KIF18A inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a compound as shown in a formula (1), a preparation method of the compound, a composition containing the compound as shown in the formula (1) and / or pharmaceutically acceptable salt of the compound, and application of the compound as a KIF18A inhibitor in preparation of antitumor drugs.

Description

KIF18A inhibitors and preparation methods and uses thereof Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a class of KIF18A inhibitors and preparation methods and uses thereof. Background Art

[0002] Cell division can be divided into three types: mitosis, amitosis, and meiosis. Mitosis is characterized by the reorganization of chromosomes under the guidance of the spindle, with sister chromosomes separated and evenly distributed to daughter cells. This is a common method for proliferation and other life activities in higher plants and animals. Various kinases and kinesins have been identified as playing key roles in regulating and progressing the cell cycle and mitosis in both normally dividing cells and cancer cells.

[0003] Kinesins are motor proteins that use microtubules as their tracks and play an important role in organelle migration, tissue and organ development, signal transduction, mitosis, and meiosis [Nature Review Cancer, 2012, 12, 527-539]. KIF18A, a member of the kinesin-8 family, is a molecular kinesin that uses microtubules as its tracks and moves toward the plus ends of microtubules. It regulates chromosome midplate assembly by influencing the dynamic instability of microtubule ends, exerting its function during mitosis. KIF18A is believed to influence the dynamics of the plus ends of centromeric microtubules to control correct chromosome positioning and spindle tension.

[0004] Changes in the number of chromosomal gene copies can produce aneuploid cells, which is the most common genetic change in human cancer. Because cancer cells are almost always aneuploid, while normal cells are almost always euploid, aneuploid cells exhibit abnormal spindle geometry and dynamics and continue to divide when the spindle assembly checkpoint is inhibited, resulting in an increasing number of mitotic defects and a less stable and mismatched karyotype. Studies have found that the activity of the mitotic kinesin KIF18A in aneuploid cancer cells is disturbed. Depletion of KIF18A can significantly inhibit aneuploid cancer cells, while overexpression of KIF18A can restore their response to spindle assembly checkpoint inhibitors. The synthetic lethal interaction between aneuploidy and the spindle assembly checkpoint has therapeutic significance. Aneuploidy can sensitize cancer cells to mitotic checkpoint inhibitors. KIF18A is expected to become a new target for aneuploid malignancies such as triple-negative breast cancer [Nature, 2021, 590, 486-491].

[0005] KIF18A is overexpressed in multiple types of cancer, including but not limited to hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, prostate cancer, bladder cancer, head and neck cancer, uterine cancer, and ovarian cancer.

[0006] Amgen's KIF18A inhibitor AMG-650 has entered Phase 1 clinical trials for the treatment of adult patients with locally advanced or metastatic solid tumors carrying p53 gene mutations (TP53MUT) or triple-negative breast cancer (TNBC), high-grade serous ovarian cancer (HGSOC), or serous endometrial cancer.

[0007] However, current KIF18A inhibitors still have disadvantages such as insufficient activity or high toxic side effects. Therefore, there is an urgent need in the art to develop new KIF18A inhibitors with high activity, strong specificity and / or high safety.

[0008] Summary of the Invention

[0009] The purpose of the present invention is to provide a novel KIF18A inhibitor with high activity, strong specificity and / or high safety, and a preparation method and application thereof.

[0010] In the first aspect of the present invention, a compound having a general structural formula as shown in formula (1), or its isomers (such as optical isomers), various crystal forms, pharmaceutically acceptable salts, hydrates or solvates is provided:

[0011] In formula (1):

[0012] Ring A is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic group, and the heteroaryl and heterocyclic group may be further substituted by 0-3 of the following groups: halogen, C 1-3 Alkyl or C 1-3 alkoxy;

[0013] L is selected from -C(O)NR a 、-NR a C(O)- or 5-6 membered heteroaromatic ring;

[0014] Y is selected from the following group: chemical bond, -NR a -、-SO2-、-O-、-NR a S(O)2-、-S(O)2NR a -、C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0015] R a Selected from the following group: H or C 1-3 alkyl;

[0016] X1, X2 and X3 are each independently selected from the group consisting of N or CR 4 , where R 4 H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C1-3 Haloalkyl or C 1-3 haloalkoxy;

[0017] R 1 Select from the following group: C 3-6 Cycloalkyl or 4-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 0-3 groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0018] R 2 Selected from the group consisting of H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 haloalkoxy;

[0019] R 3 Selected from the following group: H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-8 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 0-3 groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclic group or -O(CO)R 5 ;

[0020] R 5 Select from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group; the alkyl, cycloalkyl or heterocyclic group is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group or NR d R e ; where R d and R e Each independently selected from the group consisting of: H or C 1-3 Alkyl; or R d and R eThe nitrogen atom to which it is attached forms a 3-6 membered ring structure, wherein the ring structure optionally contains 1 or 2 heteroatoms selected from N, O, and S;

[0021] Z is Wherein, the dotted line is a chemical bond or does not exist. When the dotted line connected to V is a chemical bond, V is C; when the dotted line connected to V does not exist, V is N or CH.

[0022] R 6 and R 7 Each independently selected from the group consisting of H, halogen, CN, C 1-3 Alkyl, C 1-3 Oxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; or R 6 and R 7 The C atoms connected to it form a 3-6 membered ring structure; or R 6 and R 7 The C atom connected thereto forms C=T, wherein T is selected from CR b R c ; Among them, R b and R c Each independently selected from the group consisting of H, halogen, CN or C 1-3 Alkyl; or R b and R c The C atoms connected thereto form a 3-6 membered ring structure; the ring structure optionally contains 0, 1 or 2 heteroatoms selected from N, O, and S.

[0023] In another preferred embodiment, Z is selected from the following group: where R 6 and R 7 As defined above.

[0024] In another preferred embodiment, in the formula (1), Z is selected from the following group:

[0025] In another preferred embodiment, ring A is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic group, and the heteroaryl and heterocyclic group may be further substituted by 0-3 of the following groups: halogen, C 1-3 Alkyl or C 1-3 alkoxy;

[0026] L is selected from -C(O)NR a or -NR a C(O)-;

[0027] Y is selected from the following group: chemical bond, -NR a-、-SO2-、-O-、-NR a S(O)2-、-S(O)2NR a -、C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0028] R a Selected from the following group: H or C 1-3 alkyl;

[0029] X1, X2 and X3 are each independently selected from the group consisting of N or CR 4 , where R 4 H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 haloalkoxy;

[0030] R 1 Select from the following group: C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0031] R 2 Selected from the group consisting of H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 haloalkoxy;

[0032] R 3 Selected from the following group: H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group or -O(CO)R 5 ;

[0033] R 5 Select from the following group: C 1-6 Alkyl, C3-6 Cycloalkyl or 4-7 membered heterocyclic group; the alkyl, cycloalkyl or heterocyclic group is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group or NR d R e ; where R d and R e Each independently selected from the group consisting of: H or C 1-3 Alkyl; or R d and R e The nitrogen atom to which it is attached forms a 3-6 membered ring structure, which optionally contains 1 or 2 heteroatoms selected from N, O, and S;

[0034] Z is independently selected from the following group:

[0035] R 6 and R 7 Each independently selected from the group consisting of H, halogen, CN, C 1-3 Alkyl; or R 6 and R 7 The connected C atoms form a 3-6 membered ring structure, and the ring structure optionally contains 0, 1 or 2 heteroatoms selected from N, O, and S;

[0036] R 8 and R 9 Each independently selected from the group consisting of H, halogen, CN, C 1-3 Alkyl or C 1-3 Alkoxy, or R 8 and R 9 The connected C atoms form a 3-6 membered ring structure, and the ring structure optionally contains 0, 1 or 2 heteroatoms selected from N, O and S.

[0037] In another preferred embodiment, the compound has a structure shown in formula (2):

[0038] in:

[0039] The dotted line is a chemical bond or does not exist. When the dotted line connected to V is a chemical bond, V is C; when the dotted line connected to V does not exist, V is N or CH;

[0040] Ring A is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic group, and the heteroaryl and heterocyclic group may be further substituted by 0-2 of the following groups: halogen, C 1-3 Alkyl or C 1-3 alkoxy;

[0041] Ring B is a 5-6 membered heteroaromatic ring;

[0042] Y is selected from the following group: chemical bond, -NR a -、-SO2-、-O-、-NR a S(O)2-、-S(O)2NR a -、C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0043] R a Selected from the following group: H or C 1-3 alkyl;

[0044] X1, X2 and X3 are each independently selected from the group consisting of N or CR 4 , where R 4 H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 haloalkoxy;

[0045] R 1’ and R 2’ Each independently selected from the group consisting of H, halogen, CN, C 1-3 Alkyl, C 1-3 Oxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; or R 1’ and R 2’ The C atom connected thereto forms a 3-6 membered cyclic structure, wherein the cyclic structure optionally contains 0, 1 or 2 heteroatoms selected from N, O, S; or R 1’ and R 2’ The C atom connected thereto forms C=T, wherein T is selected from CR b R c ; Among them, R b and R c Each independently selected from the group consisting of H, halogen, CN or C 1-3 Alkyl; or R b and R c The C atom to which it is connected forms a 3-6 membered ring structure, wherein the ring structure optionally contains 0, 1 or 2 heteroatoms selected from N, O, and S;

[0046] R 1 Select from the following group: C 3-6 Cycloalkyl or 4-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0047] R 2 Selected from the group consisting of H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 haloalkoxy;

[0048] R 3 Selected from the following group: H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group or -O(CO)R 5 ;

[0049] R 5 Select from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group; the alkyl, cycloalkyl or heterocyclic group is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group or NR d R e ; where R d and R e Each independently selected from the group consisting of: H or C 1-3 Alkyl; or R d and R e The nitrogen atom to which it is connected forms a 3-6 membered ring structure, and the ring structure optionally contains 1 or 2 heteroatoms selected from N, O, and S.

[0050] In another preferred embodiment, the compound has a structure shown in formula (3):

[0051] in:

[0052] L is

[0053] Y is selected from the following group: chemical bond, -NRa -、-SO2-、-NR a S(O)2- or -S(O)2NR a -, R a Selected from the following group: H or C 1-3 alkyl;

[0054] X1, X2 and X3 are each independently selected from the group consisting of N or CR 4 , where R 4 H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 haloalkoxy;

[0055] R 1” and R 2” Each independently selected from the group consisting of halogen or C 1-3 Alkyl; or R 1” and R 2” The C atom connected to it forms a divalent C 3-6 saturated or partially unsaturated carbocyclic group;

[0056] R 1 Select from the following group: C 3-6 Cycloalkyl or 4-8 membered heterocyclic group, the cycloalkyl and heterocyclic group may be further substituted by 0-3 groups selected from the following groups: halogen, CN, C 1-3 Alkyl or C 1-3 alkyl halide;

[0057] R 2 Selected from the group consisting of H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 haloalkoxy;

[0058] R 3 Selected from the following group: H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-8 membered heterocyclic group, said alkyl, cycloalkyl or heterocyclic group may be further substituted by 0-3 of the following groups: OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-8 membered heterocycloalkyl;

[0059] Ring A is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic group, and the heteroaryl and heterocyclic group may be further substituted by 0-3 of the following groups: halogen, C 1-3 Alkyl or C 1-3Alkoxy.

[0060] In another preferred embodiment, X1, X2 and X3 are each independently selected from the following group: N, CH, CF, CCl, CMe, C(OMe), CCF3 or C(OCF3).

[0061] In another preferred embodiment, R 1 Select from the following groups:

[0062] In another preferred embodiment, R 2 Selected from the group consisting of H, Me, F, or OMe.

[0063] In another preferred embodiment, in the formula (1), YR 3 Select from the following groups:

[0064] In another preferred embodiment, the compound has a structure shown in formula (4):

[0065] in:

[0066] R 1 for

[0067] Z is

[0068] YR 3 Select from the following groups:

[0069] Ring A is a 5-membered oxygen-containing heteroaryl group or a 5-membered oxygen-containing heterocyclic group.

[0070] In another preferred embodiment, Select from the following groups:

[0071] In another preferred embodiment, Z is

[0072] In another preferred embodiment, the compound has a structure selected from the group consisting of:

[0073] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0074] (1) a compound as described in the first aspect of the present invention as an active ingredient, or any isomer, crystal form, pharmaceutically acceptable salt (inorganic salt or organic salt), hydrate or solvate thereof; and

[0075] (2) Pharmaceutically acceptable excipients and / or carriers.

[0076] In the third aspect of the present invention, there is provided a use of the compound described in the first aspect of the present invention, or its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition described in the second aspect of the present invention, for preparing a medicament for preventing and / or treating diseases mediated by KIF18A.

[0077] In the fourth aspect of the present invention, a method for treating, regulating and / or preventing diseases mediated by KIF18A is provided, comprising the steps of administering to an individual in need thereof the compound of the first aspect of the present invention, or its isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of the second aspect of the present invention.

[0078] In another preferred embodiment, the related diseases mediated by KIF18A are selected from the following groups: glioblastoma, bile duct cancer, bladder cancer, head and neck cancer, ovarian cancer, brain tumor, gastric cancer, liver cancer, lung cancer, intestinal cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, leukemia, lymphoma and other solid tumors and blood tumors.

[0079] In another preferred embodiment, the individual includes humans and non-human mammals.

[0080] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] FIG1A shows the effects of compounds A39, A43, and AMG650 on tumor volume in OVCAR-3 xenograft model mice.

[0082] FIG1B shows the effects of compounds A39, A43, and AMG650 on body weight in OVCAR-3 xenograft model mice.

[0083] FIG2A shows the effects of compounds B83, B86, C105, and AMG650 on tumor volume in OVCAR-3 xenograft model mice.

[0084] FIG2B shows the effects of compounds B83, B86, C105, and AMG650 on body weight in OVCAR-3 xenograft model mice. DETAILED DESCRIPTION

[0085] After extensive and in-depth research, and through extensive screening and testing, the present inventors have discovered for the first time a class of compounds of formula (1), which have significant therapeutic effects on diseases mediated by KIF18A. The compounds of the present invention have strong inhibitory activity against the KIF18 enzyme and have good cell proliferation inhibitory activity against the OVCAR-3 cell line with TP53 mutation and CCNE1 amplification. The compounds are well absorbed orally and show strong and sustained ability to inhibit tumor growth in vivo. This is the basis for the completion of the present invention.

[0086] Compounds of the present invention and their synthesis

[0087] The present invention provides an inhibitor targeting KIF18A, namely, a compound of formula (1), or each isomer thereof, or an isomer, crystal form, pharmaceutically acceptable salt (inorganic salt or organic salt), hydrate or solvate thereof. Preferably, the compound of the present invention is as described in the first aspect.

[0088] The present invention also provides a method for preparing the compound of formula (1). The following specifically describes the method for preparing the compound of general formula (1), but these specific methods do not constitute any limitation to the present invention.

[0089] In one aspect, the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of the compounds used, reaction temperatures, reaction times, etc., are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art. In one aspect, the present invention also provides a method for preparing the compound of formula (1), which is prepared using the following general reaction schemes 1 to 6:

[0090] General reaction scheme 1:

[0091] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein G1, G2, G3 are independently halogen, nitro, hydroxyl, A, X1, X2, X3, R 1 、R 2 、R3 , Z and Y are as defined above.

[0092] General reaction scheme 2:

[0093] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 2, wherein G1 and G2 are independently halogen, nitro, or hydroxyl, and A, X1, X2, X3, and R 1 、R 2 、R 3 , Z and Y are as defined above.

[0094] General reaction scheme 3:

[0095] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 3, wherein G1 is halogen, nitro, hydroxyl, A, X1, X2, X3, R 1 、R 2 、R 3 , Z and Y are as defined above.

[0096] General reaction scheme 4:

[0097] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 4, wherein G1 is halogen, nitro, or hydroxyl, A, X1, X2, X3, and R 1 、R 2 、R 3 , Z and Y are as defined above.

[0098] General reaction scheme 5:

[0099] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 5, wherein G1 is halogen, nitro, hydroxyl, A, X1, X2, X3, R 1 、R 2 、R 3 , Z and Y are as defined above.

[0100] General reaction scheme 6:

[0101] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 6, wherein G1, G2, G3 are independently halogen, nitro, hydroxyl, A, B, X1, X2, X3, R 1 、R 2 、R 3 , Z and Y are as defined above.

[0102] Related definitions

[0103] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0104] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0105] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0106] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0107] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.

[0108] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0109] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0110] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0111] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0112] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed bond

[0113] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0114] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0115] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14( 14 C). For example, deuterated compounds can be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0116] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0117] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0118] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0119] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0120] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0121] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring and a 6-10-membered ring, etc.

[0122] Unless otherwise specified, “C 1-6 "Alkyl" is used to represent a straight or branched saturated aliphatic hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-2 、C 1-3 、C 1-4 、C 1-5 、C 2-4 、C 2-6 、C 3-5, C5 and C6 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6 Non-limiting examples of alkyl groups include methyl, ethyl, propyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and various branched chain isomers thereof, and the like.

[0123] Unless otherwise specified, “C 1-3 "Alkyl" is used to represent a straight or branched saturated aliphatic hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Non-limiting examples of alkyl groups include methyl, ethyl, propyl, n-propyl, isopropyl, and the like.

[0124] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic aliphatic hydrocarbon group consisting of 3 to 6 carbon atoms, including monocyclic and bicyclic ring systems. The C3-6 cycloalkyl group includes C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0125] Unless otherwise specified, “C 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom. 1-3 Alkoxy groups include C 1-2 , C2 and C3 alkoxy, etc.; C 1-3 Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, and the like.

[0126] "Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur or nitrogen. Heteroaryl is preferably 5- to 10-membered, more preferably 5- or 6-membered, for example, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like.

[0127] Unless otherwise specified, "heterocyclyl" by itself or in combination with other terms refers to a saturated or partially saturated cyclic group consisting of 4 to 14 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur atoms are optionally oxidized (i.e., C(=O), NO, SO and SO2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spirocyclic, fused and bridged rings. In addition, a heteroatom can occupy the position at which the heterocyclyl is connected to the rest of the molecule, and the heterocyclyl includes saturated and partially unsaturated heterocyclyls. Non-limiting examples of heterocyclic groups include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, and the like.

[0128] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0129] "Hydroxyl" refers to -OH.

[0130] "Cyano" refers to -CN.

[0131] Specific pharmaceutical and medical terms

[0132] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0133] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, upon administration, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether the administration is fixed or temporary, continuous or intermittent, the circumstances attributable to or related to the administration can be explained.

[0134] "Active ingredient" refers to the compound shown in the general formula (1), as well as the pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the present invention may contain one or more asymmetric centers (axial chirality) and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0135] The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), induces a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0136] The term "administered," "administering," or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound.

[0137] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate, the numerical values ​​of the specific examples are presented herein as precisely as possible. However, any numerical value inherently and inevitably contains standard deviations resulting from individual testing methods. As used herein, "about" generally refers to the actual value being within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as determined by one skilled in the art. Except in the experimental examples, or unless otherwise expressly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe material amounts, time periods, temperatures, operating conditions, quantitative ratios, and the like) are to be understood as modified by the word "about." Therefore, unless otherwise indicated, the numerical parameters disclosed in this specification and the appended claims are approximate and may be modified as needed. At a minimum, these numerical parameters should be understood to include the number of significant digits indicated and to include normal rounding.

[0138] Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless otherwise defined in this specification, singular terms used in this specification include the plural form of the term, and plural terms also include the singular form of the term, unless otherwise defined in the context.

[0139] Route of administration

[0140] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various formulations containing a safe and effective amount of the compounds of the present invention or their pharmaceutically acceptable salts and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound will be determined based on the patient's age, condition, and duration of treatment, among other factors.

[0141] "Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0142] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0143] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or solubilizers, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0144] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0145] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0146] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0147] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0148] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0149] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0150] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0151] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0152] The main advantages of the present invention include:

[0153] (a) Unexpectedly, the compound of formula (1) of the present invention exhibited superior in vitro inhibition of KIF18A enzyme activity compared to AMG650.

[0154] (b) The compounds of the present invention showed excellent anti-proliferative activity against OVCAR3 cells.

[0155] (c) The compounds of the present invention exhibit excellent ability to continuously inhibit tumor growth in vivo and have good drugability.

[0156] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features.

[0157] The following description will elaborate on various specific aspects, characteristics, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions so that the present invention will be readily apparent. It should be understood that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the present description, those skilled in the art may make various changes or modifications to the present invention, and such equivalents are within the scope of the present invention.

[0158] The structures of the compounds of the present invention can be confirmed using conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed using conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is performed by collecting diffraction intensity data from a cultured single crystal using a Bruker D8 venture diffractometer with CuKα radiation and a φ / ω scanning mode. After collecting relevant data, the crystal structure can be further analyzed using a direct method (Shelxs97) to confirm the absolute configuration.

[0159] The solvents used in the present invention can be obtained commercially. Compounds are named according to conventional nomenclature principles in the art or using ChemDraw@ software. Commercially available compounds use the supplier's catalog names.

[0160] In all embodiments, 1 H-NMR was recorded on a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were by volume.

[0161] The present invention uses the following abbreviations: Ac2O represents acetic anhydride; AcOH represents acetic acid; ACN (CH3CN) represents acetonitrile; BBr3 represents boron tribromide; CHCl3 represents chloroform; Cs2CO3 represents cesium carbonate; CuI represents cuprous iodide; EA (EtOAc) represents ethyl acetate; DABSO represents 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinic acid; DCM represents dichloromethane; DEAD represents diethyl azodicarboxylate; DIAD represents diisopropyl azodicarboxylate; DIPEA (DIEA) represents diisopropylethylamine; Dioxane represents 1,4-dioxane; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; DH P stands for 3,4-dihydro-2H-pyran; EtOH stands for ethanol; FA stands for formic acid; Fe stands for iron; h stands for hour; HNO3 stands for nitric acid; H2SO4 stands for sulfuric acid; I2 stands for iodine; IPA stands for isopropyl alcohol; K2CO3 stands for potassium carbonate; K3PO4 stands for potassium phosphate; LDA stands for lithium diisopropylamide; LiAlH4 stands for lithium aluminum tetrahydride; m-CPBA stands for meta-chloroperbenzoic acid; MeI stands for iodomethane; MeOH stands for methanol; min stands for minute; MS stands for mass spectrometry; N2 stands for nitrogen; NaBH4 stands for sodium borohydride; NaClO2 stands for sodium hypochlorite; NaH stands for sodium hydride; NaHCO3 stands for sodium bicarbonate; NaOH stands for sodium hydroxide; Na2S2O3 stands for sodium thiosulfate; n- BuLi represents n-butyllithium; NH4Cl represents ammonium chloride; NH2OH.HCl represents hydroxylamine hydrochloride; NiCl2 represents nickel dichloride; NMI represents N-methylimidazole; NMP represents N-methylpyrrolidone; NMR represents nuclear magnetic resonance; Oxone represents potassium monopersulfate; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium; Pd(OAc)2 represents palladium acetate; Pd(Ph3P)2Cl2 represents bis(triphenylphosphine)palladium(II) chloride; PE represents petroleum ether; Ph3P represents triphenylphosphine; POBr3 represents phosphorus oxybromide; POCl3 represents phosphorus oxychloride; Ruphos-Pd-G3 represents methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); TBAF represents tetra-n-butylammonium fluoride; THP represents tetrahydro-2H-pyran; t- BuOK stands for potassium tert-butoxide; t- BuONa represents sodium tert-butoxide; Ts2O represents p-toluenesulfonic anhydride; t-BuXphos-Pd-G3 stands for [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II); TCFH stands for tetramethylchlorouronium hexafluorophosphate; TEA stands for triethylamine; TFA stands for trifluoroacetic acid; TLC stands for thin-layer chromatography; THF stands for tetrahydrofuran; and Xantphos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0162] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0163] Preparation Example 1: Synthesis of Intermediate 1

[0164] Step 1:

[0165] 2,6-Dibromopyridin-3-ol (5.00 g, 19.77 mmol) and NaHCO₃ (5.28 g, 69.19 mmol) were dissolved in H₂O (50 mL) and stirred for 15 minutes. I₂ (5.98 g, 23.72 mmol) was added and the mixture was stirred at 25°C for 48 hours. LC-MS monitoring indicated that the reaction was complete. Na₂S₂O₃ was added and the mixture was stirred for 10 minutes. HCl was added to adjust the pH to 2, and the mixture was extracted with water and EA. Drying, filtration, and concentration afforded the crude product, which was purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford a white solid (4.4 g, 59.4% yield). ESI-MS m / z: 379.8 [M+H] + .

[0166] Step 2:

[0167] 2,6-Dibromo-4-iodopyridin-3-ol (4.4 g, 11.64 mmol) was dissolved in CHCl₃ (33 mL) and THF (16 mL). Ethynyltrimethylsilane (1.71 g, 17.46 mmol), Pd(Ph₃P)₂Cl₂ (408 mg, 0.58 mmol), CuI (66.5 mg, 0.35 mmol), and TEA (3.52 g, 35 mmol) were added and reacted at 25°C for 3 h. After complete reaction, LC-MS monitoring was performed. Water was added and the mixture was extracted with DCM. The crude product was dried, filtered, and concentrated to obtain a brown oil (5.0 g, 100% yield), which was used directly in the next step. ESI-MS m / z: 349.9 [M+H] + .

[0168] Step 3:

[0169] 2,6-Dibromo-4-(trimethylsilyl)ethynyl)pyridin-3-ol (5.0 g, 11.64 mmol) was dissolved in EtOH (50 mL), and CuI (88 mg, 0.46 mmol) and TEA (20 mL) were added. The mixture was reacted at 70°C for 2 h. KCO (9.6 g, 69.84 mmol) was then added and the mixture was spin-dried and dissolved in EA. The mixture was then washed with saturated sodium bicarbonate. The crude product was dried, filtered, and concentrated to afford a brown oil. Column chromatography (PE / EA = 20 / 1 to 2 / 1) afforded a solid (500 mg, 15.5% yield). ESI-MS m / z: 277.9 [M+H] + .

[0170] Step 4:

[0171] 5,7-Dibromofuro[2,3-c]pyridine (500 mg, 1.81 mmol) was dissolved in DMF (5 mL). DIPEA (933.9 mg, 7.24 mmol) and 4,4-difluoropiperidine hydrochloride (570 mg, 3.62 mmol) were added. The reaction mixture was heated to 120°C and allowed to react for 12 h. LC-MS monitoring indicated that the starting material had not yet reacted completely. The reaction mixture was poured into water and extracted with EA. The crude product was dried, filtered, and concentrated to afford the crude product. Column chromatography (PE / EA = 20 / 1 to 5 / 1) afforded a white solid (430 mg, 75% yield). ESI-MS m / z: 317.0 [M+H] + .

[0172] Step 5:

[0173] 5-Bromo-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (430 mg, 1.36 mmol) was dissolved in dioxane (15 mL) and added with Xantphos (78 mg, 0.136 mmol), Pd(dba) (124 mg, 0.136 mmol), CsCO (1.32 g, 4.08 mmol), and benzophenone imine (368 mg, 2.03 mmol). The mixture was reacted at 90°C overnight. LC-MS monitoring confirmed the complete reaction. The reaction was washed with NH4Cl, and the aqueous phase was extracted with DCM, dried, filtered, and concentrated to afford the crude product. Column chromatography (PE / EA = 100 / 1 to 3 / 1) afforded a light yellow solid (460 mg, 81.1% yield). ESI-MS m / z: 418.2 [M+H] + .

[0174] Step 6:

[0175] N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,1-diphenylmethanamine (460 mg, 1.10 mmol) and NH2OH.HCl (138 mg, 2 mmol) were dissolved in MeOH (15 mL) and reacted at 25°C for 2 h. LC-MS monitoring was performed. After completion of the reaction, the mixture was directly spin-dried and then dissolved in DCM. The mixture was washed with water and the aqueous phase was extracted with DCM. The organic phases were combined, dried, filtered, and concentrated to obtain the crude product. Column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) afforded Intermediate 1 (260 mg, 93.5% yield) as a yellow solid. ESI-MS m / z: 254.1 [M+H] + .

[0176] Preparation Example 2: Synthesis of Intermediate 2

[0177] Step 1:

[0178] 2-Chloropyridin-3-ol (10 g, 76.9 mmol) and Na2CO3 (16.3 g, 153.8 mmol) were dissolved in ACN (100 mL). Bromo(methoxy)methane (10.6 g, 84.6 mmol) was added dropwise at 0°C and allowed to react at room temperature for 1 h. LC-MS monitoring indicated complete reaction. The reaction mixture was filtered, and the filtrate was concentrated and purified by column chromatography (PE / EA = 50 / 1 to 5 / 1) to afford a white solid (10 g, 74% yield). ESI-MS m / z: 174.0 [M+H] + .

[0179] Step 2:

[0180] 2-Chloro-3-(methoxymethoxy)pyridine (11.5 g, 66.2 mmol) was dissolved in THF (120 mL), protected by argon, cooled to -78 °C, and added dropwise n- BuLi (2.5M in hexane, 40mL) was added dropwise and allowed to react at -78°C for 1 hour. Ethylene oxide in tetrahydrofuran (3.0M in THF, 100mL) was added. The mixture was allowed to warm to room temperature and stirred overnight. LC-MS monitoring indicated a slight residual amount of starting material. Ice water and ethyl acetate were added, the mixture was separated, concentrated, and purified by column chromatography (PE / EA = 50 / 1 to 5 / 1). The product was concentrated to afford a white solid (10g, 74% yield). ESI-MS m / z: 218.0 [M+H] + .

[0181] Step 3:

[0182] 2-(2-chloro-3-(methoxymethoxy)pyridin-4-yl)ethan-1-ol (3.9 g, 17.92 mmol) was dissolved in HCl / Dioxane (4.0 M, 60 mL) and allowed to react at room temperature for 30 min. The reaction solution was concentrated, diluted with water, and the pH was adjusted to 7 with Na2CO3. The organic phase was extracted with EA, washed with water, and concentrated to give a white solid (2.7 g, 96% yield). ESI-MS m / z: 174.0 [M+H] + .

[0183] Step 4:

[0184] 2-Chloro-4-(2-hydroxyethyl)pyridin-3-ol (2.5 g, 14.36 mmol) and PPh3 (4.5 g, 17.24 mmol) were dissolved in THF (50 mL). DEAD (3 g, 17.24 mmol) was added dropwise at 10°C. The mixture was allowed to react overnight at room temperature. LC-MS monitoring confirmed the complete reaction. The reaction mixture was diluted with saturated NH4Cl, extracted with EA, and the organic phase was washed with water and concentrated. The organic phase was purified by column chromatography (PE / EA = 50 / 1 to 5 / 1) and concentrated to afford a white solid (1.8 g, 80% yield). ESI-MS m / z: 156.1 [M+H] + .

[0185] Step 5:

[0186] 7-Chloro-2,3-dihydrofuro[2,3-c]pyridine (1.8 g, 11.53 mmol) was dissolved in concentrated sulfuric acid (30 mL). Fuming nitric acid (3 mL) was added at 0°C and allowed to react at 50°C for 3 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was poured into an ice-water mixture. The precipitated solid was filtered, collected, and purified by column chromatography (PE / EA = 50 / 1 to 3 / 1). The product was concentrated to a yellow solid (500 mg, 21.6% yield). ESI-MS m / z: 201.0 [M+H] + .

[0187] Step 6:

[0188] 7-Chloro-5-nitro-2,3-dihydrofuro[2,3-c]pyridine (500 mg, 2.487 mmol), 4,4-difluoropiperidine hydrochloride (589 mg, 3.731 mmol), Cs2CO3 (2.4 g, 7.462 mmol), Pd2(dba)3 (113 mg, 0.124 mmol), and Xantphos (143 mg, 0.248 mmol) were dissolved in dioxane (20 mL) and reacted at 100°C under argon overnight. The reaction mixture was filtered and concentrated by column chromatography (PE / EA = 50 / 1 to 3 / 1) to afford a yellow solid (250 mg, 35% yield). ESI-MS m / z: 286.1 [M+H] + .

[0189] Step 7:

[0190] 7-(4,4-difluoropiperidin-1-yl)-5-nitro-2,3-dihydrofuro[2,3-c]pyridine (250 mg, 0.877 mmol), Fe (343 mg, 6.14 mmol), and NH4Cl (331 mg, 6.14 mmol) were dissolved in EtOH / H2O (2 / 1, 30 mL) and reacted at 80°C for 4 h. LC-MS monitoring confirmed the complete reaction. The reaction solution was concentrated, filtered, concentrated, and then purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford intermediate 2 (180 mg, 80% yield) as a yellow solid. ESI-MS m / z: 256.1 [M+H] + .

[0191] Intermediate 3 can be synthesized in a similar manner to Intermediate 2.

[0192] Preparation Example 3: Synthesis of Intermediate 4

[0193] Step 1:

[0194] 4-Chlorofuro[3,2-c]pyridine (3.5 g, 22.72 mmol) was dissolved in DCM (100 mL) and m-CPBA (7.8 g, 45.43 mmol) was added. The mixture was allowed to react overnight at room temperature. LC-MS monitoring indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was collected and concentrated by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford a white solid (2.1 g, 54% yield). ESI-MS m / z: 169.9 [M+H] + .

[0195] Step 2:

[0196] 4-Chlorofuro[3,2-c]pyridine 5-oxide (500 mg, 2.94 mmol), 4,4-difluoropiperidine hydrochloride (929 mg, 5.88 mmol), and TEA (890 mg, 8.82 mmol) were dissolved in dioxane (10 mL) and reacted overnight at 110°C. LC-MS monitoring indicated complete reaction. The reaction mixture was filtered, and the filtrate was collected and concentrated by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford a yellow solid (600 mg, 80% yield). ESI-MS m / z: 255.1 [M+H] + .

[0197] Step 3:

[0198] 4-(4,4-Difluoropiperidin-1-yl)furo[3,2-c]pyridine 5-oxide (600 mg, 4.72 mmol) was dissolved in 1.4-dioxane and POBr3 (2.7 g, 9.44 mmol) was added. The mixture was allowed to react at 70°C for 5 hours. LC-MS monitoring indicated complete reaction. The reaction mixture was diluted with water, the pH adjusted to 8 with Na2CO3, and extracted twice with EA, washed with water, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a yellow solid (320 mg, 42% yield). ESI-MS m / z: 317.0 [M+H] + .

[0199] Step 4:

[0200] 6-Bromo-4-(4,4-difluoropiperidin-1-yl)furo[3,2-c]pyridine (280 mg, 0.883 mmol), benzophenone imine (320 mg, 1.766 mmol), Cs2CO3 (574 mg, 1.766 mmol), XantPhos (162 mg, 0.176 mmol), and Pd2(dba)3 (50 mg, 0.088 mol) were dissolved in dioxane (10 mL) and reacted overnight at 110°C under argon. LC-MS monitoring indicated complete reaction. The reaction mixture was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 3 / 1) to afford a yellow solid (350 mg, 95% yield). ESI-MS m / z: 418.2 [M+H] + .

[0201] Step 5:

[0202] N-(4-(4,4-difluoropiperidin-1-yl)furo[3,2-c]pyridin-6-yl)-1,1-diphenylmethaneimine (330 mg, 0.791 mmol) was dissolved in MeOH (10 mL), and NH2OH.HCl (218 mg, 3.165 mmol) was added. The mixture was reacted at room temperature for 20 min. The reaction solution was concentrated and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give yellow solid intermediate 4 (180 mg, yield 89%). ESI-MS m / z: 254.1 [M+H] + .

[0203] Preparation Example 4: Synthesis of Intermediate 5

[0204] Step 1:

[0205] 2,3-Dihydrofuro[3,2-c]pyridin-4-ol (4 g, 29.6 mmol) was dissolved in AcOH / MeOH (1 / 1, 100 mL) and Pd / C (400 mg, 10%) was added. Hydrogen was introduced and the mixture was reacted at 80°C under normal pressure for 2 days. LC-MS monitoring indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was collected and purified by column chromatography (DCM / MeOH = 100 / 1 to 30 / 1). The resulting mixture was concentrated to afford a white solid (4 g, 98% yield). ESI-MS m / z: 138.1 [M+H] + .

[0206] Step 2:

[0207] 3,5-Dihydrofuro[3,2-c]pyridin-4(2H)-one (4 g, 29.19 mmol) was dissolved in dioxane (50 mL) and POCl3 (10 mL) was added. The mixture was reacted at 100°C for 2 h. LC-MS monitoring indicated complete reaction. The reaction mixture was concentrated, the crude product diluted with water, and the pH adjusted to 8 with sodium carbonate. The organic phase was extracted with EA, washed with water, and concentrated. The product was purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a white solid (1.6 g, 35% yield). ESI-MS m / z: 156.0 [M+H] + .

[0208] Step 3:

[0209] 4-Chloro-2,3-dihydrofuro[3,2-c]pyridine (1.5 g, 9.61 mmol) was dissolved in DCM (40 mL) and m-CPBA (3.32 g, 19.23 mmol) was added. The mixture was allowed to react overnight at 40°C. LC-MS monitoring indicated complete reaction. The reaction mixture was filtered, the filtrate collected, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a white solid (1.2 g, 72% yield). ESI-MS m / z: 172.0 [M+H] + .

[0210] Step 4:

[0211] 4-Chloro-2,3-dihydrofuro[3,2-c]pyridine 5-oxide (1100 mg, 6.39 mmol) and TsO (5 g, 15.34 mmol) were dissolved in EA / DCM (1 / 2, 30 mL). Tert-butylamine (2.8 g, 38.34 mmol) was added dropwise at 40°C. The mixture was allowed to react for 5 minutes. LC-MS monitoring indicated that the reaction was complete. The reaction solution was filtered, the filtrate collected, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a white solid (900 mg, 62% yield). ESI-MS m / z: 227.1 [M+H] + .

[0212] Step 5:

[0213] N-(tert-Butyl)-4-chloro-2,3-dihydrofuro[3,2-c]pyridin-6-amine (850 mg, 3.74 mmol), 4,4-difluoropiperidine hydrochloride (886 mg, 5.61 mmol), Cs2CO3 (3.6 g, 11.23 mmol), and Ruphos Pd-G3 (313 mg, 0.374 mmol) were dissolved in dioxane (20 mL) and reacted overnight at 110°C under argon. The reaction solution was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to obtain a yellow liquid (1 g, 85% yield). ESI-MS m / z: 312.2 [M+H] + .

[0214] Step 6:

[0215] N-(tert-Butyl)-4-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridin-6-amine (900 mg, 2.89 mmol) was dissolved in TFA (10 mL) and reacted at 80°C for 1 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was concentrated, diluted with water, and the pH was adjusted to 7 with NaHCO₃. The product was extracted with EA, washed with water, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford Intermediate 5 as a yellow gum (737 mg, 100% yield). ESI-MS m / z: 256.1 [M+H] + .

[0216] Intermediate 6 can be synthesized in a similar manner to Intermediate 5.

[0217] Preparation Example 5: Synthesis of Intermediate 7

[0218] Step 1:

[0219] 2-Chloro-3-(methoxymethoxy)pyridine (Intermediate 2-A, 5.8 g, 33.4 mmol) was added to a 250 mL three-necked flask, anhydrous THF (80 mL) was added to dissolve, and the mixture was cooled to -78 °C under argon protection and slowly added dropwise. n- BuLi (2.5M in hexane, 33.4mL, 83.5mmol). Stir at room temperature for 1 hour, then add iodine solution in THF (20mL) dropwise, stir at room temperature for 1 hour. LC-MS monitors the reaction for completion, and then add aqueous NH4Cl solution for quenching. Extract with EA, dry, filter, and concentrate. The crude product is directly used in the next reaction. ESI-MS m / z: 299.9 [M+H] + .

[0220] Step 2:

[0221] 2-Chloro-4-iodo-3-(methoxymethoxy)pyridine (theoretical amount, 33.4 mmol) was dissolved in DCM (100 mL), and HCl / Dioxane (4.0 M, 10 mL) was added. The mixture was stirred at room temperature for 1 h. The reaction was completed after LC-MS monitoring. The mixture was concentrated, and EA (50 mL) was added. The pH was adjusted to about 6 with aqueous sodium bicarbonate solution. The layers were separated, and the aqueous phase was extracted with EA (50 mL*3). The organic phases were combined, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 30 / 1) to give a yellow solid (7.4 g, yield 87%). ESI-MS m / z: 255.9 [M+H] + .

[0222] Step 3:

[0223] 2-Chloro-4-iodopyridin-3-ol (3 g, 11.74 mmol) was dissolved in DMF, and TEA (1.42 g, 14.08 mmol), Ph3P (62 mg, 0.234 mmol), Pd(OAc)2 (79 mg, 0.352 mmol), and ethyl acrylate (2.8 g, 28.18 mmol) were added. The atmosphere was replaced with nitrogen five times, and the mixture was stirred at 100°C for 2 h. LC-MS monitoring was performed. After the reaction was complete, the mixture was washed with water, extracted with EA, dried, filtered, concentrated, and subjected to column chromatography (DCM / MeOH = 100 / 1 to 30 / 1) to afford a yellow solid (2.4 g, 89.8% yield). ESI-MS m / z: 228.0 [M+H] + .

[0224] Step 4:

[0225] Ethyl (Z)-3-(2-chloro-3-hydroxypyridin-4-yl)acrylate (1.75 g, 7.68 mmol) was dissolved in MeOH (50 mL), and water (5 mL) was added. NiCl2 (1.95 g, 15.26 mmol) was then added. Under argon, the mixture was cooled to 0°C in an ice bath, and NaBH4 (872 mg, 23.04 mmol) was slowly added. The mixture was allowed to react at room temperature for 3 h, during which time four equal amounts of NaBH4 were added. LC / MS monitored the reaction for completion, and the mixture was poured into an ice-water solution (30 mL) for quenching. Dilute hydrochloric acid was added to adjust the pH to 6-7, and the mixture was washed with water, extracted with EA, dried, filtered, and concentrated to afford a slightly green oil (1.35 g, 76.7% yield). ESI-MS m / z: 230.1 [M+H] + .

[0226] Step 5:

[0227] Ethyl 3-(2-chloro-3-hydroxypyridin-4-yl)propanoate (2.1 g, 9.14 mmol) was dissolved in THF (40 mL). Under argon, the mixture was cooled to 0°C in an ice bath. LiAlH4 (382 mg, 10.05 mmol) was slowly added portionwise. The reaction was stirred at room temperature for 1.5 h. LC-MS monitored the reaction to be complete. The reaction was quenched by adding aqueous NH4Cl solution and adjusted to pH 6-7 by adding dilute hydrochloric acid. The mixture was washed with water, extracted with EA, dried, filtered, and concentrated to afford a yellow solid (1.4 g, 82.3% yield). ESI-MS m / z: 188.0 [M+H] + .

[0228] Step 6:

[0229] 2-Chloro-4-(3-hydroxypropyl)pyridin-3-ol (1.2 g, 6.39 mmol) was dissolved in THF (50 mL), and Ph3P (2 g, 7.67 mmol) was added. Under argon protection, the mixture was cooled to 0°C in an ice bath, and DIAD (1.55 g, 7.67 mol) was added dropwise. The mixture was stirred at room temperature for 2.5 h. The reaction was completed after LC-MS monitoring. The product was washed with water, extracted with EA, dried, filtered, concentrated, and the sample was subjected to column chromatography (PE / EA = 10 / 1 to 5 / 1) to give a white solid (1.5 g, yield 100%). ESI-MS m / z: 170.0 [M+H] + .

[0230] Step 7:

[0231] Concentrated sulfuric acid (6 mL) was cooled to 0°C, and 8-chloro-3,4-dihydro-2H-pyrano[2,3-c]pyridine (1.4 g, 8.25 mmol) was added. A mixture of fuming nitric acid (3 mL) and concentrated sulfuric acid (2 mL) was added dropwise. The mixture was stirred at 60°C for 2 h. The reaction was complete as monitored by LC-MS. The mixture was cooled, diluted with acetonitrile, and poured into ice water (30 mL). Solid sodium bicarbonate was added to adjust the pH to 6-7. The product was extracted with EA, dried, filtered, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 5 / 1) to give a yellow solid (886 mg, 50% yield). ESI-MS m / z: 215.0 [M+H] + .

[0232] Step 8:

[0233] 8-Chloro-6-nitro-3,4-dihydro-2H-pyrano[2,3-c]pyridine (760 mg, 3.54 mmol) was dissolved in dioxane (20 mL), and 4,4-difluoropiperidine hydrochloride (837 mg, 5.31 mmol) was added. Cs2CO3 (3.4 g, 10.62 mmol) and Ruphos-pd-G3 (296 mg, 0.354 mmol) were then added. The atmosphere was purged with nitrogen five times and the temperature was raised to 90°C for overnight reaction. LC-MS monitoring indicated that the reaction was complete. The product was filtered, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 5 / 1) to afford a yellow solid (870 mg, 82.1% yield). ESI-MS m / z: 300.1 [M+H] + Step 9:

[0234] 8-(4,4-difluoropiperidin-1-yl)-6-nitro-3,4-dihydro-2H-pyrano[2,3-c]pyridine (400 mg, 1.33 mmol) was dissolved in EtOH / H₂O (5 / 1, 24 mL). NH₄Cl (570 mg, 10.64 mmol) and Fe (448 mg, 8.02 mmol) were added. The atmosphere was purged with nitrogen five times and the reaction was heated to 90°C for 1 h. LC-MS monitoring indicated that the reaction was complete. The reaction mixture was filtered, concentrated, washed with water, extracted with EA, dried, filtered, and concentrated to afford intermediate 7 (440 mg, 99% yield) as a dark brown solid. ESI-MS m / z: 270.1 [M+H] + .

[0235] Preparation Example 6: Synthesis of Intermediate 8

[0236] Step 1:

[0237] 2-Chloro-5-fluoropyridine (6 g, 45.6 mmol) was added to a three-necked flask and dissolved in anhydrous THF (100 mL). The atmosphere was replaced with argon and the temperature was lowered to -78°C. LDA (27.3 mL, 54.72 mmol, 2 mol / L in THF) was slowly added dropwise. The reaction was incubated for 0.5 h. Iodine solution in THF (20 mL) was added dropwise and the reaction was stirred for 2 h. The reaction was complete as monitored by LC-MS. The product was quenched with aqueous NH4Cl solution, extracted with EA, dried, filtered, and concentrated to afford a yellow solid (11.8 g, 100% yield). ESI-MS m / z: 257.9 [M+H] + .

[0238] Step 2:

[0239] 2-Chloro-5-fluoro-4-iodopyridine (11.8 g, 45.83 mmol) was dissolved in NMP (100 mL), ethylene glycol (50 mL) was added, and t- BuOK (10.3 g, 91.6 mmol) was stirred at 65°C under argon for 1.5 h. LC-MS monitored the complete consumption of the starting material. The product was washed with water, extracted with EA, dried, filtered, concentrated, and purified by reverse phase purification (acetonitrile: 0.1% FA). The product was collected, adjusted to pH 7 with aqueous sodium bicarbonate solution, extracted with DCM, dried, filtered, and concentrated to give a light brown oil (3.3 g, yield 24%). ESI-MS m / z: 299.9 [M+H] + .

[0240] Step 3:

[0241] 2-((6-chloro-4-iodopyridin-3-yl)oxy)ethan-1-ol (3.1 g, 10.34 mmol) was dissolved in IPA, and CuI (118 mg, 0.62 mmol) was added. t- BuOK (1.73 g, 15.5 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (244 mg, 1.034 mmol). The reaction was stirred at 80°C under argon for 1 h. LC-MS monitored the complete consumption of the starting material. The mixture was filtered, concentrated, washed with water, extracted with EA, dried, filtered, concentrated, and subjected to column chromatography (PE / EA = 15 / 1 to 8 / 1) to afford a white solid (1.51 g, yield 85.3%). ESI-MS m / z: 172.0 [M+H] + .

[0242] Step 4:

[0243] 7-Chloro-2,3-dihydro-[1,4]dioxano[2,3-c]pyridine (1.24 g, 7.22 mmol) was dissolved in DCM (20 mL), and m-CPBA (2.93 g, 14.45 mmol, 85%) was added. The mixture was allowed to react overnight at 25°C. LC-MS monitoring indicated 50% reaction of the starting material. Na₂S₂O₃ was added, stirred for 10 minutes, and then extracted with water and EA. The mixture was dried, filtered, and concentrated to yield the crude product. Column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) afforded a slightly yellow solid (600 mg, 44.4% yield). ESI-MS m / z: 188.0 [M+H] + .

[0244] Step 5:

[0245] 7-Chloro-2,3-dihydro-[1,4]dioxano[2,3-c]pyridine 6-oxide (900 mg, 5.32 mmol) was dissolved in dioxane (30 mL), and POBr3 (2.2 g, 7.93 mmol) was added. The mixture was reacted at 80°C for 2 h, and then directly dried by rotary evaporation, washed with water and NaHCO3, and extracted with EA. The product was dried, filtered, concentrated, and subjected to column chromatography (PE / EA = 15 / 1 to 8 / 1) to afford a white solid (800 mg, 66.6% yield). ESI-MS m / z: 251.9 [M+H] + .

[0246] Step 6:

[0247] 5-Bromo-7-chloro-2,3-dihydro-[1,4]dioxano[2,3-c]pyridine (610 mg, 2.43 mmol) was dissolved in dioxane (10 mL), and 4,4-difluoropiperidine hydrochloride (410 mg, 2.59 mmol) was added. Cs2CO3 (1.52 g, 4.87 mmol), SPhos (120 mg, 0.2917 mmol), and Pd2(dba)3 (223 mg, 0.243 mmol) were also added. The atmosphere was purged with nitrogen five times, and the temperature was raised to 90°C for 8 h. LC-MS monitoring indicated that the reaction was complete. The product was filtered, concentrated, and purified by column chromatography (PE / EA = 15 / 1 to 5 / 1) to afford a yellow solid (548 mg, 77.5% yield). ESI-MS m / z: 291.0 [M+H] + .

[0248] Step 7:

[0249] 7-Chloro-5-(4,4-difluoropiperidin-1-yl)-2,3-dihydro-[1,4]dioxano[2,3-c]pyridine (400 mg, 1.37 mmol) was dissolved in dioxane (10 mL). t-Butyl carbamate (806 mg, 6.88 mmol), Cs2CO3 (1.3 g, 4.11 mmol), and Ruphos-Pd-G3 (115 mg, 0.137 mmol) were added. The atmosphere was purged with nitrogen five times and the temperature was raised to 110°C for overnight reaction. LC-MS monitoring indicated that the reaction was complete. The product was filtered, concentrated, and purified by column chromatography (PE / EA = 15 / 1 to 5 / 1) to afford a yellow solid (200 mg, 39.1% yield). ESI-MS m / z: 372.2 [M+H] + .

[0250] Step 8:

[0251] Tert-butyl (5-(4,4-difluoropiperidin-1-yl)-2,3-dihydro-[1,4]dioxano[2,3-c]pyridin-7-yl)carbamate (200 mg, 0.53 mol) was dissolved in DCM (20 mL) and TFA (5 mL) was added. The mixture was stirred at 35°C for 2 h. LC-MS monitoring indicated that the reaction was complete. The pH was adjusted to 7 with aqueous sodium bicarbonate solution, and the mixture was extracted with DCM, dried, filtered, and concentrated to afford a light brown sticky solid, Intermediate 8 (100 mg, 68.4% yield). ESI-MS m / z: 272.1 [M+H] + .

[0252] Preparation Example 7: Synthesis of Intermediate 9

[0253] Step 1:

[0254] 2,6-Dibromo-4-methoxypyridine (4.4 g, 16.5 mmol) was dissolved in sulfuric acid (30 mL) and placed in an ice bath. Nitric acid (5 mL) was added dropwise and the mixture was reacted at 100°C for 2 h. LC-MS monitoring indicated that the reaction was complete. The mixture was poured into ice water to precipitate a solid, which was filtered and dried to give a light yellow solid (4.9 g, 95% yield). ESI-MS m / z: 312.9 [M+H] + .

[0255] Step 2:

[0256] 2,6-Dibromo-4-methoxy-3-nitropyridine (4.9 g, 15.7 mmol) was dissolved in dioxane (120 mL), and TEA (4.77 mg, 47.1 mmol) and 4,4-difluoropiperidine hydrochloride (3.2 g, 20.4 mmol) were added. The mixture was allowed to react overnight at 110°C. LC-MS monitoring indicated a satisfactory reaction. The product was diluted with EA, washed with water, dried, filtered, and concentrated by column chromatography (PE / EA = 50 / 1 to 5 / 1) to afford a light yellow gum (4.4 g, 80% yield). ESI-MS m / z: 352.0 [M+H] + .

[0257] Step 3:

[0258] 6-Bromo-2-(4,4-difluoropiperidin-1-yl)-4-methoxy-3-nitropyridine (4.4 g, 12.5 mol) was dissolved in DCM (150 mL) and the mixture was cooled under argon and ice-bath. BBr3 (2.0 M in DCM, 7.5 mL) was added dropwise and reacted at room temperature for 2 h. The reaction was monitored by LC-MS. After completion of the reaction, ice water was slowly added under ice-bath to quench the reaction. The pH was adjusted to neutral with saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted with DCM, dried, filtered, and concentrated to give a light yellow gum (4.2 g, yield 99%). ESI-MS m / z: 338.0 [M+H] + .

[0259] Step 4:

[0260] 6-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-nitropyridin-4-ol (540 mg, 1.6 mmol), Fe (447 mg, 8.0 mmol), and NH4Cl (428 mg, 8.0 mmol) were dissolved in EtOH / H2O (2 / 1, 15 mL) and reacted at 80°C for 2 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was concentrated, filtered, and then dissolved in EA and washed with water. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain a brown solid (500 mg, crude yield 100%). ESI-MS m / z: 308.0 [M+H] +.

[0261] Step 5:

[0262] 3-Amino-6-bromo-2-(4,4-difluoropiperidin-1-yl)pyridin-4-ol (500 mg, 1.6 mmol) was dissolved in toluene (15 mL). Trimethyl orthoformate (849 mg, 8.0 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.08 mmol) were added. The reaction was heated to 100°C for 2 h. LC-MS monitoring indicated the reaction was complete. The product was concentrated and directly purified by column chromatography (PE / EA = 50 / 1 to 5 / 1) to afford a light yellow solid (230 mg, 45% yield). ESI-MS m / z: 318.0 [M+H] + .

[0263] Step 6:

[0264] 6-Bromo-4-(4,4-difluoropiperidin-1-yl)oxazolo[4,5-c]pyridine (318 mg, 1.0 mmol) was dissolved in dioxane (30 mL) and added with Xantphos (58 mg, 0.1 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Cs2CO3 (652 mg, 2.0 mmol), and benzophenone imine (181 mg, 1.0 mmol). The mixture was reacted at 90°C overnight. LC-MS monitoring confirmed the complete reaction. NH4Cl aqueous solution was added, and the mixture was extracted with EA. The mixture was dried, filtered, and concentrated by column chromatography (PE / EA = 100 / 1 to 2 / 1) to afford a light yellow solid (300 mg, 71% yield). ESI-MS m / z: 419.2 [M+H] + .

[0265] Step 7:

[0266] N-(4-(4,4-difluoropiperidin-1-yl)oxazolo[4,5-c]pyridin-6-yl)-1,1-diphenylcarbamate (300 mg, 0.71 mmol) and NH2OH.HCl (99 mg, 1.42 mmol) were dissolved in MeOH (15 mL) and reacted at 25°C for 2 h. LC-MS monitoring was performed. After the reaction was complete, the product was directly spin-dried and then dissolved in DCM. The product was washed with water, dried, filtered, and concentrated by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to give intermediate 9 (150 mg, yield 59%) as a yellow solid. ESI-MS m / z: 255.1 [M+H] + .

[0267] Preparation Example 8: Synthesis of Intermediate 10

[0268] Step 1:

[0269] 3-Amino-6-bromo-2-(4,4-difluoropiperidin-1-yl)pyridin-4-ol (500 mg, 1.6 mmol) was dissolved in toluene (15 mL). Trimethyl orthoacetate (961 mg, 8.0 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.08 mmol) were added. The reaction was heated to 100°C for 2 h. The reaction was complete after LC-MS monitoring. The product was concentrated and directly purified by column chromatography (PE / EA = 50 / 1 to 10 / 1) to afford a light yellow solid (270 mg, 51% yield). ESI-MS m / z: 332.0 [M+H] + .

[0270] Step 2:

[0271] 6-Bromo-4-(4,4-difluoropiperidin-1-yl)oxazolo[4,5-c]pyridine (270 mg, 0.813 mmol) was dissolved in dioxane (30 mL), and Xantphos (47 mg, 0.0818 mmol), Pd2(dba)3 (74 mg, 0.0813 mmol), Cs2CO3 (531 mg, 1.63 mmol), and benzophenone imine (147 mg, 0.813 mmol) were added. The mixture was reacted at 100°C overnight. LC-MS monitoring showed that the reaction of the starting material was complete. Aqueous NH4Cl solution was added, and the mixture was extracted with EA, dried, filtered, and concentrated (crude product 600 mg). ESI-MS m / z: 433.2 [M+H] + , directly put into the next reaction.

[0272] Step 3:

[0273] N-(4-(4,4-difluoropiperidin-1-yl)-2-methyloxazolo[4,5-c]pyridin-6-yl)-1,1-diphenylcarbamate (theoretical amount, 0.813 mmol) and NH2OH.HCl (113 mg, 1.63 mmol) were dissolved in MeOH (15 mL) and reacted at 25°C for 2 h. LC-MS monitoring was performed. After the reaction was completed, the raw material was directly dried and then dissolved in DCM, washed with water, dried, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to give yellow solid intermediate 10 (180 mg, yield 82%). ESI-MS m / z: 269.1 [M+H] + .

[0274] Preparation Example 9: Synthesis of Intermediate 11

[0275] Step 1:

[0276] 2-Bromopyridin-3-ol (20 g, 115 mmol) was dissolved in concentrated sulfuric acid (100 mL), cooled to 0°C, and nitric acid (20 mL) was added dropwise. The reaction was continued at 0°C for two days. After completion of the reaction, the mixture was poured into ice water (600 mL) and extracted with EA (200 mL*3). The organic phases were combined, dried, and concentrated to give a yellow solid (19.4 g, yield 77%). ESI-MS m / z: 218.9 [M+H] + .

[0277] Step 2:

[0278] 2-Bromo-4-nitropyridin-3-ol (11 g, 50 mmmol), Fe (16.8 mg, 300 mmol), and NH4Cl (16.05 mg, 300 mmol) were dissolved in EtOH / H2O (5 / 1, 360 mL) and reacted at 80°C for 4 h. LC-MS monitoring confirmed the complete reaction. The reaction solution was concentrated, filtered, and then purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford a yellow solid (7.1 g, 75% yield). ESI-MS m / z: 188.9 [M+H] + .

[0279] Step 3:

[0280] Dissolve 4-amino-2-bromopyridin-3-ol (1.89 g, 10 mmol) in dioxane (30 mL), add trimethyl orthoformate (5.31 g, 50.0 mmol) and p-toluenesulfonic acid monohydrate (95 mg, 0.5 mmol), and heat to 100°C for 4 h. The reaction is complete after LC-MS monitoring. Concentrate and directly column chromatography (PE / EA = 50 / 1 to 10 / 1) affords a light yellow solid (1.5 g, 75% yield). ESI-MS m / z: 198.9 [M+H] + .

[0281] Step 4:

[0282] 4-Bromooxazolo[5,4-c]pyridine (1.5 g, 7.5 mmol) was dissolved in DCM (30 mL) and m-CPBA (1.94 g, 11.25 mmol) was added. The mixture was allowed to react overnight at room temperature. LC-MS monitoring indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was collected and concentrated by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford a white solid (800 g, 50% yield). ESI-MS m / z: 214.9 [M+H] + .

[0283] Step 5:

[0284] 4-Bromooxazolo[5,4-c]pyridine-5-oxide (800 mg, 3.72 mmol), 4,4-difluoropiperidine hydrochloride (879 mg, 5.58 mmol), and TEA (1.13 g, 11.16 mmol) were dissolved in dioxane (15 mL) and reacted overnight at 110°C. LC-MS monitoring indicated complete reaction. The reaction mixture was filtered, and the filtrate was collected and concentrated by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford a yellow solid (620 mg, 65% yield). ESI-MS m / z: 256.1 [M+H] + .

[0285] Step 6:

[0286] 4-(4,4-Difluoropiperidin-1-yl)oxazolo[5,4-c]pyridine 5-oxide (620 mg, 2.43 mmol) was dissolved in 1.4-dioxane (10 mL), and POBr3 (1.39 g, 4.86 mmol) was added. The mixture was allowed to react at 70°C for 5 h. LC-MS monitoring indicated complete reaction. The reaction mixture was diluted with EA and the pH was adjusted to alkaline with NaHCO3. The layers were separated, and the aqueous phase was extracted twice with EA. The combined organic phases were concentrated by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a yellow solid (320 mg, 41% yield). ESI-MS m / z: 318.0 [M+H] + .

[0287] Step 7:

[0288] 6-Bromo-4-(4,4-difluoropiperidin-1-yl)oxazolo[5,4-c]pyridine (318 mg, 1.0 mmol), benzophenone imine (217 mg, 1.2 mmol), Cs2CO3 (651 mg, 2.0 mmol), XantPhos (58 mg, 0.1 mmol), and Pd2(dba)3 (92 mg, 0.1 mol) were dissolved in dioxane (12 mL) and reacted at 110°C under argon overnight. LC-MS monitoring confirmed the complete reaction. The reaction mixture was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 3 / 1) to afford a yellow solid (335 mg, 80% yield). ESI-MS m / z: 419.2 [M+H] + .

[0289] Step 8:

[0290] N-(4-(4,4-difluoropiperidin-1-yl)oxazolo[5,4-c]pyridin-6-yl)-1,1-diphenylcarbamate (335 mg, 0.8 mmol) was dissolved in MeOH (10 mL) and NH2OH.HCl (111 mg, 1.6 mmol) was added. The mixture was reacted at room temperature for 20 min. The reaction solution was concentrated and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give intermediate 11 (150 mg, yield 74%) as a yellow solid. ESI-MS m / z: 255.1 [M+H] + .

[0291] Preparation Example 10: Synthesis of Intermediate 12

[0292] Step 1:

[0293] Dissolve 4-amino-2-bromopyridin-3-ol (1.89 g, 10 mmol) in dioxane (30 mL), add trimethyl orthoacetate (6.01 g, 50.0 mmol) and p-toluenesulfonic acid monohydrate (95 mg, 0.5 mmol), and heat to 100°C for 4 h. The reaction is complete after LC-MS monitoring. Concentrate and directly column chromatography (PE / EA = 50 / 1 to 10 / 1) affords a light yellow solid (1.8 g, 84% yield). ESI-MS m / z: 112.9 [M+H] + .

[0294] Step 2:

[0295] 4-Bromo-2-methyloxazolo[5,4-c]pyridine (1.8 g, 8.4 mmol) was dissolved in DCM (40 mL) and m-CPBA (2.17 g, 12.6 mmol) was added. The mixture was allowed to react overnight at room temperature. LC-MS monitoring indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was collected and concentrated by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford a white solid (1.06 g, 55% yield). ESI-MS m / z: 228.9 [M+H] + .

[0296] Step 3:

[0297] 4-Bromo-2-methyloxazolo[5,4-c]pyridine-5-oxide (1.06 mg, 4.63 mmol), 4,4-difluoropiperidine hydrochloride (1.1 g, 6.95 mmol), and TEA (1.41 g, 13.89 mmol) were dissolved in dioxane (20 mL) and reacted overnight at 110°C. LC-MS monitoring indicated complete reaction. The reaction mixture was filtered, and the filtrate was collected and concentrated by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford a yellow solid (823 mg, 66% yield). ESI-MS m / z: 270.1 [M+H] + .

[0298] Step 4:

[0299] 4-(4,4-Difluoropiperidin-1-yl)-2-methyloxazolo[5,4-c]pyridine 5-oxide (823 mg, 3.06 mmol) was dissolved in dioxane (15 mL) and POBr3 (1.75 g, 6.12 mmol) was added. The mixture was allowed to react at 70°C for 5 h. LC-MS monitoring indicated complete reaction. The reaction mixture was diluted with EA and the pH was adjusted to alkaline with NaHCO3. The layers were separated, and the aqueous phase was extracted twice with EA. The combined organic phases were concentrated by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a yellow solid (427 mg, 42% yield). ESI-MS m / z: 332.0 [M+H] + .

[0300] Step 5:

[0301] 6-Bromo-4-(4,4-difluoropiperidin-1-yl)-2-methyloxazolo[5,4-c]pyridine (332 mg, 1.0 mmol), benzophenone imine (217 mg, 1.2 mmol), Cs2CO3 (651 mg, 2.0 mmol), XantPhos (58 mg, 0.1 mmol), and Pd2(dba)3 (92 mg, 0.1 mol) were dissolved in dioxane (12 mL) and reacted overnight at 110°C under argon. LC-MS monitoring indicated complete reaction. The reaction mixture was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 3 / 1) to afford a yellow solid (346 mg, 80% yield). ESI-MS m / z: 433.2 [M+H] + .

[0302] Step 6:

[0303] N-(4-(4,4-difluoropiperidin-1-yl)oxazolo[5,4-c]pyridin-6-yl)-1,1-diphenylcarbamate (346 mg, 0.8 mmol) was dissolved in MeOH (10 mL) and NH2OH.HCl (111 mg, 1.6 mmol) was added. The mixture was reacted at room temperature for 20 min. The reaction solution was concentrated and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give a yellow solid intermediate 12 (150 mg, yield 70%). ESI-MS m / z: 269.1 [M+H] + .

[0304] Preparation Example 11: Synthesis of Intermediate 13

[0305] Step 1:

[0306] 5-Bromo-1H-pyrazolo[3,4-c]pyridine (9.00 g, 45.7 mmol) and MeI (12.87 g, 90 mmol) were dissolved in ACN (100 mL). KCO (15.3 g, 114.25 mmol) was added and stirred at 80°C for 2 h. LC-MS monitoring confirmed the complete reaction. The mixture was then spin-dried and extracted with water and EA. Drying, filtration, and concentration afforded the crude product, which was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford a white solid (3.0 g, 31% yield). ESI-MS m / z: 211.9 [M+H] + .

[0307] Step 2:

[0308] 5-Bromo-2-methylpyrazolo[3,4-c]pyridine (1.5 g, 7.07 mmol) was dissolved in DCM (20 mL), and m-CPBA (1.8 g, 10.61 mmol) was added. The mixture was allowed to react at 25°C for 16 h. LC-MS monitoring indicated 50% reaction. Na₂S₂O₃ was added and stirred for 10 min. The mixture was then extracted with water and DCM. The mixture was dried, filtered, and concentrated to afford the crude product. Column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) afforded a white solid (1.3 g, 80% yield). ESI-MS m / z: 227.9 [M+H] + .

[0309] Step 3:

[0310] Dissolve 5-bromo-2-methylpyrazolo[3,4-c]pyridine-6-oxide (1.3 g, 5.7 mmol) in dioxane (30 mL), add POCl3 (2.61 g, 17.1 mmol), and react at 80°C for 2 h. Directly spin dry, dissolve in EA, and wash with a saturated aqueous solution of NaHCO3. Dry, filter, and concentrate to obtain a crude brown oil (2.5 g, overweight). ESI-MS m / z: 245.9 [M+H] + . It was directly used in the next reaction.

[0311] Step 4:

[0312] The above-mentioned 5-bromo-7-chloro-2-methylpyrazolo[3,4-c]pyridine (1.5 g, 6.1 mmol) was dissolved in DMSO (15 mL), and DIPEA (2.36 g, 18.3 mmol) and 4,4-difluoropiperidine hydrochloride (1.43 g, 9.15 mmol) were added. The mixture was reacted at 100°C for 16 h. LC-MS monitoring showed that the starting material was half-reacted, and water was added and extracted with DCM. The crude product was dried, filtered, and concentrated to obtain a crude product. Column chromatography (PE / EA = 100 / 1 to 10 / 1) afforded a yellow solid (640 mg, 31% yield). ESI-MS m / z: 331.0 [M+H] + .

[0313] Step 5:

[0314] 5-Bromo-7-(4,4-difluoropiperidin-1-yl)-2-methylpyrazolo[3,4-c]pyridine (640 mg, 1.94 mmol) was dissolved in dioxane (20 mL) and added with Xantphos (112 mg, 0.194 mmol), Pd2(dba)3 (178 mg, 0.194 mmol), Cs2CO3 (1.89 g, 5.82 mmol), and benzophenone imine (526 mg, 2.9 mmol). The reaction was allowed to proceed at 90°C for 16 h. LC-MS monitoring confirmed the complete reaction. The product was washed with NH4Cl, extracted with water and DCM, dried, filtered, and concentrated to obtain the crude product. Column chromatography (PE / EA = 100 / 1 to 2 / 1) afforded a yellow gum (700 mg, 84% yield). ESI-MS m / z: 432.1 [M+H] + .

[0315] Step 6:

[0316] N-(7-(4,4-difluoropiperidin-1-yl)-1-methylpyrazolo[3,4-c]pyridin-5-yl)-1,1-diphenylmethanamine (700 mg, 1.62 mmol) and NH2OH.HCl (276 mg, 3.24 mmol) were dissolved in MeOH and reacted at 25°C for 2 h. LC-MS monitoring was performed. After the reaction was complete, the mixture was directly dried by spin drying, added with EA, washed with water, dried with EA, filtered, and concentrated to give the crude product. Column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) gave intermediate 13 (380 mg, yield 88%) as a brown oil. ESI-MS m / z: 268.1 [M+H] + .

[0317] Preparation Example 12: Synthesis of Intermediate 14

[0318] Step 1:

[0319] 5-Bromo-1H-pyrazolo[3,4-c]pyridine (9.00 g, 45.7 mmol) and MeI (12.87 g, 90 mmol) were dissolved in ACN (100 mL). KCO (15.3 g, 114.25 mmol) was added and stirred at 80°C for 2 h. LC-MS monitoring confirmed the complete reaction. The mixture was then spin-dried and extracted with water and EA. Drying, filtration, and concentration afforded the crude product, which was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford a white solid (1.1 g, 11.3% yield). ESI-MS m / z: 211.9 [M+H] + .

[0320] Step 2:

[0321] 5-Bromo-2-methylpyrazolo[3,4-c]pyridine (1.1 g, 5.18 mmol) was dissolved in DCM (20 mL), and m-CPBA (1.34 g, 7.77 mmol) was added. The mixture was allowed to react at 25°C for 16 h. LC-MS monitoring indicated 50% reaction. Na₂S₂O₃ was added, stirred for 10 min, and extracted with water and DCM. The mixture was dried, filtered, and concentrated to yield the crude product. Column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) afforded a white solid (660 mg, 55.8% yield). ESI-MS m / z: 227.9 [M+H] + .

[0322] Step 3:

[0323] 5-Bromo-2-methylpyrazolo[3,4-c]pyridine-6-oxide (660 mg, 2.9 mmol) was dissolved in dioxane (10 mL), and POCl3 (1.33 g, 8.68 mmol) was added. The mixture was reacted at 80°C for 2 h. After direct spin drying, the mixture was dissolved in EA and washed with saturated aqueous NaHCO3. Drying, filtration, and concentration afforded a crude brown oil. Column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) afforded a white solid (220 mg, 30.8% yield). ESI-MS m / z: 245.9 [M+H] + .

[0324] Step 4:

[0325] 5-Bromo-7-chloro-2-methylpyrazolo[3,4-c]pyridine (220 mg, 0.89 mmol) was dissolved in DMSO (5 mL), and DIPEA (344 mg, 2.67 mmol) and 4,4-difluoropiperidine hydrochloride (210 mg, 1.33 mmol) were added. The mixture was reacted at 100°C for 16 h. LC-MS monitoring indicated that the starting material was halfway through reaction. Water was added and the mixture was extracted with DCM. The product was dried, filtered, and concentrated to afford the crude product. Column chromatography (PE / EA = 100 / 1 to 5 / 1) afforded a yellow solid (200 mg, 68.2% yield). ESI-MS m / z: 331.0 [M+H] + .

[0326] Step 5:

[0327] 5-Bromo-7-(4,4-difluoropiperidin-1-yl)-2-methylpyrazolo[3,4-c]pyridine (200 mg, 0.6 mmol) was dissolved in dioxane (10 mL), and Xantphos (34 mg, 0.06 mmol), Pd2(dba)3 (54 mg, 0.06 mmol), Cs2CO3 (585 mg, 1.8 mmol), and benzophenone imine (181 mg, 0.9 mmol) were added. The mixture was reacted at 90°C for 16 h. LC-MS monitoring indicated that the reaction was complete. The product was washed with NH4Cl, extracted with water and DCM, dried, filtered, and concentrated to obtain the crude product. Column chromatography (PE / EA = 100 / 1 to 2 / 1) afforded a yellow oil (160 mg, 62% yield). ESI-MS m / z: 432.1 [M+H] + .

[0328] Step 6:

[0329] N-(7-(4,4-difluoropiperidin-1-yl)-2-methylpyrazolo[3,4-c]pyridin-5-yl)-1,1-diphenylmethanamine (160 mg, 0.37 mmol) and NH2OH.HCl (51.6 mg, 0.74 mmol) were dissolved in MeOH and reacted at 25°C for 2 h. LC-MS monitoring was performed. After the reaction was complete, the product was directly dried by spin drying, added with EA, washed with water, dried with EA, filtered, and concentrated to give a crude product. Column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) gave intermediate 14 (100 mg, 100% yield) as a green oil. ESI-MS m / z: 268.1 [M+H] + .

[0330] Preparation Example 13: Synthesis of Intermediate 15

[0331] 8-Bromo-1,7-naphthyridin-6-amine (1.12 g, 5.0 mmol), 4,4-difluoropiperidine hydrochloride (1.26 g, 8.0 mmol), sodium tert-butoxide (961 mg, 10.0 mmol), and Ruphos-Pd-G3 (418 mg, 0.5 mmol) were dissolved in dioxane (40 mL) and reacted overnight at 110°C under argon. LC-MS monitoring confirmed the complete reaction. The reaction solution was filtered, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford Intermediate 15 (400 mg, 30% yield) as a yellow solid. ESI-MS m / z: 265.1 [M+H] + .

[0332] Preparation Example 14: Synthesis of Intermediate 16

[0333] Step 1:

[0334] 5,7-Dibromofuro[2,3-c]pyridine (500 mg, 1.81 mmol) was dissolved in DMF (5 mL), and DIPEA (933.9 mg, 7.24 mmol) and 3,3-difluoroazetidine hydrochloride (469 mg, 3.62 mmol) were added. The mixture was reacted at 120°C for 12 h. LC-MS monitoring indicated that the starting material had not reacted completely, so the product was extracted with water and EA. The product was dried, filtered, and concentrated to afford the crude product. Column chromatography (PE / EA = 20 / 1 to 5 / 1) afforded a white solid (400 mg, 76% yield). ESI-MS m / z: 288.9 [M+H] + .

[0335] Step 2:

[0336] 5-Bromo-7-(3,3-difluoroazetidin-1-yl)furo[2,3-c]pyridine (400 mg, 1.38 mmol) was dissolved in dioxane (15 mL) and Xantphos (80 mg, 0.138 mmol), Pd(dba) (126 mg, 0.138 mmol), CsCO (1.35 g, 4.14 mmol), and benzophenone imine (375 mg, 2.07 mmol) were added. The mixture was reacted at 90°C for 12 h. LC-MS monitoring confirmed the complete reaction. The product was washed with NH4Cl, extracted with water and DCM, dried, filtered, and concentrated to obtain the crude product. Column chromatography (PE / EA = 100 / 1 to 3 / 1) afforded a light yellow solid (410 mg, 76% yield). ESI-MS m / z: 390.1 [M+H] + .

[0337] Step 3:

[0338] N-(7-(3,3-Difluoroazetidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,1-diphenylcarbamate (400 mg, 1.03 mmol) and NH2OH.HCl (143 mg, 2.06 mmol) were dissolved in MeOH (15 mL) and reacted at 25°C for 2 h. LC-MS monitoring indicated that the reaction was complete. The mixture was then spin-dried and extracted with water and DCM. The crude product was dried, filtered, and concentrated to afford the crude product. Column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) afforded Intermediate 16 (200 mg, 86% yield) as a yellow solid. ESI-MS m / z: 226.1 [M+H] + .

[0339] Intermediates 17-23 can be synthesized by a similar method to that of Intermediate 16.

[0340] Preparation Example 15: Synthesis of Intermediate 24

[0341] Step 1: Preparation of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid

[0342] 2-Fluoro-4-iodobenzoic acid (11.2 g, 42.1 mmol) and 6-azaspiro[2.5]octane (8.08 g, 54.73 mmol) were dissolved in DMSO (150 mL). K2CO3 (17.4 g, 126.3 mmol) was added, and the mixture was heated to 140°C overnight under N2 protection. LC-MS monitoring indicated that the reaction was complete. The mixture was poured into ice water and extracted with PE (50 mL x 3). The aqueous phase was adjusted to pH 6 with 1 M dilute hydrochloric acid. A gray solid precipitated, which was filtered and dried to obtain a gray solid (12.2 g, 81% yield). ESI-MS m / z: 358.0 [M+H] + .

[0343] Step 2: Preparation of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride

[0344] 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (357 mg, 1 mmol) was dissolved in DCM (10 mL) and placed in an ice bath under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. The mixture was allowed to react at room temperature for 1 h. The reaction was monitored by TLC and concentrated to afford intermediate 24 (410 mg, 100% yield) as a pale yellow solid. This was used directly in the next reaction.

[0345] Intermediates 25 to 30 can be synthesized by a method similar to that of Intermediate 24 (ESI-MS shows the ion peak of methyl ester).

[0346] Preparation Example 16: Synthesis of Intermediate 31

[0347] Step 1:

[0348] Methyl 6-bromo-2-fluoronicotinate (5.0 g, 21.4 mmol) and 6-azaspiro[2.5]octane (3.16 g, 21.4 mmol) were dissolved in IPA (50 mL). DIPEA (8.3 g, 64.2 mmol) was added, and the mixture was heated to 80°C and allowed to react overnight under N2 protection. LC-MS monitoring confirmed the complete reaction. The mixture was concentrated and dissolved in EA (70 mL). The organic phase was washed with water (50 mL x 2), dried, filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a light yellow solid (5.5 g, 79% yield). ESI-MS m / z: 325.0 [M+H] + .

[0349] Step 2:

[0350] Methyl 6-bromo-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (5.2 g, 16.0 mmol) was dissolved in MeOH (50 mL) and a 10 mL aqueous solution of NaOH (3.2 g, 80 mmol) was added. The mixture was allowed to react overnight at room temperature. LC-MS monitoring indicated that the reaction was complete. The pH was adjusted to approximately 5 with dilute hydrochloric acid and the mixture was concentrated to obtain a solid which was filtered and dried to afford an off-white solid (2.1 g, 42% yield). ESI-MS m / z: 311.0 [M+H] + .

[0351] Step 3:

[0352] 6-Bromo-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (311 mg, 1 mmol) was dissolved in DCM (10 mL) and the mixture was cooled on ice under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC. The reaction was concentrated to give a gray-yellow solid intermediate 31 (366 mg, 100% yield), which was used directly in the next reaction.

[0353] Intermediates 32 and 33 can be synthesized by a method similar to that of Intermediate 31 (ESI-MS shows the ion peak of methyl ester).

[0354] Preparation Example 17: Synthesis of Intermediate 34

[0355] Step 1:

[0356] Methyl 4-bromo-2,5-difluorobenzoate (5.02 g, 20 mmol) and 6-azaspiro[2.5]octane (2.95 g, 20 mmol) were dissolved in NMP (50 mL). TEA (6.07 g, 60 mmol) was added, and the mixture was heated to 120°C and allowed to react overnight under N2 protection. LC-MS monitoring confirmed the complete reaction. The mixture was cooled and poured into ice water (150 mL). Extraction was performed with EA (70 mL x 2), dried, filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1) to afford a light yellow solid (5.47 g, 80% yield). ESI-MS m / z: 342.0 [M+H] + .

[0357] Step 2:

[0358] Methyl 4-bromo-5-fluoro-2-(6-azaspiro[2.5]octan-6-yl)benzoate (5.47 g, 16.0 mmol) was dissolved in MeOH (50 mL) and a 10 mL aqueous solution of NaOH (3.2 g, 80 mmol) was added. The mixture was allowed to react overnight at rt. LC-MS monitoring indicated that the reaction was complete. The pH was adjusted to approximately 5 with dilute hydrochloric acid and the mixture was concentrated to precipitate a solid, which was filtered and dried to afford an off-white solid (2.8 g, 53% yield). ESI-MS m / z: 328.0 [M+H] + .

[0359] Step 3:

[0360] 4-Bromo-5-fluoro-2-(6-azaspiro[2.5]octan-6-yl)phenol (328 mg, 1 mmol) was dissolved in DCM (10 mL) and the mixture was cooled on ice under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC. The reaction was concentrated to give a gray-yellow solid intermediate 34 (383 mg, yield 100%), which was used directly in the next reaction.

[0361] Preparation Example 18: Synthesis of Intermediate 35

[0362] Step 1:

[0363] Methyl 2-fluoro-5-methyl-4-nitrobenzoate (4.26 g, 20.0 mmol) and 6-azaspiro[2.5]octane (2.95 g, 20.0 mmol) were dissolved in dioxane (60 mL), and TEA (6.07 g, 60.0 mmol) was added. Under nitrogen protection, the reaction was carried out at 100°C under reflux under condensation overnight. The reaction was monitored by LC-MS, and the mixture was directly dried, concentrated, and purified by column chromatography (PE / EA=20 / 1 to 5 / 1) to give a yellow solid (4.6 g, yield 76%). ESI-MS m / z: 305.1 [M+H] + .

[0364] Step 2:

[0365] Methyl 5-methyl-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoate (4.6 g, 15.1 mmol) was dissolved in MeOH (50 mL) and a 10 mL aqueous solution of NaOH (3.2 g, 80 mmol) was added. The mixture was allowed to react overnight at room temperature. LC-MS monitoring indicated that the reaction was complete. The pH was adjusted to approximately 5 with dilute hydrochloric acid and the mixture was concentrated to precipitate a solid, which was filtered and dried to afford an off-white solid (3.1 g, 71% yield). ESI-MS m / z: 291.1 [M+H] + .

[0366] Step 3:

[0367] 5-Methyl-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (290 mg, 1 mmol) was dissolved in DCM (10 mL) and the mixture was cooled on ice under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC until completion. The product was concentrated to give a gray-yellow solid intermediate 35 (366 mg, yield 100%), which was used directly in the next reaction.

[0368] Preparation Example 19: Synthesis of Intermediate 36

[0369] Step 1:

[0370] Methyl 4-bromo-2,6-difluorobenzoate (2.51 g, 10 mmol) and 6-azaspiro[2.5]octane (1.48 g, 10 mmol) were dissolved in NMP (20 mL). TEA (3.03 g, 30 mmol) was added under N2 protection. The reaction was heated to 100°C and allowed to react overnight. LC-MS monitoring confirmed the complete reaction. The mixture was cooled and poured into ice water (80 mL). Extraction was performed with EA (40 mL x 2), dried, filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1) to afford a light yellow solid (2.6 g, 76% yield). ESI-MS m / z: 342.0 [M+H] + .

[0371] Step 2:

[0372] Methyl 4-bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzoate (2.6 g, 7.6 mmol) was dissolved in MeOH (25 mL) and a 10 mL aqueous solution of NaOH (1.52 g, 38 mmol) was added. The mixture was allowed to react overnight at room temperature. LC-MS monitoring indicated that the reaction was complete. The pH was adjusted to approximately 5 with dilute hydrochloric acid and the mixture was concentrated to obtain a solid which was filtered and dried to give an off-white solid (1.5 g, 60% yield). ESI-MS m / z: 328.0 [M+H] + .

[0373] Step 3:

[0374] 4-Bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)phenol (328 mg, 1 mmol) was dissolved in DCM (10 mL) and the mixture was cooled on ice under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC. The reaction was concentrated to give a gray-yellow solid intermediate 36 (383 mg, yield 100%), which was used directly in the next reaction.

[0375] Preparation Example 20: Synthesis of Intermediate 37

[0376] Step 1:

[0377] Methyl 2-fluoro-4-nitrobenzoate (4.00 g, 20.08 mmol) and 6-azaspiro[2.5]octane (2.96 g, 20.08 mmol) were dissolved in dioxane (60 mL), and TEA (6.07 g, 60.24 mmol) was added. The mixture was refluxed at 100°C under N2 protection for 12 h. The reaction was monitored by LC-MS, and the mixture was directly dried and extracted with EA. The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA=20 / 1 to 5 / 1) to give a light yellow solid (5.454 g, yield 93.5%). ESI-MS m / z: 291.0 [M+H] + .

[0378] Step 2:

[0379] Methyl 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoate (2.90 g, 10 mmol) was dissolved in MeOH (30 mL) and aqueous sodium hydroxide (2.0 g, 50 mmol, in 10 mL H2O) was added. The mixture was allowed to react at room temperature overnight. LC-MS monitoring indicated that the reaction was complete. The pH was adjusted to approximately 4 with dilute hydrochloric acid and the mixture was concentrated to precipitate a solid. The filter cake was filtered and dried to afford a light yellow solid (1.38 g, 50% yield). ESI-MS m / z: 277.1 [M+H] + .

[0380] Step 3:

[0381] 4-Nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (276 mg, 1 mmol) was dissolved in DCM (10 mL) and the mixture was cooled on ice under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC. The reaction was concentrated to give a yellow solid intermediate 37 (331 mg, yield 100%), which was used directly in the next reaction.

[0382] Preparation Example 21: Synthesis of Intermediate 38

[0383] Step 1:

[0384] 4-Bromo-2-fluoro-1-nitrobenzene (4.40 g, 20 mmol) and 6-azaspiro[2.5]octane (2.95 g, 20 mmol) were added to K2CO3 (5.53 g, 40 mmol) and dissolved in DMSO. Under nitrogen protection, the reaction temperature was raised to 60°C for 10 minutes, followed by a temperature increase to 90°C for 1 hour. LC-MS monitoring confirmed the complete reaction. The product was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1) to afford an orange-red solid (5.77 g, 92.8% yield). ESI-MS m / z: 311.0 [M+H] + .

[0385] Step 2:

[0386] 6-(5-Bromo-2-nitrophenyl)-6-azaspiro[2.5]octane (1.5 g, 4.82 mmol) was dissolved in DMF (20 mL), and 2-hydroxyethane-1-sulfonamide (1.21 g, 9.64 mmol) was added quickly, followed by K2CO3 (1.33 g, 9.64 mmol), (1R, 2R)-N 1 ,N 2 1,2-dimethylcyclohexane-1,2-diamine (343 mg, 2.41 mmol) was quickly added to CuI (918 mg, 4.82 mmol). N2 was used for protection and the reaction was heated to 100°C for 16 h. LC-MS monitoring confirmed the complete reaction. The reaction was quenched with water and extracted with DCM (50 mL x 3). The organic phases were combined, dried, concentrated, and mixed. Column chromatography (PE / EA = 5 / 1 to 2 / 1) afforded a yellow solid (1.10 g, 65% yield). ESI-MS m / z: 356.1 [M+H] + .

[0387] Step 3:

[0388] 2-Hydroxy-N-(4-nitro-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethane-1-sulfonamide (710 mg, 2 mmol) was dissolved in DMF, and imidazole was added. TBSCl (392 mg, 2.6 mmol) was added under ice-cooling. N2 protection was applied and the reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was quenched with water (30 mL) and extracted with EA (50 mL x 3). The organic phase was washed with water (150 mL), dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1). A yellow gum (890 mg, 94% yield) was obtained. ESI-MS m / z: 470.2 [M+H] + .

[0389] Step 4:

[0390] 2-(tert-Butyldimethylsilyloxy)-N-(4-nitro-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethane-1-sulfonamide (500 mg, 1.07 mmol) was dissolved in EtOH / H₂O (5 / 1, 15 mL) and Fe powder (310 mg, 5.35 mmol) and NH₄Cl (300 mg, 5.35 mmol) were added. Under N₂ protection, the mixture was heated to 80°C for 1 h. LC-MS confirmed the complete reaction. The product was filtered, concentrated under reduced pressure, extracted with EA, dried, concentrated, and stirred. Column chromatography (PE / EA = 10 / 1 to 2 / 1) afforded intermediate 38 as a tan solid (480 mg, 93% yield). ESI-MS m / z: 440.2 [M+H] + .

[0391] Preparation Example 22: Synthesis of Intermediate 39

[0392] Step 1:

[0393] Dissolve 2-fluoro-4-iodobenzoic acid (11.2 g, 42.1 mmol) and 4-(difluoromethylene)piperidine hydrochloride (9.28 g, 54.73 mmol) in DMSO (150 mL). Add KCO (17.4 g, 126.3 mmol). Under N protection, heat to 180°C and react overnight. LC-MS monitoring indicates complete reaction. Pour into ice water and extract with PE (50 mL x 3). Adjust the pH of the aqueous phase to 6 with 1 M dilute hydrochloric acid. A gray solid precipitates, which is filtered and dried to obtain a gray solid (12.7 g, 80% yield). ESI-MS m / z: 380.0 [M+H]. + .

[0394] Step 2:

[0395] 2-(4-(Difluoromethylene)piperidin-1-yl)-4-iodobenzoic acid (379 mg, 1 mmol) was dissolved in DCM (10 mL) and placed in an ice bath under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. After addition, the mixture was allowed to react at room temperature for 1 h. The reaction was monitored by TLC and concentrated to afford intermediate 39 (435 mg, 100% yield) as a pale yellow solid. This was used directly in the next reaction.

[0396] Intermediates 40-43 can be synthesized by a method similar to that of intermediate 39 (ESI-MS shows the ion peak of methyl ester).

[0397] Preparation Example 23: Synthesis of Intermediate 44

[0398] Step 1:

[0399] Methyl 6-bromo-2-fluoronicotinate (5.0 g, 21.4 mmol) and 4-(difluoromethylene)piperidine hydrochloride (3.63 g, 21.4 mmol) were dissolved in IPA (50 mL). DIPEA (8.3 g, 64.2 mmol) was added, and the mixture was heated to 80°C and allowed to react overnight under N2 protection. LC-MS monitoring confirmed the complete reaction. The mixture was concentrated and dissolved in EA (70 mL). The organic phase was washed with water (50 mL x 2), dried, filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a light yellow solid (5.57 g, 75% yield). ESI-MS m / z: 347.0 [M+H] + .

[0400] Step 2:

[0401] Methyl 6-bromo-2-(4-(difluoromethylene)piperidin-1-yl)nicotinate (5.5 g, 16.0 mmol) was dissolved in MeOH (50 mL) and a 10 mL aqueous solution of NaOH (3.2 g, 80 mmol) was added. The mixture was allowed to react overnight at room temperature. LC-MS monitoring indicated that the reaction was complete. The pH was adjusted to approximately 5 with dilute hydrochloric acid and the mixture was concentrated to obtain a solid which was filtered and dried to afford an off-white solid (2.1 g, 40% yield). ESI-MS m / z: 333.1 [M+H] + .

[0402] Step 3:

[0403] 6-Bromo-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (333 mg, 1 mmol) was dissolved in DCM (10 mL) and the mixture was cooled on ice under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC. The reaction was concentrated to give a gray-yellow solid intermediate 44 (388 mg, yield 100%), which was used directly in the next step.

[0404] Intermediates 45 and 46 can be synthesized by a method similar to that of Intermediate 44 (ESI-MS shows the ion peak of methyl ester).

[0405] Preparation Example 24: Synthesis of Intermediate 47

[0406] Step 1:

[0407] Methyl 4-bromo-2,5-difluorobenzoate (5.02 g, 20 mmol) and 4-(difluoromethylene)piperidine hydrochloride (3.4 g, 20 mmol) were dissolved in NMP (50 mL). TEA (6.07 g, 60 mmol) was added, and the mixture was heated to 120°C and allowed to react overnight under N2 protection. LC-MS monitoring confirmed the complete reaction. The mixture was cooled and poured into ice water (150 mL). Extraction was performed with EA (70 mL x 2), dried, filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1) to afford a light yellow solid (5.46 g, 75% yield). ESI-MS m / z: 364.0 [M+H] + .

[0408] Step 2:

[0409] Methyl 4-bromo-2-(4-(difluoromethylene)piperidin-1-yl)-5-fluorobenzoate (5.46 g, 15.0 mmol) was dissolved in MeOH (50 mL) and a NaOH solution (3.0 g, 75 mmol) (10 mL) was added. The reaction was allowed to proceed overnight at rt. LC-MS monitoring indicated that the reaction was complete. The pH was adjusted to approximately 5 with dilute hydrochloric acid and the mixture was concentrated to precipitate a solid, which was filtered and dried to afford an off-white solid (2.6 g, 50% yield). ESI-MS m / z: 350.0 [M+H] + .

[0410] Step 3:

[0411] 4-Bromo-2-(4-(difluoromethylene)piperidin-1-yl)-5-fluorobenzoic acid (350 mg, 1 mmol) was dissolved in DCM (10 mL) and the mixture was cooled on ice under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC. The reaction was concentrated to give a gray-yellow solid intermediate 47 (403 mg, 100% yield), which was used directly in the next step.

[0412] Preparation Example 25: Synthesis of Intermediate 48

[0413] Step 1:

[0414] Methyl 2-fluoro-5-methyl-4-nitrobenzoate (4.26 g, 20.0 mmol) and 4-(difluoromethylene)piperidine hydrochloride (3.4 g, 20.0 mmol) were dissolved in dioxane (60 mL), and TEA (6.07 g, 60.0 mmol) was added. Under nitrogen protection, the reaction was carried out at 100°C under reflux overnight. The reaction was monitored by LC-MS, and the mixture was directly dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to give a yellow solid (5.2 g, yield 80%). ESI-MS m / z: 327.1 [M+H] + .

[0415] Step 2:

[0416] Methyl 2-(4-(difluoromethylene)piperidin-1-yl)-5-methyl-4-nitrobenzoate (5.2 g, 16.0 mmol) was dissolved in MeOH (50 mL) and a 10 mL aqueous solution of NaOH (3.2 g, 80 mmol) was added. The mixture was allowed to react overnight at room temperature. LC-MS monitoring indicated that the reaction was complete. The pH was adjusted to approximately 5 with dilute hydrochloric acid and the mixture was concentrated to precipitate a solid, which was filtered and dried to afford an off-white solid (3.65 g, 70% yield). ESI-MS m / z: 313.1 [M+H] + .

[0417] Step 3:

[0418] 2-(4-(Difluoromethylene)piperidin-1-yl)-5-methyl-4-nitrobenzoic acid (312 mg, 1 mmol) was dissolved in DCM (10 mL) and the mixture was cooled on ice under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC. The reaction was concentrated to give a gray-yellow solid intermediate 48 (366 mg, yield 100%), which was used directly in the next step.

[0419] Preparation Example 26: Synthesis of Intermediate 49

[0420] Step 1:

[0421] Methyl 4-bromo-2,6-difluorobenzoate (2.51 g, 10 mmol) and 4-(difluoromethylene)piperidine hydrochloride (1.69 g, 10 mmol) were dissolved in NMP (20 mL). TEA (3.03 g, 30 mmol) was added, and the mixture was heated to 100°C overnight under N2 protection. LC-MS monitoring confirmed the complete reaction. The mixture was cooled and poured into ice water (80 mL). Extraction was performed with EA (40 mL x 2), dried, filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1) to afford a light yellow solid (2.55 g, 70% yield). ESI-MS m / z: 364.0 [M+H] + .

[0422] Step 2:

[0423] Methyl 4-bromo-2-(4-(difluoromethylene)piperidin-1-yl)-6-fluorobenzoate (2.55 g, 7.0 mmol) was dissolved in MeOH (25 mL) and a 10 mL aqueous solution of NaOH (1.4 g, 35 mmol) was added. The mixture was allowed to react overnight at room temperature. LC-MS monitoring indicated that the reaction was complete. The pH was adjusted to approximately 5 with dilute hydrochloric acid and the mixture was concentrated to precipitate a solid, which was filtered and dried to afford an off-white solid (1.23 g, 50% yield). ESI-MS m / z: 350.0 [M+H] + Step 3:

[0424] 4-Bromo-2-(4-(difluoromethylene)piperidin-1-yl)-6-fluorobenzoic acid (350 mg, 1 mmol) was dissolved in DCM (10 mL) and the mixture was cooled on ice under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC. The reaction was concentrated to give a gray-yellow solid intermediate 49 (405 mg, 100% yield), which was used directly in the next step.

[0425] Preparation Example 27: Synthesis of Intermediate 50

[0426] Step 1:

[0427] Methyl 2-fluoro-4-nitrobenzoate (4.00 g, 20.08 mmol) and 4-(difluoromethylene)piperidine hydrochloride (3.4 g, 20.08 mmol) were dissolved in dioxane (60 mL), and TEA (6.07 g, 60.24 mmol) was added. The mixture was refluxed at 100°C under N2 protection for 12 h. The reaction was monitored by LC-MS, and the mixture was directly dried and extracted with EA. The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to give a light yellow solid (5.64 g, yield 90%). ESI-MS m / z: 313.0 [M+H]+ .

[0428] Step 2:

[0429] Methyl 2-(4-(difluoromethylene)piperidin-1-yl)-4-nitrobenzoate (3.12 g, 10 mmol) was dissolved in MeOH (30 mL) and aqueous sodium hydroxide (2.0 g, 50 mmol in 10 mL H₂O) was added. The mixture was allowed to react at room temperature overnight. LC-MS monitoring indicated that the reaction was complete. The pH was adjusted to approximately 4 with dilute hydrochloric acid and the mixture was concentrated to precipitate a solid. The filter cake was filtered and dried to afford a light yellow solid (1.79 g, 60% yield). ESI-MS m / z: 299.1 [M+H] + .

[0430] Step 3:

[0431] 2-(4-(Difluoromethylene)piperidin-1-yl)-4-nitrobenzoic acid (298 mg, 1 mmol) was dissolved in DCM (10 mL) and placed in an ice bath under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC. The reaction was concentrated to give a yellow solid intermediate 50 (353 mg, yield 100%), which was used directly in the next reaction.

[0432] Preparation Example 28: Synthesis of Intermediate 51

[0433] Step 1:

[0434] Dissolve spiro[2.5]octan-6-one (621 mg, 5.0 mmol) in dry tetrahydrofuran (15 mL), cool to -78°C under nitrogen, and add lithium bis(trimethylsilyl)amide (7.5 mL, 1 mol / L) dropwise. Stir at -78°C for 30 minutes. Dissolve N-phenylbis(trifluoromethanesulfonyl)imide (2.68 g, 7.5 mmol) in tetrahydrofuran (10 mL) and add dropwise to the reaction mixture. Allow to react at -78°C for 1 hour. Slowly warm to room temperature and allow to react for 1 hour. TLC confirms the reaction is complete. Quench with saturated ammonium chloride and extract with ethyl acetate (30 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and dried. The resulting crude product is then purified by column chromatography (PE / EA = 100 / 1) to afford spiro[2.5]octan-5-en-6-yl trifluoromethanesulfonic acid as a pale yellow liquid (450 mg, 35% yield). LC-Ms does not produce ion current.

[0435] Step 2:

[0436] Spiro[2.5]octane-5-en-6-yl trifluoromethanesulfonate (256 mg, 1.0 mmol) was dissolved in dioxane (10 mL), and potassium acetate (295 mg, 3.0 mmol), bispinacol borate (508 mg, 2.0 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol) were added. The temperature was raised to 100 ° C under nitrogen protection and the reaction was carried out for 5 hours. The reaction was complete after TLC detection. The reaction solution was cooled to room temperature, quenched with water, filtered, and the filter cake was rinsed with EA. The filtrate was extracted with EA (15 mL*2). The combined organic phases were spin-dried to obtain the crude product, which was passed through a column (PE / EA=100 / 1) to give 4,4,5,5-tetramethyl-2-(spiro[2.5]-5-octen-6-yl)-1,3,2-dioxaborolane as a colorless liquid (100 mg, yield 42%). ESI-MS m / z: 235.1 [M+H] + .

[0437] Step 3:

[0438] 4,4,5,5,5-Tetramethyl-2-spiro[2.5]octane-5-en-6-yl-1,3,2-dioxaborolane (1.17 g, 5.0 mmol), potassium phosphate (2.12 g, 10.0 mmol), 1,1-(diphenylphosphino)ferrocenepalladium dichloride (366 mg, 0.5 mmol), and methyl 4-bromo-2-iodobenzoate (1.7 g, 5.0 mmol) were added sequentially to 1,4-dioxane (50 mL). Under argon, the reaction was incubated at 100°C for 1 hour. The reaction mixture was quenched with water (100 mL). Extraction was performed with EA (50 mL x 2). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA = 100 / 1 to 10 / 1) to give methyl 4-bromo-2-(spiro[2.5]octane-5-en-6-yl)benzoate (800 mg, yield 50%) as a white solid. ESI-MS m / z: 321.0 [M+H] + .

[0439] Step 4:

[0440] Methyl 4-bromo-2-(spiro[2.5]oct-5-en-6-yl)benzoate (642 mg, 2 mmol) was dissolved in MeOH (10 mL) and aqueous sodium hydroxide (400 mg, 10 mmol, in 3 mL H₂O) was added. The mixture was allowed to react at room temperature overnight. LC-MS monitoring was used to monitor the reaction. The pH was adjusted to approximately 4 with dilute hydrochloric acid, and the mixture was concentrated and extracted with EA (20 mL x 3). The organic phases were combined, dried, and purified by column chromatography (PE / EA = 100 / 1 to 2 / 1) to afford a light yellow solid (430 mg, 70% yield). ESI-MS m / z: 307.0 [M+H] + .

[0441] Step 5:

[0442] 4-Bromo-2-(spiro[2.5]oct-5-en-6-yl)benzoic acid (307 mg, 1 mmol) was dissolved in DCM (10 mL) and the mixture was cooled on ice under N2 protection. Oxalyl chloride (381 mg, 3 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC. The reaction was concentrated to give a yellow solid intermediate 51 (326 mg, 100% yield), which was used directly in the next reaction.

[0443] Intermediates 52-54 can be synthesized using spiro[3.5]nonan-7-one, 4,4-difluorocyclohexane-1-one, and 4,4-dimethylcyclohexane-1-one as raw materials, respectively, according to a method similar to that of intermediate 51 (ESI-MS shows the ion peak of methyl ester).

[0444] Preparation Example 29: Synthesis of Intermediate 55

[0445] Step 1:

[0446] 4,4,5,5,5-Tetramethyl-2-spiro[2.5]octane-5-en-6-yl-1,3,2-dioxaborolane (1.17 g, 5.0 mmol), potassium phosphate (2.12 g, 10.0 mmol), 1,1-(diphenylphosphino)ferrocenepalladium dichloride (366 mg, 0.5 mmol), and methyl 4-bromo-2-iodobenzoate (1.79 g, 5.0 mmol, synthesis reference WO2022 / 020244) were sequentially added to 1,4-dioxane (50 mL). Under argon protection, the reaction was incubated at 100°C for 1 hour. The reaction solution was quenched with water (100 mL). Extraction was performed with EA (50 mL x 2). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA = 100 / 1 to 10 / 1) to give methyl 4-bromo-2-fluoro-6-(spiro[2.5]oct-5-en-6-yl)benzoate (650 mg, yield 38%) as a white solid. ESI-MS m / z: 339.0 [M+H] + .

[0447] Step 2:

[0448] Methyl 4-bromo-2-fluoro-6-(spiro[2.5]oct-5-en-6-yl)benzoate (339 mg, 1 mmol) was dissolved in MeOH (10 mL) and aqueous sodium hydroxide (200 mg, 5 mmol, in 3 mL H₂O) was added. The mixture was allowed to react at room temperature overnight. LC-MS monitoring was used to monitor the reaction. The pH was adjusted to approximately 4 with dilute hydrochloric acid, and the mixture was concentrated and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried, and purified by column chromatography (PE / EA = 100 / 1 to 2 / 1) to afford a light yellow solid (211 mg, 65% yield). ESI-MS m / z: 325.0 [M+H] + .

[0449] Step 3:

[0450] 4-Bromo-2-fluoro-6-(spiro[2.5]oct-5-en-6-yl)benzoic acid (163 mg, 0.5 mmol) was dissolved in DCM (10 mL) and the mixture was cooled on ice under N2 protection. Oxalyl chloride (191 mg, 1.5 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC. The reaction was concentrated to give a yellow solid intermediate 55 (190 mg, 100% yield), which was used directly in the next step.

[0451] Preparation Example 30: Synthesis of Intermediate 56

[0452] Step 1:

[0453] 4-Bromo-2-fluoro-1-nitrobenzene (4.40 g, 20 mmol) and 4-(difluoromethylene)piperidine hydrochloride (3.39 g, 20 mmol) were added to K2CO3 (5.53 g, 40 mmol) and dissolved in DMSO. Under nitrogen protection, the reaction temperature was raised to 60°C for 10 minutes, followed by a temperature increase to 90°C for 1 hour. LC-MS monitoring confirmed the complete reaction. The product was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1) to afford an orange-red solid (5.77 g, 92.8% yield). ESI-MS m / z: 333.0 [M+H] + .

[0454] Step 2:

[0455] 1-(5-Bromo-2-nitrophenyl)-4-(difluoromethylene)piperidine (1.5 g, 4.5 mmol) was dissolved in DMF (20 mL), and 2-hydroxyethane-1-sulfonamide (1.13 g, 9.0 mmol) was added quickly, followed by K3PO4 (1.9 g, 9.0 mmol), (1R, 2R)-N 1 ,N 2 1,2-dimethylcyclohexane-1,2-diamine (320 mg, 2.25 mmol) was quickly added to CuI (857 mg, 4.5 mmol). N2 was used for protection and the reaction was heated to 100°C for 5 h. LC-MS monitoring confirmed the complete reaction. The reaction was quenched with water and extracted with DCM (50 mL x 3). The organic phases were combined, dried, concentrated, and mixed. Column chromatography (PE / EA = 5 / 1 to 2 / 1) afforded a yellow solid (1.19 g, 70% yield). ESI-MS m / z: 379.1 [M+H] + .

[0456] Step 3:

[0457] N-(3-(4-(difluoromethylene)piperidin-1-yl)-4-nitrophenyl)-2-hydroxyethane-1-sulfonamide (755 mg, 2 mmol) was dissolved in DCM, PPTS (100 mg, 0.4 mmol) was added, and DHP (252 mg, 3.0 mmol) was added under ice-cooling. The mixture was protected by N2 and allowed to react at room temperature. LC-MS monitoring indicated that the reaction was complete. The reaction was quenched by the addition of water (30 mL) and extracted with DCM (50 mL x 3). The organic phase was washed with water (150 mL x 1), dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1). A yellow gum (692 mg, 75% yield) was obtained. ESI-MS m / z: 462.1 [M+H] + .

[0458] Step 4:

[0459] N-(3-(4-(difluoromethylene)piperidin-1-yl)-4-nitrophenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-sulfonamide (461 mg, 1.0 mmol) was dissolved in EtOH / H₂O (5 / 1, 15 mL) and Fe powder (280 mg, 5.0 mmol) and NH₄Cl (267 mg, 5.0 mmol) were added. The mixture was heated to 80°C for 1 h under N₂ protection. LC-MS confirmed the complete reaction. The product was filtered, concentrated under reduced pressure, extracted with EA, dried, concentrated, and stirred. Column chromatography (PE / EA = 10 / 1 to 2 / 1) afforded intermediate 56 (367 mg, 85% yield) as a yellow-brown solid. ESI-MS m / z: 432.1 [M+H] + .

[0460] Preparation Example 31: Synthesis of Intermediate 57

[0461] Step 1:

[0462] 4,4,5,5,5-Tetramethyl-2-spiro[2.5]octane-5-en-6-yl-1,3,2-dioxaborolane (1.17 g, 5.0 mmol), potassium phosphate (2.12 g, 10.0 mmol), 1,1-(diphenylphosphino)ferrocenepalladium dichloride (366 mg, 0.5 mmol), and 4-bromo-2-iodo-1-nitrobenzene (1.64 g, 5.0 mmol) were added sequentially to 1,4-dioxane (50 mL). Under argon, the reaction was incubated at 100°C for 1 hour. The reaction mixture was quenched with water (100 mL). Extraction was performed with EA (50 mL x 2). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA = 100 / 1 to 10 / 1) to give methyl 4-bromo-2-fluoro-6-(spiro[2.5]oct-5-en-6-yl)benzoate (925 mg, yield 60%) as a white solid. ESI-MS m / z: 308.0 [M+H] + .

[0463] Step 2:

[0464] 6-(5-Bromo-2-nitrophenyl)spiro[2.5]oct-5-ene (1.23 g, 4.0 mmol) was dissolved in DMF (20 mL), and 2-hydroxyethane-1-sulfonamide (1.0 g, 8.0 mmol) was added quickly followed by K3PO4 (1.7 g, 8.0 mmol), (1R,2R)-N 1 ,N 21,2-dimethylcyclohexane-1,2-diamine (285 mg, 2.0 mmol) was quickly added to CuI (762 mg, 4.0 mmol). N2 was used for protection and the reaction was heated to 100°C for 5 h. LC-MS monitoring confirmed the complete reaction. The reaction was quenched with water and extracted with DCM (50 mL x 3). The organic phases were combined, dried, concentrated, and mixed. Column chromatography (PE / EA = 5 / 1 to 2 / 1) afforded a yellow solid (930 g, 66% yield). ESI-MS m / z: 353.1 [M+H] + .

[0465] Step 3:

[0466] 2-Hydroxy-N-(4-nitro-3-(spiro[2.5]oct-5-en-6-yl)phenyl)ethane-1-sulfonamide (704 mg, 2 mmol) was dissolved in DCM, PPTS (100 mg, 0.4 mmol) was added, and DHP (252 mg, 3.0 mmol) was added under ice-cooling. The mixture was protected by N2 and allowed to react at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was quenched with water (30 mL) and extracted with DCM (50 mL x 3). The organic phase was washed with water (150 mL), dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1). A yellow gum (698 mg, 80% yield) was obtained. ESI-MS m / z: 437.1 [M+H] + .

[0467] Step 4:

[0468] N-(3-(4-(difluoromethylene)piperidin-1-yl)-4-nitrophenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-sulfonamide (436 mg, 1.0 mmol) was dissolved in EtOH / H₂O (5 / 1, 15 mL) and Fe powder (280 mg, 5.0 mmol) and NH₄Cl (267 mg, 5.0 mmol) were added. Under N₂ protection, the mixture was heated to 80°C for 1 h. LC-MS confirmed the complete reaction. The product was filtered, concentrated under reduced pressure, extracted with EA, dried, concentrated, and stirred. Column chromatography (PE / EA = 10 / 1 to 2 / 1) afforded intermediate 57 (366 mg, 90% yield) as a yellow-brown solid. ESI-MS m / z: 407.1 [M+H] + .

[0469] Intermediate 58 was synthesized in a similar manner to Intermediate 57.

[0470] Preparation Example 32: Synthesis of Intermediate 59

[0471] 5-Bromo-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (634 mg, 2.0 mmol) was dissolved in DMF (10 mL), and oxalic acid dihydrate (378 mg, 3.0 mmol) was added. Xantphos (58 mg, 0.1 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), Ac2O (306 mg, 3.0 mmol), and DIPEA (390 mg, 3.0 mmol) were also added. The mixture was sealed and reacted at 100°C for 6 h. LC-MS monitoring confirmed the complete reaction of the starting material. The mixture was washed with H2O, and the aqueous phase was extracted with EA, dried, filtered, and concentrated to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 to 5 / 1) afforded Intermediate 59 (320 mg, 57% yield) as a light yellow solid. ESI-MS m / z: 283.1 [M+H] + .

[0472] Preparation Example 33: Synthesis of Intermediate 60

[0473] Step 1:

[0474] 5,7-Dibromofuro[2,3-c]pyridine (500 mg, 1.81 mmol) was dissolved in DMF (5 mL). DIPEA (933.9 mg, 7.24 mmol) and 3,3-difluoroazetidine hydrochloride (469 mg, 3.62 mmol) were added. The reaction mixture was heated to 120°C and allowed to react for 12 h. LC-MS monitoring indicated that the starting material had essentially reacted. The reaction mixture was poured into water and extracted with EA. The crude product was dried, filtered, and concentrated to afford the crude product. Column chromatography (PE / EA = 20 / 1 to 5 / 1) afforded the product as a white solid (377 mg, 72% yield). ESI-MS m / z: 289.0 [M+H] + .

[0475] Step 2:

[0476] 5-Bromo-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (578 mg, 2.0 mmol) was dissolved in DMF (10 mL), and oxalic acid dihydrate (378 mg, 3.0 mmol) was added. Xantphos (58 mg, 0.1 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), Ac2O (306 mg, 3.0 mmol), and DIPEA (390 mg, 3.0 mmol) were also added. The mixture was sealed and reacted at 100°C for 6 h. LC-MS monitoring confirmed the complete reaction of the starting material. The mixture was washed with H2O, and the aqueous phase was extracted with EA, dried, filtered, and concentrated to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 to 5 / 1) afforded Intermediate 60 (265 mg, 52% yield) as a light yellow solid. ESI-MS m / z: 255.0 [M+H] + .

[0477] Intermediates 61-64 can be synthesized by a similar method to that of intermediate 60.

[0478] Preparation Example 34: Synthesis of Intermediate 65

[0479] Step 1:

[0480] 2-Chloro-4-(2-hydroxyethyl)pyridin-3-ol (2.5 g, 14.36 mmol) was dissolved in THF / H₂O (50 mL, V / V = 1 / 1), and K₂CO₃ (2.98 g, 21.54 mmol) and iodine (5.47 g, 21.54 mmol) were added. The mixture was allowed to react overnight at room temperature. LC-MS monitoring indicated that the reaction was complete. Aqueous sodium thiosulfate solution was added, and the mixture was extracted with EA, dried, and concentrated to afford a light yellow viscous solid (4.15 g, 96% yield). ESI-MS m / z: 299.9 [M+H] + .

[0481] Step 2:

[0482] 2-Chloro-4-(2-hydroxyethyl)-6-iodopyridin-3-ol (4.15 g, 13.86 mmol) and PPh3 (4.36 g, 16.63 mmol) were dissolved in THF (50 mL). DEAD (2.90 g, 16.63 mmol) was added dropwise at 10°C. The mixture was allowed to react overnight at room temperature. LC-MS monitoring indicated that the reaction was complete. The reaction solution was diluted with saturated NH4Cl, extracted with EA, and the organic phase was washed with water and concentrated. The organic phase was purified by column chromatography (PE / EA = 50 / 1 to 5 / 1) and concentrated to afford a white solid (3.88 g, 83% yield). ESI-MS m / z: 281.9 [M+H] + .

[0483] Step 3:

[0484] 7-Chloro-5-iodo-2,3-dihydrofuro[2,3-c]pyridine (2.81 g, 10.0 mmol) was dissolved in DMF (40 mL), and oxalic acid dihydrate (1.89 g, 15.0 mmol) was added. Xantphos (579 mg, 1.0 mmol), Pd(OAc)2 (225 mg, 1.0 mmol), Ac2O (1.53 g, 15.0 mmol), and DIPEA (1.94 g, 15.0 mmol) were then added. The mixture was sealed and reacted at 100°C for 8 h. LC-MS monitoring confirmed the complete reaction of the starting material. The product was washed with H2O, and the aqueous phase was extracted with EA, dried, filtered, and concentrated to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 to 5 / 1) afforded a light yellow solid (900 mg, 45% yield). ESI-MS m / z: 200.0 [M+H] + .

[0485] Step 4:

[0486] 7-Chloro-2,3-dihydrofuro[2,3-c]pyridine-5-carboxylic acid (900 mg, 4.5 mmol) was dissolved in MeOH, and SOCl2 (2.68 g, 22.5 mmol) was added. The reaction was allowed to proceed at 50°C for 3 h. LC-MS monitoring indicated that the reaction was complete. The product was then concentrated, dissolved in EA, washed with aqueous sodium bicarbonate, dried, filtered, and concentrated to give the crude product as a light yellow solid (960 mg, 100% yield). ESI-MS m / z: 214.0 [M+H] + .

[0487] Step 5:

[0488] Methyl 7-chloro-2,3-dihydrofuro[2,3-c]pyridine-5-carboxylate (852 mg, 4.0 mmol), 4,4-difluoropiperidine hydrochloride (946 mg, 6.0 mmol), Cs2CO3 (3.91 g, 12.0 mmol), Pd2(dba)3 (366 mg, 0.4 mmol), and Xantphos (231 mg, 0.4 mmol) were dissolved in dioxane (40 mL) and reacted at 100°C under argon overnight. The reaction mixture was filtered and concentrated by column chromatography (PE / EA = 50 / 1 to 3 / 1) to afford a yellow solid (600 mg, 50% yield). ESI-MS m / z: 299.1 [M+H] + .

[0489] Step 6:

[0490] Methyl 7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxylate (600 mg, 2.0 mmol) was dissolved in MeOH / H₂O (5 / 1, 20 mL). NaOH (400 mg, 10 mmol) was added and the mixture was allowed to react at 50°C for 6 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was adjusted to pH approximately 5, concentrated, and filtered to afford intermediate 65 (284 mg, 50% yield) as a light yellow solid. ESI-MS m / z: 285.1 [M+H] + .

[0491] Preparation Example 35: Synthesis of Intermediate 66

[0492] Step 1:

[0493] 4-Chlorofuro[3,2-c]pyridine 5-oxide (500 mg, 2.94 mmol), 4,4-difluoropiperidine hydrochloride (929 mg, 5.88 mmol), and TEA (890 mg, 8.82 mmol) were dissolved in dioxane (10 mL) and reacted overnight at 110°C. LC-MS monitoring indicated complete reaction. The reaction mixture was filtered, and the filtrate was collected and concentrated by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford a yellow solid (600 mg, 80% yield). ESI-MS m / z: 255.1 [M+H] + .

[0494] Step 2:

[0495] 4-(4,4-Difluoropiperidin-1-yl)furo[3,2-c]pyridine 5-oxide (600 mg, 4.72 mmol) was dissolved in 1.4-dioxane and POBr3 (2.7 g, 9.44 mmol) was added. The mixture was allowed to react at 70°C for 5 hours. LC-MS monitoring indicated complete reaction. The reaction mixture was diluted with water, the pH adjusted to 8 with Na2CO3, and extracted twice with EA, washed with water, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a yellow solid (320 mg, 42% yield). ESI-MS m / z: 317.0 [M+H] + .

[0496] Step 3:

[0497] 6-Bromo-4-(4,4-difluoropiperidin-1-yl)furo[3,2-c]pyridine (634 mg, 2.0 mmol) was dissolved in DMF (10 mL), and oxalic acid dihydrate (378 mg, 3.0 mmol) was added. Xantphos (58 mg, 0.1 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), Ac2O (306 mg, 3.0 mmol), and DIPEA (390 mg, 3.0 mmol) were also added. The mixture was sealed and reacted at 100°C for 6 h. LC-MS monitoring confirmed the complete reaction of the starting material. The mixture was washed with H2O, and the aqueous phase was extracted with EA, dried, filtered, and concentrated to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 to 5 / 1) afforded Intermediate 66 (254 mg, 45% yield) as a light yellow solid. ESI-MS m / z: 283.1 [M+H] + .

[0498] Intermediate 67 can be synthesized by a similar method to that of Intermediate 66.

[0499] Preparation Example 36: Synthesis of Intermediate 68

[0500] Step 1:

[0501] 4-Chloro-2,3-dihydrofuro[3,2-c]pyridine 5-oxide (913 mg, 5.32 mmol) was dissolved in dioxane (30 mL) and POBr3 (2.2 g, 7.93 mmol) was added. The mixture was reacted at 80°C for 2 h, then spin-dried to dryness, washed with water and NaHCO3, and extracted with EA. The product was dried, filtered, concentrated, and purified by column chromatography (PE / EA = 15 / 1 to 8 / 1) to afford a white solid (600 mg, 48% yield). ESI-MS m / z: 233.9 [M+H] + .

[0502] Step 2:

[0503] 6-Bromo-4-chloro-2,3-dihydrofuro[3,2-c]pyridine (2.34 g, 10.0 mmol) was dissolved in DMF (40 mL), and oxalic acid dihydrate (1.89 g, 15.0 mmol) was added. Xantphos (579 mg, 1.0 mmol), Pd(OAc)2 (225 mg, 1.0 mmol), Ac2O (1.53 g, 15.0 mmol), and DIPEA (1.94 g, 15.0 mmol) were then added. The mixture was sealed and reacted at 100°C for 8 h. LC-MS monitoring confirmed the complete reaction of the starting material. The product was washed with H2O, and the aqueous phase was extracted with EA, dried, filtered, and concentrated to afford the crude product. Column chromatography (DCM / MeOH = 100 / 1 to 5 / 1) afforded a light yellow solid (800 mg, 40% yield). ESI-MS m / z: 200.0 [M+H] + .

[0504] Step 3:

[0505] 4-Chloro-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylic acid (800 mg, 4.0 mmol) was dissolved in MeOH, and thionyl chloride (2.38 g, 20.0 mmol) was added. The reaction was allowed to proceed at 50°C for 3 h. LC-MS monitoring indicated that the reaction was complete. The product was then concentrated, dissolved in EA, washed with aqueous sodium bicarbonate, dried, filtered, and concentrated to afford the crude product as a pale yellow solid (852 mg, 100% yield). ESI-MS m / z: 214.0 [M+H] + .

[0506] Step 4:

[0507] Methyl 4-chloro-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylate (852 mg, 4.0 mmol), 4,4-difluoropiperidine hydrochloride (946 mg, 6.0 mmol), Cs2CO3 (3.91 g, 12.0 mmol), Pd2(dba)3 (366 mg, 0.4 mmol), and Xantphos (231 mg, 0.4 mmol) were dissolved in dioxane (40 mL) and reacted at 100°C under argon overnight. The reaction mixture was filtered and concentrated by column chromatography (PE / EA = 50 / 1 to 3 / 1) to afford a yellow solid (600 mg, 50% yield). ESI-MS m / z: 299.1 [M+H] + .

[0508] Step 5:

[0509] Methyl 4-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylate (600 mg, 2.0 mmol) was dissolved in MeOH / H₂O (5 / 1, 20 mL). NaOH (400 mg, 10 mmol) was added and the mixture was allowed to react at 50°C for 6 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was adjusted to pH approximately 5, concentrated, and filtered to afford intermediate 68 (341 mg, 60% yield) as a light yellow solid. ESI-MS m / z: 285.1 [M+H] + .

[0510] Preparation Example 37: Synthesis of Intermediate 69

[0511] Step 1:

[0512] 7-Chloro-5-(4,4-difluoropiperidin-1-yl)-2,3-dihydro-[1,4]dioxano[2,3-c]pyridine (4.95 g, 17.0 mmol) was dissolved in MeOH (60 mL), and Pd(dppf)Cl2·CH2Cl2 (695 mg, 0.85 mmol) and TEA (4.9 mL, 35 mmol) were added. The mixture was heated at 100°C under carbon monoxide (100 psi) for 6 h. LC-MS monitoring indicated that the starting material had reacted completely. The product was concentrated and purified by column chromatography (PE / EA = 15 / 1 to 3 / 1) to afford a yellow solid (2.08 g, 39% yield). ESI-MS m / z: 315.1 [M+H] + .

[0513] Step 2:

[0514] Methyl 5-(4,4-difluoropiperidin-1-yl)-2,3-dihydro-[1,4]dioxy[2,3-c]pyridine-7-carboxylate (628 mg, 2.0 mmol) was dissolved in MeOH / H₂O (5 / 1, 20 mL). NaOH (400 mg, 10 mmol) was added and the mixture was allowed to react at 50°C for 6 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was adjusted to pH approximately 5, concentrated, and filtered to afford intermediate 69 (270 mg, 45% yield) as a light yellow solid. ESI-MS m / z: 301.1 [M+H] + .

[0515] Preparation Example 38: Synthesis of Intermediate 70

[0516] 5-Bromo-7-(4,4-difluoropiperidin-1-yl)-1-methylpyrazolo[3,4-c]pyridine (662 mg, 2.0 mmol) was dissolved in DMF (10 mL), and oxalic acid dihydrate (378 mg, 3.0 mmol) was added. Xantphos (58 mg, 0.1 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), Ac2O (306 mg, 3.0 mmol), and DIPEA (390 mg, 3.0 mmol) were also added. The mixture was sealed and reacted at 100°C for 6 h. LC-MS monitoring confirmed the complete reaction of the starting material. The mixture was washed with H2O, and the aqueous phase was extracted with EA, dried, filtered, and concentrated to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 to 5 / 1) afforded Intermediate 70 (284 mg, 48% yield) as a light yellow solid. ESI-MS m / z: 297.1 [M+H] + .

[0517] Preparation Example 39: Synthesis of Intermediate 71

[0518] 5-Bromo-7-(4,4-difluoropiperidin-1-yl)-2-methylpyrazolo[3,4-c]pyridine (200 mg, 0.6 mmol) was dissolved in DMF (3 mL), and oxalic acid dihydrate (113 mg, 0.9 mmol) was added. Xantphos (35 mg, 0.06 mmol), Pd(OAc)2 (14 mg, 0.06 mmol), Ac2O (92 mg, 0.9 mmol), and DIPEA (116 mg, 0.9 mmol) were also added. The mixture was sealed and reacted at 100°C for 6 h. LC-MS monitoring confirmed the complete reaction of the starting material. The mixture was washed with H2O, and the aqueous phase was extracted with EA, dried, filtered, and concentrated to obtain the crude product. Column chromatography (DCM / MeOH = 100 / 1 to 5 / 1) afforded Intermediate 71 (90 mg, 34% yield) as a light yellow solid. ESI-MS m / z: 297.1 [M+H] + .

[0519] Preparation Example 40: Synthesis of Intermediate 72

[0520] Step 1:

[0521] Methyl 7-chloro-2,3-dihydrofuro[2,3-c]pyridine-5-carboxylate (852 mg, 4.0 mmol), 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (933 mg, 6.0 mmol), Cs2CO3 (3.91 g, 12.0 mmol), Pd2(dba)3 (366 mg, 0.4 mmol), and Xantphos (231 mg, 0.4 mmol) were dissolved in dioxane (40 mL) and reacted at 100°C under argon overnight. The reaction mixture was filtered and concentrated by column chromatography (PE / EA = 50 / 1 to 3 / 1) to afford a yellow solid (635 mg, 53% yield). ESI-MS m / z: 297.1 [M+H] + .

[0522] Step 2:

[0523] Methyl 7-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-2,3-dihydrofuro[2,3-c]pyridine-5-carboxylate (593 mg, 2.0 mmol) was dissolved in MeOH / H₂O (5 / 1, 20 mL). NaOH (400 mg, 10 mmol) was added and the mixture was allowed to react at 50°C for 6 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was adjusted to pH ~5, concentrated, filtered, and dried to afford intermediate 72 (300 mg, 53% yield) as a light yellow solid. ESI-MS m / z: 283.1 [M+H] + .

[0524] Preparation Example 41: Synthesis of Intermediate 73

[0525] Step 1:

[0526] Methyl 4-chloro-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylate (852 mg, 4.0 mmol), 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (933 mg, 6.0 mmol), Cs2CO3 (3.91 g, 12.0 mmol), Pd2(dba)3 (366 mg, 0.4 mmol), and Xantphos (231 mg, 0.4 mmol) were dissolved in dioxane (40 mL) and reacted at 100°C under argon overnight. The reaction mixture was filtered and concentrated by column chromatography (PE / EA = 50 / 1 to 3 / 1) to afford a yellow solid (650 mg, 55% yield). ESI-MS m / z: 297.1 [M+H] + .

[0527] Step 2:

[0528] Methyl 4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylate (593 mg, 2.0 mmol) was dissolved in MeOH / H₂O (5 / 1, 20 mL). Sodium hydroxide (400 mg, 10 mmol) was added and the mixture was allowed to react at 50°C for 6 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was adjusted to a pH of approximately 5, concentrated, filtered, and dried to afford Intermediate 73 (260 mg, 46% yield) as a light yellow solid. ESI-MS m / z: 283.1 [M+H] + .

[0529] Preparation Example 42: Synthesis of Intermediate 74

[0530] Step 1:

[0531] 5,7-Dibromofuro[2,3-c]pyridine (500 mg, 1.81 mmol) was dissolved in DMF (5 mL). DIPEA (933.9 mg, 7.24 mmol) and 4,4-difluoropiperidine hydrochloride (570 mg, 3.62 mmol) were added. The reaction mixture was heated to 120°C and allowed to react for 12 h. LC-MS monitoring indicated that the starting material had not yet reacted completely. The reaction mixture was poured into water and extracted with EA. The crude product was dried, filtered, and concentrated to afford the crude product. Column chromatography (PE / EA = 20 / 1 to 5 / 1) afforded a white solid (430 mg, 75% yield). ESI-MS m / z: 317.0 [M+H] + .

[0532] Step 2:

[0533] 5-Bromo-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (1.27 g, 4.0 mmol) was dissolved in THF (20 mL). Ethynyltrimethylsilane (1.18 g, 12.0 mmol), Pd(Ph3P)2Cl2 (281 mg, 0.4 mmol), CuI (76 mg, 0.4 mmol), and TEA (1.21 g, 12.0 mmol) were added and reacted at 50°C for 7 h. LC-MS monitoring confirmed the complete reaction. The crude product was concentrated and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a light yellow solid (600 mg, 45% yield). ESI-MS m / z: 335.1 [M+H] + .

[0534] Step 3:

[0535] 7-(4,4-Difluoropiperidin-1-yl)-5-((trimethylsilyl)ethynyl)furo[2,3-c]pyridine (600 mg, 1.8 mmol) was dissolved in MeOH (10 mL), and K2CO3 (498 mg, 3.6 mmol) was added. The reaction was allowed to proceed at room temperature for 5 h. LC-MS monitoring indicated that the reaction was complete. The product was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford intermediate 74 (300 mg, 64% yield) as a light yellow solid. ESI-MS m / z: 263.1 [M+H] + .

[0536] Intermediate 75 can be synthesized by a similar method to that of Intermediate 74.

[0537] Preparation Example 43: Synthesis of Intermediate 76

[0538] Step 1:

[0539] 7-Chloro-5-iodo-2,3-dihydrofuro[2,3-c]pyridine (1.13 g, 4.0 mmol) was dissolved in THF (20 mL). Ethynyltrimethylsilane (1.18 g, 12.0 mmol), Pd(Ph3P)2Cl2 (281 mg, 0.4 mmol), CuI (76 mg, 0.4 mmol), and TEA (1.21 g, 12.0 mmol) were added and reacted at 50°C for 7 h. LC-MS monitoring confirmed the complete reaction of the starting material. The crude product was concentrated and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a light yellow solid (504 mg, 50% yield). ESI-MS m / z: 252.0 [M+H] + .

[0540] Step 2:

[0541] 7-Chloro-5-((trimethylsilyl)ethynyl)-2,3-dihydrofuro[2,3-c]pyridine (504 mg, 2.0 mmol), 4,4-difluoropiperidine hydrochloride (473 mg, 3.0 mmol), Cs2CO3 (1.95 g, 6.0 mmol), Pd2(dba)3 (183 mg, 0.2 mmol), and Xantphos (116 mg, 0.2 mmol) were dissolved in dioxane (40 mL) and reacted at 100°C under argon overnight. The reaction mixture was filtered and concentrated by column chromatography (PE / EA = 50 / 1 to 3 / 1) to afford a yellow solid (400 mg, 60% yield). ESI-MS m / z: 337.2 [M+H] + .

[0542] Step 3:

[0543] 7-(4,4-Difluoropiperidin-1-yl)-5-((trimethylsilyl)ethynyl)-2,3-dihydrofuro[2,3-c]pyridine (400 mg, 1.2 mmol) was dissolved in MeOH (10 mL), and K2CO3 (332 mg, 2.4 mmol) was added. The reaction was allowed to proceed at room temperature for 5 h. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford intermediate 76 (168 mg, 53% yield) as a light yellow solid. ESI-MS m / z: 265.1 [M+H] + .

[0544] Intermediate 77 can be synthesized by a similar method to Intermediate 76.

[0545] Preparation Example 44: Synthesis of Intermediate 78

[0546] Step 1:

[0547] 6-Bromo-4-chloro-2,3-dihydrofluoro[3,2-c]pyridine (938 mg, 4.0 mmol) was dissolved in THF (20 mL). Ethynyltrimethylsilane (1.18 g, 12.0 mmol), Pd(Ph3P)2Cl2 (281 mg, 0.4 mmol), CuI (76 mg, 0.4 mmol), and TEA (1.21 g, 12.0 mmol) were added and reacted at 50°C for 7 h. LC-MS monitoring confirmed the complete reaction. The crude product was concentrated and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a light yellow solid (554 mg, 55% yield). ESI-MS m / z: 252.0 [M+H] + .

[0548] Step 2:

[0549] 4-Chloro-6-((trimethylsilyl)ethynyl)-2,3-dihydrofluoro[3,2-c]pyridine (504 mg, 2.0 mmol), 4,4-difluoropiperidine hydrochloride (473 mg, 3.0 mmol), Cs2CO3 (1.95 g, 6.0 mmol), Pd2(dba)3 (183 mg, 0.2 mmol), and Xantphos (116 mg, 0.2 mmol) were dissolved in dioxane (40 mL) and reacted at 100°C under argon overnight. The reaction mixture was filtered and concentrated by column chromatography (PE / EA = 50 / 1 to 3 / 1) to afford a yellow solid (336 mg, 50% yield). ESI-MS m / z: 337.2 [M+H] + .

[0550] Step 3:

[0551] 4-(4,4-Difluoropiperidin-1-yl)-6-((trimethylsilyl)ethynyl)-2,3-dihydrofluoro[3,2-c]pyrrolidone (336 mg, 1.0 mmol) was dissolved in MeOH (10 mL), and K2CO3 (276 mg, 2.0 mmol) was added. The reaction was allowed to proceed at room temperature for 5 h. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford intermediate 78 (130 mg, 49% yield) as a light yellow solid. ESI-MS m / z: 265.1 [M+H] + .

[0552] Intermediate 79 can be synthesized by a similar method to Intermediate 78

[0553] Preparation Example 45: Synthesis of Intermediate 80

[0554] Step 1:

[0555] 5,7-Dibromofuro[2,3-c]pyridine (500 mg, 1.81 mmol) was dissolved in DMF (5 mL). DIPEA (933.9 mg, 7.24 mmol) and 4,4-difluoropiperidine hydrochloride (570 mg, 3.62 mmol) were added. The reaction mixture was heated to 120°C and allowed to react for 12 h. LC-MS monitoring indicated that the starting material had not yet reacted completely. The reaction mixture was poured into water and extracted with EA. The crude product was dried, filtered, and concentrated to afford the crude product. Column chromatography (PE / EA = 20 / 1 to 5 / 1) afforded a white solid (430 mg, 75% yield). ESI-MS m / z: 317.0 [M+H] + .

[0556] Step 2:

[0557] 5-Bromo-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (430 mg, 1.36 mmol) was dissolved in dioxane (15 mL) and added with Xantphos (78 mg, 0.136 mmol), Pd(dba) (124 mg, 0.136 mmol), CsCO (1.32 g, 4.08 mmol), and benzophenone imine (368 mg, 2.03 mmol). The mixture was reacted at 90°C overnight. LC-MS monitoring confirmed the complete reaction of the starting material. The product was washed with NH4Cl, and the aqueous phase was extracted with DCM, dried, filtered, and concentrated to afford the crude product. Column chromatography (PE / EA = 100 / 1 to 3 / 1) afforded a light yellow solid (460 mg, 81.1% yield). ESI-MS m / z: 418.2 [M+H] + .

[0558] Step 3:

[0559] N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,1-diphenylmethanamine (460 mg, 1.10 mmol) and NH2OH.HCl (138 mg, 2 mmol) were dissolved in MeOH (15 mL) and reacted at 25°C for 2 h. LC-MS monitoring indicated that the reaction was complete. The mixture was then spin-dried and then dissolved in DCM, washed with water, and the aqueous phase was extracted with DCM. The organic phases were combined, dried, filtered, and concentrated to obtain the crude product. Column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) afforded a yellow solid (260 mg, 93.5% yield). ESI-MS m / z: 254.1 [M+H] + .

[0560] Step 4:

[0561] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (380 mg, 1.5 mmol) was dissolved in MeCN (35 mL). A solution of TMSN3 (0.48 mL, 3.7 mmol) in MeCN (2.5 mL) was added at 0°C. The mixture was stirred at 0°C for 0.5 h. A solution of tert-butyl nitrite (0.44 mL, 3.7 mmol) in MeCN (2.5 mL) was added dropwise. The mixture was stirred at 20°C for 6 h. The mixture was diluted with H2O (40 mL) and extracted with EA (40 mL x 2). The mixture was dried over Na2SO4, filtered, concentrated, and purified by column chromatography (PE / EA = 100 / 1 to 3 / 1) to afford Intermediate 80 (84 mg, 20% yield) as a light yellow solid. ESI-MS m / z: 280.1 [M+H] + .

[0562] Intermediate 81 can be synthesized by a similar method to that of Intermediate 80.

[0563] Preparation Example 46: Synthesis of Intermediate 82

[0564] Step 1:

[0565] 7-Chloro-5-nitro-2,3-dihydrofuro[2,3-c]pyridine (500 mg, 2.487 mmol), 4,4-difluoropiperidine hydrochloride (589 mg, 3.731 mmol), Cs2CO3 (2.4 g, 7.462 mmol), Pd2(dba)3 (113 mg, 0.124 mmol), and Xantphos (143 mg, 0.248 mmol) were dissolved in dioxane (20 mL) and reacted at 100°C under argon overnight. The reaction mixture was filtered and concentrated by column chromatography (PE / EA = 50 / 1 to 3 / 1) to afford a yellow solid (250 mg, 35% yield). ESI-MS m / z: 286.1 [M+H] + .

[0566] Step 2:

[0567] 7-(4,4-difluoropiperidin-1-yl)-5-nitro-2,3-dihydrofuro[2,3-c]pyridine (250 mg, 0.877 mmol), Fe (343 mg, 6.14 mmol), and NH4Cl (331 mg, 6.14 mmol) were dissolved in EtOH / H2O (2 / 1, 30 mL) and reacted at 80°C for 4 h. LC-MS monitoring confirmed the complete reaction. The reaction solution was concentrated, filtered, concentrated, and then purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford intermediate 2 (180 mg, 80% yield) as a yellow solid. ESI-MS m / z: 256.1 [M+H] + .

[0568] Step 3:

[0569] 4-(4,4-Difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridin-6-amine (383 mg, 1.5 mmol) was dissolved in MeCN (35 mL). A solution of TMSN3 (426 mg, 3.7 mmol) in MeCN (2.5 mL) was added at 0°C. The mixture was stirred at 0°C for 0.5 h. A solution of tert-butyl nitrite (382 mg, 3.7 mmol) in MeCN (2.5 mL) was added dropwise. The mixture was stirred at 20°C for 6 h. The mixture was diluted with H2O (40 mL) and extracted with EA (40 mL x 2). The mixture was dried over Na2SO4, filtered, concentrated, and purified by column chromatography (PE / EA = 100 / 1 to 3 / 1) to afford Intermediate 82 (76 mg, 18% yield) as a light yellow solid. ESI-MS m / z: 282.1 [M+H] + .

[0570] Intermediate 83 can be synthesized by a similar method to that of Intermediate 82.

[0571] Preparation Example 47: Synthesis of Intermediate 84

[0572] Step 1:

[0573] N-(tert-Butyl)-4-chloro-2,3-dihydrofuro[3,2-c]pyridin-6-amine (850 mg, 3.74 mmol), 4,4-difluoropiperidine hydrochloride (886 mg, 5.61 mmol), Cs2CO3 (3.6 g, 11.23 mmol), and Ruphos-Pd-G3 (313 mg, 0.374 mmol) were dissolved in dioxane (20 mL) and reacted at 110°C under argon overnight. The reaction solution was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to obtain a yellow liquid (1 g, 85% yield). ESI-MS m / z: 312.2 [M+H] + .

[0574] Step 2:

[0575] N-(tert-Butyl)-4-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridin-6-amine (900 mg, 2.89 mmol) was dissolved in TFA (10 mL) and reacted at 80°C for 1 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was concentrated, diluted with water, and the pH was adjusted to 7 with NaHCO₃. The product was extracted with EA, washed with water, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford Intermediate 4 as a yellow gum (737 mg, 100% yield). ESI-MS m / z: 256.1 [M+H] + .

[0576] Step 3:

[0577] 4-(4,4-Difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridin-6-amine (383 mg, 1.5 mmol) was dissolved in MeCN (35 mL). A solution of TMSN3 (426 mg, 3.7 mmol) in MeCN (2.5 mL) was added at 0°C. The mixture was stirred at 0°C for 0.5 h. A solution of tert-butyl nitrite (382 mg, 3.7 mmol) in MeCN (2.5 mL) was added dropwise. The mixture was stirred at 20°C for 6 h. The mixture was diluted with H2O (40 mL) and extracted with EA (40 mL x 2). The mixture was dried over Na2SO4, filtered, concentrated, and purified by column chromatography (PE / EA = 100 / 1 to 3 / 1) to afford Intermediate 84 (76 mg, 18% yield) as a light yellow solid. ESI-MS m / z: 282.1 [M+H] + .

[0578] Intermediate 85 can be synthesized by a similar method to that of Intermediate 84.

[0579] Preparation Example 48: Synthesis of Intermediate 86

[0580] Step 1:

[0581] 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (7.14 g, 20 mmol) was dissolved in ACN (10 mL), and tert-butyl hydrazinecarboxylate (2.91 g, 22 mmol) was added. The mixture was cooled under N2 and ice-bathed. TCFH (6.73 g, 24 mmol) and NMI (5.75 g, 70 mmol) were added and stirred at room temperature for 2 h. LC-MS monitoring indicated that the reaction was complete. The mixture was poured into ice water (100 mL) and extracted with EA (100 mL x 2). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (7.73 g, 82% yield). ESI-MS m / z: 472.1 [M+H] + .

[0582] Step 2:

[0583] Tert-butyl 2-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl)hydrazine-1-carboxylate (7.73 g, 16.4 mmmol) was dissolved in DCM (100 mL) and HCl / Dioxane (4.0 M, 20 mL) was added. The mixture was reacted at room temperature for 3 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was concentrated to obtain an off-white solid intermediate 86 (6.7 g, 100% yield). ESI-MS m / z: 372.1 [M+H] + .

[0584] Intermediates 87-88 can be synthesized by a similar method to that of Intermediate 86.

[0585] Preparation Example 49: Synthesis of Intermediate 89

[0586] Step 1:

[0587] 2-Bromo-1-fluoro-4-nitrobenzene (778 mg, 3.54 mmol) was dissolved in dioxane (20 mL), and 4,4-difluoropiperidine hydrochloride (837 mg, 5.31 mmol) was added. Cs2CO3 (3.4 g, 10.62 mmol) and Ruphos-pd-G3 (296 mg, 0.354 mmol) were then added. The atmosphere was purged with nitrogen five times and the temperature was raised to 90°C for overnight reaction. LC-MS monitoring indicated that the reaction was complete. The product was filtered, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 5 / 1) to afford a yellow solid (510 mg, 58% yield). ESI-MS m / z: 251.1 [M+H] + .

[0588] Step 2:

[0589] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (388 g, 2.0 mmol) and 6-(2-fluoro-5-nitrophenyl)-6-azaspiro[2.5]octane (500 g, 2.0 mmol) were dissolved in DMSO (10 mL). KCO (830 mg, 6.0 mmol) was added, and the mixture was heated to 110°C under nitrogen protection and allowed to react overnight. LC-MS monitoring indicated that the starting material had reacted completely. The mixture was poured into ice water and extracted with EA (50 mL x 2). The organic phases were combined, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 89 as a light yellow solid (424 mg, 50% yield). ESI-MS m / z: 425.2 [M+H] + .

[0590] Preparation Example 50: Synthesis of Intermediate 90

[0591] Step 1:

[0592] 2-Hydroxy-N-(4-nitro-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethane-1-sulfonamide (710 mg, 2 mmol) was dissolved in DCM (15 mL) along with p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol). DHP (420 mg, 5.0 mmol) was added under nitrogen and allowed to react at rt. LC-MS monitoring indicated the reaction was complete. The mixture was quenched with aqueous sodium bicarbonate (20 mL), extracted with DCM (30 mL x 2), dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1) to afford a red gum (700 mg, 80% yield). ESI-MS m / z: 440.2 [M+H] + .

[0593] Step 2:

[0594] 2-(tert-Butyldimethylsilyloxy)-N-(4-nitro-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethane-1-sulfonamide (700 mg, 1.6 mmol) was dissolved in ethanol / water (v / v = 5 / 1, 15 mL). Fe powder (448 mg, 8.0 mmol) and NH4Cl (430 mg, 8.0 mmol) were added. Under nitrogen, the temperature was raised to 80°C for 2 h. LC-MS confirmed the complete reaction. The product was filtered, concentrated under reduced pressure, extracted with EA, dried, concentrated, and stirred. Column chromatography (PE / EA = 10 / 1 to 2 / 1) afforded a tan solid (590 mg, 90% yield). ESI-MS m / z: 410.2 [M+H] + .

[0595] Step 3:

[0596] N-(4-Amino-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-sulfonamide (614 mg, 1.5 mmol) was dissolved in MeCN (20 mL). A solution of TMSN3 (426 mg, 3.7 mmol) in MeCN (2.5 mL) was added at 0°C. The mixture was stirred at 0°C for 0.5 h. A solution of tert-butyl nitrite (382 mg, 3.7 mmol) in MeCN (2.5 mL) was added dropwise. The mixture was stirred at 20°C for 6 h. The mixture was diluted with H2O (40 mL) and extracted with EA (40 mL*2). The mixture was dried over Na2SO4, filtered, concentrated, and purified by column chromatography (PE / EA = 100 / 1 to 3 / 1) to afford Intermediate 90 (490 mg, 75% yield) as a light yellow solid. ESI-MS m / z: 436.2 [M+H] +.

[0597] Intermediates 91-93 can be synthesized by a similar method to that of Intermediate 90.

[0598] Preparation Example 51: Synthesis of Intermediate 94

[0599] Step 1:

[0600] 4-Bromo-2-fluoro-1-nitrobenzene (4.40 g, 20 mmol) and 6-azaspiro[2.5]octane (2.95 g, 20 mmol) were added to K2CO3 (5.53 g, 40 mmol) and dissolved in DMSO. Under nitrogen, the mixture was heated to 60°C for 10 minutes, then to 90°C for 1 hour. LC-MS monitoring confirmed the complete reaction. The product was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1) to afford an orange-red solid (5.77 g, 92.8% yield). ESI-MS m / z: 311.0 [M+H] + .

[0601] Step 2:

[0602] 6-(5-Bromo-2-nitrophenyl)-6-azaspiro[2.5]octane (622 mg, 2.0 mmol) was dissolved in ethanol / water (V / V = 5 / 1, 15 mL). Fe powder (559 mg, 10.0 mmol) and NH4Cl (535 mg, 10.0 mmol) were added. Under nitrogen, the temperature was raised to 80°C and the reaction was allowed to proceed for 2 h. LC-MS confirmed the complete reaction. The product was filtered, concentrated under reduced pressure, extracted with EA, dried, concentrated, and stirred. Column chromatography (PE / EA = 10 / 1 to 2 / 1) afforded a tan solid (506 mg, 90% yield). ESI-MS m / z: 281.1 [M+H] + .

[0603] Step 3:

[0604] 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)aniline (422 mg, 1.5 mmol) was dissolved in 6 M HCl (2.6 mL, 16 mmol) and cooled to 0°C with an ice bath. A solution of NaNO₂ (0.14 g, 2.1 mmol) in H₂O (1 mL) was added. After stirring at 0°C for 15 min, a solution of KI (1.0 g, 6.2 mmol) in H₂O (4.5 mL) was added and stirred for approximately 15 min. After addition, the mixture was heated to 25°C and stirred for 2 h. LC-MS confirmed the complete reaction. Extraction was performed with EA (25 mL x 2). The combined organic phases were washed with saturated NaHCO₃ (15 mL x 2) and saturated brine, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a light yellow solid (294 mg, 50% yield). ESI-MS m / z: 391.9 [M+H]. + .

[0605] Step 4:

[0606] 6-(5-Bromo-2-iodophenyl)-6-azaspiro[2.5]octane (1.57 g, 4.0 mmol) was dissolved in THF (50 mL). Ethynyltrimethylsilane (491 mg, 5.0 mmol), Pd(Ph3P)2Cl2 (281 mg, 0.4 mmol), CuI (76 mg, 0.4 mmol), and TEA (1.21 g, 12.0 mmol) were added and reacted at 50°C for 7 h. LC-MS monitoring confirmed the complete reaction of the starting material. The crude product was concentrated and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a light yellow solid (652 mg, 45% yield). ESI-MS m / z: 362.1 [M+H] + .

[0607] Step 5:

[0608] 6-(5-Bromo-2-((trimethylsilyl)ethynyl)phenyl)-6-azaspiro[2.5]octane (362 mg, 1.0 mmol) was dissolved in MeOH (10 mL), and K2CO3 (276 mg, 2.0 mmol) was added. The reaction was allowed to proceed at room temperature for 5 h. LC-MS monitoring indicated that the reaction was complete. The reaction mixture was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford intermediate 94 (150 mg, 51% yield) as a light yellow solid. ESI-MS m / z: 290.1 ​​[M+H] + .

[0609] Intermediates 95-96 can be synthesized by a similar method to that of Intermediate 94.

[0610] Preparation Example 52: Synthesis of Intermediate 97

[0611] Step 1:

[0612] 4-Bromo-2-(spiro[2.5]oct-5-en-6-yl)benzoic acid (614 mg, 2 mmol) was dissolved in ACN (10 mL), and tert-butyl hydrazinecarboxylate (291 mg, 2.2 mmol) was added. The mixture was cooled under N2 and cooled on ice. TCFH (673 mg, 2.4 mmol) and NMI (575 mg, 7 mmol) were added and stirred at room temperature for 2 h. LC-MS monitoring indicated that the reaction was complete. The mixture was poured into ice water (100 mL) and extracted with EA (20 mL x 2). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (673 mg, 80% yield). ESI-MS m / z: 472.1 [M+H] + .

[0613] Step 2:

[0614] Tert-butyl 2-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl)hydrazine-1-carboxylate (673 g, 1.6 mmmol) was dissolved in DCM (15 mL) and HCl / Dioxane (4.0 M, 5 mL) was added. The mixture was reacted at room temperature for 3 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was concentrated to afford an off-white solid intermediate 97 (572 mg, 100% yield). ESI-MS m / z: 321.1 [M+H] + .

[0615] Preparation Example 53: Synthesis of Intermediate 98

[0616] Step 1:

[0617] 4,4,5,5,5-Tetramethyl-2-spiro[2.5]octane-5-en-6-yl-1,3,2-dioxaborolane (1.17 g, 5.0 mmol), K2CO3 (2.12 g, 10.0 mmol), Pd(dppf)2Cl2 (366 mg, 0.5 mmol), and 4-bromo-2-iodo-1-nitrobenzene (1.64 g, 5.0 mmol) were sequentially added to dioxane (50 mL). Under argon, the reaction was incubated at 100°C for 1 hour. The reaction mixture was quenched with water (100 mL). Extraction was performed with EA (50 mL x 2). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA = 100 / 1 to 10 / 1) to give a light yellow solid (1.08 mg, yield 70%). ESI-MS m / z: 308.0 [M+H] + .

[0618] Step 2:

[0619] 6-(5-Bromo-2-nitrophenyl)spiro[2.5]oct-5-ene (616 mg, 2.0 mmol) was dissolved in ethanol / water (v / v = 5 / 1, 15 mL). Fe powder (559 mg, 10.0 mmol) and NH4Cl (535 mg, 10.0 mmol) were added. Under nitrogen, the mixture was heated to 80°C for 2 h. LC-MS confirmed the complete reaction. The product was filtered, concentrated under reduced pressure, extracted with EA, dried, concentrated, and stirred. Column chromatography (PE / EA = 20 / 1 to 5 / 1) afforded a tan solid (529 mg, 95% yield). ESI-MS m / z: 278.1 [M+H] + .

[0620] Step 3:

[0621] 4-Bromo-2-(spiro[2.5]oct-5-en-6-yl)aniline (417 mg, 1.5 mmol) was dissolved in MeCN (20 mL). A solution of TMSN3 (426 mg, 3.7 mmol) in MeCN (2.5 mL) was added at 0°C. The mixture was stirred at 0°C for 0.5 h. A solution of tert-butyl nitrite (382 mg, 3.7 mmol) in MeCN (2.5 mL) was added dropwise. The mixture was stirred at 20°C for 6 h. The mixture was diluted with H2O (40 mL) and extracted with EA (40 mL x 2). The mixture was dried over Na2SO4, filtered, concentrated, and purified by column chromatography (PE / EA = 100 / 1 to 3 / 1) to afford Intermediate 98 (198 mg, 65% yield) as a light yellow solid. ESI-MS m / z: 304.0 [M+H] + .

[0622] Preparation Example 54: Synthesis of Intermediate 99

[0623] Step 1:

[0624] 4-Bromo-2-(spiro[2.5]oct-5-en-6-yl)aniline (417 mg, 1.5 mmol) was dissolved in 6 M HCl (2.6 mL, 16 mmol) and cooled to 0°C with an ice bath. A solution of NaNO₂ (0.14 g, 2.1 mmol) in H₂O (1 mL) was added. After stirring at 0°C for 15 minutes, a solution of KI (1.0 g, 6.2 mmol) in H₂O (4.5 mL) was added over approximately 15 minutes. After addition, the mixture was heated to 25°C and stirred for 2 hours. LC-MS confirmed the complete reaction. Extraction was performed with EA (25 mL x 2). The combined organic phases were washed with saturated NaHCO₃ (15 mL x 2) and saturated brine, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a light yellow solid (292 mg, 50% yield).

[0625] Step 2:

[0626] 6-(5-Bromo-2-iodophenyl)spiro[2.5]oct-5-ene (1.56 g, 4.0 mmol) was dissolved in THF (50 mL), and ethynyltrimethylsilane (491 mg, 5.0 mmol), Pd(Ph3P)2Cl2 (281 mg, 0.4 mmol), CuI (76 mg, 0.4 mmol), and TEA (1.21 g, 12.0 mmol) were added. The mixture was reacted at 50°C for 7 h. LC-MS monitoring confirmed the complete reaction of the starting material. The crude product was concentrated and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a light yellow solid (618 mg, 43% yield).

[0627] Step 3:

[0628] (4-Bromo-2-(spiro[2.5]oct-5-en-6-yl)phenyl)ethynyl)trimethylsilane (359 mg, 1.0 mmol) was dissolved in MeOH (10 mL), and K2CO3 (276 mg, 2.0 mmol) was added. The reaction was allowed to proceed at room temperature for 5 h. After monitoring by LC-MS, the reaction was completed. The reaction mixture was filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to give a light yellow solid intermediate 99 (140 mg, 49% yield).

[0629] Preparation Example 55: Synthesis of Intermediate 100

[0630] Step 1:

[0631] 4-Nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (387 mg, 1.4 mmol) was dissolved in ACN (10 mL), and tert-butyl hydrazinecarboxylate (204 mg, 1.54 mmol) was added. The mixture was cooled under N2 and ice-bath. TCFH (471 mg, 1.68 mmol) and NMI (402 mg, 4.9 mmol) were added. The reaction was stirred at room temperature for 2 h. LC-MS monitoring indicated that the reaction was complete. The mixture was poured into ice water (30 mL) and extracted with EA (20 mL x 2). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (465 mg, 85% yield). ESI-MS m / z: 391.2 [M+H] + .

[0632] Step 2:

[0633] Tert-butyl 2-(4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoyl)hydrazine-1-carboxylate (465 mg, 1.19 mmol) was dissolved in DCM (10 mL) and HCl / Dioxane (4.0 M, 5 mL) was added. The mixture was reacted at room temperature for 3 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was concentrated to obtain an off-white solid intermediate 100 (389 mg, 100% yield). ESI-MS m / z: 291.1 [M+H] + .

[0634] Example 1: Synthesis of N-(4-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (Compound 1)

[0635] Step 1: Preparation of N-(4-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0636] 4-(4,4-Difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridin-6-amine (Intermediate 5, 128 mg, 0.5 mmol) was dissolved in THF and cooled on ice under N2 protection. NaH (100 mg, 2.5 mmol) was added and stirred at room temperature for 1 h. 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (Intermediate 24, 206 mg, 0.5 mmol) was added and allowed to react overnight at room temperature. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (10 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford a light yellow solid (210 mg, 71% yield). ESI-MS m / z: 595.1 [M+H]. + .

[0637] Step 2: Preparation of N-(4-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0638] N-(4-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Intermediate A1-1, 210 mg, 0.354 mmol), 2-hydroxyethane-1-sulfonamide (89 mg, 0.708 mmol), CuI (67 mg, 0.354 mmol), K3PO4 (150 mg, 0.708 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (25 mg, 0.177 mmol) was dissolved in DMF (10 mL) under N2 protection and allowed to react overnight at 100°C. LC-MS monitoring indicated complete reaction. The mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, dried, concentrated, purified by reverse phase chromatography, and lyophilized to afford Compound A1 (100 mg, 48% yield) as a light yellow solid.

[0639] 1H NMR (400MHz, DMSO-d6) δ: 12.76 (s, 1H), 10.15 (S, 1H), 8.04 (d, J = 8.6Hz, 1H), 7.30 (s,1H),7.25(d,J=1.9Hz,1H),7.11(dd,J=8.6,1.9Hz,1H),4.94(s,1H),4.60(t, J=8.6Hz,2H),3.76(t,J=6.4Hz,2H),3.69-3.58(m,4H),3.39-3.34(m,2H),3.23( t,J=8.6Hz,2H),2.97(s,4H),2.09-1.96(m,4H),1.71(s,4H),0.38(s,4H).ESI-MS m / z:592.2[M+H] + .

[0640] Example 2-11: Synthesis of Compounds A2-A11

[0641] Intermediate 10, intermediate 12, intermediate 14, intermediate 17, intermediate 18, intermediate 20, intermediate 21, intermediate 22, intermediate 3, and intermediate 6 were used as raw materials and reacted with intermediate 24 respectively, and the target compounds A2-A11 were obtained according to a similar synthesis method in Example 1.

[0642] Example 12: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-methoxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound A12)

[0643] Step 1: Preparation of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0644] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 253 mg, 1.0 mmol) was dissolved in THF (15 mL) and cooled under N2 protection. NaH (60% in oil, 200 mg, 5.0 mmol) was added and stirred at room temperature for 1 h. 4-Nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (Intermediate 37, 331 mg, 1.0 mmol) was added under ice-cooling. The reaction was allowed to proceed overnight at room temperature. LC-MS monitoring confirmed the complete reaction of the starting material. The product was poured into ice water (10 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford a light yellow solid (363 mg, 71% yield). ESI-MS m / z: 512.2 [M+H] + .

[0645] Step 2: 4-amino-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0646] N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (363 mg, 0.71 mmol) obtained in the previous step was dissolved in EtOH / H₂O (5 / 1, 10 mL). Iron powder (238 mg, 4.26 mmol) and NH₄Cl (228 mg, 4.26 mmol) were added. The mixture was refluxed at 80°C under N₂ protection for 1 h. LC-MS monitoring indicated that the reaction was complete. The mixture was filtered, and the filtrate was diluted with water (40 mL). The mixture was extracted with EA (40 mL x 3). The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford a light yellow solid (330 mg, 97% yield). ESI-MS m / z: 482.2 [M+H] + .

[0647] Step 3: Preparation of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-methoxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0648] 4-Amino-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Intermediate A12-2, 241 mg, 0.5 mmol) was dissolved in DCM (10 mL). TEA (152 mg, 1.5 mol) was added. Under N2 protection, the mixture was cooled to 0°C in an ice bath. A solution of 2-methoxyethane-1-sulfonyl chloride (95 mg, 0.6 mmol) in DCM was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. LC-MS monitoring confirmed the complete reaction. The product was washed with water, extracted with DCM, dried, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford Compound A12 (136 mg, 45% yield) as a light yellow solid.

[0649] 1 H NMR (400MHz, DMSO-d6) δ: 12.88 (s, 1H), 8.18 (d, J = 8.7Hz, 1H), 8.07 (d, J = 2.2Hz, 1H), 7.96 (s, 1H), 7.30 (d, J = 2.2Hz, 1H), 7.15 (dd, J = 8.7, 2.1Hz, 1H),7.01(d,J=2.1Hz,1H),4.03(s,4H),3.77(t,J=6.5Hz,2H),3.52(s,3H),3.3 3-3.32(m,2H),2.96(s,4H),2.18-2.06(m,4H),1.78(s,4H),0.40(s,4H); ESI-MS m / z:604.2[M+H] + .

[0650] Example 13: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-(methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound A13)

[0651] Step 1: Preparation of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0652] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 127 mg, 0.5 mmol) was dissolved in THF and cooled on ice under N2 protection. NaH (100 mg, 2.5 mmol) was added and stirred at room temperature for 1 h. 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (Intermediate 24, 206 mg, 0.5 mmol) was added after addition and allowed to react at room temperature overnight. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (10 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford a light yellow solid (210 mg, 71% yield). ESI-MS m / z: 593.1 [M+H] + .

[0653] Step 2: Preparation of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-(methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0654] N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Intermediate A13-1, 296 mg, 0.5 mmol), methanesulfonamide (95 mg, 1.0 mmol), CuI (95 mg, 0.5 mmol), K3PO4 (212 mg, 1 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (36 mg, 0.25 mmol) was dissolved in DMF (10 mL) and reacted at 100°C overnight under N2 protection. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (40 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound A13 (110 mg, 39% yield) as a light yellow solid.

[0655] 1H NMR (400MHz, DMSO-d6) δ: 12.59 (s, 1H), 8.15 (d, J = 8.7Hz, 1H), 8.05 (d, J = 2.2Hz, 1H), 7.98 (s, 1H), 7.23 (d, J = 2.2Hz, 1H), 7.10 (dd, J = 8. 7, 2.1Hz, 1H), 6.97 (d, J = 2.1Hz, 1H), 3.68 (s, 4H), 2.96 (s, 4H), 2.46 (s, 3H), 2.15-2.02 (m, 4H), 1.85-1.45 (m, 4H), 0.38 (s, 4H); ESI-MS m / z:560.2[M+H] + .

[0656] Examples 14-15: Synthesis of Compounds A14-A15

[0657] Intermediate A13-1 was reacted with different sulfonamides to obtain target compounds A14-A15 according to a similar synthesis method in Example 13.

[0658] Example 16: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound A16)

[0659] N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Intermediate A13-1, 163 mg, 0.275 mmol), 2-amino-2-methylpropane-1-ol (49 mg, 0.55 mmol), t- BuXPhos-Pd-G3(21mg,0.0275mmol), t- BuONa (78 mg, 0.825 mmol) was dissolved in dioxane (10 mL) and reacted at 90°C overnight under N2 protection. LC-MS monitoring indicated complete reaction. The product was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and purified by column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to afford Compound A16 (45 mg, 30% yield) as a light yellow solid.

[0660] 1H NMR (400MHz, DMSO-d6) δ: 12.71 (s, 1H), 8.15 (d, J = 8.6Hz, 1H), 7.98 (d, J = 2.3Hz, 1H), 7.86 (s, 1H), 7.30 (d, J = 2.2Hz, 1H), 7.08 (d, J = 2.2Hz, 1H), 6. 98(dd,J=8.6,2.1Hz,1H),3.76(s,2H),3.21-3.13(m,4H),3.05(t,J=5.1 Hz,4H),2.19-2.02(m,4H),1.65(s,4H),1.16(s,6H),0.39(s,4H); ESI-MS m / z:554.3[M+H] + .

[0661] Example 17: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-(isopropylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound A17)

[0662] Step 1: N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-(isopropylthio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0663] N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Intermediate A13-1, 592 mg, 1.0 mmol), XantPhos (58 mg, 0.1 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), DIPEA (259 mg, 2.0 mmol), and propane-2-thiol (114 mg, 1.5 mmol) were dissolved in dioxane under N2 protection and heated to 80°C overnight. LC-MS monitoring revealed a slight residual starting material. The product was then concentrated and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (300 mg, 55% yield). ESI-MS m / z: 541.3 [M+H] + .

[0664] Step 2: N-(7-(4,4-difluoropiperidin-1-yl)furfuryl[2,3-c]pyridin-5-yl)-4-(isopropylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0665] N-(6-(4,4-difluoropiperidin-1-yl)-5-methoxypyridin-2-yl)-4-(isopropylthio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (300 mg, 0.554 mmol) obtained in the previous step was dissolved in dioxane (12 mL). A solution of potassium monopersulfate (682 mg, 1.11 mmol) in water (5 mL) was added and stirred at room temperature overnight. LC-MS monitoring indicated that the starting material had essentially reacted. The product was then concentrated and purified by column chromatography (PE / EA = 20 / 1 to 1 / 1) to afford Compound A17 (120 mg, 38% yield) as a light yellow solid.

[0666] 1 H NMR (400MHz, DMSO-d6) δ: 12.95 (s, 1H), 8.17 (d, J = 8.7Hz, 1H), 8.07 (d, J = 2.2Hz, 1H), 7.92 (s, 1H), 7.88 (d, J = 2.2Hz, 1H), 7.02 (d, J = 2.2Hz, 1H), 6.96 ( dd,J=8.6,2.1Hz,1H),3.31-3.23(m,4H),3.22-3.15(m,1H),3.07(t,J=5. 1Hz,4H),2.21-2.06(m,4H),1.63(s,4H),1.38(s,6H),0.38(s,4H); ESI-MS m / z:573.2[M+H] + .

[0667] Example 18: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-(N-methylsulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound A18)

[0668] N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Intermediate A13-1, 296 mg, 0.5 mmol), n-butyldi(1-adamantyl)phosphine (36 mg, 0.1 mmol), and Pd(OAc)2 (22 mg, 0.1 mmol) were dissolved in IPA (8 mL). TEA (152 mg, 1.5 mmol) was added, and argon was bubbled through the mixture for 2 min. DABSO (120 mg, 0.5 mmol) was added, and the mixture was sealed. The reaction was carried out at 90°C for 3 h, cooled to room temperature, and NaClO2 solution (744 mg, 10%, 1.0 mmol) was added. Methylamine hydrochloride (68 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature overnight. LC-MS monitoring indicated that the starting materials were substantially reacted. The mixture was diluted with water (50 mL) and extracted with EA (50 mL*2). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH=100 / 1 to 10 / 1) to give a light yellow solid compound A18 (130 mg, yield 46%).

[0669] 1 H NMR(400MHz, DMSO-d6)δ:12.83(s,1H),8.12(d,J=8.6Hz,1H),8.01(d,J=2.2Hz,1H),7.96(s,1H),7.33(d,J=8.6Hz,1H),7.11(d,J= 2.2Hz,1H),7.02(dd,J=8.6,2.1Hz,1H),3.20-3.01(m,8H),2.49(s,3H),2.20-2.04(m,4H),1.75-1.45(m,4H),0.37(s,4H); ESI-MS m / z:560.2[M+H] + .

[0670] Example 19: Synthesis of Compound A19

[0671] According to the similar synthesis method in Example 18, isopropylamine was added to obtain the target compound A19.

[0672] Example 20: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-6-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Compound A20)

[0673] Step 1: 6-Bromo-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide

[0674] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 127 mg, 0.5 mmol) was dissolved in THF and cooled under N2 protection. NaH (60 mg, 1.5 mmol) was added and stirred at room temperature for 1 h. 6-Bromo-2-(6-azaspiro[2.5]octan-6-yl)nicotinoyl chloride (Intermediate 31, 183 mg, 0.5 mmol) was added and allowed to react overnight at room temperature. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (178 mg, 65% yield). ESI-MS m / z: 546.1 [M+H]. + .

[0675] Step 2: N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-6-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide

[0676] 6-Bromo-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (191 mg, 0.35 mmol), 2-hydroxyethane-1-sulfonamide (88 mg, 0.7 mmol), CuI (67 mg, 0.35 mmol), K3PO4 (149 mg, 0.7 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (25 mg, 0.175 mmol) was dissolved in DMF (10 mL) and reacted at 100°C overnight under N2 protection. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound A20 (85 mg, 41% yield) as a light yellow solid.

[0677] 1H NMR (400MHz, DMSO-d6) δ: 12.63 (s, 1H), 8.26 (d, J = 8.7Hz, 1H), 8.06 (d, J = 2.3Hz, 1H), 7.97 (s, 1H), 7.42 (d, J = 8.6Hz, 1H), 7.32 ( d,J=2.3Hz,1H),3.72(t,J=6.7Hz,2H),3.32(brs,2H),3.19-3.11(m,4H),2.98(brt,J=5.0Hz,4H),2.19-2.02(m,4H),1.62(br s,4H),0.36(s,4H); ESI-MS m / z:591.2[M+H] + .

[0678] Examples 21-23: Synthesis of Compounds A21-A23

[0679] Intermediate 1 was reacted with intermediate 32, intermediate 33 and intermediate 34 in sequence to obtain target compounds A21-A23 according to a similar synthesis method in Example 20.

[0680] Example 24: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound A24)

[0681] Step 1: N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-5-methyl-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0682] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 253 mg, 1.0 mmol) was dissolved in THF and cooled under N2 protection. NaH (120 mg, 3.0 mmol) was added and stirred at room temperature for 1 h. 5-Methyl-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (Intermediate 35, 345 mg, 1.0 mmol) was added after addition and allowed to react overnight at room temperature. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (368 mg, 70% yield). ESI-MS m / z: 526.2 [M+H] + .

[0683] Step 2: 4-amino-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0684] N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-5-methyl-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (368 mg, 0.70 mmol) was dissolved in EtOH / H₂O (5 / 1, 10 mL). Iron powder (235 mg, 4.2 mmol) and NH₄Cl (225 mg, 4.2 mmol) were added. The mixture was refluxed at 80°C under N₂ protection for 1 h. LC-MS monitoring indicated the reaction was complete. The mixture was filtered, the filtrate diluted with water (30 mL), and extracted with EA (30 mL x 3). The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford a light yellow solid (312 mg, 90% yield). ESI-MS m / z: 496.3 [M+H] + .

[0685] Step 3: Ethyl 2-(N-(4-((7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)carbamoyl)-2-methyl-5-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate

[0686] 4-Amino-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (248 mg, 0.5 mmol) was dissolved in DCM and TEA (152 mg, 1.5 mol) was added. Under N2 protection, the mixture was cooled to -10°C in an ice-salt bath. A solution of ethyl 2-(chlorosulfonyl)acetate (121 mg, 0.65 mmol) in DCM was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. LC-MS monitoring confirmed the complete reaction of the starting material. The product was washed with water, extracted with DCM, dried, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford a brown solid (180 mg, 56% yield). ESI-MS m / z: 646.3 [M+H] + .

[0687] Step 4: N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0688] Ethyl 2-(N-(4-((6-(4,4-difluoropiperidin-1-yl)-5-methoxypyridin-2-yl)carbamoyl)-2-methyl-5-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (160 mg, 0.25 mmol) was dissolved in anhydrous THF. Under N2 protection, the mixture was cooled to 0°C in an ice bath. LiAlH4 (1.0 M in THF, 0.5 mL, 0.50 mmol) was slowly added and the reaction was stirred at room temperature for 2 h. LC-MS monitoring indicated that the reaction was complete. The reaction was quenched with aqueous ammonium chloride, extracted with EA, dried, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to afford Compound A24 (90 mg, 60% yield) as a yellow solid.

[0689] 1 H NMR (400MHz, DMSO-d6) δ: 12.36 (s, 1H), 8.12 (d, J = 2.2Hz, 1H), 7.68 (s, 1H), 7. 45(s,1H),7.28(d,J=2.2Hz,1H),7.03(s,1H),3.79(t,J=6.7Hz,2H),3.30(br s,2H),3.22-3.11(m,4H),2.97(br t,J=5.0Hz,4H),2.51(s,3H),2.17-1.97(m,4H),1.67(br s,4H),0.38(s,4H); ESI-MS m / z:594.2[M+H] + .

[0690] Example 25: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound A25)

[0691] Step 1: 4-Bromo-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzamide

[0692] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 127 mg, 0.5 mmol) was dissolved in THF and cooled under N2 protection. NaH (60 mg, 1.5 mmol) was added and stirred at room temperature for 1 h. 4-Bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (Intermediate 36, 192 mg, 0.5 mmol) was added and stirred at room temperature overnight. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (200 mg, 71% yield). ESI-MS m / z: 563.1 [M+H]. + .

[0693] Step 2: N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)benzamide

[0694] 4-Bromo-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.355 mmol), 2-hydroxyethane-1-sulfonamide (89 mg, 0.71 mmol), CuI (68 mg, 0.355 mmol), K3PO4 (151 mg, 0.71 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (26 mg, 0.178 mmol) was dissolved in DMF (10 mL) under N2 protection and allowed to react overnight at 100°C. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound A25 (100 mg, 46% yield) as a light yellow solid.

[0695] 1H NMR(400MHz,DMSO-d6)δ:12.88(s,1H),8.10(d,J=2.2Hz,1H),8.01(s,1H),7 .38(d,J=2.2Hz,1H),7.15(dd,J=8.9,2.1Hz,1H),7.02(d,J=2.1Hz,1H),3.8 8(dd,J=7.2,4.3Hz,4H),3.75(t,J=6.5Hz,2H),3.38(t,J=6.5Hz,2H),2.92( t,J=5.3Hz,4H),2.20-2.03(m,4H),1.85-1.50(brs,4H),0.38(s,4H); ESI-MS m / z:608.2[M+H] + .

[0696] Examples 26-27: Synthesis of Compounds A26-A27

[0697] Intermediate 2, intermediate 14 and intermediate 36 were reacted in sequence to obtain target compounds A26-A27 according to a similar synthesis method in Example 25.

[0698] Example 28: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-fluoro-4-((1-methylethyl)sulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound A28)

[0699] 4-Bromo-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.355 mmol), propane-2-sulfonamide (87 mg, 0.71 mmol), CuI (68 mg, 0.355 mmol), K3PO4 (151 mg, 0.71 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (26 mg, 0.178 mmol) was dissolved in DMF (10 mL) under N2 protection and allowed to react overnight at 100°C. LC-MS monitoring indicated complete reaction. The mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound A28 (120 mg, 46% yield) as a light yellow solid.

[0700] 1H NMR (400MHz, DMSO-d6) δ: 12.75 (s, 1H), 8.14 (d, J = 2.2Hz, 1H), 8.03 (s, 1H), 7.4 2(d,J=2.2Hz,1H),7.26(dd,J=8.9,2.1Hz,1H),7.01(d,J=2.1Hz,1H),3.43(p, J=6.7Hz,1H),3.11(t,J=5.5Hz,4H),2.91(t,J=5.3Hz,4H),2.10(dt,J=14.2,8 .1Hz,4H),1.85-1.50(brs,4H),1.29(s,3H),1.27(s,3H),0.37(s,4H); ESI-MS m / z:606.2[M+H] + .

[0701] Example 29: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-(4,4-tetramethylpiperidin-1-alkyl)-4-((2-hydroxyethyl)sulfonamido)benzamide (Compound A29)

[0702] Step 1: N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-(4,4-tetramethylpiperidin-1-alkyl)-4-iodobenzamide

[0703] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 127 mg, 0.5 mmol) was dissolved in THF and cooled under N2 on ice. NaH (60 mg, 1.5 mmol) was added and stirred at room temperature for 1 h. 2-(4,4-Dimethylpiperidin-1-yl)-4-iodobenzoyl chloride (Intermediate 25, hydrochloride, 207 mg, 0.5 mmol) was added on ice. The reaction was allowed to proceed overnight at room temperature. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (155 mg, 52% yield). ESI-MS m / z: 595.2 [M+H] + .

[0704] Step 2: N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-(4,4-tetramethylpiperidin-1-alkyl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0705] The N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-(4,4-tetramethylpiperidin-1-alkyl)-4-iodobenzamide (155 mg, 0.261 mmol), 2-hydroxyethane-1-sulfonamide (65 mg, 0.522 mmol), CuI (50 mg, 0.261 mmol), K3PO4 (111 mg, 0.522 mmol), (1R,2R)-N 1 ,N 2 Dimethylcyclohexane-1,2-diamine (19 mg, 0.133 mmol) was dissolved in DMF (8 mL) under N2 protection and allowed to react overnight at 100°C. LC-MS monitoring indicated complete reaction. The product was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound A29 (50 mg, 32% yield) as a light yellow solid.

[0706] 1 H NMR(400MHz, DMSO-d6)δ:12.93(s,1H),8.21(d,J=8.7Hz,1H),8.07(d,J=2.3Hz,1H),8 .02(s,1H),7.31(d,J=2.2Hz,1H),7.15(dd,J=8.7,2.2Hz,1H),7.05(d,J=2.Hz,1H),3 .76(t,J=6.6Hz,2H),3.33-3.30(m,4H),2.96(t,J=5.3Hz,4H),2.78(t,J=9.2Hz,2H), 1.98(d,J=12.8Hz,2H),1.87(d,J=12.8Hz,2H),1.71-1.50(m,4H),1.03(s,6H); ESI-MS m / z:592.2[M+H] + .

[0707] Examples 30-34: Synthesis of Compounds A30-A34

[0708] Target compounds A30-A34 were obtained according to a similar synthetic method in Example 29.

[0709] Example 35: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(4-methoxy-4-methylpiperidin-1-ylbenzamide (Compound A35)

[0710] Step 1: N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-4-iodo-2-(4-methoxy-4-methylpiperidin-1-ylbenzamide

[0711] 7-(4,4-Difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-amine (Intermediate 2, 128 mg, 0.5 mmol) was dissolved in THF and cooled under N2 on ice. NaH (60 mg, 1.5 mmol) was added and stirred at room temperature for 1 h. 2-(4-methoxy-4-methylpiperidin-1-yl)-4-iodobenzoyl chloride (Intermediate 28, hydrochloride, 215 mg, 0.5 mmol) was added on ice. The reaction was allowed to proceed overnight at room temperature. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (155 mg, 52% yield). ESI-MS m / z: 595.2 [M+H] + .

[0712] Step 2: N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(4-methoxy-4-methylpiperidin-1-yl)benzamide

[0713] The N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-4-iodo-2-(4-methoxy-4-methylpiperidin-1-ylbenzamide (160 mg, 0.261 mmol), 2-hydroxyethane-1-sulfonamide (65 mg, 0.522 mmol), CuI (50 mg, 0.261 mmol), K3PO4 (111 mg, 0.522 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (19 mg, 0.133 mmol) was dissolved in DMF (8 mL) and reacted at 100°C overnight under N2 protection. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound A35 (50 mg, 32% yield) as a light yellow solid.

[0714] 1H NMR(400MHz, DMSO-d6)δ:12.21(s,1H),8.01(d,J=8.6Hz,1H),7.78(s,1H),7.22(d,J=2 .2Hz,1H),7.10(dd,J=8.6,2.0Hz,1H),4.57(t,J=8.8Hz,2H),3.76(t,J=6.5Hz,2H),3.6 2(t,J=5.8Hz,4H),3.45-3.30(m,2H),3.19(t,J=8.9Hz,2H),3.16(s,3H),2.99(t,J=10 .6Hz,2H),2.92-2.81(m,2H),2.10-1.89(m,6H),1.87-1.74(m,2H),1.19(s,3H); ESI-MS m / z:610.2[M+H] + .

[0715] Examples 36-37: Synthesis of Compounds A36-A37

[0716] According to the similar synthetic method in Example 35, Intermediate 2, Intermediate 6 and Intermediate 29 were respectively used to obtain the target compounds A36-A37.

[0717] Example 38: Synthesis of 2-(N-(4-(4-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)aminosulfonyl)ethyl dimethylglycinate (Compound A38)

[0718] To a solution of N-(4-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound A1, 193 mg, 0.327 mmol) and acetic acid (170 mg, 1.64 mmol) in THF (10 mL) was added 3-nitro-1,2,4-triazole (93 mg, 0.818 mmol), BOPCl (208 mg, 0.818 mmol), and DIPEA (212 mg, 1.64 mmol). The mixture was allowed to react at room temperature for 2 h. LC-MS monitoring indicated complete reaction of the starting material. The mixture was poured into ice water (30 mL), extracted with EA (20 mL*2), and the organic phases were combined, dried, concentrated, and purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / ACN) to give a light yellow solid compound A38 (120 mg, yield 54%).

[0719] 1H NMR(400MHz, DMSO-d6)δ:12.71(s,1H),8.04(d,J=8.6Hz,1H),7.30(s,1H),7.21(d,J=2.1Hz,1H),7.10(dd,J=8.6,2.1Hz,1H),4.59(t,J=8.6H z,2H),4.34(t,J=5.6Hz,2H),3.67-3.58(m,6H),3.22(t,J=8.6Hz,4H),3.03-2.87(m,7H),2.17(s,6H),2.09-1.96(m,5H),0.37(s,4H); ESI-MS m / z:677.3[M+H] + .

[0720] Examples 39-49: Synthesis of Compounds A39-A49

[0721] Target compounds A39-A49 were obtained according to a similar synthetic method as in Example 38.

[0722] Example 50: Synthesis of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (Compound B1)

[0723] Step 1: Preparation of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)-4-iodobenzamide

[0724] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 127 mg, 0.5 mmol) was dissolved in THF and cooled on ice under N2 protection. NaH (100 mg, 2.5 mmol) was added and stirred at room temperature for 1 h. 2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzoyl chloride (Intermediate 39, 217 mg, 0.5 mmol) was added on ice. The reaction was allowed to proceed overnight at room temperature. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (10 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford Intermediate 1-1 (217 mg, 71% yield) as a light yellow solid. ESI-MS m / z: 593.1 [M+H] + .

[0725] Step 2: Preparation of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0726] 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)-4-iodobenzamide (Intermediate B1-1, 217 mg, 0.354 mmol), 2-hydroxyethane-1-sulfonamide (89 mg, 0.708 mmol), CuI (67 mg, 0.354 mmol), K3PO4 (150 mg, 0.708 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (25 mg, 0.177 mmol) was dissolved in DMF (10 mL) under N2 protection and allowed to react overnight at 100°C. LC-MS monitoring confirmed the complete reaction. The product was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, dried, concentrated, purified by reverse phase chromatography, and lyophilized to afford Compound B1 (108 mg, 50% yield) as a light yellow solid.

[0727] 1 H NMR (400MHz, DMSO-d6) δ: 12.45 (s, 1H), 10.21 (s, 1H), 8.07 (dd, J = 8.3, 5.3Hz, 2H), 7.96 (s, 1H), 7.13 (dd, J = 15.9, 7.4Hz, 2H), 7.00 (d, J = 1.8Hz, 1H),4.94(s,1H),3.90(s,4H),3.76(s,2H),3.36(d,J=6.5Hz,2H),3.00(t,J=4.8Hz,4H),2.55(s,4H),2.08-1.96(m,4H); ESI-MS m / z:612.2[M+H] + .

[0728] Examples 51-69: Synthesis of Compounds B2-B20

[0729] Intermediate 2, intermediate 4, intermediate 5, intermediate 7-intermediate 16, intermediate 18-intermediate 23 were used as raw materials and reacted with intermediate 39 respectively, and the target compounds B2-B20 were obtained according to a similar synthesis method in Example 50.

[0730] Example 70: Synthesis of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)-4-((2-methoxyethyl)sulfonamido)benzamide (Compound B21)

[0731] Step 1: Preparation of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-nitrobenzamide

[0732] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 253 mg, 1.0 mmol) was dissolved in THF (15 mL) and cooled under N2 protection. NaH (60% in oil, 200 mg, 5.0 mmol) was added and stirred at room temperature for 1 h. 2-(4-(difluoromethylene)piperidin-1-yl)-4-nitrobenzoyl chloride (Intermediate 50, 316 mg, 1.0 mmol) was added under ice-cooling. The reaction was allowed to proceed overnight at room temperature. LC-MS monitoring confirmed the complete reaction of the starting material. The product was poured into ice water (10 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford a light yellow solid (373 mg, 70% yield). ESI-MS m / z: 534.2 [M+H]. + .

[0733] Step 2: 4-amino-2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)benzamide

[0734] 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-nitrobenzamide (373 mg, 0.70 mmol) obtained in the previous step was dissolved in EtOH / H₂O (5 / 1, 10 mL). Iron powder (235 mg, 4.2 mmol) and NH₄Cl (225 mg, 4.2 mmol) were added. The reaction was refluxed at 80°C under N₂ protection for 1 h. LC-MS monitoring indicated that the reaction was complete. The mixture was filtered, and the filtrate was diluted with water (40 mL). The mixture was extracted with EA (40 mL x 3). The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford a light yellow solid (330 mg, 95% yield). ESI-MS m / z: 504.2 [M+H] + .

[0735] Step 3: Preparation of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-methoxyethyl)sulfonamido)benzamide

[0736] 4-Amino-2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)benzamide (Intermediate 21-2, 251 mg, 0.5 mmol) was dissolved in DCM (10 mL) and TEA (152 mg, 1.5 mol) was added. Under N2 protection, the mixture was cooled to 0°C in an ice bath. A solution of 2-methoxyethane-1-sulfonyl chloride (95 mg, 0.6 mmol) in DCM was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. LC-MS monitoring confirmed the complete reaction of the starting material. The product was washed with water, extracted with DCM, dried, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford Compound B21 (188 mg, 60% yield) as a light yellow solid.

[0737] 1 H NMR(400MHz, DMSO-d6)δ:12.55(s,1H),8.18(d,J=8.7Hz,1H),8.07(d,J=2.3Hz,1H),7.96(s,1H),7.16(dd,J=8.7,2.3Hz,2H),7.01(d,J =2.2Hz,1H),3.97(s,4H),3.77(s,2H),3.52(s,3H),3.36(d,J=6.5Hz,2H),2.96(t,J=4.8Hz,4H),2.56(s,4H),2.08-1.98(m,4H); ESI-MS m / z:626.2[M+H] + .

[0738] Example 71: Synthesis of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-fluoroethyl)sulfonamido)benzamide (Compound B22)

[0739] Intermediate B21-2 and 2-fluoroethyl-1-sulfonyl chloride were used as raw materials (synthesis reference CN105622469) and the target compound B22 was obtained according to a similar synthesis method in Example 70.

[0740] Example 72: Synthesis of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)-4-(methylsulfonamido)benzamide (Compound B23)

[0741] 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-iodobenzamide (Intermediate B1-1, 307 mg, 0.5 mmol), methanesulfonamide (95 mg, 1.0 mmol), CuI (95 mg, 0.5 mmol), K3PO4 (212 mg, 1 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (36 mg, 0.25 mmol) was dissolved in DMF (10 mL) under N2 protection and allowed to react overnight at 100°C. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (40 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound B23 (131 mg, 45% yield) as a light yellow solid.

[0742] 1 H NMR (400MHz, DMSO-d6) δ: 12.58 (s, 1H), 8.12 (d, J = 8.7Hz, 1H), 8.04 (d, J = 2.2Hz, 1H), 7.99 (s, 1H), 7.25 (d, J = 2.2Hz, 1H), 7.09 (dd, J=8.7,2.1Hz,1H),6.99(d,J=2.1Hz,1H),3.87(s,4H),2.96(t,J=4.8Hz,4H),2.56(s,4H),2.47(s,3H),2.07-1.96(m,4H); ESI-MS m / z:582.2[M+H] + .

[0743] Examples 73-77: Synthesis of Compounds B24-B28

[0744] Intermediate B1-1 was reacted with different sulfonamides to obtain target compounds B24-B28 according to a similar synthetic method in Example 72.

[0745] Example 78: Synthesis of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)-4-((1-hydroxy-2-methylpropan-2-yl)amino)benzamide (Compound B29)

[0746] 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-iodobenzamide (Intermediate B1-1, 169 mg, 0.275 mmol), 2-amino-2-methylpropane-1-ol (49 mg, 0.55 mmol), t- BuXPhos-Pd-G3(21mg,0.0275mmol), t- BuONa (78 mg, 0.825 mmol) was dissolved in dioxane (10 mL) and reacted at 90°C overnight under N2 protection. LC-MS monitoring indicated complete reaction. The mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and purified by column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to afford Compound B29 (40 mg, 25% yield) as a light yellow solid.

[0747] 1 H NMR(400MHz, DMSO-d6)δ:12.28(s,1H),8.18(d,J=8.6Hz,1H),7.99(d,J=2.3Hz,1H),7.78(s,1H),7.29(d,J=2.2Hz,1H),7.06(d,J=2.2Hz,1H) ,6.98(dd,J=8.6,2.1Hz,1H),3.45(s,2H),3.21-3.13(m,4H),3.05(t,J=5.1Hz,4H),2.19-2.02(m,4H),1.75-1.66(m,4H),1.16(s,6H); ESI-MS m / z:576.3[M+H] + .

[0748] Example 79: Synthesis of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)-4-(isopropylsulfonyl)benzamide (Compound B30)

[0749] Step 1: 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-(isopropylthio)benzamide

[0750] 2-(4-(Difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-iodobenzamide (Intermediate B1-1, 614 mg, 1.0 mmol), XantPhos (58 mg, 0.1 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), DIPEA (259 mg, 2.0 mmol), and propane-2-thiol (114 mg, 1.5 mmol) were dissolved in dioxane under N2 protection and heated to 80°C overnight. LC-MS monitoring revealed a slight residual starting material. The product was then concentrated and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (281 mg, 50% yield). ESI-MS m / z: 563.2 [M+H] + .

[0751] Step 2: 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)-4-(isopropylsulfonyl)benzamide

[0752] 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-(isopropylthio)benzamide (281 mg, 0.5 mmol) obtained in the previous step was dissolved in dioxane (12 mL). A solution of potassium monopersulfate (615 mg, 1.0 mmol) in water (5 mL) was added and stirred at room temperature overnight. LC-MS monitoring indicated that the starting material had essentially reacted. The product was then concentrated and purified by column chromatography (PE / EA = 20 / 1 to 1 / 1) to afford Compound B30 (104 mg, 35% yield) as a light yellow solid.

[0753] 1H NMR (400MHz, DMSO-d6) δ: 12.48 (s, 1H), 8.21 (d, J = 8.7Hz, 1H), 8.06 (d, J = 2.2Hz, 1H), 7.95 (s, 1H), 7.65 (d, J = 2.2Hz, 1H), 7.07 (d, J = 2.2Hz, 1H) ,6.99(dd,J=8.6,2.1Hz,1H),3.31-3.23(m,4H),3.22-3.15(m,1H),3.07(t,J=5.1Hz,4H),2.21-2.06(m,4H),1.85(s,4H),1.35(s,6H); ESI-MS m / z:595.2[M+H] + .

[0754] Example 80: Synthesis of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)-4-(N-methylaminosulfonyl)benzamide (Compound B31)

[0755] 2-(4-(Difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)-4-iodobenzamide (Intermediate B1-1, 307 mg, 0.5 mmol), n-butyldi(1-adamantyl)phosphine (36 mg, 0.1 mmol), and Pd(OAc)2 (22 mg, 0.1 mmol) were dissolved in IPA (8 mL). TEA (152 mg, 1.5 mmol) was added, and argon was bubbled through the mixture for 2 min. DABSO (120 mg, 0.5 mmol) was added, and the mixture was sealed. The reaction was carried out at 90°C for 3 h, cooled to room temperature, and NaClO2 solution (744 mg, 10%, 1.0 mmol) was added. Methylamine hydrochloride (68 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature overnight. LC-MS monitoring indicated that the starting materials were substantially reacted. The mixture was diluted with water (50 mL) and extracted with EA (50 mL*2). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH=100 / 1 to 10 / 1) to give a light yellow solid compound B31 (116 mg, yield 40%).

[0756] 1H NMR(400MHz, DMSO-d6)δ:12.53(s,1H),8.15(d,J=8.6Hz,1H),8.02(d,J=2.2Hz,1H),7.98(s,1H),7.30(d,J=8.6Hz,1H),7.0 9(d,J=2.2Hz,1H),7.01(dd,J=8.6,2.1Hz,1H),3.20-3.01(m,8H),2.49(s,3H),2.20-2.04(m,4H),1.85-1.75(m,4H); ESI-MS m / z:582.2[M+H] + .

[0757] Example 81: Synthesis of Compound B32

[0758] According to the similar synthesis method in Example 80, ethanolamine was added to obtain the target compound B32.

[0759] Example 82: Synthesis of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-6-((2-hydroxyethyl)sulfonamido)nicotinamide (Compound B33)

[0760] Step 1: 6-Bromo-2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)nicotinamide

[0761] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 127 mg, 0.5 mmol) was dissolved in THF and cooled under N2 on ice. NaH (60 mg, 1.5 mmol) was added and stirred at room temperature for 1 h. 6-Bromo-2-(4-(difluoromethylene)piperidin-1-yl)nicotinoyl chloride (Intermediate 44, 194 mg, 0.5 mmol) was added on ice. The reaction was allowed to proceed overnight at room temperature. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (199 mg, 70% yield). ESI-MS m / z: 568.1 [M+H]. + .

[0762] Step 2: 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-6-((2-hydroxyethyl)sulfonamido)nicotinamide

[0763] 6-Bromo-2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)nicotinamide (199 mg, 0.35 mmol), 2-hydroxyethane-1-sulfonamide (88 mg, 0.7 mmol), CuI (67 mg, 0.35 mmol), K3PO4 (149 mg, 0.7 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (25 mg, 0.175 mmol) was dissolved in DMF (10 mL) under N2 protection and allowed to react overnight at 100°C. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound B33 (90 mg, 42% yield) as a light yellow solid.

[0764] 1 H NMR (400MHz, DMSO-d6) δ: 12.43 (s, 1H), 8.26 (d, J = 8.7Hz, 1H), 8.06 (d, J = 2.3Hz, 1H), 7.97 (s, 1H), 7.42 (d, J = 8.6Hz, 1H), 7.32 (d ,J=2.3Hz,1H),3.72(t,J=6.7Hz,2H),3.32(brs,2H),3.25-3.16(m,4H),3.06-2.98(brs,4H),2.19-2.02(m,4H),1.95-1.78(br s,4H); ESI-MS m / z:613.2[M+H] + .

[0765] Examples 83-85: Synthesis of Compounds B34-B36

[0766] Intermediate 1 was reacted with Intermediate 45, Intermediate 46 and Intermediate 47 in sequence to obtain target compounds B34-B36 according to a similar synthesis method in Example 82.

[0767] Example 86: Synthesis of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methylbenzamide (Compound B37)

[0768] Step 1: 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-5-methyl-4-nitrobenzamide

[0769] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 253 mg, 1.0 mmol) was dissolved in THF and cooled under N2 protection. NaH (120 mg, 3.0 mmol) was added and stirred at room temperature for 1 h. 2-(4-(difluoromethylene)piperidin-1-yl)-5-methyl-4-nitrobenzoyl chloride (Intermediate 48, 367 mg, 1.0 mmol) was added after addition and allowed to react at room temperature overnight. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (410 mg, 75% yield). ESI-MS m / z: 548.2 [M+H] + .

[0770] Step 2: 4-amino-2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-5-methylbenzamide

[0771] 2-(4-(Difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-5-methyl-4-nitrobenzamide (383 mg, 0.70 mmol) was dissolved in EtOH / H₂O (5 / 1, 10 mL). Iron powder (235 mg, 4.2 mmol) and NH₄Cl (225 mg, 4.2 mmol) were added. The mixture was refluxed at 80°C under N₂ protection for 1 h. LC-MS monitoring indicated that the reaction was complete. The mixture was filtered, the filtrate was diluted with water (30 mL), and extracted with EA (30 mL x 3). The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford a light yellow solid (337 mg, 93% yield). ESI-MS m / z: 518.2 [M+H] + .

[0772] Step 3: Ethyl 2-(N-(5-(4-(difluoromethylene)piperidin-1-yl)-4-((7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)carbamoyl)-2-methylphenyl)sulfamoyl)acetate

[0773] 4-Amino-2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-5-methylbenzamide (259 mg, 0.5 mmol) was dissolved in DCM and TEA (152 mg, 1.5 mol) was added. Under N2 protection, the mixture was cooled to -10°C in an ice-salt bath. A solution of ethyl 2-(chlorosulfonyl)acetate (121 mg, 0.65 mmol) in DCM was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. LC-MS monitoring confirmed the complete reaction of the starting material. The product was washed with water, extracted with DCM, dried, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford a brown solid (200 mg, 60% yield). ESI-MS m / z: 668.2 [M+H] + .

[0774] Step 4: 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methylbenzamide

[0775] Ethyl 2-(N-(5-(4-(difluoromethylene)piperidin-1-yl)-4-((7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)carbamoyl)-2-methylphenyl)sulfamoyl)acetate (167 mg, 0.25 mmol) was dissolved in anhydrous THF. Under N2 protection, the mixture was cooled to 0°C in an ice bath. LiAlH4 (1.0 M in THF, 0.5 mL, 0.50 mmol) was slowly added and the reaction was stirred at room temperature for 2 h. LC-MS monitoring indicated that the reaction was complete. The reaction was quenched with aqueous ammonium chloride, extracted with EA, dried, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to afford Compound B37 (80 mg, 51% yield) as a yellow solid.

[0776] 1 H NMR (400MHz, DMSO-d6) δ: 12.37 (s, 1H), 8.14 (d, J = 2.2Hz, 1H), 7.58 (s, 1H), 7. 41(s,1H),7.26(d,J=2.2Hz,1H),7.02(s,1H),3.79(t,J=6.7Hz,2H),3.30(br s,2H),3.22-3.11(m,4H),2.97(br t,J=5.0Hz,4H),2.51(s,3H),2.17-1.97(m,4H),1.92-1.83(br s,4H); ESI-MS m / z:626.2[M+H] + .

[0777] Example 87: Synthesis of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide (Compound B38)

[0778] Step 1: 4-Bromo-2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-6-fluorobenzamide

[0779] 7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 127 mg, 0.5 mmol) was dissolved in THF and cooled under N2 on ice. NaH (60 mg, 1.5 mmol) was added and stirred at room temperature for 1 h. 4-Bromo-2-(4-(difluoromethylene)piperidin-1-yl)-6-fluorobenzoyl chloride (Intermediate 49, 203 mg, 0.5 mmol) was added on ice. The reaction was allowed to proceed overnight at room temperature. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (220 mg, 75% yield). ESI-MS m / z: 585.1 [M+H]. + .

[0780] Step 2: 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide

[0781] 4-Bromo-2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-6-fluorobenzamide (220 mg, 0.376 mmol), 2-hydroxyethane-1-sulfonamide (94 mg, 0.752 mmol), CuI (72 mg, 0.376 mmol), K3PO4 (160 mg, 0.752 mmol), (1R,2R)-N 1 ,N 21,2-Dimethylcyclohexane-1,2-diamine (27 mg, 0.189 mmol) was dissolved in DMF (10 mL) under N2 protection and allowed to react overnight at 100°C. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound B38 (100 mg, 42% yield) as a light yellow solid.

[0782] 1 H NMR (400MHz, DMSO-d6) δ: 12.18 (s, 1H), 8.10 (d, J = 2.2Hz, 1H), 8.01 (s, 1H),7.38(d,J=2.2Hz,1H),7.15(dd,J=8.9,2.1Hz,1H),7.02(d,J=2.1Hz,1H),3.80(dd,J=7.2,4.3Hz,4H),3. 75(t,J=6.5Hz,2H),3.38(t,J=6.5Hz,2H),3.12-3.05(m,4H),2.20-2.03(m,4H),1.90-1.81(brs,4H); ESI-MS m / z:630.2[M+H] + .

[0783] Examples 88-91: Synthesis of Compounds B39-B42

[0784] Intermediate 2, Intermediate 14, Intermediate 4 and Intermediate 5 were reacted with Intermediate 49 in sequence to obtain target compounds B39-B42 according to a similar synthesis method in Example 87.

[0785] Example 92: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(4-methylenepiperidin-1-yl)benzamide (Compound B43)

[0786] Step 1: N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-iodo-2-(4-methylenepiperidin-1-yl)benzamide

[0787] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 127 mg, 0.5 mmol) was dissolved in THF and cooled under N2 on ice. NaH (60 mg, 1.5 mmol) was added and stirred at room temperature for 1 h. 4-Iodo-2-(4-methylenepiperidin-1-yl)benzoyl chloride (Intermediate 40, hydrochloride, 199 mg, 0.5 mmol) was added on ice. The reaction was allowed to proceed overnight at room temperature. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (179 mg, 62% yield). ESI-MS m / z: 579.1 [M+H]. + .

[0788] Step 2: N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(4-methylenepiperidin-1-yl)benzyl

[0789] The N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-iodo-2-(4-methylenepiperidin-1-yl)benzamide (179 mg, 0.31 mmol) obtained in the previous step, 2-hydroxyethane-1-sulfonamide (78 mg, 0.62 mmol), CuI (59 mg, 0.31 mmol), K3PO4 (132 mg, 0.62 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (22 mg, 0.155 mmol) was dissolved in DMF (8 mL) under N2 protection and allowed to react overnight at 100°C. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound B43 (85 mg, 48% yield) as a light yellow solid.

[0790] 1H NMR (400MHz, DMSO-d6) δ: 12.51 (s, 1H), 8.15-8.07 (m, 2H), 8.01 (s, 1H), 7.29 (d, J = 2.2Hz, 1H), 7.14 (dd, J = 8.7, 2.1Hz, 1H), 7.01 (d, J = 2.1Hz, 1H), 5 .02(d,J=3.3Hz,2H),3.81-3.69(m,J=6.6Hz,6H),3.43-3.30(m,6H),2.6 7(t,J=5.3Hz,4H),1.98(d,J=10.8Hz,2H),1.87(d,J=10.8Hz,2H); ESI-MS m / z:576.2[M+H] + .

[0791] Examples 93-95: Synthesis of Compounds B44-B46

[0792] Intermediate 41, intermediate 42, and intermediate 43 were reacted with intermediate 1 in sequence to obtain target compounds B44-B46 according to a similar synthesis method in Example 92.

[0793] Example 96: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(spiro[2.5]oct-5-en-6-yl)benzamide (Compound B47)

[0794] Step 1: 4-Bromo-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-(spiro[2.5]oct-5-en-6-yl)benzamide

[0795] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-amine (Intermediate 1, 127 mg, 0.5 mmol) was dissolved in THF and cooled under N2 on ice. NaH (60 mg, 1.5 mmol) was added and stirred at room temperature for 1 h. 4-Bromo-2-(spiro[2.5]oct-5-en-6-yl)benzoyl chloride (Intermediate 51, 163 mg, 0.5 mmol) was added on ice. The reaction was allowed to proceed overnight at room temperature. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (155 mg, 57% yield). ESI-MS m / z: 542.1 [M+H]. + .

[0796] Step 2: N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(spiro[2.5]oct-5-en-6-yl)benzamide

[0797] The 4-bromo-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-(spiro[2.5]oct-5-en-6-yl)benzamide (155 mg, 0.285 mmol), 2-hydroxyethane-1-sulfonamide (71 mg, 0.57 mmol), CuI (54 mg, 0.285 mmol), K3PO4 (121 mg, 0.57 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (20 mg, 0.143 mmol) was dissolved in DMF (8 mL) under N2 protection and allowed to react overnight at 100°C. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound B47 (90 mg, 54% yield) as a light yellow solid.

[0798] 1 H NMR(400MHz, DMSO-d6)δ:12.33(s,1H),8.28(d,J=8.7Hz,1H),8.11(d,J=2.3 Hz,1H),8.05(s,1H),7.31(d,J=2.2Hz,1H),7.13(dd,J=8.7,2.2Hz,1H),7.01 (d,J=2.Hz,1H),5.79(s,1H),3.76(t,J=6.6Hz,2H),3.66-3.51(m,4H),3.33- 3.30(m,2H),1.99-1.81(m,8H),1.68(d,J=12.8Hz,2H),0.37(s,4H);;ESI-MS m / z:587.2[M+H] + .

[0799] Examples 97-99: Synthesis of Compounds B48-B50

[0800] Intermediate 52, intermediate 53, and intermediate 54 were reacted with intermediate 1 in sequence to obtain target compounds B48-B50 according to a similar synthesis method in Example 96.

[0801] Example 100: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(spiro[2.5]oct-5-en-6-yl)benzamide (Compound B51)

[0802] Step 1: 4-Bromo-N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2-(spiro[2.5]oct-5-en-6-yl)benzamide

[0803] 7-(4,4-Difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-amine (Intermediate 2, 128 mg, 0.5 mmol) was dissolved in THF and cooled under N2 protection. NaH (60 mg, 1.5 mmol) was added and stirred at room temperature for 1 h. 4-Bromo-2-(spiro[2.5]oct-5-en-6-yl)benzoyl chloride (Intermediate 34, 163 mg, 0.5 mmol) was added and stirred at room temperature overnight. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a light yellow solid (177 mg, 65% yield). ESI-MS m / z: 544.1 [M+H]. + .

[0804] Step 2: N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(spiro[2.5]oct-5-en-6-yl)benzamide

[0805] The 4-bromo-N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2-(spiro[2.5]oct-5-en-6-yl)benzamide (163 mg, 0.3 mmol), 2-hydroxyethane-1-sulfonamide (75 mg, 0.6 mmol), CuI (57 mg, 0.3 mmol), K3PO4 (127 mg, 0.6 mmol), (1R,2R)-N 1 ,N 21,2-Dimethylcyclohexane-1,2-diamine (21 mg, 0.15 mmol) was dissolved in DMF (8 mL) under N2 protection and allowed to react overnight at 100°C. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound B51 (100 mg, 57% yield) as a light yellow solid.

[0806] 1 H NMR(400MHz, DMSO-d6)δ:12.12(s,1H),8.15(s,1H),8.06(d,J=8.6Hz,1H),7.28(d,J=2.2Hz,1H),7.10(dd,J=8.7,2.2Hz,1H),5.79(s,1H),4.3 1(t,J=5.3Hz,2H),3.76-3.68(m,4H),3.65-3.50(m,4H),3.41(t,J=6.6Hz,2H),1.98-1.80(m,8H),1.73(d,J=12.8Hz,2H),0.40(s,4H); ESI-MS m / z:589.2[M+H] + .

[0807] Examples 101-105: Synthesis of Compounds B52-B56

[0808] Intermediate 14, intermediate 5, intermediate 17, intermediate 3, intermediate 6 were reacted with intermediate 51 in sequence, and the target compounds B52-B56 were obtained according to a similar synthesis method in Example 57.

[0809] Example 106: Synthesis of N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-(spiro[2.5]oct-5-en-6-yl)benzamide (Compound B57)

[0810] Step 1: 4-Bromo-N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2-fluoro-6-(spiro[2.5]oct-5-en-6-yl)benzamide

[0811] 7-(4,4-Difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-amine (Intermediate 2, 128 mg, 0.5 mmol) was dissolved in THF and cooled under N2 on ice. NaH (60 mg, 1.5 mmol) was added and stirred at room temperature for 1 h. 4-Bromo-2-fluoro-6-(spiro[2.5]oct-5-en-6-yl)benzoyl chloride (Intermediate 38, 172 mg, 0.5 mmol) was added on ice. The reaction was allowed to proceed overnight at room temperature. LC-MS monitoring confirmed the complete reaction. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford a light yellow solid (155 mg, 55% yield). ESI-MS m / z: 562.1 [M+H]. + .

[0812] Step 2: N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-(spiro[2.5]oct-5-en-6-yl)benzamide

[0813] The 4-bromo-N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2-fluoro-6-(spiro[2.5]oct-5-en-6-yl)benzamide (155 mg, 0.275 mmol), 2-hydroxyethane-1-sulfonamide (69 mg, 0.55 mmol), CuI (52 mg, 0.275 mmol), K3PO4 (117 mg, 0.55 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (20 mg, 0.138 mmol) was dissolved in DMF (8 mL) under N2 protection and heated to 100°C overnight. LC-MS monitoring indicated complete reaction. The mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound B57 (80 mg, 48% yield) as a light yellow solid.

[0814] 1H NMR(400MHz, DMSO-d6)δ:11.73(s,1H),8.01(d,J=8.6Hz,1H),7.31(d,J=2.2Hz,1H),7.12(dd,J=8.7,2.2Hz,1H),5.82(s,1H),4.29(t,J =5.3Hz,2H),3.76-3.68(m,4H),3.65-3.50(m,4H),3.41(t,J=6.6Hz,2H),1.96-1.81(m,8H),1.68(d,J=12.8Hz,2H),0.38(s,4H); ESI-MS m / z:607.2[M+H] + .

[0815] Example 107: Synthesis of N-(2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)phenyl)-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine-5-carboxamide (Compound B58)

[0816] Step 1: 7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine-5-carboxylic acid

[0817] 5-Bromo-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (1.0 g, 3.15 mmol) was dissolved in DMF (10 mL). Xantphos (91 mg, 0.158 mmol), Pd(OAc)2 (35 mg, 0.158 mmol), DIPEA (611 mg, 4.73 mmol), Ac2O (483 mg, 4.73 mmol), and oxalic acid dihydrate (596 mg, 4.73 mmol) were added. The mixture was quickly sealed and the tube was sealed. The reaction was carried out at 100°C overnight. LC-MS monitoring indicated that the reaction was complete. The mixture was cooled, poured into ice water, and the pH was adjusted to about 5 with dilute hydrochloric acid. A light yellow solid precipitated, which was filtered and dried to obtain a light yellow solid (300 mg, 34% yield). ESI-MS m / z: 283.1 [M+H] + .

[0818] Step 2: N-(2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)sulfonamido)phenyl)-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine-5-carboxamide

[0819] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridine-5-carboxylic acid (282 mg, 1.0 mmol) and N-(4-amino-3-(4-(difluoromethylene)piperidin-1-yl)phenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-sulfonamide (Intermediate 56, 432 mg, 1.0 mmol) were dissolved in ACN (10 mL). TCFH (421 mg, 1.5 mmol) and N-methylimidazole (287 mg, 3.5 mmol) were added, and the reaction was stirred at room temperature overnight. LC-MS monitoring indicated that the reaction was complete. The product was concentrated, dissolved in EA (30 mL), washed with water (40 mL), concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 3 / 1) to give a light yellow solid (417 mg, yield 60%), ESI-MS m / z: 696.2 [M+H] + .

[0820] Step 3: N-(2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)phenyl)-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine-5-carboxamide

[0821] N-(2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)sulfonamido)phenyl)-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine-5-carboxamide (140 mg, 0.2 mmol) was dissolved in MeOH (10 mL). Hydrochloric acid (2 M, 0.5 mL) was added dropwise and stirred at room temperature for 1 hour. LC-MS monitoring indicated complete reaction. The reaction mixture was concentrated, the pH was adjusted to a weak base with aqueous sodium bicarbonate solution, and the mixture was extracted with DCM. The mixture was concentrated and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound B58 (80 mg, 65% yield) as an off-white powder.

[0822] 1 H NMR (400MHz, DMSO-d6) δ: 11.05 (s, 1H), 8.71 (s, 1H), 8.48 (d, J = 2.2Hz, 1H), 8.25 (d, J = 8.6Hz, 1H), 7.78 (d, J = 8 .6Hz,1H),7.27(d,J=2.2Hz,1H),7.05(d,J=2.3Hz,1H),3.86-3.70(m,6H),3.56(s,4H),3.23(t,J=6.7Hz,2H), 2.98(t,J=5.0Hz,4H),2.13-2.02(m,4H); ESI-MS m / z:612.2[M+H] + .

[0823] Examples 108-109: Synthesis of Compounds B59-B60

[0824] Intermediate 57, intermediate 58 and intermediate 59 were reacted in sequence to obtain target compounds B59-B60 according to a similar synthesis method in Example 93.

[0825] Example 110: Synthesis of ethyl 2-(N-(3-(4-(difluoromethylene)piperidin-1-yl)-4-((7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)carbamoyl)phenyl)sulfamoyl)acetate (Compound B61)

[0826] To a solution of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-alkyl)furo[2,3-c]pyridin-5-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (Compound B1, 200 mg, 0.327 mmol) and acetic acid (111 mg, 1.64 mmol) in THF (10 mL) was added 3-nitro-1,2,4-triazole (93 mg, 0.818 mmol), BOPCl (208 mg, 0.818 mmol), and DIPEA (212 mg, 1.64 mmol). The mixture was allowed to react at room temperature for 2 h. LC-MS monitoring indicated complete reaction of the starting material. The mixture was poured into ice water (30 mL), extracted with EA (20 mL*2), and the organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA=10 / 1 to 1 / 1) to give a light yellow solid compound B61 (128 mg, yield 60%).

[0827] 1 H NMR(400MHz, DMSO-d6)δ:12.25(s,1H),10.11(s,1H),8.09(dd,J=8.3,5.3Hz,2H),7.96(s,1H),7.10(dd,J=15.9,7.4Hz,2H),6.98(d,J= 1.8Hz,1H),4.91(s,1H),3.91(s,4H),3.69(s,2H),3.39(d,J=6.5Hz,2H),2.96(t,J=4.8Hz,4H),2.52(s,4H),2.11-1.99(m,7H); ESI-MS m / z:654.2[M+H] + .

[0828] Examples 111-147: Synthesis of Compounds B62-B98

[0829] Target compounds B62-B98 were obtained according to a similar synthetic method in Example 110.

[0830] Example 148: Synthesis of N-(4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound C1)

[0831] Step 1: Preparation of 7-(4,4-difluoropiperidin-1-yl)-N'-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl)furo[2,3-c]pyridine-5-carboxylic acid hydrazide

[0832] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridine-5-carboxylic acid (282 mg, 1.0 mmol) was dissolved in ACN (10 mL), and 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzohydrazide (408 mg, 1.1 mmol) was added. The mixture was cooled under N2 and cooled on ice. TCFH (337 mg, 1.2 mmol) and NMI (288 mg, 3.5 mmol) were added and stirred at room temperature for 2 h. LC-MS monitoring indicated that the reaction was complete. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 2). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 1 / 1) to afford a light yellow solid (445 mg, 70% yield). ESI-MS m / z: 636.1 [M+H] + .

[0833] Step 2: Preparation of 7-(4,4-difluoropiperidin-1-yl)-5-(5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine

[0834] 7-(4,4-difluoropiperidin-1-yl)-N'-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl)furo[2,3-c]pyridine-5-carboxylic acid hydrazide (Intermediate C1-1, 200 mg, 0.315 mmol) was dissolved in dioxane (15 mL), POCl3 (2 mL) was added, and the reaction was heated to 90°C overnight. LC-MS monitoring indicated that the reaction was complete. The product was directly concentrated, and the residue was dissolved in EA, washed with saturated sodium bicarbonate solution, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (150 mg, 77% yield). ESI-MS m / z: 618.1 [M+H] + .

[0835] Step 3: Preparation of N-(4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0836] 7-(4,4-difluoropiperidin-1-yl)-5-(5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine (150 mg, 0.243 mmol), 2-hydroxyethane-1-sulfonamide (61 mg, 0.486 mmol), CuI (46 mg, 0.243 mmol), K3PO4 (103 mg, 0.486 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (17 mg, 0.122 mmol) was dissolved in DMF (8 mL) under N2 protection and heated to 100°C overnight. LC-MS monitoring indicated complete reaction. The product was poured into ice water (30 mL) and extracted with EA (30 mL x 2). The combined organic phases were dried, concentrated, purified by reverse phase chromatography, and lyophilized to afford Compound C1 (100 mg, 67% yield) as a light yellow solid.

[0837] 1H NMR (400MHz, DMSO-d6) δ: 10.13 (s, 1H), 8.26 (d, J = 2.1Hz, 1H), 8.00 (s, 1H), 7.84 (d, J = 8.5Hz, 1H), 7.16 (d, J = 2.2Hz, 1H), 7.06 (d, J = 2.1Hz, 1H), 6.96(dd,J=8.5,2.1Hz,1H),4.94(s,1H),4.08(t,J=5.8Hz,4H),3.77(t,J=6.5Hz,2H),3.37(t,J=6. 5Hz, 2H), 2.93 (t, J=5.1Hz, 4H), 2.16 (dq, J=13.8, 7.1, 5.8Hz, 4H), 1.52 (s, 4H), 0.30 (s, 4H); ESI-MS m / z:615.2[M+H] + .

[0838] Examples 149-162: Synthesis of Compounds C2-C15

[0839] Intermediate 60-Intermediate 73 were used as raw materials and reacted with Intermediate 86 to obtain target compounds C2-C15 according to a similar synthesis method in Example 148.

[0840] Example 163: Synthesis of N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound C16)

[0841] Step 1: Preparation of N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-sulfonamide

[0842] 7-(4,4-Difluoropiperidin-1-yl)-5-ethynylfuro[2,3-c]pyridine (92 mg, 0.35 mmol) and N-(4-azido-3-(6-azaspiro[2.5]oct-6-yl)phenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-sulfonamide (153 mg, 0.35 mmol) were dissolved in DCM (15 mL), and CuSO4·5H2O (11 mg, 0.045 mmol) and sodium ascorbate (80 mg, 0.40 mmol) were added. The reaction was stirred at 25°C overnight and monitored by LC-MS. The reaction of the raw material was complete. Add ice water (30 mL) and extract with DCM (20 mL*3). Combine the organic phases, dry, concentrate, and column chromatography (DCM / MeOH=100 / 1 to 10 / 1) to give a light yellow solid (110 mg, yield 45%). ESI-MS m / z: 698.3 [M+H] + .

[0843] Step 2: Preparation of N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0844] N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-sulfonamide (110 mg, 0.158 mmol) obtained in the previous step was dissolved in MeOH (10 mL). Hydrochloric acid (2 M, 0.5 mL) was added dropwise and the reaction was stirred at room temperature for 1 h. LC-MS monitoring indicated that the reaction was complete. The reaction mixture was concentrated, the pH was adjusted to a weak base with aqueous sodium bicarbonate solution, and the mixture was extracted with DCM. The mixture was concentrated and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound C16 (60 mg, 61% yield) as an off-white powder.

[0845] 1H NMR (400MHz, DMSO-d6): δ8.36(d,J=2.1Hz,1H),8.23(s,1H),8.05(s,1H),7.86(d, J=8.5Hz,1H),7.19(d,J=2.2Hz,1H),7.10(d,J=2.1Hz,1H),6.99(dd,J=8.5,2.1Hz ,1H),3.98(t,J=5.8Hz,4H),3.78(t,J=6.5Hz,2H),3.38(t,J=6.5Hz,2H),2.89(t, J=5.1Hz, 4H), 2.21 (dq, J=13.8, 7.1, 5.8Hz, 4H), 1.58 (s, 4H), 0.35 (s, 4H); ESI-MS m / z:614.2[M+H] + .

[0846] Examples 164-168: Synthesis of Compounds C17-C21

[0847] Intermediate 76, intermediate 78, intermediate 75, intermediate 77, and intermediate 79 were used as raw materials and reacted with intermediate 90 to obtain the target compounds C17-C21 according to a similar synthesis method in Example 163.

[0848] Example 169: Synthesis of N-(4-(1-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound C22)

[0849] Step 1: Preparation of 5-(4-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-1,2,3-triazol-1-yl)-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine

[0850] 5-Azido-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (98 mg, 0.35 mmol) and 6-(5-bromo-2-ethynylphenyl)-6-azaspiro[2.5]octane (102 mg, 0.35 mmol) were dissolved in DCM (10 mL). CuSO4.5H2O (11 mg, 0.045 mmol) and sodium ascorbate (80 mg, 0.40 mmol) were added. The mixture was stirred at 25°C overnight. LC-MS monitoring indicated that the reaction was complete. The mixture was added to ice water (30 mL) and extracted with DCM (20 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford a light yellow solid (100 mg, 50% yield). ESI-MS m / z: 569.1 [M+H] + .

[0851] Step 2: Preparation of N-(4-(1-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0852] 5-(4-(4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-1,2,3-triazol-1-yl)-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (Intermediate C22-1, 100 mg, 0.176 mmol), 2-hydroxyethane-1-sulfonamide (44 mg, 0.352 mmol), CuI (34 mg, 0.176 mmol), K3PO4 (75 mg, 0.352 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (13 mg, 0.088 mmol) was dissolved in DMF (6 mL) and reacted overnight at 100°C under N2 protection. LC-MS monitoring indicated complete reaction. The product was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, purified by reverse phase chromatography, and lyophilized to afford Compound C22 (55 mg, 51% yield) as a light yellow solid.

[0853] 1H NMR(400MHz, DMSO-d6)δ:8.38(d,J=2.1Hz,1H),8.22(s,1H),8.03(s,1H),7.82(d,J=8.5Hz,1H),7.16(d,J=2.2Hz,1H),7.09(d,J=2.1Hz,1H), 6.96(dd,J=8.5,2.1Hz,1H),3.99(t,J=5.8Hz,4H),3.76(t,J=6.5Hz,2H),3.35(t,J=6.5Hz,2 H), 2.95 (t, J=5.1Hz, 4H), 2.15 (dq, J=13.8, 7.1, 5.8Hz, 4H), 1.56 (s, 4H), 0.38 (s, 4H); ESI-MS m / z:614.2[M+H] + .

[0854] Examples 170-174: Synthesis of Compounds C23-C27

[0855] Intermediates 81-85 were used as raw materials and reacted with intermediate 94 to obtain target compounds C23-C27 according to a similar synthesis method in Example 169.

[0856] Example 175: Synthesis of N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound C28)

[0857] Step 1: 7-(4,4-difluoropiperidin-1-yl)-5-(1-(4-nitro-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-pyrazol-4-yl)furo[2,3-c]pyridine

[0858] 6-(5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)phenyl)-6-azaspiro[2.5]octane (2.12 g, 5.0 mmol), K2CO3 (2.12 g, 10.0 mmol), 1,1-(diphenylphosphino)ferrocenepalladium dichloride (366 mg, 0.5 mmol), and 5-bromo-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (1.59 g, 5.0 mmol) were added sequentially to dioxane (80 mL). Under argon, the reaction was carried out at 100°C for 3 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was quenched with water (100 mL) and extracted with EA (50 mL x 2). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE / EA = 100 / 1 to 5 / 1) to give a light yellow solid (1.74 g, yield 65%). ESI-MS m / z: 535.2 [M+H] + .

[0859] Step 2: 4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)aniline

[0860] 7-(4,4-difluoropiperidin-1-yl)-5-(1-(4-nitro-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-pyrazol-4-yl)furo[2,3-c]pyridine (535 mg, 1.0 mmol) was dissolved in EtOH / H₂O (5 / 1, 20 mL). Iron powder (280 mg, 5.0 mmol) and NH₄Cl (268 mg, 5.0 mmol) were added. The mixture was refluxed at 80°C under N₂ protection for 1 h. LC-MS monitoring indicated the reaction was complete. The mixture was filtered, the filtrate was diluted with water (30 mL), and extracted with EA (30 mL x 2). The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford a light yellow solid (404 mg, 80% yield). ESI-MS m / z: 505.2 [M+H] + .

[0861] Step 3: Ethyl 2-(N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-pyrazol-1-yl)-3-)6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate

[0862] 4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)aniline (252 mg, 0.5 mmol) was dissolved in DCM and TEA (152 mg, 1.5 mol) was added. Under N2 protection, the mixture was cooled to -10°C in an ice-salt bath. A solution of ethyl 2-(chlorosulfonyl)acetate (121 mg, 0.65 mmol) in DCM was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. LC-MS monitoring confirmed the complete reaction of the starting material. The product was washed with water, extracted with DCM, dried, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford a brown solid (183 mg, 56% yield). ESI-MS m / z: 655.2 [M+H] + .

[0863] Step 4: N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0864] Ethyl 2-(N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (164 mg, 0.25 mmol) was dissolved in anhydrous THF. Under nitrogen protection, the mixture was cooled to 0°C in an ice bath. LiAlH4 (1.0 M in THF, 0.5 mL, 0.50 mmol) was slowly added and the reaction was stirred at room temperature for 2 h. LC-MS monitoring indicated that the reaction was complete. The reaction was quenched with aqueous ammonium chloride, extracted with EA, dried, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to afford Compound C28 (70 mg, 46% yield) as a yellow solid.

[0865] 1H NMR (400MHz, DMSO-d6) δ: 8.51 (s, 1H), 8.32 (s, 1H), 8.25 (d, J = 2.1Hz, 1H), 8.01 (s, 1H),7.87(d,J=8.5Hz,1H),7.18(d,J=2.2Hz,1H),7.03(d,J=2.1Hz,1H),6.98(dd, J=8.5,2.1Hz,1H),4.02(t,J=5.8Hz,4H),3.76(t,J=6.5Hz,2H),3.39(t,J=6.5Hz, 2H), 2.95 (t, J=5.1Hz, 4H), 2.12 (d, J=5.8Hz, 4H), 1.57 (s, 4H), 0.36 (s, 4H); ESI-MS m / z:613.2[M+H] + .

[0866] Example 176: Synthesis of N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound C29)

[0867] Step 1: 7-Chloro-5-(1-(4-nitro-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-pyrazol-4-yl)-2,3-dihydrofluoro[2,3-c]pyridine

[0868] 6-(5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)phenyl)-6-azaspiro[2.5]octane (2.12 g, 5.0 mmol), K2CO3 (2.12 g, 10.0 mmol), 1,1-(diphenylphosphino)ferrocenepalladium dichloride (366 mg, 0.5 mmol), and 7-chloro-5-iodo-2,3-dihydrofuro[2,3-c]pyridine (1.41 g, 5.0 mmol) were added sequentially to dioxane (80 mL). Under argon, the reaction was continued at 100°C for 3 hours. LC-MS monitoring indicated that the reaction was complete. The reaction mixture was quenched with water (100 mL). Extraction was performed with EA (50 mL x 2). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA = 100 / 1 to 5 / 1) to give a light yellow solid (1.49 g, yield 66%). ESI-MS m / z: 452.1 [M+H] + .

[0869] Step 2: 7-(4,4-difluoropiperidin-1-yl)-5-(1-(4-nitro-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-pyrazol-4-yl)-2,3-dihydrofuro[2,3-c]pyridine

[0870] 7-Chloro-5-(1-(4-nitro-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-pyrazol-4-yl)-2,3-dihydrofluoro[2,3-c]pyridine (904 mg, 2.0 mmol), 4,4-difluoropiperidine hydrochloride (473 mg, 3.0 mmol), Cs2CO3 (1.95 g, 6.0 mmol), Pd2(dba)3 (183 mg, 0.2 mmol), and Xantphos (116 mg, 0.2 mmol) were dissolved in dioxane (40 mL) and reacted at 100°C under argon overnight. The reaction mixture was filtered and concentrated by column chromatography (PE / EA = 50 / 1 to 3 / 1) to afford a yellow solid (590 mg, 55% yield). ESI-MS m / z: 537.2 [M+H] + .

[0871] Step 3: 4-(4-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)aniline

[0872] 7-(4,4-difluoropiperidin-1-yl)-5-(1-(4-nitro-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-pyrazol-4-yl)-2,3-dihydrofuro[2,3-c]pyridine (537 mg, 1.0 mmol) was dissolved in EtOH / H2O (5 / 1, 20 mL), and iron powder (280 mg, 5.0 mmol) and NH4Cl (268 mg, 5.0 mmol) were added. The mixture was heated to 80°C under N2 protection and refluxed for 1 h. The reaction was completed after LC-MS monitoring. The filtrate was filtered, diluted with water (30 mL), extracted with EA (30 mL*2), and the organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (PE / EA=10 / 1 to 1 / 1) to give a light yellow solid (456 mg, yield 85%). ESI-MS m / z: 507.2 [M+H] + .

[0873] Step 4: Ethyl 2-(N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate

[0874] 4-(4-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)aniline (253 mg, 0.5 mmol) was dissolved in DCM and TEA (152 mg, 1.5 mol) was added. Under N2 protection, the mixture was cooled to -10°C in an ice-salt bath. A solution of ethyl 2-(chlorosulfonyl)acetate (121 mg, 0.65 mmol) in DCM was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. LC-MS monitoring confirmed the complete reaction of the starting material. The product was washed with water, extracted with DCM, dried, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford a brown solid (197 mg, 60% yield). ESI-MS m / z: 655.2 [M+H] + .

[0875] Step 5: N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonyl

[0876] Ethyl 2-(N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (164 mg, 0.25 mmol) was dissolved in anhydrous THF. Under N2 protection, the mixture was cooled to 0°C in an ice bath. LiAlH4 (1.0 M in THF, 0.5 mL, 0.50 mmol) was slowly added and the reaction was stirred at room temperature for 2 h. LC-MS monitoring indicated that the reaction was complete. The reaction was quenched with aqueous ammonium chloride, extracted with EA, dried, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to afford Compound C29 (80 mg, 52% yield) as a yellow solid.

[0877] 1H NMR(400MHz, DMSO-d6)δ:8.51(s,1H),8.32(s,1H),7.89(s,1H),7.57(d,J=8.5Hz, 1H),7.03(d,J=2.1Hz,1H),6.98(dd,J=8.5,2.1Hz,1H),4.25(t,J=6.6Hz,2H),4.0 2(t,J=5.8Hz,4H),3.82(t,J=6.6Hz,2H),3.77(t,J=6.5Hz,2H),3.35(t,J=6.5Hz, 2H), 2.96 (t, J=5.1Hz, 4H), 2.15 (d, J=5.8Hz, 4H), 1.61 (s, 4H), 0.39 (s, 4H); ESI-MS m / z:615.2[M+H] + .

[0878] Example 177: Synthesis of N-(4-(4-(4,4-difluoropiperidin-1-yl)-2,3-dihydrofuro[3,2-c]pyridin-6-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)-2-hydroxy (C30)

[0879] Using intermediate 68-A and intermediate 89 as raw materials, the target compound 30 was obtained according to a similar synthetic method in Example 29.

[0880] Example 178: Synthesis of N-(4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(4-fluoro-4-methylpiperidin-1-ylphenyl)-2-hydroxyethane-1-sulfonamide (Compound C31)

[0881] Step 1: Preparation of 7-(4,4-difluoropiperidin-1-yl)-N'-(2-(4-fluoro-4-methylpiperidin-1-yl)-4-iodobenzoyl)furo[2,3-c]pyridine-5-carboxylic acid hydrazide

[0882] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridine-5-carboxylic acid (282 mg, 1.0 mmol) was dissolved in ACN (10 mL), and 2-(4-fluoro-4-methylpiperidin-1-yl)-4-iodobenzohydrazide (415 mg, 1.1 mmol) was added. The mixture was cooled under N2 and ice-cooled. TCFH (337 mg, 1.2 mmol) and NMI (288 mg, 3.5 mmol) were added and stirred at room temperature for 2 h. LC-MS monitoring indicated that the reaction was complete. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 2). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 1 / 1) to afford a light yellow solid (462 mg, 72% yield). ESI-MS m / z: 642.1 [M+H] + .

[0883] Step 2: Preparation of 7-(4,4-difluoropiperidin-1-yl)-5-(5-(2-(4-fluoro-4-methylpiperidin-1-yl)-4-iodophenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine

[0884] 7-(4,4-difluoropiperidin-1-yl)-N'-(2-(4-fluoro-4-methylpiperidin-1-yl)-4-iodobenzoyl)furo[2,3-c]pyridine-5-carboxylic acid hydrazide (150 mg, 0.234 mmol) was dissolved in dioxane (15 mL), POCl3 (2 mL) was added, and the mixture was heated to 90°C overnight. LC-MS monitoring indicated that the reaction was complete. The product was directly concentrated, and the residue was dissolved in EA, washed with saturated sodium bicarbonate solution, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (117 mg, 80% yield). ESI-MS m / z: 624.1 [M+H] + .

[0885] Step 3: Preparation of N-(4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(4-fluoro-4-methylpiperidin-1-ylphenyl)-2-hydroxyethane-1-sulfonamide

[0886] 7-(4,4-difluoropiperidin-1-yl)-5-(5-(2-(4-fluoro-4-methylpiperidin-1-yl)-4-iodophenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine (117 mg, 0.188 mmol), 2-hydroxyethane-1-sulfonamide (47 mg, 0.375 mmol), CuI (36 mg, 0.188 mmol), K3PO4 (80 mg, 0.375 mmol), (1R,2R)-N1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (13 mg, 0.094 mmol) was dissolved in DMF (8 mL) under N2 protection and heated to 100°C overnight. LC-MS monitoring indicated complete reaction. The product was poured into ice water (30 mL) and extracted with EA (30 mL x 2). The combined organic phases were dried, concentrated, purified by reverse phase chromatography, and lyophilized to afford Compound C31 (58 mg, 50% yield) as a light yellow solid.

[0887] 1 H NMR(400MHz, DMSO-d6)δ:8.29(d,J=2.1Hz,1H),8.06(s,1H),7.88(d,J=8.5Hz,1H),7.19(d,J=2.2Hz,1H),7.08(d,J=2.1Hz,1H),6.98(dd,J=8.5,2.1Hz ,1H),4.01(t,J=5.8Hz,4H),3.79(t,J=6.5Hz,2H),3.35(t,J=6.5Hz,2H),2. 98(t,J=5.1Hz,4H),2.25(d,J=5.8Hz,4H),1.86(s,4H),1.45(s,3H); ESI-MS m / z:621.2[M+H] + .

[0888] Examples 179-186: Synthesis of Compounds C32-C39

[0889] Using different acids (Intermediate 65, Intermediate 68, Intermediate 59) and appropriate hydrazides (Intermediate 87, Intermediate 88, Intermediate 97), target compounds C32-C39 were obtained according to a similar synthetic method in Example 178.

[0890] Example 187: Synthesis of N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)-3-(4-fluoro-4-methylpiperidin-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound C40)

[0891] Step 1: Preparation of N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)-3-(4-fluoro-4-methylpiperidin-1-yl)phenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-sulfonamide

[0892] 7-(4,4-Difluoropiperidin-1-yl)-5-ethynylfuro[2,3-c]pyridine (92 mg, 0.35 mmol) and N-(4-azido-3-(4-fluoro-4-methylpiperidin-1-yl)phenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-sulfonamide (155 mg, 0.35 mmol) were dissolved in DCM (15 mL), and CuSO4.5H2O (11 mg, 0.045 mmol) and sodium ascorbate (80 mg, 0.40 mmol) were added. The reaction was stirred at 25°C overnight. LC-MS monitoring showed that the reaction of the raw material was complete. Add ice water (30 mL) and extract with DCM (20 mL*3). Combine the organic phases, dry, concentrate, and column chromatography (DCM / MeOH=100 / 1 to 10 / 1) to give a light yellow solid (126 mg, yield 51%). ESI-MS m / z: 704.3 [M+H] + .

[0893] Step 2: Preparation of N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0894] N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)-3-(4-fluoro-4-methylpiperidin-1-yl)phenyl)-2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-sulfonamide (126 mg, 0.179 mmol) obtained in the previous step was dissolved in MeOH (10 mL). Hydrochloric acid (2 M, 0.5 mL) was added dropwise and the reaction was stirred at room temperature for 1 h. LC-MS monitoring indicated that the reaction was complete. The reaction mixture was concentrated, the pH was adjusted to a weak base with aqueous sodium bicarbonate solution, and the mixture was extracted with DCM. The mixture was concentrated and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford Compound C40 (65 mg, 58% yield) as an off-white powder.

[0895] 1H NMR(400MHz,DMSO-d6)δ:8.38(d,J=2.1Hz,1H),8.20(s,1H),8.04(s,1H),7.85 (d,J=8.5Hz,1H),7.17(d,J=2.2Hz,1H),7.09(d,J=2.1Hz,1H),6.97(dd,J=8.5, 2.1Hz,1H),4.00(t,J=5.8Hz,4H),3.77(t,J=6.5Hz,2H),3.36(t,J=6.5Hz,2H) ,2.96(t,J=5.1Hz,4H),2.24(d,J=5.8Hz,4H),1.79(s,4H),1.46(s,3H); ESI-MS m / z:620.2[M+H] + .

[0896] Examples 188-195: Synthesis of Compounds C41-C48

[0897] Using different alkynes (Intermediate 16, Intermediate 18, Intermediate 20) and appropriate azide compounds (Intermediate 33, Intermediate 34, Intermediate 35), target compounds C41-C48 were obtained according to a similar synthetic method in Example 40.

[0898] Example 196: Synthesis of N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)-3-(spiro[2.5]oct-5-en-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound C49)

[0899] Step 1: Preparation of 5-(1-(4-bromo-2-(spiro[2.5]oct-5-en-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine

[0900] 7-(4,4-Difluoropiperidin-1-yl)-5-ethynylfuro[2,3-c]pyridine (92 mg, 0.35 mmol) and 6-(2-azido-5-bromophenyl)spiro[2.5]oct-5-ene (106 mg, 0.35 mmol) were dissolved in DCM (15 mL). CuSO4·5H2O (11 mg, 0.045 mmol) and sodium ascorbate (80 mg, 0.40 mmol) were added. The mixture was stirred at 25°C overnight. LC-MS monitoring indicated that the reaction was complete. The mixture was added to ice water (30 mL) and extracted with DCM (20 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford a light yellow solid (100 mg, 50% yield). ESI-MS m / z: 566.1 [M+H] + .

[0901] Step 2: Preparation of N-(4-(4-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)-3-(spiro[2.5]oct-5-en-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0902] 5-(1-(4-bromo-2-(spiro[2.5]oct-5-en-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (100 mg, 0.176 mmol), 2-hydroxyethane-1-sulfonamide (44 mg, 0.353 mmol), CuI (34 mg, 0.176 mmol), K3PO4 (75 mg, 0.353 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (13 mg, 0.088 mmol) was dissolved in DMF (6 mL) under N2 protection and heated to 130°C for 3 h. LC-MS monitoring confirmed the complete reaction. The product was poured into ice water (30 mL) and extracted with EA (30 mL x 2). The combined organic phases were dried, concentrated, purified by reverse phase purification, and lyophilized to afford Compound C49 (50 mg, 46% yield) as a light yellow solid.

[0903] 1H NMR(400MHz, DMSO-d6)δ:8.39(s,1H),8.28(d,J=8.7Hz,1H),8.11(d,J=2.3H z,1H),8.05(s,1H),7.31(d,J=2.2Hz,1H),7.13(dd,J=8.7,2.2Hz,1H),7.01 (d,J=2.Hz,1H),5.79(s,1H),3.76(t,J=6.6Hz,2H),3.66-3.51(m,4H),3.33 -3.30(m,2H),1.99-1.81(m,8H),1.68(d,J=12.8Hz,2H),0.37(s,4H); ESI-MS m / z:611.2[M+H] + .

[0904] Examples 197-198: Synthesis of Compounds C50-C51

[0905] Different alkynes (Intermediate 76, Intermediate 78) were used to react with Intermediate 98 respectively, and the target compounds C50-C51 were obtained according to a similar synthesis method in Example 196.

[0906] Example 199: Synthesis of N-(4-(1-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-4-yl)-3-(4-fluoro-4-methylpiperidin-1-ylphenyl)-2-hydroxyethane-1-sulfonamide (Compound C52)

[0907] Step 1: Preparation of 5-(4-(4-bromo-2-(4-fluoro-4-methylpiperidin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine

[0908] 5-Azido-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (98 mg, 0.35 mmol) and 1-(5-bromo-2-ethynylphenyl)-4-fluoro-4-methylpiperidine (104 mg, 0.35 mmol) were dissolved in DCM (10 mL). CuSO4·5H2O (11 mg, 0.045 mmol) and sodium ascorbate (80 mg, 0.40 mmol) were added. The mixture was stirred at 25°C overnight. LC-MS monitoring indicated that the reaction was complete. The mixture was added to ice water (30 mL) and extracted with DCM (20 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford a light yellow solid (110 mg, 55% yield). ESI-MS m / z: 575.1 [M+H] + .

[0909] Step 2: Preparation of N-(4-(1-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1H-1,2,3-triazol-4-yl)-3-(4-fluoro-4-methylpiperidin-1-ylphenyl)-2-hydroxyethane-1-sulfonamide

[0910] 5-(4-(4-bromo-2-(4-fluoro-4-methylpiperidin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (101 mg, 0.176 mmol), 2-hydroxyethane-1-sulfonamide (44 mg, 0.352 mmol), CuI (34 mg, 0.176 mmol), K3PO4 (75 mg, 0.352 mmol), (1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (13 mg, 0.088 mmol) was dissolved in DMF (6 mL) under N2 protection and heated to 130°C for 3 h. LC-MS monitoring confirmed the complete reaction. The product was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, purified by reverse phase purification, and lyophilized to afford Compound C52 (50 mg, 46% yield) as a light yellow solid.

[0911] 1H NMR(400MHz, DMSO-d6)δ:8.37(d,J=2.1Hz,1H),8.20(s,1H),8.06(s,1H),7.72(d, J=8.5Hz,1H),7.19(d,J=2.2Hz,1H),7.08(d,J=2.1Hz,1H),6.98(dd,J=8.5,2.1Hz ,1H),3.94(t,J=5.8Hz,4H),3.76(t,J=6.5Hz,2H),3.34(t,J=6.5Hz,2H),2.96(t, J=5.1Hz, 4H), 2.13 (dq, J=13.8, 7.1, 5.8Hz, 4H), 1.86 (s, 4H), 1.42 (s, 3H); ESI-MS m / z:620.2[M+H] + .

[0912] Examples 200-207: Synthesis of Compounds C53-C60

[0913] Using different azide compounds (Intermediate 80, Intermediate 82, Intermediate 84) and appropriate alkynes (Intermediate 95, Intermediate 96, Intermediate 99), the target compounds C53-C60 were obtained according to a similar synthetic method in Example 199.

[0914] Example 208: Synthesis of N-(4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)-2-methoxyethane-1-sulfonamide (Compound C61)

[0915] Step 1: Preparation of 7-(4,4-difluoropiperidin-1-yl)-N'-(4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoyl)furo[2,3-c]pyridine-5-carboxylic acid hydrazide

[0916] 7-(4,4-Difluoropiperidin-1-yl)furo[2,3-c]pyridine-5-carboxylic acid (282 mg, 1.0 mmol) was dissolved in ACN (10 mL), and 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzohydrazide (290 mg, 1.0 mmol) was added. The mixture was cooled under N2 and cooled on ice. TCFH (337 mg, 1.2 mmol) and NMI (288 mg, 3.5 mmol) were added and stirred at room temperature for 2 h. LC-MS monitoring indicated that the reaction was complete. The mixture was poured into ice water (30 mL) and extracted with EA (30 mL x 2). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 1 / 1) to afford a light yellow solid (416 mg, 75% yield). ESI-MS m / z: 555.2 [M+H] + .

[0917] Step 2: Preparation of 7-(4,4-difluoropiperidin-1-yl)-5-(5-(4-nitro-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine

[0918] 7-(4,4-difluoropiperidin-1-yl)-N'-(4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoyl)furo[2,3-c]pyridine-5-carboxylic acid hydrazide (416 mg, 0.75 mmol) was dissolved in dioxane (15 mL), POCl3 (2 mL) was added, and the mixture was heated to 90°C overnight. LC-MS monitoring indicated that the reaction was complete. The product was concentrated directly, and the residue was dissolved in EA, washed with saturated sodium bicarbonate solution, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 2 / 1) to afford a light yellow solid (374 mg, 93% yield). ESI-MS m / z: 537.2 [M+H] + .

[0919] Step 3: 4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)aniline

[0920] The 7-(4,4-difluoropiperidin-1-yl)-5-(5-(4-nitro-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine (374 mg, 0.70 mmol) obtained in the previous step was dissolved in EtOH / H2O (5 / 1, 10 mL), and iron powder (235 mg, 4.2 mmol) and NH4Cl (225 mg, 4.2 mmol) were added. The mixture was heated to 80°C under N2 protection and refluxed for 1 h. The reaction was completed after LC-MS monitoring. The filtrate was filtered, diluted with water (40 mL), extracted with EA (40 mL * 3), and the organic phases were combined, dried, filtered, concentrated, and column chromatography (PE / EA = 10 / 1 to 1 / 1) was performed to give a light yellow solid (300 mg, yield 85%), ESI-MS m / z: 507.2 [M+H] + .

[0921] Step 4: Preparation of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-((2-methoxyethyl)sulfonamido)benzamide

[0922] 4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)aniline (253 mg, 0.5 mmol) was dissolved in DCM (10 mL), and TEA (152 mg, 1.5 mol) was added. Under N2 protection, the mixture was cooled to 0°C in an ice bath, and a solution of 2-methoxyethane-1-sulfonyl chloride (95 mg, 0.6 mmol) in DCM was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. LC-MS monitoring confirmed the complete reaction of the starting material. The product was washed with water, extracted with DCM, dried, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to afford Compound C61 (173 mg, 55% yield) as a light yellow solid.

[0923] 1H NMR (400MHz, DMSO-d6) δ: 10.18 (s, 1H), 8.31 (d, J = 2.1Hz, 1H), 8.01 (s, 1H), 7.92 (d ,J=8.5Hz,1H),7.19(d,J=2.2Hz,1H),7.05(d,J=2.1Hz,1H),6.97(dd,J=8.5,2.1Hz ,1H),4.02(t,J=5.8Hz,4H),3.76(t,J=6.5Hz,2H),3.38(s,3H),3.34(t,J=6.5Hz, 2H), 2.88 (t, J=5.1Hz, 4H), 2.16 (d, J=5.8Hz, 4H), 1.58 (s, 4H), 0.37 (s, 4H); ESI-MS m / z:629.2[M+H] + .

[0924] Example 209: Synthesis of N-(4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-fluoroethane-1-sulfonamide (Compound C62)

[0925] Intermediate C61-3 and 2-fluoroethyl-1-sulfonyl chloride were used as raw materials (synthesis reference CN105622469) and the target compound C62 was obtained according to a similar synthesis method in Example 208.

[0926] Example 210: Synthesis of N-(4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)propane-2-sulfonamide (Compound C63)

[0927] 7-(4,4-difluoropiperidin-1-yl)-5-(5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine (150 mg, 0.243 mmol), 2-hydroxyethane-1-sulfonamide (60 mg, 0.486 mmol), CuI (46 mg, 0.243 mmol), K3PO4 (103 mg, 0.486 mmol), (1R,2R)-N 1 ,N 21,2-Dimethylcyclohexane-1,2-diamine (17 mg, 0.122 mmol) was dissolved in DMF (8 mL) and reacted at 100°C overnight under N2 protection. LC-MS monitoring indicated complete reaction. The product was poured into ice water (30 mL) and extracted with EA (30 mL x 2). The combined organic phases were dried, concentrated, purified by reverse phase chromatography, and lyophilized to afford Compound C63 (85 mg, 57% yield) as a light yellow solid.

[0928] 1 H NMR(400MHz, DMSO-d6)δ:8.28(d,J=2.1Hz,1H),8.04(s,1H),7.81(d,J=8.5Hz,1H),7.12(d,J=2.2Hz,1H),7.05 (d,J=2.1Hz,1H),6.95(dd,J=8.5,2.1Hz,1H),4.03(t,J=5.8Hz,4H),3.30-3.22(m,1H),2.93(t,J=5.1Hz,4H), 2.07-1.96(m,4H),1.82-1.68(m,4H),1.41(s,6H),0.38(s,4H); ESI-MS m / z:613.2[M+H] + .

[0929] Example 211: Synthesis of N-(4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)cyclopropanesulfonamide (Compound C64)

[0930] Intermediate C1-2 was used as raw material and reacted with cyclopropylsulfonamide to obtain the target compound C64 according to a similar synthesis method in Example 210.

[0931] Example 212: Synthesis of 2-((4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)amino)-2-methylpropan-1-ol (Compound C65)

[0932] 7-(4,4-difluoropiperidin-1-yl)-5-(5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine (Intermediate C1-2, 170 mg, 0.275 mmol), 2-amino-2-methylpropane-1-ol (49 mg, 0.55 mmol),t- BuXPhos-Pd-G3(21mg,0.0275mmol), t- BuONa (78 mg, 0.825 mmol) was dissolved in dioxane (10 mL) and reacted at 90°C overnight under N2 protection. LC-MS monitoring indicated complete reaction. The product was poured into ice water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and purified by column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to afford Compound C65 (45 mg, 28% yield) as a light yellow solid.

[0933] 1 H NMR(400MHz, DMSO-d6)δ:8.22(d,J=2.1Hz,1H),8.03(s,1H),7.56(d,J=8.5Hz,1H),7.12(d,J=2.2Hz,1H),6.92(d,J=2.1Hz,1H),6.66(dd,J=8 .5,2.1Hz,1H),3.89-3.76(m,4H),3.45(s,2H),2.93(t,J=5.1Hz,4H),2.07-1.96(m,4H),1.82-1.68(m,4H),1.37(s,6H),0.38(s,4H); ESI-MS m / z:579.3[M+H] + .

[0934] Examples 213-214: Synthesis of Compounds C66-C67

[0935] Intermediate C1-2 was used as raw material and reacted with different substituted amines to obtain target compounds C66-C67 according to a similar synthesis method in Example 212.

[0936] Example 215: Synthesis of 7-(4,4-difluoropiperidin-1-yl)-5-(5-(4-(isopropylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine (Compound C68)

[0937] Step 1: 7-(4,4-difluoropiperidin-1-yl)-5-(5-(4-(isopropylthio)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine

[0938] 7-(4,4-Difluoropiperidin-1-yl)-5-(5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine (Intermediate C1-2, 617 mg, 1.0 mmol), XantPhos (58 mg, 0.1 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), DIPEA (259 mg, 2.0 mmol), and propane-2-thiol (114 mg, 1.5 mmol) were dissolved in dioxane under N2 protection and heated to 80°C overnight. LC-MS monitoring indicated a slight residual starting material. After treatment, the product was directly concentrated and purified by column chromatography (PE / EA=20 / 1 to 2 / 1) to give a light yellow solid (283 mg, yield 50%), ESI-MS m / z: 566.2 [M+H] + .

[0939] Step 2: 7-(4,4-difluoropiperidin-1-yl)-5-(5-(4-(isopropylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine

[0940] 7-(4,4-difluoropiperidin-1-yl)-5-(5-(4-(isopropylthio)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine (283 mg, 0.5 mmol) obtained in the previous step was dissolved in dioxane (12 mL). A solution of potassium monopersulfate (615 mg, 1.0 mmol) in water (5 mL) was added and stirred at room temperature overnight. LC-MS monitoring indicated that the starting material had essentially reacted. The product was then concentrated and purified by column chromatography (PE / EA = 20 / 1 to 1 / 1) to afford Compound C68 (90 mg, 30% yield) as a light yellow solid.

[0941] 1 H NMR(400MHz, DMSO-d6)δ:8.35(d,J=2.1Hz,1H),8.08(s,1H),7.98(d,J=8.5Hz,1H),7.43(dd,J=8.5,2.1Hz,1H),7.26(d,J=2.1Hz,1H),7.16(d, ESI-MS m / z:598.2[M+H] + .

[0942] Example 216: Synthesis of 5-(5-(4-(cyclopropylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridine (Compound C69)

[0943] Intermediate C1-2 was used as a raw material, reacted with cyclopropylthiol (for synthesis, see US2017 / 291910), and then subjected to an oxidation reaction to obtain the target compound C69 according to a similar synthesis method in Example 215.

[0944] Example 217: Synthesis of 4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-N-isopropyl-3-(6-azaspiro[2.5]octan-6-yl)benzenesulfonamide (Compound C70)

[0945] 7-(4,4-difluoropiperidin-1-yl)-5-(5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine (Intermediate C1-2, 309 mg, 0.5 mmol), n-butyldi(1-adamantyl)phosphine (36 mg, 0.1 mmol), and Pd(OAc)2 (22 mg, 0.1 mmol) were dissolved in IPA (8 mL). TEA (152 mg, 1.5 mmol) was added, and argon was bubbled through the mixture for 2 min. DABSO (120 mg, 0.5 mmol) was added, and the tube was sealed. The reaction was carried out at 90°C for 3 h, cooled to room temperature, and NaClO2 solution (744 mg, 10%, 1.0 mmol) was added. Methylamine hydrochloride (68 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature overnight. LC-MS monitoring indicated that the reaction of the starting material was essentially complete. The mixture was diluted with water (50 mL) and extracted with EA (50 mL x 2). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford compound C70 (123 mg, 40% yield) as a pale yellow solid.

[0946] 1H NMR(400MHz, DMSO-d6)δ:8.33(d,J=2.1Hz,1H),8.07(s,1H),7.95(d,J=8.5Hz,1H),7.46(d,J=2.1Hz,1H),7.33(dd,J=8.5,2.1Hz,1H),7.12(d ,J=2.2Hz,1H),3.98-3.87(m,4H),3.22-3.15(m,1H),2.97(t,J=5.1Hz,4H),2.21-2.06(m,4H),1.85(s,4H),1.05(s,6H),0.37(s,4H); ESI-MS m / z:613.2[M+H] + .

[0947] Examples 218-219: Synthesis of Compounds C71-C72

[0948] According to the similar synthetic method in Example 217, different amines were added to obtain the target compounds C71-C72.

[0949] Example 220: Synthesis of ethyl 2-(N-(4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfamoyl)acetate (Compound C73)

[0950] N-(4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound C1, 200 mg, 0.327 mmol) and acetic acid (111 mg, 1.64 mmol) were dissolved in THF (10 mL). 3-Nitro-1,2,4-triazole (93 mg, 0.818 mmol), BOPCl (208 mg, 0.818 mmol), and DIPEA (212 mg, 1.64 mmol) were added and reacted at room temperature for 2 h. LC-MS monitoring indicated complete reaction of the starting material. The mixture was poured into ice water (30 mL), extracted with EA (20 mL*2), and the organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA=10 / 1 to 1 / 1) to give a light yellow solid compound C73 (160 mg, yield 75%).

[0951] 1H NMR(400MHz, DMSO-d6)δ:8.29(d,J=2.1Hz,1H),8.03(s,1H),7.87(d,J=8.5Hz,1H),7.18(d,J=2.2Hz,1H),7.07(d,J=2.1Hz,1H),6.98(dd,J=8.5,2.1H z,1H),4.07(t,J=5.8Hz,4H),3.78(t,J=6.5Hz,2H),3.39(t,J=6.5Hz,2H), 2.95(t,J=5.1Hz,4H),2.11-1.99(m,7H),1.55(s,4H),0.37(s,4H); ESI-MS m / z:657.2[M+H] + .

[0952] Examples 221-316: Synthesis of Compounds C74-C169

[0953] Target compounds C74-C169 were obtained according to a similar synthetic method in Example 220.

[0954] Example 317: KIF18A enzyme activity screening

[0955] This study evaluated the ability of compounds of the invention to inhibit KIF18A protease activity in vitro. KIF18A inhibitors were characterized using the ADP-Glo ​​(Promega) kinase assay in the presence of 10 μM ATP (Promega). The final enzyme concentration was 1 nM, the final substrate concentration was 10 μM, and the final DMSO concentration was 0.5%.

[0956] Compounds were dissolved in DMSO to obtain a 20 mM stock solution. Dose gradient reactions were prepared with an initial compound concentration of 10 μM and then four-fold dilutions were performed in DMSO (control compounds were three-fold diluted) for a total of ten data points. Using an ECHO acoustic pipetting device (LABCYTE), 0.025 μL of the diluted compound solution was transferred to a 384-well assay plate (Greiner). 2.5 μL of KIF18A enzyme working solution was added to the 384-well assay plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. The reaction was then initiated by adding 2.5 μL of ATP working solution and incubated at 25°C for 60 minutes. 4 μL of ADP-Glo ​​working solution was added to the reaction, which was incubated at 25°C for 40 minutes. Finally, 8 μL of detection working solution was added and incubated at 25°C for 40 minutes. Detection was then performed using an HTS high-throughput drug screening multi-functional microplate reader (BMG).

[0957] The inhibition rate of the compound on KIF18A protein activity was calculated using the following formula:

[0958] Inhibition percentage (%) = 100*(mean value of DMSO group - mean value of compound) / (mean value of DMSO group - mean value of blank control group).

[0959] The IC values ​​of the compounds were fitted according to the nonlinear regression equation using the software XLfit 5.5.0. 50 The screening results are shown in Table 1.

[0960] Example 318: Screening of OVCAR3 cell anti-proliferative activity

[0961] This study used a cell proliferation assay to analyze the cytotoxicity of OVCAR3 ovarian cancer cells after four days of treatment with a KIF18A inhibitor. The OVCAR3 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. and cultured in a Thermo Fisher Scientific cell culture incubator at 37°C and 5% carbon dioxide using 1640 medium. In this experiment, the KIF18A inhibitor was dissolved in DMSO to an initial concentration of 10 μM and diluted threefold in DMSO for a total of eight data points. The final DMSO concentration was 0.5%.

[0962] OVCAR3 cells were seeded in a white 96-well plate, with 80 μL of cell suspension per well, containing 2,000 OVCAR3 cells. The plate was incubated overnight in a CO2 incubator. Then, 20 μL of KIF18A inhibitor solution at varying concentrations was added to the plate, and the 96-well plate was incubated for four days. A separate plate was prepared, and the signal value was read on the day of drug addition, which was used as the maximum value (Max value in the equation below) for data analysis. 25 μL of cell viability chemiluminescent detection reagent was added to each well of this plate, and the plate was incubated at room temperature for 10 minutes to stabilize the luminescent signal. The readings were performed using a multi-label analyzer.

[0963] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The values ​​can be obtained by four-parameter curve fitting (using the "log (inhibitor) vs. response"--Variable slope mode in GraphPad Prism). Min: wells with cells treated with 0.5% DMSO; Max: wells on Day 0. The screening results are shown in Table 1.

[0964] Table 1: Inhibitory activity of compounds against KIF18A protein (IC 50 ) and antiproliferative activity against OVCAR3 cells (IC 50 ) Note: +++: indicates IC 50 ≤100nM ++: indicates 100nM <IC 50 ≤500nM +: indicates IC 50 >500nM

[0965] From the data in the above table, it can be seen that the compounds of the present invention have strong inhibitory activity on KIF18A protein. At the same time, the compounds of the present invention also have strong anti-proliferative activity against TP53-deficient / CCNE1-amplified OVCAR3 cells. The anti-proliferative activity IC of most compounds on OVCAR-3 cells is 50 Compared with the control drug AMG650, the compound of the present invention has stronger inhibitory effect on KIF18A protein activity and anti-proliferative activity on OVCAR3 cells.

[0966] Example 319: Evaluation of blood drug concentration in mice after oral administration

[0967] This study evaluated the blood concentration of the compound of the present invention in mice. The experiment used ICR mice from Zhaoyan (Suzhou) New Drug Research Center Co., Ltd. At the start of dosing, the animals were 6-8 weeks old and weighed 18-25 grams. The animals were housed in transparent resin plastic cages (400mm*240mm*200mm). Fluorescent lighting was used, with 12 hours of lighting (07:00-19:00) and 12 hours of no lighting per day. The dark time can be intermittently interrupted due to the needs of research-related activities. The ambient temperature and relative humidity of the animal room should be controlled within the range of 20-26°C and 40-70%, respectively. The feed was qualified rodent feed, and the drinking water was filtered and sterilized by an ultrapure water machine. All animals had free access to water during the experiment. The animals were fasted for at least 12 hours before dosing, and food was resumed 4 hours after dosing.

[0968] Animal body weight was measured before administration. Healthy animals of similar weight were selected for inclusion in the experiment and randomly divided into groups of 3 per group. Compounds were prepared using a 0.5% CMC aqueous solution at a concentration of 10 mg / kg. A single oral dose was administered. At least 0.2 mL of venous blood was collected 1 and 4 hours after administration. Blood was collected using EDTA-K2 anticoagulant tubes and gently inverted to mix. After collection, the blood samples were placed in an ice-water bath and rapidly centrifuged to separate plasma at 4000 rpm for 10 minutes at 4°C. Plasma was then stored at -70°C until testing.

[0969] Plasma sample standard curve and quality control: Prepare standard curve working solution and quality control working solution using 80% methanol in water (Thermo Fisher) as the diluent. Add 45 μL of blank plasma to 5 μL of each working solution to prepare the plasma standard curve and quality control samples. Add 300 μL of internal standard (8 μg / mL tolbutamide, acetonitrile (Thermo Fisher)) to the prepared standard curve and quality control samples. Vortex mix for 1 minute, then centrifuge at 4°C, 15,400 g for 10 minutes using an Eppendorf, 5810 centrifuge. The supernatant is analyzed by liquid chromatography-mass spectrometry (AB Sciex, API5000).

[0970] Plasma sample pretreatment: After thawing at room temperature, 50 μL of plasma was added to 300 μL of internal standard (8 μg / mL tolbutamide, acetonitrile (Thermo Fisher)). After vortex mixing for 1 min, the sample was centrifuged at 4°C and 15,400 g for 10 min using an Eppendorf 5810 centrifuge. The supernatant was analyzed by liquid chromatography-mass spectrometry (AB Sciex, API5000).

[0971] Analyst 1.6.3 software was used to output the original spectra, concentration, accuracy and other data. Microsoft Excel 2007 software was used to calculate the mean and standard error. The compound concentration-time results in the plasma samples of each group of animals are shown in Table 2.

[0972] Table 2. Concentrations of the compounds of the present invention in plasma samples at different time points (Mean ± SEM) Note: AMG650 detects the drug prototype. The compound of the present invention is a prodrug, and the corresponding original drug is detected.

[0973] It can be seen from the data in the above table that the compound of the present invention has good oral absorption characteristics in mice after oral administration, and the blood concentration of the compound is high.

[0974] Example 320: In vivo evaluation of the anti-tumor efficacy of the compounds of the present invention

[0975] To evaluate the effects of the compounds of the present invention on tumor growth, an OVCAR-3 ovarian cancer xenograft animal model was established. Female BALB / c nude mice, 6-7 weeks old and weighing 18-21 grams, were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd. After purchase, the mice were housed in SPF-grade IVC cages, 2-6 mice per cage, with free access to food and water. The housing temperature was maintained between 20-26°C (68-79°F), with a relative humidity of 40-70%. The lighting conditions included 12 hours of fluorescent light exposure (05:00-17:00) and 12 hours of no light per day. The experiments were conducted after one week of adaptive breeding.

[0976] OVCAR-3 (ATCC, HTB-161) cells were cultured in vitro in RPMI-1640 medium (Gibco, A1049101) supplemented with 20% heat-inactivated fetal bovine serum (Gibco, 10099141C) and 0.01 mg / mL recombinant human insulin (Vivacell, C6010-0100). The cells were cultured in a cell culture incubator at 37°C and 5% CO2, and passaged 2-3 times per week. When the cells reached the exponential growth phase, they were harvested, counted, and injected subcutaneously into the right flank of female BALB / c nude mice with 1×10 cells / mL (200 μL). 7 OVCAR-3 cell suspension (100 μL basal medium + 100 μL Matrigel (Corning, 2181001)). 25 days after cell inoculation, select tumors with good shape and a volume of 100 mm 3 -300mm 3Tumor-bearing mice within the range were randomly divided into groups according to the experimental plan, with 5 mice in each group. They were orally administered (PO, OQ) once a day starting from the day of grouping. All compounds of the present invention were administered at a concentration of 30 mg / kg. The administration was stopped after 28 days, and the observation was continued. The administration of compounds A39 and A43 was observed for 80 days, and the administration of compounds B83, B86, and C105 was observed for 70 days. During the administration period, the tumor diameter was measured with a digital vernier caliper twice a week, and the mice were weighed; after the administration was stopped, the tumor diameter was measured once a week during the observation period, and the mice were weighed. The calculation formula for tumor volume is: V = 0.5a*b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.

[0977] The tumor inhibition efficacy of the compound was evaluated by TGI (%), TGI (%) = [1-(TVi-TV0) / (TVVi-TVV0)] * 100% (TV0 is the average volume of the treatment group on day 0, TVV0 is the average volume of the control group on day 0; TVi is the average volume of the treatment group on day i, TVVi is the average volume of the control group on day i). Data were plotted using GraphPad Prism software, and tumor volume and body weight data were expressed as the mean plus or minus the standard error of the mean and plotted as a function of time.

[0978] The results for compounds A39 and A43 are shown in Figures 1A-B, and those for compounds B83, B86, and C105 are shown in Figures 2A-B. As shown, daily oral administration of the compounds significantly inhibited OVCAR-3 tumor growth and led to tumor regression, without any weight loss in the animals, demonstrating that the compounds were well tolerated. Even after a 28-day observation period following drug withdrawal, the compounds continued to inhibit tumor recurrence for an extended period, demonstrating a significantly greater efficacy than the control compound AMG650.

[0979] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound having a structure as shown in formula (1), or its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate: In formula (1): Ring A is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic group, and the heteroaryl and heterocyclic group may be further substituted by 0-3 of the following groups: halogen, C 1-3 Alkyl or C 1-3 Alkoxy; L is selected from -C(O)NR a 、-NR a C(O)- or 5-6 membered heteroaromatic ring; Y is selected from the following group: chemical bond, -NR a -、-SO 2 -、-O-、-NR a S(O) 2 -、-S(O) 2 NR a -、C 3-6 Cycloalkyl or 4-7 membered heterocyclic group; R a Selected from the following group: H or C 1-3 alkyl; X 1 , X 2 and X 3 Each independently selected from the following group: N or CR 4 , where R 4 H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; R 1 Select from the following group: C 3-6 Cycloalkyl or 4-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by 0-3 groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group; R 2 Selected from the group consisting of H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; R 3 Selected from the following group: H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-8 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 0-3 groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclic group or -O(CO)R 5 ; R 5 Select from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclyl; the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group or NR d R e ; where R d and R e Each independently selected from the following group: H or C 1-3 Alkyl; or R d and R e The N atom connected thereto forms a 3-6 membered ring structure, wherein the ring structure optionally contains 1 or 2 heteroatoms selected from N, O, and S; Z is in, The dotted line is a chemical bond or does not exist. When the dotted line connected to V is a chemical bond, V is C; when the dotted line connected to V does not exist, V is N or CH; R 6 and R 7 Each independently selected from the group consisting of H, halogen, CN, C 1-3 Alkyl, C 1-3 Oxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; or R 6 and R 7 The C atom connected to it forms a 3-6 membered ring structure; or R 6 and R 7 The C atom connected to it forms C=T, where T is selected from CR b R c ; Among them, R b and R c Each independently selected from the group consisting of H, halogen, CN or C 1-3 Alkyl; or R b and R c The C atom connected thereto forms a 3-6 membered ring structure; the ring structure optionally contains 0, 1 or 2 heteroatoms selected from N, O, and S.

2. The compound according to claim 1, in, Z is selected from the following group: Where R 6 and R 7 Definitions as set forth in claim 1.

3. The compound according to claim 1, in, In the formula (1), Z is selected from the following group:

4. The compound according to claim 1, in: Ring A is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic group, and the heteroaryl and heterocyclic group may be further substituted by 0-3 of the following groups: halogen, C 1-3 Alkyl or C 1-3 Alkoxy; L is selected from -C(O)NR a or -NR a C(O)-; Y is selected from the following group: chemical bond, -NR a -、-SO 2 -、-O-、-NR a S(O) 2 -、-S(O) 2 NR a -、C 3-6 Cycloalkyl or 4-7 membered heterocyclic group; R a Selected from the following group: H or C 1-3 alkyl; X 1 , X 2 and X 3 Each independently selected from the following group: N or CR 4 , where R 4 H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; R 1 Select from the following group: C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group; R 2 Selected from the group consisting of H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; R 3 Selected from the following group: H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group or -O(CO)R 5 ; R 5 Select from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclyl; the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group or NR d R e ; where R d and R e Each independently selected from the following group: H or C 1-3 Alkyl; or R d and R e The N atom connected thereto forms a 3-6 membered ring structure, and the ring structure optionally contains 1 or 2 heteroatoms selected from N, O, and S; Z is independently selected from the following group: R 6 and R 7 Each independently selected from the group consisting of H, halogen, CN, C 1-3 Alkyl; or R 6 and R 7 The connected C atoms form a 3-6 membered ring structure, and the ring structure optionally contains 0, 1 or 2 heteroatoms selected from N, O, and S; R 8 and R 9 Each independently selected from the group consisting of H, halogen, CN, C 1-3 Alkyl or C 1-3 Alkoxy, or R 8 and R 9 The connected C atoms form a 3-6 membered ring structure, and the ring structure optionally contains 0, 1 or 2 heteroatoms selected from N, O and S.

5. The compound according to claim 1, in, The compound has a structure shown in formula (2): in: The dotted line is a chemical bond or does not exist. When the dotted line connected to V is a chemical bond, V is C; when the dotted line connected to V does not exist, V is N or CH; Ring A is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic group, and the heteroaryl and heterocyclic group may be further substituted by 0-2 of the following groups: halogen, C 1-3 Alkyl or C 1-3 Alkoxy; Ring B is a 5-6 membered heteroaromatic ring; Y is selected from the following group: chemical bond, -NR a -、-SO 2 -、-O-、-NR a S(O) 2 -、-S(O) 2 NR a -、C 3-6 Cycloalkyl or 4-7 membered heterocyclic group; R a Selected from the following group: H or C 1-3 alkyl; X 1 , X 2 and X 3 Each independently selected from the following group: N or CR 4 , where R 4 H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; R 1’ and R 2’ Each independently selected from the group consisting of H, halogen, CN, C 1-3 Alkyl, C 1-3 Oxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; or R 1’ and R 2’ The C atom connected thereto forms a 3-6 membered cyclic structure, wherein the cyclic structure optionally contains 0, 1 or 2 heteroatoms selected from N, O, S; or R 1’ and R 2’ The C atom connected to it forms C=T, where T is selected from CR b R c ; Among them, R b and R c Each independently selected from the group consisting of H, halogen, CN or C 1-3 Alkyl; or R b and R c The C atom connected thereto forms a 3-6 membered ring structure, wherein the ring structure optionally contains 0, 1 or 2 heteroatoms selected from N, O and S; R 1 Select from the following group: C 3-6 Cycloalkyl or 4-10 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group; R 2 Selected from the group consisting of H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; R 3 Selected from the following group: H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group or -O(CO)R 5 ; R 5 Select from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group; the alkyl, cycloalkyl or hetero The ring group is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group or NR d R e ; where R d and R e Each independently selected from the following group: H or C 1-3 Alkyl; or R d and R e The nitrogen atom connected thereto forms a 3-6 membered ring structure, and the ring structure optionally contains 1 or 2 heteroatoms selected from N, O, and S.

6. The compound according to claim 1, in, The compound has a structure shown in formula (3): in: L is Y is selected from the following group: chemical bond, -NR a -、-SO 2 -、-NR a S(O) 2 -or-S(O) 2 NR a -, R a Selected from the following group: H or C 1-3 alkyl; X 1 , X 2 and X 3 Each independently selected from the following group: N or CR 4 , where R 4 H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; R 1 ” and R 2 " are each independently selected from the group consisting of halogen or C 1-3 Alkyl; or R 1 ” and R 2 "The C atom connected to it forms a divalent C 3-6 saturated or partially unsaturated carbocyclic group; R 1 Select from the following group: C 3-6 Cycloalkyl or 4-8 membered heterocyclic group, wherein the cycloalkyl and heterocyclic group may be further substituted by 0-3 groups selected from the following groups: halogen, CN, C 1-3 Alkyl or C 1-3 Haloalkyl; R 2 Selected from the group consisting of H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Haloalkoxy; R 3 Selected from the following group: H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-8 membered heterocyclic group, the alkyl, cycloalkyl or heterocyclic group may be further substituted by 0-3 of the following groups: OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-8 membered heterocycloalkyl; Ring A is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic group, and the heteroaryl and heterocyclic group may be further substituted by 0-3 of the following groups: halogen, C 1-3 Alkyl or C 1-3 Alkoxy.

7. The compound according to claim 1, in, X 1 , X 2 and X 3 Each independently selected from the group consisting of N, CH, CF, CCl, CMe, C(OMe), CCF 3 or C(OCF 3 ).

8. The compound according to claim 1, in, R 1 Select from the following group:

9. The compound according to claim 1, in, R 2 Selected from the group consisting of H, Me, F, or OMe.

10. The compound according to claim 1, in, In the formula (1), YR 3 Select from the following group:

11. The compound according to claim 1, in, The compound has a structure shown in formula (4): in: R 1 for Z is Y 3 Select from the following group: Ring A is a 5-membered oxygen-containing heteroaryl group or a 5-membered oxygen-containing heterocyclic group.

12. The compound according to claim 1, or its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, It is characterized in that The compound has a structure selected from the group consisting of:

13. A pharmaceutical composition for treating, regulating and / or preventing diseases mediated by KIF18A, It is characterized in that The pharmaceutical composition contains: (1) a compound according to any one of claims 1 to 12, or an isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof as an active ingredient; and (2) Pharmaceutically acceptable excipients and / or carriers.

14. Use of a compound according to any one of claims 1 to 12, or an isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 13, It is characterized in that Used for preparing drugs for preventing and / or treating diseases mediated by KIF18A.

15. A method for treating, regulating and / or preventing diseases mediated by KIF18A. It is characterized in that The method comprises the steps of administering to an individual in need thereof the compound according to any one of claims 1 to 12, or its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition according to claim 13.

16. The use according to claim 14 or the method according to claim 15, It is characterized in that The KIF18A-mediated related diseases are selected from the following group: glioblastoma, bile duct cancer, bladder cancer, head and neck cancer, ovarian cancer, brain tumor, gastric cancer, liver cancer, lung cancer, intestinal cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, leukemia, lymphoma.

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