers to a polycyclic structure in which at least two rings share one atom (usually a C atom), and in this polycyclic structure, One or more of the chemical bonds are double or triple bonds, and one or more heteroatoms may be present.
  • the spirocyclic group can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3 - C6cycloalkyl, halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group can be the
  • bridged ring group used in the present invention refers to a polycyclic structure in which at least two rings share two or more atoms, and in this polycyclic structure there may be One or more of the chemical bonds are double or triple bonds, and one or more heteroatoms may be present.
  • the bridged ring group can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3 - C6cycloalkyl, halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group can be the same or
  • cycloalkenyl refers to a non-aromatic hydrocarbon group having three to ten carbon atoms in a monocyclic or polycyclic ring (two monocyclic rings are linked by chemical bonds or bridged or spiro or fused) And it contains at least one double bond, preferably cyclobutenyl, cyclopentenyl, cyclohexenyl, etc., wherein one or two carbon atoms can be replaced by an oxygen atom.
  • the cycloalkenyl can be unsubstituted or substituted, and its substituents are selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3 - C6cycloalkyl, halogenated C3 - C6cycloalkyl , alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10-membered heterocyclic group, or amino group or mono- or polysubstituted amino group, wherein the substituents of the amino group can be the
  • hydroxyalkyl refers to -alkyl-OH, wherein alkyl is as defined above.
  • alkyl is as defined above.
  • examples of "hydroxyalkyl” as used herein include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and the like.
  • Hydroalkyl also includes substituted hydroxyalkyl groups, the substituents of which may be D, halogen, amino, hydroxy, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy , C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • aminoalkyl refers to -alkyl- NH2 , wherein alkyl is as defined above.
  • alkyl is as defined above.
  • aminoalkyl include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, and the like.
  • Aminoalkyl also includes substituted aminoalkyl, the substituents of which may be D, halogen, amino, hydroxy, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy , C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl, and its substituents can be substituted on alkyl or N .
  • alkylcarbonyl refers to alkyl-C(O)-, wherein alkyl is as defined above.
  • Alkylcarbonyl also includes substituted alkylcarbonyl, the substituents of which may be D, halogen, amino, hydroxy, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy , C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • alkoxycarbonyl refers to alkyl-OC(O)-, wherein alkyl is as defined above.
  • Alkoxycarbonyl also includes substituted alkoxycarbonyl, the substituents of which may be D, halogen, amino, hydroxy, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy , C 1 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • halohydroxyalkyl refers to a hydroxyalkyl group substituted with halogen (preferably fluorine, chlorine, bromine, iodine), wherein hydroxyalkyl is as defined above. "Halohydroxyalkyl” may be substituted one or more times with halogen.
  • haloalkylamino refers to an alkylamino group substituted with halogen (preferably fluorine, chlorine, bromine, iodine), wherein alkylamino is as defined above. "Haloalkylamino” may be substituted one or more times with halogen.
  • alkyl, cycloalkyl, heterocyclylalkyl, aryl and/or heteroaryl substitution it means that each of these groups is substituted individually, or that these Group mixed substitution.
  • “Pharmaceutically acceptable salts” refers to salts prepared with pharmaceutically acceptable non-toxic acid and base salts, including inorganic or organic bases and inorganic or organic acids. Salts of inorganic bases can be selected from, for example, ammonium, calcium, magnesium, potassium, sodium, zinc salts. Further, salts of pharmaceutically acceptable inorganic bases may be selected from ammonium, calcium, magnesium, potassium and sodium salts. One or more crystal structures may exist in solid salts, and hydrated forms may also exist.
  • “Pharmaceutically acceptable base-added salts” are those that retain the biological potency and properties of the free acid of the compound and require the preparation of salts thereof with at least one pharmaceutically acceptable non-toxic base selected from inorganic and organic bases .
  • primary, secondary and tertiary amine salts, substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethyl Diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, heba amine, isopropylamine, lysine, morpholine, piperazine, piperidine, purine, theobromine, triethylamine, trimethylamine and tripropyl
  • “Pharmaceutically acceptable addition salts” refers to those that retain the biological potency and properties of the compound's free base and require the preparation of its salts with at least one pharmaceutically acceptable non-toxic acid selected from inorganic and organic acids .
  • administering or “administering” a compound or a pharmaceutically acceptable salt thereof refers to providing a compound of the present invention or a pharmaceutically acceptable salt thereof to an individual in need of treatment.
  • an "effective amount” refers to a dose of a compound, or a pharmaceutically acceptable salt thereof, that elicits a biological or medical response in a tissue, system, animal or human observable by a researcher, veterinarian, clinician or other clinician.
  • the result can be a reduction and/or amelioration of signs, symptoms or causes, or any other desired change in the biological system.
  • “Pharmaceutical composition” includes: a product mixed with the compound of the present invention (active ingredient) and an inert ingredient as a carrier, and any two or more ingredients directly or indirectly made by combining, compounding or aggregating A product, or a product that results from the decomposition of one or more components, or a product that results from other types of reactions or interactions of one or more components.
  • “Pharmaceutically acceptable” means those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues and are not unacceptable to the subject of administration of poison.
  • “Individual” refers to an individual suffering from a disease, disorder, or the like, including mammals and non-mammals. Mammals include, but are not limited to, any member of the mammalian species: humans, non-human primates (such as chimpanzees, and other apes and monkeys); farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as Rabbits, dogs and cats; experimental animals include rodents such as rats, mice and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish, etc. In one embodiment of the present invention, the mammal is a human.
