Pyridyl-containing compounds

Abstract

The present disclosure provides pyridyl-containing compounds of formula I and methods for their preparation and use in the manufacture of medicaments for treating tumors. [Formula 1] TIFF2024539922000176.tif49170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure claims the benefit of and priority to Chinese invention patent application No. 202111269381.X filed with the State Intellectual Property Office of the People's Republic of China on October 29, 2021, Chinese invention patent application No. 202210233624.2 filed with the State Intellectual Property Office of the People's Republic of China on March 10, 2022, Chinese invention patent application No. 202210849103.X filed with the State Intellectual Property Office of the People's Republic of China on July 19, 2022, and Chinese invention patent application No. 202211274771.0 filed with the State Intellectual Property Office of the People's Republic of China on October 18, 2022, the contents of which are incorporated herein by reference in their entireties.

[0002] The present disclosure is in the field of medicinal chemistry and provides pyridyl-containing compounds (nuclear export protein inhibitors) and methods for their preparation and use in the manufacture of medicaments for treating tumors. [Background technology]

[0003] Nuclear exportin-1 (also called CRM-1 and XPO-1) is an important "carrier" protein for transporting some important growth regulatory proteins and tumor suppressors from the nucleus to the cytoplasm of eukaryotic cells. When nuclear exportin-1 efflux becomes abnormally high (e.g., due to overexpression of XPO-1), depletion of these nuclear regulators can lead to various diseases.

[0004] XPO1 is the only nuclear export factor that transports tumor suppressors (e.g., p53, p27, FOXO1, IkB) and is overexpressed in various solid tumors and hematological malignancies (e.g., GBM, ovarian cancer, pancreatic cancer, cervical cancer, AML, MM, CLL, and NHL). Here, the main point where XPO1 develops cancer is that XPO1 protein is overexpressed in multiple types of cancer cells and is associated with amplified cell cycle, depleting tumor suppressor proteins (e.g., p53, p27, FOXO1, IkB) in the cell nucleus and allowing the growth of cancer cells (e.g., ML Crochiere et al., Oncotarget v.7, p1863-1877 (2015)). In general, selective inhibitors of nuclear export (SINEs) are small molecules that exert their antiproliferative effects by covalently binding to the cysteine ​​at position 528 (Cys528) in the cargo-binding pocket of Exportin-1 (XPO1, also known as CRM1 (chromosome maintenance protein 1)). The interaction of XPO1 with the activated small GTP protein Ran (Ran-GTP) in the cell nucleus promotes the binding of XPO1 to cargo proteins that contain a short amino acid sequence of hydrophobic residues called the nuclear export signal (NES).

[0005] Preclinical results show that similar pathologies are also involved in many inflammatory, neurodegenerative and autoimmune diseases. Thus, for example, glucocorticoids are widely used anti-inflammatory and immunomodulatory drugs, whose therapeutic effect / mechanism of action is mainly to interfere with the overactivity of transcription factors such as NF-κB in the cell nucleus by sufficiently restoring the steroid-activated glucocorticoid receptor (GR). Summary of the Invention [Problem to be solved by the invention]

[0006] Currently, the clinical efficacy of drugs that suppress diseases caused by excessive XPO-1 shedding has been proven by the US FDA, but new drug therapies are still urgently needed for many diseases. [Means for solving the problem]

[0007] The present disclosure provides a compound according to Formula I, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof:

[0008] [ka]

[0009] (In the formula, R 1 is -NH2, C 1~6 Alkyl-O-, C 1~6 Alkyl-NH- or (C 1~6 alkyl)2N-; Ring A is C 6~10 selected from an aromatic ring group or a 5- to 10-membered heteroaromatic ring group; R is halogen, CN, OH, NH2, C 1~6 Alkyl, C 1~6 Alkyl-O-, C 1~6 Alkyl-S-, halogenated C 1~6 Alkyl-O-, halogenated C 1~6 Alkyl-S-, halogenated C 1~6 C substituted with alkyl, 3-10 membered heterocycloalkyl 1~6 Alkyl, R a NH- or (R a )2N- selected from; R a is C 1~6 Alkyl, C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, a are halogens, CN, OH, NH2, C 1~6 Alkyl, C 1~6 may be substituted by one or more groups selected from alkylO- or 5- to 6-membered heterocycloalkyl; n is selected from 0, 1, 2, 3 or 4; R 2 is selected from cyclopropyl or trifluoromethyl.

[0010] In some embodiments, the R 1 is -NH2, C 1~4 Alkyl-O- or C 1~4 Alkyl-NH- or (C 1~4 alkyl)2N-.

[0011] In some embodiments, the R 1 is -NH2, C 1~3 Alkyl-O- or C 1~3 Alkyl-NH- or (C 1~3 alkyl)2N-.

[0012] In some embodiments, the R 1 is selected from -NH2, isopropyl-O-, or methyl-NH-. 1 is selected from -NH2, or isopropyl-O-. 1 is selected from -NH2.

[0013] In some embodiments, ring A is selected from phenyl or a 5-10 membered heteroaromatic ring group. In some embodiments, ring A is selected from a 5-, 6-, 7-, 8-, 9- or 10-membered heteroaromatic ring group. In some embodiments, ring A is selected from a 5- or 6-membered or 9- or 10-membered heteroaromatic ring group. In some embodiments, ring A is selected from a 6- or 10-membered heteroaromatic ring group. In some embodiments, ring A is selected from a 10-membered heteroaromatic ring group. In some embodiments, ring A is selected from a 5- or 6-membered heteroaromatic ring group. In some embodiments, ring A is selected from a 6-membered heteroaromatic ring group.

[0014] In some embodiments, Ring A is selected from pyrimidinyl, pyridyl, pyrazolyl, isoxazolyl, oxazolyl, quinolyl, indazolyl, pyridazinyl, thiazolyl, furanyl, pyranyl, thienyl, pyrrolyl, pyrazinyl, isothiazolyl, oxazolyl, indolyl, naphthyridinyl, isoquinolinyl, quinazolinyl, benzofuranyl.

[0015] In some embodiments, ring A is selected from pyrimidinyl, pyridyl, pyrazolyl, isoxazolyl, quinolyl, indazolyl, naphthyridinyl or isoquinolinyl. In some specific embodiments, ring A is selected from pyrimidinyl or pyridyl; in some specific embodiments, ring A is selected from pyrimidinyl; in some specific embodiments, ring A is selected from pyridyl; in some specific embodiments, ring A is selected from pyrazolyl or isoxazolyl; in some specific embodiments, ring A is selected from quinolyl, indazolyl, naphthyridinyl or isoquinolinyl; in some specific embodiments, ring A is selected from quinolyl or naphthyridinyl.

[0016] In some embodiments, ring A is

[0017] [ka]

[0018] is selected from. In some embodiments, ring A is

[0019] [ka]

[0020] is selected from. In some other embodiments, Ring A is selected from pyrimidinyl, pyridyl, pyrazolyl, isoxazolyl, quinolyl, indazolyl, pyridazinyl, thiazolyl, furanyl, thienyl, pyrrolyl, pyrazinyl, isothiazolyl, oxazolyl, or indolyl.

[0021] In some other embodiments, Ring A is selected from pyrimidinyl, pyridyl, pyrazolyl, isoxazolyl, quinolyl, or indazolyl.

[0022] In some other embodiments, ring A is

[0023] [ka]

[0024] is selected from. In some other embodiments, ring A is

[0025] [ka]

[0026] is selected from. In some embodiments, R is halogen, CN, OH, NH, C 1~4 Alkyl, C 1~4 Alkyl-O-, C 1~4 Alkyl-S-, halogenated C 1~4 Alkyl-O-, halogenated C 1~4 Alkyl-S-, halogenated C 1~4 Alkyl, R a NH- or (R a )2N-.

[0027] In some embodiments, R is halogen, CN, OH, NH, C 1~3 Alkyl, C 1~3 Alkyl-O-, C 1~3 Alkyl-S-, halogenated C 1~3 Alkyl-O-, halogenated C1~3 Alkyl-S-, halogenated C 1~3 Alkyl, R a NH- or (R a In some embodiments, R is selected from fluorine, chlorine, CN, OH, NH, C 1~3 Alkyl, C 1~3 Alkyl-O-, halogenated C 1~3 Alkyl or R a NH-.

[0028] In some embodiments, R is fluorine, CN, NH, methyl, methoxy, trifluoromethyl or R a NH-.

[0029] In some embodiments, the R a is C 1~4 Alkyl, C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl, a is optionally substituted by one or more groups selected from halogen, CN, OH, NH2, or 5- to 6-membered heterocycloalkyl.

[0030] In some embodiments, the R a is C 1~3 Alkyl, C 5~6 cycloalkyl or 5- to 6-membered heterocycloalkyl, a is optionally substituted by one or more groups selected from halogen, CN, OH, NH2, or 5- to 6-membered heterocycloalkyl.

[0031] In some embodiments, the R a is C 1~3 alkyl or 5- to 6-membered heterocycloalkyl, a is optionally substituted by one or more groups selected from halogen, CN, OH, NH2, or 5- to 6-membered heterocycloalkyl.

[0032] In some embodiments, the R a is C 1~3 alkyl or 6-membered heterocycloalkyl, a is optionally substituted by one or more groups selected from fluorine, chlorine, bromine, CN, OH, NH2 or 6-membered heterocycloalkyl.

[0033] In some embodiments, the R a is selected from methyl, ethyl, propyl, or tetrahydropyranyl; a may be substituted by one or more fluorines or dioxanes.

[0034] In some embodiments, the R a is selected from FCH2CH2-, F2CHCH2-, F3CCH2-, CF3CH(CH3)-, CH3CF2CH2-, tetrahydropyranyl or dioxane-CH2-.

[0035] In some embodiments, R is fluorine, CN, NH, methyl, methoxy, trifluoromethyl,

[0036] [ka]

[0037] is selected from. In some embodiments, n is selected from 0, 1, 2, or 3.

[0038] In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1. In some embodiments, n is selected from 0;

[0039] In some embodiments, R 2 is selected from cyclopropyl. In some embodiments, the structural unit

[0040] [ka]

[0041] teeth,

[0042] [ka]

[0043] is selected from. In some embodiments, the structural unit

[0044] [ka]

[0045] teeth,

[0046] [ka]

[0047] is selected from. In some embodiments, the structural unit

[0048] [ka]

[0049] teeth,

[0050] [ka]

[0051] In some embodiments, the structural unit is selected from

[0052] [ka]

[0053] teeth,

[0054] [ka]

[0055] In some embodiments, the structural unit is selected from

[0056] [ka]

[0057] teeth,

[0058] [ka]

[0059] is selected from. In some embodiments, the structural unit

[0060] [ka]

[0061] teeth,

[0062] [ka]

[0063] is selected from. In some embodiments, the structural unit

[0064] [ka]

[0065] teeth,

[0066] [ka]

[0067] is selected from. In some embodiments, the structural unit

[0068] [ka]

[0069] teeth,

[0070] [ka]

[0071] is selected from. In some other embodiments, the structural unit

[0072] [ka]

[0073] teeth,

[0074] [ka]

[0075] is selected from. In some embodiments, the structural unit

[0076] [ka]

[0077] teeth,

[0078] [ka]

[0079] is selected from. In some embodiments, the structural unit

[0080] [ka]

[0081] teeth,

[0082] [ka]

[0083] is selected from. In some embodiments, the structural unit

[0084] [ka]

[0085] teeth,

[0086] [ka]

[0087] is selected from. In some embodiments, the structural unit

[0088] [ka]

[0089] teeth,

[0090] [ka]

[0091] In some embodiments, the structural unit is selected from

[0092] [ka]

[0093] teeth,

[0094] [ka]

[0095] is selected from. In some embodiments, the structural unit

[0096] [ka]

[0097] teeth,

[0098] [ka]

[0099] is selected from. In some other embodiments, the structural unit

[0100] [ka]

[0101] teeth,

[0102] [ka]

[0103] is selected from. In some embodiments, the structural unit

[0104] [ka]

[0105] teeth,

[0106] [ka]

[0107] is selected from. In some other embodiments, the structural unit

[0108] [ka]

[0109] teeth,

[0110] [ka]

[0111] is selected from. In some other embodiments, the structural unit

[0112] [ka]

[0113] teeth,

[0114] [ka]

[0115] is selected from. In some embodiments, the compound represented by formula I, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof is selected from the compounds represented by formula I-1, I-2, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

[0116] [ka]

[0117] (In the formula, R and n are as described in this disclosure.) T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from a bond, O, S, N, or CH, provided that no more than one is selected from a bond and at least one is selected from N;

[0118] [ka]

[0119] represents a single bond or a double bond. In some embodiments, T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from N or CH, with at least one selected from N.

[0120] In some embodiments, T 2 and T 4 is selected from N, T 1 , T 3 and T 5 is selected from CH.

[0121] In some embodiments, T 3 is selected from N, T 1 , T 2 , T 4 and T 5 is selected from CH.

[0122] In some embodiments, T 2 is selected from N, T 1 , T 3 , T 4 and T 5 is selected from CH.

[0123] In some embodiments, the structural unit

[0124] [ka]

[0125] teeth,

[0126] [ka]

[0127] is selected from. In some embodiments, the structural unit

[0128] [ka]

[0129] teeth,

[0130] [ka]

[0131] is selected from. In some embodiments, the structural unit

[0132] [ka]

[0133] teeth,

[0134] [ka]

[0135] In some embodiments, the structural unit is selected from

[0136] [ka]

[0137] teeth,

[0138] [ka]

[0139] In some embodiments, the structural unit is selected from

[0140] [ka]

[0141] teeth,

[0142] [ka]

[0143] In some embodiments, the structural unit is selected from

[0144] [ka]

[0145] teeth,

[0146] [ka]

[0147] is selected from. In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0148] The heteroatoms in the heterocycloalkyl or heteroaromatic ring group are selected from nitrogen, oxygen or sulfur, and the other ring atoms are selected from carbon. The heteroatoms in the heterocycloalkyl or heteroaromatic ring group are selected from nitrogen or oxygen, and the other ring atoms are selected from carbon. The heteroatoms in the heterocycloalkyl or heteroaromatic ring group are selected from nitrogen, and the other ring atoms are selected from carbon. In some embodiments, the number of heteroatoms is selected from 1, 2, 3 or 4. In some embodiments, the number of heteroatoms is selected from 1, 2 or 3. In some embodiments, the number of heteroatoms is selected from 1 or 2.

[0149] The present disclosure provides the following compounds, pharma- ceutically acceptable salts thereof, or stereoisomers thereof:

[0150] [ka]

[0151] [ka]

[0152] [ka]

[0153] [ka]

[0154] [ka]

[0155] [ka]

[0156] [ka]

[0157] In another aspect, the present disclosure further provides a pharmaceutical composition comprising the above compound, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharma- ceutically acceptable additive component.

[0158] In another aspect, the present disclosure further provides methods for treating various XPO-1-related diseases, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound according to the present disclosure, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition thereof.

[0159] In another aspect, the present disclosure further provides the use of a compound according to the present disclosure, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating various XPO-1-related diseases.

[0160] In another aspect, the present disclosure further provides the use of a compound according to the present disclosure, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition thereof, in the treatment of various XPO-1-related diseases.

[0161] In another aspect, the present disclosure further provides a compound according to the present disclosure, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition thereof for treating various XPO-1-related diseases.

[0162] In some embodiments, the XPO-1-associated disease is selected from a tumor; in some embodiments, the XPO-1-associated disease is selected from a leukemia or lymphoma. Effect of the Invention

[0163] The compounds of the present disclosure have cell (e.g., Jurkat cells and / or OCI-LY10 cells) proliferation inhibitory activity, stable in vitro liver microsomal metabolism, good human whole blood stability, good in vivo pharmacokinetic data (parameters such as AUC, Cmax, Tmax or absolute bioavailability), in vivo pharmacodynamic data, and in vivo safety data (parameters such as brain-blood ratio). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0164] definition Unless otherwise specified, the following terms in the present invention are defined as follows. Certain terms should not be considered uncertain or unclear in the absence of a specific definition, but should be understood according to their usual meaning in the art. Trade names in this specification are intended to refer to the corresponding products or their active ingredients.

[0165] When a covalent bond in any structural unit or group in this disclosure is not attached to a specific atom, it is meant that the covalent bond may be attached to any atom in that structural unit or group, unless valence bond conventions are violated.

[0166] The term "substituted" means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, provided that the valence state of the specified atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Substitution with oxo does not occur on aromatic groups.

[0167] The term "may" or "optionally" means that the event or circumstance described below may or may not occur, and the phrase includes both the occurrence and non-occurrence of such an event or circumstance. For example, ethyl "may" be substituted by a halogen means that ethyl can be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is not spatially possible and / or cannot be synthesized is introduced.

[0168] As used herein, "one or more" refers to an integer between 1 and 10. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten. Alternatively, "one or more" refers to one, two, three, four, five, or six. Alternatively, "one or more" refers to one, two, or three.

[0169] In this specification, C m~n means that the moiety has an integer number of carbon atoms within a specified range. For example, "C 1~6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. For example, C 1~3 means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0170] When any variable (e.g., R) occurs more than one time in any composition or structure of a compound, its definition at each occurrence is independent. Thus, for example, when a group is substituted with two R, each R has independent choice.

[0171] For example, when the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0172] When a variable is selected from a covalent bond, it means that the two groups connected to it are directly linked, for example, when L' in A-L'-Z represents a covalent bond, it means that the structure is actually AZ.

[0173] If a bond of a substituent crosses two atoms on a ring, then such substituent may be bonded to any atom on the ring. For example, the structural unit

[0174] [ka]

[0175] means that it can be substituted at any one position on the cyclohexyl or cyclohexadiene.

[0176] The term "halogen" refers to fluorine, chlorine, bromine and iodine. The term "alkyl" refers to a group having the general formula C n H 2n+1 The alkyl group may be linear or branched. For example, the term "C 1~6 "Alkyl" refers to an alkyl having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio are as defined above. Also, for example, the term "C 1~3 "Alkyl" refers to an alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl).

[0177] The term "alkoxy" refers to --O-alkyl. The term "cycloalkyl" refers to a carbocycle that is fully saturated and can exist as a monocyclic, bridged, or spirocycle. Unless otherwise specified, the carbocycle is typically 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 membered). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pentan-1-yl, and the like. For example, C 3~4 Cycloalkyl includes cyclopropyl and cyclobutyl.

[0178] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged (including fused) or spirocyclic ring. Unless otherwise specified, the heterocycle is typically a 3- to 7-membered ring (e.g., a 3-, 4-, 5-, 6- or 7-membered ring) containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Examples of 3-membered heterocycloalkyls include, but are not limited to, oxiranyl, thiiranyl, and aziranyl. Non-limiting examples of 4-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocycloalkyls include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-oxathianyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Monocyclic heterocycloalkyls having 5 or 6 ring atoms are preferred.

[0179] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system. For example, an aryl can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetralin.

[0180] The term "heteroaryl" or the term "heteroaromatic ring group" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, S, the other ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have one 5-8 membered ring (e.g., 5-, 6-, 7-, or 8-membered ring) or multiple fused rings (e.g., 6-, 7-, 8-, 9-, or 10-membered rings) containing 6-14, especially 6-10, ring atoms. Non-limiting examples of heteroaryl include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, naphthyridinyl, indazolyl, isoindolyl, and the like.

[0181] The term "treating" means administering a compound or formulation according to the present disclosure to improve or eliminate a disease or one or more symptoms associated with said disease, including:

[0182] (i) To inhibit the disease or condition, i.e., to arrest its progression. (ii) Alleviating the disease or condition, i.e., reducing or eliminating the disease or condition.

[0183] The term "preventing" refers to administering a compound or formulation according to the present disclosure to prevent a disease or one or more symptoms associated with said disease, and includes preventing the occurrence of a disease or disease state in a mammal, particularly where such a mammal is predisposed to the disease state but has not yet been diagnosed as suffering from it.

[0184] The term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the method of administration, and the age of the mammal being treated, but can be routinely determined by one of ordinary skill in the art based on his or her own knowledge and the contents of this disclosure.

[0185] The term "pharmacologically acceptable" means that the compound, material, composition, and / or dosage form is, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0186] Examples of pharma- ceutically acceptable salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.

[0187] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharma- ceutical acceptable additives. Pharmaceutical compositions are intended to facilitate administration of the compounds of the present disclosure to a living organism.

[0188] The term "pharmaceutical acceptable additive" refers to an additive that has no significant irritating effect on the living body and does not impair the biological activity and performance of the active compound. Suitable additives are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0189] The terms "comprise" or "comprise" and their English variants, such as comprises or comprising, are to be understood in an open, non-exclusive sense, i.e., "including but not limited to."

[0190] The compounds and intermediates of the present disclosure may exist in different tautomeric forms, and all such forms are within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via the transfer of a proton, such as keto-enol isomerization and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can transfer between two ring nitrogens. Valence tautomers include interconversions via recombination of some of the bonding electrons.

[0191] The present disclosure further includes isotopic labels as described herein, except that one or more atoms are replaced with an atom having an atomic mass or mass number different from that typically found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O.31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 It is Cl.

[0192] Some isotopically labeled versions of the compounds of the present disclosure (e.g., 3 H and 14 C) can be used in compound and / or substrate tissue distribution assays. 3 H) isotopes and carbon-14 (i.e. 14 C) Isotopes are particularly preferred because they are easy to prepare and detect. 15 O. 13 N, 11 C. 18 Positron emitting isotopes such as F are useful for Positron Emission Topography (PET) studies to measure substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared following procedures similar to those disclosed in the schemes and / or examples below by substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0193] Additionally, heavier isotopes (e.g. deuterium (i.e. 2 H)) substitution may confer certain therapeutic benefits (e.g., increased in vivo half-life and reduced dosage needs) resulting from greater metabolic stability and therefore may be preferred in some circumstances. Deuterium substitution may be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium. All such forms of the compound are within the scope of the present disclosure.

[0194] The compounds of the present disclosure may be asymmetric, such as having one or more stereoisomers.Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers.Compounds of the present disclosure that contain asymmetric carbon atoms can be isolated in optically pure or racemic form.Optical pure forms can be resolved from racemic mixtures or synthesized using chiral raw materials or chiral reagents.

[0195] The pharmaceutical composition of the present disclosure can be prepared by combining the compound of the present disclosure with suitable pharma- ceutical acceptable additives.For example, the pharmaceutical composition of the present disclosure can be prepared into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0196] Typical routes of administration of the disclosed compounds or pharma- ceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0197] The pharmaceutical compositions of the present disclosure can be manufactured by using conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, and lyophilizing methods which are well known in the art.

[0198] In some embodiments, pharmaceutical composition is in oral form.For oral administration, active compound can be mixed with pharmaceutically acceptable additives known in the art to prepare said pharmaceutical composition.These additives can allow the compound of the present disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, syrups, suspensions, etc. for oral administration to patients.

[0199] The solid oral composition can be prepared by conventional mixing, filling or tabletting methods. For example, the mixture of the active compound and solid additives is optionally milled, other suitable additives are added as necessary, and the mixture is then processed into granules to obtain tablets or sugar-coated cores. Suitable additives include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0200] The pharmaceutical compositions are suitable for parenteral administration, such as sterile solutions, suspensions, or lyophilized products in appropriate unit dosage forms.

[0201] The therapeutic dose of the compounds of the present disclosure may be determined, for example, based on the specific application of the treatment, the method of administration of the compound, the health of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present disclosure in a pharmaceutical composition is not fixed and depends on a variety of factors, including the dose, chemical properties (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present application may be provided for parenteral administration in an aqueous physiological buffer solution containing about 0.1 to 10% w / v of the compound. Typical dose ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dose will depend on such variables as the type and progression of the disease or condition, the general health of the particular patient, the relative biological potency of the selected compound, the formulation of excipients and their route of administration. Effective doses may be obtained by extrapolation of dose-response curves derived from in vitro or animal model test systems.

[0202] The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those of skill in the art, including the specific embodiments exemplified below, embodiments formed in combination with other chemical synthetic methods, and equivalent alternative embodiments known to those of skill in the art, and preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0203] The chemical reactions in the specific embodiments of the present disclosure are completed in a suitable solvent, which must be suitable for the chemical transformations of the present disclosure and the necessary reagents and materials thereof. In order to obtain the compounds of the present disclosure, in some cases, those skilled in the art may need to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0204] One important consideration in designing a synthetic route in the art is the selection of a suitable protecting group for a reactive functional group (e.g., an amino group in the present disclosure). For example, Greene's Protective Groups in Organic Synthesis (4th Ed.), Hoboken, New Jersey: John Wiley & Sons, Inc. may be referred to.

[0205] In some embodiments, compounds of the present disclosure can be prepared by the following preparation schemes in combination with methods known in the art.

[0206] [ka]

[0207] In the formula, ring A, R, n, R 2 and R 1 are as defined in this disclosure. The following abbreviations are used in this disclosure:

[0208] Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium, DMF represents N,N-dimethylformamide, DABCO represents triethylenediamine, THF represents tetrahydrofuran, and SEM represents trimethylsilylethoxymethyl.

[0209] The present disclosure will be described in detail with reference to the following examples, which are not intended to limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification. EXAMPLES

[0210] Example 1

[0211] [ka]

[0212] (1) Preparation of Compound 1-2 Bis(pinacolato)diboron (2.13 g), 4,4'-di-tert-butyl-2,2'-dipyridine (18.7 mg), and methoxy(cyclooctadiene)iridium dimer (23.1 mg) were added to cyclohexane (30 mL) and stirred for 10 minutes under nitrogen gas protection. 3,5-bis(trifluoromethyl)pyridine (compound 1-1, 3.0 g) was added and stirred under nitrogen gas protection at 55°C. After the reaction was completed, the reaction solution was quenched by adding ice water (20 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain compound 1-2, which was used as is in the next reaction.

[0213] (2) Preparation of Compound 1-3 Compound 1-2 (4.7 g) was added to ethylene glycol dimethyl ether (50 mL), 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (3.9 g), potassium carbonate (5.8 g) aqueous solution (10 mL) were added, and the mixture was stirred at room temperature under nitrogen gas protection. After 1 hour, tetrakis(triphenylphosphine)palladium (805.8 mg) was added, and the mixture was stirred at 90 ° C under nitrogen gas protection. After the reaction was completed, the reaction solution was quenched by adding ice water (40 mL), extracted with ethyl acetate (100 mL), the organic phase was collected, washed with brine (50 mL × 2), the organic layer was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 1-3, which was used directly in the next reaction.

[0214] (3) Preparation of Compound 1-4 Compound 1-3 (5.7 g) was dispersed in 4M HCl / dioxane (50 mL) and stirred at 60°C. After the reaction was completed, the reaction solution was slowly poured into ice-cooled saturated sodium bicarbonate solution, adjusted to pH = 6-7 with sodium bicarbonate, and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated saline (100 mL) and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure until no liquid flowed out, and purified by column chromatography to obtain compound 1-4.

[0215] (4) Preparation of Compounds 1-5 Compound 1-4 (900 mg) was dispersed in DMF (20 mL), DABCO (716 mg) was added, and the mixture was stirred at 20-25°C for 30 minutes. The temperature was then lowered to 0-10°C, and compound 1-4a (1.15 g) was added dropwise. After the addition was completed, the mixture was stirred at 20-25°C for 1.5 hours. After the reaction was completed, the reaction solution was poured into 50 mL of water and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain compound 1-5 (750 mg).

[0216] (5) Preparation of Compounds 1-6 Compound 1-5 (750 mg) was added to dichloromethane (20 mL), the temperature was lowered to 0°C, and liquid bromine (605 mg) was added dropwise over 15 minutes. The temperature was then slowly raised to room temperature and stirred for 4 hours. After the reaction was completed, the reaction mixture was poured into 30 mL of ice water and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated sodium hydrogen sulfite solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure until no liquid flowed out, and purified by column chromatography to obtain compound 1-6.

[0217] (6) Preparation of Compounds 1-7 Compound 1-6 (1.05 g) was added to THF (20 mL), the temperature was lowered to 0°C, and triethylamine (383.5 mg) was added dropwise. After the dropwise addition was completed, the temperature was slowly raised to room temperature and the reaction was allowed to proceed for 12 hours. After the reaction was completed, 20 mL of water was added to dilute the reaction solution, and the solution was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 1-7.

[0218] (7) Preparation of Compounds 1-8 Compound 1-7 (700 mg), 5-pyrimidineboronic acid (220 mg), potassium acetate (435.7 mg), and Pd(dppf)Cl2 (54 mg) were added to 20 mL of dioxane and 2 mL of water, and the mixture was heated to 90°C under nitrogen gas protection to allow the reaction to proceed completely. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and purified by column chromatography to give compound 1-8 (200 mg).

[0219] (8) Preparation of Compound 1-9 Compound 1-8 (200 mg) was dissolved in tetrahydrofuran (15 mL), and a solution of sodium hydroxide (33.9 mg) and water (15 mL) was added dropwise in an ice-water bath, and the mixture was allowed to react at room temperature overnight. The reaction solution was adjusted to acidic (pH 3-5) with hydrochloric acid, and extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 1-9, which was used directly in the next reaction.

[0220] (9) Preparation of Example 1 Compound 1-9 (182 mg) was added to tetrahydrofuran (15 mL), and N-methylmorpholine (85.6 mg) and isobutyl chloroformate (115.5 mg) were added under ice water bath, and the mixture was stirred for 30 minutes. Ammonia water (88.8 mg) was added, and the mixture was reacted for 10 minutes in an ice water bath, and the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified to obtain Example 1 (13 mg). ESI-MS: m / z = 430.26 [M + H]+ . 1 HNMR (500MHz, DMSO-d6) δ9.22 (d, J = 9.8 Hz, 2H), 8.74 (s, 2H), 8.45 (s, 1H), 8.07 (s, 2H), 7.68 (s, 1H), 7.44 (s, 1H).

[0221] Example 2

[0222] [ka]

[0223] (1) Preparation of Compound 2-2 Compounds 1-7 (394 mg) and 2-1 (285 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (244 mg), Pd(dppf)Cl2 (29 mg) and water (0.8 mL) were added, and the mixture was heated to 90°C under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 2-2.

[0224] (2) Preparation of Compound 2-3 Compound 2-2 (100 mg) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (38.1 mg) and water (5 mL) was added dropwise in an ice-water bath. The reaction was allowed to proceed at room temperature for 2 hours, and the pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, followed by extraction with ethyl acetate (20 mL x 2). The solution was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 2-3, which was used directly in the next reaction.

[0225] (3) Preparation of Compound 2 Compound 2-3 (91 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (36 mg) and isobutyl chloroformate (49 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (38 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 2 (41 mg) was obtained by fractionation and purification. ESI-MS: m / z = 509.32 [M + H]+ .

[0226] 1 HNMR(500MHz,DMSO-d6)δ9.14(s,1H),8.25(d,J=10.4Hz,5H),7.76(t,J=6.2Hz,1H),7.58(s ,1H),7.43(s,1H),6.09(tt,J=56.5,4.2Hz,1H),3.74(dddd,J=19.0,14.9,8.2,5.2Hz,2H).

[0227] Example 3

[0228] [ka]

[0229] (1) Preparation of Compound 3-2 Compounds 1-7 (394 mg) and 3-1 (299 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (244 mg), Pd(dppf)Cl2 (29 mg) and water (0.8 mL) were added, and the mixture was heated to 90°C under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 3-2.

[0230] (2) Preparation of Compound 3-3 Compound 3-2 (360 mg) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (133.6 mg) and water (5 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 3-3, which was used directly in the next reaction.

[0231] (3) Preparation of Compound 3 Compound 3-3 (335 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (129 mg) and isobutyl chloroformate (175 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (134 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 3 (90 mg) was obtained by fractional purification. ESI-MS: m / z = 523.37 [M + H] + .

[0232] 1 HNMR(500MHz,DMSO-d6)δ9.14(s,1H),8.26(s,2H),8.21(d,J=5.5Hz,3H),7.76(t,J=6.6 Hz,1H),7.57(s,1H),7.45(s,1H),3.83(td,J=13.6,6.6Hz,2H),1.61(t,J=19.0Hz,3H).

[0233] Example 4

[0234] [ka]

[0235] (1) Preparation of Compound 4-2 Compounds 1-7 (300 mg) and 4-1 (230 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (46 mg) and water (0.8 mL) were added, and the mixture was heated to 90°C under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 4-2.

[0236] (2) Preparation of Compound 4-3 Compound 4-2 (302 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (44.6 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 4-3, which was used as is in the next reaction.

[0237] (3) Preparation of Compound 4 Compound 4-3 (280 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (107 mg) and isobutyl chloroformate (145 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (111 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 4 (30 mg) was obtained by fractionation and purification. ESI-MS: m / z = 527.17 [M + H] + .

[0238] 1 HNMR(500MHz,DMSO-d6)δ9.16(s,1H),8.24(d,J=4.6Hz,5H),7.99(t,J=6.7Hz,1H),7.57(s,1H),7.45(s,1H),4.18(q,J=8.7,8.3Hz,2H).

[0239] Example 5

[0240] [ka]

[0241] (1) Preparation of Compound 5-2 Compounds 1-7 (300 mg) and 5-1 (241 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (187 mg), Pd(dppf)Cl2 (23 mg) and water (0.8 mL) were added, and the mixture was heated to 90°C under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 5-2.

[0242] (2) Preparation of Compound 5-3 Compound 5-2 (200 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (29 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at 0 to 10°C for 3 hours. The pH of the reaction solution was adjusted to 3 to 5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 5-3, which was used directly in the next reaction.

[0243] (3) Preparation of Compound 5 Compound 5-3 (185 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (69 mg) and isobutyl chloroformate (94 mg) were added in an ice-water bath and stirred for 30 minutes. Aqueous ammonia (72 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 5 (50 mg) was obtained by fractionation and purification. ESI-MS: m / z = 541.25 [M + H] + .

[0244] 1 HNMR(500MHz,DMSO-d6)δ9.17(d,J=3.5Hz,1H),8.25(q,J=3.8Hz,5H),7.96(dd,J=9.3 ,3.2Hz,1H),7.58(s,1H),7.47(s,1H),5.02-4.86(m,1H),1.36(dd,J=7.3,3.2Hz,3H).

[0245] Example 6

[0246] [ka]

[0247] (1) Preparation of Compound 6-1 Compound 1-7 (200 mg) and pyridine-4-boronic acid (62.35 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (124.4 mg), Pd(dppf)Cl2 (15.5 mg) and water (1 mL) were added, and the mixture was heated to 90° C. under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 6-1.

[0248] (2) Preparation of Compound 6-2 Compound 6-1 (150 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (67.14 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 6-2, which was used directly in the next reaction.

[0249] (3) Preparation of Compound 6 Compound 6-2 (137.4 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (64.74 mg) and isobutyl chloroformate (87.41 mg) were added in an ice-water bath and stirred for 30 minutes. Aqueous ammonia (67.2 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 6 (10 mg) was obtained by fractional purification. ESI-MS: m / z = 429.19 [M + H] + .

[0250] 1 HNMR(500MHz,DMSO-d6)δ9.02(s,1H),8.65(d,J=5.0Hz,2H),8.26(s,1H),8.10(s,2H),7.66(s,1H),7.32(d,J=5.0Hz,2H),7.23(s,1H).

[0251] Example 7

[0252] [ka]

[0253] (1) Preparation of Compound 7-1 Compound 1-7 (300 mg) and 1-methylpyrazole-4-boronic acid pinacol ester (158.3 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (46 mg) and water (0.8 mL) were added, and the mixture was heated to 90° C. under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 7-1, which was used as it was in the next reaction.

[0254] (2) Preparation of Compound 7-2 Compound 7-1 (298 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (52.87 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 7-2, which was used as is in the next reaction.

[0255] (3) Preparation of Compound 7 Compound 7-2 (270 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (127.45 mg) and isobutyl chloroformate (154.41 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (132.3 mg) was added dropwise and reacted in an ice-water bath for 10 minutes, then water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 7 (77 mg) was obtained by fractionation and purification. ESI-MS: m / z = 432.18 [M + H] + .

[0256] 1HNMR (500MHz, DMSO-d6) δ8.87(s,1H),8.48(s,2H),7.84(s,1H),7.73(s,1H),7.58(s,1H),7.54(s,1H),7.26(d,J=0.9Hz,1H),3.85(s,3H).

[0257] Example 8

[0258] [ka]

[0259] (1) Preparation of Compound 8-1 Compound 1-7 (200 mg) and 5-fluoro-3-pyridineboronic acid (75.03 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (124.4 mg), Pd(dppf)Cl2 (15.5 mg) and water (1 mL) were added, and the mixture was heated to 90 ° C. under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 8-1.

[0260] (2) Preparation of Compound 8-2 Compound 8-1 (150 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (65.1 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 8-2, which was used as is in the next reaction.

[0261] (3) Preparation of Compound 8 Compound 8-2 (138.65 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (62.71 mg) and isobutyl chloroformate (84.68 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (65.1 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 8 (43 mg) was obtained by fractionation and purification. ESI-MS: m / z = 447.14 [M + H] + .

[0262] 1 HNMR(500MHz,DMSO-d6)δ9.15(s,1H),8.63(d,J=2.8Hz,1H),8.39(s,1H),8.34(d, J=1.8Hz,1H),8.09(s,2H),7.76(dt,J=10.0,2.2Hz,1H),7.67(s,1H),7.28(s,1H).

[0263] Example 9

[0264] [ka]

[0265] (1) Preparation of Compound 9-1 Compound 1-7 (500 mg) was dissolved in tetrahydrofuran (12 mL), and a solution of sodium hydroxide (84.5 mg) and water (12 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature overnight. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 9-1, which was used directly in the next reaction.

[0266] (2) Preparation of Compound 9-2 Compound 9-1 (455 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (213.7 mg) and isobutyl chloroformate (288.6 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (222 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate and concentrated until no liquid flowed out, to obtain 9-2. ESI-MS: m / z = 430.04 / 432.06 [M + H] + .

[0267] (3) Preparation of Compound 9 Compound 9-2 (180 mg) and 4-boronic acid-2-trifluoromethylpyridine (95.9 mg) were dispersed in 1,4-dioxane (6 mL), potassium acetate (123 mg), Pd(dppf)Cl2 (15.3 mg) and water (0.6 mL) were added, and the mixture was heated to 90°C under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure and separated and purified to obtain compound 9 (18 mg). ESI-MS: m / z = 497.09 [M + H] + .

[0268] 1 HNMR(500MHz,DMSO-d6)δ9.21(s,1H),8.83(d,J=4.9Hz,1H),8.39(s,1H),7.99(s,2H),7.89(s,1H),7.69(s,1H),7.62(d,J=4.9Hz,1H),7.29(s,1H).

[0269] Example 10

[0270] [ka]

[0271] (1) Preparation of Compound 10-1 Compound 1-7 (200 mg) and 5-cyano-3-pyridylboronic acid (75.03 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (124.4 mg), Pd(dppf)Cl2 (15.5 mg) and water (1 mL) were added, and the mixture was heated to 90° C. under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 10-1.

[0272] (2) Preparation of Compound 10-2 Compound 10-1 (173 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (73.12 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 10-2, which was used as is in the next reaction.

[0273] (3) Preparation of Compound 10 Compound 10-2 (159 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (70.8 mg) and isobutyl chloroformate (95.6 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (73.5 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 10 (23 mg) was obtained by fractionation and purification. ESI-MS: m / z = 454.20 [M + H] + .

[0274] 1 HNMR(500MHz,DMSO-d6)δ9.21(s,1H),9.09(d,J=2.0Hz,1H),8.76(d,J=2.1Hz, 1H),8.45(s,1H),8.36(t,J=2.1Hz,1H),8.05(s,2H),7.70(s,1H),7.30(s,1H).

[0275] Example 11

[0276] [ka]

[0277] (1) Preparation of Compound 11-1 Compound 1-7 (300 mg) and 3-quinolineboronic acid (131.61 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (46 mg) and water (0.8 mL) were added, and the mixture was heated to 90° C. under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 11-1, which was used as it was in the next reaction.

[0278] (2) Preparation of Compound 11-2 Compound 11-1 (328 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (52.87 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 11-2, which was used as it was in the next reaction.

[0279] (3) Preparation of Compound 11 Compound 11-2 (301 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (127.45 mg) and isobutyl chloroformate (154.41 mg) were added in an ice-water bath, and the mixture was stirred for 30 minutes. Ammonia water (132.3 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 11 (30 mg) was obtained by fractionation and purification. ESI-MS: m / z = 479.31 [M + H] + .

[0280] 1HNMR(500MHz,DMSO-d6)δ9.17(s,1H),8.76(d,J=2.2Hz,1H),8.43(s,1H),8.30(d,J=2.2Hz,1H),8.08(d,J=8.4Hz ,1H),8.01(dd,J=8.1,1.4Hz,1H),7.88(s,2H),7.84(ddd,J=8.5,6.9,1.5Hz,1H),7.70-7.62(m,2H),7.36(s,1H).

[0281] Example 12

[0282] [ka]

[0283] (1) Preparation of Compound 12-1 Compound 1-7 (300 mg) and indazole-6-boronic acid (123.22 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (46 mg) and water (0.8 mL) were added, and the mixture was heated to 90° C. under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 12-1, which was used as it was in the next reaction.

[0284] (2) Preparation of Compound 12-2 Compound 12-1 (321 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (52.87 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 12-2, which was used as is in the next reaction.

[0285] (3) Preparation of Compound 12 Compound 12-2 (295 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (127.45 mg) and isobutyl chloroformate (154.41 mg) were added in an ice-water bath, and the mixture was stirred for 30 minutes. Aqueous ammonia (132.3 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 12 (40 mg) was obtained by fractionation and purification. ESI-MS: m / z = 468.22 [M + H] + .

[0286] 1 HNMR(500MHz,DMSO-d6)δ13.11(s,1H),8.63(s,1H),8.19(s,1H),8.13(t,J=1.3Hz,1H),8.09(s,2H) ),7.82(d,J=8.2Hz,1H),7.62(s,1H),7.47-7.43(m,1H),7.11(s,1H),6.95(dd,J=8.3,1.4Hz,1H).

[0287] Example 13

[0288] [ka]

[0289] (1) Preparation of Compound 13-2 Compound 13-1 (15 g), cyclopropylboronic acid (11.4 g), potassium carbonate (27.5 g), and Pd(dppf)Cl2 (2.4 g) were dispersed in 150 mL of dioxane and 15 mL of water, and the mixture was heated to 90 ° C under nitrogen gas protection to react. After the reaction was completed, the reaction solution was diluted with water (1000 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and purified by column chromatography to obtain compound 13-2.

[0290] (2) Preparation of compound 13-3 Bis(pinacolato)diboron (6.51 g), 4,4'-di-tert-butyl-2,2'-dipyridine (76.16 mg), and methoxy(cyclooctadiene)iridium dimer (70.82 mg) were dispersed in cyclohexane (80 mL) and stirred for 10 minutes under nitrogen gas protection. Compound 13-2 (8.0 g) was added and stirred at 55°C under nitrogen gas protection. After the reaction was completed, the reaction solution was quenched by adding ice water (80 mL) and extracted with ethyl acetate (80 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain compound 13-3, which was used directly in the next reaction.

[0291] (3) Preparation of compound 13-4 13-3 (10.7 g) was dispersed in ethylene glycol dimethyl ether (80 mL), 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (10.5 g), potassium carbonate (14.18 g) aqueous solution (16 mL) were added, and the mixture was stirred at room temperature under nitrogen gas protection. After 1 hour, tetrakis(triphenylphosphine)palladium (1.97 g) was added, and the mixture was stirred at 90°C under nitrogen gas protection. After the reaction was completed, the reaction solution was quenched by adding ice water (60 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was collected and washed with brine (60 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain compound 13-4, which was used directly in the next reaction.

[0292] (4) Preparation of Compound 13-5 Compound 13-4 (6.0 g) was dispersed in hydrogen chloride 1,4-dioxane solution (4.0 M, 50 mL) and stirred at 60 ° C until the reaction was completed. The reaction solution was slowly poured into ice-cooled saturated sodium bicarbonate solution, adjusted to pH = 7-8 with sodium bicarbonate, and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure until no liquid flowed out, and purified by column chromatography to obtain compound 13-5.

[0293] (5) Preparation of compound 13-6 Compound 13-5 (4 g) was dispersed in DMF (20 mL) and dioxane (20 mL), DABCO (3.5 g) was added, and the mixture was stirred at 20-25 ° C for 30 minutes, then the temperature was lowered to 0-10 ° C, and compound 13-5a (5.6 g) was added dropwise. After the dropwise addition was completed, the mixture was stirred at 20-25 ° C for 1.5 hours. After the reaction was completed, the reaction solution was poured into 100 mL of water and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 13-6 (3.0 g).

[0294] (6) Preparation of compound 13-7 Compound 13-6 (3 g) was dispersed in dichloromethane (30 mL), the temperature was lowered to 0°C, and liquid bromine (2.6 g) was added dropwise over 15 minutes. The temperature was then gradually raised to room temperature and stirred for 6 hours. After the reaction was completed, the reaction mixture was poured into 40 mL of ice water and extracted with dichloromethane (40 mL x 3). The organic phases were combined and washed with saturated sodium hydrogen sulfite solution (30 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure until no liquid flowed out, and purified by column chromatography to obtain compound 13-7.

[0295] (7) Preparation of compound 13-8 Compound 13-7 (4.3 g) was dispersed in tetrahydrofuran (40 mL), the temperature was lowered to 0°C, and triethylamine (1.65 g) was added dropwise. After the dropwise addition was completed, the temperature was gradually raised to room temperature and the reaction was carried out for 6 hours. After the reaction was completed, 40 mL of water was added to dilute the reaction solution, and the solution was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 13-8 (2 g).

[0296] (8) Preparation of compound 13-9 13-8 (300 mg), 5-pyrimidineboronic acid (100 mg), potassium acetate (198 mg), and Pd(dppf)Cl2 (24.6 mg) were dispersed in 8 mL of dioxane and 0.8 mL of water, and the mixture was heated to 90 °C under nitrogen gas protection to react. After the reaction was completed, water (15 mL) was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and purified by column chromatography to obtain compound 13-9 (200 mg).

[0297] (9) Preparation of Compound 13-10 Compound 13-9 (200 mg) was dissolved in tetrahydrofuran (8 mL), and a solution of sodium hydroxide (36 mg) and water (8 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature overnight. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compounds 13-10, which were used directly in the next reaction.

[0298] (10) Preparation of compound 13 Compound 13-10 (181 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (91 mg) and isobutyl chloroformate (123 mg) were added in an ice-water bath and stirred for 30 minutes. Aqueous ammonia (95 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 13 (57 mg) was obtained by fractional purification. ESI-MS: m / z = 402.27 [M + H] + .

[0299] 1 HNMR(500MHz,DMSO-d6)δ9.24(s,1H),9.13(s,1H),8.73(s,2H),8.42(s,1H),7.69(s,1H),7.65(s,1H) ,7.49(s,1H),7.41(s,1H),2.28(tt,J=8.3,4.7Hz,1H),1.10(dq,J=6.6,3.8Hz,2H),0.99-0.91(m,2H).

[0300] Example 14

[0301] [ka]

[0302] (1) Preparation of Compound 14-2 Compounds 13-8 (300 mg) and 14-1 (228 mg) were dispersed in 1,4-dioxane (15 mL), potassium acetate (196 mg), Pd(dppf)Cl2 (22 mg) and water (1.5 mL) were added, and the mixture was heated to 90° C. under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 14-2.

[0303] (2) Preparation of compound 14-3 Compound 14-2 (100 mg) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (40.1 mg) and water (5 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 14-3, which was used as is in the next reaction.

[0304] (3) Preparation of Compound 14 Compound 14-3 (60 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (26 mg) and isobutyl chloroformate (35 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (27 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 14 (10 mg) was obtained by fractionation and purification. ESI-MS: m / z = 481.3 [M + H] + .

[0305] 1HNMR(500MHz,DMSO-d6)δ9.05(s,1H),8.21(s,3H),7.84(d,J=1.3Hz,1H),7.76(t,J=6.2Hz,1H),7.71(d,J=1.3Hz,1H),7.55(s,1H),7.40(s,1H) ),6.10(tt,J=56.5,4.2Hz,1H),3.74(tdd,J=15.0,6.2,4.1Hz,2H),2.30(tt,J=8.1,4.7Hz,1H),1.08(dt,J=8.1,3.2Hz,2H),0.99-0.95(m,2H).

[0306] Example 15

[0307] [ka]

[0308] (1) Preparation of Compound 15-2 Compound 13-8 (371 mg) and 15-1 (299 mg) were dispersed in 1,4-dioxane (55 mL), potassium acetate (244 mg), Pd(dppf)Cl2 (30 mg) and water (1.5 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 15-2.

[0309] (2) Preparation of compound 15-3 Compound 15-2 (340 mg) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (132.7 mg) and water (5 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 15-3, which was used as is in the next reaction.

[0310] (3) Preparation of Compound 15 Compound 15-3 (312 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (127 mg) and isobutyl chloroformate (172 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (132 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 15 (70 mg) was obtained by fractionation and purification. ESI-MS: m / z = 495.39 [M + H] + .

[0311] 1 HNMR(500MHz,DMSO-d6)δ9.05(s,1H),8.20(d,J=3.2Hz,3H),7.84(d,J=1.2Hz,1H),7.77(t,J=6.6Hz,1H),7.73(d,J=1.3Hz,1H),7.54(s,1H), 7.42(s,1H),3.83(td,J=13.6,6.6Hz,2H),2.29(tt,J=8.3,4.7Hz,1H), 1.61(t,J=19.0Hz,3H),1.08(dt,J=8.0,3.2Hz,2H),1.00-0.94(m,2H).

[0312] Example 16

[0313] [ka]

[0314] (1) Preparation of Compound 16-2 Compound 13-8 (400 mg) and 16-1 (327 mg) were dispersed in 1,4-dioxane (15 mL), potassium acetate (264 mg), Pd(dppf)Cl2 (65.7 mg) and water (1.5 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 16-2.

[0315] (2) Preparation of compound 16-3 Compound 16-2 (300 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (46.5 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 16-3, which was used as is in the next reaction.

[0316] (3) Preparation of Compound 16 Compound 16-3 (276 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (112 mg) and isobutyl chloroformate (151 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (116 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 16 (58.4 mg) was obtained by fractionation and purification. ESI-MS: m / z = 499.28 [M + H] + .

[0317] 1 HNMR(500MHz,DMSO-d6)δ9.07(s,1H),8.23(d,J=6.1Hz,3H),8.00(t,J=6.7Hz,1H),7.83(d,J=1.3Hz,1H),7.70(d,J=1.3Hz,1H),7 .55(s,1H),7.42(s,1H),4.18(qd,J=9.5,6.6Hz,2H),2.28(tt,J=8.1,4.7Hz,1H),1.08(dt,J=8.0,3.2Hz,2H),0.99-0.94(m,2H).

[0318] Example 17

[0319] [ka]

[0320] (1) Preparation of Compound 17-2 Compound 13-8 (400 mg) and 17-1 (342 mg) were dispersed in 1,4-dioxane (15 mL), potassium acetate (264 mg), Pd(dppf)Cl2 (65.7 mg) and water (1.5 mL) were added, and the mixture was heated to 90°C under nitrogen gas protection to react. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 17-2.

[0321] (2) Preparation of compound 17-3 Compound 17-2 (400 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (91 mg) and water (10 mL) was added dropwise in an ice-water bath. The temperature was controlled to 0-10°C and the reaction was allowed to proceed for 3 hours. The pH of the reaction solution was adjusted to 3-5 with hydrochloric acid, and the solution was extracted with ethyl acetate (20 mL x 2). The solution was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 17-3, which was used directly in the next reaction.

[0322] (3) Preparation of Compound 17 Compound 17-3 (370 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (146 mg) and isobutyl chloroformate (197 mg) were added in an ice-water bath and stirred for 30 minutes. Aqueous ammonia (151 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 17 (49 mg) was obtained by fractional purification. ESI-MS: m / z = 513.33 [M + H] + .

[0323] 1HNMR(500MHz,DMSO-d6)δ9.07(s,1H),8.23(d,J=7.2Hz,3H),7.96(d,J=9.1Hz,1H),7.85(s,1H),7.71(d,J=1.3Hz,1H),7.54(s,1H),7.43( s,1H),4.95(h,J=7.2Hz,1H),2.29(tt,J=8.3,4.7Hz,1H),1.35(d,J=7.0Hz,3H),1.07(dt,J=8.3,3.1Hz,2H),0.98(dq,J=7.0,3.4Hz,2H).

[0324] Example 18

[0325] [ka]

[0326] (1) Preparation of Compound 18-2 Compound 1-7 (300 mg), 2-fluoropyridine-4-boronic acid (18-1, 107 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (23.2 mg) and water (0.8 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react, and TLC showed that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 18-2.

[0327] (2) Preparation of compound 18-3 Compound 18-2 (240 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (61.7 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at 0-5°C for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 18-3, which was used as it was in the next reaction.

[0328] (3) Preparation of Compound 18 Compound 18-3 (219 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (99 mg) and isobutyl chloroformate (133.8 mg) were added in an ice-water bath, and the mixture was stirred for 30 minutes. Ammonia water (102.9 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 18 (57 mg) was obtained by fractionation and purification. ESI-MS: m / z = 447.17 [M + H] + .

[0329] 1 HNMR(500MHz,DMSO-d6)δ9.13(s,1H),8.34(s,1H),8.30(d,J=5.1Hz,1H),8.09(s, 2H),7.68(s,1H),7.26(dt,J=5.1,1.7Hz,1H),7.21(s,1H),7.19(d,J=1.6Hz,1H).

[0330] Example 19

[0331] [ka]

[0332] (1) Preparation of Compound 19-2 Compound 1-7 (200 mg), 2-fluoropyridine-5-boronic acid (19-1, 71.5 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (124.4 mg), Pd(dppf)Cl2 (15.5 mg) and water (1 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react, and TLC detected that the raw material had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 19-2.

[0333] (2) Preparation of compound 19-3 Compound 19-2 (205 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (35.4 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 19-3, which was used as it was in the next reaction.

[0334] (3) Preparation of Compound 19 Compound 19-3 (137.4 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (64.74 mg) and isobutyl chloroformate (87.41 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (67.2 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 19 (70 mg) was obtained by fractionation and purification. ESI-MS: m / z = 447.15 [M + H] + .

[0335] 1 HNMR(500MHz,DMSO-d6)δ9.14(s,1H),8.37(s,1H),8.14(d,J=2.4Hz,1H),8.11 (s,2H),7.89(td,J=8.1,2.5Hz,1H),7.64(s,1H),7.27(dd,J=8.4,2.7Hz,2H).

[0336] Example 20

[0337] [ka]

[0338] (1) Preparation of Compound 20-2 Compound 1-7 (200 mg), 2-fluoropyridine-3-boronic acid (20-1, 71.5 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (124.4 mg), Pd(dppf)Cl2 (15.5 mg) and water (1 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react, and TLC detected that the raw material had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 20-2.

[0339] (2) Preparation of Compound 20-3 Compound 20-2 (205 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (35.4 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 20-3, which was used directly in the next reaction.

[0340] (3) Preparation of Compound 20 Compound 20-3 (137.4 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (64.74 mg) and isobutyl chloroformate (87.41 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (67.2 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 20 (15 mg) was obtained by fractional purification. ESI-MS: m / z = 447.16 [M + H] +

[0341] Example 21

[0342] [ka]

[0343] (1) Preparation of Compound 21-2 Compound 1-7 (300 mg), 6-methylpyridine-3-boronic acid (21-1, 104 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (23.2 mg) and water (0.8 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react, and TLC detected that the raw material had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 21-2.

[0344] (2) Preparation of compound 21-3 Compound 21-2 (120 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (20.7 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at 0-5°C for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 21-3, which was used directly in the next reaction.

[0345] (3) Preparation of Compound 21 Compound 21-3 (109 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (50 mg) and isobutyl chloroformate (67.5 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (51.9 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 21 (42 mg) was obtained by fractionation and purification. ESI-MS: m / z = 443.17 [M + H] + .

[0346] 1 HNMR(500MHz,DMSO-d6)δ9.05(s,1H),8.32(d,J=2.1Hz,1H),8.29(s,1H),8.11(s,2H),7 .61(s,1H),7.57(dd,J=7.9,2.3Hz,1H),7.34(d,J=7.9Hz,1H),7.23(s,1H),2.54(s,3H).

[0347] Example 22

[0348] [ka]

[0349] (1) Preparation of Compound 22-2 Compound 1-7 (300 mg), 2-methylpyridine-4-boronic acid (22-1, 104 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (23.2 mg) and water (0.8 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react, and TLC detected that the raw material had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 22-2.

[0350] (2) Preparation of Compound 22-3 Compound 22-2 (170 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (29 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at 0-5°C for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 22-3, which was used as is in the next reaction.

[0351] (3) Preparation of Compound 22 Compound 22-3 (155 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (70.8 mg) and isobutyl chloroformate (95.6 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (73.5 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 22 (57 mg) was obtained by fractionation and purification. ESI-MS: m / z = 443.16 [M + H] + .

[0352] 1HNMR(500MHz,DMSO-d6)δ8.99(s,1H),8.49(dd,J=5.0,0.8Hz,1H),8.23(s,1H),8.12(s,2 H),7.64(s,1H),7.21-7.19(m,1H),7.17(s,1H),7.06(dd,J=5.1,1.6Hz,1H),2.49(s,3H).

[0353] Example 23

[0354] [ka]

[0355] (1) Preparation of Compound 23-2 Compound 1-7 (300 mg), 6-methoxy-3-pyridineboronic acid (23-1, 116.23 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (186.7 mg), Pd(dppf)Cl2 (23.2 mg) and water (1 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react, and TLC detected that the raw material had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 23-2.

[0356] (2) Preparation of compound 23-3 Compound 23-2 (306 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (53.2 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 23-3, which was used as it was in the next reaction.

[0357] (3) Preparation of Compound 23 Compound 23-3 (289 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (128.3 mg) and isobutyl chloroformate (173.2 mg) were added in an ice-water bath, and the mixture was stirred for 30 minutes. Aqueous ammonia (133.1 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 23 (100 mg) was obtained by fractionation and purification. ESI-MS: m / z = 459.22 [M + H] + .

[0358] 1 HNMR(500MHz,DMSO-d6)δ9.04(s,1H),8.25(s,1H),8.17(s,2H),8.07-8.04(m,1H), 7.58(dd,J=8.5,2.5Hz,2H),7.23(s,1H),6.90(dd,J=8.6,0.7Hz,1H),3.91(s,3H).

[0359] Example 24

[0360] [ka]

[0361] (1) Preparation of Compound 24-2 Compound 1-7 (300 mg), 2-methylpyridine-3-boronic acid (24-1, 104 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (23.2 mg) and water (0.8 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react, and TLC detected that the raw material had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 24-2.

[0362] (2) Preparation of compound 24-3 Compound 24-2 (150 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (38.9 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at 0 to 25°C for 2 hours. The pH of the reaction solution was adjusted to 6 to 7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 24-3, which was used directly in the next reaction.

[0363] (3) Preparation of Compound 24 Compound 24-3 (137 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (62.5 mg) and isobutyl chloroformate (84.4 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (64.9 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 24 (82 mg) was obtained by fractionation and purification. ESI-MS: m / z = 443.28 [M + H] + .

[0364] 1 HNMR(500MHz,DMSO-d6)δ9.07(s,1H),8.51(dd,J=4.9,1.7Hz,1H),8.34(s,1H),8.05(s,2H),7 .59(s,1H),7.51(dd,J=7.6,1.7Hz,1H),7.29(dd,J=7.6,4.9Hz,1H),7.18(s,1H),2.28(s,3H).

[0365] Example 25

[0366] [ka]

[0367] (1) Preparation of Compound 25-2 Compound 1-7 (300 mg) and 25-1 (195 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (186.6 mg), Pd(dppf)Cl2 (46 mg) and water (0.8 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react. TLC showed that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure to obtain compound 25-2.

[0368] (2) Preparation of compound 25-3 Compound 25-2 (240 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (57.8 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 25-3, which was used as it was in the next reaction.

[0369] (3) Preparation of Compound 25 Compound 25-3 (220 mg) was dispersed in tetrahydrofuran (15 mL), and N-methylmorpholine (93 mg) and isobutyl chloroformate (125 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (96 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 25 (86 mg) was obtained by fractional purification. ESI-MS: m / z = 480.24 [M + H] + .

[0370] 1 HNMR(500MHz,DMSO-d6)δ9.22(s,1H),9.04(dd,J=4.2,1.7Hz,1H),8.89(d,J=2.1Hz,1H),8.53-8.4 5(m,2H),8.34(d,J=2.1Hz,1H),7.88(dd,J=8.5,4.2Hz,1H),7.82(s,2H),7.70(s,1H),7.38(s,1H).

[0371] Example 26

[0372] [ka]

[0373] (1) Preparation of Compound 26-2 Compound 13-8 (200 mg), 3-quinolineboronic acid (26-1, 76.6 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react, and TLC showed that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure, and compound 26-2 was obtained by column chromatography.

[0374] (2) Preparation of compound 26-3 Compound 26-2 (120 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (30.6 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 26-3, which was used as it was in the next reaction.

[0375] (3) Preparation of Compound 26 Compound 26-3 (100 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (44.5 mg) and isobutyl chloroformate (60.1 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (46.2 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 26 (40 mg) was obtained by fractionation and purification. ESI-MS: m / z = 451.20 [M + H] + .

[0376] 1HNMR(500MHz,DMSO-d6)δ9.07(s,1H),8.74(d,J=2.2Hz,1H),8.40(s,1H),8.29(d,J=2. 2Hz,1H),8.09(dd,J=8.4,1.1Hz,1H),8.01(dd,J=8.1,1.5Hz,1H),7.82(ddd,J=8.5,6. 9,1.5Hz,1H),7.64(ddd,J=8.1,6.9,1.2Hz,2H),7.48(d,J=1.4Hz,1H),7.33(s,1H),7. 29(d,J=1.3Hz,1H),2.07(tt,J=8.1,4.7Hz,1H),1.06-0.97(m,2H),0.83-0.75(m,2H).

[0377] Example 27

[0378] [ka]

[0379] (1) Preparation of Compound 27-2 Compound 13-8 (200 mg), 5-fluoro-3-pyridineboronic acid (27-1, 76.1 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react, and TLC detected that the raw material had completely reacted. The reaction solution was concentrated under reduced pressure, and compound 27-2 was obtained by column chromatography.

[0380] (2) Preparation of compound 27-3 Compound 27-2 (120 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (32.8 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 27-3, which was used as it was in the next reaction.

[0381] (3) Preparation of Compound 27 Compound 27-3 (100 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (48.6 mg) and isobutyl chloroformate (65.6 mg) were added in an ice-water bath, and the mixture was stirred for 30 minutes. Ammonia water (50.4 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 27 (40 mg) was obtained by fractionation and purification. ESI-MS: m / z = 419.22 [M + H] + .

[0382] 1 HNMR(500MHz,DMSO-d6)δ9.05(s,1H),8.63(d,J=2.8Hz,1H),8.34(d,J=19.3Hz,2H),7.79-7.69(m,2H),7.64(s,1H) ),7.51(s,1H),7.25(s,1H),2.28(tt,J=8.4,4.7Hz,1H),1.10(dd,J=8.0,3.0Hz,2H),0.93(dd,J=4.7,2.6Hz,2H).

[0383] Example 28

[0384] [ka]

[0385] (1) Preparation of Compound 28-2 Compound 13-8 (200 mg), 2-aminopyrimidine-5-boronic acid (28-1, 75 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react, and TLC detected that the raw material had completely reacted. The reaction solution was concentrated under reduced pressure, and compound 28-2 was obtained by column chromatography.

[0386] (2) Preparation of compound 28-3 Compound 28-2 (102 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (27.7 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 28-3, which was used as it was in the next reaction.

[0387] (3) Preparation of Compound 28 Compound 28-3 (100 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (48.6 mg) and isobutyl chloroformate (65.6 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (50.4 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 28 (45 mg) was obtained by fractionation and purification. ESI-MS: m / z = 417.22 [M + H] + .

[0388] 1 HNMR(500MHz,DMSO-d6)δ9.00(s,1H),8.15(s,1H),8.08(s,2H),7.85(d,J=1.2Hz,1H),7.78(d,J=1.3Hz,1H),7. 53(s,1H),7.41(s,1H),6.84(s,2H),2.36-2.28(m,1H),1.09(dt,J=8.0,3.2Hz,2H),0.98(dq,J=6.9,3.9Hz,2H).

[0389] Example 29

[0390] [ka]

[0391] (1) Preparation of Compound 29-2 Compound 13-8 (200 mg), 1-methyl-1H-pyrazole-4-boronic acid (29-1, 68 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react, and TLC detected that the raw material had completely reacted. The reaction solution was concentrated under reduced pressure, and compound 29-2 was obtained by column chromatography.

[0392] (2) Preparation of compound 29-3 Compound 29-2 (100 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (27.7 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 29-3, which was used as it was in the next reaction.

[0393] (3) Preparation of Compound 29 Compound 29-3 (88.96 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (44.5 mg) and isobutyl chloroformate (60.09 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (46.2 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 29 (30 mg) was obtained by fractionation and purification. ESI-MS: m / z = 404.24 [M + H] + .

[0394] 1 HNMR(500MHz,DMSO-d6)δ8.75(s,1H),8.08-8.03(m,1H),7.94(d,J=1.3Hz,1H),7.82(s,1H),7.72(s,1H),7.55(s,1H),7.49 (s,1H),7.25(s,1H),3.85(s,3H),2.37(tt,J=8.1,4.7Hz,1H),1.10(dt,J=8.1,3.2Hz,2H),1.00(dq,J=7.0,4.3,3.9Hz,2H).

[0395] Example 30

[0396] [ka]

[0397] (1) Preparation of Compound 30-2 Compound 13-8 (200 mg), 5-cyano-pyridine-3-boronic acid (30-1, 79.8 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure, and compound 30-2 was obtained by column chromatography.

[0398] (2) Preparation of Compound 30-3 Compound 30-2 (150 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (40.28 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 30-3, which was used directly in the next reaction.

[0399] (3) Preparation of Compound 30 Compound 30-3 (136.44 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (64.74 mg) and isobutyl chloroformate (87.4 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (67.2 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 30 (45 mg) was obtained by fractionation and purification. ESI-MS: m / z = 426.21 [M + H] + .

[0400] 1HNMR(500MHz,DMSO-d6)δ9.12(s,1H),9.09(d,J=2.0Hz,1H),8.75(d,J=2.1Hz,1H),8.42(s,1H),8.35(t,J=2.1Hz,1H),7.70(d,J=1.3 Hz,1H),7.66(s,1H),7.45(d,J=1.3Hz,1H),7.28(s,1H),2.29(tt,J=8.1,4.7Hz,1H),1.10(dt,J=8.1,3.3Hz,2H),0.97-0.89(m,2H).

[0401] Example 31

[0402] [ka]

[0403] (1) Preparation of Compound 31-2 Compound 13-8 (200 mg), 3,5-dimethylisoxazole-4-boronic acid (31-1, 76.1 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.6 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 31-2.

[0404] (2) Preparation of Compound 31-3 Compound 31-2 (150 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (41.54 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 31-3, which was used as it was in the next reaction.

[0405] (3) Preparation of Compound 31 Compound 31-3 (134 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (64.74 mg) and isobutyl chloroformate (87.4 mg) were added in an ice-water bath, and the mixture was stirred for 30 minutes. Ammonia water (67.2 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 31 (30 mg) was obtained by fractionation and purification. ESI-MS: m / z = 419.23 [M + H] + .

[0406] 1 HNMR(500MHz,DMSO-d6)δ9.07(s,1H),8.38(s,1H),7.86(d,J=1.3Hz,1H),7.78(d,J=1.3Hz,1H),7.52(s,1H) ),7.37(s,1H),2.31(tt,J=8.1,4.7Hz,1H),2.17(s,3H),1.96(s,3H),1.14-1.08(m,2H),1.01-0.95(m,2H).

[0407] Example 32

[0408] [ka]

[0409] (1) Preparation of Compound 32-2 Compound 13-8 (200 mg), 2-fluoro-pyridine-3-boronic acid (32-1, 76.1 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.6 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 32-2.

[0410] (2) Preparation of compound 32-3 Compound 32-2 (70 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (18.9 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 32-3, which was used as it was in the next reaction.

[0411] (3) Preparation of Compound 32 Compound 32-3 (50 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (24.3 mg) and isobutyl chloroformate (32.7 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (25.2 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 32 (10 mg) was obtained by fractional purification. ESI-MS: m / z = 419.21 [M + H].

[0412] 1 HNMR(500MHz,DMSO-d6)δ9.13(s,1H),8.39(s,1H),8.32(dd,J=5.0,1.9Hz,1H),7.86(ddd,J=9.5,7.3,1.9Hz,1H),7.69(d,J=1.3Hz,1H),7.59(s,1H) ),7.50(d,J=1.3Hz,1H),7.44(ddd,J=7.1,4.9,1.9Hz,1H),7.40(s,1H),2 .27(tt,J=8.2,4.7Hz,1H),1.10(dt,J=8.1,3.3Hz,2H),0.97-0.90(m,2H).

[0413] Example 33

[0414] [ka]

[0415] (1) Preparation of Compound 33-2 Compound 13-8 (200 mg) and [1,5] naphthyridine-3-boronic acid (33-1, 138.3 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 33-2.

[0416] (2) Preparation of compound 33-3 Compound 33-2 (160 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (40.28 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 33-3, which was used as it was in the next reaction.

[0417] (3) Preparation of Compound 33 Compound 33-3 (144.7 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (64.74 mg) and isobutyl chloroformate (87.4 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (67.2 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 33 (20 mg) was obtained by fractionation and purification. ESI-MS: m / z = 452.21 [M + H] + .

[0418] 1HNMR(500MHz,DMSO-d6)δ9.12(s,1H),9.03(dd,J=4.2,1.7Hz,1H),8.87(d,J=2. 2Hz,1H),8.51(d,J=8.5Hz,1H),8.46(s,1H),8.31(d,J=2.2Hz,1H),7.86(dd,J= 8.5,4.2Hz,1H),7.65(s,1H),7.51(s,1H),7.34(s,1H),7.20-7.14(m,1H),2.10 (tt,J=8.4,4.7Hz,1H),1.01(dt,J=6.4,3.3Hz,2H),0.79(dq,J=6.9,4.0Hz,2H).

[0419] Example 34

[0420] [ka]

[0421] (1) Preparation of Compound 34-2 Compound 13-8 (200 mg), 2-methoxypyridine-5-boronic acid (34-1, 82.6 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 34-2.

[0422] (2) Preparation of compound 34-3 Compound 34-2 (180 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (47.9 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 34-3, which was used as it was in the next reaction.

[0423] (3) Preparation of Compound 34 Compound 34-3 (163.9 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (76.8 mg) and isobutyl chloroformate (103.8 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (79.8 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 34 (80 mg) was obtained by fractionation and purification. ESI-MS: m / z = 431.19 [M + H] + .

[0424] 1 HNMR(500MHz,DMSO-d6)δ8.91(s,1H),8.21(s,1H),8.04(d,J=2.4Hz,1H),7.81(d,J=1.3Hz,1H),7.61(d,J=1.3Hz,1H),7.58(d,J=2.4Hz,1H),7.56 (d,J=2.5Hz,1H),7.55(s,1H),7.20(s,1H),6.89(d,J=8.5Hz,1H),3.91( s, 3H), 2.29 (tt, J=8.1, 4.8Hz, 1H), 1.12-1.05 (m, 2H), 0.98-0.93 (m, 2H).

[0425] Example 35

[0426] [ka]

[0427] (1) Preparation of Compound 35-1 Compound 13-8 (200 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (56.65 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 35-1, which was used as it was in the next reaction.

[0428] (2) Preparation of Compound 35-2 Compound 35-1 (181.4 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (91.04 mg) and isobutyl chloroformate (122.9 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (94.5 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated until no liquid flowed out to obtain compound 35-2, which was used as it was in the next reaction.

[0429] (3) Preparation of Compound 35 Compound 35-2 (200 mg) and 2-fluoro-pyrimidine-5-boronic acid (35-3, 134.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (147.21 mg), Pd(dppf)Cl2 (18.3 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure, and compound 35 (30 mg) was obtained by fractionation and purification. ESI-MS: m / z = 420.19 [M + H] + .

[0430] 1 HNMR(500MHz,DMSO-d6)δ9.18(s,1H),8.74(s,2H),8.47(s,1H),7.74(s,1H),7.66(s,1H),7.49( s,1H),7.35(s,1H),2.28(tt,J=8.4,4.7Hz,1H),1.11(dq,J=6.7,3.9Hz,2H),1.00-0.89(m,2H).

[0431] Example 36

[0432] [ka]

[0433] (1) Preparation of compound 36-2 Compound 13-8 (200 mg), 2-fluoro-pyridine-4-boronic acid (36-1, 76.09 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 36-2.

[0434] (2) Preparation of compound 36-3 Compound 36-2 (150 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (40.3 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 36-3, which was used as it was in the next reaction.

[0435] (3) Preparation of Compound 36 Compound 36-3 (100 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (48.5 mg) and isobutyl chloroformate (65.5 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (50.4 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 36 (30 mg) was obtained by fractionation and purification. ESI-MS: m / z = 419.19 [M + H] + .

[0436] 1 HNMR(500MHz,DMSO-d6)δ9.03(s,1H),8.29(d,J=5.3Hz,2H),7.68(s,1H),7.63(s,1H),7.53(s,1H),7.25(d,J=5.0H) z,1H),7.18(d,J=6.6Hz,2H),2.26(tt,J=8.3,4.7Hz,1H),1.10(dq,J=6.8,3.9Hz,2H),0.94(dq,J=6.7,4.0Hz,2H).

[0437] Example 37

[0438] [ka]

[0439] (1) Preparation of Compound 37-2 Compound 13-8 (200 mg), 6-fluoro-pyridine-2-boronic acid (37-1, 76.09 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 37-2.

[0440] (2) Preparation of compound 37-3 Compound 37-2 (170 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (46.4 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 37-3, which was used as it was in the next reaction.

[0441] (3) Preparation of Compound 37 Compound 37-3 (155.2 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (74.8 mg) and isobutyl chloroformate (101.1 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (77.7 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 37 (40 mg) was obtained by fractionation and purification. ESI-MS: m / z = 419.19 [M + H] + .

[0442] 1HNMR(500MHz,DMSO-d6)δ9.01(d,J=1.4Hz,1H),8.27(d,J=1.4Hz,1H),8.05(q,J=8.1Hz,1H),7.73(s,1H),7.60(s,1H),7.51(d,J=1.4Hz,1H), 7.34(dd,J=7.4,2.3Hz,1H),7.23(dd,J=8.5,2.3Hz,2H),2.29(tt,J=8.4,4.7Hz,1H),1.09(dq,J=6.5,3.8Hz,2H),0.94(dt,J=5.0,3.3Hz,2H).

[0443] Example 38

[0444] [ka]

[0445] (1) Preparation of compound 38-2 Compound 13-8 (200 mg), 2-methyl-pyridine-5-boronic acid (38-1, 73.95 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 38-2.

[0446] (2) Preparation of compound 38-3 Compound 38-2 (105 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (28.95 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 38-3, which was used as it was in the next reaction.

[0447] (3) Preparation of Compound 38 Compound 38-3 (95.5 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (46.5 mg) and isobutyl chloroformate (62.8 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (48.3 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 38 (30 mg) was obtained by fractionation and purification. ESI-MS: m / z = 415.24 [M + H] + .

[0448] 1 HNMR(500MHz,DMSO-d6)δ8.93(s,1H),8.30(d,J=2.3Hz,1H),8.24(s,1H),7.78(s,1H),7.56(dd,J=8.0,2.4Hz,2H),7.53(d,J=1.3H) z,1H),7.33(d,J=7.9Hz,1H),7.20(s,1H),2.54(s,3H),2.29(tt,J=8.3,4.7Hz,1H),1.09(dt,J=8.1,3.3Hz,2H),1.00-0.89(m,2H).

[0449] Example 39

[0450] [ka]

[0451] (1) Preparation of compound 39-2 Compound 13-8 (200 mg), 2-fluoro-pyridine-5-boronic acid (39-1, 76.09 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C. under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 39-2.

[0452] (2) Preparation of compound 39-3 Compound 39-2 (180 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (49.1 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 39-3, which was used as it was in the next reaction.

[0453] (3) Preparation of Compound 39 Compound 39-3 (163 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (78.9 mg) and isobutyl chloroformate (106.5 mg) were added in an ice-water bath, and the mixture was stirred for 30 minutes. Ammonia water (81.9 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 39 (40 mg) was obtained by fractionation and purification. ESI-MS: m / z = 419.20 [M + H] + .

[0454] 1 HNMR(500MHz,DMSO-d6)δ9.04(s,1H),8.33(s,1H),8.13(d,J=2.4Hz,1H),7.88(td,J=8.2,2.5Hz,1H),7.75(d,J=1.2Hz,1H),7.61(s,1H),7 .52(d,J=1.3Hz,1H),7.27(dd,J=8.4,2.7Hz,1H),7.24(s,1H),2.28(tt,J=8.0,4.7Hz,1H),1.09(dt,J=8.0,3.3Hz,2H),0.99-0.89(m,2H).

[0455] Example 40

[0456] [ka]

[0457] (1) Preparation of Compound 40-2 Compound 13-8 (200 mg, 0.45 mmol, 1.0 eq), 2-trifluoroethylaminopyridine-5-boronic acid (40-1, 118.08 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 40-2.

[0458] (2) Preparation of compound 40-3 Compound 40-2 (130 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (30.3 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 40-3, which was used as it was in the next reaction.

[0459] (3) Preparation of Compound 40 Compound 40-3 (119.6 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (48.6 mg) and isobutyl chloroformate (65.6 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (50.4 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 40 (50 mg) was obtained by fractional purification. ESI-MS: m / z = 498.29 [M + H] + .

[0460] 1HNMR(500MHz,DMSO-d6)δ8.78(s,1H),8.05(s,1H),7.88(d,J=2.0Hz,2H),7. 75(d,J=1.3Hz,1H),7.56-7.49(m,1H),7.39(t,J=6.6Hz,1H),7.32(dd,J=8.5 ,2.4Hz,1H),7.24(s,1H),6.69(d,J=8.5Hz,1H),4.19(qd,J=9.7,6.5Hz,2H) ,2.30(tt,J=8.2,4.7Hz,1H),1.08(dt,J=8.0,3.2Hz,2H),1.02-0.91(m,2H).

[0461] Example 41

[0462] [ka]

[0463] (1) Preparation of compound 41-2 Compound 13-8 (200 mg), 6-(2,2-difluoroethylamino)pyridine-3-boronic acid (41-1, 108.86 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C. under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure, and compound 41-2 was obtained by column chromatography.

[0464] (2) Preparation of compound 41-3 Compound 41-2 (120 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (28.9 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 41-3, which was used as it was in the next reaction.

[0465] (3) Preparation of Compound 41 Compound 41-3 (110.5 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (46.5 mg) and isobutyl chloroformate (62.8 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (48.3 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 41 (40 mg) was obtained by fractional purification. ESI-MS: m / z = 480.31 [M + H] + .

[0466] 1 HNMR(500MHz,DMSO-d6)δ8.74(s,1H),8.03(s,1H),7.90(d,J=1.3Hz,1H),7.87(d,J=2 .4Hz,1H),7.77(d,J=1.2Hz,1H),7.53(s,1H),7.27(dd,J=8.6,2.4Hz,1H),7.25-7.18 (m,2H),6.64(d,J=8.6Hz,1H),6.09(tt,J=56.6,4.1Hz,1H),3.73(tdd,J=15.4,6.1,4 .1Hz,2H),2.31(tt,J=8.1,4.7Hz,1H),1.08(dt,J=8.0,3.2Hz,2H),1.00-0.94(m,2H).

[0467] Example 42

[0468] [ka]

[0469] (1) Preparation of compound 42-2 Compound 13-8 (200 mg) and pyridine-3-boronic acid (42-1, 66.37 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure, and compound 42-2 was obtained by column chromatography.

[0470] (2) Preparation of compound 42-3 Compound 42-2 (85 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (24.1 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 42-3, which was used as it was in the next reaction.

[0471] (3) Preparation of Compound 42 Compound 42-3 (76.28 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (38.4 mg) and isobutyl chloroformate (51.9 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (39.9 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 42 (20 mg) was obtained by fractionation and purification. ESI-MS: m / z = 401.32 [M + H] + .

[0472] Example 43

[0473] [ka]

[0474] (1) Preparation of compound 43-2 Compound 13-8 (200 mg) and 4-pyridineboronic acid (43-1, 66.37 mg) were dispersed in 1,4-dioxane (5 mL), potassium acetate (132.5 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 43-2.

[0475] (2) Preparation of compound 43-3 Compound 43-2 (120 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (34.06 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 43-3, which was used as it was in the next reaction.

[0476] (3) Preparation of Compound 43 Compound 43-3 (108.4 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (54.6 mg) and isobutyl chloroformate (73.7 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (56.7 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 43 (60 mg) was obtained by fractional purification. ESI-MS: m / z = 401.24 [M + H] + .

[0477] Example 44

[0478] [ka]

[0479] (1) Preparation of compound 44-2 Compound 1-7 (200 mg) and pyridine-3-boronic acid (44-1, 62.4 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (175 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 44-2.

[0480] (2) Preparation of compound 44-3 Compound 44-2 (100 mg) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (290 mg) and water (5 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 44-3, which was used as it was in the next reaction.

[0481] (3) Preparation of Compound 44 Compound 44-3 (91 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (42.9 mg) and isobutyl chloroformate (58 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (44.5 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 44 (60 mg) was obtained by fractionation and purification. ESI-MS: m / z = 429.29 [M + H] + .

[0482] 1 HNMR(500MHz,DMSO-d6)δ9.05(s,1H),8.62(d,J=4.9Hz,1H),8.46(d,J=2.2Hz,1H),8.31(s,1H), 8.10(s,2H),7.70(dt,J=7.9,1.9Hz,1H),7.64(s,1H),7.48(dd,J=7.8,4.8Hz,1H),7.28(s,1H).

[0483] Example 45

[0484] [ka]

[0485] (1) Preparation of compound 45-2 Compound 1-7 (200 mg), 3,5-dimethylisoxazole-4-boronic acid (45-1, 71.6 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (175 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 45-2.

[0486] (2) Preparation of compound 45-3 Compound 45-2 (159 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (44.7 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 45-3, which was used as it was in the next reaction.

[0487] (3) Preparation of Compound 45 Compound 45-3 (145 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (65.7 mg) and isobutyl chloroformate (88.7 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (68 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 45 (66 mg) was obtained by fractional purification. ESI-MS: m / z = 447.29 [M + H] + .

[0488] 1 HNMR (500MHz, DMSO-d6) δ 9.16 (s, 1H), 8.41 (s, 1H), 8.31 (s, 2H), 7.57 (s, 1H), 7.42 (s, 1H), 2.18 (s, 3H), 1.97 (s, 3H).

[0489] Example 46

[0490] [ka]

[0491] (1) Preparation of compound 46-2 Compound 1-7 (250 mg), 6-(2,2,2-trifluoroethylamino)pyridine-3-boronic acid (46-1, 140 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (219 mg), Pd(dppf)Cl2 (19.3 mg) and water (0.8 mL) were added, and the temperature was raised to 90 ° C under nitrogen gas protection to react. TLC detected that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 46-2.

[0492] (2) Preparation of compound 46-3 Compound 46-2 (220 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (48.7 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 46-3, which was used as it was in the next reaction.

[0493] (3) Preparation of Compound 46 Compound 46-3 (203 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (78 mg) and isobutyl chloroformate (106 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (81 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 46 (30 mg) was obtained by fractionation and purification. ESI-MS: m / z = 526.33 [M + H] + .

[0494] 1HNMR(500MHz,DMSO-d6)δ8.91(s,1H),8.28(s,2H),8.08(s,1H),7.89(d,J=2.3Hz,1H),7.55(s,1H),7.40(t ,J=6.5Hz,1H),7.33(dd,J=8.6,2.4Hz,1H),7.27(s,1H),6.68(d,J=8.6Hz,1H),4.18(qd,J=9.7,6.4Hz,2H).

[0495] Example 47

[0496] [ka]

[0497] (1) Preparation of compound 47-2 Compound 1-7 (200 mg) and 4-quinoline boronic acid (47-1, 87.7 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (124 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react. TLC showed that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 47-2.

[0498] (2) Preparation of compound 47-3 Compound 47-2 (200 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (48 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 47-3, which was used as it was in the next reaction.

[0499] (3) Preparation of Compound 47 Compound 47-3 (184 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (77.7 mg) and isobutyl chloroformate (105 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (80 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 47 (90 mg) was obtained by fractionation and purification. ESI-MS: m / z = 479.22 [M + H] + .

[0500] 1 HNMR(500MHz,DMSO-d6)δ9.10(s,1H),8.95(d,J=4.4Hz,1H),8.57(s,1H),8.12(d,J=8.4Hz,1H),7.77(dd,J=8.4,1.4Hz,1H),7. 74(ddd,J=8.3,6.8,1.4Hz,1H),7.63(s,1H),7.61(s,2H),7.52(ddd,J=8.2,6.8,1.2Hz,1H),7.42(d,J=4.4Hz,1H),7.22(s,1H).

[0501] Example 48

[0502] [ka]

[0503] (1) Preparation of compound 48-2 Compound 1-7 (200 mg) and 8-isoquinolineboronic acid (48-1, 87.7 mg) were dispersed in 1,4-dioxane (8 mL), potassium acetate (124 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react. TLC showed that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 48-2.

[0504] (2) Preparation of compound 48-3 Compound 48-2 (170 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (41 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 48-3, which was used as it was in the next reaction.

[0505] (3) Preparation of Compound 48 Compound 48-3 (156 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (66 mg) and isobutyl chloroformate (89 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (68 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 48 (45 mg) was obtained by fractionation and purification. ESI-MS: m / z = 479.24 [M + H] + .

[0506] 1 HNMR(500MHz,DMSO-d6)δ9.10(d,J=43.7Hz,2H),8.54(d,J=37.6Hz,2H),8.08(d, J=8.1Hz,1H),7.99-7.81(m,2H),7.66(s,3H),7.55(d,J=7.0Hz,1H),7.28(s,1H).

[0507] Example 49

[0508] [ka]

[0509] (1) Preparation of compound 49-2 Compound 1-7 (200 mg) and 5-quinolineboronic acid (49-1, 87.7 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (175 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react. TLC showed that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 49-2.

[0510] (2) Preparation of compound 49-3 Compound 49-2 (200 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (48 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 49-3, which was used as it was in the next reaction.

[0511] (3) Preparation of Compound 49 Compound 49-3 (184 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (77.7 mg) and isobutyl chloroformate (105 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (80 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 49 (62 mg) was obtained by fractionation and purification. ESI-MS: m / z = 479.25 [M + H] + .

[0512] 1 HNMR(500MHz,DMSO-d6)δ8.98(s,1H),8.93(d,J=4.4Hz,1H),8.56(s,1H),8.18(dd,J=18.0, 8.5Hz, 2H), 7.88 (t, J=7.8Hz, 1H), 7.72 (s, 2H), 7.63 (s, 1H), 7.59-7.43 (m, 2H), 7.15 (s, 1H).

[0513] Example 50

[0514] [ka]

[0515] (1) Preparation of Compound 50-2 Compound 1-7 (200 mg) and 6-quinolineboronic acid (50-1, 87.7 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (175 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react. TLC showed that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 50-2.

[0516] (2) Preparation of compound 50-3 Compound 50-2 (150 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (36 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 50-3, which was used as it was in the next reaction.

[0517] (3) Preparation of Compound 50 Compound 50-3 (138 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (58 mg) and isobutyl chloroformate (78.7 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (60.5 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 50 (87 mg) was obtained by fractionation and purification. ESI-MS: m / z = 479.22 [M + H] + .

[0518] 1HNMR(500MHz,DMSO-d6)δ9.00(dd,J=4.3,1.7Hz,1H),8.95(s,1H),8.45(dd,J=8.4,1.8Hz,1H),8.32(s,1H),8.09(d ,J=8.6Hz,1H),7.98(d,J=1.9Hz,1H),7.92(s,2H),7.67(s,1H),7.65-7.62(m,1H),7.62-7.58(m,1H),7.19(s,1H).

[0519] Example 51

[0520] [ka]

[0521] (1) Preparation of compound 51-2 Compound 1-7 (200 mg) and 5-quinolineboronic acid (51-1, 87.7 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (175 mg), Pd(dppf)Cl2 (15.5 mg) and water (0.8 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react. TLC showed that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 51-2.

[0522] (2) Preparation of compound 51-3 Compound 51-2 (200 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (48 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 51-3, which was used as it was in the next reaction.

[0523] (3) Preparation of Compound 51 Compound 51-3 (184 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (77.7 mg) and isobutyl chloroformate (105 mg) were added in an ice-water bath, and the mixture was stirred for 30 minutes. Ammonia water (80 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 51 (29 mg) was obtained by fractionation and purification. ESI-MS: m / z = 479.23 [M + H] + .

[0524] 1 HNMR(500MHz,DMSO-d6)δ9.39(s,1H),9.02(s,1H),8.56(s,1H),8.42(d,J=5.8Hz,1H),8.24(d,J=8.2Hz,1H),7.90-7.49(m,6H),7.16(s,1H).

[0525] Example 52

[0526] [ka]

[0527] (1) Preparation of Compound 52-1 Compound 1-7 (300 mg) and 5-quinolineboronic acid (131.6 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (263 mg), Pd(dppf)Cl2 (23.2 mg) and water (0.8 mL) were added, and the mixture was heated to 90°C under nitrogen gas protection to react completely. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 52-1.

[0528] (2) Preparation of compound 52-2 Compound 52-1 (200 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (48 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 52-2, which was used as is in the next reaction.

[0529] (3) Preparation of Compound 52 Compound 52-2 (184 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (77.7 mg) and isobutyl chloroformate (105 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (80 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified to obtain a total of 90 mg of compound 52. ESI-MS: m / z = 479.14 [M + H] + .

[0530] 1 HNMR(500MHz,DMSO-d6)δ8.96(s,1H),8.92(dd,J=4.2,1.7Hz,1H),8.44(dd,J=8.5,1.8Hz,1H),8.31(s,1H),8.04(d,J=8.4Hz) ,1H),7.94(d,J=1.6Hz,1H),7.91(s,2H),7.65(s,1H),7.61(dd,J=8.3,4.2Hz,1H),7.47(dd,J=8.3,1.7Hz,1H),7.19(s,1H).

[0531] Example 53

[0532] [ka]

[0533] (1) Preparation of Compound 53-1 Compound 1-7 (300 mg) and 6-trifluoromethyl-3-pyridineboronic acid (145 mg) were dispersed in 1,4-dioxane (8 mL), potassium carbonate (138.2 mg), Pd(dppf)Cl2 (23.2 mg) and water (0.8 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react completely. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 53-1.

[0534] (2) Preparation of compound 53-2 Compound 53-1 (300 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide hydrate (70 mg) and water (10 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 3 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 53-2, which was used as is in the next reaction.

[0535] (3) Preparation of Compound 53 Compound 53-2 (276 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (112 mg) and isobutyl chloroformate (152 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (117 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and a total of 150 mg of compound 53 was obtained by fractionation and purification. ESI-MS: m / z = 497.05 [M + H] + .

[0536] 1 HNMR(500MHz,DMSO-d6)δ9.22(s,1H),8.68(d,J=2.0Hz,1H),8.44(s,1H),8.01(d,J=4.4Hz,3H),7.98(d,J=8.0Hz,1H),7.67(s,1H),7.33(s,1H).

[0537] Example 54

[0538] [ka]

[0539] (1) Preparation of Compound 54-1 The compounds 5-bromo-2-chloropyridine (2.4 g) and 2,2-difluoroethylamine (1.76 g) were dispersed in 1,4-dioxane (30 mL), bis(dibenzylideneacetone)palladium (420 mg), 1,1'-bis(di-t-butylphosphino)ferrocene (710 mg) and potassium tert-butoxide (5.6 g) were added, and the mixture was heated to 90°C under nitrogen gas protection to react completely. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 54-1.

[0540] (2) Preparation of compound 54-2 Compound 54-1 (200 mg) was dispersed in 1,4-dioxane (10 mL), bis(pinacolato)diboron (236 mg), potassium acetate (331 mg), and Pd(dppf)Cl2 (62 mg) were added, and the mixture was reacted at 90°C for 3 hours under nitrogen gas protection. Water (10 ml) was added for dilution, and ethyl acetate (20 mL x 2) was added for extraction. The mixture was dried over anhydrous sodium sulfate and concentrated until no liquid flowed out, to obtain compound 54-2.

[0541] (3) Preparation of compound 54-3 Compound 1-7 (332 mg) and 54-2 (240 mg) were dispersed in 1,4-dioxane (10 mL), potassium acetate (207 mg), Pd(dppf)Cl2 (25.7 mg) and water (1 mL) were added, and the mixture was heated to 90° C. under nitrogen gas protection to react completely. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 54-3.

[0542] (4) Preparation of compound 54-4 Compound 54-3 (180 mg) was dissolved in tetrahydrofuran (8 mL), and a solution of lithium hydroxide hydrate (41 mg) and water (8 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 54-4, which was used as is in the next reaction.

[0543] (5) Preparation of Compound 54 Compound 54-4 (166 mg) was dispersed in tetrahydrofuran (10 mL), and N-methylmorpholine (66 mg) and isobutyl chloroformate (89 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (69 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and 73 mg of compound 54 was obtained by fractionation and purification. ESI-MS: m / z = 508.16 [M + H] + .

[0544] 1 HNMR(500MHz,DMSO-d6)δ8.87(s,1H),8.31(s,2H),8.06(s,1H),7.88(d,J=2.4Hz,1H),7.55(s,1H),7.31- 7.19(m,3H),6.64(dd,J=8.6,0.8Hz,1H),6.08(tt,J=56.6,4.1Hz,1H),3.73(tdd,J=15.4,6.1,4.2Hz,2H).

[0545] Example 55

[0546] [ka]

[0547] (1) Preparation of Compound 55-1 Compound 13-8 (200 mg) and isoquinoline-8-boronic acid (93.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90° C. under nitrogen gas protection to react completely. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 55-1.

[0548] (2) Preparation of compound 55-2 Compound 55-1 (170 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (43.4 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 55-2, which was used as is in the next reaction.

[0549] (3) Preparation of Compound 55 Compound 55-2 (171.5 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (76.8 mg) and isobutyl chloroformate (103.8 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (79.8 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and 30 mg of compound 55 was obtained by fractionation and purification. ESI-MS: m / z = 451.23 [M + H] + .

[0550] 1 HNMR(500MHz,DMSO-d6)δ9.12(s,1H),8.93(s,1H),8.51(d,J=12.6Hz,2H),8.07(d,J=8.2Hz,1H),8.01-7.76(m, 2H),7.71-7.47(m,2H),7.38(s,1H),7.22(s,1H),7.03(s,1H),2.18(s,1H),1.05(d,J=8.3Hz,2H),0.84(s,2H).

[0551] Example 56

[0552] [ka]

[0553] (1) Preparation of Compound 56-1 Compound 13-8 (200 mg) and quinoline-4-boronic acid (93.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react completely. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 56-1.

[0554] (2) Preparation of compound 56-2 Compound 56-1 (160 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (40.8 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 56-2, which was used as is in the next reaction.

[0555] (3) Preparation of Compound 56 Compound 56-2 (144.4 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (64.7 mg) and isobutyl chloroformate (87.4 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (67.2 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and 60 mg of compound 56 was obtained by fractionation and purification. ESI-MS: m / z = 451.26 [M + H] + .

[0556] 1HNMR(500MHz,DMSO-d6)δ9.00(s,1H),8.95(d,J=4.3Hz,1H),8.54(s,1H),8.13(d,J=8.4Hz,1H),7.82-7.70(m,2H),7.59(s,1H),7.52(t,J=7.6H) z,1H),7.42(d,J=4.3Hz,1H),7.23(s,1H),7.18(s,1H),7.05(s,1H),2.1 4(tt,J=8.3,4.7Hz,1H),1.06(dd,J=8.1,3.0Hz,2H),0.90-0.75(m,2H).

[0557] Example 57

[0558] [ka]

[0559] (1) Preparation of Compound 57-1 Compound 13-8 (200 mg) and quinoline-6-boronic acid (93.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90° C. under nitrogen gas protection to react completely. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 57-1.

[0560] (2) Preparation of compound 57-2 Compound 57-1 (150 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (38.3 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 57-2, which was used as is in the next reaction.

[0561] (3) Preparation of Compound 57 Compound 57-2 (135.4 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (60.7 mg) and isobutyl chloroformate (81.9 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (63 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and 30 mg of compound 57 was obtained by fractionation and purification. ESI-MS: m / z = 451.21 [M + H] + .

[0562] 1 HNMR(500MHz,DMSO-d6)δ8.96(dd,J=4.2,1.7Hz,1H),8.81(s,1H),8.39(dd,J=8.6,1.8Hz,1H),8.27(s,1H),8.07(d,J=8.6Hz,1H),7.93(d,J =1.9Hz,1H),7.65-7.53(m,4H),7.37(d,J=1.3Hz,1H),7.15(s,1H),2.10(ddd,J=8.2,6.5,4.1Hz,1H),1.03-0.98(m,2H),0.82-0.77(m,2H).

[0563] Example 58

[0564] [ka]

[0565] (1) Preparation of Compound 58-1 Compound 13-8 (200 mg) and isoquinoline-5-boronic acid (93.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 °C under nitrogen gas protection to react completely. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 58-1.

[0566] (2) Preparation of compound 58-2 Compound 58-1 (160 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (40.8 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 58-2, which was used as is in the next reaction.

[0567] (3) Preparation of Compound 58 Compound 58-2 (144.4 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (64.7 mg) and isobutyl chloroformate (87.4 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (67.2 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and 40 mg of compound 58 was obtained by fractionation and purification. ESI-MS: m / z = 451.20 [M + H] + .

[0568] 1 HNMR(500MHz,DMSO-d6)δ9.39(s,1H),8.89(s,1H),8.51(s,1H),8.41(d,J=5.9Hz,1H ),8.23(d,J=8.2Hz,1H),7.76(dd,J=8.2,7.1Hz,1H),7.66(dd,J=7.0,1.2Hz,1H),7.5 6(s,1H),7.54(d,J=5.9Hz,1H),7.37(d,J=1.2Hz,1H),7.11(s,1H),7.04(d,J=1.2Hz ,1H),2.18(tt,J=8.1,4.7Hz,1H),1.05(dd,J=8.2,2.9Hz,2H),0.85(d,J=7.0Hz,2H).

[0569] Example 59

[0570] [ka]

[0571] (1) Preparation of Compound 59-1 Compound 13-8 (200 mg) and quinoline-7-boronic acid (93.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react completely. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 59-1.

[0572] (2) Preparation of compound 59-2 Compound 59-1 (145 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (37 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 59-2, which was used as is in the next reaction.

[0573] (3) Preparation of Compound 59 Compound 59-2 (135.4 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (60.6 mg) and isobutyl chloroformate (81.9 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (63 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and 40 mg of compound 59 was obtained by fractionation and purification. ESI-MS: m / z = 451.22 [M + H] + .

[0574] 1HNMR(500MHz,DMSO-d6)δ8.93(dd,J=4.2,1.8Hz,1H),8.83(s,1H),8.44(dd,J =8.4,1.8Hz,1H),8.27(s,1H),8.04(d,J=8.4Hz,1H),7.93(d,J=1.6Hz,1H),7. 66-7.55(m,3H),7.46(dd,J=8.4,1.7Hz,1H),7.32(d,J=1.3Hz,1H),7.17(s,1H ),2.12(tt,J=8.4,4.7Hz,1H),1.01(dt,J=8.1,3.3Hz,2H),0.83-0.77(m,2H).

[0575] Example 60

[0576] [ka]

[0577] (1) Preparation of Compound 60-1 Compound 13-8 (200 mg) and 6-trifluoromethylpyridine-3-boronic acid (103.1 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react completely. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 60-1.

[0578] (2) Preparation of compound 60-2 Compound 60-1 (130 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (32 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 60-2, which was used as it was in the next reaction.

[0579] (3) Preparation of Compound 60 Compound 60-2 (117.3 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (50.6 mg) and isobutyl chloroformate (68.3 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (52.5 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and 45 mg of compound 60 was obtained by fractionation and purification. ESI-MS: m / z = 469.19 [M + H] + .

[0580] 1 HNMR(500MHz,DMSO-d6)δ9.13(s,1H),8.66(d,J=2.0Hz,1H),8.41(s,1H),8.04-7.94(m,2H),7.74(s,1H),7.64 (s,1H),7.38(s,1H),7.30(s,1H),2.24(tt,J=8.3,4.7Hz,1H),1.06(dt,J=8.0,3.3Hz,2H),0.99-0.86(m,2H).

[0581] Example 61

[0582] [ka]

[0583] (1) Preparation of Compound 61-1 Compound 13-8 (200 mg) and quinoline-5-boronic acid (93.4 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.57 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react completely. The reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain compound 61-1.

[0584] (2) Preparation of compound 61-2 Compound 61-1 (220 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide hydrate (56.6 mg) and water (4 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 61-2, which was used as is in the next reaction.

[0585] (3) Preparation of Compound 61 Compound 61-2 (203.1 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (91 mg) and isobutyl chloroformate (123 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (94 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and 70 mg of compound 61 was obtained by fractionation and purification. ESI-MS: m / z = 451.21 [M + H] + .

[0586] 1 HNMR(500MHz,DMSO-d6)δ8.89(dd,J=4.1,1.7Hz,1H),8.83(s,1H),8.51(s,1H),8.1 8-8.08(m,2H),7.84(dd,J=8.5,7.1Hz,1H),7.57(s,1H),7.50(dd,J=7.0,1.2Hz,1H) ,7.45(dd,J=8.5,4.1Hz,1H),7.32(d,J=1.3Hz,1H),7.17(d,J=1.4Hz,1H),7.09(s, 1H),2.16(tt,J=8.0,4.7Hz,1H),1.06(dd,J=8.2,2.8Hz,2H),0.85(q,J=4.2Hz,2H).

[0587] Example 62

[0588] [ka]

[0589] (1) Preparation of Compound 62-1 Compound 13-8 (200 mg) and 2-methylpyridine-3-boronic acid (73.95 mg) were dispersed in 1,4-dioxane (5 mL), potassium carbonate (186.6 mg), Pd(dppf)Cl2 (14.6 mg) and water (0.5 mL) were added, and the mixture was heated to 90 ° C under nitrogen gas protection to react completely. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 62-1.

[0590] (2) Preparation of compound 62-2 Compound 62-1 (140 mg) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (38.5 mg) and water (5 mL) was added dropwise in an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 6-7 with hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness under reduced pressure to obtain compound 62-2, which was used as is in the next reaction.

[0591] (3) Preparation of Compound 62 Compound 62-2 (124.6 mg) was dispersed in tetrahydrofuran (5 mL), and N-methylmorpholine (60.7 mg) and isobutyl chloroformate (81.9 mg) were added in an ice-water bath and stirred for 30 minutes. Ammonia water (63 mg) was added dropwise, and the mixture was reacted in an ice-water bath for 10 minutes, and the reaction was quenched by adding water and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound 62 (72 mg) was obtained by fractional purification. ESI-MS: m / z = 415.27 [M + H] + .

[0592] 1HNMR(500MHz,DMSO-d6)δ8.95(s,1H),8.52(dd,J=4.9,1.8Hz,1H),8.31(s,1H),7.66(d,J=1.3Hz,1H),7.57-7.52(m,1H),7.50(dt,J=4. 4,2.4Hz,2H),7.29(dd,J=7.6,4.9Hz,1H),7.14(s,1H),2.28(s,3H),2.27-2.23(m,1H),1.09(dt,J=8.3,3.2Hz,2H),0.96-0.90(m,2H).

[0593] Test Example 1: In vitro cell proliferation inhibitory activity 1.1 Jurkat cell proliferation inhibitory activity assay Jurkat cells in good growth condition were harvested in a centrifuge tube and the cell density was adjusted to 5 × 10 4 The concentration was adjusted to 1000 cells / mL, seeded on a 96-well plate (100 μL / well), and cultured overnight in a cell incubator. Using a nanoliter pipetter, compounds were added to a final concentration of 1000 nM to 0.46 nM, and two wells were set up as controls at the same time. After continuing to culture in a cell culture incubator for 72 hours, detection reagent CCK-8 (Dojindo Laboratories, 10 μL / well) was added and incubated in a cell culture incubator for 2 hours. After that, the absorbance at 450 nm was measured using an Envision microplate reader, a four-parameter analysis was performed, a dose-response curve was fitted, and the IC 50 was calculated.

[0594] 1.2 OCI-LY10 cell proliferation inhibition assay OCI-LY10 cells in good growth condition were harvested in a centrifuge tube and the cell density was adjusted to 9 × 10 4The concentration was adjusted to 100 cells / mL, seeded on a 96-well plate (100 μL / well), and cultured overnight in a cell incubator. Using a nanoliter pipetter, compounds were added to a final concentration of 1000 nM to 0.46 nM, and two wells were set up as controls at the same time. After continuing to culture in the cell incubator for 72 hours, detection reagent CCK-8 (Dojindo Laboratories, 10 μL / well) was added and incubated in the cell incubator for 2 hours. After that, the absorbance at 450 nm was measured using an Envision microplate reader, a four-parameter analysis was performed, a dose-response curve was fitted, and the IC 50 was calculated.

[0595] 1.3 RPMI-8226 cell proliferation inhibition assay RPMI-8226 cells in good growth condition were harvested in a centrifuge tube, the cell density was adjusted, and the cells were seeded in a 96-well plate and cultured overnight in a cell culture incubator. Compounds were added using a nanoliter pipettor and controls were set up. Culture was continued in the cell incubator, and detection reagents were added. After incubation in the cell incubator for a certain period, the absorbance was measured using an Envision microplate reader. A four-parameter analysis was performed, and dose-response curves were fitted to determine the IC 50 was calculated.

[0596] Detailed results are shown in Table 1. Regarding the inhibitory activity against Jurkat cell proliferation, A is IC 50 For the inhibitory activity against OCI-LY10 cell proliferation, + indicates IC 50 ≦40nM.

[0597] [Table 1]

[0598] The compounds of the present disclosure show good results in in vitro cell proliferation inhibitory activity tests.

[0599] Test Example 2: In vitro liver microsome stability The liver microsome incubation sample was prepared by mixing PBS buffer (pH=7.4), liver microsome solution (0.5mg / mL), test compound and NADPH+MgCl2 solution, and incubating at 37℃ and 300rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH=7.4), liver microsome solution (0.5mg / mL) and test compound. An acetonitrile solution containing an internal standard was added to the sample, proteins were precipitated, and the supernatant was prepared, diluted, and used for LC / MS / MS measurement. The test results are shown in Table 2.

[0600] [Table 2]

[0601] The compounds of the present disclosure exhibit good properties in liver microsomal stability studies.

[0602] Test Example 3: In vivo pharmacokinetics 3.1 Pharmacokinetics in mice ICR mice weighing 18 to 22 g were acclimated for 3 to 5 days, then randomly divided into groups (9 mice per group) and intragastrically administered with a dose of 3 mg / kg.

[0603] Blood was collected from the orbit at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours, and plasma samples for testing were prepared.

[0604] 20 μL of the test plasma sample and the calibration curve sample were taken, and an acetonitrile solution containing an internal standard was added to precipitate the proteins to obtain the supernatant. After dilution, the supernatant was used for LC / MS / MS measurement.

[0605] The pharmacokinetic parameters were fitted using a non-compartmental model. The study results are shown in Table 3.

[0606] [Table 3]

[0607] The compounds of the present disclosure have shown good properties in pharmacokinetic studies, including, but not limited to, good bioavailability and AUC.

[0608] 3.2 Mouse brain distribution ICR mice weighing 20 to 26 g were acclimated for 3 to 5 days, then randomly divided into groups (3 mice per group) and intragastrically administered with a dose of 5 mg / kg.

[0609] At the 3-hour blood collection time point, blood was collected via the orbit and plasma samples were prepared for testing, while brain tissue was removed at each time point and the homogenates were weighed.

[0610] 20 μL of the homogenate samples of the test plasma and tissues and the calibration curve samples were taken, and acetonitrile solution was added to precipitate the proteins to obtain the supernatant, which was then diluted and used for LC / MS / MS measurement to calculate the brain-blood ratio.

[0611] Compounds of the present disclosure had brain-blood ratios of less than 1, indicating low brain uptake.

[0612] Test Example 4: In vivo pharmacodynamics Efficacy evaluation of OCI-LY10 human diffuse large B-cell lymphoma in a subcutaneous xenograft tumor model in NOD-SCID mice (1) Inject 1 × 10 OCI-LY10 human diffuse large B-cell lymphoma cells into the right armpit of SPF female NOD-SCID mice (origin: Jiangsu Huachuang Xinnuo Pharmaceutical Technology Co., Ltd.). 7 Cells were inoculated subcutaneously per mouse. The average tumor volume was approximately 200 mm. 3 When the animals reached this age, they were divided into control (solvent control) and treatment (compound) groups.

[0613] The doses were 1 mg / kg, 2 mg / kg, and 4 mg / kg, and the administration frequency was once a day. The day of grouping was set as day 0, and intragastric administration was started from day 0 for 21 consecutive days.

[0614] Alternatively, the dose was set at 4 mg / kg, the administration frequency was set at 5 times a week, the day of grouping was set as day 0, and intragastric administration was started from day 0, 5 times a week for 2 consecutive weeks.

[0615] Tumor volumes were measured every 3 days, and the weights of the mice were measured and recorded. The general performance of the mice was observed and recorded every day. After the experiment, the tumors were excised, weighed, and photographed.

[0616] The detection index and calculation formula are as follows: Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ) (where a is the longest diameter of the tumor and b is the shortest diameter of the tumor.) Relative tumor volume, RTV=TV t / TV0 (where TV0 is the tumor volume on day 0 and TV t is the tumor volume at each measurement.) Relative tumor growth rate, T / C(%)=T RTV / C RTV ×100% (where T RTV is the RTV of the treatment group, and C RTV is the RTV of the vehicle control group.) Tumor growth inhibition rate, TGI(%)=(1-TW / TW0)×100% (where TW is the tumor weight of the treatment group and TW0 is the tumor weight of the vehicle control group). Weight change rate, WCR(%)=(Wt t -Wt0) / Wt0 × 100% (where Wt0 is the mouse weight on day 0 and Wt t is the body weight of the mouse at each measurement.) The specific test results are shown in Tables 4 and 5.

[0617] [Table 4]

[0618] Note: Compared to the control group, * p<0.05, ** p<0.01.

[0619] [Table 5]

[0620] Note: Compared to the control group, ** p<0.01.

[0621] The compounds of the present disclosure did not show significant toxicity in the tests and, as a result, showed good tumor growth inhibition rates.

Claims

1. A compound of formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 【Chemistry 1】 (In the formula, R １ is -NH ２ , C １～６ Alkyl-O-, C １～６ Alkyl-NH- or (C １～６ alkyl) ２ N-; Ring A is C ６～１０ selected from an aromatic ring group or a 5- to 10-membered heteroaromatic ring group; R is halogen, CN, OH, NH ２ , C １～６ Alkyl, C １～６ Alkyl-O-, C １～６ Alkyl-S-, halogenated C １～６ Alkyl-O-, halogenated C １～６ Alkyl-S-, halogenated C １～６ C substituted with alkyl, 3-10 membered heterocycloalkyl １～６ Alkyl, R ａ NH- or (R ａ ) ２ N-; R ａ is C １～６ Alkyl, C ３～１０ cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein R ａ is halogen, CN, OH, NH ２ , C １～６ Alkyl, C １～６ optionally substituted by one or more substituents selected from alkylO- or 5- to 6-membered heterocycloalkyl; n is selected from 0, 1, 2, 3 or 4; R ２ is selected from cyclopropyl or trifluoromethyl.

2. The R １ is -NH ２ , C １～４ Alkyl-O— or C １～４ Alkyl-NH- or (C １～４ alkyl) ２ N-; Alternatively, the R １ is -NH ２ , C １～３ Alkyl-O— or C １～３ Alkyl-NH- or (C １～３ alkyl) ２ N-; Alternatively, the R １ is -NH ２ , isopropyl-O—, or methyl-NH—; Alternatively, the R １ is -NH ２ or isopropyl-O—; Alternatively, the R １ is -NH ２ 2. The compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:

3. Ring A is selected from phenyl or a 5- to 10-membered heteroaromatic ring group; Alternatively, said ring A is selected from a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaromatic ring group; Alternatively, said ring A is selected from a 5- to 6-membered or 9- to 10-membered heteroaromatic ring group; Alternatively, said ring A is selected from a 10-membered heteroaromatic ring group; Alternatively, said ring A is selected from a 5- to 6-membered heteroaromatic ring group; Alternatively, said ring A is selected from a 6-membered heteroaromatic ring group; Alternatively, said Ring A is selected from pyrimidinyl, pyridyl, pyrazolyl, isoxazolyl, oxazolyl, quinolyl, indazolyl, pyridazinyl, thiazolyl, furanyl, pyranyl, thienyl, pyrrolyl, pyrazinyl, isothiazolyl, oxazolyl, indolyl, naphthyridinyl, isoquinolinyl, quinazolinyl, or benzofuranyl; Alternatively, said Ring A is selected from pyrimidinyl, pyridyl, pyrazolyl, isoxazolyl, quinolyl, indazolyl, naphthyridinyl, or isoquinolinyl; Alternatively, said ring A is selected from pyrimidinyl or pyridyl; Alternatively, said ring A is selected from pyrimidinyl; Alternatively, said ring A is selected from pyridyl; Alternatively, said ring A is selected from pyrazolyl or isoxazolyl; Alternatively, said ring A is selected from quinolyl, indazolyl, naphthyridinyl, or isoquinolinyl; Alternatively, the ring A is 【Chemistry 2】 2. The compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:

4. The R is a halogen, CN, OH, NH ２ , C １～４ Alkyl, C １～４ Alkyl-O-, C １～４ Alkyl-S-, halogenated C １～４ Alkyl-O-, halogenated C １～４ Alkyl-S-, halogenated C １～４ Alkyl, R ａ NH- or (R ａ ) ２ N-; Alternatively, the R is halogen, CN, OH, NH ２ , C １～３ Alkyl, C １～３ Alkyl-O-, C １～３ Alkyl-S-, halogenated C １～３ Alkyl-O-, halogenated C １～３ Alkyl-S-, halogenated C １～３ Alkyl, R ａ NH- or (R ａ ) ２ N-; Alternatively, the R is fluorine, chlorine, CN, OH, NH ２ , C １～３ Alkyl, C １～３ Alkyl-O-, halogenated C １～３ Alkyl or R ａ NH-; Alternatively, the R is fluorine, CN, NH ２ , methyl, methoxy, trifluoromethyl or R ａ NH-; Alternatively, the R is fluorine, CN, NH ２ , methyl, methoxy, trifluoromethyl, 【Transformation 3】 2. The compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:

5. The R ａ is C １～４ Alkyl, C ３～６ cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein R ａ is halogen, CN, OH, NH ２ or 5-6 membered heterocycloalkyl; Alternatively, the R ａ is C １～３ Alkyl, C ５～６ cycloalkyl or 5- to 6-membered heterocycloalkyl, wherein R ａ is halogen, CN, OH, NH ２ or 5-6 membered heterocycloalkyl; Alternatively, the R ａ is C １～３ alkyl or 5- to 6-membered heterocycloalkyl, ａ is halogen, CN, OH, NH ２ or 5-6 membered heterocycloalkyl; Alternatively, the R ａ is C １～３ alkyl or 6-membered heterocycloalkyl, wherein R ａ are fluorine, chlorine, bromine, CN, OH, NH ２ or 6-membered heterocycloalkyl; Alternatively, the R ａ is selected from methyl, ethyl, propyl, or tetrahydropyranyl, and said R ａ may be substituted by one or more fluorines or dioxanes; Alternatively, the R ａ is FCH ２ CH ２ -, F ２ CHCH ２ -, F ３ CCH ２ -, CF ３ CH (CH ３ ) -, CH ３ CF ２ CH ２ -, tetrahydropyranyl or dioxane -CH ２ 2. The compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:

6. n is selected from 0, 1, 2 or 3; Alternatively, n is selected from 0, 1 or 2; Alternatively, n is selected from 0 or 1. The compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

7. R ２ is selected from cyclopropyl, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

8. Structural Unit 【Chemistry 4】 teeth, 【Transformation 5】 Selected from: Or, structural units 【Transformation 6】 teeth, 【Transformation 7】 Selected from: Or, structural units 【Transformation 8】 teeth, 【Chemistry 9】 Selected from: Or, structural units 【Chemistry 10】 teeth, 【Chemistry 11】 Selected from: Or, structural units 【Chemistry 12】 teeth, 【Chemistry 13】 Selected from: Or, structural units 【Chemistry 14】 teeth, 【Chemistry 15】 2. The compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:

9. Structural Unit 【Chemistry 16】 teeth, 【Chemistry 17】 Selected from: Optionally, the structural unit [Chemistry 18] teeth, 【Chemistry 19】 2. The compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:

10. The compound represented by formula I according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from the compounds represented by formula I-1 and I-2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 【Chemistry 20】 (In the formula, T １ , T ２ , T ３ , T ４ or T ５ are each independently selected from a bond, O, S, N, or CH, provided that no more than one is selected from a bond and at least one is selected from N; 【Chemistry 21】 represents a single or double bond; Optionally, T １ , T ２ , T ３ , T ４ or T ５ are each independently selected from N or CH, with at least one selected from N; Or, T ２ and T ４ is selected from N, and T １ , T ３ and T ５ is selected from CH; Or, T ３ is selected from N, and T １ , T ２ , T ４ and T ５ is selected from CH; Or, T ２ is selected from N, and T １ , T ３ , T ４ and T ５ is selected from CH.

11. Structural Unit 【Chemistry 22】 teeth, 【Chemistry 23】 Selected from: Or, structural units 【Chemistry 24】 teeth, 【Chemistry 25】 Selected from: Or, structural units 【Chemistry 26】 teeth, 【Chemistry 27】 Selected from: Or, structural units 【Chemistry 28】 【Chemistry 29】 Selected from: Or, structural units 【Transformation 30】 teeth, 【Chemistry 31】 Selected from: Or, structural units 【Chemistry 32】 teeth, 【Transformation 33】 11. The compound of formula I according to claim 10, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:

12. The following compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】

13. A pharmaceutical composition comprising the compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

14. Use of the compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition of claim 13 in the manufacture of a medicament for treating various XPO-1-associated diseases, comprising: Optionally, the various XPO-1 associated diseases are selected from tumors; Alternatively, the various XPO-1-associated diseases are selected from leukemia or lymphoma.

15. Use of the compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition of claim 13 for treating various XPO-1-related diseases, comprising: Optionally, the various XPO-1 associated diseases are selected from tumors; Alternatively, the various XPO-1-associated diseases are selected from leukemia or lymphoma.

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