Inhibitor of kinin KIF18A and application thereof

Abstract

The invention provides a KIF18 inhibitor and a synthesis method thereof, and the compound provided by the invention can regulate KIF18A protein so as to influence the cell cycle and the cell proliferation process to treat cancers and cancer-related diseases. The invention also includes pharmaceutical compositions comprising the compounds 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 number 202310475180.8, filed with the State Intellectual Property Office of China on April 27, 2023, entitled “Kinesin KIF18A Inhibitors and Their Applications”;

[0009] The entire contents thereof are incorporated into this application by reference. Technical Field

[0010] 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

[0011] 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.

[0012] 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.

[0013] Summary of the Invention

[0014] 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.

[0015] 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.

[0016] 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).

[0017] 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:

[0018] A compound having the structure of formula (I) or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof:

[0019] Among them, W 1 Indicates CR W1 or N;

[0020] Among them, W 2 Indicates CR W2 or N;

[0021] Among them, Z represents -CR T R T' or -NR S R S' ;

[0022] 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:

[0023] 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:

[0024] Among them, Y 1 、Y 2 、Y 3 Each independently represents -(CR a R b ) o -(NR a ) p -(CR a' Rb' ) q -;

[0025] Wherein, A and B each independently represent -(CR a R b ) m -;

[0026] Among them, L 1 represents -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl,

[0027] 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 )-;

[0028] Among them, R 1 Indicates L 3 -R 3 ;

[0029] 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 ;

[0030] 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;

[0031] Among them, R3 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;

[0032] 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 ;

[0033] Among them, Cy 1 It means having the following structural groups;

[0034] 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 、-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 2represents 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 ;

[0035] 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;

[0036] Wherein, the dotted line represents a single bond or a double bond;

[0037] Here, m, o, p, and q represent integers from 0 to 3.

[0038] In the preferred technical solution of the present invention, wherein W 1 Indicates CH or N.

[0039] In the preferred technical solution of the present invention, wherein W 2 Indicates CH or N.

[0040] In the preferred technical solution of the present invention, wherein L 3 Indicates -NR a SO2-、-SO2NRa -or-S(=O)(NR a )-.

[0041] In the preferred technical solution of the present invention, wherein L 3 Indicates -NR a SO2-.

[0042] In the preferred technical solution of the present invention, 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 -O-halogenated C1-C6 alkyl.

[0043] 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.

[0044] In the preferred technical solution of the present invention, wherein Z represents -NR S R S' .

[0045] In the preferred technical solution of the present invention, Z represents:

[0046] 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: 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.

[0048] In the preferred technical solution of the present invention, Z represents:

[0049] In the preferred technical solution of the present invention, wherein L 1 represents -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl,

[0050] In the preferred technical solution of the present invention, wherein L 1 It represents -C(O)NH-.

[0051] In the preferred technical solution of the present invention, wherein Cy 1 Represents the following groups:

[0052] In the preferred technical solution of the present invention, wherein L 1 Represents: -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl,

[0053] In the preferred technical solution of the present invention, wherein L 1 represents any of the following groups:

[0054] In the preferred technical solution of the present invention, wherein L 2 represents the absence of -C1-C6 alkylene- or -NH-.

[0055] In the preferred technical solution of the present invention, wherein L 2 Indicates that it does not exist.

[0056] 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 to 3 N heteroatoms and 0 to 2 O or S heteroatoms, and the monocyclic ring or cyclic ring is substituted by 0 to 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 bsubstituted 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.

[0057] In the preferred technical solution of the present invention, wherein Cy 2 express:

[0058] Specifically, the present invention provides compounds having the following structure:

[0059] 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.

[0060] 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.

[0061] definition

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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-.

[0068] 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:

[0069] "Aryl" refers to an all-carbon monocyclic or fused-ring polycyclic group of 6 to 12 carbon atoms with a complete conjugated π-electron system. Examples of aryl groups are, but are not limited to, phenyl, naphthyl, and anthracenyl. Aryl groups may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, sulfinyl, sulfonyl, amino, and -NR a R b , where R a With R b As defined above. Aryl-fused saturated or unsaturated cycloalkyl / saturated or unsaturated heterocycloalkyl can be considered as special substituents of aryl, typical examples of which include but are not limited to:

[0070] "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.

[0071] 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.

[0072] 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.

[0073] "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.

[0074] "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-.

[0075] 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.

[0076] 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.

[0077] In the context of the present invention, one or more halogens may be independently selected from fluorine, chlorine, bromine and iodine.

[0078] 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).

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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 administrations, applications, or dosages and is not intended to be limited by a specific formulation or route of administration. The term also includes within its scope an effective amount that enhances normal physiological function.

[0083] 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.

[0084] Likewise, "therapeutic agent" also includes agents or reagents that have therapeutic and / or prophylactic effects on a subject.

[0085] 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.

[0086] Specific pharmaceutical and medical terms

[0087] 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).

[0088] 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.

[0089] 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.

[0090] 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.

[0091] The terms "kit" and "product packaging" are synonymous.

[0092] 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.

[0093] 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.

[0094] Route of administration

[0095] 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.

[0096] 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.

[0097] Pharmaceutical composition and dosage

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] Such carriers may include a variety of ingredients and additives in addition to the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, binding agents, etc. Descriptions of suitable pharmaceutical carriers and factors involved in carrier selection can be found in a number of readily available sources, such as Allen LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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).

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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).

[0112] Kit / Product Packaging

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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

[0121] 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.

[0122] NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the measurements are indicated in the spectral analysis.

[0123] 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.

[0124] HPLC analysis was performed using a SHIMADZU 20A high performance liquid chromatograph.

[0125] 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, Agilent1260 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.

[0126] 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.

[0127] 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.

[0128] Flash column chromatography separation was performed using a Biotage IsoleraOne flash preparative chromatograph.

[0129] 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.

[0130] Pressurized hydrogenation reaction hydride bottles and hydrogen gas cylinders.

[0131] Microwave reactions were performed using a Biotage Initiator+ microwave synthesizer.

[0132] The glove box is customized by DELLIX.

[0133] The present invention is described in detail below by examples, but it 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 combining them 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 the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0134] It will be apparent that various changes and modifications can be made in the embodiments.

[0135] Intermediate A1: 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine

[0136] Step 1: To a solution of 2,4-dichloro-6-methylpyrimidine (3.00 g, 18.40 mmol) in dimethyl sulfoxide (30 mL) at 25°C was added aqueous ammonia (2.5 mL, 18.04 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow oil. The product was purified by slurrying (ethyl acetate:petroleum ether = 1:1, 10 mL) to afford 2-chloro-6-methylpyrimidin-4-amine (2.00 g, 75% yield) as a white solid. LCMS (ESI): [M+H] + =144.1.

[0137] Step 2: To a solution of 2-chloro-6-methylpyrimidin-4-amine (7.50 g, 41.79 mmol) and 4,4-difluoropiperidine hydrochloride (12.00 g, 76.13 mmol) in N-methylpyrrolidone (75 mL) was added N,N-diisopropylethylamine (25 mL) at 25°C. The reaction mixture was stirred at 160°C for 6 hours. The reaction mixture was then concentrated to dryness and dissolved in dichloromethane (50 mL). Purification by flash column chromatography (silica gel, 0-10% methanol / dichloromethane gradient) afforded a crude yellow oil. This crude product was dissolved in ethyl acetate (50 mL) and washed with water (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford a pale yellow solid, which was stirred in petroleum ether (30 mL) for 30 minutes. The white precipitate was filtered to obtain 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (3.00 g, yield 38%). LCMS (ESI): [M+H] + =229.1.

[0138] Intermediate A2: 4-Bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0139] Step 1: Dissolve 4-bromo-2-fluorobenzoic acid (20.00 g, 90.41 mmol) and sodium carbonate (14.52 g, 135.61 mmol) in N,N-dimethylformamide (200 mL). Benzyl bromide (17.18 g, 99.45 mmol) was added to the solution at 30 ° C. The reaction mixture was stirred at 30 ° C for 15 hours. The reaction mixture was quenched with water (400 mL) and extracted with methyl tert-butyl ether (3 x 300 mL). The combined organic extracts were washed with brine (400 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 4-bromo-2-fluorobenzoic acid benzyl ester (29.00 g) as a white solid. LCMS (ESI): [M+H] + =308.

[0140] The second step: sodium carbonate (21.82g, 203.8mmol) was added to a solution of 4-bromo-2-fluorobenzoic acid benzyl ester (20.00g, 59.79mmol) in dimethyl sulfoxide (120mL), followed by 6-azaspiro [2.5] octane hydrochloride (13.38g, 89.69mmol), and the reaction mixture was stirred at 100°C for 15 hours. The reaction mixture was quenched with water (200mL) and extracted with methyl tert-butyl ether (3 x 200mL). The combined organic extracts were washed with brine (3 x 200mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a red oily substance 4-bromo-2- (6-azaspiro [2.5] octane-6-yl) benzoic acid benzyl ester (23.00g, yield: 89%). LCMS (ESI): [M+H] + =402.1.

[0141] Step 3: To a solution of benzyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (7.00 g, 16.24 mmol) in methanol / water (60 mL / 15 mL) was added lithium hydroxide monohydrate (1.15 g, 48.72 mmol) and stirred at 35°C for 15 hours. The reaction mixture was concentrated, and the residue was dissolved in water (50 mL). The aqueous phase was washed with ethyl acetate (3 x 70 mL), then adjusted to pH 5 with aqueous hydrogen chloride (1 M aq, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated to afford 2-(6-azaspiro[2.5]octan-6-yl)-4-bromobenzoic acid (4.00 g, yield: 73%) as a red solid. LCMS (ESI): [M+H] + =311.7.

[0142] Step 4: To a solution of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1000 mg, 3.22 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (0.2 mL) was added thionyl chloride (1.10 g, 9.67 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was spin-dried to dryness, toluene (10 mL) was added, and the mixture was concentrated. This process was repeated three times. 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (735 mg, 3.22 mmol) and potassium tert-butoxide (1096 mg, 9.67 mmol) were added to tetrahydrofuran (10 mL). The crude product from the previous step was dissolved in tetrahydrofuran (20 mL) and slowly added dropwise to the reaction mixture. The mixture was stirred at room temperature for 4 hours. The reaction solution was filtered, concentrated, and purified by flash column chromatography (silica gel, 0-25% gradient of ethyl acetate / petroleum ether) to give 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (600 mg, yield 35%) as a light yellow solid.

[0143] Intermediate A3: 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride

[0144] Step 1: A mixed solution containing 2-fluoro-4-nitrobenzoic acid (10.00 g, 53.48 mmol), 6-azaspiro[2.5]octane hydrochloride (8.69 g, 58.83 mmol), potassium carbonate (22.60 g, 160.45 mmol), and dimethyl sulfoxide (50 mL) was stirred at 140°C for 12 hours. 2M aqueous hydrochloric acid was added dropwise to the reaction solution to adjust the pH to approximately 5, and then filtered. The filter cake was dried to obtain the compound 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (10.60 g) as a yellow solid.

[0145] Step 2: A mixture of 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (500 mg, 1.81 mmol) and thionyl chloride (5 mL) was stirred at 90°C for 1 hour. The reaction mixture was concentrated with dichloromethane to afford 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (620 mg) as a yellow solid. LCMS (ESI): [M+H] + =291.1.

[0146] Intermediate A4: ethyl 2-sulfamoyl acetate

[0147] Step 1: Ethyl 2-(chlorosulfonyl)acetate (5.00 g, 26.53 mmol) was added to dichloromethane (25 mL). The reaction mixture was cooled to 0°C. Hexamethyldisilazane (4.32 g, 26.53 mmol) was slowly added dropwise to the reaction mixture. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was evaporated to dryness to obtain a residue. The residue was dissolved in ethanol (20 mL) at 0°C and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was evaporated to dryness to obtain ethyl 2-sulfamoylacetate (4.20 g, 94% yield) as a white solid.

[0148] Intermediate A5: 4,6-dichloro-1-methyl-1,3-dihydrofuro[3,4-c]pyridine

[0149] Step 1: Under nitrogen, dissolve 2,2,6,6-tetramethylpiperidine (8.91 g, 62.50 mmol) in tetrahydrofuran (40 mL). Stir the mixture at -70°C for 1 hour. Then, slowly add n-butyllithium solution (72 mL, 125 mmol, 2.5 M in n-hexane) dropwise. Stir the mixture at -70°C for 3 hours. Dissolve 2,6-dichloronicotinic acid (6.0 g, 31.2 mmol) in tetrahydrofuran (40 mL) and slowly inject it into the reaction system. Stir at -70°C for 1 hour, then slowly warm to room temperature and stir for 4 hours. Return the temperature to -70°C and slowly add acetaldehyde solution (13.76 g, 312.50 mmol). After the addition is complete, warm to room temperature and stir for 24 hours. Adjust the pH to 2 with dilute hydrochloric acid (200 mL, 6 M aqueous solution). Ethyl acetate (200 mL x 3) was added and extracted three times. The organic phases were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was stirred with methanol (50 mL) for 1 hour and filtered to obtain a white solid 4,6-dichloro-1-methylhydrofuro[3,4-c]pyridin-3-one (4.00 g, 59%). LCMS (ESI): [M+H] + =218.0

[0150] Step 2: Under nitrogen, 4,6-dichloro-1-methylhydrofuro[3,4-c]pyridin-3-one (4.00 g, 18.30 mmol) was dissolved in tetrahydrofuran (40 mL) and the mixture was cooled to -78°C and stirred for 1 hour. Diisobutylaluminum hydride (46 mL, 45.87 mmol, 1.0 M in n-hexane) was then slowly added dropwise. The reaction mixture was stirred at -78°C for 1.5 hours and quenched by the addition of saturated ammonium chloride (30 mL) at -78°C. The mixture was slowly warmed to room temperature and stirred for 30 minutes. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography to give 4,6-dichloro-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol (2.40 g, 59%). LCMS(ESI):[M+H] + =221.0

[0151] Step 3: (4,6-dichloro-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol (2.40 g, 10.80 mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (6.15 g, 54.00 mmol) and triethylsilane (3.76 g, 32.40 mmol) were added, and the reaction mixture was stirred at 25 ° C for 5 hours. The solvent was removed under reduced pressure, and the residue was dissolved in water (50 mL), and then adjusted to pH = 8 with saturated sodium bicarbonate aqueous solution, and washed with ethyl acetate (50 mL x 10% ethyl acetate). 3) Extraction, combined organic phases, washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to give a colorless oily product 4,6-dichloro-1-methyl-1,3-dihydrofuro[3,4-c]pyridine (1.70 g, 77%). LCMS (ESI): [M+H] + =204.0

[0152] Intermediate A6: 4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine

[0153] Step 1: n-Butyl lithium (52.1 mL, 130 mmol) was added dropwise to a solution of diisopropylamine (15.8 g, 156 mmol) in tetrahydrofuran (50 mL) at -70°C and stirred at -70°C for 40 minutes. A solution of 2,6-dichloronicotinic acid (10.0 g, 52.1 mmol) in tetrahydrofuran (100.00 mL) was added dropwise to the reaction system at -70°C and stirred at -70°C for 3 hours. Then, butanone (33.8 g, 468 mmol) was added dropwise to the reaction at -70°C, the temperature was raised to 25°C, and the mixture was stirred for 16 hours. The mixture was quenched with saturated ammonium chloride solution (200 mL), diluted with water (100 mL), extracted with ethyl acetate (200 mL x 2), and the organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-11% gradient of tetrahydrofuran / petroleum ether) to give 4,6-dichloro-1-ethyl-1-methylfuro[3,4-c]pyridin-3(1H)-one (1.90 g, 7.29 mmol, 14% yield) as a yellow solid. LCMS (ESI): [M+H] + =246.0. H NMR (400MHz, DMSO-d6) δ8.11 (s, 1H), 2.10-1.93 (m, 2H), 1.63 (s, 3H), 0.71 (t, J = 7.6Hz, 3H)

[0154] Step 2: Dissolve 4,6-dichloro-1-ethyl-1-methylfuro[3,4-c]pyridin-3(1H)-one (1.90 g, 7.72 mmol) in toluene (40 mL). Add diisobutylaluminum hydride (17.76 mL, 17.76 mmol) dropwise at -70°C and stir at -70°C for 2 hours. The reaction mixture is quenched by pouring into water (200 mL). After filtration, the filtrate is extracted with ethyl acetate (200 mL x 2). The organic phase is dried, filtered, and concentrated. The residue is purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / petroleum ether) to afford 4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol (1.80 g, 7.02 mmol, 91% yield) as a yellow oil. LCMS (ESI): [M+H] + =247.9. 1 H NMR(400MHz,DMSO-d6)δppm 7.69(d,J=2.8Hz,1H),7.23-7.11(m,1H),6.29(dd,J=6.8,14.0Hz,1H),1.81-1.76(m,2H),1.53-1.38(m,3H),0.86-0.60(m,3H)

[0155] Step 3: Dissolve 4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-3-ol (1.80 g, 7.25 mmol) in dichloromethane (36 mL), add trifluoroacetic acid (3.52 g, 36.3 mmol) at 0°C, and stir at 0°C for 30 minutes. Add triethylsilane (2.56 g, 21.7 mmol) at 0°C, warm to 25°C and stir for 3 hours. The reaction mixture was poured into water (50 mL), the pH was adjusted to 7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of tetrahydrofuran / petroleum ether) to give 4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine (1.40 g, 5.94 mmol, 82% yield) as a white solid. LCMS (ESI): [M+H] + =232.0. 1 H NMR(400MHz, DMSO-d6)δppm 7.64(s,1H),5.09-4.90(m,2H),1.80(td,J=7.2,14.0Hz,2H),1.42(s,3H), 0.73(t,J=7.6Hz,3H)

[0156] Intermediate A7: 1,3-dibromopyrrolo[1,2-a]pyrazine

[0157] Step 1: To a solution of methyl 2-pyrrolecarboxylate (37.0 g, 296 mmol) in N,N-dimethylformamide (400 mL) were added 2-chloroacetamide (33.2 g, 355 mmol) and cesium carbonate (128 g, 384 mmol), and the mixture was stirred at 20°C for 14 hours. The reaction solution was poured into ice water (500 mL) and extracted with ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain methyl 1-(2-amino-2-oxyylideneethyl)-1H-pyrrole-2-carboxylate (17.4 g crude product) as a white solid. LCMS (ESI): [M+H] + =182.9.

[0158] Step 2: To a solution of 1-(2-amino-2-oxyylideneethyl)-1H-pyrrole-2-carboxylic acid methyl ester (17.4 g, 95.5 mmol) in tetrahydrofuran (200 mL) was added potassium tert-butoxide (32.7 g, 288 mmol) and the mixture was stirred at 70 ° C for 14 hours. The reaction solution was adjusted to pH 6 with 2N hydrochloric acid 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 slurried with ethanol and filtered to obtain a brown solid pyrrolo[1,2-a]pyrazine-1,3(2H,4H)-dione (6.50 g, 43.3 mmol, yield 45%). LCMS (ESI): [M+H] + =151.1. 1 H NMR(400MHz,DMSO-d6)δppm 11.31(br s,1H),7.17(s,1H),6.89(m,1H),6.35(m,1H),4.99(s,2H)

[0159] Step 3: To a solution of pyrrolo[1,2-a]pyrazine-1,3(2H,4H)-dione (6.50 g, 43.3 mmol) in dioxane (60 mL) was added phosphorus oxybromide (24.8 g, 86.6 mmol). The reaction mixture was heated to 100°C and stirred for 2 hours. The reaction solution was concentrated, ethyl acetate was added, and the pH was adjusted to 7 with aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (200 mL x 3), the organic phases were combined, washed with saturated brine (200 mL), 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 1,3-dibromopyrrolo[1,2-a]pyrazine (3.19 g, 11.6 mmol, yield 27%) as a yellow solid. LCMS (ESI): [M+H] + =276.9.

[0160] Intermediate A8: 6,8-dichloro-3-methylimidazo[1,5-a]pyrazine

[0161] Step 1: Add 3,5-dichloropyrazine-2-carbonitrile (25.0 g, 144 mmol) to acetic acid (250 mL), followed by the addition of Raney nickel (2.50 g). The mixture was replaced with hydrogen three times and heated to 50°C under a hydrogen atmosphere (50 psi) and stirred for 24 hours. The reaction solution was filtered and the filtrate was dried to give a green solid (3,5-dichloropyrazine-2-yl)methylamine (12.3 g, 69.1 mmol, 48% yield). LCMS (ESI): [M+H] + =177.9.

[0162] Step 2: A solution of (3,5-dichloropyrazin-2-yl)methylamine (12.0 g, 67.4 mmol) in acetic anhydride (60 mL) was stirred at 25°C for 16 hours. Ethyl acetate (250 mL) was added to the reaction mixture and washed with saturated sodium bicarbonate solution. The organic phases were combined, washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give a yellow solid N-((3,5-dichloropyrazin-2-yl)methyl)acetamide (10.8 g, 49.1 mmol, 73% yield). LCMS (ESI): [M+H] + =219.9.

[0163] Step 3: Add N-((3,5-dichloropyrazin-2-yl)methyl)acetamide (10.8g, 49.1mmol) to phosphorus oxychloride (110mL). The mixture was stirred at 100°C for 2 hours. The reaction solution was added dropwise to water (500mL), extracted with ethyl acetate (300mL x 3), and washed with saturated aqueous sodium bicarbonate solution. The organic phases were combined, washed with saturated brine (300mL), 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, 0-100% gradient of ethyl acetate / petroleum ether) to give a yellow solid 6,8-dichloro-3-methylimidazo[1,5-a]pyrazine (2.7g, 13.3mmol, yield 27%). LCMS (ESI): [M+H] + =201.9.

[0164] Intermediate A9: 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine

[0165] Step 1: 3,5-dibromopyrazin-2-amine (20.00 g, 79.08 mmol) was dissolved in ethanol (200 mL), and N,N-dimethylformamide dimethyl acetal (48.08 g, 395.41 mmol) was added. The temperature was raised to 70°C under nitrogen protection and the reaction was carried out for 4 hours. The reaction solution was cooled to room temperature, and a large amount of solid precipitated. The solid was filtered and the filter cake was dried to obtain (E)-N'-(3,5-dibromopyrazin-2-yl)-N,N-dimethylformamide (23.00 g, yield 94%); LCMS (SI): [M+H] + =308.6

[0166] Step 2: Dissolve (E)-N'-(3,5-dibromopyrazin-2-yl)-N,N-dimethylformamide (20.00 g, 64.94 mmol) in methanol (200 mL), add hydroxylamine hydrochloride (6.77 g, 97.41 mmol), and heat to 60°C under nitrogen for 16 hours. The reaction solution was cooled to room temperature, and a large amount of solid precipitated. The solid was filtered and the filter cake was dried to obtain (E)-N-(3,5-dibromopyrazin-2-yl)-N'-hydroxyformamide as a bright yellow solid (10.00 g, yield 52%); LCMS (ESI): [M+H] + =295.6.

[0167] Step 3: Dissolve (E)-N-(3,5-dibromopyrazin-2-yl)-N'-hydroxycarboxamide (10.00 g, 33.79 mmol) in toluene (100 mL), add trifluoroacetic anhydride (35.49 g, 168.97 mmol) and p-methylbenzenesulfonyl chloride (7.23 g, 37.17 mmol), and heat to 90°C under nitrogen for 16 hours. The reaction solution was slowly poured into saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and spin-dried. Purification by flash column chromatography (silica gel, 5-20% gradient of ethyl acetate / petroleum ether) afforded 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine as a yellow solid (5.8 g, 62% yield); LCMS (ESI): [M+H] + =444.2

[0168] Intermediate A10: 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine

[0169] Step 1: 2,3-Dichloropyrazine (25.00 g, 167.81 mmol) was added to ethanol (50 mL). Hydrazine hydrate (80%, 21.53 g, 344.00 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 85°C for 2 hours. The reaction mixture was concentrated and filtered, and the solid was washed with water (50 mL x 3) and dried to obtain 2-chloro-3-hydrazinopyrazine as an orange-red solid (19.00 g, 78.32%). LCMS (ESI): [M+H] + =145.1,147.1.

[0170] Step 2: 2-Chloro-3-hydrazinopyrazine (19.00 g, 131.43 mmol) and N,N-diisopropylethylamine (34.67 g, 262.87 mmol) were added to dichloromethane (50 mL), and the reaction solution was cooled to 0°C. Trifluoroacetic anhydride (30.67 g, 144.58 mmol) was slowly added dropwise to the reaction solution. After complete addition, the reaction solution was stirred at 25°C for 1 hour. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 0-25% ethyl acetate / petroleum ether gradient) to obtain N'-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide as a light yellow solid (14.00 g, 44.28%). LCMS(ESI):[M+H] + =241.0

[0171] Step 3: N'-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetylhydrazine (14.00 g, 58.20 mmol) was added to N,N-dimethylformamide (45 mL), and the reaction solution was cooled to 0°C. N-bromosuccinimide (11.39 g, 64.02 mmol) was slowly added to the reaction solution in three portions. After complete addition, the reaction solution was stirred at 25°C for 4 hours. The reaction solution was slowly quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 0-25% ethyl acetate / petroleum ether gradient) to obtain N'-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetylhydrazine as a white solid (5.90 g, 31.73%). LCMS(ESI):[M+H] + =321.0.

[0172] Step 4: N'-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetylhydrazine (5.90 g, 18.47 mmol) was added to ethanol (50 mL). Concentrated hydrochloric acid (12 M, 10 mL) was added to the reaction solution, and the reaction solution was stirred at 80°C for 4 hours. The reaction solution was concentrated to obtain the crude product, which was neutralized with saturated sodium bicarbonate aqueous solution to pH = 7 and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 5-bromo-3-chloro-2-hydrazinopyrazine as a brown solid (3.50 g, 85%). LCMS (ESI): [M+H] + =225.0.

[0173] Step 5: 5-Bromo-3-chloro-2-hydrazinylpyrazine (3.50 g, 15.73 mmol) was added to triethyl orthoformate (10 mL). p-Toluenesulfonic acid (138 mg, 0.79 mmol) was added to the reaction mixture, and the reaction mixture was reacted at 130°C for 4 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine as a brown solid (2.10 g, 57.17%). LCMS (ESI): [M+H] + =234.9

[0174] Intermediate A11: 5,7-dichloroimidazole[1,2-c]pyrimidine

[0175] Step 1: A mixture containing 6-chloro-2-(methylthio)pyrimidin-4-amine (5.00 g, 28.47 mmol), 2-bromo-1,1-dimethoxyethane (5.77 g, 34.16 mmol), and dioxane / water = 4 / 1 (50 mL) was stirred at 100°C for 12 hours. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine (7.90 g) as a brown solid. LCMS (ESI): [M+H] + =200.0.

[0176] Step 2: A mixed solution containing 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine (7.90 g, 39.57 mmol), aqueous potassium hydroxide solution (60 mL, 2 M), and methanol (20 mL) was stirred at 100°C for 12 hours. The reaction solution was extracted with ethyl acetate (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 7-chloroimidazo[1,2-c]pyrimidin-5-ol (3.50 g) as a yellow solid. LCMS (ESI): [M+H] + =170.0.

[0177] Step 3: A mixed solution containing 7-chloroimidazo[1,2-c]pyrimidin-5-ol (3.40 g, 20.05 mmol) and phosphorus oxychloride (20 mL) was stirred at 90°C for 2 hours. The reaction solution was concentrated, and then saturated aqueous sodium bicarbonate solution (100 mL) was added to adjust the pH to about 8. The solution was then extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5,7-dichloroimidazo[1,2-c]pyrimidine (2.80 g) as a brown solid. LCMS (ESI): [M+H] +=188.0.

[0178] Intermediate A12: 5,7-dichloro-[1,2,4]triazolo[4,3-c]pyrimidine

[0179] Step 1: To a solution of 2,4,6-trichloropyrimidine (35.0 g, 191 mmol) and triethylamine (57.9 g, 572 mmol) in ethanol (700 mL) was added hydrazine monohydrochloride (12.0 mL, 28.5 mmol), and the mixture was stirred at 25 ° C for 2 hours. The reaction solution was directly spin-dried and then slurried with ethanol (200 mL) for purification to obtain a yellow solid 2,4-dichloro-6-hydrazinopyrimidine (60.0 g, 175 mmol, yield 86%). LCMS (ESI): [M+H] + = 179.1

[0180] Step 2: Formic acid (100 ml) was added dropwise to a solution of acetic anhydride (200 mL) at 0°C, stirred at 0°C for 10 minutes, heated to 50°C and stirred for 15 minutes. The mixture was then cooled to 0°C, 2,4-dichloro-6-hydrazinopyrimidine (55.0 g, 307 mmol) was added to the mixture, and the reaction solution was stirred at 0-25°C for 2 hours. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (800 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by slurrying with methyl tert-butyl ether (200 mL) to obtain a pink solid N-[(2,6-dichloropyrimidin-4-yl)amino]formamide (22.0 g, 106 mmol, yield 35%). LCMS (ESI): [M+H] + =207.1

[0181] Step 3: Under nitrogen, add N'-(2,6-dichloropyrimidin-4-yl)carboxylic acid hydrazide (22.0 g, 106 mmol) to a solution of phosphorus oxychloride (180 mL, 1937 mmol). Heat the mixture to 100°C and stir for 4 hours. The reaction mixture was spun off to remove most of the phosphorus oxychloride and slowly poured into 500 mL of water in portions to quench. Extraction was performed with dichloromethane (500 x 3 mL). The combined organic phases were washed with saturated sodium chloride (500 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spun down to dryness to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether gradient) to afford 5,7-dichloro-[1,2,4]triazolo[4,3-c]pyrimidine (1.04 g, 5.3 mmol, 5% yield) as a light brown solid. LCMS (ESI): [M+H] + =189.1.

[0182] Intermediate A13: 5,7-dichloro-3-methyl-[1,2,4]triazolo[4,3-c]pyrimidine

[0183] Step 1: Add acetic anhydride (30 mL) to 2,4-dichloro-6-hydrazinopyrimidine (30.0 g, 168 mmol), heat the mixture to 50 ° C and stir for 1 hour, add water (500 mL) to the reaction mixture, and extract with ethyl acetate (200 mL x 3). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and the filtrate is spin-dried to obtain a residue. The residue is slurried with methyl tert-butyl ether (200 mL) and filtered. The filter residue is a yellow solid N'-(2,6-dichloropyrimidin-4-yl)acetohydrazide (6.00 g, 27.1 mmol, yield 16%). LCMS (ESI): [M+H] + =221.0

[0184] Step 2: N'-(2,6-dichloropyrimidin-4-yl)acetohydrazide (6.00 g, 27.1 mmol) was slowly added to phosphorus oxychloride (60 mL), and the reaction mixture was stirred at 100 ° C for 4 hours. The reaction mixture was quenched by adding water (200 mL) at 25 ° C and extracted with ethyl acetate (200 mL x 2). The organic phases were combined, 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, 0-25% gradient of ethyl acetate / petroleum ether) to give a yellow solid 5,7-dichloro-3-methyl-[1,2,4]triazolo[4,3-c]pyrimidine (2.00 g, 9.85 mmol, yield 36%). LCMS (ESI): [M+H] + =203.0. 1 H NMR(400MHz,DMSO-d6)δppm 8.11(s,1H),2.55(s,3H)

[0185] Intermediate A14: 5,7-dibromothieno[2,3-c]pyridine

[0186] Step 1: To a solution of methyl 3-methylthiophene-2-carboxylate (20.0 g, 128 mmol) in carbon tetrachloride (400 mL) was added 2,2'-azobis(2-methylpropionylcarbonitrile) (6.31 g, 38.4 mmol) and N-bromosuccinimide (27.3 g, 153 mmol). The mixture was heated to 80°C and stirred for 16 hours. Water (200 mL) was added to the reaction mixture and extracted with ethyl acetate (200 mL x 2). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to give methyl 3-(bromomethyl)thiophene-2-carboxylate (43.0 g, 128 mmol, crude) as a yellow oil.

[0187] Step 2: To a solution of sodium cyanide (11.6 g, 237 mmol) in water (170 mL) was added a solution of methyl 3-(bromomethyl)thiophene-2-carboxylate (43.0 g, 182 mmol) in methanol (350 mL) under an ice bath. The reaction mixture was heated to 55°C and stirred for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (300 mL x 3). The organic phases were combined, 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, 0-4% gradient of ethyl acetate / petroleum ether) to obtain methyl 3-(cyanomethyl)thiophene-2-carboxylate (8.5 g, 182 mmol, 26% yield) as a white solid. LCMS (ESI): [M+H] + =182.0

[0188] Step 3: To a mixed solution of methyl 3-(cyanomethyl)thiophene-2-carboxylate (8.50 g, 46.9 mmol) in methanol (45.0 mL) and water (45.0 mL) was added lithium hydroxide monohydrate (5.96 g, 140 mmol). The mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was a white solid 3-(cyanomethyl)thiophene-2-carboxylic acid (6.00 g, 46.9 mmol, crude product). LCMS (ESI): [M+H] + =168.0

[0189] Step 4: To a solution of tribromophosphorus (20.0 mL) in N,N-dimethylformamide (4.00 mL) was added 3-(cyanomethyl)thiophene-2-carboxylic acid (2.70 g, 0.00 mmol) at 0°C, and the reaction mixture was heated to 120°C and stirred for 3 hours. The reaction mixture was cooled to room temperature in an ice-water bath. The reaction mixture was then poured into ice water, and the precipitate was collected by filtration to obtain a brown solid 5,7-dibromothieno[2,3-c]pyridine (2.1 g, crude product). LCMS (ESI): [M+H] + =293.7

[0190] Intermediate A15: 5,7-dibromofuro[2,3-c]pyridine

[0191] Step 1: Add iodine (17.2 g, 67.2 mmol) to a solution of 6-dibromopyridin-3-ol (10.0 g, 39.5 mmol) and sodium bicarbonate (11.7 g, 138 mmol) in water (200 mL). Stir the mixture at 25°C for 16 hours. Dilute the reaction solution with saturated sodium thiosulfate solution (200 mL) and adjust the pH to 2 with dilute hydrochloric acid. Extract with dichloromethane (900 mL*2). Wash the organic layer with saturated brine (1000 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. Flash silica gel chromatography (silica gel, 0-0% gradient of ethyl acetate / petroleum ether) yielded 2,6-dibromo-4-iodopyridin-3-ol (12.0 g, 39.5 mmol, 76% yield) as a white solid. LCMS (ESI): [M+H] + =379.7.

[0192] Step 2: Dichlorobis(triphenylphosphine)palladium(II) (1.12 g, 1.58 mmol) was added to a solution of 2,6-dibromo-4-iodopyridin-3-ol (6.00 g, 15.8 mmol), ethynyltrimethylsilane (2.33 g, 23.7 mmol), cuprous iodide (0.31 g, 1.58 mmol), and triethylamine (4.91 g, 47.5 mmol) in chloroform (2.00 mL) and tetrahydrofuran (120 mL). 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 mixture, and the mixture was extracted with ethyl acetate (300 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 silica gel chromatography (silica gel, 0-1% gradient of ethyl acetate / petroleum ether) to give 2,6-dibromo-4-((trimethylsilyl)ethynyl)pyridin-3-ol (1.0 g, 15.8 mmol, yield 18.1%) as a white solid. LCMS (ESI): [M+H] + =349.8.

[0193] Step 3: Add 2,6-dibromo-4-((trimethylsilyl)ethynyl)pyridin-3-ol (1.20 g, 3.44 mmol) and cuprous iodide (0.33 g, 1.72 mmol) to a mixture of triethylamine (10.0 mL) and ethanol (10.0 mL). The atmosphere was replaced with nitrogen three times and the mixture was heated to 70°C and stirred for 4 hours under nitrogen. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (60 mL*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 silica gel chromatography (silica gel, 0-1% gradient of ethyl acetate / petroleum ether) to obtain 5,7-dibromofuro[2,3-c]pyridine (0.40 g, 3.44 mmol, 42% yield) as a yellow solid. LCMS (ESI): [M+H] + =277.8

[0194] Intermediate A16: 4,6-dichlorofuro[3,2-c]pyridine

[0195] Step 1: To a solution of 4-chlorofuro[3,2-c]pyridine (5.00 g, 32.6 mmol) in chloroform (100 mL) was added m-chloroperbenzoic acid (9.92 g, 48.8 mmol). 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 silica gel chromatography (silica gel, 0-2% gradient of methanol / dichloromethane) to obtain a brown solid 4-chlorofuro[3,2-c]pyridine 5-oxide (3.00 g, 32.5 mmol, 54% yield). LCMS (ESI): [M+H] + =170.0

[0196] Step 2: 4-chlorofuro[3,2-c]pyridine 5-oxide (3.00 g, 17.7 mmol) was slowly added to a solution of 1,2-dichloroethane (30.0 mL) and phosphorus oxychloride (3.00 mL). The mixture was heated to 85°C and stirred for 16 hours. Water (20 mL) was added to the reaction solution and extracted with dichloromethane (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 silica gel chromatography (silica gel, 0-35% gradient of tetrahydrofuran / petroleum ether) to obtain a yellow solid 4,6-dichlorofuro[3,2-c]pyridine (1.00 g, 17.7 mmol, 30% yield). LCMS (ESI): [M+H] + =188.0

[0197] Intermediate A17: 4,6-dichloro-[1,2,5]thiadiazole[3,4-c]pyridine

[0198] Step 1: A solution containing 4-amino-2,6-dichloro-3-nitropyridine (10 g, 48.08 mmol), iron powder (27.1 g, 480.76 mmol), ammonium chloride (26.0 g, 480.76 mmol), ethanol (100 mL), and water (20 mL) was stirred at 60°C for 2 hours. The reaction solution was filtered and concentrated, then extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound 2,6-dichloropyridine-3,4-diamine (8 g, 44.94 mmol, yield: 93%) as a light yellow solid. LCMS (ESI): [M+H] + =178.0.

[0199] Step 2: A reaction mixture containing 2,6-dichloropyridine-3,4-diamine (8 g, 44.94 mmol) and thionyl chloride (80 mL) was stirred at 90°C for 12 hours. The reaction mixture was concentrated, and then saturated aqueous sodium bicarbonate (200 mL) was added to adjust the pH to approximately 8. The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to afford 4,6-dichloro-[1,2,5]thiadiazo[3,4-c]pyridine (2.1 g, 10.19 mmol, yield: 23%) as a yellow solid. LCMS (ESI): [M+H] + =223.1.

[0200] Intermediate A18: 6-bromo-4-fluorobenzo[c]1,2,5-thiadiazole

[0201] Step 1: Dissolve 4-bromo-2-fluoro-6-nitroaniline (5.00 g, 21.30 mmol) in a mixture of tetrahydrofuran (50 mL), ethanol (10 mL), and water (5 mL). Add iron powder (6.00 g, 106.30 mmol) and ammonium chloride (1.72 g, 31.90 mmol) and stir at 90°C for 22 hours. Cool the reaction mixture to room temperature, filter through celite, and wash the solid with ethanol until no further color passes through the filter. Concentrate the filtrate, and the residue is dissolved in ethyl acetate (50.00 mL) and extracted three times. The organic phases are combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-bromo-3-fluorophenylenediamine (3.10 g, 71%) as a brown solid. LCMS (ESI): [M+H] +=205.0

[0202] Step 2: Dissolve 5-bromo-3-fluorophenylenediamine (3.00 g, 14.50 mmol) in dichloromethane (30.00 mL), add triethylamine (5.89 g, 58.00 mmol) and thionyl chloride (2.81 g, 31.9 mmol). Reflux the mixture at 60°C for 12 hours. Concentrate the mixture, dissolve the residue in water (20.00 mL), and extract three times with ethyl acetate (30.00 mL). Combine the organic phases, wash once with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product, which is purified by flash column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether) to afford 6-bromo-4-fluorobenzo[c]1,2,5-thiadiazole (3.10 g, 91%). 1 H NMR (400MHz, DMSO) δ8.34 (d, J=1.6Hz, 1H), 7.89–7.86 (m, 1H)

[0203] Intermediate A19: 6-bromo-4-iodo-1,3-benzothiazol-2-amine

[0204] Step 1: At 25°C, potassium thiocyanate (16.3g, 168mmol) was added to a solution of 4-bromo-2-iodoaniline (10.0g, 33.6mmol) in acetic acid (100mL). The mixture was stirred at 20°C for 10 minutes, and then bromine (5.36g, 33.57mmol) was slowly added dropwise. The reaction solution was stirred at 25°C for 3 hours. The reaction solution was filtered, the filter cake was washed with acetic acid (30mL), and then the filter cake was dissolved in hot water (100mL) and the pH was adjusted to 11 with aqueous ammonia. The resulting precipitate was filtered, washed with water, and dried to obtain a yellow solid product 6-bromo-4-iodo-1,3-benzothiazol-2-amine (3.30g, 9.41mmol, yield 28%). LCMS (ESI): [M+H]+=356.6

[0205] Step 2: At 25°C, 6-bromo-4-iodo-1,3-benzothiazol-2-amine (1.20 g, 3.38 mmol) was added to tetrahydrofuran (20 mL), followed by the dropwise addition of tert-butyl nitrite (0.42 g, 4.06 mmol) and dimethyl sulfoxide (2.00 mL). The reaction mixture was stirred at 50°C for 4 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with 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, 0-6% gradient of tetrahydrofuran / petroleum ether) to obtain 6-bromo-4-iodo-1,3-benzothiazol-2-amine (0.69 g, 2.03 mmol, 60% yield) as a brown solid. LCMS (ESI): [M+H]+ = 339.6

[0206] Intermediate A20: 6,8-dichloro-2-[(4-methoxyphenyl)methyl]-2,3,4-trihydropyrido[3,4-c]pyridin-1-one

[0207] Step 1: To a solution of methyl 2,6-dichloro-4-methylpyridine-3-carboxylate (3.00 g, 13.6 mmol) in N,N-diisopropylethylamine (30 mL) was added N,N-dimethylformamide dimethyl acetal (4.97 g, 40.9 mmol) at 25°C. The mixture was stirred at 100°C for 12 hours. The reaction solution was slowly added dropwise to water (60 mL), resulting in the precipitation of a yellow precipitate. The precipitate was then collected and dried using an oil pump to afford crude methyl 4-[(1E)-2-(dimethylamino)vinyl]-2,6-dichloropyridine-3-carboxylate (3.60 g, 39.3 mmol, 96% yield) as a yellow solid.

[0208] Step 2: Methyl 4-[(1E)-2-(dimethylamino)vinyl]-2,6-dichloropyridine-3-carboxylate (2.10 g, 7.63 mmol) was added to tetrahydrofuran (30 mL) at 25°C, followed by the dropwise addition of concentrated hydrochloric acid (18 mL). The reaction mixture was stirred at 25°C for 4 hours. Brine (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to afford crude methyl 2,6-dichloro-4-(2-oxyylideneethyl)pyridine-3-carboxylate (1.80 g, 7.25 mmol, 95% yield) as a yellow oil. 1 H NMR(400MHz,CHLOROFORM-d)δppm 9.65(s,1H),7.18-7.10(m,1H),3.88(s,3H),3.76(s,2H)

[0209] Step 3: To a solution of isopropanol (18 mL) and methanol (18 mL) at 25°C, add methyl 2,6-dichloro-4-(2-oxyylideneethyl)pyridine-3-carboxylate (1.8 g, 7.26 mmol) and 4-methoxybenzylamine (1.01 g, 7.26 mmol). The mixture is stirred at 25°C for 2 hours. Acetic acid (1.31 g, 21.8 mmol) and sodium cyanoborohydride (1.35 g, 21.8 mmol) are then added to the reaction solution, which is then heated to 80°C and stirred for 12 hours. Saturated sodium bicarbonate solution (100 mL) is slowly poured into the reaction solution in portions to adjust the pH to 7-8. Ethyl acetate (150 x 2 mL) is then added for extraction. The combined organic phases are washed with saturated sodium chloride (100 mL). The organic phase is dried over anhydrous magnesium sulfate, filtered, and the filtrate is spun down to dryness to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to give 6,8-dichloro-2-[(4-methoxyphenyl)methyl]-2,3,4-trihydropyrido[3,4-c]pyridin-1-one (1.60 g, 4.72 mmol, 65% yield) as a white solid. LCMS (ESI): [M+H]+ = 336.6

[0210] Intermediate A21: 6-chloro-8-(4,4-difluoropiperidin-1-yl)pyrido[3,4-d]pyrimidine

[0211] Step 1: N-chlorosuccinimide (19.3 g, 144.59 mmol) was added portionwise to a mixed solution containing methyl 3-aminopyridine-4-carboxylate (10 g, 65.73 mmol) and N,N-dimethylformamide (100 mL). The reaction solution was stirred at 20°C for 12 hours. The reaction solution was poured into water (500 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound methyl 3-amino-2,6-dichloroisonicotinate (11 g, 49.76 mmol, yield: 75.7%) as a white solid. LCMS (ESI): [M+H] + =221.0.

[0212] Step 2: Under a nitrogen atmosphere, diisobutylaluminum hydride (113 mL, 113 mmol) was slowly added dropwise to a solution containing methyl 3-amino-2,6-dichloropyridine-4-carboxylate (10 g, 45.24 mmol) and tetrahydrofuran (200 mL) at -78°C. The temperature was then raised to 20°C. The reaction solution was stirred at 20°C for 12 hours. Sodium sulfate decahydrate was added to the reaction solution to quench the reaction. The solution was then filtered and concentrated to obtain the compound (3-amino-2,6-dichloropyridin-4-yl)methanol (6 g, 31.08 mmol, yield: 68.7%) as a white solid. LCMS (ESI): [M+H] + =193.0.

[0213] Step 3: Dess-Martin periodinane (20 g, 46.63 mmol) was added portionwise to a mixed solution of (3-amino-2,6-dichloro-4-pyridyl)methane-1-ol (6 g, 31.08 mmol), dichloromethane (60 mL), and tetrahydrofuran (60 mL). The reaction mixture was stirred at 20°C for 12 hours. Aqueous sodium bicarbonate (500 mL) was added to the reaction system to quench the reaction. The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain 3-amino-2,6-dichloroisonicotinaldehyde (2 g, 10.47 mmol, yield: 33.7%). LCMS (ESI): [M+H] + =228.3.

[0214] Step 4: A mixed solution containing 3-amino-2,6-dichloropyridine-4-carbaldehyde (1.5 g, 7.85 mmol), formamidine acetate (1.24 g, 11.78 mmol), 4,4-difluoropiperidine hydrochloride (6.25 g, 39.26 mmol), triethylamine (8.11 g, 78.53 mmol), pyridine (3.3 g, 39.26 mmol) and tert-butanol (70 mL) was stirred at 90 ° C for 12 h, the reaction solution was poured into water (50 mL) and washed with ethyl acetate (50 mL). 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 afford 6-chloro-8-(4,4-difluoropiperidin-1-yl)pyrido[3,4-d]pyrimidine (700 mg, 2.46 mmol, yield: 31.3%) as a yellow solid. LCMS (ESI): [M+H] + =285.10

[0215] Intermediate A22: 6-bromo-8-iodo-2-methoxyquinoline

[0216] Step 1: Dissolve 4-bromo-2-iodoaniline (25.00 g, 84.17 mmol) in tetrahydrofuran (250 mL), add (E)-3-ethoxyacryloyl chloride (22.70 g, 168.34 mmol) and N,N-diisopropylethylamine (43.70 g, 336.68 mmol), and stir at 25°C for 12 hours. The reaction solution was slowly poured into water (200 mL), and ethyl acetate (200 mL x 3) was added and extracted three times. The organic phases were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was stirred with methanol (50 mL) for 1 hour and filtered to obtain (E)-N-4-bromo-2-iodophenyl-3-ethoxyacrylamide (17.00 g, 51%) as a white solid. LCMS (ESI): [M+H] + =396.0.

[0217] Step 2: (E)-N-4-bromo-2-iodophenyl-3-ethoxyacrylamide (17.00 g, 42.90 mmol) was added to concentrated sulfuric acid (34 mL) in batches. The reaction mixture was stirred at 25°C for 3 hours. After the reaction was completed, the mixture was slowly added dropwise to ice water (100 mL) and stirred for 1 hour. A white solid precipitated in the mixture. The mixture was filtered, the white solid was collected, and dried to obtain 6-bromo-8-iodoquinolin-2(1H)one (11.00 g, 73%) as a white solid. LCMS (ESI): [M+H] + =350.0

[0218] Step 3: 6-bromo-8-iodoquinolin-2(1H)one (11.00 g, 31.40 mmol) was dissolved in phosphorus oxychloride (50 mL), and the reaction mixture was stirred at 100°C for 5 hours. The phosphorus oxychloride was removed under reduced pressure, and the residue was dissolved in water (50 mL). The aqueous layer was then adjusted to pH 8 with saturated aqueous sodium bicarbonate (40 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to give 6-bromo-2-chloro-8-iodoquinoline (8.00 g, 69%) as a yellow solid. LCMS (ESI): [M+H] + =367.9

[0219] Step 4: 6-Bromo-2-chloro-8-iodoquinoline (5.00 g, 13.50 mmol) and sodium methoxide (5.10 g, 9.50 mmol) were dissolved in methanol (50 mL). The reaction mixture was stirred at reflux at 70°C for 8 hours. The solvent was removed under reduced pressure, and the residue was dissolved in water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL), and dried over anhydrous sodium sulfate to obtain 6-bromo-8-iodo-2-methoxyquinoline (4.00 g, 80%) as a white solid. LCMS (ESI): [M+H] + =364.0

[0220] Intermediate A24: 6-Bromo-8-iodoquinoline-2-carbonitrile

[0221] Step 1: 4-Bromo-2-iodoaniline (5.00 g, 16.62 mmol), glycerol (7.73 g, 83.08 mmol), and sodium 3-nitrobenzenesulfonate (4.91 g, 21.60 mmol) were added to a solution of concentrated sulfuric acid (30 mL) and water (20 mL). The reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was poured into water (100 mL) and the pH was adjusted to 10 with 2M sodium hydroxide solution. The resulting solution was filtered and the solid was washed with water (50 mL x 3) and dried to obtain 6-bromo-8-iodoquinoline (3.00 g, crude) as a light yellow solid. LCMS (ESI): [M+H] + =333.9

[0222] Step 2: 6-Bromo-8-iodoquinoline (3.00 g, 8.98 mmol) and m-chloroperbenzoic acid (4.56 g, 22.16 mmol) were added to dichloromethane (50 mL), and the reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Flash column chromatography (silica gel, 0-8% methanol / dichloromethane gradient) of the crude product afforded 6-bromo-8-iodoquinoline-1-oxide (1.20 g, 3.44 mmol, yield: 38.2%) as a light yellow solid. LCMS (ESI): [M+H] + =349.9

[0223] Step 3: 6-Bromo-8-iodoquinoline-1-oxide (1.10 g, 3.14 mmol), trimethylsilyl cyanide (955 mg, 9.43 mmol), and iodobenzene acetate (3.10 g, 9.43 mmol) were added to 1,2-dichloroethane (10 mL). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Flash column chromatography (silica gel, 5-10% gradient of ethyl acetate / petroleum ether) of the crude product gave 6-bromo-8-iodoquinoline-2-carbonitrile (800 mg, 2.23 mmol, yield: 70.9%) as a white solid. LCMS (ESI): [M+H] + =358.9

[0224] Intermediate A25: 6-bromo-8-iodo-2-(trifluoromethyl)quinoline

[0225] Step 1: Add 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (4.27 g, 25.17 mmol) to a solution of 4-bromo-2-iodoaniline (5.00 g, 16.78 mmol) in acetonitrile (50 mL) at 25°C. The resulting reaction mixture is stirred at 50°C for 4 hours. The residue is purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to afford (3E)-4-[(4-bromo-2-iodophenyl)amino]-1,1,1-trifluorobut-3-en-2-one (6.00 g, 14.18 mmol, yield: 84.5%) as a yellow solid. LCMS (ESI): [M+H] + =421.9, 1 H NMR (400MHz, DMSO) δ11.81(d,J=12.9Hz,1H),8.29(dd,J=12.9,7.6Hz,1H),8.13(d,J= 2.2Hz,1H),7.68(dd,J=8.8,2.2Hz,1H),7.59(d,J=8.8Hz,1H),5.79(d,J=7.4Hz,1H).

[0226] Step 2: Phosphorus oxychloride (7.5 mL) was added to (3E)-4-[(4-bromo-2-iodophenyl)amino]-1,1,1-trifluorobut-3-en-2-one (3.00 g, 7.14 mmol) and 4-bromo-2-iodoaniline (2.15 g, 7.14 mmol) at 25°C. The resulting reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated and diluted with ethyl acetate (100 mL). The filtrate was washed with saturated sodium bicarbonate solution (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-20% ethyl acetate / petroleum ether gradient) to afford 6-bromo-8-iodo-2-(trifluoromethyl)quinoline (2.30 g, 5.72 mmol, yield: 80.1%) as a light yellow solid. LCMS (ESI): [M+H] + =402.0, 1 H NMR (400MHz, DMSO) δ8.70–8.62(m,2H),8.51(q,J=1.7Hz,1H),8.09(dd,J=8.5,1.5Hz,1H).

[0227] Intermediate A26: 6-bromo-7-fluoro-8-iodoquinoline

[0228] Step 1: A mixture containing 3-fluoro-2-iodo-1-nitrobenzene (9.50 g, 35.58 mmol), iron powder (10.00 g, 177.90 mmol), ammonium chloride (9.60 g, 177.90 mmol), ethanol (100 mL), and water (20 mL) was stirred at 60°C for 1 hour. The reaction mixture was filtered while hot and concentrated, then extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether gradient) to obtain 3-fluoro-2-iodoaniline (6.70 g, 79.5%) as a white solid. LCMS (ESI): [M+H] + =238.0

[0229] Step 2: N-bromosuccinimide (5.0 g, 28.27 mmol) was added to a mixed solution containing 3-fluoro-2-iodoaniline (6.70 g, 28.27 mmol) and N,N-dimethylformamide (60 mL). The reaction solution was stirred at 20°C for 1 hour, poured into water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain the compound 4-bromo-3-fluoro-2-iodoaniline (7.00 g, 78.7%) as a gray solid. LCMS (ESI): [M+H] + =317.9.

[0230] Step 3: Glycerol (5.60 g, 59.83 mmol) and 3-nitrobenzenesulfonic acid sodium salt (5.40 g, 23.93 mmol) were added to a solution containing concentrated sulfuric acid (20 mL) and water (15 mL). The mixture was heated to 110°C, and then 4-bromo-3-fluoro-2-iodoaniline (6.30 g, 19.94 mmol) was slowly added. The resulting mixture was stirred at 130°C for 12 hours. The reaction solution was poured into ice / water and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to obtain the compound 6-bromo-7-fluoro-8-iodoquinoline (2.20 g, 31%) as a gray solid. LCMS (ESI): [M+H] + =353.9.

[0231] Intermediate A27: 8-(4,4-difluoropiperidinyl)-6-bromo-7-(trifluoromethyl)quinoline

[0232] Step 1: To a solution of 2-fluoro-3-(trifluoromethyl)aniline (9.00 g, 50 mmol) in N,N-dimethylformamide (100 mL) at 25°C was added N-bromosuccinimide (9.80 g, 55 mmol). The resulting reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with saturated sodium chloride solution (200 mL x 3) and water (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-15% ethyl acetate / petroleum ether gradient) to afford 4-bromo-2-fluoro-3-(trifluoromethyl)aniline (12.00 g, 93% yield) as a purple solid. LCMS (ESI): [M+H] + =259.9.

[0233] Step 2: A mixture of glycerol (11.00 g, 116 mmol) and 3-nitrobenzenesulfonic acid sodium salt (9.70 g, 42 mmol) in water (70 mL) and concentrated sulfuric acid (30 mL) was heated to 100°C. 4-Bromo-2-fluoro-3-(trifluoromethyl)aniline (10.00 g, 39.00 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at 100°C for 36 hours. The reaction mixture was poured into crushed ice (400 mL), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-20% ethyl acetate / petroleum ether gradient) to afford 6-bromo-8-fluoro-7-(trifluoromethyl)quinoline (6.70 g, 59%) as a purple solid. LCMS (ESI): [M+H] + =296.0.

[0234] Step 3: To a solution of 6-bromo-8-fluoro-7-(trifluoromethyl)quinoline (3.7 g, 12 mmol) and 4,4-difluoropiperidine hydrochloride (3.0 g, 19 mmol) in dimethyl sulfoxide (50 mL) was added cesium carbonate (5.3 g, 38 mmol) at 25°C. The reaction mixture was stirred at 100°C for 24 h. The reaction mixture was filtered and the filtrate was diluted with ethyl acetate (200 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to a residue. The residue was stirred in a solution of petroleum ether:ethyl acetate (10:1, 11 mL) for 10 minutes, filtered, and the filtrate was concentrated to a residue. The residue was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to give 8-(4,4-difluoropiperidinyl)-6-bromo-7-(trifluoromethyl)quinoline (450 mg, 9%) as a white solid. LCMS (ESI): [M+H] + =395.1.

[0235] Intermediate A28: 6-bromo-7-chloro-8-fluoroquinoline

[0236] Step 1: Heat a mixture of glycerol (12.40 g, 133.65 mmol), 3-nitrobenzenesulfonic acid sodium salt (12.20 g, 53.46 mmol), water (60 mL), and concentrated sulfuric acid (80 mL) to 100°C. 4-Bromo-3-chloro-2-fluoroaniline (10.00 g, 44.55 mmol) was added to the mixture, and the mixture was stirred at 120°C for 12 hours. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford 6-bromo-7-chloro-8-fluoroquinoline (9.50 g, 36.47 mmol, yield: 81.9%) as a brown solid. LCMS (ESI): [M+H] + =260.1

[0237] Intermediate A29: 6-Chloro-8-fluoroquinoline-7-carbonitrile

[0238] Step 1: To a solution of 3-bromo-2-fluoroaniline (10.00 g, 52.63 mmol) in N,N-dimethylacetamide (100 mL) at 25°C was added chlorosuccinimide (7.00 g, 52.60 mmol). The resulting reaction mixture was stirred at 55°C for 16 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with saturated brine (150 mL x 3). The organic phase was concentrated, dried, filtered, and concentrated to a residue. Flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) afforded 3-bromo-4-chloro-2-fluoroaniline (6.00 g, 26.67 mmol, 55.0% yield) as a purple solid. LCMS (ESI): [M+H] + =226.0; 1 H NMR (400MHz, DMSO) δ7.12 (dd, J=8.8, 1.8Hz, 1H), 6.82–6.74 (m, 1H), 5.60 (s, 2H)

[0239] Step 2: A mixture of glycerol (10.00 g, 111.4 mmol) in concentrated sulfuric acid (50 mL) and water (30 mL) was stirred at 100°C for 15 minutes, then the mixture was cooled to 40°C. To this reaction mixture were added 3-bromo-4-chloro-2-fluoroaniline (5.00 g, 22.3 mmol) and sodium 3-nitrobenzenesulfonate (5.57 g, 24.50 mmol). The resulting reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was poured into ice water (500 mL), and the pH was adjusted to 8 with potassium carbonate. The mixture was extracted with ethyl acetate (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified by flash column chromatography (silica gel, 0-20% ethyl acetate / petroleum ether gradient) to afford 7-bromo-6-chloro-8-fluoroquinoline (3.80 g, 14.56 mmol, 65.5% yield) as a gray solid. LCMS(ESI):[M+H] + =262.1; 1 H NMR (400MHz, DMSO) δ9.04–9.00(m,1H),8.46(dq,J=8.4,1.5Hz,1H),8.26(t,J=2.0Hz,1H),7.74(dd,J=8.4,4.2Hz,1H).

[0240] Step 3: To 7-bromo-6-chloro-8-fluoroquinoline (2.50 g, 9.60 mmol), zinc cyanide (5.17 g, 43.19 mmol), and tetrakis(triphenylphosphine)palladium (1.13 g, 0.96 mmol) was added N,N-dimethylformamide (40 mL) at 25°C. The resulting reaction mixture was purged with nitrogen for 1 minute and stirred at 120°C for 16 hours. The reaction mixture was filtered, and the filtrate was diluted with ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride (50 mL x 3). The organic phase was dried, filtered, and concentrated to a residue. The residue was purified by flash column chromatography (silica gel, 0-30% ethyl acetate / petroleum ether gradient) to afford 6-chloro-8-fluoroquinoline-7-carbonitrile (650 mg, 3.15 mmol, 32.8% yield) as a white solid. LCMS (ESI): [M+H] + =207.1

[0241] Intermediate A30: 6-bromo-7-fluoro-8-iodo-2-methylquinoxaline

[0242] Step 1: A solution of 4-bromo-3-fluoro-2-iodoaniline (4.40 g, 14.00 mmol) and (2E) crotonaldehyde (3.90 g, 56.00 mmol) in aqueous hydrochloric acid (116 mL, 6 M) was stirred at 100°C for 16 hours. The reaction mixture was poured into crushed ice (500 mL) and the pH was adjusted to 8. The mixture was extracted with ethyl acetate (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to a residue. The residue was purified by flash column chromatography (silica gel, 0-20% ethyl acetate / petroleum ether) to afford 6-bromo-7-fluoro-8-iodo-2-methylquinoxaline (1.00 g, 20%) as a white solid. LCMS (ESI): [M+H] + =365.9.

[0243] Intermediate A31: 6-bromo-8-fluoroisoquinoline

[0244] Step 1: Dissolve 4-bromo-2-fluorobenzaldehyde (5.00 g, 24.63 mmol) in toluene (100 mL) and add 2,2-dimethoxyethane-1-amine (3.88 g, 36.94 mmol). Heat the reaction mixture to 140°C and stir for 16 hours. After cooling to room temperature, concentrate the reaction mixture to obtain crude (E)-1-(4-bromo-2-fluorophenyl)-N-(2,2-dimethoxyethyl)methanamine (7.00 g, crude) as a brown oil, which was used directly in the next step without purification.