  • Treatment means the treatment of an associated disease or condition in mammals, particularly humans, including prevention of other symptoms, amelioration or prevention of underlying metabolic factors of symptoms, inhibition of disease or symptoms, for example, arresting the progression of disease or symptoms, alleviation of disease or symptoms , to promote the remission of a disease or symptom, or to stop the symptoms of a disease or symptom, and by extension to include prevention; alleviation, alleviation or amelioration of a disease or symptom; inhibition of a disease or condition, i.e. controlling its progression.
  • Treatment also includes achieving a therapeutic benefit and/or a prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the condition being treated.
  • therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, although the patient may still have the underlying disease, but improvement in the patient's disease may be observed.
  • Prophylactic benefit refers to the use of a composition by a patient to prevent a risk of a disease, or when a patient develops one or more physiological conditions of the disease, even though the disease has not been diagnosed.
  • Protecting group refers to a class of substituents used to block or protect a particular functional group by reacting with other functional groups on a compound. These functional groups include amino, carboxyl, sulfhydryl and hydroxyl groups. For a general description and instructions for use of protecting groups, see reference: T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
  • NH protecting groups include, but are not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), p-nitro Benzylcarbonyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-pentyloxycarbonyl, tertiary Butoxycarbonyl (Boc), p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl , phthaloyl
  • C(O)OH protecting groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, Naphthyl, benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, Acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidylmethyl, cyclopropyl, methoxymethyl, methoxy Ethoxymethyl,
  • OH or SH protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl Oxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2, 2,2-Trichloroethoxycarbonyl, 2,2,2-Tribromoethoxycarbonyl, 2-(trimethylsilane)ethoxycarbonyl, 2-(benzenesulfonyl)ethoxycarbonyl, 2 -(Triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-
  • Geometric isomers may exist in the compounds of the present invention.
  • the compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in E or Z configuration, wherein "E” represents the preferred substituent on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond, and "Z” represents that the preferred substituent is on the same side of the carbon-carbon double bond or carbon-nitrogen double bond, and the preferred substituent can be determined according to the Cahn-Ingold-Prelog precedence rule.
  • the compounds of the present invention may also exist as mixtures of "E” and "Z” isomers. Substituents around a cycloalkyl or heterocyclyl group can be designated in either the cis or trans configuration.
  • the present invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system.
  • the two substituents around a single ring in the adamantane ring system are assigned the Z or E relative configuration. See, for example, C.D. Jones, M. Kaselj, R.N. Salvatore, W.J.le Noble J.Org.Chem. 1998, 63, 2758-2760.
  • the compounds of the present invention may contain asymmetric centers, which may independently be in the R or S configuration.
  • R and S are defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45 , 13-10.
  • a compound containing an asymmetrically substituted carbon atom is a racemate if the amounts of R and S configurations are the same. If one of the configurations is present in greater quantity than the other, the configuration of the chiral carbon atom is represented by the configuration in which the quantity is greater, preferably about 85-90% enantiomeric excess, more preferably about 95-99% , further about 99% above. Accordingly, the present invention encompasses racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
  • the compounds of the present invention may exist in isotopically labeled or enriched forms, containing one or more atoms that differ in atomic mass and mass number from those most commonly found in nature.
  • Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, nitrogen, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I.
  • Isotopically-labeled compounds of the present invention can be used as standard compounds in binding assays to determine the efficacy of Bcl-2 inhibitors.
  • Compounds containing isotopes can be used in pharmaceutical research to evaluate the mechanism of action and metabolic pathways of non-isotopically labeled parent compounds, and to study the in vivo metabolic fate of compounds (Blake et al.J.Pharm.Sci.64,3,367-391( 1975)).
  • Such metabolic studies are very important for the design of safe and effective therapeutic drugs, which can determine whether the active compound administered to the patient or the metabolite of the parent compound is toxic or carcinogenic (Foster et al., Advances in Drug Research Vol.14, pp.
  • the second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds described in any one of the above technical solutions.
  • the pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any of the above technical solutions and other compounds, or one or more of the compounds described in any of the above-mentioned technical solutions composition.
  • the compounds or pharmaceutically acceptable salts of the present invention may be used alone or in combination with other therapeutic agents.
  • an adjuvant drug enhances the therapeutic effect of a compound of the invention (eg, the adjuvant drug alone has minimal therapeutic benefit, but when used in combination with another drug, enhances the individual's therapeutic benefit), or
  • the combination of a compound of the present invention with another therapeutic agent that is also therapeutic can enhance the therapeutic benefit of an individual.
  • an anti-nausea drug may be used in combination.
  • therapies that may be combined include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy on the diseased area, rest, dietary modification, and the like. Regardless of the disease, disorder or condition being treated, the two therapies should have an additive or synergistic effect to benefit the individual's treatment.
