Inhibitor of kinin KIF18A and application thereof

Abstract

Provided is a compound having a structure of formula (I) or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof. The compounds are capable of modulating the KIF18A protein, thereby affecting the cell cycle and cell proliferation processes to treat cancer and cancer-related diseases. Also provided are methods of synthesis of the compounds, 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 No. 202310475180.8, filed with the State Intellectual Property Office of China on April 27, 2023, entitled “Kinetic protein KIF18A inhibitors and their applications”, all contents of which are incorporated herein by reference. Technical Field

[0009] The present invention belongs to the field of medicine and relates to a class of kinesin KIF18A inhibitors and their use in inhibiting cancer cell proliferation and treating cancer. Background Art

[0010] KIF18A, a member of the kinesin-8 family of kinesins, uses the energy released by ATP hydrolysis to propel it along microtubules toward the positive pole within the cell. KIF18A is localized at the positive end of microtubules, where it regulates microtubule dynamic instability, exerting an activity similar to that of a microtubule depolymerase. During mitosis, KIF18A regulates spindle microtubule dynamics and chromosome amplitude, playing a key role in ensuring the timely alignment of chromosomes during mitosis, maintaining genomic stability, and enabling the successful completion of mitosis.

[0011] The KIF18A gene belongs to the kinesin-8 subfamily of kinesins and is a plus-end-directed motor. KIF18A is thought to affect the dynamics of the plus ends of centromere microtubules to control correct chromosome positioning and spindle tension. Depletion of human KIF18A in HeLa cervical cancer cells leads to longer spindles, increased chromosome oscillation in metaphase, and activation of the mitotic spindle assembly checkpoint (MI Mayr et al., Current Biology 17, 488–98, 2007). KIF18A appears to be a viable target for cancer therapy. KIF18A is overexpressed in many types of cancer, including but not limited to colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, and ovarian cancer. In addition, in cancer cell lines, gene deletion or knockout or KIF18A inhibition affects the mitotic spindle apparatus. In particular, inhibition of KIF18A has been found to induce mitotic cell arrest, a known vulnerability that can promote mitotic cell death by apoptosis, mitotic catastrophe, or multiphase-driven lethality or death following mitotic slippage in interphase. Consequently, there is intense interest in finding inhibitors of the KIF18A protein. Therefore, inhibition of KIF18A ATPase activity is a promising approach for developing new anticancer agents.

[0012] Summary of the Invention

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

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

[0015] The compounds provided herein have MT-based KIF18A modulatory activity, particularly KIF18A inhibitory activity. To this end, the present invention also provides the use of these compounds and pharmaceutically acceptable salts thereof in the preparation and manufacture of pharmaceutical compositions or medicaments for the therapeutic, prophylactic, acute or chronic treatment of KIF18A-mediated diseases and disorders (including but not limited to cancer).

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

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

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

[0019] Among them, W 3 Indicates CR W3 or N;

[0020] Among them, Z represents -CR T R T ' or -NR S R S ';

[0021] Among them, R T and R T ' together with the C atoms to which they are commonly attached form a ring having a structure selected from the following:

[0022] Among them, R S and R S ' together with the N atom to which it is commonly attached, form a ring having a structure selected from the following:

[0023] Among them, Y 1 、Y 2 、Y 3 Each independently represents -(CR a R b ) o -(NR a ) p -(CR a 'Rb ') q -;

[0024] Wherein, A and B each independently represent -(CR a R b ) m -;

[0025] Among them, L 1 represents -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl,

[0026] 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 )-;

[0027] Among them, R 1 Indicates L 3 -R 3 ;

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

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

[0030] Among them, R W1 、R W2 and R W3Each independently represents hydrogen, halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a , -SF5 or -NR a R b ;

[0031] Among them, Cy 1 represents a 6-12 membered aryl or a 5-12 membered heteroaryl; 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 ;

[0032] 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)Ra 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b ;

[0033] Wherein, Ring A represents a saturated or unsaturated 4-12 membered ring, preferably a 5-12 membered ring; and the ring may optionally contain 0-3 heteroatoms selected from O, N and S, and the Ring A may also be arbitrarily substituted with 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, halo 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 ;

[0034] 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;

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

[0036] In addition, the present invention provides a compound having a structure of formula (II) or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof:

[0037] Among them, W 1 Indicates CR W1 or N;

[0038] Among them, W 2 Indicates CR W2 or N;

[0039] Among them, Z represents -CR T R T' or -NR S R S' ;

[0040] 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:

[0041] 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:

[0042] Among them, Y 1 、Y 2 、Y 3 Each independently represents -(CR a R b ) o -(NR a ) p -(CR a' R b' ) q -;

[0043] Wherein, A and B each independently represent -(CR a R b ) m -;

[0044] Among them, L 1 represents -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl,

[0045] 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)(NRa )-;

[0046] Among them, R 1 Indicates L 3 -R 3 ;

[0047] 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;

[0048] Among them, R 3 Represents absence, hydrogen or 0-3 selected from halogen, -OR a 、-NR a R b , cyano and -O-halogenated C1-C6 alkyl groups substituted C1-C6 alkyl or C3-C6 cycloalkyl;

[0049] 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 ;

[0050] Among them, Cy 1 represents a 6-12 membered aryl or a 5-12 membered heteroaryl; 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)NRa 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 ;

[0051] 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 ;

[0052] Wherein, Ring A represents a saturated or unsaturated 4-12 membered ring, preferably a 5-12 membered ring; and the ring may optionally contain 0-3 heteroatoms selected from O, N and S, and the Ring A may also be arbitrarily substituted with 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, halo 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)Ra 、-S(O)2R a and -S(O)2NR a R b ;

[0053] 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;

[0054] Here, m, o, p, and q represent integers from 0 to 3.

[0055] In the preferred technical solution of the present invention, wherein W 1 Indicates CH or N.

[0056] In the preferred technical solution of the present invention, wherein W 2 Indicates CH or N.

[0057] In the preferred technical solution of the present invention, wherein L 3 Indicates -NR a SO2-、-SO2NR a -or-S(=O)(NR a )-.

[0058] In the preferred technical solution of the present invention, wherein L 3 Indicates -NR a SO2-.

[0059] In the preferred technical solution of the present invention, R 3 represents hydrogen or is selected from 0-3 halogens, -OR a 、-NR a R b C1-C6 alkyl or C3-C6 cycloalkyl substituted with -O-halogenated C1-C6 alkyl.

[0060] In the preferred technical solution of the present invention, R 3 It represents 0-3 selected from halogen, -OR a 、-NR aR b C1-C6 alkyl substituted with -O-halogenated C1-C6 alkyl.

[0061] In the preferred technical solution of the present invention, wherein Z represents -NR S R S' .

[0062] In the preferred technical solution of the present invention, Z represents:

[0063] 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.

[0064] 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.

[0065] In the preferred technical solution of the present invention, Z represents:

[0066] In the preferred technical solution of the present invention, wherein L 1 represents -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl,

[0067] In the preferred technical solution of the present invention, wherein L 1 It represents -C(O)NH-.

[0068] In the preferred technical solution of the present invention, wherein L 1 Represents: -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl,

[0069] In the preferred technical solution of the present invention, L 1 represents any of the following groups:

[0070] In the preferred technical solution of the present invention, wherein Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a 、-SF5、cyano、nitro、-NR a R b 、-NR a C(O)R b 、-C(O)NR a R b 、-OC(O)R a 、-C(O)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Any of the following groups substituted:

[0071] For example:

[0072] In the preferred technical solution of the present invention, wherein Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a 、-SF5、cyano、nitro、-NR a R b 、-NR a C(O)R b 、-C(O)NR a R b 、-OC(O)R a 、-C(O)R a 、-P(O)R a R b 、-C(O)ORa 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Any of the following groups substituted:

[0073] In the preferred technical solution of the present invention, wherein Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a 、-SF5、cyano、nitro、-NR a R b 、-NR a C(O)R b 、-C(O)NR a R b 、-OC(O)R a 、-C(O)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Replaced

[0074] In the preferred technical solution of the present invention, wherein Cy 1 represents a phenyl group, a pyridyl group, a thiazolyl group, an oxazolyl group, a pyrazolyl group, an imidazolyl group, or an N-methylpyrazolyl group.

[0075] In the preferred technical solution of the present invention, wherein Cy 1 Represents the following groups:

[0076] In the preferred technical solution of the present invention, wherein Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a 、-SF5、cyano、nitro、-NR a R b 、-NR a C(O)Rb 、-C(O)NR a R b 、-OC(O)R a 、-C(O)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Replaced

[0077] In the preferred technical solution of the present invention, wherein L 2 represents the absence of -C1-C6 alkylene- or -NH-.

[0078] In the preferred technical solution of the present invention, wherein L 2 Indicates that it does not exist.

[0079] In the preferred technical solution of the present invention, wherein Cy 2 represents 0-3 substituents selected from the following: halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O halo C1-C6 alkyl、-SR a , -SF5 or NR a R b substituted morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl or tetrahydrofuranyl, wherein R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl or hydroxy C1-C6 alkyl; or R 1a 、R 1b 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.

[0080] In the preferred technical solution of the present invention, wherein Cy 2 express

[0081] In the preferred technical solution of the present invention, wherein ring A represents a benzene ring or

[0082] Among them, W 1 Indicates CH or N,

[0083] Wherein, the dotted line represents a single bond or a double bond;

[0084] Ring A may also be arbitrarily 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 .

[0085] In the preferred technical solution of the present invention, wherein ring A represents

[0086] Among them, W 1 Indicates CH or N;

[0087] Ring A may also be arbitrarily 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 .

[0088] In the preferred technical solution of the present invention, wherein ring A represents: a benzene ring, a pyridine ring, a pyrazine ring, a cyclobutane ring, a cyclopentane ring, a tetrahydrofuran ring, an oxazole ring, a thiazole ring, a thiophene ring, a pyrazole ring, an imidazole ring, a piperidine ring, a hexahydropyran ring, or a cyclohexane ring;

[0089] Ring A may also be arbitrarily 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 .

[0090] In the preferred technical solution of the present invention, wherein ring A is fused with Together the rings form the following structure:

[0091] Ring A may also be arbitrarily 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 .

[0092] In the preferred technical solution of the present invention, wherein ring A is fused with Together the rings form the following structure:

[0093] Specifically, the present invention provides a compound having the following structure:

[0094] 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.

[0095] 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.

[0096] definition

[0097] 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.

[0098] 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.

[0099] 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 yIndependently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and combined 5- or 6-membered heterocyclyl rings.

[0100] 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.

[0101] 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.

[0102] 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-.

[0103] 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:

[0104] "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:

[0105] "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, imidazoline phenyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthiazinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- Oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, perylene diazepine, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1 ,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolyl, thienyl, thiazolyl pyridinyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthene, quinoline quinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, dihydroindolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-"; the present invention also includes fused ring and spiro compounds containing, for example, the above-mentioned heterocycles.

[0106] 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.

[0107] 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 Middle R a (or R b ) must be hydrogen.

[0108] "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.

[0109] "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-.

[0110] 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.

[0111] 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.

[0112] In the context of the present invention, one or more halogens may be independently selected from fluorine, chlorine, bromine and iodine.

[0113] 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).

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] Likewise, "therapeutic agent" also includes agents or reagents that have therapeutic and / or prophylactic effects on a subject.

[0120] 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.

[0121] Specific pharmaceutical and medical terms

[0122] 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).

[0123] 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.

[0124] 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.

[0125] 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.

[0126] The terms "kit" and "product packaging" are synonymous.

[0127] The terms "subject," "subject," or "patient" include both 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.

[0128] 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.

[0129] Route of administration

[0130] 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.

[0131] 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.

[0132] Pharmaceutical composition and dosage

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] Such carriers may include many different ingredients and additives in addition to the active agent, and such other ingredients 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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).

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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).

[0147] Kit / Product Packaging

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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

[0156] 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.

[0157] NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the measurements are indicated in the spectral analysis.

[0158] 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.

[0159] HPLC analysis was performed using a SHIMADZU 20A high performance liquid chromatograph.

[0160] 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, Agilent1260with 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.

[0161] 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, and Gilson 156 UV Detector.

[0162] 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.

[0163] Flash column chromatography separation was performed using a Biotage IsoleraOne flash preparative chromatograph.

[0164] 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.

[0165] Pressurized hydrogenation reaction hydride bottles and hydrogen cylinders.

[0166] Microwave reactions were performed using a Biotage Initiator+ microwave synthesizer.

[0167] The glove box is customized by DELLIX.

[0168] 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.

[0169] Example 1: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(2-hydroxyethylsulfonylamino)-7-(6-azaspiro[2.5]octan-6-yl)imidazo[1,2-a]pyridine-8-carboxamide

[0170] Step 1: To a solution of dimethyl 3-oxopentanediol (20.0 g, 114 mmol) and aminonitrile (7.24 g, 172 mmol) in dioxane (100 mL) was added nickel acetylacetonate (2.95 g, 11.5 mmol). The mixture was heated to 100°C and stirred for 16 hours, resulting in the precipitation of a large amount of yellow solid. The precipitated solid was filtered and dried to afford methyl 2-amino-4,6-dihydroxynicotine ester (7.50 g, 40.2 mmol, 35% yield) as a yellow solid. LCMS (ESI): [M+H] + =184.9.

[0171] Step 2: To a solution of methyl 2-amino-4,6-dihydroxynicotin ester (5.50 g, 29.9 mmol) in phosphorus oxychloride (50 mL) was added N,N-diisopropylethylamine (11.6 g, 89.6 mmol), and the reaction mixture was stirred at 25 ° C for 6 hours. The reaction solution was concentrated and dried, and 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 2-amino-4,6-dichloronicotin ester (2.30 g, 10.4 mmol, yield 35%) as a yellow solid. LCMS (ESI): [M+H] + =221.0.

[0172] Step 3: To a solution of methyl 2-amino-4,6-dichloronicotin ester (2.30 g, 10.4 mmol) and 6-azaspiro[2.5]octane hydrochloride (1.54 g, 10.4 mmol) in dimethyl sulfoxide (23 mL) was added potassium carbonate (3.74 g, 27.1 mmol). The mixture was heated to 110 ° C and stirred for 16 hours. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to obtain methyl 2-amino-6-chloro-4-(6-azaspiro[2.5]octane-6-yl)nicotin ester (1.40 g, 4.68 mmol, yield 45%) as a yellow solid. LCMS (ESI): [M+H] + =296.0. 1 H NMR(400MHz,DMSO-d6)δppm 6.74-6.57(m,2H),6.30-6.13(m,1H),3.86-3.69(m,3H),3.21-3.07(m,4H),1.49-1.33(m,4H),0.37-0.31(m,4H)

[0173] Step 4: To a solution of 2-amino-6-chloro-4-(6-azaspiro[2.5]octan-6-yl) nicotine methyl ester (1.40 g, 4.73 mmol) and sodium bicarbonate (0.80 g, 9.47 mmol) in methanol (12 mL) and water (6 mL) was added 2-chloroacetaldehyde (2.79 g, 14.2 mmol). The mixture was heated to 80°C and stirred for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to give methyl 5-chloro-7-(6-azaspiro[2.5]octan-6-yl)imidazo[1,2-a]pyridine-8-carboxylate (1.20 g, 3.40 mmol, 72% yield) as a yellow solid. LCMS (ESI): [M+H] + =319.9.

[0174] Step 5: To a solution of methyl 5-chloro-7-(6-azaspiro[2.5]octan-6-yl)imidazo[1,2-a]pyridine-8-carboxylate (1.00 g, 3.13 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise a toluene solution of trimethylaluminum (4.69 mL, 2M, 9.38 mmol) at a temperature of 5-10°C. The mixture was stirred at 15°C for 0.5 hours. 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (1.07 g, 4.69 mmol) was added to the reaction solution, and the mixture was heated to 90°C and stirred for 4 hours. The reaction solution was cooled to 25°C and poured into ice water (20 mL) to quench. Extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to give 5-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-7-(6-azaspiro[2.5]octan-6-yl)imidazo[1,2-a]pyridine-8-carboxamide (0.30 g, 0.59 mmol, 19% yield) as a yellow solid. LCMS (ESI): [M+H] + =516.1.

[0175] Step 6: To a solution of 5-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-7-(6-azaspiro[2.5]octan-6-yl)imidazo[1,2-a]pyridine-8-carboxamide (300 mg, 0.58 mmol), 2-hydroxyethanesulfonamide (94.6 mg, 0.76 mmol), potassium phosphate (500 mg, 2.33 mmol), and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (49.4 mg, 0.12 mmol) in dioxane (10 mL) was added tris(dibenzylideneacetone)dipalladium (54.3 mg, 0.06 mmol). The mixture was heated to 90°C and stirred under nitrogen for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by preparative HPLC (C18, 20-60% gradient of acetonitrile / water) to obtain a yellow solid compound N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(2-hydroxyethylsulfonylamino)-7-(6-azaspiro[2.5]octane-6-yl)imidazo[1,2-a]pyridine-8-carboxamide (122 mg, 0.04 mmol, 35% yield). LCMS (ESI): [M+H] + =605.1. 1 H NMR(400MHz,DMSO-d6)δppm 13.08-12.87(m,1H),12.83-12.58(m,1H),7.93-7.79(m,1H),7.71-7.63(m,1H),7.49-7.41(m,1H),6.87-6.78(m,1H),3.99-3.88(m,4H ),3.85-3.77(m,2H),3.28-3.20(m,2H),3.11-3.01(m,4H),2.39-2.32(m,3H),2.11-1.96(m,4H),1.87-1.61(m,4H),0.45-0.33(m,4H).

[0176] Example 2: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(2-hydroxyethylsulfonylamino)-6-(6-azaspiro[2.5]octan-6-yl)benzofuran-7-carboxamide

[0177] Step 1: To a solution of 2,2-dimethoxyethanol (8.88 g, 83.6 mmol) in tetrahydrofuran (400 mL) at 0°C was slowly added sodium hydride (3.51 g, 87.6 mmol, 60% purity). The mixture was stirred at 25°C for 1 hour, then methyl 4-bromo-2,6-difluorobenzoate (20.0 g, 79.6 mmol) was added to the mixture, and the mixture was stirred at 25°C for 2 hours. Water (200 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (200 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether gradient) to afford methyl 4-bromo-2-(2,2-dimethoxyethoxy)-6-fluorobenzoate (17.0 g, 50.2 mmol, 63% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δppm 7.34-7.27 (m, 2H), 4.61 (dd, J=4.8 5.6Hz, 1H), 4.11 (d, J=5.2Hz, 2H), 3.82 (s, 3H), 3.34 (s, 6H)

[0178] Step 2: A solution of polyphosphoric acid (52.0 g, 113 mmol) in toluene (400 mL) was stirred at 60 ° C for 30 minutes. Methyl 4-bromo-2-(2,2-dimethoxyethoxy)-6-fluorobenzoate (19.0 g, 56.4 mmol) was then added to the mixture, and the mixture was stirred at 60 ° C for 4 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 sodium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to give methyl 4-bromo-6-fluorobenzofuran-7-carboxylate (9.70 g, 35.5 mmol, yield 63%) as a yellow solid. LCMS (ESI): [M+H] + =274.8. 1 H-NMR(400MHz,DMSO-d6)δppm 8.26(d,J=1.0Hz,1H),7.70(d,J=10.8Hz,1H),7.04(d,J=1.0Hz,1H),3.93(s,3H)

[0179] Step 3: To a solution of methyl 4-bromo-6-fluorobenzofuran-7-carboxylate (3.00 g, 11.0 mmol) and triethylamine (3.33 g, 32.9 mmol) in dimethyl sulfoxide (30 mL) was added 6-azaspiro[2.5]octane hydrochloride (1.78 g, 12.1 mmol). The mixture was stirred at 130°C for 16 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-8% gradient of tetrahydrofuran / petroleum ether) to obtain methyl 4-bromo-6-(6-azaspiro[2.5]octan-6-yl)benzofuran-7-carboxylate (1.20 g, 0.30 mmol, 30% yield) as a yellow solid. LCMS(ESI):[M+H] + =363.8. 1 H-NMR(400MHz,DMSO-d6)δppm 8.04(d,J=2.4Hz,1H),7.27(s,1H),6.87(d,J=2.0Hz,1H),3.89(s,3H),2.94-2.87(m,4H),1.35-1.27(m,4H),0.31(s,4H)

[0180] Step 4: To a toluene solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (1.13 g, 4.94 mmol) in trimethylaluminum (9.90 mL, 2 M) was added methyl 4-bromo-6-(6-azaspiro[2.5]octan-6-yl)benzofuran-7-carboxylate (1.20 g, 3.29 mmol) at 0°C. The mixture was heated to 120°C and stirred for 16 hours. The mixture was cooled to room temperature and then slowly poured into ice water (30 mL) and extracted with ethyl acetate (30 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, 0-8% gradient of tetrahydrofuran / petroleum ether) to give 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-(6-azaspiro[2.5]octan-6-yl)benzofuran-7-carboxamide (0.65 g, 1.15 mmol, 35% yield) as a yellow solid. LCMS (ESI): [M+H] + =562.0.

[0181] Step 5: To a solution of 2-hydroxyethanesulfonamide (174 mg, 1.39 mmol), 2-(methylamino)acetic acid (95.4 mg, 1.07 mmol), and potassium phosphate (927 mg, 4.28 mmol) in N,N-dimethylformamide (12 mL) was added cuprous iodide (104 mg, 0.54 mmol). The mixture was stirred at 50°C for 5 minutes. 4-Bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-(6-azaspiro[2.5]octan-6-yl)benzofuran-7-carboxamide (600 mg, 1.07 mmol) was then added to the reaction mixture at 50°C. The mixture was heated to 100°C under nitrogen and stirred for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give a residue. The residue was purified by preparative HPLC (C18, 38-78% gradient of water (formic acid) / acetonitrile) to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(2-hydroxyethylsulfonylamino)-6-(6-azaspiro[2.5]octan-6-yl)benzofuran-7-carboxamide (260 mg, 0.40 mmol, 38% yield) as a white solid compound. LCMS (ESI): [M+H] + =605.5. 1 H-NMR(400MHz,DMSO-d6)δppm 12.87(s,1H),10.31(s,1H),8.01(d,J=2.0Hz,1H),7.51-7.23(m,3H),4.94(m,1H),4.09-3.81(m,4H),3.81-3. 70(m,2H),3.44-3.36(m,2H),3.09-2.94(m,4H),2.32(s,3H),2.08-1.90(m,4H),1.79-1.57(m,4H),0.38(s,4H)

[0182] Example 3: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(2-hydroxyethylsulfonylamino)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide

[0183] Step 1: To a solution of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(2-hydroxyethylsulfonylamino)-6-(6-azaspiro[2.5]octan-6-yl)benzofuran-7-carboxamide (100 mg, 0.17 mmol) in methanol (2 mL) was added palladium on carbon (20 mg, 10% purity). The mixture was stirred at 25°C under 50 psi of hydrogen pressure for 16 hours. The mixture was filtered through celite, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (C18, 24-64% gradient of water (formic acid) / acetonitrile) to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(2-hydroxyethylsulfonylamino)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide (40.0 mg, 0.07 mmol, 40% yield) as a white solid compound. LCMS (ESI): [M+H] + =607.5. 1 H-NMR(400MHz,DMSO-d6)δppm 11.88(s,1H),9.58(s,1H),7.31(s,1H),6.82(s,1H),5.01(br s,1H),4.56(t,J=1.0Hz,2H),3.99-3.81(m,4H),3.76(t,J=1.0Hz,2H),3.32-3.30(m,2H),3.13(t ,J=1.0Hz,2H),2.98-2.84(m,4H),2.26(s,3H),2.03-1.91(m,4H),1.64-1.45(m,4H),0.32(s,4H)

[0184] Example 4: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)-1-naphthamide

[0185] Step 1: Dissolve 4-bromonaphthalene-1-amine (30.0 g, 135 mmol) in tetrahydrofuran (300 mL), add N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (51.1 g, 162 mmol), and stir at 25°C for 12 hours. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate / petroleum ether) to obtain a brown solid 4-bromo-2-fluoronaphthalene-1-amine (12.8 g, 52.7 mmol, yield 39%). LCMS (ESI): [M+H] + =239.9.

[0186] Step 2: Boron trifluoride etherate (8.87 g, 62.5 mmol) was placed in a three-necked flask and cooled to -15°C. 4-Bromo-2-fluoronaphthalene-1-amine (10.0 g, 41.6 mmol) dissolved in N,N-dimethylacetamide (100 mL) was added dropwise. Tert-butyl nitrite (5.70 g, 54.1 mmol) dissolved in N,N-dimethylacetamide (100 mL) was also added dropwise. The mixture was stirred at -15°C for 1 hour. The temperature was raised to 5°C, and n-pentane (200 mL) was added. The mixture was filtered and washed with n-pentane (200 mL) to obtain a brown solid. The filtered brown solid was dissolved in acetonitrile (180 mL). Potassium cyanide (7.52 g, 115.47 mmol) and cuprous cyanide (4.00 g, 43.7 mmol) were dissolved in acetonitrile (90 mL) and purified water (30 mL). The brown solid dissolved in acetonitrile was then added to the reaction solution, heated to 80°C and stirred for 2 hours. The reaction solution was quenched with saturated sodium carbonate solution (500 mL) and extracted with ethyl acetate (400 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 obtain 4-bromo-2-fluoro-1-naphthalenecarbonitrile (4.90 g, 14.99 mmol, 36% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.33-8.25(m,2H),8.15-8.08(m,1H),7.96-7.84(m,2H)

[0187] Step 3: Add 4-bromo-2-fluoro-1-naphthocarbonitrile (4.90 g, 19.6 mmol) to sulfuric acid (100 mL, 70%) and stir at 80°C for 16 hours. Add sodium nitrite (1.94 g, 28.1 mmol) at 80°C and stir at 80°C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (200 mL, 100 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by slurrying with dichloromethane (80 mL) at 25°C for 16 hours to obtain 4-bromo-2-fluoro-1-naphthoic acid (4.00 g, 14.9 mmol, 76% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δppm 8.25-8.19 (m, 1H), 8.07 (d, J = 9.2Hz, 2H), 7.79-7.72 (m, 2H)

[0188] Step 4: Dissolve 4-bromo-2-fluoro-1-naphthoic acid (2.00 g, 7.43 mmol) and N,N-carbonyldiimidazole (7.23 g, 44.6 mmol) in N,N-dimethylformamide (40.0 mL) and heat to 60°C with stirring for 4 hours. Dissolve 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (2.04 g, 8.92 mmol) in N,N-dimethylformamide (40 mL) and add sodium hydroxide (0.89 g, 22.3 mmol, 60% by mass) at 0°C. Stir at 25°C for 30 minutes. Add the above solution to the reaction system and stir at 25°C for 16 hours. The reaction mixture is quenched with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The organic phase is dried, filtered, and concentrated to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-7% gradient of tetrahydrofuran / petroleum ether) to give 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-1-naphthamide (1.10 g, 2.19 mmol, 20% yield) as a yellow solid. LCMS (ESI): [M+H] + =480.9, 1 H NMR (400MHz, DMSO-d6) δppm 11.29 (br s, 1H), 8.26-8.21 (m, 1H), 8.10 (d, J = 8.8Hz, 1H), 7.87 (br d, J = 2.0Hz, 1H), 7.76-7.71 (m, 2H), 7.47 (br s,1H),3.86(br s,4H),2.36(br s,3H),1.97(br s,4H)

[0189] Step 5: Dissolve 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-1-naphthamide (1.10 g, 93%) and 6-azaspiro[2.5]octane hydrochloride (0.44 g, 2.98 mmol) in dimethyl sulfoxide (40.0 mL), add potassium carbonate (0.95 g, 6.89 mmol), and stir at 120°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-7% gradient of tetrahydrofuran / petroleum ether) to obtain 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-1-naphthamide (0.36 g, 0.71 mmol, 31% yield) as a yellow solid. LCMS (ESI): [M+H] + =572.2, 1H NMR(400MHz,DMSO-d6)δppm 10.75(br s,1H),8.18-8.08(m,1H),7.91-7.78(m,2H),7.63-7.57(m,2H),7.49(br s,1H),3.87(br s,4H),3.11(br s,4H),2.36(br s,3H),2.12-1.94(m,4H),1.42-1.35(m,4H),0.28(s,4H)