[0245] Step 2: Dissolve (E)-1-(4-bromo-2-fluorophenyl)-N-(2,2-dimethoxyethyl)methanamine (3.00 g, 10.34 mmol) in methanol (30 mL). Cool to 0°C, add sodium cyanoborohydride (270 mg, 7.24 mmol), and stir at room temperature for 2 hours. Add ice water to the reaction mixture, concentrate to remove methanol, and extract with ethyl acetate (30 mL x 3). The combined organic phases are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a residue that is purified by flash column chromatography (silica gel, 10-20% ethyl acetate / petroleum ether gradient) to afford N-(4-bromo-2-fluorobenzyl)-2,2-dimethoxyethane-1-amine (2.50 g, 8.50 mmol, yield: 83.3%) as a white solid. LCMS (ESI): [M+H] + =292.0

[0246] Step 3: Dissolve N-(4-bromo-2-fluorobenzyl)-2,2-dimethoxyethane-1-amine (2.50 g, 8.50 mmol) in dichloromethane (20 mL). Add 4-dimethylaminopyridine (156 mg, 1.28 mmol) and triethylamine (2.59 g, 25.5 mmol) sequentially. Cool the reaction mixture to 0°C under nitrogen and add p-toluenesulfonyl chloride (2.44 g, 12.75 mmol). After warming to room temperature and stirring for 16 hours, the reaction mixture was quenched with ice water (20 mL). The aqueous phase was extracted with dichloromethane (30 mL x 3). The separated organic phase was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to give N-(4-bromo-2-fluorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (3.04 g, 6.81 mmol, yield: 80.2%).

[0247] LCMS(ESI):[M+H] + =446.0

[0248] Step 4: Dichloromethane (20 mL) was added to a reaction flask containing aluminum trichloride (1.34 g, 10.08 mmol). The mixture was cooled to 0°C under nitrogen and a solution of N-(4-bromo-2-fluorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (3.00 g, 6.72 mmol) in dichloromethane (10 mL) was added. The reaction mixture was stirred at room temperature for 16 hours and quenched with ice water (30 mL). The pH of the solution was adjusted to 10 with aqueous ammonia, and the aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue which was purified by flash column chromatography (silica gel, 10-20% gradient of ethyl acetate / petroleum ether) to afford 6-bromo-8-fluoroisoquinoline (1.36 g, 6.00 mmol, yield: 89.4%). LCMS (ESI): [M+H] + =228.0

[0249] Intermediate A32: 6-Bromo-8-fluorocinnoline

[0250] Step 1: A mixture of (1E)-1-(4-bromo-2-ethynyl-6-fluorophenyl)-3,3-diethyltriaza-1-ene (2.00 g, 6.71 mmol) in 1,2-dichlorobenzene (20.0 mL) was stirred at 200°C for 5 hours. The reaction mixture was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to afford 6-bromo-8-fluorocinnoline (500 mg, 2.14 mmol, 33% yield) as a black solid. LCMS (ESI): [M+H]+ = 229.0

[0251] Intermediate A33: 7-bromo-5-iodoquinoxaline

[0252] Step 1: Ammonium chloride (3.90 g, 73.00 mmol) was added to a mixture of 4-bromo-6-iodo-2-nitroaniline (5.00 g, 14.00 mmol) and iron (2.5 g, 44 mmol) in water (10 mL) and ethanol (50 mL) at 25°C. The resulting reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was filtered and washed with ethanol (20 mL x 2). The organic phase was concentrated, dried, filtered, and concentrated to give a residue (4.50 g, 98%) as a brown solid, which was used in the next step without purification. LCMS (ESI): [M+H] + =312.9.

[0253] Step 2: Potassium carbonate (6.00 g, 43.00 mmol) was added to a solution of 5-bromo-3-iodobenzene-1,2-diamine (4.50 g, 14.00 mmol) and glyoxal (1.70 g, 29.00 mmol) in ethanol (50 mL) at 25°C. The resulting reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was filtered and washed with ethyl acetate (30 mL). The filtrate was then washed with saturated sodium chloride solution (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-20% ethyl acetate / petroleum ether gradient) to afford 7-bromo-5-iodoquinoxaline (970 mg, 20%) as a light yellow solid. LCMS (ESI): [M+H] + =336.9. 1 H NMR (400MHz, DMSO) δ9.04(d,J=1.8Hz,1H),8.98(d,J=1.8Hz,1H),8.62(d,J=2.1Hz,1H),8.40(d,J=2.1Hz,1H).

[0254] Intermediate A34: 6-bromo-7,8-difluoro-3-iodoquinoline

[0255] Step 1: Add concentrated sulfuric acid (400 mL) dropwise to pure water (308 mL). Add sodium 3-nitrobenzenesulfonate (23.2 g, 102 mmol) and glycerol (32.2 g, 346 mmol). Heat the reaction mixture to 110°C. Add 4-bromo-2,3-difluoroaniline (20.0 g, 96.2 mmol) in portions and stir at 140°C for 16 hours. Slowly add the reaction mixture to 500 mL of stirred ice water. Adjust the pH to 7 with sodium hydroxide solution (2000 mL, 600 g). After filtration, disperse the filter cake in water (1000 mL) and extract with 2000 mL of ethyl acetate (1000 mL x 2). Wash the organic phase with saturated brine (400 mL), dry, filter, and concentrate. The residue was purified by slurrying with methyl tert-butyl ether (250 mL) for 16 hours and filtered to give 6-bromo-7,8-difluoroquinoline (22.0 g, 88.5 mmol, 92.0% yield) as a brown solid. LCMS (ESI): [M+H] + =245.9; 1 H NMR (400MHz, DMSO-d6) δppm 9.01 (d, J = 4.0Hz, 1H), 8.44 (br d, J = 8.4Hz, 1H), 8.34 (dd, J = 2.0, 7.2Hz, 1H), 7.67 (dd, J = 4.4, 8.4Hz, 1H)

[0256] Step 2: Dissolve 6-bromo-7,8-difluoroquinoline (9.50 g, 59%) in acetic acid (160 mL), add N-iodosuccinimide (17.7 g, 78.7 mmol), and stir at 95°C for 16 hours. The reaction solution was slowly poured into saturated sodium bicarbonate solution (1500 mL) and extracted with 1000 mL of ethyl acetate (500 mL x 2). The organic phase was washed with saturated brine (400 mL), dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-7% gradient of tetrahydrofuran / petroleum ether) to obtain 6-bromo-7,8-difluoro-3-iodoquinoline (6.40 g, 17.1 mmol, 26.0% yield) as a brown solid. LCMS (ESI): [M+H] + =371.7; 1 H NMR(400MHz,CHLOROFORM-d)δppm 9.02(d,J=1.6Hz,1H),8.40(s,1H),7.70(dd,J=2.4,6.4Hz,1H)

[0257] Example 1: N-(2-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0258] Step 1: A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.00 g, 26.45 mmol), aqueous ammonia (9.90 g, 79.35 mmol), and ethanol (50 mL) was stirred at 40°C for 12 hours. The reaction mixture was directly concentrated to afford 2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (4.60 g) as a white solid. LCMS (ESI): [M+H] + =170.1.

[0259] Step 2: A reaction mixture containing 2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (4.60 g, 27.12 mmol), 4,4-difluoropiperidine (3.90 g, 32.55 mmol), N,N-diisopropylethylamine (10.70 g, 81.36 mmol), and dioxane (50 mL) was stirred at 100°C for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether gradient) to afford 2-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (3.60 g) as a white solid. LCMS (ESI): [M+H] + =255.1

[0260] Step 3: 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (2.10 g, 7.08 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to a reaction solution containing 2-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (1.00 g, 3.93 mmol), potassium tert-butoxide (1.30 g, 11.80 mmol) and tetrahydrofuran (10 mL). After stirring at room temperature for 30 minutes, the reaction solution was poured into water (50 mL) and washed with ethyl acetate (50 mL x 10 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound N-(2-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (620 mg, contains isomers) as a yellow solid. LCMS (ESI): [M+H] + =513.3.

[0261] Step 4: A solution of N-(2-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (620 mg, 1.21 mmol), iron (341 mg, 6.05 mmol), ammonium chloride (327 mg, 6.05 mmol), ethanol (5 mL), water (2 mL) and tetrahydrofuran (5 mL) was stirred at 60 ° C for 30 minutes. The reaction solution was filtered while hot, then poured into water (20 mL) and washed with ethyl acetate (20 mL x 40 mL). 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 afford the compound 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide as a yellow solid (290 mg). LCMS (ESI): [M+H] + =483.4.

[0262] Step 5: At 0°C, ethyl chlorosulfonylacetate (136 mg, 0.721 mmol) was added dropwise to a reaction solution containing 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (290 mg, 0.60 mmol), N,N-diisopropylethylamine (238 mg, 1.80 mmol) and dichloromethane (2 mL). The mixture was stirred at 25°C for 1 hour. The reaction solution was poured into water (30 mL) and washed with ethyl acetate (30 mL x 10 mmol). 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 ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (100 mg) as a yellow solid. LCMS (ESI): [M+H] + =633.3.

[0263] Step 6: Lithium aluminum tetrahydride (17 mg, 0.474 mmol) was added to the reaction solution containing ethyl 2-(N-(4-(2-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopentane[d]pyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ethyl ethyl ester (100 mg, 0.16 mmol) and tetrahydrofuran (3 mL). The mixture was stirred at 25°C for 30 minutes. Saturated aqueous ammonium chloride solution (20 mL) was added dropwise to the reaction flask and ethyl acetate (20 mL x 10 mL) was added. 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by HPLC (C18, 30%-100% gradient of water / acetonitrile) to give the compound N-(2-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (16.3 mg) as a white solid. LCMS (ESI): [M+H] + =591.3; 1H NMR (400MHz, DMSO) δ12.70 (s, 1H), 10.22 (s, 1H), 7.94 (d, J = 8.8Hz, 1H), 7.24 (d,J=2.4Hz,1H),7.10(dd,J=8.4,2.0Hz,1H),4.96(s,1H),3.75(t,J=6.8Hz ,2H),3.29-3.43(m,6H),2.91-3.04(m,4H),2.88(t,J=7.2Hz,2H),2.78(t,J =7.6Hz,2H),2.08(s,2H),1.86-2.03(m,6H),1.66-1.74(m,2H),0.38(s,4H).

[0264] Example 2: N-(2-(4,4-difluoropiperidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0265] Example 2 was prepared by a similar synthetic route according to Example 1: LCMS (ESI): [M+H] + =593.4; 1 H NMR (500MHz, DMSO) δ13.29 (s, 1H), 10.32 (s, 1H), 9.06 (s, 1H), 8.01 (d, J = 7.2Hz ,1H),7.28-7.32(m,1H),7.14(dd,J=6.8,1.6Hz,1H),5.19(s,3H),4.79(s,2H) ,3.87-4.01(m,4H),3.75(t,J=5.2Hz,2H),3.36(t,J=5.2Hz,2H),2.92-3.04(m ,4H),1.93-2.09(m,4H),1.61-1.84(m,3H),1.54(d,J=5.6Hz,2H),0.39(s,4H).

[0266] Example 3: N-(4-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopentadienyl[d]pyrimidin-2-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0267] Step 1: 2,4-Dichloro-5,6-trimethylpyrimidine (2.00 g, 10.47 mmol), 4,4-difluoropiperidine hydrochloride (1.75 g, 10.99 mmol), and N,N-diisopropylethylamine (4.14 g, 31.42 mmol) were added to acetonitrile (10 mL). The reaction mixture was heated to 60°C and stirred for 4 hours. After the reaction mixture cooled to room temperature, water (50 mL) was poured into the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The mixture was washed with saturated sodium chloride solution (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude brown solid of 2-chloro-4-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopentadi[d]pyrimidine (2.60 g, 90% yield). LCMS (ESI): [M+H] + =274.1,276.1.

[0268] Step 2: 2-Chloro-4-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopentadi[d]pyrimidine (2.80 g, 10.23 mmol), 4-methoxybenzylamine (1.70 g, 12.28 mmol) and cesium carbonate (11.90 g, 35.80 mmol) were added to N,N-dimethylformamide (30 mL). The reaction solution was heated to 140 ° C and stirred for 6 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was poured into the reaction mixture, extracted with dichloromethane (50 mL x 3), and washed with saturated aqueous sodium chloride solution (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude brown solid of 4-(4,4-difluoropiperidin-1-yl)-N-(4-methoxybenzyl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidin-2-amine (3.70 g, yield 96%). LCMS (ESI): [M+H] + =375.3.

[0269] Step 3: 4-(4,4-difluoropiperidin-1-yl)-N-(4-methoxybenzyl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-2-amine (3.70 g, 9.88 mmol) was added to tetrahydrofuran (20 mL) and trifluoroacetic acid (20 mL). The reaction mixture was heated to 50°C and stirred for 30 minutes. After cooling to room temperature, water (50 mL) was poured into the reaction mixture. The pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to flash column chromatography (silica gel, 0-6% methanol / dichloromethane gradient) to afford 4-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-2-amine (1.50 g, 59%) as a pale yellow solid. LCMS(ESI):[M+H] + =255.3.

[0270] Step 4: 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (878 mg, 2.83 mmol) was added to dichloromethane (5 mL). One drop of N,N-dimethylformamide was added to the reaction mixture. Thionyl chloride (1.13 g, 9.44 mmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was evaporated to dryness to obtain a residue. 4-(4,4-Difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-2-amine (600 mg, 2.36 mmol) and potassium tert-butoxide (802 mg, 7.08 mmol) were added to tetrahydrofuran (5 mL). The residue from the previous step was dissolved in tetrahydrofuran (5 mL) and slowly added dropwise to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered, concentrated, and flash column chromatography (silica gel, 0-10% gradient of methanol / dichloromethane) was performed to obtain a brown solid of 4-bromo-N-(4-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (450 mg, 35% yield). LCMS (ESI): [M+H] + =546.2,548.2.

[0271] Step 5: Under nitrogen protection, 4-bromo-N-(4-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.37 mmol), cuprous iodide (71 mg, 0.37 mmol), potassium phosphate (159 mg, 0.73 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (53 mg, 0.37 mmol) and ethyl 2-sulfamoyl acetate (62 mg, 0.37 mmol) were added to N,N-dimethylformamide (4 mL), and the reaction solution was heated to 100°C and stirred for 6 hours. After the reaction mixture was cooled to room temperature, water (30 mL) was added to the reaction mixture, extracted with dichloromethane (30 mL x 3), and washed with saturated aqueous sodium chloride solution (30 mL x 3). The organic phases were combined and concentrated to obtain a residue. The residue was subjected to flash column chromatography (silica gel, 0-10% gradient of methanol / dichloromethane) to obtain ethyl 2-(N-(4-((4-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate as a pale yellow solid (100 mg, 43% yield). LCMS (ESI): [M+H] + =633.4.

[0272] Step 6: Ethyl 2-(N-(4-((4-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (100 mg, 0.16 mmol) was added to tetrahydrofuran (2 mL), and the reaction solution was cooled to 0°C. Lithium aluminum hydride (12 mg, 0.32 mmol) was added to the reaction solution in three portions over 30 minutes, and the reaction solution was stirred at 0°C for 1 hour. Saturated aqueous ammonium chloride (30 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was subjected to preparative HPLC (40-60% acetonitrile / water gradient) to afford N-(4-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (5 mg, 5.98%). LCMS (ESI): [M+H] + =591.4. 1 HNMR(400MHz,DMSO)δppm 13.20-13.00(m,1H),10.23(s,1H),7.97(s,1H),7.23(s,1H),7.12-7.09(m,1H),4.96(s,1H),3.83-3.74(m ,6H),3.01-2.98(m,6H),2.97-2.80(m,2H),2.62-2.53(m,2H),2.10-2.00(m,6H),1.66(s,4H),0.38(s,4H).

[0273] Example 4: N-(4-(4,4-difluoropiperidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0274] Example 4 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =593.3. 1H NMR(400MHz,DMSO-d6)δppm 12.72(s,1H),10.15(s,1H),7.93(br d,J=8.4Hz,1H),7.20(s,1H),7.07(dd,J=1.8,8.6Hz,1H),5.19(s,2H),4.79(s,2H),3.75(t,J=6.5Hz,2H), 3.62-3.72(m,4H),3.34-3.40(m,3H),2.92-3.00(m,4H),1.96-2.09(m,4H),1.48-1.80(m,4H),0.37(s,4H)

[0275] Example 5: N-(4-(4,4-difluoropiperidin-1-yl)-1,3-dihydrofuro[3,4-c]pyridin-6-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0276] Example 5 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =592.2. 1 H NMR(400MHz,DMSO-d6)δppm 12.87(s,1H),10.19(s,1H),8.04(d,J=8.6Hz,1H),7.69(s,1H),7.24(d,J=1.6Hz,1H) ,7.10(dd,J=1.9,8.6Hz,1H),5.07(s,2H),4.94(s,2H),3.75(t,J=6.4Hz,2H),3.57(br t,J=4.9Hz,4H),3.35-3.38(m,3H),2.90-3.05(m,4H),1.96-2.08(m,4H),1.37-1.93(m,4H),0.38(s,4H)

[0277] Example 6: tert-Butyl 4-(4,4-difluoropiperidin-1-yl)-2-(4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate

[0278] Example 6 was prepared by a similar synthetic route to Example 3: LCMS (ESI): [M+H]+=692.5. 1H NMR (400MHz, DMSO-d6) δppm 12.68 (br s, 1H), 10.17 (br s, 1H), 7.95 (d, J = 1.2Hz, 1H), 7.22 (s, 1H), 7.09 (br d,J=8.8Hz,1H),5.08-4.84(m,1H),4.80-4.62(m,2H),4.49-4.27(m,2H),3.76(m,7H) ),2.96(m,4H),2.15-1.98(m,4H),1.73-1.58(m,4H),1.50-1.44(m,9H),0.38(s,4H)

[0279] Example 7: N-(4-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0280] Step 1: To a solution of tert-butyl 4-(4,4-difluoropiperidin-1-yl)-2-(4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (40.0 mg, 0.06 mmol) in dichloromethane (6.00 mL) was added trifluoroacetic acid (1.00 mL). The mixture was stirred at 25°C for 2 hours. The mixture was purified by preparative HPLC (C18, 0-38% gradient of water (formic acid) / acetonitrile) to give N-(4-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (15 mg, 0.06 mmol, 44% yield) as a white solid. LCMS (ESI): [M+H] + =592.5. 1 H NMR(400MHz,DMSO-d6)δppm 12.44(s,1H),8.17(s,1H),7.94(br d,J=8.4Hz,1H),7.21(s,1H),7.08(dd,J=2.0,8.8Hz,1H),4.30-4.21(m,2H),3.96-3.88(m,2H),3.79 -3.70(m,6H),3.36-3.34(m,2H),3.01-2.93(m,4H),2.10-1.98(m,4H),1.83-1.46(m,4H),0.38(s,4H)

[0281] Example 8: N-(4-(4,4-difluoropiperidin-1-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0282] Step 1: To a solution of N-(4-(4,4-difluoropiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (40.0 mg, 0.07 mmol) and triethylamine (13.9 mg, 0.14 mmol) in acetonitrile (1.00 mL) was added aqueous formaldehyde (9.23 mg, 0.10 mmol) and sodium acetate borohydride (14.6 mg, 0.07 mmol). The mixture was stirred at 25°C for 2 hours. The reaction solution was extracted with ethyl acetate and filtered. The solid was slurried with pure water (5 mL) at 25°C for one hour, filtered to obtain a crude product, and pure water (5 mL) was added and lyophilized to obtain N-(4-(4,4-difluoropiperidin-1-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (12 mg, 0.07 mmol, yield 29%) as a white solid. LCMS (ESI): [M+H] + =606.5. 1 H NMR (400MHz, DMSO-d6) δppm 12.62 (br s, 1H), 10.16 (br s, 1H), 7.93 (br d, J = 8.0Hz, 1H), 7.20 (br s,1H),7.12-7.02(dd,J=1.6Hz,8.4Hz,1H),5.19-4.72(m,1H),4.03-3.97(m,2H),3.81-3.62(m,8H), 3.36-3.34(m,2H),3.04-2.90(m,4H),2.49(s,3H),2.09-1.95(m,4H),1.81-1.47(m,4H),0.37(s,4H)

[0283] Example 9: N-(4-(4,4-difluoropiperidin-1-yl)-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0284] Example 9 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+1] + =606.1.1H NMR (400MHz, DMSO) δ12.89 (s, 1H), 9.98 (s, 1H), 8.05 (d, J = 8.6Hz, 1H), 7.63 (s, 1H) ),7.26(d,J=2.0Hz,1H),7.12(dd,J=8.8,2.0Hz,1H),6.25–4.36(m,4H),3.76(t, J=6.4Hz,2H),3.57(dt,J=7.2,3.8Hz,4H),3.33(d,J=3.2Hz,2H),2.97(d,J=5.6H z,4H),2.11–2.00(m,4H),2.00–1.47(m,4H),1.39(d,J=6.4Hz,3H),0.38(s,4H).

[0285] Example 10: N-(4-(4,4-difluoropiperidin-1-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-6-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0286] Example 10 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =634.3. 1 H NMR(400MHz,DMSO-d6)δppm 12.96(s,1H),11.06-9.21(m,1H),8.06(d,J=8.8Hz,1H),7.57(s,1H),7.26(d,J=2.0Hz ,1H),7.12(dd,J=2.0,8.4Hz,1H),5.04(d,J=1.6Hz,3H),3.76(t,J=6.8Hz,2H),3.56(br d,J=4.0Hz,4H),3.38-3.34(m,2H),3.06-2.92(m,4H),2.10-1.99(m,4H),1.98-1.40(m,6H),1.37(s,3H),0.76(t,J=7.2Hz,3H),0.38(s,4H)

[0287] Example 11 N-(1-(4,4-difluoropiperidin-1-yl)-pyrrolo[1,2-a]pyrazin-3-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0288] Example 11 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =589.1. 1 H NMR(400MHz,DMSO-d6)δppm 12.62-12.88(m,1H),9.98-10.41(m,1H),8.64-8.87(m,1H),8.02(s,1H),7.69-7.83(m,1H),7.26-7.33(m,1H),7.09 -7.21(m,1H),6.81-6.90(m,1H),6.68-6.79(m,1H),3.86-3.92(m,4H),2.97-3.06(m,4H),2.12-2.24(m,4H),1.78(br s,4H),1.26(s,4H),0.34-0.48(m,4H)

[0289] Example 12: N-(8-(4,4-difluoropiperidin-1-yl)-3-methylimidazo[1,5-a]pyrazin-6-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0290] LCMS(ESI):[M+H] + =604.4. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.81(s,1H),10.38-10.05(m,1H),8.36(s,1H),8.07(d,J=8.8Hz,1H),7. 81(s,1H),7.27(d,J=2.0Hz,1H),7.13(dd,J=2.0,8.8Hz,1H),5.14-4.77(m ,1H),4.03-3.88(m,4H),3.76(t,J=6.4Hz,2H),3.40-3.34(m,2H),3.07-2 .85(m,4H),2.53(s,3H),2.20-2.04(m,4H),2.04-1.32(m,4H),0.40(s,4H)

[0291] Example 13: N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0292] Example 13 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =590.0. 1 HNMR (400MHz, DMSO) δ12.89(s,1H),10.21(s,1H),8.84(s,1H),8.08(d,J=8.8Hz,2H),7.56(d,J=0.8Hz,1H),7.28(d,J=2.0Hz,1H),7. 14(dd,J=8.6,2.0Hz,1H),4.43(s,5H),3.76(t,J=6.6Hz,2H),3.34(s,2H),2.99(s,4H),2.54(s,4H),2.16–2.06(m,4H),0.41(s,4H).

[0293] Example 14: N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0294] Step 1: A solution containing 8-bromo-6-nitro-4-hydroimidazo[1,2-a]pyridine (3.50 g, 14.46 mmol), iron powder (2.40 g, 43.38 mmol), ammonium chloride (2.30 g, 43.38 mmol), ethanol (50 mL), and water (10 mL) was stirred at 90°C for 6 hours. The reaction solution was concentrated and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% ethyl acetate / petroleum ether gradient) to afford 8-bromoimidazo[1,2-a]pyridin-6-amine (3.00 g, 14.15 mmol, yield: 97.8%) as a black solid. LCMS (ESI): [M+H] + =214.0

[0295] Step 2: A solution containing 8-bromo-4-hydroimidazo[1,2-a]pyridin-6-ylamine (3.00 g, 14.15 mmol), di-tert-butyl dicarbonate (3.70 g, 16.98 mmol), N,N-diisopropylethylamine (5.60 g, 42.44 mmol), and dichloromethane (20 mL) was stirred at 50°C for 12 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to provide tert-butyl (8-bromoimidazo[1,2-a]pyridin-6-yl)carbamate (1.80 g, 5.77 mmol, yield: 40.8%) as a white solid. LCMS (ESI): [M+H]+ = 312.1

[0296] Step 3: Under nitrogen atmosphere, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (340 mg, 0.58 mmol) and tris(dibenzylideneacetone)dipalladium (539 mg, 0.58 mmol) were added to a mixed solution containing tert-butyl(8-bromoimidazo[1,2-a]pyridin-6-yl)carbamate (1.80 g, 5.77 mmol), 4,4-difluoropiperidine hydrochloride (1.40 g, 8.65 mmol), cesium carbonate (7.70 g, 23.07 mmol) and 1,4-dioxane (20 mL). The reaction mixture was stirred at 100 ° C for 12 hours. The reaction mixture 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 purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain tert-butyl (8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)carbamate (500 mg, 1.42 mmol, yield: 24.6%) as a yellow solid. LCMS (ESI): [M+H] + =353.3

[0297] Step 4: A solution containing tert-butyl (8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)carbamate (500 mg, 1.42 mmol), trifluoroacetic acid (5 mL), and dichloromethane (5 mL) was stirred at 20°C for 1 hour. The reaction solution was concentrated and the pH was adjusted to approximately 8 by adding aqueous sodium bicarbonate. The mixture was then extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford 8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-amine (360 mg, crude) as a brown solid. LCMS (ESI): [M+H] + =253.1

[0298] Step 5: 2-(6-azaspiro[2.5]octan-6-yl)-4-bromobenzoyl chloride (502 mg, 1.53 mmol) was added to a solution containing 8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-amine (350 mg, 1.39 mmol), N,N-diisopropylethylamine (915 mg, 6.94 mmol) and tetrahydrofuran (5 mL). The reaction solution was stirred at 20 ° C for 30 minutes, poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-30% gradient ethyl acetate / petroleum ether) to obtain compound 4-bromo-N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-amine). Pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (390 mg, 0.72 mmol, yield: 51.6%), as a yellow solid. LCMS (ESI): [M+H] + =544.3; 1 HNMR (400MHz, DMSO) δ11.25(s,1H),9.04(d,J=1.6Hz,1H),8.00(d,J=1.2Hz,1H),7.67(d,J=8.4Hz,1H),7.46(dd,J=2.8,1.6Hz,2H),7.39(d d,J=8.4,2.0Hz,1H),6.59(d,J=1.6Hz,1H),3.77(t,J=5.6Hz,4H),3.03(t,J=5.2Hz,4H),2.26-2.05(m,4H),1.58-1.44(m,4H),0.32(s,4H).

[0299] Step 6: A reaction mixture containing 4-bromo-N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (370 mg, 0.68 mmol), 2-hydroxyethanesulfonamide (174 mg, 1.36 mmol), potassium phosphate (442 mg, 2.04 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (29 mg, 0.068 mmol), tris(dibenzylideneacetone)dipalladium (64 mg, 0.068 mmol) and 1,4-dioxane (5 mL) was stirred at 100 °C under nitrogen atmosphere for 12 hours. The reaction mixture 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 purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (50.04 mg, 0.085 mmol, yield: 12.5%) as a white solid. LCMS (ESI): [M+H] + =589.4; 1 HNMR (400MHz, DMSO) δ11.60 (s, 1H), 10.15–10.02 (m, 1H), 9.05 (d, J = 1.6Hz, 1H), 7.98 ( d,J=1.2Hz,1H),7.80(d,J=8.4Hz,1H),7.46(d,J=1.2Hz,1H),7.16(d,J=2.0Hz,1H),7. 04(dd,J=8.4,2.0Hz,1H),6.57(d,J=1.6Hz,1H),4.96(s,1H),3.86-3.66(m,6H),3.37- 3.32(m,2H),2.98(t,J=5.2Hz,4H),2.25-2.09(m,4H),1.67-1.48(m,4H),0.35(s,4H).

[0300] Example 15: N-(8-(4,4-difluoropiperidin-1-yl)-2,3-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0301] Step 1: 5-Bromo-3-chloropyrazin-2-amine (2.00 g, 9.50 mmol), 4,4-difluoropiperidine hydrochloride (2.27 g, 14.25 mmol), and potassium carbonate (4.02 g, 28.50 mmol) were added to N-methylpyrrolidone (5 mL). The reaction mixture was stirred at 130°C for 16 hours. The reaction mixture was filtered and the filtrate was poured into saturated ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Flash column chromatography (silica gel, 10-15% ethyl acetate / petroleum ether gradient) of the crude product afforded 5-bromo-3-(4,4-difluoropiperidin-1-yl)pyrazin-2-amine (2.20 g, 67%) as a brown solid. LCMS (ESI): [M+H] + =293.1,295.1.

[0302] Step 2: To a 100 mL sealed reactor, add 5-bromo-3-(4,4-difluoropiperidin-1-yl)pyrazin-2-amine (2.20 g, 6.38 mmol), 3-bromo-2-butanone (1.49 g, 9.57 mmol), and 1,4-dioxane (5 mL). The reaction mixture was stirred at 120°C for 24 hours. 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. Flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) of the crude product afforded 6-bromo-8-(4,4-difluoropiperidin-1-yl)-2,3-dimethylimidazo[1,2-a]pyrazine (1.85 g, 85%) as a pale yellow solid. LCMS (ESI): [M+H] + =345.1,347.1.

[0303] Step 3: 6-Bromo-8-(4,4-difluoropiperidin-1-yl)-2,3-dimethylimidazo[1,2-a]pyrazine (1.90 g, 4.13 mmol), benzophenone imine (1.53 g, 8.26 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (262 mg, 0.41 mmol), tris(dibenzylideneacetone)dipalladium (193 mg, 0.21 mmol), and cesium carbonate (2.74 g, 8.26 mmol) were added to 1,4-dioxane (20 mL). The reaction mixture was stirred at 115°C for 16 hours. The reaction mixture was filtered, the filtrate was poured into water (50 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 subjected to flash column chromatography (silica gel, 0-6% gradient of ethyl acetate / petroleum ether) to give N-(8-(4,4-difluoropiperidin-1-yl)-2,3-dimethylimidazo[1,2-a]pyrazin-6-yl)-1,1-diphenylmethanamine (990 mg, 54%) as a yellow solid.

[0304] Step 4: N-(8-(4,4-difluoropiperidin-1-yl)-2,3-dimethylimidazo[1,2-a]pyrazin-6-yl)-1,1-diphenylcarbamate (500 mg, 1.12 mmol) was added to dichloromethane (5 mL). 4M hydrochloric acid in dioxane (1.5 mL) was slowly added to the reaction mixture, and the reaction mixture was stirred at 25°C for 30 minutes. The reaction mixture was concentrated to obtain the crude product. The crude product was added to acetonitrile (5 mL), and 2-fluoro-4-iodobenzoic acid (508 mg, 1.91 mmol), N,N-diisopropylethylamine (1.01 g, 7.63 mmol), and 1-propylphosphonic anhydride (50% solution in ethyl acetate, 2.43 g, 3.81 mmol) were added to the reaction mixture. The reaction mixture was stirred at 85°C for 16 hours. 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. Flash column chromatography (silica gel, 0-9% gradient of ethyl acetate / petroleum ether) yielded the crude product, N-(8-(4,4-difluoropiperidin-1-yl)-2,3-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-fluoro-4-iodobenzamide (320 mg, 48%). LCMS (ESI): [M+H] + =530.1. 1 H NMR (400MHz, DMSO-d6) δ10.44–10.40(m,1H),8.34(s,1H),7.80(ddd,J=9.2,8.1,1.5Hz,1H),7.70(dd d,J=9.8,8.1,1.5Hz,1H),7.48–7.32(m,1H),4.36(s,4H),2.33(d,J=12.4Hz,6H),2.09–1.95(m,4H).

[0305] Step 5: N-(8-(4,4-difluoropiperidin-1-yl)-2,3-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-fluoro-4-iodobenzamide (320 mg, 0.60 mmol), 6-aza-spiro[2.5]octane hydrochloride (135 mg, 0.91 mmol), and potassium carbonate (256 mg, 1.81 mmol) were added to toluene (5 mL). The reaction mixture was stirred at 130°C for 18 hours. The reaction mixture was filtered and the filtrate was poured into saturated ammonium chloride solution (30 mL). The mixture was 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 subjected to flash column chromatography (silica gel, 5-15% gradient of ethyl acetate / petroleum ether) to afford N-(8-(4,4-difluoropiperidin-1-yl)-2,3-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (120 mg, 32%) as a pale yellow solid.

[0306] Step 6: N-(8-(4,4-difluoropiperidin-1-yl)-2,3-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (120 mg, 0.19 mmol), 2-hydroxy-1-sulfonamide (37 mg, 0.19 mmol), potassium phosphate (126 mg, 0.58 mmol), cuprous iodide (38 mg, 0.19 mmol) and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (56 mg, 0.38 mmol) were added to N,N-dimethylformamide (2 mL), the atmosphere was replaced with nitrogen, and the reaction solution was stirred at 115°C for 2 hours. The reaction mixture was filtered, and the filtrate was poured into a saturated ammonium chloride solution (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (C18, 25-55% acetonitrile / water gradient) to obtain N-(8-(4,4-difluoropiperidin-1-yl)-2,3-dimethylimidazo[1,2-a]pyrazin-6-yl)-4-(2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide as a white solid.

[0307] LCMS(ESI):[M+H] + =618.3. 1H NMR (400MHz, DMSO-d6) δ12.90(s,1H),10.21(s,1H),8.46(s,1H),8.09(d,J=8.7H z,1H),7.29(d,J=2.1Hz,1H),7.14(dd,J=8.6,2.1Hz,1H),4.95(s,1H),4.41(t,J =5.6Hz,4H),3.77(t,J=6.5Hz,2H),3.37(d,J=6.4Hz,2H),2.99(t,J=5.3Hz,4H), 2.35(d,J=14.3Hz,6H),2.16–2.01(m,4H),1.60(d,J=111.7Hz,4H),0.42(s,4H).

[0308] Example 16: Azaspiro[2.5]octan-6-yl)-4-{(2-hydroxyethylsulfonyl]amino}phenyl)-N-[8-(4,4-difluoropiperidinyl)(4-hydrogen-1,2,4-triazolyl[1,5-a]pyrazin-6-yl)]formamide

[0309] Example 16 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =591.3; 1 H NMR (400MHz, DMSO) δ13.39(s,1H),8.91(s,1H),8.42(s,1H),7.90(d,J=8.7Hz,1H) ,7.15(s,1H),7.03(s,1H),6.87(d,J=8.3Hz,1H),6.61(s,1H),6.06(s,1H),5.26( t,J=4.8Hz,1H),4.32(m,4H),3.67(t,J=6.6Hz,2H),3.31(m,2H),3.09(s,2H),2.9 1(s,4H),2.09(dd,J=15.2,9.5Hz,4H),1.94(dd,J=14.4,6.8Hz,4H),0.35(s,4H).

[0310] Example 17: N-(4-(4,4-difluoropiperidin-1-yl)pyrazolo[1,5-a]pyrazin-6-yl)-4-(2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0311] Example 17 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+1] + =590.0. 1H NMR (400MHz, DMSO) δ13.06(s,1H),10.24(s,1H),8.95(d,J=0.9Hz,1H),8.09(d,J=8.6 Hz,1H),7.98(d,J=2.4Hz,1H),7.30(d,J=2.2Hz,1H),7.15(dd,J=8.7,2.1Hz,1H),7.0 6(d,J=2.7Hz,1H),3.95(dd,J=7.1,4.5Hz,4H),3.77(d,J=6.5Hz,3H),3.36(t,J=6.5H z,2H),2.99(d,J=10.5Hz,4H),2.17(td,J=13.6,6.6Hz,4H),1.76(s,4H),0.41(s,4H).

[0312] Example 18: N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0313] Example 18 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+1] + =590.0. 1 H NMR (400MHz, DMSO) δ12.23–12.16(m,1H),9.23(d,J=1.6Hz,1H),8.37(s,1H ),7.76(d,J=8.6Hz,1H),7.03(d,J=2.0Hz,1H),6.95–6.85(m,2H),5.99(s, 1H),3.81(t,J=5.6Hz,4H),3.74(t,J=6.8Hz,2H),3.18(d,J=13.4Hz,3H),2 .97(t,J=5.2Hz,4H),2.21–2.12(m,4H),1.58(t,J=5.2Hz,4H),0.36(s,4H).

[0314] Example 19: N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0315] Example 19 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =591.1. 1H NMR (400MHz, DMSO-d6) δ13.08 (s, 1H), 10.20 (s, 1H), 9.37 (d, J = 1.1Hz, 1H), 8. 79(d,J=1.1Hz,1H),8.08(d,J=8.6Hz,1H),7.29(d,J=2.2Hz,1H),7.15(dd,J= 8.8,1.9Hz,1H),4.97(s,1H),4.45(s,4H),3.76(t,J=6.4Hz,2H),3.17(d,J=5 .1Hz,2H),2.98(t,J=5.2Hz,4H),2.22–2.11(m,4H),1.74(s,4H),0.42(s,4H).

[0316] Example 20: N-(1-(4,4-difluoropiperidin-1-yl)pyrrolo[1,2-c]pyrimidin-3-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0317] Step 1: To a solution of (±)-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester (17.8 g, 53.7 mmol) in dichloromethane (170 mL) was added tetramethylguanidine (6.66 g, 57.8 mmol) and the mixture was stirred at 25°C for 15 minutes. A solution of 2-pyrrolecarboxaldehyde (5.00 g, 52.5 mmol) in dichloromethane (12 mL) was then slowly added to the mixture at -30°C and stirred for 45 minutes. The mixture was heated to 50°C and stirred for 24 hours. Water (100 mL) was added to the reaction mixture and extracted with dichloromethane (100 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, 0-15% gradient of ethyl acetate / petroleum ether) to give methyl 1-hydroxypyrrolo[1,2-c]pyrimidine-3-carboxylate (5.00 g, 52.5 mmol, yield 49%) as a yellow solid. LCMS (ESI): [M+H] + =193.2.

[0318] Step 2: To a solution of methyl 1-hydroxypyrrolo[1,2-c]pyrimidine-3-carboxylate (5.00 g, 26.01 mmol) in phosphorus oxychloride (50 mL) was added N,N-diisopropylethylamine (10.1 g, 78.0 mmol), and the reaction mixture was stirred at 100 ° C for 16 hours. The reaction solution was concentrated to dryness, water (100 mL) was added to the reaction mixture, 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, 0-15% gradient of ethyl acetate / petroleum ether) to obtain methyl 1-chloropyrrolo[1,2-c]pyrimidine-3-carboxylate (1.20 g, 26.0 mmol, yield 21.9%) as a yellow solid. LCMS (ESI): [M+H] + =210.9.

[0319] Step 3: To a solution of methyl 1-chloropyrrolo[1,2-c]pyrimidine-3-carboxylate (1.20 g, 5.70 mmol) and 4,4-difluoropiperidine hydrochloride (1.08 g, 6.84 mmol) in tert-butanol (24 mL) was added triethylamine (1.73 g, 17.1 mmol). The mixture was heated to 90 ° C and stirred 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, 0-10% gradient of ethyl acetate / petroleum ether) to obtain methyl 1-(4,4-difluoropiperidin-1-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (1.70 g, 5.69 mmol, yield 96%) as a yellow solid. LCMS (ESI): [M+H] + =295.9.

[0320] Step 4: Sodium hydroxide (0.69 g, 17.2 mmol) was added to a solution of methyl 1-(4,4-difluoropiperidin-1-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (1.70 g, 5.76 mmol) in methanol (17 mL) and water (17 mL). The mixture was stirred at 25°C for 16 hours. The methanol in the reaction solution was concentrated to dryness, and the remaining aqueous phase was adjusted to pH 4 with 1N hydrochloric acid and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to obtain the residue 1-(4,4-difluoropiperidin-1-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylic acid (1.70 g, 5.75 mmol, yield 100%). LCMS (ESI): [M+H] + =281.9.

[0321] Step 5: To a solution of 1-(4,4-difluoropiperidin-1-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylic acid (1.00 g, 3.13 mmol), benzyl alcohol (0.52 g, 4.80 mmol), and triethylamine (0.65 g, 6.40 mmol) in toluene (9 mL) was added diphenylphosphoryl azide (1.32 g, 4.80 mmol). The mixture was heated to 90°C and stirred for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was 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 give benzyl(1-(4,4-difluoropiperidin-1-yl)pyrrolo[1,2-c]pyrimidin-3-yl)aminomethyl ester (0.70 g, 3.19 mmol, 56.6% yield) as a yellow solid. LCMS (ESI): [M+H] + =387.0.

[0322] Step 6: To a solution of benzyl (1- (4,4-difluoropiperidin-1-yl) pyrrolo [1,2-c] pyrimidin-3-yl) aminomethyl ester (600 mg, 1.55 mmol) in acetonitrile (3 mL) and water (3 mL) was added hydrogen bromide acetic acid solution (6 mL, 35%). The mixture was stirred at 25 ° C for 48 hours. The reaction solution was spin-dried. The residue was purified by preparative HPLC (C18, 0-60% gradient of acetonitrile / water) to give a yellow solid compound 1- (4,4-difluoropiperidin-1-yl) pyrrolo [1,2-c] pyrimidin-3-amine (200 mg, 1.55 mmol, yield 51%). LCMS (ESI): [M+H] + =253.2.

[0323] Step 7: To a solution of 1-(4,4-difluoropiperidin-1-yl)pyrrolo[1,2-c]pyrimidin-3-amine (200 mg, 0.79 mmol) and 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (357 mg, 0.95 mmol) in tetrahydrofuran (4 mL) was added triethylamine (0.65 g, 6.40 mmol) in toluene (9 mL). N,N-diisopropylethylamine (313 mg, 2.38 mmol) was added. 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 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, 0-10% gradient of ethyl acetate / petroleum ether) to afford N-(1-(4,4-difluoropiperidin-1-yl)pyrrolo[1,2-c]pyrimidin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (255 mg, 0.79 mmol, 54.3% yield) as a yellow solid. LCMS (ESI): [M+H] + =592.3.

[0324] Step 8: To a solution of 2-hydroxyethanesulfonamide (67.4 mg, 0.54 mmol), 2-(methylamino)acetic acid (36.9 mg, 0.41 mmol), and potassium phosphate (358 mg, 1.66 mmol) in N,N-dimethylformamide (5 mL) was added cuprous iodide (40.2 mg, 0.21 mmol). The mixture was stirred at 50°C for 5 minutes. N-(1-(4,4-difluoropiperidin-1-yl)pyrrolo[1,2-c]pyrimidin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (245 mg, 0.41 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 obtain a residue. The residue was purified by preparative HPLC (C18, 0-60% gradient of acetonitrile / water) to obtain a yellow solid compound, N-(1-(4,4-difluoropiperidin-1-yl)pyrrolo[1,2-c]pyrimidin-3-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (29 mg, 0.41 mmol, yield 11%). LCMS (ESI): [M+H] + =589.5. 1H NMR(400MHz,DMSO-d6)δppm 13.15-12.87(m,1H),10.39-9.98(m,1H),8.16-8.02(m,1H),7.98-7.82(m,1H),7 .46-7.36(m,1H),7.31-7.23(m,1H),7.20-7.05(m,1H),6.94-6.74(m,1H),6.49-6 .28(m,1H),5.05-4.81(m,1H),3.81-3.70(m,2H),3.57-3.45(m,4H),3.42-3.35( m,2H),3.06-2.91(m,4H),2.35-2.19(m,4H),2.05-1.49(m,4H),0.49-0.32(m,4H)

[0325] Example 21: N-(5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-c]pyrimidin-7-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0326] Example 21 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =590.3; 1 H NMR (400MHz, DMSO) δ13.86(s,1H),10.37(s,1H),8.13(s,1H),8.11(s,2H),8.03(s,1H),7.32-7.36(m,1H),7.16-7.22(m,1H),3.77(t,J=6. 4Hz,2H),3.66-3.73(m,4H),2.96-3.04(m,4H),2.22-2.32(m,4H),1.6 5-1.83(s,4H),1.54(d,J=6.8Hz,1H),1.20-1.34(m,2H),0.42(s,4H).

[0327] Example 22: N-(7-(4,4-difluoropiperidin-1-yl)imidazo[1,2-c]pyrimidin-5-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0328] Example 22 was prepared by a similar synthetic route to Example 3: LCMS (ESI): [M+H]+=590.4. 1H-NMR (400MHz, DMSO) δ12.27(s,1H),10.13(s,1H),7.79–7.61(m,2H),7.40(d,J=1.5Hz,1H),7.05(d,J=7.2Hz,2H),6.53(s ,1H),4.96(s,1H),3.77(t,J=6.5Hz,2H),3.46–3.32(m,6H),2.80(s,4H),1.89(d,J=16.2Hz,4H),1.28(s,4H),0.25(s,4H).

[0329] Example 23: N-(5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-c]pyrimidin-7-yl)-6-((2-hydroxyethyl)sulfonamido)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide

[0330] Example 23 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =633.3.

[0331] Example 24: N-(5-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-7-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0332] Example 24 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =591.5. 1 H NMR(400MHz,DMSO-d6)δppm 13.37(s,1H),10.27(br s,1H),8.42(s,1H),8.11(d,J=8.6Hz,1H),7.91(s,1H),7.30(d,J=1.9Hz,1H),7.16(dd,J=1.9,8.7Hz,1H),4.96(br s,1H),4.23(br t,J=5.2Hz,4H),3.77(br s,2H),3.40-3.35(m,2H),3.00(br s,4H),2.31-2.11(m,4H),2.01-1.30(m,4H),0.41(s,4H)

[0333] Example 25: (2-(6-Azaspiro[2.5]octan-6-yl)-5-fluoro-4-{[(2-hydroxyethyl)sulfonyl]amino}phenyl)-N-[5-(4,4-difluoropiperidinyl)(4-hydrogen-1,2,4-triazolo[4,3-e]pyrimidin-7-yl)]formamide

[0334] Example 25 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =609.2. 1 H NMR(400MHz,DMSO-d6)δppm 13.69(s,1H),10.12(br s,1H),8.44(s,1H),7.97-7.84(m,2H),7.61(d,J=7.2Hz,1H),5.17-4.80(m,1H),4.31-4.17(m ,4H),3.88-3.76(m,2H),3.43-3.40(m,2H),3.05–2.95(m,4H),2.28-1.51(m,8H),0.42(s,4H)

[0335] Example 26: N-(5-(4,4-difluoropiperidin-1-yl)-8-fluoro-[1,2,4]triazolo[4,3-c]pyrimidin-7-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0336] Example 26 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =609.2. 1 H NMR (400MHz, DMSO-d6) δppm 12.68 (s, 1H), 10.12 (s, 1H), 8.55 (s, 1H), 7.94 (br d, J=8.4Hz, 1H), 7.24 (br s,1H),7.10(dd,J=1.6,8.4Hz,1H),5.11(s,1H),4.10(br s,4H),3.76(t,J=6.4Hz,2H),3.33-3.31(m,2H),3.03-2.91(m,4H),2.26-2.08(m,4H),1.80-1.55(m,4H),0.39(s,4H)

[0337] Example 27: N-(5-(4,4-difluoropiperidin-1-yl)-3-methyl-[1,2,4]triazolo[4,3-c]pyrimidin-7-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0338] Example 27 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =605.0. 1 H NMR (400MHz, DMSO-d6) δppm 13.34 (s, 1H), 10.31 (s, 1H), 8.10 (d, J = 8.4Hz, 1H), 7.81 (s, 1H), 7.30 (s, 1H), 7.15 (br d,J=8.4Hz,1H),5.29-4.67(m,1H),4.21(br s,4H),3.77(br t,J=6.4Hz,2H),3.39-3.38(m,2H),2.99(br s,4H),2.47-2.40(m,3H),2.25-2.14(m,4H),1.92-1.58(m,4H),0.41(s,4H)

[0339] Example 28: N-(7-(4,4-difluoropiperidin-1-yl)thieno[2,3-c]pyridin-5-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0340] Example 28 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =606.5. 1H NMR (400MHz, DMSO-d6) δppm 12.91(s,1H),10.21(s,1H),8.30(s,1H),8.09(d,J=8.6Hz,1H),8.01(d,J=5.4Hz,1H),7.51(d,J=5.4Hz, 1H),7.27(d,J=1.9Hz,1H),7.13(dd,J=2.0,8.6Hz,1H),3.82-3.80(m,4H),3.76(t,J=6.5Hz,2H),3.37(br d,J=6.5Hz,2H),3.05-2.95(m,4H),2.25-2.10(m,4H),2.06-1.40(m,4H),0.47-0.35(m,4H)

[0341] Example 29: N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0342] Example 29 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =590.5. 1 H NMR(400MHz,DMSO-d6)δppm 12.82(s,1H),10.18(s,1H),8.12-8.05(m,2H),7.99(s,1H),7.27(d,J=1.9Hz,1H),7.12(dd,J=1.8,8.6Hz,1H),6.99(d,J=2.0Hz,1H),4.95(br d,J=1.4Hz,1H),3.97(br t,J=5.6Hz,4H),3.76(br t,J=5.9Hz,2H),3.37-3.36(m,2H),2.98(br s,4H),2.22-2.03(m,4H),1.99-1.37(m,4H),0.40(s,4H)

[0343] Example 30: N-(7-(4,4-difluoropiperidin-1-yl)benzofuran-5-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0344] Example 30 was prepared by a similar synthetic route to Example 3: LCMS (ESI): [M+H]+=589.3. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.68(s,1H),10.09(s,1H),7.96(d,J=2.0Hz,1H),7.84(d,J=1.2Hz,2H),7.17 (d,J=2.0Hz,1H),7.10(d,J=1.6Hz,1H),7.04(dd,J=2.0,8.4Hz,1H),6.96(d,J =2.0Hz,1H),5.33-4.50(m,1H),3.80-3.72(m,2H),3.48-3.44(m,4H),3.33-3. 29(m,2H),3.01-2.95(m,4H),2.23-2.13(m,4H),1.60-1.53(m,4H),0.35(s,4H)

[0345] Example 31: N-(4-(4,4-difluoropiperidin-1-yl)furo[3,2-c]pyridin-6-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0346] Example 31 was prepared by a similar synthetic route to Example 3: LCMS (ESI): [M+H]+=590.5. 1 H NMR (400MHz, DMSO-d6) δppm 12.98 (s, 1H), 10.22 (br s, 1H), 8.08 (d, J = 8.8Hz, 1H), 7.95 (d, J = 0.8Hz, 1H), 7.91 (d, J =2.4Hz,1H),7.27(d,J=2.0Hz,1H),7.18(d,J=1.2Hz,1H),7.12(dd,J=2.0,8.6Hz,1H),5.14-4.79(m,1H),3.87-3.8 1(m,4H),3.78-3.73(m,2H),3.38-3.35(m,2H),3.02-2.94(m,4H),2.16-2.05(m,4H),1.99-1.25(m,4H),0.40(s,4H)

[0347] Example 32: N-(4-(4,4-difluoropiperidin-1-yl)furo[3,2-d]pyrimidin-2-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0348] Example 32 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =591.4. 1 H NMR (400MHz, DMSO-d6) δ12.69(s,1H),9.90(s,1H),8.24(d,J=2.2Hz,1H),7.9 7(d,J=8.6Hz,1H),7.22(s,1H),7.09(dd,J=8.6,2.1Hz,1H),6.96(d,J=2.2Hz ,1H),5.47(s,1H),4.07(t,J=5.7Hz,4H),3.76(t,J=6.5Hz,2H),3.35(d,J=6. 7Hz, 2H), 2.96 (d, J = 5.5Hz, 4H), 2.13 (s, 4H), 1.85–1.43 (m, 4H), 0.38 (s, 4H).

[0349] Example 33: N-(4-chloro-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0350] Step 1: To a solution of N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (30.0 mg, 0.05 mmol) in acetonitrile (1.00 mL) was added N-chlorosuccinimide (8.15 mg, 0.06 mmol). The mixture was heated to 50°C and stirred for 4 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to obtain a residue. Purification by preparative HPLC (C18, 18-58% gradient of water (formic acid) / acetonitrile) gave N-(4-chloro-7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (8.00 mg, 0.05 mmol, 25% yield) as a white solid. LCMS (ESI): [M+H] + =624.2. 1 H NMR (400MHz, DMSO-d6) δppm 11.72 (s, 1H), 10.13 (br s, 1H), 8.26 (d, J = 2.1Hz, 1H), 7.90 (br d, J = 8.3Hz, 1H), 7.21 (br s,1H),7.14-6.99(m,2H),4.95(br s,1H),4.08-3.85(m,4H),3.82-3.72(m,2H),3.43-3.37(m,2H),3.07-2.95(m,4H),2.18-2.02(m,4H),1.76-1.55(m,4H),0.37(s,4H)

[0351] Example 34: 4-(4,4-difluoropiperidinyl)-3-methyl-3H-imidazopyridin-6-yl-4-hydroxyethylsulfonamido-2-(2-hydroxyethyl)benzamide

[0352] Example 34 was prepared by a similar synthetic route according to Example 3: LCMS (ESI) m / z: 604 [M+H] + ; 1H NMR (400MHz, DMSO) δ13.05 (s, 1H), 10.18 (s, 1H), 8.24 (d, J = 18.6Hz, 2H), 8.10 (d, J=8.6Hz,1H),7.27(d,J=2.2Hz,1H),7.13(dd,J=8.6,2.1Hz,1H),4.95(s,1H),4.0 4(s,3H),3.76(q,J=5.4,4.7Hz,2H),3.38–3.33(m,5H),3.17(d,J=5.2Hz,1H),2. 99(t,J=5.2Hz,5H),2.22(td,J=13.6,12.7,6.6Hz,4H),1.78(s,4H),0.39(s,5H).

[0353] Example 35: N-(4-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0354] Example 35 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =604.4. 1 H NMR (400MHz, DMSO) δ12.71(s,1H),10.18(s,1H),8.10–8.02(m,2H),7.86(s,1H),7.26(d,J=2.2Hz,1H),7.13(dd,J=8.6,2.1Hz,1H) ,4.94(s,1H),4.29(t,J=5.7Hz,4H),3.77(s,5H),3.36(t,J=6.5Hz,2H),2.99(s,4H),2.12–1.98(m,4H),1.74(s,4H),0.40(s,4H).

[0355] Example 36: 2-(4-cyclopropylpiperazin-1-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0356] Example 36 was prepared by a similar synthetic route according to Example 3: LCMS (ESI) m / z: 604 [M+H] + ; 1H NMR (400MHz, DMSO) δ12.80(s,1H),8.24(d,J=1.0Hz,1H),8.08(d,J=8.6Hz,1H),7. 79(d,J=0.8Hz,1H),7.26(d,J=2.2Hz,1H),7.13(dd,J=8.6,2.1Hz,1H),4.99(s,1H) ,3.97(dd,J=6.8,4.6Hz,4H),3.92(s,3H),3.77(t,J=6.4Hz,2H),3.36(t,J=6.4Hz, 2H), 2.98 (d, J=5.6Hz, 4H), 2.10 (dt, J=14.8, 5.5Hz, 4H), 1.23 (s, 1H), 0.39 (s, 4H).

[0357] Example 37: N-(7-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-4-(2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0358] Example 37 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =603.4. 1 H NMR (400MHz, DMSO) δ12.86 (s, 1H), 10.15 (s, 1H), 8.16 (s, 1H), 8.08 (d, J = 8.4Hz, 1H), 7 .45(d,J=3.2Hz,1H),7.26(d,J=2.4Hz,1H),7.12(dd,J=8.4,2.0Hz,1H),6.46(d,J=3. 2Hz,1H),4.94(s,1H),4.05(s,3H),3.76(t,J=6.4Hz,2H),3.35(t,J=6.4Hz,2H),3.30 (d,J=6.4Hz,4H),2.98(t,J=5.2Hz,4H),2.25-2.08(m,4H),1.75(s,4H),0.39(s,4H).

[0359] Example 38: 4-(4,4-difluoropiperidinyl)-1-methylpyrrol-3,2-pyridin-6-yl)-4-hydroxyethylsulfonamido-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0360] Example 38 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+1] + =603.1 H NMR (400MHz, DMSO) δ12.79(s,1H),10.27(s,1H),7.96(d,J=8.6Hz,1H),7.90(d,J=0.8Hz, 1H),7.20(d,J=3.2Hz,1H),7.07(d,J=2.0Hz,1H),6.93(dd,J=8.6,2.0Hz,1H),6.55(dd,J =3.2,0.8Hz,1H),5.80(s,2H),3.87–3.77(m,4H),3.72(d,J=9.8Hz,5H),3.17(t,J=6.6Hz ,3H),2.97(t,J=5.2Hz,4H),2.34(s,4H),2.09(ddd,J=14.3,7.6,3.5Hz,4H),0.38(s,4H).

[0361] Example 39: N-(4-(4,4-difluoropiperidin-1-yl)-[1,2,5]thiadiazo[3,4-c]pyridin-6-yl)-4-(2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-ylbenzamide

[0362] Example 39 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =608.3. 1 H NMR (400MHz, DMSO) δ12.92(s,1H),10.23(s,1H),8.10(d,J=8.4Hz,1H),8.06(s,1H),7.29(d,J=2.0Hz,1H),7.14(dd,J=8.4,2.0Hz,1H),4.95(t,J= 5.6Hz,1H),4.43(t,J=5.6Hz,4H),3.77(q,J=6.4Hz,2H),3.37(t,J=6.4Hz ,2H),3.00(t,J=5.2Hz,4H),2.24–2.14(m,4H),1.74(s,4H),0.41(s,4H).

[0363] Example 40: 2-(6-azaspiro[2.5]octan-6-yl)-4-(2-hydroxyethylsulfonyl]aminophenyl)-N-[4-(4,4-difluoropiperidinyl)benzo[3,4-c]1,2,5-thiadiazol-5-ylcarboxamide

[0364] Example 40 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+1] + =607.1 H NMR (400MHz, DMSO) δ11.95 (s, 1H), 10.10 (s, 1H), 8.29 (d, J = 1.6Hz, 1H), 7.8 5(d,J=8.4Hz,1H),7.18(d,J=2.4Hz,1H),7.10–7.02(m,2H),4.99(s,1H),3 .78(d,J=6.4Hz,2H),3.76–3.72(m,4H),3.35(d,J=6.4Hz,2H),3.00(t,J=5 .2Hz,4H),2.21(tt,J=13.6,5.5Hz,4H),1.57(t,J=5.2Hz,4H),0.35(s,4H).

[0365] Example 41: 2-{6-azaspiro[2.5]octan-6-yl}-N-[4-(4,4-difluoropiperidin-1-yl)-1,3-benzothiazol-6-yl]-4-(2-hydroxyethanesulfonylamino)benzamide

[0366] Example 41 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =606.2, 1 H NMR(400MHz,DMSO-d6)δppm 11.88(s,1H),10.11(s,1H),9.20(s,1H),8.37(d,J=1.2Hz,1H),7.85(d,J=8.4Hz,1H) ,7.17(dd,J=1.6,14.0Hz,2H),7.05(dd,J=2.0,8.4Hz,1H),5.06-4.86(m,1H),3.77(br t,J=6.4Hz,2H),3.65(br s,4H),3.36(br s,2H),2.99(br s,4H),2.26-2.11(m,4H),1.58(br s,4H),0.36(s,4H)

[0367] Example 42: N-[2-amino-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-6-yl]-2-{6-azaspiro[2.5]octan-6-yl}-4-(2-hydroxyethanesulfonylamino)benzamide

[0368] Step 1: To a solution of 1-bromo-2,3-difluoro-4-nitrobenzene (10.0 g, 42.0 mmol) and 4,4-difluoropiperidine hydrochloride (7.28 g, 46.2 mmol) in dimethyl sulfoxide (200 mL) was added potassium carbonate (17.8 g, 126 mmol). The mixture was heated to 100°C and stirred under nitrogen for 16 hours. 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 give a yellow solid 1-(3-bromo-2-fluoro-6-nitrophenyl)-4,4-difluoropiperidine (12.0 g, 35.3 mmol, yield 84%). LCMS (ESI): [M+H]+=338.9; 1 H NMR(400MHz,DMSO-d6)δ7.72-7.61(m,2H),3.16(br t,J=5.3Hz,4H),2.16-2.01(m,4H)

[0369] Step 2: Iron powder (13.3 g, 236 mmol) was added in batches to a solution of 1-(3-bromo-2-fluoro-6-nitrophenyl)-4,4-difluoropiperidine (12.0 g, 35.4 mmol) and ammonium chloride (7.64 g, 141 mmol) in methanol (240 mL) and water (80 mL). The mixture was heated to 60 ° C and stirred for 16 hours under nitrogen protection. The reaction solution was filtered. Water (160 mL) was added to the filtrate 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 give a yellow solid 4-bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoroaniline (10.8 g, 34.9 mmol, yield 98.7%). LCMS (ESI): [M+H] + = 308.9;

[0370] Step 3: To a solution of 4-bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoroaniline (1.00 g, 2.73 mmol) and di-tert-butyl dicarbonate (1.79 g, 8.19 mmol) in dichloromethane (20.0 mL) were added triethylamine (846 mg, 8.19 mmol) and 4-dimethylaminopyridine (34.0 mg, 0.27 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, and filtered. The filtrate was then dried and the residue was purified by flash silica gel chromatography (silica gel, 0-8% gradient of ethyl acetate / petroleum ether) to afford tert-butyl N-[6-bromo-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]aminomethyl ester (490 mg, 1.04 mmol, 38% yield) as a yellow oil. LCMS (ESI): [M+H]+ = 465.9; 1 H NMR (400MHz, DMSO-d6) δppm 11.86 (s, 1H), 7.93 (d, J = 6.4Hz, 1H), 3.44 (br t, J = 5.2Hz, 4H), 2.18-2.01 (m, 4H), 1.50 (s, 9H)

[0371] Step 4: To a solution of tert-butyl N-[6-bromo-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]aminomethyl ester (480 mg, 1.03 mmol), diphenylmethaneimine (280 mg, 1.54 mmol) and cesium carbonate (1027 mg, 3.09 mmol) in dioxane (20.0 mL) were added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (60.1 mg, 0.10 mmol) and (2-amino-1,1-biphenyl-2-yl)palladium(II) (96.2 mg, 0.10 mmol). The mixture was replaced with nitrogen three times and heated to 100 ° C. under nitrogen protection and stirred for 12 hours. The reaction solution was diluted with water (5 mL) and extracted with dichloromethane (15 mL x 2). The organic layer was washed with saturated brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure 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 tert-butyl N-[6-bromo-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]aminomethyl ester (260 mg, 0.46 mmol, 45% yield) as a yellow solid. LCMS (ESI): [M+H] + =567.1; 1H NMR(400MHz,DMSO-d6)δppm 11.61(br s,1H),7.71-7.65(m,2H),7.60-7.54(m,1H),7.52-7.46(m,2H),7.34-7.32(m,2H),7.16(dd,J=2.8,6.4Hz,2H),6.99(d,J=7.2Hz,1H),3.27(br t,J=5.6Hz,4H),2.10-2.00(m,4H),1.48(s,10H)

[0372] Step 5: To a mixed solution of tert-butyl N-[6-bromo-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]carbamate (240 mg, 0.42 mmol) and methanol (2.00 mL) were added hydroxylamine hydrochloride (59.0 mg, 0.85 mmol) and sodium acetate (104 mg, 1.27 mmol). The mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (15 mL x 2). 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, 0-50% gradient of ethyl acetate / petroleum ether) to give yellow solid tert-butyl N-[6-amino-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]aminomethyl ester (120 mg, 0.30 mmol, yield 70%). LCMS (ESI): [M+H] + =403.0.

[0373] Step 6: To a solution of tert-butyl N-[6-amino-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]carbamate (120 mg, 0.30 mmol) and 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (168 mg, 0.45 mmol) in tetrahydrofuran (4.00 mL) was added N,N-diisopropylethylamine (118 mg, 0.89 mmol). The mixture was stirred at 25°C for 3 hours. The reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (15 mL x 2). 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 tert-butyl N-[6-(2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzamido)-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]aminomethyl ester (80 mg, 0.10 mmol, 36% yield) as a yellow solid. LCMS (ESI): [M+H] +=742.2

[0374] Step 7: To a solution of 2-hydroxyethanesulfonamide (23.6 mg, 0.19 mmol), trans-N,N-dimethyl-1,2-cyclohexanediamine (13.6 mg, 0.09 mmol), and potassium phosphate (80.1 mg, 0.38 mmol) in N,N-dimethylformamide (4.00 mL) was added cuprous iodide (9.17 mg, 0.05 mmol). The mixture was stirred at 50°C for 5 minutes. Tert-butyl N-[6-(2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzamido)-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]carbamate (70.0 mg, 0.09 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 the mixture was 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 yellow solid compound, tert-butyl N-[6-(2-{6-azaspiro[2.5]octane-6-yl}-4-(2-hydroxyethanesulfonylamino)benzamido)-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]aminomethyl ester (69 mg, crude product). LCMS (ESI): [M+H] + =739.2.

[0375] Step 8: To a mixed solution of trifluoroacetic acid (1.00 mL) and dichloromethane (3.00 mL) was added tert-butyl N-[6-(2-{6-azaspiro[2.5]octan-6-yl}-4-(2-hydroxyethanesulfonylamino)benzamido)-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]carbamate (60.0 mg, 0.08 mmol). The mixture was stirred at 25°C for 16 hours. Water (5 mL) was added to the reaction solution, and the mixture was 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, 30%-70% gradient of water (formic acid) / acetonitrile) to give N-[2-amino-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-6-yl]-2-{6-azaspiro[2.5]octan-6-yl}-4-(2-hydroxyethanesulfonylamino)benzamide (2.5 mg, 0.04 mmol, 4.8% yield) as a white solid. LCMS (ESI): [M+H] + =639.2; 1H NMR(400MHz,DMSO-d6)δppm 12.07(s,1H),10.17(s,1H),8.43(d,J=6.4Hz,1H),8.23-7.44(m,3H),7.27(d,J=1.6Hz,1H),7.11(dd,J=2.0,8.4H z,1H),3.77-3.74(m,2H),3.41-3.34(m,6H),3.03-2.94(m,4H),2.24-2.05(m,4H),1.67-1.50(m,4H),0.37(s,4H)

[0376] Example 43: N-(1-(4,4-difluoropiperidin-1-yl)-8-oxyylidene-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0377] Example 43 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =619.3. 1 H NMR (400MHz, DMSO-d6) δppm 13.30 (s, 1H), 10.53-9.86 (m, 1H), 8.06 (d, J = 8.8Hz, 1H), 7.83 (br s,1H),7.63(s,1H),7.26(d,J=2.0Hz,1H),7.13(dd,J=2.0,6.8Hz,1H),5.14-4.76(m,1H),3.76(br t,J=6.4Hz,2H),3.56-3.46(m,4H),3.30(br d,J=5.6Hz,4H),2.90-3.00(m,4H),2.84(br t,J=5.6Hz,2H),2.20-1.35(m,8H),0.39(s,4H)

[0378] Example 44: N-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-4-(2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0379] Step 1: A mixture containing 8-bromo-1,7-naphthyridin-6-amine (2 g, 8.93 mmol), 4,4-difluoropiperidine hydrochloride (1.7 g, 10.71 mmol), cesium carbonate (3.6 g, 10.71 mmol), and DMF (20 mL) was stirred at 100°C for 12 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to afford 8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-amine (1.9 g) as a yellow solid. LCMS (ESI): [M+H] + =265.1.

[0380] Step 2: A mixed solution containing 8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-amine (1.9 g, 7.19 mmol), 2-fluoro-4-nitrobenzoic acid (1.5 g, 7.91 mmol), propylphosphonic tricyclic anhydride (9.2 g, 14.38 mmol, 50% in EA), N,N-diisopropylethylamine (2.8 g, 21.57 mmol) and 1,2-dichloroethane (20 mL) was stirred at 80 °C for 12 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to afford N-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-2-fluoro-4-nitrobenzamide (1.7 g) as a yellow solid. LCMS (ESI): [M+H] + =432.2.

[0381] Step 3: A mixed solution containing N-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-2-fluoro-4-nitrobenzamide (900 mg, 2.09 mmol), 6-aza-spiro[2.5]octane hydrochloride (373 mg, 2.50 mmol), potassium carbonate (883 mg, 6.26 mmol) and dimethyl sulfoxide (10 mL) was stirred at 110 ° C for 12 hours. The reaction solution was poured into water (30 mL) and washed with ethyl acetate (30 mL x 10 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-20% gradient of methanol / dichloromethane) to obtain the compound N-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (820 mg) as a yellow solid. LCMS (ESI): [M+H] +=523.3.

[0382] Step 4: A solution containing N-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (700 mg, 1.34 mmol), iron powder (756 mg, 13.40 mmol), ammonium chloride (724 mg, 13.40 mmol) and ethanol / water (5:1) (24 mL) was stirred at 60 ° C for 30 minutes. The reaction solution was filtered while hot and poured into water (30 mL), ethyl acetate (30 mL x 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound 4-amino-N-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (500 mg, yield: 88.5%) as a yellow solid. LCMS (ESI): [M+H] + =493.4

[0383] Step 5: Ethyl chlorosulfonyl acetate (230 mg, 1.22 mmol) was added dropwise to a mixed solution containing 4-amino-N-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (500 mg, 1.02 mmol), N,N-diisopropylethylamine (402 mg, 3.05 mmol) and tetrahydrofuran (5 mL) at 0°C. The reaction solution was stirred at 20°C for 1 hour, poured into water (30 mL) and washed with ethyl acetate (30 mL x 10% ethanol). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the compound ethyl 2-(N-(4-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (310 mg) as a yellow solid. LCMS (ESI): [M+H] + =643.4.

[0384] Step 6: Lithium aluminum hydride (50 mg, 1.40 mmol) was added in portions to a solution containing ethyl 2-(N-(4-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (300 mg, 0.467 mmol) and tetrahydrofuran (5 mL) at 0°C. The reaction solution was stirred at 20°C for 3 hours. After 10 minutes, sodium sulfate decahydrate was added to the reaction solution. After stirring for 30 minutes, the reaction solution was filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound N-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-4-(2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (35.77 mg) as a yellow solid. LCMS (ESI): [M+H] + =601.4. 1 H NMR(400MHz,DMSO)δ12.90(s,1H),10.65–9.58(m,1H),8.75–8.68(m,1H),8.24(dd, J=8.4,2.0Hz,1H),8.10(t,J=4.4Hz,2H),7.61(dd,J=8.4,4.0Hz,1H),7.28(d,J=2.4 Hz,1H),7.14(dd,J=8.4,2.0Hz,1H),5.23–4.64(m,1H),4.20(t,J=5.6Hz,4H),3.77( t,J=6.4Hz,2H),3.01(d,J=5.2Hz,6H),2.22–2.13(m,4H),1.76(s,4H),0.41(s,4H).

[0385] Example 45: N-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0386] Example 45 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =619.4. 1H NMR (400MHz, DMSO) δ13.22 (s, 1H), 10.07 (s, 1H), 8.73 (dd, J = 4.0, 1.6Hz, 1H), 8.25 (d d,J=8.4,2.0Hz,1H),8.10(s,1H),7.91(d,J=11.6Hz,1H),7.62(dd,J=8.4,4.0Hz,1H ),7.58(d,J=7.2Hz,1H),5.01(s,1H),4.27–4.11(m,4H),3.81(t,J=6.4Hz,2H),3.42 (t,J=6.4Hz,2H),3.00(t,J=5.2Hz,4H),2.23-2.12(m,4H),1.76(s,4H),0.42(s,4H).

[0387] Example 46: N-(8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)benzamide

[0388] Example 46 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =310.30. 1 H NMR (400MHz, DMSO) δ10.69(s,1H),10.17(s,1H),8.72(dd,J=4.1,1.7Hz,1H),8.26(dd,J=8. 5,1.7Hz,1H),7.96(s,1H),7.61(dd,J=8.4,4.1Hz,1H),6.80(d,J=2.0Hz,1H),6.71(dd,J=11 .9,1.9Hz,1H),4.97(s,1H),4.21(t,J=5.7Hz,4H),3.77(d,J=6.9Hz,2H),3.37(t,J=6.5Hz, 2H), 3.02 (t, J=5.2Hz, 4H), 2.13 (td, J=14.2, 7.0Hz, 4H), 1.44 (t, J=5.2Hz, 4H), 0.27 (s, 4H).

[0389] Example 47: (R)-4-(2-hydroxyethyl)sulfonyl)-N-(8-(2-methylmorpholinyl)-1,7-naphthyridin-6-yl)-2-(6-azaspiro[2.5]octane-6-methyl)benzamide

[0390] Example 47 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H / 2] + =581.4.1H NMR (400MHz, DMSO) δ12.81(s,1H),10.21(s,1H),8.70(dd,J=4.0,2.0Hz,1H),8.22(dd,J=8.4,1.8Hz,1H), 8.14-8.04(m,2H),7.59(dd,J=8.4,4.0Hz,1H),7.29(d,J=2.0Hz,1H),7.14(dd,J=8.4,2.0Hz,1H),5.00–4 .80(m,3H),3.99-3.91(m,1H),3.85-3.73(m,4H),3.37(t,J=6.4Hz,2H),3.17-3.07(m,1H),3.01(d,J=5.6 Hz,4H),2.83(dd,J=12.8,10.2Hz,1H),2.55-2.47(m,4H),1.76(s,4H),1.19(d,J=6.0Hz,3H),0.41(s,4H).

[0391] Example 48: 4-(2-Hydroxyethyl)sulfonyl)-N-(8-(4-methylpiperazin-1-yl)-1,7-naphthyridin-6-yl)-2-(6-azaspiro[2.5]octane-6-methyl)benzamide

[0392] Example 48 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H / 2] + =580.4.1H NMR (400MHz, DMSO) δ12.95 (s, 1H), 10.74-9.50 (m, 1H), 8.69 (d, J = 4.0Hz, 1H), 8.20 (d, J = 8.0Hz, 1H),8.11(d,J=8.4Hz,1H),8.04(s,1H),7.58(dd,J=8.4,4.0Hz,1H),7.29(d,J=2.0Hz,1H),7.14 (dd,J=8.8,2.0Hz,1H),5.48-4.58(m,1H),4.07(d,J=6.0Hz,4H),3.77(t,J=6.4Hz,2H),3.37(d ,J=6.4Hz,2H),3.00(t,J=5.2Hz,4H),2.52–2.48(m,4H),2.28(s,3H),1.77(s,4H),0.41(s,4H).

[0393] Example 49: 4-(2-Hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)-N-(8-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-1,7-naphthyridin-6-yl)benzamide

[0394] Example 49 was prepared by a similar synthetic route to Example 3: LCMS (ESI): [M+H]+=648.3. 1 H NMR(400MHz,DMSO-d6)δppm 13.02(s,1H),10.21(br s,1H),8.69(dd,J=1.6,4.0Hz,1H),8.21(dd,J=1.6,8.4Hz,1H),8.11(d,J=8.8Hz ,1H),8.05(s,1H),7.59(dd,J=4.0,8.4Hz,1H),7.29(d,J=2.0Hz,1H),7.14(dd,J =2.0,8.8Hz,1H),5.23-4.71(m,1H),4.16-3.99(m,4H),3.83-3.70(m,2H),3.33- 3.11(m,4H),3.08-2.93(m,4H),2.91-2.77(m,4H),2.31-1.27(m,4H),0.40(s,4H)

[0395] Example 50: 4-(2-Hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)-N-(8-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1,7-naphthyridin-6-yl)benzamide

[0396] Step 1: To a solution of 8-bromo-1,7-naphthyridin-6-amine (2.00 g, 8.93 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,5,6-tetrahydropicolinate (3.31 g, 10.7 mmol) in dioxane (16.0 mL) / water (4.00 mL) was added 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (0.60 g, 0.89 mmol) and potassium carbonate (3.78 g, 26.8 mmol). The mixture 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 combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain a residue. (Silica gel, 0-25% gradient of ethyl acetate / petroleum ether) to give a yellow oily substance, tert-butyl 4-(6-amino-1,7-naphthyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.90 g, 5.78 mmol, yield 65%). LCMS (ESI): [M+H]+=327.1

[0397] Step 2: To a solution of tert-butyl 4-(6-amino-1,7-naphthyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.50 g, 4.60 mmol) in methanol (20.0 mL) was added wet palladium carbon (0.50 g, 10% purity) and hydrogen was introduced. The mixture was stirred at 25 ° C for 2 hours. The solution was spin-dried to obtain a residue. The residue was purified by preparative HPLC (C18, 18-58% gradient of water (formic acid) / acetonitrile) to give a yellow oily substance tert-butyl 4-(6-amino-1,7-naphthyridin-8-yl)piperidine-1-carboxylate (210 mg, 0.60 mmol, yield 8%). LCMS (ESI): [M+H] + = 329.1

[0398] Step 3: To a solution of tert-butyl 4-(6-amino-1,7-naphthyridin-8-yl)piperidin-1-carboxylate (200 mg, 0.61 mmol) and 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoyl chloride (343 mg, 0.91 mmol) in tetrahydrofuran (4 mL) was added potassium tert-butoxide (1.83 mL, 1 M) in tetrahydrofuran and N,N-diisopropylethylamine (241 mg, 1.83 mmol). 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 sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-13% gradient of ethyl acetate / petroleum ether) to afford tert-butyl 4-(6-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1,7-naphthyridin-8-yl)piperidine-1-carboxylate (250 mg, 0.23 mmol, 61% yield) as a yellow solid. LCMS (ESI): [M+Na]+ = 690.1

[0399] Step 4: To a solution of tert-butyl 4-(6-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1,7-naphthyridin-8-yl)piperidine-1-carboxylate (230 mg, 0.34 mmol) in dioxane (2 mL) was added dioxane hydrochloride (2 mL). The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to yield 4-iodo-N-(8-(piperidin-4-yl)-1,7-naphthyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide hydrochloride (200 mg, crude).

[0400] Step 5: To a solution of 4-iodo-N-(8-(piperidin-4-yl)-1,7-naphthyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide hydrochloride (200 mg, crude) (330 mg, 0.58 mmol) and 2,2,2-trifluoroethyl triflate (202 mg, 0.87 mmol) in acetonitrile (5.00 mL) was added triethylamine (180 mg, 1.74 mmol). The mixture was stirred at 70°C for 16 hours. The solution was evaporated to dryness to obtain a residue. (Silica gel, 0-8% gradient of ethyl acetate / petroleum ether) to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(8-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1,7-naphthyridin-6-yl)benzamide (130 mg, 0.19 mmol, 34% yield) as a white solid. LCMS (ESI): [M+H]+=650.1

[0401] Step 6: To a solution of potassium phosphate (133 mg, 0.62 mmol), 2-hydroxyethanesulfonamide (38.5 mg, 0.31 mmol), and sarcosine (14.0 mg, 0.15 mmol) in dimethylformamide (5.00 mL) was added cuprous iodide (29.9 mg, 0.15 mmol). The mixture was heated to 50°C and stirred for 5 minutes. 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(8-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1,7-naphthyridin-6-yl)benzamide (100 mg, 0.15 mmol) was added to the mixture, which was then heated to 100°C under nitrogen and stirred 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, 46-86% gradient of water (formic acid) / acetonitrile) to give 4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)-N-(8-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1,7-naphthyridin-6-yl)benzamide (33 mg, 0.05 mmol, 33% yield) as a white solid. LCMS (ESI): [M+H]+ = 647.3. 1 H NMR(400MHz,DMSO-d6)δppm 13.57(s,1H),10.26(br s,1H),8.89(dd,J=1.2Hz,1H),8.53(s,1H),8.39(d,J=8.0Hz,1H),8.14(d,J=8.4Hz,1H),7.71(dd,J=4.0,8.4Hz,1H),7.31(s,1H),7.17(br d,J=8.4Hz,1H),5.07-4.87(m,1H),4.24-4.06(m,1H),3.84-3.72(m,2H),3.41-3.35(m,2H ),3.27-3.16(m,2H),3.14-2.93(m,6H),2.63-2.52(m,2H),2.37-1.32(m,8H),0.41(s,4H)

[0402] Example 51: N-(8-(4,4-difluoropiperidin-1-yl)-2-methyl-1,7-naphthyridin-6-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0403] Step 1: To a solution of 2-(pyridin-3-yl)acetonitrile (23.0 g, 194 mmol) in acetic acid (200 mL) was added hydrogen peroxide (55.1 g, 584 mmol, 36% purity). The mixture was stirred at 95°C for 16 hours. The reaction mixture was concentrated and dried to afford 3-(cyanomethyl)pyridine 1-oxide (24.0 g, 178 mmol, 91.9% yield) as a yellow solid.

[0404] Step 2: To a solution of 3-(cyanomethyl)pyridine 1-oxide (24.0 g, 178 mmol) in toluene (240 mL) were added dimethylaminomethyl chloride (19.2 g, 178 mmol) and trimethylsilyl cyanide (21.7 g, 214 mmol). The mixture was stirred at 60°C for 16 hours. The reaction solution was quenched with an aqueous solution of potassium carbonate (240 mL, 1 M) and then extracted with ethyl acetate (240 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain a residue. The residue was purified by column chromatography (silica gel, 0-45% gradient of ethyl acetate / petroleum ether) to yield 3-(cyanomethyl)cyanopyridine (21.0 g, 146 mmol, 81.9% yield).

[0405] Step 3: To a solution of 3-(cyanomethyl)pyridinecyanide (14.0 g, 97.8 mmol) in acetic acid (140 mL) was added hydrogen peroxide (18.5 g, 196 mmol, 36% purity). The mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated to dryness to afford 2-cyano-3-(cyanomethyl)pyridine 1-oxide (15.6 g, 75.4 mmol, 77.1% yield). 1 H NMR (400MHz, DMSO-d6) δ8.46(br d,J=6.4Hz,1H),7.73(br t,J=7.2Hz,1H),7.54(br d,J=8.0Hz,1H),4.31(s,2H)

[0406] Step 4: Phosphorus oxychloride (6 mL) was added to a solution of 2-cyano-3-(cyanomethyl)pyridine 1-oxide (6.00 g, 37.7 mmol) in dichloroethane (60 mL). The mixture was stirred at 90°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (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, 0-30% gradient of ethyl acetate / petroleum ether) to yield 6-chloro-3-(cyanomethyl)pyridine cyanide (3.50 g, 19.7 mmol, 52.3% yield). 1H NMR (400MHz, DMSO-d6) δ8.17(d,J=8.4Hz,1H),7.96(d,J=8.4Hz,1H),4.36(s,2H)

[0407] Step 5: 6-chloro-3-(cyanomethyl)cyanopyridine (3.50 g, 19.7 mmol) was added to a mixture of hydrobromic acid and acetic acid (30 mL), and the mixture was stirred at 25°C for 16 hours. The reaction solution was poured into water (100 mL), adjusted to pH 8 with an aqueous solution of sodium carbonate (240 mL, 1 M), and then extracted with ethyl acetate (500 mL x 3). The organic layer was washed with saturated brine (100 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 2,8-dibromo-1,7-naphthyridin-6-amine (3.70 g, 12.2 mmol, yield 62.0%). LCMS (ESI): [M+H] + =303.9

[0408] Step 6: To a solution of 2,8-dibromo-1,7-naphthyridin-6-amine (3.20 g, 10.6 mmol) in tert-butanol (60 mL) were added 4,4-difluoropiperidine (3.33 g, 21.1 mmol) and N,N-diisopropylethylamine (6.97 g, 52.8 mmol). The mixture was stirred at 140°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 purified by column chromatography (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to afford 2-bromo-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-amine (1.50 g, 4.38 mmol, 41.4% yield). LCMS(ESI):[M+H] + =342.9

[0409] Step 7: To a solution of 2-bromo-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-amine (300 mg, 0.87 mmol), potassium carbonate (247 mg, 1.75 mmol), and 50% trimethylboroxine in tetrahydrofuran (0.37 mL, 1.31 mol) in dioxane (6 mL) and water (1.2 mL) was added 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (59.0 mg, 0.09 mmol). The mixture was heated to 90°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 combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain a residue. The residue was separated by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to give 8-(4,4-difluoropiperidin-1-yl)-2-methyl-1,7-naphthyridin-6-amine (110 mg, 0.39 mmol, yield 45.2%). LCMS (ESI): [M+H] + =279.2

[0410] Step 8: To a solution of 8-(4,4-difluoropiperidin-1-yl)-2-methyl-1,7-naphthyridin-6-amine (100 mg, 0.36 mmol) and 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (162 mg, 0.43 mmol) in tetrahydrofuran (1.00 mL) was added potassium tert-butoxide (1.08 mL, 1.08 mmol, 1 M) and N,N-diisopropylethylamine (142 mg, 1.08 mol). The mixture was stirred at 25°C 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, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was separated by column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to give N-(8-(4,4-difluoropiperidin-1-yl)-2-methyl-1,7-naphthyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (120 mg, 0.19 mmol, yield 54.1%). LCMS (ESI): [M+H] + =618.2

[0411] Step 9: To a solution of 2-hydroxyethanesulfonamide (48.6 mg, 0.39 mmol), sarcosine (17.3 mg, 0.19 mmol), and potassium phosphate (168 mg, 0.78 mmol) in N,N-dimethylformamide (2 mL) was added cuprous iodide (18.9 mg, 0.10 mmol). The mixture was stirred at 100°C for 16 hours. N-(8-(4,4-difluoropiperidin-1-yl)-2-methyl-1,7-naphthyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (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 (20 mL) was added to the reaction mixture, and the mixture was 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 preparative HPLC (C18, 50-90% gradient of water (formic acid) / acetonitrile) to obtain a white solid compound N-(8-(4,4-difluoropiperidin-1-yl)-2-methyl-1,7-naphthyridin-6-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (51.0 mg, 0.08 mmol, yield 42.7%). LCMS (ESI): [M+H] + =615.1. 1 H NMR(400MHz,DMSO-d6)δ12.85(s,1H),10.22(s,1H),8.22-8.01(m,3H),7.52(d,J=8.4Hz,1H),7 .28(d,J=1.6Hz,1H),7.14(dd,J=2.0,8.8Hz,1H),5.06-4.85(m,1H),4.31-4.05(m,4H),3.77(br t,J=6.4Hz,2H),3.40-3.36(m,2H),3.12-2.88(m,4H),2.63(s,3H),2.28-2.10(m,4H),1.98-1.42(m,4H),0.41(s,4H)

[0412] Example 52: N-(8-(4,4-difluoropiperidin-1-yl)-2-methoxy-1,7-naphthyridin-6-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0413] Step 1: To a solution of 2-bromo-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-amine (500 mg, 1.46 mmol) in dichloromethane (10 mL) were added triethylamine (451 mg, 4.37 mmol), 4-dimethylaminopyridine (36.3 mg, 0.29 mmol), and di-tert-butyl dicarbonate (954 mg, 4.37 mmol). The mixture was stirred at 25°C for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to give tert-butyl (2-bromo-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl) tert-butoxycarbonylcarbamate (200 mg, 1.46 mmol, yield 25.3%). LCMS (ESI): [M+H] + =543.1.

[0414] Step 2: To a solution of tert-butyl (2-bromo-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl) tert-butoxycarbonylcarbamate (300 mg, 0.55 mmol) in dioxane (1 mL) was added methanol (53.1 mg, 1.66 mmol), potassium hydroxide (93.9 mg, 1.66 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl) palladium(II) (50.5 mg, 0.06 mmol). The mixture was heated to 100°C under nitrogen and stirred for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic layer was washed with saturated brine (10 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, 0-20% gradient of ethyl acetate / petroleum ether) to give tert-butyl (8-(4,4-difluoropiperidin-1-yl)-2-methoxy-1,7-naphthyridin-6-yl)aminomethyl ester (200 mg, 0.55 mmol, yield 91.9%) as a yellow solid. LCMS (ESI): [M+H] + =395.1.

[0415] Step 3: To a solution of tert-butyl (8-(4,4-difluoropiperidin-1-yl)-2-methoxy-1,7-naphthyridin-6-yl)aminomethyl ester (200 mg, 0.51 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 ° C for 2 hours. The reaction solution was quenched with sodium bicarbonate (5 mL), extracted with dichloromethane (10 mL x 2), and the organic layer was washed with saturated brine (10 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid 8-(4,4-difluoropiperidin-1-yl)-2-methoxy-1,7-naphthyridin-6-amine (130 mg, 0.44 mmol, yield 87.1%). LCMS (ESI): [M+H] + =295.1.

[0416] Step 4: To a solution of 8-(4,4-difluoropiperidin-1-yl)-2-methoxy-1,7-naphthyridin-6-amine (130 mg, 0.44 mmol) in tetrahydrofuran (4 mL) was added 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride (199 mg, 0.53 mmol) and N,N-diisopropylethylamine (174 mg, 132 mmol). The mixture was stirred at 25 ° C for 16 hours. The reaction solution was cooled to room temperature, extracted with water (10 mL) and ethyl acetate (10 mL x 2), the organic phases were combined, washed with saturated brine (10 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, 0-10% gradient of ethyl acetate / petroleum ether) to afford N-(8-(4,4-difluoropiperidin-1-yl)-2-methoxy-1,7-naphthyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.31 mmol, 71.5% yield) as a yellow solid. LCMS (ESI): [M+H] + =634.5.

[0417] Step 5: To a solution of 2-hydroxyethanesulfonamide (39.5.0 mg, 0.32 mmol), sarcosine (22.7 mg, 0.16 mmol), and potassium phosphate (137 mg, 0.63 mmol) in N,N-dimethylformamide (2 mL) was added cuprous iodide (15.3 mg, 0.08 mmol). The mixture was stirred at 50°C for 5 minutes. N-(8-(4,4-difluoropiperidin-1-yl)-2-methoxy-1,7-naphthyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.16 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 (20 mL) was added to the reaction mixture, and the mixture was extracted with 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, 50-90% gradient of water (formic acid) / acetonitrile) to obtain a white solid compound, N-(8-(4,4-difluoropiperidin-1-yl)-2-methoxy-1,7-naphthyridin-6-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (43 mg, 0.07 mmol, yield 43.2%). LCMS (ESI): [M+H] + =631.2. 1 H NMR (400MHz, DMSO-d6) δ12.90(s,1H),10.22(s,1H),8.18(d,J=9.2Hz,1H),8.12-8.06(m,2H),7.27(d,J=2.0Hz,1H),7.19-7.10(m,2H),4.97(br s,1H),4.07(br s,4H),3.96(s,3H),3.76(br t,J=6.0Hz,2H),3.44(br s,2H),2.99(br s,4H),2.27-2.15(m,4H),2.01-1.40(m,4H),0.40(s,4H)

[0418] Example 53: N-(2-amino-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0419] Step 1: To a solution of 2-bromo-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-amine (600 mg, 1.75 mmol) in dioxane (12 mL) were added cesium carbonate (1709 mg, 5.25 mmol) and tert-butyl carbamate (310 mg, 2.62 mmol), and finally chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (137 mg, 0.17 mmol). The mixture was purged with nitrogen three times and stirred at 100 ° C for 16 hours. The reaction solution was cooled to room temperature, extracted with water (50 mL) and ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 2), 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 ethyl acetate / petroleum ether) to give tert-butyl (6-amino-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-2-yl)aminomethyl ester (200 mg, 0.52 mmol, 30.2% yield) as a yellow solid. LCMS (ESI): [M+H] + =380.1.

[0420] Step 2: To a solution of tert-butyl (6-amino-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-2-yl)aminomethyl ester (200 mg, 0.53 mmol) in tetrahydrofuran (4 mL) was added 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride (238 mg, 0.63 mmol) and N,N-diisopropylethylamine (209 mg, 1.58 mmol). The mixture was stirred at 25 ° C for 16 hours. The reaction solution was cooled to room temperature, extracted with water (10 mL) and ethyl acetate (10 mL x 2), the organic phases were combined, washed with saturated brine (10 mL x 2), 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 give tert-butyl (8-(4,4-difluoropiperidin-1-yl)-6-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1,7-naphthyridin-2-yl)aminomethyl ester (110 mg, 0.15 mmol, 29.0% yield). LCMS (ESI): [M+H] + =719.1

[0421] Step 3: To a solution of 2-hydroxyethanesulfonamide (34.8 mg, 0.28 mmol), sarcosine (19.9 mg, 0.14 mmol), and potassium phosphate (121 mg, 0.56 mmol) in N,N-dimethylformamide (2 mL) was added cuprous iodide (13.5 mg, 0.07 mmol). The mixture was stirred at 50°C for 5 minutes. Tert-butyl (8-(4,4-difluoropiperidin-1-yl)-6-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1,7-naphthyridin-2-yl)aminomethyl ester (100 mg, 0.14 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. The reaction mixture was cooled to room temperature and 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 give crude tert-butyl (8-(4,4-difluoropiperidin-1-yl)-6-(4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1,7-naphthyridin-2-yl)aminomethyl ester (80.0 mg, 0.11 mmol, yield 80.0%). LCMS (ESI): [M+H] + =716.2

[0422] Step 4: To a solution of tert-butyl (8-(4,4-difluoropiperidin-1-yl)-6-(4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)benzamido)-1,7-naphthyridin-2-yl)aminomethyl ester (80 mg, 0.11 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.40 mL), and the mixture was stirred at 25 ° C for 2 hours. The reaction mixture was concentrated to a residue, which was purified by preparative HPLC (C18, 10-50% gradient of water (formic acid) / acetonitrile) to afford N-(2-amino-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (19.0 mg, 0.03 mmol, 28.0% yield) as a yellow solid. LCMS (ESI): [M+H] + =616.1. 1H NMR (400MHz, DMSO-d6) δ12.68(s,1H),10.44-9.80(m,1H),8.07(br d,J=8.4Hz,1H),7.94(s,1H),7.83(br d,J=8.9Hz,1H),7.25(br s,1H),7.11(br d,J=8.5Hz,1H),6.87(br d,J=8.8Hz,1H),6.43(br s,2H),4.96(br s,1H),4.01(br s,4H),3.86-3.64(m,2H),3.59-3.47(m,2H),2.98(br s,4H),2.24-2.05(m,4H),1.96-1.38(m,4H),0.39(br s,4H)

[0423] Example 54: 2-{6-Azaspiro[2.5]octan-6-yl}-N-[8-(4,4-difluoropiperidin-1-yl)-2-hydroxy-1,7-naphthyridin-6-yl]-4-(2-hydroxyethanesulfonylamino)benzamide

[0424] Step 1: To a solution of 2-bromo-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-amine (1.00 g, 2.91 mmol) in dichloromethane (20 mL) were added triethylamine (902 mg, 8.74 mmol), 4-dimethylaminopyridine (36.3 mg, 2.91 mmol), and di-tert-butyl dicarbonate (1.91 g, 8.74 mmol). The mixture was stirred at 25°C for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to give tert-butyl N-[2-bromo-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl]-N-{[2-bromo-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl]aminocarbonyl}aminomethyl ester (1.00 g, 1.22 mmol, 42% yield). LCMS (ESI): [M+H] + =812.9.

[0425] Step 2: To a solution of tert-butyl N-[2-bromo-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl]-N-{[2-bromo-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-6-yl]aminocarbonyl}aminomethyl ester (1.00 g, 1.23 mmol) in dioxane (20 mL) was added water (0.22 g, 12.3 mmol), potassium hydroxide (0.69 g, 12.3 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.11 g, 0.122 mmol). The mixture was heated to 100°C and stirred under nitrogen for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 2). The organic layer was washed with saturated brine (50 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, 0-10% gradient of ethyl acetate / petroleum ether) to obtain tert-butyl N-[8-(4,4-difluoropiperidin-1-yl)-2-hydroxy-1,7-naphthyridin-6-yl]aminomethyl ester (301 mg, 0.78 mmol, yield 64.0%) as a yellow solid. LCMS (ESI): [M+H] + =381.1.

[0426] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl N-[8-(4,4-difluoropiperidin-1-yl)-2-hydroxy-1,7-naphthyridin-6-yl]aminomethyl ester (300 mg, 0.78 mmol) in dichloromethane (6 mL). The mixture was stirred at 25 ° C for 2 hours. The reaction solution was quenched with sodium bicarbonate (5 mL), extracted with dichloromethane (10 mL x 2), and the organic layer was washed with saturated brine (10 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid 6-amino-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-2-ol (452 ​​mg, crude). LCMS (ESI): [M+H] + =281.0.

[0427] Step 4: To a solution of 6-amino-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-2-ol (450 mg, 1.60 mmol) in tetrahydrofuran (10 mL) was added 2-{6-azaspiro[2.5]octane-6-yl}-4-iodobenzoyl chloride (723 mg, 1.92 mmol) and N,N-diisopropylethylamine (635 mg, 4.81 mmol). The mixture was stirred at 25 ° C for 16 hours. The reaction solution was cooled to room temperature, extracted with water (10 mL) and ethyl acetate (10 mL x 2), the organic phases were combined, washed with saturated brine (10 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, 0-10% gradient of ethyl acetate / petroleum ether) to give 6-(2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzamido)-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-2-yl 2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzoate (200 mg, 0.21 mmol, 13.0% yield) as a yellow solid. LCMS (ESI): [M+H] + =959.0.

[0428] Step 5: To a solution of 6-(2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzamido)-8-(4,4-difluoropiperidin-1-yl)-1,7-naphthyridin-2-yl 2-{6-azaspiro[2.5]octan-6-yl}-4-iodobenzoate (200 mg, 0.20 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium hydroxide (25.3 mg, 0.60 mmol). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to obtain a yellow solid 2-{6-azaspiro[2.5]octan-6-yl}-N-[8-(4,4-difluoropiperidin-1-yl)-2-hydroxy-1,7-naphthyridin-6-yl]-4-iodobenzamide (120 mg, 0.19 mmol, yield 93.8%). LCMS (ESI): [M+H] + =620.1

[0429] Step 6: To a solution of 2-hydroxyethanesulfonamide (48.5 mg, 0.38 mmol), trans-N,N-dimethyl-1,2-cyclohexanediamine (27.8 mg, 0.19 mmol), and potassium phosphate (164 mg, 0.77 mmol) in N,N-dimethylformamide (3 mL) was added cuprous iodide (36.9 mg, 0.19 mmol). The mixture was stirred at 50°C for 5 minutes. 2-{6-azaspiro[2.5]octan-6-yl}-N-[8-(4,4-difluoropiperidin-1-yl)-2-hydroxy-1,7-naphthyridin-6-yl]-4-iodobenzamide 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 (20 mL) was added to the reaction mixture, and the mixture was extracted with 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, 26-66% gradient of water (formic acid) / acetonitrile) to obtain a white solid compound 2-{6-azaspiro[2.5]octane-6-yl}-N-[8-(4,4-difluoropiperidin-1-yl)-2-hydroxy-1,7-naphthyridin-6-yl]-4-(2-hydroxyethanesulfonylamino)benzamide (23 mg, 0.03 mmol, yield 19.2%). LCMS (ESI): [M+H] + =632.5. 1 H NMR (400MHz, DMSO-d6) δ13.15(s,1H),11.53-10.45(m,1H),10.16(s,1H),8.12(s,1H),8.01(d,J=8.8Hz,1H),7.90(d ,J=9.6Hz,1H),7.19(d,J=1.6Hz,1H),7.06(dd,J=1.6,8.8Hz,1H),6.69(d,J=9.6Hz,1H),5.30-4.75(m,1H),3.69(br t,J=6.4Hz,2H),3.29-3.27(m,2H),3.22-3.16(m,4H),2.94-2.82(m,4H),2.27-2.16(m,4H),1.98-1.42(m,4H),0.31(s,4H)

[0430] Example 55: Synthesis of N-(1-(4,4-difluoropiperidin-1-yl)isoquinolin-3-yl)-4-(2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0431] Example 55 was prepared by a similar synthetic route according to Example 3: LCMS (ESI) m / z: [M+H] + =600.4. 1 H-NMR (400MHz, DMSO) δ13.14(s,1H),10.21(s,1H),8.27(s,1H),8.09(dd,J=18.6,8.4Hz,2H),7. 85(d,J=8.2Hz,1H),7.66(ddd,J=8.0,6.8,1.2Hz,1H),7.47(ddd,J=8.4,6.8,1.2Hz,1H),7.29(d ,J=2.4Hz,1H),7.15(dd,J=8.8,2.0Hz,1H),4.95(s,1H),3.77(s,2H),3.51(t,J=5.6Hz,4H),3.3 7(t,J=6.4Hz,2H),3.00(s,4H),2.34–2.23(m,4H),2.08–1.54(m,5H),1.24(s,1H),0.40(s,4H).

[0432] Example 56: N-(1-(4,4-difluoropiperidin-1-yl)-2,7-naphthyridin-3-yl)-4-(2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0433] Step 1: 4-Methylnicotinonitrile (5.00 g, 42.32 mmol) and diethyl oxalate (9.37 g, 63.48 mmol) were added to toluene (50 mL). The reaction mixture was stirred at 25°C for 5 minutes. Potassium tert-butoxide (19.18 g, 169.30 mmol) was added to the reaction mixture in three portions over half an hour. The reaction mixture was stirred at 25°C for 48 hours. The reaction mixture was filtered, and the solid was dissolved in water (2 L). The pH of the reaction mixture was adjusted to 3 with 1 M hydrochloric acid. The resulting solution was stirred at 25°C for 24 hours. The solution was extracted with dichloromethane (300 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was added to phosphorus oxychloride (10 mL), and the reaction mixture was stirred at 95°C for 2 hours. The reaction mixture was concentrated, and the crude product was slowly added to ice water (100 mL) with stirring. The resulting solution was adjusted to pH 7 with solid sodium bicarbonate and extracted with dichloromethane (100 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 obtain ethyl 1-chloro-2,7-naphthyridine-3-carboxylate (2.40 g, 37%) as a white solid. LCMS (ESI): [M+H] + =237.1,239.1. 1H NMR (400MHz, DMSO-d6) δ9.73(d,J=1.0Hz,1H),8.99(d,J=5.6Hz,1H),8.72(d,J=0. 9Hz, 1H), 8.23 ​​(dd, J=5.7, 1.1Hz, 1H), 4.43 (q, J=7.1Hz, 2H), 1.39 (t, J=7.1Hz, 3H).

[0434] Step 2: Ethyl 1-chloro-2,7-naphthyridine-3-carboxylate (2.40 g, 10.14 mmol), 4,4-difluoropiperidine hydrochloride (1.94 g, 12.17 mmol), and potassium carbonate (5.00 g, 35.49 mmol) were added to N-methylpyrrolidone (5 mL). The reaction mixture was stirred at 95°C for 24 hours. The reaction mixture was poured into saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 3), 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% ethyl acetate / petroleum ether gradient) to afford ethyl 1-(4,4-difluoropiperidin-1-yl)-2,7-naphthyridine-3-carboxylate (2.20 g, 68%) as a pale yellow solid. LCMS (ESI): [M+H] + =322.2.

[0435] Step 3: Ethyl 1-(4,4-difluoropiperidin-1-yl)-2,7-naphthyridine-3-carboxylate (1.00 g, 3.11 mmol) was added to a 100 mL sealed tube. 7 M ammonia methanol solution (5 mL) was added to the reaction tube, which was sealed and stirred at 85°C for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated to obtain a pale yellow solid, 1-(4,4-difluoropiperidin-1-yl)-2,7-naphthyridine-3-carboxamide (850 mg, 93%). LCMS (ESI): [M+H] + =293.1.

[0436] Step 4: 1-(4,4-difluoropiperidin-1-yl)-2,7-naphthyridine-3-carboxamide (600 mg, 2.05 mmol) was added to 1,4-dioxane (60 mL). Potassium hydroxide (291 mg, 5.13 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 5 minutes. 8% aqueous sodium hypochlorite solution (4.25 g) was then added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 6 hours. Saturated aqueous sodium thiosulfate solution (30 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The mixture was 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. Flash column chromatography (silica gel, 10-33% ethyl acetate / dichloromethane gradient) of the crude product afforded 1-(4,4-difluoropiperidin-1-yl)-2,7-naphthyridine-3-amine (420 mg, 77%) as a yellow solid. LCMS (ESI): [M+H] + =265.1.

[0437] Step 5: 1-(4,4-Difluoropiperidin-1-yl)-2,7-naphthyridin-3-amine (420 mg, 1.59 mmol), 2-fluoro-4-iodobenzoic acid (635 mg, 2.38 mmol), N,N-diisopropylethylamine (1.05 g, 7.95 mmol), and 1-propylphosphonic anhydride (50% ethyl acetate solution, 3.03 g, 4.77 mmol) were added to acetonitrile (5 mL). The reaction mixture was stirred at 85°C for 16 hours. 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, 30-50% gradient of ethyl acetate / petroleum ether) to give N-(1-(4,4-difluoropiperidin-1-yl)-2,7-naphthyridin-3-yl)-2-fluoro-4-iodobenzamide (560 mg, 69%) as a pale yellow solid. LCMS (ESI): [M+H] + =513.1.

[0438] Step 6: N-(1-(4,4-difluoropiperidin-1-yl)-2,7-naphthyridin-3-yl)-2-fluoro-4-iodobenzamide (190 mg, 0.37 mmol), 6-aza-spiro[2.5]octane hydrochloride (83 mg, 0.56 mmol), and potassium carbonate (131 mg, 0.93 mmol) were added to toluene (5 mL). The reaction mixture was stirred at 130°C for 16 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, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 20-50% ethyl acetate / dichloromethane gradient) to afford N-(1-(4,4-difluoropiperidin-1-yl)-2,7-naphthyridin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 89%) as a pale yellow solid. LCMS (ESI): [M+H] + =604.3.

[0439] Step 7: N-(1-(4,4-difluoropiperidin-1-yl)-2,7-naphthyridin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.33 mmol), 2-hydroxyethanesulfonamide (63 mg, 0.50 mmol), cuprous iodide (64 mg, 0.33 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (48 mg, 0.33 mmol), and potassium phosphate (179 mg, 0.83 mmol) were added to N,N-dimethylformamide (2 mL), the atmosphere was replaced with nitrogen, and the reaction solution was stirred 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. Flash column chromatography (silica gel, 10-50% gradient of ethyl acetate / dichloromethane) of the crude product afforded N-(1-(4,4-difluoropiperidin-1-yl)-2,7-naphthyridin-3-yl)-4-(2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (93 mg, 47%) as a white solid.

[0440] LCMS(ESI):[M+H] + =601.4. 1HNMR(400MHz,DMSO-d6)δ13.32(s,1H),10.49(s,1H),9.33(s,1H),8.53(d,J=5.8Hz,1H), 8.18(s,1H),8.10(d,J=8.6Hz,1H),7.72(d,J=5.8Hz,1H),7.30(d,J=2.2Hz,1H),7.15(dd, J=8.6,2.1Hz,1H),5.76(s,1H),3.77(t,J=6.4Hz,2H),3.65(dd,J=7.2,4.2Hz,4H),3.40–3.32( m,2H),3.00(t,J=5.3Hz,4H),2.29(tt,J=14.3,5.6Hz,4H),1.89(d,J=84.2Hz,4H),0.41(s,4H).

[0441] Example 57: N-(5-(4,4-difluoropiperidin-1-yl)-1,6-naphthyridin-7-yl)-4-(2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0442] Example 57 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =601.3. 1 H NMR (400MHz, DMSO) δ13.29(s,1H),10.24(s,1H),8.95(d,J=4.0Hz,1H),8.44(d,J= 8.4Hz,1H),8.32(s,1H),8.13(d,J=8.8Hz,1H),7.44(dd,J=8.4,4.4Hz,1H),7.30( s,1H),7.15(d,J=8.8Hz,1H),5.16–4.84(m,1H),3.77(q,J=6.0Hz,2H),3.56(t,J= 5.6Hz,4H),3.17(s,2H),3.01(s,4H),2.47-2.10(m,4H),1.78(s,4H),0.41(s,4H).

[0443] Example 58: N-(8-(4,4-difluoropiperidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octane-6-methyl)benzamide

[0444] Example 58 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H]+=602.10.1H NMR (400MHz, CDCl3) δ12.99 (s, 1H), 9.30 (d, J = 2.0Hz, 1H), 9.14 (s, 1H), 8. 28(d,J=8.4Hz,1H),8.20(s,1H),7.35(d,J=7.2Hz,1H),7.11(s,2H),5.46– 5.29(m,1H),4.30(t,J=6.0Hz,4H),4.15(t,J=5.2Hz,2H),3.35(t,J=5.2Hz ,2H),3.11(s,4H),2.21(dd,J=12.8,6.8Hz,4H),1.43(s,4H),0.44(s,4H).

[0445] Example 59: N-(5-(4,4-difluoropiperidin-1-yl)pyrido[3,4-b]pyrazin-7-yl)-4-(2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0446] Example 59 was prepared by a similar synthetic route according to Example 3: LCMS (ESI) m / z: [M+H] + =602.4. 1 H NMR (400MHz, DMSO) δ13.07 (s, 1H), 10.24 (s, 1H), 8.93 (d, J = 1.6Hz, 1H), 8.69 ( d,J=2.0Hz,1H),8.17–8.08(m,2H),7.30(d,J=2.0Hz,1H),7.15(d,J=8.4,2.1 Hz,1H),4.95(s,1H),4.25-4.21(m,4H),3.78(t,J=5.6Hz,2H),3.37(t,J=6.4 Hz,2H),3.06-2.96(m,4H),2.22-2.15(m,4H),1.77-1.73(m,4H),0.41(s,4H).

[0447] Example 60: N-(8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazin-6-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0448] Step 1: To a solution of tert-butyl ethyl malonate (21.8 g, 116 mmol) in N,N-dimethylformamide (220 mL) was added sodium hydride (4.25 g, 106 mmol, 60% purity). The mixture was stirred at 0°C for 1 hour. Methyl 4,6-dichloropyridazine-3-carboxylate (20.0 g, 96.6 mmol) was then added to the reaction mixture at 0°C. The mixture was stirred at 25°C under nitrogen for 16 hours. The reaction mixture was slowly poured into water (50 mL) and extracted with ethyl acetate (100 mL x 2). The mixture was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated by column chromatography (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to give a yellow oily substance, 1-tert-butyl 3-ethyl 2-(6-chloro-3-(carbomethoxy)pyridazin-4-yl)malonate (32.0 g, 89.2 mmol, yield 92.3%). LCMS (ESI): [M+H] + =359.1

[0449] Step 2: To a solution of 1-tert-butyl 3-ethyl 2-(6-chloro-3-(carbomethoxy)pyridazin-4-yl)malonate (32.0 g, 89.2 mmol) in dichloromethane (320 mL) was added trifluoroacetic acid (160 mL), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate and extracted with dichloromethane (500 mL x 2). The organic layer was washed with saturated brine (500 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 6-chloro-4-(2-ethoxy-2-oxyylideneethyl)pyridazine-3-carboxylate (22.0 g, 85.1 mmol, 95.4% yield) as a white solid. LCMS (ESI): [M+H] + =259.0.

[0450] Step 3: Dissolve methyl 6-chloro-4-(2-ethoxy-2-oxyylideneethyl)pyridazine-3-carboxylate (20.0 g, 77.3 mmol) in methanolic ammonia (200 mL). Stir the mixture at 90°C for 16 hours. Concentrate the reaction mixture and spin dry to obtain a yellow solid ammonium 3-chloro-6-hydroxypyrido[3,4-c]pyridazin-8-ol anion (15.0 g, 75.9 mmol, 98.2% yield). LCMS (ESI): [M+H] + =198.0. 1 H NMR(400MHz,DMSO-d6)δ10.67-9.72(m,1H),7.64-6.86(m,4H),6.81(s,1H),4.65(s,1H)

[0451] Step 4: To a solution of ammonium 3-chloro-6-hydroxypyrido[3,4-c]pyridazine-8-ol anion (7.50 g, 38.0 mmol) in phosphorus oxychloride (150 mL) was added N,N-diisopropylethylamine (10.0 g, 75.9 mol) and the mixture was stirred at 100 ° C for 6 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was separated by column (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to obtain 3,6,8-trichloropyrido[3,4-c]pyridazine (6.50 g, 27.7 mmol, yield 73.0%). LCMS (ESI): [M+H] + =233.9.

[0452] Step 5: To a solution of 3,6,8-trichloropyrido[3,4-c]pyridazine (6.50 g, 27.7 mmol) in tert-butanol (130 mL) were added 4,4-difluoropiperidine (4.37 g, 27.7 mmol) and N,N-diisopropylethylamine (36.6 g, 277 mol). The mixture was stirred at 100°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 purified by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to obtain 3,6-dichloro-8-(4,4-difluoropiperidin-1-yl)pyrido[3,4-c]pyridazine (6.10 g, 19.1 mmol, 69.0% yield) as a yellow solid. LCMS(ESI):[M+H] + =319.0. 1 H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.10(s,1H),4.40-4.30(m,4H),2.27-2.14(m,4H)

[0453] Step 6: Dissolve 3,6-dichloro-8-(4,4-difluoropiperidin-1-yl)pyrido[3,4-c]pyridazine (150 mg, 0.47 mmol) in a solution of sodium methoxide (3 mL). The mixture was stirred at 25°C for 16 hours. The reaction solution was poured into ice water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was washed with saturated brine (10 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid 6-chloro-8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazine (125 mg, 0.39 mmol, yield 84.5%). LCMS (ESI): [M+H] + =315.0. 1H NMR(400MHz,DMSO-d6)δ7.37(s,1H),7.04(s,1H),4.47-4.34(m,4H),4.16(s,3H),2.25-2.15(m,4H)

[0454] Step 7: To a solution of 6-chloro-8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazine (100 mg, 0.31 mmol) in dioxane (2 mL) were added cesium carbonate (311 mg, 0.95 mmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (29.1 mg, 0.03 mmol), 5-bis(diphenylphosphino-99-dimethyloxanthene) (36.7 mg, 0.06 mmol), and benzophenone imine (70.5 mg, 0.38 mmol). The mixture was purged with nitrogen three times and stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with water (10 mL) and ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 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, 0-15% gradient of ethyl acetate / petroleum ether) to obtain 8-(4,4-difluoropiperidin-1-yl)-N-(benzylidene)-3-methoxypyrido[3,4-c]pyridazin-6-amine (110 mg, 0.24 mmol, 75.3% yield) as a white solid. LCMS (ESI): [M+H] + =460.2

[0455] Step 8: To a solution of 8-(4,4-difluoropiperidin-1-yl)-N-(benzylidene)-3-methoxypyrido[3,4-c]pyridazin-6-amine (100 mg, 0.22 mmol) in methanol (2 mL) were added sodium acetate (53.6 mg, 0.65 mmol) and hydroxylamine hydrochloride (30.3 mg, 0.44 mol). The mixture was stirred at 25°C for 2 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic layer was washed with saturated brine (10 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, 0-10% gradient of ethyl acetate / petroleum ether) to give 8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazin-6-amine (50.0 mg, 0.17 mmol, yield 77.8%) as a yellow solid. LCMS (ESI): [M+H] + =296.1

[0456] Step 9: To a solution of 8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazin-6-amine (45 mg, 0.15 mmol) and 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (68.7 mg, 0.18 mmol) in tetrahydrofuran (2 mL) was added N,N-diisopropylethylamine (60.3 mg, 0.46 mmol) and potassium tert-butoxide (0.45 mL, 0.18 mmol, 1 M) in tetrahydrofuran, and the mixture was stirred at 25°C for 16 hours. The reaction solution was cooled to room temperature and extracted with water (10 mL) and ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 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, 0-10% gradient of ethyl acetate / petroleum ether) to afford N-(8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (80.0 mg, 0.124 mmol, 82.7% yield) as a yellow solid. LCMS (ESI): [M+H] + =635.1

[0457] Step 10: To a solution of 2-hydroxyethanesulfonamide (31.6 mg, 0.25 mmol), sarcosine (11.2 mg, 0.13 mmol), and potassium phosphate (109 mg, 0.50 mmol) in N,N-dimethylformamide (2 mL) was added cuprous iodide (12.3 mg, 0.06 mmol). The mixture was stirred at 50°C for 5 minutes. N-(8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (80 mg, 0.13 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. The reaction solution was cooled to room temperature and 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, 42-82% gradient of water (formic acid) / acetonitrile) to obtain a yellow solid N-(8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazin-6-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (31.0 mg, 0.05 mmol, yield 38.9%). LCMS (ESI): [M+H] + =632.5.1 H NMR (400MHz, DMSO-d6) δ12.99(s,1H),10.26(s,1H),8.09(d,J=8.8Hz,1H),7.87(d,J=1.2 Hz,1H),7.39(d,J=2.0Hz,1H),7.29(d,J=2.0Hz,1H),7.15(dd,J=2.0,8.4Hz,1H),4.97(br t,J=5.6Hz,1H),4.50-4.28(m,4H),4.14(s,3H),3.85-3.67(m,2H),3.45-3.3 7(m,2H),3.12-2.91(m,4H),2.30-2.12(m,4H),2.02-1.47(m,4H),0.41(s,4H)

[0458] Example 61: 2-{6-Azaspiro[2.5]octan-6-yl}-N-[8-(4,4-difluoropiperidin-1-yl)-3-hydroxypyrido[3,4-c]pyridazin-6-yl]-4-(2-hydroxyethanesulfonylamino)benzamide

[0459] Step 1: To a solution of 1-{3,6-dichloropyrido[3,4-c]pyridazin-8-yl}-4,4-difluoropiperidine (600 mg, 1.88 mmol) in tetrahydrofuran (6 mL) was added sodium methoxide methanol solution (6 mL, 5.4 M). The mixture was stirred at 25°C for 2 hours. The reaction solution was poured into ice water (20 mL) 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 give 1-{6-chloro-3-methoxypyrido[3,4-c]pyridazin-8-yl}-4,4-difluoropiperidine (250 mg, 0.79 mmol, 42% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 315.0. 1 H NMR(400MHz,DMSO-d6)δppm 7.37(s,1H),7.04(s,1H),4.46-4.27(m,4H),4.16(s,3H),2.26-2.12(m,4H)

[0460] Step 2: To a solution of 1-{6-chloro-3-methoxypyrido[3,4-c]pyridazin-8-yl}-4,4-difluoropiperidine (250 mg, 0.79 mmol) in dioxane (5 mL) were added benzophenone imine (151 mg, 0.83 mmol), cesium carbonate (528 mg, 1.59 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (93.8 mg, 0.16 mmol), and tris(dibenzylideneacetone)dipalladium (74.2 mg, 0.08 mmol). The reaction mixture was purged with nitrogen three times and heated to 100°C under a nitrogen atmosphere with stirring for 16 hours. The reaction mixture was cooled to room temperature 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 sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of tetrahydrofuran / petroleum ether) to give N-[8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazin-6-yl]-1,1-diphenylmethanimine (230 mg, 0.50 mmol, 63% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 460.2

[0461] Step 3: To a solution of N-[8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazin-6-yl]-1,1-diphenylcarbamate (210 mg, 0.46 mmol) in methanol (4 mL) was added sodium acetate (112 mg, 1.37 mmol) and hydroxylamine hydrochloride (63.7 mg, 0.91 mmol). The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into ice water (20 mL) 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, 0-12% gradient of tetrahydrofuran / petroleum ether) to afford 8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazin-6-amine (130 mg, 0.44 mmol, 96% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 296.0. 1 H NMR(400MHz,DMSO-d6)δppm 6.77(s,1H),6.42(br s,2H),5.70(s,1H),4.29-4.18(m,4H),4.02(s,3H),2.21-2.04(m,4H)

[0462] Step 4: To a solution of 8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazin-6-amine (100 mg, 0.34 mmol) and 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoyl chloride (165 mg, 0.44 mmol) in tetrahydrofuran (2 mL) was added potassium tert-butoxide (1.02 mL, 1 M) in tetrahydrofuran and N,N-diisopropylethylamine (134 mg, 1.02 mmol). 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 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}-N-[8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazin-6-yl]-4-iodobenzamide (110 mg, 0.17 mmol, 51% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 635.1

[0463] Step 5: Pyridine hydrochloride (200 mg, 1.73 mmol) was added to a solution of 2-{6-azaspiro[2.5]octan-6-yl}-N-[8-(4,4-difluoropiperidin-1-yl)-3-methoxypyrido[3,4-c]pyridazin-6-yl]-4-iodobenzamide (110 mg, 0.17 mmol) in N,N-dimethylformamide (5.00 mL). The mixture was stirred at 120°C for 16 hours. The reaction solution was cooled to room temperature 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 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 methanol / dichloromethane) to afford 2-{6-azaspiro[2.5]octan-6-yl}-N-[8-(4,4-difluoropiperidin-1-yl)-3-hydroxypyrido[3,4-c]pyridazin-6-yl]-4-iodobenzamide (100 mg, 0.16 mmol, 93% yield) as an orange solid. LCMS (ESI): [M+H]+ = 621.4

[0464] Step 6: To a solution of 2-hydroxyethanesulfonamide (21.0 mg, 0.17 mmol) and (1R,2R)-(-)-N,N-dimethylcyclohexane-1,2-diamine (18.5 mg, 0.13 mmol) in N,N-dimethylformamide (2 mL) were added cuprous iodide (12.5 mg, 0.06 mmol) and potassium phosphate (112 mg, 0.52 mmol). The mixture was heated to 50°C and stirred for 5 minutes. 2-{6-azaspiro[2.5]octan-6-yl}-N-[8-(4,4-difluoropiperidin-1-yl)-3-hydroxypyrido[3,4-c]pyridazin-6-yl]-4-iodobenzamide (80.0 mg, 0.13 mmol) was added to the mixture, which was then heated to 100°C and stirred under nitrogen for 16 hours. The reaction solution was cooled to room temperature 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 sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by preparative HPLC (C18, 22-62% gradient of water (formic acid) / acetonitrile) to give an orange solid 2-{6-azaspiro[2.5]octane-6-yl}-N-[8-(4,4-difluoropiperidin-1-yl)-3-hydroxypyrido[3,4-c]pyridazine-6-yl]-4-(2-hydroxyethanesulfonylamino)benzamide (2.50 mg, 0.005 mmol, 3% yield). LCMS (ESI): [M+H] + = 618.4. 1 H NMR (400MHz, DMSO-d6) δppm 13.82(s,1H),12.81(s,1H),10.27(s,1H),8.05(d,J=8.8Hz,1H),7.52(s,1H),7.24(s,1H),7.11(br d,J=8.8Hz,1H),6.79(s,1H),5.01(s,1H),4.18(br s,4H),3.76(t,J=6.4Hz,2H),3.31-3.30(m,2H),2.98(br s,4H),2.22-2.11(m,4H),1.88-1.55(m,4H),0.40(s,4H)

[0465] Example 62: N-[3-amino-8-(4,4-difluoropiperidin-1-yl)pyrido[3,4-c]pyridazin-6-yl]-2-{6-azaspiro[2.5]octan-6-yl}-4-(2-hydroxyethanesulfonylamino)benzamide

[0466] Example 62 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =617.3,1 H NMR (400MHz, DMSO-d6) δ12.80 (s, 1H), 10.94-9.71 (m, 1H), 8.07 (d, J = 8.4Hz, 1H), 7.63 (s, 1H), 7.27 (d,J=1.6Hz,1H),7.13(dd,J=1.8,8.8Hz,1H),6.71(s,2H),6.62(s,1H),5.32-4.67(m,1H),4.30(br s,4H),3.76(t,J=6.4Hz,2H),3.52-3.41(m,2H),2.99(br s,4H),2.24-2.10(m,4H),1.92-1.49(m,4H),0.41(s,4H)

[0467] Example 63: N-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0468] Step 1: Under nitrogen atmosphere, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (420 mg, 0.711 mmol) and tris(dibenzylideneacetone)dipalladium (665 mg, 0.81 mmol) were added to a mixed solution containing 8-bromo-6-nitroquinoline (1.8 g, 7.11 mmol), 4,4-difluoropiperidine hydrochloride (1.7 g, 10.67 mmol), cesium carbonate (9.9 g, 29.64 mmol) and dioxane (20 mL). The resulting mixture was stirred at 120 ° C for 12 hours. The reaction solution was poured into water (50 ml) and washed with ethyl acetate (50 ml x 10% ethanol). 3) Extraction, drying the organic phase over anhydrous sodium sulfate, filtration, and concentration followed by column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) afforded the compound 8-(4,4-difluoropiperidin-1-yl)-6-nitroquinoline (1.4 g, 4.77 mmol, yield: 67%) as a yellow solid. LCMS (ESI): [M+H] + =294.1.

[0469] Step 2: A mixture containing 8-(4,4-difluoropiperidin-1-yl)quinolin-6-amine (500 mg, 1.70 mmol), iron powder (962 mg, 17.05 mmol), ammonium chloride (921 mg, 17.05 mmol), ethanol (10 mL), and water (2 mL) was stirred at 60°C for 1 hour. The reaction solution was filtered while hot, and the filtrate was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 8-(4,4-difluoropiperidin-1-yl)quinolin-6-amine (420 mg, 1.60 mmol, yield: 93.6%) as a yellow solid. LCMS (ESI): [M+H] + =264.2.