  • the route of administration may be the same as that of other drugs, or the route of administration may be different due to different physical and chemical properties.
  • a compound described herein and another therapeutic agent can be administered simultaneously, sequentially or separately.
  • condition, disorder or focus includes, but is not limited to, infectious disease, immune disease, inflammatory disease or abnormal cell proliferation.
  • infectious diseases, immune diseases, and inflammatory diseases described therein include, but are not limited to, asthma, diseases caused by neutrophil chemotaxis (eg, myocardial infarction and stroke, reperfusion injury and inflammatory joints). inflammation), septic shock, T cell-mediated diseases, immunosuppression-related diseases (eg, prevention of organ transplant rejection, graft-versus-host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis), pancreatitis, and angiogenesis or angiogenesis-related diseases (eg acute and chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma); chronic obstructive pulmonary disease (COPD) and other diseases .
  • COPD chronic obstructive pulmonary disease
  • abnormal cell proliferation diseases include cancerous proliferative diseases, non-cancerous proliferative diseases, including but not limited to lymphoma, osteosarcoma, skin cancer, breast cancer, kidney cancer, prostate cancer, colorectal cancer, Thyroid, ovarian, pancreatic, glioma, epidermoid, hemangioma, lung or gastric cancer, restenosis and benign prostatic hypertrophy (BPH).
  • cancerous proliferative diseases including but not limited to lymphoma, osteosarcoma, skin cancer, breast cancer, kidney cancer, prostate cancer, colorectal cancer, Thyroid, ovarian, pancreatic, glioma, epidermoid, hemangioma, lung or gastric cancer, restenosis and benign prostatic hypertrophy (BPH).
  • non-cancerous proliferative diseases including but not limited to lymphoma, osteosarcoma, skin cancer, breast cancer, kidney cancer, prostate cancer, colorectal cancer, Thyroid, ovarian, pancre
  • the compounds of the present invention can be administered in the form of pharmaceutical compositions, which can be administered by any conventional route; the compounds of the present invention can be formed into pharmaceutical preparations in the form of solid, semi-solid, liquid or gas, such as tablets, capsules, and injections , suspensions, lotions, gels, ointments, creams, suppositories, inhalants and the like.
  • composition containing the compound of the present invention in the form of a free base or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier or diluent can be mixed, granulated, coated, dissolved or lyophilized in a conventional manner. process to manufacture.
  • a unit dosage form for oral administration contains, for example, from about 0.1 mg to about 500 mg of active substance.
  • the inventors of the present invention have confirmed through experiments that the compounds of the present invention have potent BCL2/BAK blocking activity and in vitro anti-tumor cell proliferation inhibitory activity. It can be used alone or in combination with other drugs to treat infectious diseases, immune diseases, inflammatory diseases or abnormal cell proliferation that benefit from the inhibition of anti-apoptotic protein BCL-2.
  • Step 1 Dissolve (S)-2-(2-bromophenyl)pyrrolidine-1-carboxylate tert-butyl ester (4.5g) and isopropylboronic acid (3.1g) in 15mL of 1,4-epoxyhexanol To a mixed solvent of ring and 3 mL of water, potassium carbonate (6 g) and Pd(dffp) 2 Cl 2 (0.9 g) were added under nitrogen protection, and heated to reflux for overnight reaction.
  • step 2 (S)-2-(2-isopropylphenyl)pyrrolidine-1-carboxylate tert-butyl ester (3g) was dissolved in 18mL of dichloromethane, trifluoroacetic acid (9mL) was added, and The reaction was stirred at room temperature overnight. TLC monitoring, after the completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude product (S)-2-(2-isopropylphenyl)pyrrolidine (1.92g), which was used in the next reaction without further purification.
  • Step 3 (S)-2-(2-isopropylphenyl)pyrrolidine (1.85g) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (2.4g) was dissolved in 25mL of 1,2-dichloroethane, stirred at room temperature for 15 minutes, and then added sodium borohydride (4.2g), after about 4 hours of reaction, TLC monitoring the completion of the reaction, adding sodium bicarbonate aqueous solution to quench The reaction was extracted with dichloromethane.
  • Step 4 (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester ( 3g) was dissolved in 15 mL of dichloromethane, trifluoroacetic acid (7.5 mL) was added, and the reaction was stirred at room temperature overnight. TLC monitoring, after the reaction was completed, the solvent was concentrated under reduced pressure to dry, and dichloromethane was added to redissolve, washed with saturated aqueous sodium bicarbonate solution and water, respectively, and the organic phase was separated.
  • Step 5 Methyl 2,4-difluorobenzoate (3.5 g) and 1H-pyrrolo[2,3-b]pyridin-5-ol (4.1 g) were dissolved in 50 mL diethylene glycol dimethyl ether , adding potassium phosphate (6.4g), heating to reflux reaction for about 12 hours. TLC monitoring, after completion of the reaction, the temperature was lowered to room temperature, water and ethyl acetate were added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 6 (S)-2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (1.56g) and 2-((1H -Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid methyl ester (1.72g) was dissolved in 20mL DMF, sodium carbonate (3.2g) was added, and the reaction was heated to reflux overnight. TLC monitoring, after the reaction was basically completed, it was lowered to room temperature, water and a large amount of ethyl acetate were added for extraction, the separated organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 7 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl) Methyl pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)benzoate (1.5 g) was dissolved in a mixed solvent of 15 mL methanol and 15 mL tetrahydrofuran, and 3N aqueous sodium hydroxide solution (10 mL) was added. ), heated to 50°C for reaction for about 3 hours, TCL monitored the completion of the reaction, neutralized with 4N aqueous hydrochloric acid solution to about pH 5.
  • Step 8 dissolve 3-bromo-4-chloro-5-nitrobenzenesulfonamide (3.2g) and 1-aminocyclopropanemethanol (0.78g) in 40mL acetonitrile, add DIPEA (N,N-diisopropyl alcohol) ethylethylamine, 8.2 mL), heated to reflux and stirred the reaction overnight. TLC monitoring, after the reaction was completed, the temperature was lowered to room temperature, and the dry solvent was concentrated under reduced pressure.
  • DIPEA N,N-diisopropyl alcohol
  • Step 9 dissolve 3-bromo-4-((1-(hydroxymethyl)cyclopropyl)amino)-5-nitrobenzenesulfonamide (1.83g) in 30mL of toluene, add cesium carbonate (3.26g) , CuI (200 mg) and 3,4,7,8-tetramethyl-1,10-phenanthroline (118 mg), heated and refluxed for about 6 hours under nitrogen protection.
  • Step 10 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)benzoic acid (0.17g) was dissolved in 3mL of dichloromethane, triethylamine (0.2mL) was added, HATU (N,N ,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea, 0.15g), stirred at room temperature for about 1 hour, then added 5-nitro- 2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]-7-sulfonamide (0.11 g) and DMAP (4-dimethylaminopyridine, 6 mg), plus After completion, the reaction was continued at room temperature
  • the target compound (S)-2-(((1H-pyrrolo) can be synthesized [2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]- 7-yl)sulfonyl)benzamide (66 mg), LC-MS (ESI-MS): 850 [M+H] + .
  • the target compound (S)-2-(((1H) can be synthesized -pyrrolo[2,3-b]pyridin-5-yl)oxy)-3,5-difluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-Azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1' -Cyclopropan]-7-yl)sulfonyl)benzamide (73 mg), LC-MS (ESI-MS): 868 [M+H] + .
  • Example 6 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-((S)-2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((((S)-3-(morpholinomethyl)-5-nitro -3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (006)
  • Example 7 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)pyridineamide (024)
  • 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (10.00g, 42.00mmol) was dissolved in 1,4-dioxane (52.00mL), and 4mol/ L HCl (52.00 mL) in 1,4-dioxane (52.00 mL) was heated to 60 °C for 4 h.
  • Step 9 Preparation of Compound 24: 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy- 4-Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1- yl)-7-azaspiro[3.5]nonan-7-yl)pyridineamide (024)
  • Example 8 N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-(( 1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)pyridineamide (025)
  • Example 11 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-cyclopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)-N-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino )-3-Nitrophenyl)sulfonyl)pyridineamide (028)
  • Example 12 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-(trifluoromethyl)phenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)pyridineamide (029)
  • Example 13 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-((S)-2-(2-methoxyphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]non-7-yl)pyridineamide (030)
  • Example 14 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-((S)-2-(2-fluorophenyl)pyrrolidine -1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)pyridineamide (031)
  • Example 15 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-N-((4-(((((1r,4r)-4- Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (032)
  • Example 16 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1r,4r)-4- Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (033)
  • Example 17 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3,5-difluoro-N-((4-((((((1r,4r) )-4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (034)
  • Example 18 (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methan yl)amino)phenyl)sulfonyl)nicotinamide (035)
  • Example 19 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methan yl)amino)phenyl)sulfonyl)benzamide (084)
  • Example 20 N-((4-(((((1,4-dioxane-2 -yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4 -(2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (085)
  • Example 21 N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo [2,3-b]pyridin-5-yl)oxy)-6-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)benzamide (086)
  • Methyl 4-bromo-2,6-difluorobenzoate (5.00 g, 19.92 mmol), 1H-pyrrolo[2,3-b]pyridin-5-ol (2.94 g, 21.91 mmol), potassium phosphate ( 5.07 g, 23.91 mmol) was dissolved in diethylene glycol dimethyl ether (70.00 mL), and the temperature was raised to 100 °C for 21 h. After the completion of the TLC monitoring reaction, H 2 O and 2M hydrochloric acid aqueous solution were added to adjust the pH to neutrality.
  • Example 22 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methan yl)amino)phenyl)sulfonyl)benzamide (087)
  • Example 21 Referring to the synthesis method of Example 21, replacing (1,4-dioxan-2-yl)methanamine hydrochloride with (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride, it can be synthesized
  • Example 24 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoropiperidin-4-yl)methyl )amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)picolinamide (089)
  • Example 25 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((morpholin-2-ylmethyl)amino)-3-nitrophenyl)sulfonyl) Picolinamide (090)
  • Example 26 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(2-morpholinoacetyl) yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)picolinamide (091)
  • Example 27 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1-(2-(dimethylamino)acetyl) )-4-Fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (092)
  • Example 28 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[ b][1,4]oxazin-7-yl)sulfonyl)benzamide (093)
  • Example 29 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-(2-morpholinoacetyl)morpholin-2-yl)methyl)amino )-3-Nitrophenyl)sulfonyl)picolinamide (094)
  • Example 30 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-(2-(dimethylamino)acetyl) )morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)picolinamide (095)
  • Example 31 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(oxetane -3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)picolinamide (096)
  • Example 32 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((4-(oxetan-3-yl)morpholine- 2-yl)methyl)amino)phenyl)sulfonyl)picolinamide (097)
  • Example 33 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoropiperidin-4-yl)methoxy) )-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7 -yl)picolinamide (099)
  • Example 34 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetane- 3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)picolinamide (098)
  • Example 35 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(2-morpholinoacetyl) )piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7 -Azaspiro[3.5]nonan-7-yl)picolinamide (100)
  • Example 36 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl) -4-Fluoropiperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)picolinamide (101)
  • Example 37 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-hydroxy-4-methylcyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (102)
  • Example 38 4-(((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-( 2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoyl)sulfamoyl)-2-nitrophenyl) Amino)methyl)-4-fluoropiperidine-1-carboxylic acid ethyl ester (103)
  • Example 39 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((2-(dimethylamino)ethyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (104)
  • Example 40 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((3-isopropyloxypropyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (105)
  • Example 41 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3, 4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (106)
  • Example 42 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((3-(dimethylamino)propyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (107)
  • Example 43 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino )phenyl)sulfonyl)nicotinamide (108)
  • Example 44 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-(2-(dimethylamino)acetyl) yl)-4-fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (109)
  • the target compound 109 can be synthesized by replacing methyl 3,5-difluoropicolinate with methyl 2,6-dichloronicotinate.
  • LC-MS (ESI-MS): m/ z 965[M+H] + .
  • Example 45 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl)) -4-Fluoropiperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (110)
  • Example 36 methyl 3,5-difluoropicolinate was replaced with methyl 2,6-dichloronicotinate, and the target compound 110 could be synthesized.
  • LC-MS (ESI-MS): m/ z 966[M+H] + .
  • Example 46 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(2-morpholinoacetyl) )piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7 - Azaspiro[3.5]nonan-7-yl)nicotinamide (111)
  • Example 48 N-((4-((1,4-dioxan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2 ,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (113)
  • the methyl 3,5-difluoropyridine-2-carboxylate was replaced by methyl 2,6-dichloronicotinate, and the 4-fluoro-4-(hydroxymethyl)piperidine-
  • Example 50 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((morpholin-2-ylmethyl)amino)-3-nitrophenyl)sulfonyl) Niacinamide (114)
  • the target compound 114 can be synthesized by replacing methyl 3,5-difluoropyridine-2-carboxylate with methyl 2,6-dichloronicotinate.
  • Example 51 N-((4-((1,4-dioxan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2 ,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)picolinamide (116)
  • Example 52 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((4-(oxetan-3-yl)morpholine- 2-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (117)
  • Example 53 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-(2-(dimethylamino)acetyl) -4-Fluoropiperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (118)
  • the target compound 118 can be synthesized by replacing methyl 3,5-difluoropyridine-2-carboxylate with methyl 4,6-dichloronicotinate.
  • Example 54 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetane- 3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (119)
  • the target compound 121 can be synthesized by replacing methyl 2,3,4-trifluorobenzoate with methyl 2,4,5-trifluorobenzoate.
  • LC-MS (ESI-MS ): m/z 880 [M+H] + .
  • Example 56 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoropiperidin-4-yl)methyl )amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (135)
  • Example 57 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(oxetane -3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (125)
  • Example 58 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(6-(oxetan-3-yl)-2,6- Diazaspiro[3.3]heptan-2-yl)phenyl)sulfonyl)benzamide (122)
  • Example 59 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(6-(oxetan-3-yl)-2,6- Diazaspiro[3.4]octan-2-yl)phenyl)sulfonyl)benzamide (123)
  • Example 60 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(7-(oxetan-3-yl)-2,7- Diazaspiro[3.5]nonan-2-yl)phenyl)sulfonyl)benzamide (124)
  • Example 61 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetane- 3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (126)
  • Example 62 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-(2-(dimethylamino)acetyl) yl)-4-fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (127)
  • Example 64 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl) Methyl)amino)phenyl)sulfonyl)benzamide (120)
  • Example 65 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1-(2-(dimethylamino)acetyl) yl)-4-fluoropiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (130)
  • Example 66 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((4-fluoro-1-(oxa Cyclobutan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (128)
  • Example 68 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((S)-pyrrolidin-3-ylmethyl) Amino)phenyl)sulfonyl)benzamide (134)
  • Example 69 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((R)-1-(oxetane) -3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (131)
  • Example 70 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((R)-1-(oxetane) -3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (132)
  • Example 69 Referring to the synthesis method of Example 69, substituting (R)-3-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester with (S)-3-(aminomethyl)pyrrolidine-1-carboxylic acid
  • Example 71 2-((1H-pyrro[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((1r,4r)-4-hydroxy- 4-Methylcyclohexyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)benzamide (136)
  • Example 72 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1r,4r)-4- Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-phenylpyrrolidin-1-yl)-7-azaspiro[ 3.5] Nonan-7-yl)benzamide (137)
  • Example 73 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-phenylpyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)nicotinamide (138)
  • Example 74 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-fluorophenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)benzamide (139)
  • Example 75 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(tert-butyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)-5-fluoro-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino )-3-Nitrophenyl)sulfonyl)benzamide (140)
  • Example 76 4-(((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-( 2-(2-Isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoyl)sulfamoyl)-2-nitrophenyl) Amino)methyl)-4-fluoropiperidine-1-carboxylic acid methyl ester (141)
  • Example 77 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)nicotinamide (142)
  • Example 78 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)nicotinamide (143)
  • Example 64 Referring to the synthetic method of Example 64, substituting 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylic acid for tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate
  • Example 80 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((piperidin-4-ylmethyl)amino)phenyl )sulfonyl)benzamide (148)
  • Example 81 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((piperidin-4-ylmethyl)amino)phenyl)sulfonyl) Niacinamide (147)
  • Example 82 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((1-(oxetan-3-yl)piperidine- 4-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (145)
  • Example 83 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((1-(oxetan-3-yl) )piperidin-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (146)
  • Example 84 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((5-oxopyrrolidin-2-yl)methan yl)amino)phenyl)sulfonyl)benzamide (149)
  • Example 85 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(2-oxoimidazolidine-1-yl) )ethyl)amino)phenyl)sulfonyl)benzamide (150)
  • Example 86 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((((4-fluoro- 1-(oxetan-3-yl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-iso) Propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (151)
  • Example 87 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-isopropyl ylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)benzamide (153)
  • Example 88 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-fluoro-1-(2 ,2,2-Trifluoroethyl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylbenzene) yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (155)
  • Example 90 (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-isopropyl ylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonan-7-yl)nicotinamide (154)
  • Example 91 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(2,2,2 -Trifluoroethyl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (156)
  • Example 92 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(oxetane -3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-5-methylbenzamide (157)
  • Example 93 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-2,3-difluoro-N-((4-(((4-fluoro-1 -(oxetan-3-yl))piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (158)
  • the target compound 158 can be synthesized by replacing methyl 2,4,5-trifluorobenzoate with methyl 2,3,4,6-tetrafluorobenzoate.
  • LC-MS (ESI -MS): m/z 971 [M+H] + .
  • Example 94 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(1-(oxetane-3 -yl)piperidin-4-yl)ethyl)amino)phenyl)sulfonyl)benzamide (159)
  • Example 63 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate tert-butyl ester was replaced with 4-carbamoylpiperidine-1-carboxylate tert-butyl ester, which can be synthesized
  • Example 96 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(piperidin-4-carboxamido)phenyl)sulfonyl)nicotinamide ( 161)
  • Example 56 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate tert-butyl ester was replaced with 4-carbamoylpiperidine-1-carboxylate tert-butyl ester, which can be synthesized
  • Example 97 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((1r,4r)-4-hydroxy -4-Methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1- yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (162)
  • Example 98 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((4-hydroxycyclohexyl)methyl )amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)benzamide (163)
  • Example 99 4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-hydroxycyclohexyl)methyl)amino)- 3-Nitrophenyl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) Niacinamide (164)
  • Example 100 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1s,3s)-3- Hydroxy-3-methylcyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine) -1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (165)
  • Example 101 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,3s)-3-hydroxy-3- Methylcyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) )-7-azaspiro[3.5]nonan-7-yl)nicotinamide (166)
  • Example 102 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-(((((1r,3r)-3- Hydroxycyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonan-7-yl)benzamide (167)
  • Example 103 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-(((4-((((1r,3r)-3-hydroxycyclobutyl) )methyl)amino)-3-nitrophenyl)sulfonyl)-6-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonan-7-yl)nicotinamide (168)
  • Example 104 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((azetidin-3-yl Methyl)amino)-3-nitrophenyl)sulfonyl)-5-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)benzamide (169)
  • Example 105 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((((1-(oxetane) -3-yl)azetidin-3-yl)methyl)amino)phenyl)sulfonyl)benzamide (170)
  • Example 106 (S)-4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((1-(oxetan-3-yl) )azetidin-3-yl)methyl)amino)phenyl)sulfonyl)nicotinamide (171)
  • Example 107 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-(2-(2-isopropyl) ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((3-methylazetidin-3-yl )methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (172)
  • Example 108 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-N-((4-((((1-isopropyl) yl-3-methylazetidin-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (173)
  • Example 109 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2,3-difluorophenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-(((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (174)
  • Example 110 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2,3-difluorophenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl) )methyl)amino)-3-nitrophenyl)sulfonyl)nicotinamide (175)
  • Example 111 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2,6-difluorophenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-5-fluoro-N-(((4-((((1r,4r)-4-hydroxy-4- Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (176)
  • Example 112 4-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-((S)-2-(2,6-difluorophenyl) )pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((((1r,4r)-4-hydroxy-4-methylcyclohexyl) )methyl)amino)-3-nitrophenyl)sulfonyl)nicotinamide (177)
  • Example 88 With reference to the synthetic method of Example 88, the following compounds can be synthesized by a similar synthetic route and method:
  • Example 91 With reference to the synthetic method of Example 91, the following compounds can be synthesized by a similar synthetic route and method:
  • the 500nM Tag1-BCL2 protein stock solution was diluted to 5nM with the dilution buffer in the kit (model: BCL2/BAK(BH3) BINDING ASSAY KIT, Cisbio), and the 20 ⁇ M Tag2-BAK protein stock solution was diluted to 120nM.
  • Tag1-BCL2 protein dilution Add 5 ⁇ L of Tag1-BCL2 protein dilution to the well, and then add compounds of different concentrations (10000nM, 4-fold dilution, 8 points, respectively: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM), DMSO
  • 5 ⁇ L of Tag2-BAK protein dilution solution was added to each well, centrifuged to mix well, and incubated at room temperature for 15 minutes. Then add anti-Tag1-Eu3+ and anti-Tag2-XL665 in the kit, and react at room temperature for 2 hours.
  • the plate was read with a BIO-Tek NEO2 multifunctional microplate reader (excitation 620 nM, emission 665 nM), and IC 50 was calculated with GraphPad Prism 5.0. The results are shown in Table 1.
  • the total volume of the reaction was 10 ⁇ L. Specifically, 2 ⁇ L of the test compound (2% DMSO), 4 ⁇ L of His-tagged recombinant protein and 4 ⁇ L of Biotin-tagged BIM protein polypeptide were added. After 1 hour of reaction, anti-His and streptavidin-tagged XL665 antibodies diluted with detection buffer were added respectively. After 4 hours of incubation at room temperature, the Envision multi-function microplate microplate reader was used to read the value, so as to detect the effect of the test compound on the binding ability of BCL-XL and Bim protein polypeptide. Envision parameter settings are excitation light 320nm, emission light 615nm and 665nm.
  • binding ability of anti-apoptotic protein to Bim protein polypeptide is indirectly reflected by the ratio of 665nm and 615nm signals.
  • background wells without BCL2 and full binding activity wells of recombinant protein without compound and Bim protein polypeptide were set.
  • anti-apoptotic protein BCL2(G101V) The binding ability of anti-apoptotic protein BCL2(G101V) to apoptosis pro-apoptotic protein Bim was detected by time homogeneous phase-resolved fluorescence technique. Reactions for this method were in 384 white shallow well plates and the total reaction volume was 10 ⁇ L. Specifically, 2 ⁇ L of the test compound (2% DMSO), 4 ⁇ L of His-tagged recombinant protein and 4 ⁇ L of Biotin-tagged BIM protein polypeptide were added. After 1 hour of reaction, anti-His and streptavidin-tagged XL665 antibodies diluted with detection buffer were added respectively.
  • Envision multi-function microplate microplate reader After incubation at room temperature for 4 hours, use the Envision multi-function microplate microplate reader to read the value, so as to detect the effect of the test compound on the binding ability of BCL2 (G101V) and Bim protein polypeptide.
  • Envision parameter settings are excitation light 320nm, emission light 615nm and 665nm.
  • the binding ability of anti-apoptotic protein to Bim protein polypeptide is indirectly reflected by the ratio of 665nm and 615nm signals.
  • background wells without BCL2 and full binding activity wells of recombinant protein without compound and Bim protein polypeptide were set.
  • anti-apoptotic protein BCL2(D103Y) The binding ability of anti-apoptotic protein BCL2(D103Y) to apoptosis pro-apoptotic protein Bim was detected by time homogeneous phase-resolved fluorescence technique. Reactions for this method were in 384 white shallow well plates and the total reaction volume was 10 ⁇ L. Specifically, 2 ⁇ L of the test compound (2% DMSO), 4 ⁇ L of His-tagged recombinant protein and 4 ⁇ L of Biotin-tagged BIM protein polypeptide were added. After 1 hour of reaction, anti-His and streptavidin-tagged XL665 antibodies diluted with detection buffer were added respectively.
  • the Envision multi-function microplate microplate reader was used to read the value, so as to detect the effect of the test compound on the binding ability of BCL2 (D103Y) and Bim protein polypeptide.
  • Envision parameter settings are excitation light 320nm, emission light 615nm and 665nm.
  • the binding ability of anti-apoptotic protein to Bim protein polypeptide is indirectly reflected by the ratio of 665nm and 615nm signals.
  • background wells without BCL2 and full binding activity wells of recombinant protein without compound and Bim protein polypeptide were set.
  • RS4;11 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, respectively. The cells were digested, and the cells were seeded in a 96-well plate at a cell concentration of RS4; 11 30000/well and incubated overnight at 37°C with 5% CO 2 . Compounds at different concentrations (10000nM, 4-fold dilution, 8 points, respectively: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM) were added to the 96-well plate and incubated at 37°C with 5% CO2 , RS4 ; 11 Incubation for 72 hours.
  • Molt-4 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, respectively. The cells were digested, and Molt-4 cells were seeded at a cell concentration of 30,000/well in a 96-well plate and incubated overnight at 37°C with 5% CO 2 . Compounds at different concentrations (10000nM, 4-fold dilution, 8 points, respectively: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM) were added to the 96-well plate and incubated at 37°C with 5% CO2 , Molt -4 Incubation for 72 hours. Add 20 ⁇ L of MTS to each well.
  • mice There were 3 female mice, and the animals were reared for at least 3 days before the experiment to adapt to the environment. Animals were fasted overnight before administration and had free access to water.
  • the blood samples were centrifuged at 8000 rpm for 5 minutes at 4 degrees Celsius within 30 minutes after the blood samples were obtained to extract the plasma.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • Psychiatry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Transplantation (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un agent induisant l'apoptose de la protéine BCL-2. L'invention concerne également le composé et une utilisation d'une composition pharmaceutique comprenant le composé dans la préparation d'un médicament pour le traitement de maladies associées à la protéine BCL-2 anti-apoptotique telle que des maladies infectieuses, des maladies immunitaires, des maladies inflammatoires et des maladies de prolifération cellulaire anormale. Le composé selon la présente invention a une puissante activité de blocage de BCL2/BAK, une activité inhibitrice puissante sur BCL-2(G101V) et BCL-2(D103Y), et une activité inhibitrice de prolifération puissante sur des souches de cellules mutantes. Le composé peut être utilisé pour traiter, en tant qu'agent seul ou en combinaison avec d'autres médicaments, des maladies infectieuses, des maladies immunitaires, des maladies inflammatoires, ou des maladies de prolifération cellulaire anormale, etc. qui bénéficient de l'inhibition de la protéine anti-apoptotique BCL-2.
PCT/CN2021/126588 2020-10-28 2021-10-27 Agent induisant l'apoptose de protéine bcl-2 et son utilisation WO2022089463A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011168924 2020-10-28
CN202011168924.4 2020-10-28

