WO2021088885A1 - Composé ciblant prmt de type i, son procédé de préparation et son utilisation - Google Patents

Composé ciblant prmt de type i, son procédé de préparation et son utilisation Download PDF

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WO2021088885A1
WO2021088885A1 PCT/CN2020/126557 CN2020126557W WO2021088885A1 WO 2021088885 A1 WO2021088885 A1 WO 2021088885A1 CN 2020126557 W CN2020126557 W CN 2020126557W WO 2021088885 A1 WO2021088885 A1 WO 2021088885A1
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余洛汀
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四川大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the technical field of chemical medicine, in particular to a compound targeting Type I PRMT, and a preparation method and application thereof.
  • Protein arginine methylation is a high-abundance post-translational modification that is widespread in the cytoplasm and nucleus.
  • the protein arginine methyltransferase (PRMTs) family is a key enzyme involved in the protein arginine methylation process. It mainly uses S-adenosylmethionine (SAM) as the methyl donor to methylate and modify the nitrogen atom of the side chain of protein arginine to generate S-adenosyl homocysteine and methylarginine. .
  • SAM S-adenosylmethionine
  • the PRMTs family contains 9 types of PRMT.
  • PRMT can be divided into type I (PRMT1 ⁇ PRMT2 ⁇ PRMT3 ⁇ PRMT4 ⁇ PRMT6 ⁇ PRMT8), type II (PRMT5 ⁇ PRMT9) and type III (PRMT7).
  • Type I PRMT is responsible for asymmetric double methylated arginine (ADMA)
  • type II PRMT is responsible for symmetric double methylated arginine (SDMA)
  • type III PRMT is responsible for monomethylated arginine (MMA).
  • PRMT1 has been found to exert carcinogenic functions in leukemia, lung cancer, liver cancer, stomach cancer, colon cancer, breast cancer, pancreatic cancer, head and neck tumors and other cancers.
  • PRMT2 is found to be highly expressed at the protein level and is closely related to poor prognosis.
  • PRMT4 expression can be observed to have at least a two-fold increase.
  • PRMT6 was found to be highly expressed in 52.6% of gastric cancer cells, and its expression level was significantly positively correlated with the modification level of its substrate.
  • type I PRMT is mainly responsible for catalyzing the asymmetric dimethylation of arginine
  • changes in the level of asymmetric dimethylation in the body are inseparable from cardiovascular diseases, diabetes, renal failure, asthma and chronic non-obstructive diseases. relationship. Therefore, it can be said that the abnormal expression of type I PRMT is related to the occurrence and development of a variety of diseases.
  • small molecule inhibitors targeting type I PRMT there have been some reports of small molecule inhibitors targeting type I PRMT, but these small molecules are all reversible inhibitors and have a relatively simple structure. There are few reports about covalent inhibitors targeting type I PRMT.
  • the first objective of the present invention is to provide a new class of compounds, which are type I PRMT covalent inhibitors.
  • the second object of the present invention is to provide a preparation method of the above compound, which has simple operation and mild conditions.
  • the third object of the present invention is to provide a pharmaceutical composition, which uses the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the fourth object of the present invention is to provide an application of the above compound in the preparation of a medicine for inhibiting the activity of type I PRMT enzyme or the preparation of a type I PRMT inhibitor.
  • Ar is selected from substituted or unsubstituted six-membered aromatic rings, substituted or unsubstituted six-membered and five-membered aromatic rings;
  • Linker is selected from X is selected from methylene Or carbonyl
  • R 1 is selected from H, C 1-3 alkyl or substituted sulfonyl
  • R 2 is selected from H or C 1-3 alkyl
  • R 3 is selected from a group that can covalently react with cysteine
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H or C 1-3 alkyl;
  • n is an integer between 1 and 6;
  • m is an integer between 0 and 3.
  • the nitrogen atom in the Linker is connected to R 3 .
  • the wavy line involved in the present invention indicates the connection position of Ar with the rest of the compound.
  • Ar is selected from
  • n can be 0, 1, 2 and 3; preferably, m is 0, 1, or 2.
  • Linker is selected from
  • X is methylene
  • R 8 is selected from C 1-3 alkyl groups. In a specific embodiment of the present invention, the R 1 is selected from H or methyl.
  • R 2 is methyl
  • R 3 includes an alkenyl group and/or a halogen atom group. R 3 is selected from
  • n can be 1, 2, 3, 4, 5, or 6; preferably, n is 1, 2, or 3.
  • the compound may be selected from the following structures:
  • the present invention also provides a preparation method of the above compound, which includes the following steps:
  • the acid in step (a), includes one or a mixture of trifluoroacetic acid and hydrochloric acid.
  • the molar ratio of the compound B to the acid is 1: (3-10).
  • the reaction temperature in step (a) is 15-30°C.
  • step (a) further includes a solvent, and the solvent includes any one or a mixture of ethanol, dichloromethane, dioxane, ethyl acetate, and methanol.
  • the preparation method of the compound B includes: (b 1 ) under the action of a base and a palladium catalyst, the compound C and the compound D undergo a Suzuki coupling reaction to obtain the compound B; the structural formulas of the compound C and the compound D are as follows:
  • the palladium catalyst includes [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex, acetic acid Any one or more of palladium and tetrakis (triphenylphosphine) palladium are mixed.
  • the base is selected from inorganic bases.
  • the alkali includes any one or a mixture of sodium carbonate, potassium carbonate and cesium carbonate.
  • the molar ratio of compound C, compound D, palladium catalyst and base is 1:(1-2):(0.05-0.15):(1-5).
  • step (b 1 ) the reaction temperature in step (b 1 ) is 90-110°C.
  • step (b 1 ) further includes a solvent, and the solvent includes dioxane and water.
  • the volume ratio of dioxane to water is (1-5):1.
  • the preparation method of the compound B includes: (b 2 ) the compound C 1 and the compound Q are reacted under the action of an acid binding agent to obtain the compound B; the structural formulas of the compound C 1 and the compound Q are as follows:
  • the acid binding agent is a base.
  • the base includes any one or more of triethylamine, N,N-diisopropylethylamine, potassium carbonate, and sodium carbonate.
  • the molar ratio of compound C 1 , compound Q and acid binding agent is 1:(1 ⁇ 2):(3-10).
  • the reaction temperature in step (b 2 ) is 0-25°C.
  • Optional step (b 2 ) further includes a solvent, and the solvent includes any one or a mixture of any one or more of tetrahydrofuran, dichloromethane and chloroform.