[0470] Step 3: 2-(6-azaspiro[2.5]octan-6-yl)-4-bromobenzoyl chloride (599 mg, 1.82 mmol) was added to a mixed solution containing 8-(4,4-difluoropiperidinyl)-6-quinolinamine (400 mg, 1.52 mmol), N,N-diisopropylethylamine (601 mg, 4.56 mmol) and tetrahydrofuran (10 mL). The resulting mixture was stirred at 20°C for 1 hour. The reaction solution was poured into water (30 mL) and washed with ethyl acetate (30 mL x 10 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to obtain the compound 4-bromo-N-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (700 mg, 1.26 mmol, yield: 83%). LCMS (ESI): [M+H] + =555.3.

[0471] Step 4: Under nitrogen atmosphere, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (23 mg, 0.054 mmol) and tris(dibenzylideneacetone)dipalladium (50 mg, 0.054 mmol) were added to a mixed solution containing [2-(6-azaspiro[2.5]octan-6-yl)-4-bromophenyl]-N-[8-(4.4-difluoropropiperidinyl)(6-quinolinyl)]carboxamide (300 mg, 0.54 mmol), 2-hydroxyethanesulfonylamide (83 mg, 0.648 mmol), potassium phosphate (351 mg, 1.62 mmol) and dioxane (5 mL). The resulting mixture was stirred at 100° C. for 12 hours. The reaction solution was poured into water (30 mL) and washed with ethyl acetate (30 mL x 40 mL). 3) extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to obtain the compound N-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (115.74 mg, 0.19 mmol, yield: 35.7%) as a white solid. LCMS (ESI): [M+H / 2] + =300.8. 1 H NMR (400MHz, DMSO) δ11.95(s,1H),10.12(s,1H),8.76(dd,J=4.0,2.0Hz,1H),8.30–8.20(m,2H ),7.87(d,J=8.4Hz,1H),7.48(dd,J=8.4,4.0Hz,1H),7.33(d,J=2.0Hz,1H),7.19(d,J=2.0Hz, 1H),7.07(dd,J=8.4,2.0Hz,1H),4.97(s,1H),3.76(d,J=6.8Hz,2H),3.54(t,J=5.6Hz,4H),3. 36(d,J=6.4Hz,2H),3.00(t,J=5.2Hz,4H),2.30–2.17(m,4H),1.67–1.51(m,4H),0.35(s,4H).

[0472] Example 64: N-(8-(4,4-difluoropiperidin-1-yl)-2-methylquinolin-6-yl)-4-(2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0473] Step 1: 4-Bromo-2-fluoro-1-nitrobenzene (10.00 g, 45.45 mmol), 4,4-difluoropiperidine hydrochloride (8.59 g, 54.55 mmol), and potassium carbonate (19.23 g, 136.36 mmol) were added to N,N-dimethylformamide (100 mL). The reaction mixture was stirred at 120°C for 6 hours. The reaction mixture was filtered, and the filtrate was poured into saturated ammonium chloride solution (200 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 0-20% ethyl acetate / petroleum ether gradient) to obtain 1-(5-bromo-2-nitrophenyl)-4,4-difluoropiperidine (22.00 g, 75%) as a yellow solid. LCMS (ESI): [M+H] + =321.0

[0474] Step 2: 1-(5-Bromo-2-nitrophenyl)-4,4-difluoropiperidine (4.00 g, 12.46 mmol), iron powder (3.51 g, 62.28 mmol), and ammonium chloride (1.01 g, 18.69 mmol) were added to water (4 mL), ethanol (20 mL), and tetrahydrofuran (20 mL). The reaction mixture was stirred at 85°C for 16 hours. The reaction mixture was filtered, and the filtrate was poured into water (50 mL). The mixture was 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 purified by flash column chromatography (silica gel, 10-15% ethyl acetate / petroleum ether gradient) to afford 4-bromo-2-(4,4-difluoropiperidin-1-yl)aniline (3.50 g, 96%) as a yellow solid. LCMS (ESI): [M+H] + =291.0

[0475] Step 3: 4-Bromo-2-(4,4-difluoropiperidin-1-yl)aniline (3.50 g, 12.02 mmol) and crotonaldehyde (4.26 g, 60.11 mmol) were added to hydrochloric acid (6 M, 20 mL). The reaction mixture was stirred at reflux at 100°C for 16 hours. The reaction mixture was slowly poured into water (100 mL) and the pH was adjusted to 7 with solid sodium hydroxide. The mixture was 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 purified by flash column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether gradient) to afford 6-bromo-8-(4,4-difluoropiperidin-1-yl)-2-methylquinoline (1.20 g, 29%) as a pale yellow solid. LCMS (ESI): [M+H] + =341.0

[0476] Step 4: 6-Bromo-8-(4,4-difluoropiperidin-1-yl)-2-methylquinoline (1.10 g, 3.22 mmol), tert-butyl carbamate (572 mg, 4.84 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (190 mg, 0.32 mmol), tris(dibenzylideneacetone)dipalladium (301 mg, 0.32 mmol), and cesium carbonate (2.14 g, 6.45 mmol) were added to 1,4-dioxane (10 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered, poured into water (50 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 added to dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added to the reaction mixture. The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was slowly poured into water (50 mL), and the pH was adjusted to 7 with solid sodium bicarbonate. The mixture was 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 purified by flash column chromatography (silica gel, 10-25% gradient of ethyl acetate / dichloromethane) to afford 8-(4,4-difluoropiperidin-1-yl)-2-methylquinolin-6-amine (450 mg, 50%) as a brown solid. LCMS (ESI): [M+H] + =278.2

[0477] Step 5: 8-(4,4-Difluoropiperidin-1-yl)-2-methylquinolin-6-amine (200 mg, 0.72 mmol) and N,N-diisopropylethylamine (285 mg, 2.16 mmol) were added to tetrahydrofuran (10 mL). 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (355 mg, 1.08 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 25°C for 2 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, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 10-25% gradient of ethyl acetate / dichloromethane) to afford 4-bromo-N-(8-(4,4-difluoropiperidin-1-yl)-2-methylquinolin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (300 mg, 73%) as a pale yellow solid. LCMS (ESI): [M+H] + =569.3

[0478] Step 6: 4-Bromo-N-(8-(4,4-difluoropiperidin-1-yl)-2-methylquinolin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (300 mg, 0.53 mmol), 2-hydroxyethanesulfonamide (101 mg, 0.79 mmol), cuprous iodide (102 mg, 0.53 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (113 mg, 0.79 mmol), and potassium phosphate (342 mg, 1.58 mmol) were added to N,N-dimethylformamide (4 mL), the atmosphere was replaced with nitrogen, and the reaction solution was stirred 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, 30-50% gradient of ethyl acetate / dichloromethane) to afford N-(8-(4,4-difluoropiperidin-1-yl)-2-methylquinolin-6-yl)-4-(2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (165 mg, 51%).

[0479] LCMS(ESI):[M+H] + =614.4. 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),10.11(s,1H),8.17(d,J=2.0Hz,1H),8.13(d,J=8.4Hz,1H), 7.87(d,J=8.5Hz,1H),7.37(d,J=8.4Hz,1H),7.29(d,J=2.2Hz,1H),7.19(d,J=2.1Hz,1H),7.07(dd ,J=8.5,2.1Hz,1H),4.96(s,1H),3.77(q,J=5.6,5.0Hz,2H),3.53(t,J=5.5Hz,4H),3.36(d,J=6.5 Hz,2H),3.00(t,J=5.2Hz,4H),2.64(s,3H),2.30–2.19(m,4H),1.59(t,J=5.0Hz,4H),0.35(s,4H).

[0480] Example 65: N-(8-(4,4-difluoropiperidin-1-yl)-2-methoxyquinolin-6-yl)-4-(2-hydroxyethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0481] Example 65 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+1] + =630.3.1H NMR (400MHz, DMSO) δ11.89 (s, 1H), 10.06 (s, 1H), 8.18–8.11 (m, 2H), 7.86 (d, J = 8.4Hz, 1H), 7. 32(d,J=2.0Hz,1H),7.19(d,J=2.0Hz,1H),7.06(dd,J=8.4,2.0Hz,1H),6.99(d,J=8.8Hz,1H), 5.04(s,1H),3.98(s,3H),3.77(t,J=6.4Hz,2H),3.49(t,J=5.6Hz,4H),3.35(d,J=6.4Hz,2H), 3.00(t,J=5.2Hz,4H),2.26(td,J=14.4,13.0,6.9Hz,4H),1.59(t,J=5.2Hz,4H),0.36(s,4H).

[0482] Example 66: N-(8-(4,4-difluoropiperidin-1-yl)-2-hydroxyquinolin-6-yl)-4-(2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0483] Step 1: To a solution of 4-bromo-N-(8-(4,4-difluoropiperidin-1-yl)-2-methoxyquinolin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.34 mmol) in tetrahydrofuran (4 mL) was added a solution of pyridine hydrochloride (276 mg, 2.39 mmol). The mixture was stirred at 105°C for 8 hours. Stirring was stopped after a solid compound precipitated, and the mixture was diluted with water (8 mL). The solid was filtered, and the filter cake was rinsed with methanol (1 mL). The filter cake was collected and dried to give 2-(6-azaspiro[2.5]octan-6-yl)-4-bromophenyl]-N-[8-(4,4-difluoropiperidin-1-yl)-2-hydroxy(6-quinolinyl)]carboxamide (150 mg, 77%) as a white solid. LCMS (ESI): [M+H] +=571.3.1H NMR (400MHz, DMSO) δ11.30 (s, 1H), 10.61 (s, 1H), 8.02 (d, J = 2.0Hz, 1H), 7.96–7.92 (m, 1H),7.71–7.64(m,2H),7.44(d,J=2.0Hz,1H),7.38(dd,J=8.4,1.9Hz,1H),6.55(d,J= 9.6Hz,1H),3.03(t,J=5.2Hz,4H),2.89(s,6H),2.73(s,2H),1.49(t,J=5.2Hz,4H),0.31(s,4H).

[0484] Step 2: 2-(6-azaspiro[2.5]octan-6-yl)-4-bromophenyl]-N-[8-(4,4-difluoropiperidinyl)-2-hydroxy(6-quinolyl)]formamide (100 mg, 0.17 mmol), 2-hydroxyethanesulfonamide (44 mg, 0.30 mmol), cuprous iodide (34 mg, 0.17 mmol), potassium phosphate (150 mg, 0.70 mmol), and N,N'-dimethyl-1,2-cyclohexanediamine (100 mg, 0.70 mmol) were added sequentially to N,N-dimethylformamide (3 mL), and the atmosphere was replaced with nitrogen three times. The reaction mixture was heated and stirred at 110°C for 2 hours. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (C18, 30-55% gradient of acetonitrile / water) to give N-(8-(4,4-difluoropiperidin-1-yl)-2-hydroxyquinolin-6-yl)-4-(2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (32 mg, 29%) as a white solid. LCMS (ESI): [M+1] + =616. 1H NMR (400MHz, DMSO) δ11.73 (s, 1H), 10.60 (s, 1H), 9.76 (s, 1H), 8.03 (d, J = 2.1Hz, 1H), 7.9 3(d,J=9.6Hz,1H),7.81(d,J=8.4Hz,1H),7.67(d,J=2.0Hz,1H),7.15(d,J=2.0Hz,1H),7 .02(dd,J=8.4,2.1Hz,1H),6.55(d,J=9.6Hz,1H),5.07(s,1H),3.76(t,J=6.4Hz,2H),3. 30(d,J=6.4Hz,2H),3.08–2.80(m,8H),2.01(s,4H),1.55(t,J=5.2Hz,4H),0.34(s,4H).

[0485] Example 67: N-(2-amino-8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-4-(2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0486] Step 1: 8-bromoquinolin-2(1H)-one (5.00 g, 22.32 mmol) was added to concentrated sulfuric acid (20 mL), and the reaction mixture was stirred in an ice bath for 15 minutes. Concentrated nitric acid (65%, 12 mL) was slowly added dropwise to the reaction mixture, maintaining the reaction temperature below 5°C. After the addition was complete, the reaction mixture was transferred to 25°C and stirred for 16 hours. The reaction mixture was slowly poured into ice water (200 mL), stirred vigorously, and filtered. The filtered solid was washed with water (200 mL), saturated sodium bicarbonate solution (200 mL), and water (200 mL), and dried to obtain a crude light yellow solid 8-bromo-6-nitroquinolin-2(1H)-one (purity 50%, 5.77 g, 47%). LCMS (ESI): [M+H] + =269.0,271.0.

[0487] Step 2: 8-Bromo-6-nitroquinolin-2(1H)-one (50% purity, 5.70 g, 10.59 mmol) was added to phosphorus oxychloride (10 mL), and the reaction mixture was stirred at 90°C for 4 hours. The reaction mixture was slowly poured into ice water (200 mL), stirred, and adjusted to pH 7 with saturated sodium bicarbonate solution. The mixture was 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 purified by flash column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether gradient) to obtain 8-bromo-2-chloro-6-nitroquinoline (2.60 g, 73%) as a pale yellow solid. LCMS (ESI): [M+H] + =286.9. 1H NMR (400MHz, DMSO-d6) δ9.15 (d, J = 2.5 Hz, 1H), 8.83 (d, J = 8.6 Hz, 1H), 8.80 (d, J = 2.5 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H).

[0488] Step 3: 8-Bromo-2-chloro-6-nitroquinoline (2.60 g, 9.04 mmol), 4-methoxybenzylamine (1.88 g, 13.56 mmol), and cesium carbonate (4.51 g, 13.56 mmol) were added to N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 95°C for 16 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 with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 0-15% ethyl acetate / petroleum ether gradient) to afford 8-bromo-N-(4-methoxybenzyl)-6-nitroquinolin-2-amine (2.90 g, 83%) as a brown solid. LCMS (ESI): [M+H] + =388.0

[0489] Step 4: 8-Bromo-N-(4-methoxybenzyl)-6-nitroquinolin-2-amine (2.90 g, 7.47 mmol), 4,4-difluoropiperidine hydrochloride (1.78 g, 11.20 mmol), cesium carbonate (7.45 g, 22.41 mmol), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (319 mg, 0.37 mmol) were added to 1,4-dioxane (10 mL). The atmosphere was replaced with nitrogen and the reaction mixture was stirred at 100°C for 16 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 purified by flash column chromatography (silica gel, 10-25% gradient of ethyl acetate / petroleum ether) to give 8-(4,4-difluoropiperidin-1-yl)-N-(4-methoxybenzyl)-6-nitroquinolin-2-amine (1.70 g, 53%) as a red solid. LCMS (ESI): [M+H] + =429.3.

[0490] Step 5: 8-(4,4-difluoropiperidin-1-yl)-N-(4-methoxybenzyl)-6-nitroquinolin-2-amine (800 mg, 1.87 mmol), iron powder (527 mg, 9.34 mmol), and ammonium chloride (151 mg, 2.80 mmol) were added to a solution of water (1 mL), ethanol (5 mL), and tetrahydrofuran (5 mL). The reaction solution was reacted at 90°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated, 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 8-(4,4-difluoropiperidin-1-yl)-N-(4-methoxybenzyl)-6-nitroquinolin-2-amine. 2 -(4-methoxybenzyl)quinoline-2,6-diamine (700 mg, 94%). LCMS (ESI): [M+H] + =399.3.

[0491] Step 6: 8-(4,4-difluoropiperidin-1-yl)-N 2 8-(4-Methoxybenzyl)quinoline-2,6-diamine (700 mg, 1.76 mmol) was added to trifluoroacetic acid (4 mL), and the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was slowly poured into saturated ammonium chloride solution (50 mL) and extracted with dichloromethane (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% methanol / dichloromethane gradient) to obtain 8-(4,4-difluoropiperidin-1-yl)quinoline-2,6-diamine (220 mg, 45%). LCMS (ESI): [M+H] + =279.1.

[0492] Step 7: 8-(4,4-difluoropiperidin-1-yl)quinoline-2,6-diamine (140 mg, 0.50 mmol) and N,N-diisopropylethylamine (133 mg, 1.01 mmol) were added to tetrahydrofuran (2 mL). The reaction mixture was stirred at 25°C for 10 minutes. 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (174 mg, 0.53 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution (30 mL) and extracted with dichloromethane (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% methanol / dichloromethane gradient) to afford N-(2-amino-8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (140 mg, 49%) as a brown solid. LCMS (ESI): [M+H] + =570.3

[0493] Step 8: N-(2-Amino-8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (140 mg, 0.25 mmol), potassium phosphate (159 mg, 0.74 mmol), cuprous iodide (48 mg, 0.25 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (35 mg, 0.25 mmol), and 2-hydroxyethanesulfonamide (47 mg, 0.37 mmol) were added to N,N-dimethylformamide (1 mL), the atmosphere was replaced with nitrogen, and the reaction solution was stirred at 110°C for 16 hours. The reaction mixture was poured into saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (C18, 10-40% gradient of acetonitrile / water) to afford N-(2-amino-8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-4-(2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (27 mg, 18%) as a pale yellow solid. LCMS (ESI): [M+H] + =615.4. 1 H NMR (400MHz, DMSO-d6) δ11.81(d,J=4.2Hz,1H),10.09(s,1H),7.94(q,J=2.1Hz,1H),7.85( ddd,J=18.0,8.7,4.3Hz,2H),7.18(dt,J=6.0,2.9Hz,2H),7.06(dq,J=7.3,2.1Hz,1H),6.75 (dd,J=8.8,4.2Hz,1H),6.25(s,2H),4.98(s,1H),3.77(q,J=5.9Hz,2H),3.46–3.40(m,6H), 2.99(q,J=4.9Hz,4H), 2.23(t,J=10.4Hz,4H), 1.59(d,J=6.6Hz,4H), 0.36(d,J=4.2Hz,4H).

[0494] Example 68: N-(2-cyano-8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0495] Example 68 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =625.4, 1H NMR (400MHz, DMSO-d6) δ12.01(s,1H),10.13(s,1H),8.52(d,J=8.6Hz,1H),8.34(d,J=2 .0Hz,1H),7.95(d,J=8.4Hz,1H),7.84(d,J=8.5Hz,1H),7.43(d,J=2.2Hz,1H),7.18(d,J =2.1Hz,1H),7.06(dd,J=8.5,2.1Hz,1H),4.97(s,1H),3.77(s,2H),3.55(d,J=6.2Hz,4H ),3.36(m,2H),3.00(t,J=5.2Hz,4H),2.23(d,J=15.1Hz,4H),1.56(s,4H),0.34(s,4H).

[0496] Example 69: (2-(6-azaspiro[2.5]octan-6-yl)-4-{[(2-hydroxyethyl)sulfonyl]amino}phenyl)-N-[8-(4,4-difluoropiperidinyl)-2-(trifluoromethyl)(6-quinolinyl)]formamide

[0497] Example 69 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =668.4, 1 H NMR (400MHz, DMSO) δ11.99(s,1H),10.13(s,1H),8.57(d,J=8.6Hz,1H),8.35(d,J=2.0Hz,1H),7.87(dd,J=13.1,8.5Hz,2H ),7.43(d,J=2.1Hz,1H),7.19(d,J=2.1Hz,1H),7.06(dd,J=8.5,2.1Hz,1H),4.97(s,1H),3.77(t,J=5.1Hz,2H),3.58(t,J= 5.5Hz,4H),3.35(t,J=6.6Hz,2H),3.00(t,J=5.2Hz,4H),2.25(dt,J=14.4,8.5Hz,4H),1.57(s,4H),0.35(s,4H).

[0498] Example 70: N-(8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl-7-d)-4-((2-hydroxyethyl)sulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0499] Example 70 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =601.2; 1 H NMR(400MHz,DMSO-d6)δppm 11.95(s,1H),10.53-9.68(m,1H),8.75(dd,J=1.2,4.0Hz,1H),8.35-8.16(m,2H),7.87(d,J=8.8Hz,1H),7.47(dd,J=4.0, 8.0Hz,1H),7.19(s,1H),7.07(dd,J=1.6,8.4Hz,1H),5.16-4.76(m,1H),3.77(t,J=6.4Hz,2H),3.57-3.49(m,4H),3.35(br t,J=6.4Hz,2H),3.00(br t,J=4.4Hz,4H),2.31-2.16(m,4H),1.63-1.53(m,4H),0.35(s,4H)

[0500] Example 71: N-(8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl]benzamide

[0501] Example 71 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H]+=618.4. 1 H NMR (400MHz, DMSO) δ12.48(d,J=2.7Hz,1H),10.22(s,1H),8.82(dd,J=4.2,1.7Hz,1H),8.74(d,J=7.9H z,1H),8.32(dd,J=8.4,1.7Hz,1H),8.05(d,J=8.5Hz,1H),7.49(dd,J=8.3,4.2Hz,1H),7.31(d,J=2.2H z,1H),7.14(dd,J=8.6,2.1Hz,1H),4.95(t,J=5.7Hz,1H),3.77(q,J=5.8Hz,2H),3.58(t,J=5.6Hz,4H) ,3.38(t,J=6.5Hz,2H),2.99(t,J=5.3Hz,4H),2.19(tt,J=14.1,5.6Hz,4H),1.60(s,4H),0.38(s,4H).

[0502] Example 72: N-(8-(4,4-difluoropiperidin-1-yl)-7-(trifluoromethyl)quinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)

[0503] Example 72 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =668.4. 1 H NMR (400MHz, DMSO) δ12.00(s,1H),10.18(s,1H),9.02(dd,J=4.1,1.7Hz,1H),8.47(dd,J=8 .5,1.7Hz,1H),8.30(s,1H),7.98(d,J=8.5Hz,1H),7.68(dd,J=8.4,4.1Hz,1H),7.27(d,J= 2.1Hz,1H),7.10(dd,J=8.6,2.1Hz,1H),4.95(s,1H),4.18–3.96(m,2H),3.78(s,2H),3.37 (t,J=6.5Hz,2H),3.02(t,J=5.4Hz,6H),2.08(d,J=35.4Hz,4H),1.48(s,4H),0.33(s,4H).

[0504] Example 73: N-(7-chloro-8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0505] Example 73 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =634.6; 1 H NMR(400MHz,DMSO)δ11.66(s,1H),10.20(s,1H),8.90–8.83(m,1H),8.78(s,1H),8.3 8(d,J=8.4Hz,1H),7.96(d,J=8.4Hz,1H),7.54(dd,J=8.3,4.1Hz,1H),7.26(d,J=2.1H z,1H),7.09(dd,J=8.4,2.0Hz,1H),4.96(t,J=5.6Hz,1H),3.98-3.62(m,4H),3.47-3 .30(m,4H),3.04(t,J=5.2Hz,4H),2.27-2.03(m,4H),1.65-1.47(m,4H),0.34(s,4H).

[0506] Example 74: N-(7-cyano-8-(4,4-difluoropiperidin-1-yl)quinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0507] Example 74 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =625.4;1H NMR (400MHz, DMSO) δ11.71(s,1H),10.19(s,1H),8.91(dd,J=4.0,1.6Hz,1H),8.40(dd,J= 8.4,2.0Hz,1H),8.26(s,1H),7.92(d,J=8.4Hz,1H),7.64(dd,J=8.4,4.0Hz,1H),7.24(d,J =2.0Hz,1H),7.08(dd,J=8.4,2.0Hz,1H),4.96(d,J=5.6Hz,1H),3.79-3.62(m,6H),3.38( t,J=6.4Hz,2H),3.04(t,J=5.2Hz,4H),2.28-2.14(m,4H),1.58-1.47(m,4H),0.34(s,4H).

[0508] Example 75: N-(8-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-methylquinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0509] Example 75 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =632.4. 1H NMR (400MHz, DMSO) δ12.40(d,J=2.5Hz,1H),10.21(s,1H),8.66(d,J=7.9Hz,1H),8.19(d,J=8 .4Hz,1H),8.04(d,J=8.6Hz,1H),7.37(d,J=8.3Hz,1H),7.30(d,J=2.1Hz,1H),7.14(dd,J=8. 6,2.1Hz,1H),4.95(s,1H),3.77(t,J=6.5Hz,2H),3.57(t,J=5.9Hz,4H),3.37(t,J=6.5Hz,2H ),2.99(t,J=5.2Hz,4H),2.66(s,3H),2.20(tt,J=14.3,5.6Hz,4H),1.60(s,4H),0.38(s,4H).

[0510] Example 76: N-(8-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-hydroxyquinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0511] Step 1: A solution containing 3-fluoro-2-iodo-1-nitrobenzene (25.00 g, 93.63 mmol), iron powder (10.00 g, 177.90 mmol), ammonium chloride (9.60 g, 177.90 mmol), ethanol (100 mL), and water (20 mL) was stirred at 60°C for 1 hour. The reaction mixture was filtered while hot and concentrated, then extracted with ethyl acetate (100 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether gradient) to obtain 3-fluoro-2-iodoaniline (22.00 g, 92.82 mmol, yield: 99.1%) as a white solid. LCMS (ESI): [M+H] + =238.0

[0512] Step 2: N-bromosuccinimide (16.50 g, 92.82 mmol) was added to a solution containing 3-fluoro-2-iodoaniline (22.00 g, 92.82 mmol) and N,N-dimethylformamide (200 mL). The reaction solution was stirred at 20°C for 1 hour, poured into water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to obtain the compound 4-bromo-3-fluoro-2-iodoaniline (21.50 g, 68.06 mmol, yield: 73.3%) as a gray solid. LCMS (ESI): [M+H] + =317.9

[0513] Step 3: 3-Ethoxyacryloyl chloride (9.00 g, 66.48 mmol) was added to a solution containing 4-bromo-3-fluoro-2-iodoaniline (21.00 g, 66.48 mmol), N,N-diisopropylethylamine (26.30 g, 199.42 mmol), and tetrahydrofuran (210 mL). The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to obtain compound (E)-N-(4-bromo-3-fluoro-2-iodophenyl)-3-ethoxyacrylamide (15.00 g, 36.23 mmol, yield: 54.5%) as a yellow solid. LCMS (ESI): [M+H] + =416.1

[0514] Step 4: A solution containing (2E)-N-(4-bromo-2-fluoro-2-iodophenyl)-3-methoxypropyl-2-enamide (15.00 g, 36.23 mmol) and concentrated sulfuric acid (100 mL) was stirred at 20°C for 12 hours. The reaction mixture was poured into ice water and filtered to obtain the compound 6-bromo-7-fluoro-8-iodoquinolin-2(1H)-one (12.00 g, 32.61 mmol, yield: 90.0%) as a yellow solid. LCMS (ESI): [M+H] + =369.9

[0515] Step 5: A reaction mixture containing 6-bromo-7-fluoro-8-iodoquinolin-2(1H)-one (12.00 g, 32.61 mmol) and phosphorus oxychloride (80 mL) was stirred at 25°C for 2 hours. The reaction mixture was concentrated, poured into water (30 mL), and filtered to obtain 6-bromo-2-chloro-7-fluoro-8-iodoquinoline (9.00 g, 23.29 mmol, yield: 71.4%) as a yellow solid. LCMS (ESI): [M+H] + =385.9

[0516] Step 6: A reaction mixture containing 6-bromo-2-chloro-7-fluoro-8-iodoquinoline (1.00 g, 2.59 mmol), sodium methoxide (30%) (2.30 g, 12.94 mmol), and methanol (10 mL) was stirred at 20°C for 12 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to obtain 6-bromo-7-fluoro-8-iodo-2-methoxyquinoline (800 mg, 2.09 mmol, yield: 80.9%) as a yellow solid. LCMS (ESI): [M+H] + =383.9

[0517] Step 7: Under nitrogen atmosphere, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (124 mg, 0.21 mmol) and tris(dibenzylideneacetone)dipalladium (196 mg, 0.21 mmol) were added to a mixed solution containing 6-bromo-7-fluoro-8-iodo-2-methoxyquinoline (800 mg, 2.09 mmol), 4,4-difluoropiperidine hydrochloride (367 mg, 2.30 mmol), cesium carbonate (2.10 g, 6.28 mmol) and 1,4-dioxane (10 mL). The reaction mixture was stirred at 100 ° C for 12 hours, and the reaction mixture was poured into water (30 mL) and washed with ethyl acetate (30 mL x 10 mL). 3) Extraction, drying the organic phase over anhydrous sodium sulfate, filtration, and concentration followed by purification by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) afforded the compound 6-bromo-8-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-methoxyquinoline (600 mg, 1.60 mmol, yield: 76.4%) as a yellow solid. LCMS (ESI): [M+H] + =377.1

[0518] Step 8: Under nitrogen atmosphere, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (94 mg, 0.16 mmol) and tris(dibenzylideneacetone)dipalladium (149 mg, 0.16 mmol) were added to a solution containing 6-bromo-8-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-methoxyquinoline (600 mg, 1.60 mmol), tert-butyl carbamate (227 mg, 1.92 mmol), cesium carbonate (1.60 g, 4.80 mmol) and 1,4-dioxane (10 mL). The reaction solution was stirred at 100 ° C for 12 hours, the reaction solution was poured into water (30 mL), and washed with ethyl acetate (30 mL x 10 mL). 3) Extraction, drying the organic phase over anhydrous sodium sulfate, filtration, and concentration followed by purification by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) afforded the compound N-[8-(4,4-difluoropiperidinyl)-7-fluoro-2-methoxy(6-quinolinyl)](tert-butoxy)formamide (400 mg, 0.97 mmol, yield: 60.8%) as a yellow solid. LCMS (ESI): [M+H] + =412.3

[0519] Step 9: A reaction mixture containing N-[8-(4,4-difluoropiperidinyl)-7-fluoro-2-methoxy(6-quinolinyl)](tert-butoxy)formamide (400 mg, 0.97 mmol) and trifluoroacetic acid (2 mL) was stirred at 20°C for 1 hour. After concentration, the reaction mixture was adjusted to pH 8 by adding saturated aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford 8-(4,4-difluoropiperidinyl)-7-fluoro-2-methoxy-6-quinolinamine (300 mg, crude) as a yellow solid. LCMS (ESI): [M+H] + =312.1

[0520] Step 10: 2-(6-azaspiro[2.5]octan-6-yl)-4-bromobenzoyl chloride (380 mg, 1.16 mmol) was added to a solution containing 8-(4,4-difluoropiperidinyl)-7-fluoro-2-methoxy-6-quinolinamine (300 mg, 0.96 mmol), N,N-diisopropylethylamine (635 mg, 4.82 mmol) and tetrahydrofuran (5 mL). The reaction solution was stirred at 20 ° C for 12 hours, poured into water (30 mL) and washed with ethyl acetate (30 mL x 10% acetic acid). 3) Extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to obtain the compound [2-(6-azaspiro[2.5]octan-6-yl)-4-bromophenyl]-N-[8-(4,4-difluoropiperidinyl)-7-fluoro-2-methoxy(6-quinolinyl)]carboxamide (260 mg, 0.43 mmol, yield: 44.7%) as a yellow solid. LCMS (ESI): [M+H] + =603.3

[0521] Step 11: A solution containing [2-(6-azaspiro[2.5]octan-6-yl)-4-bromophenyl]-N-[8-(4,4-difluoropiperidinyl)-7-fluoro-2-methoxy(6-quinolinyl)]formamide (200 mg, 0.33 mmol), pyridine hydrochloride (391 mg, 3.31 mmol), and N,N-dimethylformamide (5 mL) was stirred at 100°C for 12 hours. The reaction mixture was filtered to obtain 4-bromo-N-(8-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-hydroxyquinolin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (140 mg, 0.24 mmol, yield: 71.7%) as a white solid. LCMS (ESI): [M+H] + =589.1

[0522] Step 12: A reaction solution containing [2-(6-azaspiro[2.5]octan-6-yl)-4-bromophenyl]-N-[8-(4,4-difluoropiperidinyl)-7-fluoro-2-hydroxy(6-quinolinyl)]formamide (140 mg, 0.24 mmol), 2-hydroxyethanesulfonamide (45 mg, 0.36 mmol), potassium phosphate (154 mg, 0.71 mmol), cuprous iodide (46 mg, 0.24 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (34 mg, 0.24 mmol) and 1,4-dioxane (5 mL) was stirred at 100°C for 12 hours under nitrogen atmosphere. The reaction solution was poured into water (20 mL) and washed with ethyl acetate (20 mL x 10% ethanol). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography (C18, 0-100% acetonitrile / water gradient) to obtain the compound N-(8-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-hydroxyquinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (22.2 mg, 0.035 mmol, yield: 14.8%) as a white solid. LCMS (ESI): [M+H] + =634.4, 1 H NMR (400MHz, DMSO) δ12.30(s,1H),10.90(s,1H),8.62(s,1H),8.04–7.97(m,1H),7.95(d,J=9.6Hz,1H),7.26-6.98(m,2H),7.08(s,1H),6.52( d,J=9.6Hz,1H),3.76(t,J=6.0Hz,2H),3.23-2.97(m,4H),2.87-2.76( m,4H),2.72-2.58(m,2H),2.06–1.97(m,4H),1.57(s,4H),0.37(s,4H).

[0523] Example 77: N-(8-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-methoxyquinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0524] Step 1: A reaction solution containing [2-(6-azaspiro[2.5]octan-6-yl)-4-bromophenyl]-N-[8-(4,4-difluoropiperidinyl)-7-fluoro-2-methoxy(6-quinolinyl)]formamide (40 mg, 0.07 mmol), 2-hydroxyethanesulfonamide (13 mg, 0.10 mmol), potassium phosphate (43 mg, 0.20 mmol), cuprous iodide (13 mg, 0.066 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (10 mg, 0.066 mmol) and 1,4-dioxane (5 mL) was stirred under nitrogen for 12 h. The reaction solution was poured into water (20 mL) and washed with ethyl acetate (20 mL x 10% ethanol). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by flash column chromatography (C18, 0-100% gradient of acetonitrile / water) to obtain the compound N-(8-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-methoxyquinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (4.0 mg, 6.2 umol, yield: 9.3%) as a white solid. LCMS (ESI): [M+H] + =648.4; 1 H NMR (400MHz, DMSO) δ12.38–12.32(m,1H),10.21(s,1H),8.67(d,J=8.0Hz,1H),8.23(d, J=8.8Hz,1H),8.05(d,J=8.4Hz,1H),7.31(d,J=2.0Hz,1H),7.15(dd,J=8.4,2.0Hz,1H), 7.01(d,J=8.8Hz,1H),4.99(s,1H),4.02(s,3H),3.79(t,J=6.4Hz,2H),3.58(t,J=5.6H z,4H),3.37(s,2H),3.01(t,J=5.2Hz,4H),2.26-2.15(m,4H),1.61(s,4H),0.40(s,4H).

[0525] Example 78: N-(2-amino-8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0526] Step 1: A reaction mixture containing 6-bromo-2-chloro-7-fluoro-8-iodoquinoline (1.00 g, 2.59 mmol), p-methoxybenzylamine (2.30 g, 12.94 mmol), N,N-diisopropylethylamine (3.10 g, 23.29 mmol), and acetonitrile (30 mL) was stirred at 60°C for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether gradient) to obtain 6-bromo-7-fluoro-8-iodo-N-(4-methoxybenzyl)quinolin-2-amine (1.20 g, 2.46 mmol, yield: 31.7%) as a yellow solid. LCMS (ESI): [M+H] + =487.0

[0527] Step 2: Under nitrogen atmosphere, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (145 mg, 0.25 mmol) and tris(dibenzylideneacetone)dipalladium (230 mg, 0.25 mmol) were added to a mixed solution containing 6-bromo-7-fluoro-8-iodo-N-(4-methoxybenzyl)quinolin-2-amine (1.20 g, 2.46 mmol), 4,4-difluoropiperidine hydrochloride (431 mg, 2.71 mmol), cesium carbonate (2.50 g, 7.39 mmol) and 1,4-dioxane (20 mL). The reaction mixture was stirred at 100 ° C for 12 hours, and the reaction mixture was poured into water (30 mL) and washed with ethyl acetate (30 mL x 10% ethanol). 3) Extraction, drying the organic phase over anhydrous sodium sulfate, filtration, and concentration followed by purification by column chromatography (silica gel, 0-40% gradient of ethyl acetate / petroleum ether) afforded the compound 6-bromo-8-(4,4-difluoropiperidin-1-yl)-7-fluoro-N-(4-methoxybenzyl)quinolin-2-amine (400 mg, 0.83 mmol, yield: 33.8%) as a yellow solid. LCMS (ESI): [M+H] + =480.2

[0528] Step 3: Under nitrogen atmosphere, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (43 mg, 0.073 mmol) and tris(dibenzylideneacetone)dipalladium (68 mg, 0.073 mmol) were added to a solution containing 6-bromo-8-(4,4-difluoropiperidin-1-yl)-7-fluoro-N-(4-methoxybenzyl)quinolin-2-amine (350 mg, 0.73 mmol), tert-butyl carbamate (103 mg, 0.87 mmol), cesium carbonate (727 mg, 2.19 mmol) and 1,,4-dioxane (5 mL). The reaction solution was stirred at 100 ° C for 12 hours, the reaction solution was poured into water (30 mL), and washed with ethyl acetate (30 mL x 40 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to obtain tert-butyl (8-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-((4-methoxybenzyl)amino)quinolin-6-yl)carbamate (240 mg, 0.46 mmol, yield: 63.8%) as a yellow solid. LCMS (ESI): [M+H] + =517.3

[0529] Step 4: A reaction mixture containing tert-butyl (8-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-((4-methoxybenzyl)amino)quinolin-6-yl)carbamate (240 mg, 0.46 mmol) and trifluoroacetic acid (2 mL) was stirred at 20°C for 1 hour. The reaction mixture was concentrated and the pH was adjusted to approximately 8 by adding saturated aqueous sodium bicarbonate. The mixture was then extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford 8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinoline-2,6-diamine (140 mg, crude) as a yellow solid. LCMS (ESI): [M+H] + =297.1

[0530] Step 5: 2-(6-azaspiro[2.5]octan-6-yl)-4-bromobenzoyl chloride (186 mg, 0.57 mmol) was added to a solution containing 8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinoline-2,6-diamine (140 mg, 0.47 mmol), N,N-diisopropylethylamine (312 mg, 2.36 mmol) and tetrahydrofuran (5 mL). The reaction solution was stirred at 20 ° C for 12 hours, poured into water (30 mL) and washed with ethyl acetate (30 mL x 10% acetic acid). 3) Extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound N-(2-amino-8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)-4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (80 mg, 0.14 mmol, yield: 28.8%) as a yellow solid. LCMS (ESI): [M+H] + =590.3

[0531] Step 6: A reaction mixture containing N-(2-amino-8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)-4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (80 mg, 0.14 mmol), 2-hydroxyethanesulfonamide (26 mg, 0.20 mmol), potassium phosphate (88 mg, 0.41 mmol), cuprous iodide (26 mg, 0.14 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (20 mg, 0.14 mmol) and 1,4-dioxane (5 mL) was stirred at 100 °C under nitrogen atmosphere for 12 h. The reaction mixture was poured into water (20 mL) and washed with ethyl acetate (20 mL x 4 ). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash column chromatography (C18, 0-100% gradient of acetonitrile / water) to obtain the compound N-(2-amino-8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (3.60 mg, 5.7 umol, yield: 4.2%) as a yellow solid. LCMS (ESI): [M+H] + =633.4, 1H NMR (400MHz, DMSO) δ12.19(s,1H),10.21(s,1H),8.43(s,1H),8.01(d,J=8.4 Hz,1H),7.29(d,J=2.0Hz,1H),7.13(dd,J=8.4,2.0Hz,1H),6.76(s,3H),6.40 (s,1H),4.94(t,J=5.6Hz,1H),3.78–3.76(m,2H),3.32-3.27(m,4H),3.15(t ,J=6.8Hz,2H),2.97(d,J=5.6Hz,4H),2.17(s,4H),1.58(s,4H),0.37(s,4H).

[0532] Example 79: N-(8-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-(methylamino)quinolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0533] Example 79 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H]+=647.4; 1H NMR (400 MHz, DMSO) δ12.10 (s, 1H), 10.16 (s, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.27 (d, J=2.4 Hz, 1H), 7.11 (dd, J=8.4, 2.0 Hz, 1H), 7.06 (d,J=4.8Hz,1H),6.71(d,J=8.8Hz,1H),4.94(t,J=5.6Hz,1H),3.76(q,J=6.4Hz,2H),3.54(d,J=5.6Hz,4H),3.36(d ,J=6.4Hz,2H),2.98(d,J=5.2Hz,4H),2.91(d,J=4.8Hz,3H),2.16(q,J=15.2,13.6Hz,4H),1.58(s,4H),0.37(s,4H).

[0534] Example 80: N-(8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl)-6-((2-hydroxyethyl)sulfonamido)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide

[0535] Example 80 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =619.4,1 H NMR (400MHz, DMSO) δ10.69(s,1H),8.84(dd,J=4.0,1.6Hz,1H),8.43(d,J=7.6Hz,1H),8.38–8.30(m,1H),8.23(s,1H),7.50(dd,J=8.4,4.0Hz,1H ),6.66(s,1H),3.78(t,J=6.8Hz,2H),3.55(t,J=5.6Hz,4H),3.42(s,2H ),3.23–3.05(m,4H),2.26–2.08(m,4H),1.52–1.44(m,4H),0.34(s,4H).

[0536] Example 81: N-(8-(4,4-difluoropiperidin-1-yl)isoquinolin-6-yl)-4-(2-hydroxyethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0537] Example 81 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =600.4, 1 H NMR (400MHz, DMSO) δ11.96(s,1H),10.18(s,1H),9.18(s,1H),8.26(d,J=5.8Hz,1H),8.11(d,J=1.6Hz ,1H),7.68(d,J=8.4Hz,1H),7.56(d,J=5.6Hz,1H),7.22(d,J=1.8Hz,1H),6.99(d,J=2.0Hz,1H),6.86 (dd,J=8.4,2.1Hz,1H),5.28–4.88(m,1H),3.60(t,J=6.4Hz,2H),3.17(s,2H),3.10(dd,J=26.0,6.2H z,4H),2.83(t,J=5.2Hz,4H),2.15(tt,J=13.6,11.6,5.4Hz,4H),1.41(t,J=5.2Hz,4H),0.18(s,4H).

[0538] Example 82: 2-{6-Azaspiro[2.5]octan-6-yl}-N-[8-(4,4-difluoropiperidin-1-yl)cinnolin-6-yl]-4-(2-hydroxyethanesulfonylamino)benzamide

[0539] Example 82 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H]+=601.2,1 H NMR(400MHz,DMSO-d6)δppm 12.06(s,1H),10.15(s,1H),9.24(br s,1H),8.24(s,1H),8.12(br s,1H),7.84(d,J=8.4Hz,1H),7.35(s,1H),7.18(s,1H),7.06(dd,J=1.6,8.4Hz,1H),5.53-4.23(m,1H),3.77(t,J=6. 4Hz,2H),3.72-3.64(m,4H),3.42-3.39(m,2H),3.07-2.94(m,4H),2.33-2.22(m,4H),1.64-1.52(m,4H),0.35(s,4H)

[0540] Example 83: N-(8-(4,4-difluoropiperidin-1-yl)quinoxalin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0541] Example 83 was prepared by a similar synthetic route according to Example 3: LCMS (ESI): [M+H] + =601.4. 1 H NMR (400MHz, CDCl3) δ12.95(s,1H),8.80(d,J=1.9Hz,1H),8.69(d,J=1.9Hz,1H),8.21(d,J=8.6Hz,1H),7.98(d,J=2.1Hz,1 H),7.91(d,J=2.2Hz,1H),7.39(d,J=2.2Hz,1H),7.15(dd,J=8.6,2.1Hz,1H),4.02(t,J=5.6Hz,2H),3.59(t,J=5.7Hz,4H), 3.33(s,2H),3.11(t,J=5.4Hz,4H),2.31(tt,J=12.9,5.5Hz,4H),1.71(s,4H),0.45(s,4H).

[0542] Example 84: N-(2-amino-8-(4,4-difluoropiperidin-1-yl)quinazolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0543] Step 1: 3-Fluoro-2-nitrobenzaldehyde (5.00 g, 28.68 mmol), ethylene glycol (2.68 g, 43.01 mmol), and p-toluenesulfonic acid monohydrate (278 mg, 1.43 mmol) were added to toluene (40 mL), and the reaction mixture was stirred at 100°C for 4 hours. The reaction mixture was poured into water (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 subjected to flash column chromatography (silica gel, 10-25% gradient of ethyl acetate / petroleum ether) to afford 2-(3-fluoro-2-nitrophenyl)-1,3-dioxolane (6.40 g, crude) as a light yellow oil. LCMS (ESI): [M+H] + =214.1

[0544] Step 2: 2-(3-Fluoro-2-nitrophenyl)-1,3-dioxolane (5.10 g, 23.93 mmol), 4,4-difluoropiperidine hydrochloride (5.71 g, 35.89 mmol), and potassium carbonate (8.43 g, 59.81 mmol) were added to dimethyl sulfoxide (40 mL), and the reaction solution was stirred at 130°C for 16 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated to give 1-(3-(1,3-dioxolan-2-yl)-2-nitrophenyl)-4,4-difluoropiperidine (6.00 g, crude product). LCMS (ESI): [M+H] + =315.2

[0545] Step 3: 1-(3-(1,3-dioxolan-2-yl)-2-nitrophenyl)-4,4-difluoropiperidine (5.00 g, 15.91 mmol), ammonium chloride (1.72 g, 31.82 mmol), and iron powder (4.49 g, 79.54 mmol) were added to tetrahydrofuran (20 mL), ethanol (20 mL), and water (5 mL). The reaction mixture was heated to 80°C for 16 hours. The reaction mixture was filtered, the filtrate 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. Flash column chromatography (silica gel, 0-9% ethyl acetate / petroleum ether gradient) of the crude product afforded 2-amino-3-(4,4-difluoropiperidin-1-yl)benzaldehyde (2.10 g, 8.75 mmol, yield: 54.9%) as a yellow solid. LCMS(ESI):[M+H] + =241.1

[0546] Step 4: 2-Amino-3-(4,4-difluoropiperidin-1-yl)benzaldehyde (1.80 g, 7.49 mmol) was added to N,N-dimethylformamide (15 mL). N-bromosuccinimide (1.47 g, 8.24 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was subjected to flash column chromatography (silica gel, 0-9% gradient of ethyl acetate / petroleum ether) to afford 2-amino-5-bromo-3-(4,4-difluoropiperidin-1-yl)benzaldehyde (1.60 g, 5.01 mmol, yield: 66.9%) as a yellow solid. LCMS (ESI): [M+H] + =319.1

[0547] Step 5: 2-Amino-5-bromo-3-(4,4-difluoropiperidin-1-yl)benzaldehyde (1.60 g, 5.01 mmol) and guanidine carbonate (9.12 g, 50.13 mmol) were added to N,N-dimethylacetamide (10 mL). The reaction mixture was heated to 130°C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and filtered. The solid was dried to obtain 6-bromo-8-(4,4-difluoropiperidin-1-yl)quinazolin-2-amine (1.60 g, 4.66 mmol, yield: 93.0%) as a yellow solid. LCMS (ESI): [M+H] + =343.1; 1 H NMR (400MHz, DMSO-d6) δ9.82(s,1H),7.59(d,J=2.2Hz,1H),7.30(d,J=2.3Hz,1H),6.98(s,2H),2.91(s,4H),2.29–2.06(m,4H).

[0548] Step 6: 6-Bromo-8-(4,4-difluoropiperidin-1-yl)quinazolin-2-amine (1.45 g, 4.22 mmol), di-tert-butyl dicarbonate (4.61 g, 21.13 mmol), 4-dimethylaminopyridine (105 mg, 0.85 mmol), and triethylamine (2.18 g, 21.13 mmol) were added to dichloromethane (20 mL). The reaction mixture was stirred at 50°C for 4 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (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, 0-9% gradient of ethyl acetate / petroleum ether) to afford tert-butyl (6-bromo-8-(4,4-difluoropiperidin-1-yl)quinazolin-2-yl)(tert-butoxycarbonyl)carbamate (1.72 g, 3.16 mmol, yield: 74.9%) as a light yellow solid. LCMS (ESI): [M+H] + =369.1; 1 H NMR (400MHz, Chloroform-d) δ9.22 (s, 1H), 7.64 (d, J = 2.0Hz, 1H), 7.28 (d, J = 2.0Hz, 1H), 3.54 (t, J = 5.5Hz, 4H), 2.24 (tt, J = 13.2, 5.3Hz, 4H), 1.50 (s, 18H).

[0549] Step 7: Under a nitrogen atmosphere, tert-butyl (6-bromo-8-(4,4-difluoropiperidin-1-yl)quinazolin-2-yl)(tert-butoxycarbonyl) carbamate (1.00 g, 1.84 mmol), tert-butyl carbamate (653 mg, 5.52 mmol), methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2'-amino-1,1'-biphenyl] palladium (II) dichloromethane adduct (178 mg, 0.18 mmol), and cesium carbonate (1.23 g, 3.68 mmol) were added to 1,4-dioxane (10 mL). After nitrogen replacement, the reaction solution was heated to 110°C and stirred for 3 hours. The reaction solution 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, 10-25% gradient of ethyl acetate / petroleum ether) to afford tert-butyl(tert-butoxycarbonyl)(6-(tert-butoxycarbonyl)amino)-8-(4,4-difluoropiperidin-1-yl)quinazolin-2-yl)carbamate (800 mg, 1.38 mmol, yield: 75.0%) as a yellow solid. LCMS (ESI): [M+H] + =580.6

[0550] Step 8: tert-Butyl(tert-butoxycarbonyl)(6-(tert-butoxycarbonyl)amino)-8-(4,4-difluoropiperidin-1-yl)quinazolin-2-yl)carbamate (1.00 g, 1.72 mmol) was added to a mixture of dichloromethane (5 mL) and trifluoroacetic acid (5 mL). The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated to obtain a crude product, which was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 8-(4,4-difluoropiperidin-1-yl)quinazoline-2,6-diamine (200 mg, 0.72 mmol, yield: 41.5%) as a green solid. LCMS (ESI): [M+H] + =280.4; 1 H NMR (400MHz, DMSO-d6) δ8.73(s,1H),6.66(d,J=2.3Hz,1H),6.37(d,J=2.2Hz,1 H),6.14(s,2H),5.05(s,2H),3.34(s,4H),2.17(td,J=14.1,13.5,6.4Hz,4H).

[0551] Step 9: 8-(4,4-Difluoropiperidin-1-yl)quinazoline-2,6-diamine (200 mg, 0.72 mmol), N,N-diisopropylethylamine (236 mg, 1.79 mmol), and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (471 mg, 1.43 mmol) were added to dichloromethane (5 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was subjected to flash column chromatography (silica gel, 25-50% ethyl acetate / dichloromethane gradient) to afford N-(2-amino-8-(4,4-difluoropiperidin-1-yl)quinazolin-6-yl)-4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (190 mg, 0.33 mmol, yield: 46.4%) as a blue-green solid. LCMS (ESI): [M+H] + =573.3

[0552] Step 10: Under nitrogen atmosphere, N-(2-amino-8-(4,4-difluoropiperidin-1-yl)quinazolin-6-yl)-4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (60 mg, 0.10 mmol), 2-hydroxyethanesulfonamide (27 mg, 0.21 mmol), potassium phosphate (91 mg, 0.42 mmol), cuprous iodide (41 mg, 0.21 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (60 mg, 0.42 mmol) were added to N-dimethylformamide (1 mL), the atmosphere was replaced with nitrogen, and the reaction solution was stirred at 115 ° C for 2 hours. The reaction mixture was filtered, and the filtrate was poured into a saturated ammonium chloride solution (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Flash column chromatography (C18, 25-45% gradient of acetonitrile / water) of the crude product afforded N-(2-amino-8-(4,4-difluoropiperidin-1-yl)quinazolin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (15 mg, 0.105 mmol, yield: 23.2%) as a gray-green solid. LCMS (ESI): [M+H] + =616.6; 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),9.02(s,1H),8.08(s,1H),7.85(d,J=7.2Hz,1H),7.14(d,J=95.5Hz,3H),6.64(s,2H), 3.75(d,J=6.0Hz,2H),3.45(d,J=5.5Hz,6H),2.98(t,J=5.0Hz,4H),2.21(dd,J=16.6,10.2Hz,4H),1.58(s,4H),0.35(s,4H).

[0553] Example 85: N-(8-(4,4-difluoropiperidin-1-yl)-3-(dimethylphosphoryl)quinolin-6-yl)-4-(2-hydroxyethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0554] Step 1: To a mixture of concentrated sulfuric acid (20 mL) and water (15 mL) was added glycerol (63.00 g, 684.17 mmol). The mixture was heated to 100°C and stirred for 15 minutes. After cooling the mixture to 40°C, 4-bromo-2-fluoroaniline (10.00 g, 52.63 mmol) and 3-nitrobenzenesulfonic acid sodium salt (11.96 g, 52.63 mmol) were added to the mixture. The mixture was heated to 100°C and stirred for 15 hours. After the reaction was completed, the reaction mixture was added to 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, 0-25% ethyl acetate / petroleum ether gradient) to afford 6-bromo-8-fluoroquinoline (10.00 g, 44.25 mmol, yield: 84.0%) as a yellow solid. LCMS(ESI):[M+H] + =226.0

[0555] Step 2: To a solution of 6-bromo-8-fluoroquinoline (8.00 g, 35.39 mmol) in acetic acid (80 mL) was added N-iodosuccinimide (11.94 g, 53.08 mmol). The mixture was heated to 120°C and stirred for 36 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were combined and washed with a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-20% ethyl acetate / petroleum ether gradient) to afford 6-bromo-8-fluoro-3-iodoquinoline (4.20 g, 11.93 mmol, yield: 33.7%) as a yellow solid. LCMS (ESI): [M+H] + =351.9; 1 HNMR (400MHz, DMSO) δ9.12(d,J=2.0Hz,1H),8.92(t,J=1.7Hz,1H),8.07(t,J=1.6Hz,1H),7.92(dd,J=10.2,2.1Hz,1H).

[0556] Step 3: To a solution of 6-bromo-8-fluoro-3-iodoquinoline (4.00 g, 11.36 mmol) and 4,4-difluoropiperidine hydrochloride (2.71 g, 17.05 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (4.81 g, 34.09 mmol), and the mixture was stirred at 100°C for 24 hours. After the reaction was complete, water (40 mL) was added to the reaction mixture, and the mixture 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 dryness to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to obtain 8-(4,4-difluoropiperidinyl)-6-bromo-3-iodoquinoline (4.20 g, 9.27 mmol, yield: 81.6%) as a yellow solid. LCMS (ESI): [M+H] + =453.0

[0557] Step 4: Under a nitrogen atmosphere, to a solution of 8-(4,4-difluoropiperidinyl)-6-bromo-3-iodoquinoline (2.00 g, 4.41 mmol) and dimethylphosphine oxide (344 mg, 4.41 mmol) in ethanol (20 mL) were added triphenylphosphine (231 mg, 0.88 mmol), palladium acetate (101 mg, 0.44 mmol), and triethylamine (1367 mg, 13.24 mmol). The mixture was stirred at 80°C for 6 hours. After the reaction was complete, water (40 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (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 column chromatography (silica gel, 0-20% gradient of methanol / dichloromethane) to give 6-bromo-8-(4,4-difluoropiperidin-1-yl)quinolin-3-yl)dimethylphosphine oxide (1.10 g, 2.73 mmol, yield: 61.8%) as a yellow solid. LCMS (ESI): [M+H] + =403.1; 1 HNMR(400MHz,DMSO)δ9.16(dd,J=4.2,2.0Hz,1H),8.71(dd,J=12.5,2.1Hz,1H),7.94(d,J=2.0Hz,1H ), 7.34 (d, J = 2.1Hz, 1H), 3.53 (t, J = 5.7Hz, 4H), 2.20 (td, J = 14.0, 6.9Hz, 4H), 1.80 (d, J = 13.6Hz, 6H).

[0558] Step 5: Under nitrogen atmosphere, 6-bromo-8-(4,4-difluoropiperidin-1-yl)quinolin-3-yl)dimethylphosphine oxide (1.00 g, 2.48 mmol), tert-butyl carbamate (435 mg, 3.72 mmol), tris(dibenzylideneacetone)dipalladium (227 mg, 0.25 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (287 mg, 0.50 mmol), cesium carbonate (2.42 g, 7.44 mmol) were placed in a bottle, 1,4-dioxane (10 mg, 4% HCl) and 1% ethanol. L) was added to the reaction flask, and the mixture was stirred at 110°C for 8 hours. After the reaction, the mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (silica gel, 0-10% gradient of methanol / dichloromethane) to obtain tert-butyl (8-(4,4-difluoropiperidin-1-yl)-3-(dimethylphosphoryl)quinolin-6-yl)carbamate (600 mg, 1.36 mmol, yield: 55.0%) as a yellow solid. LCMS (ESI): [M+H] + =440.3

[0559] Step 6: Dissolve tert-butyl (8-(4,4-difluoropiperidin-1-yl)-3-(dimethylphosphoryl)quinolin-6-yl)carbamate (500 mg, 1.13 mmol) in dichloromethane (5 mL) and add trifluoroacetic acid (2.5 mL) dropwise. The reaction mixture is stirred at 25°C for 5 hours. The solvent is removed under reduced pressure, and the residue is dissolved in water (10 mL). The aqueous layer is then adjusted to pH 8 with saturated aqueous sodium bicarbonate (40 mL) and extracted with dichloromethane (50 mL x 3). The organic phases are combined, washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6-amino-8-(4,4-difluoropiperidin-1-yl)quinolin-3-yl)dimethylphosphine oxide (400 mg, 1.17 mmol, yield: 93.2%) as a green solid. LCMS (ESI): [M+H] + =340.2

[0560] Step 7: To a solution of 6-amino-8-(4,4-difluoropiperidin-1-yl)quinolin-3-yl)dimethylphosphine oxide (400 mg, 1.17 mmol) and 2-(6-azaspiro[2.5]octan-6-yl)-4-bromobenzoic acid (402 mg, 1.30 mmol) in dichloromethane (8 mL) were added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (686 mg, 1.77 mmol) and N,N-diisopropylethylamine (466 mg, 3.54 mmol). The mixture was stirred at 100°C for 24 hours. After the reaction was complete, water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (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, 0-20% gradient of methanol / dichloromethane) to give 4-bromo-N-(8-(4,4-difluoropiperidin-1-yl)-3-(dimethylphosphoryl)quinolin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (500 mg, 0.792 mmol, yield: 67.2%) as a yellow solid. LCMS (ESI): [M+H] + =631.3

[0561] Step 8: Under a nitrogen atmosphere, 2-hydroxyethanesulfonamide (61 mg, 0.47 mmol), cuprous iodide (61 mg, 0.32 mmol), potassium phosphate (274 mg, 1.27 mmol) and trans-N, N'-dimethylcyclohexane-1,2-diamine (91 mg, 0.63 mmol) were placed in a bottle, N, N-dimethylformamide (4 mL) was added to the reaction bottle, and the mixture was stirred at 50 ° C for 0.5 hours. Then, 4-bromo-N-(8-(4,4-difluoropiperidin-1-yl)-3-(dimethylphosphoryl)quinolin-6-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (200 mg, 0.32 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 5 hours. After the reaction was complete, the system was cooled to room temperature and poured into water (10 mL). The mixture was extracted with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC (C18, 0-100% acetonitrile / water gradient) to afford N-(8-(4,4-difluoropiperidin-1-yl)-3-(dimethylphosphoryl)quinolin-6-yl)-4-(2-hydroxyethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (105 mg, 0.15 mmol, yield: 49.0%) as a white solid. LCMS (ESI) m / z: [M+H] +=676.4;1H NMR (400MHz, DMSO) δ11.94(s,1H),10.12(s,1H),9.02(dd,J=4.3,2.0Hz,1H),8.64(dd,J=12.7,2.0Hz ,1H),8.29(d,J=2.0Hz,1H),7.86(d,J=8.5Hz,1H),7.50(d,J=2.2Hz,1H),7.19(d,J=2.1Hz,1H),7.06 (dd,J=8.5,2.0Hz,1H),4.97(s,1H),3.77(ddt,J=8.0,6.1,2.0Hz,2H),3.55(t,J=5.6Hz,4H),3.35(t ,J=6.7Hz,2H),3.01(t,J=5.3Hz,4H),2.24(s,4H),1.80(d,J=13.5Hz,6H),1.58(s,4H),0.35(s,4H).

[0562] Example 86: Ethyl 6-(2-{6-azaspiro[2.5]octan-6-yl}-4-(2-hydroxyethanesulfonylamino)benzamido)-8-(4,4-difluoropiperidin-1-yl)quinoline-3-carboxylate

[0563] Step 1: Dissolve 2-amino-5-bromo-3-fluorobenzoic acid (5.00 g, 21.3 mmol) in tetrahydrofuran (50.0 mL). Add borane tetrahydrofuran (64.1 mL, 64.1 mmol) at 0°C under a nitrogen atmosphere and stir at 20-40°C for 48 hours. Quench the reaction with methanol (100 mL) at 0°C, and concentrate the reaction mixture under reduced pressure. The residue is purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / petroleum ether) to give (2-amino-5-bromo-3-fluorophenyl)methanol (4.48 g, 14.9 mmol, 70.0% yield) as a white solid. LCMS (ESI): [M+H] + =221.9; 1 H NMR (400MHz, DMSO-d6) δppm 7.19 (dd, J=2.4, 10.8Hz, 1H), 7.13 (s, 1H), 5.27 (t, J=5.6Hz, 1H), 5.07 (br s, 2H), 4.41 (d, J=5.6Hz, 2H)

[0564] Step 2: Dissolve (2-amino-5-bromo-3-fluorophenyl)methanol (4.28 g, 19.4 mmol) in 1,2-dichloroethane (84.0 mL), add manganese dioxide (19.7 g, 194 mmol), and stir at 25°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to yield 2-amino-5-bromo-3-fluorobenzaldehyde (4.00 g, 16.5 mmol, 85.0% yield) as a brown solid. LCMS (ESI): [M+H] + =220.0; 1 H NMR (400MHz, DMSO-d6) δppm 9.85 (s, 1H), 7.67 (br s, 1H), 7.58 (br d, J = 10.8Hz, 1H), 7.14 (br s, 2H)

[0565] Step...

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 -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl, 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 ; 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 It means having the following structural groups; 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 、-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 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 connected, they form 3-6 A saturated or unsaturated ring, which may 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 -O-halogenated C1-C6 alkyl.

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 -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl, 13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: L 1 It represents -C(O)NH-.

14. The compound according to claim 13 or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 1 Represents the following groups:

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: L 1 Represents: -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl, 16. The compound according to claim 15 or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: L 1 represents any one of the following groups:

17. The compound according to any one of claims 1 to 16, 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-.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: L 2 Indicates that it does not exist.

19. The compound according to any one of claims 1 to 18, 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 to 3 N heteroatoms and 0 to 2 O or S heteroatoms, and the monocyclic ring or cyclic ring is substituted by 0 to 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.

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: Cy 2 express:

21. A compound having the following structure: