Polycyclic compounds inhibiting RNA helicase DHX33 and their applications

Abstract

The present invention relates to a polycyclic compound that inhibits RNA helicase DHX33 and its application. In particular, the present invention relates to a compound represented by formula I or a pharma- ceutical acceptable form thereof, a pharmaceutical composition comprising the compound, a method for preparing the compound, and a pharmaceutical use thereof for preventing and / or treating DHX33-related diseases. JPEG2024524766000096.jpg3478

Description

[Technical field]

[0001] The present invention belongs to the field of medicinal chemistry and relates to small molecule inhibitors of DHX33, pharmaceutical compositions containing same, methods for their preparation, and their use in medicine for the prevention and / or treatment of DHX33-related diseases. [Background technology]

[0002] The present invention relates to a compound that inhibits the RNA helicase activity of DHX33. DHX33 belongs to the RNA helicase protein family that contains a DEAD / H box. Among them, DEAD / H is an abbreviation of the amino acids Asp-Glu-Ala-Asp / His, and this sequence appears in the protein sequences of RNA helicase family members along with several other conserved amino acid sequences, and is deeply involved in the binding of nucleic acid substrates and ATP hydrolysis. Although these family members have the same sequence, each RNA helicase has its own specificity and unique biological function. Human DHX33 protein has a molecular weight of about 72 kDa and has the function of unwinding nucleic acids, and uses the bioenergy released by ATP hydrolysis to change the conformation of the RNA-protein complex, thereby participating in various RNA metabolic activities. Specifically, RNA metabolic activities include a series of biological processes such as RNA transcription, splicing, editing, translation, and degradation. The function of DHX33 is not limited to the modification of RNA molecules, and research has revealed that in addition to unwinding double-stranded RNA, DHX33 protein is also involved in DNA metabolism. Specifically, DHX33 protein can unwind the double-stranded structure of DNA and play an important role in gene expression.

[0003] Research has revealed that DHX33 affects the DNA methylation state by binding to various gene promoters related to cancer, controls the expression of various cancer genes and signal pathways related to tumor progression at the genome level, and plays an important role in various cellular activities such as cell growth, proliferation, migration, apoptosis, and glucose metabolism. In addition, DHX33 can sense the invasion of foreign double-stranded RNA molecules and has been found to play an important role in the innate immunity of cells.

[0004] As a very important cell growth control gene, DHX33 is highly expressed in various cancers, including lung cancer, lymphoma, glioma, breast cancer, colon cancer, and liver cancer. The onset and progression of various cancers depend on the high expression of DHX33 protein. Genetic knockout of DHX33 can significantly suppress the onset and progression of lung cancer driven by RAS oncogene. In vivo and in vitro studies have demonstrated that inhibition of DHX33 protein significantly suppressed the onset and progression of many cancers, including breast cancer, colon cancer, glioma, and lymphoma.

[0005] Research has shown that the protein function of DHX33 depends on its helicase activity. A mutant lacking the helicase activity of DHX33 does not have the function of the DHX33 protein and cannot replace the function of the wild-type DHX33 gene. The present invention provides structures and methods for synthesis of various compounds with enzymatic activity that inhibit DHX33, and these compounds have utility in the manufacture of medicaments for treating diseases or conditions mediated at least in part by DHX33. Summary of the Invention [Problem to be solved by the invention]

[0006] As a result of extensive research, the present invention has discovered a series of small molecule compounds that inhibit the RNA helicase activity of DHX33 and have potential value in the prevention and / or treatment of DHX33-related diseases.

[0007] In a first aspect, the present invention provides a compound having the structure of Formula I, or a pharma- ceutically acceptable form thereof. [ka] (In the formula, X 1 is N or CR 1 Selected from X 2 is N or CR 2 Selected from X 3 is N or CR 3 Selected from X 4 is N or CR 4 Selected from; R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, amino, nitro, hydroxyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl)2, C 1~6 Hydroxyalkyl, -O-(C 1~6 alkylene)-O-(C 1~6 alkyl), -C(=O)-NH-(C 1~6 alkyl), -C(=O)-NH-(C 1~6 Alkylene)-N(C 1~6 alkyl)2 or -C(=O)-O-(C 1~6 alkyl); X 5 is N or CR 5 Selected from R 5 is hydrogen, halogen or C 1~6 alkyl, 1~6 Alkyl is halogen, C 1~6 Alkyl, -(C 1~6 alkylene)-O-(C 1~6 alkyl) or -(C 1~6 alkylene)-OC(=O)-(C 1~6alkyl); L 1 -NR 6 C(=O)-, -NR 6 S(=O)2-, -NR 6 S(=O)-, -C(=O)NR 6 -, -S(=O)2NR 6 -or-S(=O)NR 6 - Selected from; Each R 6 are each independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl or C 6~10 aryl; Ring A is selected from a 5- to 10-membered heteroaryl or a 3- to 8-membered heterocyclic group, and Ring A is selected from one or more R 7 may be substituted with; Each R 7 are each independently a halogen, C 1~6 Alkyl or C 1~6 haloalkyl; L 2 is a single bond, O, S or CR 8 R 9 Selected from; R 8 and R 9 are each independently hydrogen, halogen or C 1~6 alkyl; Ring B is C 6~10 aryl, 5- to 12-membered heteroaryl, or 3- to 8-membered heterocyclic group; Ring B is selected from one or more R 10 may be substituted with; Each R 10 are each independently halogen, cyano, amino, nitro, hydroxyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~6 Cycloalkyl, -C(=O)-O-(C 1~6alkyl), phenyl, benzyl, pyridyl, -C(=O)-NH2, or -NH-C(=O)-(C 1~6 alkyl), wherein the phenyl, benzyl, and pyridyl are selected from hydrogen, halogen, cyano, amino, hydroxyl, C 1~6 Alkyl or C 1~6 alkoxy), The pharma- ceutically acceptable forms are selected from pharma- ceutically acceptable salts, esters, stereoisomers, tautomers, solvates, nitrogen oxides, isotopically labeled products, metabolites and prodrugs.

[0008] In some embodiments, R in the compound of formula I or a pharma- ceutically acceptable form thereof is 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, amino, nitro, hydroxyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl)2 or C 1~6 hydroxyalkyl.

[0009] In some preferred embodiments, R in the compound of formula I or a pharma- ceutically acceptable form thereof is 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, amino, nitro, hydroxyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 haloalkoxy.

[0010] In some more preferred embodiments, R in the compound of formula I or a pharma- ceutically acceptable form thereof is 1 , R 2, R 3 and R 4 are each independently selected from hydrogen, halogen, amino, nitro, hydroxyl, methyl, methoxy, or trifluoromethoxy. In some embodiments, R in the compound of formula I or a pharma- ceutically acceptable form thereof is 5 is hydrogen, halogen or C 1~4 alkyl, 1~4 Alkyl is halogen, C 1~4 Alkyl, -(C 1~4 alkylene)-O-(C 1~4 alkyl) or -(C 1~4 alkylene)-OC(=O)-(C 1~4 alkyl).

[0011] In some embodiments, R in the compound of formula I or a pharma- ceutically acceptable form thereof is 5 is hydrogen, halogen or C 1~4 alkyl, 1~4 Alkyl is halogen, C 1~4 It may be optionally substituted with one or more substituents selected from alkyl, -CH2-O-CH3 or -CH2-OC(=O)-CH3.

[0012] In some preferred embodiments, R in the compound of formula I or a pharma- ceutically acceptable form thereof is 5 is selected from hydrogen, halogen or methyl.

[0013] In some embodiments, L in the compound of formula I or a pharma- ceutically acceptable form thereof is 1 -NR 6 C(=O)-, -NR 6 S(=O)2-, -C(=O)NR 6 - or -S(=O)NR 6 - selected from, each R 6 are each independently hydrogen, C 1~4 Alkyl or C 3~6cycloalkyl.

[0014] In some preferred embodiments, L in the compound of formula I or a pharma- ceutical acceptable form thereof is 1 -NR 6 C(=O)-, -NR 6 S(=O)2-, -C(=O)NR 6 - or -S(=O)NR 6 - selected from, each R 6 are each independently hydrogen or C 1~4 is selected from alkyl.

[0015] In some more preferred embodiments, L in the compound of formula I or a pharma- ceutical acceptable form thereof is 1 is selected from -NHC(=O)-, -N(CH3)-C(=O)-, -NHS(=O)2-, -C(=O)NH- or -S(=O)2NH-.

[0016] In some embodiments, ring A in the compound of formula I or a pharma- ceutically acceptable form thereof is selected from 5-10 membered heteroaryl, and ring A is selected from one or more R 7 and each R 7 are each independently a halogen, C 1~4 Alkyl or C 1~4 haloalkyl.

[0017] In some preferred embodiments, ring A in the compound of formula I or a pharma- ceutically acceptable form thereof is selected from pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, or oxazolyl, and ring A is selected from one or more R 7 and each R 7 are each independently selected from halogen, methyl, ethyl, or trifluoromethyl.

[0018] In some more preferred embodiments, ring A in the compound of formula I or a pharma- ceutically acceptable form thereof is selected from pyrrolyl or imidazolyl, and ring A is selected from one or more R 7 and each R 7 are each independently selected from halogen or methyl.

[0019] In some particularly preferred embodiments, ring A in the compound of formula I or a pharma- ceutically acceptable form thereof is [ka] or [ka] is selected from.

[0020] In some embodiments, L in the compound of formula I or a pharma- ceutically acceptable form thereof is 2 is a single bond or CR 8 R 9 Selected from; R 8 and R 9 are each independently hydrogen, halogen or C 1~4 is selected from alkyl.

[0021] In some preferred embodiments, L in the compound of formula I or a pharma- ceutical acceptable form thereof is 2 is selected from a single bond, -CH2- or -CH(CH3)-.

[0022] In some embodiments, ring B in the compound of formula I or a pharma- ceutically acceptable form thereof is C 6~10 aryl or 5-12 membered heteroaryl, and ring B is selected from one or more R 10 and each R 10 are each independently halogen, cyano, amino, nitro, hydroxyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Alkoxy, C 1~6 Haloalkoxy, C 3~6 It is selected from cycloalkyl or -C(=O)-NH2.

[0023] In some preferred embodiments, ring B in the compound of formula I or a pharma- ceutically acceptable form thereof is C 6~10 aryl or 5-10 membered heteroaryl, and ring B is selected from one or more R 10 and each R 10 are each independently halogen, cyano, amino, nitro, hydroxyl, C 1~4 Alkyl, C 1~4 It is selected from alkoxy or -C(=O)-NH2.

[0024] In some more preferred embodiments, Ring B in the compound of Formula I or a pharma- ceutically acceptable form thereof is selected from phenyl, pyrazinyl, pyridyl, pyrimidinyl, furyl, oxazolyl, thienyl, thiazolyl, pyrazolyl, or imidazolyl, and Ring B is selected from one or more R 10 and each R 10 are each independently selected from halogen, cyano, amino, nitro, hydroxyl, methyl, or -C(=O)-NH2.

[0025] In some particularly preferred embodiments, ring B in the compound of formula I or a pharma- ceutically acceptable form thereof is [ka] is selected from.

[0026] In some embodiments, the compound of Formula I, or a pharma- ceutically acceptable form thereof, is a compound having the structure of Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-19, or Formula I-20, or a pharma- ceutically acceptable form thereof. [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 6 , L 1 , L 2 and Ring B is as defined in Formula I.

[0027] In some preferred embodiments, the compound of Formula I, or a pharma- ceutically acceptable form thereof, is a compound having the structure of Formula I-7, Formula I-8, Formula I-9, Formula I-10, Formula I-11, Formula I-12, Formula I-13, Formula I-14, Formula I-15, Formula I-16, Formula I-17, Formula I-18, Formula I-21, or Formula I-22, or a pharma- ceutically acceptable form thereof. [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 6 and Ring B is as defined in Formula I.

[0028] It should be understood by those skilled in the art that the present invention encompasses compounds obtained by any combination of the embodiments. The embodiments obtained by combining the constituent elements or preferred elements of one embodiment with the constituent elements or preferred elements of another embodiment are also included in the scope of the present invention.

[0029] In a second aspect, the present invention also provides the following compound, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, solvate, nitrogen oxide, isotopically labeled product, metabolite, or prodrug thereof: [ka] [ka] [ka] [ka]

[0030] In a third aspect, the present invention provides pharmaceutical compositions comprising at least one of the above compounds, or a pharma- ceutically acceptable form thereof, and one or more pharma- ceutically acceptable carriers.

[0031] In a fourth aspect, the present invention provides the above compound or a pharma- ceutically acceptable form thereof, or the above pharmaceutical composition, for use as a DHX33 inhibitor for the prevention and / or treatment of a disease or condition mediated at least in part by DHX33.

[0032] In a fifth aspect, the present invention provides the use of the above compound or a pharma- ceutically acceptable form thereof or the above pharmaceutical composition for the manufacture of a medicament for the prophylaxis and / or treatment of a disease or condition mediated at least in part by DHX33.

[0033] In a sixth aspect, the present invention provides a method for preventing and / or treating a disease or condition mediated at least in part by DHX33, comprising administering to an individual in need thereof a prophylactically and / or therapeutically effective amount of the compound or a pharma- ceutically acceptable form thereof or the pharmaceutical composition as described above.

[0034] The present invention is not limited to the specific embodiments described herein, and the terminology used herein is for the purpose of description only and is not intended to be limiting of specific embodiments.

[0035] Definition of Terms

[0036] Unless otherwise specified, the following terms in the present invention have the following definitions:

[0037] The terms "comprise," "include," "have," "contain," or any variation thereof, are intended to cover non-exclusive or open-ended inclusions. For example, a composition, method, or device that includes a set of features is not necessarily limited to the features explicitly recited, but may include other features not explicitly recited or that are inherent in the composition, method, or device.

[0038] When a lower and upper limit of a numerical range is disclosed, it is meant that any number or subrange within that range is specifically disclosed. In particular, each numerical range of a parameter disclosed herein (e.g., "about a to b," or, equivalently, "approximately a to b," or, equivalently, "about a to b") should be understood to cover every number and subrange within that range. For example, "C 1~4 " is C 2~4 , C 3~4 , C 1~2 , C 1~3 , C 1~4 It should be understood that this includes any subranges such as 5-6 members, 5-7 members, 5-8 members, 5-9 members, 6-7 members, 6-8 members, etc., and each individual value such as 5 members, 6 members, 7 members, 8 members, 9 members, 10 members, etc. Also, for example, "5-10 members" should be understood to include any subranges such as 5-6 members, 5-7 members, 5-8 members, 5-9 members, 6-7 members, 6-8 members, etc., and each individual value such as 5 members, 6 members, 7 members, 8 members, 9 members, 10 members, etc.

[0039] The term "pharmaceutical composition" refers to a composition that can be used as a medicine and includes a medicament, a medicament active ingredient (or therapeutic agent), and optionally one or more pharma- ceutically acceptable carriers. The term "pharmaceutical acceptable carrier" refers to an additive ingredient administered with a therapeutic agent that is suitable for use in contact with the tissues of humans and / or other animals without causing excessive toxicity, irritation, allergic response, or other problems or complications that are commensurate with a reasonable benefit-risk ratio within the scope of sound medical judgment. Pharmaceutically acceptable carriers that can be used in the present invention include, but are not limited to, a) diluents, b) lubricants, c) binders, d) disintegrants, e) absorbents, colorants, flavorings, and / or sweeteners, f) emulsifiers or dispersants, and / or g) substances that enhance absorption of the compound.

[0040] The pharmaceutical compositions may act systemically and / or locally and may thus be administered via any suitable route of administration, such as, for example, parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular, or as an inhalant.

[0041] The above-mentioned administration routes can be realized through suitable dosage forms, including, but not limited to, tablets, capsules, lozenges, candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, water-soluble injections, elixirs, syrups, etc.

[0042] When administered orally, the pharmaceutical composition may be in any orally acceptable dosage form, including, but not limited to, tablets, capsules, aqueous solutions, and aqueous suspensions.

[0043] The pharmaceutical composition can also be administered as a sterile injection preparation, including a sterile injection water or oil suspension, or a sterile injection water or oil solution preparation.Here, the carriers that can be used include, but are not limited to, water, Ringer's solution, and isotonic sodium chloride solution.In addition, sterile non-volatile oils such as monoglycerides or diglycerides can also be used as a solvent or suspension medium.

[0044] The pharmaceutical composition may contain 0.01 mg to 1000 mg of at least one of the compounds or a pharma- ceutically acceptable form thereof.

[0045] The term "disease or condition mediated at least in part by DHX33" refers to diseases whose pathological mechanisms involve, at least in part, DHX33-associated factors, such as cancer, viral infection and inflammation.

[0046] The term "effective amount" means an amount sufficient to elicit a biological or medical response in a cell, tissue, organ or organism (eg, an individual) and achieve a desired prophylactic and / or therapeutic effect.

[0047] The dosage regimen can be adjusted to provide the optimum desired response. For example, it can be administered in a single dose, in divided doses over time, or in a proportionally reduced or increased dose according to the actual situation. It is understood that for any particular individual, the specific dosage regimen should be adjusted according to the needs and professional judgment of the person administering or administering the composition.

[0048] The term "in need thereof" refers to the judgment of a physician or other caregiver, based on a variety of factors within their field of expertise, that an individual needs or will benefit from prevention and / or treatment.

[0049] The term "individual" (or subject) refers to a human or non-human animal. In the present invention, individuals include diseased and / or pathological individuals (patients) and normal individuals. Non-human animals in the present invention include all vertebrates, e.g., non-mammals such as birds, amphibians, reptiles, and mammals such as non-human primates, farm animals and / or domesticated animals (e.g., sheep, dogs, cats, dairy cows, pigs, etc.).

[0050] The term "treat" means to alleviate or eliminate the targeted disease or condition. A subject receiving a therapeutic amount of a compound of the present invention or a pharma- ceutically acceptable form thereof, or a pharmaceutical composition of the present invention, is considered to be successfully "treated" if at least one indicator or symptom shows observable and / or detectable alleviation and / or improvement. It is understood that treatment includes not only complete treatment, but also cases where some biologically or medically relevant results are achieved that are less than complete treatment. Specifically, "treatment" means that the compound of the present invention or a pharma- ceutically acceptable form thereof, or the pharmaceutical composition of the present invention can achieve at least one of the following effects. For example, (1) preventing the onset of disease in an animal that is believed to be prone to the disease but has not yet experienced or exhibited the pathology or symptomology of the disease, (2) inhibiting the disease (i.e., preventing further progression of the pathology or symptomology) in an animal that is experiencing or exhibiting the pathology or symptomology of the disease, or (3) ameliorating the disease (i.e., reversing the pathology or symptomology) in an animal that is experiencing or exhibiting the pathology or symptomology of the disease.

[0051] The term "pharmaceutical acceptable salt" refers to a salt of the compound of the present invention that is substantially non-toxic to living organisms. Pharmaceutically acceptable salts include, but are not limited to, salts that are generally formed by the reaction of the compound of the present invention with a pharmaceutical acceptable inorganic / organic acid or inorganic / organic base. Such salts are also called acid addition salts or base addition salts. For reviews of suitable salts, see, for example, Jusiak, Soczewinski, et al., Remington's Pharmaceutical Sciences [M], Mack Publishing Company, 2005 and Stahl, Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use [M], Wiley-VCH, 2002. Methods for preparing pharmaceutical acceptable salts of the compound of the present invention are known to those skilled in the art.

[0052] The term "pharmaceutical acceptable ester" refers to an ester that is substantially non-toxic to living organisms and is hydrolyzed in vivo to the compound of the present invention or a salt thereof. Pharmaceutically acceptable esters typically include, but are not limited to, esters of the compound of the present invention with pharmaceutical acceptable carboxylic or sulfonic acids. Such esters are also called carboxylic acid esters or sulfonic acid esters.

[0053] The term "isomers" refers to compounds that have the same number and types of atoms and therefore the same molecular weight, but differ in the spatial arrangement or configuration of the atoms.

[0054] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has at least one chirality (including chiral center, chiral axis, chiral plane, etc.) and thus has a perpendicular plane of asymmetry, thereby capable of rotating linearly polarized light. Since the compounds of the present invention have asymmetric centers and other chemical structures that can give rise to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Unless otherwise specified, all stereoisomers of the compounds of the present invention are within the scope of the present invention.

[0055] The term "tautomers" (or "tautomeric forms") refers to structural isomers that have different energies and can be converted into one another via a low barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called proton transfer tautomers) include, but are not limited to, interconversions via migration of a proton, such as, for example, keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, and the like. Unless otherwise indicated, all tautomers of the compounds of the invention are within the scope of the invention.

[0056] The term "solvate" refers to a compound of the present invention (or a pharma- ceutically acceptable salt thereof) and at least one solvent molecule bound together by non-covalent intermolecular forces. For example, solvates include, but are not limited to, hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetonates, etc.

[0057] The term "nitrogen oxide" refers to a compound formed by oxidation of a nitrogen atom in the structure of a tertiary amine or a nitrogen-containing (aromatic) heterocyclic compound. For example, the nitrogen atom in the parent nucleus of the above compounds can form the corresponding nitrogen oxide.

[0058] The term "isotopically labeled compound" refers to a derivative compound in which a specific atom in the compound of the present invention is replaced with its isotope atom. Unless otherwise specified, the compound of the present invention includes various isotopes of H, C, N, O, F, P, S, and Cl, for example, 2 H(D), 3 H(T), 13C , 14 C. 15 N, 17 O. 18 O. 18 F, 31 P, 32 P, 35 S, 36 S, and 37 Examples of suitable amines include, but are not limited to, Cl.

[0059] The term "metabolite" refers to a derivative compound formed by metabolism of the compounds of the present invention. Further information on metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9 thed.) [M], McGraw-Hill International Editions, 1996. The present invention encompasses all possible metabolic forms of the compounds of the invention, i.e., substances formed in an individual to which a compound of the invention is administered. Metabolites of a compound can be identified by techniques known in the art and their activities characterized by assays.

[0060] The term "prodrug" refers to a derivative compound that can provide the compound of the present invention directly or indirectly when administered to an individual. Particularly preferred derivative compounds or prodrugs are compounds that can increase the bioavailability of the compound of the present invention when administered to an individual (e.g., more easily absorbed into the blood) or enhance the delivery of the parent compound to the site of action (e.g., lymphatic system). Unless otherwise specified, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art. See, for example, T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14, 1975. The present invention also encompasses the compounds of the present invention having protecting groups. In any of the manufacturing processes of the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule involved, thereby forming a chemically protected form of the compound of the present invention. This can be achieved by conventional protecting groups, such as those described in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups may be removed at a suitable subsequent stage using methods known in the art.

[0061] The term "independently" refers to at least two groups (or ring systems) present in a structure that have the same or similar numerical ranges may have the same or different meanings under certain circumstances. For example, if the substituents X and Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when the substituent X is hydrogen, the substituent Y may be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl. Similarly, when the substituent Y is hydrogen, the substituent X may be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0062] As used herein, the term "halogen", alone or in combination with other groups, means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0063] As used herein, the term "alkyl" when used alone or in combination with other groups means a straight or branched chain aliphatic hydrocarbon group. For example, the term "C 1~6 "Alkyl" means an alkyl having 1 to 6 carbon atoms. For example, alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or t-butyl. Alkyl may be substituted or unsubstituted.

[0064] As used herein, the term "alkylene," whether used alone or in combination with other groups, means a straight or branched chain, divalent, saturated, aliphatic hydrocarbon group, the two groups (or segments) linked thereto may be linked to the same or different carbon atoms. For example, the term "C 1~6 "Alkylene" means an alkylene having 1 to 6 carbon atoms (e.g., methylene, 1,1-ethylene, 1,2-ethylene, 1,2-propylene, 1,3-butylene, etc.). Alkylene may be substituted or unsubstituted.

[0065] As used herein, the term "haloalkyl" when used alone or in combination with other groups means an alkyl substituted with one or more (e.g., 1 to 3) of the same or different halogen atoms. For example, the term "C 1~6 "Haloalkyl" means a haloalkyl having 1 to 6 carbon atoms. For example, haloalkyl includes, but is not limited to, -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3, -CH2Cl, and the like. Haloalkyl may be substituted or unsubstituted.

[0066] As used herein, the term "hydroxyalkyl" when used alone or in combination with other groups means an alkyl substituted with one or more (e.g., 1 to 3) hydroxyl groups. For example, the term "C 1~6 The term "hydroxyalkyl" refers to a hydroxyalkyl having 1 to 6 carbon atoms. For example, the hydroxyalkyl is: [ka] and the like. Hydroxyalkyl may be substituted or unsubstituted.

[0067] As used herein, the term "alkoxy" refers to an alkyl group linked to another part of the molecule via an oxygen atom. For example, alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc. Alkoxy may be substituted or unsubstituted.

[0068] As used herein, alone or in combination with other groups, the term "haloalkoxy" refers to a monovalent straight or branched chain haloalkyl-O- group substituted with at least one atom selected from fluorine, chlorine, bromine and iodine, which may contain unsaturation and is linked to other groups via one single bond connected to an oxygen atom. For example, C 1~6 Examples of haloalkoxy include, but are not limited to, fluoromethoxy (-OCCH2F), difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), 1-fluoroethoxy (-OCHFCH3), 2-fluoroethoxy (-OCH2CH2F), 1,2-difluoroethoxy (-OCHFCH2F), 2,2-difluoroethoxy (-OCH2CHF2), 1,2,2-trifluoroethoxy (-OCHFCHF2), 2,2,2-trifluoroethoxy (-OCH2CF3), and the like.

[0069] As used herein, either alone or in combination with other groups, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (e.g., bicyclic) non-aromatic hydrocarbon group. For example, "C 3~6 "Cycloalkyl" means a cycloalkyl having 3 to 6 carbon atoms. For example, cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cycloalkyl may be substituted or unsubstituted.

[0070] As used herein, alone or in combination with other groups, the term "heterocyclic group" refers to a saturated or partially saturated, monocyclic or polycyclic (e.g., bicyclic, e.g., fused, bridged, or spiro) non-aromatic group whose ring atoms consist of carbon atoms and at least one heteroatom selected from N, O, and S, where the S atom is S(=O), S(=O)2, or S(=O)(=NR x )(wherein, R x are independently H or C 1~4The heterocyclic group may be substituted to form a heterocyclic group. The heterocyclic group may be linked to the rest of the molecule through any one of the ring atoms, provided that the valence requirements are met. For example, the term "3-8 membered heterocyclic group" as used herein means a heterocyclic group having 3-8 ring atoms. Common heterocyclic groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidine, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl or trithianyl. The heterocyclic group in the present invention may be substituted with one or more of the substituents described in the present invention.

[0071] As used herein, the term "aryl" when used alone or in combination with other groups, refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated π-electron system. For example, the term "C 6~10 "Aryl" means an aryl having 6 to 10 carbon atoms. Common aryls include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like. The aryl in the present invention may be substituted with one or more substituents described in the present invention.

[0072] As used herein, the term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic group having a conjugated π-electron system. The ring atoms consist of carbon atoms and at least one heteroatom selected from N, O and S. The heteroaryl can be linked to the remainder of the molecule through any one ring atom, provided that the valence requirements are met. For example, the term "5-10 membered heteroaryl" as used herein refers to a heteroaryl having 5-10 ring atoms. Common heteroaryls include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and its benzo derivatives, pyrrolopyridyl, pyrrolopyrazinyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, purinyl, etc. Heteroaryls in the present invention may be one or more substituents described in the present invention (e.g., halogen, C 1~6 It may be substituted with alkyl.

[0073] As used herein, the term "hydroxyl," alone or in combination with other groups, means --OH. As used herein, the term "cyano," alone or in combination with other groups, means --CN. As used herein, the term "amino," when used alone or in combination with other groups, means --NH.sub.2. As used herein, the term "nitro," alone or in combination with other groups, means --NO.sub.2. [Brief description of the drawings]

[0074] [Figure 1] FIG. 1 shows the analysis results of recombinant DHX33 protein produced by the method of the present invention, separated by SDS-PAGE and stained with Coomassie Brilliant Blue. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0075] In order to clarify the purpose and means of the present invention, the embodiments of the present invention will be described in detail below based on examples. However, those skilled in the art will understand that the following examples are only used to explain the present invention and do not limit the scope of the present invention.

[0076] The reagents and devices used in the examples are all common products available on the market. Unless otherwise specified, the usual conditions or the conditions recommended by the manufacturer shall be followed. The term "room temperature" as used in the present invention means 20°C ± 5°C. The term "about" as used in the present invention, when used to modify a numerical value or a numerical range, means that the numerical value or numerical range and the error range of the numerical value or numerical range that is acceptable to a person skilled in the art (for example, the error range is ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.).

[0077] The structures of the compounds described in the examples below are characterized by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0078] The nuclear magnetic resonance (NMR) measurement device used was a nuclear magnetic resonance device (Bruker 400MHz). The measurement solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS). 1 In H NMR, some hydrogens may not appear as peaks due to interference from salts or solvents.

[0079] The meanings of the abbreviations in the nuclear magnetic resonance (NMR) data in the following examples are as follows.

[0080] s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quadruple doublet, ddd: double double doublet, ddt: double double triplet, dddd: double double doublet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, δ: chemical shift.

[0081] All chemical shifts (δ) are reported in parts per million (ppm).

[0082] The mass spectrometer (Agilent 6120B) was used as the measuring device for mass spectrometry (MS), and the ion source was an electrospray ionization source (ESI).

[0083] HPLC measurements are performed using an Agilent 1200DAD high performance liquid chromatograph (Sunfirc C18, 150X 4.6 mm, chromatographic column 5 μm) and a Waters 2695-2996 high performance liquid chromatograph (Gimini C18, 150X 4.6 mm, chromatographic column 5 μm).

[0084] The silica gel plates used for thin layer chromatography were Qingdao Ocean GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm to 0.2mm, while the specifications of silica gel plates used to separate and purify products by thin layer chromatography are 0.4mm to 0.5mm.

[0085] In column chromatography, silica gel (200 to 300 mesh) manufactured by Qingdao Kaiyo Co., Ltd. is usually used as a carrier.

[0086] In the examples, the progress of the reaction is monitored by thin layer chromatography (TLC). The developing solvent system used in the reaction is A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, and the volume ratio of the solvents is adjusted according to the polarity of the compounds.

[0087] The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, but can also be adjusted by adding a small amount of triethylamine and acidic or basic reagents.

[0088] Compound synthesis

[0089] Example 1: Synthesis of compound AB29502 (1-(4-cyano-2-methylthiazol-5-yl)-N-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide)

[0090] (1) Preparation of Compound 3 (Ethyl 5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylthiazole-4-carboxylate) [ka]

[0091] Compound 1 (ethyl 5-amino-2-methyl-1,3-thiazole-4-carboxylate) (5 g, 26.84 mmol, 1.0 eq) was dissolved in toluene (100 mL) and compound 2 (2,5-hexanedione) (4.6 g, 40.26 mmol, 1.5 eq), molecular sieves 3A (10 g) and p-toluenesulfonic acid (1.8 g, 10.73 mmol, 0.4 eq) were added. The mixture was heated to reflux and stirred overnight. The solid was filtered and concentrated, and the residue was separated by flash column chromatography (petroleum ether / ethyl acetate=10 / 1) to give compound 3 (ethyl 5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylthiazole-4-carboxylate) as a white solid (3 g, yield: 42.8%). MS (ESI) m / z: 265 [M+H]+. TLC: petroleum ether / ethyl acetate (5 / 1); f (Compound 1)=0.2;R f (Compound 3)=0.5.

[0092] (2) Method for producing compound 4 (5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylthiazole-4-carboxamide) [ka]

[0093] Compound 3 (ethyl 5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylthiazole-4-carboxylate) (3.0 g, 11.4 mmol, 1.0 eq) was dissolved in ammonia / methanol mixture (40 mL), and the mixture was sealed in a reaction tube and heated and stirred at 80° C. for 16 hours. The solid was filtered to obtain compound 4 (5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylthiazole-4-carboxamide) as a white solid (1.9 g, yield: 71.2%). MS (ESI) m / z: 236 [M+H]+. TLC: petroleum ether / ethyl acetate (3 / 1); R f (Compound 3)=0.6;R f (Compound 4)=0.4.

[0094] (3) Preparation of Compound 5 (5-(3-formyl-2,5-dimethyl-1H-pyrrol-1-yl)-2-methylthiazole-4-nitrile) [ka]

[0095] Phosphorus oxychloride (2.48 g, 16.2 mmol, 2.0 eq) was added dropwise to dimethylformamide (30 mL) at 0° C. under nitrogen gas protection. The mixture was stirred at 0° C. for 30 minutes and then warmed to room temperature. Compound 4 (5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylthiazole-4-carboxamide) (1.9 g, 8.09 mmol, 1.0 eq) dissolved in dimethylformamide (4 mL) was added to the reaction system. Then, under nitrogen gas protection, the reaction solution was heated to 100° C. and stirred for 1 hour. After cooling the reaction solution, the mixture was poured into ice water and adjusted to pH=10 with 30% NaOH aqueous solution. The mixture was extracted with ethyl acetate and washed with brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate=2 / 1) to give compound 5 (5-(3-formyl-2,5-dimethyl-1H-pyrrol-1-yl)-2-methylthiazole-4-nitrile) as a white solid (1.3 g, yield: 65.6%). MS (ESI) m / z: 246 [M+H]+. TLC: petroleum ether / ethyl acetate (2 / 1); R f (Compound 4)=0.3;R f (Compound 5)=0.5.

[0096] (4) Preparation of Compound 6 (1-(4-cyano-2-methylthiazol-5-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid) [ka]

[0097] Compound 5 (5-(3-formyl-2,5-dimethyl-1H-pyrrol-1-yl)-2-methylthiazole-4-nitrile) (1.7 g, 6.93 mmol, 1.0 eq) was dissolved in tetrahydrofuran / tert-butanol / water (1 / 1 / 1, 45 mL) and potassium dihydrogen phosphate (4.71 g, 34.65 mmol, 5.0 eq), 2-methyl-1-butene (4.86 g, 69.3 mmol, 10.0 eq) and sodium chlorite (3.76 g, 41.58 mmol, 6.0 eq) were added at 0°C. The reaction was stirred and refluxed at room temperature for 16 h. After the reaction was completed, the mixture was concentrated and then purified by preparative HPLC to obtain a white solid, compound 6 (1-(4-cyano-2-methylthiazol-5-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid) (450 mg, yield: 25%). MS(ESI) m / z: 262 [M+H + ].

[0098] (5) Method for producing compound AB29502 (1-(4-cyano-2-methylthiazol-5-yl)-N-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) [ka]

[0099] Compound 6 (1-(4-cyano-2-methylthiazol-5-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid) (55 mg, 0.21 mmol, 1.0 eq) was dissolved in acetonitrile (2.0 mL), and compound 8 (6-methoxy-3H-imidazo[4,5-c]pyridin-2-amine) (46 mg, 0.273 mmol, 1.3 eq), 2-methylimidazole NMI (69 mg, 0.84 mmol, 4.0 eq) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate TCFH (71 mg, 0.25 mmol, 1.2 eq) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated and then separated and purified by preparative HPLC to obtain a yellow solid compound AB29502 (1-(4-cyano-2-methylthiazol-5-yl)-N-(6-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) (2.5 mg, yield: 2.9%). MS (ESI) m / z: 408.3 [M+H + ].

[0100] 1 H NMR (400MHz, CD3OD-d4) δ8.33(s, 1H), 7.21(s, 1H), 6.70(s, 1H), 4.09(s, 3H), 2.78(s, 3H), 2.48(s, 3H), 2.15(s, 3H).

[0101] Example 2: Method for preparing compound AB29509 (1-(4-cyano-2-methylthiazol-5-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) [ka]

[0102] Compound 6 (1-(4-cyano-2-methylthiazol-5-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid) (100 mg, 0.38 mmol, 1.0 eq) was dissolved in acetonitrile (5.0 mL), and compound 9 (6-methoxy-1H-benzo[d]imidazol-2-amine) (81 mg, 0.50 mmol, 1.3 eq), 2-methylimidazole NMI (126 mg, 1.53 mmol, 4.0 eq) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate TCFH (129 mg, 0.46 mmol, 1.2 eq) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated and purified by preparative HPLC to obtain a yellow solid, compound AB29509 (1-(4-cyano-2-methylthiazol-5-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) (3.0 mg, yield: 1.9%). MS(ESI) m / z: 407.10 [M+H + ].

[0103] 1 H NMR (400MHz, DMSO-d6) δ7.45(d,J=10Hz,1H),7.10(s,1H),6.88(d,J=8.8Hz,1H),6.81(s,1H),3.76(s,3H),2.76(s,3H),2.42(s,3H),2.09(s,3H).

[0104] Example 3: Synthesis of compound AB24386 (1-(3-cyano-5-methylthiophen-2-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide)

[0105] (1) Method for producing compound 3 (ethyl 2-acetyl-4-levulinate) [ka]

[0106] Compound 1 (ethyl acetoacetate) (5 g, 38.42 mmol, 1.0 eq) was dissolved in triethylamine (75 mL) and compound 2 (chloroacetone) (3.5 g, 38.42 mmol, 1.0 eq) was added. Under nitrogen gas protection, the reaction was reacted at 110° C. for 2 h. After concentration, the residue was dissolved in water (100 mL) and then extracted twice with dichloromethane (50 mL each time). The organic phase was washed with brine, then dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate=100 / 1-50 / 1-20 / 1) to give compound 3 (ethyl 2-acetyl-4-levulinate) as a colorless oil (1.3 g, yield: 18.3%). MS(ESI) m / z: 187[M+H + ]. TLC:PE / EA(2 / 1);R f (Compound 1)=0.6;R f (Compound 3)=0.4.

[0107] (2) Preparation of Compound 5 (Ethyl 1-(3-cyano-5-methylthiophen-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylate) [ka]

[0108] Compound 3 (ethyl 2-acetyl-4-levulinate) (1 g, 7.23 mmol, 1.0 eq) was dissolved in toluene (20 mL) and compound 4 (2-amino-3-cyano-5-methylthiophene) (1.6 g, 8.68 mmol, 1.2 eq) and p-toluenesulfonic acid (249 mg, 1.45 mmol, 0.2 eq) were added. The reaction was stirred at 110° C. for 16 h. The solid was filtered and concentrated. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate=50 / 1 to 30 / 1) to give compound 5 (ethyl 1-(3-cyano-5-methylthiophen-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylate) as a yellow oil (860 mg, yield: 41%). MS(ESI) m / z: 289 [M+H + TLC: petroleum ether / ethyl acetate (10 / 1);f (Compound 3)=0.2;R f (Compound 5)=0.4.

[0109] (3) Method for producing compound AB24386 (1-(3-cyano-5-methylthiophen-2-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) [ka]

[0110] To compound 5 (ethyl 1-(3-cyano-5-methylthiophen-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylate) (50 mg, 0.306 mmol, 1.0 eq) and compound 7 (5-methoxy-1H-benzimidazol-2-amine) (88 mg, 0.306 mmol, 1.0 eq) dissolved in 1 mL of toluene was added trimethylaluminum (0.15 mL, 0.306 mmol, 1.0 eq, 2M in toluene). The reaction was stirred at 100° C. for 16 h. The mixture was cooled to room temperature and quenched with methanol (10 mL) before being adjusted to pH 3 with 3 M hydrochloric acid. The mixture was diluted with water (30 mL) and then extracted three times with 20 mL portions of ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative Prep-HPLC (acetonitrile / water (containing 0.1% formic acid)) to give compound AB24386 (1-(3-cyano-5-methylthiophen-2-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) as a white solid (5 mg, yield: 4%). MS(ESI) m / z: 406 [M+H + ].

[0111] 1H NMR(400 MHz,DMSO-d6):δ12.04(s,1H),11.20(s,1H),7.32(s,1H),7.29(s,1H),6.98(s,1H),6 .89(s,1H),6.69(d,J=7.2Hz,1H),3.73(s,3H),2.47(s,3H),2.38(s,3H),2.04(s,3H).

[0112] Example 4: Method for preparing compound AB24387 (1-(3-carbamoyl-5-methylthiophen-2-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) [ka]

[0113] Compound AB24386 (1-(3-cyano-5-methylthiophen-2-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) (15 mg, 0.037 mmol, 1.0 eq) was dissolved in ethanol (4 mL) and sodium hydroxide (0.5 mL, 4 M in H2O) was added. The mixture was stirred at 80 °C for 2 h. After cooling the reaction, the mixture was diluted with water (10 mL) and then adjusted to pH = 6-7 with 3N hydrochloric acid. The mixture was extracted with ethyl acetate three times (20 mL * 3) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile / water / 0.1% formic acid) to give compound AB24387 (1-(3-carbamoyl-5-methylthiophen-2-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) as a white solid (6 mg, yield: 38.4%). MS(ESI) m / z: 424 [M+H + ].

[0114] 1H NMR(400MHz,DMSO-d6):δ11.98(s,1H),11.02(s,1H),7.27(s,2H),7.23(s,1H),6.95(s,1H) ),6.76(s,1H),6.66(d,J=8.4Hz,1H),3.71(s,3H),3.31(s,3H),2.31(s,3H),1.94(s,3H).

[0115] Example 5: Synthesis of compound AB29505 (1-(2,4-dimethylthiazol-5-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide)

[0116] (1) Method for synthesizing compound 2 (tert-butyl (2,4-dimethylthiazol-5-yl)carbamate) [ka]

[0117] Compound 1 (2,4-dimethyl-1,3-thiazole-5-carboxylic acid) (2 g, 12.72 mmol, 1.0 eq) was dissolved in tert-butanol (40 mL) and diphenylphosphoryl azide DPPA (4.5 g, 16.53 mmol, 1.3 eq) and triethylamine (TEA) (3.2 g, 31.8 mmol, 2.5 eq) were added. The mixture was stirred at 85° C. under nitrogen gas protection for 3 h. The reaction was then concentrated and the residue was dissolved in water (80 mL) and then extracted three times with ethyl acetate (80 mL*3). The organic phases were then combined, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (dichloromethane / methanol=200 / 1 to 150 / 1) to give compound 2 ((2,4-dimethylthiazol-5-yl)carbamate tert-butyl ester) as a yellow solid (2.7 g, yield: 93.1%). MS (ESI) m / z: 229.0 [M+H]+. TLC: dichloromethane / methanol (20:1); R f (Compound 1)=0.2;R f (Compound 2)=0.7.

[0118] (2) Method for producing compound 3 (2,4-dimethylthiazol-5-amine hydrochloride) [ka]

[0119] Compound 2 (tert-butyl (2,4-dimethylthiazol-5-yl) carbamate) (1.7 g, 7.44 mmol, 1.0 eq) was dissolved in ethyl acetate / hydrochloric acid mixture HCl / EA (20 mL, 4 M) and stirred at room temperature for 3 h. The solid was then filtered and washed twice with ethyl ether (5 mL*2) before being concentrated to give compound 3 (2,4-dimethylthiazol-5-amine hydrochloride) as a yellow solid (1.1 g, yield: 91.6%). MS (ESI) m / z: 129.0 [M+H]+. TLC: petroleum ether / ethyl acetate (1:1); R f (Compound 2)=0.5;R f (Compound 3)=0.2.

[0120] (3) Preparation of Compound 5 (1-(2,4-dimethylthiazol-5-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylate methyl ester) [ka]

[0121] Compound 3 (2,4-dimethylthiazol-5-amine hydrochloride) (1.1 g, 6.68 mmol, 1.0 eq) was dissolved in toluene (20 mL) and compound 4 (2-acetyl-4-methyl levulinate) (1.7 g, 10.02 mmol, 1.5 eq), molecular sieves 3A (2 g) and p-toluenesulfonic acid (459 mg, 2.67 mmol, 0.4 eq) were added. The mixture was stirred at 85° C. for 4 h. The solid was then filtered and concentrated. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate=30 / 1) to give compound 5 (1-(2,4-dimethylthiazol-5-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylate methyl) as a yellow solid (1.6 g, yield: 90.9%). MS (ESI) m / z: 265 [M+H]+. TLC: petroleum ether / ethyl acetate (5:1); R f (Compound 3)=0.1;R f (Compound 5)=0.7.

[0122] (4) Method for producing compound 6 (1-(2,4-dimethylthiazol-5-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid) [ka]

[0123] Compound 5 (1.6 g, 6.05 mmol, 1 eq) was dissolved in methanol / water solution MeOH / HO (10 mL / 10 mL), and then lithium hydroxide LiOH (579 mg, 24.2 mmol, 4 eq) was added. The mixture was stirred at 50° C. for 1 h. After the reaction was completed, the product was concentrated, then diluted with water (50 mL), and then adjusted to pH=5 with 3N hydrochloric acid. The solid was filtered and concentrated to give compound 6 (1-(2,4-dimethylthiazol-5-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid) as a yellow solid (950 mg, yield: 62.7%). MS (ESI) m / z: 251 [M+H]+. TLC: petroleum ether / ethyl acetate (5:1); R f (Compound 5)=0.7;R f (Compound 6)=0.2.

[0124] (5) Method for producing compound AB29505 (1-(2,4-dimethylthiazol-5-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) [ka]

[0125] Compound 6 (1-(2,4-dimethylthiazol-5-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid) (100 mg, 0.399 mmol, 1.0 eq) was dissolved in dimethylformamide (5 mL), and then compound 7 (6-methoxy-1H-benzo[d]imidazol-2-amine) (65 mg, 0.399 mmol, 1.0 eq), N,N-diisopropylethylamine DIEA (206 mg, 1.596 mmol, 4.0 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium HATU (167 mg, 0.439 mmol, 1.1 eq) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated aqueous sodium chloride solution (20 mL*3). The organic phase was dried, filtered and concentrated. The residue was purified by preparative HPLC to give compound AB29505 (1-(2,4-dimethylthiazol-5-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) as a yellow solid (10.8 mg, yield: 6.8%). MS(ESI) m / z: 395[M+H]+.

[0126] 1 H NMR(400MHz,DMSO-d6)δ7.30(d,J=8.8Hz,1H),6.98(s,1H),6.83(s,1H),6.70- 6.68(m,1H),3.73(s,3H),2.64(s,3H),2.31(s,3H),2.01(s,3H),1.96(s,3H).

[0127] Example 6: Synthesis of compound AB29510 (1-(3-cyano-4,5-dimethylfuran-2-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide)

[0128] (1) Method for producing compound 2 (1-(3-cyano-4,5-dimethylfuran-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid) [ka]

[0129] Compound 1 (2-(3-formyl-2,5-dimethyl-1H-pyrrol-1-yl)-4,5-dimethylfuran-3-carbonitrile) (1.2 g, 4.9 mmol, 1.0 eq) was dissolved in a mixture of tetrahydrofuran, tert-butanol, and water, THF / t-BuOH / H2O (1 / 1 / 1, 30 mL), and potassium dihydrogen phosphate KH2PO4 (2.9 g, 24.7 mmol, 5.0 eq), 2-methyl-1-butene (3.0 g, 49.5 mmol, 10.0 eq), and sodium chlorite (2.4 g, 29.7 mmol, 6.0 eq) were added at 0°C. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated and then purified by preparative HPLC to obtain a white solid, compound 6 (1-(3-cyano-4,5-dimethylfuran-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid) (1.0 g, yield: 78.1%). MS (ESI) m / z: 259 [M+H + ].

[0130] (2) Method for producing compound AB29510 (1-(3-cyano-4,5-dimethylfuran-2-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) [ka]

[0131] Compound 2 (1-(3-cyano-4,5-dimethylfuran-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid) (60 mg, 0.23 mmol, 1.0 eq) was dissolved in acetonitrile (2.0 mL), and compound 3 (6-methoxy-1H-benzo[d]imidazol-2-amine hydrochloride) (50 mg, 0.30 mmol, 1.3 eq), N-methylimidazole NMI (77 mg, 0.94 mmol, 4.0 eq) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate TCFH (79 mg, 0.28 mmol, 1.2 eq) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated and then purified by preparative HPLC to obtain a yellow solid compound AB29510 (1-(3-cyano-4,5-dimethylfuran-2-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1H-pyrrole-3-carboxamide) (2.4 mg, yield: 78.1%). MS(ESI)m / z: 404.30[M+H + ].

[0132] 1 H NMR(400MHz,DMSO-d6)7.49(d,J=8.8Hz,1H),7.11(s,1H),6.91(d,J=8.8Hz,1H) ,6.74(s,1H),3.77(s,3H),2.41(s,3H),2.29(s,3H),2.10(s,3H),2.07(s,3H).

[0133] Example 7: Synthesis of compound AB29513 (N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrole-3-carboxamide)

[0134] (1) Method for synthesizing compound 3 (methyl 2,5-dimethyl-1-(((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrole-3-carboxylate) [ka] Compound 1 (4-(aminomethyl)-1-methylpyrazole) (500 mg, 4.5 mmol, 1.0 eq) was dissolved in toluene (20 mL), and compound 2 (2-acetyl-4-methyl levulinate) (1.16 g, 6.75 mmol, 1.5 eq), molecular sieve 3A (1 g) and p-toluenesulfonic acid (310 mg, 1.8 mmol, 0.4 eq) were added. The mixture was stirred at 100° C. for 8 hours. The solid was filtered and concentrated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate=10 / 1 to 5 / 1) to give compound 3 (methyl 2,5-dimethyl-1-(((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrole-3-carboxylate) as a yellow solid (650 mg, yield: 58.4%). MS (ESI) m / z: 248 [M+H]+. TLC: petroleum ether / ethyl acetate (2:1); R f (Compound 1)=0.1;R f (Compound 3)=0.6.

[0135] (2) Method for producing compound 4 (2,5-dimethyl-1-(((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrole-3-carboxylic acid) [ka]

[0136] Compound 3 (methyl 2,5-dimethyl-1-(((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrole-3-carboxylate) (300 mg, 1.21 mmol, 1 eq) was dissolved in a methanol / water solution (10 mL / 10 mL) and lithium hydroxide (43 mg, 1.81 mmol, 1.5 eq) was added. The mixture was heated to 85° C. and stirred for 3 h. The reaction was concentrated and then diluted with water (20 mL) and then adjusted to pH=5 with 3N hydrochloric acid. The solid was filtered and concentrated to give compound 4 (methyl 2,5-dimethyl-1-(((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrole-3-carboxylate) as a yellow solid (110 mg, yield: 39%). MS (ESI) m / z: 234 [M+H]+. TLC: dichloromethane / methanol (20:1); Rf (Compound 3)=0.7;R f (Compound 4)=0.3.

[0137] (3) Method for producing compound AB29513 (N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrole-3-carboxamide) [ka]

[0138] Compound 4 (2,5-dimethyl-1-(((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrole-3-carboxylic acid) (110 mg, 0.47 mmol, 1.0 eq) was dissolved in acetonitrile (5 mL) and the solution of compound 5 (6-methoxy-1H-benzo[d]imidazol-2-amine) (100 mg, 0.61 mmol, 1.0 eq), N-methylimidazole NMI (154 mg, 1.88 mmol, 4.0 eq) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate TCFH (158 mg, 0.56 mmol, 1 .2eq) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (30mL) and washed with saturated aqueous sodium chloride solution three times (20mL*3). The organic phase was dried, filtered and concentrated. The residue was purified by preparative HPLC to give compound AB29513 (N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrole-3-carboxamide) as a yellow solid (35mg, yield: 19.6%). MS(ESI) m / z: 379[M+H]+.

[0139] 1H NMR(400MHz,DMSO-d6)δ7.55(s,1H),7.49(d,J=8.8Hz,1H),7.25(s,1H),7.13(s,1H),6.93( d,J=8.8Hz,1H),6.52(s,1H),4.90(s,2H),3.76(d,J=10.8Hz,6H),2.59(s,3H),2.23(s,3H).

[0140] Example 8: Synthesis of compound AB29522

[0141] (1) Synthesis of Compound 5 [ka]

[0142] Compound 4 (5.00g, 31.6mmol, 5.24mL, 1.00eq) was added with tetrahydrofuran (25.0mL), the reaction solution was cooled to 0°C, sodium hydride (1.52g, 37.9mmol, 632uL, 60% purity, 1.20eq) was added at 0°C, and the reaction solution was reacted at 0°C for 30 minutes. Tetrahydrofuran (10.0mL) was added to chloroacetone (2.95g, 31.9mmol, 1.01eq), and then slowly added dropwise to the above reaction solution at 0°C. After the addition was completed, sodium iodide (473mg, 3.16mmol, 0.100eq) was added, and the reaction solution was stirred at 20°C for 16 hours to react. TLC (petroleum ether:ethyl acetate=3:1, R f =0.25), which indicated that some raw materials remained and a new spot with increased polarity was formed. After the reaction was completed, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution to quench, and extracted with ethyl acetate (50.0 mL*3). The organic phases were combined and backwashed once with saturated saline (30.0 mL), and the separated organic phase was dried over anhydrous sodium sulfate and then concentrated. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain compound 5 (4.00 g, 16.8 mmol, yield 53.16%, purity 90%) as a pale yellow oil.

[0143] (2) Synthesis of Compound 2 [ka]

[0144] Compound 1 (3.00g, 11.8mmol, 1.00eq) was added with 1-methyl-2-pyrrolidone (10mL), acetyl chloride (1.12g, 14.2mmol, 1.01mL, 1.20eq) was added to the reaction solution, and the reaction solution was stirred at 20℃ for 16 hours to react. TLC (petroleum ether: ethyl acetate = 1:1) detected the formation of a strong UV spot. LCMS showed that the peak of the target product was detected. Water (30.0mL) was added to the reaction solution, and the pH was adjusted to 7-8 by adding saturated aqueous sodium bicarbonate solution, and the solution was extracted twice with ethyl acetate (50.0mL*2). The organic phases were combined and backwashed once with saturated brine (20.0 mL), and the separated organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 2 (1.66 g, crude) as a yellow solid (LCMS: Ms: M+H+=124.5), which was used as such in the next reaction.

[0145] (3) Synthesis of Compound 3 [ka]

[0146] Compound 2 (500mg, 4.06mmol, 1.00eq) was added with toluene (5.00mL), compound 5 (870mg, 4.06mmol, 1.00eq) and anhydrous p-toluenesulfonic acid (140mg, 812umol, 0.200eq) were added to the reaction solution, and the reaction solution was stirred at 110℃ for 16 hours to react. LCMS showed that the raw material was completely consumed and the main peak of the target product was detected. Water (30.0mL) was added directly to the reaction solution, and it was extracted twice with ethyl acetate (50.0mL*2). The organic phases were combined and backwashed once with saturated saline (20.0mL). The separated organic phase was dried over anhydrous sodium sulfate and then concentrated. Ethyl acetate (20.0mL) was added to the crude product, stirred for 20 minutes, filtered, and the cake was collected to obtain 300mg. The filtrate was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain 140 mg of compound 3 (440 mg, 1.70 mmol, yield 41.97%, purity 95%) as a gray solid.

[0147] 1 H NMR (400MHz, CDCl3) δppm 6.47 (s, 1H), 2.58 (s, 3H), 2.47 (s, 3H), 2.15 (s, 3H).

[0148] (4) Synthesis of compound AB29522 [ka]

[0149] Compound 3 (50.0 mg, 204 umol, 1.00 eq) was added with N,N-dimethylformamide (1.00 mL), and compound A014 (33.3 mg, 204 umol, 1.00 eq), N,N-diisopropylethylamine (105 mg, 815 umol, 142 uL, 4.00 eq), and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (117 mg, 224 umol, 1.10 eq) were added to the reaction solution, and the reaction solution was stirred at 100 ° C for 16 hours to react. LCMS showed that the raw material was completely consumed and the peak of the target product was detected. The reaction solution was concentrated as it was. The crude product was separated and purified by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 27%~57%, 2min) to obtain a brown solid compound AB29522 (20.0mg, 48.05umol, yield 23.57%, purity 93.8%).

[0150] 1 H NMR(400MHz,DMSO-d6)δppm 11.83-12.34(m,1H),10.96-11.64(m,1H),7.33(d,J=8.63Hz,1H),7.01(br s,1H),6.92(s,1H),6.73(dd,J=8.63,2.38Hz,1H),3.76(s,3H),2.57(s,3H),2.50(s,3H),2.17(s,3H). LCMS:Ms:M+H + =391.

[0151] Example 9: Synthesis of compound AB29553

[0152] (1) Synthesis of Compound 2 [ka]

[0153] Compound 1 (25.0 g, 215 mmol, 23.1 mL, 1.00 eq) was added with acetone (140 mL), potassium carbonate (59.5 g, 430 mmol, 2.00 eq) and potassium fluoride (12.5 g, 215 mmol, 1.00 eq) were added to the reaction solution, and the reaction mixture was stirred at 60° C. for 1 hour to react. The reaction solution was cooled to 20° C., and a solution of chloroacetone (25.7 g, 278 mmol, 1.29 eq) dissolved in acetone (35.0 mL) was slowly added dropwise to the reaction mixture. After the addition was completed, the reaction mixture was heated to 60° C. and stirred at 60° C. for 7 hours to react. TLC (petroleum ether: ethyl acetate = 5:1, R f =0.38), indicating that compound 1 had reacted completely, the formation of a new spot with increased polarity was detected. The reaction solution was cooled to room temperature and then filtered, the filtrate was collected and slowly poured into water (500 mL), and extracted with ethyl acetate (500 mL*3). The organic phases were combined and washed with saturated saline (200 mL), and the separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography (silica, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to obtain compound 2, a pale yellow liquid (21.0 g, 122 mmol, yield 56.6%).

[0154] 1 H NMR(400MHz,CDCl3)δppm 4.03(dd,J=8.19,5.69Hz,1H),3.74(s,3H),3.09-3.22(m,1H),2.89-3.02(m,1H),2.36(s,3H),2.19(s,3H).

[0155] (2) Synthesis of compound 4 [ka]

[0156] Compound 2 (10.0 g, 58.0 mmol, 1.00 eq) was added to toluene (70.0 mL), and compound 3 (8.83 g, 63.9 mmol, 1.10 eq) and p-toluenesulfonic anhydride (2.00 g, 11.6 mmol, 0.2 eq) were added to the reaction solution, and the reaction solution was stirred at 110° C. for 5 hours to react. TLC (petroleum ether: ethyl acetate = 10:1, R f =0.43) indicated that compound 2 had completely reacted and a new spot with lower polarity was formed. The reaction solution was concentrated as it was, and water (100 mL) was added to the residue, which was then extracted three times with ethyl acetate (100 mL*3). The organic phases were combined and backwashed once with saturated saline (50.0 mL), and the separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography (silica, petroleum ether: ethyl acetate = 20: 1 to 1: 1) to obtain compound 4 as a yellow solid (11.2 g, 39.5 mmol, yield 67.9%).

[0157] (3) Synthesis of Compound 5 [ka]

[0158] Compound 4 (6.00 g, 21.9 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL) and methanol (20 mL), and a solution of lithium hydroxide monohydrate (2.29 g, 54.7 mmol, 2.50 eq) dissolved in water (6.00 mL) was added to the above reaction solution, and the reaction mixture was stirred at 60 ° C for 3 hours to react. LCMS showed that about 25% of compound 4 remained and 50% of the target product was detected. The reaction solution was concentrated with a water pump to remove the solvent, and 2N hydrochloric acid solution was gradually added to the concentrated residue until the pH was 5-6. Then, it was extracted twice with ethyl acetate (80.0 mL * 2). The organic phase was backwashed with saturated saline (50.0 mL), and the separated organic phase was dried over anhydrous sodium sulfate and then concentrated. The crude product was separated and purified by column chromatography (silica, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 5 (2.10 g, 8.07 mmol, yield 36.9%) as a yellow solid (LCMS: Ms: M+H + =261.3).

[0159] (4) Synthesis of compound AB29553 [ka]

[0160] Compound 5 (50.0 mg, 192 umol, 1.00 eq) was added with N,N-dimethylformamide (1 mL), and diisopropylethylamine (99.3 mg, 768 umol, 134 uL, 4.00 eq) and compound A12 (25.6 mg, 192 umol, 1.00 eq) were added to the reaction solution. Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (110 mg, 211 umol, 1.10 eq) was then added to the reaction solution, and the reaction mixture was stirred at 100°C for 16 hours to react. LCMS showed that the raw material had completely reacted and the peak of the target product was detected. The reaction solution was concentrated as it was. The crude product was separated and purified by high performance liquid chromatography (column: Welch Ultimate C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; B%: 26%~56%, 10min) to obtain a white solid compound AB29553 (15.0mg, 30.3umol, yield 15.8%, purity 98.9%, trifluoroacetate salt).

[0161] 1 H NMR(400MHz,DMSO-d6)δppm 7.61(dd,J=5.88,3.13Hz,2H),7.37(d,J=1.13Hz,1H),7.29(br dd,J=5.44,2.81Hz,2H),6.84(s,1H),2.56(br d,J=1.00Hz,3H),2.44(s,3H),2.11(s,3H).LCMS:Ms:M+H + =376.

[0162] Example 10: Synthesis of compound AB29556 [ka]

[0163] N,N-dimethylformamide (1.00mL) was added to compound 5 (60.0mg, 230umol, 1.00eq) obtained in Example 16, N,N-diisopropylethylamine (119mg, 922umol, 160uL, 4.00eq) was added to the reaction solution, compound A020 ​​(34.8mg, 230umol, 1.00eq) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (132mg, 253umol, 1.10eq) were added to the reaction solution, and the reaction solution was stirred at 100°C for 8 hours to react. LCMS showed that the raw material was completely consumed, and the production of the peak of the target product was detected. The reaction solution was concentrated with an oil pump. The crude product was separated and purified by high performance liquid chromatography (column: Welch Ultimate C18 150*25mm*5um; mobile phase: [water(TFA)-ACN]; B%: 30%~60%, 15min), and then purified a second time (column: Waters xbridge 150*25mm10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 38%~68%, 8min) to obtain the white solid compound AB29556 (6.03mg, 15.2umol, yield 6.58%, purity 99%). 1 H NMR(400MHz,DMSO-d6)δppm 12.29(br s,1H),11.33(td,J=6.13,1.63Hz,1H),7.38-7.51(m,1H),7.35(d,J=1.13Hz,1H),7.14-7.31(m,1H),6.83-7.06(m,2H),2.55(br d,J=0.88Hz,3H),2.41(s,3H),2.06(s,3H). LCMS:Ms:M+H + =394.

[0164] Example 11: Synthesis of compound AB29557

[0165] (1) Synthesis of Compound 2 [ka]

[0166] Compound 1 (500mg, 3.51mmol, 1.00eq) was added with water (1.00mL) and ethanol (5.00mL). Cyanogen bromide (446mg, 4.21mmol, 309uL, 1.20eq) was added to the reaction solution at 20℃, and the reaction solution was stirred at 70℃ for 2 hours. LCMS showed that the raw material was completely consumed, and the main peak of the target product was detected. After the reaction was completed, the reaction solution was concentrated as it was. Ethyl acetate (30.0mL) was added to the crude product, stirred for 30 minutes, and then filtered. The cake was washed twice with ethyl acetate (5.00mL*2), and the cake was collected to obtain compound 2 (700mg, 2.68mmol, yield 76.3%, purity 95%, hydrobromide salt) as a black solid.

[0167] 1 H NMR(400MHz,MeOD)δppm 7.39(d,J=1.38Hz,1H),7.32-7.36(m,1H),7.25-7.30(m,1H).LCMS:Ms:M+H + =168.

[0168] (2) Synthesis of compound AB29557 [ka]

[0169] Compound 2 (50.0 mg, 192 umol, 1.00 eq) was added with N,N-dimethylformamide (1.00 mL), compound 5 (35.4 mg, 211 umol, 1.10 eq), N,N-diisopropylethylamine (99.3 mg, 768 umol, 134 uL, 4.00 eq) was added to the reaction solution, and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (110 mg, 211 umol, 1.10 eq) was added to the reaction solution, and the reaction solution was stirred at 100 °C for 16 hours. LCMS showed that the raw material was completely consumed, and the peak of the target product was detected. The reaction solution was concentrated with an oil pump. The crude product was separated and purified by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(NH4HCO3)-ACN]; B%: 43%~73%, 2min) to obtain a yellow solid, compound AB29557 (0.022g, 50.9umol, yield 26.5%, purity 94.9%).

[0170] 1 H NMR(400MHz,DMSO-d6)δppm 12.31-12.45(m,1H),11.38-11.45(m,1H),7.39-7.54(m,2H),7.36(d,J=1.13Hz,1H),7.08-7.16(m,1H),6.95(s,1H),2.55(br s,3H),2.42(s,3H),2.07(s,3H).LCMS:Ms:M+H + =410.

[0171] Example 12: Synthesis of compound AB29558

[0172] (1) Synthesis of Compound 2 [ka]

[0173] Compound 1 (350 mg, 2.52 mmol, 1.00 eq) was dissolved in ethanol (2.00 mL) and water (0.40 mL), and cyanogen bromide (0.26 g, 2.45 mmol, 180 uL, 1.10 eq) was added slowly to the above mixture at 20° C. The reaction was stirred at 70° C. for 2 hours. LCMS showed that compound 1 was completely consumed, and the molecular weight of the desired compound was detected. The reaction was concentrated under vacuum. Purification by thin layer chromatography (dichloromethane:methanol=5:1, ammonia water 2.00 mL) gave compound 2 (80.0 mg, 487 umol, 19.3% yield) as a brown oil. LCMS: Ms: M+H + =165.

[0174] (2) Synthesis of compound AB29558 [ka]

[0175] Compound 2 (69.3 mg, 266 umol, 1.00 eq) was dissolved in N,N-dimethylformamide (2.00 mL), compound 5 (70.0 mg) and N,N-diisopropylethylamine (137 mg, 1.07 mmol, 185 uL, 4.00 eq) were added, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (152 mg, 293 umol, 1.10 eq) was added to the reaction solution, and the reaction mixture was stirred at 100 °C for 12 hours. LCMS showed that the raw material was completely consumed, and the molecular weight of the desired compound was detected. The reaction solution was concentrated under vacuum. The first purification was performed by high performance liquid chromatography (column: Welch Xtimate C18 150 * 25 mm * 5 um; mobile phase: [water (NH3H2O) -ACN]; B%: 25% ~ 55%, 8 min). A second purification was performed by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(HCl)-ACN]; B%: 16%~46%, 8min). A white solid, compound AB29558, was obtained (8.68mg, 19.4umol, 7.28%yield, 99%purity, hydrochloride).

[0176] 1 H NMR(400MHz,DMSO-d6)δppm 11.68-11.92(m,1.00H),8.27(br s,1.00H),7.25(d,J=1.13Hz,1.00H),6.96-7.06(m,1.00H),6.86(s,1.00H),3.89( s,3.00H),2.44(d,J=1.00Hz,3.00H),2.31(s,3.00H),1.97(s,3.00H).LCMS:Ms:M+H + =407.

[0177] Example 13: Synthesis of compound AB29559

[0178] (1) Synthesis of Compound 2 [ka]

[0179] Compound 1 (500mg, 3.62mmol, 1.00eq) was added with ethanol (5.00mL) and water (1.00mL), and cyanogen bromide (460mg, 4.34mmol, 319uL, 1.20eq) was added to the reaction solution at 20℃, and the reaction solution was stirred at 70℃ for 3 hours. LCMS showed that the raw material was completely consumed, and the main peak of the target product was detected. After the reaction was completed, the reaction solution was concentrated as it was. Ethyl acetate (30mL) was added to the crude product, stirred for 0.5 hours, and filtered. The cake was washed with ethyl acetate twice (5.00mL*2), and the cake was collected to obtain compound 2 (700mg, crude) as a brown solid (LCMS: Ms: M+H). + =164.2).

[0180] (2) Synthesis of compound AB29559 [ka]

[0181] Compound 2 (60.0 mg, 230 umol, 1.00 eq) was added with N,N-dimethylformamide (1.00 mL), and N,N-diisopropylethylamine (119 mg, 922 umol, 160 uL, 4.00 eq) and compound 5 (37.6 mg, 230 umol, 1.00 eq) were added to the reaction solution. Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (132 mg, 253 umol, 1.10 eq) was then added to the reaction solution, and the reaction mixture was stirred at 100°C for 16 hours to react. LCMS showed that the raw material was completely consumed, and the main peak of the target product was detected. The reaction solution was concentrated as it was. The crude product was separated and purified by high performance liquid chromatography (column: Welch Ultimate C18 150*25mm*5um; mobile phase: [water(FA)-ACN]; B%: 32%~62%, 10min) to obtain a gray-white solid, compound AB29559 (20.0mg, 43.8umol, yield 19.0%, purity 98.9%, formate salt).

[0182] 1 H NMR(400MHz,DMSO-d6)δppm 12.04-13.00(m,1H),11.04-11.86(m,1H),8.14(s,1H),7.36(d,J=1.13Hz,1H),7.12-7.18(m,1H),7.02-7.09(m,1H) ),6.90(s,1H),6.73(d,J=8.00Hz,1H),3.93(s,3H),2.55(d,J=0.75Hz,3H),2.42(s,3H),2.08(s,3H).LCMS:Ms:M+H + =406.

[0183] Example 14: Synthesis of compound AB29560

[0184] (1) Synthesis of Compound 2 [ka]

[0185] Methylamine hydrochloride (1.44g, 21.4mmol, 5.00eq, HCl) was dissolved in N-methylpyrrolidone (10.0mL), and compound 1 (780mg, 4.27mmol, 1.00eq) and potassium carbonate (2.95g, 21.4mmol, 5.00eq) were added. The mixture was stirred at 150°C for 24 hours to react. LCMS showed that compound 1 was completely consumed, and the molecular weight of the desired compound was detected. Water (50.0mL) was added to the reaction solution, and then ethyl acetate (50mL*3) was added and extracted three times. The organic phases were combined and backwashed once with saturated saline (20.0mL). The separated organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product compound 2 (1.00g, crude) (LCMS: Ms: M+H + = 178.2) and was used as is in the next step.

[0186] (2) Synthesis of compound AB29560 [ka]

[0187] Compound 5 (0.05g, 192umol, 1.00eq) was added with N,N-dimethylformamide (1.00mL), compound 2 (34.04mg, 192umol, 1.00eq), N,N-diisopropylethylamine (99.3mg, 768umol, 134uL, 4.00eq), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (110mg, 211umol, 1.10eq) were added to the reaction solution, and the reaction solution was stirred at 100°C for 16 hours to react. LCMS showed that the raw material was completely consumed, and the main peak of the target product was detected. The reaction solution was concentrated as it was. The crude product was separated and purified by high performance liquid chromatography (column: Phenomenex C18 150*25mm*10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 36%~66%, 10min) to obtain compound AB29560 as an off-white solid (23.0mg, 52.9umol, yield 13.8%, purity 96.5%).

[0188] 1 H NMR(400MHz,DMSO-d6)δppm 12.20(br s,1H),7.29-7.44(m,2H),6.97-7.11(m,1H),6.76(dd,J=8.69,2.19Hz,1H),5.98-6.11(m,1H),3.77(s,3H),3.56(br d,J=11.76Hz,3H),2.54(s,3H),2.22(s,3H),1.99(br d,J=4.75Hz,3H).LCMS:Ms:M+H + =420.

[0189] Example 15: Synthesis of compound AB29561

[0190] (1) Synthesis of Compound 2 [ka]

[0191] Compound 1 (5.00 g, 29.2 mmol, 1.00 eq) was dissolved in dichloromethane (50.0 mL), then methylamine (3.95 g, 58.4 mmol, 2.00 eq, hydrochloride) and potassium carbonate (6.06 g, 43.8 mmol, 1.50 eq) were added, and the reaction mixture was stirred at 20° C. for 12 h. TLC (petroleum ether:ethyl acetate=3:1) showed that compound 1 was completely consumed, and a new spot with increased polarity was detected. Purification by thin layer chromatography (petroleum ether:ethyl acetate=3:1) gave compound 2 as a yellow solid (3.50 g, 82.3 umol, 70.0% yield).

[0192] (2) Synthesis of Compound 3 [ka]

[0193] Compound 2 (5.00 g, 27.4 mmol, 1.00 eq) was dissolved in methanol (500 mL) and Pd / C (2.00 g, 10% purity) was added, followed by purging with hydrogen gas three times. The mixture was stirred at 25° C. and 15 Psi for 12 h. LCMS showed that compound 2 was completely consumed, and the molecular weight of the desired compound was detected. The reaction was filtered under vacuum, and the filtrate was collected and concentrated under reduced pressure to give compound 3 (3.5 g, crude product) as a brown oil. (LCMS: Ms: M+H) + =153.2).

[0194] (3) Synthesis of compound 4 [ka] Compound 3 (500 mg, 3.29 mmol, 1.00 eq) was dissolved in water (1.00 mL) and ethanol (5.00 mL), and then cyanogen bromide (417 mg, 3.94 mmol, 289 uL, 1.20 eq) was added slowly to the above mixture at 25° C. The reaction was stirred slowly at 70° C. for 4 hours. LCMS showed that compound 3 was completely consumed, and the molecular weight of the desired compound was detected. The reaction was concentrated under vacuum, and ethyl acetate (20.0 mL) was added and beaten, then filtered under vacuum, and the cake was collected and concentrated under reduced pressure to give a white solid (LCMS: Ms: M+H). + =178.1) Compound 4 was obtained (340 mg, crude product).

[0195] (4) Synthesis of compound AB29561 [ka]

[0196] Compound 4 (163 mg, 921 umol, 3.00 eq) was dissolved in N,N-dimethylformamide (2.00 mL), N,N-diisopropylethylamine (238 mg, 1.84 mmol, 321 uL, 6.00 eq) was added, compound 5 (80.0 mg, 307 umol, 1.00 eq) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (175 mg, 338 umol, 1.10 eq) were added to the reaction solution, and the mixture was stirred at 100° C. for 12 hours. LCMS showed that the compound raw material was completely consumed, and the molecular weight of the target product was detected. The reaction mixture was concentrated under vacuum and the crude product was purified by high performance liquid chromatography (column: Waters xbridge 150*25mm 10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 41%~71%, 9min) to obtain a white solid, compound AB29561 (10.9mg, 26.1umol, 8.50% yield).

[0197] 1 H NMR(400MHz,DMSO-d6)δppm 12.32-12.45(m,1H),7.27-7.34(m,2H),7.04(br d,J=2.00Hz,1H),6.75(br dd,J=8.76,2.13Hz,1H),6.51(s,1H),3.79(s,3H),3.59(s,3H),2.52(s,6H),1.98-2.09(m,3H).LCMS:Ms:M+H + =420.

[0198] Example 16: Synthesis of compounds AB29562 and AB29563 [ka]

[0199] Compound 1 (100mg, 246umol, 1.00eq) was added with tetrahydrofuran (0.5mL) and dimethylsulfoxide (0.5mL), potassium tert-butoxide (55.2mg, 493umol, 2.00eq) was added to the reaction solution, chloromethyl methyl ether (29.8mg, 369umol, 28.1uL, 1.50eq) was added dropwise to the reaction solution, and the reaction solution was stirred at 20℃ for 2 hours to react. LCMS showed that the raw material was completely consumed, and the peak of the target product was detected. After the reaction was completed, water (5.00mL) was added directly to the reaction solution, and it was extracted twice with ethyl acetate (5.00mL*2). The organic phases were combined, dried and concentrated. The crude product was separated and purified by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(NH4HCO3)-ACN]; B%: 42%~72%, 10min), and the obtained product was further separated by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm, 10um); mobile phase: [0.1%NH3H2O ​​MEOH]; B%: 35%~35%, C6.8; 68min) to obtain compound AB29562 as an off-white solid (5.49mg, 11.66umol, yield 4.73%, purity 95.51%) and compound AB29563 as an off-white solid (7.44mg, 15.9umol, yield 6.47%, purity 96.38%).

[0200] Compound AB29562: 1 H NMR(400MHz,DMSO-d6)δppm 7.40(br d,J=8.25Hz,1H),7.26(s,1H),7.04(br s,1H),6.82(br d,J=8.25Hz,1H),6.55(br s,1H),5.57(br s,2H),3.83(s,3H),3.37(s,3H),2.56(s,3H),2.50(br s,3H),2.08(s,3H).LCMS:Ms:M+H + =450.

[0201] Compound AB29563: 1H NMR(400MHz,DMSO-d6)δppm 12.41-12.65(m,1H),7.27-7.41(m,2H),7.10(d,J=2.38Hz,1H),6.82(dd,J=8.76,2.38 Hz,1H),6.54(s,1H),5.55(s,2H),3.69-3.84(m,3H),3.30(s,3H),2.54(s,3H),2.48(br s,3H),2.05(s,3H).LCMS:Ms:M+H + =450.

[0202] Example 17: Synthesis of compounds AB29564 and AB29565

change

[0203] Compound 1 (100mg, 246umol, 1.00eq) was added with dimethylsulfoxide (1.00mL), potassium tert-butoxide (60.9mg, 542umol, 2.20eq) was added to the reaction solution, trimethylchloroacetic acid chloromethyl ester (74.3mg, 493umol, 71.4uL, 2.00eq) was added to the reaction solution, and the reaction solution was stirred at 30℃ for 5 hours to react. LCMS showed that about 5% of the raw material remained, and the main peak of the target product was detected. Water (10.0mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (20.0mL*2). The organic phases were combined and backwashed once with saturated saline (10.0mL), and the separated organic phase was dried over anhydrous sodium sulfate and then concentrated. The crude product was separated and purified by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(NH3H2O)-ACN]; B%: 55%~85%, 8min), and the obtained product was further separated by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm, 10um); mobile phase: [0.1%NH3H2O ​​MeOH]; B%: 35%~35%, C7.5; 60min) to obtain compound AB29564 (5.36mg, 9.62umol, yield 3.90%, purity 93.2%) as an off-white solid, and compound AB29565 (5.39mg, 9.81umol, yield 3.98%, purity 94.6%) as an off-white solid.

[0204] Compound AB29564: 1 H NMR(400MHz,DMSO-d6)δppm 7.38(br d,J=8.63Hz,1H),7.25(s,1H),7.12(s,1H),6.79-6.94(m,1H),6.52(s,1H),6.06-6.30(m,2H),3.82(s,3H),2.55(s,3H),2.49(br s,3H),2.07(s,3H),1.14(s,9H).LCMS:Ms:M+H + =520.

[0205] Compound AB29565: 1H NMR(400MHz,DMSO-d6)δppm 12.32-12.70(m,1H),7.39(br d,J=8.38Hz,1H),7.31(s,1H),7.08(br s,1H),6.84(br d,J=8.38Hz,1H),6.50(br s,1H),6.16(br s,2H),3.77(s,3H),2.53(s,3H),2.46(br s,3H),2.05(s,3H),1.09(s,9H).LCMS:Ms:M+H + =520.

[0206] Example 18: Synthesis of compound AB29572 [ka]

[0207] Compound 5 (50.0 mg, 192 umol, 1.00 eq) was added with N,N-dimethylformamide (1.00 mL), and compound A007 (41.7 mg, 192 umol, 1.00 eq), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (110 mg, 211 umol, 1.10 eq), and N,N-diisopropylethylamine (99.3 mg, 768 umol, 134 uL, 4.00 eq) were added to the reaction solution, and the reaction solution was stirred at 100 °C for 8 hours to react. LCMS showed that the raw material was completely consumed, and the peak of the target product was detected. The reaction solution was concentrated with an oil pump. The crude product was purified by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(NH4HCO3)-ACN]; B%: 48%~78%, 2min) to obtain a yellow solid, compound AB29572 (6.39mg, 12.7umol, yield 6.61%, purity 91.3%).

[0208] 1H NMR(400MHz,DMSO-d6)δppm 12.45(br s,1H),11.44(br s,1H),7.38-7.59(m,2H),7.35(s,1H),7.08(br d,J=8.50Hz,1H),6.96(s,1H),2.55(s,3H),2.42(s,3H),2.07(s,3H).LCMS:Ms:M+H + =460.

[0209] Example 19: Synthesis of compound AB29540 [ka]

[0210] (1) Synthesis of Compound 2

[0211] Compound 1 (0.7g, 5.07mmol, 1eq) was added with hydrochloric acid (15mL, 5.5M), glycolic acid (424mg, 5.57mmol, 339uL, 1.10eq) was added to the reaction solution, and the reaction solution was stirred at 100℃ for 16 hours to react. LCMS showed that the raw material was completely consumed, and the peak of the target product was detected. Saturated aqueous sodium bicarbonate solution was gradually added to the reaction solution to adjust the pH to 7-8. Extracted twice with ethyl acetate (50mL*2), the organic phases were combined, dried, and concentrated. The crude product was purified by column chromatography (ethyl acetate:methanol=1:1) to obtain compound 2 (160mg, 808umol, 15.9% yield, 90% purity) as a brown solid (LCMS:Ms:M+H + =179.4).

[0212] (2) Synthesis of Compound 3 [ka]

[0213] A mixture of sodium hydroxide (71.8 mg, 1.80 mmol, 2.00 eq) and water (2 mL) was added to compound 2 (160 mg, 898 umol, 1.00 eq), and the reaction solution was stirred at 100 °C for 2 hours to react. After the reaction solution was cooled to room temperature, potassium permanganate (150 mg, 949 umol, 1.06 eq) was added, and the mixture was heated to 100 °C and stirred for 2 hours to react. LCMS showed that the raw materials were completely consumed, and the main peak of the target product was detected. After the reaction was completed, the reaction solution was cooled to room temperature and filtered, and the filtrate was adjusted to pH = 4-5 with hydrochloric acid (2N) and filtered. The cake was washed once with water, collected and dried under vacuum to obtain compound 3 (0.1 g, crude) as a red solid (LCMS: Ms: M+H + =193.3).

[0214] (3) Synthesis of compound 6 [ka]

[0215] Compound 5 (500mg, 1.92mmol, 1.00eq) was added with toluene (5mL), DPPA (1.48g, 5.38mmol, 1.17mL, 2.80eq) and triethylamine (777mg, 7.68mmol, 1.07mL, 4.00eq) were added to the reaction solution, and the reaction solution was stirred at 110℃ for 1 hour. tert-Butanol (5mL) was added to the reaction solution, and the reaction solution was stirred at 110℃ for 2 hours. The formation of the target product was detected by LCMS. Water (10mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (15mL*2). The organic phases were combined and concentrated. The crude product was separated and purified by thin layer chromatography (petroleum ether:ethyl acetate=5:1) to obtain compound 6 (50.0mg, 105umol, 5.50% yield, 70% purity) as a yellow oil.

[0216] (4) Synthesis of compound 7 [ka]

[0217] A mixture of trifluoroacetic acid (0.1 mL) and dichloromethane (2 mL) was added to compound 6 (30.0 mg, 90.5 umol, 1.00 eq), and the reaction solution was stirred at 20°C for 16 hours. LCMS showed that the raw material was completely consumed, and the main peak of the target product was detected. The reaction solution was directly concentrated to obtain a pale yellow oily product, compound 7 (0.04 g, crude, TFA), which was used directly in the next reaction.

[0218] (5) Synthesis of compound AB29540 [ka]

[0219] Compound 3 (20.0 mg, 104 umol, 1.00 eq) was added with pyridine (1 mL), and compound 7 (35.9 mg, 104 umol, 1.00 eq, TFA) and EDCI (21.9 mg, 114 umol, 1.10 eq) were added to the reaction solution, and the reaction solution was stirred at 20 ° C for 16 hours to react. LCMS showed that the raw material had reacted completely, and the peak of the target product was detected. The reaction solution was concentrated as it was. The crude product was separated and purified by high performance liquid chromatography (column: Waters xbridge 150 * 25 mm 10 um; mobile phase: [water (NH4HCO3) -ACN]; B%: 38% ~ 68%, 9 min) to obtain compound AB29540 (3.08 mg, 7.33 umol, 7.05% yield, 96.53% purity).

[0220] 1 H NMR(400MHz,DMSO-d6)δppm13.17(dt,J=4.41,2.11Hz,1H),10.06(s,1H),7.45- 7.73(m,1H),7.29(s,1H),6.87-7.13(m,2H),6.26(s,1H),3.82(s,3H),2.53(br s,3H),2.08(s,3H),2.04(s,3H).LCMS:Ms:M+H + =406.

[0221] Example 20: Synthesis of compound AB29554

[0222] (1) Synthesis of Compound 2 [ka]

[0223] Acetonitrile (20.0 mL) was added to compound 1 (500 mg, 4.58 mmol, 1.00 eq), triethylamine (463 mg, 4.58 mmol, 638 uL, 1.00 eq) was added to the reaction solution, and then ethoxycarbonyl isothiocyanate (661 mg, 5.04 mmol, 1.10 eq) was added dropwise to the reaction solution, and the reaction solution was stirred at 25 ° C for 15 minutes to react. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.05 g, 5.50 mmol, 1.20 eq) was added to the reaction solution, and then triethylamine (695 mg, 6.87 mmol, 956 uL, 1.50 eq) was added to the reaction solution, and the reaction mixture was stirred at 80 ° C for 3 hours to react. The reaction mixture was filtered, the cake was washed once with a small amount of acetonitrile (10.0 mL), and the cake was collected to give compound 2 (900 mg, crude) as a gray solid.

[0224] (2) Synthesis of Compound 3 [ka]

[0225] Methanol (4.00 mL) was added to compound 2 (900 mg, 4.36 mmol, 1.00 eq), sodium hydroxide solution (1 M, 8.73 mL, 2.00 eq) was added to the reaction solution, and the reaction solution was stirred at 100 °C for 16 hours. LCMS showed that the raw materials were completely consumed, and the peak of the target product was detected. After cooling the reaction solution, methanol was removed, and 2 M HCl solution was slowly added until pH = 7-8, and a solid precipitated. This was directly filtered, and the cake was collected to obtain compound 3 (500 mg, 3.73 mmol, 85.4% yield) as a gray solid.

[0226] (3) Synthesis of compound 6 [ka]

[0227] Compound 4 (200 mg, 1.75 mmol, 205 uL, 1.00 eq) was added to toluene (2 mL), and compound 5 (242 mg, 1.75 mmol, 1.00 eq) and p-toluenesulfonic anhydride (60.3 mg, 350 umol, 0.200 eq) were added to the reaction solution, and the reaction solution was stirred at 110°C for 4 hours to react. TLC (petroleum ether: ethyl acetate = 5:1, R f =0.43) indicated that a small amount of compound 5 remained and the main point with reduced polarity was produced. Water (10 mL) was added to the reaction solution, and it was extracted twice with ethyl acetate (10 mL * 2). The organic phases were combined and then concentrated. The crude product was separated and purified by thin layer chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain compound 6 as a brown solid (215 mg, 994 umol, 56.7% yield).

[0228] 1 H NMR(400MHz,CDCl3)δppm 6.88(d,J=1.00Hz,1H),5.93(s,2H),2.52(d,J=1.00Hz,3H),2.12(s,6H).LCMS:Ms:M+H + =217.

[0229] (4) Synthesis of compound 7 [ka]

[0230] Compound 6 (100 mg, 462 umol, 1.00 eq) was added with 1,2-dichloroethane (2 mL), 4-dimethylaminopyridine (56.5 mg, 462 umol, 1.00 eq) was added to the reaction solution, trichloroacetyl chloride (252 mg, 1.39 mmol, 154 uL, 3.00 eq) was added dropwise to the reaction solution, and the reaction solution was stirred at 50°C for 16 hours to react. TLC (petroleum ether: ethyl acetate = 5:1, R f =0.24), indicating that about 20% of the raw material was not completely reacted, and the formation of a new spot with increased polarity was detected. Water (10 mL) was added to the reaction solution, and it was extracted twice with ethyl acetate (10 mL * 2). The organic phases were combined, dried, and concentrated. The crude product was separated and purified by thin layer chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain compound 7 (80.0 mg, 221 umol, 47.8% yield) as a pale yellow oil.

[0231] 1 H NMR(400MHz,CDCl3)δppm 6.97(d,J=0.75Hz,1H),6.73(s,1H),2.57(d,J=0.75Hz,3H),2.47(s,3H),2.12(s,3H).

[0232] (5) Synthesis of compound AB29554 [ka]

[0233] Compound 7 (60.0 mg, 166 umol, 1.00 eq) was added with N,N-dimethylformamide (2 mL), compound 3 (26.7 mg, 199 umol, 1.20 eq) and anhydrous sodium carbonate (35.2 mg, 332 umol, 2.00 eq) were added to the reaction solution, and the reaction solution was stirred at 85 ° C for 2 hours to react. LCMS showed that the raw material was completely consumed, and the main peak of the target product was detected. The reaction solution was concentrated and dried as it was. The crude product was separated and purified by high performance liquid chromatography (column: Waters xbridge 150 * 25 mm 10 um; mobile phase: [water (NH4HCO3) -ACN]; B%: 27% ~ 57%, 9 min) to obtain a white solid compound AB29554 (20.0 mg, 52.4 umol, 31.6% yield, 98.66% purity).

[0234] 1 H NMR(400MHz,DMSO-d6)δppm 12.27-12.45(m,1H),11.41-11.63(m,1H),8.16-8.28(m,1H),7.78(br d,J=8.00Hz,1H),7.35(d,J=1.13Hz,1H),7.09(br d,J=4.38Hz,1H),6.91-7.01(m,1H),2.56(s,3H),2.42(s,3H),2.08(s,3H).LCMS:Ms:M+H + =377.

[0235] Example 21: Synthesis of compound AB29566

[0236] (1) Synthesis of Compound 2 [ka]

[0237] Compound 1 (5.00g, 28.9mmol, 1.00eq) was dissolved in dichloromethane (50.0mL), and ethyl chloroformate (3.36g, 30.9mmol, 2.95mL, 1.07eq) was added to the mixture, and then pyridine (6.86g, 86.7mmol, 7.00mL, 3.00eq) was slowly added dropwise to the above reaction solution. The temperature was controlled at 25℃-30℃, and the system was stirred at 25℃ for 1.5 hours. LCMS showed that compound 1 was completely consumed, and the molecular weight of the desired compound was detected. After the reaction was completed, the reaction solution was slowly poured into ice water (100mL), stirred and quenched, and then extracted by adding dichloromethane (100mL*3). The organic phase was washed with saturated saline (50.0mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid (LCMS:Ms:M+H + =245.0) Compound 2 was obtained (5.00 g, crude product).

[0238] (2) Synthesis of Compound 3 [ka]

[0239] Fuming nitric acid (1.08g, 17.1mmol, 771uL, 1.00eq) was dissolved in sulfuric acid (12.0mL), and compound 2 (4.20g, 17.1mmol, 1.00eq) was added slowly to the above mixture at 0°C. The reaction solution was stirred at 0°C for 0.1h, then gradually warmed to 25°C and stirred for 12h. LCMS showed that compound 2 was completely consumed, and the molecular weight of the desired compound was detected. The reaction solution was poured into ice water, and the precipitated solid was filtered under vacuum, and the cake was collected and concentrated under reduced pressure to give compound 3 (4.30g, crude product) as a white solid (LCMS: Ms: M+H). + =291.9).

[0240] (3) Synthesis of compound 4 [ka]

[0241] Compound 3 (2.50 g, 8.62 mmol, 1.00 eq) was dissolved in methanol (10.0 mL) and sodium methoxide (6.21 g, 34.4 mmol, 30% purity, 4.00 eq) was added. The mixture was stirred at 65° C. for 12 h. LCMS showed that compound 3 was completely consumed and the molecular weight of the desired compound was detected. The reaction was concentrated under vacuum, water (20.0 mL) was added, filtered under vacuum, and the cake was collected and concentrated under reduced pressure to give compound 4 (900 mg, crude) as a grey solid. (LCMS: Ms: M+H) + =170.1).

[0242] (4) Synthesis of Compound 5 [ka]

[0243] Compound 4 (1.19 g, 7.04 mmol, 1.00 eq) was dissolved in ethyl acetate (100 mL) and wet palladium on carbon (0.50 g, 10% purity) was added, followed by purging with hydrogen gas three times. The reaction was stirred at 25° C. and 15 Psi for 12 hours. LCMS showed that compound 4 was completely consumed, and the molecular weight of the desired compound was detected. The reaction was filtered under vacuum, and the filtrate was collected and concentrated under reduced pressure to give compound 5 (800 mg, crude product) as a brown oil. (LCMS: Ms: M+H) + =140.2).

[0244] (5) Synthesis of compound 6 [ka]

[0245] Compound 5 (800 mg, 5.75 mmol, 1.00 eq) was dissolved in water (2.00 ml) and ethanol (8.00 mL) was added. The temperature was lowered to 0° C., and then cyanogen bromide (730 mg, 6.90 mmol, 507 uL, 1.20 eq) was slowly added. The mixture was heated to 70° C. and reacted for 12 hours. LCMS showed that 20% of compound 5 remained, and the molecular weight of the desired compound was detected. The reaction was concentrated under vacuum. Purification by TLC (ethyl acetate:methanol=10:1) gave compound 6 (400 mg, 2.44 mmol, 42.3% yield) as a grey solid (LCMS: Ms: M+H). + =165.2).

[0246] (6) Compound AB29566 synthesis [ka]

[0247] Compound 6 (50.0 mg, 138 umol, 1.00 eq) was dissolved in N,N-dimethylformamide (2.00 mL), and then sodium carbonate (43.96 mg, 414 umol, 3.00 eq) and compound 7 (22.7 mg, 138 umol, 1.00 eq) were added. The mixture was stirred at 80°C for 2 hours. LCMS showed that the compound raw material was completely consumed, and the molecular weight of the desired compound was detected. The reaction solution was concentrated under vacuum and purified by high performance liquid chromatography (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (NH3H2O)-ACN]; B%: 27%~57%, 8 min) to obtain compound AB29566 (10.7 mg, 26.4 umol, 19.1% yield) as a yellow solid.

[0248] 1 H NMR(400MHz,DMSO-d6)δppm 7.74-7.96(m,1H)7.32(br d,J=1.13Hz,2H)6.72-6.90(m,1H)3.80(s,3H)2.53(s,3H)2.41(s,3H)2.05(s,3H). LCMS:Ms:M+H+ =407.

[0249] Example 22: Synthesis of compound AB29552

[0250] (1) Synthesis of Compound 4 [ka]

[0251] Compound 2 (100mg, 467umol, 1.00eq) was added to toluene (2mL), and compound 3 (52.8mg, 467umol, 48.0uL, 1.00eq) and p-toluenesulfonic anhydride (16.0mg, 93.3umol, 0.200eq) were added to the reaction solution, and the reaction solution was stirred at 110°C for 2 hours to react. LCMS showed that the raw material was completely consumed, and the main peak of the target product was detected. The reaction solution was concentrated as it was. The crude product was separated and purified by thin layer chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 4 as a brown solid (110mg, 377umol, 80.9% yield).

[0252] (2) Synthesis of Compound 5 [ka]

[0253] Compound 4 (110 mg, 377 umol, 1.00 eq) was added with HCl / EtOAc (2 mL, 4 M), and the reaction solution was stirred at 20° C. for 3 hours. TLC (petroleum ether:ethyl acetate=3:1, R f =0.24), indicating complete consumption of the starting material, and a new spot of increased polarity was formed. The reaction mixture was concentrated directly to give compound 5 (0.07 g, crude) as a brown solid, which was used directly in the next reaction.

[0254] (3) Synthesis of compound AB29552 [ka]

[0255] Compound 5 (60.0 mg, 255 umol, 1.00 eq) was added with N,N-dimethylformamide (1 mL), and compound A014 (45.8 mg, 280 umol, 1.10 eq), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (146 mg, 280 umol, 1.10 eq) and N,N-diisopropylethylamine (132 mg, 1.02 mmol, 178 uL, 4.00 eq) were added to the reaction solution, and the reaction solution was stirred at 100°C for 6 hours to react. LCMS showed that the raw materials had completely reacted, and the production of the target product was detected. The reaction solution was concentrated as it was. The crude product was separated and purified by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(HCl)-ACN]; B%: 22%~52%, 10min), and then purified a second time (column: Waters xbridge 150*25mm 10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 40%~70%, 9min) to obtain compound AB29552 as a white solid (2.34mg, 6.15umol, 2.41% yield).

[0256] 1 H NMR(400MHz,DMSO-d6)δppm 12.00(br d,J=0.75Hz,1H),10.84-10.96(m,1H),7.46(dd,J=5.07,1.19Hz,1H),7.24-7.37(m,1H),6.89-7 .09(m,3H),6.62-6.80(m,2H),5.32(s,2H),3.75(s,3H),2.60(s,3H),2.22(s,3H).LCMS:Ms:M+H + =381.

[0257] Example 23: Synthesis of compound AB29555

[0258] (1) Synthesis of Compound 2 [ka]

[0259] Compound 1 (1.00 g, 9.16 mmol, 1.00 eq) was dissolved in ethanol (2.00 mL) and water (10.0 mL) and cyanogen bromide (1.16 g, 11.0 mmol, 808 uL, 1.20 eq) was added slowly. The reaction mixture was stirred at 70° C. for 12 hours. LCMS showed that 30% compound 1 remained, and the molecular weight of the desired compound was detected. The mixture was concentrated under vacuum to give compound 2 (2.00 g, crude product) as a yellow solid (LCMS: Ms: M+H). + =130.4).

[0260] (2) Synthesis of compound AB29555 [ka]

[0261] Compound 2 (29.6 mg, 220 umol, 2.00 eq) was dissolved in N,N-dimethylformamide (2.00 mL), and sodium carbonate (35.1 mg, 331 umol, 3.00 eq) and compound 3 (40.0 mg, 110 umol, 1.00 eq) were added. The mixture was stirred at 80°C for 12 hours. LCMS showed that the raw material was completely consumed, and the molecular weight of the desired compound was detected. The reaction solution was concentrated under vacuum. The crude product was purified by high performance liquid chromatography (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water(HCl)-ACN]; B%: 14%~44%, 8 min) to obtain compound AB29555 as a yellow solid (10.0 mg, 24.2 umol, 21.9% yield, hydrochloric acid).

[0262] 1H NMR(400MHz,MeOD)δppm 8.88(s,1H)8.32-8.49(m,1H)7.80-8.02(m,1H)7.16(d,J=1.00Hz,1H)6.71(s,1H)2.59(s,3H)2.48(s,3H)2.15(s,3H). LCMS:Ms:M+H + =377.

[0263] Example 24: Synthesis of compound AB29573

[0264] (1) Synthesis of Compound 2 [ka]

[0265] Compound 1 (500mg, 2.54mmol, 1.00eq) was added with tert-butanol (5mL), triethylamine (643mg, 6.36mmol, 885uL, 2.50eq) and DPPA (910mg, 3.31mmol, 716uL, 1.30eq) were added to the reaction solution, and the reaction solution was stirred at 85°C for 2 hours to react. LCMS showed that the raw material was completely consumed, and the main peak of the target product was detected. The reaction solution was concentrated as it was. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain compound 2 as a white solid (100mg, 374umol, 14.7% yield).

[0266] (2) Synthesis of Compound 3 [ka]

[0267] Compound 2 (75.0 mg, 285 umol, 1.00 eq) was reacted with HCl / EtOAc (7 mL) at 20° C. for 2 hours with stirring. LCMS showed that the raw material was completely consumed, and the main peak of the target product was detected. The reaction solution was directly concentrated to obtain compound 3 (0.06 g, crude, HCl) as a yellow solid, which was used directly in the next reaction.

[0268] (3) Synthesis of compound AB29573 [ka]

[0269] Compound 4 (50.0 mg, 138 umol, 1.00 eq) was added to N,N-dimethylformamide (1 mL), and compound 3 (55.2 mg, 276 umol, 2.00 eq, HCl) and anhydrous sodium carbonate (58.6 mg, 553 umol, 4.00 eq) were added to the reaction solution, and the reaction solution was stirred at 100°C for 2 hours to react. LCMS showed that the raw materials had reacted completely, and a small amount of the target product was detected. The reaction solution was concentrated, and then methanol was added and filtered, and the filtrate was collected and concentrated. The crude product was separated and purified by thin layer chromatography (petroleum ether: ethyl acetate = 1:1), and then further separated and purified by high performance liquid chromatography (column: Welch Xtimate C18 150 * 25mm * 5um; mobile phase: [water (NH3H2O) -ACN]; B%: 30% ~ 60%, 8min) to obtain a yellow solid compound AB29573 (1mg, 2.30umol, 1.66% yield, 93.06% purity).

[0270] 1 H NMR(400MHz,DMSO-d6)δppm 11.17-11.40(m,1H),10.58-10.74(m,1H),8.25(s,1H),7.34(d,J=1.13Hz,1H),6.73(s,1H),6.65 (s,1H),6.06(s,1H),3.79(s,3H),2.54(d,J=0.63Hz,3H),2.38(s,3H),2.09(s,3H).LCMS:Ms:M+H + =406.

[0271] Pharmacological activity assays and result analysis

[0272] Production of recombinant DHX33

[0273] For protein isolation and purification, see Wang X, Ge W, and Zhang Y. Recombinant DHX33 Protein Possesses Dual DNA / RNA Helicase Activity. Biochemistry. 2019;58(4):250-8. The RNA helicase gene (mouse DHX33 gene) was cloned between the BamH I / Not I restriction enzyme cleavage sites of the pET32M-3C vector. The plasmid was then transformed into E. coli strain BL-21pLysS(DE3), and recombinant protein expression was induced for 16 hours at 16°C by adding 0.5 mM isopropyl 1-thio-β-D-galactopyranoside (IPTG). The cells were pelleted and resuspended in cell lysis buffer [50 mM Tris-HCl (pH 7.2), 150 mM NaCl, 1% Triton® X-100, and 50 mM imidazole supplemented with protease inhibitors]. The cells were then sonicated and centrifuged at 13,000 rpm for 25 min. The supernatant was incubated with nickel-nitrilotriacetic acid beads equilibrated with Tris buffer and then washed extensively. The purified protein was then eluted with 300 mM imidazole in Tris buffer and dialyzed overnight at 4°C against imidazole-free Tris buffer.

[0274] Figure 1 shows the analysis of the recombinant DHX33 protein produced by the above method, separated by SDS-PAGE and stained with Coomassie Brilliant Blue. The arrow in the figure indicates the recombinant DHX33 protein of interest (containing a thioredoxin tag), and the molecular weight of the band of interest was 90 kDa.

[0275] DHX33 helicase activity analysis

[0276] The reaction components with helicase activity were added to an opaque 96-well white plate. The procedure is as follows: Neutravidin was coated on a 96-well plate at a final concentration of 10 μg / mL (100 μL / well) overnight at 4°C. The Neutravidin-coated plate was then blocked with 100 μL of 0.1% (w / v) BSA (dissolved in normal PBS) for 2 hours at 22°C. After washing, a double-stranded DNA [2.5 ng, annealing reaction was performed in 1M PBS (pH 7.0) containing 1M NaCl] was added and incubated at 22°C for 4 hours. Two single-stranded oligo DNAs (one was biotin-labeled 5'-GCTGACCCTGCTCCCAATCGTAATCTATAG-3' and the other was DIG-labeled 5'-CGATTGGGAGCAGGGTCAGC-3') were annealed to form a double-stranded DNA. After adding 90 μL of reaction mixture, the helicase reaction [0.25 μg of purified full-length DHX33 protein was dissolved in 25 mM 4-MOPS (pH 7.0), 5 mM ATP, 2 mM DTT, 3 mM MnCl2, and 100 μg BSA] was started. The reaction was allowed to proceed for 60 min at 37 °C. After washing, each well was incubated with blocking solution [10% (w / v) BSA in 0.1 M maleic acid and 0.15 M NaCl (pH 7.5)] for 30 min, followed by incubation with 20 μL antibody solution for 30 min (anti-DIG-AP, Roche, in blocking buffer). After washing with 100 μL of detection buffer [0.1 M Tris-HCl and 0.1 M NaCl (pH 9.5)], 1 μL of chemiluminescent substrate (CSPD-0.25 mM) was added to each well, and the plate was incubated at 17 °C for 5 min. The plate was then tapped dry and incubated at 37°C for 30 minutes. The DIG-AP marker control remaining in each well was measured for 10 minutes using a luminescence multi-well plate reader (Enspire, PerkinElmer). A higher measured value indicates a weaker helicase activity. In this activity analysis experiment, a positive control and a negative control were set up.One negative control was a control under the same conditions except that ATP was not added, and the other negative control was a control under the same conditions except that DHX33 protein was not added. The positive control was compared with a wild-type DHX33 protein standard. As a result of comparison with the DHX33 protein standard, it was found that the DHX33 protein prepared by the above method had helicase activity.

[0277] For specific methods of helicase activity analysis, see Wang X, Ge W, and Zhang Y. Recombinant DHX33 Protein Possesses Dual DNA / RNA Helicase Activity. Biochemistry. 2019;58(4):250-8.

[0278] Inhibition of DHX33 helicase activity by compounds

[0279] The helicase activity of DHX33 protein was measured in vitro using a series of compounds (concentrations in the range of 1 nM, 5 nM, 10 nM, 20 nM, 50 nM, 100 nM, 250 nM, 500 nM, and 1000 nM). The half-maximal inhibitory concentrations of the compounds of the present invention against the helicase activity of DHX33 protein are shown in Table 1. As is clear from Table 1, it was found that the compounds of the present invention have a significant inhibitory effect against the helicase activity of DHX33 protein.

[0280] [Table 1]

[0281] Cell culture and origin

[0282] U251-MG cells were purchased from the Cell Bank of the Chinese Academy of Sciences. They were cultured in MEM medium containing 10% fetal bovine serum (FBS), 2 mM L-glutamine, streptomycin and penicillin, and the growth conditions were 37°C, 5% CO2, and a humidified incubator. The cells were passaged every 3 days and discarded after the 10th passage.

[0283] Cellular half inhibitory concentration (IC 50 ) Measurement

[0284] 1 × 10 cells of the cancer cell line U251-MG, which overexpresses DHX33 4 The cells were seeded in a 96-well plate at 100μl / well. After the cells were completely attached to the wall, the compounds were added to the cell culture medium at concentrations of 5nM, 10nM, 25nM, 50nM, 100nM, 250nM, 500nM, 1000nM, 2000nM, 5000nM, 10μM, and 20μM, and mixed uniformly with a multichannel pipette. After 48 hours of incubation of the compounds and cells, the compounds were added to the medium of the 96-well plate according to standard procedures using CCK-8 reagent (Yeasen Biotechnology (Shanghai)). After 2 hours of incubation, the plate was measured with a microplate reader (OD=450nm). The test was repeated three times, and inhibition curves at each concentration of the compounds were drawn to determine the half-inhibitory concentration (IC 50 ) was calculated.

[0285] [Table 2-1] [Table 2-2] [Table 2-3]

[0286] As is clear from Table 2, it was revealed that the compounds of the present invention have a significant inhibitory effect on the cancer cell line U251-MG cells in which DHX33 is overexpressed.

Claims

1. A compound having the structure: 【Chemistry 1】 (In the formula R １ , R ２ , R ３ and R ４ are each independently hydrogen, halogen, amino, nitro, hydroxyl, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, -NH(C １～６ Alkyl), -N(C １～６ Alkyl) ２ , C １～６ Hydroxyalkyl, —O—(C １～６ alkylene)-O-(C １～６ alkyl), -C(=O)-NH-(C １～６ alkyl), -C(=O)-NH-(C １～６ alkylene)-N(C １～６ Alkyl) ２ Or -C(=O)-O-(C １～６ alkyl); L １ is -NR ６ C(=O)-, -NR ６ S (=O) ２ --, --NR ６ S(=O)-, -C(=O)NR ６ -, -S(=O) ２ N.R. ６ - or -S(=O)NR ６ - selected from; Each R ６ are each independently hydrogen, C １～６ Alkyl, C ３～８ Cycloalkyl or C ６～１０ aryl; L ２ is a single bond, O, S or CR ８ R ９ Selected from: R ８ and R ９ are each independently hydrogen, halogen or C １～６ alkyl; Ring B is C ６～１０ aryl, 5- to 12-membered heteroaryl, or 3- to 8-membered heterocyclic group; Ring B is selected from one or more R １０ may be substituted with; Each R １０ are each independently a halogen, a cyano, an amino, a nitro, a hydroxyl, １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～６ Cycloalkyl, -C(=O)-O-(C １～６ alkyl), phenyl, benzyl, pyridyl, -C(=O)-NH ２ or -NH-C(=O)-(C １～６ alkyl), wherein the phenyl, benzyl, and pyridyl are selected from hydrogen, halogen, cyano, amino, hydroxyl, C １～６ Alkyl or C １～６ alkoxy; The pharma- ceutically acceptable forms are selected from pharma- ceutically acceptable salts, stereoisomers, tautomers, solvates, nitrogen oxides, and isotopic labels.

2. R １ , R ２ , R ３ and R ４ are each independently hydrogen, halogen, amino, nitro, hydroxyl, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, -NH(C １～６ Alkyl), -N(C １～６ Alkyl) ２ Or C １～６ 2. The compound of claim 1 or a pharma- ceutically acceptable form thereof, wherein said compound is selected from: hydroxyalkyl.

3. L １ is -NR ６ C(=O)-, -NR ６ S (=O) ２ -, -C(=O)NR ６ - or -S(=O) ２ N.R. ６ -, each R ６ are each independently hydrogen, C １～４ Alkyl or C ３～６ 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable form thereof, selected from cycloalkyl.

4. L ２ is a single bond or CR ８ R ９ is selected from; ８ and R ９ are each independently hydrogen, halogen or C １～４ 4. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable form thereof, wherein: R is selected from the group consisting of alkyl, aryl, aryl, arylsulfates ...

5. Ring B is C ６～１０ aryl or 5-12 membered heteroaryl, and Ring B is selected from one or more R １０ may be substituted with Each R １０ are each independently a halogen, a cyano, an amino, a nitro, a hydroxyl, １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～６ Cycloalkyl or -C(=O)-NH ２ 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable form thereof, selected from:

6. Formula I-7, Formula I-8, Formula I-9, Formula I-10, Formula I-11, Formula I-12, Formula I-13, Formula I-14, Formula I-15, Formula I-16, Formula I-17, Formula I-18, Formula I-21 or Formula I-22: 【Chemistry 2】 (In the formula, R １ , R ２ , R ３ , R ４ , R ６ and Ring B are as defined in any one of claims 1 to 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable form thereof, having the structure:

7. A compound or a pharma- ceutically acceptable form thereof, said compound being the compound 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 is selected from The compound or a pharma- ceutically acceptable form thereof, wherein the pharma- ceutically acceptable form is selected from a pharma- ceutically acceptable salt, a stereoisomer, a tautomer, a solvate, a nitrogen oxide, and an isotopically labeled compound.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable form thereof, and one or more pharma- ceutically acceptable carriers.

9. Use of a compound according to any one of claims 1 to 7 or a pharma- ceutically acceptable form thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the prophylaxis and / or treatment of a disease or condition mediated at least in part by DHX33.

10. The use according to claim 9, wherein the disease is selected from cancer, viral infection and inflammation mediated by DHX33.

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