  • the preparation method of compound C includes: (c 1 ) under acidic conditions, compound E and compound F are carried out under the action of a reducing agent Reductive amination reaction yields compound C; the structural formulas of compound E and compound F are as follows:
  • step (c 1 ) the acid in the acidic condition is glacial acetic acid.
  • the reducing agent includes any one or a mixture of sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride.
  • the molar ratio of the compound E, the compound F, the reducing agent, and the acid is 1: (1.2-2): (2-5): (5-10).
  • the reaction temperature in step (c 1 ) is 10-30°C.
  • step (c 1 ) further includes a solvent, and the solvent includes any one or a mixture of dichloroethane, chloroform, and dichloromethane.
  • the preparation method of the compound C includes: (c 2 ) compound G and compound F undergo an amide condensation reaction under the action of a condensing agent to obtain compound C ;
  • the structural formula of the compound G is as follows:
  • the condensing agent in step (c 2 ), includes 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, N-hydroxy-7 -Azabenzotriazole, O-(7-azabenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate or 1-hydroxybenzotriazole Kind or mixed.
  • the molar ratio of the compound G, the compound F and the condensing agent is 1:(1-2):(1-3).
  • the reaction temperature in step (c 2 ) is 15-30°C.
  • step (c 2 ) further includes a solvent, and the solvent includes any one or more of dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, and dichloromethane.
  • the method includes: (c 31 ) under acidic conditions, compound E and compound H undergo reductive amination reaction under the action of a reducing agent to obtain compound J; (c 32 ) compound J is removed under acidic conditions Protecting group obtains compound K; (c 33 ) under the action of acid binding agent, compound K reacts with compound L to obtain compound C;
  • the acid in the acidic condition is glacial acetic acid.
  • the reducing agent includes any one or a mixture of sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride.
  • the molar ratio of the compound E, the compound H, the reducing agent and the acid is 1: (1.2-2): (2-5): (5-10).
  • the reaction temperature in step (c 31 ) is 10-30°C.
  • step (c 31 ) further includes a solvent, and the solvent includes any one or a mixture of dichloroethane, chloroform, and dichloromethane.
  • the acid in step (c 32 ), includes one or a mixture of trifluoroacetic acid and hydrochloric acid.
  • the molar ratio of the compound J to the acid is 1: (3-10).
  • the reaction temperature in step (c 32 ) is 15-30°C.
  • step (c 32 ) further includes a solvent, and the solvent includes any one or more of ethanol, dichloromethane, dioxane, ethyl acetate, and methanol.
  • the acid binding agent is a base.
  • the base includes any one or more of triethylamine, N,N-diisopropylethylamine, potassium carbonate, and sodium carbonate.
  • the molar ratio of compound K, compound L and acid binding agent is 1:(1 ⁇ 2):(3-10).
  • the reaction temperature in step (c 33 ) is 0-25°C.
  • step (c 33 ) further includes a solvent, and the solvent includes any one or a mixture of any one or more of tetrahydrofuran, dichloromethane, and chloroform.
  • the preparation method of the compound C 1 includes: (c 34 ) under the action of a base and a catalyst, the compound C and the compound Y undergo a Suzuki coupling reaction to obtain the compound C 1 ;
  • the structural formula of the compound Y is as follows:
  • the palladium catalyst includes [1,1'-bis(diphenylphosphine)ferrocene] dichloropalladium dichloromethane complex, acetic acid Any one or more of palladium and tetrakis (triphenylphosphine) palladium are mixed.
  • the base is selected from inorganic bases.
  • the alkali includes any one or a mixture of sodium carbonate, potassium carbonate and cesium carbonate.
  • the molar ratio of compound C, compound Y, palladium catalyst and base is 1:(1-2):(0.05-0.15):(1-5).
  • step (c 34 ) the reaction temperature in step (c 34 ) is 90-110°C.
  • step (c 34 ) further includes a solvent, and the solvent includes dioxane and water.
  • the volume ratio of dioxane to water is (1-5):1.
  • the preparation method of the compound C includes: (c 4 ) the compound V and the compound F are reacted under the action of a base to obtain the compound C;
  • the structural formula of the compound V is as follows:
  • the base in step (c 4 ), includes any one or more of triethylamine, N,N-diisopropylethylamine, potassium carbonate, and cesium carbonate.
  • the molar ratio of the compound V, the compound F and the base is 1:(2 ⁇ 4):(1 ⁇ 3).
  • the reaction temperature in step (c 4 ) is 15-30°C.
  • step (c 4 ) further includes a solvent, and the solvent includes any one or a mixture of tetrahydrofuran, dichloromethane, and chloroform.
  • the preparation method of the compound D includes: (d) the compound Y and the compound Q are reacted under the action of an acid binding agent to obtain the compound D.
  • the acid binding agent in step (d), is a base.
  • the base includes any one or more of triethylamine, N,N-diisopropylethylamine, potassium carbonate, and sodium carbonate.
  • the molar ratio of compound Y, compound Q and acid binding agent is 1:(1 ⁇ 2):(3-10).
  • the reaction temperature in step (d) is 0-25°C.
  • step (d) further includes a solvent, and the solvent includes any one or a mixture of tetrahydrofuran, dichloromethane, and chloroform.
  • the preparation method of the compound Y includes: (y) the compound S 1 , the compound S 2 or the compound S 3 is deprotected under the action of an acid to obtain the compound Y; the structural formulas of the compound S 1 , the compound S 2 and the compound S 3 They are as follows:
  • the acid in step (y), includes one or a mixture of trifluoroacetic acid and hydrochloric acid.
  • the molar ratio of the compound S 1 to the acid is 1: (3-10); the molar ratio of the compound S 2 to the acid is 1: (3-10); the molar ratio of the compound S 3 to The molar ratio of the acid is 1: (3-10).
  • the reaction temperature in step (y) is 15-30°C.
  • step (y) further includes a solvent, and the solvent includes any one or more of ethanol, dichloromethane, dioxane, ethyl acetate, and methanol.
  • the preparation method of the compound S 1 includes: (s 1 ) under alkaline conditions, the compound T 1 is reacted with pinacol diborate under the action of a palladium catalyst to obtain the compound S 1 ;
  • the structural formula of the compound T 1 is as follows:
  • the palladium catalyst in step (s 1 ), includes [1,1'-bis(diphenylphosphine)ferrocene] dichloropalladium dichloromethane complex, acetic acid Any one or more of palladium and tetrakis (triphenylphosphine) palladium are mixed.
  • the alkali in the alkaline conditions includes any one or a mixture of potassium acetate, sodium acetate, sodium carbonate, and potassium carbonate.
  • step (s 1 ) the molar ratio of compound T 1 , pinacol diboronic acid ester, palladium catalyst, and base is 1:(1-2):(0.005-0.02):(1-3).
  • the reaction temperature in step (s 1 ) is 90-110°C.
  • step (s 1 ) further includes a solvent, and the solvent includes any one or more of anhydrous dioxane, anhydrous toluene, and anhydrous acetonitrile.
  • the preparation method of the compound T 1 includes: (t 1 ) under basic conditions, the compound U 1 is reacted with Boc anhydride under basic conditions to obtain compound T 1 ; the structural formula of the compound U 1 is as follows:
  • the base in the basic condition includes any one or more of triethylamine, N,N-diisopropylethylamine, potassium carbonate, and cesium carbonate.
  • the molar ratio of the compound U 1 , Boc anhydride, and base is 1:(1 ⁇ 2):(2 ⁇ 5).
  • the reaction temperature in step (t 1 ) is 60-80°C.
  • step (t 1 ) further includes a solvent, and the solvent includes tetrahydrofuran and water.
  • the volume ratio of tetrahydrofuran and water in the solvent is 1: (1 to 3).
  • the preparation method of the compound S 2 includes: (s 2 ) under alkaline conditions, the compound T 2 is reacted with pinacol borane under the action of zirconocene hydrochloride to obtain the compound S 2 ; the structural formula of the compound T 2 as follows:
  • the base in the alkaline condition includes any one of triethylamine and N,N-diisopropylethylamine or a mixture of two.
  • the molar ratio of the compound T 2 , pinacol borane, zirconocene hydrochloride, and base is 1:(1 ⁇ 3):(0.05 ⁇ 0.2):(0.05) ⁇ 2).
  • the reaction temperature in step (s 2 ) is 60-80°C.
  • the preparation method of the compound T 2 includes: (t 2 ) under alkaline conditions, the compound U 2 is reacted with Boc anhydride to obtain the compound T 2 ; the structural formula of the compound U 2 is as follows:
  • the base in the basic condition includes any one or more of triethylamine, N,N-diisopropylethylamine, potassium carbonate, and cesium carbonate.
  • the molar ratio of the compound U 2 , Boc acid anhydride, and base is 1:(1-2):(2-5).
  • the reaction temperature in step (t 2 ) is 0-25°C.
  • step (t 2 ) further includes a solvent, and the solvent includes any one or a mixture of tetrahydrofuran, dichloromethane, and chloroform.
  • the present invention also provides a pharmaceutical composition, which comprises the above-mentioned compound (A) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition includes pharmaceutically acceptable excipients or auxiliary components.
  • the present invention also provides the use of the compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicine for inhibiting the activity of type I PRMT enzyme or the preparation of a type I PRMT inhibitor.
  • the present invention also provides that the compound A or a pharmaceutically acceptable salt thereof is used in the preparation of anti-tumor drugs or for the treatment of cardiovascular diseases, neurodegenerative diseases, malaria, AIDS, gout, diabetes, renal failure, and chronic lung. Diseases, ophthalmopharyngeal muscular dystrophy, cocaine addiction, pulmonary hypertension, amyotrophic lateral sclerosis and alcoholic liver cirrhosis.
  • the tumor includes brain cancer, glioblastoma, leukemia, lymphoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, Wilms tumor , Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, stomach cancer, bladder cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, kidney cancer, ovarian cancer, pancreatic cancer , Prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone and thyroid cancer.
  • the compound A of the present invention and its pharmaceutically acceptable salt belong to the targeting type I PRMT covalent inhibitory compound, which can continuously inhibit the protein function through covalent action and has high selectivity; its preparation method is simple to operate and the conditions are mild. ; It can be used to prepare drugs that inhibit the activity of type I PRMT enzyme or prepare type I PRMT inhibitors, and has a wide range of applications in the preparation of anti-tumor drugs.
  • Figure 1 is a diagram showing the inhibitory effects of some compounds of the present invention and their reversible analogues on PRMT6 in vitro enzyme activity in Experimental Example 2 of the present invention; it also includes the structural diagrams of the corresponding reversible analogues A 2 ′, A 6 ′, and A 12 ′;
  • Figure 2 is a diagram showing the in vitro enzyme activity inhibition effects of some compounds A 12 and its reversible analogues A 12 ′ of the present invention on PRMT1, PRMT3, PRMT4, PRMT5, PRMT7, and PRMT8 in Experimental Example 3 of the present invention;
  • Figure 3 is a graph showing the in vitro enzymatic activity inhibitory effects of some compound A 27 and its reversible analogue A 27 ' on PRMT1, PRMT3, PRMT4, PRMT5, PRMT7, and PRMT8 in Experimental Example 3 of the present invention; which also includes the corresponding reversible analogues The structure diagram of A 27'.
  • the compounds and derivatives provided by the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming system.
  • alkyl is a linear or branched saturated hydrocarbon group.
  • Examples of C 1-3 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), and isopropyl (C 3 ).
  • pharmaceutically acceptable means that a certain carrier, carrier, diluent, excipient, and/or the formed salt is usually chemically or physically compatible with other ingredients constituting a certain pharmaceutical dosage form, and physiologically Compatible with the receptor.
  • pharmaceutically acceptable salt refers to the acid and/or basic salt formed by the compound of the present invention with inorganic and/or organic acids and bases, and also includes zwitterionic salts (internal salts), and also includes quaternary ammonium salts, For example, alkyl ammonium salts.
  • zwitterionic salts internal salts
  • quaternary ammonium salts For example, alkyl ammonium salts.
  • These salts can be obtained directly in the final isolation and purification of the compound. It can also be obtained by appropriately mixing the above-mentioned compound with a certain amount of acid or base (e.g., equivalent).
  • These salts may form a precipitate in the solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by freeze-drying after reacting in an aqueous medium.
  • the salt in the present invention can be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butane Acid salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • an isotope-labeled compound is included.
  • the isotope-labeled compound refers to the same compound as listed herein, but one or more of its atoms is replaced by another atom.
  • the atomic mass of the atom is Or the mass number is different from the atomic mass or mass number commonly found in nature.
  • the isotopes that can be introduced into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, and sulfur, namely 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S.
  • the compounds of the present invention containing the above-mentioned isotopes and/or other atomic isotopes and the pharmaceutically acceptable salts of the compounds should all be included in the scope of the present invention.
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or solubilizers, such as starch, Lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants such as glycerin; (d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, such as Quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl
  • the dosage form may also contain buffering agents.
  • the solid dosage form can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 -Butylene glycol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances.
  • the composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage forms of the compound of the present invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the pharmaceutically acceptable excipients in the present invention refer to substances contained in the dosage form in addition to the active ingredients.
  • the pharmaceutically acceptable auxiliary component of the present invention has certain physiological activity, but the addition of the component will not change the dominant position of the above-mentioned pharmaceutical composition in the course of disease treatment, but only exerts auxiliary functions. These auxiliary functions only It is the use of the known activity of the ingredient, and it is a commonly used adjuvant therapy in the medical field. If the aforementioned auxiliary components are used in conjunction with the pharmaceutical composition of the present invention, they should still fall within the protection scope of the present invention.
  • the active hydrogen is easily exchanged with deuterium; in deuterated reagents, especially deuterated methanol/ When deuterated chloroform is used as a reagent for nuclear magnetic detection, the exchange of active hydrogen and deuterium makes the nuclear magnetic results have a few hydrogen deviations.
  • the combination of nuclear magnetic data and high-resolution mass spectrometry data can be further used as characterization data for determining compounds.
  • This example provides a method for preparing compound A 1 , and the synthetic route is as above:
  • the present embodiment provides a method for preparing the compound A 2: Compound A prepared in Reference Example 2 Preparation of compound 1 A 1, except that: the step of replacing F 1-1 (5) in an equimolar Tert-butyl methyl(2-(methylamino)ethyl)carbamate F 2-2 .
  • the prepared target compound A 2 is an off-white solid 71 mg, and the yield of the compound A 2 obtained in the last step is 49.1%.
  • the present embodiment provides a method of preparing compound A 3: Compound 3 A method of preparing a compound of Reference Production A 1 in Example 1, except that: in step E 1-1 (5) is replaced by an equimolar The 2-bromoisonicotinaldehyde E 2-2 .
  • the prepared target compound A 3 was 78 mg of off-white solid, and the yield of compound A 3 was 57.5% in the last step.
  • the present embodiment provides a method for the preparation of compound 4 A: Preparation of Compound A Reference Production Method 4 Compound A 1 in Example 1, except that: in step E 1-1 (5) is replaced by an equimolar Of 2-bromoisonicotinaldehyde E 2-2 , replace F 1-1 in step (5) with equimolar tert-butyl methyl(2-(methylamino)ethyl)carbamate F 2-2 .
  • the prepared target compound A 4 is 59 mg of a yellow-brown solid, and the yield of the compound A 4 obtained in the last step is 38.9%.
  • the present embodiment provides a method for preparing a Compound A 5: A preparation method of Compound 5 with reference to the preparation of compounds A 1 in Example 1, except that: in step E 1-1 (5) is replaced by an equimolar ⁇ 5-Bromopyridine-3-carbaldehyde.
  • the prepared target compound A 5 is 73 mg of a yellow-brown solid, and the yield of the compound A 5 obtained in the last step is 54.3%.
  • the present embodiment provides a method for preparing Compound 6 A: Preparation of Compound A Reference Production Method 6 Compound A 1 in Example 1, except that: in step E 1-1 (5) is replaced by an equimolar Replace F 1-1 in step (5) with equimolar tert-butyl methyl(2-(methylamino)ethyl)carbamate F 2-2 .
  • the prepared target compound A 6 is 57 mg of yellow-brown solid, and the yield of compound A 6 obtained in the last step is 41.2%.
  • the present embodiment provides a method for preparing Compound 7 A: Preparation of Compound A Reference Production Method 7 Compound A 1 in Example 1, except that: does not include the step (1) - (3), the step (4 Y 1-1 in ) is replaced with equimolar 4-aminophenylboronic acid pinacol ester Y 2-2 , and E 1-1 in step (5) is replaced with equimolar 5-bromopyridine-3-carbaldehyde .
  • the prepared target compound A 7 is 98 mg of yellow-brown solid, and the yield of compound A 7 obtained in the last step is 67.5%.
  • the present embodiment provides a method for the preparation of compound 8 A: Compound 8 A method of preparing a compound of Reference Production 1 A in Example 1, except that: does not include the step (1) - (3), the step (4 ) Y 1-1 is replaced with equimolar 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Y 2-2 , Replace E 1-1 in step (5) with equimolar 5-bromopyridine-3-carbaldehyde, and replace F 1-1 in step (5) with equimolar methyl (2-(methyl Amino) ethyl) tert-butyl carbamate F 2-2 .
  • the prepared target compound A 8 is 87 mg of yellow-brown solid, and the yield of compound A 8 obtained in the last step is 60.1%.
  • the present embodiment provides a method for preparing a compound 9 A: Compound 9 A method of preparing a compound of Reference Production A 1 in Example 1, except that: in step E 1-1 (5) is replaced by an equimolar Replace F 1-1 in step (5) with equimolar tert-butyl (2-aminoethyl) carbamate F 3-3 .
  • the prepared target compound A 9 is a yellow-brown solid 53 mg, and the yield of the compound A 9 obtained in the last step is 57.2%.
  • the present embodiment provides a method of preparing Compound A 10: Compound 10 A method of preparing a compound of Reference Production A 1 in Example 1, except that: in step E 1-1 (5) is replaced by an equimolar Replace F 1-1 in step (5) with an equimolar (2-aminoethyl) (methyl) carbamate tert-butyl ester F 4-4 .
  • the prepared target compound A 10 is 68 mg of a yellow-brown solid, and the yield of the compound A 10 obtained in the last step is 45.6%.
  • the present embodiment provides a method of preparing compound A 11: Compound 11 A method of preparing a compound of Reference Production 1 A in Example 1, except that: The compound (1) is replaced with other U 1-1 For moles of 3-bromobenzylamine, replace E 1-1 in step (5) with equimolar 5-bromopyridine-3-carbaldehyde, and replace F 1-1 in step (5) with equimolar F 2-2 .
  • the prepared target compound A 11 was an off-white solid 51 mg, and the yield of the compound A 11 obtained in the last step was 46.9%.
  • the present embodiment provides a method of preparing Compound A 12: Compound 12 A method of preparing a compound of Reference Production 1 A in Example 1, except that: does not include the step (1) - (3), the step (4 Replace Y 1-1 in step (5) with equimolar 3-aminophenylboronic acid pinacol ester, replace E 1-1 in step (5) with equimolar 5-bromopyridine-3-carbaldehyde, and replace step ( F 1-1 in 5) is replaced with equimolar F 2-2 .
  • the prepared target compound A 12 is 73 mg of pale yellow solid, and the yield of compound A 12 obtained in the last step is 71.7%.
  • the present embodiment provides a method of preparing Compound A 13: Compound 13 A method of preparing a compound of Reference Production A 1 in Example 1, except that: in step E 1-1 (5) is replaced by an equimolar Replace F 1-1 in step (5) with an equimolar 2-(methylamino)propyl carbamate tert-butyl ester F 5-5 .
  • the prepared target compound A 13 is a brown solid 45 mg, and the yield of the compound A 13 obtained in the last step is 39.8%.
  • This embodiment provides a method for preparing Compound A 14: Compound 14 A method of preparing a compound of Reference Production 1 A in Example 1, except that: does not include the step (1), the step T (2) of Replace 1-1 with equimolar N-BOC-2-tetrabromophenethylamine T 2-2 , and replace E 1-1 in step (5) with equimolar 5-bromopyridine-3-carbaldehyde.
  • the prepared target compound A 14 is 55 mg of a brown solid, and the yield of the compound A 14 obtained in the last step is 42.6%.
  • the present embodiment provides a method of preparing compound A 15: Compound 15 A method of preparing a compound of Reference Production 1 A in Example 1, except that: does not include the step (1), the step T (2) of 1-1 is replaced with equimolar N-BOC-2-tetrabromophenethylamine T 2-2 , E 1-1 in step (5) is replaced with equimolar 5-bromopyridine-3-carbaldehyde, and F 1-1 in step (5) is replaced with equimolar F 2-2 .
  • the prepared target compound A 15 is 61 mg of a brown solid, and the yield of the compound A 15 obtained in the last step is 45.8%.
  • the present embodiment provides a method of preparing Compound A 16: Compound 16 A method of preparing a compound of Reference Production 1 A in Example 1, except that: does not include the step (1) - (3), the step (4 In ), Y 1-1 is replaced with equimolar 3-aminophenylboronic acid pinacol ester, and E 1-1 in step (5) is replaced with equimolar 5-bromopyridine-3-carbaldehyde.
  • the prepared target compound A 16 was a brown solid of 83 mg, and the yield of the compound A 16 obtained in the last step was 67.2%.
  • the present embodiment provides a method for the preparation of compound 17 A: Compound A prepared in Reference Example 17 Preparation of compound 1 A 1, except that: The compound of step U (1) is replaced with other 1-1 For moles of 3-bromobenzylamine, replace E 1-1 in step (5) with an equimolar of 5-bromopyridine-3-carbaldehyde.
  • the prepared target compound A 17 was 47 mg of brown solid, and the yield of compound A 17 was 51.3% in the last step.
  • the present embodiment provides a method for preparing a Compound 18 A: Compound A prepared in Reference Example 18 Preparation of compound 1 A 1, except that: in step E 1-1 (5) is replaced by an equimolar Replace F 1-1 in step (5) with an equimolar 4-(methylamino)butylcarbamate tert-butyl ester F 6-6 .
  • the prepared target compound A 18 was 41 mg of a pale yellow solid, and the yield of the compound A 18 obtained in the last step was 39.3%.
  • This embodiment provides a method for preparing Compound A 19:
  • Compound 19 A method of preparing the compound of Reference Example 1 A 1 is prepared, except that: immediately using a commercially available Y 1-1, the step (4) Replace Q 1-1 in step (5) with equimolar trans-4-dimethylamino crotonyl chloride hydrochloride, and replace E 1-1 in step (5) with equimolar 5-bromopyridine-3- For formaldehyde, replace F 1-1 in step (5) with equimolar F 2-2 .
  • the prepared target compound A 19 was 50 mg of yellowish brown solid, and the yield of compound A 19 was 42.7% in the last step.
  • This embodiment provides a method for preparing Compound A 20: Compound 20 A method of preparing a compound of Reference Production 1 A in Example 1, except that: does not include the step (1), the step T (2) of 1-1 is replaced with equimolar N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, and E 1-1 in step (5) is replaced with equimolar 5- Bromopyridine-3-carbaldehyde.
  • the prepared target compound A 20 was 69 mg of a yellowish brown solid, and the yield of the compound A 20 obtained in the last step was 51.3%.
  • This embodiment provides a method for preparing Compound A 21: Compound 21 A method of preparing a compound of Reference Production 1 A in Example 1, except that: does not include the step (1), the step T (2) of 1-1 is replaced with equimolar N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, and E 1-1 in step (5) is replaced with equimolar 5- Bromopyridine-3-carbaldehyde, F 1-1 in step (5) is replaced with equimolar F 2-2 .
  • the prepared target compound A 21 is 72 mg of a yellow-brown solid, and the yield of the compound A 21 obtained in the last step is 50.4%.
  • the present embodiment provides a method of preparing Compound A 22: Compound 22 A method of preparing a compound of Reference Production 1 A in Example 1, except that: does not include the step (1) - (3), the step (4 Replace Y 1-1 in step (5) with equimolar 3-aminophenylboronic acid pinacol ester, replace E 1-1 in step (5) with equimolar 5-bromoindole-3-carbaldehyde, and replace step F 1-1 in (5) is replaced with equimolar F 2-2 .
  • the prepared target compound A 22 is 88 mg of a yellow-brown solid, and the yield of the compound A 22 obtained in the last step is 89.3%.
  • the present embodiment provides a method of preparing compound A 23: Compound 23 A method of preparing a compound of Reference Production A 1 in Example 1, except that: in step E 1-1 (5) is replaced by an equimolar Replace F 1-1 in step (5) with equimolar F 2-2 .
  • the prepared target compound A 23 was 79 mg of pale yellow solid, and the yield of compound A 23 was 76.9% in the last step.
  • This embodiment provides a method for preparing Compound A 24: Compound 24 A method of preparing a compound of Reference Production 1 A in Example 1, except that: does not include the step (1) - (3), the step (4 Replace Y 1-1 in) with equimolar 3-aminophenylboronic acid pinacol ester, and replace E 1-1 in step (5) with equimolar 6-bromoimidazo[1,2-a] Pyridine-3-carbaldehyde.
  • the prepared target compound A 24 is 67 mg of yellow-brown solid, and the yield of compound A 24 obtained in the last step is 60.3%.
  • the present embodiment provides a method for the preparation of compound 25 A: Compound A prepared in Reference Example 25 Preparation of compound 1 A 1, except that: in step E 1-1 (5) is replaced by an equimolar 6-Bromoimidazo[1,2-a]pyridine-3-carbaldehyde.
  • the prepared target compound A 25 is 61 mg of yellow-brown solid, and the yield of compound A 25 obtained in the last step is 57.8%.
  • This embodiment provides a method for preparing Compound A 26: Compound 26 A method of preparing a compound of Reference Production 1 A in Example 1, except that: does not include the step (1) - (3), the step (4 Replace Y 1-1 in) with equimolar 3-aminophenylboronic acid pinacol ester, and replace E 1-1 in step (5) with equimolar 5-bromo-1H-indole-3-carbaldehyde .
  • the prepared target compound A 26 is 59 mg of yellow-brown solid, and the yield of compound A 26 obtained in the last step is 45.2%.
  • This embodiment provides a method for preparing Compound A 27: Compound 27 A method of preparing a compound of Reference Production A 1 in Example 1, except that: in step E 1-1 (5) is replaced by an equimolar The 5-bromo-1H-indole-3-carbaldehyde.
  • the prepared target compound A 27 is 64 mg of yellowish brown solid, and the yield of compound A 27 obtained in the last step is 49.1%.
  • the present embodiment provides a method for the preparation of compound 28 A: Compound A prepared in Reference Example 28 Preparation of compound 1 A 1, except that: in step E 1-1 (5) is replaced by an equimolar 5-bromo-1-tosyl-1H-indole-3-carbaldehyde.
  • the prepared target compound A 28 was 73 mg of off-white solid, and the yield of compound A 28 was 78.5% in the last step.
  • This embodiment provides a method for preparing Compound A 29: Compound 29 A method of preparing a compound of Reference Production 1 A in Example 1, except that: does not include the step (1) - (3), the step (4 Y 1-1 in ) is replaced with equimolar 4-aminophenylboronic acid pinacol ester Y 2-2 , and E 1-1 in step (5) is replaced with equimolar 5-bromo-1-toluenesulfonate Acyl-1H-indole-3-carbaldehyde.
  • the prepared target compound A 29 was 79 mg of off-white solid, and the yield of compound A 29 was 81.2% in the last step.
  • This embodiment provides a method for preparing Compound A 30: Compound 30 A method of preparing a compound of Reference Production 1 A in Example 1, except that: does not include the step (1) - (3), the step (4 Y 1-1 in ) is replaced with equimolar 3-aminophenylboronic acid pinacol ester, and E 1-1 in step (5) is replaced with equimolar 5-bromo-1-tosyl-1H- For indole-3-carbaldehyde, replace F 1-1 in step (5) with an equimolar F 2-2 .
  • the prepared target compound A 30 was 57 mg of off-white solid, and the yield of compound A 30 was 53.8% in the last step.
  • This embodiment provides a method for the preparation of compound 31 A: Preparation of Compound A 31 Compound A Reference Production Method 1 in Example 1, except that: does not include the step (1) - (3), the step (4 Y 1-1 in ) is replaced with equimolar 3-aminophenylboronic acid pinacol ester, and E 1-1 in step (5) is replaced with equimolar 5-bromo-1-tosyl-1H- Indole-3-carbaldehyde.
  • the prepared target compound A 31 was 68 mg of off-white solid, and the yield of compound A 31 was 58.8% in the last step.
  • This example provides a method for preparing compound A 32 , and the synthetic route is as follows:
  • the present embodiment provides a method for the preparation of compound 33 A: Preparation of Compound A 33 Reference Example 32 A compound 32 was prepared, except that: in step (a) is replaced by an equimolar F 3-3 The F 4-4 .
  • the prepared target compound A 33 was 82 mg of a yellowish brown solid, and the yield of the compound A 33 obtained in the last step was 80.3%.
  • the present embodiment provides a method for the preparation of compound 34 A: Preparation of Compound A 34 Reference Example 32 A compound 32 was prepared, except that: in step (a) is replaced by an equimolar F 3-3 The F 1-1 .
  • the prepared target compound A 34 is 54 mg of a yellowish-brown solid, and the yield of the compound A 34 obtained in the last step is 46.3%.
  • the present embodiment provides a method for the preparation of compound 35 A: Preparation of Compound A prepared in Reference Example 35 Compound A 32 32 embodiment, except that: in step (a) is replaced by an equimolar F 3-3 The F 2-2 .
  • the prepared target compound A 35 is 59 mg of yellow-brown solid, and the yield of compound A 35 obtained in the last step is 52.4%.
  • This example provides a preparation method of compound A 36.
  • the preparation method of compound A 36 refer to the preparation method of compound A 32 in Example 32.
  • the difference lies in: replacing F 3-3 in step (a) with equimolar For F 4-4 , replace E 3-3 in step (a) with equimolar 6-bromo-1H-indole-4-carboxylic acid, and replace D 1-1 in step (b) with etc.
  • Moles of 3-acrylamidophenylboronic acid pinacol ester D 2-2 The prepared target compound A 36 is 67 mg of yellow-brown solid, and the yield of compound A 36 obtained in the last step is 59.3%.
  • This embodiment provides a method for preparing the compound A 37: Preparation of compound A 37 Reference Example 32 Preparation of Compound 32 Method A, except that the embodiment: the molar step (a) is replaced with other F 3-3 the F 4-4, the step (a) is replaced E 3-3 equimolar -1H- indole-6-bromo-4-carboxylate.
  • the prepared target compound A 37 is 57 mg of yellow-brown solid, and the yield of compound A 37 obtained in the last step is 49.8%.
  • the present embodiment provides a method for the preparation of compound 38 A: Preparation of Compound A prepared in Reference Example 38 Compound A 32 32 embodiment, except that: in step (a) is replaced by an equimolar F 3-3 the F 1-1, the step (a) is replaced E 3-3 equimolar -1H- indole-6-bromo-4-carboxylate, the D 1-1 replacing step (b) is from other Moore's D 2-2 .
  • the prepared target compound A 38 is a yellow-brown solid 81 mg, and the yield of the compound A 38 obtained in the last step is 78.4%.
  • the present embodiment provides a method for the preparation of compound 39 A: Preparation of Compound A 39 Reference Example 32 A compound 32 was prepared, except that: in step (a) is replaced by an equimolar F 3-3 the F 1-1, the step (a) is replaced E 3-3 equimolar -1H- indole-6-bromo-4-carboxylate.
  • the prepared target compound A 39 is a yellow-brown solid 63 mg, and the yield of the compound A 39 obtained in the last step is 56.9%.
  • This embodiment provides a method for preparing the compound A 40: Preparation of compound A 40 Reference Example 32 A compound 32 is prepared, except that: in step (a) is replaced by an equimolar F 3-3 the F 1-1, the step (a) is replaced by an equimolar E 3-3 4-bromo -1H- indazole-6-carboxylic acid, the D 1-1 replacing step (b) is from other Moore's D 2-2 .
  • the prepared target compound A 40 is 74 mg of yellowish brown solid, and the yield of compound A 40 obtained in the last step is 63.8%.
  • the present embodiment provides a method for the preparation of compound 41 A: Compound A prepared in Reference Example 41 Preparation of compound 32 A 32, except that: in step (a) is replaced by an equimolar F 3-3 the F 1-1, the step (a) is replaced by an equimolar E 3-3 4-bromo -1H- indazole-6-carboxylic acid.
  • the prepared target compound A 41 is 57 mg of yellow-brown solid, and the yield of compound A 41 obtained in the last step is 53.4%.
  • the present embodiment provides a method for the preparation of compound 42 A: Preparation of Compound A 42 Reference Example 32 A compound 32 was prepared, except that: in step (a) is replaced by an equimolar F 3-3 For F 4-4 , replace E 3-3 in step (a) with equimolar 4-bromo-1H-indazole-6-carboxylic acid, and replace D 1-1 in step (b) with etc. Moore's D 2-2 .
  • the prepared target compound A 42 is 85 mg of a yellow-brown solid, and the yield of the compound A 42 obtained in the last step is 75.3%.
  • the present embodiment provides a method for the preparation of compound 43 A: Preparation of Compound A prepared in Reference Example 43 Compound A 32 32 embodiment, except that: in step (a) is replaced by an equimolar F 3-3 the F 4-4, the step (a) is replaced by an equimolar E 3-3 4-bromo -1H- indazole-6-carboxylic acid.
  • the prepared target compound A 43 is a yellow-brown solid 62 mg, and the yield of the compound A 43 obtained in the last step is 56.8%.
  • This example provides a method for preparing compound A 44 , and the synthetic route is shown above.
  • the present embodiment provides a method for the preparation of compound 45 A: Compound A prepared in Reference Example 45, preparation of Compound 44 A 44, except that: in step (e 1) Synthesis of C 4-4 embodiment with reference to In step (5) of Example 1, replace E 1-1 with 5-bromopyridine-3-carbaldehyde, and replace F 3-3 with equimolar F 4-4 .
  • the prepared target compound was 62 mg of yellow-brown solid, and the yield of compound A 45 was 50.8% in the last step.
  • This embodiment provides a method for preparing Compound A 46: Preparation of Compound A prepared in Reference Example 46 Compound A 44 44 embodiment, except that: in step (e 1) Synthesis of C 4-4 embodiment with reference to In step (5) of Example 1, replace E 1-1 in step (5) with an equimolar 5-bromo-1-tosyl-1H-indole-3-carbaldehyde.
  • the prepared target compound was 71 mg of brown solid, and the yield of compound A 46 was 67.2% in the last step.
  • the present embodiment provides a method for the preparation of compound 47 A: Preparation of Compound A prepared in Reference Example 47 Compound A 44 44 embodiment, except that: in step (e 1) Synthesis of C 4-4 embodiment with reference to In step (5) of Example 1, replace E 1-1 in step (5) with equimolar 5-bromo-1-tosyl-1H-indole-3-carbaldehyde, and replace F 1-1 with etc. Mole of F 2-2 .
  • the prepared target compound was 47 mg of brown solid, and the yield of compound A 47 was 48.3% in the last step.
  • This example provides a method for preparing compound A 48 , and the synthetic route is as follows:
  • the present embodiment provides a method for the preparation of compound 49 A: Preparation of Compound A 49 Compound A 48 Reference Example 48 Preparation embodiment, except that: in step (c 2) are replaced with an equimolar D 2-2 The D 1-1 .
  • the prepared target compound was 42 mg of light yellow viscous liquid, and the yield of compound A 49 was 40.1% in the last step.
  • the present embodiment provides a method for the preparation of compound 50 A: Compound A prepared in Reference Example 50 48 48 Compound A prepared embodiment, except that: in step (b 2) of the L 4- ethylsulfonyl chloride 4 Replace with equimolar methanesulfonyl chloride.
  • the prepared target compound A 50 is 62 mg of a pale yellow viscous liquid, and the yield of the compound A 50 obtained in the last step is 57.2%.
  • This embodiment provides a method for preparing the compound A 51: Preparation of compound A 51 Reference Example 48 Preparation of compound A 48, except that: in step (c 2) are replaced with an equimolar D 2-2 D 1-1 , replace the ethylsulfonyl chloride L 4-4 in step (b 2 ) with an equimolar methanesulfonyl chloride.
  • the prepared target compound A 51 is 48 mg of pale yellow viscous liquid.
  • the yield of compound A 51 obtained in the last step is 43.9%.
  • This example provides a method for preparing compound A 52 , and the synthetic route is as follows:
  • the present embodiment provides a method for the preparation of compound 53 A: Compound A prepared in Reference Example 53 Compound 52.
  • a manufacturing method of 52 except that: in step (b 3) is replaced with other F 2-2 Moore's F 1-1 .
  • the prepared target compound A 53 is 68 mg of off-white solid, and the yield of compound A 53 is 50.1% in the last step.
  • This example provides a method for preparing compound A 54 , and the synthetic route is as follows:
  • the present embodiment provides a method for the preparation of compound 55 A: Compound A prepared in Reference Example 55 Preparation of compound 54 A 54, except that: the step of replacing 3-chloropropionyl chloride (c 4) is from Equimolar chloroacetyl chloride.
  • the prepared target compound A 55 is 61 mg of yellow-brown solid, and the yield of compound A 55 is 57.3% in the last step.
  • the present embodiment provides a method for the preparation of compound 56 A: Preparation Example 54 Compound A 54 Compound A production method of Reference Example 56, except that: the step of replacing 3-chloropropionyl chloride (c 4) is from Equimolar dichloroacetyl chloride.
  • the prepared target compound A 56 is 49 mg of yellowish brown solid, and the yield of compound A 56 is 39.8% in the last step.
  • the present embodiment provides a method for the preparation of compound 57 A: Compound A prepared in Reference Example 57 Preparation of compound 54 A 54, except that: the step of replacing 3-chloropropionyl chloride (c 4) is from Equimolar chloromethylsulfonyl chloride.
  • the prepared target compound A 57 is a yellow-brown solid 43 mg, and the yield of compound A 57 is 35.1% in the last step.
  • PRMT6 enzyme is selected for initial compound screening, and in vitro enzyme activity tests of multiple PRMTs are performed for compounds with better activity.
  • the compound of the present invention inhibits PRMT6 enzyme activity: the compound is tested for PRMT6 enzyme activity by using the AlphaLISA screening method. The method is as follows: respectively take 100 ⁇ L of compound solutions of different concentrations and add them to a 384-well detection plate, using a five-fold dilution method, the highest concentration is 5000 nM, the lowest concentration is 0.32 nM, and two replicate wells are set for each drug concentration.
  • the compound of the present invention inhibits cell proliferation: the lymphoma cell line Toledo and the pancreatic cancer cell line Capan-2 were purchased from the American Type Culture Collection (ATCC), RPMI 1640 medium, fetal bovine serum ( FBS) were purchased from GIBICO, the United States; penicillin and streptomycin were purchased from Dalian Bao Biological Company; plates and 96-well plates for cell culture were purchased from Corning; centrifuge tubes of various specifications were purchased from BD; MTT reagents were purchased from Japan Tongren Chemical Research Institute (Donjindo).
  • ATCC American Type Culture Collection
  • FBS fetal bovine serum
  • FBS fetal bovine serum
  • plates and 96-well plates for cell culture were purchased from Corning
  • centrifuge tubes of various specifications were purchased from BD
  • MTT reagents were purchased from Japan Tongren Chemical Research Institute (Donjindo).
  • Lymphoma cell line Toledo and pancreatic cancer cell line Capan-2 were cultured in conventional high glucose RPMI1640 or DMEM complete medium containing 10% fetal bovine serum (FBS), 100IU/mL penicillin, and 100 ⁇ g/ml streptomycin at 37°C, Culture in a 5% CO 2 incubator.
  • the purpose of this experiment is to detect the effect of the compound of the present invention on the proliferation of the lymphoma cell line Toledo and the pancreatic cancer cell line Capan-2. Collect the cells in the logarithmic growth phase, adjust the single cell suspension with a cell concentration of 1000-2000 cells/mL, and inoculate 100 uL per well in a 96-well plate.
  • the compound stock solution (10mM/L dissolved in DMSO) was diluted with the culture medium to different concentrations, using the three-fold dilution method. Add 100uL per well to a 96-well plate with the highest concentration of 50 ⁇ M and the lowest concentration of 0.08 ⁇ M. Set 2 replicate wells for each drug concentration, and treat the cells with 0.1% DMSO medium and pure medium as a negative control. incubator set to continue for 6 days using MTT mitochondrial succinate dehydrogenase activity detection cell, and calculating a new compound on tumor cells median effective inhibitory concentration (IC 50) values.
  • IC 50 median effective inhibitory concentration
  • the data in Table 1 shows that the compounds of the present invention can effectively inhibit the proliferation of lymphoma and pancreatic cancer.
  • a 2 , A 17 , A 27 , A 42 , A 43 , A 57 and other test compounds have an effect on lymphoma cells.
  • the pancreatic cancer cell line Capan-2 has good proliferation inhibitory activity, with IC 50 value at the micromolar level.
  • the covalent inhibitor in the present invention groups such as acrylamide are used as electrophilic reactive groups to react with the electron-rich sulfhydryl group at Cys50 of the PRMT6 protein to form a covalent bond. If the acrylamide at the corresponding position of the inhibitor is replaced with propane amide, the inhibitor cannot undergo an addition reaction with the sulfhydryl group at Cys50, and its IC 50 value will be greatly increased. Accordingly, the present invention has designed and synthesized A 2 , A 6 , and A 12 propanoyl reversible analogues A 2 ′, A 6 ′, and A 12 ′ (as shown in Fig. 1 ). The AlphaLISA method was used to test the inhibitory effect of the compound on PRMT6 enzyme activity, and the results are shown in Figure 1.
  • the covalent inhibitors A 2 , A 6 , and A 12 have significantly stronger inhibitory effects on PRMT6 enzyme activity than their reversible analogs A 2 ′, A 6 ′, and A 12 ′. It shows that the compound of the present invention covalently interacts with the PRMT6 protein is the key to its higher inhibitory activity.
  • the AlphaLISA method was used to test the inhibitory effect of the compounds on the enzyme activity of PRMTs other than PRMT6 type I (PRMT1 ⁇ PRMT3 ⁇ PRMT4 ⁇ PRMT8), type II (PRMT5) and type III (PRMT7). The results are shown in Figure 2 and Figure 3.
  • the reversible analogues of compound A 12 and A 27 , A 12 ', A 27 ' have significantly worse inhibitory activity against other type I (PRMT1 ⁇ PRMT3 ⁇ PRMT4 ⁇ PRMT8) PRMTs than covalent inhibitors, indicating that the compounds of the present invention have been combined with PRMT1, PRMT3, PRMT4, and PRMT8 proteins covalently play a role in inhibiting activity.

Abstract

La présente invention relève du domaine technique de la médecine chimique, en particulier un composé ciblant PRMT de type I, son procédé de préparation et son utilisation. Le composé A et un sel pharmaceutiquement acceptable de celui-ci selon la présente invention sont des composés inhibiteurs covalents ciblant PRMT de type I, et peuvent inhiber en continu la fonction protéique par action covalente, et ont une sélectivité élevée. Le procédé de préparation selon l'invention est simple à mettre en œuvre et a des conditions modérées. Le composé peut être utilisé pour préparer un médicament qui inhibe l'activité enzymatique de PRMT de type I ou pour préparer un inhibiteur de PRMT de type I, et a une large gamme d'applications dans la préparation de médicaments antitumoraux et d'autres médicaments.
PCT/CN2020/126557 2019-11-07 2020-11-04 Composé ciblant prmt de type i, son procédé de préparation et son utilisation WO2021088885A1 (fr)

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KR102481635B1 (ko) * 2020-09-28 2022-12-26 서울대학교산학협력단 메타-치환된 니코틴 유도체의 신규 합성방법
CN114685415B (zh) * 2020-12-30 2023-12-01 福建医科大学 一种曲酸二聚体的合成方法
CN115368246A (zh) * 2021-05-21 2022-11-22 上海赛岚生物科技有限公司 一类精氨酸甲基转移酶抑制剂及其用途
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