WDR5 inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a compound as shown in a general formula (I), or pharmaceutically acceptable salts, tautomers, enantiomers, diastereomers, racemate, hydrates, esters, solvates, metabolic precursors or prodrugs of the compound, and a preparation method and application of the compound, or the pharmaceutically acceptable salts, tautomers, enantiomers, diastereomers, racemate, hydrates, esters, solvates, metabolic precursors or prodrugs of the compound. The compound of the formula I is targeted to WDR5 protein, can effectively prevent and / or treat diseases or symptoms related to abnormal activity of WDR5, and can be applied to drugs for treating diseases or symptoms related to selective WDR5. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a WDR5 inhibitor having a structure of formula I and a preparation method and use thereof. Background Art

[0002] WDR5 belongs to the WD40 domain repeat family (WD40-repeat) protein, which usually acts as a scaffold protein to participate in the interaction of various oncogenic proteins. WDR5 has two important protein interaction sites: one is the WIN site (WDR5 interaction site). By recognizing the WIN sequence, WDR5 forms a core functional catalytic complex with MLL1, RBBP5, ASH2L and DYP-30, catalyzing the methylation of chromatin histone H3K4, thereby inducing the abnormal expression of its downstream genes; the other is WBM (WDR5 binding motif), which can bind to proteins other than the MLL1 complex (c-MYC, etc.) to induce tumor occurrence. Studies have shown that in acute myeloid leukemia with MLL gene rearrangement (MLL-r AML), removing the WDR5-MLL1 complex can effectively inhibit and block the occurrence of leukemia. In addition, WDR5 is also involved in the occurrence of many other tumors and diseases, such as breast cancer, pancreatic ductal adenocarcinoma (PDAC), neuroblastoma, Burkitt lymphoma, etc.

[0003] Therefore, developing small molecule inhibitors to block the WDR5-MLL1 or WDR5-cMYC protein-protein interaction is an important strategy for effectively inhibiting and treating cancer and related diseases. Currently, a variety of small molecule inhibitors that block the protein-protein interaction between WDR5 and MLL1 and WDR5 and c-MYC have been reported. Summary of the invention

[0004] An object of the present invention is to provide a small molecule WDR5 inhibitor and a preparation method thereof and its use in preparing a drug for blocking WDR5-MLL1 or WDR5-cMYC protein-protein interaction, thereby effectively inhibiting cancer and related diseases.

[0005] In a first aspect of the present invention, there is provided a compound of formula (1), or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor or prodrug thereof;

[0006]

[0007] in,

[0008] A is H, halogen, amino, nitro, cyano, hydroxyl, mercapto, and a substituted or unsubstituted group selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -S-C1-C6 alkyl, substituted or unsubstituted benzyl, a 3-8 membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, a C6-C10 aryl, and a 3-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S;

[0009] B is H, halogen, amino, nitro, cyano, hydroxyl, carboxyl, -C(O)NHR, and a substituted or unsubstituted group selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, benzyl, a 3-8 membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, a C6-C10 aryl, and a 3-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S;

[0010] C is a substituted or unsubstituted 3-8 membered heterocyclic group containing 1-4 heteroatoms independently selected from N, O, and S, or a substituted or unsubstituted 3-10 membered heteroaryl group containing 1-4 heteroatoms independently selected from N, O, and S, wherein the group C is connected to L through a carbon atom on the heterocyclic group or the heteroaryl group;

[0011] X1, X2 and X3 are each independently selected from the group consisting of CH, N or C;

[0012] L is selected from C1-C3 methylene;

[0013] X is selected from C1-C3 methylene, NH, O, S;

[0014] Y is selected from the group consisting of NH, O;

[0015] Z is selected from the following groups: H, hydroxyalkyl, carboxyl, -C(O)NHR, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkoxy.

[0016] R is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy;

[0017] Unless otherwise stated, the substitution refers to one or more hydrogen atoms being replaced by a substituent selected from the group consisting of halogen, hydroxy, hydroxymethyl, nitro, amino, C1-C4 alkyl, trifluoromethyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C8 cycloalkoxy.

[0018] In another preferred embodiment,

[0019] A is H, halogen, amino, nitro, and a substituted or unsubstituted group selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 hydroxyalkyl, -S-C1-C6 alkyl, C6-C10 aryl, and a 3-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from N, O, and S;

[0020] B is halogen, amino, nitro, carboxyl, -C(O)NHR, and a substituted or unsubstituted group selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, benzyl, phenyl, and a 3-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from N, O, and S;

[0021] C is a substituted or unsubstituted 3-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from N, O, and S, wherein the group C is connected to L through a carbon atom on the heterocyclic group or the heteroaryl group;

[0022] X1, X2 and X3 are each independently selected from the group consisting of CH or C;

[0023] L is selected from C1-C3 alkylene;

[0024] X is selected from NH, O, S;

[0025] Y is selected from NH;

[0026] Z is selected from the group consisting of H, hydroxyalkyl, carboxyl, -C(O)NHR, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl.

[0027] R is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy;

[0028] Unless otherwise stated, the substitution refers to one or more hydrogen atoms being replaced by a substituent selected from the group consisting of halogen, hydroxy, hydroxymethyl, nitro, amino, C1-C4 alkyl, trifluoromethyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C8 cycloalkoxy.

[0029] In another preferred embodiment,

[0030] A is halogen, substituted or unsubstituted -S-C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted phenyl;

[0031] B is halogen, carboxyl, -C(O)NHR, or substituted or unsubstituted benzyl;

[0032] C is a substituted or unsubstituted heterocyclic group, wherein the group C is connected to L through a carbon atom on the heterocyclic group or the heteroaryl group;

[0033] X is NH;

[0034] L is a C1-C3 alkylene group;

[0035] Y is NH;

[0036] Z is H, substituted or unsubstituted benzyl, -C(O)NHR;

[0037] X1, X2 and X3 are each independently selected from the group consisting of CH or C;

[0038] R is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy;

[0039] The substitution refers to one or more hydrogen being replaced by a substituent selected from the group consisting of halogen, hydroxyl, hydroxymethyl, nitro, amino, C1-C4 alkyl, trifluoromethyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C8 cycloalkoxy.

[0040] In another preferred embodiment, A is fluorine, bromine, methylthio, cyclopropyl, trifluoromethyl-substituted phenyl, hydroxymethyl-substituted phenyl, or alkyl-substituted phenyl;

[0041] B is fluorine- or chlorine-substituted benzyl, -C(O)NHR, carboxyl,

[0042] C is a 5-membered heterocyclic group substituted with methyl;

[0043] X is NH;

[0044] L is a methylene group;

[0045] Y is NH;

[0046] Z is H, fluorine-substituted benzyl, nitro-substituted benzyl, -C(O)NHR,

[0047] X1, X2 and X3 are each independently selected from the group consisting of CH or C;

[0048] R is hydroxy, H, halogen, or C1-C4 alkyl.

[0049] In another preferred embodiment, C is

[0050] In another preferred embodiment, Y is NH.

[0051] In another preferred embodiment, Z is H.

[0052] In another preferred embodiment, Z is a carboxyl group.

[0053] In another preferred embodiment, the compound is selected from the following group:

[0054]

[0055]

[0056] In the second aspect of the present invention, there is provided a method for preparing the compound of formula I, comprising the following steps:

[0057]

[0058] (a1) In an inert solvent, in the presence of a condensing agent, a compound of formula 1A and a compound of formula 1B undergo a condensation reaction to obtain an intermediate compound of formula 1C; wherein A B C L, X, X1, X2, X3, Y, Z are as defined in the first aspect of the present invention;

[0059] (a2) reacting a compound of formula 1C with a compound of formula 1D in an inert solvent in the presence of a reductive amination agent to obtain a compound of formula I;

[0060] Or the method comprises the steps of:

[0061]

[0062] (b1) reacting the compound represented by formula 1A with the compound represented by formula 1E to obtain a compound represented by formula 1F;

[0063] (b2) reacting a compound of formula 1F with a compound of formula 1D to obtain a compound of formula 1G;

[0064] (b2) Suzuki reaction of the compound of formula 1G with the compound of formula 1H to obtain a compound of formula I;

[0065] Wherein, R1 is selected from the following group: I, Br, CF3SO2, OSO2(C n F 2n+1 ), where n = 0, 1, 4,

[0066] A B C L, X, X1, X2, X3, Y, and Z are as defined in the first aspect of the present invention.

[0067] In another preferred embodiment, the molar ratio of the compound represented by Formula 1A to the compound represented by Formula 1B is 1:(1-2); preferably 1:(1.3-1.8).

[0068] In another preferred embodiment, the molar ratio of the compound represented by Formula 1C to the compound represented by Formula 1D is 1:(1±0.3); preferably 1:1.

[0069] In another preferred embodiment, the condensing agent is selected from the following group: HOBT, HBTU, TBTU, PyBOP, EDCI, DIC, DCC, DMTMM, T3P, or a combination thereof.

[0070] In another preferred embodiment, the reductive amination reagent is selected from the following group: NaBH4, NaBH3CN, NaBH(OAc)3], CO / Rh2(OAc)4, or a combination thereof.

[0071] In another preferred embodiment, the compound of formula 1H is selected from the following group:

[0072] In another preferred embodiment, the inert solvent is selected from the following group: C1-C6 alcohol solvents, C2-C6 ether solvents, amide solvents, aromatic hydrocarbon solvents, C1-C6 nitrile solvents, sulfone solvents, or a combination thereof.

[0073] In another preferred embodiment, the inert solvent is selected from the group consisting of EtOH, dioxane, DMF, toluene, DMSO, acetonitrile, methanol, or a combination thereof.

[0074] In the third aspect of the present invention, a pharmaceutical compound is provided, comprising a therapeutically effective amount of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor or prodrug thereof, and a pharmaceutically acceptable carrier.

[0075] In another preferred embodiment, the pharmaceutical composition is an injection, capsule, tablet, pill, powder or granule.

[0076] In another preferred embodiment, the pharmaceutical composition may further include one or more second therapeutic agents; wherein the second therapeutic agent is a traditional cytotoxic chemotherapy drug or other anti-tumor immune drug.

[0077] In the fourth aspect of the present invention, there is provided a use of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor or prodrug thereof, or the pharmaceutical composition described in the third aspect of the present invention for preparing a drug or preparation for blocking WDR5-MLL1 or WDR5-cMYC protein-protein interaction.

[0078] In the fifth aspect of the present invention, there is provided a use of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor or prodrug thereof, or the pharmaceutical composition described in the third aspect of the present invention, for preparing a drug or preparation for preventing and / or treating a disease associated with the abnormal activity of WDR5.

[0079] In another preferred embodiment, the disease associated with the abnormal activity of WDR5 is selected from the following group: diabetes, inflammation, macular degeneration and related functional disorders, skin cancer (such as melanoma), uterine cancer, digestive tract cancer, prostate cancer, colon cancer, rectal cancer, brain tumor, head and neck cancer, pharyngeal cancer, testicular cancer, kidney cancer, pancreatic cancer, spleen cancer, myeloid leukemia, pancreatic ductal adenocarcinoma, neuroblastoma, Burkitt lymphoma, gastrointestinal cancer, cervical cancer, bladder cancer, laryngeal cancer, liver cancer, breast cancer, lung cancer, oral cancer, ovarian cancer, lung functional disorders, pain (including but not limited to complex regional pain syndrome), immunodeficiency diseases, damage and functional disorders of the central nervous system, diseases related to AIDS, or a combination thereof.

[0080] In another preferred embodiment, the disease associated with abnormal activity of WDR5 is selected from hematological tumors and myeloma.

[0081] In another preferred embodiment, the disease associated with abnormal activity of WDR5 is selected from multiple myeloma and acute and chronic leukemia.

[0082] In another preferred embodiment, the disease associated with abnormal activity of WDR5 is selected from primary tumors and metastatic tumors.

[0083] In the sixth aspect of the present invention, a method for inhibiting the abnormal activity of WDR5 is provided, wherein a therapeutically effective amount of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor or prodrug thereof, or the pharmaceutical composition described in the third aspect of the present invention is administered to a subject in need.

[0084] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0085] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0086] After extensive and in-depth research, the inventors have provided a small molecule WDR5 inhibitor and its preparation method and use for the first time. The small molecule inhibitor of the present invention has a structure shown in Formula I, can target WDR5 protein, effectively block the protein-protein interaction between WDR5 and MLL1 and WDR5 and c-MYC, thereby preventing and / or treating diseases related to abnormal activity of WDR5. Based on this, the inventors have completed the present invention.

[0087] the term

[0088] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0089] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0090] In the present invention, "C1-C6 alkyl" refers to a straight or branched alkyl group including 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl or the like. The terms "C1-C4 alkyl" and "C1-C2 alkyl" have similar meanings.

[0091] In the present invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term "C3-C10 cycloalkyl" has a similar meaning.

[0092] In the present invention, the term "C1-C6 alkoxy" refers to but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentyl, neopentyl, hexyl, etc. Preferably, it is C1-C4 alkoxy.

[0093] In the present invention, the term "C3-C8 cycloalkyloxy" refers to but is not limited to a cycloalkyloxy group containing 3-8 carbon atoms, and non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0094] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, preferably "C6-C10 aryl group".

[0095] The term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and containing no heteroatom in the ring, such as phenyl, naphthyl and the like.

[0096] In the present invention, the term "heterocyclic aryl" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen and 3-10 carbon atoms. Non-limiting examples include: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0097] In the present invention, the term "halo" means substituted with halogen.

[0098] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent described above, or a substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0099] The term "tautomer" refers to structural isomers that readily interconvert via chemical reactions that generally result in the formal shift of a hydrogen atom or proton accompanied by a conversion of a single bond and an adjacent double bond.

[0100] The term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0101] The term "enantiomer" refers to stereoisomers that are mirror images of each other and are non-superimposable.

[0102] The term "diastereomer" refers to stereoisomers that have two or more chiral neutrals and are not mirror images.

[0103] The term "racemate" refers to two stereoisomers that are mirror images of each other, having opposite optical rotations and can cancel each other out.

[0104] The term "hydrate" refers to a compound that contains water.

[0105] The term "metabolic precursor" refers to a class of compounds that are inactive or less active in vitro, but release active drugs through conversion through metabolic pathways in vivo to exert their pharmacological effects.

[0106] The term "prodrug" includes a compound that may be biologically active or inactive, and when taken by an appropriate method, undergoes metabolism or chemical reaction in the human body to be converted into a compound of formula (I), or a salt or solution composed of a compound of formula (I). A compound that is inactive or less active in vitro, and releases active drugs through enzymatic or non-enzymatic conversion in vivo to exert its pharmacological effect. The prodrug includes (but is not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and other forms of the compound.

[0107] In this application, each abbreviation is an abbreviation of a compound commonly used in the art, for example:

[0108] HOBT: 1-hydroxybenzotriazole;

[0109] HBTU: benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0110] TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate;

[0111] PyBOP: 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate;

[0112] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide;

[0113] DIC: N,N'-diisopropylcarbodiimide;

[0114] DCC: N,N'-dicyclohexylcarbodiimide;

[0115] T3P: 1-propylphosphoric anhydride;

[0116] DMTMM: 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride.

[0117] Compound

[0118] The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor or prodrug thereof;

[0119]

[0120] Wherein, each group is defined as above.

[0121] In another preferred embodiment, in the compound, any one of ring A, ring B, ring C, Z, Y, L, X, X1, X2 and X3 is a corresponding group in the specific compound of the present invention.

[0122] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0123] Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0124] Preparation method

[0125] The preparation method of formula (I) structure compound of the present invention is described in more detail below, but these specific methods do not constitute any restriction to the present invention. The compounds of this invention can also be optionally combined with various synthetic methods described in this specification or known in the art and easily make, and such combination can be easily carried out by the technicians in the field of the present invention. In some cases, the order of steps of the execution scheme can be changed to promote reaction or avoid unwanted side reaction products.

[0126] Typically, the process flow for preparing the compounds of the present invention is as shown in the examples of the present invention, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0127] Pharmaceutical compositions and methods of administration

[0128] Since the compounds of the present invention have excellent activity in blocking the protein-protein interactions between WDR5 and MLL1 and between WDR5 and c-MYC, the compounds of the present invention and their various crystal forms, or their pharmaceutically acceptable salts, tautomers, enantiomers, diastereomers, racemates, hydrates, esters, solvates, metabolic precursors or prodrugs, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases associated with the abnormal activity of WDR5.

[0129] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0130] A typical formulation is prepared by mixing the compound represented by the general formula (I) of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents or excipients are well known to those skilled in the art, and include substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, and the like.

[0131] The specific carrier, diluent or excipient used will be determined according to the method and purpose of use of the compound of the present invention. Solvents are generally selected based on solvents that are considered safe and effective for administration to mammals by those skilled in the art. Generally speaking, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more sustained-release agents, stabilizers, surfactants, lubricants, emulsifiers, suspoemulsions, preservatives, antioxidants, sunscreens, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents or other known additives to make the drug in an acceptable form for manufacture or use.

[0132] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0133] When the compound of formula (I) of the present invention is used in combination with at least one or other drugs, two drugs or multiple drugs can be used separately or in combination, preferably administered in the form of a pharmaceutical composition. The compound of formula (I) of the present invention or the pharmaceutical composition can be administered orally, by suction, parenteral, oral, sublingual, rectal, vaginal, patch, pump or transdermal administration, and is configured to a pharmaceutical composition accordingly. Parenteral administration includes, for example, intravenous, intraarterial, subcutaneous, nasal, intrapulmonary, rectal, and topical application methods.

[0134] These pharmaceutical compositions may also contain one or more sustained-release agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents or other known additives so that the pharmaceutical compositions can be manufactured or used in an acceptable form.

[0135] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0136] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0137] The drug of the present invention is preferably administered orally. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0138] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0139] In the case of capsules and tablets, the dosage form may also include a buffer. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using lactose and polyethylene glycol as excipients. Liposomes are composed of a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

[0140] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0141] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0142] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, aluminum methoxide and agar, or mixtures of these substances, and the like.

[0143] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0144] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0145] The compounds or pharmaceutical compositions of the present invention may be administered using other topical administration agents, including creams, powders, sprays, suppositories and inhalants. The drug may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier and any desired preservative, buffer or propellant. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.

[0146] The compounds or pharmaceutical compositions of the present invention can be used for nasal administration or administration by inhalation. The compounds can be conveniently delivered in the form of solutions, dry powders, or suspensions from a pump spray system. The sealed pump spray container is an integral dispensing device, and when the dosage form contains an aerosol dispenser, it will contain compressed gas. Including but not limited to heptafluoroalkane, carbon dioxide, dichlorodifluoromethane, etc.

[0147] In the case of suppositories, the compound in the form of a suppository is usually a mixture of substances that are solid at room temperature and melt at body temperature. It can be applied topically to the vagina, rectum and urethra. The materials commonly used to make the carrier of the suppository include, but are not limited to, a mixture of polyethylene glycols, glycerin gelatin, cocoa butter, hydrogenated vegetable oils, and the like.

[0148] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0149] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0150] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0151] Compared with the prior art, the main advantages of the present invention include:

[0152] (1) The compound has the characteristics of simple structure, easy synthesis, stable metabolism, high safety and diverse administration methods;

[0153] (2) The compound has a good inhibitory effect on WDR5, thereby achieving effective treatment of diseases related to WDR5 dysfunction.

[0154] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0155] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0156] The present invention is further described in detail and completely below in conjunction with the embodiments, but the present invention is by no means limited to the contents of the embodiments.

[0157] 1HNMR was recorded by a Bruker Avance III-500 nuclear magnetic resonance instrument, and the chemical shift was expressed in δ (ppm); the mass spectrum was determined by MS UPLC-MS (ESI): the UPLC model was Waters HPLCH-CLASS, and the MS (ESI) model was Waters sSQDetector2; petroleum ether, ethyl acetate, dichloromethane and other solvents used for column chromatography mobile phase were purchased from Sinopharm Chemical Reagent Co., Ltd.; the thin layer chromatography silica gel plate (HSGF254) used in reaction detection was from Sinopharm Chemical Reagent Co., Ltd.; 200-300 mesh silica gel from Sinopharm Chemical Reagent Co., Ltd. was used for compound separation; chiral amino acids, aromatic acids, reagents for preparing buffer solutions and other reagents were purchased from Sinopharm Chemical Reagent Co., Ltd.

[0158] Example 1

[0159]

[0160] (R)-2-amino-3-(4-chlorophenyl)propionic acid methyl ester (100 mg, 0.47 mmol) was dissolved in DMF (5 ml), and 3-amino-4-fluorobenzoic acid (110 mg, 0.70 mmol), HATU (214 mg, 0.56 mmol), and DIPEA (181 mg, 1.41 mmol) were added respectively. The reaction was carried out at room temperature for 3 hours. The target product was obtained by extraction and directly carried out to the next step.

[0161] (R)-2-(3-amino-4-fluorobenzamido)-3-(4-chlorophenyl)propionic acid methyl ester (120mg, 0.34mmol) was dissolved in 1,2-dichloroethane (5ml), and 5-methyl-1H-pyrazole-4-carboxaldehyde (37.4mg, 0.34mmol), sodium triacetoxyborohydride (143mg, 0.68mmol), and trifluoroacetic acid (77.5mg, 0.68mmol) were added respectively. The reaction was allowed to proceed overnight at room temperature. The solvent was removed by rotary evaporation and purified by silica gel chromatography using DCM / MeOH=10:1 as the eluent to obtain 105mg of a light yellow solid with a yield of 70%.

[0162] (R)-3-(4-chlorophenyl)-2-(4-fluoro-3-(((5-methyl-1H-imidazol-4-yl)methyl)amino)benzamido)propanoic acid methyl ester (105 mg, 0.24 mmol) was dissolved in methanol (3 ml). Lithium hydroxide (30 mg, 0.72 mmol) was dissolved in 3 ml of water and poured into the reaction system. The reaction was allowed to proceed overnight at room temperature. The solvent was removed by rotary evaporation, and the crude product was purified by high performance liquid chromatography to obtain 83 mg of product with a yield of 82%.

[0163] 1H NMR(400MHz,MeOD)δ8.69(s,1H),7.25(s,4H),7.11–7.00(m,3H),4.85–4.78(m,1H),4.44(s,2H),3.36–3.03(m,2H),2.39(s,3H).13C NMR(151MHz,MeOD)δ174.69,169.57,155.80,154.17,137.70,137.37,133.68,131.91,129. 44,127.96,127.78,117.66,115.42,112.58,55.53,37.63,37.58,8.96.LCMS(ESI-HR):m / z 429.1138[MH]-

[0164] Example 2

[0165]

[0166] (R)-2-amino-3-(4-nitrophenyl)propionic acid methyl ester (100 mg, 0.45 mmol) was dissolved in DMF, and 3-amino-4-fluorobenzoic acid (104 mg, 0.67 mmol), HATU (205 mg, 0.54 mmol), and DIPEA (174 mg, 1.35 mmol) were added respectively. The reaction was carried out at room temperature for 3 hours. The target product was extracted and directly carried out to the next step.

[0167] (R)-2-(3-amino-4-fluorobenzamido)-3-(4-nitrophenyl)propionic acid methyl ester (121 mg, 0.33 mmol) was dissolved in 1,2-dichloroethane (5 ml), and 5-methyl-1H-pyrazole-4-carboxaldehyde (36.3 mg, 0.33 mmol), sodium triacetoxyborohydride (140 mg, 0.66 mmol), and trifluoroacetic acid (75.2 mg, 0.66 mmol) were added respectively. The reaction was allowed to proceed overnight at room temperature. The solvent was removed by rotary evaporation and purified by silica gel chromatography using DCM / MeOH=10:1 as the eluent to obtain 76 mg of the product with a yield of 69%.

[0168] (R)-2-(4-fluoro-3-(((5-methyl-1H-imidazol-4-yl)methyl)amino)benzamido)-3-(4-nitrophenyl)propanoic acid methyl ester (116 mg, 0.25 mmol) was dissolved in methanol (3 ml). Lithium hydroxide (30 mg, 0.75 mmol) was dissolved in 3 ml of water and poured into the reaction system. The reaction was allowed to proceed overnight at room temperature. The solvent was removed by rotary evaporation, and the crude product was purified by high performance liquid chromatography to obtain 104 mg of product with a yield of 93%.

[0169] 1H NMR (400MHz, MeOD) δ8.68(s,1H),8.14(d,J=8.8Hz,2H),7.51(d,J=8.7Hz,2H),7.10–7.00(m,3H),4.43(s,2H),3.52–3.18(m,2H),2.38(s,3H).13C NMR(151MHz,MeOD)δ174.41,169.52,155.82,154.19,148.32,147.12,137.33,133.68,131.84,131. 49,127.95,127.77,124.39,117.56,115.44,112.54,55.21,38.14,37.63,8.94.LCMS(ESI-HR):m / z 440.1376[MH]-

[0170] Example 3

[0171]

[0172] (a1) 2-(4-Chlorophenyl)ethylamine (100 mg, 0.64 mmol) was dissolved in DMF (5 ml), and 3-amino-5-bromobenzoic acid (207 mg, 0.96 mmol), HATU (288 mg, 0.76 mmol), and DIPEA (247 mg, 1.92 mmol) were added respectively. The reaction was carried out at room temperature for 3 hours. The target product was obtained by extraction and directly carried out to the next step.

[0173] (a2) 3-Amino-5-bromo-N-(4-chlorophenethyl)benzamide (160 mg, 0.45 mmol) was dissolved in 1,2-dichloroethane (5 ml), and 5-methyl-1H-pyrazole-4-carboxaldehyde (49.5 mg, 0.45 mmol), sodium triacetoxyborohydride (190 mg, 0.9 mmol), and trifluoroacetic acid (102.6 mg, 0.9 mmol) were added respectively. The reaction was allowed to proceed overnight at room temperature. The solvent was removed by rotary evaporation, water was added, and the mixture was extracted with ethyl acetate three times, and the extract was dried by vacuum rotary evaporation. The crude product was purified by high performance liquid chromatography to obtain 120 mg of the product, with a yield of 60%.

[0174] 1H NMR(400MHz,MeOD)δ8.72(s,1H),7.29–7.21(m,4H),7.16(s,1H),6.96(d,J=10.6Hz,2H) ,4.38(s,2H),3.54(t,J=7.3Hz,2H),2.87(t,J=7.3Hz,2H),2.39(s,3H).13CNMR(151MHz, MeOD)δ169.08,150.69,139.34,138.40,133.70,133.20,131.51,129.51,127.81,124.0 3,119.51,119.29,111.15,42.34,37.75,35.73,8.92.LCMS(ESI-HR):m / z445.0437[MH]-

[0175] Example 4

[0176]

[0177] (R)-2-amino-3-(4-chlorophenyl)propionic acid methyl ester (100 mg, 0.47 mmol) was dissolved in DMF (5 ml), and 3-amino-5-bromobenzoic acid (152 mg, 0.70 mmol), HATU (214 mg, 0.56 mmol), and DIPEA (181 mg, 1.41 mmol) were added respectively. The reaction was carried out at room temperature for 3 hours. The target product was obtained by extraction and directly carried out to the next step.

[0178] (R)-2-(3-amino-5-bromobenzamido)-3-(4-chlorophenyl)propionic acid methyl ester (162mg, 0.39mmol) was dissolved in 1,2-dichloroethane (5ml), and 5-methyl-1H-pyrazole-4-carboxaldehyde (42.9mg, 0.39mmol), sodium triacetoxyborohydride (165mg, 0.78mmol), and trifluoroacetic acid (88.9mg, 0.78mmol) were added respectively. The reaction was allowed to proceed overnight at room temperature. The solvent was removed by rotary evaporation and purified by silica gel chromatography using DCM / MeOH=10:1 as the eluent to obtain 161.7mg of the product with a yield of 82%.

[0179] (R)-2-(3-bromo-5-(((5-methyl-1H-imidazol-4-yl)methyl)amino)benzamido)-3-(4-chlorophenyl)propanoic acid methyl ester (161.7 mg, 0.32 mmol) was dissolved in methanol (3 ml). Lithium hydroxide (39 mg, 0.96 mmol) was dissolved in 3 ml of water and poured into the reaction system. The reaction was allowed to proceed overnight at room temperature. The solvent was removed by rotary evaporation, and the crude product was purified by high performance liquid chromatography to obtain 106 mg of product with a yield of 68%.

[0180] 1H NMR(400MHz,MeOD)δ8.68(s,1H),7.25(t,J=4.0Hz,4H),7.14(s,1H),6.97–6.87(m,2H), 4.78(dd,J=9.6,5.0Hz,1H),4.36(s,2H),3.37–3.02(m,2H),2.37(s,3H).13CNMR(151MHz ,MeOD)δ174.81,168.97,150.63,138.00,137.70,133.69,131.91,129.44,127.81,124.0 1,119.70,119.52,111.06,55.68,37.78,37.56,8.95.LCMS(ESI-HR):m / z489.0339[MH]-

[0181] (R)-2-(3-Bromo-5-(((5-methyl-1H-imidazol-4-yl)methyl)amino)benzamido)-3-(4-chlorophenyl)propanoic acid (50 mg, 0.1 mmol) was dissolved in DMF (3 ml), and methylamine hydrochloride (10 mg, 0.15 mmol), HATU (45.6 mg, 0.12 mmol), and DIPEA (64.5 mg, 0.5 mmol) were added respectively. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, water was added to the system and extracted with ethyl acetate three times, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by high performance liquid chromatography to give 33 mg of product with a yield of 66%.

[0182] 1H NMR(400MHz,MeOD)δ8.71(s,1H),7.28–7.21(m,4H),7.18(s,1H),6.93(d,J=13.2Hz,2H), 4.71(dd,J=9.0,6.2Hz,1H),4.37(s,2H),3.21–2.96(m,2H),2.71(s,3H),2.38(s,3H).13C NMR(126MHz,MeOD)δ173.78,168.96,150.61,137.87,137.45,133.69,131.90,129.47,127 .78,124.01,119.83,119.53,111.18,56.59,38.28,37.72,26.34,8.93.LCMS(ESI-HR):m / z 504.0798[M+H]+

[0183] (R)-2-(3-Bromo-5-(((5-methyl-1H-imidazol-4-yl)methyl)amino)benzamido)-3-(4-chlorophenyl)propanoic acid (50 mg, 0.1 mmol) was dissolved in DMF (3 ml), and cyclopropylamine (5.7 mg, 0.1 mmol), HATU (45.6 mg, 0.12 mmol), and DIPEA (38.7 mg, 0.3 mmol) were added respectively. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, water was added to the system and extracted with ethyl acetate three times, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by high performance liquid chromatography to obtain 33 mg of product with a yield of 63%.

[0184] Example 5

[0185]

[0186] (R)-3-Bromo-N-(3-(4-chlorophenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(((5-methyl-1H-imidazole-4-yl)methyl)amino)benzamide (100 mg, 0.2 mmol) and (DPPF)PdCl2 (16.3 mg, 0.02 mmol), (4-fluoro-2-methylphenyl)boric acid (29 mg, 0.2 mmol) were dissolved in DME (5 ml), and Na2CO3 (106 mg, 1 mmol) was dissolved in water (5 ml) and placed in the reaction system. Nitrogen was replaced three times. The reaction was allowed to proceed overnight at 80°C. After the reaction was completed, the filtrate was filtered and vacuum dried. After the system was dried, water was added and extracted three times with ethyl acetate. It was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by high performance liquid chromatography to obtain 74 mg of the product with a yield of 70%.

[0187] 1H NMR(500MHz,MeOD)δ8.71(s,1H),7.28–7.20(m,4H),7.16(dd,J=8.6,5.8Hz,1H),7.02(dd,J=9.7,2.9Hz,1H),7.01–6.92(m ,3H),6.70(s,1H),4.75(dd,J=8.9,6.1Hz,1H),4.41(s,2H),3.25–2.95(m,2H),2.71(s,3H),2.37(s,3H),2.19(s,3H).13C NMR(126MHz,MeOD)δ173.90,170.28,149.28,143.60,139.08,137.48,136.23,133.64,133.56,132.16,132.10,131.93,129.48 ,128.33,127.60,118.41,117.70,117.53,113.51,113.34,110.89,56.43,38.35,38.09,26.33,20.57,8.94.LCMS(ESI-HR):m / z 532.1921[MH]-

[0188] Example 6

[0189]

[0190] (R)-3-Bromo-N-(3-(4-chlorophenyl)-1-(cyclopropylamino)-1-oxopropan-2-yl)-5-(((5-methyl-1H-imidazol-4-yl)methyl)amino)benzamide (100 mg, 0.19 mmol) and (DPPF)PdCl2 (16.3 mg, 0.02 mmol), (4-fluoro-2-methylphenyl)boric acid (29 mg, 0.19 mmol) were dissolved in DME (5 ml), and Na2CO3 (106 mg, 1 mmol) was dissolved in water (5 ml) and placed in the reaction system. Nitrogen was replaced three times. The reaction was allowed to proceed overnight at 80°C. After the reaction was completed, the filtrate was filtered and dried in vacuo. After drying, water was added to the system and extracted three times with ethyl acetate. The mixture was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by HPLC to give 68 mg of product with a yield of 61%.

[0191] 1H NMR(500MHz,MeOD)δ8.71(s,1H),7.29–7.20(m,4H),7.16(dd,J=8.4,5.9Hz,1H),7.05–6.89(m,4H),6.71(s,1H),4.73–4.66( m,1H),4.42(s,2H),3.17–2.95(m,2H),2.65–2.57(m,1H),2.37(s,3H),2.19(s,3H),0.73–0.63(m,2H),0.46–0.33(m,2H).13C NMR (126MHz, MeOD) δ174.82,170.22,149.26,143.60,139.07,138.94,137.23,136.23,133.68,133.56,132.10,132.03,129.45,128. 32,127.61,118.43,117.52,113.33,110.87,56.23,38.47,38.07,23.27,20.57,8.96,6.46,6.25.LCMS(ESI-HR):m / z558.2074[MH]-

[0192] Example 7

[0193]

[0194] (R)-3-Bromo-N-(3-(4-chlorophenyl)-1-(cyclopropylamino)-1-oxopropan-2-yl)-5-(((5-methyl-1H-imidazol-4-yl)methyl)amino)benzamide (100 mg, 0.19 mmol) and (DPPF)PdCl2 (16.3 mg, 0.02 mmol), (6-fluoro-4-methylpyridin-3-yl)boric acid (29 mg, 0.19 mmol) were dissolved in DME (5 ml), and Na2CO3 (106 mg, 1 mmol) was dissolved in water (5 ml) and placed in the reaction system. Nitrogen was replaced three times. The reaction was allowed to proceed overnight at 80°C. After the reaction was completed, the reaction was filtered and the filtrate was dried in vacuum. After drying, water was added to the system and extracted three times with ethyl acetate. Drying was performed over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. The crude product was purified by HPLC to obtain 70 mg of product with a yield of 66%.

[0195] 1H NMR(500MHz,MeOD)δ8.72(s,1H),7.96(s,1H),7.31–7.16(m,6H),7.03(s,2H),6.99(s,1H),6.75(s,1H),4.75–4.67(m,1H),4. 43(s,2H),3.18–2.95(m,2H),2.62(tt,J=7.3,3.8Hz,1H),2.38(s,3H),2.29(s,3H),0.73–0.62(m,2H),0.48–0.30(m,2H).13C NMR (126MHz, MeOD) δ174.78,169.93,165.45,163.55,153.28,149.62,147.65,139.22,137.23,136.66,133.63,132.03,129.45,128. 16,127.70,118.19,111.69,111.35,111.06,56.25,38.48,37.97,23.28,20.27,8.95,6.46,6.25.LCMS(ESI-HR):m / z559.2032[MH]-

[0196] Example 8

[0197]

[0198] (R)-3-Bromo-N-(3-(4-chlorophenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(((5-methyl-1H-imidazol-4-yl)methyl)amino)benzamide (100 mg, 0.2 mmol) and (DPPF)PdCl2 (16.3 mg, 0.02 mmol), (6-fluoro-4-methylpyridin-3-yl)boric acid (29 mg, 0.19 mmol) were dissolved in DME (5 ml), and Na2CO3 (106 mg, 1 mmol) was dissolved in water (5 ml) and placed in the reaction system. Nitrogen was replaced three times. The reaction was carried out at 80°C overnight. After the reaction was completed, the filtrate was filtered and vacuum dried. After the system was dried, water was added and extracted with ethyl acetate three times. It was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The obtained crude product was purified by high performance liquid chromatography to obtain 69 mg of product with a yield of 65%.

[0199] 1H NMR(500MHz,MeOD)δ8.72(s,1H),7.96(s,1H),7.03(s,4H),6.97(s,2H),6.74(s,1H),4.76(dd ,J=9.1,6.2Hz,1H),4.43(s,2H),3.25–2.92(m,2H),2.71(s,3H),2.38(s,3H),2.29(s,3H).13C NMR(126MHz,MeOD)δ173.87,169.98,165.45,163.55,153.28,153.22,149.62,147.76,147.64,139.20,137.48,137.35,136.65,133.63,13 1.92,129.47,128.16,127.70,118.20,111.71,111.34,111.06,56.46,38.34,37.97,26.33,20.27,8.94.LCMS(ESI-HR):m / z533.1873[MH]-

[0200] Example 9

[0201]

[0202] (R)-3-Bromo-N-(3-(4-chlorophenyl)-1-(cyclopropylamino)-1-oxopropan-2-yl)-5-(((5-methyl-1H-imidazol-4-yl)methyl)amino)benzamide (100 mg, 0.19 mmol) and (DPPF)PdCl2 (16.3 mg, 0.02 mmol), (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boric acid (39 mg, 0.19 mmol) were dissolved in DME (5 ml), and Na2CO3 (106 mg, 1 mmol) was dissolved in water (5 ml) and placed in the reaction system. Nitrogen was replaced three times. The reaction was carried out at 80°C overnight. After the reaction was completed, the filtrate was filtered and vacuum dried. After the system was dried, water was added and extracted with ethyl acetate three times. It was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by HPLC to obtain 80 mg of product with a yield of 68%.

[0203] 1H NMR(500MHz,MeOD)δ8.70(s,2H),7.88(s,2H),7.29–7.21(m,6H),7.09(s,1H),6.99(s,1H),6.79(s,1H),4.70(t,J=7.6Hz,2H),4.41(s,4H) ,4.26(q,J=7.3Hz,4H),3.17–2.95(m,3H),2.66–2.58(m,1H),2.36(s,6H),1.51(t,J=7.3Hz,6H),0.73–0.63(m,3H),0.48–0.33(m,1H).13C NMR (126MHz, MeOD) δ174.76,170.07,149.43,137.17,136.55,133.68,133.50,133.43,132.04,131.86,129.46,128.19,127. 44,122.78,117.79,117.00,111.80,56.26,38.51,38.16,23.28,15.73,8.93,6.46,6.24.LCMS(ESI-HR):m / z612.2110[MH]-

[0204] Example 10

[0205]

[0206] (R)-3-Bromo-N-(3-(4-chlorophenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(((5-methyl-1H-imidazol-4-yl)methyl)amino)benzamide (100 mg, 0.2 mmol) and (DPPF)PdCl2 (16.3 mg, 0.02 mmol), (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boric acid (41.6 mg, 0.2 mmol) were dissolved in DME (5 ml), and Na2CO3 (106 mg, 1 mmol) was dissolved in water (5 ml) and placed in the reaction system. Nitrogen was replaced three times. The reaction was allowed to proceed overnight at 80°C. After the reaction was completed, the reaction was filtered and the filtrate was dried in vacuum. After drying, water was added to the system and extracted three times with ethyl acetate. Drying was performed over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. The crude product was purified by HPLC to obtain 78 mg of product with a yield of 67%.

[0207] 1H NMR(500MHz,MeOD)δ8.71(s,1H),7.88(s,1H),7.29–7.21(m,4H),7.08(s,1H),6.98(s,1H),6.78(s,1H),4.75(dd,J=8.8 ,6.1Hz,1H),4.41(s,2H),4.26(q,J=7.4Hz,2H),3.24–2.95(m,2H),2.71(s,3H),2.36(s,3H),1.52(t,J=7.3Hz,3H).13C NMR(126MHz,MeOD)δ173.85,170.13,149.44,137.42,136.56,133.64,133.51,133.43,131.94,131.84,129.49,128.21 ,127.43,122.79,117.79,117.00,111.83,56.47,38.40,38.18,26.33,15.74,8.93.LCMS(ESI-HR):m / z586.1953[MH]-

[0208] Example 11: WDR5-MLL PPI inhibitory activity test

[0209] The test compounds were used to investigate the effects of the compounds on the interaction between WDR5 (WD Repeat Domain 5) and MLL1 (mixed-lineageleukemia 1) peptides at the molecular level.

[0210] HTRF (Homogeneous Time-Resolved Fluorescence) technology was used to detect the effect of compounds on the interaction between WDR5 protein (22-334aa) and MLL1 peptide (3672-3773aa). When the WDR5 with a His tag at the N-terminus recognized by the Anti-6His-Eu cryptate donor interacts with the MLL1 peptide with a biotin tag recognized by the streptavidin-APC receptor, the donor and the receptor are pulled close enough to produce fluorescence resonance energy transfer (FRET). When the compound inhibits the interaction between WDR5 and MLL1 peptide, the donor and the receptor no longer undergo FRET. Therefore, the reduction of the FRET signal can reflect the inhibition of the interaction between WDR5 and MLL1 peptide by the compound.

[0211] The test compound was diluted 3 times with DMSO, and a total of 12 concentration gradients were set, with 2 replicates for each concentration. The reaction buffer was 25mM HEPES pH=7.5, 100mM NaCl, 0.05% Tween 20. In a 384-well plate, 120nL of compound and 4μL 37.5nM WDR5 protein were added, centrifuged at 1000rpm for 1 minute, incubated at room temperature for 30min, 4μL 300nM MLL1 peptide was added, incubated at room temperature for 10min, and then 4μL Anti-6His-Eu cryptate and streptavidin-APC mixture was added, centrifuged at 1000rpm for 1 minute, incubated at room temperature in the dark for 60min, and a multifunctional microplate reader ( 2105) read the signal. The following controls were set up for each plate: control group (120nL DMSO, 4μL 37.5nM WDR5, 4μL MLL1 polypeptide, 4μL Anti-6His-Eu cryptate and streptavidin-APC). Blank group (120nL DMSO, 4μL reaction buffer, 4μL MLL1 polypeptide, 4μL Anti-6His-Eu cryptate and streptavidin-APC). The test data was calculated based on the signal ratio of two beams of fluorescence with different wavelengths: (665nm signal / 620nm signal)*10000. The calculation formula for the inhibition rate is: inhibition rate (%) = 100-(experimental group-blank group) / (control group-blank group)*100. IC 50 The values ​​were calculated using XLfit software.

[0212] Experimental results:

[0213]

[0214]

[0215] It can be seen that the compounds of the present invention have lower IC 50 The value indicated that the inhibitory effect on the interaction between WDR5 and MLL1 polypeptide was good.

[0216] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound of formula (1), or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor or prodrug thereof; in, is H, halogen, amino, nitro, cyano, hydroxyl, mercapto, and a substituted or unsubstituted group selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -S-C1-C6 alkyl, substituted or unsubstituted benzyl, a 3-8 membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, a C6-C10 aryl, and a 3-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S; is H, halogen, amino, nitro, cyano, hydroxyl, carboxyl, -C(O)NHR, and a substituted or unsubstituted group selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, benzyl, a 3-8 membered heterocyclyl containing 1-4 heteroatoms independently selected from N, O, and S, a C6-C10 aryl, and a 3-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S; is a substituted or unsubstituted 3-8 membered heterocyclic group containing 1-4 heteroatoms independently selected from N, O, and S, or a substituted or unsubstituted 3-10 membered heteroaryl group containing 1-4 heteroatoms independently selected from N, O, and S, wherein the group C is connected to L through a carbon atom on the heterocyclic group or the heteroaryl group; X1, X2 and X3 are each independently selected from the group consisting of CH, N or C; L is selected from C1-C3 methylene; X is selected from C1-C3 methylene, NH, O, S; Y is selected from the group consisting of NH, O; Z is selected from the following groups: H, hydroxyalkyl, carboxyl, -C(O)NHR, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkoxy. R is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy; Unless otherwise stated, the substitution refers to one or more hydrogen atoms being replaced by a substituent selected from the group consisting of halogen, hydroxy, hydroxymethyl, nitro, amino, C1-C4 alkyl, trifluoromethyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C8 cycloalkoxy.

2. The compound according to claim 1, characterized in that is H, halogen, amino, nitro, and a substituted or unsubstituted group selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 hydroxyalkyl, -S-C1-C6 alkyl, C6-C10 aryl, and a 3-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from N, O, and S; is halogen, amino, nitro, carboxyl, -C(O)NHR, and a substituted or unsubstituted group selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, benzyl, phenyl, and a 3-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from N, O, and S; is a substituted or unsubstituted 3-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from N, O, and S, wherein the group C is connected to L through a carbon atom on the heterocyclic group or the heteroaryl group; X1, X2 and X3 are each independently selected from the group consisting of CH or C; L is selected from C1-C3 alkylene; X is selected from NH, O, S; Y is selected from NH; Z is selected from the group consisting of H, hydroxyalkyl, carboxyl, -C(O)NHR, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl. R is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy; Unless otherwise stated, the substitution refers to one or more hydrogen atoms being replaced by a substituent selected from the group consisting of halogen, hydroxy, hydroxymethyl, nitro, amino, C1-C4 alkyl, trifluoromethyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C8 cycloalkoxy.

3. The compound according to claim 1, characterized in that A is halogen, substituted or unsubstituted -S-C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted phenyl; B is halogen, carboxyl, -C(O)NHR, or substituted or unsubstituted benzyl; C is a substituted or unsubstituted heterocyclic group, wherein the group C is connected to L through a carbon atom on the heterocyclic group or the heteroaryl group; X is NH; L is a C1-C3 alkylene group; Y is NH; Z is H, substituted or unsubstituted benzyl, -C(O)NHR; X1, X2 and X3 are each independently selected from the group consisting of CH or C; R is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy; The substitution refers to one or more hydrogen being replaced by a substituent selected from the group consisting of halogen, hydroxyl, hydroxymethyl, nitro, amino, C1-C4 alkyl, trifluoromethyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C8 cycloalkoxy.

4. The compound according to claim 1, characterized in that A is fluorine, bromine, methylthio, cyclopropyl, trifluoromethyl-substituted phenyl, hydroxymethyl-substituted phenyl, or alkyl-substituted phenyl; B is fluorine- or chlorine-substituted benzyl, -C(O)NHR, carboxyl, C is a 5-membered heterocyclic group substituted with methyl; X is NH; L is a methylene group; Y is NH; Z is H, fluorine-substituted benzyl, nitro-substituted benzyl, -C(O)NHR, X1, X2 and X3 are each independently selected from the group consisting of CH or C; R is hydroxy, H, halogen, or C1-C4 alkyl.

5. The compound according to claim 1, characterized in that The compound is selected from the following group:

6. A method for preparing a compound of formula I, characterized in that: The steps include: (a1) In an inert solvent, in the presence of a condensing agent, a compound of formula 1A and a compound of formula 1B undergo a condensation reaction to obtain an intermediate compound of formula 1C; wherein, L, X, X1, X2, X3, Y, Z as defined in claim 1; (a2) reacting a compound of formula 1C with a compound of formula 1D in an inert solvent in the presence of a reductive amination agent to obtain a compound of formula I; Or the method comprises the steps of: (b1) reacting the compound represented by formula 1A with the compound represented by formula 1E to obtain a compound represented by formula 1F; (b2) reacting a compound of formula 1F with a compound of formula 1D to obtain a compound of formula 1G; (b2) Suzuki reaction of the compound of formula 1G with the compound of formula 1H to obtain a compound of formula I; Wherein, R1 is selected from the following group: I, Br, CF3SO2, OSO2(C n F 2n+1 ), where n = 0, 1, 4, L, X, X1, X2, X3, Y, and Z are as defined in claim 1.

7. A pharmaceutical compound, characterized in that A therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor or prodrug thereof, and a pharmaceutically acceptable carrier.

8. Use of the compound of claim 1, or its pharmaceutically acceptable salts, tautomers, enantiomers, diastereomers, racemates, hydrates, esters, solvates, metabolic precursors or prodrugs, or the pharmaceutical composition of claim 7, characterized in that: Used to prepare drugs or preparations for blocking WDR5-MLL1 or WDR5-cMYC protein-protein interactions.

9. Use of the compound of claim 1, or its pharmaceutically acceptable salts, tautomers, enantiomers, diastereomers, racemates, hydrates, esters, solvates, metabolic precursors or prodrugs, or the pharmaceutical composition of claim 7, characterized in that: Used for preparing drugs or preparations for preventing and / or treating diseases associated with abnormal activity of WDR5.

10. A method for inhibiting abnormal activity of WDR5, characterized in that: A therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor or prodrug thereof, or the pharmaceutical composition of claim 7 is administered to a subject in need thereof.

Images