CBP / p300 inhibitor, preparation method thereof, medicinal composition and application of CBP / p300 inhibitor

Abstract

The invention discloses a compound shown in a general formula (I) or pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, deuterated substance, hydrate, ester, solvate, metabolic precursor or prodrug thereof, and a preparation method and application thereof, and all groups are defined in the specification. The compound of the formula (I) is targeted to CBP / p300 protein, can effectively prevent and / or treat diseases or symptoms related to abnormal activity of CBP / p300, and can be applied to drugs for treating diseases or symptoms related to selective CBP / p300. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceuticals, and particularly to a CBP / p300 inhibitor, a preparation method thereof, a pharmaceutical composition thereof, and uses thereof. Background Art

[0002] The transcriptional co-activator p300 / CREB-binding protein (CBP) is one of the main members of the histone acetyltransferase (HAT) family. Due to the high homology of their structures, they are considered to have the same function. CBP / p300 is involved in cell cycle progression, cell growth, differentiation and development, and is a very important co-activator.

[0003] More and more studies have confirmed that the dysfunction of CBP / p300 is related to various human diseases, such as tumors, diabetes, inflammation, heart diseases, etc., especially related to the incidence of tumor diseases. For example, inhibiting the histone acetyltransferase activity of CBP / p300 or inhibiting the activity of CBP as a transcriptional co-activator has been found to inhibit the growth of neuroblastoma, pancreatic cancer, and acute myeloid leukemia in vitro and in vivo; the expression level of CBP / p300 is up-regulated in colon cancer, human small cell lung cancer, and non-small cell lung cancer, which is an indicator of poor prognosis of patients. The highly expressed p300 in breast cancer may promote tumor recurrence and is related to the invasive characteristics of breast cancer. In hepatocellular carcinoma, the high expression of p300 is related to enhanced vascular invasion, intrahepatic metastasis, and shortened survival time. In prostate cancer, the androgen-induced recruitment of androgen receptor (AR) to chromatin is closely related to H3K27 acetylation. By preventing H3K27 acetylation to block the co-activator function of CBP / p300 on AR, the expression of key proliferation genes and tumor growth can be blocked, showing the potential of CBP / p300 inhibitors in the treatment of prostate cancer.

[0004] Mutant CBP / p300 is associated with many hematological malignancies. Experiments such as in vitro and in vivo gene knockout in mouse models have demonstrated the role of the epigenetic regulator CBP / p300 in the induction and maintenance of acute myeloid leukemia (AML). The use of small molecule inhibitors of CBP / p300 induces cell cycle arrest and apoptosis and is effective in multiple AML subtypes. Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy. Studies have shown that CBP / p300 is involved in recurrent ALL-related chromosomal translocations and is a key regulator of tumour cell growth. CBP / p300 has always been considered an important target for the treatment of diseases including cancer. However, due to the selectivity issues of the bromodomain (BRD) domain and HAT domain of CBP / p300 for other HATs or protein families with BRD, it is difficult to develop highly selective inhibitors of CBP / p300.

[0005] Although academic research has developed small molecule inhibitors of CBP / p300 with various structural types, currently only the BRD domain inhibitor CCS1477 of CellCentric targeting CBP / p300 has been approved for marketing for the treatment of advanced drug-resistant prostate cancer. Therefore, the development of selective inhibitors of CBP / p300, especially small molecule inhibitors for tumours, is still of great significance. Summary of the Invention

[0006] One object of the present invention is to provide a compound having the structure shown in general formula (I).

[0007] Another object of the present invention is to provide a pharmaceutical composition containing the compound shown in general formula (I).

[0008] Another object of the present invention is to provide the use of the compound shown in general formula (I) as a small molecule CBP / p300 inhibitor.

[0009] Another object of the present invention is to provide the use of the compound shown in general formula (I) in the preparation of a drug for preventing and / or treating diseases related to the abnormal activity of CBP / p300.

[0010] In the first aspect of the present invention, there is provided a compound shown in formula (1), or a pharmaceutically acceptable salt, ester, tautomer, enantiomer, diastereomer, racemate, deuterated compound, hydrate, solvate, metabolic precursor or prodrug thereof;

[0011]

[0012] Wherein,

[0013] A is H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10-membered heteroaryl group containing 1-4 heteroatoms each independently selected from N, O, S, a substituted or unsubstituted 4-9-membered heterocyclic group containing 1-4 heteroatoms each independently selected from N, O, S, or a substituted or unsubstituted C3-C8 cycloalkyl group;

[0014] B is H, -COOH, a C3-C7 non-linear alkyl group, -NRaRb, a C3-C8 cycloalkyl group, or a 3-8-membered heterocyclic group containing 1-4 heteroatoms each independently selected from N, O, S; wherein Ra and Rb are each independently a substituted or unsubstituted C1-C4 alkyl group, or Ra, Rb, and the nitrogen atom to which they are commonly attached form a substituted or unsubstituted 5-8-membered heterocyclic group containing 1-3 heteroatoms each independently selected from N, O, S;

[0015] C is a substituted or unsubstituted 5-10-membered heteroaryl group containing 1-4 heteroatoms each independently selected from N, O, S, or a substituted or unsubstituted C6-C10 aryl group;

[0016] L is absent, a C1-6 alkylene group, -O-, or -NH-;

[0017] R1, R2, and R3 are each independently H, a hydroxyl group, a halogen, a nitro group, a cyano group, an amino group, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, or a C1-C6 alkoxy group;

[0018] Unless otherwise specified, the substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following group: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, -C(O)NH-(C1-C4 alkyl), -C(O)NH-(C1-C4 hydroxyalkyl), a 3- to 12-membered heterocyclic group, a C6-10 aryl group, a 5-7-membered heteroaryl group, a C1-C8 aldehyde group, a C2-C10 acyl group, a C2-C10 ester group, or a C1-C10 sulfonyl group.

[0019] In another preferred embodiment,

[0020] A is a substituted or unsubstituted group selected from the following group: a C6 aryl group, a 5-10-membered heteroaryl group containing 1-3 heteroatoms each independently selected from N, O, S;

[0021] B is H, -COOH, a C3-C6 non-linear alkyl group, -NRaRb, or a 5-7 membered heterocyclic group containing 1-3 heteroatoms each independently selected from N, O, and S; wherein Ra and Rb are each independently a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, or Ra, Rb, and the nitrogen atom to which they are commonly attached form a substituted or unsubstituted 5-7 membered heterocyclic group containing 1-2 heteroatoms each independently selected from N, O, and S;

[0022] C is a substituted or unsubstituted C6 aryl group;

[0023] L is absent or CH2;

[0024] R1, R2, and R3 are each independently H, a halogen, a C1-C4 alkyl group, or a halogenated C1-C4 alkyl group.

[0025] In another preferred example, Ra, Rb, and the nitrogen atom to which they are commonly attached form a substituted or unsubstituted 5-7 membered heterocyclic group containing one nitrogen atom.

[0026] In another preferred example, R1, R2, and R3 are each independently H, a halogen, or a C1-C4 alkyl group.

[0027] In another preferred example, A is a substituted or unsubstituted group selected from the group consisting of: a phenyl group, a pyridyl group, a 9 membered heteroaryl group containing 1-3 heteroatoms each independently selected from N, O, and S.

[0028] In another preferred example, A is selected from the following substituted or unsubstituted groups:

[0029] In another preferred example, A is selected from

[0030] In another preferred example, C is a halogenated phenyl group.

[0031] In another preferred example, B is selected from H, -COOH,

[0032] In another preferred example, B is

[0033] In another preferred example, there is a conformation in the B group.

[0034] In another preferred example, the compound has the structure shown in Formula II:

[0035]

[0036] Wherein,

[0037] R4 and R5 are each independently selected from the group consisting of: H, halogen, hydroxy, nitro, cyano, amino, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, -C(O)NH-(C1-C4 alkyl), -C(O)NH-(C1-C4 hydroxyalkyl); or R1 and R2 together with the carbon atoms to which they are attached form a substituted or unsubstituted 5- or 6-membered heteroaryl group, a substituted or unsubstituted 5- or 6-membered heterocyclic group;

[0038] R1, R2, R3, B and C are as described in the first aspect of the present invention.

[0039] In another preferred embodiment, the compound is selected from the group consisting of:

[0040]

[0041]

[0042] In another preferred embodiment, the compound is selected from the group consisting of:

[0043]

[0044]

[0045] In a second aspect of the present invention, there is provided a process for preparing a compound of formula I, comprising the following steps:

[0046]

[0047] (a, b) In an inert solvent and in the presence of a condensing agent, a compound of formula 1A reacts with a compound of formula 1B to undergo a condensation reaction, and after removing the Boc protecting group, an intermediate compound of formula 1C is obtained;

[0048] (c) In an inert solvent and in the presence of a condensing agent, a compound of formula 1C reacts with a compound of formula 1D to obtain a compound of formula (I);

[0049] wherein, L, R1, R2, R3 are as defined in the first aspect of the present invention.

[0050] In another preferred embodiment, the condensing agent is selected from the group consisting of: HOBT, HBTU, TBTU, PyBOP, EDCI, DIC, DCC, DMTMM, T3P, or a combination thereof.

[0051] In another preferred embodiment, the inert solvent is selected from the group consisting of: C1-C6 alcohol solvents, C2-C6 ether solvents, amide solvents, aromatic solvents, C1-C6 nitrile solvents, sulfone solvents, or a combination thereof.

[0052] In the third aspect of the present invention, there is provided a pharmaceutical compound comprising a therapeutically effective amount of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, ester, tautomer, enantiomer, diastereomer, racemate, deuterated compound, hydrate, solvate, metabolic precursor or prodrug thereof, and a pharmaceutically acceptable carrier.

[0053] In another preferred example, the pharmaceutical composition is an injection, capsule, tablet, pill, powder or granule.

[0054] In the fourth aspect of the present invention, there is provided a pharmaceutical composition comprising (a1) a therapeutically effective amount of the compound described in the first aspect of the present invention as a first active ingredient, or a pharmaceutically acceptable salt, ester, tautomer, enantiomer, diastereomer, racemate, deuterated compound, hydrate, solvate, metabolic precursor or prodrug thereof, (a2) another therapeutic agent as a second active ingredient; and (b) a pharmaceutically acceptable carrier.

[0055] In another preferred example, the other therapeutic agent is a radiotherapy drug, chemotherapy drug, anti-tumor drug, antibody, immunological drug, or a combination thereof.

[0056] In the fifth aspect of the present invention, there is provided the use of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, ester, tautomer, enantiomer, diastereomer, racemate, deuterated compound, hydrate, solvate, metabolic precursor or prodrug thereof, or the pharmaceutical composition described in the third aspect of the present invention, for the preparation of (a) a drug or preparation targeting histone acetyltransferase CBP / p300 protein, and / or (b) a drug or preparation for preventing and / or treating a disease associated with abnormal CBP / p300 activity.

[0057] In another preferred example, the diseases associated with abnormal CBP / p300 activity are selected from the group consisting of: diabetes, inflammation, macular degeneration and related functional disorders, skin cancer, uterine cancer, digestive tract cancer, prostate cancer, colon cancer, rectal cancer, brain tumor, head and neck cancer, throat 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, hematological tumor, myeloma, lung function disorder, pain, immunodeficiency disease, damage and functional disorder of the central nervous system, diseases associated with AIDS, or a combination thereof.

[0058] In another preferred example, the skin cancer is melanoma.

[0059] In another preferred example, the pain is complex regional pain syndrome

[0060] In another preferred embodiment, the diseases associated with the abnormal activity of CBP / p300 are selected from hematological tumors and myelomas.

[0061] In another preferred embodiment, the hematological tumor is acute or chronic leukemia.

[0062] In another preferred embodiment, the myeloma is multiple myeloma.

[0063] In another preferred embodiment, the diseases associated with the abnormal activity of CBP / p300 are selected from multiple myeloma, acute and chronic leukemia.

[0064] In another preferred embodiment, the diseases associated with the abnormal activity of CBP / p300 are selected from primary tumors and metastatic tumors.

[0065] In a sixth aspect of the present invention, a method for inhibiting the abnormal activity of CBP / p300 is provided, which comprises administering 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, deuterated compound, hydrate, ester, solvate, metabolic precursor or prodrug thereof, or the pharmaceutical composition described in the third aspect of the present invention to a subject in need.

[0066] In another preferred embodiment, the method is in vitro.

[0067] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0068] 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 in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. Detailed Embodiments

[0069] Through extensive and in-depth research, the inventors have provided a compound having the structure shown in Formula I. The compound is easy to synthesize, metabolically stable, highly safe, has a good inhibitory effect on the p300 HAT domain, and thus is expected to effectively treat related diseases. Based on this, the inventors have completed the present invention.

[0070] Terms

[0071] In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0072] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0073] In the present invention, "C1-C6 alkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl or similar groups. The terms "C1-C4 alkyl" and "C3-C7 non-straight-chain alkyl" have similar meanings.

[0074] 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-C6 cycloalkyl" has a similar meaning.

[0075] In the present invention, the term "heterocyclic group" is a 4- to 9-membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, preferably a 5- to 7-membered heterocyclic group, including (but not limited to) the following groups: oxiranyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyranyl, thiomorpholinyl. The terms "3- to 8-membered heterocyclic group", "5- to 8-membered heterocyclic group" and "5- to 6-membered heterocyclic group" have similar definitions.

[0076] In the present invention, the term "C1-C6 alkoxy" refers to including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc. Preferably it is C1-C4 alkoxy.

[0077] In the present invention, the term "C3-C8 cycloalkoxy" refers to including but not limited to cycloalkyloxy groups containing 3 to 8 carbons, and non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.

[0078] In the present invention, the terms "aromatic ring" or "aryl" have the same meaning, preferably "C6-C10 aryl".

[0079] The term "C6-C10 aryl" refers to an aromatic ring group having 6 to 10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.

[0080] In the present invention, the terms "heteroaryl ring" or "heteroaryl" have the same meaning, referring to a heteroaromatic group containing one or more heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 carbon atoms. Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is the heteroaryl ring. The heteroaryl can be optionally substituted or unsubstituted.

[0081] In the present invention, the term "halogenated" means substituted by a halogen.

[0082] In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are substituted by specific substituents. The specific substituents are the substituents described correspondingly in the foregoing, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. Those skilled in the art should understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. The substituents are, for example (but not limited to): halogen, hydroxyl, carboxyl, nitro, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, -C(O)NH-(C1-C4 alkyl), -C(O)NH-(C1-C4 hydroxyalkyl), 3- to 12-membered heterocyclic group, C6-10 aryl, 5-7-membered heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, C1-C10 sulfonyl group, etc.

[0083] In the present invention, the term "1-6" means 1, 2, 3, 4, 5 or 6. Other similar terms each independently have a similar meaning.

[0084] The term "tautomer" refers to structural isomers that are easily interconverted by a chemical reaction of isomers, and this reaction generally results in a formal shift of a hydrogen atom or proton accompanied by the conversion of a single bond and an adjacent double bond.

[0085] The term "solvate" refers to a complex formed by the coordination of a compound of the present invention with solvent molecules in a specific ratio.

[0086] The term "enantiomer" refers to stereoisomers that are mirror images of each other and cannot be superimposed.

[0087] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and are not mirror images.

[0088] The term "racemate" refers to two stereoisomers that are mirror images of each other, have opposite optical activities, and can cancel each other's optical activities.

[0089] The term "hydrate" refers to a compound containing water.

[0090] The term "prodrug" refers to a class of compounds that are inactive or have low activity in vitro and release active drugs through in vivo metabolic pathway transformation in vivo to exert pharmacological effects.

[0091] The term "prodrug" includes those which may be biologically active or inactive per se and, when administered by an appropriate method, are metabolized or undergo a chemical reaction in the human body to be converted into a class of compounds of formula (I), or a salt or solution composed of a compound of formula (I). A class of compounds that are inactive or have low activity in vitro and release active drugs through enzymatic or non-enzymatic conversion in vivo to exert their pharmacological effects. The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc. of the said compounds.

[0092] It should be understood that when a certain group exists at multiple different positions of a compound simultaneously, its definitions at each position are independent of each other and may be the same or different. That is, the term "selected from the group consisting of:" has the same meaning as the term "each independently selected from the group consisting of:".

[0093] In this application, each abbreviation is a commonly used abbreviation for compounds in the art, for example:

[0094] For example:

[0095] HOBT: 1-Hydroxybenzotriazole;

[0096] HBTU: Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0097] TBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate;

[0098] PyBOP: 1H-Benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate;

[0099] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide;

[0100] DIC: N,N'-Diisopropylcarbodiimide;

[0101] DCC: N,N'-Dicyclohexylcarbodiimide;

[0102] T3P: 1-Propylphosphonic anhydride;

[0103] DMTMM: 4-(4,6-Dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride.

[0104] CBP / p300 inhibitor

[0105] The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, ester, tautomer, enantiomer, diastereomer, racemate, deuterated compound, hydrate, solvate, metabolic precursor or prodrug thereof;

[0106]

[0107] Wherein, the definitions of each group are as described above.

[0108] In another preferred embodiment, each group in the compound of formula I independently corresponds to the group in the specific compound described in the present invention.

[0109] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention with an acid or a base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salts formed by the compound of the present invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, 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, naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid.

[0110] Another preferred class of salts is the salts formed by the compound of the present invention with bases, such as alkali metal salts (e.g., sodium salt or potassium salt), alkaline earth metal salts (e.g., magnesium salt or calcium salt), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as 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 by morpholine, piperazine, lysine respectively.

[0111] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0112] Preparation method

[0113] The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains. In some cases, the order of the steps of the implementation scheme can be changed to promote the reaction or avoid unwanted side reaction products.

[0114] Typically, the preparation process of the compounds of the present invention is as shown in the examples of the present invention. The raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0115] Pharmaceutical Compositions and Administration Methods

[0116] The present invention also provides a pharmaceutical composition comprising a compound represented by formula (I), or a pharmaceutically acceptable salt, ester, tautomer, enantiomer, diastereomer, racemate, deuterated compound, hydrate, solvate, metabolic precursor or prodrug thereof.

[0117] Since the compounds of the present invention have excellent activity in targeting CBP / p300 protein, the compounds of the present invention and their various crystal forms, or pharmaceutically acceptable salts, tautomers, enantiomers, diastereomers, racemates, deuterated compounds, hydrates, esters, solvates, metabolic precursors or prodrugs thereof, as well as pharmaceutical compositions containing the compounds of the present invention as the main active ingredient, can be used for treating, preventing and alleviating diseases related to the abnormal activity of CBP / p300.

[0118] The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount range. The "safe and effective amount" refers to: an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dose, more preferably, contains 10 - 1000 mg of the compound of the present invention per dose. Preferably, the "per dose" is a capsule or a tablet.

[0119] Typical formulations are prepared by mixing a compound represented by the general formula (I) of the present invention with carriers, diluents or excipients. 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, etc.

[0120] The specific carrier, diluent or excipient used will depend on the method of use and purpose of the compound of the present invention. Generally, the solvent is selected based on a solvent that those skilled in the art consider to be safe and effective for administering to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents soluble in 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, suspension agents, preservatives, antioxidants, light-blocking agents, glidants, processing aids, colorants, sweeteners, flavoring agents, flavor enhancers or other known additives to make the drug be manufactured or used in an acceptable form.

[0121] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gelling substances that 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 admixed 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 are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, 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.), polyhydric alcohols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0122] When the compound of formula (I) described in the present invention is used in combination with at least one or other drugs, the two drugs or multiple drugs can be used separately or in combination, and are preferably administered in the form of a pharmaceutical composition. The compound of formula (I) or the pharmaceutical composition of the present invention can be administered orally, by inhalation, parenterally, orally, sublingually, rectally, vaginally, by patch, pump or transdermally, and is accordingly formulated into a pharmaceutical composition. Parenteral administration includes, for example, intravenous, intraarterial, subcutaneous, nasal, intralung, rectal, topical administration methods.

[0123] These pharmaceutical compositions may also contain one or more sustained-release agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-shielding agents, glidants, processing aids, coloring agents, sweetening agents, flavoring agents or other known additives to make the pharmaceutical composition manufactured or used in an acceptable form.

[0124] The pharmaceutical compositions mentioned above are injection solutions, capsules, tablets, pills, powders or granules.

[0125] There is no particular limitation on the administration mode of the compound or pharmaceutical composition of the present invention. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0126] 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 dibasic calcium phosphate, or with the following components: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxypropylmethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0127] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax-like substances. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0128] In the case of capsules and tablets, the dosage form can also include buffering agents. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules, using lactose and polyethylene glycol, etc. as excipients. Liposomes are composed of various phospholipids, such as cholesterol, stearamide, or phosphatidamide.

[0129] 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 can contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0130] In addition to these inert diluents, the composition can also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0131] In addition to the active compound, the suspension may contain suspending agents, such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, aluminum methoxide and agar or mixtures of these substances, etc.

[0132] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0133] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

[0134] The compounds or pharmaceutical compositions of the present invention may be administered by other topical dosage forms, 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 preservatives, buffers or propellants that are required. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be covered within the scope of the present invention.

[0135] The compounds of the present invention may be used for nasal administration or administration by inhalation, and the compounds may be conveniently delivered from a pump spray system in the form of a solution, dry powder gum, suspension. A sealed pump spray container is an integral dispensing device, and when the dosage form contains an aerosol dispenser, it will contain a compressed gas. Including but not limited to heptafluorohydrocarbons, carbon dioxide, dichlorodifluoromethane, etc.

[0136] In the case of suppositories, the compounds in suppository form are usually composed of a mixture of substances that are solid at room temperature and melt at body temperature. They can be used locally for the vagina, rectum and urethra. Substances commonly used as carriers for manufacturing suppositories include but are not limited to mixtures of polyethylene glycols, glycerogelatin, cocoa butter, hydrogenated vegetable oils, etc.

[0137] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0138] The treatment methods of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.

[0139] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal in need of treatment (such as a human), wherein the dosage during administration is an effective dosage considered pharmaceutically. For a person weighing 60 kg, the daily dosage is usually 1 - 2000 mg, preferably 50 - 1000 mg. Of course, the specific dosage should also consider factors such as the administration route and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0140] Compared with the prior art, the main advantages of the present invention include:

[0141] (1) The compounds of the present invention have the characteristics of simple structure, easy synthesis, stable metabolism, high safety, and diverse administration methods;

[0142] (2) The compounds of the present invention have a good inhibitory effect on the p300 HAT domain, and thus are expected to effectively treat related diseases.

[0143] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out 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 according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0144] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to a person skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are only for demonstration purposes.

[0145] Example 1

[0146]

[0147] (a) Dissolve HATU (1.2552 g, 1.1 eq), BOC-D-proline (0.5013 g, 1.0 eq) and DIPEA (0.8553 g, 2.2 eq) in 10 mL of DMF, stir at room temperature for 30 minutes, then add 3-amino-N-methylbenzamide (0.6510 g, 1.1 eq), continue to react at room temperature for 2 hours, extract three times with ethyl acetate, wash once with saturated NaCl solution, remove the solvent under reduced pressure and purify by silica gel chromatography using DCM / MeOH = 10:1 as the eluent to obtain 0.8919 g of a pale yellow solid with a yield of 85%;

[0148] (b) (R)-tert-Butyl 2-(((3-(methylcarbamoyl)phenyl)amino)carbonyl)pyrrolidine-1-carboxylate (0.8919 g) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to obtain the crude product of 1-1;

[0149] (c) Cyclo(iso)propylidene malonate (0.2148 g, 1.0 eq), 4-chlorobenzaldehyde (0.2095 g, 1.0 eq), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.3774 g, 1.0 eq) and L-proline (0.0343 g, 0.2 eq) were dissolved in 5 mL of absolute ethanol. The mixture was purged with nitrogen three times and stirred at room temperature overnight. Filtration gave 0.3454 g of the target product 1-2 in a yield of 86%;

[0150] (d) Compound 1-1 (about 0.85 mmol, 2.5 eq) and 4-dimethylaminopyridine (0.1041 g, 2.5 eq) were dissolved in 3 mL of 1,4-dioxane. N,O-Bis(trimethylsilyl)acetamide (0.1741 g, 2.5 eq) was added, and the mixture was stirred at room temperature for 2 hours. Subsequently, compound 1-2 (0.0918 g, 1.0 eq) was added, and the reaction was continued at room temperature for 48 hours. The reaction was quenched by adding 1 mL of dilute hydrochloric acid. The mixture was extracted with ethyl acetate three times and washed with saturated NaCl solution once. After removing the solvent under reduced pressure, purification by high performance liquid chromatography gave 0.0631 g of product 1-3 in a yield of 43%.

[0151] 1 H NMR (500 MHz, Methanol-d4) δ 7.97 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.40 (td, J = 7.9, 2.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 4.58 (dd, J = 8.3, 3.7 Hz, 1H), 3.95 (t, J = 7.3 Hz, 1H), 3.78 (dt, J = 9.8, 7.0 Hz, 1H), 3.57 (dt, J = 10.1, 6.4 Hz, 1H), 3.18 (d, J = 6.2 Hz, 2H), 2.92 (s, 3H), 2.30–1.91 (m, 4H).

[0152] 1313C NMR (126 MHz, MeOD) δ 172.43, 171.97, 170.49, 170.12, 139.95, 138.72, 136.46, 133.35, 131.73, 130.07, 129.49, 124.13, 123.72, 120.09, 62.45, 53.38, 49.28, 35.07, 30.56, 26.95, 25.76.

[0153] Example 2

[0154]

[0155] (a) Methyl 2-amino-3-(4-chlorophenyl)propionate hydrochloride (0.5142 g, 1.0 eq), 1-bromo-2-(2-bromoethoxy)ethane (0.7113 g, 1.5 eq) and K2CO3 (1.4109 g, 5 eq) were dissolved in 30 mL of acetonitrile and refluxed with stirring at 90 °C for 48 hours. Extracted with ethyl acetate three times and washed once with saturated NaCl solution. After removing the solvent under reduced pressure, 0.4074 g of crude product was obtained, and the yield was about 70%;

[0156] (b) The crude product of methyl 3-(4-chlorophenyl)-2-morpholinopropionate (0.4074 g) and sodium hydroxide (0.1842 g) were dissolved in 15 mL of a methanol / water mixed solution (methanol: water = 5:1), and refluxed at 80 °C for 6 hours. The solvent was removed under reduced pressure to obtain the crude product of product 2-1;

[0157] (c) HATU (0.1887 g, 1.1 eq), the crude product of product 2-1 (about 0.45 mmol, 1.0 eq) and DIPEA (0.1299 g, 2.2 eq) were dissolved in 5 mL of DMF and stirred at room temperature for 30 minutes. Subsequently, product 1-1 (about 0.51 mmol, 1.1 eq) was added, and the reaction continued at room temperature for 2 hours. Extracted with ethyl acetate three times and washed once with saturated NaCl solution. After removing the solvent under reduced pressure, it was purified by high performance liquid chromatography to obtain 0.1054 g of product 2-2, and the yield was 47%.

[0158] 11H NMR (500 MHz, Methanol-d4) δ 8.01 (t, J = 1.9 Hz, 1H), 7.65 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 7.51 (dt, J = 7.7, 1.4 Hz, 1H), 7.42–7.36 (m, 3H), 7.31 (d, J = 8.4 Hz, 2H), 4.56 (dd, J = 11.5, 4.8 Hz, 1H), 4.30 (dd, J = 8.3, 4.9 Hz, 1H), 3.96 (s, 4H), 3.63–3.34 (m, 6H), 3.04 (t, J = 11.8 Hz, 1H), 2.91 (s, 3H), 2.65–2.57 (m, 1H), 2.05–1.94 (m, 1H), 1.94–1.82 (m, 2H), 1.38 (q, J = 6.2, 5.4 Hz, 1H).

[0159] 13 13C NMR (126 MHz, MeOD) δ 171.69, 170.37, 166.21, 139.91, 136.52, 135.16, 133.39, 132.66, 130.11, 130.03, 123.99, 123.68, 120.17, 68.40, 64.88, 62.15, 49.51, 49.34, 49.17, 49.08, 49.00, 48.83, 48.66, 48.49, 34.32, 30.71, 26.93, 25.49.

[0160] Example 3

[0161]

[0162] (a) Methyl 2-bromo-2-(4-chlorophenyl)acetate (0.5539 g, 1.0 eq), morpholine (0.2022 g, 1.1 eq) and DIPEA (0.8135 g, 3 eq) were dissolved in 20 mL of acetonitrile and stirred under reflux at 80 °C for 4 h. It was extracted three times with ethyl acetate and washed once with saturated NaCl solution. After removing the solvent under reduced pressure, 0.4153 g of crude product was obtained, and the yield was about 73%;

[0163] (b) The crude product of methyl 2-(4-chlorophenyl)-2-morpholinoacetate (0.4153 g) and sodium hydroxide (0.1871 g) were dissolved in 15 mL of a methanol / water mixed solution (methanol: water = 5:1) and reacted under reflux at 80 °C for 6 h. The solvent was removed under reduced pressure to obtain the crude product of 3-1;

[0164] (c) HATU (0.2015 g, 1.1 eq), crude product 3-1 (approx. 0.48 mmol, 1.0 eq) and DIPEA (0.1371 g, 2.2 eq) were dissolved in 5 mL of DMF and stirred at room temperature for 30 minutes. Subsequently, product 1-1 (approx. 0.53 mmol, 1.1 eq) was added and the reaction was continued at room temperature for 2 hours. The mixture was extracted three times with ethyl acetate and washed once with saturated NaCl solution. After removing the solvent under reduced pressure, it was purified by high performance liquid chromatography to obtain 0.0976 g of product 3-2 with a yield of 42%.

[0165] 1 H NMR (500 MHz, Methanol-d4) δ 7.99 (t, J = 2.0 Hz, 1H), 7.67–7.63 (m, 1H), 7.60–7.58 (m, 4H), 7.52 (dt, J = 7.7, 1.3 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 5.43 (s, 1H), 4.85 (s, 1H), 4.66 (dd, J = 8.4, 5.5 Hz, 1H), 4.25–3.57 (m, 7H), 3.01 (dt, J = 10.0, 7.2 Hz, 1H), 2.93 (s, 1H), 2.92 (s, 3H), 2.35–2.29 (m, 1H), 2.05–1.91 (m, 3H).

[0166] 13 C NMR (126 MHz, MeOD) δ 171.70, 170.40, 164.95, 139.96, 138.60, 136.51, 133.60, 131.14, 130.11, 126.91, 124.04, 123.68, 120.16, 71.53, 64.70, 62.58, 49.32, 49.21, 49.11, 49.00, 48.89, 48.79, 48.68, 48.50, 30.53, 26.94, 25.89.

[0167] Example 4

[0168]

[0169] (a) HATU (0.4192 g, 1.1 eq), BOC-D-proline (0.2369 g, 1.1 eq) and DIPEA (0.2855 g, 2.2 eq) were dissolved in 5 mL of DMF and stirred at room temperature for 30 minutes. Subsequently, 4-amino-N-methylbenzamide (0.1517 g, 1.0 eq) was added and the reaction was continued at room temperature for 2 hours. The mixture was extracted three times with ethyl acetate and washed once with saturated NaCl solution. After removing the solvent under reduced pressure, it was purified by silica gel chromatography using DCM / MeOH = 10:1 as the eluent to obtain 0.2366 g of a pale yellow solid with a yield of 68%;

[0170] (b) (R)-tert-Butyl 2-((4-(methylcarbamoyl)phenyl)carbamoyl)pyrrolidine-1-carboxylate (0.2366 g) was dissolved in 2 mL of dichloromethane, 0.2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to obtain the crude product 4-1;

[0171] (c) HATU (0.1299 g, 1.1 eq), the crude product 2-1 (about 0.31 mmol, 1.0 eq) and DIPEA (0.0891 g, 2.2 eq) were dissolved in 5 mL of DMF and stirred at room temperature for 30 minutes. Subsequently, product 4-1 (about 0.34 mmol, 1.1 eq) was added and the reaction was continued at room temperature for 2 hours. The mixture was extracted three times with ethyl acetate and washed once with saturated NaCl solution. After removing the solvent under reduced pressure, it was purified by high performance liquid chromatography to obtain 0.0588 g of product 4-2 with a yield of 38%.

[0172] 1 H NMR (500 MHz, Methanol-d4) δ 7.78 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 4.56 (dd, J = 11.5, 4.8 Hz, 1H), 4.30 (dd, J = 8.4, 5.1 Hz, 1H), 3.99–3.93 (m, 4H), 3.54 (dt, J = 10.8, 6.1 Hz, 6H), 3.04 (t, J = 11.8 Hz, 1H), 2.90 (s, 3H), 2.66–2.58 (m, 1H), 2.04–1.96 (m, 1H), 1.88 (qt, J = 9.9, 4.9 Hz, 2H), 1.38 (dq, J = 10.7, 5.6 Hz, 1H).

[0173] 13¹³C NMR (126 MHz, MeOD) δ 171.70, 170.00, 166.20, 142.70, 135.17, 133.37, 132.65, 130.87, 130.03, 129.12, 120.34, 68.39, 64.87, 62.21, 49.51, 49.34, 49.17, 49.09, 49.00, 48.83, 48.66, 48.49, 34.31, 30.69, 26.89, 25.50.

[0174] Example 5

[0175]

[0176] (a) HATU (0.1313 g, 1.1 eq), crude product 3-1 (approx. 0.31 mmol, 1.0 eq) and DIPEA (0.0888 g, 2.2 eq) were dissolved in 5 mL of DMF and stirred at room temperature for 30 minutes. Subsequently, product 4-1 (approx. 0.34 mmol, 1.1 eq) was added and the reaction was continued at room temperature for 2 hours. The mixture was extracted three times with ethyl acetate and washed once with saturated NaCl solution. After removing the solvent under reduced pressure, it was purified by high performance liquid chromatography to obtain 0.0406 g of product 5-1 with a yield of 27%.

[0177] 1 ¹H NMR (500 MHz, Methanol-d4) δ 7.79 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.59 (s, 4H), 5.42 (s, 1H), 4.84 (s, 1H), 4.65 (dd, J = 8.4, 5.3 Hz, 1H), 4.13–3.63 (m, 7H), 3.00 (dt, J = 9.9, 7.1 Hz, 1H), 2.92 (s, 1H), 2.91 (s, 3H), 2.32 (m, 1H), 2.05–1.90 (m, 3H).

[0178] 13 ¹³C NMR (126 MHz, MeOD) δ 171.68, 170.06, 164.93, 142.83, 138.63, 133.62, 131.12, 130.80, 129.12, 126.91, 120.32, 71.55, 64.70, 62.65, 30.52, 26.89, 25.90.

[0179] Example 6

[0180]

[0181] (a) Dissolve 5-chloro-1H-pyrazolo[4,3-b]pyridine (1.2190 g, 1.0 eq), Pd2(dba)3 (0.2188 g, 3%), XPhos (0.1899 g, 0.05 eq) and LHMDS (1.09 mol / L tetrahydrofuran solution, 16 mL, 2.2 eq) in 16 mL of tetrahydrofuran, displace with nitrogen three times, and reflux and stir at 65 °C for 8 hours. Cool the reaction solution to room temperature and let it stand for 12 hours, then cool to 0 °C, gradually add (Boc)2O (2.0915 g, 1.2 eq) and stir at 0 °C for 40 minutes. Subsequently, add tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 23.8 mL, 3 eq) at 0 °C and continue to stir at 0 °C for 1 hour. After the reaction is completed, extract three times with ethyl acetate, wash once with saturated NaCl solution, remove the solvent under reduced pressure, and purify by silica gel chromatography using hexane / ethyl acetate = 1:1 as the eluent to obtain 1.4912 g of a yellow solid with a yield of 80%;

[0182] (b) Dissolve N-Cbz-D-proline (1.7513 g, 1.1 eq) in 15 mL of dichloromethane, slowly add thionyl chloride (2.4890 g, 3.3 eq) dropwise at 0 °C, stir at 0 °C for 30 minutes, and then reflux and stir at 80 °C for 2 hours. Remove the excess solvent under reduced pressure, then add triethylamine (2.1423 g, 3.3 eq), tert-butyl 5-amino-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (1.4912 g, 1.1 eq) and 20 mL of dichloromethane at 0 °C, and reflux and stir at 60 °C for 2 hours. After the reaction is completed, extract three times with dichloromethane, wash once with saturated NaCl solution, remove the solvent under reduced pressure, and purify by silica gel chromatography using hexane / ethyl acetate = 5:1 as the eluent to obtain 2.6648 g of a pale yellow solid with a yield of 90%;

[0183] (c) Dissolve tert-butyl (R)-5-(1-((benzyloxy)carbonyl)pyrrolidine-2-carboxamido)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (2.6648 g, 1.0 eq) and palladium on carbon (0.6015 g, 10%) in 10 mL of anhydrous methanol, displace with hydrogen three times, and stir at room temperature overnight. Filter to remove impurities and purify by silica gel chromatography using hexane / ethyl acetate = 9:1 as the eluent to obtain 1.5044 g of a pale yellow solid 6-1 with a yield of 79%;

[0184] (d) HATU (0.1388 g, 1.2 eq), crude product 2-1 (approx. 0.33 mmol, 1.1 eq), and DIPEA (0.0950 g, 2.4 eq) were dissolved in 5 mL of DMF and stirred at room temperature for 30 minutes. Subsequently, product 6-1 (0.1008 g, 1.0 eq) was added, and the reaction was continued at room temperature for 2 hours. The mixture was extracted three times with ethyl acetate and washed once with saturated NaCl solution, and the solvent was removed under reduced pressure. Subsequently, 5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, purification by high-performance liquid chromatography gave 0.1259 g of product 6-2 with a yield of 87%.

[0185] 1 H NMR (500 MHz, Methanol-d4) δ 8.23–8.14 (m, 2H), 7.92 (d, J = 9.1 Hz, 1H), 7.40–7.26 (m, 4H), 4.79–4.40 (m, 2H), 3.96 (s, 4H), 3.65–3.41 (m, 6H), 3.22–3.02 (m, 1H), 2.71–2.57 (m, 1H), 2.26–1.64 (m, 4H).

[0186] 13 C NMR (126 MHz, MeOD) δ 167.14, 166.38, 161.42, 148.58, 135.20, 133.33, 132.64, 132.24, 130.26, 130.07, 125.17, 115.55, 68.34, 64.90, 62.14, 49.51, 49.34, 49.17, 49.00, 48.83, 48.66, 48.49, 34.35, 30.51, 29.86, 25.80, 25.51.

[0187] Example 7

[0188]

[0189] (a) HATU (0.1371 g, 1.2 eq), crude product 3-1 (approx. 0.33 mmol, 1.1 eq), and DIPEA (0.0993 g, 2.4 eq) were dissolved in 5 mL of DMF and stirred at room temperature for 30 minutes. Subsequently, product 6-1 (0.1029 g, 1.0 eq) was added, and the reaction was continued at room temperature for 2 hours. The mixture was extracted three times with ethyl acetate and washed once with saturated NaCl solution, and the solvent was removed under reduced pressure. Subsequently, 5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, purification by high-performance liquid chromatography gave 0.1120 g of product 7-1 with a yield of 80%.

[0190] 1 1H NMR (500 MHz, Methanol-d4) δ 8.22–8.14 (m, 2H), 7.91 (dd, J = 55.4, 8.8 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 5.50 (d, J = 8.7 Hz, 1H), 4.75 (d, J = 4.6 Hz, 1H), 4.19–3.38 (m, 7H), 3.26–2.63 (m, 3H), 2.40–2.24 (m, 1H), 2.15–1.89 (m, 3H).

[0191] 13 13C NMR (126 MHz, MeOD) δ 165.48, 165.21, 161.67, 148.64, 138.59, 133.59, 132.89, 132.11, 131.34, 131.12, 126.89, 115.50, 71.38, 64.67, 62.87, 49.32, 49.21, 49.11, 49.00, 48.89, 48.79, 48.68, 30.58, 30.33, 25.86, 25.59.

[0192] Example 8

[0193]

[0194] (a) Methyl 2-amino-3-(4-chlorophenyl)propionate hydrochloride (0.1709 g, 1.0 eq), 1,5-dibromopentane (0.2356 g, 1.5 eq) and K2CO3 (0.4712 g, 5 eq) were dissolved in 10 mL of acetonitrile and refluxed with stirring at 90 °C for 48 h. It was extracted three times with ethyl acetate and washed once with saturated NaCl solution. After removing the solvent under reduced pressure, 0.1268 g of crude product was obtained, and the yield was about 66%;

[0195] (b) The crude product of methyl 3-(4-chlorophenyl)-2-(piperidin-1-yl)propionate (0.1268 g) and sodium hydroxide (0.0591 g) were dissolved in 5 mL of a methanol / water mixed solution (methanol: water = 5:1) and refluxed at 80 °C for 6 h. The solvent was removed under reduced pressure to obtain the crude product of Product 8-1;

[0196] (c) Dissolve HATU (0.1384 g, 1.2 eq), crude product 8-1 (about 0.33 mmol, 1.1 eq) and DIPEA (0.0988 g, 2.4 eq) in 5 mL of DMF, stir at room temperature for 30 minutes, then add product 6-1 (0.1052 g, 1.0 eq), continue to react at room temperature for 2 hours, extract with ethyl acetate three times, wash once with saturated NaCl solution, and remove the solvent under reduced pressure. Then add 5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid, stir at room temperature for 2 hours, remove the solvent under reduced pressure and purify by high performance liquid chromatography to obtain 0.1252 g of product 8-2 with a yield of 87%.

[0197] 1 H NMR (500 MHz, Methanol-d4) δ 8.22–8.14 (m, 2H), 7.94 (d, J = 9.2 Hz, 1H), 7.36 (dd, J = 18.9, 8.1 Hz, 2H), 7.27 (dd, J = 32.7, 8.2 Hz, 2H), 4.77–4.36 (m, 2H), 3.85 (d, J = 12.8 Hz, 1H), 3.67 (d, J = 11.9 Hz, 1H), 3.56 (ddd, J = 17.1, 11.5, 4.3 Hz, 2H), 3.24–2.99 (m, 3H), 2.66 (td, J = 16.4, 6.9 Hz, 1H), 2.12–1.67 (m, 10H).

[0198] 13 C NMR (126 MHz, MeOD) δ 167.56, 166.80, 161.48, 148.63, 135.11, 133.60, 132.65, 132.27, 130.20, 130.01, 125.10, 115.52, 67.84, 62.44, 62.08, 49.51, 49.34, 49.17, 49.00, 48.83, 48.66, 48.49, 34.81, 30.50, 29.80, 25.80, 25.47, 22.77.

[0199] Example 9

[0200]

[0201] (a) Dissolve methyl 2-bromo-2-(4-chlorophenyl)acetate (0.1054 g, 1.0 eq), piperidine (0.0379 g, 1.1 eq) and DIPEA (0.0801 g, 3 eq) in 10 mL of acetonitrile, reflux and stir at 80 °C for 4 hours. Extract with ethyl acetate three times, wash once with saturated NaCl solution, and obtain 0.0953 g of crude product after removing the solvent under reduced pressure, with a yield of about 89%;

[0202] (b) Crude methyl 2-(4-chlorophenyl)-2-morpholinoacetate (0.0953 g) and sodium hydroxide (0.0426 g) were dissolved in 5 mL of a methanol / water mixed solution (methanol: water = 5:1), and the mixture was refluxed at 80 °C for 6 hours. The solvent was removed under reduced pressure to obtain crude product 9-1;

[0203] (c) HATU (0.1376 g, 1.2 eq), crude product 9-1 (approx. 0.33 mmol, 1.1 eq), and DIPEA (0.0995 g, 2.4 eq) were dissolved in 5 mL of DMF, and the mixture was stirred at room temperature for 30 minutes. Subsequently, product 6-1 (0.1025 g, 1.0 eq) was added, and the reaction was continued at room temperature for 2 hours. The mixture was extracted three times with ethyl acetate and washed once with saturated NaCl solution. The solvent was removed under reduced pressure. Subsequently, 5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, purification by high-performance liquid chromatography gave 0.1248 g of product 9-2 with a yield of 89%.

[0204] 1 H NMR (500 MHz, Methanol-d4) δ 8.22 (dd, J = 15.7, 9.2 Hz, 1H), 8.17 (d, J = 5.1 Hz, 1H), 7.89 (dd, J = 41.0, 9.2 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 8.8 Hz, 2H), 5.41 (d, J = 4.1 Hz, 1H), 4.82–4.64 (m, 1H), 3.99–3.73 (m, 2H), 3.24–3.03 (m, 2H), 3.00–2.75 (m, 2H), 2.44–2.19 (m, 1H), 2.19–2.07 (m, 1H), 2.03–1.74 (m, 7H), 1.51 (m, 1H).

[0205] 13 C NMR (126 MHz, MeOD) δ 165.96, 165.68, 148.67, 138.51, 138.37, 133.50, 132.76, 131.25, 131.03, 127.94, 127.53, 115.46, 71.00, 62.83, 62.50, 49.51, 49.34, 49.17, 49.00, 48.83, 48.66, 48.49, 30.57, 30.32, 25.88, 25.58, 22.72.

[0206] Example 10

[0207]

[0208] (a) Potassium tert-butoxide (0.0851 g, 1.2 eq) was dissolved in 5 mL of DMF. The solution was purged with nitrogen three times. Methyl 2-(4-chlorophenyl)acetate (0.1133 g, 1.0 eq) was slowly added dropwise via syringe at 0 °C and stirred at 0 °C for 10 minutes. Subsequently, 4-bromotetrahydro-2H-pyran (0.1221 g, 1.2 eq) was slowly added dropwise via syringe at 0 °C and then gradually warmed to room temperature and stirred for an additional 2 hours. After completion of the reaction, the mixture was extracted three times with dichloromethane and washed once with saturated NaCl solution. The solvent was removed under reduced pressure to obtain 0.1116 g of the crude product, with a yield of approximately 68%;

[0209] (b) The crude product of methyl 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)acetate (0.1116 g) and sodium hydroxide (0.0534 g) were dissolved in 5 mL of a methanol / water mixed solution (methanol:water = 5:1). The reaction was refluxed at 80 °C for 6 hours, and the solvent was removed under reduced pressure to obtain the crude product of Compound 10-1;

[0210] (c) HATU (0.1331 g, 1.2 eq), the crude product of Compound 10-1 (approx. 0.33 mmol, 1.1 eq), and DIPEA (0.0933 g, 2.4 eq) were dissolved in 5 mL of DMF and stirred at room temperature for 30 minutes. Subsequently, Compound 6-1 (0.1083 g, 1.0 eq) was added, and the reaction continued at room temperature for 2 hours. The mixture was extracted three times with ethyl acetate and washed once with saturated NaCl solution. The solvent was removed under reduced pressure. Subsequently, 5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the product was purified by high performance liquid chromatography to obtain 0.1056 g of Compound 10-2, with a yield of 73%.

[0211] 11H NMR (500 MHz, Methanol-d4) δ 8.23 (dd, J = 9.1, 4.0 Hz, 1H), 8.15 (d, J = 4.8 Hz, 1H), 7.76 (dd, J = 69.0, 9.2 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.64 (ddd, J = 68.5, 8.2, 3.9 Hz, 1H), 3.92 (ddt, J = 15.3, 9.5, 5.2 Hz, 1H), 3.83 (dt, J = 10.8, 3.3 Hz, 2H), 3.70–3.59 (m, 1H), 3.59–3.51 (m, 1H), 3.40–3.31 (m, 1H), 3.26 (tt, J = 11.7, 2.2 Hz, 1H), 2.31–1.76 (m, 6H), 1.48–1.33 (m, 1H), 1.30–0.99 (m, 2H).

[0212] 13 13C NMR (126 MHz, MeOD) δ 173.58, 173.25, 148.37, 137.04, 136.78, 134.37, 134.21, 131.53, 131.43, 131.13, 129.77, 115.16, 68.88, 68.66, 62.52, 62.00, 56.64, 49.51, 49.34, 49.17, 49.00, 48.83, 48.66, 48.49, 39.81, 33.03, 31.46, 30.25, 25.80.

[0213] Example 11

[0214]

[0215] (a) Methyl 2-bromo-2-(4-chlorophenyl)acetate (0.1146 g, 1.0 eq), dimethylamine hydrochloride (0.0395 g, 1.1 eq) and DIPEA (0.1669 g, 3 eq) were dissolved in 10 mL of acetonitrile and refluxed with stirring at 80 °C for 4 h. Extracted with ethyl acetate three times and washed with saturated NaCl solution once. After removing the solvent under reduced pressure, 0.0820 g of crude product was obtained, and the yield was about 84%;

[0216] (b) The crude product of methyl 2-(4-chlorophenyl)-2-morpholinoacetate (0.0820 g) and sodium hydroxide (0.0445 g) were dissolved in 5 mL of a methanol / water mixed solution (methanol: water = 5:1) and refluxed at 80 °C for 6 h. The solvent was removed under reduced pressure to obtain the crude product of 11-1;

[0217] (c) HATU (0.1362 g, 1.2 eq), crude product 11-1 (approx. 0.33 mmol, 1.1 eq), and DIPEA (0.0935 g, 2.4 eq) were dissolved in 5 mL of DMF and stirred at room temperature for 30 minutes. Subsequently, product 6-1 (0.1048 g, 1.0 eq) was added, and the reaction was continued at room temperature for 2 hours. The mixture was extracted three times with ethyl acetate and washed once with saturated NaCl solution. The solvent was removed under reduced pressure. Subsequently, 5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, purification by high-performance liquid chromatography gave 0.1004 g of product 11-2 with a yield of 78%.

[0218] 1 H NMR (500 MHz, Methanol-d4) δ 8.21–8.13 (m, 2H), 7.93 (dd, J = 49.1, 9.1 Hz, 1H), 7.66–7.54 (m, 4H), 5.44 (s, 1H), 4.74 (ddd, J = 61.7, 8.6, 3.8 Hz, 1H), 3.87 (ddd, J = 81.1, 13.8, 8.2 Hz, 1H), 3.26–2.49 (m, 7H), 2.40–1.91 (m, 4H).

[0219] 13 C NMR (126 MHz, MeOD) δ 166.04, 165.70, 148.80, 138.60, 133.18, 132.39, 131.35, 131.14, 128.65, 128.20, 124.38, 115.64, 71.26, 62.83, 49.51, 49.34, 49.17, 49.00, 48.83, 48.66, 48.49, 30.60, 30.37, 25.86, 25.58.

[0220] Example 12

[0221]

[0222] (a) HATU (0.1372 g, 1.2 eq), 2-(4-chlorophenyl)-3-methylbutyric acid (0.0704 g, 1.1 eq), and DIPEA (0.0949 g, 2.4 eq) were dissolved in 5 mL of DMF and stirred at room temperature for 30 minutes. Subsequently, product 6-1 (0.1065 g, 1.0 eq) was added, and the reaction was continued at room temperature for 2 hours. The mixture was extracted three times with ethyl acetate and washed once with saturated NaCl solution. The solvent was removed under reduced pressure. Subsequently, 5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, purification by high performance liquid chromatography gave 0.1148 g of product 12-1 with a yield of 90%.

[0223] 1 H NMR (500 MHz, Methanol-d4) δ 8.19 (t, J = 8.7 Hz, 1H), 8.15–8.10 (m, 1H), 7.73 (dd, J = 82.0, 9.1 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 4.64 (ddd, J = 73.0, 8.2, 3.9 Hz, 1H), 4.01–3.78 (m, 1H), 3.61 (dq, J = 12.0, 6.0, 4.9 Hz, 1H), 3.47 (dd, J = 10.3, 3.5 Hz, 1H), 2.39–1.88 (m, 5H), 1.07 (dd, J = 29.8, 6.4 Hz, 3H), 0.68 (dd, J = 6.7, 3.4 Hz, 3H).

[0224] 13 C NMR (126 MHz, MeOD) δ 174.23, 173.88, 148.31, 138.57, 138.27, 134.11, 133.95, 133.38, 131.51, 131.07, 129.59, 115.11, 61.99, 58.38, 49.51, 49.34, 49.17, 49.00, 48.83, 48.66, 48.49, 33.23, 30.27, 25.82, 21.95, 20.41.

[0225] Example 13

[0226]

[0227] (a) Dissolve N-Cbz-D-proline (0.3025 g, 1.1 eq) in 10 mL of dichloromethane. Slowly add thionyl chloride (0.4326 g, 3.3 eq) dropwise at 0 °C, stir at 0 °C for 30 minutes, and then reflux and stir at 80 °C for 2 hours. Remove the excess solvent under reduced pressure. Then add triethylamine (0.3677 g, 3.3 eq), methyl 6-aminonicotinate (0.1684 g, 1.1 eq) and 10 mL of dichloromethane at 0 °C, reflux and stir at 60 °C for 2 hours. After the reaction is completed, extract with dichloromethane three times and wash with saturated NaCl solution once. Remove the solvent under reduced pressure and purify by silica gel chromatography using hexane / ethyl acetate = 5:1 as the eluent to obtain 0.3705 g of a pale yellow solid with a yield of 88%;

[0228] (b) Dissolve methyl (R)-6-(1-((benzyloxy)carbonyl)pyrrolidin-2-ylcarboxamido)nicotinate (0.3705 g, 1.0 eq) and palladium on carbon (0.1036 g, 10%) in 10 mL of anhydrous methanol. Replace with hydrogen three times and stir at room temperature overnight. Filter off the impurities and directly use the residue after removing the solvent under reduced pressure for the next reaction;

[0229] (c) Dissolve HATU (0.4346 g, 1.2 eq), 2-(4-chlorophenyl)-3-methylbutyric acid (0.2232 g, 1.1 eq) and DIPEA (0.2986 g, 2.4 eq) in 10 mL of DMF, stir at room temperature for 30 minutes, and then add the crude product of methyl (R)-6-(pyrrolidin-2-ylcarboxamido)nicotinate (about 0.95 mmol, 1.0 eq). Continue the reaction at room temperature for 2 hours. Extract with ethyl acetate three times and wash with saturated NaCl solution once. Remove the solvent under reduced pressure and purify by silica gel chromatography using hexane / ethyl acetate = 5:1 as the eluent to obtain 0.3549 g of a pale yellow solid with a yield of about 84%;

[0230] (d) Dissolve methyl 6-((2R)-1-(2-(4-chlorophenyl)-3-methylbutanoyl)pyrrolidin-2-ylcarboxamido)nicotinate and sodium hydroxide (0.0981 g) in 10 mL of a methanol / water mixed solution (methanol:water = 5:1), reflux at 80 °C for 6 hours, and remove the solvent under reduced pressure to obtain the crude product of 13-1;

[0231] (e) HATU (0.1481 g, 1.1 eq), product 13-1 (0.1506 g, 1.0 eq) and DIPEA (0.1012 g, 2.2 eq) were dissolved in 5 mL of DMF, stirred at room temperature for 30 minutes, then methylammonium hydrochloride (0.0271 g, 1.1 eq) was added, and the reaction was continued at room temperature for 2 hours. It was extracted three times with ethyl acetate and washed once with saturated NaCl solution. After removing the solvent under reduced pressure, it was purified by high performance liquid chromatography to obtain 0.1290 g of product 13-2 with a yield of 83%.

[0232] 1 H NMR (500 MHz, Methanol-d4) δ 8.72 (dd, J = 17.2, 2.5 Hz, 1H), 8.24 (ddd, J = 14.4, 8.8, 2.3 Hz, 1H), 7.99 (dd, J = 82.2, 8.8 Hz, 1H), 7.38–7.23 (m, 4H), 4.62 (ddd, J = 74.3, 8.3, 4.0 Hz, 1H), 3.95–3.76 (m, 1H), 3.69–3.51 (m, 1H), 3.45 (dd, J = 10.4, 4.2 Hz, 1H), 2.66 (s, 3H), 2.37–1.85 (m, 5H), 1.00 (s, 3H), 0.67 (s, 3H).

[0233] 13 C NMR (126 MHz, MeOD) δ 176.38, 174.42, 173.55, 154.27, 146.85, 139.87, 133.76, 131.47, 130.89, 129.64, 129.33, 114.79, 62.42, 61.63, 58.53, 32.37, 26.89, 26.26, 21.99, 20.65.

[0234] Example 14

[0235]

[0236] (a) HATU (0.1477 g, 1.1 eq), product 13-1 (0.1527 g, 1.0 eq) and DIPEA (0.1015 g, 2.2 eq) were dissolved in 5 mL of DMF, stirred at room temperature for 30 minutes, then 2-amino-1-ethanol hydrochloride (0.0271 g, 1.1 eq) was added, and the reaction was continued at room temperature for 2 hours. It was extracted three times with ethyl acetate and washed once with saturated NaCl solution. After removing the solvent under reduced pressure, it was purified by high performance liquid chromatography to obtain 0.0666 g of product 14-1 with a yield of 40%.

[0237] 11H NMR (500 MHz, Methanol-d4) δ 8.74 (dd, J = 17.2, 2.4 Hz, 1H), 8.28 (ddd, J = 11.0, 8.8, 2.4 Hz, 1H), 7.99 (dd, J = 80.0, 8.8 Hz, 1H), 7.39–7.26 (m, 4H), 4.61 (ddd, J = 74.6, 8.3, 4.0 Hz, 1H), 3.86 (ddt, J = 49.9, 10.1, 7.1 Hz, 1H), 3.72 (td, J = 5.8, 3.3 Hz, 2H), 3.62–3.42 (m, 4H), 2.36–1.82 (m, 5H), 1.09–1.02 (m, 3H), 0.68 (dd, J = 6.7, 4.5 Hz, 3H).

[0238] 13 13C NMR (126 MHz, MeOD) δ 174.48, 173.63, 167.31, 154.33, 147.01, 140.16, 138.61, 134.12, 131.33, 129.67, 127.38, 114.73, 62.47, 62.01, 61.49, 58.57, 49.52, 49.34, 49.17, 49.00, 48.83, 48.66, 48.49, 43.58, 33.67, 30.42, 25.81, 22.00, 20.50.

[0239] Example 15

[0240]

[0241] (a) Dissolve HATU (0.1301 g, 1.2 eq), (R)-2-(4-chlorophenyl)-3-methylbutyric acid (0.0685 g, 1.1 eq) and DIPEA (0.0893 g, 2.4 eq) in 5 mL of DMF, stir at room temperature for 30 minutes, then add product 6-1 (0.0981 g, 1.0 eq), continue the reaction at room temperature for 2 hours, extract three times with ethyl acetate and wash once with saturated NaCl solution, remove the solvent under reduced pressure. Then add 5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid, stir at room temperature for 2 hours, remove the solvent under reduced pressure and purify by high performance liquid chromatography to obtain 0.0762 g of product 15-1 with a yield of 60%.

[0242] 11H NMR (500 MHz, Methanol-d4) δ 8.18 (dd, J = 9.2, 0.9 Hz, 1H), 8.12 (d, J = 0.9 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 4.71 (dd, J = 8.6, 3.5 Hz, 1H), 3.84 (dt, J = 10.0, 7.0 Hz, 1H), 3.60 (dt, J = 10.3, 6.4 Hz, 1H), 3.47 (d, J = 10.2 Hz, 1H), 2.38–2.15 (m, 2H), 2.12–1.92 (m, 3H), 1.05 (d, J = 6.5 Hz, 3H), 0.69 (d, J = 6.6 Hz, 3H).

[0243] 13 13C NMR (126 MHz, MeOD) δ 174.24, 173.78, 148.44, 138.30, 133.98, 133.42, 131.52, 131.09, 129.87, 129.61, 126.57, 115.19, 62.00, 58.41, 49.51, 49.34, 49.17, 49.00, 48.83, 48.66, 48.49, 33.23, 30.26, 25.82, 21.97, 20.41.

[0244] Example 16

[0245]

[0246] (a) Dissolve HATU (0.1311 g, 1.2 eq), (R)-2-(4-chlorophenyl)-3-methylbutyric acid (0.0733 g, 1.1 eq) and DIPEA (0.0935 g, 2.4 eq) in 5 mL of DMF, stir at room temperature for 30 minutes, then add product 6-1 (0.1016 g, 1.0 eq), continue the reaction at room temperature for 2 hours, extract three times with ethyl acetate and wash once with saturated NaCl solution, remove the solvent under reduced pressure. Then add 5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid, stir at room temperature for 2 hours, remove the solvent under reduced pressure and purify by high performance liquid chromatography to obtain 0.0740 g of product 15-1 with a yield of 59%.

[0247] 11H NMR (500 MHz, Methanol-d4) δ 8.24 (dd, J = 9.1, 1.0 Hz, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 4.54 (dd, J = 8.2, 4.8 Hz, 1H), 3.93 (ddd, J = 9.9, 7.4, 5.6 Hz, 1H), 3.62 (dt, J = 9.9, 6.9 Hz, 1H), 3.48 (d, J = 10.5 Hz, 1H), 2.39–2.04 (m, 4H), 1.93 (dt, J = 12.8, 6.7 Hz, 1H), 1.10 (d, J = 6.4 Hz, 3H), 0.68 (d, J = 6.7 Hz, 3H).

[0248] 13 13C NMR (126 MHz, MeOD) δ 174.52, 174.05, 148.66, 138.61, 134.14, 133.46, 131.56, 131.34, 129.68, 129.11, 126.37, 115.36, 62.46, 58.55, 49.51, 49.34, 49.17, 49.00, 48.83, 48.66, 48.49, 33.68, 30.51, 25.86, 22.02, 20.50.

[0249] Example 17: Determination of Radioactive Acetyltransferase Activity

[0250] The reaction system for the determination of radioactive acetyltransferase activity contains: 25 μL of reaction mixture containing 250 μM 3 [3H]Ac-CoA, 600 nM H3(1-21), 0.2 nM p300, in 50 mM Tris-HCl (pH 7.5) containing 0.01% Tween-20. The protein is pre-incubated with a series of concentration gradients of the test compound at room temperature for 15 minutes, and then the substrate and 3 [3H]Ac-CoA are added to the system.

[0251] After incubation at 37 °C for 60 minutes, the reaction system is transferred to a MultiScreen HTS filter plate (Millipore), and the filter plate is washed three times with double-distilled water. The radioactive readings are measured by liquid scintillation counting (MicroBeta, PerkinElmer). The data of the percentage of inhibition are fitted into a dose-inhibition rate curve using non-linear regression in GraphPad Prism 5.0 to obtain the IC 50 value.

[0252] Table 1

[0253]

[0254]

[0255] It can be seen that the compounds of the present invention have a low IC 50 value, indicating a good inhibitory effect on CBP / p300.

[0256] All documents mentioned in the present invention are cited herein by reference as if each individual document was cited separately. Further, 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 appended claims of the present application.

Claims

1. A compound represented by formula (1), or a pharmaceutically acceptable salt, ester, tautomer, enantiomer, diastereomer, racemate, deuterated compound, hydrate, solvate, metabolic precursor or prodrug thereof; Wherein, A is H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-4 heteroatoms each independently selected from N, O, S, a substituted or unsubstituted 4-9 membered heterocyclic group containing 1-4 heteroatoms each independently selected from N, O, S, a substituted or unsubstituted C3-C8 cycloalkyl group; B is H, -COOH, a C3-C7 non-linear alkyl group, -NRaRb, a C3-C8 cycloalkyl group, and a 3-8 membered heterocyclic group containing 1-4 heteroatoms each independently selected from N, O, S; wherein, Ra and Rb are each independently a substituted or unsubstituted C1-C4 alkyl group, or Ra, Rb and the nitrogen atom to which they are commonly attached form a substituted or unsubstituted 5-8 membered heterocyclic group containing 1-3 heteroatoms each independently selected from N, O, S; C is a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-4 heteroatoms each independently selected from N, O, S, a substituted or unsubstituted C6-C10 aryl group; L is absent, a C1-6 alkylene group, -O-, -NH-; R1, R2 and R3 are each independently H, a hydroxyl group, a halogen, a nitro group, a cyano group, an amino group, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C6 alkoxy group; Unless otherwise specified, the substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following group: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, -C(O)NH-(C1-C4 alkyl), -C(O)NH-(C1-C4 hydroxyalkyl), a 3- to 12 membered heterocyclic group, a C6-10 aryl group, a 5-7 membered heteroaryl group, a C1-C8 aldehyde group, a C2-C10 acyl group, a C2-C10 ester group, a C1-C10 sulfonyl group.

2. The compound according to claim 1, wherein, A is a substituted or unsubstituted group selected from the following group: a C6 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms each independently selected from N, O, S; B is H, -COOH, a C3-C6 non-linear alkyl group, -NRaRb, and a 5-7 membered heterocyclic group containing 1-3 heteroatoms each independently selected from N, O, S; wherein, Ra and Rb are each independently a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, or Ra, Rb and the nitrogen atom to which they are commonly attached form a substituted or unsubstituted 5-7 membered heterocyclic group containing 1-2 heteroatoms each independently selected from N, O, S; C is a substituted or unsubstituted C6 aryl group; L is absent or CH2; R1, R2 and R3 are each independently H, a halogen, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group.

3. The compound according to claim 1, wherein B is selected from H, -COOH, 4. The compound according to claim 1, wherein The described compound is selected from the following group:

5. A method for preparing a compound represented by formula I, characterized in that, Comprising the following steps: (a, b) In an inert solvent, in the presence of a condensing agent, the compound of formula 1A reacts with the compound of formula 1B to undergo a condensation reaction. After removing the Boc protecting group, the intermediate compound of formula 1C is obtained; (c) In an inert solvent, in the presence of a condensing agent, the compound of formula 1C reacts with the compound of formula 1D to obtain the compound of formula (I); In the formula, L, R1, R2, and R3 are as defined in claim 1.

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

7. A pharmaceutical composition, characterized in that, Comprising (a1) a therapeutically effective amount of the compound described in claim 1 as a first active ingredient, or a pharmaceutically acceptable salt, ester, tautomer, enantiomer, diastereomer, racemate, deuterated compound, hydrate, solvate, metabolic precursor or prodrug thereof, (a2) another therapeutic agent as a second active ingredient; And (b) a pharmaceutically acceptable carrier.

8. Use of the compound according to claim 1, or a pharmaceutically acceptable salt, ester, tautomer, enantiomer, diastereomer, racemate, deuterated compound, hydrate, solvate, metabolic precursor or prodrug thereof, or the pharmaceutical composition according to claim 6, characterized in that, For the preparation of (a) a drug or preparation targeting histone acetyltransferase CBP / p300 protein, and / or (b) a drug or preparation for preventing and / or treating diseases associated with abnormal CBP / p300 activity.

9. The use according to claim 8, characterized in that, The diseases associated with abnormal CBP / p300 activity are selected from the following group: diabetes, inflammation, macular degeneration and related functional disorders, skin cancer, uterine cancer, digestive tract cancer, prostate cancer, colon cancer, rectal cancer, brain tumor, head and neck cancer, throat 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, hematological tumor, myeloma, lung function disorder, pain, immunodeficiency diseases, damage and functional disorders of the central nervous system, diseases associated with AIDS, or combinations thereof.

10. A method for inhibiting the abnormal activity of CBP / p300, characterized in that, Administering to a subject in need a therapeutically effective amount of the compound described in claim 1, or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, deuterated compound, hydrate, ester, solvate, metabolic precursor or prodrug thereof, or the pharmaceutical composition described in claim 6.

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