WO2021233371A1 - Compound functioning as bromodomain protein inhibitor, and composition - Google Patents

Compound functioning as bromodomain protein inhibitor, and composition Download PDF

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Publication number
WO2021233371A1
WO2021233371A1 PCT/CN2021/094838 CN2021094838W WO2021233371A1 WO 2021233371 A1 WO2021233371 A1 WO 2021233371A1 CN 2021094838 W CN2021094838 W CN 2021094838W WO 2021233371 A1 WO2021233371 A1 WO 2021233371A1
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Prior art keywords
methyl
ethyl
oxo
pyridine
dihydro
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PCT/CN2021/094838
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French (fr)
Chinese (zh)
Inventor
徐琰
于波
郭晶
刘湘永
王家炳
丁列明
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贝达药业股份有限公司
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Priority to CN202180033928.8A priority Critical patent/CN115667254A/en
Publication of WO2021233371A1 publication Critical patent/WO2021233371A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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
    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to compounds that can inhibit bromodomain-containing proteins or otherwise modulate their activity, compositions and preparations containing such compounds, and methods of using and preparing such compounds.
  • the bromodomain (bromodomain, BRD) protein containing the BET (bromodomain and terminal extradomain) family includes 4 types: BRD2, BRD3, BRD4 and BRDT, each protein includes 2 different bromodomains (BD1 and BD2).
  • the proteins of the BET family are readers of epigenetic coding, acetylation of lysine residues coupled to histones to change chromatin structure and gene expression.
  • BRD2, BRD3 and BRD4 are ubiquitously expressed, while BRDT is restricted to germ cells.
  • BET protein plays a necessary but non-overlapping role in regulating gene transcription and controlling cell growth.
  • BET proteins are related to large protein complexes that regulate the transcription of many genes, including RNA polymerase II (Pol II) and forward transcription elongation factor (P-TEFb). It has been confirmed that BRD2 and BRD4 proteins remain bound to chromosomes during mitosis, and the proteins are required to promote the transcription of important genes (including cyclin D and c-MYC) that initiate the cell cycle (Mochizuki, J Biol. Chem. 2008 283: 9040 -9048).
  • RNA polymerase II Polymerase II
  • P-TEFb forward transcription elongation factor
  • BRD4 protein combines with RNA polymerase II (Pol II) and positive transcription elongation factor (P-TEFb) to jointly promote a variety of cancer cell proliferation and apoptosis-related genes such as c-MYC, cyclin,
  • RNA polymerase II Polymerase II
  • P-TEFb positive transcription elongation factor
  • the kinase activity of BRD4 can directly phosphorylate and activate RNA polymerase II (Devaiah et al., PNAS 2012 109: 6927-6932). Cells lacking BRD4 show impaired cell cycle progression.
  • BRD2 and BRD3 are related to histones and actively transcribed genes and can participate in promoting transcription elongation (Leroy et al., Mol. Cell. 2008 30:51-60).
  • BET protein has been shown to selectively bind to acetylated transcription factors, including NF-kB and the RelA subunit of GATAl, thereby directly regulating the transcriptional activity of these proteins to control the expression of genes involved in inflammation and hematopoietic differentiation ( Huang et al., Mol. Cell Biol. 2009 29:1375-1387; Lamonica Proc. Nat. Acad. Sci. 2011108: E159-168).
  • BD1 selective inhibitors can Accelerate the differentiation of oligodendrocytes, which is the opposite of the effect of non-selective inhibitors; BD2 selective inhibitors have a broader effect on other acetylation substrates, while BD1 only recognizes H4 acetylation markers.
  • BRD4 small molecule inhibitors such as the compound Mivebresib (ABBV-075), the compound ABBV-744, the compound Apabetalone (RVX-208), etc., among which ABBV-744 is highly selective for BRD4-BD2 Small molecule inhibitors, whose selectivity for BRD4 (D2) is more than 100 times greater than that for BRD4 (D1), are currently in the clinical phase I and can be used for solid tumors and hematomas.
  • ABBV-744 is highly selective for BRD4-BD2 Small molecule inhibitors, whose selectivity for BRD4 (D2) is more than 100 times greater than that for BRD4 (D1), are currently in the clinical phase I and can be used for solid tumors and hematomas.
  • Inhibitors provide a new drug choice for the clinical treatment of diseases or disorders mediated by BET.
  • the present invention relates to compounds as bromodomain inhibitors, especially BRD4 inhibitors, and their use in the treatment of diseases mediated by BET.
  • the present invention first provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-10 heterocyclic group;
  • R 2 , R 3 , R 4 and R 5 are each independently selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-10 heterocyclic group;
  • Ring A is a C 6-10 aryl group, a C 5-10 heteroaryl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group or a C 3-10 heterocyclic group;
  • E 1 is CR 7 or N
  • E 2 is CR 8 or N
  • D 1 is C or N
  • D 2 is C or N
  • D 3 is C or N
  • At least one of D 1 , D 2 and D 3 is N, and at least one is C;
  • R 7 and R 8 are each independently selected from H, halogen, hydroxy, oxo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-10 heterocyclic group;
  • R a and R b are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3 -10 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl;
  • N atom or R a and R b are commonly connected thereto form C 3-10 heterocyclyl group, wherein the C 3-10 heterocyclyl group may be allowed to H, halo, cyano, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;
  • R c is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-10 heterocycle base;
  • R x is selected from C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, wherein the R x may May be substituted by H, halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or -NR a R b ;
  • n 0, 1, 2, or 3.
  • the present invention further provides some preferred technical solutions.
  • R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 3-6 cycloalkyl.
  • the R 1 is a C 1-6 alkyl group.
  • R 2 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.
  • R 2 is C 1-6 alkyl.
  • R 3 is H or C 1-6 alkyl.
  • R 4 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl Or C 3-10 heterocyclic group.
  • R 4 is H or C 1-6 alkyl.
  • ring A is C 6-10 aryl or C 5-10 heteroaryl.
  • R 5 is selected from halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy.
  • R 5 is selected from halogen or C 1-6 alkyl.
  • R 7 and R 8 are selected from H or C 1-6 alkyl.
  • R a and R b are each independently selected from H, C 1-6 alkyl or C 5-10 heteroaryl;
  • N atom or R a and R b are commonly connected thereto form C 3-10 heterocyclyl group, wherein the C 3-10 heterocyclyl group may be allowed to H, halo, cyano, C 1-6 alkyl or C 1-6 substituted by haloalkyl;
  • R c is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R x is selected from C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, wherein the R x may It is optionally substituted by H, halogen, cyano, C 1-6 alkyl or -NR a R b .
  • R 10 is selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or -OR c .
  • R 10 is selected from H, C 1-6 alkyl or C 1-6 alkoxy.
  • R a and R b are each independently selected from H, C 1-6 alkyl or a C 5-10 heteroaryl; N atoms, or R a and R b are commonly connected thereto form C 4-6 heteroaryl Cyclic groups, wherein the C 4-6 heterocyclic group can be optionally substituted by H or C 1-4 alkyl.
  • R c is selected from H, methyl, or ethyl.
  • R x is selected from
  • the C 1-6 alkyl group is optionally substituted by H, halogen, -OH, -NH 2 , -N(CH 3 ) 2 or cyclopropane;
  • R a and R b are each independently selected from H or C 1-6 alkyl
  • R c is selected from H or C 1-6 alkyl
  • R x is cyclopropane, and the R x can be optionally substituted by H, halogen, -NH 2 or -N(CH 3 ) 2 .
  • the compound is represented by formula (II),
  • the compound is represented by formula (III),
  • the W 1 , W 2 and W 3 are C or N.
  • E 1 and E 2 are both CH.
  • E 1 is CH and E 2 is N.
  • W 1 , W 2 and W 3 are all C.
  • W 1 is C
  • W 2 and W 3 are C or N, provided that when W 2 and W 3 are not all C, only one of W 2 and W 3 is N.
  • R 1 is methyl or ethyl.
  • R 2 is methyl
  • R 3 and R 4 are H.
  • R 5 is methyl or halogen.
  • D 1 is N and D 2 is C.
  • D 1 is C and D 2 is N.
  • the bicyclic moiety containing D 1 atom is selected from:
  • the present invention further provides a compound or a pharmaceutically acceptable salt thereof, and the compound refers to:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-mentioned compounds and pharmaceutically acceptable excipients, such as hydroxypropyl methylcellulose.
  • pharmaceutically acceptable excipients such as hydroxypropyl methylcellulose.
  • the weight ratio of the compound to the excipient is about 0.001-10.
  • the present invention also provides a method for treating a subject suffering from a disease or condition that responds to the inhibition of a bromodomain-containing protein, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof .
  • the bromodomain-containing protein is BRD4.
  • the disease or condition is selected from autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, renal diseases, viral infections.
  • the disease or condition is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive Airway disease, pneumonia, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), Acute rejection of transplanted organs.
  • the disease or condition is cancer, including hematological tumors (e.g., lymphoma, multiple myeloma, leukemia) and solid tumors.
  • the disease or condition is colon, rectum, prostate (e.g. castrate resistant prostate cancer), lung (e.g.
  • non-small cell lung cancer and/or small cell lung cancer pancreas, liver, kidney , Cervix, uterus, stomach, ovary, breast (such as basal or basal-like breast cancer and/or triple negative breast cancer), skin (such as melanoma), nervous system (including brain, meninges and central nervous system, including Neuroblastoma, glioblastoma, meningioma, and medulloblastoma) tumors or cancers.
  • the disease or condition is cancer.
  • the disease or condition is hepatocellular carcinoma.
  • the disease or condition is myelodysplastic syndrome.
  • the disease or condition is myeloproliferative neoplasms.
  • the disease or condition is primary myelofibrosis. In certain aspects, the disease or condition is polycythemia vera and polycythemia vera secondary to myelofibrosis. In certain aspects, the disease or condition is essential thrombocythemia and essential thrombocythemia secondary to myelofibrosis. In certain aspects, the disease or condition is lymphoma. In certain aspects, the disease or condition is B-cell lymphoma. In certain aspects, the disease or condition is Burkitt's lymphoma. In certain aspects, the disease or condition is diffuse large B-cell lymphoma. In certain aspects, the disease or condition is multiple myeloma.
  • the disease or condition is chronic lymphocytic leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML).
  • the disease or condition is NUT midline cardinoma.
  • the subject is a human.
  • the compound is administered intravenously, intramuscularly, parenterally, nasally, or orally. In one aspect, the compound is administered orally.
  • the present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of diseases or disorders responsive to the inhibition of the bromodomain protein.
  • the present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for use in therapy. There is further provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a subject suffering from a disease or condition responsive to the inhibition of a bromodomain-containing protein.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • Preferred halogen groups refer to fluorine, chlorine and bromine.
  • alkyl includes linear, branched or cyclic saturated monovalent hydrocarbon groups.
  • alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2 -Methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
  • C 1-6 in C 1-6 alkyl refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or branched chain.
  • alkoxy refers to an oxyether formed from the aforementioned linear, branched or cyclic alkyl group.
  • alkylene refers to a divalent alkyl linking group.
  • alkylene refers to an alkane in which two CH bonds are replaced with the point of attachment of the alkylene to the rest of the compound.
  • C 1-4 in the C 1-4 alkylene group refers to an alkylene group containing 1, 2, 3, or 4 carbon atoms.
  • haloalkyl refers to an alkyl group in which one or more H has been replaced by a halogen atom.
  • haloalkoxy refers to the group -O-haloalkyl.
  • oxo refers to an oxygen atom in the form of a dimethyl substituent, which forms a carbonyl group when connected to C, and forms a sulfoxide or sulfone group or an N-oxide group when connected to a heteroatom.
  • aromatic ring means having aromatic characteristics (having (4n+2) non-localized ⁇ electrons, where n is Integer) carbocyclic or heterocyclic polyunsaturated ring.
  • aryl is a substituted or unsubstituted, stable, 6 to 10 ring carbon atom aromatic hydrocarbon group, which may contain one aromatic ring or multiple aromatic rings (for example, fused bicyclic rings). The aromatic ring does not contain heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and the like.
  • heteroaryl refers to a monocyclic or polycyclic (eg, fused bicyclic) aromatic heterocyclic ring having at least one heteroatom ring member selected from N, O and/or S.
  • heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, benzimidazole, benzothienyl, benzofuranyl and the like.
  • cycloalkyl refers to a ring system having at least one cyclized alkyl group.
  • C 3-10 in the term C 3-10 cycloalkyl means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms.
  • Cycloalkyl groups may include monocyclic and polycyclic rings (e.g., having 2, 3 or 4 fused rings, spiro rings, fused rings, etc.).
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; in some embodiments, cycloalkyl groups also include those having one or more aromatic rings fused with cyclized alkyl rings. Part, such as benzo or thienyl derivatives of cyclohexane.
  • cycloalkenyl refers to a ring system having at least one cyclized alkenyl group with one or more carbon-carbon double bonds in the cycloalkenyl group.
  • C 3-10 in the term C 3-10 cycloalkenyl means that the cycloalkenyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms.
  • Cycloalkenyl groups may include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.).
  • cycloalkenyl includes, but is not limited to, cyclohexenyl, cyclohexadiene, cycloheptatrienyl, etc.; in some embodiments, cycloalkenyl also includes those having one or more fused rings with cyclized alkenyl Part of the aromatic ring, such as benzo or thienyl derivatives of the cyclohexene ring.
  • heterocyclyl refers to a ring system having at least one cyclized alkyl or cyclized alkenyl containing a heterocyclic ring, and the heteroatom is selected from N, O and/or S.
  • the heterocyclic group may include a single ring or a polycyclic ring (for example, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.).
  • the heterocyclic group can be connected to other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom.
  • heterocyclic group also includes moieties having one or more aromatic rings fused with a cyclized alkyl or cyclized alkenyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, etc. .
  • heterocyclic groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, morpholinyl, azepanyl, dihydrobenzofuranyl, etc. .
  • composition in the present invention is intended to include a product containing a specific amount of a specific component, as well as any product obtained directly or indirectly from a specific amount of a specific component. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient and a method for preparing the compound are also the content of the present invention. Furthermore, the crystal forms of some compounds may exist in polymorphic forms, and these are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and these solvates are also included in the present invention.
  • the prodrug of the compound of the present invention is included in the protection scope of the present invention.
  • the prodrug refers to a functional derivative that is easily converted into a desired compound in the body. Therefore, the term "administration" in the method of treatment provided by the present invention includes the administration of the compound disclosed in the present invention, or although it is not clearly disclosed but can be transformed into the compound disclosed in the present invention after administration to a subject in vivo.
  • Various diseases include the conventional methods for selecting and preparing suitable prodrug derivatives.
  • the conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as "Design of Prodrugs” (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
  • the compound of the present invention may contain one or more asymmetric centers, and may produce diastereomers and optical isomers from this.
  • the present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
  • the above formula (I) does not exactly define the three-dimensional structure of a certain position of the compound.
  • the present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. In the synthetic process of preparing such compounds, or in the process of using racemization or epimerization methods well known to those of ordinary skill in the art, the product obtained may be a mixture of stereoisomers.
  • the present invention includes any possible tautomers, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • the present invention includes any possible solvate and polymorph.
  • the type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone and similar solvents can be used.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
  • the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are the salts of ammonium, calcium, magnesium, potassium, and sodium.
  • non-toxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents.
  • non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, ammonia Butanetriol and so on.
  • ion exchange resins and arginine betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -
  • the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pyruvic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, Cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharic acid, trifluoroacetic acids, acetic acid, benzene
  • citric acid Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, especially at least 98% purity (% is a weight ratio ).
  • the pharmaceutical composition provided by the present invention includes as an active component a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
  • a pharmaceutical composition of the present invention includes oral, rectal, topical and A pharmaceutical composition for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration).
  • the pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.
  • the compound represented by formula (I) of the present invention can be used as an active component and mixed with a drug carrier to form a drug combination Things.
  • the pharmaceutical carrier can take a variety of forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may take the form of a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient.
  • the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device.
  • the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both. Then, the product can be easily prepared into the desired appearance.
  • the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and one or more other compounds with therapeutic activity are also included in the pharmaceutical composition of the present invention.
  • the drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier.
  • Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil and water.
  • the gas carrier includes carbon dioxide and nitrogen.
  • any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here.
  • standard aqueous or non-aqueous formulation techniques can be used for tablet coating.
  • Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by compressing or molding one or more auxiliary components or adjuvants together.
  • the active ingredient is in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surfactant or dispersant, and compressed in a suitable machine to obtain compressed tablets.
  • the powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet.
  • each tablet contains about 0.05 mg to 5 g of active ingredient
  • each cachet or capsule contains about 0.05 mg to 5 g of active ingredient.
  • a dosage form intended for oral administration to humans contains about 0.5 mg to about 5 g of active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 95% of the total pharmaceutical composition.
  • the unit dosage form generally contains about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
  • the pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water.
  • a suitable surfactant such as hydroxypropyl cellulose may be included.
  • glycerol, liquid polyethylene glycol, and their mixture in oil, dispersion systems can also be prepared.
  • a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.
  • the present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems.
  • the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for immediate preparation of sterile injection or dispersion.
  • the final injection form must be sterile, and for easy injection, it must be easy to flow.
  • the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred.
  • the carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
  • the pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting powder or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device.
  • these preparations can be prepared by conventional processing methods.
  • an emulsion or ointment is prepared by adding a hydrophilic material and water to about 5 wt% to 10 wt% of the above-mentioned compound to prepare an emulsion or ointment having the desired consistency.
  • the pharmaceutical composition provided by the present invention can be made into a form that takes a solid as a carrier and is suitable for rectal administration.
  • the preferred dosage form is a suppository in which the mixture forms a unit dose.
  • Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared. First, the pharmaceutical composition is mixed with softened or melted excipients, and then cooled and molded.
  • the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants and preservatives (including antioxidants), etc.
  • other adjuvants can also include penetration enhancers that regulate the isotonic pressure between the drug and the blood.
  • the pharmaceutical composition containing the compound represented by formula (I), or a pharmaceutically acceptable salt thereof can also be prepared in the form of a powder or a concentrated solution.
  • the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day.
  • the specific dosage level for any particular patient will depend on many factors, including age, weight, overall health, gender, diet, time of administration, route of administration, excretion rate, combination of drugs and acceptance The severity of the specific disease being treated.
  • ACN or CH 3 CN Acetonitrile
  • BRD4 Bromodomain protein 4 (domain 1);
  • BRD4 Bromodomain protein 4 (domain 2);
  • DIEA N,N-diisopropylethylamine
  • DMSO dimethyl sulfoxide
  • HATU 2-(O-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • H 2 O 2 hydrogen peroxide
  • K 2 CO 3 potassium carbonate
  • LDA lithium diisopropylamide
  • NaNO 2 Sodium nitrite
  • n-Hex n-hexane
  • Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride;
  • Pd(dppf)Cl 2 .DCM [1,1'-bis(diphenylphosphine)ferrocene] palladium dichloride dichloromethane complex;
  • Pd(PPh 3 ) 4 Palladium tetrakistriphenylphosphide
  • Pd(PPh 3 ) 2 Cl 2 Bistriphenylphosphorus palladium dichloride
  • PE petroleum ether
  • PtO 2 platinum dioxide
  • THF Tetrahydrofuran
  • TsCl p-toluenesulfonyl chloride
  • TMSCl trimethylchlorosilane
  • Zn(CN) 2 zinc cyanide
  • the organic phase was washed three times with saturated brine, and concentrated to obtain a crude product.
  • the crude product was slurried with ACN, filtered with suction, and the filter cake was washed with a small amount of ACN to obtain 102 g of the title compound M1-3.
  • Dissolve M1-3 (102.5g) in THF (1000mL), cool to -5°C in an ice-salt bath, add NaH (59.6g) in batches at -5°C, return to room temperature and stir for 2.0hrs after addition.
  • a solution of TsCl (111.9 g) in THF (600 mL) was added dropwise to the reaction solution at -5°C. After the addition is complete, return to room temperature naturally and stir overnight.
  • Example 1 and Example 2 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)- N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (compound 1) and 4-(5-( 2,6-Dimethylphenoxy)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-6-yl)-N-ethyl-6-methyl-7-oxy Preparation of Subo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 2)
  • Step 1 Synthesis of compound 1-1 and compound 2-1
  • the corresponding 2,6-dimethylphenol derivative was used to replace the (2,6-Dimethylphenol)
  • the examples in Table 1 below were prepared.
  • the corresponding 2,6-dimethylphenol derivatives, for example Etc. can be purchased through commercial channels.
  • the corresponding iodomethane analogue was used to replace CH 3 I (methyl iodide) in the examples to prepare the examples in Table 2 below.
  • the corresponding analog of methyl iodide such as ethyl iodide or Etc. can be purchased through commercial channels.
  • Step 1 Synthesis of compound 51-1 (a mixture of compound 51A-1 and compound 52B-1)
  • Step 2 Synthesis of compound 51-2 (a mixture of compound 51A-2 and compound 52B-2)
  • Step 3 Synthesis of compound 51-3 (a mixture of compound 51A-3 and compound 52B-3)
  • Step 3 Synthesis of compound 55-3 (a mixture of compound 55A-3 and compound 56B-3)
  • Example 55 Using a method basically similar to that in Example 55, the corresponding 1-fluorocyclopropylmethanol analogue was used to replace the (1-Fluorocyclopropylmethanol)
  • the following examples in Table 4 were prepared.
  • the corresponding 1-fluorocyclopropylmethanol analogues, for example Etc. can be purchased through commercial channels.
  • the corresponding cyclopropyl boronic acid analogue was used to replace the (Cyclopropylboronic acid)
  • the following examples were prepared.
  • N,N,N'-trimethylethylenediamine analogues were used to replace the (N,N,N'-Trimethylethylenediamine)
  • the following examples in Table 6 were prepared.
  • Reactant 85-4 (200mg), intermediate M1 (176.90mg), K 2 CO 3 (141.65mg), Pd(dppf)Cl 2 (30mg) were sequentially added to dioxane (5mL) and H 2 O (5 mL) of the mixed solution, protected by N 2 and stirred at 80°C for 12 hrs.
  • the inhibition rate of the compound was detected on BRD4 (D1) and BRD4 (D2).
  • the compounds were dissolved into 20mM with DMSO respectively, and then the compounds were diluted with DMSO to the initial concentration of 3uM, and then diluted 3 times with 10 concentration points to prepare the working solution. Transfer the compound working solution to the wells of the 384 plate. Add 2 times the volume of the protein/peptide mixture to the wells of the 384 plate, and then add 2 times the volume of the test mixture, and shake for 30 seconds. The plate was incubated for 1.5 h at room temperature, and then the HTRF signal was read on EnVision.
  • Inhibition rate (%) (maximum value-signal value) / (maximum value-minimum value) * 100
  • the IC 50 data of the examples are provided in Table 9, where A1 represents 0nM ⁇ IC 50 ⁇ 0.5nM; A2 represents 0.5nM ⁇ IC 50 ⁇ 1nM; A3 represents 1nM ⁇ IC 50 ⁇ 3nM; A4 represents 3nM ⁇ IC 50 ⁇ 10nM; B1 represents 10nM ⁇ IC 50 ⁇ 300nM; B2 represents 300nM ⁇ IC 50 ⁇ 1000nM; B3 represents IC 50> 1000nM.
  • Table 9 exemplarily lists the inhibitory ability of the compounds of the present invention on BRD4 (D1) and BRD4 (D2). It can be seen that the compounds of the present invention exhibit excellent BRD4 (D2) selectivity.
  • the compounds are The selectivity of BRD4 (D2) is about 300-800 times that of BRD4 (D1); in some embodiments, the selectivity of the compound to BRD4 (D2) is comparable to that of BRD4 (D1). The ratio is about 800-1200 times;.
  • the effect of the compound on the proliferation of MV-4-11 cells was detected by the CellTiter-Glo Luminescent Cell Viability Assay (CellTiter-Glo Luminescent Cell Viability Assay) method.
  • MV-4-11 cells were cultured in complete medium (IMDM (Iscove's Modified Dubecco's Medium) medium containing 10% (v/v) FBS (fetal bovine serum)). Then, the MV-4-11 cells were adjusted to a cell suspension of 3.7 ⁇ 10 4 cells/mL with complete medium. Add 135 ⁇ L of cell suspension (three multiple wells for each concentration) to a 96-well plate, and the final cell density is 5000 cells/well. The test compound was dissolved in DMSO (concentration of 3 mM). Dilute with DMSO 3-fold gradient, 9 concentrations, and the 10th well is DMSO control. Add the compound from the compound plate to the cells of the corresponding well plate.
  • IMDM Iscove's Modified Dubecco's Medium
  • FBS fetal bovine serum
  • the final concentration of DMSO is 0.1%, and the highest concentration of compound is 3000 nM.
  • the wells without adding cells and medium are used as blank control wells, and 0.1% DMSO is used as the DMSO control well.
  • Inhibition rate% ((DMSO control well-compound well)/(DMSO control well-blank control well)) ⁇ 100
  • the IC 50 data of the MV4-11 cells of the examples are provided in Table 10, where * means IC 50 ⁇ 200 nM; ** means 200 nM ⁇ IC 50 ⁇ 500 nM; *** means IC 50 >500 nM.
  • Example number MV-4-11(cell)IC 50 Example number MV-4-11(cell)IC 50
  • Example number MV-4-11(cell)IC 50 1 21.8 30 43.7 59 21.4 2 3.7 31 1.4 60 51.2 3 1.0 32 83.4 61 52.7 4 * 33 * 62 11.7 5 21.9 34 * 63 5.6 6 44.3 35 12.4 64 3.9 7 31.9 36 * 65 1.2 8 *** 37 9.4 66 11.1 9 *** 38 ** 67 37
  • Example number MV-4-11(cell)IC 50 Example number MV-4-11(cell)IC 50
  • Example number MV-4-11(cell)IC 50 Example number MV-4-11(cell)IC 50 10 ** 39 *** 68 13.4 11 28 40 ** 69 13.7 12 3 41 42.9 70 9 13 *** 42 ** 71 56.3 14 ** 43 62.4 72 0.8 15 45.4 44 10.4 73 3.9 16 16.8 45 73.2 74 3.9 17 * 46 58.7 75 40 18 * 47 1.4 76 40.4 19 39 48 ** 77 1.0 20 * 49 30.3 78 5.3 twenty one * 50 ** 79 6.9 twenty two 36.8 51 * 80 13.1 twenty three 3.3 52 2.3 81 90.9 twenty four 50.7 53 * 82 3 25 38 54 ** 83 13.7 26 * 55 * 84 16.8 27 2.0 56 * 85 34.4 28 10.7 57 * 86 3.6 29 5.9 58 2.7 To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To
  • mice Female were subcutaneously inoculated with MV-4-11 cells to establish an animal model of MV-4-11 xenograft tumors.
  • the inoculated mice were randomly divided into a solvent control group and an experimental group.
  • the experimental groups were given different doses of the compound of the present invention, with 6 experimental animals in each group.
  • 0.1mL (1 ⁇ 10 7 cells) MV-4-11 cells (with matrigel, volume ratio 1:1) were subcutaneously inoculated on the back of each mouse, when the average tumor volume reached about 100-200mm 3 Start grouping administration.
  • the test compound was administered intragastrically from the day of grouping, once or twice a day, for a total of 28-32 days.
  • the safety evaluation is based on the changes in animal weight and death, and the efficacy evaluation is based on the relative tumor inhibition rate (TGI%).
  • each dose group showed obvious anti-tumor effect compared with the control group.
  • the tumor growth inhibition rate was up to 99%, and all animals had no significant weight loss during the administration period, indicating that the compound of the present invention at the experimental dose Well tolerated and well tolerated.

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Abstract

The present invention provides a bromodomain inhibitor. The present invention also provides a composition and a preparation containing such a compound, a method for using such a compound, and a method for preparing such a compound.

Description

作为溴结构域蛋白质抑制剂的化合物和组合物Compounds and compositions as inhibitors of bromodomain proteins 技术领域Technical field
本发明涉及可抑制含溴结构域蛋白质或以其它方式调节其活性的化合物，及包含这样的化合物的组合物和制剂，及使用和制备这样的化合物的方法。The present invention relates to compounds that can inhibit bromodomain-containing proteins or otherwise modulate their activity, compositions and preparations containing such compounds, and methods of using and preparing such compounds.
背景技术Background technique
含BET(溴结构域和末端外结构域)家族的溴结构域(bromodomain，BRD)蛋白质包括4种：BRD2、BRD3、BRD4和BRDT，每一种蛋白质包括2个不同的溴结构域(BD1和BD2)。BET家族的蛋白质是表观遗传编码的读取子，将赖氨酸残基乙酰化偶联在组蛋白上以改变染色质结构和基因表达。BRD2、BRD3和BRD4得以普遍表达，而BRDT局限于生殖细胞。BET蛋白在调控基因转录和控制细胞生长方面起必要但不重叠的作用。BET蛋白质与调控许多基因转录方面的大蛋白质复合物相关，包括RNA聚合酶II(Pol II)、正向转录延长因子(P-TEFb)。已证实BRD2和BRD4蛋白在有丝分裂期间保持与染色体结合，且需要所述蛋白质促进起始细胞周期的重要基因(包括周期素D和c-MYC)转录(Mochizuki,J Biol.Chem.2008 283:9040-9048)。BRD4蛋白与RNA聚合酶II(Pol II)，正向转录延长因子(Positive transcription elongation factor，P-TEFb)结合，共同促进多种癌症细胞增殖和凋亡相关基因如c-MYC，细胞周期蛋白、抗凋亡蛋白BCL-2等基因的转录表达，调控肿瘤细胞生长增殖过程(Jang等人，Mol.Cell 2005 19:523-534)。在一些情况下，BRD4的激酶活性可直接使RNA聚合酶II磷酸化和活化(Devaiah等人，PNAS 2012 109:6927-6932)。缺乏BRD4的细胞显示细胞周期进展受损。据报导，BRD2和BRD3与组蛋白以及积极转录基因相关并且可参与促进转录伸长(Leroy等人，Mol.Cell.2008 30:51-60)。除乙酰化组蛋白以外，已证实BET蛋白选择性结合乙酰化转录因子，包括NF-kB和GATAl的RelA亚单位，从而直接调控这些蛋白质的转录活性以控制参与发炎和造血分化的基因的表达(Huang等人，Mol.Cell Biol.2009 29:1375-1387；Lamonica Proc.Nat.Acad.Sci.2011108:E159-168)。在结构上，虽然BRD4蛋白的2个溴结构域BD1和BD2在底物结合位点上显示出较高的序列相似性，但是不同的溴结构域具有不同的功能，例如BD1选择性抑制剂 可以加速少突胶质细胞的分化，这与非选择性抑制剂作用相反；BD2选择性抑制剂对其他乙酰化底物具有更广泛的作用，而BD1只识别H4乙酰化标记。(Junlong Ma等人，Bioorganic&Medicinal Chemistry 27(2019)1871–1881)。The bromodomain (bromodomain, BRD) protein containing the BET (bromodomain and terminal extradomain) family includes 4 types: BRD2, BRD3, BRD4 and BRDT, each protein includes 2 different bromodomains (BD1 and BD2). The proteins of the BET family are readers of epigenetic coding, acetylation of lysine residues coupled to histones to change chromatin structure and gene expression. BRD2, BRD3 and BRD4 are ubiquitously expressed, while BRDT is restricted to germ cells. BET protein plays a necessary but non-overlapping role in regulating gene transcription and controlling cell growth. BET proteins are related to large protein complexes that regulate the transcription of many genes, including RNA polymerase II (Pol II) and forward transcription elongation factor (P-TEFb). It has been confirmed that BRD2 and BRD4 proteins remain bound to chromosomes during mitosis, and the proteins are required to promote the transcription of important genes (including cyclin D and c-MYC) that initiate the cell cycle (Mochizuki, J Biol. Chem. 2008 283: 9040 -9048). BRD4 protein combines with RNA polymerase II (Pol II) and positive transcription elongation factor (P-TEFb) to jointly promote a variety of cancer cell proliferation and apoptosis-related genes such as c-MYC, cyclin, The transcriptional expression of genes such as the anti-apoptotic protein BCL-2 regulates the growth and proliferation of tumor cells (Jang et al., Mol. Cell 2005 19:523-534). In some cases, the kinase activity of BRD4 can directly phosphorylate and activate RNA polymerase II (Devaiah et al., PNAS 2012 109: 6927-6932). Cells lacking BRD4 show impaired cell cycle progression. It is reported that BRD2 and BRD3 are related to histones and actively transcribed genes and can participate in promoting transcription elongation (Leroy et al., Mol. Cell. 2008 30:51-60). In addition to acetylated histones, BET protein has been shown to selectively bind to acetylated transcription factors, including NF-kB and the RelA subunit of GATAl, thereby directly regulating the transcriptional activity of these proteins to control the expression of genes involved in inflammation and hematopoietic differentiation ( Huang et al., Mol. Cell Biol. 2009 29:1375-1387; Lamonica Proc. Nat. Acad. Sci. 2011108: E159-168). Structurally, although the two bromodomains BD1 and BD2 of BRD4 protein show high sequence similarity in the substrate binding site, different bromodomains have different functions. For example, BD1 selective inhibitors can Accelerate the differentiation of oligodendrocytes, which is the opposite of the effect of non-selective inhibitors; BD2 selective inhibitors have a broader effect on other acetylation substrates, while BD1 only recognizes H4 acetylation markers. (Junlong Ma et al., Bioorganic&Medicinal Chemistry 27(2019)1871-1881).
目前已有一批BRD4小分子抑制剂进入临床试验阶段，例如化合物Mivebresib(ABBV-075)，化合物ABBV-744，化合物Apabetalone(RVX-208)等，其中ABBV-744是具有BRD4-BD2高效选择性的小分子抑制剂，其对BRD4(D2)的选择性与对BRD4(D1)的选择性的比值大于100倍，目前处于临床一期阶段，可用于实体瘤和血液瘤。At present, a number of BRD4 small molecule inhibitors have entered clinical trials, such as the compound Mivebresib (ABBV-075), the compound ABBV-744, the compound Apabetalone (RVX-208), etc., among which ABBV-744 is highly selective for BRD4-BD2 Small molecule inhibitors, whose selectivity for BRD4 (D2) is more than 100 times greater than that for BRD4 (D1), are currently in the clinical phase I and can be used for solid tumors and hematomas.
Figure PCTCN2021094838-appb-000001
Figure PCTCN2021094838-appb-000001
尽管已报道了一些小分子BET抑制剂用于临床研究，但是，目前仍没有批准上市的品种，因此，对开发用作溴结构域抑制剂的化合物存在巨大需求，仍需要开发新的小分子BET抑制剂，为临床上治疗由BET介导的疾病或病症提供一种新的用药选择。Although some small molecule BET inhibitors have been reported to be used in clinical research, there are still no approved varieties. Therefore, there is a huge demand for the development of compounds used as bromodomain inhibitors, and there is still a need to develop new small molecule BET inhibitors. Inhibitors provide a new drug choice for the clinical treatment of diseases or disorders mediated by BET.
发明内容Summary of the invention
本发明涉及作为溴结构域抑制剂，特别是BRD4抑制剂的化合物，及其在治疗由BET介导的疾病中的应用。本发明首先提供了式(I)所示的化合物或其药学上可接受的盐，The present invention relates to compounds as bromodomain inhibitors, especially BRD4 inhibitors, and their use in the treatment of diseases mediated by BET. The present invention first provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021094838-appb-000002
Figure PCTCN2021094838-appb-000002
其中，in,
Figure PCTCN2021094838-appb-000003
表示单键或双键；
Figure PCTCN2021094838-appb-000003
Represents a single bond or a double bond;
R 1选自H、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或C 3-10杂环基； R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-10 heterocyclic group;
R 2、R 3、R 4和R 5分别独立地选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或C 3-10杂环基； R 2 , R 3 , R 4 and R 5 are each independently selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-10 heterocyclic group;
环A为C 6-10芳基、C 5-10杂芳基、C 3-10环烷基、C 3-10环烯基或C 3-10杂环基； Ring A is a C 6-10 aryl group, a C 5-10 heteroaryl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group or a C 3-10 heterocyclic group;
E 1为CR 7或N； E 1 is CR 7 or N;
E 2为CR 8或N； E 2 is CR 8 or N;
D 1为C或N； D 1 is C or N;
D 2为C或N； D 2 is C or N;
D 3为C或N； D 3 is C or N;
其中，D 1、D 2和D 3中至少有一个为N，且至少有一个为C； Wherein, at least one of D 1 , D 2 and D 3 is N, and at least one is C;
R 7和R 8分别独立地选自H、卤素、羟基、氧代基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或C 3-10杂环基； R 7 and R 8 are each independently selected from H, halogen, hydroxy, oxo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-10 heterocyclic group;
R 6选自H、卤素、氰基、-NO 2、C 1-10烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基、C 5-10杂芳基、-OR c、-SR c、-C(＝O)R c、-C(＝O)OR c、-C(＝O)NR aR b、-OC(＝O)R c、-S(＝O) 2R c、-S(＝O)R c、-NR aR b、-NC(＝O)R a、-NC(＝O)OR a、-NR aC(＝O)NR aR b、-NR aC(＝O)ONR b、-O(C 1-4亚烷基)R x、-(C 1-4亚烷基)R x、-NR a(C 1-4亚烷基)R x、-O(C 1-4亚烷基)OR c、-O(C 1-4亚烷基)NR aR b、-O(C 1-4亚烷基)C(＝O)NR aR b、C(＝O)ONR aR b、-O(C 1-4亚烷基)S(＝O) 2R c、-(C 1-4亚烷基)C(＝O)NR aR b、-(C 1-4亚烷基)C(＝O)ONR aR b、-(C 1-4亚烷基)NR aR b、-(C 1-4亚烷基)S(＝O) 2R c、-NR a(C 1-4亚烷基)NR aR b、-NR a(C 1-4亚烷基)OR c、-NR a(C 1-4亚烷基)C(＝O)NR aR b、-NR a(C 1-4亚烷基)C(＝O)ONR aR b或-NR a(C 1-4亚烷基)S(＝O) 2R c，其中，所述C 1-10烷基、C 2-6烯基和C 2-6炔基任选地被R 9取代，所述C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基和C 5-10杂芳基任选地被R 10取代； R 6 is selected from H, halogen, cyano, -NO 2 , C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkene Group, C 3-10 heterocyclic group, C 6-10 aryl group, C 5-10 heteroaryl group, -OR c , -SR c , -C(=O)R c , -C(=O)OR c , -C(=O)NR a R b , -OC(=O)R c , -S(=O) 2 R c , -S(=O)R c , -NR a R b , -NC(= O)R a , -NC(=O)OR a , -NR a C(=O)NR a R b , -NR a C(=O)ONR b , -O(C 1-4 alkylene) R x , -(C 1-4 alkylene) R x , -NR a (C 1-4 alkylene) R x , -O(C 1-4 alkylene) OR c , -O(C 1- 4 alkylene)NR a R b , -O(C 1-4 alkylene) C(=O)NR a R b , C(=O)ONR a R b , -O(C 1-4 alkylene Group) S(=O) 2 R c , -(C 1-4 alkylene)C(=O)NR a R b , -(C 1-4 alkylene)C(=O)ONR a R b , -(C 1-4 alkylene)NR a R b , -(C 1-4 alkylene)S(=O) 2 R c , -NR a (C 1-4 alkylene)NR a R b , -NR a (C 1-4 alkylene) OR c , -NR a (C 1-4 alkylene) C(=O)NR a R b , -NR a (C 1-4 alkylene )C(=O)ONR a R b or -NR a (C 1-4 alkylene)S(=O) 2 R c , wherein the C 1-10 alkyl, C 2-6 alkenyl and The C 2-6 alkynyl group is optionally substituted by R 9 , the C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 3-10 heterocyclic group, C 6-10 aryl group and C 5- 10 heteroaryl is optionally substituted by R 10;
R 9选自H、卤素、氰基、氧代基、-OR c、-SR c、-C(＝O)R c、-C(＝O)OR c、-C(＝O)NR aR b、-OC(＝O)R c、-S(＝O) 2R c、-S(＝O)R c、-NR aR b、-NC(＝O)R a、-NR aC(＝O)NR aR b、-NR aC(＝O)ONR c、C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基或C 5-10杂芳基，其中，所述C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基和C 5-10杂芳基任选地被H、卤素、氰基、羟基、-NR aR b、-C(＝O)R c、-C(＝O)OR c、-S(＝O) 2R c、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基或C 2-6炔基取代； R 9 is selected from H, halogen, cyano, oxo, -OR c , -SR c , -C(=O)R c , -C(=O)OR c , -C(=O)NR a R b , -OC(=O)R c , -S(=O) 2 R c , -S(=O)R c , -NR a R b , -NC(=O)R a , -NR a C( ═O)NR a R b , -NR a C(=O)ONR c , C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl group, wherein the C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 3-10 heterocyclic group, C 6-10 aryl group and C 5-10 heteroaryl group Optionally by H, halogen, cyano, hydroxyl, -NR a R b , -C(=O)R c , -C(=O)OR c , -S(=O) 2 R c , C 1- 6 Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl substituted;
R 10选自H、卤素、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-OR c、-SR c、-C(＝O)R c、-C(＝O)OR c、-C(＝O)NR aR b、-OC(＝O)R c、-S(＝O) 2R c、-S(＝O)R c、-NR aR b、-NC(＝O)R a、-NR aC(＝O)NR aR b或-NR aC(＝O)ONR b； R 10 is selected from H, halogen, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR c , -SR c , -C(=O)R c , -C(=O)OR c , -C(=O)NR a R b , -OC(=O)R c , -S(=O) 2 R c ,- S(=O)R c , -NR a R b , -NC(=O)R a , -NR a C(=O)NR a R b or -NR a C(=O)ONR b ;
R a和R b分别独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-10杂环基、C 6-10芳基或C 5-10杂芳基； R a and R b are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3 -10 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl;
或R a和R b与其共同连接的N原子形成C 3-10杂环基，其中，所述C 3-10杂环基可任由H、卤素、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基和C 1-6卤代烷氧基所取代； N atom or R a and R b are commonly connected thereto form C 3-10 heterocyclyl group, wherein the C 3-10 heterocyclyl group may be allowed to H, halo, cyano, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;
R c选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或C 3-10杂环基； R c is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-10 heterocycle base;
R x选自C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基或C 5-10杂芳基，其中，所述R x可任由H、卤素、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或-NR aR b所取代； R x is selected from C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, wherein the R x may May be substituted by H, halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or -NR a R b ;
m和n为0、1、2或3。m and n are 0, 1, 2, or 3.
关于式(I)所示化合物，本发明进一步提供了一些优选的技术方案。Regarding the compound represented by formula (I), the present invention further provides some preferred technical solutions.
一些实施方式中，R 1选自C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 3-6环烷基。 In some embodiments, R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 3-6 cycloalkyl.
一些实施方式中，所述R 1为C 1-6烷基。 In some embodiments, the R 1 is a C 1-6 alkyl group.
一些实施方式中，R 2选自C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基。 In some embodiments, R 2 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.
一些实施方式中，R 2为C 1-6烷基。 In some embodiments, R 2 is C 1-6 alkyl.
一些实施方式中，R 3为H或C 1-6烷基。 In some embodiments, R 3 is H or C 1-6 alkyl.
一些实施方式中，R 4选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-6环烷基或C 3-10杂环基。 In some embodiments, R 4 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl Or C 3-10 heterocyclic group.
一些实施方式中，R 4为H或C 1-6烷基。 In some embodiments, R 4 is H or C 1-6 alkyl.
一些实施方式中，环A为C 6-10芳基或C 5-10杂芳基。 In some embodiments, ring A is C 6-10 aryl or C 5-10 heteroaryl.
一些实施方式中，R 5选自卤素、氰基、C 1-6烷基、C 1-6烷氧基。 In some embodiments, R 5 is selected from halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy.
一些实施方式中，R 5选自卤素或C 1-6烷基。 In some embodiments, R 5 is selected from halogen or C 1-6 alkyl.
一些实施方式中，R 7和R 8选自H或C 1-6烷基。 In some embodiments, R 7 and R 8 are selected from H or C 1-6 alkyl.
一些实施方式中，R 6选自H、卤素、氰基、C 1-10烷基、C 3-10环烷基、C 3-10杂环基、C 6-10芳基、C 5-10杂芳基、-OR c、-S(＝O) 2R c、-NR aR b、-C(＝O)NR aR b、-O(C 1-4亚烷基)R x、-(C 1-4亚烷基)R x、-NR a(C 1-4亚烷基)R x、-O(C 1-4亚烷基)OR c、-O(C 1-4亚烷基)NR aR b、-(C 1-4亚烷基)C(＝O)NR aR b、-(C 1-4亚烷基)NR aR b、-(C 1-4亚烷基)S(＝O) 2R c、-NR a(C 1-4亚烷基)OR c或-NR a(C 1-4亚烷基)NR aR b，其中，所述C 1-10烷基任选地被R 9取代，所述C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基和C 5-10杂芳基任选地被R 10取代； In some embodiments, R 6 is selected from H, halogen, cyano, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl, C 5-10 Heteroaryl, -OR c , -S(=O) 2 R c , -NR a R b , -C(=O)NR a R b , -O(C 1-4 alkylene) R x ,- (C 1-4 alkylene) R x , -NR a (C 1-4 alkylene) R x , -O(C 1-4 alkylene) OR c , -O(C 1-4 alkylene Group) NR a R b , -(C 1-4 alkylene) C(=O)NR a R b , -(C 1-4 alkylene) NR a R b , -(C 1-4 alkylene Group) S(=O) 2 R c , -NR a (C 1-4 alkylene) OR c or -NR a (C 1-4 alkylene)NR a R b , wherein the C 1- 10 alkyl is optionally substituted by R 9 , the C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 heterocyclyl, C 6-10 aryl and C 5-10 heteroaryl The group is optionally substituted by R 10;
R a和R b分别独立地选自H、C 1-6烷基或C 5-10杂芳基； R a and R b are each independently selected from H, C 1-6 alkyl or C 5-10 heteroaryl;
或R a和R b与其共同连接的N原子形成C 3-10杂环基，其中，所述C 3-10杂环基可任由H、卤素、氰基、C 1-6烷基或C 1-6卤代烷基所取代； N atom or R a and R b are commonly connected thereto form C 3-10 heterocyclyl group, wherein the C 3-10 heterocyclyl group may be allowed to H, halo, cyano, C 1-6 alkyl or C 1-6 substituted by haloalkyl;
R c选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R c is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R x选自C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基或C 5-10杂芳基，其中，所述R x可任由H、卤素、氰基、C 1-6烷基或-NR aR b所取代。 R x is selected from C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, wherein the R x may It is optionally substituted by H, halogen, cyano, C 1-6 alkyl or -NR a R b .
一些实施方式中，R 9选自H、卤素、氰基、氧代基、-OR c、-C(＝O)NR aR b、-NR aR b、-S(＝O) 2R c、C 3-6环烷基或C 3-10杂环基。 In some embodiments, R 9 is selected from H, halogen, cyano, oxo, -OR c , -C(=O)NR a R b , -NR a R b , -S(=O) 2 R c , C 3-6 cycloalkyl or C 3-10 heterocyclic group.
一些实施方式中，R 10选自H、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或-OR c。 In some embodiments, R 10 is selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or -OR c .
一些实施方式中，R 10选自H、C 1-6烷基或C 1-6烷氧基。 In some embodiments, R 10 is selected from H, C 1-6 alkyl or C 1-6 alkoxy.
一些实施方式中，R a和R b分别独立地选自H、C 1-6烷基或C 5-10杂芳基；或R a和R b与其共同连接的N原子形成C 4-6杂环基，其中，所述C 4-6杂环基可任由H或C 1-4烷基所取代。 In some embodiments, R a and R b are each independently selected from H, C 1-6 alkyl or a C 5-10 heteroaryl; N atoms, or R a and R b are commonly connected thereto form C 4-6 heteroaryl Cyclic groups, wherein the C 4-6 heterocyclic group can be optionally substituted by H or C 1-4 alkyl.
一些实施方式中，R c选自H、甲基或乙基。 In some embodiments, R c is selected from H, methyl, or ethyl.
一些具体实施方式中，R x选自
Figure PCTCN2021094838-appb-000004
Figure PCTCN2021094838-appb-000005
In some embodiments, R x is selected from
Figure PCTCN2021094838-appb-000004
Figure PCTCN2021094838-appb-000005
一些实施方式中，R 6选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、-(C 1-4亚烷基)R x、-(C 1-4亚烷基)C(＝O)NR aR b、-(C 1-4亚烷基)NR aR b或-(C 1-4亚烷基)S(＝O) 2R c；其中，所述C 1-6烷基任选地被H、卤素、-OH、-NH 2、-N(CH 3) 2或环丙烷所取代； In some embodiments, R 6 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(C 1-4 alkylene) R x , -(C 1-4 alkylene) C(=O)NR a R b , -(C 1-4 alkylene)NR a R b or -(C 1-4 alkylene)S(=O) 2 R c ; Wherein, the C 1-6 alkyl group is optionally substituted by H, halogen, -OH, -NH 2 , -N(CH 3 ) 2 or cyclopropane;
R a和R b分别独立地选自H或C 1-6烷基； R a and R b are each independently selected from H or C 1-6 alkyl;
R c选自H或C 1-6烷基； R c is selected from H or C 1-6 alkyl;
R x为环丙烷，所述R x可任由H、卤素、-NH 2或-N(CH 3) 2所取代。 R x is cyclopropane, and the R x can be optionally substituted by H, halogen, -NH 2 or -N(CH 3 ) 2 .
一些实施方式中，所述化合物如式(II)所示，In some embodiments, the compound is represented by formula (II),
Figure PCTCN2021094838-appb-000006
Figure PCTCN2021094838-appb-000006
Figure PCTCN2021094838-appb-000007
Figure PCTCN2021094838-appb-000007
其中，in,
D 1和D 3有且只有一个为N。 Only one of D 1 and D 3 is N.
一些实施方式中，所述化合物如式(III)所示，In some embodiments, the compound is represented by formula (III),
Figure PCTCN2021094838-appb-000008
Figure PCTCN2021094838-appb-000008
其中，所述W 1、W 2和W 3为C或N。 Wherein, the W 1 , W 2 and W 3 are C or N.
一些具体实施方式中，E 1和E 2均为CH。 In some embodiments, E 1 and E 2 are both CH.
一些具体实施方式中，E 1为CH，E 2为N。 In some specific embodiments, E 1 is CH and E 2 is N.
一些具体实施方式中，W 1、W 2和W 3均为C。 In some embodiments, W 1 , W 2 and W 3 are all C.
一些具体实施方式中，W 1为C，W 2和W 3为C或N，条件是：当W 2和W 3不全为C时，W 2和W 3中有且仅有一个为N。 In some specific embodiments, W 1 is C, W 2 and W 3 are C or N, provided that when W 2 and W 3 are not all C, only one of W 2 and W 3 is N.
一些具体实施方式中，R 1为甲基或乙基。 In some embodiments, R 1 is methyl or ethyl.
一些具体实施方式中，R 2为甲基。 In some embodiments, R 2 is methyl.
一些具体实施方式中，R 3和R 4为H。 In some embodiments, R 3 and R 4 are H.
一些具体实施方式中，R 5为甲基或卤素。 In some embodiments, R 5 is methyl or halogen.
一些具体实施方式中，D 1为N，D 2为C。 In some embodiments, D 1 is N and D 2 is C.
一些具体实施方式中，D 1为C，D 2为N。 In some embodiments, D 1 is C and D 2 is N.
一些具体实施方式中，含有D 1原子的双环部分选自：
Figure PCTCN2021094838-appb-000009
Figure PCTCN2021094838-appb-000010
In some embodiments, the bicyclic moiety containing D 1 atom is selected from:
Figure PCTCN2021094838-appb-000009
Figure PCTCN2021094838-appb-000010
本发明进一步提供了一种化合物或其药学上可接受的盐，所述化合物是指：The present invention further provides a compound or a pharmaceutically acceptable salt thereof, and the compound refers to:
1)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧 代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；1) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
2)4-(5-(2,6-二甲基苯氧基)-2-(2-羟基-2-甲基丙基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；2) 4-(5-(2,6-Dimethylphenoxy)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
3)4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；3) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
4)4-(5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；4) 4-(5-(2,6-Dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-di Hydrogen-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
5)N-乙基-4-(5-(4-氟-2,6-二甲基苯氧基)-1H-吲唑-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；5) N-ethyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-1H-indazol-6-yl)-6-methyl-7-oxo-6 ,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
6)N-乙基-4-(5-(4-氟-2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；6) N-ethyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazole-6 -Yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
7)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；7) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
8)4-(5-((3,5-二甲基吡啶-4-基)氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；8) 4-(5-((3,5-dimethylpyridin-4-yl)oxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
9)4-(5-((3,5-二甲基吡啶-4-基)氧基)-2-(2-羟基-2-甲基丙基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；9) 4-(5-((3,5-dimethylpyridin-4-yl)oxy)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
10)N-乙基-4-(1-(2-羟基-2-甲基丙基)-5-(2,3,6-三甲基苯氧基)-1H-吲唑-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；10) N-ethyl-4-(1-(2-hydroxy-2-methylpropyl)-5-(2,3,6-trimethylphenoxy)-1H-indazol-6-yl )-6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
11)N-乙基-4-(5-(4-氟-2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；11) N-ethyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6 -Yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
12)N-乙基-4-(5-(4-氟-2,6-二甲基苯氧基)-2-(2-氟-2-甲基丙基)-2H-吲唑-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；12) N-ethyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-2-(2-fluoro-2-methylpropyl)-2H-indazole-6 -Yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
13)4-(5-((3,5-二甲基吡啶-4-基)氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；13) 4-(5-((3,5-dimethylpyridin-4-yl)oxy)-1-(2-fluoro-2-methylpropyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
14)4-(5-((3,5-二甲基吡啶-4-基)氧基)-2-(2-氟-2-甲基丙基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；14) 4-(5-((3,5-dimethylpyridin-4-yl)oxy)-2-(2-fluoro-2-methylpropyl)-2H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
15)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；15) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2-fluoro-2-methylpropyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
16)4-(5-((2,4-二甲基吡啶-3-基)氧基)-2-(2-氟-2-甲基丙基)-2H-吲唑-6-基)-N-乙基-6-甲 基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；16) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-2-(2-fluoro-2-methylpropyl)-2H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
17)N-乙基-4-(1-(2-氟-2-甲基丙基)-5-(2,3,6-三甲基苯氧基)-1H-吲唑-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；17) N-ethyl-4-(1-(2-fluoro-2-methylpropyl)-5-(2,3,6-trimethylphenoxy)-1H-indazol-6-yl )-6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
18)4-(5-(2,6-二甲基苯氧基)-1-甲基-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；18) 4-(5-(2,6-Dimethylphenoxy)-1-methyl-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo- 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
19)4-(5-(2,6-二甲基苯氧基)-2-甲基-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；19) 4-(5-(2,6-Dimethylphenoxy)-2-methyl-2H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo- 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
20)4-(5-(2,6-二甲基苯氧基)-1-乙基-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；20) 4-(5-(2,6-Dimethylphenoxy)-1-ethyl-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo- 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
21)4-(5-(2,6-二甲基苯氧基)-2-乙基-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；21) 4-(5-(2,6-Dimethylphenoxy)-2-ethyl-2H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo- 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
22)4-(1-(2-(二甲基氨基)乙基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；22) 4-(1-(2-(Dimethylamino)ethyl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
23)4-(2-(2-(二甲基氨基)乙基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；23) 4-(2-(2-(Dimethylamino)ethyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
24)4-(5-(2,6-二甲基苯氧基)-1-(3-羟基-3-甲基丁基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；24) 4-(5-(2,6-Dimethylphenoxy)-1-(3-hydroxy-3-methylbutyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
25)4-(5-(2,6-二甲基苯氧基)-2-(3-羟基-3-甲基丁基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；25) 4-(5-(2,6-Dimethylphenoxy)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
26)4-(5-(2,6-二甲基苯氧基)-1-(3-氟-3-甲基丁基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；26) 4-(5-(2,6-Dimethylphenoxy)-1-(3-fluoro-3-methylbutyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
27)4-(5-(2,6-二甲基苯氧基)-2-(3-氟-3-甲基丁基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；27) 4-(5-(2,6-Dimethylphenoxy)-2-(3-fluoro-3-methylbutyl)-2H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
28)4-(5-(2,6-二甲基苯氧基)-1-(2-氟乙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；28) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoroethyl)-1H-indazol-6-yl)-N-ethyl-6-methyl- 7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
29)4-(5-(2,6-二甲基苯氧基)-2-(2-氟乙基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；29) 4-(5-(2,6-Dimethylphenoxy)-2-(2-fluoroethyl)-2H-indazol-6-yl)-N-ethyl-6-methyl- 7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
30)4-(1-(环丙基甲基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；30) 4-(1-(Cyclopropylmethyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl-6-methyl- 7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
31)4-(2-(环丙基甲基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7- 二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；31) 4-(2-(Cyclopropylmethyl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)-N-ethyl-6-methyl- 7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
32)4-(5-(2,6-二甲基苯氧基)-1-(2,2,2-三氟乙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；32) 4-(5-(2,6-Dimethylphenoxy)-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
33)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2,2,2-三氟乙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；33) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
34)4-(1-(2-(二甲基氨基)乙基)-5-(4-氟-2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；34) 4-(1-(2-(Dimethylamino)ethyl)-5-(4-fluoro-2,6-dimethylphenoxy)-1H-indazol-6-yl)-N -Ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
35)4-(2-(2-(二甲基氨基)乙基)-5-(4-氟-2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；35) 4-(2-(2-(Dimethylamino)ethyl)-5-(4-fluoro-2,6-dimethylphenoxy)-2H-indazol-6-yl)-N -Ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
36)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-新戊基-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；36) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-neopentyl-1H-indazol-6-yl)-N-ethyl-6-methyl Group-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
37)4-(5-((2,4-二甲基吡啶-3-基)氧基)-2-新戊基-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；37) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-2-neopentyl-2H-indazol-6-yl)-N-ethyl-6-methyl Group-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
38)4-(1-(氮杂环丁烷-3-基甲基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；38) 4-(1-(azetidin-3-ylmethyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl -6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
39)4-(2-(氮杂环丁烷-3-基甲基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；39) 4-(2-(azetidin-3-ylmethyl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)-N-ethyl -6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
40)4-(5-(2,6-二甲基苯氧基)-1-(吡咯烷-3-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；40) 4-(5-(2,6-Dimethylphenoxy)-1-(pyrrolidin-3-yl)-1H-indazol-6-yl)-N-ethyl-6-methyl -7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
41)4-(5-(2,6-二甲基苯氧基)-2-(吡咯烷-3-基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；41) 4-(5-(2,6-Dimethylphenoxy)-2-(pyrrolidin-3-yl)-2H-indazol-6-yl)-N-ethyl-6-methyl -7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
42)4-(1-(氮杂环丁烷-3-基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；42) 4-(1-(azetidin-3-yl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl-6 -Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
43)4-(2-(氮杂环丁烷-3-基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；43) 4-(2-(azetidin-3-yl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)-N-ethyl-6 -Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
44)4-(1-(2-氨基-2-氧乙基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；44) 4-(1-(2-Amino-2-oxyethyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl-6 -Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
45)4-(5-(2,6-二甲基苯氧基)-1-((甲磺酰基)甲基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；45) 4-(5-(2,6-Dimethylphenoxy)-1-((methylsulfonyl)methyl)-1H-indazol-6-yl)-N-ethyl-6-methyl Group-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
46)4-(5-(2,6-二甲基苯氧基)-1-(2-(甲磺酰基)乙基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧 代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；46) 4-(5-(2,6-Dimethylphenoxy)-1-(2-(methylsulfonyl)ethyl)-2H-indazol-6-yl)-N-ethyl-6 -Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
47)4-(5-(2,6-二甲基苯氧基)-2-(2-(甲磺酰基)乙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；47) 4-(5-(2,6-Dimethylphenoxy)-2-(2-(methylsulfonyl)ethyl)-1H-indazol-6-yl)-N-ethyl-6 -Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
48)4-(1-环丙基-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；48) 4-(1-Cyclopropyl-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo -6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
49)4-(1-((1-氨基环丙基)甲基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；49) 4-(1-((1-Aminocyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
50)4-(1-(2-氨基-2-甲基丙基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；50) 4-(1-(2-Amino-2-methylpropyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
51)4-(1-((1-(二甲基氨基)环丙基)甲基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；51) 4-(1-((1-(dimethylamino)cyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)- N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
52)4-(2-((1-(二甲基氨基)环丙基)甲基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；52) 4-(2-((1-(dimethylamino)cyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)- N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
53)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2-甲氧基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；53) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2-methoxy-2-methylpropyl)-1H-indazole-6- Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
54)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2-乙基-2-羟基丁基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；54) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2-ethyl-2-hydroxybutyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
55)4-(5-(2,6-二甲基苯氧基)-1-((1-氟环丙基)甲基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；55) 4-(5-(2,6-Dimethylphenoxy)-1-((1-fluorocyclopropyl)methyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
56)4-(5-(2,6-二甲基苯氧基)-2-((1-氟环丙基)甲基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；56) 4-(5-(2,6-Dimethylphenoxy)-2-((1-fluorocyclopropyl)methyl)-2H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
57)4-(1-((1-氰基环丙基)甲基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；57) 4-(1-((1-cyanocyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl -6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
58)4-(2-((1-氰基环丙基)甲基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；58) 4-(2-((1-cyanocyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)-N-ethyl -6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
59)4-(5-(2,6-二甲基苯氧基)-2-(氧杂环丁-3-基甲基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；59) 4-(5-(2,6-Dimethylphenoxy)-2-(oxetan-3-ylmethyl)-2H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
60)4-(3-环丙基-5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；60) 4-(3-Cyclopropyl-5-(2,6-dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
61)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧 代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；61) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
62)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2-羟基-2-甲基丙基)-3-甲基-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；62) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-indazole -6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
63)4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-3-(吡啶-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；63) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-3-(pyridin-4-yl)-1H-indazole- 6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
64)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(1,2,3,6-四氢吡啶-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；64) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(1,2,3,6-tetrahydropyridine- 4-yl)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- 2-formamide;
65)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(3-甲氧基吡啶-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；65) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(3-methoxypyridin-4-yl)- 1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
66)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；66) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(1-methyl-1H-pyrazole-4- Yl)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2- Formamide
67)4-(3-(3,6-二氢-2H-吡喃-4-基)-5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；67) 4-(3-(3,6-Dihydro-2H-pyran-4-yl)-5-(2,6-dimethylphenoxy)-1-(2-hydroxy-2-methyl Propyl)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- 2-formamide;
68)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(吡啶-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；68) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(pyridin-4-yl)-1H-indazole- 6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
69)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(3-吗啉代丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；69) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(3-morpholinopropyl)-1H-indyl (Azol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
70)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(四氢2H-吡喃-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；70) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(tetrahydro 2H-pyran-4-yl)- 1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
71)5-(2,6-二甲基苯氧基)-6-(2-(乙基氨基甲酰基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-3-甲酰胺；71) 5-(2,6-Dimethylphenoxy)-6-(2-(ethylcarbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrole And [2,3-c]pyridin-4-yl)-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxamide;
72)4-(3-((2-(二甲基氨基)乙基)(甲基)氨基)-5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；72)4-(3-((2-(dimethylamino)ethyl)(methyl)amino)-5-(2,6-dimethylphenoxy)-1-(2-fluoro-2 -Methylpropyl)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] Pyridine-2-carboxamide;
73)4-(3-(二甲基氨基)-5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；73) 4-(3-(Dimethylamino)-5-(2,6-dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6 -Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
74)4-(3-((3-(二甲基氨基)丙基)(甲基)氨基)-5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；74) 4-(3-((3-(dimethylamino)propyl)(methyl)amino)-5-(2,6-dimethylphenoxy)-1-(2-fluoro-2 -Methylpropyl)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] Pyridine-2-carboxamide;
75)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(2-吗啉代乙氧基)-1H-吲唑-6- 基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；75) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(2-morpholinoethoxy)-1H- Indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
76)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(2-羟基乙氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；76) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(2-hydroxyethoxy)-1H-indazole -6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
77)4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；77) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-3-(methyl(2-(4-methylpiperazine -1-yl)ethyl)amino)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2, 3-c]pyridine-2-carboxamide;
78)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(甲基氨基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；78) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(methylamino)-1H-indazole-6- Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
79)4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-3-(2-羟基乙氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；79) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-3-(2-hydroxyethoxy)-1H-indazole -6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
80)4-(3-(氮杂环丁烷-1-基)-5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；80)4-(3-(azetidin-1-yl)-5-(2,6-dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H -Indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
81)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-甲氧基-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；81) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-methoxy-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
82)4-(3-氨基-5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；82) 4-(3-Amino-5-(2,6-dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazol-6-yl)-N -Ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
83)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-吗啉代-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；83) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-morpholino-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
84)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-((2-羟基乙基)(甲基)氨基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；84) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-((2-hydroxyethyl)(methyl)amino )-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-methyl Amide
85)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吡唑o[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；85) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole o[4,3-b]pyridine-6 -Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
86)4-(5-(2,6-二甲基苯氧基)-2-(2-羟基-2-甲基丙基)-2H-吡唑o[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；86) 4-(5-(2,6-Dimethylphenoxy)-2-(2-hydroxy-2-methylpropyl)-2H-pyrazole o[4,3-b]pyridine-6 -Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
87)4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吡唑并[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；87) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-pyrazolo[4,3-b]pyridine-6 -Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
88)N-乙基-4-(5-(4-氟-2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吡唑并[4,3-b]吡啶-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；88)N-ethyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazolo[ 4,3-b]pyridin-6-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
89)4-(3-环丙基-5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吡唑并[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；89) 4-(3-Cyclopropyl-5-(2,6-dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazolo[4,3 -b]pyridin-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
90)4-(3-环丙基-5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吡唑并[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；90) 4-(3-Cyclopropyl-5-(2,6-dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-pyrazolo[4,3 -b]pyridin-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
91)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(吡啶-4-基)-1H-吡唑并[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；91) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(pyridin-4-yl)-1H-pyrazolo [4,3-b]pyridin-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2 -Formamide;
92)4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-3-(吡啶-4-基)-1H-吡唑并[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺。92) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-3-(pyridin-4-yl)-1H-pyrazolo [4,3-b]pyridin-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2 -Formamide.
本发明还提供了一种药物组合物，包含治疗有效量的至少一种上述化合物和药学上可接受的辅料，例如羟丙基甲基纤维素。在一些组合物中，所述化合物与所述辅料的重量比大约为0.001～10。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-mentioned compounds and pharmaceutically acceptable excipients, such as hydroxypropyl methylcellulose. In some compositions, the weight ratio of the compound to the excipient is about 0.001-10.
此外，本发明还提供一种治疗患有对含溴结构域蛋白质的抑制响应的疾病或病症的受试者的方法，包括给药治疗有效量的式(I)的化合物或其可药用盐。在某些方面，所述含溴结构域蛋白质为BRD4。In addition, the present invention also provides a method for treating a subject suffering from a disease or condition that responds to the inhibition of a bromodomain-containing protein, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof . In certain aspects, the bromodomain-containing protein is BRD4.
在某些方面，疾病或病症选自自身免疫疾病、炎性疾病、神经变性疾病、心脑血管疾病、肾病症、病毒感染。在某些方面，所述疾病或病症选自类风湿性关节炎、骨关节炎、动脉粥样硬化、银屑病、系统性红斑狼疮、多发性硬化、炎性肠病、哮喘、慢性阻塞性气道病、肺炎、皮炎、脱发、肾炎、血管炎、动脉粥样硬化、阿尔茨海默病、肝炎、原发性胆汁性肝硬变、硬化性胆管炎、糖尿病(包括I型糖尿病)、移植器官的急性排斥反应。在某些方面，所述疾病或病症是癌症，包括血液学肿瘤(例如淋巴瘤、多发性骨髓瘤、白血病)和实体肿瘤。在某些方面，所述疾病或病症为结肠、直肠、前列腺(例如去势抗性(castrate resistant)前列腺癌)、肺(例如非小细胞肺癌和/或小细胞肺癌)、胰腺、肝、肾、子宫颈、子宫、胃、卵巢、乳腺(例如基底或基底样乳腺癌和/或三重阴性乳腺癌)、皮肤(例如黑色素瘤)、神经系统(包括脑、脑脊膜和中枢神经系统，包括成神经细胞瘤、成胶质细胞瘤、脑膜瘤和髓母细胞瘤)的瘤或癌症。在某些方面，所述疾病或病症为癌瘤。在某些方面，所述疾病或病症为肝细胞癌。在某些方面，所述疾病或病症为骨髓增生异常综合征。在某些方面，所述疾病或病症为骨髓增殖性肿瘤(myeloproliferative neoplasms)。在某些方面，所述疾病或病症为原发性骨髓纤维化(primary myelofibrosis)。在某些方面，所述疾病或病症为真性红细胞增多症(polycythemia vera)和真性红细胞增多症继发性骨髓纤维化。在某些方面，所述疾病或病症为原发性血小板增多症(essential thrombocythemia)和原发性血小板增多症继发性骨髓纤维化。在某些方面，所述疾病或病症为淋巴瘤。在某些方面，所述疾病或病症为B-细胞淋巴瘤。在某些方面，所述疾病或病症为伯基特淋巴瘤。在某些 方面，所述疾病或病症为弥漫性大B-细胞淋巴瘤。在某些方面，所述疾病或病症为多发性骨髓瘤。在某些方面，所述疾病或病症为慢性淋巴细胞性白血病、急性髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)和慢性髓细胞性白血病(CML)。在某些方面，所述疾病或病症是NUT中线癌(midline cardinoma)。在某些方面，所述受试者是人类。In some aspects, the disease or condition is selected from autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, renal diseases, viral infections. In certain aspects, the disease or condition is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive Airway disease, pneumonia, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), Acute rejection of transplanted organs. In certain aspects, the disease or condition is cancer, including hematological tumors (e.g., lymphoma, multiple myeloma, leukemia) and solid tumors. In certain aspects, the disease or condition is colon, rectum, prostate (e.g. castrate resistant prostate cancer), lung (e.g. non-small cell lung cancer and/or small cell lung cancer), pancreas, liver, kidney , Cervix, uterus, stomach, ovary, breast (such as basal or basal-like breast cancer and/or triple negative breast cancer), skin (such as melanoma), nervous system (including brain, meninges and central nervous system, including Neuroblastoma, glioblastoma, meningioma, and medulloblastoma) tumors or cancers. In certain aspects, the disease or condition is cancer. In certain aspects, the disease or condition is hepatocellular carcinoma. In certain aspects, the disease or condition is myelodysplastic syndrome. In some aspects, the disease or condition is myeloproliferative neoplasms. In certain aspects, the disease or condition is primary myelofibrosis. In certain aspects, the disease or condition is polycythemia vera and polycythemia vera secondary to myelofibrosis. In certain aspects, the disease or condition is essential thrombocythemia and essential thrombocythemia secondary to myelofibrosis. In certain aspects, the disease or condition is lymphoma. In certain aspects, the disease or condition is B-cell lymphoma. In certain aspects, the disease or condition is Burkitt's lymphoma. In certain aspects, the disease or condition is diffuse large B-cell lymphoma. In certain aspects, the disease or condition is multiple myeloma. In certain aspects, the disease or condition is chronic lymphocytic leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML). In certain aspects, the disease or condition is NUT midline cardinoma. In certain aspects, the subject is a human.
在某些方面，所述化合物是静脉内、肌内、胃肠外、鼻或口服给药的。在一个方面，所述化合物是口服给药的。In certain aspects, the compound is administered intravenously, intramuscularly, parenterally, nasally, or orally. In one aspect, the compound is administered orally.
本发明还提供式(I)的化合物或其可药用盐在制备用于治疗对溴结构域蛋白质的抑制响应的疾病或病症的药物中的用途。The present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of diseases or disorders responsive to the inhibition of the bromodomain protein.
本发明还提供用于治疗的式(I)所示化合物或其可药用盐。进一步提供用于治疗患有对含溴结构域蛋白质的抑制响应的疾病或病症的受试者的式(I)的化合物或其可药用盐。The present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for use in therapy. There is further provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a subject suffering from a disease or condition responsive to the inhibition of a bromodomain-containing protein.
本发明中，除另有说明，术语“卤素”(halogen)是指氟、氯、溴或碘。优选的卤素基团是指氟、氯和溴。In the present invention, unless otherwise specified, the term "halogen" refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups refer to fluorine, chlorine and bromine.
本发明中，除另有说明，术语“烷基”包括直链、支链或环状的饱和单价烃基。例如，烷基包括甲基、乙基、丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、环戊基、正己基、2-己基、2-甲基戊基和环己基。类似的，C 1-6烷基中的“C 1-6”是指含有1、2、3、4、5或6个碳原子以直链或支链形式排列的基团。 In the present invention, unless otherwise specified, the term "alkyl" includes linear, branched or cyclic saturated monovalent hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2 -Methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, "C 1-6 "in C 1-6 alkyl refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or branched chain.
术语“烷氧基”是指由上述的直链、支链或环状烷基所形成的氧醚。The term "alkoxy" refers to an oxyether formed from the aforementioned linear, branched or cyclic alkyl group.
术语“亚烷基”是指二价烷基连接基团。亚烷基在形式上是指两个C-H键替换为亚烷基与化合物其余部分的连接点的烷烃。类似的，C 1-4亚烷基中的“C 1-4”是指含有1、2、3或4个碳原子的亚烷基。 The term "alkylene" refers to a divalent alkyl linking group. Formally, alkylene refers to an alkane in which two CH bonds are replaced with the point of attachment of the alkylene to the rest of the compound. Similarly, the "C 1-4 "in the C 1-4 alkylene group refers to an alkylene group containing 1, 2, 3, or 4 carbon atoms.
术语“卤代烷基”是指一个或多个H已经被卤素原子置换的烷基。术语“卤代烷氧基”是指-O-卤代烷基的基团。The term "haloalkyl" refers to an alkyl group in which one or more H has been replaced by a halogen atom. The term "haloalkoxy" refers to the group -O-haloalkyl.
术语“氧代”是指呈二甲取代基形式的氧原子，其与C连接时形成羰基，其与杂原子连接时形成亚砜基或砜基或N-氧化物基团。The term "oxo" refers to an oxygen atom in the form of a dimethyl substituent, which forms a carbonyl group when connected to C, and forms a sulfoxide or sulfone group or an N-oxide group when connected to a heteroatom.
本发明中，除另有说明，术语“芳香环”、“芳香族环”或“芳香族杂环”即为具有芳香族特征(具有(4n+2)个非定域π电子，其中n为整数)的多不饱和环的碳环或杂环。In the present invention, unless otherwise specified, the term "aromatic ring", "aromatic ring" or "aromatic heterocyclic ring" means having aromatic characteristics (having (4n+2) non-localized π electrons, where n is Integer) carbocyclic or heterocyclic polyunsaturated ring.
术语“芳基”取代或未取代的稳定的6到10个环碳原子的芳香族烃基，其可以包含1个芳香环或多个芳香环(例如稠和双环)。所述的芳香环不含有杂原子。芳基的实施例包括但不限于，苯基、萘基、茚基等。The term "aryl" is a substituted or unsubstituted, stable, 6 to 10 ring carbon atom aromatic hydrocarbon group, which may contain one aromatic ring or multiple aromatic rings (for example, fused bicyclic rings). The aromatic ring does not contain heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and the like.
术语“杂芳基”是指具有至少一个杂原子环成员的单环或多环(例如稠合双环)芳香族杂环，所述杂原子选自N、O和/或S。此类杂芳基的实例包括但不限于，吡啶基、嘧啶基、吡咯基、咪唑基、噻唑基、噻吩基、苯并咪唑、苯并噻吩基、苯并呋喃基等。The term "heteroaryl" refers to a monocyclic or polycyclic (eg, fused bicyclic) aromatic heterocyclic ring having at least one heteroatom ring member selected from N, O and/or S. Examples of such heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, benzimidazole, benzothienyl, benzofuranyl and the like.
术语“环烷基”是指具有至少一个环化烷基的环系统。术语C 3-10环烷基中的“C 3-10”是指环烷基可以具有3、4、5、6、7、8、9或10个成环原子。环烷基可以包括单环和多环(例如具有2、3或4个稠合环，螺环、并环等)。一些实施例中环烷基包括但不限于环丙基、环丁基、环戊基等；在一些实施例中环烷基还包括具有一个或多个与环化烷基环稠合的芳香族环的部分，例如环己烷的苯并或噻吩基衍生物等。 The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. The "C 3-10 "in the term C 3-10 cycloalkyl means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms. Cycloalkyl groups may include monocyclic and polycyclic rings (e.g., having 2, 3 or 4 fused rings, spiro rings, fused rings, etc.). In some embodiments, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; in some embodiments, cycloalkyl groups also include those having one or more aromatic rings fused with cyclized alkyl rings. Part, such as benzo or thienyl derivatives of cyclohexane.
术语“环烯基”是指具有至少一个环化烯基的环系统，所述环烯基中具有一个或多个碳碳双键。术语C 3-10环烯基中的“C 3-10”是指环烯基可以具有3、4、5、6、7、8、9或10个成环原子。环烯基可以包括单环和多环(例如具有2、3或4个稠合环，螺环、桥环等)。一些实施例中环烯基包括但不限于环己烯基、环己二烯、环庚三烯基等；在一些实施例中环烯基还包括具有一个或多个与环化烯基环稠合的芳香族环的部分，例如环己烯环的苯并或噻吩基衍生物等。 The term "cycloalkenyl" refers to a ring system having at least one cyclized alkenyl group with one or more carbon-carbon double bonds in the cycloalkenyl group. The "C 3-10 "in the term C 3-10 cycloalkenyl means that the cycloalkenyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms. Cycloalkenyl groups may include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, cycloalkenyl includes, but is not limited to, cyclohexenyl, cyclohexadiene, cycloheptatrienyl, etc.; in some embodiments, cycloalkenyl also includes those having one or more fused rings with cyclized alkenyl Part of the aromatic ring, such as benzo or thienyl derivatives of the cyclohexene ring.
术语“杂环基”是指具有至少一个含有杂环子的环化烷基或环化烯基的环系统，所述杂原子选自N、O和/或S。所述杂环基可以包括单环或多环(例如具有2、3或4个稠合环，螺环、桥环等)。杂环基可以经由成环碳原子或成环杂原子与化合物其他部分相连接。所述杂环基的定义中还包括具有一个或多个与环化烷基或环化烯基环稠合的芳香族环的部分，例如哌啶、吗啉等的苯并或噻吩基衍生物。在一些实施方案中，杂环基包括但不限于吡咯烷基、吡咯啉基、四氢噻吩基、四氢呋喃基、哌啶基、吗啉基、氮杂环庚烷、二氢苯并呋喃基等。The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl containing a heterocyclic ring, and the heteroatom is selected from N, O and/or S. The heterocyclic group may include a single ring or a polycyclic ring (for example, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclic group can be connected to other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom. The definition of the heterocyclic group also includes moieties having one or more aromatic rings fused with a cyclized alkyl or cyclized alkenyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, etc. . In some embodiments, heterocyclic groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, morpholinyl, azepanyl, dihydrobenzofuranyl, etc. .
本发明中术语“组合物”旨在包括含有特定数量的特定组分的产品，也包括任何由特定数量的特定组分直接或间接得到的产品。因此，包含本发明中的化合物作为活性组分的药物组合物和制备该化合物的方法也是本发明的内容。而且，一些化合物的晶型可以多晶型形式存在，这些也包括在本发明中。此外，一些化合物与水(如水合物)或普通有机溶剂形成溶剂化物，这些溶剂化物也包含在本发明中。The term "composition" in the present invention is intended to include a product containing a specific amount of a specific component, as well as any product obtained directly or indirectly from a specific amount of a specific component. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient and a method for preparing the compound are also the content of the present invention. Furthermore, the crystal forms of some compounds may exist in polymorphic forms, and these are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and these solvates are also included in the present invention.
本发明化合物的药物前体包含在本发明的保护范围内。通常，所述药物前体是指很容易在体内转化成所需要的化合物的功能性衍生物。因此，本发明提供的治疗方法中的术语“给药”包括施用本发明公开的化合物，或虽未明确公开但对受试者给药后能够在体内转化为本发明公开的化合物治疗所述的各种疾病。有关选择和制备合适药物前体衍生物的常规方法，已记载在例如《药物前体设计》(Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985)这类书中。The prodrug of the compound of the present invention is included in the protection scope of the present invention. Generally, the prodrug refers to a functional derivative that is easily converted into a desired compound in the body. Therefore, the term "administration" in the method of treatment provided by the present invention includes the administration of the compound disclosed in the present invention, or although it is not clearly disclosed but can be transformed into the compound disclosed in the present invention after administration to a subject in vivo. Various diseases. The conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as "Design of Prodrugs" (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
显然的，一个分子中任何取代基或特定位置的变量的定义是独立于分子中其他位置的。很容易理解，本领域普通技术人员可以通过现有技术手段及本发明中所述的方法，选择本发明中的化合物的取代基或取代形式，以提供化学上稳定且容易合成的化合物。Obviously, the definition of any substituent or variable at a specific position in a molecule is independent of other positions in the molecule. It is easy to understand that a person of ordinary skill in the art can select the substituent or substituted form of the compound of the present invention through the existing technical means and the method described in the present invention to provide a chemically stable and easy-to-synthesize compound.
本发明所述化合物可能含有一个或多个不对称中心，并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药学上可接受的盐。The compound of the present invention may contain one or more asymmetric centers, and may produce diastereomers and optical isomers from this. The present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
上述式(I)没有确切定义该化合物某一位置的立体结构。本发明包括式(I)所示化合物的所有立体异构体及其药学上可接受的盐。进一步地，立体异构体的混合物及分离出的特定的立体异构体也包括在本发明中。制备此类化合物的合成过程中，或使用本领域普通技术人员公知的外消旋化或差向异构化方法的过程中，制得的产品可以是立体异构体的混合物。The above formula (I) does not exactly define the three-dimensional structure of a certain position of the compound. The present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. In the synthetic process of preparing such compounds, or in the process of using racemization or epimerization methods well known to those of ordinary skill in the art, the product obtained may be a mixture of stereoisomers.
当式(I)所示化合物存在互变异构体时，除非特别声明，本发明包括任何可能的互变异构体和其药学上可接受的盐，及它们的混合物。When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers, pharmaceutically acceptable salts thereof, and mixtures thereof.
当式(I)所示化合物及其药学上可接受的盐为溶剂化物或多晶型的形式时，本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定，只要该溶剂是药理学上可以接受的。例如，水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。When the compound represented by formula (I) and its pharmaceutically acceptable salt are in the form of a solvate or polymorph, the present invention includes any possible solvate and polymorph. The type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.
术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。当本发明提供的化合物是酸时，可以从药学上可接受的无毒的碱，包括无机碱和有机碱，方便地制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(高价和低价)、三价铁、亚铁、锂、镁、锰(高价和低价)、钾、钠、锌之类的盐。特别优选铵、钙、镁、钾和钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺，也包括环胺及含有取代基的胺，如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱，包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡 萄糖胺、氨基葡萄糖、组氨酸、哈胺、异丙胺、赖氨酸，甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、氯普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are the salts of ammonium, calcium, magnesium, potassium, and sodium. The non-toxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, ammonia Butanetriol and so on.
当本发明提供的化合物是碱时，可以从药学上可接受的无毒的酸，包括无机酸和有机酸，方便制得其相应的盐。这样的酸包括，如，醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、草酸、丙酸、乙醇酸、氢碘酸、高氯酸、环己氨磺酸、水杨酸、2-萘磺酸、糖精酸、三氟乙酸、酒石酸和对甲苯磺酸等。较优地，柠檬酸、氢溴酸、甲酸、盐酸、马来酸、磷酸、硫酸和酒石酸。更优地，甲酸和盐酸。由于式(I)所示化合物将作为药物应用，所以优选使用基本上纯的形式，例如，至少60％纯度，更适当地至少75％的纯度，特别地至少98％的纯度(％是重量比)。When the compound provided by the present invention is a base, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pyruvic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, Cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid, etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, especially at least 98% purity (% is a weight ratio ).
本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(或其药学上可接受的盐)、一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。尽管任何给定的情况下，最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度，但是本发明的药物组合物包括适于口腔、直肠、局部和不经肠道(包括皮下给药、肌肉注射、静脉给药)给药的药物组合物。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。The pharmaceutical composition provided by the present invention includes as an active component a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories. Although in any given case, the most suitable way of administering the active ingredient depends on the particular subject to be administered, the nature of the subject and the severity of the disease, the pharmaceutical composition of the present invention includes oral, rectal, topical and A pharmaceutical composition for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration). The pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.
实际上，根据常规的药物混合技术，本发明式(I)所示化合物，或药物前体，或代谢物，或药学上可接受的盐，可以作为活性组分，与药物载体混合成药物组合物。所述药物载体可以采取各种各样的形式，这取决于期望采用的给药方式，例如，口服或注射(包括静脉注射)。因此，本发明的药物组合物可以采用适于口服给药的独立单位的形式，如包含预定剂量的活性组分的胶囊剂、扁囊剂或片剂。进一步地，本发明的药物组合物可采用粉末、颗粒、溶液、水性悬浮液、非水液体、水包油型乳液，或油包水型乳液形式。另外，除了上述提到的常见的剂型，式(I)所示化合物或其药学上可接受的盐，也可以通过控释的方式和/或输送装置给药。本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下，这种方法包括使活性组分和组成一个或多个必要成分的载体缔合的步骤。一般情况下，所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过均匀的密切的混合制得。然后，该产品可以方便地制备成所需要的外观。In fact, according to conventional drug mixing technology, the compound represented by formula (I) of the present invention, or prodrug, or metabolite, or pharmaceutically acceptable salt, can be used as an active component and mixed with a drug carrier to form a drug combination Things. The pharmaceutical carrier can take a variety of forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may take the form of a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition, in addition to the common dosage forms mentioned above, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both. Then, the product can be easily prepared into the desired appearance.
因此，本发明的药物组合物包括药学上可接受的载体和式(I)所示化合物或其药学上可接受的盐。式(I)所示化合物或其药学上可接受的盐，与其他一种或多种具有治疗活性的化合物也包括在本发明的药物组合物中。Therefore, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and one or more other compounds with therapeutic activity are also included in the pharmaceutical composition of the present invention.
本发明采用的药物载体可以是，例如，固体载体、液体载体或气体载体。固体载体，包括乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸。液体载体，包括糖浆、花生油、橄榄油和水。气体载体，包括二氧化碳和氮气。制备药物口服制剂时，可以使用任何方便的制药学上的介质。例如，水、乙二醇、油类、醇类、增味剂、防腐剂、着色剂等可用于口服的液体制剂如悬浮剂、酏剂和溶液剂；而载体，如淀粉类、糖类、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等可用于口服的固体制剂如散剂、胶囊剂和片剂。考虑到易于施用，口服制剂首选片剂和胶囊，在此应用固体药学载体。可选地，片剂包衣可使用标准的水制剂或非水制剂技术。The drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier. Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil and water. The gas carrier includes carbon dioxide and nitrogen. When preparing oral pharmaceutical preparations, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used in oral solid preparations such as powders, capsules and tablets. In view of ease of administration, tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here. Alternatively, standard aqueous or non-aqueous formulation techniques can be used for tablet coating.
含有本发明化合物或药物组合物的片剂可通过，任选一种或多种辅助组分或辅药一起压制或成型制备。活性组分以自由流动的形式如粉末或颗粒，与粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂混合，在适当的机器中，通过压制可以制得压制片剂。用一种惰性液体稀释剂浸湿粉末状的化合物或药物组合物，然后在适当的机器中，通过成型可以制得模制片。较优地，每个片剂含有大约0.05mg到5g的活性组分，每个扁囊剂或胶囊剂含有大约0.05mg到5g的活性组分。例如，拟用于人类口服给药的剂型包含约0.5mg到约5g的活性组分，与合适且方便计量的辅助材料复合，该辅助材料约占药物组合物总量的5％至95％。单位剂型一般包含约1mg到约2g的活性组分，典型的是25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by compressing or molding one or more auxiliary components or adjuvants together. The active ingredient is in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surfactant or dispersant, and compressed in a suitable machine to obtain compressed tablets. The powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet. Preferably, each tablet contains about 0.05 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of active ingredient. For example, a dosage form intended for oral administration to humans contains about 0.5 mg to about 5 g of active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 95% of the total pharmaceutical composition. The unit dosage form generally contains about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
本发明提供的适用于胃肠外给药的药物组合物可将活性组分加入水中制备成水溶液或悬浮液。可以包含适当的表面活性剂如羟丙基纤维素。在甘油、液态聚乙二醇，及其在油中的混合物，也可以制得分散体系。进一步地，防腐剂也可以包含在本发明的药物组合物中用于防止有害的微生物生长。The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water. A suitable surfactant such as hydroxypropyl cellulose may be included. In glycerol, liquid polyethylene glycol, and their mixture in oil, dispersion systems can also be prepared. Further, a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.
本发明提供适用于注射的药物组合物，包括无菌水溶液或分散体系。进一步地，上述药物组合物可以制备成可用于即时配制无菌注射液或分散液的无菌粉末的形式。无论如何，最终的注射形式必须是无菌的，且为了易于注射，必须是易于流动的。此外，所述药物组合物在制备和储存过程中必须稳定。因此，优选抗微生物如细菌和真菌污染的保存。载体可以是溶剂或分散介质，例如，水、乙醇、多元醇(如甘油、丙二醇、液态聚乙二醇)、植物油及其适当的混合物。The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems. Further, the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for immediate preparation of sterile injection or dispersion. In any case, the final injection form must be sterile, and for easy injection, it must be easy to flow. In addition, the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
本发明提供的药物组合物，可以是适于局部用药的形式，例如，气溶胶、乳剂、软膏、洗液、撒粉或其他类似的剂型。进一步地，本发明提供的药物组合物可以采用适于经皮给药装置使用的形式。利用本发明式(I)所示化合物，或其药学上可接受的盐，通过常规的加工方法，可以制备这些制剂。作为一个例子，乳剂或软膏剂的制备是通过在约5wt％到10wt％的上述化合物中加入亲水性材料和水，制得具有预期一致性的乳剂或软膏。The pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting powder or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device. Using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, these preparations can be prepared by conventional processing methods. As an example, an emulsion or ointment is prepared by adding a hydrophilic material and water to about 5 wt% to 10 wt% of the above-mentioned compound to prepare an emulsion or ointment having the desired consistency.
本发明提供的药物组合物，可以制成以固体为载体，适用于直肠给药的形式。优选的剂型为混合物形成单位剂量的栓剂。适当的辅料包括本领域常用的可可脂和其他材料。栓剂可以方便地制备，首先药物组合物与软化或熔化的辅料混合，然后冷却和模具成型而制得。The pharmaceutical composition provided by the present invention can be made into a form that takes a solid as a carrier and is suitable for rectal administration. The preferred dosage form is a suppository in which the mixture forms a unit dose. Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared. First, the pharmaceutical composition is mixed with softened or melted excipients, and then cooled and molded.
除了上述提到的载体组分外，上述药学制剂还可以包括，适当的，一种或多种附加的辅料组分，如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂和防腐剂(包括抗氧化剂)等。此外，其他的辅药还可以包括调节药物与血液等渗压的促渗剂。包含式(I)所示化合物，或其药学上可接受的盐的药物组合物，也可以制备成粉剂或浓缩液的形式。In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants and preservatives (including antioxidants), etc. In addition, other adjuvants can also include penetration enhancers that regulate the isotonic pressure between the drug and the blood. The pharmaceutical composition containing the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, can also be prepared in the form of a powder or a concentrated solution.
一般情况下，治疗上述所示的状况或不适，药物的剂量水平约为每天0.01mg/kg体重到150mg/kg体重，或者每个病人每天0.5mg到7g。但是，可以理解，任何特定病人的具体剂量水平将取决于多种因素，包括年龄、体重、综合健康状况、性别、饮食、给药时间、给药途径、排泄率、药物联用的情况和接受治疗的特定疾病的严重程度。In general, to treat the above-mentioned conditions or discomforts, the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day. However, it is understood that the specific dosage level for any particular patient will depend on many factors, including age, weight, overall health, gender, diet, time of administration, route of administration, excretion rate, combination of drugs and acceptance The severity of the specific disease being treated.
具体实施方式Detailed ways
为使本发明更加容易理解，下面将结合实施例来详细说明本发明，这些实施例仅起说明性作用，并不局限于本发明的应用范围，下列实施例中未提及的具体实验方法，通常按照常规实验方法进行。In order to make the present invention easier to understand, the present invention will be described in detail below in conjunction with examples. These examples are only illustrative and are not limited to the scope of application of the present invention. Specific experimental methods not mentioned in the following examples, It is usually carried out in accordance with conventional experimental methods.
除另有说明，所有的部分和百分数均以重量计算，所有的温度均为摄氏度。Unless otherwise stated, all parts and percentages are calculated by weight, and all temperatures are in degrees Celsius.
实施例中使用了下列缩略语：The following abbreviations are used in the examples:
AcOH：乙酸；AcOH: acetic acid;
AcOK或KAcO：乙酸钾；AcOK or KAcO: potassium acetate;
ACN或CH 3CN：乙腈； ACN or CH 3 CN: Acetonitrile;
NH 4Cl：氯化铵； NH 4 Cl: ammonium chloride;
BRD4(D1)：溴结构域蛋白4(结构域1)；BRD4 (D1): Bromodomain protein 4 (domain 1);
BRD4(D2)：溴结构域蛋白4(结构域2)；BRD4 (D2): Bromodomain protein 4 (domain 2);
Cs 2CO 3：碳酸铯； Cs 2 CO 3 : Cesium carbonate;
CH 3I：碘甲烷； CH 3 I: methyl iodide;
CuI：碘化亚铜；CuI: Cuprous iodide;
DAST：二乙胺基三氟化硫；DAST: Diethylaminosulfur trifluoride;
DCM：二氯甲烷；DCM: dichloromethane;
DIEA：N,N-二异丙基乙胺；DIEA: N,N-diisopropylethylamine;
DMA：N,N-二甲基乙酰胺；DMA: N,N-dimethylacetamide;
DMF：N,N-二甲基甲酰胺；DMF: N,N-dimethylformamide;
DMSO：二甲基亚砜；DMSO: dimethyl sulfoxide;
EA：乙酸乙酯；EA: ethyl acetate;
EtOH：乙醇；EtOH: ethanol;
Et 3N：三乙胺； Et 3 N: triethylamine;
h或hrs：小时；h or hrs: hours;
1HNMR：核磁共振； 1 HNMR: nuclear magnetic resonance;
HATU：2-(O-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；HATU: 2-(O-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate;
H 2O 2：过氧化氢； H 2 O 2 : hydrogen peroxide;
K 2CO 3：碳酸钾； K 2 CO 3 : potassium carbonate;
LCMS：液质联用；LCMS: Liquid Mass Spectrometry;
LDA：二异丙基氨基锂；LDA: lithium diisopropylamide;
MeOH：甲醇；MeOH: methanol;
min：分钟；min: minutes;
NaH：氢化钠；NaH: sodium hydride;
NaI：碘化钠；NaI: sodium iodide;
NaNO 2：亚硝酸钠； NaNO 2 : Sodium nitrite;
NH 4BF 4：氟硼酸铵； NH 4 BF 4 : Ammonium fluoroborate;
n-Hex：正己烷；n-Hex: n-hexane;
Pd 2(dba) 3：三(二亚苄基丙酮)二钯； Pd 2 (dba) 3 : Tris(dibenzylideneacetone)dipalladium;
Pd(dppf)Cl 2：[1,1'-双(二苯基膦)二茂铁]二氯化钯； Pd(dppf)Cl 2 : [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride;
Pd(dppf)Cl 2.DCM：[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物； Pd(dppf)Cl 2 .DCM: [1,1'-bis(diphenylphosphine)ferrocene] palladium dichloride dichloromethane complex;
Pd(PPh 3) 4：四三苯基磷化钯； Pd(PPh 3 ) 4 : Palladium tetrakistriphenylphosphide;
Pd(PPh 3) 2Cl 2：双三苯基磷二氯化钯； Pd(PPh 3 ) 2 Cl 2 : Bistriphenylphosphorus palladium dichloride;
PE：石油醚；PE: petroleum ether;
PtO 2：二氧化铂； PtO 2 : platinum dioxide;
s：秒；s: seconds;
THF：四氢呋喃；THF: Tetrahydrofuran;
TsCl：对甲基苯磺酰氯；TsCl: p-toluenesulfonyl chloride;
TMSCl：三甲基氯硅烷；TMSCl: trimethylchlorosilane;
XPhos：2-二环己基磷-2',4',6'-三异丙基联苯；XPhos: 2-Dicyclohexylphosphorus-2',4',6'-triisopropylbiphenyl;
Zn(CN) 2：氰化锌； Zn(CN) 2 : zinc cyanide;
1N：1摩尔每升。1N: 1 mole per liter.
中间体M1(N-乙基-6-甲基-7-氧代-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺)的合成Intermediate M1 (N-ethyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) Synthesis of -6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide)
Figure PCTCN2021094838-appb-000011
Figure PCTCN2021094838-appb-000011
步骤1：化合物M1-2的合成Step 1: Synthesis of compound M1-2
将5-溴-2-甲氧基-4-甲基-3-硝基吡啶(200.0g)溶于DMF(1600mL)，升温至85℃，并在此温度下将DMF-DMA(819.99g)滴加到反应液中。滴加完毕后，升温至95℃，搅拌4.0hrs。冷却，将反应液加入至冰水中(1000mL)淬灭，加入EA(1000mL)萃取分液，水相再用EA(1000mL*2)萃取，合并有机相，饱和食盐水(1000mL*3)洗涤，浓缩，得红棕色固体粗品，直接投下一步。Dissolve 5-bromo-2-methoxy-4-methyl-3-nitropyridine (200.0g) in DMF (1600mL), raise the temperature to 85°C, and mix DMF-DMA (819.99g) at this temperature Add dropwise to the reaction solution. After the dropwise addition was completed, the temperature was raised to 95°C and stirred for 4.0 hrs. Cool, add the reaction solution to ice water (1000mL) for quenching, add EA (1000mL) for extraction and liquid separation, and then extract the aqueous phase with EA (1000mL*2), combine the organic phases, and wash with saturated brine (1000mL*3). Concentrate to obtain a red-brown solid crude product, which is directly cast to the next step.
步骤2：化合物M1-3的合成Step 2: Synthesis of compound M1-3
将化合物M1-2(242g)溶于EtOH(1800mL)和H 2O(200mL)混合溶液中，然后将Fe粉(242g)加入至反应液中，升温至回流。缓慢加入NH 4Cl(242g)的水溶液(200mL)。搅拌3.0hrs，反应完毕后，降温至60℃，硅藻土热过滤，滤饼用EtOH多次洗涤，收集滤液并浓缩得残余物。向残余物中加入EA和稀盐酸水溶液(1mol/L)后分液。有机相用饱和食盐水洗涤三次，浓缩后得到粗品。粗品用ACN打浆，抽滤，滤饼用少量ACN洗涤，得102g所述标题化合物M1-3。 Compound M1-2 (242g) was dissolved in a mixed solution of EtOH (1800 mL) and H 2 O (200 mL), then Fe powder (242 g) was added to the reaction solution, and the temperature was raised to reflux. An aqueous solution (200 mL) of NH 4 Cl (242 g) was slowly added. Stir for 3.0 hrs. After the reaction is completed, the temperature is lowered to 60° C., then filtered with diatomaceous earth. The filter cake is washed with EtOH several times. The filtrate is collected and concentrated to obtain a residue. To the residue were added EA and a dilute aqueous hydrochloric acid solution (1 mol/L) and then separated. The organic phase was washed three times with saturated brine, and concentrated to obtain a crude product. The crude product was slurried with ACN, filtered with suction, and the filter cake was washed with a small amount of ACN to obtain 102 g of the title compound M1-3.
步骤3：化合物M1-4的合成Step 3: Synthesis of compound M1-4
将M1-3(102.5g)溶于THF(1000mL)中，冰盐浴降温至-5℃，在-5℃下分批次加入NaH(59.6g)，加毕，恢复至室温搅拌2.0hrs。-5℃下向反应液中滴加TsCl(111.9g)的THF(600mL)溶液。加毕后，自然恢复至室温，搅拌过夜。将反应液在5℃下倒入冰水中淬灭，然后加入EA(1000mL)分液，水相用EA萃取2-3次，合并有机相，饱和碳酸钠洗涤，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(PE:EA＝10:1)，得130g所述标题化合物M1-4。Dissolve M1-3 (102.5g) in THF (1000mL), cool to -5°C in an ice-salt bath, add NaH (59.6g) in batches at -5°C, return to room temperature and stir for 2.0hrs after addition. A solution of TsCl (111.9 g) in THF (600 mL) was added dropwise to the reaction solution at -5°C. After the addition is complete, return to room temperature naturally and stir overnight. The reaction solution was poured into ice water for quenching at 5°C, then EA (1000 mL) was added for separation, the aqueous phase was extracted with EA 2-3 times, the organic phases were combined, washed with saturated sodium carbonate, saturated brine, and anhydrous sulfuric acid Drying with sodium, concentration, column chromatography (PE:EA=10:1), to obtain 130 g of the title compound M1-4.
步骤4：化合物M1-5的合成Step 4: Synthesis of compound M1-5
将M1-4(74g)溶于THF(1000mL)，氮气真空置换3次，降温至-70至-80℃，并在-70℃以下滴加LDA(31.19g)至反应液中，滴加完毕，保持该温度继续搅拌1.0h，然后滴加氯甲酸乙酯(31.60g)，保持该温度继续搅拌2-3hrs。取样检测，反应完毕后控温-50℃以下，滴加饱和氯化铵(150mL)进行淬灭，加入EA(1500mL)进行萃取，分液，有机相再用饱和氯化铵水溶液洗涤(500mL*2)，饱和碳酸钠洗涤(500mL*2)，饱和食盐水洗涤(500mL*2)，浓缩，得85g所述标题化合物M1-5。Dissolve M1-4 (74g) in THF (1000mL), replace with nitrogen 3 times, cool to -70 to -80℃, and add LDA (31.19g) dropwise to the reaction solution below -70℃. The addition is complete , Keep the temperature and continue to stir for 1.0h, then add ethyl chloroformate (31.60g) dropwise, keep the temperature and continue to stir for 2-3hrs. Sampling and testing, after the reaction, the temperature is controlled below -50℃, saturated ammonium chloride (150mL) is added dropwise for quenching, EA (1500mL) is added for extraction, liquid separation, and the organic phase is washed with saturated ammonium chloride aqueous solution (500mL* 2) Wash with saturated sodium carbonate (500 mL*2), wash with saturated brine (500 mL*2), and concentrate to obtain 85 g of the title compound M1-5.
步骤5：化合物M1-6的合成Step 5: Synthesis of compound M1-6
向M1-5(73g)的ACN(1000mL)溶液中加入NaI(36.21g)和TMSCl(26.23g)，搅拌0.5h后加入H 2O(10mL)，然后升温至65℃，搅拌2.0hrs。反应完毕，加入DCM(1000mL)稀释，依次用硫代硫酸钠溶液(200mL*2)、饱和碳酸钠溶液(200mL)洗涤和饱和食盐水(200mL)洗涤，无水硫酸钠干燥，浓缩，得67g所述标题化合物M1-6。 (1000mL) was added to the M1-5 (73g) in ACN NaI (36.21g) and TMSCl (26.23g), stirred 0.5h added H 2 O (10mL), then warmed to 65 ℃, stirred for 2.0hrs. After the reaction is complete, add DCM (1000mL) to dilute, and sequentially wash with sodium thiosulfate solution (200mL*2), saturated sodium carbonate solution (200mL) and saturated brine (200mL), dry with anhydrous sodium sulfate, and concentrate to obtain 67g The title compound M1-6.
步骤6：化合物M1-7的合成Step 6: Synthesis of compound M1-7
向M1-6(67g)的DMF(1000mL)溶液中加入Cs 2CO 3(99.39g)和CH 3I(25.98g)，反应液搅拌2.0hrs。反应完毕，反应液倾倒于冰水当中，加入EA(1000ml)分液，水相EA(500ml*2)萃取，合并有机相，饱和食盐水洗涤(200ml*2)，无水硫酸钠干燥，浓缩， 得60g所述标题化合物M1-7。 Cs 2 CO 3 (99.39 g) and CH 3 I (25.98 g) were added to the DMF (1000 mL) solution of M1-6 (67 g), and the reaction solution was stirred for 2.0 hrs. After the reaction is completed, the reaction solution is poured into ice water, added EA (1000ml) for separation, the aqueous phase EA (500ml*2) is extracted, the organic phases are combined, washed with saturated brine (200ml*2), dried with anhydrous sodium sulfate, and concentrated , 60 g of the title compound M1-7 was obtained.
步骤7：化合物M1-8的合成Step 7: Synthesis of compound M1-8
向M1-7(60g)的1,4-二氧六环(480mL)溶液中加入NaOH(26.47g)的H 2O(120mL)溶液，反应液升温至80℃，反应2.0hrs。反应完毕后，调节PH＝4后析出固体，过滤，滤饼少量水洗，干燥，得30g所述标题化合物M1-8。 To the 1,4-dioxane (480 mL) solution of M1-7 (60 g) was added a solution of NaOH (26.47 g) in H 2 O (120 mL), the reaction solution was heated to 80° C. and reacted for 2.0 hrs. After the completion of the reaction, after adjusting the pH=4, a solid precipitated out, filtered, the filter cake was washed with a small amount of water, and dried to obtain 30 g of the title compound M1-8.
步骤8：化合物M1-9的合成Step 8: Synthesis of compound M1-9
向M1-8(30.0g)的DMF(300mL)溶液中依次加入HATU(63.1g)和乙胺盐酸盐(13.5g)。反应液降至0℃后加入DIEA(71.52g)，自然恢复至室温，搅拌2.0hrs。反应完毕后，将反应液缓慢倾倒至冰水(300mL)中，析出固体，抽滤，滤饼用少量水洗涤，干燥，得21g所述标题化合物M1-9。To a solution of M1-8 (30.0 g) in DMF (300 mL), HATU (63.1 g) and ethylamine hydrochloride (13.5 g) were sequentially added. After the reaction solution was reduced to 0°C, DIEA (71.52g) was added, returned to room temperature naturally, and stirred for 2.0hrs. After the completion of the reaction, the reaction solution was slowly poured into ice water (300 mL), a solid was separated out, filtered with suction, the filter cake was washed with a small amount of water, and dried to obtain 21 g of the title compound M1-9.
步骤9：中间体M1的合成Step 9: Synthesis of intermediate M1
将M1-9(17g)，联硼酸频那醇酯(28.96g)，Pd 2(dba) 3(5.22g)，Xphos(5.44g)依次加入至反应瓶内，然后加入1,4-二氧六环(300mL)，搅拌下加入AcOK(16.79g)。氮气置换3次，反应液升温至85℃，搅拌过夜。反应完毕后，降温至室温，向反应液中加入DCM(500mL)和水(200mL)，萃取分液，水相用DCM(200mL)萃取2-3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(DCM:MeOH＝10:1)纯化，得13g所述中间体M1。 Add M1-9 (17g), pinacol diborate (28.96g), Pd 2 (dba) 3 (5.22g), Xphos (5.44g) into the reaction flask, and then add 1,4-diox Six rings (300 mL), AcOK (16.79 g) was added with stirring. Nitrogen replacement was performed three times, and the reaction solution was heated to 85°C and stirred overnight. After the completion of the reaction, the temperature was lowered to room temperature, DCM (500mL) and water (200mL) were added to the reaction solution, and the liquids were extracted and separated. The aqueous phase was extracted with DCM (200mL) for 2-3 times. The organic phases were combined and washed with saturated brine. Drying with aqueous sodium sulfate, concentration, and purification by column chromatography (DCM:MeOH=10:1), to obtain 13g of the intermediate M1.
LCMS:[M+1] +＝346.2。 LCMS: [M+1] + = 346.2.
中间体M2(6-溴-5-(2,6-二甲基苯氧基)-1H-吲唑)的合成Synthesis of intermediate M2 (6-bromo-5-(2,6-dimethylphenoxy)-1H-indazole)
Figure PCTCN2021094838-appb-000012
Figure PCTCN2021094838-appb-000012
步骤1：化合物M2-2的合成Step 1: Synthesis of compound M2-2
将化合物M2-1(2.34g)，2,6-二甲基苯酚(1.22g)，碳酸铯(9.78g)置于50mL乙腈中,反应液加热至70℃反应2hrs。将反应液倒入200mL水中，EA萃取(50ml*3)，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得3.12g所述标题化合物M2-2。Compound M2-1 (2.34g), 2,6-dimethylphenol (1.22g), and cesium carbonate (9.78g) were placed in 50mL acetonitrile, and the reaction solution was heated to 70°C for 2hrs. The reaction solution was poured into 200 mL of water, extracted with EA (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 3.12 g of the title compound M2-2.
步骤2：化合物M2-3的合成Step 2: Synthesis of compound M2-3
将化合物M2-2(2.36g)，铁粉(2.80g)置于30mL冰醋酸中，反应液加热到60℃反应2hrs，过滤，浓缩滤液，向浓缩液中加入饱和碳酸钠溶液，EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(PE:EA＝2:1)纯化，得到2.52g所述标题化合 物M2-3。Put compound M2-2 (2.36g) and iron powder (2.80g) in 30mL of glacial acetic acid, heat the reaction solution to 60°C for 2hrs, filter, concentrate the filtrate, add saturated sodium carbonate solution to the concentrate, and extract with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=2:1) to obtain 2.52 g of the title compound M2-3.
步骤3：中间体M2的合成Step 3: Synthesis of intermediate M2
将化合物M2-3(3.00g)置于90mL冰乙酸/水(V/V＝2/1)混合液中，搅拌溶清，反应液降温至0℃后，加入氟硼酸铵(1.26g)，浓HCl(0.5mL)和NaNO 2(0.83g)，缓慢恢复至室温，搅拌1h。反应液浓缩至干，加入EA(200mL)和乙酸钾(10g)，室温搅拌过夜。加水稀释反应液，EA萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到所述中间体M2。 Put compound M2-3 (3.00g) in 90mL glacial acetic acid/water (V/V=2/1) mixed solution, stir to clear, after the reaction solution is cooled to 0°C, add ammonium fluoroborate (1.26g), Concentrated HCl (0.5 mL) and NaNO 2 (0.83 g), slowly returned to room temperature, and stirred for 1 h. The reaction solution was concentrated to dryness, EA (200 mL) and potassium acetate (10 g) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water, extracted with EA, washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated to obtain the intermediate M2.
LCMS:[M+1] +＝317.0。 LCMS: [M+1] + = 317.0.
中间体M3(6-溴-5-((2,4-二甲基吡啶-3-基)氧基)-1H-吲唑)的合成Synthesis of intermediate M3 (6-bromo-5-((2,4-dimethylpyridin-3-yl)oxy)-1H-indazole)
参考中间体M2的制备方法，将2,6-二甲苯酚替换为2,4-二甲基吡啶-3-醇，即得中间体M3。Referring to the preparation method of intermediate M2, replace 2,6-xylenol with 2,4-dimethylpyridin-3-ol to obtain intermediate M3.
LCMS:[M+1] +＝318.0。 LCMS: [M+1] + = 318.0.
实施例1和实施例2 4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物1)和4-(5-(2,6-二甲基苯氧基)-2-(2-羟基-2-甲基丙基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物2)的制备Example 1 and Example 2 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)- N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (compound 1) and 4-(5-( 2,6-Dimethylphenoxy)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-6-yl)-N-ethyl-6-methyl-7-oxy Preparation of Subo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 2)
Figure PCTCN2021094838-appb-000013
Figure PCTCN2021094838-appb-000013
步骤1：化合物1-1和化合物2-1的合成Step 1: Synthesis of compound 1-1 and compound 2-1
将中间体M2(3.17g)，甲基环氧丙烷(1.44g)，碳酸钾(4.14g)置于DMF(50mL)中，90℃反应6hrs。冷却至室温，将水加入至反应液中，EA萃取3次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(PE/EA＝3/1)分离纯化，浓缩前峰洗脱液得到化合物1-1(2.10g)，浓缩后峰洗脱液得到化合物2-1(1.01g)。Intermediate M2 (3.17 g), methyl propylene oxide (1.44 g), potassium carbonate (4.14 g) were placed in DMF (50 mL) and reacted at 90° C. for 6 hrs. Cool to room temperature, add water to the reaction solution, extract 3 times with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, separate and purify by column chromatography (PE/EA=3/1), before concentration The peak eluate gave compound 1-1 (2.10 g), and the peak eluate was concentrated to give compound 2-1 (1.01 g).
步骤2：化合物1的合成Step 2: Synthesis of compound 1
将化合物1-1(3.17g)，中间体M1(3.46g)，碳酸钾(4.14g)，Pd(dppf)Cl 2(0.73g)置于二氧六环/H 2O(60ml，V/V＝5/1)混合溶液中，置换氮气3次，85℃反应6hrs。冷却至室温，将水加入至反应液中，DCM萃取3次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(DCM:MeOH＝100:4)纯化，得到3.02g化合物1。 Compound 1-1 (3.17g), intermediate M1 (3.46g), potassium carbonate (4.14g), Pd(dppf)Cl 2 (0.73g) were placed in dioxane/H 2 O (60ml, V/ V=5/1) In the mixed solution, replace with nitrogen 3 times, and react at 85°C for 6 hrs. After cooling to room temperature, water was added to the reaction solution, DCM was extracted 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH=100:4) to obtain 3.02g Compound 1.
LCMS:[M+1] +＝528.6。 LCMS: [M+1] + =528.6.
1HNMR(500MHz,DMSO)δ12.25(s,1H),8.30(t,J＝5.3Hz,1H),7.88(s,1H),7.80(s,1H),7.40(s,1H),7.14(d,J＝7.5Hz,2H),7.10–7.00(m,1H),6.90(s,1H),6.55(s,1H),4.62(s,1H),4.30(s,2H),3.62(s,3H),3.17(d,J＝5.2Hz,2H),2.05(d,J＝24.7Hz,6H),1.12(s,6H),1.10(d,J＝7.2Hz,3H)。 1 HNMR (500MHz, DMSO) δ 12.25 (s, 1H), 8.30 (t, J = 5.3 Hz, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.40 (s, 1H), 7.14 (d,J=7.5Hz,2H),7.10–7.00(m,1H),6.90(s,1H),6.55(s,1H), 4.62(s,1H), 4.30(s,2H),3.62( s, 3H), 3.17 (d, J = 5.2 Hz, 2H), 2.05 (d, J = 24.7 Hz, 6H), 1.12 (s, 6H), 1.10 (d, J = 7.2 Hz, 3H).
步骤3：化合物2的合成Step 3: Synthesis of compound 2
采用实施例1步骤2的合成方法，将化合物1-1替换为化合物2-1，即得化合物2。Using the synthetic method of step 2 in Example 1, replace compound 1-1 with compound 2-1 to obtain compound 2.
LCMS:[M+1] +＝528.6。 LCMS: [M+1] + =528.6.
1HNMR(500MHz,DMSO)δ12.22(s,1H),8.33(s,1H),8.08(s,1H),7.67(s,1H),7.41(s,1H),7.13(d,J＝7.5Hz,2H),7.07(d,J＝7.1Hz,1H),6.90(s,1H),6.47(s,1H),4.81(s,1H),4.27(s,2H),3.61(s,3H),3.29–3.18(m,2H),2.04(s,6H),1.15–1.08(m,9H)。 1 HNMR (500MHz, DMSO) δ 12.22 (s, 1H), 8.33 (s, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.41 (s, 1H), 7.13 (d, J = 7.5Hz, 2H), 7.07 (d, J = 7.1Hz, 1H), 6.90 (s, 1H), 6.47 (s, 1H), 4.81 (s, 1H), 4.27 (s, 2H), 3.61 (s, 3H), 3.29–3.18 (m, 2H), 2.04 (s, 6H), 1.15–1.08 (m, 9H).
实施例3 4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物3)的合成Example 3 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazol-6-yl)-N-ethyl Synthesis of -6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (compound 3)
Figure PCTCN2021094838-appb-000014
Figure PCTCN2021094838-appb-000014
步骤1：化合物3-1的合成Step 1: Synthesis of compound 3-1
氮气保护下，在0℃将DAST(3.22g)缓慢滴加至化合物1-1(3.89g)的DCM(50mL)溶液中。反应液缓慢升温至10℃，搅拌2hrs。将反应液倒入冰水中，DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(PE/EA＝3/1)纯化，得3.11g所述标题化合物3-1。Under the protection of nitrogen, DAST (3.22 g) was slowly added dropwise to the solution of compound 1-1 (3.89 g) in DCM (50 mL) at 0°C. The reaction solution was slowly heated to 10°C and stirred for 2hrs. The reaction solution was poured into ice water, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE/EA=3/1) to obtain 3.11 g of the title compound 3- 1.
步骤2：化合物3的合成Step 2: Synthesis of compound 3
将化合物3-1(3.91g)，中间体M1(3.46g)，碳酸钾(4.14g)，Pd(dppf)Cl 2(0.73g)置于二氧六环/H 2O(60ml，V/V＝5/1)混合液中，氮气置换3次，反应液在85℃反应6hrs。冷 却至室温，反应液加水稀释，DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(DCM:MeOH＝100:4)纯化，得3.21g所述标题化合物3。 Compound 3-1 (3.91g), intermediate M1 (3.46g), potassium carbonate (4.14g), Pd(dppf)Cl 2 (0.73g) were placed in dioxane/H 2 O (60ml, V/ V=5/1) In the mixed solution, nitrogen was replaced 3 times, and the reaction solution was reacted at 85°C for 6 hrs. After cooling to room temperature, the reaction solution was diluted with water, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH=100:4) to obtain 3.21 g of the title compound 3. .
LCMS:[M+1] +＝530.6。 LCMS: [M+1] + =530.6.
1HNMR(500MHz,DMSO)δ12.34(s,1H),8.30(d,J＝3.3Hz,2H),7.99(s,1H),7.47(s,1H),7.08(d,J＝7.4Hz,2H),7.03(dd,J＝8.5,6.3Hz,1H),6.93(d,J＝2.3Hz,1H),4.66(s,1H),4.34(s,2H),3.62(s,3H),3.26(dd,J＝7.5,5.6Hz,2H),2.00(s,6H),1.12(d,J＝7.7Hz,9H)。 1 HNMR(500MHz,DMSO)δ12.34(s,1H), 8.30(d,J=3.3Hz,2H),7.99(s,1H),7.47(s,1H),7.08(d,J=7.4Hz ,2H),7.03(dd,J=8.5,6.3Hz,1H),6.93(d,J=2.3Hz,1H),4.66(s,1H),4.34(s,2H),3.62(s,3H) , 3.26 (dd, J = 7.5, 5.6 Hz, 2H), 2.00 (s, 6H), 1.12 (d, J = 7.7 Hz, 9H).
采用与实施例1-3基本类似的方法，应用相应的2,6-二甲基苯酚衍生物替换实施例中的
Figure PCTCN2021094838-appb-000015
(2,6-二甲基苯酚)制备以下表1中的实施例。所述相应的2,6-二甲基苯酚衍生物，例如
Figure PCTCN2021094838-appb-000016
等均可以通过市售渠道购买得到。其中，部分化合物的异构体通过制备HPLC获得，制备条件为：流动相B(乙腈)：流动相A(0.1％甲酸水溶液)＝15％-35％。 Using a method basically similar to that in Examples 1-3, the corresponding 2,6-dimethylphenol derivative was used to replace the
Figure PCTCN2021094838-appb-000015
(2,6-Dimethylphenol) The examples in Table 1 below were prepared. The corresponding 2,6-dimethylphenol derivatives, for example
Figure PCTCN2021094838-appb-000016
Etc. can be purchased through commercial channels. Among them, the isomers of some compounds were obtained by preparative HPLC, and the preparation conditions were: mobile phase B (acetonitrile): mobile phase A (0.1% formic acid aqueous solution) = 15%-35%.
表1Table 1
Figure PCTCN2021094838-appb-000017
Figure PCTCN2021094838-appb-000017
Figure PCTCN2021094838-appb-000018
Figure PCTCN2021094838-appb-000018
Figure PCTCN2021094838-appb-000019
Figure PCTCN2021094838-appb-000019
实施例18和19 4-(5-(2,6-二甲基苯氧基)-1-甲基-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物18)和4-(5-(2,6-二甲基苯氧基)-2-甲基-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物19)的合成Examples 18 and 19 4-(5-(2,6-dimethylphenoxy)-1-methyl-1H-indazol-6-yl)-N-ethyl-6-methyl-7- Oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 18) and 4-(5-(2,6-dimethylphenoxy)- 2-Methyl-2H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- Synthesis of 2-formamide (Compound 19)
Figure PCTCN2021094838-appb-000020
Figure PCTCN2021094838-appb-000020
步骤1：化合物18-1和19-1的合成Step 1: Synthesis of compounds 18-1 and 19-1
将中间体M2(0.80g)溶于THF(20ml)，降温至0℃，加入NaH(0.50g)，搅拌0.5h，加入碘甲烷(1.79g)，保持该温度继续搅拌10min，恢复至室温搅拌4.0hrs。反应液加水淬灭，EA萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到粗品，柱层析(PE:EA＝80:10)分离纯化，浓缩前峰层析液得到化合物18-1(0.20g)，浓缩后峰层析液得到化合物19-1(0.26g)。Intermediate M2 (0.80g) was dissolved in THF (20ml), the temperature was reduced to 0°C, NaH (0.50g) was added, stirred for 0.5h, methyl iodide (1.79g) was added, and the temperature was kept at this temperature and the stirring was continued for 10 minutes, then returned to room temperature and stirred 4.0hrs. The reaction solution was quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by column chromatography (PE:EA=80:10), and the former peak chromatographic solution was concentrated to obtain compound 18-1 (0.20g), the peak chromatography solution was concentrated to obtain compound 19-1 (0.26g).
步骤2：化合物18的合成Step 2: Synthesis of compound 18
将化合物18-1(0.14g)，中间体M1(0.15g)，Pd(dppf)Cl 2.DCM(0.034g)溶于二氧六环(2.5mL)中，加入碳酸钾(0.058g)，水(0.5mL)，氮气保护，90℃搅拌过夜。将反应液倒入50mL水中，EA萃取三次。有机相合并，饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品柱层析(DCM:MeOH＝100:10)纯化，得0.058g所述标题化合物18。 Compound 18-1 (0.14g), intermediate M1 (0.15g), Pd(dppf)Cl 2 .DCM (0.034g) were dissolved in dioxane (2.5mL), potassium carbonate (0.058g) was added, Water (0.5 mL), protected by nitrogen, stirred at 90°C overnight. The reaction solution was poured into 50 mL of water, and EA was extracted three times. The organic phases were combined, washed with saturated brine for 3 times, dried over anhydrous sodium sulfate, concentrated, and purified by crude column chromatography (DCM:MeOH=100:10) to obtain 0.058 g of the title compound 18.
LCMS:[M+1] +＝470.5。 LCMS: [M+1] + = 470.5.
1HNMR(400MHz,DMSO)δ8.31–8.29(m,1H),7.87(s,1H),7.74(s,1H),7.43(s,1H),7.15–7.13(m,2H),7.07(m,1H),6.90(s,1H),6.58(s,1H),4.04(s,3H),3.62(s,3H),3.29–3.23(m,3H),2.02(s,6H),1.07(s,3H)。 1 HNMR (400MHz, DMSO) δ 8.31-8.29 (m, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.43 (s, 1H), 7.15-7.13 (m, 2H), 7.07 ( m, 1H), 6.90 (s, 1H), 6.58 (s, 1H), 4.04 (s, 3H), 3.62 (s, 3H), 3.29-3.23 (m, 3H), 2.02 (s, 6H), 1.07 (s,3H).
步骤3：化合物19的合成Step 3: Synthesis of compound 19
采用实施例18步骤2的合成方法，将化合物18-1替换为化合物化合物19-1，即得化合物19。Using the synthetic method of step 2 in Example 18, compound 18-1 was replaced with compound 19-1 to obtain compound 19.
LCMS:[M+1] +＝470.5。 LCMS: [M+1] + = 470.5.
1HNMR(400MHz,DMSO)δ12.23(s,1H),8.34(m,1H),8.09(s,1H),7.65(s,1H),7.40(s,1H),7.14–7.13(m,2H),7.08–7.05(m,1H),6.90–6.89(m,1H),6.44(s,1H),4.11(s,3H),3.61(s,3H),3.30–3.22(m,2H),2.03(s,6H),1.12–1.10(m,3H)。 1 HNMR (400MHz, DMSO) δ 12.23 (s, 1H), 8.34 (m, 1H), 8.09 (s, 1H), 7.65 (s, 1H), 7.40 (s, 1H), 7.14-7.13 (m, 2H), 7.08--7.05(m,1H), 6.90--6.89(m,1H), 6.44(s,1H), 4.11(s,3H), 3.61(s,3H), 3.30--3.22(m,2H) ,2.03(s,6H),1.12–1.10(m,3H).
采用与实施例18基本类似的方法，应用相应的碘甲烷类似物替换实施例中的CH 3I(碘甲烷)制备以下表2中的实施例。所述相应的碘甲烷类似物，例如碘乙烷或
Figure PCTCN2021094838-appb-000021
等均可以通过市售渠道购买得到。其中，部分化合物的异构体通过制备HPLC获得，制备条件为：流动相B(乙腈)：流动相A(0.1％甲酸水溶液)＝15％-35％，或者为流动相B(乙腈)：流动相A(0.1％盐酸水溶液)＝15％-35％。 Using a method basically similar to that of Example 18, the corresponding iodomethane analogue was used to replace CH 3 I (methyl iodide) in the examples to prepare the examples in Table 2 below. The corresponding analog of methyl iodide, such as ethyl iodide or
Figure PCTCN2021094838-appb-000021
Etc. can be purchased through commercial channels. Among them, the isomers of some compounds were obtained by preparative HPLC, and the preparation conditions were: mobile phase B (acetonitrile): mobile phase A (0.1% formic acid aqueous solution) = 15%-35%, or mobile phase B (acetonitrile): mobile phase Phase A (0.1% aqueous hydrochloric acid) = 15%-35%.
表2Table 2
Figure PCTCN2021094838-appb-000022
Figure PCTCN2021094838-appb-000022
Figure PCTCN2021094838-appb-000023
Figure PCTCN2021094838-appb-000023
Figure PCTCN2021094838-appb-000024
Figure PCTCN2021094838-appb-000024
Figure PCTCN2021094838-appb-000025
Figure PCTCN2021094838-appb-000025
Figure PCTCN2021094838-appb-000026
Figure PCTCN2021094838-appb-000026
实施例44 4-(1-(2-氨基-2-氧乙基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物44)的合成Example 44 4-(1-(2-Amino-2-oxoethyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl- Synthesis of 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 44)
Figure PCTCN2021094838-appb-000027
Figure PCTCN2021094838-appb-000027
步骤1：化合物44-1的合成Step 1: Synthesis of compound 44-1
将碳酸钾(4.14g)和溴乙酸乙酯(2.51g)加入到中间体M2(3.16g)溶于DMF(30mL)的溶液中，反应液升温至80℃，搅拌2hrs。反应液倒入水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品柱层析(PE/EA＝3/1)纯化，得3.19g所述标题化合物44-1。Potassium carbonate (4.14g) and ethyl bromoacetate (2.51g) were added to the solution of intermediate M2 (3.16g) dissolved in DMF (30mL), the reaction solution was heated to 80°C and stirred for 2hrs. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude column chromatography (PE/EA=3/1) to obtain 3.19 g of the title compound 44 -1.
步骤2：化合物44-2的合成Step 2: Synthesis of compound 44-2
将水(5mL)和氢氧化锂(1.20g)加入到化合物44-1(4.03g)溶于甲醇(50mL)的溶液中，60℃反应2hrs。将反应液浓缩后，加入20mL水，用1N稀盐酸调节至pH＝5，过滤，收集滤饼并烘干，得2.11g所述标题化合物44-2。Water (5 mL) and lithium hydroxide (1.20 g) were added to a solution of compound 44-1 (4.03 g) dissolved in methanol (50 mL), and reacted at 60° C. for 2 hrs. After the reaction solution was concentrated, 20 mL of water was added, adjusted to pH=5 with 1N dilute hydrochloric acid, filtered, and the filter cake was collected and dried to obtain 2.11 g of the title compound 44-2.
步骤3：化合物44-3的合成Step 3: Synthesis of compound 44-3
向化合物44-2(3.75g)的DMF(30mL)溶液中加入氯化铵(1.08g)，HATU(4.56g)，DIEA(8.05g)，室温反应两小时。反应液倒入水中，EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得2.56g所述标题化合物44-3。Ammonium chloride (1.08 g), HATU (4.56 g), DIEA (8.05 g) was added to the DMF (30 mL) solution of compound 44-2 (3.75 g), and reacted at room temperature for two hours. The reaction solution was poured into water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 2.56 g of the title compound 44-3.
步骤4：化合物44的合成Step 4: Synthesis of compound 44
将化合物44-3(374mg)，中间体M1(345mg)，碳酸钾(414mg)，Pd(dppf)Cl 2(72mg)置于二氧六环/H 2O(10mL，V/V＝5/1)，置换氮气，85℃反应6hrs。反应液加水稀释，用DCM萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品柱层析(DCM:MeOH＝100:4)，得105mg所述标题化合物44。 Compound 44-3 (374mg), intermediate M1 (345mg), potassium carbonate (414mg), Pd(dppf)Cl 2 (72mg) were placed in dioxane/H 2 O (10 mL, V/V=5/ 1) Replace with nitrogen and react at 85°C for 6hrs. The reaction solution was diluted with water, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and crude column chromatography (DCM:MeOH=100:4) was used to obtain 105 mg of the title compound 44.
LCMS：[M+1] +＝513.6。 LCMS: [M+1] + = 513.6.
1HNMR：(500MHz,DMSO)δ12.26(s,1H),8.30(t,J＝5.2Hz,1H),7.90(s,1H),7.69(s,1H),7.57(s,1H),7.39(s,1H),7.24(s,1H),7.14(d,J＝7.5Hz,2H),7.08(d,J＝7.3Hz,1H), 6.88(s,1H),6.58(s,1H),5.05(s,2H),3.62(s,3H),2.03(s,6H),1.23(s,2H),1.10(t,J＝7.2Hz,3H)。1HNMR: (500MHz,DMSO)δ12.26(s,1H), 8.30(t,J=5.2Hz,1H),7.90(s,1H),7.69(s,1H),7.57(s,1H),7.39 (s,1H),7.24(s,1H),7.14(d,J=7.5Hz,2H),7.08(d,J=7.3Hz,1H), 6.88(s,1H),6.58(s,1H) , 5.05 (s, 2H), 3.62 (s, 3H), 2.03 (s, 6H), 1.23 (s, 2H), 1.10 (t, J=7.2 Hz, 3H).
实施例45 4-(5-(2,6-二甲基苯氧基)-1-((甲磺酰基)甲基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物45)的合成Example 45 4-(5-(2,6-Dimethylphenoxy)-1-((methylsulfonyl)methyl)-1H-indazol-6-yl)-N-ethyl-6- Synthesis of Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 45)
Figure PCTCN2021094838-appb-000028
Figure PCTCN2021094838-appb-000028
步骤1：化合物45-1的合成Step 1: Synthesis of compound 45-1
向中间体M2(3.16g)的ACN(30mL)溶液中，加入DIEA(8.50g)，氯甲基甲硫醚(2.51g)，反应液升温到80℃，搅拌2hrs。将反应液倒入水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品柱层析(PE/EA＝3/1)纯化，得3.02g所述标题化合物45-1。To the ACN (30 mL) solution of intermediate M2 (3.16 g), DIEA (8.50 g) and chloromethyl methyl sulfide (2.51 g) were added, and the reaction solution was heated to 80° C. and stirred for 2 hrs. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude column chromatography (PE/EA=3/1) to obtain 3.02 g of the title compound 45-1.
步骤2：化合物45-2的合成Step 2: Synthesis of compound 45-2
在0℃条件下，将间氯过氧苯甲酸(5.16g)加入到化合物45-1(3.77g)的二氯甲烷(50mL)溶液中，室温搅拌过夜。将反应液倒入水中，二氯甲烷萃取，有机相依次用饱和硫代硫酸钠水溶液和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品柱层析(PE/EA＝1/2)纯化，得2.22g所述标题化合物45-2。Under the condition of 0°C, m-chloroperoxybenzoic acid (5.16 g) was added to a solution of compound 45-1 (3.77 g) in dichloromethane (50 mL), and the mixture was stirred at room temperature overnight. Pour the reaction solution into water, extract with dichloromethane, and wash the organic phase with saturated aqueous sodium thiosulfate solution and saturated brine successively, dry with anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography (PE/EA=1/2) , To obtain 2.22 g of the title compound 45-2.
步骤3：化合物45的合成Step 3: Synthesis of compound 45
将化合物45-2(409mg)，中间体M1(345mg)，碳酸钾(414mg)，Pd(dppf)Cl 2(72mg)置于二氧六环/H 2O(10mL，V/V＝5/1)，置换氮气，85℃反应6hrs。反应液加水稀释，DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品柱层析(DCM:MeOH＝100:4)纯化，得80mg所述标题化合物45。 Compound 45-2 (409mg), intermediate M1 (345mg), potassium carbonate (414mg), Pd(dppf)Cl 2 (72mg) were placed in dioxane/H 2 O (10 mL, V/V=5/ 1) Replace with nitrogen and react at 85°C for 6hrs. The reaction solution was diluted with water, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude column chromatography (DCM:MeOH=100:4) to obtain 80 mg of the title compound 45.
LCMS：[M+1] +＝548.6。 LCMS: [M+1] + = 548.6.
1HNMR：(500MHz,DMSO)δ12.24(s,1H),8.29(s,2H),7.72(s,1H),7.44(s,1H),7.14(s,2H),7.10–7.00(m,1H),6.91(s,1H),6.53(s,1H),6.05(s,2H),3.61(s,3H),3.27-3.23(m,2H),3.14(s,3H),2.05(s,6H),1.10(t,J＝7.3Hz,3H)。 1 HNMR: (500MHz,DMSO)δ12.24(s,1H),8.29(s,2H),7.72(s,1H),7.44(s,1H),7.14(s,2H),7.10–7.00(m ,1H),6.91(s,1H),6.53(s,1H),6.05(s,2H),3.61(s,3H),3.27-3.23(m,2H),3.14(s,3H),2.05( s, 6H), 1.10 (t, J=7.3 Hz, 3H).
采用与以上实施例基本类似的方法，将氯甲基甲硫醚换成氯乙基甲硫醚，可以合成表 3中的化合物。Using a method basically similar to the above example, replacing chloromethyl methyl sulfide with chloroethyl methyl sulfide, the compounds in Table 3 can be synthesized.
表3table 3
Figure PCTCN2021094838-appb-000029
Figure PCTCN2021094838-appb-000029
实施例48 4-(1-环丙基-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物48)的合成Example 48 4-(1-Cyclopropyl-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxy Synthesis of Subo-6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 48)
Figure PCTCN2021094838-appb-000030
Figure PCTCN2021094838-appb-000030
步骤1：化合物48-1的合成Step 1: Synthesis of compound 48-1
向中间体M2(0.50g)的1,2-二氯乙烷(10mL)溶液中加入Na 2CO 3(0.84g)，1,2-二甲基乙二胺(0.28g)，环丙基硼酸(0.28g)，所得反应液室温搅拌24hrs。反应液中加入饱和氯化铵淬灭，EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到粗品，粗品经柱层析(PE:EA＝100:10)纯化，得0.39g所述标题化合物48-1。 To the solution of intermediate M2 (0.50g) in 1,2-dichloroethane (10mL) was added Na 2 CO 3 (0.84g), 1,2-dimethylethylenediamine (0.28g), cyclopropyl Boric acid (0.28g), the resulting reaction solution was stirred at room temperature for 24hrs. The reaction solution was quenched by adding saturated ammonium chloride, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA=100:10) to obtain 0.39 g The title compound 48-1.
步骤2：化合物48的合成Step 2: Synthesis of compound 48
氮气保护条件下，将碳酸钾(0.24g)和水0.5mL加入到化合物48-1(0.25g)，中间体M1，Pd(dppf)Cl 2.DCM(0.047g)和二氧六环(2.5mL)的混合溶液中，85℃搅拌过夜。 反应液冷却，倒入50mL水中，EA萃取三次。有机相合并，饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品柱层析(DCM:MeOH＝100:10)纯化，得0.012g所述标题化合物48。 Under nitrogen protection, potassium carbonate (0.24g) and 0.5 mL of water were added to compound 48-1 (0.25g), intermediate M1, Pd(dppf)Cl 2 .DCM (0.047g) and dioxane (2.5 mL) in the mixed solution, stirred at 85°C overnight. The reaction solution was cooled, poured into 50 mL of water, and extracted with EA three times. The organic phases were combined, washed with saturated brine three times, dried over anhydrous sodium sulfate, concentrated, and purified by crude column chromatography (DCM:MeOH=100:10) to obtain 0.012 g of the title compound 48.
LCMS：[M+1] +＝496.6。 LCMS: [M+1] + = 496.6.
1HNMR：(500MHz,DMSO-d6)δ12.28(s,1H),8.32–8.30(m,1H),7.85(s,1H),7.74(s,1H),7.45(s,1H),7.15–7.13(m,2H),7.09–7.06(m,1H),6.91–6.90(m,1H),6.58(s,1H),3.76–3.72(m,1H),3.63(s,3H),3.29–3.22(m,2H),2.02(s,6H),1.12–1.09(m,7H)。1HNMR: (500MHz,DMSO-d6)δ12.28(s,1H), 8.32–8.30(m,1H),7.85(s,1H),7.74(s,1H),7.45(s,1H),7.15– 7.13(m,2H), 7.09--7.06(m,1H), 6.91--6.90(m,1H), 6.58(s,1H), 3.76--3.72(m,1H), 3.63(s,3H), 3.29-- 3.22 (m, 2H), 2.02 (s, 6H), 1.12–1.09 (m, 7H).
实施例49 4-(1-((1-氨基环丙基)甲基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物49)的合成Example 49 4-(1-((1-aminocyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl Synthesis of -6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 49)
Figure PCTCN2021094838-appb-000031
Figure PCTCN2021094838-appb-000031
步骤1：化合物49-1的合成Step 1: Synthesis of compound 49-1
向中间体M2(3.16g)置于DMF(30mL)的溶液中加入碳酸铯(9.78g)和1-(溴甲基)环丙基氨基甲酸叔丁酯(2.51g)，升温至80℃，搅拌2hrs。将反应液倒入水中，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品柱层析(PE/EA＝3/1)纯化，得3.19g所述标题化合物49-1。To the solution of intermediate M2 (3.16g) in DMF (30mL) was added cesium carbonate (9.78g) and tert-butyl 1-(bromomethyl)cyclopropylcarbamate (2.51g), and the temperature was raised to 80°C, Stir for 2hrs. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude column chromatography (PE/EA=3/1) to obtain 3.19 g of the title compound 49 -1.
步骤2：化合物49-2的合成Step 2: Synthesis of compound 49-2
将化合物化合物49-1(4.86g)，中间体M1(3.46g)，碳酸钾(4.14g)，Pd(dppf)Cl 2(0.73g)置于二氧六环/H 2O(60mL，V/V＝5/1)，置换氮气，85℃反应6hrs。反应液加水稀释，DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，干燥，浓缩，粗品经柱层析(DCM:MeOH＝100:4)纯化，得3.51g所述标题化合物49-2。 Compound 49-1 (4.86g), intermediate M1 (3.46g), potassium carbonate (4.14g), Pd(dppf)Cl 2 (0.73g) were placed in dioxane/H 2 O (60 mL, V /V=5/1), replace nitrogen, react at 85°C for 6hrs. The reaction solution was diluted with water, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, dried, and concentrated. The crude product was purified by column chromatography (DCM:MeOH=100:4) to obtain 3.51 g of the title compound 49 -2.
步骤3：化合物49的合成Step 3: Synthesis of compound 49
将化合物49-2(500mg)置于盐酸/1,4二氧六环溶液(5mL，4mol/L)中搅拌1h。反应液倒入冰水中，用碳酸钠调节pH至8，然后乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析(DCM/MeOH＝100/5)纯化，得100mg所述标题化合物49。Compound 49-2 (500 mg) was placed in hydrochloric acid/1,4 dioxane solution (5 mL, 4 mol/L) and stirred for 1 h. The reaction solution was poured into ice water, adjusted to pH 8 with sodium carbonate, and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to column chromatography (DCM/MeOH=100/5). ) Purification to obtain 100 mg of the title compound 49.
LCMS：[M+1] +＝525.6。 LCMS: [M+1] + = 525.6.
1HNMR：(500MHz,DMSO-d6)δ12.28(s,1H),8.32(t,J＝5.4Hz,1H),7.91(s,1H),7.85(s,1H),7.43(s,1H),7.14(d,J＝7.5Hz,2H),7.09-7.06(m,1H),6.90(s,1H),6.57(s,1H),4.39(s,2H),3.62(s,3H),3.30–3.21(m,2H),2.03(s,6H),1.23(s,2H),1.10(t,J＝7.2Hz,3H),0.63(d,J＝2.1Hz,2H),0.47(d,J＝2.2Hz,2H)。 1 HNMR: (500MHz,DMSO-d6)δ12.28(s,1H), 8.32(t,J=5.4Hz,1H),7.91(s,1H),7.85(s,1H),7.43(s,1H) ), 7.14 (d, J = 7.5Hz, 2H), 7.09-7.06 (m, 1H), 6.90 (s, 1H), 6.57 (s, 1H), 4.39 (s, 2H), 3.62 (s, 3H) ,3.30–3.21(m,2H),2.03(s,6H),1.23(s,2H),1.10(t,J=7.2Hz,3H),0.63(d,J=2.1Hz,2H),0.47( d, J=2.2 Hz, 2H).
实施例50 4-(1-(2-氨基-2-甲基丙基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物50)的合成Example 50 4-(1-(2-Amino-2-methylpropyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl Synthesis of -6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 50)
Figure PCTCN2021094838-appb-000032
Figure PCTCN2021094838-appb-000032
向化合物1(527mg)置于乙酸(5mL)的溶液中加入氯乙腈(150mg)，然后在0℃条件下滴加浓硫酸(1g)，室温搅拌过夜。反应液倒入冰水中，用碳酸钠调节pH至8，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析(DCM/MeOH＝100/4)纯化，得50mg所述标题化合物50。To a solution of compound 1 (527 mg) in acetic acid (5 mL) was added chloroacetonitrile (150 mg), then concentrated sulfuric acid (1 g) was added dropwise at 0° C., and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water, adjusted to pH 8 with sodium carbonate, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to column chromatography (DCM/MeOH=100/4) After purification, 50 mg of the title compound 50 was obtained.
LCMS：[M+1] +＝527.3。 LCMS: [M+1] + =527.3.
1HNMR：(500MHz,DMSO-d6)δ12.33(s,1H),8.33(t,J＝5.4Hz,1H),8.03(s,1H),7.90(s,1H),7.43(s,1H),7.15(d,J＝7.5Hz,2H),7.09-7.06(m,1H),6.87(s,1H),6.62(s,1H),5.32(t,J＝4.9Hz,2H),4.49(s,2H),3.63(s,3H),3.29–3.21(m,2H),2.03(s,6H),1.23(d,J＝8.4Hz,6H),1.11(t,J＝7.2Hz,3H)。 1 HNMR: (500MHz,DMSO-d6)δ12.33(s,1H), 8.33(t,J=5.4Hz,1H), 8.03(s,1H),7.90(s,1H),7.43(s,1H) ), 7.15 (d, J = 7.5Hz, 2H), 7.09-7.06 (m, 1H), 6.87 (s, 1H), 6.62 (s, 1H), 5.32 (t, J = 4.9Hz, 2H), 4.49 (s,2H),3.63(s,3H),3.29–3.21(m,2H),2.03(s,6H),1.23(d,J=8.4Hz,6H),1.11(t,J=7.2Hz, 3H).
实施例51和52 4-(1-((1-(二甲基氨基)环丙基)甲基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物51)和4-(2-((1-(二甲基氨基)环丙基)甲基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物52)的合成Examples 51 and 52 4-(1-((1-(dimethylamino)cyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-1H-indazole-6- Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (compound 51) and 4-( 2-((1-(Dimethylamino)cyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)-N-ethyl- Synthesis of 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 52)
Figure PCTCN2021094838-appb-000033
Figure PCTCN2021094838-appb-000033
步骤1：化合物51-1(化合物51A-1与化合物52B-1的混合物)的合成Step 1: Synthesis of compound 51-1 (a mixture of compound 51A-1 and compound 52B-1)
向中间体M2(3.16g)的DMF(30mL)溶液中加入碳酸铯(9.78g)和1-(溴甲基)环丙基氨基甲酸叔丁酯(2.51g)，升温至80℃，搅拌2hrs。反应液倒入水中，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析(PE/EA＝1/1)纯化，得3.19g所述标题化合物51-1。Cesium carbonate (9.78g) and tert-butyl 1-(bromomethyl)cyclopropylcarbamate (2.51g) were added to the DMF (30mL) solution of intermediate M2 (3.16g), heated to 80°C, and stirred for 2hrs . The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE/EA=1/1) to obtain 3.19 g of the title compound 51 -1.
步骤2：化合物51-2(化合物51A-2与化合物52B-2的混合物)的合成Step 2: Synthesis of compound 51-2 (a mixture of compound 51A-2 and compound 52B-2)
将化合物51-1(1g)置于盐酸/1,4二氧六环溶液(10mL，4mol/L)中搅拌1h，倒入冰水，碳酸钠调节pH至8，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析(DCM/MeOH＝100/5)纯化，得300mg所述标题化合物51-2。Put compound 51-1 (1g) in hydrochloric acid/1,4 dioxane solution (10mL, 4mol/L) and stir for 1h, pour into ice water, adjust pH to 8 with sodium carbonate, extract with ethyl acetate, and saturated salt It was washed with water, dried with anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (DCM/MeOH=100/5) to obtain 300 mg of the title compound 51-2.
步骤3：化合物51-3(化合物51A-3与化合物52B-3的混合物)的合成Step 3: Synthesis of compound 51-3 (a mixture of compound 51A-3 and compound 52B-3)
将化合物51-2(386mg)置于DCM(5mL)中，加入甲醛水溶液(1g，37％)，2滴醋酸，搅拌10min，然后加入氰基硼氢化钠(600mg)搅拌1h。将反应液倒入冰水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析(DCM/MeOH＝100/5)纯化，得300mg所述标题化合物51-3。Compound 51-2 (386 mg) was placed in DCM (5 mL), aqueous formaldehyde solution (1 g, 37%), 2 drops of acetic acid, stirred for 10 min, and then sodium cyanoborohydride (600 mg) was added and stirred for 1 h. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (DCM/MeOH=100/5) to obtain 300 mg of the title compound 51-3.
步骤4：化合物51和化合物52的合成Step 4: Synthesis of compound 51 and compound 52
将化合物51-3(414mg)，中间体M1(345mg)，碳酸钾(414mg)，Pd(dppf)Cl 2(72mg)置于二氧六环/H 2O(10mL，V/V＝5/1)，置换氮气，85℃反应6hrs。反应液加水稀释，DCM萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析(DCM:MeOH＝100:6)纯化，得108mg混合物。化合物51和化合物52通过高效液相色谱法分离，流动相B(乙 腈)：流动相A(0.1％甲酸水溶液)＝40％-90％，浓缩前峰层析液得到化合物51(29mg)，浓缩后峰层析液得到化合物52(17mg)。 Compound 51-3 (414mg), intermediate M1 (345mg), potassium carbonate (414mg), Pd(dppf)Cl 2 (72mg) were placed in dioxane/H 2 O (10 mL, V/V=5/ 1) Replace with nitrogen and react at 85°C for 6hrs. The reaction solution was diluted with water, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM:MeOH=100:6) to obtain 108 mg of a mixture. Compound 51 and compound 52 were separated by high performance liquid chromatography, mobile phase B (acetonitrile): mobile phase A (0.1% formic acid aqueous solution) = 40%-90%, the pre-peak chromatographic solution was concentrated to obtain compound 51 (29 mg), which was concentrated The latter peak chromatography solution yielded compound 52 (17 mg).
LCMS：[M+1] +＝553.3； LCMS: [M+1] + = 553.3;
1HNMR：(500MHz,DMSO-d6)δ12.27(s,1H),8.33(t,J＝5.4Hz,1H),7.90(s,1H),7.77(s,1H),7.43(s,1H),7.13(d,J＝7.4Hz,2H),7.09-7.06(m,1H),6.90(s,1H),6.58(s,1H),4.52(s,2H),3.63(s,3H),3.29–3.21(m,2H),2.15(s,6H),2.02(s,6H),1.11(t,J＝7.2Hz,3H),0.68–0.54(m,4H)。(化合物51) 1 HNMR: (500MHz,DMSO-d6)δ12.27(s,1H), 8.33(t,J=5.4Hz,1H),7.90(s,1H),7.77(s,1H),7.43(s,1H) ), 7.13 (d, J = 7.4 Hz, 2H), 7.09-7.06 (m, 1H), 6.90 (s, 1H), 6.58 (s, 1H), 4.52 (s, 2H), 3.63 (s, 3H) , 3.29-3.21 (m, 2H), 2.15 (s, 6H), 2.02 (s, 6H), 1.11 (t, J = 7.2 Hz, 3H), 0.68-0.54 (m, 4H). (Compound 51)
1HNMR(500MHz,DMSO-d6)δ12.27(s,1H),8.33(t,J＝5.4Hz,1H),7.90(s,1H),7.77(s,1H),7.43(s,1H),7.13(d,J＝7.4Hz,2H),7.09-7.06(m,1H),6.90(s,1H),6.58(s,1H),4.52(s,2H),3.63(s,3H),3.29–3.21(m,2H),2.15(s,6H),2.02(s,6H),1.11(t,J＝7.2Hz,3H),0.68–0.54(m,4H)。(化合物52) 1 HNMR(500MHz,DMSO-d6)δ12.27(s,1H), 8.33(t,J=5.4Hz,1H),7.90(s,1H),7.77(s,1H),7.43(s,1H) ,7.13(d,J=7.4Hz,2H),7.09-7.06(m,1H),6.90(s,1H),6.58(s,1H),4.52(s,2H),3.63(s,3H), 3.29–3.21(m, 2H), 2.15(s, 6H), 2.02(s, 6H), 1.11(t, J=7.2Hz, 3H), 0.68–0.54(m, 4H). (Compound 52)
实施例53 4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2-甲氧基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物53)的合成Example 53 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2-methoxy-2-methylpropyl)-1H-indazole-6 -Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 53)
Figure PCTCN2021094838-appb-000034
Figure PCTCN2021094838-appb-000034
步骤1：化合物53-1的合成Step 1: Synthesis of compound 53-1
参考实施例1步骤1中化合物1-1的制备方法，将中间体M2替换为中间体M3，即得化合物53-1。Referring to the preparation method of compound 1-1 in step 1 of Example 1, replace intermediate M2 with intermediate M3 to obtain compound 53-1.
步骤2：化合物53-2的合成Step 2: Synthesis of compound 53-2
向化合物53-1(390mg)的DMF(5mL)溶液中加入碳酸钾(276mg)和碘甲烷(160mg)，室温反应2hrs。将反应液倒入水中，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析(PE/EA＝1/5)纯化，得330mg所述标题化合物53-2。Potassium carbonate (276 mg) and methyl iodide (160 mg) were added to the DMF (5 mL) solution of compound 53-1 (390 mg), and the reaction was carried out at room temperature for 2 hrs. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE/EA=1/5) to obtain 330 mg of the title compound 53 -2.
步骤3：化合物53的合成Step 3: Synthesis of compound 53
将化合物53-2(404mg)，中间体M1(345mg)，碳酸钾(414mg)，Pd(dppf)Cl 2(72mg)置于二氧六环/H 2O(10mL，V/V＝5/1)中，置换氮气，85℃反应6hrs。反应液加水稀释，DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析 (DCM:MeOH＝100:3)纯化，得95mg所述标题化合物53。 Compound 53-2 (404mg), intermediate M1 (345mg), potassium carbonate (414mg), Pd(dppf)Cl 2 (72mg) were placed in dioxane/H 2 O (10 mL, V/V=5/ In 1), replace with nitrogen and react at 85°C for 6hrs. The reaction solution was diluted with water, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (DCM:MeOH=100:3) to obtain 95 mg of the title compound 53.
LCMS：[M+1] +＝543.6； LCMS: [M+1] + = 543.6;
1HNMR：(500MHz,DMSO-d6)δ12.34(d,J＝2.3Hz,1H),8.34(t,J＝5.4Hz,1H),8.23(d,J＝4.9Hz,1H),7.91(d,J＝0.9Hz,1H),7.78(s,1H),7.43(s,1H),7.22(d,J＝5.0Hz,1H),6.88(d,J＝2.2Hz,1H),6.61(s,1H),4.40(s,2H),3.62(s,3H),3.29-3.23(m,2H),3.16(s,3H),2.21(s,3H),2.07(s,3H),1.14(s,6H),1.14–1.05(m,3H)。 1 HNMR: (500MHz, DMSO-d6) δ12.34 (d, J = 2.3 Hz, 1H), 8.34 (t, J = 5.4 Hz, 1H), 8.23 (d, J = 4.9 Hz, 1H), 7.91 ( d, J = 0.9Hz, 1H), 7.78 (s, 1H), 7.43 (s, 1H), 7.22 (d, J = 5.0 Hz, 1H), 6.88 (d, J = 2.2 Hz, 1H), 6.61 ( s,1H),4.40(s,2H),3.62(s,3H),3.29-3.23(m,2H),3.16(s,3H),2.21(s,3H),2.07(s,3H),1.14 (s, 6H), 1.14–1.05 (m, 3H).
实施例54 4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2-乙基-2-羟基丁基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物54)的合成Example 54 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2-ethyl-2-hydroxybutyl)-1H-indazol-6-yl )-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 54)
Figure PCTCN2021094838-appb-000035
Figure PCTCN2021094838-appb-000035
步骤1：化合物54-1的合成Step 1: Synthesis of compound 54-1
向中间体M3(3.16g)溶于DMF(30mL)的溶液中加入碳酸铯(9.78g)和溴丁酮(2.00g)，室温搅拌2hrs。将反应液倒入水中，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析(PE/EA＝1/2)纯化，得3.11g所述标题化合物54-1。Cesium carbonate (9.78 g) and bromobutyl ketone (2.00 g) were added to the solution of intermediate M3 (3.16 g) dissolved in DMF (30 mL), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE/EA = 1/2) to obtain 3.11 g of the title compound 54-1.
步骤2：化合物54-2的合成Step 2: Synthesis of compound 54-2
将化合物54-1(387mg)置于THF(5mL)，氮气置换，0℃滴加乙基溴化镁(5mL)的四氢呋喃溶液(1mol/L)，反应2hrs。将反应液倒入冰水中，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析(PE/EA＝1/2)纯化，得209mg所述标题化合物54-2。Compound 54-1 (387 mg) was placed in THF (5 mL), replaced with nitrogen, and ethyl magnesium bromide (5 mL) in tetrahydrofuran (1 mol/L) was added dropwise at 0° C., and the reaction was carried out for 2 hrs. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE/EA = 1/2) to obtain 209 mg of the title compound 54-2.
步骤3：化合物54的合成Step 3: Synthesis of compound 54
将化合物54-2(209mg)，中间体M1(173mg)，碳酸钾(207mg)，Pd(dppf)Cl 2(36mg)置于二氧六环/H 2O(10mL，V/V＝5/1)，置换氮气，85℃反应6hrs。反应液中加水稀释，DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经反相制备，其条件为：流动相B(乙腈)：流动相A(0.1％甲酸水溶液)＝15％-35％，得52mg所述标题化合物54。 Compound 54-2 (209mg), intermediate M1 (173mg), potassium carbonate (207mg), Pd(dppf)Cl 2 (36mg) were placed in dioxane/H 2 O (10 mL, V/V=5/ 1) Replace with nitrogen and react at 85°C for 6hrs. The reaction solution was diluted with water, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and prepared by reverse phase. The conditions were: mobile phase B (acetonitrile): mobile phase A (0.1% formic acid aqueous solution) = 15%-35%, 52 mg of the title compound 54 is obtained.
LCMS：[M+1] +＝557.3。 LCMS: [M+1] + = 557.3.
1HNMR：(500MHz,DMSO-d6)δ12.28(s,1H),8.30(t,J＝5.4Hz,1H),8.24–8.17(m, 2H),7.89(s,1H),7.85(s,1H),7.41(s,1H),7.21(d,J＝4.9Hz,1H),6.90(s,1H),6.59(s,1H),4.30(s,2H),3.62(s,3H),3.29–3.21(m,2H),2.21(s,3H),2.07(s,3H),1.42–1.30(m,4H),1.11(t,J＝7.2Hz,3H),0.87(t,J＝7.4Hz,6H)。1HNMR: (500MHz,DMSO-d6)δ12.28(s,1H), 8.30(t,J=5.4Hz,1H), 8.24–8.17(m, 2H), 7.89(s,1H), 7.85(s, 1H), 7.41 (s, 1H), 7.21 (d, J = 4.9 Hz, 1H), 6.90 (s, 1H), 6.59 (s, 1H), 4.30 (s, 2H), 3.62 (s, 3H), 3.29–3.21(m,2H),2.21(s,3H),2.07(s,3H),1.42–1.30(m,4H),1.11(t,J=7.2Hz,3H),0.87(t,J= 7.4Hz, 6H).
实施例55和56 4-(5-(2,6-二甲基苯氧基)-1-((1-氟环丙基)甲基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物55)和4-(5-(2,6-二甲基苯氧基)-2-((1-氟环丙基)甲基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物56)的合成Examples 55 and 56 4-(5-(2,6-dimethylphenoxy)-1-((1-fluorocyclopropyl)methyl)-1H-indazol-6-yl)-N- Ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (compound 55) and 4-(5-(2, 6-Dimethylphenoxy)-2-((1-fluorocyclopropyl)methyl)-2H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo- Synthesis of 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 56)
Figure PCTCN2021094838-appb-000036
Figure PCTCN2021094838-appb-000036
步骤1：化合物55-1的合成Step 1: Synthesis of compound 55-1
在0℃条件下，向1-氟环丙烷羧酸(5.2g)置于THF(50mL)的溶液中缓慢加入氢化铝锂(5.48g)，并搅拌2hrs。向反应液中滴加冰水淬灭，EA萃取，有机相合并，无水硫酸钠干燥，浓缩，得2g所述标题化合物55-1。At 0°C, to a solution of 1-fluorocyclopropanecarboxylic acid (5.2 g) in THF (50 mL) was slowly added lithium aluminum hydride (5.48 g), and stirred for 2 hrs. The reaction solution was quenched with ice water dropwise, extracted with EA, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 2 g of the title compound 55-1.
步骤2：化合物55-2的合成Step 2: Synthesis of compound 55-2
将化合物55-1(1.8g)溶于二氯甲烷(20mL)，加入三乙胺(3g)，氮气置换，0℃滴加甲基磺酰氯(2.5g)，搅拌2hrs。将反应液倒入冰水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得1.5g所述标题化合物55-2。Compound 55-1 (1.8g) was dissolved in dichloromethane (20mL), added triethylamine (3g), replaced with nitrogen, methylsulfonyl chloride (2.5g) was added dropwise at 0°C, and stirred for 2hrs. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 1.5 g of the title compound 55-2.
步骤3：化合物55-3(化合物55A-3和化合物56B-3的混合物)的合成Step 3: Synthesis of compound 55-3 (a mixture of compound 55A-3 and compound 56B-3)
向中间体M2(3.16g)置于DMF(30mL)的溶液中加入碳酸钾(9.78g)和化合物55-2(1.68g)，升温至80℃，搅拌2hrs。将反应液倒入水中，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析(PE/EA＝3/1)纯化，得3.05g所述标题化合物55-3。Potassium carbonate (9.78 g) and compound 55-2 (1.68 g) were added to the solution of intermediate M2 (3.16 g) in DMF (30 mL), the temperature was raised to 80° C., and the mixture was stirred for 2 hrs. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE/EA=3/1) to obtain 3.05 g of the title compound 55-3.
步骤4：化合物55和化合物56的合成Step 4: Synthesis of compound 55 and compound 56
将化合物55-3(389mg)，中间体M1(345mg)，碳酸钾(414mg)，Pd(dppf)Cl 2(72mg)置于二氧六环/H 2O(10mL，V/V＝5/1)，置换氮气，85℃反应6hrs。反应液加水稀释，DCM 萃取，有机相饱和食盐水洗涤，干燥，浓缩，粗品经柱层析(DCM:MeOH＝100:3)纯化，得混合物。化合物55和化合物56通过高效液相色谱法分离，制备条件为：流动相B(乙腈)：流动相A(0.1％甲酸水溶液)＝20％-50％，浓缩前峰层析液得到化合物55，浓缩后峰层析液得到化合物56。 Compound 55-3 (389mg), intermediate M1 (345mg), potassium carbonate (414mg), Pd(dppf)Cl 2 (72mg) were placed in dioxane/H 2 O (10 mL, V/V=5/ 1) Replace with nitrogen and react at 85°C for 6hrs. The reaction solution was diluted with water, extracted with DCM, the organic phase was washed with saturated brine, dried, and concentrated. The crude product was purified by column chromatography (DCM:MeOH=100:3) to obtain a mixture. Compound 55 and compound 56 were separated by high performance liquid chromatography, and the preparation conditions were: mobile phase B (acetonitrile): mobile phase A (0.1% formic acid in water) = 20%-50%. Concentrate the pre-peak chromatographic solution to obtain compound 55. After concentration, the peak chromatography solution yielded compound 56.
LCMS:[M+1] +＝528.2。 LCMS: [M+1] + =528.2.
1HNMR(500MHz,DMSO-d6)δ12.30(s,1H),8.32(t,J＝5.4Hz,1H),7.89(d,J＝0.8Hz,1H),7.81(s,1H),7.43(s,1H),7.14(d,J＝7.5Hz,2H),7.09-7.06(m,1H),6.90(d,J＝1.6Hz,1H),6.57(s,1H),4.29(d,J＝7.0Hz,2H),3.62(s,3H),3.28-3.23(m,2H),2.03(s,6H),1.10(t,J＝7.2Hz,3H),0.55-0.46(m,2H),0.44-0.38(m,2H)。(化合物55) 1 HNMR (500MHz, DMSO-d6) δ 12.30 (s, 1H), 8.32 (t, J = 5.4 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.81 (s, 1H), 7.43 (s, 1H), 7.14 (d, J = 7.5 Hz, 2H), 7.09-7.06 (m, 1H), 6.90 (d, J = 1.6 Hz, 1H), 6.57 (s, 1H), 4.29 (d, J = 7.0Hz, 2H), 3.62 (s, 3H), 3.28-3.23 (m, 2H), 2.03 (s, 6H), 1.10 (t, J = 7.2Hz, 3H), 0.55-0.46 (m, 2H) ), 0.44-0.38 (m, 2H). (Compound 55)
1HNMR(500MHz,DMSO-d6)δ12.30(s,1H),8.32(t,J＝5.4Hz,1H),7.89(d,J＝0.8Hz,1H),7.81(s,1H),7.43(s,1H),7.14(d,J＝7.5Hz,2H),7.09-7.06(m,1H),6.90(d,J＝1.6Hz,1H),6.57(s,1H),4.29(d,J＝7.0Hz,2H),3.62(s,3H),3.28-3.23(m,2H),2.03(s,6H),1.10(t,J＝7.2Hz,3H),0.55-0.46(m,2H),0.44-0.38(m,2H)。(化合物56) 1 HNMR (500MHz, DMSO-d6) δ 12.30 (s, 1H), 8.32 (t, J = 5.4 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.81 (s, 1H), 7.43 (s, 1H), 7.14 (d, J = 7.5 Hz, 2H), 7.09-7.06 (m, 1H), 6.90 (d, J = 1.6 Hz, 1H), 6.57 (s, 1H), 4.29 (d, J = 7.0Hz, 2H), 3.62 (s, 3H), 3.28-3.23 (m, 2H), 2.03 (s, 6H), 1.10 (t, J = 7.2Hz, 3H), 0.55-0.46 (m, 2H) ), 0.44-0.38 (m, 2H). (Compound 56)
采用与实施例55基本类似的方法，应用相应的1-氟环丙基甲醇类似物替换实施例中的
Figure PCTCN2021094838-appb-000037
(1-氟环丙基甲醇)制备表4中以下实施例。所述相应的1-氟环丙基甲醇类似物，例如
Figure PCTCN2021094838-appb-000038
等均可以通过市售渠道购买得到。 Using a method basically similar to that in Example 55, the corresponding 1-fluorocyclopropylmethanol analogue was used to replace the
Figure PCTCN2021094838-appb-000037
(1-Fluorocyclopropylmethanol) The following examples in Table 4 were prepared. The corresponding 1-fluorocyclopropylmethanol analogues, for example
Figure PCTCN2021094838-appb-000038
Etc. can be purchased through commercial channels.
表4Table 4
Figure PCTCN2021094838-appb-000039
Figure PCTCN2021094838-appb-000039
Figure PCTCN2021094838-appb-000040
Figure PCTCN2021094838-appb-000040
实施例60 4-(3-环丙基-5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物60)的合成Example 60 4-(3-Cyclopropyl-5-(2,6-dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl )-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 60)
Figure PCTCN2021094838-appb-000041
Figure PCTCN2021094838-appb-000041
步骤1：化合物60-1的合成Step 1: Synthesis of compound 60-1
向中间体M2(3.16g)置于DMF(30mL)的溶液中加入氢氧化钾(1.6g)和碘单质(5.08g)，搅拌2hrs。将反应液倒入水中，乙酸乙酯萃取，有机相依次用饱和硫代硫酸钠水溶液和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得3.89g所述标题化合物60-1。Potassium hydroxide (1.6g) and iodine elemental substance (5.08g) were added to the solution of intermediate M2 (3.16g) in DMF (30mL) and stirred for 2hrs. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium thiosulfate solution and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated to obtain 3.89 g of the title compound 60-1.
步骤2：化合物60-2的合成Step 2: Synthesis of compound 60-2
向化合物60-1(4.43g)置于DMF(30mL)的溶液中加入碳酸钾(4.14g)，甲基环氧丙烷(1.44g)，90℃反应6hrs。反应液中加水稀释，EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品柱层析(PE/EA＝3/1)纯化，得3.56g所述标题化合物60-2。Potassium carbonate (4.14 g) and methyl propylene oxide (1.44 g) were added to a solution of compound 60-1 (4.43 g) in DMF (30 mL), and reacted at 90° C. for 6 hrs. The reaction solution was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude column chromatography (PE/EA=3/1) to obtain 3.56 g of the title compound 60-2 .
步骤3：化合物60-3的合成Step 3: Synthesis of compound 60-3
将化合物60-2(5.16g)，环丙基硼酸(4.12g)，磷酸钾(6.36g)，Pd(dppf)Cl 2(0.73g)置于二氧六环/H 2O(60mL,V/V＝5/1)，置换氮气，85℃反应6hrs。反应液加水稀释，EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品柱层析(PE/EA＝3/1)纯化，得3.02g所述标题化合物60-3。 Compound 60-2 (5.16g), cyclopropylboronic acid (4.12g), potassium phosphate (6.36g), Pd(dppf)Cl 2 (0.73g) were placed in dioxane/H 2 O (60mL, V /V=5/1), replace nitrogen, react at 85°C for 6hrs. The reaction solution was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and purified by crude column chromatography (PE/EA=3/1) to obtain 3.02 g of the title compound 60-3.
步骤4：化合物60的合成Step 4: Synthesis of compound 60
将化合物60-3(429mg)，中间体M1(345mg)，碳酸钾(414mg)，Pd(dppf)Cl 2(72mg)置于二氧六环/H 2O(10mL，V/V＝5/1)，置换氮气，85℃反应6hrs。反应液中加水稀释，DCM萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品柱层析(DCM:MeOH＝100:4)纯化，得100mg所述标题化合物60。 Compound 60-3 (429mg), intermediate M1 (345mg), potassium carbonate (414mg), Pd(dppf)Cl 2 (72mg) were placed in dioxane/H 2 O (10 mL, V/V=5/ 1) Replace with nitrogen and react at 85°C for 6hrs. The reaction solution was diluted with water, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude column chromatography (DCM:MeOH=100:4) to obtain 100 mg of the title compound 60.
LCMS:[M+1] +＝568.7。 LCMS: [M+1] + = 568.7.
1H NMR(500MHz,DMSO)δ12.24(s,1H),8.29(s,1H),7.71(s,1H),7.38(s,1H),7.15(d,J＝7.5Hz,2H),7.08(d,J＝7.0Hz,1H),6.89(s,1H),6.50(s,1H),4.55(s,1H),4.18(s,2H),3.62(s,3H),3.28–3.22(m,2H),2.04(s,6H),1.99-1.96(m,1H),1.14–1.03(m,9H),0.86(d,J＝6.7Hz,2H),0.76(d,J＝3.2Hz,2H)。 1 H NMR (500MHz, DMSO) δ 12.24 (s, 1H), 8.29 (s, 1H), 7.71 (s, 1H), 7.38 (s, 1H), 7.15 (d, J = 7.5 Hz, 2H), 7.08(d,J=7.0Hz,1H), 6.89(s,1H), 6.50(s,1H), 4.55(s,1H), 4.18(s,2H), 3.62(s,3H), 3.28–3.22 (m,2H),2.04(s,6H),1.99-1.96(m,1H),1.14–1.03(m,9H),0.86(d,J=6.7Hz,2H),0.76(d,J=3.2 Hz, 2H).
采用与实施例基本类似的方法，应用相应的环丙基硼酸类似物替换实施例中的
Figure PCTCN2021094838-appb-000042
(环丙基硼酸)制备以下实施例。所述相应的碘甲烷类似物，例如甲基硼酸、
Figure PCTCN2021094838-appb-000043
Figure PCTCN2021094838-appb-000044
等均可以通过市售渠道购买得到。部分化合物的获得是通过制备HPLC纯化获得，其条件为：流动相B(乙腈)：流动相A(0.1％甲酸水溶液)＝5％-65％，或者为流动相B(乙腈)：流动相A(0.1％盐酸水溶液)＝15％-35％。 Using the method basically similar to the example, the corresponding cyclopropyl boronic acid analogue was used to replace the
Figure PCTCN2021094838-appb-000042
(Cyclopropylboronic acid) The following examples were prepared. The corresponding analogs of methyl iodide, such as methylboronic acid,
Figure PCTCN2021094838-appb-000043
Figure PCTCN2021094838-appb-000044
Etc. can be purchased through commercial channels. Part of the compounds are obtained by preparative HPLC purification, and the conditions are: mobile phase B (acetonitrile): mobile phase A (0.1% formic acid in water) = 5%-65%, or mobile phase B (acetonitrile): mobile phase A (0.1% aqueous hydrochloric acid) = 15%-35%.
表5table 5
Figure PCTCN2021094838-appb-000045
Figure PCTCN2021094838-appb-000045
Figure PCTCN2021094838-appb-000046
Figure PCTCN2021094838-appb-000046
实施例69 4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(3-吗啉代丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物69)的合成Example 69 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(3-morpholinopropyl)-1H- Indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (compound 69 )Synthesis
Figure PCTCN2021094838-appb-000047
Figure PCTCN2021094838-appb-000047
步骤1：化合物69-1的合成Step 1: Synthesis of compound 69-1
将化合物60-2(500mg)，4-丙炔-1-吗啉(145.78mg)，CuI(36.97mg)，Et 3N(294.62mg)，Pd(PPh 3) 2Cl 2(68.12mg)依次加入到THF(10mL)中，N 2保护，在80℃下加热12hrs。反应液冷却，并倒入水中，EA萃取3次，合并有机相，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品经柱层析(正己烷:EA＝1:1)纯化，得300mg所述标题化合物69-1。 Compound 60-2 (500 mg), 4-propyne-1-morpholine (145.78 mg), CuI (36.97 mg), Et 3 N (294.62 mg), Pd(PPh 3 ) 2 Cl 2 (68.12 mg) in turn Add to THF (10 mL), N 2 protection, and heat at 80° C. for 12 hrs. The reaction solution was cooled and poured into water, extracted 3 times with EA, combined the organic phases, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to column chromatography (n-hexane:EA=1:1) After purification, 300 mg of the title compound 69-1 was obtained.
步骤2：化合物69-2的合成Step 2: Synthesis of compound 69-2
将化合物69-1(300mg)，中间体M1(142.89mg)，K 2CO 3(104.01mg)，Pd(dppf)Cl 2(27.53mg)依次加入到二氧六环(5mL)和H 2O(5mL)的混合溶液中，N 2保护，在80℃下加热12hrs。将反应液倒入水中，DCM萃取3次，合并有机相，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品柱层析(DCM:MeOH＝10:1)纯化，得100mg所述标题化合物69-2。 Compound 69-1 (300mg), intermediate M1 (142.89mg), K 2 CO 3 (104.01mg), Pd(dppf)Cl 2 (27.53mg) were sequentially added to dioxane (5mL) and H 2 O (5 mL) of the mixed solution, protected by N 2 and heated at 80°C for 12 hrs. The reaction solution was poured into water, extracted with DCM 3 times, the organic phases were combined, the organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH=10:1) to obtain 100 mg The title compound 69-2.
步骤3：化合物69的合成Step 3: Synthesis of compound 69
将化合物69-2(100mg)和PtO 2(30mg)加入到MeOH(10mL)中，H 2氛围下，室温搅拌3hrs。将反应液抽滤，滤饼用甲醇洗涤，浓缩滤液得到粗品，粗品经制备薄层色谱(DCM:MeOH＝10:1)纯化，得30mg所述标题化合物69。 Compound 69-2 (100 mg) and PtO 2 (30 mg) were added to MeOH (10 mL), and stirred at room temperature for 3 hrs under an H 2 atmosphere. The reaction solution was suction filtered, the filter cake was washed with methanol, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (DCM:MeOH=10:1) to obtain 30 mg of the title compound 69.
LCMS:[M+1] +＝655.3。 LCMS: [M+1] + = 655.3.
1HNMR(500MHz,DMSO-d6)δ12.25(s,1H),8.29(s,1H),7.74(s,1H),7.38(s,1H),7.14(d,J＝7.5Hz,2H),7.07(t,J＝7.5Hz,1H),6.89(s,1H),6.43(s,1H),4.59(s,1H),4.23(s,2H),3.62(s,3H),3.49(s,3H),3.26-3.25(m,2H),3.15(s,1H),3.00(s,1H),2.72(s,3H),2.20(s,4H),2.02(s,6H),1.23(s,2H),1.14–1.07(m,9H)。 1 HNMR(500MHz,DMSO-d6)δ12.25(s,1H),8.29(s,1H),7.74(s,1H),7.38(s,1H),7.14(d,J=7.5Hz,2H) ,7.07(t,J=7.5Hz,1H),6.89(s,1H),6.43(s,1H),4.59(s,1H),4.23(s,2H),3.62(s,3H),3.49( s, 3H), 3.26-3.25 (m, 2H), 3.15 (s, 1H), 3.00 (s, 1H), 2.72 (s, 3H), 2.20 (s, 4H), 2.02 (s, 6H), 1.23 (s, 2H), 1.14–1.07 (m, 9H).
实施例70 4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(四氢2H-吡喃-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物70)的合成Example 70 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(tetrahydro 2H-pyran-4-yl) -1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 70) Synthesis
Figure PCTCN2021094838-appb-000048
Figure PCTCN2021094838-appb-000048
H 2氛围下，向化合物67(0.20g)置于二氧六环(25mL)的溶液中加入Pd/C，室温搅拌2.0hrs。硅藻土助滤，滤饼用甲醇和二氯洗涤，浓缩滤液得粗品，粗品经柱层析(DCM:MeOH＝80:10)纯化，得0.013g所述标题化合物70。 Under an H 2 atmosphere, Pd/C was added to a solution of compound 67 (0.20 g) in dioxane (25 mL), and the mixture was stirred at room temperature for 2.0 hrs. The filter cake was washed with methanol and dichloromethane, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (DCM:MeOH=80:10) to obtain 0.013 g of the title compound 70.
LCMS:[M+1] +＝612.3。 LCMS: [M+1] + = 612.3.
1HNMR(500MHz,DMSO-d6)δ12.27(s,1H),8.39–8.37(m,1H),7.76(s,1H),7.38(s,1H),7.14(d,J＝7.4Hz,2H),7.12–7.04(m,1H),6.91(s,1H),6.50(s,1H),4.62(s,1H),4.24(s,2H),3.86(d,J＝11.2Hz,2H),3.62(s,3H),3.45–3.40(m,2H),3.34(s,1H),3.29–3.23(m,2H),2.03(s,6H),1.99(s,1H),1.71(d,J＝8.5Hz,3H),1.12(s,6H),1.10(d,J＝7.2Hz,3H)。 1 HNMR(500MHz,DMSO-d6)δ12.27(s,1H), 8.39–8.37(m,1H), 7.76(s,1H), 7.38(s,1H), 7.14(d,J=7.4Hz, 2H), 7.12–7.04(m,1H), 6.91(s,1H), 6.50(s,1H), 4.62(s,1H), 4.24(s,2H), 3.86(d,J=11.2Hz,2H ), 3.62(s, 3H), 3.45–3.40(m, 2H), 3.34(s, 1H), 3.29–3.23(m, 2H), 2.03(s, 6H), 1.99(s, 1H), 1.71( d, J=8.5 Hz, 3H), 1.12 (s, 6H), 1.10 (d, J=7.2 Hz, 3H).
实施例71 5-(2,6-二甲基苯氧基)-6-(2-(乙基氨基甲酰基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-3-甲酰胺(化合物71)的合成Example 71 5-(2,6-Dimethylphenoxy)-6-(2-(ethylcarbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H- Synthesis of pyrrolo[2,3-c]pyridin-4-yl)-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxamide (Compound 71)
Figure PCTCN2021094838-appb-000049
Figure PCTCN2021094838-appb-000049
步骤1：化合物71-1的合成Step 1: Synthesis of compound 71-1
将化合物60-2(300mg)，Zn(CN) 2(136.76mg)和Pd(PPh 3) 4(67.29mg)依次加入到DMF(1mL)中，N 2保护，微波120℃，反应2hrs。将反应液倒入水中，EA萃取3次，合并有机相，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品经柱层析(PE:EA＝10:1)纯化，得200mg所述标题化合物71-1。 Compound 60-2 (300 mg), Zn(CN) 2 (136.76 mg) and Pd(PPh 3 ) 4 (67.29 mg) were sequentially added to DMF (1 mL), protected by N 2 and microwaved at 120° C., and reacted for 2 hrs. The reaction solution was poured into water, extracted with EA 3 times, the organic phases were combined, the organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA=10:1) to obtain 200 mg of the title compound 71-1.
步骤2：化合物71-2的合成Step 2: Synthesis of compound 71-2
在冰浴条件下，向化合物71-1(200mg)的DMSO(5mL)溶液中加入H 2O 2(1mL)和K 2CO 3(119.84mg)，室温搅拌2hrs。将反应液倒入水中，EA萃取3次，合并有机相，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品经柱层析(正己烷:EA＝5:1)纯化，得100mg所述标题化合物71-2。 Under ice bath conditions, H 2 O 2 (1 mL) and K 2 CO 3 (119.84 mg) were added to the DMSO (5 mL) solution of compound 71-1 (200 mg), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was poured into water, extracted with EA 3 times, the organic phases were combined, the organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (n-hexane:EA=5:1). 100 mg of the title compound 71-2 was obtained.
步骤3：化合物71的合成Step 3: Synthesis of compound 71
将化合物71-2(100mg)，中间体M1(79.85mg)，K 2CO 3(63.94mg)，Pd(dppf)Cl 2(16.93mg)依次加入到二氧六环(5mL)和H 2O(5mL)混合溶液中，N 2保护，在80℃下搅拌12hrs。将反应液倒入水中，DCM萃取3次，合并有机相，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品经柱层析(DCM:MeOH＝8:1)纯化，得20mg所述标题化合物71。 Compound 71-2 (100mg), intermediate M1 (79.85mg), K 2 CO 3 (63.94mg), Pd(dppf)Cl 2 (16.93mg) were sequentially added to dioxane (5mL) and H 2 O (5mL) The mixed solution was protected with N 2 and stirred at 80°C for 12 hrs. The reaction solution was poured into water, extracted with DCM 3 times, the organic phases were combined, the organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (DCM:MeOH=8:1) to obtain 20 mg of the title compound 71.
LCMS:[M+1] +＝571.3。 LCMS: [M+1] + = 571.3.
1HNMR(500MHz,DMSO-d6)δ12.26(s,1H),8.18(s,1H),7.88(s,1H),7.48(s,1H),7.26(d,J＝22.4Hz,2H),7.15(d,J＝7.5Hz,2H),7.11-7.06(m,1H),7.03(s,1H),6.79(s,1H),4.70(s,1H),4.35(s,2H),3.59(s,3H),3.25-3.24(m,2H),2.03(s,6H),1.13-1.10(m,9H).1HNMR(500MHz,DMSO-d6)δ12.26(s,1H), 8.18(s,1H), 7.88(s,1H), 7.48(s,1H), 7.26(d,J=22.4Hz,2H), 7.15(d,J=7.5Hz,2H),7.11-7.06(m,1H),7.03(s,1H),6.79(s,1H),4.70(s,1H),4.35(s,2H),3.59 (s,3H),3.25-3.24(m,2H),2.03(s,6H),1.13-1.10(m,9H).
实施例72 4-(3-((2-(二甲基氨基)乙基)(甲基)氨基)-5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物72)的合成Example 72 4-(3-((2-(dimethylamino)ethyl)(methyl)amino)-5-(2,6-dimethylphenoxy)-1-(2-fluoro- 2-methylpropyl)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c ] Synthesis of pyridine-2-carboxamide (Compound 72)
Figure PCTCN2021094838-appb-000050
Figure PCTCN2021094838-appb-000050
步骤1：化合物72-1的合成Step 1: Synthesis of compound 72-1
向化合物60-2(3.16g)和N,N,N'-三甲基乙二胺(5.10g)置于乙二醇(30mL)的溶液中加入磷酸钾(6.36g)和碘化亚铜(0.2g)，氮气置换，升温到80℃，搅拌2hrs。将反应液倒入水中，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品柱层析(DCM/MeOH＝100/3)纯化，得3.02g所述标题化合物72-1。To compound 60-2 (3.16g) and N,N,N'-trimethylethylenediamine (5.10g) in ethylene glycol (30mL) was added potassium phosphate (6.36g) and cuprous iodide (0.2g), replaced with nitrogen, heated to 80°C, and stirred for 2hrs. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by crude column chromatography (DCM/MeOH=100/3) to obtain 3.02 g of the title compound 72 -1.
步骤2：化合物72-2的合成Step 2: Synthesis of compound 72-2
氮气保护，在0℃条件下，向化合物72-1(4.89g)置于DCM(50mL)的溶液中缓慢滴加DAST(3.22g)，滴加结束，反应液缓慢升至10℃，搅拌2hrs。反应液倒入冰水，DCM萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析(DCM/MeOH＝100/3)纯化，得3.55g所述标题化合物72-2。Under nitrogen protection, under the condition of 0℃, DAST (3.22g) was slowly added dropwise to the solution of compound 72-1 (4.89g) in DCM (50mL). After the addition, the reaction solution was slowly raised to 10℃ and stirred for 2hrs. . The reaction solution was poured into ice water, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM/MeOH=100/3) to obtain 3.55 g of the title compound 72- 2.
步骤3：化合物72的合成Step 3: Synthesis of compound 72
将化合物72-2(491mg)，中间体M1(345mg)，碳酸钾(414mg)，Pd(dppf)Cl 2(72mg)置于二氧六环/H 2O(10mL，V/V＝5/1)，置换氮气，85℃反应6hrs。反应液中加水稀释， DCM萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析(DCM:MeOH＝100:6)纯化，得108mg所述标题化合物72。 Compound 72-2 (491mg), intermediate M1 (345mg), potassium carbonate (414mg), Pd(dppf)Cl 2 (72mg) were placed in dioxane/H 2 O (10 mL, V/V=5/ 1) Replace with nitrogen and react at 85°C for 6hrs. The reaction solution was diluted with water, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM:MeOH=100:6) to obtain 108 mg of the title compound 72.
LCMS:[M+1]+＝630.3。LCMS: [M+1]+=630.3.
1HNMR(500MHz,DMSO)δ12.31(s,1H),8.35(s,1H),7.58(s,1H),7.39(s,1H),7.25–6.98(m,3H),6.88(s,1H),6.54(s,1H),4.40(d,J＝20.8Hz,2H),3.62(s,3H),3.36(s,2H),3.25(m,2H),2.83(s,3H),2.68(s,2H),2.40–2.12(m,6H),2.03(s,6H),1.33(d,J＝21.5Hz,6H),1.11(t,J＝7.2Hz,3H)。 1 HNMR (500MHz, DMSO) δ 12.31 (s, 1H), 8.35 (s, 1H), 7.58 (s, 1H), 7.39 (s, 1H), 7.25-6.98 (m, 3H), 6.88 (s, 1H), 6.54 (s, 1H), 4.40 (d, J = 20.8 Hz, 2H), 3.62 (s, 3H), 3.36 (s, 2H), 3.25 (m, 2H), 2.83 (s, 3H), 2.68 (s, 2H), 2.40-2.12 (m, 6H), 2.03 (s, 6H), 1.33 (d, J = 21.5 Hz, 6H), 1.11 (t, J = 7.2 Hz, 3H).
采用与实施例69-72基本类似的方法，应用相应的N,N,N'-三甲基乙二胺类似物替换实施例中的
Figure PCTCN2021094838-appb-000051
(N,N,N'-三甲基乙二胺)制备表6中以下实施例。所述相应的N,N,N'-三甲基乙二胺类似物，例如二甲胺盐酸盐或
Figure PCTCN2021094838-appb-000052
等均可以通过市售渠道购买得到。部分化合物的获得是通过制备HPLC纯化获得，其条件为：流动相B(乙腈)：流动相A(0.1％甲酸水溶液)＝15％-65％。 Using a method substantially similar to that in Examples 69-72, the corresponding N,N,N'-trimethylethylenediamine analogues were used to replace the
Figure PCTCN2021094838-appb-000051
(N,N,N'-Trimethylethylenediamine) The following examples in Table 6 were prepared. The corresponding N,N,N'-trimethylethylenediamine analogs, such as dimethylamine hydrochloride or
Figure PCTCN2021094838-appb-000052
Etc. can be purchased through commercial channels. Part of the compounds were obtained by preparative HPLC purification, and the conditions were: mobile phase B (acetonitrile): mobile phase A (0.1% formic acid aqueous solution) = 15%-65%.
表6Table 6
Figure PCTCN2021094838-appb-000053
Figure PCTCN2021094838-appb-000053
Figure PCTCN2021094838-appb-000054
Figure PCTCN2021094838-appb-000054
Figure PCTCN2021094838-appb-000055
Figure PCTCN2021094838-appb-000055
实施例85和86 4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吡唑o[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物85)和4-(5-(2,6-二甲基苯氧基)-2-(2-羟基-2-甲基丙基)-2H-吡唑o[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物86)的合成Examples 85 and 86 4-(5-(2,6-dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole o[4,3-b] (Pyridin-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 85) And 4-(5-(2,6-dimethylphenoxy)-2-(2-hydroxy-2-methylpropyl)-2H-pyrazole o[4,3-b]pyridine-6- Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 86)
Figure PCTCN2021094838-appb-000056
Figure PCTCN2021094838-appb-000056
步骤1：化合物85-1的合成Step 1: Synthesis of compound 85-1
将3-溴-2-氯-6-甲基-5-硝基吡啶(1.0g)，2,6-二甲基苯酚(534.39mg)，Cs 2CO 3(2.59g)和CH 3CN(20mL)的混合物在80℃下搅拌2hrs。反应液冷却，并倒入水中，EA萃取3次，合并有机相，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品经柱层析(正己烷:EA＝1:1)纯化，得1.00g所述标题化合物85-1。 Combine 3-bromo-2-chloro-6-methyl-5-nitropyridine (1.0g), 2,6-dimethylphenol (534.39mg), Cs 2 CO 3 (2.59g) and CH 3 CN ( 20mL) was stirred at 80°C for 2hrs. The reaction solution was cooled and poured into water, extracted 3 times with EA, combined the organic phases, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to column chromatography (n-hexane:EA=1:1) After purification, 1.00 g of the title compound 85-1 was obtained.
步骤2：化合物85-2的合成Step 2: Synthesis of compound 85-2
将化合物85-1(1.0g)，Fe(828.22mg)，NH 4Cl(317.30mg)和MeOH(20mL)的混合物在80℃下加热3hrs。反应液过滤，滤饼用甲醇淋洗3次，浓缩滤液，向残余物中加入饱和碳酸钠溶液，EA萃取3次，合并有机相，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品经柱层析(正己烷:EA＝3:1)纯化，得800mg所述标题化合物85-2。 A mixture of compound 85-1 (1.0 g), Fe (828.22 mg), NH 4 Cl (317.30 mg) and MeOH (20 mL) was heated at 80° C. for 3 hrs. The reaction solution was filtered, the filter cake was rinsed with methanol 3 times, the filtrate was concentrated, saturated sodium carbonate solution was added to the residue, EA extraction 3 times, the organic phases were combined, the organic phases were washed 3 times with saturated brine, and dried with anhydrous sodium sulfate. After concentration, the crude product was purified by column chromatography (n-hexane:EA=3:1) to obtain 800 mg of the title compound 85-2.
步骤3：化合物85-3的合成Step 3: Synthesis of compound 85-3
在0℃下，向化合物85-2(800mg)，氯化氢(12M,21.70uL)，乙酸(5mL)和水(2.5mL)的混合液中加入NH 4BF 4(152.69mg,)和NaNO 2(269.53mg)，反应液升至室温，TLC监控反应完全。向反应液中加入碳酸钠水溶液，调节pH呈碱性，然后EA萃取，旋干，向残余物中加入EA(10mL)，KAcO(2.56g)，室温搅拌2h。将反应液倒入水中，EA萃取3次，合并有机相，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品柱层析(正己烷:EA＝3:1)纯化，得500mg所述标题化合物85-3。 At 0°C, NH 4 BF 4 (152.69 mg,) and NaNO 2 ( 269.53 mg), the reaction solution was warmed to room temperature, and TLC monitored the reaction to be complete. An aqueous sodium carbonate solution was added to the reaction solution to adjust the pH to make it alkaline, and then EA was extracted and spin-dried, EA (10 mL) and KAcO (2.56 g) were added to the residue, and the mixture was stirred at room temperature for 2 h. Pour the reaction solution into water, extract 3 times with EA, combine the organic phases, wash the organic phase with saturated brine 3 times, dry with anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography (n-hexane:EA=3:1) to obtain 500 mg of the title compound 85-3.
步骤4：化合物85-4和化合物86-4的合成Step 4: Synthesis of compound 85-4 and compound 86-4
将化合物85-3(500mg)，甲基环氧丙烷(226.63mg)，Cs 2CO 3(1.02g)和DMF(5mL)的混合物在80℃下搅拌12hrs。反应液冷却并倒入水中，EA萃取3次，合并有机相，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩得粗品。通过柱层析(正己烷:EA＝5:1)分离纯化，浓缩前峰层析液得到化合物85-4(200mg)，浓缩后峰层析液得到化合物86-4(130mg)。 A mixture of compound 85-3 (500 mg), methyl propylene oxide (226.63 mg), Cs 2 CO 3 (1.02 g) and DMF (5 mL) was stirred at 80° C. for 12 hrs. The reaction solution was cooled and poured into water, extracted with EA 3 times, the organic phases were combined, the organic phases were washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. It was separated and purified by column chromatography (n-hexane:EA=5:1), the former peak chromatographic solution was concentrated to obtain compound 85-4 (200 mg), and the peak chromatographic solution was concentrated to obtain compound 86-4 (130 mg).
步骤5：化合物85的合成Step 5: Synthesis of compound 85
将反应物85-4(200mg)，中间体M1(176.90mg)，K 2CO 3(141.65mg)，Pd(dppf)Cl 2(30mg)依次加入到二氧六环(5mL)和H 2O(5mL)的混合溶液中，N 2保护，在80℃下搅拌12hrs。将反应液倒入水中，DCM萃取3次，合并有机相，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品制备薄层色谱(DCM:MeOH＝10:1)纯化，得95mg所述标题化合物85。 Reactant 85-4 (200mg), intermediate M1 (176.90mg), K 2 CO 3 (141.65mg), Pd(dppf)Cl 2 (30mg) were sequentially added to dioxane (5mL) and H 2 O (5 mL) of the mixed solution, protected by N 2 and stirred at 80°C for 12 hrs. The reaction solution was poured into water, extracted with DCM three times, the organic phases were combined, the organic phase was washed with saturated brine three times, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative thin-layer chromatography (DCM:MeOH=10:1) to obtain 95 mg of the title compound 85.
步骤6：化合物86的合成Step 6: Synthesis of compound 86
采用实施例85步骤5的合成方法，将化合物85-4替换为化合物化合物86-4，即得化合物86。Using the synthetic method of step 5 in Example 85, replace compound 85-4 with compound 86-4 to obtain compound 86.
LCMS:[M+1] +＝529.6。 LCMS: [M+1] + = 529.6.
1HNMR(500MHz,DMSO)δ12.34(s,1H),8.30(d,J＝3.3Hz,2H),7.99(s,1H),7.47(s,1H),7.08(d,J＝7.4Hz,2H),7.03(dd,J＝8.5,6.3Hz,1H),6.93(d,J＝2.3Hz,1H),4.66(s,1H),4.34(s,2H),3.62(s,3H),3.26(dd,J＝7.5,5.6Hz,2H),2.00(s,6H),1.12(d,J＝7.7Hz,9H)。(化合物85) 1 HNMR(500MHz,DMSO)δ12.34(s,1H), 8.30(d,J=3.3Hz,2H),7.99(s,1H),7.47(s,1H),7.08(d,J=7.4Hz ,2H),7.03(dd,J=8.5,6.3Hz,1H),6.93(d,J=2.3Hz,1H),4.66(s,1H),4.34(s,2H),3.62(s,3H) , 3.26 (dd, J = 7.5, 5.6 Hz, 2H), 2.00 (s, 6H), 1.12 (d, J = 7.7 Hz, 9H). (Compound 85)
1HNMR(500MHz,DMSO)δ12.31(s,1H),8.34(t,J＝5.3Hz,1H),8.21(s,1H),8.16(s,1H),7.49(s,1H),7.08(d,J＝7.3Hz,2H),7.03(dd,J＝8.5,6.3Hz,1H),6.92(d,J＝2.4Hz,1H),4.77(s,2H)，4.28(s,2H),3.60(s,3H),3.26(dd,J＝7.5,5.5Hz,2H),2.00(s,6H),1.14–1.07(m,9H)。(化合物86) 1 HNMR (500MHz, DMSO) δ 12.31 (s, 1H), 8.34 (t, J = 5.3 Hz, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.49 (s, 1H), 7.08 (d,J=7.3Hz,2H), 7.03(dd,J=8.5,6.3Hz,1H), 6.92(d,J=2.4Hz,1H), 4.77(s,2H), 4.28(s,2H) , 3.60 (s, 3H), 3.26 (dd, J = 7.5, 5.5 Hz, 2H), 2.00 (s, 6H), 1.14-1.07 (m, 9H). (Compound 86)
采用与实施例85-86基本类似的方法，应用相应的2,6-二甲基苯酚类似物替换实施例中的2，-6-二甲基苯酚制备表7中以下实施例。所述相应的2,6-二甲基苯酚类似物，例如
Figure PCTCN2021094838-appb-000057
等均可以通过市售渠道购买得到。 The following examples in Table 7 were prepared by adopting a method basically similar to that in Examples 85-86, using corresponding 2,6-dimethylphenol analogs to replace 2,-6-dimethylphenol in the examples. The corresponding 2,6-dimethylphenol analogues, for example
Figure PCTCN2021094838-appb-000057
Etc. can be purchased through commercial channels.
表7Table 7
Figure PCTCN2021094838-appb-000058
Figure PCTCN2021094838-appb-000058
对比例Comparison
基本按照WO2015081189中实施例5所描述的方法制备如下对比例(如表8所示)。The following comparative examples were prepared basically according to the method described in Example 5 in WO2015081189 (as shown in Table 8).
表8Table 8
Figure PCTCN2021094838-appb-000059
Figure PCTCN2021094838-appb-000059
药理实验Pharmacological experiment
实验例1本发明化合物抑制BRD4(D1)和BRD4(D2)蛋白活性的检测(IC 50) Experimental example 1 The compound of the present invention inhibits BRD4 (D1) and BRD4 (D2) protein activity detection (IC 50 )
利用HTRF的方法，在BRD4(D1)和BRD4(D2)上检测化合物的抑制率。首先将化合物分别用DMSO溶解成20mM，然后将化合物用DMSO稀释至3uM起始浓度，然后3倍稀释，10浓度点，配制为工作液。将化合物工作液转移至384板孔中。在384板孔中添加2倍体积的蛋白/多肽混合物，然后再添加2倍体积的检定混合物，震荡30s。在室温下将板培育1.5h，随后在EnVision上读HTRF信号。Using the method of HTRF, the inhibition rate of the compound was detected on BRD4 (D1) and BRD4 (D2). First, the compounds were dissolved into 20mM with DMSO respectively, and then the compounds were diluted with DMSO to the initial concentration of 3uM, and then diluted 3 times with 10 concentration points to prepare the working solution. Transfer the compound working solution to the wells of the 384 plate. Add 2 times the volume of the protein/peptide mixture to the wells of the 384 plate, and then add 2 times the volume of the test mixture, and shake for 30 seconds. The plate was incubated for 1.5 h at room temperature, and then the HTRF signal was read on EnVision.
用方程式(1)在Excel中将数据拟合以获得抑制率的值，其中最大值是指DMSO对照的转化率，最小值是指无酶活对照的转化率，信号值为待测化合物的转化率。Use equation (1) to fit the data in Excel to obtain the value of inhibition rate, where the maximum value refers to the conversion rate of the DMSO control, the minimum value refers to the conversion rate of the control without enzyme activity, and the signal value is the conversion of the test compound Rate.
方程式(1)：抑制率(％)＝(最大值-信号值)/(最大值-最小值)*100Equation (1): Inhibition rate (%) = (maximum value-signal value) / (maximum value-minimum value) * 100
使用XL-Fit软件中的数据拟合IC 50值，然后使用方程式(2)进行非线性回归分析。 Use the data in the XL-Fit software to fit the IC 50 value, and then use equation (2) for nonlinear regression analysis.
方程式(2):Y＝底部+(顶部-底部)/(1+((IC 50/X)*斜率))；其中，Y表示抑制百分数(％)；X表示待测化合物的浓度。 Equation (2): Y = bottom + (top - bottom) / (1 + ((IC 50 / X) * slope)); wherein, Y represents percent inhibition (%); X represents the concentration of the test compound.
实施例的IC 50数据提供于表9中，其中，A1表示0nM＜IC 50≤0.5nM；A2表示0.5nM＜IC 50≤1nM；A3表示1nM＜IC 50≤3nM；A4表示3nM＜IC 50≤10nM；B1表示10nM＜IC 50≤300nM；B2表示300nM＜IC 50≤1000nM；B3表示IC 50>1000nM。 The IC 50 data of the examples are provided in Table 9, where A1 represents 0nM<IC 50 ≤0.5nM; A2 represents 0.5nM＜IC 50 ≤1nM; A3 represents 1nM＜IC 50 ≤3nM; A4 represents 3nM＜IC 50 ≤ 10nM; B1 represents 10nM <IC 50 ≤300nM; B2 represents 300nM <IC 50 ≤1000nM; B3 represents IC 50> 1000nM.
表9Table 9
Figure PCTCN2021094838-appb-000060
Figure PCTCN2021094838-appb-000060
Figure PCTCN2021094838-appb-000061
Figure PCTCN2021094838-appb-000061
表9示范性地列举了本发明化合物对于BRD4(D1)和BRD4(D2)的抑制能力，可以看出，本发明化合物表现出优异的BRD4(D2)选择性，在一些实施例中，化合物对BRD4(D2)的选 择性与对BRD4(D1)的选择性相比约为300-800倍；在一些实施例中，化合物对BRD4(D2)的选择性与对BRD4(D1)的选择性相比为约800-1200倍；。Table 9 exemplarily lists the inhibitory ability of the compounds of the present invention on BRD4 (D1) and BRD4 (D2). It can be seen that the compounds of the present invention exhibit excellent BRD4 (D2) selectivity. In some embodiments, the compounds are The selectivity of BRD4 (D2) is about 300-800 times that of BRD4 (D1); in some embodiments, the selectivity of the compound to BRD4 (D2) is comparable to that of BRD4 (D1). The ratio is about 800-1200 times;.
实验例2本发明化合物对MV-4-11细胞增殖活性的检测Experimental Example 2 Detection of the compound of the present invention on the proliferation activity of MV-4-11 cells
通过CellTiter-Glo发光法细胞活力检测试剂盒(CellTiter-Glo Luminescent Cell Viability Assay)方法检测化合物对MV-4-11细胞增殖的影响。The effect of the compound on the proliferation of MV-4-11 cells was detected by the CellTiter-Glo Luminescent Cell Viability Assay (CellTiter-Glo Luminescent Cell Viability Assay) method.
检测方法：将MV-4-11细胞用完全培养基(含有10％(v/v)FBS(胎牛血清)的IMDM(Iscove's Modified Dubecco's Medium)培养基)培养。然后用完全培养基将MV-4-11细胞调节为3.7×10 4细胞/mL的细胞悬浮液。向96孔板中加入135μL细胞悬浮液(每个浓度设置三个复孔)，最终细胞密度为5000细胞/孔。测试化合物溶于DMSO中(浓度为3mM)。以DMSO 3倍梯度稀释，9个浓度，第10个孔为DMSO对照。从化合物板中吸取化合物加到相应的孔板细胞中，DMSO最终浓度为0.1％，化合物最高浓度为3000nM，以不加细胞仅加培养基孔为空白对照孔，以0.1％DMSO为DMSO对照孔。将培养板放置于37℃，5％CO 2培养箱中孵育120小时后，每孔加入50μL的CellTiter-Glo Luminescent Cell Viability Assay溶液，于室温继续孵育10min，在酶标仪上测定各孔的数值。采用GraphPad Prism对数据进行分析，计算IC 50。 Detection method: MV-4-11 cells were cultured in complete medium (IMDM (Iscove's Modified Dubecco's Medium) medium containing 10% (v/v) FBS (fetal bovine serum)). Then, the MV-4-11 cells were adjusted to a cell suspension of 3.7×10 4 cells/mL with complete medium. Add 135 μL of cell suspension (three multiple wells for each concentration) to a 96-well plate, and the final cell density is 5000 cells/well. The test compound was dissolved in DMSO (concentration of 3 mM). Dilute with DMSO 3-fold gradient, 9 concentrations, and the 10th well is DMSO control. Add the compound from the compound plate to the cells of the corresponding well plate. The final concentration of DMSO is 0.1%, and the highest concentration of compound is 3000 nM. The wells without adding cells and medium are used as blank control wells, and 0.1% DMSO is used as the DMSO control well. . Place the culture plate in a 37°C, 5% CO 2 incubator and incubate for 120 hours. Add 50μL of CellTiter-Glo Luminescent Cell Viability Assay to each well. Incubate for 10 minutes at room temperature. Measure the value of each well on a microplate reader. . Using GraphPad Prism data analysis, calculated IC 50.
1.先通过Excel软件计算待测样品各个浓度点抑制率，计算公式为：1. Calculate the inhibition rate of each concentration point of the sample to be tested through Excel software, the calculation formula is:
抑制率％＝((DMSO对照孔-化合物孔)/(DMSO对照孔-空白对照孔))×100Inhibition rate%=((DMSO control well-compound well)/(DMSO control well-blank control well))×100
2.再通过Graphpad Prism软件以四参数法回归计算计算化合物的IC 50，Y表示抑制百分数(％)；X表示待测化合物的浓度： 2. The re-calculation to the compound by a four-parameter regression Graphpad Prism software IC 50, Y represents percent inhibition (%); X represents the concentration of test compound:
Y＝底部+(顶部-底部)/(1+10^((LogIC 50-X)*斜率))。 Y=bottom+(top-bottom)/(1+10^((LogIC 50 -X)*slope)).
实施例的MV4-11细胞IC 50数据提供于表10中，其中，*表示IC 50≤200nM；**表示200nM＜IC 50≤500nM；***表示IC 50>500nM。 The IC 50 data of the MV4-11 cells of the examples are provided in Table 10, where * means IC 50 ≤200 nM; ** means 200 nM<IC 50 ≤500 nM; *** means IC 50 >500 nM.
表10Table 10
实施例编号Example number MV-4-11(cell)IC 50 MV-4-11(cell)IC 50 实施例编号Example number MV-4-11(cell)IC 50 MV-4-11(cell)IC 50 实施例编号Example number MV-4-11(cell)IC 50 MV-4-11(cell)IC 50
11 21.821.8 3030 43.743.7 5959 21.421.4
22 3.73.7 3131 1.41.4 6060 51.251.2
33 1.01.0 3232 83.483.4 6161 52.752.7
44 ** 3333 ** 6262 11.711.7
55 21.921.9 3434 ** 6363 5.65.6
66 44.344.3 3535 12.412.4 6464 3.93.9
77 31.931.9 3636 ** 6565 1.21.2
88 ****** 3737 9.49.4 6666 11.111.1
99 ****** 3838 **** 6767 3737
实施例编号Example number MV-4-11(cell)IC 50 MV-4-11(cell)IC 50 实施例编号Example number MV-4-11(cell)IC 50 MV-4-11(cell)IC 50 实施例编号Example number MV-4-11(cell)IC 50 MV-4-11(cell)IC 50
1010 **** 3939 ****** 6868 13.413.4
1111 2828 4040 **** 6969 13.713.7
1212 33 4141 42.942.9 7070 99
1313 ****** 4242 **** 7171 56.356.3
1414 **** 4343 62.462.4 7272 0.80.8
1515 45.445.4 4444 10.410.4 7373 3.93.9
1616 16.816.8 4545 73.273.2 7474 3.93.9
1717 ** 4646 58.758.7 7575 4040
1818 ** 4747 1.41.4 7676 40.440.4
1919 3939 4848 **** 7777 1.01.0
2020 ** 4949 30.330.3 7878 5.35.3
21twenty one ** 5050 **** 7979 6.96.9
22twenty two 36.836.8 5151 ** 8080 13.113.1
23twenty three 3.33.3 5252 2.32.3 8181 90.990.9
24twenty four 50.750.7 5353 ** 8282 33
2525 3838 5454 **** 8383 13.713.7
2626 ** 5555 ** 8484 16.816.8
2727 2.02.0 5656 ** 8585 34.434.4
2828 10.710.7 5757 ** 8686 3.63.6
2929 5.95.9 5858 2.72.7  To  To
实验例3异种移植肿瘤生长抑制测定Experimental Example 3 Determination of xenograft tumor growth inhibition
方法:Balb/c nude小鼠(雄性)皮下接种MV-4-11细胞，建立MV-4-11异种移植肿瘤动物模型。将接种的小鼠随机分为溶剂对照组和实验组，实验组分别给予不同剂量的本发明化合物，每组6只实验动物。将0.1mL(1×10 7个)MV-4-11细胞(加基质胶，体积比为1:1)皮下接种于每只小鼠的后背，肿瘤平均体积达到约100-200mm 3左右时开始分组给药。测试化合物从分组当天开始灌胃给药，每天一次或两次，共给药28-32天。根据动物体重变化和死亡情况进行安全性评价，根据相对肿瘤抑制率(TGI％)进行疗效评价。 Methods: Balb/c nude mice (male) were subcutaneously inoculated with MV-4-11 cells to establish an animal model of MV-4-11 xenograft tumors. The inoculated mice were randomly divided into a solvent control group and an experimental group. The experimental groups were given different doses of the compound of the present invention, with 6 experimental animals in each group. 0.1mL (1×10 7 cells) MV-4-11 cells (with matrigel, volume ratio 1:1) were subcutaneously inoculated on the back of each mouse, when the average tumor volume reached about 100-200mm 3 Start grouping administration. The test compound was administered intragastrically from the day of grouping, once or twice a day, for a total of 28-32 days. The safety evaluation is based on the changes in animal weight and death, and the efficacy evaluation is based on the relative tumor inhibition rate (TGI%).
小鼠给药后各剂量组较对照组均表现出明显的抗肿瘤作用，肿瘤生长抑制率最高可达99％，且所有动物在给药期间均无明显体重下降，表明实验剂量下本发明化合物耐受性良好耐受良好。After the administration of the mice, each dose group showed obvious anti-tumor effect compared with the control group. The tumor growth inhibition rate was up to 99%, and all animals had no significant weight loss during the administration period, indicating that the compound of the present invention at the experimental dose Well tolerated and well tolerated.
虽然本发明已通过其实施方式进行了全面的描述，但是值得注意的是，各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。Although the present invention has been fully described through its implementation modes, it is worth noting that various changes and modifications are obvious to those skilled in the art. Such changes and modifications should be included in the scope of the appended claims of the present invention.

Claims (46)

  1. 式(I)所示的化合物或者其药学上可接受的盐，The compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021094838-appb-100001
    Figure PCTCN2021094838-appb-100001
    其中，in,
    Figure PCTCN2021094838-appb-100002
    表示单键或双键；
    Figure PCTCN2021094838-appb-100002
    Represents a single bond or a double bond;
    R 1选自H、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或C 3-10杂环基； R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-10 heterocyclic group;
    R 2、R 3、R 4和R 5分别独立地选自H、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或C 3-10杂环基； R 2 , R 3 , R 4 and R 5 are each independently selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-10 heterocyclic group;
    环A为C 6-10芳基、C 5-10杂芳基、C 3-10环烷基、C 3-10环烯基或C 3-10杂环基； Ring A is a C 6-10 aryl group, a C 5-10 heteroaryl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group or a C 3-10 heterocyclic group;
    E 1为CR 7或N； E 1 is CR 7 or N;
    E 2为CR 8或N； E 2 is CR 8 or N;
    D 1为C或N； D 1 is C or N;
    D 2为C或N； D 2 is C or N;
    D 3为C或N； D 3 is C or N;
    其中，D 1、D 2和D 3中至少有一个为N，且至少有一个为C； Wherein, at least one of D 1 , D 2 and D 3 is N, and at least one is C;
    R 7和R 8分别独立地选自H、卤素、羟基、氧代基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或C 3-10杂环基； R 7 and R 8 are each independently selected from H, halogen, hydroxy, oxo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-10 heterocyclic group;
    R 6选自H、卤素、氰基、-NO 2、C 1-10烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基、C 5-10杂芳基、-OR c、-SR c、-C(＝O)R c、-C(＝O)OR c、-C(＝O)NR aR b、-OC(＝O)R c、-S(＝O) 2R c、-S(＝O)R c、-NR aR b、-NC(＝O)R a、-NC(＝O)OR a、-NR aC(＝O)NR aR b、-NR aC(＝O)ONR b、-O(C 1-4亚烷基)R x、-(C 1-4亚烷基)R x、-NR a(C 1-4亚烷基)R x、-O(C 1-4亚烷基)OR c、-O(C 1-4亚烷基)NR aR b、-O(C 1-4亚烷基)C(＝O)NR aR b、C(＝O)ONR aR b、-O(C 1-4亚烷基)S(＝O) 2R c、-(C 1-4亚烷基)C(＝O)NR aR b、-(C 1-4亚烷 基)C(＝O)ONR aR b、-(C 1-4亚烷基)NR aR b、-(C 1-4亚烷基)S(＝O) 2R c、-NR a(C 1-4亚烷基)NR aR b、-NR a(C 1-4亚烷基)OR c、-NR a(C 1-4亚烷基)C(＝O)NR aR b、-NR a(C 1-4亚烷基)C(＝O)ONR aR b或-NR a(C 1-4亚烷基)S(＝O) 2R c，其中，所述C 1-10烷基、C 2-6烯基和C 2-6炔基任选地被R 9取代，所述C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基和C 5-10杂芳基任选地被R 10取代； R 6 is selected from H, halogen, cyano, -NO 2 , C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkene Group, C 3-10 heterocyclic group, C 6-10 aryl group, C 5-10 heteroaryl group, -OR c , -SR c , -C(=O)R c , -C(=O)OR c , -C(=O)NR a R b , -OC(=O)R c , -S(=O) 2 R c , -S(=O)R c , -NR a R b , -NC(= O)R a , -NC(=O)OR a , -NR a C(=O)NR a R b , -NR a C(=O)ONR b , -O(C 1-4 alkylene) R x , -(C 1-4 alkylene) R x , -NR a (C 1-4 alkylene) R x , -O(C 1-4 alkylene) OR c , -O(C 1- 4 alkylene)NR a R b , -O(C 1-4 alkylene) C(=O)NR a R b , C(=O)ONR a R b , -O(C 1-4 alkylene Group) S(=O) 2 R c , -(C 1-4 alkylene)C(=O)NR a R b , -(C 1-4 alkylene)C(=O)ONR a R b , -(C 1-4 alkylene)NR a R b , -(C 1-4 alkylene)S(=O) 2 R c , -NR a (C 1-4 alkylene)NR a R b , -NR a (C 1-4 alkylene) OR c , -NR a (C 1-4 alkylene) C(=O)NR a R b , -NR a (C 1-4 alkylene )C(=O)ONR a R b or -NR a (C 1-4 alkylene)S(=O) 2 R c , wherein the C 1-10 alkyl, C 2-6 alkenyl and The C 2-6 alkynyl group is optionally substituted by R 9 , the C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 3-10 heterocyclic group, C 6-10 aryl group and C 5- 10 heteroaryl is optionally substituted by R 10;
    R 9选自H、卤素、氰基、氧代基、-OR c、-SR c、-C(＝O)R c、-C(＝O)OR c、-C(＝O)NR aR b、-OC(＝O)R c、-S(＝O) 2R c、-S(＝O)R c、-NR aR b、-NC(＝O)R a、-NR aC(＝O)NR aR b、-NR aC(＝O)ONR c、C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基或C 5-10杂芳基，其中，所述C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基和C 5-10杂芳基任选地被H、卤素、氰基、羟基、-NR aR b、-C(＝O)R c、-C(＝O)OR c、-S(＝O) 2R c、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基或C 2-6炔基取代； R 9 is selected from H, halogen, cyano, oxo, -OR c , -SR c , -C(=O)R c , -C(=O)OR c , -C(=O)NR a R b , -OC(=O)R c , -S(=O) 2 R c , -S(=O)R c , -NR a R b , -NC(=O)R a , -NR a C( ═O)NR a R b , -NR a C(=O)ONR c , C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl group, wherein the C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 3-10 heterocyclic group, C 6-10 aryl group and C 5-10 heteroaryl group Optionally by H, halogen, cyano, hydroxyl, -NR a R b , -C(=O)R c , -C(=O)OR c , -S(=O) 2 R c , C 1- 6 Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl substituted;
    R 10选自H、卤素、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-OR c、-SR c、-C(＝O)R c、-C(＝O)OR c、-C(＝O)NR aR b、-OC(＝O)R c、-S(＝O) 2R c、-S(＝O)R c、-NR aR b、-NC(＝O)R a、-NR aC(＝O)NR aR b或-NR aC(＝O)ONR b； R 10 is selected from H, halogen, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR c , -SR c , -C(=O)R c , -C(=O)OR c , -C(=O)NR a R b , -OC(=O)R c , -S(=O) 2 R c ,- S(=O)R c , -NR a R b , -NC(=O)R a , -NR a C(=O)NR a R b or -NR a C(=O)ONR b ;
    R a和R b分别独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-10杂环基、C 6-10芳基或C 5-10杂芳基； R a and R b are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3 -10 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl;
    或R a和R b与其共同连接的N原子形成C 3-10杂环基，其中，所述C 3-10杂环基可任由H、卤素、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基和C 1-6卤代烷氧基所取代； N atom or R a and R b are commonly connected thereto form C 3-10 heterocyclyl group, wherein the C 3-10 heterocyclyl group may be allowed to H, halo, cyano, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;
    R c选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或C 3-10杂环基； R c is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-10 heterocycle base;
    R x选自C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基或C 5-10杂芳基，其中，所述R x可任由H、卤素、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或-NR aR b所取代； R x is selected from C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, wherein the R x may May be substituted by H, halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or -NR a R b ;
    m和n为0、1、2或3。m and n are 0, 1, 2, or 3.
  2. 根据权利要求1所述的化合物，其特征在于，R 1选自C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 3-6环烷基。 The compound of claim 1, wherein R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 3-6 cycloalkyl.
  3. 根据权利要求1或2所述的化合物，其特征在于，所述R 1为C 1-6烷基。 The compound of claim 1 or 2, wherein the R 1 is a C 1-6 alkyl group.
  4. 根据权利要求1所述的化合物，其特征在于，R 2选自C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基。 The compound of claim 1, wherein R 2 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.
  5. 根据权利要求1或4所述的化合物，其特征在于，R 2为C 1-6烷基。 The compound of claim 1 or 4, wherein R 2 is a C 1-6 alkyl group.
  6. 根据权利要求1所述的化合物，其特征在于，R 3为H或C 1-6烷基。 The compound of claim 1, wherein R 3 is H or C 1-6 alkyl.
  7. 根据权利要求1所述的化合物，其特征在于，R 4选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-6环烷基或C 3-10杂环基。 The compound of claim 1, wherein R 4 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 3-6 cycloalkyl or C 3-10 heterocyclic group.
  8. 根据权利要求1或7所述的化合物，其特征在于，R 4为H或C 1-6烷基。 The compound of claim 1 or 7, wherein R 4 is H or C 1-6 alkyl.
  9. 根据权利要求1所述的化合物，其特征在于，环A为C 6-10芳基或C 5-10杂芳基。 The compound of claim 1, wherein ring A is a C 6-10 aryl group or a C 5-10 heteroaryl group.
  10. 根据权利要求1所述的化合物，其特征在于，R 5选自卤素、氰基、C 1-6烷基、C 1-6烷氧基。 The compound of claim 1, wherein R 5 is selected from halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy.
  11. 根据权利要求1或10所述的化合物，其特征在于，R 5选自卤素或C 1-6烷基。 The compound according to claim 1 or 10, wherein R 5 is selected from halogen or C 1-6 alkyl.
  12. 根据权利要求1所述的化合物，其特征在于，R 7和R 8选自H或C 1-6烷基。 The compound of claim 1, wherein R 7 and R 8 are selected from H or C 1-6 alkyl.
  13. 根据权利要求1所述的化合物，其特征在于，R 6选自H、卤素、氰基、C 1-10烷基、C 3-10环烷基、C 3-10杂环基、C 6-10芳基、C 5-10杂芳基、-OR c、-S(＝O) 2R c、-NR aR b、-C(＝O)NR aR b、-O(C 1-4亚烷基)R x、-(C 1-4亚烷基)R x、-NR a(C 1-4亚烷基)R x、-O(C 1-4亚烷基)OR c、-O(C 1-4亚烷基)NR aR b、-(C 1-4亚烷基)C(＝O)NR aR b、-(C 1-4亚烷基)NR aR b、-(C 1-4亚烷基)S(＝O) 2R c、-NR a(C 1-4亚烷基)OR c或-NR a(C 1-4亚烷基)NR aR b，其中，所述C 1-10烷基任选地被R 9取代，所述C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基和C 5-10杂芳基任选地被R 10取代； The compound of claim 1, wherein R 6 is selected from H, halogen, cyano, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6- 10 aryl, C 5-10 heteroaryl, -OR c , -S(=O) 2 R c , -NR a R b , -C(=O)NR a R b , -O(C 1-4 Alkylene) R x , -(C 1-4 alkylene) R x , -NR a (C 1-4 alkylene) R x , -O(C 1-4 alkylene) OR c ,- O(C 1-4 alkylene)NR a R b , -(C 1-4 alkylene)C(=O)NR a R b , -(C 1-4 alkylene)NR a R b , -(C 1-4 alkylene) S(=O) 2 R c , -NR a (C 1-4 alkylene) OR c or -NR a (C 1-4 alkylene) NR a R b , Wherein the C 1-10 alkyl group is optionally substituted by R 9 , the C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 3-10 heterocyclic group, C 6-10 aryl group And C 5-10 heteroaryl groups are optionally substituted by R 10;
    R a和R b分别独立地选自H、C 1-6烷基或C 5-10杂芳基； R a and R b are each independently selected from H, C 1-6 alkyl or C 5-10 heteroaryl;
    或R a和R b与其共同连接的N原子形成C 3-10杂环基，其中，所述C 3-10杂环基可任由H、卤素、氰基、C 1-6烷基或C 1-6卤代烷基所取代； N atom or R a and R b are commonly connected thereto form C 3-10 heterocyclyl group, wherein the C 3-10 heterocyclyl group may be allowed to H, halo, cyano, C 1-6 alkyl or C 1-6 substituted by haloalkyl;
    R c选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R c is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R x选自C 3-10环烷基、C 3-10环烯基、C 3-10杂环基、C 6-10芳基或C 5-10杂芳基，其中，所述R x可任由H、卤素、氰基、C 1-6烷基或-NR aR b所取代。 R x is selected from C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, wherein the R x may It is optionally substituted by H, halogen, cyano, C 1-6 alkyl or -NR a R b .
  14. 根据权利要求1-13任一项所述的化合物，其特征在于，R 9选自H、卤素、氰基、氧代基、-OR c、-NR aR b、-S(＝O) 2R c、C 3-6环烷基或C 3-10杂环基。 The compound according to any one of claims 1-13, wherein R 9 is selected from H, halogen, cyano, oxo, -OR c , -NR a R b , -S(=O) 2 R c , C 3-6 cycloalkyl or C 3-10 heterocyclic group.
  15. 根据权利要求1-14任一项所述的化合物，其特征在于，R 10选自H、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或-OR c。 The compound according to any one of claims 1-14, wherein R 10 is selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy or -OR c .
  16. 根据权利要求1-15任一项所述的化合物，其特征在于，R 10选自H、C 1-6烷基或C 1-6烷氧基。 The compound according to any one of claims 1-15, wherein R 10 is selected from H, C 1-6 alkyl or C 1-6 alkoxy.
  17. 根据权利要求1-15任一项所述的化合物，其特征在于，R a和R b分别独立地选自H、C 1-6烷基或C 5-10杂芳基；或R a和R b与其共同连接的N原子形成C 4-6杂环基，其中，所述C 4-6杂环基可任由H或C 1-4烷基所取代。 Compound according to any of claims 1 to 15, wherein, R a and R b are each independently selected from H, C 1-6 alkyl or a C 5-10 heteroaryl; or R a and R b and the N atom to which it is connected together form a C 4-6 heterocyclic group, wherein the C 4-6 heterocyclic group may be optionally substituted by H or a C 1-4 alkyl group.
  18. 根据权利要求1-15任一项所述的化合物，其特征在于，R c选自H、甲基或乙基。 The compound according to any one of claims 1-15, wherein R c is selected from H, methyl or ethyl.
  19. 根据权利要求1-15任一项所述的化合物，其特征在于，R x选自
    Figure PCTCN2021094838-appb-100003
    Figure PCTCN2021094838-appb-100004
    The compound according to any one of claims 1-15, wherein R x is selected from
    Figure PCTCN2021094838-appb-100003
    Figure PCTCN2021094838-appb-100004
  20. 根据权利要求1-15任一项所述的化合物，其特征在于，R 6选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、-(C 1-4亚烷基)R x、-(C 1-4亚烷基)C(＝O)NR aR b、-(C 1-4亚烷基)NR aR b或-(C 1-4亚烷基)S(＝O) 2R c；其中，所述C 1-6烷基任选地被H、卤素、-OH、-NH 2、-N(CH 3) 2或环丙烷所取代； The compound according to any one of claims 1-15, wherein R 6 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(C 1-4 alkylene) R x , -(C 1-4 alkylene)C(=O)NR a R b , -(C 1-4 alkylene)NR a R b or -(C 1- 4 alkylene) S(=O) 2 R c ; wherein the C 1-6 alkyl group is optionally substituted by H, halogen, -OH, -NH 2 , -N(CH 3 ) 2 or cyclopropane replace;
    R a和R b分别独立地选自H或C 1-6烷基； R a and R b are each independently selected from H or C 1-6 alkyl;
    R c选自H或C 1-6烷基； R c is selected from H or C 1-6 alkyl;
    R x为环丙烷，所述R x可任由H、卤素、-NH 2或-N(CH 3) 2所取代。 R x is cyclopropane, and the R x can be optionally substituted by H, halogen, -NH 2 or -N(CH 3 ) 2 .
  21. 根据权利要求1-20任一项所述的化合物或者其药学上可接受的盐，其特征在于，所述化合物如式(II)所示，The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein the compound is represented by formula (II),
    Figure PCTCN2021094838-appb-100005
    Figure PCTCN2021094838-appb-100005
    其中，in,
    D 1和D 3有且只有一个为N。 Only one of D 1 and D 3 is N.
  22. 根据权利要求1-20任一项所述的化合物或者其药学上可接受的盐，其特征在于，所述化合物如式(III)所示，The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein the compound is represented by formula (III),
    Figure PCTCN2021094838-appb-100006
    Figure PCTCN2021094838-appb-100006
    其中，所述W 1、W 2和W 3为C或N。 Wherein, the W 1 , W 2 and W 3 are C or N.
  23. 根据权利要求1-22任一项所述的化合物，其特征在于，E 1和E 2均为CH。 The compound according to any one of claims 1-22, wherein E 1 and E 2 are both CH.
  24. 根据权利要求1-22任一项所述的化合物，其特征在于，E 1为CH，E 2为N。 The compound according to any one of claims 1-22, wherein E 1 is CH and E 2 is N.
  25. 根据权利要求22所述的化合物，其特征在于，W 1为C，W 2和W 3为C或N，条件是：当W 2和W 3不全为C时，W 2和W 3中有且仅有一个为N。 The compound of claim 22, wherein W 1 is C, W 2 and W 3 are C or N, provided that when W 2 and W 3 are not all C, W 2 and W 3 have and Only one is N.
  26. 根据权利要求22所述的化合物，其特征在于，W 1、W 2和W 3均为C。 The compound of claim 22, wherein W 1 , W 2 and W 3 are all C.
  27. 根据权利要求1-26任一项所述的化合物，其特征在于，R 1为甲基或乙基。 The compound according to any one of claims 1-26, wherein R 1 is methyl or ethyl.
  28. 根据权利要求1-26任一项所述的化合物，其特征在于，R 2为甲基。 The compound of any one of claims 1-26, wherein R 2 is methyl.
  29. 根据权利要求1-26任一项所述的化合物，其特征在于，R 3和R 4为H。 The compound of any one of claims 1-26, wherein R 3 and R 4 are H.
  30. 根据权利要求1-26任一项所述的化合物，其特征在于，R 5为甲基或卤素。 The compound according to any one of claims 1-26, wherein R 5 is methyl or halogen.
  31. 根据权利要求21-22所述的化合物，其特征在于，D 1为N，D 2为C。 The compound of claims 21-22, wherein D 1 is N and D 2 is C.
  32. 根据权利要求21-22所述的化合物，其特征在于，D 1为C，D 2为N。 The compound of claims 21-22, wherein D 1 is C and D 2 is N.
  33. 根据权利要求1所述的化合物，其特征在于，含有D 1原子的双环部分选自：
    Figure PCTCN2021094838-appb-100007
    The compound of claim 1, wherein the bicyclic moiety containing D 1 atom is selected from:
    Figure PCTCN2021094838-appb-100007
  34. 根据权利要求1所述的化合物，其特征在于，所述化合物是：The compound of claim 1, wherein the compound is:
    1)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；1) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    2)4-(5-(2,6-二甲基苯氧基)-2-(2-羟基-2-甲基丙基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；2) 4-(5-(2,6-Dimethylphenoxy)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    3)4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；3) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    4)4-(5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；4) 4-(5-(2,6-Dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-di Hydrogen-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    5)N-乙基-4-(5-(4-氟-2,6-二甲基苯氧基)-1H-吲唑-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；5) N-ethyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-1H-indazol-6-yl)-6-methyl-7-oxo-6 ,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    6)N-乙基-4-(5-(4-氟-2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；6) N-ethyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazole-6 -Yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    7)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；7) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    8)4-(5-((3,5-二甲基吡啶-4-基)氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；8) 4-(5-((3,5-dimethylpyridin-4-yl)oxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    9)4-(5-((3,5-二甲基吡啶-4-基)氧基)-2-(2-羟基-2-甲基丙基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；9) 4-(5-((3,5-dimethylpyridin-4-yl)oxy)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    10)N-乙基-4-(1-(2-羟基-2-甲基丙基)-5-(2,3,6-三甲基苯氧基)-1H-吲唑-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；10) N-ethyl-4-(1-(2-hydroxy-2-methylpropyl)-5-(2,3,6-trimethylphenoxy)-1H-indazol-6-yl )-6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    11)N-乙基-4-(5-(4-氟-2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；11) N-ethyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6 -Yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    12)N-乙基-4-(5-(4-氟-2,6-二甲基苯氧基)-2-(2-氟-2-甲基丙基)-2H-吲唑-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；12) N-ethyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-2-(2-fluoro-2-methylpropyl)-2H-indazole-6 -Yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    13)4-(5-((3,5-二甲基吡啶-4-基)氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；13) 4-(5-((3,5-dimethylpyridin-4-yl)oxy)-1-(2-fluoro-2-methylpropyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    14)4-(5-((3,5-二甲基吡啶-4-基)氧基)-2-(2-氟-2-甲基丙基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；14) 4-(5-((3,5-dimethylpyridin-4-yl)oxy)-2-(2-fluoro-2-methylpropyl)-2H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    15)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；15) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2-fluoro-2-methylpropyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    16)4-(5-((2,4-二甲基吡啶-3-基)氧基)-2-(2-氟-2-甲基丙基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；16) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-2-(2-fluoro-2-methylpropyl)-2H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    17)N-乙基-4-(1-(2-氟-2-甲基丙基)-5-(2,3,6-三甲基苯氧基)-1H-吲唑-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；17) N-ethyl-4-(1-(2-fluoro-2-methylpropyl)-5-(2,3,6-trimethylphenoxy)-1H-indazol-6-yl )-6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    18)4-(5-(2,6-二甲基苯氧基)-1-甲基-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；18) 4-(5-(2,6-Dimethylphenoxy)-1-methyl-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo- 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    19)4-(5-(2,6-二甲基苯氧基)-2-甲基-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；19) 4-(5-(2,6-Dimethylphenoxy)-2-methyl-2H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo- 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    20)4-(5-(2,6-二甲基苯氧基)-1-乙基-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；20) 4-(5-(2,6-Dimethylphenoxy)-1-ethyl-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo- 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    21)4-(5-(2,6-二甲基苯氧基)-2-乙基-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；21) 4-(5-(2,6-Dimethylphenoxy)-2-ethyl-2H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo- 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    22)4-(1-(2-(二甲基氨基)乙基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；22) 4-(1-(2-(Dimethylamino)ethyl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    23)4-(2-(2-(二甲基氨基)乙基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；23) 4-(2-(2-(Dimethylamino)ethyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    24)4-(5-(2,6-二甲基苯氧基)-1-(3-羟基-3-甲基丁基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；24) 4-(5-(2,6-Dimethylphenoxy)-1-(3-hydroxy-3-methylbutyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    25)4-(5-(2,6-二甲基苯氧基)-2-(3-羟基-3-甲基丁基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；25) 4-(5-(2,6-Dimethylphenoxy)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    26)4-(5-(2,6-二甲基苯氧基)-1-(3-氟-3-甲基丁基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；26) 4-(5-(2,6-Dimethylphenoxy)-1-(3-fluoro-3-methylbutyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    27)4-(5-(2,6-二甲基苯氧基)-2-(3-氟-3-甲基丁基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；27) 4-(5-(2,6-Dimethylphenoxy)-2-(3-fluoro-3-methylbutyl)-2H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    28)4-(5-(2,6-二甲基苯氧基)-1-(2-氟乙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；28) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoroethyl)-1H-indazol-6-yl)-N-ethyl-6-methyl- 7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    29)4-(5-(2,6-二甲基苯氧基)-2-(2-氟乙基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；29) 4-(5-(2,6-Dimethylphenoxy)-2-(2-fluoroethyl)-2H-indazol-6-yl)-N-ethyl-6-methyl- 7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    30)4-(1-(环丙基甲基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；30) 4-(1-(Cyclopropylmethyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl-6-methyl- 7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    31)4-(2-(环丙基甲基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；31) 4-(2-(Cyclopropylmethyl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)-N-ethyl-6-methyl- 7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    32)4-(5-(2,6-二甲基苯氧基)-1-(2,2,2-三氟乙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；32) 4-(5-(2,6-Dimethylphenoxy)-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    33)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2,2,2-三氟乙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；33) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    34)4-(1-(2-(二甲基氨基)乙基)-5-(4-氟-2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；34) 4-(1-(2-(Dimethylamino)ethyl)-5-(4-fluoro-2,6-dimethylphenoxy)-1H-indazol-6-yl)-N -Ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    35)4-(2-(2-(二甲基氨基)乙基)-5-(4-氟-2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；35) 4-(2-(2-(Dimethylamino)ethyl)-5-(4-fluoro-2,6-dimethylphenoxy)-2H-indazol-6-yl)-N -Ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    36)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-新戊基-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；36) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-neopentyl-1H-indazol-6-yl)-N-ethyl-6-methyl Group-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    37)4-(5-((2,4-二甲基吡啶-3-基)氧基)-2-新戊基-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；37) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-2-neopentyl-2H-indazol-6-yl)-N-ethyl-6-methyl Group-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    38)4-(1-(氮杂环丁烷-3-基甲基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；38) 4-(1-(azetidin-3-ylmethyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl -6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    39)4-(2-(氮杂环丁烷-3-基甲基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；39) 4-(2-(azetidin-3-ylmethyl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)-N-ethyl -6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    40)4-(5-(2,6-二甲基苯氧基)-1-(吡咯烷-3-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；40) 4-(5-(2,6-Dimethylphenoxy)-1-(pyrrolidin-3-yl)-1H-indazol-6-yl)-N-ethyl-6-methyl -7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    41)4-(5-(2,6-二甲基苯氧基)-2-(吡咯烷-3-基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；41) 4-(5-(2,6-Dimethylphenoxy)-2-(pyrrolidin-3-yl)-2H-indazol-6-yl)-N-ethyl-6-methyl -7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    42)4-(1-(氮杂环丁烷-3-基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；42) 4-(1-(azetidin-3-yl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl-6 -Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    43)4-(2-(氮杂环丁烷-3-基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；43) 4-(2-(azetidin-3-yl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)-N-ethyl-6 -Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    44)4-(1-(2-氨基-2-氧乙基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；44) 4-(1-(2-Amino-2-oxyethyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl-6 -Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    45)4-(5-(2,6-二甲基苯氧基)-1-((甲磺酰基)甲基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；45) 4-(5-(2,6-Dimethylphenoxy)-1-((methylsulfonyl)methyl)-1H-indazol-6-yl)-N-ethyl-6-methyl Group-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    46)4-(5-(2,6-二甲基苯氧基)-1-(2-(甲磺酰基)乙基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；46) 4-(5-(2,6-Dimethylphenoxy)-1-(2-(methylsulfonyl)ethyl)-2H-indazol-6-yl)-N-ethyl-6 -Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    47)4-(5-(2,6-二甲基苯氧基)-2-(2-(甲磺酰基)乙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；47) 4-(5-(2,6-Dimethylphenoxy)-2-(2-(methylsulfonyl)ethyl)-1H-indazol-6-yl)-N-ethyl-6 -Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    48)4-(1-环丙基-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；48) 4-(1-Cyclopropyl-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo -6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    49)4-(1-((1-氨基环丙基)甲基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；49) 4-(1-((1-Aminocyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    50)4-(1-(2-氨基-2-甲基丙基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；50) 4-(1-(2-Amino-2-methylpropyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    51)4-(1-((1-(二甲基氨基)环丙基)甲基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；51) 4-(1-((1-(dimethylamino)cyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)- N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    52)4-(2-((1-(二甲基氨基)环丙基)甲基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；52) 4-(2-((1-(dimethylamino)cyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)- N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    53)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2-甲氧基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；53) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2-methoxy-2-methylpropyl)-1H-indazole-6- Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    54)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2-乙基-2-羟基丁基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；54) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2-ethyl-2-hydroxybutyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    55)4-(5-(2,6-二甲基苯氧基)-1-((1-氟环丙基)甲基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；55) 4-(5-(2,6-Dimethylphenoxy)-1-((1-fluorocyclopropyl)methyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    56)4-(5-(2,6-二甲基苯氧基)-2-((1-氟环丙基)甲基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；56) 4-(5-(2,6-Dimethylphenoxy)-2-((1-fluorocyclopropyl)methyl)-2H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    57)4-(1-((1-氰基环丙基)甲基)-5-(2,6-二甲基苯氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；57) 4-(1-((1-cyanocyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-1H-indazol-6-yl)-N-ethyl -6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    58)4-(2-((1-氰基环丙基)甲基)-5-(2,6-二甲基苯氧基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；58) 4-(2-((1-cyanocyclopropyl)methyl)-5-(2,6-dimethylphenoxy)-2H-indazol-6-yl)-N-ethyl -6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    59)4-(5-(2,6-二甲基苯氧基)-2-(氧杂环丁-3-基甲基)-2H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；59) 4-(5-(2,6-Dimethylphenoxy)-2-(oxetan-3-ylmethyl)-2H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    60)4-(3-环丙基-5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；60) 4-(3-Cyclopropyl-5-(2,6-dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    61)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；61) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)-N-ethyl- 6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    62)4-(5-((2,4-二甲基吡啶-3-基)氧基)-1-(2-羟基-2-甲基丙基)-3-甲基-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；62) 4-(5-((2,4-dimethylpyridin-3-yl)oxy)-1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-indazole -6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    63)4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-3-(吡啶-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；63) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-3-(pyridin-4-yl)-1H-indazole- 6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    64)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(1,2,3,6-四氢吡啶-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；64) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(1,2,3,6-tetrahydropyridine- 4-yl)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- 2-formamide;
    65)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(3-甲氧基吡啶-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；65) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(3-methoxypyridin-4-yl)- 1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    66)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；66) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(1-methyl-1H-pyrazole-4- Yl)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2- Formamide
    67)4-(3-(3,6-二氢-2H-吡喃-4-基)-5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；67) 4-(3-(3,6-Dihydro-2H-pyran-4-yl)-5-(2,6-dimethylphenoxy)-1-(2-hydroxy-2-methyl Propyl)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- 2-formamide;
    68)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(吡啶-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；68) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(pyridin-4-yl)-1H-indazole- 6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    69)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(3-吗啉代丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；69) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(3-morpholinopropyl)-1H-indyl (Azol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    70)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(四氢2H-吡喃-4-基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；70) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(tetrahydro 2H-pyran-4-yl)- 1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    71)5-(2,6-二甲基苯氧基)-6-(2-(乙基氨基甲酰基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-3-甲酰胺；71) 5-(2,6-Dimethylphenoxy)-6-(2-(ethylcarbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrole And [2,3-c]pyridin-4-yl)-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxamide;
    72)4-(3-((2-(二甲基氨基)乙基)(甲基)氨基)-5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；72)4-(3-((2-(dimethylamino)ethyl)(methyl)amino)-5-(2,6-dimethylphenoxy)-1-(2-fluoro-2 -Methylpropyl)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] Pyridine-2-carboxamide;
    73)4-(3-(二甲基氨基)-5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；73) 4-(3-(Dimethylamino)-5-(2,6-dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6 -Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    74)4-(3-((3-(二甲基氨基)丙基)(甲基)氨基)-5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；74) 4-(3-((3-(dimethylamino)propyl)(methyl)amino)-5-(2,6-dimethylphenoxy)-1-(2-fluoro-2 -Methylpropyl)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c] Pyridine-2-carboxamide;
    75)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(2-吗啉代乙氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；75) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(2-morpholinoethoxy)-1H- Indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    76)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(2-羟基乙氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；76) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(2-hydroxyethoxy)-1H-indazole -6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    77)4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-3-(甲基(2-(4-甲基哌嗪-1-基)乙基)氨基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰 胺；77) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-3-(methyl(2-(4-methylpiperazine -1-yl)ethyl)amino)-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2, 3-c]pyridine-2-carboxamide;
    78)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(甲基氨基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；78) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(methylamino)-1H-indazole-6- Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    79)4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-3-(2-羟基乙氧基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；79) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-3-(2-hydroxyethoxy)-1H-indazole -6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    80)4-(3-(氮杂环丁烷-1-基)-5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；80)4-(3-(azetidin-1-yl)-5-(2,6-dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H -Indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    81)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-甲氧基-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；81) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-methoxy-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    82)4-(3-氨基-5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；82) 4-(3-Amino-5-(2,6-dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazol-6-yl)-N -Ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    83)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-吗啉代-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；83) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-morpholino-1H-indazol-6-yl) -N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    84)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-((2-羟基乙基)(甲基)氨基)-1H-吲唑-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；84) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-((2-hydroxyethyl)(methyl)amino )-1H-indazol-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-methyl Amide
    85)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吡唑o[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；85) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole o[4,3-b]pyridine-6 -Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    86)4-(5-(2,6-二甲基苯氧基)-2-(2-羟基-2-甲基丙基)-2H-吡唑o[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；86) 4-(5-(2,6-Dimethylphenoxy)-2-(2-hydroxy-2-methylpropyl)-2H-pyrazole o[4,3-b]pyridine-6 -Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    87)4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吡唑并[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；87) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-pyrazolo[4,3-b]pyridine-6 -Yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    88)N-乙基-4-(5-(4-氟-2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吡唑并[4,3-b]吡啶-6-基)-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；88)N-ethyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazolo[ 4,3-b]pyridin-6-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    89)4-(3-环丙基-5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-1H-吡唑并[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；89) 4-(3-Cyclopropyl-5-(2,6-dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazolo[4,3 -b]pyridin-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    90)4-(3-环丙基-5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-1H-吡唑并[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；90) 4-(3-Cyclopropyl-5-(2,6-dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-1H-pyrazolo[4,3 -b]pyridin-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
    91)4-(5-(2,6-二甲基苯氧基)-1-(2-羟基-2-甲基丙基)-3-(吡啶-4-基)-1H-吡唑并[4,3-b]吡啶-6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺；91) 4-(5-(2,6-Dimethylphenoxy)-1-(2-hydroxy-2-methylpropyl)-3-(pyridin-4-yl)-1H-pyrazolo [4,3-b]pyridin-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2 -Formamide;
    92)4-(5-(2,6-二甲基苯氧基)-1-(2-氟-2-甲基丙基)-3-(吡啶-4-基)-1H-吡唑并[4,3-b]吡啶 -6-基)-N-乙基-6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺。92) 4-(5-(2,6-Dimethylphenoxy)-1-(2-fluoro-2-methylpropyl)-3-(pyridin-4-yl)-1H-pyrazolo [4,3-b]pyridin-6-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2 -Formamide.
  35. 一种药物组合物，其特征在于，包含治疗有效量的权利要求1-32中任一项所述的化合物和药学上可接受的辅料。A pharmaceutical composition characterized by comprising a therapeutically effective amount of the compound according to any one of claims 1-32 and pharmaceutically acceptable excipients.
  36. 权利要求35所述的药物组合物，其特征在于，所述化合物与所述辅料的比重在约0.001至约10的范围内。The pharmaceutical composition of claim 35, wherein the specific gravity of the compound and the excipient is in the range of about 0.001 to about 10.
  37. 权利要求35或36所述的药物组合物在制备药物中的应用。The use of the pharmaceutical composition according to claim 35 or 36 in the preparation of medicines.
  38. 根据权利要求37所述的应用，其特征在于，所述药物组合物用于治疗或预防癌症、自身免疫疾病、炎性疾病、神经变性疾病、心脑血管疾病、肾病症和/或病毒感染。The application according to claim 37, wherein the pharmaceutical composition is used for the treatment or prevention of cancer, autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, renal diseases and/or viral infections.
  39. 根据权利要求38所述的应用，其特征在于，所述的癌症选自淋巴瘤、多发性骨髓瘤、白血病、骨髓纤维化、真性红细胞增多症、原发性血小板增多症和/或实体瘤。The use according to claim 38, wherein the cancer is selected from lymphoma, multiple myeloma, leukemia, myelofibrosis, polycythemia vera, essential thrombocythemia and/or solid tumors.
  40. 根据权利要求38所述的应用，其特征在于，所述的癌症选自伯基特淋巴瘤、弥漫性大B-细胞淋巴瘤、霍奇金氏淋巴瘤、滤泡性淋巴瘤、骨髓增生异常综合征/骨髓增殖性肿瘤、多发性骨髓瘤、真性红细胞增多症继发性骨髓纤维化、原发性血小板增多症继发性骨髓纤维化、慢性淋巴细胞性白血病、急性髓细胞性白血病、急性淋巴细胞性白血病、慢性髓细胞性白血病、B急性淋巴细胞白血病、原发性浆细胞白血病、大细胞神经内分泌癌、结肠癌、直肠癌、套细胞淋巴瘤、乳腺癌、前列腺癌、胶质母细胞瘤、鳞状细胞食管癌、脂肪肉瘤、黑色素瘤、胰腺癌、脑癌或肺癌。The use according to claim 38, wherein the cancer is selected from Burkitt’s lymphoma, diffuse large B-cell lymphoma, Hodgkin’s lymphoma, follicular lymphoma, and myelodysplastic Syndrome/myeloproliferative tumor, multiple myeloma, polycythemia vera secondary myelofibrosis, primary thrombocythemia secondary myelofibrosis, chronic lymphocytic leukemia, acute myeloid leukemia, acute Lymphocytic leukemia, chronic myeloid leukemia, B-acute lymphocytic leukemia, primary plasma cell leukemia, large cell neuroendocrine carcinoma, colon cancer, rectal cancer, mantle cell lymphoma, breast cancer, prostate cancer, glioblastoma Cell tumor, squamous cell esophageal cancer, liposarcoma, melanoma, pancreatic cancer, brain cancer, or lung cancer.
  41. 根据权利要求37所述的应用，其特征在于，所述药物组合物用作BET抑制剂。The use according to claim 37, wherein the pharmaceutical composition is used as a BET inhibitor.
  42. 根据权利要求41所述的应用，其特征在于，所述药物组合物用作BRD4抑制剂。The use according to claim 41, wherein the pharmaceutical composition is used as a BRD4 inhibitor.
  43. 一种治疗由BET介导的疾病的方法，其特征在于，向治疗对象施用包括权利要求1-31中任一项所述的化合物和/或权利要求35或36所述的药物组合物。A method for treating diseases mediated by BET, characterized in that the compound comprising any one of claims 1-31 and/or the pharmaceutical composition according to claim 35 or 36 is administered to a subject to be treated.
  44. 根据权利要求43所述的方法，其特征在于，所述的BET包括BRD4。The method of claim 43, wherein the BET includes BRD4.
  45. 根据权利要求43或44所述的方法，其特征在于，所述BET介导的疾病是癌症。The method of claim 43 or 44, wherein the BET-mediated disease is cancer.
  46. 根据权利要求45所述的方法，其特征在于，所述的癌症选自伯基特淋巴瘤、弥漫性大B-细胞淋巴瘤、霍奇金氏淋巴瘤、滤泡性淋巴瘤、骨髓增生异常综合征/骨髓增殖性肿瘤、多发性骨髓瘤、真性红细胞增多症继发性骨髓纤维化、原发性血小板增多症继发性骨髓纤维化、慢性淋巴细胞性白血病、急性髓细胞性白血病、急性淋巴细胞性白血病、慢性髓细胞性白血病、B急性淋巴细胞白血病、原发性浆细胞白血病、大细胞神经内分泌癌、结肠癌、直肠癌、套细胞淋巴瘤、乳腺癌、前列腺癌、胶质母细胞瘤、鳞状细胞食管癌、脂肪肉瘤、黑色素瘤、胰腺癌、脑癌或肺癌。The method of claim 45, wherein the cancer is selected from Burkitt’s lymphoma, diffuse large B-cell lymphoma, Hodgkin’s lymphoma, follicular lymphoma, and myelodysplastic Syndrome/myeloproliferative tumor, multiple myeloma, polycythemia vera secondary myelofibrosis, primary thrombocythemia secondary myelofibrosis, chronic lymphocytic leukemia, acute myeloid leukemia, acute Lymphocytic leukemia, chronic myeloid leukemia, B-acute lymphocytic leukemia, primary plasma cell leukemia, large cell neuroendocrine carcinoma, colon cancer, rectal cancer, mantle cell lymphoma, breast cancer, prostate cancer, glioblastoma Cell tumor, squamous cell esophageal cancer, liposarcoma, melanoma, pancreatic cancer, brain cancer, or lung cancer.
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