Inhibitor of kinin KIF18A and application thereof

Abstract

The invention relates to a KIF18 inhibitor with a structure as shown in a formula (I) and a synthesis method thereof, and the compound can regulate KIF18A protein so as to influence a cell cycle and a cell proliferation process to treat cancers and cancer-related diseases. And pharmaceutical compositions comprising the compounds, methods for treating conditions associated with KIF18A activity.

Description

Kinesin KIF18A inhibitors and their applications Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to a class of kinesin KIF18A inhibitors and their use in inhibiting cancer cell proliferation and treating cancer. Background Art

[0002] KIF18A, a member of the kinesin-8 family of kinesins, uses the energy released by ATP hydrolysis to propel it along microtubules toward the positive pole within the cell. KIF18A is localized at the positive end of microtubules, where it regulates their dynamic instability, exerting an activity similar to that of a microtubule depolymerase. During mitosis, KIF18A regulates spindle microtubule dynamics and chromosome amplitude, playing a key role in ensuring the timely alignment of chromosomes during mitosis, maintaining genomic stability, and enabling the successful completion of mitosis.

[0003] The KIF18A gene belongs to the kinesin-8 subfamily of kinesins and is a plus-end-directed motor. KIF18A is thought to affect the dynamics of the plus ends of centromere microtubules to control correct chromosome positioning and spindle tension. Depletion of human KIF18A in HeLa cervical cancer cells leads to longer spindles, increased chromosome oscillation in metaphase, and activation of the mitotic spindle assembly checkpoint (MI Mayr et al., Current Biology 17, 488–98, 2007). KIF18A appears to be a viable target for cancer therapy. KIF18A is overexpressed in many types of cancer, including but not limited to colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, and ovarian cancer. In addition, in cancer cell lines, gene deletion or knockout or KIF18A inhibition affects the mitotic spindle apparatus. In particular, inhibition of KIF18A has been found to induce mitotic cell arrest, a known vulnerability that can promote mitotic cell death by apoptosis, mitotic catastrophe, or multiphase-driven lethality or death following mitotic slippage in interphase. Consequently, there is intense interest in finding inhibitors of the KIF18A protein. Therefore, inhibition of KIF18A ATPase activity is a promising approach for developing new anticancer agents.

[0004] Summary of the Invention

[0005] The present disclosure belongs to the field of medicine and relates to a class of kinesin KIF18A inhibitors, specifically to the compounds or their stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof or their pharmaceutically acceptable salts, cocrystals, metabolites, solvates, prodrugs or isotope-labeled forms, methods for preparing the compounds, and pharmaceutical compositions containing the compounds and their use as therapeutic agents, in particular, as agents for inhibiting cancer cell proliferation and treating cancer.

[0006] The present disclosure provides a novel class of compounds for use in regulating KIF18A protein, alone or in a binding complex with microtubules, for treating KIF18A-mediated conditions and / or diseases, including cancer, inflammation, or ciliary pathology.

[0007] The present disclosure provides compounds having MT-based KIF18A modulatory activity, particularly KIF18A inhibitory activity. To this end, the present disclosure also provides the use of these compounds and pharmaceutically acceptable salts thereof in the preparation and manufacture of pharmaceutical compositions or medicaments for the therapeutic, prophylactic, acute or chronic treatment of KIF18A-mediated diseases and disorders (including but not limited to cancer).

[0008] The present disclosure provides a technical solution: a compound having a structure of Formula I, and pharmaceutically acceptable salts, stereoisomers, and isotope isomers thereof:

[0009] in, Indicates a single bond or a double bond;

[0010] Among them, X 1 Indicates CR W1 or N;

[0011] Among them, X 2 Indicates CR W2 or N;

[0012] Among them, X 3 Indicates CR W3 or N;

[0013] Among them, X 4 Indicates CR W4 or N;

[0014] Among them, X 5 Indicates CR W5 or N;

[0015] Among them, X 6 Indicates CR W6 or N;

[0016] Among them, X 7 Indicates CR W7 or N;

[0017] Among them, R W1 、R W2 、R W3 、R W4 、R W5 、R W6 、R W7 Each independently represents hydrogen, halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)NR a R b , -SF5 or -NR a R b ;

[0018] Wherein, the chemical bond between X2, X3 or X5, X6 or X6, X7 may further be fused with ring A to form a 5-6 membered saturated or unsaturated ring, which may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, and N; and the ring may further be substituted with 0-3 of the following: halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)NR a R b , -SF5 or -NR a R b substituted by a substituent;

[0019] Wherein, L1 represents -C(O)NH- or a triazole group;

[0020] Among them, Y 1 Indicates -(CR a R b ) m -;Y 2 Indicates -(CR a R b ) n -;

[0021] Among them, arbitrarily CR a R b Can be -O-, -S-, -NRa -、-NR a SO2-、-NR a C(O)-、-C(O)NR a -,-SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、 replaced by;

[0022] Among them, R L Indicates L2-R M ;

[0023] Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a -S(=O)(=NH), -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -、-C=N(OH)-、-NR a (C=O), -P(O)(OR a )2、-NR a P(O)(OR a )2 or -NR a P(O)(R a )2-;

[0024] Among them, R M It represents 0-3 selected from halogen, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted C1-C6 alkyl or C3-C6 cycloalkyl;

[0025] Or, LR M Indicates -N=S(=O)-(R L )2, where two R L Together with the sulfur atom to which they are attached, they may form a saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1 or 2 heteroatoms selected from N, O and S;

[0026] Wherein, m and n each independently represent an integer from 0 to 10;

[0027] Among them, when When it represents a single bond, Y represents -O-, -NH-, or the following groups:

[0028] or

[0029] Wherein, * indicates the site of connection with ring A; the wavy line indicates the site of connection with Y2;

[0030] Where X represents CR 1 R 1’ 、O、NR a ;

[0031] Among them, R 1 、R 1’ 、R 2 、R 2’ 、R 3 、R 3’ 、R 4 、R 4’ , each independently represents hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl;

[0032] or R 1 、R 1’ Together with the carbon atom to which it is attached, they form a 3-6 membered ring;

[0033] or R 2 、R 2’ Together with the carbon atom to which it is attached, they form a 3-6 membered ring;

[0034] or R 3 、R 3’ Together with the carbon atom to which it is attached, they form a 3-6 membered ring;

[0035] or R 4 、R 4’ Together with the carbon atom to which it is attached, they form a 3-6 membered ring;

[0036] Among them, R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a 、R bTogether with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N.

[0037] In one technical solution of the present disclosure, X1, X2, X3, X4, and X5 represent CH or N.

[0038] In one technical solution of the present disclosure, X1 and X2 represent CH or N.

[0039] In one technical solution of the present disclosure, X4 and X5 represent CH or N.

[0040] In a technical solution of the present disclosure, wherein Y1 represents -(CR a R b ) m -.

[0041] In one technical solution of the present disclosure, Y1 represents -NH-C(=O)-.

[0042] In a technical solution of the present disclosure, wherein Y1 represents -O(CR a R b ) m -or-(CR a R b ) m O-.

[0043] In a technical solution of the present disclosure, wherein Y1 represents -CR a =CR a -or-CR a R b -CR a =CR b -.

[0044] In a technical solution of the present disclosure, wherein Y2 represents -(CR a R b ) n -.

[0045] In a technical solution of the present disclosure, wherein Y2 represents -NR a -C(=O)-.

[0046] In a technical solution of the present disclosure, wherein Y2 represents -O(CR a R b ) n -or-(CR a R b ) n O-.

[0047] In a technical solution of the present disclosure, wherein Y2 represents -CR a =CR a -、-CR a =CR b -CR a R b -or-CR a R b -CR a =CR a -.

[0048] In a technical solution of the present disclosure, wherein -Y1-Y2 represents -CR a =CR a -.

[0049] In a technical solution of the present disclosure, wherein -Y1-Y2 represents -CR a Rb-NR a C(O)-.

[0050] In a technical solution of the present disclosure, wherein -Y1-Y2 represents-

[0051] In one technical solution of the present disclosure, Y represents -O- or -NH-.

[0052] In a technical solution of the present disclosure, wherein Y represents

[0053] In a technical solution of the present disclosure, wherein Y represents

[0054] In a technical solution of the present disclosure, wherein Y represents

[0055] In a technical solution of the present disclosure, wherein Y represents

[0056] In a technical solution of the present disclosure, wherein Y represents

[0057] In a technical solution of the present disclosure, wherein X represents O, NH, CR 1 R 1’ .

[0058] In one technical solution of the present disclosure, X represents CH2 or CF2.

[0059] In a technical solution of the present disclosure, R 2 、R 2’ 、R 3 、R 3’ 、R4 、R 4’ Each independently represents hydrogen, CH3 or together with the carbon atom to which it is attached forms a cyclopropyl group.

[0060] In a technical solution disclosed herein, the chemical bond between X5 and X6 in ring A is fused with ring A to form a 5-6 membered saturated or unsaturated ring, which may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, and N; and the ring may further be substituted with 0-3 of the following: halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)NR a R b , -SF5 or -NR a R b substituted by a substituent.

[0061] In a technical solution disclosed herein, the chemical bond between X5 and X6 in ring A is fused with a benzene ring or a pyridine ring; and the ring may further be substituted with 0-3 of the following substituents: halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)NR a R b , -SF5 or -NR a R b substituted by a substituent.

[0062] In a technical solution disclosed herein, the chemical bond between X5 and X6 in ring A is fused with a pyrrole ring, and the ring may be further substituted with 0-3 of the following substituents: halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)NR a Rb , -SF5 or -NR a R b substituted by a substituent.

[0063] In a technical solution of the present disclosure, R L Represents LR M ; Wherein, L represents -NR a SO2-、-SO2NR a -.

[0064] In a technical solution of the present disclosure, R M represents a C1-C1 alkyl group substituted by 0, 1, 2 or 3 OH groups.

[0065] Specifically, the present disclosure provides a compound having the following structure:

[0066] In addition, the present disclosure also provides a pharmaceutical composition containing any one of the compounds in the technical solutions of the present disclosure or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, and a pharmaceutically acceptable carrier thereof.

[0067] In addition, the present disclosure also provides a method for treating tumors by inhibiting KIF18A, comprising administering any one of the compounds of the present disclosure or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof to an individual in need thereof.

[0068] definition

[0069] Unless otherwise indicated, the compounds of the present disclosure may be interpreted to include, in addition to the specific structures of the compounds, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotopomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, and metabolites. In other words, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotopomers, solvates, hydrates, prodrugs, and metabolites also fall within the scope of protection of the compounds.

[0070] Unless otherwise indicated, the following terms used in this patent specification and claims have the meanings discussed below. Furthermore, many of the groups defined herein may be optionally substituted. The list of typical substituents in this definitions section is provided as an example and is not intended to limit the substituents defined elsewhere in this patent specification and claims.

[0071] The term "alkyl" refers to a saturated aliphatic hydrocarbon group or linker, comprising straight and branched chain groups of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. "Lower alkyl" particularly refers to an alkyl group having 1 to 4 carbon atoms. Examples of alkyl groups include -(CH2)3-, methyl, trifluoromethyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like. Alkyl groups may be substituted or unsubstituted. Typical substituents include cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, C-carboxyl, O-carboxyl, nitro, silyl, amino, and -NR x R y , where R x With R y Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and combined 5- or 6-membered heterocyclyl rings.

[0072] The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

[0073] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkynyl" group contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and the like.

[0074] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above having the specified number of carbon atoms attached via a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0075] The term "cycloalkyl" refers to a 3- to 8-membered all-carbon monocyclic or bicyclic ring structure, an all-carbon 5-membered / 6-membered or 6-membered / 6-membered fused bicyclic ring, or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares at least one adjacent carbon atom with another ring in the system), wherein one or more rings may contain one or more double bonds, but none of such rings have a complete conjugated π-electron system, or the bicyclic rings may form a spirocycle by sharing a carbon atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, and cycloheptatriene. Bicyclic cycloalkyl groups include bridged, spiro, or fused cycloalkyl groups. Illustrative examples of cycloalkyl groups are derived from, but are not limited to, the following:

[0076] "Aryl" refers to an all-carbon monocyclic or fused-ring polycyclic group of 6 to 12 carbon atoms with a complete conjugated π-electron system. Examples of aryl groups are, but are not limited to, phenyl, naphthyl, and anthracenyl. Aryl groups may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, sulfinyl, sulfonyl, amino, and -NR a R b , where R a With R b As defined above. Aryl-fused saturated or unsaturated cycloalkyl / saturated or unsaturated heterocycloalkyl can be considered as special substituents of aryl, typical examples of which include but are not limited to:

[0077] "Heteroaryl" refers to a monocyclic or fused ring of 5 to 12 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O and S, the remaining ring atoms being C, and further, having a complete conjugated π-electron system.Examples of typical heteroaryl groups are, but are not limited to, acridinyl, azetidinyl, azcinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furanyl, furanyl, furanyl, pyridin ... oxazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthiazinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3- Oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, perylene, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyridinyl pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1 ,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolyl, thiazolyl, thiazolyl, thiazolopyridyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, dihydroindolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-"; wherein the present disclosure also includes fused ring and spiro compounds containing, for example, the above-mentioned heterocycles.

[0078] A pharmaceutically acceptable heteroaryl group is sufficiently stable to be attached to the compounds of the present disclosure, formulated into a pharmaceutical composition, and subsequently administered to a patient in need thereof.

[0079] Unless otherwise defined, the definitions of substituents disclosed herein are independent of each other and not interrelated. For example, for a substituent R a (or R b ), they are independent of each other in the definitions of different substituents. Specifically, for R a (or R b ) When a definition is selected in a substituent, it does not mean that the R a (or R b ) has the same definition in other substituents. More specifically, for example (listing only non-exhaustive) for NR a R b In the case of R a (or R b ) is selected from hydrogen, it does not mean that in -C(O)-NR a R b Middle R a (or R b ) must be hydrogen.

[0080] "Halo" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl," which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms.

[0081] "Haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group as defined above with the specified number of carbon atoms attached via an oxygen bridge. For example, "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" refers to a haloalkyl group as defined above with the specified number of carbon atoms attached via a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0082] In the present disclosure, when referring to certain substituent groups, the expression Cx1-Cx2 is used, which means that the number of carbon atoms in the substituent group may be x1 to x2. For example, C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C1-C8 means that the group contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C2-C8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C3-C8 means that the group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C4-C8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6 means that the group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C1-C6 means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6 means that the group contains 2, 3, 4, 5 or 6 carbon atoms, and C3-C6 means that the group contains 3, 4, 5 or 6 carbon atoms.

[0083] In the present disclosure, when referring to a cyclic group (such as an aryl, heteroaryl, cycloalkyl and heterocycloalkyl), the expression "x1-x2 membered ring" is used, which means that the number of ring atoms of the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; the 3-6 membered ring means that the cyclic group can be a 3-, 4-, 5- or 6-membered ring, and the number of its ring atoms can be 3, 4, 5 or 6; the 3-8 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7- or 8-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7 or 8; the 3-9 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7, 8 or 9-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, The term "4-7 membered ring" refers to a 4-, 5-, 6-, or 7-membered ring having 4, 5, 6, or 7 ring atoms; a 5-, 8-, or 5-membered ring refers to a 5-, 6-, 7-, or 8-membered ring having 5, 6, 7, or 8 ring atoms; a 5-, 12-, or 5-membered ring refers to a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; and a 6-, 12-, or 6-membered ring refers to a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms may be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, such as heteroatoms selected from N, O and S.

[0084] In the present disclosure, one or more halogens may each be independently selected from fluorine, chlorine, bromine and iodine.

[0085] As used herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valence is maintained and the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0086] Where nitrogen atoms (e.g., amines) are present on the compounds of the present disclosure, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the present disclosure. Thus, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxide to obtain the derivatives of the present disclosure.

[0087] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0088] The term "patient" as used herein refers to an organism to be treated by the methods of the present disclosure. Such organisms preferably include, but are not limited to, mammals (e.g., mice, apes / monkeys, horses, cows, pigs, dogs, cats, etc.) and most preferably refer to humans.

[0089] The term "effective amount" as used herein means the amount of a drug or pharmaceutical agent (i.e., a compound of the present disclosure) that will cause a biological or medical response of a tissue, system, animal, or human being, such as that sought by a researcher or clinician. In addition, the term "therapeutically effective amount" means an amount that results in improved treatment, cure, prevention, or alleviation of a disease, condition, or side effect, or reduces the rate of progression of a disease or condition, compared to a corresponding subject that has not received the above amount. An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited by a specific formulation or route of administration. The term also includes within its scope an effective amount that enhances normal physiological function.

[0090] The term "treatment" as used herein includes its broad meaning, covering therapeutic treatment and / or prophylactic treatment of a subject. Specifically, the "treatment" includes any treatment that leads to the alleviation, suppression, elimination and improvement and / or prevention of a condition, disease, disorder, etc., such as alleviating, reducing, regulating, improving, eliminating, preventing, preventing or improving its symptoms. The therapeutic treatment includes alleviating, suppressing or improving the symptoms or conditions of the disease; suppressing the occurrence of complications; improving potential metabolic syndrome; suppressing the occurrence of the disease or symptoms, such as controlling the development of the disease or condition; alleviating the disease or symptoms; reducing the disease or symptoms; alleviating complications caused by the disease or symptoms, or treating signs caused by the disease or symptoms. The prophylactic treatment includes prior treatment to prevent, block or delay, slow down the occurrence or development of the disease or condition or reduce the severity of the disease or condition.

[0091] Likewise, "therapeutic agent" also includes agents or reagents that have therapeutic and / or prophylactic effects on a subject.

[0092] The terms "pharmaceutically acceptable" or "pharmaceutically acceptable" are used herein to refer to those compounds, substances, 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 and / or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0093] Specific pharmaceutical and medical terms

[0094] The term "cancer," as used herein, refers to an abnormal, uncontrolled growth of cells that can metastasize (spread) under certain conditions. This type of cancer includes, but is not limited to, solid tumors (such as those of the bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (such as the thyroid), prostate, skin (melanoma), or blood tumors (such as non-leukemic leukemias).

[0095] The term "combination administration" or its like, as used herein, refers to the administration of several selected therapeutic agents to a single patient, using the same or different administration routes at the same or different times.

[0096] The terms "enhance" or "enhancing," as used herein, refer to the ability to increase or prolong the potency or duration of a desired effect. Thus, in the context of enhancing the therapeutic effect of a drug, the term "enhancing" refers to the ability of the drug to increase or prolong the potency or duration of the drug in a system. "Potentiation," as used herein, refers to the ability of another therapeutic agent to maximize its potency in an ideal system.

[0097] The term "immune disease" refers to a disease or condition that results from an adverse or deleterious response to an endogenous or exogenous antigen. The result is usually cellular dysfunction, or the resulting damage and malfunction of, or destruction of, organs or tissues that may be responsible for the immune condition.

[0098] The terms "kit" and "product packaging" are synonymous.

[0099] The terms "subject," "subject," or "patient" include mammals and non-mammals. Mammals include, but are not limited to, mammals such as humans, non-human primates such as gorillas, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; livestock such as rabbits and dogs; and experimental animals including rodents such as rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds and fish. In a preferred embodiment, the mammal is a human.

[0100] As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration, regardless of whether the administration is fixed or temporary, continuous or intermittent, and can be attributed to or related to the administration.

[0101] Route of administration

[0102] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, auricular, nasal, and topical administration. In addition, parenteral administration, by way of example only, includes intramuscular, subcutaneous, intravenous, intramedullary, intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0103] The administration of the disclosed compounds can be local. In certain embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. In another embodiment, the drug is administered via a targeted drug delivery system. For example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are selectively directed to and absorbed by a specific organ.

[0104] Pharmaceutical composition and dosage

[0105] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutical substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., a lubricant, talc, magnesium stearate, calcium stearate, or zinc stearate, or stearic acid), or solvent encapsulating substance, which is involved in carrying or transporting the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0106] The term "pharmaceutical composition" means a composition comprising a compound of the present disclosure and optionally other pharmaceutically acceptable carriers. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals (particularly mammals), including (i.e.) adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the nature of the dosage form.

[0107] The pharmaceutical compositions of the present disclosure may include a therapeutically effective amount of one or more compounds of the present disclosure formulated with optional one or more pharmaceutically acceptable carriers (additives) and / or diluents, and optionally one or more other therapeutic agents. The compounds of the present disclosure may be administered in any suitable manner for any of the above-mentioned purposes, for example, orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion technology (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membrane, such as by inhalation spray; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories; or by intratumoral injection. They can be administered alone, but are typically administered using a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice.

[0108] Pharmaceutically acceptable carriers are formulated based on a variety of factors well within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media and various solid and semisolid dosage forms.

[0109] Such carriers may include a variety of ingredients and additives in addition to the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, binding agents, etc. Descriptions of suitable pharmaceutical carriers and factors involved in carrier selection can be found in a number of readily available sources, such as Allen LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0110] Of course, the dosage regimen of the disclosed compounds varies depending on known factors, such as the pharmacodynamic properties of the specific agent and its mode and route of administration; the species, age, sex, health condition, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and hepatic function and the desired effect. As a general guide, when used for a specified effect, the daily oral dose of each active ingredient should be from about 0.001 mg / day to about 10-5000 mg / day, preferably from about 0.01 mg / day to about 1000 mg / day, and most preferably from about 0.1 mg / day to about 250 mg / day. During a constant rate infusion, the most preferred intravenous dose should be from about 0.01 mg / kg / minute to about 10 mg / kg / minute. The disclosed compounds can be administered in a single daily dose, or the total daily dose can be administered in divided doses twice, three times or four times a day.

[0111] The compounds are usually administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected according to the intended administration form (e.g., oral tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice.

[0112] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight based on the total weight of the composition.

[0113] The present disclosure includes pharmaceutical compositions comprising, alone or in combination with a pharmaceutically acceptable carrier, a therapeutically effective amount of at least one compound of the present disclosure as an active ingredient. Optionally, the compounds of the present disclosure may be used alone, in combination with other compounds of the present disclosure, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).

[0114] Regardless of the route of administration selected, the compounds of the present invention (which may be used in a suitable hydrated form) and / or the pharmaceutical compositions of the present disclosure are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.

[0115] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0116] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the present disclosure employed, or its ester, salt, or amide; the route of administration; the time of administration; the rate of excretion of the particular compound employed; the rate and extent of absorption; the duration of the treatment; other drugs, compounds, and / or substances used in combination with the particular compound employed; and the age, sex, weight, condition, general health and prior medical history of the patient being treated, and other factors well known in the medical art.

[0117] A doctor or veterinarian with ordinary skills in the art can easily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, in order to achieve the desired therapeutic effect, the physician or veterinarian can start the dosage of the disclosed compound used in the pharmaceutical composition at a level lower than the desired level, and gradually increase the dosage until the desired effect is achieved. Typically, a suitable daily dose of the disclosed compound will be the amount of the compound at the lowest dose that effectively produces a therapeutic effect. Such an effective dose generally depends on the above-mentioned factors. Typically, oral, intravenous, intracerebroventricular and subcutaneous doses of the disclosed compound for patients range from about 0.01 to about 50 mg / kg body weight / day. If necessary, the effective daily dose of the active compound can be administered separately at appropriate intervals throughout the day in two, three, four, five, six or more subdoses, optionally in unit dosage form. In certain aspects of the present disclosure, medication is administered once a day.

[0118] While it is possible for a compound of the present disclosure to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0119] Kit / Product Packaging

[0120] Kits / product packaging are also described herein for use in treating the aforementioned indications. These kits can consist of a carrier, a pouch, or a container box, each of which can be divided into compartments to accommodate one or more containers, such as vials, test tubes, and the like, each containing a single component of the method. Suitable containers include bottles, vials, syringes, and test tubes. The containers can be made of acceptable materials such as glass or plastic.

[0121] For example, a container may contain one or more compounds described herein, either as a pharmaceutical composition or in admixture with other ingredients described herein. The container may have a sterile delivery port (e.g., an IV bag or bottle with a stopper pierceable by a hypodermic needle). Such a kit may include a compound and instructions, labeling, or operating instructions for use as described herein.

[0122] A typical kit may include one or more containers, each containing one or more materials (e.g., reagents, concentrated stock solutions, and / or instruments) to suit the commercialization and user needs of the compound. These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, delivery devices, bags, containers, bottles, and / or test tubes, accompanied by a list of contents and / or instructions for use, including instructions for use within the packaging. The complete set of instructions should be included.

[0123] The label may be displayed on or closely associated with the container. Labeling on a container means that the label letters, numbers, or other features are affixed, molded, or engraved onto the container. Labels may also appear inside a container or shipping box containing multiple containers, such as in a product insert. A label may indicate a specific therapeutic use of the contents. A label may also indicate instructions for use of the contents, such as those described in the above methods.

[0124] All features described in this specification (including any claims, abstracts and figures), and / or all steps involved in any method or process, may exist in any combination, unless certain features or steps are mutually exclusive in the same combination.

[0125] The features described above, or the features described in the examples, 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.

[0126] The present disclosure will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present disclosure only and are not intended to limit the scope of the present disclosure. The experimental methods in the following examples, where specific conditions are not specified, were generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise indicated, all percentages, ratios, proportions, or parts are by weight.

[0127] The units used in this disclosure for weight-volume percentages are well known to those skilled in the art, for example, referring to the weight of solute in 100 ml of solution. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the disclosed methods. The preferred embodiments and materials described herein are for illustrative purposes only. DETAILED DESCRIPTION

[0128] The present disclosure is further illustrated by way of examples below, but the present disclosure is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0129] NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the measurements are indicated in the spectral analysis.

[0130] MS was determined using an Agilent 1200-G1956A / 1200-6110A / 1200-6140A / 1260-6125B / Prime-6125B / 1260-6120 LC / MS, a SHIMADZU 20A-2010 / 20A-2020 LC / MS, and a Waters ACQ-QDA LC / MS.

[0131] HPLC analysis was performed using a SHIMADZU 20A high performance liquid chromatograph.

[0132] SFC analysis was performed using a Waters UPCC with PDA Detector and QDa Detector ultra-high performance convergence chromatograph, a Waters UPC 2 with PDA detector ultra high performance convergence chromatograph, Agilent 1260 with DAD detector high performance liquid chromatograph, Shimadzu LC-20AB with PDA detector high performance liquid chromatograph, Shimadzu LC-20AD with PDA detector high performance liquid chromatograph.

[0133] Preparative HPLC separation was performed using a Shimadzu LC-20AP pump, Shimadzu LH-40 Liquid Handler, Shimadzu SPD-20A Detector, Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV Detector preparative chromatograph.

[0134] SFC separation uses The Berger MG II, MG III, Sepiatec's Prep SFC 100 system, Waters Prep 80Q SFC SYSTEM, Prep 150 AP SFC SYSTEM, Prep 200 SFC SYSTEM, and Prep 350 SFC SYSTEM.

[0135] Flash column chromatography separation was performed using a Biotage IsoleraOne flash preparative chromatograph.

[0136] The thin layer chromatography silica gel plate used was GF254 acrylic adhesive silica gel plate produced by Anhui Liangchen Silicon Source Material Co., Ltd. The specification of the silica gel plate used in thin layer chromatography (TLC) was 0.25 mm, and the specification of the thin layer chromatography separation and purification product was 0.5 mm.

[0137] The pressurized hydrogenation reaction uses a hydrogenation bottle and a hydrogen cylinder.

[0138] Microwave reactions were performed using a Biotage Initiator+ microwave synthesizer.

[0139] The glove box is customized by DELLIX.

[0140] The present disclosure is described in detail below by way of examples, but is not intended to limit the present disclosure in any way. The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present disclosure. It will be apparent to those skilled in the art that various changes and improvements will be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0141] Example 1: 2-Hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-ene-5-ol 4 -yl)ethane-1-sulfonamide

[0142] Step 1: Under a nitrogen atmosphere at 20°C, methyltriphenylphosphonium bromide (24.06 g, 66.00 mmol) was dissolved in dry tetrahydrofuran (350.00 mL). The solution was cooled to 0°C, followed by the slow addition of a 1.0 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (66.00 mL, 66.00 mmol) and stirring for 1 hour. A solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (10.00 g, 44.00 mmol) in tetrahydrofuran (20.00 mL) was added to the reaction system, and the temperature was raised to 20°C and stirred for 16 hours. After completion of the reaction, saturated sodium bicarbonate solution (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give tert-butyl 4-allylpiperidine-1-carboxylate (10.00 g, 66.00 mmol, 100.0% yield) as a colorless liquid.

[0143] Step 2: At 20°C, tert-butyl 4-allylpiperidine-1-carboxylate (10.00 g, 66.00 mmol) was dissolved in dichloromethane (200.00 mL). Trifluoroacetic acid (10.02 mL, 131.81 mmol) was added and stirred at 20°C for 16 hours. After the reaction was complete, the solvent and excess trifluoroacetic acid were removed to yield crude 4-allylpiperidinium trifluoroacetate (approximately 15.50 g). This crude product was then dissolved in dimethyl sulfoxide (200.00 mL), potassium carbonate (30.98 g, 219.68 mmol) and 4-bromo-2-fluorobenzoic acid (9.62 g, 43.94 mmol) were added, and the mixture was heated to 140°C and stirred for 48 hours. After the reaction was complete, the mixture was cooled, quenched by the addition of cold water (100 mL), and the pH of the solution was adjusted to 6-7 by the addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined and washed with saturated sodium chloride solution (100 mL). The organic phases were dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-20% ethyl acetate / petroleum ether) to give 4-bromo-2-(4-allylpiperidinyl)benzoic acid (11.50 g, 35.15 mmol, 80.3% yield) as an orange solid. 1H NMR(400MHz,Chloroform-d)δ8.14(d,J=8.3Hz,1H),7.61–7.48(m,2H),5.85–5.68(m,1H),5.14–4.98(m,2H),3.19–3.05(m,2H),2 .91(td,J=11.7,2.5Hz,2H),2.11(t,J=6.8Hz,2H),2.07–1.99(m,1H),2.00–1.86(m,2H),1.67–1.44(m,3H)ppm; LCMS(ESI):[M+H] + =324.1.

[0144] Step 3: Under a nitrogen atmosphere at 20°C, methyltriphenylphosphonium bromide (25.64 g, 70.33 mmol) was dissolved in dry tetrahydrofuran (350.00 mL). The solution was cooled to 0°C, followed by the slow addition of a 1.0 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (70.33 mL, 70.33 mmol) and stirring for 1 hour. A solution of 1-tert-butyloxycarbonyl-3-piperidinecarboxaldehyde (10.00 g, 46.89 mmol) in tetrahydrofuran (20.00 mL) was added to the reaction system, and the temperature was then raised to 20°C and stirred for 16 hours. Upon completion of the reaction, the reaction was quenched by the addition of saturated sodium bicarbonate solution (100 mL), and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give tert-butyl 3-vinylpiperidine-1-carboxylate (10.00 g, 70.33 mmol, 100.0% yield) as a colorless liquid.

[0145] Step 4: tert-Butyl 3-vinylpiperidine-1-carboxylate (2.94 g, 13.93 mmol) was dissolved in dichloromethane (100.00 mL) at 20°C, and trifluoroacetic acid (5.01 mL, 65.70 mmol) was added. The mixture was stirred at 20°C for 16 hours. After the reaction was complete, the solvent and excess trifluoroacetic acid were removed to obtain crude 3-vinylpiperidine trifluoroacetate (approximately 5.30 g). This crude product was then dissolved in N,N-dimethylformamide (100.00 mL), potassium carbonate (9.82 g, 69.65 mmol) and 2-chloro-6-methylpyrimidin-4-amine (9.62 g, 43.94 mmol) were added, and the mixture was heated to 130°C and stirred for 48 hours. After the reaction was completed, the mixture was cooled naturally, and cold water (200 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined and washed with saturated sodium chloride solution (100 mL). The organic phase was dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-20% ethyl acetate / petroleum ether) to give 6-methyl-2-(3-vinylpiperidinyl)pyrimidin-4-amine (2.31 g, 10.73 mmol, yield 77.0%) as an orange liquid. 1 H NMR(400MHz,Chloroform-d)δ5.79(ddd,J=17.2,10.6,6.5Hz,1H),5.60(s,1H),δ5.09(dt,J =17.4,1.6Hz,1H),5.02(dt,J=10.5,1.5Hz,1H),4.75–4.59(m,2H),4.53(brs,2H),2.78(ddd ,J=13.0,11.8,3.0Hz,1H),2.62(dd,J=12.9,10.6Hz,1H),2.25–2.12(m,1H),2.19(s,3H),1 .95–1.83(m,1H),1.77–1.67(m,1H),1.61–1.44(m,1H),1.42–1.28(m,1H); LCMS(ESI):[M+H] + =219.2.

[0146] Step 5: At 20 ° C, 6-methyl-2-(3-vinylpiperidinyl)pyrimidin-4-amine (0.67 g, 3.08 mmol), 4-bromo-2-(4-allylpiperidinyl)benzoic acid (1.00 g, 3.08 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.99 g, 7.71 mmol) and 4-dimethylaminopyridine (1.88 g, 15.42 mmol) were dissolved in dry N,N-dimethylformamide (20.00 mL), heated to 60 ° C and stirred for 24 hours. After the reaction was completed, the mixture was cooled naturally and cold water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phase was dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give 2-(4-allylpiperidin-1-yl)-4-bromo-N-(6-methyl-2-(3-vinylpiperidin-1-yl)pyrimidin-4-yl)benzamide (0.88 g, 1.67 mmol, yield 54.4%) as a yellow liquid. LCMS (ESI): [M+H] + =524.3.

[0147] Step 6: At 20°C, 2-(4-allylpiperidin-1-yl)-4-bromo-N-(6-methyl-2-(3-vinylpiperidin-1-yl)pyrimidin-4-yl)benzamide (500 mg, 0.76 mmol) was dissolved in dry dichloromethane (40.00 mL) and nitrogen was bubbled through for 15 minutes. Grubbs second-generation catalyst (33 mg, 0.038 mmol) was added and the reaction was heated under reflux for 16 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to obtain 5 4 -Br-2 6 -methyl-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-en-4-one (350 mg, 0.56 mmol, yield 74.0%), as a white solid, LCMS (ESI): [M+H] + =496.3.

[0148] Step 7: 20℃, 5 4 -Br-2 6-Methyl-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-en-4-one (200 mg, 0.40 mmol), 2-hydroxyethylsulfonamide (103 mg, 0.81 mmol), potassium phosphate (262 mg, 1.21 mmol), tris(dibenzylideneacetone)dipalladium (38 mg, 0.04 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (17 mg, 0.04 mmol) were dissolved in 1,4-dioxane (5.00 mL), and the resulting reaction mixture was bubbled with nitrogen for 15 minutes and stirred at 100°C for 5 hours. After the reaction was complete, cold water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain a crude product, which was purified by flash column chromatography (silica, 30-95% ethyl acetate / petroleum ether) to obtain 170 mg of the product, which was further purified by preparative HPLC (C18, 70-95% gradient of acetonitrile / water) to obtain 2-hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-ene-5-ol 4 -yl)ethane-1-sulfonamide (149 mg, 0.27 mmol, yield 68.4%), Z / E=3:7, as a white solid. 1H NMR(400MHz,DMSO-d6)δ12.90(s,0.3H),10.73(s,0.7H),10.19(brs,1H),8.05(d,J=8.6H z,0.3H),7.81(d,J=8.5Hz,0.7H),7.32(s,0.7H),7.22(d,J=2.2Hz,0.3H),7.17–7.11(m,0 .6H),7.05(d,J=1.4Hz,0.7H),7.00(dd,J=8.6,2.0Hz,0.7H),5.73–5.53(m,1.4H),5.48(d dd,J=11.2,11.1,5.3Hz,0.3H),5.35(dd,J=10.1,10.1Hz,0.3H),4.94(brs,1H),4.85(d,J =13.0Hz,0.7H),4.68(d,J=12.7Hz,0.7H),4.60(d,J=13.1Hz,0.3H),4.45(d,J=12.6Hz,0 .3H),3.76(t,J=6.5Hz,2H),3.38–3.34(m,1.7H),3.27(d,J=10.9Hz,0.7H),3.16(d,J=11. 0Hz,0.3H),3.09–2.87(m,2H),2.84–2.62(m,2.3H),2.56–2.44(m,2H),2.31–2.20(m,4H), 2.19–2.08(m,0.6H),1.91–1.36(m,8.7H),1.24(d,J=11.7Hz,0.7H)ppm; LCMS(ESI):[M+H] + =541.4.

[0149] Step 8: Example 1(E)-2-Hydroxy-N-(2,6-methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzazepine-8-en-4-yl)ethane-1-sulfonamide (650 mg, 1.20 mmol) was separated by SFC (AD, carbon dioxide-ethanol (0.1% ammonia water)) to give four corresponding isomers: Example 1A to Example 1D.

[0150] Example 1A: 2-Hydroxy-N-((1 3 S, E)-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzazepine-8-en-5 4 -yl)ethane-1-sulfonamide. LCMS (ESI): [M+H]+=541.2.1 H NMR (400MHz, DMSO-d6) δppm 10.74 (s, 1H), 10.49-9.58 (m, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.32 (s, 1H), 7.14-6.89 (m, 2H), 5.76-5.51 (m, 2H), 4.85 (br d,J=12.4Hz,2H),4.68(br d,J=12.8Hz,1H),3.75(t,J=6.4Hz,2H),3.41-3.34(m,2H),3.28(br d,J=10.8Hz,1H),3.11-2.92(m,2H),2.87-2.66(m,2H),2.58-2.52(m,1H),2.48-2.4 5(m,1H),2.32-2.17(m,4H),1.95-1.82(m,1H),1.81-1.50(m,8H),1.32-1.18(m,1H)

[0151] Example 1B: 2-Hydroxy-N-((1 3 R, E)-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzazepine-8-en-5 4 -yl)ethane-1-sulfonamide. LCMS (ESI): [M+H]+=541.2. 1 H NMR(400MHz,DMSO-d6)δppm 10.74(s,1H),10.17(br d,J=1.0Hz,1H),7.81(d,J=8.4Hz,1H),7.32(s,1H),7.14-6.92(m,2H),5.75-5.51(m,2H),5.05-4.89(m,1H),4.85(br d,J=13.2Hz,1H),4.68(br d,J=12.4Hz,1H),3.75(br t,J=6.4Hz,2H),3.42-3.34(m,2H),3.28(br d,J=9.2Hz,1H),3.11-2.94(m,2H),2.87-2.66(m,2H),2.54(br s,1H),2.48-2.43(m,1H),2.31-2.20(m,4H),1.95-1.82(m,1H),1.82-1.50(m,8H),1.29-1.18(m,1H)

[0152] Example 1C: 2-Hydroxy-N-((1 3 S, Z)-2 6-methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzazepine-8-en-5 4 -yl)ethane-1-sulfonamide. LCMS (ESI): [M+H]+=541.2. 1 H NMR (400MHz, DMSO-d6) δppm 13.55-13.15(m,1H), 10.33(s,1H),8.06(d,J=8.8Hz,1H),7.31(br s,1H),7.25(d,J=2.0Hz,1H),7.17(dd,J=2.0,8.8Hz,1H),5.60-5.43(m, 1H),5.42-5.28(m,1H),4.62-4.40(m,2H),3.76(t,J=6.4Hz,2H),3.37(br s,2H),3.18(br s,1H),3.07-2.96(m,2H),2.88-2.71(m,3H),2.39(s,3H),2.32-2.23(m,1H),2.19-1.98(m,2H),1.91-1.69(m,6H),1.62-1.42(m,3H)

[0153] Example 1D: 2-Hydroxy-N-((1 3 R, Z)-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzazepine-8-en-5 4 -yl)ethane-1-sulfonamide. LCMS (ESI): [M+H]+=541.2. 1H NMR(400MHz,DMSO-d6)δppm 12.90(br s,1H),10.58-9.89(m,1H),8.05(d,J=8.4Hz,1H),7.22(d,J=2.0Hz,1H),7.18-7.08 (m,2H),5.48(dt,J=5.2,11.2Hz,1H),5.41-5.30(m,1H),5.08-4.82(m,1H),4.60(br d,J=12.8Hz,1H),4.45(br d,J=12.4Hz,1H),3.76(t,J=6.4Hz,2H),3.42-3.34(m,2H),3.16(br d,J=10.8Hz,1H),3.03-2.87(m,2H),2.77(q,J=12.4Hz,2H),2.70-2.61(m,1H),2.36-2.20(m,4H),2.19-2.07(m,2H),1.91-1.37(m,9H)

[0154] Example 2: (Z)-2-Hydroxy-N-(26-methyl-4-oxo-3-aza-2(2,4)-pyrimidin-5(2,3)-pyridine-1(1,3),6(1,4)-dipiperidinylcyclononane-8-en-55-yl)ethane-1-sulfonamide

[0155] Step 1: To a solution of 5-bromo-3-fluoropyridine-2-carboxylic acid (2.00 g, 9.09 mmol) and cesium carbonate (9.07 g, 27.3 mmol) in dimethyl sulfoxide (40 mL) was added 4-(prop-2-en-1-yl)piperidine hydrochloride (1.91 g, 11.8 mmol). The mixture was stirred at 100°C for 16 hours. The reaction mixture was poured into water (400 mL) and the pH was adjusted to 2-3 with 1N dilute hydrochloric acid. The mixture was extracted with ethyl acetate (400 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of dichloromethane / methanol) to afford 5-bromo-3-[4-(prop-2-en-1-yl)piperidin-1-yl]pyridine-2-carboxylic acid (2.90 g, 26.8 mmol, 98% yield) as a brown solid. LCMS (ESI): [M+H]+ = 327.2. 1H NMR (400MHz, DMSO-d6) δppm 8.66 (s, 1H), 7.90 (d, J = 1.2Hz, 1H), 5.85-5.69 (m, 1H), 5.07 (br d, J = 5.2Hz, 1H), 5.03 (s, 1H), 3.21 (br d,J=11.6Hz,2H),2.90(br t,J=11.6Hz,2H),2.10(br t,J=6.4Hz,2H),1.94(br d,J=11.2Hz,2H),1.64-1.41(m,3H)

[0156] Step 2: To a solution of 5-bromo-3-[4-(prop-2-en-1-yl)piperidin-1-yl]pyridine-2-carboxylic acid (1.00 g, 3.08 mmol) in dichloromethane (20.0 mL) was added thionyl chloride (0.55 g, 4.61 mmol) at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was used directly in the next step without post-treatment or purification. LCMS (ESI): [M+H] + =341.2.

[0157] Step 3: To a solution of 5-bromo-3-[4-(prop-2-en-1-yl)piperidin-1-yl]pyridine-2-carbonyl chloride (1.00 g, 2.91 mmol) in dichloromethane (20 mL) was added 2-(3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-amine (640 mg, 2.91 mmol) at 25°C, followed by N,N-diisopropylethylamine (2.05 g, 15.9 mmol) and a tetrahydrofuran solution of potassium tert-butoxide (11.6 mL, 11.6 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of tetrahydrofuran / petroleum ether) to give 5-bromo-N-[2-(3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl]-3-[4-(prop-2-en-1-yl)piperidin-1-yl]pyridine-2-carboxamide (0.59 g, 1.13 mmol, 39% yield) as a brown solid. LCMS (ESI): [M+H]+ = 525.3

[0158] Step 4: 5-Bromo-N-[2-(3-vinylpiperidin-1-yl)-6-methylpyrimidin-4-yl]-3-[4-(prop-2-en-1-yl)piperidin-1-yl]pyridine-2-carboxamide (560 mg, 1.07 mmol) was dissolved in dry dichloromethane (40.0 mL) at 20°C, nitrogen was bubbled for 15 minutes, Grubbs second-generation catalyst (462 mg, 0.53 mmol) was added, and the reaction was heated under reflux at 50°C for 16 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 0-10% tetrahydrofuran / petroleum ether) to obtain (Z)-5 5 -Br-2 6 -methyl-3-aza-2(2,4)-pyrimidin-5(2,3)-pyridine-1(1,3),6(1,4)-dipiperidinylcyclononane-8-en-4-one, as a yellow solid. LCMS (ESI): [M+H]+=497.0.

[0159] Step 5: Towards (Z)-5 5 -Br-2 6To a solution of 2-methyl-3-aza-2(2,4)-pyrimidin-5(2,3)-pyridine-1(1,3),6(1,4)-dipiperidinylcyclononane-8-en-4-one (20 mg, 0.04 mmol), 2-hydroxyethanesulfonamide (5.03 mg, 0.04 mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (3.41 mg, 0.008 mmol), and potassium phosphate (26.1 mg, 0.12 mmol) in dioxane (0.50 mL) was added tris(dibenzylideneacetone)dipalladium (3.76 mg, 0.004 mmol). The atmosphere was purged with nitrogen three times, and the mixture was heated to 100°C and stirred for 3 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by preparative HPLC (C18, 12-52% gradient of water (formic acid) / acetonitrile) to obtain (Z)-2-hydroxy-N-(2,6-methyl-4-oxo-3-aza-2(2,4)-pyrimidin-5(2,3)-pyridine-1(1,3),6(1,4)-dipiperidinylcyclononane-8-en-55-yl)ethane-1-sulfonamide as a white solid (2.13 mg, 0.004 mmol, 10% yield). LCMS (ESI): [M+H]+=542.3. 1H NMR (400MHz, DMSO-d6) δppm 10.28(s,1H),8.09(d,J=2.0Hz,1H),7.36-7.26(m,2H),5.71-5.48(m,2H),5.24-4.95(m,1H),4.88(br d,J=13.2Hz,1H),4.75(br d,J=12.8Hz,1H),3.76(t,J=6.4Hz,2H),3.28-3.21(m,2H),3.05-3.00(m,2H),2.81-2.71(m,2H), 2.63-2.55(m,1H),2.49-2.39(m,2H),2.28(s,3H),2.24-2.17(m,1H),1.92-1.45(m,10H),1.19(br d,J=11.6Hz,1H)

[0160] Example 3: 2-Hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,3)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5- ... 4 -yl)ethane-1-sulfonamide

[0161] Step 1: At 20°C, 2-hydroxy-N-(26 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-ene-5-ol 4 -yl)ethane-1-sulfonamide (70 mg, 0.13 mmol) and 10% palladium / carbon (70 mg, 100% w / w) were dissolved in methanol (5.00 mL), acetic acid (0.10 g, 1.67 mmol) was added to replace the hydrogen, and the mixture was stirred at 20°C for 24 hours until the reaction was complete. The mixture was filtered through celite, rinsed with dichloromethane (50 mL), concentrated, and purified by flash column chromatography (silica, 30-95% ethyl acetate / petroleum ether) to obtain 70 mg of the product, which was further purified by preparative HPLC (C18, 50-70% gradient acetonitrile / water) to obtain 2-hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,3)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5- ... 4 -yl)ethane-1-sulfonamide (55 mg, 0.10 mmol, yield 78.6%), as a white solid. LCMS (ESI): [M+H] + =543.4. 1 H NMR (400MHz, DMSO-d6) δ11.69(s,1H),10.19(s,1H),7.96(d,J=8.6Hz,1H),7.33(s,1 H),7.11(d,J=2.2Hz,1H),7.05(dd,J=8.6,2.1Hz,1H),4.93(brs,1H),4.13(d,J=12. 8Hz,1H),3.95(d,J=12.7Hz,1H),3.74(t,J=6.5Hz,2H),3.52–3.43(m,1H),3.24–3.0 0(m,3H),2.77–2.61(m,2H),2.24(s,3H),2.07–1.82(m,2H),1.75–1.15(m,16H)ppm.

[0162] Step 2: 2-Hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzazepine-5-cyclononyl 4 -yl)ethane-1-sulfonamide (173 mg, 0.32 mmol) was separated by SFC (AD, carbon dioxide-ethanol (0.1% ammonia water)) to give the corresponding two isomers: Example 3A and Example 3B.

[0163] Example 3A: 2-Hydroxy-N-((1 3R)-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzazepine-5-cyclononyl 4 -yl)ethane-1-sulfonamide. LCMS (ESI): [M+H]+=543.3. 1 H NMR(400MHz,DMSO-d6)δppm 11.72(s,1H),10.22(s,1H),7.98(d,J=8.4Hz,1H),7.36(s,1H),7.13(d,J=2.0Hz,1H),7.07(dd,J=2.0,8.8Hz,1H),5.08-4.75(m,1H),4.15(br d,J=11.2Hz,1H),4.04-3.88(m,1H),3.76(br t,J=6.4Hz,2H),3.59-3.47(m,1H),3.41-3.35(m,2H),3.28-3.20(m,1H),3.19-3 .06(m,2H),2.80-2.65(m,2H),2.27(s,3H),2.12-1.81(m,2H),1.78-1.22(m,14H)

[0164] Example 3B: 2-Hydroxy-N-((1 3 S)-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzazepine-5-cyclononyl 4 -yl)ethane-1-sulfonamide. LCMS (ESI): [M+H]+=543.3. 1 H NMR(400MHz,DMSO-d6)δppm 11.71(s,1H),10.21(br s,1H),7.97(d,J=8.8Hz,1H),7.34(s,1H),7.12(d,J=2.0Hz,1H),7.06(dd,J=2.0,8.8Hz,1H),4.93(br t,J=5.6Hz,1H),4.14(br d,J=10.4Hz,1H),4.03-3.91(m,1H),3.75(q,J=6.0Hz,2H),3.56-3.46(m,1H),3.39-3.34(m,2H),3.27 -3.19(m,1H),3.16-3.05(m,2H),2.77-2.65(m,2H),2.26(s,3H),2.08-1.82(m,2H),1.78-1.31(m,14H)

[0165] Example 4: 2-Hydroxy-N-(1 6 -methyl-7-oxo-8-aza-1(2,4)-pyrimidin-2(1,3),5(4,1)-dipiperidin-6(1,2)-benzene heterocyclooct-3-ene-6- 5 -yl)ethane-1-sulfonamide

[0166] Example 5: 2-Hydroxy-N-(1 6 -methyl-7-oxo-8-aza-1(2,4)-pyrimidin-2(1,3),5(4,1)-dipiperidin-6(1,2)-benzoxan-6 5 -yl)ethane-1-sulfonamide

[0167] Step 1: At 20°C, tert-butyl 4-vinylpiperidine-1-carboxylate (5.00 g, 23.66 mmol) was dissolved in dichloromethane (50.00 mL). Trifluoroacetic acid (10.02 mL, 131.81 mmol) was added and stirred at 20°C for 16 hours. After the reaction was complete, the solvent and excess trifluoroacetic acid were removed to yield crude 4-allylpiperidinium trifluoroacetate (approximately 10.50 g). This crude product was then dissolved in dimethyl sulfoxide (50.00 mL), potassium carbonate (16.69 g, 118.32 mmol) and 4-bromo-2-fluorobenzoic acid (5.18 g, 23.66 mmol) were added, and the mixture was heated to 140°C and stirred for 48 hours. After the reaction was complete, the mixture was cooled, quenched by the addition of cold water (100 mL), and the pH of the solution was adjusted to 6-7 by the addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL x 3), and the combined organic phases were washed with sodium bicarbonate solution (100 mL x 2). The organic phases were dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-20% ethyl acetate / petroleum ether) to give 4-bromo-2-(4-vinylpiperidinyl)benzoic acid (4.77 g, 15.42 mmol, 65.2% yield) as an orange solid. LCMS (ESI): [M+H] + =310.1. 1 H NMR(400MHz,Chloroform-d)δ8.16(d,J=8.2Hz,1H),7.59–7.50(m,2H),5.84(ddd,J=17.0,10.5,6.2Hz,1H),5.10(dt,J=17.3,2.2Hz,1H) ,5.07(d,J=9.7Hz,1H),3.16(dt,J=12.0,3.7Hz,2H),2.96(td,J=11.8,2.7Hz,2H),2.26(s,1H),2.08–1.89(m,2H),1.80–1.60(m,2H)ppm.

[0168] Step 2: At 20°C, 6-methyl-2-(3-vinylpiperidinyl)pyrimidin-4-amine (0.70 g, 3.22 mmol), 4-bromo-2-(4-vinylpiperidinyl)benzoic acid (1.00 g, 3.22 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.13 g, 8.06 mmol) and 4-dimethylaminopyridine (1.21 g, 9.67 mmol) were dissolved in dry N,N-dimethylformamide (20.00 mL), heated to 60°C and stirred for 24 hours. After the reaction was completed, the mixture was cooled naturally and cold water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phases were dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give 4-bromo-N-(6-methyl-2-(3-vinylpiperidin-1-yl)pyrimidin-4-yl)-2-(4-vinylpiperidin-1-yl)benzamide (0.75 g, 1.47 mmol, yield 45.5%) as a yellow liquid. LCMS (ESI): [M+H] + =510.3.

[0169] Step 3: Under nitrogen atmosphere at 20°C, 4-bromo-N-(6-methyl-2-(3-vinylpiperidin-1-yl)pyrimidin-4-yl)-2-(4-vinylpiperidin-1-yl)benzamide (748 mg, 1.47 mmol) was dissolved in dry dichloromethane (80.00 mL), Grubbs second-generation catalyst (100 mg, 0.11 mmol) was added, and the reaction was heated under reflux for 36 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to obtain 6 5 -Br-1 6 -methyl-8-aza-1(2,4)-pyrimidin-2(1,3),6(4,1)-dipiperidin-6(1,2)-benzene heterocyclooct-3-ene-7-one (432 mg, 0.90 mmol, yield 60.9%), as a white solid, LCMS (ESI): [M+H] + =482.3.

[0170] Step 4: Under nitrogen atmosphere at 20℃, 5 -Br-1 6-Methyl-8-aza-1(2,4)-pyrimidin-2(1,3),6(4,1)-dipiperidin-6(1,2)-benzeneheterocyclooct-3-en-7-one (432 mg, 0.90 mmol), 2-hydroxyethylsulfonamide (343 mg, 2.69 mmol), potassium phosphate (776 mg, 3.58 mmol), tris(dibenzylideneacetone)dipalladium (84 mg, 0.09 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (38 mg, 0.09 mmol) were dissolved in 1,4-dioxane (15.00 mL) and the reaction was stirred at 100°C for 5 hours. After the reaction was complete, cold water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain a crude product, which was purified by flash column chromatography (silica, 30-95% ethyl acetate / petroleum ether) to obtain 2-hydroxy-N-(1 6 -methyl-7-oxo-8-aza-1(2,4)-pyrimidin-2(1,3),5(4,1)-dipiperidin-6(1,2)-benzene heterocyclooct-3-ene-6- 5 -yl)ethane-1-sulfonamide (282 mg, 0.54 mmol, yield 59.8%), Z / E=94:6, LCMS (ESI): [M+H] + =527.4. 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H),10.27(brs,1H),8.02(d,J=8.5Hz,1H),7.24(s,1H),7.20(d,J=2.2Hz,1H),7.13(dd,J=8.6,2.0Hz ,1H),5.58(dd,J=12.3,6.7Hz,1H),5.15(dd,J=12.5,7.4Hz,1H),4.95(brs,1H),4.60(d,J=13.0Hz,1H),4.39(d,J=8.6Hz,1H),3.76(t,J =6.5Hz,2H),3.37(t,J=6.5Hz,2H),3.29–3.03(m,3H),2.97(dd,J=12.3,9.8Hz,1H),2.88(t,J=12.6Hz,1H),2.66–2.46(m,3H),2.31(s, 3H),2.30–2.19(m,1H),2.00(d,J=12.9Hz,1H),1.91–1.71(m,2H),1.65(d,J=12.4Hz,1H),1.55(d,J=12.5Hz,1H),1.48–1.22(m,2H)ppm.

[0171] Step 5: At 20°C, 2-hydroxy-N-(16 -methyl-7-oxo-8-aza-1(2,4)-pyrimidin-2(1,3),5(4,1)-dipiperidin-6(1,2)-benzene heterocyclooct-3-ene-6- 5 -yl)ethane-1-sulfonamide (88 mg, 0.18 mmol) and 10% palladium / carbon (88 mg, 100% w / w) were dissolved in methanol (10.00 mL), acetic acid (0.10 g, 1.67 mmol) was added to replace the hydrogen, and the mixture was stirred at 20°C for 24 hours. The reaction was almost complete. Filtered on celite, rinsed with dichloromethane / methanol (50 mL), concentrated, and purified by flash column chromatography (silica, 50-70% ethyl acetate / petroleum ether) to obtain 2-hydroxy-N-(1 6 -methyl-7-oxo-8-aza-1(2,4)-pyrimidin-2(1,3),5(4,1)-dipiperidin-6(1,2)-benzoxan-6 5 -yl)ethane-1-sulfonamide (25 mg, 0.05 mmol, yield 28.3%). LCMS (ESI): [M+H] + =529.4. 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),7.95(d,J=8.6Hz,1H),7.23(s,1H),7.16(d,J=2.1Hz,1H),7.09(dd,J=8.6,2.1Hz,1H),4.54(d,J=13.2Hz,1H ),4.40(d,J=12.7Hz,1H),3.76(t,J=6.4Hz,2H),3.36(t,J=6.4Hz,2H),3 .31–2.80(m,5H),2.57–2.41(m,1H),2.30(s,3H),1.95–1.00(m,14H)ppm.

[0172] Example 6: 2-Hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzoheterocyclodec-9-ene-5-yl- 4 -yl)ethane-1-sulfonamide

[0173] Example 7: 2-Hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclodecane-5 4 -yl)ethane-1-sulfonamide

[0174] Step 1: At 20°C, N-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperidine (5.0 g, 20.55 mmol) was dissolved in dry dichloromethane (200.00 mL). The solution was cooled to 0°C, and Dess-Martin periodinane (13.21 g, 30.82 mmol) was added portionwise. The mixture was then heated to 20°C and stirred for 1 hour. After completion, the reaction was quenched with saturated sodium bicarbonate solution (100 mL) and sodium sulfite solution (100 mL), and extracted with dichloromethane (200 mL x 3). The organic phases were combined, dried, filtered, and concentrated to afford crude N-tert-butoxycarbonyl-4-(3-oxoenyl)piperidine (3.00 g, 12.43 mmol, 60.5% yield) as a colorless liquid.

[0175] Step 2: Under a nitrogen atmosphere at 20°C, methyltriphenylphosphonium bromide (6.80 g, 18.65 mmol) was dissolved in dry tetrahydrofuran (100.00 mL). The solution was cooled to 0°C, followed by the slow addition of a 1.0 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (18.65 mL, 18.65 mmol) and stirring for 1 hour. A solution of crude N-tert-butyloxycarbonyl-4-(3-oxoenyl)piperidine (3.00 g, 12.43 mmol) in tetrahydrofuran (10.00 mL) was added to the reaction system, and the temperature was then raised to 20°C and stirred for 16 hours. Upon completion, the reaction was quenched by the addition of saturated sodium bicarbonate solution (100 mL), and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give N-tert-butyloxycarbonyl-4-(3-buten-1-yl)piperidine (2.60 g, 10.86 mmol, 87.4% yield) as a colorless liquid.

[0176] Step 3: At 20°C, N-tert-butoxycarbonyl-4-(3-buten-1-yl)piperidine (2.60 g, 10.86 mmol) was dissolved in dichloromethane (50.00 mL), and trifluoroacetic acid (6.20 mL, 80.98 mmol) was added. The mixture was stirred at 20°C for 16 hours. After the reaction was complete, the solvent and excess trifluoroacetic acid were removed to yield crude 4-(3-buten-1-yl)piperidine trifluoroacetate (approximately 5.50 g). This crude product was then dissolved in dimethyl sulfoxide (50.00 mL), potassium carbonate (7.66 g, 54.31 mmol) and 4-bromo-2-fluorobenzoic acid (2.38 g, 10.86 mmol) were added, and the mixture was heated to 140°C and stirred for 48 hours. After the reaction was complete, the mixture was cooled, quenched by the addition of cold water (100 mL), and the pH of the solution was adjusted to 7-8 by the addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL x 3), and the combined organic phases were washed with sodium bicarbonate solution (100 mL). The organic phases were dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-20% ethyl acetate / petroleum ether) to give 4-bromo-2-(4-(3-buten-1-yl)piperidin-1-yl)benzoic acid (2.44 g, 7.21 mmol, 66.4% yield) as an orange solid. LCMS (ESI): [M+H] + =338.2. 1 H NMR(400MHz,Chloroform-d)δ8.15(d,J=8.3Hz,1H),7.54(s,1H),7.57–7.51(m,1H),5.90–5.70(m,1H),5.07–4 .95(m,2H),3.16–3.07(m,2H),3.04–2.79(m,2H),2.17–2.07(m,2H),2.00–1.91(m,2H),1.61–1.40(m,4H)ppm.

[0177] Step 4: At 20 ° C, 6-methyl-2-(3-vinylpiperidinyl)pyrimidin-4-amine (0.65 g, 2.96 mmol), 4-bromo-2-(4-(3-buten-1-yl)piperidin-1-yl)benzoic acid (1.00 g, 2.96 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.87 g, 7.39 mmol) and 4-dimethylaminopyridine (1.11 g, 8.87 mmol) were dissolved in dry N,N-dimethylformamide (20.00 mL), heated to 60 ° C and stirred for 24 hours. After the reaction was completed, the mixture was cooled naturally and cold water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phases were dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give 4-bromo-2-(4-(3-buten-1-yl)piperidin-1-yl)-N-(6-methyl-2-(3-vinylpiperidin-1-yl)pyrimidin-4-yl)benzamide (0.71 g, 1.32 mmol, yield 44.6%) as a yellow liquid. LCMS (ESI): [M+H] + =538.3.

[0178] Step 5: At 20°C, 4-bromo-2-(4-(3-butene-1-yl)piperidin-1-yl)-N-(6-methyl-2-(3-vinylpiperidin-1-yl)pyrimidin-4-yl)benzamide (710 mg, 1.32 mmol) was dissolved in dry dichloromethane (80.00 mL) and nitrogen was bubbled for 15 minutes. Grubbs second-generation catalyst (114 mg, 0.066 mmol) was added and the reaction was heated under reflux for 36 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to obtain 5 4 -Br-2 6 -methyl-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzoheterocyclodec-9-en-4-one (580 mg, 1.14 mmol, yield 86.2%), as a white solid, LCMS (ESI): [M+H] + =510.3.

[0179] Step 6: Under nitrogen atmosphere at 20℃, 4 -Br-2 6-Methyl-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzoheterocyclodec-9-en-4-one (580 mg, 1.14 mmol), 2-hydroxyethylsulfonamide (290 mg, 2.27 mmol), potassium phosphate (738 mg, 3.41 mmol), tris(dibenzylideneacetone)dipalladium (106 mg, 0.11 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (48 mg, 0.11 mmol) were dissolved in 1,4-dioxane (10.00 mL) and stirred at 100 ° C for 5 hours. After the reaction was complete, cold water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was purified by flash column chromatography (silica, 50-70% ethyl acetate / petroleum ether) and further purified by preparative HPLC (C18, 70-95% gradient acetonitrile / water) to obtain 2-hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzoheterocyclodec-9-ene-5-yl- 4 -yl)ethane-1-sulfonamide (178 mg, 0.32 mmol, yield 28.3%), Z / E=3:7. LCMS (ESI): [M+H] + =555.4. 1H NMR (400MHz, DMSO-d6) δ12.00(s,0.7H),11.88(s,0.3H),10.20(brs,1H),7.99(d,J=8.6Hz,0.7H),7.87(d,J=8.6Hz,0.3H),7.33(s,0.7H),7.20( s,1H),7.33(s,0.3H),7.11–7.02(m,1H),5.75–5.58(m,0.3H),5.50(dd, J=7.9,7.5Hz,0.3H),5.43(dd,J=11.5,9.8Hz,0.7H),5.14(dd,J=9.7Hz, 0.7H),4.93(brs,1H),4.80(d,J=13.3Hz,0.3H),4.71(d,J=13.2Hz,0.3H ),4.53(d,J=12.9Hz,0.7H),4.41(d,J=12.5Hz,0.7H),3.74(t,J=6.6Hz, 2H),3.26–3.02(m,2H),3.02–2.90(m,1H),2.87–2.64(m,2H),2.59(t,J= 11.6Hz,0.7H),2.48–2.33(m,2.3H),2.26(s,3H),1.98–1.30(m,14H)ppm.

[0180] Step 7: At 20°C, 2-hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzoheterocyclodec-9-ene-5-yl- 4 -yl)ethane-1-sulfonamide (100 mg, 0.18 mmol) and 10% palladium / carbon (100 mg, 100% w / w) were dissolved in methanol (10.00 mL), acetic acid (0.20 g, 3.34 mmol) was added to replace the hydrogen, and the mixture was stirred at 20°C for 24 hours until the reaction was complete. Filtered on celite, rinsed with dichloromethane / methanol (50 mL), concentrated, and purified by flash column chromatography (silica, 30-95% ethyl acetate / petroleum ether) to obtain 2-hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,3)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5- ... 4 -yl)ethane-1-sulfonamide (17 mg, 0.03 mmol, yield 17.0%). LCMS (ESI): [M+H] + =557.4. 1H NMR (400MHz, DMSO-d6) δ12.25(s,1H),8.02(d,J=8.7Hz,1H),7.39(s,1H),7.23(d,J=2.1Hz,1H),7.10(dd,J=8.7,2.1Hz,1H),4.59(dd,J=31.7,12 .9Hz,2H),3.75(t,J=6.5Hz,2H),3.21–3.05(m,2H),2.95–2.75(m,2H),2 .67–2.52(m,2H),2.25(s,3H),1.97–1.78(m,2H),1.77–1.05(m,18H)ppm.

[0181] Example 8: (Z)-2-hydroxy-N-(1 6 -methyl-7-oxo-8-aza-1(2,4)-pyrimidin-2(1,3),5(3,1)-dipiperidin-6(1,2)-benzene heterocyclooct-3-ene-6- 5 -yl)ethane-1-sulfonamide

[0182] Example 9: 2-Hydroxy-N-(1 6 -methyl-7-oxo-8-aza-1(2,4)-pyrimidin-2(1,3),5(3,1)-dipiperidin-6(1,2)-benzene heterocyclooctane-6 5 -yl)ethane-1-sulfonamide

[0183] Step 1: 6-Methyl-2-(3-vinylpiperidin-1-yl)pyrimidin-4-amine (0.61 g, 2.80 mmol), 4-iodo-2-(3-vinylpiperidin-1-yl)benzoic acid (1.00 g, 2.80 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.72 g, 7.00 mmol) and 4-dimethylaminopyridine (1.05 g, 8.40 mmol) were dissolved in dry N,N-dimethylacetamide (10.00 mL) at 20 °C, heated to 60 °C and stirred for 24 hours. After the reaction was completed, the mixture was cooled naturally, and cold water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3), and the organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phase was dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give 4-iodo-N-(6-methyl-2-(3-vinylpiperidin-1-yl)pyrimidin-4-yl)-2-(3-vinylpiperidin-1-yl)benzamide (1.30 g, 2.33 mmol, yield 83.3%) as a yellow liquid. LCMS (ESI): [M+H] +=558.3.

[0184] Step 2: Under nitrogen atmosphere at 20°C, 4-iodo-N-(6-methyl-2-(3-vinylpiperidin-1-yl)pyrimidin-4-yl)-2-(3-vinylpiperidin-1-yl)benzamide (1.30 g, 2.33 mmol) was dissolved in dry toluene (120.00 mL) and Grubbs second-generation catalyst (108 mg, 0.12 mmol) was added. Subsequently, Grubbs second-generation catalyst (108 mg, 0.12 mmol) was added every 24 hours for a total reaction time of 72 hours. Subsequently, the concentrated reaction solution was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to obtain (Z)-6 5 -Iodine-1 6 -methyl-8-aza-1(2,4)-pyrimidin-2(1,3),5(3,1)-dipiperidin-6(1,2)-benzene heterocyclooct-3-ene-7-one (281 mg, 0.53 mmol, yield 22.8%), as a white solid, LCMS (ESI): [M+H] + =530.3.

[0185] Step 3: Under nitrogen atmosphere at 20℃, (Z)-6 5 -Iodine-1 6 -Methyl-8-aza-1(2,4)-pyrimidin-2(1,3),5(3,1)-dipiperidin-6(1,2)-benzeneheterocyclooct-3-ene-7-one (281 mg, 0.53 mmol), 2-hydroxyethylsulfonamide (135 mg, 1.06 mmol), potassium phosphate (460 mg, 2.12 mmol), and cuprous iodide (103 mg, 0.53 mmol) were placed in a dry reaction flask. After nitrogen was replaced, trans-N,N'-dimethyl-1,2-cyclohexanediamine (153 mg, 1.06 mmol) and 1,4-dioxane (20.00 mL) were added. After the solid dissolved, the mixture was stirred at 100 ° C for 12 hours. After the reaction was complete, a saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride, dried, filtered, and concentrated to obtain a crude product, which was purified by flash column chromatography (silica, 50-70% ethyl acetate / petroleum ether) and preparative HPLC (C18, 50-60% acetonitrile / water) to obtain a white solid. Example 8: (Z)-2-hydroxy-N-(1 6 -methyl-7-oxo-8-aza-1(2,4)-pyrimidin-2(1,3),5(3,1)-dipiperidin-6(1,2)-benzene heterocyclooct-3-ene-6- 5 -yl)ethane-1-sulfonamide (43 mg, 0.08 mmol, yield 15.4%). LCMS (ESI): [M+H]+ =527.4. 1 H NMR (400MHz, DMSO-d6) δ14.38(s,1H),10.31(s,1H),8.15(d,J=8.7Hz,1H),7.31(d,J=2.2Hz,1H),7.25–7.15(m ,2H),5.34(t,J=10.5Hz,1H),5.15(dd,J=10.1,4.8Hz,1H),4.94(s,1H),4.48(d,J=12.9Hz,1H),4.21(dd,J=30. 7,12.0Hz,2H),3.76(t,J=6.4Hz,2H),3.36(t,J=6.5Hz,2H),3.07–2.88(m,3H),2.83(td,J=11.1,4.3Hz,1H),2 .77–2.54(m,3H),2.32(s,3H),1.96–1.80(m,2H),1.73(t,J=13.5Hz,2H),1.62–1.33(m,3H),1.32–1.14(m,1H).

[0186] Step 4: At 20°C, (Z)-2-hydroxy-N-(1 6 -methyl-7-oxo-8-aza-1(2,4)-pyrimidin-2(1,3),5(3,1)-dipiperidin-6(1,2)-benzene heterocyclooct-3-ene-6- 5 -yl)ethane-1-sulfonamide (30 mg, 0.06 mmol) and 10% palladium / carbon (30 mg, 100% w / w) were dissolved in methanol (5.00 mL), and formic acid (0.10 g, 2.17 mmol) was added to replace the hydrogen atmosphere. The mixture was stirred at 20°C for 24 hours until the reaction was complete. After concentration, the mixture was purified by flash column chromatography (silica, 30-95% ethyl acetate / petroleum ether) to give 2-hydroxy-N-(1 6 -methyl-7-oxo-8-aza-1(2,4)-pyrimidin-2(1,3),5(3,1)-dipiperidin-6(1,2)-benzene heterocyclooctane-6 5 -yl)ethane-1-sulfonamide (18.6 mg, 0.04 mmol, yield 62.0%). LCMS (ESI): [M+H] + =529.4. 1H NMR (400MHz, DMSO-d6) δ13.87(s,1H),10.28(s,1H),8.15(d,J=8.7Hz,1H),7.30(d,J=2.2Hz,1H),7.24–7.14(m,2H), 4.95(t,J=5.7Hz,1H),4.52(d,J=13.1Hz,1H),4.29(d,J=12.9Hz,1H),3.77(q,J=6.1Hz,2H),3.37(t,J=6.5Hz,2H),3 .07(d,J=10.9Hz,1H),2.97–2.83(m,3H),2.59(t,J=11.6Hz,1H),2.39(t,J=10.9Hz,1H),2.31(s,3H),2.10(d,J=12. 8Hz,1H),1.95–1.71(m,2H),1.66(d,J=11.8Hz,1H),1.52(d,J=12.4Hz,1H),1.45–1.14(m,7H),1.13–0.91(m,2H)ppm.

[0187] Example 10: 2-Hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1,6(1,3)-dipiperidin-5(1,2)-benzeneheterocyclononane-8-ene-5-ol 4 -yl)ethane-1-sulfonamide

[0188] Step 1: Under a nitrogen atmosphere at 20°C, (methoxymethyl)triphenylphosphonium bromide (12.30 g, 35.17 mmol) was dissolved in dry tetrahydrofuran (150.00 mL). The solution was cooled to 0°C, followed by the slow addition of a 1.0 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (35.17 mL, 35.17 mmol) and stirring for 1 hour. A solution of N-tert-butyloxycarbonyl-3-piperidinecarboxaldehyde (5.00 g, 23.44 mmol) in tetrahydrofuran (10.00 mL) was added to the reaction system, and the temperature was raised to 20°C and stirred for 16 hours. After completion of the reaction, the reaction was quenched by the addition of saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried, filtered, and concentrated to yield the crude product (approximately 19 g).

[0189] The crude product was dissolved in formic acid (10.00 mL) and stirred for 7 hours. The reaction was then quenched by adding saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 8-12% ethyl acetate / petroleum ether) to give N-tert-butyloxycarbonyl-3-(2-oxoethyl)piperidine (3.90 g, 17.15 mmol, 73.2% yield) as a colorless liquid.

[0190] Step 2: Under a nitrogen atmosphere at 20°C, methyltriphenylphosphonium bromide (9.38 g, 25.74 mmol) was dissolved in dry tetrahydrofuran (100.00 mL). The solution was cooled to 0°C, followed by the slow addition of a 1.0 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (25.74 mL, 25.74 mmol) and stirring for 1 hour. A solution of N-tert-butyloxycarbonyl-3-(2-oxoethyl)piperidine (3.90 g, 17.15 mmol) in tetrahydrofuran (10.00 mL) was added to the reaction system, and the temperature was then raised to 20°C and stirred for 16 hours. Upon completion of the reaction, the reaction was quenched by the addition of saturated sodium bicarbonate solution (100 mL), and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give N-tert-butyloxycarbonyl-3-allylpiperidine (3.10 g, 13.76 mmol, 80.1% yield) as a colorless liquid.

[0191] Step 3: At 20°C, N-tert-butyloxycarbonyl-3-allylpiperidine (3.10 g, 13.76 mmol) was dissolved in dichloromethane (50.00 mL), and trifluoroacetic acid (5.26 mL, 68.79 mmol) was added. The mixture was stirred at 20°C for 16 hours. After the reaction was complete, the solvent and excess trifluoroacetic acid were removed to yield crude 3-(prop-2-en-1-yl)piperidine trifluoroacetate (approximately 6.50 g). This crude product was then dissolved in dimethyl sulfoxide (50.00 mL), potassium carbonate (9.70 g, 68.79 mmol) and 4-bromo-2-fluorobenzoic acid (3.01 g, 13.76 mmol) were added, and the mixture was heated to 140°C and stirred for 48 hours. After the reaction was complete, the mixture was cooled, quenched by the addition of cold water (100 mL), and the pH of the solution was adjusted to 7-8 by the addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL x 3), and the combined organic phases were washed with sodium bicarbonate solution (100 mL). The organic phases were dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-20% ethyl acetate / petroleum ether) to give 4-bromo-2-(3-allylpiperidin-1-yl)benzoic acid (3.77 g, 11.63 mmol, 84.5% yield) as an orange solid. LCMS (ESI): [M+H]+ =324.1. 1 H NMR(400MHz,Chloroform-d)δ8.15(d,J=8.9Hz,1H),7.57–7.50(m,2H),5.83–5.65(m,1H),5.10–4.98(m,2H) ,3.19–3.00(m,2H),2.83(t,J=11.5Hz,1H),2.53(t,J=9.1Hz,1H),2.22–1.66(m,6H),1.22–1.03(m,1H)ppm.

[0192] Step 4: At 20 ° C, 6-methyl-2-(3-vinylpiperidin)pyrimidin-4-amine (0.96 g, 4.41 mmol), 4-bromo-2-(3-allylpiperidin-1-yl)benzoic acid (1.30 g, 4.10 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (5.38 g, 13.88 mmol) and 4-dimethylaminopyridine (2.88 g, 23.13 mmol) were dissolved in dry N,N-dimethylformamide (20.00 mL), heated to 60 ° C and stirred for 48 hours. After the reaction was completed, the mixture was cooled naturally and cold water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phases were dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give 2-(3-allylpiperidin-1-yl)-4-bromo-N-(6-methyl-2-(3-vinylpiperidin-1-yl)pyrimidin-4-yl)benzamide (1.15 g, 2.24 mmol, yield 54.8%) as a yellow liquid. LCMS (ESI): [M+H] + =524.3.

[0193] Step 5: Under nitrogen atmosphere at 20°C, 2-(3-allylpiperidin-1-yl)-4-bromo-N-(6-methyl-2-(3-vinylpiperidin-1-yl)pyrimidin-4-yl)benzamide (1.60 g, 3.05 mmol) was dissolved in dry dichloromethane (120.00 mL), Grubbs second-generation catalyst (132 mg, 0.15 mmol) was added, and the reaction was heated under reflux for 24 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to obtain 5 4 -Br-2 6-methyl-3-aza-2(2,4)-pyrimidin-1,6(1,3)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-en-4-one (1.31 g, 2.64 mmol, yield 86.6%), as a white solid, LCMS (ESI): [M+H] + =496.3.

[0194] Step 6: Under nitrogen atmosphere at 20℃, 4 -Br-2 6 -Methyl-3-aza-2(2,4)-pyrimidin-1,6(1,3)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-en-4-one (1.31 g, 2.64 mmol), 2-hydroxyethylsulfonamide (1.01 g, 7.92 mmol), potassium phosphate (2.29 g, 10.56 mmol), tris(dibenzylideneacetone)dipalladium (247 mg, 0.26 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (112 mg, 0.26 mmol) were dissolved in 1,4-dioxane (25.00 mL) and stirred at 100 ° C for 12 hours. After the reaction was complete, cold water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was purified by flash column chromatography (silica, 50-70% ethyl acetate / petroleum ether) to obtain 2-hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1,6(1,3)-dipiperidin-5(1,2)-benzeneheterocyclononane-8-ene-5-ol 4 -yl)ethane-1-sulfonamide (1.15 g, 2.13 mmol, yield 80.6%). LCMS (ESI): [M+H] + =541.4. 1 H NMR(400MHz,DMSO-d6)δ13.28(s,0.18H),12.69(s,0.55H),11.24(s,0.27H),10.24(br s,1H),8.23–7.76(m,1H),7.52–7.00(m,3H),5.68–5.21(m,2H),4.94(brs,1H),4.74–4. 55(m,1H),4.35–4.08(m,1H),3.78(t,J=6.5Hz,2H),3.67–3.41(m,1H),3.37(td,J=6.6 ,2.5Hz,2H),3.29–2.84(m,4H),2.71–2.37(m,3H),2.32(s,3H),2.18–1.23(m,10H)ppm.

[0195] Example 11: 2-Hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1,6(1,3)-dipiperidin-5(1,2)-benzoylcyclononyl-5 4 -yl)ethane-1-sulfonamide

[0196] Step 1: At 25°C, 2-hydroxy-N-(2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1,6(1,3)-dipiperidin-5(1,2)-phenylcyclononane-8-en-5 4 To a solution of 2-hydroxy-1-(2-(2-hydroxy-N-(2-hydroxy-1-nitropropane)-1-sulfonamide) (200 mg, 0.37 mmol) in methanol (4 mL) was added wet palladium carbon (20 mg). The reaction mixture was replaced with argon three times, and then replaced with hydrogen three times. Finally, the mixture was stirred for 16 hours under the protection of hydrogen (50 Psi). The reaction mixture was filtered under vacuum to remove palladium carbon, and then concentrated under vacuum to obtain the residue as a white solid compound 2-hydroxy-N-(2-hydroxy-1-nitropropane)-1-sulfonamide. 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidine-1,6(1,3)-dipiperidin-5(1,2)-benzoylcyclononyl-5 4 -yl)ethane-1-sulfonamide (190 mg, 0.35 mmol, yield 95%). LCMS (ESI): [M+H]+=543.2. 1 H NMR(400MHz,DMSO-d6)δppm 12.60-11.32(m,1H),11.01-8.79(m,1H),8.32-7.57(m,1H),7.52-6.58(m,3H),6.00-4.86(m,1H ),4.70-4.00(m,2H),3.83-3.55(m,2H),3.23-2.67(m,6H),2.38-2.10(m,5H),2.05-0.98(m,16H)

[0197] Example 12: N-(6,6-dioxo-3-oxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-diphenylheterocyclododec-9-ene-2 5 -yl)-2-hydroxy-1-ethanesulfonamide

[0198] Example 13: N-(6,6-dioxo-3-oxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-diphenylheterocyclododecane-2 5 -yl)-2-hydroxy-1-ethanesulfonamide

[0199] Step 1: At 20 ° C, N-allyl-3-aminobenzenesulfonamide (628 mg, 2.96 mmol), 4-bromo-2-(4-(3-buten-1-yl)piperidin-1-yl)benzoic acid (1.00 g, 2.96 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.87 g, 7.39 mmol) and 4-dimethylaminopyridine (1.11 g, 8.87 mmol) were dissolved in dry N,N-dimethylformamide (20.00 mL) and stirred at 25 ° C for 24 hours. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), and the organic phase was dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 20-25% ethyl acetate / petroleum ether) to give N-(3-(N-allylsulfamoyl)phenyl)-4-bromo-2-(4-(3-buten-1-yl)piperidin-1-yl)benzamide (1.30 g, 1.89 mmol, yield 63.7%) as a yellow liquid. LCMS (ESI): [M+H] + =532.2.

[0200] Step 2: At 20°C, N-(3-(N-allylsulfamoyl)phenyl)-4-bromo-2-(4-(3-buten-1-yl)piperidin-1-yl)benzamide (1.30 g, 1.89 mmol) was dissolved in dry toluene (80.00 mL), and Grubbs second-generation catalyst (180 mg, 0.20 mmol) was added. The reaction was heated under reflux for 16 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 25-30% ethyl acetate / petroleum ether) to obtain 2 5 -Bromo-6,6-dioxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-dibenzocyclododecan-9-en-3-one (410 mg, 0.81 mmol, yield 43.0%), as a white solid, LCMS (ESI): [M+H] + =504.2.

[0201] Step 3: Under nitrogen atmosphere at 20℃, 5-Bromo-6,6-dioxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-dibenzocyclododecan-9-en-3-one (410 mg, 0.81 mmol), 2-hydroxyethylsulfonamide (311 mg, 2.44 mmol), potassium phosphate (704 mg, 3.25 mmol), cuprous iodide (158 mg, 0.81 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (234 mg, 1.63 mmol) were dissolved in N,N-dimethylformamide (10.00 mL) and stirred at 100 ° C for 15 hours. After the reaction was complete, the mixture was cooled to 25°C and quenched by adding ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried, filtered, and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (silica, 50-70% ethyl acetate / petroleum ether) and further separated by preparative liquid chromatography (C18, 40-50% acetonitrile / water) to obtain N-(6,6-dioxo-3-oxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-diphenylheterocyclododec-9-ene-2 5 -yl)-2-hydroxy-1-ethanesulfonamide (189 mg, 0.34 mmol, yield 42.4%), as a white solid Example 12. LCMS (ESI): [M+H] + =549.3. 1 H NMR(400MHz,DMSO-d6)δ11.44(s,0.18H),11.18(s,0.50H),11.10(s,0.11H),10.51(s,0.20H),8.7 3(dd,J=8.3,2.0Hz,0.50H),8.62(dd,J=8.1,2.1Hz,0.18H),8.57(dd,J=8.3,2.1Hz,0.11H),8.17(t ,J=1.9Hz,0.20H),7.95–7.41(m,5H),7.13–6.85(m,2H),5.62–4.66(m,2H),3.76(t,J=6.6Hz,2H), 3.54–3.27(m,2H),3.25–3.12(m,2H),2.84–2.52(m,2H),2.29–2.06(m,1H),1.98–1.02(m,10H)ppm.

[0202] Step 4: At 20 ° C, N-(6,6-dioxo-3-oxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-diphenylheterocyclododec-9-ene-2 5-yl)-2-hydroxy-1-ethanesulfonamide (12 mg, 0.023 mmol) and 10% palladium / carbon (100 mg, 100% w / w) were dissolved in methanol (10.00 mL), and formic acid (0.20 g, 3.34 mmol) was added to replace the hydrogen atmosphere. The reaction was stirred at 20°C for 24 hours until the reaction was complete. The reaction solution was concentrated and purified by flash column chromatography (silica, 30-95% ethyl acetate / petroleum ether) to obtain N-(6,6-dioxo-3-oxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-diphenylheterocyclododecane-2 5 -yl)-2-hydroxy-1-ethanesulfonamide (17 mg, 0.03 mmol, yield 17.0%), as a white solid Example 13. LCMS (ESI): [M+H] + = 551.3. 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.04(s,1H),8.64(dd,J=8.1,2.1Hz,1H),7.73(t,J=5.2Hz,1H),7. 66(d,J=8.3Hz,1H),7.63–7.54(m,2H),7.44(d,J=8.1Hz,1H),7.00–6.90(m,2H),4.94(t,J=5.6Hz,1H),3. 72(q,J=6.2Hz,2H),3.29(t,J=6.6Hz,2H),3.13(d,J=11.1Hz,2H),2.64(t,J=10.8Hz,2H),2.58–2.48(m,2 H),1.64(d,J=10.7Hz,2H),1.60–1.48(m,2H),1.44–1.32(m,2H),1.30–1.17(m,5H),1.15–1.02(m,2H)ppm.

[0203] Example 14: N-(6,6-dioxo-3-oxo-6-thia-1(1,4)-piperidin-2(1,2),5(1,3)-dibenzocycloundecane-2 5 -yl)-2-hydroxy-1-ethanesulfonamide

[0204] Step 1: A mixture containing tert-butyl 4-(4-aminobutyl)piperidinecarboxylate (7.00 g, 27.30 mmol), 3-nitrobenzenesulfonyl chloride (6.70 g, 30.03 mmol), N,N-diisopropylethylamine (18.00 g, 136.51 mmol), and tetrahydrofuran (70.00 mL) was stirred at 20°C for 12 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether gradient) to obtain tert-butyl 4-(4-((3-nitrophenyl)sulfonamido)butyl)piperidine-1-carboxylate (10.30 g, 23.33 mmol, 85.4% yield) as a yellow oil. LCMS (ESI): [M-100] + =342.2.

[0205] Step 2: A mixture containing tert-butyl 4-(4-((3-nitrophenyl)sulfonamido)butyl)piperidine-1-carboxylate (5.00 g, 11.32 mmol) and hydrochloric acid / ethyl acetate solution (20.00 mL, 4.0 M) was stirred at 20°C for 1 hour. The reaction solution was concentrated to obtain 3-nitro-N-(4-(piperidin-4-yl)butyl)benzenesulfonamide (3.90 g, crude) as a white solid. LCMS (ESI): [M+H] + =342.2.

[0206] Step 3: A mixed solution containing 3-nitro-N-(4-(piperidin-4-yl)butyl)benzenesulfonamide (3.5.0 g, 10.25 mmol), 4-bromo-2-fluorobenzoic acid (2.90 g, 12.30 mmol), potassium carbonate (4.30 g, 30.75 mmol) and dimethyl sulfoxide (50.00 mL) was stirred at 120 ° C for 12 hours. The reaction solution was poured into water (50 mL), and the pH was adjusted to near 5 by adding 4.0 M hydrochloric acid / ethyl acetate solution (20 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to give compound 4-bromo-2-(4-(4-((3-nitrophenyl)sulfonamido)butyl)piperidin-1-yl)benzoic acid (7.20 g, crude product) as a black oil. LCMS(ESI):[M+H] + =540.2.

[0207] Step 4: A solution containing 4-bromo-2-(4-(4-((3-nitrophenyl)sulfonamido)butyl)piperidin-1-yl)benzoic acid (7.00 g, 12.95 mmol), iron powder (3.70 g, 64.76 mmol), ammonium chloride (3.50 g, 64.76 mmol), ethanol (50.00 mL) and water (10.00 mL) was stirred at 60°C for 1 hour. The reaction solution was filtered while hot and concentrated to remove ethanol. It was then extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (C18, 0-50% gradient of acetonitrile / water) to give compound 2-(4-(4-((3-aminophenyl)sulfonamido)butyl)piperidin-1-yl)-4-bromobenzoic acid (1.10 g, 2.15 mmol, yield 16.6%) as a yellow solid. LCMS(ESI):[M+H] + =510.2.

[0208] Step 5: 2-(4-(4-((3-aminophenyl)sulfonamido)butyl)piperidin-1-yl)-4-bromobenzoic acid (1.10 g, 2.16 mmol) was dissolved in dichloromethane (100.00 mL) and added dropwise to a solution containing 2-chloro-1-methylpyridinium iodide (843 mg, 3.23 mmol), N,N-diisopropylethylamine (853 mg, 6.46 mmol) and dichloromethane (500.00 mL). The resulting mixture was stirred at 20° C. for 2 hours, the reaction solution was poured into water (100 mL) and extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to obtain compound 2 5 -Bromo-6,6-dioxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-diphenylheterocycloundec-3-one (700 mg, 1.42 mmol, yield 66.0%), as a white solid. LCMS (ESI): [M+H] + =492.2.

[0209] Step 6: Contains 2 5A mixed solution of 2-bromo-6,6-dioxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-diphenylheterocycloundec-3-one (500 mg, 1.02 mmol), 2-hydroxyethanesulfonamide (259 mg, 2.03 mmol), potassium phosphate (660 mg, 3.05 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (43 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium (95 mg, 0.10 mol) and 1,4-dioxane (5.00 mL) was stirred at 100 ° C for 8 hours under nitrogen atmosphere. The reaction solution was poured into water (30 mL) and washed with ethyl acetate (30 mL x 40 mL). 3) extraction, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) and (C18, 0-60% gradient of acetonitrile / water) to obtain the compound N-(6,6-dioxo-3-oxo-6-thia-1(1,4)-piperidin-2(1,2),5(1,3)-dibenzocycloundecane-2 5 -yl)-2-hydroxy-1-ethanesulfonamide (120 mg, 0.22 mmol, yield 22.0%), as a white solid. LCMS (ESI): [M+H] + =537.3. 1 H NMR(400MHz,DMSO)δ10.86(s,1H),10.05(brs,1H),8.77–8.70(m,1H),7.67–7.61(m ,3H),7.60–7.49(m,2H),7.00–6.93(m,2H),4.99(brs,1H),3.78(t,J=6.8Hz,2H),3 .34-3.28(m,2H),3.17(d,J=11.2Hz,2H),3.02(q,J=6.0Hz,2H),2.66(t,J=10.8Hz, 2H),1.66-1.51(m,3H),1.43-1.30(m,4H),1.28-1.18(m,2H),1.14-0.99(m,2H)ppm.

[0210] Example 15: (E)-N-(6,6-dioxo-3-oxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-dibenzoheterocyclodec-9-ene-2 5 -yl)-2-hydroxy-1-ethanesulfonamide

[0211] Step 1: At 20°C, 3-nitrobenzenesulfonyl chloride (5.00 g, 22.56 mmol) and allylamine hydrochloride (2.56 g, 27.07 mmol) were dissolved in dry dichloromethane (50.00 mL). The solution was cooled to 0°C, followed by the addition of triethylamine (9.60 mL, 67.68 mmol) and stirring for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution (100 mL) and sodium sulfite solution (100 mL) were added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried, filtered, and concentrated to yield N-allyl-3-nitrobenzenesulfonamide (5.47 g, 22.56 mmol, 100%). LCMS (ESI): [M+H] + =243.1.

[0212] Step 2: At 20°C, N-allyl-3-nitrobenzenesulfonamide (5.47 g, 22.56 mmol) was dissolved in ethanol (100.00 mL) and water (20.00 mL). Ammonium chloride (12.19 g, 225.60 mmol) and iron powder (12.73 g, 225.60 mmol) were added, and the mixture was heated to 85°C and stirred for 4 hours. After the reaction was complete, the mixture was filtered and washed with ethyl acetate (100 mL). After concentration under reduced pressure to remove ethanol, the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was purified by flash column chromatography (silica, 30-40% ethyl acetate / petroleum ether) to afford N-allyl-3-aminobenzenesulfonamide (3.50 g, 16.49 mmol, 73.1% yield) as a white solid. LCMS (ESI): [M+H] + =213.1. 1 H NMR(400MHz,Chloroform-d)δ7.29–7.12(m,3H),6.82(ddd,J=7.8,2.4,1.2Hz,1H),5.76–5.62(m,1H), 5.18–5.10(m,2H),5.05(dq,J=10.3,1.4Hz,1H),4.15(brs,2H),3.54(ddt,J=6.0,6.0,1.6Hz,2H)ppm.

[0213] Step 3: At 20 ° C, N-allyl-3-aminobenzenesulfonamide (684 mg, 3.22 mmol), 4-bromo-2-(4-vinylpiperidin-1-yl)benzoic acid (1.00 g, 3.22 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.13 g, 8.06 mmol) and 4-dimethylaminopyridine (1.20 g, 9.67 mmol) were dissolved in dry N,N-dimethylformamide (20.00 mL) and stirred at 25 ° C for 24 hours. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), and the organic phase was dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 20-25% ethyl acetate / petroleum ether) to give N-(3-(N-allylsulfamoyl)phenyl)-4-bromo-2-(4-vinylpiperidin-1-yl)benzamide (970 mg, 1.92 mmol, yield 59.6%) as a yellow liquid. LCMS (ESI): [M+H] + =504.2.

[0214] Step 4: At 20°C, N-(3-(N-allylsulfamoyl)phenyl)-4-bromo-2-(4-vinylpiperidin-1-yl)benzamide (970 mg, 1.92 mmol) was dissolved in dry toluene (80.00 mL), and Grubbs second-generation catalyst (180 mg, 0.20 mmol) was added. The reaction was heated under reflux for 16 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 25-30% ethyl acetate / petroleum ether) to obtain (E)-2 5 -Bromo-6,6-dioxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-dibenzoheterocyclodec-9-en-3-one (280 mg, 0.59 mmol, yield 30.6%), as a white solid, LCMS (ESI): [M+H] + =476.3.

[0215] Step 5: Under nitrogen atmosphere at 20℃, (E)-2 5-Bromo-6,6-dioxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-dibenzoheterocyclodec-9-en-3-one (145 mg, 0.30 mmol), 2-hydroxyethylsulfonamide (233 mg, 1.83 mmol), potassium phosphate (659 mg, 3.04 mmol), cuprous iodide (118 mg, 0.61 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (175 mg, 1.22 mmol) were dissolved in N,N-dimethylformamide (10.00 mL) and stirred at 100 ° C for 15 hours. After the reaction was complete, the mixture was cooled to 25°C and quenched by adding ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried, filtered, and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (silica, 50-70% ethyl acetate / petroleum ether) to obtain the product. The product was further recrystallized (anhydrous acetonitrile) to obtain (E)-N-(6,6-dioxo-3-oxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-dibenzoheterocyclodec-9-ene-2 5 -yl)-2-hydroxy-1-ethanesulfonamide (12 mg, 0.023 mmol, yield 7.6%), as a white solid. LCMS (ESI): [M+H] + =521.3. 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),10.07(s,1H),8.64(d,J=8.0Hz,1H),7.84(t,J=5.4Hz,1H),7.67(d,J=8.9 Hz,1H),7.57(t,J=8.0Hz,1H),7.49(d,J=7.9Hz,1H),7.31(t,J=2.1Hz,1H),7.01–6.94(m,2H),5.76(d,J=15.9Hz ,1H),4.96(d,J=5.9Hz,1H),4.82(dt,J=14.3,6.5Hz,1H),3.76(q,J=6.2Hz,2H),3.66(t,J=5.6Hz,2H),3.32–3.2 8(m,2H),3.15(d,J=11.4Hz,2H),2.87–2.70(m,2H),2.21–2.09(m,1H),1.82–1.66(m,2H),1.66–1.47(m,2H)ppm.

[0216] Example 16: N-(6,6-dioxo-3-oxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-diphenylheterocyclodecane-25 -yl)-2-hydroxy-1-ethanesulfonamide

[0217] Step 1: At 20 ° C, (E)-N-(6,6-dioxo-3-oxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-dibenzoheterocyclodec-9-ene-2 5 -yl)-2-hydroxy-1-ethanesulfonamide (30 mg, 0.58 mmol) and 10% palladium / carbon (30 mg, 100% w / w) were dissolved in methanol (10.00 mL), and formic acid (0.20 g, 3.34 mmol) was added to replace the hydrogen atmosphere. The reaction mixture was stirred at 20°C for 24 hours until the reaction was complete. The reaction solution was concentrated and purified by flash column chromatography (silica, 70-95% ethyl acetate / petroleum ether), and then purified by preparative HPLC (C18, 4-44% gradient of water (ammonia + ammonium bicarbonate) / acetonitrile) to obtain N-(6,6-dioxo-3-oxo-6-thia-4,7-diaza-1(1,4)-piperidin-2(1,2),5(1,3)-diphenylheterocyclodecane-2 5 -yl)-2-hydroxy-1-ethanesulfonamide (17 mg, 0.33 mmol, yield 57.4%), as a white solid. LCMS (ESI): [M+H]+=523.1. 1 H NMR(400MHz,DMSO-d6)δppm 10.77(s,1H),10.31–9.66(m,1H),8.60(br d,J=8.4Hz,1H),7.70(s,1H),7.63(t,J=8.0Hz,1H),7.58(d,J=8.8Hz,1H),7.49–7.38(m,2H),7.03–6.92(m,2H),4.98(br s,1H),3.76(t,J=6.4Hz,2H),3.32–3.29(m,2H),3.11(br d,J=10.4Hz,2H),2.79(br d,J=4.4Hz,2H),2.59(br t,J=10.4Hz,2H),1.61–1.28(m,9H)ppm.

[0218] Example 17: N-(6,6-dioxide-9-oxo-6-thia-8-aza-5(1,4)-piperazine-2(1,4)-piperidin-1(1,2),7(1,3)-diphenylheterocyclononane-1 5 -yl)-2-hydroxyethane-1-sulfonamide

[0219] Step 1: Dissolve tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (9.00 g, 39.60 mmol) in 1,2-dichloroethane (100.00 mL), and add dropwise a solution containing piperazine (17.10 g, 197.98 mmol), sodium cyanoborohydride (3.70 g, 59.39 mmol), N,N-diisopropylethylamine (15.70 g, 118.79 mmol) and dichloroethane (100.00 mL). The resulting mixture is stirred at 20 ° C for 12 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-30% methanol / dichloromethane gradient) to obtain tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate (2.30 g, 7.73 mmol, 19.5% yield) as a white solid. LCMS (ESI): [M-55] + =298.3.

[0220] Step 2: A solution containing tert-butyl 4-(2-piperazinylethyl)piperidinecarboxylate (2.30 g, 7.73 mmol), 3-nitrobenzenesulfonyl chloride (2.10 g, 9.28 mmol), N,N-diisopropylethylamine (5.51 g, 38.66 mmol), and tetrahydrofuran (30.00 mL) was stirred at 20°C for 1 hour. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether gradient) to obtain tert-butyl 4-(2-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)ethyl)piperidine-1-carboxylate (1.80 g, 3.73 mmol, 48.2% yield) as a white solid. LCMS (ESI): [M+Na] + =505.3.

[0221] Step 3: A reaction mixture containing tert-butyl 4-(2-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)ethyl)piperidine-1-carboxylate (1.80 g, 3.73 mmol) and a hydrochloric acid / ethyl acetate solution (10.00 mL, 4.0 M) was stirred at 20°C for 1 hour. The reaction mixture was concentrated to afford 1-(3-nitrophenyl)sulfonyl)-4-(2-(piperidin-4-yl)ethyl)piperazine (1.60 g, crude) as a white solid. LCMS (ESI): [M+H] + =383.3.

[0222] Step 4: A solution containing 1-(3-nitrophenyl)sulfonyl)-4-(2-(piperidin-4-yl)ethyl)piperazine (1.30 g, 3.40 mmol), 4-bromo-2-fluorobenzoic acid (1.10 g, 5.10 mmol), potassium carbonate (1.40 g, 10.20 mmol) and dimethyl sulfoxide (50.00 mL) was stirred at 100 ° C for 12 hours. The reaction solution was poured into water (100 mL), and hydrochloric acid / ethyl acetate solution (5 mL) was added to adjust the pH to about 7. The reaction mixture was quenched with ethyl acetate (30 mL x 10 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-25% gradient of methanol / dichloromethane) to obtain the compound 4-bromo-2-(4-(2-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)ethyl)piperidin-1-yl)benzoic acid (760 mg, 1.31 mmol, 38.5% yield) as a yellow oil. LCMS (ESI): [M+H] + =581.3.

[0223] Step 5: A solution containing 4-bromo-2-(4-(2-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)ethyl)piperidin-1-yl)benzoic acid (760 mg, 1.31 mmol), iron powder (369 mg, 6.54 mmol), ammonium chloride (353 mg, 6.54 mmol), ethanol (20.00 mL) and water (5.00 mL) was stirred at 60°C for 1 hour. The reaction solution was filtered and washed with ethyl acetate (30 mL x 10% acetic acid). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was then purified by column chromatography (C18, 0-100% gradient of acetonitrile / water) to afford 2-(4-(2-(4-((3-aminophenyl)sulfonyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-bromobenzoic acid (150 mg, 0.27 mmol, 20.8% yield) as a white solid. LCMS (ESI): [M+H] + =551.2.

[0224] Step 6: 2-(4-(2-(4-((3-aminophenyl)sulfonyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-bromobenzoic acid (150 mg, 0.27 mmol) was dissolved in dichloromethane (10.00 mL) and added dropwise to a solution containing 2-chloro-1-methylpyridinium iodide (106 mg, 0.41 mmol), N,N-diisopropylethylamine (179 mg, 1.36 mmol) and dichloromethane (75.00 mL). The mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain compound 1. 5-Bromo-6-thia-8-aza-5(1,4)-piperazin-2(1,4)-piperidin-1(1,2),7(1,3)-diphenylheterocyclononan-9-one-6,6-dioxide (50 mg, 0.094 mmol, yield 34.5%), as a white solid. LCMS (ESI): [M+H] + =533.2.

[0225] Step 7: Contains 1 5 A solution of 6-bromo-6-thia-8-aza-5(1,4)-piperazin-2(1,4)-piperidin-1(1,2),7(1,3)-diphenylheterocyclononan-9-one-6,6-dioxide (50 mg, 0.094 mmol), 2-hydroxyethanesulfonamide (24 mg, 0.19 mmol), potassium phosphate (61 mg, 0.28 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (4 mg, 0.0094 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.0094 mmol) and 1,4-dioxane (5.00 mL) was stirred at 100 °C under nitrogen for 8 h. The reaction solution was poured into water (30 mL) and dried with ethyl acetate (30 mL x 40 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-25% gradient of methanol / dichloromethane) and (C18, 0-100% gradient of acetonitrile / water) to obtain the compound N-(6,6-dioxido-9-oxo-6-thia-8-aza-5(1,4)-piperazin-2(1,4)-piperidin-1(1,2),7(1,3)-diphenylheterocyclononane-1 5 -yl)-2-hydroxyethane-1-sulfonamide (2.5 mg, 0.0043 mmol, yield 4.6%). LCMS (ESI): [M+H] + =578.30.

[0226] Example 18: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide

[0227] Step 1: Under a nitrogen atmosphere at 20°C, methyltriphenylphosphonium bromide (24.06 g, 66.00 mmol) was dissolved in dry tetrahydrofuran (350.00 mL). The solution was cooled to 0°C, followed by the slow addition of a 1.0 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (66.00 mL, 66.00 mmol) and stirring for 1 hour. A solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (10.00 g, 44.00 mmol) in tetrahydrofuran (20.00 mL) was added to the reaction system, and the temperature was raised to 20°C and stirred for 16 hours. After completion of the reaction, saturated sodium bicarbonate solution (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give tert-butyl 4-allylpiperidine-1-carboxylate (10.00 g, 66.00 mmol, 100.0% yield) as a colorless liquid.

[0228] Step 2: At 20°C, tert-butyl 4-allylpiperidine-1-carboxylate (10.00 g, 66.00 mmol) was dissolved in dichloromethane (200.00 mL). Trifluoroacetic acid (10.02 mL, 131.81 mmol) was added and stirred at 20°C for 16 hours. After the reaction was complete, the solvent and excess trifluoroacetic acid were removed to yield crude 4-allylpiperidinium trifluoroacetate (approximately 15.50 g). This crude product was then dissolved in dimethyl sulfoxide (200.00 mL), potassium carbonate (30.98 g, 219.68 mmol) and 4-bromo-2-fluorobenzoic acid (9.62 g, 43.94 mmol) were added, and the mixture was heated to 140°C and stirred for 48 hours. After the reaction was complete, the mixture was cooled, quenched by the addition of cold water (100 mL), and the pH of the solution was adjusted to 6-7 by the addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined and washed with saturated sodium chloride solution (100 mL). The organic phases were dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-20% ethyl acetate / petroleum ether) to give 4-bromo-2-(4-allylpiperidinyl)benzoic acid (11.50 g, 35.15 mmol, 80.3% yield) as an orange solid. 1H NMR(400MHz,Chloroform-d)δ8.14(d,J=8.3Hz,1H),7.61–7.48(m,2H),5.85–5.68(m,1H),5.14–4.98(m,2H),3.19–3.05(m,2H),2 .91(td,J=11.7,2.5Hz,2H),2.11(t,J=6.8Hz,2H),2.07–1.99(m,1H),2.00–1.86(m,2H),1.67–1.44(m,3H)ppm; LCMS(ESI):[M+H] + =324.1.

[0229] Step 3: To a solution of N-tert-butoxycarbonyl-4-piperidone (600.00 g, 3011.29 mmol) and phenylacetylene (307.54 g, 3011.29 mmol) in DMSO (6.00 L) at 20°C was added potassium tert-butoxide (341.31 g, 3011.29 mmol). The reaction was stirred in an oil bath at 100°C for 1 hour, and the reaction was complete. The reaction mixture was poured into cold water (1500 mL) to quench the reaction and extracted with ethyl acetate (1500 mL x 2). The organic phases were combined and concentrated to obtain the crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to afford N-tert-butoxycarbonyl-3-((1E)-2-phenylvinyl)-4-piperidone (220.00 g, 729.94 mmol, 24.2% yield) as a yellow oil.

[0230] Step 4: To a solution of N-tert-butyloxycarbonyl-3-((1E)-2-phenylvinyl)-4-piperidone (100.00 g, 33.81 mmol) in dichloromethane (1800.00 mL) at -40°C was added DAST (160.45 g, 995.41 mmol). The reaction mixture was heated to 0°C and stirred for 5 hours, until the reaction was complete. The reaction solution was quenched with sodium bicarbonate solution (1000 mL) and extracted with dichloromethane (1000 mL x 3). The organic phase was dried, filtered, and concentrated to obtain the crude product, which was purified by flash column chromatography (silica, 0-8% ethyl acetate / petroleum ether) to afford N-tert-butyloxycarbonyl-3-((1E)-2-phenylvinyl)-4,4-difluoropiperidine (33.00 g, 102.03 mmol, 30.8% yield) as a yellow oil.

[0231] Step 5: To a solution of N-tert-butyloxycarbonyl-3-((1E)-2-phenylvinyl)-4,4-difluoropiperidine (10.00 g, 30.92 mmol) in dichloromethane (40.00 mL) was added trifluoroacetic acid (8.00 mL) at 20°C. The reaction was stirred for 16 hours and then concentrated under reduced pressure to yield crude 3-((1E)-2-phenylvinyl)-4,4-difluoropiperidine (8.00 g) as a yellow oil. The crude 3-((1E)-2-phenylvinyl)-4,4-difluoropiperidine (8.00 g) was dissolved in dimethyl sulfoxide (140.00 mL), and potassium carbonate (12.81 g, 92.71 mmol) and 2-chloro-6-methylpyrimidin-4-amine (4.44 g, 30.92 mmol) were added. The reaction was stirred in an oil bath at 100°C for 16 hours, and the reaction was essentially complete. The reaction mixture was poured into cold water (100 mL) to quench the reaction and extracted with dichloromethane (300 mL x 3). The organic phases were combined, washed with sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-35% ethyl acetate / petroleum ether) to give 2-(3-((1E)-2-phenylvinyl)-4,4-difluoropiperidinyl)-6-methylpyrimidin-4-amine (4.00 g, 9.55 mmol, 39% yield) as a yellow solid.

[0232] Step 6: At 20 ° C, 2-(3-((1E)-2-phenylvinyl)-4,4-difluoropiperidinyl)-6-methylpyrimidin-4-amine (2.0 g, 6.05 mmol), 4-bromo-2-(4-allylpiperidinyl)benzoic acid (2.16 g, 6.66 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (11.74 g, 30.27 mmol) and 4-dimethylaminopyridine (3.77 g, 30.27 mmol) were dissolved in dry 1,2-dichloroethane (50.00 mL), heated to 80 ° C and stirred for 48 hours. After the reaction was completed, the mixture was cooled naturally, and cold water (50 mL) was added to quench the reaction. The mixture was extracted with dichloroethane (50 mL x 3), and the organic phases were combined, dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 0-8% ethyl acetate / petroleum ether) to give 2-(4-allylpiperidin-1-yl)-4-bromo-N-(2-(4,4-difluoro-3-phenylvinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)benzamide (1.05 g, 1.65 mmol, yield 27.3%) as a white solid. LCMS (ESI): [M+H] + =636.4 / [M / 2+H] + =319.6.

[0233] Step 7: Under nitrogen atmosphere at 20°C, 2-(4-allylpiperidin-1-yl)-4-bromo-N-(2-(4,4-difluoro-3-phenylvinylpiperidin-1-yl)-6-methylpyrimidin-4-yl)benzamide (1.05 g, 1.65 mmol) was dissolved in dry dichloroethane (100.00 mL), Grubbs second-generation catalyst (136 mg, 0.15 mmol) was added, and the reaction was heated under reflux for 48 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 0-8% ethyl acetate / petroleum ether) to obtain 5 4 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-en-4-one (400 mg, 0.75 mmol, yield 45.4%), as a white solid, LCMS (ESI): [M+H] + =532.3.

[0234] Step 8: Under nitrogen atmosphere at 20℃, 4 -Br-1 4 ,1 4 -Difluoro-2 6 -Methyl-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-en-4-one (400 mg, 0.75 mmol), 2-hydroxyethylsulfonamide (288 mg, 2.25 mmol), potassium phosphate (488 mg, 2.25 mmol), cuprous iodide (146 mg, 0.75 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (216 mg, 1.50 mmol) were dissolved in N,N-dimethylformamide (10.00 mL), and the resulting reaction mixture was stirred at 100 ° C for 5 hours. After the reaction was complete, cold water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated to obtain a crude product, which was purified by flash column chromatography (silica, 50-70% ethyl acetate / petroleum ether) to obtain 430 mg of the product, which was further purified by preparative HPLC (C18, 70-95% gradient acetonitrile / water) to obtain N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-ene-5-ol 4-yl)-2-hydroxyethane-1-sulfonamide (80 mg, 0.14 mmol, yield 18.5%), as a white solid. LCMS (ESI): [M+H] + =577.4. 1 H NMR(400MHz,DMSO-d6)δ12.98(s,0.66H),10.84(s,0.32H),10.23(brs,1H),8.24–6.88(m,4H),5.94–5.36(m,2H),5.08 –4.31(m,3H),3.75(t,J=6.4Hz,2H),3.36(d,J=6.3Hz,2H),3.22–2.68(m,7H),2.36–2.25(m,4H),2.19–1.47(m,8H)ppm.

[0235] Example 18A: N-((1 3 S,E)-1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide

[0236] Example 18B: N-(1 3 R,E)-1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide

[0237] Example 18C: N-((1 3 S,Z)-1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide

[0238] Example 18D: N-((1 3 R,Z)-1 4 ,1 4 -Difluoro-2 6-methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide

[0239] Step 1: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide (400 mg, 0.69 mmol) was purified by preparative HPLC (C18, 38%-78% gradient of water (ammonia + ammonium bicarbonate) / acetonitrile), freeze-dried and separated by SFC (chromatographic column type: REGIS (s, s) WHELK-O1 (250 mm * 30 mm, 5 um), mobile phase type: CO2-EtOH (0.1% NH3H2O), gradient: isocratic 45%, flow rate: 80 mL / min, column temperature: 40 ° C) to give P1, P2 and P34.

[0240] Example 18A: wherein P1 was lyophilized and then purified by preparative HPLC (C18, 32%-72% gradient of water (ammonia + ammonium bicarbonate) / acetonitrile) to obtain a purple solid N-((1 3 S,E)-1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide (5.76 mg, 0.01 mmol, 1.00% yield). SFC (column type: (S,S)-Whelk-0-1.850*4.6 mm ID, 1.8 μm, mobile phase type: CO2-EtOH (0.05% DEA), gradient: isocratic 45%, flow rate: 2.2 mL / min, column temperature: 35°C, retention time Rt=0.879); LCMS (ESI): [M+H] + =577.2; 1H NMR (400MHz, DMSO-d6) δ10.86(s,1H),7.81(d,J=8.4Hz,1H),7.42(s,1H),7.04(d,J=1.6Hz,1H),6.99(dd,J= 1.6,8.4Hz,1H),5.83(ddd,J=6.4,9.2,15.6Hz,1H),5.46(dd,J=8.8,15.2Hz,1H),5.00-4.93(m,1H),4.79(br d,J=13.6Hz,1H),3.75(t,J=6.4Hz,2H),3.27(br s,2H),3.20(br d,J=12.4Hz,1H),3.02-2.78(m,4H),2.56-2.53(m,1H),2.48-2.41(m,1H),2.32-2.19(m,4H),2.18-1.99(m,2H),1.89(br dd,J=9.6,12.8Hz,1H),1.81-1.62(m,4H),1.25(br d,J=11.2Hz,1H)ppm

[0241] Example 18B: P2 was lyophilized to obtain a yellow solid N-(1 3 R,E)-1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide (16.45 mg, 0.03 mmol, 4.00% yield). SFC (column type: (S,S)-Whelk-O-1.850*4.6 mm ID, 1.8 μm, mobile phase type: CO2-EtOH (0.05% DEA), gradient: isocratic 45%, flow rate: 2.2 mL / min, column temperature: 35°C, retention time Rt = 1.016). LCMS (ESI): [M+H] + =577.2. 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),10.27(s,1H),7.87(d,J=8.8Hz,1H),7.48(s,1H),7.12(d,J =1.6Hz,1H),7.07(dd,J=1.6,8.4Hz,1H),5.95-5.82(m,1H),5.51(dd,J=8.8,15.6Hz,1H),5.02(br d,J=10.0Hz,2H),4.85(br d,J=13.2Hz,1H),3.81(br t,J=6.0Hz,2H),3.37-3.30(m,2H),3.25(br d,J=12.4Hz,1H),3.08-2.83(m,4H),2.62-2.58(m,1H),2.53-2.47(m,1H),2.37-2.23(m,4H),2 .20-2.03(m,2H),1.98-1.90(m,1H),1.87-1.78(m,2H),1.74-1.66(m,2H),1.32-1.29(m,1H)ppm

[0242] P34 was lyophilized and then separated by SFC (column type: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase type: CO2-MeCN / EtOH (0.1% NH3H2O), gradient: isocratic 60%, flow rate: 80mL / min, column temperature: 40°C) to obtain P3 and P4.

[0243] Example 18C: P3 was lyophilized to obtain a white solid N-((1 3 S,Z)-1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide (23.34 mg, 0.04 mmol, 6.00% yield). SFC (Chromatographic column: Chiralpak IG 50*4.6 mm ID, 3 μm, mobile phase: CO2-EtOH (0.05% DEA), gradient: isocratic 40%, flow rate: 4 mL / min, column temperature: 35°C, retention time Rt = 2.977); LCMS (ESI): [M+H] + =577.3. 1H NMR(400MHz,DMSO-d6)δppm 13.01(br s,1H),8.02(d,J=8.8Hz,1H),7.26(s,1H),7.18(d,J=1.6Hz,1H),7.11(dd,J=2.0,8.4Hz,1H),5.77(dt,J=5.2,11.2Hz,1H),5.52(br t,J=10.0Hz,1H),4.78-4.61(m,1H),4.55-4.39(m,1H),3.75(t,J=6.8Hz,2H),3.22-2.92(m,6H),2.78(q,J =12.4Hz,2H),2.55-2.52(m,1H),2.35-2.28(m,4H),2.18-1.93(m,4H),1.90-1.79(m,2H),1.76-1.66(m,1H),1.62-1.49(m,1H)ppm

[0244] Example 18D: P4 was lyophilized to obtain N-((1 3 R,Z)-1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide (22.78 mg, 0.03 mmol, 5.00% yield). SFC (Chromatographic column: Chiralpak IG 50*4.6 mm ID, 3 μm, mobile phase: CO2-EtOH (0.05% DEA), gradient: isocratic 40%, flow rate: 4 mL / min, column temperature: 35°C, retention time Rt = 1.682); LCMS (ESI): [M+H] + =577.3. 1H NMR(400MHz,DMSO-d6)δppm 13.01(br s,1H),8.03(d,J=8.4Hz,1H),7.26(s,1H),7.19(d,J=2.0Hz,1H),7.12(dd,J=2.0,8.8Hz,1H),5.77(dt,J=5.2,11.2Hz,1H),5.52(br t,J=10.0Hz,1H),4.70(br d,J=12.0Hz,1H),4.47(br d,J=12.4Hz,1H),3.75(t,J=6.4Hz,2H),3.24-2.92(m,5H),2.78(q,J=12.4Hz,2H),2.54-2.52(m, 1H),2.37-2.28(m,4H),2.18-1.92(m,4H),1.89-1.79(m,2H),1.75-1.67(m,1H),1.63-1.50(m,1H)

[0245] Example 19: (E)-N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-7-ene-5-yl- 4 -yl)-2-hydroxyethane-1-sulfonamide

[0246] Example 19 was prepared by a similar synthetic route to Example 18. LCMS (ESI): [M+H] + =577.4. 1 H NMR (400MHz, DMSO-d6) δ12.78(s,1H),10.28(s,1H),8.07(d,J=8.7Hz,1H),7.39(s,1H),7.22(d,J=2. 2Hz,1H),7.13(dd,J=8.7,2.2Hz,1H),5.71–5.55(m,1H),5.37(dt,J=15.4,7.1Hz,1H),5.05–4.82(m,2 H),4.73(d,J=13.6Hz,1H),3.76(t,J=6.4Hz,2H),3.36(t,J=6.5Hz,2H),3.20–2.94(m,3H),2.93–2.7 3(m,2H),2.50–2.39(m,2H),2.33–2.22(m,1H),2.27(s,3H),2.18–2.07(m,1H),2.02–1.62(m,7H)ppm.

[0247] Example 20: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,3)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5- ... 4 -yl)-2-hydroxyethane-1-sulfonamide

[0248] Example 20 was prepared by a similar synthetic route to Example 18. LCMS (ESI): [M+H] + =577.5. 1 H NMR (400MHz, DMSO) δ13.89 (s, 1H), 10.28 (s, 1H), 8.11 (d, J = 9.2Hz, 1H), 7.32 (s, 1H) ),7.21–7.16(m,2H),5.35(d,J=11.2Hz,1H),5.02-4.86(m,2H),3.77(t,J=6.4Hz,2 H),3.40–3.36(m,2H),3.24–3.09(m,3H),2.97–2.86(m,2H),2.78–2.54(m,4H),2.3 0(s,3H),2.13–2.05(m,2H),1.89–1.74(m,2H),1.37(s,1H),1.27-1.22(m,4H)ppm.

[0249] Example 21: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-9-ene-5-yl)- 4 -yl)-2-hydroxyethane-1-sulfonamide

[0250] Step 1: Under nitrogen protection at 0°C, add acetyl chloride (7.84 g, 97.87 mmol) dropwise to a solution of N,N,N',N'-tetramethylmethanediamine (10.0 g, 97.87 mmol) in methyl tert-butyl ether (250 ml). After the addition is complete, stir for 30 minutes, filter, and wash the filter cake with methyl tert-butyl ether (25 ml). Evaporate the filter cake under reduced pressure to dryness to obtain N-methyl-N-methylene-methylammonium iodide (9.0 g, 96.20 mmol, 98.3% yield) as a white solid (highly hygroscopic).

[0251] Step 2: To a solution of N-tert-butyloxycarbonyl-4-piperidone (5.00 g, 25.09 mmol) in acetonitrile (50.00 mL) was added N-methyl-N-methylene-methylammonium iodide (2.82 g, 30.11 mmol) at 20°C. The reaction was allowed to proceed to completion after 10 hours at 40°C. The reaction solution was concentrated, quenched with a saturated sodium bicarbonate solution (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product of N-tert-butyloxycarbonyl-3-((dimethylamino)methyl)-4-piperidone (6.50 g, 25.36 mmol, quantitative yield). LCMS (ESI): [M+H] + =257.2.

[0252] Step 3: Under a nitrogen atmosphere at 0°C, N-tert-butoxycarbonyl-3-((dimethylamino)methyl)-4-piperidone (6.50 g, 25.36 mmol) was dissolved in dichloromethane (120.00 mL), and DAST (12.91 g, 76.07 mmol) was added. The temperature was then raised to 25°C for 2 hours. The mixture was quenched with a saturated sodium bicarbonate solution (300 mL) and extracted with dichloromethane (100 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give a crude product of N-tert-butoxycarbonyl-3-((dimethylamino)methyl)-4,4-difluoropiperidine (5.50 g, 19.76 mmol, 77.9% yield) as a yellow liquid. LCMS (ESI): [M+H] + =279.2.

[0253] Step 4: At 20°C under a nitrogen atmosphere, N-tert-butoxycarbonyl-3-((dimethylamino)methyl)-4,4-difluoropiperidine (5.50 g, 19.76 mmol) was dissolved in dichloromethane (150.00 mL), and m-chloroperbenzoic acid (6.02 g, 29.64 mmol) was added and stirred for 2 hours. Solid sodium carbonate (10.0 g) was added, stirred for 1 hour, filtered, and concentrated to obtain a crude product which was purified by flash column chromatography (silica, 0-100% methanol / dichloromethane) to give 1-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-3-yl)-N,N-dimethylmethanamine oxide (2.50 g, 8.49 mmol, 43.0% yield) as a yellow liquid. LCMS (ESI): [M+H] + =295.2.

[0254] Step 5: 1-(1-(tert-Butyloxycarbonyl)-4,4-difluoropiperidin-3-yl)-N,N-dimethylmethanamine oxide (2.50 g, 8.49 mmol) was dissolved in dimethyl sulfoxide (50 mL) at 20°C and stirred at 130°C for 2 hours. The reaction was quenched by adding water (100 mL) and extracted with ethyl acetate (100 mL x 3). The mixture was washed with saturated sodium chloride solution. The organic phases were combined, dried, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give N-tert-Butyloxycarbonyl-4,4-difluoro-3-methylenepiperidine (1.20 g, 5.14 mmol, 60.5% yield) as a colorless liquid. LCMS (ESI): [M-55] + =178.1.

[0255] Step 6: At 20°C, N-tert-butyloxycarbonyl-4,4-difluoro-3-methylenepiperidine (1.20 g, 5.14 mmol) was dissolved in dichloromethane (50.00 mL), trifluoroacetic acid (6.00 mL) was added, and the mixture was stirred at 20°C for 16 hours. After the reaction was complete, the solvent and excess trifluoroacetic acid were removed to obtain a crude trifluoroacetic acid salt of 4,4-difluoro-3-methylenepiperidine (approximately 2.50 g). This crude product was then dissolved in N,N-dimethylformamide (20.00 mL), potassium carbonate (3.55 g, 25.72 mmol) and 2-chloro-6-methylpyrimidin-4-amine (1.11 g, 7.72 mmol) were added, and the mixture was heated to 130°C and stirred for 24 hours. After the reaction was completed, the mixture was cooled naturally and cold water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (100 mL). The organic phases were dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 0-30% ethyl acetate / petroleum ether) to give 2-(4,4-difluoro-3-methylenepiperidin-1-yl)-6-methylpyrimidin-4-amine (450 mg, 1.87 mmol, yield 36.4%) as a colorless liquid. LCMS (ESI): [M+H] + =241.2.

[0256] Step 7: At 20 ° C, 2-(4,4-difluoro-3-methylenepiperidin-1-yl)-6-methylpyrimidin-4-amine (450 mg, 1.87 mmol), 4-bromo-2-(4-(3-buten-1-yl)piperidin-1-yl)benzoic acid (634 mg, 1.87 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.18 g, 5.62 mmol) and 4-dimethylaminopyridine (934 mg, 7.49 mmol) were dissolved in dry N,N-dimethylacetamide (10.00 mL), heated to 60 ° C and stirred for 24 hours. After the reaction was completed, the mixture was cooled naturally and cold water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (100 mL). The organic phase was dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 0-8% ethyl acetate / petroleum ether) to give 4-bromo-2-(4-(3-buten-1-yl)piperidin-1-yl)-N-(2-(4,4-difluoro-3-methylenepiperidin-1-yl)-6-methylpyrimidin-4-yl)benzamide (260 mg, 0.46 mmol, yield 24.8%) as a white solid. LCMS (ESI): [M+H] + =.

[0257] Step 8: Under nitrogen atmosphere at 20°C, 4-bromo-2-(4-(3-butene-1-yl)piperidin-1-yl)-N-(2-(4,4-difluoro-3-methylenepiperidin-1-yl)-6-methylpyrimidin-4-yl)benzamide (260 mg, 0.46 mmol) was dissolved in dry dichloroethane (50.00 mL), Grubbs second-generation catalyst (50 mg, 0.058 mmol) was added, and the reaction was heated under reflux for 48 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 0-8% ethyl acetate / petroleum ether) to obtain 5 4 -Br-1 4 ,1 4 -Difluoro-2 6 -methyl-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-9-en-4-one (240 mg, 0.45 mmol, yield 97.2%), as a white solid, LCMS (ESI): [M+H] + =532.3.

[0258] Step 9: Under nitrogen atmosphere at 20℃, 4 -Br-1 4 ,1 4 -Difluoro-2 6-Methyl-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-9-en-4-one (240 mg, 0.45 mmol), 2-hydroxyethylsulfonamide (475 mg, 3.72 mmol), potassium phosphate (1.07 g, 1.24 mmol), cuprous iodide (241 mg, 1.24 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (356 mg, 2.48 mmol) were dissolved in N,N-dimethylformamide (5.00 mL), and the resulting reaction mixture was stirred at 100 ° C for 5 hours. After the reaction was complete, cold water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated to obtain a crude product, which was purified by flash column chromatography (silica, 50-70% ethyl acetate / petroleum ether) and subsequently purified by preparative HPLC (C18, 40%-80% gradient of water (ammonia + ammonium bicarbonate) / acetonitrile) to obtain a white solid N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-9-ene-5-yl)- 4 -yl)-2-hydroxyethane-1-sulfonamide (1.08 mg, 0.41 mmol, 0.43% yield). LCMS (ESI): [M+H] + =577.4.

[0259] Example 23: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,3)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5- ... 4 -yl)-2-hydroxyethane-1-sulfonamide

[0260] Step 1: At 20°C, (E)-N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-7-ene-5-yl- 4-yl)-2-hydroxyethane-1-sulfonamide (120 mg, 0.21 mmol) and 10% palladium / carbon (120 mg, 100% w / w) were dissolved in methanol (10.00 mL), and formic acid (0.20 g, 3.34 mmol) was added to replace the hydrogen. The mixture was stirred at 20°C for 24 hours. The reaction was complete. After concentration, the mixture was purified by flash column chromatography (silica, 30-95% ethyl acetate / petroleum ether) to obtain N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,3)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5- ... 4 -yl)-2-hydroxyethane-1-sulfonamide (43 mg, 0.07 mmol, yield 35.7%), as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),10.22(brs,1H),7.93(d,J=8.5Hz,1H),7.50(s,1H),7.10(d,J= 2.1Hz,1H),7.05(dd,J=8.6,2.0Hz,1H),4.95(brs,1H),4.27–4.10(m,1H),4.08–3.91(m,1H),3.85–3 .67(m,3H),3.67–3.51(m,1H),3.36(t,J=7.3Hz,2H),3.21(d,J=11.0Hz,1H),3.08(d,J=11.6Hz,1H), 2.77(t,J=11.3Hz,1H),2.65(t,J=11.7Hz,1H),2.31(s,3H),2.10–1.82(m,5H),1.76–1.31(m,9H)ppm.

[0261] Example 23A: N-((1 3 S)-1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,3)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5- ... 4 -yl)-2-hydroxyethane-1-sulfonamide

[0262] Example 23B: N-((1 3 R)-1 4 ,1 4 -Difluoro-2 6-methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,3)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5- ... 4 -yl)-2-hydroxyethane-1-sulfonamide

[0263] Step 1: N-(1 4 ,1 4 -Difluoro-2 6 -methyl-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,3)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5- ... 4 -yl)-2-hydroxyethane-1-sulfonamide (50 mg, 0.086 mmol) was separated by SFC (Column REGIS (s, s) WHELK-O1 (250 mm*30 mm, 5 μm), mobile phase type: CO2-EtOH (0.1% NH3H2O), gradient: isocratic 35%, flow rate: 80 mL / min, column temperature: 40°C) to give Example 23A and Example 23B

[0264] Example 23A: SFC (chromatographic column type: (S,S)-Whelk-0-1.8 ID, 1.8 μm, mobile phase: CO2-EtOH (0.05% DEA), gradient: isocratic to 45%, flow rate: 2.2 mL / min, column temperature: 35°C, retention time Rt = 1.108). LCMS (ESI): [M+H]+ = 579.2. 1 H NMR (400MHz, DMSO-d6)δppm 11.63-11.22(m,1H),7.89(d,J=8.4Hz,1H),7.49(s,1H),7.12-6.91(m,2H),4.27-4.06(m,1H),3.95(br dd,J=2.8,12.0Hz,1H),3.85-3.67(m,3H),3.67-3.56(m,1H),3.27-3.24(m,2H),3.18(br d,J=9.8Hz,1H),3.11-3.05(m,1H),2.81-2.57(m,2H),2.37-2.21(m,3H),2.11-1.80(m,5H),1.77-1.62(m,3H),1.60-1.26(m,6H)ppm

[0265] Example 23B: SFC (chromatographic column type: (S,S)-Whelk-0-1.8 ID, 1.8um, mobile phase type: CO2-EtOH (0.05% DEA), gradient: isocratic 45%, flow rate: 2.2mL / min, column temperature: 35°C, retention time Rt=1.226) LCMS (ESI): [M+H]+=579.2. 1 H NMR (400MHz, DMSO-d6) δppm 11.74-11.24(m,1H),7.88(d,J=8.8Hz,1H),7.49(s,1H),7.13-6.84(m,2H),4.28-4.04(m,1H),3.95(br d,J=10.0Hz,1H),3.85-3.67(m,3H),3.67-3.56(m,1H),3.28(br d,J=6.8Hz,2H),3.18(br d,J=10.4Hz,1H),3.06(br d,J=11.6Hz,1H),2.80-2.59(m,2H),2.37-2.20(m,3H),1.84(br s,5H),1.70(br s,9H)ppm

[0266] Example 24: (Z)-N-(1 4 ,1 4 -Difluoro-2 6 -Methoxy-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide

[0267] Step 1: Dissolve 2,4-dichloro-6-methoxypyrimidine (1.50 g, 8.38 mmol) and (E)-4,4-difluoro-3-phenylvinylpiperidine (0.88 g, 5.59 mmol) in tert-butanol (30.0 mL), add diisopropylethylamine (5.42 g, 41.9 mmol), and stir at 100°C for 3 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 2). The organic phase was washed with saturated brine (300 mL), dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-3% gradient of tetrahydrofuran / petroleum ether) to give (E)-4-chloro-2-(4,4-difluoro-3-phenylvinylpiperidin-1-yl)-6-methoxypyrimidine (2.60 g,

[0268] 7.12 mmol, 85.0% yield). LCMS (ESI): [M+H] + =366.0

[0269] Step 2: (E)-4-chloro-2-(4,4-difluoro-3-phenylvinylpiperidin-1-yl)-6-methoxypyrimidine (2.10 g, 5.74 mmol) and diphenylmethaneimine (1.59 g, 8.61 mmol) were dissolved in dioxane (40.0 mL). Cesium carbonate (5.61 g, 17.2 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylanthracene (0.66 g, 1.15 mmol), and tris(dibenzylideneacetone)dipalladium (0.53 g, 0.57 mmol) were added. The mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 2). The organic phase was dried, filtered, and concentrated. The brown oily residue was purified by flash column chromatography (silica gel, 0-3% gradient of tetrahydrofuran / petroleum ether) to give (E)-N-(2-(4,4-difluoro-3-phenylvinylpiperidin-1-yl)-6-methoxypyrimidin-4-yl)-1,1-diphenylmethanimine (2.90 g, 5.74 mmol, crude) as a yellow oil. LCMS (ESI): [M+H] + =511.3

[0270] Step 3: (E)-N-(2-(4,4-difluoro-3-phenylvinylpiperidin-1-yl)-6-methoxypyrimidin-4-yl)-1,1-diphenylcarbamate (2.90 g, 5.67 mmol) was dissolved in methanol (60.0 mL). Sodium acetate (1.40 g, 17.0 mmol) and hydroxylamine hydrochloride (0.79 g, 11.3 mmol) were added and stirred at 25°C for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 2). The organic phase was dried, filtered, and concentrated. The resulting brown oily residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / petroleum ether) to afford (E)-2-(4,4-difluoro-3-phenylvinylpiperidin-1-yl)-6-methoxypyrimidin-4-amine (1.40 g, 3.46 mmol, 61.0% yield) as a yellow oil. LCMS(ESI):[M+H] + =347.5. 1H NMR (400MHz, DMSO-d6) δ7.47-7.43(m,2H),7.37-7.33(m,2H),7.29-7.25(m,1H),6.68(d,J=16.0Hz,1H),6.28(br s,2H),6.23(br dd,J=8.4,16.0Hz,1H),5.14(s,1H),4.54-4.45(m,2H),3.72(s,3H),3.24(br t,J=11.2Hz,2H),2.89-2.74(m,1H),2.17-2.07(m,1H),1.98-1.83(m,1H)ppm

[0271] Step 4: (E)-2-(4,4-difluoro-3-phenylvinylpiperidin-1-yl)-6-methoxypyrimidin-4-amine (1.48 g, 4.27 mmol) and 2-(4-allylpiperidin-1-yl)-4-bromobenzoic acid (1.39 g, 4.27 mmol) were dissolved in N,N-dimethylacetamide (28.0 mL). 4-Dimethylaminopyridine (28.2 mg, 0.23 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (4.06 g, 10.6 mmol) were added and stirred at 60°C for 72 hours. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of tetrahydrofuran / petroleum ether) to give (E)-2-(4-allylpiperidin-1-yl)-4-bromo-N-(2-(4,4-difluoro-3-phenylvinylpiperidin-1-yl)-6-methoxypyrimidin-4-yl)benzamide (1.30 g, 1.84 mmol, 43.0% yield) as a yellow solid. LCMS (ESI): [M+H] + =654.0. 1H NMR(400MHz,CHLOROFORM-d)δ12.35(s,1H),8.02(d,J=8.4Hz,1H),7.35-7.28(m,4H),7.24(t,J=7.2Hz, 2H),7.20-7.09(m,2H),7.08-7.04(m,1H),6.57(d,J=16.0Hz,1H),6.14(dd,J=8.4,16.0Hz,1H),5.63(br dd,J=8.4,17.2Hz,1H),4.94-4.86(m,2H),4.57-4.49(m,2H),3.84(s,3H),3.43 -3.27(m,2H),3.13-3.06(m,2H),2.82-2.64(m,3H),2.14-2.02(m,1H),1.93(br t,J=6.4Hz,2H),1.77(br d,J=12.0Hz,2H),1.63-1.53(m,2H),1.44-1.36(m,1H)ppm

[0272] Step 5: (E)-2-(4-allylpiperidin-1-yl)-4-bromo-N-(2-(4,4-difluoro-3-phenylvinylpiperidin-1-yl)-6-methoxypyrimidin-4-yl)benzamide (100 mg, 0.15 mmol) was dissolved in anhydrous dichloromethane (80.0 mL), Grubbs second-generation catalyst (13.2 mg, 0.02 mmol) was added, and stirred at 50 ° C for 16 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-3% gradient of tetrahydrofuran / petroleum ether) to obtain (E)-5 as a brown oil. 4 -Br-1 4 ,1 4 -Difluoro-2 6 -methoxy-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-8-en-4-one (30.0 mg, 0.05 mmol, 35.5% yield). LCMS (ESI): [M+H] + =549.8

[0273] Step 6: (E)-5 4 -Br-1 4 ,1 4 -Difluoro-2 61-Methoxy-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzheterocyclononane-8-en-4-one (80.0 mg, 0.15 mmol) and 2-hydroxyethane-1-sulfonamide (21.9 mg, 0.18 mmol) were dissolved in dioxane (1.00 mL). Potassium phosphate (94.7 mg, 0.44 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (12.3 mg, 0.03 mmol), and tris(dibenzylideneacetone)dipalladium (13.6 mg, 0.01 mmol) were added to the mixture. The mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 38%-78% gradient of water (formic acid) / acetonitrile) to give (Z)-N-(1 4 ,1 4 -Difluoro-2 6 -Methoxy-4-oxo-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclonon-8-ene-5-ol 4 -yl)-2-hydroxyethane-1-sulfonamide (30.07 mg, 0.05 mmol, 34.0% yield). LCMS (ESI): [M+H] + =593.3. 1 H NMR (400MHz, DMSO-d6) δ13.10-10.62(m,1H),8.06-7.74(m,1H),7.22-6.97(m,2H),6.94-6.74(m,1H),5.90-5.71(m,1H),5.56-5. 38(m,1H),4.93-4.44(m,2H),3.87(s,3H),3.76(t,J=6.4Hz,2H),3.31-3.08(m,4H),3.07-2.88(m,3H),2.87-2.67(m,2H),2.32(br dd,J=4.4,11.2Hz,1H),2.15-1.54(m,8H)ppm.

[0274] Example 25: 2-Hydroxy-N-((1 2 S)-2 6 -methyl-4-oxo-3-aza-1(4,2)-morpholino-2(2,4)-pyrimidin-6(1,4)-piperidin-5(1,2)-benzeneheterocyclonon-8-ene-5- 4 -yl)ethane-1-sulfonamide

[0275] Step 1: (R)-N-tert-Butyloxycarbonyl-2-hydroxymethylmorpholine (5.0 g, 23.01 mmol) was dissolved in dry dichloromethane (150.00 mL) at 20°C. The solution was cooled to 0°C, and Dess-Martin periodinane (11.83 g, 27.62 mmol) was added portionwise. The temperature was then raised to 20°C and stirred for 1 hour. After completion, the reaction was quenched with saturated sodium bicarbonate solution (100 mL) and sodium sulfite solution (100 mL), and extracted with dichloromethane (200 mL x 3). The organic phases were combined, dried, filtered, and concentrated to afford crude (R)-N-tert-Butyloxycarbonyl-2-formylmorpholine (3.70 g, 17.19 mmol, 74.7% yield) as a colorless liquid.

[0276] Step 2: Under a nitrogen atmosphere at 20°C, methyltriphenylphosphonium bromide (5.99 g, 35.82 mmol) was dissolved in dry tetrahydrofuran (100.00 mL). The solution was cooled to 0°C, followed by the slow addition of a 1.0 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (35.82 mL, 35.82 mmol) and stirring for 1 hour. A solution of crude (R)-N-tert-butyloxycarbonyl-2-formylmorpholine (3.70 g, 17.19 mmol) in tetrahydrofuran (10.00 mL) was added to the reaction system, and the temperature was raised to 20°C and stirred for 16 hours. Upon completion of the reaction, the reaction was quenched by the addition of saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give (S)-N-tert-butyloxycarbonyl-2-vinylmorpholine (1.10 g, 5.16 mmol, 30.0% yield) as a colorless liquid. 1 H NMR (400MHz, Chloroform-d) δ5.79 (ddd, J=17.4, 10.7,5.4Hz,1H),5.35(dt,J=17.4,1.5Hz,1H),5.22(dt,J=10.7,1.4Hz,1H),4.00–3.76( m,4H),3.55(td,J=11.6,2.8Hz,1H),2.94(t,J=12.6Hz,1H),2.67(s,1H),1.46(s,9H)ppm.

[0277] Step 3: (S)-N-tert-Butoxycarbonyl-2-vinylmorpholine (1.10 g, 5.16 mmol) was dissolved in dichloromethane (50.00 mL) at 20°C, and trifluoroacetic acid (6.20 mL, 80.98 mmol) was added. The mixture was stirred at 20°C for 16 hours. After the reaction was complete, the solvent and excess trifluoroacetic acid were removed to obtain crude 2-vinylmorpholine trifluoroacetate (approximately 2.40 g). This crude product was then dissolved in N,N-dimethylformamide (50.00 mL), potassium carbonate (3.64 g, 25.79 mmol) and 2-chloro-6-methylpyrimidin-4-amine (1.11 g, 7.74 mmol) were added, and the mixture was heated to 130°C and stirred for 48 hours. After the reaction was completed, the mixture was cooled naturally and cold water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (100 mL). The organic phases were dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 0-20% ethyl acetate / petroleum ether) to give (S)-6-methyl-2-(2-vinylmorpholino)pyrimidin-4-amine (1.14 g, 4.18 mmol, yield 81.0%) as a white solid. LCMS (ESI): [M+H] + =221.2.

[0278] Step 4: (S)-6-Methyl-2-(2-vinylmorpholino)pyrimidin-4-amine (0.92 g, 4.18 mmol), 2-(4-allylmorpholin-1-yl)-4-bromo-benzoic acid (1.49 g, 4.59 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (4.86 g, 12.53 mmol) and 4-dimethylaminopyridine (2.08 g, 16.71 mmol) were dissolved in dry N,N-dimethylacetamide (20.00 mL) at 20 °C, heated to 60 °C and stirred for 24 hours. After the reaction was completed, the mixture was cooled naturally and cold water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL). The organic phases were dried, filtered, and concentrated to give a crude product, which was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to give (S)-2-(4-allylmorpholin-1-yl)-4-bromo-N-(6-methyl-2-(2-vinylmorpholinyl)pyrimidin-4-yl)benzamide (1.00 g, 1.90 mmol, yield 45.5%) as a yellow liquid. LCMS (ESI): [M+H] + =526.3.

[0279] Step 5: Under nitrogen atmosphere at 20°C, (S)-2-(4-allylmorpholin-1-yl)-4-bromo-N-(6-methyl-2-(2-vinylmorpholinyl)pyrimidin-4-yl)benzamide (1.00 g, 1.90 mmol) was dissolved in dry dichloromethane (100.00 mL), Grubbs second-generation catalyst (82 mg, 0.095 mmol) was added, and the reaction was heated under reflux for 36 hours. After the reaction was complete, the concentrated reaction solution was purified by flash column chromatography (silica, 0-10% ethyl acetate / petroleum ether) to obtain (1 2 S)-5 4 -Br-2 6 -methyl-3-aza-1(4,2)-morpholino-2(2,4)-pyrimidin-6(1,4)-piperidin-5(1,2)-benzeneheterocyclonon-8-en-4-one (260 mg, 0.52 mmol, yield 27.4%), as a white solid, LCMS (ESI): [M+H] + =499.3.

[0280] Step 6: Under nitrogen atmosphere at 20℃, (1 2 S)-5 4 -Br-2 6 -Methyl-3-aza-1(4,2)-morpholino-2(2,4)-pyrimidin-6(1,4)-piperidin-5(1,2)-benzeneheterocyclonon-8-en-4-one (260 mg, 0.52 mmol), 2-hydroxyethylsulfonamide (307 mg, 2.41 mmol), potassium phosphate (695 mg, 3.21 mmol), cuprous iodide (156 mg, 0.80 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (231 mg, 1.61 mmol) were dissolved in N,N-dimethylformamide (10.00 mL) and stirred at 100 ° C for 5 hours. After the reaction was complete, cold water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried, filtered, and concentrated to obtain a crude product, which was purified by flash column chromatography (silica, 60-80% ethyl acetate / petroleum ether) to obtain 2-hydroxy-N-((1 2 S)-2 6 -methyl-4-oxo-3-aza-1(4,2)-morpholino-2(2,4)-pyrimidin-6(1,4)-piperidin-5(1,2)-benzeneheterocyclonon-8-ene-5- 4 -yl)ethane-1-sulfonamide (200 mg, 0.37 mmol, yield 70.7%), Z / E=1:7, as a white solid, LCMS (ESI): [M+H] + =543.4.

[0281] 1H NMR (400MHz, DMSO-d6) δ12.97(s,0.15H),10.82(s,0.85H),10.25(s,0.15H),10.17(s,0.85H),8.03(d,J=8.7Hz,0.15H),7.95(s,0.15H) ,7.79(d,J=8.5Hz,0.85H),7.34(s,0.85H),7.22–7.11(m,0.3H),7.07–6.95(m,1.70H),5.96–5.47(m,2H),4.93(brs,1H),4.56(t,J=12.8 Hz,2H),4.45–4.18(m,1H),3.86–3.53(m,3H),3.67–3.55(m,1H),3.31–3.21(m,2H),3.14(t,J=6.9Hz,1H),3.09–2.93(m,2H),2.89(s,1H ),2.84–2.75(m,1H),2.73(s,1H),2.37–2.21(m,1H),2.28(s,3H),1.92(dd,J=13.4,8.2Hz,1H),1.82–1.49(m,4H),1.33–1.15(m,1H)ppm.

[0282] Example 26: 2-Hydroxy-N-((1 2 S)-2 6 -methyl-4-oxo-3-aza-1(4,2)-morpholino-2(2,4)-pyrimidin-6(1,4)-piperidin-5(1,2)-benzeneheterocyclononane-5-(1,2)-methylenedianiline) 4 -yl)ethane-1-sulfonamide

[0283] The first step: to 2-hydroxy-N-((1 2 S)-2 6 To a solution of -methyl-4-oxo-3-aza-1(4,2)-morpholino-2(2,4)-pyrimidin-6(1,4)-piperidin-5(1,2)-phenylheterocyclonon-8-en-4-yl)ethane-1-sulfonamide (140 mg, 0.26 mmol) in methanol (10.00 mL) was added wet palladium carbon (200 mg, mass fraction 10%). The reaction mixture was replaced with argon protection three times, and then replaced with hydrogen three times. The mixture was stirred at 25°C under a hydrogen (50 Psi) atmosphere for 16 hours. The reaction mixture was filtered under reduced pressure to remove palladium carbon, and then concentrated under vacuum to obtain a crude product. The residue was purified by preparative HPLC (C18, 22%-62% gradient of water (ammonia + ammonium bicarbonate) / acetonitrile) to obtain a white solid 2-hydroxy-N-((1 2 S)-2 6-methyl-4-oxo-3-aza-1(4,2)-morpholino-2(2,4)-pyrimidin-6(1,4)-piperidin-5(1,2)-benzeneheterocyclononane-5-(1,2)-methylenedianiline) 4 -yl)ethane-1-sulfonamide (52.2 mg, 0.09 mmol, 35.0% yield). LCMS (ESI): [M+H]+=545.3. 1 H NMR (400MHz, DMSO-d6) δ12.05(s,1H),8.00(d,J=8.4Hz,1H),7.36(s,1H),7.13(s,1H),7.07(dd,J=1.6,8.4Hz,1H),4.58(br d,J=12.8Hz,1H),4.20(br d,J=12.8Hz,1H),3.75(t,J=6.8Hz,2H),3.50-3.43(m,1H),3.42-3.33(m,5H),3.12(br d,J=10.0Hz,2H),3.03(br dd,J=8.0,12.8Hz,1H),2.77(br t,J=11.2Hz,1H),2.67(br t,J=11.2Hz,1H),2.28(s,3H),2.01-1.84(m,2H),1.80-1.70(m,2H),1.62-1.37(m,7H)ppm.

[0284] Example 27: N-(2 6 -methyl-4,9-dioxo-3,8-diaza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,3)-dimethyl-4,9-dioxo-3,8-diaza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1, 4 -yl)-2-hydroxyethane-1-sulfonamide

[0285] Step 1: A solution containing 2-chloro-6-methylpyrimidin-4-amine (5.00 g, 34.83 mmol), methyl piperidine-3-carboxylate (5.50 g, 38.31 mmol), potassium carbonate (4.70 g, 104.48 mmol), and dimethyl sulfoxide (100.00 mL) was heated at 100°C for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-30% ethyl acetate / petroleum ether gradient) to afford methyl 1-(4-amino-6-methylpyrimidin-2-yl)piperidine-3-carboxylate (5.2 g, 20.78 mmol, 59.7% yield) as a yellow oil. LCMS (ESI): [M-55] + =251.2.

[0286] Step 2: A solution containing (tert-butoxy)-N-(4-piperidinylmethyl)carboxamide (5.00 g, 23.33 mmol), 4-bromo-2-fluorobenzoic acid (5.60 g, 25.66 mmol), potassium carbonate (9.90 g, 69.99 mmol), and dimethyl sulfoxide (100.00 mL) was stirred at 100°C for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-30% ethyl acetate / petroleum ether gradient) to afford 4-bromo-2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)benzoic acid (4.50 g, crude) as a yellow oil. LCMS (ESI): [M+H] + =413.2.

[0287] Step 3: A solution containing 4-bromo-2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)benzoic acid (4.00 g, 9.68 mmol), 1-(4-amino-6-methylpyrimidin-2-yl)piperidine-3-carboxylic acid methyl ester (2.70 g, 10.65 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.60 g, 14.52 mmol) and 4-dimethylaminopyridine (3.60 g, 29.03 mmol) and N,N-dimethylacetamide (50.00 mL) was stirred at 60 °C for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to obtain the compound 1-(4-(4-bromo-2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)benzamido)-6-methylpyrimidin-2-yl)piperidine-3-carboxylic acid methyl ester (700 mg, 1.08 mmol, yield 11.2%) as a white solid. LCMS (ESI): [M+H] + =645.4.

[0288] Step 4: A reaction mixture containing methyl 1-(4-(4-bromo-2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)benzamido)-6-methylpyrimidin-2-yl)piperidine-3-carboxylate (700 mg, 1.08 mmol) and a hydrochloric acid / ethyl acetate solution (10.00 mL, 4.0 M) was stirred at 20°C for 1 hour. The reaction mixture was concentrated to afford methyl 1-(4-(2-(4-(aminomethyl)piperidin-1-yl)-4-bromobenzamido)-6-methylpyrimidin-2-yl)piperidine-3-carboxylate (500 mg, crude) as a white solid. LCMS (ESI): [M+H] + =545.3.

[0289] Step 5: A solution containing methyl 1-(4-(2-(4-(aminomethyl)piperidin-1-yl)-4-bromobenzamido)-6-methylpyrimidin-2-yl)piperidine-3-carboxylate (500 mg, 0.92 mmol), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (195 mg, 1.38 mmol) and toluene (250.00 mL) was stirred at 250° C. for 48 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain compound 5. 4 -Br-2 6 -methyl-3,8-diaza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-4,9-dione (260 mg, 0.51 mmol, yield 55.2%), as a white solid. LCMS (ESI): [M+H] + =513.3.

[0290] Step 6: Contains 5 4 -Br-2 6A solution of 2-methyl-3,8-diaza-2(2,4)-pyrimidinyl-1(1,3),6(1,4)-dipiperidinyl-5(1,2)-benzeneheterocyclononane-4,9-dione (240 mg, 0.47 mmol), 2-hydroxyethanesulfonamide (119 mg, 0.93 mmol), potassium phosphate (304 mg, 1.40 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (20 mg, 0.047 mmol), tris(dibenzylideneacetone)dipalladium (44 mg, 0.047 mmol) and 1,4-dioxane (5.00 mL) was stirred at 100 °C under nitrogen for 8 h. The reaction solution was poured into water (30 mL) and dried with ethyl acetate (30 mL x 40 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-25% gradient of methanol / dichloromethane) to obtain compound N-(2 6 -methyl-4,9-dioxo-3,8-diaza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,3)-dimethyl-4,9-dioxo-3,8-diaza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1, 4 -yl)-2-hydroxyethane-1-sulfonamide (80 mg, 0.14 mmol, yield 30.7%). LCMS (ESI): [M+H] + =558.40. 1 H NMR (400MHz, DMSO) δ11.22(s,1H),10.21(s,1H),7.89(d,J=8.4Hz,1H),7.68(dd,J=9.2,4.0Hz,1H),7.35(s,1H),7.15–7. 08(m,1H),7.03(dd,J=8.4,2.0Hz,1H),4.97–4.84(m,2H),4.74(d,J=12.8Hz,1H),3.81–3.70(m,2H),3.66–3.55(m,1H),3 .44–3.35(m,2H),3.22–3.11(m,1H),3.05-2.96(m,1H),2.93–2.83(m,1H),2.79–2.68(m,2H),2.57(s,2H),2.48–2.40(m, 1H),2.25(s,3H),2.06(d,J=12.7Hz,1H),1.94–1.68(m,4H),1.63–1.52(m,2H),1.51–1.40(m,1H),1.32–1.21(m,1H)ppm.

[0291] Example 28: 2-Hydroxy-N-(2 6-methyl-4-oxo-8-oxa-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,2)- 4 -yl)ethane-1-sulfonamide

[0292] Step 1: To a solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 49.2 mmol) and potassium carbonate (17.80 g, 129.0 mmol) in dimethyl sulfoxide (200.00 mL) was added piperidin-4-ylmethanol (5.93 g, 51.5 mmol). The mixture was stirred at 100°C for 12 hours. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (400 mL x 2). The combined organic phases were washed with saturated brine (250 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-16% gradient of tetrahydrofuran / petroleum ether) to afford methyl 4-bromo-2-(4-(hydroxymethyl)piperidin-1-yl)benzoate (12.0 g, 41.70 mmol, 85% yield) as a yellow oil. LCMS(ESI):[M+H] + =328.1

[0293] Step 2: To a solution of methyl 4-bromo-2-(4-(hydroxymethyl)piperidin-1-yl)benzoate (7.00 g, 21.3 mmol) in dichloromethane (140.00 mL) was added triethylamine (4.32 g, 42.7 mmol), 4-dimethylaminopyridine (434 mg, 2.13 mmol), and 4-methylbenzenesulfonyl chloride (4.47 g, 23.5 mmol) at 25°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-8% gradient of tetrahydrofuran / petroleum ether) to give methyl 4-bromo-2-(4-((tosyloxy)methyl)piperidin-1-yl)benzoate (6.0 g, 12.4 mmol, 58% yield) as a yellow oil. LCMS (ESI): [M+H] + =484.1. 1H NMR (400MHz, DMSO-d6) δ7.80(d,J=8.4Hz,2H),7.49(d,J=8.4Hz,3H),7.17-7.09(m,2H),3.94(d,J=6.4Hz,2H),3.76(s,3H),3.17(br d,J=12.0Hz,2H),2.67(br t,J=11.2Hz,2H),2.42(s,3H),1.80-1.68(m,1H),1.62(br d,J=11.2Hz,2H),1.33-1.19(m,2H)ppm.

[0294] Step 3: To a solution of methyl 4-bromo-2-(4-((tosyloxy)methyl)piperidin-1-yl)benzoate (1.0 g, 2.07 mmol) and tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (0.67 g, 3.11 mmol) in tetrahydrofuran (20.0 mL) was added sodium hydroxide (0.21 g, 3.11 mmol), and the mixture was stirred at 60 ° C for 12 hours. The reaction mixture was diluted with water (80 mL), and the pH was adjusted to 2-3 with saturated citric acid solution. The mixture was extracted with ethyl acetate solution (100 mL x 2). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-35% gradient of ethyl acetate / petroleum ether) to give 4-bromo-2-(4-(((1-(tert-butoxycarbonyl)piperidin-3-yl)methoxy)methyl)piperidin-1-yl)benzoic acid (0.45 g, 0.87 mmol, 42% yield) as a yellow oil. LCMS (ESI): [M+H] + =513.1

[0295] Step 4: Dissolve 4-bromo-2-(4-(((1-(tert-butoxycarbonyl)piperidin-3-yl)methoxy)methyl)piperidin-1-yl)benzoic acid (400 mg, 0.78 mmol) in dichloromethane (20.00 mL) and trifluoroacetic acid (5.00 mL) and stir at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give 4-bromo-2-(4-((piperidin-3-ylmethoxy)methyl)piperidin-1-yl)benzoic acid (300 mg, crude) as a yellow oil. LCMS (ESI): [M+H]+ = 413.1

[0296] Step 5: 4-Bromo-2-(4-((piperidin-3-ylmethoxy)methyl)piperidin-1-yl)benzoic acid (0.35 g, 0.85 mmol) was dissolved in tert-butanol (7.00 mL), and N,N-diisopropylethylamine (1.10 g, 8.51 mmol) and 2-chloro-6-methylpyrimidin-4-amine (147 mg, 1.02 mmol) were added. The mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with water (20 mL) and the pH was adjusted to 2-3 with 1N hydrochloric acid. The mixture was then extracted with chloroform / isopropanol (3:1, 40 mL x 3). The organic phase was dried, filtered, and concentrated. The brown oily residue was purified by flash column chromatography (silica gel, 0-10% gradient of dichloromethane / methanol) to afford 2-(4-(((1-(4-amino-6-methylpyrimidin-2-yl)piperidin-3-yl)methoxy)methyl)piperidin-1-yl)-4-bromobenzoic acid (470 mg, crude) as a yellow oil. LCMS (ESI): [M+H]+ = 518.3

[0297] Step 6: Dissolve N,N-diisopropylethylamine (763 mg, 5.78 mmol) and 2-chloro-1-methylpyridinium iodide (444 mg, 1.74 mmol) in tetrahydrofuran (30.00 mL), add 2-(4-(((1-(4-amino-6-methylpyrimidin-2-yl)piperidin-3-yl)methoxy)methyl)piperidin-1-yl)-4-bromobenzoic acid (300 mg, 0.58 mmol) dissolved in tetrahydrofuran (120.00 ml) at 60°C, and stir at 60°C for 12 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-12% gradient of tetrahydrofuran / petroleum ether) to give 5 as a colorless oil. 4 -Br-2 6 -methyl-8-oxa-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzheterocyclononan-4-one (60 mg, crude product). LCMS (ESI): [M+H]+=501.7

[0298] Step 7: Put 5 4 -Br-2 62-Methyl-8-oxa-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzheterocyclononan-4-one (50 mg, 0.1 mmol) and 2-hydroxyethane-1-sulfonamide (15 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1.00 mL). Potassium phosphate (63.6 mg, 0.3 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (14.4 mg, 0.1 mmol), and cuprous iodide (19.1 mg, 0.1 mmol) were added, and the mixture was stirred at 100°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (10.0 mL + 0.5 mL of aqueous ammonia) and extracted with ethyl acetate (20 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 6%-46% gradient of water (formic acid) / acetonitrile) to give 2-hydroxy-N-(2 6 -methyl-4-oxo-8-oxa-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,2)- 4 -yl)ethane-1-sulfonamide (8 mg, 0.01 mmol, 14.7% yield). LCMS (ESI): [M+H]+ = 545.2. 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 11.59-9.41 (m, 1H), 8.16 (br s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.22-7.16 (m, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.03 (dd, J = 2.0, 8.8 Hz, 1H), 5.69-5.10 (m, 1H), 5.08-4.89 (m, 1H), 4.79-4.63 (m, 1H), 3.80-3.68 (m, 2H) ,3.62-3.52(m,1H),3.48-3.39(m,2H),3.30-3.27(m,2H),3.27-3.09(m,4H),2.95-2.70 (m,4H),2.32-2.14(m,4H),1.99-1.73(m,2H),1.73-1.32(m,5H),1.13-0.95(m,1H)ppm.

[0299] Example 28A: 2-Hydroxy-N-((1 3 R)-2 6 -methyl-4-oxo-8-oxa-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,2)- 4 -yl)ethane-1-sulfonamide

[0300] Example 28B: 2-Hydroxy-N-((1 3 S)-2 6 -methyl-4-oxo-8-oxa-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,2)- 4 -yl)ethane-1-sulfonamide

[0301] Step 1: 2-Hydroxy-N-(2 6 -methyl-4-oxo-8-oxa-3-aza-2(2,4)-pyrimidin-1(1,3),6(1,4)-dipiperidin-5(1,2)-benzeneheterocyclononane-5-(1,2)- 4 -yl)ethane-1-sulfonamide (25 mg, 0.046 mmol) was separated by SFC (Column DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um), mobile phase type: CO2-EtOH (0.1% NH3H2O), gradient: isocratic 45%, flow rate: 80 mL / min, column temperature: 40°C) to give Example 28A and Example 28B.

[0302] Example 28A: SFC (Chromatographic column type: Chiralpak AD ID, 3 μm, mobile phase: CO2-EtOH (0.05% DEA), gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min, flow rate: 4 mL / min, column temperature: 35°C, retention time Rt = 1.204). LCMS (ESI): [M+H]+ = 545.2. 1 H NMR(400MHz,DMSO-d6)δppm 12.09(s,1H),10.68-9.79(m,1H),7.86(d,J=8.4Hz,1H),7.19(s,1H),7.10(d,J=1. 6Hz,1H),7.03(dd,J=2.0,8.8Hz,1H),5.42-4.82(m,2H),4.77-4.63(m,1H),3.76(br t,J=6.4Hz,2H),3.60-3.48(m,2H),3.28(br s,5H),2.92-2.70(m,4H),2.30-2.14(m,4H),1.98-1.31(m,8H),1.15-0.96(m,1H)

[0303] Example 28B: SFC (Chromatographic column type: Chiralpak AD ID, 3 μm, mobile phase type: CO2-EtOH (0.05% DEA), gradient: from 20% to 40% of B in 1.5 min and hold 40% for 1 min, then 20% of B for 0.5 min, flow rate: 4 mL / min, column temperature: 35°C, retention time Rt=1.942), LCMS (ESI): [M+H] + =545.2. 1 H NMR(400MHz,DMSO-d6)δppm 12.50(br s,1H),11.13-9.09(m,1H),7.93(d,J=8.8Hz,1H),7.26-7.14(m,2H),7.05(dd,J=2.0,8.4Hz,1H),5.51-5.03(m,1H),4.93(br d,J=10.4Hz,1H),4.57(br d,J=12.8Hz,1H),3.75(t,J=6.4Hz,2H),3.64(td,J=4.8,9.2Hz,1H),3.55(br dd,J=3.2,10.4Hz,1H),3.30-3.25(m,2H),3.22-2.97(m,5H),2.90-2.75(m,3H),2.30-2.18(m,4H),1.96-1.29(m,8H),1.11-1.00(m,1H)

[0304] Example 29: 2-Hydroxy-N-(5 6 -methyl-3-oxo-6,9-dioxa-4-aza-5(4,2)-pyrimidin-1(1,4)-piperidin-2(1,2)-benzene heterocycloundecane-2 5 (Methyl)ethane-1-sulfonamide

[0305] Step 1: Dissolve methyl 4-bromo-2-(4-(2-(tosyloxy)ethyl)piperidin-1-yl)benzoate (5.00 g, 10.0 mmol) in tetrahydrofuran (80.0 mL), add ethylene glycol (4.38 g, 70.5 mmol) and sodium hydroxide (1.01 g, 15.1 mmol), and stir at 70°C for 16 hours. The reaction mixture was filtered and concentrated, and the residue was purified by flash column chromatography (silica gel, 0-7% methanol / dichloromethane gradient) to afford 4-bromo-2-(4-(2-(2-hydroxyethoxy)ethyl)piperidin-1-yl)benzoic acid (1.70 g, 3.62 mmol, 36.0% yield) as a yellow oil. LCMS (ESI): [M+H]+ =374.0. 1 H NMR(400MHz,CHLOROFORM-d)δ8.17(d,J=8.4Hz,1H),7.60-7.54(m,2H),3.81-3.73(m,2H),3.65-3.52(m,4H),3.16(br d,J=11.6Hz,2H),2.97(br t,J=11.6Hz,2H),2.00(br d,J=12.8Hz,2H),1.81-1.72(m,1H),1.67(q,J=6.0Hz,2H),1.63-1.52(m,2H)ppm.

[0306] Step 2: Dissolve 4-bromo-2-(4-(2-(2-hydroxyethoxy)ethyl)piperidin-1-yl)benzoic acid (1.00 g, 2.69 mmol) in tetrahydrofuran (20.0 mL). Add sodium hydroxide (0.32 g, 8.06 mmol, 60% mass fraction) at 0°C and stir at 0°C for 30 minutes. Add 2-chloro-6-methylpyrimidin-4-amine (0.77 g, 5.37 mmol) and stir at 60°C for 16 hours. The reaction mixture is quenched with methanol, filtered, and concentrated to afford 2-(4-(2-(2-((4-amino-6-methylpyrimidin-2-yl)oxy)ethoxy)ethyl)piperidin-1-yl)-4-bromobenzoic acid (1.80 g, 2.68 mmol, crude) as an orange oil. LCMS (ESI): [M+H] + =480.9

[0307] Step 3: Dissolve N,N-diisopropylethylamine (1.05 g, 8.14 mmol) and 2-chloro-1-methylpyridin-1-iodide (1.07 g, 2.82 mmol) in tetrahydrofuran (120 mL), add 2-(4-(2-(2-((4-amino-6-methylpyrimidin-2-yl)oxy)ethoxy)ethyl)piperidin-1-yl)-4-bromobenzoic acid (300 mg, 0.63 mmol) dissolved in tetrahydrofuran (30.0 mL) dropwise at 60 ° C, and stir at 60 ° C for 16 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (200 mL x 2), and the organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-13% gradient of tetrahydrofuran / petroleum ether) to give a yellow solid 2 5 -Br-5 6 -methyl-6,9-dioxa-4-aza-5(4,2)-pyrimidin-1(1,4)-piperidin-2(1,2)-benzeneheterocycloundecane-3-one (53.0 mg, 0.11 mmol, 18.0% yield). LCMS (ESI): [M+H] + =462.9

[0308] Step 4: Put 2 5 -Br-5 6 4-Methyl-6,9-dioxa-4-aza-5(4,2)-pyrimidin-1(1,4)-piperidin-2(1,2)-benzheterocycloundecan-3-one (48.0 mg, 0.10 mmol) and 2-hydroxyethane-1-sulfonamide (2.03 mg, 0.02 mmol) were dissolved in N,N-dimethylformamide (2.50 mL). Potassium phosphate (66.2 mg, 0.31 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (14.9 mg, 0.10 mmol), and cuprous iodide (19.8 mg, 0.10 mmol) were added to the solution. The mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. 0.5 mL of aqueous ammonia was added to the reaction solution, which was then filtered and concentrated. The residue was purified by preparative HPLC (C18, 4%-46% gradient of water (ammonia+ammonium bicarbonate) / acetonitrile) to give 2-hydroxy-N-(5-hydroxy-N- 6 -methyl-3-oxo-6,9-dioxa-4-aza-5(4,2)-pyrimidin-1(1,4)-piperidin-2(1,2)-benzene heterocycloundecane-2 5 1-Hydroxyethane-1-sulfonamide (17.71 mg, 0.02 mmol, 31.8% yield). LCMS (ESI): [M+H] + =570.2. 1 H NMR (400MHz, DMSO-d6) δ12.71(s,1H),7.98(d,J=8.8Hz,1H),7.77(s,1H),7.19(s,1H),7.08(br d,J=8.4Hz,1H),4.56(br t,J=5.6Hz,2H),3.75(t,J=6.4Hz,2H),3.58(t,J=5.6Hz,2H),3.50(br t,J=4.4Hz,2H),3.32-3.27(m,2H),3.14(br d,J=10.8Hz,2H),2.75-2.66(m,2H),2.37(s,3H),2.10-1.99(m,2H),1.72-1.64(m,3H),1.61(br d,J=12.8Hz,2H)ppm

[0309] Effect Example 1: Enzyme activity detection experiment

[0310] Materials: Human KIF18A (amino acid sequence 1-417), purchased from Shanghai Via Biotechnology Co., Ltd.; ADP-Glo TMProtein kinase kit was purchased from Promega, USA; tubulin was purchased from Cytoskeleton, USA; 384-well assay plate and multifunctional microplate reader Envision were purchased from PerkinElmer, USA.

[0311] Enzyme activity assay: Compound powder was dissolved in DMSO to a 10 mM stock solution. Compounds were serially diluted in a microplate to a final concentration of 0–10 μM. Tubulin, compound, ATP, and KIF18A protein (2.5 μL each) were then added to the microplate in sequence and incubated at room temperature for 120 minutes. The final concentrations of the enzyme reaction were 60 μg / mL tubulin, 25 μM ATP, and 2.5 nM KIF18A protein. After the enzyme reaction, 10 μL of ADP-GLO reagent was added to each well and incubated at room temperature for 30 minutes. Subsequently, 20 μL of detection reagent was added to each well and incubated at room temperature for 30 minutes in the dark. Chemiluminescence detection was performed using a PerkinElmer Envision.

[0312] Effect Example 2: Cell proliferation activity detection experiment

[0313] Materials and cells: OVCAR3 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. RPMI-1640 medium, fetal bovine serum, and the CyQUANT Direct Cell Proliferation Assay kit were purchased from Thermo Fisher Scientific; 96-well cell culture plates were purchased from Corning.

[0314] Cell culture: OVCAR3 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum in a 37°C, 5% CO2 incubator. Cells in the logarithmic growth phase were used for experiments.

[0315] Cell proliferation activity assay:

[0316] OVCAR3 cells were seeded into 96-well cell culture plates, with 90 μl per well, and incubated overnight in a 37°C, 5% CO2 incubator. Compound powder was dissolved in DMSO to a 10 mM stock solution. Compounds were serially diluted in a microplate to a final concentration of 0–10 μM. 10 μL of cell culture medium containing compound was added to each well, resulting in a final DMSO content of 0.2%. The cell plates were incubated at 37°C, 5% CO2 for 3 days. 100 μL of CyQUANT detection reagent was added to each well, incubated at 37°C for 60 minutes, and fluorescence detection was performed using PerkinElmer Envision.

[0317] Effect Example 3: CyQuant Cell Proliferation Activity Detection Experiment

[0318] Materials and cells: HT29 cells were purchased from Nanjing Kebai Biotechnology; RPMI-1640 medium was purchased from ThermoFisher (USA); fetal bovine serum was purchased from ThermoFisher (USA); Trypsin-EDTA (0.25%) was purchased from ThermoFisher (USA); DMSO was purchased from SIGMA (USA); 96-well plates were purchased from ThermoFisher (USA); and CyQuant reagents were purchased from ThermoFisher (USA).

[0319] Cell culture: HT29 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum at 37°C and 5% CO2. Cells in the logarithmic growth phase were used for experiments.

[0320] Cell proliferation activity assay: CyQuant reagent was used to detect the inhibitory activity of compounds on HT29 cell proliferation. Adjust the cell density, inoculate 100 μl per well of a 96-well plate (2000 / well for HT29), and culture overnight at 37°C and 5% CO2. Add the target compound at each concentration (starting concentration 3000 nM, 3-fold dilution, 9 concentration gradients), with a DMSO content of 0.2%. Incubate the cell plate at 37°C and 5% CO2 for 3 days. Add CyQuant reagent and incubate for 1 hour. Read the plate with Envision and calculate the IC using XLFIT. 50 .

Claims

1. A compound having the structure of Formula I, and a pharmaceutically acceptable salt, stereoisomer, or isotope isomer thereof: in, Indicates a single bond or a double bond; Among them, X 1 Represents CR W1 or N; Among them, X 2 Represents CR W2 or N; Among them, X 3 Represents CR W3 or N; Among them, X 4 Represents CR W4 or N; Among them, X 5 Represents CR W5 or N; Among them, X 6 Represents CR W6 or N; Among them, X 7 Represents CR W7 or N; Among them, R W1 , R W2 , R W3 , R W4 , R W5 , R W6 , R W7 Each independently represents hydrogen, halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)NR a R b , -SF5 or -NR a R b ; Wherein, the chemical bond between X2, X3 or X5, X6 or X6, X7 can also be fused with ring A to form a 5-6 membered saturated or unsaturated ring, which can arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, and N; and the ring can also be selected from 0-3 of the following substituents: halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)NR a R b , -SF5 or -NR a R b substituted by a substituent; Wherein, L1 represents -C(O)NH- or a triazole group; Among them, Y 1 Indicates -(CR a R b ) m -;Y 2 Indicates -(CR a R b ) n -; Among them, arbitrarily CR a R b Can be -O-, -S-, -NR a -、-NR a SO2-、-NR a C(O)-、-C(O)NR a -、-SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2-、-NR a P(O)(OR a )2-or-NR a P(O)(R a )2-、-CR a =CR b -、 replaced by; Among them, R L Indicates L2-R M ; Wherein, L2 represents absence, -C1-C6 alkyl-, -NR a -、-NR a SO2-、-SO2NR a -、-NR a -S(=O)(=NH), -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C1-C6 alkyl-O-, -(C=O)-, -(C=O)NR a -, -C=N(OH)-, -NR a (C=O), -P(O)(OR a )2, -NR a P(O)(OR a )2 or -NR a P(O)(R a )2-; Among them, R M It represents 0-3 selected from halogen, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted with C1-C6 alkyl or C3-C6 cycloalkyl; Or, LR M It means -N=S(=O)-(R L )2, where two R L Together with the sulfur atom to which they are attached, they may form a saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1 or 2 heteroatoms selected from N, O and S; Wherein, m and n each independently represent an integer from 0 to 10; Among them, when When it represents a single bond, Y represents -O-, -NH-, or the following groups: or Wherein, * indicates the site connected to ring A; the wavy line indicates the site connected to Y2; Among them, X represents CR 1 R 1’ , O, NR a ; Among them, R 1 , R 1’ , R 2 , R 2’ , R 3 , R 3’ , R 4 , R 4’ , each independently represents hydrogen, C1-C6 alkyl, halogen, C3-C6 cycloalkyl; hydroxy C1-C6 alkyl; or R 1 , R 1’ Together with the carbon atom to which it is attached, they form a 3-6 membered ring; or R 2 , R 2’ Together with the carbon atom to which it is attached, they form a 3-6 membered ring; or R 3 , R 3’ Together with the carbon atom to which it is attached, they form a 3-6 membered ring; or R 4 , R 4’ Together with the carbon atom to which it is attached, they form a 3-6 membered ring; Among them, R a , R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered cycloalkyl, C1-C6 alkyl substituted by saturated or unsaturated 5-6 membered heterocycloalkyl; or R a , R b Together with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N.

2. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: X1, X2, X3, X4, and X5 represent CH or N.

3. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: X1 and X2 represent CH or N.

4. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: X4 and X5 represent CH or N.

5. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y1 means -(CR a R b ) m -.

6. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y1 represents -NH-C(=O)-.

7. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y1 represents -O(CR a R b ) m -or-(CR a R b ) m O-.

8. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y1 means -CR a =CR a -or-CR a R b -CR a =CR b -.

9. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y2 means -(CR a R b ) n -.

10. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y2 stands for -NR a -C(=O)-.

11. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y2 represents -O(CR a R b ) n -or-(CR a R b ) n O-.

12. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y2 represents -CR a =CR a -, -CR a =CR b -CR a R b - or -CR a R b -CR a =CR a -.

13. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: -Y1-Y2 means -CR a =CR a -.

14. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: -Y1-Y2 means -CR a Rb-NR a C(O)-.

15. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: -Y1-Y2 means- 16. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y represents -O- or -NH-.

17. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y stands for 18. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y stands for 19. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y stands for 20. The compound having the structure of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Y stands for 21. The compound of claim 1 having a structure of formula I, or a pharmaceutically acceptable salt, stereoisomer, or isotope isomer thereof, wherein: Y stands for 22. The compound of formula I according to claim 17 or 18, or a pharmaceutically acceptable salt, stereoisomer, or isotope isomer thereof, wherein: X represents O, NH, CR 1 R 1’ .

23. The compound having the structure of formula I according to claim 20, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: X represents CH2 or CF2.

24. The compound having the structure of formula I according to any one of claims 17 to 19, or a pharmaceutically acceptable salt, stereoisomer, or isotope isomer thereof, wherein: R 2 , R 2’ , R 3 , R 3’ , R 4 , R 4’ Each independently represents hydrogen, CH3 or together with the carbon atom to which it is attached forms a cyclopropyl group.

25. The compound of claim 1 having a structure of formula I, or a pharmaceutically acceptable salt, stereoisomer, or isotope isomer thereof, wherein: The chemical bond between X5 and X6 in ring A is fused with ring A to form a 5-6 membered saturated or unsaturated ring, which may contain 0, 1, or 2 heteroatoms selected from O, S, and N; and the ring may also be substituted with 0-3 of the following: halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)NR a R b , -SF5 or -NR a R b substituted by a substituent.

26. The compound of claim 1 having the structure of formula I, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: The chemical bond between X5 and X6 in ring A is fused with a benzene ring or a pyridine ring; and the ring may also be selected to have 0-3 of the following substituents: halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)NR a R b , -SF5 or -NR a R b substituted by a substituent.

27. The compound of claim 1 having the structure of formula I, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: The chemical bond between X5 and X6 in ring A is fused with a pyrrole ring, and the ring can also be selected to have 0-3 of the following substituents: halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a 、-C(=O)OR a 、-C(=O)NR a R b , -SF5 or -NR a R b substituted by a substituent.

28. The compound of claim 1 having the structure of formula I, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: R L Represents LR M ; Wherein, L represents -NR a SO2-、-SO2NR a -.

29. The compound of claim 1 having a structure of formula I, or a pharmaceutically acceptable salt, stereoisomer, or isotope isomer thereof, wherein: R M represents a C1-C1 alkyl group substituted by 0, 1, 2 or 3 OH groups.

30. A compound having the following structure: