WO2018086604A1 - Composés hétérocycliques contenant de l'azote, leur procédé de préparation, leur composition pharmaceutique et leurs applications - Google Patents

Composés hétérocycliques contenant de l'azote, leur procédé de préparation, leur composition pharmaceutique et leurs applications Download PDF

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WO2018086604A1
WO2018086604A1 PCT/CN2017/110539 CN2017110539W WO2018086604A1 WO 2018086604 A1 WO2018086604 A1 WO 2018086604A1 CN 2017110539 W CN2017110539 W CN 2017110539W WO 2018086604 A1 WO2018086604 A1 WO 2018086604A1
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group
linear
branched
methyl
phenyl
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PCT/CN2017/110539
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Chinese (zh)
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WO2018086604A8 (fr
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胡永韩
朱久香
蔡冬梅
董平
黄玮
李曼华
董加强
王铁林
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山东罗欣药业集团股份有限公司
罗欣生物科技（上海）有限公司
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Priority to CN201780067845.4A priority Critical patent/CN110088102A/zh
Publication of WO2018086604A1 publication Critical patent/WO2018086604A1/fr
Publication of WO2018086604A8 publication Critical patent/WO2018086604A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07D487/02—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 two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a nitrogen-containing heterocyclic compound, a process for the preparation thereof, a pharmaceutical composition and use thereof.
  • Tumors are one of the leading causes of human death worldwide in recent years.
  • the overall cure rate of tumors is low and the recurrence rate is high, so the treatment of tumors has important value.
  • Epigenetics refers to changes in gene expression levels based on non-gene sequence changes, including DNA methylation, histone modification, chromosomal remodeling, and non-coding RNA regulation, primarily through regulation of gene transcription or translation processes. Its functions and features. Histones are the core of chromatin and are involved in post-transcriptional modifications, including acetylation, methylation, phosphorylation, and ubiquitination.
  • the bromodomain is an evolutionarily highly conserved protein consisting of 110 amino acids. It can affect the transcriptional regulation of genes by recognizing the acetylated lysine residues on histones and mediating protein interactions. In the human genome, 61 bromodomains were found and found in 46 different proteins. The bromodomain typically has a deep hydrophobic pocket with a small, tight binding site for binding to acetylated lysine. Moreover, the conserved water molecules at the bottom of the pocket have a significant effect on the medicinal properties. Bromo and binding domains of protein acetylation generally weak (K D values in the low micromolar to mmole scale), which also increases the likelihood of finding potential inhibitors. Evaluation of the medicinal properties of the bromodomain family revealed that the BET (bromodomain and extra C-terminal domain) subfamily scores are high, as evidenced by some small molecule inhibitors with different skeletal structures that have been identified so far. .
  • the human BET family consists of four members: BRD2, BRD3, BRD4 and BRDT. Each member contains two tandem bromodomains (BD1 and BD2) for recognition of histone end acetylated lysine residues, as well as an additional C-terminal domain.
  • BRD2 can regulate the body's energy balance, and abnormal regulation of dyslipidemia or lipogenesis, inflammation level and autoimmune disease;
  • BRD3 binds acetylated GATA1, regulates red blood cell target gene;
  • BRD4 marks mitosis and promotes transcription;
  • BRDT is expressed only in the testis and is important for the expression of genes that produce sperm.
  • BRD2 and BRD3 bind to histones and are involved in promoting transcriptional elongation.
  • BRD4 binds to positive transcription elongation factor b (P-TEFb), resulting in phosphorylation of RNA polymerase and increased transcriptional output.
  • P-TEFb positive transcription elongation factor b
  • BRD4 binds to different transcription factors and regulates downstream gene expression. It binds to acetylated RelA, leading to nuclear Stimulation and transcriptional activity of the inflammatory genes.
  • BRD4 is associated with the N-terminal region of the retinoic acid receptor alpha, regulates a discrete set of genes, associates with p53, and regulates p21 expression.
  • BRD4 also interacts with several chromatin-modifying enzymes, including the histone methylase NSD3 and the hydroxylase JMJD6.
  • BRD4 target genes such as c-Myc, C-Fos, aurora B, cyclin D1, and cyclin D2, are involved in cell cycle control. Research data show that BRD4 is also involved in DNA damage signaling.
  • BRD4 is involved in the regulation of the apolipoprotein A1 gene, which regulates the level of high-density lipoprotein, which is associated with the pathology of arteriosclerosis.
  • BRD4 BRD3
  • NUT nuclear protein
  • BRD4 plays an important role in many hematological malignancies, including acute myeloid lymphoma, acute lymphoblastic leukemia, lymphoma, and multiple myeloma.
  • BRD4 is also associated with a range of solid tumors, such as neuroblastoma, malignant glioma, lung cancer and melanoma.
  • BRD4 is also associated with inflammation and the life cycle of some viruses.
  • BET inhibitors of different chemical types, and some have entered the clinical testing phase.
  • a series of patent applications for BET inhibitors are disclosed, including WO2011054553, WO2011054845, WO2013097052, WO2013185284, WO2014139324, WO2014164771, WO2015100282, WO2015075665, WO2015080707, WO2015164480, WO2015195862, WO2016050821, and the like.
  • Abbvie discloses a class of bromodomain inhibitors in WO2013097052, in which ABBV-075 is highly developed in the treatment of acute myeloid leukemia (AML), multiple myeloma (MM) and solid tumors. Prospects are currently in the phase of clinical trials.
  • AML acute myeloid leukemia
  • MM multiple myeloma
  • solid tumors Prospects are currently in the phase of clinical trials.
  • bromodomain inhibitors that can be used to treat diseases and indications involving bromodomain function, including BET domain function, are in need of development.
  • the technical problem to be solved by the present invention is to develop more novel bromodomain inhibitors, thereby providing more therapeutic methods for diseases and indications involving bromodomain function including BET domain function, thus providing a series of existing and existing A completely different nitrogen-containing heterocyclic compound having a bromine domain inhibition effect.
  • the nitrogen-containing heterocyclic compound of the present invention can effectively bind to the bromine domains of the BET family BRD4, BRD3, BRD2 and BRDT, thereby regulating the transcription of the downstream gene c-myc and its related target genes, thereby regulating the downstream signaling pathway and exerting Specific effects, including treatment of diseases such as inflammatory diseases, cancer and AIDS; some of the compounds have high activity, and have good cell activity and metabolic stability, and thus can be an effective drug for treating tumors.
  • the present invention solves the above technical problems by the following technical solutions.
  • the present invention provides a nitrogen-containing heterocyclic compound, a tautomer, an optical isomer, a hydrate, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, of the formula I, wherein ,
  • the ⁇ ring is a saturated, semi-saturated or aromatic heterocyclic ring; the ⁇ ring is an aromatic ring or an aromatic heterocyclic ring;
  • R 1C and R 1N are each independently selected from -H or a C 1 -C 5 alkyl group substituted by R 1A ;
  • R 1A is selected from -H, -CN, halogen, C 1 -C 6 straight chain Or a branched alkoxy group, a 3-7 membered cycloalkyl group, or a C 1 -C 6 straight or branched alkyl group;
  • R 3 is selected from -H, halogen, -CN, 3-7 membered cycloalkyl, C 1 -C 3 straight or branched alkyl or C 1 -C 3 straight or branched haloalkyl;
  • Z is a nitrogen atom or a carbon atom
  • R 4 is selected from -H, C 1 -C 3 linear or branched haloalkyl, C 1 -C 3 linear or branched alkyl, or cyclopropyl;
  • R 5 is selected from -H, C 1 -C 3 straight or branched haloalkyl, C 1 -C 3 straight or branched alkyl, 3-7 membered cycloalkyl, or halogen;
  • R 6 is selected from -H, 3-7 membered cycloalkyl, or C 1 -C 3 straight or branched alkyl;
  • R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h , R 7i , R 7j , R 7k , R 7l , R 7m , R 7n and R 7o are each independently selected From -H, C 1 -C 3 linear or branched alkyl, 3-7 membered cycloalkyl, -N(CH 3 ) 2 , or 5-6 membered nitrogen-containing heteroaryl;
  • R 7p is selected from -H, a 3-7 membered cycloalkyl group, or a C 1 -C 3 linear or branched alkyl group;
  • n 7A , n 7B , n 7C , n 7D , n 7E , n 7F , n 7G and n 7H are each Independently selected from 0, 1, 2 or 3;
  • R A1 , R 7 together with the carbon atom directly connected to each of them constitute a 5-7 membered heterocyclic ring, and the 5-7 membered heterocyclic ring may be a fatty heterocyclic ring or an aromatic heterocyclic ring; wherein the hetero atom is N or O , the number of heteroatoms is 1-3;
  • R A2 is selected from a C 1 -C 3 linear or branched haloalkyl group, a C 1 -C 3 linear or branched alkyl group, a 3-7 membered cycloalkyl group, or a halogen;
  • the structural unit "A 1 -A 2 " together constitute -S-, -O- or -N(R AN )-; wherein R AN is selected from -H, C 1 -C 3 linear or branched haloalkane a C 1 -C 3 linear or branched alkyl group, a 3-7 membered cycloalkyl group, or a halogen;
  • Q is selected from a phenyl group substituted by R Q1 , a 3-6 membered cycloalkyl-(CH 2 )n 2 - substituted by R Q2 , and a 3-6 membered heterocycloalkyl-(CH 2 )m 2 substituted by R Q3 - or a 5-6 membered heteroaryl group substituted by R Q4 ;
  • n 2 , m 2 are each independently selected from 0, 1 or 2;
  • R Q1 , R Q2 , R Q3 and R Q4 are each independently selected from -H , -CN or halogen; the substitution is mono- or poly-substituted; the hetero atom in the heterocycloalkyl or heteroaryl group is N or O, and the number of the hetero atoms is 1-3.
