CN110845474A - Target I-type PRMT compound and preparation method and application thereof - Google Patents

Target I-type PRMT compound and preparation method and application thereof Download PDF

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CN110845474A
CN110845474A CN201911080051.9A CN201911080051A CN110845474A CN 110845474 A CN110845474 A CN 110845474A CN 201911080051 A CN201911080051 A CN 201911080051A CN 110845474 A CN110845474 A CN 110845474A
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余洛汀
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Abstract

The invention relates to the technical field of chemical drugs, in particular to a compound targeting type I PRMT, a preparation method and application thereof. The compound A and the pharmaceutically acceptable salt thereof belong to a targeting I-type PRMT covalent inhibition compound, can continuously inhibit the protein function through covalent action, and have higher selectivity; the preparation method is simple to operate and mild in condition; can be used for preparing a medicine for inhibiting the activity of I-type PRMT enzyme or preparing an I-type PRMT inhibitor, and has wide application in preparing anti-tumor medicines and the like.

Description

Target I-type PRMT compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of chemical drugs, in particular to a compound targeting type I PRMT, a preparation method and application thereof.
Background
Protein arginine methylation is a high-abundance posttranslational modification mode widely existing in cytoplasm and nucleus, and a protein arginine methyltransferase (PRMTs) family is a key enzyme participating in the methylation process of protein arginine, and takes S-adenosylmethionine (SAM) as a methyl donor to carry out methylation modification on a nitrogen atom of an arginine side chain of a protein to generate S-adenosylhomocysteine and methyl arginine. The family of PRMTs contains 9 PRMTs. According to different catalytic reaction types, PRMT can be divided into I type (PRMT1\ PRMT2\ PRMT3\ PRMT4\ PRMT6\ PRMT8), II type (PRMT5\ PRMT9) and III type (PRMT 7). Type I PRMT is responsible for Asymmetric Double Methylated Arginine (ADMA), type II PRMT is responsible for Symmetric Double Methylated Arginine (SDMA), and type III PRMT is responsible for monomethylated arginine (MMA).
Various documents show that the abnormal expression of the I type PRMT is closely related to the occurrence and the development of various diseases. For example, PRMT1 is found to play a carcinogenic role in leukemia, lung cancer, liver cancer, stomach cancer, colon cancer, breast cancer, pancreatic cancer, head and neck tumors, and other cancers. In malignant gliomas, PRMT2 was found to be highly expressed at the protein level and was strongly associated with poor prognosis. At least a two-fold increase in PRMT4 expression was observed in 70% of Acute Myeloid Leukemia (AML) patients. PRMT6 was found to be highly expressed in 52.6% of gastric cancer cells, and the expression level thereof was significantly and positively correlated with the modification level of its substrate. Meanwhile, since type I PRMT is mainly responsible for catalyzing asymmetric dimethylation of arginine, the change of the asymmetric dimethylation level in vivo has a close and inseparable relationship with cardiovascular diseases, diabetes, renal failure, asthma and chronic non-obstructive diseases. Therefore, it can be said that the abnormal expression of type I PRMT is associated with the occurrence and development of various diseases. At present, small molecule inhibitors targeting type I PRMT are partially reported, but the small molecules are all reversible inhibitors and have single structures, and covalent inhibitors targeting type I PRMT are rarely reported.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The first object of the present invention is to provide a novel class of compounds which are type i PRMT covalent inhibitors.
The second purpose of the invention is to provide a preparation method of the compound, which has simple operation and mild conditions.
The third objective of the invention is to provide a pharmaceutical composition, which takes the compound or the pharmaceutically acceptable salt thereof as an active ingredient.
The fourth purpose of the invention is to provide the application of the compound in preparing a medicament for inhibiting the activity of I type PRMT enzyme or preparing I type PRMT inhibitors.
A compound, or a pharmaceutically acceptable salt thereof, having a structural formula as shown in formula (A):
Figure BDA0002263662510000011
wherein Ar is selected from a substituted or unsubstituted six-membered aromatic ring, a substituted or unsubstituted six-membered and five-membered aromatic ring; linker is selected fromX is selected from methylene
Figure BDA0002263662510000013
Or a carbonyl group
Figure BDA0002263662510000014
R1Selected from H, C1～3Alkyl or substituted sulfonyl; r2Is selected from H or C1～3An alkyl group; r3Selected from groups that covalently react with cysteine; r4、R5、R6、R7Each independently selected from H or C1～3An alkyl group; n is an integer between 1 and 6; m is an integer of 0 to 3.
Specifically, the nitrogen atom in the Linker is connected to R3。
The wavy line referred to in the present invention indicates the bonding position of Ar to the rest of the compound.
In one embodiment of the invention, Ar is selected from
Figure BDA0002263662510000021
Figure BDA0002263662510000022
As in various embodiments, m can be 0, 1,2, and 3; preferably, m is 0, 1 or 2.
In one embodiment of the invention, Linker is selected from
Figure BDA0002263662510000023
In one embodiment of the invention, X is methylene.
R1The substituted sulfonyl structure in (A) is
Figure BDA0002263662510000025
R8Is selected from C1～3An alkyl group. In one embodiment of the invention, R is1Selected from H or methyl.
In one embodiment of the invention, R2Is methyl.
In one embodiment of the invention, R3Including alkenyl groups and/or halogen atom groups. R3Is selected from
Figure BDA0002263662510000026
As in various embodiments, n can be 1,2, 3, 4,5, or 6; preferably, n is 1,2 or 3.
In a particular embodiment of the invention, the compound may be selected from the following structures:
Figure BDA0002263662510000028
Figure BDA0002263662510000031
Figure BDA0002263662510000041
Figure BDA0002263662510000061
the invention also provides a preparation method of the compound, which comprises the following steps:
(a) deprotecting the compound B under the action of acid to obtain a compound A; the structural formula of the compound B is as follows:
Figure BDA0002263662510000062
in a specific embodiment of the present invention, in step (a), the acid comprises one or a mixture of trifluoroacetic acid and hydrochloric acid. Optionally, the molar ratio of the compound B to the acid is 1: 3-10. Optionally, the reaction temperature in the step (a) is 15-30 ℃. Optionally, step (a) further comprises a solvent, wherein the solvent comprises any one or more of ethanol, dichloromethane, dioxane, ethyl acetate and methanol.
The preparation method of the compound B comprises the following steps: (b)1) Under the action of alkali and a palladium catalyst, carrying out Suzuki coupling reaction on the compound C and the compound D to obtain a compound B; the structural formulas of the compound C and the compound D are as follows:
Figure BDA0002263662510000063
in a specific embodiment of the present invention, step (b)1) Wherein the palladium catalyst comprises [1,1' -bis (diphenylphosphino) ferrocene]Any one or more of palladium dichloride dichloromethane complex, palladium acetate and tetrakis (triphenylphosphine) palladium. Optionally, step (b)1) Wherein the base is selected from inorganic bases. Optionally, the base comprises any one or more of sodium carbonate, potassium carbonate and cesium carbonate in admixture. Optionally, the molar ratio of compound C, compound D, palladium catalyst and base is 1: 1 (1-2): 0.05-0.15: 1-5. Optionally, step (b)1) The reaction temperature in (1) is 90-110 ℃. Optionally, step (b)1) Also comprises a solvent, wherein the solvent comprises dioxane and water. Optionally, the volume ratio of dioxane to water in the solvent is (1-5): 1.
Alternatively, the preparation method of the compound B comprises the following steps: (b)2) Compound C1Reacting with a compound Q under the action of an acid binding agent to obtain a compound B; the compound C1And the structural formula of compound Q is as follows:
Figure BDA0002263662510000071
in a specific embodiment of the present invention, step (b)2) Wherein the acid-binding agent is alkali. Optionally, the base comprises any one or more of triethylamine, N-diisopropylethylamine, potassium carbonate and sodium carbonate. Optionally, step (b)2) In (C), compound1The molar ratio of the compound Q to the acid-binding agent is 1: 2: 3-10. Optionally, step (b)2) The reaction temperature in (1) is 0-25 ℃. Optional step (b)2) Also comprises a solvent, wherein the solvent comprises any one or a mixture of tetrahydrofuran, dichloromethane and chloroform.
When X is methylene, R1Selected from H and C1～3When the alkyl is adopted, the preparation method of the compound C comprises the following steps: (c)1) Under the acidic condition, carrying out reductive amination reaction on the compound E and the compound F under the action of a reducing agent to obtain a compound C; the compounds E andthe structural formula of compound F is as follows:
Figure BDA0002263662510000072
in a specific embodiment of the present invention, step (c)1) Wherein the acid in the acidic condition is glacial acetic acid. Optionally, step (c)1) The reducing agent comprises any one or more of sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride. Optionally, step (c)1) The molar ratio of the compound E, the compound F, the reducing agent and the acid is 1: 1 (1.2-2): 2-5: 5-10. Optionally, step (c)1) The reaction temperature in (1) is 10-30 ℃. Optionally, step (c)1) Also comprises a solvent, wherein the solvent comprises any one or a mixture of dichloroethane, chloroform and dichloromethane.
When X is carbonyl, R1Selected from H and C1～3When the alkyl is adopted, the preparation method of the compound C comprises the following steps: (c)2) Carrying out amide condensation reaction on the compound G and the compound F under the action of a condensing agent to obtain a compound C; the structural formula of the compound G is as follows:
Figure BDA0002263662510000073
in a specific embodiment of the present invention, step (c)2) The condensing agent comprises any one or more of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, N-hydroxy-7-azabenzotriazole, O- (7-azabenzotriazole) -N, N, N, N-tetramethylurea hexafluorophosphate and 1-hydroxybenzotriazole. Optionally, step (c)2) The molar ratio of the compound G to the compound F to the condensing agent is 1: 1 (1: 2): 1: 3. Optionally, step (c)2) The reaction temperature in (1) is 15-30 ℃. Optionally, step (c)2) Also comprises a solvent, wherein the solvent comprises any one or a mixture of more of dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran and dichloromethane.
When R is1To substituteSulfonyl radicalThe preparation method of the compound C comprises the following steps: (c)31) Under the acidic condition, carrying out reductive amination reaction on the compound E and the compound H under the action of a reducing agent to obtain a compound J; (c)32) Deprotecting the compound J under an acidic condition to obtain a compound K; (c)33) Under the action of an acid binding agent, reacting the compound K with the compound L to obtain a compound C;
the structural formulae of compounds H, J, K and L are as follows:
Figure BDA0002263662510000075
in a specific embodiment of the present invention, step (c)31) Wherein the acid in the acidic condition is glacial acetic acid. Optionally, step (c)31) The reducing agent comprises any one or more of sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride. Optionally, step (c)31) The molar ratio of the compound E, the compound H, the reducing agent and the acid is 1: 1 (1.2-2): 2-5: 5-10. Optionally, step (c)31) The reaction temperature in (1) is 10-30 ℃. Optionally, step (c)31) Also comprises a solvent, wherein the solvent comprises any one or a mixture of dichloroethane, chloroform and dichloromethane.
In a specific embodiment of the present invention, step (c)32) Wherein the acid comprises one or two of trifluoroacetic acid and hydrochloric acid. Optionally, the molar ratio of the compound J to the acid is 1: 3-10. Optionally, step (c)32) The reaction temperature in (1) is 15-30 ℃. Optionally, step (c)32) Also comprises a solvent, wherein the solvent comprises any one or a mixture of ethanol, dichloromethane, dioxane, ethyl acetate and methanol.
In a specific embodiment of the present invention, step (c)33) Wherein the acid-binding agent is alkali. Optionally, the base comprises triethylamine, N-diisopropylethylamine, potassium carbonate andany one or more of sodium carbonate. Optionally, step (c)33) The molar ratio of the compound K to the compound L to the acid binding agent is 1: 1 (1-2): 3-10. Optionally, step (c)33) The reaction temperature in (1) is 0-25 ℃. Optionally, step (c)33) Also comprises a solvent, wherein the solvent comprises any one or a mixture of tetrahydrofuran, dichloromethane and chloroform.
The compound C1The preparation method comprises the following steps: (c)34) Under the action of alkali and catalyst, compound C and compound Y are subjected to Suzuki coupling reaction to obtain compound C1(ii) a The structural formula of the compound Y is as follows:
Figure BDA0002263662510000081
in a specific embodiment of the present invention, step (c)34) Wherein the palladium catalyst comprises [1,1' -bis (diphenylphosphino) ferrocene]Any one or more of palladium dichloride dichloromethane complex, palladium acetate and tetrakis (triphenylphosphine) palladium. Optionally, step (c)34) Wherein the base is selected from inorganic bases. Optionally, the base comprises any one or more of sodium carbonate, potassium carbonate and cesium carbonate in admixture. Optionally, step (c)34) In the above formula, the molar ratio of the compound C, the compound Y, the palladium catalyst and the base is 1: 1 (1-2): 0.05-0.15: 1-5. Optionally, step (c)34) The reaction temperature in (1) is 90-110 ℃. Optionally, step (c)34) Also comprises a solvent, wherein the solvent comprises dioxane and water. Optionally, the volume ratio of dioxane to water in the solvent is (1-5): 1.
When Ar is
Figure BDA0002263662510000082
The preparation method of the compound C comprises the following steps: (c)4) Reacting the compound V with the compound F under the action of alkali to obtain a compound C; the structural formula of the compound V is as follows:
Figure BDA0002263662510000083
in a specific embodiment of the present invention, step (c)4) Wherein the base comprises one or more of triethylamine, N-diisopropylethylamine, potassium carbonate and cesium carbonate. Optionally, step (c)4) The molar ratio of the compound V to the compound F to the base is 1: 2: 4: 1: 3. Optionally, step (c)4) The reaction temperature in (1) is 15-30 ℃. Optionally, step (c)4) Also comprises a solvent, wherein the solvent comprises any one or a mixture of tetrahydrofuran, dichloromethane and chloroform.
The preparation method of the compound D comprises the following steps: (d) and reacting the compound Y with the compound Q under the action of an acid-binding agent to obtain a compound D.
In a specific embodiment of the present invention, in the step (d), the acid-binding agent is a base. Optionally, the base comprises any one or more of triethylamine, N-diisopropylethylamine, potassium carbonate and sodium carbonate. Optionally, in the step (d), the molar ratio of the compound Y, the compound Q and the acid-binding agent is 1: 1 (1-2): 3-10. Optionally, the reaction temperature in the step (d) is 0-25 ℃. Optionally, step (d) further comprises a solvent comprising any one or more of tetrahydrofuran, dichloromethane and chloroform.
The preparation method of the compound Y comprises the following steps: (y) Compound S1Compound S2Or compounds S3Deprotecting under the action of acid to obtain a compound Y; the compound S1Compound S2And a compound S3The structural formulas are respectively as follows:
Figure BDA0002263662510000091
in a specific embodiment of the present invention, in the step (y), the acid includes one or a mixture of two of trifluoroacetic acid and hydrochloric acid. Optionally, the compound S1The molar ratio of the acid to the acid is 1: 3-10; the compound S2The molar ratio of the acid to the acid is 1: 3-10; compound S3The molar ratio of the acid to the acid is 1: 3-10. Optionally, the reaction temperature in the step (y) is 15-30 ℃. Optionally, step (y) further comprises a solvent, wherein the solvent comprises any one or more of ethanol, dichloromethane, dioxane, ethyl acetate and methanol.
The compound S1The preparation method comprises the following steps: (s)1) Under basic conditions, compound T1Reacting with pinacol ester of diboronic acid under the action of palladium catalyst to obtain a compound S1(ii) a The compound T1The structural formula of (A) is as follows:
Figure BDA0002263662510000092
in a specific embodiment of the present invention, step(s)1) Wherein the palladium catalyst comprises [1,1' -bis (diphenylphosphino) ferrocene]Any one or more of palladium dichloride dichloromethane complex, palladium acetate and tetrakis (triphenylphosphine) palladium. Optionally, step(s)1) Wherein the alkali in the alkaline condition comprises any one or more of potassium acetate, sodium carbonate and potassium carbonate. Optionally, step(s)1) In (1), compound T1The mole ratio of the diboron pinacol ester, palladium catalyst and base is 1: 1 (1-2): 0.005-0.02: 1-3. Optionally, step(s)1) The reaction temperature in (1) is 90-110 ℃. Optionally, step(s)1) The solvent comprises any one or a mixture of anhydrous dioxane, anhydrous toluene and anhydrous acetonitrile.
The compound T1The preparation method comprises the following steps: (t)1) Under basic conditions, compound U1Reacting with Boc anhydride under alkaline condition to obtain compound T1(ii) a The compound U1The structural formula of (A) is as follows:
in a specific embodiment of the present invention, step (t)1) The base in the alkaline condition includesAny one or more of triethylamine, N-diisopropylethylamine, potassium carbonate and cesium carbonate. Optionally, step (t)1) In (1), the compound U1And the mole ratio of Boc anhydride to base was 1: 1 (2: 2) (2-5). Optionally, step (t)1) The reaction temperature in the reaction is 60-80 ℃. Optionally, step (t)1) Also includes a solvent, which includes tetrahydrofuran and water. Optionally, the volume ratio of tetrahydrofuran to water in the solvent is 1: 1-3.
The compound S2The preparation method comprises the following steps: (s)2) Under basic conditions, compound T2Reacting with pinacolborane under the action of hydrochlorozirconocene to obtain a compound S2(ii) a The compound T2The structural formula of (A) is as follows:
in a specific embodiment of the present invention, step(s)2) The alkali in the alkaline condition comprises any one or two of triethylamine and N, N-diisopropylethylamine. Optionally, step(s)2) In (1), the compound T2The mol ratio of the pinacol borane to the zirconocene hydrochloride to the alkali is 1: 1 (1-3): 0.05-0.2: 0.05-2. Optionally, step(s)2) The reaction temperature in the reaction is 60-80 ℃.
The compound T2The preparation method comprises the following steps: (t)2) Under basic conditions, compound U2Reacting with Boc anhydride to obtain compound T2(ii) a The compound U2The structural formula of (A) is as follows:
Figure BDA0002263662510000101
in a specific embodiment of the present invention, step (t)2) The base in the alkaline condition comprises any one or a mixture of triethylamine, N-diisopropylethylamine, potassium carbonate and cesium carbonate. Optionally, step (t)2) In (1), the compound U2Boc anhydride, base molesThe molar ratio is 1: 2: 5. Optionally, step (t)2) The reaction temperature in (1) is 0-25 ℃. Optionally, step (t)2) Also comprises a solvent, wherein the solvent comprises any one or a mixture of tetrahydrofuran, dichloromethane and chloroform.
The present invention also provides a pharmaceutical composition comprising the above compound (a) or a pharmaceutically acceptable salt thereof.
In a specific embodiment of the present invention, the pharmaceutical composition comprises pharmaceutically acceptable adjuvants or auxiliary components.
The invention also provides application of the compound A or pharmaceutically acceptable salts thereof in preparing medicaments for inhibiting the activity of I-type PRMT enzyme or I-type PRMT inhibitors.
The invention also provides application of the compound A or pharmaceutically acceptable salt thereof in preparing an anti-tumor medicament or preparing a medicament for treating cardiovascular diseases, neurodegenerative diseases, malaria, AIDS, gout, diabetes, renal failure, chronic lung diseases, oculopharyngeal muscular dystrophy, cocaine addiction, pulmonary hypertension diseases, amyotrophic lateral sclerosis and alcoholic cirrhosis.
Specifically, the tumor includes any one of brain cancer, glioblastoma, leukemia, lymphoma, Bannayan-Zonana syndrome, cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, wilms 'tumor, ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, stomach cancer, cancer of the shoulder skin, cancer of the head and neck, 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.
Compared with the prior art, the invention has the beneficial effects that:
the compound A and the pharmaceutically acceptable salt thereof belong to a targeting I-type PRMT covalent inhibition compound, can continuously inhibit the protein function through covalent action, and have higher selectivity; the preparation method is simple to operate and mild in condition; can be used for preparing a medicine for inhibiting the activity of I-type PRMT enzyme or preparing an I-type PRMT inhibitor, and has wide application in preparing anti-tumor medicines and the like.
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In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a graph showing the effect of a partial compound of the present invention and its reversible analogs on the in vitro enzyme activity inhibition of PRMT6 in Experimental example 2 of the present invention; also included are the corresponding reversible analogs A2’、A6’、A12The structural drawing of';
FIG. 2 shows a part of Compound A of the present invention in Experimental example 3 of the present invention12And their reversible analogs A12' in vitro enzyme activity inhibition effect profile on PRMT1, PRMT3, PRMT4, PRMT5, PRMT7, PRMT 8;
FIG. 3 shows a part of Compound A of the present invention in Experimental example 3 of the present invention27And their reversible analogs A27' in vitro enzyme activity inhibition effect profile on PRMT1, PRMT3, PRMT4, PRMT5, PRMT7, PRMT 8; also included are the corresponding reversible analogs A27The structural diagram of `.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings and the detailed description, but those skilled in the art will understand that the following described embodiments are some, not all, of the embodiments of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Definition of terms:
the compounds and derivatives provided by the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
The term "alkyl" is a radical of a straight or branched chain saturated hydrocarbon group. C1～3Examples of alkyl groups include methyl (C)1) Ethyl (C)2) N-propyl (C)3) Isopropyl (C)3)。
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The term "pharmaceutically acceptable salts" refers to acid and/or base salts of the compounds of the present invention with inorganic and/or organic acids and bases, and also includes zwitterionic salts (inner salts), and also includes quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by appropriately (e.g., equivalent) mixing the above compound with a certain amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
In certain embodiments of the invention, isotopically-labeled compounds are included, by which is meant the same compounds as listed herein but for the fact that one or more atoms are replaced by another atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Isotopes that can be incorporated into compounds of the invention include hydrogen,Carbon, nitrogen, oxygen, sulfur, i.e.2H,3H、13C、14C、15N、17O、18O、35And S. The compounds of the present invention containing the aforementioned isotopes and/or other atomic isotopes, as well as pharmaceutically acceptable salts of such compounds, are intended to be included within the scope of the present invention.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration 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. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, such as glycerol; (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin; and (i) a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid dosage forms can be prepared using coatings and shells, such as enteric coatings and other materials well known in the art. If desired, the active compound may also be in microencapsulated 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. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like. In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like. Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof. Dosage forms for topical administration of the compounds of the present invention 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 which may be required if necessary.
The pharmaceutically acceptable auxiliary material of the present invention refers to a material contained in a dosage form in addition to the active ingredient. The pharmaceutically acceptable auxiliary components have certain physiological activity, but the addition of the components does not change the dominant position of the pharmaceutical composition in the disease treatment process, but only plays auxiliary effects, and the auxiliary effects are only the utilization of the known activity of the components and are auxiliary treatment modes which are commonly used in the field of medicine. If the auxiliary components are used in combination with the pharmaceutical composition of the present invention, the protection scope of the present invention should still be included.
In the characterization data of the compound structure in each embodiment of the invention, as most of the compound structure has one or more active hydrogen connected with N and the like, the active hydrogen is easy to exchange with deuterium; when a deuterated reagent, particularly deuterated methanol/deuterated chloroform, is used as a reagent for nuclear magnetic detection, active hydrogen is exchanged with deuterium, so that the nuclear magnetic result has deviation of a few hydrogen. The nuclear magnetic data and the high-resolution mass spectrum data can be further used as characterization data for determining the compound.
Some of the compounds referred to in the following specific examples have the following structures:
Figure BDA0002263662510000121
example 1
Figure BDA0002263662510000122
This example provides a Compound A1The synthesis route is as above:
the method comprises the following specific steps:
(1) reacting (4-bromophenyl) methylamine (U)1-14.0g, 21.50mmol), Boc anhydride (5.63g, 25.80mmol), and sodium carbonate (5.13g, 48.38mmol) were added to a tetrahydrofuran/water mixed solution (20ml/50ml), and the reaction mixture was reacted at 60 ℃ for 12 hours. After the reaction was monitored by TCL, the reaction was concentrated under vacuum. Water and ethyl acetate were added for extraction and the organic phase was collected. Concentrating, and vacuum drying to obtain target compound (4-bromobenzyl) carbamic acid tert-butyl ester T1-1. White crystalline solid 6.10g, yield: 99.15 percent.
(2) Reacting (4-bromobenzyl) carbamic acid tert-butyl ester (T)1-12.6g, 9.09mmol), pinacol diboron (2.77g, 10.91mmol), and potassium acetate (1.07g, 10.91mmol) were added to anhydrous dioxane, and replaced with nitrogen five times. Followed by addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (53.16mg, 0.073mmol) was replaced five times with nitrogen. Heating at 100 deg.C for 12h, vacuum concentrating, extracting with ethyl acetate, mixing organic layers, and adding petroleum ether: ethyl acetate ═ 20: 1 to obtain the product of tert-butyl (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) carbamate S1-13.01g of a transparent viscous liquid, yield: 99.37 percent.
(3) Tert-butyl (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzyl) carbamate (S)1-12.4g, 7.2mmol) was added to dichloromethane and 2 was added67mL of trifluoroacetic acid was reacted at room temperature overnight. After the TCL detection reaction is finished, the reaction solution is concentrated under reduced pressure. To obtain a target compound (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methylamine Y1-12.3g of a pale yellow viscous liquid (containing trifluoroacetic acid), yield: 100 percent.
(4) Reacting (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methylamine (Y)1-11.68g, 7.2mmol) and potassium carbonate (2.98g, 21.6mmol) were added to dichloromethane and acryloyl chloride (698. mu.L, 8.64mmol) was added dropwise at 0 ℃. The reaction solution was reacted at room temperature for 4 hours. After the reaction was monitored by TCL, water and dichloromethane were added for extraction, and the organic phase was collected. Performing column chromatography to obtain target compound D1-11.73g of white crystalline solid, yield: 83.70 percent.
(5) Reacting 3-bromoisonicotinic aldehyde (E)1-1300mg, 1.61mmol), (2- (methylamino) ethyl) carbamic acid tert-butyl ester (F)1-1421mg, 2.42mmol), glacial acetic acid (552. mu.M, 9.66mmol) were added to dichloroethane and sodium triacetoxyborohydride (682.45mg, 3.22mmol) was added portionwise at 0 ℃. The reaction mixture was reacted at room temperature overnight. And (3) monitoring the reaction completion by TCL, adding a saturated sodium bicarbonate solution to adjust the pH to 7-8, adding dichloromethane to extract, and collecting an organic phase. Column chromatography to obtain target compound C1-1260mg of pale yellow oily liquid, yield: 46.91 percent.
(6) Compound C1-1(260mg, 0.755mmol), Compound D1-1(281.9mg, 0.982mmol), sodium carbonate (320.12mg, 3.02mmol) was added to dioxane/water 4: 1, the nitrogen gas was replaced five times. Followed by addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (55.2mg, 0.076mmol) was replaced five times with nitrogen. Heating at 100 ℃ for 4h, concentrating under reduced pressure under vacuum, extracting with ethyl acetate, combining organic layers, and adding dichloromethane as a mobile phase: methanol 15: 1 purifying under column chromatography to obtain product B1-1150mg of a pale yellow viscous liquid, yield: 46.8 percent.
(7) Compound B1-1(150mg, 0.353mmol) was added to 1M ethanol hydrochloride solution and stirred at room temperatureAnd the time is 8 hours. After TLC detection reaction is finished, vacuum concentration is carried out under the vacuum condition to obtain a crude product. Adding the crude product into dry ethyl acetate, pulping, separating out a large amount of gray solid, filtering and drying a filter cake to obtain a final product A1Brown solid 92mg, yield: 72.2 percent.1H NMR(400MHz,DMSO-d6)δ8.65(t,J＝6.0Hz,1H),8.51(d,J＝5.1Hz,1H),8.36(d,J＝0.6Hz,1H),7.59(d,J＝5.1Hz,1H),7.36(s,4H),6.65(t,J＝5.8Hz,1H),6.31(dd,J＝17.1,10.1Hz,1H),6.15(dd,J＝17.1,2.3Hz,1H),5.64(dd,J＝10.1,2.2Hz,1H),4.42(d,J＝6.0Hz,2H),3.45(s,2H),2.99(q,J＝6.4Hz,2H),2.30(t,J＝6.7Hz,2H),2.06(s,3H).ESI-MS m/z325.2026(M+H)+Calculating the value: 325.2028.
example 2
This example provides a Compound A2The preparation method comprises the following steps: compound A2Preparation of compound A of reference example 11The difference is that: f in the step (5)1-1Replacement by equimolar of methyl (2- (methylamino) ethyl) carbamic acid tert-butyl ester F2-2. Preparation of the obtained object Compound A271mg as an off-white solid, to give Compound A in the last step2The yield of (a) was 49.1%.1H NMR(400MHz,DMSO-d6)δ8.65(t,J＝6.0Hz,1H),8.50(d,J＝5.1Hz,1H),8.37(s,1H),7.53(d,J＝4.9Hz,1H),7.36(s,4H),6.31(dd,J＝17.1,10.1Hz,1H),6.15(dd,J＝17.1,2.3Hz,1H),5.64(dd,J＝10.1,2.3Hz,1H),4.42(d,J＝6.0Hz,2H),3.48(s,2H),3.26–3.14(m,2H),2.74(d,J＝14.6Hz,3H),2.36(s,2H),2.12(s,3H).ESI-MS m/z339.2186(M+H)+Calculating the value: 339.2185.
example 3
This example provides a Compound A3The preparation method comprises the following steps: compound A3Preparation of compound A of reference example 11The difference is that: e in the step (5)1-1Replacement by equimolar 2-bromoisonicotinic aldehyde E2-2. Preparation of the obtained object Compound A378mg as an off-white solid, to give Compound A in the last step3The yield of (a) was 57.5%.1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),8.75(dd,J＝14.7,5.5Hz,2H),8.40(s,1H),8.11(d,J＝8.1Hz,2H),7.65–7.54(m,1H),7.42(d,J＝8.1Hz,2H),6.32(dd,J＝17.1,10.2Hz,1H),6.15(dd,J＝17.1,2.2Hz,1H),5.64(dd,J＝10.1,2.2Hz,1H),4.53(d,J＝36.8Hz,2H),4.43(d,J＝6.0Hz,2H),3.34(d,J＝14.5Hz,4H),2.79(s,3H).ESI-MS m/z 325.2032(M+H)+Calculating the value: 325.2028.
example 4
This example provides a Compound A4The preparation method comprises the following steps: compound A4Preparation of compound A of reference example 11The difference is that: e in the step (5)1-1Replacement by equimolar 2-bromoisonicotinic aldehyde E2-2F in the step (5)1-1Replacement by equimolar of methyl (2- (methylamino) ethyl) carbamic acid tert-butyl ester F2-2. Preparation of the obtained object Compound A459mg of a tan solid, the final step provides Compound A4The yield of (a) was 38.9%.1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),8.77(d,J＝5.1Hz,1H),8.73(t,J＝6.0Hz,1H),8.41(s,1H),8.16–8.04(m,2H),7.65(dd,J＝5.1,1.5Hz,1H),7.47–7.35(m,2H),6.32(dd,J＝17.1,10.2Hz,1H),6.15(dd,J＝17.1,2.2Hz,1H),5.64(dd,J＝10.1,2.2Hz,1H),4.59(s,2H),4.43(d,J＝6.0Hz,2H),3.47(s,4H),2.77(s,3H),2.60(t,J＝5.3Hz,3H).ESI-MS m/z 339.2188(M+H)+Calculating the value: 339.2185.
example 5
This example provides a Compound A5The preparation method comprises the following steps: compound A5Preparation of compound A of reference example 11The difference is that: e in the step (5)1-1Replacement was with equimolar 5-bromopyridine-3-carbaldehyde. Preparation of the obtained object Compound A573mg as a tan solid, the final step yielded Compound A5The yield of (a) was 54.3%.1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),9.06(d,J＝2.2Hz,1H),8.81(d,J＝2.0Hz,1H),8.74(t,J＝6.0Hz,1H),8.68–8.61(m,1H),7.86–7.78(m,2H),7.46–7.39(m,2H),6.32(dd,J＝17.1,10.1Hz,1H),6.14(dd,J＝17.1,2.2Hz,1H),5.64(dd,J＝10.1,2.3Hz,1H),4.57(d,J＝34.7Hz,2H),4.42(d,J＝6.0Hz,2H),3.36(s,4H),2.79(s,3H).ESI-MS m/z 325.2024(M+H)+Calculating the value: 325.2028.
example 6
This example provides a Compound A6The preparation method comprises the following steps: compound A6Preparation of compound A of reference example 11The difference is that: e in the step (5)1-1Replacing with equimolar 5-bromopyridine-3-carbaldehyde, F in step (5)1-1Replacement by equimolar of methyl (2- (methylamino) ethyl) carbamic acid tert-butyl ester F2-2. Preparation of the obtained object Compound A657mg as a tan solid, the final step to give Compound A6The yield of (a) was 41.2%.1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),9.05(d,J＝2.1Hz,1H),8.81–8.77(m,1H),8.73(t,J＝6.0Hz,1H),8.60(s,1H),7.81(d,J＝8.2Hz,2H),7.43(d,J＝8.1Hz,2H),6.31(dd,J＝17.1,10.1Hz,1H),6.14(dd,J＝17.1,2.2Hz,1H),5.64(dd,J＝10.1,2.2Hz,1H),4.56(d,J＝60.3Hz,2H),4.42(d,J＝6.0Hz,2H),3.46(s,4H),2.77(s,3H),2.60(d,J＝5.2Hz,3H).ESI-MS m/z339.2181(M+H)+Calculating the value: 339.2185.
example 7
This example provides a Compound A7The preparation method comprises the following steps: compound A7Preparation of compound A of reference example 11The difference is that: excluding steps (1) to (3), and subjecting Y in step (4) to1-1Replacement by equimolar of pinacol ester Y of 4-aminophenylboronic acid2-2E in step (5)1-1Replacement was with equimolar 5-bromopyridine-3-carbaldehyde. Preparation of the obtained object Compound A798mg of a tan solid, the last step provides the compound A7The yield of (3) was 67.5%.1H NMR(400MHz,DMSO-d6)δ11.75(s,1H),10.48(s,1H),9.07(d,J＝2.1Hz,1H),8.79(d,J＝1.9Hz,1H),8.68(s,1H),7.86(s,4H),6.51(dd,J＝16.9,10.2Hz,1H),6.29(dd,J＝17.0,2.0Hz,1H),5.79(dd,J＝10.1,2.0Hz,1H),4.52(s,2H),3.37(s,4H),2.79(s,3H).ESI-MS m/z311.1864(M+H)+Calculating the value: 311.1872.
example 8
This example provides a Compound A8The preparation method comprises the following steps: compound A8Preparation of compound A of reference example 11The difference is that: excluding steps (1) to (3), and subjecting Y in step (4) to1-1Replacement with equimolar 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline Y2-2E in step (5)1-1Replacing with equimolar 5-bromopyridine-3-carbaldehyde, F in step (5)1-1Replacement by equimolar of methyl (2- (methylamino) ethyl) carbamic acid tert-butyl ester F2-2. Preparation of the obtained object Compound A887mg as a tan solid, the final step provided Compound A8The yield of (a) was 60.1%.1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.44(s,1H),9.05(d,J＝2.2Hz,1H),8.77(d,J＝1.9Hz,1H),8.59(s,1H),7.89–7.81(m,4H),6.50(dd,J＝17.0,10.2Hz,1H),6.29(dd,J＝17.0,1.9Hz,1H),5.79(dd,J＝10.1,2.0Hz,1H),4.52(s,2H),3.45(s,4H),2.77(s,3H),2.64–2.57(m,3H).ESI-MS m/z 325.2023(M+H)+Calculating the value: 325.2028.
example 9
This example provides a Compound A9The preparation method comprises the following steps: compound A9Preparation of compound A of reference example 11The difference is that: e in the step (5)1-1Replacing with equimolar 5-bromopyridine-3-carbaldehyde, F in step (5)1-1Replacement by equimolar of tert-butyl (2-aminoethyl) carbamate F3-3. Preparation of the obtained object Compound A953mg as a tan solid, the final step gave Compound A9The yield of (a) was 57.2%.1H NMR(400MHz,Methanol-d4)δ9.36(s,1H),9.30–9.20(m,1H),9.14(s,1H),7.93(d,J＝7.9Hz,2H),7.54(d,J＝7.9Hz,2H),6.43–6.24(m,2H),5.72(dd,J＝9.7,2.2Hz,1H),4.71(s,2H),4.55(s,2H),3.51(d,J＝6.2Hz,2H),2.02(s,2H).ESI-MS m/z 311.1869(M+H)+Calculating the value: 311.1872.
example 10
This example provides a Compound A10Preparation ofThe method comprises the following steps: compound A10Preparation of compound A of reference example 11The difference is that: e in the step (5)1-1Replacing with equimolar 5-bromopyridine-3-carbaldehyde, F in step (5)1-1Replacement by equimolar of tert-butyl (2-aminoethyl) (methyl) carbamate F4-4. Preparation of the obtained object Compound A1068mg as a tan solid, to give Compound A in the last step10The yield of (a) was 45.6%.1H NMR(400MHz,Chloroform-d)δ8.70(d,J＝2.2Hz,1H),8.53(d,J＝2.0Hz,1H),7.87(t,J＝2.2Hz,1H),7.59–7.53(m,2H),7.41(d,J＝8.0Hz,2H),6.36(dd,J＝17.0,1.4Hz,1H),6.15(dd,J＝17.0,10.3Hz,1H),5.70(dd,J＝10.3,1.4Hz,1H),4.59(d,J＝5.9Hz,2H),3.90(s,2H),3.39(s,2H),2.87(s,3H),2.83(t,J＝6.3Hz,2H).ESI-MS m/z 325.2025(M+H)+Calculating the value: 325.2028.
example 11
This example provides a Compound A11The preparation method comprises the following steps: compound A11Preparation of compound A of reference example 11The difference is that: reacting the compound U in the step (1)1-1Replacement with equimolar 3-bromobenzylamine, E in step (5)1-1Replacing with equimolar 5-bromopyridine-3-carbaldehyde, F in step (5)1-1Replacement by equimolar F2-2. Preparation of the obtained object Compound A1151mg as an off-white solid, to give Compound A in the last step11The yield of (a) was 46.9%.1HNMR(400MHz,Chloroform-d)δ8.72(s,1H),8.46(d,J＝24.4Hz,1H),7.90(d,J＝27.9Hz,1H),7.64(s,1H),7.52(dt,J＝7.6,1.6Hz,1H),7.43(t,J＝7.6Hz,1H),7.38(d,J＝7.5Hz,1H),7.17(s,1H),6.34(dd,J＝17.1,1.8Hz,1H),6.23(t,J＝13.7Hz,1H),5.62(d,J＝10.3Hz,1H),4.61(d,J＝5.9Hz,2H),3.60(s,2H),3.34(s,2H),2.79(s,3H),2.53(d,J＝36.5Hz,2H),2.32(d,J＝28.5Hz,3H).ESI-MS m/z 339.2183(M+H)+Calculating the value: 339.2185.
example 12
This example provides a Compound A12The preparation method comprises the following steps: compound A12Reference examples of the preparation of1 Compound A1The difference is that: excluding steps (1) to (3), and subjecting Y in step (4) to1-1Replacing E in step (5) with equimolar amount of pinacol ester of 3-aminophenylboronic acid1-1Replacing with equimolar 5-bromopyridine-3-carbaldehyde, F in step (5)1-1Replacement by equimolar F2-2. Preparation of the obtained object Compound A1273mg as a pale yellow solid, the final step provided Compound A12The yield of (a) was 71.7%.1H NMR(400MHz,Methanol-d4)δ9.60(d,J＝10.1Hz,1H),9.38(s,1H),9.33(s,1H),9.28(s,1H),8.30(s,1H),7.75(dd,J＝16.2,7.8Hz,2H),7.69(s,1H),7.60(t,J＝7.7Hz,1H),6.52(dd,J＝17.0,9.8Hz,1H),6.43(dd,J＝16.9,2.0Hz,1H),5.84(dd,J＝9.8,2.0Hz,1H),3.86–3.79(m,4H),3.71(d,J＝5.7Hz,3H),2.85(s,3H),2.81(s,2H).ESI-MS m/z 325.2025(M+H)+Calculating the value: 325.2028.
example 13
This example provides a Compound A13The preparation method comprises the following steps: compound A13Preparation of compound A of reference example 11The difference is that: e in the step (5)1-1Replacing with equimolar 5-bromopyridine-3-carbaldehyde, F in step (5)1-1Replacement by equimolar of tert-butyl 2- (methylamino) propylcarbamate F5-5. Preparation of the obtained object Compound A13As a brown solid 45mg, which in the last step gives Compound A13The yield of (a) was 39.8%.1H NMR(400MHz,Chloroform-d)δ8.70(d,J＝2.2Hz,1H),8.49(d,J＝2.0Hz,1H),7.83(t,J＝2.1Hz,1H),7.57(d,J＝8.2Hz,2H),7.44–7.36(m,2H),6.35(dd,J＝16.9,1.4Hz,1H),6.14(dd,J＝17.0,10.3Hz,1H),5.99(s,1H),5.70(dd,J＝10.3,1.4Hz,1H),5.07(s,1H),4.58(d,J＝5.9Hz,2H),3.56(s,2H),3.19(d,J＝6.6Hz,2H),2.48(t,J＝6.7Hz,2H),2.22(s,3H),1.71(t,J＝6.7Hz,2H).ESI-MS m/z 339.2182(M+H)+Calculating the value: 339.2185.
example 14
This example provides a Compound A14The preparation method comprises the following steps: compound A14Preparation of compound A of reference example 11The difference is that: excluding step (1), and adding T in step (2)1-1Replacement with equimolar N-BOC-2-tetrabromobenzethylamine T2-2E in step (5)1-1Replacement was with equimolar 5-bromopyridine-3-carbaldehyde. Preparation of the obtained object Compound A1455mg as a brown solid, to give Compound A in the last step14The yield of (a) was 42.6%.1H NMR(400MHz,Chloroform-d)δ8.73(d,J＝2.2Hz,1H),8.49(d,J＝2.0Hz,1H),7.82(d,J＝2.2Hz,1H),7.56(d,J＝8.2Hz,2H),7.32(d,J＝8.0Hz,2H),6.28(dd,J＝17.0,1.4Hz,1H),6.05(dd,J＝17.0,10.3Hz,1H),5.64(dd,J＝10.3,1.4Hz,1H),4.94(s,1H),3.65(q,J＝6.7Hz,2H),3.59(s,2H),3.31–3.24(m,2H),2.93(t,J＝7.0Hz,2H),2.55(t,J＝6.1Hz,2H),2.24(s,3H).ESI-MS m/z 339.2182(M+H)+Calculating the value: 339.2185.
example 15
This example provides a Compound A15The preparation method comprises the following steps: compound A15Preparation of compound A of reference example 11The difference is that: excluding step (1), and adding T in step (2)1-1Replacement with equimolar N-BOC-2-tetrabromobenzethylamine T2-2E in step (5)1-1Replacing with equimolar 5-bromopyridine-3-carbaldehyde, F in step (5)1-1Replacement by equimolar F2-2. Preparation of the obtained object Compound A15As a brown solid, 61mg, obtained in the last step as Compound A15The yield of (a) was 45.8%.1H NMR(400MHz,Chloroform-d)δ8.72(d,J＝2.2Hz,1H),8.48(d,J＝2.0Hz,1H),7.85(s,1H),7.59–7.50(m,2H),7.31(d,J＝8.0Hz,2H),6.28(dd,J＝17.0,1.5Hz,1H),6.06(dd,J＝17.0,10.3Hz,1H),5.63(dd,J＝10.3,1.4Hz,1H),3.65(q,J＝6.8Hz,2H),3.61(s,2H),3.37(d,J＝27.3Hz,2H),2.92(t,J＝6.9Hz,2H),2.84(s,3H),2.56(s,2H),2.29(s,3H).ESI-MS m/z 353.2340(M+H)+Calculating the value: 353.2341.
example 16
This example provides a Compound A16The preparation method comprises the following steps: compound A16Preparation of compound A of reference example 11Preparation ofThe method is characterized in that: excluding steps (1) to (3), and subjecting Y in step (4) to1-1Replacing E in step (5) with equimolar amount of pinacol ester of 3-aminophenylboronic acid1-1Replacement was with equimolar 5-bromopyridine-3-carbaldehyde. Preparation of the obtained object Compound A1683mg as brown solid, the last step gave Compound A16The yield of (3) was 67.2%.1H NMR(400MHz,Methanol-d4)δ9.37–9.31(m,2H),9.26(d,J＝1.7Hz,1H),8.32(t,J＝1.9Hz,1H),7.74(ddd,J＝10.0,8.2,1.9Hz,2H),7.60(t,J＝8.0Hz,1H),6.52(dd,J＝16.9,9.7Hz,1H),6.44(dd,J＝16.9,2.1Hz,1H),5.85(dd,J＝9.7,2.2Hz,1H),3.72(t,J＝6.7Hz,2H),3.62(dd,J＝6.8,2.8Hz,4H),3.02(s,3H).ESI-MS m/z311.1870(M+H)+Calculating the value: 311.1872.
example 17
This example provides a Compound A17The preparation method comprises the following steps: compound A17Preparation of compound A of reference example 11The difference is that: reacting the compound U in the step (1)1-1Replacement with equimolar 3-bromobenzylamine, E in step (5)1-1Replacement was with equimolar 5-bromopyridine-3-carbaldehyde. Preparation of the obtained object Compound A1747mg as a brown solid, which in the last step gives Compound A17The yield of (a) was 51.3%.1H NMR(400MHz,Methanol-d4)δ9.42(t,J＝1.9Hz,1H),9.35(d,J＝1.9Hz,1H),9.25(d,J＝1.7Hz,1H),7.93(d,J＝1.8Hz,1H),7.91–7.87(m,1H),7.61(t,J＝7.6Hz,1H),7.55(d,J＝8.2Hz,1H),6.37(dd,J＝17.1,9.8Hz,1H),6.28(dd,J＝17.1,2.2Hz,1H),5.72(dd,J＝9.8,2.3Hz,1H),5.12(s,1H),4.59(d,J＝3.3Hz,2H),3.75(t,J＝6.8Hz,2H),3.63(td,J＝6.8,4.4Hz,2H),3.03(s,3H),3.00(d,J＝6.6Hz,2H).ESI-MS m/z 325.2028(M+H)+Calculating the value: 325.2028.
example 18
This example provides a Compound A18The preparation method comprises the following steps: compound A18Preparation of compound A of reference example 11The difference is that: e in the step (5)1-1Replacing with equimolar 5-bromopyridine-3-carbaldehyde, step (5)F in (1)1-1Replacement by equimolar of tert-butyl 4- (methylamino) butylcarbamate F6-6. Preparation of the obtained object Compound A1841mg of a pale yellow solid, the last step to obtain Compound A18The yield of (a) was 39.3%.1H NMR(400MHz,Chloroform-d)δ8.59(d,J＝2.3Hz,1H),8.45(d,J＝2.0Hz,1H),7.82(s,1H),7.51(d,J＝8.0Hz,2H),7.38(d,J＝7.8Hz,2H),6.88(s,1H),6.34(dd,J＝17.1,1.7Hz,1H),6.21(dd,J＝16.9,10.1Hz,1H),5.66(dd,J＝10.1,1.7Hz,1H),4.97(s,1H),4.55(d,J＝5.8Hz,2H),3.53(s,2H),3.10(d,J＝6.8Hz,2H),2.40(d,J＝7.0Hz,2H),2.20(s,3H),1.53(h,J＝5.9,5.5Hz,4H).ESI-MS m/z 353.2337(M+H)+Calculating the value: 353.2341.
example 19
This example provides a Compound A19The preparation method comprises the following steps: compound A19Preparation of compound A of reference example 11The difference is that: directly using commercially available Y1-1Q in the step (4)1-1Replacing E in step (5) with equimolar trans-4-dimethylaminocrotonyl chloride hydrochloride1-1Replacing with equimolar 5-bromopyridine-3-carbaldehyde, F in step (5)1-1Replacement by equimolar F2-2. Preparation of the obtained object Compound A19As a tan solid, 50mg, to give compound A in the last step19The yield of (a) was 42.7%.1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),10.76(s,1H),9.05(s,1H),8.93(s,1H),8.81(s,1H),8.65(s,1H),7.82(d,J＝7.9Hz,2H),7.44(d,J＝7.9Hz,2H),6.70(dt,J＝14.7,7.1Hz,1H),6.35(d,J＝15.4Hz,1H),4.48(s,2H),4.43(d,J＝5.9Hz,2H),3.87(t,J＝6.1Hz,2H),3.47(s,4H),2.77(s,3H),2.73(d,J＝4.8Hz,6H),2.60(t,J＝5.2Hz,3H).ESI-MS m/z 396.2767(M+H)+Calculating the value: 396.2763.
example 20
This example provides a Compound A20The preparation method comprises the following steps: compound A20Preparation of compound A of reference example 11The difference is that: excluding step (1), and adding T in step (2)1-1Replacement by equimolarN-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester of (a) A1, 2,5, 6-tetrahydropyridine-4-boronic acid, reacting E in step (5) with a compound of formula (b)1-1Replacement was with equimolar 5-bromopyridine-3-carbaldehyde. Preparation of the obtained object Compound A2069mg as a tan solid, to give Compound A in the last step20The yield of (a) was 51.3%.1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.38(d,J＝1.9Hz,1H),7.73(s,1H),6.95–6.77(m,1H),6.69(s,1H),6.30(s,1H),6.19–6.05(m,1H),5.71(dd,J＝10.5,2.4Hz,1H),4.24(d,J＝35.2Hz,2H),3.77(d,J＝8.2Hz,2H),3.52(s,2H),3.28(s,2H),3.07(d,J＝6.7Hz,2H),2.38(s,2H),2.14(s,3H).ESI-MS m/z301.2029(M+H)+Calculating the value: 301.2028.
example 21
This example provides a Compound A21The preparation method comprises the following steps: compound A21Preparation of compound A of reference example 11The difference is that: excluding step (1), and adding T in step (2)1-1Replacing E in step (5) with equimolar N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester1-1Replacing with equimolar 5-bromopyridine-3-carbaldehyde, F in step (5)1-1Replacement by equimolar F2-2. Preparation of the obtained object Compound A2172mg as a tan solid, to give Compound A in the last step21The yield of (3) was 50.4%.1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.37(d,J＝2.0Hz,1H),7.70(s,1H),6.86(dq,J＝26.1,14.8,12.6Hz,1H),6.29(s,1H),6.14(d,J＝16.6Hz,1H),5.71(dd,J＝10.4,2.4Hz,1H),4.23(d,J＝35.9Hz,2H),3.77(s,2H),3.53(s,2H),3.28(s,2H),2.74(d,J＝16.6Hz,4H),2.44(s,3H),2.20(s,3H).ESI-MSm/z 315.2183(M+H)+Calculating the value: 315.2185.
example 22
This example provides a Compound A22The preparation method comprises the following steps: compound A22Preparation of compound A of reference example 11The difference is that: excluding steps (1) to (3), and subjecting Y in step (4) to1-1Replacing E in step (5) with equimolar amount of pinacol ester of 3-aminophenylboronic acid1-1Substitution with equimolar 5-bromineIndole-3-carbaldehyde prepared by reacting F in step (5)1-1Replacement by equimolar F2-2. Preparation of the obtained object Compound A2288mg of a tan solid, the final step provides Compound A22The yield of (b) was 89.3%.1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.18(s,1H),7.94(s,1H),7.82(s,1H),7.64(s,1H),7.44–7.32(m,4H),7.25(d,J＝2.2Hz,1H),6.47(dd,J＝17.0,10.1Hz,1H),6.28(dd,J＝16.8,2.1Hz,1H),5.79–5.74(m,1H),3.68(s,2H),3.28(s,3H),2.75(s,3H),2.43–2.49(m,2H),2.19(s,2H).ESI-MS m/z 363.2184(M+H)+Calculating the value: 363.2185.
example 23
This example provides a Compound A23The preparation method comprises the following steps: compound A23Preparation of compound A of reference example 11The difference is that: e in the step (5)1-1Replacing with equimolar 5-bromoindole-3-carbaldehyde, and adding F in step (5)1-1Replacement by equimolar F2-2. Preparation of the obtained object Compound A23As a pale yellow solid, 79mg, the final step gave Compound A23The yield of (3) was 76.9%.1H NMR(400MHz,Methanol-d4)δ8.06(t,J＝1.2Hz,1H),7.73(d,J＝2.0Hz,1H),7.71(s,2H),7.54(dd,J＝2.4,1.2Hz,2H),7.40(d,J＝8.2Hz,2H),6.38–6.29(m,2H),5.72(dd,J＝9.0,3.1Hz,1H),4.74(d,J＝9.2Hz,2H),4.51(s,2H),3.52(d,J＝4.8Hz,2H),3.37(s,2H),2.98(d,J＝1.8Hz,3H),2.76(s,3H).ESI-MS m/z 377.2337(M+H)+Calculating the value: 377.2341.
example 24
This example provides a Compound A24The preparation method comprises the following steps: compound A24Preparation of compound A of reference example 11The difference is that: excluding steps (1) to (3), and subjecting Y in step (4) to1-1Replacing E in step (5) with equimolar amount of pinacol ester of 3-aminophenylboronic acid1-1Substitution to equimolar 6-bromoimidazo [1,2-a ]]Pyridine-3-carbaldehyde. Preparation of the obtained object Compound A2467mg as a tan solid, to give Compound A in the last step24Has a yield of 60.3％。1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.62(s,1H),8.05(s,1H),7.70–7.62(m,2H),7.55–7.50(m,2H),7.49–7.40(m,2H),6.48(dd,J＝17.0,10.1Hz,1H),6.30(dd,J＝17.0,2.0Hz,1H),5.79(dd,J＝10.1,2.1Hz,1H),3.90(s,2H),3.07(q,J＝6.5Hz,2H),2.44(t,J＝6.9Hz,2H),2.18(s,3H).ESI-MS m/z350.1981(M+H)+Calculating the value: 350.1981.
example 25
This example provides a Compound A25The preparation method comprises the following steps: compound A25Preparation of compound A of reference example 11The difference is that: e in the step (5)1-1Substitution to equimolar 6-bromoimidazo [1,2-a ]]Pyridine-3-carbaldehyde. Preparation of the obtained object Compound A2561mg as a tan solid, the final step gave Compound A25The yield of (a) was 57.8%.1H NMR(400MHz,DMSO-d6)δ8.64(t,J＝6.1Hz,1H),8.60(t,J＝1.4Hz,1H),7.68(d,J＝7.9Hz,2H),7.64(d,J＝9.3Hz,1H),7.56(dd,J＝9.4,1.8Hz,1H),7.50(s,1H),7.40(d,J＝8.0Hz,2H),6.30(dd,J＝17.1,10.1Hz,1H),6.14(dd,J＝17.1,2.3Hz,1H),5.63(dd,J＝10.1,2.3Hz,1H),4.40(d,J＝5.8Hz,2H),3.89(s,2H),3.05(d,J＝6.7Hz,2H),2.43(t,J＝6.8Hz,2H),2.16(s,3H).ESI-MS m/z 364.2141(M+H)+Calculating the value: 364.2137.
example 26
This example provides a Compound A26The preparation method comprises the following steps: compound A26Preparation of compound A of reference example 11The difference is that: excluding steps (1) to (3), and subjecting Y in step (4) to1-1Replacing E in step (5) with equimolar amount of pinacol ester of 3-aminophenylboronic acid1-1Replacement was with equimolar 5-bromo-1H-indole-3-carbaldehyde. Preparation of the obtained object Compound A2659mg of a tan solid, the final step provides Compound A26The yield of (a) was 45.2%.1H NMR(400MHz,DMSO-d6)δ13.67(s,1H),11.12(s,1H),10.35(s,1H),8.31(s,1H),8.12(d,J＝2.0Hz,1H),7.71(s,1H),7.63(dd,J＝7.7,2.0Hz,1H),7.46(dt,J＝15.5,7.7Hz,2H),6.52(dd,J＝17.0,10.1Hz,1H),6.29(dd,J＝17.0,2.0Hz,1H),5.78(dd,J＝10.1,2.1Hz,1H),4.85(s,2H),3.31(s,4H),2.89(s,3H).ESI-MS m/z 350.1974(M+H)+Calculating the value: 350.1981.
example 27
This example provides a Compound A27The preparation method comprises the following steps: compound A27Preparation of compound A of reference example 11The difference is that: e in the step (5)1-1Replacement was with equimolar 5-bromo-1H-indole-3-carbaldehyde. Preparation of the obtained object Compound A2764mg as a tan solid, the final step to give Compound A27The yield of (a) was 49.1%.1H NMR(400MHz,DMSO-d6)δ13.64(s,1H),11.30(s,1H),8.67(t,J＝6.0Hz,1H),8.38(s,1H),7.75(dd,J＝8.6,1.7Hz,2H),7.68(d,J＝8.8Hz,1H),7.38(d,J＝8.0Hz,2H),6.31(dd,J＝17.1,10.2Hz,1H),6.14(dd,J＝17.1,2.2Hz,1H),5.63(dd,J＝10.1,2.2Hz,1H),4.84(s,2H),4.40(d,J＝5.8Hz,2H),3.37–3.27(m,4H),2.88(s,3H).ESI-MS m/z 364.2136(M+H)+Calculating the value: 364.2137.
example 28
This example provides a Compound A28The preparation method comprises the following steps: compound A28Preparation of compound A of reference example 11The difference is that: e in the step (5)1-1Replacement was with equimolar 5-bromo-1-tosyl-1H-indole-3-carbaldehyde. Preparation of the obtained object Compound A2873mg as an off-white solid, to give Compound A in the last step28The yield of (a) was 78.5%.1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),8.65(t,J＝6.0Hz,1H),8.29–8.15(m,2H),7.96(dd,J＝14.8,8.4Hz,3H),7.69(t,J＝8.6Hz,2H),7.42(d,J＝8.1Hz,2H),7.36(d,J＝8.1Hz,2H),6.30(dd,J＝17.1,10.1Hz,1H),6.13(dd,J＝17.1,2.3Hz,1H),5.63(dd,J＝10.2,2.3Hz,1H),4.62(d,J＝19.2Hz,2H),4.39(d,J＝5.9Hz,2H),3.33(s,4H),2.78(s,3H),2.33(s,3H).ESI-MS m/z 517.2276(M+H)+Calculating the value: 517.2273.
example 29
This example provides a Compound A29Preparation method of (1): compound A29Preparation of compound A of reference example 11The difference is that: excluding steps (1) to (3), and subjecting Y in step (4) to1-1Replacement by equimolar of pinacol ester Y of 4-aminophenylboronic acid2-2E in step (5)1-1Replacement was with equimolar 5-bromo-1-tosyl-1H-indole-3-carbaldehyde. Preparation of the obtained object Compound A2979mg as an off-white solid, to give Compound A in the last step29The yield of (a) was 81.2%.1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),10.32(s,1H),8.22(s,1H),7.95(t,J＝9.0Hz,3H),7.82–7.66(m,5H),7.42(d,J＝8.2Hz,2H),6.48(dd,J＝17.0,10.1Hz,1H),6.27(dd,J＝17.0,2.0Hz,1H),5.77(dd,J＝10.1,2.1Hz,1H),4.63(d,J＝22.0Hz,2H),3.34(s,4H),2.78(s,3H),2.33(s,3H).ESI-MS m/z503.2174(M+H)+Calculating the value: 503.2117.
example 30
This example provides a Compound A30The preparation method comprises the following steps: compound A30Preparation of compound A of reference example 11The difference is that: excluding steps (1) to (3), and subjecting Y in step (4) to1-1Replacing E in step (5) with equimolar amount of pinacol ester of 3-aminophenylboronic acid1-1Replacing with equimolar 5-bromo-1-tosyl-1H-indole-3-carbaldehyde, and reacting F in step (5)1-1Replacement by equimolar F2-2. Preparation of the obtained object Compound A3057mg as an off-white solid, to give Compound A in the last step30The yield of (a) was 53.8%.1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),10.39(s,1H),8.16(s,1H),8.09–8.00(m,2H),7.98–7.91(m,3H),7.64(td,J＝8.9,8.4,3.9Hz,2H),7.48–7.40(m,4H),6.52(dd,J＝17.0,10.1Hz,1H),6.27(dd,J＝17.0,2.0Hz,1H),5.77(dd,J＝10.1,2.1Hz,1H),4.65(d,J＝31.2Hz,2H),2.75(d,J＝16.8Hz,4H),2.60(s,6H),2.34(s,3H).ESI-MS m/z 517.2265(M+H)+Calculating the value: 517.2273.
example 31
This example provides a Compound A31The preparation method comprises the following steps: compound A31Preparation method ofCompound A of reference example 11The difference is that: excluding steps (1) to (3), and subjecting Y in step (4) to1-1Replacing E in step (5) with equimolar amount of pinacol ester of 3-aminophenylboronic acid1-1Replacement was with equimolar 5-bromo-1-tosyl-1H-indole-3-carbaldehyde. Preparation of the obtained object Compound A3168mg as an off-white solid, to give Compound A in the last step31The yield of (a) was 58.8%.1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),10.40(s,1H),8.16(s,1H),8.08–7.99(m,2H),7.98–7.91(m,2H),7.65(ddd,J＝13.4,8.1,1.8Hz,2H),7.43(t,J＝6.5Hz,4H),6.52(dd,J＝17.0,10.2Hz,1H),6.28(dd,J＝17.0,2.0Hz,1H),5.77(dd,J＝10.2,2.1Hz,1H),4.64(d,J＝20.1Hz,2H),3.35(s,4H),2.84(s,3H),2.34(s,3H).ESI-MS m/z 503.2121(M+H)+Calculating the value: 503.2117.
example 32
This example provides a Compound A32The preparation method comprises the following synthetic route:
Figure BDA0002263662510000191
the method comprises the following specific steps:
(a)C3-3the synthesis of (2): mixing 5-bromonicotinic acid (E)3-3500mg, 2.48mmol), (2-aminoethyl) carbamic acid tert-butyl ester (F)3-3475.3mg, 2.73mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (855.0mg, 4.46mmol), 1-hydroxy-7-azobenzotriazol (HOAT) (607.1mg, 4.46mmol), N-methylmorpholine (1.36mL, 12.40mmol) were added to 20mL of dimethyl sulfoxide (DMSO) and reacted overnight at room temperature. After the TLC detection reaction is finished, the reaction solution is poured into ice water, and dichloromethane is added for extraction. Collecting organic phase, concentrating, and performing column chromatography to obtain target product C3-3Light yellow viscous liquid 570mg, yield: 66.8 percent.
(b)B3-3The synthesis of (2): compound C3-3(200mg, 0.58mmol), Compound D1-1(200mg, 0.70mmol), sodium carbonate (246mg, 2.32mmol) was added to dioxane/water-4: 1 ofIn the solution, nitrogen was replaced five times. Followed by addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (43mg, 0.06mmol) was replaced five times with nitrogen. Heating at 100 ℃ for 4h, concentrating under reduced pressure under vacuum, extracting with ethyl acetate, combining organic layers, and adding dichloromethane as a mobile phase: methanol 15: 1 purifying under column chromatography to obtain product B3-3118mg of a pale yellow viscous liquid, yield: 47.9 percent.
(c)A32The synthesis of (2): referring to step (7) in example 1, Compound B1-1Substitution by Compound B3-3(118mg, 0.278mmol) under the same conditions to give the final product A32Brown solid 90mg, yield: 89.7 percent.1H NMR(400MHz,Methanol-d4)δ8.05(s,1H),8.03(s,1H),7.97(d,J＝1.8Hz,1H),6.63(d,J＝8.0Hz,2H),6.27(d,J＝8.0Hz,2H),5.10–4.94(m,2H),4.42(dd,J＝9.3,2.7Hz,1H),3.26(s,2H),2.49(t,J＝5.9Hz,2H),1.98(t,J＝5.9Hz,2H).ESI-MS m/z 325.1658(M+H)+Calculating the value: 325.1664.
example 33
This example provides a Compound A33The preparation method comprises the following steps: compound A33Preparation of compound A of reference example 3232The difference is that: subjecting F in step (a) to3-3Replacement by equimolar F4-4. Preparation of the obtained object Compound A3382mg of yellow brown solid is obtained in the last step33The yield of (a) was 80.3%.1H NMR(400MHz,Methanol-d4)δ9.35(t,J＝1.9Hz,1H),9.33(d,J＝2.0Hz,1H),9.27(d,J＝1.7Hz,1H),7.99–7.88(m,2H),7.58(d,J＝8.2Hz,2H),6.40–6.26(m,2H),5.73(dd,J＝9.3,2.8Hz,1H),4.57(s,2H),3.83(dd,J＝6.2,5.0Hz,2H),3.36(d,J＝5.7Hz,2H),2.80(s,3H).ESI-MS m/z339.1816(M+H)+Calculating the value: 339.1821.
example 34
This example provides a Compound A34The preparation method comprises the following steps: compound A34Preparation of compound A of reference example 3232The difference is that: subjecting F in step (a) to3-3Replacement by equimolar F1-1. Preparation of the obtained object Compound A3454mg of a tan solid, the last step to obtain Compound A34The yield of (a) was 46.3%.1H NMR(400MHz,Chloroform-d)δ8.85(d,J＝2.2Hz,1H),8.64(s,1H),7.93(s,1H),7.56(d,J＝8.0Hz,2H),7.42(d,J＝7.9Hz,2H),6.36(dd,J＝17.0,1.4Hz,1H),6.15(dd,J＝17.0,10.3Hz,1H),5.96(s,1H),5.71(dd,J＝10.3,1.4Hz,1H),4.59(d,J＝5.9Hz,2H),3.71(s,2H),3.47(s,2H),3.13(s,3H).ESI-MS m/z 339.1818(M+H)+Calculating the value: 339.1821.
example 35
This example provides a Compound A35The preparation method comprises the following steps: compound A35Preparation of compound A of reference example 3232The difference is that: subjecting F in step (a) to3-3Replacement by equimolar F2-2. Preparation of the obtained object Compound A3559mg of a tan solid, the final step provides Compound A35The yield of (a) was 52.4%.1H NMR(400MHz,Chloroform-d)δ8.84(s,1H),8.64(s,1H),7.91(d,J＝11.6Hz,1H),7.55(d,J＝7.8Hz,2H),7.42(d,J＝7.7Hz,2H),6.36(dd,J＝17.0,1.5Hz,1H),6.15(dd,J＝16.9,10.3Hz,1H),5.96(s,1H),5.70(dd,J＝10.3,1.4Hz,1H),4.59(d,J＝5.9Hz,2H),3.66(s,3H),3.14(s,3H),2.96(s,2H),2.54(s,2H).ESI-MS m/z 353.1975(M+H)+Calculating the value: 353.1977.
example 36
This example provides a Compound A36A process for the preparation of compound A36Preparation of compound A of reference example 3232The difference is that: subjecting F in step (a) to3-3Replacement by equimolar F4-4Converting E in step (a)3-3Replacing D in step (b) with equimolar 6-bromo-1H-indole-4-carboxylic acid1-1Replacing with equimolar 3-acrylamidophenylboronic acid pinacol ester D2-2. Preparation of the obtained object Compound A3667mg as a tan solid, to give Compound A in the last step36The yield of (a) was 59.3%.1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.35(s,1H),8.62(t,J＝5.6Hz,1H),8.12(t,J＝1.9Hz,1H),7.84–7.76(m,2H),7.68–7.61(m,1H),7.54–7.40(m,4H),6.93(t,J＝2.5Hz,1H),6.57–6.44(m,1H),6.29(dd,J＝17.0,2.1Hz,1H),5.78(dd,J＝10.1,2.0Hz,1H),3.64(q,J＝5.9Hz,2H),3.15(q,J＝6.1Hz,2H),2.61(t,J＝5.5Hz,3H).ESI-MS m/z 363.1822(M+H)+Calculating the value: 363.1821.
example 37
This example provides a Compound A37The preparation method comprises the following steps: compound A37Preparation of compound A of reference example 3232The difference is that: subjecting F in step (a) to3-3Replacement by equimolar F4-4Converting E in step (a)3-3Replacement was with equimolar 6-bromo-1H-indole-4-carboxylic acid. Preparation of the obtained object Compound A3757mg as a tan solid, the final step to give Compound A37The yield of (a) was 49.8%.1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),8.78(s,1H),8.67(d,J＝5.9Hz,1H),7.83(d,J＝1.5Hz,1H),7.79(s,1H),7.76–7.71(m,2H),7.48(t,J＝2.7Hz,1H),7.40–7.35(m,2H),6.94–6.90(m,1H),6.32(dd,J＝17.1,10.2Hz,1H),6.22–6.01(m,1H),5.63(dd,J＝10.1,2.3Hz,1H),4.40(d,J＝5.9Hz,2H),3.63(q,J＝5.9Hz,2H),3.13(d,J＝5.8Hz,2H),2.61(t,J＝5.4Hz,3H).ESI-MS m/z 377.1974(M+H)+Calculating the value: 377.1977.
example 38
This example provides a Compound A38The preparation method comprises the following steps: compound A38Preparation of compound A of reference example 3232The difference is that: subjecting F in step (a) to3-3Replacement by equimolar F1-1Converting E in step (a)3-3Replacing D in step (b) with equimolar 6-bromo-1H-indole-4-carboxylic acid1-1Replacement by equimolar D2-2. Preparation of the obtained object Compound A38As a tan solid, 81mg, which in the last step gives Compound A38The yield of (a) was 78.4%.1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.36(s,1H),8.12(s,1H),7.71(t,J＝1.2Hz,1H),7.63(dt,J＝6.5,2.3Hz,1H),7.50(t,J＝2.8Hz,1H),7.43–7.38(m,2H),6.52(dd,J＝17.0,10.1Hz,1H),6.41(s,1H),6.29(dd,J＝17.0,2.0Hz,1H),5.78(dd,J＝10.1,2.0Hz,1H),3.77(s,2H),3.13(s,2H),2.96(d,J＝8.7Hz,3H).ESI-MS m/z 363.1820(M+H)+Calculating the value: 363.1821.
example 39
This example provides a Compound A39The preparation method comprises the following steps: compound A39Preparation of compound A of reference example 3232The difference is that: subjecting F in step (a) to3-3Replacement by equimolar F1-1Converting E in step (a)3-3Replacement was with equimolar 6-bromo-1H-indole-4-carboxylic acid. Preparation of the obtained object Compound A3963mg of a tan solid, the final step gives Compound A39The yield of (a) was 56.9%.1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.67(t,J＝6.0Hz,1H),8.04(s,2H),7.70(t,J＝1.2Hz,1H),7.67(s,1H),7.65(s,1H),7.47(t,J＝2.8Hz,1H),7.36(d,J＝8.1Hz,2H),6.39(s,1H),6.32(dd,J＝17.1,10.1Hz,1H),6.14(dd,J＝17.1,2.2Hz,1H),5.63(dd,J＝10.1,2.2Hz,1H),4.40(d,J＝5.9Hz,2H),3.13(s,3H),2.96(d,J＝10.9Hz,4H).ESI-MS m/z 377.1974(M+H)+Calculating the value: 377.1977.
example 40
This example provides a Compound A40The preparation method comprises the following steps: compound A40Preparation of compound A of reference example 3232The difference is that: subjecting F in step (a) to3-3Replacement by equimolar F1-1Converting E in step (a)3-3Replacing D in step (b) with equimolar 4-bromo-1H-indazole-6-carboxylic acid1-1Replacement by equimolar D2-2. Preparation of the obtained object Compound A4074mg as a tan solid, to give Compound A in the last step40The yield of (a) was 63.8%.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.49(s,1H),8.17(s,1H),8.11(d,J＝8.8Hz,1H),7.91–7.74(m,2H),7.68(q,J＝4.1,3.3Hz,1H),7.58(s,1H),7.46(d,J＝5.1Hz,2H),7.44(d,J＝6.4Hz,1H),6.51(dd,J＝17.0,10.2Hz,1H),6.29(dd,J＝16.9,2.0Hz,1H),5.79(dd,J＝10.1,2.1Hz,1H),3.79(s,2H),2.98(s,5H).ESI-MS m/z 364.1790(M+H)+Calculating the value: 364.1773.
EXAMPLE 41
This example provides a Compound A41The preparation method comprises the following steps: compound A41Preparation of compound A of reference example 3232The difference is that: subjecting F in step (a) to3-3Replacement by equimolar F1-1Converting E in step (a)3-3Replacement was with equimolar 4-bromo-1H-indazole-6-carboxylic acid. Preparation of the obtained object Compound A4157mg as a tan solid, the final step to give Compound A41The yield of (a) was 53.4%.1H NMR(400MHz,DMSO-d6)δ13.28(s,1H),8.65(t,J＝6.0Hz,1H),8.03(s,1H),7.76(s,1H),7.71(d,J＝8.2Hz,2H),7.38(d,J＝8.0Hz,3H),6.30(dd,J＝17.1,10.1Hz,1H),6.14(dd,J＝17.1,2.2Hz,1H),5.63(dd,J＝10.1,2.2Hz,1H),4.41(d,J＝6.0Hz,2H),3.28(s,2H),3.07(s,2H),2.90(s,3H).ESI-MS m/z 378.1925(M+H)+Calculating the value: 378.1930.
example 42
This example provides a Compound A42The preparation method comprises the following steps: compound A42Preparation of compound A of reference example 3232The difference is that: subjecting F in step (a) to3-3Replacement by equimolar F4-4Converting E in step (a)3-3Replacing D in step (b) with equimolar 4-bromo-1H-indazole-6-carboxylic acid1-1Replacement by equimolar D2-2. Preparation of the obtained object Compound A4285mg of a tan solid, and the compound A is obtained in the last step42The yield of (a) was 75.3%.1H NMR(400MHz,DMSO-d6)δ13.30(s,1H),10.28(s,1H),8.73(s,1H),8.40(s,1H),8.09(s,1H),7.85(d,J＝13.8Hz,2H),7.75–7.67(m,1H),7.54–7.44(m,2H),6.48(dd,J＝16.9,10.1Hz,1H),6.30(dd,J＝17.0,2.1Hz,1H),5.79(dd,J＝10.1,2.1Hz,1H),3.46(t,J＝5.3Hz,2H),3.42(d,J＝5.2Hz,2H),2.85(s,3H).ESI-MS m/z 364.1775(M+H)+Calculating the value: 364.1773.
example 43
This example provides a Compound A43The preparation method comprises the following steps: compound A43Preparation of compound A of reference example 3232The difference is that: subjecting F in step (a) to3-3Replacement by equimolar F4-4Converting E in step (a)3-3Replacement was with equimolar 4-bromo-1H-indazole-6-carboxylic acid. Preparation of the obtained object Compound A4362mg as a tan solid, to give Compound A in the last step43The yield of (a) was 56.8%.1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),8.72(s,1H),8.65(t,J＝6.1Hz,1H),8.39(s,1H),7.86(s,1H),7.77(d,J＝8.1Hz,2H),7.41(d,J＝8.0Hz,2H),6.31(dd,J＝17.1,10.1Hz,1H),6.15(dd,J＝17.1,2.3Hz,1H),5.64(dd,J＝10.1,2.3Hz,1H),4.42(d,J＝5.9Hz,2H),3.45(t,J＝5.4Hz,2H),3.42(d,J＝5.1Hz,2H),2.84(s,3H).ESI-MS m/z 378.1927(M+H)+Calculating the value: 378.1930.
example 44
Figure BDA0002263662510000211
This example provides a Compound A44The synthetic route of the preparation method is shown as above.
The method comprises the following specific steps:
(a1)T2the synthesis of (2): propargylamine (U) was added dropwise to a solution of Boc anhydride (4.8g,22mmol) in dichloromethane at 0 deg.C21.1g,20mmol) followed by dropwise addition of triethylamine (4.05g,40 mmol). After the dropwise addition, the reaction system is moved to room temperature for further reaction for 2 hours. After the TLC detection reaction is finished, saturated ammonium chloride solution/ethyl acetate is added for extraction. Collecting organic phase, washing with saturated ammonium chloride, saturated sodium bicarbonate and saturated sodium chloride solution, collecting organic phase, and vacuum concentrating to obtain target compound T22.6g of a yellow oily liquid, yield: 83.9 percent.
(b1)S2The synthesis of (2): reacting a compound T2(1g,6.4mmol), pinacolborane (1.4mL, 9.6mmol), triethylamine (100. mu.L, 0.64mmol) and bis (cyclopentadienyl) zirconium dichloride hydride (165 mg)0.64mmol) was added to a round bottom flask and reacted at 65 ℃ for 16 h. After completion of the reaction, the reaction system was cooled to room temperature, extracted with saturated ammonium chloride solution/ethyl acetate, and the organic phase was collected. Washing the organic phase with saturated sodium bicarbonate solution and saturated sodium chloride solution, collecting the organic phase, concentrating, and performing column chromatography to obtain target product S21.3g of oily liquid, yield: 71.7 percent.
(c1)Y3-3The synthesis of (2): reacting a compound S2(200mg, 0.71mmol) was added to dichloromethane, 400. mu.L of trifluoroacetic acid was added, and the reaction was carried out overnight at room temperature. After the TCL detection reaction is finished, the reaction solution is concentrated under reduced pressure. Obtaining the target compound Y3-3210mg of a pale yellow viscous liquid (containing trifluoroacetic acid), yield: 100 percent.
(d1)D3-3The synthesis of (2): compound D3-3(129.4mg, 0.71mmol) and potassium carbonate (292.7mg, 2.13mmol) were added to methylene chloride and acryloyl chloride (Q) was added dropwise at 0 deg.C1-186 μ L, 1.06 mmol). The reaction solution was reacted at room temperature for 4 hours. After the reaction was monitored by TCL, water and dichloromethane were added for extraction, and the organic phase was collected. Performing column chromatography (dichloromethane/methanol is 30: 1) to obtain a target compound D3-3130mg of pale yellow viscous liquid, yield: 77.2 percent.
(e1)B4-4The synthesis of (2): compound C4-4(200mg, 0.58mmol), Compound D3-3(165mg, 0.70mmol), sodium carbonate (246mg, 2.32mmol) was added to dioxane/water-4: 1, the nitrogen gas was replaced five times. Followed by addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (43mg, 0.06mmol) was replaced five times with nitrogen. Heating at 100 ℃ for 4h, concentrating under reduced pressure under vacuum, extracting with ethyl acetate, combining organic layers, and adding dichloromethane as a mobile phase: methanol 15: 1 purifying under column chromatography to obtain product B4-4150mg of a tan oily liquid, yield: 46.8 percent.
Wherein, C4-4Reference example 1, except that: will E1-1The substitution is 5-bromopyridine-3-formaldehyde. 1.5g of a pale yellow oily liquid was obtained, yield: 67.6％
(f1)A44The synthesis of (2): referring to step (7) in example 1, Compound B1-1Substitution by Compound B4-4(150mg, 0.40mmol) under the same conditions to give the final product A44Light yellow solid 43mg, yield: 39.1 percent.1H NMR(400MHz,Methanol-d4)δ9.14(d,J＝13.2Hz,1H),9.05(s,1H),9.00(s,1H),8.97(s,1H),8.93(d,J＝1.8Hz,1H),6.77(t,J＝5.2Hz,1H),6.67(d,J＝1.5Hz,1H),6.66–6.62(m,1H),6.24–6.17(m,2H),5.62(dd,J＝9.5,2.4Hz,1H),4.68(s,2H),3.58(t,J＝6.8Hz,2H),3.50(dd,J＝11.6,6.8Hz,2H),2.88(d,J＝4.4Hz,2H),2.86(s,3H).ESI-MS m/z 275.1871(M+H)+Calculating the value: 275.1872.
example 45
This example provides a Compound A45The preparation method comprises the following steps: compound A45Preparation of compound A of reference example 4444The difference is that: step (e)1) C in (1)4-4Synthesis of reference example 1, step (5) of reference example 1, E1-1Replacement by 5-bromopyridine-3-carbaldehyde, F3-3Replacement by equimolar F4-4. The target compound was prepared as a tan solid 62mg, and compound A was obtained in the last step45Yield of (a): 50.8 percent.1H NMR(400MHz,Chloroform-d)δ8.40(s,2H),8.32(s,1H),7.81(s,1H),6.54(d,J＝16.1Hz,2H),6.41–6.28(m,2H),5.67(s,2H),4.15(t,J＝5.6Hz,2H),3.53(s,3H),3.30(s,2H),2.81(s,4H),2.37(s,3H).ESI-MS m/z289.2027(M+H)+Calculating the value: 289.2028.
example 46
This example provides a Compound A46The preparation method comprises the following steps: compound A46Preparation of compound A of reference example 4444The difference is that: step (e)1) C in (1)4-4Reference to step (5) of example 1, E in step (5)1-1Replacement was with equimolar 5-bromo-1-tosyl-1H-indole-3-carbaldehyde. The target compound was prepared as a brown solid 71mg, which in the last step gave compound A46Yield of (a): 67.2％。1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),8.41(t,J＝5.7Hz,1H),8.21(s,1H),7.97(s,1H),7.91(d,J＝8.2Hz,2H),7.85(d,J＝8.7Hz,1H),7.46(dd,J＝8.9,1.6Hz,1H),7.40(d,J＝8.2Hz,2H),6.54(d,J＝15.9Hz,1H),6.38–6.24(m,2H),6.11(dd,J＝17.1,2.3Hz,1H),5.61(dd,J＝10.2,2.3Hz,1H),4.61–4.50(m,2H),3.95(dt,J＝6.4,3.2Hz,2H),3.32(s,4H),2.73(s,3H),2.33(s,3H).ESI-MS m/z 467.2113(M+H)+Calculating the value: 467.2117.
example 47
This example provides a Compound A47The preparation method comprises the following steps: compound A47Preparation of compound A of reference example 4444The difference is that: step (e)1) C in (1)4-4Reference to step (5) of example 1, E in step (5)1-1Replacement with equimolar 5-bromo-1-tosyl-1H-indole-3-carbaldehyde, F1-1Replacement by equimolar F2-2. The title compound was prepared as a brown solid 47mg, which in the last step gave Compound A47Yield of (a): 48.3 percent.1HNMR(400MHz,DMSO-d6)δ11.17(s,1H),8.41(t,J＝5.8Hz,1H),8.22(s,1H),7.97(s,1H),7.91(d,J＝8.3Hz,2H),7.85(d,J＝8.6Hz,1H),7.46(dd,J＝8.8,1.6Hz,1H),7.40(d,J＝8.1Hz,2H),6.55(d,J＝16.0Hz,1H),6.38–6.31(m,1H),6.31–6.23(m,1H),6.11(dd,J＝17.1,2.2Hz,1H),5.61(dd,J＝10.2,2.3Hz,1H),4.57(d,J＝41.0Hz,2H),3.97–3.92(m,2H),2.73(s,4H),2.59(s,6H),2.33(s,3H).ESI-MS m/z481.2281(M+H)+Calculating the value: 481.2273.
example 48
This example provides a Compound A48The preparation method comprises the following synthetic route:
Figure BDA0002263662510000231
the method comprises the following specific steps:
(a2) Compound K4-4The synthesis of (2): compound C4-4(1g, 2.90mmol) was added to dichloromethane, and 1mL of trifluoro-vinegar was addedAcid, and reacting at room temperature overnight. After the TCL detection reaction is finished, the reaction solution is concentrated under reduced pressure. Obtaining a target compound K4-41100mg of a pale yellow viscous liquid (containing trifluoroacetic acid), yield: 100 percent.
(b2) Compound C5-5The synthesis of (2): reacting a compound K4-4(220mg, 0.614mmol) and triethylamine (427. mu.M, 3.07mmol) were added to dichloromethane and ethylsulfonyl chloride (L) was added under ice-bath conditions4-470 μ M, 0.74mmol), and reacting at room temperature for 5 h. After TCL detection reaction, adding water and dichloromethane for extraction, collecting an organic phase, and concentrating the reaction solution under reduced pressure. Column chromatography to obtain target compound C5-5100mg of pale yellow oily liquid, yield: 48.5 percent.
(c2) Compound A48The synthesis of (2): compound C5-5(100mg, 0.30mmol), Compound D2-2(97.5mg, 0.36mmol), sodium carbonate (126mg, 1.2mmol) was added to dioxane/water-4: 1, the nitrogen gas was replaced five times. Followed by addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (22mg, 0.03mmol) was replaced five times with nitrogen. Heating at 100 ℃ for 4h, concentrating under reduced pressure under vacuum, extracting with ethyl acetate, combining organic layers, and adding dichloromethane as a mobile phase: purifying the methanol under column chromatography to obtain a product A4850mg of a pale yellow viscous liquid, yield: 41.4 percent.1HNMR(400MHz,Chloroform-d)δ8.77(d,J＝2.2Hz,1H),8.41(d,J＝2.0Hz,1H),8.34(s,1H),8.18(d,J＝8.1Hz,1H),7.98(t,J＝2.2Hz,1H),7.51(t,J＝2.0Hz,1H),7.45(t,J＝7.9Hz,1H),7.37(dt,J＝7.9,1.3Hz,1H),6.46(dd,J＝16.9,1.5Hz,1H),6.32(dd,J＝16.9,10.1Hz,1H),5.75(dd,J＝10.1,1.6Hz,1H),5.16(s,1H),3.64(s,2H),3.49(s,2H),3.22(s,2H),2.61–2.53(m,2H),2.37(s,3H),1.37(t,J＝7.4Hz,3H).ESI-MS m/z 403.1809(M+H)+Calculating the value: 403.1804.
example 49
This example provides a Compound A49The preparation method comprises the following steps: compound A49Preparation of compound A of reference example 4848The difference is that: step (c)2) In D2-2Replacement by equimolar D1-1. The prepared target compound is 42mg of light yellow viscous liquid, and the compound A is obtained in the last step49Yield of (a): 40.1 percent.1H NMR(400MHz,Chloroform-d)δ8.73(d,J＝2.2Hz,1H),8.48(d,J＝2.0Hz,1H),7.81(t,J＝2.2Hz,1H),7.59–7.53(m,2H),7.42(d,J＝8.1Hz,2H),6.35(dd,J＝17.0,1.5Hz,1H),6.15(dd,J＝17.0,10.3Hz,1H),6.00(s,1H),5.70(dd,J＝10.3,1.5Hz,1H),4.82(s,1H),4.58(d,J＝5.9Hz,2H),3.62(s,2H),3.22(s,2H),2.63(dd,J＝6.6,5.0Hz,2H),2.25(s,3H),1.32(t,J＝7.4Hz,3H).ESI-MS m/z 417.1952(M+H)+Calculating the value: 417.1960.
example 50
This example provides a Compound A50The preparation method comprises the following steps: compound A50Preparation of compound A of reference example 4848The difference is that: step (b)2) Ethyl sulfonyl chloride L in (1)4-4Replacement was with equimolar methanesulfonyl chloride. Preparation of the obtained object Compound A5062mg of light yellow viscous liquid is obtained in the last step50Yield of (a): 57.2 percent.1H NMR(400MHz,Chloroform-d)δ8.80(s,1H),8.68(s,1H),8.38(s,1H),8.06(d,J＝8.2Hz,1H),7.93(s,1H),7.56(s,1H),7.38(t,J＝7.8Hz,1H),7.28(d,J＝8.2Hz,1H),6.50–6.34(m,2H),5.83(s,1H),5.72(d,J＝9.5Hz,1H),3.59(s,2H),3.23(t,J＝5.6Hz,2H),2.97(s,3H),2.54(t,J＝5.6Hz,2H),2.32(s,3H).ESI-MS m/z 389.1642(M+H)+Calculating the value: 389.1647.
example 51
This example provides a Compound A51The preparation method comprises the following steps: compound A51Preparation of compound A of reference example 4848The difference is that: step (c)2) In D2-2Replacement by equimolar D1-1Step (b)2) Ethyl sulfonyl chloride L in (1)4-4Replacement was with equimolar methanesulfonyl chloride. Preparation of the obtained object Compound A51Is a yellowish viscous liquid (48 mg) to obtain compound A51Yield of (a): 43.9 percent.1H NMR(400MHz,Chloroform-d)δ8.58(d,J＝2.2Hz,1H),8.42(d,J＝2.0Hz,1H),7.80(t,J＝2.1Hz,1H),7.48(d,J＝7.9Hz,2H),7.35(d,J＝7.9Hz,2H),7.01(t,J＝6.0Hz,1H),6.32(dd,J＝17.0,1.9Hz,1H),6.21(dd,J＝17.0,10.0Hz,1H),5.64(dd,J＝9.9,1.9Hz,1H),5.48–5.35(m,1H),4.50(d,J＝5.8Hz,2H),3.58(s,2H),3.23(t,J＝5.8Hz,2H),2.89(s,3H),2.62(t,J＝5.9Hz,2H),2.24(s,3H).ESI-MS m/z 403.1807(M+H)+Calculating the value: 403.1804.
example 52
This example provides a Compound A52The preparation method comprises the following synthetic route:
the method comprises the following specific steps:
(a3) Compound V1-1The synthesis of (2): (3-bromophenyl) methanol (1g, 5.35mmol) and triethylamine (967. mu.M, 6.95mmol) were added to dichloromethane, and methanesulfonyl chloride (497. mu.M, 6.42mmol) was added under ice-bath conditions and reacted at room temperature for 2 h. After the TCL detection reaction is finished, adding saturated sodium bicarbonate solution for extraction, collecting an organic phase, and concentrating the reaction solution under reduced pressure. Column chromatography to obtain target compound V1-11.12g of a pale yellow oily liquid, yield: 79.0 percent.
(b3) Compound C6-6The synthesis of (2): reacting a compound V1-1(300mg, 1.13mmol), Compound F2-2(638mg, 3.39mmol) and potassium carbonate (156.2mg, 1.13mmol) were added to dry tetrahydrofuran and reacted under reflux overnight. After TCL detection reaction, adding saturated ammonium chloride/ethyl acetate for extraction, collecting organic phase, and concentrating under reduced pressure. Column chromatography to obtain target compound C6-6392mg of a pale yellow oily liquid, yield: 97.1 percent.
(c3) Compound B52The synthesis of (2): compound C6-6(186mg, 0.52mmol), Compound D1-1(178mg, 0.62mmol), sodium carbonate (221mg, 2.08mmol) was added to dioxane/water-4: 1, the nitrogen gas was replaced five times. Followed by the addition of [1,1' -bis (diphenyl)Phosphine) ferrocene]Palladium dichloride dichloromethane complex (38mg, 0.05mmol) was replaced five times with nitrogen. Heating at 100 ℃ for 4g, concentrating under reduced pressure under vacuum, extracting with ethyl acetate, combining organic layers, and adding dichloromethane as a mobile phase: purifying the methanol under column chromatography to obtain a product B52133mg of pale yellow viscous liquid, yield: 58.5 percent.
(d3)A52The synthesis of (2): referring to step (7) in example 1, Compound B1-1Substitution by Compound B52(133mg, 0.30mmol) under the same conditions to give the final product A52Off-white solid 74mg, yield: 56.4 percent.1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),8.67(t,J＝5.9Hz,1H),8.00(s,1H),7.76(d,J＝7.0Hz,1H),7.72(d,J＝8.1Hz,2H),7.57(s,1H),7.38(d,J＝8.0Hz,2H),6.31(dd,J＝17.1,10.2Hz,1H),6.14(dd,J＝17.1,2.2Hz,1H),5.63(dd,J＝10.1,2.2Hz,1H),4.40(d,J＝6.0Hz,2H),3.55(s,2H),3.40–3.34(m,2H),2.81–2.69(m,3H),2.62–2.57(m,3H),2.43–2.48(m,2H).ESI-MSm/z 338.2226(M+H)+Calculating the value: 338.2432.
example 53
This example provides a Compound A53The preparation method comprises the following steps: compound A53Preparation of compound A of reference example 5252The difference is that: step (b)3) F in (1)2-2Replacement by equimolar F1-1. Preparation of the obtained object Compound A5368mg as an off-white solid, to give Compound A in the last step53Yield of (a): 50.1 percent.1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),8.01(s,1H),7.74(dd,J＝13.6,7.3Hz,3H),7.55(d,J＝7.4Hz,2H),7.38(d,J＝8.0Hz,2H),6.31(dd,J＝17.0,10.0Hz,1H),6.14(d,J＝17.0Hz,1H),5.63(d,J＝10.3Hz,1H),4.57–4.48(m,2H),4.40(d,J＝6.2Hz,2H),3.42–3.37(m,2H),2.76(d,J＝4.1Hz,3H),2.61–2.50(m,2H).ESI-MS m/z 324.2077(M+H)+Calculating the value: 324.2076.
example 54
This example provides a Compound A54The preparation method comprises the following synthetic route:
Figure BDA0002263662510000251
the method comprises the following specific steps:
(a4) Compound C7-7The synthesis of (2): compound E1-1Compound F2-2Glacial acetic acid is added into dichloroethane, and sodium triacetoxyborohydride is added in batches at the temperature of 0 ℃). The reaction mixture was reacted at room temperature overnight. And (3) monitoring the reaction completion by TCL, adding a saturated sodium bicarbonate solution to adjust the pH to 7-8, adding dichloromethane to extract, and collecting an organic phase. Column chromatography to obtain target compound C7-7。
(b4) Compound C1-7-7The synthesis of (2): compound C7-7(500mg, 1.4mmol), 3-aminophenylboronic acid pinacol ester (368mg, 1.68mmol), sodium carbonate (592mg, 5.6mmol) was added to dioxane/water ═ 4: 1, the nitrogen gas was replaced five times. Followed by addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (102mg, 0.14mmol) was replaced five times with nitrogen. Heating at 100 deg.C for 4h, vacuum concentrating, extracting with ethyl acetate, mixing organic layers, and adding dichloromethane as mobile phase: purifying the methanol under column chromatography to obtain a product C1-7-7Brown oily liquid 240mg, yield: 46.3 percent.
(c4) Compound B54The synthesis of (2): compound C1-7-7(75mg, 0.20mmol), potassium carbonate (83mg, 0.6mmol) were added to dichloromethane and 3-chloropropionyl chloride (29. mu.L, 0.3mmol) was added at 0 ℃. The reaction solution was reacted at room temperature for 4 hours. After the reaction was monitored by TCL, water and dichloromethane were added for extraction, and the organic phase was collected. Performing column chromatography (dichloromethane/methanol 25: 1) to obtain the target compound B54Light yellow viscous liquid 71mg, yield: 77.0 percent.
(d4) Compound A54The synthesis of (2): referring to step (7) in example 1, Compound B1-1Substitution by Compound B54(71mg, 0.154mmol) under the same conditions to give the final product A54Brown solid 49mg, yield: 80.0％。1H NMR(400MHz,Methanol-d4)δ9.60(d,J＝10.1Hz,1H),9.38(s,1H),9.33(s,1H),9.28(s,1H),8.30(s,1H),7.75(dd,J＝16.2,7.8Hz,2H),7.69(s,1H),7.60(t,J＝7.7Hz,1H),3.89(t,J＝2.4Hz,2H),3.86–3.79(m,4H),3.71(d,J＝5.7Hz,3H),2.85(s,3H),2.83(t,J＝3.1Hz,2H),2.81(s,2H).ESI-MS m/z361.1789(M+H)+Calculating the value: 361.1795.
example 55
This example provides a Compound A55The preparation method comprises the following steps: compound A55Preparation of compound A of reference example 5454The difference is that: step (c)4) The 3-chloropropionyl chloride in the (C) is replaced by equimolar chloroacetyl chloride. Preparation of the obtained object Compound A5561mg as a tan solid, the final step gave Compound A55Yield of (a): 57.3 percent.1HNMR(400MHz,Methanol-d4)δ9.63(d,J＝10.1Hz,1H),9.36(s,1H),9.32(s,1H),9.28(s,1H),8.31(s,1H),7.70(dd,J＝16.2,7.8Hz,2H),7.64(s,1H),7.60(t,J＝7.7Hz,1H),4.32(s,2H),3.86–3.79(m,4H),3.71(d,J＝5.1Hz,3H),2.84(s,3H),2.80(s,2H).ESI-MS m/z347.1632(M+H)+Calculating the value: 347.1638
Example 56
This example provides a Compound A56The preparation method comprises the following steps: compound A56Preparation of compound A of reference example 5454The difference is that: step (c)4) The 3-chloropropionyl chloride in the (A) is replaced by equimolar dichloroacetyl chloride. Preparation of the obtained object Compound A5649mg of a tan solid, the final step to give Compound A56Yield of (a): 39.8 percent.1H NMR(400MHz,Methanol-d4)δ9.85(s,1H),9.53(s,1H),9.30(s,1H),9.28(s,1H),8.47(s,1H),7.89(dd,J＝16.2,7.8Hz,2H),7.76(s,1H),7.63(t,J＝6.8Hz,1H),3.89–3.81(m,4H),3.71(d,J＝5.1Hz,3H),2.80(s,3H),2.78(s,2H).ESI-MS m/z 381.1243(M+H)+Calculating the value: 381.1249.
example 57
This example provides a Compound A57The preparation method comprises the following steps: transformingCompound A57Preparation of compound A of reference example 5454The difference is that: step (c)4) The 3-chloropropionyl chloride in (A) is replaced by equimolar chloromethylsulfonyl chloride. Preparation of the obtained object Compound A5743mg as a tan solid, the final step to give Compound A57Yield of (a): 35.1 percent.1H NMR(400MHz,Methanol-d4)δ10.21(s,1H),9.49(s,1H),9.38(s,1H),9.36(s,1H),8.58(s,1H),7.68(dd,J＝16.2,7.8Hz,2H),7.62(s,1H),7.57(t,J＝7.7Hz,1H),5.12(s,2H),3.76–3.70(m,4H),3.66(d,J＝5.1Hz,3H),2.95(s,3H),2.83(s,2H).ESI-MS m/z383.1303(M+H)+Calculating the value: 383.1308.
experimental example 1 the compound of the present invention inhibits the in vitro enzymatic activity of PRMT6 and inhibits the proliferation of lymphoma cell line Toledo and pancreatic cancer cell line Capan-2
(1) Because the related PRMT family targets are more, in order to save time and cost, PRMT6 enzyme is selected for the compound primary screening, and the compound with better activity is subjected to in vitro enzyme activity test of a plurality of PRMTs. The compounds of the invention inhibit PRMT6 enzyme activity: compounds were tested for PRMT6 enzyme activity using the AlphaLISA screening method. The method comprises the following steps: 100 mul of compound solutions with different concentrations were added to 384-well assay plates, and five-fold dilution was used, with a maximum concentration of 5000nM and a minimum concentration of 0.32nM, with 2 duplicate wells per drug concentration. Then 5. mu.L of PRMT6 enzyme solution was added to each well, and the wells were centrifuged at 1000rpm/min for 1min and incubated for 15 min. Then 5. mu.L of substrate (SAM: S-adenosylmethionine) was added, centrifuged at 1000rpm/min for 1min, and incubated at room temperature for 1 h. And after the incubation is finished, adding 5 mu L of acceptor magnetic beads to terminate the enzyme reaction, centrifuging at 1000rpm/min for 1min, incubating at room temperature for 1h, finally adding 10 mu L of donor magnetic beads under the condition of keeping out of the light, centrifuging at 1000rpm/min for 1min, incubating at room temperature for 30min, and detecting the signal intensity by using the Alpha mode of EnSpire. Calculate half maximal Inhibitory Concentration (IC) of compound on PRMT6 enzyme activity50)。
(2) The compounds of the invention inhibit cell proliferation: lymphoma cell lines Toledo and pancreatic cancer cell lines Capan-2 were purchased from American Type Culture Collection (ATCC), RPMI1640 medium, Fetal Bovine Serum (FBS) were purchased from gibioc corporation, usa; penicillin and streptomycin were purchased from Dalibao bio; cultured cells were purchased from Corning, such as plates and 96-well plates; centrifuge tubes of various specifications were purchased from BD corporation; MTT reagent was purchased from Donjind, Japan institute of Homond chemistry.
Lymphoma cell line Toledo and pancreatic cancer cell line Capan-2 were cultured in conventional high-sugar RPMI1640 or DMEM complete medium containing 10% Fetal Bovine Serum (FBS), 100IU/mL penicillin and 100. mu.g/mL streptomycin at 37 ℃ with 5% CO2Cultured in an incubator. The purpose of the experiment is to detect the proliferation influence of the compound on lymphoma cell strains Toledo and pancreatic cancer cell strains Capan-2. Collecting cells in a logarithmic growth phase, adjusting the cell concentration to be 1000-2000 single cell suspension, and inoculating the single cell suspension into a 96-well plate according to 100uL per well. Stock solutions of compounds (10mM/L in DMSO) were diluted in medium to different concentrations using a three-fold dilution. Adding the extract into a 96-well plate according to the volume of 100uL per well, wherein the highest concentration is 50 muM, the lowest concentration is 0.08 muM, 2 multiple wells are arranged for each drug concentration, treating cells by using a culture medium containing 0.1% DMSO and a pure culture medium as negative controls, placing the cells in a cell culture box for continuous culture for 6 days, detecting the activity of mitochondrial succinate dehydrogenase of the cells by adopting MTT, and calculating the half effective Inhibition Concentration (IC) of the new compound on tumor cells50) The value is obtained.
The results of the compounds of the present invention on inhibition of PRMT6 in vitro enzyme activity and inhibition of proliferation of lymphoma cells Toledo and pancreatic cancer cell line Capan-2 are shown in Table 1 below, wherein the letter α represents IC50The value is 50nM or less, the letter β denotes 50nM<IC50The value is less than or equal to 500 nM; the letter gamma denotes 0.5. mu.M<IC50The value is less than or equal to 5 mu M; letter delta denotes 5. mu.M<IC50The value is less than or equal to 50 mu M; the letter ε denotes IC50Value of>50μM。
TABLE 1 Effect on in vitro enzyme Activity of PRMT6, proliferation of lymphoma cells Toledo and pancreatic cancer cell line Capan-2
Compound (I) PRMT6 Toledo Capan-2 Compound (I) PRMT6 Toledo Capan-2
A1 β γ δ A30 δ δ ε
A2 α γ δ A31 δ δ ε
A3 γ δ δ A32 β γ δ
A4 γ δ δ A33 β δ γ
A5 α γ δ A34 β γ δ
A6 α δ γ A35 β δ δ
A7 β δ δ A36 δ γ γ
A8 β γ δ A37 γ δ γ
A9 β δ δ A38 δ γ γ
A10 α δ δ A39 δ γ γ
A11 α δ δ A40 γ γ δ
A12 α γ γ A41 β γ γ
A13 β δ δ A42 β γ γ
A14 α δ δ A43 β γ γ
A15 α γ δ A44 β δ δ
A16 β δ δ A45 α δ δ
A17 α γ γ A46 δ δ ε
A18 γ δ δ A47 δ ε ε
A19 γ δ δ A48 δ ε δ
A20 α δ γ A49 δ ε ε
A21 β δ δ A50 δ ε ε
A22 β γ γ A51 δ δ ε
A23 β γ γ A52 β δ δ
A24 γ γ δ A53 β δ δ
A25 β γ γ A54 α δ δ
A26 β δ γ A55 β δ δ
A27 α γ γ A56 β δ δ
A28 δ ε δ A57 β γ γ
A29 δ δ δ
As can be seen from Table 1, most of the compounds of the present invention were effective in inhibiting PRMT6 enzyme activity in vitro at nanomolar concentrations, with half the inhibitory concentration of over ten compounds being less than 50nM and Compound A12、A15The half inhibitory concentration of the compounds was less than 10 nM. The compound of the invention has obvious inhibitory effect on PRMT 6.
At the same time, the data in Table 1 show that the compounds of the present invention are effective in inhibiting the proliferation of lymphoma and pancreatic cancer, wherein A2、A17、A27、A42、A43、A57The proliferation inhibition activity of a plurality of tested compounds on lymphoma cells Toledo and pancreatic cancer cell strains Capan-2 is good, and IC50Values are micromolar.
Experimental example 2 the inhibitory effect of reversible analogs of the compounds of the present invention on the in vitro enzymatic activity of PRMT6 is significantly weaker than that of covalent inhibitors
The covalent inhibitor is designed by adopting acrylamide and other groups as electrophilic reactive groups to react with Cys50 electron-rich sulfydryl of PRMT6 protein to form a covalent bond. If the acrylamide at the position corresponding to the inhibitor is replaced by propane amide, the inhibitor cannot undergo an addition reaction with the mercapto group at Cys50, and the IC thereof50The value will increase greatly. Accordingly, the invention designs and synthesizes A2、A6、A12Propanoyl reversible analogs of (A)2’、A6’、A12' (as shown in FIG. 1). The compounds were tested for inhibition of PRMT6 enzyme activity using the AlphaLISA method, and the results are shown in figure 1.
As shown in FIG. 1, covalent inhibitor A2、A6、A12The inhibition effect on the enzyme activity of PRMT6 is obviously stronger than that of the reversible analogue A thereof2’、A6’、A12'. The covalent interaction between the compound and PRMT6 protein is shown to be the key point of higher inhibitory activity of the compound. Experimental example 3 the in vitro enzyme activity inhibition of the compound of the invention on other Tpye I class PRMTs is obviously better than that of Tpye II class and Tpye III class PRMTs, and the inhibition activity of the corresponding reversible analogue is obviously worse than that of covalent inhibitor
The results of the test of the inhibition of the enzyme activities of the compounds on types I (PRMT1\ PRMT3\ PRMT4\ PRMT8), II (PRMT5) and III (PRMT7) PRMTs other than PRMT6 by the AlphaLISA method are shown in FIG. 2 and FIG. 3.
As shown in FIGS. 2 and 3, Compound A12、A27The in vitro enzyme inhibition activity of the I type (PRMT1\ PRMT3\ PRMT4\ PRMT8) PRMTs except PRMT6 is obviously higher than that of the II type (PRMT5) and the III type (PRMT7) PRMTs. Indicating Compound A12、A27Can be selectively used for Tpye I PRMTs, and has better selectivity. At the same time, compound A12、A27Reversible analogs of (A)12’、A27' the inhibitory activity to other types I (PRMT1\ PRMT3\ PRMT4\ PRMT8) PRMTs is greatly inferior to that of covalent inhibitors, which shows that the compound of the invention plays an inhibitory activity through the covalent interaction with PRMT1, PRMT3, PRMT4 and PRMT8 proteins.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims (10)

1. A compound targeting PRMT type I or a pharmaceutically acceptable salt thereof, wherein the compound has the structural formula shown in formula (a):
Figure FDA0002263662500000011
wherein Ar is selected from a substituted or unsubstituted six-membered aromatic ring, a substituted or unsubstituted six-membered and five-membered aromatic ring; linker is selected fromX is selected from methylene and carbonyl; r1Selected from H, C1～3Alkyl and substituted sulfonyl; r2Is selected from H or C1～3An alkyl group; r3Selected from groups that covalently react with cysteine; r4、R5、R6、R7Each independently selected from H and C1～3An alkyl group; n is an integer between 1 and 6; m is an integer of 0 to 3.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar is selected from
Figure FDA0002263662500000013
Figure FDA0002263662500000014
Figure FDA0002263662500000015
Any one of (a);
optionally, m is 0, 1 or 2;
optionally, Linker is selected from
Figure FDA0002263662500000016
Any one of (a);
optionally, X is methylene;
optionally, R2Is methyl;
optionally, n is 1,2 or 3.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is3Is selected from
Figure FDA0002263662500000021
Figure FDA0002263662500000022
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the structures:
Figure FDA0002263662500000023
Figure FDA0002263662500000031
Figure FDA0002263662500000041
Figure FDA0002263662500000051
Figure FDA0002263662500000061
5. a process for the preparation of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) deprotecting the compound B under the action of acid to obtain a compound A;
the structural formula of the compound B is as follows:
the preparation method of the compound B comprises the following steps: (b)1) Under the action of alkali and a palladium catalyst, carrying out Suzuki coupling reaction on the compound C and the compound D to obtain a compound B;
the structural formulas of the compound C and the compound D are as follows:
Figure FDA0002263662500000072
alternatively, the preparation method of the compound B comprises the following steps: (b)2) Compound C1Reacting with a compound Q under the action of an acid binding agent to obtain a compound B;
the compound C1And the structural formula of compound Q is as follows:
Figure FDA0002263662500000073
6. a process for preparing a compound according to claim 5, wherein when X is methylene, R is1Selected from H and C1～3When alkyl, preparation of said compound CThe method comprises the following steps: (c)1) Under the acidic condition, carrying out reductive amination reaction on the compound E and the compound F under the action of a reducing agent to obtain a compound C;
the structural formulas of the compound E and the compound F are as follows:
Figure FDA0002263662500000074
when X is carbonyl, R1Selected from H and C1～3When the alkyl is adopted, the preparation method of the compound C comprises the following steps: (c)2) Carrying out amide condensation reaction on the compound G and the compound F under the action of a condensing agent to obtain a compound C;
the structural formula of the compound G is as follows:
Figure FDA0002263662500000081
when R is1Is a substituted sulfonyl group
Figure FDA0002263662500000082
When R is8Is selected from C1～3Alkyl, the preparation method of the compound C comprises the following steps: (c)31) Under the acidic condition, carrying out reductive amination reaction on the compound E and the compound H under the action of a reducing agent to obtain a compound J; (c)32) Deprotecting the compound J under an acidic condition to obtain a compound K; (c)33) Under the action of an acid binding agent, reacting the compound K with the compound L to obtain a compound C;
the structural formulae of compounds H, J, K and L are as follows:
Figure FDA0002263662500000083
when Ar is
Figure FDA0002263662500000084
The preparation method of the compound C comprises the following steps: (c)4) Reacting the compound V with the compound F under the action of alkali to obtainTo compound C;
the structural formula of the compound V is as follows:
7. the method of claim 5, wherein Compound C is prepared as described in claim 5, or a pharmaceutically acceptable salt thereof1The preparation method comprises the following steps: (c)34) Under the action of alkali and catalyst, compound C and compound Y are subjected to Suzuki coupling reaction to obtain compound C1；
The structural formula of the compound Y is as follows:
Figure FDA0002263662500000086
alternatively, the preparation method of the compound D comprises the following steps: (d) reacting the compound Y with the compound Q under the action of an acid-binding agent to obtain a compound D;
alternatively, the preparation method of the compound Y comprises: (y) Compound S1Compound S2Or compounds S3Deprotecting under the action of acid to obtain a compound Y;
the compound S1Compound S2And a compound S3The structural formulas are respectively as follows:
Figure FDA0002263662500000091
optionally, the compound S1The preparation method comprises the following steps: (s)1) Under basic conditions, compound T1Reacting with pinacol ester of diboronic acid under the action of palladium catalyst to obtain a compound S1；
The compound T1The structural formula of (A) is as follows:
Figure FDA0002263662500000092
alternatively, the compound T1The preparation method comprises the following steps: (t)1) Under basic conditions, compound U1Reacting with Boc anhydride under alkaline condition to obtain compound T1；
The compound U1The structural formula of (A) is as follows:
Figure FDA0002263662500000093
optionally, the compound S2The preparation method comprises the following steps: (s)2) Under basic conditions, compound T2Reacting with pinacolborane under the action of hydrochlorozirconocene to obtain a compound S2；
The compound T2The structural formula of (A) is as follows:
Figure FDA0002263662500000094
alternatively, the compound T2The preparation method comprises the following steps: (t)2) Under basic conditions, compound U2Reacting with Boc anhydride to obtain compound T2；
The compound U2The structural formula of (A) is as follows:
Figure FDA0002263662500000095
8. a pharmaceutical composition comprising a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof;
optionally, the pharmaceutical composition further comprises pharmaceutically acceptable auxiliary materials or auxiliary components.
9. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the activity of type i PRMT enzyme or in the manufacture of a type i PRMT inhibitor.
10. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of an anti-neoplastic medicament, or in the manufacture of a medicament for use in the treatment of cardiovascular disease, neurodegenerative disease, malaria, aids, gout, diabetes, renal failure, chronic lung disease, oculopharyngeal muscular dystrophy, cocaine addiction, pulmonary hypertension disease, amyotrophic lateral sclerosis, or alcoholic cirrhosis;
optionally, the tumor comprises any one of brain cancer, glioblastoma, leukemia, lymphoma, Bannayan-Zonana syndrome, cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, wilms 'tumor, ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, stomach cancer, cancer of the shoulder skin, cancer of the head and neck, 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.
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