KIF18a inhibitor and use thereof

Abstract

Disclosed in the present invention is a KIF18A inhibitor. More specifically, disclosed in the present invention is a compound as shown in formula (1), or a pharmaceutically acceptable salt thereof. The compound has KIF18A inhibitory activity, and can be used for treating cancers.

Description

A KIF18A inhibitor and its use Technical Field

[0001] The present invention relates to a KIF18A inhibitor and uses thereof. Background Art

[0002] Genetic instability is a common feature of tumor cells, with many tumor cells exhibiting chromosome losses or gains. This chromosomal instability (CIN) is primarily due to cellular defects that lead to abnormal interactions between chromosomes and spindle microtubules, which in turn increase chromosome segregation errors. While CIN contributes to tumor progression, heterogeneity, drug resistance, and metastasis, some have proposed that the same properties that drive instability may be a potential Achilles' heel for CIN cell-specific targeted therapies. Compared to cells with stable chromosomes, CIN cells exhibit increased spindle microtubule polymerization and decreased turnover of attachments between spindle microtubules and centromeres—specific protein structures that aggregate at the centromere region of mitotic chromosomes. Microtubule-targeting drugs are effective therapeutics for a variety of tumors. Paclitaxel, a microtubule-stabilizing drug routinely used in the treatment of solid tumors, induces cytotoxicity by preventing cells from completing mitosis. However, due to its broad-spectrum tubulin inhibition, paclitaxel also exhibits significant side effects on normal cells, including myelosuppression and neurotoxicity.

[0003] The KIF18A protein is a member of the kinesin superfamily and plays an important role in many cellular processes, such as microtubule dynamics, organelle transport, and cell division. KIF18A can bind to microtubules and use the energy released by hydrolyzing ATP to move along the microtubules, thereby playing an important role in the positioning of membrane organelles and protein complexes. KIF18A not only promotes microtubule depolymerization during mitosis by gathering at the plus ends of microtubules, but also controls the stability of microtubule ends in the mitotic spindle. Studies have shown that KIF18A regulates chromosomes and inhibits centromere movement by controlling the arrangement of mitotic chromosomes. Dysfunction of KIF18A can lead to chromosomal instability. Studies have shown that KIF18A is associated with the occurrence and development of non-small cell lung cancer, colorectal cancer, breast cancer, liver cancer, and gastric cancer.

[0004] Studies have shown that KIF18A affects the movement of the plus ends of kinetochore microtubules to control correct chromosome positioning and spindle tension. In tumor cells with chromosomal instability, abnormal microtubule movement makes these cells particularly dependent on KIF18A protein to reduce the contact conversion between spindle microtubules and centromeres and limit microtubule growth (Nat Commun. 2021, 12, 1213). When KIF18A protein is missing in tumor cells with chromosomal instability, the centrosome of the cell will fragment, and the mitotic process will slow down or terminate. However, this phenomenon does not occur in cells with normal chromosomes. Therefore, the activity of KIF18A protein has no effect on the proliferation of normal cells, but it is crucial for the growth of tumor cells with chromosomal instability.

[0005] Therefore, the development of KIF18A inhibitors is a new potential approach for treating tumors with chromosomal instability.

[0006] There are currently some inhibitors targeting KIF18A, such as Sovilnesib (AMG 650):

[0007] The bioavailability of this type of inhibitor needs to be further improved.

[0008] Summary of the Invention

[0009] Targeting KIF18A, the present invention provides a new KIF18A inhibitor that not only has good KIF18A inhibitory activity but also has more significant bioavailability, bringing good news to patients.

[0010] Specifically, the compound represented by general formula (1) or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvent

[0011] Compound:

[0012] in:

[0013] X1, X4, X6, X7, X8 are each independently N or C;

[0014] X2, X5 are each independently N, S or C;

[0015] X3 is independently at each occurrence a bond, N or C;

[0016] R1 is halogen or group -YR 13 , where Y is a chemical bond, -C 0-4 Hydrocarbyl-, -N(C 0-1 Hydrocarbon)-C 0-4 Hydrocarbyl-, -C(=O)NR a-(C 1-4 Hydrocarbon)-、-OC 0-4 Hydrocarbyl-, -S-, -S(=O)-, -SO2-, -SO2NR9 or -S(=O)(=NH)-;

[0017] R3 is -CN or a group -ZR 12 , where Z is -C 0-4 Alkyl-, -NR 11 -、-NR 11 SO2-、-SO2NR 11 -、-NR 11 -S(=O)(=NH), -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, C 0-4 Alkyl-O-, -(C=O)-, -(C=O)NR 11 -, -C=N(OH)- or -NR 11 (C=O); or the group -ZR 12 -N=S(=O)-(R 12 )2, where two R 12 Alternatively, they may be combined with their respective attached S to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N and 0, 1, or 2 selected from O or S;

[0018] R4 is H, halogen, R 4a or R 4b ;

[0019] R5 is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0020] R 11 H, R 11a or R 11b ;

[0021] R 12 H, R 12a or R 12b ;

[0022] R 13 R 13a or R 13b ;

[0023] R a is independently H or R b ;and

[0024] R b In each case, independently C 1-6 alkyl, phenyl or benzyl, wherein the C 1-6The alkyl group is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C 1-4 Alkyl)C 1-4 Alkyl; and the phenyl or benzyl is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-3 Halogenated alkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C 1-4 Alkyl)C 1-4 alkyl;

[0025] R 4a 、R 11a 、R 12a 、R 13a is independently selected in each case from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N and 0, 1 or 2 O or S, substituted with 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, C 1-6 Alkyl, C 1-4 Haloalkyl, -OR a 、-OC 1-4 Haloalkyl, CN, -C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC 2-6 Alkyl NR a R a 、-OC 2-6 Alkyl OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NRaRa、-NR a C 2-6 Alkyl NR a R a 、-NR a C 2-6 Alkyl OR a 、-C 1-6 Alkyl NR a R a 、-C 1-6 Alkyl OR a 、-C 1-6 Alkyl N(R a )C(=O)R b 、-C 1-6 Alkyl OC(=O)R b 、-C 1-6 Alkyl C(=O)NR a R a 、-C 1-6 Alkyl C(=O)OR a 、R 14 and oxo;

[0026] R 4b 、R 11b 、R 12b 、R 13b In each case, independently selected from the group consisting of: C 1-6 Alkyl, which is replaced by F, Cl, Br, -OR a 、-OC 1-4 substituted with haloalkyl or CN, the number of substituents being selected from 0, 1, 2, 3, 4 or 5;

[0027] R 14is independently selected in each case from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N and 0 or 1 O or S, substituted with 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, C 1-6 Alkyl, C 1-4 Haloalkyl, -OR a 、-OC 1-4 Haloalkyl, CN, -C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(= NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC 2-6 Alkyl NR a R a 、-OC 2-6 Alkyl OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(Ra)C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2-6 Alkyl NR a R a 、-NR a C 2-6 Alkyl OR a 、-C1-6 Alkyl NR a R a 、-C 1-6 Alkyl OR a 、-C 1-6 Alkyl N(R a )C(=O)R b 、-C 1-6 Alkyl OC(=O)R b 、-C 1-6 Alkyl C(=O)NR a R a 、-C 1-6 Alkyl C(=O)OR a and oxo;

[0028] R2 is selected from the group consisting of:

[0029] E is a chemical bond, -O-, -S- or -ZR 201 -;

[0030] Wherein, Z is a chemical bond, -O- or -S-, R 201 C 1-3 Alkyl, wherein the C 1-3 The alkyl group is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-2 Alkyl, -NH2;

[0031] R 100 、R 101 、R 102 、R 103 、R 104 、R 105 、R 106 、R 107 、R 108 、R 109 and R 110 Each of H, halogen, R 100a ; or, R 100 and R 101 、R 102 and R 103 、R 104 and R 105 , or R 106 and R 107 independently combine with their respective attached C to form a saturated or partially saturated 3-membered or 4-membered monocyclic ring; wherein the 3-membered or 4-membered monocyclic ring contains 0, 1 N and 0, 1 or 2 selected from O or S, wherein the 3-membered or 4-membered monocyclic ring is substituted with 0, 1, 2 or 3 substituents selected from the following: F, Cl, Br, C 1-2 Alkyl, C 1-2 Haloalkyl, -ORa 、-OC 1-4 Haloalkyl, CN, -NR a R a or oxo;

[0032] R 100a In each case, independently C 1-6 Alkyl, phenyl or benzyl, wherein the C1-6 alkyl is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C 1-4 Alkyl)C 1-4 Alkyl; and the phenyl or benzyl is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-3 Halogenated alkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C 1-4 Alkyl)C 1-4 alkyl;

[0033] R 16 Selected from -CN, H, deuterium, -C(=O)-R 16a 、-C(=O)-R 16b ;

[0034] R 16a is a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 N and 0 or 1 O or S, which is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, C 1-6 Alkyl, C 1-4 Haloalkyl, -OR a 、-OC 1-4 Haloalkyl, CN, -C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC 2-6 Alkyl NR a R a 、-OC2-6 Alkyl OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(Ra)C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2-6 Alkyl NR a R a 、-NR a C 2-6 Alkyl OR a 、-C 1-6 Alkyl NR a R a 、-C 1-6 Alkyl OR a 、-C 1-6 Alkyl N(R a )C(=O)R b 、-C 1-6 Alkyl OC(=O)R b 、-C 1-6 Alkyl C(=O)NR a R a 、-C 1-6 Alkyl C(=O)OR a and oxo;

[0035] R 16b -NH2, C 1-4 Alkyl, substituted by 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C 1-4 Alkyl)C 1-4alkyl.

[0036] Furthermore, provided are compounds represented by general formula (1a), (1b), (1c) or (1d) or stereoisomers, pharmaceutically acceptable salts, hydrates or solvates thereof:

[0037] Alternatively, provided is a compound represented by general formula (2a), formula (2b), formula (2c) or formula (2d), or a stereoisomer, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0038] Alternatively, provided are compounds represented by general formula (3a), formula (3b), formula (3c), formula (3d), or stereoisomers, pharmaceutically acceptable salts, hydrates, or solvates thereof:

[0039] Alternatively, provided is a compound represented by general formula (4a), formula (4b), formula (4c) or formula (4d) or a stereoisomer, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0040] Alternatively, provided is a compound represented by general formula (5a), formula (5b), formula (5c) or formula (5d), or a stereoisomer, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0041] Alternatively, provided is a compound represented by general formula (6a), formula (6b), formula (6c) or formula (6d) or a stereoisomer, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0042] Furthermore, the structural unit Can be

[0043] According to the quality of the activity, the present invention can be preferably

[0044] Furthermore, R5 is H, methyl or ethyl, preferably H.

[0045] Wherein, E is a chemical bond, -O- or -S-, R 201 C 1-3 Alkyl, wherein the C 1-3 The alkyl group is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-2 Alkyl, -NH2.

[0046] Among them, R 100 、R101 、R 102 、R 103 、R 104 、R 105 、R 106 、R 107 、R 108 、R 109 and R 110 Each of H, halogen, R 100a ; or alternatively, R 100 and R 101 、R 102 and R 103 、R 104 and R 105 or R 106 and R 107 Each of the 3-membered, 4-membered rings independently combines with their respective attached C to form a saturated or partially saturated 3-membered, 4-membered monocyclic ring; wherein the 3-membered, 4-membered monocyclic ring contains 0, 1 N and 0, 1 or 2 selected from O or S, and further wherein the 3-membered, 4-membered monocyclic ring is substituted with 0, 1, 2 or 3 substituents selected from the following: F, Cl, Br, C 1-2 Alkyl, C 1-2 Haloalkyl, -OR a 、-OC 1-4 Haloalkyl, CN, -NR a R a or oxo.

[0047] Among them, R 100a In each case, independently C 1-6 alkyl, phenyl or benzyl, wherein the C 1-6 The alkyl group is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C 1-4 Alkyl)C 1-4 Alkyl; and the phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-3 Halogenated alkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C1 -4 Alkyl or -N(C 1-4 Alkyl)C 1-4 alkyl.

[0048] Wherein, R1 is halogen or group YR 13 , where Y is a chemical bond or -NH-; R13 is a saturated, partially saturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1 or 2 N and 0 or 1 selected from O or S, wherein each of said rings is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, C 1-6 Alkyl, C 1-4 Halogenated alkyl, -OH, -OC 1-4 Haloalkyl, CN, R 14 and oxo; or R 13 C 1-6 Hydrocarbyl, which may be substituted with 0, 1, 2, 3, 4 or 5 of the following substituents: F, Cl, Br, -OH, -OC 1-4 Halogenated hydrocarbon or CN.

[0049] Further, R1 is a saturated 5-membered or 6-membered monocyclic ring, wherein each of the rings contains 0, 1 or 2 N and 0, 1 O, and wherein each of the rings is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, -OH, -OC 1-4 Hydrocarbon, C 1-4 Halogenated hydrocarbon, CN, R 14 and oxo.

[0050] Furthermore, R1 is:

[0051] (a) halogen;

[0052] (b) Group -YR 13 , where Y is a chemical bond, R 13 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, wherein each of said rings is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, methyl, -CF3, -OH, -OCHF2, -CN and oxo;

[0053] or (c) group -YR 13 , wherein Y is -NH-, -O-, -O-(CH2)-, -O-(CH2)-(CH2)- or -O-(CH2)-(CH2)-(CH2)- and wherein R 13 for or R 13 is C substituted with 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, methyl, CF3, -OH or CN 1-6 alkyl.

[0054] , R1 is morpholinyl or piperidinyl, and the morpholinyl and piperidinyl may be optionally substituted by 0, 1, 2 or 3 of the following substituents: F, Cl, Br, methyl, CF3, -OH, -OCHF2, CN.

[0055] Furthermore, R1 can be selected from

[0056] Wherein, R3 is -CN or group -ZR 12 , wherein Z is a chemical bond, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH- or -NH(C=O)-.

[0057] Among them, R 12 Selected from:

[0058] (a)H;

[0059] (b)C 1-6 Hydrocarbyl, which may be optionally substituted with 0, 1, 2 or 3 of the following substituents: -OH, F, Cl, Br or -OCH3;

[0060] or (c) when the group -ZR 12 -N=S(=O)-(R 12 )2, wherein the two R 12 and the S to which they are attached form a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 N and 1 selected from O or S, which is substituted by 0, 1, 2 or 3 substituents selected from the following: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -C 1-6 Hydrocarbyl -OH, -OH, -OCH3, -NH2 or oxo.

[0061] Furthermore, R 12 Selected from:

[0062] (a)H;

[0063] (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, and wherein each of said rings may be independently substituted with 0, 1, 2 or 3 of the following substituents: -OH, F, methyl, -CH2OH, -C(=O)OCH3, -C(=O)-OC(CH3)3, NH2, CN and oxo;

[0064] or (c) C substituted with 0, 1, 2 or 3 -OH, F, methyl, -C(=O)OCH3, NH2, -NH(CH3)- or -N(CH3)2 1-6 Hydrocarbyl; preferably C substituted with 0, 1, 2 or 3 -OH 1-6 Hydrocarbyl; more preferably C substituted by 1 -OH 1-6 Hydrocarbon group.

[0065] Furthermore, the group -ZR 12 -N=S(=O)-(R 12 )2, where two R 12 Combined with the S to which they are attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N and 0, 1 or 2 selected from O or S; preferably -ZR 12 Selected from

[0066] Among them, R3 is -ZR 12 , wherein Z is -NHSO2- or -SO2NH-; and R 12 is oxetane, cyclopropyl, or R 12 C substituted with 0, 1, 2 or 3 -OH groups 1-6 Hydrocarbyl; preferably, R3 is -ZR 12 , wherein Z is -NHSO2- or -SO2NH-, and R 12 is -CH2CH2OH or -CH(CH3)-CH2OH; more preferably -NHSO2-, and R 12 It is -CH2CH2OH.

[0067] Wherein, R4 is H, halogen, R 4a or R 4b .

[0068] Further, R4 is selected from (a) H; or (b) C substituted by 0, 1, 2 or 3 halogens. 1-6 or (c) cyclopropyl; preferably, the group R4 is selected from -H, -F or -CH3.

[0069] Among them, R 16a is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl; which is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, C 1-6 Alkyl, C 1-4 alkyl halide;

[0070] R 16b -NH2, C1-4 Alkyl, substituted by 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, -OH.

[0071] Alternatively, a compound represented by general formula (7) or a stereoisomer, pharmaceutically acceptable salt, hydrate or solvate thereof is provided:

[0072] R1 is

[0073] X3 is N or C;

[0074] R4 is H, deuterium, C 1-4 alkyl;

[0075] R 15 -(CH2) n -OH, substituted or unsubstituted C 1-4 Alkyl, substituents are selected from halogen.

[0076] Furthermore, the halogen is selected from F; and n is selected from 1-4.

[0077] Furthermore, formula (7) is selected from formula (7a) or (7b):

[0078] Where X3 is N.

[0079] Wherein, R4 is H, deuterium, or methyl.

[0080] Among them, R 15 It is -CH2F, -(CH2)2-OH, and methyl.

[0081] Alternatively, a compound represented by general formula (8) or a stereoisomer, pharmaceutically acceptable salt, hydrate or solvate thereof is provided:

[0082] X3 is N or C;

[0083] R4 is H, deuterium, or methyl.

[0084] More specifically, the compound of the present invention is selected from one of the following:

[0085] More specifically, the compound of the present invention can also be selected from one of the following:

[0086] According to the activity, the present invention can preferably use one of the following compounds:

[0087] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and the aforementioned compound, or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate as an active ingredient.

[0088] The present invention also provides use of the above-mentioned compound or its stereoisomers, pharmaceutically acceptable salts, hydrates or solvates in the preparation of KIF18A inhibitors.

[0089] The KIF18A inhibitor is a drug for treating related diseases mediated by KIF18A protein.

[0090] Furthermore, the disease is cancer, including blood cancer and solid tumors.

[0091] Therapeutic uses

[0092] The compounds or pharmaceutical compositions of the present invention are generally useful for inhibiting KIF18A protein, and are therefore useful for treating one or more diseases associated with KIF18A protein activity. Therefore, in certain embodiments, the present invention provides a method for treating a disease mediated by KIF18A protein, comprising administering to a patient in need thereof an effective dose of the aforementioned compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0093] In some embodiments, the present invention may also provide a method for treating cancer, comprising administering an effective dose of the aforementioned compound, or a stereoisomer thereof, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof. These cancers may be mediated by the KIF18A protein.

[0094] In other embodiments, the cancer is a hematological cancer or a solid tumor.

[0095] The cancers described in the present invention include, but are not limited to, hematological malignancies (hematologic malignancies, lymphomas, myelomas including multiple myeloma, myelodysplastic syndrome and myeloproliferative syndrome) and solid tumors (cancers such as prostate, breast, lung, colon, pancreas, kidney, ovary and soft tissue cancers and osteosarcoma, as well as stromal tumors).

[0096] Furthermore, the cancers described herein include, but are not limited to, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute or chronic myeloid leukemia, myelodysplastic syndrome, promyelocytic leukemia, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratoma, osteosarcoma, pigmentoma, keratoma, follicular thyroid carcinoma, and Kaposi's sarcoma.

[0097] Route of administration

[0098] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various formulations containing a safe and effective amount of the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined based on the specific circumstances of the patient, such as the patient's age, condition, and duration of treatment.

[0099] The term "pharmaceutically acceptable" as used herein includes any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.

[0100] The pharmaceutically acceptable excipients described in the present invention are a general term for all additional materials in a drug other than the main drug. Excipients should have the following properties: (1) be non-toxic to the human body and have almost no side effects; (2) be chemically stable and not easily affected by temperature, pH, storage time, etc.; (3) have no incompatibility with the main drug and do not affect the efficacy and quality inspection of the main drug; (4) do not interact with the packaging material. Excipients in the present invention include but are not limited to fillers (diluents), lubricants (glidants or anti-adhesives), dispersants, wetting agents, adhesives, regulators, solubilizers, antioxidants, antibacterial agents, emulsifiers, disintegrants, etc. Binders include syrup, gum arabic, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methyl cellulose, etc.), gelatin slurry, syrup, starch slurry or polyvinyl pyrrolidone, etc.; fillers include lactose, powdered sugar, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; lubricants include micropowdered silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrants include starch and its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, etc. , pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinyl pyrrolidone or microcrystalline cellulose, etc.; wetting agents include sodium lauryl sulfate, water or alcohol, etc.; antioxidants include sodium sulfite, sodium bisulfite, sodium metabisulfite, dibutyl benzoic acid, etc.; antibacterial agents include 0.5% phenol, 0.3% cresol, 0.5% trichlorobutanol, etc.; regulators include hydrochloric acid, citric acid, potassium (sodium) hydroxide, sodium citrate and buffers (including sodium dihydrogen phosphate and disodium hydrogen phosphate), etc.; emulsifiers include polysorbate 80, sorbitan monophosphate, Pluronic F-68, lecithin, soy lecithin, etc.; solubilizers include Tween-80, bile, glycerol, etc.

[0101] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include, but are not limited to, oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0102] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0103] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0104] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0105] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0106] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0107] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0108] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0109] The compounds of the present invention can also be used in injectable preparations. The injectable preparations are selected from liquid injections (water injections), sterile powders for injection (powder injections), or injectable tablets (which are molded or machine-pressed tablets made using aseptic techniques, dissolved in water for injection, and intended for subcutaneous or intramuscular injection).

[0110] The powder for injection contains, in addition to the above-mentioned compound, at least an excipient. The excipient herein is an ingredient intentionally added to a drug and should not have pharmacological properties in the amount used. However, the excipient may aid in drug processing, solubility or dissolution, drug delivery via targeted routes of administration, or contribute to drug stability.

[0111] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0112] Explanation of terms

[0113] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention formed with acids or bases suitable for pharmaceutical use. The aforementioned acids and bases are broadly defined as Lewis acids and bases. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0114] The term "membered" refers to the number of atoms constituting the backbone of a ring or heteroalkyl group.

[0115] The "chemical bond" mentioned in the present invention means that there is only one connecting bond.

[0116] "Hydrocarbon group" refers to an organic compound containing only carbon and hydrogen. The group remaining after a hydrocarbon loses a hydrogen atom (H) is called a "hydrocarbon group". Hydrocarbons include aliphatic hydrocarbons, alicyclic hydrocarbons, and aromatic hydrocarbons. Aliphatic hydrocarbons are divided into saturated hydrocarbons (alkanes, such as methane and ethane) and unsaturated hydrocarbons (alkenes such as ethylene and propylene, and alkynes such as acetylene and propyne); aliphatic hydrocarbons include cycloalkanes (such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane), cycloalkenes (such as cyclopropene, cyclobutene, cyclopentene, and cyclohexene); aromatic hydrocarbons include monocyclic aromatic hydrocarbons (such as benzene), condensed-ring aromatic hydrocarbons (such as naphthalene and anthracene), and polycyclic aromatic hydrocarbons (such as biphenyl).

[0117] "Alkyl" refers to an aliphatic hydrocarbon group, including saturated hydrocarbon groups. The alkyl portion can be either straight-chain or branched. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

[0118] The C used in the present invention 1-n Including C 1-2 、C 1-3 ...C 1-n , n is an integer greater than one, indicating the minimum and maximum number of carbon atoms, for example, "C 1-6 "Alkyl" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms.

[0119] Heteroatoms include, but are not limited to, O, S, N, P, Si, and the like.

[0120] "Ring" refers to any covalently closed structure, including, for example, a carbocyclic ring (e.g., an aryl or cycloalkyl group), a heterocyclic ring (e.g., a heteroaryl or heterocycloalkyl group), an aromatic group (e.g., an aryl or heteroaryl group), or a non-aromatic group (e.g., a cycloalkyl or heterocycloalkyl group). The "ring" herein may be a monocyclic ring or a polycyclic ring, and may be a fused ring, a spirocyclic ring, or a bridged ring.

[0121] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0122] "Deuterium" refers to the isotope of hydrogen (H), also known as heavy hydrogen, and the element symbol is generally D or 2 H, deuterium can be used to replace the position of H in the present invention. The compounds disclosed in the present invention include all pharmaceutically acceptable isotope-labeled (or substituted) compounds; substitution with heavier isotopes, such as D, can provide certain therapeutic advantages, such as extended half-life, reduced dosage, etc.

[0123] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0124] "Halogenation" means that the hydrogen atoms in a molecule are replaced by halogens. For example, "C 1-4 "Haloalkyl" refers to C 1-4 One or more hydrogen atoms in the alkyl group are substituted with halogen, for example, -CH2F, -CHF2, -CF3, -CH2CH2Cl, -CH2CH2CH2Br and the like.

[0125] A "substituent" generally refers to a group that replaces a hydrogen atom in an organic compound.

[0126] "Inhibitor" refers to a product that reduces the biological activity of a protein. For example, the compound of the present invention can reduce the activity of KIF18A protein, which is a KIF18A inhibitor.

[0127] "Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in molecules. They can be divided into cis-trans isomers and enantiomers, or into two major categories: enantiomers and diastereomers.

[0128] "Hydrate" usually refers to crystalline hydrate, which is a substance containing a certain amount of crystal water.

[0129] "Solvate" refers to a complex formed by an active compound and a pharmaceutically acceptable solvent. BRIEF DESCRIPTION OF THE DRAWINGS

[0130] Figure 1 shows the changes in tumor volume (Mean ± SEM) in the first batch of experimental mice OVCAR-3 subcutaneous tumor models. Figure 1 shows that compound 819 of the present invention can effectively inhibit tumor growth in the OVCAR-3 subcutaneous transplanted tumor model in mice at doses of 30 mpk (mpk, i.e., mg / kg, the same below).

[0131] Figure 2 shows the changes in tumor volume in the OVCAR-3 subcutaneous tumor model of the second batch of experimental mice (Mean ± SEM). Figure 2 shows that the compound 819 of the present invention at 30 mpk, 834 at 15 mpk and 30 mpk, and 834b at 15 mpk and 30 mpk can effectively inhibit tumor growth in the OVCAR-3 subcutaneous tumor model of mice.

[0132] Figure 3 shows the blood neutrophil count of mice. Figure 3 shows that after 21 days of administration of compounds 834 and 834b at a dose of 30 mpk, and after 7 days of observation, there was no significant difference in the blood neutrophil count between the mice in the treatment group and the control group, indicating that 834 and 834b at a dose of 30 mpk had no significant cytotoxicity to mice. DETAILED DESCRIPTION

[0133] 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 test methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0134] Some representative compounds of the present invention can be prepared by the following synthetic methods. In the following reaction formulas, the reagents and conditions of each step can be selected from conventional reagents or conditions for such preparation methods in the art. After the structures of the compounds of the present invention are disclosed, the above selection can be made by those skilled in the art based on their knowledge in the art.

[0135] Ac=Acetyl

[0136] Me = methyl

[0137] Boc = tert-butyloxycarbonyl

[0138] t-BuOK = Potassium tert-butoxide

[0139] m-CPBA = meta-chloroperbenzoic acid

[0140] DAST = diethylaminosulfur trifluoride

[0141] DCM = dichloromethane

[0142] PE = Petroleum Ether

[0143] EA = ethyl acetate

[0144] DMF=N,N-dimethylformamide

[0145] DMSO = dimethyl sulfoxide

[0146] DMAP = 4-dimethylaminopyridine

[0147] TEA = triethylamine

[0148] DIPEA=N,N-diisopropylethylamine

[0149] NMP = N-methylpyrrolidone

[0150] Ph = phenyl

[0151] TFA = trifluoroacetic acid

[0152] THF = Tetrahydrofuran

[0153] Pre-HPLC = Preparative High Performance Liquid Chromatography

[0154] Dioxane=1,4-dioxane

[0155] Example 1 Synthesis of compound intermediate IM-01.

[0156] CM-03 (3.2 g, 22.3 mmol, 1.0 eq) and 4,4-difluoropiperidine hydrochloride (5.25 g, 33.5 mmol, 1.5 eq) were dispersed in 1,4-dioxane (30 mL). A catalytic amount of sodium iodide and DIPEA (11.63 mL, 66.9 mmol, 3 eq) were added and heated to 85°C for overnight reaction. After the starting material disappeared, the resulting reaction solution was cooled to room temperature, separated by addition of water (150 mL), and extracted with dichloromethane (40 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to afford compound IM-01 (4.1 g, yield: 80%) as a white solid.

[0157] ESI-MS m / z:229.1[M+H] + .

[0158] Example 2 Synthesis of compound intermediate IM-02

[0159] Step 1: Synthesis of compound CM-02

[0160] Under nitrogen protection, CM-01 (5 g, 27.0 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (20 mL). One drop of DMF was added, and oxalyl chloride (3.43 mL, 40.5 mmol, 1.5 eq) was slowly added under ice-bath. After the addition was complete, the ice-bath was removed and the mixture was reacted at room temperature for 30 min. When LC-MS monitoring showed the reaction was complete, the solvent was removed under reduced pressure to obtain the crude compound CM-02 for later use.

[0161] Step 2: Synthesis of compound IM-02

[0162] Under nitrogen, IM-01 (4.95 g, 21.6 mmol, 0.8 eq) and a catalytic amount of DMAP were dissolved in 2-methyltetrahydrofuran (40 mL). DIPEA (9.4 mL, 54 mmol, 2.0 eq) was added, and a solution of CM-02 (obtained in step 1) in anhydrous tetrahydrofuran (20 mL) was added dropwise under an ice bath. After completion, the reaction system was heated to reflux and allowed to react overnight. After LC-MS monitoring indicated the reaction was complete, the resulting solution was cooled to room temperature and diluted with water (100 mL). The product precipitated and was filtered. Petroleum ether (150 mL) was added, and the resulting mixture was purified by slurrying to afford compound IM-02 (6.35 g, 59% yield) as a yellow solid.

[0163] ESI-MS m / z:396.1[M+H]+ .

[0164] Example 3 Synthesis of Compound Intermediate IM-31

[0165] 2-Amino-6-chloro-4-methylpyridine (1.0 g, 7.04 mmol, 1.0 eq), 4,4-difluoropiperidine hydrochloride (1.66 g, 10.56 mmol, 1.5 eq), and sodium carbonate (746 mg, 7.04 mmol, 1.0 eq) were dispersed in NMP (10 mL). DIPEA (1.84 mL, 10.56 mmol, 1.5 eq) was added and the mixture was heated to 230°C in a microwave oven at 12 atm for 3 h. After the starting material disappeared, the reaction solution was cooled to room temperature, separated by addition of water (50 mL), and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by pre-HPLC to afford compound IM-31 (1.06 g, yield: 66%) as a white solid.

[0166] ESI-MS:m / z:228.1[M+H] + .

[0167] Example 4 Synthesis of Compound Intermediate IM-32

[0168] Step 1: Synthesis of CM-02

[0169] Under nitrogen protection, CM-01 (1.08 g, 5.84 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL). One drop of DMF was added thereto. Oxalyl chloride (0.74 mL, 8.76 mmol, 1.5 eq) was slowly added under ice bath. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 30 min. After the reaction was complete, the solvent was removed under reduced pressure to obtain crude CM-02 for use.

[0170] Step 2: Synthesis of intermediate IM-32

[0171] Under nitrogen, IM-31 (1.06 g, 4.67 mmol, 0.8 eq) and a catalytic amount of DMAP were dissolved in 2-methyltetrahydrofuran (20 mL). DIPEA (2.03 mL, 11.68 mmol, 2.0 eq) was added, and a solution of CM-02 in anhydrous tetrahydrofuran (10 mL) was added dropwise under an ice bath. The reaction system was heated to reflux for 1 h. Upon completion, the reaction solution was cooled to room temperature and diluted with water (40 mL). The product precipitated, filtered, and petroleum ether (150 mL) was added. The mixture was then purified by slurrying to afford compound IM-32 (1.82 g, 79% yield) as a yellow solid.

[0172] ESI-MS:m / z:395.1[M+H] + .

[0173] Example 5 Synthesis of Compound Intermediate IM-41

[0174] Step 1: Synthesis of compound IM-40

[0175] m-Fluoronitrobenzene (1.0 g, 7.09 mmol, 1.0 eq), 4,4-difluoropiperidine hydrochloride (1.34 g, 8.50 mmol, 1.2 eq), and potassium carbonate (1.96 g, 14.18 mmol, 2.0 eq) were dispersed in DMSO (10 mL) and heated to 120°C overnight. Upon completion, the resulting reaction solution was cooled to room temperature, diluted with water (60 mL), and extracted with dichloromethane (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 6:1) to afford compound IM-40 (1.40 g, yield: 81%) as a light yellow solid.

[0176] ESI-MS:m / z:243.1[M+H] + .

[0177] Step 2: Synthesis of compound IM-41

[0178] Intermediate IM-40 (1.40 g, 5.78 mmol, 1.0 eq) obtained in Step 1 was dissolved in methanol (30 mL). Ammonium chloride (618 mg, 11.56 mmol, 2.0 eq) and zinc powder (756 mg, 11.56 mmol, 2.0 eq) were added sequentially under ice. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain public intermediate IM-41 (1.15 g, 94% yield) as an off-white solid.

[0179] ESI-MS: m / z: 213.1 [M+H] + .

[0180] Example 6 Synthesis of Compound Intermediate IM-42

[0181] Under nitrogen, CM-01 (1 g, 5.40 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (20 mL). Two drops of N,N-dimethylformamide were added. Oxalyl chloride (0.68 mL, 8.10 mmol, 1.5 eq) was then added dropwise under ice-cooling. The mixture was stirred at room temperature for 30 minutes until the reaction was complete. The resulting reaction solution was then distilled to remove the solvent under dry conditions to obtain the acyl chloride intermediate for later use.

[0182] Under nitrogen, IM-41 (1.15 g, 5.40 mmol, 1.0 eq) was dissolved in anhydrous DCE (20 mL). N,N-diisopropylethylamine (1.8 mL, 10.8 mmol, 2.0 eq) was added. A solution of the acid chloride intermediate in anhydrous dichloromethane (5 mL) was added dropwise under an ice bath. The mixture was then stirred at 120°C overnight. After completion, the reaction mixture was cooled to room temperature and diluted with water (50 mL). Solid precipitated, which was filtered and slurried in petroleum ether (75 mL) to afford compound IM-42 (1.25 g, 61% yield) as a light yellow solid.

[0183] ESI-MS:m / z:380.1[M+H] + .

[0184] Example 7 Synthesis of Compound 301

[0185] Step 1: Synthesis of compound 301-01

[0186] IM-02 (1.0 g, 2.53 mmol, 1.0 eq), cyclopropylethanol (218 mg, 2.53 mmol, 1.0 eq), and potassium carbonate (0.70 g, 5.06 mmol, 2.0 eq) were dispersed in DMSO (10 mL). The reaction mixture was stirred at 100°C for 4 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 301-01 (930 mg, 80% yield) as a yellow solid.

[0187] ESI-MS m / z:462.2[M+H] + .

[0188] Step 2: Synthesis of compound 301-2

[0189] Dissolve 301-01 (580 mg, 1.26 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (133 mg, 2.5 mmol, 2.0 eq) and zinc powder (163 mg, 2.5 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After LC-MS monitoring indicates the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 301-02 for later use.

[0190] ESI-MS m / z:432.2[M+H] + .

[0191] Step 3: Synthesis of compound 301-3

[0192] Under nitrogen, intermediate 301-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). Triethylamine (0.35 mL, 2.52 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.2 mL, 1.26 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 301-03, which was used directly in the next step without purification.

[0193] ESI-MS m / z:568.2[M+H] + .

[0194] Step 4: Synthesis of compound 301

[0195] Under nitrogen, the product 301-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (95.7 mg, 2.52 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 301 (380 mg, 55% yield) as an off-white solid.

[0196] ESI-MS m / z:540.2[M+H] + .

[0197] 1H NMR (400MHz, DMSO) δ = 10.44 (s, 1H), 7.85 (d, J = 8.7, 1H), 7.39 (s, 1H), 6.84 (s ,1H),6.76(d,J=8.7,1H),4.18(t,J=6.0,2H),3.91–3.80(m,4H),3.73(t,J=6 .6,2H),3.20(t,J=6.5,2H),2.29(s,3H),2.07–1.92(m,4H),1.82(dd,J=12. 8,6.2,2H),1.03(dd,J=9.8,5.0,1H),0.51–0.40(m,2H),0.18(q,J=4.8,2H).

[0198] Example 8 Synthesis of Compound 310

[0199] Step 1: Synthesis of compound 310-01

[0200] IM-02 (500 mg, 1.26 mmol, 1.0 eq), cyclopropylmethylcarbinol (435 mg, 5.06 mmol, 4.0 eq), and potassium carbonate (1.05 g, 7.59 mmol, 6.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 90°C for 4 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 310-01 (444 mg, yield: 76%) as a yellow solid.

[0201] ESI-MS:m / z:462.2[M+H] + .

[0202] Step 2: Synthesis of compound 310-02

[0203] Dissolve 310-01 (444 mg, 0.96 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (103 mg, 1.92 mmol, 2.0 eq) and zinc powder (126 mg, 1.92 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 310-02 for later use.

[0204] ESI-MS:m / z:432.2[M+H] + .

[0205] Step 3: Synthesis of compound 310-03

[0206] Under nitrogen, the intermediate 310-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.32 mL, 1.92 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (166 mg, 0.96 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 310-03, which was used directly in the next step without purification.

[0207] ESI-MS:m / z:568.2[M+H] + .

[0208] Step 4: Synthesis of compound 310

[0209] Under nitrogen, the product 310-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (72 mg, 1.92 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction system and stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 310 (280 mg, 54% yield) as an off-white solid.

[0210] ESI-MS:m / z:540.2[M+H] + .

[0211] 1 H NMR (400MHz, DMSO) δ = 10.63 (s, 1H), 7.90 (d, J = 8.7, 1H), 7.38 (s, 1H), 6.90 (d,J=1.5,1H),6.84(dd,J=8.7,1.7,1H),4.19–4.09(m,1H),3.98–3.81(m, 4H),3.74(t,J=6.5,2H),3.26(t,J=6.5,2H),2.30(s,3H),2.09–1.86(m,4H ),1.46(d,J=6.1,3H),1.26(ddd,J=12.9,8.0,3.0,1H),0.68–0.36(m,4H).

[0212] Example 9 Synthesis of Compound 317

[0213] Step 1: Synthesis of compound 317-01

[0214] IM-02 (1.0 g, 2.53 mmol, 1.0 eq), cyclopentaneethanol (1.16 g, 10.12 mmol, 4.0 eq), and potassium carbonate (2.09 g, 15.18 mmol, 6.0 eq) were dispersed in dimethyl sulfoxide (10 mL). The reaction mixture was stirred at 120°C overnight. After LC-MS monitoring indicated the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 317-01 (989 mg, 80% yield) as a yellow solid.

[0215] ESI-MS m / z::490.2[M+H] + .

[0216] Step 2: Synthesis of compound 317-02

[0217] Dissolve 317-01 (500 mg, 1.02 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (108 mg, 2.04 mmol, 2.0 eq) and zinc powder (132 mg, 2.04 mol, 2.0 eq) sequentially. Stir at room temperature for 30 minutes. After the starting material disappears, remove the solid by filtration. The filtrate is concentrated under reduced pressure to obtain intermediate 317-02.

[0218] ESI-MS m / z:460.2[M+H] + .

[0219] Step 3: Synthesis of compound 317-03

[0220] Under nitrogen, intermediate 317-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). DIPEA (0.355 mL, 2.04 mmol, 2.0 eq) was added, and a dichloromethane solution (5 mL) of methyl 2-(chlorosulfonyl)acetate (0.12 mL, 1.02 mmol, 1.0 eq) was added dropwise in batches under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford crude product 317-03, which was used directly in the next step without purification.

[0221] ESI-MS m / z:596.2[M+H] + .

[0222] Step 4: Synthesis of compound 317

[0223] Under nitrogen, the crude product 317-03 obtained in step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (77.5 mg, 2.04 mmol, 2.0 eq) was slowly added portionwise at room temperature. The reaction was continued for 30 min. Upon disappearance of the starting material, acetone was added dropwise to quench the reaction. After completion of the addition, the reaction was stirred at room temperature for 30 min. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 317 (200 mg, 30% yield) as an off-white solid.

[0224] 1 H NMR (400MHz, DMSO) δ = 10.54 (s, 1H), 7.68 (d, J = 8.7, 1H), 7.41 (s, 1H), 6.63–6.37 (m, 2H), 4.52–4.25 (m, 1H), 3.85 (s, 4H), 3 .69(t,J=6.6,2H),2.92(t,J=6.6,2H),2.30(d,J=13.0,4H),1.99(d,J=12.7,4H),1.85–1.46(m,6H),1.33(d,J=5.7,4H).

[0225] ESI-MS m / z:568.2[M+H] + .

[0226] Example 10 Synthesis of Compound 318

[0227] Step 1: Synthesis of compound 318-01

[0228] IM-02 (700 mg, 1.77 mmol, 1.0 eq), cyclobutanecarbinol (305 mg, 3.54 mmol, 2.0 eq), and potassium carbonate (0.73 g, 5.31 mmol, 3.0 eq) were dispersed in dimethyl sulfoxide (10 mL). The reaction mixture was stirred at 120°C for 6 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 318-01 (670 mg, yield: 82%) as a yellow solid.

[0229] ESI-MS:m / z:462.2[M+H] + .

[0230] Step 2: Synthesis of compound 318-02

[0231] Dissolve 318-01 (270 mg, 0.58 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (62 mg, 1.17 mmol, 2.0 eq) and zinc powder (76 mg, 1.17 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 318-02 for later use.

[0232] ESI-MS:m / z:432.2[M+H] + .

[0233] Step 3: Synthesis of compound 318-03

[0234] Under nitrogen, intermediate 318-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.19 mL, 1.17 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (100 mg, 0.58 mmol, 1.0 eq) was added under an ice bath. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL). The mixture was extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 318-03, which was used directly in the next step without purification.

[0235] ESI-MS:m / z:568.2[M+H] + .

[0236] Step 4: Synthesis of compound 318

[0237] Under nitrogen, the product 318-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (44.2 mg, 1.17 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction system and stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 318 (172 mg, 55%) as an off-white solid.

[0238] ESI-MS:m / z:540.2[M+H] + .

[0239] 1 H NMR (400MHz, DMSO) δ = 10.23 (s, 1H), 7.94 (d, J = 8.6, 1H), 7.39 (s, 1H), 6.99 (s, 1H), 6.93 (d, J = 8.7, 1H), 4.14 (d, J = 6.8, 2H), 3.88 (s, 4H),3.76(t,J=6.4,2H),3.38(t,J=6.4,2H),3.01–2.82(m,1H),2.30(s,3H),2.22–2.13(m,2H),1.95(ddd,J=20.2,16.8,10.9,9H).

[0240] Example 11 Synthesis of Compound 320

[0241] Step 1: Synthesis of compound 320-01

[0242] IM-02 (300 mg, 0.76 mmol, 1.0 eq), (2,2-dimethylcyclopropyl)methanol (304 mg, 3.04 mmol, 4.0 eq), and potassium carbonate (629 mg, 4.56 mmol, 6.0 eq) were dispersed in dimethyl sulfoxide (4 mL). The reaction mixture was stirred at 120°C for 2 hours. After LC-MS monitoring indicated the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted three times with dichloromethane (20 mL). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 320-01 (280 mg, 75% yield) as a yellow solid.

[0243] ESI-MS m / z:476.2[M+H] + .

[0244] Step 2: Synthesis of compound 320-02

[0245] Dissolve 320-01 (93 mg, 0.196 mmol, 1.0 eq) in methanol (5 mL). Add ammonium chloride (50 mg, 0.4 mmol, 2.0 eq) and zinc powder (26 mg, 0.4 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After LC-MS monitoring indicates the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain product 320-02.

[0246] ESI-MS m / z:446.2[M+H] + .

[0247] Step 3: Synthesis of compound 320-03

[0248] Under nitrogen, the product 320-02 obtained in step 1 was dissolved in anhydrous dichloromethane (3 mL). N,N-diisopropylethylamine (0.14 mL, 0.784 mmol, 4.0 eq) was added, and a dichloromethane solution (1 mL) of methyl 2-(chlorosulfonyl)acetate (0.023 mL, 0.196 mmol, 1.0 eq) was slowly added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After LC-MS monitoring indicated the reaction was complete, the resulting reaction solution was added to water (5 mL), partitioned, and extracted with dichloromethane (5 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain crude product 320-03, which was pumped dry for later use.

[0249] ESI-MS m / z:582.2[M+H] + .

[0250] Step 4: Synthesis of compound 320

[0251] Under nitrogen, the crude product 320-03 from step 3 was dissolved in tetrahydrofuran (5 mL). Sodium borohydride (14.9 mg, 0.392 mmol, 2.0 eq) was slowly added portionwise at room temperature. The reaction was continued for 30 min. Upon disappearance of the starting material, acetone was added dropwise to quench the reaction. After completion of the addition, the reaction was stirred at room temperature for 30 min. The resulting reaction solution was separated by adding water (15 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to afford 320 (50 mg, 45% yield) as a white solid.

[0252] 1H NMR (400MHz, DMSO) δ = 10.34 (s, 1H), 7.88 (d, J = 8.6, 1H), 7.41 (s, 1H), 6.93 (s, 1H), 6. 88(d,J=8.7,1H),4.29(dd,J=10.1,6.9,1H),4.14–4.05(m,1H),3.89–3.81(m,5H),3. 74(t,J=6.5,2H),3.27(t,J=6.4,2H),2.30(s,3H),2.02–1.88(m,4H),1.21(d,J=9.9, 2H),1.15(d,J=11.5,3H),1.06(s,3H),0.61(dd,J=8.5,4.3,1H),0.45(t,J=4.7,1H).

[0253] ESI-MS m / z:554.2[M+H] + .

[0254] Example 12 Synthesis of Compound 321

[0255] Step 1: Synthesis of compound 321-01

[0256] Disperse 1-cyclopropylacetone (124 mg, 1.26 mmol, 1.0 eq) in tetrahydrofuran (5 mL). Add NaBH4 (47.6 mg, 1.26 mmol, 1.0 eq) to the reaction mixture. Stir the mixture at room temperature for 1 hour. After the starting material disappears, quench the reaction by adding 0.1 ml of acetone dropwise. Stir at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and used directly in the next step without purification.

[0257] ESI-MS: m / z: 101.1 [M+H] + .

[0258] Step 2: Synthesis of compound 321-02

[0259] 321-01, IM-02 (500 mg, 1.26 mmol, 1.0 eq) obtained in Step 1, and potassium carbonate (348 mg, 2.52 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 100°C for 9 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 321-02 (437 mg, yield: 73%) as a yellow solid.

[0260] ESI-MS:m / z:476.2[M+H] + .

[0261] Step 3: Synthesis of compound 321-03

[0262] The crude product 321-02 (437 mg, 0.92 mmol, 1.0 eq) obtained in step 2 was dissolved in methanol (10 mL). Ammonium chloride (97 mg, 1.84 mmol, 2.0 eq) and zinc powder (120 mg, 1.84 mmol, 2.0 eq) were added sequentially. The mixture was stirred at room temperature for 15 minutes. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain intermediate 321-03 for later use.

[0263] ESI-MS:m / z:446.2[M+H] + .

[0264] Step 4: Synthesis of compound 321-04

[0265] Under nitrogen, Intermediate 321-03 obtained in Step 3 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.30 mL, 1.84 mmol, 2.0 eq) was added. Methyl 2-(chlorosulfonyl)acetate (159 mg, 0.92 mmol, 1.0 eq) in dichloromethane was then added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 321-04, which was used directly in the next step without purification.

[0266] ESI-MS:m / z:582.2[M+H] + .

[0267] Step 5: Synthesis of compound 321

[0268] Under nitrogen, the product 321-04 from step 4 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (70 mg, 1.84 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. After addition, the reaction mixture was allowed to react for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction system and stirred at room temperature for 30 min. The resulting reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 321 (249 mg, 49% yield) as an off-white solid.

[0269] ESI-MS:m / z:554.2[M+H] + .

[0270] Example 13 Synthesis of Compound 323

[0271] Step 1: Synthesis of compound 323-01

[0272] IM-02 (500 mg, 1.26 mmol, 1.0 eq), neopentyl alcohol (446 mg, 5.06 mmol, 4.0 eq), and potassium carbonate (1.05 g, 7.59 mmol, 6.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 100°C for 6 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 323-01 (420 mg, yield: 72%) as a yellow solid.

[0273] ESI-MS:m / z:464.2[M+H] + .

[0274] Step 2: Synthesis of compound 323-02

[0275] Dissolve 323-01 (420 mg, 0.91 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (96 mg, 1.81 mmol, 2.0 eq) and zinc powder (118 mg, 1.81 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 323-02 for later use.

[0276] ESI-MS:m / z:434.2[M+H] + .

[0277] Step 3: Synthesis of compound 323-03

[0278] Under nitrogen, intermediate 323-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.30 mL, 1.81 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (157 mg, 0.91 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 323-03, which was used directly in the next step without purification.

[0279] ESI-MS:m / z:570.2[M+H] + .

[0280] Step 4: Synthesis of compound 323

[0281] Under nitrogen, the product 323-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (69 mg, 1.81 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction system and stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 323 (261 mg, 53% yield) as an off-white solid.

[0282] ESI-MS:m / z:542.2[M+H] + .

[0283] 1 H NMR (400MHz, DMSO) δ=10.19(s,1H),7.85(d,J=8.7,1H),7.47(s,1H),6.79(s,1H),6.75(d,J=8.7,1H),3.90–3 .84(m,4H),3.82(s,2H),3.72(t,J=6.6,2H),3.16(t,J=6.6,2H),2.30(s,3H),2.03–1.89(m,4H),1.16(s,9H).

[0284] Example 14 Synthesis of Compound 325

[0285] Step 1: Synthesis of compound 325-01

[0286] IM-02 (600 mg, 1.52 mmol, 1.0 eq), cyclobutanol (0.508 g, 3.04 mmol, 2.0 eq), and potassium carbonate (0.63 g, 4.56 mmol, 3.0 eq) were dispersed in dimethyl sulfoxide (7 mL). The reaction mixture was stirred at 120°C for 2 hours. After LC-MS monitoring indicated the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (35 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 325-01 (446 mg, yield: 66%) as a yellow solid.

[0287] ESI-MS m / z:448.2[M+H] + .

[0288] Step 2: Synthesis of compound 325-02

[0289] Dissolve 325-01 (223 mg, 0.5 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (53 mg, 1.0 mmol, 2.0 eq) and zinc powder (65 mg, 1.0 mmol, 2.0 eq) sequentially. Stir at room temperature for 15 minutes. Once the starting material disappears, remove the solid by suction filtration. Concentrate the filtrate under reduced pressure to obtain product 325-02 for later use.

[0290] ESI-MS m / z:418.2[M+H] + .

[0291] Step 3: Synthesis of compound 325-03

[0292] Under nitrogen, the product 325-02 from step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.17 mL, 1.0 mmol, 2.0 eq) was added. A dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.06 mL, 0.5 mmol, 1.0 eq) was slowly added dropwise to the reaction system under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, water (20 mL) was added to the reaction system, and the mixture was separated. The mixture was extracted with dichloromethane (5 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain crude product 325-03, which was used directly in the next step without purification.

[0293] ESI-MS m / z:554.2[M+H] + .

[0294] Step 4: Synthesis of compound 325

[0295] Under nitrogen, the crude product 325-03 obtained in step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (38 mg, 1.0 mmol, 2.0 eq) was slowly added portionwise at room temperature. The reaction was continued for 30 min. Acetone was added dropwise to quench the reaction. After completion of the addition, stirring was continued at room temperature for 30 min. The resulting reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 325 (160 mg, 60% yield) as a white solid.

[0296] 1 H NMR (400MHz, DMSO) δ=10.47(s,1H),7.93(d,J=8.6,1H),7.35(s,1H),6.91(d,J=8.7,1H),6.86(s,1H),4.94–4.82(m,1H),3.85(s,4H) ,3.75(t,J=6.4,2H),3.36(t,J=6.2,2H),2.54(d,J=8.0,2H),2.31(s,3H),2.29–2.19(m,2H),1.96(d,J=13.7,5H),1.92–1.67(m,2H).

[0297] ESI-MS m / z:526.2[M+H] + .

[0298] Example 15 Synthesis of Compound 328

[0299] Step 1: Synthesis of compound 328-01

[0300] IM-02 (300 mg, 0.76 mmol, 1.0 eq), 1-cyclobutyl-1-ethanol (152 mg, 1.52 mmol, 2.0 eq), and potassium carbonate (315 mg, 2.28 mmol, 3.0 eq) were dispersed in dimethyl sulfoxide (4 mL). The reaction mixture was stirred at 120°C for 2 hours. After LC-MS monitoring indicated the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 328-01 (312 mg, yield: 86%) as a yellow solid.

[0301] ESI-MS m / z:476.2[M+H] + .

[0302] Step 2: Synthesis of compound 328-02

[0303] 328-01 (156 mg, 0.33 mmol, 1.0 eq) was dissolved in methanol (5 mL). Ammonium chloride (17.8 mg, 0.33 mmol, 1.0 eq) and zinc powder (21.4 mg, 0.33 mmol, 1.0 eq) were added sequentially. The mixture was stirred at room temperature for 15 minutes. After LC-MS monitoring indicated the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain intermediate 328-02.

[0304] ESI-MS m / z:446.2[M+H] + .

[0305] Step 3: Synthesis of compound 328-03

[0306] Under nitrogen, the product 328-02 from step 2 was dissolved in anhydrous dichloromethane (3 mL). N,N-diisopropylethylamine (0.23 mL, 1.32 mmol, 4.0 eq) was added, and a dichloromethane solution (2 mL) of methyl 2-(chlorosulfonyl)acetate (0.04 mL, 0.33 mmol, 1.0 eq) was slowly added dropwise under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After LC-MS monitoring indicated the reaction was complete, the resulting reaction solution was added to water (15 mL), separated, and extracted with dichloromethane (5 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain crude product 328-03 for future use.

[0307] ESI-MS m / z:582.2[M+H] + .

[0308] Step 4: Synthesis of compound 328

[0309] Under nitrogen, the crude product 328-03 from step 3 was dissolved in tetrahydrofuran (5 mL). Sodium borohydride (25.1 mg, 0.66 mmol, 2.0 eq) was slowly added portionwise at room temperature. The reaction was continued for 30 min. Acetone was added dropwise to quench the reaction. After completion of the addition, stirring was continued at room temperature for 30 min. The resulting reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to yield 328 (84 mg, 45% yield) as an off-white solid.

[0310] 1H NMR (400MHz, DMSO) δ = 10.35 (s, 1H), 7.92 (d, J = 8.7, 1H), 7.34 (s, 1H), 6.98 (d, J = 1.6 ,1H),6.88(dd,J=8.7,1.8,1H),4.52(dd,J=12.9,6.5,1H),3.91–3.80(m,4H),3.72 (t,J=6.4,2H),3.37–3.31(m,2H),2.69(dd,J=16.1,8.1,1H),2.26(s,3H),2.14–2. 04(m,1H),2.03–1.89(m,6H),1.79(ddd,J=36.2,18.5,9.2,3H),1.24(d,J=6.0,3H).

[0311] ESI-MS m / z:554.2[M+H] + .

[0312] Example 16 Synthesis of Compound 338

[0313] Step 1: Synthesis of compound 338-01

[0314] IM-02 (500 mg, 1.26 mmol, 1.0 eq), cyclopentanol (108 mg, 1.26 mmol, 1.0 eq), and potassium carbonate (348 mg, 2.52 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 100°C for 9 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 338-01 (421 mg, yield: 72%) as a yellow solid.

[0315] ESI-Ms:m / z:462.2[M+H] + .

[0316] Step 2: Synthesis of compound 338-02

[0317] Dissolve 338-01 (421 mg, 0.91 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (96 mg, 1.82 mmol, 2.0 eq) and zinc powder (118 mg, 1.82 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 338-02 for later use.

[0318] ESI-Ms:m / z:432.2[M+H] + .

[0319] Step 3: Synthesis of compound 338-03

[0320] Under nitrogen, Intermediate 338-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.30 mL, 1.82 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (157 mg, 0.91 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was added to water (20 mL) and separated. The mixture was then extracted with dichloromethane (10 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain Intermediate 338-03, which was used directly in the next step without purification.

[0321] ESI-Ms:m / z:568.2[M+H] + .

[0322] Step 4: Synthesis of compound 338

[0323] Under nitrogen, the product 338-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (69 mg, 1.82 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 338 (261 mg, 53% yield) as an off-white solid.

[0324] ESI-Ms:m / z:540.2[M+H] + .

[0325] 1 H NMR (400MHz, DMSO) δ = 10.42 (s, 1H), 7.97 (d, J = 8.6, 1H), 7.36 (s, 1H), 7.03 (s, 1H), 6.93 (d, J = 8.6, 1H), 5.03 (s, 1H), 3.85 ( s,4H),3.76(t,J=6.3,2H),3.37(t,J=6.4,2H),2.30(s,3H),2.00(dd,J=13.2,5.1,8H),1.84(d,J=4.5,2H),1.69(s,2H).

[0326] Example 17 Synthesis of Compound 339

[0327] Step 1: Synthesis of compound 339-01

[0328] IM-02 (500 mg, 1.26 mmol, 1.0 eq), 2-cyclobutylethanol (436 mg, 1.26 mmol, 1.0 eq), and potassium carbonate (348 mg, 2.52 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 100°C for 9 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 339-01 (427 mg, yield: 71%) as a yellow solid.

[0329] ESI-Ms:m / z:476.2[M+H] + .

[0330] Step 2: Synthesis of compound 339-02

[0331] Dissolve 339-01 (421 mg, 0.90 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (96 mg, 1.80 mmol, 2.0 eq) and zinc powder (118 mg, 1.80 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 339-02 for later use.

[0332] ESI-Ms:m / z:446.2[M+H] + .

[0333] Step 3: Synthesis of compound 339-03

[0334] Under nitrogen, Intermediate 339-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.30 mL, 1.80 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (157 mg, 0.90 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was added to water (20 mL) and separated. The mixture was then extracted with dichloromethane (10 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain Intermediate 339-03, which was used directly in the next step without purification.

[0335] ESI-Ms:m / z:582.2[M+H] + .

[0336] Step 4: Synthesis of compound 339

[0337] Under nitrogen, the product 339-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (69 mg, 1.80 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 339 (261 mg, 53% yield) as an off-white solid.

[0338] ESI-Ms:m / z:554.2[M+H] + .

[0339] 1 H NMR (400MHz, DMSO) δ = 10.34 (s, 1H), 7.87 (d, J = 8.6, 1H), 7.36 (s, 1H), 6.88 (s, 1H), 6.84 (d, J = 8.7, 1H), 4.06 (t, J = 6.3, 2H), 3.85 (s, 4H), 3.72(t,J=6.5,2H), 3.27(d,J=6.4,2H), 2.52(d,J=7.8,1H), 2.28(s,3H), 1.99(dt,J=22.4,10.3,9H), 1.75(ddd,J=44.5,15.8,8.7,4H).

[0340] Example 18 Synthesis of Compound 342

[0341] Step 1: Synthesis of compound 342-01

[0342] IM-02 (500 mg, 1.26 mmol, 1.0 eq), 2-cyclopropyl-1-ol (126 mg, 1.26 mmol, 1.0 eq), and potassium carbonate (348 mg, 2.52 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 95°C for 8 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 342-01 (431 mg, yield: 72%) as a yellow solid.

[0343] ESI-MS:m / z:476.2[M+H] + .

[0344] Step 2: Synthesis of compound 342-02

[0345] Intermediate 342-01 (431 mg, 0.91 mmol, 1.0 eq) obtained in Step 1 was dissolved in methanol (10 mL). Ammonium chloride (96 mg, 1.82 mmol, 2.0 eq) and zinc powder (118 mg, 1.82 mmol, 2.0 eq) were added sequentially. The mixture was stirred at room temperature for 15 minutes. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain Intermediate 342-02 for later use.

[0346] ESI-MS:m / z:446.2[M+H] + .

[0347] Step 3: Synthesis of compound 342-03

[0348] Under nitrogen, Intermediate 342-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.30 mL, 1.82 mmol, 2.0 eq) was added. Methyl 2-(chlorosulfonyl)acetate (157 mg, 0.91 mmol, 1.0 eq) in dichloromethane was then added under an ice bath. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. Upon disappearance of the starting material, the reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 342-03, which was used directly in the next step without purification.

[0349] ESI-MS:m / z:582.2[M+H] + .

[0350] Step 4: Synthesis of compound 342

[0351] Under nitrogen, the product 342-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (69 mg, 1.82 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction system and stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by pre-HPLC to afford product 342 (262 mg, 52% yield) as an off-white solid.

[0352] 1 H NMR (400MHz, DMSO) δ10.27(s,1H),7.97(d,J=8.7Hz,1H),7.41(s,1H),7.03(d,J=2.0Hz,1 H),6.94(dd,J=8.7,2.0Hz,1H),4.18(dd,J=8.7,3.8Hz,1H),4.09(dd,J=8.7,5.8Hz,1H),3 .95–3.85(m,4H),3.76(d,J=12.8Hz,2H),3.44–3.31(m,2H),1.97(dt,J=13.6,5.9Hz,4H) ,1.76–1.45(m,2H),1.25(d,J=6.6Hz,3H),0.91(dt,J=8.8,4.7Hz,1H),0.45–0.15(m,4H).

[0353] ESI-MS:m / z:554.2[M+H] + .

[0354] Example 19 Synthesis of Compound 702

[0355] Step 1: Synthesis of compound 702-01

[0356] IM-02 (500 mg, 1.26 mmol, 1.0 eq), sodium ethoxide (258 mg, 3.79 mmol, 3.0 eq), and a few drops of ethanol were dispersed in DMF (5 mL). The reaction mixture was stirred at room temperature for 16 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 702-01 (383 mg, yield: 72%) as a yellow solid.

[0357] ESI-MS:m / z:422.2[M+H] + .

[0358] Step 2: Synthesis of compound 702-02

[0359] Dissolve 702-01 (383 mg, 0.91 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (97 mg, 1.82 mmol, 2.0 eq) and zinc powder (119 mg, 1.82 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 702-02 for later use.

[0360] ESI-MS:m / z:392.2[M+H] + .

[0361] Step 3: Synthesis of Compound 702-03

[0362] Under nitrogen, intermediate 702-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.30 mL, 1.82 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (157 mg, 0.91 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 702-03, which was used directly in the next step without purification.

[0363] ESI-MS:m / z:528.2[M+H] + .

[0364] Step 4: Synthesis of Compound 702

[0365] Under nitrogen, the product 702-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (69 mg, 1.82 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction system and stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 702 (236 mg, 52% yield) as an off-white solid.

[0366] ESI-MS: m / z: 500.2 [M+H]+ .

[0367] 1 H NMR (400MHz, DMSO) δ = 10.47 (s, 1H), 7.94 (d, J = 8.6, 1H), 7.35 (s, 1H), 6.99 (d, J = 1.6, 1H), 6.94 (dd, J = 8.6, 1.7, 1H), 4.23 (q, J=6.8,2H),3.85(d,J=5.2,4H),3.77(t,J=6.5,2H),3.38(t,J=6.4,2H),2.31(s,3H),2.04–1.89(m,4H),1.53(t,J=6.8,3H).

[0368] Example 20 Synthesis of Compound 703

[0369] Step 1: Synthesis of compound 703-01

[0370] IM-02 (500 mg, 1.26 mmol, 1.0 eq), n-propanol (375 mg, 5.06 mmol, 4.0 eq), and potassium carbonate (1.05 g, 7.59 mmol, 6.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 100°C for 6 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 703-01 (433 mg, yield: 79%) as a yellow solid.

[0371] ESI-MS:m / z:436.2[M+H] + .

[0372] Step 2: Synthesis of compound 703-02

[0373] Dissolve 703-01 (433 mg, 0.99 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (105 mg, 1.98 mmol, 2.0 eq) and zinc powder (129 mg, 1.98 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 703-02 for later use.

[0374] ESI-MS:m / z:406.2[M+H] + .

[0375] Step 3: Synthesis of compound 703-03

[0376] Under nitrogen, intermediate 703-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.33 mL, 1.98 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (171 mg, 0.99 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 703-03, which was used directly in the next step without purification.

[0377] ESI-MS:m / z:542.2[M+H] + .

[0378] Step 4: Synthesis of compound 703

[0379] Under nitrogen, the product 703-03 obtained in step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (75 mg, 1.98 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction system and stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 703 (250 mg, yield: 49%) as an off-white solid.

[0380] ESI-MS:m / z:514.2[M+H] + .

[0381] 1 H NMR (400MHz, DMSO) δ=10.40(s,1H),7.89(d,J=8.7,1H),7.39(s,1H),6.88(d,J=1.7,1H),6.83(dd,J=8.7,1.8,1H),4.12(t,J=5.9,2H),3.95–3.81 (m,4H),3.75(t,J=6.5,2H),3.27(t,J=6.5,2H),2.30(s,3H),2.05–1.87(m,6H),1.14(t,J=7.4,3H).

[0382] Example 21 Synthesis of Compound 706

[0383] Step 1: Synthesis of compound 706-01

[0384] IM-02 (200 mg, 0.50 mmol, 1.0 eq), n-butanol (56 mg, 0.76 mmol, 1.5 eq), and potassium carbonate (209 mg, 1.52 mmol, 3.0 eq) were dispersed in dimethyl sulfoxide (10 mL). The reaction mixture was stirred at 120°C for 6 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to yield compound 706-01 (200 mg, 88%) as a yellow solid.

[0385] ESI-MS:m / z:450.2[M+H] + .

[0386] Step 2: Synthesis of Compound 706-02

[0387] Dissolve 706-01 (200 mg, 0.44 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (47 mg, 0.89 mmol, 2.0 eq) and zinc powder (58 mg, 0.89 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 706-02 for later use.

[0388] ESI-MS:m / z:420.2[M+H] + .

[0389] Step 3: Synthesis of Compound 706-03

[0390] Under nitrogen, intermediate 706-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.15 mL, 0.89 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (77 mg, 0.44 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 706-03, which was used directly in the next step without purification.

[0391] ESI-MS:m / z:556.2[M+H] + .

[0392] Step 4: Synthesis of Compound 706

[0393] Under nitrogen, the product 706-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (44.2 mg, 1.17 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction system. The reaction mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 706 (123 mg, 53% yield) as an off-white solid.

[0394] ESI-MS:m / z:528.2[M+H] + .

[0395] 1 H NMR (400MHz, DMSO) δ = 10.33 (s, 1H), 7.94 (d, J = 8.7, 1H), 7.39 (s, 1H), 6.98 (d,J=1.6,1H),6.92(dd,J=8.6,1.8,1H),4.18(t,J=6.3,2H),3.92–3.82(m ,4H),3.76(t,J=6.5,2H),3.38–3.33(m,2H),2.32(d,J=14.2,3H),1.95(d dd,J=21.8,14.2,8.4,6H), 1.56(dd,J=15.0,7.5,2H), 0.95(t,J=7.4,3H).

[0396] Example 22 Synthesis of Compound 707

[0397] Step 1: Synthesis of compound 707-01

[0398] IM-02 (500 mg, 1.26 mmol, 1.0 eq), isobutanol (375 mg, 5.06 mmol, 4.0 eq), and potassium carbonate (1.05 g, 7.59 mmol, 6.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 100°C for 6 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 707-01 (432 mg, yield: 76%) as a yellow solid.

[0399] ESI-MS:m / z:450.2[M+H] + .

[0400] Step 2: Synthesis of Compound 707-02

[0401] Dissolve 707-01 (432 mg, 0.96 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (102 mg, 1.92 mmol, 2.0 eq) and zinc powder (125 mg, 1.92 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 707-02 for later use.

[0402] ESI-MS:m / z:420.2[M+H] + .

[0403] Step 3: Synthesis of Compound 707-03

[0404] Under nitrogen, Intermediate 707-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.32 mL, 1.92 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (166 mg, 0.96 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was added to water (20 mL) and separated. The mixture was then extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain Intermediate 707-03, which was used directly in the next step without purification.

[0405] ESI-MS:m / z:556.2[M+H] + .

[0406] Step 4: Synthesis of Compound 707

[0407] Under nitrogen, the product 707-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (72 mg, 1.92 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction system. The mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 707 (238 mg, 47% yield) as an off-white solid.

[0408] ESI-MS:m / z:528.2[M+H]+ .

[0409] 1 H NMR (400MHz, DMSO) δ = 10.31 (s, 1H), 7.80 (d, J = 8.0, 1H), 7.42 (s, 1H), 6.82–6.58 (m, 2H), 3.94 (s, 2H), 3.85 ( s,4H),3.71(s,2H),3.11(t,J=6.4,2H),2.29(s,3H),2.21(s,1H),1.93(d,J=27.6,4H),1.14(d,J=4.9,6H).

[0410] Example 23 Synthesis of Compound 709

[0411] Step 1: Synthesis of compound 709-01

[0412] IM-02 (500 mg, 1.26 mmol, 1.0 eq), n-pentanol (375 mg, 5.06 mmol, 4.0 eq), and potassium carbonate (1.05 g, 7.59 mmol, 6.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 100°C for 3 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 709-01 (484 mg, yield: 83%) as a yellow solid.

[0413] ESI-MS:m / z:464.2[M+H] + .

[0414] Step 2: Synthesis of Compound 709-02

[0415] Dissolve 709-01 (486 mg, 1.05 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (111 mg, 1.92 mmol, 2.0 eq) and zinc powder (136 mg, 1.92 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 709-02 for later use.

[0416] ESI-MS:m / z:434.2[M+H] + .

[0417] Step 3: Synthesis of compound 709-03

[0418] Under nitrogen, intermediate 709-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.35 mL, 1.92 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (181 mg, 1.05 mmol, 1.0 eq) was added under an ice bath. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was added to water (20 mL) and separated. The mixture was then extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 709-03, which was used directly in the next step without purification.

[0419] ESI-MS:m / z:570.2[M+H] + .

[0420] Step 4: Synthesis of Compound 709

[0421] Under nitrogen, the product 709-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (79 mg, 1.92 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction system and stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 709 (295 mg, 52% yield) as an off-white solid.

[0422] ESI-MS:m / z:542.2[M+H] + .

[0423] 1 H NMR (400MHz, DMSO) δ = 10.35 (s, 1H), 7.94 (d, J = 8.6, 1H), 7.39 (s, 1H), 7.00 ( d,J=1.8,1H),6.93(dd,J=8.6,1.9,1H),4.17(t,J=6.4,2H),3.96–3.81(m,4 H),3.76(t,J=6.5,2H),3.38(t,J=6.5,2H),2.31(s,3H),2.08–1.87(m,6H) ,1.50(dd,J=10.6,4.8,2H), 1.36(dd,J=14.8,7.3,2H), 0.88(t,J=7.3,3H).

[0424] Example 24 Synthesis of Compound 710

[0425] Step 1: Synthesis of compound 710-01

[0426] IM-02 (500 mg, 1.26 mmol, 1.0 eq), 2-pentanol (111 mg, 1.26 mmol, 1.0 eq), and potassium carbonate (348 mg, 2.52 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 100°C for 9 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 710-01 (433 mg, yield: 74%) as a yellow solid.

[0427] ESI-Ms:m / z:464.2[M+H] + .

[0428] Step 2: Synthesis of Compound 710-02

[0429] Dissolve 710-01 (433 mg, 0.93 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (99 mg, 1.86 mmol, 2.0 eq) and zinc powder (121 mg, 1.86 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 710-02 for later use.

[0430] ESI-Ms:m / z:434.2[M+H] + .

[0431] Step 3: Synthesis of compound 710-03

[0432] Under nitrogen, Intermediate 710-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.31 mL, 1.86 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (160 mg, 0.93 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was added to water (20 mL) and separated. The mixture was then extracted with dichloromethane (10 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain Intermediate 710-03, which was used directly in the next step without purification.

[0433] ESI-Ms:m / z:570.2[M+H] + .

[0434] Step 4: Synthesis of Compound 710

[0435] Under nitrogen, the product 710-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (70 mg, 1.86 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction. The mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 710 (295 mg, 52% yield) as an off-white solid.

[0436] ESI-Ms:m / z:542.2[M+H] + .

[0437] 1 H NMR (400MHz, DMSO) δ = 10.51 (s, 1H), 7.98 (d, J = 8.7, 1H), 7.37 (s, 1H), 7.03 (d, J=1.6,1H),6.94(dd,J=8.7,1.9,1H),4.71–4.61(m,1H),3.93–3.83(m,4H),3. 77(t,J=6.4,2H),3.38(t,J=6.4,2H),2.31(s,3H),1.97(td,J=13.6,6.6,4H), 1.92–1.69(m,2H),1.59–1.43(m,2H),1.41(d,J=6.0,3H),0.92(t,J=7.3,3H).

[0438] Example 25 Synthesis of Compound 711

[0439] Step 1: Synthesis of compound 711-01

[0440] IM-02 (300 mg, 0.76 mmol, 1.0 eq), 2-methylbutanol (134 mg, 1.52 mmol, 2.0 eq), and potassium carbonate (315 mg, 2.28 mmol, 3.0 eq) were dispersed in dimethyl sulfoxide (5 mL). The reaction mixture was stirred at 120°C for 2 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (25 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 711-01 (326 mg, yield: 92%) as a yellow solid.

[0441] ESI-MS m / z:464.2[M+H] + .

[0442] Step 2: Synthesis of compound 711-02

[0443] Dissolve 711-01 (163 mg, 0.35 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (18.6 mg, 0.35 mmol, 1.0 eq) and zinc powder (22.8 mg, 0.35 mmol, 1.0 eq) sequentially. Stir at room temperature for 15 minutes. Once the starting material disappears, remove the solid by suction filtration. Concentrate the filtrate under reduced pressure to obtain product 711-02 for later use.

[0444] ESI-MS m / z:434.2[M+H] + .

[0445] Step 3: Synthesis of compound 711-03

[0446] Under nitrogen, the product 711-02 from step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.12 mL, 0.7 mmol, 2.0 eq) was added, and a dichloromethane solution (2 mL) of methyl 2-(chlorosulfonyl)acetate (0.04 mL, 0.35 mmol, 1.0 eq) was slowly added dropwise under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After LC-MS monitoring indicated the reaction was complete, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (5 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product 711-03 was used directly in the next step without purification.

[0447] ESI-MS m / z:570.2[M+H] + .

[0448] Step 4: Synthesis of Compound 711

[0449] Under nitrogen, the crude product 711-03 obtained in step 3 was dissolved in tetrahydrofuran (5 mL). Sodium borohydride (26.6 mg, 0.7 mmol, 2.0 eq) was slowly added portionwise at room temperature. After the starting material disappeared, acetone was added dropwise to quench the reaction. After the addition was complete, the reaction was stirred at room temperature for 30 minutes. The resulting reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to afford 711 (114 mg, yield: 60%) as an off-white solid.

[0450] 1 H NMR (400MHz, DMSO) δ = 10.22 (s, 1H), 7.91 (d, J = 8.6, 1H), 7.40 (s, 1H), 6.94 ( s,1H),6.88(d,J=8.7,1H),4.05(dd,J=8.5,4.5,1H),4.03–3.96(m,1H),3.8 4(s,4H),3.74(t,J=6.4,2H),3.30(t,J=6.3,2H),2.29(s,3H),1.96(s,5H) ,1.50(ddd,J=21.0,13.7,6.7,2H),1.13(d,J=6.7,3H),0.92(t,J=7.4,3H).

[0451] ESI-MS m / z:542.2[M+H] + .

[0452] Example 26 Synthesis of Compound 712

[0453] Step 1: Synthesis of compound 712-01

[0454] IM-02 (300 mg, 0.76 mmol, 1.0 eq), isoamyl alcohol (134 mg, 1.52 mmol, 2.0 eq), and potassium carbonate (315 mg, 2.28 mmol, 3.0 eq) were dispersed in dimethyl sulfoxide (5 mL). The reaction mixture was stirred at 120°C for 2 hours. After LC-MS monitoring indicated the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (25 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 712-01 (215 mg, 60% yield) as a yellow solid.

[0455] ESI-MS m / z:464.2[M+H] + .

[0456] Step 2: Synthesis of compound 712-02

[0457] Dissolve 712-01 (215 mg, 0.46 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (24.4 mg, 0.46 mmol, 1.0 eq) and zinc powder (29.9 mg, 0.46 mmol, 1.0 eq) sequentially. Stir and react at room temperature for 15 minutes. After LC-MS monitoring indicates the reaction is complete, filter to remove the solids, and concentrate the filtrate under reduced pressure to obtain product 712-02 for later use.

[0458] ESI-MS m / z:434.2[M+H] + .

[0459] Step 3: Synthesis of compound 712-03

[0460] Under nitrogen, the product 712-02 from step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.16 mL, 0.92 mmol, 2.0 eq) was added, and a dichloromethane solution (2 mL) of methyl 2-(chlorosulfonyl)acetate (0.05 mL, 0.46 mmol, 1.0 eq) was slowly added dropwise under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After LC-MS monitoring indicated the reaction was complete, the resulting reaction solution was added to water (10 mL), separated, and extracted with dichloromethane (5 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain crude product 712-03 for future use.

[0461] ESI-MS m / z:570.2[M+H] + .

[0462] Step 4: Synthesis of compound 712

[0463] Under nitrogen, the crude product 712-03 obtained in step 3 was dissolved in tetrahydrofuran (5 mL). Sodium borohydride (35 mg, 0.92 mmol, 2.0 eq) was slowly added portionwise at room temperature. After the starting material disappeared, acetone was added dropwise to quench the reaction. Stirring was continued at room temperature for 30 minutes. The resulting reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to afford 712 (99 mg, 39% yield) as an off-white solid.

[0464] 1 H NMR (400MHz, DMSO) δ=10.30(s,1H),7.93(d,J=8.5,1H),7.37(s,1H),7.00(s,1H),6.92(d,J=8.6,1H),4.18(t,J=6.1,1H ),3.85(s,4H),3.74(t,J=6.4,2H),3.38–3.34(m,2H),2.29(s,3H),1.96(s,4H),1.90–1.78(m,2H),0.93(d,J=6.0,6H).

[0465] ESI-MS m / z:542.2[M+H] + .

[0466] Example 27 Synthesis of Compound 713

[0467] Step 1: Synthesis of compound 713-01

[0468] IM-02 (300 mg, 0.76 mmol, 1.0 eq), 3-methyl-2-butanol (268 mg, 3.04 mmol, 4.0 eq), and potassium carbonate (629 mg, 4.56 mmol, 6.0 eq) were dispersed in dimethyl sulfoxide (5 mL). The reaction mixture was stirred at 100°C for 2 hours. After LC-MS monitoring indicated the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (25 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 713-01 (237 mg, yield: 67%) as a yellow solid.

[0469] ESI-MS m / z:464.2[M+H] + .

[0470] Step 2: Synthesis of Compound 713-02

[0471] Dissolve 713-01 (237 mg, 0.51 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (54 mg, 1.02 mmol, 2.0 eq) and zinc powder (65 mg, 1.02 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After LC-MS monitoring indicates the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain product 713-02.

[0472] ESI-MS m / z:434.2[M+H] + .

[0473] Step 3: Synthesis of Compound 713-03

[0474] Under nitrogen, the product 713-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.175 mL, 1.02 mmol, 2.0 eq) was added, and a dichloromethane solution (2 mL) of methyl 2-(chlorosulfonyl)acetate (0.06 mL, 0.51 mmol, 1.0 eq) was slowly added dropwise under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After LC-MS monitoring indicated the reaction was complete, the resulting reaction solution was added to water (20 mL), separated, and extracted with dichloromethane (5 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain crude product 713-03 for future use.

[0475] ESI-MS m / z:570.2[M+H] + .

[0476] Step 4: Synthesis of compound 713

[0477] Under nitrogen, the crude product 713-03 obtained in step 3 was dissolved in tetrahydrofuran (5 mL). Sodium borohydride (38.8 mg, 1.02 mmol, 2.0 eq) was slowly added portionwise at room temperature. After the starting material disappeared, acetone was added dropwise to quench the reaction. Stirring was continued at room temperature for 30 minutes. The resulting reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to afford 713 (190 mg, 70% yield) as an off-white solid.

[0478] 1 H NMR (400MHz, DMSO) δ=10.34(s,1H),7.96(d,J=8.7,1H),7.37(s,1H),7.02(s,1H),6.92(dd,J=8.6,1.5,1H),4.55–4.43(m,1H),3.84(s,4H),3.7 5(t,J=6.4,2H),3.36(t,J=6.4,2H),2.29(s,3H),2.07(dd,J=11.7,6.7 ,1H),2.01–1.85(m,4H),1.32(d,J=6.1,3H),1.04(dd,J=20.1,6.8,6H).

[0479] ESI-MS m / z:542.2[M+H] + .

[0480] Example 28 Synthesis of Compound 715

[0481] Step 1: Synthesis of compound 715-01

[0482] IM-02 (300 mg, 0.76 mmol, 1.0 eq), 4-penten-1-ol (262 mg, 3.04 mmol, 4.0 eq), and potassium carbonate (629 mg, 4.56 mmol, 6.0 eq) were dispersed in dimethyl sulfoxide (5 mL). The reaction mixture was stirred at 100°C for 2 hours. After LC-MS monitoring indicated the reaction was complete, the reaction mixture was cooled to room temperature and diluted with water (25 mL). The mixture was extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 715-01 (170 mg, 48% yield) as a yellow solid.

[0483] ESI-MS m / z:462.2[M+H] + .

[0484] Step 2: Synthesis of Compound 715-02

[0485] Dissolve 715-01 (170 mg, 0.37 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (39 mg, 0.74 mmol, 2.0 eq) and zinc powder (48 mg, 0.74 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After LC-MS monitoring indicates the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain product 715-02.

[0486] ESI-MS m / z:432.2[M+H] + .

[0487] Step 3: Synthesis of compound 715-03

[0488] Under nitrogen, the product 715-02 from step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.13 mL, 0.74 mmol, 2.0 eq) was added, and a dichloromethane solution (2 mL) of methyl 2-(chlorosulfonyl)acetate (0.04 mL, 0.37 mmol, 1.0 eq) was slowly added dropwise under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After LC-MS monitoring indicated the reaction was complete, the resulting reaction solution was added to water (20 mL), partitioned, and extracted with dichloromethane (5 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain crude product 715-03 for later use.

[0489] ESI-MS m / z:568.2[M+H]+ .

[0490] Step 4: Synthesis of Compound 715

[0491] Under nitrogen, the crude product 715-03 obtained in step 3 was dissolved in tetrahydrofuran (5 mL). Sodium borohydride (28.1 mg, 0.74 mmol, 2.0 eq) was slowly added portionwise at room temperature. After the starting material disappeared, acetone was added dropwise to quench the reaction. After completion of the addition, the reaction was stirred at room temperature for 1 hour. The resulting reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to afford 715 (80 mg, 45% yield) as an off-white solid.

[0492] 1 H NMR (400MHz, DMSO) δ = 10.32 (s, 1H), 7.91 (d, J = 8.6, 1H), 7.39 (s, 1H), 6.95 (s, 1H), 6.90 (dd, J = 8.6, 1.6, 1H), 5.88 (ddd, J = 17.0, 6.6, 3.7, 1H), 5.03(dd,J=23.2,6.0,2H),4.17(t,J=6.1,2H),3.84(s,4H),3.75(t,J =6.5,2H),3.33(t,J=6.3,2H),2.30(s,4H),1.98(dd,J=13.8,6.5,4H).

[0493] ESI-MS m / z:540.2[M+H] + .

[0494] Example 29 Synthesis of Compound 716

[0495] Step 1: Synthesis of compound 716-01

[0496] IM-02 (300 mg, 0.76 mmol, 1.0 eq), 1-penten-3-ol (131 mg, 1.52 mmol, 2.0 eq), and potassium carbonate (315 mg, 2.28 mmol, 3.0 eq) were dispersed in dimethyl sulfoxide (5 mL). The reaction mixture was stirred at 100°C for 2 hours. After LC-MS monitoring indicated the reaction was complete, the reaction mixture was cooled to room temperature and separated by addition of water (25 mL). The mixture was then extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 716-01 (232 mg, yield: 66%) as a yellow solid.

[0497] ESI-MS m / z:462.2[M+H] + .

[0498] Step 2: Synthesis of Compound 716-02

[0499] Dissolve 716-01 (232 mg, 0.5 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (53 mg, 1.0 mmol, 2.0 eq) and zinc powder (65 mg, 1.0 mmol, 2.0 eq) sequentially. Stir at room temperature for 15 minutes. After LC-MS monitoring indicates the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain product 716-02.

[0500] ESI-MS m / z:432.2[M+H] + .

[0501] Step 3: Synthesis of Compound 716-03

[0502] Under nitrogen, the product 716-02 from step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.175 mL, 1.0 mmol, 2.0 eq) was added, and a dichloromethane solution (2 mL) of methyl 2-(chlorosulfonyl)acetate (0.06 mL, 0.5 mmol, 1.0 eq) was slowly added dropwise under an ice bath. The ice bath was removed and the mixture was allowed to react at room temperature for 2 h. After LC-MS monitoring indicated the reaction was complete, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (5 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain crude product 716-03, which was used directly in the next step without purification.

[0503] ESI-MS m / z:568.2[M+H] + .

[0504] Step 4: Synthesis of Compound 716

[0505] Under nitrogen, the crude product 716-03 from step 3 was dissolved in tetrahydrofuran (5 mL). Sodium borohydride (38 mg, 1.0 mmol, 2.0 eq) was slowly added portionwise at room temperature. After the starting material disappeared, acetone was added dropwise to quench the reaction. Stirring was continued at room temperature for 30 minutes. The resulting reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 716 (120 mg, 45% yield) as an off-white solid.

[0506] 1 H NMR (400MHz, DMSO) δ=10.44(s,1H),7.93(d,J=8.6,1H),7.36(s,1H),7.00(s,1H),6.88(d,J=8.6,1H),5.88(td,J=10.5,5.2,1H),5.35(dd,J =18.6,14.1,2H),4.95–4.83(m,1H),3.83(s,5H),3.73(t,J=6.5,2H), 3.31–3.26(m,2H),2.29(s,3H),2.05–1.84(m,7H),1.04(t,J=7.3,3H).

[0507] ESI-MS m / z:540.2[M+H] + .

[0508] Example 30 Synthesis of Compound 717

[0509] Step 1: Synthesis of compound 717-01

[0510] IM-02 (400 mg, 1.01 mmol, 1.0 eq), cis-2-pentenol (87 mg, 1.01 mmol, 1.0 eq), and potassium carbonate (278 mg, 2.02 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 100°C for 4 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 717-01 (372 mg, 80% yield) as a yellow solid.

[0511] ESI-MS:m / z:462.2[M+H] + .

[0512] Step 2: Synthesis of Compound 717-02

[0513] Dissolve 717-01 (270 mg, 0.58 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (61 mg, 1.16 mmol, 2.0 eq) and zinc powder (75 mg, 1.16 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After LC-MS monitoring indicates the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 717-02 for later use.

[0514] ESI-MS:m / z:432.2[M+H] + .

[0515] Step 3: Synthesis of Compound 717-03

[0516] Under nitrogen, intermediate 717-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). DIPEA (0.2 mL, 1.16 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.07 mL, 0.58 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 717-03, which was used directly in the next step without purification.

[0517] ESI-MS:m / z:568.2[M+H] + .

[0518] Step 4: Synthesis of Compound 717

[0519] Under nitrogen, the product 717-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (44 mg, 1.16 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to afford 717 (170 mg, 54% yield) as an off-white solid.

[0520] 1 H NMR (400MHz, DMSO) δ=10.39(s,1H),7.93(d,J=8.6,1H),7.33(s,1H),7.02(s,1H),6.93(dd,J=8.6,1.4,1H),5.79(d,J=5.7,2H),4.77(d, J=4.7,2H),3.85(s,4H),3.75(t,J=6.4,2H),3.37(t,J=6.5,2H),2.28(s,3H),2.25–2.10(m,2H),2.10–1.86(m,5H),0.95(t,J=7.5,3H).

[0521] ESI-MS:m / z:540.2[M+H] + .

[0522] Example 31 Synthesis of Compound 719

[0523] Step 1: Synthesis of compound 719-01

[0524] IM-02 (300 mg, 0.76 mmol, 1.0 eq), 3-methyl-3-buten-1-ol (65 mg, 0.76 mmol, 1.0 eq), and potassium carbonate (210 mg, 1.52 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 100°C for 4 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 719-01 (273 mg, yield: 78%) as a yellow solid.

[0525] ESI-MS:m / z:462.2[M+H] + .

[0526] Step 2: Synthesis of Compound 719-02

[0527] Dissolve 719-01 (170 mg, 0.37 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (39 mg, 0.74 mmol, 2.0 eq) and zinc powder (48 mg, 0.74 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After LC-MS monitoring indicates the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 719-02 for later use.

[0528] ESI-MS:m / z:432.2[M+H] + .

[0529] Step 3: Synthesis of Compound 719-03

[0530] Under nitrogen, intermediate 719-02 obtained in step 1 was dissolved in anhydrous dichloromethane (5 mL). DIPEA (0.13 mL, 0.74 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.04 mL, 0.37 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 719-03, which was used directly in the next step without purification.

[0531] ESI-MS:m / z:568.2[M+H] + .

[0532] Step 4: Synthesis of Compound 719

[0533] Under nitrogen, the product 719-03 obtained in step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (28 mg, 0.74 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to afford 719 (100 mg, 50% yield) as an off-white solid.

[0534] 1 H NMR (400MHz, DMSO) δ=10.23(s,1H),7.84(d,J=8.6,1H),7.31(s,1H),6.92(d,J=1.5,1H),6.85(dd,J=8.6,1.6,1H),4.78(d,J=15.6,2H),4.2 4(t,J=6.4,2H),3.89–3.78(m,4H),3.71(t,J=6.5,2H),3.28(t,J=6.4 ,2H),2.59(t,J=6.2,2H),2.25(s,3H),2.00–1.84(m,4H),1.73(s,3H).

[0535] ESI-MS:m / z:540.2[M+H] + .

[0536] Example 32 Synthesis of Compound 721

[0537] Step 1: Synthesis of compound 721-01

[0538] IM-02 (300 mg, 0.76 mmol, 1.0 eq), prenol (65 mg, 0.76 mmol, 1.0 eq), and potassium carbonate (210 mg, 1.52 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 95°C for 2 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 721-01 (300 mg, yield: 85%) as a yellow solid.

[0539] ESI-MS:m / z:462.2[M+H] + .

[0540] Step 2: Synthesis of compound 721-02

[0541] Dissolve 721-01 (300 mg, 0.65 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (69 mg, 1.3 mmol, 2.0 eq) and zinc powder (85 mg, 1.3 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After LC-MS monitoring indicates the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 721-02 for later use.

[0542] ESI-MS:m / z:432.2[M+H] + .

[0543] Step 3: Synthesis of Compound 721-03

[0544] Under nitrogen, intermediate 721-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). DIPEA (0.23 mL, 1.3 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.075 mL, 0.65 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 721-03, which was used directly in the next step without purification.

[0545] ESI-MS:m / z:568.2[M+H] + .

[0546] Step 4: Synthesis of Compound 721

[0547] Under nitrogen, the product 721-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (49 mg, 1.3 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to afford 721 (170 mg, 49% yield) as an off-white solid.

[0548] 1 H NMR (400MHz, DMSO) δ = 10.35 (s, 1H), 7.94 (d, J = 8.6, 1H), 7.39 (s, 1H), 7.00 (d, J = 1.3, 1H), 6.91 (dd, J = 8.7, 1.6, 1H), 5.60 (t, J = 6.2, 1H),4.73(d,J=6.6,2H),3.86(s,4H),3.76(t,J=6.5,2H),3.35(t,J=6.2,2H),2.30(s,3H),2.07–1.91(m,4H),1.77(d,J=5.4,6H).

[0549] ESI-MS:m / z:540.2[M+H] + .

[0550] Example 33 Synthesis of Compound 722

[0551] Step 1: Synthesis of compound 722-01

[0552] IM-02 (300 mg, 0.76 mmol, 1.0 eq), cyclopentylmethanol (76 mg, 0.76 mmol, 1.0 eq), and potassium carbonate (210 mg, 1.52 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 100°C overnight. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 722-01 (350 mg, yield: 97%) as a yellow solid.

[0553] ESI-MS:m / z:476.2[M+H] + .

[0554] Step 2: Synthesis of Compound 722-02

[0555] Dissolve 722-01 (350 mg, 0.74 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (78 mg, 1.48 mmol, 2.0 eq) and zinc powder (96 mg, 1.48 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 minutes. After LC-MS monitoring indicates the reaction is complete, filter the solids and concentrate the filtrate under reduced pressure to obtain intermediate 722-02 for later use.

[0556] ESI-MS:m / z:446.2[M+H] + .

[0557] Step 3: Synthesis of Compound 722-03

[0558] Under nitrogen, intermediate 722-02 obtained in step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.26 mL, 1.48 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.085 mL, 0.74 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. After the starting material disappeared, the resulting reaction solution was added to water (20 mL) and separated. The mixture was then extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 722-03, which was used directly in the next step without purification.

[0559] ESI-MS:m / z:582.2[M+H] + .

[0560] Step 4: Synthesis of Compound 722

[0561] Under nitrogen, the product 722-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (56 mg, 1.48 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to yield 722 (200 mg, 48% yield) as an off-white solid.

[0562] 1H NMR (400MHz, DMSO) δ=10.27(s,1H),7.90(d,J=8.6,1H),7.42(s,1H),6.90(d,J =1.5,1H),6.85(dd,J=8.7,1.7,1H),4.05(d,J=7.2,2H),3.93–3.81(m,4H),3. 75(t,J=6.5,2H),3.28(t,J=6.5,2H),2.46(d,J=7.7,1H),2.30(s,3H),2.07–1 .93(m,6H),1.64(d,J=6.7,2H),1.60–1.50(m,2H),1.37(dd,J=12.2,7.2,2H).

[0563] ESI-MS:m / z:554.2[M+H] + .

[0564] Example 34 Synthesis of Compound 726

[0565] Step 1: Synthesis of Compound 726-01

[0566] IM-02 (300 mg, 0.76 mmol, 1.0 eq), 3,3-dimethyl-1-butyl ester (78 mg, 0.76 mmol, 1.0 eq), and potassium carbonate (210 mg, 1.52 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 105°C for 2 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 726-01 (333 mg, yield: 92%) as a yellow solid.

[0567] ESI-MS:m / z:478.2[M+H] + .

[0568] Step 2: Synthesis of Compound 726-02

[0569] Dissolve 726-01 (333 mg, 0.7 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (74 mg, 1.4 mmol, 2.0 eq) and zinc powder (91 mg, 1.4 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 726-02 for later use.

[0570] ESI-MS:m / z:448.2[M+H] + .

[0571] Step 3: Synthesis of Compound 726-03

[0572] Under nitrogen, intermediate 726-02 obtained in step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.24 mL, 1.4 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.08 mL, 0.7 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 726-03, which was used directly in the next step without purification.

[0573] ESI-MS:m / z:584.2[M+H] + .

[0574] Step 4: Synthesis of Compound 726

[0575] Under nitrogen, the product 726-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (53 mg, 1.4 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction. The mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 726 (192 mg, 49% yield) as an off-white solid.

[0576] ESI-MS:m / z:556.2[M+H] + .

[0577] 1 H NMR (400MHz, DMSO) δ=10.37(s,1H),7.92(d,J=8.6,1H),7.35(s,1H),6.99(d,J=1.5,1H),6.92(dd,J=8.6,1.7,1H),4.20(t,J=7 .1,2H),3.93–3.80(m,4H),3.74(t,J=6.4,2H),3.35(t,J=6.5,2H),2.27(s,3H),1.92(ddd,J=23.4,13.8,7.5,6H),0.96(s,9H).

[0578] Example 35 Synthesis of Compound 729

[0579] Step 1: Synthesis of compound 729-01

[0580] IM-02 (300 mg, 0.76 mmol, 1.0 eq), 4-methyl-2-pentanol (78 mg, 0.76 mmol, 1.0 eq), and potassium carbonate (210 mg, 1.52 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 110°C for 3 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 729-01 (301 mg, yield: 83%) as a yellow solid.

[0581] ESI-MS:m / z:478.2[M+H] + .

[0582] Step 2: Synthesis of Compound 729-02

[0583] Dissolve 729-01 (243 mg, 0.51 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (54 mg, 1.02 mmol, 2.0 eq) and zinc powder (66 mg, 1.02 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 729-02 for later use.

[0584] ESI-MS:m / z:448.2[M+H] + .

[0585] Step 3: Synthesis of Compound 729-03

[0586] Under nitrogen, intermediate 729-02 obtained in step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.18 mL, 1.02 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.059 mL, 0.51 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 729-03, which was used directly in the next step without purification.

[0587] ESI-MS:m / z:584.2[M+H] + .

[0588] Step 4: Synthesis of Compound 729

[0589] Under nitrogen, the product 729-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (59 mg, 1.02 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction. The mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 729 (145 mg, 51% yield) as an off-white solid.

[0590] ESI-MS:m / z:556.2[M+H] + .

[0591] 1 H NMR (400MHz, DMSO) δ = 10.45 (s, 1H), 7.92 (d, J = 8.7, 1H), 7.32 (s, 1H), 6.99 (d, J=1.2,1H),6.88(dd,J=8.7,1.6,1H),4.64(d,J=6.1,1H),3.90–3.77(m,4H),3 .71(t,J=6.4,2H),3.31(t,J=6.4,2H),2.25(s,3H),2.01–1.86(m,4H),1.85– 1.71(m,2H),1.62–1.50(m,1H),1.34(d,J=5.9,3H),0.88(dd,J=9.9,6.3,6H).

[0592] Example 36 Synthesis of Compound 730

[0593] Step 1: Synthesis of compound 730-01

[0594] IM-02 (300 mg, 0.76 mmol, 1.0 eq), 2-(2,2-difluorocyclopropyl)ethanol (93 mg, 0.76 mmol, 1.0 eq), and potassium carbonate (210 mg, 1.52 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 100°C for 2 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 730-01 (297 mg, 78% yield) as a yellow solid.

[0595] ESI-MS:m / z:498.2[M+H] + .

[0596] Step 2: Synthesis of compound 730-02

[0597] Dissolve 730-01 (270 mg, 0.54 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (57 mg, 1.08 mmol, 2.0 eq) and zinc powder (70 mg, 1.08 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 730-02 for later use.

[0598] ESI-MS:m / z:468.2[M+H] + .

[0599] Step 3: Synthesis of compound 730-03

[0600] Under nitrogen, Intermediate 730-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.19 mL, 1.08 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.06 mL, 0.54 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain Intermediate 730-03, which was used directly in the next step without purification.

[0601] ESI-MS:m / z:604.2[M+H] + .

[0602] Step 4: Synthesis of Compound 730

[0603] Under nitrogen, the product 730-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (41 mg, 1.08 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 730 (151 mg, 49% yield) as an off-white solid.

[0604] ESI-MS:m / z:576.2[M+H] + .

[0605] 1 H NMR (400MHz, DMSO) δ=10.32(s,1H),7.92(d,J=8.6,1H),7.37(s,1H),7.01(s,1H),6.95(d,J=8.6,1H),4.24(d,J=5.9,2H),3.84(s,2H) ,3.76(t,J=6.4,1H),3.39(t,J=6.4,1H),2.30(s,2H),2.28–2.18(m,1H),1.95(d,J=14.4,3H),1.58(d,J=11.1,1H),1.41–1.27(m,1H).

[0606] Example 37 Synthesis of Compound 731

[0607] Step 1: Synthesis of compound 731-01

[0608] IM-02 (300 mg, 0.76 mmol, 1.0 eq), (3,3-difluorocyclobutyl)methanol (93 mg, 0.76 mmol, 1.0 eq), and potassium carbonate (210 mg, 1.52 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 100°C for 2 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 731-01 (310 mg, yield: 82%) as a yellow solid.

[0609] ESI-MS:m / z:498.2[M+H] + .

[0610] Step 2: Synthesis of compound 731-02

[0611] Dissolve 731-01 (310 mg, 0.62 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (66 mg, 1.24 mmol, 2.0 eq) and zinc powder (81 mg, 1.24 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 731-02 for later use.

[0612] ESI-MS:m / z:468.2[M+H] + .

[0613] Step 3: Synthesis of compound 731-03

[0614] Under nitrogen, intermediate 731-02 obtained in step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.22 mL, 1.24 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.072 mL, 0.62 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 731-03, which was used directly in the next step without purification.

[0615] ESI-MS:m / z:604.2[M+H] + .

[0616] Step 4: Synthesis of Compound 731

[0617] Under nitrogen, the product 731-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (47 mg, 1.24 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 731 (161 mg, 45% yield) as an off-white solid.

[0618] ESI-MS:m / z:576.2[M+H] + .

[0619] 1H NMR (400MHz, DMSO) δ=10.16(s,1H),7.87(d,J=8.6,1H),7.39(s,1H),6.94(d,J=1.6,1H),6.90(dd,J=8.6,1.7,1H),4.24(d,J=5.7,2H ),3.91–3.84(m,4H),3.76(t,J=6.5,2H),3.35(t,J=6.4,2H),2.87–2.68(m,4H),2.63(d,J=6.5,1H),2.30(s,3H),2.05–1.92(m,4H).

[0620] Example 38 Synthesis of Compound 732

[0621] Step 1: Synthesis of compound 732-01

[0622] IM-02 (300 mg, 0.76 mmol, 1.0 eq), CM-05 (76 mg, 0.76 mmol, 1.0 eq), and potassium carbonate (210 mg, 1.52 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 100°C for 3 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 732-01 (349 mg, yield: 96%) as a yellow solid.

[0623] ESI-MS:m / z:476.2[M+H] + .

[0624] Step 2: Synthesis of Compound 732-02

[0625] Dissolve 732-01 (349 mg, 0.73 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (77 mg, 1.46 mmol, 2.0 eq) and zinc powder (95 mg, 1.46 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 732-02 for later use.

[0626] ESI-MS:m / z:446.2[M+H] + .

[0627] Step 3: Synthesis of compound 732-03

[0628] Under nitrogen, Intermediate 732-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.25 mL, 1.46 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.084 mL, 0.73 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain Intermediate 732-03, which was used directly in the next step without purification.

[0629] ESI-MS:m / z:582.2[M+H] + .

[0630] Step 4: Synthesis of Compound 732

[0631] Under nitrogen, the product 732-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (55 mg, 1.46 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 732 (200 mg, 49% yield) as an off-white solid.

[0632] ESI-MS:m / z:554.2[M+H] + .

[0633] 1 H NMR: (400MHz, DMSO-d6) δ10.40(s,1H),7.93(d,J=8.6Hz,1H),7.36(s,1H),7.02( d,J=1.7Hz,1H),6.94(dd,J=8.6,1.8Hz,1H),4.28(t,J=6.3Hz,2H),3.92–3.84(m, 4H),3.77(t,J=6.3Hz,2H),3.38(t,J=6.3Hz,2H),2.31(s,3H),2.05–1.92(m,4H) ,1.89(t,J=6.3Hz,2H),1.11(s,3H),0.38(t,J=8.0Hz,2H),0.28(t,J=8.0Hz,2H).

[0634] Example 39 Synthesis of Compound 733

[0635] Step 1: Synthesis of compound 733-01

[0636] IM-02 (300 mg, 0.76 mmol, 1.0 eq), bicyclo[1.1.1]pentan-1-ylmethanol (74 mg, 0.76 mmol, 1.0 eq), and potassium carbonate (210 mg, 1.52 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 90°C for 3 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 733-01 (324 mg, 90% yield) as a yellow solid.

[0637] ESI-MS:m / z:474.2[M+H] + .

[0638] Step 2: Synthesis of Compound 733-02

[0639] Dissolve 733-01 (324 mg, 0.68 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (73 mg, 1.37 mmol, 2.0 eq) and zinc powder (89 mg, 1.37 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 733-02 for later use.

[0640] ESI-MS:m / z:444.2[M+H] + .

[0641] Step 3: Synthesis of Compound 733-03

[0642] Under nitrogen, intermediate 733-02 obtained in step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.24 mL, 1.37 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.078 mL, 0.68 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 733-03, which was used directly in the next step without purification.

[0643] ESI-MS:m / z:580.2[M+H] + .

[0644] Step 4: Synthesis of compound 733

[0645] Under nitrogen, the product 733-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (52 mg, 1.37 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 733 (203 mg, 54% yield) as an off-white solid.

[0646] ESI-MS:m / z:552.2[M+H] + .

[0647] 1 H NMR (400MHz, DMSO) δ=10.06(s,1H),7.97(d,J=8.6,1H),7.49(s,1H),6.95(s,1H),6.91(d,J=8.6,1H),4.11(s,2H ),3.87(s,4H),3.75(t,J=6.4,2H),3.37(t,J=6.5,2H),2.61(s,1H),2.31(s,3H),2.00(s,6H),1.99–1.90(m,4H).

[0648] Example 40 Synthesis of Compound 735

[0649] Step 1: Synthesis of compound 735-01

[0650] IM-02 (300 mg, 0.76 mmol, 1.0 eq), (1-methylcyclobutyl)methanol (76 mg, 0.76 mmol, 1.0 eq), and potassium carbonate (210 mg, 1.52 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 100°C overnight. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 735-01 (280 mg, yield: 78%) as a yellow solid.

[0651] ESI-MS:m / z:476.2[M+H] + .

[0652] Step 2: Synthesis of Compound 735-02

[0653] Dissolve 735-01 (280 mg, 0.59 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (63 mg, 1.18 mmol, 2.0 eq) and zinc powder (77 mg, 1.18 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 1 h. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 735-02 for later use.

[0654] ESI-MS:m / z:446.2[M+H] + .

[0655] Step 3: Synthesis of Compound 735-03

[0656] Under nitrogen, Intermediate 735-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.21 mL, 1.18 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.068 mL, 0.59 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. After the starting material disappeared, the resulting reaction solution was added to water (20 mL) and separated. The mixture was then extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain Intermediate 735-03, which was used directly in the next step without purification.

[0657] ESI-MS:m / z:582.2[M+H] + .

[0658] Step 4: Synthesis of Compound 735

[0659] Under nitrogen, the product 735-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (45 mg, 1.18 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 735 (174 mg, 53% yield) as an off-white solid.

[0660] ESI-MS:m / z:554.2[M+H] + .

[0661] 1H NMR (400MHz, DMSO) δ=10.29(s,1H),10.07(s,1H),7.97(d,J=8.6,1H),7.43(s,1H),7.04(s,1H),6.95(d,J=8.6,1H ),4.06(s,2H),3.88(s,4H),3.76(t,J=6.3,2H),3.41(t,J=6.4,2H),2.30(s,3H),2.11–1.80(m,10H),1.38(s,3H).

[0662] Example 41 Synthesis of Compound 737

[0663] Step 1: Synthesis of Compound 737-01

[0664] IM-02 (500 mg, 1.26 mmol, 1.0 eq), 2,3-dimethylbutanol (129 mg, 1.26 mmol, 1.0 eq), and potassium carbonate (348 mg, 2.52 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 90°C for 8 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 737-01 (447 mg, yield: 74%) as a yellow solid.

[0665] ESI-MS:m / z:478.2[M+H] + .

[0666] Step 2: Synthesis of Compound 737-02

[0667] Dissolve 737-01 (447 mg, 0.94 mmol, 1.0 eq) obtained in Step 1 in methanol (10 mL). Add ammonium chloride (100 mg, 1.88 mmol, 2.0 eq) and zinc powder (122 mg, 1.88 mmol, 2.0 eq) sequentially to the reaction mixture. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 737-02 for later use.

[0668] ESI-MS:m / z:448.2[M+H] + .

[0669] Step 3: Synthesis of Compound 737-03

[0670] Under nitrogen, Intermediate 737-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.31 mL, 1.88 mmol, 2.0 eq) was added. Methyl 2-(chlorosulfonyl)acetate (162 mg, 0.94 mmol, 1.0 eq) in dichloromethane was then added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 737-03, which was used directly in the next step without purification.

[0671] ESI-MS:m / z:584.2[M+H] + .

[0672] Step 4: Synthesis of Compound 737

[0673] Under nitrogen, the product 737-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (71 mg, 1.88 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction system and stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 737 (276 mg, 53% yield) as an off-white solid.

[0674] ESI-MS:m / z:556.2[M+H] + .

[0675] 1 H NMR: (400MHz, DMSO-d6) δ10.23(s,1H),7.97(d,J=8.7Hz,1H),7.41(s,1H),7.03(d,J=1.7Hz,1H),6 .96(dd,J=8.6,1.8Hz,1H),4.13(dd,J=8.9,4.4Hz,1H),4.07–3.99(m,1H),3.91–3.83(m,4H),3.77( t,J=6.4Hz,2H),3.39(t,J=6.4Hz,2H),2.31(s,3H),1.98(dt,J=14.0,7.9Hz,4H),1.90(dt,J=13.9 ,8.0Hz,4H),1.89–1.79(m,1H),1.11(d,J=6.8Hz,3H),0.94(d,J=6.7Hz,3H),0.91(d,J=6.7Hz,3H).

[0676] Example 42 Synthesis of Compound 739

[0677] Step 1: Synthesis of compound 739-01

[0678] IM-02 (500 mg, 1.27 mmol, 1.0 eq), 2,3,3-trimethyl-1-butanol (147 mg, 1.27 mmol, 1.0 eq), and potassium carbonate (350 mg, 2.54 mmol, 2.0 eq) were dispersed in DMSO (6 mL). The reaction mixture was stirred at 100°C for 2 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with dichloromethane (15 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 739-01 (497 mg, yield: 79%) as a yellow solid.

[0679] ESI-MS:m / z:492.2[M+H] + .

[0680] Step 2: Synthesis of Compound 739-02

[0681] Dissolve 739-01 (497 mg, 1.01 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (107 mg, 2.02 mmol, 2.0 eq) and zinc powder (131 mg, 2.02 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 1 h. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 739-02 for future use.

[0682] ESI-MS:m / z:462.2[M+H] + .

[0683] Step 3: Synthesis of Compound 739-03

[0684] Under nitrogen, Intermediate 739-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.35 mL, 2.02 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.12 mL, 1.01 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. After the starting material disappeared, the resulting reaction solution was added to water (20 mL) and separated. The mixture was then extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain Intermediate 739-03, which was used directly in the next step without purification.

[0685] ESI-MS:m / z:598.2[M+H] + .

[0686] Step 4: Synthesis of Compound 739

[0687] Under nitrogen, the product 739-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (77 mg, 2.02 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 739 (276 mg, 48% yield) as an off-white solid.

[0688] ESI-MS:m / z:570.2[M+H] + .

[0689] 1 H NMR: (400MHz, DMSO-d6) δ10.31(s,1H),7.97(d,J=8.6Hz,1H),7.40(s,1H),7.03 (d,J=1.7Hz,1H),6.96(dd,J=8.6,1.8Hz,1H),4.30(dd,J=8.7,3.3Hz,1H),3.92 (t,J=8.7Hz,1H),3.94–3.83(m,4H),3.77(t,J=6.4Hz,2H),3.39(t,J=6.4Hz,2H ), 2.31 (s, 3H), 1.98 (dt, J = 13.9, 8.0Hz, 4H), 1.14 (d, J = 6.8Hz, 3H), 0.96 (s, 9H).

[0690] Example 43 Synthesis of Compound 803

[0691] Step 1: Synthesis of compound 803-01

[0692] IM-02 (500 mg, 1.26 mmol, 1.0 eq), 1-methylcyclopropanemethanol (109 mg, 1.26 mmol, 1.0 eq), and potassium carbonate (348 mg, 2.52 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 100°C for 9 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 803-01 (482 mg, yield: 83%) as a yellow solid.

[0693] ESI-Ms:m / z:462.2[M+H] + .

[0694] Step 2: Synthesis of compound 803-02

[0695] Dissolve 803-01 (482 mg, 1.04 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (110 mg, 2.08 mmol, 2.0 eq) and zinc powder (135 mg, 2.08 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 803-02 for later use.

[0696] ESI-Ms: m / z: 432.2 [M+H].

[0697] Step 3: Synthesis of compound 803-03

[0698] Under nitrogen, Intermediate 803-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.34 mL, 2.08 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (179 mg, 1.04 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was added to water (20 mL) and separated. The mixture was then extracted with dichloromethane (10 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain Intermediate 803-03, which was used directly in the next step without purification.

[0699] ESI-Ms: m / z: 568.2 [M+H].

[0700] Step 4: Synthesis of compound 803

[0701] Under nitrogen, the product 803-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (79 mg, 2.08 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 803 (286 mg, 51% yield) as an off-white solid.

[0702] ESI-Ms: m / z: 540.2 [M+H].

[0703] 1 H NMR (400MHz, DMSO) δ=10.36(s,1H),7.99(d,J=9.2,1H),7.45(s,1H),7.00–6.91(m,2H),3.98(s,2H),3.94–3.84(m,4H),3.76(t ,J=6.5,2H),3.37(t,J=6.6,2H),2.31(s,3H),1.97(dd,J=12.5,6.9,4H),1.35(s,3H),0.68(t,J=4.5,2H),0.50(d,J=4.9,2H).

[0704] Example 44 Synthesis of Compound 805

[0705] Step 1: Synthesis of compound 805-01

[0706] 2-(Trimethylsilyl)ethanol (1.28 g, 10.80 mmol, 1.0 eq) was dispersed in dry tetrahydrofuran (20 mL). NaH (1.08 g, 27.0 mmol, 2.5 eq) was added at 0°C and stirred for 0.5 hours. A solution of CM-01 (2.0 g, 10.80 mmol, 1.0 eq) in tetrahydrofuran (5 mL) was slowly added, and the reaction was continued at room temperature for 3 hours. Upon disappearance of the starting material, the pH was adjusted to 5-6 with 2M dilute hydrochloric acid. The precipitated solid was filtered. The solid was slurried with petroleum ether-ethyl acetate to afford compound 805-01 (2.14 g, 70% yield) as a yellow solid.

[0707] ESI-MS:m / z:284.1[M+H] + .

[0708] Step 2: Synthesis of compound 805-02

[0709] Under nitrogen, 805-01 (2 g, 7.06 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (20 mL). Two drops of DMF were added as a catalyst. Oxalyl chloride (0.9 mL, 10.59 mmol, 1.5 eq) was then added dropwise under an ice bath. After the addition, the ice bath was removed and the mixture was stirred at room temperature for 30 minutes until the starting material disappeared. The resulting reaction solution was then distilled to remove the solvent under anhydrous conditions to obtain the crude acyl chloride, which was then pumped dry with an oil pump for later use.

[0710] Under nitrogen, IM-01 (1.61 g, 7.06 mmol, 1.0 eq) was dissolved in DCE (20 mL). N,N-diisopropylethylamine (2.3 mL, 14.12 mmol, 2.0 eq) was added. The acid chloride solution prepared above and dissolved in anhydrous dichloromethane was added dropwise under an ice bath. After addition, the ice bath was removed and the mixture was stirred at 100°C overnight. After completion of the reaction, the resulting solution was cooled to room temperature and diluted with water (50 mL). A solid precipitated, which was filtered and petroleum ether (75 mL) was added. The product was then purified by slurrying to afford compound 805-02 (2.02 g, 58%) as a yellow solid.

[0711] ESI-MS: m / z: 494.2 [M+H].

[0712] Step 3: Synthesis of compound 805-03

[0713] Dissolve 805-02 (500 mg, 1.01 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (107 mg, 2.02 mmol, 2.0 eq) and zinc powder (131 mg, 2.02 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 15 minutes. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 805-03 for later use.

[0714] ESI-MS: m / z: 464.2 [M+H].

[0715] Step 4: Synthesis of Compound 805-04

[0716] Under nitrogen, Intermediate 805-03 obtained in Step 3 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.33 mL, 2.02 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (174 mg, 1.01 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 805-04, which was used directly in the next step without purification.

[0717] ESI-MS: m / z: 600.2 [M+H].

[0718] Step 5: Synthesis of Compound 805

[0719] Under nitrogen, the product 805-04 from step 4 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (76 mg, 2.02 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction. The mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 805 (323 mg, yield: 56%) as an off-white solid.

[0720] ESI-MS: m / z: 572.2 [M+H].

[0721] 1 H NMR (400MHz, DMSO) δ=10.57(s,1H),7.95(d,J=8.6,1H),7.36(s,1H),7.00(s,1H),6.98–6.92(m,1H),4.32–4.22(m,2H) ,3.85(s,4H),3.76(t,J=6.4,2H),3.38(t,J=6.4,2H),2.30(s,3H),2.05–1.88(m,4H),1.39–1.27(m,2H),0.08(s,9H).

[0722] Example 45 Synthesis of Compound 812

[0723] Step 1: Synthesis of compound 812-01

[0724] Under nitrogen, methyl hydroxytrimethylacetate (2.0 g, 15.15 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL). 3M methylmagnesium chloride / THF solution (10 mL, 30.3 mmol, 2.0 eq) was added dropwise at 0°C. After addition, the reaction was stirred at room temperature for 2 h. After the starting material disappeared, saturated aqueous ammonium chloride (15 mL) was added to quench the reaction. The solid was removed by filtration, and the filtrate was extracted with ethyl acetate (15 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate to obtain Intermediate 812-01, which was used directly in the next step without purification.

[0725] ESI-MS:m / z:133.1[M+H] + .

[0726] Step 2: Synthesis of compound 812-02

[0727] IM-02 (1.0 g, 2.53 mmol, 1.0 eq), intermediate 812-01 obtained in step 1, and potassium carbonate (698 mg, 5.06 mmol, 2.0 eq) were dispersed in DMSO (10 mL). The reaction mixture was stirred at 95°C for 4 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (20 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 812-02 (1.02 g, yield: 79%) as a yellow solid.

[0728] ESI-MS:m / z:508.2[M+H] + .

[0729] Step 3: Synthesis of compound 812-03

[0730] Under nitrogen, 812-02 (1.02 g, 2.01 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL). DAST (0.27 mL, 2.01 mmol, 1.0 eq) was added dropwise at -60°C. The reaction was stirred at room temperature for 2 h. Upon completion, the reaction solution was quenched by adding 10% saturated potassium carbonate solution (20 mL) dropwise under an ice bath. The mixture was then extracted with dichloromethane (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting intermediate 812-03 was used directly in the next step without purification.

[0731] ESI-MS:m / z:490.2[M+H] + .

[0732] Step 4: Synthesis of Compound 812-04

[0733] Intermediate 812-03 obtained in Step 3 was dissolved in methanol (10 mL) and palladium on carbon (680 mg, 10 wt%) was added. After addition, the atmosphere was replaced with argon three times, and hydrogen was introduced. The reaction was allowed to proceed at room temperature overnight under 1 atm. After the starting material disappeared, the solid was removed by filtration. The filtrate was concentrated under reduced pressure and purified by Pre-HPLC to afford Intermediate 812-04 (470 mg, 50% yield).

[0734] ESI-MS:m / z:462.3[M+H] + .

[0735] Step 5: Synthesis of Compound 812-05

[0736] Under nitrogen, 812-04 (470 mg, 1.02 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.35 mL, 2.04 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.12 mL, 1.02 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 812-05, which was used directly in the next step without purification.

[0737] ESI-MS:m / z:598.2[M+H] + .

[0738] Step 6: Synthesis of Compound 812

[0739] Under nitrogen, the product 812-05 from step 5 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (77 mg, 2.04 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 812 (269 mg, 46% yield) as an off-white solid.

[0740] ESI-MS:m / z:570.2[M+H] + .

[0741] 1H NMR: (400MHz, DMSO-d6) δ10.19(s,1H), δ7.97(d,J=8.6Hz,1H),7.40(s,1H),7.03(d,J=1.7Hz,1H),6.96(dd,J=8.6,1.8Hz,1H),3.95(s,2H),3. 94–3.83(m,4H),3.76(t,J=6.4Hz,2H),3.67(t,J=6.4Hz,2H),2.45(dt, J=13.9,8.0Hz,4H),2.27(s,3H),2.05(s,1H),1.01(s,6H),1.00(s,6H).

[0742] Example 46 Synthesis of Compound 829

[0743] Step 1: Synthesis of compound 829-01

[0744] Under nitrogen, methyl hydroxytrimethylacetate (2.0 g, 15.15 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL). A 3M methylmagnesium chloride / THF solution (10 mL, 30.3 mmol, 2.0 eq) was added dropwise at 0°C. After addition, the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the reaction was quenched with saturated aqueous ammonium chloride (15 mL). The solid was removed by filtration, and the filtrate was extracted with ethyl acetate (15 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate to obtain Intermediate 829-01, which was used directly in the next step without purification.

[0745] ESI-MS:m / z:133.1[M+H] + .

[0746] Step 2: Synthesis of compound 829-02

[0747] IM-02 (1.0 g, 2.53 mmol, 1.0 eq), intermediate 829-01 obtained in step 1, and potassium carbonate (698 mg, 5.06 mmol, 2.0 eq) were dispersed in DMSO (10 mL). The reaction mixture was stirred at 95°C for 4 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (20 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 829-02 (1.02 g, yield: 79%) as a yellow solid.

[0748] ESI-MS:m / z:508.2[M+H] + .

[0749] Step 3: Synthesis of compound 829-03

[0750] Under nitrogen, 829-02 (1.02 g, 2.01 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL). DAST (0.27 mL, 2.01 mmol, 1.0 eq) was added dropwise at -60°C. The reaction was stirred at room temperature for 2 h. Upon completion, the reaction solution was quenched by adding 10% saturated potassium carbonate solution (20 mL) under an ice bath. The solution was then extracted with dichloromethane (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting intermediate 829-03 was used directly in the next step without purification.

[0751] ESI-MS:m / z:510.2[M+H] + .

[0752] Step 4: Synthesis of compound 829-04

[0753] Intermediate 829-03 obtained in Step 3 was dissolved in methanol (10 mL) and palladium on carbon (680 mg, 10 wt%) was added. After addition, the atmosphere was replaced with argon three times, and hydrogen was introduced. The reaction was allowed to proceed overnight at room temperature and 1 atm. After the starting material disappeared, the solid was removed by filtration. The filtrate was concentrated under reduced pressure and purified by Pre-HPLC to afford Intermediate 829-04 (500 mg, 51% yield).

[0754] ESI-MS:m / z:480.3[M+H] + .

[0755] Step 5: Synthesis of Compound 829-05

[0756] Under nitrogen, 829-04 (500 mg, 1.04 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.36 mL, 2.08 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.12 mL, 1.04 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 829-05, which was used directly in the next step without purification.

[0757] ESI-MS:m / z:616.2[M+H] + .

[0758] Step 6: Synthesis of Compound 829

[0759] Under nitrogen, the product 829-05 from step 5 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (79 mg, 2.08 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 829 (280 mg, 46% yield) as an off-white solid.

[0760] ESI-MS:m / z:588.2[M+H] + .

[0761] 1 H NMR: (400MHz, DMSO-d6) δ10.22 (s, 1H), δ7.97 (d, J = 8.6Hz, 1H), 7.40 (s, 1H), 7.03 (d, J=1.7Hz,1H),6.96(dd,J=8.6,1.8Hz,1H),4.22(s,2H),3.96–3.85(m,4H),3.76(t,J =6.4Hz,2H),3.67(t,J=6.4Hz,2H),2.47(dt,J=13.9,8.0Hz,4H),2.27(s,3H),1.42( d,J=5.0Hz,3H), 1.36(d,J=4.9Hz,3H), 1.29(d,J=7.0Hz,3H), 1.22(d,J=7.0Hz,3H).

[0762] Example 47 Synthesis of Compound 830A

[0763] Step 1: Synthesis of compound 830A-01

[0764] Under nitrogen, methyl (R)-(-)-3-hydroxy-2-methylpropanoate (1.0 g, 8.47 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL). 3M methylmagnesium chloride / THF solution (5.6 mL, 16.94 mmol, 2.0 eq) was added dropwise at 0°C. After addition, the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the reaction was quenched with saturated aqueous ammonium chloride (15 mL). The solid was removed by filtration, and the filtrate was extracted with ethyl acetate (15 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate to afford Intermediate 830A-01, which was used directly in the next step without purification.

[0765] ESI-MS: m / z: 119.1 [M+H]+ .

[0766] Step 2: Synthesis of compound 830A-02

[0767] IM-02 (2.0 g, 5.06 mmol, 1.0 eq), intermediate 830A-01 obtained in step 1, and potassium carbonate (1.4 g, 10.12 mmol, 2.0 eq) were dispersed in DMSO (20 mL). The reaction mixture was stirred at 95°C for 2 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with dichloromethane (30 mL x 3). The organic layers were combined and backwashed twice with water (20 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 830A-02 (1.89 g, yield: 76%) as a yellow solid.

[0768] ESI-MS:m / z:494.2[M+H] + .

[0769] Step 3: Synthesis of Compound 830A-03

[0770] Under nitrogen, 830A-02 (1.89 g, 3.83 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (20 mL). DAST (0.5 mL, 3.83 mmol, 1.0 eq) was added dropwise at -60°C. The reaction was stirred at room temperature for 2 h. Upon completion, the reaction solution was quenched by adding 10% saturated potassium carbonate solution (40 mL) dropwise under an ice bath. The mixture was then extracted with dichloromethane (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 830A-03 (1.44 g, 76% yield) as a yellow solid.

[0771] ESI-MS:m / z:496.2[M+H] + .

[0772] Step 4: Synthesis of Compound 830A-04

[0773] Dissolve 830A-03 (1.0 g, 2.02 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (214 mg, 4.04 mmol, 2.0 eq) and zinc powder (263 mg, 4.04 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 830A-04 for later use.

[0774] ESI-MS:m / z:466.2[M+H] + .

[0775] Step 5: Synthesis of Compound 830A-05

[0776] Under nitrogen, Intermediate 830A-04 obtained in Step 4 was dissolved in anhydrous dichloromethane (10 mL). DIPEA (0.70 mL, 4.04 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.23 mL, 2.02 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford Intermediate 830A-05, which was used directly in the next step without purification.

[0777] ESI-MS:m / z:602.2[M+H] + .

[0778] Step 6: Synthesis of Compound 830A

[0779] Under nitrogen, the product 830A-05 from Step 5 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (153 mg, 4.04 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 830A (580 mg, 50% yield) as an off-white solid.

[0780] ESI-MS:m / z:574.2[M+H] + .

[0781] 1H NMR: (400MHz, DMSO-d6) δ10.21(s,1H),7.94(d,J=8.6Hz,1H),7.40(s,1H),7.02(d,J=1.5Hz,1 H),6.97(dd,J=8.7,1.5Hz,1H),4.29(dd,J=9.0,4.1Hz,1H),4.11–4.03(m,1H),3.90–3.83(m,4 H),3.77(t,J=6.4Hz,2H),3.40(d,J=6.4Hz,2H),2.37(dd,J=13.1,5.9Hz,1H),2.31(s,3H),1. 97 (dt, J = 13.9, 8.0 Hz, 4H), 1.42 (d, J = 5.0 Hz, 3H), 1.36 (d, J = 4.9 Hz, 3H), 1.22 (d, J = 7.0 Hz, 3H).

[0782] Example 48 Synthesis of Compound 830B

[0783] Step 1: Synthesis of compound 830B-01

[0784] Under nitrogen, methyl (S)-(+)-3-hydroxy-2-methylpropanoate (1.0 g, 8.47 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL). 3M methylmagnesium chloride / THF solution (5.6 mL, 16.94 mmol, 2.0 eq) was added dropwise at 0°C. After addition, the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the reaction was quenched with saturated aqueous ammonium chloride (15 mL). The solid was removed by filtration, and the filtrate was extracted with ethyl acetate (15 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate to obtain intermediate 830B-01, which was used directly in the next step without purification.

[0785] ESI-MS: m / z: 119.1 [M+H] + .

[0786] Step 2: Synthesis of compound 830B-02

[0787] IM-02 (2.0 g, 5.06 mmol, 1.0 eq), intermediate 830B-01 obtained in step 1, and potassium carbonate (1.4 g, 10.12 mmol, 2.0 eq) were dispersed in DMSO (20 mL). The reaction mixture was stirred at 95°C for 2 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with dichloromethane (30 mL x 3). The organic layers were combined and backwashed twice with water (20 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 830B-02 (1.76 g, 70% yield) as a yellow solid.

[0788] ESI-MS:m / z:494.2[M+H] + .

[0789] Step 3: Synthesis of compound 830B-03

[0790] Under nitrogen, 830B-02 (1.76 g, 3.57 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (20 mL). DAST (0.47 mL, 3.57 mmol, 1.0 eq) was added dropwise at -60°C. The mixture was stirred at room temperature for 2 h. Upon completion, the reaction was quenched by adding 10% saturated potassium carbonate solution (40 mL) dropwise under an ice bath. The mixture was then extracted with dichloromethane (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain intermediate 830B-03 (1.26 g, 71% yield) as a yellow solid.

[0791] ESI-MS:m / z:496.2[M+H] + .

[0792] Step 4: Synthesis of compound 830B-04

[0793] Dissolve 830B-03 (1.0 g, 2.02 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (214 mg, 4.04 mmol, 2.0 eq) and zinc powder (263 mg, 4.04 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 830B-04 for later use.

[0794] ESI-MS:m / z:466.2[M+H] + .

[0795] Step 5: Synthesis of compound 830B-05

[0796] Under nitrogen, intermediate 830B-04 obtained in step 4 was dissolved in anhydrous dichloromethane (10 mL). DIPEA (0.70 mL, 4.04 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.23 mL, 2.02 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford intermediate 830B-05, which was used directly in the next step without purification.

[0797] ESI-MS:m / z:602.2[M+H] + .

[0798] Step 6: Synthesis of Compound 830B

[0799] Under nitrogen, the product 830B-05 from step 5 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (153 mg, 4.04 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 830B (554 mg, 47% yield) as an off-white solid.

[0800] ESI-MS:m / z:574.2[M+H] + .

[0801] 1 H NMR (400MHz, DMSO-d6): δ10.22(s,1H),7.92(d,J=8.6Hz,1H),7.40(s,1H),6.98(d,J=1.5Hz,1H ),6.93(dd,J=8.7,1.5Hz,1H),4.28(dd,J=8.6,3.5Hz,1H),4.06(t,J=8.0Hz,1H),3.90–3.83(m ,4H),3.76(t,J=6.3Hz,2H),3.40(d,J=6.4Hz,2H),2.36(dd,J=13.1,5.9Hz,1H),2.31(s,3H),1 .97(dt,J=13.9,8.0Hz,4H), 1.42(d,J=3.7Hz,3H), 1.36(d,J=3.7Hz,3H), 1.22(d,J=6.9Hz,3H).

[0802] Example 49 Synthesis of Compound 832

[0803] Step 1: Synthesis of compound 832-01

[0804] IM-22 (300 mg, 0.79 mmol, 1.0 eq), CM-05 (79 mg, 0.79 mmol, 1.0 eq), and potassium carbonate (218 mg, 1.58 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 105°C for 2 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 832-01 (278 mg, 77% yield) as a yellow solid.

[0805] ESI-MS:m / z:461.2[M+H] + .

[0806] Step 2: Synthesis of compound 832-02

[0807] Dissolve 832-01 (278 mg, 0.6 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (64 mg, 1.2 mmol, 2.0 eq) and zinc powder (78 mg, 1.2 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 832-02 for later use.

[0808] ESI-MS:m / z:431.2[M+H] + .

[0809] Step 3: Synthesis of compound 832-03

[0810] Under nitrogen, Intermediate 832-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.21 mL, 1.2 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.07 mL, 0.6 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford Intermediate 832-03, which was used directly in the next step without purification.

[0811] ESI-MS:m / z:567.2[M+H] + .

[0812] Step 4: Synthesis of compound 832

[0813] Under nitrogen, the product 832-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (45 mg, 1.2 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 832 (162 mg, 50% yield) as an off-white solid.

[0814] ESI-MS:m / z:539.2[M+H] + .

[0815] 1 H NMR (400MHz, DMSO-d6): δ10.31(s,1H),7.96(d,J=8.6Hz,1H),7.62–7.57(m,1H),7.56(d,J =7.6Hz,1H),7.00(s,1H),6.91(dd,J=8.6,1.2Hz,1H),6.70(d,J=7.8Hz,1H),4.28(t,J=6.7 Hz,2H),3.76(t,J=6.5Hz,2H),3.40(d,J=6.5Hz,2H),3.72–3.65(m,4H),1.99(dt,J=14.3,8 .3Hz, 4H), 1.92 (t, J = 6.8Hz, 3H), 1.12 (s, 3H), 0.39 (t, J = 8.0Hz, 2H), 0.30 (t, J = 8.0Hz, 2H).

[0816] Example 50 Synthesis of Compound 833

[0817] Step 1: Synthesis of compound 833-01

[0818] IM-32 (400 mg, 1.02 mmol, 1.0 eq), CM-04 (126 mg, 1.02 mmol, 1.0 eq), and potassium carbonate (282 mg, 2.04 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 95°C for 1 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 833-01 (340 mg, yield: 67%) as a yellow solid.

[0819] ESI-MS:m / z:499.2[M+H] + .

[0820] Step 2: Synthesis of compound 833-02

[0821] Dissolve 833-01 (340 mg, 0.68 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (72 mg, 1.36 mmol, 2.0 eq) and zinc powder (88 mg, 1.36 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 833-02 for later use.

[0822] ESI-MS:m / z:469.2[M+H] + .

[0823] Step 3: Synthesis of compound 833-03

[0824] Under nitrogen, Intermediate 833-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.24 mL, 1.36 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.078 mL, 0.68 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. After the starting material disappeared, the resulting reaction solution was added to water (20 mL) and separated. The mixture was then extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford Intermediate 833-03, which was used directly in the next step without purification.

[0825] ESI-MS:m / z:605.2[M+H] + .

[0826] Step 4: Synthesis of compound 833

[0827] Under nitrogen, the product 833-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (51 mg, 1.36 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 833 (165 mg, 42% yield) as an off-white solid.

[0828] ESI-MS:m / z:577.2[M+H] + .

[0829] Example 51 Synthesis of Compound 834

[0830] Step 1: Synthesis of compound 834-01

[0831] IM-32 (500 mg, 1.32 mmol, 1.0 eq), CM-04 (164 mg, 1.32 mmol, 1.0 eq), and potassium carbonate (364 mg, 2.64 mmol, 2.0 eq) were dispersed in DMSO (6 mL). The reaction mixture was stirred at 95°C for 2 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with dichloromethane (15 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 834-01 (462 mg, yield: 72%) as a yellow solid.

[0832] ESI-MS:m / z:485.2[M+H] + .

[0833] Step 2: Synthesis of compound 834-02

[0834] Dissolve 834-01 (462 mg, 0.95 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (101 mg, 1.9 mmol, 2.0 eq) and zinc powder (124 mg, 1.9 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 834-02 for later use.

[0835] ESI-MS:m / z:455.2[M+H] + .

[0836] Step 3: Synthesis of compound 834-03

[0837] Under nitrogen, Intermediate 834-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.33 mL, 1.9 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.11 mL, 0.95 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. After the starting material disappeared, the resulting reaction solution was added to water (20 mL) and separated. The mixture was then extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain Intermediate 834-03, which was used directly in the next step without purification.

[0838] ESI-MS:m / z:591.2[M+H] + .

[0839] Step 4: Synthesis of compound 834

[0840] Under nitrogen, the product 834-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (72 mg, 1.9 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 834 (258 mg, 48% yield) as an off-white solid.

[0841] ESI-MS:m / z:563.2[M+H] + .

[0842] 1 H NMR (400MHz, DMSO-d6): δ9.78(s,1H),7.88(d,J=8.6Hz,1H),7.64(d,J=7.8Hz,1H ),7.58(t,J=8.0Hz,1H),6.86(d,J=7.8Hz,1H),6.83(d,J=1.7Hz,1H),6.68(dd,J =8.7,1.6Hz,1H),6.15(t,J=56.3Hz,1H),4.04(s,2H),3.74(t,J=6.5Hz,2H),3.7 1–3.62(m,4H),3.23(t,J=6.5Hz,2H),1.97(dt,J=14.3,8.3Hz,4H),1.23(s,6H).

[0843] .

[0844] Example 52 Synthesis of Compound 851

[0845] Step 1: Synthesis of compound 851-01

[0846] IM-22 (500 mg, 1.31 mmol, 1.0 eq), 2-(1-methylcyclopropyl)ethanol (131 mg, 1.31 mmol, 1.0 eq), and potassium carbonate (363 mg, 2.63 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 95°C for 8 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 851-01 (466 mg, yield: 77%) as a yellow solid.

[0847] ESI-MS:m / z:461.2[M+H] + .

[0848] Step 2: Synthesis of compound 851-02

[0849] At room temperature, intermediate 851-01 (466 mg, 1.01 mmol, 1.0 eq) obtained in step 1 was dissolved in methanol (10 mL). Ammonium chloride (107 mg, 2.02 mmol, 2.0 eq) and zinc powder (131 mg, 2.02 mmol, 2.0 eq) were added sequentially. The reaction was continued for 15 minutes. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain intermediate 851-02 for later use.

[0850] ESI-MS:m / z:431.2[M+H] + .

[0851] Step 3: Synthesis of compound 851

[0852] Under nitrogen, intermediate 851-02 obtained in step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.33 mL, 2.02 mmol, 2.0 eq) was added, and a dichloromethane solution of ethylsulfonyl chloride (130 mg, 1.01 mmol, 1.0 eq) was added dropwise under an ice bath. The ice bath was removed and the mixture was allowed to react at room temperature for 2 h. Upon disappearance of the starting material, the reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (10 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by pre-HPLC to afford product 851 (285 mg, 54% yield) as an off-white solid.

[0853] ESI-MS:m / z:523.2[M+H] + .

[0854] 1 H NMR (400MHz, DMSO) δ10.25(s,1H),7.71(d,J=7.5Hz,1H),7.40(t,J=7.5Hz,1H),7.28(s,1H) ,6.76(dd,J=7.5,1.4Hz,1H),6.65(d,J=1.6Hz,1H),6.56(dd,J=7.5,1.4Hz,1H),4.10(t,J=7 .6Hz, 2H), 3.93–3.76 (m, 4H), 2.96 (q, J=7.0Hz, 2H), 1.92 (dt, J=20.9, 5.7Hz, 4H), 1.83 (t, J= 7.6Hz, 2H), 1.38 (t, J = 7.0Hz, 3H), 0.89 (s, 3H), 0.39 (t, J = 4.7Hz, 2H), 0.27 (t, J = 4.7Hz, 2H).

[0855] Example 53 Synthesis of Compound 902

[0856] Step 1: Synthesis of Compound 902-01

[0857] IM-12 (500 mg, 1.31 mmol, 1.0 eq), 2-(1-methylcyclopropyl)ethanol (131 mg, 1.31 mmol, 1.0 eq), and potassium carbonate (362 mg, 2.62 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 105°C for 12 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 902-01 (448 mg, 74% yield) as a yellow solid.

[0858] ESI-MS:m / z:462.2[M+H] + .

[0859] Step 2: Synthesis of Compound 902-02

[0860] Intermediate 902-01 (448 mg, 0.97 mmol, 1.0 eq) obtained in Step 1 was dissolved in methanol (10 mL). Ammonium chloride (102 mg, 1.94 mmol, 2.0 eq) and zinc powder (126 mg, 1.94 mmol, 2.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 15 minutes. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain Intermediate 902-02 for later use.

[0861] ESI-MS:m / z:432.2[M+H] + .

[0862] Step 3: Synthesis of Compound 902-03

[0863] Under nitrogen, Intermediate 902-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.32 mL, 1.94 mmol, 2.0 eq) was added. Methyl 2-(chlorosulfonyl)acetate (103 mg, 0.97 mmol, 1.0 eq) in dichloromethane was then added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was quenched with water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 902-03, which was used directly in the next step without purification.

[0864] ESI-MS:m / z:568.2[M+H] + .

[0865] Step 4: Synthesis of compound 902

[0866] Under nitrogen, the product 902-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (73 mg, 1.94 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction system and stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 902 (262 mg, 52% yield) as an off-white solid.

[0867] ESI-MS:m / z:540.2[M+H] + .

[0868] 1 H NMR (400MHz, DMSO) δ10.45(s,1H),8.33(d,J=5.5Hz,1H),7.92(d,J=8.6Hz,1H),7.4 4(d,J=5.5Hz,1H),7.01(s,1H),6.93(d,J=8.6Hz,1H),4.28(t,J=6.6Hz,2H),3.94–3 .77(m,4H),3.76(t,J=6.4Hz,2H),3.38(d,J=6.4Hz,2H),1.98(dt,J=19.2,6.5Hz,4 H), 1.89 (t, J = 6.5Hz, 2H), 1.11 (s, 3H), 0.38 (t, J = 4.5Hz, 2H), 0.28 (t, J = 4.5Hz, 2H).

[0869] Example 54 Synthesis of Compound 907

[0870] Step 1: Synthesis of compound 907-01

[0871] Under nitrogen, CM-05 (1 g, 4.55 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (20 mL). Two drops of N,N-dimethylformamide were added. Oxalyl chloride (0.58 mL, 6.82 mmol, 1.5 eq) was then added dropwise under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 30 minutes. The reaction was complete. The resulting reaction solution was distilled under reduced pressure under anhydrous conditions to obtain the acyl chloride intermediate for later use.

[0872] Under nitrogen, IM-01 (1.04 g, 4.55 mmol, 1.0 eq) was dissolved in DCE (20 mL). N,N-diisopropylethylamine (1.5 mL, 9.10 mmol, 2.0 eq) was added. A solution of the acid chloride intermediate in anhydrous dichloromethane (5 mL) was added dropwise under an ice bath. After completion, the ice bath was removed and the mixture was allowed to react overnight at 120°C. Upon completion, the resulting solution was cooled to room temperature and diluted with water (50 mL). Solid precipitated and was filtered. Petroleum ether (75 mL) was added and the mixture was purified by slurrying to afford compound 907-01 (0.98 g, 50% yield) as a yellow solid.

[0873] ESI-MS:m / z:431.0[M+H] + .

[0874] Step 2: Synthesis of Compound 907-02

[0875] Intermediate 907-01 (500 mg, 1.16 mmol, 1.0 eq) obtained in Step 1, 2-(1-methylcyclopropyl)ethanol (116 mg, 1.16 mmol, 1.0 eq), and potassium carbonate (321 mg, 2.32 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 95°C for 1 hour. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 907-02 (415 mg, yield: 70%) as a yellow solid.

[0876] ESI-MS: m / z: 511.1 [M+H] + .

[0877] Step 3: Synthesis of Compound 907-03

[0878] Intermediate 907-02 (415 mg, 0.81 mmol, 1.0 eq) obtained in Step 2 was dissolved in 1,2-acetone glycerol acetal (2 mL). NaOH (65 mg, 2.02 mmol, 2.0 eq) and 2 mL of water were added. The reaction mixture was stirred at 90°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature to obtain a solution of Intermediate 907-03. The reaction mixture was used directly in the next step without post-treatment.

[0879] ESI-MS:m / z:562.3[M+H] + .

[0880] Step 4: Synthesis of compound 907

[0881] Under ice, 1 mL of 2M dilute hydrochloric acid was added to the solution of product 907-03 obtained in step 3. After addition, the reaction was continued at a controlled temperature for 30 min. After the starting material disappeared, the system was diluted with 30 mL of water and the pH was adjusted to 7-8 with 0.1 M aqueous sodium bicarbonate solution. The solution was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by Pre-HPLC to yield product 907 (228 mg, 54% yield) as an off-white solid.

[0882] ESI-MS:m / z:522.2[M+H] + .

[0883] 1 H NMR (400MHz, DMSO) δ10.21(s,1H),8.26(d,J=8.4Hz,1H),7.35(s,1H),6.59(d,J=8.4Hz,1H),5.00(d,J=5.1Hz ,1H),4.71(t,J=5.6Hz,1H),4.63(t,J=6.4Hz,2H),4.31(d,J=5.3Hz,1H),3.87-3.82(m,4H),3.81(dt,J=19.3, 5.1Hz,1H),3.44(d,J=8.1Hz,2H),2.30(s,3H),1.97(dt,J=19.2,6.5Hz,4H),1 .83(t,J=6.4Hz,2H),1.12(s,3H),0.34(t,J=4.7Hz,1H),0.26(t,J=4.7Hz,4H).

[0884] Example 55 Synthesis of Compound 615

[0885] Step 1: Synthesis of compound 615-01

[0886] 4-Amino-2-chloropyrimidine (1.0 g, 7.72 mmol, 1.0 eq) and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (1.79 g, 11.58 mmol, 1.5 eq) were dispersed in 1,4-dioxane (30 mL). DIPEA (4.03 mL, 23.16 mmol, 3.0 eq) and a catalytic amount of sodium iodide were added, and the mixture was heated to 120°C and allowed to react overnight. After the starting material disappeared, the reaction mixture was cooled to room temperature, separated by addition of water (150 mL), and extracted with dichloromethane (40 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 5:1) to afford compound 615-01 (1.21 g, yield: 74%) as a white solid.

[0887] ESI-MS: m / z: 213.1 [M+H] +

[0888] Step 2: Synthesis of compound 615-02

[0889] Under nitrogen protection, IM-51 (500 mg, 1.73 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL), 1 drop of DMF was added thereto, and oxalyl chloride (0.21 mL, 2.59 mmol, 1.5 eq) was slowly added under ice bath. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 30 min. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude acyl chloride for use.

[0890] Under nitrogen, 615-01 (367 mg, 1.73 mmol, 1.0 eq) and a catalytic amount of DMAP were dissolved in 2-methyltetrahydrofuran (10 mL). DIPEA (0.6 mL, 3.46 mmol, 2.0 eq) was added, and a solution of the acid chloride in anhydrous tetrahydrofuran (5 mL) was added dropwise under an ice bath. The reaction system was heated to reflux and allowed to react overnight. Upon completion, the reaction solution was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (10 mL x 3), and purified on a silica gel column (dichloromethane:methanol = 40:1) to afford compound 615-02 (626 mg, yield: 75%) as a yellow solid.

[0891] ESI-MS:m / z:484.2[M+H] +

[0892] Step 3: Synthesis of compound 615-03

[0893] Dissolve 615-02 (626 mg, 1.30 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (138 mg, 2.60 mmol, 2.0 eq) and zinc powder (169 mg, 2.60 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 615-03 for later use.

[0894] ESI-MS:m / z:454.2[M+H] +

[0895] Step 4: Synthesis of Compound 615-04

[0896] Under a nitrogen atmosphere, Intermediate 615-03 obtained in Step 3 was dissolved in anhydrous dichloromethane (8 mL). DIPEA (0.45 mL, 2.60 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.15 mL, 1.30 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 615-04, which was used directly in the next step without purification.

[0897] ESI-MS:m / z:590.2[M+H] +

[0898] Step 5: Synthesis of compound 615

[0899] Under nitrogen, the product 615-04 from step 4 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (98 mg, 2.60 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 615 (372 mg, 51% yield) as an off-white solid.

[0900] 1H NMR: (400MHz, DMSO-d6) δ10.03(s,1H),8.30(d,J=5.6Hz,1H),7.94(d,J=8.6Hz,1H),7.52(d,J=5.6Hz,1H),7.01(d,J=1.6Hz,1H),6.97(dd,J=8.6,1 .7Hz,1H),6.18(t,J=56.2Hz,1H),4.07(s,2H),3.83–3.76(m,4H),3.77(t ,J=6.5Hz,2H),3.38(t,J=6.5Hz,2H),2.67(d,J=10.0Hz,2H),1.25(s,6H).

[0901] ESI-MS:m / z:562.2[M+H] +

[0902] Example 56 Synthesis of Compound 619

[0903] Step 1: Synthesis of compound 619-01

[0904] Under nitrogen protection, 5-bromo-3-fluoropyridine-2-carboxylic acid (500 mg, 2.27 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL), 1 drop of DMF was added thereto, and oxalyl chloride (0.29 mL, 3.41 mmol, 1.5 eq) was slowly added under ice bath. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 30 min. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude acyl chloride for use.

[0905] Under nitrogen, IM-01 (486 mg, 2.27 mmol, 1.0 eq) and a catalytic amount of DMAP were dissolved in 2-methyltetrahydrofuran (10 mL). DIPEA (0.79 mL, 4.54 mmol, 2.0 eq) was added, and a solution of the acid chloride in anhydrous tetrahydrofuran (5 mL) was added dropwise under an ice bath. The reaction system was heated to reflux and allowed to react overnight. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (10 mL x 3), and purified on a silica gel column (dichloromethane:methanol = 40:1) to afford compound 619-01 (738 mg, yield: 78%) as a yellow solid.

[0906] ESI-MS:m / z:417.0[M+H] +

[0907] Step 2: Synthesis of compound 619-02

[0908] 619-01 (738 mg, 1.77 mmol, 1.0 eq), CM-04 (219 mg, 1.77 mmol, 1.0 eq), and potassium carbonate (489 mg, 3.54 mmol, 2.0 eq) were dispersed in DMSO (8 mL). The reaction mixture was stirred at 100°C for 1 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (20 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane) to afford compound 619-02 (653 mg, yield: 71%) as a yellow solid.

[0909] ESI-MS:m / z:521.1[M+H] +

[0910] Step 3: Synthesis of compound 619

[0911] 619-02 (653 mg, 1.26 mmol, 1.0 eq), 2-hydroxyethanesulfonamide (189 mg, 1.51 mmol, 1.2 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (62 mg, 0.13 mmol, 0.1 eq) and cesium carbonate (819 mg, 2.52 mmol, 2.0 eq) were dispersed in 1,4-dioxane (8 mL). The reaction solution was degassed three times, and tris(dibenzylideneacetone)palladium (119 mg, 0.13 mmol, 0.1 eq) was added under nitrogen protection and degassed twice. After completion of the treatment, the temperature was raised to 100°C and stirred under nitrogen protection for 1 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (20 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford compound 619 (348 mg, yield: 49%) as an off-white solid.

[0912] 1 H NMR: (400MHz, DMSO-d6) δ10.22(s,1H),8.31(d,J=5.5Hz,1H),7.91(d,J=1.7Hz,1H),7.46(d,J=5.4Hz,1H),7.22(d,J=1.7Hz,1H),6.15(t ,J=57.0Hz,1H),3.93(s,2H),3.87–3.81(m,4H),3.76(t,J=6.5Hz,2H),3.27(t,J=6.5Hz,2H),1.98(dt,J=13.8,7.9Hz,4H),1.12(s,6H).

[0913] ESI-MS:m / z:565.2[M+H] +

[0914] Example 57 Synthesis of Compound 627

[0915] Step 1: Synthesis of compound 627-01

[0916] Under nitrogen protection, 2-fluoro-6-bromonicotinic acid (500 mg, 2.27 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL). One drop of DMF was added thereto. Oxalyl chloride (0.29 mL, 3.41 mmol, 1.5 eq) was slowly added under ice bath. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 30 min. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude acyl chloride for use.

[0917] Under nitrogen, IM-21 (484 mg, 2.27 mmol, 1.0 eq) and a catalytic amount of DMAP were dissolved in 2-methyltetrahydrofuran (10 mL). DIPEA (0.79 mL, 4.54 mmol, 2.0 eq) was added, and a solution of the acid chloride in anhydrous tetrahydrofuran (5 mL) was added dropwise under an ice bath. The reaction system was heated to reflux and allowed to react overnight. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (10 mL x 3), and purified on a silica gel column (dichloromethane:methanol = 40:1) to afford compound 627-01 (697 mg, 74% yield) as a yellow solid.

[0918] ESI-MS:m / z:416.0[M+H] +

[0919] Step 2: Synthesis of compound 627-02

[0920] 627-01 (697 mg, 1.68 mmol, 1.0 eq), CM-04 (208 mg, 1.68 mmol, 1.0 eq), and potassium carbonate (464 mg, 3.36 mmol, 2.0 eq) were dispersed in DMSO (8 mL). The reaction mixture was stirred at 95°C for 1 hour. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (20 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane) to afford compound 627-02 (654 mg, 75% yield) as a yellow solid.

[0921] ESI-MS:m / z:520.1[M+H]+

[0922] Step 3: Synthesis of compound 627

[0923] 627-02 (654 mg, 1.26 mmol, 1.0 eq), 2-hydroxyethanesulfonamide (189 mg, 1.51 mmol, 1.2 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (62 mg, 0.13 mmol, 0.1 eq) and cesium carbonate (819 mg, 2.52 mmol, 2.0 eq) were dispersed in 1,4-dioxane (8 mL). The reaction solution was degassed three times, and tris(dibenzylideneacetone)palladium (119 mg, 0.13 mmol, 0.1 eq) was added under nitrogen protection and degassed twice. After completion of the treatment, the temperature was raised to 100°C and stirred under nitrogen protection for 1 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (20 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford compound 627 (369 mg, yield: 52%) as an off-white solid.

[0924] 1H NMR: (400MHz, DMSO-d6) δ9.80(s,1H),8.30(d,J=8.3Hz,1H),7.61(d,J=5.0Hz,2H),6.71(q,J=4.4Hz,1H),6.67(d,J=8.3Hz,1H),6.21(t ,J=56.1Hz,1H),4.39(s,2H),3.81(t,J=6.3Hz,2H),3.70–3.64(m,4H),3.69(t,J=6.3Hz,2H),1.96(dt,J=13.8,6.7Hz,4H),1.22(s,6H).

[0925] ESI-MS:m / z:564.2[M+H] +

[0926] Example 58 Synthesis of Compound 855

[0927] Step 1: Synthesis of compound 855-01

[0928] IM-12 (300 mg, 0.79 mmol, 1.0 eq), CM-04 (98 mg, 0.79 mmol, 1.0 eq), and potassium carbonate (218 mg, 1.58 mmol, 2.0 eq) were dispersed in DMSO (6 mL). The reaction mixture was stirred at 95°C for 2 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with dichloromethane (15 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane) to afford compound 855-01 (280 mg, yield: 73%) as a yellow solid.

[0929] ESI-MS:m / z:486.2[M+H] +

[0930] Step 2: Synthesis of compound 855-02

[0931] Dissolve 855-01 (280 mg, 0.58 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (61 mg, 1.16 mmol, 2.0 eq) and zinc powder (75 mg, 1.16 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 855-02 for later use.

[0932] ESI-MS:m / z:456.2[M+H] +

[0933] Step 3: Synthesis of compound 855-03

[0934] Under a nitrogen atmosphere, Intermediate 855-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.2 mL, 1.16 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.067 mL, 0.58 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Intermediate 855-03, which was used directly in the next step without purification.

[0935] ESI-MS:m / z:592.2[M+H] +

[0936] Step 4: Synthesis of Compound 855

[0937] Under nitrogen, the product 855-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (44 mg, 1.16 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 855 (146 mg, 45% yield) as an off-white solid.

[0938] 1 H NMR: (400MHz, DMSO-d6) δ10.02 (s, 1H), 8.32 (d, J = 5.5 Hz, 1H), 7.84 (d, J = 8. 5Hz,1H),7.53(d,J=5.5Hz,1H),6.84(d,J=1.5Hz,1H),6.82(dd,J=8.5,1.6H z,1H),6.22(t,J=56.2Hz,1H),4.04(s,2H),3.88–3.82(m,4H),3.74(t,J=6 .6Hz, 2H), 3.23 (t, J = 6.6Hz, 2H), 1.97 (dt, J = 13.6, 7.8Hz, 4H), 1.22 (s, 6H).

[0939] ESI-MS:m / z:564.2[M+H] +

[0940] Example 59 Synthesis of Compound 808

[0941] Step 1: Synthesis of compound 808-01

[0942] Under nitrogen, 855 (400 mg, 0.712 mmol, 1.0 eq), N-tert-butyloxycarbonyl-L-alanine (160 mg, 0.855 mmol, 1.2 eq), and 4-dimethylaminopyridine (131 mg, 1.07 mmol, 1.5 eq) were dispersed in anhydrous dichloromethane (10 mL). The mixture was stirred at room temperature for 15 min. A dichloromethane solution (5 mL) of N,N'-dicyclohexylcarbodiimide (221 mg, 1.07 mmol, 1.5 eq) was slowly added dropwise under an ice bath. The ice bath was removed and the mixture was allowed to react at room temperature for 2 h. After the starting material disappeared, the reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 808-01, which was used directly in the next step without purification.

[0943] ESI-MS:m / z:735.3[M+H] +

[0944] Step 2: Synthesis of Compound 808

[0945] Under nitrogen, compound 808-01 obtained in step 1 was dissolved in 4.0 M HCl / dioxane solution (10 mL) and allowed to react at room temperature for 1 h. After the starting material disappeared, compound 808 (229 mg, 51% yield) was purified by pre-HPLC without further treatment.

[0946] 1 H NMR: (400MHz, DMSO-d6) δ10.04(s,1H),8.34(d,J=5.5,1.7Hz,1H),7.91(dd,J=8.6,5.8Hz,1H),7.5 2(dd,J=5.5,1.8Hz,1H),7.00(dd,J=15.5,1.8Hz,1H),6.96–6.90(m,1H),6.14(t,J=56.3Hz,1H),4 .46–4.36(m,1H),4.06(s,2H),3.88–3.83(m,4H),3.76(t,J=6.5Hz,1H),3.66(t,J=5.9Hz,1H),3.5 8(t,J=5.9Hz,1H),3.37(t,J=6.5Hz,1H),2.02–1.91(m,4H),1.26(s,3H),1.21(s,3H),1.19(s,3H).

[0947] ESI-MS:m / z:635.2[M+H] +

[0948] Example 60 Synthesis of Compound 856

[0949] Step 1: Synthesis of compound 856-01

[0950] 4-Amino-2,6-dichloropyrimidine (1.0 g, 6.10 mmol, 1.0 eq) and 4,4-difluoropiperidine hydrochloride (1.44 g, 9.15 mmol, 1.5 eq) were dispersed in 1,4-dioxane (30 mL). DIPEA (3.18 mL, 18.3 mmol, 3.0 eq) and a catalytic amount of sodium iodide were added, and the mixture was heated to 95°C and allowed to react overnight. After the starting material disappeared, the resulting reaction solution was cooled to room temperature, separated by addition of water (150 mL), and extracted with dichloromethane (40 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 6:1) to afford compound 856-01 (1.26 g, yield: 83%) as a white solid.

[0951] ESI-MS:m / z:249.1[M+H] +

[0952] Step 2: Synthesis of compound 856-02

[0953] 856-01 (1.26 g, 5.08 mmol, 1.0 eq) was dissolved in methanol (15 mL), and acetic acid (0.5 mL) was added dropwise. Palladium on carbon (10%) catalyst (630 mg, 50 wt%) was added to the reaction mixture. The system was then replaced with deuterium three times and allowed to react at room temperature for 1 h. Upon disappearance of the starting material, the palladium on carbon was removed by filtration, and the filtrate was concentrated to afford intermediate 856-02 (988 mg, 90% yield) as an off-white solid.

[0954] ESI-MS:m / z:216.1[M+H] +

[0955] Step 3: Synthesis of compound 856-03

[0956] Under nitrogen protection, CM-01 (500 mg, 2.70 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL). One drop of DMF was added thereto. Oxalyl chloride (0.34 mL, 4.05 mmol, 1.5 eq) was slowly added at 0°C. The mixture was reacted at room temperature for 30 min. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude acyl chloride for later use.

[0957] Under nitrogen, 856-02 (581 mg, 2.70 mmol, 1.0 eq) and a catalytic amount of DMAP were dissolved in 2-methyltetrahydrofuran (10 mL). DIPEA (0.94 mL, 5.40 mmol, 2.0 eq) was added, followed by the addition of a solution of the acyl chloride in anhydrous tetrahydrofuran (5 mL) at 0°C. The reaction system was then heated to reflux and allowed to react overnight. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (10 mL x 3), and purified on a silica gel column (dichloromethane:methanol = 40:1) to afford compound 856-03 (722 mg, 70% yield) as a yellow solid.

[0958] ESI-MS:m / z:383.1[M+H] +

[0959] Step 4: Synthesis of Compound 856-04

[0960] 856-03 (722 mg, 1.89 mmol, 1.0 eq), CM-04 (234 mg, 1.89 mmol, 1.0 eq), and potassium carbonate (522 mg, 3.78 mmol, 2.0 eq) were dispersed in DMSO (8 mL). The reaction mixture was stirred at 95°C for 3 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and washed twice with water (20 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified on a silica gel column to afford compound 856-04 (634 mg, yield: 69%) as a yellow solid.

[0961] ESI-MS:m / z:487.2[M+H] +

[0962] Step 5: Synthesis of Compound 856-05

[0963] Dissolve 856-04 (634 mg, 1.30 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (138 mg, 2.60 mmol, 2.0 eq) and zinc powder (169 mg, 2.60 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, filter the mixture and concentrate the filtrate under reduced pressure to obtain intermediate 856-05 for later use.

[0964] ESI-MS:m / z:457.2[M+H] +

[0965] Step 6: Synthesis of Compound 856-06

[0966] Under a nitrogen atmosphere, Intermediate 856-05 obtained in Step 5 was dissolved in anhydrous dichloromethane (10 mL). DIPEA (0.45 mL, 2.60 mmol, 2.0 eq) was added. Methyl 2-(chlorosulfonyl)acetate (0.15 mL, 1.30 mmol, 1.0 eq) in dichloromethane was then added at 0°C. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 856-06, which was used directly in the next step without purification.

[0967] ESI-MS:m / z:593.2[M+H] +

[0968] Step 7: Synthesis of Compound 856

[0969] Under nitrogen, the product 856-06 from step 6 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (98 mg, 2.60 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction. The mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 856 (352 mg, 48% yield) as an off-white solid.

[0970] 1 H NMR: (400MHz, DMSO-d6) δ10.02(s,1H),8.32(d,J=5.5Hz,1H),7.53(d,J=5.5Hz,1H),6.84(d,J=1.5Hz,1H),6.82(s,1H),6.22(t,J=5 6.2Hz,1H),4.04(s,2H),3.88–3.82(m,4H),3.74(t,J=6.6Hz,2H),3.23(t,J=6.6Hz,2H),1.97(dt,J=13.6,7.8Hz,4H),1.22(s,6H).

[0971] ESI-MS:m / z:565.2[M+H]

[0972] Example 61 Synthesis of Compound 857

[0973] Step 1: Synthesis of compound 857

[0974] Under nitrogen, 855 (400 mg, 0.712 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL) and stirred at room temperature for 10 min. Diethylaminosulfur trifluoride (115 mg, 0.712 mmol, 1.0 eq) was slowly added dropwise under an ice bath. The ice bath was removed and the mixture was allowed to react at room temperature for 1 h. After the starting material disappeared, the reaction solution was cooled to room temperature and quenched with aqueous potassium carbonate under an ice bath. The solution was extracted with dichloromethane (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 857 (161 mg, 40% yield).

[0975] 1 H NMR: (400MHz, DMSO-d6) δ9.97(s,1H),8.13(d,J=4.9Hz,1H),7.97(d,J=7.5Hz,1H),7.54(d,J=4.9Hz,1H),7.21(d,J=2.0Hz,1H),7.02(dd,J=7.5 ,2.0Hz,1H),6.09(t,J=56.2Hz,1H),4.43(s,2H),4.20–4.12(m,4H),3. 76(t,J=6.6Hz,2H),3.56(t,J=6.6Hz,2H),2.45(dt,J=13.6,7.8Hz,4H), 1.13(s,6H).

[0976] ESI-MS:m / z:566.2[M+H] +

[0977] Example 62 Synthesis of Compound 865

[0978] Step 1: Synthesis of compound 865-01

[0979] 4-Amino-2,5,6-trichloropyrimidine (1.0 g, 5.04 mmol, 1.0 eq) and 4,4-difluoropiperidine hydrochloride (1.19 g, 7.56 mmol, 1.5 eq) were dispersed in DMSO (20 mL). Potassium carbonate (2.09 g, 15.12 mmol, 3.0 eq) and a catalytic amount of sodium iodide were added, and the mixture was heated to 90°C for 1 h. After the starting material disappeared, the resulting reaction solution was cooled to room temperature, separated by addition of water (150 mL), and extracted with dichloromethane (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 6:1) to afford compound 865-01 (856 mg, 60% yield) as a yellow solid.

[0980] ESI-MS:m / z:284.0[M+H]+

[0981] Step 2: Synthesis of compound 865-02

[0982] 865-01 (856 mg, 3.02 mmol, 1.0 eq) was dissolved in methanol (10 mL), and acetic acid (0.5 mL) was added dropwise. Palladium-on-carbon (10%) catalyst (428 mg, 50 wt%) was added to the reaction mixture. The system was then purged with deuterium three times and allowed to react at room temperature for 1 h. After the starting material disappeared, the mixture was filtered and the filtrate was concentrated to afford intermediate 865-02 (594 mg, 91% yield) as an off-white solid.

[0983] ESI-MS:m / z:217.1[M+H] +

[0984] Step 3: Synthesis of compound 865-03

[0985] Under nitrogen protection, CM-01 (500 mg, 2.70 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL), 1 drop of DMF was added thereto, and oxalyl chloride (0.34 mL, 4.05 mmol, 1.5 eq) was slowly added under ice bath. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 30 min. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude acyl chloride for use.

[0986] Under nitrogen, 865-02 (583 mg, 2.70 mmol, 1.0 eq) and a catalytic amount of DMAP were dissolved in 2-methyltetrahydrofuran (10 mL). DIPEA (0.94 mL, 5.40 mmol, 2.0 eq) was added, and a solution of the acid chloride in anhydrous tetrahydrofuran (5 mL) was added dropwise under an ice bath. The reaction system was heated to reflux and allowed to react overnight. Upon completion, the reaction solution was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (10 mL x 3), and purified on a silica gel column (dichloromethane:methanol = 40:1) to afford compound 865-03 (693 mg, yield: 67%) as a yellow solid.

[0987] ESI-MS:m / z:384.1[M+H] +

[0988] Step 4: Synthesis of Compound 865-04

[0989] 865-03 (693 mg, 1.81 mmol, 1.0 eq), CM-04 (234 mg, 1.81 mmol, 1.0 eq), and potassium carbonate (500 mg, 3.62 mmol, 2.0 eq) were dispersed in DMSO (8 mL). The reaction mixture was stirred at 95°C for 3 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (20 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane) to afford compound 865-04 (573 mg, yield: 65%) as a yellow solid.

[0990] ESI-MS:m / z:488.2[M+H] +

[0991] Step 5: Synthesis of Compound 865-05

[0992] Dissolve 865-04 (573 mg, 1.18 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (125 mg, 2.36 mmol, 2.0 eq) and zinc powder (153 mg, 2.36 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 865-05 for later use.

[0993] ESI-MS:m / z:458.2[M+H] +

[0994] Step 6: Synthesis of Compound 865-06

[0995] Under a nitrogen atmosphere, Intermediate 865-05 obtained in Step 5 was dissolved in anhydrous dichloromethane (10 mL). DIPEA (0.41 mL, 2.36 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.14 mL, 1.18 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 865-06, which was used directly in the next step without purification.

[0996] ESI-MS:m / z:594.2[M+H] +

[0997] Step 7: Synthesis of Compound 865

[0998] Under nitrogen, the product 865-06 from step 6 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (89 mg, 2.36 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction. The mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 865 (327 mg, yield: 49%) as an off-white solid.

[0999] 1 H NMR: (400MHz, DMSO-d6) δ10.03(s,1H),7.88(d,J=8.6Hz,1H),6.93(d,J=1.6Hz,1H),6.90(dd,J=8.6,1.8Hz,1H),6.14(t,J=56.2 Hz,1H),4.05(s,2H),3.90–3.82(m,4H),3.75(t,J=6.5Hz,2H),3.29(t,J=6.5Hz,2H),1.96(dt,J=13.7,6.7Hz,4H),1.22(s,6H).

[1000] ESI-MS:m / z:566.2[M+H] +

[1001] Example 63 Synthesis of Compound 868

[1002] Step 1: Synthesis of compound 868-01

[1003] 3,5-Difluoronitrobenzene (1.0 g, 6.29 mmol, 1.0 eq) and 4,4-difluoropiperidine hydrochloride (1.49 g, 9.44 mmol, 1.5 eq) were dispersed in DMSO (20 mL). Potassium carbonate (2.61 g, 18.87 mmol, 3.0 eq) was added and the mixture was heated to 120°C with stirring overnight. After the starting material disappeared, the resulting reaction solution was cooled to room temperature, separated by addition of water (150 mL), and extracted with dichloromethane (40 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 6:1) to afford compound 868-01 (1.14 g, yield: 70%) as a yellow solid.

[1004] ESI-MS:m / z:261.1[M+H] +

[1005] Step 2: Synthesis of compound 868-02

[1006] 868-01 (1.14 g, 4.38 mmol, 1.0 eq) was dissolved in methanol (10 mL). Ammonium chloride (464 mg, 8.76 mmol, 2.0 eq) and zinc powder (569 mg, 8.76 mmol, 2.0 eq) were added sequentially. The mixture was stirred at room temperature for 30 min. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified on a silica gel column (dichloromethane) to afford compound 868-02 (907 mg, 90% yield) as a white solid.

[1007] ESI-MS:m / z:231.1[M+H] +

[1008] Step 3: Synthesis of compound 868-03

[1009] Under nitrogen protection, IM-51 (500 mg, 1.73 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL), 1 drop of DMF was added thereto, and oxalyl chloride (0.21 mL, 2.59 mmol, 1.5 eq) was slowly added under ice bath. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 30 min. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude acyl chloride for use.

[1010] Under nitrogen, 868-02 (398 mg, 1.73 mmol, 1.0 eq) and a catalytic amount of DMAP were dissolved in 2-methyltetrahydrofuran (10 mL). DIPEA (0.6 mL, 3.46 mmol, 2.0 eq) was added, and a solution of the acid chloride in anhydrous tetrahydrofuran (5 mL) was added dropwise under an ice bath. The reaction system was heated to reflux and allowed to react overnight. Upon completion, the reaction solution was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (10 mL x 3), and purified on a silica gel column (dichloromethane:methanol = 40:1) to afford compound 868-03 (659 mg, yield: 76%) as a yellow solid.

[1011] ESI-MS:m / z:502.2[M+H] +

[1012] Step 4: Synthesis of compound 868-04

[1013] Dissolve 868-03 (659 mg, 1.32 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (140 mg, 2.64 mmol, 2.0 eq) and zinc powder (172 mg, 2.64 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 868-04 for later use.

[1014] ESI-MS:m / z:472.2[M+H] +

[1015] Step 5: Synthesis of Compound 868-05

[1016] Under a nitrogen atmosphere, Intermediate 868-04 obtained in Step 4 was dissolved in anhydrous dichloromethane (8 mL). DIPEA (0.46 mL, 2.64 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.15 mL, 1.32 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 868-05, which was used directly in the next step without purification.

[1017] ESI-MS:m / z:608.2[M+H] +

[1018] Step 6: Synthesis of Compound 868

[1019] Under nitrogen, the product 868-05 from step 5 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (100 mg, 2.64 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction. The mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 868 (359 mg, yield: 47%) as an off-white solid.

[1020] 1H NMR: (400MHz, DMSO-d6) δ9.93 (s, 1H), 7.57 (d, J = 8.4Hz, 1H), 7.16 (d, J = 11.0Hz, 1H),7.01(s,1H),6.92(d,J=1.7Hz,1H),6.87(dd,J=8.4,1.8Hz,1H),6.60(dt,J= 12.4,2.1Hz,1H),6.01(t,J=56.6Hz,1H),3.93(s,2H),3.76(t,J=6.6Hz,2H),3.4 0–3.34(m,4H),3.29(t,J=6.6Hz,2H),2.03(dt,J=14.0,5.6Hz,4H),1.07(s,6H).

[1021] ESI-MS:m / z:580.2[M+H] +

[1022] Example 64 Synthesis of Compound 870

[1023] Step 1: Synthesis of compound 870-01

[1024] IM-12 (300 mg, 0.79 mmol, 1.0 eq), CM-04 (98 mg, 0.79 mmol, 1.0 eq), and potassium carbonate (218 mg, 1.58 mmol, 2.0 eq) were dispersed in DMSO (6 mL). The reaction mixture was stirred at 95°C for 2 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with dichloromethane (15 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane) to afford compound 870-01 (280 mg, yield: 73%) as a yellow solid.

[1025] ESI-MS:m / z:486.2[M+H] +

[1026] Step 2: Synthesis of compound 870-02

[1027] Dissolve 870-01 (280 mg, 0.58 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (61 mg, 1.16 mmol, 2.0 eq) and zinc powder (75 mg, 1.16 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 870-02 for later use.

[1028] ESI-MS:m / z:456.2[M+H] +

[1029] Step 3: Synthesis of Compound 870

[1030] Under a nitrogen atmosphere, intermediate 870-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.2 mL, 1.16 mmol, 2.0 eq) was added, and a dichloromethane solution of methanesulfonic anhydride (100 mg, 0.58 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by Pre-HPLC to afford 870 (132 mg, 43% yield) as a white solid.

[1031] 1 H NMR: (400MHz, DMSO-d6) δ10.01(s,1H),8.31(d,J=5.5Hz,1H),7.82(d,J=8.5Hz,1H),7.54(d,J=5.6Hz,1H),6.78(d,J=1.8Hz,1H),6.76 (dd,J=8.5,1.8Hz,1H),6.14(t,J=56.3Hz,1H),4.04(s,2H),3.89–3.82(m,4H),2.90(s,3H),1.97(dt,J=13.8,8.0Hz,4H),1.23(s,6H).

[1032] ESI-MS:m / z:534.2[M+H] +

[1033] Example 65 Synthesis of Compound 872

[1034] Step 1: Synthesis of compound 872-01

[1035] 4-Amino-2,6-difluoropyridine (1.0 g, 7.69 mmol, 1.0 eq), 4,4-difluoropiperidine hydrochloride (2.42 g, 15.38 mmol, 2.0 eq), and sodium carbonate (815 mg, 7.69 mmol, 1.0 eq) were dispersed in NMP (10 mL). DIPEA (2.01 mL, 11.54 mmol, 1.5 eq) was added, and the reaction mixture was stirred at 230°C for 3 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (20 mL x 3). The organic layers were combined and backwashed twice with water (20 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 872-01 (1.5 g, yield: 84%) as an off-white solid.

[1036] ESI-MS:m / z:232.1[M+H] +

[1037] Step 2: Synthesis of compound 872-02

[1038] Under nitrogen protection, IM-51 (500 mg, 1.73 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL), 1 drop of DMF was added thereto, and oxalyl chloride (0.21 mL, 2.59 mmol, 1.5 eq) was slowly added under ice bath. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 30 min. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude acyl chloride for use.

[1039] Under nitrogen, 872-01 (400 mg, 1.73 mmol, 1.0 eq) and a catalytic amount of DMAP were dissolved in 2-methyltetrahydrofuran (10 mL). DIPEA (0.6 mL, 3.46 mmol, 2.0 eq) was added, and a solution of the acid chloride in anhydrous tetrahydrofuran (5 mL) was added dropwise under an ice bath. The reaction system was heated to reflux and allowed to react overnight. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (10 mL x 3), and purified on a silica gel column (dichloromethane:methanol = 40:1) to afford compound 872-02 (670 mg, yield: 77%) as a yellow solid.

[1040] ESI-MS:m / z:503.2[M+H] +

[1041] Step 3: Synthesis of compound 872-03

[1042] Dissolve 872-02 (670 mg, 1.33 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (141 mg, 2.66 mmol, 2.0 eq) and zinc powder (173 mg, 2.66 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 872-03 for later use.

[1043] ESI-MS:m / z:473.2[M+H] +

[1044] Step 4: Synthesis of Compound 872-04

[1045] Under a nitrogen atmosphere, Intermediate 872-03 obtained in Step 3 was dissolved in anhydrous dichloromethane (8 mL). DIPEA (0.46 mL, 2.66 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.15 mL, 1.33 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 872-04, which was used directly in the next step without purification.

[1046] ESI-MS:m / z:609.2[M+H] +

[1047] Step 5: Synthesis of Compound 872

[1048] Under nitrogen, the product 872-04 from step 4 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (101 mg, 2.66 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction. The mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 872 (393 mg, 50% yield) as an off-white solid.

[1049] 1H NMR (400MHz, DMSO-d6) δ10.31(s,1H),7.55(d,J=8.4Hz,1H),7.01(s,1H),6.95(d,J=1.7Hz,1H),6.91(dd,J=8.4,1.8Hz,1H),6.72(s,1H),5. 97(t,J=56.5Hz,1H),3.92(s,2H),3.77(t,J=6.5Hz,2H),3.63–3.56(m,4H),3.32(t,J=6.5Hz,2H),2.00(dt,J=13.7,6.7Hz,4H),1.05(s,6H).

[1050] ESI-MS:m / z:581.2[M+H] +

[1051] 、

[1052] Example 66 Synthesis of Compound 888

[1053] Step 1: Synthesis of compound 888-01

[1054] Under nitrogen, IM-51 (500 mg, 1.73 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL). One drop of DMF was added, and oxalyl chloride (0.21 mL, 2.59 mmol, 1.5 eq) was slowly added under an ice bath. After the addition, the ice bath was removed and the mixture was allowed to react at room temperature for 30 min. Upon completion, aqueous ammonia (3 mL) was added dropwise under an ice bath. The pH of the system was adjusted to 7-8 and stirred for 30 min. The mixture was diluted with water (15 mL) and extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to afford Intermediate 888-01 (432 mg, 87% yield) as a yellow solid.

[1055] ESI-MS:m / z:288.1[M+H] +

[1056] Step 2: Synthesis of Compound 888-02

[1057] Under nitrogen, 888-01 (432 mg, 1.51 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL). Pyridine (0.24 mL, 3.02 mmol, 2.0 eq) was added, and trifluoroacetic anhydride (0.63 mL, 4.53 mmol, 3.0 eq) was slowly added dropwise under an ice bath. After completion, the ice bath was removed and the mixture was allowed to react at room temperature for 2 h. Upon completion, the reaction was diluted with water (10 mL) and extracted with dichloromethane (15 mL x 3). Purification on a silica gel column (dichloromethane) afforded compound 888-02 (326 mg, 80% yield) as a yellow solid.

[1058] ESI-MS:m / z:271.1[M+H] +

[1059] Step 3: Synthesis of Compound 888-03

[1060] Under nitrogen, sodium hydride (73 mg, 1.82 mmol, 1.5 eq) was weighed into a three-necked flask. 888-02 (326 mg, 1.21 mmol, 1.0 eq) and IM-21 (283 mg, 1.33 mmol, 1.1 eq) were added sequentially under ice-cooling, followed by DMSO (10 mL). The mixture was allowed to react under ice-cooling for 30 min and then at room temperature overnight. Upon completion, the reaction was quenched with water (50 mL), extracted with dichloromethane (20 mL x 3), and purified on a silica gel column (petroleum ether:ethyl acetate = 3:1) to afford compound 888-03 (427 mg, yield: 73%) as a reddish-brown solid.

[1061] ESI-MS:m / z:484.2[M+H] +

[1062] Step 4: Synthesis of Compound 888-04

[1063] Dissolve 888-03 (427 mg, 0.88 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (93 mg, 1.76 mmol, 2.0 eq) and zinc powder (114 mg, 1.76 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 888-04 for later use.

[1064] ESI-MS:m / z:454.2[M+H] +

[1065] Step 5: Synthesis of Compound 888-05

[1066] Under a nitrogen atmosphere, Intermediate 888-04 obtained in Step 4 was dissolved in anhydrous dichloromethane (8 mL). DIPEA (0.31 mL, 1.76 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.10 mL, 0.88 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 888-05, which was used directly in the next step without purification.

[1067] ESI-MS:m / z:590.2[M+H] +

[1068] Step 6: Synthesis of Compound 888

[1069] Under nitrogen, the product 888-05 from step 5 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (67 mg, 1.76 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction. The mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 888 (232 mg, 47% yield) as an off-white solid.

[1070] 1 H NMR: (400MHz, DMSO-d6) δ9.46 (s, 1H), 8.13 (s, 1H), 7.81 (d, J = 7.5Hz, 1H), 7.59 (t, J = 8. 0Hz,1H),7.54(dd,J=7.5,2.0Hz,1H),7.31(d,J=2.0Hz,1H),7.00(dd,J=8.0,1.0Hz,1H ),6.85(dd,J=8.1,0.9Hz,1H),6.09(t,J=56.3Hz,1H),4.20(s,2H),3.90–3.84(m,4H), 3.82(t,J=6.5Hz,2H), 3.67(t,J=6.5Hz,2H), 2.47(dt,J=13.7,6.7Hz,4H), 1.14(s,6H).

[1071] ESI-MS:m / z:562.2[M+H] +

[1072] Example 67 Synthesis of Compound 8103

[1073] Step 1: Synthesis of compound 8103-01

[1074] 3-Chloro-5-aminopyridazine (1.0 g, 7.72 mmol, 1.0 eq), 4,4-difluoropiperidine hydrochloride (1.82 g, 11.58 mmol, 1.5 eq), and sodium carbonate (818 mg, 7.72 mmol, 1.0 eq) were dispersed in NMP (10 mL). DIPEA (2.01 mL, 11.58 mmol, 1.5 eq) was added and the mixture was heated to 220°C in a microwave oven at 12 atm for 1 h. After the starting material disappeared, the reaction mixture was cooled to room temperature, separated by addition of water (50 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by pre-HPLC to afford compound 8103-01 (1.05 g, yield: 63%) as a yellow solid.

[1075] ESI-MS: m / z: 215.1 [M+H] +

[1076] Step 2: Synthesis of compound 8103-02

[1077] Under nitrogen protection, IM-51 (500 mg, 1.73 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL), 1 drop of DMF was added thereto, and oxalyl chloride (0.21 mL, 2.59 mmol, 1.5 eq) was slowly added under ice bath. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 30 min. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude acyl chloride for use.

[1078] Under nitrogen, 8103-01 (370 mg, 1.73 mmol, 1.0 eq) and a catalytic amount of DMAP were dissolved in 2-methyltetrahydrofuran (10 mL). DIPEA (0.6 mL, 3.46 mmol, 2.0 eq) was added, and a solution of the acid chloride in anhydrous tetrahydrofuran (5 mL) was added dropwise under an ice bath. The reaction system was heated to reflux and allowed to react overnight. Upon completion, the reaction solution was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (10 mL x 3), and purified on a silica gel column (dichloromethane:methanol = 40:1) to afford compound 8103-02 (646 mg, yield: 77%) as a yellow solid.

[1079] ESI-MS:m / z:486.2[M+H] +

[1080] Step 3: Synthesis of compound 8103-03

[1081] Dissolve 8103-02 (646 mg, 1.33 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (141 mg, 2.66 mmol, 2.0 eq) and zinc powder (173 mg, 2.66 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 8103-03 for later use.

[1082] ESI-MS:m / z:456.2[M+H] +

[1083] Step 4: Synthesis of compound 8103-04

[1084] Under a nitrogen atmosphere, Intermediate 8103-03 obtained in Step 3 was dissolved in anhydrous dichloromethane (8 mL). DIPEA (0.46 mL, 2.66 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.15 mL, 1.33 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 8103-04, which was used directly in the next step without purification.

[1085] ESI-MS:m / z:592.2[M+H] +

[1086] Step 5: Synthesis of compound 8103

[1087] Under nitrogen, the product 8103-04 from step 4 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (101 mg, 2.66 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction. The mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 8103 (322 mg, yield: 43%) as an off-white solid.

[1088] 1H NMR: (400MHz, DMSO-d6) δ9.54(s,1H), δ8.02(s,1H),7.96(d,J=7.5Hz,1H),7.59(dd,J=7.5,2.0Hz,1H),7.31(d,J=2.0Hz,1H),7.06(s,1H),6. 14(t,J=56.3Hz,1H),4.20(s,2H),3.88–3.82(m,4H),3.88(t,J=6.7Hz,2H),3.67(t,J=6.7Hz,2H),2.47(dt,J=13.7,6.7Hz,4H),1.13(s,6H).

[1089] ESI-MS:m / z:564.2[M+H] +

[1090] Example 68 Synthesis of Compound 839

[1091] Step 1: Synthesis of compound 839-01

[1092] IM-42 (500 mg, 1.32 mmol, 1.0 eq), 2-(1-methylcyclopropyl)ethanol (132 mg, 1.32 mmol, 1.0 eq), and potassium carbonate (364 mg, 2.64 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 95°C for 2 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 839-01 (466 mg, 77% yield) as a yellow solid.

[1093] ESI-MS:m / z:460.2[M+H] + .

[1094] Step 2: Synthesis of compound 839-02

[1095] At room temperature, intermediate 839-01 (466 mg, 1.01 mmol, 1.0 eq) obtained in step 1 was dissolved in methanol (10 mL). Ammonium chloride (108 mg, 2.03 mmol, 2.0 eq) and zinc powder (132 mg, 2.03 mmol, 2.0 eq) were added sequentially. The reaction was continued for 15 minutes. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain intermediate 839-02 for later use.

[1096] ESI-MS:m / z:430.2[M+H]+ .

[1097] Step 3: Synthesis of compound 839-03

[1098] Under nitrogen, Intermediate 839-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.33 mL, 2.03 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (174 mg, 1.01 mmol, 1.0 eq) was added dropwise under an ice bath. After the addition, the ice bath was removed and the mixture was allowed to react at room temperature for 2 h. Upon disappearance of the starting material, the reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 839-03 for later use.

[1099] ESI-MS:m / z:566.2[M+H] + .

[1100] Step 4: Synthesis of compound 839

[1101] Under nitrogen, the product 839-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (76 mg, 2.03 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. After addition, the reaction mixture was allowed to react for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction mixture, and the mixture was stirred at room temperature for 30 min. The resulting reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 839 (260 mg, 48% yield) as an off-white solid.

[1102] ESI-MS:m / z:538.2[M+H] + .

[1103] 1H NMR (400MHz, DMSO) δ9.85 (s, 1H), 7.69 (d, J = 8.4Hz, 1H), 7.40 (s, 1H), 7.18 (t, J = 8.0Hz, 1H), 7.11 ( d,J=7.9Hz,1H),6.95(d,J=1.3Hz,1H),6.85(dd,J=8.5,1.7Hz,1H),6.73(dd,J=8.1,1.6Hz,1H),4 .18(t,J=6.8Hz,2H),3.76(t,J=6.6Hz,2H),3.94–3.80(m,4H),3.29(t,J=6.6Hz,2H),2.05(dt,J= 19.4, 6.8Hz, 4H), 1.79 (t, J = 6.8Hz, 2H), 1.07 (s, 3H), 0.34 (t, J = 4.6Hz, 2H), 0.22 (t, J = 4.6Hz, 2H).

[1104] Example 69 Synthesis of Compound 850

[1105] Step 1: Synthesis of compound 850-01

[1106] IM-02 (500 mg, 1.26 mmol, 1.0 eq), 2-(1-methylcyclopropyl)ethanol (126 mg, 1.26 mmol, 1.0 eq), and potassium carbonate (350 mg, 2.53 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 95°C for 8 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 850-01 (432 mg, 72% yield) as a yellow solid.

[1107] ESI-MS:m / z:476.2[M+H] + .

[1108] Step 2: Synthesis of compound 850-02

[1109] At room temperature, intermediate 850-01 (432 mg, 0.91 mmol, 1.0 eq) obtained in step 1 was dissolved in methanol (10 mL). Ammonium chloride (97 mg, 1.82 mmol, 2.0 eq) and zinc powder (119 mg, 1.82 mmol, 2.0 eq) were added sequentially. The reaction was continued for 15 minutes. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain intermediate 850-02 for later use.

[1110] ESI-MS:m / z:446.2[M+H] + .

[1111] Step 3: Synthesis of Compound 850

[1112] Under nitrogen, the product 850-02 from step 2 was dissolved in pyridine (5 mL). Methanesulfonic anhydride (158 mg, 0.91 mmol, 1.0 eq) was added to the reaction system at room temperature. After addition, the reaction mixture was allowed to react for 1 hour until the starting material disappeared. The resulting reaction solution was diluted with water (30 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to yield product 850 (237 mg, yield: 50%) as an off-white solid.

[1113] ESI-MS:m / z:524.2[M+H] + .

[1114] 1 H NMR (400MHz, DMSO) δ10.40 (s, 1H), 7.92 (d, J = 8.6Hz, 1H), 7.36 (s, 1H), 6.97(d,J=1.9Hz,1H),6.90(dd,J=8.6,1.9Hz,1H),4.28(t,J=6.6Hz,2H),3.94–3.79(m,4H),3.09(s,3H),2.30(s, 3H), 1.97 (dt, J = 19.5, 6.8 Hz, 4H), 1.89 (t, J = 6.6 Hz, 2H), 1.11 (s, 3H), 0.38 (t, J = 4.7 Hz, 2H), 0.28 (t, J = 4.7 Hz, 2H).

[1115] Example 70 Synthesis of Compound 818

[1116] Step 1: Synthesis of compound 818-01

[1117] IM-12 (500 mg, 1.31 mmol, 1.0 eq), 3,3-difluoro-2,2-dimethylpropan-1-ol (163 mg, 1.31 mmol, 1.0 eq), and potassium carbonate (362 mg, 2.62 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 95°C for 8 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 818-01 (454 mg, yield: 71%) as a yellow solid.

[1118] ESI-MS:m / z:486.2[M+H] + .

[1119] Step 2: Synthesis of compound 818-02

[1120] At room temperature, intermediate 818-01 (454 mg, 0.93 mmol, 1.0 eq) obtained in step 1 was dissolved in methanol (10 mL). Ammonium chloride (100 mg, 1.87 mmol, 2.0 eq) and zinc powder (122 mg, 1.87 mmol, 2.0 eq) were added sequentially. The reaction was continued for 15 minutes. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain intermediate 818-02 for later use.

[1121] ESI-MS:m / z:456.2[M+H] + .

[1122] Step 3: Synthesis of Compound 818

[1123] Under nitrogen, the product 818-02 from step 2 was dissolved in pyridine (5 mL). Fluoromethanesulfonyl chloride (124 mg, 0.93 mmol, 1.0 eq) was added to the reaction system at room temperature. After addition, the reaction mixture was allowed to react for 1 hour until the starting material disappeared. The resulting reaction solution was diluted with water (30 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 818 (226 mg, yield: 44%) as an off-white solid.

[1124] ESI-MS:m / z:553.2[M+H] + .

[1125] 1H NMR (400MHz, DMSO) δ10.06(s,1H),8.34(d,J=5.5Hz,1H),7.91(d,J=8.5Hz,1H),7.50(d,J=5.5Hz,1H),7.01(d,J=1.8Hz,2H),6.97(dd,J=8. 6,1.9Hz,1H),6.12(t,J=56.2Hz,1H),5.69(s,1H),5.57(s,1H),4.06(s,2H),3.89–3.76(m,4H),1.95(dt,J=19.5,6.7Hz,4H),1.20(s,6H).

[1126] Example 71 Synthesis of Compound 886

[1127] Step 1: Synthesis of compound 886-01

[1128] 6-Amino-2-chloro-3-cyanopyridine (1 g, 6.51 mmol, 1.0 eq), 4,4-difluoropiperidine hydrochloride (1.03 g, 6.51 mmol, 1.0 eq), and potassium carbonate (1.80 g, 13.02 mmol, 2.0 eq) were dispersed in DMSO (10 mL). The reaction mixture was stirred at 120°C for 8 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (60 mL). The mixture was extracted with dichloromethane (40 mL x 3). The organic layers were combined and backwashed twice with water (30 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 886-01 (1.3 g, yield: 84%) as a pale yellow solid.

[1129] ESI-MS:m / z:239.1[M+H] + .

[1130] Step 2: Synthesis of compound 886-02

[1131] Under nitrogen, CM-01 (1 g, 5.40 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (20 mL). Two drops of N,N-dimethylformamide were added. Oxalyl chloride (0.68 mL, 8.10 mmol, 1.5 eq) was then added dropwise under ice-cooling. The mixture was stirred at room temperature for 30 minutes until the reaction was complete. The resulting reaction solution was then distilled to remove the solvent under dry conditions to obtain the acyl chloride intermediate for later use.

[1132] Under nitrogen, 886-01 (1.29 g, 5.40 mmol, 1.0 eq) was dissolved in anhydrous DCE (20 mL). N,N-diisopropylethylamine (1.8 mL, 10.8 mmol, 2.0 eq) was added, and a solution of the acid chloride intermediate in anhydrous dichloromethane (5 mL) was added dropwise under an ice bath. The reaction mixture was then heated to 100°C overnight. Upon completion, the resulting solution was cooled to room temperature and diluted with water (50 mL). Solid precipitated and was filtered. The resulting filter cake was slurried in petroleum ether (75 mL) and filtered to afford compound 886-02 (1.70 g, 78% yield) as a light yellow solid.

[1133] ESI-MS:m / z:406.1[M+H] + .

[1134] Step 3: Synthesis of compound 886-03

[1135] 886-02 (500 mg, 1.23 mmol, 1.0 eq), 3,3-difluoro-2,2-dimethylpropan-1-ol (153 mg, 1.23 mmol, 1.0 eq), and potassium carbonate (341 mg, 2.47 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 95°C for 5 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 886-03 (435 mg, yield: 69%) as a yellow solid.

[1136] ESI-MS:m / z:510.2[M+H] + .

[1137] Step 4: Synthesis of Compound 886-04

[1138] At room temperature, intermediate 886-03 (435 mg, 0.85 mmol, 1.0 eq) obtained in step 3 was dissolved in methanol (10 mL). Ammonium chloride (91 mg, 1.71 mmol, 2.0 eq) and zinc powder (112 mg, 1.71 mmol, 2.0 eq) were added sequentially. The reaction was continued for 15 minutes. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain intermediate 886-04 for future use.

[1139] ESI-MS:m / z:480.2[M+H] + .

[1140] Step 5: Synthesis of Compound 886-05

[1141] Under nitrogen, Intermediate 886-04 obtained in Step 4 was dissolved in anhydrous dichloromethane (5 mL). N,N-diisopropylethylamine (0.28 mL, 1.71 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (147 mg, 0.85 mmol, 1.0 eq) was added dropwise under an ice bath. After completion of the addition, the ice bath was removed and the mixture was allowed to react at room temperature for 2 h. Upon disappearance of the starting material, the resulting reaction solution was quenched with water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 886-05 for later use.

[1142] ESI-MS:m / z:616.2[M+H] + .

[1143] Step 6: Synthesis of Compound 886

[1144] Under nitrogen, the product 886-05 from step 5 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (64 mg, 1.71 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. After addition, the reaction mixture was allowed to react for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction mixture, and the mixture was stirred at room temperature for 30 min. The resulting reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 886 (254 mg, 51% yield) as an off-white solid.

[1145] ESI-MS:m / z:588.2[M+H] + .

[1146] 1 H NMR (400MHz, DMSO) δ10.19(s,1H),8.09(d,J=8.5Hz,1H),7.87(d,J=8.5Hz,1H),7.82(d,J=8.5Hz,1H),7.01(d,J=1.6Hz,1H),6.96(dd,J=8.6,1.7Hz, 1H),6.10(t,J=56.2Hz,1H),4.03(s,2H),3.76(t,J=6.5Hz,2H),3.74–3.6 6(m,4H),3.37(t,J=6.5Hz,2H),2.09(dt,J=19.3,6.8Hz,4H),1.17(s,6H).

[1147] Example 72 Synthesis of Compound 863

[1148] Step 1: Synthesis of compound 863-01

[1149] IM-12 (500 mg, 1.31 mmol, 1.0 eq), 3,3-difluoro-2,2-dimethylpropan-1-ol (163 mg, 1.31 mmol, 1.0 eq), and potassium carbonate (362 mg, 2.62 mmol, 2.0 eq) were dispersed in DMSO (5 mL). The reaction mixture was stirred at 95°C for 8 hours. After the starting material disappeared, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined and backwashed twice with water (15 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford compound 863-01 (460 mg, yield: 72%) as a yellow solid.

[1150] ESI-MS:m / z:486.2[M+H] + .

[1151] Step 2: Synthesis of compound 863-02

[1152] At room temperature, intermediate 863-01 (460 mg, 0.95 mmol, 1.0 eq) obtained in step 1 was dissolved in methanol (10 mL). Ammonium chloride (100 mg, 1.90 mmol, 2.0 eq) and zinc powder (123 mg, 1.90 mmol, 2.0 eq) were added sequentially. The reaction was continued for 15 minutes. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain intermediate 863-02 for later use.

[1153] ESI-MS:m / z:456.2[M+H] + .

[1154] Step 3: Synthesis of compound 863

[1155] Under nitrogen, the product 863-02 from step 2 was dissolved in pyridine (5 mL). 2-Methoxy-1-ethylsulfonyl chloride (151 mg, 0.95 mmol, 1.0 eq) was added to the reaction system at room temperature. After addition, the reaction mixture was allowed to react for 1 hour until the starting material disappeared. The resulting reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford product 863 (237 mg, yield: 43%) as an off-white solid.

[1156] ESI-MS:m / z:578.2[M+H] + .

[1157] 1 H NMR (400MHz, DMSO) δ10.04(s,1H),8.34(d,J=5.5Hz,1H),7.91(d,J=8.6Hz,1H ),7.51(d,J=5.5Hz,1H),7.01(d,J=1.6Hz,1H),6.95(dd,J=8.6,1.7Hz,1H),6 .13(t,J=56.2Hz,1H),4.06(s,2H),3.93–3.78(m,4H),3.68(t,J=5.9Hz,2H), 3.50(t,J=5.9Hz,2H),3.18(s,3H),1.95(dt,J=19.3,6.8Hz,4H),1.21(s,6H).

[1158] Example 73 Synthesis of Compound 819

[1159] Step 1: Synthesis of compound 819-01

[1160] IM-02 (300 mg, 0.76 mmol, 1.0 eq), CM-04 (94 mg, 0.76 mmol, 1.0 eq), and potassium carbonate (210 mg, 1.52 mmol, 2.0 eq) were dispersed in DMSO (4 mL). The reaction mixture was stirred at 70°C overnight. After the starting material disappeared, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL x 3). The organic layers were combined and backwashed twice with water (10 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified on a silica gel column (dichloromethane) to afford compound 819-01 (332 mg, yield: 87%) as a yellow solid.

[1161] ESI-MS: m / z: 500.2 [M+H] +

[1162] Step 2: Synthesis of compound 819-02

[1163] Dissolve 819-01 (332 mg, 0.66 mmol, 1.0 eq) in methanol (10 mL). Add ammonium chloride (70 mg, 1.32 mmol, 2.0 eq) and zinc powder (86 mg, 1.32 mmol, 2.0 eq) sequentially. Stir the mixture at room temperature for 30 min. After the reaction is complete, remove the solid by filtration, and concentrate the filtrate under reduced pressure to obtain intermediate 819-02 for later use.

[1164] ESI-MS:m / z:470.2[M+H] +

[1165] Step 3: Synthesis of compound 819-03

[1166] Under a nitrogen atmosphere, Intermediate 819-02 obtained in Step 2 was dissolved in anhydrous dichloromethane (6 mL). DIPEA (0.23 mL, 1.32 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.076 mL, 0.66 mmol, 1.0 eq) was added under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. After the starting material disappeared, the resulting reaction solution was separated by adding water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Intermediate 819-03, which was used directly in the next step without purification.

[1167] ESI-MS:m / z:606.2[M+H] +

[1168] Step 4: Synthesis of Compound 819

[1169] Under nitrogen, the product 819-03 from step 3 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (50 mg, 1.32 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 819 (178 mg, 46% yield) as an off-white solid.

[1170] ESI-MS:m / z:578.2[M+H] +

[1171] 1 H NMR: (400MHz, DMSO-d6) δ9.98(s,1H),7.92(d,J=8.6Hz,1H),7.43(s,1H),7.01(d,J=1.7Hz,1H),6.97(dd,J=8.7,1.5Hz,1H),6.14(t,J=56.2 Hz,1H),4.06(s,2H),3.92–3.84(m,4H),3.76(t,J=6.4Hz,2H),3.39(d,J=6.4Hz,2H),2.31(s,3H),1.96(dt,J=13.8,7.9Hz,4H),1.21(s,6H).

[1172] Example 74 Synthesis of Compound 834b

[1173] Step 1: Synthesis of compound 834b-01

[1174] 2-Amino-4,6-dichloropyridine (1.0 g, 6.13 mmol, 1.0 eq), 4,4-difluoropiperidine hydrochloride (1.45 g, 8.58 mmol, 1.4 eq), and sodium carbonate (975 mg, 9.20 mmol, 1.5 eq) were dispersed in NMP (10 mL). DIPEA (1.07 mL, 6.13 mmol, 1.0 eq) was added and the mixture was heated to 230°C in a microwave oven at 12 atm for 2 h. After the starting material disappeared, the reaction solution was cooled to room temperature, separated by addition of water (50 mL), and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by pre-HPLC to afford compound 834b-01 (1.02 g, yield: 67%) as a white solid. ESI-MS: m / z: 249 [M+H] +

[1175] Step 2: Synthesis of compound 834b-02

[1176] 834b-01 (1.02 g, 4.11 mmol, 1.0 eq) was dissolved in deuterated methanol (10 mL), deuterated acetic acid (1 mL) was added, and palladium-carbon catalyst (500 mg, 50 wt%) was added. The mixture was replaced with deuterium three times and heated to 60°C under deuterium protection for 2 h. After the starting material disappeared, the palladium catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain compound 834b-02 (839 mg, yield: 95%) as a white solid. ESI-MS: m / z: 216 [M+H] +

[1177] Step 3: Synthesis of compound 834b-03

[1178] Under nitrogen protection, IM-51 (500 mg, 1.73 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL), 1 drop of DMF was added thereto, and oxalyl chloride (0.21 mL, 2.59 mmol, 1.5 eq) was slowly added under ice bath. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 30 min. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude acyl chloride for use.

[1179] Under nitrogen, 834b-02 (371 mg, 1.73 mmol, 1.0 eq) and a catalytic amount of DMAP were dissolved in 2-methyltetrahydrofuran (10 mL). DIPEA (0.6 mL, 3.46 mmol, 2.0 eq) was added dropwise to the solution. A solution of the acid chloride in anhydrous tetrahydrofuran (5 mL) was added dropwise under an ice bath. The reaction system was heated to reflux and allowed to react overnight. Upon completion, the reaction solution was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (10 mL x 3), and purified on a silica gel column (dichloromethane:methanol = 40:1) to afford compound 834b-03 (612 mg, yield: 73%) as a yellow solid. ESI-MS: m / z: 487 [M+H] +

[1180] Step 4: Synthesis of compound 834b-04

[1181] 834b-03 (612 mg, 1.26 mmol, 1.0 eq) was dissolved in methanol (10 mL). Ammonium chloride (134 mg, 2.52 mmol, 2.0 eq) and zinc powder (164 mg, 2.52 mmol, 2.0 eq) were added sequentially. The mixture was stirred at room temperature for 30 min. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain intermediate 834b-04 for use. ESI-MS: m / z: 457 [M+H] +

[1182] Step 5: Synthesis of compound 834b-05

[1183] Under a nitrogen atmosphere, intermediate 834b-04 obtained in step 4 was dissolved in anhydrous dichloromethane (8 mL). DIPEA (0.44 mL, 2.52 mmol, 2.0 eq) was added, and a dichloromethane solution of methyl 2-(chlorosulfonyl)acetate (0.14 mL, 1.26 mmol, 1.0 eq) was added under an ice bath. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 2 h. After the starting material disappeared, the resulting reaction solution was added to water (20 mL) and separated. The mixture was extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 834b-05, which was used directly in the next step without purification. ESI-MS: m / z: 593 [M+H] +

[1184] Step 6: Synthesis of compound 834b

[1185] Under nitrogen, the product 834b-05 from step 5 was dissolved in tetrahydrofuran (10 mL). Sodium borohydride (95 mg, 2.52 mmol, 2.0 eq) was slowly added portionwise to the reaction system at room temperature. The reaction was continued for 30 min. After the starting material disappeared, acetone was added dropwise to quench the reaction, and the mixture was stirred at room temperature for 30 min. The resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to afford 834b (404 mg, 57% yield) as an off-white solid.

[1186] 1 H NMR (400MHz, DMSO-d6) δ9.80(s,1H),7.96(d,J=8.6Hz,1H),7.63(s,1H),7.02(d,J=2.0Hz,1H),6.97(dd,J=8.6,1.9Hz,1H),6.70(s,1H),6.1 5(t,J=56.2Hz,1H),4.06(s,2H),3.77(t,J=6.5Hz,2H),3.70–3.64(m,4H),3.37(t,J=6.5Hz,2H),1.97(tt,J=14.1,5.5Hz,4H),1.23(s,6H). ESI-MS:m / z:565[M+H] +

[1187] The synthesis methods of the remaining compounds are similar to those of the above examples, and only the corresponding reaction raw materials need to be replaced according to the target compounds. The corresponding identification data are as follows:

[1188] Experimental Example 1 Inhibition of KIF18A Enzyme Activity by Compounds

[1189] KIF18A enzyme assay: KIF18A enzyme activity after compound treatment was measured using a microtubule-stimulated ATPase activity assay. This assay measures the ADP generated by the ATPase reaction. Starting at a 10 μM concentration, the compound was serially diluted 4-fold in DMSO over a 10-concentration range. Recombinant human KIF18A (1-467His-tagged) protein was expressed using a baculovirus system. The concentrations of KIF18A protein, microtubules, and ATP in the reaction were optimized using the ADP-Glo ​​Kinase / ATPase Assay Kit for standardized homogenous enzyme assays. Prepare the reaction solution [(15 Mm Tris, pH 7.5), 10 Mm MgCl2, 0.01% Pluronic F-68, 1 μM paclitaxel, and 30 μg / mL porcine microtubules]. Compounds and KIF18A protein (30 nM) were added to the prepared reaction buffer and incubated at room temperature for 15 min. ATP (Km, 75 μM) was then added to the reaction mixture and incubated for another 15 min at room temperature. 5 μl of ADP-Glo ​​reagent and 2.5 μl of the reaction mixture were mixed and incubated at room temperature for 40 min. 10 μl of ADP-Glo ​​detection reagent was added and incubated at room temperature for 40 min. Luminescence was read using a microplate reader and the compound inhibition percentage and IC were calculated compared to the DMSO group. 50 The enzyme activity inhibition results of representative compounds are shown in Table 1 below.

[1190] Table 1 Inhibitory activity of some compounds of the present invention against KIF18A (IC50, nM)

[1191] The reference compound AMG650 is compound 4 in WO2020132648A1.

[1192] From the data in Table 1, it can be seen that some compounds of the present invention have strong inhibitory activity on the enzyme activity of KIF18A.

[1193] Experimental Example 2 Inhibition of proliferation of ovarian cancer cell line OVCAR-3 by some compounds

[1194] Well-grown OVCAR-3, BT-549, Hs 578T, and HCC 1806 cells were selected and nitrated with trypsin. Fresh culture medium was added, mixed thoroughly, and centrifuged at 800 rpm for 3 minutes. 4000 OVCAR-3 cells, 3000 BT-549 cells, 3000 Hs 578T cells, and 3000 HCC 1806 cells were seeded into 96-well plates, respectively, and incubated overnight at 37°C. The next day, the plates were removed and the compounds were administered using a four-fold serial dilution. Blank control wells contained normal culture medium without cells and DMSO, while DMSO wells contained cells in the presence of 0.5% DMSO. The 96-well plates were incubated at 37°C for 96 hours.

[1195] The cell culture plate was equilibrated at room temperature for 30 minutes. 100 μl of CellTiter Glo assay reagent was added to each well and mixed on a plate shaker for 2 minutes to induce cell lysis. The 96-well plate was left at room temperature for 10 minutes to allow the luminescence signal to stabilize. A white film was applied to the bottom of the culture plate. Chemiluminescence values ​​were measured using Enspire and calculated using the following formula: Inhibition rate (%) = (1-(compound reading - blank control reading) / (DMSO control reading - blank control reading)) × 100%. The IC values ​​of each compound were calculated. 50 The values ​​were analyzed by nonlinear regression using XLFit software. The activity data of some compounds in inhibiting cell proliferation are shown in Table 2 below.

[1196] Table 2 Antiproliferative activity of some compounds of the present invention against OVCAR-3, BT-549, Hs 578T, and HCC 1806 cells (IC50, nM)

[1197] +++ indicates IC50 less than or equal to 100 nM

[1198] ++ indicates IC50 is 100nM to 500nM

[1199] + indicates IC50 greater than 500nM

[1200] From the data in Table 2, it can be seen that some compounds of the present invention have good anti-proliferative activity against OVCAR-3, BT-549, Hs 578T and HCC 1806 cells.

[1201] Experimental Example 3 Pharmacokinetic Study in Rats

[1202] Instrument: Waters XEVO TQ-S LC-MS / MS. All measurement data were collected and processed by Masslynx V4.1 software, and calculated and processed using Microsoft Excel. Pharmacokinetic parameters were calculated using WinNonLin 8.0 software using the statistical moment method. These parameters included Tmax, Tl / 2, Cmax, and AUC. 0-24h Chromatographic column: ACQUITY UPLC BEH Cl8 (2.1 mm x 50 mm, 1.7 μm); column temperature: 40°C; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 0.350 mL / min; gradient elution: 0.50 min: 10% B; 1.50 min: 90% B; 2.50 min: 90% B; 2.51 min: 10% B; 3.50 min: stop. Injection volume: 1 μl.

[1203] Animals: Three male Sprague-Dawley rats, weighing 200-220 g, were housed in the laboratory of the Experimental Animal Center for two days before use. They were fasted for 12 hours before and 4 hours after dosing, with free access to water during the experiment. Blood samples were collected at designated intervals after gavage.

[1204] Solvent: 0.4% ethanol + 0.4% Tween 80 + 99.2% (0.5% methylcellulose M450) Preparation of oral administration solution: Accurately weigh the compound, add it to the solvent, and ultrasonicate at room temperature for 5 minutes to prepare a 4 mg / mL suspension solution.

[1205] Drug samples: Typically, multiple structurally similar samples (molecular weights differing by at least 2 units) are collected, accurately weighed, and administered together (cassette PK). This allows for simultaneous screening of multiple compounds and comparison of their oral absorption rates. Single administration is also used to study the pharmacokinetics of drug samples in rats.

[1206] Blood was collected from the orbital cavity at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after oral administration. Fifty microliters of plasma was added to 200 microliters of acetonitrile (containing the internal standard verapamil, 2 ng / mL). The mixture was vortexed for 3 minutes and centrifuged at 20,000 rpm at 4°C for 10 minutes. The supernatant was then analyzed by LC-MS / MS.

[1207] The compound is accurately weighed and prepared into different concentrations, and quantitative analysis is performed on the mass spectrometer to establish a standard curve. Then the concentration of the compound in the plasma is tested to obtain the concentration of the compound at different time points. All the measurement data are collected and processed by relevant software, and the pharmacokinetic parameters are calculated using the statistical moment method (mainly including kinetic parameters Tmax, T l / 2, Cmax, AUC0-24h, etc.). The kinetic parameters of some representative compounds are shown in Table 3.

[1208] Table 3 Pharmacokinetic parameters in rats

[1209] Experimental Example 4 Study on the absolute bioavailability of the compound in rats

[1210] Instrument: Waters XEVO TQ-S LC-MS / MS. All measurement data were collected and processed by Masslynx V4.1 software, and calculated and processed using Microsoft Excel. Pharmacokinetic parameters were calculated using WinNonLin 8.0 software using the statistical moment method. These parameters included Tmax, Tl / 2, Cmax, and AUC. 0-24h Chromatographic column: ACQUITY UPLC BEH Cl8 (2.1 mm x 50 mm, 1.7 μm); column temperature: 40°C; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 0.350 mL / min; gradient elution: 0.50 min: 10% B; 1.50 min: 90% B; 2.50 min: 90% B; 2.51 min: 10% B; 3.50 min: stop. Injection volume: 1 μl.

[1211] Animals: Three male Sprague-Dawley rats, weighing 170-200 g, were housed in the laboratory of the Experimental Animal Center for three days before use. They were fasted for 12 hours before and after dosing and had free access to water during the experiment. Blood samples were collected at designated time points after dosing.

[1212] Intragastric administration of the test substance: solvent: 10% DMSO + 90% (aqueous solution containing 0.5% CMC-Na). Preparation of intragastric administration solution: accurately weigh the compound, add it to the solvent, and ultrasonicate it at room temperature for 5 minutes to prepare a 4 mg / mL suspension solution.

[1213] Intravenous administration of the test substance solvent: 5% DMSO + 95% (containing 30% HS-15 aqueous solution) Intravenous administration preparation: accurately weigh the compound, add it to the solvent, and sonicate at room temperature for 5 minutes to completely dissolve the drug to prepare a 1 mg / mL clear solution.

[1214] Drug samples: Typically, multiple structurally similar samples (molecular weights differing by at least 2 units) are collected, accurately weighed, and administered together (cassette PK). This allows for simultaneous screening of multiple compounds and comparison of their oral absorption rates. Single administration is also used to study the pharmacokinetics of drug samples in rats.

[1215] Blood was collected from the orbital cavity at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after oral administration. Fifty microliters of plasma was added to 200 microliters of acetonitrile (containing the internal standard verapamil, 2 ng / mL). The mixture was vortexed for 3 minutes and centrifuged at 20,000 rpm at 4°C for 10 minutes. The supernatant was then analyzed by LC-MS / MS.

[1216] Blood was collected from the eye socket at 5 minutes, 40 minutes, 1.5 hours, 3 hours, 5 hours, 7 hours, and 9 hours after intravenous administration. Fifty microliters of plasma was added to 200 microliters of acetamide (containing the internal standard verapamil, 2 ng / mL). The mixture was vortexed for 3 minutes and centrifuged at 20,000 rpm at 4°C for 10 minutes. The supernatant was then analyzed by LC-MS / MS.

[1217] The compound is accurately weighed and prepared into different concentrations, and quantitative analysis is performed on the mass spectrometer to establish a standard curve. Then the concentration of the compound in the plasma is tested to obtain the concentration of the compound at different time points. All the measurement data are collected and processed by relevant software, and the pharmacokinetic parameters are calculated using the statistical moment method (mainly including kinetic parameters Tmax, T l / 2 , Cmax, AUC0-24h, etc.). The kinetic parameters of some representative compounds are shown in Table 4.

[1218] Table 4 Absolute bioavailability parameters of compounds in rats

[1219] AMG650 is an orally effective KIF18A inhibitor. According to the above experimental results, the bioavailability of the compound provided by the present invention is significantly higher than that of AMG650.

[1220] Experimental Example 5 In vivo efficacy study - mouse OVCAR-3 subcutaneous tumor inhibition model

[1221] BALB / c nude mice were subcutaneously inoculated with 5×10 6OVCAR-3 cells were randomly divided into groups and administered orally after the tumors grew to 100-150 mm3: in the first batch of experiments, group 1: vehicle control group (Vehicle), group 4: compound 819 (30 mg / Kg), group 5: compound 819 (60 mg / Kg); in the second batch of experiments, group 1: vehicle control group (Vehicle), group 2: compound 819 (15 mg / Kg), group 3: compound 819 (30 mg / Kg), group 4: compound 834 (15 mg / Kg), group 5: compound 834 (30 mg / Kg), group 6: compound 834b (15 mg / Kg), group 7: compound 834b (30 mg / Kg); twice a day for 21 consecutive days, and observed for 7 days after drug withdrawal. Tumor volume was measured twice a week and at the end of the administration. According to the tumor growth inhibition rate (% TGI TV )=(1-TV T / TV C )×100%, TV C is the average tumor volume of the negative control group, TV T The tumor growth inhibition rate of the compound was calculated based on the average tumor volume of the treatment group. The results of some compounds are shown in Tables 5 and 6 and Figures 1-2.

[1222] Table 5 Inhibitory rate of growth of OVCAR-3 subcutaneous transplanted tumor in mice (first batch test)

[1223] Table 6 Inhibition rate of growth of OVCAR-3 subcutaneous transplanted tumor in mice (second batch test)

[1224] Experimental Example 6 Neutrophil Count

[1225] In vivo efficacy study - After the 28th day of the mouse OVCAR-3 subcutaneous transplant tumor model experiment, blood was collected to measure the rat's blood routine and calculate the number of neutrophils. The results for some compounds are shown in Figure 3.

[1226] The results showed that 30 mpk of compound 834 and 30 mpk of compound 834b had no significant effect on the number of neutrophils in mice after 28 days of administration, and there was no statistically significant difference (P>0.5), indicating that the drugs had no obvious cytotoxicity to mice.

[1227] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of prot...

Claims

1. A compound represented by the general formula (1) or a stereoisomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof: in: X1, X4, X6, X7, X8 are independently N or C at each occurrence; X2, X5 are each independently N, S or C; X3 is independently at each occurrence a bond, N or C; R1 is halogen or group -YR 13 , where Y is a chemical bond, -C 0-4 Hydrocarbyl-, -N(C 0-1 Hydrocarbon)-C 0-4 Hydrocarbyl-, -C(=O)NR a -(C 1-4 Hydrocarbon)-、-OC 0-4 Hydrocarbyl-, -S-, -S(=O)-, -SO2-, -SO2NR9 or -S(=O)(=NH)-; R3 is -CN or a group -ZR 12 , where Z is -C 0-4 Alkyl-, -NR 11 -、-NR 11 SO2-、-SO2NR 11 -、-NR 11 -S(=O)(=NH), -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, C 0-4 Alkyl-O-, -(C=O)-, -(C=O)NR 11 -, -C=N(OH)- or -NR 11 (C=O); or the group -ZR 12 =N = S (= O) - (R 12 )2, where two R 12 Alternatively combined with their respective attached S to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N and 0, 1 or 2 selected from O or S; R4 is H, halogen, R 4a or R 4b ; R5 is H, C 1-4 Alkyl or C 1-4 Haloalkyl; R 11 H, R 11a or R 11b ; R 12 H, R 12a or R 12b ; R 13 For R 13a or R 13b ; R a is independently H or R b ;and R b In each case independently C 1-6 alkyl, phenyl or benzyl, wherein the C 1-6 The alkyl group is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C 1-4 Alkyl)C 1-4 Alkyl; and the phenyl or benzyl is substituted by 0, 1, 2 or 3 substituents selected from the following: halogen, C 1-4 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C 1-4 Alkyl)C 1-4 alkyl; R 4a , R 11a , R 12a , R 13a is independently selected in each case from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N and 0, 1 or 2 O or S, substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: F, Cl, Br, C 1-6 Alkyl, C 1-4 Haloalkyl, -OR a 、-OC 1-4 Haloalkyl, CN, -C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC 2-6 Alkyl NR a R a 、-OC 2-6 Alkyl OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NRaRa、-NR a C 2-6 Alkyl NR a R a 、-NR a C 2-6 Alkyl OR a , -C 1-6 Alkyl NR a R a , -C 1-6 Alkyl OR a , -C 1-6 Alkyl N(R a )C(=O)R b , -C 1-6 Alkyl OC(=O)R b , -C 1-6 Alkyl C(=O)NR a R a , -C 1-6 Alkyl C(=O)OR a , R 14 and oxo; R 4b , R 11b , R 12b , R 13b In each case independently selected from the group consisting of: C 1-6 Alkyl, which is replaced by F, Cl, Br, -OR a 、-OC 1-4 haloalkyl or CN substituted, the number of substituents is selected from 0, 1, 2, 3, 4 or 5; R 14 is independently selected in each case from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N and 0 or 1 O or S, substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: F, Cl, Br, C 1-6 Alkyl, C 1-4 Haloalkyl, -OR a 、-OC 1-4 Haloalkyl, CN, -C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC 2-6 Alkyl NR a R a 、-OC 2-6 Alkyl OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(Ra)C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2-6 Alkyl NR a R a 、-NR a C 2-6 Alkyl OR a , -C 1-6 Alkyl NR a R a , -C 1-6 Alkyl OR a , -C 1-6 Alkyl N(R a )C(=O)R b , -C 1-6 Alkyl OC(=O)R b , -C 1-6 Alkyl C(=O)NR a R a , -C 1-6 Alkyl C(=O)OR a and oxo; R2 is selected from: E is a chemical bond, -O-, -S- or -ZR 201 -; Where Z is a chemical bond, -O- or -S-, R 201 C 1-3 Alkyl, wherein the C 1-3 The alkyl group is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-2 Alkyl, -NH2; R 100 , R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 and R 110 Each of H, halogen, R 100a or, R 100 and R 101 , R 102 and R 103 , R 104 and R 105 , or R 106 and R 107 independently combine with their respective attached C to form a saturated or partially saturated 3-membered or 4-membered monocyclic ring; wherein the 3-membered or 4-membered monocyclic ring contains 0, 1 N and 0, 1 or 2 selected from O or S, wherein the 3-membered or 4-membered monocyclic ring is substituted with 0, 1, 2 or 3 substituents selected from the following: F, Cl, Br, C 1-2 Alkyl, C 1-2 Haloalkyl, -OR a 、-OC 1-4 Haloalkyl, CN, -NR a R a or oxo; R 100a In each case independently C 1-6 Alkyl, phenyl or benzyl, wherein the C1-6 alkyl is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C 1-4 Alkyl)C 1-4 Alkyl; and the phenyl or benzyl is substituted by 0, 1, 2 or 3 substituents selected from the following: halogen, C 1-4 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C 1-4 Alkyl)C 1-4 alkyl; R 16 Selected from -CN, H, deuterium, -C(=O)-R 16a , -C(=O)-R 16b ; R 16a is a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 N and 0 or 1 O or S, which is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, C 1-6 Alkyl, C 1-4 Haloalkyl, -OR a 、-OC 1-4 Haloalkyl, CN, -C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC 2-6 Alkyl NR a R a 、-OC 2-6 Alkyl OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(Ra)C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2-6 Alkyl NR a R a 、-NR a C 2-6 Alkyl OR a , -C 1-6 Alkyl NR a R a , -C 1-6 Alkyl OR a , -C 1-6 Alkyl N(R a )C(=O)R b , -C 1-6 Alkyl OC(=O)R b , -C 1-6 Alkyl C(=O)NR a R a , -C 1-6 Alkyl C(=O)OR a and oxo; R 16b -NH2, C 1-4 Alkyl, substituted by 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C 1-4 Alkyl)C 1-4 alkyl.

2. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: As shown in formula (1a), (1b), (1c) or (1d):

3. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: As shown in formula (2a), formula (2b), formula (2c) or formula (2d):

4. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: As shown in formula (3a), formula (3b), formula (3c) or formula (3d):

5. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: As shown in formula (4a), formula (4b), formula (4c) or formula (4d):

6. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: As shown in formula (5a), formula (5b), formula (5c) or formula (5d):

7. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: As shown in formula (6a), formula (6b), formula (6c) or formula (6d):

8. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: Structural unit for 9. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: Structural unit for 10. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: R5 is H, methyl or ethyl.

11. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: Where E is a chemical bond, -O- or -S-, R 201 C 1-3 Alkyl, wherein the C 1-3 The alkyl group is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-2 Alkyl, -NH2; R 100 , R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 and R 110 Each of H, halogen, R 100a ; or alternatively, R 100 and R 101 , R 102 and R 103 , R 104 and R 105 or R 106 and R 107 Each of the above independently combines with their respective attached C to form a saturated or partially saturated 3-membered or 4-membered monocyclic ring; wherein the 3-membered or 4-membered monocyclic ring contains 0, 1 N and 0, 1 or 2 selected from O or S, wherein the 3-membered or 4-membered monocyclic ring is substituted with 0, 1, 2 or 3 substituents selected from the following: F, Cl, Br, C 1-2 Alkyl, C 1-2 Haloalkyl, -OR a 、-OC 1-4 Haloalkyl, CN, -NR a R a or oxo; R 100a In each case independently C 1-6 alkyl, phenyl or benzyl, wherein the C 1-6 The alkyl group is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl or -N(C 1-4 Alkyl)C 1-4 Alkyl; and the phenyl or benzyl is substituted by 0, 1, 2 or 3 substituents selected from the following: halogen, C 1-4 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C1 -4 Alkyl or -N(C 1-4 Alkyl)C 1-4 alkyl.

12. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: R1 is halogen or group YR 13 , where Y is a chemical bond or -NH-; R 13 is a saturated, partially saturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1 or 2 N and 0 or 1 selected from O or S, wherein each of the rings is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, C 1-6 Alkyl, C 1-4 Haloalkyl, -OH, -OC 1-4 Haloalkyl, CN, R 14 and oxo; or R 13 C 1-6 A hydrocarbon group, which may be substituted with 0, 1, 2, 3, 4 or 5 of the following substituents: F, Cl, Br, -OH, -OC 1-4 Halogenated hydrocarbon or CN.

13. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: wherein R1 is a saturated 5-membered or 6-membered monocyclic ring, wherein each of said rings contains 0, 1 or 2 N and 0, 1 O, and wherein each of said rings is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, -OH, -OC 1-4 Hydrocarbon, C 1-4 Halogenated hydrocarbon, CN, R 14 and oxo.

14. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: in, R1 is: (a) halogen; (b) Group -YR 13 , where Y is a chemical bond, R 13 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, wherein each of said rings is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, methyl, -CF3, -OH, -OCHF2, -CN and oxo; or (c) group -YR 13 , wherein Y is -NH-, -O-, -O-(CH2)-, -O-(CH2)-(CH2)- or -O-(CH2)-(CH2)-(CH2)- and wherein R 13 for or R 13 is C substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, methyl, CF3, -OH or CN 1-6 alkyl.

15. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: Wherein R1 is morpholinyl or piperidinyl, and the morpholinyl and piperidinyl may be optionally substituted by 0, 1, 2 or 3 of the following substituents: F, Cl, Br, methyl, CF3, -OH, -OCHF2, CN.

16. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: Where R1 is Where R3 is -CN or a group -ZR 12 , wherein Z is a chemical bond, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH- or -NH(C=O)-.

17. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: Where R 12 Selected from: (a) H; (b)C 1-6 A hydrocarbon group which may be optionally substituted with 0, 1, 2 or 3 of the following substituents: -OH, F, Cl, Br or -OCH3; or (c) when the group -ZR 12 =N = S (= O) - (R 12 )2, wherein the two R 12 The S to which they are attached form a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 N and 1 selected from O or S, which is substituted by 0, 1, 2 or 3 substituents selected from the following: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -C 1-6 Hydrocarbyl -OH, -OH, -OCH3, -NH2 or oxo.

18. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: R 12 Selected from: (a) H; (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, Each of the rings can be independently selected from 0, 1, 2 or 3 of the following substituents: -OH, F, methyl, -CH2OH, -C(=O)OCH3, -C(=O)-OC(CH3)3, NH2, CN and oxo; or (c) C substituted with 0, 1, 2 or 3 -OH, F, methyl, -C(=O)OCH3, NH2, -NH(CH3)- or -N(CH3)2 1-6 Hydrocarbon.

19. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The group -ZR 12 =N = S (= O) - (R 12 )2, two of which R 12 Combined with the respective S to which it is attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N and 0, 1 or 2 selected from O or S.

20. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: Group-ZR 12 Selected from 21. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: Where R3 is -ZR 12 , wherein Z is -NHSO2- or -SO2NH-; and R 12 is oxetane, cyclopropyl, or R 12 is C substituted with 0, 1, 2 or 3 -OH groups 1-6 Hydrocarbon.

22. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: Where R3 is -ZR 12 , wherein Z is -NHSO2- or -SO2NH-, and R 12 It is -CH2CH2OH or -CH(CH3)-CH2OH.

23. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: Where R4 is H, halogen, R 4a or R 4b .

24. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: wherein R4 is selected from (a) H; or (b) C substituted by 0, 1, 2 or 3 halogens 1-6 or (c) cyclopropyl.

25. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The group R4 is selected from -H, -F or -CH3.

26. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: R 16a is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl; which is substituted by 0, 1, 2 or 3 substituents selected from the following: F, Cl, Br, C 1-6 Alkyl, C 1-4 Haloalkyl; R 16b -NH2, C 1-4 Alkyl, substituted by 0, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, -OH.

27. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: As shown in formula (7): R1 is X3 is N or C; R4 is H, deuterium, C 1-4 alkyl; R 15 -(CH2) n -OH, substituted or unsubstituted C 1-4 Alkyl, the substituent is selected from halogen, and n is selected from 1-4.

28. The compound according to claim 27 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: As shown in formula (7a) or (7b):

29. The compound according to claim 27 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: X3 is N.

30. The compound according to claim 27 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: R4 is H, deuterium, or methyl.

31. The compound according to claim 27 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: R 15 It is -CH2F, -(CH2)2-OH, and methyl.

32. The compound of claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: As shown in formula (8): X3 is N or C; R4 is H, deuterium, or methyl.

33. The compound of claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: As one of the following:

34. The compound of claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: As one of the following:

35. A pharmaceutical composition, characterized in that It contains pharmaceutically acceptable excipients and the compound according to any one of claims 1 to 34, or its or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate as an active ingredient.

36. Use of the compound according to any one of claims 1 to 34 or its stereoisomer, pharmaceutically acceptable salt, hydrate or solvate in the preparation of a KIF18A inhibitor.

37. The use according to claim 36, characterized in that The KIF18A inhibitor is a drug for treating related diseases mediated by KIF18A protein.

38. The use according to claim 37, characterized in that The disease is cancer.

39. The use according to claim 38, characterized in that The cancers are blood cancers and solid tumors.

40. The use according to claim 38, characterized in that The cancer is selected from the group consisting of endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, Burkett lymphoma, acute or chronic myeloid leukemia, myelodysplastic syndrome, promyelocytic leukemia, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratoma, osteosarcoma, pigmentoma, keratoma, follicular thyroid carcinoma, Kaposi's sarcoma.

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