WO2019196720A1 - Inhibiteur d'arginine méthyltransférase, composition pharmaceutique de celui-ci et son utilisation - Google Patents

Inhibiteur d'arginine méthyltransférase, composition pharmaceutique de celui-ci et son utilisation Download PDF

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WO2019196720A1
WO2019196720A1 PCT/CN2019/081252 CN2019081252W WO2019196720A1 WO 2019196720 A1 WO2019196720 A1 WO 2019196720A1 CN 2019081252 W CN2019081252 W CN 2019081252W WO 2019196720 A1 WO2019196720 A1 WO 2019196720A1
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substituted
unsubstituted
methyl
group
alkyl
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Chinese (zh)
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熊兵
耿美玉
郭祖浩
黄洵
沈竞康
丁健
杨红
张竹青
陈丹琦
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中国科学院上海药物研究所
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
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    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to the technical field of chemical medicine, in particular to a kind of arginine methyltransferase inhibitor, a pharmaceutical composition thereof and use thereof.
  • Epigenetics causes heritable changes in gene expression without altering the nucleotide sequence of the gene. It plays a very important role in many physiological and biochemical processes such as protein expression, cell proliferation, and cell cycle, and is closely related to the occurrence and development of various diseases. Post-translational modifications of histones are an important part of epigenetics.
  • Arginine methylation is a common histone post-translational modification that plays an important role in signal transduction, DNA repair, transcription, protein subcellular localization and RNA processing.
  • Protein arginine methyltransferase Family are a class of enzymes with methyltransferase activity. According to the different ways of catalyzing the methylation of arginine, the PRMTs family is mainly divided into three types.
  • Type I (PRMT1, 2, 3, 4, 6, 8) catalyzes the formation of arginine monomethyl and asymmetric dimethylation
  • type II PRMTs catalyze the formation of monomethyl and symmetrical arginine
  • PRMT5 and PRMT9 type III PRMTs with PRMT7 can only catalyze the formation of monomethylation.
  • PRMT4 also known as coactivator-associated arginine methyltransferase 1, CARM1 asymmetrically dimethylated arginine residues of histones H3R2, H3R17, and H3R26, and can also methylate many non-groups. Protein substrates, such as CBP/P300, PABP1, HuR, CA150, SAP49, and the like. PRMT4 is also a coactivator of various tumor-associated proteins, such as p53, NF- ⁇ B, ⁇ -catenin, and ER ⁇ . PRMT4 has been reported to be highly expressed in breast cancer, colon cancer, bladder cancer, lung cancer, and is closely related to the occurrence of immune response, inflammation, and diabetes. PRMT4 is therefore considered to be a very potential therapeutic target.
  • the invention provides a compound of formula (I), a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex, hydrate or solvate thereof.
  • R 1 is hydrogen, C 1 -C 3 alkyl; preferably hydrogen or methyl;
  • R 2 is hydrogen, C 1 -C 3 alkyl; preferably hydrogen or methyl;
  • R 1 and R 2 are hydrogen;
  • R 3 is hydrogen, C 1 -C 3 alkyl; preferably hydrogen or methyl;
  • R 4 is hydrogen, halogen, C 1 -C 3 alkyl; preferably hydrogen, fluorine, chlorine or methyl;
  • R 5 is hydrogen, halogen, C 1 -C 3 alkyl; preferably hydrogen, fluorine, chlorine or methyl;
  • X is N or CR 6 ;
  • R 6 is hydrogen, halogen, substituted or unsubstituted C 1 -C 3 alkyl substituted by one or more halogen, cyano or hydroxy; preferably hydrogen, chloro, fluoro, by one or more halogens, cyano or a substituted or unsubstituted C 1 -C 3 alkyl group of a hydroxy group; more preferably hydrogen, chlorine, fluorine, a substituted or unsubstituted methyl group substituted by one or more halogens, a cyano group or a hydroxy group or one or more halogens a substituted or unsubstituted ethyl group of a cyano group or a hydroxy group;
  • Y is N or CH
  • L 1 is -NH, -N(C 1 -C 3 alkyl)-, -O- or absent;
  • L 2 is -NH, -N(C 1 -C 3 alkyl)-, -O- or absent;
  • R 7 is selected from substituted or unsubstituted saturated 3-10 membered cycloalkyl, substituted or unsubstituted saturated 3-10 membered heterocyclic group, substituted or unsubstituted C 6 -C 10 aryl group, substituted or unsubstituted a 5-12 membered heteroaryl, substituted or unsubstituted oxazabicyclo[3.2.1]octyl group, preferably selected from substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutane, Substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexane, substituted or unsubstituted cycloheptyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted nitrogen heterocycle Pentyl, substituted or unsubstituted azetidiny
  • R 8 is selected from H, halogen, substituted or unsubstituted C 6 -C 10 aryl or substituted or unsubstituted 5-12 membered heteroaryl, preferably selected from H, halogen, substituted or unsubstituted phenyl, substituted Or unsubstituted C 1 -C 6 alkylphenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted isoxazolyl, substituted Or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzo Thienyl, substituted
  • R 1 is methyl or H; and R 2 is H.
  • R 3 is methyl or H; R 4 is H; and R 5 is H, fluoro, methyl or chloro.
  • X is CR 6 or N; R 6 is methyl.
  • Y is N or CH.
  • L 1 is -NH-, -NCH 3 -, -O- or is absent.
  • L 2 is -NH-, -O- or is absent.
  • R 7 is tetrahydropyranyl, methoxyphenylpiperazinyl, phenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, fluorophenyl, chlorophenyl, Difluorophenyl, trifluoromethylpyridyl, dimethylisoxazolyl or morphinolinyl, methanesulfonyl piperazinyl, methanesulfonylpiperidinyl, thiomorpholinyl, methylpiperazinyl, Acetyl piperazinyl, cyclopropylpiperazinyl, dihydropyrrolopyridyl, oxazabicyclo[3.2.1]octyl; preferably tetrahydropyranyl, 1-(2-methoxy Phenyl) piperazinyl, phenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2-fluorine
  • R 8 is H, chloro, phenyl, benzyl, phenylmethylsulfonyl, pyridyl, trimethylpyrazolyl, dimethylpyrazolyl, methylbromopyrazolyl, Pyrimidinyl, methylpyrazolyl, fluorobenzyl, trifluoromethylphenyl, trifluoromethoxyphenyl, fluorophenyl, chlorophenyl, difluorophenyl, trifluoromethylpyridyl, aza Indenyl, fluorenyl, methoxyindenyl, difluoromethylbenzimidazolyl, aminopyrimidinyl, quinolyl, isoquinolyl, morphinolinyl, benzothienyl, phenol, two Methyl isoxazolyl, methanesulfonyl piperazinyl, methanesulfonylpiperidinyl, thiomorpholinyl,
  • the compound of formula (I) is selected from the compounds represented by the following formula:
  • R 1 , R 3 , R 4 , R 5 , L 1 , L 2 , R 7 and R 8 have the same meanings as defined in claim 1.
  • the compound of formula (I) is selected from the group consisting of:
  • the compounds of the invention may contain one or more asymmetric centers and thus may occur as racemates and single enantiomers, mixtures of diastereomers and single diastereomers.
  • the scope of the invention includes all possible optical isomers and mixtures of diastereomers and pure or partially pure compounds.
  • the present invention includes free forms of the compounds of formula (I), as well as the pharmaceutically acceptable salts and stereoisomers thereof.
  • the solubility of the free form in certain physical properties, such as in polar solvents, is somewhat different from its respective salt form, but the salts for the purposes of the invention are pharmaceutically equivalent to their respective free forms.
  • C 1 -C 6 alkyl means a straight or branched saturated hydrocarbon group having from 1 to 6 carbon atoms in the chain, and includes, without limitation, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, and the like.
  • C 1 -C 6 alkoxy means a straight or branched alkyl-O- group having from 1 to 6 carbon atoms in the alkyl moiety, for example, methoxy, ethoxy, positive Propyloxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
  • C 1 -C 6 alkylsulfonyl means a straight or branched alkylsulfonyl group having from 1 to 6 carbon atoms in the alkyl moiety, for example, methylsulfonyl, ethylsulfonyl, N-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl or tert-butylsulfonyl.
  • C 1 -C 6 alkylsulfinyl means a straight or branched alkylsulfinyl group having from 1 to 6 carbon atoms in the alkyl moiety, for example, methylsulfinyl, ethyl Sulfonyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl or tert-butylsulfinyl.
