Inhibitor of kinin KIF18A and application thereof

Abstract

Provided are a kinin KIF18A inhibitor of formula (I) and uses thereof, the compound being capable of modulating the KIF18A protein, thereby affecting the cell cycle and cell proliferation process to treat cancer and cancer-related diseases, pharmaceutical compositions comprising the compound and methods for treating conditions associated with KIF18A activity.

Description

Kinesin KIF18A inhibitors and their applications

[0001] This application claims priority from the following applications:

[0002] 1) Chinese patent application number 202210520744.0, filed with the State Intellectual Property Office of China on May 13, 2022, entitled “Kinesin KIF18A Inhibitors and Their Applications”;

[0003] 2) Chinese patent application number 202210878192.0, filed with the State Intellectual Property Office of China on July 25, 2022, entitled “Kinesin KIF18A Inhibitors and Their Applications”;

[0004] 3) Chinese patent application number 202211183092.2, filed with the State Intellectual Property Office of China on September 27, 2022, entitled “Kinesin KIF18A Inhibitors and Their Applications”;

[0005] 4) Chinese patent application number 202211537992.2, filed with the State Intellectual Property Office of China on December 2, 2022, entitled “Kinesin KIF18A inhibitors and their applications”;

[0006] 5) Chinese patent application number 202310071265.X, filed with the State Intellectual Property Office of China on January 16, 2023, entitled “Kinesin KIF18A Inhibitors and Their Applications”;

[0007] 6) Chinese patent application number 202310288871.7, filed with the State Intellectual Property Office of China on March 22, 2023, entitled “Kinesin KIF18A Inhibitors and Their Applications”;

[0008] 7) Chinese patent application No. 202310475180.8, filed with the State Intellectual Property Office of China on April 27, 2023, entitled “Kinetic protein KIF18A inhibitors and their applications”, all contents of which are incorporated herein by reference. Technical Field

[0009] The present invention 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

[0010] 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 microtubule 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.

[0011] 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.

[0012] Summary of the Invention

[0013] The present invention belongs to the field of medicine and relates to a class of kinesin KIF18A inhibitors, specifically the compounds or their stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof or their pharmaceutically acceptable salts, cocrystals, metabolites, solvates, prodrugs or isotope labels, preparation methods thereof, and drug combinations containing such compounds and their use as therapeutic agents, in particular as agents for inhibiting cancer cell proliferation and treating cancer.

[0014] The present invention provides a novel class of compounds for use in regulating KIF18A protein alone or in a complex with microtubules for treating KIF18A-mediated conditions and / or diseases, including cancer, inflammation or ciliary pathology.

[0015] The compounds provided herein have MT-based KIF18A modulatory activity, particularly KIF18A inhibitory activity. To this end, the present invention 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).

[0016] The present invention provides a technical solution: a compound having a structure of formula (I) or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof:

[0017] Among them, W 1 Indicates CR W1 or N;

[0018] Among them, W 2 Indicates CR W2 or N;

[0019] Among them, Z represents -CR T R T ' or -NR S R S ';

[0020] Among them, R T and R T ' together with the C atoms to which they are commonly attached form a ring having a structure selected from the following:

[0021] Among them, R S and R S ' together with the N atom to which it is commonly attached, form a ring having a structure selected from the following:

[0022] Among them, Y 1 、Y 2 、Y 3 Each independently represents -(CR a R b ) o -(NR a ) p -(CR a 'R b ') q -;

[0023] Wherein, A and B each independently represent -(CR a R b ) m -;

[0024] Among them, L 1 represents a 5-6 membered heteroaryl group,

[0025] Among them, L 2 Indicates absence, -C1-C6 alkylene-, -NR a -、-NR a (C1-C6 alkylene)-, -C(O)NR a (C1-C6 alkylene)-, -O-, -O-(C1-C6 alkylene), -S-, -S(O)-, -S(O)2-, -S(O)2NR a -or-S(O)(NR a )-;

[0026] Among them, R 1 Indicates L 3 -R 3 or

[0027] Among them, R 2 represents hydrogen, halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-SR a 、-SF5、-S(O)R a , -O-, halogenated C1-C6 alkyl or -NR a R b ;

[0028] Among them, L 3 Indicates absence, C1-C6 alkylene, -NR a -、-NR a SO2-、-SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2、-NR a P(O)(OR a )2 or -NR a P(O)(R a )2;

[0029] Among them, R 3 Represents absence, hydrogen or 0-3 selected from halogen, -OR a 、-NRa R b , cyano, -O-halogenated C1-C6 alkyl or C3-C6 cycloalkyl;

[0030] Among them, R W1 and R W2 Each independently represents hydrogen, 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 , -SF5 or -NR a R b ;

[0031] Among them, Cy 1 represents a 6-12 membered aryl group or a 5-12 membered heteroaryl group; and the Cy 1 It may also be optionally substituted by 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a 、-SF5、cyano、nitro、-NR a R b 、-NH-(C0-C6 alkyl)-R M 、-NR a C(O)R b 、-C(O)NR a R b 、-OC(O)R a 、-C(O)R a 、-P(O)R a R b 、-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 optionally substituted by 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, 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 ;

[0032] Among them, R M Indicates -OR a 、-NR a R b , 5-6 membered heterocyclyl, 5-10 membered heteroaryl, 6-10 membered aryl;

[0033] Among them, R a 、R b 、R a '、R b 'Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 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 saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N; or R a '、R b 'Together with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N;

[0034] Wherein, the dotted line represents a single bond or a double bond;

[0035] Here, m, o, p, and q represent integers from 0 to 3.

[0036] In the preferred technical solution of the present invention, wherein W 1 Indicates CH or N.

[0037] In the preferred technical solution of the present invention, wherein W 2 Indicates CH or N.

[0038] In the preferred technical solution of the present invention, wherein L 3 Indicates -NR a SO2-、-SO2NR a -or-S(=O)(NR a )-.

[0039] In the preferred technical solution of the present invention, wherein L 3 Indicates -NR a SO2-.

[0040] In the preferred technical solution of the present invention, R 3 represents hydrogen or is selected from 0-3 halogens, -OR a 、

[0041] -NR a R b C1-C6 alkyl or C3-C6 cycloalkyl substituted with a group consisting of: -O-halogenated C1-C6 alkyl, -C1-C6 alkyl, -C3-C6 cycloalkyl, ...

[0042] In the preferred technical solution of the present invention, R 3 It represents 0-3 selected from halogen, -OR a 、-NR a R b C1-C6 alkyl substituted with -O-halogenated C1-C6 alkyl.

[0043] In the preferred technical solution of the present invention, wherein Z represents -NR S R S '.

[0044] In the preferred technical solution of the present invention, Z represents:

[0045] Among them, R a 、R b Each independently represents hydrogen, C1-C6 alkyl, C3-C6 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 saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N.

[0046] In the preferred technical solution of the present invention, Z represents: Among them, R a 、R b Each independently represents hydrogen, C1-C6 alkyl, C3-C6 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 saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N.

[0047] In the preferred technical solution of the present invention, Z represents:

[0048] In the preferred technical solution of the present invention, wherein L 1 represents a 5-6 membered heteroaryl group,

[0049] In the preferred technical solution of the present invention, wherein Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -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)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Any of the following groups substituted:

[0050] For example:

[0051] In the preferred technical solution of the present invention, wherein L 1 Represents: 5-6 membered heteroaryl,

[0052] In the preferred technical solution of the present invention, wherein L 1 represents any one of the following groups:

[0053] In the preferred technical solution of the present invention, wherein Cy 1represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -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)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Any of the following groups substituted:

[0054] In the preferred technical solution of the present invention, wherein Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -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)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Replaced

[0055] In the preferred technical solution of the present invention, wherein Cy 1 represents a phenyl group, a pyridyl group, a thiazolyl group, an oxazolyl group, a pyrazolyl group, an imidazolyl group, or an N-methylpyrazolyl group.

[0056] In the preferred technical solution of the present invention, wherein Cy 1 Represents the following groups:

[0057] In the preferred technical solution of the present invention, wherein L 2 represents the absence of -C1-C6 alkylene- or -NH-.

[0058] In the preferred technical solution of the present invention, wherein L 2 Indicates that it does not exist.

[0059] In the preferred technical solution of the present invention, wherein Cy 2 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 contains 0-3 N heteroatoms and 0-2 O or S heteroatoms, and the monocyclic ring or cyclic ring is 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 substituted morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl or tetrahydrofuranyl, wherein 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.

[0060] In the preferred technical solution of the present invention, wherein Cy 2 express

[0061] Specifically, the present invention provides a compound having the following structure:

[0062] In addition, the present invention also provides a pharmaceutical composition containing any one of the compounds in the technical solution of the present invention or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate, and a pharmaceutically acceptable carrier thereof.

[0063] In addition, the present invention also provides a method for treating tumors by inhibiting KIF18A, comprising administering to an individual in need thereof any one of the compounds of the present invention or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof.

[0064] definition

[0065] Unless otherwise indicated, the compounds of the present invention may be interpreted to include, in addition to the specific structures of the compounds, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotope isomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, and metabolites. In other words, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotope isomers, solvates, hydrates, prodrugs, and metabolites also fall within the scope of protection of the compounds.

[0066] Unless otherwise indicated, the following terms used in this patent specification and claims have the meanings discussed below. Furthermore, many of the groups defined herein may be optionally substituted. The list of typical substituents in this definitions section is provided as an example and is not intended to limit the substituents defined elsewhere in this patent specification and claims.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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-.

[0071] 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:

[0072] "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 bAs 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:

[0073] "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-"; the present invention also includes fused ring and spiro compounds containing, for example, the above-mentioned heterocycles.

[0074] The pharmaceutically acceptable heteroaryl group is sufficiently stable to be attached to the compound of the present invention, formulated into a pharmaceutical composition, and subsequently administered to a patient in need thereof.

[0075] Unless otherwise defined, the definitions of the substituents of the present invention are independent of each other and not related to each other. For example, for a substituent R a (or R b ), they are independent of each other in the definitions of different substituents. Specifically, for R a (or R b ) When a definition is selected in a substituent, it does not mean that the R a (or R b ) has the same definition in other substituents. More specifically, for example (listing only non-exhaustive) for NR a R b In the case of R a (or R b ) is selected from hydrogen, it does not mean that in -C(O)-NR a R b Medium R a (or R b ) must be hydrogen.

[0076] "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.

[0077] "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-.

[0078] 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.

[0079] 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.

[0080] In the context of the present invention, one or more halogens may be independently selected from fluorine, chlorine, bromine and iodine.

[0081] 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).

[0082] Where nitrogen atoms (e.g., amines) are present on the compounds of the invention, 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 invention. Thus, the shown and claimed nitrogen atoms are considered to encompass both the shown nitrogen and its N-oxide to obtain the derivatives of the invention.

[0083] 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.

[0084] The term "patient" as used herein refers to an organism to be treated by the method of the present invention. 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.

[0085] The term "effective amount" as used herein means the amount of a drug or pharmaceutical agent (i.e., a compound of the present invention) 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 doses, 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.

[0086] 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.

[0087] Likewise, "therapeutic agent" also includes agents or reagents that have therapeutic and / or prophylactic effects on a subject.

[0088] 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.

[0089] Specific pharmaceutical and medical terms

[0090] 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).

[0091] 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.

[0092] 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.

[0093] 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.

[0094] The terms "kit" and "product packaging" are synonymous.

[0095] 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.

[0096] 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.

[0097] Route of administration

[0098] 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.

[0099] The administration of the compounds of the present invention 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.

[0100] Pharmaceutical composition and dosage

[0101] 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.

[0102] The term "pharmaceutical composition" means a composition comprising a compound of the present invention 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.

[0103] The pharmaceutical compositions of the present invention may comprise a therapeutically effective amount of one or more compounds of the present invention formulated together with one or more optional pharmaceutically acceptable carriers (additives) and / or diluents, and optionally one or more other therapeutic agents. The compounds of the present invention may be administered in any suitable manner for any of the above-mentioned uses, 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 techniques (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.

[0104] 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.

[0105] 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 are available from a number of readily available sources, such as Allen LV Jr. et al. Remington:

[0106] The Science and Practice of Pharmacy (2Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0107] Of course, the dosage regimen of the compounds of the present invention will vary 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 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 the 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. The most preferred intravenous dose during a constant rate infusion should be from about 0.01 mg / kg / minute to about 10 mg / kg / minute. The compounds of the present invention 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 daily.

[0108] 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.

[0109] 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.

[0110] The present invention includes within its scope pharmaceutical compositions comprising (alone or in combination with a pharmaceutically acceptable carrier) a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).

[0111] Regardless of the route of administration selected, the compound of the present invention (which may be used in a suitable hydrated form) and / or the pharmaceutical composition of the present invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.

[0112] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention 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.

[0113] The selected dosage level will depend upon a variety of factors, including the activity of the specific compound of the present invention being employed, or its ester, salt or amide; the route of administration; the time of administration; the rate of excretion of the specific compound being employed; the rate and extent of absorption; the duration of the treatment; other drugs, compounds and / or substances used in combination with the specific compound being employed; and factors well known in the medical arts such as the age, sex, weight, condition, general health and prior medical history of the patient being treated.

[0114] 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 compound of the present invention 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 compound of the present invention 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 factors. Typically, oral, intravenous, intracerebroventricular and subcutaneous doses of the compound of the present invention for patients range from about 0.01 to about 50 mg / kg body weight / day. If necessary, the active compound of the effective daily dose can be administered separately at appropriate intervals in two, three, four, five, six or more subdoses in the middle of the day, optionally in unit dosage form. In certain aspects of the present invention, medication is administered once a day.

[0115] While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0116] Kit / Product Packaging

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features.

[0123] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0124] The units used in the present invention 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 can be applied to the present invention. The preferred embodiments and materials described herein are for illustrative purposes only. DETAILED DESCRIPTION

[0125] The present invention is further illustrated by way of examples below, but the present invention 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.

[0126] NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the measurements are indicated in the spectral analysis.

[0127] 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.

[0128] HPLC analysis was performed using a SHIMADZU 20A high performance liquid chromatograph.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] Flash column chromatography separation was performed using a Biotage IsoleraOne flash preparative chromatograph.

[0133] 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.

[0134] Pressurized hydrogenation reaction hydride bottles and hydrogen cylinders.

[0135] Microwave reactions were performed using a Biotage Initiator+ microwave synthesizer.

[0136] The glove box is customized by DELLIX.

[0137] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. The compounds of the present invention 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 their combination with other chemical synthesis methods, and equivalent replacement modes well known to those skilled in the art. Preferred embodiments include, but are not limited to, embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments without departing from the spirit and scope of the present invention.

[0138] Example 1: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-[(1Z)-2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-2-fluorovinyl]phenyl)-2-hydroxyethane-1-sulfonamide

[0139] Step 1: To a solution of 2-fluoro-4-nitrobenzaldehyde (4.50 g, 26.6 mmol) in dimethyl sulfoxide (50 mL) were added 6-azaspiro[2.5]octane hydrochloride (4.32 g, 29.3 mmol) and potassium carbonate (11.3 g, 79.8 mmol). The mixture was stirred at 100°C for 6 hours. The reaction mixture was cooled to room temperature and extracted with water (150 mL) and ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (150 mL x 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-9% ethyl acetate / petroleum ether gradient) to afford 2-{6-azaspiro[2.5]octan-6-yl}-4-nitrobenzaldehyde (4.60 g, 17.7 mmol, 66% yield) as an orange solid. LCMS (ESI): [M+H]+=261.2; 1 H NMR (400MHz, DMSO-d6) δppm 10.19 (s, 1H), 7.90 (d, J = 2.0Hz, 1H), 7.88-7.82 (m, 2H), 3.23-3.15 (m, 4H), 1.61-1.51 (m, 4H), 0.37 (s, 4H)

[0140] Step 2: Add 2-{6-azaspiro[2.5]octan-6-yl}-4-nitrobenzaldehyde (4.60 g, 17.7 mmol) and tribromofluoromethane (12.8 g, 47.3 mmol) to tetrahydrofuran (50 mL), and slowly add hexamethyltriamidophosphine (8.74 g, 53.0 mmol) dropwise. The mixture is stirred at 20°C for 4 hours. The reaction mixture is poured into water (150 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases are combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate is spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-6% gradient of ethyl acetate / petroleum ether) to afford 6-[2-(2-bromo-2-fluorovinyl)-5-nitrophenyl]-6-azaspiro[2.5]octane (4.50 g, 12.7 mmol, 72% yield) as an orange solid. LCMS (ESI): [M+H]+ = 355.0; 1 H NMR (400MHz, DMSO-d6) δppm 7.97-7.87(m,1H),7.81(dd,J=2.4,8.4Hz,1H),7.76(dd,J=4.0,8.4Hz,1H),6.51-6.32(m,1H),2.98(br d,J=4.4Hz,4H),1.52(br d,J=3.6Hz,4H),0.36(s,4H)

[0141] Step 3: To a solution of 6-[2-(2-bromo-2-fluorovinyl)-5-nitrophenyl]-6-azaspiro[2.5]octane (4.50 g, 12.7 mmol) in dioxane (50 mL) were added bis-naphthalene borate (4.83 g, 19.0 mmol), potassium acetate (3.77 g, 38.0 mmol) and [1,1-bis(diphenylphosphino)ferrocene] palladium dichloride (0.96 g, 1.27 mmol). The mixture was purged with nitrogen three times and heated to 90 ° C under a nitrogen atmosphere and stirred for 16 hours. The reaction solution was cooled to room temperature and extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to afford 6-{2-[2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]-5-nitrophenyl}-6-azaspiro[2.5]octane (2.10 g, 5.22 mmol, 39% yield) as an orange solid. LCMS (ESI): [M+H]+ = 320.9; 1 H NMR (400MHz, DMSO-d6) δppm 7.94-7.87(m,2H),7.82(d,J=2.0Hz,1H),6.75-6.57(m,1H),2.99(br t,J=5.2Hz,4H),1.51(br s,4H),1.28(s,12H),0.37(s,4H)

[0142] Step 4: 6-Bromo-8-(4,4-difluoropiperidin-1-yl)quinoline (1.14 g, 3.48 mmol) and 6-{2-[2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]-5-nitrophenyl}-6-azaspiro[2.5]octane (2.10 g, 5.22 mmol) were added to dioxane (40 mL) / water (8 mL), followed by potassium carbonate (0.98 g, 6.96 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (0.26 g, 0.35 mmol). The mixture was purged with nitrogen three times and heated to 80° C. under a nitrogen atmosphere and stirred for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with dioxane (50 mL) / water (10 mL) to obtain 6-[2-(2-{6-azaspiro[2.5]octan-6-yl}-4-nitrophenyl)-1-fluorovinyl]-8-(4,4-difluoropiperidin-1-yl)quinoline (1.10 g, 2.10 mmol, 60% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 523.1; 1H NMR (400MHz, CDCl3) δppm 8.94 (br d, J=3.2Hz, 1H), 8.21 (br d, J=8.0Hz, 1H), 8.08 (br d,J=9.2Hz,1H),8.01-7.91(m,2H),7.81(s,1H),7.50-7.40(m,2H),7.01-6.85(m,1H), 3.63-3.55(m,4H),3.17-3.06(m,4H),2.42-2.31(m,4H),1.71-1.61(m,4H),0.43(s,4H)

[0143] Step 5: To a solution of 6-[2-(2-{6-azaspiro[2.5]octan-6-yl}-4-nitrophenyl)-1-fluorovinyl]-8-(4,4-difluoropiperidin-1-yl)quinoline (1.10 g, 2.10 mmol) in methanol (18 mL) / saturated aqueous ammonium chloride (6 mL) was added iron powder (1.19 g, 21.0 mmol). The mixture was stirred at 60°C for 16 hours. The reaction solution was filtered while hot, extracted with water (50 mL) and ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a green solid 3-{6-azaspiro[2.5]octane-6-yl}-4-{2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-2-fluorovinyl}aniline (0.25 g, crude product). LCMS (ESI): [M+H]+ = 493.3

[0144] Step 6: To a solution of 3-{6-azaspiro[2.5]octan-6-yl}-4-{2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-2-fluorovinyl}aniline (250 mg, 0.51 mmol) and N,N-diisopropylethylamine (134 mg, 1.02 mmol) in dichloromethane (5 mL) was slowly added dropwise ethyl 2-(chlorosulfonyl)acetate (114 mg, 0.61 mmol). The mixture was stirred at 20°C for 2 hours. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-33% gradient of ethyl acetate / petroleum ether) to afford ethyl 2-[(3-{6-azaspiro[2.5]octan-6-yl}-4-{2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-2-fluorovinyl}phenyl)sulfamoyl]acetate (150 mg, 0.24 mmol, 46% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 643.2

[0145] Step 7: Ethyl 2-[(3-{6-azaspiro[2.5]octan-6-yl}-4-{2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-2-fluorovinyl}phenyl)sulfamoyl]acetate (150 mg, 0.24 mmol) was added to a tetrahydrofuran (3 mL) solution. Lithium aluminum tetrahydride (12.8 mg, 0.36 mmol) was added portionwise at 0°C, and the mixture was stirred at 0°C for 1 hour. The reaction solution was quenched with water (0.02 mL) and 10% aqueous sodium hydroxide solution (0.04 mL), filtered, and the filtrate was dried to obtain a residue. The residue was purified by preparative HPLC (C18, 48-88% gradient of water (formic acid) / acetonitrile) to give N-(3-{6-azaspiro[2.5]octan-6-yl}-4-[(1Z)-2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-2-fluorovinyl]phenyl)-2-hydroxyethane-1-sulfonamide (11.4 mg, 0.02 mmol, 8% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 601.6; 1 H NMR (400MHz, DMSO-d6) δppm 9.79 (s, 1H), 8.88 (br s, 1H), 8.42 (br d, J=8.0Hz, 1H), 7.92-7.69 (m, 2H), 7.57 (br dd, J=4.0, 8.0Hz, 1H), 7.35 (br s,1H),7.01(br s,1H),6.98-6.78(m,2H),4.98(s,1H),3.75(br t,J=6.4Hz,2H),3.60-3.50(m,4H),3.28(br s,2H),3.02 -2.84(m,4H),2.31-2.15(m,4H),1.70-1.44(m,4H),0.36(s,4H)

[0146] Example 2: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-[(1Z)-2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-1-fluorovinyl]phenyl)-2-hydroxyethane-1-sulfonamide

[0147] Example 3: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-[(1E)-2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-1-fluorovinyl]phenyl)-2-hydroxyethane-1-sulfonamide

[0148] Step 1: To a solution of 6-bromo-8-fluoroquinoline (5.00 g, 22.1 mmol) in N-methylpyrrolidone (50 mL) were added 4,4-difluoropiperidine hydrochloride (5.23 g, 33.2 mmol) and potassium carbonate (9.17 g, 66.4 mmol). The mixture was stirred at 180°C for 48 hours. The reaction solution was cooled to room temperature and extracted with water (100 mL) and ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to obtain the product 6-bromo-8-(4,4-difluoropiperidin-1-yl)quinoline (6.80 g, 20.8 mmol, 94% yield) as a colorless oil. LCMS (ESI): [M+H]+ = 326.9

[0149] Step 2: To a solution of 6-bromo-8-(4,4-difluoropiperidin-1-yl)quinoline (5.00 g, 15.3 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (9.17 mL, 22.9 mmol) dropwise at -40°C, maintaining the temperature below -40°C. After completion of the addition, the mixture was stirred at -40°C for half an hour. N,N-Dimethylformamide (10.00 mL) was added dropwise to the reaction mixture at the same temperature, and stirring was continued at the same temperature for 2 hours. Water (200 mL) and ethyl acetate (300 mL x 3) were added to the reaction mixture for extraction. The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-8% gradient of tetrahydrofuran / petroleum ether) to give 8-(4,4-difluoropiperidin-1-yl)quinoline-6-carbaldehyde (1.60 g, 5.81 mmol, 38% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 277.0; 1 H NMR(400MHz,DMSO-d6)δppm 10.12(s,1H),9.04(dd,J=2.0,4.4Hz,1H),8.57(dd,J=2.0,8.4Hz,1H),8.24 (d,J=1.2Hz,1H),7.67(dd,J=4.0,8.0Hz,1H),7.52(d,J=1.2Hz,1H),3.53(br t,J=5.2Hz,4H),2.28-2.13(m,4H)

[0150] Step 3: At 0°C, 8-(4,4-difluoropiperidin-1-yl)quinoline-6-carbaldehyde (5.00 g, 18.1 mmol) and tribromofluoromethane (14.7 g, 54.2 mmol) were added to tetrahydrofuran (100 mL). Triphenylphosphine (14.2 g, 54.2 mmol) was slowly added, followed by dropwise addition of a solution of diethylzinc (54.2 mL, 54.2 mmol). The mixture was stirred at 0-25°C for 2 hours. The reaction solution was poured into water (150 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to give 6-[(1E)-2-bromo-2-fluorovinyl]-8-(4,4-difluoropiperidin-1-yl)quinoline (3.60 g, 9.77 mmol, 54% yield) as an orange solid. LCMS (ESI): [M+H]+ = 372.8

[0151] Step 4: To a solution of 6-[(1E)-2-bromo-2-fluorovinyl]-8-(4,4-difluoropiperidin-1-yl)quinoline (3.60 g, 9.70 mmol) in dioxane (50 mL) were added bis-naphthalene borate (3.69 g, 14.5 mmol), potassium acetate (2.88 g, 29.1 mmol) and [1,1-bis(diphenylphosphino)ferrocene] palladium dichloride (0.73 g, 0.97 mmol). The mixture was purged with nitrogen three times and heated to 80°C under a nitrogen atmosphere and stirred for 12 hours. The reaction solution was cooled to room temperature and extracted with water (150 mL) and ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to give [(1Z)-2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-1-fluorovinyl]boronic acid (1.90 g, 5.63 mmol, 58% yield) as an orange solid. LCMS (ESI): [M+H]+ = 337.1

[0152] Step 5: 2-Fluoro-1-iodo-4-nitrobenzene (2.14 g, 8.03 mmol) and [(1Z)-2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-1-fluorovinyl]boronic acid (1.80 g, 5.36 mmol) were added to dioxane (40 mL) / water (8 mL), followed by potassium carbonate (2.22 g, 16.1 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (0.41 g, 0.54 mmol). The mixture was purged with nitrogen three times and heated to 80°C under a nitrogen atmosphere with stirring for 6 hours. The reaction mixture was cooled to room temperature and extracted with water (150 mL) and ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to afford 6-[2-(2-{6-azaspiro[2.5]octan-6-yl}-4-nitrophenyl)-1-fluorovinyl]-8-(4,4-difluoropiperidin-1-yl)quinoline (0.83 g, 1.93 mmol, 36% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 432.1

[0153] Step 6: To a solution of 6-[2-(2-{6-azaspiro[2.5]octane-6-yl}-4-nitrophenyl)-1-fluorovinyl]-8-(4,4-difluoropiperidin-1-yl)quinoline (400 mg, 0.93 mmol) in dimethyl sulfoxide (8 mL) was added 6-azaspiro[2.5]octane hydrochloride (207 mg, 1.39 mmol) and potassium carbonate (384 mg, 2.78 mmol). The mixture was stirred at 120°C for 12 hours. The reaction solution was cooled to room temperature and extracted with water (20 mL) and ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-8% gradient of tetrahydrofuran / petroleum ether) to give 6-[(1Z)-2-(2-{6-azaspiro[2.5]octan-6-yl}-4-nitrophenyl)-2-fluorovinyl]-8-(4,4-difluoropiperidin-1-yl)quinoline (0.34 g, 0.65 mmol, 70% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 523.1

[0154] Step 7: Iron powder (302 mg, 5.36 mmol) was added to a solution of 6-[(1Z)-2-(2-{6-azaspiro[2.5]octan-6-yl}-4-nitrophenyl)-2-fluorovinyl]-8-(4,4-difluoropiperidin-1-yl)quinoline (280 mg, 0.54 mmol) in acetic acid (6 mL). The mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered while hot and extracted with water (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to afford 3-{6-azaspiro[2.5]octan-6-yl}-4-[(1Z)-2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-1-fluorovinyl]aniline (67.0 mg, 0.14 mmol, 25% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 493.1

[0155] Step 8: To a solution of 3-{6-azaspiro[2.5]octan-6-yl}-4-[(1Z)-2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-1-fluorovinyl]aniline (150 mg, 0.30 mmol) and N,N-diisopropylethylamine (80.3 mg, 0.61 mmol) in tetrahydrofuran (4 mL) was slowly added dropwise ethyl 2-(chlorosulfonyl)acetate (68.2 mg, 0.37 mmol). The mixture was stirred at 20°C for 2 hours. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give ethyl 2-{[(4-{(1Z)-2-[8-(4,4-difluoropiperidinyl)(6-quinolinyl)]-1-fluorovinyl}-3-(6-azaspiro[2.5]octan-6-yl)phenyl)amino]sulfonyl}acetate (120 mg, 0.18 mmol, 61% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 643.1

[0156] Step 9: Ethyl 2-{[(4-{(1Z)-2-[8-(4,4-difluoropiperidinyl)(6-quinolyl)]-1-fluorovinyl}-3-(6-azaspiro[2.5]octan-6-yl)phenyl)amino]sulfonyl}acetate (100 mg, 0.16 mmol) was added to a tetrahydrofuran (3 mL) solution. Lithium aluminum tetrahydride (8.33 mg, 0.23 mmol) was added portionwise at 0°C, and the mixture was stirred at 0°C for 2 hours. The reaction solution was quenched with water (0.02 mL) and 10% aqueous sodium hydroxide solution (0.04 mL), filtered, and the filtrate was dried to obtain a residue. The residue was first purified by preparative HPLC (C18, 46-86% gradient of water (ammonium bicarbonate) / acetonitrile) and lyophilized to give a white mixture, which was separated by chiral SFC (IG, system: carbon dioxide / ethanol (0.1% ammonia)) to further obtain N-(3-{6-azaspiro[2.5]octan-6-yl}-4-[(1Z)-2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-1-fluorovinyl]benzene The mixture was prepared by mixing N-(3-{6-azaspiro[2.5]octan-6-yl}-4-[(1E)-2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-1-fluorovinyl]phenyl)-2-hydroxyethane-1-sulfonamide (12.0 mg, 0.02 mmol, 13% yield) (Example 2) and N-(3-{6-azaspiro[2.5]octan-6-yl}-4-[(1E)-2-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-1-fluorovinyl]phenyl)-2-hydroxyethane-1-sulfonamide (5.00 mg, 0.008 mmol, 5% yield) (Example 3).

[0157] Example 2: LCMS (ESI): [M+H] + = 601.2; 1 H NMR(400MHz, DMSO-d6)δppm 9.98(s,1H),8.77(dd,J=1.6,4.0Hz,1H),8.13(dd,J=1.6,8.4Hz,1H),7.44(dd,J=4.0,8.4Hz,1H),7.33(br dd,J=0.8,8.8Hz,1H),7.30(br s,1H),6.93-6.86(m,2H),6.71(d,J=1.6Hz,1H),6.67-6.59(m,1H),4.99(br s,1H),3.81-3.75(m,2H),3.32-3.30(m,2H),3.13(br s,4H),2.87(br s,4H),2.13-2.00(m,4H),1.03(br s,4H),0.16(s,4H)

[0158] Example 3: LCMS (ESI): [M+H] + = 601.2; 1H NMR (400MHz, DMSO-d6) δppm 9.98 (s, 1H), 8.85 (br d, J = 3.2Hz, 1H), 8.35 (br d, J = 8.0Hz, 1H), 7.75 (s, 1H), 7.51 (br d,J=8.0Hz,2H),7.44(s,1H),7.09-6.86(m,3H),4.96(br t,J=5.6Hz,1H),3.76(q,J=6.0Hz,2H),3.50(br s,4H),3.31-3.27(m,2H),3.04(br s,4H),2.31-2.15(m,4H),1.52(br s,4H),0.34(s,4H)

[0159] Example 4: N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-1-yl-2-hydroxyethylsulfonamide

[0160] Step 1: To a solution of 2-chloro-6-methylpyrimidine-4-carbonitrile (1.80 g, 11.7 mmol) in 1-methyl-2-pyrrolidone (30 mL) were added 4,4-difluoropiperidine hydrochloride (2.77 g, 17.5 mmol) and potassium carbonate (4.96 g, 35.1 mmol). The mixture was heated to 120°C and stirred for 16 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Flash silica gel chromatography (silica gel, 0-6% ethyl acetate / petroleum ether) afforded 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbonitrile (1.60 g, 11.7 mmol, 57.3% yield) as a white solid. LCMS (ESI): [M+H] + =239.0

[0161] Step 2: To a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbonitrile (1.50 g, 6.30 mmol) in ethanol (20.0 mL) was added hydrazine hydrate (1.97 g, 31.48 mmol). The mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboximidohydrazide (1.60 g, 6.29 mmol, 94.0% yield) as a white solid. LCMS (ESI): [M+H] + =271.1

[0162] Step 3: To a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboximidohydrazide (0.50 g, 1.85 mmol) in tetrahydrofuran (5.00 mL) were added 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (1.04 g, 2.77 mmol) and N,N-diisopropylethylamine (0.73 g, 5.55 mmol). The reaction mixture was heated to 60°C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain N'-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)(aminoylidene)methyl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzohydrazide (1.2 g, 1.84 mmol, crude) as a white solid. LCMS(ESI):[M+H] + =610.1

[0163] Step 4: Add N'-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)(aminoylidene)methyl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzohydrazide (1.10 g, 1.80 mmol) to acetic acid (20.0 mL). Heat the mixture to 100°C and stir for 4 hours. Add water (10 mL) to the reaction solution, and extract with dichloromethane (10 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. Flash silica gel chromatography (silica gel, 0-7% ethyl acetate / petroleum ether) yielded 6-(2-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)-5-iodophenyl)-6-azaspiro[2.5]octane (0.56 g, 1.80 mmol, 54.3% yield) as a white solid. LCMS (ESI): [M+H] + =592.2

[0164] Step 5: To a solution of 6-(2-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)-5-iodophenyl)-6-azaspiro[2.5]octane (1.35 g, 2.28 mmol) in tetrahydrofuran (20.0 mL) were added triethylamine (0.71 g, 6.85 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (0.46 g, 2.74 mmol). The mixture was heated to 55°C and stirred for 4 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Flash silica gel chromatography (silica gel, 0-6% ethyl acetate / petroleum ether) gave 6-(2-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-5-iodophenyl)-6-azaspiro[2.5]octane (0.43 g, 2.28 mmol, 26.1% yield) as a colorless, transparent oil. LCMS (ESI): [M+H] + =722.3

[0165] Step 6: 2-Hydroxyethylsulfonylamide (103 mg, 0.83 mmol) and sarcosine (56.8 mg, 0.63 mmol) were added to a solution of N,N-dimethylformamide (4.00 mL), followed by the addition of cuprous iodide (61.9 mg, 0.32 mmol) and potassium phosphate (552 mg, 2.54 mmol) at 25°C, and the mixture was stirred at 50°C for 5 minutes. Subsequently, 6-(2-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-5-iodophenyl)-6-azaspiro[2.5]octane (460 mg, 0.63 mmol) was added portionwise, and the mixture was stirred at 100°C for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed twice with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to give a yellow oily substance, N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-1-yl-2-hydroxyethanesulfonamide (0.35 g, 0.63 mmol, crude). LCMS (ESI): [M+H] + =719.7

[0166] Step 7: To a mixture of trifluoroacetic acid (2.00 mL) and dichloromethane (2.00 mL) was added N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octane-6-yl)phenyl)-1-yl-2-hydroxyethanesulfonamide (0.35 g, 0.63 mmol), and the mixture was stirred at 25 ° C for 4 hours. Water (20 mL) and ethyl acetate (60 mL x 2) were added to the reaction mixture for extraction. The organic phases were combined, washed twice with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by preparative HPLC (C18, 18-58% gradient of water (formic acid) / acetonitrile) to give N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-1-yl-2-hydroxyethylsulfonamide (92 mg, 0.59 mmol, 26% yield) as a white solid. LCMS (ESI): [M+H] + =589.5. 1H NMR (400MHz, DMSO-d6) δppm 14.19 (s, 1H), 9.99 (s, 1H), 7.72 (br d,J=7.5Hz,1H),7.23(s,1H),7.18-6.78(m,2H),5.54-4.38(m,1H),4.01(br s,4H),3.76(t,J=6.6Hz,2H),3.30(br s,2H),2.99-2.76(m,4H),2.39(s,3H),2.10-1.92(m,4H),1.62-1.32(m,4H),0.40-0.18(m,4H)

[0167] Example 5: (2-(6-azaspiro[2.5]oct-6-yl)-4-{[(2-hydroxyethyl)sulfonyl]amino}phenyl)-N-[5-(4,4-difluoropiperidinyl)(4-hydrogen-1,2,4-triazolo[4,3-e]pyrimidin-7-yl)]formamide

[0168] Step 1: To a solution of 1-(4-bromo-2-fluorophenyl)ethanone (5.00 g, 23.0 mmol) and potassium carbonate (9.55 g, 69.1 mmol) in dimethyl sulfoxide (50 mL) was added 6-azaspiro[2.5]octane hydrochloride (3.40 g, 23.0 mmol). The mixture was stirred at 130°C for 16 hours. The reaction mixture was filtered and poured into water (300 mL). Extraction was performed with ethyl acetate (400 mL x 2). The combined organic phases were washed with saturated brine (250 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-15% ethyl acetate / petroleum ether gradient) to afford 1-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)ethanone (6.60 g, 21.4 mmol, 93% yield) as a yellow oil. LCMS (ESI): [M+H]+=309.9.

[0169] Step 2: To a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (5.00 g, 26.8 mmol) and triethylamine (8.13 g, 80.4 mmol) in dimethyl sulfoxide (50 mL) was added 4,4-difluoropiperidine hydrochloride (4.22 g, 26.8 mmol). The mixture was stirred at 130°C for 16 hours. The reaction mixture was poured into 300 mL of water. Extraction was performed with ethyl acetate (400 mL x 2). The combined organic phases were washed with saturated brine (250 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to afford methyl 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (2.70 g, 9.92 mmol, 37% yield) as a white solid. LCMS(ESI):[M+H] + =272.0

[0170] Step 3: Under nitrogen, sodium bicarbonate (0.39 g, 9.73 mmol, 60% purity) was added to a solution of 1-acetyl-2-(6-azaspiro[2.5]octan-6-yl)-4-bromobenzene (2.00 g, 6.49 mmol) in tetrahydrofuran (40 mL). The mixture was stirred at 25°C for 15 minutes. Methyl 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (1.76 g, 6.49 mmol) was then added, and the reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered and poured into water (80 mL). The mixture was extracted with methyl tert-butyl ether (100 mL x 3). The organic phases were separated and combined, washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to afford 1-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-3-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)propane-1,3-dione (2.40 g, 4.41 mmol, 68% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 548.8.

[0171] Step 4: To a solution of 1-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-3-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)propane-1,3-dione (1.00 g, 1.83 mmol) in ethanol (20 mL) was added hydroxylamine hydrochloride (0.25 g, 3.65 mmol) at 25°C. The reaction mixture was stirred at 100°C for 12 hours. The reaction solution was slowly added dropwise to water (50 mL). A precipitate was formed and the filter cake was collected by filtration using a sand core funnel and dried using an oil pump to obtain a crude product. The crude product was purified by chiral separation to afford 5-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-3-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)isothiazole (0.46 g, 0.84 mmol, 46% yield) as a white solid. LCMS (ESI): [M+H]+ = 545.8.

[0172] Step 5: To a solution of 2-hydroxyethanesulfonamide (55.2 mg, 0.44 mmol) and 2-(methylamino)acetic acid (32.7 mg, 0.37 mmol) in N,N-dimethylformamide (4 mL) at 25°C were added cuprous iodide (35.0 mg, 0.18 mmol) and potassium phosphate (312 mg, 1.47 mmol). The reaction mixture was heated to 50°C under nitrogen and stirred for 5 minutes. Then, 5-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-3-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)isothiazole (200 mg, 0.37 mmol) was added at 50°C and the nitrogen atmosphere was replaced. Finally, the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was diluted with N,N-dimethylformamide (10 mL). The dilution solution was purified by preparative HPLC (C18, 48-88% gradient of water (formic acid) / acetonitrile) to give a white solid compound N-(4-(3-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)isothiazol-5-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide (120 mg, 0.20 mmol, yield 55%). LCMS (ESI): [M+H] + =589.5. 1 H NMR (400MHz, DMSO-d6) δppm 10.11(s,1H),7.82(d,J=8.5Hz,1H),7.69(s,1H),7.16-7.15(m,2H),7.04(dd,J=1.9,8.5Hz,1H),4.94(br s,1H),4.08-3.91(m,4H),3.76(br t,J=6.4Hz,2H),3.16-3.05(m,2H),2.95-2.81(m,4H),2.42(s,3H),2.14-1.93(m,4H),1.69-1.44(m,4H),0.36(s,4H)

[0173] Example 6: N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-pyrazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0174] Step 1: To a solution of 1-(4-bromo-2-(6-azaspiro[2.5]octane-6-yl)phenyl)-3-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)propane-1,3-dione (500 mg, 0.91 mmol) in ethanol (10 mL) were added hydrazine monohydrochloride (93.9 mg, 1.37 mmol) and potassium carbonate (190 mg, 2.74 mmol) at 25 ° C. The reaction mixture was stirred at 100 ° C for 12 hours. The reaction solution was slowly added dropwise to water (50 mL). A precipitate was precipitated and filtered through a sand core funnel to collect the filter cake. The filter cake was washed with water (50 mL) and dried over an oil pump to obtain a bright yellow solid compound, 6-(5-bromo-2-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-pyrazol-3-yl)phenyl)-6-azaspiro[2.5]octane (410 mg, 0.76 mmol, 83% yield). LCMS (ESI): [M+H] + =542.9

[0175] Step 2: To a solution of 6-(5-bromo-2-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-pyrazol-3-yl)phenyl)-6-azaspiro[2.5]octane (250 mg, 0.46 mmol) in dioxane (5 mL) at 25°C were added 2-hydroxyethanesulfonamide (57.6 mg, 0.46 mmol), potassium phosphate (391 mg, 1.84 mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (39.1 mg, 0.09 mmol), and tris(dibenzylideneacetone)dipalladium (42.1 mg, 0.05 mmol). The reaction mixture was heated to 100°C under nitrogen and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was diluted with N,N-dimethylformamide (10 mL). The dilution solution was purified by preparative HPLC (C18, 24-64% gradient of water (formic acid) / acetonitrile) to give a white solid compound N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-pyrazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide (133 mg, 0.23 mmol, yield 49%). LCMS (ESI): [M+H] + =588.3. 1H-NMR (400MHz, DMSO-d6) δppm 14.52-12.29(m,1H),9.84(br s,1H),7.59(br d,J=8.0Hz,1H),7.50(br s,1H),7.12-7.03(m,2H),6.95(t,J=1.0Hz,1H),4.08-3.92(m,4H),3.76(t,J=6.7Hz,2H),3.35-3.30(m,1H ),3.29(t,J=6.6Hz,2H),2.98-2.74(m,4H),2.37(s,3H),2.09-1.94(m,4H),1.66-1.34(m,4H),0.32(s,4H)

[0176] Example 7: N-(4-(3-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0177] Step 1: To a solution of 2-chloro-6-methylpyrimidine-4-carbonitrile (5.00 g, 32.5 mmol) in dimethyl sulfoxide (50.0 mL) was added 4,4-difluoropiperidine hydrochloride (7.70 g, 48.8 mmol) and potassium carbonate (13.8 g, 97.6 mmol). The mixture was heated to 120°C and stirred for 16 hours. Water (50 mL) was added to the reaction solution, 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 dried to dryness to obtain a residue. The residue was purified by flash silica gel chromatography (silica gel, 0-6% gradient of ethyl acetate / petroleum ether) to obtain 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbonitrile (4.50 g, 25.5 mmol, 58% yield) as a white solid. LCMS (ESI): [M+H] + =239.0

[0178] Step 2: Triethylamine (1.30 g, 12.6 mmol) was added to a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbonitrile (1.00 g, 4.20 mmol) and hydroxylamine hydrochloride (0.58 g, 8.39 mmol) in ethanol (20.0 mL). The mixture was heated to 80°C and stirred for 16 hours. Water (20 mL) was added to the reaction solution to precipitate a white solid. The residue was collected by filtration to obtain (Z)-2-(4,4-difluoropiperidin-1-yl)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide (1.10 g, 4.19 mmol, 97% yield) as a white solid. LCMS (ESI): [M+H] +=272.0

[0179] Step 3: To a solution of (Z)-2-(4,4-difluoropiperidin-1-yl)-N'-hydroxy-6-methylpyrimidine-4-carboximidamide (500 mg, 1.84 mmol) and 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (900 mg, 2.40 mmol) in tetrahydrofuran (4.00 mL) was added N,N-diisopropylethylamine (729 mg, 5.53 mmol). The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (5 mL x 3). The organic layer was washed with saturated brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to give a brown solid (Z)-N-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)(oximino)methyl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.30 g, 1.80 mmol, yield 79%). LCMS (ESI): [M+H] + =611.1

[0180] Step 4: A mixed solution of (Z)-N-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)(oxime)methyl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.10 g, 1.80 mmol) in toluene (10.00 mL) was heated to 120°C and stirred for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 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, 0-3% gradient of ethyl acetate / petroleum ether) to afford 3-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,2,4-oxadiazole (420 mg, 1.80 mmol, 39% yield) as a yellow solid. LCMS (ESI): [M+H] + =593.1

[0181] Step 5: To a solution of potassium phosphate (512 mg, 2.36 mmol), 2-hydroxyethanesulfonamide (148 mg, 1.18 mmol), and sarcosine (53.7 mg, 0.59 mmol) in dimethylformamide (5.00 mL) was added cuprous iodide (115 mg, 0.59 mmol). The mixture was heated to 50°C and stirred for 5 minutes. 3-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,2,4-oxadiazole (900 mg, 1.30 mmol) was added to the mixture, which was then heated to 100°C and stirred under nitrogen for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). 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, 50-90% gradient of water (formic acid) / acetonitrile) to give N-(4-(3-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,2,4-oxadiazol-5-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide (227 mg, 0.59 mmol, 65% yield) as a white solid compound. LCMS (ESI): [M+H] + =590.5. 1 H NMR (400MHz, DMSO-d6) δppm 10.27(s,1H),8.00(d,J=8.4Hz,1H),7.26(s,1H),7.10(d,J=2.0Hz,1H),6.99(dd,J=2.0,8.8Hz,1H),4.95(br s,1H),4.00(br t,J=5.6Hz,4H),3.78(br t,J=6.0Hz,2H),3.39(br t,J=6.4Hz,2H),2.98(br t,J=4.8Hz,4H),2.45(s,3H),2.13-1.98(m,4H),1.55(m,4H),0.35(s,4H)

[0182] Example 8: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{5-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2H-1,2,3,4-tetrazol-2-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0183] Step 1: To a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (5.00 g, 26.8 mmol) and N,N-diisopropylethylamine (10.6 g, 80.4 mmol) in tert-butanol (100 mL) was added 4,4-difluoropiperidine hydrochloride (4.22 g, 26.8 mmol). The mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was washed with saturated brine (100 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, 0-15% ethyl acetate / petroleum ether gradient) to afford methyl 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (5.60 g, 20.6 mmol, 77.0% yield) as a yellow solid. LCMS(ESI):[M+H] + =271.9.

[0184] Step 2: Sodium borohydride (2.51 g, 66.3 mmol) was added to a solution of methyl 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (6.00 g, 22.1 mmol) in methanol (100 mL), and the mixture was stirred at 25°C for 16 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was washed with saturated brine (100 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain crude [2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]methanol (5.00 g, 20.5 mmol, yield 92.9%). LCMS (ESI): [M+H] + =244.1.

[0185] Step 3: Pyridine sulfur trioxide (9.81 g, 61.6 mmol) was added to a solution of [2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]methanol (5.00 g, 20.5 mmol) and triethylamine (10.4 g, 102 mmol) in dimethyl sulfoxide (100 mL), and the mixture was stirred at 25°C for 16 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was washed with saturated brine (100 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain crude 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbaldehyde (3.00 g, 12.4 mmol, yield 60.5%). LCMS (ESI): [M+H] + =242.0.

[0186] Step 4: To a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbaldehyde (1.00 g, 4.14 mmol) in methanol (20 mL) was added 4-methylbenzene-1-sulfonylhydrazide (0.77 g, 4.14 mmol), and the mixture was stirred at 25°C for 2 hours. The reaction solution was filtered, and the solid was dried to give N'-[(Z)-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]methylidene]-4-methylbenzene-1-sulfonylhydrazide (0.68 g, 1.66 mmol, 40.0% yield). LCMS (ESI): [M+H] + =410.2.

[0187] Step 5: To a solution of 2-{6-azaspiro[2.5]octan-6-yl}-4-bromoaniline (453 mg, 1.61 mmol) in acetonitrile (6 mL) was added tert-butyl nitrite (308 mg, 2.93 mmol). The mixture was stirred at 25°C for 1 hour. A solution of N'-[(Z)-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]methylidene]-4-methylbenzene-1-sulfonylhydrazine (0.22 g, 0.44 mmol) in pyridine (6 mL) was then added to the reaction solution. The mixture was stirred at 25°C for 16 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was washed with saturated brine (100 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated by column chromatography (silica gel, 0-5% gradient of ethyl acetate / petroleum ether) to give 6-(5-bromo-2-{5-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2H-1,2,3,4-tetrazol-2-yl}phenyl)-6-azaspiro[2.5]octane (390 mg, 0.72 mmol, 49.0% yield) as a yellow solid. LCMS (ESI): [M+H] + =545.1

[0188] Step 6: Dissolve 6-(5-bromo-2-{5-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2H-1,2,3,4-tetrazol-2-yl}phenyl)-6-azaspiro[2.5]octane (365 mg, 0.67 mmol) and 2-hydroxyethanesulfonamide (108 mg, 0.87 mmol) in dioxane (8.00 mL), and add potassium phosphate (426 mg, 2.00 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (56.8 mg, 0.13 mmol), and tris(dibenzylideneacetone)dipalladium (61.3 mg, 0.06 mmol). Heat the mixture to 100° C. and stir under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature, extracted with water (20 mL) and ethyl acetate (20 mL x 2), the organic phases were combined, washed with aqueous ammonia (20 mL x 2), dried over anhydrous magnesium 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 obtain a yellow solid N-(3-{6-azaspiro[2.5]octane-6-yl}-4-{5-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2H-1,2,3,4-tetrazol-2-yl}phenyl)-2-hydroxyethane-1-sulfonamide (220 mg, 0.37 mmol, yield 55.7%). LCMS (ESI): [M+H] + =590.3, 1 H NMR (400MHz, DMSO-d6) δ9.96 (s, 1H), 7.35 (d, J = 8.4Hz, 1H), 7.12 (s, 1H), 6.93 (d, J = 2.4Hz, 1H), 6.79 (dd, J = 2.0, 8.4 Hz,1H),5.32-4.63(m,1H),3.76(br t,J=5.6Hz,4H),3.55(t,J=6.4Hz,2H),3.18-3.15(m,2H),2.55-2.49(m,4H),2.22(s,3H),1.88-1.74(m,4H),1.00-0.93(m,4H),0.00(s,4H)

[0189] Example 9: N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2H-tetrazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0190] Example 9 was prepared by a similar synthetic route according to Example 8: LCMS (ESI): [M+H] +=589.3. 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),7.95(d,J=8.4Hz,1H),7.38(s,1H),7.33(s,1H),7.14(d,J=2.0 Hz,1H),7.02(dd,J=2.0,8.4Hz,1H),5.51-4.53(m,1H),3.85-3.72(m,6H),3.36-3.33(m,2H),2.93(br t,J=4.8Hz,4H),2.48(br s,3H),2.11-2.00(m,4H),1.55-1.38(m,4H),0.32(s,4H)

[0191] Example 10: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-imidazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0192] Step 1: To a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (5.00 g, 26.8 mmol) in tert-butanol (50 mL) were added 4,4-difluoropiperidine hydrochloride (4.64 g, 29.5 mmol) and N,N-diisopropylethylamine (10.6 g, 80.4 mmol). The mixture was stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature and extracted with water (100 mL) and ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to give methyl 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (6.20 g, 22.9 mmol, yield 85%) as a yellow solid. LCMS (ESI): [M+H]+ = 272.0

[0193] Step 2: Methyl 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (6.20 g, 22.9 mmol) was added to methanol (90 mL) / water (15 mL), and sodium borohydride (2.56 g, 66.21 mmol) was added in portions at 0°C. The mixture was stirred at 20°C for 16 hours. The reaction solution was slowly poured into water (150 mL) to quench the mixture, and then extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to give a yellow oil [2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]methanol (5.10 g, 21.0 mmol, yield 92%). LCMS (ESI): [M+H]+ = 244.0

[0194] Step 3: To a solution of [2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]methanol (5.10 g, 21.0 mmol) in dimethyl sulfoxide (100 mL) was added triethylamine (10.4 g, 103 mmol) dropwise, and then pyridine trisulfur oxide complex (10.0 g, 62.9 mmol) was slowly added in batches. The mixture was stirred at 20 ° C for 5 hours. The reaction solution was extracted with water (100 mL) and ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to give a brown oily substance 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxaldehyde (5.00 g, crude product). LCMS (ESI): [M+H] + = 242.1

[0195] Step 4: To a solution of N-[(E)-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]methylidene]-2-methylpropane-2-sulfenamide (5.00 g, 20.7 mmol) in dichloromethane (60 mL) was added 2-methyl-2-propanesulfenamide (2.64 g, 21.8 mmol) and cesium carbonate (8.27 g, 24.9 mmol). The mixture was stirred at 20°C for 16 hours. The reaction mixture was extracted with water (100 mL) and ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to give an orange solid N-[(E)-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]methylidene]-2-methylpropane-2-sulfenamide (6.20 g, 18.0 mmol, yield 87%). LCMS (ESI): [M+H]+ = 345.0

[0196] Step 5: To a solution of N-[(E)-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]methylidene]-2-methylpropane-2-sulfinamide (6.20 g, 18.0 mmol) in methanol (70 mL) were added potassium carbonate (6.35 g, 45.0 mmol) and p-toluenesulfonylmethyl isocyanide (3.87 g, 19.8 mmol). The mixture was stirred at 20°C for 2 hours. The reaction solution was cooled to room temperature and extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-6% gradient of methanol / dichloromethane) to afford 2-(4,4-difluoropiperidin-1-yl)-4-(1H-imidazol-4-yl)-6-methylpyrimidine (4.20 g, 15.12 mmol, 84% yield) as an off-white solid. LCMS (ESI): [M+H]+ = 280.0

[0197] Step 6: To a solution of 2-(4,4-difluoropiperidin-1-yl)-4-(1H-imidazol-4-yl)-6-methylpyrimidine (1.00 g, 3.58 mmol) in dimethyl sulfoxide (20 mL) was added 1,2-difluoro-4-nitrobenzene (0.57 g, 3.58 mmol) and potassium carbonate (1.51 g, 10.7 mmol). The mixture was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature and extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-33% gradient of ethyl acetate / petroleum ether) to give 2-(4,4-difluoropiperidin-1-yl)-4-[1-(2-fluoro-4-nitrophenyl)-1H-imidazol-4-yl]-6-methylpyrimidine (1.20 g, 2.87 mmol, 87% yield) as a pale yellow solid. LCMS (ESI): [M+H]+ = 419.1

[0198] Step 7: 6-azaspiro[2.5]octane hydrochloride (0.47 g, 3.16 mmol) and potassium carbonate (1.21 g, 8.60 mmol) were added to a solution of 2-(4,4-difluoropiperidin-1-yl)-4-[1-(2-fluoro-4-nitrophenyl)-1H-imidazol-4-yl]-6-methylpyrimidine (1.20 g, 2.87 mmol) in dimethyl sulfoxide (20 mL). The mixture was stirred at 120°C for 16 hours. The reaction mixture was extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to afford 6-(2-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-imidazol-1-yl}-5-nitrophenyl)-6-azaspiro[2.5]octane (0.60 g, 1.18 mmol, 41% yield) as a white solid. LCMS (ESI): [M+H]+ = 510.3

[0199] Step 8: To a solution of 6-(2-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-imidazol-1-yl}-5-nitrophenyl)-6-azaspiro[2.5]octane (500 mg, 0.98 mmol) in methanol (9 mL) / saturated aqueous ammonium chloride solution (3 mL) was added iron powder (332 mg, 5.89 mmol) in portions. The mixture was stirred at 60 ° C for 16 hours. The reaction solution was filtered while hot and extracted with water (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to give 3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-imidazol-1-yl}aniline (380 mg, 0.75 mmol, 81% yield). LCMS (ESI): [M+H]+=480.2

[0200] Step 9: To a solution of 3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-imidazol-1-yl}aniline (350 mg, 0.73 mmol) and N,N-diisopropylethylamine (193 mg, 1.46 mmol) in dichloromethane (7 mL) was slowly added dropwise methyl chlorosulfonylacetate (294 mg, 1.58 mmol). The mixture was stirred at 20°C for 2 hours. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to afford methyl 2-[(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-imidazol-1-yl}phenyl)sulfamoyl]acetate (210 mg, 0.34 mmol, 47% yield) as a white solid. LCMS (ESI): [M+H]+ = 616.2

[0201] Step 10: Methyl 2-[(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-imidazol-1-yl}phenyl)sulfamoyl]acetate (200 mg, 0.32 mmol) was added to a tetrahydrofuran (4 mL) solution. Lithium aluminum tetrahydride (34.8 mg, 0.97 mmol) was added portionwise at 0°C, and the mixture was stirred at 0°C for 1 hour. The reaction solution was quenched with water (0.03 mL) and 10% aqueous sodium hydroxide solution (0.06 mL), filtered, and the filtrate was dried to obtain a residue. The residue was purified by preparative HPLC (C18, 32-72% gradient of water (formic acid) / acetonitrile) to give a white solid compound N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-imidazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide (35.0 mg, 0.06 mmol, yield 18%). LCMS (ESI): [M+H] + = 588.6, 1H NMR(400MHz,DMSO-d6)δppm 9.88(s,1H),8.30(d,J=1.2Hz,1H),8.09(d,J=1.2Hz,1H),7.39(d,J=8.4Hz ,1H),7.10-7.03(m,2H),6.96(dd,J=2.4,8.4Hz,1H),4.97(s,1H),3.95(br t,J=5.2Hz,4H),3.76(t,J=6.8Hz,2H),3.27(br s,2H),2.71-2.64(m,4H),2.34(s,3H),2.06-1.91(m,4H),1.32(br s,4H),0.25(s,4H)

[0202] Example 11: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl]-1H-imidazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0203] LCMS (ESI): [M+H]+=604.5; 1 H NMR(400MHz,DMSO-d6)δppm 9.89(s,1H),8.25(d,J=1.2Hz,1H),8.07(d,J=1.2Hz,1H),7.38(d,J=8.4Hz,1H),7. 07(d,J=2.4Hz,1H),6.95(dd,J=2.4,8.4Hz,1H),6.53(s,1H),4.97(m,1H),3.95(br t,J=5.2Hz,4H),3.88(s,3H),3.76(t,J=6.4Hz,2H),3.30-3.26(m,2H),2.69(br t,J=5.2Hz,4H),2.09-1.91(m,4H),1.32(br s,4H),0.25(s,4H)

[0204] Example 12: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{1-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-imidazol-4-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0205] Step 1: To a solution of 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzaldehyde (1.50 g, 4.40 mmol) in dichloromethane (20 mL) was added 2-methyl-2-propanesulfenamide (0.53 g, 4.40 mmol) and cesium carbonate (1.61 g, 4.84 mmol). The mixture was stirred at 25°C for 16 hours. The reaction solution was extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-11% gradient of ethyl acetate / petroleum ether) to give N-[(E)-(2-{6-azaspiro[2.5]octan-6-yl}-4-iodophenyl)methylidene]-2-methyl-2-propanesulfenamide (1.80 g, 4.05 mmol, 92% yield) as a brown solid. LCMS (ESI): [M+H]+ = 445.0

[0206] Step 2: To a solution of N-[(E)-(2-{6-azaspiro[2.5]octan-6-yl}-4-iodophenyl)methylidene]-2-methyl-2-propanesulfenamide (1.80 g, 4.05 mmol) in methanol (30 mL) were added potassium carbonate (1.43 g, 10.1 mmol) and p-toluenesulfonylmethyl isocyanide (5.10 g, 90.3 mmol). The mixture was stirred at 60°C for 2 hours. The reaction solution was cooled to room temperature and extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-6% gradient of methanol / dichloromethane) to give 6-[2-(1H-imidazol-4-yl)-5-iodophenyl]-6-azaspiro[2.5]octane (0.90 g, 2.38 mmol, 59% yield) as an off-white solid. LCMS (ESI): [M+H]+ = 380.0

[0207] Step 3: To a solution of 6-[2-(1H-imidazol-4-yl)-5-iodophenyl]-6-azaspiro[2.5]octane (560 mg, 1.48 mmol) in N,N-dimethylformamide (10 mL) was added 2-methylthio-4-chloro-6-methylpyrimidine (284 mg, 1.62 mmol) and potassium carbonate (312 mg, 2.21 mmol). The mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with water (50 mL) and ethyl acetate (80 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-25% gradient of ethyl acetate / petroleum ether) to afford 6-(5-iodo-2-{1-[6-methyl-2-(methylmercapto)pyrimidin-4-yl]-1H-imidazol-4-yl}phenyl)-6-azaspiro[2.5]octane (570 mg, 1.15 mmol, 78% yield) as an off-white solid. LCMS (ESI): [M+H]+ = 518.0

[0208] Step 4: To a solution of 6-(5-iodo-2-{1-[6-methyl-2-(methylmercapto)pyrimidin-4-yl]-1H-imidazol-4-yl}phenyl)-6-azaspiro[2.5]octane (560 mg, 1.08 mmol) in tert-butanol (3 mL) / water (3 mL) was added potassium monopersulfate (455 mg, 2.71 mmol), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was extracted with water (20 mL) and ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to afford 6-{5-iodo-2-[1-(2-methylsulfinyl-6-methylpyrimidin-4-yl)-1H-imidazol-4-yl]phenyl}-6-azaspiro[2.5]octane (420 mg, crude) as a brown solid. LCMS (ESI): [M+H]+=534.0

[0209] Step 5: To a solution of 6-{5-iodo-2-[1-(2-methylsulfinyl-6-methylpyrimidin-4-yl)-1H-imidazol-4-yl]phenyl}-6-azaspiro[2.5]octane (400 mg, 0.75 mmol) in N,N-dimethylformamide (5 mL) was added 4,4-difluoropiperidine hydrochloride (126 mg, 0.80 mmol) and cesium carbonate (363 mg, 1.09 mmol). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with water (30 mL) and ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-25% gradient of ethyl acetate / petroleum ether) to give 6-(2-{1-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-imidazol-4-yl}-5-iodophenyl)-6-azaspiro[2.5]octane (130 mg, 0.22 mmol, 29% yield) as a white solid. LCMS (ESI): [M+H]+=591.1

[0210] Step 6: 2-Hydroxyethylsulfonylamide (33.1 mg, 0.26 mmol) and (1R,2R)-(-)-N,N-dimethylcyclohexane-1,2-diamine (29.2 mg, 0.20 mmol) were added to N,N-dimethylformamide (2.5 mL), and cuprous iodide (19.8 mg, 0.10 mmol) and potassium phosphate (176 mg, 0.81 mmol) were added at 25°C, and the mixture was stirred at 50°C for 5 minutes. Subsequently, 6-(2-{1-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-imidazol-4-yl}-5-iodophenyl)-6-azaspiro[2.5]octane (120 mg, 0.20 mmol) was added portionwise. The mixture was purged with nitrogen three times and heated to 100°C under a nitrogen atmosphere with stirring for 3 hours. The reaction solution was cooled to room temperature and extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to give a residue. The residue was purified by preparative HPLC (C18, 16-56% gradient of water (formic acid) / acetonitrile) to give a white solid N-(3-{6-azaspiro[2.5]octane-6-yl}-4-{1-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-imidazol-4-yl}phenyl)-2-hydroxyethane-1-sulfonamide (40.5 mg, 0.07 mmol, 34% yield). LCMS (ESI): [M+H]+=590.3, 1H NMR (400MHz, DMSO-d6) δppm 10.72(s,1H),9.11(s,1H),8.20(s,1H),7.22(s,1H),6.66(s,1H),4.97(s,1H),3.97(br t,J=5.2Hz,4H),3.84-3.75(m,2H),3.63(br d,J=2.8Hz,2H),2.83-2.71(m,4H),2.39(s,3H),2.06-1.91(m,4H),1.29-1.22(m,4H),0.24(s,4H)

[0211] Example 13: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{1-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl]-1H-imidazol-4-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0212] LCMS(ESI):[M+H] + =587.3; 1 H NMR (400MHz, DMSO-d6) δppm 9.73 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 7.90 (d, J = 8.4Hz, 1H), 7.10 (s, 1H), 7.02-6.93 (m, 2H), 6.90 (s, 1H), 4.95 (br s,1H),3.86-3.69(m,6H),3.26(br t,J=6.4Hz,2H),2.95–2.80(m,4H),2.39(s,3H),2.07- 1.93(m,4H),1.6-1.4(m,4H),0.34(s,4H)

[0213] Example 14: N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-thiadiazol-2-yl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0214] Step 1: Methyl 2-chloro-6-methylpyrimidine-4-carboxylate (3.00 g, 16.08 mmol), 4,4-difluoropiperidine hydrochloride (3.04 g, 19.29 mmol), and N,N-diisopropylethylamine (7.46 g, 56.54 mmol) were added to N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed three times with saturated aqueous sodium chloride (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated to give crude methyl 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (4.40 g, 86%). LCMS (ESI): [M+H] + =272.1.

[0215] Step 2: Add methyl 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (4.40 g, 16.22 mmol) to 85% hydrazine hydrate (10 mL). Stir the reaction mixture at 40°C for 2 hours. Pour the mixture into water (50 mL) and filter. Wash the solid with water (50 mL x 3) and dry to obtain the crude product 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbohydrazide (4.40 g, 100%). LCMS (ESI): [M+H] + =272.1.

[0216] Step 3: 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbohydrazide (2.00 g, 7.37 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (2.74 g, 8.85 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.72 g, 14.74 mmol), and N,N-diisopropylethylamine (1.94 g, 14.74 mmol) were added to N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was washed with methanol (50 mL x 3) to give N'-(4-bromo-2-(6-azaspiro[2.5]octyl-6-yl)benzoyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbohydrazide (3.50 g, 84%). 1H NMR(400MHz,Chloroform-d)δ13.82(s,1H),10.69(s,1H),8.13(d,J=8.4Hz,1H),7.56(d,J=1.9Hz,1H),7.51–7.42(m,1H), 7.26(s,1H),4.05(dd,J=6.8,5.0Hz,4H),3.05(t,J=5.4Hz,4H),2.46(s,3H),2.12–1.98(m,4H),1.78(s,4H),0.44(s,4H).

[0217] Step 4: N'-(4-Bromo-2-(6-azaspiro[2.5]octyl-6-yl)benzoyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbohydrazide (800 mg, 1.42 mmol) and Lawesson's reagent (580 mg, 1.42 mmol) were added to 1,4-dioxane (5 mL). The reaction mixture was microwave-heated at 110°C for 15 minutes. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to afford 2-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-thiadiazole (500 mg, 63%). 1 H NMR(400MHz,Chloroform-d)δ8.33(d,J=8.5Hz,1H),7.47(s,1H),7.43(d,J=10.5Hz,2H),4.0 7(dd,J=7.0,4.7Hz,4H),2.97(t,J=5.4Hz,4H),2.12–1.98(m,4H),1.67(s,4H),0.41(s,4H).

[0218] Step 5: 2-(4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-thiadiazole (400 mg, 0.71 mmol), 2-hydroxy-1-sulfonamide (136 mg, 1.07 mmol), cuprous iodide (692 mg, 3.56 mmol), potassium phosphate (463 mg, 2.14 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (1.02 g, 7.12 mmol) were added to N,N-dimethylformamide (4 mL), the atmosphere was replaced with nitrogen, and the reaction solution was reacted at 115°C for 4 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to give N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-thiadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (46 mg, 11%). LCMS (ESI): [M+H] + =606.4. 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),8.29(d,J=8.7Hz,1H),7.38–7.31(m,2H),7.17(dd,J=8.7,2.2Hz,1H),4.95(s,1H),3.98(t,J=5.8Hz, 4H),3.77(t,J=6.5Hz,2H),3.36(t,J=6.5Hz,2H),2.89(t,J=5.3Hz,4H),2.45(s,3H),2.10–1.99(m,4H),1.65(d,J=7.0Hz,4H),0.39(s,4H).

[0219] Example 15: N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0220] Step 1: Methyl 2-chloro-6-methylpyrimidine-4-carboxylate (3.00 g, 16.08 mmol), 4,4-difluoropiperidine hydrochloride (3.04 g, 19.29 mmol), and N,N-diisopropylethylamine (7.46 g, 56.54 mmol) were added to N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed three times with saturated aqueous sodium chloride (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated to give crude methyl 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (4.40 g, 86%). LCMS (ESI): [M+H] + =272.1.

[0221] Step 2: Add methyl 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (4.40 g, 16.22 mmol) to 85% hydrazine hydrate (10 mL). Stir the reaction mixture at 40°C for 2 hours. Pour the mixture into water (50 mL) and filter. Wash the solid with water (50 mL x 3) and dry to obtain the crude product 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbohydrazide (4.40 g, 100%). LCMS (ESI): [M+H] + =272.1.

[0222] Step 3: 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbohydrazide (2.00 g, 7.37 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (2.74 g, 8.85 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.72 g, 14.74 mmol), and N,N-diisopropylethylamine (1.94 g, 14.74 mmol) were added to N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was washed with methanol (50 mL x 3) to give N'-(4-bromo-2-(6-azaspiro[2.5]octyl-6-yl)benzoyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbohydrazide (3.50 g, 84%). 1H NMR(400MHz,Chloroform-d)δ13.82(s,1H),10.69(s,1H),8.13(d,J=8.4Hz,1H),7.56(d,J=1.9Hz,1H),7.51–7.42(m,1H), 7.26(s,1H),4.05(dd,J=6.8,5.0Hz,4H),3.05(t,J=5.4Hz,4H),2.46(s,3H),2.12–1.98(m,4H),1.78(s,4H),0.44(s,4H).

[0223] Step 4: Add N'-(4-bromo-2-(6-azaspiro[2.5]octyl-6-yl)benzoyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbohydrazide (800 mg, 1.42 mmol) and Burgess reagent (345 mg, 1.42 mmol) to 1,4-dioxane (5 mL). Microwave the reaction at 115°C for 2 hours. Pour the reaction mixture into water (30 mL) and extract with ethyl acetate (30 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to give 2-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-oxadiazole (450 mg, 58%). 1 H NMR(400MHz,Chloroform-d)δ7.90(d,J=8.4Hz,1H),7.38–7.30(m,2H),7.26–7.23(m,1H),4.12(t,J=5.8Hz ,4H),3.05(t,J=5.3Hz,4H),2.49(s,3H),2.06(tt,J=13.7,5.9Hz,4H),1.67(d,J=70.8Hz,4H),0.35(s,4H).

[0224] Step 5: 2-(4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-oxadiazole (400 mg, 0.73 mmol), 2-hydroxy-1-sulfonamide (140 mg, 1.10 mmol), potassium phosphate (477 mg, 2.20 mmol), cuprous iodide (427 mg, 2.20 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (632 mg, 4.40 mmol) were added to N,N-dimethylformamide (4 mL), the atmosphere was replaced with nitrogen, and the reaction solution was reacted at 115°C for 4 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with a saturated aqueous sodium chloride solution (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to give N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (78 mg, 18%). LCMS (ESI): [M+H] + =590.2. 1 H NMR(400MHz,DMSO-d6)δ10.18(s,1H),7.92(d,J=8.6Hz,1H),7.36(s,1H),7.0 7(d,J=2.1Hz,1H),6.97(dd,J=8.5,2.1Hz,1H),4.94(s,1H),4.02(td,J=5.3, 2.4Hz,4H),3.77(t,J=6.5Hz,2H),3.37(t,J=6.5Hz,2H),2.92(t,J=5.2Hz,4H ),2.44(s,3H),2.05(qd,J=13.8,13.1,6.6Hz,4H),1.52(s,4H),0.31(s,4H).

[0225] Examples 16 to 27 were prepared by referring to the synthesis method of Example 15:

[0226] Example 16: 2-Hydroxy-N-(4-5-(4-hydroxy-4-methylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethane-1-sulfonamide

[0227] LCMS (ESI) m / z: [M+H]+ =558. 1 H NMR (400MHz, DMSO) δ10.23(s,1H),7.82(d,J=8.6Hz,1H),7.36(s,1H),7.11(d,J=2.0Hz,1H),6.99(dd,J=8.4,2.0Hz,1H),5.02(s,2H),3. 77(t,J=6.4Hz,2H),3.55(s,2H),3.37(t,J=6.4Hz,2H),2.97(t,J=5.2Hz,4H),2.44(s,3H),1.53–1.44(m,4H),1.40(s,6H),0.30(s,4H).

[0228] Example 17: 2-Hydroxy-N-(5-2-(3-hydroxypiperidin-1-yl)-6-methylpyrimidin-4-yl-1,3,4-oxadiazol-2-yl)-3-(6-octan-6-ylphenyl)ethane-1-sulfonamide

[0229] LCMS (ESI) m / z: [M+H] + =570. 1 H NMR (400MHz, DMSO) δ10.21(s,1H),7.90(d,J=8.6Hz,1H),7.24(s,1H),7.10(d,J=2.0Hz,1H), 6.98(dd,J=8.6,2.0Hz,1H),5.35–5.31(m,2H),4.58–4.37(m,2H),3.77(t,J=6.4Hz,2H),3.5 1(dt,J=8.8,4.4Hz,1H),3.37(t,J=6.4Hz,2H),3.17(ddd,J=13.2,9.6,2.8Hz,1H),3.05–2.8 9(m,5H),2.41(s,3H),1.98–1.88(m,1H),1.82–1.71(m,1H),1.61–1.38(m,6H),0.31(s,4H).

[0230] Example 18: (R)-2-Hydroxy-N-(4-(5-(6-methyl-2-methyl-2-methylmorpholinyl)pyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenylethane-1-sulfonamide

[0231] LCMS (ESI) m / z: [M+H] + =570. 1H NMR (400MHz, DMSO) δ10.21(s,1H),7.92(d,J=8.5Hz,1H),7.34(s,1H),7.08(d,J=2.1Hz,1H),6.97(dd,J=8.4,2.0Hz,1H),4.59(t,J=14.0Hz,2H) ,4.24(s,1H),3.94(dd,J=11.2,3.2Hz,1H),3.77(t,J=6.4Hz,2H),3.59– 3.48(m,2H),3.37(t,J=6.4Hz,2H),3.02(ddd,J=15.2,12.2,3.6Hz,1H), 2.92(t,J=5.2Hz,4H),2.71(dd,J=13.4,10.4Hz,1H),2.43(s,3H),1.53(s,4H),1.18(d,J=6.0Hz,3H),0.31(s,4H).

[0232] Example 19: 2-Hydroxy-N-(4-5-(4-hydroxy-4-methylpiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethane-1-sulfonamide

[0233] LCMS (ESI) m / z: [M+H] + =584. 1 H NMR (400MHz, DMSO) δ10.20 (s, 1H), 7.90 (d, J = 8.6Hz, 1H), 7.23 (s, 1H), 7.08 (d,J=2.0Hz,1H),6.97(dd,J=8.4,2.0Hz,1H),5.00(s,2H),4.36(d,J=12.4H z,2H),3.77(t,J=6.4Hz,2H),3.60–3.42(m,2H),3.37(t,J=6.4Hz,2H),2.92 (t,J=5.2Hz,4H),2.40(s,3H),1.61–1.22(m,8H),1.17(s,3H),0.31(s,4H).

[0234] Example 20: N-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0235] LCMS (ESI) m / z: [M+H] +=606.4, 1 H NMR (400MHz, DMSO) δ10.19(s,1H),7.89(d,J=8.5Hz,1H),7.06(d,J=2.0Hz,1H),6.95(dd,J=8.5,2.0Hz,1H),6.83(s,1H),4.98(s,1H),4.02(t,J= 5.8Hz,4H),3.96(s,3H),3.76(t,J=6.5Hz,2H),3.35(t,J=6.5Hz,2H),2. 91(t,J=5.2Hz,4H),2.08(q,J=7.2,5.8Hz,4H),1.52(s,4H),0.31(s,4H).

[0236] Example 21: N-(4-(2-(4,4-difluoropiperidin-1-yl)-6-hydroxypyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0237] LCMS (ESI) m / z: [M+H] + =592.6, 1H NMR (400MHz, DMSO) δ10.32(s,1H),7.85(d,J=8.5Hz,1H),7.06(d,J=2.1Hz,1H),6.95(dd,J=8.5,2.0Hz,1H),6.51(s,1H),3.92(q ,J=4.0,3.0Hz,4H),3.78(t,J=6.4Hz,2H),3.40(s,2H),2.92(t,J=5.2Hz,4H),2.03(d,J=15.6Hz,4H),1.53(s,4H),0.33(s,4H).

[0238] Example 22: N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0239] LCMS(ESI):[M+H] + =605.5, 1H NMR (400MHz, DMSO-d6) δ10.17(s,1H),7.91(d,J=8.5Hz,1H),7.10(d,J=2.1 Hz,1H),7.01–6.95(m,2H),6.65(d,J=0.8Hz,1H),4.95(t,J=5.7Hz,1H),3. 88(s,3H),3.77(dt,J=12.3,5.9Hz,6H),3.36(t,J=6.5Hz,2H),2.93(t,J=5 .2Hz,4H),2.06(td,J=13.7,6.7Hz,4H),1.47(t,J=5.1Hz,4H),0.32(s,4H).

[0240] Example 23: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{5-[2-(4,4-difluoropiperidin-1-yl)-3-fluoro-6-methylpyridin-4-yl]-1,3,4-oxadiazol-2-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0241] LCMS(ESI):[M+H] + =607.3; 1 H NMR (400MHz, DMSO-d6) δppm 10.75-9.64(m,1H),7.88(d,J=8.8Hz,1H),7.35(d,J=3.2Hz,1H),7.09(s,1H),6.98(br d,J=8.8Hz,1H),5.31-4.55(m,1H),3.76(t,J=6.4Hz,2H),3.62(br t,J=4.8Hz,4H),3.39-3.35(m,2H),2.93(br d,J=4.8Hz,4H),2.43(s,3H),2.18-2.05(m,4H),1.50-1.40(m,4H),0.30(s,4H)

[0242] Example 24: N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octyl-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0243] LCMS(ESI):[M+H] +=589.9.1H NMR (400MHz, DMSO) δ10.17(s,1H),7.92(d,J=8.4Hz,1H),7.25(s,1H),7.18(s,1H),7.10(d,J=2.0Hz,1H),6.99(dd,J=8.4,2.0Hz,1H),4.94( t,J=5.6Hz,1H),3.84-3.71(m,6H),3.37(t,J=6.4Hz,2H),3.00-2.89( m,4H),2.44(s,3H),2.08–1.97(m,4H),1.54-1.43(m,4H),0.32(s,4H).

[0244] Example 25: N-(4-(5-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0245] LCMS(ESI):[M+H] + =589.4. 1 HNMR (400MHz, DMSO-d6) δ10.15(s,1H),7.86(d,J=8.5Hz,1H),7.43(s,1H),7.06(d,J=1.9Hz,2H),6.96(dd,J=8.5,2.0Hz,1H),4.96(t,J =5.6Hz,1H),3.80(dt,J=28.5,5.8Hz,6H),3.30(s,2H),2.92(t,J=5.2Hz,4H),2.37(s,3H),2.11–1.98(m,4H),1.51(s,4H),0.31(s,4H).

[0246] Example 26: N-(4-(5-(3-chloro-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0247] LCMS(ESI):[M+H] + =623.3. 1H NMR (400MHz, DMSO-d6) δ10.16(s,1H),7.82(d,J=8.4Hz,1H),7.37–7.28(m,1H),7.08(d,J=2.1Hz,1H),6.97(dd,J=8.5,2.1Hz,1H),4.98(s,1H) ,3.79(q,J=7.3,6.7Hz,6H),3.37(d,J=6.4Hz,2H),2.93(t,J=5.2Hz,4H),2.41(s,3H),2.04(dd,J=13.0,7.1Hz,4H),1.46(s,4H),0.30(s,4H).

[0248] Example 27: N-(4-(5-(4-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0249] LCMS(ESI):[M+H] + =590.4. 1 H NMR(400MHz,DMSO-d6)δppm 11.04-8.85(m,1H),7.88(d,J=8.8Hz,1H),7.10-7.02(m,2H),6.96(dd,J=2.0,8.4Hz,1H), 5.52-4.34(m,1H),3.96-3.82(m,4H),3.77(t,J=6.8Hz,2H),3.36(t,J=6.8Hz,2H),2.92(br t,J=4.8Hz,4H),2.41(s,3H),2.15-2.00(m,4H),1.62-1.44(m,4H),0.31(s,4H)

[0250] Example 28: 2-(4-(5-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-octan-6-yl)phenylphenylisothiazolidine

[0251] Step 1: To a solution of 4,4-difluoropiperidine hydrochloride (20.47 g, 128.62 mmol) and 2-chloro-6-methylpyrimidine-4-carboxylic acid methyl ester (6.0 g, 32.15 mmol) in N,N-dimethylacetamide (60 mL) was added potassium carbonate (13.6 g, 96.4 mmol), and the mixture was heated to 120 ° C and stirred for 12 hours. After the reaction was completed, water (120 mL) was added to the reaction mixture and extracted with ethyl acetate (120 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, 0-25% gradient of ethyl acetate / petroleum ether) to obtain a yellow solid 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylic acid methyl ester (4.7 g, 17.32 mmol, yield 53.89%). LCMS(ESI):[M+H] + =272

[0252] Step 2: Add methyl 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylate (2.0 g, 7.37 mmol) to a solution of methanol (20 mL) and stir at -10°C for 5 minutes. Then, slowly add a solution of hydrazine hydrate (1.15 g, 18.43 mmol) dropwise to the mixture and continue stirring for 4 hours. After the reaction is complete, the mixture is concentrated under reduced pressure to a solid mixture, slurried with acetonitrile (4 mL), and the solid is filtered. The filter cake is rinsed twice with acetonitrile (1 mL), collected, and dried to obtain 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylic acid hydrazide (1.8 g, 6.61 mmol, 90% yield) as a white solid. LCMS (ESI): [M+H] + =272

[0253] Step 3: To a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylic acid hydrazide (1.0 g, 3.6 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (1.0 g, 3.6 mmol) in tetrahydrofuran (20 mL) was added a solution of N,N-diisopropylethylamine (2.37 g, 18.38 mmol). The mixture was stirred at room temperature for 4 hours. Stirring was stopped after a solid compound precipitated. The solid was filtered and the filter cake was rinsed with tetrahydrofuran (1 mL). The filter cake was collected and dried to obtain 4-bromo-2-(6-azaspiro[2.5]octan-6-ylbenzoyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylic acid hydrazide (1.1 g, 1.95 mmol, 53.4% ​​yield) as a yellow solid. LCMS(ESI):[M+H] + =563

[0254] Step 4: To a solution of 4-bromo-2-(6-azaspiro[2.5]octan-6-ylbenzoyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylic acid hydrazide (1.0 g, 1.77 mmol) in dioxane (10 mL) was added a solution of Burgess reagent (1.69 g, 7.1 mmol), and the mixture was heated to 120 ° C and stirred for 12 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (40 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, 0-50% gradient of ethyl acetate / petroleum ether) to give 2-(4-bromo-2-6-azaspiro[2.5]octane-6-phenyl)-5-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl-1,3,4-oxadiazole (400 mg, 0.73 mmol, 41.3% yield) as a yellow solid. LCMS (ESI): [M+H] + =545

[0255] Step 5: Under a nitrogen atmosphere, 2-hydroxyethane-1-sulfonamide (277 mg, 2.17 mmol), cuprous iodide (105 mg, 0.54 mmol), potassium phosphate (471 mg, 2.2 mmol) and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (316.1 mg, 2.2 mmol) were placed in a bottle, N,N-dimethylformamide (6 mL) was added to the reaction bottle, and the mixture was stirred at 50 ° C for 0.5 hour, and then 2-(4-bromo-2-6-azaspiro[2.5]octane-6-phenyl)-5-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl-1,3,4-oxadiazole (300 mg, 0.55 mmol) was added to the bottle, and the mixture was stirred at 50 ° C for 5 minutes. The reaction system was heated to 120°C and stirred for 12 hours. After the reaction was completed, the system was cooled to room temperature and poured into water (5 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative chromatography (column: BRIX-2860AQ-C18, 20 × 250 mm The elution was performed using a 10 μm column, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 20 ml / min, elution gradient: mobile phase B increased from 15% to 65% over 30 minutes, detection wavelength: 220 nm, retention time: 40 minutes. After purification, 2-(4-(5-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-octan-6-yl)phenylphenylisothiazolidine (10 mg, 0.544 mmol, 3.04% yield) was obtained as a yellow solid. LCMS (ESI) m / z: [M+H] + =586. 1 H NMR (400MHz, DMSO) δ8.00–7.95(m,1H),7.36(s,1H),7.00–6.89(m,2H),4.20(s,2H),4.03(t,J=5.6Hz,4H),3.85(t,J=6. 4Hz, 2H), 3.60 (t, J = 7.2Hz, 2H), 2.44 (d, J = 4.0Hz, 5H), 2.07 (td, J = 13.6, 6.4Hz, 4H), 1.53 (d, J = 6.4Hz, 4H), 0.32 (s, 4H).

[0256] Example 29: N-(4-(5-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0257] Step 1: Dissolve 3-methylcyanopyridine (10.0 g, 84.6 mmol) in tert-butanol (30.0 mL), stir at 70°C for 20 minutes, add concentrated sulfuric acid (10.0 mL, 178 mmol), and stir at 70°C for 30 minutes. The reaction mixture was poured into 150 mL of water (with 2 mL of aqueous ammonia) 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, 0-8% gradient of tetrahydrofuran / petroleum ether) to afford N-(tert-butyl)-3-methylpicolinamide (14.5 g, 72.8 mmol, 86% yield) as a yellow oil. LCMS (ESI): [M+H] + =193.1.

[0258] Step 2: N-(tert-Butyl)-3-methylpicolinamide (14.5 g, 75.4 mmol) was dissolved in tetrahydrofuran (400 mL), and n-butyl lithium (10.6 g, 166 mmol) was added dropwise under a nitrogen atmosphere at -70 ° C., and [2-(dimethylamino)ethyl]dimethylamine (8.85 g, 75.4 mmol) was added dropwise. The reaction solution was stirred at -70 ° C for 30 minutes, and diethyl oxalate (22.0 g, 151 mmol) dissolved in tetrahydrofuran (200 mL) was added dropwise, and the reaction was stirred at -70 ° C for 1 hour. The reaction mixture was poured into saturated ammonium chloride solution (500 mL) for quenching and extracted with ethyl acetate (400 mL x 2). The organic phase was dried, filtered, and concentrated to afford ethyl 3-(2-(tert-butylaminocarbonyl)pyridin-3-yl)-2-oxygenated propan ester (29.1 g, 39.2 mmol, 52% yield) as a brown oil. The crude product was used directly in the next step. LCMS (ESI): [M+H] + =293.1

[0259] Step 3: Dissolve ethyl 3-(2-(tert-butylaminocarbonyl)pyridin-3-yl)-2-oxygenated propionate (29.0 g, 99.2 mmol) in acetic acid (290.0 mL), add ammonium acetate (15.3 g, 198 mmol), and stir at 110°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-4% gradient of tetrahydrofuran / petroleum ether) to give ethyl 8-oxygenated-7,8-dihydro-1,7-naphthyridine-6-carboxylate (3.30 g, 14.9 mmol, 15% yield) as a brown solid. LCMS (ESI): [M+H] + =219.1.

[0260] Step 4: Ethyl 8-oxyylidene-7,8-dihydro-1,7-naphthyridine-6-carboxylate (3.30 g, 15.1 mmol) was added to phosphorus oxychloride (35.0 mL) and stirred at 110°C for 1 hour. The reaction solution was concentrated under reduced pressure and diluted with dichloromethane (100 mL). The dilution was slowly added to stirring water (500 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (500 mL x 2). The organic phase was dried, filtered, and concentrated to obtain brown solid ethyl 8-chloro-1,7-naphthyridine-6-carboxylate (3.30 g, 12.5 mmol, 83% yield). The crude product was used directly in the next step. LCMS (ESI): [M+H] + =237.0

[0261] Step 5: Dissolve 8-chloro-1,7-naphthyridine-6-carboxylic acid ethyl ester (1.00 g, 4.23 mmol) and 4,4-difluoropiperidine hydrochloride (1.20 g, 7.61 mmol) in dimethyl sulfoxide (20.0 mL), add potassium carbonate (1.75 g, 12.67 mmol), and stir at 100°C for 16 hours. The reaction solution was diluted with water (100 mL) and extracted with 400 mL of ethyl acetate (200 mL x 2). The organic phase was washed with saturated brine (300 mL), dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-14% gradient of tetrahydrofuran / petroleum ether) to obtain 8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridine-6-carboxylic acid ethyl ester (0.72 g, 2.19 mmol, 52% yield) as a yellow solid. LCMS (ESI): [M+H] + =322.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.97(dd,J=2.0,4.4Hz,1H),8.48(dd,J=2.0,8.4Hz,1H),8.02(s,1H),7.77(dd,J=4.0,8.4 Hz,1H),4.35(q,J=7.2Hz,2H),4.20-4.12(m,4H),2.23-2.09(m,4H),1.34(t,J=7.2Hz,3H)

[0262] Step 6: Dissolve ethyl 8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridine-6-carboxylate (900 mg, 2.80 mmol) in anhydrous ethanol (18.0 mL), add hydrazine hydrate (1200 mg, 23.5 mmol), and stir at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a white solid 8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridine-6-carboxylic acid hydrazide (840 mg, 2.68 mmol, 96% yield). The crude product was used directly in the next step. LCMS (ESI): [M+H] + =308.1. 1 H NMR(400MHz, DMSO-d6)δppm 9.70(br s,1H),8.93(dd,J=1.6,4.4Hz,1H),8.46(dd,J=1.6,8.4Hz,1H),7.91(s,1H),7.74(dd,J=4.0,8.0Hz,1H),4.61(br d,J=2.8Hz,2H),4.28-4.18(m,4H),2.20-2.06(m,4H)

[0263] Step 7: Dissolve 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (2.00 g, 133%) in dichloromethane (30.0 mL), add thionyl chloride (0.99 g, 8.40 mmol), add N,N-dimethylformamide (0.03 g, 0.42 mmol), and stir at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a brown solid 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (2.00 g, 4.20 mmol, crude). The crude product was used directly in the next step. LCMS (ESI): [M+H] + =371.9

[0264] Step 8: 8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridine-6-carboxylic acid hydrazide (0.89 g, 2.90 mmol) was dissolved in tetrahydrofuran (36.00 mL), and diisopropylethylamine (3.74 g, 28.9 mmol) was added, followed by 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (1.31 g, 3.48 mmol). The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by slurrying with dichloromethane to obtain 8-(4,4-difluoropiperidin-1-yl)-N'-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl)-1,7-naphthyridine-6-carboxylic acid hydrazide (1.50 g, 2.31 mmol, 80% yield) as a brown solid. LCMS(ESI):[M+H] +=647.1 Step 9: 8-(4,4-difluoropiperidin-1-yl)-N'-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl)-1,7-naphthyridine-6-carboxylic acid hydrazide (700 mg, 1.08 mmol) was dissolved in toluene (14.00 mL), and Burgess reagent (789 mg, 3.25 mmol) was added. The mixture was stirred at 120°C for 3 hours. The reaction solution was purified by flash column chromatography (silica gel, 0-18% gradient of tetrahydrofuran / petroleum ether) to obtain 2-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridine-6-yl)-5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazole as a yellow solid (700 mg, 1.08 mmol, 100% yield). LCMS(ESI):[M+H] + =629.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.74(dd,J=1.6,4.0Hz,1H),8.27(dd,J=1.6,8.0Hz,1H),7.97(s,1H),7.56(dd,J=4.0,8.0Hz,1H),7.41(d,J=8.0H z,1H),7.31-7.25(m,2H),4.05-3.98(m,4H),2.26-2.24(m,4H),2.02-1.92(m,4H),1.34-1.20(m,4H),0.05(s,4H)

[0265] Step 10: 2-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,3,4-oxadiazole (700 mg, 1.11 mmol) and 2-hydroxyethanesulfonamide (278 mg, 2.23 mmol) were dissolved in N,N-dimethylformamide (14.0 mL), potassium phosphate (709 mg, 3.34 mmol), cuprous iodide (212 mg, 1.11 mmol) and 2-(methylamino)acetic acid (99.2 mg, 1.11 mmol) were added, and the mixture was stirred at 100 ° C for 24 hours under nitrogen atmosphere. The reaction solution was diluted with 100 mL of water (1 mL of NH3H2O) and 400 mL of ethyl acetate (200 mL x 10% ethyl acetate) was added. 2) extraction, the organic phase was dried, filtered, and concentrated, and the residue was purified by normal phase separation (NP-5, 30-80% gradient of n-hexane / ethanol (0.1% aqueous ammonia)) to give a yellow solid N-(4-(5-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide (38.0 mg, 0.05 mmol, 5% yield). LCMS (ESI): [M+H] + =626.3. 1 H NMR(400MHz,DMSO-d6)δppm 10.64-9.66(m,1H),8.98(dd,J=1.6,4.0Hz,1H),8.52(dd,J=1.6,8.4Hz,1H),8.21(s,1H),7.87(d,J =8.4Hz,1H),7.80(dd,J=4.0,8.4Hz,1H),7.06(d,J=1.6Hz,1H),6.96(dd,J=1.6,8.4Hz,1H),4.26(br d,J=4.8Hz,4H),3.77(t,J=6.4Hz,2H),3.37(t,J=6.4Hz,2H),2.94(br d,J=4.4Hz,4H),2.28-2.16(m,4H),1.58-1.48(m,4H),0.30(s,4H)

[0266] Examples 30 to 33 were prepared by referring to Example 29 and following a similar synthetic route:

[0267] Example 30: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{5-[2-(4,4-difluoropiperidin-1-yl)-3-fluoro-6-methylpyridin-4-yl]-1,3,4-oxadiazol-2-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0268] LCMS(ESI):[M+H] + =643.2; 1 H NMR (400MHz, DMSO-d6) δppm 10.48-9.84(m,1H),9.12-8.90(m,1H),8.69-8.55(m,1H),8.54-8.43(m,1H),7.93(br d,J=8.0Hz,1H),7.64(br d,J=2.4Hz,1H),7.17-7.08(m,1H),7.01(br d,J=7.6Hz,1H),5.26-4.70(m,1H),3.87-3.73(m,2H),3.69-3.54(m,4H),3.44-3.37(m,2H),3.06-2.88(m,4H),2.30-2.11(m,4H),1.49(br s,4H),0.30(s,4H)

[0269] Example 31: N-(4-(5-(6-(4,4-difluoropiperidin-1-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0270] LCMS(ESI):[M+H] + =655.4. 1 H NMR (600MHz, DMSO) δ10.14(s,1H),8.36(s,1H),8.06(s,1H),8.01(d,J=7.6Hz,1 H),7.89(d,J=7.6Hz,1H),7.87(d,J=8.4Hz,1H),7.06(d,J=2.0Hz,1H),6.95(dd, J=8.4,2.0Hz,1H),4.94(s,1H),3.93(s,3H),3.77(t,J=6.4Hz,2H),3.37(t,J=6.4Hz,2H), 3.27(t,J=5.6Hz,4H),2.93(t,J=5.2Hz,4H),2.22-2.09(m,4H),1.54(s,4H),0.30(s,4H).

[0271] Example 32: N-(4-(5-(1-(4,4-difluoropiperidin-1-yl)pyrrolo[1,2-c]pyrimidin-3-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0272] LCMS(ESI):[M+H] + =614.3. 1 H NMR (400MHz, DMSO-d6)10.14(s,1H),8.11(s,1H),7.87(d,J=8.4Hz,1H),7.70( d,J=2.8Hz,1H),7.11-7.03(m,2H),6.96(dd,J=2.0,8.4Hz,1H),6.89-6.87(m, 1H),4.95(t,J=5.6Hz,1H),3.77(q,J=6.4Hz,2H),3.63-3.50(m,4H),3.41-3.3 4(m,2H),3.00-2.88(m,4H),2.38-2.23(m,4H),1.70-1.41(m,4H),0.31(s,4H)

[0273] Example 33: N-(4-(5-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0274] LCMS(ESI):[M+H] + =615.7. 1 H NMR(400MHz,DMSO-d6)δppm 12.72(br s,1H),10.14(s,1H),8.26(d,J=2.0Hz,1H),8.14(s,1H),8.01(s,1H),7.84(d,J=8.4Hz ,1H),7.16(d,J=2.0Hz,1H),7.06(d,J=2.0Hz,1H),6.96(dd,J=2.0,8.4Hz,1H),4.95(br s,1H),4.15-4.03(m,4H),3.83-3.73(m,2H),3.42-3.36(m,2H),3.02-2.85(m,4H),2.24-2.10(m,4H),1.62-1.42(m,4H),0.30(s,4H)

[0275] Example 34: 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

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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 give 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.

[0282] 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. 1H NMR(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)

[0283] Example 35: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0284] Step 1: To a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (2.00 g, 10.7 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.37 g, 16.1 mmol), and potassium carbonate (4.53 g, 32.2 mmol) in water (8.00 mL) and dioxane (40.0 mL) was added 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (0.81 g, 1.07 mmol). The atmosphere was purged with nitrogen three times, and the mixture was heated to 100°C and stirred for 16 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The aqueous phase was adjusted to pH 3 with 1 mol / L dilute hydrochloric acid solution, resulting in the precipitation of a brown solid. The solid was collected, washed twice with water (40 mL), filtered, and dried with an oil pump to obtain a brown solid 2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidine-4-carboxylic acid (2.50 g, 10.7 mmol, yield 100%). LCMS (ESI): [M+H] + =221.0

[0285] Step 2: To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidine-4-carboxylic acid (2.00 g, 9.08 mmol) and 1,1-carbonyldiimidazole (2.25 g, 13.6 mmol) in tetrahydrofuran (30.0 mL) was added N,N-diisopropylethylamine (3.52 g, 27.2 mmol). The reaction mixture was heated to 60°C and stirred for 1 hour. Methanol (10 mL) was added to the reaction mixture, and stirring was continued at 60°C for half an hour. Sodium borohydride (1.37 g, 36.3 mmol) and water (4 mL) were then added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1) (200 mL x 2). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-12% gradient of tetrahydrofuran / petroleum ether) to give [2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidin-4-yl]methanol (1.20 g, 5.81 mmol, yield 64%) as a yellow solid. LCMS (ESI): [M+H] + =206.9

[0286] Step 3: To a solution of [2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidin-4-yl]methanol (860 mg, 4.17 mmol) and triethylamine (2.11 g, 20.9 mmol) in dimethyl sulfoxide (8 mL) was added pyridine sulfur trioxide (1.99 g, 12.5 mmol). The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (80 mL) and extracted with a mixture of chloroform and isopropanol (3:1) (80 mL x 2). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield crude 2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidine-4-carbaldehyde (0.56 g, 2.75 mmol, 66% yield). LCMS (ESI): [M+H] + =200.9.

[0287] Step 4: Dissolve 2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidine-4-carbaldehyde (0.50 g, 2.45 mmol) and dimethyl(1-diazo-2-oxyylidenepropyl)phosphonate (564 mg, 2.94 mmol) in methanol (10.0 mL), add potassium carbonate (1.02 g, 7.34 mmol), and stir at 25°C for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-12% gradient of tetrahydrofuran / petroleum ether) to afford 2-(3,6-dihydro-2H-pyran-4-yl)-4-ethynyl-6-methylpyrimidine (180 mg, 0.91 mmol, 37% yield) as a yellow solid. LCMS (ESI): [M+H] + =201.0

[0288] Step 5: Dissolve 2-(3,6-dihydro-2H-pyran-4-yl)-4-ethynyl-6-methylpyrimidine (150 mg, 0.75 mmol) and 6-(2-azido-5-bromophenyl)-6-azaspiro[2.5]octane (184 mg, 0.43 mmol) in tert-butanol (1.50 mL), tetrahydrofuran (1.50 mL), and purified water (1.50 mL). Add sodium ascorbate (148 mg, 0.75 mmol) and anhydrous copper sulfate (120 mg, 0.75 mmol) and stir at 25°C for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-12% gradient of tetrahydrofuran / petroleum ether) to afford 6-(5-bromo-2-{4-[2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-6-azaspiro[2.5]octane (150 mg, 0.29 mmol, 39% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 508.9

[0289] Step 6: To a solution of 6-(5-bromo-2-{4-[2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-6-azaspiro[2.5]octane (180 mg, 0.35 mmol), 2-hydroxyethanesulfonamide (54.4 mg, 0.43 mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (30.1 mg, 0.07 mmol), and potassium phosphate (307 mg, 1.42 mmol) in dioxane (4.00 mL) was added tris(dibenzylideneacetone)dipalladium (33.2 mg, 0.04 mmol). The atmosphere was replaced with nitrogen three times, and the mixture was heated to 90°C and stirred for 16 hours. Water (10 mL) was added to the reaction solution and extracted with ethyl acetate (20 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, 26-66% gradient of water (ammonia plus ammonium bicarbonate) / acetonitrile) to give a white solid compound N-(3-{6-azaspiro[2.5]octane-6-yl}-4-{4-[2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide (111 mg, 0.20 mmol, yield 57%). LCMS (ESI): [M+H] + =552.2, 1H NMR (400MHz, DMSO-d6) δppm 9.89 (s, 1H), 9.29 (s, 1H), 7.81 (s, 1H), 7.60 (d, J = 8.4Hz, 1H), 7.31 (br s,1H),7.14(d,J=2.4Hz,1H),7.04(dd,J=2.0,8.4Hz,1H),4.99(s,1H),4.34(br d,J=2.4Hz,2H),3.84(t,J=5.2Hz,2H),3.79(t,J=6.4Hz,2H),3.36(br s,2H),2.75-2.65(m,6H),2.56(s,3H),1.31(br s,4H),0.25(s,4H)

[0290] Example 36: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[6-methyl-2-(oxan-4-yl)pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0291] Step 1: To a solution of N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide (80 mg, 0.15 mmol) in methanol (2 mL) was added wet palladium on carbon (5 mg, 20% by mass) at 25°C. The reaction mixture was purged with argon three times, then replaced with hydrogen three times, and finally stirred under hydrogen (50 psi) for 16 hours. The reaction mixture was vacuum filtered to remove the palladium on carbon, and then concentrated under vacuum to obtain a residue. The residue was diluted with N,N-dimethylformamide (3 mL), and the diluent was purified by preparative HPLC (C18, 24-64% gradient of water (formic acid) / acetonitrile) to give a yellow solid compound N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[6-methyl-2-(oxan-4-yl)pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide (60.00 mg, 0.11 mmol, yield 75%). LCMS (ESI): [M+H]+=554.3, 1 H NMR(400MHz,DMSO-d6)δppm 10.27-9.75(m,1H),9.23(s,1H),7.81(s,1H),7.58(d,J=8.4Hz,1H),7.13(d,J=2.0 Hz,1H),7.03(dd,J=2.0,8.8Hz,1H),5.14-4.85(m,1H),4.02-3.89(m,2H),3.78(br t,J=6.4Hz,2H),3.48(dt,J=3.2,10.8Hz, 2H),3.36-3.34(m,2H),3.11-3.04(m,1H),2.71-2.65(m,4H),2.53(br s,3H),1.93-1.85(m,4H),1.29(br s,4H),0.23(s,4H)

[0292] Examples 37 to 39 were prepared by a similar synthetic route with reference to Example 35:

[0293] Example 37: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluorocyclohex-1-en-1-en-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0294] LCMS (ESI): [M+H]+=586.3,1 H NMR (400MHz, DMSO-d6) δppm 9.28 (s, 1H), 7.81 (s, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.24-7.10 (m, 2H), 7.04 (br d,J=8.4Hz,1H),3.78(t,J=6.4Hz,2H),3.32-3.29(m,2H),2.94-2.77(m,4H),2.73-2.62(m,4H),2.59-2.52(m,3H),2.26-2.13(m,2H),1.30(br s,4H),0.24(s,4H)

[0295] Example 38: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(5,6-dihydro-1,4-dioxin-2-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0296] LCMS (ESI): [M+H]+=554.2, 1 H NMR(400MHz,DMSO-d6)δppm 9.89(s,1H),8.94(s,1H),7.49(s,1H),7.40(s,1H),7.28(d,J=8.8Hz,1H) ,6.89(d,J=2.0Hz,1H),6.78(dd,J=2.4,8.8Hz,1H),4.99(s,1H),3.96(br d,J=3.2Hz,4H),3.54(t,J=6.4Hz,2H),3.13-3.09(m,2H),2.50-2.41(m,4H),2.26(s,3H),1.02(br s,4H),0.23(s,4H)

[0297] Example 39: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0298] LCMS (ESI): [M+H]+=549.3; 1H NMR(400MHz,DMSO-d6)δppm 10.06(s,1H),9.20(s,1H),8.31(s,1H),8.03(s,1H),7.98(s,1H),7.59(s,1H),7 .50(d,J=8.4Hz,1H),7.14(d,J=2.0Hz,1H),7.02(dd,J=2.0,8.4Hz,1H),4.98(br s,1H),3.90(s,3H),3.78(br t,J=6.4Hz,2H),3.38-3.34(m,2H),2.72-2.64(m,4H),2.54(s,3H),1.25(br s,4H),0.23(s,4H)

[0299] Example 40: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(1,4-dioxan-2-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0300] Example 40 was prepared according to the synthetic route of Example 36; LCMS (ESI): [M+H]+=554.3, 1 H NMR(400MHz,DMSO-d6)δppm 10.27-9.75(m,1H),9.23(s,1H),7.81(s,1H),7.58(d,J=8.4Hz,1H),7.13(d,J=2.0 Hz,1H),7.03(dd,J=2.0,8.8Hz,1H),5.14-4.85(m,1H),4.02-3.89(m,2H),3.78(br t,J=6.4Hz,2H),3.48(dt,J=3.2,10.8Hz,2H),3.36-3.34(m,2H),3.11-3.04(m,1H),2.71-2.65(m,4H),2.53(br s,3H),1.93-1.85(m,4H),1.29(br s,4H),0.23(s,4H)

[0301] Example 41: 2-Hydroxy-N-(4-(4-(6-methyl-2-(piperidin-1-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethanesulfonamide

[0302] Step 1: 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.

[0303] Step 2: 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.

[0304] Step 3: 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.

[0305] Step 4: To tetrahydrofuran (100 mL) and triethylamine (9.31 g, 92.02 mmol) were added bistriphenylphosphine palladium dichloride (0.11 g, 0.15 mmol) and triphenylphosphine (0.08 g, 0.31 mmol), and under a nitrogen atmosphere, 2,4-dichloro-6-methylpyrimidine (5.00 g, 30.7 mmol) and cuprous iodide (0.06 g, 0.31 mmol) and ethynyltrimethylsilane (3.31 g, 33.74 mmol) were added, and the mixture was stirred at 70 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was poured into water (100 mL). The mixture 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, 0-2% gradient of tetrahydrofuran / petroleum ether) to give 2-chloro-4-methyl-6-((trimethylsilyl)ethynyl)pyrimidine (5.60 g, 15.95 mmol, 52% yield) as a yellow oil. LCMS (ESI): [M+H] + =225.0

[0306] Step 5: Add 2-chloro-4-methyl-6-((trimethylsilyl)ethynyl)pyrimidine (500 mg, 2.22 mmol) and 6-(2-azido-5-iodophenyl)-6-azaspiro[2.5]octane (787 mg, 2.22 mmol) to tert-butanol (3.50 mL), tetrahydrofuran (5.00 mL) and pure water (3.50 mL), add sodium ascorbate (440 mg, 2.22 mmol) and copper sulfate (355 mg, 2.22 mmol), and stir at 25 ° C for 16 hours. The reaction solution was poured into 50 mL of water 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, 0-9% gradient of tetrahydrofuran / petroleum ether) to give 6-(2-(4-(2-chloro-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-5-iodophenyl)-6-azaspiro[2.5]octane (760 mg, 1.38 mmol, 62% yield) as a yellow solid. LCMS (ESI): [M+H] + =507.0.

[0307] Step 6: To a solution of 1-[2-(6-azaspiro[2.5]octan-6-yl)-4-iodophenyl]-4-(2-chloro-6-methylpyrimidin-4-yl)-1,2,3-triazole (250 mg, 0.49 mmol) in tert-butanol (5 mL) was added N,N-diisopropylethylamine (191 mg, 1.48 mmol) and piperidine (84 mg, 0.99 mmol) at 25°C. The reaction mixture was stirred at 80°C for 12 hours. The reaction system was diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 3). The organic phase was washed with saturated sodium chloride (40 mL). The organic phase was dried over anhydrous magnesium 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 tetrahydrofuran / petroleum ether) to give a yellow solid compound 1-[2-(6-azaspiro[2.5]octan-6-yl)-4-iodophenyl]-4-(6-methyl-2-piperidinylpyrimidin-4-yl)-1,2,3-triazole (0.10 g, 0.18 mmol, yield 36%). LCMS (ESI): [M+H]+=556.4

[0308] Step 7: To a solution of 2-hydroxyethanesulfonamide (40.6 mg, 0.32 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (23.2 mg, 0.16 mmol) in N,N-dimethylformamide (2 mL) were added cuprous iodide (15.4 mg, 0.08 mmol) and potassium phosphate (138 mg, 0.65 mmol) at 25 ° C. The reaction mixture was heated to 50 ° C under nitrogen and stirred for 5 minutes. Then, 1-[2-(6-azaspiro[2.5]octan-6-yl)-4-iodophenyl]-4-(6-methyl-2-piperidinylpyrimidin-4-yl)-1,2,3-triazole (90 mg, 0.16 mmol) was added at 50 ° C. The nitrogen atmosphere was replaced again, and the reaction solution was stirred at 100 ° C for 16 hours. Aqueous ammonia (5 mL) and water (15 mL) were added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined and washed once with saturated brine (20 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was diluted with N,N-dimethylformamide (5 mL). The dilution was purified by preparative HPLC (C18, 46-86% gradient of water (formic acid) / acetonitrile) to obtain a yellow solid compound 2-hydroxy-N-(4-(4-(6-methyl-2-(piperidin-1-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethanesulfonamide (43 mg, 0.08 mmol, yield 48%). LCMS (ESI): [M+H] + =553.3. 1H NMR(400MHz,DMSO-d6)δppm 10.06(s,1H),9.18(s,1H),7.60(d,J=8.4Hz,1H),7.14(d,J=2.0Hz,1H),7.11(s,1H),7.04(d d,J=2.0,8.8Hz,1H),3.87-3.80(m,4H),3.78(t,J=6.4Hz,2H),3.34(t,J=6.4Hz,2H),2.68(br t,J=4.8Hz,4H),2.37(s,3H),1.65(br d,J=4.4Hz,2H),1.54(br d,J=4.0Hz,4H),1.39-1.26(m,4H),0.25(s,4H)

[0309] Examples 42 to 50 were prepared by a similar synthetic route as Example 41:

[0310] Example 42: 2-Hydroxy-N-(4-(4-(6-methyl-2-morpholinopyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethanesulfonamide

[0311] LCMS(ESI):[M+H] + =554.9. 1 H NMR(400MHz,DMSO-d6)δppm 10.06(s,1H),9.19(s,1H),7.58(d,J=8.8Hz,1H),7.20(s,1H),7.13(d,J=2.0Hz,1H),7.03(dd,J=2.0 ,6.4Hz,1H),4.98(t,J=5.6Hz,1H),3.89-3.73(m,6H),3.72-3.63(m,4H),3.37-3.34(m,2H),2.68(br t,J=4.8Hz,4H),2.39(s,3H),1.29(br s,4H),0.25(s,4H)

[0312] Example 43: 2-Hydroxy-N-(4-(4-(6-methyl-2-morpholinopyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethanesulfonamide

[0313] LCMS(ESI):[M+H] + =569.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.06(s,1H),9.22(s,1H),7.59(d,J=8.4Hz,1H),7.18(s,1H),7.13(d,J=2 .0Hz,1H),7.03(dd,J=2.0,8.8Hz,1H),5.45-4.74(m,1H),4.70-4.45(m,2H) ,3.90(dd,J=2.4,11.2Hz,1H),3.78(t,J=6.4Hz,2H),3.54-3.47(m,2H),3. 33-3.31(m,2H),3.01-2.91(m,1H),2.75-2.64(m,5H),2.39(s,3H),1.30(br s,4H),1.17(d,J=6.0Hz,3H),0.25(s,4H)

[0314] Example 44: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-(4-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-methylpyrimidin-4-yl}-1H-1,2,3-triazol-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0315] LCMS(ESI):[M+H] + =583.3, 1 H NMR(400MHz,DMSO-d6)δppm 10.05 (s,1H),9.23(s,1H),7.59(d,J=8.4Hz,1H),7.17(s,1H),7.13(d,J=2.0Hz,1H),7.03(dd,J=2.0,8.8Hz,1H),5.33-4.77(m,1H),4.64(br d,J=13.2Hz,2H),3.78(t,J=6.4Hz,2H),3.64-3.53(m,2H),3.34-3.31(m,4H),2.67(br t,J=4.4Hz,4H),2.38(s,3H),1.30(br s,4H),1.17(d,J=6.4Hz,6H),0.25(s,4H)

[0316] Example 45: 2-Hydroxy-N-(4-(4-(6-methyl-2-(3-methylmorpholinopyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethanesulfonamide

[0317] LCMS(ESI):[M+H]+ =569.5. 1 H NMR (400MHz, DMSO-d6) δppm 10.05 (s, 1H), 9.19 (s, 1H), 7.60 (d, J = 8.4Hz, 1H), 7.18 (s, 1H), 7.13 (d, J = 2.0Hz, 1H), 7.03 (dd, J = 2.0, 8.8Hz, 1H), 4.98 (br s,1H),4.75(br dd,J=1.6,6.4Hz,1H),4.38(br d,J=12.8Hz,1H),3.92(br dd,J=2.8,11.2Hz,1H),3.81-3.69(m,3H),3.60(br dd,J=2.8,11.2Hz,1H),3.49-3.40(m,1H),3.35(br s,1H),3.32(s,1H),3.22-3.11(m,1H),2.74-2.59(m,4H),2.38(s,3H),13.4-1.25(m,4H),1.24-1.19(m,3H),0.24(s,4H)

[0318] Example 46: N-(4-(4-(2-((3S,5R)-3,5-dimethylmorpholino)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)2-hydroxyethanesulfonamide

[0319] LCMS (ESI): [M+H]+=583.5. 1 H NMR(400MHz,DMSO-d6)δppm 10.05(s,1H),9.18(s,1H),7.62(d,J=8.4Hz,1H),7.18(s,1H),7.13(d,J=2.0Hz,1H),7.04(dd,J=2.0,8.8Hz,1H),5.29-4.73(m,1H),4.60(br dd,J=3.6,6.8Hz,2H),3.81-3.74(m,4H),3.63-3.56(m,2H),3.32(br s,2H),2.71-2.61(m,4H),2.39(s,3H),1.39-1.22(m,10H),0.23(s,4H)

[0320] Example 47: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-[4-(6-methyl-2-{2-oxa-5-azabicyclo[2.2.1]heptan-5-yl}pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl]phenyl)-2-hydroxyethane-1-sulfonamide

[0321] LCMS(ESI):[M+H] + =567.3, 1 H NMR(400MHz,DMSO-d6)δppm 10.05(br s,1H),9.37-8.93(m,1H),7.59(d,J=8.4Hz,1H),7.18(s,1H),7.14(d,J=2.0Hz,1H),7.04(dd,J=2.0,8.8Hz,1H),5.16-4.90(m,2H) ,4.68(s,1H),3.91-3.63(m,4H),3.55-3.43(m,2H),3.38-3.34(m,2H),2.74-2.63(m,4H),2.38(s,3H),2.02-1.84(m,2H),1.30(br s,4H),0.25(s,4H)

[0322] Example 48: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-[4-(6-methyl-2-{3-oxa-8-azabicyclo[3.2.1]octan-8-yl}pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl]phenyl)-2-hydroxyethane-1-sulfonamide

[0323] LCMS(ESI):[M+H] + =581.3, 1 H NMR(400MHz,DMSO-d6)δppm 10.03(s,1H),9.20(s,1H),7.60(d,J=8.8Hz,1H),7.19(s,1H),7.12(d,J=2.0Hz ,1H),7.03(dd,J=2.0,8.4Hz,1H),5.11-4.83(m,1H),4.78-4.59(m,2H),3.77(br t,J=6.4Hz,2H),3.69-3.53(m,4H),3.33(br s,2H),2.75-2.64(m,4H),2.39(s,3H),2.05-1.83(m,4H),1.29(br s,4H),0.24(s,4H)

[0324] Example 49: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-[4-(6-methyl-2-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl]phenyl)-2-hydroxyethane-1-sulfonamide

[0325] LCMS(ESI):[M+H] + =567.2; 1 H NMR (400MHz, DMSO-d6) δppm 10.04 (s, 1H), 9.10 (s, 1H), 7.59 (d, J=8.4Hz, 1H), 7.30 (s, 1H), 7.12 (d, J= 2.0Hz,1H),7.03(dd,J=2.0,8.4Hz,1H),5.20-4.76(m,1H),4.37(br d,J=6.0Hz,2H),4.29-4.05(m,2H),3.86-3.63(m,4H),3.45-3.34(m,2H),2.83-2.61(m,5H),2.40(s,3H),1.77(br d,J=8.4Hz,1H),1.27(br s,4H),0.25(s,4H)

[0326] Example 50 N-(3-{6-azaspiro[2.5]octan-6-yl}-4-(4-{2-[(2R,6S)-4,4-difluoro-2,6-dimethylpiperidin-1-yl]-6-methylpyrimidin-4-yl}-1H-1,2,3-triazol-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0327] Step 1: A solution of 3-oxoglutaric acid (100 g, 684 mmol), 1-(4-methoxyphenyl)methylamine (93.9 g, 684 mmol), and acetaldehyde (150 g, 1368 mmol, 40% purity) in water (500 mL) was stirred at 25°C for 72 hours. The reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (1000 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-40% gradient of tetrahydrofuran / petroleum ether) to afford (2R,6S)-1-[(4-methoxyphenyl)methyl]-2,6-dimethylpiperidin-4-one (77.0 g, 310 mmol, 45.4% yield) as a colorless oil. LCMS (ESI): [M+H] + =287.0; 1H NMR (400MHz, CDCl3) δppm 7.32 (br d, J=8.4Hz, 2H), 6.89 (br d,J=8.8Hz,2H),3.95-3.84(m,1H),3.82(s,3H),3.62-3.51(m,1H),3.34-3 .21(m,2H),2.56-2.41(m,2H),2.26-2.12(m,2H),1.11(s,3H),1.09(s,3H)

[0328] Step 2: Palladium on carbon (10.0 g, 10% purity) was added to (2R,6S)-1-[(4-methoxyphenyl)methyl]-2,6-dimethylpiperidin-4-one (70.0 g, 283 mmol) and di-tert-butyl dicarbonate (66.2 g, 303 mmol) in ethanol (500 mL). The mixture was heated to 80°C under 50 psi of hydrogen pressure and stirred for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated to obtain tert-butyl (2R,6S)-2,6-dimethyl-4-oxyylidenepiperidin-1-carboxylate (70.0 g, crude) as a yellow solid. 1 H NMR (400MHz, CDCl3) δppm 4.45-4.33(m,2H),2.93-2.78(m,2H),2.44-2.34(m,2H),1.50(s,9H),1.26(s,3H),1.24(s,3H)

[0329] Step 3: To a solution of tert-butyl (2R,6S)-2,6-dimethyl-4-oxyylidenepiperidin-1-carboxylate (40.0 g, 176 mmol) in dioxane (400 mL) was added dioxane hydrochloride (400 mL, 4 M), and the mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated to yield (2R,6S)-2,6-dimethylpiperidin-4-one hydrochloride (28.0 g, crude product). 1 H NMR (400MHz, DMSO-d6) δppm 10.21-9.74(m,2H),3.92-3.80(m,2H),2.72(dd,J=4.4,15.2Hz,2H),2.49-2.39(m,2H),1.31(s,3H),1.28(s,3H)

[0330] Step 4: To a solution of (2R,6S)-2,6-dimethylpiperidin-4-one hydrochloride (30.0 g, 183 mmol) and N,N-diisopropylethylamine (96.7 g, 733 mmol) in dichloromethane (400 mL) was added benzyl chloride (31.2 g, 183 mmol). The mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (400 mL) and extracted with dichloromethane (400 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / petroleum ether) to afford benzyl (2R,6S)-2,6-dimethyl-4-oxyylidenepiperidin-1-carboxylate (30.0 g, 114 mmol, 62.6% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm 7.47-7.38(m,5H),5.28-5.12(m,2H),4.55-4.42(m,2H),2.88(dd,J=6.4,18.0Hz,2H),2.42(dd,J=1.6,18.0Hz,2H),1.30(s,3H),1.27(s,3H)

[0331] Step 5: To a solution of benzyl (2R,6S)-2,6-dimethyl-4-oxyylidenepiperidin-1-carboxylate (46.0 g, 176 mmol) and boron trifluoride etherate (150 g, 1056 mmol) in dichloromethane (1200 mL) was added ethanedithiol (49.7 g, 528 mmol) and stirred at 25°C for 1 hour. The reaction mixture was diluted with water (1000 mL) and extracted with dichloromethane (1000 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-8% gradient of tetrahydrofuran / petroleum ether) to afford benzyl (7R,9S)-7,9-dimethyl-1,4-dithia-8-azaspiro[4.5]decane-8-carboxylate (46.0 g, 135 mmol, 77.0% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm 7.39-7.20(m,5H),5.13-4.97(m,2H),4.16-3.99(m,2H),3.36-3.26(m,2H),3.23-3.08(m ,2H),2.53(dd,J=5.2,15.2Hz,2H),2.23(dd,J=4.0,15.2Hz,2H),1.29(s,3H),1.27(s,3H)

[0332] Step 6: To a solution of 1,3-dibromo-5,5-dimethylhydantoin (25.4 g, 88.8 mmol) in dichloromethane (200 mL) was added pyridine hydrofluoride (41.9 g, 296 mmol, 70% purity) at -70°C, and the reaction mixture was stirred at -40°C for 0.5 h. Subsequently, a solution of benzyl (7R,9S)-7,9-dimethyl-1,4-dithia-8-azaspiro[4.5]decane-8-carboxylate (10.0 g, 29.6 mmol) in dichloromethane (50 mL) was added to the reaction mixture at -40°C, and stirred at -40°C for 10 min. The reaction mixture was added with water (100.0 mL) and extracted with dichloromethane (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-8% gradient of tetrahydrofuran / petroleum ether) to obtain benzyl (2R,6S)-4,4-difluoro-2,6-dimethylpiperidine-1-carboxylate (1.20 g, 12.4 mmol, yield 14.0%) as a yellow oil. LCMS (ESI): [M+H] + =284.0; 1 H NMR (400MHz, CDCl3) δppm 7.34-7.22(m,3H),5.13-5.00(m,2H),4.25-4.10(m,2H),2.44-2.20(m,2H),2.16-2.02(m,2H),1.23(s,3H),1.21(s,3H)

[0333] Step 7: To a solution of benzyl (2R,6S)-4,4-difluoro-2,6-dimethylpiperidine-1-carboxylate (3.60 g, 12.7 mmol) in tetrahydrofuran (200 mL) was added wet palladium on carbon (1.0 g, 10% purity). The mixture was stirred at 80°C under 50 psi of hydrogen pressure for 16 hours. Filtered through celite, wet palladium on carbon (1.0 g, 10% purity) was added to the filtrate, and the mixture was stirred at 80°C under 50 psi of hydrogen pressure for 16 hours. This reaction was repeated three times. Filtered through celite, the filtrate was concentrated to yield (2R,6S)-4,4-difluoro-2,6-dimethylpiperidine (1.60 g, 10.6 mmol, 84% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm 3.59-3.49(m,2H),2.26-2.06(m,2H),1.96-1.82(m,2H),1.26(s,3H),1.24(s,3H)

[0334] Step 8: (2R,6S)-4,4-difluoro-2,6-dimethylpiperidine (648 mg, 4.35 mmol) and 6-{5-bromo-2-[4-(2-chloro-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-azaspiro[2.5]octane (200 mg, 0.435 mmol) were stirred at 140 °C for 48 hours. The mixture was purified by flash column chromatography (silica gel, 0-5% gradient of tetrahydrofuran / petroleum ether) to give 6-[5-bromo-2-(4-{2-[(2R,6S)-4,4-difluoro-2,6-dimethylpiperidin-1-yl]-6-methylpyrimidin-4-yl}-1H-1,2,3-triazol-1-yl)phenyl]-6-azaspiro[2.5]octane (40.0 mg, 0.07 mmol, 16% yield) as a yellow solid. LCMS (ESI): [M+H] + =574.2

[0335] Step 9: 6-[5-bromo-2-(4-{2-[(2R,6S)-4,4-difluoro-2,6-dimethylpiperidin-1-yl]-6-methylpyrimidin-4-yl}-1H-1,2,3-triazol-1-yl)phenyl]-6-azaspiro[2.5]octane (40 mg, 0.07 mmol) and 2-hydroxyethanesulfonamide (17.4 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (10 mL) at 25°C. Potassium phosphate (44.5 mg, 0.21 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (10.0 mg, 0.07 mmol) and cuprous iodide (13.3 mg, 0.07 mmol) were added, and the mixture was stirred at 100°C under nitrogen atmosphere for 4 hours. The reaction mixture was added with water (20.0 mL + 0.50 mL of aqueous ammonia) and extracted with ethyl acetate (20 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 50%-90% gradient of water (formic acid) / acetonitrile) to give N-(3-{6-azaspiro[2.5]octan-6-yl}-4-(4-{2-[(2R,6S)-4,4-difluoro-2,6-dimethylpiperidin-1-yl]-6-methylpyrimidin-4-yl}-1H-1,2,3-triazol-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide (28.0 mg, 0.04 mmol, yield 65.0%) as a white solid. LCMS (ESI): [M+H] + =617.6; 1H NMR (400MHz, DMSO-d6)10.04(s,1H),9.14(s,1H),7.61(d,J=8.4Hz,1H),7.25-7.10(m,2H),7.04(dd,J=2.0,8.4Hz,1H),4.97(br t,J=5.2Hz,1H),4.71(br s,2H),3.85-3.71(m,2H),3.33-3.25(m,2H),2.78-2.57(m,6H),2.43-2.30(m,5H),1.36-1.22(m,10H),0.23(s,4H)

[0336] Example 51: N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidine-4-

[0337] 1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0338] Step 1: To triethylamine (5.09 g, 50.3 mmol) and tetrahydrofuran (60 mL) was added bistriphenylphosphine palladium dichloride (0.06 g, 0.08 mmol) and triphenylphosphine (0.04 g, 0.17 mmol). 2,4-dichloro-6-methoxypyrimidine (3.00 g, 16.7 mmol), cuprous iodide (0.03 g, 0.17 mmol), and ethynyltrimethylsilane (1.81 g, 18.4 mmol) were added under nitrogen. The mixture was stirred at 70°C under nitrogen for 16 hours. The reaction mixture was used directly in the next step.

[0339] Step 2: Add 4,4-difluoropiperidine hydrochloride (3.14 g, 19.94 mmol) and diisopropylethylamine (6.44 g, 49.8 mmol) to the reaction solution of the first step and stir at 80 ° C for 16 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate 400 mL (200 mL x 2), and the organic phase was washed with saturated brine (300 mL), dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of tetrahydrofuran / petroleum ether) to give a brown oily 2-(4,4-difluoropiperidin-1-yl)-4-methoxy-6-((trimethylsilyl)ethynyl)pyrimidine (2.00 g, 2.33 mmol, 14% yield). LCMS (ESI): [M+H] +=326.2 Step 3: Dissolve 2-(4,4-difluoropiperidin-1-yl)-4-methoxy-6-((trimethylsilyl)ethynyl)pyrimidine (1.00 g, 3.07 mmol) and 6-(2-azido-5-bromophenyl)-6-azaspiro[2.5]octane (0.94 g, 3.07 mmol) in tert-butanol (10 mL), tetrahydrofuran (10 mL), and purified water (10.00 mL). Add sodium ascorbate (0.61 g, 3.07 mmol) and anhydrous copper sulfate (0.49 g, 3.07 mmol). Stir the mixture at 25°C for 16 hours. Dilute the reaction mixture with water (50 mL) and extract with 200 mL of ethyl acetate (100 mL x 2). The organic phase is dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-13% gradient of tetrahydrofuran / petroleum ether) to give 6-(5-bromo-2-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)phenyl)-6-azaspiro[2.5]octane (0.56 g, 0.89 mmol, 29% yield) as a yellow solid. LCMS (ESI): [M+H] + =562.3. 1 H NMR(400MHz,CHLOROFORM-d)δppm 8.92(s,1H),7.50(d,J=8.4Hz,1H),7.28-7.21(m,2H),6.82(s,1H),4.00-3.93(m,4H) ,3.89(s,3H),2.72(t,J=5.2Hz,4H),2.03-1.85(m,4H),1.35-1.25(m,4H),0.23(s,4H)

[0340] Step 4: 6-(5-bromo-2-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)phenyl)-6-azaspiro[2.5]octane (260 mg, 0.46 mmol) and 2-hydroxyethanesulfonamide (75.5 mg, 0.60 mmol) were dissolved in dioxane (5.00 mL), and potassium phosphate (295 mg, 1.39 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (39.4 mg, 0.09 mmol) and tris(dibenzylideneacetone)dipalladium (42.5 mg, 0.05 mmol) were added and stirred at 80 ° C for 16 hours under nitrogen atmosphere. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate 200 mL (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 40-80% gradient of water (ammonia + ammonium bicarbonate) / acetonitrile) to give N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide (110.60 mg, 0.18 mmol, 39% yield) as a white solid. LCMS (ESI): [M+H] + =605.2. 1 H NMR(400MHz,DMSO-d6)δppm 9.17(s,1H),7.57(d,J=8.4Hz,1H),7.14(d,J=2.4Hz,1H),7.04(dd,J=2.0,8.4Hz,1H),6.69(s,1H),5.39-4.57(m,1H),3.98(br t,J=5.2Hz,4H),3.92(s,3H),3.78(t,J=6.8Hz,2H),3.34-3.30(m,2H),2.67(br t,J=4.4Hz,4H),2.08-1.94(m,4H),1.36-1.24(m,4H),0.25(s,4H)

[0341] Example 52: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-hydroxypyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0342] Step 1: Dissolve 6-(5-bromo-2-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-6-azaspiro[2.5]octane (5.80 g, 10.3 mmol) in N,N-dimethylformamide (120 mL), add pyridine hydrochloride (23.9 g, 206 mmol), and stir at 110°C for 48 hours. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (200 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-8% gradient of tetrahydrofuran / dichloromethane) to obtain 6-[1-(2-{6-azaspiro[2.5]octan-6-yl}-4-bromophenyl)-1H-1,2,3-triazol-4-yl]-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-ol (4.67 g, 7.14 mmol, 69% yield) as a yellow solid. LCMS (ESI): [M+H] + =548.0, 1 H NMR(400MHz,CHLOROFORM-d)δppm 13.07-11.51(m,1H),8.87(s,1H),7.50(d,J=8.0Hz,1H),7.26 -7.21(m,2H),6.62(s,1H),3.90(br t,J=5.2Hz,4H),2.70(t,J=5.2Hz,4H),2.10-1.96(m,4H),1.32-1.25(m,4H),0.22(s,4H)

[0343] Step 2: 6-[1-(2-{6-azaspiro[2.5]octan-6-yl}-4-bromophenyl)-1H-1,2,3-triazol-4-yl]-2-(4,4-difluoropiperidin-1-yl)pyrimidine-4-ol (500 mg, 0.92 mmol) and 2-hydroxyethane-1-sulfonamide (229 mg, 1.83 mmol) were dissolved in N,N-dimethylformamide (10.0 mL), and potassium phosphate (582 mg, 2.75 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (131 mg, 0.92 mmol) and cuprous iodide (174 mg, 0.92 mmol) were added and stirred at 100°C for 16 hours. The reaction solution was diluted with water (50 mL + 0.5 mL of aqueous ammonia) and extracted with dichloromethane (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 20-60% gradient of water (formic acid) / acetonitrile) to give N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-hydroxypyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide (76.9 mg, 0.13 mmol, yield 14%) as a white solid. LCMS (ESI): [M+H] + =591.2, 1 H NMR(400MHz, DMSO-d6)δppm 9.10(s,1H),7.57(d,J=8.8Hz,1H),7.13(d,J=2.4Hz,1H),7.03(dd,J=2.8,9.2Hz,1H),6.39(br s,1H),3.92-3.85(m,4H),3.78(t,J=6.8Hz,2H),3.39-3.34(m,2H),2.67(br t,J=4.8Hz,4H),2.09-1.97(m,4H),1.34-1.26(m,4H),0.26(s,4H)

[0344] Example 53: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-(4-{2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-methoxypyrimidin-4-yl}-1H-1,2,3-triazol-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0345] Step 1: 2,4-Dichloro-6-methoxypyrimidine (1.00 g, 5.59 mmol) and (3R,5S)-3,5-dimethylmorpholine (0.64 g, 5.59 mmol) were stirred at 100°C for 3 days. The mixture was purified by flash column chromatography (silica gel, 0-4% gradient of tetrahydrofuran / petroleum ether) to give (3R,5S)-4-(4-chloro-6-methoxypyrimidin-2-yl)-3,5-dimethylmorpholine (0.20 g, 0.71 mmol, 12.7% yield). LCMS (ESI): [M+H] + =258.1; 1 H NMR(400MHz,CHLOROFORM-d)δppm 6.02(s,1H),4.52(dd,J=4.0,7.2Hz,2H),3.89(s,3H),3.82(d,J=11.6Hz,2H),3.65(dd,J=3.6,11.2Hz,2H),1.36(d,J=6.8Hz,6H)

[0346] Step 2: Dissolve (3R,5S)-4-(4-chloro-6-methoxypyrimidin-2-yl)-3,5-dimethylmorpholine (150 mg, 0.58 mmol) in acetonitrile (3.00 mL), add triethylamine (235 mg, 2.33 mmol) and ethynyltrimethylsilane (571 mg, 5.82 mmol) and tetrakistriphenylphosphine palladium (134 mg, 0.12 mmol), and stir at 100 ° C for 16 hours under nitrogen atmosphere. The reaction mixture was diluted with water (50.0 mL) and extracted with 200 mL (100 mL x 2) of ethyl acetate. The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-4% gradient of tetrahydrofuran / petroleum ether) to obtain (3R,5S)-4-{4-methoxy-6-[2-(trimethylsilyl)ethynyl]pyrimidin-2-yl}-3,5-dimethylmorpholine (120 mg, 0.28 mmol, 49.0% yield) as a white solid. LCMS (ESI): [M+H] + =320.1; 1 H NMR(400MHz,CHLOROFORM-d)δppm 6.15(s,1H),4.58(br dd,J=3.6,6.8Hz,2H),3.88(s,3H),3.81(d,J=11.2Hz,2H),3.64(dd,J=3.6,11.2Hz,2H),1.36(s,3H),1.35(s,3H),0.26(s,9H)

[0347] Step 3: (3R,5S)-4-{4-methoxy-6-[2-(trimethylsilyl)ethynyl]pyrimidin-2-yl}-3,5-dimethylmorpholine (100 mg, 0.31 mmol) and 6-(2-azido-5-bromophenyl)-6-azaspiro[2.5]octane (96.1 mg, 0.31 mmol) were dissolved in tert-butyl alcohol (1.00 mL), tetrahydrofuran (1.00 mL), and purified water (1.00 mL). Sodium ascorbate (62.0 mg, 0.31 mmol) and anhydrous copper sulfate (49.9 mg, 0.31 mmol) were added and stirred at 25°C for 16 hours. The reaction solution was diluted with water (50.0 mL) and extracted with ethyl acetate (200 mL, 100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-7% gradient of tetrahydrofuran / petroleum ether) to give 6-[5-bromo-2-(4-{2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-methoxypyrimidin-4-yl}-1H-1,2,3-triazol-1-yl)phenyl]-6-azaspiro[2.5]octane (160 mg, 0.23 mmol, 75.0% yield) as a yellow solid. LCMS (ESI): [M+H] + =555.9; 1 H NMR(400MHz,CHLOROFORM-d)δppm 8.97(s,1H),7.56(d,J=8.0Hz,1H),7.27-7.24(m,1H),7.21(s,1H),6.83(s,1H),4.61(br dd,J=3.6,6.8Hz,2H),3.90(s,3H),3.81(d,J=11.2Hz,2H),3.66(dd,J=4.0,11.6Hz,2H),2.74(t,J=5.2Hz,4H),1.39-1.30(m,10H),0.23(s,4H)

[0348] Step 4: 6-[5-Bromo-2-(4-{2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-methoxypyrimidin-4-yl}-1H-1,2,3-triazol-1-yl)phenyl]-6-azaspiro[2.5]octane (140 mg, 0.25 mmol) and 2-hydroxyethane-1-sulfonamide (41.1 mg, 0.33 mmol) were dissolved in N,N-dimethylformamide (3.00 mL), potassium phosphate (160 mg, 0.76 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (36.2 mg, 0.25 mmol) and cuprous iodide (48.1 mg, 0.25 mmol) were added, and the mixture was stirred at 100°C for 4 hours. The reaction solution was diluted with water (50.0 mL + 0.50 mL ammonia) and extracted with ethyl acetate 200 mL (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 42%-82% gradient of water (ammonia + ammonium bicarbonate) / acetonitrile) to give N-(3-{6-azaspiro[2.5]octan-6-yl}-4-(4-{2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-methoxypyrimidin-4-yl}-1H-1,2,3-triazol-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide (90.9 mg, 0.15 mmol, 60.0% yield) as a white solid. LCMS (ESI): [M+H] + =599.3; 1 H NMR (400MHz, DMSO-d6) δppm10.60-9.47(m,1H),9.13(s,1H),7.60(d,J=8.8Hz,1H),7.1 3(d,J=2.0Hz,1H),7.04(dd,J=2.0,8.4Hz,1H),6.66(s,1H),5.37-4.72(m,1H),4.58(br dd,J=3.6,6.4Hz,2H),3.90(s,3H),3.83-3.74(m,4H),3.60(br dd,J=3.6,11.6Hz,2H),3.36-3.33(m,2H),2.66(br t,J=4.4Hz,4H),1.38-1.22(m,10H),0.23(s,4H)

[0349] Example 54: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-(dimethylamino)pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0350] Step 1: Dissolve 6-[1-(2-{6-azaspiro[2.5]octan-6-yl}-4-bromophenyl)-1H-1,2,3-triazol-4-yl]-2-(4,4-difluoropiperidin-1-yl)pyrimidine-4-ol (2.90 g, 5.31 mmol) in N,N-dimethylformamide (60.0 mL), add 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (2.84 g, 7.96 mmol) and diisopropylethylamine (3.43 g, 26.5 mmol), and stir at 25 ° C for 16 hours. The reaction mixture was diluted with 100 mL of water and 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, 0-2% gradient of tetrahydrofuran / dichloromethane) to obtain 6-[1-(2-{6-azaspiro[2.5]octan-6-yl}-4-bromophenyl)-1H-1,2,3-triazol-4-yl]-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl trifluoromethanesulfonate (3.50 g, 5.10 mmol, yield 96%) as a yellow oil. LCMS (ESI): [M+H] + =679.8, 1 H NMR(400MHz,CHLOROFORM-d)δppm9.00(s,1H),7.53-7.49(m,1H),7.36-7.32(m,1H),7.29(s,1H),7.10(s,1H),3.96(br s,4H),2.73(br t,J=4.8Hz,4H),2.05-1.91(m,4H),1.34-1.25(m,4H),0.24(s,4H)

[0351] Step 2: Dissolve dimethylamine hydrochloride (0.24 g, 2.95 mmol) in tetrahydrofuran (20.0 mL), add potassium carbonate (0.81 g, 5.90 mmol) and 6-[1-(2-{6-azaspiro[2.5]octane-6-yl}-4-bromophenyl)-1H-1,2,3-triazol-4-yl]-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl trifluoromethanesulfonate (1.00 g, 1.47 mmol), and stir at 80 ° C for 2 hours. The reaction mixture was diluted with 50 mL of water 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, 0-11% gradient of tetrahydrofuran / petroleum ether) to give 6-[1-(2-{6-azaspiro[2.5]octan-6-yl}-4-bromophenyl)-1H-1,2,3-triazol-4-yl]-2-(4,4-difluoropiperidin-1-yl)-N,N-dimethylpyrimidin-4-amine (0.68 g, 1.08 mmol, 73% yield) as a white solid. LCMS (ESI): [M+H]+ =575.0, 1 H NMR (400MHz, DMSO-d6) δppm 9.14 (s, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.47-7.39 (m, 2H), 6.65 (s, 1H), 3.93 (br t,J=5.2Hz,4H),3.10(s,6H),2.75-2.67(m,4H),2.03-1.90(m,4H),1.33-1.25(m,4H),0.24(s,4H)

[0352] Step 3: 6-[1-(2-{6-azaspiro[2.5]octan-6-yl}-4-bromophenyl)-1H-1,2,3-triazol-4-yl]-2-(4,4-difluoropiperidin-1-yl)-N,N-dimethylpyrimidin-4-amine (640 mg, 1.12 mmol) and 2-hydroxyethane-1-sulfonamide (279 mg, 2.23 mmol) were dissolved in N,N-dimethylformamide (12.0 mL), and potassium phosphate (710 mg, 3.35 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (160 mg, 1.12 mmol) and cuprous iodide (212 mg, 1.12 mmol) were added and stirred at 100 ° C for 16 hours. The reaction mixture was diluted with water (100 mL + 1 mL of aqueous ammonia) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried, filtered, and concentrated. The product was purified by HPLC (C18, 26-66% gradient of water (formic acid) / acetonitrile). The residue was purified by normal phase separation (XB-CN, 5%-35% gradient of n-heptane-ethanol (0.1% aqueous ammonia)) to afford N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-(dimethylamino)pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide (244 mg, 0.39 mmol, 35% yield) as a white solid. LCMS (ESI): [M+H] + =618.3, 1H NMR(400MHz,DMSO-d6)δppm 10.49-9.60(m,1H),9.05(s,1H),7.57(d,J=8.4Hz,1H),7.12(d,J=2.0Hz,1H),7.03(dd,J=2.0,8.4Hz,1H),6.6 4(s,1H),5.17-4.76(m,1H),3.94-3.86(m,4H),3.78(t,J=6.4Hz,2H),3.34-3.30(m,2H),3.09(s,6H),2.66(br t,J=4.4Hz,4H),2.02-1.89(m,4H),1.35-1.22(m,4H),0.24(s,4H)

[0353] Examples 55 to 61 were prepared by a similar synthetic route with reference to Example 54:

[0354] Example 55: N-(4-{4-[6-amino-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}-3-{6-azaspiro[2.5]octan-6-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0355] LCMS(ESI):[M+H] + =590.3, 1 H NMR (400MHz, DMSO-d6) δ10.02(s,1H),9.02(br s,1H),7.58(br d,J=8.0Hz,1H),7.13(br s,1H),7.03(br d,J=8.0Hz,1H),6.70(br s,2H),6.52(br s,1H),5.19-4.73(m,1H),3.90(br s,4H),3.78(br s,2H),3.40-3.37(m,2H),2.67(br s,4H),2.05-1.85(br s,4H),1.40-1.24(m,4H),0.26(br s,4H)

[0356] Example 56: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-(methylamino)pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0357] LCMS(ESI):[M+H] + =604.5,1 H NMR (400MHz, DMSO-d6) δppm 9.01 (s, 1H), 7.55 (d, J = 8.4Hz, 1H), 7.26 (br s,1H),7.10(d,J=2.0Hz,1H),7.01(dd,J=2.0,8.4Hz,1H),6.52(s,1H),3.98-3.8 8(m,4H),3.78(t,J=6.8Hz,2H),3.33-3.30(m,2H),2.84(d,J=4.4Hz,3H),2.67(br t,J=4.8Hz,4H),2.03-1.87(m,4H),1.36-1.25(m,4H),0.25(s,4H)

[0358] Example 57: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-[(2-hydroxyethyl)amino]pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0359] LCMS(ESI):[M+H] + =634.2, 1 H NMR (400MHz, DMSO-d6) δppm 10.51-9.43 (m, 1H), 9.00 (s, 1H), 7.57 (d, J = 8.8Hz, 1H), 7.36 (br s,1H),7.11(d,J=2.0Hz,1H),7.02(dd,J=2.0,8.4Hz,1H),6.55(s,1H),4.72(br s,2H),3.95-3.86(m,4H),3.77(t,J=6.4Hz,2H),3.58-3.51(m,2H),3.43-3.36(m,2H), 3.33-3.27(m,2H),2.70-2.61(m,4H),2.01-1.89(m,4H),1.35-1.24(m,4H),0.24(s,4H)

[0360] Example 58: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-[(oxan-4-yl)amino]pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0361] LCMS(ESI):[M+H] + =674.7;1 H NMR(400MHz,DMSO-d6)δppm 9.01(s,1H),7.57(d,J=8.4Hz,1H),7.38-7.23(m,1H),7.12(d,J=1.6Hz,1H),7.02(dd,J=1.6,8.4Hz, 1H),6.55(s,1H),4.12-3.95(m,1H),3.95-3.83(m,6H),3.78(t,J=6.4Hz,2H),3.49-3.39(m,2H),3.32 (br s,2H),2.66(br t,J=4.8Hz,4H),2.54-2.52(m,1H),2.02-1.85(m,6H),1.54-1.40(m,2H),1.34-1.26(m,4H),0.25(s,4H)

[0362] Example 59: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-{[(pyridin-2-yl)methyl]amino}pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0363] LCMS(ESI):[M+H] + =681.3; 1 H NMR (400MHz, DMSO-d6) δppm 10.24-9.76(m,1H),9.01(s,1H),8.51(br d,J=4.4Hz,1H),8.02(br s,1H),7.74(br t,J=7.6Hz,1H),7.57(br d,J=8.4Hz,1H),7.35(d,J=7.6Hz,1H),7.30-7.20(m,1H),7.11(s,1H),7.02(br d,J=8.8Hz,1H),6.66(br s,1H),4.98(br d,J=2.4Hz,1H),4.61(br d,J=3.6Hz,2H),3.90-3.70(m,6H),3.34-3.30(m,2H),2.70-2.60(m,4H),1.90-1.70(m,4H),1.34-1.24(m,4H),0.24(s,4H)

[0364] Example 60: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-{[(pyridin-3-yl)methyl]amino}pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0365] LCMS(ESI):[M+H] + =681.3; 1 H NMR (400MHz, DMSO-d6) δppm 10.03 (s, 1H), 9.02 (s, 1H), 8.76-8.39 (m, 2H), 7.96 (br d, J=1.2Hz, 1H), 7.78 (br d,J=7.6Hz,1H),7.57(d,J=8.4Hz,1H),7.39(br d,J=2.0Hz,1H),7.11(d,J=2.0Hz,1H),7.02(dd,J=2.0,8.4Hz,1H),6.59(br s,1H),4.97(br s,1H),4.56(br d,J=5.6Hz,2H),3.87(br s,4H),3.77(br t,J=5.6Hz,2H),2.68-2.62(m,4H),2.52(br d,J=2.0Hz,2H),1.98-1.78(m,4H),1.35-1.22(m,4H),0.24(s,4H)

[0366] Example 61: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-{[(pyridin-2-yl)methyl]amino}pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0367] LCMS(ESI):[M+H] + =681.2; 1H NMR (400MHz, DMSO-d6) δppm 10.03(s,1H),9.02(s,1H),8.54(br s,2H),8.03(br s,1H),7.57(d,J=8.8Hz,1H),7.41(br d,J=4.8Hz,2H),7.12(d,J=2.4Hz,1H),7.02(dd,J=2.4,8.8Hz,1H),6.65(br s,1H),4.96(br s,1H),4.58(br d,J=4.8Hz,2H),3.91-3.74(m,6H),3.35-3.30(m,2H),2.71-2.62(m,4H),1.93-1.63(m,4H),1.36-1.24(m,4H),0.24(s,4H)

[0368] Examples 62 to 65 were prepared by a similar synthetic route with reference to Example 34:

[0369] Example 62 N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methoxypyridin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0370] LCMS(ESI):[M+H] + =604.0; 1 H NMR(400MHz,DMSO-d6)δppm 10.04(s,1H),9.17(s,1H),7.48(d,J=8.4Hz,1H),7.12(d,J=2.0Hz,1H),7.05-6.9 8(m,2H),6.64(s,1H),5.21-4.51(m,1H),3.84(s,3H),3.81-3.72(m,6H),3.34(br t,J=6.4Hz,2H),2.66(br t,J=4.4Hz,4H),2.11-1.95(m,4H),1.24(br s,4H),0.23(s,4H)

[0371] Example 63: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-3-fluoro-6-methoxypyridin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0372] LCMS (ESI): [M+H]+=622.3;1 H NMR(400MHz,DMSO-d6)δppm 10.07(s,1H),8.93(d,J=3.6Hz,1H),7.53(d,J=8.4Hz,1H),7.15(d,J=2.0Hz,1H),7.04(dd,J=2.0,8 .4Hz,1H),6.91(d,J=2.8Hz,1H),4.98(t,J=5.6Hz,1H),3.86(s,3H),3.79(q,J=6.4Hz,2H),3.64(br t,J=5.2Hz,4H),3.41-3.34(m,2H),2.72-2.65(m,4H),2.21-2.01(m,4H),1.25(br s,4H),0.25(s,4H)

[0373] Example 64: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0374] LCMS(ESI):[M+H] + =588.3, 1 H NMR (400MHz, DMSO-d6) δppm 9.84(s,1H),8.94(s,1H),7.25(d,J=8.4Hz,1H),7.03(s,1H),6.90(d,J=2.8Hz,2H),6.79(dd,J=2.0,8.8Hz,1H),4.77(br s,1H),3.61-3.47(m,6H),3.12-3.09(m,2H),2.43(br t,J=4.4Hz,4H),2.16(s,3H),1.85-1.69(m,4H),1.06-0.96(m,4H),0.00(s,4H)

[0375] Example 65: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-3-fluoro-6-methylpyridin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0376] LCMS(ESI):[M+H] + =606.3; 1H NMR(400MHz,DMSO-d6)δppm 10.06(br s,1H),8.91(d,J=3.6Hz,1H),7.52(d,J=8.4Hz,1H),7.48(d,J=3.6Hz,1H),7.14(d,J=2.0Hz,1H),7.03(dd, J=1.6,8.4Hz,1H),5.40-4.58(m,1H),3.78(t,J=6.4Hz,2H),3.65-3.50(m,4H),3.42-3.33(m,2H),2.66(br d,J=4.8Hz,4H),2.42(s,3H),2.20-2.04(m,4H),1.35-1.15(m,4H),0.24(s,4H)

[0377] Example 66: N-(6-{6-azaspiro[2.5]octan-6-yl}-5-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}pyridin-2-yl)-2-hydroxyethane-1-sulfonamide

[0378] Step 1: To a solution of 6-bromo-2-chloro-3-nitropyridine (5.00 g, 21.0 mmol) and N,N-diisopropylethylamine (8.33 g, 63.2 mmol) in tert-butanol (100 mL) was added 6-azaspiro[2.5]octane hydrochloride (2.34 g, 21.0 mmol). The mixture was heated to 80°C and stirred for 16 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 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, 0-30% gradient of ethyl acetate / petroleum ether) to afford 6-(6-bromo-3-nitropyridin-2-yl)-6-azaspiro[2.5]octane (4.60 g, 15.0 mmol, 70% yield) as a yellow solid. LCMS (ESI): [M+H] + =311.9

[0379] Step 2: To a solution of 6-(6-bromo-3-nitropyridin-2-yl)-6-azaspiro[2.5]octane (2.00 g, 6.41 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 mixture 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 spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to afford 2-{6-azaspiro[2.5]octan-6-yl}-6-bromopyridin-3-amine (1.50 g, 5.3 mmol, 83% yield) as a yellow solid. LCMS (ESI): [M+H]+=283.9.

[0380] Step 3: To a solution of 2-{6-azaspiro[2.5]octan-6-yl}-6-bromopyridin-3-amine (500 mg, 2.28 mmol) in acetonitrile (5.00 mL) was added tert-butyl nitrite (0.28 g, 2.66 mmol). Trimethylsilyl azide (0.31 g, 2.66 mmol) was then added to the reaction mixture, and the mixture was stirred at 25°C for 16 hours. The reaction mixture 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 spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether gradient) to afford 6-(3-azido-6-bromopyridin-2-yl)-6-azaspiro[2.5]octane (400 mg, 1.29 mmol, 73% yield) as a yellow oil. LCMS (ESI): [M+H]+=309.9.

[0381] Step 4: To a solution of 6-(3-azido-6-bromopyridin-2-yl)-6-azaspiro[2.5]octane (200 mg, 0.65 mmol), 2-(4,4-difluoropiperidin-1-yl)-4-ethynyl-6-methylpyrimidine (154 mg, 0.65 mmol) in tert-butanol (5 mL), tetrahydrofuran (5 mL), and water (5 mL) were added copper sulfate (104 mg, 0.65 mmol) and sodium ascorbate (129 mg, 0.65 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, 0-10% gradient of ethyl acetate / petroleum ether) to afford 6-(6-bromo-3-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}pyridin-2-yl)-6-azaspiro[2.5]octane (165 mg, 0.30 mmol, 46% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 547.2

[0382] Step 5: To a solution of 2-hydroxyethanesulfonamide (52.7 mg, 0.41 mmol), (1R,2R)-(-)-N,N-dimethylcyclohexane-1,2-diamine (39.5 mg, 0.27 mmol), and potassium phosphate (178 mg, 0.83 mmol) in N,N-dimethylformamide (5.00 mL) was added cuprous iodide (26.7 mg, 0.14 mmol). The mixture was stirred at 50°C for 5 minutes. 6-(6-bromo-3-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}pyridin-2-yl)-6-azaspiro[2.5]octane (150 mg, 0.28 mmol) was 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 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 dried to give a residue. The residue was purified by preparative HPLC (C18, 42-82% 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, 0.12 mmol, yield 44%). LCMS (ESI): [M+H]+=590.3, 1H NMR (400MHz, DMSO-d6) δppm 10.74(s,1H),9.12(s,1H),7.75(d,J=8.4Hz,1H),7.21(s,1H),6.47(d,J=8.4Hz,1H),5.13-4.74(m,1H),3.97(br t,J=5.6Hz,4H),3.86-3.67(m,4H),3.06-2.85(m,4H),2.39(s,3H),2.14-1.85(m,4H),1.32-1.19(m,4H),0.24(s,4H)

[0383] Example 67 and Example 68 were prepared by a similar synthetic route to Example 66:

[0384] Example 67: N-(4-{6-azaspiro[2.5]octan-6-yl}-5-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}pyridin-2-yl)-2-hydroxyethane-1-sulfonamide

[0385] LCMS (ESI): [M+H]+=590.3. 1 H NMR (400MHz, DMSO-d6) δppm 10.72(s,1H),9.11(s,1H),8.20(s,1H),7.22(s,1H),6.66(s,1H),4.97(s,1H),3.97(br t,J=5.2Hz,4H),3.84-3.75(m,2H),3.63(br d,J=2.8Hz,2H),2.83-2.71(m,4H),2.39(s,3H),2.06-1.91(m,4H),1.29-1.22(m,4H),0.24(s,4H)

[0386] Example 68: N-(4-{6-azaspiro[2.5]octan-6-yl}-5-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl]-1H-1,2,3-triazol-1-yl}pyridin-2-yl)-2-hydroxyethane-1-sulfonamide

[0387] LCMS (ESI): [M+H]+=589.5, 1H NMR(400MHz,DMSO-d6)δppm 10.77(s,1H),9.10(s,1H),8.15(s,1H),7.24(s,1H),7.12(s,1H),6.67(s,1H),4.98(s,1H),3.83-3.78(m,2H),3.78-3.71(m,4H),3.63(br d,J=5.2Hz,2H),2.84-2.72(m,4H),2.39(s,3H),2.12-1.92(m,4H),1.32-1.20(m,4H),0.25(s,4H)

[0388] Example 69: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-5-methyl-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0389] Step 1: To a solution of 2,4-dichloro-6-methylpyrimidine (25.0 g, 153 mmol), ethynyltrimethylsilane (15.1 g, 153 mmol), cuprous iodide (0.30 g, 1.53 mmol), and triphenylphosphine (0.40 g, 1.53 mmol) in triethylamine (39.6 g, 383 mmol) and tetrahydrofuran (500 mL) was added dichlorobis(triphenylphosphine)palladium(II) (1.09 g, 1.53 mmol). The atmosphere was replaced with nitrogen three times, and the mixture was heated to 85°C and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was used directly in the next step.

[0390] Step 2: To the filtrate of 2-chloro-4-methyl-6-[2-(trimethylsilyl)ethynyl]pyrimidine (30.0 g, 133 mmol) was added 4,4-difluoropiperidine hydrochloride (21.0 g, 133 mmol) and triethylamine (41.3 g, 400 mmol). The mixture was heated to 80°C and stirred under nitrogen for 16 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 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, 0-5% ethyl acetate / petroleum ether gradient) to afford 2-(4,4-difluoropiperidin-1-yl)-4-methyl-6-[2-(trimethylsilyl)ethynyl]pyrimidine (21.0 g, 67.8 mmol, 51% yield) as a yellow oil. LCMS (ESI): [M+H] + =310.0

[0391] Step 3: Potassium hydroxide (6.35 g, 113 mmol) was added to a solution of 2-(4,4-difluoropiperidin-1-yl)-4-methyl-6-[2-(trimethylsilyl)ethynyl]pyrimidine (17.5 g, 56.5 mmol) in methanol (200 mL), and the mixture was stirred at 25 ° C for 1 hour. Water (200 mL) was added to the reaction solution and extracted with ethyl acetate (200 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 silica gel chromatography (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to obtain a yellow solid 2-(4,4-difluoropiperidin-1-yl)-4-ethynyl-6-methylpyrimidine (8.00 g, 1.30 mmol, yield 60%). LCMS (ESI): [M+H] + = 238.0

[0392] Step 4: To a solution of 6-(2-azido-5-bromophenyl)-6-azaspiro[2.5]octane (2.07 g, 6.75 mmol) in tetrahydrofuran (5 mL) were added copper(II) perchlorate hexahydrate (5.00 g, 13.5 mmol), tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (0.36 g, 0.67 mmol), and potassium iodide (4.57 g, 26.9 mmol). The mixture was stirred at 25°C for 5 minutes. Then, 2-(4,4-difluoropiperidin-1-yl)-4-ethynyl-6-methylpyrimidine (1.76 g, 7.42 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.04 g, 6.75 mmol) were added to the reaction mixture, and the mixture was heated to 60°C and stirred for 16 hours. The reaction mixture was filtered to obtain a brown solid 6-(5-bromo-2-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-5-iodo-1H-1,2,3-triazol-1-yl}phenyl)-6-azaspiro[2.5]octane (3.80 g, 5.66 mmol, 84% yield). LCMS (ESI): [M+H]+ = 672.0; 1 H NMR(400MHz,DMSO-d6)δppm 7.54-7.36(m,3H),7.29(br s,1H),4.14-3.93(m,4H),2.74(br s,4H),2.42-2.37(m,3H),2.12-1.97(m,4H),1.25-0.99(m,4H),0.19(br s,4H)

[0393] Step 5: To a solution of 6-(5-bromo-2-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-5-iodo-1H-1,2,3-triazol-1-yl}phenyl)-6-azaspiro[2.5]octane (500.00 mg, 0.75 mmol), trimethyl-1,3,5,2,4,6-trioxatriborin (28.09 mg, 0.22 mmol), and cesium carbonate (729.08 mg, 2.24 mmol) in tetrahydrofuran (20.0 mL) was added dichlorobis(triphenylphosphine)palladium(II) (52.88 mg, 0.07 mmol). The atmosphere was replaced with nitrogen three times, and the mixture was heated to 100°C and stirred for 16 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 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 silica gel chromatography (silica gel, 0-8% gradient of ethyl acetate / petroleum ether) to obtain 6-(5-bromo-2-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-5-methyl-1H-1,2,3-triazol-1-yl}phenyl)-6-azaspiro[2.5]octane (180 mg, 0.32 mmol, 43% yield) as a white solid. LCMS (ESI): [M+H] + =560.0.

[0394] Step 6: To a solution of 2-hydroxyethanesulfonamide (71.7 mg, 0.57 mmol), trans-N,N-dimethyl-1,2-cyclohexanediamine (41.2 mg, 0.29 mmol), and potassium phosphate (243 mg, 1.15 mmol) in N,N-dimethylformamide (4.00 mL) was added cuprous iodide (27.8 mg, 0.14 mmol). The mixture was stirred at 50°C for 5 minutes. 6-(5-bromo-2-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-5-methyl-1H-1,2,3-triazol-1-yl}phenyl)-6-azaspiro[2.5]octane (160 mg, 0.29 mmol) was then added to the reaction mixture at 50°C. The mixture was heated to 100°C under nitrogen and stirred for 4 hours. Water (5 mL) was added to the reaction solution and extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with aqueous ammonia (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by preparative HPLC (C18, 26%-66% gradient of water (hydrochloric acid) / acetonitrile) to obtain a white solid compound N-(3-{6-azaspiro[2.5]octane-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-5-methyl-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide (17.0 mg, 0.03 mmol, yield 10%). LCMS (ESI): [M+H] + =603.3; 1 H NMR(400MHz,DMSO-d6)δppm 10.17(s,1H),7.36(d,J=1.4Hz,2H),7.13(d,J=2.0Hz,1H),7.04(dd,J=2.0,8.4Hz,1H),4.02-3.92(m,4H),3.79(t,J=6.4Hz, 2H),3.37(t,J=6.4Hz,2H),2.77-2.61(m,4H),2.52(s,3H),2.43(s,3H),2.14-1.97(m,4H),1.19-1.02(m,4H),0.20(s,4H)

[0395] Example 70: N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)-5-(2-hydroxypropan-2-yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0396] Step 1: To a solution of 2,6-dichloronicotinyl methyl ester (10.0 g, 48.5 mmol) in dioxane (100 mL) were added 4,4-difluoropiperidine hydrochloride (11.5 g, 72.8 mmol) and potassium carbonate (20.5 g, 146 mmol). The mixture was heated to 100°C and stirred for 16 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 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, 0-10% gradient of ethyl acetate / petroleum ether) to obtain 6-chloro-2-(4,4-difluoropiperidin-1-yl)nicotinyl ester (11.0 g, 37.8 mmol, 78% yield) as a yellow oil. LCMS (ESI): [M+H] + =327.0.

[0397] Step 2: To a solution of 6-chloro-2-(4,4-difluoropiperidin-1-yl) methyl nicotinate (5.00 g, 17.2 mmol), ethynyltrimethylsilane (1.86 g, 18.9 mmol), cuprous iodide (0.33 g, 1.72 mmol), and triphenylphosphine (0.45 g, 1.72 mmol) in triethylamine (30.0 mL) and tetrahydrofuran (20.0 mL) was added dichlorobis(triphenylphosphine)palladium(II) (1.86 g, 18.9 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, 0-10% gradient of ethyl acetate / petroleum ether) to afford methyl 2-(4,4-difluoropiperidin-1-yl)-6-((trimethylsilyl)ethynyl)nicotinate (4.30 g, 15.3 mmol, 89% yield) as a yellow oil. LCMS (ESI): [M+H] + =353.1.

[0398] Step 3: To a solution of 2-(4,4-difluoropiperidin-1-yl)-6-((trimethylsilyl)ethynyl)nicotine methyl ester (1.00 g, 3.57 mmol) in tetrahydrofuran (20.0 mL) was added methylmagnesium bromide (3.57 mL, 10.7 mmol). The atmosphere was replaced with nitrogen three times, and the mixture was stirred at -20°C for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 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, 0-5% gradient of ethyl acetate / petroleum ether) to afford (2-(4,4-difluoropiperidin-1-yl)-6-((trimethylsilyl)ethynyl)pyridin-3-yl)propan-2-ol (600 mg, 2.13 mmol, 60% yield) as a yellow solid. LCMS (ESI): [M+H]+=353.1

[0399] Step 4: To a solution of 6-(2-azido-5-iodophenyl)-6-azaspiro[2.5]octane (500 mg, 1.41 mmol), 2-(2-(4,4-difluoropiperidin-1-yl)-6-((trimethylsilyl)ethynyl)pyridin-3-yl)propan-2-ol (498 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, 0-10% gradient of ethyl acetate / petroleum ether) to afford 2-(2-(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)pyridin-3-yl)propan-2-ol (800 mg, 1.24 mmol, 89% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 635.1

[0400] Step 5: To a solution of 2-hydroxyethanesulfonamide (118 mg, 0.95 mmol), sarcosine (43.0 mg, 0.47 mmol), and potassium phosphate (410 mg, 1.89 mmol) in N,N-dimethylformamide (6 mL) was added cuprous iodide (91.9 mg, 0.47 mmol). The mixture was stirred at 50°C for 5 minutes. 2-(2-(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)pyridin-3-yl)propan-2-ol (300 mg, 0.47 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, 32-72% gradient of water (formic acid) / acetonitrile) to give N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)-5-(2-hydroxypropane-2-yl)pyridin-2-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]+ = 632.3. 1 H NMR(400MHz,DMSO-d6)δppm 10.05(br d,J=1.2Hz,1H),9.13(s,1H),8.14(d,J=8.0Hz,1H),7.89(d,J=8.0Hz,1H),7.63(d,J =8.8Hz,1H),7.13(d,J=2.0Hz,1H),7.04(dd,J=2.4,8.6Hz,1H),6.05(s,1H),4.98(br s,1H),3.78(br t,J=6.4Hz,2H),3.37-3.34(m,2H),3.17-3.06(m,4H),2.74-2.61(m,4H),2.23-2.07(m,4H),1.58(s,6H),1.43-1.30(m,4H),0.25(s,4H)

[0401] Example 71: N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0402] LCMS(ESI):[M+H] + =633.5. 1 H NMR(400MHz,DMSO-d6)δppm 10.05(s,1H),9.24(s,1H),7.69-7.50(m,2H),7.13(d,J=2.4Hz,1H),7.03(dd,J=2.4,8.4Hz,1H),5.36(s,1H),5.14-4.82(m,1H),4.05 -3.92(m,4H),3.83-3.72(m,2H),3.38-3.33(m,2H),2.71-2.64(m,4H),2.07-1.94(m,4H),1.44(s,6H),1.35-1.24(m,4H),0.25(s,4H)

[0403] Example 72: 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

[0404] 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.

[0405] 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.

[0406] 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.

[0407] 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. 1 H 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)

[0408] Examples 73 to 82 were prepared by referring to a similar synthetic route to Example 72:

[0409] Example 73: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0410] LCMS(ESI):[M+H] + =642.6, 1 H NMR (400MHz, DMSO-d6) δppm 10.17 (s, 1H), 9.30 (br d, J = 4.4Hz, 2H), 9.07 (d, J = 4.0Hz, 1H), 9.01 (br d,J=6.4Hz,1H),8.14-8.05(m,1H),7.55(d,J=8.4Hz,1H),7.20(d,J=2.0Hz,1H),7.07(dd,J=2.0,8.4Hz,1H),3.79(br t,J=6.4Hz,2H),3.43-3.32(m,6H),2.76-2.67(m,4H),2.47-2.30(m,4H),1.33-1.19(m,4H),0.23(s,4H)

[0411] Example 74: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[8-(4,4-difluoropiperidin-1-yl)-2-methylquinolin-6-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0412] LCMS(ESI):[M+H] + =638.3, 1 H NMR(400MHz,DMSO-d6)δppm 10.26-9.83(m,1H),9.16(s,1H),8.26(d,J=8.4Hz,1H),8.06(d,J=1.2Hz,1H),7.67(d,J=1.6Hz,1H),7 .51(d,J=8.4Hz,1H),7.43(d,J=8.4Hz,1H),7.14(d,J=2.0Hz,1H),7.03(dd,J=2.4,8.8Hz,1H),5.00(br s,1H),3.79(br t,J=6.0Hz,2H),3.62-3.50(m,4H),3.40-3.35(m,2H),2.74-2.65(m,7H),2.32-2.19(m,4H),1.35-1.20(m,4H),0.22(s,4H)

[0413] Example 75: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[8-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-methylquinolin-6-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0414] LCMS (ESI): [M+H]+=656.3, 1 H NMR(400MHz,DMSO-d6)δppm 10.68-9.47(m,1H),8.87(d,J=4.4Hz,1H),8.38(dd,J=3.2,8.0Hz,2H),7.61-7.38(m,2H),7.15(d,J=1.6Hz,1H),7 .04(dd,J=2.0,8.8Hz,1H),5.30-4.65(m,1H),3.79(t,J=6.4Hz,2H),3.64-3.56(m,4H),3.39-3.36(m,2H),2.67(br s,7H),2.28-2.13(m,4H),1.35-1.24(m,4H),0.24(s,4H)

[0415] Example 76: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[8-(4,4-difluoropiperidin-1-yl)cinnolin-6-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0416] LCMS(ESI):[M+H] + =625.2, 1 H NMR(400MHz,DMSO-d6)δppm 10.39-9.65(m,1H),9.45-9.24(m,2H),8.18(d,J=6.0Hz,1H),8.13(d,J=1.2Hz,1H),7.79(d,J=1.2Hz,1H),7.52(d, J=8.8Hz,1H),7.15(d,J=2.0Hz,1H),7.04(dd,J=2.4,8.4Hz,1H),5.45-4.52(m,1H),3.79(t,J=6.4Hz,2H),3.74(br d,J=4.4Hz,4H),3.35(t,J=6.4Hz,2H),2.77-2.66(m,4H),2.36-2.21(m,4H),1.32-1.2(br s,4H),0.22(s,4H)

[0417] Example 77: N-(4-{4-[3-amino-8-(4,4-difluoropiperidin-1-yl)cinnolin-6-yl]-1H-1,2,3-triazol-1-yl}-3-{6-azaspiro[2.5]octan-6-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0418] LCMS(ESI):[M+H] + =640.3, 1 H NMR (400MHz, DMSO-d6) δ10.14-9.53(m,1H),9.00(s,1H),7.52(br s,1H),7.28(br d,J=8.4Hz,1H),7.09(br s,1H),6.91(br s,1H),6.87-6.61(m,2H),6.36-6.16(m,2H),4.86-4.64(m,1H),3.67-3.52(m,2H),3.50-3.30(m,4H),3.11(br s,2H),2.53-2.42(m,4H),2.05-1.90(m,4H),1.05(br s,4H),0.00(s,4H)

[0419] Example 78: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[3-(4,4-difluoropiperidin-1-yl)-5-methyl-4-nitrophenyl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0420] LCMS (ESI): [M+H]+=632.3, 1 H NMR(400MHz,DMSO-d6)δppm 10.05(s,1H),9.18(s,1H),7.92-7.77(m,2H),7.48(d,J=8.4Hz,1H),7.13(d,J=2.0H z,1H),7.02(dd,J=2.0,8.4Hz,1H),5.19-4.75(m,1H),3.78(t,J=6.4Hz,2H),3.36(br s,2H),3.11(br t,J=5.2Hz,4H),2.74-2.61(m,4H),2.31(s,3H),2.11-2.00(m,4H),1.32-1.19(m,4H),0.24(s,4H)

[0421] Example 79: N-(4-{4-[5-amino-6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl]-1H-1,2,3-triazol-1-yl}-3-{6-azaspiro[2.5]octan-6-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0422] LCMS(ESI):[M+H] + =590.3, 1H NMR (400MHz, DMSO-d6) δ10.20-9.84(m,1H),8.87(s,1H),8.60-8.09(m,1H),7.58(br d,J=8.4Hz,1H),7.12(br s,1H),7.03(br d,J=8.4Hz,1H),6.36(br s,2H),5.11-4.84(m,1H),3.78(br t,J=5.6Hz,2H),3.33-3.22(m,6H),2.68(br t,J=4.4Hz,4H),2.27-2.13(m,4H),1.34(br s,4H),0.25(s,4H)

[0423] Example 80: N-(4-{4-[2-amino-8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl]-1H-1,2,3-triazol-1-yl}-3-{6-azaspiro[2.5]octan-6-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0424] LCMS(ESI):[M+H] + =657.3; 1 H NMR(400MHz,DMSO-d6)δ13.17-11.36(m,1H),10.05(s,1H),8.92-8.66(m,1H),8 .42-7.92(m,2H),7.53(d,J=8.4Hz,1H),7.14(d,J=2.0Hz,1H),7.03(dd,J=2.0, 8.8Hz,1H),6.95-6.54(m,2H),4.99(t,J=5.6Hz,1H),3.78(q,J=6.4Hz,2H),3.5 2-3.41(m,4H),3.31-3.24(m,2H),2.73-2.66(m,4H),2.39-2.07(m,4H),1.28(br s,4H),0.24(s,4H)

[0425] Example 81: N-(4-{4-[2-amino-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-6-yl]-1H-1,2,3-triazol-1-yl}-3-{6-azaspiro[2.5]octan-6-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0426] LCMS(ESI):[M+H] + =663.2; 1H NMR (400MHz, DMSO-d6) δ10.05 (s, 1H), 8.68 (d, J = 3.9Hz, 1H), 8.16-8.06 (m, 1H), 7.77 (br s,2H),7.51(d,J=8.5Hz,1H),7.13(d,J=2.1Hz,1H),7.02(dd,J=2.2,8.6Hz,1H),3.78(t,J=6. 6Hz,2H),3.48-3.42(m,4H),3.28-3.24(m,2H),2.72-2.64(m,4H),2.18-2.04(m,4H),1.27(br s,4H),0.24(s,4H)

[0427] Example 82: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-[3,3'-bipyridyl]-6-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0428] LCMS(ESI):[M+H] + =651.3, 1 H NMR(400MHz,DMSO-d6)δppm 10.06(br s,1H),9.16(s,1H),8.87(d,J=2.0Hz,1H),8.59(dd,J=1.6,4.8Hz,1H),8.1 3(td,J=2.0,8.0Hz,1H),7.81(d,J=7.6Hz,1H),7.73(d,J=7.6Hz,1H),7.63 (d,J=8.4Hz,1H),7.52(dd,J=5.2,8.0Hz,1H),7.14(d,J=2.0Hz,1H),7.05( dd,J=2.0,8.4Hz,1H),5.00(t,J=5.6Hz,1H),3.79(q,J=6.4Hz,2H),3.33(br s,2H),3.28-3.22(m,4H),2.74-2.65(m,4H),2.09-1.87(m,4H),1.37(br s,4H),0.26(s,4H)

[0429] Example 83: (2R)-N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-1-hydroxypropane-2-sulfonamide

[0430] Example 84: (2S)-N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-1-hydroxypropane-2-sulfonamide

[0431] Step 1: To a solution of bis(4-methoxybenzyl)amine (5.00 g, 19.4 mmol) and N,N-diisopropylethylamine (5.12 g, 38.9 mmol) in dichloromethane (50 mL) was added dropwise ethyl 2-(chlorosulfonyl)acetate (3.63 g, 19.4 mmol). The mixture was stirred at 20°C for 2 hours. The reaction solution was extracted with water (100 mL) and dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to dryness to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / petroleum ether) to afford ethyl 2-{bis[(4-methoxyphenyl)methyl]sulfamoyl}acetate (3.10 g, 7.60 mmol, 39% yield) as a pale yellow oil. 1 H NMR (400MHz, DMSO-d6) δppm7.14(d,J=8.4Hz,4H),6.86(d,J=8.4Hz,4H),4.29(s,2H),4.25(s,4H),3.73(s,8H),1.21(t,J=7.2Hz,3H)

[0432] Step 2: To a solution of ethyl 2-{bis[(4-methoxyphenyl)methyl]sulfamoyl}acetate (3.10 g, 7.60 mmol) in N,N-dimethylformamide (40 mL) was added cesium carbonate (3.79 g, 11.4 mmol), followed by the slow dropwise addition of iodomethane (1.32 g, 9.13 mmol). The mixture was stirred at 20°C for 16 hours. The reaction solution was extracted with water (100 mL) and ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to dryness to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / petroleum ether) to afford ethyl 2-{bis[(4-methoxyphenyl)methyl]sulfamoyl}propyl ester (2.60 g, 7.60 mmol, 81% yield) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δppm 7.13(d,J=8.4Hz,4H),6.85(d,J=8.4Hz,4H),4.36-4.23(m,3H),4.23-4.11(m,4H),3.73(s,6H),1.46(d,J=7.2Hz,3H),1.21(t,J=7.2Hz,3H)

[0433] Step 3: Add anisole (2 mL) to a solution of ethyl 2-{bis[(4-methoxyphenyl)methyl]sulfamoyl}propyl ester (1.20 g, 2.85 mmol) in trifluoroacetic acid (10 mL). The mixture was stirred at 20°C for 3 hours. The reaction solution was concentrated, saturated sodium bicarbonate aqueous solution was added to adjust the pH to 7, and then extracted with ethyl acetate (25 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to dryness to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran / petroleum ether) to obtain ethyl 2-sulfamoylpropyl ester (0.42 g, 1.92 mmol, 81% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm7.13(s,2H),4.14(q,J=7.2Hz,2H),3.97(d,J=6.8Hz,1H),1.44(d,J=6.8Hz,3H),1.21(t,J=7.2Hz,3H)

[0434] Step 4: To a solution of 6-(5-bromo-2-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-6-azaspiro[2.5]octane (800 mg, 1.47 mmol) and ethyl 2-sulfamoylpropyl ester (399 mg, 2.20 mmol) in dioxane (15 mL) was added 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (125 mg, 0.29 mmol), potassium phosphate (955 mg, 4.41 mmol), and tris(dibenzylideneacetone)dipalladium (137 mg, 0.15 mmol). The reaction mixture was purged with nitrogen three times and heated to 90°C under a nitrogen atmosphere with stirring for 2 hours. The reaction mixture was cooled to room temperature and extracted with water (30 mL) and ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-33% gradient of ethyl acetate / petroleum ether) to give ethyl 2-[(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)sulfamoyl]propyl ester (830 mg, 1.29 mmol, 88% yield) as a white solid. LCMS (ESI): [M+H]+ = 645.4; 1 H NMR (400MHz, DMSO-d6) δppm 10.53 (s, 1H), 9.22 (s, 1H), 7.59 (d, J = 8.8Hz, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 7.05 (br d,J=8.8Hz,1H),4.27(q,J=6.8Hz,1H),4.14-4.06(m,2H),3.98(br t,J=5.6Hz,4H),2.71-2.61(m,4H),2.40(s,3H),2.05-1.97(m,4H),1.48(d,J=6.8Hz,3H),1.28(br s,4H),1.19-1.15(m,3H),0.24(s,4H)

[0435] Step 5: Ethyl 2-[(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)sulfamoyl]propyl ester (590 mg, 0.92 mmol) was added to a tetrahydrofuran (12 mL) solution. Lithium aluminum tetrahydride (49.0 mg, 1.37 mmol) was added portionwise at 0°C, and the mixture was stirred at 0°C for 1 hour. The reaction solution was quenched with water (0.05 mL) and 10% aqueous sodium hydroxide solution (0.10 mL), filtered, and the filtrate was dried to obtain a residue. The residue was purified by preparative HPLC (C18, 48-88% gradient of water (formic acid) / acetonitrile) and resolved by chiral SFC (IG, system: carbon dioxide / methanol (0.1% of aqueous ammonia)) to give a white solid compound (2R)-N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-1- Hydroxypropane-2-sulfonamide (107 mg, 0.17 mmol, yield 19%) (Example 83) and (2S)-N-(3-{6-azaspiro[2.5]octane-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-1-hydroxypropane-2-sulfonamide (91.0 mg, 0.15 mmol, yield 17%) (Example 84).

[0436] Example 83: LCMS (ESI): [M+H] + = 603.3; 1 H NMR (400MHz, DMSO-d6) δppm 10.08(s,1H),9.22(s,1H),7.57(d,J=8.8Hz,1H),7.21(s,1H),7.15(d,J=2.4Hz,1H),7.05(dd,J=2.4,8.4Hz,1H),5.04(br t,J=5.6Hz,1H),3.98(br t,J=5.6Hz,4H),3.90-3.83(m,1H),3.49(td, J=6.8,11.2Hz,1H),3.30-3.21(m,1H),2.66(br t,J=5.2Hz,4H),2.40(s,3H),2.07-1.93(m,4H),1.36-1.24(m,7H),0.24(s,4H)

[0437] Example 84: LCMS (ESI): [M+H] + = 603.3; 1H NMR(400MHz,DMSO-d6)δppm 10.03(s,1H),9.22(s,1H),7.56(d,J=8.8Hz,1H),7.21(s,1H),7.14(d,J=2.4Hz,1H),7.04(dd,J=2.4,8.4Hz,1H),5.09(s,1H),3.98(br t,J=5.6Hz,4H),3.86(dd,J=4.4,11.2Hz,1H),3.49(dd,J=7.6,11.2Hz,1H),3.29-3.19(m,1H),2.66(br t,J=5.2Hz,4H),2.40(s,3H),2.07-1.92(m,4H),1.37-1.21(m,7H),0.24(s,4H)

[0438] Examples 85 to 87 were prepared by referring to a similar synthetic route to Example 84:

[0439] Example 85: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-1-(hydroxymethyl)cyclopropane-1-sulfonamide

[0440] LCMS (ESI): [M+H]+=603.3; 1 H NMR (400MHz, DMSO-d6) δppm 9.21(s,1H),7.50(d,J=8.8Hz,1H),7.22(s,1H),7.13(d,J=2.0Hz,1H),6.99(dd,J=2.0,8.8Hz,1H),3.98(br t,J=5.2Hz,4H),3.76(s,2H),2.65(br t,J=5.2Hz,4H),2.40(s,3H),2.06-1.88(m,4H),1.28(br s,4H),1.14-1.07(m,2H),0.99-0.90(m,2H),0.24(s,4H)

[0441] Example 86: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-1-hydroxy-2-methylpropane-2-sulfonamide

[0442] LCMS (ESI): [M+H]+=617.5;1 H NMR (400MHz, DMSO-d6) δppm 10.05-9.69 (m, 1H), 9.23 (s, 1H), 7.54 (d, J = 8.4Hz, 1H), 7.25 (d, J = 2.0 Hz,1H),7.21(s,1H),7.08(dd,J=2.4,8.8Hz,1H),5.21-5.03(m,1H),3.98(br t,J=5.6Hz,4H),3.57(s,2H),2.70-2.62(m,4H),2.40(s,3H),2.15-1.91(m,4H),1.35-1.18(m,10H),0.24(s,4H)

[0443] Example 87A: (2R)-N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl]-1H-1,2,3-triazol-1-yl}phenyl)-1-hydroxypropane-2-sulfonamide

[0444] LCMS (ESI): [M+H]+=656.1; 1 H NMR(400MHz,DMSO-d6)δppm 10.07(br d,J=3.6Hz,1H),9.04-8.84(m,2H),8.65-8.31(m,2H),7.88-7.37(m,2H),7.17(d,J=2.0Hz,1H),7.06(dd,J=2.0,8.8Hz,1H),5.04(br s,1H),3.87(br d,J=7.2Hz,1H),3.59(br t,J=4.8Hz,4H),3.53-3.43(m,1H),3.30-3.26(m,1H),2.70(br t,J=4.8Hz,4H),2.25-2.10(m,4H),1.35-1.23(m,7H),0.24(s,4H)

[0445] Example 87B: (2S)-N-(3-{6-Azaspiro[2.5]octan-6-yl}-4-{4-[8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl]-1H-1,2,3-triazol-1-yl}phenyl)-1-hydroxypropane-2-sulfonamide

[0446] LCMS (ESI): [M+H]+=656.1; 1H NMR(400MHz,DMSO-d6)δppm 10.08(s,1H),9.02-8.81(m,2H),8.49(dd,J=7.6,18.4Hz,2H),7.66-7.41(m,2H),7.17(d,J=2.0Hz,1H),7.06(dd,J=2.0,8.8Hz,1H),5.05(br s,1H),3.93-3.81(m,1H),3.59(br s,4H),3.53-3.44(m,1H),3.29-3.24(m,1H),2.70(br t,J=4.8Hz,4H),2.26-2.10(m,4H),1.36-1.23(m,7H),0.24(s,4H)

[0447] Example 88: N-{3-[4-(difluoromethylidene)piperidin-1-yl]-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl}-2-hydroxyethane-1-sulfonamide

[0448] Step 1: To a solution of tert-butyl 4-oxyylidenepiperidin-1-carboxylate (5.00 g, 25.1 mmol) and 2-difluoromethanesulfonylpyridine (4.85 g, 25.1 mmol) in N,N-dimethylformamide (100 mL) was slowly added dropwise at -40°C. A solution of potassium tert-butoxide (4.27 g, 37.6 mmol) in N,N-dimethylformamide (100 mL) was added. The mixture was stirred at -40°C for 0.5 hours. Saturated ammonium chloride (12 mL) and 3M hydrochloric acid (30 mL) were then added to the reaction solution. The temperature was then slowly raised to room temperature. The mixture was extracted with ethyl acetate (100 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 flash column chromatography (silica gel, 0-8% gradient of ethyl acetate / petroleum ether) to give tert-butyl 4-(difluoromethylidene)piperidine-1-carboxylate (3.50 g, 15.0 mmol, 60% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δppm 3.42-3.28 (m, 4H), 2.08 (br t, J = 5.6Hz, 4H), 1.46-1.32 (m, 9H)

[0449] Step 2: To a solution of tert-butyl 4-(difluoromethylidene)piperidine-1-carboxylate (3.50 g, 15.0 mmol) in dioxane (35 mL) was added hydrochloric acid / dioxane (35 mL, 4 M). The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated and dried to afford 4-(difluoromethylidene)piperidine hydrochloride (2.50 g, 14.7 mmol, 98.2% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.52-9.06(m,2H),3.14-3.02(m,4H),2.45-2.32(m,4H)

[0450] Step 3: To a solution of 4-bromo-2-fluoro-1-nitrobenzene (2.70 g, 12.3 mmol) and N,N-diisopropylethylamine (4.86 g, 36.8 mmol) in acetonitrile (54 mL) was added 4-(difluoromethylidene)piperidine hydrochloride (2.08 g, 12.3 mmol). The mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated and dried to obtain 1-(5-bromo-2-nitrophenyl)-4-(difluoromethylidene)piperidine (3.80 g, 11.4 mmol, 93% yield) as a yellow solid. LCMS (ESI): [M+H] + =332.9; 1 H NMR(400MHz, DMSO-d6)δppm 7.80(d,J=8.8Hz,1H),7.48(d,J=2.0Hz,1H),7.29(dd,J=2.0,8.4Hz,1H),3.06(t,J=5.6Hz,4H),2.31-2.21(m,4H)

[0451] Step 4: To a solution of 1-(5-bromo-2-nitrophenyl)-4-(difluoromethylidene)piperidine (3.70 g, 11.1 mmol) in methanol (80 mL) and water (20 mL) was added ammonium chloride (1.80 g, 33.3 mmol) and iron powder (3.13 g, 55.5 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 give a brown solid 4-bromo-2-[4-(difluoromethylidene)piperidin-1-yl]aniline (3.35 g, 10.9 mmol, yield 99%). LCMS (ESI): [M+H] + =304.9; 1H NMR (400MHz, DMSO-d6) δppm 7.02-6.95 (m, 2H), 6.69 (d, J = 8.4Hz, 1H), 5.02 (s, 2H), 2.83 (br t, J = 4.8Hz, 4H), 2.36 (br t, J = 5.2Hz, 4H)

[0452] Step 5: To a solution of 4-bromo-2-[4-(difluoromethylidene)piperidin-1-yl]aniline (3.30 g, 10.9 mmol) in acetonitrile (60 mL) at 0°C was added tert-butyl nitrite (1.71 g, 16.3 mmol). Trimethylsilylazide (1.88 g, 16.3 mmol) was then added to the reaction mixture, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 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, 0-10% gradient of ethyl acetate / petroleum ether) to afford 1-(2-azido-5-bromophenyl)-4-(difluoromethylidene)piperidine (3.00 g, 9.15 mmol, 84% yield) as a yellow solid. LCMS(ESI):[M+H] + =330.9; 1 H NMR (400MHz, DMSO-d6) δppm 7.31 (dd, J=2.0, 8.4Hz, 1H), 7.24 (d, J=2.0Hz, 1H), 7.16 (d, J=8.4Hz, 1H), 3.04 (br t, J=5.6Hz, 4H), 2.35 (br t, J=5.4Hz, 4H)

[0453] Step 6: To a solution of 1-(2-azido-5-bromophenyl)-4-(difluoromethylidene)piperidine (500 mg, 1.52 mmol), 2-(4,4-difluoropiperidin-1-yl)-4-methyl-6-[2-(trimethylsilyl)ethynyl]pyrimidine (470 mg, 1.52 mmol) in tert-butanol (5 mL) and water (5 mL) were added copper sulfate (242 mg, 1.52 mmol) and sodium ascorbate (301 mg, 1.51 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, 0-15% gradient of ethyl acetate / petroleum ether) to afford 4-(1-{4-bromo-2-[4-(difluoromethylidene)piperidin-1-yl]phenyl}-1H-1,2,3-triazol-4-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine (800 mg, 1.41 mmol, 93% yield) as a yellow solid. LCMS (ESI): [M+H] + =568.0; 1 H NMR(400MHz,DMSO-d6)δppm 8.78(s,1H),7.48(d,J=8.4Hz,1H),7.31(dd,J=2.0,8.4Hz,1H),7.24(d,J=2.0Hz ,1H),7.22(s,1H),4.01-3.96(m,4H),2.73(t,J=5.6Hz,4H),2.40(s,3H),2.13(br t,J=5.6Hz,4H),2.00-1.90(m,4H)

[0454] Step 7: To a solution of 2-hydroxyethanesulfonamide (177 mg, 1.41 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (101 mg, 0.71 mmol), and potassium phosphate (450 mg, 2.12 mmol) in N,N-dimethylformamide (8 mL) was added cuprous iodide (134 mg, 0.71 mmol). The mixture was stirred at 50°C for 5 minutes. 4-(1-{4-bromo-2-[4-(difluoromethylidene)piperidin-1-yl]phenyl}-1H-1,2,3-triazol-4-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine (400 mg, 0.71 mmol) was then added to the reaction mixture at 50°C. The mixture was heated to 100°C and stirred for 4 hours under nitrogen. 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, 44-84% gradient of water (formic acid) / acetonitrile) to obtain a white solid compound N-{3-[4-(difluoromethylidene)piperidin-1-yl]-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl}-2-hydroxyethane-1-sulfonamide (210 mg, 0.35 mmol, yield 49%). LCMS (ESI): [M+H] + =611.1; 1 H NMR (400MHz, DMSO-d6) δppm 10.10(br s,1H),9.22(s,1H),7.57(d,J=8.4Hz,1H),7.23(s,1H),7.12-7.02(m,2H),4.99(br t,J=5.6Hz,1H),3.96(br t,J=5.2Hz,4H),3.82-3.74(m,2H), 3.38-3.35(m,2H),2.69(br t,J=5.2Hz,4H),2.40(s,3H),2.12-2.04(m,4H),2.03-1.90(m,4H)

[0455] Example 89: N-(4-(1-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide

[0456] Step 1: To a solution of 2-fluoro-4-iodobenzaldehyde (1.00 g, 4.00 mmol) and potassium carbonate (1.65 g, 12.00 mmol) in dimethyl sulfoxide (20 mL) was added 6-azaspiro[2.5]octane hydrochloride (0.49 g, 4.40 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 (1.00 g, 2.93 mmol, yield 73%) as a yellow solid. LCMS (ESI): [M+H] + =341.9.

[0457] Step 2: To a solution of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzaldehyde (1.00 g, 2.93 mmol) and potassium carbonate (0.81 g, 5.86 mmol) in methanol (20 mL) was added dimethyl(1-diazo-2-oxyidenepropyl)phosphonate (0.68 g, 3.52 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 obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate / petroleum ether) to give 6-(2-ethynyl-5-iodophenyl)-6-azaspiro[2.5]octane (0.90 g, 2.67 mmol, 91% yield) as a yellow solid. LCMS (ESI): [M+H] + =338.0.

[0458] Step 3: Sodium azide (2.54 g, 39.1 mmol) was added to a solution of 4-chloro-6-methyl-2-(methylthio)pyrimidine (4.50 g, 25.7 mmol) in N,N-dimethylformamide (45 mL). The mixture was stirred at 25 ° C for 16 hours. Water (100 mL) was added to 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, 0-7% gradient of ethyl acetate / petroleum ether) to give a yellow solid 4-azido-6-methyl-2-(methylthio)pyrimidine (3.00 g, 16.5 mmol, yield 64%). LCMS (ESI): [M+H] + =181.9.

[0459] Steps 4 to 5: To a solution of 4-azido-6-methyl-2-(methylthio)pyrimidine (1.50 g, 8.28 mmol) in dichloromethane (45 mL) was added potassium monopersulfate (13.9 g, 82.8 mmol) in portions. The mixture was stirred at 25°C for 36 hours. The mixture was filtered. 4,4-difluoropiperidine hydrochloride (1.66 g, 10.5 mmol) and triethylamine (2.13 g, 21.1 mmol) were added to the filtrate. The mixture was stirred at 25°C for 16 hours. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (50 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, 0-12% gradient of ethyl acetate / petroleum ether) to give 4-azido-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine (1.00 g, 3.93 mmol, yield 56%) as a yellow solid. LCMS (ESI): [M+H] + =254.9.

[0460] Step 6: To a solution of 4-azido-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine (575 mg, 2.26 mmol), 6-(2-ethynyl-5-iodophenyl)-6-azaspiro[2.5]octane (762 mg, 2.26 mmol) in tert-butanol (5 mL), tetrahydrofuran (5 mL) and water (5 mL) were added copper sulfate (360 mg, 2.26 mmol) and sodium ascorbate (448 mg, 2.26 mmol). The mixture was stirred at 25 ° C for 16 hours. Water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 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, 0-12% gradient of ethyl acetate / petroleum ether) to give 6-(2-(1-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-iodophenyl)-6-azaspiro[2.5]octane (500 mg, 0.84 mmol, 37% yield) as a yellow solid. LCMS (ESI): [M+H] + =592.0.

[0461] Step 7: To a solution of 2-hydroxyethanesulfonamide (253 mg, 2.02 mmol), 2-(methylamino)acetic acid (90.3 mg, 1.01 mmol), and potassium phosphate (878 mg, 4.05 mmol) in N,N-dimethylformamide (12 mL) was added cuprous iodide (98.5 mg, 0.50 mmol). The mixture was stirred at 50°C for 5 minutes. 6-(2-(1-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-iodophenyl)-6-azaspiro[2.5]octane (600 mg, 1.01 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, 48-88% gradient of water (formic acid) / acetonitrile) to give N-(4-(1-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethanesulfonamide (324.6 mg, 0.54 mmol, yield 54%) as a white solid compound. LCMS (ESI): [M+H] + =589.5. 1 H NMR(400MHz,DMSO-d6)δppm 9.80(s,1H),9.56(s,1H),8.09(d,J=8.4Hz,1H),7.29(s,1H),7.18(d,J=2.0Hz,1H),7.07(dd,J=2.0,8.4Hz,1H),4.95(t,J=5.6Hz,1H),4.01(br t,J=5.2Hz,4H),3.76(q,J=6.4Hz,2H),3.32-3.28(m,2H),2.84(br t,J=4.8Hz,4H),2.47(s,3H),2.11-2.01(m,4H),1.78-1.30(m,4H),0.36(s,4H)

[0462] Example 90 and Example 91 were prepared by referring to the similar synthetic route of Example 89:

[0463] Example 90: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{1-[2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl]-1H-1,2,3-triazol-4-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0464] LCMS(ESI):[M+H] + =605.1; 1 H NMR(400MHz,DMSO-d6)δppm 9.89(s,1H),9.43(s,1H),8.08(d,J=8.4Hz,1H),7.18(d,J=2.0Hz,1H),7.07(dd,J=2.0,8.4Hz,1H),6.72(s,1H),4.95(s,1H),4.01(br t,J=5.6Hz,4H),3.98(s,3H),3.76(t,J=6.8Hz,2H),3.31-3.26(m,2H),2.85(br t,J=4.8Hz,4H),2.21-2.00(m,4H),1.75-1.31(m,4H),0.37(s,4H)

[0465] Example 91: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{2-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl]-2H-1,2,3,4-tetrazol-5-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0466] LCMS(ESI):[M+H] + =588.3, 1 H NMR (400MHz, DMSO-d6) δ9.62(s,1H),8.95(s,1H),7.56(d,J=8.4Hz,1H),7.01(s,1H),6.94(s,1H),6.88(d, J=2.0Hz,1H),6.76(dd,J=2.0,8.4Hz,1H),5.04-4.38(m,1H),3.60-3.49(m,6H),3.05-3.03(m,2H),2.58(br t,J=4.8Hz,4H),2.20(s,3H),1.85-1.72(m,4H),1.25-1.15(m,4H),0.06(s,4H)

[0467] Example 92: (2R)-N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{1-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-4-yl}phenyl)-1-hydroxypropane-2-sulfonamide

[0468] Example 93 (2S)-N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{1-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-4-yl}phenyl)-1-hydroxypropane-2-sulfonamide

[0469] Example 92: LCMS (ESI): [M+H] + = 603.3; 1 H NMR(400MHz,DMSO-d6)δppm 9.92(s,1H),9.46(s,1H),8.08(d,J=8.4Hz,1H),7.30(s,1H),7.20(d,J=2.0Hz,1H),7.08(dd,J=2.0,8.4Hz,1H),4.99(s,1H),4.01(br t,J=5.6Hz,4H),3.85(dd,J=4.4,10.8Hz,1H),3.43(m,1H),3.22(m,1H),2.84(br t,J=4.8Hz,4H),2.47(s,3H),2.14-1.96 (m,4H),1.55(br s,4H),1.29(d,J=6.8Hz,3H),0.36(s,4H)

[0470] Example 93: LCMS (ESI): [M+H] + = 603.1; 1 H NMR(400MHz,DMSO-d6)δppm 9.91(s,1H),9.46(s,1H),8.08(d,J=8.4Hz,1H),7.29(s,1H),7.20(d,J=2.0Hz,1H),7.08(dd,J=2.0,8.4Hz,1H),4.99(s,1H),4.01(br t,J=5.6Hz,4H),3.85(dd,J=3.6,10.8Hz,1H),3.45(br t,J=8.4Hz,1H),3.22(m,1H),2.84(br t,J=4.8Hz,4H),2.47(s,3H),2.14-1.96(m,4H),1.55(br s,4H),1.29(d,J=6.8Hz,3H),0.36(s,4H)

[0471] Example 94: 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

[0472] 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

[0473] 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.

[0474] 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.

[0475] 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.

[0476] 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 under nitrogen and stirred 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)

[0477] Example 95: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0478] Example 95 was prepared by a similar synthetic route according to Example 54; LCMS (ESI): [M+H] + = 635.3; 1 H NMR(400MHz,DMSO-d6)δppm 10.13(s,1H),9.16(s,1H),7.55(d,J=8.4Hz,1H),7.11(d,J=1.6Hz,1H),7.01(dd,J=2.0,8 .8Hz,1H),6.68(s,1H),5.29(s,1H),4.88(t,J=5.6Hz,1H),4.36(t,J=5.2Hz,2H),3.96(br s,4H),3.81-3.67(m,4H),3.32-3.29(m,2H),2.66(br t,J=4.8Hz,4H),2.11-1.90(m,4H),1.29(br s,4H),0.24(s,4H)

[0479] Example 96: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-(oxolane-3-oxy)pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0480] Example 96 was prepared by a similar synthetic route according to Example 54; LCMS (ESI): [M+H]+=661.2; 1 H NMR(400MHz,DMSO-d6)δppm 10.13(s,1H),9.17(s,1H),7.56(d,J=8.4Hz,1H),7.13(d,J=2.4Hz,1H),7.03(dd,J=2.0,8.8Hz,1H),6.67(s,1H),5.56(tt ,J=2.4,4.8Hz,1H),5.14-4.79(m,1H),4.01-3.92(m,5H),3.90-3.80(m,2H),3.80-3.71(m,3H),3.35-3.33(m,2H),2.66(br t,J=5.2Hz,4H),2.32-2.22(m,1H),2.11-1.95(m,5H),1.29(br s,4H),0.25(s,4H)

[0481] Example 97: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-[(oxolane-3-yl)methoxy]pyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-2-hydroxyethane-1-sulfonamide

[0482] Example 97 was prepared by a similar synthetic route according to Example 54; LCMS (ESI): [M+H]+=675.2; 1 H NMR(400MHz,DMSO-d6)δppm 10.54-9.69(m,1H),9.16(s,1H),7.57(d,J=8.4Hz,1H),7.21-6.92(m,2H),6.68(s,1H),5.19-4.78(m,1H),4.49-4.13(m,2H),3.97(br s,4H),3.86-3.74(m,4H),3.67(q,J=7.6Hz,1H),3.55(br dd,J=5.6,8.4Hz,2H),2.67(br s,6H),2.02(br t,J=12.8Hz,5H),1.69(td,J=6.8,12.8Hz,1H),1.29(br s,4H),0.25(s,4H)

[0483] Example 98: N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-1H-1,2,3-triazol-1-yl}phenyl)-1-hydroxybutane-2-sulfonamide

[0484] LCMS (ESI): [M+H]+=617.3; 1H NMR(400MHz,DMSO-d6)δppm 9.99(m,1H),9.21(s,1H),7.56(d,J=8.4Hz,1H),7.21(s,1H),7.14(d,J=2.4Hz,1H),7.03(dd,J=2.4,8.4Hz,1H),5.35-4.67(m,1H),3.98(br t,J=5.6Hz,4H),3.86(dd,J=4.8,11.2Hz,1H),3.67(dd,J=6.4,11.6Hz,1H),3.07(br t,J=5.6Hz,1H),2.66(br t,J=5.2Hz,4H),2.40(s,3H),2.06-1.93(m,4H),1.90-1.73(m,2H),1.28(br s,4H),1.00(t,J=7.2Hz,3H),0.24(s,4H)

[0485] Example 99: (2R)-N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-1H-1,2,3-triazol-1-yl}phenyl)-1-hydroxypropane-2-sulfonamide

[0486] LCMS (ESI): [M+H]+=638.1. 1 H NMR(400MHz,DMSO-d6)δppm 10.56-9.63(m,1H),9.20(s,1H),8.96-8.79(m,1H),8.39(br d,J=7.2Hz,1H),8.13(s,1H),7.73(s,1H),7.62-7.44(m,2H),7.16(d,J=1.6Hz,1H), 7.04(dd,J=2.0,8.4Hz,1H),5.45-4.58(m,1H),3.88(dd,J=4.4,11.2Hz,1H),3.58(br s,4H),3.50(br dd,J=8.0,10.8Hz,1H),3.29-3.22(m,1H),2.70(br s,4H),2.25(br t,J=13.2Hz,4H),1.35-1.22(m,7H),0.23(s,4H)

[0487] Example 100: (2S)-N-(3-{6-azaspiro[2.5]octan-6-yl}-4-{4-[8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl]-1H-1,2,3-triazol-1-yl}phenyl)-1-hydroxypropane-2-sulfonamide

[0488] LCMS (ESI): [M+H]+=638.1. 1 H NMR(400MHz,DMSO-d6)δppm 10.85-9.40(m,1H),9.20(s,1H),8.87(dd,J=2.0,4.0Hz,1H),8.38(dd,J=1.6,8.4Hz,1H),8.12(d,J=1.2Hz,1H),7.72(d,J=1.2Hz, 1H),7.58-7.44(m,2H),7.15(d,J=2.0Hz,1H),7.03(dd,J=2.0,8.4Hz,1H),5.64-4.36(m,1H),3.87(dd,J=4.4,11.2Hz,1H),3.58(br s,4H),3.49(dd,J=8.0,11.2Hz,1H),3.30-3.23(m,1H),2.69(br t,J=4.8Hz,4H),2.32-2.16(m,4H),1.37-1.24(m,7H),0.22(s,4H)

[0489] Example 101: 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)-1-hydroxy-2-methylpropane-2-sulfonamide

[0490] LCMS (ESI): [M+H]+=652.1; 1 H NMR (400MHz, DMSO-d6) δppm 10.20-9.55 (m, 1H), 9.22 (s, 1H), 8.87 (br d, J = 2.8Hz, 1H), 8.38 (br d,J=7.6Hz,1H),8.14(s,1H),7.73(s,1H),7.61-7.40(m,2H),7.27(s,1H),7.07(dd,J=1.2,8.8Hz,1H),5.63-4.61(m,1H),3.58(br s,6H),2.69(br s,4H),2.25(br t,J=13.6Hz,4H),1.27(s,10H),0.22(s,4H)

[0491] Example 102: N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-1-hydroxypropane-2-sulfonamide

[0492] LCMS(ESI):[M+H] + =619.4; 1 H NMR (400MHz, DMSO) δ10.17(s,1H),7.90(d,J=8.5Hz,1H),7.12(d,J=2.1Hz,1H),7.00 (d,J=10.7Hz,2H),6.65(s,1H),5.04(s,1H),3.95-3.82(m,4H),3.79(t,J=5.7Hz,4H) ,3.49(dd,J=11.1,7.6Hz,1H),3.28(dd,J=7.2,4.5Hz,1H),2.93(t,J=5.2Hz,4H),2. 05(tt,J=13.4,5.2Hz,4H),1.47(t,J=5.2Hz,4H),1.30(d,J=6.8Hz,3H),0.32(s,4H).

[0493] Example 103: N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-1-hydroxypropane-2-sulfonamide

[0494] LCMS(ESI):[M+H] + =603.5;1H NMR (400MHz, DMSO) δ10.18(s,1H),7.91(d,J=8.5Hz,1H),7.25(s,1H),7.18(s,1H),7.12(d,J =2.1Hz,1H),7.01(dd,J=8.5,2.1Hz,1H),5.04(s,1H),3.85(dd,J=11.1,4.4Hz,1H),3.79(t, J=5.8Hz,4H),3.49(dd,J=11.1,7.7Hz,1H),3.29(dt,J=7.2,3.6Hz,1H),2.93(t,J=5.2Hz,4H ),2.44(s,3H),2.08-1.95(m,4H),1.48(t,J=5.3Hz,4H),1.30(d,J=6.8Hz,3H),0.32(s,4H).

[0495] Example 104: N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-1-hydroxy-2-methylpropane-2-sulfonamide

[0496] LCMS(ESI):[M+H] + =617.4; 1 H NMR (400MHz, DMSO) δ9.95 (s, 1H), 7.89 (d, J = 8.6Hz, 1H), 7.28-7.11 (m, 3H), 7.05 (dd, J = 8.6, 2.1Hz, 1H), 5.12 (s, 1H), 3.79 (t, J = 5.7Hz, 4 H),3.56(s,2H),2.92(t,J=5.2Hz,4H),2.44(s,3H),2.04(td,J=14.4,13.6,7.2Hz,4H),1.48(t,J=5.3Hz,4H),1.26(s,6H),0.32(s,4H).

[0497] Example 105: N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-1-hydroxy-2-methylpropane-2-sulfonamide

[0498] LCMS(ESI):[M+H] + =633.4; 1 H NMR (400MHz, DMSO) δ9.94(s,1H),7.88(d,J=8.6Hz,1H),7.23(d,J=2.0Hz,1H),7.09-6.94(m,2H),6.65(d,J=0.8Hz,1H),5.12(s,1H),3.88(s,3H) ,3.79(t,J=5.6Hz,4H),3.56(s,2H),2.92(t,J=5.2Hz,4H),2.06(ddt,J= 20.0,14.0,5.6Hz,4H),1.47(t,J=5.2Hz,4H),1.26(s,6H),0.32(s,4H).

[0499] Example 106: N-(4-(4-(4,4-difluoropiperidin-1-yl)-6-methyl-3H-imidazo[4,5-c]pyridin-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0500] Step 1: A mixture containing 2,4-dichloro-6-methyl-3-nitropyridine (5.00 g, 24.15 mmol), methanolic ammonia (25 mL, 7 M), and tetrahydrofuran (50 mL) was stirred at 50°C for 12 hours. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain 2-chloro-6-methyl-3-nitropyridine-4-amine (1.90 g, 10.13 mmol, yield: 41.9%) as a light yellow solid. LCMS (ESI): [M+H] + =188.2. 1 H NMR (400MHz, DMSO) δ7.26 (s, 2H), 6.66-6.62 (m, 1H), 2.33-2.23 (m, 3H).

[0501] Step 2: A mixed solution containing 2-chloro-6-methyl-3-nitro-4-pyridinamine (1.90 g, 10.13 mmol), 4,4-difluoropiperidine hydrochloride (1.90 g, 12.16 mmol), potassium carbonate (4.30 g, 30.39 mmol), and dimethyl sulfoxide (20 mL) was stirred at 100°C for 12 hours. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% ethyl acetate / petroleum ether gradient) to obtain 2-(4,4-difluoropiperidin-1-yl)-6-methyl-3-nitropyridin-4-amine (2.30 g, 8.45 mmol, yield: 83.4%) as a light yellow oil. LCMS (ESI): [M+H] + =273.1

[0502] Step 3: A mixture containing 2-(4,4-difluoropiperidin-1-yl)-6-methyl-3-nitro-4-pyridinamine (2.30 g, 8.45 mmol), iron powder (1.40 g, 25.34 mmol), ammonium chloride (1.40 g, 25.34 mmol), ethanol (20 mL), and water (4 mL) was stirred at 60°C for 1 hour. The reaction mixture was filtered while hot, and the filtrate was concentrated 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, 0-30% methanol / dichloromethane gradient) to obtain 2-(4,4-difluoropiperidin-1-yl)-6-methylpyridine-3,4-diamine (1.80 g, 7.43 mmol, yield: 87.9%) as a gray solid. LCMS (ESI): [M+H] + =243.2.

[0503] Step 4: A mixed solution containing 2-(6-azaspiro[2.5]octan-6-yl)-4-bromobenzoic acid (2.80 g, 8.92 mmol), 2-(4,4-difluoropiperidinyl)-6-methylpyridine-3,4-diamine (1.80 g, 7.43 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.32 g, 11.15 mmol) and N,N-diisopropylethylamine (2.90 g, 22.29 mmol) and N,N-dimethylformamide (20 mL) was stirred at 20°C for 12 hours. The reaction solution was poured into water (30 mL) and washed with ethyl acetate (30 mL). The organic phase was extracted with 4% paraformaldehyde (5% paraformaldehyde) (x3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain N-(4-amino-2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-3-yl)-4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.30 g, 2.43 mmol, yield: 32.7%) as a yellow solid. LCMS (ESI): [M+H] + =534.3; 1 H NMR (400MHz, DMSO) δ11.29(s,1H),7.91(d,J=8.4Hz,1H),7.65(d,J=2.0Hz,1H),7.51(dd,J=8.4,2.0Hz,1H), 6.29(s,1H),5.62(s,2H),3.14-3.02(m,8H),2.21(s,3H),1.96-1.85(m,4H),1.44-1.39(m,4H),0.33(s,4H).

[0504] Step 5: A solution containing N-[4-amino-2-(4,4-difluoropiperidinyl)-6-methyl(3-pyridinyl)][2-(6-azaspiro[2.5]octan-6-yl)-4-bromophenyl]formamide (1.3 g, 2.43 mmol) and acetic acid (15 mL) was stirred at 120°C for 48 hours. The reaction solution was poured into water (100 mL) and sodium bicarbonate aqueous solution (500 mL) was added to adjust the pH to about 8. Then, ethyl acetate (100 mL x 100 mL) was added to the mixture. 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound 2-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-4-(4,4-difluoropiperidin-1-yl)-6-methyl-3H-imidazo[4,5-c]pyridine (630 mg, 1.22 mmol, yield: 50.2%) as a yellow solid. LCMS (ESI): [M+H] + =516.3

[0505] Step 6: Under nitrogen atmosphere, a reaction solution containing 2-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-4-(4,4-difluoropiperidin-1-yl)-6-methyl-3H-imidazo[4,5-c]pyridine (300 mg, 0.58 mmol), 2-hydroxyethanesulfonamide (148 mg, 1.16 mmol), potassium phosphate (377 mg, 1.74 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (25 mg, 0.058 mmol), tris(dibenzylideneacetone)dipalladium (54 mg, 0.058 mmol) and dioxane (5 mL) was stirred at 100 ° C for 8 hours. The reaction solution was poured into water (30 mL) and washed with ethyl acetate (30 mL x 40 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound N-(4-(4-(4,4-difluoropiperidin-1-yl)-6-methyl-3H-imidazo[4,5-c]pyridin-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (141.25 mg, 0.25 mmol, yield: 43.4%) as a white solid. LCMS (ESI): [M+H] +=561.0;1H NMR (400MHz, DMSO) δ12.22(s,1H),9.94(s,1H),7.79(d,J=8.4Hz,1H),7.10(d,J=2.0Hz,1H),6.99(dd,J=8.4,2.0Hz,1H),6.83(s,1H),4.95(s,1 H),4.39-4.16(m,4H),3.76(t,J=6.8Hz,2H),3.32-3.25(m,2H),2.81(t, J=5.2Hz,4H),2.38(s,3H),2.12-2.00(m,4H),1.47(s,4H),0.30(s,4H).

[0506] Effect Example 1: Enzyme activity detection experiment

[0507] 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.

[0508] 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 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.

[0509] Table 1: Biological data of enzymatic activity of the compounds of the present invention

[0510] NT means not tested

[0511] Effect Example 2: Cell proliferation activity detection experiment

[0512] 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.

[0513] 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.

[0514] Cell proliferation activity assay:

[0515] 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.

[0516] Table 2: OVCAR-3 cell activity biological data of the compounds of the present invention

[0517] NT means not tested

[0518] Effect Example 3: CyQuant Cell Proliferation Activity Detection Experiment

[0519] 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).

[0520] 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.

[0521] 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 .

[0522] Table 3: HT-29 cell activity biological data of the compounds of the present invention

[0523] NT means not tested

[0524] Effect Example 4: Cytotoxicity test of primary human hepatocytes.

[0525] Materials: One donor will be used for cytotoxicity testing. Information on primary human hepatocytes is provided in the table below. Note: Hepatocytes from other ethnic groups may be used. The specific information will be reflected in the trial report.

[0526] 1) CellTiter-Glo Luminescent Cell Viability Assay System was purchased from Promega (Madison, WI).

[0527] instrument:

[0528] Experimental design:

[0529] Warm the following media to 37°C in a water bath: Prepare hepatocyte recovery medium, seeding medium, and incubation medium according to the table below.

[0530] Recovery medium

[0531] Inoculation medium

[0532] Incubation medium

[0533] 1) Take a vial of cryopreserved hepatocytes and ensure they remain frozen before thawing. Immediately place the cells in a 37°C water bath and gently shake until all ice crystals are dispersed. Spray with 75% ethanol and transfer to a biosafety cabinet.

[0534] 2) The contents of the hepatocyte tubules (1 mL, about 5 × 10 6 Pour the cells into a 50 mL centrifuge tube containing 50 mL of recovery medium and centrifuge at 100 g for 10 minutes. After centrifugation, aspirate the recovery medium and add enough inoculation medium to obtain a cell density of approximately 1.0 × 10 6 cells / mL cell suspension. Count the hepatocytes and determine the viable cell density using a cell counter. The hepatocyte viability must be greater than 80%. Use inoculation medium to adjust the cell density to 0.2 × 10 6 cells / mL, inoculate 100 μL per well in a 96-well plate coated with collagen I. Place the plate in a 5% CO2 incubator, 95% relative humidity, and incubate at 37°C for 4–6 hours.

[0535] 3) Prepare a 200X stock solution of the test compound in DMSO (the concentration of the stock solution of the test compound can be reduced according to the solubility). The final DMSO concentration is 0.5%

[0536] 4) Add 2.5 μL of the test compound stock solution to 497.5 μL of hepatocyte culture medium to prepare a working solution in a sterile 96-well plate.

[0537] 5) Remove the hepatocyte culture medium from the cell plate and add 125 μL of the working solution to the corresponding wells. Repeat three times per well. Incubate the plate at 37°C, 5% CO2 for 72 hours. After each 24-hour treatment, replace the culture medium in the cell plate with freshly diluted test compound and positive control compound in hepatocyte culture medium. Return the cell plate to the incubator and add 50 μL of CellTiter-Glo reagent directly to each well of the 96-well plate. Shake the plate at room temperature for 10 minutes. After 10 minutes, transfer 100 μL of the above incubation medium to a new, white, flat-bottomed, opaque 96-well plate and record fluorescence.

[0538] Data Analysis:

[0539] All calculations were performed using Microsoft Excel.

[0540] The survival rate of the test compound can be calculated using the following formula:

[0541] The %Vehicle dose was plotted against the test compound concentration, and the data were then fitted to a variable-slope sigmoidal dose-response curve using GraphPad Prism 5.0. The compound's IC50 was calculated from this curve using the formula Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0542] Effect Example 5: Experimental test of human primary hepatocyte microsphere model

[0543] Cells: Donor information: Male, Caucasian, 36 years old (Lot No. NFX, BioIVT)

[0544] instrument:

[0545] Cell seeding and culture:

[0546] 1) Take a vial of cryopreserved hepatocytes and ensure they are frozen before thawing. Immediately place the cells in a 37°C water bath and gently shake until all ice crystals are dispersed. Spray with 70% ethanol and transfer to a biosafety cabinet.

[0547] 2) Pour the contents of the hepatocyte tubules into a 50 mL centrifuge tube containing 50 mL of recovery medium and centrifuge at 100 g for 3 minutes. After centrifugation, aspirate the recovery medium and add enough incubation medium to obtain a cell density of approximately 1.0 x 10 6 cells / mL cell suspension.

[0548] 3) Count the hepatocytes and determine the viable cell density using a Cellometer Vision. The hepatocyte viability must be greater than 80%. Adjust the cell density to 4,000 cells / well using inoculation medium, inoculating 100 μL per well.

[0549] 4) Place the cells in a cell culture incubator and incubate at 37°C for 7-9 days until microspheres are formed.

[0550] Preparation and administration of compounds:

[0551] 1) Dilute the compound using cell culture medium using a three-fold dilution method. The dilution gradient is shown in the table below. The maximum concentration of the control compound is 200 μM, the maximum concentration of the test compound (based on customer requirements) is 5 μM, and the final DMSO concentration is 0.1%.

[0552] 2) After microspheres have formed, administer the drug. Before each administration, aspirate the culture medium from the cell culture plate wells and add 100 μL of compound working solution. Administer the drug every three days until the fourteenth day after microsphere formation.

[0553] Test index detection:

[0554] 1) After 14 days of culture, remove the cell culture plate from the incubator and collect 80 μL of supernatant to detect the levels of albumin and lactate dehydrogenase.

[0555] 2) CellTiter-Fluor TMThaw the Cell Viability Kit at room temperature, add 10 μL of GF-AFC substrate to 10 mL of 2× working solution, and add an equal volume of PBS to dilute it to 1× working solution.

[0556] 3) Add 100 μL of working solution to each well of the cell culture plate and incubate at 37°C for 30 min. Then, aspirate 80 μL of the supernatant into a 96-well black plate and measure the absorbance at an excitation wavelength of 400 nm and an emission wavelength of 505 nm.

[0557] Data Analysis:

[0558] 1) The cell survival percentage (% Vehicle) was calculated using the following formula:

[0559] 2) IC was calculated using GraphPad Prism 8.0.2 50 The software calculation formula is as follows: Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof: in, W 1 Indicates CR W1 or N; Among them, W 2 Indicates CR W2 or N; Among them, Z represents -CR T R T' or -NR S R S' ; Among them, R T and R T' Together with the C atoms to which they are commonly attached, they form a ring having a structure selected from the following: Among them, R S and R S' Together with the nitrogen atom to which they are commonly attached, they form a ring having a structure selected from the following: Among them, Y 1 、Y 2 、Y 3 Each independently represents -(CR a R b ) o -(NR a ) p -(CR a' R b' ) q -; Wherein, A and B each independently represent -(CR a R b ) m -; Among them, L 1 represents a 5-6 membered heteroaryl group, Among them, L 2 Indicates absence, -C1-C6 alkylene-, -NR a -、-NR a (C1-C6 alkylene)-, -C(O)NR a (C1-C6 alkylene)-, -O-, -O-(C1-C6 alkylene), -S-, -S(O)-, -S(O)2-, -S(O)2NR a -or-S(O)(NR a )-; Among them, R 1 Indicates L 3 -R 3 or Among them, R 2 represents hydrogen, halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-SR a 、-SF5、-S(O)R a , -O-, halogenated C1-C6 alkyl or -NR a R b ; Among them, L 3 Indicates absence, C1-C6 alkylene, -NR a -、-NR a SO2-、-SO2NR a -、-S(=O)(NR a )-、-P(O)(OR a )2、-NR a P(O)(OR a )2 or -NR a P(O)(R a )2; Among them, R 3 Represents absence, hydrogen or 0-3 selected from halogen, -OR a 、-NR a R b , cyano, -O-halogenated C1-C6 alkyl or C3-C6 cycloalkyl; Among them, R W1 and R W2 Each independently represents hydrogen, 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 , -SF5 or -NR a R b ; Among them, Cy 1 represents a 6-12 membered aryl group or a 5-12 membered heteroaryl group; and the Cy 1 It may also be optionally substituted by 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a 、-SF5、cyano、nitro、-NR a R b 、-NH-(C0-C6 alkyl)-R M 、-NR a C(O)R b 、-C(O)NR a R b 、-OC(O)R a 、-C(O)R a 、-P(O)R a R b 、-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 optionally substituted by 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, 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, R M Indicates -OR a 、-NR a R b , 5-6 membered heterocyclyl, 5-10 membered heteroaryl, 6-10 membered aryl; Among them, R a 、R b 、R a' 、R b' Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C6 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 saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N; or R a' 、R b' Together with the atoms to which they are attached, they form a 3-6 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N; Wherein, the dotted line represents a single bond or a double bond; Here, m, o, p, and q represent integers from 0 to 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: W 1 Indicates CH or N.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: W 2 Indicates CH or N.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: L 3 Indicates -NR a SO2-、-SO2NR a -or-S(=O)(NR a )-.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: L 3 Indicates -NR a SO2-.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: R 3 represents hydrogen or is replaced by 0-3 halogens, -OR a 、-NR a R b C1-C6 alkyl or C3-C6 cycloalkyl substituted with a group consisting of: -O-halogenated C1-C6 alkyl, -C1-C6 alkyl, -C3-C6 cycloalkyl, ...

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: R 3 It represents 0-3 selected from halogen, -OR a 、-NR a R b C1-C6 alkyl substituted with -O-halogenated C1-C6 alkyl.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Z stands for -NR S R S' .

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Z stands for: Among them, R a 、R b Each independently represents hydrogen, C1-C6 alkyl, C3-C6 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 saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Z stands for: Among them, R a 、R b Each independently represents hydrogen, C1-C6 alkyl, C3-C6 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 saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Z stands for:

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: L 1 represents a 5-6 membered heteroaryl group, 13. The compound according to claim 12 or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -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)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Any of the following groups substituted: For example:

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: L 1 Represents: 5-6 membered heteroaryl, 15. The compound according to claim 14 or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: L 1 represents any one of the following groups:

16. The compound according to claim 14 or 15, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -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)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Any of the following groups substituted:

17. The compound according to claim 16 or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -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)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Replaced 18. The compound according to claim 17 or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 1 represents a phenyl group, a pyridyl group, a thiazolyl group, an oxazolyl group, a pyrazolyl group, an imidazolyl group, or an N-methylpyrazolyl group.

19. The compound according to claim 18 or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 1 Represents the following groups:

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: L 2 represents the absence of -C1-C6 alkylene- or -NH-.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: L 2 Indicates that it does not exist.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 2 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 contains 0-3 N heteroatoms and 0-2 O or S heteroatoms, and the monocyclic ring or cyclic ring is 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 substituted morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl or tetrahydrofuranyl, wherein 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.

23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 2 express 24. A compound having the following structure: