WO2019029554A1 - Dérivé sulfonamide, sa méthode de préparation et son application en médecine - Google Patents

Dérivé sulfonamide, sa méthode de préparation et son application en médecine Download PDF

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WO2019029554A1
WO2019029554A1 PCT/CN2018/099333 CN2018099333W WO2019029554A1 WO 2019029554 A1 WO2019029554 A1 WO 2019029554A1 CN 2018099333 W CN2018099333 W CN 2018099333W WO 2019029554 A1 WO2019029554 A1 WO 2019029554A1
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group
compound
formula
cancer
heteroaryl
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吕贺军
赵雯雯
王成喜
陈磊
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浙江海正药业股份有限公司
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • 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
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Definitions

  • the invention belongs to the field of medicine, and in particular relates to a novel sulfonamide derivative, a preparation method thereof and a pharmaceutical composition containing the same, and their use as a therapeutic agent, in particular as a bromodomain protein inhibitor.
  • the bromodomain is a protein domain that recognizes N-acetylated lysine residues.
  • the BET family of bromodomain-containing proteins includes four members (BRD2, BRD3, BRD4, and BRDt). Each member of the BET family uses two bromodomains to recognize, primarily (but not exclusively) the discovery of N-acetylated lysine residues at the amino-terminal tail of histone proteins.
  • Gene expression is regulated by recruiting transcription factors to specific genomic locations within the chromatin. For example, histone-linked BRD4 recruits the transcription factor P-TEFb to a promoter, resulting in the expression of a subset of genes involved in cell cycle progression (Yang et al., Mol. Cell. Biol.
  • BRD2 and BRD3 also function as transcriptional regulators of growth-promoting genes. Recent studies have demonstrated the targeting of BET bromodomains to treat a variety of cancers (Zuber et al., Nature 478: 524-528 (2011); Mertz et al., Proc. Natl. Acad. Sci. 108: 16669-16674 (2011); Delmore et al., Cell 146: 1-14, (2011); Dawson et al., Nature 478: 529-533 (2011)), atherosclerosis, inflammation (Huang et al. , Mol. Cell. Biol. 29: 1375-1387 (2009)) and HIV infection.
  • BRD4 protein-mediated epigenetic abnormalities are closely related to overexpression of oncogenes and are closely related to the growth and proliferation of cancer cells.
  • BRD4 is a member of the Bromo and extra C-terminal domain (BET) family of proteins, which has caused great potential for major pharmaceutical companies and research institutions due to its potential value in anti-tumor. attention.
  • BET Bromo and extra C-terminal domain
  • BRD4 also plays an important role in the transcriptional regulation of viral genes and is associated with the pathogenesis of viral tumors.
  • BRD4 protein is a very promising new epigenetic target, and small molecule inhibitors acting on the bromodomain of BRD4 protein have broad application prospects in tumor research, and it is possible to develop a new type of anti-tumor. drug.
  • WO2011054846 discloses the compound of Example 1.
  • the drug currently in clinical stage III is Apabetalone, and the drugs in clinical phase II include GSK-525762A, INCB-54329 and BMS-986158.
  • the drugs in clinical stage I include mivebresib and so on.
  • these studies on anti-tumor are far from enough.
  • the compounds disclosed in the prior art and the test drugs are still unsatisfactory in terms of effectiveness, safety or applicability. It is still necessary to study and develop new bromo structures. Domain protein inhibitors to meet the growing medical and health needs of people.
  • the present inventors have unexpectedly discovered through extensive experimental studies that the compound of the following formula (I) can be effectively used as a bromodomain protein inhibitor for treating or preventing a disease associated with a bromodomain protein.
  • the present invention provides a sulfonamide compound of the formula (I):
  • R 1 is selected from an aryl or heteroaryl group, preferably a phenyl group, wherein the aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, and a ring.
  • R 2 and R 3 are each independently selected from a hydrogen atom, an alkyl group, a cyano group, a halogen, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -NR 6 R 7 , -C(O)NR 6 R 7 , —OR 8 , —C(O)R 8 , —C(O)OR 8 or —NR 6 C(O)R 7 , wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group or The heteroaryl group is optionally further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C ( O) NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8
  • R 4 is selected from a hydrogen atom or an alkyl group; preferably a methyl group or an ethyl group;
  • R 5 is selected from a hydrogen atom, an alkoxy group or a halogen; preferably a hydrogen atom;
  • R 6 , R 7 and R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aromatic group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 9 Substituted by a substituent of R 10 , -C(O)NR 9 R 10 , -C(O)R 11 , -C(O)OR 11 or -NR 9 C(O)R 10 ;
  • R 6 and R 7 together with the N atom to which they are attached form a 4 to 8 membered heterocyclic group, wherein the 4 to 8 membered heterocyclic ring contains one or more N, O, S(O) m atoms, and 4
  • one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, 0
  • R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aromatic group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxy Substituted by a substituent of the acid ester group;
  • n 0, 1, or 2.
  • R 2 is selected from -OR 8 and R 3 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is selected from -OR 8 ;
  • R 8 is selected from an alkyl group, and more preferably a methyl group.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention provides a process for the preparation of a compound of formula (I), which process comprises:
  • PG is a protecting group for N, preferably a substituted benzenesulfonyl group, more preferably p-toluenesulfonyl;
  • R 4 is selected from an alkyl group
  • R 1 to R 3 and R 5 are as defined in the formula (I).
  • the present invention also provides a compound of the formula (Id), including stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
  • PG is a protecting group for N, preferably a substituted benzenesulfonyl group, more preferably p-toluenesulfonyl;
  • R 1 to R 5 is as described in the formula (I).
  • Typical compounds of formula (Id) include, but are not limited to:
  • stereoisomers include stereoisomers, tautomers or pharmaceutically acceptable salts thereof.
  • the present invention provides a process for the preparation of a compound of formula (Id), which process comprises:
  • a compound of the formula (Ib) is obtained by reducing a nitro group of the compound of the formula (Ia); and a compound of the formula (Ib) is reacted with a compound of the formula (Ic) in the presence of a palladium catalyst to obtain a compound of the formula (Id);
  • R a is selected from a boronic acid group or a boronic acid ester group; and the boronic acid ester group is preferably:
  • PG is a protecting group for N, preferably a substituted benzenesulfonyl group, more preferably p-toluenesulfonyl;
  • X is selected from halogen, preferably chlorine or bromine
  • R 1 to R 5 are as defined in formula (I);
  • the basic condition is provided by an organic base or an inorganic base, preferably from diisopropylethylamine, diisopropylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4-dimethylaminopyridine, more preferably diisopropylamine and triethylamine;
  • the inorganic base is preferably selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, more preferably sodium hydroxide;
  • the palladium catalyst is 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of formula (I), including stereoisomers, tautomers or pharmaceutically acceptable salts thereof, And pharmaceutically acceptable carriers, excipients or combinations thereof.
  • the present invention also provides a method of inhibiting a bromodomain protein comprising the protein and a compound of formula (I), including stereoisomers, tautomers or pharmaceutically acceptable salts thereof Or a pharmaceutical composition thereof, wherein said bromodomain protein is preferably BRD2, BRD3 and BRD4, more preferably BRD4.
  • the present invention further provides a compound of the formula (I) (including stereoisomers, tautomers or pharmaceutically acceptable salts thereof) or a pharmaceutical composition thereof for use as a bromodomain protein for inhibition Use of a medicament for a medicament, wherein the bromodomain protein is preferably BRD2, BRD3 and BRD4, more preferably BRD4.
  • the invention further provides a compound of formula (I), including stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of bromine Use of a medicament for a domain protein-related disease, wherein the disease is preferably cancer or inflammation; wherein the inflammation is preferably rheumatoid arthritis, Crohn's disease, eczema, giant cell arteritis, hepatitis, Inflammatory bowel disease, osteoarthritis, pancreatitis, pneumonia, psoriasis, psoriatic arthritis, systemic lupus erythematosus, glomerulonephritis, lupus nephritis, membranous glomerulonephritis or myocarditis;
  • the inflammation is more preferably rheumatoid arthritis; wherein the cancer is preferably small cell lung cancer, non-small cell lung cancer, breast cancer, colorectal cancer, prostate cancer,
  • the present invention also provides a compound (including a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof) of the formula (I) or a pharmaceutical composition thereof for use in the treatment or prevention of diabetes Kidney disease, hypertensive nephropathy, HIV-related nephropathy, polycystic kidney disease, obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, fatty liver, type 2 diabetes, insulin resistance, diabetes Use in drugs for retinopathy or diabetic neuropathy.
  • a compound including a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof
  • alkyl as a group or part of a group is meant to include a straight-chain or branched with C 1 -C 20 aliphatic hydrocarbon group. It is preferably a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group, and particularly preferably a C 1 -C 4 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1, 1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait.
  • the alkyl group can be substituted or unsubstituted.
  • Alkenyl refers to an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like.
  • the alkenyl group can be optionally substituted or unsubstituted.
  • Alkynyl as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. Preference is given to C 2 -C 10 alkynyl groups, more preferably C 2 -C 6 alkynyl groups, most preferably C 2 -C 4 alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. An alkynyl group can be substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially saturated monocyclic, fused, bridged or spiro carbon ring. It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • “Spirocycloalkyl” means a 5- to 18-membered polycyclic group having two or more cyclic structures and sharing a carbon atom (called a spiro atom) with each other, and the ring may contain 1 One or more double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiro, a spiro- or a spirocycloalkyl group, preferably a mono- and bi-spirocycloalkyl group, preferably 4 yuan/5 yuan, 4, depending on the number of common spiro atoms between the rings. Yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan.
  • spirocycloalkyl include, but are not limited to, spiro[4.5]decyl, spiro[4.4]decyl, spiro[3.5]decyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” refers to a 5 to 18 membered all carbon polycyclic group having two or more cyclic structures that share a pair of carbon atoms with each other, wherein one or more of the rings may contain one or more A double bond, but none of the rings have a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members.
  • bicyclic ring a tricyclic ring, a pyridone or a polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
  • fused cycloalkyl include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetradecafluorophenanyl.
  • “Bridge cycloalkyl” refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share two non-directly bonded carbon atoms, wherein one or more rings may contain One or more double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • a bicyclic ring a tricyclic ring, a pyridone or a polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-di Ring [3.3.1] fluorenyl, bicyclo [2.2.2] octyl, (1r, 5r)-bicyclo[3.3.2] fluorenyl.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group can be optionally substituted or unsubstituted.
  • Heterocyclyl “heterocyclic” or “heterocyclic” are used interchangeably herein to refer to a non-aromatic heterocyclic group wherein one or more of the ring-forming atoms are heteroatoms such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, fused, bridged, and spiro rings. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered double- or tricyclic ring which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetane, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine , 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl.
  • the heterocyclic group may be substituted or unsubstituted.
  • “Spiroheterocyclyl” means a 5- to 18-membered polycyclic group having two or more cyclic structures and sharing one atom between the single rings, and having one or more double bonds in the ring. , but none of the rings have a fully conjugated ⁇ -electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is selected from 0, 1 or 2) heteroatoms, the remainder The ring atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of common spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • spiroheterocyclyl include, but are not limited to, 1,7-dioxaspiro[4.5]fluorenyl, 2-oxa-7-azaspiro[4.4]decyl, 7-oxo Heterospiro[3.5]decyl and 5-oxaspiro[2.4]heptyl.
  • “Fused heterocyclic group” refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, wherein one or more of the rings may contain one or more double bonds, but none of the rings have A fully conjugated ⁇ -electron aromatic system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is selected from 0, 1 or 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bicyclic ring a tricyclic ring, a pyridone or a polycyclic fused heterocyclic group, preferably a bicyclic ring or a tricyclic ring, and more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindenyl, 3-azabicyclo[3.1. 0] hexyl, octahydrobenzo[b][1,4]dioxine.
  • “Bridge heterocyclyl” refers to a polycyclic group of 5 to 18 members, preferably 5 to 14 members, containing two or more cyclic structures and sharing two atoms which are not directly bonded to each other, one or more of which a ring may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is selected from 0, 1 or 2) of a hetero atom, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bicyclic ring a tricyclic ring, a pyridone or a polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring.
  • fused heterocyclic groups include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-aza-di Ring [3.3.2] sulfhydryl.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group.
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • Aryl means a carbocyclic aromatic system containing one or two rings wherein the rings may be joined together in a fused manner.
  • aryl includes aryl groups such as phenyl, naphthyl, tetrahydronaphthyl.
  • the aryl group is a C 6 -C 10 aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • the aryl group can be substituted or unsubstituted.
  • the "aryl” may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the parent structure is attached to an aryl ring, non-limiting examples include, but are not limited to:
  • Heteroaryl means an aromatic 5 to 6 membered monocyclic or 9 to 10 membered bicyclic ring which may contain from 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo Dioxolyl, benzimidazolyl, fluorenyl, isodecyl, 1,3-dioxo-isoindenyl, quinolyl, ox
  • Heteroaryl groups can be substituted or unsubstituted.
  • the heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include, but are not limited to:
  • Alkoxy means a group of (alkyl-O-). Among them, the alkyl group is defined in the relevant definition herein.
  • the C 1 -C 6 alkoxy group is preferred, and a C 1 -C 4 alkoxy group is particularly preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • Hydrophilicity refers to an -OH group.
  • Halogen means fluoro, chloro, bromo and iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Benzyl refers to -CH 2 - phenyl.
  • Carboxy refers to -C(O)OH.
  • Carboxylic acid ester group means -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • Ts refers to p-toluenesulfonyl.
  • DMSO dimethyl sulfoxide
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are replaced by a corresponding number of substituents independently of one another. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond such as an ethylenic bond.
  • substituted or “substituted”, unless otherwise indicated, means that the group may be substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy.
  • “Pharmaceutically acceptable salt” refers to certain salts of the above compounds which retain their original biological activity and are suitable for pharmaceutical use.
  • the pharmaceutically acceptable salt of the compound of formula (I) may be a metal salt, an ammonium salt formed with a suitable acid.
  • the metal salt is preferably an alkali metal or alkaline earth metal salt, and suitable acids include inorganic acids and organic acids.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, including a physiologically pharmaceutically acceptable salt or prodrug thereof, and optionally other pharmaceutically active ingredients, which may comprise other optional ingredients
  • the components are, for example, pharmaceutically acceptable carriers and/or excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the preparation method of the compound of the formula (I) of the invention comprises the following steps:
  • R a is selected from a boronic acid group or a boronic acid ester group; and the boronic acid ester group is preferably:
  • PG is a protecting group for N, preferably a substituted benzenesulfonyl group, more preferably p-toluenesulfonyl;
  • X is selected from halogen, preferably chlorine or bromine
  • the palladium catalyst is preferably 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride;
  • R 4 is selected from an alkyl group
  • R 1 to R 3 and R 5 are as defined in the formula (I).
  • the basic condition is provided by an organic base or an inorganic base
  • the organic base is preferably selected from the group consisting of diisopropylethylamine, diisopropylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4- Dimethylaminopyridine is more preferably diisopropylamine and triethylamine
  • the inorganic base is preferably selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, more preferably sodium hydroxide.
  • Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • CD 3 OD Deuterated methanol.
  • the argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 L.
  • the solution in the reaction means an aqueous solution unless otherwise specified.
  • the compound is purified by silica gel column chromatography and thin layer chromatography, wherein the eluent system is selected from the group consisting of: A: petroleum ether and ethyl acetate systems; B: dichloromethane and methanol systems; C: dichloromethane: acetic acid Ethyl ester; wherein the volume ratio of the solvent varies depending on the polarity of the compound, and may also be adjusted by adding a small amount of an acidic or alkaline agent such as acetic acid or triethylamine.
  • A petroleum ether and ethyl acetate systems
  • B dichloromethane and methanol systems
  • C dichloromethane: acetic acid Ethyl ester
  • the volume ratio of the solvent varies depending on the polarity of the compound, and may also be adjusted by adding a small amount of an acidic or alkaline agent such as acetic acid or triethylamine.
  • the reaction liquid was cooled to room temperature, 100 mL of water and 50 mL of ethyl acetate were added, and the layers were separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (30 mL ⁇ 3), and the organic phase was combined with saturated aqueous sodium chloride (50 mL ⁇ 1) Washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-(2,4-difluorophenoxy)-2-methoxy-1-nitrobenzene 1c (1.4 g, white solid) Rate: 85.4%.
  • 2-methoxy-4-nitroaniline 2a (5.0 g, 29.7 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled to -78 ° C, and N-bromosuccinimide (5.29 g, 29.7 mmol) was added portionwise. The mixture was stirred at -78 ° C for 0.5 hours and then at room temperature for 2 hours. The organic layer was washed with saturated aqueous sodium chloride (20 mL ⁇ 1), dried over anhydrous sodium sulfate. 2-Bromo-6-methoxy-4-nitroaniline 2b (7.3 g, brown solid), yield: 100%.
  • 2-Bromo-6-methoxy-4-nitroaniline 2b (2.48 g, 10 mmol) was dissolved in 15 mL of concentrated hydrochloric acid and stirred at 0 ° C for 0.5 hour.
  • Sodium nitrate (1.38 g, 20 mmol) was dissolved in 10 mL of water, and added dropwise to the above concentrated hydrochloric acid solution at 0 ° C. After the dropwise addition was completed, the mixture was stirred at room temperature for 1 hour to obtain an A solution.
  • the cuprous chloride was dissolved in 15 mL of concentrated hydrochloric acid, and the temperature was raised to 60 ° C, and the solution A was added (added in 0.5 hours).
  • reaction solution was heated to 80 ° C and the reaction was continued for 0.5 hours.
  • the reaction mixture was warmed to room temperature, EtOAc (3 mL, EtOAc)
  • EtOAc 3 mL, EtOAc
  • the residue was purified by silica gel column chromatography (eluent: : 94%.
  • Test Example 1 Determination of BRD4 protein activity by the compound of the present invention
  • Exemplary compounds of the invention are tested for their biological activity against the BRD4 protein by the following method.
  • This test method uses Cisbio Assays EPIGENEOUS TM BROMODOMAIN ASSAY company under in vitro conditions, test compounds on recombinant human interaction effect on the FRET (fluorescence resonance energy transfer) to express protein and BRD4 between acetylated histone peptide substrate The biological activity of the compound against BRD4.
  • the GST-tagged recombinant human BRD4(1/2) protein was derived from BPS Bioscience, and the acetylated histone polypeptide substrate [Lys(5,8,12,16)Ac]H4(1-21)-biotin peptide was purchased from AnaSpec.
  • the compounds of the invention were first dissolved in DMSO and subsequently diluted to the desired concentration for testing (final concentration range 10 ⁇ M - 0.1 nM) in the buffer provided in the kit. 2 ⁇ L of the compound was added to a 384-well microtiter plate, followed by the addition of 4 uL of GST-labeled recombinant human BRD4 (1/2) protein and 4 ⁇ L of acetylated histone polypeptide substrate diluted in buffer, and finally added to the well.
  • the inhibition rate of the compound at each concentration point was calculated by comparing with the fluorescence intensity values of the control group, and then the nonlinear regression analysis of the compound concentration log-inhibition rate in GraphPad Prism 5 software was performed to obtain the compound inhibiting BRD4 protein and acetylation.
  • Test Example 2 Inhibition of proliferation of prostate cancer cells (LNCaP) by the compound of the present invention
  • the cell-level activity of the exemplified compounds of the present invention is measured by an absorbance method by CCK-8 (Dojindo, Toray Chemical Technology) to inhibit the proliferation of the compound.
  • the prostate cancer cell LNCaP purchased from the Shanghai Institute of Biological Sciences, Chinese Academy of Sciences
  • the final concentration range is from 30 ⁇ M to 0.1 nM.
  • the cells were cultured for 72 hours at 37 ° C under 5% CO 2 .
  • CCK-8 reagent purchased from Dongren Chemical Technology (Shanghai) Co., Ltd., item number CK04
  • CK04 Dongren Chemical Technology
  • the absorbance values at 450 nM for each well were taken.
  • the inhibition rate of the compound at each concentration point was calculated by comparison with the absorbance values of the control group, and then the nonlinear regression analysis of the compound concentration log-inhibition rate in GraphPad Prism 5 software was performed to obtain the IC 50 value of the compound inhibiting cell proliferation. .
  • the exemplified compounds of the present invention have a good inhibitory effect on the proliferation of prostate cancer cells LNCaP, which is significantly better than mivebresib.
  • SD rats were used as test animals, and the mice were administered with mivebresib and the compound of Example 2 by LC/MS/MS method.
  • the drug concentration in plasma was measured at different times, and the compound of the present invention was tested in rats. Generation dynamics.
  • 0.15 mL of laryngeal vein was collected before and 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, and placed in heparinized tubes at 5500 rpm. Centrifuge for 10 minutes, store at -20 ° C, and eat 4 hours after administration. The content of the test compound in the plasma of SD male rats after intragastric administration of different compounds was determined by LC-MS/MS.
  • the compound of Example 2 of the present invention has a higher blood concentration and a lower area under the curve, a longer half-life, a shorter residence time, and an obvious pharmacokinetic advantage.

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Abstract

La présente invention concerne un nouveau dérivé sulfonamide, un procédé pour sa préparation et son utilisation en médicine. En particulier, la présente invention concerne un dérivé sulfonamide représenté par la formule (I), un procédé de préparation et un sel pharmaceutiquement acceptable de celui-ci, et une utilisation de celui-ci en tant qu'agent thérapeutique, en particulier en tant qu'inhibiteur de protéine de bromodomaine. La définition de chaque substituant dans la formule générale (I) est la même que celle donnée dans la description.
PCT/CN2018/099333 2017-08-10 2018-08-08 Dérivé sulfonamide, sa méthode de préparation et son application en médecine WO2019029554A1 (fr)

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CN105473586A (zh) * 2013-06-28 2016-04-06 艾伯维公司 晶体溴结构域抑制剂
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CN104136435A (zh) * 2011-12-30 2014-11-05 艾伯维公司 溴结构域抑制剂
CN105473586A (zh) * 2013-06-28 2016-04-06 艾伯维公司 晶体溴结构域抑制剂
CN105518007A (zh) * 2013-06-28 2016-04-20 艾伯维公司 布罗莫结构域抑制剂
WO2017037567A1 (fr) * 2015-09-03 2017-03-09 Pfizer Inc. Régulateurs de la frataxine

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