  • 3-8 membered cycloalkyl means a group containing one or more saturated and/or partially saturated rings, all of which are ring carbon atoms, including from 3 to 8 carbon atoms; for example, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptenyl, cycloheptatrienyl, cyclooctyl, indanyl, tetrahydronaphthyl, benzocycloheptyl and the like.
  • 3-8 membered heterocyclyl means containing one or more saturated and/or partially saturated rings comprising from 3 to 8 ring atoms, wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) a hetero atom of m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon; for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl , thiomorpholinyl, homopiperazinyl.
  • Halogen means fluoro, chloro, bromo and iodo.
  • C 6 -C 12 aryl means an aromatic ring group containing 6 to 12 ring atoms but no hetero atom in the ring atom, preferably a 6-10 membered aryl group (ie, 6 to 10 carbon atoms) Aryl), such as phenyl, naphthyl.
  • the "5-12 membered heteroaryl group” means an aromatic ring group containing 5 to 12 ring atoms and having 1 to 4 hetero atoms in the ring atom as a ring member.
  • the hetero atom can be selected from nitrogen, oxygen or sulfur.
  • the heteroaryl group may be a monocyclic heteroaryl group having 5 to 7 ring atoms or a bicyclic heteroaryl group having 7 to 12 ring atoms. As long as one ring of the bicyclic heteroaryl group is a heteroaromatic ring, the other may be an aromatic ring or a non-aromatic ring, containing a hetero atom or a hetero atom.
  • the bicyclic heteroaryl group may be a concentric ring structure, a spiro ring structure, or a two heterocyclic ring directly connected.
  • heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, furyl, thienyl, isoxazolyl, indolyl, and the like.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the above formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, racemic One or more of a body, a prodrug, a co-crystal complex, a hydrate or a solvent compound as an active ingredient, and a pharmaceutically acceptable carrier.
  • terapéuticaally effective amount is meant that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.
  • “Pharmaceutically acceptable salt” refers to a conventional non-toxic salt of the present invention formed by the basic present invention and an inorganic or organic acid form.
  • Conventional non-toxic salts include inorganic acids such as, but not limited to, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; organic acids such as, but not limited to, acetic acid, propionic acid, succinic acid, lactic acid, malic acid Salt prepared from tartaric acid, maleic acid, salicylic acid, fumaric acid, methanesulfonic acid, oxalic acid, trifluoroacetic acid, ascorbic acid, toluenesulfonic acid and the like.
  • the acidic moiety such as a carboxyl group
  • a protonated or alkylated basic moiety such as a tetravalent nitrogen atom, carried internally. Therefore, it should be noted that the compounds of the invention are potential internal salts and zwitterions.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • the pharmaceutical composition further comprises other pharmaceutically acceptable therapeutic agents, in particular other anti-cancer drugs, anti-inflammatory drugs, anti-autoimmune drugs, anti-diabetic drugs or combinations thereof.
  • the therapeutic agent includes, but is not limited to, a drug antitumor drug acting on the chemical structure of DNA such as cisplatin, an antitumor drug affecting nucleic acid synthesis such as methotrexate (MTX), 5-fluorouracil (5FU), etc., affecting nucleic acid transcription
  • MTX methotrexate
  • 5FU 5-fluorouracil
  • Anti-tumor drugs such as doxorubicin, epirubicin, aclarithromycin, phosfomycin, etc.
  • antitumor drugs acting on tubulin synthesis such as paclitaxel, vinorelbine, etc.
  • aromatase inhibitors such as ammonia Mitt, lantron, letrozole, ruined, etc.
  • cell signaling pathway inhibitors such as epiderma
  • compositions of the present invention may be in liquid, semi-solid or solid form, formulated in a manner suitable for the route of administration employed.
  • composition of the present invention can be administered by the following modes of administration: oral, parenteral, peritoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, liposome and the like.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex, hydrate or solvent thereof Use of a compound for the preparation of a medicament for use in a PRMT4 inhibitor or in the manufacture of a medicament for the treatment of cancer, inflammatory diseases, autoimmune diseases or diabetes.
  • the cancer includes, without limitation, bladder cancer, breast cancer, prostate cancer, pancreatic cancer, liver cancer, colon cancer, rectal cancer, cervical cancer, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocyte, Myeloblasts, angiosarcoma, astrocytoma, myelomonocytes, and promyelocytes), acute T cell leukemia, chondrosarcoma, chronic lymphocytic leukemia, chronic myeloid (granulocyte) leukemia, large cells Lymphoma, fibrosarcoma, testicular germ cell carcinoma, glioma, lymphoma (Hodgkin or non-Hodgkin type), multiple myeloma, lymphoma, myeloma, neuroblastoma, non-small cells Lung cancer, small cell lung cancer.
