Triazole compounds, their preparation methods and medicinal uses

Abstract

Disclosed are compounds of formula (I) that can be used as WRN inhibitors, methods for their preparation, pharmaceutical compositions containing these compounds, and pharmaceutical uses for treating WRN-mediated diseases or disorders. [Formula 1] TIFF2025540756000168.tif30161

Description

[Technical Field]

[0001] The present invention belongs to the pharmaceutical field and relates to triazole compounds, their preparation methods, pharmaceutical compositions containing these compounds and their medicinal uses. [Background technology]

[0002] Cells in any living organism possess various DNA repair mechanisms to maintain genome stability and integrity, which is essential for survival. DNA mismatch repair (MMR) is a highly conservative approach that plays a crucial role in maintaining genome stability by correcting errors that occur during DNA replication, recombination, and repair. (Pecina-Slaus, N., Kafka, A., Salamon, I., and Bukovac, A. Mismatch Repair Pathway, Genome Stability, and Cancer. Front Mol. Biosci. 7, 122 (2020)) Defects in the MMR mechanism lead to genome hypermutation and instability, manifesting as frequent insertions and deletions in short, repetitive DNA sequences (microsatellites) throughout the genome, a phenomenon known as microsatellite instability (MSI). (Kim, TM, Laird, PW and Park, PJ The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 155, 858-868 (2013); Vernole, P. et al. Common fragile sites in colon cancer cell lines: role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1. Mutat.Res [Mutation Research] 712, 40-48 (2011)). Microsatellites are generated by DNA polymerase slippage during replication or mismatch repair and are prone to rearrangements and frameshift mutations, which can be identified and corrected by the MMR process in normal cells. However, in cancer cells lacking normal MMR mechanisms, errors generated during replication or repair accumulate, leading to an increased mutation rate in the genome (Lower, SS, McGurk, MP, Clark, AG, et al., Satellite DNA evolution: old ideas, new approaches. Curr. Opin. Genet. Dev. [New insights in genetics and development], 2018;49:70-78). Frequent deletions and insertions in microsatellites cause MSI, which accounts for 10% to 30% of ovarian, colon, gastric, and endometrial cancer cases (Aaltonen, LA et al., "Clues to the pathogenesis of familial colorectal cancer," Science 260, 812-816 (1993); Bonneville R et al., "Landscape of Microsatellite Instability Across 39 Cancer Types," JCO Precis Oncol. 1:PO.17.00073 (2017)). Compared with MSI-high (MSI-H) cancers, patients with MSI-high (MSI-H) cancers have a better overall prognosis, lower metastatic potential, and higher tumor mutation burden and immunogenicity (Kang, S. et al. The significance of microsatellite instability in colorectal cancer after controlling for clinicopathological factors. Med. (Baltim.) [Medicine (Baltimore)] 97, e0019 (2018)), MSI-H tumors tend to be resistant to immunotherapy and chemotherapy (Le, DT et al. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High / Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164 [Phase II Open-Label Study of Pembrolizumab for the Treatment of Refractory, Microsatellite Instability-High / Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164]. J. Clin. Oncol. [Journal of Clinical Oncology] 38, 11-19 (2020), Overman, MJ et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicenter, phase 2 study [Use of nivolumab (CheckMate 142) in patients with metastatic DNA mismatch repair deficient or microsatellite instability-high colorectal cancer: an open-label, multicenter, phase 2 study]. Lancet Oncol. 18, 1182-1191 (2017), Fuca, G. et al. Ascites and resistance to immune checkpoint inhibition in dMMR / MSI-H metastatic colorectal and gastric cancers [Ascites and resistance to immune checkpoint inhibition in dMMR / MSI-H metastatic colorectal and gastric cancer]. J. Immunother. Cancer 10, 4001 (2022).

[0003] Recently, using multiple independent large-scale functional genomics screens of over 300 human cancer cell lines, we identified that the Werner syndrome RecQ helicase (WRN) is selectively required for the survival of MSI-H cells (Behan, FM et al., "Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens." Nature 568, 511-516 (2019); McDonald ER et al., "Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening." Cell 170(3):577-592 (2017); Chan, EM et al., "WRN helicase is a synthetic lethal target in microsatellite unstable"). WRN helicase is a synthetic lethal target in microsatellite-unstable cancers. Nature 568, 551-556 (2019).WRN, one of the five human RecQ-like helicases, is a multifunctional enzyme with helicase and exonuclease activities and plays important roles in various pathways of DNA repair and genome integrity maintenance, including DNA replication, transcription, DNA repair, and telomere maintenance (Bohr, V.A. Rising from the RecQ-age: the role of human RecQ helicases in genome maintenance. Trends Biochem Sci. 33, 609-620 (2008); Singh, D.K., Ahn, B., and Bohr, V.A. Roles of RECQ helicases in recombination-based DNA repair, genomic stability, and Rossi, ML, Ghosh, AK and Bohr, VA. Roles of Werner syndrome protein in protection of genome integrity. DNA Repair (Amst.) 9, 331-344 (2010).

[0004] Loss of WRN causes a variety of cellular and genomic defects, including cell cycle arrest, DNA fragmentation, mitotic catastrophe defects, chromosome fragmentation, and apoptosis in MSI but not MSS cell lines. (Behan, FM et al., Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 568, 511-516 (2019); McDonald ER et al., Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening. Cell 170(3):577-592 (2017); Chan, EM et al., WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 568, 551-556 (2019)). Furthermore, studies on loss-of-function mutations and deletions of WRN further pinpointed that the helicase function of WRN is essential for the survival of MSI cells (Lieb, S. et al., "Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells." Elife 8, e43333 (2019)). These results clearly demonstrate that targeting WRN (especially the helicase domain) may be a promising strategy for treating MSI-high cancers. Summary of the Invention

[0005] In one aspect, the present invention provides compounds of formula (I)-(XI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, including tautomers, cis or trans isomers, meso isomers, racemates, enantiomers, diastereomers, or mixtures thereof, [ka] or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Ring A and Ring B are each independently selected from an aryl group or a heteroaryl group; Y1 is CH, NH, N, O or S; Y2 is CH, NH, N, O or S; Y3 is CH, NH, N, O or S; X1 and X2 are each independently CH or N; M1, M2, M5, and M6 each independently represent CH, NH, N, O, or S; M3 and M4 are each independently -NR a , -CR a R b and R a and R b are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl, and hydroxyalkyl groups; Y2 is CH, NH, N, O or S; Y3 is CH, NH, N, O or S; [ka] is a single bond or a double bond, and the condition is as follows: [ka] is not a double bond at the same time, R1, R3 and R4 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl groups; The two R2s, together with the atoms to which they are connected, form a C3-C 10 Cycloalkyl group or C3-C 10 forming a heterocyclyl group, R5 and R6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl, and hydroxyalkyl groups; or R5 and R6 together with the atoms to which they are attached form a C3-C 10 Cycloalkyl groups, C3-C 10 Heterocyclyl groups, C6-C 14 C5-C containing aryl groups or 1 to 4 heteroatoms selected from the group consisting of O, S, and N 12 forming a heteroaryl group, R7 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl groups; Or two R7 together with the atoms to which they are connected form a C3-C 10 Cycloalkyl group or C3-C 10 forming a heterocyclyl group, L1 is a bond, O, a C1-C6 alkyl group, a C2-C6 alkenyl group, -C1-C6 alkyl group -NH-, -C2-C6 alkenyl group -NH-, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkyl group, -C3-C 10 Cycloalkyl group -CONH-, -C1-C6 alkyl group -C3-C 10 Cycloalkyl group -CONH, -C1-C6 haloalkyl group -NH-, -C3-C 10 -heterocyclo-NH-alkyl group, -C3-C 10 Cycloalkyl group -NH-, -C1-C6 alkyl group -C(NH)-NH, -C6-C 10the heteroaryl group -C1-C6 alkyl group, -S(O)2-NH-, and the -C1-C6 alkyl group, -S(O)2-NH-; L2 is a bond, O, -C(O), -CONH-, a C1-C6 alkyl group, a C2-C6 alkenyl group, -C1-C6 alkyl group-NH-, -C2-C6 alkenyl group-NH-, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C1-C6 haloalkyl group, and -CON(R c )- and R c is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl groups; Ring A is C6-C 14 C5-C containing aryl groups or 1 to 4 heteroatoms selected from the group consisting of O, S, and N 12 is a heteroaryl group, m is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; r is 0, 1, 2 or 3; s is 2 or 3; t is 0, 1, 2 or 3; w is 0, 1, 2 or 3, and n is 0, 1, 2 or 3.

[0006] In one embodiment, the compound has the formula (XII)-(XIII), (XIX)-(XXI) [ka] and R8 is C3-C 12 Fused cycloalkyl groups, C 2- C 10 and a fused heterocyclyl group, wherein the fused cycloalkyl group and the fused heterocyclyl group each optionally contain hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 Alkyl group, C 2-6Alkenyl group, C 2-6 Alkynyl group, C 1-6 substituted with one or more substituents selected from an alkoxy group and an oxo group; R9 is the bridge C3-C 10 Cycloalkyl group or bridged C3-C 10 and a heterocyclyl group, wherein the bridged cycloalkyl group and the bridged heterocyclyl group each optionally contain hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-5 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, oxo group, C 1-6 Haloalkyl group, C 3-5 substituted with one or more substituents selected from cycloalkyl groups; L6 is a bridge C3-C 10 Cycloalkyl group or bridged C2-C 10 and a heterocyclyl group, wherein the bridged cycloalkyl group and the bridged heterocyclyl group each optionally contain hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, oxo group, C 1-6 Haloalkyl group, C 3-5 substituted with one or more substituents selected from cycloalkyl groups; Y1, Y2, Y3, M1, M2, L2, X1, X2, R1, R3, R4, m, p, q, r, and t are as defined above.

[0007] In one embodiment, R1, R3, and R4 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C2-C6 alkenyl; In one preferred embodiment, R1, R3 and R4 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, C1-C3 alkyl, and -CF3.

[0008] In one embodiment, the compound has the formula (XXII) or (XXIII): [ka] each X is independently selected from F, Cl, Br, and I; Y1, Y2, Y3, M1, M2, L2, X1, X2, R1, R3, R7, m, n, p, r, t, and w are as defined above.

[0009] In one embodiment, two R2, together with the atoms to which they are connected, form a bridge C3-C 10 Cycloalkyl group or bridged C3-C 10 forming a heterocyclyl group, In one preferred embodiment, [ka] teeth, [ka] Represents.

[0010] In one embodiment, R5 and R6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl; or R5 and R6 together with the atom to which they are connected [ka] Form.

[0011] In one embodiment, R7 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl; Or two R7s together with the atoms to which they are connected form a bridge C3-C 10 Cycloalkyl group or bridged C3-C 10 Forming a heterocyclyl group, preferably [ka] teeth, [ka] Represents.

[0012] In one embodiment, R a and R b are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl; In one embodiment, L1 is a bond, O, a C1-C3 alkyl group, a C2-C3 alkenyl group, -C1-C3 alkyl group-NH-, -C2-C3 alkenyl group-NH-, a C2-C3 alkynyl group, a C1-C3 alkoxy group, a C1-C3 alkylthio group, a C1-C3 haloalkyl group, -C3-C6 cycloalkyl group-CONH-, -C1-C3 alkyl group-C3-C6 cycloalkyl group-CONH, -C1-C3 haloalkyl group-NH-, -C3-C6-heterocyclo-NH-alkyl group, -C3-C6 cycloalkyl group-NH-, -C1-C6 alkyl group-C(NH)-NH, -C6-C 10 the heteroaryl group -C1-C6 alkyl group, -S(O)2-NH-, and the -C1-C6 alkyl group, -S(O)2-NH-; In one embodiment, L2 is selected from the group consisting of a bond, O, -C(O), -CONH-, a C1-C6 alkyl group, a C2-C6 alkenyl group, -C1-C3 alkyl group -NH-, a -C2-C3 alkenyl group -NH-, a C2-C3 alkynyl group, a C1-C3 alkoxy group, a C1-C3 alkylthio group, a C1-C3 haloalkyl group, and -CON(R c )- and R c is selected from the group consisting of hydrogen, deuterium, halogen, amino group, cyano group, oxo group, hydroxy group, C1-C3 alkyl group, C1-C3 alkoxy group, C1-C3 haloalkyl group and C1-C3 hydroxyalkyl group; In one embodiment, ring A is [ka] is.

[0013] In one embodiment, Ring B is selected from the group consisting of a phenyl group, a pyridyl group, a pyrrolyl group, or a pyrimidinyl group.

[0014] In one embodiment, [ka] teeth, [ka] is.

[0015] In one embodiment, R8 is [ka] is selected from the group consisting of:

[0016] In one embodiment, R9 is [ka] and R10 is C 1-5 Alkyl group, C 3-5 It is a cycloalkyl group.

[0017] In one embodiment, L6 is [ka] or L6-L2 is [ka] is.

[0018] In one embodiment, in formula (XXII), X linked to the phenyl group is Cl and / or CH n X 3-n is CF3.

[0019] In one embodiment, in formula (XXIII), CH n X 3-n is CF3.

[0020] The present invention further provides pharmaceutical compositions, which comprise a therapeutically effective amount of a compound of any one of Formulae (I) to (X), or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0021] In another aspect, the present invention relates to a method of treating a WRN-mediated disease, the method comprising administering to a subject in need thereof an effective amount of any compound of Formula (I)-(X), or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising same.

[0022] In another aspect, the present invention relates to a method for treating cancer, the method comprising administering to a subject in need thereof an effective amount of any compound of Formula (I)-(X), or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising same.

[0023] In a preferred embodiment, the cancer is selected from the group consisting of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and is selected from colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer and ovarian cancer. DETAILED DESCRIPTION OF THE INVENTION

[0024] The following provides definitions of terms used in this application. Any term not defined herein will adopt the ordinary meaning as understood by one of ordinary skill in the art.

[0025] "Alkyl group" means C1-C 20It refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched-chain groups. Preferably, the alkyl group is an alkyl group having 1 to 12, sometimes preferably 1 to 6, sometimes more preferably 1 to 4 carbon atoms. Representative examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-methylbutyl group, a 3-methylbutyl group, an n-hexyl group, a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 2,3-dimethylbutyl group, an n-heptyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylhexyl group, a 2, Examples include, but are not limited to, 3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and branched chain isomers thereof. More preferably, the alkyl group is a lower alkyl group having 1 to 6 carbon atoms.Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the one or more substituents may be substituted at any available point of attachment, and preferably the one or more substituents are one or more substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfonic acid, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclyl, cycloalkylthio, heterocycloalkylthio, and oxo.

[0026] The term "alkenyl group" refers to an alkyl group having at least two carbon atoms and at least one carbon-carbon double bond as defined above, such as a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-, 2- or 3-butenyl group, etc., and preferably C 2-20 alkenyl group, more preferably C 2-12 alkenyl groups, most preferably C 2-6It is an alkenyl group. The alkenyl group may be substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3 groups, and these groups are independently selected from the group consisting of alkyl groups, halogens, alkoxy groups, alkenyl groups, alkynyl groups, alkylsulfonic acid groups, alkylamino groups, thiol, hydroxy groups, nitro groups, cyano groups, amino groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclyl groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0027] The term "alkynyl group" refers to an alkyl group having at least two carbon atoms and at least one carbon-carbon triple bond as defined above, such as an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-, 2- or 3-butynyl group, and preferably C 2-20 Alkynyl groups, more preferably C 2-12 Alkynyl groups, most preferably C 2-6 It is an alkynyl group. The alkynyl group may be substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3 groups, and the groups are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0028] An "alkylene group" is a saturated, straight- or branched-chain aliphatic hydrocarbon group having two residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. Straight- or branched-chain groups containing 1 to 20 carbon atoms preferably contain 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH-), 1,1-ethylene (-CH(CH)-), 1,2-ethylene (-CHCH-), 1,1-propylene (-CH(CHCH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCH-), 1,4-butylene (-CHCHCHCHCH-), and the like. Alkylene groups can be substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, in some cases preferably 1 to 5, and in some cases more preferably 1 to 3 groups, which are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0029] An "alkenylene group" is an alkylene group having at least two carbon atoms and at least one carbon-carbon double bond as defined above, and preferably C 2-20 alkenylene group, more preferably C 2-12 alkenylene group, most preferably C 2-6It is an alkenylene group. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, and the like. The alkenylene group may be substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3 groups, and the groups are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0030] An "alkynylene group" is an alkynyl group having at least two carbon atoms and at least one carbon-carbon triple bond as defined above, preferably C 2-20 Alkynylene group, more preferably C 2-12 Alkynylene groups, most preferably C 2-6 It is an alkynylene group. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, and the like. The alkenylene group may be substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3 groups, and the groups are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0031] A "cycloalkyl group" is a saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms or 3 to 6 carbon atoms. Representative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl groups include cycloalkyl groups having spiro rings, fused rings, or bridged rings.

[0032] A "spirocycloalkyl group" is a 5- to 20-membered polycyclic group in which the rings are connected by one common carbon atom (called a spiro atom), and one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Preferably, the spirocycloalkyl group has 6 to 14 members, and more preferably 7 to 10 members. Depending on the number of common spiro atoms, the spirocycloalkyl group is divided into a monospirocycloalkyl group, a bisspirocycloalkyl group, or a polyspirocycloalkyl group, and is preferably a monospirocycloalkyl group or a bisspirocycloalkyl group, and more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl group. Representative examples of spirocycloalkyl groups include: [ka] The substituents include, but are not limited to:

[0033] A "fused cycloalkyl group" is a 5- to 20-membered polycyclic hydrocarbon group, in which each ring in the system shares an adjacent pair of carbon atoms with another ring, and in which one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Preferably, the fused cycloalkyl group has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of ring members, the fused cycloalkyl group is divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl groups, and is preferably a bicyclic or tricyclic fused cycloalkyl group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyl group. Representative examples of fused cycloalkyl groups are: [ka] The substituents include, but are not limited to:

[0034] A "bridged cycloalkyl group" is a 5- to 20-membered polycyclic hydrocarbon group in which every two rings in the system share two unlinked carbon atoms. These rings may have one or more double bonds, but do not have a completely conjugated π-electron system. Preferably, the bridged cycloalkyl group has 6 to 14 members, and more preferably 7 to 10 members. Depending on the number of ring members, the bridged cycloalkyl group is divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, and is preferably a bicyclic, tricyclic, or tetracyclic bridged cycloalkyl group, more preferably a bicyclic or tricyclic bridged cycloalkyl group. Representative examples of bridged cycloalkyl groups include, but are not limited to, the following substituents: [ka]

[0035] A cycloalkyl group may be fused to the ring of an aryl group, a heteroaryl group, or a heterocycloalkyl group, where the ring connected to the parent structure is a cycloalkyl group. Representative examples include, but are not limited to, indanylacetic acid, tetrahydronaphthalene, benzocycloheptyl, and the like. A cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3, and these substituents are independently selected from the group consisting of alkyl groups, halogens, alkoxy groups, alkenyl groups, alkynyl groups, alkylsulfonic acid groups, alkylamino groups, thiol, hydroxy groups, nitro groups, cyano groups, amino groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclyl groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0036] A "heterocyclyl group" is a 3- to 20-membered saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group, which may be one or more, optionally preferably 1 to 5, and optionally more preferably N, O, and S(O). m (where m is 0, 1, or 2), the ring atoms are 1 to 3 heteroatoms selected from the group consisting of -OO-, -OS-, or -SS-, but the ring does not contain -OO-, -OS-, or -SS-, and the remaining ring atoms are C. Preferably, the heterocyclyl group is a 3- to 12-membered heterocyclyl group having 1 to 4 heteroatoms, more preferably a 3- to 10-membered heterocyclyl group having 1 to 3 heteroatoms, more preferably a 4- to 8-membered heterocyclyl group having 1 to 3 heteroatoms, and most preferably a 5- to 6-membered heterocyclyl group having 1 to 2 heteroatoms. Representative examples of monocyclic heterocyclyl groups include, but are not limited to, oxetanyl, azabutyl, pyrrolidinyl, piperidine, piperazinyl, morpholinyl, sulfonate-morpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include heterocyclyl groups having spirocyclic, fused or bridged rings.

[0037] A "spiroheterocyclyl group" is a 5- to 20-membered polycyclic heterocyclyl group, in which the rings are joined by one common carbon atom (called a spiroatom), and wherein the rings may be one or more, optionally preferably 1 to 5, and optionally more preferably N, O, and S(O). m (where m is 0, 1, or 2), and the remaining ring atoms are C, where one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, the spiroheterocyclyl group has 6 to 14 members, and more preferably 7 to 10 members. Depending on the number of common spiro atoms, the spiroheterocyclyl group is divided into a monospiroheterocyclyl group, a bisspiroheterocyclyl group, or a polyspiroheterocyclyl group, and is preferably a monospiroheterocyclyl group or a bisspiroheterocyclyl group, and more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl group. Representative examples of spiroheterocyclyl groups include: [ka] The substituents include, but are not limited to:

[0038] A "fused heterocyclyl group" is a 5- to 20-membered polycyclic heterocyclyl group, in which each ring in the system shares an adjacent pair of carbon atoms with another ring, in which one or more rings may contain one or more double bonds, but in which no ring has a completely conjugated pi-electron system, and in which the rings are not fused to N, O, and S(O) p(wherein p is 0, 1 or 2), optionally preferably 1 to 5, optionally more preferably 1 to 3 heteroatoms as ring atoms, and the remaining ring atoms are C. Preferably, the fused heterocyclyl group has 6 to 14 ring members, and more preferably 7 to 10 ring members. Depending on the number of ring members, the fused heterocyclyl group is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl groups, preferably bicyclic or tricyclic fused heterocyclyl groups, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl groups. Representative examples of fused heterocyclyl groups are: [ka] The substituents include, but are not limited to:

[0039] A "bridged heterocyclyl group" is a 5- to 14-membered polycyclic heterocycloalkyl group, in which every two rings in the system share two non-linking atoms, the rings may have one or more double bonds but do not have a completely conjugated pi-electron system, and the rings are not heterocyclic, and ... m (where m is 0, 1 or 2), and the remaining atoms are C. Preferably, the bridged heterocyclyl group has 6 to 14 ring members, and more preferably 7 to 10 ring members. Depending on the number of ring members, the bridged heterocyclyl group is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, and is preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclyl group, and more preferably a bicyclic or tricyclic bridged heterocyclyl group. Representative examples of bridged heterocyclyl groups include: [ka] The substituents include, but are not limited to:

[0040] The ring of the heterocyclyl group may be fused to the ring of an aryl group, heteroaryl group, or cycloalkyl group, where the ring attached to the parent structure is the heterocyclyl group. Representative examples are: [ka] The substituents include, but are not limited to, the following:

[0041] The heterocyclyl group is optionally substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, optionally preferably 1 to 5, optionally more preferably 1 to 3 groups, independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0042] An "aryl group" is a 6- to 14-membered all-carbon monocyclic or polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group and has a completely conjugated π-electron system. Preferably, the aryl group is 6- to 10-membered, such as phenyl and naphthyl groups, and most preferably, phenyl. An aryl group may be fused to a ring of a heteroaryl group, heterocyclyl group, or cycloalkyl group, where the ring attached to the parent structure is an aryl group. Representative examples are: [ka] The substituents include, but are not limited to:

[0043] The aryl group may be substituted or unsubstituted. When substituted, the one or more substituents are preferably one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3, and the substituents are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0044] A "heteroaryl group" is an aryl system having 1 to 4 heteroatoms selected from the group consisting of O, S, and N as ring atoms, and having 5 to 14 ring atoms. Preferably, the heteroaryl group is 5 to 10-membered, more preferably 5 or 6-membered, such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. Heteroaryl groups may be fused with a ring of an aryl, heterocyclyl, or cycloalkyl group, where the ring attached to the parent structure is the heteroaryl group. Representative examples are: [ka] The substituents include, but are not limited to:

[0045] The heteroaryl group may be substituted or unsubstituted. When substituted, the number of substituents is preferably one or more, and in some cases preferably 1 to 5, and in some cases more preferably 1 to 3, and these substituents are independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and -NR 9 R 10 is selected from the group consisting of:

[0046] The term "alkoxy group" refers to an -O-(alkylyl) or -O-(unsubstituted cycloalkylyl) group, where the alkyl group is as defined above. Representative examples include, but are not limited to, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, and the like. The alkoxy group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, and in some cases preferably 1 to 5, and in some cases more preferably 1 to 3, and the substituents are independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylsulfonic acid groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0047] A "bond" is a covalent bond and is represented by the symbol "-".

[0048] A "hydroxyalkyl group" is an alkyl group substituted with a hydroxy group, where alkyl is as defined above.

[0049] A "hydroxy group" is an -OH group.

[0050] A "halogen" is a fluorine, chlorine, bromine or iodine atom.

[0051] An "amino group" is an -NH2 group.

[0052] A "cyano group" is a -CN group.

[0053] A "nitro group" is a -NO2 group.

[0054] An "oxo group" is a =O group.

[0055] A "carboxyl group" is a -C(O)OH group.

[0056] An "alkoxycarbonyl group" is a -C(O)O(alkylyl) or -C(O)O(cycloalkylyl) group, where the alkyl and cycloalkyl groups are as defined above.

[0057] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the statement includes both cases where the event or circumstance may occur and cases where it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but does not necessarily, be present, and the statement includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0058] "Substitution" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced with the corresponding number of substituents. Needless to say, substituents exist only at their possible chemical positions. Those skilled in the art can determine whether substitution is possible without excessive effort by experiment or theory. For example, the combination of an amino group or hydroxy group having free hydrogen with a carbon atom having an unsaturated bond (e.g., an olefin) may be unstable.

[0059] A "pharmaceutical composition" is a mixture of one or more compounds according to the present invention or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism and favor absorption of the active ingredient, thereby exerting its biological activity.

[0060] A "pharmaceutically acceptable salt" is a salt of a compound of the present invention, which salt is safe and effective when used in mammals and possesses the relevant biological activity.

[0061] Dosage Form: For a subject of about 50 to 70 kg, the pharmaceutical composition or combination of the present invention may be in a unit dose of, for example, about 1 to 1000 mg of one or more active ingredients.

[0062] In some embodiments, the amount of the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 0.1% to 95% by weight of the free base, preferably about 5% to 70%, e.g., 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%.

[0063] In some embodiments, the pharmaceutical composition is prepared in tablet, capsule, liquid or injectable form.

[0064] In some embodiments, the amount of the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is about 1 to 1000 mg, which is 0.1% to 95% by weight of the free base, preferably about 1 to 500 mg, and more preferably about 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg.

[0065] In some embodiments, the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture, or a pharmaceutically acceptable salt thereof, can be administered by any suitable route of administration, for example, oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal, or transdermal, and the pharmaceutical composition is adjusted accordingly.

[0066] In some embodiments, the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture, or a pharmaceutically acceptable salt, is prepared in solid or liquid form, for example, a syrup, suspension, emulsion, tablet, capsule, powder, granule, or lozenge.

[0067] In compounds of the above formula, atoms can exhibit their natural isotopic abundance, or one or more atoms can be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. As described and claimed herein, the present disclosure is intended to include all suitable isotopic variations of compounds of the above formula and examples thereof. For example, different isotopic forms of hydrogen (H) include protium (H) and deuterium (H, also designated herein as D). Protium is the predominant hydrogen isotope found in nature. Deuterium enrichment can provide several therapeutic advantages, such as increased in vivo half-life or reduced dose requirements, or provide compounds that can be used as standards for characterization of biological samples. Isotopically enriched compounds can be prepared without undue experimentation using appropriate isotopically enriched reagents and / or intermediates by conventional techniques well known to those of skill in the art or by the methods described in the schemes and examples herein. example Synthesis procedure Synthesis of intermediates

[0068] Synthesis of ethyl 2-bromo-3-oxopentanoate 1nt 1 [ka] To a solution of ethyl 3-oxopentanoate (15 g, 104 mmol) in dichloromethane (150 mL) was added NBS (19.4 g, 109.2 mmol), and TsOH.HO (3.96 g, 20.8 mmol). The reaction mixture was stirred at room temperature for 2.5 h. The mixture was filtered, and the filter cake was washed with dichloromethane. The combined filtrate and washings were washed with water. The aqueous layer was back-extracted with dichloromethane. The combined organic layers were dried over NaSO, filtered, and concentrated to give the title compound. LCMS: m / z=221.1 / 223.1 [M+H] +

[0069] Synthesis of tert-butyl 6-(1-ethoxy-1,3-dioxolan-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate Int 2 [ka] Ethyl 2-bromo-3-oxopentanoate (1.1 g, 4.93 mmol), tert-butyl 2,6-diazaspiro[3,3]heptane-2-carboxylate (977.5 mg, 27.1 mmol), and K2CO3 (4.1 g, 29.6 mmol) were mixed in acetonitrile (20 mL). The suspension was stirred at room temperature for 30 min. The reaction mixture was filtered. The combined filtrate and washings were concentrated under reduced pressure. The residue was purified by column chromatography (0-10% MeOH in dichloromethane) to provide the title compound. LCMS(ESI): m / z=341.2[M+H] +

[0070] Synthesis of 2-chloro-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide Int 3 [ka] To a solution of 2-methyl-4-(trifluoromethyl)aniline (6 g, 34.3 mmol) in dichloromethane (50 mL) at 0 °C was added 2-chloroacetyl chloride (2.87 mL, 36 mmol) and triethylamine (9.1 mL, 65 mmol). The reaction was stirred for 30 min and then allowed to warm to room temperature and further stirred for 1.5 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over Na SO , filtered, and concentrated. The residue was suspended in a small amount of dichloromethane and filtered. The filter cake was washed with dichloromethane and Et O and dried under vacuum overnight to provide the title compound with acceptable purity. The combined filtrate and washings were concentrated, and the residue was purified by column chromatography (50% to 100% EtOAc in heptane) to provide the title compound, which was combined with the filter cake. LCMS: m / z=250.1 / 252.1 [M−H]-

[0071] Synthesis of 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide Int 4 [ka] To a solution of 2-chloro-4-(trifluoromethyl)aniline (5 g, 25.6 mmol) in dichloromethane (50 mL) at 0 °C was added 2-chloroacetyl chloride (2.14 mL, 26.9 mmol) and triethylamine (7.1 mL, 51 mmol). The reaction was stirred for 30 min and then allowed to warm to room temperature and further stirred for 1.5 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over Na SO , filtered, and concentrated. The residue was suspended in a small amount of dichloromethane and filtered. The filter cake was washed with dichloromethane and Et O and dried under vacuum overnight to provide the title compound with acceptable purity. The combined filtrate and washings were concentrated, and the residue was purified by column chromatography (50% to 100% EtOAc in heptane) to provide the title compound, which was combined with the filter cake.

[0072] Synthesis of 4-chloro-5-methoxy-6-methylpyrimidine Int 5 [ka] A mixture of 4,6-dichloro-5-methoxypyrimidine (25 g, 140 mmol), methylboronic acid (8.8 g, 147 mmol), KPO (74 g, 350 mmol), and Pd(dppf)Cl.DCM (6.86 g, 8.4 mmol) in DME (100 mL) was stirred at 85 °C for 18 h. The reaction mixture was filtered through a Celite plug, and the filtrate was concentrated. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO. The organic layer was dried over NaSO and concentrated. The residue was purified by column chromatography (0 to 5% EtOAc in heptane) to provide the title compound. 1H NMR(400 MHz,DMSO-d6)δ8.66(s,1H),3.86(s,3H),2.50(s,3H)

[0073] Synthesis of methyl 5-methoxy-6-methylpyrimidine-4-carboxylate Int 6 [ka] To a solution of 4-chloro-5-methoxy-6-methylpyrimidine (14 g, 88.2 mmol) in MeOH (70 mL) was added Pd(dppf)Cl.DCM (4.32 g, 5.3 mmol) and triethylamine (24.5 mL, 177 mmol). The resulting mixture was stirred at 60 °C under CO (0.4 MPa) for 16 h and allowed to cool to room temperature. The reaction mixture was filtered, and the collected filtrate was concentrated. The residue was dissolved in EtOAc and washed with water. The aqueous layer was back-extracted with EtOAc. The combined organic layers were concentrated, and the residue was purified by column chromatography (10% EtOAc in heptane, isocratic) to provide the title compound. 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H), 3.93(s,3H), 3.84(s,3H), 1.17(s,3H).

[0074] Synthesis of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid Int 7 [ka] Methyl 5-methoxy-6-methylpyridine-4-carboxylate (5.5 g, 29 mmol) was dissolved in HBr (40% in water) (23.5 mL, 174 mmol). The resulting mixture was stirred at 40° C. for 10 h. HI (23 mL, 174 mmol) was then added, and the mixture was further stirred for 6 h, and the pH was adjusted to 3 with 50% NaOH solution at 0° C. The yellow solid was filtered off and then resuspended in water (40 mL) and HCl (37% in water) (11 mL, 134 mmol). The resulting suspension was stirred at 60° C. for 2 h and filtered. The solid was collected and dried under vacuum to provide the title compound. 1 H NMR (400MHz, DMSO-d6) δ 11.71 (s, 2H), 8.66 (s, 1H), 2.47 (s, 3H).

[0075] Synthesis of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate Int 8 Step 1. tert-Butyl 4-(1-ethoxy-1,3-dioxolan-2-yl)piperazine-1-carboxylate [ka] Ethyl 2-bromo-3-oxopentanoate (2 g, 8.96 mmol), tert-butyl piperazine-1-carboxylate (977.5 mg, 27.1 mmol), and K2CO3 (9.18 g, 49.3 mmol) were mixed in acetonitrile (40 mL). The suspension was stirred at room temperature for 30 min. The reaction mixture was filtered. The combined filtrate and washings were concentrated under reduced pressure. The residue was purified by column chromatography (0-10% MeOH in dichloromethane) to provide the title compound.

[0076] Step 2. tert-Butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(1-ethoxy-1,3-dioxolan-2-yl)piperazine-1-carboxylate (765.2 mg, 2.33 mmol) in EtOH (4 mL) were added 3-bromo-1H-1,2,4-triazol-5-amine (400 mg, 2.33 mmol) and H₃PO₄ (282 mg, 2.95 mmol). The resulting mixture was stirred at 85°C for 24 h and allowed to cool to room temperature. DIPEA (1.22 mL, 7 mmol) and Boc₂O (255 mg, 1.17 mmol) were added, and the mixture was further stirred at room temperature for 2 h before being quenched with a small amount of water. EtOH was removed under reduced pressure, and the residue was dissolved in EtOAc and washed with water, brine, dried (Na₂SO₄), and concentrated. The residue was purified by column chromatography (0 to 75% EtOAc in heptane) to provide the title compound.

[0077] Step 3. tert-Butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] To a mixture of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (125 mg, 0.29 mmol) and 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (86.8 mg, 0.32 mmol) in 1,4-dioxane (4 mL) was added KI (48.1 mg, 0.29 mmol) and DIPEA (152 μL, 0.87 mmol). The resulting mixture was stirred at 80° C. for 3.5 h and allowed to cool to room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (NaSO), filtered, and concentrated. The residue was purified by column chromatography (0 to 50% EtOAc in heptane) to provide the title compound.

[0078] Synthesis of tert-butyl 4-(2-bromo-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate Int 9. [ka] Following the same synthetic route as Int 8, Int 9 can be prepared using 2-chloro-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide Int 3 as a synthetic intermediate.

[0079] Synthesis of tert-butyl 3-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 10. [ka] Step 1. Methyl 2-chloro-3-oxopentanoate [ka] To a solution of methyl 3-oxopentanoate (10 g, 76.84 mmol) in DCM (100 mL) was added SO2Cl2 (13.48 g, 99.89 mmol) over 10 min at 0 °C. The reaction was allowed to warm to room temperature and stirred for 16 h. The RM was concentrated under reduced pressure, and the residue was dissolved in DCM (100 mL) and washed with water (100 mL), brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (12 g, 94% yield) as a pale yellow liquid. Calculated mass for C6H9ClO3: 164.0; found: 163.0 (MH)-ESI. 1H NMR (400MHz, DMSO-d6) δ: 5.62 (s, 1H), 3.76 (s, 3H), 2.50-2.48 (m, 2H), 0.99 (t, J = 7.2Hz, 3H).

[0080] Step 2. tert-Butyl 3-(1-methoxy-1,3-dioxolan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [ka] To a solution of methyl 2-chloro-3-oxopentanoate (5.04 g, 30.62 mmol) in anhydrous ACN (25 ml) was added TEA (7.15 g, 70.66 mmol) over 15 min, followed by dropwise addition of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 23.55 mmol) in ACN over 30 min. The reaction was stirred at 60 °C for 16 h. The RM was filtered and washed with EA. The filtrate was concentrated under reduced pressure, and the residue was dissolved in EA and washed with water, dried over Na SO , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent heptane:EA 100:0 to 90:10) to give the title compound (4 g, 50% yield). Calculated mass of C17H28N2O5: 340.2, actual value: 339.1(MH)-ESI. 1H NMR(400MHz,DMSO-d6)δ:4.36(s,1H),3.61(s,3H),3.21-3.11(m,1H),2.99-2.92(m,1H),2.75 -2.60(m,4H),2.37-2.26(m,2H),1.88-1.75(m,4H),1.41-1.38(s,9H),0.96(t,J=7.3Hz,3H).

[0081] Step 3. tert-Butyl 3-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] 3-Bromo-1H-1,2,4-triazol-5-amine (843 mg, 5.17 mmol) and tert-butyl (1R,5S)-3-(1-methoxy-1,3-dioxolan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.6 g, 4.70 mmol) were mixed in EtOH (3 mL). H3PO4 (461 mg, 4.70 mmol) was added. The mixture was stirred at 80 °C under a nitrogen atmosphere for 12 hours. The mixture was concentrated in vacuo to remove EtOH and quenched by adding saturated aqueous NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica column, eluent DCM:MeOH 1:0 to 50:1) to give the title compound (300 mg, 14% yield) as a yellow solid. Calculated mass for C18H25BrN6O3: 452.1 454.1, found: 451.1 453.1 (M−H)-ESI. 1H NMR(400 MHz,DMSO-d6)δ:13.25(s,1H),4.16-4.02(m,2H),3.56-3.50(d,J=9.8Hz,2H),2.81-2.71( m,2H),2.46-2.38(d,J=9.8Hz,2H),1.93-1.80(m,4H),1.44(s,9H),1.21(t,J=7.6Hz,3H).

[0082] Step 4. tert-Butyl 3-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [ka] To a stirred solution of tert-butyl 3-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.31 mmol) and 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (84 mg, 0.31 mmol) in 1,4-dioxane (2 mL) at room temperature was added DIPEA (120 mg, 0.93 mmol), and the RM was stirred at 80 °C for 72 h. The RM was concentrated under reduced pressure. The crude product was diluted with EtOAc and water, extracted once with EtOAc, and the organic layer was washed with brine, dried over Na SO , and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent heptane: EtOAc 70:30 to 30:70) to give the title compound (130 mg, 61% yield) as a white solid. Calculated mass for C27H30BrClF3N7O4 687.1 689.1, found: 686.1 688.1 (M−H)-ESI. 1H NMR(400MHz,DMSO-d6)δ:10.34(s,1H),8.11-8.06(d,J=8.6Hz,1H),7.99-7.96(d,J=1.7Hz,1H),7.74-7.70(dd,J=8.7,1.7Hz,1H),5.29( s,2H),4.15-4.07(m,2H),3.61-3.57(m,2H),3.02-2.92(m,2H),2.49-2.43(m,2H),1.92-1.84(m,4H),1.45(s,9H),1.20(t,J=7.4Hz,3H).

[0083] Synthesis of tert-butyl 3-(2-bromo-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 11. [ka] Following the same synthetic route as Int 10, Int 11 can be prepared using 2-chloro-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide Int 3 as a synthetic intermediate.

[0084] Synthesis of tert-butyl 3-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 12. [ka] tert-Butyl 3-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (186 mg, 0.27 mol) was suspended in 1,4-dioxane (0.5 mL). 2-(3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (113 mg, 0.54 mmol) and 0.6 M aqueous NaCO (0.25 mL) were added, and the RM was degassed with argon gas for 10 minutes. PdCI(PPh) (19 mg, 0.03 mmol) was added, and the RM was stirred at 90 °C for 12 hours. The RM was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel column: 12 g silica, eluent DCM:MeOH 100:0 to 97:3) to give the crude title compound (72 mg). Calculated mass for C32H37ClF3N7O5: 691.2, found: 690.1 (MH) -ESI.

[0085] Synthesis of tert-butyl 3-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 13. [ka] Following the same method as for Int 12, Int 13 can be prepared by Suzuki coupling of Int 11 with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0086] Synthesis of tert-butyl 3-(5-ethyl-2-(5-fluoro-3,6-dihydro-2H-pyran-4-yl)-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 14. [ka] Following the same method as for Int 13, Int 14 can be prepared by Suzuki coupling of Int 11 with 2-(5-fluoro-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0087] Synthesis of tert-butyl 3-(5-ethyl-2-(4-fluoro-5,6-dihydro-2H-pyran-3-yl)-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 15. [ka] Following the same method as for Int 13, Int 15 can be prepared by Suzuki coupling of Int 11 with 2-(4-fluoro-5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0088] Synthesis of tert-butyl 3-(2-(3,6-dihydro-2H-thiopyran-4-yl)-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 16. [ka] Following the same method as for Int 13, Int 16 can be prepared by Suzuki coupling of Int 11 with 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0089] Synthesis of tert-butyl 3-(5-ethyl-2-(6-methyl-3,6-dihydro-2H-pyran-4-yl)-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 17. [ka] Following the same method as for Int 13, Int 17 can be prepared by Suzuki coupling of Int 11 with 4,4,5,5-tetramethyl-2-(6-methyl-3,6-dihydro-2H-pyran-4-yl)-1,3,2-dioxaborolane.

[0090] Synthesis of tert-butyl 3-(5-ethyl-2-(2-methyl-3,6-dihydro-2H-pyran-4-yl)-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 18. [ka] Following the same method as for Int 13, Int 18 can be prepared by Suzuki coupling of Int 11 with 4,4,5,5-tetramethyl-2-(2-methyl-3,6-dihydro-2H-pyran-4-yl)-1,3,2-dioxaborolane.

[0091] Synthesis of tert-butyl 3-(5-ethyl-2-(4-methoxycyclopent-1-en-1-yl)-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Int 19. [ka] Following the same method as for Int 13, Int 19 can be prepared by Suzuki coupling of Int 11 with 2-(4-methoxycyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0092] Synthesis of tert-butyl 3-(5-ethyl-2-(4-hydroxy-4-methylcyclopent-1-en-1-yl)-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Int 20. [ka] Following the same method as for Int 13, Int 20 can be prepared by Suzuki coupling of Int 11 with 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-en-1-ol.

[0093] Synthesis of tert-butyl 3-(5-ethyl-2-(3-methoxybicyclo[3.1.0]hexan-6-yl)-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Int 21. [ka] Following the same method as for Int 13, Int 21 can be prepared by Suzuki coupling of Int 11 with 2-(3-methoxybicyclo[3.1.0]hexan-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0094] Synthesis of tert-butyl 3-(5-ethyl-2-(3-(methoxycarbonyl)bicyclo[3.1.0]hexan-6-yl)-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Int 22. [ka] Following the same method as for Int 13, Int 22 can be prepared by Suzuki coupling of Int 11 with methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[3.1.0]hexane-3-carboxylate.

[0095] Synthesis of tert-butyl 3-(2-(3-((tert-butyldimethylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Int 23. [ka] Following the same method as for Int 13, Int 23 can be prepared by Suzuki coupling of Int 11 with tert-butyldimethyl((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[3.1.0]hexan-3-yl)oxy)silane.

[0096] Synthesis of tert-butyl 3-(2-(3-oxabicyclo[4.1.0]heptan-7-yl)-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 24. [ka] Following the same method as for Int 13, Int 24 can be prepared by Suzuki coupling of Int 11 with 2-(3-oxabicyclo[4.1.0]heptan-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0097] Synthesis of tert-butyl 3-(5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-2-(5-oxaspiro[2.4]heptan-1-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Int 25. [ka] Following the same method as for Int 13, Int 25 can be prepared by Suzuki coupling of Int 11 with 4,4,5,5-tetramethyl-2-(5-oxaspiro[2.4]heptan-1-yl)-1,3,2-dioxaborolane.

[0098] Synthesis of tert-butyl 3-(5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-2-(6-oxaspiro[2.5]octan-1-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 26. [ka] Following the same method as for Int 13, Int 26 can be prepared by Suzuki coupling of Int 11 with 4,4,5,5-tetramethyl-2-(6-oxaspiro[2.5]octan-1-yl)-1,3,2-dioxaborolane.

[0099] Synthesis of tert-butyl 3-(5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-2-(5-oxaspiro[2.5]octan-1-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 27. [ka] Following the same method as for Int 13, Int 27 can be prepared by Suzuki coupling of Int 11 with 4,4,5,5-tetramethyl-2-(5-oxaspiro[2.5]octan-1-yl)-1,3,2-dioxaborolane.

[0100] Synthesis of tert-butyl 3-(2-(cyclobut-1-en-1-yl)-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 28. [ka] Following the same method as for Int 13, Int 28 can be prepared by Suzuki coupling of Int 11 with 2-(cyclobut-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0101] Synthesis of tert-butyl 3-(2-(3,3-difluorocyclobut-1-en-1-yl)-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 29. [ka] Following the same method as for Int 13, Int 29 can be prepared by Suzuki coupling of Int 11 with 2-(3,3-difluorocyclobut-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0102] Synthesis of tert-butyl 3-(2-(3-(benzyloxy)cyclobut-1-en-1-yl)-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 30. [ka] Following the same method as for Int 13, Int 30 can be prepared by Suzuki coupling of Int 11 with 2-(3-(benzyloxy)cyclobut-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0103] Synthesis of tert-butyl 3-(5-ethyl-2-(3-(methoxycarbonyl)cyclobut-1-en-1-yl)-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Int 31. [ka] Following the same method as for Int 13, Int 31 can be prepared by Suzuki coupling of Int 11 with methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclobut-2-ene-1-carboxylate.

[0104] Synthesis of 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine Int 32. [ka] Step 1: 4-Bromo-1,2,3,6-tetrahydropyridine. tert-Butyl 4-bromo-3,6-dihydropyridine-1(2H)-carboxylate (4 g, 15.26 mmol) was suspended in hydrogen chloride (30 mL) in dioxane, and the mixture was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and used without purification. Calculated mass for CHBrN: 160.98, 162.98; found: 162.2, 164.2 (M+H). + ESI.

[0105] Step 2: 4-Bromo-1-(2,2-difluoroethyl)-1,2,3,6-tetrahydropyridine. 4-Bromo-1,2,3,6-tetrahydropyridine (1 g, 6.17 mmol) was suspended in MeCN (20 mL), 2,2-difluoroethyl trifluoromethanesulfonate (21.72 g, 8.02 mmol) and potassium carbonate (2.56 g, 18.52 mmol) were added, and the mixture was stirred at 80 °C under a N atmosphere for 16 h. The mixture was diluted with EA and water, extracted with EA, and the organic layer was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography to give the product (958 mg, 68.66% yield). CH 10 Calculated mass of BrF2N: 225.00, 226.99; Measured mass: 226.1, 228.2 (M+H) + ESI.

[0106] Step 3: 1-(2,2-Difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine. 4-Bromo-1-(2,2-difluoroethyl)-1,2,3,6-tetrahydropyridine (958 mg, 4.24 mmol) was suspended in 1,4-dioxane (20 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.18 g, 4.66 mmol) and potassium acetate (1.25 g, 12.71 mmol) were added, and the mixture was degassed with argon gas for 10 minutes. PdCl(dppf) (343.51 mg, 0.42 mmol) was added, and the mixture was stirred at 90 °C overnight. The mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography to give the product (1.05 g, 90.72% yield). 13 H 22 Calculated mass of BF2NO2: 273.17, Measured mass: 274.3 (M+H) + ESI.

[0107] Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridine Int 33. [ka] Int 33 was synthesized according to the reported procedure (WO2018067512) with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate.

[0108] Synthesis of 5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridine Int 34. [ka] Following the same method as Int 33, Int 34 was prepared with tert-butyl 5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate.

[0109] Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[4.1.0]heptane Int 35. [ka] Following the same method as for Int 33, Int 35 can be prepared with tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate.

[0110] Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)bicyclo[3.1.0]hexan-3-amine Int 36. [ka] Following the same method as for Int 33, Int 36 can be prepared with tert-butyl (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[3.1.0]hexan-3-yl)aminocarboxylate.

[0111] Synthesis of 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(2,2,2-trifluoroethyl)-6-azaspiro[2.5]octane Int 37. [ka] Following the same method as for Int 33, Int 37 can be prepared with tert-butyl 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-azaspiro[2.5]octane-6-carboxylate.

[0112] Synthesis of 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2,2,2-trifluoroethyl)-5-azaspiro[2.4]heptane Int 38. [ka] Following the same method as for Int 33, Int 38 can be prepared with tert-butyl 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-azaspiro[2.4]heptane-5-carboxylate.

[0113] Synthesis of 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2,2,2-trifluoroethyl)-5-azaspiro[2.3]hexane Int 39. [ka] Following the same method as for Int 33, Int 39 can be prepared with tert-butyl 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-azaspiro[2.3]hexane-5-carboxylate.

[0114] Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)cyclobut-2-en-1-amine Int 40. [ka] Following the same method as for Int 33, Int 40 can be prepared with tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclobut-2-en-1-yl)aminocarboxylate.

[0115] Manufacturing example 1A Synthesis of compound 86 [ka] Step 1. tert-Butyl 6-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-(1-ethoxy-1,3-dioxolan-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (793.2 mg, 2.33 mmol) in EtOH (4 mL) was added 3-bromo-1H-1,2,4-triazol-5-amine (400 mg, 2.33 mmol) and H₃PO₄ (282 mg, 2.95 mmol). The resulting mixture was stirred at 85 °C for 24 h and allowed to cool to room temperature. DIPEA (1.22 mL, 7 mmol) and Boc₂O (255 mg, 1.17 mmol) were added, and the mixture was stirred at room temperature for an additional 2 h before being quenched with a small amount of water. EtOH was removed under reduced pressure, and the residue was dissolved in EtOAc and washed with water, brine, dried (Na₂SO₄), and concentrated. The residue was purified by column chromatography (0 to 75% EtOAc in heptane) to provide the title compound.

[0116] Step 2. tert-Butyl 6-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a mixture of tert-butyl 6-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (110 mg, 0.25 mmol) and 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (76.2 mg, 0.28 mmol) in 1,4-dioxane (3 mL) was added KI (41.5 mg, 0.25 mmol) and DIPEA (131 μL, 0.75 mmol). The resulting mixture was stirred at 80° C. for 3.5 h and allowed to cool to room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (NaSO), filtered, and concentrated. The residue was purified by column chromatography (0 to 50% EtOAc in heptane) to provide the title compound.

[0117] Step 3. tert-Butyl 6-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] tert-Butyl 6-(2-bromo-5-ethyl-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (124.2 mg, 184 μmol), 2 A mixture of -(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (58 mg, 276 μmol), KPO (78.5 mg, 368 μmol), and Pd(dppf)Cl.DCM (15.1 mg, 18.4 μmol) in 1,4-dioxane (4 mL) and water (2 mL) was stirred at 80 °C for 8 h. The mixture was allowed to cool to room temperature and diluted with EtOAc. The organic layer was washed with water and brine, dried (NaSO), and concentrated. The residue was purified by column chromatography (0 to 100% EtOAc in heptane) to provide the title compound.

[0118] Step 4. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(2,6-diazaspiro[3.3]heptan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] To a solution of tert-butyl 6-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (51.5 mg, 76 μmol) in dichloromethane (1 mL) was added TFA (0.25 mL). The mixture was stirred at room temperature for 1 h and then diluted with dichloromethane and neutralized with saturated aqueous NaHCO. The organic layer was dried (NaSO), concentrated, and dried under vacuum to provide the title compound.

[0119] Step 5. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(6-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] To a mixture of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(2,6-diazaspiro[3.3]heptan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (40 mg, 69 μmol) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (12.8 mg, 82.8 μmol) in DMF (1.5 mL) at room temperature was added HATU (40.5 mg, 103.5 μmol) and DIPEA (60.2 μL, 345 μmol). The mixture was stirred at room temperature for 2 h and quenched with water. Saturated aqueous NaHCO was added, and the mixture was extracted with EtOAc. The organic layer was dried (NaSO) and concentrated. The residue was purified by column chromatography (0-10% MeOH in dichloromethane) to provide the title compound.

[0120] Manufacturing example 1B Synthesis of Compound 86: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(6-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] Step 1. tert-Butyl 6-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-(1-ethoxy-1,3-dioxolan-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (793.2 mg, 2.33 mmol) in EtOH (4 mL) was added 3-bromo-1H-1,2,4-triazol-5-amine (400 mg, 2.33 mmol) and H₃PO₄ (282 mg, 2.95 mmol). The resulting mixture was stirred at 85 °C for 24 h and allowed to cool to room temperature. DIPEA (1.22 mL, 7 mmol) and Boc₂O (255 mg, 1.17 mmol) were added, and the mixture was stirred at room temperature for an additional 2 h before being quenched with a small amount of water. EtOH was removed under reduced pressure, and the residue was dissolved in EtOAc and washed with water, brine, dried (Na₂SO₄), and concentrated. The residue was purified by column chromatography (0 to 75% EtOAc in heptane) to provide the title compound.

[0121] Step 2. tert-Butyl 6-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a mixture of tert-butyl 6-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (110 mg, 0.25 mmol) and 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (76.2 mg, 0.28 mmol) in 1,4-dioxane (3 mL) was added KI (41.5 mg, 0.25 mmol) and DIPEA (131 μL, 0.75 mmol). The resulting mixture was stirred at 80° C. for 3.5 h and allowed to cool to room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (NaSO), filtered, and concentrated. The residue was purified by column chromatography (0 to 50% EtOAc in heptane) to provide the title compound.

[0122] Step 3. tert-Butyl 6-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] tert-Butyl 6-(2-bromo-5-ethyl-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (124.2 mg, 184 μmol), 2 A mixture of -(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (58 mg, 276 μmol), KPO (78.5 mg, 368 μmol), and Pd(dppf)Cl.DCM (15.1 mg, 18.4 μmol) in 1,4-dioxane (4 mL) and water (2 mL) was stirred at 80 °C for 8 h. The mixture was allowed to cool to room temperature and diluted with EtOAc. The organic layer was washed with water and brine, dried (NaSO), and concentrated. The residue was purified by column chromatography (0 to 100% EtOAc in heptane) to provide the title compound.

[0123] Step 4. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(2,6-diazaspiro[3.3]heptan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] To a solution of tert-butyl 6-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (51.5 mg, 76 μmol) in dichloromethane (1 mL) was added TFA (0.25 mL). The mixture was stirred at room temperature for 1 h and then diluted with dichloromethane and neutralized with saturated aqueous NaHCO. The organic layer was dried (NaSO), concentrated, and dried under vacuum to provide the title compound.

[0124] Step 5. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(6-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] To a mixture of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(2,6-diazaspiro[3.3]heptan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (40 mg, 69 μmol) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (12.8 mg, 82.8 μmol) in DMF (1.5 mL) at room temperature was added HATU (40.5 mg, 103.5 μmol) and DIPEA (60.2 μL, 345 μmol). The mixture was stirred at room temperature for 2 h and quenched with water. Saturated aqueous NaHCO was added, and the mixture was extracted with EtOAc. The organic layer was dried (NaSO) and concentrated. The residue was purified by column chromatography (0-10% MeOH in dichloromethane) to provide the title compound.

[0125] Manufacturing Example 2 Synthesis of compound 163 [ka] Step 1. (E)-6-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(3-methoxyprop-1-en-1-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-Butyl [ka] tert-Butyl 6-(2-bromo-5-ethyl-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 296 μmol), (E) A mixture of 2-(3-methoxyprop-1-alkenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (88 mg, 444 μmol), KPO (126.3 mg, 592 μmol), and Pd(dppf)Cl.DCM (24.3 mg, 29.6 μmol) in 1,4-dioxane (6 mL) and water (3 mL) was stirred at 80 °C for 8 h. The mixture was allowed to cool to room temperature and diluted with EtOAc. The organic layer was washed with water and brine, dried (NaSO), and concentrated. The residue was purified by column chromatography (0 to 100% EtOAc in heptane) to provide the title compound.

[0126] Step 2. (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-methoxyprop-1-en-1-yl)-7-oxo-6-(2,6-diazaspiro[3.3]heptan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka]

[0127] To a solution of tert-butyl (E)-6-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(3-methoxyprop-1-en-1-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (70 mg, 105 μmol) in dichloromethane (1 mL) was added TFA (0.25 mL). The mixture was stirred at room temperature for 1 h and then diluted with dichloromethane and neutralized with saturated aqueous NaHCO. The organic layer was dried (NaSO), concentrated, and dried under vacuum to provide the title compound.

[0128] Step 3. (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(6-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(3-methoxyprop-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] To a mixture of (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-methoxyprop-1-en-1-yl)-7-oxo-6-(2,6-diazaspiro[3.3]heptan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (45 mg, 79.5 μmol) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (14.7 mg, 95.4 μmol) in DMF (2 mL) at room temperature was added HATU (46.7 mg, 119.3 μmol) and DIPEA (70 μL, 400 μmol). The mixture was stirred at room temperature for 2 h and quenched with water. Saturated aqueous NaHCO was added, and the mixture was extracted with EtOAc. The organic layer was dried (NaSO) and concentrated. The residue was purified by column chromatography (0-10% MeOH in dichloromethane) to provide the title compound.

[0129] Manufacturing Example 3 Synthesis of compound 71 [ka] Step 1. tert-Butyl 4-(1-ethoxy-1,3-dioxolan-2-yl)piperazine-1-carboxylate [ka] Ethyl 2-bromo-3-oxopentanoate (2 g, 8.96 mmol), tert-butyl piperazine-1-carboxylate (977.5 mg, 27.1 mmol), and K2CO3 (9.18 g, 49.3 mmol) were mixed in acetonitrile (40 mL). The suspension was stirred at room temperature for 30 min. The reaction mixture was filtered. The combined filtrate and washings were concentrated under reduced pressure. The residue was purified by column chromatography (0-10% MeOH in dichloromethane) to provide the title compound.

[0130] Step 2. tert-Butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(1-ethoxy-1,3-dioxolan-2-yl)piperazine-1-carboxylate (765.2 mg, 2.33 mmol) in EtOH (4 mL) were added 3-bromo-1H-1,2,4-triazol-5-amine (400 mg, 2.33 mmol) and H₃PO₄ (282 mg, 2.95 mmol). The resulting mixture was stirred at 85°C for 24 h and allowed to cool to room temperature. DIPEA (1.22 mL, 7 mmol) and Boc₂O (255 mg, 1.17 mmol) were added, and the mixture was further stirred at room temperature for 2 h before being quenched with a small amount of water. EtOH was removed under reduced pressure, and the residue was dissolved in EtOAc and washed with water, brine, dried (Na₂SO₄), and concentrated. The residue was purified by column chromatography (0 to 75% EtOAc in heptane) to provide the title compound.

[0131] Step 3. tert-Butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] To a mixture of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (125 mg, 0.29 mmol) and 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (86.8 mg, 0.32 mmol) in 1,4-dioxane (4 mL) was added KI (48.1 mg, 0.29 mmol) and DIPEA (152 μL, 0.87 mmol). The resulting mixture was stirred at 80° C. for 3.5 h and allowed to cool to room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (NaSO), filtered, and concentrated. The residue was purified by column chromatography (0 to 50% EtOAc in heptane) to provide the title compound.

[0132] Step 4. tert-Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (200 mg, 302 μmol), 1-methyl-2-oxo-1,2-dihydropyridin-4-ylboronic acid (69.3 mg, 453 μmol), KPO (128.9 mg, 604 μmol), and Pd(dppf)Cl.DCM (24.8 mg, 30.2 μmol) in 1,4-dioxane (6 mL) and water (3 mL) was stirred at 80° C. for 8 h. The mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (0-100% EtOAc in heptane) to provide the title compound.

[0133] Step 5. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] To a solution of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (76 mg, 110 μmol) in dichloromethane (1 mL) was added TFA (0.25 mL). The mixture was stirred at room temperature for 1 h and then diluted with dichloromethane and neutralized with saturated aqueous NaHCO. The organic layer was dried (NaSO), concentrated, and dried under vacuum to provide the title compound.

[0134] Step 6. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] To a mixture of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (55 mg, 93 μmol) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (17.2 mg, 111.6 μmol) in DMF (2.5 mL) at room temperature was added HATU (54.6 mg, 139.5 μmol) and DIPEA (81 μL, 465 μmol). The mixture was stirred at room temperature for 2 h and quenched with water. Saturated aqueous NaHCO was added, and the mixture was extracted with EtOAc. The organic layer was dried (NaSO) and concentrated. The residue was purified by column chromatography (0-10% MeOH in dichloromethane) to provide the title compound.

[0135] Production Example 4 Synthesis of compound 57 [ka] Step 1. tert-Butyl 4-(2-bromo-5-ethyl-7-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (600 mg, 1.4 mmol) in THF (8 mL) and DMF (2 mL) at 0 °C was added NaH 60% in mineral oil (67.2 mg, 1.68 mmol). The mixture was stirred for 30 min, and (2-(chloromethoxy)ethyl)trimethylsilane (285 μL, 1.61 mmol) was added dropwise. The ice cooling was removed, and the reaction mixture was allowed to warm to room temperature and stirred for 24 h. Saturated aqueous NaHCO was added, and the mixture was extracted with dichloromethane. The combined organic layers were dried (NaSO) to provide the title compound.

[0136] Step 2. tert-Butyl 4-(5-ethyl-7-oxo-2-(3-oxomorpholino)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (100 mg, 179 μmol), morpholin-3-one (36.4 mg, 360 μmol), N,N'-dimethylethylenediamine (1.6 mg, 18 μmol), CuI (1.7 mg, 9 μmol), and KCO (50 mg, 360 μmol) in toluene was stirred at 110 °C for 12 h. The mixture was allowed to cool to room temperature and poured into water. The resulting mixture was extracted with EtOAc. The organic layer was dried (NaSO) and concentrated. The residue was purified by column chromatography (0 to 100% EtOAc in heptane) to provide the title compound.

[0137] Step 3. tert-Butyl 4-(5-ethyl-7-oxo-2-(3-oxomorpholino)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(5-ethyl-7-oxo-2-(3-oxomorpholino)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (45 mg, 77.9 μmol) in dichloromethane (1 mL) was added TFA (0.5 mL). The mixture was stirred at 40° C. for 2 h and concentrated. The residue was suspended in dichloromethane (2 mL), and DIPEA (27 μL, 156 μmol) and BocO (34 mg, 156 μmol) were added. The resulting mixture was stirred at room temperature for 1.5 h and quenched with saturated aqueous NaHCO solution. The mixture was extracted with dichloromethane, and the organic layer was dried (NaSO) and concentrated to provide the title compound.

[0138] Step 4. tert-Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-(3-oxomorpholino)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] To a mixture of tert-butyl 4-(5-ethyl-7-oxo-2-(3-oxomorpholino)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (92 mg, 206 μmol) in 1,4-dioxane (4 mL) was added KI (34.2 mg, 206 μmol) and DIPEA (108 μL, 618 μmol). The resulting mixture was stirred at 80° C. for 3.5 h and allowed to cool to room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (NaSO), filtered, and concentrated. The residue was purified by column chromatography (0 to 50% EtOAc in heptane) to provide the title compound.

[0139] Step 5. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(3-oxomorpholino)-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] To a solution of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-2-(3-oxomorpholino)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (40 mg, 58.6 μmol) in dichloromethane (1 mL) was added TFA (0.25 mL). The mixture was stirred at room temperature for 1 h and then diluted with dichloromethane and neutralized with saturated aqueous NaHCO. The organic layer was dried (NaSO), concentrated, and dried under vacuum to provide the title compound.

[0140] Step 6. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-2-(3-oxomorpholino)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] To a mixture of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-7-oxo-2-(3-oxomorpholino)-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (35 mg, 60 μmol) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (11.1 mg, 72 μmol) in DMF (1.5 mL) at room temperature was added HATU (35.2 mg, 90 μmol) and DIPEA (52 μL, 300 μmol). The mixture was stirred at room temperature for 2 h and quenched with water. Saturated aqueous NaHCO was added, and the mixture was extracted with EtOAc. The organic layer was dried (NaSO) and concentrated. The residue was purified by column chromatography (0-10% MeOH in dichloromethane) to provide the title compound.

[0141] Manufacturing Example 5 Synthesis of compound 44 [ka] Step 1. tert-Butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (120 mg), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50 mg), KPO (78 mg), and Pd(dppf)Cl.DCM (15 mg) in 1,4-dioxane (4 mL) and water (2 mL) was stirred at 80 °C for 8 h. The mixture was allowed to cool to room temperature and diluted with EtOAc. The organic layer was washed with water and brine, dried (NaSO), and concentrated. The residue was purified by column chromatography (0 to 100% EtOAc in heptane) to provide the title compound.

[0142] Step 2. tert-Butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4-(propan-2-yn-1-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (430 mg), prepared according to the procedure above, in DMF (5 mL) was added with stirring at 0 °C. After 30 min, propargyl bromide (0.2 mL) was added. The reaction mixture was gradually warmed to room temperature and stirred for 24 h. Saturated NH4Cl solution was added, and the resulting solution was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (0-10% MeOH in dichloromethane) to provide tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4-(propan-2-yn-1-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (260 mg). LC-MS MS m / z [M+H-Boc] + 413

[0143] Step 3. tert-Butyl 4-(4-((1-(2-chloro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4-(propan-2-yn-1-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (250 mg) and 1-azido-2-chloro-4-(trifluoromethyl)benzene (110 mg) in DMF (3 mL) was added CuI (10 mol%) and DIPEA (0.07 mL) at 0° C. After 5 minutes, the reaction was quenched by the addition of ice-cold water. The resulting solution was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (0-10% MeOH in dichloromethane) to provide tert-butyl 4-(4-((1-(2-chloro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (200 mg). LC-MS MS m / z [M+H-Boc] + 634

[0144] Step 4. 4-((1-(2-chloro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one [ka] To tert-butyl 4-(4-((1-(2-chloro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (190 mg) was added HCl in dioxane (4 M, 2 mL). After stirring at room temperature for 16 h, it was concentrated in vacuo to give crude 4-((1-(2-chloro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one. LC-MS MS m / z[M+1] + 590

[0145] Step 5. [ka] To a stirred solution of the crude 4-((1-(2-chloro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one from Step 3 above in DMF (2 mL) was added DIPEA (0.1 mL), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (140 mg), and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (130 mg). After 24 h at room temperature, it was concentrated in vacuo. The residue was purified by HPLC preparative column to produce 4-((1-(2-chloro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (20 mg). LC-MS MS m / z [M+1] + 726

[0146] Manufacturing Example 6 Synthesis of compound 97 [ka] Synthesis scheme: [ka]

[0147] Manufacturing Example 7 Synthesis of compound 187 [ka] Step 1: tert-butyl 3-(1-ethoxy-1,3-dioxolan-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate, To a stirred solution of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (5 g, 25.22 mmol) and ethyl 2-chloro-3-oxopentanoate (4.95 g, 27.74 mmol) in ACN (50 mL) was added TEA (7.66 g, 75.66 mmol) at room temperature and stirred at 55 °C overnight. The mixture was concentrated under reduced pressure. The crude product was diluted with EA and water, extracted once with EA, and the organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA 10:1 to 5:1) to give compound 022-1 (4.5 g, 52% yield). C 17 H 28 Calculated mass of N2O5: 340.2, Measured mass: 341.2 (M+H) + ESI.

[0148] Step 2: tert-butyl 3-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate, 022-2 Int-1-2 (1.9 g, 11.66 mmol) and tert-butyl 3-(1-ethoxy-1,3-dioxolan-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (4.5 g, 13.22 mmol) were mixed in EtOH (50 mL), and HPO (1.14 g, 11.66 mmol) was added. The mixture was stirred under nitrogen gas at 80 °C for 2 days. The mixture was concentrated in vacuo to remove EtOH and quenched by adding saturated NaHCO solution and extracted with EA. The combined organic layer was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica column, eluent DCM:MeOH 20:1 to 10:1) to give compound 022-2 (650 mg, 12% yield) as a yellow oil. C 17 H 23Calculated masses for BrN6O3: 438.10, 440.10; found masses: 339.10, 341.10 (M-Boc+H) ESI.

[0149] Step 3: tert-butyl 3-(2-bromo-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate, 022-3 To a stirred solution of 002-2 (600 mg, 1.37 mmol) and 2-bromo-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide (44.83 mg, 1.50 mmol) in 1,4-dioxane (15 mL) at room temperature, DIPEA (529.55 mg, 4.10 mmol) was added and stirred at 80 °C for 6 h. The mixture was concentrated under reduced pressure. The crude product was diluted with EA and water, extracted once with EA, and the organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH 25:1 to 10:1) to give compound 022-3 (710 mg, 79% yield). C 27 H 31 Calculated mass of BrF3N7O4: 653.16, 655.16; Measured mass: 554.06, 556.04 (M-Boc+H) + ESI.

[0150] Step 4: tert-butyl 3-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate, 022-4 022-3 (750 mg, 1.15 mmol) was suspended in 1,4-dioxane (7 mL), HO (3.5 mL), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (264.81 mg, 1.26 mmol), and KPO (729.75 mg, 3.44 mmol) were added, and the mixture was degassed with argon gas for 10 minutes. PdCl(dppf) (46.44 mg, 0.06 mmol) was added, and the mixture was stirred at 80 °C for 2 hours. The mixture was concentrated under reduced pressure. The crude product was diluted with EA and water and extracted once with EA. The organic layer was washed with brine, dried over NaSO, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 022-4 (580 mg, 76.9% yield). C 32 H 38 Calculated mass of F3N7O5: 657.29, 659.30; Measured mass: 558.23, 559.25 (M-Boc+H) + ESI.

[0151] Step 5: 2-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide, 022-5 022-4 (100 mg, 0.15 mmol) was suspended in DCM (2 mL), TFA (1 mL) was added, and the RM was stirred at room temperature for 2 h. The RM was concentrated under reduced pressure and used without purification. C 27 H 30 Calculated mass of F3N7O3: 557.24, Measured mass: 558.2 (M+H) + ESI.

[0152] Step 6: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(6-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide, 5-Hydroxy-6-methylpyrimidine-4-carboxylic acid (46.44 mg, 0.30 mmol) was dissolved in DCM (5 mL), and the solution was added with HOBT (40.71 mg, 0.30 mmol), EDCI (57.70 mg, 0.30 mmol), pyridine (35.75 mg, 0.45 mmol), and 022-5 (84 mg, 0.15 mmol) and stirred at room temperature for 2 h. The RM was purified by passing through a reverse-phase column (C18 column) to give the product (60 mg, 57% yield). C 33 H 34 Calculated mass of F3N9O5: 693.26, Measured mass: 694.25 (M+H) + ESI.

[0153] Manufacturing Example 8 Synthesis of compound 189 [ka] Step 1: tert-butyl 8-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate, 005-1 Int-2 (300 mg, 0.54 mmol) was suspended in DMF (10 mL), AgBF (104.15 mg, 0.54 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.14 g, 5.4 mmol) were added, and the mixture was stirred at 140 °C for 2 h under a N atmosphere. The mixture was filtered, diluted with 10 mL HO and 10 mL EA, and the organic phase was washed with brine and concentrated in vacuo to give the crude product. The crude product was purified by reverse-phase column (C18 column) to give product 005-1 (104 mg, 28% yield) as a yellow solid. C 32 H 37 Calculated mass of ClF3N7O5: 691.25, 693.25; measured mass: 636.2, 638.2 (M-tBu+H) + ESI.

[0154] Step 2: 2-(6-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide, 005-2 005-1 (100 mg, 0.14 mmol), hydrogen chloride (2 mL) in dioxane were added, and the RM was stirred at room temperature for 2 h. The RM was concentrated under reduced pressure and used without purification. C 27 H 29 Calculated mass of ClF3N7O3: 591.20; Measured mass: 592.2 (M+H) + ESI.

[0155] Step 3: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(3-(3-hydroxypicolinoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide, 3-Hydroxypicolinic acid (14.10 mg, 0.10 mmol) was dissolved in DMF (1 mL). To the solution were added HOBT (13.69 mg, 0.10 mmol), EDCI (19.43 mg, 0.10 mmol), pyridine (12.03 mg, 0.10 mmol), and 005-2 (30 mg, 0.051 mmol). The mixture was stirred at room temperature for 2 h. The RM was purified by reverse-phase column chromatography (C18 column) to give the product (11 mg, 30% yield) as a white solid. C 33 H 32 Calculated mass values ​​for ClF3N8O5: 712.21, 714.21; measured values: 713.2, 715.4 (M+H) + ESI. 1 H NMR(400MHz,DMSO-d6)δ:10.24(s,1H),8.08-8.06(m,2H),7.97(s,1H),7.7 3-7.71(d,J=8.0Hz,1H),7.28(s,2H),6.82(s,1H),5.32(s,2H),4.31-4.25 (m,3H),3.80(s,2H),3.63(s,1H),3.44-3.41(m,4H),3.15-3.10(m,4H),2. 33-2.22(m,2H),1.86(s,1H),1.70(s,1H),2.37(s,3H),1.27-1.23(m,3H).

[0156] Manufacturing Example 9 Synthesis of compound 4 [ka] Step 1: Methyl 2-chloro-3-oxopentanoate [ka] To a solution of methyl 3-oxopentanoate (10 g, 76.84 mmol) in DCM (100 mL) was added SO2Cl2 (13.48 g, 99.89 mmol) over 10 min at 0 °C. The reaction was allowed to warm to room temperature and stirred for 16 h. The RM was concentrated under reduced pressure, and the residue was dissolved in DCM (100 mL) and washed with water (100 mL), brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (12 g, 94% yield) as a pale yellow liquid. Calculated mass of C6H9ClO3: 164.0, Found: 163.0 (MH)-ESI. 1 H NMR (400MHz, DMSO-d6) δ: 5.62 (s, 1H), 3.76 (s, 3H), 2.50-2.48 (m, 2H), 0.99 (t, J = 7.2Hz, 3H).

[0157] Step 2: (1R,5S)-tert-butyl 3-(1-methoxy-1,3-dioxolan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of methyl 2-chloro-3-oxopentanoate (5.04 g, 30.62 mmol) in anhydrous ACN (25 mL) was added TEA (7.15 g, 70.66 mmol) over 15 min, followed by dropwise addition of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 23.55 mmol) in ACN over 30 min. The reaction was stirred at 60 °C for 16 h. The RM was filtered and washed with EA. The filtrate was concentrated under reduced pressure, and the residue was dissolved in EA and washed with water, dried over Na SO , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent heptane:EA 100:0 to 90:10) to give the title compound (4 g, 50% yield). C 17 H 28 Calculated mass of N2O5: 340.2, measured: 339.1 (MH)-ESI. 1H NMR(400MHz,DMSO-d6)δ:4.36(s,1H),3.61(s,3H),3.21-3.11(m,1H),2.99-2.92(m,1H),2.75 -2.60(m,4H),2.37-2.26(m,2H),1.88-1.75(m,4H),1.41-1.38(s,9H),0.96(t,J=7.3Hz,3H).

[0158] Step 3: tert-Butyl 3-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] 3-Bromo-1H-1,2,4-triazol-5-amine (843 mg, 5.17 mmol) and tert-butyl (1R,5S)-3-(1-methoxy-1,3-dioxolan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.6 g, 4.70 mmol) were mixed in EtOH (3 mL). H3PO4 (461 mg, 4.70 mmol) was added. The mixture was stirred at 80 °C under a nitrogen atmosphere for 12 hours. The mixture was concentrated in vacuo to remove EtOH and quenched by the addition of saturated aqueous NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica column, eluent DCM:MeOH 1:0 to 50:1) to afford the title compound (300 mg, 14% yield) as a yellow solid. C 18 H 25 Calculated mass of BrN6O3: 452.1 454.1, measured: 451.1 453.1 (MH)-ESI. 1H NMR(400MHz,DMSO-d6)δ:13.25(s,1H),4.16-4.02(m,2H),3.56-3.50(d,J=9.8Hz,2H),2.81-2 .71(m,2H),2.46-2.38(d,J=9.8Hz,2H),1.93-1.80(m,4H),1.44(s,9H),1.21(t,J=7.6Hz,3H).

[0159] Step 4: tert-Butyl 3-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [ka] To a stirred solution of tert-butyl 3-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.31 mmol) and 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (84 mg, 0.31 mmol) in 1,4-dioxane (2 mL) at room temperature was added DIPEA (120 mg, 0.93 mmol), and the RM was stirred at 80 °C for 72 h. The RM was concentrated under reduced pressure. The crude product was diluted with EtOAc and water, extracted once with EtOAc, and the organic layer was washed with brine, dried over Na SO , and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent heptane: EtOAc 70:30 to 30:70) to afford the title compound (130 mg, 61% yield) as a white solid. C 27 H 30 Calculated mass of BrClF3N7O4: 687.1-689.1, found: 686.1-688.1 (MH)-ESI. 1H NMR(400MHz,DMSO-d6)δ:10.34(s,1H),8.11-8.06(d,J=8.6Hz,1H),7.99-7.96(d,J=1.7Hz,1H),7.74-7.70(dd,J=8.7,1.7Hz,1H),5.29( s,2H),4.15-4.07(m,2H),3.61-3.57(m,2H),3.02-2.92(m,2H),2.49-2.43(m,2H),1.92-1.84(m,4H),1.45(s,9H),1.20(t,J=7.4Hz,3H).

[0160] Step 5: tert-butyl 3-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] tert-Butyl 3-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (186 mg, 0.27 mol) was suspended in 1,4-dioxane (0.5 mL). 2-(3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (113 mg, 0.54 mmol) and 0.6 M aqueous NaCO (0.25 mL) were added, and the RM was degassed with argon gas for 10 minutes. PdCI(PPh) (19 mg, 0.03 mmol) was added, and the RM was stirred at 90 °C for 12 hours. The RM was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel column: 12 g silica, eluent DCM:MeOH 100:0 to 97:3) to give the crude title compound (72 mg). C 32 H 37Calculated mass of ClF3N7O5: 691.2; measured mass: 690.1 (MH)-ESI.

[0161] Step 6: 2-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide [ka] tert-Butyl 3-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.06 mmol) was suspended in DCM (2 mL), TFA (1 mL) was added, and the RM was stirred at room temperature for 4 h. The RM was concentrated under reduced pressure and used without further purification. C 27 H 29 Calculated mass for ClF3N7O3: 591.2, found: 592.1 (M+H)+ESI.

[0162] Step 7: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(8-(3-hydroxy-4-methylpicolinoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 3-Hydroxypicolinic acid (9 mg, 0.07 mmol) was dissolved in DCM (2 mL). To this solution was added pyridine (12 mg, 0.16 mmol), HOBT (14.18 mg, 0.10 mmol), EDCI (20.1 mg, 0.10 mmol), and 2-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (30 mg, 0.05 mmol). After stirring for 3 h, the RM was purified by reverse-phase column (C18 column) to provide the product (12 mg, 33% yield). C 34 H 34 Calculated mass for ClF3N8O5: 712.2, found: 713.1 (M+H)+ESI. 1 H NMR(400MHz,DMSO-d6)δ:11.84(s,1H),10.37(s,1H),8.15-8.10(m,1H),8.07-8.04(d,J=8.5Hz ,1H),7.99-7.95(d,J=1.6Hz,1H),7.74-7.68(m,1H),7.44-7.35(m,2H),6.82(s,2H),5.31(s,2 H),5.08(s,1H),4.83(s,1H),4.27-4.20(d,J=2.5Hz,1H)3.09-2.96(m,2H),2.71-2.64(d,J=8. 8Hz, 1H), 2.63-2.57 (d, J=8.7Hz, 1H), 2.49-2.45 (m, 2H), 2.08-1.91 (m, 4H), 1.25-1.20 (m, 3H).

[0163] Manufacturing Example 10 Synthesis of compounds 190 and 196 [ka] Step 1: tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (003-1) A mixture of SM1 (2 g, 9.38 mmol) in THF (30 mL) was stirred at −78 °C, LiHMDS (1.13 mL, 11.25 mmol) was added, and the mixture was stirred at −78 °C for 1.0 h. SM2 (4.02 g, 11.25 mmol) was added, and the mixture was stirred at 25 °C for 16 h. TLC (PE:EA = 5:1) showed that a new spot was detected and the starting material was completely consumed. The reaction was quenched with water (20 mL) and extracted with EA (20 mL × 3). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The resulting crude residue was purified by silica gel column chromatography with PE / EA (5 / 1) to give product 003-1 (1.6 g, 49.41% yield) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ5.88(q,J=5.5Hz,1H),3.95(dd,J=32.5,5.1Hz,2H),3.56(d t,J=21.7,6.2Hz,2H),2.68-2.49(m,2H),1.94(dt,J=13.5,6.5Hz,2H),1.46(s,9H).

[0164] Step 2: tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (003-2) To a solution of 003-1 (500 mg, 1.45 mmol) and B2pin2 (0.38 mL, 1.45 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl2 (105.94 mg, 0.14 mmol) and AcOK (426.29 mg, 4.34 mmol), and the mixture was stirred at 90 °C under N2 for 3 h. TLC (PE:EA = 5:1) showed that a new spot was detected and the starting material was completely consumed. The solvent was removed. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude residue was purified by silica gel column chromatography with PE / EA (5:1) to give 003-2 (216 mg, 46.15% yield) as a yellow oil, which was used for 2D NMR analysis. 1 H NMR (400MHz, chloroform-d) δ4.20(dd,J=14.7,5.3Hz,1H),4.00(d,J=13.4Hz,1H),2.64(s,1H),2.52-2.35(m,2H),1.60(ddt ,J=21.1,10.4,4.2Hz,4H),1.47(s,9H),1.18(d,J=1.9Hz,12H),0.96(dd,J=8.0,3.9Hz,1H),0.51(dd,J=5.3,3.9Hz,1H)

[0165] Step 3: tert-butyl 5-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (003-3) To a solution of 003-2 (100 mg, 0.31 mmol) and SM3 (118.40 mg, 0.22 mmol) in 1,4-dioxane (5 mL) and HO (0.5 mL) was added KCO (128.26 mg, 0.93 mmol) and Pd(dppf)Cl (25.26 mg, 0.03 mmol), and the mixture was stirred at 70 °C under N for 3 h. LCMS (XT221416-309-6563-Z-1) showed that the desired product was detected and the starting material was completely consumed. The solvent was removed. The mixture was diluted with water (20 mL) and extracted with EA (20 mL × 3), and the combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1 / 1) to give product 003-3 (63 mg, 28.56% yield) as a white solid. MS: m / z=621.3 (M+1, ESI+) at 1.65 min.

[0166] Step 4: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(2,5,6,7-tetrahydro-1H-azepin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (003-4) A mixture of 003-3 (63 mg, 0.01 mmol) and TFA (0.2 mL, 1.34 mmol) in DCM (2 mL) was stirred at 25 °C for 1 h. LCMS (XT221416-322-21052-LCMS06) showed that the desired MS peaks were found. The solvent was removed to give the product 003-4 (69 mg, crude) as a yellow oil. MS: m / z = 577.2 (M+1, ESI+) at 1.70 min.

[0167] Step 5: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5,6,7-tetrahydro-1H-azepin-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 190) To a solution of 003-4 (60 mg, 0.10 mmol) and SM4 (32.05 mg, 0.21 mmol) in DMF (3 mL) was added EDC (39.87 mg, 0.21 mmol), HOBt (28.10 mg, 0.21 mmol), and DIEA (0.09 mL, 0.52 mmol), and the mixture was stirred at 25 °C for 3 h. LCMS (XT221416-337-P1-25473-LCMS02) showed that the desired product was detected and the starting material was completely consumed. The reaction was diluted with water (20 mL) and extracted with EA (30 mL x 3). The organic layer was separated and diluted with water (30 mL x 3). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 190 (15.2 mg, 20.5% yield) as a white solid. MS: m / z = 713.4 (M+1, ESI+) at 1.49 min. 1H NMR (400 MHz, methanol-d4) δ 8.53 (d, J = 9.0 Hz, 1H), 8.15 (t, J = 7.6 Hz, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.03-6.90 (m, 1H), 6.06-5.76 (m, 1H), 5.48-5.28 (m, 2H), 4. 60(ddd,J=30.3,16.5,6.1Hz,1H),4.31(q,J=2.7Hz,3H),3.94-3.60(m,4H),2.96-2.73( m, 2H), 2.57 (d, J=49.0Hz, 7H), 2.40-2.23 (m, 1H), 2.14-1.91 (m, 1H), 1.33-1.18 (m, 3H).

[0168] Step 6: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(1-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5,6,7-tetrahydro-1H-azepin-4-yl)-7-oxo-2-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 196) A solution of 003 (9 mg, 0.01 mmol) and Pd / C (0.00 mL, 0.01 mmol) in IPA (5 mL) was stirred at 25 °C under H2 for 24 h. LCMS (XT221416-361-P1-27380-LCMS02) showed that the desired product was detected and the starting material was completely consumed. The solution was filtered and concentrated. The residue was purified by preparative HPLC to give compound 196 (9.87 mg, 20.14% yield) as a white solid. MS: m / z = 715.4 (M+1, ESI+) at 1.46 min. 1H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 8.14 (t, J = 7.4 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.7 Hz, 1H), 5.88 (d, J = 69.5 Hz, 1H), 5.34 (dd, J = 33.2, 17.0 Hz, 2H), 4.60 (d, J = 15.4 Hz, 2H), 4.42-4.22 (m, 1 H),4.04(dd,J=38.0,13.7Hz,3H),3.77(d,J=16.1Hz,1H),3.55(t,J=11.0Hz,2H),3.10(d,J=20 .2Hz,1H),2.97-2.75(m,2H),2.50(s,4H),1.95(d,J=6.1Hz,4H),1.25(dt,J=45.8,7.8Hz,5H).

[0169] Manufacturing Example 11 Synthesis of Compound 191 [ka] Step 1: 4-Methoxycyclopent-1-ene Under ice-cooling, 60% sodium hydride (1.71 g, 71.33 mmol) was added portionwise to a solution of cyclopent-3-en-1-ol (5.0 g, 59.44 mmol) and iodomethane (9.28 g, 65.39 mmol) in THF (50 mL), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned by adding water and ethyl ether, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure under ice-cooling to give crude 4-methoxycyclopent-1-ene (1.3 g, 22.28% yield). Calculated mass of C6H10O: 98.1, observed value: MS not given. 1 H NMR(400MHz,CD2Cl2)δ5.669(s,1H),5.468(s,1H),4.061-4.027(m,1H),3.184(s,3H),2.473-2.454(d,J =7.6Hz,1H),2.276-2.269(d,J=2.8Hz,1H),2.237-2.230(d,J=2.8Hz,1H),2.157-2.111d,J=2.8Hz,1H).

[0170] Step 2: 2-(3-methoxybicyclo[3.1.0]hexan-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Under nitrogen gas, a solution of CrCl2 (9.77 g, 79.48 mmol) and TMEDA (9.24 g, 79.48 mmol) in THF (80 mL) was stirred at room temperature for 1 h. 2-(Diiodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.82 g, 19.87 mmol) was added. The mixture was stirred at room temperature for 1 h. 4-Methoxycyclopent-1-ene (1.3 g, 13.25 mmol) was added, and the mixture was stirred at 50 °C for 20 h. The reaction was quenched with water and extracted with EA. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with 20 / 1 PE / EA to provide 200 mg, 6.3% yield of 2-(3-methoxybicyclo[3.1.0]hexan-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Calculated mass of C11H19O3B: 238.1, observed value: MS not given. 1 H NMR(400MHz,CD2Cl2)δ3.796-3.760(m,1H),3.103(s,3H),2.077-2.062(m,2H),1.921-1.8 95(m,1H),1.703-1.664(m,2H),1.351-1.342(m,1H),1.152-1.147(m,1H),1.187(s,12H).

[0171] Step 3: tert-butyl 4-(2-(3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate Under nitrogen gas, a mixture of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (500 mg, 0.75 mmol), 2-(3-methoxybicyclo[3.1.0]hexan-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (269 mg, 1.13 mmol), cataCXium A Pd G (110 mg, 0.15 mmol), and KPO (480 mg, 2.26 mmol) in DMF (10 mL) and HO (1 mL) was stirred at 100 °C for 2 h. The reaction was quenched with water and extracted with EA. The organic layers were combined, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with 1 / 1 PE / EA to give 70 mg, 4.77% yield of tert-butyl 4-(2-(3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Calculated mass of C32H39O5N7F3Cl: 693.1.0, Measured mass: 692.1 [MH] + , ESI.

[0172] Step 4: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-methoxybicyclo[3.1.0]hexan-6-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide tert-Butyl 4-(2-(3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (60 mg, 0.08 mmol) in HCl / 1′,4-dioxane (5 mL) was stirred at room temperature overnight. LC-MS showed complete conversion. The mixture was concentrated in vacuo. The crude compound was used directly in the next step without further purification. Calculated mass of C27H31O3N7F3Cl: 593.0, Measured mass: 592.0 [MH] + , ESI.

[0173] Step 5: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(3-methoxybicyclo[3.1.0]hexan-6-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide, compound 191 5-Hydroxy-6-methylpyrimidine-4-carboxylic acid (26.24 mg, 0.17 mmol), Py (20.51 mg, 0.26 mmol), HOBT (23.36 mg, 0.17 mmol), and EDCI (33.14 mg, 0.17 mmol) in DCM (2 mL) were stirred at room temperature for 0.5 h, and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-methoxybicyclo[3.1.0]hexan-6-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (60 mg, 0.08 mmol) was added and stirred at room temperature for 3 h. LC-MS showed complete conversion. The reaction mixture was diluted with another 10 mL of DCM and washed with 10 mL of water, concentrated, and purified by preparative HPLC (C18 column, ACN / water) to give 10 mg, 15.85% yield of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(3-methoxybicyclo[3.1.0]hexan-6-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Compound 191). Calculated mass of C33H35O5N9F3Cl: 730.0, Measured mass: 728.0 [MH] + , ESI. 1 H NMR(400MHz,CD2Cl2)δ10.322(s,1H),8.573(s,1H),8.065-8.044(d,J=8.4Hz,1H),7.974(s,1H),7 .740-7.714(m,1H),5.252(s,2H),4.530-4.500(d,J=12Hz,1H),3.717-3.681(m,2H),3.501-3.445 (m,2H),3.173(s,3H),2.973-2.946(m,4H),2.803-2.777(d,J=10.4Hz,1H),2.624-2.599(d,J=10H z,1H),2.445(s,3H),2.274-2.225(m,2H),1.795(s,3H),1.719-1.673(m,2H),1.183-1.146(m,3H).

[0174] Manufacturing Example 12 Synthesis of Compound 192 [ka] Step 1: 2-(3-oxabicyclo[3.1.0]hexan-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Under nitrogen gas, a solution of CrCl2 (10.52 g, 85.6 mmol, 6.0 equiv.) and TMEDA (9.95 g, 85.6 mmol, 6.0 equiv.) in THF (50 mL) was stirred at room temperature for 1 h. 2-(diiodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.43 g, 21.4 mmol, 1.5 equiv.) was added. The mixture was stirred at room temperature for 1 h. 2,5-Dihydrofuran (1.0 g, 14.27 mmol, 1 equiv.) was added, and the mixture was stirred at 50 °C for 20 h. The reaction was quenched with water and extracted with EA. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with 20 / 1 PE / EA to give 1.8 g, 60.85% yield of 2-(3-oxabicyclo[3.1.0]hexan-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Calculated mass of C11H19O3B: 210.0, observed value: MS not given. 1 H NMR (400MHz, CD2Cl2) δ3.693-3.673(d,J=8Hz,2H),3.574-3.553(d,J=8.4Hz,2H),1.664-1.655(d,J=3.6Hz,2H),1.163(s,12H).

[0175] Step 2: tert-butyl 4-(2-(3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate, Under nitrogen gas, a mixture of tert-butyl 4-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (500 mg, 0.75 mmol), 2-(3-oxabicyclo[3.1.0]hexan-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (206 mg, 0.98 mmol), cataCXium A Pd G (110 mg, 0.15 mmol), and KPO (480 mg, 2.26 mmol) in DMF (10 mL) and HO (1 mL) was stirred at 100 °C for 2 h. The reaction was quenched with water and extracted with EA. The organic layers were combined, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with 98 / 2 DCM / MeOH to afford 26 mg, 5.17% yield of tert-butyl 4-(2-(3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate. Calculated mass of C30H35O5N7F3Cl: 665.0, Measured mass: 664.0 [MH] + , ESI. 1 H NMR(400MHz,CD2Cl2)δ10.342(s,=1H),8.078-8.057(d,J=8.4Hz,1H),7.975-7.971(d,J =1.6Hz,1H),7.739-7.713(m,1H),5.279(s,2H),3.906-3.885(m,4H),3.692-3.671(d,J =8.4Hz,2H),3.406-3.353(m,2H),2.955-2.937(m,4H),2.649-2.622(d,J=10.8Hz,2H), 2.146-2.139(d,J=2.8Hz,2H),1.854-1.837(m,1H),1.433(s,9H),1.178-1.141(m,3H).

[0176] Step 3: 2-(2-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide, tert-Butyl 4-(2-(3-oxabicyclo[3.1.0]hexan-6-yl)-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (40 mg, 0.06 mmol) in HCl / 1′,4-dioxane (5 mL) was stirred at room temperature overnight. LC-MS showed complete conversion. The mixture was concentrated in vacuo. The crude compound was used directly in the next step without further purification. Calculated mass of C25H27O3N7F3Cl: 565.9, Measured mass: 564.9 [MH] + , ESI.

[0177] Step 4: 2-(2-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide, compound 192 5-Hydroxy-6-methylpyrimidine-4-carboxylic acid (21.79 mg, 0.14 mmol), Py (16.77 mg, 0.21 mmol), HOBT (19.10 mg, 0.14 mmol), and EDCI (21.70 mg, 0.14 mmol) in DCM (2 mL) were stirred at room temperature for 0.5 h, and 2-(2-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (40 mg, 0.07 mmol) was added and stirred at room temperature overnight. LC-MS showed complete conversion. The reaction mixture was diluted with another 10 mL of DCM and washed with 10 mL of water, concentrated, and purified by preparative HPLC (C18 column, ACN / water) to give 5.6 mg, 11.29% yield of 2-(2-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide Compound 192). Calculated mass of C31H31O5N9F3Cl: 702.0, Measured mass: 700.0 [MH] + , ESI. 1 H NMR(400MHz,CD2Cl2)δ10.342(s,1H),8.503(s,1H),8.071-8.050(d,J=8.4Hz,1H),7.973( s,1H),7.735-7.713(d,J=8.8Hz,1H),5.279(s,2H),3.904-3.883(d,J=8.4Hz,2H),3.731- 3.670(m,4H),3.598(s,2H),2.973-2.960(m,3H),2.802-2.775(d,J=10.8Hz,1H),2.264-2 .259(d,J=2Hz,1H),2.423(s,2H),2.142(s,2H),1.854-1.846(m,1H),1.189-1.153(m,3H).

[0178] Manufacturing Example 13 Synthesis of compound 195 [ka] Step 1: Methyl 2-chloro-3-oxopentanoate To a solution of methyl 3-oxopentanoate (10 g, 76.84 mmol) in DCM (100 mL) was added SO2Cl2 (13.48 g, 99.89 mmol) over 10 min at 0 °C. The reaction was allowed to warm to room temperature and stirred for 16 h. The RM was concentrated under reduced pressure, and the residue was dissolved in DCM (100 mL) and washed with water (100 mL), brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (12 g, 94% yield) as a pale yellow liquid. Calculated mass of C6H9ClO3: 164.0, Found: 163.0 (MH)-ESI. 1 H NMR (400MHz, DMSO-d6) δ: 5.62 (s, 1H), 3.76 (s, 3H), 2.50-2.48 (m, 2H), 0.99 (t, J = 7.2Hz, 3H).

[0179] Step 2: (1R,5S)-tert-butyl 3-(1-methoxy-1,3-dioxolan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of methyl 2-chloro-3-oxopentanoate (5.04 g, 30.62 mmol) in anhydrous ACN (25 mL) was added TEA (7.15 g, 70.66 mmol) over 15 min, followed by dropwise addition of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 23.55 mmol) in ACN over 30 min. The reaction was stirred at 60 °C for 16 h. The RM was filtered and washed with EA. The filtrate was concentrated under reduced pressure, and the residue was dissolved in EA and washed with water, dried over Na SO , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent heptane:EA 100:0 to 90:10) to give the title compound (4 g, 50% yield). C17 H 28 Calculated mass of N2O5: 340.2, measured: 339.1 (MH)-ESI. 1 H NMR(400MHz,DMSO-d6)δ:4.36(s,1H),3.61(s,3H),3.21-3.11(m,1H),2.99-2.92(m,1H),2.75 -2.60(m,4H),2.37-2.26(m,2H),1.88-1.75(m,4H),1.41-1.38(s,9H),0.96(t,J=7.3Hz,3H).

[0180] Step 3: tert-Butyl 3-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 3-Bromo-1H-1,2,4-triazol-5-amine (843 mg, 5.17 mmol) and tert-butyl (1R,5S)-3-(1-methoxy-1,3-dioxolan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.6 g, 4.70 mmol) were mixed in EtOH (3 mL). H3PO4 (461 mg, 4.70 mmol) was added. The mixture was stirred at 80 °C under a nitrogen atmosphere for 12 hours. The mixture was concentrated in vacuo to remove EtOH and quenched by the addition of saturated aqueous NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica column, eluent DCM:MeOH 1:0 to 50:1) to afford the title compound (300 mg, 14% yield) as a yellow solid. C 18 H 25 Calculated mass of BrN6O3: 452.1 454.1, measured: 451.1 453.1 (MH)-ESI. 1H NMR(400MHz,DMSO-d6)δ:13.25(s,1H),4.16-4.02(m,2H),3.56-3.50(d,J=9.8Hz,2H),2.81-2 .71(m,2H),2.46-2.38(d,J=9.8Hz,2H),1.93-1.80(m,4H),1.44(s,9H),1.21(t,J=7.6Hz,3H).

[0181] Step 4: tert-Butyl 3-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a stirred solution of tert-butyl 3-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.31 mmol) and 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (84 mg, 0.31 mmol) in 1,4-dioxane (2 mL) at room temperature was added DIPEA (120 mg, 0.93 mmol), and the RM was stirred at 80 °C for 72 h. The RM was concentrated under reduced pressure. The crude product was diluted with EtOAc and water, extracted once with EtOAc, and the organic layer was washed with brine, dried over Na SO , and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent heptane: EtOAc 70:30 to 30:70) to afford the title compound (130 mg, 61% yield) as a white solid. C 27 H 30 Calculated mass of BrClF3N7O4: 687.1-689.1, found: 686.1-688.1 (MH)-ESI. 1H NMR(400MHz,DMSO-d6)δ:10.34(s,1H),8.11-8.06(d,J=8.6Hz,1H),7.99-7.96(d,J=1.7Hz,1H),7.74-7.70(dd,J=8.7,1.7Hz,1H),5.29( s,2H),4.15-4.07(m,2H),3.61-3.57(m,2H),3.02-2.92(m,2H),2.49-2.43(m,2H),1.92-1.84(m,4H),1.45(s,9H),1.20(t,J=7.4Hz,3H).

[0182] Step 5: tert-butyl 3-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-(2-bromo-4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (186 mg, 0.27 mol) was suspended in 1,4-dioxane (0.5 mL). 2-(3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (113 mg, 0.54 mmol) and 0.6 M aqueous NaCO (0.25 mL) were added, and the RM was degassed with argon gas for 10 minutes. PdCI(PPh) (19 mg, 0.03 mmol) was added, and the RM was stirred at 90 °C for 12 hours. The RM was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel column: 12 g silica, eluent DCM:MeOH 100:0 to 97:3) to give the crude title compound (72 mg). C 32 H 37 Calculated mass of ClF3N7O5: 691.2; measured mass: 690.1 (MH)-ESI.

[0183] Step 6: 2-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide tert-Butyl 3-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.06 mmol) was suspended in DCM (2 mL), TFA (1 mL) was added, and the RM was stirred at room temperature for 4 h. The RM was concentrated under reduced pressure and used without further purification. C 27 H 29 Calculated mass for ClF3N7O3: 591.2, found: 592.1 (M+H)+ESI.

[0184] Step 7: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(8-(3-hydroxy-4-methylpicolinoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 5-Hydroxy-6-methyl-pyrimidine-4-carboxylic acid (18 mg, 0.12 mmol) was dissolved in DCM (4 mL), and to this solution was added pyridine (14 mg, 0.18 mmol), HOBT (16 mg, 0.11 mmol), EDCI (23 mg, 0.11 mmol), 2-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (35 mg, 0.06 mmol). After stirring for 3 h, the RM was purified by passing through a reverse phase column (C18 column) to provide the product Compound 195 (15 mg, 34% yield). C 34 H 34 Calculated mass for ClF3N8O5: 726.2, found: 727.1 (M+H)+ESI. 1 H NMR(400MHz,DMSO-d6)δ:11.75(s,1H),10.39(s,1H),8.62(s,1H),8.08-8.04(d,J=8.5Hz, 1H),7.99-7.97(s,1H),7.74-7.70(d,J=8.5Hz,1H),6.82(m,1H),5.32(s,2H),5.15(s,1H), 4.85-4.81(d,J=5.7Hz,1H),4.26-4.23(m,2H),3.79(t,J=5.3Hz,2H),3.72(t,J=10.6Hz,2H ),3.07-3.98(m,2H),2.73-2.61(m,2H),2.46(s,4H),2.06-1.92(m,4H),1.28-1.21(m,5H).

[0185] Manufacturing Example 14 Synthesis of Compound 202 [ka] Step 1: tert-butyl 3-(5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, 139-4 139-3 (100 mg, 0.22 mmol) was suspended in DMF (5 mL), HO (0.5 mL), 2-(4-methoxycyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105.06 mg, 0.44 mmol), and NaCO (70.14 mg, 0.66 mmol) were added, and the mixture was degassed with argon gas for 10 minutes. PdCl(PPh) (15.48 mg, 22.06 μmol) was added, and the mixture was stirred at 90 °C overnight. The mixture was concentrated under reduced pressure, and the crude product was diluted with DCM and water, extracted once with DCM, and the organic layer was washed with brine, dried over NaSO, and concentrated under reduced pressure. The product was purified by column chromatography to give compound (120 mg, 77.74% yield). C 35 H 44 Calculated mass of F3N7O5: 699.34; measured mass: 644.3 (M-tBu+H) + ESI.

[0186] Step 2: 2-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide, 139-5 139-4 (100 mg, 0.22 mmol) was suspended in DCM (5 mL), hydrogen chloride in dioxane (2 mL) was added, and the mixture was stirred at room temperature for 2 h. The RM was concentrated under reduced pressure and used without purification. C 30 H 36Calculated mass of F3N7O3: 599.28, Measured mass: 566.2, 568.2 (M+H) + ESI.

[0187] Step 3: 2-(5-ethyl-6-(8-(3-hydroxypicolinoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide. 139-5 (100 mg, 0.17 mmol) was dissolved in DCM (5 mL), and 3-hydroxypyridine-2-carboxylic acid (23.20 mg, 0.17 mmol), EDCI (63.94 mg, 0.33 mmol), and HOBT (45.07 mg, 0.33 mmol) were added to the solution. After stirring at room temperature for 2 h, the RM was purified by passing through a reverse-phase column (C18 column) to provide the product HBP-109-LY-NV-139 (38 mg, 31.62% yield). 36 H 39 Calculated mass of F3N8O5: 720.30; measured mass: 719.4 (MH) - ESI. 1 H NMR(400MHz,DMSO-d6)δ:11.88(br,1H),10.01(s,1H),8.13-8.12(m,1H),7.62(s,1H),7.72(d,J= 8.4Hz,1H),7.53(d,J=8.4Hz,1H),7.43-7.36(m,2H),6.73(s,1H),5.23(s,2H),5.11-5.10(m,1H), 4.83-4.82(m,1H),3.73-3.70(m,2H),3.52-3.50(m,1H),3.27(s,3H),3.04-3.02(m,2H),2.68-2.5 9(m,5H),2.36(s,3H),2.03-2.02(m,1H),1.96-1.93(m,5H),1.70-1.66(m,1H),1.27-1.23(m,3H).

[0188] Manufacturing Example 15 Synthesis of compound 203 [ka] Step 1: tert-butyl 3-(2-(1-(2,2-difluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-ethyl-4-(2-((2-methyl-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, 138-1 3 (390 mg, 0.58 mmol) was suspended in DMF (10 mL), water (1 mL), 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (239.01 mg, 0.88 mmol), and Na2CO3 (185.50 mg, 1.75 mmol) were added, and the mixture was degassed with argon gas for 10 minutes. PdCl2(PPh3)2 (40.95 mg, 0.06 mmol) was added, and the mixture was stirred at 90 °C for 8 h. The mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase column (C18 column) to give 138-1 (178 mg, 41.53% yield). 35 H 43 Calculated mass of F5N8O4: 734.33; measured mass: 733.51 (MH)-ESI.

[0189] Step 2: 2-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-(2,2-difluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide, 138-2 138-1 (55 mg, 0.07 mmol) was suspended in hydrogen chloride (5 mL) in dioxane, and the mixture was stirred at room temperature for 2 h. The RM was concentrated under reduced pressure and used without further purification. 30 H 35 Calculated mass of F5N8O2: 634.28, Measured mass: 635.36 (M+H) + ESI.

[0190] Step 3: 2-(2-(1-(2,2-difluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-ethyl-6-(8-(3-hydroxypicolinoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide, HBP-109-LY-NV-138 138-2 (47 mg, 0.07 mmol), 3-hydroxypyridine-2-carboxylic acid (20.60 mg, 0.15 mmol), EDCI (28.39 mg, 0.15 mmol), HOBT (20.01 mg, 0.15 mmol), and pyridine (17.57 mg, 0.22 mmol) were dissolved in DCM (3 mL) and stirred at room temperature for 2 h. The RM was purified through a reverse-phase column (C18 column) to provide the product HBP-109-LY-NV-138 (18 mg, 32.16% yield). 36 H 38 Calculated mass of F5N9O4: 755.30, Measured mass: 756.41 (M+H) + ESI. 1 H NMR(400MHz,DMSO-d6)δ:11.83(br,1H),10.00(s,1H),8.13-8.11(m,1H),7.71(d,J=8.4Hz,1H),7.6 2(s,1H),7.53(d,J=8.4Hz,1H),7.40-7.38(m,2H),6.75(s,1H),6.30-6.01(m,1H),5.23(s,2H),5.0 9-5.08(m,1H),4.83-4.82(m,1H),3.73-3.70(m,2H),3.29-3.28(m,2H),3.05-3.02(m,2H),2.86-2. 82(m,2H),2.78-2.75(m,2H),2.66-2.59(m,2H),2.35(s,3H),2.02-1.99(m,3H),1.27-1.23(m,4H).

[0191] The compounds in the table below were synthesized according to the above examples or routes analogous to the above examples.

[0192] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

[0193] [Table 2-1] [Table 2-2]

[0194] Biological assays WRN helicase assay To evaluate the inhibitory properties of the compounds of the present invention against WRN helicase activity, a fluorescent assay using branched DNA was established. 527-1072Fluorescent branched DNA prepared by annealing OLIGOA-BHQ2 (TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCCGATGTGTTCGTTC-BHQ2) and OLIGOB-TAMRA (TAMRA-GAACGAACACATCGGGTACGTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT) was used as the substrate. Seven-point, 2.5-fold serial dilutions of test compounds were prepared using DMSO, and 1.5 μl of each concentration was further diluted by adding it to 48.5 μl of assay buffer (25 mM Tris-HCl (pH 8.0), 50 mM NaCl, 2 mM MgCl2, 1 mM DTT, 0.05% Tween-20, and 2.5 μg / ml BSA). Five μl of 45 nM WRN protein and 5 μl of each diluted compound solution were transferred to a 384-well assay plate and preincubated at room temperature for 30 minutes. Each concentration of compound was added to the plate in triplicate. To validate the assay, controls were included. Assay buffer containing 3% DMSO was added instead of compound solution to the positive control (no inhibition), and no protein was added to the negative control (maximum inhibition). Branched DNA and ATP were diluted to 300 nM and 6 mM in assay buffer, respectively. To initiate the reaction, 5 μl of dsDNA and ATP solution was added to the assay plate. After 60 minutes of incubation at room temperature, the plate was transferred to a Victor Nivo multimode plate reader (Perkin Elmer, Waltham, MA), and the fluorescence output was monitored. Dose-response curves were plotted using GraphPad Prism 9 (GraphPad Software, San Diego, CA), and IC values ​​were calculated. 50 obtained.

[0195] WRN ATP enzyme assay To evaluate the inhibitory properties of the compounds of the present invention against DNA-dependent WRN ATP enzyme activity, an ATP enzyme assay was established using the ADP-Glo ​​assay kit (Promega, Madison, Wisconsin). The same WRN protein and DNA substrate as described in the helicase assay were used in the ATP enzyme assay. The serial dilution of compounds in DMSO was the same as in the helicase assay. For further dilutions, 2 μl of each concentration was transferred to 48 μl of assay buffer. 5 μl of 100 nM WRN protein and 2.5 μl of each diluted compound solution were preincubated at room temperature in a 384-well assay plate for 30 minutes. All test wells were set up in triplicate. Then, 2.5 μl of assay buffer containing 400 nM DNA substrate and 4 mM ATP was added to each well and incubated for 60 minutes. The test included a no-protein control (maximum inhibition) and a no-compound control (no inhibition). To stop the reaction and deplete excess ATP, 10 μl of ADP-Glo ​​from the assay kit was added. TM The reagent was added and incubated for 40 minutes. 20 μl of ATP detection reagent was then added. After a 30-minute incubation, luminescence was measured using a Victor Nivo multimode plate reader (PerkinElmer, Waltham, MA). Dose-response curves were generated using GraphPad Prism 9 (GraphPad Software, San Diego, CA), and IC values ​​were calculated. 50 Table 1A shows the data of selected compounds in the above test.

[0196] [Table 3]

[0197] [Table 4]

Claims

1. Compounds of Formulas (I)-(XI) 【Chemistry 1】 or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ring A and Ring B are each independently selected from an aryl group or a heteroaryl group; Y １ is CH, NH, N, O or S, Y ２ is CH, NH, N, O or S, Y ３ is CH, NH, N, O or S, X １ and X ２ are each independently CH or N; M １ , M ２ , M ５ , M ６ are each independently CH, NH, N, O, or S; M ３ and M ４ are each independently -NR ａ , -CR ａ R ｂ and R ａ and R ｂ are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl, and hydroxyalkyl groups; 【Chemistry 2】 is a single bond or a double bond, and the condition is as follows: 【Transformation 3】 But at the same time, it is not a double bond. R １ , R ３ and R ４ are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl, and hydroxyalkyl groups; Two R's ２ are C together with the atoms to which they are connected. ３ -C １０ Cycloalkyl group or C ３ -C １０ forming a heterocyclyl group, R ５ and R ６ are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl, and hydroxyalkyl groups; or R ５ and R ６ are C together with the atoms to which they are connected. ３ -C １０ Cycloalkyl group, C ３ -C １０ Heterocyclyl group, C ６ -C １４ an aryl group or a C containing 1 to 4 heteroatoms selected from the group consisting of O, S and N; ５ -C １２ forming a heteroaryl group, R ７ is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl groups; Or two R ７ are C together with the atoms to which they are connected. ３ -C １０ Cycloalkyl group or C ３ -C １０ forming a heterocyclyl group, L １ is a bond, O, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, —C １ -C ６ Alkyl group -NH-, -C ２ -C ６ Alkenyl group -NH-, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C １ -C ６ Alkylthio group, C １ -C ６ haloalkyl group, —C ３ -C １０ Cycloalkyl group -CONH-, -C １ -C ６ Alkyl group -C ３ -C １０ Cycloalkyl groups -CONH, -C １ -C ６ Haloalkyl group -NH-, -C ３ -C １０ -heterocyclo-NH-alkyl group, -C ３ -C １０ Cycloalkyl group -NH-, -C １ -C ６ Alkyl group -C(NH)-NH, -C ６ -C １０ Heteroaryl group -C １ -C ６ Alkyl group, —S(O) ２ -NH- and -C １ -C ６ Alkyl group -S(O) ２ -NH-, L ２ is a bond, O, —C(O), —CONH—, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, —C １ -C ６ Alkyl group -NH-, -C ２ -C ６ Alkenyl group -NH-, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C １ -C ６ Alkylthio group, C １ -C ６ Haloalkyl groups and —CON(R ｃ ) - and R ｃ is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl groups; m is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; r is 0, 1, 2 or 3; s is 2 or 3; t is 0, 1, 2 or 3; w is 0, 1, 2 or 3, and n is 0, 1, 2 or 3, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

2. The compounds have the formula (XII)-(XIII), (XIX)-(XXI) 【Chemistry 4】 and R ８ is C ３ -C １２ Fused cycloalkyl group, C ２－ C １０ and a fused heterocyclyl group, wherein the fused cycloalkyl group and the fused heterocyclyl group each optionally contain hydrogen, deuterium, halogen, amino, cyano, hydroxy, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ substituted with one or more substituents selected from an alkoxy group and an oxo group; R ９ is a crosslinked C ３ -C １０ Cycloalkyl group or bridge C ２ -C １０ and a heterocyclyl group, wherein the bridged cycloalkyl group and the bridged heterocyclyl group each optionally contain hydrogen, deuterium, halogen, amino, cyano, hydroxy, C １－５ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, oxo group, C １－６ Haloalkyl group, C ３－５ substituted with one or more substituents selected from cycloalkyl groups; L ６ is a crosslinked C ３ -C １０ Cycloalkyl group or bridge C ２ -C １０ and a heterocyclyl group, wherein the bridged cycloalkyl group and the bridged heterocyclyl group each optionally contain hydrogen, deuterium, halogen, amino, cyano, hydroxy, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, oxo group, C １－６ Haloalkyl group, C ３－５ substituted with one or more substituents selected from cycloalkyl groups; Y １ , Y ２ , Y ３ , M １ , M ２ , L ２ , X １ , X ２ , R １ , R ３ , R ４ 2. The compound of claim 1, wherein m, p, q, r, t are as defined in claim 1, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

3. The compounds have the formula (XXII)-(XXIII): 【Transformation 5】 each X is independently selected from F, Cl, Br, and I; Y １ , Y ２ , Y ３ , M １ , M ２ , L ２ , X １ , X ２ , R １ , R ３ , R7, m, n, p, r, t, w are as defined in claim 1, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

4. Ring A is C ６ -C １４ an aryl group or a C containing 1 to 4 heteroatoms selected from the group consisting of O, S and N; ５ -C １２ 2. The compound of claim 1, wherein R is a heteroaryl group, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

5. R １ , R ３ and R ４ are each independently hydrogen, deuterium, halogen, amino group, cyano group, oxo group, hydroxy group, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkyl group, C １ -C ６ Hydroxyalkyl group and C ２ -C ６ alkenyl groups, Preferably, R １ , R ３ and R ４ are each independently hydrogen, deuterium, halogen, amino group, cyano group, oxo group, hydroxy group, C １ -C ３ Alkyl group, —CF ３ 4. The compound of claim 1, 2 or 3, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

6. Two R's ２ are the bridging C atoms together with the atoms to which they are connected. ３ -C １０ Cycloalkyl group or bridge C ３ -C １０ forming a heterocyclyl group, Preferably, 【Transformation 6】 teeth, 【Transformation 7】 or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

7. R ５ and R ６ are each independently hydrogen, deuterium, halogen, amino group, cyano group, oxo group, hydroxy group, C １ -C ３ Alkyl group, C １ -C ３ Alkoxy group, C １ -C ３ Haloalkyl groups and C １ -C ３ hydroxyalkyl groups; or R ５ and R ６ together with the atoms they connect 【Transformation 8】 or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which forms the compound of claim 1 .

8. R ７ represents hydrogen, deuterium, halogen, amino group, cyano group, oxo group, hydroxy group, C １ -C ３ Alkyl group, C １ -C ３ Alkoxy group, C １ -C ３ Haloalkyl groups and C １ -C ３ hydroxyalkyl groups; Or two R ７ are the bridging C atoms together with the atoms to which they are connected. ３ -C １０ Cycloalkyl group or bridge C ３ -C １０ Forming a heterocyclyl group, preferably 【Chemistry 9】 teeth, 【Chemistry 10】 or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein

9. R ａ and R ｂ are each independently hydrogen, deuterium, halogen, amino group, cyano group, oxo group, hydroxy group, C １ -C ３ Alkyl group, C １ -C ３ Alkoxy group, C １ -C ３ Haloalkyl groups and C １ -C ３ 10. The compound of claim 1, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is selected from the group consisting of: hydroxyalkyl groups.

10. L １ is a bond, O, C １ -C ３ Alkyl group, C ２ -C ３ Alkenyl group, —C １ -C ３ Alkyl group -NH-, -C ２ -C ３ Alkenyl group -NH-, C ２ -C ３ Alkynyl group, C １ -C ３ Alkoxy group, C １ -C ３ Alkylthio group, C １ -C ３ haloalkyl group, —C ３ -C ６ Cycloalkyl group -CONH-, -C １ -C ３ Alkyl group -C ３ -C ６ Cycloalkyl groups -CONH, -C １ -C ３ Haloalkyl group -NH-, -C ３ -C ６ -heterocyclo-NH-alkyl group, -C ３ -C ６ Cycloalkyl group -NH-, -C １ -C ６ Alkyl group -C(NH)-NH, -C ６ -C １０ Heteroaryl group -C １ -C ６ Alkyl group, —S(O) ２ -NH- and -C １ -C ６ Alkyl group -S(O) ２ 2. The compound of claim 1, wherein the aryl group is -NH-, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

11. L ２ is a bond, O, —C(O), —CONH—, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, —C １ -C ３ Alkyl group -NH-, -C ２ -C ３ Alkenyl group -NH-, C ２ -C ３ Alkynyl group, C １ -C ３ Alkoxy group, C １ -C ３ Alkylthio group, C １ -C ３ Haloalkyl groups and —CON(R ｃ ) - and R ｃ represents hydrogen, deuterium, halogen, amino group, cyano group, oxo group, hydroxy group, C １ -C ３ Alkyl group, C １ -C ３ Alkoxy group, C １ -C ３ Haloalkyl groups and C １ -C ３ 4. The compound of claim 1, 2 or 3, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is selected from the group consisting of: hydroxyalkyl groups.

12. Ring A is 【Chemistry 11】 or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from the group consisting of:

13. 2. The compound of claim 1, wherein Ring B is selected from the group consisting of a phenyl group, a pyridyl group, a pyrrolyl group, or a pyrimidinyl group, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 【Request Item 14】 【Chemistry 12】 teeth, 【Chemistry 13】 3. The compound of claim 2, wherein:

15. In the formula (XIII), R8 is 【Chemistry 14】 3. The compound of claim 2, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, selected from the group consisting of:

16. R9 is, 【Chemistry 15】 and R10 is C １－５ Alkyl group, C ３－５ 3. The compound of claim 2, wherein the compound is a cycloalkyl group, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

17. L6 is, 【Chemistry 16】 or L6-L2 is 【Chemistry 17】 3. The compound of claim 2, wherein:

18. In the formula (XXII), X linked to the phenyl group is Cl, and / or CH ｎ X ３－ｎ is CF ３ In the formula (XXIII), ｎ X ３－ｎ is CF ３ 4. The compound of claim 3, wherein:

19. A compound comprising: [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

20. 20. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 19, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

21. 21. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 19, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of claim 20.

22. 21. A method of treating a disorder or disease in a subject treatable by WRN inhibition, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 19, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of claim 20.

23. 20. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of claims 1 to 19, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or the pharmaceutical composition of claim 20, wherein the cancer is selected from the group consisting of microsatellite instability-high (MSI-H) cancer or mismatch repair deficient (dMMR) cancer, preferably the microsatellite instability-high (MSI-H) cancer or mismatch repair deficient (dMMR) cancer is selected from colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, and ovarian cancer.

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