WO2021233371A1 - Composé fonctionnant comme inhibiteur de protéine de bromodomaine, et composition - Google Patents

Composé fonctionnant comme inhibiteur de protéine de bromodomaine, et 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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English (en)
Chinese (zh)
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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/zh
Publication of WO2021233371A1 publication Critical patent/WO2021233371A1/fr

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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.

Abstract

La présente invention concerne un inhibiteur de bromodomaine. La présente invention concerne également une composition et une préparation contenant un tel composé, un procédé d'utilisation d'un tel composé, et un procédé de préparation d'un tel composé.
PCT/CN2021/094838 2020-05-21 2021-05-20 Composé fonctionnant comme inhibiteur de protéine de bromodomaine, et composition WO2021233371A1 (fr)

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WO2022268075A1 (fr) * 2021-06-21 2022-12-29 贝达药业股份有限公司 Application d'un composé dans la préparation d'un médicament pour le traitement de la myélofibrose et de symptômes/signes associés, et utilisation du composé

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WO2015081203A1 (fr) * 2013-11-26 2015-06-04 Incyte Corporation Hétérocycles bicycliques servant d'inhibiteurs des protéines bet
WO2015081189A1 (fr) * 2013-11-26 2015-06-04 Incyte Corporation Hétérocycles bicycliques servant d'inhibiteurs des protéines bet
CN107207493A (zh) * 2014-11-10 2017-09-26 基因泰克公司 作为布罗莫结构域抑制剂的经取代的吡咯并吡啶
CN108314680A (zh) * 2017-01-16 2018-07-24 凯惠科技发展(上海)有限公司 一种含芳环化合物、其制备方法、药物组合物及应用
WO2019120234A2 (fr) * 2017-12-20 2019-06-27 贝达药业股份有限公司 Composé fonctionnant comme inhibiteur de protéine bromodomaine, et composition

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CN110577526B (zh) * 2018-06-07 2023-10-27 上海翰森生物医药科技有限公司 溴域结构蛋白抑制剂的盐及其制备方法和应用

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WO2015081203A1 (fr) * 2013-11-26 2015-06-04 Incyte Corporation Hétérocycles bicycliques servant d'inhibiteurs des protéines bet
WO2015081189A1 (fr) * 2013-11-26 2015-06-04 Incyte Corporation Hétérocycles bicycliques servant d'inhibiteurs des protéines bet
CN107207493A (zh) * 2014-11-10 2017-09-26 基因泰克公司 作为布罗莫结构域抑制剂的经取代的吡咯并吡啶
CN108314680A (zh) * 2017-01-16 2018-07-24 凯惠科技发展(上海)有限公司 一种含芳环化合物、其制备方法、药物组合物及应用
WO2019120234A2 (fr) * 2017-12-20 2019-06-27 贝达药业股份有限公司 Composé fonctionnant comme inhibiteur de protéine bromodomaine, et composition

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022268075A1 (fr) * 2021-06-21 2022-12-29 贝达药业股份有限公司 Application d'un composé dans la préparation d'un médicament pour le traitement de la myélofibrose et de symptômes/signes associés, et utilisation du composé

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