Publications (1)

Publication Number Publication Date
WO2022089463A1 true WO2022089463A1 (fr) 2022-05-05

Family

ID=81381533

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/126588 WO2022089463A1 (fr) 2020-10-28 2021-10-27 Agent induisant l'apoptose de protéine bcl-2 et son utilisation

Country Status (2)

Country Link
CN (1) CN114478520A (fr)
WO (1) WO2022089463A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023231777A1 (fr) * 2022-06-01 2023-12-07 Fochon Pharmaceuticals, Ltd. Composés en tant qu'inhibiteurs de bcl-2
WO2024012557A1 (fr) * 2022-07-15 2024-01-18 Berrybio (Hong Kong) Limited Agents de dégradation de protéines anti-apoptotiques de la famille bcl-2, compositions pharmaceutiques et applications thérapeutiques

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023104043A1 (fr) 2021-12-06 2023-06-15 杭州和正医药有限公司 Inhibiteur de la protéine bcl-2 anti-apoptotique, composition pharmaceutique et utilisations de celui-ci

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102448959A (zh) * 2009-05-26 2012-05-09 雅培制药有限公司 用于治疗癌症和免疫和自身免疫疾病的细胞程序死亡诱导药剂
WO2019210828A1 (fr) * 2018-04-29 2019-11-07 Beigene, Ltd. Inhibiteurs de bcl-2
CN110546151A (zh) * 2017-04-18 2019-12-06 上海复尚慧创医药研究有限公司 凋亡诱导剂
WO2020140005A2 (fr) * 2018-12-29 2020-07-02 Newave Pharmaceutical Inc. Inhibiteurs de bcl-2
WO2021083135A1 (fr) * 2019-10-28 2021-05-06 Beigene, Ltd. Inhibiteurs de bcl-2
WO2021223736A1 (fr) * 2020-05-08 2021-11-11 Fochon Pharmaceuticals, Ltd. Composés en tant qu'inhibiteurs de bcl-2

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108440507B (zh) * 2017-02-16 2022-10-18 南京圣和药物研发有限公司 作为细胞凋亡蛋白抑制剂的化合物及其应用
CN109456308B (zh) * 2017-09-06 2022-11-29 南京圣和药业股份有限公司 作为ask抑制剂的杂环化合物及其应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102448959A (zh) * 2009-05-26 2012-05-09 雅培制药有限公司 用于治疗癌症和免疫和自身免疫疾病的细胞程序死亡诱导药剂
CN110546151A (zh) * 2017-04-18 2019-12-06 上海复尚慧创医药研究有限公司 凋亡诱导剂
WO2019210828A1 (fr) * 2018-04-29 2019-11-07 Beigene, Ltd. Inhibiteurs de bcl-2
WO2020140005A2 (fr) * 2018-12-29 2020-07-02 Newave Pharmaceutical Inc. Inhibiteurs de bcl-2
WO2021083135A1 (fr) * 2019-10-28 2021-05-06 Beigene, Ltd. Inhibiteurs de bcl-2
WO2021223736A1 (fr) * 2020-05-08 2021-11-11 Fochon Pharmaceuticals, Ltd. Composés en tant qu'inhibiteurs de bcl-2

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023231777A1 (fr) * 2022-06-01 2023-12-07 Fochon Pharmaceuticals, Ltd. Composés en tant qu'inhibiteurs de bcl-2
WO2024012557A1 (fr) * 2022-07-15 2024-01-18 Berrybio (Hong Kong) Limited Agents de dégradation de protéines anti-apoptotiques de la famille bcl-2, compositions pharmaceutiques et applications thérapeutiques

Also Published As

Publication number Publication date
CN114478520A (zh) 2022-05-13

Similar Documents

Publication Publication Date Title
EP3774791B1 (fr) Composés hétérocycliques utilisés comme immunomodulateurs
JP6689805B2 (ja) カテプシンｃの置換２−アザ−ビシクロ［２．２．１］ヘプタン−３−カルボン酸（ベンジル−シアノ−メチル）−アミド阻害剤
JP5977779B2 (ja) ２−（２，４，５−置換−アニリノ）ピリミジン化合物
CA2938280C (fr) Composes de 4-amino-imidazoquinoline
KR102472198B1 (ko) Pi3k 베타 저해제로서의 아자벤즈이미다졸 유도체
US20200325115A1 (en) Heterocyclic compounds as immunomodulators
CA2779105C (fr) Inhibiteurs de kinases
CA3099994A1 (fr) Derives de tetrahydro-imidazo[4,5-c]pyridine en tant qu'immunomodulateurs de pd-l1
JP6404332B2 (ja) 新規な、ＮＩＫ阻害剤としての３−（１Ｈ−ピラゾール−４−イル）−１Ｈ−ピロロ［２，３−ｃ］ピリジン誘導体
WO2022089463A1 (fr) Agent induisant l'apoptose de protéine bcl-2 et son utilisation
AU2017322427A1 (en) Pyrazolopyridine derivatives as HPK1 modulators and uses thereof for the treatment of cancer
JP6616411B2 (ja) 新規な、ｎｉｋ阻害剤としてのピラゾール誘導体
KR20170134980A (ko) 암의 치료를 위한 인돌아민-2,3-디옥시게나제의 억제제
WO2018018986A1 (fr) Composé de diphénylaminopyrimidine et de triazine, composition pharmaceutique et utilisation de celui-ci
KR20140040774A (ko) 이미다조피리딘 화합물
TW201121966A (en) Fused heterocyclic compounds as orexin receptor modulators
TW202039435A (zh) 經取代之3-((3-胺基苯基)胺基)哌啶-2,6-二酮化合物、其組合物及使用彼等之治療方法
EA014918B1 (ru) Замещенные бициклические пиримидоновые производные
TW201326143A (zh) Ｇ蛋白偶合ｍａｓ受體之調節劑及與其相關病症之治療
WO2022047093A1 (fr) Composés d'imidazole vinylique en tant qu'inhibiteurs de kras
KR20130046436A (ko) 안드로겐 수용체 길항제, 항암제로서 사이클릭 n,n''-다이아릴티오우레아 및 n,n''-다이아릴우레아, 이의 제조방법 및 이의 용도
TW201917129A (zh) 含吡唑基的三并環類衍生物、其製備方法和應用
WO2020135210A1 (fr) Composé aryle substitué, procédé de préparation correspondant et utilisation associée
CA3198096A1 (fr) Derives d'aryle pour le traitement de troubles a mediation par trpm3
WO2016050201A1 (fr) Pyrimidine substituée en tant qu'inhibiteur de pi3k à sélectivité élevée

Legal Events

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

Ref document number: 21885190

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21885190

Country of ref document: EP

Kind code of ref document: A1