  • bladder cancer breast cancer, prostate cancer, pancreatic cancer, liver cancer, colon cancer
  • cervical cancer acute leukemia, acute lymphocytic le
  • Non-limiting inflammatory diseases include pneumonia, sinusitis, encephalitis, meningitis, gastritis, enteritis, ulcerative colitis, idiopathic proctitis, conjunctivitis, otitis media, reflux esophagitis, nodular arteries inflammation.
  • Non-limiting autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, organ transplant rejection, and multiple sclerosis.
  • FIG. 1 is a graph showing the antitumor effect of Compound S20 in the pancreatic cancer ASPC1 nude mouse xenograft model in Test Example 2;
  • FIG. 1A is a graph of tumor volume versus time;
  • FIG. 1B is a graph comparing tumor weight at the end of the test.
  • Figure 1C is a graph of mouse body weight versus time.
  • 1 H NMR was recorded by a Varian Mercury-300 or Varian Mercury-400 NMR spectrometer with chemical shifts expressed in ⁇ (ppm); mass spectrometry by Finnigan/MAT-95 (EI) and Finnigan LCQ/DECA and Micromass Recorded by Ultra Q-TOF (ESI) mass spectrometer; 200-300 mesh silica gel of Qingdao Ocean Chemical Co., Ltd. was used for compound separation.
  • the compounds of the invention can be prepared using the reactions shown in the schemes below. Accordingly, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily have to correspond to the number used in the claims, and as is clear, it is shown that the monosubstituted linkages allow for multiple substituted compounds under the definition of formula (I) above.
  • the boronic acid pinacol ester intermediate can be synthesized by the following route:
  • the meta-bromobenzaldehyde and 2-(N-Boc-N-methylamino)ethylamine are subjected to reductive amination to prepare the intermediate (II), and the free secondary amine is protected with Boc to obtain an intermediate (III).
  • the intermediate (III) and the bis-pinacol borate are subjected to a Miyaura-Ishiyama-Hartwig Borylation to obtain the corresponding boronic acid pinacol ester intermediate (IV).
  • the preparation method of the compound represented by the general formula (I) of the present invention may be one of the following preparation methods:
  • the target product can be obtained by the following route one,
  • the intermediate (V) is prepared by a nucleophilic substitution reaction of a trichloropyrimidine or a triazine with a corresponding secondary or primary amine, and then the intermediate (V) and the intermediate (IV) are reacted to form a Suzuki reaction.
  • the target product can be obtained by the following route 2;
  • the target product can be obtained by the following route three;
  • the intermediate (XV) is obtained by Boc protection, and the intermediate (XV) is reacted with the bis-pinacol borate to form a boronic acid pinacol ester intermediate ( XVI), the boronic acid pinacol ester intermediate (XVI) reacts with the intermediate (V) to obtain the intermediate (XVII), and the intermediate (XVII) is reacted with the corresponding boric acid or boronic acid pinacol ester via Suzuki to obtain an intermediate
  • the intermediate (XVIII) is obtained by further removing the Boc protecting group, and the intermediate (XIX) and the protected amino aldehyde are subjected to reductive amination to obtain the intermediate (XX), followed by alkylation.
  • the compound of the formula (XXII) can be prepared by reacting the intermediate (XXI) and then removing the Boc protecting group.
  • 2,4,6-trichloro-5-methylpyrimidine (7.75 g, 39.3 mmol) was added to a round bottom flask, 100 mL of ethanol was dissolved, triethylamine (11 mL, 78.6 mmol) was added, and 4-amino was added under ice bath. Tetrahydropyran (3.77 g, 37.3 mmol), which was slowly warmed to room temperature overnight, was applied to the mixture and the mixture was applied to the title compound.
  • the product S2 was obtained by reacting the intermediate e with 3,5-dimethylisoxazole-4-boronic acid via Suzuki and then removing the protecting group.
  • the product S3 was obtained by reacting the intermediate e with 4-methanesulfonylbenzeneboronic acid via Suzuki and then removing the protecting group.
  • the product S4 was obtained from the reaction of the intermediate e with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester via Suzuki, followed by removal of the protecting group.
  • the product S5 was obtained by reacting the intermediate e with 5-boric acid pyrimidine via Suzuki and then removing the protecting group.
  • the product S7 was obtained from the reaction of the intermediate e with 1,3-dimethylpyrazole-4-boronic acid pinacol ester via Suzuki, followed by removal of the protecting group.
  • Example 2 Similar to the preparation of Example 1, the intermediate E was reacted with 1,3,5-trimethyl-1-hydro-pyrazole-4-boronic acid pinacol ester via Suzuki, and the protecting group was removed to obtain the product S8. .
  • the product S9 was obtained by reacting the intermediate e with pyridine-3-boronic acid via Suzuki and then removing the protecting group.
  • the product S10 was obtained by reacting the intermediate e with pyridine-2-boronic acid via Suzuki and then removing the protecting group.
  • the product S11 was obtained from the reaction of the intermediate e with 7-methoxy-H-indole-boronic acid pinacol ester via Suzuki, followed by removal of the protecting group.
  • the product S13 was obtained from the reaction of the intermediate e with 7-azaindole-4-boronic acid pinacol ester via Suzuki, followed by removal of the protecting group.
  • the product S14 was obtained from the reaction of the intermediate e with 4-pinaboronic acid pinacol ester via Suzuki, followed by removal of the protecting group.
  • the product S15 was obtained by reacting the intermediate e with benzothiophene-2-boronic acid via Suzuki and then removing the protecting group.
  • the product S16 was obtained by reacting the intermediate e with 5-quinoline-boronic acid via Suzuki and then removing the protecting group.
  • the product S17 was obtained by reacting the intermediate e with 5-isoquinoline-boronic acid via Suzuki and then removing the protecting group.
  • product S18 was obtained by methylation of intermediate f with methyl iodide followed by removal of the protecting group.
  • the product S19 was obtained from 4-(1-(2-methoxyphenyl))piperazine and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • the product S20 was obtained from aniline and 2,4,6-trichloro-5-methylpyrimidine as a starting material.
  • the product S21 was obtained from N-cyclopropylpiperazine and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • Example 2 Similar to the preparation of Example 1, the product S22 was obtained from morpholine and 2,4,6-trichloro-5-methylpyrimidine as a starting material.
  • the product S23 was obtained by nucleophilic substitution of the intermediate e with phenol followed by removal of the protecting group.
  • the product S24 was obtained by nucleophilic substitution of the intermediate e with 4-fluorobenzyl alcohol followed by removal of the protecting group.
  • the product S29 was obtained from 1-methanesulfonyl-4-aminopiperidine and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • the product S30 was obtained from N-methanesulfonylpiperazine and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • the product S31 was obtained from 4-fluoroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • the product S33 was obtained from 4-chloroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • Example 2 Similar to the preparation of Example 1, starting from morpholine and cyanuric chloride, the intermediate was nucleophilically substituted with the morpholine ring, and the protecting group was removed to obtain the product S36.
  • the product S42 was obtained from 3,4-difluoroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • the product S43 was obtained from 2-trifluoromethyl-4-aminopyrimidine and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • the product S44 was obtained from 2-fluoroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • the product S45 was obtained from 4-trifluoromethoxyaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • the product S46 was obtained from 2,4-difluoroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • the product S47 was obtained from 4-trifluoromethylaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • the product S48 was obtained by reacting the intermediate e with aniline via Buchwald-Hartwig and then removing the protecting group.
  • the product S49 was obtained by hydrolysis of the intermediate e under a sodium hydroxide solution and then removing the protecting group.
  • Example 2 Similar to the preparation of Example 1, the intermediate e was obtained from morpholine and 2,4,6-trichloro-5-methylpyrimidine as the starting material, and the 1-carbazole-4-boronic acid pinacol ester was passed through Suzuki. The reaction, and then removal of the protecting group, gives the product S53.
  • Example 56 Similar to the preparation of Example 56, the intermediate m was reacted with N-Boc glyoxamine by reductive amination, and the protecting group was removed to give the product S57.
  • the product 1-1 was obtained by reacting the intermediate e with phenylboronic acid via Suzuki and then removing the protecting group.
  • the product 1-2 was obtained by reacting the intermediate e with 4-trifluoromethoxyphenylboronic acid via Suzuki and then removing the protecting group.
  • the product 1-3 was obtained starting from 3-chloro-4-fluoroaniline and 2,4,6-trichloro-5-methylpyrimidine.
  • the product 1-5 was obtained by reacting the intermediate e with 4-hydroxybenzeneboronic acid via Suzuki and then removing the protecting group.
  • the product 1-6 was obtained by reacting the intermediate e with 4-methoxybenzeneboronic acid via Suzuki and then removing the protecting group.
  • the product 1-8 was obtained from 4-fluoroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.
  • the product 1-10 was obtained starting from 5-amino-7-azaindole and 2,4,6-trichloro-5-methylpyrimidine.
  • the product 1-11 was obtained starting from 1,3-benzothiazol-5-amine and 2,4,6-trichloro-5-methylpyrimidine.
  • the product 1-12 was obtained starting from 1,3-benzothiazol-6-amine and 2,4,6-trichloro-5-methylpyrimidine.
  • the product 1-13 was obtained starting from 5-amino-1-methyl-1H-carbazole and 2,4,6-trichloro-5-methylpyrimidine.
  • the product 1-14 was obtained starting from 1-cyclopropylpyrazol-4-amine and 2,4,6-trichloro-5-methylpyrimidine.
  • the product 1- was obtained from 3-cyclopropyl-1-methyl-1H-pyrazole-5-ammonia and 2,4,6-trichloro-5-methylpyrimidine as starting materials. 15.
  • the product 1-17 was obtained starting from isoindoline and 2,4,6-trichloro-5-methylpyrimidine.
  • the product 1-20 was obtained starting from piperidine and 2,4,6-trichloro-5-methylpyrimidine.
  • the product 1-21 was obtained by subjecting the intermediate e to benzylamine by nucleophilic substitution reaction and then removing the protecting group.
  • the product 1-22 was obtained by subjecting the intermediate e to benzyl alcohol by a nucleophilic substitution reaction and then removing the protecting group.
  • Example 54 Similar to the preparation of Example 54, the intermediate g was subjected to an affinity substitution reaction with 8-oxo-3-azabicyclo[3.2.1]octane, followed by a reaction with Suzuki 4-pyrazoleboronic acid pinacol ester, Removal of the protecting group provides product 1-26.
  • the present invention uses the AlphaLISA detection technique to verify the ability of the compounds of the invention to inhibit PRMT4 protein.
  • the inhibitory activity of the compound of the present invention on the PRMT4 protein was determined.
  • Reagents anti-histone H3R26 methylated antibody-conjugated acceptor beads, streptavidin donor microbeads, epigenetic buffer (5-fold concentration) (purchased from PerkinElmer), PRMT4 enzyme activity reagent Box (people CARM1) (purchased from Reaction Biology), SAM (purchased from Sigma).
  • TP-064 is a small molecule inhibitor of PRMT4 jointly developed by Takeda Pharmaceutical Co., Ltd. and SGC (Structural Genomics Consortium) Joint Research Center. Its structure is as follows. TP-064 is available from R&DSystem, https://www.rndsystems.com/cn/products/tp-064_6008#product_datasheets. Compound TP-064 was dissolved in DMSO and used for subsequent bioactivity comparison evaluation.
  • EZM2302 is a selective PRMT4 inhibitor developed by Epizyme and GlaxoSmithKline (GSK). It is also the fastest-promoting compound for PRMT4 target.
  • the structure of the compound is as follows. (Compound EZM2302 was purchased from Selleck)
  • the concentrations of PRMT4 protein, S-adenosyl-L-methionine, PRMT4 inhibitor and histone H3 peptide (21-44) were plotted on the abscissa, and the competition was drawn using Graphpad prism software. The inhibition curve was used, and the obtained regression equation was used to calculate the concentration (IC 50 ) at which the compound had a binding rate to the PRMT4 protein of 50%.
  • Inhibition rate (%) ⁇ [(positive control signal value - blank control signal value) - (test compound signal value - blank control signal value)] / (positive control signal value - blank control signal value) ⁇
  • Compound number IC 50 (nM) Compound number IC 50 (nM) TP-064 A S30 A S1 A S31 A S2 A S32 A S3 A S33 A S4 A S34 A S5 A S35 A S6 A S36 B S7 A S37 B S8 A S38 B S9 A S39 B S10 A S40 B S11 B S41 B S12 B S42 A S13 A S43 A S14 B S44 A S15 B S45 A S16 A S46 A S17 A S47 A S18 A S48 B S19 A S49 B S20 A S50 A S21 A S51 A S22 A S52 A S23 C S53 A S24 B S54 B S25 B S55 B S26 A S56 B S27 B S57 B S28 A S58 B S29 A
  • Compound number IC 50 (nM) Compound number IC 50 (nM) TP-064 A 1-16 A 1-1 B 1-17 B 1-2 A 1-18 B 1-3 A 1-19 B 1-4 A 1-20 B 1-5 A 1-21 B 1-6 B 1-22 B 1-7 B 1-23 A 1-8 A 1-24 A 1-9 B 1-25 A
  • test compound S20 The antitumor efficacy of the test compound S20 on the pancreatic cancer ASPC1 nude mouse xenograft model.
  • mice (6 weeks, female, purchased from Shanghai Lingchang Biotechnology Co., Ltd.) were purchased, and the animals were adapted for one week before the experiment.
  • the ASPC1 cells were expanded in vitro, and the cells in the log phase were suspended in serum-free RPMI1640 medium, and 100 ⁇ L (4.0*10 6 cells) of the cell suspension were injected into the anterior and posterior iliac crest.
  • Animal experimental procedures are performed in accordance with the ethical guidelines for animal experiments. When the average tumor volume of the tumor-bearing mice reached 50-100 mm 3 , the mice were divided into three groups by random discrimination: solvent control group, positive drug EZM2302 100 mg/kg group and compound S20 100 mg/kg group, 7 mice in each group. .
  • TGI [1-RTV (experimental group) / RTV (control group)] * 100%.

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Abstract

L'invention concerne un inhibiteur de l'arginine méthyltransférase, une composition pharmaceutique de celui-ci et une utilisation de celui-ci. De façon spécifique, l'invention concerne un composé représenté par la formule (I), un sel pharmaceutiquement acceptable, un isomère, un racémate, un promédicament, un complexe co-cristallin, un hydrate ou un solvate de celui-ci, une composition pharmaceutique de celui-ci, et une utilisation de celui-ci Dans la préparation d'un inhibiteur de PRMT4 ou dans la préparation d'un médicament pour le traitement du cancer, d'une maladie inflammatoire, d'une maladie auto-immune ou du diabète.
PCT/CN2019/081252 2018-04-08 2019-04-03 Inhibiteur d'arginine méthyltransférase, composition pharmaceutique de celui-ci et son utilisation WO2019196720A1 (fr)

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WO2021194326A1 (fr) * 2020-03-27 2021-09-30 Dong-A St Co., Ltd. Dérivés d'aminopyrimidine et leur utilisation en tant que modulateurs du récepteur d'hydrocarbure aryle

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JP7485701B2 (ja) * 2019-06-06 2024-05-16 北京泰徳製薬股▲フン▼有限公司 Ａｔｒキナーゼ阻害剤としての２，４，６－三置換ピリミジン化合物

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WO2006113458A1 (fr) * 2005-04-15 2006-10-26 Bristol-Myers Squibb Company Inhibiteurs heterocycliques des proteines arginine methyle transferases
WO2016044585A1 (fr) * 2014-09-17 2016-03-24 Epizyme, Inc. Inhibiteurs d'arginine méthyltransférase et leurs utilisations
WO2017136699A1 (fr) * 2016-02-05 2017-08-10 Epizyme, Inc Inhibiteurs d'arginine méthyltransférase et leurs utilisations

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WO2006113458A1 (fr) * 2005-04-15 2006-10-26 Bristol-Myers Squibb Company Inhibiteurs heterocycliques des proteines arginine methyle transferases
WO2016044585A1 (fr) * 2014-09-17 2016-03-24 Epizyme, Inc. Inhibiteurs d'arginine méthyltransférase et leurs utilisations
WO2017136699A1 (fr) * 2016-02-05 2017-08-10 Epizyme, Inc Inhibiteurs d'arginine méthyltransférase et leurs utilisations

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021194326A1 (fr) * 2020-03-27 2021-09-30 Dong-A St Co., Ltd. Dérivés d'aminopyrimidine et leur utilisation en tant que modulateurs du récepteur d'hydrocarbure aryle
EP4126839A4 (fr) * 2020-03-27 2024-04-17 Dong-A ST Co., Ltd. Dérivés d'aminopyrimidine et leur utilisation en tant que modulateurs du récepteur d'hydrocarbure aryle

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