[0190] Step 6: Dissolve 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-1-naphthamide (200 mg, 0.35 mmol) and 2-hydroxyethanesulfonamide (57.0 mg, 0.46 mmol) in dioxane (10.0 mL). Add potassium phosphate (297 mg, 1.40 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (29.8 mg, 0.07 mmol), and tris(dibenzylideneacetone)dipalladium (32.1 mg, 0.04 mmol). Stir at 60°C under nitrogen for 16 hours. The reaction mixture was filtered, diluted, and purified using preparative HPLC (C18, 28-68% gradient of water (ammonia water + ammonium bicarbonate) / acetonitrile) to obtain N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(2-hydroxyethylsulfonylamino)-2-(6-azaspiro[2.5]octan-6-yl)-1-naphthamide (27.7 mg, 0.05 mmol, 13% yield) as a white solid. LCMS (ESI): [M+H] + =615.2, 1 H NMR (400MHz, DMSO-d6) δppm 10.74 (br s, 1H), 9.90 (br s, 1H), 8.25 (d, J = 8.4Hz, 1H), 7.90 (br d,J=7.6Hz,1H),7.62-7.37(m,4H),5.02(s,1H),3.97-3.71(m,6H),3.32-3.28(m,2H),3.09(br s,4H),2.40-2.29(m,3H),2.02-1.90(m,4H),1.44–1.36(m,4H),0.29(s,4H)

[0191] Example 5: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-8-(2-hydroxyethylsulfonamide)-6-(6-azaspiro[2.5]octan-6-yl)quinoline-5-carboxamide

[0192] Step 1: Iron powder (8.55 g, 151.51 mmol), 4-bromo-2-fluoro-5-nitrobenzoic acid (8.00 g, 30.30 mmol), and ammonium chloride (2.45 g, 45.45 mmol) were added to a mixed solution of ethanol (40 mL), water (10 mL), and tetrahydrofuran (40 mL). The mixture was heated to 90°C and stirred for 3 hours. The mixture was cooled to 40°C and poured into a celite funnel while hot, filtered, and the filtrate was concentrated and evaporated to dryness to obtain 5-amino-4-bromo-2-fluorobenzoic acid (6.00 g, 25.63 mmol, yield: 84.6%) as a yellow solid. LCMS (ESI): [M+H] + =234.1

[0193] Step 2: To a mixture of concentrated sulfuric acid (20 mL) and water (5 mL) was added glycerol (5.96 g, 64.10 mmol). The mixture was heated to 100°C and stirred for 15 minutes. After cooling the mixture to 40°C, 5-amino-4-bromo-2-fluorobenzoic acid (5.00 g, 21.36 mmol) and 3-nitrobenzenesulfonic acid sodium salt (4.85 g, 21.36 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, 0-20% methanol / dichloromethane gradient) to afford 8-bromo-6-fluoroquinoline-5-carboxylic acid (3.30 g, 12.21 mmol, yield: 57.3%) as a yellow solid. LCMS(ESI):[M+H] + =270.0; 1 HNMR (400MHz, DMSO) δ9.06(dd,J=4.1,1.6Hz,1H),8.60(dd,J=8.6,1.6Hz,1H),8.33(d,J=9.4Hz,1H),7.77(dd,J=8.6,4.1Hz,1H).

[0194] Step 3: To a solution of 8-bromo-6-fluoroquinoline-5-carboxylic acid (2.00 g, 7.41 mmol) in dimethyl sulfoxide (20 mL) were added 6-azaspiro[2.5]octane hydrochloride (1.66 g, 11.10 mmol) and potassium carbonate (3.13 g, 22.2 mmol), and the mixture was heated to 120 ° C and stirred for 36 hours. After the reaction was completed, the aqueous layer was adjusted to pH 6 with saturated aqueous sodium bicarbonate (20 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, 0-20% gradient of methanol / dichloromethane) to give 8-bromo-6-(6-azaspiro[2.5]octan-6-yl)quinoline-5-carboxylic acid (1.50 g, 4.15 mmol, yield: 56.2%) as a yellow solid. LCMS (ESI): [M+H] + =361.2

[0195] Step 4: To a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (758 mg, 3.32 mmol) and 8-bromo-6-(6-azaspiro[2.5]octan-6-yl)quinoline-5-carboxylic acid (1.00 g, 1.30 mmol) in dichloromethane (10.0 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.61 g, 4.15 mmol) and potassium tert-butoxide (941 mg, 8.30 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, 0-50% gradient of ethyl acetate / petroleum ether) to give 8-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-(6-azaspiro[2.5]octan-6-yl)quinoline-5-carboxamide (200 mg, 0.35 mmol, yield: 12.6%) as a yellow solid. LCMS (ESI): [M+H] + =571.3

[0196] Step 5: Under a nitrogen atmosphere, 2-hydroxyethanesulfonamide (67 mg, 1.40 mmol), tris(dibenzylideneacetone)dipalladium (33 mg, 0.03 mmol), potassium phosphate (303 mg, 1.40 mmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (30 mg, 0.06 mmol) were placed in a bottle, 1,4-dioxane (4 mL) was added to the reaction bottle, and the mixture was stirred at 50 ° C for 0.5 hours, and then 8-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-(6-azaspiro[2.5]octane-6-yl)quinoline-5-carboxamide (200 mg, 0.35 mmol) was added to the bottle. 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-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-8-(2-hydroxyethylsulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)quinoline-5-carboxamide (20 mg, 0.032 mmol, yield: 9.3%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =616.4;1H NMR (400MHz, DMSO) δ10.98(s,1H),10.06–9.08(m,1H),8.80(d,J=3.9Hz,1H),8.60(s,1H),8.00–7.39(m,3H),5.14(s,1H),4. 02–3.75(m,6H),3.50(q,J=4.9Hz,2H),3.16(s,4H),2.37(s,3H),1.96(d,J=20.8Hz,4H),1.49(s,4H),0.33(d,J=2.7Hz,4H).

[0197] Example 6: 2-{6-azaspiro[2.5]octan-6-yl}-N-[8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl]-4-(2-hydroxyethanesulfonylamino)naphthalene-1-carboxamide

[0198] Step 1: To a solution of 8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-amine (171 mg, 0.61 mmol) and 2-{6-azaspiro[2.5]octane-6-yl}-4-bromonaphthalene-1-carbonyl chloride (230 mg, 0.61 mmol) in tetrahydrofuran (6 mL) was added N,N-diisopropylethylamine (240 mg, 1.82 mmol). The mixture was stirred at 25° C. for 16 hours. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / petroleum ether) to give 2-{6-azaspiro[2.5]octan-6-yl}-4-bromo-N-[8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl]naphthalene-1-carboxamide (250 mg, 0.40 mmol, 66% yield) as a yellow solid. LCMS (ESI): [M+H] + =625.1; 1 H NMR(400MHz,DMSO-d6)δppm 0.45(s,1H),8.88(dd,J=1.2,4.4Hz,1H),8.47-8.36(m,2H),8.23-8.11(m,1H),7.97( d,J=8.0Hz,1H),7.88(s,1H),7.70-7.58(m,2H),7.53(dd,J=4.0,8.4Hz,1H),3.56(br t,J=4.8Hz,4H),3.20-3.15(m,4H),2.26-2.12(m,4H),1.49-1.39(m,4H),0.29(s,4H)

[0199] Step 2: Dissolve 2-{6-azaspiro[2.5]octan-6-yl}-4-bromo-N-[8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl]naphthalene-1-carboxamide (210 mg, 0.33 mmol) and 2-hydroxyethanesulfonamide (84.3 mg, 0.67 mmol) in dioxane (4 mL). Add potassium phosphate (214 mg, 1.01 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (14.3 mg, 0.03 mmol), and tris(dibenzylideneacetone)dipalladium (31.4 mg, 0.03 mmol). Stir at 60°C under nitrogen for 16 hours. The reaction mixture was filtered, diluted, and purified using preparative HPLC (C18, 34-74% gradient of water (formic acid) / acetonitrile) to give 2-{6-azaspiro[2.5]octan-6-yl}-N-[8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-yl]-4-(2-hydroxyethanesulfonylamino)naphthalene-1-carboxamide (56 mg, 0.08 mmol, 25% yield) as a yellow solid. LCMS (ESI): [M+H] + =668.3; 1 H NMR(400MHz,DMSO-d6)δppm 10.45(s,1H),10.16-9.47(m,1H),8.87(dd,J=1.6,4.0Hz,1H),8.42(d,J=8.0Hz,2H),8.28(d,J=8.4 Hz,1H),7.99(d,J=8.4Hz,1H),7.62-7.45(m,4H),5.31-4.83(m,1H),3.83(t,J=6.4Hz,2H),3.55(br d,J=4.8Hz,4H),3.32-3.30(m,2H),3.18-3.11(m,4H),2.26-2.12(m,4H),1.43(br s,4H),0.30(s,4H)

[0200] Example 7: 2-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl]-4-(2-hydroxyethanesulfonylamino)naphthalene-1-carboxamide

[0201] Step 1: To a solution of 4-chloro-2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidine (5.00 g, 18.9 mmol) in dioxane (100 mL) were added benzophenone imine (5.16 g, 28.5 mmol), cesium carbonate (18.9 g, 56.9 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.12 g, 1.90 mmol), and tris(dibenzylideneacetone)dipalladium (1.77 g, 1.90 mmol). The reaction mixture was purged with nitrogen three times and heated to 100°C under a nitrogen atmosphere with stirring for 12 hours. The reaction mixture was cooled to room temperature and extracted with water (200 mL) and 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 spin-dried to obtain a residue. The residue was slurried with ethyl acetate to give a yellow solid N-[2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl]-1,1-diphenylmethanimine (5.90 g, 14.4 mmol, yield 76%). LCMS (ESI): [M+H]+=409.2; 1 H NMR(400MHz,DMSO-d6)δppm 7.81-7.13(m,10H),5.50(s,1H),3.77-3.70(m,7H),1.95-1.75(m,4H)

[0202] Step 2: To a solution of N-[2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl]-1,1-diphenylcarbamylamine (1.00 g, 2.45 mmol) in methanol (10 mL) were added sodium acetate (0.60 g, 7.34 mmol) and hydroxylamine hydrochloride (0.34 g, 4.90 mmol). The mixture was stirred at 25°C for 1 hour. 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 dried to dryness to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-50% gradient of tetrahydrofuran / petroleum ether) to afford 2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-amine (0.60 mg, 2.44 mmol, 100% yield) as a yellow solid. LCMS (ESI): [M+H]+=245.1

[0203] Step 3: To a solution of 4-bromo-2-fluoronaphthalene-1-carboxylic acid (2.00 g, 7.43 mmol) and 6-azaspiro[2.5]octan-6-yl}-4-bromonaphthalene-1-carboxylic acid (1.65 g, 11.1 mmol) in dimethyl sulfoxide (40 mL) was added potassium carbonate (3.14 g, 22.3 mmol). The mixture was heated to 120° C. and stirred for 72 hours. Water (50 mL) was added to the reaction mixture, the pH was adjusted to 4 with 3M dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (50 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 2-{6-azaspiro[2.5]octan-6-yl}-4-bromonaphthalene-1-carboxylic acid (0.65 g, 1.80 mmol, 24% yield) as a yellow oil. LCMS (ESI): [M+H]+=361.9.

[0204] Step 4: To a solution of 2-{6-azaspiro[2.5]octane-6-yl}-4-bromonaphthalene-1-carboxylic acid (250 mg, 0.69 mmol) in dichloromethane (5 mL) was added oxalyl chloride (107 mg, 0.83 mmol), followed by dropwise addition of NN-dimethylformamide (5.07 mg, 0.07 mmol) to the reaction solution, and the mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated and dried to give a crude yellow solid of 2-{6-azaspiro[2.5]octane-6-yl}-4-bromonaphthalene-1-carbonyl chloride (250 mg, crude). LCMS (ESI): 376.0. (Methanol sample, mass of methyl ester)

[0205] Step 5: To a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-amine (193 mg, 0.79 mmol) and 2-{6-azaspiro[2.5]octan-6-yl}-4-bromonaphthalene-1-carbonyl chloride (300 mg, 0.79 mmol) in tetrahydrofuran (6 mL) was added N,N-diisopropylethylamine (313 mg, 2.37 mmol). The mixture was stirred at 50°C for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / petroleum ether) to give 2-{6-azaspiro[2.5]octan-6-yl}-4-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl]naphthalene-1-carboxamide (80 mg, 0.13 mmol, 17.2% yield) as a yellow solid. LCMS (ESI): [M+H] + =588.0.

[0206] Step 6: Dissolve 2-{6-azaspiro[2.5]octan-6-yl}-4-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl]naphthalene-1-carboxamide (80 mg, 0.13 mmol) and 2-hydroxyethanesulfonamide (34.1 mg, 0.27 mmol) in dioxane (4 mL), and add potassium phosphate (86.8 mg, 0.41 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (5.79 mg, 0.01 mmol), and tris(dibenzylideneacetone)dipalladium (12.7 mg, 0.01 mmol). Stir at 60°C under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered, diluted, and purified using preparative HPLC (C18, 50-90% gradient of water (formic acid) / acetonitrile) to give 2-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl]-4-(2-hydroxyethanesulfonylamino)naphthalene-1-carboxamide (9.3 mg, 0.01 mmol, 11% yield) as a white solid. LCMS (ESI): [M+H] + =631.5; 1 H NMR (400MHz, DMSO-d6) δppm 10.70 (br s, 1H), 10.02-9.64 (m, 1H), 8.25 (br d, J=8.4Hz, 1H), 7.90 (br dd, J=2.0, 4.8Hz, 1H), 7.63-7.39 (m, 3H), 7.00 (br s,1H),5.20-4.82(m,1H),4.01-3.77(m,9H),3.46-3.38(m,2H),3.09(br s,4H),1.98(br s,4H),1.40(br s,4H),0.30(s,4H)

[0207] Example 8: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-((2-hydroxyethyl)sulfonamido)-7-(6-azaspiro[2.5]octan-6-yl)quinoline-8-carboxamide

[0208] Step 1: A mixture of glycerol (1.13 g, 12.09 mmol) and sodium 3-nitrobenzenesulfonate (1.00 g, 4.43 mmol) in sulfuric acid (4.00 mL) / water (2.00 mL) was stirred at 120°C for 30 minutes at 20°C. The reaction mixture was cooled to 40°C. Methyl 2-amino-4-bromo-6-fluorobenzoate (1.00 g, 4.03 mmol) was added to the reaction mixture and stirred at 120°C for 4 hours. The reaction mixture was poured into ice water (50 mL), filtered, and the filter cake washed with ethyl acetate (30 mL). The organic phase was discarded, and the aqueous phase was adjusted to pH 9 with potassium carbonate solution and extracted with ethyl acetate (15 mL x 2). The organic phase was discarded, and the aqueous phase was adjusted to pH 4 with dilute hydrochloric acid (1 M) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried, filtered, and concentrated to give 5-bromo-7-fluoroquinoline-8-carboxylic acid (200 mg, 0.74 mmol, yield 16.7%) as a gray solid. LCMS (ESI): [M+H] + =270.0; 1 H NMR (400MHz, DMSO) δ14.02(s,1H),9.07(dd,J=4.3,1.6Hz,1H),8.60(dd,J=8.5,1.6Hz,1H),8.21(d,J=9.0Hz,1H),7.85–7.74(m,1H).

[0209] Step 2: To a solution of 5-bromo-7-fluoroquinoline-8-carboxylic acid (1.00 g, 3.70 mmol) and 6-azaspiro[2.5]octane hydrochloride (0.83 g, 5.55 mmol) in dimethyl sulfoxide (13.00 mL) at 20°C was added potassium carbonate (1.56 g, 11.10 mmol). The resulting reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was filtered, and the filter cake was stirred in water (20 mL) for 5 minutes, filtered again, and dried to afford 7-(6-azaspiro[2.5]octan-6-yl)-5-bromoquinoline-8-carboxylic acid (900 mg, 2.49 mmol, 67.4% yield) as a yellow solid. LCMS (ESI): [M+H] + =361.1; 1 H NMR(400MHz,CD3OD)δ8.78(dd,J=4.3,1.7Hz,1H),8.42(dd,J=8.4,1.7Hz,1H),7.71(d,J=1.6Hz,1H), 7.40(ddd,J=8.5,4.3,1.5Hz,1H),3.35(t,J=5.4Hz,4H),1.57(t,J=5.3Hz,4H),0.36(d,J=1.6Hz,4H).

[0210] Step 3: To a solution of 7-(6-azaspiro[2.5]octan-6-yl)-5-bromoquinoline-8-carboxylic acid (0.53 g, 1.47 mmol) in dichloromethane (3.00 mL) was added thionyl chloride (100 μL) at 20°C. The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was concentrated to dryness without purification to afford 7-(6-azaspiro[2.5]octan-6-yl)-5-bromoquinoline-8-carboxylic acid chloride (550 mg, 1.45 mmol, 98.7% yield) as an orange solid. LCMS (ESI): [M+H] + =377.1

[0211] Step 4: To a solution of 2-(4,4-difluoropiperidinyl)-6-methylpyrimidin-4-ylamine (330.63 mg, 1.45 mmol) in tetrahydrofuran (10.00 mL) at 20°C was added potassium tert-butoxide (328 mg, 2.90 mmol). The reaction mixture was stirred at 20°C for 5 minutes, and 7-(6-azaspiro[2.5]octan-6-yl)-5-bromoquinoline-8-carboxylic acid chloride (550 mg, 1.45 mmol) was added. The reaction mixture was stirred at 20°C for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL x 2), dried, filtered, and concentrated to give a residue which was purified by flash column chromatography (silica, 0-20% ethyl acetate / petroleum ether) to give [7-(6-azaspiro[2.5]octane-6-yl)-5-bromo(8-quinolinol)]-N-[2-(4,4-difluoropiperidinyl)-6-methylpyrimidin-4-yl]carboxamide (250 mg, 0.44 mmol, 30% yield). LCMS (ESI): [M+H] + =573.3

[0212] Step 5: To [7-(6-azaspiro[2.5]octan-6-yl)-5-bromo(8-quinoline)]-N-[2-(4,4-difluoropiperidinyl)-6-methylpyrimidin-4-yl]carboxamide (150 mg, 0.26 mmol), 2-hydroxyethylsulfonamide (98 mg, 0.79 mmol), potassium phosphate (170 mg, 0.79 mmol), tris(dibenzylideneacetone)dipalladium (24 mg, 0.03 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (22 mg, 0.052 mmol) was added 1,4-dioxane (7.00 mL) at 20°C, and the reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 60°C for 5 hours. Ethyl acetate (20 mL) was added to the reaction mixture, and the mixture was filtered. The filtrate was washed with saturated sodium chloride solution (10 mL x 3). The organic phase was dried, filtered, and concentrated to a residue, which was purified by flash column chromatography (silica, 0-5% methanol / dichloromethane gradient) to afford 100 mg of the product. This was further purified by preparative HPLC (C18, 70-90% acetonitrile / water gradient) to afford N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-((2-hydroxyethyl)sulfonamido)-7-(6-azaspiro[2.5]octan-6-yl)quinoline-8-carboxamide (61 mg, 0.10 mmol, 38% yield) as an orange solid. LCMS (ESI): [M+H] + =616.4; 1 H NMR (400MHz, DMSO) δ10.60(s,1H),9.95(s,1H),8.81(s,1H),8.58(d,J=8.6Hz,1H),7.53–7.43(m,3H),5.03( s,1H),3.83(d,J=14.7Hz,6H),3.31(s,2H),3.21(s,4H),2.34(s,3H),1.95(s,4H),1.40(s,4H),0.31(s,4H).

[0213] Example 9: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-7-((2-hydroxyethyl)sulfonamido)-5-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carboxamide

[0214] Step 1: A mixed solution containing methyl 4-bromo-2-fluoro-6-methylbenzoate (25.0 g, 101.19 mmol), N-bromosuccinimide (21.6 g, 121.43 mmol), azobisisobutyronitrile (8.5 g, 50.60 mmol) and acetonitrile (250 mL) was stirred at 70° C. for 3 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 and concentrated, and then purified by column chromatography (silica gel, 0-10% gradient ethyl acetate / petroleum ether) to obtain methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (18.1 g, 55.53 mmol, yield: 54.9%) as a colorless oil. LCMS (ESI): [M+H]+=326.9; 1H NMR (400MHz, DMSO) δ7.73 (m, 2H), 4.77 (s, 2H), 3.91 (s, 3H).

[0215] Step 2: A mixture containing methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (18 g, 55.22 mmol), tert-butyl ethyl malonate (11.4 g, 60.74 mmol), cesium carbonate (36.7 g, 110.44 mmol), and N,N-dimethylformamide (200 mL) was stirred at 20°C for 2 hours. The reaction solution was 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, 0-10% ethyl acetate / petroleum ether gradient) to obtain 1-(tert-butyl)-3-ethyl-2-(5-bromo-3-fluoro-2-(methoxycarbonyl)benzyl)malonic acid (15.4 g, crude) as a colorless oil. LCMS (ESI): [M+Na] + =455.3;1H NMR(400MHz,DMSO)δ7.64(dd,J=9.6,2.0Hz,1H),7.47–7.44(m,1H),4.17-4.08(m,2H),3 .88(s,3H),3.70(t,J=8.0Hz,1H),3.18–3.04(m,2H),1.35(s,9H),1.15(t,J=7.2Hz,3H).

[0216] Step 3: A solution containing 1-(tert-butyl)-3-ethyl-2-(5-bromo-3-fluoro-2-(methoxycarbonyl)benzyl)malonic acid (15 g, 34.62 mmol) and trifluoroacetic acid (60 mL) was stirred at 20°C for 1 hour. The reaction solution was concentrated to remove the trifluoroacetic acid, and then toluene (60 mL) and triethylamine (35.75 g, 346.21 mmol) were added. Stirring was continued at 120°C for 3 hours. The reaction solution was concentrated, and the pH was adjusted to approximately 8 by adding saturated aqueous sodium bicarbonate. The solution was then extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting mixture was then purified by column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether gradient) to afford methyl 4-bromo-2-(3-ethoxy-3-oxopropyl)-6-fluorobenzoate (6.8 g, 20.41 mmol, yield: 59.0%). LCMS(ESI):[M+H] + =333.0.

[0217] Step 4: A mixture containing methyl 4-bromo-2-(3-ethoxy-3-oxopropyl)-6-fluorobenzoate (6.8 g, 20.41 mmol), lithium hydroxide monohydrate (4.9 g, 204.11 mmol), tetrahydrofuran (40 mL), methanol (40 mL), and water (40 mL) was stirred at 20°C for 4 hours. The reaction mixture was concentrated to remove tetrahydrofuran and methanol, and the pH was adjusted to approximately 5 by adding 4 M hydrochloric acid in ethyl acetate (100 mL). The mixture was then extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 4-bromo-2-(2-carboxyethyl)-6-fluorobenzoic acid (5.1 g, 17.52 mmol, yield: 85.8%) as a white solid. LCMS (ESI): [M+Na] + =313.0;1H NMR (400MHz, DMSO) δ12.95(s,2H),7.58(dd,J=9.2,2.0Hz,1H),7.49(d,J=2.0Hz,1H),2.94(dd,J=8.4,7.2Hz,2H),2.60(dd,J=8.4,7.2Hz,2H).

[0218] Step 5: Add oxalyl chloride (15.3 g, 120.25 mmol) to a mixed solution containing 4-bromo-2-(2-carboxyethyl)-6-fluorobenzoic acid (5.0 g, 17.18 mmol) and dichloromethane (50 mL), and stir the resulting mixture at 20°C for 1 hour. The reaction solution was concentrated to obtain the compound 4-bromo-2-(3-chloro-3-oxopropyl)-6-fluorobenzoyl chloride (5.7 g, crude product) as a yellow oil. LCMS (ESI): [M+H] + =319.0 (corresponding methyl ester).

[0219] Step 6: 4-Bromo-2-(3-chloro-3-oxopropyl)-6-fluorobenzoyl chloride (5.0 g, 15.25 mmol) was dissolved in dichloromethane (50 mL) and added dropwise to a solution containing aluminum chloride (8.1 g, 60.98 mmol) and dichloromethane (50 mL) at 0°C. The reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain compound 7-bromo-5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (3.4 g, 12.45 mmol, yield: 81.7%) as a brown solid. LCMS (ESI): [M+H] + =273.0.

[0220] Step 7: A mixed solution containing 7-bromo-5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (3.3 g, 12.09 mmol), 6-azaspiro[2.5]octane hydrochloride (2.7 g, 18.13 mmol), potassium carbonate (6.0 g, 42.30 mmol) and dimethyl sulfoxide (30 mL) 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% acetic acid). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound 7-bromo-1-oxo-5-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carboxylic acid (2.5 g, 6.86 mmol, yield: 56.8%) as a gray solid, LCMS (ESI): [M+H] + =364.4.

[0221] Step 8: A mixed solution containing 7-bromo-1-oxo-5-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carboxylic acid (1 g, 2.75 mmol), triethylsilane (3.2 g, 27.45 mmol) and trifluoroacetic acid (10 mL) was stirred at 80° C. for 12 hours. The reaction solution was concentrated, and aqueous sodium bicarbonate (50 mL) was added. Then, a 4 M hydrochloric acid ethyl acetate solution (40 mL) was added to adjust the pH to near 4, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain compound 7-bromo-5-(6- Azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carboxylic acid (700 mg, 2.00 mmol, yield: 72.8%), as a white solid. LCMS (ESI): [M+H] + =350.2.

[0222] Step 9: Oxalyl chloride (518 mg, 4.00 mmol) was added to a mixed solution of 7-bromo-5-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carboxylic acid chloride (700 mg, 2.00 mmol) and dichloromethane (10 mL). The resulting mixture was stirred at 20° C. for 30 minutes. The reaction mixture was concentrated to obtain compound 7-bromo-5-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carbonyl chloride (760 mg, crude product) as a yellow oil. LCMS (ESI): [M+H] + =364.2 (corresponding methyl ester)

[0223] Step 10: A mixed solution containing 2-(4,4-difluoropropidinyl)-6-methylpyrimidin-4-amine (650 mg, 2.85 mmol), N,N-diisopropylethylamine (2.5 g, 18.99 mmol), potassium tert-butoxide (323 mg, 2.85 mmol) and tetrahydrofuran (10 mL) was stirred at 20 ° C for 30 minutes, and then 7-bromo-5-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carbonyl chloride (700 mg, 1.90 mmol) was added. The reaction solution was poured into water (30 mL) and washed with ethyl acetate (30 mL x 4 ). 3) extraction, 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 7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carboxamide (630 mg, 1.12 mmol, yield: 59.2%) as a gray solid. LCMS (ESI): [M+H] + =560.3.

[0224] Step 11: Under nitrogen atmosphere, a reaction solution containing 7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carboxamide (300 mg, 0.54 mmol), 2-hydroxyethanesulfonamide (137 mg, 1.07 mmol), potassium phosphate (348 mg, 1.61 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (23 mg, 0.054 mmol), tris(dibenzylideneacetone)dipalladium (50 mg, 0.054 mmol) and dioxane (5 mL) was stirred at 100 ° C for 8 hours. The reaction solution was poured into water (30 mL) and washed with ethyl acetate (30 mL x 40 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether) to obtain the compound N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-7-((2-hydroxyethyl)sulfonamido)-5-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carboxamide (149.0 mg, 0.25 mmol, yield: 46.0%) as a white solid. LCMS (ESI): [M+H] +=605.40;1H NMR (400MHz, CDCl3) δ12.79(s,1H),7.46(s,1H),7.39(s,1H),6.61(s,1H),4.12(q,J=5.2Hz,2H),3.98(t,J=5.6Hz,4H),3.45–3.37(m,4H),3.04(t ,J=5.2Hz,4H),2.79(t,J=7.6Hz,2H),2.48(t,J=5.6Hz,1H),2.37(s,3H), 2.13(q,J=7.6Hz,2H),2.03-1.92(m,4H),1.79-1.56(m,4H),0.38(s,4H).

[0225] Example 10: 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-(1-hydroxypropane-2-sulfonylamino)naphthalene-1-carboxamide

[0226] Step 1: To a solution of tert-butyl N-[6-amino-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]-N-[(tert-butyloxy)carbonyl]aminomethyl ester (120 mg, 0.30 mmol) and 2-{6-azaspiro[2.5]octan-6-yl}-4-bromonaphthalene-1-carbonyl chloride (716 mg, 1.43 mmol) in tetrahydrofuran (8.00 mL) was added N,N-diisopropylethylamine (418 mg, 3.17 mmol). The mixture was stirred at 25°C for 16 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. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate / petroleum ether) to afford tert-butyl N-[6-(2-{6-azaspiro[2.5]octan-6-yl}-4-bromonaphthalen-1-ylamino)-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]-N-[(tert-butyloxy)carbonyl]aminomethyl ester (650 mg, 0.77 mmol, 72.8% yield) as a yellow solid. LCMS (ESI): [M+H] + =846.1

[0227] Step 2: To a mixed solution of trifluoroacetic acid (0.50 mL) and dichloromethane (1.50 mL) was added tert-butyl N-[6-(2-{6-azaspiro[2.5]octan-6-yl}-4-bromonaphthalen-1-ylamino)-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]-N-[(tert-butyloxy)carbonyl]aminomethyl ester (400 mg, 0.47 mmol). The mixture was stirred at 25°C for 4 hours. Saturated aqueous sodium bicarbonate (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried to give a white solid, 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-bromonaphthalene-1-carboxamide (300 mg, 0.464 mmol, yield 98.3%). LCMS (ESI): [M+H] + =645.8

[0228] Step 3: To a solution of 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-bromonaphthalene-1-carboxamide (360 mg, 0.56 mmol) in dioxane (2 mL) was added ethyl 2-sulfamoylpropyl ester (101 mg, 0.56 mmol), potassium phosphate (363 mg, 1.68 mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (23.7 mg, 0.06 mmol), and tris(dibenzylideneacetone)dipalladium (52.2 mg, 0.06 mmol) at 25°C. The reaction mixture was heated to 90°C under nitrogen and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the filtrate was dried to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give ethyl 2-[(4-{[2-amino-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-6-yl]aminocarbonyl}-3-{6-azaspiro[2.5]octan-6-yl}naphthalen-1-yl)sulfamoyl]propyl ester (300 mg, 0.463 mmol, 83% yield) as a white solid. LCMS (ESI): [M+H]+ = 745.2

[0229] Step 4: Ethyl 2-[(4-{[2-amino-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-6-yl]aminocarbonyl}-3-{6-azaspiro[2.5]octan-6-yl}naphthalen-1-yl)sulfamoyl]propyl ester (300 mg, 0.40 mmol) was added to a tetrahydrofuran (14 mL) solution. Lithium aluminum tetrahydride (21.6 mg, 0.60 mmol) was added portionwise at 25°C, and the mixture was stirred at 25°C for 1 hour. Water (0.05 mL) was added to the reaction solution in sequence, quenched with 15% aqueous sodium hydroxide solution (0.05 mL), and filtered with water (0.1 mL). The filtrate was dried to obtain a residue. The residue was diluted with N,N-dimethylformamide (5 mL). The dilution was purified by preparative HPLC (C18, 28-68% 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-(1-hydroxypropane-2-sulfonylamino)naphthalene-1-carboxamide (37.9 mg, 0.052 mmol, 13% yield) as a white solid. LCMS (ESI): [M+H]+ = 703.1; 1 H NMR(400MHz,DMSO-d6)δppm 10.01(s,1H),9.95-9.61(m,1H),8.27(d,J=8.4Hz,1H),7.94(d,J=8.4Hz,1H),7.84(d,J=6.4Hz,1H),7. 62-7.44(m,5H),5.32-4.83(m,1H),3.92(dd,J=4.4,11.2Hz,1H),3.50(dd,J=8.0,11.2Hz,1H),3.40(br t,J=5.2Hz,4H),3.27-3.20(m,1H),3.13(br t,J=5.2Hz,4H),2.21-2.03(m,4H),1.46(br s,4H),1.34(d,J=7.2Hz,3H),0.33(s,4H)

[0230] Example 11: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-7-((2-hydroxy-1,1-dimethylethyl)sulfonamido)-5-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carboxamide

[0231] Step 1: Under nitrogen atmosphere, a reaction solution containing 7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carboxamide (300 mg, 0.54 mmol), ethyl 2-methyl-2-sulfamoylpropionate (209 mg, 1.07 mmol), potassium phosphate (348 mg, 1.61 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (23 mg, 0.054 mmol), tris(dibenzylideneacetone)dipalladium (50 mg, 0.054 mmol) and dioxane (5 mL) was stirred at 100 ° C for 8 hours. The reaction solution was poured into water (30 mL) and washed with ethyl acetate (30 mL x 40 mL). 3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain the compound 2-(N-(7-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-inden-4-yl)sulfamoyl)-2-methylpropanoic acid ethyl ester (270 mg, 0.40 mmol, yield: 76.2%) as a light yellow solid. LCMS (ESI): [M+H] + =675.5.

[0232] Step 2: Lithium aluminum tetrahydride (40 mg, 1.11 mmol) was added portionwise to a mixed solution of ethyl 2-(N-(7-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-inden-4-yl)sulfamoyl)-2-methylpropanoate (250 mg, 0.37 mmol) and tetrahydrofuran (5 mL). The reaction solution was stirred at 20°C for 1 hour, quenched by addition of saturated aqueous ammonium chloride (20 mL), and then extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate / petroleum ether). and C18 (0-100% gradient of acetonitrile / water) to afford the compound N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-7-((2-hydroxy-1,1-dimethylethyl)sulfonamido)-5-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydro-1H-indene-4-carboxamide (40.25 mg, 0.064 mmol, yield: 17.2%) as a white solid. LCMS (ESI): [M+H] +=633.40;1H NMR (400MHz, DMSO) δ13.05(s,1H),9.17(s,1H),7.46(s,1H),7.38(s,1H),5.22(s,1H),3.90(t,J=5.6Hz,4H),3.55(s, 2H),3.23(t,J=7.6Hz,2H),2.94-2.85(m,6H),2.30(s,3H),2.02-1.91(m,6H),1.66(s,4H),1.23(s,6H),0.36(s,4H).

[0233] Effect Example 1: Enzyme activity detection experiment

[0234] Materials: Human KIF18A (amino acid sequence 1-417), purchased from Shanghai Via Biotechnology Co., Ltd.; ADP-Glo TM Protein kinase kit was purchased from Promega, USA; tubulin was purchased from Cytoskeleton, USA; 384-well assay plate and multifunctional microplate reader Envision were purchased from PerkinElmer, USA.

[0235] Enzyme activity assay: Compound powder was dissolved in DMSO to a 10 mM stock solution. Compounds were serially diluted in a microplate to a final concentration of 0–10 μM. Tubulin, compound, ATP, and KIF18A protein (2.5 μL each) were then added to the microplate in sequence and incubated at room temperature for 120 minutes. The final concentrations of the enzyme reaction were 60 μg / mL tubulin, 25 μM ATP, and 2.5 nM KIF18A protein. After the reaction, 10 μL of ADP-GLO reagent was added to each well and incubated at room temperature for 30 minutes. Subsequently, 20 μL of detection reagent was added to each well and incubated at room temperature for 30 minutes in the dark. Chemiluminescence detection was performed using a PerkinElmer Envision.

[0236] Table 1: Biological data of enzymatic activity of the compounds of the present invention

[0237] NT means not tested

[0238] Effect Example 2: Cell proliferation activity detection experiment

[0239] Materials and cells: OVCAR3 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. RPMI-1640 medium, fetal bovine serum, and the CyQUANT Direct Cell Proliferation Assay kit were purchased from Thermo Fisher Scientific; 96-well cell culture plates were purchased from Corning.

[0240] Cell culture: OVCAR3 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum in a 37°C, 5% CO2 incubator. Cells in the logarithmic growth phase were used for experiments.

[0241] Cell proliferation activity assay:

[0242] OVCAR3 cells were seeded into 96-well cell culture plates, with 90 μl per well, and incubated overnight in a 37°C, 5% CO2 incubator. Compound powder was dissolved in DMSO to a 10 mM stock solution. Compounds were serially diluted in a microplate to a final concentration of 0–10 μM. 10 μL of cell culture medium containing compound was added to each well, resulting in a final DMSO content of 0.2%. The cell plates were incubated at 37°C, 5% CO2 for 3 days. 100 μL of CyQUANT detection reagent was added to each well, incubated at 37°C for 60 minutes, and fluorescence detection was performed using PerkinElmer Envision.

[0243] Table 2: OVCAR-3 cell activity biological data of the compounds of the present invention

[0244] NT means not tested

[0245] Effect Example 3: CyQuant Cell Proliferation Activity Detection Experiment

[0246] Materials and cells: HT29 cells were purchased from Nanjing Kebai Biotechnology; RPMI-1640 medium was purchased from ThermoFisher (USA); fetal bovine serum was purchased from ThermoFisher (USA); Trypsin-EDTA (0.25%) was purchased from ThermoFisher (USA); DMSO was purchased from SIGMA (USA); 96-well plates were purchased from ThermoFisher (USA); and CyQuant reagents were purchased from ThermoFisher (USA).

[0247] Cell culture: HT29 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum at 37°C and 5% CO2. Cells in the logarithmic growth phase were used for experiments.

[0248] Cell proliferation activity assay: CyQuant reagent was used to detect the inhibitory activity of compounds on HT29 cell proliferation. Adjust the cell density, inoculate 100 μl per well of a 96-well plate (2000 / well for HT29), and culture overnight at 37°C and 5% CO2. Add the target compound at each concentration (starting concentration 3000 nM, 3-fold dilution, 9 concentration gradients), with a DMSO content of 0.2%. Incubate the cell plate at 37°C and 5% CO2 for 3 days. Add CyQuant reagent and incubate for 1 hour. Read the plate with Envision and calculate the IC using XLFIT. 50 .

[0249] Table 3: HT-29 cell activity biological data of the compounds of the present invention

[0250] NT means not tested

[0251] Effect Example 4: Cytotoxicity test of primary human hepatocytes.

[0252] Materials: One donor will be used for cytotoxicity testing. Information on primary human hepatocytes is provided in the table below.

[0253] Note: Hepatocytes from other ethnic groups may be used. The specific information will be reflected in the trial report.

[0254] 1) CellTiter-Glo Luminescent Cell Viability Assay System was purchased from Promega (Madison, WI).

[0255] instrument:

[0256] Experimental design:

[0257] Warm the following media to 37°C in a water bath: Prepare hepatocyte recovery medium, seeding medium, and incubation medium according to the table below.

[0258] Recovery medium

[0259] Inoculation medium

[0260] Incubation medium

[0261] 1) Take a tube of cryopreserved hepatocytes and ensure that the hepatocytes are still in a low-temperature frozen state before thawing. Quickly place the hepatocytes in a 37°C water bath and shake gently until all ice crystals are dispersed. Spray with 75% ethanol and transfer to a biosafety cabinet.

[0262] 2) The contents of the hepatocyte tubules (1 mL, about 5 × 10 6 Pour the cells into a 50 mL centrifuge tube containing 50 mL of recovery medium and centrifuge at 100 g for 10 minutes. After centrifugation, aspirate the recovery medium and add enough inoculation medium to obtain a cell density of approximately 1.0 × 10 6 cells / mL cell suspension. The cell count and viable cell density of hepatocytes were determined using a cell counter. The viability of hepatocytes must be greater than 80%. The cell density was adjusted to 0.2 × 10 6 cells / mL, inoculate 100 μL per well in a 96-well plate coated with collagen I. Place the plate in a 5% CO2 incubator, 95% relative humidity, and incubate at 37°C for 4–6 hours.

[0263] 3) Prepare a 200X stock solution of the test compound in DMSO (the concentration of the stock solution of the test compound can be reduced according to the solubility). The final DMSO concentration is 0.5%

[0264] 4) Add 2.5 μL of the test compound stock solution to 497.5 μL of hepatocyte culture medium to prepare a working solution in a sterile 96-well plate.

[0265] 5) Remove the hepatocyte culture medium from the cell plate and add 125 μL of the working solution to the corresponding wells. Repeat three times per well. Incubate the plate at 37°C, 5% CO2 for 72 hours. After each 24-hour treatment, replace the culture medium in the cell plate with freshly diluted test compound and positive control compound in hepatocyte culture medium. Return the cell plate to the incubator and add 50 μL of CellTiter-Glo reagent directly to each well of the 96-well plate. Shake the plate at room temperature for 10 minutes. After 10 minutes, transfer 100 μL of the above incubation medium to a new, white, flat-bottomed, opaque 96-well plate and record fluorescence.

[0266] Data Analysis:

[0267] All calculations were performed using Microsoft Excel.

[0268] The survival rate of the test compound can be calculated using the following formula:

[0269] The %Vehicle concentration was fitted to the test compound concentration, and the data were then fitted to a variable slope sigmoidal dose-response curve using GraphPad Prism 5.0. The IC50 of the compound was calculated based on the curve using the following formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[0270] Effect Example 5: Experimental test of human primary hepatocyte microsphere model

[0271] Cells: Donor information: Male, Caucasian, 36 years old (Lot No. NFX, BioIVT)

[0272] instrument:

[0273] Cell seeding and culture:

[0274] 1) Take a vial of cryopreserved hepatocytes and ensure they are frozen before thawing. Immediately place the cells in a 37°C water bath and gently shake until all ice crystals are dispersed. Spray with 70% ethanol and transfer to a biosafety cabinet.

[0275] 2) Pour the contents of the hepatocyte tubules into a 50 mL centrifuge tube containing 50 mL of recovery medium and centrifuge at 100 g for 3 minutes. After centrifugation, aspirate the recovery medium and add enough incubation medium to obtain a cell density of approximately 1.0 x 10 6 cells / mL cell suspension.

[0276] 3) Count the hepatocytes and determine the viable cell density using a Cellometer Vision. The hepatocyte viability must be greater than 80%. Adjust the cell density to 4,000 cells / well using inoculation medium, inoculating 100 μL per well.

[0277] 4) Place the cells in a cell culture incubator and incubate at 37°C for 7-9 days until microspheres are formed.

[0278] Preparation and administration of compounds:

[0279] 1) Dilute the compound using cell culture medium using a three-fold dilution method. The dilution gradient is shown in the table below. The maximum concentration of the control compound is 200 μM, the maximum concentration of the test compound (depending on the customer's requirements) is 5 μM, and the final DMSO concentration is 0.1%.

[0280] 2) After microspheres have formed, administer the drug. Before each administration, aspirate the culture medium from the cell culture plate wells and add 100 μL of compound working solution. Administer the drug every three days until the fourteenth day after microsphere formation.

[0281] Test index detection:

[0282] 1) After 14 days of culture, remove the cell culture plate from the incubator and collect 80 μL of supernatant to detect the levels of albumin and lactate dehydrogenase.

[0283] 2) CellTiter-FluorTM Thaw the Cell Viability Kit at room temperature, add 10 μL of GF-AFC substrate to 10 mL of 2× working solution, and add an equal volume of PBS to dilute it to 1× working solution.

[0284] 3) Add 100 μL of working solution to each well of the cell culture plate and incubate at 37°C for 30 min. Then, aspirate 80 μL of the supernatant into a 96-well black plate and measure the absorbance at an excitation wavelength of 400 nm and an emission wavelength of 505 nm.

[0285] Data Analysis:

[0286] 1) The cell survival percentage (% Vehicle) was calculated using the following formula:

[0287] 2) IC was calculated using GraphPad Prism 8.0.2 50 The software calculation formula is as follows: Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof: in, W 1 Indicates CR W1 or N; Among them, W 2 Indicates CR W2 or N; Among them, W 3 Indicates CR W3 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, 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 and -O-halogenated C1-C6 alkyl groups substituted C1-C6 alkyl or C3-C6 cycloalkyl; Among them, R W1 、R W2 and R W3 Each independently represents hydrogen, halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a , -SF5 or -NR a R b ; Among them, Cy 1 represents a 6-12 membered aryl or a 5-12 membered heteroaryl; 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 ; Wherein, Ring A represents a saturated or unsaturated 4-12 membered ring, preferably a 5-12 membered ring; and the ring may optionally contain 0-3 heteroatoms selected from O, N and S, and the Ring A may also be arbitrarily substituted with 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, halo 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 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; Here, m, o, p, and q represent integers from 0 to 3.

2. A compound having the structure of formula (II) 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, 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 and -O-halogenated C1-C6 alkyl groups substituted C1-C6 alkyl or C3-C6 cycloalkyl; Among them, R W1 and R W2 Each independently represents hydrogen, halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O-halogenated C1-C6 alkyl、-SR a , -SF5 or -NR a R b ; Among them, Cy 1 represents a 6-12 membered aryl or a 5-12 membered heteroaryl; 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 any There are 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 ; Wherein, Ring A represents a saturated or unsaturated 4-12 membered ring, preferably a 5-12 membered ring; and the ring may optionally contain 0-3 heteroatoms selected from O, N and S, and the Ring A may also be arbitrarily substituted with 0-3 groups selected from the following substituents: halogen, C1-C6 alkyl, halo 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 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; Here, m, o, p, and q represent integers from 0 to 3.

3. 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.

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: W 2 Indicates CH or N.

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-、-SO2NR a -or-S(=O)(NR a )-.

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: L 3 Indicates -NR a SO2-.

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 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.

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: 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.

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 -NR S R S' .

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: 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.

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: Z stands for:

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 represents -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl, 14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: L 1 It represents -C(O)NH-.

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: Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a 、-SF5、cyano、nitro、-NR a R b 、-NR a C(O)R b 、-C(O)NR a R b 、-OC(O)R a 、-C(O)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Any of the following groups substituted: For example:

18. The compound according to claim 17 or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a 、-SF5、cyano、nitro、-NR a R b 、-NR a C(O)R b 、 -C(O)NR a R b 、-OC(O)R a 、-C(O)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Any of the following groups substituted:

19. The compound according to claim 18 or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a 、-SF5、cyano、nitro、-NR a R b 、-NR a C(O)R b 、-C(O)NR a R b 、-OC(O)R a 、-C(O)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Replaced 20. The compound according to claim 18 or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 1 represents a phenyl group, a pyridyl group, a thiazolyl group, an oxazolyl group, a pyrazolyl group, an imidazolyl group, or an N-methylpyrazolyl group.

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

22. The compound according to claim 18 or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 1 represents 0-3 substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, OR a , -O-halogenated C1-C6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a 、-SF5、cyano、nitro、-NR a R b 、-NR a C(O)R b 、-C(O)NR a R b 、-OC(O)R a 、-C(O)R a 、-P(O)R a R b 、-C(O)OR a 、-S(O)R a 、-S(O)2R a and -S(O)2NR a R b Replaced 23. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, stereoisomer, isotopomer, prodrug, hydrate or solvate thereof, wherein: L 2 represents the absence of -C1-C6 alkylene- or -NH-.

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

25. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Cy 2 represents 0-3 substituents selected from the following: halogen, cyano, nitro, hydroxy C1-C6 alkyl, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl, -OR a 、-SO3R a 、-S(O)R a 、-O halo C1-C6 alkyl、-SR a , -SF5 or NR a R b substituted morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl or tetrahydrofuranyl, wherein R a 、R b Each independently represents hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C1-C6 alkyl or hydroxy C1-C6 alkyl; or R 1a 、R 1b 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.

26. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, stereoisomer, isotopomer, prodrug, hydrate or solvate thereof, wherein: Cy 2 express 27. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Ring A represents a benzene ring or Among them, W 1 Indicates CH or N, Wherein, the dotted line represents a single bond or a double bond; Ring A may also be arbitrarily 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 .

28. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Ring A represents Among them, W 1 Indicates CH or N; Ring A may also be arbitrarily 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 .

29. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Ring A represents: benzene ring, pyridine ring, pyrazine ring, cyclobutane ring, cyclopentane ring, tetrahydrofuran ring, oxazole ring, thiazole ring, thiophene ring, pyrazole ring, imidazole ring, piperidine ring, hexahydropyran ring, cyclohexane ring; Ring A may also be arbitrarily 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 .

30. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof, wherein: Ring A is fused thereto Together the rings form the following structure: Ring A may also be arbitrarily 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 .

31. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, stereoisomer, isotopomer, prodrug, hydrate or solvate thereof, wherein: Ring A is fused thereto Together the rings form the following structure:

32. A compound having the following structure: