WO2020063976A1 - 一类稠杂环联芳基苄醇类化合物、制备方法和用途 - Google Patents

一类稠杂环联芳基苄醇类化合物、制备方法和用途 Download PDF

Info

Publication number
WO2020063976A1
WO2020063976A1 PCT/CN2019/109143 CN2019109143W WO2020063976A1 WO 2020063976 A1 WO2020063976 A1 WO 2020063976A1 CN 2019109143 W CN2019109143 W CN 2019109143W WO 2020063976 A1 WO2020063976 A1 WO 2020063976A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
alkyl
membered
heteroaryl
Prior art date
Application number
PCT/CN2019/109143
Other languages
English (en)
French (fr)
Inventor
万惠新
潘建峰
马金贵
Original Assignee
如东凌达生物医药科技有限公司
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 如东凌达生物医药科技有限公司 filed Critical 如东凌达生物医药科技有限公司
Publication of WO2020063976A1 publication Critical patent/WO2020063976A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a class of fused heterocyclic biaryl benzyl alcohol compounds, a preparation method and uses thereof.
  • BRD4 is a member of the BET protein family. Due to its potential value in antitumor, it has attracted great attention from major pharmaceutical companies and scientific research institutions.
  • BET protein also known as epigenetic recognition protein
  • epigenetic recognition protein can recognize changes in epigenetic information in cellular histones and transmit signals that stimulate cell division and the like.
  • a mutation in the BET protein gene in blood cells can interfere with this signal transmission, causing diseased cells to divide uncontrollably, thereby damaging human tissues and organs.
  • the translocation of the bromine domain coding region of BRD3 / BRD4 and the chromatin of the NUT (nucleoprotein in the testis) gene to form a BRD-NUT fusion proto-oncogene is the pathogenesis of midline cancer. evidence.
  • MYC is silenced directly by interfering with the binding of BRD4 at the MYC site. Since various isomers of MYC are known to be important regulators of cell proliferation and survival, and MYC is a possible oncogene that is overexpressed in many cancers, the bromodomain antagonism is also the first to target MYC-driven tumors Generation provides an opportunity for action. Recently, it has been found that BRD4 also plays an important role in the transcriptional regulation of viral genes, and it is related to the pathogenesis of viral tumors.
  • BRD4 is closely related to many tumors, especially in some tumors that have been difficult to cure or have no effective treatment methods.
  • the study of their relationship with tumors provides new strategies for tumor treatment.
  • the small molecule compound acting on the bromine domain of BRD4 protein interferes with the specific binding of bromine domain and acetylated lysine, affects the transcriptional regulation and other cellular processes in tumor cells, and can achieve targeted therapy for tumors.
  • BRD4 protein is a promising new epigenetic target, and small molecule inhibitors acting on the bromine domain of BRD4 protein also have broad application prospects in tumor research, and it is possible to develop new anti-tumor from them. drug.
  • BRD4 protein has few structural types and their selectivity is not outstanding enough, which limits people's in-depth research on the biological functions of bromodomain-containing proteins and their antitumor potential.
  • the effects of existing BRD4 protein inhibitors need to be improved, and the mechanism needs to be further clarified. Therefore, it is a hot spot to find novel small molecule BRD-BD protein inhibitors with high efficiency and high selectivity.
  • the invention provides a class of fused heterocyclic biaryl benzyl alcohol compounds different from the prior art, a preparation method and uses thereof.
  • the compound of the present invention has good inhibitory activity on BRD enzyme and BRD / c-MYc-related cell proliferation inhibitory activity, so it can be used to treat related diseases caused by BRD / c-MYc mutation or abnormal expression.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a fused heterobiphenyl benzyl alcohol compound having the general formula (IA), a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, Its tautomers, its solvates, its polymorphs or its prodrugs,
  • R 1 is hydrogen, halogen, C 1 -C 8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, or 5-8 membered aryl or heteroaryl;
  • R 2a and R 2b are hydrogen, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl, or R 2a and R 2b A 3-8 membered saturated, unsaturated or partially unsaturated ring system is formed between carbon atoms or heteroatoms;
  • R 3 is hydrogen, halogen, nitro, cyano, alkenyl, alkynyl, C 1 -C 8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl , Amino, hydroxyl, ether or sulfide, sulfone or sulfoxide, ester, amide, sulfonamide, sulfenamide, urea, sulfonylurea or sulfonylurea;
  • R 4 is halogen, C 1 -C 8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, 3-8 membered aryl or heteroaryl, ester, amido, sulfonamide, amino, ether Or thioether, urea or sulfonylurea;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 and X 11 are independently N, C, NR a or CR a , each R a is independent Is hydrogen, halogen, C 1 -C 8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl;
  • X 12 is N or C
  • One or more hydrogen atoms on any of the above groups may be substituted by a substituent selected from the group consisting of deuterium, halogen, hydroxyl, amino or cyclic amino, cyano, nitro, sulfone or sulfoxide, C 1- C 8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, alkenyl, alkynyl, acyl or sulfonyl, urea or Sulfonylurea, 5-8 membered aryl or heteroaryl, R 3-1 substituted 6-18 membered aryl, R 3-2 substituted heteroaryl, R 3-3 substituted 3-8 membered ring Alkyl or R 4- 1 substituted C 1 -C 8 alkyl;
  • R 3-1 , R 3-2 and R 3-3 are independently halogen and / or C 1 -C 4 alkyl
  • R 4-1 is halogen, methanesulfonyl, C 1 -C 4 alkoxy, halogen substituted C 1 -C 4 alkoxy, 3-8 membered cycloalkyl, And R 4-1-2 substituted 3-8 membered cycloalkyls; one or more of R 4-1 ;
  • R 4-1-1a and R 4-1-1b are independently hydrogen or C 1 -C 4 alkyl
  • R 4-1-2 is C 1 -C 4 alkyl or hydroxyl
  • the heteroaryl group includes 1-3 heteroatoms selected from the group: N, O, P, and S
  • the heterocycloalkyl group includes 1-3 heteroatoms selected from the group: N , O, P, and S
  • the ring system is independently a saturated or partially unsaturated ring system of a spiro ring, a bridge ring, a fused ring, a fused ring, or a single ring.
  • R 1 is a C 1 -C 8 alkyl group
  • the C 1 -C 8 alkyl group is a C 1 -C 4 alkyl group, and may further be methyl, ethyl, or n-propyl , Isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and further methyl.
  • the C 1 -C 6 alkyl is C 1 -C 4 alkyl (eg, methyl, ethyl, N-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), and may further be methyl.
  • R 2a and R 2b are independently C 1 -C 6 alkyl, and one or more hydrogen atoms on C 1 -C 6 alkyl are substituted with a substituent
  • the C 1 -C 6 alkyl is C 1 -C 4 alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), and further may be methyl base.
  • R 2a and R 2b are independently C 1 -C 6 alkyl, and one or more hydrogen atoms on C 1 -C 6 alkyl are substituted with a substituent, the substituents The number is one.
  • R 2a and R 2b are independently C 1 -C 6 alkyl, and one or more hydrogen atoms on C 1 -C 6 alkyl are substituted with a substituent, the substituents Is R 2a-1 , and R 2a-1 is halogen or hydroxyl.
  • R 2a-1 when R 2a-1 is a halogen, the halogen may be F, Cl, Br or I, and may also be F.
  • R 2a and R 2b are independently C 1 -C 6 alkyl, and one or more hydrogen atoms on C 1 -C 6 alkyl are substituted with a substituent, the C 1 -C 6 alkyl is
  • the ring system is a 3-5 membered saturated ring system, and may also be a 4 membered member. Saturated ring system.
  • the ring system is a single ring system.
  • the type of the hetero atom is one or more of N, O, P, and S. This can be O.
  • R 2a and R 2b form a 3-8 membered saturated ring system through a hetero atom
  • the number of the hetero atoms is 1-3, and may be one.
  • R 2a and R 2b form a 3-8 membered saturated ring system through a hetero atom
  • the ring system is
  • R 3 when R 3 is a hydroxyl group, and one hydrogen on the hydroxyl group is substituted with a substituent, the substituent is R 3-1a , and the R 3-1a is a 5- to 8-membered aromatic group. , R3-1 substituted 6-18 membered aryl, heteroaryl, R 3-2 substituted heteroaryl, 3-8 membered cycloalkyl or R 3-3 substituted 3-8 membered cycloalkyl .
  • R 3-1a is R 3-1 substituted 6-18 membered aryl group
  • the 6-18 aryl group may be 6-14 aryl group (phenyl, naphthyl, anthracenyl or (Phenanthryl), and may further be phenyl.
  • R 3-1a is a R 3-1 substituted 6-18 membered aryl group
  • the number of R 3-1 may be 1-3, and may also be 3.
  • R 3-1 when R 3-1 is halogen, the halogen may be F, Cl, Br or I, and may also be F.
  • R 3-1 is C 1 -C 4 alkyl
  • the C 1 -C 4 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl , Isobutyl or tert-butyl, and may also be methyl.
  • R 3-1a is a R 3-1 substituted 6-18 membered aryl group
  • the R 3-1 substituted 6-18 membered aryl group may be
  • the heteroaryl group may be a 5- to 8-membered heteroaryl group, and may also be a 5- or 6-membered heteroaryl group.
  • R 3-1a is R 3-2 substituted heteroaryl
  • the type of the hetero atom may be N and / or S.
  • R 3-1a is R 3-2 substituted heteroaryl
  • the number of said heteroatoms may be one.
  • R 3-1a is R 3-2 substituted heteroaryl
  • the number of R 3-2 is 1-3, and may be three.
  • R 3-2 when R 3-2 is halogen, the halogen may be F, Cl, Br or I, and may also be F.
  • R 3-2 is C 1 -C 4 alkyl
  • the C 1 -C 4 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl , Isobutyl or tert-butyl, and may also be methyl.
  • R 3-1a is a R 3-2 substituted 5-8 membered heteroaryl group
  • the R 3-2 substituted 5-8 membered heteroaryl group is
  • R 3-1a is a R 3-3 substituted 3-8 membered cycloalkyl group
  • the 3-8 membered cycloalkyl group may be a 3-6 membered cycloalkyl group, and further may be a cyclohexyl group.
  • R 3-1a is a R 3-3 substituted 3-8 membered cycloalkyl group
  • the number of R 3-3 may be 1-3, or may be one.
  • R 3-3 is C 1 -C 4 alkyl
  • the C 1 -C 4 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl , Isobutyl or tert-butyl, and may also be methyl.
  • R 3-1a is R 3-3 substituted 3-8 membered cycloalkyl
  • R 3 is a hydroxyl group
  • one hydrogen on the hydroxyl group is substituted with a substituent
  • the hydroxyl group is
  • R 4 is a heteroaryl group and one or more hydrogen atoms on the heteroaryl group are substituted with a substituent
  • the type of the hetero atom is N and / or O.
  • R 4 is a heteroaryl group and one or more hydrogen atoms on the heteroaryl group are substituted with a substituent
  • the number of the hetero atoms is 1-3, and may be 1 Or 3.
  • the 3-8 membered heteroaryl group is a 3-6 membered heteroaryl group. It may also be a 5- or 6-membered heteroaryl.
  • R 4 is a heteroaryl group and one or more hydrogen atoms on the heteroaryl group are substituted with a substituent
  • the number of the substituents is one.
  • R 4 when R 4 is heteroaryl and one or more hydrogen atoms on the heteroaryl are substituted with a substituent, the substituent is R 4-1a and the R 4-1a Independently is C 1 -C 8 alkyl, R 4-1 substituted C 1 -C 8 alkyl, 3-8 membered cycloalkyl or heteroaryl.
  • the C 1 -C 8 alkyl may be C 1 -C 4 alkyl (for example, methyl, ethyl, n-propyl, isopropyl Group, n-butyl, sec-butyl, isobutyl, or tert-butyl), and may further be methyl.
  • R 4-1a is R 4-1 substituted C 1 -C 8 alkyl
  • the C 1 -C 8 alkyl is C 1 -C 4 alkyl (for example, methyl, ethyl, n- (Propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), and may further be methyl.
  • R 4-1 when R 4-1 is a 3-8 membered cycloalkyl group, the 3-8 membered cycloalkyl group may be a 3-6 membered cycloalkyl group (cyclopropyl, cyclobutyl, cyclopentyl or cyclo Hexyl), and may further be cyclopropyl.
  • R 4-1a is R 4-1 substituted C 1 -C 8 alkyl
  • the R 4-1 substituted C 1 -C 8 alkyl may be
  • R 4-1a is a 3-8 membered cycloalkyl group
  • the 3-8 membered cycloalkyl group may be a 3-6 membered cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl or Cyclohexyl), and may further be cyclopropyl.
  • R 4-1a when R 4-1a is a heteroaryl group, the heteroaryl group may be a 5- to 8-membered heteroaryl group, and may also be a 5- or 6-membered heteroaryl group.
  • R 4-1a is a heteroaryl group
  • the type of the hetero atom is O or N.
  • R 4-1a is a heteroaryl group
  • the number of said heteroatoms is 1-3, and it may be 2 or 3.
  • R 4-1a is a heteroaryl group
  • the heteroaryl group may be Can be
  • R 4 is a heteroaryl group and one or more hydrogen atoms on the heteroaryl group are substituted with a substituent
  • the heteroaryl group is Can also be
  • R 4 is an amide group and one or more hydrogen atoms on the amide group are substituted with a substituent
  • R 4 is an amide group and one or more hydrogen atoms on the amide group are substituted with a substituent, the number of the substituents is one.
  • R 4 when R 4 is an amide group and one or more hydrogen atoms on the amide group are substituted with a substituent, the substituent is R 4-2b and the R 4-2b is C 1- C 8 alkyl or R 4-1 substituted C 1 -C 8 alkyl.
  • the C 1 -C 8 alkyl may be C 1 -C 4- alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), and further, methyl or ethyl.
  • the number of R 4-1 may be one.
  • R 4-1 when R 4-1 is halogen, the halogen may be F, Cl, Br or I, and may also be F.
  • R 4-1 is C 1 -C 4 alkoxy
  • the C 1 -C 4 alkoxy may be methoxy, ethoxy, n-propoxy, isopropoxy, n- Butoxy, sec-butoxy, isobutoxy or tert-butoxy can also be methoxy.
  • R 4-1 when R 4-1 is a halogen-substituted C 1 -C 4 alkoxy group, the C 1 -C 4 alkoxy group may be a methoxy group, an ethoxy group, an n-propoxy group, or an isopropoxy group.
  • R 4-1 when R 4-1 is a halogen-substituted C 1 -C 4 alkoxy group, the halogen may be F, Cl, Br or I, and may also be F.
  • R 4-1 is a halogen-substituted C 1 -C 4 alkoxy group
  • the halogen-substituted C 1 -C 4 alkoxy group is a trifluoromethoxy group.
  • the 3- to 8-membered cycloalkyl may be a 3- to 6-membered cycloalkyl (for example, cyclopropyl, (Cyclobutyl, cyclopentyl, or cyclohexyl), and may further be cyclopropyl.
  • R 4-1 R 4-1-2 is a substituted 3-8 membered cycloalkyl, according to the number of R 1 may be 4-1-2.
  • R 4-1-2 is C 1 -C 4 alkyl
  • the C 1 -C 4 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary Butyl, isobutyl or tert-butyl may also be methyl.
  • R 4-1 is R 4-1-2 substituted 3-8 membered cycloalkyl
  • the R 4-1-2 substituted 3-8 membered cycloalkyl may be
  • R 4-1-1a and R 4-1-1b are independently C 1 -C 4 alkyl
  • the C 1 -C 4 alkyl may be methyl, ethyl, n-propyl, Isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and may also be methyl.
  • R 4-2b is R 4-1 substituted C 1 -C 8 alkyl
  • R 4-1 substituted C 1 -C 8 alkyl is
  • the amido group when the amido group and one or more hydrogen atoms on the amido group are substituted, the amido group is Can also be
  • the cycloalkyl group is a stable non-aromatic monocyclic ring composed of carbon atoms and hydrogen atoms, and is saturated.
  • the heterocyclic group is a monocyclic ring system, and nitrogen, carbon or sulfur atoms in the heterocyclic group are not oxidized, nitrogen atoms are not quaternized, and are completely saturated.
  • the aryl group is not fused with a cycloalkyl or heterocyclic group.
  • the heteroaryl group is not fused with a cycloalkyl group or a heterocyclic group, nitrogen, carbon or sulfur atoms in the heteroaryl group are not oxidized, and nitrogen atoms are not quaternized.
  • R 1 is C 1 -C 8 alkyl.
  • R 2a and R 2b are independently C 1 -C 6 alkyl, C 1 -C 6 alkyl is one or more hydrogen atoms optionally substituted by R 2a- 1
  • the -C 6 alkyl group or R 2a and R 2b forms a 3-8 membered saturated, unsaturated or partially unsaturated ring system through a carbon atom or a hetero atom, and a C 1 -C 6 alkyl group is preferred.
  • R 3 is a “hydroxyl group, and one or more hydrogen atoms on the hydroxyl group are substituted with a substituent”, an “amino group, and one or more hydrogen atoms on the amino group are substituted with a substituent”, or "A heteroaryl group in which one or more hydrogen atoms in the heteroaryl group is substituted with a substituent" is preferably a "hydroxy group, and one or more hydrogen atoms in the hydroxyl group are substituted with a substituent".
  • R 3 is a hydroxyl group, and one hydrogen on the hydroxyl group is substituted by a substituent, the substituent is R 3-1a , and the R 3-1a is R 3-1 6-18 yuan aryl.
  • R 4 is heterocycloalkyl, "heterocycloalkyl, and heterocycloalkyl in which one or more hydrogen atoms on heterocycloalkyl are substituted with a substituent", "amide, and amido
  • R 4 is an "amide, and one or more hydrogen atoms on the amide group are substituted with a substituent"
  • the substituent is R 4-1a , and the R 4-1a C 1 -C 8 alkyl or R 4-1 substituted C 1 -C 8 alkyl.
  • R 4-1 is halogen, methanesulfonyl, C 1 -C 4 alkoxy, Or R 4-1-2 substituted 3-8 membered cycloalkyl, preferably halogen, C 1 -C 4 alkoxy or methanesulfonyl, more preferably halogen or C 1 -C 4 alkoxy.
  • X 1 , X 9 , X 10 and X 11 are independently CH.
  • X 2 is N or C, preferably N.
  • X 3 and X 6 are independently C.
  • X 4 is N.
  • X 5 is CH or N, preferably N.
  • one of X 7 and X 8 is NH and the other is CH.
  • X 12 is C or N, preferably C.
  • the compound having a fused heterocyclic biaryl benzyl alcohol represented by the general formula (IA) is a compound represented by the general formula (IA) -1:
  • R 1 is C 1 -C 8 alkyl
  • R 2a and R 2b are independently is C 1 -C 6 alkyl, "C 1 -C 6 alkyl, and C 1 -C 8 alkyl group one or more hydrogen atoms are substituted with a C 1 -C 6 alkyl "or R 2a and R 2b form a 3-8 membered saturated, unsaturated or partially unsaturated ring system through a carbon atom or a heteroatom;
  • R 2a-1 is halogen and / or hydroxyl
  • R 3 is "a hydroxyl group, and one or more hydrogen atoms on the hydroxyl group are substituted with a substituent", and / or, "an amino group, and one or more hydrogen atoms on the amino group are substituted with a substituent";
  • R 4 is a heterocycloalkyl group, a "heterocycloalkyl group, and a heterocycloalkyl group in which one or more hydrogen atoms on the heterocycloalkyl group are substituted with a substituent", an "amide group, and one or more hydrogen groups in the amido group "Aminoamido substituted with an atom”, “sulfonamido, and a sulfonyl substituted with one or more hydrogen atoms on the sulfonamido", or "C 1 -C 8 alkyl, and C 1 -C 8 alkyl on one or more hydrogen atoms are substituted with C 1 -C 8 alkyl. "Aminoamido substituted with an atom", "sulfonamido, and a sulfonyl substituted with one or more hydrogen atoms on the sulfonamido", or "C 1 -C 8 alkyl, and C 1 -C 8 alkyl on
  • the fused heterobiphenyl benzyl alcohol compound having the fused heterocyclic biaryl benzyl alcohol represented by the general formula (IA) is a compound represented by the general formula (IA) -2:
  • R 1 is C 1 -C 8 alkyl
  • R 2a and R 2b are independently C 1 -C 6 alkyl
  • R 3 is a "hydroxyl group, a hydroxyl group and one or more hydrogen atoms are substituted with a hydroxyl group substituted", the substituent is R 3- 1a, the R 3-1a 5-8 membered aryl group, R 3-1 substituted 6-18 membered aryl, heteroaryl, R 3-2 substituted heteroaryl, 3-8 membered cycloalkyl or R 3-3 substituted 3-8 membered cycloalkyl;
  • R 4 is a "heterocycloalkyl group in which one or more hydrogen atoms in the heterocycloalkyl group are substituted with a substituent", or "an amido group in which one or more hydrogen atoms in the amido group are substituted Substituted aminoamino ";
  • R 4-1a The substituent in the "heterocycloalkyl and heterocycloalkyl in which one or more hydrogen atoms on the heterocycloalkyl is substituted with a substituent" is R 4-1a , and the R 4-1a is 5 One or more of a 8-membered heteroaryl group, a C 1 -C 8 alkyl group, a R 4-1 substituted C 1 -C 8 alkyl group, and a 3-8 membered cycloalkyl group;
  • the substituent in the "aminoamide group in which one or more hydrogen atoms on the amide group are substituted with a substituent" is R 4-2a , and the R 4-2a is a C 1 -C 8 alkane And / or R 4-1 substituted C 1 -C 8 alkyl;
  • R 4-1 is halogen, methanesulfonyl, C 1 -C 4 alkoxy, halogen substituted C 1 -C 4 alkoxy, 3-8 membered cycloalkyl, And R 4-1-2 substituted 3-8 membered cycloalkyls.
  • the fused heterobiphenyl benzyl alcohol compound having the general formula (IA) is a compound represented by the general formula (IA) -3:
  • R 1 is C 1 -C 8 alkyl
  • R 2a and R 2b are independently C 1 -C 6 alkyl
  • R 3 is a "hydroxyl group, a hydroxyl group and one or more hydrogen atoms are substituted with a hydroxyl group substituted", the substituent is R 3- 1a, R 3-1a said R 3-1 is a substituted 6 18-membered aryl; R 3-1 is halogen and / or C 1 -C 4 alkyl;
  • R 4 is a "heterocycloalkyl group in which one or more hydrogen atoms in the heterocycloalkyl group are substituted with a substituent", or "an amido group in which one or more hydrogen atoms in the amido group are substituted Group substituted amido ";
  • R 4-1a The substituent in the "heterocycloalkyl and heterocycloalkyl in which one or more hydrogen atoms on the heterocycloalkyl are substituted with a substituent" is R 4-1a , and the R 4-1a is C One or more of 1- C 8 alkyl, R 4-1 substituted C 1 -C 8 alkyl, 3-8 membered cycloalkyl, heteroaryl;
  • the substituent in the "aminoamide group in which one or more hydrogen atoms on the amide group are substituted with a substituent" is R 4-2b , and the R 4-2b is a C 1 -C 8 alkane And / or R 4-1 substituted C 1 -C 8 alkyl;
  • R 4-1 is halogen, methanesulfonyl, C 1 -C 4 alkoxy, halogen substituted C 1 -C 4 alkoxy, 3-8 membered cycloalkyl, And R 4-1-2 substituted 3-8 membered cycloalkyls; one or more of R 4-1 ;
  • R 4-1-1a and R 4-1-1b are independently hydrogen or C 1 -C 4 alkyl
  • R 4-1-2 is C 1 -C 4 alkyl or hydroxyl
  • One of X 7 and X 8 is NH and the other is CH.
  • the fused heterobiphenyl benzyl alcohol compound having the general formula (IA) is a compound represented by the general formula (IA) -3:
  • R 1 is C 1 -C 8 alkyl
  • R 2a and R 2b are independently C 1 -C 6 alkyl
  • R 3 is a "hydroxyl group, a hydroxyl group and one or more hydrogen atoms are substituted with a hydroxyl group substituted", the substituents R 3- 1-substituted 6-18 membered aryl group; R 3-1 is halogen and / Or C 1 -C 4 alkyl;
  • R 4 is an "amide group, and one or more hydrogen atoms on the amide group are substituted with a substituent"; the substituent is R 4-2b , and the R 4-2b is C 1 -C 8 alkyl and / or R 4-1 substituted C 1 -C 8 alkyl;
  • R 4-1 is halogen, methanesulfonyl, C 1 -C 4 alkoxy, 3-8 membered cycloalkyl, And R 4-1-2 substituted 3-8 membered cycloalkyls; one or more of R 4-1 ;
  • R 4-1-1a and R 4-1-1b are independently hydrogen or C 1 -C 4 alkyl
  • R 4-1-2 is C 1 -C 4 alkyl or hydroxyl
  • One of X 7 and X 8 is NH and the other is CH.
  • the fused heterobiphenyl benzyl alcohol compound having the general formula (IA) is a compound represented by the general formula (IA) -3:
  • R 1 is C 1 -C 8 alkyl
  • R 2a and R 2b are independently C 1 -C 6 alkyl
  • R 3 is a “hydroxyl group, and one or more hydrogen atoms on the hydroxyl group are substituted with a substituent group”, the substituent is a 6-18 membered aryl group substituted with R3-1; R 3-1 is a halogen and / Or C 1 -C 4 alkyl;
  • R 4 is "an amido group, and one or more hydrogen atoms on the amido group are substituted with a substituent";
  • One of X 7 and X 8 is NH and the other is CH.
  • the fused heterobiphenyl benzyl alcohol compound having the general formula (IA) is a compound represented by the general formula (IA) -3:
  • R 1 is C 1 -C 8 alkyl
  • R 2a and R 2b are independently C 1 -C 6 alkyl
  • R 3 is a “hydroxyl group, and one or more hydrogen atoms on the hydroxyl group are substituted with a substituent group”, the substituent is a 6-18 membered aryl group substituted with R3-1; R 3-1 is a halogen and / Or C 1 -C 4 alkyl;
  • R 4 is an "amide group, and one or more hydrogen atoms on the amide group are substituted with a substituent group"; the substituent is a C 1-4 C 8 alkyl group substituted with R 4-1 ;
  • R 4-1 is halogen, methanesulfonyl, C 1 -C 4 alkoxy, Or R 4-1-2 substituted 3-8 membered cycloalkyl;
  • One of X 7 and X 8 is NH and the other is CH.
  • the fused heterobiphenyl benzyl alcohol compound having the general formula (IA) is a compound represented by the general formula (IA) -3:
  • R 1 is C 1 -C 8 alkyl
  • R 2a and R 2b are independently C 1 -C 6 alkyl
  • R 3 is a "hydroxyl group, a hydroxyl group and one or more hydrogen atoms are substituted with a hydroxyl group substituted", the substituents R 3- 1-substituted 6-18 membered aryl group; R 3-1 is halogen and / Or C 1 -C 4 alkyl;
  • R 4 is an "amide group, and one or more hydrogen atoms on the amide group are substituted with a substituent group"; the substituent is a C 1-4 C 8 alkyl group substituted with R 4-1 ;
  • R 4-1 is halogen, C 1 -C 4 alkoxy or methanesulfonyl
  • One of X 7 and X 8 is NH and the other is CH.
  • the fused heterobiphenyl benzyl alcohol compound having the general formula (IA) is a compound represented by the general formula (IA) -3:
  • R 1 is C 1 -C 8 alkyl
  • R 2a and R 2b are independently C 1 -C 6 alkyl
  • R 3 is a “hydroxyl group, and one or more hydrogen atoms on the hydroxyl group are substituted with a substituent group”, the substituent is a 6-18 membered aryl group substituted with R3-1; R 3-1 is a halogen and / Or C 1 -C 4 alkyl;
  • R 4 is an "amide group, and one or more hydrogen atoms on the amide group are substituted with a substituent group"; the substituent is a C 1-4 C 8 alkyl group substituted with R 4-1 ;
  • R 4-1 is halogen or C 1 -C 4 alkoxy
  • One of X 7 and X 8 is NH and the other is CH.
  • the compound having a fused heterobiphenyl benzyl alcohol represented by the general formula (IA) is a general formula (IIA), (IIB), (IIC), (IID), (IIE), ( IIF), (IIG), (IIH), (III), (IIJ), (IIK), (IIL), (IIM), (IIN), (IIO), (IIP), (IIQ) :
  • the fused heterocyclic biaryl benzyl alcohol compound represented by the general formula (IA) is any one of the following compounds:
  • the invention also provides a method for preparing the fused heterocyclic biaryl benzyl alcohol compound represented by the general formula (IA), which includes the following steps:
  • step b performing a cross-coupling reaction between the compound of formula (B) obtained in step a and the compound of formula (C) in the presence of a transition metal catalyst to obtain a compound of general formula (IA);
  • the conditions and operations in the metal-catalyzed coupling reaction in step a and the cross-coupling reaction in step b can be the conditions and operations conventional for such reactions in the art, and the following conditions and operations are particularly preferred in the present invention:
  • said steps a) and b) are each performed in a solvent.
  • the solvent is selected from one or more of water, ether solvents, alcohol solvents, aromatic solvents, chlorinated hydrocarbon solvents, nitrile solvents, sulfoxide solvents, pyrrolidone solvents and amide solvents, more Ether solvents and water are preferred, and dioxane and water are more preferred.
  • the ether-based solvent may be one or more of ethylene glycol methyl ether, tetrahydrofuran, and dioxane, and may also be dioxane.
  • the alcohol-based solvent may be one or more of methanol, ethanol, isopropanol, butanol, and ethylene glycol.
  • the aromatic hydrocarbon solvent may be toluene.
  • the chlorinated hydrocarbon solvent may be dichloromethane and / or 1,2-dichloroethane.
  • the nitrile solvent may be acetonitrile.
  • the sulfoxide-based solvent may be dimethyl sulfoxide.
  • the pyrrolidone-based solvent may be N-methylpyrrolidone.
  • the amide-based solvent may be N, N-dimethylformamide and / or N, N-dimethylacetamide.
  • the reactions of steps a) and b) are each performed in the presence of a base.
  • the base may be an inorganic base and / or an organic base, may also be an inorganic base, and may further be potassium carbonate.
  • the inorganic base is selected from sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, One or more of sodium carbonate and sodium bicarbonate.
  • the organic base is selected from pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), hexamethyl
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • hexamethyl One or more of lithium disilyl, sodium hexamethyldisilyl, and dimethylpyridine.
  • the metal catalyst may be selected from tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ), palladium acetate , Palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride , One or more of bis (tri-o-phenylmethylphosphine) palladium dichloride and 1,2-bis (diphenylphosphino) ethane palladium dichloride, and may also be Bis (diphenylphosphino) ferrocene] palladium dichloride.
  • the molar ratio of the metal catalyst to the compound of the formula (A) may be 0.05: 1 to 1.0: 1, for example, 0.1 or 0.2.
  • a molar ratio of the bona finacol ester to the compound of the formula (A) may be 5: 1 to 1: 1, for example, 1.5: 1.
  • step a the compound of formula (B) may be directly reacted in the next step without post-treatment.
  • the transition metal catalyst may be selected from tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ), acetic acid Palladium, palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis (diphenylphosphino) ferrocene] dichloride One or more of palladium, bis (tri-o-phenylmethylphosphine) palladium dichloride, and 1,2-bis (diphenylphosphino) ethane palladium dichloride, and may also be [1,1 ' -Bis (diphenylphosphino) ferrocene] palladium dichloride.
  • the molar ratio of the transition metal catalyst to the compound of formula (A) may be 0.05: 1 to 1: 1, such as 0.1: 1.
  • the cross-coupling reaction may also be performed in the presence of a ligand.
  • the ligand may be tri-t-butylphosphine, tri-t-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenyl One or more of phosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, and tri-o-phenylmethylphosphine, and may also be triphenylphosphine.
  • the molar ratio of the ligand to the compound of the formula (A) may be 0.1: 1 to 2: 1, for example, 0.2: 1.
  • the molar ratio of the compound of formula (C) to the compound of formula (A) may be 0.8: 1 to 2: 1, for example, 1.5: 1.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned fused heterocyclic biaryl benzyl alcohol compound having the general formula (IA), a pharmaceutically acceptable salt thereof, an enantiomer thereof, Its diastereomers, its tautomers, its solvates, its polymorphs or its prodrugs, and pharmaceutically acceptable carriers.
  • the amount of the isomer, its solvate, its polymorph or its prodrug may be a therapeutically effective amount.
  • the pharmaceutical composition is preferably used for treating or preventing tumors.
  • the present invention also provides the above-mentioned fused heterocyclic biaryl benzyl alcohol compound having the general formula (IA), a pharmaceutically acceptable salt thereof, an enantiomer thereof, and a diastereomer thereof. Structure, its tautomer, its solvate, its polymorph or its prodrug, or the above-mentioned pharmaceutical composition for use in the preparation of a medicament.
  • the present invention also provides the above-mentioned fused heterocyclic biaryl benzyl alcohol compound having the general formula (IA), a pharmaceutically acceptable salt thereof, an enantiomer thereof, and a diastereomer thereof. Structure, its tautomer, its solvate, its polymorph or its prodrug, or the above-mentioned pharmaceutical composition for use in the preparation of a medicament for the prevention and / or treatment of BRD , C-Myc protein activity or expression-related diseases.
  • IA fused heterocyclic biaryl benzyl alcohol compound having the general formula (IA), a pharmaceutically acceptable salt thereof, an enantiomer thereof, and a diastereomer thereof. Structure, its tautomer, its solvate, its polymorph or its prodrug, or the above-mentioned pharmaceutical composition for use in the preparation of a medicament for the prevention and / or treatment of BRD , C-Myc protein activity or expression-related diseases.
  • the disease may be one or more of a tumor, an immune disease, and an inflammatory disease.
  • the tumor is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, bowel cancer, bile duct cancer, brain cancer, leukemia, and lymph Cancer, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer or pancreatic cancer, preferably leukemia or prostate cancer.
  • the immune disease and the inflammatory disease are independently selected from rejection of transplanted organs, gout, rhinitis, hair loss, Alzheimer's disease, appendicitis, atherosclerosis, asthma, arthritis, allergic dermatitis , Bechet's disease, bullous dermatosis, cholecystitis, chronic idiopathic thrombocytopenic purpura, chronic obstructive pulmonary disease, cirrhosis, degenerative joint disease, dermatitis, dermatomyositis, eczema, enteritis, brain Inflammation, gastritis, nephritis, Hashimoto's thyroiditis, hepatitis, pituitary inflammation, inflammatory bowel disease, irritable bowel syndrome, Kawasaki disease, meningitis, multiple sclerosis, myocarditis, myasthenia gravis, mycosis fungal , Myositis, nephritis, osteomye
  • the present invention also provides the above-mentioned fused heterocyclic biaryl benzyl alcohol compound having the general formula (IA), a pharmaceutically acceptable salt thereof, an enantiomer thereof, and a diastereomer thereof. Structure, its tautomers, its solvates, its polymorphs or its prodrugs, or the use of the aforementioned pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of tumors, One or more of an immune disease and an inflammatory disease.
  • IA fused heterocyclic biaryl benzyl alcohol compound having the general formula (IA), a pharmaceutically acceptable salt thereof, an enantiomer thereof, and a diastereomer thereof. Structure, its tautomers, its solvates, its polymorphs or its prodrugs, or the use of the aforementioned pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of tumors, One or more of an immune disease and an inflammatory disease.
  • the tumor, the immune disease, and the inflammatory disease are all the same as described above.
  • the present invention also provides a method for preventing and / or treating a disease, which method comprises administering an effective amount of the above-mentioned fused heterocyclic biaryl benzyl alcohol compound having the formula (IA) to a subject in need of treatment.
  • a subject in need of treatment.
  • said disease is a disease related to BRD, c-Myc protein activity or expression.
  • the disease is the same as described above.
  • the present invention also provides a method for preventing and / or treating a disease, which method comprises administering an effective amount of the above-mentioned fused heterocyclic biaryl benzyl alcohol compound having the formula (IA) to a subject in need of treatment.
  • the tumor, immune disease and inflammatory disease are the same as described above.
  • the present invention relates to a fused heterocyclic biaryl benzyl alcohol compound represented by the general formula (I), which can inhibit a variety of tumor cells, in particular, can efficiently kill tumors associated with abnormal signal pathways such as BRD / c-Myc, For example, leukemia, prostate cancer, etc., are a new class of therapeutic drugs.
  • a compound having a fused heterocyclic biarylbenzyl alcohol as shown in Formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or a diastereomer thereof.
  • Tautomers, solvates, polymorphs or prodrugs
  • R 1 is independently selected from hydrogen, halogen, C 1 -C 8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, and 5-8 membered aryl or heteroaryl;
  • R 2a and R 2b are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl, or R A 3-8 membered saturated, unsaturated or partially unsaturated ring system may be formed between 2a and R 2b through a carbon atom or a heteroatom.
  • R 3 is independently selected from hydrogen, halogen, nitro, cyano, alkenyl, alkynyl, C 1 -C 8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, 3-8 membered aryl, or Heteroaryl, amino, hydroxyl, ether or thioether, sulfone or sulfoxide, ester, amide, sulfonamide, sulfinamide, urea, sulfonylurea, sulfonylurea, etc .;
  • R 4 is independently selected from halogen, C 1 -C 8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, 3-8 membered aryl or heteroaryl, ester, amido, sulfonamide, amino , Ether or thioether, urea or sulfonylurea, etc .;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 are each independently selected from N, NRa or CRa, Ra is selected from hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 8 alkylcycloalkyl or heterocycloalkyl;
  • One or more hydrogen atoms on any of the above groups may be substituted by a substituent selected from the group consisting of, but not limited to, deuterium, halogen, hydroxyl, amino or cyclic amino, cyano, nitro, sulfone or Sulfone, C 1 -C 8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, alkenyl, alkynyl, acyl or sulfo Acyl, urea or sulfonylurea, 5- to 8-membered aryl or heteroaryl; wherein the heteroaryl includes 1-3 heteroatoms selected from the group consisting of N, O, P or S, and The heterocycloalkyl group contains 1-3 heteroatoms selected from the group consisting of N, O, P or S, and the ring system includes a spiro ring, a bridge ring,
  • the compound having the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, Polymorphs or prodrugs preferably of general formulae (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIG), (IIH), (III), (IIJ ), (IIK), (IIL), (IIM), (IIN), (IIO)
  • R 1 , R 2a , R 2b , R 3 , R 4 , X 1 , X 5 , X 7 , X 8 , X 9 , X 10 , X 11 are as defined in claim 1.
  • the compound having the general formula (1), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or solvate thereof Polymorphs or prodrugs, characterized by:
  • R 1 is preferably selected from hydrogen, fluorine, chlorine, methyl and ethyl;
  • R 2a and R 2b are each independently selected from methyl, ethyl, alkoxymethyl, cyclopropylmethyl, halomethyl, etc., or R 2a and R 2b form 3-6 through a carbon atom or heteroatom Membered ring system, preferably from cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, etc .;
  • R 3 is preferably a C 1 -C 6 alkyl ether or thioether or amino group, a 3-8 membered cycloalkyl or heterocycloalkyl ether or thioether or amino group, a 5-8 membered aryl or heteroaryl group Ether or thioether or amino; further preferably from:
  • Rd is selected from hydrogen, halogen, cyano, sulfone, sulfoxide, C1-C3 alkyl or alkoxy, and Rd can form 3 with benzene ring or cyclohexane ring or another Rd substituent.
  • R 4 is preferably -CN, -COORb, -CONHRb, Wherein Rb and Re are each independently selected from C1-C8 alkyl or cycloalkyl or heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl, and the like;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 are preferably from N, CRa, and Ra is preferably from hydrogen and fluorine.
  • a method for preparing a compound of formula I wherein the method comprises steps a-b:
  • the steps a) and b) are each performed in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethylene glycol methyl ether, N -Methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1,2-dichloroethane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, Dioxane, or a combination thereof.
  • the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethylene glycol methyl ether, N -Methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1,2-dichloroethane,
  • the transition metal catalyst is selected from the group consisting of tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ), acetic acid Palladium, palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis (diphenylphosphino) ferrocene] dichloride Palladium, bis (tri-o-phenylmethylphosphine) palladium dichloride, 1,2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof; the catalyst ligand is selected from the group consisting of: Tri-tert-butylphosphine, tri-tert-butylphosphine t
  • the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, carbonic acid Potassium hydrogen, sodium carbonate, sodium bicarbonate, or a combination thereof;
  • the organic base is selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] Undecyl-7-ene (DBU), lithium hexamethyldisilyl, sodium hexamethyldisilyl, dimethylpyridine, or a combination thereof.
  • the present invention provides a class of preferred compounds of general formula (I), including but not limited to the following structures:
  • Another object of the present invention is to provide a medicament for treating or preventing tumor and a composition thereof.
  • a pharmaceutical composition for treating tumors which is composed of the fused heterocyclic biaryl benzyl alcohol compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer or a diastereomer thereof.
  • Enantiomers, tautomers, solvates, polymorphs or prodrugs are composed of a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide a use of the above-mentioned compound.
  • the tumor is independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, bowel cancer, bile duct cancer, brain cancer, leukemia, lymph Cancer, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
  • the immune and inflammatory diseases are independently selected from the group consisting of rejection of transplanted organs, gout, rhinitis, hair loss, Alzheimer's disease, appendicitis, atherosclerosis, asthma, arthritis, allergic dermatitis, shellfish Chet's disease, bullous skin disease, cholecystitis, chronic idiopathic thrombocytopenic purpura, chronic obstructive pulmonary disease, cirrhosis, degenerative joint disease, dermatitis, dermatomyositis, eczema, enteritis, encephalitis, Gastritis, nephritis, Hashimoto's thyroiditis, hepatitis, pituitary inflammation, inflammatory bowel disease, irritable bowel syndrome, Kawasaki disease, meningitis, multiple sclerosis, myocarditis, myasthenia gravis, mycosis fungal disease, muscle Inflammation, nephritis, osteomyelitis, pancre
  • the present invention relates to a fused heterocyclic biaryl benzyl alcohol compound having the structural characteristics of the general formula (I), which can inhibit a variety of tumor cells, and particularly can efficiently kill tumors associated with abnormal signal pathways such as BRD / c-Myc
  • BRD / c-Myc
  • leukemia, prostate cancer, etc. are a new class of therapeutic drugs.
  • the manufacturer's instructions for use of the kit can be used, or the reaction and purification can be performed in a manner known in the art or as described in the present invention.
  • the techniques and methods described above can generally be implemented according to conventional methods well known in the art, based on descriptions in several summary and more specific references that are cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituent When a substituent is described by a general chemical formula written from left to right, the substituent also includes a chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH2O- is equivalent to -OCH2-.
  • C1-6 alkyl refers to an alkyl group, as defined below, having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified symbol does not include carbons that may be present in the substituents of the group.
  • halogen refers to fluorine, chlorine, bromine or iodine
  • hydroxy refers to the -OH group
  • hydroxyalkyl refers to an alkane group as defined below substituted with a hydroxyl group (-OH)
  • nitro refers to -NO 2
  • cyano refers to -CN
  • amino refers to -NH 2
  • substituted amino Means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, and heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, arane Amino, heteroaralkylamino
  • carbboxy means -COOH.
  • alkyl means only composed of carbon atoms and hydrogen atoms, and does not contain unsaturated A straight or branched hydrocarbon chain group having a bond, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule through a single bond.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl.
  • alkenyl means composed of only carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) (More preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group attached to the rest of the molecule through a single bond, such as, but not limited to, vinyl, propenyl, allyl, butane- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
  • alkynyl means composed of only carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, A straight or branched hydrocarbon chain group of 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by a single bond, such as, but not limited to, ethynyl , Prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.
  • cycloalkyl means a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed of only carbon atoms and hydrogen atoms, which may include fused Ring system, bridged ring system or spiro ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which are saturated or unsaturated and may pass through any suitable The carbon atom is connected to the rest of the molecule by a single bond. Unless specifically stated otherwise in this specification, carbon atoms in a cycloalkyl group may be optionally oxidized.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene Acylcycloheptene-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , Fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo [
  • heterocyclyl means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Stable 3- to 20-membered non-aromatic cyclic group.
  • a heterocyclic group may be a monocyclic, bicyclic, tricyclic, or more cyclic ring system, which may include a fused ring system, a bridged ring system, or a spiro ring system; Nitrogen, carbon or sulfur atoms may be optionally oxidized; nitrogen atoms may be optionally quaternized; and heterocyclic groups may be partially or fully saturated.
  • Heterocyclyl can be attached to the rest of the molecule via a carbon atom or a heteroatom and via a single bond.
  • one or more rings may be an aryl or heteroaryl group as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the group is more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spiro ring group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro [3.5] non Alk-7-yl, 2-oxa-6-aza-spiro [3.3] heptane-6-yl, 2,5-diaza-bicyclo [2.2.1] heptane-2-yl, aza Cyclobutyl, pyranyl, tetrahydropyranyl, thioranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, deca
  • aryl means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms.
  • the aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond.
  • aryl examples include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl and the like.
  • arylalkyl refers to an alkyl group, as defined above, substituted with an aryl group, as defined above.
  • heteroaryl means having 1 to 15 carbon atoms in the ring (preferably having 1 to 10 carbon atoms) and 1 to 6 selected from nitrogen
  • a 5- to 16-membered conjugated ring system group of a heteroatom of oxygen, oxygen, and sulfur Unless otherwise specified in this specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may be fused with a cycloalkyl or heterocyclic group as defined above, provided that the The aryl group is connected to the rest of the molecule via a single bond via an atom on the aromatic ring.
  • a nitrogen, carbon or sulfur atom in a heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably 1 to 4 members.
  • heteroaryl examples include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benpyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, quinolinyl, isoquinolinyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthroline, phenanthroline, acridine Base, phenazin
  • heteroarylalkyl refers to an alkyl group, as defined above, substituted with a heteroaryl group, as defined above.
  • optionally or “optionally” means that the event or condition described later may or may not occur, and the description includes both the occurrence or non-occurrence of the event or condition.
  • optionally substituted aryl means that the aryl group is substituted or unsubstituted, and the description includes both a substituted aryl group and an unsubstituted aryl group.
  • portion refers to a specific fragment or functional group in a molecule.
  • a chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.
  • a “stereoisomer” refers to a compound that is composed of the same atom and is bonded through the same bond, but has a different three-dimensional structure.
  • the invention will cover various stereoisomers and mixtures thereof.
  • the compound of the present invention contains an olefinic double bond, unless otherwise stated, the compound of the present invention is intended to include E- and Z-geometric isomers.
  • Tautomers refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be included within the scope of the invention.
  • the compounds of the invention may contain one or more chiral carbon atoms, and may thus give rise to enantiomers, diastereomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)-or (S)-based on stereochemistry.
  • the invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the compounds of the present invention can be prepared as racemates, diastereomers or enantiomers as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc .
  • organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, propionate, hexanoate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate Salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesul
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic or organic base capable of maintaining the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin and the like.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine
  • Polymorph refers to different solid crystalline phases produced by certain compounds of the present invention due to the presence of two or more different molecular arrangements in the solid state. Certain compounds of the invention may exist in more than one crystalline form, and the invention is intended to include various crystalline forms and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules.
  • the solvent may be water, and the solvate in this case is a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
  • the compounds of the present invention can form true solvates, but in some cases it is also possible to keep only the water or a mixture of water plus a portion of the solvent.
  • the compounds of the present invention can be reacted in a solvent or precipitated or crystallized from the solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
  • the invention also includes prodrugs of the aforementioned compounds.
  • prodrug means a compound that can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis. Accordingly, the term “prodrug” refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
  • the prodrug When administered to an individual in need, the prodrug may not be active, but is transformed in vivo into the active compound of the invention.
  • Prodrugs are usually rapidly transformed in vivo to produce the parent compound of the invention, for example, by hydrolysis in blood.
  • Prodrug compounds generally provide the advantages of solubility, histocompatibility, or sustained release in mammalian organisms.
  • Prodrugs include known amino protecting groups and carboxy protecting groups.
  • prodrug preparation methods can refer to Saulnier, M.G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, R.B., et al., J. Med. Chem. 2000, 43, 475.
  • pharmaceutical composition refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing adverse biological React or interact in an undesirable manner with any of the components contained in the composition.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government authority as acceptable for human or livestock use. , Diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • tumor and abnormal cell proliferation-related diseases include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • prevention include enabling a patient to reduce the likelihood of the occurrence or worsening of a disease or disorder.
  • treatment and other similar synonyms as used herein include the following meanings:
  • an "effective amount” for use in therapy is an amount of a composition comprising a compound disclosed herein that is required to provide a significant clinically alleviating effect on a condition.
  • An effective amount suitable for any individual case can be determined using techniques such as a dose escalation test.
  • the terms "taking,” “administering,” “administering,” and the like refer to a method capable of delivering a compound or composition to a desired site for a biological effect. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration topical administration and rectal administration.
  • Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current. The ones discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • the terms “pharmaceutical combination”, “drug combination”, “combination”, “administration of other treatments”, “administration of other therapeutic agents”, etc. refer to a drug treatment obtained by mixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients.
  • the term “fixed combination” refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • the term “unfixed combination” refers to the simultaneous, combined, or sequential administration of at least one compound described herein and at least one synergistic formulation to a patient in the form of separate entities. These also apply to cocktail therapies, for example the administration of three or more active ingredients.
  • the intermediate compound functional group may need to be protected by a suitable protecting group.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , Tetrahydropyranyl, benzyl and the like.
  • Suitable protecting groups for amino, fluorenyl and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable thiol-protecting groups include -C (O) -R "(where R” is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is detailed in Greene, T.W. and P.G.M.Wuts, Protective Groups in Synthesis, (1999), 4th Ed., Wiley.
  • the protective group may also be a polymer resin.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive effect of the present invention is characterized in progress: the compound of the present invention has a better enzyme inhibitory activity BRD, an IC 50 can be as low as 0.6 nmol / L, and to the BRD c-MYc cell proliferation / inhibition activity associated quite excellent, it is possible It is used to treat diseases related to BRD / c-MYc mutation or abnormal expression such as tumor.
  • Step 1 Dissolve 4-bromo-7-chloro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridine (500mg) in anhydrous tetrahydrofuran (10mL) and cool to -70 ° C. Lithium diisopropylamide LDA (1.3 mL, 1.5 M tetrahydrofuran solution) was added. The temperature was raised to -40 degrees, stirred for 1.5 hours, and then cooled to -70 degrees, and ethyl chloroformate ClCOOEt (211 mg) was added. Reaction at -70 degrees for 2 hours.
  • Step 2 Dissolve 4-bromo-7-chloro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid ethyl ester (320 mg) and sodium hydroxide (280 mg) In a tetrahydrofuran / water (50mL / 50mL) mixed solvent, heat to 50 ° C overnight and concentrate under reduced pressure to remove most of the organic solvents. Acidify with 2M dilute hydrochloric acid, precipitate solid, filter, and dry to obtain 4-bromo-7-chloro- 1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid (white solid). LC-MS (M + H) 274.7 / 276.7.
  • Step 3 Add 4-bromo-7-chloro-1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid (1.0 g) to acetylhydrazine (10 g). The temperature was raised to 150 degrees, the solid was dissolved, and the reaction was allowed to proceed overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain 6-bromo-3-methyl-9H-pyrrolo [2,3-c] [1,2,4] triazol [4,3- a] Pyridine-8-carboxylic acid (450 mg, white solid). LC-MS (M + H) 295.1 / 297.1.
  • the fourth step 6-bromo-3-methyl-9H-pyrrolo [2,3-c] [1,2,4] triazol [4,3-a] pyridine-8-carboxylic acid (60mg , 0.21 mmol), ethylamine hydrochloride (34 mg, 0.42 mmol) and 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate (HATU ) (160 mg, 0.42 mmol) was dissolved in N, N-dimethylformamide (20 mL), N, N-diisopropylethylamine (82 mg, 0.63 mmol) was added, and the reaction was performed at room temperature for 3 hours.
  • HATU 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate
  • the intermediate A10 was prepared by referring to the synthetic route and method of the literature J. Med. Chem. 1981, 24, 1455-1460 and the intermediate A1. , LC-MS (M + H) 322.0 / 324.0.
  • the residue was diluted with dichloromethane, and the organic phase was sequentially washed with water, saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was separated and purified by silica gel column chromatography to obtain the target compound I.
  • Step 1 Add 4-bromo-7-chloro-1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid (190 mg, 0.7 mmol), ethylamine hydrochloride (254 mg, 3.12 mmol) and HATU (593mg, 1.56mmol) was dissolved in N, N-dimethylformamide DMF (20mL), diisopropylethylamine (DIEA) (536mg, 4.16mmol) was added, and the reaction was performed at room temperature for 3 hours. LCMS detection showed that the reaction was complete .
  • DIEA diisopropylethylamine
  • Step 2 Mix 4-bromo-7-chloro-N-ethyl-1H-pyrrolo [2,3-c] pyridin-2-amide (130 mg, 0.43 mmol) and acetylhydrazine (5.0 g), heat Reaction to 150 degrees for 48 hours.
  • the reaction solution was cooled to room temperature, dissolved in methanol, and purified by column chromatography to obtain 6-bromo-N-ethyl-3-methyl-9H-pyrrolo [2,3-c] [1,2,4] triazole.
  • 4,3-a] pyridine-8-amide 51 mg, white solid).
  • the third step 6-bromo-N-ethyl-3-methyl-9H-pyrrolo [2,3-c] [1,2,4] triazol [4,3-a] pyridine-8 -Amide (40 mg, 0.12 mmol), (2- (4-fluoro-2,6-dimethylphenoxy) -5- (2-hydroxypropyl-2-yl) phenyl) boronic acid (158 mg, 0.5 mmol), XPhos (12mg, 0.025mmol), Pd 2 (dba) 3 (11mg, 0.012mmol), Xphos Pd G3 (11mg, 0.012mmol) and sodium carbonate (52mg, 0.50mmol) were dissolved in ethanol / water (10mL / 0.4 mL), protected by nitrogen, heated to 80 degrees and reacted overnight.
  • Step 1 The compound 7-bromo-4-hydroxy-1H-pyrrolo [3,2-c] pyridin-2-carboxylic acid (623 mg, 2.4 mmol) was dissolved in DMF (10 mL), and HATU (1.4 g, 3.6 mmol) and DIEA (619 mg, 4.8 mmol), stirred at room temperature for 5 minutes, and then added ethylamine (2M THF, 2.4 mL, 4.8 mmol), and reacted at room temperature overnight.
  • Step 2 Dissolve 7-bromo-N-ethyl-4-hydroxy-1H-pyrrolo [3,2-c] pyridin-2-amide (695mg, 2.4mmol) in phosphorus oxychloride POCl 3 (6mL ), Heated to 80 degrees for 2 hours, cooled to room temperature, concentrated under reduced pressure, purified by column chromatography to obtain 7-bromo-4-chloro-N-ethyl-1H-pyrrolo [3,2-c] pyridine -2-amide (340 mg, yellow solid).
  • Step 3 Suspend 7-bromo-4-chloro-N-ethyl-1H-pyrrolo [3,2-c] pyridin-2-amide (320 mg, 1.1 mmol) in acetylhydrazine (5 g), The reaction was heated to 150 degrees for 4 hours. The reaction solution was cooled to room temperature, poured into cold water, extracted with ethyl acetate, combined organic phases, dried, concentrated under reduced pressure, and purified by column chromatography to obtain 6-bromo-N-ethyl-3- Methyl-7H-pyrrolo [3,2-c] [1,2,4] triazol [4,3-a] pyridine-8-amide (39 mg, yellow solid). LC-MS (M + H) 322.2 / 324.2.
  • Example 5 Using intermediate A1 as a raw material, and referring to the ring closure method of 1,2,4-oxazodiazol and the general preparation method 1 of patent WO201666742A1, Example 5 was prepared, LC-MS (M + H) 590.2.
  • Example 6 Using intermediate A1 as a raw material, and referring to the ring-closing method of 1,3,4-oxazodiazol and the general preparation method 1 of patent WO201485296A1, Example 6 was prepared, LC-MS (M + H) 590.1.
  • Example 8 6- (2- (4-fluoro-2,6-dimethylphenoxy) -5- (2-hydroxypropyl-2-yl) phenyl) -3-methyl-N- (2- (methylsulfosyl) ethyl) -9H-pyrrole [2,3-c] [1,2,4] triazol [4,3-a] pyridine-8-amide
  • Example 13 6- (2- (4-fluoro-2,6-dimethylphenoxy) -5- (2-hydroxypropyl-2-yl) phenyl) -3-methyl-N- (2- (trifluoromethoxy) ethyl) -9H-pyrrole [2,3-c] [1,2,4] triazol [4,3-a] pyridine-8-amide
  • Step 1 Put intermediate A1 (40 mg, 0.13 mmol), (2- (4-fluoro-2,6-dimethylphenoxy) -5- (2-hydroxypropyl-2-yl) phenyl ) Boric acid (57 mg, 0.14 mmol), X-Phos (6 mg, 0.013 mmol), XPhos Pd G3 (10 mg, 0.013 mmol), Pd 2 (dba) 3 (12 mg, 0.013 mmol), and sodium carbonate (Na 2 CO 3 ) (28 mg, 0.26 mmol) was dissolved in ethanol / water (EtOH / H 2 O) (2 mL, volume ratio 10/1), nitrogen N 2 was substituted, and the oil bath was heated to 85 degrees and reacted overnight.
  • EtOH / H 2 O 2 ethanol / water
  • Step 2 To 6- (2- (4-fluoro-2,6-dimethylphenoxy) -5- (2-hydroxypropane-2-yl) phenyl) -3-methyl-9H- Pyrrolop [2,3-c] [1,2,4] triazol [4,3-a] pyridine-8-carboxylic acid methyl ester (14 mg, 0.029 mmol) in EtOH / H 2 O (1 mL, 10 / 1) To the solution was added sodium hydroxide (NaOH) (3.5 mg, 0.087 mmol). The reaction was carried out at room temperature overnight.
  • NaOH sodium hydroxide
  • the third step 6- (2- (4-fluoro-2,6-dimethylphenoxy) -5- (2-hydroxypropane-2-yl) phenyl) -3-methyl-9H- Pyrrolo [2,3-c] [1,2,4] triazol [4,3-a] pyridine-8-carboxylic acid (10 mg, 0.024 mmol), 2- (trifluoromethoxy) ethylamine
  • the hydrochloride (8 mg, 0.048 mmol) and HATU (28 mg, 0.072 mmol) were dissolved in DMF (1 mL), DIEA (16 mg, 0.120 mmol) was added, and the reaction was performed at room temperature for 2 h.
  • Example 15 was prepared through General Preparation Method 1,
  • Test example 1 BRD4AlphaScreen determination
  • biotinylated tetraacetylated histone H4 peptide H4Ac4
  • BSD4-BD1 or 20nM BBD4-BD2
  • assay buffer 50mM HEPES, pH 7.4, 100mM NaCl, 0.05% CHAPS, 0.01% BSA
  • 20 ⁇ L of an assay buffer supplemented with 4 ⁇ g / mL of streptavidin donor beads and GSH acceptor beads was added under low light.
  • the plate was sealed, the plate was incubated at room temperature for 75 minutes in the dark, and then read on a PHERAstar FS plate reader (BMG Labtech).
  • IC50 determination was performed using GraphPad Prism 5.0 software through a fitted curve of the log of control activity% versus inhibitor concentration.
  • Example 1 As part of the present invention to provide Example 13 Example 1, inhibitory activity IC 50 values BRD4-BD2 average IC 50 of less than 10OnM, inhibit the activity of some embodiments even less than 10 nM IC 50, while BRD4 -BD1 has weak inhibitory activity, with IC 50 values all having IC 50 greater than 100 nM, showing strong selectivity of BRD4-BD2, and the selectivity of most of the examples is greater than 100 times.
  • the specific data is shown in Table 1.
  • Test Example 2 Test of the compound of the Example on MV4-11 cell proliferation inhibitory activity
  • the specific data is shown in Table 1.
  • Test Example 3 Tests of Example Compounds on Inhibitory Activities of Different Enzymes
  • Example 2 Using the similar BRD AlfaScreening method and the conventional test method of kinase inhibitors in Test Example 1, the compounds of some embodiments of the present invention were applied to different BRDs such as BRD2BD1 / 2, BRD3BD1 / 2 and BRD-T BD1 / 2 enzyme, HDAC, EZH2, LSD1
  • the inhibitory activities of G9a and other protein kinases such as EGFR, VEGFR, PDGFR, FGFR, RET, MET, Src, Lyn, Syk, MEK, CDK, RAF, etc. were also tested.
  • Some of the compounds of the examples are as in Examples 1 and 1. 2.
  • Examples 10, 12 and the like showed better BRD-BD2 selectivity and kinase target selectivity, with selectivity greater than 100-fold.
  • Example 1 shows higher selectivity for different BRD-BD1 / 2.
  • the specific data is shown in Table 2.
  • Test Example 4 Test of the compound of the Example for inhibiting the proliferation of different cell lines
  • Example 1 shows good proliferation inhibition activity on most AML cell lines and prostate cancer cell lines, and the inhibitory activity IC50 is less than 1000 nM, and some cell lines even Less than 100nM, such as LNCAP, SKM-1, MOLM13, KASUMI 1, THP-1, KG-1, etc .; and the IC50 of IEC6 and H1299 cell line proliferation inhibitory activity is greater than 1000nM, showing a higher selectivity of cell proliferation inhibition.
  • Metabolic stability test 150 microliters of liver microsomes (final concentration 0.5mg / mL) were used for metabolic stability incubation.
  • the system contains NADPH (final concentration 1mM), 1 ⁇ M test compound and positive control midazole Or negative control atenolol, the reaction was stopped with tinidazole-containing acetonitrile at 0min, 5min, 10min, and 30min, vortexed for 10min, centrifuged at 15000rmp for 10min, and 50 ⁇ L of the supernatant was injected in a 96-well plate.
  • the compound's metabolic stability was calculated by measuring the relative decrease of the original drug.
  • DI test Direct inhibition test: 100 ⁇ L of human liver microsomes (final concentration 0.2 mg / mL) were used for direct inhibition incubation. The system contained NADPH (final concentration 1 mM), 10 ⁇ M compound, and positive inhibitor cocktail.
  • the compounds of Examples 1, 2, 10, and 12 have high metabolic stability to liver microsomes of rats, mice, and dogs, with a half-life greater than 100 minutes, and IC 50 to the major metabolic enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 Both were larger than 15uM, showing higher drug-making properties.
  • the tumor tissue during the vigorous growth period was cut to about 1.5 mm 3 and inoculated subcutaneously in the right armpit of nude mice under sterile conditions.
  • Subcutaneously transplanted tumors in nude mice were measured with vernier calipers. The diameter of the transplanted tumors was measured, and the animals were randomly divided into groups until the average tumor volume reached about 130 mm 3 .
  • the compound of the example (configured with water for injection containing 1% Tween80 to a desired concentration for use) was orally administered daily at a given dose for three consecutive weeks, and the solvent control group was given the same amount of solvent.
  • the diameter of the transplanted tumor was measured twice a week, and the weight of the mice was weighed.
  • Some of the compounds of the examples of the present invention show a good effect of inhibiting tumor growth.
  • the oral administration was continued for 21 days, and the T / C was less than 30%, and mice are well tolerated.

Abstract

提供了一类稠杂环联芳基苄醇类化合物、制备方法和用途。所述稠杂环联芳基苄醇类化合物如式(IA)所示，其对BRD酶具有较好的抑制活性以及BRD/c-Myc相关的细胞增殖抑制活性相当优异。

Description

一类稠杂环联芳基苄醇类化合物、制备方法和用途
本申请要求申请日为2018年9月29日的中国专利申请201811144997.2的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物化学领域，具体地，涉及一类稠杂环联芳基苄醇类化合物、制备方法和用途。
背景技术
表观遗传调控的异常是导致肿瘤发生的重要因素之一。最新研究发现，BRD蛋白介导的表观遗传异常与癌基因的过表达密切相关，并与癌细胞的生长增殖关系密切。BRD4是BET蛋白家族的一员，由于在抗肿瘤方面的潜在价值，引起了各大制药公司和科研机构的极大关注。
BET蛋白也称为表观遗传识别蛋白，可以识别细胞组蛋白中的表观遗传学信息变化，并传递激发细胞***等的信号。以白血病为例，血细胞内BET蛋白的基因突变会干扰这种信号传输，导致病变细胞不受控制地***，从而损害人体的组织器官。BRD3/BRD4的溴结构域编码区与NUT(睾丸中的核蛋白)基因染色质易位形成BRD-NUT融合型原癌基因是中线癌的发病机理所在，也是目前BRD4蛋白参与肿瘤发病过程的直接证据。同时研究也发现，在造血***性癌症包括AML，Burkitt淋巴瘤，多发性骨髓瘤以及B细胞急性淋巴性白血病的模型中，通过干扰BRD4在MYC位点上的结合而直接将MYC沉默。由于已知各种MYC的异构体是细胞增殖和存活的重要调节因子，而且MYC是在许多癌症中过量表达的一个可能的癌基因，因此溴结构域拮抗性也首次为针对MYC驱动的肿瘤生成提供了一个作用机会。近期还发现BRD4在病毒基因的转录调控中也扮演了重要角色，并且与病毒瘤的发病机制存在一定联系。这些研究结果说明BRD4与多种肿瘤存在密切联系，尤其在一些至今难以治愈或者尚无有效治疗手段的肿瘤中具有重要作用，其与肿瘤关系的研究为肿瘤治疗提供了新的策略。通过作用于BRD4蛋白溴结构域的小分子化合物，干扰溴结构域与乙酰化赖氨酸的特异性结合，影响肿瘤细胞内的转录调节和其它细胞过程，可以实现对肿瘤的靶向治疗。
因此，BRD4蛋白是一个非常有前景的表观遗传新靶点，而作用于BRD4蛋白溴结构域的小分子抑制剂在肿瘤研究中也有着广阔的应用前景，而且有可能从中开发出新型抗肿瘤药物。已报道的BRD4蛋白的选择性抑制剂JQ1和IBET151，其晶体复合物表明此类小分子抑制剂正是结合在溴结构域的乙酰化赖氨酸识别口袋中，从而阻断了溴结构 域介导的乙酰化调控，这些抑制剂在几种癌症中的治疗作用已经得到了证实。目前，BRD4蛋白的小分子抑制剂结构类型少且选择性还不够突出，限制了人们对含溴结构域蛋白的生物功能及其在抗肿瘤潜力方面开展深入地研究。此外，现有BRD4蛋白抑制剂作用效果尚待提高、机制有待进一步阐明。因此，寻找高效、高选择性的新型小分子BRD-BD蛋白抑制剂是表观遗传抗肿瘤研究的一个热点。
发明内容
本发明提供了一种与现有技术不同的一类稠杂环联芳基苄醇类化合物、制备方法和用途。本发明的化合物对BRD酶具有较好的抑制活性以及BRD/c-MYc相关的细胞增殖抑制活性相当优异，因而可以用于治疗与BRD/c-MYc突变或表达量异常引起的相关疾病。
本发明通过以下技术方案解决上述技术问题。
本发明提供了一种具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，
Figure PCTCN2019109143-appb-000001
式中：R 1为氢、卤素、C 1-C 8烷基、3-8元环烃基或杂环烷基、或、5-8元的芳基或杂芳基；
R 2a和R 2b为氢、卤素、C 1-C 6的烷基、3-8元环烷基或杂环烷基、5-8元的芳基或杂芳基，或者R 2a和R 2b之间通过碳原子或者杂原子形成3-8元的饱和、不饱和或者部分不饱和的环系；
R 3为氢、卤素、硝基、氰基、烯基、炔基、C 1-C 8烷基、3-8元环烷基或杂环烷基、5-8元芳基或杂芳基、氨基、羟基、醚或硫醚、砜基或亚砜基、酯基、酰胺、磺酰胺、亚磺酰胺、脲、磺酰脲或亚磺酰脲；
R 4为卤素、C 1-C 8烷基、3-8元环烷基或杂环烷基、3-8元芳基或杂芳基、酯基、酰胺基、磺酰胺基、氨基、醚或硫醚、脲或磺酰脲；
X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、X 9、X 10和X 11独立地为N、C、NR a或CR a，每个R a独立地为氢、卤素、C 1-C 8烷基、3-8元环烷基或杂环烷基；
X 12为N或C；
上述的任一基团上的一个或多个氢原子可以被选自下组的取代基取代：氘、卤素、羟基、氨基或环氨基、氰基、硝基、砜基或亚砜基、C 1-C 8烷基、3-8元环烷基或杂环烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、烯基、炔基、酰基或磺酰基、脲或磺酰脲、5-8元芳基或杂芳基、R 3-1取代的6-18元的芳基、R 3-2取代的杂芳基、R 3-3取代的3-8元环烷基或R 4- 1取代的C 1-C 8烷基；
R 3-1、R 3-2和R 3-3独立地为卤素和/或C 1-C 4烷基；
R 4-1为卤素、甲磺酰基、C 1-C 4烷氧基、卤素取代的C 1-C 4烷氧基、3-8元环烷基、
Figure PCTCN2019109143-appb-000002
和R 4-1-2取代的3-8元环烷基中的一种或多种；R 4-1的个数为1个或多个；
R 4-1-1a和R 4-1-1b独立地为氢或C 1-C 4烷基；
R 4-1-2为C 1-C 4烷基或羟基；
其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O、P和S，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P和S，所述的环系独立地为螺环、桥环、稠环、并环或单环的饱和或部分不饱和的环系。
在一实施方式中，当R 1为C 1-C 8烷基时，所述的C 1-C 8烷基为C 1-C 4烷基，进一步可以为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，还进一步为甲基。
在一实施方式中，当R 2a和R 2b独立地为C 1-C 6烷基时，所述的C 1-C 6烷基为C 1-C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基)，进一步可为甲基。
在一实施方式中，当R 2a和R 2b独立地为C 1-C 6烷基、且C 1-C 6烷基上的一个或多个氢原子被取代基取代时，所述的C 1-C 6烷基为C 1-C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基)，进一步可为甲基。
在一实施方式中，当R 2a和R 2b独立地为C 1-C 6烷基、且C 1-C 6烷基上的一个或多个氢原子被取代基取代时，所述的取代基的个数为1个。
在一实施方式中，当R 2a和R 2b独立地为C 1-C 6烷基、且C 1-C 6烷基上的一个或多个氢原子被取代基取代时，所述的取代基为R 2a-1，所述的R 2a-1为卤素或羟基。
其中，当所述的R 2a-1为卤素时，所述的卤素可以为F、Cl、Br或I，还可以为F。
在一实施方式中，当R 2a和R 2b独立地为C 1-C 6烷基、且C 1-C 6烷基上的一个或多个氢原子被取代基取代时，所述的C 1-C 6烷基为
Figure PCTCN2019109143-appb-000003
在一实施方式中，当R 2a和R 2b之间通过杂原子形成3-8元的饱和的环系时，所述的 环系为3-5元的饱和的环系，还可以为4元的饱和的环系。
在一实施方式中，当R 2a和R 2b之间通过杂原子形成3-8元的饱和的环系时，所述的环系为单环系。
在一实施方式中，当R 2a和R 2b之间通过杂原子形成3-8元的饱和的环系时，所述的杂原子的种类为N、O、P和S中的一种或多种，可以为O。
在一实施方式中，当R 2a和R 2b之间通过杂原子形成3-8元的饱和的环系时，所述的杂原子的个数为1-3个，可为1个。
在一实施方式中，当R 2a和R 2b之间通过杂原子形成3-8元的饱和的环系时，所述的环系为
Figure PCTCN2019109143-appb-000004
在一实施方式中，当R 3为羟基，且羟基上的一个氢被被取代基取代时，所述的取代基为R 3-1a，所述的R 3-1a为5-8元的芳基、R3-1取代的6-18元的芳基、杂芳基、R 3-2取代的杂芳基、3-8元环烷基或R 3-3取代的3-8元环烷基。
其中，当R 3-1a为R 3-1取代的6-18元的芳基时，所述的6-18的芳基可以为6-14的芳基(苯基、萘基、蒽基或菲基)，进一步可以为苯基。
其中，当R 3-1a为R 3-1取代的6-18元的芳基时，所述R 3-1的个数可为1-3个，还可以为3个。
其中，当R 3-1为卤素时，所述的卤素可为F、Cl、Br或I，还可以为F。
其中，当R 3-1为C 1-C 4烷基时，所述的C 1-C 4烷基可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，还可以为甲基。
其中，当R 3-1a为R 3-1取代的6-18元的芳基时，所述的R 3-1取代的6-18元的芳基可为
Figure PCTCN2019109143-appb-000005
其中，当R 3-1a为R 3-2取代的杂芳基时，所述的杂芳基可为5-8元的杂芳基，还可为5元或6元的杂芳基。
其中，当R 3-1a为R 3-2取代的杂芳基时，所述的杂原子的种类可为N和/或S。
其中，当R 3-1a为R 3-2取代的杂芳基时，所述的杂原子的个数可为1个。
其中，当R 3-1a为R 3-2取代的杂芳基时，所述R 3-2的个数为1-3个，可以为3个。
其中，当R 3-2为卤素时，所述的卤素可为F、Cl、Br或I，还可以为F。
其中，当R 3-2为C 1-C 4烷基时，所述的C 1-C 4烷基可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，还可以为甲基。
其中，当R 3-1a为R 3-2取代的5-8元的杂芳基时，所述的R 3-2取代的5-8元的杂芳基 为
Figure PCTCN2019109143-appb-000006
其中，当R 3-1a为R 3-3取代的3-8元环烷基时，所述的3-8元环烷基可为3-6元环烷基，进一步可以为环己基。
其中，当R 3-1a为R 3-3取代的3-8元环烷基时，所述R 3-3的个数可为1-3个，还可以为1个。
其中，当R 3-3为C 1-C 4烷基时，所述的C 1-C 4烷基可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，还可以为甲基。
其中，当R 3-1a为R 3-3取代的3-8元环烷基时，所述的R 3-3取代的3-8元环烷基
Figure PCTCN2019109143-appb-000007
在一实施方式中，当R 3为羟基，且羟基上的一个氢被取代基取代时，所述的羟基为
Figure PCTCN2019109143-appb-000008
在一实施方式中，当R 4为杂芳基、且杂芳基上的一个或多个氢原子被取代基取代时，所述的杂原子的种类为N和/或O。
在一实施方式中，当R 4为杂芳基、且杂芳基上的一个或多个氢原子被取代基取代时，所述的杂原子的个数为1-3个，还可以为1或3个。
在一实施方式中，当R 4为杂芳基、且杂芳基上的一个或多个氢原子被取代基取代时，所述的3-8元杂芳基为3-6元杂芳基，还可为5或6元杂芳基。
在一实施方式中，当R 4为杂芳基、且杂芳基上的一个或多个氢原子被取代基取代时，所述的取代基的个数为1个。
在一实施方式中，当R 4为杂芳基、且杂芳基上的一个或多个氢原子被取代基取代时，所述的取代基为R 4-1a，所述的R 4-1a独立地为C 1-C 8烷基、R 4-1取代的C 1-C 8烷基、3-8元环烷基或杂芳基。
其中，当R 4-1a为C 1-C 8烷基时，所述的C 1-C 8烷基可为C 1-C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基)，还进一步可为甲基。
其中，当R 4-1a为R 4-1取代的C 1-C 8烷基时，所述的C 1-C 8烷基为C 1-C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基)，进一步可为甲基。
其中，当R 4-1为3-8元环烷基时，所述的3-8元环烷基可以为3-6元环烷基(环丙基、 环丁基、环戊基或环己基)，进一步可以为环丙基。
其中，当R 4-1a为R 4-1取代的C 1-C 8烷基时，所述的R 4-1取代的C 1-C 8烷基可以为
Figure PCTCN2019109143-appb-000009
其中，当R 4-1a为3-8元环烷基时，所述的3-8元环烷基可以为3-6元环烷基(例如环丙基、环丁基、环戊基或环己基)，进一步可以为环丙基。
其中，当R 4-1a为杂芳基时，所述的杂芳基可为5-8元杂芳基，还可以为5或6元杂芳基。
其中，当R 4-1a为杂芳基时，所述的杂原子的种类为O或N。
其中，当R 4-1a为杂芳基时，所述的杂原子的个数为1-3个，可以为2个或3个。
其中，当R 4-1a为杂芳基时，所述的杂芳基可为
Figure PCTCN2019109143-appb-000010
可以为
Figure PCTCN2019109143-appb-000011
在一实施方式中，当R 4为杂芳基、且杂芳基上的一个或多个氢原子被取代基取代时，所述的杂芳基为
Figure PCTCN2019109143-appb-000012
Figure PCTCN2019109143-appb-000013
还可以为
Figure PCTCN2019109143-appb-000014
在一实施方式中，当R 4为酰胺基，且酰胺基上的一个或多个氢原子被取代基取代时，所述的酰胺基为-C(＝O)NH-，其中，C端与
Figure PCTCN2019109143-appb-000015
相连，N端与取代基相连。
在一实施方式中，当R 4为酰胺基、且酰胺基上的一个或多个氢原子被取代基取代时，所述的取代基的个数为1个。
在一实施方式中，当R 4为酰胺基、且酰胺基上的一个或多个氢原子被取代基取代时，所述的取代基为R 4-2b，所述的R 4-2b为C 1-C 8烷基或R 4-1取代的C 1-C 8烷基。
其中，当所述的R 4-2b为C 1-C 8烷基或R 4-1取代的C 1-C 8烷基时，所述的C 1-C 8烷基可为C 1-C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基)， 进一步还可为甲基或乙基。
其中，R 4-1的个数可为1个。
其中，当R 4-1为卤素时，所述的卤素可为F、Cl、Br或I，还可以为F。
其中，当R 4-1为C 1-C 4烷氧基时，所述的C 1-C 4烷氧基可为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基，还可为甲氧基。
其中，当R 4-1为卤素取代的C 1-C 4烷氧基时，所述的C 1-C 4烷氧基可为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基，还可为甲氧基。
其中，当R 4-1为卤素取代的C 1-C 4烷氧基时，所述的卤素可为F、Cl、Br或I，还可以为F。
其中，当R 4-1为卤素取代的C 1-C 4烷氧基时，所述的卤素取代的C 1-C 4烷氧基为三氟甲氧基。
其中，当R 4-1为R 4-1-2取代的3-8元环烷基时，所述的3-8元环烷基可为3-6元环烷基(例如环丙基、环丁基、环戊基或环己基)，进一步可以为环丙基。
其中，当R 4-1为R 4-1-2取代的3-8元环烷基时，所述的R 4-1-2的个数可为1个。
其中，当R 4-1-2为C 1-C 4烷基时，所述的C 1-C 4烷基可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，还可为甲基。
其中，当R 4-1为R 4-1-2取代的3-8元环烷基时，所述的R 4-1-2取代的3-8元环烷基可为
Figure PCTCN2019109143-appb-000016
其中，当R 4-1-1a和R 4-1-1b独立地为C 1-C 4烷基时，所述的C 1-C 4烷基可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，还可为甲基。
其中，当所述的R 4-2b为R 4-1取代的C 1-C 8烷基时，所述的R 4-1取代的C 1-C 8烷基为
Figure PCTCN2019109143-appb-000017
在一实施方式中，当酰胺基、且酰胺基上的一个或多个氢原子被取代基时，所述的酰胺基为
Figure PCTCN2019109143-appb-000018
Figure PCTCN2019109143-appb-000019
还可以为
Figure PCTCN2019109143-appb-000020
Figure PCTCN2019109143-appb-000021
在一实施方式中，所述的环烷基为由碳原子和氢原子组成的稳定的非芳香族单环，且饱和。
在一实施方式中，所述的杂环基为为单环的环体系，其杂环基中的氮、碳或硫原子不被氧化，氮原子不被季铵化，且完全饱和。
在一实施方式中，所述的芳基不与环烷基或杂环基稠合。
在一实施方式中，所述的杂芳基不与环烷基或杂环基稠合，杂芳基中的氮、碳或硫原子不被氧化，氮原子不被季铵化。
在一实施方式中，R 1为C 1-C 8烷基。
在一实施方式中，R 2a和R 2b独立地为C 1-C 6的烷基、C 1-C 6的烷基上一个或多个氢原子任选地被R 2a-1取代的C 1-C 6的烷基、或者R 2a和R 2b之间通过碳原子或者杂原子形成3-8元的饱和、不饱和或者部分不饱和的环系，优选C 1-C 6的烷基。
在一实施方式中，R 3为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”、“氨基、且氨基上一个或多个氢原子被取代基取代的氨基”、或、“杂芳基、且杂芳基上一个或多个氢原子被取代基取代的杂芳基”，优选为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”。
在一实施方式中，当R 3为羟基，且羟基上的一个氢被被取代基取代时，所述的取代基为R 3-1a，所述的R 3-1a为R 3-1取代的6-18元的芳基。
在一实施方式中，R 4为杂环烷基、“杂环烷基、且杂环烷基上一个或多个氢原子被取代基取代的杂环烷基”、“酰胺、且酰胺基上一个或多个氢原子被取代基取代的酰胺”、“磺酰胺基、且磺酰胺基上一个或多个氢原子被取代基取代的磺酰基”、或、“C 1-C 8烷基、且C 1-C 8烷基上一个或多个氢原子被取代基取代的C 1-C 8烷基”，优选“酰胺、且酰胺基上一个或多个氢原子被取代基取代的酰胺”。
在一实施方式中，当R 4为“酰胺、且酰胺基上一个或多个氢原子被取代基取代的酰胺”时，所述的取代基为R 4-1a，所述的R 4-1a为C 1-C 8烷基或R 4-1取代的C 1-C 8烷基。
在一实施方式中，R 4-1为卤素、甲磺酰基、C 1-C 4烷氧基、
Figure PCTCN2019109143-appb-000022
或R 4-1-2取代的3-8元环烷基，优选卤素、C 1-C 4烷氧基或甲磺酰基，更优选卤素或C 1-C 4烷氧基。
在一实施方式中，X 1、X 9、X 10和X 11独立地为CH。
在一实施方式中，X 2为N或C，优选为N。
在一实施方式中，X 3和X 6独立地为C。
在一实施方式中，X 4为N。
在一实施方式中，X 5为CH或N，优选为N。
在一实施方式中，X 7和X 8其中一个为NH，另一个为CH。
在一实施方式中，X 12为C或N，优选为C。
在一实施方式中，所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物为如通式(IA)-1所示的化合物：
Figure PCTCN2019109143-appb-000023
其中，R 1为C 1-C 8烷基；
R 2a和R 2b独立地为C 1-C 6的烷基、“C 1-C 6烷基、且C 1-C 8烷基上一个或多个氢原子被取代基取代的C 1-C 6烷基”、或者R 2a和R 2b之间通过碳原子或者杂原子形成3-8元的饱和、不饱和或者部分不饱和的环系；
R 2a-1为卤素和/或羟基；
R 3为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”、和/或、“氨基、且氨基上一个或多个氢原子被取代基取代的氨基”；
R 4为杂环烷基、“杂环烷基、且杂环烷基上一个或多个氢原子被取代基取代的杂环烷基”、“酰胺基、且酰胺基上一个或多个氢原子被取代基取代的氨基酰胺基”、“磺酰胺基、且磺酰胺基上一个或多个氢原子被取代基取代的磺酰基”、或、“C 1-C 8烷基、且C 1-C 8烷基上一个或多个氢原子被取代基取代的C 1-C 8烷基”。
在一实施方式中，所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物为如通式(IA)-2所示的化合物：
Figure PCTCN2019109143-appb-000024
其中，R 1为C 1-C 8烷基；
R 2a和R 2b独立地为C 1-C 6的烷基；
R 3为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”，所述的取代基为R 3- 1a，所述的R 3-1a为5-8元的芳基、R 3-1取代的6-18元的芳基、杂芳基、R 3-2取代的杂芳基、3-8元环烷基或R 3-3取代的3-8元环烷基；
R 4为“杂环烷基、且杂环烷基上一个或多个氢原子被取代基取代的杂环烷基”、或、“酰胺基、且酰胺基上一个或多个氢原子被取代基取代的氨基酰胺基”；
所述的“杂环烷基、且杂环烷基上一个或多个氢原子被取代基取代的杂环烷基”中的取代基为R 4-1a，所述的R 4-1a为5-8元的杂芳基、C 1-C 8烷基、R 4-1取代的C 1-C 8烷基和3-8元环烷基中一种或多种；
所述的“酰胺基、且酰胺基上一个或多个氢原子被取代基取代的氨基酰胺基”中的取代基为R 4-2a，所述的R 4-2a为C 1-C 8烷基和/或R 4-1取代的C 1-C 8烷基；
R 4-1为卤素、甲磺酰基、C 1-C 4烷氧基、卤素取代的C 1-C 4烷氧基、3-8元环烷基、
Figure PCTCN2019109143-appb-000025
和R 4-1-2取代的3-8元环烷基中的一种或多种。
在一实施方式中，所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物为如通式(IA)-3所示的化合物：
Figure PCTCN2019109143-appb-000026
R 1为C 1-C 8烷基；
R 2a和R 2b独立地为C 1-C 6的烷基；
R 3为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”，所述的取代基为R 3- 1a，所述的R 3-1a为R 3-1取代的6-18元的芳基；R 3-1为卤素和/或C 1-C 4烷基；
R 4为“杂环烷基、且杂环烷基上一个或多个氢原子被取代基取代的杂环烷基”、或、“酰胺基、且酰胺基上一个或多个氢原子被取代基取代的酰胺基”；
所述的“杂环烷基、且杂环烷基上一个或多个氢原子被取代基取代的杂环烷基”中的取代基为R 4-1a，所述的R 4-1a为C 1-C 8烷基、R 4-1取代的C 1-C 8烷基、3-8元环烷基、杂芳基中的一种或多种；
所述的“酰胺基、且酰胺基上一个或多个氢原子被取代基取代的氨基酰胺基”中的取代基为R 4-2b，所述的R 4-2b为C 1-C 8烷基和/或R 4-1取代的C 1-C 8烷基；
R 4-1为卤素、甲磺酰基、C 1-C 4烷氧基、卤素取代的C 1-C 4烷氧基、3-8元环烷基、
Figure PCTCN2019109143-appb-000027
和R 4-1-2取代的3-8元环烷基中的一种或多种；R 4-1的个数为1个或多个；
R 4-1-1a和R 4-1-1b独立地为氢或C 1-C 4烷基；
R 4-1-2为C 1-C 4烷基或羟基；
X 7和X 8中一个为NH，另一个为CH。
在一实施方式中，所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物为如通式(IA)-3所示的化合物：
Figure PCTCN2019109143-appb-000028
R 1为C 1-C 8烷基；
R 2a和R 2b独立地为C 1-C 6的烷基；
R 3为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”，所述的取代基为R 3- 1取代的6-18元的芳基；R 3-1为卤素和/或C 1-C 4烷基；
R 4为“酰胺基、且酰胺基上一个或多个氢原子被取代基取代的酰胺基”；所述的取代基为为R 4-2b，所述的R 4-2b为C 1-C 8烷基和/或R 4-1取代的C 1-C 8烷基；
R 4-1为卤素、甲磺酰基、C 1-C 4烷氧基、3-8元环烷基、
Figure PCTCN2019109143-appb-000029
和R 4-1-2取代的3-8元环烷基中的一种或多种；R 4-1的个数为1个；
R 4-1-1a和R 4-1-1b独立地为氢或C 1-C 4烷基；
R 4-1-2为C 1-C 4烷基或羟基；
X 7和X 8中一个为NH，另一个为CH。
在一实施方式中，所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物为如通式(IA)-3所示的化合物：
Figure PCTCN2019109143-appb-000030
R 1为C 1-C 8烷基；
R 2a和R 2b独立地为C 1-C 6的烷基；
R 3为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”，所述的取代基为R3-1取代的6-18元的芳基；R 3-1为卤素和/或C 1-C 4烷基；
R 4为“酰胺基、且酰胺基上一个或多个氢原子被取代基取代的酰胺基”；
X 7和X 8中一个为NH，另一个为CH。
在一实施方式中，所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物为如通式(IA)-3所示的化合物：
Figure PCTCN2019109143-appb-000031
R 1为C 1-C 8烷基；
R 2a和R 2b独立地为C 1-C 6的烷基；
R 3为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”，所述的取代基为R3-1取代的6-18元的芳基；R 3-1为卤素和/或C 1-C 4烷基；
R 4为“酰胺基、且酰胺基上一个或多个氢原子被取代基取代的酰胺基”；所述的取代基为R 4-1取代的C 1-C 8烷基；
R 4-1为卤素、甲磺酰基、C 1-C 4烷氧基、
Figure PCTCN2019109143-appb-000032
或R 4-1-2取代的3-8元环烷基；
X 7和X 8中一个为NH，另一个为CH。
在一实施方式中，所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物为如通式(IA)-3所示的化合物：
Figure PCTCN2019109143-appb-000033
R 1为C 1-C 8烷基；
R 2a和R 2b独立地为C 1-C 6的烷基；
R 3为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”，所述的取代基为R 3- 1取代的6-18元的芳基；R 3-1为卤素和/或C 1-C 4烷基；
R 4为“酰胺基、且酰胺基上一个或多个氢原子被取代基取代的酰胺基”；所述的取代基为R 4-1取代的C 1-C 8烷基；
R 4-1为卤素、C 1-C 4烷氧基或甲磺酰基；
X 7和X 8中一个为NH，另一个为CH。
在一实施方式中，所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物为如通式(IA)-3所示的化合物：
Figure PCTCN2019109143-appb-000034
R 1为C 1-C 8烷基；
R 2a和R 2b独立地为C 1-C 6的烷基；
R 3为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”，所述的取代基为R3-1取代的6-18元的芳基；R 3-1为卤素和/或C 1-C 4烷基；
R 4为“酰胺基、且酰胺基上一个或多个氢原子被取代基取代的酰胺基”；所述的取代基为R 4-1取代的C 1-C 8烷基；
R 4-1为卤素或C 1-C 4烷氧基；
X 7和X 8中一个为NH，另一个为CH。
在一实施方式中，具有如通式(IA)所示的稠杂环联芳基苄醇类化合物为通式(IIA)、(IIB)、(IIC)、(IID)、(IIE)、(IIF)、(IIG)、(IIH)、(III)、(IIJ)、(IIK)、(IIL)、(IIM)、(IIN)、(IIO)、(IIP)、(IIQ)所示的化合物：
Figure PCTCN2019109143-appb-000035
Figure PCTCN2019109143-appb-000036
优选
Figure PCTCN2019109143-appb-000037
Figure PCTCN2019109143-appb-000038
更进一步优选
Figure PCTCN2019109143-appb-000039
Figure PCTCN2019109143-appb-000040
再更进一步优选
Figure PCTCN2019109143-appb-000041
在一实施方式中，如通式(IA)所示的稠杂环联芳基苄醇类化合物为如下任一化合物：
Figure PCTCN2019109143-appb-000042
Figure PCTCN2019109143-appb-000043
Figure PCTCN2019109143-appb-000044
本发明还提供了一种所述的如通式(IA)所示的稠杂环联芳基苄醇类化合物的制备方法，其包括以下步骤：
a)在金属催化剂存在下，将通式(A)化合物与硼酸片哪醇酯通过偶联反应转化成硼酸酯中间体(B)；和
b)在过渡金属催化剂存下，将步骤a中得到的式(B)化合物与式(C)化合物进行交叉偶联反应，得到通式(IA)化合物；
Figure PCTCN2019109143-appb-000045
步骤a的金属催化偶联反应和步骤b的交叉偶联反应中的条件和操作均可为本领域中此类反应常规的条件和操作，本发明特别优选以下条件和操作：
优选地，所述步骤a)和b)各自在溶剂中进行。所述溶剂选自水、醚类溶剂、醇类溶剂、芳烃类溶剂、氯代烃类溶剂、腈类溶剂、亚砜类溶剂、吡咯烷酮类溶剂和酰胺类溶剂中的一种或多种，更优选醚类溶剂和水，进一步更优选为二氧六环和水。其中，所述的醚类溶剂可以为乙二醇甲醚、四氢呋喃和二氧六环中的一种或多种，还可为二氧六环。所述的醇类溶剂可以为甲醇、乙醇、异丙醇、丁醇和乙二醇中的一种或多种。所述的芳烃类溶剂可以甲苯。所述的氯代烃类溶剂可以二氯甲烷和/或1，2-二氯乙烷。所述的腈类溶剂可以乙腈。所述的亚砜类溶剂可以为二甲基亚砜。所述的吡咯烷酮类溶剂可以为N-甲基吡咯烷酮。所述的酰胺类溶剂可以N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺。
优选地，所述的步骤a)和b)的反应各自在碱存在下进行碱存在下进行。所述碱可以为无机碱和/或有机碱，还可以为无机碱，进一步可以为碳酸钾。其中，所述的无机碱选自氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠和碳酸氢钠中的一种或多种。所述有机碱选自吡啶，三乙胺，N，N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠和二甲基吡啶中的一种和多种。
步骤a中，所述的金属催化剂可选自三(二亚苄基丙酮)二钯(Pd 2(dba) 3)、四(三苯基膦)钯(Pd(PPh 3) 4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯和1，2-二(二苯基膦基)乙烷二氯化钯中的一种或多种，还可以为[1,1'-双(二苯基膦基)二茂铁]二氯化钯。
步骤a中，所述的金属催化剂与所述的式(A)化合物的摩尔比可以为0.05：1～1.0:1，例如0.1、0.2。
步骤a中，所述的硼酸片哪醇酯与所述的式(A)化合物的摩尔比可以为5：1～1：1，例如1.5：1。
步骤a中，所述的式(B)化合物可以不经过后处理直接进行下步反应。
步骤b中，所述的过渡金属催化剂可选自三(二亚苄基丙酮)二钯(Pd 2(dba) 3)、四(三苯基膦)钯(Pd(PPh 3) 4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯和1，2-二(二苯基 膦基)乙烷二氯化钯中的一种或多种，还可以为[1,1'-双(二苯基膦基)二茂铁]二氯化钯。
步骤b中，所述的过渡金属催化剂与所述的式(A)化合物的摩尔比可以为0.05：1～1：1，例如0.1:1。
步骤b中，所述的交叉偶联反应还可以在配体存在进行，所述的配体可以为三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦和三邻苯甲基膦中的一种或多种，还可以为三苯基膦。所述的配体与所述的式(A)化合物的摩尔比可以为0.1:1～2：1，例如0.2：1。
步骤b中，所述的式(C)化合物与所述的式(A)化合物的摩尔比可以为0.8：1～2：1，例如1.5：1。
本发明还提供了一种药物组合物，其包括上述具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药、与药学上可接受的载体。
所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药的用量可为治疗有效量。
所述的药物组合物优选用于治疗或预防肿瘤。
本发明还提供了一种上述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药、或上述的药物组合物在制备药物中的应用。
本发明还提供了一种上述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药、或上述的药物组合物在制备药物中的应用，所述的药物用于防治和/或治疗与BRD、c-Myc蛋白活性或表达量相关的疾病。
所述的疾病可以为肿瘤、免疫性疾病和炎症性疾病中的一种或多种。
其中，所述的肿瘤选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌或胰腺癌，优选白血病或***癌。
其中，所述的免疫性疾病和炎症性疾病独立地选自移植器官的排斥反应、痛风、鼻炎、脱发、阿尔茨海默氏病、阑尾炎、动脉粥样硬化、哮喘、关节炎、过敏性皮炎、贝切特氏病、大疱性皮肤病、胆囊炎、慢性特发性血小板减少性紫癜、慢性阻塞性肺病、肝硬化、退行性关节病、皮肤炎、皮肌炎、湿疹、肠炎、脑炎、胃炎、肾炎、桥本氏甲状腺炎、肝炎、垂体炎、炎性肠病、肠易激综合征、川崎病、脑脊膜炎、多发性硬化、心肌炎、重症肌无力、蕈样真菌病、肌炎、肾炎、骨髓炎、胰腺炎、帕金森病、心包炎、恶性贫血、 肺炎、原发性胆汁性硬化性胆管炎、结节性多动脉炎、银屑病、纤维化、红斑狼疮、组织移植排斥、甲状腺炎、I型糖尿病、尿道炎、葡萄膜炎、血管炎、白癜风或瓦尔登斯特伦氏巨球蛋白血症。
本发明还提供了一种上述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药、或上述的药物组合物在制备药物中的应用，所述的药物用于防治和/或***、免疫性疾病和炎症性疾病中的一种或多种。
其中，所述的肿瘤、所述的免疫性疾病和所述的炎症性疾病中均同上所述。
本发明还提供了一种预防和/或治疗疾病的方法，所述的方法包括给予需要治疗对象有效量的上述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药、或上述的药物组合物；其中，所述的疾病为与BRD、c-Myc蛋白活性或表达量相关的疾病。
其中，所述的疾病同前所述。
本发明还提供了一种预防和/或治疗疾病的方法，所述的方法包括给予需要治疗对象有效量的上述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药、或上述的药物组合物；其中，所述的疾病为肿瘤、免疫性疾病和炎症性疾病中的一种或多种。
所述的方法中，所述的肿瘤、免疫性疾病和炎症性疾病均同前所述。
本发明涉及如通式(I)所示的稠杂环联芳基苄醇类化合物，可以抑制多种肿瘤细胞，尤其是能高效地杀死BRD/c-Myc等信号通路异常相关的肿瘤，比如白血病、***癌等，是一类全新作用机制的治疗药物。
在一实施方式中，一种具有如通式I所示的稠杂环联芳基苄醇类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，
Figure PCTCN2019109143-appb-000046
式中：
R 1独立地选自氢、卤素、C 1-C 8烷基、3-8元环烃基或杂环烷基和5-8元的芳基或杂芳基；
R 2a、R 2b分别独立地选自氢、卤素、C 1-C 6的烷基、3-8元环烷基或杂环烷基、5-8元的芳基或杂芳基，或者R 2a和R 2b之间可以通过碳原子或者杂原子形成3-8元的饱和、不饱和或者部分不饱和的环系。
R 3独立地选自氢，卤素，硝基、氰基、烯基、炔基、C 1-C 8烷基、3-8元环烷基或杂环烷基、3-8元芳基或杂芳基、氨基、羟基、醚或硫醚、砜基或亚砜基、酯基、酰胺、磺酰胺、亚磺酰胺、脲、磺酰脲、亚磺酰脲等；
R 4独立地选自卤素、C 1-C 8烷基、3-8元环烷基或杂环烷基、3-8元芳基或杂芳基、酯基、酰胺基、磺酰胺、氨基、醚或硫醚、脲或磺酰脲等；
X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、X 9、X 10、X 11分别独立地选自N、NRa或CRa,Ra选自氢，卤素，C 1-C 8烷基、C 3-C 8烷基环烷基或杂环烷基；
上述的任一基团上的一个或多个氢原子可以被选自下组的取代基取代：包括但不限于氘、卤素、羟基、氨基或环氨基、氰基、硝基、砜基或亚砜基、C 1-C 8烷基、3-8元环烷基或杂环烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、烯基、炔基、酰基或磺酰基、脲或磺酰脲、5～8元芳基或杂芳基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O、P或S，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P或S，所述的环系包含螺环、桥环、稠环、并环等饱和或部分不饱和的环系。
进一步的实施方式中，具有通式(I)所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，优选为通式(IIA)、(IIB)、(IIC)、(IID)、(IIE)、(IIF)、(IIG)、(IIH)、(III)、(IIJ)、(IIK)、(IIL)、(IIM)、(IIN)、(IIO)所示的化合物：
Figure PCTCN2019109143-appb-000047
Figure PCTCN2019109143-appb-000048
其中R 1、R 2a、R 2b、R 3、R 4、X 1、X 5、X 7、X 8、X 9、X 10、X 11如权利要求1中所定义。
更进一步的优选方式中，具有通式(1)所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于：
R 1优选自氢、氟、氯、甲基、乙基；
R 2a、R 2b分别独立地选自甲基、乙基、烷氧基甲基、环丙基甲基、卤代甲基等，或者R 2a和R 2b通过碳原子或者杂原子形成3-6元环系，优选自环丙基、环丁基、氧杂环丁基、环戊基等；
R 3优选自C 1-C 6的烷基醚或硫醚或氨基、3-8元的环烷基或杂环烷基醚或硫醚或氨基、5-8元的芳基或杂芳基醚或硫醚或氨基；进一步优选自：
Figure PCTCN2019109143-appb-000049
其中Rd选自氢、卤素、氰基、砜基、亚砜基、C1-C3的烷基或烷氧基，并且Rd跟苯环或环己烷环或另一个Rd取代基之间可以形成3-8元的饱和或部分不饱和的环系；n＝0～5，优选自2，3；
R 4优选自-CN、-COORb、-CONHRb、
Figure PCTCN2019109143-appb-000050
Figure PCTCN2019109143-appb-000051
其中Rb、Re分别独立地选自C1-C8的烷基或环烷基或杂环烷基、取代或未取代的5-6元的芳基或杂芳基等；
X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、X 9、X 10、X 11优选自N，CRa，其中Ra优选自氢，氟。
一种制备式I化合物的方法，其特征在于，所述方法包括步骤a-b：
a)将通式(A)化合物通过金属催化偶联反应转化成硼酸酯中间体(B)；和
b)将通式(B)化合物与中间体(C)在过渡金属催化剂存在的反应条件下进行交叉偶联反应，得到通式(I)化合物；
Figure PCTCN2019109143-appb-000052
所示各基团的定义如上所述；
优选地，所述步骤a)、b)各自在溶剂中进行，且所述溶剂选自下组：水、甲醇、乙醇、异丙醇、丁醇、乙二醇、乙二醇甲醚、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。
优选地，所述过渡金属催化剂选自下组：三(二亚苄基丙酮)二钯(Pd 2(dba) 3)、四(三苯基膦)钯(Pd(PPh 3) 4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯、1，2-二(二苯基膦基)乙烷二氯化钯，或其组合物；所述催化剂配体选自下组：三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦、三邻苯甲基膦，或其组合物。
优选地，所述无机碱选自下组：氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠，或其组合物；所述有机碱选自下组：吡啶，三乙胺，N，N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶，或其组合物。
本发明提供的一类通式(I)优选化合物，包括但不限于以下结构：
Figure PCTCN2019109143-appb-000053
Figure PCTCN2019109143-appb-000054
本发明的另一目的是提供一种治疗或预防肿瘤的药物及其组合物。实现上述目的的技术方案如下：
一种***的药物组合物，其由上述通式(I)所示的稠杂环联芳基苄醇类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药与药学上可接受的载体组成。
本发明的另一目的是提供一种上述化合物的用途。实现上述目的的技术方案如下：
所述通式(I)所示的稠杂环联芳基苄醇类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药用于制备治疗与BRD、c-Myc等蛋白活性或表达量相关的疾病的药物，特别是肿瘤、免疫性疾病和炎症性疾病的治疗药物。所述的肿瘤独立地选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌、胰腺癌等。所述的免疫性疾病和炎症性疾病独立地选自移植器官的排斥反应、痛风、鼻炎、脱发、阿尔茨海默氏病、阑尾炎、动脉粥样硬化、哮喘、关节炎、过敏性皮炎、贝切特氏病、大疱性皮肤病、胆囊炎、慢性特发性血小板减少性紫癜、慢性阻塞性肺病、肝硬化、退行性关节病、皮肤炎、皮肌炎、湿疹、肠炎、脑炎、胃炎、肾炎、桥本氏甲状腺炎、肝炎、垂体炎、炎性肠病、肠易激综合征、川崎病、脑脊膜炎、多发性硬化、心肌炎、重症肌无力、蕈样真菌病、肌炎、肾炎、骨髓炎、胰腺炎、帕金森病、心包炎、恶性贫血、肺炎、原发性胆汁性硬化性胆管炎、结节性多动脉炎、银屑病、纤维化、红斑狼疮、组织移植排斥、甲状腺炎、I型糖尿病、尿道炎、葡萄膜炎、血管炎、白癜风、瓦尔登斯特伦氏巨球蛋白血症等。
本发明涉及具有通式(I)结构特征的稠杂环联芳基苄醇类化合物，可以抑制多种肿瘤细胞，尤其是能高效地杀死BRD/c-Myc等信号通路异常相关的肿瘤，比如白血病、***癌等，是一类全新作用机制的治疗药物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合、从而构成新的或优选的技术方案。限于篇幅在此不再一一累述。
术语
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用 术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
在本申请中，术语“卤素”是指氟、氯、溴或碘；“羟基”是指-OH基团；“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基；“羰基”是指-C(＝O)-基团；“硝基”是指-NO 2；“氰基”是指-CN；“氨基”是指-NH 2；“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基；“羧基”是指-COOH。
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6 个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。
在本申请中，作为基团或是其它基团的一部分，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳 原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、***基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁***基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]***并[4,3-b]哒嗪、[1,2,4]***并[4,3-a]吡嗪、[1,2,4]***并[4,3-c]嘧啶、[1,2,4]***并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含 E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald G übitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、 胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型，本发明旨在包括各种晶型及其混合物。
通常，结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水，该情况下的溶剂化物为水合物。或者，溶剂可以是有机溶剂。因此，本发明的化合物可以以水合物存在，包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物，但在某些情况下，也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。
本发明还包括上述化合物的前药。在本申请中，术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此，术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时，前药可以不具有活性，但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化，而产生本发明的母体化合物，例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990；Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”，“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、 ***癌、肝癌、皮肤癌、上皮细胞癌、***、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物***的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基 或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
下面结合具体实施例、进一步阐述本发明。应理解、这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法、通常按照常规条件、或按照制造厂商所建议的条件。除非另外说明、否则百分比和份数是重量百分比和重量份数。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的化合物具有较好的BRD酶抑制活性，其IC 50可低至0.6nmol/L，并且对BRD/c-MYc相关的细胞增殖抑制活性相当优异，因而可以用于治疗与BRD/c-MYc突变或表达量异常引起的相关疾病如肿瘤。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
中间体A制备
中间体A1：6-溴-N-乙基-3-甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000055
第一步：将4-溴-7-氯-1-对甲苯磺酰基-1H-吡咯并[2,3-c]吡啶(500mg)溶于无水四氢呋喃(10mL)，冷却至-70度，加入二异丙基氨基锂LDA(1.3mL，1.5M四氢呋喃溶液)。升温至-40度，搅拌1.5小时，再冷却至-70度，加入氯甲酸乙酯ClCOOEt(211mg)。-70度下反应2小时。饱和氯化铵淬灭反应，乙酸乙酯萃取，干燥，减压浓缩，柱层析纯化得到4-溴-7-氯-1-对甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯(320mg,黄色固体)。 1H NMR(400MHz,DMSO-d 6):δ8.52(s,1H),8.18(d,J＝8.0Hz,2H),7.55(d,J＝8.0Hz,2H),7.51(s,1H),4.36(q,J＝7.2Hz,2H),2.45(s,3H),1.27(t,J＝7.2Hz,3H)。LC-MS(M+H) 456.7/458.7。
第二步：将4-溴-7-氯-1-对甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯(320mg)和氢氧化钠(280mg)溶于四氢呋喃/水(50mL/50mL)混合溶剂中，加热至50度反应过夜，减压浓缩除去大部分有机溶剂，2M稀盐酸酸化，有固体析出，过滤，干燥得到4-溴-7-氯-1H-吡咯并[2,3-c]吡啶-2-羧酸(白色固体)。LC-MS(M+H)274.7/276.7。
第三步：将4-溴-7-氯-1H-吡咯并[2,3-c]吡啶-2-羧酸(1.0g)加入到乙酰肼(10g)中。升温至150度,固体溶解，反应过夜。反应液冷却至室温，减压浓缩，柱层析纯化得到6-溴-3-甲基-9H-吡咯并[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-羧酸(450mg,白色固体)。LC-MS(M+H)295.1/297.1。
第四步：将6-溴-3-甲基-9H-吡咯并[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-羧酸(60mg，0.21mmol)，乙胺盐酸盐(34mg，0.42mmol)和2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)(160mg，0.42mmol)溶于N，N-二甲基甲酰胺(20mL)，加入N，N-二异丙基乙胺(82mg，0.63mmol)，室温下反应3小时，LCMS检测显示反应完全。乙酸乙酯稀释，饱和食盐水洗涤，干燥，减压浓缩，硅胶柱层析纯化得到中间体A1(20mg,黄色固体)。LC-MS(M+H)322.1/324.1。
中间体A2：6-溴-N-(2-(二甲胺基)乙基)-3-甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000056
操作同中间体A1，LC-MS(M+H)365.0/367.0。
中间体A3：6-溴-3-甲基-N-(2-(甲砜基)乙基)-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000057
操作同中间体A1，LC-MS(M+H)400.1/402.1。
中间体A4：6-溴-N-((1-羟基环丙基)甲基)-3-甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000058
操作同中间体A1，LC-MS(M+H)364.0/366.0。
中间体A5：6-溴-N-(2-甲氧基乙基)-3-甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000059
操作同中间体A1，LC-MS(M+H)352.2/354.2。
中间体A6：6-溴-N-(2,2-二氟丙基)-3甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000060
操作同中间体A1，LC-MS(M+H)372.0/374.0。
中间体A7：6-溴-N-(2,2-二氟乙基)-3甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000061
操作同中间体A1，LC-MS(M+H)372.0/374.0。
中间体A8：5-溴-N-乙基-3-甲基-8H-吡唑[1,5-a]吡咯[3,2-e]吡啶-7-酰胺
Figure PCTCN2019109143-appb-000062
以4-溴-1H-吡咯[2,3-b]吡啶为原料，参照专利WO2013127266A1、WO201711776A1和中间体A1的合成路线和方法，制备得到中间体A8，LC-MS(M+H)321.1/323.1。
中间体A9：6-溴-N-乙基-3-甲基吡咯[1,2-a][1,2,4]三氮唑[3,4-c]吡嗪-9-酰胺
Figure PCTCN2019109143-appb-000063
以5-溴-2-氯-3-甲基哌嗪为原料，参照专利WO201138086A2和中间体A1的合成路线和方法，制备得到中间体A9，LC-MS(M+H)322.1/324.1。
中间体A10：6-溴-N-乙基-3-甲基吡咯[1,2-c][1,2,4]三氮唑[4,3-a]嘧啶-8-酰胺
Figure PCTCN2019109143-appb-000064
以5-溴-4-甲基嘧啶-2(1H)-酮为原料，参照文献J.Med.Chem.1981,24,1455-1460和中间体A1的合成路线和方法，制备得到中间体A10，LC-MS(M+H)322.0/324.0。
中间体B制备
参照专利WO2017177955A1和WO2018068283A1的合成路线和方法，制备得到以下中间体。
中间体B1：2-(3-溴-4-(2,6-二甲基苯氧基)苯基)丙烷-2-醇
Figure PCTCN2019109143-appb-000065
LC-MS(M+H)335.2/337.2。
中间体B2：2-(3-溴-4-(4-氟-2,6-二甲基苯氧基)苯基)丙烷-2-醇
Figure PCTCN2019109143-appb-000066
1H NMR(CDCl 3,400MHz):δ7.74(d,J＝2.0Hz,1H),7.20(dd,J＝8.4Hz,J＝2.4Hz,1H),6.81(d,J＝8.4Hz,2H),6.30(d,J＝8.4Hz,1H),2.12(s,6H),1.55(s,6H)。LC-MS(M+H)353.0/355.0。
中间体B3：2-(3-溴-4-((4-甲基环己基)氧)苯基)丙烷-2-醇
Figure PCTCN2019109143-appb-000067
LC-MS(M+H)327.1/329.1。
实施例通用制备方法：
Figure PCTCN2019109143-appb-000068
将叔醇溴化物溶于无水二氧六环中，依次加入硼酸片哪醇酯(2eq.)，无水碳酸钾粉末(2.5eq.)和Pd(dppf)Cl 2(0.1eq.)，氮气保护下加热回流2小时。反应液冷却至室温，快速加入三并环溴化物(1.5eq.)和四三苯基膦钯Pd(PPh 3) 4(0.1eq.)，继续加热2小时。反应完毕，硅藻土过滤，乙酸乙酯洗涤，滤液浓缩。剩余物用二氯甲烷稀释，有机相依次用水，饱和碳酸氢钠溶液，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，剩余物用硅胶柱层析分离纯化得到目标化合物I。
实施例1：N-乙基-6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000069
第一步：将4-溴-7-氯-1H-吡咯并[2,3-c]吡啶-2-羧酸(190mg，0.7mmol)，乙胺盐酸盐(254mg，3.12mmol)和HATU(593mg，1.56mmol)溶于N,N-二甲基甲酰胺DMF(20mL)，加入二异丙基乙胺(DIEA)(536mg，4.16mmol)，室温下反应3小时，LCMS 检测显示反应完全。乙酸乙酯稀释，饱和食盐水洗涤，干燥，减压浓缩，硅胶柱层析纯化得到4-溴-7-氯-N-乙基-1H-吡咯并[2,3-c]吡啶-2-酰胺(130mg,黄色固体)。LC-MS(M+H)301.7/303.7。 1H-NMR(400MHz,DMSO-d6)δ12.82(s,1H),8.50(s,1H),8.13(s,1H),7.26(s,1H),3.35(q,J＝7.2Hz,2H),1.17(t,J＝7.2Hz,3H)。
第二步：将4-溴-7-氯-N-乙基-1H-吡咯并[2,3-c]吡啶-2-酰胺(130mg，0.43mmol)和乙酰肼(5.0g)混合，加热至150度反应48小时。反应液冷却至室温，甲醇溶解，柱层析纯化得到6-溴-N-乙基-3-甲基-9H-吡咯并[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺(51mg,白色固体)。LC-MS(M+H)321.8/323.8。 1H-NMR(400MHz,DMSO-d6)δ13.33(s,1H),8.50(t,J＝5.2Hz,1H),8.33(s,1H),7.22(d,J＝1.6Hz,1H),3.32(q,J＝7.2Hz,2H),2.68(s,3H),1.16(t,J＝7.2Hz,3H)。
第三步：将6-溴-N-乙基-3-甲基-9H-吡咯并[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺(40mg，0.12mmol)，(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)硼酸(158mg，0.5mmol)，XPhos(12mg，0.025mmol)，Pd 2(dba) 3(11mg，0.012mmol)，Xphos Pd G3(11mg，0.012mmol)和碳酸钠(52mg，0.50mmol)溶于乙醇/水(10mL/0.4mL)，氮气保护，加热至80度反应过夜。反应液冷却至室温，乙酸乙酯稀释，饱和食盐水洗涤，干燥，减压浓缩，制备色谱纯化得到N-乙基-6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺(10mg,白色固体)。LC-MS(M+H)516.2。 1H-NMR(400MHz,CD 3OD)δ7.99(s,1H),7.72(d,J＝2.4Hz,1H),7.45(dd,J＝2.4,8.8Hz,1H),7.15(s,1H),6.85(d,J＝9.2Hz,2H),6.48(d,J＝8.4Hz,1H),3.44(q,J＝7.2Hz,2H),2.81(s,3H),2.09(s,6H),1.59(s,6H),1.24(t,J＝7.2Hz,3H)。
实施例2：N-乙基-6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基-7H-吡咯[3,2-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000070
第一步：将化合物7-溴-4-羟基-1H-吡咯并[3,2-c]吡啶-2-羧酸(623mg,2.4mmol)溶于DMF(10mL)，加入HATU(1.4g,3.6mmol)和DIEA(619mg,4.8mmol)，室温下搅拌5分钟，再加入乙胺(2M in THF,2.4mL,4.8mmol)，室温下反应过夜。LCMS检测显示反应完全，乙酸乙酯稀释，饱和食盐水洗涤，干燥，减压浓缩，硅胶柱层析纯化得到7-溴-N-乙基-4-羟基-1H-吡咯并[3,2-c]吡啶-2-酰胺(695mg,白色固体)。LC-MS(M+H)284.0/286.0。
第二步：将7-溴-N-乙基-4-羟基-1H-吡咯并[3,2-c]吡啶-2-酰胺(695mg，2.4mmol)溶于三氯氧磷POCl 3(6mL)，加热至80度反应2小时，反应液冷却至室温，减压浓缩，柱层析纯化得到7-溴-4-氯-N-乙基-1H-吡咯并[3,2-c]吡啶-2-酰胺(340mg,黄色固体)。 LC-MS(M+H)302.2/304.2。
第三步：将7-溴-4-氯-N-乙基-1H-吡咯并[3,2-c]吡啶-2-酰胺(320mg，1.1mmol)混悬于乙酰肼(5g)中，加热至150度反应4小时，反应液冷却至室温，倒入冷水中，乙酸乙酯萃取，合并有机相，干燥，减压浓缩，柱层析纯化得到6-溴-N-乙基-3-甲基-7H-吡咯并[3,2-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺(39mg,黄色固体)。LC-MS(M+H)322.2/324.2。
第四步：将6-溴-N-乙基-3-甲基-7H-吡咯并[3,2-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺(10mg,0.033mmol)，(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)硼酸(13mg,0.041mmol)，XPhos(1.6mg,0.0033mmol)，XPhos Pd G3(2.6mg,0.0033mmol)和碳酸钠(7mg,0.066mmol)溶于乙醇/水(2mL/0.2mL)，氮气保护，微波加热至100度反应1小时。反应液冷却至室温，减压浓缩，柱层析纯化得到N-乙基-6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基-7H-吡咯[3,2-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺(5.3mg,白色固体)。LC-MS(M+H)516.5。 1H-NMR(400MHz,CD 3OD)δ8.09(s,1H),7.72(d,J＝2.0Hz,1H),7.62(s,1H),7.51(dd,J＝2.0,8.4Hz,1H),6.81(d,J＝8.8Hz,2H),6.50(d,J＝8.4Hz,1H),3.42(q,J＝7.2Hz,2H),2.79(s,3H),2.08(s,6H),1.59(s,6H),1.24(t,J＝7.2Hz,3H)。
实施例3：N-乙基-6-(5-(2-羟基丙基-2-基)-2-((4-甲基环己基)氧代)苯基)-3-甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000071
操作同实施例1，1H-NMR(400MHz,CD3OD)δ7.96(s,1H),7.70(d,J＝2.4Hz,1H),6.49(d,J＝8.4Hz,1H),4.32–4.25(m,1H),3.41(q,J＝7.2Hz,2H),2.79(s,3H),2.12-2.06(m,2H),1.80-1.74(m,2H),1.56(s,6H),1.53-1.47(m,2H),1.43-1.39(m,1H),1.25(t,J＝7.2Hz,3H),1.07-0.95(m,2H),0.86(d,J＝6.4Hz,3H)；LC-MS(M+H)490.3。
实施例4：N-乙基-6-(5-(2-羟基丙基-2-基)-2-((4-甲基环己基)氧代)苯基)-3-甲基-7H-吡咯[3,2-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000072
操作同实施例2，LC-MS(M+H)490.1。 1H-NMR(400MHz,CD 3OD)δ8.06(s,1H),7.72(d,J＝2.0Hz,1H),7.62(s,1H),6.81(d,J＝8.8Hz,2H),4.32-4.25(m,1H),3.43(q,J＝7.2Hz,2H),2.79(s,3H),2.11-2.06(m,2H),1.80-1.74(m,2H),1.58(s,6H),1.54-1.46(m,2H),1.42-1.38(m,1H),1.23(t,J＝7.2Hz,3H),1.07-0.95(m,2H),0.86(d,J＝6.4Hz,3H)。
实施例5：2-(4-(4-氟-2,6-二甲基苯氧基)-3-(3-甲基-8-(5-(吡啶-2-基)-1,2,4-氧杂二氮唑-3-基)-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-6-基)苯基)丙基-2-醇
Figure PCTCN2019109143-appb-000073
以中间体A1为原料，参照专利WO201666742A1的1,2,4-氧杂二氮唑闭环方法及通用制备方法一，制备得到实施例5，LC-MS(M+H)590.2。
实施例6：2-(4-(4-氟-2,6-二甲基苯氧基)-3-(3-甲基-8-(5-(吡啶-2-yl)-1,3,4-氧杂二氮唑-2-基)-7H-吡咯[3,2-c][1,2,4]三氮唑[4,3-a]吡啶-6-基)苯基)丙基-2-醇
Figure PCTCN2019109143-appb-000074
以中间体A1为原料，参照专利WO201485296A1的1,3,4-氧杂二氮唑闭环方法及通用制备方法一，制备得到实施例6，LC-MS(M+H)590.1。
实施例7：N-(2-(二甲基胺基)乙基)-6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000075
操作同实施例1，LC-MS(M+H)559.3。 1H-NMR(400MHz,CD 3OD)δ7.99(s,1H),7.70(d,J＝2.0Hz,1H),7.43(dd,J＝2.4,8.8Hz,1H),7.16(s,1H),6.84(d,J＝8.8Hz,2H),6.47(d,J＝8.8Hz,1H),3.70(t,J＝6.0Hz,2H),3.15(br s,2H),2.79-2.80(m,9H),2.07(s,6H),1.57(s,6H)。
实施例8：6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基-N-(2-(甲基砜基)乙基)-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000076
操作同实施例1，LC-MS(M+H)594.5。 1H-NMR(400MHz,CD 3OD)δ7.98(s,1H),7.68(d,J＝2.4Hz,1H),7.43(dd,J＝2.4,8.8Hz,1H),7.11(s,1H),6.83(d,J＝8.8Hz,2H),6.46(d,J＝8.8Hz,1H),3.85(t,J＝6.4Hz,2H),3.39-3.44(m,2H),3.03(s,3H),2.79(s,3H),2.07(s,6H),1.57(s,6H)。
实施例9：6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-N-((1-羟基环丙基)甲基)-3-甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000077
操作同实施例1，LC-MS(M+H)558.3。 1H-NMR(400MHz,CD 3OD)δ7.98(s,1H),7.70(d,J＝2.4Hz,1H),7.43(dd,J＝2.4,8.8Hz,1H),7.20(s,1H),6.83(d,J＝9.2Hz,2H),6.46(d,J＝8.8Hz,1H),3.55(s,2H),2.79(s,3H),2.08(s,6H),1.57(s,6H),0.68-0.73(m,4H)。
实施例10：6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-N-(2-甲氧基乙基)-3-甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000078
操作同实施例1，LC-MS(M+H)546.5。 1H-NMR(400MHz,CD 3OD)δ7.97(s,1H),7.70(d,J＝2.4Hz,1H),7.43(dd,J＝2.4,8.8Hz,1H),7.15(s,1H),6.82(d,J＝8.8Hz,2H),6.46(d,J＝8.8Hz,1H),3.57(br s,2H),3.37(s,3H),3.31(t,J＝1.6Hz,2H),2.79(s,3H),2.07(s,6H),1.57(s,6H)。
实施例11：N-(2,2-二氟丙基)-6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000079
操作同实施例1，LC-MS(M+H)566.3。 1H-NMR(400MHz,CD 3OD)δ7.98(s,1H),7.69(d,J＝2.4Hz,1H),7.43(d,J＝8.4Hz,1H),7.22(s,1H),6.83(d,J＝9.2Hz,2H),6.46(d,J＝8.8Hz,1H),3.78(t,J＝13.2Hz,2H),2.79(s,3H),2.07(s,6H),1.63(t,J＝18.4Hz,3H),1.57(s,6H)。
实施例12：N-(2,2-二氟乙基)-6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000080
操作同实施例1，LC-MS(M+H)552.4。 1H-NMR(400MHz,CD 3OD)δ7.98(s,1H),7.70(d,J＝2.0Hz,1H),7.43(dd,J＝2.4,8.8Hz,1H),7.18(s,1H),6.83(d,J＝8.8Hz,2H),6.46(d,J＝8.8Hz,1H),5.85-6.14(m,1H),3.78(dt,J＝4.0,14.8Hz,2H),2.79(s,3H), 2.07(s,6H),1.57(s,6H)。
实施例13：6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基-N-(2-(三氟甲氧基)乙基)-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺
Figure PCTCN2019109143-appb-000081
第一步：将中间体A1(40mg，0.13mmol)，(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)硼酸(57mg，0.14mmol)，X-Phos(6mg，0.013mmol)，XPhos Pd G3(10mg，0.013mmol)，Pd 2(dba) 3(12mg，0.013mmol)和碳酸钠(Na 2CO 3)(28mg，0.26mmol)溶于乙醇/水(EtOH/H 2O)(2mL，体积比10/1)中，氮气N 2置换，油浴升温至85度反应过夜。LCMS检测显示反应完全，反应液冷却至室温，减压浓缩，剩余物硅胶柱层析纯化得到6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙烷-2-基)苯基)-3-甲基-9H-吡咯并[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-羧酸甲酯(14mg,白色固体)。LC-MS(M+H)503.1。
第二步：向6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙烷-2-基)苯基)-3-甲基-9H-吡咯并[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-羧酸甲酯(14mg，0.029mmol)的EtOH/H 2O(1mL，10/1)溶液中加入氢氧化钠(NaOH)(3.5mg，0.087mmol)。室温反应过夜。减压浓缩，柱层析纯化得到6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙烷-2-基)苯基)-3-甲基-9H-吡咯并[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-羧酸(10mg,白色固体)。LC-MS(M+H)489.1。
第三步：将6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙烷-2-基)苯基)-3-甲基-9H-吡咯并[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-羧酸(10mg，0.024mmol)，2-(三氟甲氧基)乙胺盐酸盐(8mg，0.048mmol)和HATU(28mg，0.072mmol)溶于DMF(1mL)，加入DIEA(16mg，0.120mmol)，室温反应2h。甲醇稀释，制备色谱纯化得到6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基-N-(2-(三氟甲氧基)乙基)-9H-吡咯[2,3-c][1,2,4]三氮唑[4,3-a]吡啶-8-酰胺(白色固体)。LC-MS(M+H)600.3。
实施例14：N-乙基-5-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基-8H-吡唑[1,5-a]吡咯[3,2-e]吡啶-7-酰胺
Figure PCTCN2019109143-appb-000082
以中间体A2为原料，通过通用制备方法一，制备得到实施例14，LC-MS(M+H)515.4。
实施例15：N-乙基-6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基吡咯[1,2-a][1,2,4]三氮唑[3,4-c]哌嗪-9-酰胺
Figure PCTCN2019109143-appb-000083
以中间体A4为原料，通过通用制备方法一，制备得到实施例15，
LC-MS(M+H)516.4。
实施例16：N-乙基-6-(2-(4-氟-2,6-二甲基苯氧基)-5-(2-羟基丙基-2-基)苯基)-3-甲基吡咯[1,2-c][1,2,4]三氮唑[4,3-a]嘧啶-8-酰胺
Figure PCTCN2019109143-appb-000084
以中间体A5为原料，通过通用制备方法一，制备得到实施例16，LC-MS(M+H)516.4。
测试例1BRD4AlphaScreen测定
1、在测试板中进行BRD4-BD1和BRD4-BD2测定，BD1的最终体积为20μL，BD2的最终体积为40μL。首先，将抑制剂在二甲基亚砜(DMSO)中系列稀释，并加至平板孔，然后加入其他反应成分。测定中DMSO的最终浓度是1.25％(BD1)和0.83％(BD2)。在含有50nM生物素标记的四乙酰化组蛋白H4肽(H4Ac4)、3.8nM(BRD4-BD1)或20nM(BRD4-BD2)的测定缓冲液(50mM HEPES，pH 7.4,100mM NaCl,0.05％CHAPS,0.01％BSA)中，在室温下进行75分钟测定。反应后，加入补充有4μg/mL链霉亲和素供体珠和GSH受体珠的20μL测定缓冲液，在弱光照下。平板密封后，将平板在室温下暗处孵育75分钟，然后在PHERAstar FS读板仪(BMG Labtech)上读数。通过对照活性％对比抑制剂浓度的对数的拟合曲线，使用GraphPad Prism5.0软件进行IC50测定。
2.结果:本发明提供的部分如实施例1-实施例13，其对BRD4-BD2的抑制活性IC 50值均IC 50小于100nM，部分实施例的抑制活性甚至IC 50小于10nM，而对BRD4-BD1的抑制活性较弱，IC 50值均IC 50大于100nM，显示了较强的BRD4-BD2选择性，绝大部分实施例的选择性大于100倍。具体数据如表一所示。
测试例2：实施例化合物对MV4-11细胞增殖抑制活性的测试
具体实验步骤：1)Day 0:96接种细胞胰酶消化细胞并悬浮于细胞培养液中，利用细胞自动计数仪检测细胞密度并用培养液稀释细胞到合适的密度，96孔板中加入100μl细胞悬液，无细胞培养基作为对照孔，置于37℃，5％CO2的细胞培养箱孵育过夜；2)Day1:加药处理细胞待测化合物共测试8个浓度，3倍稀释，10μM为待测化合物的起始检测浓度。具体步骤：配置200x化合物母液，利用培养基稀释化合物至3x终浓度即加入3μl200x化合物到197μl培养液中，96孔板中的细胞每孔加入50μl稀释好的化合物，置于37℃，5％CO2的细胞培养箱孵育72h；3)Day 4:细胞活力检测细胞96孔板先平衡到室温，每孔加入40μl的
Figure PCTCN2019109143-appb-000085
试剂，摇床上混合2分钟使细胞充***解，室温孵育 10分钟稳定发光信号，Envision酶标仪读取发光值；4)数据处理使用GraphPad Prism 5.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC50值。抑制率％＝(DMSO处理细胞孔-化合物处理细胞孔)/(DMSO处理细胞孔-无细胞培养基孔)x 100。IC50值采用酶标仪随机附带软件以四参数法回归求得。
2.结果:本发明提供的部分实施例如实施例1-实施例13对MV4-11细胞的增殖抑制活性，绝大部分实施例的IC 50值均小于500nM，部分实施例化合物的抑制活性IC 50值甚至小于100nM,显示了较强的细胞增殖抑制活性。具体数据如表一所示。
表一、本发明实施例化合物对BRD4-BD 1/2和MV4-11细胞增殖抑制活性
Figure PCTCN2019109143-appb-000086
测试例3：实施例化合物对不同酶抑制活性的测试
采用测试例1类似的BRD AlfaScreening方法以及激酶抑制剂常规测试方法，将本发明部分实施例化合物对不同BRD如BRD2BD1/2，BRD3BD1/2和BRD-T BD1/2酶、HDAC、EZH2、LSD1、G9a等以及不同蛋白激酶如EGFR、VEGFR、PDGFR、FGFR、RET，MET，Src，Lyn、Syk、MEK、CDK、RAF等的抑制活性也进行了测试，部分实施例化合物如实施例1、实施例2、实施例10、实施例12等显示了较好的BRD-BD2选择性和激酶靶点选择性，选择性大于100倍。特别如实施例1对不同BRD-BD1/2均显示了较高的选择性。具体数据如表二所示。
表二：部分实施例化合物对不同酶抑制活性测试
Figure PCTCN2019109143-appb-000087
Figure PCTCN2019109143-appb-000088
测试例4：实施例化合物对不同细胞株增殖抑制活性的测试
采用测试例2类似的方法测试了部分实施例化合物对不同细胞株如LNCAP、SKM-1、22RV1、DU145、MOLM13、MDA-PCA-2b、KASUMI 1、THP-1、KG-1、IEC6、H1299等的增殖抑制活性。部分实施例如实施例1、实施例2、实施例10、实施例12等对大部分AML细胞株和***癌细胞株显示了较好的增殖抑制活性，抑制活性IC50均小于1000nM，部分细胞株甚至小于100nM，如LNCAP、SKM-1、MOLM13、KASUMI 1、THP-1、KG-1等；而对IEC6和H1299细胞株的增殖抑制活性IC50大于1000nM,显示了较高的细胞增殖抑制选择性。
测试例5：部分实施例化合物的ADME测试
(1)代谢稳定性试验：用体系为150μL的肝微粒体(终浓度0.5mg/mL)进行代谢稳定性温孵，体系含NADPH(终浓度1mM)、1μM受试化合物和阳性对照咪达***或阴性对照阿替洛尔，分别在0min、5min、10min和30min用含替硝唑的乙腈终止反应，涡旋10min，15000rmp离心10min，取50μL上清于96孔板中进样。通过测定原药的相对减少量计算化合物代谢稳定性。
(2)直接抑制试验(DI试验)：用体系为100μL的人肝微粒体(终浓度0.2mg/mL)进行直接抑制温孵，体系含NADPH(终浓度1mM)、10μM化合物、阳性抑制剂cocktail(酮康唑10μM，奎尼丁10μM，磺胺苯吡唑100μM，α-萘黄酮10μM，反苯环丙胺1000μM)、阴性对照(0.1％DMSO的BPS)和混合探针底物(咪达***10μM、睾酮100μM、右美沙芬10μM、双氯芬酸20μM、非那西丁100μM，美芬妥英100μM)，温孵20min后终止反应。通过测定代谢物的相对生成量计算酶相对活性。
实施例化合物1、2、10、12对大鼠、小鼠、犬的肝微粒体代谢稳定性高，半衰期大于100min，并且对主要代谢酶CYP1A2、2C8、2C9、2C19、2D6、3A4的IC 50均大于15uM，显示了较高的成药性。
测试例6：部分实施例化合物对MV4-11裸小鼠移植瘤生长抑制的测试
取生长旺盛期的瘤组织剪切成1.5mm 3左右，在无菌条件下，接种于裸小鼠右侧腋窝皮下。裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径，待肿瘤平均体积至130mm 3左右将动物随机分组。实施例化合物(用含1％Tween80的注射用水配置到所需浓度后待用)以给定剂量每天口服给药，连续给药三周，溶剂对照组给等量溶剂。整个实验过程中，每周2次 测量移植瘤直径，同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为：TV＝1/2×a×b 2，其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为1)相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：阴性对照组RTV；2)肿瘤体积增长抑制率GI％，计算公式如下：GI％＝[1-(TVt-TV0)/(CVt-CT0)]×100％，TVt为治疗组每次测量的瘤体积；TV0为治疗组分笼给药时所得瘤体积；CVt为对照组每次测量的瘤体积；CV0为对照组分笼给药时所得瘤体积；3)瘤重抑制率，计算公式如下：瘤重抑制率％＝(Wc-W T)/Wc×100％，Wc：对照组瘤重，W T：治疗组瘤重。
本发明部分实施例化合物显示了较好的抑制肿瘤生长的效果，如实施例1、2、10、12等在5～50mg/kg/day剂量下，连续口服给药21天，T/C小于30％，并且小鼠耐受性良好。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (20)

  1. 一种具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，
    Figure PCTCN2019109143-appb-100001
    式中：R 1为氢、卤素、C 1-C 8烷基、3-8元环烃基或杂环烷基、或、5-8元的芳基或杂芳基；
    R 2a和R 2b为氢、卤素、C 1-C 6的烷基、3-8元环烷基或杂环烷基、5-8元的芳基或杂芳基，或者R 2a和R 2b之间通过碳原子或者杂原子形成3-8元的饱和、不饱和或者部分不饱和的环系；
    R 3为氢、卤素、硝基、氰基、烯基、炔基、C 1-C 8烷基、3-8元环烷基或杂环烷基、5-8元芳基或杂芳基、氨基、羟基、醚或硫醚、砜基或亚砜基、酯基、酰胺、磺酰胺、亚磺酰胺、脲、磺酰脲或亚磺酰脲；
    R 4为卤素、C 1-C 8烷基、3-8元环烷基或杂环烷基、3-8元芳基或杂芳基、酯基、酰胺基、磺酰胺基、氨基、醚或硫醚、脲或磺酰脲；
    X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、X 9、X 10和X 11独立地为N、C、NR a或CR a，每个R a独立地为氢、卤素、C 1-C 8烷基、3-8元环烷基或杂环烷基；
    X 12为N或C；
    上述的任一基团上的一个或多个氢原子可以被选自下组的取代基取代：氘、卤素、羟基、氨基或环氨基、氰基、硝基、砜基或亚砜基、C 1-C 8烷基、3-8元环烷基或杂环烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、烯基、炔基、酰基或磺酰基、脲或磺酰脲、5-8元芳基或杂芳基、R 3-1取代的6-18元的芳基、R 3-2取代的杂芳基、R 3-3取代的3-8元环烷基或R 4- 1取代的C 1-C 8烷基；
    R 3-1、R 3-2和R 3-3独立地为卤素和/或C 1-C 4烷基；
    R 4-1为卤素、甲磺酰基、C 1-C 4烷氧基、卤素取代的C 1-C 4烷氧基、3-8元环烷基、
    Figure PCTCN2019109143-appb-100002
    和R 4-1-2取代的3-8元环烷基中的一种或多种；R 4-1的个数为1个或多个；
    R 4-1-1a和R 4-1-1b独立地为氢或C 1-C 4烷基；
    R 4-1-2为C 1-C 4烷基或羟基；
    其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O、P和S，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P和S，所述的环系包含螺环、桥环、稠环、并环或单环的饱和或部分不饱和的环系。
  2. 如权利要求1所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，其特征在于，当R 1为C 1-C 8烷基时，所述的C 1-C 8烷基为C 1-C 4烷基，进一步可为甲基；
    和/或，当R 2a和R 2b独立地为C 1-C 6烷基时，所述的C 1-C 6烷基为C 1-C 4烷基，进一步可为甲基；
    和/或，当R 2a和R 2b独立地为C 1-C 6烷基、且C 1-C 6烷基上的一个或多个氢原子被取代基取代时，所述的C 1-C 6烷基为C 1-C 4烷基，进一步可为甲基；
    和/或，当R 2a和R 2b独立地为C 1-C 6烷基、且C 1-C 6烷基上的一个或多个氢原子被取代基取代时，所述的取代基的个数为1个；
    和/或，当R 2a和R 2b独立地为C 1-C 6烷基、且C 1-C 6烷基上的一个或多个氢原子被取代基取代时，所述的取代基为R 2a-1，所述的R 2a-1为卤素或羟基；
    和/或，当R 2a和R 2b之间通过杂原子形成3-8元的饱和的环系时，所述的环系为3-5元的饱和的环系，还可以为4元的饱和的环系；
    和/或，当R 2a和R 2b之间通过杂原子形成3-8元的饱和的环系时，所述的环系为单环系；
    和/或，当R 2a和R 2b之间通过杂原子形成3-8元的饱和的环系时，所述的杂原子的种类为N、O、P和S中的一种或多种，可以为O；
    和/或，当R 2a和R 2b之间通过杂原子形成3-8元的饱和的环系时，所述的杂原子的个数为1-3个，可为1个；
    和/或，当R 3为羟基，且羟基上的一个氢被被取代基取代时，所述的取代基为R 3-1a，所述的R 3-1a为5-8元的芳基、R3-1取代的6-18元的芳基、杂芳基、R 3-2取代的杂芳基、3-8元环烷基或R 3-3取代的3-8元环烷基；
    和/或，当R 4为杂芳基、且杂芳基上的一个或多个氢原子被取代基取代时，所述的杂原子的种类为N和/或O；
    和/或，当R 4为杂芳基、且杂芳基上的一个或多个氢原子被取代基取代时，所述的杂原子的个数为1-3个，还可以为1或3个；
    和/或，当R 4为杂芳基、且杂芳基上的一个或多个氢原子被取代基取代时，所述的3-8元杂芳基为3-6元杂芳基，还可为5或6元杂芳基；
    和/或，当R 4为杂芳基、且杂芳基上的一个或多个氢原子被取代基取代时，所述的取代基的个数为1个；
    和/或，当R 4为杂芳基、且杂芳基上的一个或多个氢原子被取代基取代时，所述的取代基为R 4-1a，所述的R 4-1a独立地为C 1-C 8烷基、R 4-1取代的C 1-C 8烷基、3-8元环烷基或杂芳基；
    和/或，当R 4为酰胺基、且酰胺基上的一个或多个氢原子被取代基取代时，所述的取代基为R 4-2b，所述的R 4-2b为C 1-C 8烷基或R 4-1取代的C 1-C 8烷基；
    和/或，当R 4为酰胺基，且酰胺基上的一个或多个氢原子被取代基取代时，所述的酰胺基为-C(＝O)NH-，其中，C端与
    Figure PCTCN2019109143-appb-100003
    相连，N端与取代基相连；
    和/或，当R 4为酰胺基、且酰胺基上的一个或多个氢原子被取代基取代时，所述的取代基的个数为1个；
    和/或，当R 4为酰胺基、且酰胺基上的一个或多个氢原子被取代基取代时，所述的取代基为R 4-2b，所述的R 4-2b为C 1-C 8烷基或R 4-1取代的C 1-C 8烷基；
    和/或，所述的环烷基为由碳原子和氢原子组成的稳定的非芳香族单环，且饱和；
    和/或，所述的杂环基为为单环的环体系，其杂环基中的氮、碳或硫原子不被氧化，氮原子不被季铵化，且完全饱和；
    和/或，所述的芳基不与环烷基或杂环基稠合；
    和/或，所述的杂芳基不与环烷基或杂环基稠合，杂芳基中的氮、碳或硫原子不被氧化，氮原子不被季铵化。
  3. 如权利要求2所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，其特征在于，当R 3-1a为R 3-1取代的6-18元的芳基时，所述的6-18的芳基为6-14的芳基，进一步可以为苯基；
    和/或，当R 3-1a为R 3-1取代的6-18元的芳基时，所述R 3-1的个数为1-3个，还可以为3个；
    和/或，当R 3-1为卤素时，所述的卤素为F、Cl、Br或I，还可以为F；
    和/或，当R 3-1为C 1-C 4烷基时，所述的C 1-C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，还可以为甲基；
    和/或，当R 3-1a为R 3-2取代的杂芳基时，所述的杂芳基为5-8元的杂芳基，可为5元或6元的杂芳基；
    和/或，当R 3-1a为R 3-2取代的杂芳基时，所述的杂原子的种类为N和/或S；
    和/或，当R 3-1a为R 3-2取代的杂芳基时，所述的杂原子的个数为1个；
    和/或，当R 3-1a为R 3-2取代的杂芳基时，所述R 3-2的个数为1-3个，可以为3个；
    和/或，当R 3-2为卤素时，所述的卤素为F、Cl、Br或I，还可以为F；
    和/或，当R 3-2为C 1-C 4烷基时，所述的C 1-C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，还可以为甲基；
    和/或，当R 3-1a为R 3-3取代的3-8元环烷基时，所述的3-8元环烷基为3-6元环烷基，进一步可以为环己基；
    和/或，当R 3-1a为R 3-3取代的3-8元环烷基时，所述R 3-3的个数为1-3个，还可以为1个；
    和/或，当R 3-3为C 1-C 4烷基时，所述的C 1-C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，可以为甲基；
    和/或，当R 4-1a为C 1-C 8烷基时，所述的C 1-C 8烷基可为C 1-C 4烷基，进一步可为甲基；
    和/或，当R 4-1a为R 4-1取代的C 1-C 8烷基时，所述的C 1-C 8烷基为C 1-C 4烷基，进一步可为甲基；
    和/或，当R 4-1为3-8元环烷基时，所述的3-8元环烷基为3-6元环烷基，进一步可以为环丙基；
    和/或，当R 4-1a为3-8元环烷基时，所述的3-8元环烷基为3-6元环烷基，进一步可以为环丙基；
    和/或，当R 4-1a为杂芳基时，所述的杂芳基为5-8元杂芳基，还可以为5或6元杂芳基；
    和/或，当R 4-1a为杂芳基时，所述的杂原子的种类为O或N；
    和/或，当R 4-1a为杂芳基时，所述的杂原子的个数为1-3个，可以为2个或3个；
    和/或，当所述的R 4-2b为C 1-C 8烷基或R 4-1取代的C 1-C 8烷基时，所述的C 1-C 8烷基为C 1-C 4烷基，进一步还可为甲基或乙基；
    和/或，R 4-1的个数为1个；
    和/或，当R 4-1为卤素时，所述的卤素为F、Cl、Br或I，可以为F；
    和/或，当R 4-1为C 1-C 4烷氧基时，所述的C 1-C 4烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基，可为甲氧基；
    和/或，当R 4-1为卤素取代的C 1-C 4烷氧基时，所述的C 1-C 4烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基，可为甲氧基；
    和/或，当R 4-1为卤素取代的C 1-C 4烷氧基时，所述的卤素为F、Cl、Br或I，可以为F；
    和/或，当R 4-1为R 4-1-2取代的3-8元环烷基时，所述的3-8元环烷基为3-6元环烷基，进一步可以为环丙基；
    和/或，当R 4-1为R 4-1-2取代的3-8元环烷基时，所述的R 4-1-2的个数为1个；
    和/或，当R 4-1-2为C 1-C 4烷基时，所述的C 1-C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，可为甲基；
    和/或，当R 4-1-1a和R 4-1-1b独立地为C 1-C 4烷基时，所述的C 1-C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，可为甲基。
  4. 如权利要求3所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，其特征在于，当R 3-1a为R 3-1取代的6-18元的芳基时，所述的R 3-1取代的6-18元的芳基为
    Figure PCTCN2019109143-appb-100004
    和/或，当R 3-1a为R 3-2取代的5-8元的杂芳基时，所述的R 3-2取代的5-8元的杂芳基为
    Figure PCTCN2019109143-appb-100005
    和/或，当R 3-1a为R 3-3取代的3-8元环烷基时，所述的R 3-3取代的3-8元环烷基为
    Figure PCTCN2019109143-appb-100006
    和/或，当R 4-1a为R 4-1取代的C 1-C 8烷基时，所述的R 4-1取代的C 1-C 8烷基为
    Figure PCTCN2019109143-appb-100007
    和/或，当R 4-1a为杂芳基时，所述的杂芳基为
    Figure PCTCN2019109143-appb-100008
    可以为
    Figure PCTCN2019109143-appb-100009
    和/或，当R 4-1为卤素取代的C 1-C 4烷氧基时，所述的卤素取代的C 1-C 4烷氧基为三氟甲氧基；
    和/或，当所述的R 4-2b为R 4-1取代的C 1-C 8烷基时，所述的R 4-1取代的C 1-C 8烷基为
    Figure PCTCN2019109143-appb-100010
  5. 如权利要求4所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学 上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，其特征在于，当R 2a和R 2b之间通过杂原子形成3-8元的饱和的环系时，所述的环系为
    Figure PCTCN2019109143-appb-100011
    和/或，当R 3为羟基，且羟基上的一个氢被取代基取代时，所述的羟基为
    Figure PCTCN2019109143-appb-100012
    Figure PCTCN2019109143-appb-100013
    和/或，当R 4为杂芳基、且杂芳基上的一个或多个氢原子被取代基取代时，所述的杂芳基为
    Figure PCTCN2019109143-appb-100014
    Figure PCTCN2019109143-appb-100015
    还可以为
    Figure PCTCN2019109143-appb-100016
    和/或，当酰胺基、且酰胺基上的一个或多个氢原子被取代基时，所述的酰胺基为
    Figure PCTCN2019109143-appb-100017
    Figure PCTCN2019109143-appb-100018
    还可以为
    Figure PCTCN2019109143-appb-100019
    Figure PCTCN2019109143-appb-100020
  6. 如权利要求1所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，其特征在于，R 1为C 1-C 8烷基；
    和/或，R 2a和R 2b独立地为C 1-C 6的烷基、C 1-C 6的烷基上一个或多个氢原子任选地被R 2a-1取代的C 1-C 6的烷基、或者R 2a和R 2b之间通过碳原子或者杂原子形成3-8元的饱和、 不饱和或者部分不饱和的环系，优选C 1-C 6的烷基；
    和/或，R 3为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”、“氨基、且氨基上一个或多个氢原子被取代基取代的氨基”、或、“杂芳基、且杂芳基上一个或多个氢原子被取代基取代的杂芳基”，优选为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”；
    和/或，当R 3为羟基，且羟基上的一个氢被被取代基取代时，所述的取代基为R 3-1a，所述的R 3-1a为R 3-1取代的6-18元的芳基；
    和/或，R 4为杂环烷基、“杂环烷基、且杂环烷基上一个或多个氢原子被取代基取代的杂环烷基”、“酰胺、且酰胺基上一个或多个氢原子被取代基取代的酰胺”、“磺酰胺基、且磺酰胺基上一个或多个氢原子被取代基取代的磺酰基”、或、“C 1-C 8烷基、且C 1-C 8烷基上一个或多个氢原子被取代基取代的C 1-C 8烷基”，优选“酰胺、且酰胺基上一个或多个氢原子被取代基取代的酰胺”；
    和/或，当R 4为“酰胺、且酰胺基上一个或多个氢原子被取代基取代的酰胺”时，所述的取代基为R 4-1a，所述的R 4-1a为C 1-C 8烷基或R 4-1取代的C 1-C 8烷基；
    和/或，R 4-1为卤素、甲磺酰基、C 1-C 4烷氧基、
    Figure PCTCN2019109143-appb-100021
    或R 4-1-2取代的3-8元环烷基，优选卤素、C 1-C 4烷氧基或甲磺酰基，更优选卤素或C 1-C 4烷氧基；
    和/或，X 1、X 9、X 10和X 11独立地为CH；
    和/或，X 2为N或C，优选为N；
    和/或，X 3和X 6独立地为C；
    和/或，X 4为N；
    和/或，X 5为CH或N，优选为N；
    和/或，X 7和X 8其中一个为NH，另一个为CH。
  7. 如权利要求1～6至少一项所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，其特征在于，所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物为如通式(IA)-2所示的化合物：
    Figure PCTCN2019109143-appb-100022
    其中，R 1为C 1-C 8烷基；
    R 2a和R 2b独立地为C 1-C 6的烷基；
    R 3为“羟基、且羟基上一个或多个氢原子被取代基取代的羟基”，所述的取代基为R 3- 1a，所述的R 3-1a为5-8元的芳基、R 3-1取代的6-18元的芳基、杂芳基、R 3-2取代的杂芳基、3-8元环烷基或R 3-3取代的3-8元环烷基；
    R 4为“杂环烷基、且杂环烷基上一个或多个氢原子被取代基取代的杂环烷基”、或、“酰胺基、且酰胺基上一个或多个氢原子被取代基取代的氨基酰胺基”；
    所述的“杂环烷基、且杂环烷基上一个或多个氢原子被取代基取代的杂环烷基”中的取代基为R 4-1a，所述的R 4-1a为5-8元的杂芳基、C 1-C 8烷基、R 4-1取代的C 1-C 8烷基和3-8元环烷基中一种或多种；
    所述的“酰胺基、且酰胺基上一个或多个氢原子被取代基取代的氨基酰胺基”中的取代基为R 4-2a，所述的R 4-2a为C 1-C 8烷基和/或R 4-1取代的C 1-C 8烷基；
    R 4-1为卤素、甲磺酰基、C 1-C 4烷氧基、卤素取代的C 1-C 4烷氧基、3-8元环烷基、
    Figure PCTCN2019109143-appb-100023
    和R 4-1-2取代的3-8元环烷基中的一种或多种。
  8. 如权利要求7所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，其特征在于，所述的具有如通式(IA)-2所示的稠杂环联芳基苄醇类化合物为如通式(IA)-3所示的化合物：
    Figure PCTCN2019109143-appb-100024
    所述的R 3-1a为R 3-1取代的6-18元的芳基；R 3-1为卤素和/或C 1-C 4烷基；
    所述的R 4-1a为C 1-C 8烷基、R 4-1取代的C 1-C 8烷基、3-8元环烷基、杂芳基中的一种或多种；
    X 7和X 8中一个为NH，另一个为CH。
  9. 如权利要求8所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，其特征在于，所述的具有如通式(IA)-3所示的稠杂环联芳基苄醇类化合物：
    Figure PCTCN2019109143-appb-100025
    R 4-1为卤素、甲磺酰基、C 1-C 4烷氧基、3-8元环烷基、
    Figure PCTCN2019109143-appb-100026
    和R 4-1-2取代的3-8元环烷基中的一种或多种，优选卤素或C 1-C 4烷氧基；R 4-1的个数为1个。
  10. 如权利要求1所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，其特征在于，具有如通式(IA)所示的稠杂环联芳基苄醇类化合物为通式(IIA)、(IIB)、(IIC)、(IID)、(IIE)、(IIF)、(IIG)、(IIH)、(III)、(IIJ)、(IIK)、(IIL)、(IIM)、(IIN)、(IIO)、(IIP)、(IIQ)所示的化合物：
    Figure PCTCN2019109143-appb-100027
    Figure PCTCN2019109143-appb-100028
    优选
    Figure PCTCN2019109143-appb-100029
    Figure PCTCN2019109143-appb-100030
    更进一步优选
    Figure PCTCN2019109143-appb-100031
    Figure PCTCN2019109143-appb-100032
    再更进一步优选
    Figure PCTCN2019109143-appb-100033
  11. 如权利要求1所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，其特征在于，如通式(IA)所示的稠杂环联芳基苄醇类化合物为如下任一化合物：
    Figure PCTCN2019109143-appb-100034
    Figure PCTCN2019109143-appb-100035
    Figure PCTCN2019109143-appb-100036
    Figure PCTCN2019109143-appb-100037
  12. 如权利要求1所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，其特征在于，所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物为如通式I所示的稠杂环联芳基苄醇类化合物：
    Figure PCTCN2019109143-appb-100038
    式中：
    R 1独立地选自氢、卤素、C 1-C 8烷基、3-8元环烃基或杂环烷基和5-8元的芳基或杂芳基；
    R 2a、R 2b分别独立地选自氢、卤素、C 1-C 6的烷基、3-8元环烷基或杂环烷基、5-8元的芳基或杂芳基，或者R 2a和R 2b之间可以通过碳原子或者杂原子形成3-8元的饱和、不饱和或者部分不饱和的环系；
    R 3独立地选自氢，卤素，硝基、氰基、烯基、炔基、C 1-C 8烷基、3-8元环烷基或杂环烷基、3-8元芳基或杂芳基、氨基、羟基、醚或硫醚、砜基或亚砜基、酯基、酰胺、磺酰胺、亚磺酰胺、脲、磺酰脲、亚磺酰脲等；
    R 4独立地选自卤素、C 1-C 8烷基、3-8元环烷基或杂环烷基、3-8元芳基或杂芳基、酯基、酰胺基、磺酰胺、氨基、醚或硫醚、脲或磺酰脲等；
    X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、X 9、X 10、X 11分别独立地选自N、NRa或CRa,Ra选自氢，卤素，C 1-C 8烷基、C 3-C 8烷基环烷基或杂环烷基；
    上述的任一基团上的一个或多个氢原子可以被选自下组的取代基取代：包括但不限于氘、卤素、羟基、氨基或环氨基、氰基、硝基、砜基或亚砜基、C 1-C 8烷基、3-8元环烷 基或杂环烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、烯基、炔基、酰基或磺酰基、脲或磺酰脲、5～8元芳基或杂芳基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O、P或S，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P或S，所述的环系包含螺环、桥环、稠环、并环等饱和或部分不饱和的环系。
  13. 如权利要求12所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药，其特征在于，
    R 1为自氢、氟、氯、甲基、乙基；
    R 2a、R 2b独立地为甲基、乙基、烷氧基甲基、环丙基甲基、卤代甲基等，或者R2a和R2b通过碳原子或者杂原子形成3-6元环系，优选自环丙基、环丁基、氧杂环丁基、环戊基等；
    R 3为C 1-C 6的烷基醚或硫醚或氨基、3-8元的环烷基或杂环烷基醚或硫醚或氨基、5-8元的芳基或杂芳基醚或硫醚或氨基；进一步优选自：
    Figure PCTCN2019109143-appb-100039
    其中Rd选自氢、卤素、氰基、砜基、亚砜基、C 1-C 3的烷基或烷氧基，并且Rd跟苯环或环己烷环或另一个Rd取代基之间可以形成3-8元的饱和或部分不饱和的环系；n＝0-5，优选自2，3；
    R 4选自-CN、-COORb、-CONHRb、
    Figure PCTCN2019109143-appb-100040
    Figure PCTCN2019109143-appb-100041
    其中Rb、Re独立地为C 1-C 8的烷基或环烷基或杂环烷基、取代或未取代的5-6元的芳基或杂芳基等；
    X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、X 9、X 10、X 11为N或CRa，其中Ra为氢或氟。
  14. 一种药物组合物，其包括如权利要求1～13至少一项所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药、与药学上可接受的载体。
  15. 一种如权利要求1～13至少一项所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药、或如权利要求14所述的药物组合物在制备药物中的应用。
  16. 一种如权利要求1～13至少一项所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药、或如权利要求14所述的药物组合物在制备药物中的应用，所述的药物用于防治和/或治疗与BRD、c-Myc蛋白活性或表达量相关的疾病。
  17. 一种如权利要求1～13至少一项所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药、或如权利要求14所述的药物组合物在制备药物中的应用，所述的药物用于防治和/或***、免疫性疾病和炎症性疾病中的一种或多种。
  18. 如权利要求17所述的应用，其特征在于，所述的肿瘤为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌或胰腺癌，优选白血病或***癌。
  19. 一种预防和/或治疗疾病的方法，所述的方法包括给予需要治疗对象有效量的如权利要求1～13至少一项所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药、或如权利要求14所述的药物组合物；其中，所述的疾病为与BRD、c-Myc蛋白活性或表达量相关的疾病。
  20. 一种预防和/或治疗疾病的方法，所述的方法包括给予需要治疗对象有效量的如权利要求1～13至少一项所述的具有如通式(IA)所示的稠杂环联芳基苄醇类化合物、其药学上可接受的盐、其对映异构体、其非对映异构体、其互变异构体、其溶剂化物、其多晶型物或其前药、或如权利要求14所述的药物组合物；其中，所述的疾病为肿瘤、免疫性疾病和炎症性疾病中的一种或多种。
PCT/CN2019/109143 2018-09-29 2019-09-29 一类稠杂环联芳基苄醇类化合物、制备方法和用途 WO2020063976A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811144997.2 2018-09-29
CN201811144997 2018-09-29

Publications (1)

Publication Number Publication Date
WO2020063976A1 true WO2020063976A1 (zh) 2020-04-02

Family

ID=69952874

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/109143 WO2020063976A1 (zh) 2018-09-29 2019-09-29 一类稠杂环联芳基苄醇类化合物、制备方法和用途

Country Status (2)

Country Link
CN (1) CN110964012B (zh)
WO (1) WO2020063976A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11192900B2 (en) 2018-10-30 2021-12-07 Nuvation Bio Inc. Substituted 1,6-dihydropyridinones and 1,2-dihydroisoquinolinones as bet inhibitors
US11584756B2 (en) 2019-07-02 2023-02-21 Nuvation Bio Inc. Heterocyclic compounds as BET inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112661655B (zh) * 2020-12-29 2022-02-18 江苏云朴医药新材料科技有限公司 一种1-氨甲基-1-环丙醇类化合物及其合成方法
WO2023169336A1 (zh) * 2022-03-09 2023-09-14 成都科岭源医药技术有限公司 一种哒嗪类化合物及其制备方法及用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015095492A1 (en) * 2013-12-19 2015-06-25 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
CN105164135A (zh) * 2013-02-22 2015-12-16 拜耳医药股份有限公司 4-取代的吡咯并二氮杂卓和吡唑并二氮杂卓
WO2017177955A1 (en) * 2016-04-15 2017-10-19 Abbvie Inc. Bromodomain inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105164135A (zh) * 2013-02-22 2015-12-16 拜耳医药股份有限公司 4-取代的吡咯并二氮杂卓和吡唑并二氮杂卓
WO2015095492A1 (en) * 2013-12-19 2015-06-25 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
WO2017177955A1 (en) * 2016-04-15 2017-10-19 Abbvie Inc. Bromodomain inhibitors

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11192900B2 (en) 2018-10-30 2021-12-07 Nuvation Bio Inc. Substituted 1,6-dihydropyridinones and 1,2-dihydroisoquinolinones as bet inhibitors
US11584756B2 (en) 2019-07-02 2023-02-21 Nuvation Bio Inc. Heterocyclic compounds as BET inhibitors

Also Published As

Publication number Publication date
CN110964012A (zh) 2020-04-07
CN110964012B (zh) 2021-08-13

Similar Documents

Publication Publication Date Title
WO2020094104A1 (zh) 一类含氮稠杂环类shp2抑制剂化合物、制备方法和用途
WO2019158019A1 (zh) 嘧啶并环化合物及其制备方法和应用
WO2020063976A1 (zh) 一类稠杂环联芳基苄醇类化合物、制备方法和用途
US11267815B2 (en) Class of amino-substituted nitrogen-containing fused ring compounds, preparation method therefor, and use thereof
JP7131837B2 (ja) Ｃｓｆ－１ｒ阻害活性を有するアザアリール誘導体、その製造方法および応用
CN109721600B (zh) 一类含氮稠环化合物及其制备方法和用途
WO2016173557A1 (zh) 一类具有激酶抑制活性的化合物、制备方法和用途
CN110950876B (zh) 一类呋喃并内酰胺类化合物、制备方法和用途
CN112457326B (zh) 一类芳香杂环并内酰胺类化合物、制备方法和用途
WO2022135590A1 (zh) 一类嘧啶并杂环类化合物、制备方法和用途
WO2020156479A1 (zh) 环丙烯并苯并呋喃取代的氮杂芳基化合物、其中间体、制备方法及应用
CN113527299B (zh) 一类含氮稠环类化合物、制备方法和用途
WO2021032004A1 (zh) 氮杂芳基化合物及其应用
WO2020038458A1 (zh) 一类稠环三氮唑类化合物、制备方法和用途
WO2020187123A1 (zh) 一类吡咯酰胺并吡啶酮类化合物、制备方法和用途
CN112300173B (zh) 一类含氮多环类化合物、制备方法和用途
WO2021083383A1 (zh) 一类含氮稠环类sting调节剂类化合物、制备方法和用途
CN114907350B (zh) 一类含氮稠环类化合物、制备方法和用途
CN111057048B (zh) 一类氨基吡嗪/吡啶类化合物、制备方法和用途
WO2022052924A1 (zh) 一类含氮稠环类化合物的制备方法和用途
RU2809596C2 (ru) Соединение на основе пирроламидопиридона, способ его получения и его применение
CN114075196B (zh) 一类芳香环并内酰胺类化合物、其制备方法和用途
CN111763217B (zh) 一类噻吩并氮杂环类化合物、制备方法和用途
TW202312995A (zh) 氮雜芳基化合物、其製備方法及應用
WO2023134374A1 (zh) 一类嘧啶并杂环类化合物、制备方法和用途

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: 19867111

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: 19867111

Country of ref document: EP

Kind code of ref document: A1