Fto inhibitors, processes for their preparation and use thereof

Abstract

The application provides a kind of FTO inhibitor and its preparation method and application, specifically, the application discloses 2-(substituted phenyl hetero) aromatic formic acid and its derivative compound and its pharmaceutically acceptable salt, hydrate or solvate as shown in the following general formula (I), which can be used as FTO target point inhibitor for treating diseases related to FTO target point, such as leukemia, lymphoma, myelodysplastic syndrome, obesity, metabolic syndrome (metabolic syndrome, MS), type 2 diabetes (Type 2 diabetes, T2D), Alzheimer's disease, breast cancer, renal cancer, colorectal cancer, pancreatic cancer, liver cancer, small cell lung cancer, human bone marrow transverse muscle cancer, pancreatic cancer, malignant glioblastoma etc.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry. Specifically, this invention discloses 2-(substituted phenylhexyl) aromatic carboxylic acid and its derivatives having the following general formula (I), as well as pharmaceutically acceptable salts, hydrates, or solvates, which can be used as inhibitors of FTO targets for the treatment of diseases related to FTO targets, such as leukemia, lymphoma, myelodysplastic syndrome, obesity, metabolic syndrome (MS), type 2 diabetes (T2D), Alzheimer's disease, breast cancer, kidney cancer, colorectal cancer, pancreatic cancer, liver cancer, small cell lung cancer, human bone marrow rhabdomyosarcoma, pancreatic cancer, and malignant glioblastoma of the brain. Background Technology

[0002] N6-methyladenosine (m 6 A) is the most abundant chemical modification on eukaryotic messenger RNA (mRNA). Its modification state is dynamically and reversibly regulated by methyltransferases and demethylases, which have an impact on RNA splicing, translation, stability, and the epigenetic effects of certain non-coding RNAs, mediating a variety of physiological and pathological processes.

[0003] Where m 6 A demethylase, a fat mass and obesity-associated protein (FTO), is present in Fe... 2+ FTO, catalyzed by α-ketoglutarate, removes the methylation of m6A, dynamically regulates m6A modification levels, and participates in processes such as glucose and lipid metabolism and repair of neurotransmission defects. FTO has been shown to be associated with obesity, type II diabetes, Alzheimer's disease, non-alcoholic steatohepatitis, and the occurrence and progression of various hematologic malignancies and solid tumors. Furthermore, aberrant expression of FTO protein in tumors often leads to m... 6 Disorders in A modification levels have a significant impact on the maintenance of tumor stem cells, as well as the proliferation, migration, and invasion of tumor cells, and even their sensitivity to radiotherapy and chemotherapy.

[0004] Therefore, the development of small molecule inhibitors targeting FTO has the potential to treat a variety of diseases and there is still a huge demand for it. Summary of the Invention

[0005] The present application aims to provide an inhibitor specifically targeting FTO, which can treat diseases such as leukemia, lymphoma, myelodysplastic syndrome, obesity, metabolic syndrome (MS), Type 2 diabetes (T2D), Alzheimer's disease, breast cancer, renal cancer, colorectal cancer, pancreatic cancer, liver cancer, small cell lung cancer, human myeloid rhabdomyosarcoma, pancreatic cancer, malignant glioblastoma, etc. by inhibiting the function of FTO enzyme or the signal transduction process mediated by FTO protein.

[0006] In the first aspect of the present application, a compound represented by the following formula (I) and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof are provided,

[0007]

[0008] wherein,

[0009] A1, A2 and A3 are each independently N, CH or CR3;

[0010] R1 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C3-C8 cycloalkyl-O-, 3-8 membered heterocyclyl-O-; and said R1 can be substituted with one or more R f substituted, said R f is selected from the group consisting of deuterium, halogen, carbonyl (=O), carboxyl, hydroxyl, amino, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkoxycarbonyl, C1-C6 acylamino, C2-C6 ester, substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted five- or six-membered heteroaryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl said carbocyclic ring;

[0011] R2 is selected from the group consisting of H, a halogen atom, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C 3～ C 12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 acylamino, carbonyl, carboxyl, hydroxyl, amino, nitro, cyano;

[0012] R3is selected from the group consisting of H, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted C1-C6alkoxy group, a substituted or unsubstituted C1-C6alkylamino group, a substituted or unsubstituted C1-C6alkoxycarbonyl group, a substituted or unsubstituted C3-C8cycloalkyl group;

[0013] X has a structure according to the formula: COOH, CONH2, CONHOH, CONHR e , CONHOR e , CON(OH)R e , COOR e ; R e is a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted C3-C6cycloalkyl group, a substituted or unsubstituted 3-8 membered heterocyclyl group;

[0014] R a , R b are each independently selected from the group consisting of a halogen, -OH, CN, NO2, NH2, a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted -(CH2) m -C1-C6alkoxy group, a substituted or unsubstituted -(CH2) m -C1-C6alkylthio group, a substituted or unsubstituted -(CH2) m -3-8 membered heterocyclyl group, a substituted or unsubstituted -O-(CH2) m -3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8cycloalkyl group, a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8cycloalkoxy group, a substituted or unsubstituted C6-C 10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group; wherein m is selected from the group consisting of 0, 1, 2, 3, 4, or 5;

[0015] R c , R d are each independently selected from the group consisting of H, a halogen, -OH, CN, NO2, NH2, a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted C1-C6alkoxy group, a substituted or unsubstituted C3-C8cycloalkyl group, a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C6-C 10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group;

[0016] A ring is a group selected from the group consisting of a naphthalene ring, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group;

[0017] n is 0, 1, 2, 3, or 4;

[0018] wherein the substituents are one or more hydrogen atoms replaced by a substituent selected from the group consisting of deuterium, a halogen atom, a carbonyl group (=0), a carboxyl group, a hydroxyl group, an amino group, a nitro group, a cyano group, a C1-C6 alkoxy group, a deuterated C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C1-C6 alkylamino group, a C1-C6 alkoxycarbonyl group, a C1-C6 acylamino group, a C2-C6 ester group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C6-C10 aryl group, a C6-C10 aryl-C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl-C1-C6 alkyl group, a C3-C8 cycloalkenyl group, a C3-C8 cycloalkenyl-C1-C6 alkyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heterocyclyl-C1-C6 alkyl group, a 5- to 10-membered heteroaryl group, and a 5- to 10-membered heteroaryl-C1-C6 alkyl group; 10 a C6-C10 aryl group, a C6-C10 aryl-C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl-C1-C6 alkyl group, a C3-C8 cycloalkenyl group, a C3-C8 cycloalkenyl-C1-C6 alkyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heterocyclyl-C1-C6 alkyl group, a 5- to 10-membered heteroaryl group, and a 5- to 10-membered heteroaryl-C1-C6 alkyl group; 12 a C6-C10 aryl group, a C6-C10 aryl-C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl-C1-C6 alkyl group, a C3-C8 cycloalkenyl group, a C3-C8 cycloalkenyl-C1-C6 alkyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heterocyclyl-C1-C6 alkyl group, a 5- to 10-membered heteroaryl group, and a 5- to 10-membered heteroaryl-C1-C6 alkyl group;

[0019] the heterocycle or heterocyclyl group can be a saturated or partially unsaturated structure, but not aromatic; the carbocycle, heterocycle, aromatic ring, and heteroaromatic ring can be a monocyclic ring, a spiro ring, a fused ring, or a bridged ring; the heterocyclyl group or heteroaryl group each independently contains 1, 2, 3, or 4 heteroatoms selected from O, S, and N.

[0020] In another preferred example, R1is selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a 3- to 8-membered heterocyclyl group, and a C3-C8 cycloalkyl-O- group; and R1is optionally substituted by one or more R f substituents selected from the group consisting of deuterium, a halogen atom, a carbonyl group (=0), a carboxyl group, a hydroxyl group, an amino group, a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C1-C6 alkoxycarbonyl group, a C1-C6 acylamino group, a C2-C6 ester group, a substituted or unsubstituted C1-C f substituted or unsubstituted C6-C 10 substituted or unsubstituted C6-C 10 substituted or unsubstituted C6-C

[0021] R a , R b each independently selected from the group consisting of a halogen atom, -OH, CN, NO2, NH2, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted -(CH2) m -C1-C6 alkoxy group, a substituted or unsubstituted -(CH2) m -C1-C6 alkylthio group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted -(CH2) m -3- to 8-membered heterocyclyl group, a substituted or unsubstituted -O-(CH2) m -3- to 8-membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C6-C 10 aryl group, and a substituted or unsubstituted 5- to 10-membered heteroaryl group; wherein m is selected from the group consisting of 0, 1, or 2;

[0022] Rc d each independently selected from the group consisting of H, halogen, C1-C6alkyl.

[0023] In another preferred embodiment, said R c and R d are each independently H.

[0024] In another preferred embodiment, said X is selected from the group consisting of a substituted or unsubstituted structure selected from the group consisting of:

[0025]

[0026] wherein n is 0, 1, 2, 3, 4, 5 or 6; R e is selected from the group consisting of H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl; R g is selected from the group consisting of H, OH.

[0027] In another preferred embodiment, said A ring is selected from the group consisting of pyridine, pyrimidine, pyridazine, tetrazine, triazine, pyrrole, thiophene, furan, tetrazole, triazole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, oxadiazole, thiadiazole, morpholine, dihydropiperidine, thiomorpholine, piperidine, piperazine, tetrahydropyran, dihydropyran, pyrroline, tetrahydrothiophene, tetrahydrofuran, oxetane, thietane, azetidine.

[0028] In another preferred embodiment, said A ring is selected from the group consisting of:

[0029]

[0030] In another preferred embodiment, said R a , R b are each independently selected from the group consisting of F, Cl, Br, methyl, ethyl, cyclopropane, isopropyl, methoxy, methylthio, -CH2OCH3, trifluoromethyl, trifluoromethoxy, difluoromethoxy, deuterated methoxy.

[0031] In another preferred embodiment, said compound of formula (I) is selected from the group consisting of:

[0032]

[0033]

[0034]

[0035]

[0036] ​

[0037] In a second aspect of the present application, there is provided a use of a compound of formula (I) and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as described in the first aspect of the present application, for a use selected from the group consisting of:

[0038] (a) preparing a medicament for treating a disease associated with FTO protein activity or expression level;

[0039] (b) preparing a FTO protein activity targeting inhibitor;

[0040] (c) inhibiting FTO protein activity in vitro non-therapeutically; and / or

[0041] (d) treating a disease associated with FTO activity or expression level.

[0042] In another preferred embodiment, the disease is selected from the group consisting of leukemia, lymphoma, myelodysplastic syndrome, obesity, metabolic syndrome (MS), Type 2 diabetes (T2D), Alzheimer's disease, breast cancer, renal cancer, colorectal cancer, pancreatic cancer, liver cancer, small cell lung cancer, human myeloid rhabdoid tumor of bone, pancreatic cancer, malignant glioblastoma.

[0043] In a third aspect of the present application, there is provided a pharmaceutical composition comprising: (i) an effective amount of a compound of formula (I) and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and (ii) a pharmaceutically acceptable carrier.

[0044] In a fourth aspect of the present application, there is provided a method for inhibiting FTO protein activity, comprising the step of: administering to a subject to be inhibited an inhibiting effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the first aspect of the present application, or administering to a subject to be inhibited an inhibiting effective amount of a pharmaceutical composition as described in the third aspect of the present application.

[0045] It should be understood that, within the scope of the present application, each of the technical features described above and in the following (such as the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they are not listed one by one here. DETAILED DESCRIPTION

[0046] Through extensive and in-depth research, the present inventors, through a large number of screening and testing, provide a class of compounds as shown in formula (I), which can efficiently and selectively inhibit the activity of FTO protein. Compared with existing FTO inhibitors, the cell activity is significantly improved. Based on the above findings, the present inventors have completed the present application.

[0047] The term

[0048] The term "C1-C6alkyl" refers to straight or branched chain alkyl groups having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, or the like.

[0049] The term "C1-C6alkoxy" refers to straight or branched chain alkoxy groups having from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, or the like.

[0050] The term "C3-C8cycloalkyl" refers to saturated or unsaturated cyclic groups having from 3 to 8 carbon atoms, all of which are carbon ring members, in some preferred embodiments, the carbocyclic ring can be saturated or partially unsaturated, but not aromatic, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, or the like.

[0051] The term "C6-C10aryl" refers to aryl groups having from 6, 7, 8, 9, or 10 carbon atoms, including monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, or the like. 10 The term "C6-C10aryl" refers to aryl groups having from 6, 7, 8, 9, or 10 carbon atoms, including monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, or the like.

[0052] The term "3-10 membered heterocyclyl" refers to saturated or unsaturated (including aromatic) ring system substituents having from 3, 4, 5, 6, 7, 8, 9, or 10 members in the ring system, having one or more heteroatoms selected from O, S, N, or P in the ring system, such as tetrahydrofuran, pyrrolin, oxetane, or the like, preferably 4-9 membered heterocyclyl.

[0053] The term "5-6 membered heteroaryl" refers to aromatic ring system substituents having from 5, 6 members in the ring system, having one or more heteroatoms selected from O, S, N, or P in the ring system, such as pyridyl, thienyl, furanyl. The term "5-10 membered heteroaryl" has a similar definition, referring to ring systems having from 5, 6, 7, 8, 9, 10 members in the ring system, having one or more heteroatoms selected from O, S, N, or P in the ring system, wherein the heteroaryl forms an aromatic structure as a whole.

[0054] Unless otherwise indicated, the term "substituted" in the present application includes substitution with various isotopes of hydrogen, such as deuterium.

[0055] The term "halogen" refers to F, Cl, Br, and I.

[0056] The terms "comprising", "containing", or "including" in the present application mean that various components can be used together in mixtures or combinations of the present application. Thus, the terms "consisting essentially of and "consisting of are included in the term "comprising".

[0057] As used herein, the term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and / or desirable, i.e., that which is acceptable to a person or animal at dosages and in amounts necessary to achieve the desired therapeutic effect.

[0058] As used herein, the term "effective amount" means that amount of a therapeutic agent that will elicit the biological or medical response of a subject, that is, that amount required to treat, alleviate, or prevent a target disease or condition, or to exhibit a detectable therapeutic or preventative effect. The precise effective amount for a subject will depend on the subject's size and health, the nature and extent of the condition, and the therapeutic or combination of therapeutics selected for use. Thus, it is not useful to specify an exact effective amount, however, an appropriate effective amount can be determined by routine experimentation in view of the disclosure herein.

[0059] Unless otherwise indicated, all compounds appearing in the present application are intended to include all possible optical isomers, such as single enantiomers, or mixtures of different enantiomers (i.e., racemates). Each chiral carbon atom in all compounds of the present application can optionally be in the R or S configuration, or a mixture of the R and S configurations.

[0060] As used herein, the term "compound of the present application" refers to a compound of Formula (I). The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of Formula (I).

[0061] Compounds of Formula (I)

[0062]

[0063] wherein,

[0064] A1, A2, and A3 are each independently N, CH, or CR3;

[0065] R1is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C3-C8cycloalkyl-O-, 3-8 membered heterocyclyl-O-; and said R1may be substituted with one or more R f substituents selected from the group consisting of deuterium, halogen, carbonyl (=0), carboxyl, hydroxyl, amino, nitro, cyano, C1-C6alkoxy, C1-C6alkylamino, C1-C6alkoxycarbonyl, C1-C6acylamino, C2-C6ester, substituted or unsubstituted C1-C f alkyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted five- or six-membered heteroaryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl; 10 alkyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted five- or six-membered heteroaryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl; 10 alkyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted five- or six-membered heteroaryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl;

[0066] R2is selected from the group consisting of H, a halogen atom, a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted C1-C6alkoxy group, a substituted or unsubstituted C3-C6cycloalkyl group, a substituted or unsubstituted 3-12 membered heterocyclyl group, a substituted or unsubstituted C1-C6alkylamino group, a substituted or unsubstituted C1-C6amide group, a carbonyl group, a carboxyl group, a hydroxyl group, an amino group, a nitro group, a cyano group; 3～ C 12 a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted C1-C6alkoxy group, a substituted or unsubstituted C3-C6cycloalkyl group, a substituted or unsubstituted 3-12 membered heterocyclyl group, a substituted or unsubstituted C1-C6alkylamino group, a substituted or unsubstituted C1-C6amide group, a carbonyl group, a carboxyl group, a hydroxyl group, an amino group, a nitro group, a cyano group;

[0067] R3is selected from the group consisting of H, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted C1-C6alkoxy group, a substituted or unsubstituted C1-C6alkylamino group, a substituted or unsubstituted C1-C6alkoxycarbonyl group, a substituted or unsubstituted C3-C6cycloalkyl group;

[0068] X has a structure according to the formula: COOH, CONH2, CONHOH, CONHR e , CONHOR e , CON(OH)R e , COOR e ; R e is a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted C3-C6cycloalkyl group, a substituted or unsubstituted 3-8 membered heterocyclyl group;

[0069] R a , R b are each independently selected from the group consisting of a halogen, -OH, CN, NO2, NH2, a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted -(CH2) m -C1-C6alkoxy group, a substituted or unsubstituted -(CH2) m -C1-C6alkylthio group, a substituted or unsubstituted -(CH2) m -3-8 membered heterocyclyl group, a substituted or unsubstituted -O-(CH2) m -3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8cycloalkyl group, a substituted or unsubstituted C3-C8cycloalkoxy group, a substituted or unsubstituted C6-C 10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group; wherein m is selected from the group consisting of 0, 1, 2, 3, 4, or 5;

[0070] R c , R d are each independently selected from the group consisting of H, a halogen, -OH, CN, NO2, NH2, a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted C1-C6alkoxy group, a substituted or unsubstituted C3-C8cycloalkyl group, a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C6-C 10Aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;

[0071] Ring A is a group selected from the following group: naphthalene ring, 3- to 10-membered heterocyclic group, or 5- to 10-membered heteroaryl group;

[0072] n can be 0, 1, 2, 3, or 4;

[0073] The substitution mentioned above refers to the substitution of one or more hydrogen atoms by a substituent selected from the group consisting of: deuterium, halogen, carbonyl (=O), carboxyl, hydroxyl, amino, nitro, cyano, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkoxycarbonyl, C1-C6 amide, C2-C6 ester, C1-C6 alkyl, halo-C1-C6 alkyl, C6-C6... 10 Aryl, five- or six-membered heteroaryl, 3- to 12-membered heterocyclic, C3-C 12 cycloalkyl;

[0074] The heterocycle or heterocyclic group may be a saturated or partially unsaturated structure, but does not possess aromaticity; the carbocyclic, heterocyclic, aromatic, or heteroaromatic ring may be a monocyclic, spirocyclic, fused, or bridged ring; each heterocyclic group or heteroaromatic group independently contains 1, 2, 3, or 4 heteroatoms selected from O, S, and N.

[0075] The pharmaceutically acceptable salt is selected from: inorganic acid salts, organic acid salts, inorganic base salts, or organic base salts. Preferably, it is an inorganic acid salt or organic acid salt, and the inorganic acid salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, or acid phosphate; the organic acid salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate, glutamate, salicylate, ascorbate, camphorate, or camphorsulfonate.

[0076] In a preferred embodiment, the acceptable salts are inorganic or organic base salts, and the inorganic base is selected from the group consisting of aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganic, potassium, sodium, zinc salts, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically-acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethyldiamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydroxycobal, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, purines, procaine, puridine, polyamine resins, procaine, purines, puridine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0077] Pharmaceutical compositions and methods of administration

[0078] Since the compound of the present application has excellent inhibitory activity against FTO protein, the compound of the present application and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compound of the present application as an active ingredient can be used for the treatment, prevention, and alleviation of diseases associated with FTO activity or expression. According to the prior art, the compound of the present application can be used for the treatment of leukemia, lymphoma, myelodysplastic syndrome, obesity, metabolic syndrome (MS), Type 2 diabetes (T2D), Alzheimer's disease, breast cancer, renal cancer, colorectal cancer, pancreatic cancer, liver cancer, small cell lung cancer, human myeloid rhabdomyosarcoma, pancreatic cancer, malignant glioblastoma, and the like.

[0079] The pharmaceutical composition of the present application comprises a safe and effective amount of the compound of the present application or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. The "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 to 2000 mg of the compound of the present application per dose, more preferably 5 to 200 mg of the compound of the present application per dose. Preferably, the "one dose" is one capsule or tablet.

[0080] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler substances or gel materials, which are suitable for human use and which are of sufficient purity and sufficiently low toxicity. By "compatible" it is meant that the components of the composition are capable of being commingled with the compounds of the application, with each other, and with other ingredients, and that the resulting mixture is stable enough to be manufactured, used, and / or stored. Examples of suitable pharmaceutically acceptable carriers are celluloses and their derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose sodium, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween 20®, Tween 80®, etc.), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0081] The mode of administration of the compounds or pharmaceutical compositions of the present application is not narrowly critical and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0082] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such other ingredients as binders, (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) absorbents, e.g., kaolin and bentonite clay; and (i) lubricants, e.g., 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 also can contain buffering agents.

[0083] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They can contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0084] ​Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, or elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, and the like, or mixtures thereof.

[0085] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0086] Suspensions, in addition to the active compounds, can contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, agar-agar, or mixtures thereof, and the like.

[0087] The compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

[0088] Dosage forms of the compounds of the present application for topical administration include ointments, powders, sprays, and inhalers. The active compound is admixed under sterile conditions with physiologically acceptable carriers and any preservatives, buffers, or propellants as can be required.

[0089] The compounds of the present application can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0090] In using the pharmaceutical compositions, therapeutically effective amounts of the compounds of the present application are administered to a mammal (e.g., human) in need of treatment in dosages, and the dosages are determined by the judgment of the practitioner, taking into account the pharmacokinetics of the particular compound being used, the age, weight, and health of the recipient, and the severity of the disease being treated. In general, oral dosages in the range of 1 to 2000 mg, preferably 5 to 500 mg, per day are appropriate for administering the compounds of the present application to a 60 kg person. Of course, the specific dose used will depend on the specific compound being used, on the condition of the patient being treated, and on the judgment of the practitioner.

[0091] The primary advantages of the present application include:

[0092] (1) The present application provides a class of demethylase FTO inhibitors, which can inhibit the activity of FTO protein at very low concentrations (IC 50 values are generally lower than 30 μM).

[0093] (2) The FTO inhibitors of the present application have high selectivity, and can regulate m6 The role of A.

[0094] (3) The FTO inhibitor of the present invention has strong anti-cell proliferation activity.

[0095] (4) The FTO protein activity inhibitor of the present invention exhibits good pharmacokinetic effects in mice.

[0096] The invention is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise 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 as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0097] The experimental reagents used in the experiment were mainly purchased from China National Pharmaceutical Group, Sigma, and Shanghai Sangon Biotech.

[0098] Example 1: Synthesis of R02

[0099]

[0100] Step 1: In a 250 mL round-bottom flask, add A-1a (4.2 g, 15 mmol, 1.0 eq), K₂CO₃ (2.1 g, 15 mmol, 1.0 eq), diethyl sulfate (2.3 g, 15 mmol, 1.0 eq), and N,N-dimethylformamide (75 mL) sequentially. Stir overnight at room temperature. Add water (75 mL) to the system and adjust the pH to neutral with saturated ammonium chloride solution. Wash the solution with ethyl acetate (75 mL × 3). Combine the organic phases and wash them sequentially with water (75 mL × 3) and saturated brine (75 mL × 3). Dry the organic phase with anhydrous magnesium sulfate and filter. Concentrate the filtrate, and separate the crude product by silica gel column chromatography (100% petroleum ether) to obtain compound A-2a (yellow oil, 4.2 g), which can be used directly in the next step.

[0101] Step 2: Into a 500 mL round-bottom flask, was added A-2a (4.2 g, 14 mmol, 1.2 eq), 2,6-dichloro-4-bromoaniline (2.8 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL) under nitrogen atmosphere. The reaction mixture was heated to 110 °C and stirred for 24 h. The reaction mixture was concentrated by rotary evaporation. The crude product was purified by column chromatography on silica gel (100% petroleum ether) to give compound A-3a (white solid, 3.2 g), which was used directly in the next step.

[0102] Step 3: Into a 25 mL round-bottom flask, was added compound A-3a (419 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL) under nitrogen atmosphere. The reaction mixture was heated to 100 °C and stirred overnight. The reaction mixture was concentrated by rotary evaporation. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5:1) to give compound A-4a-1 (white solid, 200 mg), which was used directly in the next step.

[0103] Step 4: Into a 25 mL round-bottom flask, was added compound A-4a-1 (200 mg, 0.49 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3.2 mL / 6.4 mL), was added lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.6 mL). The reaction mixture was heated to 45 °C and stirred overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R02 (white solid, 97 mg). LCMS: [M+H] = 407. + 1 H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.46-7.41 (m, 3H), 7.35 (d, J = 2.6 Hz, 1H), 6.90 (dd, J = 8.4, 2.6 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H).

[0104] Example 2: Synthesis of R29

[0105]

[0106] ​Step 1: In a 500 mL round-bottom flask, under nitrogen atmosphere, was added A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2-fluoro-6-methoxyaniline (2.6 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL), and the reaction was heated to 110 °C and stirred for 24 h. The reaction was concentrated by rotary evaporation, and the crude product was purified by column chromatography on silica gel (100% petroleum ether) to give compound A-3p (yellow solid, 2.6 g), which was used directly in the next step.

[0107] Step 2: In a 25 mL round-bottom flask, was added compound A-3p (398 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL), and the reaction was heated to 100 °C and stirred overnight under nitrogen atmosphere. The reaction was concentrated by rotary evaporation, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 3:1) to give compound A-4p-1 (yellow solid, 254 mg), which was used directly in the next step.

[0108] Step 3: In a 25 mL round-bottom flask, was added compound A-4p-1 (207 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), and a solution of lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added. The reaction was heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R29 (yellow solid, 119 mg).

[0109] LCMS: [M+H] + = 387; 1 H-NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.45 (d, J = 3.2

[0110] Hz,1H),6.90(dd,J=11.3,1.8Hz,1H),6.86–6.83(m,1H),6.70(dd,J=8.8,3.2Hz,1H ),6.29(dd,J=8.8,4.9Hz,1H),3.82(s,3H),3.66(s,3H),2.45(s,3H),2.28(s,3H).

[0111] Example 3: Synthesis of R35

[0112]

[0113] Step 1: In a 500 mL round-bottom flask under a nitrogen atmosphere, add A-2a (4.2 g, 14 mmol, 1.2 eq), 2,6-difluoro-4-bromoaniline (2.4 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), and toluene (117 mL) sequentially. Heat the reaction system to 110 °C and stir for 24 h. Concentrate by rotary evaporation. Separate the crude product by silica gel column chromatography (100% petroleum ether) to obtain compound A-3c (white solid, 3.4 g), which is used directly in the next step.

[0114] Step 2: In a 25 mL round-bottom flask, add compound A-3c (402 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boric acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), and dioxane / water (5 mL / 0.5 mL). Heat to 100 °C and stir overnight under a nitrogen atmosphere. Concentrate by rotary evaporation and separate by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound A-4c-1 (white solid, 183 mg), which can be used directly in the next step.

[0115] Step 3: Weigh 156 mg (0.38 mmol, 1.0 eq) of compound A-4c-1 from the previous step into a tetrahydrofuran / ethanol solution (2.4 mL / 4.8 mL), add a 1.2 mL solution of lithium hydroxide (44 mg, 1.85 mmol, 5.0 eq) in water, and heat to 45 °C with stirring overnight. Cool the reaction solution to room temperature, adjust the pH to 5-6 with dilute hydrochloric acid (2 M), concentrate under reduced pressure to dryness, and separate the crude product by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R35 (white solid, 88 mg). LCMS: [M+H] + =375;1 H-NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.36 - 7.24 (m, 2H), 7.09 (dd, J = 9.1, 3.1 Hz, 1H), 6.60 (dt, J = 9.1, 2.7 Hz, 1H), 3.73 (s, 3H), 2.46 (s, 3H), 2.28 (s, 3H).

[0116] Example 4: Synthesis of R36

[0117]

[0118] Step 1: Into a 500 mL round-bottom flask, was added A-2a (4.2 g, 14 mmol, 1.2 eq), 2,6-dimethyl-4-bromoaniline (2.3 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL) under nitrogen atmosphere, and heated to 110 °C with stirring for 24 h. Concentrated by rotary evaporation, and the crude product was separated by silica gel column chromatography (100% petroleum ether) to give compound A-3d (white solid, 3.2 g), which was used directly in the next step.

[0119] Step 2: Into a 25 mL round-bottom flask, was added compound A-3d (402 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL) under nitrogen atmosphere, and heated to 100 °C with stirring overnight. Concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound A-4d-1 (white solid, 174 mg), which was used directly in the next step.

[0120] Step 3: Into a 25 mL round-bottom flask, was added compound A-4d-1 (156 mg, 0.38 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2.4 mL / 4.8 mL), and lithium hydroxide (44 mg, 1.85 mmol, 5.0 eq) in water (1.2 mL) under nitrogen atmosphere, and heated to 45 °C with stirring overnight. The reaction solution was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R36 (white solid, 94 mg). LCMS: [M+H]+ = 367; 1 H-NMR (400MHz, DMSO-d6) δ 8.85 (s, 1H), 7.39 (d, J = 3.1 Hz, 1H), 7.17 (s, 2H), 6.98 (dd, J = 9.1, 3.1 Hz, 1H), 6.13 (d, J = 9.0 Hz, 1H), 3.69 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 2.16 (s, 6H).

[0121] Example 5: Synthesis of R37

[0122]

[0123] Step 1: In a 500 mL round-bottom flask, under nitrogen atmosphere, was added A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2-chloro-6-methylaniline (2.6 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL), and the reaction was heated to 110 °C and stirred for 24 h. Concentrated by rotary evaporation, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1) to give compound A-3e (white solid, 3.4 g), which was used directly in the next step.

[0124] Step 2: In a 25 mL round-bottom flask, was added compound A-3e (402 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL), and the reaction was heated to 100 °C and stirred overnight under nitrogen atmosphere. Concentrated by rotary evaporation, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound A-4e-1 (white solid, 174 mg), which was used directly in the next step.

[0125] Step 3: The compound from previous step A-4e-1 (156 mg, 0.38 mmol, 1.0 eq) was taken in tetrahydrofuran / ethanol (2.4 mL / 4.8 mL), lithium hydroxide (44 mg, 1.85 mmol, 5.0 eq) in water (1.2 mL) was added, heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R37 (white solid, 120 mg). LCMS: [M+H]=387. + 1 H-NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 9.0, 3.1 Hz, 1H), 6.21 (d, J = 9.0 Hz, 1H), 3.70 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H).

[0126] Example 6: Synthesis of R38

[0127]

[0128] Step 1: In a 500 mL round-bottom flask, under nitrogen atmosphere, A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2-fluoro-6-methylaniline (2.4 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL) were added sequentially, and the reaction system was heated to 110 °C and stirred for 24 h. Concentrated by rotary evaporation, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1) to give compound A-3f (white solid, 3.4 g), which was used directly in the next step.

[0129] ​Step 2: In a 25 mL round-bottom flask, compound A-3f (402 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2(73 mg, 0.1 mmol, 0.1 eq), K2CO3(276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL), nitrogen atmosphere, heated to 100 °C and stirred overnight. Concentrated by rotary evaporation, separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1), compound A-4f-1 (white solid, 174 mg) was obtained, which was used directly in the next step.

[0130] Step 3: Compound A-4f-1 (156 mg, 0.38 mmol, 1.0 eq) from the previous step was weighed into tetrahydrofuran / ethanol (2.4 mL / 4.8 mL), and a solution of lithium hydroxide (44 mg, 1.85 mmol, 5.0 eq) in water (1.2 mL) was added. The mixture was heated to 45 °C and stirred overnight. The reaction solution was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2M), concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20: 1) to obtain compound R38 (white solid, 134 mg). LCMS: [M+H]=371. + 1 H-NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.40 (d, J = 3.1 Hz, 1H), 7.26-7.17 (m, 2H), 7.04 (dd, J = 9.1, 3.1 Hz, 1H), 6.37 (dd, J = 9.1, 3.0 Hz, 1H), 3.71 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H).

[0131] Example 7: Synthesis of R39

[0132]

[0133] ​Step 1: Into a 500 mL round-bottom flask, A-2a (4.2 g, 14 mmol, 1.2 eq), 2-chloro-6-fluoro-4-bromoaniline (2.6 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL) were added successively under nitrogen atmosphere, and the reaction system was heated to 110 °C and stirred for 24 h. Concentration was performed by rotary evaporation, and the crude product was separated by silica gel column chromatography (100% petroleum ether) to give compound A-3b (white solid, 3.2 g), which was directly used in the next step.

[0134] Step 2: Into a 25 mL round-bottom flask, compound A-3b (402 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL) were added under nitrogen atmosphere, and the reaction system was heated to 100 °C and stirred overnight. Concentration was performed by rotary evaporation, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound A-4b-1 (white solid, 156 mg), which was directly used in the next step.

[0135] Step 3: Into a 25 mL round-bottom flask, compound A-4b-1 (156 mg, 0.38 mmol, 1.0 eq) was weighed into tetrahydrofuran / ethanol (2.4 mL / 4.8 mL), and a solution of lithium hydroxide (44 mg, 1.85 mmol, 5.0 eq) in water (1.2 mL) was added. The reaction system was heated to 45 °C and stirred overnight. The reaction solution was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R39 (white solid, 90 mg). LCMS: [M+H] = 391; + 1 H-NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.63 (dd, J = 10.3, 2.4 Hz, 1H), 7.34 (dd, J = 2.5, 1.3 Hz, 1H), 7.28 (d, J = 3.1 Hz, 1H), 6.96 (dd, J = 9.1, 3.1 Hz, 1H), 6.39 (dd, J = 9.1, 3.4 Hz, 1H), 3.68 (s, 3H), 2.22 (s, 3H), 2.00 (s, 3H).

[0136] Example 8: Synthesis of R40 ​

[0137]

[0138] Step 1: Into a 500 mL round-bottom flask, was added A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2-chloro-6-(trifluoromethyl)aniline (3.2 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL) under nitrogen atmosphere. The reaction mixture was heated to 110 °C and stirred for 24 h. Concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1) to give compound A-3g (white solid, 3.4 g), which was used directly in the next step.

[0139] Step 2: Into a 25 mL round-bottom flask, was added compound A-3g (402 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL) under nitrogen atmosphere. The reaction mixture was heated to 100 °C and stirred overnight. Concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound A-4g-1 (white solid, 175 mg), which was used directly in the next step.

[0140] Step 3: Into a 25 mL round-bottom flask, was added compound A-4g-1 (156 mg, 0.38 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2.4 mL / 4.8 mL), was added lithium hydroxide (44 mg, 1.85 mmol, 5.0 eq) in water (1.2 mL) under nitrogen atmosphere. The reaction mixture was heated to 45 °C and stirred overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R40 (white solid, 98 mg). LCMS: [M+H]=441; + 1 H-NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.03 (dd, J = 9.1, 3.1 Hz, 1H), 6.29 (d, J = 9.0 Hz, 1H), 3.72 (s, 3H), 2.46 (s, 3H), 2.28 (s, 3H).​

[0141] Example 9: Synthesis of R41

[0142]

[0143] Step 1: In a 500 mL round-bottom flask, under nitrogen atmosphere, was added A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2,6-diisopropylaniline (3.0 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL), and the reaction was heated to 110 °C and stirred for 24 h. Concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (100% petroleum ether) to give compound A-3h (white solid, 3.1 g), which was used directly in the next step.

[0144] Step 2: In a 25 mL round-bottom flask, was added compound A-3h (434 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL), and the reaction was heated to 100 °C and stirred overnight under nitrogen atmosphere. Concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound A-4h-1 (off-white solid 151 mg), which was used directly in the next step.

[0145] Step 3: The compound A-4h-1 (151 mg, 0.33 mmol, 1.0 eq) from the previous step was weighed into tetrahydrofuran / ethanol (2.4 mL / 4.8 mL), and a solution of lithium hydroxide (39.6 mg, 1.65 mmol, 5.0 eq) in water (1.2 mL) was added, and the reaction was heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R41 (white solid, 93 mg). LCMS: [M+H] = 423. + 1 ​H-NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.38 (d, J = 3.1 Hz, 1H), 7.23 (s, 2H), 6.99 (dd, J = 9.1, 3.1 Hz, 1H), 6.11 (d, J = 9.1 Hz, 1H), 3.68 (s, 3H), 3.05 (p, J = 6.9 Hz, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 1.14 (d, J = 6.8 Hz, 6H), 1.10 (d, J = 6.9 Hz, 6H).

[0146] Example 10: Synthesis of R44

[0147]

[0148] Step 1: In a 500 mL round-bottom flask, under nitrogen atmosphere, was added A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2,6-dimethoxyaniline (2.7 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL), and the reaction was heated to 110 °C and stirred for 24 h. Concentrated by rotary evaporation, and the crude product was separated by silica gel column chromatography (100% petroleum ether) to give compound A-3i (white solid, 3.1 g), which was used directly in the next step.

[0149] Step 2: In a 25 mL round-bottom flask, was added compound A-3i (410 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL), and the reaction was heated to 100 °C and stirred overnight under nitrogen atmosphere. Concentrated by rotary evaporation, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound A-4i-1 (white solid, 190 mg), which was used directly in the next step.

[0150] Step 3: Take the compound A-4i-1 (151 mg, 0.44 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2.4 mL / 4.8 mL), add lithium hydroxide (52.8 mg, 2.2 mmol, 5.0 eq) in water (1.2 mL), heat to 45 °C and stir overnight. Cool the reaction to room temperature, adjust to pH = 5-6 with dilute hydrochloric acid (2 M), concentrate to dryness under reduced pressure, and separate the crude product by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R44 (yellow solid, 92 mg). LCMS: [M+H]=399; + 1 H-NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.33 (d, J = 3.1 Hz, 1H), 6.97 (dd, J = 9.1, 3.1 Hz, 1H), 6.72 (s, 2H), 6.30 (d, J = 9.2 Hz, 1H), 3.78 (s, 6H), 3.69 (s, 3H), 2.47 (s, 3H), 2.30 (s, 3H).

[0151] Example 11: Synthesis of R114

[0152]

[0153] Step 1: In a 500 mL round-bottom flask, under a nitrogen atmosphere, add A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2-ethyl-6-methyl-aniline (2.5 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL), heat to 110 °C and stir for 24 h. Concentrate under reduced pressure, and separate the crude product by column chromatography on silica gel (100% petroleum ether) to obtain compound A-3n (white solid, 2.3 g), which is used directly in the next step.

[0154] Step 2: In a 25 mL round-bottom flask, add compound A-3n (392 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL), under a nitrogen atmosphere, heat to 100 °C and stir overnight. Concentrate under reduced pressure, and separate the crude product by column chromatography on silica gel (petroleum ether: ethyl acetate = 4:1) to obtain compound A-4n-1 (white solid, 208 mg), which is used directly in the next step.​

[0155] Step 3: The compound A-4n-1 (208 mg, 0.51 mmol, 1.0 eq) from previous step was taken in tetrahydrofuran / ethanol (2.4 mL / 4.8 mL), lithium hydroxide (62.4 mg, 2.6 mmol, 5.0 eq) in water (1.2 mL) was added, heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R114 (white solid, 87 mg). LCMS: [M+H] + = 381; 1 H-NMR (500 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.39 (d, J = 3.1 Hz, 1H), 7.22 - 7.13 (m, 2H), 6.98 (dd, J = 9.1, 3.1 Hz, 1H), 6.12 (d, J = 9.1 Hz, 1H), 3.69 (s, 4H), 2.53 (d, J = 7.5 Hz, 2H), 2.43 (s, 3H), 2.26 (s, 3H), 2.14 (s, 3H), 1.09 (t, J = 7.5 Hz, 3H).

[0156] Example 12: Synthesis of R116

[0157]

[0158] Step 1: In a 500 mL round-bottom flask, under a nitrogen atmosphere, A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2-isopropyl-6-methyl-aniline (2.7 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL) were added sequentially, and the reaction system was heated to 110 °C and stirred for 24 h. Concentration by rotary evaporation was performed, and the crude product was separated by column chromatography on silica gel (100% petroleum ether) to give compound A-3o (white solid, 1.9 g), which was used directly in the next step.

[0159] Step 2: In a 25 mL round-bottom flask, compound A-3o (406 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2(73 mg, 0.1 mmol, 0.1 eq), K2CO3(276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL), nitrogen atmosphere, heated to 100 °C and stirred overnight. Concentrated by rotary evaporation, separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1), compound A-4o-1 (brown solid, 169 mg) was obtained, which was used directly in the next step.

[0160] Step 3: Compound A-4o-1 (169 mg, 0.40 mmol, 1.0 eq) from the previous step was weighed into tetrahydrofuran / ethanol (2.4 mL / 4.8 mL), and a solution of lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.2 mL) was added. The mixture was heated to 45 °C and stirred overnight. The reaction solution was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2M), concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20: 1) to obtain compound R116 (yellow solid, 79 mg). LCMS: [M+H]=395; + 1 H-NMR (500 MHz, DMSO-d6) δ 8.91 (s, 1H), 7.38 (d, J = 3.1 Hz, 1H), 7.26-7.14 (m, 2H), 6.98 (dd, J = 9.1, 3.1 Hz, 1H), 6.11 (d, J = 9.1 Hz, 1H), 3.69 (s, 3H), 3.09 (p, J = 6.9 Hz, 1H), 2.44 (s, 3H), 2.27 (s, 3H), 2.13 (s, 3H), 1.13 (dd, J = 22.0, 6.9 Hz, 7H).

[0161] Example 13: Synthesis of R27

[0162]

[0163] ​Step 1: Into a 500 mL round-bottom flask, was added A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2,6-dicyclopropylphenylamine (2.9 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL) under nitrogen atmosphere. The reaction mixture was heated to 110 °C and stirred for 24 h. Concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (100% petroleum ether) to give compound A-3q (yellow solid, 2.5 g), which was used directly in the next step.

[0164] Step 2: Into a 25 mL round-bottom flask, was added compound A-3q (430 mg, 1.0 mmol, 1.0 eq), 3,5-dimethyl-lH-pyrazole-4-boronic acid (210 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL) under nitrogen atmosphere. The reaction mixture was heated to 100 °C and stirred overnight. Concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give compound A-4q-2 (yellow solid, 228 mg), which was used directly in the next step.

[0165] Step 3: Into a 25 mL round-bottom flask, was added compound A-4q-2 (223 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), was added lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) under nitrogen atmosphere. The reaction mixture was heated to 45 °C and stirred overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R27 (yellow solid, 112 mg). LCMS: [M+H] = 418. + 1 H-NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.38 (d, J = 3.1 Hz, 1H), 7.01 (dd, J = 9.1, 3.1 Hz, 1H), 6.67 (s, 2H), 6.35 (d, J = 9.1 Hz, 1H), 3.69 (s, 4H), 2.26 (s, 6H), 1.88 (tt, J = 8.5, 5.3 Hz, 2H), 0.83 (d, J = 34.7 Hz, 4H), 0.63 (d, J = 37.8 Hz, 4H).

[0166] Example 14: Synthesis of R32​

[0167]

[0168] Step 1: Into a 500 mL round-bottom flask, was added A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2-ethyl-6-methylaniline (2.5 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL) under nitrogen atmosphere. The reaction mixture was heated to 110 °C and stirred for 24 h. Concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography (100% petroleum ether) to give compound A-3n (yellow solid, 3.1 g), which was used directly in the next step.

[0169] Step 2: Into a 25 mL round-bottom flask, was added compound A-3n (392 mg, 1.0 mmol, 1.0 eq), 3,5-dimethyl-lH-pyrazole-4-boronic acid (210 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL) under nitrogen atmosphere. The reaction mixture was heated to 100 °C and stirred overnight. Concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give compound A-4n-2 (yellow solid, 278 mg), which was used directly in the next step.

[0170] Step 3: Into a 25 mL round-bottom flask, was added compound A-4n-2 (204 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), was added lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL). The reaction mixture was heated to 45 °C and stirred overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R32 (yellow solid, 145 mg). LCMS: [M+H] = 380; + 1 H-NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.38 (d, J = 3.1 Hz, 1H), 7.07 (q, J = 2.2 Hz, 2H), 6.97 (dd, J = 9.1, 3.1 Hz, 1H), 6.12 (d, J = 9.1 Hz, 1H), 3.68 (s, 3H), 2.22 (s, 6H), 2.12 (s, 3H), 1.08 (t, J = 7.5 Hz, 3H).​

[0171] Example 15: Synthesis of R33

[0172]

[0173] Step 1: In a 500 mL round-bottom flask, under nitrogen atmosphere, was added A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2-cyclopropyl-6-fluoroaniline (2.7 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL), and the reaction was heated to 110 °C and stirred for 24 h. Concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (100% petroleum ether) to give compound A-3k (yellow solid, 2.5 g), which was used directly in the next step.

[0174] Step 2: In a 25 mL round-bottom flask, was added compound A-3k (408 mg, 1.0 mmol, 1.0 eq), 3,5-dimethyl-lH-pyrazole-4-boronic acid (210 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL), and the reaction was heated to 100 °C and stirred overnight under nitrogen atmosphere. Concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to give compound A-4k-2 (brown solid, 264 mg), which was used directly in the next step.

[0175] Step 3: The compound A-4k-2 (212 mg, 0.5 mmol, 1.0 eq) from the previous step was weighed into tetrahydrofuran / ethanol (3 mL / 6 mL), and a solution of lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added. The reaction was heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20: 1) to give compound R33 (brown solid, 101 mg). LCMS: [M+H] = 396. + 1 ​H-NMR (400 MHz, DMSO-d6) δ 9.34 - 8.97 (m, 1H), 7.39 (s, 1H), 7.03 (td, J = 7.2, 2.9 Hz, 2H), 6.67 (d, J = 1.8 Hz, 1H), 6.45 (d, J = 9.2 Hz, 1H), 3.70 (s, 4H), 2.21 (s, 7H), 1.93 (s, 1H), 1.01 - 0.85 (m, 2H), 0.77 - 0.59 (m, 2H).

[0176] Example 16: Synthesis of R55

[0177]

[0178] Step 1: In a 500 mL round-bottom flask, under nitrogen atmosphere, was added A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2-chloro-6-methoxyaniline (2.8 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL), and the reaction was heated to 110 °C and stirred for 24 h. Concentrated by rotary evaporation, and the crude product was separated by silica gel column chromatography (100% petroleum ether) to give compound A-3j (white solid, 3.1 g), which was used directly in the next step.

[0179] Step 2: In a 25 mL round-bottom flask, was added compound A-3j (410 mg, 1.0 mmol, 1.0 eq), 3,5-dimethyl-lH-pyrazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL), and the reaction was heated to 100 °C and stirred overnight under nitrogen atmosphere. Concentrated by rotary evaporation, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1) to give compound A-4j-2 (brown solid 190 mg), which was used directly in the next step.

[0180] Step 3: Take the compound A-4j-2 (190 mg, 0.44 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2.4 mL / 4.8 mL), add lithium hydroxide (52.8 mg, 2.2 mmol, 5.0 eq) in water (1.2 mL), heat to 45 °C and stir overnight. Cool the reaction to room temperature, adjust to pH = 5-6 with dilute hydrochloric acid (2 M), concentrate to dryness under reduced pressure, and separate the crude product by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R55 (yellow solid, 132 mg). LCMS: [M+H] = 402. + 1 H-NMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.10 (dd, J = 9.8, 5.4 Hz, 1H), 7.01 (dd, J = 9.0, 3.2 Hz, 2H), 6.31 (dd, J = 9.2, 1.1 Hz, 1H), 3.79 (s, 3H), 3.70 (s, 3H), 2.41 - 2.21 (m, 6H).

[0181] Example 17: Synthesis of R96

[0182]

[0183] Step 1: In a 500 mL round-bottom flask, under a nitrogen atmosphere, add A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2,6-diethylaniline (2.7 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL) sequentially, and heat the reaction system to 110 °C and stir for 24 h. Concentrate by rotary evaporation, and separate the crude product by silica gel column chromatography (100% petroleum ether) to obtain compound A-3m (white solid, 2.4 g), which is directly used in the next step.

[0184] ​Step 2: In a 25 mL round-bottom flask, compound A-3m (406 mg, 1.0 mmol, 1.0 eq), 3,5-dimethyl-lH-pyrazole-4-boronic acid (210 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2(73 mg, 0.1 mmol, 0.1 eq), K2CO3(276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL), nitrogen atmosphere, heated to 100 °C and stirred overnight. Concentrated by rotary evaporation, separated by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1), compound A-4m-2 (yellow solid, 197 mg) was obtained, which was used directly in the next step.

[0185] Step 3: Compound A-4m-2 (197 mg, 0.47 mmol, 1.0 eq) from the previous step was weighed into tetrahydrofuran / ethanol (2.4 mL / 4.8 mL), and a solution of lithium hydroxide (57.6 mg, 2.4 mmol, 5.0 eq) in water (1.2 mL) was added. The mixture was heated to 45 °C and stirred overnight. The reaction solution was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20: 1) to obtain compound R96 (yellow solid, 75 mg). LCMS: [M+H]=394. + 1 H-NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.09 (s, 2H), 6.97 (dd, J = 9.1, 3.2 Hz, 1H), 6.13 (d, J = 9.1 Hz, 1H), 3.68 (s, 3H), 2.49-2.44 (m, 3H), 2.23 (s, 6H), 1.08 (t, J = 7.6 Hz, 6H).

[0186] Example 18: Synthesis of R31

[0187]

[0188] ​Step 1: Into a 500 mL round-bottom flask, was added A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-3-chloro-2,6-dimethylaniline (2.7 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL) under nitrogen atmosphere. The reaction mixture was heated to 110 °C and stirred for 24 h. The reaction mixture was concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography (100% petroleum ether) to give compound A-3r (yellow solid, 2.9 g), which was used directly in the next step.

[0189] Step 2: Into a 25 mL round-bottom flask, was added compound A-3r (413 mg, 1.0 mmol, 1.0 eq), pyridine-4-boronic acid (185 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL) under nitrogen atmosphere. The reaction mixture was heated to 100 °C and stirred overnight. The reaction mixture was concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound A-4r-4 (yellow solid, 267 mg), which was used directly in the next step.

[0190] Step 3: Into a 25 mL round-bottom flask, was added compound A-4r-4 (206 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), was added lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) under nitrogen atmosphere. The reaction mixture was heated to 45 °C and stirred overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R31 (yellow solid, 122 mg). LCMS: [M+H]=383. + 1 H-NMR (500 MHz, DMSO-d6) δ 8.69-8.61 (m, 2H), 7.50 (dt, J = 5.3, 2.9 Hz, 1H), 7.49-7.43 (m, 2H), 7.22 (s, 1H), 6.75-6.66 (m, 1H), 6.01-5.90 (m, 1H), 3.66 (s, 4H), 2.25 (s, 3H), 2.17 (s, 3H).

[0191] Example 19: Synthesis of R61

[0192] ​

[0193] Step 1: Into a 500 mL round-bottom flask, A-2a (4.2 g, 14 mmol, 1.2 eq), 4-bromo-2,6-dichloroaniline (2.8 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL) were added successively under nitrogen atmosphere, and the reaction system was heated to 110 °C and stirred for 24 h. Concentration by rotary evaporation was performed, and the crude product was separated by silica gel column chromatography (100% petroleum ether) to obtain compound A-3a (yellow solid, 2.9 g), which was directly used in the next step.

[0194] Step 2: Into a 25 mL round-bottom flask, compound A-3a (419 mg, 1.0 mmol, 1.0 eq), 2-ethoxypyridine-4-boronic acid (251 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 eq), K2CO3 (276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL) were added under nitrogen atmosphere, and the reaction system was heated to 100 °C and stirred overnight. Concentration by rotary evaporation was performed, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound A-4a-5 (brown solid, 268 mg), which was directly used in the next step.

[0195] Step 3: Into a 25 mL round-bottom flask, compound A-4a-5 (231 mg, 0.5 mmol, 1.0 eq) was weighed into tetrahydrofuran / ethanol (3 mL / 6 mL), and a lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) solution in water (1.5 mL) was added. The reaction system was heated to 45 °C and stirred overnight. The reaction solution was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R61 (brown solid, 123 mg). LCMS: [M+H] = 433. + 1 H-NMR (500 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.23 (d, J = 5.3 Hz, 1H), 8.05 (s, 2H), 7.44-7.38 (m, 2H), 7.23 (d, J = 1.6 Hz, 1H), 7.03 (dd, J = 9.0, 3.1 Hz, 1H), 6.32 (d, J = 9.0 Hz, 1H), 4.36 (q, J = 7.0 Hz, 2H), 3.72 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H).

[0196] ​Example 20: Synthesis of R82

[0197]

[0198] Step 1: In a 25 mL round-bottom flask, was added compound A-3a (419 mg, 1.0 mmol, 1.0 eq), 2,3-dichloropyridine-4-boronic acid (288 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2(73 mg, 0.1 mmol, 0.1 eq), K2CO3(276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL), and heated to 100 °C with stirring overnight in a nitrogen atmosphere. Concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound A-4a-6 (brown solid 278 mg), which was used directly in the next step.

[0199] Step 2: The compound A-4a-6 (243 mg, 0.5 mmol, 1.0 eq) from the previous step was weighed into tetrahydrofuran / ethanol (3 mL / 6 mL), and a solution of lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added, and heated to 45 °C with stirring overnight. The reaction solution was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R82 (brown solid 113 mg). LCMS: [M+H]=459. + 1 H-NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.46 (d, J = 4.9 Hz, 1H), 8.17 (s, 1H), 7.76 (s, 2H), 7.61 (d, J = 4.9 Hz, 1H), 7.56 (s, 1H), 7.31 (d, J = 2.9 Hz, 1H), 6.95 (dd, J = 9.0, 2.9 Hz, 1H), 6.33 (d, J = 8.9 Hz, 1H), 3.74 (s, 3H).

[0200] Example 21: Synthesis of R22

[0201]

[0202] ​Step 1: In a 25 mL round-bottom flask, compound A-3a (210 mg, 0.5 mmol, 1.0 eq), 2-methoxypyridine-4-boronic acid (92 mg, 0.6 mmol, 1.2 eq), Pd(dppf)Cl2(37 mg, 0.05 mmol, 0.1 eq), K2CO3(138 mg, 1.0 mmol, 2.0 eq), dioxane / water (2.5 mL / 0.25 mL, 10:1, v / v), nitrogen atmosphere, heated to 100 °C and stirred overnight. Concentrated by rotary evaporation, separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound A-4a-7 (white solid, 179 mg), which was used directly in the next step.

[0203] Step 2: Compound A-4a-7 (179 mg, 0.4 mmol, 1.0 eq) from the previous step was taken in tetrahydrofuran / ethanol (2.6 mL / 5.2 mL), and a solution of lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.3 mL) was added. The mixture was heated to 45 °C and stirred overnight. The reaction solution was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R22 (yellow solid, 145 mg). LCMS: [M+H] + = 419. 1 H-NMR (500 MHz, Chloroform-d) δ 8.55 (s, 1H), 8.29 (d, J = 4.7 Hz, 1H), 7.69 (s, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.38 - 7.33 (m, 2H), 6.90 (dt, J = 5.2, 2.7 Hz, 2H), 3.95 (s, 3H), 3.80 (s, 3H).

[0204] Example 22: Synthesis of R50

[0205]

[0206] In a 50 mL round-bottom flask, compound R39 (124 mg, 0.3 mmol, 1.0 eq), NH2O-THP (18 mg, 0.15 mmol, 0.5 eq), HOBT (49 mg, 0.36 mmol, 1.2 eq), EDCI (69 mg, 0.36 mmol, 1.2 eq), N,N-dimethylformamide (6 mL), room temperature stirring overnight. The reaction liquid precipitated solid, filtration, water washing (2 mL x 3), n-hexane washing (2 mL x 3), drying to get compound (white solid, 122 mg), directly used in the next step. In a 50 mL round-bottom flask, the product (122 mg, 0.25 mmol, 1.0 eq) of the previous step, trifluoroacetic acid (570 mg, 5 mmol, 20.0 eq), dichloromethane / methanol (1.3 mL / 1.3 mL), room temperature stirring overnight. The reaction liquid was directly filtered to obtain the target compound R50 (white solid, 37 mg). LCMS: [M+H] + = 406. 1 H-NMR (400 MHz, DMSO-d6) δ 9.94 - 9.88 (m, 2H), 8.84 (d, J = 3.8 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 2.7 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.15 (dd, J = 12.2, 2.1 Hz, 1H), 6.91 (dd, J = 8.4, 2.7 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H).

[0207] Example 23: Synthesis of R62

[0208]

[0209] Step 1: In a 500 mL round-bottom flask, under nitrogen atmosphere, B-1a (11.5 g, 50 mmol, 1.0 eq), cyclopropylboronic acid (6.5 g, 75 mmol, 1.5 eq), Pd(OAc)2 (1.1 g, 5 mmol, 0.1 eq), tricyclohexylphosphine (2.1 g, 7.5 mmol, 0.15 eq), K3PO4 (15.9 g, 75 mmol, 1.5 eq), toluene / water (250 mL / 25 mL), the reaction system was heated to 110°C and stirred for 24 h. Concentration by rotary evaporation, the crude product was separated by silica gel column chromatography (100% petroleum ether), to get compound B-2a (yellow oil, 7.6 g), directly used in the next step.

[0210] Step 2: In a 500 mL round-bottom flask, B-2a (7.6 g, 40 mmol, 4.0 eq) was weighed, water (56 mL) was added, concentrated hydrochloric acid (12 M, 56 mL) was added, and the solution was cooled in an ice water bath. A constant pressure dropping funnel was used to slowly add an aqueous solution of sodium nitrite (0.8 g, 12 mmol, 1.2 eq) (8 mL) dropwise. After the addition was complete, the solution was stirred at 0 °C for 30 min. A constant pressure dropping funnel was used to slowly add an aqueous solution of potassium iodide (5.0 g, 30 mmol, 3.0 eq) (20 mL) dropwise. After the addition was complete, the solution was warmed to 90 °C and stirred for 90 min. After the reaction was complete, the solution was washed with ethyl acetate (200 mL), the organic phases were combined, the organic phase was washed with saturated sodium bisulfite solution (200 mL), the organic phase was dried over anhydrous sodium sulfate, and the solution was filtered. The filtrate was concentrated, and the product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target B-3a (pink oil, 5.7 g), which was used directly in the next step.

[0211] Step 3: In a 50 mL round-bottom flask, B-3a (1.51 g, 5 mmol, 1.0 eq), 2,6-dichloro-4-bromoaniline (1.4 g, 6 mmol, 1.2 eq), Pd(OAc)2 (112 mg, 0.5 mmol, 0.1 eq), XantPhos (396 mg, 0.75 mmol, 0.15 eq), Cs2CO3 (2.44 g, 7.5 mmol, 1.5 eq), toluene (50 mL), were sequentially added under a nitrogen atmosphere. The reaction system was heated to 110 °C, and the reaction was allowed to proceed for 24 h. The solution was concentrated by rotary evaporation, and the product was separated by silica gel column chromatography (100% petroleum ether) to obtain compound B-4a (yellow solid, 2.2 g), which was used directly in the next step.

[0212] Step 4: In a 25 mL round-bottom flask, compound B-4a (208 mg, 0.5 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (85 mg, 0.6 mmol, 1.2 eq), Pd(dppf)Cl2 (37 mg, 0.05 mmol, 0.1 eq), K2CO3 (138 mg, 1.0 mmol, 2.0 eq), dioxane / water (2.5 mL / 0.25 mL, 10:1, v / v), were sequentially added under a nitrogen atmosphere. The solution was heated to 100 °C and stirred overnight. The solution was concentrated by rotary evaporation, and the product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound B-5a-1 (white solid, 184 mg), which was used directly in the next step.

[0213] Step 5: Take the compound B-5a-1 (172 mg, 0.4 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2.6 mL / 5.2 mL), add lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.3 mL), heat to 45 °C and stir overnight. Cool the reaction to room temperature, adjust to pH = 5-6 with dilute hydrochloric acid (2 M), concentrate to dryness under reduced pressure, and separate the crude product by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R62 (white solid, 78 mg). LCMS: [M+H] = 417. + 1 H-NMR (500 MHz, DMSO-d6) δ 9.39 (s, 1H), 7.65 (s, 2H), 7.64 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 8.6, 2.3 Hz, 1H), 6.26 (d, J = 8.6 Hz, 1H), 2.45 (s, 3H), 2.27 (s, 3H), 1.93-1.81 (m, 1H), 0.93-0.81 (m, 2H), 0.68-0.51 (m, 2H).

[0214] Example 24: Synthesis of R63

[0215]

[0216] In a 50 mL round-bottom flask, take compound R62 (125 mg, 0.3 mmol, 1.0 eq), NH2O-THP (18 mg, 0.15 mmol, 0.5 eq), HOBT (49 mg, 0.36 mmol, 1.2 eq), EDCI (69 mg, 0.36 mmol, 1.2 eq), N,N-dimethylformamide (6 mL), and stir at room temperature overnight. Precipitate the solid by adding ice to the reaction, filter, wash with water (2 mL x 3), wash with n-hexane (2 mL x 3), and dry to obtain the compound (white solid, 120 mg) for direct use in the next step. In a 50 mL round-bottom flask, take the product from the previous step (120 mg, 0.23 mmol, 1.0 eq), trifluoroacetic acid (524 mg, 4.6 mmol, 20.0 eq), dichloromethane / methanol (1.3 mL / 1.3 mL), and stir at room temperature overnight. Filter the reaction directly to obtain the target compound R63 (white solid, 45 mg). LCMS: [M+H] = 432. + 1 ​​H-NMR (400 MHz, DMSO-d6) δ 9.87 (d, J = 3.5 Hz, 1H), 9.16 (s, 1H), 7.80 (dd, J = 2.2, 0.7 Hz, 1H), 7.45 - 7.40 (m, 3H), 7.24 - 7.15 (m, 1H), 2.72 - 2.65 (m, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 1.65 (dd, J = 10.7, 5.6 Hz, 2H), 1.40 (dd, J = 10.7, 5.6 Hz, 2H).

[0217] Example 25: Synthesis of R71

[0218]

[0219] Step 1: In a 100 mL round-bottom flask, under nitrogen atmosphere, compound 2c (3.1 g, 15 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.5 g, 18 mmol, 1.2 eq), Pd(PPh3)4(3.5 g, 1.5 mmol, 0.1 eq), K3PO4(8.0 g, 30 mmol, 2.0 eq), toluene / water (40 mL / 20 mL) were added sequentially, and the reaction system was heated to 80 °C and stirred for 24 h. Concentration by rotary evaporation, silica gel column chromatography separation (petroleum ether: ethyl acetate = 10:1), compound M04 (white solid, 2.3 g) was obtained.

[0220] Step 2: In a 50 mL round-bottom flask, under nitrogen atmosphere, B-3a (1.5 g, 5 mmol, 1.0 eq), M04 (1.3 g, 6 mmol, 1.2 eq), Pd(OAc)2(112 mg, 0.5 mmol, 0.1 eq), XantPhos (396 mg, 0.75 mmol, 0.15 eq), Cs2CO3(2.44 g, 7.5 mmol, 1.5 eq), toluene (50 mL) were added sequentially, and the reaction system was heated to 110 °C and stirred for 24 h. Concentration by rotary evaporation, silica gel column chromatography separation (petroleum ether: ethyl acetate = 5:1), compound B-4c-1 (white solid, 1.7 g) was obtained, which was used directly in the next step.

[0221] Step 3: Take the compound B-4c-1 (159 mg, 0.4 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2.6 mL / 5.2 mL), add lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.3 mL), heat to 45 °C and stir overnight. Cool the reaction to room temperature, adjust to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrate to dryness under reduced pressure. Purify the crude product by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R71 (white solid, 100 mg). LCMS: [M+H]=385. + =385. 1 H-NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.46-7.41 (m, 3H), 7.35 (d, J = 2.6 Hz, 1H), 6.90 (dd, J = 8.4, 2.6 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H).

[0222] Example 26: Synthesis of R73

[0223]

[0224] Step 1: In a 100 mL round-bottom flask, under nitrogen protection, sequentially add compound 2d (3.0 g, 15 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.5 g, 18 mmol, 1.2 eq), Pd(PPh3)4 (3.5 g, 1.5 mmol, 0.1 eq), K3PO4 (8.0 g, 30 mmol, 2.0 eq), toluene / water (40 mL / 20 mL), heat the reaction system to 80 °C and stir for 24 h. Concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound M24 (white solid, 2.7 g).

[0225] Step 2: In a 50 mL round-bottom flask, under nitrogen atmosphere, sequentially add B-3a (1.5 g, 5 mmol, 1.0 eq), M24 (1.3 g, 6 mmol, 1.2 eq), Pd(OAc)2 (112 mg, 0.5 mmol, 0.1 eq), XantPhos (396 mg, 0.75 mmol, 0.15 eq), Cs2CO3 (2.44 g, 7.5 mmol, 1.5 eq), toluene (50 mL), heat the reaction system to 110 °C and react for 24 h. Concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound B-4d-1 (white solid, 1.9 g), which is used directly in the next step.

[0226] Step 3: Take the compound B-4d-1 (159 mg, 0.4 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2.6 mL / 5.2 mL), add lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.3 mL), heat to 45 °C and stir overnight. Cool the reaction to room temperature, adjust to pH = 5-6 with dilute hydrochloric acid (2 M), concentrate to dryness under reduced pressure, and separate the crude product by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R73 (white solid, 134 mg). LCMS: [M+H] + = 377. 1 H-NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.46-7.41 (m, 3H), 7.35 (d, J = 2.6 Hz, 1H), 6.90 (dd, J = 8.4, 2.6 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H).

[0227] Example 27: Synthesis of R79

[0228]

[0229] Step 1: In a 100 mL round-bottom flask, under nitrogen protection, sequentially add compound 2m (3.0 g, 15 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.5 g, 18 mmol, 1.2 eq), Pd(PPh3)4 (3.5 g, 1.5 mmol, 0.1 eq), K3PO4 (8.0 g, 30 mmol, 2.0 eq), toluene / water (40 mL / 20 mL), heat the reaction system to 80 °C and stir for 24 h. Concentrate under reduced pressure, separate by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound M05 (white solid, 2.7 g).

[0230] Step 2: In a 50 mL round-bottom flask, under nitrogen atmosphere, sequentially add B-3a (1.5 g, 5 mmol, 1.0 eq), M05 (1.3 g, 6 mmol, 1.2 eq), Pd(OAc)2 (112 mg, 0.5 mmol, 0.1 eq), XantPhos (396 mg, 0.75 mmol, 0.15 eq), Cs2CO3 (2.44 g, 7.5 mmol, 1.5 eq), toluene (50 mL), heat the reaction system to 110 °C, react for 24 h, concentrate under reduced pressure, separate by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound B-4m-1 (white solid, 1.9 g), which is directly used in the next step.

[0231] Step 3: Take the compound B-4m-1 (167 mg, 0.4 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2.6 mL / 5.2 mL), add lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.3 mL), heat to 45 °C and stir overnight. Cool the reaction to room temperature, adjust to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrate to dryness under reduced pressure. Purify the crude product by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R79 (white solid, 149 mg). LCMS: [M+H]=405. + =405. 1 H-NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.46-7.41 (m, 3H), 7.35 (d, J = 2.6 Hz, 1H), 6.90 (dd, J = 8.4, 2.6 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H).

[0232] Example 28: Synthesis of R81

[0233]

[0234] Step 1: In a 100 mL round-bottom flask, under nitrogen protection, sequentially add compound 2q (3.8 g, 15 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.5 g, 18 mmol, 1.2 eq), Pd(PPh3)4 (3.5 g, 1.5 mmol, 0.1 eq), K3PO4 (8.0 g, 30 mmol, 2.0 eq), toluene / water (40 mL / 20 mL), heat the reaction system to 80 °C and stir for 24 h. Concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound M25 (white solid, 2.7 g).

[0235] Step 2: In a 50 mL round-bottom flask, under nitrogen atmosphere, sequentially add B-3a (1.5 g, 5 mmol, 1.0 eq), M25 (1.6 g, 6 mmol, 1.2 eq), Pd(OAc)2 (112 mg, 0.5 mmol, 0.1 eq), XantPhos (396 mg, 0.75 mmol, 0.15 eq), Cs2CO3 (2.44 g, 7.5 mmol, 1.5 eq), toluene (50 mL), heat the reaction system to 110 °C and react for 24 h. Concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound B-4q-1 (white solid, 1.9 g), which is used directly in the next step.

[0236] Step 3: Take the compound B-4q-1 (177 mg, 0.4 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2.6 mL / 5.2 mL), add lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.3 mL), heat to 45 °C and stir overnight. Cool the reaction to room temperature, adjust to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrate to dryness under reduced pressure. Purify the crude product by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R81 (white solid, 158 mg). LCMS: [M+H] = 429. + = 429. 1 H-NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.46-7.41 (m, 3H), 7.35 (d, J = 2.6 Hz, 1H), 6.90 (dd, J = 8.4, 2.6 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H).

[0237] Example 29: Synthesis of R86

[0238]

[0239] Step 1: In a 100 mL round-bottom flask, under nitrogen protection, sequentially add compound 2f (3.1 g, 15 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.5 g, 18 mmol, 1.2 eq), Pd(PPh3)4 (3.5 g, 1.5 mmol, 0.1 eq), K3PO4 (8.0 g, 30 mmol, 2.0 eq), toluene / water (40 mL / 20 mL), heat the reaction system to 80 °C and stir for 24 h. Concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound M26 (white solid, 2.8 g).

[0240] Step 2: In a 50 mL round-bottom flask, under nitrogen atmosphere, sequentially add B-3a (1.5 g, 5 mmol, 1.0 eq), M26 (1.3 g, 6 mmol, 1.2 eq), Pd(OAc)2 (112 mg, 0.5 mmol, 0.1 eq), XantPhos (396 mg, 0.75 mmol, 0.15 eq), Cs2CO3 (2.44 g, 7.5 mmol, 1.5 eq), toluene (50 mL), heat the reaction system to 110 °C and react for 24 h. Concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound B-4f-1 (white solid, 1.6 g), which is directly used in the next step.

[0241] Step 3: The compound B-4f-1 (158 mg, 0.4 mmol, 1.0 eq) from previous step was taken in tetrahydrofuran / ethanol (2.6 mL / 5.2 mL), lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.3 mL) was added, heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R86 (white solid, 158 mg).

[0242] LCMS: [M+H] + = 381. 1 H-NMR (400 MHz, DMSO-d6) δ 9.87 (d, J = 3.5 Hz, 1H), 9.15 (d, J = 3.8 Hz, 1H), 7.80 (dd, J = 2.2, 0.7 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.23 - 7.17 (m, 1H), 7.11 (d, J = 2.2 Hz, 1H), 7.08 (dd, J = 12.0, 2.1 Hz, 1H), 2.73 - 2.65 (m, 1H), 2.41 (d, J = 10.3 Hz, 5H), 1.65 (dd, J = 10.7, 5.6 Hz, 2H), 1.40 (dd, J = 10.7, 5.6 Hz, 2H).

[0243] Example 30: Synthesis of R87

[0244]

[0245] Step 1: In a 25 mL round-bottom flask, compound R62 (83 mg, 0.2 mmol, 1.0 eq), HATU (114 mg, 0.3 mmol, 1.5 eq), N,N-dimethylformamide (2 mL) were added, stirred at room temperature for 5 min, then diisopropylethylamine (77 mg, 0.6 mmol, 3.0 eq), ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were added, heated to 45 °C, and stirred for 16 h. The reaction was quickly passed through a reverse-phase column (water:acetonitrile = 1:13) to give the target compound R87 (white solid, 64 mg). LCMS: [M+H] + = 416; 1H-NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.11 (s, 1H), 7.61 (s, 2H), 7.45 (s, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 8.7, 2.1 Hz, 1H), 6.24 (d, J = 8.4 Hz, 1H), 2.45 (s, 3H), 2.27 (s, 3H), 1.86 - 1.77 (m, 1H), 0.92 - 0.81 (m, 2H), 0.65 (dt, J = 6.5, 3.2 Hz, 2H).

[0246] Example 31: Synthesis of R90

[0247]

[0248] Step 1: In a 100 mL round-bottom flask, under nitrogen atmosphere, compound 2s (4.4 g, 15 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.5 g, 18 mmol, 1.2 eq), Pd(PPh3)4(3.5 g, 1.5 mmol, 0.1 eq), K3PO4(8.0 g, 30 mmol, 2.0 eq), toluene / water (40 mL / 20 mL) were added successively, and the reaction system was heated to 80 °C and stirred for 24 h. Concentration by rotary evaporation, silica gel column chromatography separation (petroleum ether: ethyl acetate = 10:1), compound M15 (white solid, 3.9 g) was obtained.

[0249] Step 2: In a 50 mL round-bottom flask, under nitrogen atmosphere, B-3a (1.5 g, 5 mmol, 1.0 eq), M15 (1.8 g, 6 mmol, 1.2 eq), Pd(OAc)2(112 mg, 0.5 mmol, 0.1 eq), XantPhos (396 mg, 0.75 mmol, 0.15 eq), Cs2CO3(2.44 g, 7.5 mmol, 1.5 eq), toluene (50 mL) were added successively, and the reaction system was heated to 110 °C and reacted for 24 h. Concentration by rotary evaporation, silica gel column chromatography separation (petroleum ether: ethyl acetate = 5:1), compound B-4s-1 (white solid, 1.9 g) was obtained, which was directly used in the next step.

[0250] Step 3: Take the compound B-4s-1 (192 mg, 0.4 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2.6 mL / 5.2 mL), add lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.3 mL), heat to 45 °C and stir overnight. Cool the reaction to room temperature, adjust to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrate to dryness under reduced pressure. Purify the crude product by column chromatography (dichloromethane:methanol = 20:1) to give compound R90 (white solid, 174 mg). LCMS: [M+H] + = 467. 1 H-NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.46-7.41 (m, 3H), 7.35 (d, J = 2.6 Hz, 1H), 6.90 (dd, J = 8.4, 2.6 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H).

[0251] Example 32: Synthesis of R218

[0252]

[0253] Step 1: In a 50 mL round-bottom flask, under a nitrogen atmosphere, add B-3a (1.51 g, 5 mmol, 1.0 eq), 4-bromo-2-fluoro-6-methoxyaniline (1.3 g, 6 mmol, 1.2 eq), Pd(OAc)2 (112 mg, 0.5 mmol, 0.1 eq), XantPhos (396 mg, 0.75 mmol, 0.15 eq), Cs2CO3 (2.44 g, 7.5 mmol, 1.5 eq), toluene (50 mL), and heat the reaction to 110 °C for 24 h. Concentrate under reduced pressure, and purify the crude product by column chromatography on silica gel (100% petroleum ether) to give compound B-4p (yellow solid, 2.4 g), which is used directly in the next step.

[0254] Step 2: In a 25 mL round-bottom flask, take compound B-4p (197 mg, 0.5 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (85 mg, 0.6 mmol, 1.2 eq), Pd(dppf)Cl2 (37 mg, 0.05 mmol, 0.1 eq), K2CO3 (138 mg, 1.0 mmol, 2.0 eq), dioxane / water (2.5 mL / 0.25 mL, 10:1, v / v), and heat to 100 °C under stirring overnight in a nitrogen atmosphere. Concentrate under reduced pressure, and purify the crude product by column chromatography on silica gel (petroleum ether:ethyl acetate = 10:1) to give compound B-5p-1 (white solid, 164 mg), which is used directly in the next step.

[0255] Step 3: Take the compound B-5p-1 (164 mg, 0.4 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2.6 mL / 5.2 mL), add lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.3 mL), heat to 45 °C and stir overnight. Cool the reaction to room temperature, adjust to pH = 5-6 with dilute hydrochloric acid (2 M), concentrate to dryness under reduced pressure, and separate the crude product by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R218 (white solid, 143 mg). LCMS: [M+H] + = 397; 1 H-NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.07 (dd, J = 8.6, 2.3 Hz, 1H), 6.98 (dd, J = 11.0, 1.8 Hz, 1H), 6.93 (d, J = 1.7 Hz, 1H), 6.40 (dd, J = 8.6, 4.2 Hz, 1H), 3.84 (s, 3H), 2.46 (s, 3H), 2.29 (s, 3H), 1.85 (s, 1H), 0.93 - 0.81 (m, 2H), 0.55 (dd, J = 5.0, 1.9 Hz, 2H).

[0256] Example 33: Synthesis of R64

[0257]

[0258] Step 1: In a 25 mL round-bottom flask, take compound B-4b (199 mg, 0.5 mmol, 1.0 eq), 3,5-dimethyl-lH-pyrazole-4-boronic acid (84 mg, 0.6 mmol, 1.2 eq), Pd(dppf)Cl2(37 mg, 0.05 mmol, 0.1 eq), K2CO3(138 mg, 1.0 mmol, 2.0 eq), dioxane / water (2.5 mL / 0.25 mL, 10:1, v / v), under nitrogen atmosphere, heat to 100 °C and stir overnight. Concentrate by rotary evaporation, and separate the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound B-5b-2 (white solid, 166 mg), which is directly used in the next step.

[0259] Step 2: Compound B-5b-2 (166 mg, 0.4 mmol, 1.0 eq) was weighed into tetrahydrofuran / ethanol (2.6 mL / 5.2 mL), and a solution of lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.3 mL) was added. The mixture was heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R64 (white solid, 135 mg). LCMS: [M+H] = 400. + 1 H-NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.46-7.41 (m, 3H), 7.35 (d, J = 2.6 Hz, 1H), 6.90 (dd, J = 8.4, 2.6 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H).

[0260] Example 34: Synthesis of R65

[0261]

[0262] In a 25 mL round-bottom flask, compound R64 (80 mg, 0.2 mmol, 1.0 eq), HATU (114 mg, 0.3 mmol, 1.5 eq), N,N-dimethylformamide (2 mL) were stirred at room temperature for 5 min, then diisopropylethylamine (77 mg, 0.6 mmol, 3.0 eq), ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were added, heated to 45 °C, and stirred for 16 h. The reaction was quickly passed through a reversed-phase column (water:acetonitrile = 1:13) to give the target compound R65 (white solid, 64 mg). LCMS: [M+H] = 399. + 1 H-NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.46-7.41 (m, 3H), 7.35 (d, J = 2.6 Hz, 1H), 6.90 (dd, J = 8.4, 2.6 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H).

[0263] Example 35: Synthesis of R66

[0264]

[0265] ​​In a 50 mL round-bottom flask, compound R64 (120 mg, 0.3 mmol, 1.0 eq), NH2O-THP (18 mg, 0.15 mmol, 0.5 eq), HOBT (49 mg, 0.36 mmol, 1.2 eq), EDCI (69 mg, 0.36 mmol, 1.2 eq), N,N-dimethylformamide (6 mL), stirred at room temperature overnight. The reaction solution was precipitated with ice to obtain solid, filtered, washed with water (2 mL x 3), washed with n-hexane (2 mL x 3), and dried to obtain compound (white solid, 104 mg), which was directly used in the next step. In a 50 mL round-bottom flask, the product of the previous step (104 mg, 0.21 mmol, 1.0 eq), trifluoroacetic acid (479 mg, 4.2 mmol, 20.0 eq), dichloromethane / methanol (1.3 mL / 1.3 mL), stirred at room temperature overnight. The reaction solution was directly filtered to obtain the target compound R66 (white solid, 55 mg). LCMS: [M+H] = 415. + 1 H-NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.46-7.41 (m, 3H), 7.35 (d, J = 2.6 Hz, 1H), 6.90 (dd, J = 8.4, 2.6 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H).

[0266] Example 36: Synthesis of R74

[0267]

[0268] Step 1: In a 25 mL round-bottom flask, compound B-4b (199 mg, 0.5 mmol, 1.0 eq), 2-hydroxypyridine-4-boronic acid (83 mg, 0.6 mmol, 1.2 eq), Pd(dppf)Cl2(37 mg, 0.05 mmol, 0.1 eq), K2CO3(138 mg, 1.0 mmol, 2.0 eq), dioxane / water (2.5 mL / 0.25 mL, 10:1, v / v), stirred at 100 °C overnight under nitrogen atmosphere. Concentrated by rotary evaporation, separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1), to obtain compound B-5b-8 (white solid, 166 mg), which was directly used in the next step.

[0269] ​Step 2: The compound B-5b-8 (172 mg, 0.4 mmol, 1.0 eq) from previous step was taken in tetrahydrofuran / ethanol (2.6 mL / 5.2 mL), lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.3 mL) was added, and heated to 45 °C with stirring overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R74 (yellow solid, 138 mg). LCMS: [M+H] = 415. + 1 H-NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.46-7.41 (m, 3H), 7.35 (d, J = 2.6 Hz, 1H), 6.90 (dd, J = 8.4, 2.6 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H).

[0270] Example 37: Synthesis of R127

[0271]

[0272] Step 1: In a 25 mL round-bottom flask, compound B-4b (199 mg, 0.5 mmol, 1.0 eq), pyridine-4-boronic acid (74 mg, 0.6 mmol, 1.2 eq), Pd(dppf)Cl2(37 mg, 0.05 mmol, 0.1 eq), K2CO3(138 mg, 1.0 mmol, 2.0 eq), dioxane / water (2.5 mL / 0.25 mL, 10:1, v / v) were taken in nitrogen atmosphere, heated to 100 °C with stirring overnight. Concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound B-5b-4 (white solid, 166 mg), which was used directly in the next step.

[0273] Step 2: The compound B-5b-4 (165 mg, 0.4 mmol, 1.0 eq) from previous step was taken in tetrahydrofuran / ethanol (2.6 mL / 5.2 mL), lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.3 mL) was added, and heated to 45 °C with stirring overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R127 (yellow solid, 145 mg). LCMS: [M+H] = 399; + 1 ​​H-NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.72-8.60 (m, 3H), 8.08 (s, 3H), 7.90-7.80 (m, 3H), 7.64 (d, J = 2.3 Hz, 1H), 7.07 (dd, J = 8.6, 2.3 Hz, 1H), 6.24 (d, J = 8.5 Hz, 1H), 1.86 (s, 1H), 0.93-0.82 (m, 3H), 0.63-0.47 (m, 3H).

[0274] Example 38: Synthesis of R77

[0275]

[0276] Step 1: In a 250 mL round-bottom flask, C-la (5.0 g, 15 mmol, 1.0 eq), K2CO3 (2.1 g, 15 mmol, 1.0 eq), diethyl sulfate (2.3 g, 15 mmol, 1.0 eq), N,N-dimethylformamide (75 mL) were added sequentially, stirred at room temperature overnight. Water (75 mL) was added to the system, the pH was adjusted to neutral with saturated ammonium chloride solution, the solution was extracted with ethyl acetate (75 mL x 3), the organic phase was combined, washed with water (75 mL x 3), saturated brine (75 mL x 3), the organic phase was dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated, and the crude product was separated by silica gel column chromatography (100% petroleum ether), to give compound C-2a (yellow oil, 5.0 g), which was used directly in the next step.

[0277] Step 2: In a 500 mL round-bottom flask, C-2a (5.0 g, 14 mmol, 1.2 eq), 4-bromo-2-fluoro-6-methylaniline (2.8 g, 11.7 mmol, 1.0 eq), Pd(OAc)2 (259 mg, 1.2 mmol, 0.1 eq), XantPhos (915 mg, 1.7 mmol, 0.15 eq), Cs2CO3 (5.6 g, 17 mmol, 1.5 eq), toluene (117 mL) were added sequentially under nitrogen atmosphere, the reaction system was heated to 110°C, and the reaction was allowed to proceed for 24 h. The reaction was concentrated by rotary evaporation, and the crude product was separated by silica gel column chromatography (100% petroleum ether) to give compound C-3f (white solid, 4.8 g), which was used directly in the next step.

[0278] Step 3: Into a 25 mL round-bottom flask, was added compound C-3f (436 mg, 1.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (211 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2(73 mg, 0.1 mmol, 0.1 eq), K2CO3(276 mg, 2.0 mmol, 2.0 eq), dioxane / water (5 mL / 0.5 mL), and heated to 100 °C under nitrogen atmosphere overnight. The reaction was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound C-4f-1 (white solid, 234 mg), which was used directly in the next step.

[0279] Step 4: Into a 25 mL round-bottom flask, was added compound C-4f-1 (234 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3.2 mL / 6.4 mL), lithium hydroxide (62 mg, 2.6 mmol, 5.0 eq) in water (1.6 mL), and heated to 45 °C under nitrogen atmosphere overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R77 (white solid, 175 mg). LCMS: [M+H]=425. + 1 H-NMR (500 MHz, DMSO-d6) δ 13.71 (s, 1H), 9.59 (s, 1H), 7.80 (d, J = 2.9 Hz, 1H), 7.70 (s, 2H), 7.42 (dd, J = 9.1, 2.9 Hz, 1H), 6.43 (d, J = 9.2 Hz, 1H), 2.47 (s, 3H), 2.29 (s, 3H).

[0280] Example 39: Synthesis of R161

[0281]

[0282] Step 1: Into a 25 mL round-bottom flask, was added compound 2t (82 mg, 0.34 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (73 mg, 0.52 mmol, 1.5 eq), Pd(dppf)Cl2(25.2 mg, 0.03 mmol, 0.1 eq), potassium carbonate (95.1 mg, 0.69 mmol, 2.0 eq), dioxane / water (4 mL / 0.4 mL, 10:1, v / v), and heated to 95 °C under nitrogen atmosphere overnight. The reaction was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound M32 (white solid, 45.5 mg).

[0283] ​Step 2: Into a 50 mL round-bottom flask, under nitrogen atmosphere, was added B-3a (64.7 mg, 0.2 mmol, 1.2 eq), M32 (45.5 mg, 0.18 mmol, 1.0 eq), Pd(OAc)2(10 mg, 0.2 mmol, 0.1 eq), XantPhos (20 mg, 0.03 mmol, 0.15 eq), cesium carbonate (87.3 mg, 0.27 mmol, 1.5 eq), toluene (5 mL), and the reaction was heated to 110 °C for 24 h. The reaction was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound B-4t-1 (white solid, 107.5 mg).

[0284] Step 3: Into a 50 mL round-bottom flask, under nitrogen atmosphere, was added the compound from previous step B-4t-1 (53.7 mg, 0.1 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2 mL / 4 mL), lithium hydroxide (12 mg, 0.5 mmol, 5.0 eq) in water (1 mL), and the reaction was heated to 45 °C for overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and the solution was extracted with (dichloromethane:methanol = 10: 1) (50 mL). The organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R161 (white solid, 27.4 mg). LCMS: [M+H]=415. + 1 H-NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.50 (m, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.31 (t, J = 10.2 Hz, 1H), 7.13 (dd, J = 8.6, 2.2 Hz, 1H), 6.57-6.21 (m, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 2.09 (s, 3H), 1.89 (qd, J = 8.6, 4.4 Hz, 1H), 1.00-0.80 (m, 2H), 0.65-0.35 (m, 2H).

[0285] Example 40: Synthesis of R162

[0286]

[0287] ​Step 1: Into a 25 mL round-bottom flask, was placed compound 2u (67 mg, 0.28 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (59.5 mg, 0.42 mmol, 1.5 eq), Pd(dppf)Cl2(20.6 mg, 0.03 mmol, 0.1 eq), potassium carbonate (77.7 mg, 0.56 mmol, 2.0 eq), dioxane / water (4 mL / 0.4 mL, 10:1, v / v), and heated to 95 °C with stirring overnight under nitrogen atmosphere. Concentrated, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound M49 (white solid, 30.5 mg).

[0288] Step 2: Into a 50 mL round-bottom flask, was placed B-3a (30.5 mg, 0.10 mmol, 1.2 eq), M49 (45.5 mg, 0.08 mmol, 1.0 eq), Pd(OAc)2(10 mg, 0.1 mmol, 0.1 eq), XantPhos (20 mg, 0.01 mmol, 0.15 eq), cesium carbonate (87.3 mg, 0.27 mmol, 1.5 eq), toluene (5 mL), and heated to 110 °C with stirring for 24 h under nitrogen atmosphere. Concentrated, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound B-4u-1 (white solid, 35.1 mg).

[0289] Step 3: Into a 50 mL round-bottom flask, was placed compound B-4u-1 (35.1 mg, 0.08 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2 mL / 4 mL), lithium hydroxide (5.8 mg, 0.2 mmol, 5.0 eq) in water (0.5 mL), and heated to 45 °C with stirring overnight under nitrogen atmosphere. The reaction solution was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and extracted with (dichloromethane:methanol = 10:1) (50 mL). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. Concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R162 (white solid, 11.9 mg). LCMS: [M+H]=415; + 1 ​H-NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.39 (s, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.36 (t, J = 4.1 Hz, 1H), 7.12 (dd, J = 8.6, 2.3 Hz, 1H), 6.46 (dd, J = 8.6, 4.1 Hz, 1H), 2.28 (s, 3H), 2.10 (s, 3H), 2.03 (d, J = 2.7 Hz, 3H), 1.93-1.84 (m, 1H), 0.92-0.84 (m, 2H), 0.61-0.55 (m, 2H).

[0290] Example 41: Synthesis of R154

[0291]

[0292] Step 1: In a 100 mL round-bottom flask, was placed compound 2b (2.00 g, 8.89 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (1.88 g, 13.3 mmol, 1.5 eq), Pd(dppf)Cl2(651 mg, 0.9 mmol, 0.1 eq), potassium carbonate (2.45 g, 17.8 mmol, 2.0 eq), dioxane / water (30 mL / 3 mL, 10:1, v / v), and heated to 95 °C with stirring overnight under nitrogen atmosphere. Concentration, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound M33 (white solid, 1.94 g).

[0293] Step 2: In a 50 mL round-bottom flask, was placed M33 (100 mg, 0.41 mmol, 1.0 eq), 2-methoxy-5-bromopyridine-4-carboxylic acid methyl ester (122 mg, 0.49 mmol, 1.2 eq), Pd(OAc)2(10 mg, 0.04 mmol, 0.1 eq), XantPhos (36 mg, 0.06 mmol, 0.15 eq), cesium carbonate (203 mg, 0.62 mmol, 1.5 eq), toluene (4 mL), and heated to 110 °C for 24 h under nitrogen atmosphere. Concentration, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound D-4b-1 (yellow solid, 144 mg).

[0294] Step 3: To the compound from previous step D-4b-1 (90 mg, 0.22 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2 mL / 4 mL), lithium hydroxide (16 mg, 0.66 mmol, 5.0 eq) in water (1 mL) was added, heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), the solution was washed with (dichloromethane:methanol = 10:1) (50 mL), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. Concentrated to dryness under reduced pressure, the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R154 (yellow solid, 68.4 mg). LCMS: [M+H]=392; + 1 H-NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.60 (d, J = 3.9 Hz, 1H), 7.50 (s, 1H), 7.43 (d, J = 11.5 Hz, 1H), 7.19 (s, 1H), 5.76 (s, 1H), 3.81 (s, 3H), 2.46 (s, 3H), 2.29 (s, 3H).

[0295] Example 42: Synthesis of R157

[0296]

[0297] Step 1: In a 100 mL round-bottom flask, E01 (600 mg, 3.8 mmol, 1.0 eq), deuterated iodomethane (1.00 g, 6.8 mmol, 3.0 eq), potassium carbonate (2.09 g, 9.1 mmol, 4.0 eq), DMF (10 mL) were added sequentially, heated to 40 °C and stirred overnight. After the reaction was completed, it was filtered. The filtrate was concentrated to dryness to give E02 (white oil, 834 mg), which was used directly in the next step.

[0298] Step 2: In a 50 mL round-bottom flask, under nitrogen atmosphere, E02 (186.7 mg, 0.62 mmol, 1.0 eq), M33 (100 mg, 0.41 mmol, 1.2 eq), Pd(OAc)2 (10 mg, 0.04 mmol, 0.1 eq), XantPhos (36 mg, 0.06 mmol, 0.15 eq), cesium carbonate (203 mg, 0.62 mmol, 1.5 eq), toluene (4 mL) were added sequentially, the reaction system was heated to 110 °C, and reacted for 24 h. Concentration, the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound E-03-1 (white solid, 88.8 mg).

[0299] ​Step 3: To the compound E-03-1 (49.5 mg, 0.12 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2 mL / 4 mL), lithium hydroxide (8.7 mg, 0.36 mmol, 3.0 eq) in water (1 mL) was added, and the mixture was stirred at 45 °C overnight. The reaction was cooled to room temperature, and the pH was adjusted to 6-7 with dilute hydrochloric acid (2 M). The solution was washed with dichloromethane:methanol (10:1) (50 mL), and the combined organic phases were washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R157 (white solid, 34.5 mg). LCMS: [M+H]=394; + 1 H-NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.50 (s, 1H), 7.48-7.39 (m, 2H), 7.07 (dd, J=9.1, 3.1 Hz, 1H), 6.53 (dd, J=9.0, 4.4 Hz, 1H), 2.46 (s, 3H), 2.29 (s, 3H).

[0300] Example 43: Synthesis of R164

[0301]

[0302] Step 1: In a 100 mL round-bottom flask, compound 2ac (518.0 mg, 2.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (422.2 mg, 3.0 mmol, 1.5 eq), Pd(dppf)Cl2(146.3 mg, 0.2 mmol, 0.1 eq), potassium carbonate (276.4 mg, 2.0 mmol, 2.0 eq), dioxane / water (30 mL / 3 mL, 10:1, v / v) were added, and the mixture was stirred at 95 °C overnight under a nitrogen atmosphere. The mixture was concentrated, and the crude product was separated by column chromatography on silica gel (petroleum ether:ethyl acetate = 20:1) to give compound M50 (white solid, 350 mg).

[0303] ​Step 2: Into a 50 mL three-necked flask equipped with a mechanical stirrer, a thermometer, and a pressure-equalizing addition funnel, was placed M50 (324.4 mg, 1.18 mmol, 1.0 eq), THF (20 mL), and the resulting solution was cooled to -78 °C. n-BuLi (1 mL, 1.53 mmol, 1.3 eq) was added dropwise. After the addition was completed, the reaction mixture was stirred at -78 °C for 1 h. Iodine (600 mg, 2.36 mmol, 2.0 eq) was dissolved in THF (2 mL) and added dropwise to the above reaction mixture. The reaction mixture was stirred at -78 °C for 2 h. The reaction was quenched with water. The solution was washed with ethyl acetate (100 mL). The combined organic phase was washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was separated by column chromatography (petroleum ether: ethyl acetate = 40: 1) to give compound M50-1 (white solid, 293.6 mg).

[0304] Step 3: Into a 25 mL round-bottom flask, was placed M50-1 (90.8 mg, 0.23 mmol, 1.2 eq), B-2a (36 mg, 0.19 mmol, 1.0 eq), Pd(OAc)2 (10 mg, 0.02 mmol, 0.1 eq), XantPhos (16.4 mg, 0.03 mmol, 0.15 eq), cesium carbonate (92.3 mg, 0.28 mmol, 1.5 eq), and toluene (4 mL). The reaction mixture was heated to 110 °C. After 24 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was separated by column chromatography (petroleum ether: ethyl acetate = 50: 1) to give compound B-4ad-1 (white solid, 54.5 mg).

[0305] Step 4: Into a 25 mL round-bottom flask, was placed compound B-4ad-1 (54.5 mg, 0.12 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2 mL / 4 mL), and lithium hydroxide (14.4 mg, 0.60 mmol, 5.0 eq) in water (1 mL). The reaction mixture was heated to 45 °C and stirred overnight. The reaction mixture was cooled to room temperature, and the pH was adjusted to 6-7 with dilute hydrochloric acid (2 M). The solution was washed with dichloromethane:methanol = 10: 1 (50 mL). The combined organic phase was washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was separated by column chromatography (dichloromethane:methanol = 20: 1) to give compound R164 (white solid, 6.9 mg). LCMS: [M+H] = 451. + 1 ​H-NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 11.2, 1.8 Hz, 1H), 7.43 (s, 1H), 7.14 (dd, J = 8.6, 2.3 Hz, 1H), 6.52 (dd, J = 8.6, 4.6 Hz, 1H), 2.47 (s, 3H), 2.30 (s, 3H), 1.89 (ddd, J = 13.5, 8.5, 5.1 Hz, 1H), 0.94 - 0.81 (m, 2H), 0.68 - 0.52 (m, 2H).

[0306] Example 44: Synthesis of R165

[0307]

[0308] Step 1: In a 500 mL round-bottom flask, was added M33 (1.00 g, 4.2 mmol, 1.0 eq), water (10 mL), concentrated hydrochloric acid (12 M, 10 mL), and the reaction mixture was cooled in an ice water bath. A solution of sodium nitrite (345 mg, 5.0 mmol, 1.2 eq) in water (2 mL) was added dropwise via constant pressure addition funnel. After the addition was complete, the reaction mixture was stirred at 0 °C for 0.5 h. A solution of potassium iodide (1.0 g, 6.3 mmol, 1.5 eq) in water (5 mL) was added dropwise via constant pressure addition funnel. After the addition was complete, the reaction mixture was warmed to 40 °C and stirred for 10 min. The reaction was quenched with saturated aqueous sodium bicarbonate solution. The solution was washed with ethyl acetate (200 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to give M33-1 (white solid, 766 mg).

[0309] Step 2: In a 25 mL round-bottom flask, was added M33-1 (13.7 mg, 0.08 mmol, 1.0 eq), methyl 2-amino-5-ethylbenzoate (32.3 mg, 0.09 mmol, 1.2 eq), Pd(OAc)2 (10 mg, 0.01 mmol, 0.1 eq), XantPhos (10 mg, 0.01 mmol, 0.15 eq), cesium carbonate (37.4 mg, 0.11 mmol, 1.5 eq), and toluene (4 mL). The reaction mixture was heated to 110 °C and stirred for 24 h. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to give compound F-4b-1 (white solid, 10.8 mg).

[0310] Step 3: To the compound F-4b-1 (10.8 mg, 0.03 mmol, 1.0 eq) in tetrahydrofuran / ethanol (1 mL / 2 mL), lithium hydroxide (7.2 mg, 0.3 mmol, 10.0 eq) in water (1 mL) was added, and the mixture was stirred at 45 °C overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and the solution was washed with dichloromethane:methanol (10:1) (50 mL). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R165 (white solid, 7.7 mg). LCMS: [M+H]=389. + 1 H-NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.54 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.55-7.50 (m, 1H), 7.44 (dt, J = 24.1, 12.0 Hz, 1H), 7.29-7.21 (m, 1H), 6.47 (dd, J = 8.5, 4.3 Hz, 1H), 2.61-2.53 (m, 3H), 2.47 (s, 3H), 2.31 (d, J = 18.5 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H).

[0311] Example 45: Synthesis of R168

[0312]

[0313] Step 1: In a 25 mL round-bottom flask, compound 2u (54.9 mg, 0.23 mmol, 1.0 eq), 3,5-dimethylpyrazole-4-boronic acid pinacol ester (77 mg, 0.35 mmol, 1.5 eq), Pd(dppf)Cl2(16.9 mg, 0.02 mmol, 0.1 eq), potassium carbonate (63.7 mg, 0.46 mmol, 2.0 eq), dioxane / water (4 mL / 0.4 mL, 10:1, v / v) were added, and the mixture was stirred at 95 °C overnight under a nitrogen atmosphere. The mixture was concentrated, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20:1) to give compound M47 (white solid, 52.9 mg), which was used directly in the next step.

[0314] ​Step 2: Into a 50 mL round-bottom flask, was added B-3a (58.3 mg, 0.19 mmol, 1.2 eq), M47 (52.9 mg, 0.16 mmol, 1.0 eq), Pd(OAc)2(10 mg, 0.02 mmol, 0.1 eq), XantPhos (15 mg, 0.03 mmol, 0.15 eq), cesium carbonate (78.7 mg, 0.24 mmol, 1.5 eq), toluene (4 mL) under nitrogen atmosphere, the reaction was heated to 110 °C for 24 h. The reaction was concentrated and the crude was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound B-4u-2 (yellow oil, 36.4 mg) which was used directly in the next step.

[0315] Step 3: Into a 50 mL round-bottom flask, was added the compound from previous step B-4u-2 (32.4 mg, 0.07 mmol, 1.0 eq) in tetrahydrofuran / ethanol (2 mL / 4 mL), lithium hydroxide (10.1 mg, 0.42 mmol, 6.0 eq) in water (1 mL), the reaction was heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), the solution was washed with (dichloromethane:methanol = 10: 1) (50 mL), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated to dryness under reduced pressure, the crude was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R168 (white solid, 5.4 mg). LCMS: [M+H]=414; + 1 H-NMR (400 MHz, DMSO-d6) δ 12.76 (s, 2H), 9.36 (s, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.18-7.16 (m, 1H), 7.14-7.08 (m, 1H), 6.41 (dd, J = 8.6, 3.7 Hz, 1H), 2.04 (s, 6H), 2.01 (d, J = 2.8 Hz, 3H), 1.88 (ddd, J = 13.5, 8.6, 5.2 Hz, 1H), 0.90-0.85 (m, 2H), 0.60-0.53 (m, 2H).

[0316] Example 46: Synthesis of R79

[0317]

[0318] ​Step 1: Into a 250 mL round-bottom flask, was placed compound 2m (2.28 g, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v), and was heated to 95 °C under nitrogen atmosphere overnight. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1) to give compound M05 (white solid, 1.50 g).

[0319] Step 2: Into a 50 mL round-bottom flask, was placed B-3a (302 mg, 1.0 mmol, 1.2 eq), M05 (196 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL), and was heated to 110 °C under nitrogen atmosphere for 24 h. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound B-4m-1 (white solid, 256 mg).

[0320] Step 3: Into a 50 mL round-bottom flask, was placed compound B-4m-1 (209 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL), and was heated to 45 °C under nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and extracted with dichloromethane:methanol = 10:1 (50 mL). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R79 (white solid, 154 mg). LCMS: [M+H]=405. + 1 ​HNMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.20 (s, 2H), 7.02 (dd, J = 8.3, 2.1 Hz, 1H), 6.08 (d, J = 8.5 Hz, 1H), 2.45 (s, 3H), 2.28 (s, 3H), 2.01 (q, J = 7.2 Hz, 1H), 1.82 (tt, J = 8.9, 5.1 Hz, 1H), 1.24 (s, 2H), 1.09 (t, J = 7.5 Hz, 6H), 0.88 - 0.81 (m, 2H), 0.53 (q, J = 5.3 Hz, 2H).

[0321] Example 47: Synthesis of R207

[0322]

[0323] Step 1: In a 250 mL round-bottom flask, compound 2b (2.24 g, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v), nitrogen atmosphere, heated to 95 °C and stirred overnight. Concentration, the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1) to give compound M33 (white solid, 1.25 g).

[0324] Step 2: In a 50 mL round-bottom flask, under nitrogen atmosphere, B-3a (302 mg, 1.0 mmol, 1.2 eq), M33 (193 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL), the reaction system was heated to 110 °C, and reacted for 24 h. Concentration, the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound B-4b-1 (white solid, 326 mg).

[0325] Step 3: To the compound B-4b-1 (208 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added, and the mixture was stirred at 45 °C overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and extracted with dichloromethane:methanol (10:1) (50 mL). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R207 (white solid, 192 mg). LCMS: [M+H]=401. + 1 H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.51 (s, 1H), 7.45 (d, J = 11.2 Hz, 1H), 7.13 (dd, J = 8.4, 2.2 Hz, 1H), 6.45 (dd, J = 8.7, 4.1 Hz, 1H), 2.47 (s, 3H), 2.29 (s, 3H), 2.08 (s, 1H), 2.03 - 1.94 (m, 1H), 1.88 (td, J = 8.6, 4.4 Hz, 1H), 1.24 (s, 4H), 0.88 (p, J = 6.6 Hz, 2H), 0.59 (t, J = 5.2 Hz, 2H).

[0326] Example 48: Synthesis of R208

[0327]

[0328] Step 1: In a 250 mL round-bottom flask, compound 2h (2562 mg, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v) were added, and the mixture was stirred at 95 °C overnight under a nitrogen atmosphere. The mixture was concentrated, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 40:1) to give compound M28 (white solid, 1.46 g).

[0329] ​Step 2: Into a 50 mL round-bottom flask, under nitrogen atmosphere, was added B-3a (302 mg, 1.0 mmol, 1.2 eq), M28 (218 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL), and the reaction was heated to 110 °C for 24 h. The reaction was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound B-4h-1 (white solid, 386 mg).

[0330] Step 3: Into a 50 mL round-bottom flask, under nitrogen atmosphere, was added the compound from previous step B-4h-1 (208 mg, 0.4 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (48 mg, 2.0 mmol, 5.0 eq) in water (1.5 mL), and the reaction was heated to 45 °C for overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and extracted with (dichloromethane:methanol = 10: 1) (50 mL). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R208 (white solid, 192 mg). LCMS: [M+H]=433. + 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.60 (t, J = 1.8 Hz, 1H), 7.23 (s, 2H), 7.07 - 6.99 (m, 1H), 6.07 (d, J = 8.6 Hz, 1H), 3.04 (p, J = 6.9 Hz, 2H), 2.47 (s, 3H), 2.30 (s, 3H), 2.06 - 1.93 (m, 1H), 1.82 (tt, J = 8.8, 5.1 Hz, 1H), 1.24 (s, 2H), 1.13 (dd, J = 15.4, 6.8 Hz, 11H), 0.89 - 0.79 (m, 2H), 0.54 (t, J = 5.3 Hz, 2H).

[0331] Example 49: Synthesis of R90

[0332]

[0333] ​Step 1: Into a 250 mL round-bottom flask, was placed compound 2s (2905 mg, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v), and was heated to 95 °C under nitrogen atmosphere overnight. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1) to give compound M46 (white solid, 2106 mg).

[0334] Step 2: Into a 50 mL round-bottom flask, was placed B-3a (302 mg, 1.0 mmol, 1.2 eq), M46 (246 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), and toluene (8 mL) and was heated to 110 °C under nitrogen atmosphere for 24 h. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound B-4s-1 (white solid, 356 mg).

[0335] Step 3: Into a 50 mL round-bottom flask, was placed compound B-4s-1 (208 mg, 0.7 mmol, 1.0 eq) in tetrahydrofuran / ethanol (4 mL / 8 mL), lithium hydroxide (84 mg, 3.5 mmol, 5.0 eq) in water (2.0 mL) and was heated to 45 °C under nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and extracted with dichloromethane:methanol = 10:1 (50 mL). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and the crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R90 (white solid, 115 mg). LCMS: [M+H] = 467. + 1 ​HNMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 7.74 (s, 1H), 7.64 (s, 1H), 7.56 (s, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.37 (d, J = 8.7 Hz, 1H), 2.47 (d, J = 1.7 Hz, 3H), 2.29 (d, J = 1.8 Hz, 3H), 2.00 (s, 1H), 1.88 (s, 1H), 1.24 (s, 3H), 0.88 (t, J = 7.4 Hz, 2H), 0.58 (d, J = 5.4 Hz, 2H).

[0336] Example 50: Synthesis of R210

[0337]

[0338] Step 1: In a 250 mL round-bottom flask, was added compound 2e (2205 mg, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v), and stirred at 95 °C under nitrogen atmosphere overnight. Concentration, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1) to give compound M36 (white solid, 1.65 g).

[0339] Step 2: In a 50 mL round-bottom flask, was added B-3a (302 mg, 1.0 mmol, 1.2 eq), M36 (190 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL) under nitrogen atmosphere. The reaction was heated to 110 °C for 24 h. Concentration, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound B-4e-1 (white solid, 314 mg).

[0340] Step 3: To the compound B-4e-1 (288 mg, 0.7 mmol, 1.0 eq) in tetrahydrofuran / ethanol (4 mL / 8 mL), lithium hydroxide (84 mg, 3.5 mmol, 5.0 eq) in water (2.0 mL) was added, and the mixture was stirred at 45 °C overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and the solution was extracted with dichloromethane:methanol (10:1) (50 mL). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R210 (white solid, 192 mg). LCMS: [M+H]=397. + 1 H NMR (600 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.23 (s, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.47 (s, 1H), 7.35 (s, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.15 (d, J = 8.3 Hz, 1H), 2.45 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 1.85 (tt, J = 8.8, 4.9 Hz, 1H), 0.89 - 0.84 (m, 2H), 0.55 (d, J = 5.3 Hz, 2H).

[0341] Example 51: Synthesis of R211

[0342]

[0343] Step 1: In a 250 mL round-bottom flask, compound 2v (2.34 g, 10.0 mmol, 1.0 eq), 3,5-3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v) were added, and the mixture was stirred at 95 °C overnight under a nitrogen atmosphere. The mixture was concentrated, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 40:1) to give compound M37 (white solid, 1.46 mg).

[0344] ​Step 2: Into a 50 mL round-bottom flask, was added B-3a (302 mg, 1.0 mmol, 1.2 eq), M37 (201 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2 (18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL) under nitrogen atmosphere, the reaction was heated to 110 °C for 24 h. The reaction was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound B-4v-1 (white solid, 300 mg).

[0345] Step 3: Into a 50 mL round-bottom flask, was added the compound from previous step B-4v-1 (221 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added, the reaction was heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), the solution was extracted with (dichloromethane:methanol = 10:1) (50 mL), the organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R211 (white solid, 144 mg). LCMS: [M+H]=411. + 1 H NMR (600 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.24 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.06 (dd, J = 8.5, 2.6 Hz, 1H), 6.17 - 6.10 (m, 1H), 2.58 (q, J = 7.7 Hz, 2H), 2.46 (d, J = 1.7 Hz, 3H), 2.28 (d, J = 1.7 Hz, 3H), 1.88 - 1.81 (m, 1H), 1.14 - 1.08 (m, 3H), 0.86 (d, J = 8.0 Hz, 2H), 0.55 (d, J = 5.2 Hz, 2H).

[0346] Example 52: Synthesis of R212

[0347]

[0348] ​Step 1: Into a 250 mL round-bottom flask, was placed compound 2g (2.75 mg, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v), and was heated to 95 °C under nitrogen atmosphere overnight. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1) to give compound M11 (white solid, 1.37 g).

[0349] Step 2: Into a 50 mL round-bottom flask, was placed B-3a (302 mg, 1.0 mmol, 1.2 eq), M11 (233 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), and toluene (8 mL) and was heated to 110 °C under nitrogen atmosphere for 24 h. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound B-4g-1 (white solid, 315 mg).

[0350] Step 3: Into a 50 mL round-bottom flask, was placed compound B-4g-1 (279 mg, 0.6 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (72 mg, 3.0 mmol, 5.0 eq) in water (1.5 mL) and was heated to 45 °C under nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and extracted with dichloromethane:methanol = 10:1 (50 mL). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and the crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R212 (white solid, 135 mg). LCMS: [M+H] = 451. + 1 ​H NMR (600 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.57 (s, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 6.22 (d, J = 8.6 Hz, 1H), 2.47 (d, J = 1.8 Hz, 3H), 2.29 (d, J = 1.7 Hz, 3H), 1.90 - 1.84 (m, 1H), 0.88 (d, J = 8.1 Hz, 2H), 0.57 (d, J = 5.2 Hz, 2H).

[0351] Example 53: Synthesis of R213

[0352]

[0353] Step 1: Into a 250 mL round-bottom flask, was placed compound 2j (2.36 g, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v), and stirred at 95 °C under nitrogen atmosphere overnight. Concentration, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1) to give compound M38 (white solid, 1.69 g).

[0354] Step 2: Into a 50 mL round-bottom flask, was placed B-3a (302 mg, 1.0 mmol, 1.2 eq), M38 (203 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), and toluene (8 mL). The reaction system was heated to 110 °C under nitrogen atmosphere for 24 h. Concentration, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound B-4j-1 (white solid, 331 mg).

[0355] Step 3: To the compound B-4j-1 (221 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added, and the mixture was heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and the solution was extracted with dichloromethane:methanol (10:1) (50 mL). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R213 (white solid, 138 mg). LCMS: [M+H]=413. + 1 H NMR (600 MHz, DMSO-d6) δ 13.01 (s, 1H), 9.15 (s, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.26 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 2.47 (s, 3H), 2.29 (s, 3H), 1.86 (dd, J = 8.9, 4.4 Hz, 1H), 0.90 - 0.83 (m, 2H), 0.55 (d, J = 5.2 Hz, 2H).

[0356] Example 54: Synthesis of R214

[0357]

[0358] Step 1: In a 250 mL round-bottom flask, compound 2w (2.50 g, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v) were added, and the mixture was heated to 95 °C and stirred overnight under a nitrogen atmosphere. The mixture was concentrated, and the crude product was separated by column chromatography on silica gel (petroleum ether: ethyl acetate = 40:1) to give compound M39 (white solid, 2.02 g).

[0359] ​Step 2: Into a 50 mL round-bottom flask, under nitrogen atmosphere, was added B-3a (302 mg, 1.0 mmol, 1.2 eq), M39 (214 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL), and the reaction was heated to 110 °C for 24 h. The reaction was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound B-4w-1 (white solid, 245 mg).

[0360] Step 3: Into a 50 mL round-bottom flask, under nitrogen atmosphere, was added the compound from previous step B-4w-1 (221 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL), and the reaction was heated to 45 °C for overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and extracted with (dichloromethane:methanol = 10: 1) (50 mL). The organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R214 (white solid, 144 mg). LCMS: [M+H]=427. + 1 H NMR (600 MHz, DMSO-d6) δ 13.01 (s, 1H), 9.22 (s, 1H), 7.60 (d, J = 2.7 Hz, 1H), 7.17 (s, 1H), 7.10 - 7.02 (m, 2H), 6.31 (d, J = 8.7 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 3.31 (s, 2H), 2.46 (s, 3H), 2.28 (d, J = 2.0 Hz, 3H), 1.87 (d, J = 6.7 Hz, 1H), 1.18 (t, J = 6.9 Hz, 3H), 0.87 (dq, J = 8.8, 3.2 Hz, 2H), 0.56 (d, J = 5.2 Hz, 2H).

[0361] Example 55: Synthesis of R215

[0362]

[0363] ​Step 1: Into a 250 mL round-bottom flask, was placed compound 2o (2.28 g, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v), and was heated to 95 °C under nitrogen atmosphere overnight. The reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 40:1) to give compound M40 (white solid, 1.71 g).

[0364] Step 2: Into a 50 mL round-bottom flask, was placed B-3a (302 mg, 1.0 mmol, 1.2 eq), M40 (196 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), and toluene (8 mL) and was heated to 110 °C under nitrogen atmosphere for 24 h. The reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 9:1) to give compound B-4o-1 (white solid, 227 mg).

[0365] Step 3: Into a 50 mL round-bottom flask, was placed compound B-4o-1 (210 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL), and was heated to 45 °C under nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and extracted with dichloromethane:methanol = 10:1 (50 mL). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography on silica gel (dichloromethane:methanol = 20:1) to give compound R215 (white solid, 125 mg). LCMS: [M+H]=405. + 1 ​H NMR (600 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.10 (s, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.21 (d, J = 11.2 Hz, 2H), 7.03 (d, J = 8.7 Hz, 1H), 6.07 (d, J = 8.4 Hz, 1H), 3.31 (s, 2H), 3.11 - 3.05 (m, 1H), 2.45 (d, J = 2.0 Hz, 3H), 2.28 (d, J = 1.9 Hz, 3H), 2.13 (s, 3H), 1.82 (d, J = 7.7 Hz, 1H), 1.16 (d, J = 6.9 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 0.85 (dq, J = 8.8, 3.1 Hz, 2H), 0.54 (d, J = 5.1 Hz, 2H).

[0366] Example 56: Synthesis of R216

[0367]

[0368] Step 1: Into a 250 mL round-bottom flask, was placed compound 2x (2.46 g, 10.0 mmol, 1.0 eq), dimethyl isoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v), and heated to 95 °C with stirring overnight under nitrogen atmosphere. Concentration, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1) to give compound M41 (white solid, 1.47 g).

[0369] Step 2: Into a 50 mL round-bottom flask, was placed B-3a (302 mg, 1.0 mmol, 1.2 eq), M41 (211 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL), and heated to 110 °C for 24 h under nitrogen atmosphere. Concentration, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound B-4x-1 (white solid, 296 mg).

[0370] Step 3: To the compound B-4x-1 (263 mg, 0.6 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (72 mg, 3.0 mmol, 5.0 eq) in water (1.5 mL) was added, and the mixture was stirred at 45 °C overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and the solution was extracted with dichloromethane:methanol (10:1) (50 mL). The organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R216 (white solid, 125 mg). LCMS: [M+H]=423. + 1 H NMR (600 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.36 (s, 1H), 7.63 (d, J = 2.8 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 6.27 (d, J = 8.5 Hz, 1H), 2.43 (s, 3H), 2.25 (s, 3H), 1.91 (t, J = 6.9 Hz, 1H), 1.85 (q, J = 6.8 Hz, 1H), 0.94 - 0.85 (m, 4H), 0.79 - 0.67 (m, 2H), 0.56 (d, J = 5.4 Hz, 2H).

[0371] Example 57: Synthesis of R217

[0372]

[0373] Step 1: In a 250 mL round-bottom flask, compound 2y (2.15 g, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v) were added, and the mixture was stirred at 95 °C overnight under a nitrogen atmosphere. The mixture was concentrated, and the crude product was separated by column chromatography on silica gel (petroleum ether: ethyl acetate = 40:1) to give compound M42 (white solid, 1.16 g).

[0374] ​Step 2: Into a 50 mL round-bottom flask, under nitrogen atmosphere, was added B-3a (302 mg, 1.0 mmol, 1.2 eq), M42 (185 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL), and the reaction was heated to 110 °C for 24 h. The reaction was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound B-4y-1 (white solid, 297 mg).

[0375] Step 3: Into a 50 mL round-bottom flask, under nitrogen atmosphere, was added the compound from the previous step (284 mg, 0.7 mmol, 1.0 eq) in tetrahydrofuran / ethanol (4 mL / 8 mL), lithium hydroxide (84 mg, 3.5 mmol, 5.0 eq) in water (2.0 mL), and the reaction was heated to 45 °C for overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and extracted with (dichloromethane:methanol = 10: 1) (50 mL). The organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R217 (white solid, 185 mg). LCMS: [M+H]=392. + 1 H NMR (600 MHz, DMSO-d6) δ 13.32 (s, 1H), 9.64 (s, 1H), 7.82-7.75 (m, 2H), 7.66 (d, J = 2.3 Hz, 1H), 7.17 (dd, J = 8.6, 2.3 Hz, 1H), 6.64 (dd, J = 8.6, 3.8 Hz, 1H), 2.47 (s, 3H), 2.29 (s, 3H), 1.96-1.87 (m, 1H), 0.95-0.86 (m, 2H), 0.66-0.54 (m, 2H).

[0376] Example 58: Synthesis of R219

[0377]

[0378] ​Step 1: Into a 250 mL round-bottom flask, was placed compound 2z (2.48 g, 10.0 mmol, 1.0 eq), dimethyl isoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v), and was heated to 95 °C under nitrogen atmosphere overnight. The reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 40:1) to give compound M43 (white solid, 1.84 g).

[0379] Step 2: Into a 50 mL round-bottom flask, was placed B-3a (302 mg, 1.0 mmol, 1.2 eq), M43 (212 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), and toluene (8 mL) and was heated to 110 °C under nitrogen atmosphere for 24 h. The reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 9:1) to give compound B-4z-1 (white solid, 205 mg).

[0380] Step 3: Into a 50 mL round-bottom flask, was placed compound B-4z-1 (176 mg, 0.4 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (84 mg, 2.0 mmol, 5.0 eq) in water (1.5 mL), and was heated to 45 °C under nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and extracted with dichloromethane:methanol = 10:1 (50 mL). The organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography on silica gel (dichloromethane:methanol = 20:1) to give compound R219 (white solid, 102 mg). LCMS: [M+H]=425. + 1 ​H NMR (600 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.17 (s, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.12 (dd, J = 8.7, 2.3 Hz, 1H), 7.02 - 6.90 (m, 2H), 6.48 (dd, J = 8.6, 4.8 Hz, 1H), 4.67 (hept, J = 6.1 Hz, 1H), 2.46 (s, 3H), 2.29 (s, 3H), 1.87 (tt, J = 8.4, 5.1 Hz, 1H), 1.23 (d, J = 6.0 Hz, 6H), 0.90 - 0.85 (m, 2H), 0.60 - 0.53 (m, 2H).

[0381] Example 59: Synthesis of R220

[0382]

[0383] Step 1: Into a 250 mL round-bottom flask, was placed compound 2aa (2.18 g, 10.0 mmol, 1.0 eq), dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL, 10:1, v / v), and stirred at 95 °C under nitrogen atmosphere overnight. Concentration, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1) to give compound M44 (white solid, 1.09 g).

[0384] Step 2: Into a 50 mL round-bottom flask, was placed B-3a (302 mg, 1.0 mmol, 1.2 eq), M44 (188 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL), and heated to 110 °C under nitrogen atmosphere for 24 h. Concentration, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound B-4aa-1 (white solid, 220 mg).

[0385] Step 3: To the compound B-4aa-1 (205 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added, and the mixture was stirred at 45 °C overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and the solution was extracted with dichloromethane:methanol (10:1) (50 mL). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R220 (white solid, 145 mg). LCMS: [M+H]=395. +

[0386] 1 H NMR (600 MHz, DMSO-d6) δ 13.06 (s, 1H), 9.17 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 11.1, 2.0 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.6, 2.3 Hz, 1H), 6.32 (dd, J = 8.6, 3.2 Hz, 1H), 2.62 (q, J = 7.6 Hz, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 1.85 (td, J = 8.5, 4.3 Hz, 1H), 1.13 (t, J = 7.5 Hz, 3H), 0.92 - 0.81 (m, 2H), 0.61 - 0.51 (m, 2H).

[0387] Example 60: Synthesis of R221

[0388]

[0389] Step 1: In a 250 mL round-bottom flask, compound 2bb (5000 mg, 20.7 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (4388 mg, 31.1 mmol, 1.5 eq), Pd(dppf)Cl2 (1519 mg, 2.1 mmol, 0.1 eq), potassium carbonate (5726 mg, 41.5 mmol, 2.0 eq), dioxane / water (30 mL / 3 mL, 10:1, v / v) were added, and the mixture was stirred at 95 °C overnight under a nitrogen atmosphere. The reaction was concentrated, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20:1) to give compound M45 (white solid, 5 g).

[0390] ​Step 2: Into a 100 mL round-bottom flask, was added M45-1 (3.2 g, 8.4 mmol, 1.0 eq), B-2a (1929 mg, 10.1 mmol, 1.2 eq), Pd(OAc)2(189 mg, 0.8 mmol, 0.1 eq), XantPhos (727.6 mg, 1.3 mmol, 0.15 eq), cesium carbonate (4097 mg, 12.6 mmol, 1.5 eq), toluene (40 mL) under nitrogen atmosphere. The reaction mixture was heated to 110 °C for 24 h. The reaction mixture was concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1) to give compound B-4ac-1 (yellow oil, 1.6 g).

[0391] Step 3: Into a 100 mL round-bottom flask, was added M45-1 (3.2 g, 8.4 mmol, 1.0 eq), B-2a (1929 mg, 10.1 mmol, 1.2 eq), Pd(OAc)2(189 mg, 0.8 mmol, 0.1 eq), XantPhos (727.6 mg, 1.3 mmol, 0.15 eq), cesium carbonate (4097 mg, 12.6 mmol, 1.5 eq), toluene (40 mL) under nitrogen atmosphere. The reaction mixture was heated to 110 °C for 24 h. The reaction mixture was concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 50: 1) to give compound B-4ac-1 (yellow oil, 1.6 g).

[0392] Step 4: Into a 100 mL round-bottom flask, was added compound B-4ac-1 (1.6 g, 3.6 mmol, 1.0 eq) in tetrahydrofuran / ethanol (10 mL / 20 mL), lithium hydroxide (525 mg, 21.9 mmol, 6.0 eq) in water (5 mL) was added. The reaction mixture was stirred at 45 °C overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), washed with (dichloromethane:methanol = 10: 1) (50 mL), combined the organic phase, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to dryness. The crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R221 (white solid, 1.4 g). LCMS: [M+H]=433. +

[0393] 1 ​H-NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.26 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.37 (dd, J = 11.0, 1.7 Hz, 1H), 7.20 (s, 1H), 7.12 (dd, J = 8.7, 2.3 Hz, 1H), 6.48 (dd, J = 8.6, 4.3 Hz, 1H), 2.47 (s, 3H), 2.29 (s, 3H), 2.03 - 1.68 (m, 1H), 0.95 - 0.76 (m, 2H), 0.65 - 0.44 (m, 2H).

[0394] Example 61: Synthesis of R240

[0395]

[0396] Step 1: In a 250 mL round-bottom flask, was added compound R240-1 (2.18 g, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL), and heated to 95 °C under nitrogen atmosphere overnight. Concentration, the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1) to give compound R240-2 (white solid, 1.09 g).

[0397] Step 2: In a 50 mL round-bottom flask, was added 2-iodo-5-methylbenzoic acid methyl ester (302 mg, 1.0 mmol), R240-2 (188 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL) under nitrogen atmosphere, and heated to 110 °C for 24 hours. Concentration, the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound R240-3 (white solid, 220 mg).

[0398] Step 3: Compound R240-3 (205 mg, 0.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added, and the mixture was stirred at 45 °C overnight. The reaction solution was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and the solution was extracted with dichloromethane / methanol (v / v = 10:1) (50 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R240-4 (white solid, 145 mg).

[0399] Step 4: Compound R240-4 (78 mg, 0.2 mmol, 1.0 eq) was dissolved in N,N- dimethylformamide (2 mL), HATU (115 mg, 0.3 mmol, 1.5 eq) was added, and the mixture was stirred for 10 minutes. DIPEA (78 mg, 0.6 mmol, 3.0 eq) and ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were then added, and the mixture was stirred at 45 °C overnight. The reaction solution was cooled to room temperature and separated by reverse phase column chromatography (column type: Spherical C18, 20-45 μM; mobile phase water:acetonitrile = 1:5) to give compound R240 (white solid, 56 mg). LCMS: [M+H] = 386. + 1 H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.66-7.62 (m, 1H), 7.30-7.23 (m, 1H), 7.19-7.13 (m, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.74 (s, 1H), 3.89 (s, 2H), 2.55 (s, 2H), 2.42 (s, 2H).

[0400] Example 62: Synthesis of R241

[0401]

[0402] ​Step 1: Into a 50 mL round-bottom flask, was added B-3a (303 mg, 1.0 mmol, 1.2 eq), R240-2 (205 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL) under nitrogen atmosphere, and heated to 110 °C for 24 h. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound R241-1 (white solid, 245 mg).

[0403] Step 2: Compound R241-1 (214 mg, 0.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran / ethanol (3 mL / 6 mL), and lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added. The reaction mixture was stirred at 45 °C overnight. The reaction mixture was cooled to room temperature, and adjusted to pH = 6-7 with dilute hydrochloric acid (2 M). The solution was extracted with dichloromethane / methanol (v / v = 10: 1) (50 mL x 2), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R241-2 (white solid, 178 mg).

[0404] Step 3: Compound R241-2 (83 mg, 0.2 mmol, 1.0 eq) was dissolved in N,N- dimethylformamide (2 mL), and HATU (115 mg, 0.3 mmol, 1.5 eq) was added. The reaction mixture was stirred for 10 min, and then DIPEA (78 mg, 0.6 mmol, 3.0 eq) and ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were added. The reaction mixture was stirred at 45 °C overnight. The reaction mixture was cooled to room temperature, and purified by reverse phase column chromatography (water: acetonitrile = 1:5) to give compound R241 (white solid, 56 mg). LCMS: [M+H]=412; + 1 H NMR (500 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.81 (dd, J = 2.1, 0.7 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.29 (s, OH), 7.20 - 7.14 (m, 1H), 7.09 - 7.05 (m, 3H), 3.89 (s, 2H), 2.73 - 2.65 (m, 1H), 2.55 (s, 2H), 1.73 - 1.65 (m, 2H), 1.48 - 1.40 (m, 2H).

[0405] ​Example 63: Synthesis of R242

[0406]

[0407] Step 1: Into a 250 mL round-bottom flask, was placed compound R242-1 (2.14 g, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL), and heated to 95 °C with stirring overnight under nitrogen atmosphere. Concentration, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1) to give compound R242-2 (white solid, 0.98 g).

[0408] Step 2: Into a 50 mL round-bottom flask, was placed B-3a (303 mg, 1.0 mmol, 1.2 eq), R242-2 (185 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL), and heated to 110 °C with stirring for 24 h under nitrogen atmosphere. Concentration, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound R242-3 (white solid, 231 mg).

[0409] Step 3: Into a 50 mL round-bottom flask, was placed compound R242-3 (202 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), and lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added. The reaction mixture was heated to 45 °C with stirring overnight. The reaction mixture was cooled to room temperature, and adjusted to pH = 6-7 with dilute hydrochloric acid (2 M). The solution was extracted with dichloromethane / methanol (v / v = 10: 1) (50 mL x 2), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R242-4 (white solid, 155 mg).

[0410] Step 4: Compound R242-4 (78 mg, 0.2 mmol, 1.0 eq) was dissolved in N,N- dimethylformamide (2 mL), HATU (115 mg, 0.3 mmol, 1.5 eq) was added and stirred for 10 min, then DIPEA (78 mg, 0.6 mmol, 3.0 eq) and ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were added and heated to 45 °C and stirred overnight. The reaction was cooled to room temperature and separated by reverse phase column chromatography (column type: Spherical C18, 20-45 μM; mobile phase water: acetonitrile = 1:5) to give compound R242 (white solid, 44 mg). LCMS: [M+H]=390. + 1 H NMR (500 MHz, DMSO-d6) d 7.81 (dd, J = 2.1, 0.8 Hz, 1H), 7.68 (s, 1H), 7.33 (s, 1H), 7.21 (dt, J = 1.8, 0.9 Hz, 1H), 7.20 - 7.14 (m, 1H), 7.10 (d, J = 2.6 Hz, 1H), 7.07 (s, 1H), 2.73 - 2.65 (m, 1H), 2.59 (qd, J = 7.1, 0.9 Hz, 2H), 2.55 (s, 2H), 2.42 (s, 2H), 1.73 - 1.65 (m, 2H), 1.48 - 1.40 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H).

[0411] Example 64: Synthesis of R243

[0412]

[0413] Step 1: In a 50 mL round-bottom flask, methyl 2-iodo-5-methylbenzoate (302 mg, 1.0 mmol, 1.2 eq), R242-2 (185 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol), toluene (8 mL) were added sequentially under nitrogen atmosphere, and the reaction system was heated to 110 °C and reacted for 24 h. The reaction was concentrated, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound R243-1 (white solid, 216 mg).

[0414] ​Step 2: Compound R240-1 (190 mg, 0.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added, and the mixture was stirred at 45 °C overnight. The reaction solution was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and the solution was extracted with dichloromethane / methanol (v / v = 10:1) (50 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R243-2 (white solid, 143 mg).

[0415] Step 3: Compound R243-2 (73 mg, 0.2 mmol, 1.0 eq) was dissolved in N,N- dimethylformamide (2 mL), HATU (115 mg, 0.3 mmol, 1.5 eq) was added, and the mixture was stirred for 10 minutes. DIPEA (78 mg, 0.6 mmol, 3.0 eq) and ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were then added, and the mixture was stirred at 45 °C overnight. The reaction solution was cooled to room temperature and separated by reverse phase column chromatography (column type: Spherical C18, 20-45 μM; mobile phase water:acetonitrile = 1:5) to give compound R243 (white solid, 51 mg). LCMS: [M+H] = 364. + 1 H NMR (500 MHz, DMSO-d6) δ 7.66-7.62 (m, 2H), 7.58 (s, 1H), 7.28-7.14 (m, 4H), 7.10 (d, J = 2.6 Hz, 1H), 6.76 (s, 2H), 2.59 (qd, J = 7.1, 0.9 Hz, 3H), 2.55 (s, 4H), 2.42 (s, 4H), 2.37 (s, 4H), 2.26 (s, 5H), 1.25 (t, J = 7.1 Hz, 5H).

[0416] Example 65: Synthesis of R244

[0417]

[0418] ​Step 1: In a 250 mL round-bottom flask, was placed compound R244-1 (2.28 g, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL), and heated to 95 °C under nitrogen atmosphere overnight. Concentration, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1) to give compound R244-2 (white solid, 1.20 g).

[0419] Step 2: In a 50 mL round-bottom flask, was placed B-3a (303 mg, 1.0 mmol, 1.2 eq), R244-2 (196 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), and toluene (8 mL), and heated to 110 °C under nitrogen atmosphere for 24 h. Concentration, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to give compound R244-3 (white solid, 252 mg).

[0420] Step 3: Compound R244-3 (209 mg, 0.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran / ethanol (3 mL / 6 mL), and lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added. The reaction mixture was stirred at 45 °C overnight. The reaction mixture was cooled to room temperature, and adjusted to pH = 6-7 with dilute hydrochloric acid (2 M). The solution was extracted with dichloromethane / methanol (v / v = 10:1) (50 mL x 2), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. Concentration to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R244-4 (white solid, 163 mg).

[0421] Step 4: Compound R244-4 (81 mg, 0.2 mmol, 1.0 eq) was dissolved in N,N- dimethylformamide (2 mL), HATU (115 mg, 0.3 mmol, 1.5 eq) was added and stirred for 10 min, then DIPEA (78 mg, 0.6 mmol, 3.0 eq) and ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were added and heated to 45 °C and stirred overnight. The reaction was cooled to room temperature and separated by reverse phase column chromatography (column type: Spherical C18, 20-45 μM; mobile phase water: acetonitrile = 1:5) to give compound R244 (white solid, 49 mg). LCMS: [M+H]=404. + 1 H NMR (500 MHz, DMSO-d6) δ 7.81 (dd, J = 2.1, 0.8 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.20 - 7.14 (m, 1H), 7.07 (s, 2H), 2.73 - 2.65 (m, 1H), 2.63 - 2.53 (m, 6H), 1.73 - 1.65 (m, 2H), 1.48 - 1.40 (m, 2H), 1.25 (t, J = 7.1 Hz, 6H).

[0422] Example 66: Synthesis of R247

[0423]

[0424] Step 1: In a 250 mL round-bottom flask, compound R247-1 (2.41 g, 10.0 mmol, 1.0 eq), 3-methylpyrazole-4-boronic acid (1.89 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL), nitrogen atmosphere, heated to 95 °C and stirred overnight. Concentration, the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1) to give compound R247-2 (white solid, 1.08 g).

[0425] ​Step 2: Into a 50 mL round-bottom flask, was added B-3a (303 mg, 1.0 mmol, 1.2 eq), R247-2 (194 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol), toluene (8 mL) under nitrogen atmosphere. The reaction was heated to 110 °C for 24 h. The reaction was concentrated and the crude was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound R247-3 (white solid, 226 mg).

[0426] Step 3: Into a 50 mL round-bottom flask, was added compound R247-3 (202 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) under nitrogen atmosphere. The reaction was heated to 45 °C for overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), extracted with dichloromethane / methanol (v / v = 10: 1) (50 mL x 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The crude was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R247 (white solid, 166 mg). LCMS: [M+H]=402. + 1 H NMR (500 MHz, DMSO-d6) d 8.26 (s, 1H), 8.02 (s, 1H), 7.90 (dd, J = 2.1, 0.7 Hz, 1H), 7.56 (s, 2H), 7.29 (d, J = 8.6 Hz, 1H), 7.26 - 7.21 (m, 1H), 2.69 - 2.61 (m, 1H), 1.73 - 1.65 (m, 2H), 1.48 - 1.40 (m, 2H).

[0427] Example 67: Synthesis of R248

[0428]

[0429] ​Step 1: In a 250 mL round-bottom flask, was placed compound R244-1 (2.28 g, 10.0 mmol, 1.0 eq), 3,5-dimethylpyrazole-4-boronic acid pinacol ester (3.33 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL), and heated to 95 °C under nitrogen atmosphere overnight. Concentrated, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1) to give compound R248-1 (white solid, 1.22 g).

[0430] Step 2: In a 50 mL round-bottom flask, was placed B-3a (303 mg, 1.0 mmol, 1.2 eq), R248-1 (195 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol), toluene (8 mL), and heated to 110 °C under nitrogen atmosphere for 24 h. Concentrated, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound R248-2 (white solid, 233 mg).

[0431] Step 3: Compound R248-2 (209 mg, 0.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran / ethanol (3 mL / 6 mL), and lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added. The reaction mixture was stirred at 45 °C overnight. The reaction mixture was cooled to room temperature, and adjusted to pH = 6-7 with dilute hydrochloric acid (2 M). The solution was extracted with dichloromethane / methanol (v / v = 10: 1) (50 mL x 2), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R248-3 (white solid, 168 mg).

[0432] Step 4: Compound R248-3 (81 mg, 0.2 mmol, 1.0 eq) was dissolved in N,N- dimethylformamide (2 mL), HATU (115 mg, 0.3 mmol, 1.5 eq) was added and stirred for 10 min, then DIPEA (78 mg, 0.6 mmol, 3.0 eq) and ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were added and heated to 45 °C and stirred overnight. The reaction was cooled to room temperature and separated by reverse phase column chromatography (column type: Spherical C18, 20-45 μM; mobile phase water: acetonitrile = 1:5) to give compound R248 (white solid, 52 mg). LCMS: [M+H]=403. + 1 H NMR (500 MHz, DMSO-d6) δ 7.81 (dd, J = 2.1, 0.8 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.20 - 7.14 (m, 1H), 7.07 (s, 2H), 2.73 - 2.65 (m, 1H), 2.59 (qd, J = 7.1, 0.9 Hz, 4H), 2.47 (s, 2H), 1.73 - 1.65 (m, 2H), 1.48 - 1.40 (m, 2H), 1.25 (t, J = 7.1 Hz, 6H).

[0433] Example 68: Synthesis of R249

[0434]

[0435] Step 1: In a 250 mL round-bottom flask, compound R242-1 (2.14 g, 10.0 mmol, 1.0 eq), 3,5-dimethylpyrazole-4-boronic acid pinacol ester (3.33 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL), nitrogen atmosphere, heated to 95 °C and stirred overnight. Concentration, the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1) to give compound R249-1 (white solid, 1.18 g).

[0436] ​Step 2: Into a 50 mL round-bottom flask, was added methyl 2-iodo-5-methylbenzoate (302 mg, 1.0 mmol, 1.2 eq), R249-1 (183 mg, 0.8 mmol), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL) under nitrogen atmosphere. The reaction was heated to 110 °C for 24 h. The reaction was concentrated and the crude was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound R249-2 (white solid, 202 mg).

[0437] Step 3: Into a 50 mL round-bottom flask, was added compound R249-2 (189 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) under nitrogen atmosphere. The reaction was heated to 45 °C for overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), extracted with dichloromethane / methanol (v / v = 10: 1) (50 mL x 2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The crude was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R249-3 (white solid, 155 mg).

[0438] Step 4: Into a 50 mL round-bottom flask, was added compound R249-3 (73 mg, 0.2 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), HATU (115 mg, 0.3 mmol, 1.5 eq), stirred for 10 min, DIPEA (78 mg, 0.6 mmol, 3.0 eq) and ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were added. The reaction was heated to 45 °C for overnight. The reaction was cooled to room temperature, purified by reverse phase column chromatography (column type: Spherical C18, 20-45 μM; mobile phase water: acetonitrile = 1:5) to give compound R249 (white solid, 48 mg). LCMS: [M+H]=363. + 1 ​H NMR (500 MHz, DMSO-d6) d 7.66 - 7.62 (m, 1H), 7.58 (s, 1H), 7.28 - 7.20 (m, 2H), 7.19 - 7.14 (m, 1H), 7.11 - 7.06 (m, 1H), 6.76 (s, 1H), 2.59 (qd, J = 7.1, 0.9 Hz, 2H), 2.47 (s, 2H), 2.42 (s, 2H), 2.37 (s, 2H), 2.26 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0439] Example 69: Synthesis of R250

[0440]

[0441] Step 1: Into a 250 mL round-bottom flask, was placed compound R240-1 (2.37 g, 10.0 mmol, 1.0 eq), 3,5-dimethylpyrazole-4-boronic acid pinacol ester (3.33 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL), and heated to 95 °C with stirring overnight under nitrogen atmosphere. Concentration, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1) to give compound R250-1 (white solid, 1.38 g).

[0442] Step 2: Into a 50 mL round-bottom flask, was placed 2-iodo-5-methylbenzoic acid methyl ester (302 mg, 1.0 mmol, 1.2 eq), R250-1 (201 mg, 0.8 mmol), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL), and heated to 110 °C for 24 h under nitrogen atmosphere. Concentration, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound R250-2 (white solid, 231 mg).

[0443] Step 3: Compound R250-2 (200 mg, 0.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added, and the mixture was stirred at 45 °C overnight. The reaction solution was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and the solution was extracted with dichloromethane / methanol (v / v = 10:1) (50 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R250-3 (white solid, 186 mg).

[0444] Step 4: Compound R250-3 (77 mg, 0.2 mmol, 1.0 eq) was dissolved in N,N- dimethylformamide (2 mL), HATU (115 mg, 0.3 mmol, 1.5 eq) was added, and the mixture was stirred for 10 minutes. DIPEA (78 mg, 0.6 mmol, 3.0 eq) and ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were then added, and the mixture was stirred at 45 °C overnight. The reaction solution was cooled to room temperature and separated by reverse phase column chromatography (column type: Spherical C18, 20-45 μM; mobile phase water:acetonitrile = 1:5) to give compound R250 (white solid, 51 mg). LCMS: [M+H] = 385. + 1 H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.66-7.62 (m, 1H), 7.28-7.24 (m, 1H), 7.16 (ddd, J = 7.7, 2.5, 0.9 Hz, 1H), 7.05 (d, J = 2.2 Hz, 1H), 6.74 (s, 1H), 3.89 (s, 2H), 2.47 (s, 2H), 2.42 (s, 2H).

[0445] Example 70: Synthesis of R251

[0446]

[0447] ​Step 1: Into a 250 mL round-bottom flask, was placed compound R244-1 (2.28 g, 10.0 mmol, 1.0 eq), 3,5-dimethylpyrazole-4-boronic acid pinacol ester (3.33 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL), and the reaction mixture was stirred at 95 °C under nitrogen overnight. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1) to give compound R251-1 (white solid, 1.24 g).

[0448] Step 2: Into a 50 mL round-bottom flask, was placed 2-iodo-5-methyl-benzoic acid methyl ester (302 mg, 1.0 mmol, 1.2 eq), R251-1 (195 mg, 0.8 mmol), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), and toluene (8 mL). The reaction mixture was heated to 110 °C for 24 h. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound R251-2 (white solid, 224 mg).

[0449] Step 3: Into a 50 mL round-bottom flask, was placed compound R251-2 (196 mg, 0.5 mmol, 1.0 eq) in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL), and the reaction mixture was stirred at 45 °C overnight. The reaction mixture was cooled to room temperature and adjusted to pH = 6-7 with dilute hydrochloric acid (2 M). The solution was extracted with dichloromethane / methanol (v / v = 10: 1) (50 mL x 2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and the crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R251-3 (white solid, 155 mg).

[0450] Step 4: Compound R251-3 (76 mg, 0.2 mmol, 1.0 eq) was dissolved in N,N- dimethylformamide (2 mL), HATU (115 mg, 0.3 mmol, 1.5 eq) was added and stirred for 10 min, then DIPEA (78 mg, 0.6 mmol, 3.0 eq) and ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were added and heated to 45 °C and stirred overnight. The reaction was cooled to room temperature and separated by reverse phase column chromatography (column type: Spherical C18, 20-45 μM; mobile phase water: acetonitrile = 1:5) to give compound R251 (white solid, 45 mg). LCMS: [M+H] = 377. + 1 H NMR (500 MHz, DMSO-d6) d 7.66 - 7.62 (m, 1H), 7.31 (s, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.19 - 7.14 (m, 1H), 6.76 (s, 1H), 2.59 (qd, J = 7.1, 0.9 Hz, 3H), 2.47 (s, 2H), 2.42 (s, 2H), 2.37 (s, 2H), 1.25 (t, J = 7.1 Hz, 5H).

[0451] Example 71: Synthesis of R252

[0452]

[0453] Step 1: In a 50 mL round-bottom flask, B-3a (303 mg, 1.0 mmol, 1.2 eq), R249-1 (183 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2 (18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL) were added sequentially under a nitrogen atmosphere, and the reaction was heated to 110 °C and stirred for 24 h. The reaction was concentrated, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound R252-1 (white solid, 214 mg).

[0454] ​Step 2: Compound R252-1 (202 mg, 0.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran / ethanol (3 mL / 6 mL), lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added, and the mixture was heated to 45 °C and stirred overnight. The reaction solution was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and the solution was extracted with dichloromethane / methanol (v / v = 10:1) (50 mL x 2), the organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R252-2 (white solid, 170 mg).

[0455] Step 3: Compound R252-2 (78 mg, 0.2 mmol, 1.0 eq) was dissolved in N,N- dimethylformamide (2 mL), HATU (115 mg, 0.3 mmol, 1.5 eq) was added, and the mixture was stirred for 10 min, then DIPEA (78 mg, 0.6 mmol, 3.0 eq) and ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were added, and the mixture was heated to 45 °C and stirred overnight. The reaction solution was cooled to room temperature, and separated by reverse phase column chromatography (column type: Spherical C18, 20-45 μM; mobile phase water:acetonitrile = 1:5) to give compound R252 (white solid, 61 mg). LCMS: [M+H] = 389. + 1 H NMR (500 MHz, DMSO-d6) δ 7.81 (dd, J = 2.1, 0.8 Hz, 1H), 7.68 (s, 1H), 7.33 (s, 1H), 7.22 (dt, J = 2.0, 0.8 Hz, 1H), 7.20 - 7.14 (m, 1H), 7.11 - 7.06 (m, 1H), 7.07 (s, 2H), 2.73 - 2.65 (m, 1H), 2.59 (qd, J = 7.1, 0.9 Hz, 2H), 2.47 (s, 2H), 2.42 (s, 2H), 1.73 - 1.65 (m, 2H), 1.48 - 1.40 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H).

[0456] Example 72: Synthesis of R253

[0457]

[0458] ​Step 1: Into a 50-mL round-bottom flask under nitrogen, was added B-3a (303 mg, 1.0 mmol, 1.2 eq), R250-2 (201 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2 (18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL), and the reaction was heated to 110 °C for 24 h. The reaction was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) to give compound R253-1 (white solid, 228 mg).

[0459] Step 2: Compound R253-1 (213 mg, 0.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran / ethanol (3 mL / 6 mL), and a solution of lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added. The reaction was stirred at 45 °C overnight. The reaction was cooled to room temperature, and the pH was adjusted to 6-7 with dilute hydrochloric acid (2 M). The solution was extracted with dichloromethane / methanol (v / v = 10: 1) (50 mL x 2), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R253-2 (white solid, 190 mg).

[0460] Step 3: Compound R253-2 (82 mg, 0.2 mmol, 1.0 eq) was dissolved in N,N- dimethylformamide (2 mL), and HATU (115 mg, 0.3 mmol, 1.5 eq) was added. The reaction was stirred for 10 min, and then DIPEA (78 mg, 0.6 mmol, 3.0 eq) and ammonium chloride (13 mg, 0.24 mmol, 1.2 eq) were added. The reaction was stirred at 45 °C overnight. The reaction was cooled to room temperature, and purified by reverse phase column chromatography (column type: Spherical C18, 20-45 μM; mobile phase: water: acetonitrile = 1:5) to give compound R253 (white solid, 56 mg). LCMS: [M+H]=411. + 1 H NMR (500 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.81 (dd, J = 2.1, 0.7 Hz, 1H), 7.38 (s, 0H), 7.26 (d, J = 2.0 Hz, 1H), 7.20 - 7.14 (m, 1H), 7.09 - 7.03 (m, 2H), 3.89 (s, 2H), 2.73 - 2.65 (m, 1H), 2.47 (s, 2H), 1.73 - 1.65 (m, 2H), 1.48 - 1.40 (m, 2H).​

[0461] Example 73: Synthesis of R254

[0462]

[0463] Step 1: In a 250 mL round-bottom flask, was placed compound R254-1 (2.30 g, 10.0 mmol, 1.0 eq), 3,5-dimethylisoxazole-4-boronic acid (2.11 g, 15 mmol, 1.5 eq), Pd(dppf)Cl2(732 mg, 1.0 mmol, 0.1 eq), potassium carbonate (2.76 g, 20.0 mmol, 2.0 eq), dioxane / water (50 mL / 5 mL), and heated to 95 °C with stirring overnight under nitrogen atmosphere. Concentration, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 60:1) to give compound R254-2 (white solid, 1.25 g).

[0464] Step 2: In a 50 mL round-bottom flask, was placed B-3a (302 mg, 1.0 mmol), R254-2 (197 mg, 0.8 mmol, 1.0 eq), Pd(OAc)2(18 mg, 0.08 mmol, 0.1 eq), XantPhos (70 mg, 0.12 mmol, 0.15 eq), cesium carbonate (392 mg, 1.2 mmol, 1.5 eq), toluene (8 mL), and heated to 110 °C with stirring for 24 h. Concentration, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound R254-3 (white solid, 220 mg).

[0465] Step 3: Compound R254-3 (210 mg, 0.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran / ethanol (3 mL / 6 mL), and lithium hydroxide (60 mg, 2.5 mmol, 5.0 eq) in water (1.5 mL) was added. The reaction was heated to 45 °C with stirring overnight. The reaction was cooled to room temperature, and adjusted to pH = 6-7 with dilute hydrochloric acid (2 M). The solution was extracted with dichloromethane / methanol (v / v = 20:1) (50 mL x 2), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. Concentration to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R254 (white solid, 120 mg). LCMS: [M+H] = 407; + 1 ​H NMR (500 MHz, DMSO-d6) δ 8.34 (d, J = 4.0 Hz, 1H), 7.90 (dd, J = 2.1, 0.7 Hz, 1H), 7.31 - 7.18 (m, 4H), 3.02 (pd, J = 5.6, 0.7 Hz, 1H), 2.69 - 2.61 (m, 1H), 2.55 (s, 2H), 2.02 - 1.93 (m, 2H), 1.77 - 1.65 (m, 4H), 1.48 - 1.40 (m, 2H).

[0466] Example 74: Synthesis of R383

[0467]

[0468] Step 1: Into a 100 mL round-bottom flask, was placed compound R383-1 (1.0 g, 3.9 mmol), 3,5-dimethyl-l-(2-tetrahydropyranyl)-lH-pyrazole-4-boronic acid pinacol ester (1.8 g, 5.8 mmol), Pd(dppf)Cl2(282.6 mg, 0.4 mmol), potassium carbonate (1.1 g, 7.7 mmol), dioxane / water (30 mL / 3 mL), and heated to 95 °C under nitrogen atmosphere with stirring overnight. Concentration, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to give compound R383-2 (white solid, 1.7 g).

[0469] Step 2: Into a 250 mL three-necked flask was placed R383-2 (1.4 g, 3.9 mmol) and tetrahydrofuran (50 mL) under nitrogen protection, the reaction system was cooled to -78 °C, and n-butyllithium (2.5 M, 2.1 mL, 5.2 mmol) was added dropwise. After the addition was completed, the reaction was incubated at -78 °C for 1 hour. Iodine (1.8 g, 7.0 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to the above reaction system. After incubation for 2 hours, the reaction was quenched with saturated sodium thiosulfate / sodium carbonate aqueous solution (10 / 1, v / v), extracted with ethyl acetate (100 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 40: 1) to give compound R383-3 (white solid, 1.2 g).

[0470] Step 3: Into a 25 mL round-bottom flask, was added R383-3 (200 mg, 0.4 mmol), B-2a (115 mg, 0.6 mmol), Pd2(dba)3(45.8 mg, 0.04 mmol), XantPhos (43 mg, 0.08 mmol), cesium carbonate (244.5 mg, 0.8 mmol), toluene (5 mL) under nitrogen atmosphere. The reaction mixture was heated to 115 °C for 24 h. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to give compound R383-4 (white solid, 94.3 mg).

[0471] Step 4: Compound R383-4 (94.3 mg, 0.17 mmol) was dissolved in tetrahydrofuran / methanol (2 mL / 4 mL), and lithium hydroxide (41.4 mg, 1.70 mmol) in water (1 mL) was added. The reaction mixture was stirred at 45 °C overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R383-4 (white solid, 80 mg).

[0472] Step 5: Compound R383-4 (50 mg, 0.09 mmol) was dissolved in hydrochloric acid / ethyl acetate (4 M, 2 mL), and the reaction was stirred at room temperature overnight. A solid was precipitated, and the mixture was filtered to give compound R383 (hydrochloride, white solid, 25 mg). LCMS: [M+H] + = 450; 1 HNMR (400 MHz, DMSO-d6) δ 9.39 (d, J = 3.7 Hz, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.49 - 7.34 (m, 1H), 7.28 (d, J = 30.2 Hz, 1H), 7.14 (dd, J = 8.7, 2.1 Hz, 1H), 6.51 (dd, J = 8.6, 4.4 Hz, 1H), 2.37 - 2.18 (m, 7H), 0.95 - 0.84 (m, 2H), 0.61 - 0.57 (m, 2H).

[0473] Example 75: Synthesis of R375

[0474]

[0475] Step 1: Into a 25-mL round-bottom flask under nitrogen, was added M50-1 (200 mg, 0.5 mmol), 2-amino-5-methyl-benzoic acid methyl ester (68 mg, 0.4 mmol), Pd2(dba)3 (38 mg, 0.04 mmol), XantPhos (36 mg, 0.06 mmol), cesium carbonate (204 mg, 0.6 mmol), toluene (4 mL), and the reaction was heated to 110 °C for 24 h. The reaction was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1) to give compound R375-1 (white solid, 247 mg).

[0476] Step 2: Into a 25-mL round-bottom flask under nitrogen, was added compound 375-1 (54.5 mg, 0.12 mmol) in tetrahydrofuran / methanol (2 mL / 4 mL), lithium hydroxide (14.4 mg, 0.60 mmol) in water (1 mL), and the reaction was heated to 45 °C for overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R375 (white solid, 87 mg). LCMS: [M+H] = 425. + 1 HNMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 9.52 (s, 1H), 7.73 (s, 1H), 7.55 (dd, J = 11.2, 1.5 Hz, 1H), 7.43 (s, 1H), 7.25 (dd, J = 8.5, 1.5 Hz, 1H), 6.53 (dd, J = 8.4, 4.6 Hz, 1H), 2.47 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H).

[0477] Example 76: Synthesis of R377

[0478]

[0479] Step 1: Into a 25-mL round-bottom flask under nitrogen, was added R383-3 (200 mg, 0.41 mmol), 2-amino-5-methylbenzoic acid methyl ester (56.0 mg, 0.3 mmol), Pd2(dba)3 (32 mg, 0.03 mmol), XantPhos (30 mg, 0.05 mmol), cesium carbonate (168 mg, 0.5 mmol), toluene (5 mL), and the reaction was heated to 115 °C for 24 h. The reaction was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to give compound R377-1 (white solid, 33.5 mg).

[0480] ​Step 2: In a 25 mL round-bottom flask, compound R377-1 (97.5 mg, 0.06 mmol) was dissolved in tetrahydrofuran / methanol (2 mL / 4 mL), and a solution of lithium hydroxide (15.4 mg, 0.6 mmol) in water (1 mL) was added. The reaction was heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R377-2 (white solid, 35 mg).

[0481] Step 5: Compound R377-2 (35 mg, 0.06 mmol) was dissolved in hydrochloric acid / ethyl acetate (4 M, 2 mL), and the reaction was stirred at room temperature overnight. A solid precipitated, which was filtered to give compound R377 (hydrochloride, white solid, 20 mg). LCMS: [M+H] + = 424; 1 HNMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.72 (s, 1H), 7.49-7.36 (m, 1H), 7.28 (s, 1H), 7.24 (dd, J = 8.6, 1.8 Hz, 1H), 6.51 (dd, J = 8.5, 4.3 Hz, 1H), 2.29 (s, 6H), 2.24 (s, 3H).

[0482] Example 77: Synthesis of R385

[0483]

[0484] In a 25 mL round-bottom flask, compound R383-5 (30 mg, 0.06 mmol) was dissolved in toluene (2 mL), and dichlorosulfoxide (28.6 mg, 0.24 mmol) was slowly added. The reaction was heated to 100 °C and stirred for 50 min. It was concentrated to dryness, the crude product was dissolved in dichloromethane (2 mL), and it was added dropwise to a 25 mL vial containing aqueous ammonia (1 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred overnight. It was concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R385 (white solid, 25 mg). LCMS: [M+H] + = 449; 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.94 (s, 1H), 8.13 (s, 1H), 7.56 - 7.38 (m, 2H), 7.37 - 7.26 (m, 1H), 7.21 (s, 1H), 7.07 (dd, J = 8.5, 1.7 Hz, 1H), 6.46 (dd, J = 8.5, 4.6 Hz, 1H), 2.30 (d, J = 31.3 Hz, 6H), 1.83 (ddd, J = 13.5, 8.7, 5.2 Hz, 1H), 0.93 - 0.81 (m, 2H), 0.71 - 0.62 (m, 2H).

[0485] Example 78: Synthesis of R334

[0486]

[0487] Step 1: Into a 100 mL round-bottom flask, was added M45-1 (100 mg, 0.3 mmol), methyl 2-amino-5-methoxybenzoate (52 mg, 0.3 mmol), Pd(OAc)2(10 mg, 0.03 mmol), XantPhos (23 mg, 0.04 mmol), cesium carbonate (128 mg, 0.4 mmol), toluene (4 mL) under nitrogen atmosphere, the reaction was heated to 110 °C for 24 h, concentrated, the crude was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to give compound R334-1 (yellow oil 50 mg).

[0488] Step 2: Into a 100 mL round-bottom flask, was added compound R334-1 (50 mg, 0.11 mmol) in tetrahydrofuran / methanol (1 mL / 2 mL), lithium hydroxide (13.7 mg, 0.57 mmol) in water (1 mL), the reaction was heated to 45 °C for overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), concentrated to dryness under reduced pressure, the crude was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound R334 (white solid, 33 mg). LCMS: [M+H] = 423; + 1 H NMR (400 MHz, DMSO) δ 13.30 (s, 1H), 9.06 (d, J = 15.8 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.36 (dd, J = 11.2, 1.7 Hz, 1H), 7.29 (s, 1H), 7.20 (s, 1H), 7.11 - 7.04 (m, 1H), 6.57 (dd, J = 9.1, 4.3 Hz, 1H), 3.73 (s, 3H), 2.47 (s, 3H), 2.29 (s, 3H).​

[0489] Example 79: Synthesis of R335

[0490]

[0491] Step 1: Into a 100 mL round-bottom flask, was added M45-1 (100 mg, 0.3 mmol), 2- amino-5-methylbenzoic acid methyl ester (48 mg, 0.3 mmol), Pd(OAc)2(10 mg, 0.03 mmol), XantPhos (23 mg, 0.04 mmol), cesium carbonate (128 mg, 0.4 mmol), toluene (4 mL) under nitrogen atmosphere. The reaction was heated to 110 °C for 24 h. The reaction was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to give compound R335-1 (yellow oil, 52 mg).

[0492] Step 2: Into a 100 mL round-bottom flask, was added compound R335-1 (42 mg, 0.1 mmol) in tetrahydrofuran / methanol (1 mL / 2 mL), lithium hydroxide (14 mg, 0.6 mmol) in water (1 mL) under nitrogen atmosphere. The reaction was heated to 45 °C for overnight. The reaction was cooled to room temperature, adjusted to pH = 6-7 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R335 (white solid, 32 mg). LCMS: [M+H] = 407. + 1 HNMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.72 (d, J = 1.7 Hz, 1H), 7.47, 7.29, 7.10 (m, 1H), 7.37 (dd, J = 11.1, 1.8 Hz, 1H), 7.25 - 7.17 (m, 2H), 6.49 (dd, J = 8.5, 4.3 Hz, 1H), 2.48 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H).

[0493] Example 80: Synthesis of R340

[0494]

[0495] ​Step 1: In a 100 mL round-bottom flask, add compound R340-1 (441 mg, 2.0 mmol), 3,5-dimethyl-1-(2-tetrahydropyranyl)-1H-pyrazole-4-boronic acid pinacol ester (796 mg, 2.6 mmol), Pd(dppf)Cl2 (47 mg, 0.2 mmol), potassium carbonate (552 mg, 4.0 mmol), and dioxane / water (20 mL / 2 mL). Heat to 95 °C and stir overnight under a nitrogen atmosphere. Concentrate, and separate the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain compound R340-2 (white solid, 334 mg).

[0496] Step 2: In a 25 mL round-bottom flask under a nitrogen atmosphere, add R340-2 (334 mg, 1.0 mmol), methyl 2-iodo-5-methylbenzoate (355 mg, 1.3 mmol), Pd2(dba)3 (95.7 mg, 0.10 mmol), XantPhos (90.7 mg, 0.16 mmol), cesium carbonate (515 mg, 1.6 mmol), and toluene (10 mL) sequentially. Heat the reaction system to 115 °C and react for 24 hours. Concentrate the mixture, and separate the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain compound R340-3 (white solid, 396 mg).

[0497] Step 3: Dissolve compound R340-3 (390 mg, 0.8 mmol) in tetrahydrofuran / methanol (5 mL / 10 mL), add a solution of lithium hydroxide (100 mg, 4.2 mmol) in water (2 mL), and heat to 45 °C with stirring overnight. Cool the reaction solution to room temperature, adjust the pH to 5-6 with dilute hydrochloric acid (2 M), concentrate under reduced pressure to dryness, and separate the crude product by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R340-4 (white solid, 157 mg).

[0498] Step 4: In a 25 mL round-bottom flask, compound R340-4 (125 mg, 0.3 mmol) was dissolved in toluene (2 mL), and thionyl chloride (130 mg, 1.2 mmol) was slowly added. The reaction mixture was heated to 100 °C and stirred for 50 minutes. The reaction solution was concentrated to dryness, and the crude product was dissolved in 6 mL of dichloromethane. The solution was then added dropwise at 0 °C to a 25 mL single-necked flask containing 3 mL of ammonia. The mixture was allowed to warm naturally to room temperature and stirred overnight. The solution was concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R340 (white solid, 25 mg). LCMS: [M+H] + =369; 1HNMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.65 (s, 1H), 8.00 (s, 1H), 7.56 (s, 1H), 7.36 (s, 1H), 7.28 (s, 1H), 7.21 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.13 (d, J = 8.3 Hz, 1H), 2.23 (s, 6H), 2.21 (s, 3H), 2.19 (s, 3H).

[0499] Example 81: Synthesis of R308

[0500]

[0501] Step 1: In a 100 mL round-bottom flask, compound R308-1 (1.0 g, 5.0 mmol), N- chlorosuccinimide (665 mg, 5.0 mmol), N,N-dimethylformamide (20 mL) were added, the reaction was heated to 70 °C and stirred overnight. The reaction was poured into water (150 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to give compound R308-2 (white solid, 1.2 g).

[0502] Step 2: In a 100 mL round-bottom flask, compound R308-2 (1.2 g, 5.0 mmol), 3,5- dimethyl-1-(2-tetrahydropyranyl)-1H-pyrazole-4-boronic acid pinacol ester (2.3 g, 7.5 mmol), Pd(dppf)Cl2(366 mg, 0.5 mmol), potassium carbonate (1.4 g, 10 mmol), dioxane / water (20 mL / 2 mL) were added, heated to 95 °C and stirred overnight under nitrogen atmosphere. Concentration, the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to give compound R308-3 (white solid, 1.1 g).

[0503] Step 3: In a 25 mL round-bottom flask, R308-3 (100 mg, 0.30 mmol), 2-iodo-5- methylbenzoic acid methyl ester (105 mg, 0.4 mmol), Pd2(dba)3(55 mg, 0.06 mmol), XantPhos (52 mg, 0.09 mmol), cesium carbonate (145 mg, 0.5 mmol), toluene (5 mL) were added sequentially under nitrogen atmosphere, the reaction system was heated to 115 °C for 24 hours, concentrated, the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to give compound R308-4 (white solid, 124 mg).

[0504] Step 4: Compound R308-4 (123.6 mg, 0.26 mmol) was dissolved in tetrahydrofuran / methanol (5 mL / 10 mL), lithium hydroxide (63 mg, 2.6 mmol) in water (1 mL) was added, the reaction was heated to 45 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R308-4 (white solid, 111 mg).

[0505] Step 5: In a 25 mL round-bottom flask, compound R308-4 (50.0 mg, 0.11 mmol) was dissolved in toluene 4 mL, dichlorosulfoxide (50.8 mg, 0.43 mmol) was slowly added, and the reaction system was heated to 100 °C and stirred for 50 minutes. Concentrated to dryness, the crude product was dissolved in 6 mL of dichloromethane, and added dropwise to a 25 mL single-neck flask containing 3 mL of ammonia water at 0 °C, and stirred overnight after natural warming to room temperature. Concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 40:1) to obtain compound R308 (white solid, 18 mg). LCMS: [M+H]=383. + 1 HNMR (600 MHz, DMSO-d6) δ 12.36 (s, 1H), 9.70 (s, 1H), 7.99 (s, 1H), 7.55 (s, 1H), 7.35 (s, 1H), 7.29 (d, J = 1.9 Hz, 1H), 7.21 (d, J = 1.7 Hz, 1H), 7.04 (dd, J = 8.4, 1.4 Hz, 1H), 6.12 (d, J = 8.4 Hz, 1H), 2.55 (m, 2H), 2.26 (d, J = 26.5 Hz, 6H), 2.20 (s, 3H), 1.09 (t, J = 7.5 Hz, 3H).

[0506] Example 82: Synthesis of R431

[0507]

[0508] Step 1: In a 25 mL round-bottom flask, R86 (50.0 mg, 0.13 mmol), toluene (5 mL), dichlorosulfoxide (0.5 mL) were added in turn, and the reaction system was heated to 100 °C and stirred for 0.5 hours. Concentrated to dryness under reduced pressure to obtain compound R431-1 (yellow solid, crude), which was directly used in the next step.

[0509] ​Step 2: Into a 25 mL round-bottom flask, dichloromethane (2 mL), methylamine hydrochloride (17.4 mg, 0.26 mmol) and triethylamine (51.0 mg, 0.5 mmol) were added successively, and then a dichloromethane (2 mL) solution of compound R431-1 was added. The reaction mixture was stirred at 25 °C overnight. The pH was adjusted to 5-6 with dilute hydrochloric acid, and then the mixture was concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 40:1) to give compound R431 (white solid, 23.4 mg). LCMS: [M+H]=394. + 1 HNMR (400 MHz, CDC13) δ 8.99 (s, 1H), 7.19 (s, 1H), 7.00 (dd, J = 8.6, 2.1 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J = 10.9 Hz, 1H), 6.49 (dd, J = 8.6, 3.6 Hz, 1H), 6.21 (s, 1H), 3.05 (d, J = 4.8 Hz, 3H), 2.46 (s, 3H), 2.34 (s, 3H), 1.98 - 1.85 (m, 1H), 0.94 - 0.89 (m, 3H), 0.68 - 0.62 (m, 2H).

[0510] Example 83: Synthesis of R434

[0511]

[0512] Into a 25 mL round-bottom flask, dichloromethane (2 mL), cyclobutylamine (18.6 mg, 0.26 mmol) and triethylamine (51.0 mg, 0.5 mmol) were added successively, and then a dichloromethane (2 mL) solution of compound R431-1 was added. The reaction mixture was stirred at 25 °C overnight. The pH was adjusted to 5-6 with dilute hydrochloric acid, and then the mixture was concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 40:1) to give compound R434 (white solid, 9.4 mg). LCMS: [M+H]=434. + 1 HNMR (400 MHz, CDC13) δ 8.99 (s, 1H), 7.19 (s, 1H), 7.00 (dd, J = 8.6, 2.1 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J = 10.9 Hz, 1H), 6.49 (dd, J = 8.6, 3.6 Hz, 1H), 6.21 (s, 1H), 3.05 (d, J = 4.8 Hz, 3H), 2.46 (s, 3H), 2.34 (s, 3H), 1.98 - 1.85 (m, 1H), 0.94 - 0.89 (m, 3H), 0.68 - 0.62 (m, 2H).

[0513] ​​Example 84: Synthesis of R422

[0514]

[0515] Step 1: In a 100 mL round-bottom flask, add compound R422-1 (1.0 g, 4.1 mmol), 3,5-dimethyl-1-(2-tetrahydropyranyl)-1H-pyrazole-4-boronate pinacol ester (2.0 g, 6.5 mmol), Pd(dppf)Cl2·CH2Cl2 (175 mg, 0.2 mmol), sodium carbonate (1.1 g, 10.6 mmol), and DMSO / water (20 mL / 2.4 mL). Heat to 80 °C and stir overnight under a nitrogen atmosphere. Dilute the reaction solution with ethyl acetate (200 mL), wash with saturated brine (100 mL x 3), dry the organic phase with anhydrous sodium sulfate, concentrate, and separate the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound R422-2 (white solid, 780 mg).

[0516] Step 2: In a 25 mL round-bottom flask, under a nitrogen atmosphere, add R422-2 (530.5 mg, 1.56 mmol), methyl 2-iodo-5-methylbenzoate (516 mg, 1.87 mmol), XantPhos (135 mg, 0.23 mmol), Cs₂CO₃ (763 mg, 2.34 mmol), toluene (8 mL), and Pd₂(dba)₃ (143 mg, 0.15 mmol). Heat the reaction system to 110 °C and stir for 24 hours. Concentrate the reaction solution to dryness, and separate the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain compound R422-3 (pale yellow solid, 738.7 mg).

[0517] Step 3: Weigh compound R422-3 (738.7 mg, 1.5 mmol) into tetrahydrofuran / methanol (6 mL / 12 mL), add lithium hydroxide (218 mg, 9.1 mmol) in water (5 mL), and heat the reaction mixture to 50 °C with stirring overnight. Cool the reaction solution to room temperature, adjust the pH to 5-6 with dilute hydrochloric acid (2 M), concentrate under reduced pressure to dryness, and separate the crude product by column chromatography (dichloromethane:methanol = 30:1) to obtain compound R422-4 (pale yellow solid, 494.2 mg).

[0518] Step 4: In a 25 mL round-bottom flask, compound R422-4 (91 mg, 0.2 mmol) was dissolved in toluene 2 mL, dichlorosulfoxide (98.4 mg, 0.8 mmol) was added slowly, the reaction system was heated to 100 °C and stirred for 50 min. The reaction was concentrated to dryness, the crude product was dissolved in dichloromethane (2 mL), and was added dropwise to a 25 mL single-neck flask containing ammonia water (1 mL) at 0 °C, and was allowed to warm to room temperature and stirred overnight. The reaction was concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R422 (white solid, 37.5 mg). LCMS: [M+H]=389. + = 389. 1 H NMR 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.88 (s, 1H), 8.04 (s, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.45 (s, 3H), 7.09 (dd, J = 8.5, 2.0 Hz, 1H), 6.23 (d, J = 8.4 Hz, 1H), 2.23 (s, 3H).

[0519] Example 85: Synthesis of R426

[0520]

[0521] Step 1: In a 25 mL round-bottom flask, R340-2 (260 mg, 0.8 mmol), B-3a (319 mg, 1.1 mmol), XantPhos (69.5 mg, 0.12 mmol), Cs2CO3 (396 mg, 1.2 mmol), toluene (5 mL), Pd2(dba)3 (74.2 mg, 0.1 mmol) were added sequentially under a nitrogen atmosphere, and the reaction system was heated to 110 °C and stirred for 24 h. The reaction was concentrated to dryness, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound R426-1 (off-white solid, 433 mg).

[0522] Step 2: Compound R426-1 (430 mg, 0.8 mmol) was dissolved in tetrahydrofuran / methanol (5 mL / 10 mL), and a lithium hydroxide (126 mg, 5.3 mmol) solution in water (5 mL) was added, and the reaction was heated to 50 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound R426-2 (pale yellow solid, 285 mg).

[0523] Step 3: In a 25 mL round-bottom flask, compound R426-2 (285 mg, 0.6 mmol) in toluene 5 mL, dichlorosulfoxide (285 mg, 2.4 mmol) was added, the reaction was heated to 100 °C and stirred for 50 min. After the solvent was spun dry, it was dissolved in 5 mL of dichloromethane and added dropwise to a 25 mL single-neck flask containing 5 mL of ammonia water at 0 °C, and stirred at room temperature overnight, concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R426 (white solid, 101 mg). LCMS: [M+H] = 395. + 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.64 (s, 1H), 8.05 (s, 1H), 7.43 - 7.33 (m, 2H), 7.28 (d, J = 2.0 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 8.5, 2.1 Hz, 1H), 6.11 (d, J = 8.5 Hz, 1H), 2.23 (s, 5H), 2.18 (s, 3H), 1.89 - 1.80 (m, 1H), 0.92 - 0.85 (m, 2H), 0.69 - 0.60 (m, 2H).

[0524] Example 86: Synthesis of R427

[0525]

[0526] Step 1: In a 100 mL round-bottom flask, compound R422-1 (1.0 g, 4.1 mmol), R427-1 (1.7 g, 6.5 mmol), Pd(dppf)Cl2CH2Cl2(175 mg, 0.2 mmol), sodium carbonate (1.1 g, 10.7 mmol), DMSO / water (20 mL / 2.4 mL) were added successively, and stirred at 80 °C under nitrogen atmosphere overnight. The reaction was diluted with ethyl acetate (300 mL), washed with saturated brine (100 mL x 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound R427-2 (white solid, 980 mg).

[0527] ​Step 2: Into a 25 mL round-bottom flask, was added R427-2 (275 mg, 0.8 mmol), B-3a (350 mg, 1.2 mmol), XantPhos (67 mg, 0.12 mmol), Cs2CO3(380 mg, 1.2 mmol), toluene (5 mL), Pd2(dba)3(71 mg, 0.1 mmol) under nitrogen atmosphere. The reaction was heated to 110 °C and stirred for 24 h. The reaction was concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give compound R427-3 (yellow oil, 256 mg).

[0528] Step 3: Into a 25 mL round-bottom flask, was added compound R427-3 (256 mg, 0.5 mmol) in tetrahydrofuran / methanol (5 mL / 10 mL), lithium hydroxide (72 mg, 3.0 mmol) in water (5 mL) under nitrogen atmosphere. The reaction was heated to 50 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure to give crude compound R427-4 (yellow oil, 189 mg).

[0529] Step 4: Into a 25 mL round-bottom flask, was added compound R427-4 (190 mg, 0.4 mmol) in toluene (5 mL), dichlorosulfoxide (180 mg, 1.5 mmol) under nitrogen atmosphere. The reaction was heated to 100 °C and stirred for 50 min. The reaction was concentrated to dryness under reduced pressure. The crude product was dissolved in dichloromethane (5 mL) and added dropwise to a 25 mL vial containing ammonia (5 mL) at 0 °C. The reaction was stirred overnight at room temperature. The reaction was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20: 1) to give compound R427 (white solid, 64.9 mg). LCMS: [M+H]=415; + 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.88 (d, J = 9.0 Hz, 1H), 8.10 (s, 1H), 7.54 - 7.35 (m, 3H), 7.03 (s, 1H), 6.22 (t, J = 9.0 Hz, 1H), 2.25 (s, 4H), 1.82 (br s, 1H), 0.86 - 0.82 (s, 2H), 0.66 - 0.62 (q, J = 7.4, 6.0 Hz, 2H).

[0530] Example 87: Synthesis of R501

[0531]

[0532] ​Step 1 : Compound R308-3 (167 mg, 0.5 mmol) was dissolved in toluene (2.0 mL), B-3a (227 mg, 0.75 mmol), Pd2(dba)3(91 mg, 0.1 mmol), XantPhos (116 mg, 0.2 mmol), Cs2CO3(250 mg, 0.8 mmol) were added successively. The reaction was heated to 115 °C under nitrogen atmosphere and stirred for 20 h. The reaction was concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give compound R501-1 (yellow solid, 200 mg).

[0533] Step 2: Compound R501-1 (200 mg, 0.49 mmol) was dissolved in tetrahydrofuran / methanol / water (2 mL / 2 mL / 1 mL), lithium hydroxide (92 mg, 4.0 mmol) was added. The reaction was heated to 50 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid, and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R501-2 (white solid, 120 mg).

[0534] Step 3: Compound R501-2 (120 mg, 0.24 mmol) was dissolved in toluene (4 mL), dichlorosulfoxide (0.5 mL) was added slowly. The reaction was heated to 100 °C and stirred for 45 min. The reaction was concentrated to dryness under reduced pressure. The crude product was dissolved in dichloromethane (2 mL) and added to ammonia water (1 mL) at 0 °C. The reaction was stirred at room temperature for 3 h. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (5 mL x 2). The combined dichloromethane phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by preparative TLC (dichloromethane:methanol = 20:1) to give compound R501 (yellow solid, 27 mg). LCMS: [M+H]=409; + 1 H NMR (600 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.69 (s, 1H), 8.05 (s, 1H), 7.45-7.31 (m, 2H), 7.29 (d, J = 2.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.11 (d, J = 8.4 Hz, 1H), 2.57-2.53 (m, 2H), 2.50 (s, 6H), 1.24 (s, 1H), 1.11 (m, 3H), 0.92-0.84 (m, 2H), 0.72-0.58 (m, 2H).

[0535] Example 88: Synthesis of R502

[0536] ​

[0537] Step 1: Into a 100-mL round-bottom flask, was added compound R502-1 (2.2 g, 10 mmol), 3,5-dimethyl-l-(2-tetrahydropyranyl)-lH-pyrazole-4-boronic acid pinacol ester (1.7 g, 12 mmol), Pd(PPh3)4(557 mg, 0.5 mmol), potassium carbonate (4.14 g, 30 mmol), toluene / water / ethanol (25 mL / 5 mL / 5 mL), and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated brine (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to give compound R502-2 (white solid, 1780 mg).

[0538] Step 2: Into a 100-mL round-bottom flask, was added R502-2 (480 mg, 1.5 mmol), sodium thiomethoxide (315 mg, 4.5 mmol), and methanol (10 mL). The reaction mixture was stirred at room temperature for 3 hours and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to give compound R502-3 (white solid, 300 mg).

[0539] Step 3: Into a 50-mL round-bottom flask, was added compound R502-3 (300 mg, 0.75 mmol), water / ethanol (2 mL / 10 mL), ammonium chloride (200 mg, 3.75 mmol), and iron powder (208 mg, 3.75 mmol). The reaction mixture was stirred at 80 °C for 6 hours. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5: 1) to give compound R502-4 (white solid, 210 mg).

[0540] Step 4: Into a 50-mL round-bottom flask, was added compound R502-4 (120 mg, 0.32 mmol), 2-iodo-5-methylbenzoic acid methyl ester (176 mg, 0.64 mmol), Pd2(dba)3(59 mg, 0.064 mmol), XantPhos (74 mg, 0.128 mmol), and Cs2CO3(156 mg, 0.48 mmol). The reaction mixture was stirred at 115 °C under a nitrogen atmosphere for 20 hours. The reaction mixture was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to give compound R502-5 (yellow solid, 160 mg).

[0541] Step 5: Compound R502-5 (160 mg, 0.32 mmol) was taken in tetrahydrofuran / methanol / water (2 mL / 2 mL / 1 mL), lithium hydroxide (61 mg, 2.56 mmol) was added and the reaction was heated to 50 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M) and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R502-6 (white solid, 80 mg).

[0542] Step 6: Compound R502-6 (80 mg, 0.24 mmol) was taken in toluene (4 mL), thionyl chloride (0.5 mL) was added and the reaction was heated to 100 °C and stirred for 45 min. The reaction was concentrated to dryness under reduced pressure. The crude product was dissolved in dichloromethane (2 mL) and added to ammonia water (1 mL) at 0 °C and then allowed to warm to room temperature and stirred for 3 h. The organic phase was separated and the aqueous phase was extracted with dichloromethane (5 mL x 2). The combined dichloromethane phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by preparative TLC (dichloromethane:methanol = 20:1) to give compound R502 (yellow solid, 33 mg). LCMS: [M+H] = 401. + 1 H NMR (600 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.69 (s, 1H), 8.03 - 7.93 (m, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.40 - 7.29 (m, 1H), 7.22 (d, J = 1.8 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 8.4, 2.0 Hz, 1H), 6.13 (d, J = 8.4 Hz, 1H), 2.40 (s, 3H), 2.26 (s, 6H), 2.21 (s, 3H).

[0543] Example 89: Synthesis of R503

[0544]

[0545] ​Step 1: Into a 100-mL round-bottom flask, was placed compound R503-1 (2.37 g, 10 mmol), 3,5-dimethyl-l-(2-tetrahydropyranyl)-lH-pyrazole-4-boronic acid pinacol ester (1.7 g, 12 mmol), Pd(PPh3)4(557 mg, 0.5 mmol), potassium carbonate (4.14 g, 30 mmol), toluene / water / ethanol (25 mL / 5 mL / 5 mL), and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere overnight. The reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated brine (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to give compound R503-2 (white solid, 1680 mg).

[0546] Step 2: Into a 100-mL round-bottom flask, was placed R503-2 (211 mg, 0.56 mmol), sodium hydroxide (2.74 g, 18 mmol), DMSO / water (2.5 mL / 0.5 mL), and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to give compound R503-3 (white solid, 160 mg).

[0547] Step 3: Into a 100-mL round-bottom flask, was placed R503-3 (2.4 g, 7.2 mmol), sodium difluorochloroacetate (56 mg, 1.4 mmol), potassium carbonate (1.98 g, 14.4 mmol), N,N-dimethylformamide / water (45 mL / 6 mL), and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to give compound R503-4 (yellow solid, 1.8 g).

[0548] Step 4: Into a 50-mL round-bottom flask, was placed compound R503-4 (251 mg, 0.75 mmol), water / ethanol (2 mL / 10 mL), ammonium chloride (200 mg, 3.75 mmol), and iron powder (208 mg, 3.75 mmol), and the reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was concentrated, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5: 1) to give compound R503-5 (white solid, 189 mg).

[0549] Step 5: Compound R503-5 (113 mg, 0.32 mmol) was dissolved in toluene (2 mL), followed by the addition of 2-iodo-5-methylbenzoic acid methyl ester 176 mg, 0.64 mmol), Pd2(dba)3(59 mg, 0.064 mmol), XantPhos (74 mg, 0.128 mmol), Cs2CO3(156 mg, 0.48 mmol). The reaction was heated to 115 °C under nitrogen atmosphere for 20 h. The reaction was concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give compound R503-6 (yellow solid, 140 mg).

[0550] Step 6: Compound R503-6 (160 mg, 0.32 mmol, 1.0 eq) was dissolved in tetrahydrofuran / methanol / water (2 mL / 2 mL / 1 mL), followed by the addition of lithium hydroxide (61 mg, 2.56 mmol). The reaction was heated to 50 °C under stirring overnight. The reaction was cooled to room temperature, and adjusted to pH = 5-6 with dilute hydrochloric acid (2 M). The crude product was separated by column chromatography (dichloromethane:methanol = 20: 1) to give R503-7 (110 mg).

[0551] Step 7: The crude product R503-7 (50 mg) was added to HCl / dioxane (4 M, 5 mL) and stirred at 25 °C for 12 h. The compound R503 (hydrochloride, white solid, 20 mg) was obtained by filtration. LCMS: [M+H] + = 406.

[0552] Example 90: Synthesis of R504

[0553]

[0554] Step 1: Compound R503-5 (113 mg, 0.32 mmol) was dissolved in toluene (2 mL), followed by the addition of B-3a (186 mg, 0.64 mmol), Pd2(dba)3(59 mg, 0.064 mmol), XantPhos (74 mg, 0.128 mmol), Cs2CO3(156 mg, 0.48 mmol). The reaction was heated to 115 °C under nitrogen atmosphere for 20 h. The reaction was concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give compound R504-1 (yellow solid, 140 mg), which was used directly in the next step.

[0555] Step 2: Compound R504-1 (160 mg, 0.32 mmol) was dissolved in THF / MeOH / H20 (2 mL / 2 mL / 1 mL), and LiOH (61 mg, 2.56 mmol) was added. The reaction was heated to 50 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute HCl (2 M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound R504-2 (white solid, 80 mg).

[0556] Step 3: R504-2 (30 mg) was added to HC1 / dioxane (4 M, 3 mL) and stirred at 25 °C for 12 h. A solid precipitated, which was filtered to give compound R504 (HC1 salt, white solid, 10 mg). LCMS: [M+H] + = 432; 1 H NMR (600 MHz, DMSO-c / 6) δ 12.41 (s, 1H), 9.93 (s, 1H), 8.05 (s, 1H), 7.77-7.69 (m, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.27-7.17 (m, 1H), 6.68 (t, J = 7.5 Hz, 1H), 6.20 (d, J = 8.3 Hz, 1H), 2.57 (d, J = 7.4 Hz, 1H), 2.25 (s, 6H), 1.20-1.01 (m, 4H).

[0557] Example 91: Synthesis of R505

[0558]

[0559] Compound R504-2 (103 mg, 0.24 mmol) was dissolved in toluene (4 mL), and thionyl chloride (0.5 mL) was added slowly. The reaction was heated to 100 °C and stirred for 45 min. The reaction was cooled to room temperature, concentrated to dryness under reduced pressure, and the crude product was dissolved in dichloromethane (1 mL) and added to ammonia water (1 mL) at 0 °C. The reaction was stirred at room temperature for 3 h. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (5 mL x 2). The combined dichloromethane phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by preparative TLC (dichloromethane:methanol = 20:1) to give compound R505 (white solid, 18 mg). LCMS: [M+H] + = 431.

[0560] Example 92: Synthesis of R506

[0561]

[0562] Compound R503-7 (97 mg, 0.24 mmol) was dissolved in toluene (4 mL), and thionyl chloride (0.5 mL) was added slowly. The reaction was heated to 100 °C and stirred for 45 min. The reaction was cooled to room temperature, concentrated to dryness under reduced pressure, and the crude product was dissolved in dichloromethane (1 mL) and added to ammonia water (1 mL) at 0 °C. The reaction was stirred at room temperature for 3 h, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (5 mL x 2), and the combined dichloromethane phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by preparative TLC (dichloromethane:methanol = 20:1) to give compound R506 (white solid, 29 mg). LCMS: [M+H]=405. + 1 H NMR (600 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.66 (s, 1H), 8.02 (s, 1H), 7.54 (s, 1H), 7.38 (d, J = 21.6 Hz, 1H), 7.24 (s, 1H), 7.20 - 7.06 (m, 2H), 7.03 (s, 1H), 6.44 (dd, J = 8.5, 4.0 Hz, 1H), 2.26 (s, 6H), 2.23 (s, 3H).

[0563] Example 93: Synthesis of R551

[0564]

[0565] Step 1: In a 100 mL round-bottom flask, R551-1 (1.5 g, 7.3 mmol), N-iodosuccinimide (2.5 g, 11.0 mmol), and N,N-dimethylformamide (30 mL) were added sequentially. The reaction was heated to 70 °C and stirred overnight. Water (100 mL) was added to the reaction, and dichloromethane (50 mL x 3) was used to extract the organic phase. The combined organic phase was washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography (100% petroleum ether) to give compound R551-2 (white solid, 800 mg).

[0566] ​Step 2: Into a 50-mL round-bottom flask, was added compound R551-2 (800 mg, 2.4 mmol), 3,5-dimethyl-l-(2-tetrahydropyranyl)-lH-pyrazole-4-boronic acid pinacol ester (705 mg, 2.3 mmol), Pd(dppf)Cl2(8 mg, 0.01 mmol), potassium carbonate (954 mg, 6.9 mmol), dioxane / water (15 mL / 3 mL), and the reaction mixture was stirred at 80 °C under nitrogen overnight. The reaction mixture was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5: 1) to give compound R551-3 (yellow solid, 490 mg).

[0567] Step 3: Into a 50-mL round-bottom flask, was added R551-3 (200 mg, 0.5 mmol), methyl 2-iodo-5-methylbenzoate (288 mg, 1.1 mmol), Pd2(dba)3(40 mg, 0.04 mmol), XantPhos (80 mg, 0.1 mmol), Cs2CO3(256 mg, 0.8 mmol), toluene (15 mL), and the reaction mixture was stirred at 115 °C overnight. The reaction mixture was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5: 1) to give compound R551-4 (yellow solid, 118 mg).

[0568] Step 4: Into a 50-mL round-bottom flask, was added compound R551-4 (118 mg, 0.22 mmol) in methanol / water (2 mL / 1 mL), and lithium hydroxide (80 mg, 3.33 mmol). The reaction mixture was stirred at 50 °C overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane:methanol = 20: 1) to give compound R551-5 (white solid, 110 mg).

[0569] Step 5: Into a 25-mL round-bottom flask, was added compound R551-5 (110 mg, 0.2 mmol), 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (122 mg, 0.32 mmol), and N,N-dimethylformamide (10 mL), diisopropylethylamine (83 mg, 0.64 mmol), ammonium chloride (28 mg, 0.53 mmol), and the reaction mixture was stirred at 45 °C for 16 hours. To the reaction mixture was added 20 mL of water, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give R551-6 crude (yellow solid, 170 mg), which was used directly in the next step.

[0570] Step 6: Compound R551-6 (100 mg) was dissolved in dioxane (3 mL), HCl / dioxane solution (4 M, 1 mL) was added slowly, the reaction was stirred at room temperature for 24 hours, the solid was precipitated, filtered, washed with dioxane, dried, and the product compound R551 (hydrochloride, white solid, 40 mg) was obtained. LCMS: [M+H] + = 433; 1 H NMR (600 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.05 (s, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 2.0 Hz, 2H), 7.42 (s, 1H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 6.22 (d, J = 8.3 Hz, 1H), 2.33 (s, 6H), 2.23 (s, 3H).

[0571] Example 94: Synthesis of R554

[0572]

[0573] Step 1: In a 100 mL round-bottom flask, R554-1 (4.5 g, 22.4 mmol), concentrated sulfuric acid (2.5 g, 24.6 mmol), and methanol (30 mL) were sequentially added, and the reaction system was heated to 50°C and stirred for 7 hours. The reaction solution was neutralized to pH = 8-9 with a saturated sodium carbonate solution, extracted with dichloromethane (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain compound R554-2 (white solid, 3.8 g).

[0574] Step 2: In a 100 mL round-bottom flask, R554-2 (3.5 g, 16.3 mmol), N-chlorosuccinimide (2.4 g, 17.9 mmol), and N,N-dimethylformamide (30 mL) were sequentially added, and the reaction system was heated to 70°C and stirred overnight. Water (100 mL) was added to the reaction system, extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed sequentially with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 13: 1) to obtain compound R554-3 (white solid, 2.6 g).

[0575] Step 3: In a 50 mL round-bottom flask, compound R554-3 (1.85 g, 7.4 mmol), 3,5-dimethyl-1-(2-tetrahydropyranyl)-1H-pyrazole-4-boronic acid pinacol ester (2.5 g, 8.2 mmol), Pd(dppf)Cl2(19 mg, 0.02 mmol), potassium carbonate (3.1 g, 22.3 mmol), dioxane / water (30 mL / 5 mL), nitrogen atmosphere, heated to 80 °C and stirred overnight. The reaction was concentrated to dryness under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to give compound R554-4 (yellow solid, 1.5 g), which was used directly in the next step.

[0576] Step 4: In a 50 mL round-bottom flask, R554-4 (350 mg, 1.0 mmol), methyl 2-iodo-5-methylbenzoate (554 mg, 2.0 mmol), Pd2(dba)3(70 mg, 0.07 mmol), XantPhos (140 mg, 0.2 mmol), Cs2CO3(490 mg, 1.5 mmol), toluene (25 mL), heated to 115 °C and stirred overnight. Concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound R554-5 (yellow solid, 450 mg).

[0577] Step 5: Compound R554-5 (150 mg, 0.3 mmol) was dissolved in methanol / water (2 mL / 1 mL), and lithium hydroxide (145 mg, 6.0 mmol) was added. The reaction was heated to 50 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound R554-6 (white solid, 58 mg).

[0578] Step 6: In a 25 mL round-bottom flask, compound R554-6 (58 mg, 0.12 mmol), HATU (69 mg, 0.18 mmol), and N,N-dimethylformamide (10 mL) were added sequentially. After stirring at room temperature for 5 minutes, DIEA (47 mg, 0.36 mmol) and ammonium chloride (16 mg, 0.3 mmol) were added. The reaction was heated to 45 °C and stirred for 16 hours. Water (20 mL) was added to the reaction, and dichloromethane (3 x 10 mL) was used to extract the organic phase. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give R554-7 crude (yellow solid, 58 mg), which was used directly in the next step.

[0579] Step 7: The crude compound R554-7 (58 mg) was dissolved in dioxane (3 mL), and HCI / dioxane solution (4 M, 1 mL) was added slowly. The reaction was stirred at room temperature for 24 h. The solid was filtered, washed with dioxane, and dried to give the product compound R554 (HCI salt, white solid, 40 mg). LCMS: [M+H] + = 399; 1 H NMR (600 MHz, DMSO-d6) δ 7.56 - 7.54 (m, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.05 (dd, J = 8.4, 1.9 Hz, 1H), 6.18 (d, J = 8.4 Hz, 1H), 4.33 (s, 2H), 3.29 (s, 3H), 2.36 (s, 6H), 2.22 (s, 3H).

[0580] Example 95: Synthesis of R555

[0581]

[0582] Step 1: In a 50 mL round-bottom flask, R554-4 (226 mg, 0.6 mmol), B-3a (150 mg, 0.5 mmol), Pd2(dba)3 (30 mg, 0.03 mmol), XantPhos (60 mg, 0.1 mmol), Cs2CO3 (243 mg, 0.7 mmol), toluene (25 mL) were added sequentially under nitrogen atmosphere. The reaction was heated to 115 °C and stirred overnight. The reaction was concentrated to dryness under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to give compound R555-1 (yellow solid, 260 mg).

[0583] Step 2: Compound R555-1 (260 mg, 0.5 mmol) was dissolved in tetrahydrofuran / methanol / water (4 mL / 4 mL / 2 mL), and lithium hydroxide (145 mg, 6.0 mmol) was added. The reaction was heated to 50 °C and stirred overnight. The reaction was cooled to room temperature, adjusted to pH = 5-6 with dilute hydrochloric acid (2 M), and concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give compound R555-2 (white solid, 130 mg).

[0584] Step 3: Compound R555-2 (120 mg, 0.2 mmol) was dissolved in toluene (15 mL), and thionyl chloride (1.5 mL) was added slowly. The reaction system was heated to 100 °C and stirred for 4 min. Concentrated to dryness under reduced pressure, the crude product was dissolved in dichloromethane (4 mL) and added to ammonia water (4 mL) at 0 °C. Stirred at room temperature overnight, concentrated to dryness under reduced pressure, and the crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound R555 (yellow solid, 20 mg). LCMS: [M+H]=425. + 1 HNMR (600 MHz, DMSO-d6) δ 12.38 (s, 1H), 9.70 (s, 1H), 8.04 (s, 1H), 7.41-7.31 (m, 3H), 6.98 (d, J = 8.6 Hz, 1H), 6.14 (d, J = 8.5 Hz, 1H), 4.31 (s, 2H), 2.23 (s, 3H), 1.24 (s, 1H), 0.85 (d, J = 8.3 Hz, 2H), 0.64 (d, J = 5.4 Hz, 2H).

[0585] Other compounds were synthesized according to the method described in the above examples.

[0586] Bioexample 1 FTO inhibitory activity assay

[0587] High purity FTO protein was purified by nickel column affinity chromatography.

[0588] FTO enzyme activity inhibition reaction system: 50 mM Tris-HCl, pH = 7.5, 0.3 μM FTO, 1 μM 39 nt-m 6 A modified double-stranded DNA, 300 μM 2OG, 280 μM (NH4)2Fe(SO4)2, 2 mM L-Ascorbic Acid and different concentrations of compounds, incubated at room temperature for 2 h, slowly heated at 65 °C to inactivate, and 1 μM 39 nt antisense strand DNA was annealed into double-stranded. Take 8 μL of the reaction solution, and use methylation-sensitive enzyme DpnII to cut the double-stranded substrate. The enzyme-cleaved sample was detected by 15% non-denaturing polyacrylamide gel electrophoresis, and the gel was imaged after Gel-Red staining. The obtained band was read for inhibition rate.

[0589] The following Table 1 is the inhibition rate of 2-(substituted phenyl heteroaryl) aromatic carboxylic acid and its derivatives represented by general formula (I) at a concentration of 50 μM:

[0590] Table 1 Inhibition rate of compounds at a concentration of 50 μM on FTO enzyme

[0591]

[0592] ​

[0593]

[0594] From the analysis of the test results in Table 1, the compounds have strong inhibitory activity on FTO enzyme.

[0595] The following are compounds of 2-(substituted benzoheteroaryl) aromatic carboxylic acids and their derivatives represented by general formula (I) with an inhibition rate of more than 70% at a concentration of 50 μΜ, and further determination of the IC50of enzyme activity by the PAGE method. 50 The FTO enzyme activity test results of representative compounds described herein are shown in Table 2.

[0596] Table 2 FTO enzyme activity IC50of representative compounds 50

[0597]

[0598]

[0599] From the analysis of the test results in Table 2, most of the compounds have excellent FTO enzyme inhibitory activity.

[0600] Biological Example 2 Cell activity determination

[0601] The following are cytotoxicity studies of 2-(substituted benzoheteroaryl) aromatic carboxylic acids and their derivatives represented by general formula (I) as FTO inhibitors on human acute promyelocytic leukemia cells (NB4) and human acute myeloid leukemia cells (Molm13):

[0602] Leukemia cell lines such as NB4 and Molm13 were cultured respectively, and cells were seeded in 96-well plates at a density of 5000 cells per well. The cells were cultured until they adhered, different compounds were added for continued culture for 72 hours, 10 μL of MTS solution was directly added for incubation for 4 hours, and the absorbance value at 490 nm was detected. The inhibition rate was calculated with the DMSO group as a control.

[0603] The following are 2-(substituted benzoheteroaryl) aromatic carboxylic acid compounds represented by general formula (I) as FTO inhibitors with an inhibition rate of more than 60% on NB4 and Molm13 at a concentration of 10 μΜ and 40 μΜ at a time point of 72 hours, and further determination of the half maximal inhibitory concentration IC50. 50 The anti-cell proliferation activity test results of representative compounds described herein are shown in Table 3.

[0604] Table 3 Anti-cell proliferation activity of representative compounds

[0605]

[0606]

[0607]

[0608] From the analysis of the test results in Table 3, most of the compounds have excellent anti-cell proliferation activity.

[0609] Biological Example 3 Renal cancer cell line 786-O cell activity assay

[0610] The following is the study of the anti-proliferative activity of 2-(substituted phenyl heteroaryl) aromatic carboxylic acid and its derivatives of general formula (I) as FTO inhibitors on human renal cancer cells (786-O):

[0611] The 786-O cells were cultured and seeded in 96-well plates at a density of 2500 cells per well. After the cells adhered, different compounds were added for continuous culture for 72 hours. After the end of the culture, 10 μL of MTT solution was added for incubation for 4 hours, and the absorbance value at 490 nm was detected. The inhibition rate was calculated with the DMSO group as the control.

[0612] The single-point concentration of the preliminary screening compounds was 10 μM and 1 μM, and the half-inhibitory concentration (IC 50 The anti-cell proliferation activity test results of the representative compounds described herein are shown in Table 4:

[0613] Table 4 Anti-cell proliferation activity of representative compounds

[0614] Compound No. 1 2 3 4 5 Cell viability (IC 50 )(μM)786-O R248 0.074 R249 0.34 R250 0.30 R251 0.17 R252 0.22 R253 0.60 R335 0.16 R340 0.76 R308 0.71 R422 0.75 R426 0.74 R427 0.77 R501 0.44 R502 0.69 R506 0.5 R551 0.54 R554 0.70

[0615] Biological Example 4 Compound pharmacokinetic evaluation

[0616] Purpose of the experiment: to test the pharmacokinetics of the compound in mice

[0617] Experimental materials: ICR mice (male, 4-6 weeks old, Beijing Weitong Lihua)

[0618] Experimental operation: After the test compound was dissolved to obtain a clear solution, it was given to ICR mice (overnight fasting) by gavage (2 mg / kg). After gavage, blood samples of about 0.05 mL were collected from the cheeks of ICR mice at time points of 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours, and plasma was obtained after centrifugation. The drug concentration in the mouse plasma sample was determined by LC-MS / MS method, and the relevant pharmacokinetic parameters were calculated using WinNolin pharmacokinetic software. The test results are shown in Table 5:

[0619] Table 5 PK test results of the compound in mice

[0620]

[0621]

[0622] Note: T 1 / 2 : half-life; C max : peak concentration; T max : peak time; AUC 0-1ast : area under the plasma concentration-time curve from 0 time to 24 h.

[0623] Conclusion: The compound of the application has good oral exposure, and intragastrical administration is beneficial to produce good in vivo efficacy.

[0624] In vivo pharmacodynamic study of human acute myeloid leukemia Molm13 tail vein transplantation model

[0625] Purpose of the experiment: to evaluate the in vivo efficacy of the compound of the application in human acute myeloid leukemia Molm13 tail vein transplantation model.

[0626] Experimental animals: female NSG mice, 6-8 weeks old; supplier: Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0627] Experimental design:

[0628] Table 6 Experimental grouping

[0629]

[0630] Note: vehicle: vehicle control group; PO: intragastrical administration: QD: once a day;

[0631] Experimental process:

[0632] After irradiation, the NSG mice were injected with a certain number of Molm13 cells through the tail vein, and after 3-7 days, they were randomly divided into groups, and the experimental animals were given blank solvent (5% DMSO+5% Tween 80+40% PEG400+50% normal saline) or a certain dose (shown in Table 6) of the test product once a day by intragastrical administration, and the body weight and survival of the experimental animals in each group were recorded.

[0633] Experimental results:

[0634] The NSG mice were injected with Molm13 cells through the tail vein, and all the control groups were sick and died within 2-3 weeks. After treatment with the compound of the application, the experimental mice were delayed in the onset of the disease, and the survival rate and survival time of the mice were significantly prolonged.

[0635] Conclusion: The compound of the application has a significant therapeutic effect in the human acute myeloid leukemia Molm13 tail vein transplantation model.

[0636] All documents referred to in the present application are incorporated herein by reference as if each were individually incorporated. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that embodiments can be practiced without the specific details that are set forth herein. Further, it should be noted that, in this application, "exemplary" or "for example" is used on a purely illustrative basis to aid the reader in understanding the application. Any process steps, or sequences of steps, or examples, or embodiments, or materials, or components, or compounds, or elements, or techniques described herein are understood not to be limiting, but are exemplary.

Claims

1. A compound represented by formula (I) below, and a pharmaceutically acceptable salt thereof, in, A1 and A3 are each independently CH; A2 is N or CH; R1is selected from the group consisting of methyl, methoxy, cyclopropyl; and said R1may be substituted with one or more R f substituted, said R f is selected from the group consisting of deuterium; R2is selected from the group consisting of H, a halogen atom, a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted C1-C6alkoxy group, an unsubstituted or deuterated C3-C6cycloalkyl group, an unsubstituted or deuterated 3- to 6-membered heterocyclyl group; and 12 a C3-C6cycloalkyl group, a 3- to 6-membered heterocyclyl group; X has the structure of COOH, CONH2, CONHOH, CONHR e , COOR e ; R e is C1-C6 alkyl, C3-C6 cycloalkyl; R a , R b each independently is selected from the group consisting of halogen, CN, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted -(CH2) m -C1-C6alkoxy, C1-C6alkylthio, C3-C8cycloalkyl; wherein m is selected from the group consisting of 0, 1 or 2; R c R d Each is independently selected from the following group: H, halogens, C1-C6 alkyl groups; Ring A is a group selected from the following group: 5-6 membered heterocyclic group or 5-6 membered heteroaryl group; n is 0, 1, or 2; The substitution mentioned therein refers to the substitution of one or more hydrogen atoms by a substituent selected from the group consisting of: deuterium, halogen atom, carbonyl, hydroxyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, and halogenated C1-C6 alkoxy. The heterocyclic group is a saturated or partially unsaturated structure, but does not possess aromaticity; the carbocyclic ring, heterocyclic group, and heteroaromatic ring are monocyclic, spirocyclic, fused, or bridged rings; each heterocyclic group or heteroaromatic group independently contains 1, 2, 3, or 4 heteroatoms selected from O, S, and N.

2. The pharmaceutically acceptable salt of the compound as claimed in claim 1, characterized in that, R a R b Each is independently selected from the following group: halogen, CN, C1-C6 alkyl, halo-C1-C6 alkyl, -(CH2). m -C1~C6 alkoxy, halo-C1~C6 alkoxy, deuterated-C1~C6 alkoxy, C1~C6 alkylthio, C3~C8 cycloalkyl; wherein m is selected from the group consisting of 0 or 1; R c R d Each is independently selected from the following groups: H, halogen, methyl.

3. The compound of claim 1, and its pharmaceutically acceptable salt, characterized in that, The R mentioned c and R d Each is independently represented by H.

4. The compound of claim 1, and its pharmaceutically acceptable salt, characterized in that, The X is selected from the following group of structures: Where n is 0, 1, or 2; R e Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl; R g For H.

5. The compound of claim 1, and its pharmaceutically acceptable salt, characterized in that, The A ring is selected from the following group: pyridine, pyrimidine, pyridazine, thiophene, furan, tetrazolium, triazole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, oxadiazole, thiadiazole.

6. The compound of claim 1, and its pharmaceutically acceptable salt, characterized in that, The A ring mentioned above is selected from the following group:

7. The compound of claim 1, and its pharmaceutically acceptable salt, characterized in that, The R mentioned a R b Each of the following groups is selected independently: F, Cl, Br, methyl, ethyl, cyclopropane, isopropyl, methoxy, methylthio, -CH2OCH3, trifluoromethyl, trifluoromethoxy, difluoromethoxy, deuterated methoxy.

8. A compound selected from the group consisting of:

9. Use of a compound of formula (I) as claimed in claim 1 and a pharmaceutically acceptable salt thereof, characterized in that, For use in the group selected below: (a) To prepare drugs for treating diseases related to FTO protein activity or expression levels; (b) Preparation of FTO protein activity targeting inhibitors.

10. The use as described in claim 9, characterized in that, The diseases mentioned are selected from the following group: leukemia, lymphoma, myelodysplastic syndrome, obesity, metabolic syndrome, type II diabetes, Alzheimer's disease, breast cancer, kidney cancer, colorectal cancer, pancreatic cancer, liver cancer, small cell lung cancer, human bone marrow rhabdomyosarcoma, pancreatic cancer, and malignant glioblastoma of the brain.

11. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (i) an effective amount of a compound of formula (I) as described in any one of claims 1-8, and a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

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