Triazolo-pyrimidine analogs for treating diseases associated with inhibition of werner syndrome recq helicase (WRN)

Abstract

To provide inhibitors of Werner syndrome RecQDNA helicase (WRN) useful for the treatment of mismatch repair function-deficient cancers.SOLUTION: There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided are therapeutic uses of the compounds, uses of the compounds as research chemicals, pharmaceutical compositions and combinations comprising the compounds, and methods of making the compounds of the invention.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to bicyclic compounds, such as 7-oxo-[1,2,4]triazolo[1,5-a ]pyrimidin-4(7H)-yl) compounds and their analogues and derivatives, Werner syndrome R and their use for inhibiting ecQ DNA helicase (WRN), as well as methods for treating cancer using said compounds. and methods for treating diseases using the same, particularly for use in the treatment of cancer, particularly for use in the treatment of high frequency microsatellite Cancer characterized by instability (MSI-H) or mismatch repair deficiency (dMMR) (colon The present invention also provides for the use of steroids in the treatment of cancer, including gastric cancer and endometrial cancer. and the use of said compounds as chemical substances, intermediate compounds, combinations, processes and formulations. do. [Background technology]

[0002] Loss of DNA mismatch repair function is a major risk factor for colon, endometrial, ovarian, and gastric cancers. It is a common initiating event in cancer development, occurring in 30% of cases (Aaltonen, L.A.e t al.Clues to the pathogenesis of family colorectal cancer,Science 260,812-816 (1993), Bonneville R et al., Landscape of Microsatellite Instability Across 39 Can cer Types.JCO Precis Oncol.1:PO.17.00073 (2017). Cancers that have lost their mismatch repair (MMR) capacity have high mutation burden and repeat D Frequent deletion and insertion events in the NA tract, microsatellite instability (MSI) Microsatellite instability-high (MSI-H) cancers have a phenotype known as Treatment has progressed, and pembrolizumab (anti-PD1) therapy has been shown to improve MSI-H-dMMR progression. When given as first-line therapy for metastatic colorectal cancer, it provides significantly longer progression-free survival than chemotherapy. The demonstrated benefits of Pembrolizumab as a first-line treatment for these cancers have led to its adoption. Although mab was recently approved, its market share remains low in CRC and other MSI-H indications. There is a significant unmet medical need (Andre T., et al. Pemb rolizumab in Microsatellite-Instability- High Advanced Colorectal Cancer.N Engl J Med;383(23):2207-2218(2020)). Cancer Cell Line Encyclopedia Pedia (CCLE) (McDonald ER et al., Project D RIVE A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Unco verified by Large-Scale,Deep RNAi Screening Cell 170(3):577-592(2017)) using the 398 cell line Several large-scale functional genomics studies across a large panel of cell lines, including vartis By screening, we identified cell lines with defective mismatch repair function that had become MSI-H. Identification of the Werner syndrome RecQ helicase (WRN) selectively required for survival (Behan,FMet al.Prioritization of cance r therapeutic targets using CRISPR-Cas9 screens.Nature 568,511-516(2019), Chan,E. M.et al.WRN helicase is a synthetic leth al target in microsatellite unstable can cers.Nature 568,551-556(2019), Kategaya,L .,Perumal,SK,Hager,JH& Belmont,LDW erner syndrome helicase is required for the survival of cancer cells with micros atellite instability.iScience 13,488-497 (2019), Lieb, S. et al. Werner syndrome heli case is a selective vulnerability of mic rosatellite instability-high tumor cells .eLife8,e43333(2019)). WRN is synthetically lethal to MSI cancer. Depletion of WRN leads to antiproliferative effects and inhibits multiple DNA damage signals in MMR cancer models Activation of nucleoside signaling markers, induction of cell cycle arrest, and apoptosis, while leaving intact These findings suggest that WRN has a role in MSI cancers, but not in cancer cells with the MMR pathway. It has been shown that they provide DNA repair and maintenance functions essential for cell survival in the The WRN-dependent mechanism was elucidated. The dinucleotide TA repeats were selected in MSI cells. These expanded TAs are selectively unstable and have been shown to undergo large-scale expansion. The repeats form secondary DNA structures that require WRN helicase for unwinding (v an Wietmarschen,N.et al.Repeat expansion s confer WRN dependence in microsatellit e-unstable cancers.Nature 586,292-298,20 20) In the absence of WRN (or when WRN helicase is inhibited), proliferation in MSI cells is suppressed. Large TA repeats are subject to nuclease cleavage and chromosome breakage. Inhibiting casein is an attractive strategy for the treatment of mismatch repair-deficient cancers. Summary of the Invention

[0003] Cancer, especially those with microsatellite instability-high (MSI-H) or mismatch repair deficiency for treating cancers characterized by loss of MMMR (dMMR), including colorectal cancer, gastric cancer, or endometrial cancer There remains a need for new treatments and therapies. The present invention relates to compounds, their pharmaceutical The compounds are also provided as well as acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof. The present invention further relates to an inhibitor of the WRN syndrome RecQ DNA helicase. or a method for treating, preventing, or ameliorating a condition, comprising administering to a subject in need thereof an effective amount of a WRN inhibitor. The present invention also provides a method for treating cancer, particularly high-frequency microsatellite tumors, comprising administering a cytotoxic agent to the tumor. Cancers characterized by light instability (MSI-H) or mismatch repair deficiency (dMMR) Compounds useful in the treatment of It also provides compounds that bind to and / or inhibit WRN and thus are useful in research chemists. To provide compounds useful as materials, for example as chemical probes and as tool compounds. Various embodiments of the present invention are described herein. In certain embodiments, there is provided herein a compound of formula (I) or a pharmaceutically acceptable salt thereof: Provide salt. [ka] [In the formula, R, M, W, L, V and T are independently selected from C, CH and N; Subformulas 1a, 1b, 1c, 1d, 1e and 1f: [ka] Forming; A is -C(O)-, -S(O)-, -S(O)2- and [ka] is a linker selected from: Y is N, C or CH; y is 0, 1, 2, 3 or 4; [ka] When Y is CH, it is connected to the adjacent carbon atom via a single bond, or when Y is C, means that the adjacent atoms are connected via a double bond, [ka] is a single bond, then Y is unsubstituted or substituted by OH or F; If Y is N, [ka] is a single bond; [ka] means that K is connected to the adjacent carbon atom via a single or double bond; where: [ka] If is a double bond, [ka] is a single bond, K is CH, J is C, and A is -C(O)-, -S(O)-, - S(O)2- and [ka] is a linker selected from: or [ka] When is a single bond, K is -CH2-, -CH2CH2-, -NH- and (5-membered ring: [ka] and J is N, and A is selected from -C(O)-, -S(O)-, -S (O)2- and [ka] is a linker selected from: or [ka] is a single bond, K is -CH2-, J is CH, A is -S(O)-, -S(O )2- and [ka] is a linker selected from: R5 is independent, -(C 1~ C4) alkyl, -(C 3~ C5) cycloalkyl, where two R5 substituents on the same ring carbon atom are in the same position as the carbon atom to which they are attached. Together, (C 3~ C4) cycloalkylspirocycle or 3- or 4-membered heterocyclyl A spiro ring may be formed, wherein said heterocyclylspiro ring is composed of ring carbon atoms and and one ring heteroatom selected from O, N, and S; · [ka] is a carbon-nitrogen single bond, K and the R5 substituents on the adjacent carbon atom are joined to form ring C: [ka] wherein ring C is a fused (C3-C6) cycloalkyl ring, a fused (C3 -C6) heterocyclyl ring or fused phenyl ring, wherein the fused (C3-C6) A heterocyclyl ring consists of ring carbon atoms and one ring heteroatom selected from O, N, and S. containing · [ka] is a carbon-carbon single bond, Y is N, [ka] is a single bond, A is -S(O)-, -S(O)2- and [ka] When K is a linker selected from the group consisting of Ring C: [ka] may form where K is -CH2- and J is N, the two R5 substituents are linked to form (C1 C3) may form an alkylene bridge or a heteroalkylene bridge, wherein the hetero The alkylene bridge is one heteroatom selected from N and O, or -CH2- O-CH2- Selected from Here, the ring: [ka] One or more H atoms on the above may be replaced by deuterium: R1 is cycloalkenyl, wherein the cycloalkenyl has 5 or 6 ring carbon atoms; and a partially unsaturated monocyclic ring containing 1, 2, 3 or 4, preferably 1 or 2 R 33 where R 33 is halo, and said cycloalkenyl or halo-substituted cycloalkenyl is 0, 1 or 2 R 15 Is substituted by a substituent, Alternatively, R1 is heterocyclyl, wherein said heterocyclyl is and 1 or 2 ring heteroatoms independently selected from N, O, and S. a partially unsaturated 5- or 6-membered group, said heterocyclyl being unbridged or bridged; the bridge is 1 or 2 carbon atoms, and wherein the heterocyclyl is a non-substituted or 1, 2, 3 or 4, preferably 1 or 2 R 33 is replaced by where R 33 is halo, and said heterocyclyl or halo-substituted heterocyclyl is independently Then, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 Selected from or is substituted by 0, 1 or 2 substituents Alternatively, the heterocyclyl or halo-substituted heterocyclyl is fused to a cyclopropyl ring. wherein the cyclopropyl ring is unsubstituted or substituted with 1, 2 or 3 F. Are you Alternatively, the heterocyclyl or halo-substituted heterocyclyl may be attached to a cyclopropyl group. have two substituents on the same ring carbon atom forming a pyrocyclic ring, Alternatively, the heterocyclyl or halo-substituted heterocyclyl is a (C3-C5)heterocyclyl. and an alkyl ring, wherein the (C3-C5) heterocycloalkyl ring is fused to the ring carbon atom. containing a nitrogen atom and one ring O atom, or Alternatively, R1 is heteroaryl, wherein said heteroaryl is a ring carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, preferably 1 or a 5- or 6-membered fully unsaturated monocyclic group containing two ring heteroatoms, wherein the ring S atom the total number of ring O atoms does not exceed 1, and the total number of ring O atoms does not exceed 1, wherein said heteroaryl is a non-substituted Exchange, or R 21 and R 30 by one, two or three substituents independently selected from substituted, where R 21 and R 30 is independent of halo and (C1-C4) alkyl wherein the (C1-C4) alkyl is unsubstituted or selected from the group consisting of 1, 2 or 3 alkyl groups. Is substituted with a halo, Alternatively, R1 is phenyl, wherein said phenyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2 R 33 where R 33 It's Halo and the phenyl or halo-substituted phenyl is selected from the group consisting of 0, 1 or 2 R 15 Substituted with a substituent Ruka, Alternatively, R1 is (C2-C4)alkynyl or (C2-C4)alkenyl, wherein wherein the (C2-C4)alkynyl and (C2-C4)alkenyl are unsubstituted or (C1- C4) substituted by alkyl-OC(O)- or morpholinyl; Each R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 is, independently, Hello, unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C4) Alkyl-O- , unsubstituted or substituted with OH, —O—(C1-C2) alkyl or 1, 2 or 3 halo substituted (C1-C4) alkyl, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (C1-C4) alkyl-OC(O)(CH2) n , =O, azetidinyl or pyrrolidinyl (wherein the azetidinyl and pyrrolidinyl are N-atoms) and each is unsubstituted or substituted with 1 or 2 F. (which has been replaced), ·R 25 (R 24 )N-(where R 24 is H or unsubstituted or 1, 2 or 3 H is (C1-C4) alkyl substituted with . 25 is H or unsubstituted or 1, 2 or (C1-C4) alkyl substituted with 3 halo groups OH is selected from where n is 0, 1 or 2; R 26 is CH3, H or deuterium; R 27 is CH3, H or deuterium; Or, R 26 and R 27 together with the carbon atoms to which they are attached form a cyclopro Forming a pill ring; R2 is part: [ka] and; R6 is ·H, Hello, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, (C3-C5)cycloalkyl unsubstituted or substituted with 1, 2 or 3 halo , -O-(C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo , ·OH, and ·CN Selected from; R8 is H, halo, and unsubstituted or substituted with 1, 2 or 3 halo (C1 C4) alkyl; R9 is selected from H, O-CH3, OH, CN, CH3, and halo; R 28 teeth, SF5, ·H, ·-C(O)H, Hello, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, ·(C1-C4)alkynyl; (C1-C4) alkenyl, (C3-C5)cycloalkyl unsubstituted or substituted with 1, 2 or 3 halo , and OCF3 Selected from; X is selected from C-R7 and N, where R7 is H or halo, or R7 is R 28 or R6 and the atom to which they are attached form a condensed group (C4-C 6) Form a cycloalkyl ring, wherein the fused (C4-C6) cycloalkyl ring is not substituted or substituted with 1, 2 or 3 halo; or R2 is [ka] is selected from where: R 31 is selected from H, halo, and CH3; R 32 is selected from H, halo, and CH3; R3 is Cyclopropyl, ·O-CH3, N(CH3)2, ·S-CH3, unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo and OH is a (C1-C4) alkyl; R4 is [ka] Selected from where: R 10 , R 11 , R 12 , R 13 and R 14 is, independently, ·H, Hello, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents , -O-(C1-C2) alkyl or (C1-C2) alkyl substituted by OH Lu, -S-(C1-C3) alkyl, -O-(C1-C4) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents Lukil, ·OH, (C3-C5)cycloalkyl (wherein the (C3-C5)cycloalkyl is unsubstituted or is substituted with one or two halo groups), -O-(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent ohhh, o(C1-C4) alkyl (wherein the (C1-C4) alkyl is unsubstituted or substituted with OH or or -O(C1-C2) alkyl substituted), o and where R 34 and R 35 together with the carbon atoms to which they are attached azetidine, pyrrolidinyl and piperidine rings can be formed (wherein Zetidine, pyrrolidinyl and piperidine are unsubstituted or substituted with CH3 selected from ·CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -C(O)H, and -C(O)(C1-C4) alkyl Selected from; and * indicates point of attachment].

[0004] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable carriers. The present invention provides a pharmaceutical composition comprising:

[0005] In another aspect, the present invention provides combinations, in particular compounds of formula (I) according to the invention and one or more Pharmaceutical combinations containing therapeutically active agents are provided.

[0006] In another aspect, the present invention provides a method for treating a disease, particularly a disease caused by WRN inhibition, for use as a medicine. The present invention provides compounds of formula (I) for the treatment of disorders or diseases that can be treated with steroids.

[0007] In another aspect, the present invention provides a compound of formula (I) of the present invention for use in the treatment of cancer. In particular, cancers with high microsatellite instability (MSI-H) or mismatch repair dysfunction Compounds characterized by a deficiency (dMMR) are provided.

[0008] In another aspect, the present invention provides a method for treating a disorder that can be treated by WRN inhibition in a subject. or a method for treating a disease, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) of the present invention. The present invention provides a method for detecting a stoichiometric amount of a substance comprising:

[0009] In another aspect, the present invention provides a method of treating cancer in a subject, more particularly a subject in which cancer is prevalent. Microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) 1. A method comprising administering to a subject a therapeutically effective amount of a compound of formula (I) of the present invention. The present invention provides a method comprising:

[0010] In another aspect, a compound for the treatment of a disorder or disease that can be treated by WRN inhibition. There is provided the use of a compound of formula (I) of the present invention in the manufacture of a medicament.

[0011] In another aspect, the present invention provides a method for the preparation of a compound of formula (I) or a compound of formula (II) as a research chemical, e.g., as a chemical probe or tool. The present invention provides a compound of formula (I) for use as a steroid compound.

[0012] In another aspect, the invention provides a solid form, process, or intermediate described herein. . [Brief explanation of the drawings]

[0013] [Figure 1] 1 shows the powder X-ray diffractogram of Example 42. [Figure 2] 1 shows the powder X-ray diffractogram of Example 86. [Figure 3] 1 shows the powder X-ray diffractogram of Example 47. [Figure 4] 1 shows the powder X-ray diffractogram of Example 57. [Figure 5] 1 shows the powder X-ray diffractogram of Example 96. [Figure 6] Showing efficacy and tolerability after once daily (qd) administration of Example 58 in female nude mice bearing SW48 xenografts [Figure 7] 1 shows the powder X-ray diffractogram of Example 42. [Figure 8]1 shows colony formation assay data for the compound of Example 42 using MSI and MSS cells. [Figure 9] Shows efficacy of Example 42 after administration in female nude mice bearing SW48 xenografts [Figure 10] Shows efficacy of Example 96 after administration in female nude mice bearing SW48 xenografts [Figure 11] Shows efficacy of Example 57 after administration in female nude mice bearing SW48 xenografts DETAILED DESCRIPTION OF THE INVENTION

[0014] The present disclosure provides compounds of formula (I): [ka] (In the formula, R1, R2, R3, R4, R5, R 26 , R 27 ,y,R,M,W,L,V,T , Y, J, K, and A are as described in the "Summary of the Invention" above.)

[0015] Unless otherwise specified, the term "compounds of the disclosure" or "compounds of formula (I)" refers to compounds of formula (I ) compounds, their subformulas, exemplified compounds, and salts thereof, as well as all zwitterions, isoforms thereof isomers (including diastereoisomers and enantiomers), rotamers, tautomers and and isotopically labeled compounds (including deuterium substitution), as well as inherently formed moieties, and the above. It refers to a combination or mixture of these aspects.

[0016] Various (enumerated) embodiments of the present invention are described herein. The features may be combined with other specified features to provide further embodiments of the present invention. will be understood.

[0017] Embodiment 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as described above.

[0018] Embodiment 2: When R1 is a ring, Each R1 ring atom adjacent to the R1 ring atom at which the R1 ring is attached to the remainder of the molecule is Independently unsubstituted or substituted only with halo, particularly independently unsubstituted or substituted with one F substituent, preferably The R1 ring is double-bonded to the rest of the molecule via the R1 ring nitrogen atom or an adjacent ring atom. R1 is linked via a ring carbon atom A compound of formula (I) as defined in embodiment 1 or a pharmaceutically acceptable salt thereof.

[0019] Embodiment 3.R1 is cycloalkenyl, wherein the cycloalkenyl has 5 or 6 ring carbon atoms; and a partially unsaturated monocyclic ring containing cycloalkenyl, wherein the cycloalkenyl is unsubstituted or is 1, 2, 3 or 4, preferably 1 or 2 R 33 is replaced by So, R 33 is halo, and the cycloalkenyl or halo-substituted cycloalkenyl is 0, 1 Or two R's 15 Is substituted by a substituent, Alternatively, R1 is heterocyclyl, wherein said heterocyclyl is and 1 or 2 ring heteroatoms independently selected from N, O, and S. a partially unsaturated 5- or 6-membered group, said heterocyclyl being unbridged or bridged; wherein the bridge is 1 or 2 carbon atoms and the heterocyclyl is unsubstituted. or 1, 2, 3 or 4, preferably 1 or 2 R 33 is replaced by R33 is halo, and said heterocyclyl or halo-substituted heterocyclyl is independently R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 Selected from 0, substituted by one or two substituents, Alternatively, R1 is heteroaryl, wherein said heteroaryl is a ring carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, preferably 1 or a 5- or 6-membered fully unsaturated monocyclic group containing two ring heteroatoms, wherein the ring S atom the total number of ring O atoms does not exceed 1, and the total number of ring O atoms does not exceed 1, wherein said heteroaryl is a non-substituted Exchange or R 21 and R 30 substituted by 1, 2 or 3 substituents independently selected from where R 21 and R 30 are independently selected from halo and (C1-C4) alkyl wherein said (C1-C4) alkyl is unsubstituted or substituted with 1, 2 or 3 halo. It has been replaced, And each R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 is independent hand, Hello, unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C4) Alkyl-O- , unsubstituted or substituted with OH, —O—(C1-C2) alkyl or 1, 2 or 3 halo substituted (C1-C4) alkyl, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (C1-C4) alkyl-OC(O)(CH2) n , =O azetidinyl or pyrrolidinyl (wherein the azetidinyl and pyrrolidinyl are N-atoms) and each is unsubstituted or substituted with 1 or 2 F. (which has been replaced), ·R 25 (R 24 )N-(where R 24 is H or unsubstituted or 1, 2 or 3 H is (C1-C4) alkyl substituted with . 25 is H or unsubstituted or 1, 2 or (C1-C4) alkyl substituted with 3 halo groups OH is selected from where n is 0, 1 or 2 A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in embodiment 1 or 2.

[0020] Embodiment 4.R1 is cycloalkenyl, wherein the cycloalkenyl has 5 or 6 ring carbon atoms; and a partially unsaturated monocyclic ring containing cycloalkenyl, wherein the cycloalkenyl is unsubstituted or is one or two R 33 where R 33 is halo, preferably F and the cycloalkenyl or halo-substituted cycloalkenyl is 0 or 1 R 15 replacement group, preferably one substituent, and R 15 teeth, a) unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C2) Alkyl-O -, b) (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 halo; c) HOC(O)-(CH2) n -, d) H3C-C(O)(CH2) n -, e) H3C-OC(O)(CH2) n , f) O, and g)R 25 (R 24 )N-, H(where R 24 is H or unsubstituted or 1, 2 or 3 (C1-C2) alkyl substituted with one halo, R 25 is H or unsubstituted or 1, (C1-C2) alkyl substituted with 2 or 3 halo is selected from n is 0 or 1, where: R of the cycloalkenyl or halo-substituted cycloalkenyl 15 The substituents a) to g) are adjacent to the ring atom where the chloroalkenyl or halo-substituted cycloalkenyl is attached to the rest of the molecule and preferably, the cycloalkenyl or halo-substituted cycloalkenyl The ring has one R in the para position relative to the rest of the molecule. 15 is a 6-membered ring having a substituent, The cycloalkenyl or halo-substituted cycloalkenyl has two adjacent R1 ring carbon atoms. is connected to the remainder of the compound via a double-bonded R1 ring carbon atom; Alternatively, R1 is heterocyclyl, wherein said heterocyclyl is a ring carbon atom and and fully saturated containing 1 or 2 ring heteroatoms independently selected from N, NH, O and S or a partially unsaturated 5- or 6-membered group, wherein the heterocyclyl is unbridged or bridged, said bridge being 1 or 2 carbon atoms, wherein said heterocyclyl is unsubstituted or has one or two R 33 where R 33 Halo, preferred or F, and said heterocyclyl or halo-substituted heterocyclyl is independently R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 0 or 1 selected from and R 15 , R 16 , R 17 , R 18 , R 19 , R2 0, R 22 and R 23 is, independently, a) unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C4) Alkyl-O -, b) unsubstituted or substituted with OH, —O—(C1-C2) alkyl, or 1, 2, or 3 halo substituted (C1-C4) alkyl, c) HOC(O)-(CH2) n -, d) H3C-C(O)(CH2) n -, e) H3C-OC(O)(CH2) n , f)=O, g)R 25 (R 24 )N-(where R 24 is H, unsubstituted or substituted with 1, 2 or 3 halo groups is (C1-C2) alkyl substituted with R 25 is H, unsubstituted or 1, 2 or 3 (C1-C2) alkyl substituted with one halo h)OH is selected from n is 0 or 1, where: The substituents a) to h) of the heterocyclyl or halo-substituted heterocyclyl are and preferably, no halo- or halo-substituted heterocyclyl is present on the ring atom that is attached to the remainder of the molecule. The heterocyclyl or halo-substituted heterocyclyl is a six-membered ring that is At the meta or para position, preferably at the para position, 0 or 1 selected from a) to h) It has a substituent, The heterocyclyl may be linked to the remainder of the compound by a double bond at the R1 ring nitrogen atom or adjacent ring atoms. linked via the R ring carbon atom to which it is attached; Alternatively, R1 is heteroaryl, wherein said heteroaryl is a ring carbon atom and Contains 1 or 2 ring heteroatoms independently selected from N, O and S, preferably N A 5- or 6-membered fully unsaturated monocyclic group, in which the total number of ring S atoms does not exceed 1 and the ring O atoms does not exceed 1, wherein said heteroaryl is unsubstituted or R 21 and R 30 From Germany substituted by one or two substituents selected arbitrarily, where R 21 and R3 0 is independently selected from (C1-C2) alkyl, and said (C1-C2) alkyl is unsubstituted. or substituted with 1, 2 or 3 halo, wherein preferably said alkyl Or the haloalkyl substituent is adjacent to the R1 ring atom where the heteroaryl is attached to the remainder of the molecule. more preferably, when the heteroaryl is a 6-membered ring, The alkyl or haloalkyl substituent is in the ring para position relative to the rest of the molecule A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1, 2 or 3. salt.

[0021] Embodiment 5.R1 is [ka] Selected from; R 33 is F; R 15 is halo, azetidinyl, or pyrrolidinyl, wherein said azetidinyl and The pyrrolidinyl is linked to the rest of the molecule through the N atom and is unsubstituted or has one or more substituted with two Fs), R 16 is R 25 (R 24 )N- (where R 24 is H or (C1-C2) alkyl R 25 is H or unsubstituted or substituted with 1, 2 or 3 halo, especially F (C1-C2) alkyl); R 17 is a halo; R 18 is a halo; R 19 is a halo; R 20 is a halo; R 21 is (C1-C2) alkyl; R 22 and R 23 are each independently (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (H3C)3C-OC(O)(CH2) n - Selected from; where n is 0, 1 or 2; and R 30 is CH3 A compound of formula (I) according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof.

[0022] Embodiment 6.R1 is [ka] Selected from; R 15 is F; R 16 is R 25 (R 24 )N- and; R 17 is F; R 18 is F; R 19 is F; R 20 is F; R 21 is CH3; R 22 are CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, ( H3C)3C-OC(O)-; R 23 are CF3, CHF2CH2-, (H3C)3C-OC(O)-; R 24 is CH3; and R 25 is CHF2CH2- A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 5.

[0023] Embodiment 7.R2 comprises the moiety: [ka] and; R6 is ·H, Hello, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, (C3-C5)cycloalkyl unsubstituted or substituted with 1, 2 or 3 halo , -O-(C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo , ·OH, and ·CN Selected from; R8 is H, halo, and unsubstituted or substituted with 1, 2 or 3 halo (C1 C4) alkyl; R9 is selected from H, O-CH3, OH, CN, CH3, and halo; R 28 teeth, SF5, ·H, ·-C(O)H, Hello, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, ·(C1-C4)alkynyl; (C1-C4) alkenyl, (C3-C5)cycloalkyl unsubstituted or substituted with 1, 2 or 3 halo , and Selected from OCF3; and X is selected from C-R7 and N (wherein R7 is H or halo). A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 6.

[0024] Embodiment 8.R2 comprises the moiety: [ka] and; where: R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R8 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R9 is selected from H, O-CH3, OH, CN, CH3, and halo; R 28 is SF5, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1 -C4) alkyl, and -C(O)H; X is selected from C-R7 and N; R7 is selected from H and halo A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 7.

[0025] Embodiment 9.R2 comprises the moiety: [ka] and; R6 is selected from H, Cl, CH3, F, and Br; R8 is selected from H, Cl, F, and CF3; R9 is selected from H, CH3, and Cl; R 28 are CF3, CF2H, -CH2CH3, Cl, SF5, Br, and -C(O)H Selected from; X is selected from C-R7 and N; R7 is selected from H and F A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 8.

[0026] Embodiment 10.R 26 is H and R 27 is H, A compound of the formula (I) or a pharmaceutically acceptable salt thereof.

[0027] Embodiment 11. R3 is unsubstituted or independently selected from halo and OH. (C1-C4) alkyl substituted with 1, 2, or 3 substituents, 11. A compound of formula (I) according to any one of 1 to 10, or a pharmaceutically acceptable salt thereof.

[0028] Embodiment 12. R3 is unsubstituted or one, two or more independently selected from halo and OH. (C1-C2) alkyl substituted with 1 or 3 substituents, preferably -CH2CH 3 or CH3, more preferably —CH2CH3. or a pharmaceutically acceptable salt thereof.

[0029] Embodiment 13. Y is N; [ka] is Y linked by a single bond. (I) or a pharmaceutically acceptable salt thereof.

[0030] Embodiment 14. [ka] is K connected by a single bond, and K is -CH2-, -CH2CH2-, - NH-, and (5-membered ring: [ka] and J is N, and A is selected from -C(O)-, -S(O)-, - S(O) 2- , and [ka] The compound of formula (I) according to any one of embodiments 1 to 13, wherein the linker is selected from or a pharmaceutically acceptable salt thereof.

[0031] Embodiment 15. [ka] are Ks linked by a single bond, K is -CH2-, J is N, and A is -C(O)-, -S(O)-, -S(O)2- and [ka] The compound of formula (I) according to any one of embodiments 1 to 14, wherein the linker is selected from or a pharmaceutically acceptable salt thereof.

[0032] Embodiment 16.A is a compound selected from -C(O)- and -S(O)2-, preferably -C(O)- The compound of formula (I) according to any one of embodiments 1 to 15, wherein and pharmaceutically acceptable salts thereof.

[0033] Embodiment 17. R5 independently comprises: -(C 1~ C4) alkyl, preferably methyl; where two R5 substituents on the same ring carbon atom are in the same position as the carbon atom to which they are attached. Together, (C 3~ C4) cycloalkylspirocycle or 3- or 4-membered heterocyclyl may form a spiro ring, wherein the heterocyclylspiro ring is formed by combining ring carbon atoms with and one ring heteroatom selected from O, N, and S; · [ka] is a carbon-nitrogen single bond, K and the R5 substituents on the adjacent carbon atom are joined to form ring C: [ka] wherein ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cycloalkyl ring. a fused (C3-C6) heterocyclyl ring, a fused phenyl ring, or a fused (C3-C6) heterocyclyl ring; A (C3-C6)heterocyclyl ring is a heterocyclyl ring consisting of ring carbon atoms and one heterocyclic group selected from O, N, and S. containing a ring heteroatom, and when K is -CH2- and J is N, the two R5 substituents are bonded to form (C1- C3) may form an alkylene bridge or a heteroalkylene bridge (wherein the hetero The alkylene bridge is one heteroatom selected from N and O, or -CH2- O-CH2- The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 16, selected from Acceptable salts.

[0034] Embodiment 18. R5 independently represents: -(C 1~ C4) alkyl, preferably methyl; · [ka] is a carbon-nitrogen single bond, K and the R5 substituents on the adjacent carbon atom are joined to form ring C: [ka] wherein ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cycloalkyl ring. a fused (C3-C6) heterocyclic ring, a fused (C3-C6) heterobutyl ring, The cyclocyclyl ring contains ring carbon atoms and one ring heteroatom selected from O, N, and S. have), and when K is -CH2- and J is N, the two R5 substituents are bonded to form (C1- C3) may form an alkylene bridge or a heteroalkylene bridge (wherein the hetero The alkylene bridge is one heteroatom selected from N and O, or -CH2- O-CH2- A compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 17, selected from Acceptable salts.

[0035] Embodiment 19. R5 independently comprises: -(C 1~ C2) alkyl, preferably methyl, and · [ka] is a carbon-nitrogen single bond, K and the R5 substituents on the adjacent carbon atom are joined to form ring C: [ka] wherein ring C is a fused (C3-C4) cycloalkyl ring, particularly a fused cycloalkyl ring. (a butyl ring) The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 18, selected from Acceptable salts.

[0036] Embodiment 20.R5 independently comprises: CH3 and y is 1 or 2, and · [ka] is a carbon-nitrogen single bond, K and the R5 substituents on the adjacent carbon atom are joined to form ring C: [ka] wherein ring C is a fused cyclobutyl ring. A compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 19, selected from Acceptable salts.

[0037] Embodiment 21. y is 0, 1, 2 or 3, preferably 0, 1 or 2. 21. A compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

[0038] Embodiment 22.R4 is [ka] (In the formula, R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 13 is H, -S-CH3, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents is selected from (C1-C2) alkyl; and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl, and cyclopropyl The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 21, selected from Acceptable salts.

[0039] Embodiment 23.R4 is [ka] (In the formula, R 10 is selected from H, F, Cl, CH3, and OCF3; R 11 is selected from H, Cl, F, and CH3; R 12 is selected from H, Cl, and CH3; R 13 is selected from H, —S—CH3, and CH3; and R 14 is H, CH3, -CH2CH3, cyclopropyl, -OCHF2, OCF3, and and Cl) The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 22, selected from Acceptable salts.

[0040] Embodiment 24. Formula (I) is a compound of formula 1a: [ka] is (Preferably, formula (I) is formula 1a), A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 23.

[0041] Embodiment 25. Formula (I) is a compound of formula 1b: [ka] 24. The compound of formula (I) according to any one of embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, Salt

[0042] Embodiment 26. Formula (I) is a compound of formula 1c: [ka] 24. The compound of formula (I) according to any one of embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, Salt

[0043] Embodiment 27. Formula (I) can be represented by formula 1d: [ka] 24. The compound of formula (I) according to any one of embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, Acceptable salt

[0044] Embodiment 28. Formula (I) is represented by formula 1e [ka] 24. The compound of formula (I) according to any one of embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, Salt

[0045] Embodiment 29. Formula (I) is a compound of formula 1f: [ka] 24. The compound of formula (I) according to any one of embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, Salt

[0046] Embodiment 30. Formula (I) is a compound of formula 1g: [ka] 25. The compound of formula (I) according to any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, Salt More preferably, formula (I) is formula 1g.

[0047] Embodiment 31. Formula (I) is a compound of formula 1h: [ka] The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 24 or 30, Acceptable salts Most preferably, formula (I) is formula 1h.

[0048] Embodiment 32. A compound of formula (Ig) as defined in any one of embodiments 1, 24, or 30. or a pharmaceutically acceptable salt thereof [ka] (Wherein R1 is [ka] Selected from; R 15 is H or F; R 16 is H or R 25 (R 24 )N- and; R 17 is H or F; R 18 is H or F; R 19 is H or F; R 20 is H or F; R 21 is H or CH3; R 22 is H, CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)- , (H3C)3C-OC(O)-; R 23 are H, CF3, CHF2CH2-, (H3C)3C-OC(O)-; R 24 is CH3; R 25is CHF2CH2-; R 26 is CH3, H or deuterium; R 27 is H or deuterium; R2 is part: [ka] and R6 is selected from H, Cl, CH3, F, and Br; R8 is selected from H, Cl, F, and CF3; R9 is selected from H, CH3, and Cl; R 28 are CF3, CF2H, -CH2CH3, Cl, SF5, Br, and -C(O)H Selected from; X is selected from C-R7 and N; R7 is selected from H and F; R3 is selected from CH3, CH2CH3, cyclopropyl, hydroxyethyl; R4 is [ka] Selected from; During the ceremony, R 10 is selected from H, F, Cl, CH3, and OCF3; R 11 is selected from H, Cl, F, and CH3; R 12 is selected from H, Cl, and CH3; R 13 is selected from H, —S—CH3, and CH3; R 14 is H, CH3, -CH2CH3, cyclopropyl, OCHF2, OCF3, and Selected from Cl; Y is N or CH, preferably N; y is 0, 1 or 2; R5 is CH3 or two R5 groups on adjacent carbon atoms are bonded together together with the carbon atom at the end to form a fused cyclobutyl ring: [ka] Forming and optionally a ring: [ka] wherein one or more H is replaced by deuterium; * indicates the point of attachment).

[0049] Embodiment 33. A compound of formula (I) according to any one of embodiments 1, 24 or 30, or and pharmaceutically acceptable salts thereof. [ka] (In the formula, R1 is [ka] Selected from; R 15 is H or F; R 16 is H or R 25 (R 24 )N- and; R 17 is H or F; R 18 is H or F; R 19 is H or F; R 20 is H or F; R 21 is H or CH3; R 22 are CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, ( H3C)3C-OC(O)-; R 23 are CF3, CHF2CH2-, (H3C)3C-OC(O)-; R 24 is CH3; R 25 is CHF2CH2-; R 26 is CH3, H or deuterium; R 27 is H or deuterium; R2 is part: [ka] and During the ceremony, R6 is selected from H, Cl, CH3, F, and Br; R8 is selected from H, Cl, F, and CF3; R9 is selected from H, CH3, and Cl; R 28 are CF3, CF2H, -CH2CH3, Cl, SF5, Br, and -C(O)H Selected from; X is selected from C-R7 and N; R7 is selected from H and F; R3 is selected from CH3, CH2CH3, cyclopropyl, and hydroxyethyl; R4 is [ka] Selected from; During the ceremony, R 10 is selected from H, F, Cl, CH3, and OCF3; R 11 is selected from H, Cl, F, and CH3; R 12 is selected from H, Cl, and CH3; R 13 is selected from H, and CH3; R 14is H, CH3, -CH2CH3, cyclopropyl, -OCHF2, OCF3, and and Cl; y is 0, 1 or 2; R5 is CH3 or two R5 groups on adjacent carbon atoms are bonded together together with the carbon atom at the end to form a fused cyclobutyl ring: [ka] and * indicates the point of attachment).

[0050] Embodiment 34.R1 is [ka] The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 33, selected from Acceptable salts.

[0051] Embodiment 35.R1 is [ka] or a pharmaceutically acceptable salt thereof. .

[0052] Embodiment 36.R1 is [ka] or a pharmaceutically acceptable salt thereof. .

[0053] Embodiment 37.R1 is [ka] or a pharmaceutically acceptable salt thereof.

[0054] Embodiment 38.R 28 is selected from CF3, SF5, and Br. 10. A compound of formula (I) according to any one of the following or a pharmaceutically acceptable salt thereof:

[0055] Embodiment 39.R 28 The compound of formula (I) according to embodiment 38, wherein is selected from CF3. or a pharmaceutically acceptable salt thereof.

[0056] Embodiment 40. X is a compound of formula (I) according to any one of embodiments 1 to 39, which is CR7. The compound or a pharmaceutically acceptable salt thereof.

[0057] Embodiment 41. A compound of formula (I) according to any one of embodiments 1 to 40, wherein R7 is H. or a pharmaceutically acceptable salt thereof.

[0058] Embodiment 42. The compound according to any one of embodiments 1 to 41, wherein R6 is Cl or CH3. A compound of formula (I) or a pharmaceutically acceptable salt thereof

[0059] Embodiment 43. A compound of formula (I) or its derivatives as described in embodiment 42, wherein R6 is Cl. Pharmaceutically acceptable salts.

[0060] Embodiment 44. A compound of formula (I) according to any one of embodiments 1 to 43, wherein R8 is F or H. ) or a pharmaceutically acceptable salt thereof.

[0061] Embodiment 45. A compound of formula (I) or its derivatives according to embodiment 44, wherein R8 is H. Pharmaceutically acceptable salts.

[0062] Embodiment 46. A compound of formula (I) according to any one of embodiments 1 to 45, wherein R9 is H. or a pharmaceutically acceptable salt thereof.

[0063] Embodiment 47.R 26 is H. The compound or a pharmaceutically acceptable salt thereof.

[0064] Embodiment 48 R 27 is H. The compound or a pharmaceutically acceptable salt thereof.

[0065] Embodiment 49.R 26 and R 27 are deuterium atoms, I) or a pharmaceutically acceptable salt thereof.

[0066] Embodiment 50. Any of embodiments 1 to 49, wherein R3 is —CH2—CH3. or a pharmaceutically acceptable salt thereof.

[0067] Embodiment 51. A compound of formula (I) according to any one of embodiments 1 to 50, wherein y is 0. or a pharmaceutically acceptable salt thereof.

[0068] Embodiment 52. Part: [ka] teeth, [ka] The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 51, selected from Acceptable salts.

[0069] Embodiment 53. Part: [ka] teeth, [ka] especially [ka] Selected from or or [ka] or a pharmaceutically acceptable salt thereof. .

[0070] Embodiment 54. Part: [ka] teeth, [ka] The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 51, selected from Acceptable salts.

[0071] Embodiment 55. Part: [ka] teeth, [ka] The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 54, selected from Acceptable salts.

[0072] Embodiment 56. Part: [ka] teeth, [ka] or a pharmaceutically acceptable salt thereof. .

[0073] Embodiment 57. Part: [ka] teeth, [ka] or a pharmaceutically acceptable salt thereof. .

[0074] Embodiment 58. Part: [ka] teeth, [ka] or a pharmaceutically acceptable salt thereof. .

[0075] Embodiment 59.R 10 is H, F, or Cl. or a pharmaceutically acceptable salt thereof.

[0076] Embodiment 60.R 11 is H or CH3. A compound of formula (I) or a pharmaceutically acceptable salt thereof

[0077] Embodiment 61.R 12 is H. or a pharmaceutically acceptable salt thereof

[0078] Embodiment 62.R 13 is H. or a pharmaceutically acceptable salt thereof.

[0079] Embodiment 63.R 14 is CH or H. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0080] Embodiment 64.R 14 is CH3, ) or a pharmaceutically acceptable salt thereof.

[0081] Embodiment 65.R4 is [ka] A compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 64, selected from Acceptable salts.

[0082] Embodiment 66.R4 is [ka] 66. The compound of formula (I) according to any of embodiments 65 or a pharmaceutically acceptable salt thereof, selected from: Acceptable salt.

[0083] Embodiment 67.R4 is [ka] 67. The compound of formula (I) according to any of embodiments 66 or a pharmaceutically acceptable salt thereof, selected from: Acceptable salt.

[0084] Embodiment 68.R1 is [ka] Selected from; R 15 is H or F; R 16 is H or R 25 (R 24 )N- and; R 17 is H or F; R 18 is H or F; R 19 is H or F; R 20 is H or F; R 21 is H or CH3; R 22 is H, CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)- , (H3C)3C-OC(O)-; R 23 are H, CF3, CHF2CH2-, (H3C)3C-OC(O)-; R 24 is CH3; R 25 is CHF2CH2-; and R4 is [ka] Selected from: where: R 10 is selected from H, F, Cl, CH3, and OCF3; R 11 is selected from H, Cl, F, and CH3; R 12 is selected from H, Cl, and CH3; R 13 is selected from H, and CH3; R 14 is H, CH3, -CH2CH3, cyclopropyl, -OCHF2, OCF3, and and Cl A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 and 24 to 31. Salt, or a pharmaceutically acceptable salt thereof.

[0085] Embodiment 69.R1 teeth, [ka] Selected from; portion: [ka] teeth, [ka] (Especially here [ka] teeth, [ka] [ka] is) Selected from; portion [ka] teeth, [ka] Selected from; and R4 is [ka] A compound of formula (I) or its derivatives according to any one of embodiments 1 and 24 to 31, selected from A pharmaceutically acceptable salt of

[0086] Embodiment 70.R1 is [ka] Selected from; portion: [ka] teeth, [ka] especially [ka] and [ka] Selected from; portion: [ka] teeth, [ka] especially, [ka] Selected from; And R4 is [ka] especially, [ka] Selected from: A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 and 24 to 31. Salt that can be used.

[0087] Embodiment 71. The compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The compound of formula (I) according to any of embodiments 1, 24, 30 and 31, selected from or a pharmaceutically acceptable salt thereof.

[0088] Embodiment 72. The compound is

[0089] [ka] [ka] [ka] The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 39, selected from Acceptable salts.

[0090] Embodiment 73. The compound is [ka] The compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1, 39 or 40, selected from Acceptable salts.

[0091] Embodiment 74. The compound of any one of embodiments 1 to 73, wherein the compound is in a non-zwitterionic form. A compound of the formula (I) or a pharmaceutically acceptable salt thereof.

[0092] Embodiment 75. The compound of any one of embodiments 1 to 73, wherein the compound is in zwitterionic form. or a pharmaceutically acceptable salt thereof.

[0093] Embodiment 76. The compound is a mixture of zwitterionic and non-zwitterionic forms. A compound of Formula (I) according to any one of Forms 1 to 73, or a pharmaceutically acceptable salt thereof.

[0094] Embodiment 77. The R4 group is present in zwitterionic form (d) or (e), 73. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 73. [ka]

[0095] Embodiment 78.R4 is [ka] 74. The compound of formula (I) according to any one of embodiments 1 to 73, which is present in a zwitterionic form selected from ) or a pharmaceutically acceptable salt thereof.

[0096] Embodiment 79. R4 is a mixture of zwitterionic forms (a) and (b) as described in embodiment 78 74. A compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 73, which is present as a compound. A commercially acceptable salt.

[0097] Embodiment 80.R4 is Non-zwitterionic form (e) and zwitterionic form (a) or (b) [ka] or The non-zwitterionic form (e) and the zwitterionic forms (a) and (b) [ka] The compound of formula (I) or its derivatives according to any one of embodiments 1 to 73, wherein the compound is present as a mixture of A pharmaceutically acceptable salt of

[0098] Embodiment 81. R4 is in the zwitterionic form (c): [ka] 74. The compound of formula (I) according to any one of embodiments 1 to 73, or a pharmaceutically acceptable salt thereof, Salt that can be used.

[0099] Embodiment 82. R4 can be obtained in a zwitterionic form (c) and a non-zwitterionic form (d): [ka] The compound of formula (I) according to any one of embodiments 1 to 73, wherein the compound is present as a mixture of both or a pharmaceutically acceptable salt thereof.

[0100] Embodiment 83. Compound N-(2-chloro-4-(trifluoromethyl)phenyl)-2 -(2-(3,6-dihydro-2H-pyran-4-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)acetate Toamide is Non-zwitterionic forms: [ka] or zwitterionic form: [ka] or zwitterionic form: [ka] or a mixture of any two or three of the foregoing forms, 1. A compound of formula (I) according to any one of claims 1 to 10.

[0101] Embodiment 84. The compound (R)—N-(2-chloro-4-(trifluoromethyl)phenyl) yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-( 4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazine (1-phenyl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4 (7H)-yl)acetamide Non-zwitterionic forms: [ka] or zwitterionic form: [ka] or zwitterionic form: [ka] or a mixture of any two or three of the foregoing forms, 1. A compound of formula (I) according to any one of claims 1 to 10.

[0102] Embodiment 85. The compound N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl) yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-( 4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl )-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H)-i Acetamide is Non-zwitterionic forms: [ka] or zwitterionic form: [ka] or zwitterionic form: [ka] or a mixture of any two or three of the foregoing forms, 1. A compound of formula (I) according to any one of claims 1 to 10.

[0103] Embodiment 86. Compound 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5 -Ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperidine) (radin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine -4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetate Toamide is Non-zwitterionic forms: [ka] or zwitterionic form: [ka] or zwitterionic form: [ka] or a mixture of any two or three of the foregoing forms, 1. A compound of formula (I) according to any one of claims 1 to 10.

[0104] Embodiment 87: Compound N-(2-chloro-4-(trifluoromethyl)phenyl)-2 -(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(3 -Hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]tri Azolo[1,5-a]pyrimidin-4(7H)-yl)acetamide is Non-zwitterionic forms: [ka] or zwitterionic form: [ka] or a mixture of said forms, I) Compound.

[0105] Embodiment 88. The compound of any one of embodiments 1 to 73, wherein the compound is a sodium salt. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0106] Embodiment 89. The compound of any one of the formulae described in any one of embodiments 1 to 88 is in amorphous form. (I) or a pharmaceutically acceptable salt thereof. For example, the compound may be in the form of sodium hydroxide in an amorphous form. It is um salt.

[0107] Embodiment 90. The compound of formula (I) according to any one of embodiments 1 to 88, in crystalline form. I) or a pharmaceutically acceptable salt thereof.

[0108] Embodiment 91. The compound is in crystalline form [ka] 32. The compound of formula (I) according to any of embodiments 1, 24, 30 and 31, wherein

[0109] Embodiment 92. The compound is in crystalline form [ka] 32. The compound of formula (I) according to any of embodiments 1, 24, 30 and 31, wherein

[0110] Embodiment 93. The compound is in crystalline form [ka] 32. The compound of formula (I) according to any of embodiments 1, 24, 30 and 31, wherein

[0111] Embodiment 94. A compound of Formula I according to any of embodiments 1 to 31. The compound is in crystalline form [ka] 32. The compound of formula (I) according to any of embodiments 1, 24, 30 and 31, wherein

[0112] Embodiment 95. The compound is in crystalline form. [ka] 32. The compound of formula (I) according to any of embodiments 1, 24, 30 and 31, wherein

[0113] Embodiment 96. The compound is a compound of the formula described in embodiments 91-95 in substantially pure form. Compound (I).

[0114] Embodiment 97. The crystalline form described in embodiment 91 has a pH of 11.85±0.05 at a temperature of about 22° C. .2, 13.71±0.2, 14.46±0.2, 15.33±0.2, 17.03±0 .2, 18.33±0.2, 19.98±0.2, 22.42±0.2, 22.95±0 or four or more 2θ values ​​selected from the group consisting of 0.2 and 27.20±0.2; At a temperature of approximately 22°C, the values ​​were 6.78±0.2, 8.97±0.2, 11.88±0.2, and 13. 55±0.2, 13.74±0.2, 14.48±0.2, 15.34±0.2, 16. 83±0.2, 17.03±0.2, 18.30±0.2, 19.49±0.2, 19. 94±0.2, 21.28±0.2, 21.51±0.2, 22.38±0.2, 22. 91±0.2, 23.27±0.2, 25.41±0.2, 27.26±0.2, 29. 4 selected from the group consisting of 29.03±0.2, 29.78±0.2 and 29.96±0.2 2. The compound of formula (I) according to embodiment 1, characterized by an X-ray powder diffraction pattern comprising at least two theta values ​​of Compound.

[0115] Embodiment 98. The crystalline form described in embodiment 91 has a pH of 11.85±0.0 at a temperature of about 22° C. .2, 13.71±0.2, 14.46±0.2, 15.33±0.2, 17.03±0 .2, 18.33±0.2, 19.98±0.2, 22.42±0.2, 22.95±0 or comprising five or more 2θ values ​​selected from the group consisting of 0.2 and 27.20±0.2; At a temperature of approximately 22°C, the values ​​were 6.78±0.2, 8.97±0.2, 11.88±0.2, and 13. 55±0.2, 13.74±0.2, 14.48±0.2, 15.34±0.2, 16. 83±0.2, 17.03±0.2, 18.30±0.2, 19.49±0.2, 19. 94±0.2, 21.28±0.2, 21.51±0.2, 22.38±0.2, 22. 91±0.2, 23.27±0.2, 25.41±0.2, 27.26±0.2, 29. 5 selected from the group consisting of 29.03±0.2, 29.78±0.2 and 29.96±0.2 2. The compound of claim 1, further characterized by an X-ray powder diffraction pattern comprising at least two theta values ​​of Compound (I).

[0116] Embodiment 99. The crystalline form of embodiment 91 has an X-ray powder diffraction pattern as shown in FIG. 1 or FIG. The compound of formula (I) according to embodiment 1, characterized by an X-ray diffraction pattern substantially the same as that of Compound.

[0117] Embodiment 100. The crystalline form described in embodiment 92 has a crystallinity of 10.29±10.29 at a temperature of about 22° C. 0.2, 13.31±0.2, 14.01±0.2, 15.26±0.2 and 17.34 characterized by a powder X-ray diffraction pattern comprising four or more 2θ values ​​selected from the group consisting of: The compound of formula (I) according to embodiment 1,

[0118] Embodiment 101. The crystalline form described in embodiment 92 has a crystallinity of 10.29±10.29 at a temperature of about 22° C. 0.2, 13.31±0.2, 14.01±0.2, 15.26±0.2 and 17.34 Further characterizing the powder X-ray diffraction pattern is a pattern comprising five 2θ values ​​selected from the group consisting of: 2. A compound of formula (I) as defined in embodiment 1,

[0119] Embodiment 102. The crystalline form described in embodiment 92 has a powder X-ray diffraction pattern as shown in FIG. The compound of formula (I) according to embodiment 1, characterized by an X-ray diffraction spectrum substantially the same as .

[0120] Embodiment 103. The crystalline form described in embodiment 93 has a pH of 9.45±0 at a temperature of about 22° C. .2, 12.75±0.2, 13.28±0.2, 21.69±0.2, 25.25±0 X-ray powder containing four or more 2θ values ​​selected from the group consisting of 0.2 and 26.85±0.2 2. The compound of formula (I) as defined in embodiment 1, characterized by its diffraction pattern.

[0121] Embodiment 104. The crystalline form described in embodiment 93 has a pH of 9.45±0 at a temperature of about 22° C. .2, 12.75±0.2, 13.28±0.2, 21.69±0.2, 25.25±0 X-ray powder containing five or more 2θ values ​​selected from the group consisting of 0.2 and 26.85±0.2 2. The compound of formula (I) as described in embodiment 1, further characterized by its diffraction pattern.

[0122] Embodiment 105. The crystalline form described in embodiment 93 has a powder X-ray diffraction pattern as shown in FIG. 2. The compound of formula (I) as defined in embodiment 1, characterized by an X-ray diffraction pattern substantially the same as:

[0123] Embodiment 106. The crystalline form described in embodiment 94 has a crystallinity of 11.81±1.00 at a temperature of about 22° C. 0.2, 13.75±0.2, 14.45±0.2, 15.32±0.2, 17.04± 0.2, 17.40±0.2, 18.27±0.2, 19.95±0.2, 22.92± Powder X containing four or more 2θ values ​​selected from the group consisting of 0.2 and 27.13±0.2 2. The compound of formula (I) as defined in embodiment 1, characterized by its ray diffraction pattern.

[0124] Embodiment 107. The crystalline form described in embodiment 94 has a crystallinity of 11.81±1.00 at a temperature of about 22° C. 0.2, 13.75±0.2, 14.45±0.2, 15.32±0.2, 17.04± 0.2, 17.40±0.2, 18.27±0.2, 19.95±0.2, 22.92± Powder X containing five or more 2θ values ​​selected from the group consisting of 0.2 and 27.13±0.2 2. The compound of formula (I) as described in embodiment 1, further characterized by its ray diffraction pattern.

[0125] Embodiment 108. The crystalline form described in embodiment 94 has a powder X-ray diffraction pattern shown in FIG. The compound of formula (I) according to embodiment 1, characterized by an X-ray diffraction spectrum substantially the same as .

[0126] Embodiment 109. The crystalline form described in embodiment 95 has a pH of 13.20±1.0 at a temperature of about 22° C. 0.2, 14.78±0.2, 15.97±0.2, 16.91±0.2, 19.95± 0.2, 20.85±0.2, 24.43±0.2, 25.47±0.2 and 31.06 characterized in that the X-ray powder diffraction pattern contains four or more 2θ values ​​selected from the group consisting of: 2. The compound of formula (I) as defined in embodiment 1,

[0127] Embodiment 110. The crystalline form described in embodiment 95 has a crystallinity of 13.20±100% at a temperature of about 22° C. 0.2, 14.78±0.2, 15.97±0.2, 16.91±0.2, 19.95± 0.2, 20.85±0.2, 24.43±0.2, 25.47±0.2 and 31.06 and an X-ray powder diffraction pattern comprising five or more 2θ values ​​selected from the group consisting of: 2. The compound of formula (I) according to embodiment 1, characterized in that:

[0128] Embodiment 111. The crystalline form described in embodiment 95 has a powder X-ray diffraction pattern shown in FIG. The compound of formula (I) according to embodiment 1, characterized by an X-ray diffraction spectrum substantially the same as .

[0129] Embodiment 112. Formula (I) is a compound of formula 1a: [ka] [Wherein R1 is [ka] Selected from; R 33 is F; R 15 is halo, azetidinyl, or pyrrolidinyl, wherein said azetidinyl and The pyrrolidinyl is linked to the rest of the molecule through the N atom and is unsubstituted or has one or more substituted with two Fs), R 16 is R 25 (R 24 )N- (where R 24 is H or (C1-C2) alkane Kill and R 25 is H or (C1-C2) alkyl; R 17 is a halo; R 18 is a halo; R 19 is a halo; R 20 is a halo; R 21 is (C1-C2) alkyl; R 22 and R 23 are each independently (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (H3C)3C-OC(O)(CH2) n -; where n is 0, 1, or 2 Selected from; and R 30 is CH3; R2 is the part [ka] and where: R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R8 is H, halo, and unsubstituted or substituted with 1, 2 or 3 halo (C1 C4) alkyl; R9 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R 28 is SF5, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1 -C4) alkyl, and -C(O)H; X is selected from C-R7 and N; R7 is selected from H and halo; R 26 is H and R 27 is H; R3 is -CH2CH3 or CH3; A is a linker selected from -C(O)- and -S(O)2-, preferably -C(O)- and; and R4 is [ka] is selected from where: R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 13 is H, -S-CH3 halo, unsubstituted or substituted with 1, 2 or 3 halo substituents and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl, and cyclopropyl or a pharmaceutically acceptable salt thereof. Preferably, formula (I) or 1a is 1g: [ka] and more preferably 1h: [ka] or a pharmaceutically acceptable salt thereof.

[0130] Embodiment 113. Formula (I) is a compound of formula 1b: [ka] [Wherein R1 is [ka] Selected from; R 33 is F; R 15 is halo, azetidinyl, or pyrrolidinyl, wherein said azetidinyl and The pyrrolidinyl is linked to the rest of the molecule through the N atom and is unsubstituted or has one or more substituted with two Fs), R 16 is R 25 (R 24 )N- (where R 24 is H or (C1-C2) alkane Kill and R 25 is H or (C1-C2) alkyl; R 17 is a halo; R 18 is a halo; R 19 is a halo; R 20 is a halo; R 21 is (C1-C2) alkyl; R 22 and R 23 are each independently (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (H3C)3C-OC(O)(CH2) n -; where n is 0, 1, or 2 Selected from; and R 30 is CH3; R2 is part: [ka] (In the formula, R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R8 is H, halo, and unsubstituted or substituted with 1, 2 or 3 halo (C1 C4) alkyl; R9 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R 28 is SF5, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1 -C4) alkyl, and -C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo and; R 26 is H and R 27 is H; R3 is -CH2CH3 or CH3; A is a linker selected from -C(O)- and -S(O)2-, preferably -C(O)- and; and R4 is [ka] (In the formula, R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 13 is H, -S-CH3 halo, unsubstituted or substituted with 1, 2 or 3 halo substituents and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl, and cyclopropyl Select from or a pharmaceutically acceptable salt thereof. Formula 1b is preferably 1b1: [ka] and In particular, where Y is N.

[0131] Embodiment 114. Formula (I) is a compound of formula 1c: [ka] [Wherein R1 is [ka] Selected from; R 33 is F; R 15 is halo, azetidinyl, or pyrrolidinyl, wherein said azetidinyl and The pyrrolidinyl is linked to the rest of the molecule through the N atom and is unsubstituted or has one or more substituted with two F's); R 16 is R 25 (R 24 )N- (where R 24 is H or (C1-C2) alkane Kill and R 25 is H or (C1-C2) alkyl; R 17 is a halo; R 18 is a halo; R 19 is a halo; R 20 is a halo; R 21 is (C1-C2)] alkyl; R 22 and R 23 are each independently (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (H3C)3C-OC(O)(CH2) n -; where n is 0, 1, or 2 Selected from; and R 30 is CH3; R2 is part: [ka] (In the formula, R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R8 is H, halo, and unsubstituted or substituted with 1, 2 or 3 halo (C1 C4) alkyl; R9 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R 28 is SF5, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1 -C4) alkyl, and -C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo and; R 26 is H and R 27 is H; R3 is -CH2CH3 or CH3; A is a linker selected from -C(O)- and -S(O)2-, preferably -C(O)- and; and R4 is [ka] (In the formula, R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 13 is H, -S-CH3 halo, unsubstituted or substituted with 1, 2 or 3 halo substituents and R 14is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl, and cyclopropyl (selected from or a pharmaceutically acceptable salt thereof. Formula 1c is preferably 1c1: [ka] and In particular, where Y is N.

[0132] Embodiment 115. Formula (I) is a compound of formula 1d: [ka] [Wherein R1 is [ka] Selected from; R 33 is F; R 15 is halo, azetidinyl, or pyrrolidinyl, wherein said azetidinyl and The pyrrolidinyl is linked to the rest of the molecule through the N atom and is unsubstituted or has one or more substituted with two Fs), R 16 is R 25 (R 24 )N- (where R 24 is H or (C1-C2) alkane Kill and R 25 is H or (C1-C2) alkyl; R 17 is a halo; R 18 is a halo; R 19is a halo; R 20 is a halo; R 21 is (C1-C2) alkyl; R 22 and R 23 teeth, Each independently, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (H3C)3C-OC(O)(CH2) n -; where n is 0, 1, or 2 Selected from; and R 30 is CH3; R2 is part: [ka] (In the formula, R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R8 is H, halo, and unsubstituted or substituted with 1, 2 or 3 halo (C1 C4) selected from; R9 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) are selected from; R 28 is SF5, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1 -C4), and -C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo and; R 26 is H and R 27 is H; R3 is -CH2CH3 or CH3; A is a linker selected from -C(O)- and -S(O)2-, preferably -C(O)- and; and R4 is [ka] (In the formula, R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 13 is H, -S-CH3 halo, unsubstituted or substituted with 1, 2 or 3 halo substituents and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl, and cyclopropyl Select from or a pharmaceutically acceptable salt thereof. Formula 1d is preferably 1d1: [ka] and In particular, where Y is N.

[0133] Embodiment 116. Formula (I) is represented by formula 1e: [ka] [Wherein R1 is [ka] Selected from; R 33 is F; R 15 is halo, azetidinyl, or pyrrolidinyl, wherein said azetidinyl and The pyrrolidinyl is linked to the rest of the molecule through the N atom and is unsubstituted or has one or more substituted with two Fs), R 16 is R 25 (R 24 )N- (where R 24 is H or (C1-C2) alkane Kill and R 25 is H or (C1-C2) alkyl; R 17 is a halo; R 18 is a halo; R 19 is a halo; R 20 is a halo; R 21 is (C1-C2) alkyl; R 22 and R 23 are each independently (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (H3C)3C-OC(O)(CH2)n -; where n is 0, 1, or 2 Selected from; and R 30 is CH3; R2 is part: [ka] (In the formula, R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R8 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) are selected from; R9 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) are selected from; R 28 is SF5, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1 -C4), and -C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo and; R 26 is H and R 27 is H; R3 is -CH2CH3 or CH3; A is a linker selected from -C(O)- and -S(O)2-, preferably -C(O)- and; and R4 is [ka] (In the formula, R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 13 is H, -S-CH3 halo, unsubstituted or substituted with 1, 2 or 3 halo substituents and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl, cyclopropyl Select from or a pharmaceutically acceptable salt thereof. Formula 1e is preferably 1e1: [ka] and In particular, where Y is N.

[0134] Embodiment 117. Formula (I) is a compound of formula 1f: [ka] [Wherein R1 is [ka] Selected from; R 33 is F; R 15 is halo, azetidinyl, or pyrrolidinyl, wherein said azetidinyl and The pyrrolidinyl is linked to the rest of the molecule through the N atom and is unsubstituted or has one or more substituted with two Fs), R 16 is R 25 (R 24 )N- (where R 24 is H or (C1-C2) alkane Kill and R 25 is H or (C1-C2) alkyl; R 17 is a halo; R 18 is a halo; R 19 is a halo; R 20 is a halo; R 21 is (C1-C2) alkyl; R 22 and R 23 are each independently (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (H3C)3C-OC(O)(CH2) n -; where n is 0, 1, or 2 Selected from; and R 30 is CH3; R2 is part: [ka] (In the formula, R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R8 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R9 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R 28 is SF5, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1 -C4) alkyl, and -C(O)H; X is selected from C-R7 and N; R7 is selected from H and halo and; R 26 is H and R 27 is H; R3 is -CH2CH3 or CH3; A is a linker selected from -C(O)- and -S(O)2-, preferably -C(O)- and; and R4 is [ka] (In the formula, R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 13is H, -S-CH3 halo, unsubstituted or substituted with 1, 2 or 3 halo substituents and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl, cyclopropyl Select from or a pharmaceutically acceptable salt thereof. Formula 1f is preferably 1f1: [ka] In particular, where Y is N.

[0135] Embodiment 1.1. A compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof (In the formula, [ka] (I) is 1 g, and R1 is [ka] Selected from; R 15 is H or F; R 16 is H or R 25 (R 24 )N- and; R 17 is H or F; R 18 is H or F; R 19 is H or F; R 20 is H or F; R 21is H or CH3; R 22 are CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, ( H3C)3C-OC(O)-; R 23 are CF3, CHF2CH2-, (H3C)3C-OC(O)-; R 24 is CH3; R 25 is CHF2CH2-; R 26 is CH3, H or deuterium; R 27 is H or deuterium; R2 is part: [ka] wherein R6 is selected from H, Cl, CH3, F, and Br; R8 is selected from H, Cl, F, and CF3; R9 is selected from H, CH3, and Cl; R 28 are CF3, CF2H, -CH2CH3, Cl, SF5, Br, and -C(O)H Selected from; X is selected from C-R7 and N; R7 is selected from H and F and; R3 is selected from CH3, CH2CH3, cyclopropyl, and hydroxyethyl; R4 is [ka] (In the formula, R 10 is selected from H, F, Cl, CH3, and OCF3; R 11 is selected from H, Cl, F, and CH3; R 12is selected from H, Cl, and CH3; R 13 is selected from H, and CH3; R 14 is H, CH3, -CH2CH3, cyclopropyl, -OCHF2, OCF3, and and Cl) Selected from; y is 0, 1 or 2; R5 is CH3 or two R5 groups on adjacent carbon atoms are bonded together together with the carbon atom at the end to form a fused cyclobutyl ring: [ka] Forming; and * indicates the attachment point A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment 1. or a pharmaceutically acceptable salt thereof.

[0136] Embodiment 2.1.R1 is [ka] or a pharmaceutically acceptable salt thereof.

[0137] Embodiment 3.1.R1 is [ka] The compound of formula (I) according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, selected from Salt.

[0138] Embodiment 4.1.R1 is [ka] The compound of formula (I) according to embodiments 1 to 3 or a pharmaceutically acceptable salt thereof, selected from salt.

[0139] Embodiment 5.1.R1 is [ka] or a pharmaceutically acceptable salt thereof,

[0140] Embodiment 6.1.R 28 is selected from CF3, SF5, and Br. or a pharmaceutically acceptable salt thereof.

[0141] Embodiment 7.1.R 28 is selected from CF3, or a pharmaceutically acceptable salt thereof.

[0142] Embodiment 8.1.X is a compound of formula (I) according to embodiments 1 to 7, which is CR7, or and pharmaceutically acceptable salts thereof.

[0143] Embodiment 9.1. A compound of formula (I) or its derivatives as described in embodiments 1 to 8, wherein R7 is H. Pharmaceutically acceptable salts.

[0144] Embodiment 10.1. The compound of formula (I) according to any one of embodiments 1 to 9, wherein R6 is Cl or CH3. or a pharmaceutically acceptable salt thereof

[0145] Embodiment 11.1. Compounds of Formula (I) according to any one of embodiments 1 to 10, wherein R6 is Cl. and pharmaceutically acceptable salts thereof.

[0146] Embodiment 12.1. The compounds of formula (I) according to embodiments 1 to 11, wherein R8 is F or H. or a pharmaceutically acceptable salt thereof.

[0147] Embodiment 13.1. A compound of formula (I) according to any one of embodiments 1 to 12, wherein R8 is H; or and pharmaceutically acceptable salts thereof.

[0148] Embodiment 14.1. A compound of formula (I) according to any one of embodiments 1 to 13, wherein R9 is H; or and pharmaceutically acceptable salts thereof.

[0149] Embodiment 15.1.R 26 is H. is a pharmaceutically acceptable salt thereof.

[0150] Embodiment 16.1.R 27 is H. A commercially acceptable salt.

[0151] Embodiment 17.1.R 26 and R 27 In embodiments 1 to 14, A compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0152] Embodiment 18.1. The compound of formula (I) according to any one of embodiments 1 to 18, wherein R3 is —CH2—CH3. I) or a pharmaceutically acceptable salt thereof.

[0153] Embodiment 19.1. A compound of formula (I) according to any one of embodiments 1 to 18, wherein y is 0; or and pharmaceutically acceptable salts thereof.

[0154] Embodiment 20.1. Part: [ka] teeth, [ka] 19. The compound of formula (I) according to embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, selected from Salt that can be used.

[0155] Embodiment 21.1 Part: [ka] teeth, [ka] The compound of formula (I) according to embodiments 1 to 18 and 20, or a pharmaceutical composition thereof, selected from Acceptable salts.

[0156] Embodiment 22.1 Part: [ka] teeth, [ka] The compound of formula (I) according to embodiments 1 to 18 and 20, or a pharmaceutical composition thereof, selected from Acceptable salts.

[0157] Embodiment 23.1 Part: [ka] teeth, [ka] 23. The compound of formula (I) according to embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, selected from: Salt that can be used.

[0158] Embodiment 24.1 Part: [ka] teeth, [ka] 24. The compound of formula (I) according to any one of embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, selected from: Salt that can be used.

[0159] Embodiment 25.1 Part: [ka] teeth, [ka] 25. The compound of formula (I) according to embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, selected from Salt that can be used.

[0160] Embodiment 26.1 Part: [ka] teeth, [ka] The compound of formula (I) according to any one of embodiments 1 to 25 or a pharmaceutically acceptable salt thereof, selected from Salt.

[0161] Embodiment 27.1 R 10 is H, F or Cl, I) or a pharmaceutically acceptable salt thereof.

[0162] Embodiment 28.1 R 11 is H or CH3, ) or a pharmaceutically acceptable salt thereof.

[0163] Embodiment 29.1 R 12Compounds of formula (I) as defined in embodiments 1-28, wherein or a pharmaceutically acceptable salt thereof.

[0164] Embodiment 30.1 R 13 Compounds of formula (I) as defined in embodiments 1 to 29, wherein or a pharmaceutically acceptable salt thereof.

[0165] Embodiment 31.1 R 14 is CH or H, ) or a pharmaceutically acceptable salt thereof.

[0166] Embodiment 32.1 R 14 is CH3. or a pharmaceutically acceptable salt thereof. Embodiment 33.1 R4 is [ka] The compound of formula (I) according to any one of embodiments 1 to 32 or a pharmaceutically acceptable salt thereof, selected from Salt.

[0167] Embodiment 34.1 R4 is [ka] The compound of formula (I) according to embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, is selected from Salt.

[0168] Embodiment 35.1 R4 is [ka] The compound of formula (I) according to embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, selected from Salt.

[0169] Embodiment 36.1 R1 is [ka] Selected from; R 15 is H or F; R 16 is H or R 25 (R 24 )N- and; R 17 is H or F; R 18 is H or F; R 19 is H or F; R 20 is H or F; R 21 is H or CH3; R 22 is H, CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)- , (H3C)3C-OC(O)-; R 23 are H, CF3, CHF2CH2-, (H3C)3C-OC(O)-; R 24 is CH3; R 25 is CHF2CH2-; and R4 is [ka] (In the formula, R 10 is selected from H, F, Cl, CH3, and OCF3; R 11 is selected from H, Cl, F, and CH3; R 12 is selected from H, Cl, and CH3; R 13 is selected from H, and CH3; R 14 is H, CH3, -CH2CH3, cyclopropyl, -OCHF2, OCF3, and and Cl) Selected from A compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiments 1 and 6 to 26, or a pharmaceutically acceptable salt thereof.

[0170] Embodiment 37.1 R1 is [ka] Selected from; And part: [ka] teeth, [ka] Selected from: [ka] teeth, [ka] Selected from; and R4 is [ka] Selected from: A compound of formula (I) as defined in embodiment 1 or a pharmaceutically acceptable salt thereof.

[0171] Embodiment 38.1 R1 is [ka] Selected from: [ka] teeth, [ka] Selected from: [ka] teeth, [ka] especially, [ka] Selected from; And R4 is [ka] especially, [ka] Selected from: A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in embodiment 37.

[0172] In a further aspect, the invention is as claimed herein.

[0173] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R1 is cycloalkenyl, wherein the cycloalkenyl has 5 or 6 ring carbon atoms; and a partially unsaturated monocyclic ring containing 1, 2, 3 or 4, preferably 1 or 2 R 33 where R33 is halo, and said cycloalkenyl or halo-substituted cycloalkenyl is 0, 1 or 2 R 15 Is substituted by a substituent, Alternatively, R1 is heterocyclyl, wherein said heterocyclyl is and 1 or 2 ring heteroatoms independently selected from N, O, and S. a partially unsaturated 5- or 6-membered group, said heterocyclyl being unbridged or bridged; the bridge is 1 or 2 carbon atoms, and wherein the heterocyclyl is a non-substituted or 1, 2, 3 or 4, preferably 1 or 2 R 33 is replaced by where R 33 is halo, and said heterocyclyl or halo-substituted heterocyclyl is independently Then, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 Selected from or is substituted by 0, 1 or 2 substituents Alternatively, R1 is heteroaryl, wherein said heteroaryl is a ring carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, preferably 1 or a 5- or 6-membered fully unsaturated monocyclic group containing two ring heteroatoms, wherein the ring S atom the total number of ring O atoms does not exceed 1, and the total number of ring O atoms does not exceed 1, wherein said heteroaryl is a non-substituted Exchange, or R 21 and R 30 by one, two or three substituents independently selected from substituted, where R 21 and R 30 is independent of halo and (C1-C4) alkyl wherein the (C1-C4) alkyl is unsubstituted or selected from the group consisting of 1, 2 or 3 alkyl groups. is substituted with halo, And each R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 is independent hand, Halo unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C4) Alkyl-O- , unsubstituted or substituted with OH, —O—(C1-C2)alkyl or 1, 2 or 3 halo substituted (C1-C4) alkyl, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (C1-C4) alkyl-OC(O)(CH2) n , =O azetidinyl or pyrrolidinyl (wherein the azetidinyl and pyrrolidinyl are N-atoms) and each is unsubstituted or substituted with 1 or 2 F. (which has been replaced), ·R 25 (R 24 )N-(where R 24 is H or unsubstituted or 1, 2 or 3 H is (C1-C4) alkyl substituted with 1, 25 is H or unsubstituted or 1, 2 or or (C1-C4) alkyl substituted with 3 halo. OH Selected from where n is 0, 1 or 2; Especially R1, cycloalkenyl, wherein the cycloalkenyl has 5 or 6 ring carbon atoms; and a partially unsaturated monocyclic ring containing cycloalkenyl, wherein the cycloalkenyl is unsubstituted or is one or two R 33 where R 33 is halo, preferably F and the cycloalkenyl or halo-substituted cycloalkenyl is 0 or 1 R 15 replacement group, preferably one substituent, and R 15 teeth, h) unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C2) Alkyl-O -, i) (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 halo; j) HOC(O)-(CH2) n -, k) H3C-C(O)(CH2) n -, l) H3C-OC(O)(CH2) n , m)=O, and n)R 25 (R 24 )N-, H(where R 24 is H or unsubstituted or 1, 2 or 3 (C1-C2) alkyl substituted with one halo, R 25 is H or unsubstituted or 1, (C1-C2) alkyl substituted with 2 or 3 halo is selected from n is 0 or 1; where: R of the cycloalkenyl or halo-substituted cycloalkenyl 15 The substituents a) to g) are adjacent to the ring atom where the chloroalkenyl or halo-substituted cycloalkenyl is attached to the rest of the molecule and preferably, the cycloalkenyl or halo-substituted cycloalkenyl The ring has one R in the para position relative to the rest of the molecule. 15 is a 6-membered ring having a substituent, The cycloalkenyl or halo-substituted cycloalkenyl has two adjacent R1 ring carbon atoms. is connected to the remainder of the compound via a double-bonded R1 ring carbon atom; Alternatively, R1 is heterocyclyl, wherein said heterocyclyl is a ring carbon atom and and fully saturated containing 1 or 2 ring heteroatoms independently selected from N, NH, O and S or a partially unsaturated 5- or 6-membered group, wherein the heterocyclyl is unbridged or bridged, said bridge being 1 or 2 carbon atoms, wherein said heterocyclyl is unsubstituted or has one or two R 33 where R 33 Halo, preferred or F, and said heterocyclyl or halo-substituted heterocyclyl is independently R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 0 or 1 selected from and R 15 , R 16 , R 17 , R 18 , R 19 , R2 0, R 22 and R 23 is, independently, i) unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C4) Alkyl-O -, j) unsubstituted or substituted with OH, —O—(C1-C2)alkyl or 1, 2 or 3 halo substituted (C1-C4) alkyl, k) HOC(O)-(CH2) n-, l) H3C-C(O)(CH2) n -, m) H3C-OC(O)(CH2) n , n)=O o)R 25 (R 24 )N-(where R 24 is H, unsubstituted or substituted with 1, 2 or 3 halo groups is (C1-C2) alkyl substituted with R 25 is H, unsubstituted or 1, 2 or 3 (C1-C2) alkyl substituted with one halo p)OH is selected from where n is 0 or 1; and The substituents a) to h) of the heterocyclyl or halo-substituted heterocyclyl are and preferably, no halo- or halo-substituted heterocyclyl is present on the ring atom that is attached to the remainder of the molecule. The heterocyclyl or halo-substituted heterocyclyl is a six-membered ring that is At the meta or para position, preferably at the para position, 0 or 1 selected from a) to h) has a substituent, and The heterocyclyl may be linked to the remainder of the compound by a double bond at the R1 ring nitrogen atom or adjacent ring atoms. linked via the R ring carbon atom to which it is attached; Alternatively, R1 is heteroaryl, wherein said heteroaryl is a ring carbon atom and Contains 1 or 2 ring heteroatoms independently selected from N, O and S, preferably N A 5- or 6-membered fully unsaturated monocyclic group, in which the total number of ring S atoms does not exceed 1 and the ring O atoms does not exceed 1, wherein said heteroaryl is unsubstituted or R 21 and R 30 From Germany substituted by one or two substituents selected arbitrarily, where R 21 and R3 0 is independently selected from (C1-C2) alkyl, and said (C1-C2) alkyl is unsubstituted. or substituted with 1, 2 or 3 halo, wherein preferably said alkyl Or the haloalkyl substituent is adjacent to the R1 ring atom where the heteroaryl is attached to the remainder of the molecule. more preferably, when the heteroaryl is a 6-membered ring, The alkyl or haloalkyl substituent is in the ring para position relative to the remainder of the molecule. is provided.

[0174] More particularly, R1 is [ka] Selected from; R 33 is F; R 15 is halo, azetidinyl, or pyrrolidinyl, wherein said azetidinyl and The pyrrolidinyl is linked to the rest of the molecule through the N atom and is unsubstituted or has one or more substituted with two Fs), R 16 is R 25 (R 24 )N- (where R 24 is H or (C1-C2) alkyl R 25 is H or unsubstituted or substituted with 1, 2 or 3 halo, especially F (C1-C2) alkyl); R 17 is a halo; R 18 is a halo; R 19 is a halo; R 20 is a halo; R 21 is (C1-C2) alkyl; R 22 and R23 are each independently (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (H3C)3C-OC(O)(CH2) n -; where n is 0, 1, or 2 Selected from; and R 30 is CH3. More particularly, R1 is [ka] Selected from; R 15 is F; R 16 is R 25 (R 24 )N- and; R 17 is F; R 18 is F; R 19 is F; R 20 is F; R 21 is CH3; R 22 are CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, ( H3C)3C-OC(O)-; R 23 are CF3, CHF2CH2-, (H3C)3C-OC(O)-; R 24 is CH3; and R 25 is CHF2CH2-.

[0175] Preferably, R1 is [ka] is selected from.

[0176] In another embodiment, R2 is the moiety: [ka] and; R6 is ·H, Hello, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, (C3-C5)cycloalkyl unsubstituted or substituted with 1, 2 or 3 halo , -O-(C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo , ·OH, and ·CN Selected from; R8 is H, halo, and unsubstituted or substituted with 1, 2 or 3 halo (C1- C4) selected from; R9 is selected from H, O-CH3, OH, CN, CH3, and halo; R 28 teeth, SF5, ·H, ·-C(O)H, ·Halo; (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, ·(C1-C4)alkynyl; (C1-C4) alkenyl, (C3-C5)cycloalkyl unsubstituted or substituted with 1, 2 or 3 halo , and OCF3 Selected from; and X is selected from C-R7 and N, where R7 is H or halo.

[0177] In particular, R2 is the part: [ka] (In the formula, R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1-C4 ) alkyl; R8 is H, halo, and unsubstituted or substituted with 1, 2 or 3 halo (C1 C4) selected from; R9 is selected from H, O-CH3, OH, CN, CH3, and halo; R 28 is SF5, halo, unsubstituted or substituted with 1, 2 or 3 halo (C1 -C4), and -C(O)H; X is selected from C-R7 and N; R7 is selected from H and halo is.

[0178] More particularly, R2 is the moiety: [ka] and; R6 is selected from H, Cl, CH3, F, and Br; R8 is selected from H, Cl, F, and CF3; R9 is selected from H, CH3, and Cl; R 28 are CF3, CF2H, -CH2CH3, Cl, SF5, Br, and -C(O)H Selected from; X is selected from C-R7 and N; R7 is selected from H and F. More particularly, R2 is [ka] , preferably [ka] is a moiety selected from

[0179] In another embodiment, R 26 is H and R 27 is H.

[0180] In another embodiment, R3 is unsubstituted or one, two or more independently selected from halo and OH. (C1-C4) alkyl substituted with one or three substituents, especially unsubstituted or halo and OH (C1-C2 ) alkyl, preferably —CH2CH3 or CH3, more preferably —CH2CH3 do.

[0181] In another embodiment, Y is N, and [ka] is a Y linked by a single bond.

[0182] In another embodiment, [ka] is K connected by a single bond, and K is -CH2-, -CH2CH2-, -NH - and (5-membered ring: [ka] and J is N, and A is selected from -C(O)-, -S(O)-, -S(O)2-, and [ka] is a linker selected from

[0183] especially, [ka] are Ks linked by a single bond, K is -CH2-, J is N, and A is -C(O)-, -S(O)-, -S(O)2- and [ka] is a linker selected from

[0184] In another embodiment, A is selected from -C(O)- and -S(O)2-, preferably -C(O)-. The linker is selected from the following:

[0185] In another embodiment, R5 is independently: -(C 1~ C4) alkyl, preferably methyl; where two R5 substituents on the same ring carbon atom are in the same position as the carbon atom to which they are attached. Together, (C 3~ C4) cycloalkylspirocycle or 3- or 4-membered heterocyclyl A spiro ring may be formed, wherein said heterocyclylspiro ring is formed by combining ring carbon atoms with O , and one ring heteroatom selected from N and S; · [ka] is a carbon-nitrogen single bond, K and the R5 substituents on the adjacent carbon atom are joined to form ring C: [ka] wherein ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cycloalkyl ring. a fused (C3-C6)heterocyclyl ring, a fused phenyl ring, or a fused (C3-C6)heterocyclyl ring; A (C3-C6)heterocyclyl ring is a heterocyclyl ring consisting of ring carbon atoms and one heterocyclic group selected from O, N and S. containing a ring heteroatom, and when K is -CH2- and J is N, the two R5 substituents are bonded to form (C1- C3) may form an alkylene bridge or a heteroalkylene bridge (wherein the hetero The alkylene bridge is one heteroatom selected from N and O, or -CH2- O-CH2- is selected from.

[0186] In particular, R5 can independently -(C 1~ C4) alkyl, preferably methyl; · [ka] is a carbon-nitrogen single bond, K and the R5 substituents on the adjacent carbon atom are joined to form ring C: [ka] wherein ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cycloalkyl ring. a butyl ring or a fused (C3-C6) heterocyclyl ring, A heterocyclyl ring consists of ring carbon atoms and one ring heteroatom selected from O, N, and S. containing and when K is -CH2- and J is N, the two R5 substituents are linked to form (C1- C3) may form an alkylene bridge or a heteroalkylene bridge (wherein the hetero The alkylene bridge is one heteroatom selected from N and O, or -CH2- O-CH2- is selected from.

[0187] More particularly, R5 is independently -(C 1~ C2) alkyl, preferably methyl, and · [ka] is a carbon-nitrogen single bond, K and the R5 substituents on the adjacent carbon atom are joined to form ring C: [ka] wherein ring C is a fused (C3-C4) cycloalkyl ring, particularly a fused cycloalkyl ring. (a butyl ring) is selected from.

[0188] More particularly, R5 is independently CH3 and y is 1 or 2, and · [ka] is a carbon-nitrogen single bond, K and the R5 substituents on the adjacent carbon atom are joined to form ring C: [ka] wherein ring C is a fused cyclobutyl ring. is selected from.

[0189] In another embodiment, y is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0190] In another embodiment, R4 is [ka] (In the formula, R10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C 2) selected from alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl; R 13 is H, -S-CH3, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents is selected from (C1-C2) alkyl; and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C 1-C2) alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents -O -(C1-C2) alkyl, and cyclopropyl is selected from.

[0191] In particular, R4 is [ka] (In the formula, R 10 is selected from H, F, Cl, CH3, and OCF3; R 11 is selected from H, Cl, F, and CH3; R 12 is selected from H, Cl, and CH3; R 13 is selected from H, —S—CH3, and CH3; and R 14is H, CH3, -CH2CH3, cyclopropyl, -OCHF2, OCF3, and and Cl) is selected from.

[0192] More particularly, R4 is [ka] is selected from.

[0193] More particularly, R4 is [ka] Preferably [ka] is selected from.

[0194] In another embodiment, Formula (I) is represented by Formula 1a: [ka] is.

[0195] In another embodiment, the moiety: [ka] teeth, [ka] especially, [ka] is selected from.

[0196] synthesis Compounds of formula (I) as described herein, in particular 1a, 1b, 1c, 1d, 1e, 1f, 1h or 1g, preferably 1a, more preferably 1g or 1h, or as described herein Also provided is a method for preparing a pharmaceutically acceptable salt thereof.

[0197] Furthermore, compounds of formula (I) as described herein, such as compounds of formula 1a, preferably 1g or is an intermediate used in the chemical synthesis of 1h, or a pharmaceutically acceptable salt thereof described herein. A compound is provided.

[0198] In another aspect, there is provided an intermediate compound, or a process including an intermediate compound, as described below. can be.

[0199] In particular, compounds or formulae such as: [ka] (Sodium salt of the compound of Example 42)

[0200] A compound of formula A or a salt thereof: [ka] (In the formula, R1, R2, R3, R 26 , R 27 , R5, y and Y are defined herein. (As shown). Compound: [ka]

[0201] Formula B: [ka] (In the formula, R1, R2, R3, R 26 , R 27 , R5, y and Y are as defined herein. and PG1 is a protecting group), or a salt thereof. Suitable protecting groups are well known to those skilled in the art. Well-known examples include BOC.

[0202] [ka] A compound or a salt thereof,

[0203] Formula C: [ka] wherein R1, R3, R5, y, and Y are as defined herein, and PG2 is A compound of formula (I) or a salt thereof, wherein the protecting group is a protecting group. Suitable protecting groups are well known to those skilled in the art. Such a protecting group PG2 includes BOC.

[0204] [ka] A compound or a salt thereof,

[0205] Formula D: [ka] wherein R, R, y, and Y are as defined herein, and PG is a protecting group. or a salt thereof. Suitable protecting groups are well known to those skilled in the art.

[0206] [ka] A compound or a salt thereof,

[0207] [ka] A compound or a salt thereof,

[0208] Also, compounds: [ka] 1. A method for making a compound of formula: [ka] The compound formula: [ka] and a compound of Coupling reagents and conditions known to those skilled in the art, in particular HOAt, EDCI and DIPEA, may be used. Such reagents are useful in the art due to their availability. Considering the speed and cost, it is a robust process with good yields while being amenable to scale-up. As known to those skilled in the art, protected forms or Unprotected forms may be used.

[0209] Also, compounds: [ka] 1. A method for making a compound of formula: [ka] and / or [ka] and / or [ka] The present invention provides a method for preparing the compound of formula (I) via an intermediate of formula (I).

[0210] formulation In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutical In a further embodiment, the composition comprises a pharmaceutical composition comprising a carrier acceptable for The pharmaceutical composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The compositions can be administered orally, parenterally (e.g., by injection, infusion, transdermally, or topically), and directly. It may be formulated for a specific route of administration, such as enteral administration. Topical administration may be by inhalation or intranasal application. The pharmaceutical composition of the present invention may also be in the form of a solid formulation (capsules, tablets, pills, granules, powders, etc.). or suppositories), or liquids (solutions, suspensions or emulsions) Tablets can be made up of any of the following known compounds: Film coating or enteric coating may be applied according to known methods. Generally, the pharmaceutical compositions are tablets or gelatin tablets containing the active ingredient in combination with one or more of the following: It is a capsule: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, Thor, cellulose, and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts; salts, and / or polyethylene glycol; in the case of tablets, c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth Cantho, methylcellulose, sodium carboxymethylcellulose, and / or polyvinyl alcohol dipyrrolidone; as needed d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or effervescent agents; Sexual mixture; and e) Absorbents, colorants, flavorings, and sweeteners.

[0211] Compounds intended for parenteral or oral administration include nanosuspensions, solid dispersions and liposomes. Solubilization can be achieved using a variety of methods, including (van Hoogevest P., X iangli L.,and Alfred F“Drug delivery str ategies for poorly water-soluble drugs:T he industrial perspective”Expert Opinion on Drug Delivery 2011,8(11),1481-1500).

[0212] Solid dispersion technology has been used to improve the dissolution properties and bioavailability of orally administered drugs. (Dhirendra K et al: 'Solid dis persions:A review”,Pakistan Journal of P Pharmaceutical Sciences,Faculty of Pharma cy,University of Karachi,Pakistan,vol.22 ,no.2.30 April 200,pages234-246).

[0213] Common methods for solubilizing compounds for parenteral administration include optimizing the pH, or Solvent (e.g., PEG300, PEG400, propylene glycol, or ethanol) If these approaches are not feasible for some reason, the use of surfactants is recommended. Use of a solvent such as Tween® 80 or Cremophor EL (registered trademark) is also possible. Cyclodextrins are established as safe solubilizers. Natural oils (e.g., Compounds with high solubility (e.g., propofol) are soluble in parenteral fat emulsions. It can become.

[0214] A compound of formula (I) as described herein, for example formula 1a, preferably 1g or 1h or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. A composition is also provided.

[0215] In another embodiment, the compound N-(2-chloro-4-(trifluoromethyl)phenyl) -2-(2-(3,6-dihydro-2H-pyran-4-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 Pharmaceutical composition which is an amorphous solid dispersion containing acetamide or a pharmaceutically acceptable salt thereof is provided.

[0216] In a further embodiment, the pharmaceutical composition comprises the compound N-(2-chloro-4-(trifluoromethyl)-2-phenylpropanol). 2-(2-(3,6-dihydro-2H-pyran-4-yl)- 5-Ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)pyrimidine Perazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin acetamide, or a pharmaceutically acceptable salt thereof, and aminomethyl Acrylate copolymers, especially Eudragit® E PO.

[0217] use The compounds of formula (I) of the present invention, in free form or in pharmaceutically acceptable salt form, can be used, for example, as described in the following paragraphs. As shown in the in vitro and in vivo tests provided, valuable pharmacological properties, such as W They exhibit RN inhibitory properties and are therefore useful in therapeutic or research chemicals, e.g. chemical probes and and used as tool compounds.

[0218] Also compounds of formula (I) as described herein, in particular 1a, 1b, 1c, 1d, 1e, 1f , 1h or 1g are provided. The compounds may be used as research chemicals, e.g., tool compounds or It can be used as a chemical probe, particularly for the study of WRN. The compounds of formula (I) as described herein, in particular 1a, 1b, 1c, 1d, 1e, 1f, 1h or of 1 g of compound for use as a research chemical, e.g., a tool compound or chemical probe. , and is particularly useful for the study of WRN.

[0219] A compound of formula (I) as described herein, in particular 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1j, 1i ... c, 1d, 1e, 1f, 1h or 1g, preferably 1a, more preferably 1g or 1h Also provided are compounds, or pharmaceutically acceptable salts thereof, that are useful in treating conditions that are treated by WRN inhibition. Cancers that may be affected include those with microsatellite instability-high (MSI-H) or mismatch repair. In particular, cancers characterized by deficient multiple myeloma repair (dMMR) are included. a compound of formula 1a, preferably 1g or 1h, or a pharmaceutically acceptable salt thereof The salts used are those that are microsatellite instability-high (MSI-H) or mismatch repair-inhibitory. It may be useful in treating cancers characterized by deficiency (dMMR).

[0220] A compound of formula (I) as described herein, in particular 1a, 1b, ... c, 1d, 1e, 1f, 1h or 1g, preferably 1a, more preferably 1g or 1h Also provided is a compound, or a pharmaceutically acceptable salt thereof. For diseases treated by WRN inhibition, For the treatment of cancer, Microsatellite instability-high (MSI-H) or mismatch repair deficiency (dM For the treatment of cancers characterized by MR, ·Colon cancer, stomach cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer Microsatellite instability-high (MSI-H) or microsatellite instability-high (MSI-H) cancers, such as ovarian cancer, renal cancer, and ovarian cancer. For the treatment of cancers characterized by deficient match repair (dMMR), High-frequency microsatellites selected from colorectal, gastric, prostate, and endometrial cancers Treatment of cancers characterized by instability (MSI-H) or mismatch repair deficiency (dMMR) For, or for the treatment of cancer (wherein the cancer is microsatellite instability-high (MSI-H) or mismatched) Cancers characterized by deficient match repair (dMMR) include endometrial cancer of the uterine corpus, colon adenocarcinoma, Gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, prostate cancer, and ovarian serous cystadenocarcinoma is.

[0221] The following methods are also provided: A method for adjusting the WRN activity of a subject, comprising administering to a subject a compound of formula (I) as described herein, in particular 1a, 1b, 1c, 1d, 1f, 1h or 1g, preferably 1a, more preferably 1g or The method comprises administering to a subject a therapeutically effective amount of a compound of formula 1h, or a pharmaceutically acceptable salt thereof. A method comprising: A method of inhibiting WRN in a subject, comprising administering to a subject a compound of formula (I) as described herein, in particular 1a , 1b, 1c, 1d, 1e, 1f, 1h or 1g, preferably 1a, more preferably 1g or 1h, or a pharmaceutically acceptable salt thereof, administering to a subject a therapeutically effective amount of the compound of formula (I) or 1h, or a pharmaceutically acceptable salt thereof. a method comprising: A method for treating a disorder or disease in a subject that can be treated by WRN inhibition. and the compounds of formula (I) described herein, in particular 1a, 1b, 1c, 1d, 1e, 1f, 1 Compounds of formula 1h or 1g, preferably 1a, more preferably 1g or 1h, or pharmaceutical compositions thereof administering to a subject a therapeutically effective amount of a salt acceptable to A method of treating cancer in a subject, comprising administering to a subject a compound of formula (I) as described herein, particularly 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1j, 1h, 1i, 1j ... b, 1c, 1d, 1e, 1f, 1h or 1g, preferably 1a, more preferably 1g or 1h, or a pharmaceutically acceptable salt thereof, Compounds of formula (I) as described herein, in particular 1a, 1b, 1c, 1d, 1e, 1f, 1h or 1g, preferably 1a, more preferably 1g or 1h, or a pharmaceutically acceptable salt thereof

[0013] The present invention provides a method for treating cancer in a subject, the method comprising administering a therapeutically effective amount of a salt of High microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) ) In particular, the method is characterized by the high frequency of microsatellite instability (MSI-H) or mismatch. Cancers characterized by deficient match repair (dMMR) include colon cancer, gastric cancer, prostate cancer, and endometrial cancer. cancer, adrenocortical carcinoma, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer, and ovarian cancer. More particularly, microsatellite instability-high (MSI-H) or mismatch repair Cancers characterized by deficient MMR (dMMR) are selected from colon cancer, gastric cancer, prostate cancer, and endometrial cancer. Examples include endometrial cancer of the uterine corpus, colon adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, and adrenal cortex adenocarcinoma. Cancer, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, prostate adenocarcinoma, and ovarian serous cystadenocarcinoma.

[0222] Compounds of formula (I) as described herein, in particular 1a, 1b, 1c, 1d, 1e, 1f, 1h or 1g, preferably 1a, more preferably 1g or 1h, or a pharmaceutically acceptable salt thereof of salt, In treatment, In pharmaceutical manufacturing, In the manufacture of a medicament for treating cancer (particularly, the cancer is a microsatellite instability high characterized by MSI-H or deficient mismatch repair (dMMR), In the manufacture of a medicament for the treatment of a disease that can be treated by inhibition of WRN, Use, In particular, the cancer is characterized by microsatellite instability-high (MSI-H) or mismatch repair It is characterized by a functional defect (dMMR), e.g., colon cancer, stomach cancer, prostate cancer, endometrial cancer, adrenal cancer Cortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, and ovarian cancer, in particular colon cancer, gastric cancer, prostate cancer or endometrial cancer, or endometrial cancer of the uterine corpus, colon adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, Uterine carcinosarcoma, cervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, and ovarian serous cystadenocarcinoma Uses are also provided.

[0223] In some embodiments, the subject has a higher or lower mitochondria, e.g., compared to a control, e.g., a normal subject. have or have been diagnosed with multisite satellite instability-high (MSI-H) cancer. In embodiments, the subject has MSI-H advanced solid tumors, colorectal cancer (CRC), endometrial cancer, uterine cancer, In some embodiments, the subject has colorectal cancer (CR). C) have endometrial cancer or gastric cancer, and the cancer is, for example, compared to a control, e.g., a normal subject. , have or have been diagnosed with microsatellite instability (MSI-H) Such diagnostic techniques are known in the art.

[0224] form Depending on the choice of starting materials and procedures, the compound may be in the form of one of the possible stereoisomers. or as mixtures thereof, for example as pure optical isomers depending on the number of asymmetric carbon atoms, Or they may exist as mixtures of stereoisomers, such as racemates and diastereomeric mixtures. The present disclosure includes racemic mixtures, diastereomeric mixtures, and optically pure forms. All such possible stereoisomers are intended to be included. Optically active (R)- and (S)- )-stereoisomers can be prepared using chiral synthons or chiral reagents, or by conventional methods. If the compound contains a double bond, the substituents may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent can be: They may have cis or trans configurations. All tautomeric forms are also included. do.

[0225] As used herein, the term "salt" or "salts" refers to any salt or salts of the present invention. "Salt" refers specifically to a "pharmaceutically acceptable salt." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention. It refers to salts that retain their original structure and are not usually biologically or otherwise undesirable. In this case, the compounds of the present invention are those having an amino and / or carboxyl group or a similar group. Depending on the presence, acid and / or base salts can be formed.

[0226] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0227] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Examples include:

[0228] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, sucralose, and the like. Acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mannitol Desulfonic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid Examples include:

[0229] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0230] Inorganic bases from which salts can be derived include, for example, ammonium salts and salts of compounds of I to XI of the periodic table. In certain embodiments, the salts include metals from column I, II, III, IV ... Particularly preferred salts are derived from ammonium, calcium, magnesium, iron, silver, zinc, and copper; Examples of the salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Examples include:

[0231] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, ammonium salts, and the like. Examples include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific organic amines include isopropylamine, benzathine, cholinate, Diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine Examples include:

[0232] In another aspect, the present invention provides a compound comprising acetate, ascorbate, adipate, aspartic acid Salt, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate Acid salt, camphorsulfonate, caprate, chloride / hydrochloride, chlorotheophyllinic acid Salt (chlortheophyllonate), citrate, ethanedisulfonate, Fumarate, gluceptate, gluconate, glucuronate, glutamate, gluta Salt, Glycolate, Hippurate, Hydroiodide / Iodide, Isethionate, Lactate Salt, lactobionate, lauryl sulfate, malate, maleate, malonate, mannose Delate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate Sodium nitrate, octadecanoate, oleate, oxalate, palmitate, palmitate Molate, Phosphate / Hydrogenphosphate / Dihydrogenphosphate, Polygalacturonate, Propionate Salt, Sebacate, Stearate, Succinate, Sulfosalicylate, Sulfate, Tartaric Acid salt, tosylate, triphenylacetate, trifluoroacetate, or xinafoate salt form The present invention provides compounds of the formula:

[0233] All formulas given herein may contain, in addition to the deuteration specifically called for in formula (I), The term "isotopically labeled compound" is intended to represent unlabeled forms of the compound as well as isotopically labeled forms. The substance is one in which one or more atoms are replaced by atoms having a selected atomic mass or mass number. The compounds of the present invention have the structure depicted by the formulas given herein, except for Isotopes that can be incorporated include, for example, isotopes of hydrogen.

[0234] Additionally, certain isotopes, particularly deuterium (i.e. 2 By incorporating H or D), Greater metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements, or therapeutic Certain therapeutic benefits may result from improvements in the index or tolerability. It is understood that deuterium is considered a substituent of the compounds of the present invention. As used herein, "isotopic enrichment" can be defined as the isotopic enrichment factor. The term "reduction factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the invention is designated as deuterium, such compound may be designated as For each deuterium atom assigned, at least 3500 (52.5% for each assigned deuterium atom) deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4 500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation) at least 5500 (82.5% deuterium incorporation), at least 6000 ( 90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), At least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) The term "isotopic enrichment factor" is used in the same way as for deuterium. It should be understood that the same method can be applied to any isotope.

[0235] Examples of isotopes that may be incorporated into compounds of the present disclosure include hydrogen, carbon, nitrogen, oxygen, phosphorus, Isotopes of fluorine and chlorine, e.g., 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 I can be mentioned. Thus, the present invention provides, for example, 3 H and 14 Radioactive isotopes such as C, or 2 H and 13 One or more of any of the aforementioned isotopes, including those in which non-radioactive isotopes such as C exist. It is to be understood that the present invention includes compounds incorporating the above. Such isotopically labeled compounds may be metabolized. test( 14 C), reaction rate tests (e.g., 2 H or 3 H), drugs or groups Positron emission tomography (PET) or single-photon emission computed tomography (SEM) including tissue distribution assays detection or imaging techniques such as SPECT, or radiology of patients It is useful in radiation therapy. 18 F or labeled compounds are used in PET or SPECT studies. Isotopically labeled compounds of the present invention may be particularly desirable for experimental purposes. by conventional techniques established or by using suitable isotopically labeled reagents in place of previously used unlabeled reagents. Prepared by methods similar to those described in the accompanying examples and preparations using the agent It is possible.

[0236] Deuterated compounds of formula (I) include the deuterated form of Example 42, Example 43: [ka] and [ka] and, Example 86: [ka] Example 50: [ka] Example 57: [ka] and Example 47: [ka] Deuterated forms of the compounds are included.

[0237] definition "Compounds of the invention" or "compounds of formula (I)" or "compounds of formula 1a" or 1g or The term "zwitterionic", "non-zwitterionic" (uncharged form), or "zwitterionic" (uncharged form) is used interchangeably with "h" and "h". Pharmaceutically acceptable salts in ionic or non-zwitterionic form are included.

[0238] A "zwitterion" or "zwitterionic form" is a compound that contains a positively charged functional group and a negatively charged functional group. By "functional groups" is meant compounds containing both functional groups.

[0239] For example, compounds of formula (I) described herein can include the following forms, wherein: , R4 is in zwitterionic form (c) or in non-zwitterionic form (d); [ka] or a mixture thereof.

[0240] Compounds of formula (I) described herein may also include the following forms, where R 4 in the zwitterionic form (a) or (b) or in the non-zwitterionic form (e); [ka] Or a mixture of two of them, or a mixture of all three of them. Halo means fluoro, chloro or bromo, especially fluoro or chloro. Alkyl and alkoxy groups, containing the requisite number of carbon atoms, may be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, and butyl. Examples include, but are not limited to, butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, Included are n-butoxy, i-butoxy, sec-butoxy and t-butoxy.

[0241] "=O" means an oxo substituent.

[0242] When R1 is a substituted or unsubstituted cycloalkenyl, the cycloalkenyl may be , cyclohexenyl, and especially cyclohex-1-en-1-yl groups. Not limited to these.

[0243] When R1 is a substituted or unsubstituted heterocyclyl, the heterocyclyl may be a moiety. Fluorinyl, piperidinyl, pyrrolidinyl, 6-oxa-3-azabicyclo[3.1.1 ]heptan-3-yl, 5,6-dihydro-1,4-dioxin-2-yl, dihydropyridin pyranyl, especially 3,4-dihydro-2H-pyran-6-yl, 5,6-dihydro-2H-pyran-6-yl 3-pyran-3-yl and 3,6-dihydro-2H-pyran-4-yl, piperazinyl, tetra Hydropyridinyl, such as 1,4,5,6-tetrahydropyridin-3-yl and 1,2 , 3,6-tetrahydropyridin-4-yl, as well as dihydropyridinyl, e.g., 3,6 -dihydropyridinyl and the like.

[0244] When R1 is a substituted or unsubstituted heteroaryl, the heteroaryl may be a pi These include, but are not limited to, groups such as lysinyl, especially pyridin-3-yl.

[0245] The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of abnormal cells. It can spread locally or through the bloodstream and lymphatic system to other parts of the body. Listed in the fine print, colon cancer, stomach cancer, endometrial cancer, prostate cancer, adrenocortical cancer, uterine cancer, cervical cancer These include, but are not limited to, esophageal cancer, breast cancer, kidney cancer, ovarian cancer, and the like.

[0246] The terms "tumor" and "cancer" are used interchangeably herein, e.g., both terms includes solid and liquid tumors, e.g., diffuse or circulating tumors. When used herein, the term "cancer" or "tumor" includes pre-cancerous and malignant cancers and tumors. .

[0247] As used herein, a "WRN inhibitor" or "WRN helicase inhibitor" refers to a compound that inhibits WRN. The term "WRN" refers to a compound that inhibits the WRN syndrome RecQ DNA helicase. The term "WRN" used in refers to the Werner syndrome RecQ DNA helicase The term "WRN" refers to a protein including mutants, fragments, variants of full-length wild-type WRN. In one embodiment, the protein is a member of the WRN gene. child (Entrez gene ID 7486; Ensembl ID ENSG000001 65392). An exemplary WRN sequence is located in U Available from the niprot database.

[0248] "WRN-mediated diseases or conditions" include diseases such as cancer that are treated by WRN inhibition. In particular, this includes microsatellite instability-high (MSI-H) ) or cancers characterized by deficient mismatch repair (dMMR).

[0249] As used herein, "microsatellite unstable cancer," "microsatellite-rich cancer," "Unstable cancer", "microsatellite-rich cancer", "MSI-rich cancer", "MSI h i " and "MSI-H" are used interchangeably and refer to simple repeat genomic mutations within microsatellites. Cancers with multiple alterations within the length of the sequence are described.

[0250] Determination of a patient's MSI-H or dMMR tumor status can be performed using, e.g., using polymerase chain reaction (PCR) testing or, for dMMR, immunohistochemistry ( IHC testing can be used to identify MSI-H or dMMR tumor status. Methods for this purpose are described, for example, in Ryan et al. Crit Rev Oncol Hemat ol.2017;116:38-57;Dietmaier and Hofstadt er.Lab Invest 2001,81:1453-1456; and Kawaka mi et al.Curr Treat Options Oncol.2015:1 6(7):30).

[0251] Microsatellite instability is associated with colorectal cancer, gastric cancer, and endometrial cancer, especially adrenocortical carcinoma, uterine cancer, and It can also be found in uterine, cervical, esophageal, breast, kidney, prostate, and ovarian cancers. Examples of high-frequency microsatellite cancers include endometrial cancer of the uterine body, colon adenocarcinoma, and gastric cancer. Adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, esophageal cancer , breast cancer, renal clear cell carcinoma, prostate cancer, and ovarian serous cystadenocarcinoma.

[0252] Cancers with "defective mismatch repair function" (dMMR) or "dMMR characteristics" , reported MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, and PMS1 mutation or epigenetic silencing, microsatellite instability Cancers associated with leukemia, encephalopathy, or other gene inactivation mechanisms include, for example, lung cancer, breast cancer, and kidney cancer. , colon cancer, ovarian cancer, prostate cancer, upper aerodigestive tract cancer, stomach cancer, endometrial cancer, liver cancer, pancreatic cancer, Blood and lymphatic tissue cancer, skin cancer, thyroid cancer, pleural cancer, autonomic ganglion cancer, central nervous system cancer, soft tissue cancer , childhood rhabdoid sarcoma, melanoma, and other cancers. Cells or cancers with "defective" mismatch repair function have a high level of mismatch repair. Decreased (e.g., at least about 25%, 30%, 40%, 50%, 60%, 70% In some cases, cells with defective mismatch repair function or Cancer does not perform mismatch repair.

[0253] As used herein, the term "pharmaceutical composition" refers to a form suitable for oral or parenteral administration. or a pharmaceutical composition thereof, in combination with at least one pharmaceutically acceptable carrier. refers to salts that are acceptable for

[0254] As used herein, the term "pharmaceutically acceptable carrier" refers to a Refers to materials useful for the preparation or use, as known to those skilled in the art, for example, suitable diluents. , solvent, dispersion medium, surfactant, antioxidant, preservative, isotonic agent, buffer, emulsifier, absorption delaying agent , salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof (e.g., Remington The Science ce and Practice of Pharmacy,22nd Ed.Phar Maceutical Press, 2013, pp. 1049-1070 stomach).

[0255] The terms "synthetic lethal" and "synthetic lethal" refer to the loss of function in two or more genes. A combination of mutations or approaches that cause loss (e.g., RNA interference or protein function inhibition) The combination of these genes causes the disease, but the loss of function of only one of these genes It is used to refer to a decrease in cell viability and / or a decrease in the rate of cell proliferation that is not caused by can be.

[0256] The term "therapeutically effective amount" of a compound of the present invention refers to a therapeutically effective amount of a compound that induces a biological or medical response in a subject, e.g., For example, to induce a reduction or inhibition of enzyme or protein activity, or to ameliorate symptoms, alleviate a pathological condition, The invention provides a method for treating a disease, such as reducing, slowing or delaying the progression of the disease, or preventing the disease. It refers to the amount of a specific compound.

[0257] In one embodiment, the term "therapeutically effective amount" refers to a dose that, when administered to a subject, ) mediated by WRN, or (ii) associated with WRN activity, or (iii) WRN (positive a pathological condition, or disorder or disease characterized, at least in part, by a specific (normal or abnormal) activity (2) effective in reducing or inhibiting the activity of WRN refers to an amount of a compound of the present invention in which

[0258] In another embodiment, the term "therapeutically effective amount" refers to a therapeutically effective amount of a cell, or tissue, or non-cellular biological material, or at least partially reduce or inhibit the activity of WRN when administered to the culture medium. Or refers to the amount of a compound of the present invention effective to reduce WRN protein levels.

[0259] As used herein, the term "subject" refers to a primate (e.g., a human, male or female). In certain embodiments, the term refers to a mammal, such as a dog, a rabbit, a guinea pig, a pig, a rat, or a mouse. The elephant is a primate, rat, or mouse. In yet another embodiment, the subject is a human. .

[0260] As used herein, the terms "inhibit," "inhibition," or "inhibiting" The term refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or the suppression of a biological activity. A significant decrease in baseline activity of a substance or process.

[0261] As used herein, "treating" or "treating" any disease or disorder means The term "treatment" also refers to the alleviation or amelioration of a disease or disorder (i.e., the treatment of a disease or disorder). slowing or halting the progression of at least one of the clinical symptoms of the disease or disorder; or At least one physical parameter or biomarker (as perceived by the patient) associated with harm This refers to the mitigation or improvement of certain conditions (including conditions that may not exist).

[0262] As used herein, "preventing" or "preventing" any disease or disorder means The term "prevention" also refers to the prophylactic treatment of a disease or disorder; or the prevention or treatment of the onset or progression of a disease or disorder. It means slowing down the progression.

[0263] As used herein, a subject is "in need of" treatment if such subject is would benefit biologically, medically, or in quality of life from such treatment. .

[0264] As used herein, "a," "an," "the" ) and its variants as used in connection with the present invention (particularly in connection with the claims) Similar terms are used in the singular unless otherwise indicated herein or clearly contradicted by context. and plurals should be construed to encompass both the plural and plurals.

[0265] "Can be linked" means to link or not to link.

[0266] "Can be substituted by deuterium" means to be substituted by deuterium or to be substituted by deuterium. means that it is not replaced.

[0267] Unless otherwise defined, all technical and scientific terms used herein are It has the same meaning as commonly understood by those skilled in the art to which this invention pertains. Methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention. Suitable methods and materials are described below. All publications, patent applications, patents, and other references are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Unless otherwise indicated or clearly contradicted by context, all references made herein to The methods may be performed in any suitable order. The use of exemplary language (e.g., "such as") is intended merely to further clarify the invention. It is intended to be illustrative and not limiting of the scope of the invention as otherwise claimed.

[0268] Isomers Any asymmetric atoms (e.g., carbon, etc.) of the compounds of the present invention may be present in racemic or enantiomeric forms. It can be merically enriched, for example, in the (R)-, (S)- or (R,S)-configuration. In certain embodiments, each asymmetric atom may be at least in the (R)- or (S)-configuration. At least 50% enantiomeric excess, at least 60% enantiomeric excess, at least At least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or At least 99% enantiomeric excess. Substituents, where possible, may be present in cis- (Z)- or trans- (E)-form.

[0269] Thus, as used herein, the compounds of the invention may be, for example, substantially pure Geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), As racemates or mixtures thereof, possible stereoisomers, rotamers, atropisomers , tautomers or mixtures thereof.

[0270] Any resulting mixture of stereoisomers can be purified by, for example, chromatography and / or fractional recombination. By crystallization, pure or substantially pure geometric or optical properties can be obtained based on the physicochemical differences of the constituent components. It can be separated into optical isomers, diastereomers, and racemates.

[0271] Any resulting racemates of the compounds or intermediates of the present invention can be prepared by known methods, e.g. The diastereomeric salts obtained with optically active acids or bases are separated and the optically active The enantiomers can be separated by liberating the reactive acidic or basic compounds. In particular, the basic moiety can be used to produce optically active acids such as tartaric acid, dibenzofuran, diethyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, by fractional recrystallization of salts formed with malic acid or camphor-10-sulfonic acid. The compounds of the present invention can be resolved into their optical antipodes by the racemization method of the present invention. The compound or racemic intermediate may also be purified by chiral chromatography, e.g., high-resolution chromatography using a chiral adsorbent. The compounds can be separated by high pressure liquid chromatography (HPLC).

[0272] The compounds of the present invention, i.e., Compounds of formula (I) containing a group that can be used to form co-crystals with a suitable co-crystal former. These co-crystals can be prepared from compounds of formula (I) by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or co-solventing of the compound of formula (I). The co-crystals formed by contacting the solution with a co-crystal former under crystallization conditions are separated into 200 μm and 100 μm. Suitable co-crystal formers include those described in WO 2004 / 07816 Therefore, the present invention further provides a compound of the formula The present invention provides a co-crystal comprising the compound of formula (I).

[0273] Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates. or may contain other solvents used for their crystallization.

[0274] The compounds of the present invention may be essentially or partially solvated with pharmaceutically acceptable solvents (including water). These may be formed intentionally, and therefore the present invention encompasses both solvated and unsolvated forms. The term "solvate" refers to a compound of the present invention (including pharmaceutically acceptable salts thereof). This refers to a molecular complex of a solvent (including a solvent molecule) with one or more solvent molecules. Commonly used in the pharmaceutical field, known to be harmless to the ent, e.g. , water, ethanol, etc. The term "hydrate" refers to the complex where the solvent molecule is water.

[0275] Dosage form The pharmaceutical composition or combination of the present invention can be administered, for example, in an amount of about 1 dose per subject weighing about 50 to 70 kg. The unit dosage may be up to 1000 mg of active ingredient.

[0276] combination A "combination" refers to a fixed combination in one unit dosage form or a combination of compounds of formula (I) or a pharmaceutically acceptable salt thereof and a combination partner (e.g., a "therapeutic agent" or "adjuvant" or (another drug, as described below, also referred to as a "drug"), is administered simultaneously and independently. or separately within a time interval (particularly if these time intervals are This refers to combined administration, which allows the two agents to exhibit a cooperative effect, e.g., a synergistic effect. The single components may be packaged as a kit or may be packaged individually. One or both of the formulations (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration. The terms "co-administration" or "administration in combination" or the like are used herein. As used herein, refers to a selected single subject (e.g., a patient) in need thereof. It is meant to encompass the administration of combination partners and not necessarily the same drugs. It is intended to include therapeutic regimens that do not require administration by route or co-administration. The term "pharmaceutical combination" as used herein refers to a mixture or administration of more than one therapeutic agent. means the product resulting from the combination, including fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" includes both fixed and fixed combinations of therapeutic agents, e.g., a compound of the present invention and a combination thereof. Both combination partners are administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means a combination of therapeutic agents, e.g., a compound of the present invention and Both combination partners may work as separate entities simultaneously, in parallel or within a specific timeframe. It is meant to be administered to a patient sequentially indefinitely, and such administration is intended to The latter also provides therapeutically effective levels of the two compounds in cocktail therapy, e.g. This also applies to the administration of three or more therapeutic drugs.

[0277] The combinations described herein comprise a compound of formula (I) and one or more additional therapeutic agents, e.g. For example, one or more anti-cancer drugs, cytotoxic or cytostatic drugs, hormone therapy, vaccines, and and / or other immunotherapies. In other embodiments, the combination may further include surgery, radiation, cryosurgery, and and / or administered or used in combination with other therapeutic modalities, including hyperthermia. Such combination therapy may advantageously utilize lower dosages of the administered therapeutic agents. This may avoid potential treatment-related toxicities or complications.

[0278] Compounds of formula (I) as described herein, in particular 1a, 1b, 1 as described herein c, 1d, 1e, 1f, 1h or 1g, preferably 1a, more preferably 1g or 1 h, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutically active agents. Combinations are also provided. Additional therapeutic agents may be administered to a patient in combination with the compounds of the present disclosure. e.g., chemical compounds that are therapeutically active or enhance therapeutic activity when administered In particular, the additional therapeutically active agent is a peptide, an antibody, an antibody fragment or a nucleic acid. Anticancer drugs, chemotherapy drugs, Anastrozole (Arimidex®), bicalutamide (Casodex®) (registered trademark), bleomycin sulfate (Blenoxane®), busulfan Myleran®, busulfan injection (Busulfex®), )), capecitabine (Xeloda®), N4-pentoxycarbonyl-5- Deoxy-5-fluorocytidine, carboplatin (Paraplatin®) ), carmustine (BiCNU®), chlorambucil (Leukeran®), (Platinol®), cisplatin (Leucine®), cladribine (Leucine®), tatin®), cyclophosphamide (Cytoxan® or Ne Cytosar®), cytarabine, cytosine arabinoside (Cytosar-U®), (Registered Trademark), Cytarabine Liposomal Injection (DepoCyt®), Dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, Co smegan), daunorubicin hydrochloride (Cerubidine®), citric acid Daunorubicin liposome injection (DaunoXome®), dexamethasone , docetaxel (Taxotere®), doxorubicin hydrochloride (Adriam ycin®, Rubex®), etoposide (Vepesid®), trademark), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulex in®), tezacitidine, gemcitabine (difluorodeoxycytidine), Hydrea (registered trademark), Idarubicin (registered trademark), trademark), ifosfamide (IFEX®), irinotecan (Camptos ar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine ( Purinethol®), methotrexate (Folex®), Mitoxantrone (Novantrone®), Mylotarg, paclitaxel (Taxol®), Phoenix (Yttrium 90 / MX-DTPA), Polyfeprosan 20 (Gliade) containing pentostatin and carmustine implant l(R)), tamoxifen citrate (Nolvadex(R)), Tenipo Vumon®, 6-thioguanine, thiotepa, tirapazamine (Tir azone®), injectable topotecan hydrochloride (Hycamptin®) , vinblastine (Velban®), vincristine (Oncovin®), (Navelbine®), and vinorelbine (Navelbine®), especially fluorouracil a compound selected from 5-FU and irinotecan (Camptosar®) chemotherapeutic agents, PD-1 inhibitors, anti-PD-1 antibody molecules, or PDR001 (Novartis), nivolumab (Bristol-Myers Sq uibb), pembrolizumab (Merck & Co), pidilizumab (CureT ech), MEDI0680 (Medimmune), cemiplimab (REGN2810 , Regeneron), dostallimab (TSR-042, Tesaro), PF-0 6801591 (Pfizer), tislelizumab (BGB-A317, Beigen) e), BGB-108 (Beigene), INCSHR1210 (Incyte), Rustilimab (AGEN2035, Agenus), Sintilimab (InnoV ent), toripalimab (Shanghai Junshi Bioscience), Camrelizumab (Jiangsu Hengrui Medicine Co.), and AMP-224 (Amplimmune), penprimab (Akeso Biopharmaceuticals) ma Inc), dimvelelimab (Arcus Biosciences Inc) and Prorugolimab (Biocad Ltd), particularly PDR001, more particularly Tislelis PD-1 inhibitors selected from mabs (BGB-A317, Beigene) is.

[0279] In a further embodiment, the additional therapeutically active agent is the chemotherapy irinotecan (Camptos ar (registered trademark).

[0280] In another embodiment, the additional therapeutically active agent is an inhibitor of PD-1, e.g., human PD-1. In another embodiment, the immunomodulatory agent inhibits PD-L1, e.g., human PD-L1. In one embodiment, the inhibitor of PD-1 or PD-L1 is a PD-1 or PD-L1 In another embodiment, the additional therapeutically active agent is an anti-PD-1 antibody molecule. He is a child. In a further embodiment, the PD-1 inhibitor is selected from the group consisting of PD-1 inhibitors described in 2015 "Antibody Molecules to PD-1" released on July 30th and Uses Thereof,” U.S. Patent Application Publication No. 2015 / 021 and anti-PD-1 antibody molecules described in US Pat. No. 5,769,769, which is incorporated herein by reference. The entirety of the above is incorporated.

[0281] In another embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent are In particular, the combination of chemotherapy and PD-1 inhibitor is The chemotherapeutic agent is selected from those mentioned above. More particularly, the chemotherapeutic agent is irinotecan (Camptosa r®) and the PD-1 inhibitor is PDR001 or tislelizumab. Tislelizumab may have a heavy chain of SEQ ID NO: 3 and a light chain of SEQ ID NO: 4. In some embodiments, the anti-PD-1 antibody is administered at 100 mg / week. Tistlelizumab is administered IV at 300 mg on day 1 of each 28-day cycle. In some embodiments, tislelizumab may be administered at 500 mg once every four weeks.

[0282] In another embodiment, the anti-PD-1 antibody molecule, e.g., tislelizumab, comprises the following heavy chain and / or or light chain, VH, VL, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 , and LCDR3.

[0283] [Table 1]

[0284] In some embodiments, the PD-1 inhibitor is tisleliz as set forth in SEQ ID NOS: 7-12. Contains the HCDR and LCDR of the mab.

[0285] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 100 m In some embodiments, the PD-1 inhibitor ( For example, tislelizumab is administered at a dose of about 100 mg to about 500 mg. In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered in an amount of from about 100 mg to about 4 In some embodiments, a PD-1 inhibitor (e.g., Tissima) is administered at a dose of 100 mg. In some embodiments, the vasopressin-relizumab (relizumab) is administered at a dose of about 100 mg to about 300 mg. Therefore, PD-1 inhibitors (e.g., tislelizumab) are used at doses of approximately 100 mg to 200 mg. In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered in an amount is administered at a dose of about 200 mg to about 600 mg. 1 inhibitors (e.g., tislelizumab) are administered at doses of approximately 200 mg to approximately 500 mg. In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a concentration of about 200 In some embodiments, the PD-1 inhibitor (e.g., For example, tislelizumab is administered at a dose of about 200 mg to about 300 mg. In this embodiment, the PD-1 inhibitor (e.g., tislelizumab) is administered in an amount of from about 300 mg to about 60 mg. In some embodiments, a PD-1 inhibitor (e.g., Tissler) is administered at a dose of 0 mg. In some embodiments, the rifacilizumab is administered at a dose of about 300 mg to about 500 mg. PD-1 inhibitors (e.g., tislelizumab) are administered at a dose of approximately 300 mg to approximately 400 mg. In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered In some embodiments, PD-1 is administered at a dose of about 400 mg to about 600 mg. Inhibitors (e.g., tislelizumab) are administered at a dose of about 400 mg to about 500 mg. In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 500 mcg. In some embodiments, the PD-1 inhibitor (e.g., Batistlelizumab is administered at a dose of approximately 600 mg to approximately 700 mg. In embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered in an amount of about 700 mg to about 800 mg. In some embodiments, a PD-1 inhibitor (e.g., Tisleritinib) is administered at a dose of 100 mg. Izumab) is administered at a dose of about 800 mg to about 900 mg. PD-1 inhibitors (e.g., tislelizumab) are administered at a dose of approximately 900 mg to approximately 1000 mg. It is administered at .

[0286] PD-1 inhibitors (e.g., tislelizumab) are administered at a flat dose of approximately 100 mg. PD-1 inhibitors (e.g., tislelizumab) are administered at a dose of approximately 200 mg. D-1 inhibitors (e.g., tislelizumab) are administered at a dose of approximately 300 mg. PD-1 inhibitors (e.g., tislelizumab) are administered at a dose of approximately 400 mg. The PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of approximately 500 mg. (e.g., tislelizumab) is administered at a dose of approximately 600 mg. PD-1 inhibitors (e.g., tislelizumab) are administered at a dose of approximately 700 mg. tislelizumab) is administered at a dose of approximately 800 mg. PD-1 inhibitors (e.g., tisle) are administered at a dose of approximately 900 mg. Lizumab) is administered in a dose of approximately 1000 mg.

[0287] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at 10 weeks. In some embodiments, the PD-1 inhibitor is administered once every 9 weeks. In some embodiments, the PD-1 inhibitor is administered once every 8 weeks. In some embodiments, the PD-1 inhibitor is administered once every seven weeks. In some embodiments, the PD-1 inhibitor is administered once every six weeks. In some embodiments, the PD-1 inhibitor is administered once every four weeks. In some embodiments, the PD-1 inhibitor is administered once every three weeks. In some embodiments, the PD-1 inhibitor is administered once every two weeks. In this setting, the PD-1 inhibitor is administered once weekly.

[0288] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered intravenously. will be done.

[0289] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered within about 20 minutes to In some embodiments, the PD-1 The inhibitor is administered over a period of about 30 minutes. In some embodiments, the PD-1 inhibitor is administered over a period of about 2 hours. In some embodiments, the PD-1 inhibitor is administered over a period of about 3 hours. In some embodiments, the PD-1 inhibitor is administered over a period of about 4 hours. In some embodiments, the PD-1 inhibitor is administered over a period of about 5 hours. In some embodiments, the PD-1 inhibitor is administered over a period of about 6 hours.

[0290] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 300 m It is administered intravenously at a dose of 100 mg to about 500 mg (e.g., about 400 mg) once every four weeks. In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 200 mg. It is administered intravenously at a dose of about 400 mg (e.g., about 300 mg) once every three weeks. In some embodiments, tislelizumab is administered at a dose of 400 mg once every four weeks. In some embodiments, tislelizumab is administered at a dose of 300 mg once every three weeks. It is administered at .

[0291] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered once every two weeks. A dose of about 300 mg to about 500 mg (e.g., about 400 mg) is administered once every 20 minutes to about 40 minutes. In some embodiments, P is administered intravenously over a period of 2 minutes (e.g., about 30 minutes). D-1 inhibitors (e.g., tislelizumab) are administered at doses of approximately 200 mg to 400 mg once every three weeks. g (e.g., about 300 mg) for about 20 to about 40 minutes (e.g., about 30 minutes) It is administered intravenously.

[0292] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 100 m g / week. For example, if a patient is given a 10-week dose, (e.g., tislelizumab) can be administered at 1000 mg. If this is the case, PD-1 inhibitors (e.g., tislelizumab) can be administered at 900 mg. For an 8-week dose, 800 mg of PD-1 inhibitor (e.g., tislelizumab) When administered in 7-week doses, PD-1 inhibitors (e.g., Tisler) may be administered. ipragliflozin) can be administered at 700 mg. When administered as a 6-week dose, PD-1 blockade The drug (e.g., tislelizumab) can be administered at 600 mg. Five weekly doses are administered. If this is the case, PD-1 inhibitors (e.g., tislelizumab) can be administered at 500 mg. For a 4-week dose, 400 mg of PD-1 inhibitor (e.g., tislelizumab) When administered in 3-week doses, PD-1 inhibitors (e.g., Tisler) may be administered. ipragliflozin) can be administered at 300 mg. When administered as a 2-week dose, PD-1 blockade The drug (e.g., tislelizumab) can be administered at 200 mg. A weekly dose is administered. If necessary, PD-1 inhibitors (e.g., tislelizumab) can be administered at 100 mg. do.

[0293] For example, when using anti-PD-1 antibodies such as tislelizumab, the drug is administered intravenously once every three weeks. It can be administered at a dose of 200 mg as an intravenous infusion. It can be administered at a dose of 300 mg as an intravenous infusion once every four weeks. When using anti-PD-1 antibodies such as ibuprofen, 300 ml is administered as an intravenous infusion once every 3 weeks. g once every four weeks. Alternatively, tislelizumab can be administered intravenously. It can be administered in a dose of 400 mg as an infusion.

[0294] The structures of the active compounds identified by code numbers, generic names or trade names are given in the standard overview "T Current editions of the Merck Index or databases such as Patents International (e.g., IMS World Publication The above compounds that can be used in combination with the compounds of the present disclosure are available from The products may be prepared as described in the art, for example in the documents cited above. and can be administered.

[0295] In one embodiment, the present invention provides a method for simultaneous, separate or sequential use in therapy. A product containing a compound of the present invention and at least one other therapeutic agent is provided as a combination product. In one embodiment, the therapy is treatment of a disease or condition mediated by WRN. Products provided as combined formulations include compounds of formula (I) combined in the same pharmaceutical composition. and another therapeutic agent, or in separate forms, e.g., in the form of a kit, Examples of the composition include:

[0296] In one embodiment, the present invention comprises two or more separate pharmaceutical compositions, at least one of which Another aspect provides a kit containing a compound of the invention. In one embodiment, the kit comprises a container The compositions may be packaged in a container that is suitable for keeping them separate, such as a divided bottle, or a divided foil pouch. An example of such a kit is a means commonly used for packaging tablets, capsules and the like. It comes in a blister pack like this.

[0297] The kit of the present invention may contain separate components for administration in different dosage forms, e.g., oral and parenteral. To administer the compositions at different dosage intervals or to titrate the separate compositions relative to each other. To aid in compliance, the kits of the present disclosure typically include instructions for administration. Includes calligraphy.

[0298] In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent may be administered in the same or different formulations. Additionally, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by (i) Prior to delivery of a combination product to a physician (e.g., a compound of the present invention and another therapeutic agent) (ii) by a physician (or under the guidance of a physician) immediately before administration; (iii) in the patient himself, e.g., by sequential administration of a compound of the invention and another therapeutic agent; In between, they can be combined into a combination therapy.

[0299] Thus, the present invention provides a method for treating a disease or condition mediated by WRN using a compound of the invention. Use of a product, wherein the medicament is prepared for administration with another therapeutic agent. The present invention also provides methods for treating diseases or conditions mediated by WRN using compounds of the present invention. The present invention provides a use in which a medicament is administered together with the compound of the present invention.

[0300] The present invention also provides a compound of the invention for use in the treatment of a disease or condition mediated by WRN. wherein the compound of the invention is formulated for administration with another therapeutic agent. The present invention also provides another method for treating a disease or condition mediated by WRN. a therapeutic agent, the other therapeutic agent being formulated for administration with a compound of the invention; The present invention also provides therapeutic agents for use in treating diseases or conditions mediated by WRN. The compounds of the invention are intended for administration with another therapeutic agent. The present invention also provides compounds for the treatment of diseases or conditions mediated by WRN. another therapeutic agent for use in combination with a compound of the present invention, We provide therapeutic drugs that can be used to treat various conditions.

[0301] The present invention also provides a method for treating a disease or condition mediated by WRN using a compound of the present invention. and the patient has been previously treated (e.g., within 24 hours) with another therapeutic agent. The present invention also provides other therapeutic agents for treating diseases or conditions mediated by WRN. wherein the patient has previously been treated (e.g., within 24 hours) with a compound of the invention. Provides for use. [Example]

[0302] Formulation example The compounds of formula (I) may be formulated as amorphous solid dispersion tablets, as described below. This can be done.

[0303] A. Amorphous Solid Dispersions:

[0304] [Table 2]

[0305] *Eudragit® E PO is available at dx.doi.org / 10.1021 / mp4000635 I Mol.Pharmaceutics 2013,10,2 630-2641 and has the registered CAS number 24938-16-7 .

[0306] The vessel was charged with dichloromethane, followed by the free form (not the sodium salt) The compound of Example 42, basic polymethacrylate and copovidone were charged to obtain a slurry. Dichloromethane was added back into the vessel and the mixture was stirred until a clear solution was obtained. The liquid was spray dried, and the resulting powder was then dried in a stirred bed vacuum dryer and then sieved. did.

[0307] B. Film-coated tablets:

[0308] [Table 3]

[0309] Mannitol, croscarmellose sodium, colloidal silicon dioxide and fumaric acid Sodium stearyl was added to the powder of Example 42 compound obtained in Part A above and mixed. The mixture was blended and then compressed into tablets. The coating agent was dispersed in water to form a uniform suspension. A suspension was obtained which was used to coat the tablets.

[0310] Biological Assays and Data The activity of the compounds according to the invention is evaluated by the following in vitro and in vivo methods. It is possible.

[0311] Materials and Methods Molecular biology and virus production. Human Werner helicase (UniProt Q14 DNA encoding 191, WRN, amino acids S2-S1432 was transformed into E. coli (Ec The four DNA strings were designed with codons optimized for expression in . The strings are manufactured by GeneArt (Life Technologies, Regensbu or by subcloning overlapping oligonucleotides. Manufactured.

[0312] His-ZZ-3C-WRN (encoded by nucleotides 578-2743 in the sequence The expression plasmid pLAF1202 (sequence number 1202) encodes the nucleotide sequence of the target gene (aa N517-P1238) Baculovirus from column 1) was transfected with the FlashBac Ultra system (Oxf Code Expression Technologies 100302) 40 ng of plasmid DNA, 5.4 μg of Flashbac Ultra DNA, and and 5.4 microliters of Lipofectin (Life Technologies 18292-011) for transfection according to the manufacturer's instructions. After 5 hours of incubation, the solution was diluted with 500 microliters of TC Dilute with 100% medium (LifeTechnologies 13055-025) and Incubated at 4°C for 7 days.

[0313] The cells were harvested by centrifugation at 800 x g for 10 minutes, and the virus-containing supernatant was transferred to a fresh For the first viral amplification, 500 microliters of virus was transferred to a new sterile tube. Add the virus to 25 mL of SF9 cells at 1 million cells / mL and incubate at 27 °C (200 rpm). The cells were incubated at RT for 5 days. Cell viability, density, and diameter were measured to determine if there were any signs of infection. The collected virus was collected by centrifugation at 3000 rpm for 15 minutes.

[0314] Baculovirus-infected insect cells (BIICs) were cultured as described by Wasilko et al., 200 9,DOI:10.1016 / j.pep.2009.01.002 Generated. Briefly, 100 mL of ESF921 medium (expression system 100 million in 1000ml of ... SF9 cells (1 million cells / mL) were transfected with 300 million baculovirus of each construct. The cells were infected with 10 ... The infected cells were transferred to a 50 mL tube and centrifuged at 100 × g for 10 min at RT. and collected it.

[0315] Cells were cultured in ESF921 (0. The cells were resuspended at 10 million / mL in 5x streptomycin / penicillin medium. A 500 μL aliquot was transferred to a 1.8 mL cryotube and incubated at -80°C overnight. The samples were frozen in a nc Cryo 1°C freezing container.

[0316] SEQ ID NO: 1 [ka] [ka] [ka]

[0317] Protein expression and purification Werner helicase protein His-ZZ-3C-WRN (aa N517-P1 238, pLAF1202) to ESF921 medium. Dilute Sf21 cells (1 million cells / mL) in 1 L of ESF921 medium to 0. Dilute 1 / 100 into an expression / production flask containing 100 mM Tris-HCl and allow for 96 hours (27 min) for protein expression. The mixture was incubated at 130 rpm (°C).

[0318] WRN protein was purified using the following protocol: Cell pellets were thawed and ribonucleotide (final concentration 40 units / mL, Merck) and cOmplete protein Add 80 mL of buffer A (50 mL) supplemented with a 500 mM ATPase inhibitor tablet (1 tablet / 50 mL, Roche). M Tris, 300 mM NaCl, 20 mM imidazole, 1 mM TCEP, 10% The cells were resuspended in glycerol (pH 7.8). The cells were homogenized at 800-1000 bar. The solution was dissolved by passing it through a filter (Avestin, Emulsiflex C3) three times. The samples were centrifuged at 48,000 x g for 40 minutes (Sorvall RC5B, SS-34 L). The supernatant was passed through a 0.45 μm filter.

[0319] The lysate was purified using an AeKTA Pure 25 chromatography system (GE Healthcare) A HisTrap crude FF 5 mL column (GE Healthcare) was attached to a Contaminating proteins were washed away with buffer A, and the bound proteins were loaded onto a 1000-well plate. 00% Buffer B (50 mM Tris, 300 mM NaCl, 300 mM imidazole, Directly over 10 column volumes to 1 mM TCEP, 10% glycerol, pH 7.8 The elution was performed with a linear gradient of 1% (w / w) HRV 3C protease (His-MBP tagged) The N-terminal purification tag was added to the eluted protein in 2 L of buffer (50 ml). M Tris pH 7.0, 150 mM NaCl, 1 mM TCEP, 10% glycerol Digestion by proteases during overnight dialysis against ethanol (0.02% CHAPS) at 5°C The protein solution was then diluted with 2 volumes of 20 mM Tris pH 7.0, 10% The solution was carefully diluted by adding glycerol, 0.02% CHAPS. The cloudy protein solution was passed through a 0.45 μm filter. 0 mM Tris, 20 mM NaCl, 1 mM TCEP, 10% glycerol, pH 7. A Resource S 6 mL column (GE Healthcare) pre-equilibrated with 0 The cleaved tag and contaminating proteins were washed away with equilibration buffer. The purified target protein was added to 20 column volumes of the same buffer containing 1 M sodium chloride. The column was eluted with a linear gradient of 1000 μL, followed by elution with 50 mM Tris pH 7.4, 300 mM NaCl. , HiLoad 16 / 600 Superdex pre-equilibrated with 10% glycerol The purified protein was injected onto a 75 pg column (GE Healthcare). The corresponding fractions were identified by SDS-PAGE and pooled. The protein was divided into aliquots and frozen on dry ice. , determined by RP-HPLC and LC-MS.

[0320] In vitro enzyme activity assay for WRN helicase An ATPase assay was set up to measure the DNA-dependent ATP hydrolysis activity of WRN helicase. This assay was also used to measure the activity of WRN in response to DNA-dependent ATPase activity. The inhibitory properties of compounds of the present invention were evaluated.

[0321] The core helicase motif of the WRN protein (aa N517-P1238) was identified in this The assay was performed as described above. .,2009,DOI:10.1074 / jbc.M111446200 The 45 oligonucleotide sequences (TTTTTTTTTT) called "FLAP26" TTTTTTTTTTTTTCCAAGTAAAACGACGGCCAGTGC;Sequence no. No. 2) was acquired by IDT (Integrated DNA Technologies, Leuv The DNA was purchased from Axen, Belgium and used as the signal strand DNA substrate. ADP-Glo ​​Assay Kit enables quantification of ADP produced during TP hydrolysis. (Promega, Madison, WI) was used to set up this assay. .

[0322] A time course experiment was first performed to determine the best enzyme assay conditions (buffer conditions, reaction time, and The concentrations of the protein, ATP, and DNA substrate were determined. 10 nM WRN protein, 0.2 nM FLAP26, and 30 nM FLAP26 in assay buffer 0 micromolar ATP, consisting of: 30 mM Tris pH 7.5, 2 mM MgCl2, 0.02% BSA, 50mM NaCl, 0.1% pluronic F127(D (Prepared in Nase-free water).

[0323] To evaluate the inhibitory properties of the compounds of the present invention, serial dilutions were prepared in DMSO (10 (10 half-log dilution from 1 mM DMSO solution). Fifty nanoliters of each concentration were added to 2.5 mL of PBS. 384 small volume assay plates containing 20 nM WRN helicase protein in 1 liter containing 600 micromolar ATP in a PBS solution (Greiner #784075). The wells were pre-incubated in assay buffer for 3 hours. Control wells contained no test compound. A "high control" (no inhibition) containing DMSO and a "low control" containing protein-free buffer were also included. A "low control" (maximal inhibition) with 0.4 nM of ATP was included. Reactions were run in 2.5 microliters. The reaction was initiated by adding 5 ml of FLAP26 and incubated at room temperature for 30 minutes. The reaction was stopped by adding 1 microliter of the first ADP-Glo ​​reagent and incubated for 1 hour. The excess ATP was removed by rinsing. Then, 10 microliters of ATP detection reagent was added. After addition and incubation for a further hour, the luminescence output was read using a Tecan 1 The compound concentrations were recorded using a 000 reader with a 5 minute delay before reading. Items were tested in duplicate on assay plates.

[0324] Data analysis was carried out by Formenko et al., 2006, DOI:10.1016 Using the method described in / j.cmpb.2006.01.008, we developed our own software. Novartis Helios software application, Novartis is Institutes for BioMedical Research, unpublished Table 10.1016 / j.cmpb.2006.01.008) The activity value of the wells was calculated as % inhibition (% inhibition = [(high control - sample) / (high control -low control)] × 100), and then duplicates present on each plate according to [4]. IC from the measured value 50 Data analysis was also performed using a four-parameter fit. (e.g., GraphPad Prism, XLfit) to calculate IC 50 Derive Value This can be done using commercially available software designed to I C 50 Values ​​are the geometric means of at least two independent replicates.

[0325] Methods for detecting effects on cell proliferation Colon cancer cell lines SW48 (RRID:CVCL_1724), HCT116 (RRID: CVCL_0291) and SNU-407 (RRID:CVCL_5058) were obtained from ATCC The WRN knockdown-insensitive colon cancer cell line DLD-1 (RRID:CVC) was obtained from L_0248 was obtained from the Korean Cell Line Bank ( and purified by CRISPR-mediated editing using standard CRISPR methods. It was used to generate derivatives in which the endogenous WRN gene copy was knocked out. Assessing potential off-target compound effects using the DLD1-WRN-KO cell line did.

[0326] SW48, SNU-407, and DLD1-WRN-KO cells were cultured in RPMI-1640 ( Amimed Catalog No. 1-41F22-I), 2 mM L-glutamine (Amim ed Catalog No. 5-10K50), 10 mM HEPES (Gibco Catalog No. No. 15630-056), 1 mM sodium pyruvate (Amimed Cat. No. 5 -60F00-H), 1× penicillin-streptomycin (Amimed catalog no. 4-01F00-H) and 10% fetal bovine serum (Amimed Cat. No. 2-01F3 The HCT 116 cells were cultured in a growth medium consisting of 0-G (lot number LB11566P). The cells were resuspended in McCoys 5A (Amimed catalog number 1-18F01-I), 2 mM L-glutamine (Amimed Catalog No. 5-10K50), 1x penicillin- Leptomycin (Amimed Catalog No. 4-01F00-H) and 10% fetal bovine milk Serum (Amimed Catalog No. 2-01F30-G, Lot No. LB11566P) All cells were cultured in a growth medium consisting of 1000 μg / ml of PBS containing 1000 μg of PBS. All cells were stored in a humidified 5% CO2 incubator. The incubation was maintained at 37°C.

[0327] Steriflip-NY 20 μm filter (Millipore Cat. No. S After filtering through a 100-microliter tube (CNY00020), trypsinized cells were collected. In a bottle of growth medium, 2,000 (SW48) or 1,500 (SNU-407, DLD 1-WRN-KO, HCT 116) cells / well in a white, clear-bottom 96-well plate (Costar Cat. No. 3903). Three replicates were seeded for each compound treatment condition. Additionally, one plate (referred to as "day 0") was prepared as a compound-added plate. The cells were incubated overnight at 37°C in a humidified 5% CO2 atmosphere to quantify the number of viable cells. After incubation, the given compound stock (obtained at a concentration of 10 mM in DMSO and stored at 4 °C) Eight three-fold serial dilutions of the 100% ATP (stored) were dispensed into a HP 300D non-contact digital dispenser (TE DMSO was directly dispensed into each of the triplicate assay plates using a CAN. Final concentrations were normalized to 0.1% in all wells. 96 hours after compound addition, cell viability Cellular ATP levels were measured as a surrogate for ATP in 50 microliters of CellTiterGlo ( Evaluated after addition of reagent (Promega Cat. No. G7573) and incubated at room temperature for 10 minutes. After incubation, luminescence was measured using an MPLEX multimode plate reader (TECAN). The number of viable cells in the "day 0" plates was similarly quantified on the day of compound addition.

[0328] For data analysis, the values ​​determined in wells containing medium but no cells were used. Assay background signal was calculated from all data points before further calculations were performed. The extent of growth inhibition and potential cell death was determined by the ATP concentration in compound-treated cells. levels (measured using CellTiterGlo, Promega) at the time of compound addition. For this purpose, the following conditional concepts are evaluated by comparing them with those that exist: The program was applied in ELIOS. ELIOS reached an optimal concentration-response curve fit. It is an in-house software that applies a multi-step decision tree to reach the l,SLAS DOI:10.1177 / 2472555217752140), compound Calculate the growth percentage (G%) of each well processed: G% = ((T - V0) / V0)) * 10 0 (when T < V0), G% = ((T - V0) / (V - V0)))*100 (when T ≥ V0) (where V0 is the survival rate level at the time of compound addition, and V and T are the vehicle - target survival level and compound - treated survival level at the end of the compound incubation, respectively). 100%, 0%, and - 100% indicate the absence of growth inhibition, growth arrest, and complete cell death, respectively. The compound concentration (GI50) that results in 50% growth inhibition and the residual cell survival rate (data (cmax), expressed as a percentage) at the highest concentration of the test compound were routinely calculated. Data analysis was also designed to derive IC50 values using commercially available software ware that uses four - parameter fitting (e.g., GraphPad Prism, XL Fit). The reported GI values are the geometric mean of at least two independent replicates. Demonstration of the in - vivo efficacy of the compounds of the present invention 50 (0) Experiments were performed on female Crl:NU(NCr) - Foxn1NU - homozygous nude mice (C harles River). Animals were housed in Allentown XJ cages (IV C, up to 6 mice per cage) under optimized hygienic conditions, given food and water ad libitum and maintained on a 12 - hour:12 - hour light:dark cycle. 12h light:dar k cycle. Animals were acclimated for at least 1 week before enrollment in the experimental design. The studies described in this specification were carried out in accordance with license 2275 approved by the Basel Cantonal Veterinary Off ice.

[0330] ​​​​​​​​ SW48 human colon cancer cells were obtained from ATCC. The cells were cultured in 10% FCS (Bio-Medical). ncept, #2-01F30-I), 2 mM L-glutamine (BioConcept Ltd. Amimed, #5-10K50-H), 1 mM sodium pyruvate (B Bio Concept #5-60F00-H) and 10 mM HEPES (Bio C RPMI-1640 medium (BioC) supplemented with oncept #5-31F00-H oncept Ltd. Amimed, #1-41F01-I), 37°C, 5% air To establish SW48 xenografts, cells were harvested and cultured under a 5% CO2 atmosphere. After resuspension in BSS (Gibco, #14175), animals anesthetized with isoflurane were 100 μL containing 5 million cells was injected subcutaneously into the right flank.

[0331] Tumor growth was monitored periodically after cell inoculation, and when tumor volume reached an appropriate volume, Animals were randomized into treatment groups (n=7). Tumor volumes were measured approximately twice weekly during the treatment period. Tumor size (mm 3 ) was calculated from ((L × W2 × π / 6), where W = tumor width , L = tumor length.

[0332] Depending on the target concentration, add 50–200 mg of amorphous sodium salt of the test compound (salinity factor (corrected by 2-hydroxypropyl-beta-cyclodextrin (HPBCD) Dissolved in 8 mL of 10% w / v aqueous solution. Adjusted to pH 7.4 with 0.1 M HCl (approximately 1 equivalent). The resulting solution was filled up to a total volume of 10 mL with 10% HPBCD aqueous solution. If present, the solution was filtered. The resulting solution formulation was used for in vivo studies.

[0333] Tumor-bearing animals were screened until their tumors reached 186 mm 3 The groups were formed with a mean tumor volume of When the animals reached a suitable size for feeding, they were enrolled into treatment groups (n=7). (10% hydroxypropyl-beta-cyclodextrin) or 240 mg / kg Treatment with compounds of the invention was performed daily (QD) by oral gavage at 20 mL / kg. Animals were weighed twice weekly and frequently examined for overt signs of adverse effects.

[0334] Tumor and body weight change data were analyzed using GraphPad Prism 7.00 (Graph Statistical analysis was performed using the Pad Software. The data were normally distributed. If so, one-way ANOVA with Dunnett's post-hoc test was used to compare treatment and control groups. Data were analyzed using one-way ANOVA. When applicable, results were averaged. Expressed as mean ± SEM.

[0335] As a measure of efficacy, %T / C% values ​​are calculated at the end of the experiment according to the following: (Δtumor volume 処置 / Δtumor volume 対照 )*100 Tumor regression was calculated as follows: -(Δtumor volume 処置 / Δtumor volume 処置開始時 )*100. Here, Δtumor volume represents the mean tumor volume on the day of evaluation minus the mean tumor volume at the start of the experiment. vinegar.

[0336] Treatment was performed, for example, on tumors with a mean tumor volume of 186 mm 3 (n=7 / group) Example 1: In 10% hydroxypropyl-beta-cyclodextrin in water using Treatment with Example 58 was initiated at 240 mg / kg. The treatment period with Example 58 was 18 days, during which The overall efficacy and tolerability were then assessed based on the tumor volume and body weight changes observed during the treatment period. The efficacy of Example 58, administered orally at 240 mg / kg qd, was evaluated (Figure 6). The anti-tumor response was induced in SW48 xenografts in mice (Figure 6). The value was −9 (p=<0.05 compared to vehicle control, Dunnett's post-hoc test The mean tumor volume at day 18 in 4 / 7 surviving animals was -2 Based on body weight, QD administration of 240 mg / kg of Example 58 showed good regression. The data for the compounds of Examples 42, 96, and 57 were shown in Table 6. As shown in Figures 9, 10 and 11.

[0337] This application contains a Sequence Listing which has been submitted electronically in ASCII format, the entirety of which is set forth below. The ASCII created on May 21, 2021 is incorporated herein by reference. The copy is named PAT059096_SL.txt and is 13184 bytes in size. It is.

[0338] The following table shows the IC5 values ​​in the WRN ATPase assay for compounds of the present invention. 0 data and proliferation assays using SW48 and DLD1-WRN-KO cell lines. GI 50 For example, Example 1 shows that 50 nM, D A proliferation GI of >10 micromolar in the LD1 WRN-KO cell line 50 having 50 nM WRN ATPase inhibitor.

[0339] [Table 4]

[0340] [Table 5]

[0341] [Table 6]

[0342] Data are geometric means from at least duplicate determinations.

[0343] In another aspect, the present invention provides a method for the treatment of cancer or for use in research applications such as chemical probes. The compounds of formula (I) as chemicals derive part of their WRN inhibitory activity from the biochemical assays described above. The present invention provides compounds that mediate the activation of ATP through mechanisms not previously evaluated.

[0344] Methods for detecting clonogenic effects on cell proliferation (CFA = colony formation assay) stomach) Cell lines were obtained from ATCC, and media and culture conditions were used as recommended by ATCC. All cells were maintained at 37°C in a humidified 5% CO2 incubator. Seed 250-2,000 cells per well in a 12-well plate in 1 ml of medium. The WRN inhibitor compound of Example 42 was added at a starting concentration of 10 μM. After overnight incubation at 37 °C in a 5% CO atmosphere, the given compound stock (DMS Ten three-fold serial dilutions of 10 mM HO (obtained at a concentration of 10 mM in HO and stored at 4°C) were Directly dispense into each assay plate using a digital dispenser (TECAN). The final concentration of DMSO was normalized to 0.1% in all wells. The cells were left in the refrigerator for 8 to 20 days, and the medium was changed every 3 to 4 days. 37% acetaldehyde was added directly to each test well and incubated at room temperature for 15 minutes. After rinsing twice with 5 ml of water, 0.5 ml of 0.05% methylene blue was applied at room temperature for 20 minutes. The wells were rinsed three times with water, and 1 ml of 3% HCl was added to the plate to completely dissolve the color. 200 μl of this solution was transferred to a 96-well plate and Absorbance was measured at 650 nM using a tarplate reader (Synergy HT). The compound concentration that results in 50% growth inhibition (GI50) is called the Dose Response. Using XLfit with One Site model 201, fit = (A + ((BA ) / (1+((x / C)^D)))). For non-adherent cell lines, cell viability To measure cellular ATP levels as a proxy for cell viability, 200 μl of Cell Evaluation was performed after adding TiterGlo (Promega Cat. No. G7573) reagent. Luminescence was quantified using the Synergy HT Probe after a 15-minute incubation at room temperature. The data were analyzed in the same manner as for methylene blue staining. The results are shown in Figure 8. Further information on MSI-H and MSS is available in the following references: be: ·Chan et Al.,WRN helicase is a synthetic lethal target in microsatellite unstabl e cancers.Nature.2019 Apr;568(7753):551- 556.doi:10.1038 / s41586-019-1102-x.Epub 2 019 Apr 10.PMID:30971823;PMCID:PMC658086 1. ·McDonald ERet al.,Project DRIVE:A Com pendium of Cancer Dependencies and Synth etic Lethal Relationships Uncovered by L arge-Scale,Deep RNAi Screening.Cell 170( 3):577-592(2017)).

[0345] Preparation of compounds Compounds of the present disclosure can be prepared as described in the Examples below. The examples are intended to illustrate the invention and should not be construed as limiting the invention. isn't it.

[0346] device Microwave: All microwave reactions were performed in a Robot Eight unless otherwise specified. 2. With a processing capacity of t / Robot Sixty / Robot Twenty-four. Biotage Initiat, which irradiates from a 45GHz magnetron at 0-400W. or performed on an Anton Paar monowave 450.

[0347] UPLC-MS method: Waters with a Waters SQ detector, unless otherwise specified. ters Acquity UPLC.

[0348] UPLC-MS 1: Column CORTECS (trademark) C18+2.7μm, Column dimensions: 2.1 x 50 mm Column temperature: 80°C Eluent A: Water + 4.76% isopropanol + 0.05% FA + 3.75mM A A B: Isopropanol + 0.05% FA Flow rate 1.0mL / min Gradient: 1 to 50% B in 1.4 min, 50 to 98% B in 0.3 min

[0349] UPLC-MS 2: Column: ACQUITY UPLC® BEH C18 1.7 μm Column dimensions: 2.1 x 100 mm Column temperature: 80°C Eluent A: Water + 4.76% isopropanol + 0.05% FA + 3.75mM A A B: Isopropanol + 0.05% FA Flow rate 0.4mL / min Gradient: 1 to 60% B in 8.4 min, 60 to 98% B in 1.0 min

[0350] UPLC-MS 3: Column: ACQUITY UPLC® BEH C18 1.7 μm Column dimensions: 2.1 x 50 mm Column temperature: 80°C Eluent A: Water + 4.76% isopropanol + 0.05% FA + 3.75mM A A B: Isopropanol + 0.05% FA Flow rate 0.6mL / min Gradient: 1 to 98% B in 1.7 min

[0351] UPLC-MS 4: Column: ACQUITY UPLC® BEH C18 1.7 μm Column dimensions: 2.1 x 50 mm Column temperature: 80°C Eluent A: Water+0.05% FA+3.75mM AA B: Isopropanol + 0.05% FA Flow rate 0.6 / 0.7mL / min Gradient: 5 to 98% B in 1.7 min

[0352] UPLC-MS 5: Column: XBridge® BEH™ C18 2.5 μm Column dimensions: 2.1 x 50 mm Column temperature: 80°C Eluent A: Water + 5mM NH4OH B: Acetonitrile + 5mM NH4OH Flow rate 1.0mL / min Gradient: 2 to 98% B in 1.4 min

[0353] UPLC-MS 6: Column: Ascentis® Express C18 2.7 μm Column dimensions: 2.1 x 50 mm Column temperature: 80°C Eluent A: Water + 4.76% isopropanol + 0.05% FA + 3.75mM A A B: Isopropanol + 0.05% FA Flow rate 1.0mL / min Gradient: 1 to 50% B in 1.4 min, 50 to 98% B in 0.3 min

[0354] UPLC-MS 7: Column: Acquity UPLC® HSS T3 1.8 μm Column dimensions: 2.1 x 50 mm Column temperature: 60℃ Eluent A: Water + 0.05% formic acid + 3.75 mM ammonium acetate B: Acetonitrile + 0.04% FA Flow rate 1.0mL / min Gradient: 2 to 98% B in 1.4 min

[0355] UPLC-MS 8: Column: Acquity UPLC® HSS T3 1.8 μm Column dimensions: 2.1 x 50 mm Column temperature: 60℃ Eluent A: Water + 0.05% formic acid + 3.75 mM ammonium acetate B: Acetonitrile + 0.04% FA Flow rate 1.0mL / min Gradient: 5 to 98% B in 1.4 min

[0356] UPLC-MS 9: Column: XBridge® BEH™ C18 2.5 μm Column dimensions: 2.1 x 50 mm Column temperature: 80°C Eluent A: Water + 5mM NH4OH B: Acetonitrile + 5mM NH4OH Flow rate 1.0mL / min Gradient: 2 to 98% B in 9.4 min

[0357] UPLC-MS 10: Column CORTECS (trademark) C18+2.7μm, Column dimensions: 2.1 x 50 mm Column temperature: 80°C Eluent A: Water+0.05% FA+3.75mM AA B: Isopropanol + 0.05% FA Flow rate 1.0mL / min 1.4 minutes concave 1%~98%B

[0358] UPLC-MS 11: Equipment Shimadzu with Shimadzu LCMS 2020 as MSD NEXERA UPLC PDA Column: Mercury MS Synergi C12 2.5 μm Column dimensions: 20 x 4.0 mm Column temperature: 40°C Eluent A: Water + 0.1% FA B: Acetonitrile Flow rate 2.0mL / min Gradient Time / %B: 0.01 / 5, 0.5 / 5, 1.0 / 95, 1.5 / 95, 2.0 / 5.3 / 5

[0359] UPLC-MS 12: Instruments: Agilent with AB Sciex API2000 TQ as MSD 1200 HPLC PDA Column: Mercury MS Synergi C12 2.5μm Column dimensions: 20 x 4.0 mm Column temperature: 30°C Eluent A: Water + 0.1% FA B: Acetonitrile Flow rate 2.0mL / min Gradient Time / %B: 0.01 / 30, 0.5 / 30, 1.0 / 95, 2.4 / 95, 2. 5 / 30, 3.0 / 30

[0360] UPLC-MS 13: Equipment: Agile with AB Sciex API3200 QTRAP as MSD nt 1200 HPLC PDA Column: Kinetex EVO C18 2.6 μm Column dimensions: 50 x 4.6 mm Column temperature: 30°C Eluent A: Water + 0.1% FA B: Acetonitrile + 0.1% FA Flow rate 1.5mL / min Gradient Time / B: 0 / 20, 0.2 / 50, 1 / 95, 2.7 / 95, 2.8 / 20, 4 / 20

[0361] UPLC-MS 14: Column: Acquity UPLC® HSS T3 1.8 μm Column dimensions: 2.1 x 100 mm Column temperature: 60℃ Eluent A: Water + 0.05% formic acid + 3.75 mM ammonium acetate B: Acetonitrile + 0.04% FA Flow rate 1.0mL / min Gradient: 5 to 98% B in 9.4 min

[0362] HPLC method: HPLC 1: Instruments: Agilent 1100 series with PDA detector Column: Kinetex C-18, 5 μm Column dimensions: 150 x 4.6 mm Column temperature: 40°C Eluent A: Water + 0.01% TFA B: Acetonitrile Flow rate 1.0mL / min Gradient Time / B: 0 / 30, 2 / 40, 5 / 90, 8 / 100, 10 / 100, 11 / 3 0, 12 / 30

[0363] HPLC 2: Equipment: Acquity Arc Waters with PDA detector (2998PDA) UHPLC Column: Kinetex EO, 2.6 μm Column dimensions: 100 x 4.6 mm Column temperature: 40°C Eluent A: Water + 0.01% TFA B: Acetonitrile Flow rate 1.0mL / min Gradient Time / B: 0 / 5, 2 / 5, 6 / 70, 10 / 100, 13 / 100, 13.5 / 5, 15 / 5

[0364] HPLC 3: Instrument Agilent 1260 HPLC Column: Agilent Poroshell 120 C18, 2.7 μm Column dimensions: 4.6 x 50 mm Column temperature: 40°C Eluent A: Water + 0.01% TFA B: Acetonitrile + 0.01% TFA Flow rate 1.2mL / min Gradient: 0%B to 50%B in 5 minutes, hold for 2 minutes

[0365] HPLC 4: Instrument Agilent 1260 Column: Agilent Poroshell 120 EC-C18, 2.7 μm Column dimensions: 4.6 x 50 mm Column temperature: 40°C Eluent A: Water + 0.1% TFA B: Acetonitrile + 0.1% TFA Flow rate 1.2mL / min Gradient: 5%B to 95%B in 5 minutes, hold for 2 minutes

[0366] HPLC 5: Instrument Agilent 1260 HPLC Column: InertSustain C18, 5 μm Column dimensions: 4.6 x 150 mm Column temperature: 30°C Eluent A: Water + 5mmol(NH4)2CO3 B: Acetonitrile Flow rate 1.0mL / min Gradient: 10%B to 90%B in 8 minutes, hold for 2 minutes

[0367] HPLC 6: Instruments: Agilent 1260 infinity series with DAD / ELSD HPLC system Column: Atlantis dC18, 5 μm Column dimensions: 4.6 x 250 mm Column temperature: 25°C Eluent A: Water + 0.1% TFA B: Acetonitrile Flow rate 1.0mL / min Gradient: 10%B to 100%B in 15 minutes, hold for 5 minutes

[0368] Chiral analytical HPLC method C-HPLC 1: Instrument: Agilent 1260 Infinity II Series with PDA detector Z Injection: 3μL Mobile phase: A: Hexane B: 0.1% HCOOH (in EtOH) Flow rate: 20mL / min Column: CELLULOSE 4 (150 x 4.6 mm, 5 μm) Detection UV: 210nm Gradient: Uniform concentration: 50:50

[0369] C-HPLC 2: Instrument: Agilent 1260 Infinity II Series with PDA detector Z Injection: 10μL Mobile phase: A: Hexane B: 0.1% HCOOH (in EtOH) Flow rate: 15mL / min Column: CELLULOSE 4 (150 x 4.6 mm, 5 μm) Detection UV: 210 nm. Gradient: uniform concentration 50:50

[0370] C-HPLC 3: Instrument: Agilent 1260 Infinity II Series with PDA detector Z Injection volume: 8μL Mobile phase: A: Hexane B: 0.1% HCOOH (in EtOH) Flow rate: 1mL / min Column: CELLULOSE 4 (150 x 4.6 mm, 5 μm) Detection UV: 210 or 254 nm Gradient: Uniform concentration: 50:50

[0371] C-HPLC 4: Instrument: Agilent 1260 Infinity II Series with PDA detector Z Injection volume: 3μL Mobile phase: A: Hexane B: 0.1% HCOOH (in EtOH) Flow rate: 1mL / min Column: CELLULOSE 4 (150 x 4.6 mm, 5 μm) Detection UV: 210 or 254 nm Gradient: Uniform concentration: 50:50

[0372] C-HPLC 5: Instrument: Agilent 1260 Infinity II Series with PDA detector Z Injection volume: 2μL Mobile phase: A: Hexane B: 0.1% TFA in EtOH Flow rate: 1mL / min Column: CELLULOSE 4 (150 x 4.6 mm, 5 μm) Detection: 210 or 254 nm Gradient: Uniform concentration: 50:50

[0373] C-HPLC 6: Instrument: Agilent 1260 Infinity II Series with PDA detector Z Injection volume: 3μL Mobile phase: A: Hexane B: 0.1% TFA in EtOH Flow rate: 1mL / min Column: CELLULOSE 4 (150 x 4.6 mm, 5 μm) Detection UV: 210 or 254 nm Gradient: uniform concentration 50:50

[0374] C-HPLC 7: Equipment:Waters UPC 2 MS Injection volume: 5μL Mobile phase: A: 25% (MeOH + 0.1% NH3); B: 75% scCO2 uniform concentration Flow rate: 3mL / min Column: Chiralpak IB-N 5μm, 100×4.6mm Detection UV: 190~400nm Oven temperature: 40°C

[0375] C-HPLC 8: Instrument: Waters UPC 2 MS Injection volume: 5 μL Mobile phase: A: 35% (MeOH + 0.1% NH3); B: 65% scCO2 homogeneous concentration Flow rate: 3 mL / min Column: Chiralpak IB-N 5 μm, 100×4.6 mm Detection: 190 - 400 nm Oven temperature: 40 °C

[0376] C-HPLC 9: Instrument: Waters UPC 2 Injection volume: 1 μL Mobile phase: A: CO2; B: MeOH + 0.05% DEA Flow rate: 2.4 mL / min Column: Chiralpak IC, 3 μm, 100×4.6 mm Detection: 220 nm Column temperature: 35 °C Back pressure: 100 bar

[0377] C-HPLC 10: Instrument: Waters UPC 2 -MS[[ID=四十八]] Injection volume: 5 μL. Mobile phase: Homogeneous concentration A = 35% (IPA + 0.1% NH3) B = 65% scCO2 Flow rate: 3 mL / min Column: Chiralpak IB, 5 μm, 100×4.6 mm Detection: DAD 210 - 400 nm Back pressure: 1800 psi

[0378] C-HPLC 11: Instrument: Waters Acquity UPC Injection volume: 5 μL Mobile phase: A: 35% (MeOH + 0.05% NH3); B: 65% scCO2 Flow rate: 3 mL / min Column: Chiralpak IB-N 5μm, 100×4.6mm Detection UV: 240nm Oven temperature: 40°C

[0379] C-HPLC 12: Equipment: Waters Acquity UPC Injection volume: 5μL Mobile phase: A: 35% (MeOH+0.05% NH3); B: 65% scCO2 Flow rate: 3mL / min Column: Chiralpak IB-N 5μm, 100×4.6mm Detection UV: 240nm Oven temperature: 40°C

[0380] C-HPLC 13: Equipment:Waters UPC 2 -MS Injection volume: 5μL Mobile phase: uniform concentration A=25%(MeOH+0.05% NH3) B=75% scC O2 Flow rate: 3mL / min Column: Chiralpak IB, 5μm, 100×4.6mm Detection: DAD 210~400nm: Back pressure: 1800 psi

[0381] Adjustment method: Column chromatography: Column chromatography was performed using prepackaged columns as detailed below unless otherwise specified. using a column or using a glass column according to standard flash chromatography techniques. This was done with silica gel. System 1 TeledyneISCO, CombiFlash Rf, CombiFl ash Rf+ System 2 Biotage Isolera Column: Pre-packed RediSep Rf cartridge or SNAP cartridge Adsorption of sample onto Isolute, onto silica gel, or as a solution

[0382] Supercritical Fluid Chromatography (SFC) Purification was performed using a Waters 2998 photodiode array detector and a Waters M Waters Prep S with ABSYS Update, featuring a single quadrupole detector The analysis was carried out using an FC-100-MS system.

[0383] SFC 1: Equipment: WATERS SFC 100 with ABSYS update Mobile phase: A: CO2, B: MeOH: Flow rate: 150mL / min MeOH + 30mL / min CO2, 180mL / min constant flow Column: 250 x 30 Reprospher PEI 100A 5μm Temperature 50℃ Back pressure: 100bar Detection UV: 210~400nm). Gradient: 18% B to 26% B in 6.86 minutes

[0384] SFC 2: Equipment: WATERS SFC 100 with ABSYS update Mobile phase: A: CO2; B: MeOH Flow rate: 150mL / min MeOH + 30mL / min CO2, 180mL / min constant flow Column: 100 x 30 Reprosil NH2100A 3 μm Temperature 50℃ Back pressure: 100bar Detection UV: 210~400nm Gradient: 34%B to 42%B in 2.8 minutes

[0385] SFC 3: Equipment: WATERS SFC 100 with ABSYS update Mobile phase: A: CO2, B: MeOH Flow rate: 150mL / min MeOH + 30mL / min CO2, 180mL / min constant flow Column: 100 x 30 Reprosil NH2100A 3 μm Temperature: 50℃ Back pressure: 100bar Detection UV: 210~400nm Gradient: (First run) 21% B to 29% B in 2.8 minutes (Second run to improve detection) 25% B to 33% B in 2.8 minutes

[0386] SFC 4: Equipment: WATERS SFC 100 Mobile phase: A.CO2, B:MeOH: Flow rate: 100mL / min Column: 250 x 30 Reprospher PEI 100A 5μm Temperature 32℃ Back pressure: 120bar Detection UV: 210~400nm Gradient: 40% B to 55% B in 10.2 min

[0387] SFC 5: Equipment: WATERS SFC 100 Mobile phase: A: CO2, B: MeOH Flow rate: 100mL / min MeOH Column: 250 x 30 Reprospher PEI 100A 5μm Temperature 32℃ Back pressure: 120bar Detection UV: 210~400nm Gradient: 35% B to 45% B in 10.3 min

[0388] SFC 6: Equipment: WATERS SFC 100 with ABSYS update Mobile phase: A: CO2, B: MeOH: Flow rate: 150mL / min MeOH+30mL / min CO2, constant flow of 180mL / min Column: 100 x 30 Reprosil NH2100A 3 μm Temperature: 50℃ Back pressure: 100bar Detection UV: 210~400nm Gradient: 31% B to 39% B in 2.8 min

[0389] SFC 7: Equipment: WATERS SFC 100 with ABSYS update Mobile phase: A: CO2, B: MeOH Flow rate: 150mL / min MeOH+30mL / min CO2, constant flow of 180mL / min Column: 250 x 30 waters Torus2-PIC 130A 5μm Temperature: 50℃ Back pressure: 100bar Detection UV: 210~400nm Gradient: 26% B to 34% B in 5.48 minutes

[0390] Reverse phase HPLC: RP-HPLC Basic 1: System Gilson Column: Waters X-Bridge Prep C18 OBD (100mm x 3 0mm), 5μm Eluent A: Water + 7.3 mM NH4OH, B: Acetonitrile Flow rate 40mL / min

[0391] RP-HPLC Basic 2: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: XBRIDGE (150 mm x 20 mm), 5.0 μm Eluent A: 0.02% ammonia (in water), B: acetonitrile Flow rate 20mL / min

[0392] RP-HPLC acidic 1: System Gilson Column: Waters SunFire Prep C18 OBD (100mm x 30 mm), 5 μm Eluent A: Water + 0.1% TFA, B: Acetonitrile Flow rate 40mL / min

[0393] RP-HPLC acidic 2: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: LUNA C18 (250 mm x 19 mm), 4.0 μm Eluent A: 0.1% HCOOH (in water), B: acetonitrile Flow rate 20mL / min

[0394] RP-HPLC acidic 3: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: LUNA (250 mm x 21.2 mm), 5.0 μm Eluent A: 0.1% HCOOH (in water), B: acetonitrile Flow rate 18mL / min

[0395] RP-HPLC acidic 4: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: LUNA (250 mm x 21.2 mm), 5.0 μm Eluent A: 0.1% HCOOH (in water), B: acetonitrile Flow rate 20mL / min

[0396] RP-HPLC acidic 5: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: LUNA Phenomenex (250 mm x 21.2 mm), 5.0 μm Eluent A: 0.1% HCOOH (in water), B: acetonitrile Flow rate 18mL / min

[0397] RP-HPLC acidic 6: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: Atlantis (250 mm x 19 mm), 5.0 μm Eluent A: 0.1% HCOOH (in water), B: acetonitrile:MeOH Flow rate 18mL / min

[0398] RP-HPLC acidic 7: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: LUNA C18 (250 mm x 21.2 mm), 5.0 μm Eluent A: 0.1% HCOOH (in water), B: acetonitrile Flow rate 20mL / min

[0399] RP-HPLC acidic 8: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: Atlantis (250 mm x 19 mm), 5.0 μm Eluent A: 0.1% HCOOH (in water), B: acetonitrile Flow rate 18mL / min

[0400] RP-HPLC acidic 9: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: Atlantis (250 mm x 21.2 mm), 5.0 μm Eluent A: 0.1% HCOOH (in water), B: acetonitrile Flow rate 20mL / min

[0401] RP-HPLC acidic 10: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: Atlantis (250 mm x 21.2 mm), 5.0 μm Eluent A: 0.1% HCOOH (in water), B: acetonitrile Flow rate 18mL / min

[0402] RP-HPLC acidic 11: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: LUNA OMEGA (250 mm x 21.2 mm), 5.0 μm Eluent A: 0.1% HCOOH (in water), B: acetonitrile:MeOH (1:1) Flow rate 20mL / min

[0403] RP-HPLC acidic 12: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: LUNA C18 (250 mm x 21.2 mm), 5.0 μm Eluent A: 0.1% HCOOH (in water), B: acetonitrile Flow rate 18mL / min

[0404] RP-HPLC acidic 13: System Gilson Column: Nucleodur C18 (21mm x 250mm) Eluent A: Water + (0.1% COOH), B: Acetonitrile + 0.1% COOH Flow rate 40mL / min

[0405] RP-HPLC acidic 14: Teledyne / Isco AccqPrep HP150 prep system Column: 50 x 100 Xbridge C18 (50 mm x 100 mm), 5 μm Eluent A: Water + 0.1% TFA, B: Acetonitrile Flow rate 100mL / min

[0406] RP-HPLC neutral 1: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: KINETEX (150 mm x 21.2 mm), 5 μm Eluent A: water, B: acetonitrile Flow rate 20mL / min

[0407] RP-HPLC Neutral 2: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: Atlantis (250mm x 21.2mm), 5μm Eluent A: water, B: acetonitrile Flow rate 17mL / min

[0408] RP-HPLC Neutral 3: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: LUNA C18 (250 mm x 21.2 mm), 5 μm Eluent A: water, B: acetonitrile Flow rate 20mL / min

[0409] RP-HPLC Neutral 4: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer Column: LUNA Phenomenex (250 mm x 21.2 mm), 5 μm Eluent A: water, B: acetonitrile Flow rate 18mL / min

[0410] RP-HPLC neutral 5: System: Agilent 1200 Series, equipped with a single quadrupole mass spectrometer LUNA column (250mm x 21.2mm) Eluent A: water, B: acetonitrile Flow rate 20mL / min

[0411] Preparation of compounds The following examples are intended to illustrate the present invention and are not to be construed as limiting the invention. Temperatures are given in degrees Celsius. Unless otherwise indicated, all evaporation The reaction is carried out under reduced pressure, usually at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The abbreviations used are those conventional in the art.

[0412] All starting materials, building blocks, reagents, acids, salts utilized to synthesize the compounds of the present invention. The groups, dehydrating agents, solvents, and catalysts are commercially available or can be prepared by organic synthesis methods known to those skilled in the art. Furthermore, the compounds of the present invention can be prepared by methods known in the art, as shown in the examples below. They can be produced by organic synthesis methods known to those skilled in the art.

[0413] The structures of final products, intermediates and starting materials may be confirmed by standard analytical spectroscopic properties, e.g., MS The absolute stereochemistry of a particular isomer can be determined by the respective compound. by analysis of the X-ray crystal structure of the complex in which α-glucan is bound to WRN, or by the precursor of the final compound. The small molecule X-ray crystal structure of Amines synthesized by acidic deprotection of Boc precursors are often deprotected using HCl or TFA. The corresponding free base was obtained as a salt by diluting with DCM and N as described for intermediate Y. It can be isolated by partitioning between saturated aqueous aHCO3.

[0414] General conditions: Mass spectra were obtained from a variety of instruments, including electrospray, chemical, or electrospray. The data were acquired on an LC-MS system using electron impact ionization: Waters SQ detector. Waters Acquity UPLC with detector, Shimadzu LCMS Shimadzu NEXERA UPLC PDA with MSD 2020, A B Agilent 120 with Sciex API 2000 TQ as MSD 0 HPLC PDA and AB Sciex API3200QTRAP as MSD. Agilent 1200 HPLC PDA equipped with [M+H] + is the proton of the chemical species It refers to the ionized molecular ion. NMR spectra were obtained using a Bruker Ultrashield™ 400 (400 M Hz), Bruker Ultrashield(TM) 400 Plus(400MH z), Bruker Ultrashield™ 600 (600 MHz) and Br All data were collected using a Berger Ascend™ 400 (400 MHz) spectrometer. The experiments were carried out with and without tetramethylsilane as an internal standard. The chemical shifts (d values) are reported in ppm downfield from tetramethylsilane, and the spectral Crack patterns can be single (s), double (d), triple (t), multiple, unresolved or even Overlapping signals (m) and broad signals (br) are designated. Shown in brackets.

[0415] Celite:Celite R (Celite Corporation) = Diatomaceous Earth Based filter aid Phase separator:Biotage-Isolute phase separator-(Part number: 120-1906- D (for 15 mL), Part Number: 120-1908-F (for 70 mL) and Part number: 120-1909-J (for 150mL) SiliaMetS® Thiol: SiliCYCLE Thiol Metal Scavenger - ( Part number: R51030B, Loading: 1.31mmol / g, Particle size: 40~63μ m) ISOLUTE® Si-Thiol: Biotage thiol metal scavenger - (parts) Product number: 9180-0100, Loading: 1.3mmol / g) PL-BnSH MP Resin: Agilent Thiol Metal Scavenger - (Part Number: PL35 82-6689, 2.2mmol / g100A 150-1kg) ISOLUTE® Si-TMT: Biotage Thiol Metal Scavenger - (Parts Number: 9538) Smopex®-301: Alfa Aesar thiol metal scavenger (Part number: 45902) PL-HCO3MP SPE Cartridge (500mg / 6mL) - (Part Number: PL3 540-C603) PL-HCO3MP SPE Cartridge (100mg / 6mL) - (Part Number: PL3 540-A603)

[0416] Selected compounds were crystallized and further characterized. Experimental procedures are outlined in the Examples below. A description of the equipment and methods is outlined below.

[0417] [Table 7]

[0418] [Table 8]

[0419] Sodium salt formation: The compound was suspended in tert-butanol. NaOH 0.1M (1 equivalent) was added. The mixture was stirred / sonicated overnight at room temperature. Once the suspension had turned into a clear solution, If the suspension was still cloudy, water was added and the resulting solution was freeze-dried. If no change occurred, add 0.1 equivalents up to a total of 2 equivalents until a clear solution was observed. M NaOH was added, which was then freeze-dried. NMR of the resulting solid was still If the solid contained tert-butanol, dissolve it in a small amount of water and freeze-dry it again. The final sodium salt was obtained as a colorless powder. It was confirmed by XRPD that it was in an amorphous state. I acknowledged it.

[0420] Synthesis scheme Generally, compounds of formula (I) can be prepared according to the schemes provided below. The examples outlining specific synthetic routes and the following general schemes will provide synthetic chemists of ordinary skill in the art with the ability to They provide guidance on solvents, concentrations, reagents, protecting groups, order of synthetic steps, time It will be readily understood that the temperature, etc. may be varied as required. The schemes provided below show the single diastereomers / enantiomers as well as their It is intended to represent a mixture of isomers. The resolution of diastereomers / enantiomers is described herein. This can be carried out according to the procedure described in

[0421] The present invention includes the novel process described herein, and further includes any of the processes. The transformation includes the use of an intermediate obtained at any stage thereof as a starting material. The remaining steps are carried out or the starting materials are formed in situ under the reaction conditions or the reaction components are are used in the form of their salts or in the form of optically pure substances. The intermediates can also be converted into each other according to methods commonly known to those skilled in the art. In one aspect, the present invention provides novel intermediate compounds described herein.

[0422] [Table 9]

[0423] [Table 10]

[0424] [Table 11]

[0425] [Table 12]

[0426] [Table 13]

[0427] Synthesis of the final compound Scheme 1: Preparation of final compounds [ka]

[0428] Example 1: 2-(6-(4-(4-chloro-3-hydroxypicolinoyl)piperazine- 1-yl)-5-ethyl-2-morpholino-7-oxo-[1,2,4]triazolo[1 ,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)pyrimidin-4(7H)-yl)- (ethyl)phenyl)acetamide [ka] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2- Morpholino-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[ 1,5-a]pyrimidin-4(7H)-yl)acetamide (Intermediate B) (630 mg, 4-Chloro-3-hydroxypicolinic acid (1.11 mmol) was suspended in DMF (6 mL). acid (384mg, 2.21mmol), DIPEA (967μL, 5.54mmol) , HOBt (299 mg, 2.21 mmol) and EDC·HCl (425 mg, 2.2 1 mmol) was added to the RM and stirred at room temperature for 12 hours. Water was added to the RM and the suspension was filtered. The obtained solid was purified by reverse phase preparative HPLC (RP-HPLC acid 5: 20-30% in 2 min). B, 30-60% B in 8 min) to give the title compound. LC-MS: Rt = 1.09 min; MS m / z [M+H] + 724.6 / 726.6 m / z[MH] - 722.3 / 724.3; UPLC-MS 1 LC-MS: Rt=5.33 min; MS m / z [M+H] + 724.2 / 726.2 m / z[MH] - 722.3 / 724.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.83(s,br,1H),1 0.34(s,1H),8.05(m,2H),7.96(d,J=2.1Hz,1H) ,7.72(dd,J=2.1Hz,8.8Hz,1H),7.55(d,J=5.1H z,1H),5.21(s,2H),4.53(m,1H),3.66(m,4H),3 .54(m,3H),3.38(m,4H),3.23(m,1H),2.96(m,3 H),2.78(m,1H),2.60(m,1H),1.16(t,J=7.3Hz, 3H)

[0429] Example 2: N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(3 -hydroxypicolinoyl)piperazin-1-yl)-2-morpholino-7-oxo-[ 1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2- Morpholino-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[ 1,5-a]pyrimidin-4(7H)-yl)acetamide (Intermediate B) (200 mg, 3-Hydroxypicolinic acid perfluorooctanoic acid (352 μmol) was suspended in DMF (5 mL). phenyl (intermediate CT) (215 mg, 703 μmol) and EtN (97.0 μL , 703 μmol) was added and the RM was stirred for 3 hours at 70° C. The RM was concentrated under reduced pressure. The crude product was first purified by column chromatography (silica gel column: 12 g silica, eluent D CM:MeOH 100:0 to 90:10). Then, reverse phase preparative HPLC (RP-HPLC) Second purification with C acidic 9: 40-50% B for 2 min, 50-55% B for 10 min This gave the title compound. LC-MS: Rt=0.98 min; MS m / z [M+H] + 690.6 / 692.6, m / z[MH] - 688.4 / 690.3; UPLC-MS 1 LC-MS: Rt=4.84 min; MS m / z [M+H] + 690.2 / 692.2m / z[MH] - 688.3 / 690.3; UPLC-MS 2 1H NMR(400MHz,DMSO-d6)δ 10.37(s,br,1H),1 0.34(s,br,1H),8.05(m,2H),7.96(d,J=2.1Hz, 1H),7.72(dd,J=2.1Hz,8.7Hz,1H),7.28(m,2H) ,5.21(s,2H),4.53(m,1H),3.66(m,4H),3.46(m ,3H),3.38(m,4H),3.20(m,1H),2.92(m,3H),2. 76(m,1H),2.58(m,1H),1.16(t,J=7.5Hz,3H)

[0430] Example 3: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl) 6-(4-(4-fluoro-3-hydroxypicolinoyl)piperazin-1-yl) -2-morpholino-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine- 4(7H)-yl)acetamide [ka]

[0431] Step 1: 2-(6-(4-(3-(benzyloxy)-4-fluoropicolinoyl)piperazine) (radin-1-yl)-5-ethyl-2-morpholino-7-oxo-[1,2,4]triazin-1-yl 2-chloro-4-(trifluoromethyl)-N-(2-chloro-4-[1,5-a]pyrimidin-4(7H)-yl)-N-( ... (fluoromethyl)phenyl)acetamide N-(2-chloro-4-(trifluoromethyl)phenyl)-2 in DMF (3 mL) -(5-ethyl-2-morpholino-7-oxo-6-(piperazin-1-yl)-[1, 2,4]Triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide.TF A (Intermediate B) (620 mg, 908 μmol) was added to EtN (503 μL, 3.63 m mol), followed by 3-(benzyloxy)-4-fluoropicolinic acid (intermediate CU) (224 mg, 908 μmol) and then HATU (380 mg, 999 μmol) The RM was stirred at room temperature for 30 minutes. The RM was diluted with water (5 mL) and the resulting suspension was The mixture was stirred at room temperature for 90 minutes. The suspension was filtered. The cake was washed with water (20 mL) and purified. Drying under air gave the title compound as an off-white solid. LC-MS: Rt=1.21 min; MS m / z [M+H] + 798.5 / 800.5m / z[MH] - 796.5 / 798.5;UPLC-MS 1.

[0432] Step 2: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl -6-(4-(4-fluoro-3-hydroxypicolinoyl)piperazin-1-yl)- 2-Morpholino-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4 (7H)-yl)acetamide 2-(6-(4-(3-(benzyloxy)-4-fluoropicolinoyl)piperazine -1-yl)-5-ethyl-2-morpholino-7-oxo-[1,2,4]triazolo[ 1,5-a]pyrimidin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)pyrimidin-4(7H)-yl)- (methyl)phenyl)acetamide (617 mg, 773 μmol) was dissolved in HBr (48% aqueous The solution was dissolved in 1.00 mL of HCl (8.84 mmol) and allowed to stand at room temperature for 3 hours. The RM was allowed to warm to room temperature and then stored in a stoppered flask in the refrigerator for several days. The mixture was heated at 35°C with stirring for 140 minutes. The RM was adjusted to pH 6.0 by adding 1M aqueous NaOH. The mixture was neutralized with 6 and extracted with DCM (2 x 30 mL). The combined organic phase was dried over Na2SO4. The crude product was purified by reverse phase preparative HPLC (RP-HPLC). 1: 30-50% B for 20 min, 50% plateau for 1 min, and RP-HPLC acidic 1 Purification was performed in two batches: 20-47% B for 20 minutes, followed by 1 minute at 20% B plateau. The product-containing fractions were combined and diluted with DCM (30 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was separated by filtration through a phase separator and concentrated under reduced pressure. The residue was recrystallized from MeOH / water to give the title compound as colorless crystals. LC-MS: Rt=0.98 min; MS m / z [M+H] + 708.5 / 710.5m / z[MH] - 706.4 / 708.4; UPLC-MS 1 LC-MS: Rt=4.89 min; MS m / z [M+H] + 708.2 / 710.2m / z[MH] - 706.2 / 708.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.72(s,br,1H),1 0.33(s,1H),8.08(dd,J=5.3Hz,6.9Hz,1H),8.0 4(d,J=8.7Hz,1H),7.96(d,J=2.1Hz,1H),7.72( dd,J=2.2Hz,8.8Hz,1H),7.35(dd,J=5.3Hz,11. 9Hz, 1H), 5.21 (s, 2H), 4.52 (m, 1H), 3.66 (m, 4H) ,3.45(m,3H),3.38(m,4H),3.21(m,1H),2.94(m ,3H),2.77(m,1H),2.59(m,1H),1.16(t,J=7.4H z,3H)

[0433] Example 4: N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2 -(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)- 2-Morpholino-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4 (7H)-yl)acetamide [ka] N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(5- Ethyl-2-morpholino-7-oxo-6-(piperazin-1-yl)-[1,2,4] Triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Intermediate C) 400 mg, 686 μmol) was suspended in DMF (5 mL). acid (191 mg, 1.37 mmol), DIPEA (599 μL, 3.43 mmol), HOBt (185 mg, 1.37 mmol) and EDC·HCl (263 mg, 1.37 (mmol) was added to the RM and stirred at room temperature for 12 hours. Water was added to the RM and filtered. The fractions were separated by reversed-phase preparative HPLC (RP-HPLC Neutral 5: 10-20% B for 2 min, 10-20% B for 10 min). Purification with 20-45% B) gave the title compound. LC-MS: Rt = 1.00 min; MS m / z [M+H] + 704.1 / 706.2m / z[MH] - 702.2 / 704.2; UPLC-MS 1 LC-MS: Rt = 5.01 min; MS m / z [M+H] + 704.2 / 706.1m / z[MH] - 702.3 / 704.3; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.37(s,br,1H),1 0.07(s,1H),8.06(m,1H),7.93(s,1H),7.75(s, 1H),7.28(m,2H),5.16(s,2H),4.53(m,1H),3.6 5(m,4H),3.46(m,3H),3.39(m,4H),3.20(m,1H) ,2.94(m,3H),2.75(m,1H),2.58(m,1H),2.34(s ,3H),1.16(t,J=7.1Hz,3H)

[0434] Example 5: 2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazine- 1-yl)-2-morpholino-7-oxo-[1,2,4]triazolo[1,5-a]pi Rimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-(trifluoro Methyl)phenyl)acetamide [ka] 2-(5-ethyl-2-morpholino-7-oxo-6-(piperazin-1-yl)-[1 ,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluro[1,5-a]pyrimidin-4(7H)-yl) (2-methyl-4-(trifluoromethyl)phenyl)acetamide.HCl (intermediate Form D) (230 mg, 381 μmol) and DIPEA (333 μL, 1.91 mmol) ) was dissolved in DCM (10 mL) and then 3-hydroxypicolinoyl chloride (intermediate Compound CV (90.0 mg, 572 μmol) was added at 0° C. and stirred for 1 hour. roxypicolinoyl chloride (Intermediate CV) (90.0 mg, 572 μmol) was added again to 0 The RM was diluted with DCM and added with water, aqueous NaHCO3 (2x20 mL), washed again with water and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by reverse-phase preparative HPLC (RP-HPLC acidic 7: 30-40% B in 2 min, 9 min Purification by 40-50% B) gave the title compound as a light brown solid. LC-MS: Rt=0.96 min; MS m / z [M+H] + 688.2, m / z [MH ] - 686.3;UPLC-MS1 LC-MS: Rt=4.81 min; MS m / z [M+H] + 688.2, m / z [MH ] - 686.3;UPLC-MS2 1 H NMR(400MHz,DMSO-d6)δ 10.35(s,boad,1H) ,10.06(s,br,1H),8.05(m,1H),7.77(d,J=13.0 Hz,1H),7.66(d,J=8.2Hz,1H),7.28(m,2H),5.1 8(s,2H),4.53(m,1H),3.66(m,4H),3.46(m,3H) ,3.38(m,4H),3.20(m,1H),2.92(m,3H),2.76(m ,1H),2.58(m,1H),2.33(s,3H),1.15(t,J=7.2H z,3H)

[0435] Example 6: 2-(6-(4-(4-chloro-3-hydroxypicolinoyl)piperazine- 1-yl)-5-ethyl-2-morpholino-7-oxo-[1,2,4]triazolo[1 ,5-a]pyrimidin-4(7H)-yl)-N-(5-fluoro-2-methyl-4-( (Trifluoromethyl)phenyl)acetamide [ka] 2-(5-ethyl-2-morpholino-7-oxo-6-(piperazin-1-yl)-[1 ,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(5-fluro[1,5-a]pyrimidin-4(7H)-yl) (2-methyl-4-(trifluoromethyl)phenyl)acetamide (Intermediate D) 220 mg, 388 μmol) was suspended in DMF (5 mL). Dipicolinic acid (101 mg, 582 μmol), DIPEA (339 μL, 1.94 m mol), HOBt (105 mg, 777 μmol) and EDC·HCl (149 mg, 777 μmol) was added to the RM and stirred at room temperature for 12 hours. Water was added to the RM, and the precipitate was The resulting solid was separated by filtration. The solid was purified by reverse phase preparative HPLC (RP-HPLC acid 5: 20-30 min). Purification at 0% B, 30-60% B in 8 min) gave the title compound. LC-MS: Rt=1.07 min; MS m / z [M+H] + 722.3 / 724.3m / z[MH] - 720.3 / 722.3; UPLC-MS 1 LC-MS: Rt=5.32 min; MS m / z [M+H] + 722.2 / 724.2 m / z[MH] - 720.2 / 722.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.82(s,br,1H),1 0.05(s,1H),8.06(d,J=5.1Hz,1H),7.77(d,J=1 2.8Hz,1H),7.67(d,J=8.1Hz,1H),7.55(d,J=4. 8Hz,1H),5.18(s,2H),4.53(m,1H),3.65(m,4H) ,3.53(m,3H),3.38(m,4H),3.24(m,1H),2.93(m ,3H),2.78(m,1H),2.60(m,1H),2.33(s,3H),1. 16(t,J=7.1Hz,3H)

[0436] Example 7: N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)- 2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl) -2-morpholino-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine- 4(7H)-yl)acetamide [ka] N-(2-chloro-5-fluoro-4-(trifluoromethyl)phenyl)-2-(5 -ethyl-2-morpholino-7-oxo-6-(piperazin-1-yl)-[1,2,4 ]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide·HCl(medium Intermediate E) (300 mg, 481 μmol) and DIPEA (420 μL, 2.41 mmol) l) was dissolved in DCM (15 mL) and then 3-hydroxypicolinoyl chloride ( The intermediate (CV) (152 mg, 962 μmol) was added at 0° C. and stirred for 2 hours. Add 152 mg (962 μmol) of methylpyridinyl chloride (Intermediate CV) again. The RM was diluted with DCM and added water, aqueous NaHCO3 (2x20 mL), washed again with water and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel column: 12 g silica, eluent: DCM) The product-containing fractions were concentrated and then purified by reversed-phase preparative HPLC. LC (RP-HPLC acidic 7: 40-50% B in 2 min, 50-60% B in 8 min) Further purification gave the title compound as an off-white solid. LC-MS: Rt = 1.01 min; MS m / z [M+H] + 708.4 / 710.4m / z[MH] - 706.4 / 708.4; UPLC-MS 1 LC-MS: Rt = 5.11 min; MS m / z [M+H] + 708.2 / 710.1 m / z[MH] - 706.2 / 708.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.44(s,1H),10.3 7(s,1H),8.07(m,2H),8.01(d,J=7.3Hz,1H),7. 28(m,2H),5.25(s,2H),4.53(m,1H),3.65(m,4H ),3.46(m,3H),3.37(m,4H),3.22(m,1H),2.93( m,3H),2.76(m,1H),2.58(m,1H),1.15(t,J=7.4 Hz, 3H)

[0437] Example 8: 2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazine- 1-yl)-2-morpholino-7-oxo-[1,2,4]triazolo[1,5-a]pi rimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl Acetamide [ka] 3-Hydroxypicolinic acid (143 mg, 1.03 mmol) in DMF (2.5 mL) To a stirred solution of EDC·HCl (197 mg, 1.03 mmol) and HOBt (13 0.0 mg, 1.03 mmol) was added at room temperature. In a separate flask, DMF (2.5 mL 2-(5-ethyl-2-morpholino-7-oxo-6-(piperazin-1-yl) -[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2 -methyl-4-(trifluoromethyl)phenyl)acetamide·HCl (Intermediate F) ( 300 mg, 513 μmol) was mixed with DIPEA (537 μL, 3.08 mmol) at room temperature. This solution was added to the first RM at room temperature and stirred for 12 hours. This RM was concentrated. Water was added and extracted with EtOAc. The organic layer was washed with aqueous NaHCO3 (twice). The crude product was purified by reverse phase preparative HPLC (RPM). - HPLC Neutral 4: 30-40% B in 2 minutes, 40-50% B in 8 minutes) to give the title compound. LC-MS: Rt=0.92 min; MS m / z [M+H] + 670.4, m / z [MH ] - 668.3;UPLC-MS 1 LC-MS: Rt=4.64 min; MS m / z [M+H] + 670.3, m / z [MH ] - 668.3;UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.40(s,1H,br),9 .98(s,1H),8.05(m,1H),7.70(d,J=8.4Hz,1H), 7.62(s,br,1H),7.53(d,J=8.3Hz,1H),7.28(m, 2H),5.14(s,2H),4.53(m,1H),3.66(m,4H),3.4 6(m,3H),3.39(m,4H),3.20(m,1H),2.95(m,3H) ,2.76(m,1H),2.58(m,1H),2.33(s,3H),1.16(t ,J=7.1Hz,3H)

[0438] Example 9: 2-(6-(4-(4-chloro-3-hydroxypicolinoyl)piperazine- 1-yl)-5-ethyl-2-morpholino-7-oxo-[1,2,4]triazolo[1 ,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl) ... (ethyl)phenyl)acetamide [ka] 4-Chloro-3-hydroxypicolinic acid (120 mg, 692 μmol) was dissolved in DMF (3 mL) and then 2-(5-ethyl-2-morpholino-7-oxo-6-(piperazine) (1,2,4)triazin-1-yl-[1,5-a]pyrimidine-4(7H) -yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide·H Cl (intermediate F) (270 mg, 462 μmol), EDC·HCl (177 mg, 92 3 μmol), DIPEA (403 μL, 2.31 mmol) and HOBt (125 mg , 923 μmol) was added at 0° C. and stirred at room temperature for 14 hours. The extract was extracted with 5% MeOH in Mg and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (RPM). - Purification by HPLC Acid 7: 30-40% B in 2 min, 40-60% B in 8 min to give the title compound. LC-MS: Rt=1.02 min; MS m / z [M+H] + 704.2 / 706.2m / z[MH] -702.2 / 704.2; UPLC-MS 1 LC-MS: Rt = 5.05 min; MS m / z [M+H] + 704.2 / 706.2m / z[MH] - 702.3 / 704.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.85(s,br,1H),9 .99(s,1H),8.03(d,J=5.1Hz,1H),7.70(d,J=8. 4Hz,1H),7.62(s,br,1H),7.53(m,2H),5.14(s, 2H),4.53(m,1H),3.66(m,4H),3.53(m,3H),3.3 9(m,4H),3.24(m,1H),2.95(m,3H),2.77(m,1H) ,2.60(m,1H),2.34(s,3H),1.17(t,J=7.1Hz,3H )

[0439] Example 10: N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2 -(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)- 2-Morpholino-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4 (7H)-yl)acetamide [ka] N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(5-chloro-6-(trifluoromethyl)pyridin-3-yl)- Chil-2-morpholino-7-oxo-6-(piperazin-1-yl)-[1,2,4]trimethyl Triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Intermediate G) (9 3-Hydroxypicoline (00 mg, 1.58 mmol) was suspended in DMF (5 mL). Perfluorophenyl ester (Intermediate CT) (964 mg, 3.16 mmol) and EtN (438 μL, 3.16 mmol) was added, and the RM was stirred at 70° C. for 3 hours. The crude product was purified by column chromatography (silica gel column: 24 g of silica gel, Purification was performed using the eluent DCM:MeOH (100:0 to 99:1) and isopropanol. The product was recrystallized to give the title compound. LC-MS: Rt=0.85 min; MS m / z [M+H] + 691.4 / 693.4m / z[MH] - 689.5 / 691.5; UPLC-MS 1 1 H NMR(400MHz,DMSO-d6)δ 10.52(s,1H),10.3 6(s,1H),8.54(d,J=8.3Hz,1H),8.06(m,1H),7. 96(d,J=8.5Hz,1H),7.28(m,2H),5.25(s,2H),4 .53(m,1H),3.65(m,4H),3.46(m,3H),3.37(m,4 H),3.20(m,1H),2.94(m,3H),2.76(m,1H),2.58 (m,1H),1.15(t,J =7.1Hz,3H)

[0440] Example 11: 2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazine -1-yl)-2-morpholino-7-oxo-[1,2,4]triazolo[1,5-a] pyrimidin-4(7H)-yl)-N-(2-fluoro-4-(trifluoromethyl) fluoride (phenyl)acetamide [ka] 3-Hydroxypicolinic acid (101 mg, 724 μmol) in DMF (3 mL), E DC·HCl (139 mg, 724 μmol) and HOBt (98.0 mg, 724 μm To a stirred solution of 2-(5-ethyl-2-morpholino-7-oxo-6-(piperazine) (1,2,4)triazolo[1,5-a]pyrimidine-4(7H)-yl (2-fluoro-4-(trifluoromethyl)phenyl)acetamide (intermediate Form H) (200 mg, 362 μmol) was added, followed by DIPEA (379 μL, 2.17 m mol) was added at room temperature. The RM was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure. Water was added. The resulting brown solid was filtered and dried under vacuum. The crude product was purified by reverse phase preparative H PLC (RP-HPLC Neutral 1: 25-35% B for 2 min, 35-50% B for 9 min) Further purification gave the title compound. LC-MS: Rt=0.95 min; MS m / z [M+H] + 674.6, m / z [MH ] - 672.4; UPLC-MS 1 LC-MS: Rt = 4.68 min; MS m / z [M+H] + 674.2, m / z [MH ] - 672.3;UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.58(s,br,2H),8 .21(m,1H),8.04(m,1H),7.79(d,J=10.9Hz,1H) ,7.57(d,J=8.7Hz,1H),7.27(m,2H),5.19(s,2H ),4.53(m,1H),3.65(m,4H),3.46(m,3H),3.37( m,4H),3.20(m,1H),2.92(m,3H),2.76(m,1H),2 0.57(m,1H),1.14(t,J=7.2Hz,3H)

[0441] Example 12: N-(4-chloro-2-methyl-5-(trifluoromethyl)phenyl)- 2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl) -2-morpholino-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine- 4(7H)-yl)acetamide [ka] 3-Hydroxypicolinic acid (84.0 mg, 605 μmol) was dissolved in DMF (8 mL). and then N-(4-chloro-2-methyl-5-(trifluoromethyl)phenyl) -2-(5-ethyl-2-morpholino-7-oxo-6-(piperazin-1-yl)-[ 1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide HCl (intermediate I) (250 mg, 404 μmol), EDC·HCI (116 mg, 6 05 μmol), DIPEA (423 μL, 2.42 mmol) and HOBt (82.0 mg, 605 μmol) was added at 0°C and stirred at room temperature for 16 hours. Dilute with water, extract with EtOAc, wash with saturated aqueous NaHCO3 and brine, and combine The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was extracted with ACN and The resulting solid was sonicated in MeOH (1:1) (5 mL) and then filtered. Wash with tOAc and pentane and dry to give the title compound as an off-white solid. Got it. LC-MS: Rt = 1.00 min; MS m / z [M+H] + 704.6 / 706.5m / z[MH] - 702.4 / 704.4; UPLC-MS 1 LC-MS: Rt=4.94 min; MS m / z [M+H] + 704.2 / 706.2m / z[MH] - 702.3 / 704.3; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.41(s,br,1H),1 0.07(s,br,1H),8.04(m,1H),7.94(s,1H),7.66 (s,1H),7.27(m,2H),5.12(s,2H),4.53(m,1H), 3.65(m,4H),3.46(m,3H),3.39(m,4H),3.20(m, 1H),2.94(m,3H),2.75(m,1H),2.58(m,1H),2.3 3(s,3H), 1.16(t,J=7.4Hz,3H)

[0442] Example 13: rac-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)- nyl)-2-(5-ethyl-2-(3-fluoropiperidin-1-yl)-6-(4-( 3-Hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]to Riazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] Rac-N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2 -(5-ethyl-2-(3-fluoropiperidin-1-yl)-7-oxo-6-(piperidine) (1,2,4)triazin-1-yl-[1,5-a]pyrimidine-4(7H) -yl)acetamide·HCl (Intermediate K) (360 mg, 566 μmol), EDC· HCl (163 mg, 850 μmol), 3-hydroxypicolinic acid (118 mg, 85 0 μmol) and HOBt (115 mg, 850 μmol) were dissolved in DMF (5 mL). Then, DIPEA (594 μL, 3.40 mmol) was added at 0° C., and the mixture was stirred at room temperature for 16 hours. The RM was diluted with water, extracted with EtOAc, and washed with saturated aqueous NaHCO3 and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The product was first subjected to column chromatography (2 x silica gel columns: 12 g silica, eluent D Purification with CM:MeOH 100:0 to 95:5 gave an off-white solid The title compound was obtained. LC-MS: Rt=1.08 min; MS m / z [M+H] + 720.1 / 722.0 m / z[MH] - 718.3 / 720.2; UPLC-MS 1 LC-MS: Rt=5.42 min; MS m / z [M+H] + 720.1 / 722.1m / z[MH] - 718.3 / 720.3; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.38(s,1H),10.0 8(s,1H),8.06(m,1H),7.92(s,1H),7.76(s,1H) ,7.29(m,2H),5.15(s,2H),4.75(d,br,J,47.5H z,1H),4.53(m,1H),3.73(m,1H),3.58(m,2H),3 .44(m,3H),3.23(m,1H),2.93(m,3H),2.76(m,1 H),2.58(m,1H),2.35(s,3H),1.81(m,4H),1.52 (m,1H),1.16(t,J=7.2Hz,3H)

[0443] Example 14: rac-2-(5-ethyl-2-(3-fluoropiperidin-1-yl)- 6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1 ,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl 4-(trifluoromethyl)phenyl)acetamide [ka] Rac-2-(5-ethyl-2-(3-fluoropiperidin-1-yl)-7-oxo -6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine -4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetate Dissolve 300 mg of methyltrimethylsilyl HCl (intermediate L) (499 μmol) in 4 mL of DMF. 3-hydroxypicolinic acid (174 mg, 1.25 mmol), EDC·HCl (239 mg, 1.25 mmol), HOBt (169 mg, 1.25 mmol) and D IPEA (436 μL, 2.50 mmol) was added at 0° C., and the RM was stirred at room temperature for 24 h. The RM was diluted with water and extracted with 5% MeOH in DCM, saturated aqueous NaHCO3, The organic layer was dried and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (R Purification by P-HPLC (acidic 6: 40-50% B in 2 min, 50-70% B in 8 min) The title compound was obtained. LC-MS: Rt = 1.01 min; MS m / z [M+H] + 686.2, m / z [MH ] - 684.3; UPLC-MS 1 LC-MS: Rt = 5.05 min; MS m / z [M+H] + 686.2, m / z [MH ]- 684.3; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.32(s,br,1H),9 .99(s,1H),8.06(m,1H),7.69(d,J=8.8Hz,1H), 7.62(s,br,1H),7.53(d,J=8.2Hz,1H),7.28(m, 2H),5.13(s,2H),4.75(d,br,J=48.2Hz,1H),4. 53(m,1H),3.72(m,1H),3.58(m,2H),3.43(m,3H ),3.21(m,2H),2.93(m,3H),2.75(m,1H),2.58( m,1H),2.34(s,3H),1.82(m,3H),1.53(m,1H),1 .16(t,J=7.4Hz,3H)

[0444] Example 14a: (R)-2-(5-ethyl-2-(3-fluoropiperidin-1-yl) )-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo- [1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2- Methyl-4-(trifluoromethyl)phenyl)acetamide and Example 14b: (S) -2-(5-ethyl-2-(3-fluoropiperidin-1-yl)-6-(4-(3-fluoropiperidin-1-yl)- Hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazo 2-[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)pyrimidin-4(7H)-yl)- (Omethyl)phenyl)acetamide [ka] rac-2-(5-ethyl-2-(3-fluoropiperidin-1-yl)-6-(4- (3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4] Triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-( Chiral separation of (trifluoromethyl)phenyl)acetamide: Preparative chiral HPLC (instrument: Agilent 1200 series, single quadrupole mass spectrometer) Equipped with analyzer: LUX CELLULOSE-4, 250 mm x 21.2 mm; Eluent: A =Hexane, B=0.1% HCOOH (in MeOH:EtOH 1:1), flow rate: 15. 0 mL / min; Detection: 210 nm; Injection volume: 0.9 mL; Gradient: Isocratic 70 (A): 3 0(B)).

[0445] Example 14a: The first eluting isomer was stirred in EtO (20 mL) and filtered to give The resulting solid was dried under vacuum to give the title compound. Chiral HPLC (C-HPLC 3): Rt = 6.17 min LC-MS: Rt = 1.01 min; MS m / z [M+H] + 686.2, m / z [MH ] - 684.3; UPLC-MS 1 LC-MS: Rt = 5.05 min; MS m / z [M+H] + 686.2, m / z [MH ] - 684.3; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.36(s,br,1H),1 0.00(s,1H),8.05(m,1H),7.69(d,J=8.5Hz,1H) ,7.62(s,br,1H),7.53(d,J=8.4Hz,1H),7.28(m ,2H),5.13(s,2H),4.85 - 4.65(d,br,J=47.5H z,1H),4.53(m,1H),3.72(m,1H),3.65-3.35(m, 6H),3.20(m,1H),2.94(m,3H),2.75(m,1H),2.5 7(m,1H),2.34(s,3H),1.81(m,3H),1.52(m,1H) 1.16 (t, J = 7.3 Hz, 3 H)

[0446] Example 14b: The second dissolution heterogeneity was reverse phase separation HPLC (RP-HPLC acidic 5:2 separation (20~30%B, 8 minutes (30~60%B) was purified, and the title compound was obtained. KIRAL HPLC (C-HPLC 4): Rt=8.20 minutes LC-MS: Rt = 1.02 min; MS m / z [M+H] + 686.4, m / z [MH ] - 684.4;UPLC-MS1 LC-MS: Rt = 5.12 minutes; MS m / z [M+H] + 686.3, m / z [MH ] - 684.3;UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.43(s,br,1H),1 0.00(s,1H),8.05(m,1H),7.69(d,J=8.5Hz,1H) ,7.62(s,br,1H),7.53(d,J=8.5Hz,1H),7.28(m ,2H),5.13(s,2H),4.85 - 4.65(d,br,J=47.7H z,1H),4.53(m,1H),3.74(m,1H),3.65-3.35(m, 6H),3.21(m,1H),2.94(m,3H),2.75(m,1H),2.5 8(m,1H),2.34(s,3H),1.78(m,3H),1.54(m,1H) 1.16 (t, J = 7.4 Hz, 3 H)

[0447] Example 15: rac-N-(2-chloro-4-(trifluoromethyl)phenyl)-2- (5-ethyl-2-(3-fluoropiperidin-1-yl)-6-(4-(3-hydroxybenzoyl) Cipocolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1 ,5-a]pyrimidin-4(7H)-yl)acetamide [ka] Rac-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl 2-(3-fluoropiperidin-1-yl)-7-oxo-6-(piperazine-1-yl)- (yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetate Intermediate M (160 mg, 274 μmol) was suspended in DMF (2 mL) and 3 -hydroxypicolinic acid (95.0 mg, 684 μmol), DIPEA (239 μL, 1.37 mmol), HOBt (92.0 mg, 684 μmol) and EDC·HCl ( 131 mg, 684 μmol) was added to the RM and stirred at room temperature for 12 hours. Water was added to the RM. The precipitate was filtered off, and the resulting crude product was purified by reverse phase preparative HPLC (RP-HPLC neutral 2:2 min). Purification by 30-40% B in 1 min, 40-75% B in 9 min afforded the title compound. LC-MS: Rt=1.06 min; MS m / z [M+H] + 706.3 / 708.2m / z[MH] - 704.3 / 706.4; UPLC-MS 1 LC-MS: Rt=5.34 min; MS m / z [M+H] + 706.2 / 708.1m / z[MH] - 704.3 / 706.3; UPLC-MS 2 1H NMR(400MHz,DMSO-d6)δ 10.36(2s,2H),8.0 4(m,2H),7.96(s,br,1H),7.72(d,J=8.7Hz,1H) ,7.28(m,2H),5.20(s,2H),4.85 - 4.5(d,br,J =48.6Hz,1H),4.53(m,1H),3.72(m,1H),3.65 - 3.35(m,5H),3.23(m,2H),2.94(m,3H),2.75(m ,1H),2.57(m,1H),1.77(m,3H),1.52(m,1H),1. 15(t,J=7.2Hz,3H)

[0448] Example 15a: ((R)—N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(5-ethyl-2-(3-fluoropiperidin-1-yl)-6-(4-(3-hydroxypiperidin-1-yl)-2-methyl-2-(5-ethyl-2-(3-fluoropiperidin-1-yl)-2-methyl-2-methyl-3-methyl-4-(3-hydroxypiperidin-1-yl) ... (Roxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazol [1,5-a]pyrimidin-4(7H)-yl)acetamide) or ((S)-N-(2 -chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoro- Oropiperidin-1-yl)-6-(4-(3-hydroxypicolinoyl)piperazine- 1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4(7 Example 15b: ((R)-N-(2-chloro-4-(trimethylsilyl)acetamide) and Example 15b: ((R)-N-(2-chloro-4-(trimethylsilyl)acetamide) (trifluoromethyl)phenyl)-2-(5-ethyl-2-(3-fluoropiperidine-1 -yl)-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-ol xo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetoacetate amide), or ((S)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(5-ethyl-2-(3-fluoropiperidin-1-yl)-6-(4-(3-hydroxypiperidin-1-yl)-2-methyl-2-(5-ethyl-2-(3-fluoropiperidin-1-yl)-2-methyl-2-methyl-3-methyl-4-(3-hydroxypiperidin-1-yl) ... (Roxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazol [1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] rac-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl) 2-(3-fluoropiperidin-1-yl)-6-(4-(3-hydroxypicolinyl)amino)- ... (yl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a] Chiral separation of pyrimidin-4(7H)-ylacetamide: Preparative chiral HPLC (instrument: SEPIATEC SFC100; column: OVEN3 C hiralpak IB-N 250×30mm 5μm; Eluent: A:28%[MeO H + 0.1% NH3]B: 72% scCO2; Flow rate: 90.0 mL / min; Detection: 236 nm; injection volume: 0.30 mL; gradient: isocratic A: 28%, B: 72% scCO

[0449] Example 15a: The first eluting stereoisomer was concentrated under reduced pressure at 35° C. to give a white solid. Chiral HPLC (C-HPLC 7): Rt = 3.33 min, 99% ee LC-MS: Rt=1.05 min; MS m / z [M+H] + 706.3 / 708.3m / z[MH] - 704.3 / 706.3; UPLC-MS 3 1 H NMR(600MHz,DMSO-d6)δ 10.35(2s,2H),8.0 5(m,1H),8.03(d,J=8.8Hz,1H),7.96(d,J=2.1H z,1H),7.71(dd,J=2.2Hz,8.7Hz,1H),7.28(m,2 H),5.20(s,2H),4.80-4.65(d,br,J=46.9Hz,1H ),4.53(m,1H),3.72(m,1H),3.65 - 3.35(m,5H ),3.29(m,1H),3.19(m,1H),2.93(m,3H),2.75( m,1H),2.58(m,1H),1.95 - 1.7(m,3H),1.52(m ,1H),1.15(t,J=7.3Hz,3H)

[0450] Example 15b: The second dissolution of heterogeneous body was obtained by concentrating at 35°C under reduced pressure and a solid color of high color. た. Kura HPLC (C-HPLC7): Rt=3.89 points, 94%ee LC-MS: Rt = 1.05 min; MS m / z [M+H] + 706.3 / 708.3,m / z[MH] - 704.3 / 706.2;UPLC-MS 3 1 H NMR(600MHz,DMSO-d6)δ 10.35(2s,2H),8.0 5(m,2H),7.96(d,J=2.1Hz,1H),7.71(dd,J=2.1 Hz,8.8Hz,1H),7.28(m,2H),5.20(s,2H),4.80- 4.70(d,br,J=47.8Hz,1H),4.53(m,1H),3.73(m ,1H),3.65 - 3.35(m,5H),3.28(m,1H),3.20(m ,1H),2.93(m,3H),2.75(m,1H),2.58(m,1H),1. 95 - 1.7(m,3H),1.52(m,1H),1.15(t,J=7.3Hz ,3H)

[0451] Example 16: rac-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl) yl)-2-(5-ethyl-2-(3-fluoropiperidin-1-yl)-6-(4-(3 -Hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]tri Azolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] Rac-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-( 5-Ethyl-2-(3-fluoropiperidin-1-yl)-7-oxo-6-(piperazine) (1,2,4)triazolo[1,5-a]pyrimidine-4(7H)-yl (I)acetamide·HCl (Intermediate N) (100 mg, 161 μmol) and DIPEA (140 μL, 803 μmol) was dissolved in DCM (5 mL) and then 3-hydroxybenzoates were added. Picolinoyl chloride (Intermediate CV) (50.6 mg, 321 μmol) was added at 0° C. The RM was diluted with DCM and added water and saturated aqueous NaHCO3 (2 x 20 mL ), then washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (RP-HPLC acid 7: 30-40°C in 2 min). % B, 40-50% B in 8 min) to give the title compound as a light brown solid. . LC-MS: Rt=0.94 min; MS m / z [M+H] + 707.6 / 709.6m / z[MH] - 705.4 / 707.4; UPLC-MS 1 LC-MS: Rt = 4.59 min; MS m / z [M+H] + 707.2 / 709.2m / z[MH] - 705.3 / 707.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.54(s,1H),10.3 7(s,1H),8.54(d,J=8.3Hz,1H),8.06(m,1H),7. 96(d,J=8.0Hz,1H),7.28(m,2H),5.25(s,2H),4 .85 - 4.65(d,br,J=47.2Hz,1H),4.53(m,1H), 3.73(m,1H),3.60(m,1H),3.46(m,4H),3.23(m, 2H),2.94(m,3H),2.75(m,1H),2.57(m,1H),1.7 9(m,3H),1.52(m,1H),1.15(t,J=7.3Hz,3H)

[0452] Example 16a: (R)—N-(2-chloro-6-(trifluoromethyl)pyridine-3- yl)-2-(5-ethyl-2-(3-fluoropiperidin-1-yl)-6-(4-( 3-Hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]to Riazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide and Example 16b (S)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2- (5-ethyl-2-(3-fluoropiperidin-1-yl)-6-(4-(3-hydroxybenzoyl) Cipocolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1 ,5-a]pyrimidin-4(7H)-yl)acetamide [ka] rac-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2- (5-ethyl-2-(3-fluoropiperidin-1-yl)-6-(4-(3-hydroxybenzoyl) Cipocolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1 Chiral separation of [(5-a)pyrimidin-4(7H)-yl]acetamide: Preparative chiral HPLC (instrument: Agilent 1200 Series, single quadrupole mass spectrometer) Equipped with analyzer; Column: CELLULOSE-4, 250 mm x 21.2 mm; Eluent: A = hexane, B = 0.1% HCOOH in MeOH:EtOH 1:1, flow rate: 18 0.0 mL / min; Detection: 210 nm; Injection volume: 0.9 mL; Gradient: Isocratic 70 (A): 30(B)). The separated and concentrated chiral isomers were taken out, washed with n-hexane, and then added to decane. The mixture was cooled, dried and analyzed.

[0453] Example 16a: First eluting stereoisomer, off-white solid. Chiral HPLC (C-HPLC5): Rt = 6.189 min LC-MS: Rt=0.93 min; MS m / z [M+H] + 707.1 / 709.1m / z[MH] - 705.3 / 705.2; UPLC-MS 1 LC-MS: Rt = 4.60 min; MS m / z [M+H] + 707.1 / 709.0m / z[MH] - 705.3 / 705.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.63,(s,br,2H), 8.53(d,J=7.6Hz,1H),8.05(m,1H),7.89(d,J=7 .6Hz,1H),7.28(m,2H),5.19(s,2H),4.85 -4.6 5(d,br,J=48.0Hz,1H),4.53(m,1H),3.71(m,1H ),3.65 - 3.15(m,7H),2.93(m,3H),2.75(m,1H ),2.58(m,1H),1.81(m,3H),1.52(m,1H),1.15( t,J=7.3Hz,3H)

[0454] Example 16b: Second eluting stereoisomer, off-white solid. Chiral HPLC (C-HPLC6): Rt = 7.575 min LC-MS: Rt=0.93 min; MS m / z [M+H] + 707.1 / 709.0m / z[MH] - 705.3 / 705.2; UPLC-MS 1 LC-MS: Rt = 4.60 min; MS m / z [M+H] + 707.1 / 709.0m / z[MH] - 705.3 / 705.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.43,(s,broad,2 H),8.54(d,J=8.2Hz,1H),8.05(m,1H),7.94(d, J=8.2Hz,1H),7.28(m,2H),5.23(s,2H),4.85 - 4.65(d,br,J=48.3Hz,1H),4.53(m,1H),3.71(m ,1H),3.60(m,1H),3.46(m,4H),3.21(m,2H),2. 93(m,3H),2.75(m,1H),2.58(m,1H),1.81(m,3H ),1.52(m,1H),1.15(t,J=7.3Hz,3H)

[0455] Example 17: 2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazine -1-yl)-7-oxo-2-(pyrrolidin-1-yl)-[1,2,4]triazolo [1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl) (trimethyl)phenyl)acetamide [ka] 3-Hydroxypicolinic acid (183 mg, 1.32 mmol) was dissolved in DMF (10 mL). and then 2-(5-ethyl-7-oxo-6-(piperazin-1-yl)-2-( Pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-4(7 H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide ·HCl (intermediate P) (500mg, 879μmol), EDC·HCl (337mg, 1.76 mmol), DIPEA (767 μL, 4.39 mmol) and HOBt (23 7 mg, 1.76 mmol) was added at 0°C and stirred at room temperature for 16 hours. The mixture was diluted, extracted with 5% MeOH in DCM, washed with saturated aqueous NaHCO3 and brine, and then combined. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (2 x silica gel columns: 12 g silica, eluent DCM:MeOH The resulting solid was purified twice with 5% ACN and MeOH (100:0 to 98:2). (in Et2O) for 30 min, then sonicated for 10 min, filtered off, and Washing with pentane and drying gave the title compound as an off-white solid. LC-MS: Rt=1.04 min; MS m / z [M+H] + 654.6, m / z [MH ] - 652.4; UPLC-MS 1 LC-MS: Rt = 5.08 min; MS m / z [M+H] + 654.3, m / z [MH ] - 652.3;UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.37(s,1H),9.99 (s,1H),8.06(m,1H),7.71(d,J=8.4Hz,1H),7.6 2(m,1H),7.53(d,J=8.4Hz,1H),7.28(m,2H),5. 14(s,2H),4.54(m,1H),3.49(m,3H),3.37(m,4H ),3.20(m,1H),2.93(m,3H),2.75(m,1H),2.58( m,1H),2.35(s,3H),1.90(m,4H),1.16(t,J=7.1 Hz, 3H)

[0456] Example 18: N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2 -(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)- 7-Oxo-2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a] Pyrimidin-4(7H)-yl)acetamide [ka] 3-hydroxypicolinic acid (166 mg, 1.19 mmol) in DMF (3 mL), EDC·HCl (228 mg, 1.19 mmol), HOBt (161 mg, 1.19 m mol), N-(2-chloro-6-(trifluoromethyl)pyridine-3- yl)-2-(5-ethyl-7-oxo-6-(piperazin-1-yl)-2-(pyrrolidine) Zin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H)- (62)-(2-methyl-2-phenyl-2-methyl ... 4 μL, 3.57 mmol) was added, and the RM was stirred at room temperature for 16 hours. The mixture was concentrated at rt and water was added. The resulting brown solid was filtered off and dried under vacuum. The crude product was Reverse-phase preparative HPLC (RP-HPLC acidic 4: 35-40% B in 2 min, 40-40% B in 10 min) 45% B) to give the title compound. LC-MS: Rt=0.94 min; MS m / z [M+H] + 675.3 / 677.3m / z[MH] - 673.3 / 675.3; UPLC-MS 1 LC-MS: Rt = 4.68 min; MS m / z [M+H] + 675.2 / 677.2m / z[MH] - 673.2 / 675.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.54(s,br,1H),1 0.38(s,br,1H),8.55(d,J=8.4Hz,1H),8.06(m, 1H),7.95(d,J=8.4Hz,1H),7.28(m,2H),5.25(s ,2H),4.53(m,1H),3.46(m,3H),3.35(m,4H),3. 19(m,1H),2.91(m,3H),2.75(m,1H),2.57(m,1H ), 1.89(m,4H), 1.15(t,3H)

[0457] Example 19: N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)- 2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl) -7-oxo-2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a ]pyrimidin-4(7H)-yl)acetamide [ka] N-(5-chloro-2-methyl-4-(trifluoromethyl)phenyl)-2-(2 ... 2-(5-ethyl-7-oxo-6-(piperazin-1-yl)-2-(pyrrolidine) Zin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H)- to a stirred solution of (methyl)acetamide·HCl (intermediate R) (150 mg, 249 μmol) , 3-hydroxypicolinoyl chloride (Intermediate CV) (43.0 mg, 273 μmol ) was added at 0°C, followed by dropwise addition of DIPEA (217 μL, 1.24 mmol). M was stirred at room temperature for 45 minutes. 3-Hydroxypicolinoyl chloride (Intermediate CV) (4 3.0 mg, 273 μmol) was added and the RM was stirred at room temperature for 12 hours. Add cipicolinoyl chloride (Intermediate CV) (43.0 mg, 273 μmol) and R The M was stirred at RT for 16 h. The RM was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC ( Purification by RP-HPLC Neutral 3: 25-35% B in 2 min, 35-60% B in 8 min This gave the title compound. LC-MS: Rt = 1.11 min; MS m / z [M+H] + 688.7 / 690.6m / z[MH] - 686.4 / 688.3; UPLC-MS 1 LC-MS: Rt=5.52 min; MS m / z [M+H] + 688.2 / 690.2m / z[MH] - 686.3 / 688.3; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.37(s,br,1H),1 0.08(s,1H),8.06(m,1H),7.95(s,1H),7.75(s, 1H),7.28(m,2H),5.17(s,2H),4.53(m,1H),3.4 6(m,3H),3.36(m,4H),3.20(m,1H),2.93(m,3H) ,2.75(m,1H),2.58(m,1H),2.35(s,3H),1.90(m ,4H),1.15(t,J=7.3Hz,3H)

[0458] Example 20: N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2 -(2-(4-((2,2-difluoroethyl)(methyl)amino)piperidin-1-yl) -5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl) -7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl ) Acetamide [ka] N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)pyridin-3-yl) (2,2-difluoroethyl)(methyl)amino)piperidine -1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4 ]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Intermediate S) (310 mg, 309 μmol)) at 5°C, 3-hydroxypicolinoyl chloride (intermediate Compound CV (61.0 mg, 387 μmol) was added and the RM was stirred for 3 minutes. A (162 μL, 928 μmol) was added and the RM was warmed to room temperature and stirred for 1 h. 3-Hydroxypicolinoyl chloride (Intermediate CV) (61.0 mg, 387 μmol ) and DIPEA (162 μL, 928 μmol), and incubate the RM at room temperature for 1 hour and 40 minutes. The RM was dissolved in DCM (20 mL) and 5% aqueous NaHCO3 (20 mL). The organic layer was separated by filtration through a phase separator. The aqueous layer was washed with DCM (20 mL). The organic layers were combined and evaporated in vacuo to give a brown gum. Phase preparative HPLC (RP-HPLC acidic 1: 25 mL / min, 5-35% for 20 min, 35% The product-containing fractions were combined and purified by 5% aqueous NaHCO3. The mixture was basified with HCl and extracted with DCM (5 x 30 mL). The combined organic layers were separated using a phase separator. Filtration and evaporation in vacuo gave an off-white foam. RediSep column: 4g silica, eluent: DCM:MeOH 100:0 to 94:6 Further purification by HCl gave a colorless solid, which was recrystallized from MeOH / water to give a colorless powder. The title compound was obtained as a final product. LC-MS: Rt=0.73 min; MS m / z [M+H] + 782.4 / 784.3m / z[MH] - 780.5 / 782.5; UPLC-MS 1 1 H NMR(400MHz,DMSO-d6)δ 10.52(s,1H),10.3 7(s,1H),8.54(d,J=8.2Hz,1H),8.07(m,1H),7. 96(d,J=8.6Hz,1H),7.29(m,2H),6.15-5.85(m, br,1H),5.25(s,2H),4.54(m,1H),4.10(m,2H), 3.45(m,3H),3.22(m,1H),2.94(m,3H),2.78(m, 4H),2.59(m,1H),2.27(s,3H),2.01(m,1H),1.7 1(m,2H),1.38(m,3H),1.16(t,J=7.4Hz,3H)

[0459] Example 21: 2-(2-(6-oxa-3-azabicyclo[3.1.1]heptane-3- yl)-5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl )-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H)-i (2-methyl-4-(trifluoromethyl)phenyl)acetamide [ka] 3-Hydroxypicolinic acid (141 mg, 992 μmol) was dissolved in DC at room temperature under argon. 1-Chloro-N,N,2-trimethylprop-1-ene- 1-Amine (149 mg, 1.09 mmol) was added and the RM was stirred at room temperature for 1.25 h. 2- in DCM (2.5 mL) and DIPEA (260 μL, 1.49 mmol) (2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-5-ethyl 1,5-triazol-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl) (phenyl)acetamide (intermediate U) (278 mg, 496 μmol) was added, and a brown The resulting brown solution was stirred at room temperature for 3.5 hours. The RM was dissolved in water (5 ml) This was quenched with DCM (4×40 ml) and saturated aqueous NaHCO3 (5 mL). The combined organic layers were washed twice with water, dried on a phase separator, and extracted four times with HCl under reduced pressure. The residue was adsorbed onto Isolute and purified by column chromatography (RediSep Column: Silica 24g, eluent: DCM:MeOH 100:0 to 90:10) The product-containing fractions were combined and concentrated. The solid was subjected to SFC (SFC 5). The product-containing fractions were combined and concentrated to give the title compound as an off-beige solid. A portion was crystallized from MeOH (1.5 mL) and DCM (2 mL). The resulting solid was Drying under reduced pressure gave the title compound. LC-MS: Rt=0.97 min; MS m / z [M+H] + 682.4, m / z [MH ] - 680.3;UPLC-MS 3 1 H NMR(600MHz,DMSO-d6)δ 10.40(s,1H),10.0 1(s,1H),8.07(m,1H),7.72(d,J=8.1Hz,1H),7. 63(s,br,1H),7.54(d,J=8.3Hz,1H),7.29(m,2H ),5.17(s,2H),4.66(m,2H),4.54(m,1H),3.67( d,J=12Hz,2H),3.58(d,J=11.8Hz,2H),3.49(m, 2H),3.40(m,1H),3.21(m,1H),3.13(m,1H),2.9 6(m,3H),2.77(m,1H),2.59(m,1H),2.35(s,3H) ,1.89(m,1H),1.15(t,J=7.6Hz,3H)

[0460] Example 22: 2-(2-(6-oxa-3-azabicyclo[3.1.1]heptane-3- yl)-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-5-methyl 7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H)-isothiazolinone (2-fluoro-4-(trifluoromethyl)phenyl)acetamide [ka] 1-chloro-N,N,2-trimethylprop-1-en-1-amine (141 mg, 1 0.06 mmol) in DCM (5 mL) with 3-hydroxypicolinic acid (134 mg, 9 61 μmol) was added under argon, and the RM was stirred at room temperature for 2 hours, then DC 2-(2-(6-oxa-3-azabicyclo[3.1.1] methyl)methyl)-3-azabicyclo[3.1.1]methyl]methyl) ... Heptan-3-yl)-5-methyl-7-oxo-6-(piperazin-1-yl)-[1 ,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-fluro[1,5-a]pyrimidin-4(7H)-yl) (441 mg, 481 μmol) was added, followed by DIPEA (420 μL, 2.40 mmol). The RM was stirred at room temperature for 2.2 hours. 0.5 equivalents of the activated 3-hydroxypyridine The choline acid solution was again added to the RM, followed by DIPEA (77.0 μL, 441 μmol). The RM was stirred at room temperature for 2 hours. The RM was quenched with water (6 mL) and saturated Aqueous NaHCO3 (6 mL) was added, and the mixture was extracted with DCM (4 x 40 mL). The organic layer was washed with saturated aqueous NaHCO3 and water, dried on a phase separator, and concentrated under reduced pressure. The crude product was adsorbed onto Isolute and subjected to column chromatography (RediSep column). Purification was performed using a mixture of 24 g silica and 100:0 to 90:10 DCM:MeOH as eluent. The product-containing fractions were combined and concentrated under reduced pressure. The solid was purified by reverse phase preparative HPLC (RP-HP Further purification by LC Acid 1: 15-85% B in 20 min, plateau at 85% for 1 min The product-containing fractions were combined and basified with a small amount of saturated aqueous NaHCO3. The solvent was removed under reduced pressure and the residue was extracted with DCM (3 x 40 mL). The combined organic layers were washed with water (1 0 mL), then dried on a phase separator and concentrated under reduced pressure to give a beige solid The title compound was obtained as a result. LC-MS: Rt=0.93 min; MS m / z [M+H] + 672.4, m / z [MH ] - 670.4;UPLC-MS 3 1 H NMR(600MHz,DMSO-d6)δ 10.69(s,br,1H),1 0.39(s,br,1H),8.22(t,J=8.1Hz,1H),8.06(t, J=3.1Hz,1H),7.80(dd,J=2.1Hz,10.9Hz,1H),7 .56(dd,J=1.7Hz,8.4Hz,1H),7.29(m,2H),5.24 (s,2H),4.65(m,2H),4.52(m,1H),3.66(m,2H), 3.57(m,2H),3.46(m,2H),3.38(m,1H),3.22(m, 1H),3.12(m,1H),2.96(m,1H),2.75(m,1H),2.5 7(m,1H), 2.47(s,3H), 1.89(m,1H)

[0461] Example 23: 2-(2-((3R,4S)-3,4-difluoropyrrolidin-1-yl) -5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7 -oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)- N-(2-methyl-4-(trifluoromethyl)phenyl)acetamide [ka] 3-Hydroxypicolinic acid (152 mg, 1.07 mmol) was added to D Dissolved in CM (6 mL). 1-Chloro-N,N,2-trimethylprop-1-ene-1 -amine (161 mg, 1.18 mmol) was added and the RM was stirred at room temperature for 1.2 hours. 2-(2-(2-methyl-2-propanol)) in DCM (3.5 mL) and DIPEA (281 μL, 1.61 mmol) -((3R,4S)-3,4-difluoropyrrolidin-1-yl)-5-ethyl-7-ol Xo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin Zin-4(7H)-yl)-N-(2-methyl-4-(trifluoromethyl)phenyl) Acetamide (Intermediate W) (430 mg, 537 μmol) was added to the brown suspension. The resulting brown solution was stirred at room temperature for 1 h. The RM was diluted with water (10 mL), saturated NaHCO3 It was quenched with aqueous solution (5 mL) and extracted with DCM (4 x 40 mL). The residue was washed twice with water, dried on a phase separator, and concentrated under reduced pressure. The resulting mixture was subjected to column chromatography (RediSep column: silica 40 g, eluent: DCM: The product was purified by eluting with MeOH (100:0 to 90:10). The product-containing fractions were combined and purified under reduced pressure. The solid was dissolved in MeOH (1.5 mL) and DCM (2 mL) to give the title compound. The resulting grey solid was crystallized from EtO, filtered, and then heated under high vacuum. Drying gave the title compound. LC-MS: Rt = 1.01 min; MS m / z [M+H] + 690.3, m / z [MH ] - 688.3; UPLC-MS 3 1 H NMR(600MHz,DMSO-d6)δ 10.39(s,br,1H),1 0.01(s,1H),8.06(m,1H),7.72(d,J=8.3Hz,1H) ,7.64(s,br,1H),7.54(d,J=8.3Hz,1H),7.29(m ,2H),5.45(m,1H),5.36(m,1H),5.16(s,2H),4. 54(m,1H),3.81(m,2H),3.57(m,2H),3.47(m,2H ),3.39(m,1H),3.21(m,1H),2.95(m,3H),2.76( m,1H),2.58(m,1H),2.36(s,3H),1.16(t,J=7.5 Hz, 3H)

[0462] Example 24a: ((R)-2-(6-(4-(4-chloro-3-hydroxypicolinoyl )piperazin-1-yl)-5-ethyl-2-(4-methoxycyclohex-1-ene- 1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4(7 H)-yl)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)a cetoamide) or ((S)-2-(6-(4-(4-chloro-3-hydroxypicolinoyl) (1-yl)piperazin-1-yl)-5-ethyl-2-(4-methoxycyclohex-1-ene -1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4( 7H)-yl)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl) Acetamide) and Example 24b: ((R)-2-(6-(4-(4-chloro-3-hydroxybenzoyl) 5-ethyl-2-(4-methoxycyclohexyl)piperazin-1-yl)- Hex-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a] pyrimidin-4(7H)-yl)-N-(2-chloro-6-(trifluoromethyl)pyrimidin (S)-2-(6-(4-(4-chloro-3-hydroxybenzoyl)acetamide) or ((S)-2-(6-(4-(4-chloro-3-hydroxybenzoyl)acetamide) (hydroxypicolinoyl)piperazin-1-yl)-5-ethyl-2-(4-methoxycyclohexyl) (1,5-a)-hexa-1-en-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a ]pyrimidin-4(7H)-yl)-N-(2-chloro-6-(trifluoromethyl) ... Lysin-3-yl)acetamide [ka] N-(2-chloro-6-(trifluoromethyl)pyridine-3- yl)-2-(5-ethyl-2-(4-methoxycyclohex-1-en-1-yl)- 7-Oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a] Pyrimidin-4(7H)-yl)acetamide (Intermediate Y) (300 mg, 504 μmol l), 4-chloro-3-hydroxypicolinic acid (140 mg, 807 μmol), HOB t(136mg, 1.01mmol) and EDC·HCl(193mg, 1.01mmol) To a stirred solution of RM (122 μL, 1.51 mmol) was added pyridine (122 μL, 1.51 mmol) at 0° C. Stirred at room temperature for 16 hours. The RM was quenched with NaHCO3 and extracted with DCM. The extract was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography ( Silica gel column: 4 g of silica, eluent: DCM:MeOH 100:0 to 98:2 Purified. The residue was purified by preparative chiral HPLC (instrument: Agilent 1200 Series, single quadruple) Equipped with a polar mass spectrometer; Column: LUX CELLULOSE-4, 250 mm x 21.1 mm, 5.0 μm; eluent: A = hexane, B = 0.1% HCOOH in EtOH; Flow rate: 15 mL / min; Detection: 210 nm; Injection volume: 0.9 mL; Gradient: isocratic 50 (A ):50(B)).

[0463] Example 24a: The product-containing fractions were concentrated at 40°C and washed with n-pentane (5 x 10 mL). Wash, decant, and dry to give the off-white title compound - the first eluting stereoisomer. Got it. Chiral HPLC (C-HPLC 2): Rt = 10.764 min LC-MS: Rt=1.08 min; MS m / z [M+H] + 750.5 / 752.5m / z[MH] - 748.4 / 750.4; UPLC-MS 1 LC-MS: Rt=5.29 min; MS m / z [M+H] + 750.2 / 752.2m / z[MH] - 748.2 / 750.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.68(s,br,2H),8 .56(d,J=8.1Hz,1H),7.98(d,J=5.6Hz,1H),7.9 4(d,J=8.1Hz,1H),7.50(d,J=5.1Hz,1H),6.72( m,1H),5.34(s,2H),4.53(m,1H),3.52(m,4H),3 .28(m,4H),2.98(m,3H),2.80(m,1H),2.63(m,1 H),2.55(m,1H),2.46(m,1H),2.16(m,2H),1.95 (m,1H),1.68(m,1H),1.17(t,J=7.3Hz,3H)

[0464] Example 24b: The product-containing fractions were concentrated at 40°C, washed with n-pentane (5 x 10 mL) and decanted. and dried to give the off-white title compound - the second eluting stereoisomer. Chiral HPLC (C-HPLC 2): Rt = 18,800 min LC-MS: Rt=1.08 min; MS m / z [M+H] + 750.1 / 752.1m / z[MH] - 748.2 / 750.2; UPLC-MS 1 LC-MS: Rt = 5.30 min; MS m / z [M+H] + 750.1 / 752.1m / z[MH] - 748.2 / 750.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.83(s,br,1H),1 0.55(s,br,1H),8.56(d,J=8.2Hz,1H),8.06(d, J=5.3Hz,1H),7.92(d,J=8.2Hz,1H),7.55(d,J= 5.3Hz,1H),6.72(m,1H),5.35(s,2H),4.54(m,1 H),3.54(m,4H),3.28(m,3H),3.25(m,1H),2.99 (m,3H),2.81(m,1H),2.62(m,1H),2.41(m,2H), 2.16(m,2H),1.96(m,1H),1.66(m,1H),1.18(t, J=7.3Hz,3H)

[0465] Example 25a: ((R)—N-(2-chloro-6-(trifluoromethyl)pyridine-3 -yl)-2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazine- 1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[ 1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide or ((S)—N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)- 2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl) -2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4 ]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide) and Examples 25b: ((R)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl )-2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)piperazine-1-yl) yl)-2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-[1,2 ,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide) or ( (S)—N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-( 5-Ethyl-6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-2- (4-Methoxycyclohex-1-en-1-yl)-7-oxo-[1,2,4]trimethylsilyl Azolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(5-ethyl) 2-(4-methoxycyclohex-1-en-1-yl)-7-oxo-6-(piperazinyl) (1,2,4)triazin-1-yl-[1,5-a]pyrimidine-4(7H) (-yl)acetamide.HCl (Intermediate Y) (120 mg, 190 μmol) and DIPE A (166 μL, 950 μmol) was dissolved in DCM (5 mL) and then 3-hydroxybenzoate was added. C. cipicolinoyl chloride (intermediate CV) (59.9 mg, 380 μmol) was added at 0° C. The mixture was stirred for 2 hours. 3-Hydroxypicolinoyl chloride (Intermediate CV) (59.9 mg, 380 μmol) was added again and the reaction was continued with stirring for 12 hours. Diluted with water and NaHCO3 (2 x 20 mL), washed with water and brine, and The extract was dried over SO4, filtered, and concentrated. Silica gel column: 4 g silica gel, eluent: DCM:MeOH 100:0-99 :1), and then further purified by reverse phase preparative HPLC (RP-HPLC acidic 10:2 min). Purify by elution with 40-50% B for 8 minutes, then 50-60% B for 8 minutes to obtain an off-white solid. The title compound was obtained as a result. The racemic compound was separated by preparative chiral HPLC (instrument: Agilent 1200 series, single Equipped with a quadrupole mass spectrometer; Column: CELLULOSE-4, 250 mm x 21.2 mm ; Eluent: A=hexane, B=0.1% HCOOH (MeOH:EtOH 1:1; flow rate : 20 mL / min; Gradient: 210 nm; Injection volume: 0.9 mL; Gradient: Isocratic 60 (A) :40(B)).

[0466] Example 25a: First eluting stereoisomer, off-white solid. Chiral HPLC (C-HPLC 1): Rt = 10.070 min LC-MS: Rt=0.98 min; MS m / z [M+H] + 716.5 / 718.6m / z[MH] - 714.3 / 716.3; UPLC-MS 1 LC-MS: Rt = 4.76 min; MS m / z [M+H] + 716.2 / 718.2m / z[MH] - 714.2 / 716.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.46(s,br,2H),8 .56(d,J=8.5Hz,1H),8.05(m,1H),7.90(d,J=8. 4Hz,1H),7.28(m,2H),6.72(m,1H),5.30(s,2H) ,4.54(m,1H),3.47(m,4H),3.27(s,3H),3.21(m ,1H),2.96(m,3H),2.79(m,1H),2.59(m,3H),2. 43(m,1H),2.14(m,1H),1.95(m,1H),1.67(m,1H ), 1.17(t, J = 7.2 Hz, 3 H)

[0467] Example 25b: The second dissolution stereoisotropic body, fluorochrome solid. KIRAL HPLC (C-HPLC 1): Rt=16.023min LC-MS: Rt = 0.96 minutes; MS m / z [M+H] + 716.3 / 718.3,m / z[MH] - 714.3 / 716.3;UPLC-MS 1 LC-MS: Rt = 4.77 min; MS m / z [M+H] + 716.2 / 718.2,m / z[MH] - 714.2 / 716.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.39(s,br,2H),8 .56(d,J=8.0Hz,1H),8.06(m,1H),7.93(d,J=8. 1Hz,1H),7.28(m,2H),6.72(m,1H),5.32(s,2H) ,4.54(m,1H),3.46(m,4H),3.27(s,3H),3.20(m ,1H),2.96(m,3H),2.79(m,1H),2.59(m,3H),2. 41(m,1H),2.14(m,1H),1.95(m,1H),1.68(m,1H ), 1.17(t,J=7.1Hz,3H)

[0468] Example 26: rac-2-(5-ethyl-6-(4-(3-hydroxypicolinoyl)pyrimidinyl)methyl)-4-(4-hydroxypicolinoyl)pyrimidinyl) Perazin-1-yl)-2-(4-methoxycyclohex-1-en-1-yl)-7- Oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N -(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetamide [ka] 4-Chloro-3-hydroxypicolinic acid (118 mg, 851 μmol) was dissolved in DMF (5 m L), and then rac-2-(5-ethyl-2-(4-methoxycyclohexa- 1-en-1-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]to Triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-6-(tri ... (trifluoromethyl)pyridin-3-yl)acetamide·HCl (Intermediate Z) (260 mg , 425 μmol), EDC·HCl (163 mg, 851 μmol), DIPEA (3 (72 μL, 2.13 mmol) and HOBt (115 mg, 851 μmol) were added at 0°C. The RM was stirred at room temperature for 14 hours. The RM was diluted with water and extracted with 5% MeOH in DCM. The extract was washed with saturated aqueous NaHCO3 and brine, and the combined organic layer was dried over Na2SO4. The crude product was purified by reverse phase preparative HPLC (RP-HPLC acid 5 The title compound was obtained by purifying the mixture by 2 min at 30-40% B and 8 min at 40-50% B. Ta. LC-MS: Rt = 0.90 min; MS m / z [M+H] + 696.3, m / z [MH ] - 694.3; UPLC-MS 1 LC-MS: Rt=4.38 min; MS m / z [M+H] + 696.3, m / z [MH ] - 694.4; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.26(m,2H),8.19 (d,J=8.3Hz,1H),8.06(m,1H),7.72(d,J=8.2Hz ,1H),7.28(m,2H),6.72(m,1H),5.27(s,2H),4. 54(m,1H),3.47(m,4H),3.28(m,4H),2.98(m,3H ),2.80(m,1H),2.57(m,6H),2.15(m,1H),1.96( m,1H),1.68(m,1H),1.19(t,J=7.5Hz,3H)

[0469] Example 27: N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2 -(2-(5,6-dihydro-1,4-dioxin-2-yl)-5-ethyl-6-(4 -(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4 ]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(2-(5 ,6-Dihydro-1,4-dioxin-2-yl)-5-ethyl-7-oxo-6-(pyridyl) Perazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H )-yl)acetamide (Intermediate AA) (492 mg, 692 μmol) was added under argon to , dissolved in DCM (7 mL) at 0° C. 3-Hydroxypicolinoyl chloride intermediate CV ) (163 mg, 1.04 mmol) was added to the suspension, followed by DIPEA (483 μL , 2.77 mmol) was slowly added and the solution was stirred at room temperature for 1.5 hours. Hydroxypicolinoyl chloride (Intermediate CV) (25.0 mg, 159 μmol) and D IPEA (320 μL, 1.84 mmol) was added again and the RM was stirred at room temperature for 2.3 h. The reaction was continued by adding water (5 mL) and saturated aqueous NaHCO3 (5 mL). The reaction was quenched by adding 10 mL of DCM. The organic layer was then extracted four times with DCM (4×40 mL). Wash with water (5 mL), saturated aqueous NaHCO3 (5 mL), and again with water (10 mL). The organic layer was dried on a phase separator and concentrated under reduced pressure. The residue was adsorbed onto Isolute. The mixture was subjected to column chromatography (RediSep column: silica 40g Gold, eluent The product was purified by DCM:MeOH (100:0 to 90:10). The resulting solid was purified by reverse phase preparative HPLC (RP-HPLC acidic 1:20 min). The product was purified by a series of elutions (15-85% B, 1 min at 85% B plateau). The mixture was combined and basified with saturated aqueous NaHCO3 (5 mL). The ACN was removed under reduced pressure. The aqueous layer was washed four times with DCM (4 x 35 mL). The combined organic layers were washed with water (10 mL). Wash, dry on a phase separator and concentrate under reduced pressure to give the title compound as a white solid. LC-MS: Rt=0.87 min; MS m / z [M+H] + 690.3 / 692.3m / z[MH] -688.1 / 690.1; UPLC-MS 1

[0470] Example 28: N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2 -(2-(3,4-dihydro-2H-pyran-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)acetate Toamide [ka]

[0471] Step 1: N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-( 2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl-6-(4-(5-methyl) (6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo -[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamido Do 5-Methoxy-6-methylpyrimidine-4-carboxylic acid (intermediate) in DCM (9 mL) CW) (133 mg, 794 μmol) at 0 °C. mg, 1.06 mmol), pyridine (128 μL, 1.59 mmol) and HOBt ( 143 mg, 1.06 mmol) was added and the RM was stirred at 0° C. for 10 min, then N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(2-(3 ,4-Dihydro-2H-pyran-6-yl)-5-ethyl-7-oxo-6-(piperazine) (1,2,4)triazolo[1,5-a]pyrimidine-4(7H)-yl Acetamide (Intermediate AC) (300 mg, 529 μmol) was added to this RM. The mixture was stirred at room temperature for 16 hours. The RM was diluted with DCM and washed with saturated aqueous NaHCO3. Washed with water and the combined organic layers were dried over Na2SO4, concentrated and dried. The mixture was subjected to column chromatography (silica gel column: 12 g silica, eluent: DCM:MeO Purification by HPLC (100:0 to 99:1) gave the title compound. LC-MS: Rt=1.51 min; MS m / z [M+H] + 717.2 / 719.2;U PLC-MS 11

[0472] Step 2: N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-( 2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl-6-(4-(5-hydroxybenzoyl) Hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo so-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetate Mido N-(2-chloro-6-(trifluoromethyl)pyridine-3- yl)-2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl-6- (4-(5-methoxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl )-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H)-i A stirred solution of LiCl (132 mg, 3 LiCl (132 mg 0.10 mmol) was added and the RM was heated at 150 °C for 3 h. , 3.10 mmol) was added again and the RM was stirred at 150° C. for 4 hours. The RM was quenched with water. The mixture was cooled, extracted with 10% MeOH in DCM (3 x 50 mL), dried over Na2SO4, and The crude product was purified by column chromatography (silica gel column) and concentrated to dryness. Purification was carried out using 12 g of silica and an eluent of DCM:MeOH (100:0 to 98:2). The residue was purified by reverse-phase preparative HPLC (RP-HPLC acidic 4: 15–25% B for 2 min, 2 for 7 min). The product-containing fractions were concentrated at a temperature below 40°C and dried. , affording the title compound as an off-white solid. LC-MS: Rt=0.97 min; MS m / z [M+H] + 703.2 / 705.2m / z[MH] - 701.3 / 703.2; UPLC-MS 1 LC-MS: Rt=4.73 min; MS m / z [M+H] + 703.2 / 705.1m / z[MH] - 701.3 / 703.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.52(s,br,1H),1 0.25(s,br,1H),8.57(m,2H),7.95(d,J=8.3Hz, 1H),5.86(m,1H),5.35(s,2H),4.52(m,1H),4.1 0(m,2H),3.49(m,3H),3.25(m,1H),2.99(m,3H) ,2.81(m,1H),2.64(m,1H),2.44(s,3H),2.17(m ,2H),1.84(m,2H),1.18(t,J=7.6Hz,3H)

[0473] Example 29: N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2 -(2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl-6-(4-(3 -Hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]tri Azolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(2-( 3,4-Dihydro-2H-pyran-6-yl)-5-ethyl-7-oxo-6-(pipera) Zin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H)- (I)-ylacetamide (Intermediate AC) (700 mg, 1.24 mmol) was dissolved in DMF (12 m L) and suspended in 75 mL of perfluorophenyl 3-hydroxypicolinate (intermediate CT) 4 mg, 2.47 mmol) and Et3N (342 μL, 2.47 mmol) were added at room temperature. The RM was stirred at 80°C for 16 hours. The RM was extracted with DCM three times. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography (silica gel column: 12 g silica, eluent hexane: EtOAc 1 The product-containing fractions were concentrated and dried under high vacuum. to give the title compound. LC-MS: Rt=0.94 min; MS m / z [M+H] + 688.5 / 690.5m / z[MH] - 686.2 / 688.2; UPLC-MS 1 LC-MS: Rt=4.58 min; MS m / z [M+H] + 688.2 / 690.2m / z[MH] - 686.2 / 688.2; UPLC-MS 2 1H NMR(400MHz,DMSO-d6)δ 10.54(s,1H),10.3 8(s,1H),8.57(d,J=8.5Hz,1H),8.06(m,1H),7. 95(d,J=8.5Hz,1H),7.28(m,2H),5.85(m,1H),5 .35(s,2H),4.54(m,1H),4.10(m,2H),3.42(m,3 H),3.21(m,1H),2.96(m,3H),2.79(m,1H),2.61 (m,1H),2.16(m,2H),1.84(m,2H),1.17(t,J=7. 3Hz, 3H)

[0474] Example 30: 2-(6-(4-(4-chloro-3-hydroxypicolinoyl)piperazine -1-yl)-2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl-7- Oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N -(2-chloro-6-(trifluoromethyl)pyridin-3-yl)acetamide [ka] 4-Chloro-3-hydroxypicolinic acid (282 mg, 1.62 m) in DMF (5 mL) A stirred solution of 1000 mg of DIPEA (354 μL, 2.03 mmol) and PyAOP (6 35 mg, 1.22 mmol) was added at 0°C. After 10 minutes, N-(2-chloro-6-(trichloroethane) (trifluoromethyl)pyridin-3-yl)-2-(2-(3,4-dihydro-2H-pyridin-3-yl)- 6-(piperazin-1-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2, 4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Intermediate A C) (460 mg, 811 μmol) was added to the RM at 0° C. The RM was then incubated at room temperature for 16 hours. Water was added and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4. The crude product was purified by reverse phase preparative HPLC (RP-HPLC acidic 5:2 in 2 min). Purification by elution with 0-30% B for 8 min, 30-60% B for 8 min) gave the title compound. LC-MS: Rt=1.04 min; MS m / z [M+H] + 722.5 / 724.5 / 7 26.5, m / z [MH] - 720.3 / 722.2 / 724.2; UPLC-MS 1 LC-MS: Rt = 5.07 min; MS m / z [M+H] + 722.2 / 724.1 / 7 26.2, m / z [MH] - 720.2 / 722.2 / 724.2; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.83(s,1H),10.5 5(s,1H),8.58(d,J=8.4Hz,1H),8.07(d,J=5.0H z,1H),7.96(d,J=8.4Hz,1H),7.56(d,J=5.0Hz, 1H),5.86(m,1H),5.36(s,2H),4.54(m,1H),4.1 0(m,2H),3.54(m,3H),3.24(m,1H),2.98(m,3H) ,2.81(m,1H),2.65(m,1H),2.16(m,2H),1.84(m ,2H),1.18(t,J=7.1Hz,3H)

[0475] Example 31: 2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl- 6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1 -yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H )-yl)-N-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetate Toamide [ka]

[0476] Step 1: 2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl-6- (4-(5-methoxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl )-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H)-i -N-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetamid Do 2-(2-(3,4-dihydro-2H-pyran-6-yl)- 5-Ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[ 1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-6-(trifluoromethyl) ... Methyl)pyridin-3-yl)acetamide (Intermediate AD) (600 mg, 1.10 mm ol), 5-methoxy-6-methylpyrimidine-4-carboxylic acid (Intermediate CW) (222 mg, 1.32 mmol) and HATU (626 mg, 1.65 mmol) DIPEA (288 μL, 1.65 mmol) was added at 0° C. The RM was stirred at room temperature for 1 Stirred for 6 h. The RM was concentrated under reduced pressure to give the title compound. LC-MS: Rt=1.48 min; MS m / z [M+H] + 697.3; UPLC-MS 11

[0477] Step 2: 2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-ethyl-6- (4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine-1-yl) 7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H)- yl)-N-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetate Mido 2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-methyl ... -ethyl-6-(4-(5-methoxy-6-methylpyrimidine-4-carbonyl)pipera Zin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine- 4(7H)-yl)-N-(2-methyl-6-(trifluoromethyl)pyridin-3-yl A stirred solution of LiCl (108 mg, 2.55 mmol) was added and the RM was stirred in a microwave oven at 200°C for 1 hour. Quench and extract with 10% MeOH in DCM (3 x 50 mL) and dry over Na2SO4 The crude product was purified by column chromatography (silica gel) Column: 12g silica, eluent: DCM:MeOH 100:0 to 98:2) The residue after column chromatography was purified by reversed-phase preparative HPLC (RP-HPLC acid 1). Purification was performed using 15-25% B for 2 minutes, followed by 15-60% B for 10 minutes. The fractions were concentrated to give 45 mg of solid, which was combined with another batch and diluted with 30% n-hexane Et2O and dried to give the title compound as an off-white solid. LC-MS: Rt = 0.90 min; MS m / z [M+H] + 683.6, m / z [MH ] - 681.4; UPLC-MS 1 LC-MS: Rt=4.34 min; MS m / z [M+H] + 683.3, m / z [MH ]- 681.3;UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.22(s,br,2H),8 .57(s,1H),8.20(d,J=8.0Hz,1H),7.73(d,J=8. 2Hz,1H),5.86(m,1H),5.27(s,2H),4.52(m,1H) ,4.10(m,2H),3.50(m,3H),3.27(m,1H),2.99(m ,3H),2.81(m,1H),2.65(m,1H),2.58(s,3H),2. 44(s,3H),2.18(m,2H),1.85(m,2H),1.19(t,J= 7.2Hz, 3H)

[0478] Example 32: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-( 3,4-Dihydro-2H-pyran-6-yl)-5-ethyl-6-(4-(3-hydroxy) Cipocolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1 ,5-a]pyrimidin-4(7H)-yl)acetamide [ka] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,4-di ... Hydro-2H-pyran-6-yl)-5-ethyl-7-oxo-6-(piperazine-1- (yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetate Dissolve 590 mg (80% purity), 833 μmol of thiaminamide (Intermediate AE) in DCM (10 3-hydroxypicolinoyl chloride (Intermediate CV) (197 mg, 1 mL) 0.25 mmol) was added, followed by DIPEA (437 μL, 2.50 mmol). The RM was stirred at room temperature for 1.5 hours. 3-Hydroxypicolinoyl chloride intermediate CV ) (36.0 mg, 228 μmol) was added. The RM was stirred at room temperature for 1 hour. EA (1.00 mL, 5.73 mmol) was added. The RM was stirred at room temperature for 2 hours. -Hydroxypicolinoyl chloride (Intermediate CV) (116 mg, 736 μmol) was added. The RM was stirred at room temperature for 1 hour. Water (10 mL), saturated aqueous NaHCO3 (10 mL) and DCM (10 mL) were added. The aqueous layer was washed twice with DCM (2 × 10 mL). The combined organic layers were dried on a phase separator and concentrated under reduced pressure. The crude product was obtained in five portions. The product was purified by reverse-phase preparative HPLC (5x RP-HPLC acidic 1:5 to 100% B). All product-containing fractions with purity greater than 5% were combined and basified with saturated aqueous NaHCO3, followed by DC The concentrate was extracted twice with M (2 x 15 mL), dried on a phase separator, and concentrated under reduced pressure. The resulting mixture was suspended in MeOH and sonicated for 1 min. It was then filtered and the cake was separated into MeO Washing with H (500 μL) and drying under HV gave the title compound. Rt=1.05 min At this point, all product-containing fractions, including impurities, were combined and made basic with saturated aqueous NaHCO3. The mixture was concentrated under reduced pressure, extracted twice with DCM (2×15 mL), dried on a phase separator and concentrated under reduced pressure. At Rt=1.13 min, all product-containing fractions, including impurities, were combined and purified with saturated NaHCO The mixture was basified with aqueous 3, extracted twice with DCM (2 x 15 mL), dried on a phase separator, and The mixture was concentrated under reduced pressure. Both impure fractions were combined and suspended in MeOH (10 mL). The mixture was sonicated for 30 minutes at rt and filtered. The cake was washed with a small amount of MeOH (10 mL). Drying under HV gave the product with 90% purity. The cake was diluted with MeOH (10 mL) and A The mixture was suspended in CN (10 mL) and stirred at 40° C. for 2 hours. The mixture was filtered and the cake was diluted with MeOH (1 mL) and dried under HV to give the title compound. Both pure fractions were dissolved in DCM (10 mL) and EtOH (10 mL) and left at room temperature for 5 days. The solid was filtered off and washed with a small amount of Et2O. The cake was dried under HV to give the title compound. The compound was obtained. LC-MS: Rt=1.08 min; MS m / z [M+H] + 687.2 / 689.2m / z[MH] - 685.4 / 687.5; UPLC-MS 1 1 H NMR(400MHz,DMSO-d6)δ 10.38(s,1H),10.3 3(s,1H),8.07(m,2H),7.96(s,1H),7.71(d,J=8 .6Hz,1H),7.29(m,2H),5.87(m,1H),5.31(s,2H ),4.55(m,1H),4.10(m,2H),3.43(m,3H),3.23( m,1H),2.97(m,3H),2.80(m,1H),2.62(m,1H),2 .17(m,2H),1.84(m,2H),1.18(t,J=7.6Hz,3H)

[0479] Example 33: N-(4-chloro-6-(trifluoromethyl)pyridin-3-yl)-2 -(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(3 -Hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]tri Azolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] N-(4-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(2-( 3,6-Dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(pipera) Zin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H)- Dissolve 340 mg (600 μmol) of acetamide (Intermediate AG) in DMF (10 mL ) and suspended in 366m g, 1.20 mmol) and EtN (166 μL, 1.20 mmol) were added, and this The RM was stirred at 70° C. for 3 h. The crude product was purified by reverse phase preparative HPLC (RP-HPLC acid 3: Purification by 2 min at 10-20% B, 10 min at 20-60% B) gave the title compound. Ta. LC-MS: Rt=0.84 min; MS m / z [M+H] + 688.3 / 690.3m / z[MH] - 686.3 / 688.3; UPLC-MS 1 LC-MS: Rt = 4.15 min; MS m / z [M+H] + 688.2 / 690.2m / z[MH] - 686.2 / 688.2; UPLC-MS 2 1 H NMR(600MHz,DMSO-d6)δ 10.65(s,1H),10.3 6(s,1H),9.06(s,1H),8.22(s,1H),8.02(m,1H) ,7.25(m,2H),6.72(m,1H),5.29(s,2H),4.50(m ,1H),4.21(m,2H),3.76(m,2H),3.42(m,2H),3. 35(m,1H),3.18(m,1H),2.93(m,3H),2.76(m,1H ),2.58(m,1H),2.52(m,2H),1.15(t,J=7.6Hz,3 H)

[0480] Example 34: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl- 6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1 ,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-methyl 6-(trifluoromethyl)pyridin-3-yl)acetamide [ka] 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo -6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine -4(7H)-yl)-N-(4-methyl-6-(trifluoromethyl)pyridine-3- (I)-ylacetamide (Intermediate AH) (450 mg, 823 μmol) in DMF (5 mL) Perfluorophenyl 3-hydroxypicolinate (Intermediate CT) (503 ml) was suspended in g, 1.65 mmol) and EtN (228 μL, 1.65 mmol) were added, and this The RM was stirred at 70° C. for 3 h. The RM was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC. (RP-HPLC acidic 11: 30-40% B in 2 minutes, 40-70% B in 10 minutes) and purified to give the title compound. LC-MS: Rt=0.77 min; MS m / z [M+H] + 668.3, m / z [MH ] - 666.3;UPLC-MS 1 LC-MS: Rt=3.79 min; MS m / z [M+H] + 668.3, m / z [MH ] - 666.3;UPLC-MS 2 1H NMR(400MHz,DMSO-d6)δ 10.36(m,br,2H),8 .78(s,1H),8.05(m,1H),7.85(s,1H),7.28(m,2 H),6.83(m,1H),5.25(s,2H),4.55(m,1H),4.26 (m,2H),3.81(m,2H),3.45(m,3H),3.22(m,1H), 3.00(m,3H),2.80(m,1H),2.62(m,1H),2.50(m, 2H),2.38(s,3H),1.20(t,J=7.3Hz,3H)

[0481] Example 35: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl- 6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1 ,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl 6-(trifluoromethyl)pyridin-3-yl)acetamide [ka] 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-2H-pyran-4-yl)-5-methyl-2H-pyran-4-yl -Ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1 ,5-a]pyrimidin-4(7H)-yl)-N-(2-methyl-6-(trifluoromethyl) ... (ethyl)pyridin-3-yl)acetamide·TFA (Intermediate AI) (400 mg, 606 To a solution of 1 μmol of 3-hydroxybenzoic acid was added EtN (252 μL, 1.82 mmol), followed by 3-hydroxybenzoic acid. Perfluorophenyl hydroxypicolinate (Intermediate CT) (185 mg, 606 μmol ) was added dropwise at 0° C. Then, the RM was warmed to room temperature and stirred at 80° C. for 14 hours. The crude product was concentrated under reduced pressure, extracted with water, and purified by column chromatography (silica gel column: Purification was performed using 12 g of silica and eluent hexane: EtOAc (100:0 to 20:80). The product was recrystallized from ACN to give the title compound. LC-MS: Rt=0.81 min; MS m / z [M+H] + 668.6, m / z [MH ] - 666.4;UPLC-MS 1 LC-MS: Rt=3.91 min; MS m / z [M+H] + 668.3, m / z [MH ] - 666.3;UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.38(s,1H),10.2 3(s,1H),8.19(d,J=8.4Hz,1H),8.06(m,1H),7. 73(d,J=8.4Hz,1H),7.28(m,2H),6.82(m,1H),5 .28(s,2H),4.55(m,1H),4.26(m,2H),3.80(m,2 H),3.44(m,3H),3.22(m,1H),2.97(m,3H),2.80 (m,1H),2.62(m,1H),2.57(s,3H),2.52(m,2H), 1.19(t,J=7.2Hz,3H)

[0482] Example 36: 2-(6-(4-(4-chloro-3-hydroxypicolinoyl)piperazine -1-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-6-(trifluoromethyl)pyridin-3-yl)acetamide [ka] 4-Chloro-3-hydroxypicolinic acid (423 mg, 2.4 mL) in DCM (10 mL) 4 mmol) with DIPEA (500 μL, 2.86 mmol) and PyAOP (829 m g, 1.59 mmol) was added. After the color changed to dark brown, the RM was stirred for 10 min. Then, 2- in DCM (10 mL) and DIPEA (500 μL, 2.86 mmol) (2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6- (Piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-4( 7H)-yl)-N-(2-methyl-6-(trifluoromethyl)pyridin-3-yl) Acetamide·TFA (Intermediate AI) (700 mg, 1.06 mmol) was added dropwise. M was stirred at room temperature for 18 hours. RM was poured into saturated aqueous NaHCO3 and washed several times with EtOAc. The combined organic layers were dried on a phase separator and concentrated. The crude product was purified by column chromatography. Graphy (silica gel column: silica 12 g, eluent hexane: EtOAc 100:0 The product-containing fractions were combined and concentrated under reduced pressure. The solid was washed with Et2O. The solid was subjected to column chromatography (silica gel column: silica 12 g The product was purified again with hexane: EtOAc (eluent 100:0 to 5:95) to give the title compound. A compound was obtained. LC-MS: Rt = 0.91 min; MS m / z [M+H] + 702.3 / 704.3m / z[MH] - 700.3 / 702.3; UPLC-MS 1 LC-MS: Rt=4.49 min; MS m / z [M+H] + 702.2 / 704.2m / z[MH] -700.3 / 702.3; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.83(s,br,1H),1 0.22(s,br,1H),8.19(d,J=8.8Hz,1H),8.06(d, J=5.0Hz,1H),7.73(d,J=8.4Hz,1H),7.55(d,J= 5.0Hz,1H),6.82(m,1H),5.28(s,2H),4.54(m,1 H),4.26(m,2H),3.80(m,2H),3.50(m,3H),3.15 (m,1H),3.00(m,3H),2.81(m,1H),2.65(m,1H), 2.57(s,3H),2.48(m,2H),1.19(t,J=7.0Hz,3H)

[0483] Example 37: 2-(6-(4-(4-chloro-3-hydroxypicolinoyl)piperazine -1-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 -(3-Fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide [ka] 4-Chloro-3-hydroxypicolinic acid (233 mg, 1.34 mmol) was dissolved in DCM ( 7 mL) and 1-chloro-N,N,2-trimethylprop-1-en-1-amine (190 μL, 1.44 mmol) was added. After 5 minutes, most of the solid had dissolved. The suspension was stirred at room temperature for 2.5 hours. The RM was cooled to 0°C and 2-(2-(3,6-dihydro- -2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl) -[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3 -fluoro-2-methyl-4-(trifluoromethyl)phenyl)acetamide (intermediate AJ) (431 mg, 765 μmol) was added, followed by DIPEA (601 μL, 3. The yellow solution turned to a black solution. The RM was stirred at room temperature for 20 minutes. Water (10 mL), saturated aqueous NaHCO3 (10 mL) and DCM (10 mL) were added. The aqueous layer was washed twice with DCM (2 x 10 mL). The combined organic layers were separated using a phase separator. The crude product was purified by column chromatography ( RediSep column: 40g silica, eluent: DCM: DCM / MeOH (8 / 2) The product-containing fractions were combined, concentrated in vacuo, and purified with H Drying under V gave a brown solid, which was then purified in three portions by reverse phase preparative HPLC ( RP-HPLC acidic 1: 20–75% B in 20 min, 75% plateau for 1 min; RP- HPLC acidic 1: 25-80% B in 20 min, 80% plateau for 1 min; and RP-H Purification by PLC acidic 1: 40-80% B for 20 min, 80% B plateau for 1 min The product-containing fractions were combined, basified with saturated aqueous NaHCO3, and diluted with DCM (2 x 15 ml). The mixture was extracted twice with 10 mL of hexane, dried on a phase separator and concentrated under reduced pressure. The combined extracts were basified with saturated aqueous NaHCO3, extracted twice with DCM, and dried on a phase separator. This was then suspended in ACN (2 mL) and sonicated for 2 minutes. The solid was extracted with 100 ml of EtOH, filtered, and the pure fractions were combined and concentrated under reduced pressure to give the title compound. (10 mL) and DCM (15 mL), filtered, and left to stand at room temperature for 3 days to crystallize. It was then filtered and washed with EtO. The cake was dried under HV to give the title compound. The compound was obtained. The sodium salt was prepared similarly to the general procedure. LC-MS: Rt = 1.11 min; MS m / z [M+H] + 719.4 / 721.4m / z[MH] - 717.5 / 719.5; UPLC-MS 1 1 H NMR(400MHz,DMSO-d6)δ 10.83(s,1H),10.2 0(s,1H),8.06(d,J=5.1Hz,1H),7.57(m,3H),6. 82(m,1H),5.26(s,2H),4.54(m,1H),4.26(m,2H ),3.81(m,2H),3.55(m,3H),3.25(m,1H),3.00( m,3H),2.81(m,1H),2.65(m,1H),2.50(m,2H),2 .24(s,3H), 1.19(t,J=7.4Hz,3H)

[0484] Example 38: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl- 6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1 ,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(3-fluoro Oro-2-methyl-4-(trifluoromethyl)phenyl)acetamide [ka] 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo -6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine -4(7H)-yl)-N-(3-fluoro-2-methyl-4-(trifluoromethyl) (phenyl)acetamide (Intermediate AJ) (504 mg, 894 μmol) and 3-hydroxybenzophenone Picolinoyl chloride (Intermediate CV) (254 mg, 1.61 mmol) was dissolved in DCM ( 7 mL) and DIPEA (312 μL, 1.79 mmol) was added. The solution was stirred at room temperature for 1 hour. Water (10 mL), saturated aqueous NaHCO3 (10 mL) and The aqueous layer was washed twice with DCM (2 x 10 mL). The combined organic layer was dried on a phase separator and concentrated under reduced pressure. Chromatography (RediSep column: silica 24 g, eluent DCM: DCM / The product was purified with MeOH (8 / 2) 100:0 to 35:65. The product-containing fractions were combined. The mixture was concentrated in vacuo and dried under high vacuum to give a white solid. The solid was diluted with EtOH (5 mL). and DCM (15 mL) and left to crystallize to give the title compound. LC-MS: Rt=1.02 min; MS m / z [M+H] + 685.3, m / z [MH ] - 683.4; UPLC-MS 1 1 H NMR(400MHz,DMSO-d6)δ 10.38(s,1H),10.2 0(s,1H),8.06(m,1H),7.58(m,2H),7.29(m,2H) ,6.82(m,1H),5.25(s,2H),4.55(m,1H),4.26(m ,2H),3.81(m,2H),3.44(m,3H),3.22(m,1H),2. 98(m,3H),2.80(m,1H),2.62(m,1H),2.52(m,2H ),2.24(s,3H),1.19(t,J=7.3Hz,3H)

[0485] Example 39: 2-(6-(4-(4-chloro-3-hydroxypicolinoyl)piperazine -1-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] The reaction was carried out in 4 batches obtained as follows: 4-chloro-3-hydroxypyridine Cholinic acid (400 mg, 2.31 mmol) was dissolved in DCM (36 mL) at room temperature under argon. 1-chloro-N,N,2-trimethylprop-1-en-1-amine (360m g, 2.66 mmol) was added and the RM was stirred at room temperature for 2.5 hours. -chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2 H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[ 1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide ( Intermediate AK) (1.10 g, 1.58 mmol) and DIPEA (1.23 mL, 7.0 8 mmol) was added. The resulting brown solution was stirred at room temperature for 1.3 hours. The RM from the mix was quenched with water (40 mL) and saturated aqueous NaHCO3 (40 mL). This was extracted four times with DCM (4 x 200 mL). The combined organic layers were washed with water (50 mL). The residue was washed with water (50 mL) and brine (50 mL), dried over a phase separator, and concentrated under reduced pressure. The sample was adsorbed onto lute and separated into two batches, and then subjected to column chromatography (RediSep column: Silica 120g Gold, eluent DCM:Silica 120g Gold, eluent Syneresis DCM:DCM / MeOH (1 / 1) 100:0 to 60:40) and (RediS EP column: Silica 120g Gold, eluent DCM: DCM / MeOH (1 / 1) The product-containing fractions were combined and concentrated under reduced pressure. , affording the title compound as a beige solid. LC-MS: Rt=1.13 min; MS m / z [M+H] + 721.4 / 723.4 / 7 25.4, m / z [MH] - 719.5 / 721.5 / 723.5; UPLC-MS 1 1 H NMR(400MHz,DMSO-d6)δ 10.83(s,1H),10.3 5(s,1H),8.06(m,2H),7.96(s,1H),7.71(dd,J= 2.1Hz,8.7Hz,1H),7.55(d,J=5.1Hz,1H),6.83( m,1H),5.32(s,2H),4.54(m,1H),4.25(m,2H),3 .80(m,2H),3.53(m,3H),3.26(m,1H),2.99(m,3 H),2.82(m,1H),2.65(m,1H),2.52(m,2H),1.19 (t,J=7.1Hz,3H)

[0486] Example 40: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-( 3,6-Dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-fluoro) -3-hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4] Triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka]

[0487] Step 1: 2-(6-(4-(3-(benzyloxy)-4-fluoropicolinoyl)piperazine) 2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl hydroxybenzoate -7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl )-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide N-(2-chloro-4-(trifluoromethyl)phenyl)- in DMF (10 mL) 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo- 6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine- 4(7H)-yl)acetamide·TFA (Intermediate AK) (300 mg, 441 μmol ), 3-(benzyloxy)-4-fluoropicolinic acid (intermediate CU) (115 mg, 4 A stirred solution of HATU (201 mg, 529 μmol) and HATU (201 mg, 529 μmol) was added to DI water at room temperature. PEA (385 μL, 2.21 mmol) was added and the RM was stirred at room temperature for 5 min. The RM was diluted with EtOAc / water and extracted twice with EtOAc, and the combined organic extracts were washed with Na The crude product was purified by column chromatography (RediSep column). Column: Silica 24g, Eluent: DCM: DCM / MeOH (8 / 2) 100:0 to 50:5 0) The product-containing fractions were combined and concentrated to give a white foam. LC-MS: Rt=1.23 min; MS m / z [M+H] + 795.3 / 797.3m / z[MH] - 793.4 / 795.4; UPLC-MS 1

[0488] Step 2: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3, 6-Dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-fluoro-3 -Hydroxypicolinoyl)piperazin-1-yl)-7-oxo-[1,2,4]tri Azolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 2-(6-(4-(3-benzyloxy)-4-fluoropicoyl)methyl)-4-hydroxybenzoate in DCM (10 mL) (linoyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl )-5-Ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4 (7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetate To a stirred solution of boron trichloride methyl sulfide (289 mg, 363 μmol) The RM was stirred at room temperature for 20 hours. The RM was quenched with MeOH, diluted with DCM / NaHCO3 and diluted with DCM for 2 min. The combined organic extracts were washed with water and brine, dried over Na2SO4, and concentrated. The crude product was subjected to column chromatography (RediSep column: silica 24 g, eluent Purification was carried out using DCM:DCM / MeOH (8 / 2) 100:0 to 60:40. The product-containing fractions were combined and concentrated to give an off-white solid. This solid was purified by EtOH (6 The RM was dissolved in 1 mL of HCl at 50°C and left at room temperature for 4 hours. The white solid was filtered and the target The title compound was obtained. The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=1.03 min; MS m / z [M+H] + 705.4 / 707.4m / z[MH] - 703.5 / 705.5; UPLC-MS 1 1H NMR(400MHz,DMSO-d6)δ 10.80(s,br,1H),1 0.36(s,1H),8.06(m,2H),7.96(m,1H),7.71(dd ,J=2.1Hz,8.8Hz,1H),7.34(dd,J=5.3Hz,10.9H z,1H),6.83(m,1H),5.31(s,2H),4.54(m,1H),4 .25(m,2H),3.80(m,2H),3.46(m,3H),3.23(m,1 H),2.98(m,3H),2.80(m,1H),2.63(m,1H),2.51 (m,2H), 1.18(t,J=7.5Hz,3H)

[0489] Example 41: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-( 3,6-Dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-fluoro) -3-hydroxy-6-methylpicolinoyl)piperazin-1-yl)-7-oxo-[ 1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka]

[0490] Step 1: 2-(6-(4-(3-(benzyloxy)-4-fluoro-6-methylpicolinic acid) (3,6-dihydro-2H-pyran-4-yl)piperazin-1-yl -5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4( 7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetami Do N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-di ... Hydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazine-1- (yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetate amide (intermediate AK) (227 mg, 334 μmol), 3-(benzyloxy)-4 -fluoro-6-methylpicolinic acid (intermediate CX) (110 mg, 371 μmol) and HATU (140 mg, 367 μmol) was suspended in DCM (5 mL) and cooled to 0° C. DIPEA (204 μL, 1.17 mmol) was then added, and the RM was stirred at room temperature for 2 h. The mixture was stirred for 0.5 hours. Water (10 mL), saturated aqueous NaHCO3 (10 mL) and DCM ( 10 mL) was added. The aqueous layer was washed twice with DCM (2 x 10 mL). The combined organic layers The residue was dried on a phase separator and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (RP-HPLC). Purification was performed using C Basic 1: 5-95% B in 20 minutes, plateau at 95% for 1 minute. The product-containing fractions were combined, basified with saturated aqueous NaHCO3, extracted twice with DCM, and the resulting solution was Dry on a separator and concentrate under reduced pressure to give the title compound. LC-MS: Rt=1.27 min; MS m / z [M+H] + 809.5 / 811.5m / z[MH] - 807.2 / 809.2; UPLC-MS 1

[0491] Step 2: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3, 6-Dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(4-fluoro-3 -hydroxy-6-methylpicolinoyl)piperazin-1-yl)-7-oxo-[1, 2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 2-(6-(4-(3-(benzyloxy)-4-fluoro-6-methylpicolinoyl )piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5- Ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidine-4(7H) -yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide(2 42 mg, 292 μmol) was dissolved in DCM (5 mL) and TFA (5.00 mL, 64 0.9 mmol) was added and the RM was stirred overnight at 60°C. After one night, approximately 50% conversion was observed. The mixture was further stirred at 60° C. overnight. The RM was concentrated under reduced pressure. The crude product was purified by reverse phase preparative IS. CO (RediSep column: C18 50g Gold, eluent: water + 0.1% TFA) The product-containing fractions were combined and purified with saturated N It was basified with aqueous HCl, extracted twice with DCM, dried on a phase separator and concentrated under reduced pressure. Condensation gave the title compound. LC-MS: Rt=1.06 min; MS m / z [M+H] + 719.5 / 721.6m / z[MH] - 717.4 / 719.4; UPLC-MS 1 LC-MS: Rt=5.31 min; MS m / z [M+H] + 719.5 / 721.5m / z[MH] - 717.5 / 719.3; UPLC-MS 2 1 H NMR(400MHz,DMSO-d6)δ 10.35(s,2H),8.05 (d,J=8.3Hz,1H),7.96(d,J=2.1Hz,1H),7.71(d d,J=2.1Hz,8.7Hz,1H),7.22(d,J=11.8Hz,1H), 6.83(m,1H),5.31(s,2H),4.52(m,1H),4.25(m, 2H),3.80(m,2H),3.47(m,3H),3.22(m,1H),2.9 8(m,3H),2.80(m,1H),2.64(m,1H),2.51(m,2H) ,2.39(s,3H),1.18(t,J=7.1Hz,3H)

[0492] Example 42: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-( 3,6-Dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy) (6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[ 1,2,4]triazolo[1,5-a]pyridin-4(7H)-yl)acetamide [ka]

[0493] Step 1: 2-(6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carboxylate) (bornyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl) -5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyridine-4(7 H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide N-(2-chloro-4-(trifluoromethyl)phenyl)- in DMF (3 mL) 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo- 6-(Piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-4 (7H)-yl)acetamide (Intermediate AK) (300 mg, 429 μmol), 5- (Benzyloxy)-6-methylpyrimidine-4-carboxylic acid (intermediate CY) (115m To a stirred solution of HATU (245 mg, 644 μmol) and DI PEA (375 μL, 2.15 mmol) was added at room temperature, and the RM was stirred at room temperature for 15 minutes. The RM was diluted with EtOAc / water and extracted twice with EtOAc, and the combined organic layers were washed with Na The crude product was purified by column chromatography (RediSep column). Purified with 24g silica (eluent: DCM:MeOH 100:0 to 90:10) The product-containing fractions were combined and concentrated to give the title compound as a beige foam. The product was dissolved in EtOH and stirred at 60° C. for 18 hours, then cooled to 0° C. The precipitate was filtered off and washed with EtOH to give the title compound as a white solid. LC-MS: Rt = 1.20 min; MS m / z [M+H] + 792.4 / 794.4m / z[MH] - 790.6 / 792.6; UPLC-MS 1

[0494] Step 2: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3, 6-Dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy- 6-Methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1, 2,4]triazolo[1,5-a]pyridin-4(7H)-yl)acetamide 2-(6-(4-(5-benzyloxy)-6-methylpyrimidinyl)-2-methylpyrimidinyl)-2-methylpyrimidinyl) (4-carbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran -4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyri Zin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl) To a stirred solution of acetamide (266 mg, 312 μmol) was added methyl boron trichloride. Sulfide complex (312 μL, 625 μmol) was added at room temperature, and the RM was stirred at room temperature for 14 hours. The RM was quenched with MeOH, then diluted with DCM / water and The mixture was extracted twice with MgO, and the combined organic extracts were washed with water and brine, dried over Na2SO4, and The crude product was purified by column chromatography (RediSep column: silica 24 g, Purification was carried out using the eluent DCM:MeOH 100:0 to 93:07. Product-containing fractions The products were combined and concentrated to give the title compound as an off-white solid. and stirred at 60°C for 18 hours, then cooled to 0°C, filtered off, and added to EtO The resulting solid was washed with H2O to give a white solid characterized by the XRPD diffractogram shown in Figure 1. The title compound was obtained. Ex 42a in the table below corresponds to the XRPD diffractogram in Figure 1. The most prominent peak (2 theta°) is shown. XRPD was repeated on a sample of the title compound, followed by column chromatography (Red Purification was performed using iSep 150g and eluent DCM:MeOH 100:0 to 90:10. The sample was subsequently triturated in EtOH. Ex42b in the table below was characterized by the XRPD diffraction pattern shown in Figure 7. The most prominent peak (2 theta°) of the chromatogram is shown. LC-MS: Rt=1.05 min; MS m / z [M+H] + 702.4 / 704.4m / z[MH] - 700.5 / 702.5; UPLC-MS 1 11H NMR (600 MHz, DMSO-d6) δ 10.40 (s, 1H), 10.2 0 (br s, 1H), 8.57 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H) , 7.97 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 8.7 Hz, J = 2. 1 Hz, 1H), 6.83 (m, 1H), 5.32 (m, 2H), 4.52 (m, 1H) , 4.25 (m, 2H), 3.80 (t, J = 5.5 Hz, 2H), 3.50 (m, 3H ), 3.25 (m, 1H), 2.99 (m, 3H), 2.81 (m, 1H), 2.63( m, 1H), 2.51 (m, 2H), 2.44 (s, 3H), 1.18 (t, J = 7.5 Hz, 3H).

[0495] The sodium salt was prepared in ...

Claims

1. A compound of formula (I) below or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, R, M, W, L, V and T are independently selected from C, CH and N; Subformulas 1a, 1b, 1c, 1d, 1e and 1f: 【Chemistry 2】 Forming; A is -C(O)-, -S(O)-, -S(O ２ ) - and 【Transformation 3】 is a linker selected from: Y is N, C or CH; y is 0, 1, 2, 3 or 4; 【Chemistry 4】 When Y is CH, it is connected to the adjacent carbon atom via a single bond, or when Y is C, means that the adjacent atoms are connected via a double bond, 【Transformation 5】 is a single bond, then Y is unsubstituted or substituted by OH or F; If Y is N, 【Transformation 6】 is a single bond; 【Transformation 7】 means that K is connected to the adjacent carbon atom via a single or double bond; where: 【Transformation 8】 If is a double bond, 【Chemistry 9】 is a single bond, K is CH, J is C, and A is —C(O)—, —S(O)—, — S (O) ２ - and 【Chemistry 10】 is a linker selected from: or 【Chemistry 11】 is a single bond, K is -CH ２ -, -CH ２ CH ２ -, -NH- and (5-membered ring: 【Chemistry 12】 and J is N, and A is selected from -C(O)-, -S(O)-, -S (O) ２ - and 【Chemistry 13】 is a linker selected from: or 【Chemistry 14】 is a single bond, K is -CH ２ -, J is CH, A is -S(O)-, -S(O ) ２ - and 【Chemistry 15】 is a linker selected from: R ５ is, independently, ・-(C １～ C ４ ) alkyl, ・-(C ３～ C ５ ) cycloalkyl, where two R on the same ring carbon atom ５ Substituents must be in the same group as the carbon atom to which they are attached. Together, (C ３～ C ４ ) cycloalkylspirocycle or 3- or 4-membered heterocyclyl A spiro ring may be formed, wherein said heterocyclylspiro ring is composed of ring carbon atoms and and one ring heteroatom selected from O, N, and S; ・ 【Chemistry 16】 When is a carbon-nitrogen single bond, K and R on the adjacent carbon atom ５ The substituents are bonded to ring C: 【Chemistry 17】 wherein ring C may be fused (C ３ ~C ６ ) cycloalkyl ring, fused (C ３ ~C ６ ) heterocyclyl ring or fused phenyl ring, wherein the fused (C ３ ~C ６ ) A heterocyclyl ring consists of ring carbon atoms and one ring heteroatom selected from O, N, and S. containing ・ [Chemistry 18] is a carbon-carbon single bond, Y is N, 【Chemistry 19】 is a single bond, A is -S(O)-, -S(O) ２ - and 【Chemistry 20】 When K is a linker selected from ５ The substituents are not together Ring C: 【Chemistry 21】 may form ・Here, K is -CH ２ - and when J is N, two R ５ The substituents are bonded to (C １ ~ C ３ ) may form an alkylene bridge or a heteroalkylene bridge, wherein the hetero The alkylene bridge is one heteroatom selected from N and O, or -CH ２ - O-CH ２ - is is selected from Here, the ring: 【Chemistry 22】 One or more H atoms on the above may be replaced by deuterium: R １ teeth, cycloalkenyl, wherein the cycloalkenyl has 5 or 6 ring carbon atoms; and a partially unsaturated monocyclic ring containing 1, 2, 3 or 4, preferably 1 or 2 R ３３ where R ３３ is halo, and said cycloalkenyl or halo-substituted cycloalkenyl is 0, 1 or 2 R １５ Is substituted by a substituent, Or, R １ is heterocyclyl, wherein said heterocyclyl is and 1 or 2 ring heteroatoms independently selected from N, O, and S. a partially unsaturated 5- or 6-membered group, said heterocyclyl being unbridged or bridged; the bridge is 1 or 2 carbon atoms, and wherein the heterocyclyl is a non-substituted or 1, 2, 3 or 4, preferably 1 or 2 R ３３ is replaced by Here, R ３３ is halo, and said heterocyclyl or halo-substituted heterocyclyl is independently Then, R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２２ and R ２３ Selected from or is substituted by 0, 1 or 2 substituents Alternatively, the heterocyclyl or halo-substituted heterocyclyl is fused to a cyclopropyl ring. wherein the cyclopropyl ring is unsubstituted or substituted with 1, 2 or 3 F. Are you Alternatively, the heterocyclyl or halo-substituted heterocyclyl may be attached to a cyclopropyl group. have two substituents on the same ring carbon atom forming a pyrocyclic ring, Alternatively, the heterocyclyl or halo-substituted heterocyclyl is (C ３ ~C ５ ) Heterocyclo and an alkyl ring, ３ ~C ５ ) Heterocycloalkyl rings are ring carbon containing a nitrogen atom and one ring O atom, or Or, R １ is heteroaryl, wherein said heteroaryl is a heteroaryl having a ring carbon atom and a 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, preferably 1 or a 5- or 6-membered fully unsaturated monocyclic group containing two ring heteroatoms, wherein the ring S atom the total number of ring O atoms does not exceed 1, and the total number of ring O atoms does not exceed 1, wherein said heteroaryl is a non-substituted Exchange, or R ２１ and R ３０ by one, two or three substituents independently selected from substituted, where R ２１ and R ３０ is halo and (C １ ~C ４ ) Independent of alkyl wherein (C １ ~C ４ ) alkyl is unsubstituted or substituted with 1, 2 or 3 Is substituted with a halo, Or, R １ is phenyl, wherein said phenyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2 R ３３ where R ３３ It's Halo and the phenyl or halo-substituted phenyl is selected from the group consisting of 0, 1 or 2 R １５ Substituted with a substituent Ruka, Or, R １ is (C ２ ~C ４ ) alkynyl or (C ２ ~C ４ ) alkenyl, And, the above (C ２ ~C ４ ) alkynyl and (C ２ ~C ４ ) alkenyl is unsubstituted or (C １ ~ C ４ ) substituted by alkyl-O—C(O)— or morpholinyl; Each R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２２ and R ２３ is, independently, ・Halo, unsubstituted or substituted with 1, 2 or 3 halo (C １～ C ４ ) alkyl-O- 、 Unsubstituted, or OH, —O—(C １ ~C ４ ) alkyl or 1, 2 or 3 halo Substituted (C １ ~C ４ ) alkyl, ・HOC(O)-(H ２ ) ｎ -、 ・H ３ C-C(O)(CH ２ ) ｎ -、 ・(C １ ~C ４ ) alkyl-O—C(O)(CH ２ ) ｎ , ・=O, Azetidinyl or pyrrolidinyl (wherein the azetidinyl and pyrrolidinyl are N atoms) and each is unsubstituted or substituted with 1 or 2 F. has been replaced), ・R ２５ (R ２４ ) N-(where R ２４ is H or unsubstituted or 1, 2 or 3 H (C １ ~C ４ ) alkyl, and R ２５ is H or unsubstituted or 1, 2 or substituted with 3 halo groups (C １ ~C ４ ) alkyl) ・OH is selected from wherein n is 0, 1 or 2; R ２６ is CH ３ , H or deuterium; R ２７ is CH ３ , H or deuterium; Or, R ２６ and R ２７ together with the carbon atoms to which they are attached form a cyclopro Forming a pill ring; R ２ Here is the part: 【Chemistry 23】 and R ６ teeth, ・H, ・Halo, unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, unsubstituted or substituted with 1, 2 or 3 halo (C ３ ~C ５ ) cycloalkyl 、 -O-(C １ ~C ４ ) alkyl 、 OH, and ・CN Selected from: R ８ is H, halo, and unsubstituted or substituted with 1, 2 or 3 halo (C １ ~ C ４ ) alkyl; R ９ is H, O-CH ３ , OH, CN, CH ３ and halo; R ２８ teeth, ・SF ５ 、 ・H, -C(O)H, ・Halo, unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, ・(C １ ~C ４ ) alkynyl; ・(C １ ~C ４ ) alkenyl, unsubstituted or substituted with 1, 2 or 3 halo (C ３ ~C ５ ) cycloalkyl , and ・OCF ３ Selected from: X is C-R ７ and N, where R ７ is H or halo, or R ７ is R ２８ Or R ６ , and together with the atoms to which they are attached form a condensed group (C ４ ~C ６ ) form a cycloalkyl ring, wherein the fused (C ４ ~C ６ ) The cycloalkyl ring is not substituted or substituted with 1, 2 or 3 halo; or R ２ teeth, 【Chemistry 24】 is selected from where: R ３１ is H, halo and CH ３ is selected from R ３２ is H, halo and CH ３ Selected from: R ３ teeth, cyclopropyl, ・O-CH ３ 、 ・N(CH) ３ ) ２ 、 ・S-CH ３ 、 unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo and OH It is being done (C １ ~C ４ ) alkyl; R ４ teeth, 【Chemistry 25】 Selected from where: R １０ , R １１ , R １２ , R １３ and R １４ is, independently, ・H, ・Halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C １ ~C ４ ) alkyl 、 -O-(C １ ~C ２ ) substituted by alkyl or OH (C １ ~C ２ ) Alki Lu, -S-(C １ ~C ３ ) alkyl, -O-(C) unsubstituted or substituted with 1, 2 or 3 halo substituents １ ~C ４ )a Lukil, ・OH, ・(C ３ ~C ５ ) cycloalkyl (wherein the above (C ３ ~C ５ ) Cycloalkyl is unsubstituted or is substituted with one or two halo groups), -O-(C ３ ~C ５ ) cycloalkyl, ・-NR ３４ R ３５ (where R ３４ and R ３５ is independent ohhh, o (C １ ~C ４ ) alkyl (wherein the above (C １ ~C ４ ) Alkyl is unsubstituted or OH or Or -O(C １ ~C ２ ) alkyl-substituted), o and where R ３４ and R ３５ together with the atoms to which they are attached azetidine, pyrrolidinyl and piperidine rings can be formed (wherein the azetidine The arylsulfonyl, pyrrolidinyl and piperidine are unsubstituted or ３ (replaced by selected from ・CN, ・-(C ２ ~C ４ ) alkenyl, ・-(C ２ ~C ４ ) alkynyl, -C(O)H, and -C(O)(C １ ~C ４ ) alkyl Selected from: and * indicates point of attachment].

2. ・The above R １ R, where the ring is attached to the rest of the molecule １ Each R adjacent to a ring atom １ The ring atoms are , independently unsubstituted or substituted only with halo, particularly independently unsubstituted or is substituted with one F substituent; ・The above R １ The ring is connected to the rest of the molecule by R １ Double bonded to a ring nitrogen atom or adjacent ring atom RuR １ linked via a ring carbon atom, 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R １ teeth, cycloalkenyl, wherein the cycloalkenyl has 5 or 6 ring carbon atoms; and a partially unsaturated monocyclic ring containing cycloalkenyl, wherein the cycloalkenyl is unsubstituted or is 1, 2, 3 or 4, preferably 1 or 2 R ３３ where So, R ３３ is halo, and said cycloalkenyl or halo-substituted cycloalkenyl is 0, 1 Or two R １５ Is substituted by a substituent, Or, R １ is heterocyclyl, wherein said heterocyclyl is and 1 or 2 ring heteroatoms independently selected from N, O, and S. a partially unsaturated 5- or 6-membered group, said heterocyclyl being unbridged or bridged; wherein the bridge is 1 or 2 carbon atoms and the heterocyclyl is unsubstituted. or 1, 2, 3 or 4, preferably 1 or 2 R ３３ is replaced by R ３３ is halo, and said heterocyclyl or halo-substituted heterocyclyl is independently R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２２ and R ２３ 0 selected from substituted by one or two substituents; Or, R １ is heteroaryl, wherein said heteroaryl is a heteroaryl having a ring carbon atom and a 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, preferably 1 or a 5- or 6-membered fully unsaturated monocyclic group containing two ring heteroatoms, wherein the ring S atom the total number of ring O atoms does not exceed 1, and the total number of ring O atoms does not exceed 1, wherein said heteroaryl is a non-substituted Exchange or R ２１ and R ３０ substituted by 1, 2 or 3 substituents independently selected from where R ２１ and R ３０ is halo and (C １ ~C ４ ) independently selected from alkyl wherein the (C １ ~C ４ ) alkyl is unsubstituted or substituted with 1, 2 or 3 halo; It has been replaced, And each R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２２ and R ２３ is independent hand, ・Halo, unsubstituted or substituted with 1, 2 or 3 halo (C １～ C ４ ) alkyl-O- 、 Unsubstituted or OH, —O—(C １ -C ２ ) alkyl or substituted with 1, 2 or 3 halo It has been replaced (C １ -C ４ ) alkyl, ・HOC(O)-(H ２ ) ｎ -、 ・H ３ C-C(O)(CH ２ ) ｎ -、 ・(C １ -C ４ ) alkyl-O—C(O)(CH ２ ) ｎ , ・=O Azetidinyl or pyrrolidinyl (wherein the azetidinyl and pyrrolidinyl are N atoms) and each is unsubstituted or substituted with 1 or 2 F. has been replaced), ・R ２５ (R ２４ ) N-(where R ２４ is H or unsubstituted or 1, 2 or 3 H (C １ ~C ４ ) alkyl, and R ２５ is H or unsubstituted or 1, 2 or substituted with 3 halo groups (C １ ~C ４ ) alkyl) ・OH is selected from wherein n is 0, 1 or 2; 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R １ teeth, 【Chemistry 26】 Selected from: R ３３ is F; R １５ is halo, azetidinyl, or pyrrolidinyl, wherein said azetidinyl and The pyrrolidinyl is linked to the rest of the molecule through the N atom and is unsubstituted or has one or more substituted with two F's), R １６ is R ２５ (R ２４ ) N- (where R ２４ is H or (C １ ~C ２ ) Alki R ２５ is H or unsubstituted or substituted with 1, 2 or 3 halo, especially F (C １ ~C ２ ) alkyl); R １７ is a halo; R １８ is a halo; R １９ is a halo; R ２０ is a halo; R ２１ is (C １ ~C ２ ) alkyl; R ２２ and R ２３ are each independently unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, ・HOC(O)-(H ２ ) ｎ -、 ・H ３ C-C(O)(CH ２ ) ｎ -、 ・(H ３ C) ３ C-O-C(O)(CH ２ ) ｎ - Selected from: where n is 0, 1 or 2; and R ３０ is CH ３ That is, A compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. R １ teeth, 【Chemistry 27】 Selected from: R １５ is F; R １６ is R ２５ (R ２４ ) N-; R １７ is F; R １８ is F; R １９ is F; R ２０ is F; R ２１ is CH ３ and R ２２ は、CF ３ ,\HF ２ CH ２ 、HOC(O)-CH ２ -、H ３ C-C(O)-、( H ３ C) ３ C—O—C(O)—; R ２３ is CF ３ , CHF ２ CH ２ -, (H ３ C) ３ C—O—C(O)—; R ２４ is CH ３ and R ２５ is CHF ２ CH ２ - is A compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. R １ teeth, 【Chemistry 28】 especially, 【Chemistry 29】 A compound of formula (I) or a pharmaceutical composition thereof according to any one of claims 1 to 5, selected from Acceptable salts.

7. R ２ is a part 【Transformation 30】 and R ６ teeth, ・H, ・Halo, unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, unsubstituted or substituted with 1, 2 or 3 halo (C ３ ~C ５ ) cycloalkyl 、 -O-(C １ ~C ４ ) alkyl 、 OH, and ・CN Selected from: R ８ is H, halo, and unsubstituted or substituted with 1, 2 or 3 halo (C １ ~ C ４ ) alkyl; R ９ is H, O-CH ３ , OH, CN, CH ３ and halo; R ２８ teeth, ・SF ５ 、 ・H, -C(O)H, ・Halo, unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, ・(C １ ~C ４ ) alkynyl; ・(C １ ~C ４ ) alkenyl, unsubstituted or substituted with 1, 2 or 3 halo (C ３ ~C ５ ) cycloalkyl , and ・OCF ３ Selected from: and X is C-R ７ and N, where R ７ is H or halo), A compound of formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

8. R ２ Here is the part: 【Chemistry 31】 and R ６ are H, Cl, CH ３ , F, and Br; R ８ is H, Cl, F, and CF ３ Selected from: R ９ is H, CH ３ and Cl; R ２８ is CF ３ , C.F. ２ H, —CH ２ CH ３ , Cl, SF ５ , Br, and —C(O)H Selected from: X is C-R ７ and N; R ７ is selected from H and F A compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. R ２ Here is the part: 【Chemistry 32】 and 【Transformation 33】 especially, 【Transformation 34】 Selected from: A compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. R ２６ is H and R ２７ is H, or a pharmaceutically acceptable salt thereof.

11. R ３ is unsubstituted or contains 1, 2 or 3 substituents independently selected from halo and OH; is substituted with a substituent (C １ ~C ２ ) alkyl, preferably —CH ２ CH ３ or CH ３ , more preferably —CH ２ CH ３ The formula ( I) or a pharmaceutically acceptable salt thereof.

12. Y is N; 【Chemistry 35】 is Y linked by a single bond, (I) or a pharmaceutically acceptable salt thereof. 【Request Item 13】 【Chemistry 36】 is K linked by a single bond, and K is —CH ２ -, -CH ２ CH ２ --, -- NH—, and (5-membered ring: 【Chemistry 37】 and J is N, and A is selected from —C(O)—, —S(O)—, — S (O) ２ - and 【Transformation 38】 (particularly, K is a linker selected from CH ２ any one of claims 1 to 12 1. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

14. A is -C(O)- and -S(O) ２ -, preferably -C(O)- The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, Acceptable salts.

15. R ５ is, independently, ・-(C １～ C ４ ) alkyl, preferably methyl, where two R on the same ring carbon atom ５ Substituents must be in the same group as the carbon atom to which they are attached. Together, (C ３～ C ４ ) cycloalkylspirocycle or 3- or 4-membered heterocyclyl may form a spiro ring, wherein the heterocyclylspiro ring is a ring carbon atom and and one ring heteroatom selected from O, N, and S; ・ 【Chemistry 39】 When is a carbon-nitrogen single bond, K and R on the adjacent carbon atom ５ The substituents are bonded to ring C: 【Chemistry 40】 wherein ring C is fused (C ３ ~C ６ ) Cycloalkyl rings, especially fused cycloalkyl rings butyl ring, fused (C ３ ~C ６ ) a heterocyclyl ring or a fused phenyl ring, (C ３ ~C ６ ) A heterocyclyl ring is a ring consisting of ring carbon atoms and one aryl selected from O, N, and S. containing a ring heteroatom), ・And K is -CH ２ - and when J is N, two R ５ The substituents are bonded to (C １ ~ C ３ ) may form an alkylene bridge or a heteroalkylene bridge (wherein the hetero The alkylene bridge is one heteroatom selected from N and O, or -CH ２ - O-CH ２ - is A compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutical composition thereof, selected from A commercially acceptable salt.

16. R ５ is, independently, ・CH ３ and y is 1 or 2, and ・ 【Chemistry 41】 When is a carbon-nitrogen single bond, K and R on the adjacent carbon atom ５ The substituents are bonded to ring C: 【Chemistry 42】 wherein ring C is a fused cyclobutyl ring. A compound of formula (I) or a pharmaceutical composition thereof according to any one of claims 1 to 15, selected from A commercially acceptable salt.

17. Compounds of formula (I) according to any one of claims 1 to 16, wherein y is 0, 1 or 2. or a pharmaceutically acceptable salt thereof.

18. portion: 【Chemistry 43】 teeth, a) 【Chemistry 44】 especially, 【Chemistry 45】 b) 【Chemistry 46】 and c) 【Chemistry 47】 especially, 【Chemistry 48】 A compound of formula (I) or a pharmaceutical composition thereof according to any one of claims 1 to 17, selected from A commercially acceptable salt.

19. R ４ teeth, 【Chemistry 49】 (In the formula, R １０ is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C １ ~C ２ ) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents; -(C １ ~C ２ ) alkyl; R １１ is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C １ ~C ２ ) alkyl; R １２ is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C １ ~C ２ ) alkyl; R １３ is H, -S-CH ３ , halo, unsubstituted or substituted with 1, 2 or 3 halo substituents It is being done (C １ ~C ２ ) alkyl; and R １４ is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C １ ~C ２ ) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents; (C １ ~C ２ ) alkyl, and cyclopropyl A compound of formula (I) or a pharmaceutical composition thereof according to any one of claims 1 to 18, selected from A commercially acceptable salt.

20. R ４ teeth, [Transformation 50] (In the formula, R １０ are H, F, Cl, CH ３ , and OCF ３ Selected from: R １１ is H, Cl, F, and CH ３ Selected from: R １２ is H, Cl, and CH ３ Selected from: R １３ is H, -S-CH ３ , and C.H. ３ is selected from: R １４ is H, CH ３ , -CH ２ CH ３ , cyclopropyl, -OCHF ２ , OCF ３ , and and Cl) A compound of formula (I) or a pharmaceutical composition thereof according to any one of claims 1 to 19, selected from A commercially acceptable salt.

21. R ４ teeth, 【Chemistry 51】 especially, 【Chemistry 52】 A compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutical composition thereof, selected from A commercially acceptable salt.

22. Formula (I) is a compound of formula 1a: 【Chemistry 53】 22. The compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, Salt to be used.

23. Formula (I) is represented by formula 1g: 【Chemistry 54】 and Y is N or CH, in particular N. (I) or a pharmaceutically acceptable salt thereof.

24. Formula (I) is 【Transformation 55】 A compound of formula (I) or a pharmaceutical composition thereof according to any one of claims 1 to 21, selected from A commercially acceptable salt. [Request Item 25] [Chemistry 56] 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 【Transformation 69】 【Transformation 70】 【Chemistry 71】 2. The compound of formula (I) according to claim 1, selected from: or a pharmaceutically acceptable salt thereof. 【Request Item 26】 【Chemistry 72】 【Transformation 73】 【Chemistry 74】 2. The compound of formula (I) according to claim 1, selected from: or a pharmaceutically acceptable salt thereof. 【Request Item 27】 【Chemistry 75】 2. The compound of formula (I) according to claim 1, wherein: 【Request Item 28】 【Chemistry 76】 2. The compound of formula (I) according to claim 1, wherein: 【Request Item 29】 【Chemistry 77】 2. The compound of formula (I) according to claim 1, wherein:

30. A compound of formula (I) according to any one of claims 1 to 29 in non-zwitterionic form or is a pharmaceutically acceptable salt thereof.

31. A compound of formula (I) according to any one of claims 1 to 29 in zwitterionic form, or and pharmaceutically acceptable salts thereof.

32. 30. A mixture of zwitterionic and non-zwitterionic forms according to any one of claims 1 to 29.

10. A compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof.

33. The compound N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3, 6-dihydro-2H-pyran-4-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)acetamide Non-zwitterionic forms: 【Transformation 78】 or the zwitterionic form: 【Chemistry 79】 or the zwitterionic form: 【Chemistry 80】 or a mixture of any two or three of the above forms 2. The compound of formula (I) according to claim 1, wherein:

34. The compound (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2 -(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydro) (6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl) -7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl ) Acetamide is Non-zwitterionic forms: 【Chemistry 81】 or the zwitterionic form: 【Chemistry 82】 or the zwitterionic form: 【Chemistry 83】 or a mixture of any two or three of the above forms 2. The compound of formula (I) according to claim 1, wherein:

35. Sodium salts, especially compounds: 【Chemical 84】 30. The compound of formula (I) according to any one of claims 1 to 29, which is a sodium salt of A pharmaceutically acceptable salt of

36. A compound of formula (I) or its derivatives according to any one of claims 1 to 35 in amorphous form. Pharmaceutically acceptable salts.

37. A compound of formula (I) or a drug thereof according to any one of claims 1 to 35, in crystalline form. A physiologically acceptable salt.

38. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dichlorophenyl)-2,6-diphenyl-2,6-dichloro-4,6-diphenyl-2 ... Hydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methyl)methyl) (1,2,4-Tyrpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4-trimethylpyrimidine-4-carbonyl]piperazin-1-yl] ... ]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide 【Chemical 85】 2. A crystalline form of the compound of formula (I) according to claim 1, which is ．７８±０．２、８．９７±０．２、１１．８８±０．２、１３．５５±０．２、１３． ７４±０．２、１４．４８±０．２、１５．３４±０．２、１６．８３±０．２、１７． ０３±０．２、１８．３０±０．２、１９．４９±０．２、１９．９４±０．２、２１． ２８±０．２、２１．５１±０．２、２２．３８±０．２、２２．９１±０．２、２３． ２７±０．２、２５．４１±０．２、２７．２６±０．２、２９．０３±０．２、２９． 78±0.2 and 29.96±0.2 Crystalline form characterized by powder X-ray diffraction pattern.

39. A compound of formula (I) according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof. A combination comprising a salt and one or more additional therapeutically active agents.

40. 40. The combination of claim 39, wherein the additional therapeutically active agent is an anti-cancer agent.

41. 41. The combination of claim 40, wherein the additional therapeutically active anti-cancer agent is a chemotherapeutic agent.

42. Additional therapeutically active agents include anastrozole (Arimidex®), bicalcotin bleomycin sulfate (Blenoxane®), (Trademark), busulfan (Myleran®), busulfan injection (Bus ulfex®), capecitabine (Xeloda®), N4-pent hydroxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Parapla atelin (registered trademark), carmustine (BiCNU (registered trademark), chlorambucil ( Leukeran (registered trademark), cisplatin (Platinol (registered trademark), Ladribine (Leustatin®), cyclophosphamide (Cytoxan (registered trademark) or Neosar (registered trademark), cytarabine, cytosine arabinoside (C ytosar-U (registered trademark), cytarabine liposome injection (DepoCyt (registered trademark) trademark), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin®), Tinomycin D, Cosmegan, Daunorubicin Hydrochloride (Cerubidine (Registered) Daunorubicin Citrate Liposomal Injection (DaunoXome®) )), dexamethasone, docetaxel (Taxotere®), doxol hydrochloride Bicine (Adriamycin®, Rubex®), etoposide ( Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), lutemide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxyglucan), oxycytidine), hydroxyurea (Hydrea®), idarubicin (I damycin (registered trademark), ifosfamide (IFEX (registered trademark), irinotecan Camptosar®, L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6 - mercaptopurine (Purinethol®), methotrexate (Fol ex (registered trademark)), mitoxantrone (Novantrone (registered trademark)), milo Targ, paclitaxel (Taxol®), Phoenix (Yttrium 90 / MX-DTPA), pentostatin, carmustine implants containing polyphenyprosa 20 (Gliadel®), tamoxifen citrate (Nolvadex®), registered trademark), teniposide (Vumon®), 6-thioguanine, thiotepa, Tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamp vinblastine (Velban®), vincristine (Oncovin®) and vinorelbine (Navelbine®) , in particular irinotecan.

43. 40. The combination of claim 39, wherein the additional therapeutically active agent is a PD-1 inhibitor.

44. 40. The combination of claim 39, wherein the additional therapeutically active agent is an anti-PD-1 antibody molecule.

45. Additional therapeutically active agents include PDR001 (Novartis), nivolumab (Bristol), 1-Myers Squibb), pembrolizumab (Merck & Co), Pidi Lizumab (CureTech), MEDI0680 (Medimmune), Semiprima (REGN2810, Regeneron), dostallimab (TSR-042, Te saro), PF-06801591 (Pfizer), tislelizumab (BGB-A 317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), balstilimab (AGEN2035, Agenus), Sintil imab (InnoVent), toripalimab (Shanghai Junshi Bi oscience), camrelizumab (Jiangsu Hengrui Medici ne Co.), and AMP-224 (Amplimmune), especially PDR001 or 44. The combination of claim 43, wherein the PD-1 inhibitor is selected from tislelizumab 。

46. A compound of formula (I) according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the salt and one or more pharmaceutically acceptable carriers.

47. A compound of formula (I) according to any one of claims 1 to 38 for use as a medicament is a pharmaceutically acceptable salt thereof.

48. 48. The method of claim 47, wherein the use is for the treatment of a disease treated by WRN inhibition. A compound of formula (I) according to any one of claims 1 to 38 or a pharmaceutical composition thereof for use in A commercially acceptable salt.

49. 49. The use of claim 47 or 48, wherein the use is for the treatment of cancer.

39. A compound of formula (I) according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof.

50. The cancer may be microsatellite instability-high (MSI-H) or mismatch repair-deficient.

49. The method of claim 1, wherein the nucleic acid sequence of claim 1 is a sequence of a nucleic acid sequence of claim 2, wherein the nucleic acid sequence of claim 2 is a sequence of a nucleic acid sequence of claim 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.

51. Microsatellite instability-high (MSI-H) or mismatch repair deficiency (dM The cancers characterized by MR include colon cancer, gastric cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, 51. The method of claim 50, wherein the cancer is selected from esophageal cancer, breast cancer, renal cancer, prostate cancer, and ovarian cancer. A compound of formula (I) according to any one of claims 1 to 38 or a pharmaceutical formulation thereof for use. Acceptable salts.

52. Microsatellite instability-high (MSI-H) or mismatch repair deficiency (dM The cancer characterized by MR is selected from colon cancer, gastric cancer, prostate cancer, and endometrial cancer. , a compound of formula (I) according to any one of claims 1 to 38 for use according to claim 51 The compound or a pharmaceutically acceptable salt thereof.

53. Microsatellite instability-high (MSI-H) or mismatch repair deficiency (dM The cancers characterized by MR include prostate cancer, endometrial cancer, colon adenocarcinoma, gastric adenocarcinoma, and rectal adenocarcinoma. , adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, esophageal cancer, breast cancer, renal cell carcinoma 51. The method of claim 50, wherein the cancer is selected from ovarian serous cystadenocarcinoma and ovarian serous cystadenocarcinoma. Item 39. A compound of formula (I) according to any one of Items 1 to 38, or a pharmaceutically acceptable salt thereof.

54. 39. A method of modulating WRN activity in a subject, comprising administering to a subject a compound of formula (I) of any one of claims 1 to 38. administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Methods including:

55. 38. A method of inhibiting WRN in a subject, comprising administering to a subject a compound of formula (I) according to any one of claims 1 to 38. or a pharmaceutically acceptable salt thereof. method.

56. Methods for treating disorders or diseases that can be treated by inhibiting WRN in a subject A method for the treatment of a patient suffering from a disease characterized by the above-mentioned, comprising administering to a patient a compound of formula (I) according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof. administering to said subject a therapeutically effective amount of an acceptable salt.

57. A method for treating cancer in a subject, comprising administering to a subject a compound of formula (I) according to any one of claims 1 to 38. administering to said subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof. 。

58. A method for treating cancer in a subject, comprising administering to a subject a compound of formula (I) according to any one of claims 1 to 38. the cancer is a high frequency microglial tumor. characterized by satellite instability (MSI-H) or mismatch repair deficiency (dMMR) The way it is.

59. Microsatellite instability-high (MSI-H) or mismatch repair deficiency (dM The cancers characterized by MR include colon cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, and 59. The method of claim 58, wherein the cancer is selected from cervical cancer, esophageal cancer, breast cancer, renal cancer, and ovarian cancer. method.

60. Microsatellite instability-high (MSI-H) or mismatch repair deficiency (dM 5. The method of claim 4, wherein the cancer characterized by MR is selected from colon cancer, gastric cancer, and endometrial cancer.

9. The method according to claim 9.

61. Microsatellite instability-high (MSI-H) or mismatch repair deficiency (dM The cancers characterized by MR include prostate cancer, endometrial cancer of the uterine corpus, colon adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, and rectal adenocarcinoma. Intestinal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, esophageal cancer, breast cancer, 59. The method of claim 58, wherein the cancer is selected from renal clear cell carcinoma and ovarian serous cystadenocarcinoma.

62. A compound according to any one of claims 1 to 38 or a compound thereof in the manufacture of a medicament for the treatment of cancer. Use of a pharmaceutically acceptable salt of

63. The cancer may be microsatellite instability-high (MSI-H) or mismatch repair-deficient. A compound according to any one of claims 1 to 38, characterized by a deficiency (dMMR) or its 63. The use of a pharmaceutically acceptable salt according to claim 62.

64. Claims for use as research chemicals, e.g., tool compounds or chemical probes.

39. A compound of formula (I) or a salt thereof according to any one of 1 to 38.

65. Any of claims 1 to 38 as a research chemical, e.g., a tool compound or chemical probe. Use of a compound of formula (I) or a salt thereof according to any one of claims 1 to 4.

66. A method for producing the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof. How to do it.

67. Formula A: 【Chemical 86】 (In the formula, R １ , R ２ , R ３ , R ２６ , R ２７ , R ５ , y and Y are any of claims 1 to 23. (as defined in any one of the preceding paragraphs) or a salt thereof, Compound: 【Transformation 87】 、 Formula B: 【Chemical 88】 (In the formula, R １ , R ２ , R ３ , R ２６ , R ２７ , R ５ , y and Y are any of claims 1 to 23. As defined in any one of the preceding claims, １ is a protecting group, e.g., BOC) or a salt thereof, 【Chemistry 89】 Intermediate AK Step 1 product or a salt thereof, Formula C: [Chemical 90] (In the formula, R １ , R ３ , R ５ , y and Y are as defined in any one of claims 1 to 23. As stated above, PG ２ is a protecting group, e.g., BOC) or a salt thereof, 【Chemistry 91】 or a salt thereof, Formula D: 【Chemistry 92】 (In the formula, R ３ , R ５ , y and Y are defined in any one of claims 1 to 23. It is a PG ３ is a protecting group) or a salt or tautomer thereof, 【Chemistry 93】 Intermediate AF Step 1 Product or a salt thereof, and 【Chemical 94】 or a salt thereof An intermediate compound selected from:

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