  • R 1A is halogen
  • the halogen is preferably fluorine or chlorine
  • R 1A is a C 1 -C 6 linear or branched alkoxy group
  • the C 1 -C 6 linear or branched alkoxy group is preferably a C 1 -C 3 linear or branched chain.
  • Alkoxy group further preferably methoxy, ethoxy, propoxy or isopropoxy;
  • R 1A is a C 1 -C 6 linear or branched alkyl group
  • the C 1 -C 6 linear or branched alkyl group is preferably a C 1 -C 3 linear or branched alkyl group. Further preferred is methyl, ethyl, propyl or isopropyl;
  • R 1A is a 3-7 membered cycloalkyl group
  • the 3-7 membered cycloalkyl group is preferably a cyclopropyl group
  • R 2C or R 2N is a C 6 -C 10 aryl group
  • the C 6 -C 10 aryl group is preferably a phenyl group
  • R 2C or R 2N is a 5-6 membered nitrogen-containing heteroaryl group
  • the 5-6 membered nitrogen-containing heteroaryl group is preferably pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyrrolyl.
  • pyrazolyl or imidazolyl further preferably it is attached to the remaining structural units of formula I via a carbon atom on the ring;
  • n 0 is preferably 0, 1 or 2;
  • R 2C0 is a halogen
  • the halogen is preferably fluorine or chlorine
  • R 2C0 is a C 1 -C 6 linear or branched alkoxy group
  • the C 1 -C 6 linear or branched alkoxy group is preferably a C 1 -C 3 linear or branched chain.
  • Alkoxy group further preferably methoxy, ethoxy, propoxy or isopropoxy;
  • R 2C0 is a C 1 -C 6 linear or branched alkyl group
  • the C 1 -C 6 linear or branched alkyl group is preferably a C 1 -C 3 linear or branched alkyl group. Further preferred is methyl, ethyl, propyl or isopropyl;
  • R 2C0 is a C 1 -C 6 linear or branched haloalkyl group
  • the C 1 -C 6 linear or branched haloalkyl group is preferably a C 1 -C 3 linear or branched haloalkyl group.
  • said linear or branched C 1 -C 3 alkyl haloalkyl is substituted with one or more identical or different halogen atoms substituted by a straight-chain or branched-chain C 1 -C 3 alkyl, said halo It may be on the same or different carbon atoms;
  • the C 1 -C 3 linear or branched haloalkyl group is preferably a trifluoromethyl group, a difluoromethyl group or a 1,2-difluoroethyl group;
  • R 2C0 is a 3-7 membered cycloalkyl group
  • the 3-7 membered cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group or a cyclopentyl group
  • the 3-7 membered cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group or a cyclopentyl group;
  • the linear or branched haloalkyl group of 1 -C 6 is preferably a C 1 -C 3 linear or branched haloalkyl group, further preferably a trifluoromethyl group, a difluoromethyl group or a 1,2-difluoroethyl group;
  • R 2C0 is phenyl substituted with R 2C8 5-7 membered heterocycloalkyl, the preferred site of substitution on the ring hetero atom; 5-7 membered heterocycloalkyl preferably 6 or 7-membered heteroaryl a cycloalkyl group; the number of hetero atoms in the 5-7 membered heterocycloalkyl group is preferably 2 or 3; when the number of the hetero atoms is 2, the hetero atom is preferably The 5-7 membered heterocycloalkyl group is arranged on the ring at least two carbon atoms; the 5-7 membered heterocycloalkyl group is preferably bonded via a hetero atom on the ring (eg, a nitrogen atom) The remaining structural unit of formula I; the 5-7 membered heterocycloalkyl group is further preferably
  • m 0 is preferably 0, 1 or 2;
  • R 2N0 is a halogen
  • the halogen is preferably fluorine or chlorine
  • R 2N0 is a C 1 -C 6 linear or branched alkoxy group
  • the C 1 -C 6 linear or branched alkoxy group is preferably a C 1 -C 3 linear or branched chain.
  • Alkoxy group further preferably methoxy, ethoxy, propoxy or isopropoxy;
  • R 2N0 is a C 1 -C 6 linear or branched alkyl group
  • the C 1 -C 6 linear or branched alkyl group is preferably a C 1 -C 3 linear or branched alkyl group. Further preferred is methyl, ethyl, propyl or isopropyl;
  • R 2N0 is a C 1 -C 6 linear or branched haloalkyl group
  • the C 1 -C 6 linear or branched haloalkyl group is preferably a C 1 -C 3 linear or branched haloalkyl group.
  • said linear or branched C 1 -C 3 alkyl haloalkyl is substituted with one or more identical or different halogen atoms substituted by a straight-chain or branched-chain C 1 -C 3 alkyl, said halo It may be on the same or different carbon atoms;
  • the C 1 -C 3 linear or branched haloalkyl group is preferably a trifluoromethyl group, a difluoromethyl group or a 1,2-difluoroethyl group;
  • R 2N0 is a 3-7 membered cycloalkyl group
  • the 3-7 membered cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group or a cyclopentyl group
  • R 2N1, R 2N2, R 2N3, R 2N4, R 2N5 , R 2N6 , R 2N7 and R 2N8 are each independently selected from -H, C 1 -C 6 straight or branched alkyl, C 1 -C 6 straight or branched alkoxy, 3-7 a cycloalkyl group, or a C 1 -C 6 linear or branched haloalkyl group; wherein the C 1 -C 6 linear or branched alkyl group is preferably a C 1 -
  • R 2N0 is a 5-7 membered heterocycloalkyl group substituted by R 2N 8
  • the substituent site is preferably a hetero atom on the ring
  • the 5-7 membered heterocycloalkyl group is preferably 6 or 7 membered hetero a cycloalkyl group
  • the number of hetero atoms in the 5-7 membered heterocycloalkyl group is preferably 2 or 3
  • the hetero atom is preferably
  • the 5-7 membered heterocycloalkyl group is arranged on the ring at least two carbon atoms
  • the 5-7 membered heterocycloalkyl group is preferably bonded via a hetero atom on the ring (eg, a nitrogen atom)
  • the remaining structural unit of formula I; the 5-7 membered heterocycloalkyl group is further preferably
  • Z is preferably
  • R 3 or R 5 is halogen
  • the halogen is preferably fluorine or chlorine
  • R 3 , R 4 , R 5 or R 6 is a C 1 -C 3 linear or branched alkyl group
  • the C 1 -C 3 linear or branched alkyl group is preferably methyl or B.
  • Base propyl or isopropyl;
  • R 3 , R 4 or R 5 is a C 1 -C 3 linear or branched haloalkyl group
  • the C 1 -C 3 straight or branched haloalkyl group is one or more the same or different a halogen-substituted C 1 -C 3 linear or branched alkyl group, said halo group being at the same or different carbon atom
  • said C 1 -C 3 linear or branched haloalkyl group Preferred is trifluoromethyl, difluoromethyl or 1,2-difluoroethyl;
  • R 3 , R 5 or R 6 is a 3-7 membered cycloalkyl group
  • the 3-7 membered cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group or a cyclopentyl group
  • R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h and R 7i are each independently a C 1 -C 3 linear or branched alkyl group, the C The linear or branched alkyl group of 1 -C 3 is preferably methyl, ethyl, propyl or isopropyl;
  • R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h and R 7i are each independently a 3-7 membered cycloalkyl group, the 3-7 membered cycloalkyl group Preferred is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h and R 7i are each independently a 5-6 membered nitrogen-containing heteroaryl group
  • the nitrogen-containing heteroaryl group is preferably a pyridyl group, a pyrazinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrrolyl group, a pyrazolyl group or an imidazolyl group, and further preferably it is bonded to the remaining structural unit of the formula I through a carbon atom on the ring;
  • R 7p is selected from -H, a 3-7 membered cycloalkyl group, or a C 1 -C 3 linear or branched alkyl group, wherein
  • the 3-7 membered cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group or a cyclopentyl group; and the C 1 -C 3 linear or branched alkyl group is preferably a methyl group, an ethyl group or a propyl group.
  • the 5-6 membered heteroaryl group preferably wherein the hetero atom is nitrogen, further preferably pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl or imidazolyl;
  • n 1 is preferably 1 or 2;
  • R A1a and R A1b are each independently a linear chain of -H, C 1 -C 6 Or a branched alkyl group, a C 1 -C 6 straight or branched alkoxy group, a C 1 -C 6 linear or branched haloalkyl group, or a 3-7 membered cycloalkyl group; wherein said C
  • the linear or branched alkyl group of 1 -C 6 is preferably a C 1 -C 3 linear or branched alkyl group (such as methyl, ethyl, propyl or isopropyl); said C 1 -C a straight-chain or branched alkoxy preferably C 6 linear or branched alkoxy group having 1 -C 3, and more preferably methoxy, ethoxy, propoxy or isopropoxy; said C The
  • R A1a and R A1b are preferably formed together with a nitrogen atom directly connected thereto .
  • R A1c and R A1d are each independently selected from -H, C 1 -C 6 straight or branched alkyl, C 1 -C straight chain or branched alkoxy, straight-chain or branched C 1 -C 6 alkyl haloalkyl or 6 3-7 membered cycloalkyl; wherein said C 6 linear or -C.
  • the branched alkyl group is preferably a C 1 -C 3 linear or branched alkyl group, further preferably a methyl group, an ethyl group, a propyl group or an isopropyl group; the C 1 -C 6 straight or branched chain alkane
  • the oxy group is preferably a C 1 -C 3 linear or branched alkoxy group, more preferably a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group; the C 1 -C 6 straight chain or
  • the branched haloalkyl group is preferably a C 1 -C 3 linear or branched haloalkyl group, further preferably a trifluoromethyl group, a difluoromethyl group or a 1,2-difluoroethyl group; said 3-7 membered cycloalkane
  • the group is preferably a cyclopropyl group, a cyclobutyl
  • the hetero atom in the 5-7 membered heterocyclic ring is preferably nitrogen, and the number of hetero atoms is preferably 2;
  • the 5-7 membered heterocyclic ring is preferably an aromatic heterocyclic ring (such as an imidazolinone ring, a pyrazole ring, etc.);
  • R A2 is a C 1 -C 3 linear or branched haloalkyl group
  • the C 1 -C 3 straight or branched haloalkyl group is C substituted by one or more of the same or different halogen atoms.
  • a straight or branched alkyl group of 1 - C 3 said halo group being at the same or different carbon atom;
  • said C 1 -C 3 linear or branched haloalkyl group being preferably a trifluoromethyl group, Difluoromethyl or 1,2-difluoroethyl;
  • R A2 is a C 1 -C 3 linear or branched alkyl group
  • the C 1 -C 3 linear or branched alkyl group is preferably a methyl group, an ethyl group, a propyl group or an isopropyl group
  • R A2 is halogen
  • the halogen is preferably fluorine or chlorine
  • R A2 is a 3-7 membered cycloalkyl group
  • the 3-7 membered cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group or a cyclopentyl group
  • the structural units "A 1 -A 2 " preferably together constitute -O- or -N(R AN )-;
  • R AN is a C 1 -C 3 linear or branched haloalkyl group
  • the C 1 -C 3 straight or branched haloalkyl group is C substituted by one or more of the same or different halogen atoms.
  • a straight or branched alkyl group of 1 - C 3 said halo group being at the same or different carbon atom;
  • said C 1 -C 3 linear or branched haloalkyl group being preferably a trifluoromethyl group, Difluoromethyl or 1,2-difluoroethyl;
  • R AN is a C 1 -C 3 linear or branched alkyl group
  • the C 1 -C 3 linear or branched alkyl group is preferably a methyl group, an ethyl group, a propyl group or an isopropyl group
  • R AN is halogen
  • the halogen is preferably fluorine or chlorine
  • R AN is a 3-7 membered cycloalkyl group
  • the 3-7 membered cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group or a cyclopentyl group
  • L is preferably -O-, -NH- or -CH 2 -;
  • substitution is preferably a mono- or di-substitution, further preferably a para- or a 2,4-di-substitution;
  • R Q1 is preferably a halogen, further preferably fluorine or chlorine;
  • the 3-6 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group; n 2 is preferably 0 or 1
  • the substitution is preferably a di-substitution, further preferably a homo-carbon substitution; R Q2 is preferably -H or a halogen (such as fluorine);
  • the 3-6 membered heterocycloalkyl group is preferably a 3-6 membered heterocycloalkyl group; m 2 is preferably 0; the hetero atom is preferably O; the number of the hetero atoms is preferably 1; R Q3 is preferably -H; and the 3-6 membered heterocycloalkyl group is preferably bonded through a carbon atom on the ring.
  • the remaining structural unit of formula I; preferably the 3-6 membered heterocycloalkyl group is 2-piperidyl, 3-piperidyl or 2-tetrahydrofuranyl;
  • the 5-6 membered heteroaryl group is preferably a pyridyl group or a pyrimidinyl group; and R Q4 is preferably a halogen (such as fluorine or chlorine).
  • the ⁇ ring is preferably a five-membered aromatic heterocyclic ring such as a pyrrole ring, a pyrazole ring or an imidazole ring, a triazole ring, an isoxazole ring, an oxadiazole ring, an isothiazole ring, a thiazole ring, an oxazolone ring or a pyrazolone.
  • a ring or the like further preferably a pyrrole ring, a pyrazole ring, an imidazole ring, a pyrazolone ring or a 1,3,4-triazole ring;
  • the ⁇ ring is preferably a benzene ring, a pyridine ring, a pyridazine ring, a pyrrole ring, a furan ring or a thiophene ring; further preferably a benzene ring or a pyridine ring.
  • R 1N , R 2C , R 2N , R 3 , R 4 and R 5 are each independently as previously described;
  • R A1 , R A2 , R 6 , R 7 , L and Q are each independently as described above.
  • the present invention also provides a nitrogen-containing heterocyclic compound, a tautomer thereof, an optical isomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof Prodrug,
  • the ⁇ ring is a saturated, semi-saturated, or aromatic heterocyclic ring (wherein Z may be a double bond or a single bond with the fused carbon atom; the fused carbon atom may be a double bond or a single bond with W; W and X may be double bonds or single bonds; X and Y may be double bonds or single bonds; Y and Z may be double bonds or single bonds; the principle of not countering the valence bond shall prevail; Aromatic heterocycle can be ),but Fragment is not
  • R 1C and R 1N are independently -H, C 1 -C 6 alkoxy (e.g., C 1 -C 3 alkoxy, such as methoxy, ethoxy, propoxy or isopropyl) An oxy), or a C 1 -C 5 alkyl group substituted or unsubstituted by R 1A (the "C 1 -C 5 alkyl group” such as a C 1 -C 3 alkyl group, such as a methyl group
  • All R 1A are independently -CN, halogen (eg fluorine, chlorine, bromine or iodine), C 1 -C 6 linear or branched alkoxy (eg straight chain or branch of C 1 -C 3 ) Alkenyloxy, for example methoxy, ethoxy, propoxy or isopropoxy), 3-7 membered cycloalkyl (eg cyclopropyl), or C 1 -C 6 straight or branched An alkyl group (for example,
  • R 2C is a C 6 -C 10 aryl group (eg phenyl), a 5-6 membered nitrogen-containing heteroaryl group (eg pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl or imidazole)
  • the "5-6 membered nitrogen-containing heteroaryl group” may be bonded to the remaining structural unit of the formula I through a carbon atom on the ring, or -(CH 2 )n 0 R 2C0 ; n 0 is 0, 1 , 2, 3, 4 or 5 (also for example 0, 1 or 2);
  • R 2C0 is -H, halogen (for example fluorine, chlorine, bromine or iodine), C 1 -C 6 linear or branched alkoxy group (for example, a linear or branched alkoxy group of C 1 -C 3 , such as a methoxy, ethoxy, prop
  • R 2N is a C 6 -C 10 aryl group, a 5-6 membered nitrogen-containing heteroaryl group, or -(CH 2 )m 0 R 2N0 ; m 0 is 0, 1, 2, 3, 4 or 5; R 2N0 Is a linear or branched alkoxy group of -H, halogen (such as fluorine or chlorine), C 1 -C 6 (for example, a C 1 -C 3 linear or branched alkoxy group, such as methoxy, B a linear or branched alkyl group of an oxy group, n-propoxy group, or isopropoxy group), C 1 -C 6 (for example, a linear or branched alkyl group of C 1 -C 3 , such as a methyl group, Ethyl or isopropyl), C 1 -C 6 linear or branched haloalkyl (eg trifluoromethyl, difluoromethyl or 1,2-difluoroethyl
  • R 3 is -H, halogen, -CN, 3-7 membered cycloalkyl, C 1 -C 3 linear or branched alkyl, or C 1 -C 3 linear or branched haloalkyl
  • the number of halogens in the halogenated group may be one or more ⁇ e.g., 2, 3, 4 or 5>; the halogen in the halogenated group may be independently fluorine, chlorine or bromine: a C 1 -C 3 linear or branched alkyl group such as methyl, ethyl, n-propyl, or isopropyl; a C 1 -C 3 linear or branched haloalkyl group such as three Fluoromethyl);
  • R 3-1 is a C 1 -C 3 linear or branched alkyl group (eg methyl, ethyl, n-propyl, or isopropyl, further methyl);
  • Z is a nitrogen atom or a carbon atom
  • R 4 is -H, C 1 -C 3 linear or branched haloalkyl, C 1 -C 3 linear or branched alkyl (eg methyl, ethyl, n-propyl, or isopropyl) , for example, methyl) or cyclopropyl;
  • R 5 is -H, a C 1 -C 3 linear or branched haloalkyl group, a C 1 -C 3 linear or branched alkyl group, a 3-7 membered cycloalkyl group, or a halogen;
  • the ⁇ ring is an aromatic ring or an aromatic heterocyclic ring
  • R 6 is -H, D, 3-7 membered cycloalkyl, halogen (such as fluorine, chlorine, bromine or iodine), or a linear or branched alkyl group of C 1 -C 3 ;
  • R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h , R 7i , R 7j , R 7k , R 7l , R 7m , R 7n and R 7o are each independently -H, C 1 -C 3 linear or branched alkyl (eg methyl, ethyl, n-propyl, or isopropyl, further methyl or ethyl), 3-7-membered cycloalkyl , -N(CH 3 ) 2 , or a 5-6 membered nitrogen-containing heteroaryl group;
  • R 7p is -H, a 3-7 membered cycloalkyl group, or a C 1 -C 3 linear or branched alkyl group; n 7A , n 7B , n 7C , n 7D , n 7E , n 7F , n 7G
  • halogen e.g., fluor
  • R A1 , R 7 together with the carbon atom directly connected to each of them constitute a 5-7 membered heterocyclic ring, and the 5-7 membered heterocyclic ring may be a fatty heterocyclic ring or an aromatic heterocyclic ring; wherein the hetero atom is N or O , the number of heteroatoms is 1-3;
  • R A2 is a linear or branched haloalkyl group of -H, D, C 1 -C 3 , a linear or branched alkyl group of C 1 -C 3 , a 3-7 membered cycloalkyl group, or a halogen (for example, fluorine, Chlorine, bromine or iodine, again such as fluorine);
  • a halogen for example, fluorine, Chlorine, bromine or iodine, again such as fluorine
  • the structural unit "A 1 -A 2 " together constitute -S-, -O- or -N(R AN )-; wherein R AN is -H, C 1 -C 3 linear or branched haloalkyl a linear or branched alkyl group of C 1 -C 3 or a 3-7 membered cycloalkyl group;
  • R L is a C 1 -C 3 linear or branched alkyl group (eg methyl, ethyl, n-propyl, or isopropyl);
  • R Q is a phenyl group substituted by R Q1 (the number of R Q1 may be one or more ⁇ for example, 2, 3, 4 or 5>; all R Q1 may be independently located in the benzene An ortho, meta or para position of a radical, for example, when the number of R Q1 is two, the R Q1 is located at the "ortho and para", or "two meta positions" of the phenyl group.
  • the R Q1 when the number of R Q1 is 3, the R Q1 is located at "two ortho and para positions" of the phenyl group; and the "phenyl group substituted by R Q1 " is, for example, 2 ,4-difluorophenyl, 4-cyanophenyl, 4-chlorophenyl, 2-fluoro-4-chlorophenyl, 2-fluoro-4-cyanophenyl, 2,4-dichlorophenyl , 2-chloro-4-fluorophenyl, 2-cyano-4-chlorophenyl, 2-cyano-4-fluorophenyl, 2,4,6-trifluorophenyl, 2-fluoro-4- Trifluoromethylphenyl, or 3,5-dichlorophenyl), 3-6 membered cycloalkyl-(CH 2 )n 2 - substituted by R Q2 (the 3-6 membered cyclic hydrocarbon group such as 3 a 6-membered cycloalkyl group, such as
  • All R Q1 , R Q2 , R Q3 and R Q4 are independently -H, -CH 3 , -CF 3 , -CN or halogen (for example fluorine, chlorine or bromine); said heterocycloalkyl or heteroaryl
  • the hetero atom in the group is N and/or O, and the number of the hetero atoms is 1-3;
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • the alpha ring is an aromatic heterocyclic ring, but Fragment is not Further, it may be a five-membered aromatic heterocyclic ring, and may also be a pyrrole ring, a pyrazole ring, an imidazole ring, a triazole ring, an isoxazole ring, an oxadiazole ring, an isothiazole ring, a thiazole ring, an oxazolone ring or a pyridyl group.
  • the oxazolone ring may further be a pyrrole ring, a pyrazole ring, an imidazole ring, a pyrazolone ring, a 1,2,3-triazole ring or a 1,3,4-triazole ring.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • Fragment can be Can also be
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 1C may be -H, or a C 1 -C 5 alkyl group or a -H.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 1N may be -H, a C 1 -C 6 alkoxy group, or a C 1 -C 5 alkyl group, or a -H or a C 1 -C 5 alkyl group.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 2C is -(CH 2 )n 0 R 2C0 .
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • n 0 is 0 or 1.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 2N is -(CH 2 )m 0 R 2N0 .
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • m 0 is 0, 1 or 2, and may be 0 or 1, and may be 0.
  • R 2N0 may be -H, a C 1 -C 6 straight or branched alkyl group, a 3-7 membered cycloalkyl group, or a C 1 -C 6 linear or branched alkoxy group, or may be C a straight-chain or branched-chain 1 -C 6 alkyl or, C 1 -C straight or branched C 1-6 alkoxy group, may also be a C 1 -C straight or branched alkyl of 6.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 3 is -H, or a C 1 -C 3 linear or branched haloalkyl group, which may also be -H.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • Z is a carbon atom.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 4 is a C 1 -C 3 linear or branched alkyl group.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 5 is -H.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • the ⁇ ring is an aromatic ring, and may be a benzene ring, a pyridine ring, a pyridazine ring, a pyrrole ring, a furan ring or a thiophene ring; further preferably a benzene ring or a pyridine ring.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • a 0 C(R 6 )-.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 6 may be -H, -D or -F, may be -H or -F, and may also be -H.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 7c , R 7d , R 7e , R 7f , R 7g , R 7j , R 7k and R 7l are each independently a linear or branched alkyl group of -H, or C 1 -C 3 ; n 7B , n 7C , n 7E and n 7F are each independently 0 or 1.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 7c is a linear or branched alkyl group (also, for example, a methyl group) of -H, or C 1 -C 3 .
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 7d is a C 1 -C 3 linear or branched alkyl group (also for example ethyl).
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 7e and R 7f are -H.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 7g is a C 1 -C 3 linear or branched alkyl group (also for example a methyl group).
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 7j is -H.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 7k is a C 1 -C 3 linear or branched alkyl group (also for example ethyl).
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • n 7F is 0 or 1.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 71 is a C 1 -C 3 linear or branched alkyl group (also for example methyl or ethyl).
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • a 1 C(R A1 )-.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R A2 is -H, D or halogen, and may be -H or halogen.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • L is -O-, -S- or -NH-, and may be -O- or -NH-.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R Q may be a phenyl group substituted by R Q1 , a 3-6 membered cycloalkyl group-(CH 2 )n 2 - substituted by R Q2 , or a 5-6 membered heteroaryl group substituted by R Q4 , or may be
  • the R Q1 substituted phenyl group or the 5-6 membered heteroaryl group substituted by R Q4 may also be a phenyl group substituted by R Q1 or a 3-6 membered cyclic hydrocarbon group substituted by R Q2 - (CH 2 n 2 -, more preferably a phenyl group substituted by R Q1 .
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • L is -O-.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • n 2 may be 1 or 2, and may be 1.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • All R Q1 , R Q2 and R Q4 are each independently -H, -CN, -CF 3 or halogen, and may be -H, -CN or halogen, more preferably -H or halogen.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • the alpha ring is an aromatic heterocyclic ring, but Fragment is not
  • R 1N is -H, a C 1 -C 6 alkoxy group, or a C 1 -C 5 alkyl group;
  • R 2N is -(CH 2 )m 0 R 2N0 ; m 0 is 0; R 2N0 is a C 1 -C 6 linear or branched alkyl group, or a C 1 -C 6 linear or branched chain Alkoxy group;
  • Y C(R 3 )-
  • R 3 is -H, or a C 1 -C 3 linear or branched haloalkyl group
  • Z is a carbon atom or a nitrogen atom
  • R 4 is a C 1 -C 3 linear or branched alkyl group
  • R 5 is -H
  • the ⁇ ring is an aromatic ring or an aromatic heterocyclic ring
  • a 0 C(R 6 )-;
  • R 6 is -H or -F
  • R 7c , R 7d , R 7j , R 7k and R 7l are each independently a linear or branched alkyl group of -H, or C 1 -C 3 ; n 7B , n 7E and n 7F are each independently Is 0 or 1;
  • a 1 C(R A1 )-;
  • R A1 is -H, D or F
  • R A2 is -H, D or F
  • L is -O-, -S- or -NH-;
  • Q is a phenyl group substituted by R Q1 or a 5-6 membered heteroaryl group substituted by R Q4 ;
  • All R Q1 and R Q4 are each independently -H, -CN or halogen.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • the alpha ring is an aromatic heterocyclic ring, but Fragment is not
  • R 1C and R 1N are each independently -H, or a C 1 -C 5 alkyl group
  • R 2N is -(CH 2 )m 0 R 2N0 ; m 0 is 0, 1 or 2; R 2N0 is -H, C 1 -C 6 linear or branched alkoxy group, C 1 -C 6 a linear or branched alkyl group, or a 3-7 membered cycloalkyl group;
  • R 3 is -H, or a C 1 -C 3 linear or branched haloalkyl group
  • R 3-1 is a C 1 -C 3 linear or branched alkyl group
  • Z is a carbon atom or a nitrogen atom
  • R 4 is a C 1 -C 3 linear or branched alkyl group
  • R 5 is -H
  • the ⁇ ring is an aromatic ring or an aromatic heterocyclic ring
  • a 0 C(R 6 )-;
  • R 6 is -H or -F
  • R 7c , R 7d , R 7e , R 7f , R 7g , R 7j , R 7k and R 7l are each independently a linear or branched alkyl group of -H, or C 1 -C 3 ; n 7B , n 7C , n 7E and n 7F are each independently 0 or 1;
  • a 1 C(R A1 )-;
  • R A2 is -H, D, or halogen (eg, fluorine, chlorine, bromine or iodine);
  • L is -O-, -S- or -NH-;
  • Q is a phenyl group substituted by R Q1 , a 3-6 membered cycloalkyl group-(CH 2 )n 2 - substituted by R Q2 , or a 5-6 membered heteroaryl group substituted by R Q4 ;
  • n 2 is 1 or 2;
  • R Q1 , R Q2 and R Q4 are each independently -H, -CN, -CF 3 or halogen.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 1N is -H, or a C 1 -C 5 alkyl group
  • R 3 is -H, or a C 1 -C 3 linear or branched haloalkyl group
  • R 4 is a C 1 -C 3 linear or branched alkyl group
  • R 5 is -H
  • the ⁇ ring is an aromatic ring or an aromatic heterocyclic ring
  • a 0 C(R 6 )-;
  • R 6 is -H or -F
  • R 7c , R 7d , R 7j , R 7k and R 7l are each independently a linear or branched alkyl group of -H, or C 1 -C 3 ; n 7B , n 7E and n 7F are each independently Is 0 or 1;
  • a 1 C(R A1 )-;
  • R A1 is -H, D or -F;
  • R A2 is -H, D or -F;
  • L is -O- or -NH-
  • Q is a phenyl group substituted by R Q1 or a 5-6 membered heteroaryl group substituted by R Q4 ;
  • R Q1 , R Q2 and R Q4 are each independently -H, -CN, -CF 3 or halogen.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 2N is -(CH 2 )m 0 R 2N0 ; m 0 is 0, 1 or 2; R 2N0 is -H, C 1 -C 6 straight or branched alkoxy, C 1 -C 6 straight a chain or branched alkyl group, or a 3-7 membered cycloalkyl group;
  • R 3 is -H
  • R 4 is a C 1 -C 3 linear or branched alkyl group
  • R 5 is -H
  • the ⁇ ring is an aromatic ring
  • a 0 C(R 6 )-;
  • R 6 is -H or -F
  • R 7c , R 7d , R 7e , R 7f , R 7g , and R 7l are each independently a linear or branched alkyl group of -H, or C 1 -C 3 ; n 7B , n 7C and n 7F are each independently 0 or 1;
  • a 1 C(R A1 )-;
  • R A1 is -H, D or halogen
  • a 2 C(R A2 )-;
  • R A2 is -H, D or halogen
  • L is -O- or -NH-
  • Q is a phenyl group substituted by R Q1 , a 3-6 membered cycloalkyl group-(CH 2 )n 2 - substituted by R Q2 , or a 5-6 membered heteroaryl group substituted by R Q4 ;
  • n 2 is 1 or 2;
  • R Q1 , R Q2 and R Q4 are each independently -H, -CN, -CF 3 or halogen.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 2N is a C 1 -C 6 straight or branched alkyl group, or a C 1 -C 6 linear or branched alkoxy group;
  • R 4 is a C 1 -C 3 linear or branched alkyl group
  • R 5 is -H
  • the ⁇ ring is an aromatic ring or an aromatic heterocyclic ring
  • a 0 C(R 6 )-; wherein R 6 is -H, D or -F;
  • R 7c and R 7d are each independently -H, or a C 1 -C 3 linear or branched alkyl group; n 7B is 0 or 1;
  • a 1 C(R A1 )-; wherein R A1 is -H, D or -F;
  • L is -O- or -NH-
  • Q is a phenyl group substituted by R Q1 or a 5-6 membered heteroaryl group substituted by R Q4 ;
  • All R Q1 and R Q4 are each independently -H, -CN or halogen.
  • the definition of certain groups in the compound I can be as follows, and the definition of a group not mentioned is as described in any of the schemes above:
  • R 2N is a C 1 -C 6 straight or branched alkyl group, or a C 1 -C 6 linear or branched alkoxy group;
  • R 4 is a C 1 -C 3 linear or branched alkyl group
  • R 5 is -H
  • the ⁇ ring is an aromatic ring or an aromatic heterocyclic ring
  • a 0 C(R 6 )-; wherein R 6 is -H, D or -F;
  • R 7c and R 7d are each independently -H, or a C 1 -C 3 linear or branched alkyl group; n 7B is 0;
  • a 1 C(R A1 )-; wherein R A1 is -H, D or -F;
  • L is -O- or -NH-
  • Q is a phenyl group substituted by R Q1 or a 3-6 membered cyclic hydrocarbon group -(CH 2 )n 2 - substituted by R Q2 ; n 2 is 1 or 2;
  • R Q1 and R Q2 are each independently -H, -CN, -CF 3 or halogen.
  • the nitrogen-containing heterocyclic compound represented by Formula I a tautomer thereof, an optical isomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or A prodrug, which is further preferably one of the following compounds:
  • the present invention also provides a method for producing a nitrogen-containing heterocyclic compound as shown in Formula I, which comprises the steps of: bromide intermediate represented by formula (IA) and formula (IB) The pinacol borate intermediate is subjected to a Suzuki coupling reaction;
  • the Suzuki coupling reaction can be carried out using conventional reaction conditions and parameters of such reactions in the art.
  • the present invention preferably carries out the reaction in the presence of a palladium catalyst and a base in a solvent; or it may be promoted by microwave irradiation.
  • the solvent is a conventional solvent for performing Suzuki coupling reaction in the art, including but not limited to 1,4-dioxane, acetonitrile, water or a mixture thereof.
  • the reaction temperature of the Suzuki coupling reaction is a conventional temperature at which the reaction is carried out in the art, such as from 80 °C to 110 °C.
  • the palladium catalysts are conventional catalysts for Suzuki coupling reactions in the art including, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).
  • the bases are conventional catalysts for Suzuki coupling reactions in the art including, but not limited to, carbonates or phosphates of sodium, potassium and rubidium.
  • the present invention still further provides a bromide intermediate represented by (I-A) or a pinacol borate intermediate represented by the formula (I-B).
  • the reactant in the above reaction may be substituted with the corresponding chlorine or iodide intermediate as the bromide intermediate represented by (IA); likewise, as in the formula (IB)
  • the pinacol borate intermediate shown can also be replaced by its boronic acid or other boronate derivative intermediate.
  • R 1N in the nitrogen-containing heterocyclic compound represented by Formula I is H
  • those skilled in the art can conceive that the bromide intermediate as shown in (IA) should be passed first.
  • the Suzuki coupling reaction as described above is carried out to remove the protecting group to obtain a nitrogen-containing heterocyclic compound as shown in Formula I.
  • the introduction and removal of protecting groups can be achieved by conventional reactions well known to those skilled in the art; such protecting groups can be conventionally used in the art to protect imidazole, pyrrole or other aryl heterocycles.
  • the preparation method of the nitrogen-containing heterocyclic compound as shown in Formula I preferably further comprises the following reaction route:
  • the present invention also provides the nitrogen-containing heterocyclic compound as described in Formula I, a tautomer thereof, an optical isomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or The use of its prodrugs in the preparation of bromodomain inhibitors.
  • the present invention also provides the nitrogen-containing heterocyclic compound as described in Formula I, a tautomer thereof, an optical isomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or
  • a prodrug thereof for the preparation of a medicament for treating and preventing a disease which requires modulation of the binding ability of a bromodomain to an acetylated protein for treatment and/or prevention (i.e., "a disease associated with a bromodomain and an acetylated protein" .
  • the disease which requires modulation of the binding ability of the bromodomain to the acetylated protein for treatment and/or prevention may be cancer, lung disease, inflammatory disease or autoimmune disease.
  • the cancer may include: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic cells) And promyelocytic), acute t-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, Chronic lymphocytic leukemia, Chronic myeloid (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (development) Adverse and metaplastic), embryonal cancer, endometri
  • the pulmonary disease, inflammatory disease or autoimmune disease may include: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin disease, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypopituitaritis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, muscle Inflammation, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, nodular polyarteritis, localized pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid Arthritis, scleritis, sclerosing cholangitis,
  • the present invention still further provides the nitrogen-containing heterocyclic compound represented by Formula I, a tautomer thereof, an optical isomer thereof, a hydrate thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof Or its prodrugs for the preparation of bromodomain inhibitors.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the nitrogen-containing heterocyclic compound of the formula I, a tautomer thereof, an optical isomer, a hydrate, a solvate thereof, and a pharmaceutically thereof thereof.
  • the mass percentage is from 0.1% to 99.9%, and the mass percentage refers to the nitrogen-containing heterocyclic compound as shown in Formula I, which is mutually mutated.
  • the nitrogen-containing heterocyclic ring, the tautomer, the optical isomer, the hydrate, the solvate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof as shown in Formula I, and the medicinal preparation thereof The sum of the mass fractions of the excipients is 100%.
  • the choice of the pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and is usually a filler, a diluent, a binder, a wetting agent, a disintegrating agent, a lubricant, an emulsifier or a suspending agent.
  • the invention also provides the use of the pharmaceutical composition for the preparation of a bromodomain inhibitor.
  • the present invention also provides the use of the pharmaceutical composition for the preparation of a medicament for treating and preventing a disease requiring modulation of the binding ability of a bromodomain to an acetylated protein for treatment and/or prevention.
  • the diseases which require modulation of the binding ability of the bromodomain to the acetylated protein for treatment and/or prevention are as described above.
  • the invention also provides a method of treating a disease or condition in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a nitrogen-containing heterocyclic compound of formula I, a tautomer thereof, An optical isomer, hydrate, solvate, pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein the disease or condition is selected from the group consisting of the ability to modulate the binding of a bromodomain to an acetylated protein as previously described.
  • Each of the atoms in the compound I is generally a natural atom, that is, a mixture of isotopes under natural conditions.
  • Hydrogen (H) for example, to which a mixture of natural proportions of protium (1 H) deuterium (2 H) and tritium (3 H).
  • the element symbol "D” means that the position is a germanium atom (which is not present in a natural proportion, but 100% is a germanium atom).
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • compositions of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like.
  • Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • the chemical formulae of the present invention may exhibit tautomerism, structural isomerism, and stereoisomerism.
  • the invention includes any interconversion or structural or stereoisomeric forms thereof, and mixtures thereof, the ability of which is not limited to any one or a mixture thereof.
  • a structural fragment of certain compounds contained in a compound of the formula of the present invention (R 4 is -H) isomerized to It is also within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be synthesized by asymmetric or Derivatization with a chiral auxiliary is prepared in which the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer.
  • a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art.
  • the diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and after substitution The compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • R 3 is directly bonded to the parent of the compound, and the substituents represented by R 1 , R 2 , and R 3 are sequentially bonded to each other by a chemical bond; otherwise, as “R 1 —R 2
  • the substituent represented by -R 3 -" can also be defined by a textual description, as described in the present invention, "3-6 membered cycloalkyl-(CH 2 )n 2 - substituted by R Q2 ", the meaning of which Is "R Q2 -3-6-membered cycloalkyl-(CH 2 )n 2 -", which means the substituent as indicated by "R Q2 substituted 3-6 membered cycloalkyl-(CH 2 )n 2 -"
  • the (CH 2 )n 2 is
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
  • the hydrocarbon radical or a combination thereof may be fully saturated, unitary or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may include divalent or polyvalent radicals having a specified number of carbon atoms (eg, C1 ) -C 10 represents 1 to 10 carbons).
  • the hydrocarbon group includes an aliphatic hydrocarbon group including an chain hydrocarbon group and a cyclic hydrocarbon group, and includes, but not limited to, an alkyl group, an alkenyl group, and an alkynyl group, and the aromatic hydrocarbon group includes, but not limited to, a 6-12 member aromatic hydrocarbon group.
  • alkyl refers to a straight or branched or cyclic group of atoms or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, a (cyclohexyl)methyl group, a cyclopropylmethyl group, and a homologue or isomer of an atomic group such as n-pentyl, n-hexyl, n-heptyl or n-octyl.
  • the unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.
  • heteroalkyl, heterocyclyl, hydrocarbyl, cyclohetero, heteroalkylhetero, heterocyclylhetero group means a hetero atom or a hetero atom group, a hetero atom or a hetero atom group on a specific group.
  • hetero atom or hetero atom group may be located within the ring system or outside the ring system (such as cyclopropyl sulfone group, cyclopropyl acyl group), wherein the so-called heterohydrocarbyl group and heterocyclic group are through the carbon atom and the rest of the molecule.
  • Linking that is, a hetero atom can be located anywhere in the group (except where the group is attached to the rest of the molecule); the so-called hydrocarbon heterocycle, cyclohetero is attached to the rest of the molecule through a heteroatom, ie, The atom is located at a position where the group is attached to the rest of the molecule; the so-called heterohydroalkyl heterocyclyl, heterocyclylhetero is attached to the remainder of the molecule through a heteroatom, wherein the heteroatom can be located anywhere in the group (including the The group is attached to the rest of the molecule).
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and the like), by itself or in combination with another term, means a stable straight chain.
  • the heteroatoms are selected from the group consisting of B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatoms B, O, N and S may be located at any internal position of the heterohydrocarbyl group (except where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkoxy alkylamino
  • alkylthio or thioalkoxy
  • cycloalkyl Unless otherwise specified, the terms “cycloalkyl”, “heterocycloalkyl”, “cyclohetero” or subordinates thereof (such as aryl, heteroaryl, aryl, cycloalkyl, heterocycloalkyl, ring) Alkyl, cycloalkenyl, heterocycloalkenyl, cycloalkenyl, cycloalkynyl, heterocycloalkynyl, cycloalkynyl, and the like, by themselves or in combination with other terms, respectively denote a cyclized “hydrocarbyl group", Heterohydrocarbyl” or “hydrocarbyl”.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), They are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl
  • aryl groups when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include the attachment of an aryl group to an alkane.
  • Those radicals of the group eg, benzyl, phenethyl, pyridylmethyl, etc.
  • a carbon atom eg, a methylene group
  • an oxygen atom such as phenoxymethyl, 2- Pyridinoxymethyl 3-(1-naphthyloxy)propyl and the like.
  • ring means substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted hetero Aryl.
  • the so-called ring includes a fused ring.
  • the number of atoms on the ring is usually defined as the number of elements of the ring.
  • 5-7 membered ring means 5-7 atoms arranged around.
  • the ring optionally contains from 1 to 3 heteroatoms.
  • 5-7 membered ring includes, for example, phenylpyridine and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • hetero atom as used herein, unless otherwise specified, includes atoms other than carbon (C) and hydrogen (H), including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), antimony ( Ge), aluminum (Al) and boron (B).
  • leaving group refers to a functional group or atom that can be substituted by another functional group or atom by a substitution reaction (eg, an affinity substitution reaction).
  • a substitution reaction eg, an affinity substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, “amino protecting group”, “hydroxy protecting group” or “thiol protecting group.”
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.
  • acyl such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxy
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo refers to fluoro, chloro, bromo and iodo.
  • heterocycle or “heterocyclyl” means a stable monocyclic or bicyclic or bicyclic heterocyclic ring which may be saturated, partially unsaturated or unsaturated (aromatic), which A carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocyclic rings may be fused to a phenyl ring to form a bicyclic ring.
  • heterocyclic compounds include, but are not limited to, acridinyl, anthracycline, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazole , benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH -carbazolyl, porphyrinyl, chromanyl, chromene, porphyrinyldecahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuran[2 ,3-b]tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthesis methods, and techniques of the art. Preferred embodiments are well known to those skilled in the art, and preferred embodiments include, but are not limited to, embodiments of the invention.
  • reaction conditions and reaction times for each individual step may vary depending on the particular reactant employed and the substituents present in the reactants employed. Solvents, temperatures and other reaction conditions can be readily selected by one skilled in the art, unless otherwise indicated. Specific methods are provided in the Synthesis Examples section.
  • the reaction can be worked up in a conventional manner, for example by removing the solvent from the residue and learning according to methods known in the art.
  • One-step purification such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography.
  • the starting materials and reagents are either commercially available or can be prepared from the commercially available materials by those skilled in the art using methods described in the chemical literature.
  • starting materials may be selected from techniques selected from standard organic chemistry techniques, similar to techniques for synthesizing known, structurally similar compounds, or similar to those described above in the Reaction Schemes section or in the Synthesis Examples section. Method to prepare.
  • an optically active form of the compound when desired, it can be obtained by performing an optically active starting material (e.g., by asymmetrically inducing a suitable reaction step) in one of the methods described herein, or by using standard methods. Obtained as a mixture of stereoisomers of a compound or an intermediate, such as by chromatographic separation, recrystallization or enzymatic resolution.
  • the invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, etc.
  • CDI carbonyl diimidazole
  • DCM dichloromethane
  • PE petroleum ether
  • DIAD diisopropyl azodicarboxylate
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EtOAc stands for ethyl acetate
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • CBz stands for benzyloxycarbonyl, an amine protecting group
  • BOC stands for t-butylcarbonyl is an amine protecting group
  • HOAc stands for acetic acid
  • NaCNBH 3 stands for cyanide Sodium borohydride
  • rt stands for room temperature
  • O/N stands for overnight
  • THF stands for tetrahydrofuran
  • Boc 2 O stands for di-tert-butyldicarbonate
  • TFA trifluoroacetic acid
  • DIPEA stands for diisopropylethylamine
  • the compounds of the invention are either by hand or Software naming, commercially available compounds using the supplier catalog name.
  • the positive progress of the present invention is that the nitrogen-containing heterocyclic compound of the present invention can effectively bind to the bromine domains of the BET family BRD4, BRD3, BRD2 and BRDT to regulate the transcription of the downstream gene c-myc and its related target genes. In turn, it regulates the downstream signaling pathway and plays a specific role, including the treatment of diseases such as inflammatory diseases, cancer and AIDS; some of the compounds have high activity, and have good cell activity and metabolic stability, so they can be used to treat tumors. Effective drugs.
  • Example 1001 N-(4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2- c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 3 4-(2,4-Difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)aniline
  • Step 8 7-Bromo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine
  • Step 10 7-Bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine-4(5H) -ketone
  • Step 11 7-(5-amino-2-(2,4-difluorophenoxy)phenyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Step 12 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)) Methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • N-(4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl) -4,5-Dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide (1.06 g, 1.80 mmol) was dissolved in trifluoroacetic acid (15 mL) then Stir at 80 ° C for 2 hours.
  • Example 1002 N-(4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2- c]pyridin-7-yl)phenyl)-N-methylethanesulfonamide
  • Step 1 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)) Methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)-N-methylethanesulfonamide
  • N-(4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl) -4,5-Dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide 100 mg, 0.17 mmol was dissolved in N,N-dimethylformamide ( 2 mL) was slowly added dropwise to a solution of sodium hydride (60% oil dispersion, 14 mg, 0.34 mmol) in N,N-dimethylformamide (2 mL) at 0 ° C under nitrogen.
  • Step 2 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c Pyridine-7-yl)phenyl)-N-methylethanesulfonamide
  • Example 1008 N-(4-(2,4-difluorophenoxy)-3-(1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3 ,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 5 N-(4-(2,4-Difluorophenoxy)-3-(1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3, 2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 5 2-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2 -dioxoborolan
  • Step 6 7-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl)-5-methyl-1-((2-(trimethylsilyl)) Ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Step 7 7-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl)-5-methyl-1H-pyrrolo[3,2-c]pyridine -4(5H)-ketone
  • Example 1012 4-(2,4-Difluorophenoxy)-N-ethyl-3-(5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3, 2-c]pyridin-7-yl)phenylsulfonamide
  • Step 3 2-(2,4-Difluorophenoxy)-5-(N-ethylaminoamide) phenylboronic acid
  • Step 4 4-(2,4-Difluorophenoxy)-N-ethyl-3-(5-methyl-4-oxo-1-((2-(trimethylsilyl))ethoxy) Methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)benzenesulfonamide
  • Step 3 6-(2,4-Difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine 3-amine
  • Step 4 7-(5-Amino-2-(2,4-difluorophenoxy)pyridin-3-yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy) Methyl)-1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Step 5 N-(6-(2,4-Difluorophenoxy)-5-(5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)) Methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)pyridin-3-yl)ethanesulfonamide
  • Step 6 N-(6-(2,4-Difluorophenoxy)-5-(5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c Pyridine-7-yl)pyridin-3-yl)ethanesulfonamide
  • N-(6-(2,4-Difluorophenoxy)-5-(5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl) -4,5-Dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)pyridin-3-yl)ethanesulfonamide (40 mg, 0.08 mmol) was dissolved in trifluoroacetic acid (2 mL). It was then stirred at 80 ° C for 2 hours.
  • Step 2 4-(4-Amino-2-bromophenoxy)benzene cyanide
  • Step 3 4-(4-Amino-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenoxy)phenyl cyanide
  • Step 4 4-(4-Amino-2-(5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro) -1H-pyrrolo[3,2-c]pyridin-7-yl)phenoxy)phenyl cyanide
  • Step 5 N-(4-(4-Cyanophenoxy)-3-(5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl) -4,5-Dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 6 N-(4-(4-Cyanophenoxy)-3-(5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine -7-yl)phenyl)ethanesulfonamide
  • N-(4-(4-Cyanophenoxy)-3-(5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-) 4,5-Dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide 230 mg, 0.4 mmol was dissolved in trifluoroacetic acid (3 mL) then stirred at 80 ° C 2 hours. The reaction mixture was concentrated, the ⁇ The reaction mixture was cooled to EtOAc EtOAc m.
  • Step 4 2-Amino-5-(2,4-difluorophenoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2 -based)benzamide
  • Step 5 2-Amino-5-(2,4-difluorophenoxy)-4-(5-methyl-4-oxo-1-((2-(trimethylsilyl))ethoxy) )methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)benzamide
  • Step 6 5-(2,4-Difluorophenoxy)-2-(ethylsulfonylamino)-4-(5-methyl-4-oxo-1-((2-(trimethylsilyl)) Ethyl)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)benzamide
  • Step 7 5-(2,4-Difluorophenoxy)-2-(ethylsulfonylamino)-4-(5-methyl-4-oxo-4,5-dihydro-1H-pyrrole [3,2-c]pyridin-7-yl)benzamide
  • Step 1 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-4-oxo-6-(trifluoromethyl)-4,5-dihydro-1H -pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 2 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H -pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Example 1006 N-(3-(2-((1,4-Dicyclocycloheptan-1-yl)methyl)-5-methyl-4-oxo-4,5-dihydro-1H -pyrrolo[3,2-c]pyridin-7-yl)-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide
  • Step 1 5-Bromo-2-methoxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)-1-propyn-1-yl)pyridin-4-amine
  • Step 3 7-Bromo-4-methoxy-2-((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((2-(trimethylsilyl)) Oxy)methyl)-1H-pyrrolo[3,2-c]pyridine
  • Step 4 7-Bromo-2-((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1H-pyrrolo[3,2-c]pyridine-4-hydroxyl
  • Step 5 7-Bromo-5-methyl 2-((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy) )methyl)-1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Step 6 7-Bromo-2-(hydroxymethyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2- c]pyridine-4(5H)-one
  • Step 7 7-Bromo-2-(chloromethyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2- c]pyridine-4(5H)-one
  • Step 8 4-((7-Bromo-5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H) -pyrrolo[3,2-c] Pyridin-2-yl)methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester
  • Step 9 4-((7-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-5-methyl-4-oxo-1-((2-(tri)) Silyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-1,4-diazacycloheptane- 1-carboxylic acid tert-butyl ester
  • Step 10 4-((7-(2-(2,4-Difluorophenoxy)-5-(ethanesulfonamido)phenyl)-5-methyl-4-oxo-1-(( 2-(Trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-1,4-di N-cycloheptane-1-carboxylic acid tert-butyl ester
  • Step 11 N-(3-(2-((1,4-Dicyclocycloheptan-1-yl)methyl)-5-methyl-4-oxo-4,5-dihydro-1H- Pyrrolo[3,2-c]pyridin-7-yl)-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide
  • Step 1 7-Bromo-5-methyl-2-((4-methyl-1,4-diazacycloheptan-1-yl)methyl)-1-((2-(trimethylsilane) Ethyl)methyl)-1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Step 2 7-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-5-methyl-2-((4-methyl-1,4-diazacycloheptane) -1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Step 3 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-2-((4-methyl-1,4-diazacycloheptan-1-yl) )methyl)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine -7-yl)phenyl)ethanesulfonamide
  • Step 4 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-2-((4-methyl-1,4-diazacycloheptan-1-yl) )methyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 1 7-Bromo-5-methyl-2-(morpholinemethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2 -c]pyridine-4(5H)-one
  • Step 2 7-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-5-methyl-2-(morpholinylmethyl)-1-((2-(tri-) Silyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Step 3 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-2-(morphinolinyl)-4-oxo-1-((2-(3) Methylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 4 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-2-(morpholinemethyl)-4-oxo-4,5-dihydro-1H -pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 1 7-Bromo-5-methyl-2-((4-methylpiperazin-1-yl)methyl l)-1-((2-(trimethylsilyl)ethoxy) A -1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Step 2 7-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-5-methyl-2-((4-methylpiperazin-1-yl)methyl) 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Step 3 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-2-((4-methylpiperazin-1-yl)methyl)-4-oxo 1-((2-(Trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl) Ethyl sulfonamide
  • Step 4 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-2-((4-methylpiperazin-1-yl)methyl)-4-oxo 4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Example 1021 N-(4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxo-2-(piperazin-1-ylmethyl)-4,5 -dihydro-1H-pyridyl [3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 1 4-((7-Bromo-5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H) -pyrrolo[3,2-c]pyridin-2-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 2 4-((7-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-5-methyl-4-oxo-1-((2-(tri)) Ethyl silicon)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 3 4-((7-(2-(2,4-Difluorophenoxy)-5-(ethanesulfonyl)phenyl)-5-methyl-4-oxo-1-(( 2-(Trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)piperazine-1-carboxylic acid Tert-butyl ester
  • Step 4 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-4-oxo-2-(piperazin-1-ylmethyl)-4,5- Dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Example 1004 N-(4-(2,4-difluorophenoxy)-3-(2-(hydroxymethyl)-5-methyl-4-oxo-4,5-dihydro-1H -pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 1 7-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-5-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy )methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Step 2 N-(4-(2,4-Difluorophenoxy)-3-(5-methyl-4-oxo-2-((tetrahydro-2H-pyran-2-yl)) Oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl Phenyl)ethanesulfonamide
  • Step 3 N-(4-(2,4-Difluorophenoxy)-3-(2-(hydroxymethyl)-5-methyl-4-oxo-4,5-dihydro-1H- Pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 1 7-Bromo-5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[ 3,2-c]pyridine-2-carbaldehyde
  • Step 2 (E)-7-Bromo-5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H -pyrrolo[3,2-c]pyridine-2-carboxaldehyde
  • Step 3 7-Bromo-5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[ 3,2-c]pyridine-2-carbonitrile
  • Step 4 7-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-5-methyl-4-oxo-1-((2-(trimethylsilyl)) Ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carbonitrile
  • Step 5 N-(3-(2-Cyano-5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-di Hydrogen-1H-pyrrolo[3,2-c]pyridin-7-yl)-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide
  • Step 6 N-(3-(2-Cyano-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)-4 -(2,4-difluorophenoxy)phenyl)ethanesulfonamide
  • Example 1018 7-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl)-5-methyl-4-oxo-4,5-dihydro -1H-pyrrolo[3,2-c]pyridine-2-carbonitrile
  • Step 1 7-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl)-5-methyl-4-oxo-1-((2- Trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carbonitrile
  • Step 2 7-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl)-5-methyl-4-oxo-4,5-dihydro- 1H-pyrrolo[3,2-c]pyridine-2-carbonitrile
  • Step 1 7-(5-Amino-2-(2,4-difluorophenoxy)pyridin-3-yl)-5-methyl-4-oxo-1-((2-(trimethyl)) Silyl)ethoxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
  • Step 2 N-(5-(2-Cyano-5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-di Hydrogen-1H-pyrrolo[3,2-c]pyridin-7-yl)-6-(2,4-difluorophenoxy)pyridin-3-yl)ethanesulfonamide
  • Step 3 N-(5-(2-Cyano-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)-6 -(2,4-difluorophenoxy)pyridin-3-yl)ethanesulfonamide and 7-(2-(2,4-difluorophenoxy)-5-(ethanesulfonylamino)pyridine-3 -yl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
  • Example 1003 2-((1,4-Diazinocycloheptan-1-yl)methyl)-5-methyl-7-(3-((pyridin-2-ylmethyl)amino)phenyl )-1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Step 1 N-(pyridin-2-ylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)aniline
  • Step 2 4-((5-Methyl-4-oxo-7-(3-((pyridin-2-ylmethyl)amino)phenyl)-1-((2-(trimethylsilyl)) Ethyloxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl-1,4-diazacycloheptane-1-carboxylic acid Butyl ester
  • Step 3 2-((1,4-Diazinocycloheptan-1-yl)methyl)-5-methyl-7-(3-((pyridin-2-ylmethyl)amino)phenyl) -1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Trimethylsilyl iodide (821 mg, 4.1 mmol) was added to 7-bromo-4-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-Pyrolo[3,2-c]pyridine (760 mg, 2.05 mmol) in EtOAc (10 mL). The reaction solution was stirred at 60 ° C for 2 hours and then cooled to room temperature. Water was added to the reaction mixture and the mixture was evaporated.
  • Step 5 7-Bromo-2,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]-pyridine- 4(5H)-ketone
  • Step 6 7-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-2,5-dimethyl-1-((2-(trimethylsilyl)ethoxy) Methyl)-1H-pyrrolo[3,2-c]-pyridine-4(5H)-one
  • Step 7 N-(4-(2,4-Difluorophenoxy)-3-(2,5-dimethyl-4-oxo-1-((2-(trimethylsilyl))) Oxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 8 N-(4-(2,4-difluorophenoxy)-3-(2,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3, 2-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Example 1010 N-(4-(2,4-difluorophenoxy)-3-(2,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3 ,2-c]pyridin-7-yl)phenyl)-N-methylethanesulfonamide
  • Step 1 N-(4-(2,4-Difluorophenoxy)-3-(2,5-dimethyl-4-oxo-1-((2-(trimethylsilyl))) Oxy)methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-7-yl)phenyl)-N-methylethanesulfonamide
  • Step 2 N-(4-(2,4-Difluorophenoxy)-3-(2,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3, 2-c]pyridin-7-yl)phenyl)-N-methylethanesulfonamide
  • Example 1005 N-(4-(2,4-difluorophenoxy)-3-(6-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine -8-yl)phenyl)ethanesulfonamide
  • Step 4 8-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-6-methylimidazo[1,2-c]pyrimidin-5(6H)-one
  • Step 5 N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine- 8-yl)phenyl)ethanesulfonamide
  • Step 4 5-(2,4-Difluorophenoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)- 1H-carbazole
  • Step 5 8-(5-(2,4-Difluorophenoxy)-1H-indazol-6-yl)-6-methylimidazo[1,2-c]pyrimidine-5(6H)- ketone
  • Step 4 7-Bromo-1,5-dimethyl-1H-pyrazolo[4,3-c]pyridine-4(5H)-one and 7-bromo-2,5-dimethyl-2, 5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one
  • Step 5 7-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-1,5-dimethyl-1H-pyrazolo[4,3-c]pyridine-4 (5H)-ketone and 7-(5-amino-2-(2,4-difluorophenoxy)phenyl)-2,5-dimethyl-2,5-dihydro-4H-pyrazole [4,3-c]pyridin-4-one
  • Step 6 N-(4-(2,4-Difluorophenoxy)-3-(1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrazolo[4 ,3-c]pyridin-7-yl)phenyl)ethanesulfonamide and N-(4-(2,4-difluorophenoxy)-3-(2,5-dimethyl-4-oxo -4,5-dihydro-2H-pyrazolo[4,3-c]pyridin-7-yl)phenyl)ethanesulfonamide
  • Step 3 7-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-2-methyl-2H-pyrazolo[4,3-c]pyridine-4-hydroxy
  • Step 1 7-(2-Fluoro-5-nitrophenyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3, 2-c]pyridine-4(5H)-one
  • Step 2 7-(2-(5-Fluoropyridin-2-yl)oxy)-5-nitrophenyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy) )methyl)-1H-pyrrolo[3,2-c]pyridine-4(5H)-one
  • Step 3 7-(5-Amino-2-(5-fluoropyridin-2-yl)oxy)phenyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy) )methyl)-1H-pyrrolo[3,2-c]pyridine-4(5H)-one

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Abstract

La présente invention concerne des composés hétérocycliques contenant de l'azote, leur procédé de préparation, une composition pharmaceutique de ceux-ci, et leurs applications. Les composés hétérocycliques contenant de l'azote représentés par la formule I peuvent être efficacement combinés avec des bromodomaines de BRD4, BRD3, BRD2 et BRDT d'une famille BET, de manière à réguler la transcription d'un gène aval c-myc ou et de gènes cibles associés, de manière à réguler une voie de signal aval et joue un rôle spécifique, comprenant le traitement de maladies telles que des maladies inflammatoires, des cancers et le SIDA. Une partie des composés ont une activité très élevée et ont une bonne activité cellulaire et une bonne stabilité métabolique, et par conséquent, les composés peuvent devenir des médicaments efficaces pour traiter des tumeurs.
PCT/CN2017/110539 2016-11-10 2017-11-10 Composés hétérocycliques contenant de l'azote, leur procédé de préparation, leur composition pharmaceutique et leurs applications WO2018086604A1 (fr)

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US10618910B2 (en) 2014-09-15 2020-04-14 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US10626114B2 (en) 2016-06-20 2020-04-21 Incyte Corporation Crystalline solid forms of a BET inhibitor
US10781209B2 (en) 2014-04-23 2020-09-22 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US10858372B2 (en) 2015-10-29 2020-12-08 Incyte Corporation Amorphous solid form of a BET protein inhibitor
US10919912B2 (en) 2013-03-15 2021-02-16 Incyte Holdings Corporation Tricyclic heterocycles as BET protein inhibitors
US11091484B2 (en) 2013-12-19 2021-08-17 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US11192900B2 (en) 2018-10-30 2021-12-07 Nuvation Bio Inc. Substituted 1,6-dihydropyridinones and 1,2-dihydroisoquinolinones as bet inhibitors
WO2022033542A1 (fr) * 2020-08-14 2022-02-17 南京明德新药研发有限公司 Composés de pyridone hétéroaromatiques à 5 chaînons et leur application
JP2022529575A (ja) * 2019-03-17 2022-06-23 シャンハイ リンジーン バイオファーマ カンパニー リミテッド ピロールアミドピリドン系化合物、製造方法及び使用
US11584756B2 (en) 2019-07-02 2023-02-21 Nuvation Bio Inc. Heterocyclic compounds as BET inhibitors
EP4043462A4 (fr) * 2019-10-08 2023-11-01 Haihe Biopharma Co., Ltd. Composé ayant une activité inhibitrice de brd4, son procédé de préparation et son utilisation
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
RU2809596C2 (ru) * 2019-03-17 2023-12-13 Шанхай Ринджин Биофарма Ко., Лтд. Соединение на основе пирроламидопиридона, способ его получения и его применение
CN118388401A (zh) * 2024-06-28 2024-07-26 成都凯斯坦生物医药有限公司 一种4-氨基-2-氯烟醛的制备方法

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CN112300154B (zh) * 2019-07-31 2023-01-24 上海弘翊生物科技有限公司 一类含氮杂环化合物、其制备方法和用途
CN115028646B (zh) * 2022-05-31 2023-06-30 山东第一医科大学(山东省医学科学院) 一种含氮杂环类化合物、制备方法及在抗肿瘤制剂中的应用

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US11498926B2 (en) 2013-03-15 2022-11-15 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US10919912B2 (en) 2013-03-15 2021-02-16 Incyte Holdings Corporation Tricyclic heterocycles as BET protein inhibitors
US11091484B2 (en) 2013-12-19 2021-08-17 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US10781209B2 (en) 2014-04-23 2020-09-22 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US11059821B2 (en) 2014-04-23 2021-07-13 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US11702416B2 (en) 2014-04-23 2023-07-18 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US10618910B2 (en) 2014-09-15 2020-04-14 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US10858372B2 (en) 2015-10-29 2020-12-08 Incyte Corporation Amorphous solid form of a BET protein inhibitor
US11091480B2 (en) 2016-06-20 2021-08-17 Incyte Corporation Crystalline solid forms of a BET inhibitor
US12030882B2 (en) 2016-06-20 2024-07-09 Incyte Corporation Crystalline solid forms of a bet inhibitor
US11377446B2 (en) 2016-06-20 2022-07-05 Incyte Corporation Crystalline solid forms of a BET inhibitor
US10626114B2 (en) 2016-06-20 2020-04-21 Incyte Corporation Crystalline solid forms of a BET inhibitor
US11192900B2 (en) 2018-10-30 2021-12-07 Nuvation Bio Inc. Substituted 1,6-dihydropyridinones and 1,2-dihydroisoquinolinones as bet inhibitors
JP2022529575A (ja) * 2019-03-17 2022-06-23 シャンハイ リンジーン バイオファーマ カンパニー リミテッド ピロールアミドピリドン系化合物、製造方法及び使用
RU2809596C2 (ru) * 2019-03-17 2023-12-13 Шанхай Ринджин Биофарма Ко., Лтд. Соединение на основе пирроламидопиридона, способ его получения и его применение
US11584756B2 (en) 2019-07-02 2023-02-21 Nuvation Bio Inc. Heterocyclic compounds as BET inhibitors
EP4043462A4 (fr) * 2019-10-08 2023-11-01 Haihe Biopharma Co., Ltd. Composé ayant une activité inhibitrice de brd4, son procédé de préparation et son utilisation
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
WO2022033542A1 (fr) * 2020-08-14 2022-02-17 南京明德新药研发有限公司 Composés de pyridone hétéroaromatiques à 5 chaînons et leur application
CN118388401A (zh) * 2024-06-28 2024-07-26 成都凯斯坦生物医药有限公司 一种4-氨基-2-氯烟醛的制备方法

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