Inhibitor of kinin KIF18A and application thereof

Abstract

The invention provides a KIF18 inhibitor and a synthesis method thereof, and particularly provides a compound shown as a formula (I), and the compound can regulate KIF18A protein, so that the cell cycle and the cell proliferation process are influenced to treat cancers and cancer-related diseases. Also provided are pharmaceutical compositions comprising the compounds and 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] Public content

[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 compound having a structure of Formula I or a pharmaceutically acceptable salt, stereoisomer, or isotope isomer thereof:

[0009] Among them, X 1 Indicates CR W1 or N;

[0010] Among them, X 2 Indicates CR W2 or N;

[0011] Among them, X 3 Indicates CR W3 or N;

[0012] Among them, R W1 、R W2 、R W3 Each independently represents hydrogen, deuterium, 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 and X3 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;

[0013] Wherein, L1 represents -C(O)NH-, -NHC(O)- or triazole;

[0014] Wherein, Cy1 represents a 6-14 membered aryl or heteroaryl group; and the Cy1 can be arbitrarily substituted by 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-O-halogenated C1-C6 alkyl、-SR a 、-SF5、cyano、nitro、-NR a R b 、-NR a C(O)R b 、-C(O)NR a R b 、-OC(O)R a 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b ;

[0015] Among them, Cy 2 represents a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring, which may contain 0-3 heteroatoms selected from O, N and S, and the Cy 2 It may also be optionally substituted by 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-O-halogenated C1-C6 alkyl、-SR a、-SF5、cyano、nitro、-NR a R b 、-NR a C(O)R b 、-C(O)NR a R b 、-OC(O)R a 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b ;

[0016] Wherein, L2 represents a linear or branched C1-C6 methylene, and any hydrogen atom can be replaced by deuterium, hydroxyl, or halogen; or any two hydrogen atoms connected to the same carbon atom can form structure;

[0017] Among them, R a 、R b Each independently represents hydrogen, C1-C6 alkyl, or the R a 、R b Together with the atoms to which it is attached, it forms a 3-6 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, S, and N;

[0018] Among them, R M 、R N represents hydrogen, halogen, halogenated C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl, or the R M 、R N Together with the atoms to which it is attached, it forms a 3-6 membered saturated or unsaturated ring;

[0019] Where n represents 0, 1, 2, or 3;

[0020] Among them, P 1 represents hydrogen or a protecting group;

[0021] Among them, P 2 represents hydrogen or a protecting group;

[0022] The premise is that P 1 、P 2 Not hydrogen at the same time.

[0023] In one technical solution of the present disclosure, L1 represents -C(O)NH- or -NHC(O)-.

[0024] In one technical solution of the present disclosure, L1 represents a triazole group.

[0025] In one technical solution of the present disclosure, L1 represents the following group: or

[0026] In a technical solution of the present disclosure, wherein Cy1 represents phenyl, pyridyl, pyrimidinyl, quinolinyl, and said Cy1 can be arbitrarily substituted by 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-O-halogenated C1-C6 alkyl、-SR a 、-SF5、cyano、nitro、-NR a R b .

[0027] In one technical solution of the present disclosure, Cy1 represents the following group:

[0028] And the Cy1 can be arbitrarily substituted by 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-O-halogenated C1-C6 alkyl、-SR a 、-SF5、cyano、nitro、-NR a R b .

[0029] In a technical solution of the present disclosure, Cy2 represents a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, 7-membered monocyclic ring, or a 3-, 4-, 5-, 6-, 7-membered cyclic ring, and the Cy2 may arbitrarily contain 0-3 N heteroatoms and 0-2 O or S heteroatoms, and the Cy2 may be arbitrarily substituted by 0-3 substituents selected from 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 halo C1-C6 alkyl、-SR a , -SF5 or NR a R b , where R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl or hydroxy C1-C6 alkyl; or R a 、R bTogether with the atoms to which they are attached, they form a 3-6 membered ring containing 0-2 heteroatoms selected from O, N and S.

[0030] In the preferred technical solution of the present disclosure, Cy2 represents any of the following groups:

[0031] Furthermore, the Cy2 can be arbitrarily substituted by 0-3 substituents selected from 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 halo C1-C6 alkyl、-SR a , -SF5 or NR a R b , where R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl or hydroxy C1-C6 alkyl; or R a 、R b Together with the atoms to which they are attached, they form a 3-6 membered ring containing 0-2 heteroatoms selected from O, N and S.

[0032] In a technical solution of the present disclosure, wherein Cy2 is selected from

[0033] In a technical solution of the present disclosure, wherein L2 represents -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH(OH)CH2-, -CH2CH(OH)-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH(OH)CH2-, -CH2CH(CH3)-, -CF2CH2-, -CH2CF2-, -CHFCH2-, -CH2CHF-,

[0034] In a technical solution of the present disclosure, R M 、R N Each independently represents hydrogen, C1-C6 alkyl, or the R M 、R N Together with the atoms to which it is attached, it forms a 3-6 membered saturated or unsaturated ring.

[0035] In a technical solution of the present disclosure, wherein the P 1 represents hydrogen, -C(O)R a 、-C(O)(CR T RT’ ) m NH2、-P(O)(OR a )2, -P(O)(ONa)2, where R a represents a C1-C6 alkyl group, wherein R T 、R T’ Each independently represents hydrogen, substituted or unsubstituted C1-C6 alkyl, and the substituent is halogen, hydroxyl, phenyl, or 5-6 membered heteroaryl.

[0036] In a technical solution of the present disclosure, wherein the P 2 represents hydrogen, -C(O)R a 、-C(O)(CR T R T’ ) m NH2、-P(O)(OR a )2, -P(O)(ONa)2, where R a represents a C1-C6 alkyl group, wherein R T 、R T’ Each independently represents hydrogen, substituted or unsubstituted C1-C6 alkyl, and the substituent is halogen, hydroxyl, phenyl, or 5-6 membered heteroaryl.

[0037] Specifically, the present disclosure provides a compound having the following structure:

[0038] 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.

[0039] 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.

[0040] definition

[0041] 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.

[0042] Unless otherwise indicated, the following terms used in this disclosure 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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-.

[0047] 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:

[0048] "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:

[0049] "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, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolenyl, dihydroindole , indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolidinyl, oxazolopyridinyl, oxazolidinyl, perylene, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiol, phenoxazinyl , phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 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 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.

[0050] 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.

[0051] Unless otherwise defined, the definitions of substituents disclosed herein are independent of each other and not interrelated, for example, for Ra (or Rb) in a substituent, it is independent of each other in the definitions of different substituents. Specifically, when a definition is selected for Ra (or Rb) in a substituent, it does not mean that the Ra (or Rb) has the same definition in other substituents. More specifically, for example (listing only non-exhaustive) for NRaRb, when the definition of Ra (or Rb) is selected from hydrogen, it does not mean that Ra (or Rb) in -C(O)-NRaRb is necessarily hydrogen.

[0052] "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.

[0053] "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-.

[0054] 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.

[0055] 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.

[0056] In the present disclosure, one or more halogens may each be independently selected from fluorine, chlorine, bromine and iodine.

[0057] 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).

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] Likewise, "therapeutic agent" also includes agents or reagents that have therapeutic and / or prophylactic effects on a subject.

[0064] 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.

[0065] Specific pharmaceutical and medical terms

[0066] 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).

[0067] 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.

[0068] 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.

[0069] 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.

[0070] The terms "kit" and "product packaging" are synonymous.

[0071] 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.

[0072] 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.

[0073] Route of administration

[0074] 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.

[0075] 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.

[0076] Pharmaceutical composition and dosage

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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).

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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).

[0091] Kit / Product Packaging

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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

[0100] 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.

[0101] NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the measurements are indicated in the spectral analysis.

[0102] 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.

[0103] HPLC analysis was performed using a SHIMADZU 20A high performance liquid chromatograph.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] Flash column chromatography separation was performed using a Biotage IsoleraOne flash preparative chromatograph.

[0108] 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.

[0109] Pressurized hydrogenation reaction hydride bottles and hydrogen cylinders.

[0110] Microwave reactions were performed using a Biotage Initiator+ microwave synthesizer.

[0111] The glove box is customized by DELLIX.

[0112] 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.

[0113] Example 1: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{1-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-1H-1,2,3-triazol-4-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0114] Step 1: To a solution of 2-fluoro-4-iodobenzaldehyde (2.00 g, 8.00 mmol) and potassium carbonate (3.31 g, 24.0 mmol) in dimethyl sulfoxide (20.0 mL) was added 6-azaspiro[2.5]octane hydrochloride (1.33 g, 12.0 mmol). The mixture was heated to 120°C and stirred for 16 hours. Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (20 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 flash column chromatography (silica gel, 0-8% gradient of ethyl acetate / petroleum ether) to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzaldehyde (1.70 g, 4.95 mmol, 62% yield) as a yellow solid. LCMS (ESI): [M+H] + =342.0

[0115] Step 2: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzaldehyde (1.70 g, 4.98 mmol) and potassium carbonate (1.37 g, 9.97 mmol) in methanol (20.0 mL) was added dimethyl(1-diazo-2-oxyidenepropyl)phosphonate (1.15 g, 5.98 mmol). The mixture was stirred at 25°C for 16 hours. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to dryness to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate / petroleum ether) to afford 6-(2-ethynyl-5-iodophenyl)-6-azaspiro[2.5]octane (1.50 g, 4.43 mmol, 89% yield) as a yellow solid. LCMS(ESI):[M+H] + =338.4.

[0116] Step 3: To a solution of 8-(4,4-difluoropiperidin-1-yl)quinolin-6-amine (600 mg, 2.28 mmol) in acetonitrile (5.00 mL) was added tert-butyl nitrite (599 mg, 5.70 mmol). Trimethylsilylazide (525 mg, 4.56 mmol) was then added to the reaction solution, and the mixture was stirred at 25°C for 16 hours. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). 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 flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to obtain 6-azido-8-(4,4-difluoropiperidin-1-yl)quinoline (240 mg, 0.83 mmol, 36% yield) as a white solid. LCMS (ESI): [M+H]+ = 290.0.

[0117] Step 4: To a solution of 6-azido-8-(4,4-difluoropiperidin-1-yl)quinoline (160 mg, 0.55 mmol), 6-(2-ethynyl-5-iodophenyl)-6-azaspiro[2.5]octane (224 mg, 0.66 mmol) in tert-butanol (5.00 mL) and water (5.00 mL) were added copper sulfate (88.3 mg, 0.55 mmol) and sodium ascorbate (110 mg, 0.55 mmol). The mixture was stirred at 25 ° C for 16 hours. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL x 3). 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 flash column chromatography (silica gel, 0-5% ethyl acetate / petroleum ether gradient) to afford 6-[4-(2-{6-azaspiro[2.5]octan-6-yl}-4-iodophenyl)-1H-1,2,3-triazol-1-yl]-8-(4,4-difluoropiperidin-1-yl)quinoline (240 mg, 0.38 mmol, 69% yield) as a brown solid. LCMS (ESI): [M+H]+ = 627.2.

[0118] Step 5: To a solution of 2-hydroxyethanesulfonamide (47.9 mg, 0.38 mmol), (1R,2R)-(-)-N,N-dimethylcyclohexane-1,2-diamine (27.5 mg, 0.19 mmol), and potassium phosphate (163 mg, 0.77 mmol) in N,N-dimethylformamide (5.0 mL) was added cuprous iodide (18.6 mg, 0.10 mmol). The mixture was stirred at 50°C for 5 minutes. 6-[4-(2-{6-azaspiro[2.5]octan-6-yl}-4-iodophenyl)-1H-1,2,3-triazol-1-yl]-8-(4,4-difluoropiperidin-1-yl)quinoline (120 mg, 0.19 mmol) was then added to the reaction mixture at 50°C. The mixture was heated to 100°C and stirred under nitrogen for 16 hours. Water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by preparative HPLC (C18, 36-76% gradient of water (formic acid) / acetonitrile) to give a white solid compound N-(3-{6-azaspiro[2.5]octane-6-yl}-4-{1-[8-(4,4-difluoropiperidin-1-yl)quinoline-6-yl]-1H-1,2,3-triazol-4-yl}phenyl)-2-hydroxyethane-1-sulfonamide (53 mg, 0.084 mmol, 44% yield). LCMS (ESI): [M+H]+=624.3. 1H NMR (400MHz, DMSO-d6) δppm 9.88 (s, 1H), 9.26 (s, 1H), 8.96 (br d,J=2.8Hz,1H),8.51(d,J=0.8Hz,1H),8.15(d,J=1.6Hz,1H),7.91(d,J=8.4 Hz,1H),7.71-7.58(m,2H),7.16(d,J=1.6Hz,1H),7.04(dd,J=2.0,8.4Hz,1H) ,5.73-3.98(m,1H),3.77(t,J=6.8Hz,2H),3.70-3.62(m,4H),3.30(t,J=1.2 Hz,2H),2.92-2.82(m,4H),2.32-2.21(m,4H),1.60-1.43(m,4H),0.33(s,4H)

[0119] Example 2: N-(4-(4-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0120] Step 1: To a solution of 6-bromo-8-fluoroquinoline (5.00 g, 22.1 mmol) in 1-methyl-2-pyrrolidone (50.0 mL) was added 4,4-difluoropiperidine hydrochloride (5.22 g, 33.2 mmol) and potassium carbonate (9.36 g, 66.4 mmol). The mixture was heated to 180°C and stirred for 50 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to dryness to obtain a residue. The residue was purified by flash silica gel chromatography (silica gel, 0-1% gradient of ethyl acetate / petroleum ether) to obtain 6-bromo-8-(4,4-difluoropiperidin-1-yl)quinoline (4.30 g, 13 mmol, 59.4% yield) as a yellow solid. LCMS (ESI): [M+H] + =327.0.

[0121] Step 2: To a solution of 6-bromo-8-(4,4-difluoropiperidin-1-yl)quinoline (4.00 g, 12.2 mmol), ethynyltrimethylsilane (1.32 g, 13.4 mmol), cuprous iodide (0.24 g, 1.22 mmol), and triphenylphosphine (0.32 g, 1.22 mmol) in triethylamine (30.0 mL) and tetrahydrofuran (20.0 mL) was added dichlorobis(triphenylphosphine)palladium(II) (0.87 g, 1.22 mmol). The atmosphere was purged with nitrogen three times, and the mixture was heated to 85°C and stirred for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash silica gel chromatography (silica gel, 0-1% gradient of ethyl acetate / petroleum ether) to give 8-(4,4-difluoropiperidin-1-yl)-6-((trimethylsilyl)ethynyl)quinoline (2.5 g, 9.15 mmol, 75% yield) as a white solid. LCMS (ESI): [M+H] + =345.1.

[0122] Step 3: To a solution of 6-(2-azido-5-iodophenyl)-6-azaspiro[2.5]octane (500 mg, 1.41 mmol), 8-(4,4-difluoropiperidin-1-yl)-6-((trimethylsilyl)ethynyl)quinoline (490 mg, 1.41 mmol) in tert-butanol (5 mL), tetrahydrofuran (5 mL), and water (5 mL) were added copper sulfate (225 mg, 1.41 mmol) and sodium ascorbate (279 mg, 1.41 mmol). The mixture was stirred at 25°C for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate / petroleum ether) to afford 8-(4,4-difluoropiperidin-1-yl)-6-(1-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)quinoline (600 mg, 0.95 mmol, 68% yield) as a yellow solid. LCMS (ESI): [M+H] = 627.0.

[0123] Step 4: To a solution of 2-hydroxyethanesulfonamide (120 mg, 0.96 mmol), sarcosine (43.5 mg, 0.48 mmol), and potassium phosphate (415 mg, 1.92 mmol) in N,N-dimethylformamide (6 mL) was added cuprous iodide (93.1 mg, 0.48 mmol). The mixture was stirred at 50°C for 5 minutes. 8-(4,4-difluoropiperidin-1-yl)-6-(1-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)quinoline (300 mg, 0.48 mmol) was then added to the reaction mixture at 50°C. The mixture was heated to 100°C under nitrogen and stirred for 16 hours. Water (10 mL) was added to the reaction mixture, 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 dryness to obtain a residue. The residue was purified by preparative HPLC (C18, 32-72% gradient of water (formic acid) / acetonitrile) to obtain N-(4-(4-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide (133 mg, 0.48 mmol, 45% yield) as a white solid. LCMS (ESI): [M+H]+ = 648.3. 1H NMR(400MHz,DMSO-d6)δppm 10.06(br s,1H),9.22(s,1H),8.88(br s,1H),8.40(br d,J=2.4Hz,1H),8.15(br s,1H),7.76(br s,1H),7.66-7.44(m,2H),7.14(br s,1H),7.03(br d,J=8.8Hz,1H),5.23-4.72(m,1H),3.88-3.72(m,2H), 3.67-3.45(m,4H),3.39-3.34(m,2H),2.82-2.61(m,4H),2.39-2.12(m,4H),1.37-1.18(m,4H),0.23(s,4H)

[0124] Example 3: N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0125] Step 1: To a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbonitrile (2.00 g, 8.39 mmol) in tetrahydrofuran was added a 1 M solution of diisobutylaluminum hydride in toluene (25.2 mL, 25.2 mmol) at -40°C. The mixture was slowly warmed to 25°C and stirred for 1 hour. The mixture was quenched by adding ice water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to dryness to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-8% gradient of ethyl acetate / petroleum ether) to obtain 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbaldehyde (0.35 g, 1.45 mmol, 17% yield) as a yellow oil. LCMS (ESI): [M+H] + =241.9.

[0126] Step 2: To a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxaldehyde (0.35 g, 1.45 mmol) and potassium carbonate (0.40 g, 2.90 mmol) in methanol (7 mL) was added dimethyl (1-diazo-2-oxyidenepropyl) phosphonate (0.33 g, 1.74 mmol). The mixture was stirred at 25 ° C for 16 hours. Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give a yellow oil 2-(4,4-difluoropiperidin-1-yl)-4-ethynyl-6-methylpyrimidine (0.30 g, 1.26 mmol, yield 87%). LCMS (ESI): [M+H] + =237.9.

[0127] Step 3: To a solution of 2-fluoro-4-iodo-1-nitrobenzene (3.00 g, 11.2 mmol) and potassium carbonate (4.65 g, 33.7 mmol) in dimethyl sulfoxide (45 mL) was added 6-azaspiro[2.5]octane hydrochloride (1.82 g, 12.3 mmol). The mixture was heated to 140°C and stirred for 16 hours. Water (100 mL) was poured into the reaction solution and extracted with ethyl acetate (100 mL x 3). 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 flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to give 6-(5-iodo-2-nitrophenyl)-6-azaspiro[2.5]octane (3.00 g, 8.37 mmol, 75% yield) as a yellow solid. LCMS (ESI): [M+H] + =358.8.

[0128] Step 4: To a solution of 6-(5-iodo-2-nitrophenyl)-6-azaspiro[2.5]octane (3.00 g, 8.37 mmol) in methanol (60 mL) and water (20 mL) was added ammonium chloride (1.36 g, 25.1 mmol) and iron powder (4.73 g, 83.7 mmol). The mixture was heated to 60 ° C and stirred for 16 hours. The reaction solution was filtered through celite, and the filtrate was extracted with ethyl acetate (100 mL x 3). 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 flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)aniline (2.20 g, 6.69 mmol, 80% yield) as a yellow solid. LCMS (ESI): [M+H] + =329.0.

[0129] Step 5: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)aniline (2.26 g, 6.89 mmol) in acetonitrile (40 mL) was added tert-butyl nitrite (1.09 g, 10.3 mmol) at 0°C. Trimethylsilyl azide (1.19 g, 10.3 mmol) was then added to the reaction solution, and the mixture was stirred at 25°C for 16 hours. The reaction solution was poured into water (40 mL) and extracted with ethyl acetate (40 mL x 3). 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 flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to give 6-(2-azido-5-iodophenyl)-6-azaspiro[2.5]octane (1.75 g, 4.95 mmol, 72% yield) as a yellow solid. LCMS (ESI): [M+H] + =354.9.

[0130] Step 6: To a solution of 6-(2-azido-5-iodophenyl)-6-azaspiro[2.5]octane (500 mg, 1.41 mmol), 2-(4,4-difluoropiperidin-1-yl)-4-ethynyl-6-methylpyrimidine (334 mg, 1.41 mmol) in tert-butanol (5 mL) and water (5 mL) were added copper sulfate (225 mg, 1.41 mmol) and sodium ascorbate (279 mg, 1.41 mmol). The mixture was stirred at 25 ° C for 16 hours. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate / petroleum ether) to afford 6-(2-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-5-iodophenyl)-6-azaspiro[2.5]octane (350 mg, 0.59 mmol, 42% yield) as a yellow solid. LCMS (ESI): [M+H] + =592.5.

[0131] Step 7: To a solution of 2-hydroxyethanesulfonamide (82.5 mg, 0.66 mmol), 2-(methylamino)acetic acid (45.2 mg, 0.51 mmol), and potassium phosphate (439 mg, 2.03 mmol) in N,N-dimethylformamide (6 mL) was added cuprous iodide (49.2 mg, 0.25 mmol). The mixture was stirred at 50°C for 5 minutes. 6-(2-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-5-iodophenyl)-6-azaspiro[2.5]octane (300 mg, 0.51 mmol) was then added to the reaction mixture at 50°C. The mixture was heated to 100°C under nitrogen and stirred for 16 hours. Water (10 mL) was added to the reaction mixture, 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 give a residue. The residue was purified by preparative HPLC (C18, 44-84% gradient of water (formic acid) / acetonitrile) to give a white solid compound N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide (108 mg, 0.18 mmol, yield 36%). LCMS (ESI): [M+H] + =589.5. 1 HNMR(400MHz,DMSO-d6)δppm 10.04(s,1H),9.22(s,1H),7.58(d,J=8.4Hz,1H),7.22(s,1H),7.14(d,J=2.0Hz,1H),7.04(dd,J=2.0,8.4Hz,1H),5.13-4.77(m,1H),4.15 -3.88(m,4H),3.79(t,J=6.4Hz,2H),3.42-3.35(m,2H),2.74-2.63(m,4H),2.41(s,3H),2.08-1.93(m,4H),1.41-1.18(m,4H),0.25(s,4H)

[0132] Example 4: N-(8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl]benzamide

[0133] Step 1: A mixture containing 3-fluoro-2-iodo-1-nitrobenzene (9.50 g, 35.58 mmol), iron powder (10.00 g, 177.90 mmol), ammonium chloride (9.60 g, 177.90 mmol), ethanol (100 mL), and water (20 mL) was stirred at 60°C for 1 hour. The reaction mixture was filtered while hot and concentrated, then 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 3-fluoro-2-iodoaniline (6.70 g, 79.5%) as a white solid. LCMS (ESI): [M+H] + =238.0

[0134] Step 2: N-bromosuccinimide (5.0 g, 28.27 mmol) was added to a mixed solution containing 3-fluoro-2-iodoaniline (6.70 g, 28.27 mmol) and N,N-dimethylformamide (60 mL). The reaction solution was stirred at 20°C for 1 hour, poured into water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain the compound 4-bromo-3-fluoro-2-iodoaniline (7.00 g, 78.7%) as a gray solid. LCMS (ESI): [M+H] + =317.9.

[0135] Step 3: Glycerol (5.60 g, 59.83 mmol) and 3-nitrobenzenesulfonic acid sodium salt (5.40 g, 23.93 mmol) were added to a solution containing concentrated sulfuric acid (20 mL) and water (15 mL). The mixture was heated to 110°C, and then 4-bromo-3-fluoro-2-iodoaniline (6.30 g, 19.94 mmol) was slowly added. The resulting mixture was stirred at 130°C for 12 hours. The reaction solution was poured into ice / water 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% gradient of ethyl acetate / petroleum ether) to obtain the compound 6-bromo-7-fluoro-8-iodoquinoline (2.20 g, 31%) as a gray solid. LCMS (ESI): [M+H] + =353.9.

[0136] Step 4: Under nitrogen atmosphere, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (336 mg, 0.57 mmol) and tris(dibenzylideneacetone)dipalladium (531 mg, 0.57 mmol) were added to a mixed solution containing 6-bromo-7-fluoro-8-iodoquinoline (2.00 g, 5.68 mmol), 4,4-difluoropiperidine hydrochloride (1.00 g, 6.25 mmol), cesium carbonate (5.70 g, 17.05 mmol) and dioxane (20 mL). The resulting mixture was stirred at 100 ° C for 12 hours. The reaction solution was poured into water (50 mL) and washed with ethyl acetate (50 mL x 10% acetic acid). 3) Extraction, drying the organic phase over anhydrous sodium sulfate, filtration, and concentration followed by purification by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) afforded the compound 6-bromo-8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinoline (1.60 g, 82%) as a yellow solid. LCMS (ESI): [M+H] + =347.0

[0137] Step 5: Under nitrogen atmosphere, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (137 mg, 0.23 mmol) and tris(dibenzylideneacetone)dipalladium (217 mg, 0.23 mol) were added to a mixed solution containing 8-(4,4-difluoropropiophene)-6-bromo-7-fluoroquinoline (800 mg, 2.32 mmol), tert-butyl carbamate (329 mg, 2.78 mmol), cesium carbonate (2.30 g, 6.95 mmol) and dioxane (10 mL). The resulting mixture was stirred at 100 ° C for 12 hours. The reaction solution was poured into water (30 mL) and washed 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, 0-30% gradient of ethyl acetate / petroleum ether) to obtain tert-butyl (8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)carbamate (620 mg, 70%) as a yellow solid. LCMS (ESI): [M+H] + =382.2. 1HNMR (400MHz, DMSO) δ9.20(d,J=1.6Hz,1H),8.80(dd,J=4.0,1.6Hz,1H),8.28(dd,J=8.4,1.6Hz,1H ),7.94(d,J=8.0Hz,1H),7.45(dd,J=8.4,4.0Hz,1H),3.50(t,J=6.0Hz,4H),2.22-2.08(m,4H),1.50(s,9H).

[0138] Step 6: A mixed solution containing N-[8-(4,4-difluoropiperidinyl)-7-fluoro(6-quinolinyl)](tert-butoxy)formamide (600 mg, 1.57 mmol) and trifluoroacetic acid (4 mL) was stirred at 25°C for 30 minutes. The reaction solution was concentrated and saturated aqueous sodium bicarbonate (30 mL) was added to adjust the pH to approximately 8. The solution was then extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford 8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-amine (450 mg, crude) as a yellow solid. LCMS (ESI): [M+H] + =282.1.

[0139] Step 7: 2-(6-azaspiro[2.5]octan-6-yl)-4-bromobenzoyl chloride (631 mg, 1.92 mmol) was added to a mixed solution containing 8-(4,4-difluoropiperidinyl)-7-fluoro-6-quinolinamine (450 mg, 1.60 mmol), N,N-diisopropylethylamine (1.10 g, 8.00 mmol) and tetrahydrofuran (5 mL). The reaction solution was stirred at 25 ° C for 1 hour, poured into water (30 mL) 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, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound 4-bromo-N-(8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)-2-(6-azaspiro[2.5]octyl-6-yl]benzamide (550 mg, 60.0%) as a white solid. LCMS (ESI): [M+H] + =573.3.1H NMR (400MHz, CDCl3) δ12.52(s,1H),8.86(s,2H),8.14(dd,J=8.4,1.6Hz,2H),7.52(d,J=1.6Hz,1H),7.48- 7.42(m,1H),7.41-7.33(m,1H),3.64(s,4H),3.09(t,J=5.6Hz,4H),2.29(s,4H),1.75(s,4H),0.42(s,4H).

[0140] Step 8: Under a nitrogen atmosphere, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (37 mg, 0.087 mmol) and tris(dibenzylideneacetone)dipalladium (81 mg, 0.087 mmol) were added to a mixed solution containing [2-(6-azaspiro[2.5]octan-6-yl)-4-bromophenyl]-N-[8-(4,4-difluoropiperidinyl)-7-fluoro(6-quinolyl)]formamide (500 mg, 0.87 mmol), 2-hydroxyethanesulfonamide (137 mg, 1.05 mmol), potassium phosphate (567 mg, 2.62 mmol) and dioxane (10 mL), and the reaction solution was stirred at 100°C for 12 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, concentrated, and purified by column chromatography (silica gel, 0-100% ethyl acetate / petroleum ether gradient) to afford the compound (252 mg, 46.8%) as a pale yellow solid. LCMS (ESI): [M+H] = 618.4.

[0141] 1 H NMR (400MHz, DMSO) δ12.48(d,J=2.7Hz,1H),10.22(s,1H),8.82(dd,J=4.2,1.7Hz,1H),8.74(d,J=7.9H z,1H),8.32(dd,J=8.4,1.7Hz,1H),8.05(d,J=8.5Hz,1H),7.49(dd,J=8.3,4.2Hz,1H),7.31(d,J=2.2H z,1H),7.14(dd,J=8.6,2.1Hz,1H),4.95(t,J=5.7Hz,1H),3.77(q,J=5.8Hz,2H),3.58(t,J=5.6Hz,4H) ,3.38(t,J=6.5Hz,2H),2.99(t,J=5.3Hz,4H),2.19(tt,J=14.1,5.6Hz,4H),1.60(s,4H),0.38(s,4H).

[0142] Example 5: 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl L-valine ester hydrochloride

[0143] Step 1: Dissolve N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (400 mg, 0.64 mmol) and (tert-butyloxycarbonyl)-L-valine (696 mg, 3.20 mmol) in tetrahydrofuran (8.0 mL), add N,N-diisopropylethylamine (9.92 mg, 0.05 mmol) and 3-nitro-1H-1,2,4-triazole (169 mg, 1.28 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (408 mg, 1.60 mmol), and stir at 25 ° C for 16 hours. The reaction solution 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, 0-23% gradient of tetrahydrofuran / petroleum ether) to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butyloxycarbonyl)-L-valine ester (350 mg, 0.48 mmol, 75.5% yield) as a yellow solid. LCMS (ESI): [M+H] + =823.4

[0144] Step 2: Dissolve 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butoxycarbonyl)-L-valine ester (350 mg, 0.42 mmol) in dichloromethane (8.00 mL) and trifluoroacetic acid (1.6 mL) and stir at 25°C for 1 hour. The reaction mixture was poured into aqueous sodium bicarbonate (20.0 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 10%-50% gradient of water (hydrochloric acid) / acetonitrile) and freeze-dried to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl L-valine ester hydrochloride (11.0 mg, 0.14 mmol, 3.42% yield) as a white solid. LCMS (ESI): [M / 2+1] + =723.3. 1H NMR (400MHz, DMSO-d6) δppm 10.21(br s,1H),9.29(br s,1H),8.98(br s,1H),8.55(br d,J=6.4Hz,1H),8.52-8.28(m,3H),8.18(br s,1H),7.93(d,J=8.4Hz,1H),7.69(br s,2H),7.20(br s,1H),7.08(br d,J=8.8Hz,1H),4.65-4.43(m,2H),3.88(br d,J=1.2Hz,1H),3.73-3.61(m,6H),2.91(br s,4H),2.38-2.21(m,4H),2.19-2.09(m,1H),1.54(br s,4H),0.94(d,J=6.8Hz,6H),0.34(s,4H)

[0145] Example 6: 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl phosphate sodium salt

[0146] Step 1: Dissolve N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (400 mg, 0.64 mmol) and tetrazole (220 mg, 3.21 mmol) in dichloromethane (8.00 mL). Add di-tert-butyldiethylphosphoramide (711 mg, 2.56 mmol) and stir the mixture at 25°C for 1 hour. Then, add hydrogen peroxide (302 mg, 3.20 mmol, 36% purity) to the reaction mixture, and stir the mixture at 25°C for 16 hours. The reaction mixture is diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phase is dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-35% gradient of tetrahydrofuran / petroleum ether) to give di-tert-butyl (2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl)phosphate (200 mg, 0.24 mmol, 38.2% yield) as a yellow oil. LCMS (ESI): [M+H] + =816.4

[0147] Step 2: Dissolve di-tert-butyl (2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl)phosphate (200 mg, 0.24 mmol) in dichloromethane (4.00 mL) and trifluoroacetic acid (1.00 mL) and stir at 25°C for 1 hour. The reaction mixture was concentrated to dryness using a stream of nitrogen. The residue was converted to a phosphate salt with sodium bicarbonate and purified by preparative HPLC (C18, 0%-90% gradient of water / acetonitrile) to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl phosphate sodium salt (78.5 mg, 0.10 mmol, 42.8% yield) as a yellow solid. LCMS (ESI): [M+1] + =704.2. 1 H NMR (400MHz, D2O) δppm 8.44 (d, J = 2.8Hz, 1H), 8.18 (s, 1H), 7.80 (br d,J=8.0Hz,1H),7.26(s,1H),7.20(d,J=8.4Hz,1H),7.15(dd,J=4.4,8.4Hz,1H),6.86(s,1H),6.61(d,J=2.0Hz,1H),6.55(dd,J =2.0,8.4Hz,1H),3.86(q,J=6.8Hz,2H),3.18(t,J=6.8Hz,2H),2.99-2.83(m,4H),2.43-2.27(m,4H),2.05-1.88(m,4H),1.01(br d, J=2.4Hz,4H),0.00(s,4H)

[0148] Example 7: 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl dimethylglycinate hydrochloride

[0149] Step 1: Dissolve N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (200 mg, 0.32 mmol) and dimethylglycine (165 mg, 1.6 mmol) in tetrahydrofuran (4.00 mL). Add N,N-diisopropylethylamine (105 mg, 0.8 mmol) and 3-nitro-1H-1,2,4-triazole (91.4 mg, 0.8 mmol) and bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (204 mg, 0.8 mmol). Stir at 25°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 6%-46% gradient of water (hydrochloric acid) / acetonitrile) to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl dimethylglycinate hydrochloride (210 mg, 0.29 mmol, 92%) as a yellow solid. LCMS (ESI): [M+1] + =709.2. 1 H NMR (400MHz, DMSO-d6) δppm 10.42 (s, 1H), 10.25 (s, 1H), 9.32 (s, 1H), 9.00 (dd, J = 1.6, 4.2Hz, 1H), 8.59 (br d,J=7.6Hz,1H),8.22(d,J=2.0Hz,1H),7.95(d,J=8.4Hz,1H),7.80-7.68(m, 2H),7.24(s,1H),7.10(dd,J=1.2,8.0Hz,1H),4.52(t,J=5.6Hz,2H),4.16(br s,2H),3.67-3.60(m,6H),2.95(br s,4H),2.84(br s,6H),2.39-2.19(m,4H),1.56(br s,4H),0.35(s,4H)

[0150] Example 8: 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethylglycinate hydrochloride

[0151] Step 1: Dissolve N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (200 mg, 0.32 mmol) and (tert-butyloxycarbonyl)glycine (281 mg, 1.6 mmol) in tetrahydrofuran (4.00 mL), add N,N-diisopropylethylamine (105 mg, 0.8 mmol) and 3-nitro-1H-1,2,4-triazole (91.4 mg, 0.8 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (204 mg, 0.8 mmol), and stir at 25 ° C for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butoxycarbonyl)glycine ester (300 mg, 0.3 mmol, crude) as a yellow solid. LCMS (ESI): [M+H]+ = 781.3

[0152] Step 2: Dissolve 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butoxycarbonyl)glycine ester (300 mg, 0.38 mmol) in dichloromethane (5.00 mL) and trifluoroacetic acid (1.00 mL) and stir at 25°C for 1 hour. The reaction mixture was concentrated to dryness using a stream of nitrogen. The residue was purified by preparative HPLC (C18, 6%-46% gradient of water (hydrochloric acid) / acetonitrile) to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethylglycine ester hydrochloride (180 mg, 0.26 mmol, 69%) as a yellow solid. LCMS (ESI): [M+1] + =681.3. 1H NMR (400MHz, DMSO-d6) δppm10.25(s,1H),9.35(s,1H),9.00(dd,J=1.6,4.4Hz,1H),8.61(d,J=7.2Hz,1H),8.43(br s,3H),8.24(d,J=2.0Hz,1H),7.94(d,J=8.4Hz,1H),7.81-7.67(m,2H),7.25(s,1H),7.10(dd,J=1.6,8.4Hz,1H),4.48(t,J=5.6Hz,2H),3.75(br d,J=5.6Hz,2H),3.69-3.66(m,4H),3.57-3.53(m,2H),2.96(br s,4H),2.40-2.20(m,4H),1.56(br s,4H),0.35(s,4H)

[0153] Example 9: 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl histidine ester hydrochloride

[0154] Step 1: Dissolve N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (220 mg, 0.35 mmol) and (tert-butyloxycarbonyl)histidine (333 mg, 1.76 mmol) in tetrahydrofuran (4.00 mL), add N,N-diisopropylethylamine (116 mg, 0.88 mmol) and 3-nitro-1H-1,2,4-triazole (100 mg, 0.88 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (224 mg, 0.88 mmol), and stir at 25 ° C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-52% gradient of tetrahydrofuran / petroleum ether) to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butyloxycarbonyl)histidine ester (330 mg, 0.35 mmol, crude) as a yellow solid. LCMS (ESI): [M+H] + =861.3. 1H NMR(400MHz,DMSO-d6)δppm 10.68-9.83(m,1H),9.24(s,1H),8.95(dd,J=1.6,4.0Hz,1H),8.50(dd,J=1.6,8.4Hz ,1H),8.14(d,J=2.4Hz,1H),7.93(d,J=8.4Hz,1H),7.67(s,1H),7.65-7.63(m,1H),7 .15(d,J=1.6Hz,1H),7.11(d,J=8.0Hz,1H),7.07(dd,J=2.0,8.4Hz,1H),6.85(s,1H) ,4.43-4.31(m,2H),4.29-4.22(m,1H),3.86-3.74(m,2H),3.68-3.64(m,4H),3.52(br t,J=6.0Hz,2H),2.85(br t,J=4.8Hz,4H),2.32-2.21(m,4H),1.56-1.44(m,4H),1.36(s,9H),0.31(s,4H)

[0155] Step 2: Dissolve 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butoxycarbonyl)histidine (310 mg, 0.36 mmol) in dichloromethane (6.00 mL) and trifluoroacetic acid (1.20 mL) and stir at 25°C for 1 hour. The reaction mixture was concentrated to dryness using a stream of nitrogen. The residue was purified by preparative HPLC (C18, 36%-76% gradient of water (hydrochloric acid) / acetonitrile) to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl histidine ester hydrochloride (51.76 mg, 0.06 mmol, 18.0% yield) as a yellow solid. LCMS (ESI): [M+1] + =761.3. 1H NMR(400MHz,DMSO-d6)δppm 15.04-14.60(m,1H),14.51(br s,1H),10.43(br s,1H),9.40(br s,1H),9.08(s,1H),9.05-9.01(m,1H),8.87(br s,3H),8.67(br d,J=8.0Hz,1H),8.30(s,1H),7.95(d,J=8.4Hz,1H),7.82(br s,1H),7.77(dd,J=4.4,8.0Hz,1H),7.52(s,1H),7.32(br s,1H),7.17(br d,J=8.0Hz,1H),4.59-4.56(m,1H),4.52-4.45(m,2H),3.69-3.56(m,6H),3.36-3 .22(m,2H),3.12-2.87(m,4H),2.37-2.27(m,4H),1.70-1.40(m,4H),0.35(s,4H)

[0156] Example 10: 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl alaninate hydrochloride

[0157] Step 1: Dissolve N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (220 mg, 0.35 mmol) and (tert-butyloxycarbonyl)alanine (333 mg, 1.76 mmol) in tetrahydrofuran (4.00 mL), add N,N-diisopropylethylamine (116 mg, 0.88 mmol) and 3-nitro-1H-1,2,4-triazole (100 mg, 0.88 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (224 mg, 0.88 mmol), and stir at 25 ° C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-26% gradient of tetrahydrofuran / petroleum ether) to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butoxycarbonyl)alaninate (300 mg, 0.35 mmol, crude) as a yellow solid. LCMS (ESI): [M+H] + =795.8. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.12(s,1H),9.25(s,1H),8.95(dd,J=1.6,4.0Hz,1H),8.88(s,1H),8.50(dd,J =1.6,8.4Hz,1H),8.13(d,J=2.0Hz,1H),7.92(d,J=8.4Hz,1H),7.67-7.61(m,2H) ,7.15(d,J=2.0Hz,1H),7.05(dd,J=2.0,8.4Hz,1H),4.49-4.39(m,1H),4.38-4.2 9(m,1H),3.86-3.73(m,1H),3.70-3.62(m,4H),3.54(brt,J=6.0Hz,2H),2.87(br t,J=4.4Hz,4H),2.33-2.20(m,4H),1.59-1.44(m,4H),1.36-1.34(m,9H),1.19(d,J=7.6Hz,3H),0.32(s,4H)

[0158] Step 2: Dissolve 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butoxycarbonyl)alaninate (280 mg, 0.35 mmol) in dichloromethane (5.00 mL) and trifluoroacetic acid (1.00 mL) and stir at 25°C for 1 hour. The reaction mixture was concentrated to dryness using a stream of nitrogen. The residue was purified by preparative HPLC (C18, 6%-46% gradient of water (hydrochloric acid) / acetonitrile) to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethylalaninate hydrochloride (120 mg, 0.17 mmol, 48.0%) as a yellow solid. LCMS (ESI): [M+1] + =695.2. 1 H NMR (400MHz, DMSO-d6) δppm10.48(br s,1H),9.51(br s,1H),9.10(dd,J=1.2,4.4Hz,1H),8.79(br d,J=8.0Hz,1H),8.69(br d,J=4.4Hz,3H),8.42(s,1H),8.01-7.92(m,2H),7.86(dd,J=4.4,8.0Hz,1H),7.38(br s,1H),7.21(br d,J=8.0Hz,1H),4.58-4.45(m,2H),4.00(td,J=6.0,12.0Hz,1H),3.67(br t,J=6.0Hz,2H),3.61-3.51(m,4H),3.25-3.00(m,4H),2.43-2.29(m,4H),1.75-1.50(m,4H),1.37(d,J=7.2Hz,3H),0.39(s,4H)

[0159] Example 11: 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethylserine ester hydrochloride

[0160] Step 1: Dissolve (tert-Butyloxycarbonyl)serine (5.00 g, 24.3 mmol) in N,N-dimethylformamide (50.0 mL). Add imidazole (5.31 g, 77.9 mmol) and stir at 25°C for 30 minutes. Then, add tert-butyldimethylsilyl chloride (5.51 g, 36.5 mmol) dropwise at 0°C and stir at 25°C for 16 hours. The reaction mixture was diluted with ethyl acetate (60.0 mL) and added to a stirred solution of dilute 1.2 M hydrochloric acid (200 mL). Stir for 30 minutes. After separation, the aqueous phase was extracted with ethyl acetate (200 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-5% tetrahydrofuran / petroleum ether gradient) to afford N-(tert-Butyloxycarbonyl)-O-(tert-Butyldimethylsilyl)serine (3.70 g, 11.7 mmol, 48.0% yield) as a colorless oil. 1 H NMR (400MHz, CHLOROFORM-d) δppm 6.40 (br s, 1H), 5.36 (br d, J=8.0Hz, 1H), 4.37 (br d,J=8.0Hz,1H),4.12-3.97(m,1H),3.84(dd,J=3.2,10.0Hz,1H),1.46(s,9H),0.87(s,9H),0.07-0.03(m,6H)

[0161] Step 2: N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (500 mg, 0.80 mmol) and N-(tert-butyloxycarbonyl)-O-(tert-butyldimethylsilyl)serine (1.28 g, 4.01 mmol) were dissolved in tetrahydrofuran (10.0 mL), and N,N-diisopropylethylamine (264 mg, 2.00 mmol) and 3-nitro-1H-1,2,4-triazole (228 mg, 2.00 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (510 mg, 2.00 mmol) were added and stirred at 25 ° C for 1 hour. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-28% gradient of tetrahydrofuran / petroleum ether) to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl N-(tert-butyloxycarbonyl)-O-(tert-butyldimethylsilyl)serine ester (390 mg, 0.42 mmol, 53.0% yield) as a yellow oil. LCMS (ESI): [M-56+H] + =869.4. 1 H NMR(400MHz,DMSO-d6)δppm 10.18(s,1H),9.28(s,1H),8.99(dd,J=1.2,3.6Hz,1H),8.60-8.47(m,1H),8.17(d,J=2.0Hz,1 H),7.97(d,J=8.4Hz,1H),7.72-7.66(m,2H),7.19(s,1H),7.08(dd,J=1.2,8.4Hz,1H),6.95(br d,J=8.4Hz,1H),4.42(dt,J=5.2,11.6Hz,2H),4.23(br dd,J=3.2,5.6Hz,1H),3.86-3.76(m,2H),3.73-3.67(m,4H),3.57(br t,J=6.0Hz,2H),2.95-2.85(m,4H),2.30-2.28(m,4H),1.62-1.52(m,4H),1.41(s,9H),0.87-0.80(m,9H),0.37(s,4H),0.06--0.04(m,6H)

[0162] Step 3: 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl N-(tert-butyloxycarbonyl)-O-(tert-butyldimethylsilyl)serine ester (390 mg, 0.42 mmol) was dissolved in tetrahydrofuran (8.00 mL), tetrabutylammonium fluoride (tetrahydrofuran solution) (0.63 mL, 0.63 mmol) was added, and stirred at 25 ° C for 2 hours. The reaction solution was quenched by adding saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL x 2), and the organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-32% gradient of tetrahydrofuran / petroleum ether) to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butoxycarbonyl)serine ester (250 mg, 0.23 mmol, 54.0% yield) as a yellow oil. LCMS (ESI): [M+1] + =811.3. 1 H NMR(400MHz,DMSO-d6)δppm 10.10(br s,1H),9.26(s,1H),8.95(dd,J=1.6,4.4Hz,1H),8.50(dd,J=1.6,8.4Hz,1H),8.14(d,J=2.0Hz,1H),7.92(d,J=8.4Hz,1H) ,7.68-7.62(m,2H),7.15(d,J=1.6Hz,1H),7.05(dd,J=2.0,8.4Hz,1H),6.92(d,J=8.0Hz,1H),4.98-4.87(m,1H),4.38(br t,J=6.0Hz,2H),4.13-4.06(m,1H),3.69-3.62(m,4H),3.62-3.59(m,2H),3.54(br t,J=5.6Hz,2H),2.92-2.81(m,4H),2.27-2.24(m,4H),1.56-1.46(m,4H),1.37(s,9H),0.32(s,4H)

[0163] Step 4: Dissolve 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butoxycarbonyl)serine ester (250 mg, 0.31 mmol) in dioxane (2.00 mL), add dioxane hydrochloride (2.00 mL), and stir at 25 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (C18, 6%-46% gradient of water (hydrochloric acid) / acetonitrile) to give 2-(N-(4-(1-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethylserine ester hydrochloride (128.44 mg, 0.18 mmol, 58.0% yield) as a yellow solid. LCMS (ESI): [M+1] + =711.2. 1 H NMR (400MHz, DMSO-d6) δppm 10.37(br s,1H),9.43(br s,1H),9.05(br d,J=4.0Hz,1H),8.69(br d,J=8.4Hz,1H),8.58(br d,J=3.6Hz,3H),8.32(s,1H),7.95(d,J=8.4Hz,1H),7.85(br s,1H),7.79(br dd,J=4.4,8.4Hz,1H),7.32(br s,1H),7.17(br d,J=8.4Hz,1H),4.50(br t,J=6.0Hz,2H),4.11-4.01(m,1H),3.81-3.71(m,2H),3.70-3.63(m,2H),3.62-3 .55(m,4H),3.17-2.91(m,4H),2.38-2.27(m,4H),1.72-1.45(m,4H),0.37(s,4H)

[0164] Example 12: 2-(N-(4-((8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)aminocarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl L-valine ester hydrochloride

[0165] Step 1: Dissolve N-(8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (500 mg, 0.81 mmol) and (tert-butyloxycarbonyl)-L-valine (879 mg, 4.05 mmol) in tetrahydrofuran (10.0 mL). Add N,N-diisopropylethylamine (9.92 mg, 0.05 mmol), 3-nitro-1H-1,2,4-triazole (230 mg, 2.02 mmol), and bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (515 mg, 2.02 mmol). Stir at 25°C for 16 hours. The reaction mixture is diluted with water (50.0 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase is dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-23% gradient of tetrahydrofuran / petroleum ether) to give 2-(N-(4-((8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)aminocarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butoxycarbonyl)-L-valine ester (340 mg, 0.38 mmol, 47.0% yield) as a yellow solid. LCMS (ESI): [M+H] + =817.3. 1 H NMR(400MHz,DMSO-d6)δppm 12.46(br s,1H),10.88-9.85(m,1H),8.82(dd,J=1.6,4.0Hz,1H),8.74(d,J=8.0Hz,1H),8.37- 8.27(m,1H),8.05(d,J=8.4Hz,1H),7.49(dd,J=4.0,8.0Hz,1H),7.29(s,1H),7.14(br d,J=8.4Hz,1H),7.08(br d,J=8.0Hz,1H),4.39(br t,J=5.2Hz,2H),3.85-3.76(m,2H),3.64-3.60(m,2H),3.58(br d,J=5.2Hz,4H),3.05-2.95(m,4H),2.25-2.13(m,4H),1.66-1.55(m,4H),1.40-1.33(m,9H),0.78(br dd,J=4.8,6.4Hz,6H),0.38(s,4H)

[0166] Step 2: Dissolve 2-(N-(4-((8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)aminocarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butoxycarbonyl)-L-valine ester (320 mg, 0.39 mmol) in dichloromethane (8.00 mL) and trifluoroacetic acid (1.60 mL) and stir at 25°C for 1 hour. The reaction mixture was poured into aqueous sodium bicarbonate (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, 6%-46% gradient of water (formic acid) / acetonitrile) and freeze-dried to give 2-(N-(4-((8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)aminocarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl L-valine ester (104.92 mg, 0.14 mmol, 36.0% yield) as a white solid. LCMS (ESI): [M / 2+1] + =359.8. 1 HNMR(400MHz,DMSO-d6)δppm 12.46(br s,1H),8.82(dd,J=1.2,4.0Hz,1H),8.74(d,J=8.0Hz,1H),8.32(dd,J=1.6,8.4Hz,1H),8.04(d,J=8.8Hz,1H),7.49(dd,J=4.4,8.4 Hz,1H),7.26(d,J=1.6Hz,1H),7.11(dd,J=1.6,8.4Hz,1H),4.39(t,J=5.6Hz,2H),3.63-3.60(m,2H),3.59-3.55(m,4H),3.07(d,J= 5.2Hz,1H),3.03-2.95(m,4H),2.25-2.14(m,4H),1.77(br dd,J=6.8,12.0Hz,1H),1.60(br s, 4H), 0.81 (d, J = 6.8Hz, 3H), 0.76 (d, J = 7.2Hz, 3H), 0.38 (s, 4H).

[0167] The product was dissolved in 0.6 M dilute hydrochloric acid and freeze-dried to give a yellow solid, 2-(N-(4-((8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)aminocarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl L-valine ester hydrochloride (27.48 mg, 0.03 mmol, 9.00% yield). LCMS (ESI): [M / 2+H] + =359.4. 1H NMR (400MHz, DMSO-d6) δppm 12.84 (br s, 1H), 10.73 (s, 1H), 9.24 (br d, J = 6.8Hz, 1H), 9.21-9.07 (m, 2H), 8.64 (br d,J=4.0Hz,3H),8.09(d,J=8.8Hz,1H),8.06-7.98(m,1H),7.41(d,J=1.6Hz,1 H),7.24(dd,J=1.6,8.8Hz,1H),4.57-4.48(m,2H),3.82-3.78(m,1H),3.71(br t,J=6.0Hz,2H),3.43-3.31(m,4H),3.10-2.95(m,4H),2.50-2.35(m,4H) ,2.17-2.08(m,1H),1.68-1.50(m,4H),0.92(d,J=7.2Hz,6H),0.39(s,4H)

[0168] Example 13: 2-(N-(4-(4-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl L-valine ester formate

[0169] Step 1: Dissolve N-(4-(4-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (400 mg, 0.64 mmol) and (tert-butyloxycarbonyl)-L-valine (696 mg, 3.20 mmol) in tetrahydrofuran (8.0 mL), add N,N-diisopropylethylamine (9.92 mg, 0.05 mmol) and 3-nitro-1H-1,2,4-triazole (169 mg, 1.28 mmol), bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (408 mg, 1.60 mmol), and stir at 25 ° C for 2 hours. The reaction solution 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, 0-23% gradient of tetrahydrofuran / petroleum ether) to give 2-(N-(4-(4-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butyloxycarbonyl)-L-valine ester (201 mg, 0.27 mmol, 43.3% yield) as a yellow solid. LCMS (ESI): [M+H]+ =823.3.

[0170] Step 2: Dissolve 2-(N-(4-(4-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butoxycarbonyl)-L-valine ester (200 mg, 0.24 mmol) in dichloromethane (4.00 mL) and trifluoroacetic acid (0.8 mL) and stir at 25°C for 2 hours. The reaction mixture was poured into aqueous sodium bicarbonate (20.0 mL) and extracted with dichloromethane (50 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) and freeze-dried to give 2-(N-(4-(4-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl L-valine ester formate (39.0 mg, 0.09 mmol, 39.2% yield) as a white solid. LCMS (ESI): [M / 2+1] + =723.4. 1 H NMR(400MHz,DMSO-d6)δppm 9.19(s,1H),8.95-8.79(m,1H),8.51-8.32(m,1H),8.24-7.98(m,1H),7.73(s,1H),7.62-7.45(m,2H) ,7.12(d,J=2.0Hz,1H),7.03(dd,J=2.0,8.4Hz,1H),4.41(t,J=6.0Hz,2H),3.67-3.58(m,6H),3.12(br d,J=5.2Hz,1H),2.71(brt,J=4.8Hz,4H),2.25(br t,J=13.2Hz,4H),1.91-1.75(m,1H),1.29(br s,4H),0.92-0.67(m,6H),0.23(s,4H)

[0171] Example 14: 2-(N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl L-valine ester formate

[0172] Step 1: Dissolve N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (500 mg, 0.85 mmol) in dichloromethane (10.0 mL), add (tert-butyloxycarbonyl)-L-valine (184 mg, 0.85 mmol) and triethylamine (263 mg, 2.55 mmol) and 1-hydroxybenzotriazole (34.4 mg, 0.25 mmol), add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (244 mg, 1.27 mmol), and stir at 25 ° C for 16 hours. The reaction solution 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, 0-20% gradient of tetrahydrofuran / petroleum ether) to give 2-(N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butyloxycarbonyl)-L-valine ester (540 mg, 0.59 mmol, 70.0% yield) as a white solid. LCMS (ESI): [M+H] + =789.0

[0173] Step 2: Dissolve 2-(N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl(tert-butoxycarbonyl)-L-valine ester (520 mg, 0.66 mmol) in dichloromethane (10.0 mL) and trifluoroacetic acid (2.00 mL) and stir at 25°C for 1 hour. The reaction mixture was poured into aqueous sodium bicarbonate (50.0 mL) and extracted with ethyl acetate (50.0 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 12%-52% gradient of water (formic acid) / acetonitrile) to give 2-(N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl L-valine ester formate (264.83 mg, 0.37 mmol, 56.0% yield) as a white solid. LCMS (ESI): [M+H] + =688.3. 1H NMR(400MHz,DMSO-d6)δppm 9.19(s,1H),8.20(s,1H),7.57(d,J=8.4Hz,1H),7.21(s,1H),7.10(d,J=2.4Hz,1H),7.03(dd,J=2.0,8.4Hz,1H),5.25-4.54(m,3H),4.39(br t,J=5.6Hz,2H),3.98(br t,J=5.2Hz,4H),3.59(br t,J=5.6Hz,2H),3.10(d,J=5.2Hz,1H),2.67(br t,J=4.8Hz,4H),2.39(s,3H),2.07-1.91(m,4H),1.81(br dd,J=6.8,12.4Hz,1H),1.34-1.20(m,4H),0.89-0.74(m,6H),0.23(s,4H)

[0174] Effect Example 1: Enzyme activity detection experiment

[0175] Materials: Human KIF18A (amino acid sequence 1-417), purchased from Shanghai Via Biotechnology Co., Ltd.; ADP-Glo TM Protein 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.

[0176] 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.

[0177] Effect Example 2: Cell proliferation activity detection experiment

[0178] 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.

[0179] 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.

[0180] Cell proliferation activity assay:

[0181] 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.

[0182] Effect Example 3: CyQuant Cell Proliferation Activity Detection Experiment

[0183] 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).

[0184] 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.

[0185] 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 or a pharmaceutically acceptable salt, stereoisomer, or isotope isomer thereof: in, 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, R W1 , R W2 , R W3 Each independently represents hydrogen, deuterium, 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 bonds of X2 and X3 may also be 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; Wherein, L1 represents -C(O)NH-, -NHC(O)- or triazole; Wherein, Cy1 represents a 6-14 membered aryl or heteroaryl group; and the Cy1 may be arbitrarily substituted by 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-O-halogenated C1-C6 alkyl、-SR a 、-SF5、cyano、nitro、-NR a R b 、-NR a C(O)R b 、-C(O)NR a R b 、-OC(O)R a 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b ; Among them, Cy 2 represents a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring, which may contain 0-3 heteroatoms selected from O, N and S, and the Cy 2 It may also be arbitrarily substituted by 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-O-halogenated C1-C6 alkyl、-SR a 、-SF5、cyano、nitro、-NR a R b 、-NR a C(O)R b 、-C(O)NR a R b 、-OC(O)R a 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b ; Wherein, L2 represents a straight or branched C1-C6 methylene, and any hydrogen atom may be substituted by deuterium, hydroxyl, or halogen; or any two hydrogen atoms connected to the same carbon atom may form structure; Among them, R a , R b Each independently represents hydrogen, C1-C6 alkyl, or the R a , R b Together with the atoms to which it is attached, it forms a 3-6 membered saturated or unsaturated ring, and the ring may also contain 0, 1, or 2 heteroatoms selected from O, S, and N; Among them, R M , R N represents hydrogen, halogen, halogenated C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl, or the R M , R N Together with the atoms to which it is attached, it forms a 3-6 membered saturated or unsaturated ring; Where n represents 0, 1, 2, 3; Among them, P 1 represents hydrogen or a protecting group; Among them, P 2 represents hydrogen or a protecting group; The premise is that P 1 , P 2 Not hydrogen at the same time.

2. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: L1 represents -C(O)NH- or -NHC(O)-.

3. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: L1 represents a triazole group.

4. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: L1 represents the following group: or 5. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Cy1 represents phenyl, pyridyl, pyrimidinyl, quinolyl, and the Cy1 can be arbitrarily substituted by 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-O-halogenated C1-C6 alkyl、-SR a 、-SF5、cyano、nitro、-NR a R b .

6. The compound of formula I according to claim 5 or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Cy1 represents the following groups: And the Cy1 can be arbitrarily substituted by 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-O-halogenated C1-C6 alkyl、-SR a 、-SF5、cyano、nitro、-NR a R b .

7. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Cy2 represents a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, 7-membered monocyclic ring, or a 3-, 4-, 5-, 6-, 7-membered cyclic ring, and the Cy2 may arbitrarily contain 0-3 N heteroatoms and 0-2 O or S heteroatoms, and the Cy2 may be arbitrarily substituted by 0-3 substituents selected from 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 halo C1-C6 alkyl、-SR a , -SF5 or NR a R b , where R a , R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl or hydroxy C1-C6 alkyl; or R a , R b Together with the atoms to which they are attached, they form a 3-6 membered ring containing 0-2 heteroatoms selected from O, N and S.

8. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Cy2 represents any of the following groups: Furthermore, the Cy2 may be arbitrarily substituted by 0-3 substituents selected from 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 halo C1-C6 alkyl、-SR a , -SF5 or NR a R b , where R a , R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl or hydroxy C1-C6 alkyl; or R a , R b Together with The connected atoms form a 3-6 membered ring containing 0-2 heteroatoms selected from O, N and S.

9. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: Cy2 is selected from 10. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: <h2 style=";text-align:left;direction:ltr">L2-CH2CH2-,-CH(CH3)CH2-,-CH2CH(CH3)-,-CH(OH)CH2-,-CH2CH(OH)-,-CH(CH3)CH2-,-CH2CH(CH3)-,-CH(OH)CH2-,-CH2CH(CH3)-,-CH(OH)CH2-,-CH2CH(CH3)-,-CF2CH2-,-CH2CF2-,-CHFCH2-,-CH2CHF-,<h2 style=";text-align:left;direction:ltr"> 11. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: R M , R N Each independently represents hydrogen, C1-C6 alkyl, or the R M , R N Together with the atoms to which it is attached, it forms a 3-6 membered saturated or unsaturated ring.

12. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: The P 1 Represents hydrogen, -C(O)R a 、-C(O)(CR T R T’ ) m NH2、-P(O)(OR a )2, -P(O)(ONa)2, where R a represents a C1-C6 alkyl group, wherein R T , R T’ Each independently represents hydrogen, substituted or unsubstituted C1-C6 alkyl, and the substituent is halogen, hydroxyl, phenyl, or 5-6 membered heteroaryl.

13. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, wherein: The P 2 Represents hydrogen, -C(O)R a 、-C(O)(CR T R T’ ) m NH2、-P(O)(OR a )2, -P(O)(ONa)2, where R a represents a C1-C6 alkyl group, wherein R T , R T’ Each independently represents hydrogen, substituted or unsubstituted C1-C6 alkyl, and the substituent is halogen, hydroxyl, phenyl, or 5-6 membered heteroaryl.

14. A compound having the following structure: