Tricyclic compounds and their uses

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [Formula 1] TIFF2025536259000594.tif33170 (where R1, R2, R3, x, R4, R5, y, R, M, W, L, V, T, Y, J, K and A are as described in the specification), therapeutic uses of said compounds, research uses of said compounds The compounds of the present invention are useful as chemical compounds, pharmaceutical compositions and combinations containing the compounds, and the compounds of the present invention are also useful as chemical compounds. A method for producing the compound is provided.

Description

[Technical Field]

[0001] The present invention relates to tricyclic heterocyclic compounds, such as 5-oxo-5,7,8,9-tetrahydro Pyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine compounds and their Analogs and derivatives inhibit Werner syndrome RecQ DNA helicase (WRN) and methods of using said compounds to treat diseases, particularly in the treatment of cancer. Uses of genomic DNA fragments, particularly those with microsatellite instability-high (MSI-H) or mismatch repair function in the treatment of cancers characterized by defective (dMMR) gene expression (including colorectal, gastric, and endometrial cancers) The present invention also provides research chemicals, intermediate compounds, combinations, processes, and the use of said compounds as pharmaceutical preparations. [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 therapy for these cancers have led to the development of Although a new anti-cancer drug was recently approved, there are still unmet medical needs in CRC and other MSI-H indications. There is a significant unmet medical need (Andre T., et al. Pembrokeshire, NY). olizumab in Microsatellite-Instability-H igh Advanced Colorectal Cancer.N Engl J Med;383(23):2207-2218(2020)). Cancer Cell Line Encyclopedia CCLE (McDonald ER et al., Project DR IVE A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncov ered by Large-Scale,Deep RNAi Screening. Nov 398 cell line (Cell 170(3):577-592(2017)) Several large-scale functional genomic studies across a large panel of cell lines, including artis The results of the analysis showed that cell lines with defective mismatch repair function became MSI-H by lean- ing. 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 binds to and / or inhibits WRN, and thus is useful for research purposes. The present invention provides compounds that are useful as chemical probes and tool compounds. For example, such uses may be useful in the study of WRN-associated diseases or frequent MSI disorders. Various embodiments of the present invention are described herein.

[0004] In certain embodiments, there is provided herein a compound of formula (I) or a pharmaceutically acceptable salt thereof: Salts are provided: [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; [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, Y is a carbon atom that is unsubstituted or substituted by OH or F. can be; If Y is N, [ka] is a single bond; [ka] means that K is connected to the adjacent 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: y is 0, 1, 2, 3 or 4; R5 is independent of -(C 1~C4) alkyl, -(C 3~ C5) cycloalkyl, where two R5 substituents on the same ring carbon atom are Together with 3~ C4) cycloalkylspiro ring or 3- or 4-membered heterocycle may form a heterocyclylspiro ring, wherein the heterocyclylspiro ring is and one ring heteroatom selected from O, N and S), · [ka] When K is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom are bonded to form a ring C. You may also: [ka] Here, ring C is a fused (C3-C6) cycloalkyl ring, a fused (C3-C6) heterocyclic ring, or a heterocyclyl ring or a fused phenyl ring, wherein the fused (C3-C6) heterocyclyl ring contains ring carbon atoms and one ring heteroatom selected from O, N, and S; When ring C is a fused (C3-C6) cycloalkyl ring, the fused (C3-C6) cycloalkyl ring The chloroalkyl ring is unsubstituted or contains one or two R 40 is substituted with a group, Here, the above R 40 teeth, · (C 1~ C2) alkyl (wherein each (C 1~ C2) alkyl is independently non- substituted or substituted with OH or 1, 2 or 3 halo; Halo, especially F, or where two R on the same ring carbon atom 40 The substituents are Together with the carbon atom present, (C3~ C4) cycloalkyl spiro ring or 3 or 4 may form a membered heterocyclyl spiro ring, wherein said heterocyclyl spiro ring is containing ring carbon atoms and one ring heteroatom selected from O, N, and S; Or, two R on adjacent carbon atoms 40 The substituents are attached to the carbon atoms to which they are attached. Together with the atom, forms a fused cyclopropyl ring Selected from: · [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 may form ring C: [ka] Here, ring C is a fused (C3-C6) cycloalkyl ring, a fused (C3-C6) heterocyclic ring, or a heterocyclyl ring or a fused phenyl ring, wherein the fused (C3-C6) heterocyclyl ring contains ring carbon atoms and one ring heteroatom selected from O, N, and S; When ring C is a fused (C3-C6) cycloalkyl ring, the fused (C3-C6) cycloalkyl ring The chloroalkyl ring is unsubstituted or contains one or two R 40 is substituted with a group, Here, the above R 40 teeth, · (C 1~ C2) alkyl (wherein each (C1~ C2) alkyl is independently non- substituted or substituted with OH or 1, 2 or 3 halo; Halo, especially F, or where two R on the same ring carbon atom 40 The substituents are Together with the carbon atom present, (C 3~ C4) cycloalkyl spiro ring or 3 or 4 may form a membered heterocyclyl spiro ring, wherein said heterocyclyl spiro ring is containing ring carbon atoms and one ring heteroatom selected from O, N, and S; or where two R on adjacent carbon atoms 40 Substituents are the groups to which they are attached. together with the carbon atom at the end of the cyclopropyl ring to form a fused cyclopropyl ring. Selected from: where K is -CH2- and J is N, the two R5 substituents are linked to form (C 1-C3) alkylene bridge or heteroalkylene bridge may be formed (wherein The heteroalkylene bridge is one heteroatom selected from N and O, or -CH 2-O-CH2-) Selected from; R1: cycloalkenyl, wherein the cycloalkenyl has 5 or 6 ring carbon atoms; The cycloalkenyl is unsubstituted or 1, 2 , 3 or 4, preferably 1 or 2 R 33 where R3 3 is halo, and said cycloalkenyl or halo-substituted cycloalkenyl is 0, 1 or 2 R's 15 Is substituted by a substituent, Alternatively, R1 is heterocyclyl, wherein said heterocyclyl is and one or two 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 The group is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2, R 33 where R 33 is halo, and the heterocyclyl or halo-substituted hetero Tetracyclyl can be independently R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 or substituted by 0, 1 or 2 substituents selected from 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. Has it been replaced? 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. wherein the (C3-C5) heterocycloalkyl ring is fused to a heterocycloalkyl ring. containing carbon atoms 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 two ring heteroatoms, and preferably a 5- or 6-membered fully unsaturated monocyclic group containing the total number of S atoms does not exceed 1, the total number of ring O atoms does not exceed 1, and the heteroaryl is unsubstituted or R 21 and R 30 are selected independently from substituted by 1, 2 or 3 substituents, where R 21 and R 30 teeth, independently selected from halo and (C1-C4) alkyl, wherein said (C1-C4) Alkyl is unsubstituted or substituted by 1, 2 or 3 halo; Alternatively, R1 is phenyl, wherein said phenyl is unsubstituted or has 1, 2, 3 or four, preferably one or two R 33 where R 33 teeth halo, and said phenyl or halo-substituted phenyl is selected from 0, 1 or 2 R 15 Substituted with a substituent Is it being done? Alternatively, R1 is (C2-C4)alkynyl or (C2-C4)alkenyl, wherein wherein the (C2-C4)alkynyl and (C2-C4)alkenyl are unsubstituted or substituted by (C1-C4)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) A Rukill-O-, unsubstituted or OH, —O—(C1-C2) alkyl or 1, 2 or 3 (C1-C4) alkyl substituted with one halo; 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 are connected to the rest of the molecule through an atom, and each is unsubstituted or one or substituted with two Fs), R 25 (R 24 )N-(where R 24 is H or unsubstituted or 1, 2 or is (C1-C4) alkyl substituted with at most three halo groups, and R 25 is H or unsubstituted or (C1-C4) alkyl substituted with 1, 2 or 3 halo. OH is selected from where n is 0, 1 or 2; R2 is the part [ka] and R6 is H, Hello, (C1-C4) alkyl groups unsubstituted or substituted with 1, 2 or 3 halo groups Rukill-O-, (C3-C5) cyclohexyl methyl ether unsubstituted or substituted with 1, 2 or 3 halo groups chloroalkyl, -O-(C1-C2) unsubstituted or substituted with 1, 2 or 3 halo 4) alkyl, 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 groups unsubstituted or substituted with 1, 2 or 3 halo groups Lukil, · (C1-C4)alkynyl; (C1-C4) alkenyl, (C3-C5) cyclohexyl methyl ether unsubstituted or substituted with 1, 2 or 3 halo groups chloroalkyl, 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) A cycloalkyl ring can be formed, wherein the fused (C4-C6) cycloalkyl The alkyl ring is unsubstituted 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 Halo, and unsubstituted or containing 1, 2 or 3 substituents independently selected from halo and OH (C1-C4) alkyl substituted with a substituent; Or, two R3 substituents on the same ring carbon atom are incompatible with the carbon atom to which they are attached. may be taken together to form a cyclopropyl ring Selected from; x is 0, 1 or 2; R4 is -(C1-C4) alkyl, Heteroaryl 1, wherein said heteroaryl 1 is a heteroaryl consisting of ring carbon atoms and N, O and S. and 1, 2, 3, or 4 independently selected ring heteroatoms. is a monocyclic ring; heteroaryl2, wherein said heteroaryl2 is a heteroaryl consisting of ring carbon atoms and N, O and S; and 9- or 10-membered fused bicyclic rings containing 1, 2, 3, or 4 independently selected ring heteroatoms. rings, both rings being fully unsaturated, or one ring being fully unsaturated and the other being saturated. is saturated or partially unsaturated, and heteroatoms may be in one or both rings; -phenyl Selected from; Here, heteroaryl 1, heteroaryl 2, and phenyl are each R 10 , R 11 , R 12 , R 13 and R 14 and substituted by 1, 2 or 3 substituents independently selected from where each R 10 , R 11 , R 12 , R 13 and R 14 is, independently, H, Hello, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C 4) alkyl, -O-(C1-C2) alkyl or (C1-C2) alkyl substituted by OH Lukil, -S-(C1-C3) alkyl, -O-(C 1-C4) alkyl, · OH, (C3-C5)cycloalkyl (wherein the (C3-C5)cycloalkyl is a substituted or substituted with 1 or 2 halo), -O-(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent o H, (C1-C4) alkyl, wherein said (C1-C4) alkyl is unsubstituted; or substituted with OH or —O(C1-C2)alkyl), o and where R 34 and R 35 together with the atoms to which they are attached. can form an azetidine, pyrrolidinyl or piperidine ring, Zetidine, pyrrolidinyl and piperidine are unsubstituted or substituted with CH3 selected from CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, =O, -C(O)H, and -C(O)(C1-C4) alkyl Selected from; * indicates point of attachment].

[0005] In another aspect, the present invention provides a compound of formula (I) of the present invention and one or more pharmaceutically acceptable salts thereof. A pharmaceutical composition is provided that includes a carrier.

[0006] 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.

[0007] 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 treating disorders or diseases that can be treated with steroids.

[0008] 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.

[0009] 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:

[0010] In another aspect, the present invention provides a method of treating cancer in a subject, more particularly, a method of treating cancer in a subject, wherein the cancer is a high-frequency myeloma. Microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) The method comprises administering to a subject a therapeutically effective amount of a compound of formula (I) of the present invention. A method is provided that includes:

[0011] In another aspect, the present invention provides a method for treating a disorder or disease that can be treated by WRN inhibition. The present invention also provides the use of a compound of formula (I) of the present invention in the manufacture of a medicament for the treatment of

[0012] 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.

[0013] In another aspect, the invention provides a solid form, process, or intermediate described herein. . [Brief explanation of the drawings]

[0014] [Figure 1] 1 shows a powder X-ray diffractogram of the compound of Example 18A. [Figure 2] 1 shows the efficacy of Example 18A against SW48 colon xenografts in Crl:Nu(NCR)Foxn1nu mice. [Figure 3] 1 shows the tolerability of Example 18A in SW48 colon xenografts in Crl:Nu(NCR)Foxn1nu mice. [Figure 4] 1 shows the efficacy of Example 21A against SW48 colon xenografts in Crl:Nu(NCR)Foxn1nu mice. [Figure 5] 1 shows the tolerability of Example 21A in SW48 colon xenografts in Crl:Nu(NCR)Foxn1nu mice. [Figure 6] 1 shows a powder X-ray diffractogram of the compound of Example 21A. DETAILED DESCRIPTION OF THE INVENTION

[0015] Thus, the present invention provides compounds of formula (I): [ka] (wherein R1, R2, R3, x, Y, K, J, R4, R5 and A are as defined in the Summary of the Invention above.) exactly as stated).

[0016] Unless otherwise specified, the term "compounds of the invention" refers to "compound of the present invention" or "compound of the present invention" of the present invention)" or "compound of formula (I)" means Compounds or compounds of formula (I), parts thereof The formulas, exemplified compounds, and their salts, as well as all zwitterions, stereoisomers (diastereoisomers) (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), as well as the essentially formed moieties and their embodiments as described above. Refers to a combination or mixture.

[0017] 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.

[0018] Embodiment 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as described above.

[0019] 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 are independently unsubstituted or substituted only with halo, and particularly are independently unsubstituted or substituted only with halo. is substituted or substituted with one F substituent, Preferably, the R1 ring is connected to the rest of the molecule via the R1 ring nitrogen atom or an adjacent is linked via an R1 ring carbon atom that is double bonded to an R1 ring atom; A compound of formula (I) as defined in embodiment 1 or a pharmaceutically acceptable salt thereof.

[0020] Embodiment 3.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 33is replaced by , R 33 is halo, and said cycloalkenyl or halo-substituted cycloalkenyl is 0, 1 or more. Or two R 15 Is substituted by a substituent, Alternatively, R1 is heterocyclyl, wherein said heterocyclyl is and one or two 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 are unsubstituted or 1, 2, 3 or 4, for example 1, 2 or 3, in particular 1 or Two R's 33 where R 33 is halo, and said heterocyclyl or halo-substituted heterocyclyl, independently R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 substituted by 0, 1 or 2 substituents selected from Ruka, 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 does not exceed 1, and the total number of ring O atoms does not exceed 1, wherein said heteroaryl is Substitution or R 21 and R 30 one, two or three substituents independently selected from where R21 and R 30 is halo and (C1-C4) alkyl wherein said (C1-C4) alkyl is unsubstituted or substituted with 1, 2 or 3 halo; 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~ C4) A Rukill-O-, unsubstituted or OH, —O—(C1-C2) alkyl or 1, 2 or 3 (C1-C4) alkyl substituted with one halo; 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 are connected to the rest of the molecule through an atom, and each is unsubstituted or one or substituted with two Fs), R 25 (R 24 )N-(where R 24 is H or unsubstituted or 1, 2 or is (C1-C4) alkyl substituted with at most three halo groups, and R 25 is H or unsubstituted or (C1-C4) alkyl substituted with 1, 2 or 3 halo. 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.

[0021] Embodiment 4. R1 is cycloalkenyl, wherein said cycloalkenyl is 5 or a partially unsaturated monocyclic ring containing 6 ring carbon atoms, R is unsubstituted or has one or two R 33 where R 33 Haha Preferably, F, and the cycloalkenyl or halo-substituted cycloalkenyl is 0 or 1 R 15 substituted with a substituent, preferably one substitution, where R 15 teeth, a) unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C2) A Rukill-O-, b) (C1-C2) alkyl groups unsubstituted or substituted with 1, 2 or 3 halo groups Lukil, 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-, (where R 24 is H, unsubstituted or 1, 2 or is (C1-C2) alkyl substituted with 3 halo, and R 25 is H, unsubstituted or or (C1-C2) alkyl substituted with 1, 2, or 3 halo. is selected from n is 0 or 1, where: R of the cycloalkenyl or halo-substituted cycloalkenyl15 Substituents a) to g) are , the ring in which the cycloalkenyl or halo-substituted cycloalkenyl is attached to the rest of the molecule is not present on an atom adjacent to said cycloalkenyl or halo-substituted cycloalkenyl. A methylalkenyl has one R in the ring para position relative to the rest of the molecule. 15 6-membered with substituents It is a ring, The cycloalkenyl or halo-substituted cycloalkenyl is preferably a cycloalkenyl having an adjacent R ring carbon atom. is connected to the remainder of the compound via an R1 ring carbon atom that is double bonded to 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 Ha halo and preferably F, wherein 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 or substituted by one substituent, wherein R 15 , R 16 , R 17 , R1 8. R 19 , R 20 , R 22 and R 23 is, independently, a) unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C4) A Rukill-O-, b) unsubstituted or substituted with OH, —O—(C1-C2) alkyl or 1, 2 or 3 (C1-C4) alkyl substituted with one halo; 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 1, 2 or is (C1-C2) alkyl substituted with 3 halo, and R 25 is H, unsubstituted or is (C1-C2) alkyl substituted with 1, 2 or 3 halo; h)OH is selected from where n is 0 or 1, where: The substituents a) to h) of the heterocyclyl or halo-substituted heterocyclyl are No halo-substituted heterocyclyl or halo-substituted heterocyclyl is present on the ring atom that is attached to the remainder of the molecule. Preferably, when the heterocyclyl or halo-substituted heterocyclyl is a 6-membered ring, It is in the meta or para position, preferably the para position, relative to the rest of the molecule, selected from a) to h). has 0 or 1 substituent selected from the group consisting of: The heterocyclyl may be attached to the remainder of the compound via the R1 ring nitrogen atom or the adjacent ring is linked via an R1 ring carbon atom that is double bonded to the atom; Alternatively, R1 is heteroaryl, wherein said heteroaryl is a ring carbon atom and 1 or 2 ring heteroatoms independently selected from N, O and S, preferably 5 including N or a 6-membered fully unsaturated monocyclic group, wherein the total number of ring S atoms does not exceed 1 and the number of ring O atoms is the total number does not exceed 1, wherein said heteroaryl is unsubstituted or R 21 and R 30 and wherein R2 is substituted by one or two substituents independently selected from 1 and R 30 are independently selected from (C1-C2) alkyl, The alkyl is unsubstituted or substituted with 1, 2 or 3 halo, wherein preferably Alternatively, the alkyl or haloalkyl substituent may be a heteroaryl group that is bonded to the remainder of the molecule. is not present on the R1 ring atom adjacent to the R1 ring atom to which it is bonded, and more preferably, is When the ring is six-membered, the alkyl or haloalkyl substituent is in the ring para position relative to the rest of the molecule. Located in A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1, 2 or 3. salt.

[0022] Embodiment 5.R1 is [ka] Selected from; Alternatively, in each of the above moieties, 0 to 2 R 33 There is a substituent, 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 or substituted by two F; 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. substituted (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 groups unsubstituted or substituted with 1, 2 or 3 halo groups Rukill-O-, 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, A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 4.

[0023] 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.

[0024] Embodiment 7.R1 is [ka] The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 6, selected from Acceptable salts.

[0025] Embodiment 8.R1 is [ka] or a pharmaceutically acceptable salt thereof.

[0026] Embodiment 9.R1 is [ka] or a pharmaceutically acceptable salt thereof.

[0027] Embodiment 10.R1 is [ka] or a pharmaceutically acceptable salt thereof.

[0028] Embodiment 11.R2 comprises the moiety: [ka] and R6 is H, Hello, (C1-C4) alkyl groups unsubstituted or substituted with 1, 2 or 3 halo groups Lukil, (C3-C5) cyclohexyl methyl ether unsubstituted or substituted with 1, 2 or 3 halo groups chloroalkyl, -O-(C1-C2) unsubstituted or substituted with 1, 2 or 3 halo 4) alkyl, OH, and CN Selected from; R8 is H, halo, and unsubstituted or substituted with 1, 2 or 3 halo. (C1 to 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 groups unsubstituted or substituted with 1, 2 or 3 halo groups Lukil, · (C1-C4)alkynyl; (C1-C4) alkenyl, (C3-C5) cyclohexyl methyl ether unsubstituted or substituted with 1, 2 or 3 halo groups chloroalkyl, and Selected from OCF3; X is selected from C-R7 and N, where R7 is H or halo; A compound of formula (I) according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof.

[0029] Embodiment 12.R2 comprises the moiety: [ka] and where: R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-C4) alkyl; 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 is SF5, halo, C(O)H, and unsubstituted or substituted with 1, 2 or 3 halo groups. (C1-C4) alkyl substituted with ; X is selected from C-R7 and N; R7 is selected from H and halo; 12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11.

[0030] Embodiment 13.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; 13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 12.

[0031] Embodiment 14. Part: [ka] teeth, [ka] The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 13, selected from Acceptable salts.

[0032] Embodiment 15. Part: [ka] teeth, [ka] or a pharmaceutically acceptable salt thereof, .

[0033] Embodiment 16. Part: [ka] teeth, [ka] or a pharmaceutically acceptable salt thereof, .

[0034] Embodiment 17. Part: [ka] teeth, [ka] or a pharmaceutically acceptable salt thereof, .

[0035] Embodiment 18. Formula (I) according to any one of embodiments 1 to 17, wherein x is 0 or 1. or a pharmaceutically acceptable salt thereof. In particular, x is 1.

[0036] Embodiment 19. R3 is unsubstituted or independently selected from halo and OH. (C1-C4) alkyl substituted with 2 or 3 substituents. 18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of 18.

[0037] Embodiment 20. R3 is unsubstituted or independently selected from halo and OH. (C1-C2) alkyl substituted with 2 or 3 substituents, preferably R3 is -CH2CH3 or CH3, more preferably -CH3. 10. A compound of formula (I) according to any one of the following or a pharmaceutically acceptable salt thereof:

[0038] Embodiment 21. The compound of formula (I) according to any one of embodiments 1 to 20, wherein R3 is CH3. or a pharmaceutically acceptable salt thereof.

[0039] Embodiment 22. R3 is a compound of formula 1i: [ka] 22. The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 21, A commercially acceptable salt.

[0040] Embodiment 23. Y is N; [ka] is Y linked by a single bond, I) or a pharmaceutically acceptable salt thereof.

[0041] Embodiment 24. [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] 24. The compound of formula (I) according to any one of embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, Salt that can be used.

[0042] Embodiment 25. [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] 25. The compound of formula (I) according to any one of embodiments 1 to 24, wherein the linker is selected from or a pharmaceutically acceptable salt thereof.

[0043] Embodiment 26.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 25, wherein and pharmaceutically acceptable salts thereof.

[0044] Embodiment 27.R5 independently comprises: -(C 1~ C4) alkyl, preferably methyl; where two R5 substituents on the same ring carbon atom are Together with 3~ C4) cycloalkylspiro ring or 3- or 4-membered heterocycle may form a heterocyclylspiro ring, wherein the heterocyclylspiro ring is and one ring heteroatom selected from O, N and S), · [ka] When K is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom are bonded to form ring C. May be formed: [ka] Here, ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring, a fused (C3-C6) heterocyclyl ring or fused phenyl ring, C6) A heterocyclyl ring has ring carbon atoms and one ring heteroatom selected from O, N, and S. and When ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring, The fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, wherein said R 40 teeth, · (C 1~ C2) alkyl (wherein each (C 1~ C2) alkyl is independently non- substituted or substituted with OH or 1, 2 or 3 halo; Halo, especially F, or where two RR on the same ring carbon atom 40 Substituents are the groups to which they are attached. Together with the carbon atom (C 3~ C4) cycloalkyl spiro ring or 3 or may form a four-membered heterocyclyl spiro ring, wherein the heterocyclyl spiro ring is , containing ring carbon atoms and one ring heteroatom selected from O, N and S; Or, two R on adjacent carbon atoms 40 The substituents are attached to the carbon atoms to which they are attached. Together with the atom, forms a fused cyclopropyl ring Selected from: and wherein when K is -CH2- and J is N, the two R5 substituents are bonded. may form a (C1-C3) alkylene bridge or a heteroalkylene bridge (wherein wherein the heteroalkylene bridge is one heteroatom selected from N and O; or is -CH2-O-CH2-) A compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 26, selected from Acceptable salts.

[0045] Embodiment 28. R5 independently comprises: -(C 1~ C4) alkyl, preferably methyl; · [ka] When K is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom are bonded to form ring C. May be formed: [ka] wherein ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring; is a fused (C3-C6) heterocyclyl ring, wherein said fused (C3-C6) hetero A cyclyl ring contains ring carbon atoms and one ring heteroatom selected from O, N, and S. death, When ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring, The fused (C3-C6) cycloalkyl ring is unsubstituted or has one or two R4 0 group, wherein the R 40 teeth, · (C 1~ C2) alkyl (wherein each (C 1~ C2) alkyl is independently non- substituted or substituted with OH or 1, 2 or 3 halo; Halo, especially F, or where two R on the same ring carbon atom 40 The substituents are Together with the carbon atom present, (C 3~ C4) cycloalkyl spiro ring or 3 or 4 may form a membered heterocyclyl spiro ring, wherein said heterocyclyl spiro ring is containing ring carbon atoms and one ring heteroatom selected from O, N, and S; Or, two R on adjacent carbon atoms 40 The substituents are attached to the carbon atoms to which they are attached. Together with the atom, forms a fused cyclopropyl ring Selected from: where K is -CH2- and J is N, the two R5 substituents are linked to form (C 1-C3) alkylene bridge or heteroalkylene bridge may be formed (wherein The heteroalkylene bridge is one heteroatom selected from N and O, or -CH 2-O-CH2-) The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 27, selected from Acceptable salts.

[0046] Embodiment 29. R5 independently comprises: -(C 1~ C2) alkyl, preferably methyl, and · [ka] When K is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom are bonded to form ring C. May be formed: [ka] wherein ring C is a fused (C3-C4) cycloalkyl ring, particularly a fused cyclobutyl ring. The fused (C3-C4) cycloalkyl ring, particularly the fused cyclobutyl ring, is unsubstituted. or one or two R as described in embodiment 28 40 substituted with a group The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 28, selected from Acceptable salts.

[0047] Embodiment 30. y is 0, 1, 2 or 3, preferably 0, 1 or 2. 30. A compound of formula (I) according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

[0048] Embodiment 31. R5 independently comprises: CH3, y is 1 or 2, and · [ka] When K is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom are bonded to form ring C. May be formed: [ka] wherein ring C is a fused cyclobutyl ring The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 30, selected from Acceptable salts.

[0049] Embodiment 32. The compound of formula (I) comprises the moiety: [ka] ,especially, A: [ka] , more particularly, [ka] Contains or Alternatively, the linker -C(O)- can be replaced by the alternative linker -S(O)-, -S(O)2 and according to claim 1 [ka] is replaced by 32. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 31.

[0050] Embodiment 33.R4 is -(C1-C4) alkyl, - heteroaryl1, wherein said heteroaryl1 is selected from the group consisting of ring carbon atoms and N, O and S; and 1, 2, 3 or 4 ring heteroatoms independently selected from the group consisting of 5- or 6-membered fully unsaturated alkylenes. a monocyclic ring, the total number of ring S atoms not exceeding 1, and the total number of ring O atoms not exceeding 1); - heteroaryl2, wherein said heteroaryl2 is selected from the group consisting of ring carbon atoms and N, O and S; and 1, 2, 3 or 4 ring heteroatoms independently selected from cyclic rings, both rings being fully unsaturated, or one ring being fully unsaturated and the other saturated; The heteroatoms may be present in one or both rings, and the ring S atoms does not exceed 1, the total number of ring O atoms does not exceed 1, and in particular, the ring connecting it to the rest is fully unsaturated); -phenyl Selected from; Here, heteroaryl 1, heteroaryl 2, and phenyl are each R 10 , R 11 , R 12 , R 13 and R 14 and substituted by 1, 2 or 3 substituents independently selected from where each R 10 , R 11 , R 12 , R 13 and R 14 is, independently, H, Hello, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C 4) alkyl, -O-(C1-C2) alkyl or (C1-C2) alkyl substituted by OH Lukil, -S-(C1-C3) alkyl, -O-(C 1-C4) alkyl, · OH, (C3-C5)cycloalkyl (wherein the (C3-C5)cycloalkyl is a substituted or substituted with 1 or 2 halo), -(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent o H, (C1-C4) alkyl, wherein said (C1-C4) alkyl is unsubstituted; or substituted with OH or —O(C1-C2)alkyl), o and where R 34 and R 35 together with the atoms to which they are attached. can form an azetidine, pyrrolidinyl or piperidine ring, Zetidine, pyrrolidinyl and piperidine are unsubstituted or substituted with CH3 selected from CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, =O, -C(O)H, and -C(O)(C1-C4) alkyl Selected from; However, one OH substituent is present on heteroaryl 1, heteroaryl 2, and phenyl. and the remaining R 10 , R 11 , R 12 , R 13 and R 14 is as defined herein That is, 33. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 32.

[0051] Embodiment 34.R4 is -(C1-C4) alkyl, especially -CH3; heteroaryl 1, and -heteroaryl 2, -phenyl Selected from; Here, heteroaryl 1, heteroaryl 2, and phenyl are each R 10 , R 11 , R 12 , R 13 and R 14and substituted by 1, 2 or 3 substituents independently selected from where each R 10 , R 11 , R 12 , R 13 and R 14 is, independently, H, Hello, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C 4) alkyl, -O-(C1-C2) alkyl or (C1-C2) alkyl substituted by OH Lukil, -S-(C1-C3) alkyl, -O-(C 1-C4) alkyl, · OH, (C3-C5)cycloalkyl (wherein the (C3-C5)cycloalkyl is a substituted or substituted with 1 or 2 halo), -(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent o H, (C1-C4) alkyl, wherein said (C1-C4) alkyl is unsubstituted; or substituted with OH or —O(C1-C2)alkyl), o and where R 34 and R 35 together with the atoms to which they are attached. can form an azetidine, pyrrolidinyl or piperidine ring, Zetidine, pyrrolidinyl and piperidine are unsubstituted or substituted with CH3 selected from CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, =O, -C(O)H, and -C(O)(C1-C4) alkyl Selected from; however, - one OH substituent is present on heteroaryl 1, heteroaryl 2 and phenyl; , the OH is in the ortho position of the R4 ring relative to the position connecting R4 to the linker-A-; , or - one =O substituent is present on Heteroaryl1 and Heteroaryl2, Remaining R 10 , R 11 , R 12 , R 13 and R 14 is defined as herein A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 33.

[0052] Embodiment 35.R4 is -(C1-C4) alkyl, especially -CH3; heteroaryl 1, and -heteroaryl 2, -phenyl Selected from; Here, heteroaryl 1, heteroaryl 2, and phenyl are each R 10 , R 11 , R 12 , R 13 and R 14 and substituted by 1, 2 or 3 substituents independently selected from where each R 10 , R 11 , R 12 , R 13 and R 14 OH, =O, independently selected from H, F, Cl, and CH3; - one OH substituent is present on heteroaryl 1, heteroaryl 2 and phenyl; wherein said OH is in the ortho position of the R4 ring relative to the position connecting R4 to the linker-A-; the remaining substituents are selected from H, F, Cl and CH3; or - one =O substituent is present on Heteroaryl 1 and Heteroaryl 2, the remaining substituents are The substituents are selected from H, F, Cl and CH3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 34.

[0053] Embodiment 36. R4 is selected from CH3, heteroaryl1 and heteroaryl2. wherein the substituents are as defined above. or a pharmaceutically acceptable salt thereof. In particular, said heteroaryl 1 is and one or two nitrogen atoms only. More particularly, heteroaryl 1 is pyridyl or pyridyl. It is rimidinyl.

[0054] Embodiment 37.R4 is -(C1-C4) alkyl, especially CH3; [ka] is selected from where: R 10 , R 11 , R 12 , R 13 and R 14 is, independently, H, Hello, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C 4) alkyl, -O-(C1-C2) alkyl or (C1-C2) alkyl substituted by OH Lukil, -S-(C1-C3) alkyl, -O-(C 1-C4) alkyl, (C3-C5)cycloalkyl (wherein the (C3-C5)cycloalkyl is a substituted or substituted with 1 or 2 halo), -O-(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent o H, (C1-C4) alkyl, wherein said (C1-C4) alkyl is unsubstituted; or substituted with OH or —O(C1-C2)alkyl), o and where R 34 and R 35 together with the atoms to which they are attached. can form an azetidine, pyrrolidinyl or piperidine ring, 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: 37. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 36.

[0055] Embodiment 38.R4 is [ka] is selected from where: R 10is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted —O—(C1-C2)alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 13 is H, —S—CH 3 , halo, unsubstituted or 1, 2 or 3 halo substituted (C1-C2) alkyl substituted with a group; R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted O-(C1-C2)alkyl, and cyclopropyl; 38. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 37.

[0056] Embodiment 39.R4 is [ka] is selected from where: R 10 is selected from H, F, Cl, CH3 and OCF3; R 11 is selected from H, F, Cl and CH3; R 12 is selected from H, F, Cl and CH3; R 13 is selected from H, F, Cl, —S—CH and CH, and R 14 are H, F, Cl, CH3, -CH2CH3, cyclopropyl, -OCHF2, O CF3, or a compound of formula (I) according to any one of embodiments 1 to 38, Pharmaceutically acceptable salts, especially R 10 , R 11 and R 12 At least one substituent of H. In particular, R 13 and R 14 At least one substituent of is H.

[0057] Embodiment 40.R4 is [ka] The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 39, selected from Acceptable salts.

[0058] Embodiment 41.R4 is [ka] The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 40, selected from Acceptable salts.

[0059] Embodiment 42.R4 is [ka] ,especially [ka] The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 41, selected from Acceptable salts.

[0060] Embodiment 43. The compound of formula (I) has the formula (I') [ka] The compound of formula (I) according to any one of embodiments 1 to 42, or A pharmaceutically acceptable salt of In particular, the compound of formula (I) has the formula (I"): [ka] is a compound of More particularly, the compound has the formula (I"'): [ka] It has the stereochemistry:

[0061] Embodiment 44. Formula (I) is a compound of formula 1a: [ka] is (Preferably, formula (I) is formula 1a), 44. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 43. In certain embodiments, Formula 1a' [ka] The compound of formula (I) is provided.

[0062] Embodiment 45. Formula (I) is a compound of formula 1b: [ka] [ka] 44. The compound of formula (I) according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, Salt that can be used.

[0063] Embodiment 46. Formula (I) is a compound of formula 1c: [ka] 44. The compound of formula (I) according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, Salt that can be used.

[0064] Embodiment 47. Formula (I) is a compound of formula 1d: [ka] 44. The compound of formula (I) according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, Salt that can be used.

[0065] Embodiment 48. Formula (I) is represented by formula 1e: [ka] 44. The compound of formula (I) according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, Salt that can be used.

[0066] Embodiment 49. Formula (I) is a compound of formula 1f: [ka] 44. The compound of formula (I) according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, Salt that can be used.

[0067] Embodiment 50. Formula (I) is a compound of formula 1g: [ka] 45. The compound of formula (I) according to any one of embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, Salt that can be used. More preferably, formula (I) is formula 1g.

[0068] Also, Formula 1g': [ka] There is provided a compound of formula (I) wherein:

[0069] Embodiment 51. Formula (I) is represented by formula 1h: [ka] The compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 44 and 50, Acceptable salts. Most preferably, formula (I) is formula 1h.

[0070] Also, formula 1h': [ka] There is provided a compound of formula (I) wherein:

[0071] Embodiment 52. A compound of formula 1g or 1g' according to embodiment 50 or a pharmaceutically acceptable salt thereof Acceptable salts [ka] [Wherein 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; R2 is the part [ka] and where: R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-C4) alkyl; R8 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-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 -C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo; R3 is unsubstituted or contains 1, 2, or 3 independently selected from halo and OH. is a (C1-C4) alkyl substituted with a substituent; x is 0 or 1; Y is CH or N, in particular N; y is 0, 1 or 2; R5 is selected from CH3; Or, part: [ka] wherein two R5 substituents on adjacent carbon atoms are joined to form a ring C: [ka] (wherein ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring) wherein the fused (C-C)cycloalkyl ring is unsubstituted or contains one or two R 40 group, wherein said R 40 teeth, · (C 1~ C2) alkyl (wherein each (C 1~ C2) alkyl is independently a non-substituted or substituted by OH or 1, 2 or 3 halo), Halo, especially F, or where two R on the same ring carbon atom 40 Substituents are the groups to which they are attached. Together with the carbon atom (C 3~ C4) cycloalkyl spiro ring or 3- or 4-membered A heterocyclylspiro ring may be formed (wherein the heterocyclylspiro ring is a ring containing carbon ring atoms and one ring heteroatom selected from O, N and S; Or, two R on adjacent carbon atoms 40 Substituents are attached to the carbon together with the atoms to form a fused cyclopropyl ring (selected from especially, [ka] and; R4 is CH3, [ka] ,especially [ka] ,especially [ka] is selected from where: R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted —O—(C1-C2)alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 13 is H, —S—CH 3 , halo, unsubstituted or 1, 2 or 3 halo substituted (C1-C2) alkyl substituted with a group; and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted O-(C1-C2) alkyl, and cyclopropyl. In particular, formula 1g is formula 1g* or formula 1g**.

[0072] Embodiment 53. A compound of formula 1h or 1h' according to embodiment 51 or a pharmaceutically acceptable salt thereof Acceptable salts [ka] [In the formula, R1 is [ka] Selected from; R2 is [ka] is selected from R3 is CH3; x is 0 or 1; R4 is [ka] is selected from y is 0 or 1; R5 is selected from CH3; or part [ka] teeth, [ka] is].

[0073] Embodiment 54. The compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0074] Embodiment 55. The compound is [ka] [ka] The compound of formula (I) as defined in embodiment 1, wherein

[0075] Embodiment 56. The compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)methyl)- (R)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(phenyl)- -4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperane 1-(2 ... ,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof, Compounds of formula (I) according to any of claims 4 and 55 [ka] .

[0076] Embodiment 57. The compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)methyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S ,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)2,5-di Azabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7, 8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pi rimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof, as in embodiments 1-4. 4, 50, 51, 52, 53, 54 or 55. [ka] .

[0077] Embodiment 58. A compound of formula (1b) according to any one of embodiments 1 to 43 or 45, or pharmaceutically acceptable salts thereof [ka] [Wherein 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-; R2 is part: [ka] and where: R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-C4) alkyl; R8 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-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 -C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo; R3 is unsubstituted or contains 1, 2, or 3 independently selected from halo and OH. is a (C1-C4) alkyl substituted with a substituent; x is 0 or 1; portion: [ka] is as described in embodiment 1, or in particular [ka] and y is 0 or 1; R5 is selected from CH3; Or, part: [ka] wherein two R5 substituents on adjacent carbon atoms are joined to form a ring C: [ka] (wherein ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring) The fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, wherein said R 40 teeth, · (C1~ C2) alkyl (wherein each (C 1~ C2) alkyl is independently a non-substituted or substituted by OH or 1, 2 or 3 halo), Halo, especially F, or where two R on the same ring carbon atom 40 Substituents are the groups to which they are attached. Together with the carbon atom (C 3~ C4) cycloalkyl spiro ring or 3- or 4-membered A heterocyclylspiro ring may be formed (wherein the heterocyclylspiro ring is a ring containing carbon ring atoms and one ring heteroatom selected from O, N and S; Or, two R on adjacent carbon atoms 40 Substituents are attached to the carbon together with the atoms to form a fused cyclopropyl ring selected from especially, [ka] and; R4 is CH3, [ka] ,especially [ka] ,especially [ka] is selected from where: R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted —O—(C1-C2)alkyl; R11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 13 is H, —S—CH 3 , halo, unsubstituted or 1, 2 or 3 halo substituted (C1-C2) alkyl substituted with a group; and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted O-(C1-C2) alkyl, and cyclopropyl.

[0078] Embodiment 59. The compound of formula (1b) according to any one of embodiments 1 to 43, 45, or 58. or a pharmaceutically acceptable salt thereof [ka] [In the formula, R1 is [ka] Selected from; R2 is [ka] Selected from; R3 is CH3; x is 0 or 1; R4 is -CH3, [ka] Selected from: [ka] teeth, [ka] and; y is 0 or 1; R5 is selected from CH3; Or part [ka] is].

[0079] Embodiment 60. A compound of formula (1c) according to any one of embodiments 1 to 43 or 46, or pharmaceutically acceptable salts thereof [ka] [Wherein R1 is [ka] 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 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 25is CHF2CH2-; R2 is the part [ka] and where: R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-C4) alkyl; 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 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; R3 is unsubstituted or contains 1, 2, or 3 independently selected from halo and OH. is a (C1-C4) alkyl substituted with a substituent; x is 0 or 1; portion: [ka] is as described in embodiment 1, or in particular [ka] and y is 0 or 1; R5 is selected from CH3; Or, here, the part: [ka] wherein two R5 substituents on adjacent carbon atoms are joined to form a ring C: [ka] (wherein ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring) The fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, wherein said R 40 teeth, · (C 1~ C2) alkyl (wherein each (C 1~ C2) alkyl is independently a non-substituted or substituted by OH or 1, 2 or 3 halo), Halo, especially F, or where two R on the same ring carbon atom 40 Substituents are the groups to which they are attached. Together with the carbon atom (C 3~ C4) cycloalkyl spiro ring or 3- or 4-membered A heterocyclylspiro ring may be formed (wherein the heterocyclylspiro ring is a ring containing carbon ring atoms and one ring heteroatom selected from O, N and S; Or, two R on adjacent carbon atoms 40 Substituents are attached to the carbon together with the atoms to form a fused cyclopropyl ring selected from); especially, [ka] and; R4 is CH3, [ka] ,especially, [ka] ,especially [ka] is selected from where: R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted —O—(C1-C2)alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 13 is H, —S—CH 3 , halo, unsubstituted or 1, 2 or 3 halo substituted (C1-C2) alkyl substituted with a group; and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted O-(C1-C2) alkyl, and cyclopropyl.

[0080] Embodiment 61. A compound of formula (Ic) according to any one of embodiments 1 to 43, 46, or 60. or a pharmaceutically acceptable salt thereof [ka] [In the formula, R1 is [ka] Selected from; R2 is [ka] Selected from; R3 is CH3; x is 0 or 1; R4 is -CH3, [ka] is selected from portion: [ka] teeth, [ka] and y is 0 or 1; R5 is selected from CH3; or where the part is [ka] is].

[0081] Embodiment 62. A compound of formula (1d) according to any one of embodiments 1 to 43 or 47, or pharmaceutically acceptable salts thereof [ka] [Wherein R1 is [ka] Selected from; R 15 is F; R 16 is R 25 (R 24 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-; R2 is the part [ka] and where: R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-C4) alkyl; R8 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-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), and —C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo; R3 is unsubstituted or contains 1, 2, or 3 independently selected from halo and OH. is a (C1-C4) alkyl substituted with a substituent; x is 0 or 1; portion: [ka] is as described in embodiment 1, or in particular [ka] and y is 0 or 1; R5 is selected from CH3; Or, here, the part: [ka] wherein two R5 substituents on adjacent carbon atoms are joined to form a ring C: [ka] (wherein ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring) The fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, wherein said R 40 teeth, · (C 1~ C2) alkyl (wherein each ( 1~ C2) alkyl is independently unsubstituted or substituted by OH or 1, 2 or 3 halo), Halo, especially F, or where two R on the same ring carbon atom 40 Substituents are the groups to which they are attached. Together with the carbon atom (C 3~ C4) cycloalkyl spiro ring or 3- or 4-membered A heterocyclylspiro ring may be formed (wherein the heterocyclylspiro ring is a ring containing carbon ring atoms and one ring heteroatom selected from O, N and S; Or, two R on adjacent carbon atoms 40 Substituents are attached to the carbon together with the atoms to form a fused cyclopropyl ring selected from especially, [ka] and; R4 is CH3, [ka] ,especially, [ka] ,especially [ka] is selected from where: R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted —O—(C1-C2)alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 13 is H, —S—CH 3 , halo, unsubstituted or 1, 2 or 3 halo substituted (C1-C2) alkyl substituted with a group; and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted O-(C1-C2) alkyl, and cyclopropyl.

[0082] Embodiment 63. A compound of formula (Id) according to any one of embodiments 1 to 43, 47, or 62. or a pharmaceutically acceptable salt thereof [ka] [In the formula, R1 is [ka] Selected from; R2 is [ka] Selected from; R3 is CH3; x is 0 or 1; R4 is -CH3, [ka] Selected from; portion: [ka] teeth, [ka] and y is 0 or 1; R5 is selected from CH3; or where the part is [ka] is].

[0083] Embodiment 64. A compound of formula (1e) according to any one of embodiments 1 to 43 or 48, or pharmaceutically acceptable salts thereof [ka] [Wherein 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 is CF3, CHF2CH2-, (H3C)3C-OC(O)-; R 24 is CH3; and R 25 is CHF2CH2-; R2 is part: [ka] and where: R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-C4) alkyl; R8 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-C4) alkyl; R9 is selected from H, O-CH3, OH, CN, CH3, and halo; R 28 is SF5, halo, C(O)H, unsubstituted or substituted with 1, 2 or 3 halo selected from substituted (C1-C4) alkyl, and —C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo; R3 is unsubstituted or contains 1, 2, or 3 independently selected from halo and OH. is a (C1-C4) alkyl substituted with a substituent; x is 0 or 1; portion: [ka] is as described in embodiment 1, or in particular [ka] and y is 0 or 1; R5 is selected from CH3; Or, part: [ka] wherein two R5 substituents on adjacent carbon atoms are joined to form a ring C: [ka] (wherein ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring) The fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, wherein said R 40 teeth, · (C 1~ C2) alkyl (wherein each (C 1~ C2) alkyl is independently a non-substituted or substituted by OH or 1, 2 or 3 halo), Halo, especially F, or where two R on the same ring carbon atom 40 Substituents are the groups to which they are attached. Together with the carbon atom (C 3~ C4) cycloalkyl spiro ring or 3- or 4-membered A heterocyclylspiro ring may be formed (wherein the heterocyclylspiro ring is a ring containing carbon ring atoms and one ring heteroatom selected from O, N and S; Or, two R on adjacent carbon atoms 40 Substituents are attached to the carbon together with the atoms to form a fused cyclopropyl ring selected from especially, [ka] and; R4 is CH3, [ka] ,especially, [ka] ,especially [ka] is selected from where: R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted —O—(C1-C2)alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 13 is H, —S—CH 3 , halo, unsubstituted or 1, 2 or 3 halo substituted (C1-C2) alkyl substituted with a group; and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted O-(C1-C2) alkyl, and cyclopropyl.

[0084] Embodiment 65. The compound of formula (1e) according to any one of embodiments 1 to 43, 48, or 64. or a pharmaceutically acceptable salt thereof [ka] [In the formula, R1 is [ka] Selected from; R2 is [ka] Selected from; R3 is CH3; x is 0 or 1; R4 is [ka] Selected from; portion: [ka] teeth, [ka] and y is 0 or 1; R5 is selected from CH3; or where the moiety is [ka] is].

[0085] Embodiment 66. A compound of formula (1f) according to any one of embodiments 1 to 43 or 49, or pharmaceutically acceptable salts thereof [ka] [Wherein R1 is [ka] Selected from; R 15 is F; R 16 teeth, 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-; R2 is part: [ka] and where: R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-C4) alkyl; R8 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-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; and R7 is selected from H and halo; R3 is unsubstituted or contains 1, 2, or 3 independently selected from halo and OH. is a (C1-C4) alkyl substituted with a substituent; x is 0 or 1; portion: [ka] is as described in embodiment 1, or in particular [ka] and y is 0 or 1; R5 is selected from CH3; Or, part: [ka] wherein two R5 substituents on adjacent carbon atoms are joined to form a ring C: [ka] (wherein ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring) The fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, wherein said R 40 teeth, · (C 1~C2) alkyl (wherein each (C 1~ C2) alkyl is independently a non-substituted or substituted by OH or 1, 2 or 3 halo), Halo, especially F, or where two R on the same ring carbon atom 40 Substituents are the groups to which they are attached. Together with the carbon atom (C 3~ C4) cycloalkyl spiro ring or 3- or 4-membered A heterocyclylspiro ring may be formed (wherein the heterocyclylspiro ring is a ring containing carbon ring atoms and one ring heteroatom selected from O, N and S; Or, two R on adjacent carbon atoms 40 Substituents are attached to the carbon together with the atoms to form a fused cyclopropyl ring (selected from especially, [ka] and; R4 is CH3, [ka] ,especially, [ka] ,especially [ka] is selected from where: R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted —O—(C1-C2)alkyl; R11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 13 is H, —S—CH 3 , halo, unsubstituted or 1, 2 or 3 halo substituted (C1-C2) alkyl substituted with a group; and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted O-(C1-C2) alkyl, and cyclopropyl.

[0086] Embodiment 67. The compound of formula (1f) according to any one of embodiments 1 to 43, 49, or 66. or a pharmaceutically acceptable salt thereof [ka] [In the formula, R1 is [ka] Selected from; R2 is [ka] Selected from; R3 is CH3; x is 0 or 1; R4 is -CH3, [ka] Selected from; portion: [ka] teeth, [ka] and y is 0 or 1; R5 is selected from CH3; or where the part is [ka] is].

[0087] Embodiment 68. The compound is [ka] A compound of formula (I) or a pharmaceutical composition thereof according to any one of embodiments 1 to 67, selected from Acceptable salts.

[0088] Embodiment 69. The compound contains the R4 moiety in a non-zwitterionic form. 10. A compound of formula (I) according to any one of the following or a pharmaceutically acceptable salt thereof:

[0089] Embodiment 70. The compound of any one of embodiments 1 to 68, wherein the R4 moiety is in zwitterionic form. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of the preceding claims.

[0090] Embodiment 71. The compound has an R4 moiety that is a mixture of zwitterionic and non-zwitterionic forms. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 68, comprising Acceptable salts.

[0091] Embodiment 72. The R4 moiety is shown below, wherein said R4 moiety is in a non-zwitterionic form ( d) or (e): [ka] 69. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 68, Acceptable salt.

[0092] Embodiment 73. The R4 moiety is shown below, wherein said R4 moiety is: [ka] 69. The compound of formula (I) according to any one of embodiments 1 to 68, which is present in a zwitterionic form selected from ) or a pharmaceutically acceptable salt thereof.

[0093] Embodiment 74. The R4 moiety is in the zwitterionic form (a) and (b) of embodiment 72. The compound of formula (I) or its derivatives according to any one of embodiments 1 to 68, which is present as a mixture. Pharmaceutically acceptable salts.

[0094] Embodiment 75. The R4 moiety is Non-zwitterionic form (e) and zwitterionic form (a) or (b) [ka] or Non-zwitterionic form (e) and zwitterionic forms (a) and (b) [ka] The compound of formula (I) or its derivatives according to any one of embodiments 1 to 74, wherein the compound is present as a mixture of A pharmaceutically acceptable salt of

[0095] Embodiment 76. The R4 moiety is in the zwitterionic form (c): [ka] 75. The compound of formula (I) according to any one of embodiments 1 to 74, or a pharmaceutically acceptable salt thereof, Salt that can be used.

[0096] Embodiment 77. The R4 moiety can be in the zwitterionic form (c) and in the non-zwitterionic form (d): [ka] The compound of formula (I) according to any one of embodiments 1 to 74, wherein the compound is present as a mixture of both or a pharmaceutically acceptable salt thereof.

[0097] Embodiment 78. The compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)methyl)- (R)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(phenyl)- -4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperane 1-(2 ... ,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide , Non-zwitterionic forms: [ka] or zwitterionic form: [ka] or zwitterionic form: [ka] or a mixture of any two or three of the above forms In any one of embodiments 1 to 44, 50, 51, 52, 53, 54, 55, or 56, A compound of formula (I) as described above.

[0098] Embodiment 79. The compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)methyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S ,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- Diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo 5,7, 8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pi of rimidine-9-carboxamide Non-zwitterionic forms: [ka] or zwitterionic form: [ka] or zwitterionic form: [ka] or a mixture of any two or three of the above forms In any one of embodiments 1 to 44, 50, 51, 52, 53, 54, 55, or 57, A compound of formula (I) as described above.

[0099] Embodiment 80. The compound of formula (I) according to any one of embodiments 1 to 79, in crystalline form. I) or a pharmaceutically acceptable salt thereof.

[0100] Embodiment 81. The compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)methyl)- (R)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(phenyl)- -4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperane 1-(2 ... ,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide 50, 51, 52, 53, 54, 55 or 56, or 78. A compound of formula (I) according to any one of claims 1 to 78.

[0101] Embodiment 82. The compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)methyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S ,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)2,5-di Azabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7, 8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pi Embodiments 1 to 44, 50, 51, 52, which are crystalline forms of rimidine-9-carboxamide , 53, 54, 55 or 57 or 79.

[0102] Embodiment 83. Any of Embodiments 80-82, wherein the compound is in substantially pure form. A compound of formula (I) according to the formula (I).

[0103] Embodiment 84. The crystalline form of embodiment 81 has a pH of 8.6±0.2, 11.2, or 12.5 at a temperature of about 22° C. ±0.2, 13.0±0.2, 14.9±0.2, 15.5±0.2, 17.9±0.2 , 19.4±0.2, 22.0±0.2, 24.3±0.2, 26.0±0.2, 28. Four or more selected from the group consisting of 2±0.2, 29.1±0.2, and 29.7±0.2 characterized by a powder X-ray diffraction pattern comprising 2θ values ​​of The crystalline form of embodiment 82 has a pH of 5.77±0.2, 6.6 at a temperature of about 22°C. 7±0.2, 10.54±0.2, 12.36±0.2, 12.90±0.2, 13.0 2±0.2, 14.83±0.2, 15.27±0.2, 15.65±0.2, 15.9 9±0.2, 17.34±0.2, 18.52±0.2, 19.18±0.2, 20.0 4±0.2, 21.17±0.2, 21.47±0.2, 21.86±0.2, 22.9 Four or more selected from the group consisting of 23.6±0.2, 23.18±0.2, and 23.9±0.2 characterized by a powder X-ray diffraction pattern comprising 2θ values ​​above, A compound of formula (I) as described in embodiment 1.

[0104] Embodiment 85. The crystalline form of embodiment 81 has a pH of 8.6±0.2, 11.2, or 12.5 at a temperature of about 22° C. ±0.2, 13.0±0.2, 14.9±0.2, 15.5±0.2, 17.9±0.2 , 19.4±0.2, 22.0±0.2, 24.3±0.2, 26.0±0.2, 28. Five or more selected from the group consisting of 2±0.2, 29.1±0.2, and 29.7±0.2 characterized by a powder X-ray diffraction pattern comprising 2θ values ​​of The crystalline form of embodiment 82 has a pH of 5.77±0.2, 6.6 at a temperature of about 22°C. 7±0.2, 10.54±0.2, 12.36±0.2, 12.90±0.2, 13.0 2±0.2, 14.83±0.2, 15.27±0.2, 15.65±0.2, 15.9 9±0.2, 17.34±0.2, 18.52±0.2, 19.18±0.2, 20.0 4±0.2, 21.17±0.2, 21.47±0.2, 21.86±0.2, 22.9 Five or more selected from the group consisting of 23.6±0.2, 23.18±0.2, and 23.9±0.2 characterized by a powder X-ray diffraction pattern comprising 2θ values ​​above, A compound of formula (I) as described in embodiment 1.

[0105] Embodiment 86. The crystalline form of embodiment 81 has a powder X-ray diffraction pattern substantially identical to that shown in FIG. It is characterized by the same X-ray diffraction pattern, The crystalline form of embodiment 82 has an X-ray powder diffraction pattern substantially the same as that shown in FIG. characterized by a diffraction pattern, A compound of formula (I) as described in embodiment 1.

[0106] Embodiment 87. Any of embodiments 1 to 79 and 83, wherein the compound is in amorphous form. A compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0107] Embodiment 88. The compound of any one of embodiments 1 to 83, wherein the compound is a sodium salt. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0108] In one embodiment, when R 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 are independently unsubstituted or substituted only with halo, and in particular are independently unsubstituted or is substituted with one F substituent; Preferably, the R1 ring is connected to the rest of the molecule via the R1 ring nitrogen atom or an adjacent is linked via an R1 ring carbon atom that is double bonded to an R1 ring atom; There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof: In particular, 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 said cycloalkenyl or halo-substituted cycloalkenyl is 0 , 1 or 2 R 15Is substituted by a substituent, Alternatively, R1 is heterocyclyl, wherein said heterocyclyl is and one or two 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 The group is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2, R 33 where R 33 is halo, and the heterocyclyl or halo-substituted hetero Tetracyclyl can be independently R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 or substituted by 0, 1 or 2 substituents selected from 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 does not exceed 1, and the total number of ring O atoms does not exceed 1, wherein said heteroaryl is Substitution or R 21 and R 30 one, two or three substituents independently selected from where R 21 and R 30 is halo and (C1-C4) alkyl wherein said (C1-C4) alkyl is unsubstituted or substituted with 1, 2 or 3 halo; 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~ C4) A Rukill-O-, unsubstituted or OH, —O—(C1-C2) alkyl or 1, 2 or 3 (C1-C4) alkyl substituted with one halo; 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 are connected to the rest of the molecule through an atom, and each is unsubstituted or one or substituted with two Fs), R 25 (R 24 )N-(where R 24 is H or unsubstituted or 1, 2 or is (C1-C4) alkyl substituted with at most three halo groups, and R 25 is H or unsubstituted or (C1-C4) alkyl substituted with 1, 2 or 3 halo. OH is selected from Here, n is 0, 1 or 2.

[0109] More particularly, R1 is cycloalkenyl, wherein the cycloalkenyl has 5 or 6 ring carbon atoms; and a partially unsaturated monocyclic ring containing 1 or 2 R 33 where R 33 is halo, preferably F wherein the cycloalkenyl or halo-substituted cycloalkenyl is 0 or 1 R 15 substituent, preference Preferably, it is substituted with one substituent, where R 15 teeth, h) unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C2) A Rukill-O-, i) (C1-C2) alkyl groups unsubstituted or substituted with 1, 2 or 3 halo groups Rukill-O-, 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 (C1-C2) alkyl substituted with 3 halo, R 25 Is H or non-placed or (C1-C2) alkyl substituted with 1, 2, or 3 halo. is selected from n is 0 or 1, where: R of the cycloalkenyl or halo-substituted cycloalkenyl 15 Substituents a) to g) are , the ring in which the cycloalkenyl or halo-substituted cycloalkenyl is attached to the rest of the molecule is not present on an atom adjacent to said cycloalkenyl or halo-substituted cycloalkenyl. A methylalkenyl has one R in the ring para position relative to the rest of the molecule. 15 6-membered with substituents is a ring; and The cycloalkenyl or halo-substituted cycloalkenyl is preferably a cycloalkenyl having an adjacent R ring carbon atom. is connected to the remainder of the compound via an R1 ring carbon atom that is double bonded to 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 Ha halo and preferably F, wherein 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 or substituted by one substituent, wherein R 15 , R 16 , R 17 , R1 8. R 19 , R 20 , R 22 and R 23 is, independently, i) unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C4) A Rukill-O-, j) unsubstituted or OH, —O—(C1-C2) alkyl or 1, 2 or 3 Substituted with halos (C1-C 4)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-, H(where R 24 is H or unsubstituted or 1, 2 or (C1-C2) alkyl substituted with 3 halo, R 25 Is H or non-placed or (C1-C2) alkyl substituted with 1, 2, or 3 halo. , p)OH is selected from where n is 0 or 1, where: The substituents a) to h) of the heterocyclyl or halo-substituted heterocyclyl are No halo-substituted heterocyclyl or halo-substituted heterocyclyl is present on the ring atom that is attached to the remainder of the molecule. Preferably, when the heterocyclyl or halo-substituted heterocyclyl is a 6-membered ring, It is in the meta or para position, preferably the para position, relative to the rest of the molecule, selected from a) to h). has 0 or 1 substituent selected from the group consisting of: The heterocyclyl may be attached to the remainder of the compound via the R1 ring nitrogen atom or the adjacent ring is linked via an R1 ring carbon atom that is double bonded to the atom; Alternatively, R1 is heteroaryl, wherein said heteroaryl is a ring carbon atom and 1 or 2 ring heteroatoms independently selected from N, O and S, preferably 5 including N or a 6-membered fully unsaturated monocyclic group, wherein the total number of ring S atoms does not exceed 1 and the number of ring O atoms is the total number does not exceed 1, wherein said heteroaryl is unsubstituted or R 21 and R 30 and wherein R2 is substituted by one or two substituents independently selected from 1 and R 30 are independently selected from (C1-C2) alkyl, The alkyl is unsubstituted or substituted with 1, 2 or 3 halo, wherein preferably Alternatively, the alkyl or haloalkyl substituent may be a heteroaryl group that is bonded to the remainder of the molecule. is not present on the R1 ring atom adjacent to the R1 ring atom to which it is bonded, and more preferably, is When the ring is six-membered, the alkyl or haloalkyl substituent is in the ring para position relative to the rest of the molecule. is located.

[0110] 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 each unsubstituted or substituted by 1 or 2 F; 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. substituted (C1-C2) alkyl; R 17 is a halo; R 18 is a halo; R19 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 groups unsubstituted or substituted with 1, 2 or 3 halo groups Rukill-O-, 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.

[0111] In certain embodiments, 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 23are CF3, CHF2CH2-, (H3C)3C-OC(O)-; R 24 is CH3; and R 25 is CHF2CH2-.

[0112] In another embodiment, R1 is [ka] ,especially, [ka] ,especially, [ka] , more particularly, [ka] is selected from.

[0113] In another embodiment, R2 is the moiety: [ka] and; R6 is H, Hello, (C1-C4) alkyl groups unsubstituted or substituted with 1, 2 or 3 halo groups Lukil, (C3-C5) cyclohexyl methyl ether unsubstituted or substituted with 1, 2 or 3 halo groups chloroalkyl, -O-(C1-C2) unsubstituted or substituted with 1, 2 or 3 halo 4) alkyl, 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, · Halo; (C1-C4) alkyl groups unsubstituted or substituted with 1, 2 or 3 halo groups Lukil, · (C1-C4)alkynyl; (C1-C4) alkenyl, (C3-C5) cyclohexyl methyl ether unsubstituted or substituted with 1, 2 or 3 halo groups chloroalkyl, and Selected from OCF3; X is selected from C-R7 and N, where R7 is H or halo; There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0114] In particular, R2 is the part: [ka] and where: R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-C4) alkyl; 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 is SF5, halo, C(O)H, and unsubstituted or substituted with 1, 2 or 3 halo groups. (C1-C4) alkyl substituted with ; X is selected from C-R7 and N; and R7 is selected from H and halo.

[0115] 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.

[0116] In one embodiment, the moiety: [ka] teeth, [ka] ,especially [ka] , more particularly [ka] ,especially [ka] is selected from.

[0117] In another embodiment, compounds of formula (I) or pharmaceutical compositions thereof, wherein x is 0 or 1, in particular 1. Acceptable salts are provided.

[0118] In another embodiment, R3 is unsubstituted or independently selected from halo and OH. (C1-C4) alkyl substituted with 1, 2 or 3 substituents, especially R3 is unsubstituted or substituted with 1, 2 or 3 independently selected from halo and OH; R3 is a (C1-C2) alkyl substituted with a group, preferably R3 is a —CH2CH3 or CH3, more preferably CH3, Acceptable salts are provided.

[0119] In another embodiment, R3 is selected from the group consisting of formula 1i: [ka] It is located at the position shown in.

[0120] In another embodiment, Y is N; [ka] is Y linked by a single bond, in particular [ka] is K connected by a single bond, and K is -CH2-, -CH2CH2-, - NH-, and (5-membered ring: [ka] A is selected from the group consisting of -C(O)-, -S(O)-, ... -S(O)2-, and [ka] The compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the linker is selected from More particularly, [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.

[0121] In one embodiment, A is selected from the group consisting of -C(O)- and S(O)2-, preferably -C(O)-. is the linker of choice.

[0122] In one embodiment, a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof is and an acceptable salt thereof, wherein the compound of formula (I) has the formula (I'): [ka] When the compound of formula (I) has the stereochemistry shown in formula (I"): [ka] In the case where the compound is a compound of formula (I"'), said compound is in particular a compound of formula (I"'): [ka] It has the stereochemistry:

[0123] In another embodiment, R5 is independently -(C 1~ C4) alkyl, preferably methyl; where two R5 substituents on the same ring carbon atom are Together with 3~ C4) cycloalkylspiro ring or 3- or 4-membered heterocycle may form a heterocyclylspiro ring, wherein the heterocyclylspiro ring is and one ring heteroatom selected from O, N and S), · [ka] When K is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom are bonded to form ring C. May be formed: [ka] Here, ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring, a fused (C3-C6) heterocyclyl ring or fused phenyl ring, C6) A heterocyclyl ring has ring carbon atoms and one ring heteroatom selected from O, N, and S. and When ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring, The fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, wherein said R 40 teeth, · (C 1~ C2) alkyl (wherein each (C 1~ C2) alkyl is independently non- substituted or substituted with OH or 1, 2 or 3 halo; Halo, especially F, or where two R on the same ring carbon atom 40 The substituents are Together with the carbon atom present, (C 3~ C4) cycloalkyl spiro ring or 3 or 4 may form a membered heterocyclyl spiro ring, wherein said heterocyclyl spiro ring is containing ring carbon atoms and one ring heteroatom selected from O, N, and S; Or, two R on adjacent carbon atoms 40 The substituents are attached to the carbon atoms to which they are attached. Together with the atom, forms a fused cyclopropyl ring Selected from: and wherein when K is -CH2- and J is N, the two R5 substituents are bonded. may form a (C1-C3) alkylene bridge or a heteroalkylene bridge (wherein wherein the heteroalkylene bridge is one heteroatom selected from N and O; or is -CH2-O-CH2-) or a pharmaceutically acceptable salt thereof.

[0124] In particular, R5 can independently -(C 1~ C4) alkyl, preferably methyl; · [ka] When K is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom are bonded to form ring C. May be formed: [ka] wherein ring C is a fused (C3-C6) cycloalkyl ring, in particular a fused cyclobutyl ring, or a fused (C3-C6) heterocyclyl ring, wherein said fused (C3-C6) heterocyclyl The alkyl ring contains ring carbon atoms and one ring heteroatom selected from O, N, and S. , When ring C is a fused (C3-C6) cycloalkyl ring, particularly a fused cyclobutyl ring, The fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, wherein said R 40 teeth, · (C 1~ C2) alkyl (wherein each (C 1~ C2) alkyl is independently non- substituted or substituted with OH or 1, 2 or 3 halo; Halo, especially F, or where two R on the same ring carbon atom 40 The substituents are Together with the carbon atom present, (C 3~ C4) cycloalkyl spiro ring or 3 or 4 may form a membered heterocyclyl spiro ring, wherein said heterocyclyl spiro ring is containing ring carbon atoms and one ring heteroatom selected from O, N, and S; Or, two R on adjacent carbon atoms 40 Substituents are attached to the carbon together with the atoms to form a fused cyclopropyl ring Selected from: and wherein when K is -CH2- and J is N, the two R5 substituents are bonded. may form a (C1-C3) alkylene bridge or a heteroalkylene bridge (wherein wherein the heteroalkylene bridge is one heteroatom selected from N and O; or is -CH2-O-CH2-) is selected from.

[0125] More particularly, R5 is independently · (C 1~ C2) alkyl, preferably methyl, and · [ka] When K is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom are bonded to form ring C. May be formed: [ka] Here, ring C is a fused (C3-C4) cycloalkyl ring, particularly a fused cyclobutyl ring. and the fused (C3-C4) cycloalkyl ring, particularly the fused cyclobutyl ring, is unsubstituted. or one or two R as described in embodiment 28. 40 substituted with a group is selected from.

[0126] In one embodiment, y is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0127] In a preferred embodiment, R5 is independently CH3, y is 1 or 2, and · [ka] When K is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom are bonded to form ring C. May be formed: [ka] wherein ring C is a fused cyclobutyl ring is selected from.

[0128] In another embodiment, the compound of formula (I) comprises the moiety: [ka] , especially A: [ka] , more particularly [ka] or C: [ka] or wherein the linker -C(O)- can be replaced by the alternative linker -S(O)-, -S (O))2-, and the compound according to claim 1 [ka] has been replaced by

[0129] In another embodiment, R4 is independently -(C1-C4) alkyl, - heteroaryl1, wherein said heteroaryl1 is selected from the group consisting of ring carbon atoms and N, O and S; and 1, 2, 3 or 4 ring heteroatoms independently selected from the group consisting of 5- or 6-membered fully unsaturated alkylenes. a monocyclic ring, the total number of ring S atoms not exceeding 1, and the total number of ring O atoms not exceeding 1); - heteroaryl2, wherein said heteroaryl2 is selected from the group consisting of ring carbon atoms and N, O and S; and 1, 2, 3 or 4 ring heteroatoms independently selected from cyclic rings, both rings being fully unsaturated, or one ring being fully unsaturated and the other saturated; The heteroatoms may be present in one or both rings, and the ring S atoms does not exceed 1, the total number of ring O atoms does not exceed 1, and in particular, the ring connecting it to the rest is fully unsaturated); -phenyl Selected from; Here, heteroaryl 1, heteroaryl 2, and phenyl are each R 10 , R 11 , R 12 , R 13 and R 14 and substituted by 1, 2 or 3 substituents independently selected from where each R 10 , R 11 , R 12 , R 13 and R 14 is, independently, H, Hello, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C 4) alkyl, -O-(C1-C2) alkyl or (C1-C2) alkyl substituted by OH Lukil, -S-(C1-C3) alkyl, -O-(C 1-C4) alkyl, · OH, (C3-C5)cycloalkyl (wherein the (C3-C5)cycloalkyl is a substituted or substituted with 1 or 2 halo), -O-(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent o H, (C1-C4) alkyl, wherein said (C1-C4) alkyl is unsubstituted; or substituted with OH or —O(C1-C2)alkyl), o and where R 34 and R 35 together with the atoms to which they are attached. can form an azetidine, pyrrolidinyl or piperidine ring, Zetidine, pyrrolidinyl and piperidine are unsubstituted or substituted with CH3 selected from CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, =O, -C(O)H, and -C(O)(C1-C4) alkyl Selected from; However, one OH substituent is present on heteroaryl 1, heteroaryl 2, and phenyl. and the remaining R 10 , R 11 , R 12 , R 13 and R 14 is as defined herein In particular, - one OH substituent is present on heteroaryl 1, heteroaryl 2 and phenyl; , the OH is in the ortho position of the R4 ring relative to the position connecting R4 to the linker-A-; , or - one =O substituent is present on Heteroaryl1 and Heteroaryl2, Remaining R 10 , R 11 , R 12 , R 13 and R 14 is defined as herein There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0130] In certain embodiments, R4 is -(C1-C4) alkyl, especially -CH3; -heteroaryl 1; and -heteroaryl2; -phenyl Selected from; Here, heteroaryl 1, heteroaryl 2, and phenyl are each R 10 , R 11 , R 12 , R 13 and R 14 and substituted by 1, 2 or 3 substituents independently selected from where each R 10 , R 11 , R 12 , R 13 and R 14 OH, =O, independently selected from H, F, Cl, and CH3; - one OH substituent is present on heteroaryl 1, heteroaryl 2 and phenyl; wherein said OH is in the ortho position of the R4 ring relative to the position connecting R4 to the linker-A-; the remaining substituents are selected from H, F, Cl and CH3; or - one =O substituent is present on Heteroaryl 1 and Heteroaryl 2, the remaining substituents are The substituents are selected from H, F, Cl and CH3.

[0131] More particularly, R4 is selected from CH3, heteroaryl1 and heteroaryl2; The substituents are as defined above. In particular, said heteroaryl 1 is a heteroaryl group consisting of ring carbon atoms and Preferably, Heteroaryl 1 is pyridyl or pyridyl. It's Mijinil.

[0132] In one embodiment, R4 is -(C1-C4) alkyl, especially -CH3; [ka] is selected from where: R 10 , R 11 , R 12 , R 13 and R 14 is, independently, H, Hello, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C 4) alkyl, -O-(C1-C2) alkyl or (C1-C2) alkyl substituted by OH Lukil, -S-(C1-C3) alkyl, -O-(C 1-C4) alkyl, (C3-C5)cycloalkyl (wherein the (C3-C5)cycloalkyl is a substituted or substituted with 1 or 2 halo), -O-(C3-C5)cycloalkyl, -NR 34 R35 (where R 34 and R 35 is independent o H, (C1-C4) alkyl, wherein said (C1-C4) alkyl is unsubstituted; or substituted with OH or —O(C1-C2)alkyl), o and where R 34 and R 35 together with the atoms to which they are attached. can form an azetidine, pyrrolidinyl or piperidine ring, 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 is selected from.

[0133] Preferably, R4 is [ka] is selected from where: R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents -substituted -O-(C1-C2)alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 13 is H, —S—CH 3 , halo, unsubstituted or 1, 2 or 3 halo substituted (C1-C2) alkyl substituted with a group; and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted O-(C1-C2)alkyl, and cyclopropyl;

[0134] In particular, R4 is [ka] is selected from where: R 10 is selected from H, F, Cl, CH3 and OCF3; R 11 is selected from H, F, Cl and CH3; R 12 is selected from H, F, Cl and CH3; R 13 is selected from H, F, Cl, —S—CH and CH; and R 14 is H, F, Cl, -CH3, -CH2CH3, cyclopropyl, -OCHF2, Selected from OCF3. In particular, R 10 , R 11 and R 12 At least one substituent of is H. In particular, R 13 and R 14 At least one substituent of is H.

[0135] In another embodiment, R4 is -CH3, [ka] In particular, -CH3, [ka] is selected from.

[0136] Preferably, R4 is [ka] ,especially [ka] is selected from.

[0137] In other embodiments, formula (I) is Formula 1a: [ka] (In particular, 1a is 1a': [ka] ), or formula 1b: [ka] (In particular, 1b is 1b': [ka] ), or formula 1c: [ka] (In particular, 1c is 1c': [ka] ), or formula 1d: [ka] (In particular, 1d is 1d': [ka] ), or formula 1e: [ka] (In particular, 1e is 1e': [ka] ), or formula 1f: [ka] (In particular, 1f is 1f': [ka] ), or formula 1g: [ka] (In particular, 1g is 1g': [ka] ), or formula 1h: [ka] (Especially, 1h is 1h': [ka] is) or a pharmaceutically acceptable salt thereof.

[0138] In one embodiment, the compound of formula (I), particularly formula (I') [ka] especially, [ka] (More specifically, I"': [ka] ) or a pharmaceutically acceptable salt thereof, where: R, M, W, L, V and T are independently selected from C, CH and N; Sub-formulae 1a, 1b, 1c, 1d, 1e and 1f, particularly 1a' as shown herein , 1b', 1c', 1d', 1e' and 1f', especially 1a', more especially as described herein forming 1h' or 1g' as follows; A is a linker that is -C(O)-; Y is N, C or CH; [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, Y is a carbon atom that is unsubstituted or substituted by OH or F. can be; If Y is N, [ka] is a single bond; [ka] means that K is connected to the adjacent 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)- Is it; or [ka] When is a single bond, K is -CH2-, -CH2CH2-, -NH- and (5-membered ring: [ka] wherein J is N and A is -C(O)-. Yes (in particular, K is -CH2- and J is N); y is 0, 1, 2, 3 or 4; R5 is independent of -(C 1~ C4) alkyl, -(C 3~ C5) cycloalkyl, where two R5 substituents on the same ring carbon atom are Together with 3~ C4) cycloalkylspiro ring or 3- or 4-membered heterocycle may form a heterocyclylspiro ring, wherein the heterocyclylspiro ring is and one ring heteroatom selected from O, N and S), · [ka] When K is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom are bonded to form a ring C. You may also: [ka] wherein ring C is a fused (C3-C6) cycloalkyl ring (preferably cyclobutyl), a fused (C3-C6) heterocyclyl ring or a fused phenyl ring, 3-C6) Heterocyclyl rings are ring carbon atoms and one ring atom selected from O, N, and S. containing a heteroatom, When ring C is a fused (C3-C6) cycloalkyl ring, the fused (C3-C6) cycloalkyl ring The alkyl ring is unsubstituted or has one or two R 40 is substituted with a group, And the above R 40 teeth, · (C 1~ C2) alkyl (wherein each (C 1~ C2) alkyl is independently non- substituted or substituted with OH or 1, 2 or 3 halo; Halo, especially F, or where two R on the same ring carbon atom 40 The substituents are Together with the carbon atom present, (C 3~ C4) cycloalkyl spiro ring or 3 or 4 may form a membered heterocyclyl spiro ring, wherein said heterocyclyl spiro ring is containing ring carbon atoms and one ring heteroatom selected from O, N, and S; Or, two R on adjacent carbon atoms 40 The substituents are attached to the carbon atoms to which they are attached. Together with the atom, forms a fused cyclopropyl ring Selected from: where K is -CH2- and J is N, the two R5 substituents are linked to form (C 1-C3) alkylene bridge or heteroalkylene bridge may be formed (wherein The heteroalkylene bridge is one heteroatom selected from N and O, or -CH 2-O-CH2-) Selected from; 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 is replaced by , R33 is halo, and said cycloalkenyl or halo-substituted cycloalkenyl is 0, 1 or more. Or two R 15 Is substituted by a substituent, Alternatively, R1 is heterocyclyl, wherein said heterocyclyl is and one or two 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 1, 2, 3 or 4, preferably 1 or 2, R 33 Place where R 33 is halo, and said heterocyclyl or halo-substituted heterocyclyl Krill is independently 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 or substituted by 0, 1 or 2 substituents selected from 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. Has it been replaced? 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 two ring heteroatoms, and preferably a 5- or 6-membered fully unsaturated monocyclic group containing the total number of S atoms does not exceed 1, the total number of ring O atoms does not exceed 1, The heteroaryl is unsubstituted or R 21 and R 30 1 independently selected from , substituted by 2 or 3 substituents, where R 21 and R 30 is independent and selected from halo and (C1-C4) alkyl, wherein the (C1-C4) alkyl is The halides may be unsubstituted or substituted by 1, 2 or 3 halides; Alternatively, R1 is phenyl, wherein said phenyl is unsubstituted or has 1, 2, 3 or four, preferably one or two R 33 where R 33 teeth halo, and said phenyl or halo-substituted phenyl is selected from 0, 1 or 2 R 15 Substituted with a substituent It has been; 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) A Rukill-O-, unsubstituted or OH, —O—(C1-C2) alkyl or 1, 2 or 3 (C1-C4) alkyl substituted with one halo; 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 are connected to the rest of the molecule through an atom, and each is unsubstituted or one or substituted with two Fs), R 25 (R 24 )N-(where R 24 is H or unsubstituted or 1, 2 or is (C1-C4) alkyl substituted with at most three halo groups, and R 25 is H or unsubstituted or (C1-C4) alkyl substituted with 1, 2 or 3 halo. OH is selected from where n is 0, 1 or 2; However, 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 are independently unsubstituted or substituted only with halo, and particularly are independently unsubstituted or substituted only with halo. is substituted or substituted with one F substituent, and The R1 ring is connected to the rest of the molecule by an R1 ring nitrogen atom or an adjacent R1 ring atom. linked via a double-bonded R1 ring carbon atom; R2 is the part [ka] and; R6 is H, Hello, (C1-C4) alkyl groups unsubstituted or substituted with 1, 2 or 3 halo groups Rukill-O-, (C3-C5) cyclohexyl methyl ether unsubstituted or substituted with 1, 2 or 3 halo groups chloroalkyl, -O-(C1-C2) unsubstituted or substituted with 1, 2 or 3 halo 4) alkyl, 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, · Halo; (C1-C4) alkyl groups unsubstituted or substituted with 1, 2 or 3 halo groups Lukil, · (C1-C4)alkynyl; (C1-C4) alkenyl, (C3-C5) cyclohexyl methyl ether unsubstituted or substituted with 1, 2 or 3 halo groups chloroalkyl, and Selected from OCF3; 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 Halo, and unsubstituted or containing 1, 2 or 3 substituents independently selected from halo and OH (C1-C4) alkyl substituted with a substituent; Or, two R3 substituents on the same ring carbon atom are incompatible with the carbon atom to which they are attached. may be taken together to form a cyclopropyl ring Selected from; x is 0, 1 or 2; R4 is -(C1-C4) alkyl, Heteroaryl 1, wherein said heteroaryl 1 is a heteroaryl consisting of ring carbon atoms and N, O and S. and 1, 2, 3, or 4 independently selected ring heteroatoms. is a monocyclic ring; heteroaryl2, wherein said heteroaryl2 is a heteroaryl consisting of ring carbon atoms and N, O and S; and 9- or 10-membered fused bicyclic rings containing 1, 2, 3, or 4 independently selected ring heteroatoms. rings, both rings being fully unsaturated, or one ring being fully unsaturated and the other being saturated. is saturated or partially unsaturated, and heteroatoms may be in one or both rings; -phenyl Selected from; Here, heteroaryl 1, heteroaryl 2, and phenyl are each R 10 , R 11 , R 12 , R 13 and R 14 and substituted by 1, 2 or 3 substituents independently selected from where each R 10 , R 11 , R12 , R 13 and R 14 teeth, H, Hello, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C 4) alkyl, -O-(C1-C2) alkyl or (C1-C2) alkyl substituted by OH Lukil, -S-(C1-C3) alkyl, -O-(C 1-C4) alkyl, · OH, (C3-C5)cycloalkyl (wherein the (C3-C5)cycloalkyl is a substituted or substituted with 1 or 2 halo), -O-(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent o H, (C1-C4) alkyl, wherein said (C1-C4) alkyl is unsubstituted; or substituted with OH or —O(C1-C2)alkyl), o and where R 34 and R 35 together with the atoms to which they are attached. can form an azetidine, pyrrolidinyl or piperidine ring, Zetidine, pyrrolidinyl and piperidine are unsubstituted or substituted with CH3 selected from CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, =O, -C(O)H, and -C(O)(C1-C4) alkyl Selected from; however, - one OH substituent is present on heteroaryl 1, heteroaryl 2 and phenyl; , the OH is in the ortho position of the R4 ring relative to the position connecting R4 to the linker-A-; , or - one =O substituent is present on Heteroaryl1 and Heteroaryl2, Remaining R 10 , R 11 , R 12 , R 13 and R 14 is defined as herein; * indicates the point of attachment. Particular embodiments of the compounds of formula (I), particularly formula (I') or (I"'), Embodiments are described herein.

[0139] In one embodiment, there is provided a compound of formula (1g) or a pharmaceutically acceptable salt thereof: [ka] Here, 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-; R2 is part: [ka] and where: R6 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C 1-C4) alkyl; 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 is SF5, halo, unsubstituted or substituted with 1, 2 or 3 halo selected from (C1-C4)alkyl and C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo; R3 is unsubstituted or contains 1, 2, or 3 independently selected from halo and OH. is a (C1-C4) alkyl substituted with a substituent; x is 0 or 1; Y is CH or N, in particular N; y is 0, 1 or 2; R5 is selected from CH3; Or, part: [ka] In the formula (I), two R5 substituents on adjacent carbon atoms are linked to form ring C: [ka] Forming wherein ring C is a fused (C3-C6) cycloalkyl ring, in particular a fused cyclobutyl ring; wherein the fused (C3-C6) cycloalkyl ring is unsubstituted or has one or two R 40 group, wherein said R 40 teeth, · (C 1~ C2) alkyl (wherein each (C 1~ C2) alkyl is independently a non-substituted or substituted by OH or 1, 2 or 3 halo), Halo, especially F, or where two R on the same ring carbon atom 40 Substituents are the groups to which they are attached. Together with the carbon atom (C 3~ C4) cycloalkyl spiro ring or 3- or 4-membered A heterocyclylspiro ring may be formed (wherein the heterocyclylspiro ring is a ring containing carbon ring atoms and one ring heteroatom selected from O, N and S; Or, two R on adjacent carbon atoms 40 Substituents are attached to the carbon together with the atoms to form a fused cyclopropyl ring is selected from In particular, ring C is [ka] and; R4 is CH3, [ka] ,especially, [ka] ,especially, [ka] is selected from where: R 10 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted —O—(C1-C2)alkyl; R 11 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 12 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents selected from (C1-C2) alkyl; R 13 is H, —S—CH 3 , halo, unsubstituted or 1, 2 or 3 halo substituted (C1-C2) alkyl substituted with a group; and R 14 is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents (C1-C2) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents substituted O-(C1-C2) alkyl, and cyclopropyl.

[0140] In particular, R 1、 R2, R3, x, R5, y, Y and R4 are as described in the embodiments herein. As stated.

[0141] In another embodiment, there is provided a compound of formula (1h) or a pharmaceutically acceptable salt thereof: [ka] where: R1 is [ka] Selected from; R2 is [ka] Selected from; R3 is CH3; x is 0 or 1; R4 is -CH3, [ka] Selected from; y is 0 or 1; R5 is selected from CH3; or part: [ka] teeth, [ka] is.

[0142] In particular, R 1、 R2, R3, x, R5, y and R4 are as described in the embodiments herein. This is true.

[0143] Intermediate compounds used in the chemical synthesis of compounds of formula (I) described herein or their Salt is also provided.

[0144] In another aspect, the process or steps in the synthesis of compounds of formula (I) described herein Process steps are provided.

[0145] For example, in one embodiment of the present invention, Formula FN2: [ka] An intermediate compound of the formula: (wherein Y, R1, R2, R3, x, R5 and y) is provided.

[0146] For example, intermediate compound N2: [ka] .

[0147] In another embodiment of the present invention, a compound of formula FM: [ka] wherein Y, R1, R2, R3, x, R5, and y are as defined herein; PG is any suitable protecting group, including BOC (tert-butyloxycarbonyl) ) provides an intermediate compound of formula: Suitable such protecting groups are known to those skilled in the art.

[0148] For example, intermediate compounds M1, M2, M3, M4 or QPG: [ka] is provided.

[0149] In another embodiment of the present invention, a compound of formula FL: [ka] wherein Y, R3, x, R5, and y are as defined herein; and Z' is O PG is an intermediate compound of Boc(te The protecting group may be any suitable protecting group, including rt-butyloxycarbonyl. Protecting groups are known to those skilled in the art.

[0150] For example, intermediate compound L: [ka] is provided.

[0151] In another embodiment of the present invention, a compound of the formula: [ka] wherein Y, R, R, x, R, and y are as defined herein; and Z' is OH or OC(CH3)3, Z" is H or PG, where PG is any suitable protecting group, including Boc (tert-butyloxycarbonyl) Suitable protecting groups are known to those skilled in the art.

[0152] For example, the intermediate compound LB: [ka] Or intermediate Q4: [ka] Or intermediate Q5: [ka] is provided.

[0153] In another embodiment, the intermediate compound U: [ka] is provided.

[0154] In another embodiment of the present invention, the formula FQ: [ka] wherein R, R and x are as defined herein; Z' is OH or O An intermediate compound of formula (I) is provided.

[0155] For example, intermediate compounds Q3.1, Q3.2, Q3.3 or Q3.4 [ka] In a further aspect, the present invention provides a method for treating a cancer cell comprising administering to a patient a cancer-causing agent as claimed or described herein. This is true.

[0156] formulation In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof, and an acceptable carrier. In a further embodiment, the composition comprises The pharmaceutical composition contains at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical compositions may be administered orally, parenterally (e.g., by injection, infusion, transdermally, or topically), and The composition may be formulated for a specific route of administration, such as rectal administration. Topical administration may be by inhalation or intranasal application. The pharmaceutical compositions of the present invention may also be used in solid dosage forms (such as, but not limited to, capsules). tablets, pills, granules, powders, or suppositories), or liquid formulations (for example, but not limited to, Tablets may be formulated using methods known in the art. They may be film coated or enteric coated according to the The pharmaceutical composition is a tablet or gelatin tablet 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 also c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth Cantho, methylcellulose, sodium carboxymethylcellulose, and / or polyvinyl alcohol diethylpyrrolidone; if necessary, 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.

[0157] 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).

[0158] 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,pages 234-246).

[0159] 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.

[0160] A compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, and one or more Also provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0161] 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.

[0162] In another aspect of the invention, research chemicals, such as thiazol-1, ... As a molecular compound or chemical probe, a compound of formula (I) or a salt thereof as described herein is provided. In another embodiment, the compounds of formula (I) or salts thereof as described herein, particularly W Research chemicals, e.g., tool compounds or chemical probes, for research on RNs The use of

[0163] Also provided is a compound of formula (I) as described herein, or a pharmaceutical composition thereof, for use in the treatment of cancer. Cancers that can be treated by WRN inhibition include high frequency myeloma, Microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) In particular, the compounds of formula (I) described herein or their pharmaceutically acceptable salts are useful in treating cancers. Acceptable salts include those with microsatellite instability-high (MSI-H) or mismatch repair This may be useful in treating cancers characterized by loss of function (dMMR).

[0164] A compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. Acceptable salts are also provided. In particular, the use For the treatment of diseases treated by WRN inhibition, For the treatment of cancer, Microsatellite instability-high (MSI-H) or mismatch repair deficiency ( For the treatment of cancers characterized by dMMR, · Colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, Microsatellite instability-high (MSI-H) or ovarian cancers, such as breast, kidney, and ovarian cancers for the treatment of cancers characterized by deficient mismatch repair (dMMR), High frequency microsatellites selected from colorectal cancer, gastric cancer, prostate cancer, and endometrial cancer Cancers characterized by cytoplasmic instability (MSI-H) or mismatch repair deficiency (dMMR) For treatment, or for the treatment of cancer (wherein the cancer is microsatellite instability high (MSI-H) or Cancers characterized by mismatch repair deficiency (dMMR) include endometrial cancer of the uterine corpus, colon adenocarcinoma, and Cancer, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, selected from esophageal cancer, breast cancer, renal clear cell carcinoma, prostate cancer, and ovarian serous cystadenocarcinoma is.

[0165] The following methods are also provided: A method for modulating WRN activity in a subject, comprising administering to a subject a compound of formula (I) as described herein; or a pharmaceutically acceptable salt thereof, A method of inhibiting WRN in a subject, comprising administering to a subject a compound of formula (I) as described herein, or administering to a subject a therapeutically effective amount of a pharmaceutically acceptable salt thereof; A method for treating a disorder or disease in a subject that can be treated by WRN inhibition. Thus, a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, administering to a subject A method of treating cancer in a subject, comprising administering to a subject a compound of formula (I) as described herein, or administering to a subject a therapeutically effective amount of a pharmaceutically acceptable salt; a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof 1. A method of treating cancer in a subject, comprising administering Methods for characterizing cytoplasmic instability (MSI-H) or mismatch repair deficiency (dMMR) In particular, microsatellite instability-high (MSI-H) or mismatch repair deficiency Cancers characterized by (dMMR) include colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, and uterine cancer. Cancers of the uterus, cervix, esophagus, breast, kidney, and ovary are selected from the group consisting of: High microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) The cancer characterized by is selected from colon cancer, gastric cancer, prostate cancer, and endometrial cancer. Endometrial cancer of the uterine body, 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 carcinoma Examples include cystadenocarcinoma.

[0166] A compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof In treatment, In the manufacture of medicines, in the manufacture of a medicament for the treatment of cancer (particularly when said cancer is microsatellite instable or high) characterized by mismatch repair deficiency (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.

[0167] 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.

[0168] form Depending on the choice of starting materials and procedures, the compounds may be produced in one of the possible stereoisomeric forms. It can be present as a mixture thereof, for example as a pure chiral compound, depending on the number of asymmetric carbon atoms. They can exist as pure optical isomers or as stereoisomers such as racemates and diastereoisomeric mixtures. The present disclosure provides a racemic mixture, a diastereomeric mixture, and and all such possible stereoisomers, including optically pure forms. The optically active (R)- and (S)-stereoisomers can be synthesized using chiral synthons or chiral reagents. The compound may be prepared using a reagent or isolated using conventional techniques. When present, the substituents may be in the E or Z configuration. When containing a cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0169] As used herein, the term "salt" or "salts" refers to a compound of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention. and typically refers to salts that are not biologically or otherwise undesirable. In this case, the compounds of the present invention contain amino and / or carboxyl groups or groups similar thereto. The presence of allows the formation of acid and / or base salts.

[0170] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0171] Examples of inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples include:

[0172] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycol Acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosa Licylic acid, etc.

[0173] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0174] Inorganic bases from which salts can be derived include, for example, ammonium salts and salts of compounds of the periodic table I In certain embodiments, the salts include metals from columns 11-12. derived from ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly preferred Suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Examples include sodium salts.

[0175] In certain embodiments, sodium salts of the compounds described herein are provided.

[0176] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, natural Examples include substituted amines, including those present in Specific organic amines include isopropylamine, benzathine, cholinate, diamine, Ethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine Examples include:

[0177] 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, chlortheophyllonar 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:

[0178] The formulas given herein are intended to represent unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds are compounds in which one or more atoms have a selected atomic mass or mass number. having the structure represented by the formula shown herein except for the atoms shown in Isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen. For example, the present invention includes deuterated forms of the exemplary compounds disclosed herein. .

[0179] For example, the ring: [ka] one or more H atoms on the Or one or more atoms on the R1 moiety may be substituted with deuterium: [ka] .

[0180] Additionally, certain isotopes, particularly deuterium (i.e. 2 The incorporation of H or D) is more High metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements, or therapeutic index or may offer specific therapeutic advantages resulting from improved tolerability. It is understood that deuterium present in the compound is considered a substituent of the compound of the present invention. The term "isotopic enrichment factor" as used herein may be defined as When used herein, it refers to the ratio between the isotopic abundance and the natural abundance of the specified isotope. When a substituent in a compound is indicated to be deuterium, such compound is The isotopic enrichment factor for each deuterium atom is at least 3500 (for each deuterium atom shown). 52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least At least 4500 (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), a little At least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) 6633.3 (99.5% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). The term "isotopic enrichment factor" can be applied to any isotope in a similar manner to that described for deuterium. It should be understood that the above may be used.

[0181] Other examples of isotopes that may be incorporated into compounds of the invention include hydrogen, carbon, nitrogen, oxygen, lithium, and the like. isotopes of fluorine, fluorine, and chlorine, e.g., 3 H, 11 C. 13 C. 1 4 C. 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 Therefore, the present invention includes, for example, 3 H and 14 Radioactive isotopes such as C, or 2 H and 13 Any of the aforementioned isotopes, including those for which non-radioactive isotopes exist, such as It is to be understood that compounds incorporating one or more of the following are included: The compound was tested in a metabolic test ( 14 C), reaction rate tests (e.g., 2 H or 3 H), Positron emission tomography (PET) or single-agent imaging, including drug or substrate tissue distribution assays Detection or imaging techniques such as photon emission computed tomography (SPECT) or in the radiotherapy of a patient. 18 F or labeled compounds, PET or The isotope-labeled compounds of the present invention may be particularly desirable for SPECT studies. In addition, they can be prepared by conventional techniques known to those skilled in the art or can be substituted for previously used unlabeled reagents. Alternatively, suitable isotopically labeled reagents may be used in accordance with the methods described in the accompanying examples and preparations. It can be prepared by similar methods.

[0182] definition "Compounds of the invention" or "compounds of formula (I)" or "compounds of formula 1a" etc. Zwitterions, their non-zwitterionic (uncharged) forms, or said zwitterionic or non-zwitterionic forms Pharmaceutically acceptable salts in ionic form are included.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] Halo means fluoro, chloro or bromo, especially fluoro or chloro.

[0187] The 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, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, and i-propoxy. , n-butoxy, i-butoxy, sec-butoxy and t-butoxy.

[0188] "=O" means an oxo substituent.

[0189] 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.

[0190] 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.

[0191] When R1 is heteroaryl, the heteroaryl is preferably a heteroaryl group consisting of ring carbon atoms and N, O and S. 1, 2, 3 or 4 ring heteroatoms, preferably 1 or 2 ring heteroatoms, independently selected from and a 5- or 6-membered fully unsaturated (including aromatic) monocyclic group containing a heteroatom, preferably , the total number of ring S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1. R1 is substituted or unsubstituted When the heteroaryl is a heteroaryl of the formula (I), the heteroaryl is preferably pyridinyl, particularly pyridine. Examples of substituted or unsubstituted groups include, but are not limited to, substituted or unsubstituted groups such as 3-yl.

[0192] - "heteroaryl 1" is 1, 2 independently selected from ring carbon atoms and N, O and S , 3 or 4 ring heteroatoms and a 5 or 6-membered fully unsaturated (including aromatic) monocyclic ring Preferably, the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1. In addition, the heteroaryl 1 contains only ring carbon atoms and one or two nitrogen atoms. Aryl 1 includes pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, Isoxazolyl, oxadiazolyl, oxazolyl, isothiazolyl, thiazolyl, thiazolyl Diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, triazolyl and pyrazinyl, especially pyridyl, pyrimidinyl and triazolyl, Not limited to.

[0193] - "heteroaryl2", where said heteroaryl2 is a heteroaryl consisting of ring carbon atoms and N, O and and 1, 2, 3, or 4 ring heteroatoms independently selected from S. Bicyclic rings, where both rings are fully unsaturated (including aromatic), or one ring is fully unsaturated one unsaturated (including aromatic) and the other saturated or partially unsaturated, and one heteroatom Preferably, the total number of ring S atoms does not exceed 1 and the total number of ring O atoms is 0. In particular, the ring connected to the rest of the molecule via the linker -A- is not a complete non-cyclic ring. Heteroaryl 2 is saturated. aryl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolopyridinyl, iridyl Midazopyridinyl, pyrazololpyridinyl , isoindolyl, indazolyl, purinyl, indolinyl, imidazopyridinyl, pyridinyl Zolopyridinyl, pyrrolopyridazinyl, pyrrolopyridinyl, imidazopyrimidinyl, quino Linyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl , naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyrimidopyrimidinyl, pyr Ladinopyrazinyl, hydropyranopyridinyl, especially hydrofuropyridinyl (especially dihydropyridinyl) Examples include, but are not limited to, furopyridinyl) and imidazopyridinyl.

[0194] The present invention includes all tautomeric forms of the compounds of formula (I).

[0195] For example, when heteroaryl 1 and heteroaryl 2 are substituted with ═O, they can form, for example, the following tautomers: [ka] .

[0196] 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.

[0197] 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.

[0198] 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.

[0199] "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).

[0200] 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.

[0201] 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).

[0202] 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.

[0203] 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 Cancers include, but are not limited to, rhabdoid sarcoma, childhood rhabdoid sarcoma, melanoma, and other cancers. Cells or cancers with "defective" mismatch repair function have high levels of mismatch repair. Significantly reduced (e.g., at least about 25%, 30%, 40%, 50%, 60%, 70%, In some cases, cells with defective mismatch repair function The cells or cancers do not perform mismatch repair.

[0204] 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

[0205] As used herein, the term "pharmaceutically acceptable carrier" refers to a It refers to a substance useful in the preparation or use thereof, as known to those skilled in the art, e.g., in a suitable dilution. Diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption retardants Supplementing agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes and combinations thereof (e.g., Remington The Sci ence and Practice of Pharmacy,22nd Ed.Ph See Armaceutical Press, 2013, pp. 1049-1070. I want to be.

[0206] 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.

[0207] 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.

[0208] 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

[0209] 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.

[0210] 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. .

[0211] As used herein, the terms "inhibit," "inhibition," or "inhibiting" The term refers to the alleviation or suppression of a given condition, symptom, or disorder, or disease, or the suppression of biological activity. A significant reduction in the baseline activity of a substance or process.

[0212] As used herein, "treating" or "treating" refers to any disease or disorder. The terms "treatment" and "treatment" are used to refer to the alleviation or amelioration of a disease or disorder. to slow the onset of the disease or at least one of its clinical symptoms or halting the development of a disease, including those that may not be discernible to the patient. or at least one physical parameter or biomarker associated with the disorder It means to alleviate or relieve.

[0213] As used herein, the terms "prevent" and "preventing" of any disease or disorder or "prevention" means the prophylactic treatment of a disease or disorder; or the delay in the onset or progression of a disease or disorder. It refers to making something.

[0214] As used herein, a subject is "in need of" treatment if such subject is This is when a patient would benefit biologically, medically, or in quality of life from such treatment.

[0215] 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.

[0216] "Capable of binding" means to bind or not to bind.

[0217] "Can be substituted by deuterium" means to be substituted by deuterium or to be substituted by deuterium. means that it will not be replaced.

[0218] 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.

[0219] 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 .

[0220] 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 a racemate or mixtures thereof, possible stereoisomers, rotamers, atropisomers , tautomers, or mixtures thereof.

[0221] Any resulting mixture of stereoisomers can be purified by, for example, chromatography and / or fractional recombination. Crystallization allows the creation of pure or substantially pure geometric or optical crystals based on the physicochemical differences of the constituent components. They can be separated into isomers, diastereomers and racemates.

[0222] Any resulting racemates of the compounds or intermediates of the present invention can be prepared by known methods, e.g. These diastereomeric salts obtained with optically active acids or bases are separated and the optically active compounds are obtained. The optical antipodes can be resolved by liberating the reactive acidic or basic compounds. In this way, the basic moiety can be used to produce an optically active acid (e.g., tartaric acid, dibenzoyl Tartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, apple by fractional crystallization of the salts formed with The compounds of the present invention can be resolved into their optical antipodes. The chiral intermediates can also be purified by chiral chromatography (e.g., high pressure liquid chromatography using a chiral adsorbent). The separation can also be carried out by chromatography (HPLC).

[0223] 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).

[0224] Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates. The compounds of the present invention may contain other solvents used for their crystallization. The product inherently or intentionally forms a solvate with a pharmaceutically acceptable solvent (including water). Therefore, the present invention encompasses both solvated and unsolvated forms. The term "solvate" refers to a solvate of a compound of the present invention (including pharmaceutically acceptable salts thereof). It refers to a molecular complex with one or more solvent molecules, which are harmless to the recipient. Those commonly used in the pharmaceutical field known to be The term "hydrate" refers to the complex where the solvent molecule is water.

[0225] 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.

[0226] 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" 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 at the same time. The term "pharmaceutical combination," as used herein, refers to a mixture of two or more therapeutic agents. or products resulting from combinations thereof, including fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" includes both fixed and indirect combinations of therapeutic agents (e.g., the compound and the combination partner) are both administered simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the therapeutic agent (e.g., For example, a compound of the invention and a combination partner) are both present in the same compound as separate entities. This means that they may be administered to a patient at times, in parallel, or sequentially without any specific time limit. Such administration results in therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy (e.g., the administration of three or more therapeutic agents).

[0227] The combinations described herein comprise a compound of formula (I) and one or more additional therapeutic agents, For example, one or more anti-cancer drugs, cytotoxic or cytostatic drugs, hormone therapy, vaccines In other embodiments, the combination may further include surgery and / or other immunotherapy. Combined with other therapeutic modalities including surgery, radiation, cryosurgery and / or thermotherapy Such combination therapy may involve administering or using a lower dose of the treatment. Therapeutic agents may be advantageously utilized, thereby preventing potential toxicities or complications associated with treatment. This can be avoided.

[0228] A compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof as described herein. Also provided are combinations comprising acceptable salts and one or more additional therapeutically active agents. The therapeutic agent is therapeutically active when administered to a patient in combination with a compound of the present disclosure. or enhance the therapeutic activity of, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid In particular, the additional therapeutically active agent is Anticancer drugs, chemotherapy drugs, Anastrozole (Arimidex®), bicalutamide (Casod ex (registered trademark), bleomycin sulfate (Blenoxane (registered trademark), Busul Myleran®, busulfan injection (Busulfex®), Trademark), capecitabine (Xeloda®), N4-pentoxycarbonyl- 5-deoxy-5-fluorocytidine, carboplatin (Paraplatin (registered trademark) (trademark), carmustine (BiCNU®), chlorambucil (Leukeran® (registered trademark), cisplatin (Platinol®), cladribine (Le statin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U (registered trademark), cytarabine liposome injection (DepoCyt (registered trademark), Dacal Basin (DTIC-Dome®), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), Daunorubicin phosphate liposome injection (DaunoXome®), dexamethasone doxorubicin hydrochloride (Adri), docetaxel (Taxotere®), amycin®, Rubex®), etoposide (Vepesid® phosphate (Fludara®), 5-fluorouracil (Fentanyl®), Adrucil (Adrucil®, Efudex®), flutamide (Eul exin®), tezacitabine, gemcitabine (difluorodeoxycytidine) , hydroxyurea (Hydrea®), idarubicin (Idamycin Registered Trademark), ifosfamide (IFEX®), irinotecan (Campt osar®), L-asparaginase (ELSPAR®), Leuco Boron calcium, melphalan (Alkeran®), 6-mercaptopril (Purinethol®), methotrexate (Folex®) ), mitoxantrone (Novantrone®), Mylotarg, Paclitaxel Taxol®, Phoenix (Yttrium 90 / MX-DTPA) ), pentostatin, carmustine implant containing polipheprosan 20 (Glia del®), tamoxifen citrate (Nolvadex®), Niposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (T irazone®), injectable topotecan hydrochloride (Hycamptin® )), vinblastine (Velban®), vincristine (Oncovin®) (registered trademark) and vinorelbine (Navelbine®), especially Fluorouracil selected from Rasil (5-FU) and irinotecan (Camptosar®) chemotherapy agents, PD-1 inhibitors, an anti-PD-1 antibody molecule, or PDR001 (Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co), pidilizumab (Cur eTech), MEDI0680 (Medimmune), cemiplimab (REGN28 10, Regeneron), dostallimab (TSR-042, Tesaro), PF -06801591 (Pfizer), tislelizumab (BGB-A317, Beig ene), BGB-108 (Beigene), INCSHR1210 (Incyte) , balstilimab (AGEN2035, Agenus), sintilimab (Inn oVent), toripalimab (Shanghai Junshi Bioscience ), camrelizumab (Jiangsu Hengrui Medicine Co.), and AMP-224 (Amplimmune), penprimab (Akeso Bioph arma Inc), dimvelelimab (Arcus Biosciences Inc) and prorugolimab (Biocad Ltd), particularly PDR001, more particularly Tisle PD-1 inhibitors selected from lizumab (BGB-A317, Beigene) is.

[0229] In a further embodiment, the additional therapeutically active agent is the chemotherapy irinotecan (Camptos ar (registered trademark).

[0230] 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.

[0231] In a further embodiment, the PD-1 inhibitor is selected from the group consisting of 201 "Antibody Molecules to PD-1" released on July 30, 2015 and Uses Thereof,” U.S. Patent Application Publication No. 2015 / 02 and anti-PD-1 antibody molecules described in US Pat. No. 6,10769, which is incorporated by reference. The whole thing is incorporated.

[0232] 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.

[0233] In another embodiment, the anti-PD-1 antibody molecule, e.g., tislelizumab, comprises the following heavy chains: / or light chain, VH, VL, HCDR1, HCDR2, HCDR3, LCDR1, LCDR 2, and LCDR3.

[0234] [Table 1]

[0235] 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.

[0236] 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 .

[0237] 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.

[0238] 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.

[0239] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered intravenously. will be done.

[0240] 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.

[0241] 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 .

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] In one embodiment, the present invention provides a combination for simultaneous, separate or sequential use in therapy. A preparation comprising a compound of formula (I) of the present invention and at least one other therapeutic agent as a combination preparation. In one embodiment, the therapy is treatment of a disease or condition mediated by WRN. Products provided as combination preparations include those of formula (I) combined in the same pharmaceutical composition. The compound and the other therapeutic agent, or the compound of the present invention and the other therapeutic agent in separate forms, e.g., in the form of a kit. The compositions include compositions containing a therapeutic agent.

[0247] In one embodiment, the present invention comprises two or more separate pharmaceutical compositions, at least one of which Another aspect of the present invention provides a kit containing a compound of formula (I). The container may contain the composition in separate containers, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a kit containing a means for retaining the tablet, capsule, or the like in a suitable packaging. It is a commonly used blister pack.

[0248] The kits of the present invention may be administered in different dosage forms, e.g., oral and parenteral, or at different dosage intervals. The dosage may be used to administer separate compositions at the same time or to titrate separate compositions together. To aid in compliance, the kits of the invention typically include directions for administration.

[0249] In the combination therapy of the present invention, the compound of formula (I) of the present invention and the other therapeutic agent are administered in the same or similar combination. may be manufactured and / or formulated by different manufacturers. and other therapeutic agents (i) prior to delivery of the combination product to a physician (e.g., (ii) by the physician himself / herself (or in the case of a kit containing a compound and other therapeutic agents); under the guidance of a physician; (iii) patients themselves, for example, by administering the compounds of the present invention and other While the therapeutic agents are administered sequentially, they may be combined into combination therapy.

[0250] Thus, the present invention provides a compound of the formula (I) of the present invention for treating a disease or condition mediated by WRN. Use of a compound of I), wherein the medicament is prepared for administration together with another therapeutic agent, The present invention also provides a method for treating a disease or condition mediated by WRN. Use of a compound of formula (I), wherein a medicament is administered together with the compound of the present invention. do.

[0251] The present invention also provides compounds of formula (I) of the present invention for use in the treatment of diseases or conditions mediated by WRN. ) wherein the compound of formula (I) of the present invention is suitable for administration together with another therapeutic agent. The present invention also provides compounds for treating diseases or conditions mediated by WRN. another therapeutic agent for use in, wherein the other therapeutic agent is administered together with a compound of the invention. The present invention also provides a therapeutic agent for treating a disease or disorder mediated by WRN. A compound of formula (I) of the present invention for use in the treatment of a condition in which the compound of the present invention is The present invention also provides compounds for use in treating WRN-mediated diseases. or another therapeutic agent for use in a method of treating a condition, the other therapeutic agent comprising a compound of the present invention Therapeutic agents are provided for administration with compounds of formula (I).

[0252] The present invention also relates to a compound of formula (I) of the present invention for treating a disease or condition mediated by WRN. Use of a combination of these drugs, provided the patient has not previously (e.g., within 24 hours) been treated with another therapeutic agent. The present invention also provides a method for treating a disease or condition mediated by WRN. Use of another therapeutic agent, where the patient has previously (e.g., within 24 hours) received a compound of the invention Being treated, providing use.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] Baculovirus-infected insect cells (BIICs) were cultured as described by Wasilko et al., 200 9,DOI:10.1016 / j.pep.2009.01.002 Generated.

[0258] Briefly, 100 mL of ESF921 medium (expression system) was added to an Erlenmeyer flask. 100 million in TEM-96-001-01, supplemented with 0.5x streptomycin / penicillin Infect 300 million baculoviruses of each construct into SF9 cells (1 million cells / mL). Infect the cells with 10 ... Transfer the infected cells to a 50 mL tube and centrifuge at 100 × g for 10 min at RT. and retrieved it.

[0259] 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.

[0260] SEQ ID NO: 1 [ka] [ka] [ka] [ka]

[0261] 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).

[0262] 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.

[0263] 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 fractions corresponding to the purified protein 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.

[0264] 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.

[0265] 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" TTTTTTTTTTTTCCAAGTAAAACGACGGCCAGTGC; SEQ ID NO: 2) was acquired by IDT (Integrated DNA Technologies, Leuve The DNA was purchased from AT Biosciences, Belgium, and used as the signal strand DNA substrate. ADP-Glo ​​assay kit ( Promega, Madison, WI) was used to set up this assay. A time course experiment was first performed to determine the best enzyme assay conditions (buffer conditions, reaction time, and timing). The concentrations of the enzyme, ATP, and DNA substrate were determined. 10 nM WRN protein, 0.2 nM FLAP26, and 300 nM FLAP26 in assay buffer. Consists of: 30 mM Tris pH 7.5, 2 mM MgCl, 0 .02% BSA, 50mM NaCl, 0.1% pluronic F127(DN (prepared in Ase-free water).

[0266] 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.

[0267] 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 The experiment was carried out using the 10.1016 / j.cmpb.2006.01.008 well. The activity value of each compound was compared to the % inhibition (% inhibition = [(high control - sample) / (high control - low control)] x 100). After normalization, the IC from duplicate measurements on each plate was calculated according to [4]. 50 Fitte Data analysis was also performed using a four-parameter fit (e.g., GraphPad Prism, XL fit (using IC) 50 Commercially available products designed to derive values This can be done using software. 50 The value must be at least 2 is the geometric mean of three independent replicates.

[0268] 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.

[0269] 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 100 mM MgCl 2 , 100 mM Tris-HCl (pH 7.5) and 100 mM MgCl 2 . All cells were maintained in a humidified 5% CO2 incubator. , and maintained at 37°C.

[0270] 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.

[0271] 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: Applied programmatically with ELIOS. HELIOS is in-house software that applies a multi-step decision tree to achieve the fitting of the optimal concentration-response curve (Gubler et al, SLAS DOI: 10.1177 / 2472555217752140), calculating the growth percentage (G%) of each well treated with the compound: G% = ((T - V0) / V0)) * 100 (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 control 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 can also be performed using commercially available software designed to derive IC50 values using a four-parameter fit (e.g., GraphPad Prism, XL Fit). The reported GI values are the geometric mean of at least two independent replicates. reached, and applies a multi-step decision tree to achieve the fitting of the optimal concentration-response curve (Gubler et al l, SLAS DOI: 10.1177 / 2472555217752140), calculating the growth percentage (G%) of each well treated with the compound: 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 control 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 can also be performed using commercially available software designed to derive IC50 values using a four-parameter fit (e.g., GraphPad P rism, XL Fit). The reported GI values are the geometric mean of at least two independent replicates. The efficacy of WRN inhibitors against subcutaneous SW48 colorectal xenografts experiments were performed in female Crl:NU(NCr)-Foxn1 -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. Animals were enrolled in the experimental design 50 and the reported GI values are the geometric mean of at least two independent replicates.

[0272] The efficacy of WRN inhibitors against subcutaneous SW48 colorectal xenografts Experiments were performed in female Crl:NU(NCr)-Foxn1 nu -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. Animals were enrolled in the experimental design <00​ The animals were allowed to acclimate for at least one week before the study. License approved by the National Veterinary Office 1975 was carried out in accordance with

[0273] Subcutaneous inoculation of human colon cancer SW48 cells (5 × 10 cells in 100 μL of HBSS) 6 cells / animals) Tumors were established using SW48 human colon cancer cells obtained from ATCC. The cells were cultured at 10% FCS (Bio Concept #2-01F30-I), 2 mM L-glutamine ( Bio Concept Ltd., #5-10K50-H), 1 mM sodium pyruvate 10 mM HEPES (BioConcept #5-60F00-H) RPMI-1640 medium (B) supplemented with io Concept #5-31F00-H io Concept Ltd., #1-41F01-I) at 37°C in 5% air. To establish SW48 xenografts, cells were harvested and cultured in HBSS. (Sigma, #H6648) and then the right flank of the animal anesthetized with isoflurane. 100 μL containing 5 million cells was injected subcutaneously into the tumor area. 3 ) is the expression: It was calculated according to the formula (L×W2×π / 6), where W=tumor width and L=tumor length. 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

[0274] Tumor regression was calculated as follows: -(Δtumor volume 処置 / Tumor 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. The amorphous sodium salt of the test compound (corrected by the salt content factor) was dissolved in 2-hydroxypropyl The test was dissolved in a 20% w / v aqueous solution of HPBCD. Various concentrations were prepared by serial dilution starting from the most concentrated solution of the highest dose in Ta.

[0275] Treatment began approximately 2 weeks after tumor cell inoculation, when xenografts reached an average volume of approximately 200 mm 3 reached Tumor-bearing animals were divided into groups of 6 animals per group based on tumor volume. The mice were randomized into experimental groups with the compound at 1, 3, 5 or 10 mg / kg and treatment was initiated. (Example 18A) and 0.1, 0.3, 1, 3 mg / kg (Example 21A) once a day ( qd) orally (po). In addition, vehicle (20% 2-hydroxypropyl A control group treated once daily with β-cyclodextrin (β-cyclodextrin) was included in each study. Body weight was measured twice weekly until the end of the study.

[0276] In a study evaluating the efficacy of Example 18A, tumors in the vehicle-treated group were approximately 200-300 mg / kg. 1,100mm 3 The tumor mass grew almost linearly from the injection to the termination of animals with large tumor mass. The body weight of vehicle-treated animals decreased 32 days after treatment (Fig. 1). The initial weight loss (individuals within 10 days of treatment) was observed. After the 24-hour incubation period (not exceeding 14% between individual animals), animals gained weight to 18% of their starting weight. A dose-dependent antitumor effect was observed (Fig. 1). In the control group, slight tumor growth delay was observed, with T / C% increasing by day 32 of the study (14 days after treatment). The tumor phenotype reached 22% in the first 24 hours after administration of 3, 5, and 10 mg / kg. The maximum regression was 71% and 49% on day 49 (day 30 of treatment), respectively. The overall survival rate was 83% at day 30 (day 30 of treatment) and 91% at day 63 (day 45 of treatment). Relapse was observed in the control group, and the time to relapse was dose-dependent (Figure 1). The sharp decrease in mean tumor volume observed in the groups treated with 3 and 5 mg / kg was due to the tumor quality. The amount is the result of the termination of large animals (Figure 1).

[0277] In a study evaluating the efficacy of Example 21A, tumors in the vehicle-treated group were approximately 200-300 mg / kg. 1,000mm 3 The tumor mass grew almost linearly from the injection to the termination of animals with large tumor mass. The body weight of vehicle-treated animals decreased 29 days after the first administration (Figure 3). The weight increased by up to 11% of the starting weight (Figure 4). Example 21A performed well throughout the study. It was well tolerated, with minimal weight loss in individual animals, not exceeding 15% in any individual case. (Figure 4). The weight loss observed in the study was not dose-dependent and was independent of treatment. A dose-dependent antitumor effect was observed (Figure 3). Tumor growth delay was observed at the 25th to 29th day of the study (1st day of treatment) and T / C% was At 0.3 mg / kg, the initial state (test day 0 to 14) was reached at 50%. On the 29th day of treatment and the 14th day of treatment, T / C% reached 0%. Treatment with 1 and 3 mg of IFN-γ produced significant antitumor activity. The maximum regression was 75% on day 52 of the study (day 37 of treatment) and 75% on day 85 (day 70 of treatment). During treatment, the 3 animals treated with Example 21A, 1 mg / kg, and No recurrence was observed in any group treated with 3 mg / kg. A rapid increase in mean tumor volume was observed in the treated groups after 81 and 102 days of the study, respectively. The reduction was the result of termination of animals with large tumor mass (Figure 1).

[0278] 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 Show the data.

[0279] For example, Example 1A shows a biochemical IC 50 is 0.02 μM, and the proliferation GI 50 But, S WRN was 0.04 μM in W48 and >10 μM in DLD1 WRN-KO cell lines. It is an ATPase inhibitor.

[0280] [Table 2]

[0281] [Table 3]

[0282] Data were collected in at least two replicates, except for the biochemical data in Examples 1D and 22B. is the geometric mean of the measurements taken.

[0283] In another aspect, the present invention provides compounds that can be used as research chemicals, e.g., tool compounds or chemical probes. In particular, said use is directed to the treatment of WRN In experiments involving inhibition or high-frequency MSI cancers.

[0284] Preparation of compounds Compounds of the present disclosure can be prepared as described in the following examples. The examples are intended to illustrate the invention and should not be construed as limiting the invention. stomach.

[0285] device Powder X-ray diffraction equipment and method, Figure 1:

[0286] [Table 4]

[0287] Powder X-ray diffraction equipment and method, Figure 6:

[0288] [Table 5]

[0289] For samples of the compound of Example 21A with higher crystallinity, the following alternative instrumental method Used:

[0290] [Table 6]

[0291] This alternative method gave the following peaks:

[0292] [Table 7]

[0293] UPLC-MS method: Waters Acquisition with a Waters SQ detector, unless otherwise specified. ty UPLC is used.

[0294] UPLC-MS 1: Column CORTECS (trademark) C18+2.7μm, Column dimensions: 2.1 x 50 mm Column temperature: 80℃ Eluent A: Water + 4.76% isopropanol + 0.05% FA + 3.75mM AA 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

[0295] UPLC-MS 2: Column: ACQUITY UPLC® BEH C18 1.7 μm Column dimensions: 2.1 x 100 mm Column temperature: 80℃ Eluent A: Water + 4.76% isopropanol + 0.05% FA + 3.75mM AA 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

[0296] 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+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

[0297] UPLC-MS 4: Column: ACQUITY UPLC® BEH C18 1.7 μm Column dimensions: 2.1 x 100 mm Column temperature: 80°C Eluent A: Water+0.05% FA+3.75mM AA B: Isopropanol + 0.05% FA Flow rate 0.4mL / min Gradient: 5 to 60% B in 8.4 min; 60 to 98% B in 1.0 min

[0298] UPLC-MS 5: Column: Acquity UPLC® HSS T3 1.8 μm Column dimensions: 2.1 x 50 mm Column temperature: 50°C Eluent A: Water+0.05% FA+3.75mM AA B: Acetonitrile + 0.04% FA Flow rate 1.0mL / min Gradient: 5 to 98% B in 1.4 min

[0299] 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 AA 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

[0300] UPLC-MS 7: 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

[0301] UPLC-MS 8: 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 AA B: Isopropanol + 0.05% FA Flow rate 0.6mL / min Gradient: 1 to 98% B in 1.7 min

[0302] UPLC-MS 9: 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: Acetonitrile + 0.04% FA Flow rate 1.0mL / min Gradient: 5 to 98% B in 1.4 min

[0303] 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 Gradient: 1% to 98% B in 1.4 minutes

[0304] HPLC method: HPLC 1: 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

[0305] HPLC 2: 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

[0306] Chiral HPLC Method C-HPLC 1: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5μL Mobile phase: A: 45% MeOH + 0.1% NH3, B: 55% scCO2 Flow rate: 3mL / min Column: Chiralpak AD (4.6mm x 100mm 5μm) Detection UV: DAD Gradient: Isocratic A: 45%, B: 55% Oven temperature: 40°C BPR: 1800 psi

[0307] C-HPLC 2: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5μL Mobile phase: A:45%IPA+0.1%NH3, B:55%scCO2 Flow rate: 3mL / min Column: Chiralpak IB (4.6 mm × 100 mm 5 μm) Detection UV: DAD Gradient: Isocratic A: 45%, B: 55% Oven temperature: 40 °C BPR: 1800 psi

[0308] C-HPLC 3: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5 μL Mobile phase: A: 45% MeOH + 0.1% NH3, B: 55% scCO2 Flow rate: 3 mL / min Column: Chiralpak IB (4.6 mm × 100 mm 5 μm) Detection UV: DAD Gradient: Isocratic A: 45%, B: 55% Oven temperature: 40 °C BPR: 1800 psi

[0309] C-HPLC 4: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5 μL Mobile phase: A: 40% MeOH + 0.1% NH3, B: 60% scCO2 Flow rate: 3 mL / min Column: Chiralpak IB-N (4.6 mm × 100 mm 5 μm) Detection UV: DAD Gradient: Isocratic A: 40%, B: 60% Oven temperature: 40 °C BPR: 1800 psi

[0310] C-HPLC 5: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5 μL Mobile phase: A: 55% MeOH + 0.05% NH3, B: 45% scCO2 Flow rate: 3 mL / min Column: Chiralpak IB (4.6 mm × 100 mm 5 μm) Detection UV: DAD Gradient: Isocratic composition A: 55%, B: 45% Oven temperature: 40 °C BPR: 1800 psi

[0311] C-HPLC 6: Instrument: Ultimate3000 Injection: 4 μL Mobile phase: A: 40% heptane (containing DEA), B: 60% EtOH (containing DEA); Flow rate: 0.420 mL / min Column: Chiralpak IG-3 (3.0 mm × 100 mm 3 μm) Detection UV: 240 nm Gradient: Isocratic composition A: 40%, B: 60% Oven temperature: 25 °C BPR: 1800 psi

[0312] C-HPLC 7: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5 μL Mobile phase: A: 40% MeOH + 0.1% NH3, B: 60% scCO2 Flow rate: 3 mL / min Column: Chiralpak IC (4.6 mm × 100 mm 5 μm) Detection UV: DAD Gradient: Isocratic composition A: 40%, B: 60% Oven temperature: 40 °C BPR: 1800 psi

[0313] C-HPLC 8: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5 μL Mobile phase: A: 4​​​Column: Chiralpak IB-N (4.6 mm × 100 mm 5 μm) Detection UV: DAD Gradient: Isocratic composition A: 45%, B: 55% Oven temperature: 40 °C BPR: 1800 psi

[0314] C-HPLC 9: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5 μL Mobile phase: A: 25% MeOH + 0.1% NH3, B: 75% scCO2 Flow rate: 3 mL / min Column: Chiralpak IB (4.6 mm × 100 mm 5 μm) Detection UV: DAD Gradient: Isocratic composition A: 25%, B: 75% Oven temperature: 40 °C BPR: 1800 psi

[0315] C-HPLC 10: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5 μL Mobile phase: A: 40% MeOH + 0.1% NH3, B: 60% scCO2 Flow rate: 3 mL / min Column: Chiralpak IB (4.6 mm × 100 mm 5 μm) Detection UV: DAD Gradient: Isocratic composition A: 40%, B: 60% Oven temperature: 40 °C BPR: 1800 psi

[0316] C-HPLC 11: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5 μL Mobile phase: A: 35% MeOH + 0.025% NH3, B: 65% scCO2 Flow rate: 3 mL / min Column: Chiralpak IB-N (4.6 mm × 100 mm 5 μm) Detection UV: DAD Gradient: Isocratic A: 35%, B: 65% Oven temperature: 40 °C BPR: 1800 psi

[0317] C-HPLC 12: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5 μL Mobile phase: A: 20% MeOH + 0.05% NH3, B: 80% scCO2 Flow rate: 3 mL / min Column: Chiralpak AD (4.6 mm × 100 mm 5 μm) Detection UV: DAD Gradient: Isocratic A: 20%, B: 80% Oven temperature: 40 °C BPR: 1800 psi

[0318] C-HPLC 13: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5 μL Mobile phase: A: 50% MeOH + 0.1% NH3, B: 50% scCO2 Flow rate: 3 mL / min Column: Chiralpak IB-N (4.6 mm × 100 mm 5 μm) Detection UV: DAD Gradient: Isocratic A: 50%, B: 50% Oven temperature: 40 °C BPR: 1800 psi

[0319] C-HPLC 14: Instrument: Analytical SFC-MS Waters UPC 2 Injection: 5 μL Mobile phase: A: 10% MeOH + 0.05% NH3, B: 90% scCO2 Flow rate: 3 mL / min Column: Chiralpak IG (4.6mm×100mm 5μm) Detection UV: DAD Gradient: Isocratic A: 10%, B: 90% Oven temperature: 40°C BPR: 1800 psi

[0320] 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 Teledyne ISCO, CombiFlash Rf, CombiF lash 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

[0321] Supercritical Fluid Chromatography (SFC) Purification was performed using a Waters 2998 photodiode array detector and a Waters M Waters Prep SF with ABSYS update, featuring a S single quadrupole detector This was performed on a C-100-MS system. SFC 1: 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 Reprospher PEI 100A 5μm Temperature 50℃ Back pressure: 100bar Detection UV: 210~400nm). Gradient: 23%B to 31%B in 7 minutes

[0322] 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

[0323] 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

[0324] RP-HPLC acidic 2: Teledyne / Isco AccqPrep HP150 prep system Column: Xbridge C18 (50 mm x 100 mm), 5 μm Eluent A: Water + 0.1% TFA, B: Acetonitrile Flow rate 100mL / min

[0325] RP-HPLC acidic 3: Waters automated purification system with Waters QDA MS detector M Column: Xbridge Prep C18 (30 mm x 100 mm), 5 μm Eluent A: Water + 0.1% TFA, B: Acetonitrile Flow rate 1mL / min

[0326] Preparation of compounds The following examples are intended to illustrate the present invention and are not to be construed as limiting thereof. Temperatures are in degrees Celsius. Unless otherwise stated, all evaporations are Conducted under reduced pressure, typically about 15 mmHg to 100 mmHg (= 20 to 133 mbar) The abbreviations used are those conventional in the art.

[0327] 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 those skilled in the art as shown in the examples below. It can be produced by known organic synthesis methods.

[0328] The structures of all final products, intermediates and starting materials are confirmed by standard analytical spectroscopic properties, e.g. This can be confirmed by MS, IR or NMR. Representative examples of preferred (most active) isomers The absolute stereochemistry of each compound was determined by analyzing the X-ray crystal structure of the complex in which each compound binds to WRN. by NMR analysis or by small molecule X-ray crystal structures of precursors or final compounds. do.

[0329] Amines synthesized by acidic deprotection of Boc precursors are often prepared as HCl salts or T The corresponding free base was obtained as the FA salt by addition of DCM as described for intermediate C. It can be isolated by partitioning between HCl and saturated aqueous NaHCO3.

[0330] General conditions: Mass spectra were obtained from a variety of instruments, including electrospray, chemical, and electrospray. Acquired on an LC-MS system using electron impact ionization: Waters SQ detector Analytical SFC-MS Waters UPC 2 and Agilent 1260 HPL Waters Acquity UPLC with C. [M+H] + is the protonation of the chemical species Refers to the molecular ion [MH] - refers to the deprotonated molecular ion of a chemical species.

[0331] NMR spectra were obtained using Bruke NMR spectrometer both with and without trimethylsilane as an internal standard. r Ultrashield™ 400 (400 MHz) spectrometer and Bruker Analysis was performed using an Ultrashield™ 600 (600 MHz) spectrometer. The d values ​​are reported in ppm downfield from tetramethylsilane, and the spectral splitting patterns Turns can be singlet (s), doublet (d), triplet (t), multiplet, unresolved or even overlapping. The solvent is designated as the signal (m) or broad signal (br). Shown below.

[0332] 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: 1 20-1909-J (for 150mL) SiliaMetS® Thiol: SiliCYCLE Thiol Metal Scavenger - ( Part number: R51030B, Loading: 1.31mmol / g, Particle size: 40~63μ m) ISOLUTE® Si-TMT: Biotage Thiol Metal Scavenger - (Parts No.: 9538-0100, loading: 0.49 mmol / g).

[0333] Sodium salt formation: The compound was suspended in tert-butanol. NaOH 0.1M (1 equivalent) was added. The mixture was stirred / sonicated at room temperature. Once the suspension turned into a clear solution, it was frozen. If the suspension was still cloudy, water was added and the resulting solution was freeze-dried. If no change occurred, add 0.1 M up to a total of 2 equivalents until a clear solution was observed. NaOH was added, which was then freeze-dried. The NMR of the resulting solid still showed t If it contained ert-butanol, the solid was dissolved in a small amount of water and lyophilized again. The final sodium salt was obtained as a colorless powder. Its amorphous state was confirmed by XRPD. Ta.

[0334] Abbreviation

[0335] [Table 8]

[0336] [Table 9]

[0337] [Table 10]

[0338] [Table 11]

[0339] [Table 12]

[0340] [Table 13]

[0341] Preparation of final compounds Example 1A: (7R,9R)-6-(4-(4-chloro-3-hydroxypicolinoyl) Piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 7-Methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1, 2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, and and Example 1B: (7S,9S)-6-(4-(4-chloro-3-hydroxypicolinoyl) )piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl) -7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1 ,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, and Example 1C: (7S,9R)-6-(4-(4-chloro-3-hydroxypicolinoyl) -(2-chloro-4-(trifluoromethyl)phenyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl) )-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[ 1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and Example 1D: (7R,9S)-6-(4-(4-chloro-3-hydroxypicolino) (2-chloro-4-(trifluoromethyl)phenyl)-N-(2-chloro-4-(trifluoromethyl)phenyl)- (aminomethyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo [1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide Do [ka] N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpho Lino-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolidone 1,2-c,1,2,4-triazolo[1,5-a]pyrimidine-9-carboxamide Intermediate C (707 mg, 1.22 mmol), 4-chloro-3-hydroxypicoyl Phosphoric acid (232 mg, 1.34 mmol) and HATU (486 mg, 1.28 mmol) ) in DCM (15 mL) and cooled to 0° C. Then, DIPEA (531 μL , 3.04 mmol) was added, and the mixture was stirred at room temperature for 2 days. Aqueous NaHCO3 (10 mL) and DCM (10 mL) were added. The aqueous layer was diluted with DCM ( The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude product was purified by reversed-phase preparative ISCO (RediSep column: C18 50g Gold, elution Purified with water + 0.1% TFA:ACN 95:5 to 0:100 (in 20 min) The product-containing fractions were combined, basified with saturated aqueous NaHCO3, and extracted twice with DCM. The residue was purified in three portions by reverse phase preparative HPLC (R P-HPLC Acidic 1: 20-80% B in 20 min, 45% plateau for 3 min and 55% (RP-HPLC acidic 1: 35-75% B for 19 min, 45% plateau) 2 min and 55% for 3 min), and (RP-HPLC acidic 1: 35-75% B for 16 min The first elution peak (purity >90%) was purified by HPLC (3 min at 50% plateau). All fractions containing HCl were combined, basified with saturated aqueous NaHCO3, and extracted twice with DCM. The eluate containing the second elution peak (purity >90%) was extracted with 100 ml of hexane, dried on a phase separator and concentrated under reduced pressure. All fractions were combined, basified with saturated aqueous NaHCO3, extracted twice with DCM, and the resulting mixture was The first elution peak and / or the second elution peak were dried on a separator and concentrated under reduced pressure. All other containing fractions were combined, basified with saturated aqueous NaHCO3 and washed twice with DCM. The extract was dried on a phase separator, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC (RP-HPLC). Purification was performed by elution of the first peak (purity >90%) using a 20-80% B gradient in 20 minutes. All fractions containing HCl were combined, basified with saturated aqueous NaHCO3, and extracted twice with DCM. The second elution peak was extracted, dried on a phase separator, concentrated under reduced pressure and combined with the first batch. All fractions containing HCl (purity >90%) were combined and basified with saturated aqueous NaHCO3. This was extracted twice with DCM, dried on a phase separator, concentrated under reduced pressure and combined with the first batch. Ta.

[0342] The first eluted peak (racemate of two enantiomers - 180 mg) was separated using preparative chiral SF C (Instrument: Sepiatec prep SFC-100; Column: LUX Amylo se-1 (Chiralpak-AD), 250×30mm 5μm; Eluent: A:45 %MeOH+0.1%NH3, B:55%scCO2; Flow rate: 80.0mL / min; Detection: UV; injection volume: 1 mL; gradient: isocratic A: 45%, B: 55%; oven temperature: 40 °C ; BPR: 105 bar).

[0343] Example 1C: (7S,9R)-6-(4-(4-chloro-3-hydroxypicolinoyl) Piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 7-Methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1, 2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide First eluting stereoisomer in chiral separation: 75.0 mg, purity 99%, yield: 8% LC-MS: Rt=1.05 min; MS m / z [M+H] + 736.5 / 738.5m / z[MH] - 734.3 / 736.3; UPLC-MS 1 Chiral HPLC (C-HPLC 1): Rt = 1.08 min, 99.5% ee

[0344] Example 1D: (7R,9S)-6-(4-(4-chloro-3-hydroxypicolinoyl) Piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 7-Methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1, 2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide Second eluting stereoisomer in chiral separation: 80.0 mg, purity 99%, yield: 9% LC-MS: Rt=1.07 min; MS m / z [M+H] + 736.5 / 738.4m / z[MH] - 734.2 / 736.2; UPLC-MS 1 Chiral HPLC (C-HPLC 1): Rt = 1.84 min, 99.5% ee

[0345] The second eluting peak (racemate of two enantiomers - 152 mg) was separated using preparative chiral SF C (Instrument: Sepiatec prep SFC-100; Column: LUX Amylo se-1 (Chiralpak AD), 250mm x 30mm 5μm; Eluent: A: 48%MeOH+0.1%NH3, B:52%scCO2;Flow rate:85.0mL / min;Detection Output: UV; Injection volume: 2.5 mL; Gradient: Isocratic A: 48%, B: 52%, Oven temperature : 40℃; BPR: 100bar

[0346] Example 1B: (7S,9S)-6-(4-(4-chloro-3-hydroxypicolinoyl) Piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 7-Methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1, 2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide First eluting stereoisomer in chiral separation: 65.0 mg, purity 99%, yield: 7%

[0347] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=1.07 min; MS m / z [M+H] + 736.5 / 738.6m / z[MH] - 734.3 / 736.3; UPLC-MS 1 Chiral HPLC (C-HPLC 1): Rt = 1.02 min, 99.5% ee

[0348] Example 1A: (7R,9R)-6-(4-(4-chloro-3-hydroxypicolinoyl) Piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 7-Methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1, 2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide Second eluting stereoisomer in chiral separation: 72.0 mg, purity 95%, yield: 7.5%

[0349] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=1.07 min; MS m / z [M+H] + 736.4 / 738.5m / z[MH] - 734.3 / 736.4; UPLC-MS 1 Chiral HPLC (C-HPLC 1): Rt = 1.80 min, 99.5% ee

[0350] The stereochemistry of Example 1A is (7R,9R), and that of Example 1C is (7S,9R). were assigned based on their potency and understanding of structure-activity relationships.

[0351] Example 2A: (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl )-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine -1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydrofuran Pyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carbohydrate Voxamide, and Example 2B: (7S,9S)-N-(2-chloro-4-(trifluoromethyl)-2-methyl-2-propanol methyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbo Nyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8 ,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyridine 7S,9R)-N-(2-chloro- 4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyridine) (4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5- Oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo [1,5-a]pyrimidine-9-carboxamide, and Example 2D: (7R,9S)-N -(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxyphenyl)- -6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2- Morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2 ,4]triazolo[1,5-a]pyrimidine-9-carboxamide [ka] Step 1: (7R,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine -4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)- (ethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetramethyl Hydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9- Carboxamide, and (7S,9R)-6-(4-(5-(benzyloxy)-6-methyl -N-(2-chloro-4-(trimethylpyrimidine-4-carbonyl)piperazin-1-yl)- (trifluoromethyl)phenyl)-7-methyl-2-morpholino 5-oxo-5,7,8, 9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin dine-9-carboxamide, and (7S,9S)-6-(4-(5-benzyloxy) -6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro- -4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino5oxo-5, 7,8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a ]pyrimidine-9-carboxamide, and (7R,9R)-6-(4-(5-(benzyl Oxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2 -chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5- Oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo [1,5-a]pyrimidine-9-carboxamide N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpho Lino-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolidone 1,2-c,1,2,4-triazolo[1,5-a]pyrimidine-9-carboxamide Intermediate C (650 mg, 1.12 mmol), 5-(benzyloxy)-6-methyl- Thiylpyrimidine-4-carboxylic acid (Intermediate U) (301 mg, 1.23 mmol) and H ATU (447 mg, 1.18 mmol) was mixed in DCM (20 mL) and cooled to 0°C. Then, DIPEA (489 μL, 2.80 mmol) was added. The mixture was stirred at room temperature. The mixture was stirred for 1.5 hours. Water (10 mL), saturated aqueous NaHCO3 (10 mL) and DCM ( The aqueous layer was washed with DCM (2 x 10 mL). The combined organic layers were The crude product was purified by reverse phase preparative HPLC (RP-HPLC) in six portions. - HPLC acid 1: 25-85% B in 20 min, 65% plateau for 1 min), (RP- HPLC acid 1: 40-75% B in 20 min), (RP-HPLC acid 1: 4 in 18 min 0-70% B, 60% plateau for 1 min), (RP-HPLC acidic 1: 48 for 17 min ~63%B) (RP-HPLC Acid 1: 48~61%B in 17 min) and (RP-HPLC C Acid 1: 45-60% B for 15 min, 50% B plateau for 2 min. All fractions containing the elution peak of 1 were combined and basified with saturated aqueous NaHCO3 solution. Extracted twice with DCM, dried on a phase separator and concentrated under reduced pressure to give (7R,9S)-6-( 4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazine- 1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl- 2-Morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1 ,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, and (7S,9 R)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl) Piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 7-Methyl-2-morpholino 5-oxo-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide A mixture of 100% methyl cellulose and 100% methyl cellulose was obtained. LC-MS: Rt=1.14 min; MS m / z [M+H] + 807.6 / 809.6m / z[MH] - 805.5 / 807.4; UPLC-MS 1

[0352] All fractions containing the second elution peak were combined and basified with saturated aqueous NaHCO3. The resulting mixture was extracted twice with DCM, dried on a phase separator, and concentrated under reduced pressure to give (7S,9S)-6 -(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazine N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl 2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c] [1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, and (7R ,9R)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl -(2-chloro-4-(trifluoromethyl)phenyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl) )-7-methyl-2-morpholino 5-oxo-5,7,8,9-tetrahydropyrrolo[1 ,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide A racemic mixture was obtained. LC-MS: Rt=1.16 min; MS m / z [M+H] + 807.5 / 809.5m / z[MH] - 805.3 / 807.2; UPLC-MS 1

[0353] Step 2a: (7R,9S)—N-(2-chloro-4-(trifluoromethyl)phenyl) -6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine- 1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydro Pyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carbo oxamide, and (7S,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl) (4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine) (1-phenyl-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydro- Dropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxylate Ruboxamide (7R,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4- Carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl) (phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydro Pyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carbo oxamide and (7R,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidinyl) N-(2-chloro-4-(trifluoromethyl)-4-piperazin-1-yl)-N ... (trimethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetramethyl Trihydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine- Racemic mixture of 9-carboxamides (first eluting peak) (325 mg, 403 μmol ) was dissolved in DCM (5 mL) and TFA (5.00 mL, 64.9 mmol) was added. The mixture was stirred at 60° C. overnight. The mixture was concentrated under reduced pressure. The crude product was extracted in two portions. Phase preparative HPLC (RP-HPLC Acidic 1: 20-80% B in 20 min, 40% plateau) 1 min at 50% and 2 min at 50% and (RP-HPLC acidic 1: 20 min at 25-75% B The product-containing fractions were combined, basified with saturated aqueous NaHCO3, and purified by It was extracted twice with CM, dried on a phase separator and concentrated under reduced pressure.

[0354] The racemate (224 mg, 95% purity) was separated by preparative chiral SFC (instrument: Sepiatec prep SFC-100;Column:Chiralpak IB-N 250mm×3 0mm 5μm; Eluent: A: 45%IPA+0.1%NH3, B: 55%scCO2; Flow rate: 80.0 mL / min; Detection: UV; Injection volume: 1.1 mL; Gradient: Isocratic A: 45% , B: 52%; oven temperature: 40°C; BPR: 110 bar).

[0355] First eluting stereoisomer: (7R,9S)-N-(2-chloro-4-(trifluoromethyl) )phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl) Piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9- Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine -9-carboxamide 99.0mg, purity 96%, yield: 33% LC-MS: Rt=0.98 min; MS m / z [M+H] + 717.6 / 719.6m / z[MH] - 715.4 / 717.4; UPLC-MS 1 LC-MS: Rt=4.86 min; MS m / z [M+H] + 717.5 / 719.6m / z[MH] - 715.4 / 717.4; UPLC-MS 2 Chiral HPLC (C-HPLC 2): Rt = 1.51 min, 99.5% ee

[0356] The second eluting stereoisomer (7S,9R)-N-(2-chloro-4-(trifluoromethyl) Phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)pyrimidine Perazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetramethyl- Trihydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine- 9-Carboxamide 90.0mg, purity 100%, yield: 31% LC-MS: Rt = 0.99 min; MS m / z [M+H] + 717.6 / 719.7m / z[MH] - 715.2 / 717.3; UPLC-MS 1 LC-MS: Rt = 4.90 min; MS m / z [M+H] + 717.5 / 719.5m / z[MH] - 715.5 / 717.4; UPLC-MS 2 Chiral HPLC (C-HPLC 2): Rt = 2.07 min, 97.2% ee

[0357] Step 2b: (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl) -6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine- 1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydro Pyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carbo oxamide, and (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl) (4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazine) (1-phenyl-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydro- Dropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxylate Ruboxamide (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4- Carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl) (phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydro Pyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carbo oxamide and (7R,9R)-6-(4-(5-(benzyloxy)-6-methylpyrimidinyl) N-(2-chloro-4-(trifluoromethyl)-4-piperazin-1-yl)-N ... (trimethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetramethyl Trihydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine- Racemic mixture of 9-carboxamides (second eluting peak) (359 mg, 414 μmol ) was dissolved in DCM (5 mL) and TFA (5.00 mL, 64.9 mmol) was added. The mixture was stirred at 60° C. overnight. The mixture was concentrated under reduced pressure. The crude product was extracted in two portions. Phase preparative HPLC (RP-HPLC basic 1: 25-75% B in 20 min) and (RP-H Purification was performed by PLC basic 1 (20-65% B in 20 min). The product-containing fractions were combined. The mixture was extracted twice with DCM, dried on a phase separator and concentrated under reduced pressure.

[0358] The racemic mixture (236 mg) was separated by preparative chiral HPLC (instrument: Waters Prep SF C100-MS; Column: Chiralpak IB-N 250×30mm 5μm; Eluent: A: 45% MeOH + 0.1% NH3, B: 55% scCO2; Flow rate: 80.0 mL / min; Detection: DAD; Injection volume: 1 mL; Gradient: Isocratic A: 45%, B: 55%; The purification was carried out by oven temperature: 40°C; BPR: 120 bar.

[0359] First eluting stereoisomer: (7S,9S)-N-(2-chloro-4-(trifluoromethyl) )phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl) Piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9- Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine -9-carboxamide 62.2mg, purity 87% The first eluting stereoisomer was purified by reversed-phase preparative HPLC (RP-HPLC acidic 2: 5 to 1 in 30 min). The product-containing fractions were combined and made basic with saturated aqueous NaHCO3. The resulting mixture was extracted twice with DCM, dried on a phase separator, and concentrated under reduced pressure to give the title compound (47 0.8 mg, purity 99%, yield: 16%) was obtained.

[0360] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt = 1.01 min; MS m / z [M+H]+ 717.5 / 719.5m / z[MH] - 715.3 / 717.4; UPLC-MS 1 Chiral HPLC (C-HPLC 3): Rt = 1.00 min, 97.5% ee

[0361] Second eluting stereoisomer: (7R,9R)-N-(2-chloro-4-(trifluoromethyl) )phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl) Piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9- Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine -9-carboxamide 41.3g, purity 100%, yield: 14% The sodium salt was prepared similarly to the general procedure. LC-MS: Rt = 1.00 min; MS m / z [M+H] + 717.6 / 719.6m / z[MH] - 715.5 / 717.4; UPLC-MS 1 Chiral HPLC (C-HPLC 3): Rt = 3.21 min, 99.5% ee

[0362] The stereochemistry of Example 2A is (7R,9R), and that of 2C is (7S,9R). were assigned based on their potency and understanding of structure-activity relationships.

[0363] Example 3A: (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl )-6-(4-(4-fluoro-3-hydroxy-6-methylpicolinoyl)piperazine -1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydrofuran Pyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carbohydrate Voxamide, and Example 3B: (7S,9S)-N-(2-chloro-4-(trifluoromethyl)-2-methyl-2-propanol methyl)phenyl)-6-(4-(4-fluoro-3-hydroxy-6-methylpicolino yl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8 ,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyridine Midine-9-carboxamide [ka] Step 1: (7S,9S)-6-(4-(3-(benzyloxy)-4-fluoro-6-methyl)-2-methyl ... (2-chloro-4-(trifluoromethyl)picolinoyl)piperazin-1-yl)-N-( ... (ethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetramethyl Hydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9- Carboxamide, and (7R,9R)-6-(4-(3-(benzyloxy)-4-fluoro (2-chloro-4-(trifluoro-6-methylpicolinoyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl-6-methylpicolinoyl)piperazin-1-yl) (trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8 ,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyridine Midine-9-carboxamide (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl 2-morpholino-5-oxo-6-(piperazin-1-yl)-5,7,8,9-methyl Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine -9-carboxamide and (7S,9S)-N-(2-chloro-4-(trifluoromethyl) (phenyl)phenyl)-7-methyl-2-morpholino-5-oxo-6-(piperazine-1-yl) 1,2-c-1,2,4-triazolo[1,2-c][1,2,4]triazolo[ 1,5-a]pyrimidine-9-carboxamide racemic mixture (intermediate D) (483 mg , 695 μmol), 3-(benzyloxy)-4-fluoro-6-methylpicolinic acid ( Intermediate V) (232 mg, 888 μmol) and HATU (277 mg, 730 μmol) l) was mixed in DCM (5 mL) and DIPEA (350 μL, 2.00 mmol) was added. The suspension turned into a solution and was stirred at room temperature for 1 hour. Water (10 mL), saturated NaHCO Aqueous solution of 3 (10 mL) and DCM (10 mL) were added. The aqueous layer was diluted with DCM (2 × 10 mL). The combined organic layers were dried over a phase separator and concentrated under reduced pressure. Purification was performed by reverse-phase preparative HPLC (RP-HPLC acidic 2: 35-65% B in 20 min). The product-containing fractions were combined, basified with saturated aqueous NaHCO3, and extracted twice with DCM. , dried on a phase separator and concentrated under reduced pressure to give the title compound.

[0364] This racemate (434 mg) was separated by preparative chiral HPLC (instrument: Waters Prep SFC100-MS; Column: Chiralpak IB-N 250mm x 30mm 5μm; Eluent: A: 40%MeOH+0.1%NH3, B: 60%scCO2; Flow rate: 80.0 mL / min; Detection: DAD; Injection volume: 1.3 mL; Gradient: Isocratic A: 40%, B: Purification was carried out by HPLC (BPR: 60%; BPR: 120 bar).

[0365] First eluting stereoisomer: (7S,9S)-6-(4-(3-benzyloxy)-4-furan (2-chloro-6-methylpicolinoyl)piperazin-1-yl)-N-(2-chloro-4-( (trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7, 8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pi Rimidine-9-carboxamide 181mg, purity 99%, yield: 31% LC-MS: Rt=1.25 min; MS m / z [M+H] + 824.5 / 826.3m / z[MH] - 822.1 / 824.1; UPLC-MS 1 LC-MS: Rt=6.29 min; MS m / z [M+H] + 824.3 / 826.3m / z[MH] - 822.3 / 824.2; UPLC-MS 2 Chiral HPLC (C-HPLC 4): Rt = 0.92 min, 99% ee

[0366] Second eluting stereoisomer: (7R,9R)-6-(4-(3-benzyloxy)-4-furan (2-chloro-6-methylpicolinoyl)piperazin-1-yl)-N-(2-chloro-4-( (trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7, 8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pi Rimidine-9-carboxamide 175mg, purity 99%, yield: 30% LC-MS: Rt=1.25 min; MS m / z [M+H] + 824.4 / 826.5m / z[MH] - 822.1 / 824.1; UPLC-MS 1 LC-MS: Rt=6.29 min; MS m / z [M+H] + 824.3 / 826.3m / z[MH] - 822.3 / 824.2; UPLC-MS 2 Chiral HPLC (C-HPLC 4): Rt = 3.13 min, 99% ee

[0367] Step 2a: (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl) -6-(4-(4-fluoro-3-hydroxy-6-methylpicolinoyl)piperazine- 1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydro Pyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carbo oxamide (7R,9R)-6-(4-(3-benzyloxy)-4-fluoro-6-methylpyridinyl) Corinoyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl) (phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydro Pyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carbo The oxamide (second eluting stereoisomer) (175 mg, 212 μmol) was dissolved in DCM (5 mL TFA (5.00 mL, 64.9 mmol) was added, and the mixture was heated at 60°C. The mixture was stirred for 2.5 days. The mixture was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (RP- Purification was performed by HPLC (10-90% B in 20 min). The product-containing fractions were combined. The mixture was then basified with saturated aqueous NaHCO3, extracted twice with DCM, dried on a phase separator, and reduced. Concentration under reduced pressure gave the title compound (115 mg, purity 99%, yield: 73%).

[0368] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=1.03 min; MS m / z [M+H] + 734.5 / 735.8m / z[MH] - 732.1 / 734.1; UPLC-MS 1

[0369] Step 2b: (7S,9S)—N-(2-chloro-4-(trifluoromethyl)phenyl) -6-(4-(4-fluoro-3-hydroxy-6-methylpicolinoyl)piperazine- 1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydro Pyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carbo oxamide (7S,9S)-6-(4-(3-benzyloxy)-4-fluoro-6-methylpyridinyl) Corinoyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl) (phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydro Pyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carbo The oxamide (first eluting stereoisomer) (181 mg, 219 μmol) was dissolved in DCM (5 mL TFA (5.00 mL, 64.9 mmol) was added, and the mixture was heated at 60°C. The mixture was stirred for 1.5 days. The mixture was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (RP- Purification was performed by HPLC (10-90% B in 20 min). The product-containing fractions were combined. The mixture was then basified with saturated aqueous NaHCO3, extracted twice with DCM, dried on a phase separator, and reduced. Concentration under reduced pressure gave the title compound (111 mg, purity 99%, yield: 68%).

[0370] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=1.03 min; MS m / z [M+H] + 734.5 / 735.8m / z[MH] - 732.1 / 734.1; UPLC-MS 1

[0371] Based on an understanding of potency and structure-activity relationships, the stereochemistry of Example 3A is (7R,9R). and assigned it.

[0372] Example 4A: (7R,9R)—N-(2-chloro-6-(trifluoromethyl)pyridine -3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5- Hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methylpyrimidine Thiyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4] Triazolo[1,5-a]pyrimidine-9-carboxamide [ka] Step 1: (7R,9R)-6-(4-(5-benzyloxy-6-methylpyrimidine-4 -carbonyl)piperazin-1-yl)-N-(2-chloro-6-(trifluoromethyl )pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl Thiyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4] Triazolo[1,5-a]pyrimidine-9-carboxamide (7R,9R)-N-(2-chloro-6-(trifluoromethyl) )pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl 5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolidone 1,2-c,1,2,4-triazolo[1,5-a]pyrimidine-9-carboxamide amide (intermediate E1) (127 mg, 206 μmol) and 5-(benzyloxy)-6- Methylpyrimidine-4-carboxylic acid (intermediate U) (50.4 mg, 206 μmol) DIPEA (180 μL, 1.03 mmol) was added, and the reaction mixture was stirred at room temperature for 2 minutes. The mixture was stirred, and then HATU (86.0 mg, 227 μmol) was added, and the reaction mixture was stirred at room temperature. The mixture was stirred for 13 minutes. The reaction mixture was diluted with water (3 mL) and sonicated. The resulting suspension The mixture was stirred for 1 hour. The mixture was filtered and dried to give the title compound (11) as a colorless solid. 4 mg, purity 90%, yield: 62% were obtained. LC-MS:Rt=1.08 min;MS m / z[M+H-Boc] + 805.5 / 807 .5, m / z [MH] - 803.4 / 805.4; UPLC-MS 1

[0373] Step 2: (7R,9R)-N-(2-chloro-6-(trifluoromethyl)pyridine-3 -yl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydro ((6-methyl-4-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl -5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]tri Azolo[1,5-a]pyrimidine-9-carboxamide (7R,9R)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4- Carbonyl)piperazin-1-yl)-N-(2-chloro-6-(trifluoromethyl) Pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl 5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]trimethylsilyl Riazolo[1,5-a]pyrimidine-9-carboxamide (114 mg, 142 μmol ) was dissolved in TFA (1.00 mL, 13.0 mmol) and stirred at 55° C. for 5.5 hours. The reaction mixture was evaporated and the crude product was purified by reverse phase preparative HPLC (RP-HPLC acidic 1:15 min). The product was purified by 20-50% B. The product-containing fractions were combined and lyophilized. The resulting powder (TFA solvate) was redissolved in DCM (5 mL) and solid NaHCO3 (50 0.0 mg) was added. The suspension was kept at room temperature for 20 minutes, filtered and evaporated under reduced pressure to give The title compound was obtained as a colorless solid (62.0 mg, purity 99%, yield: 61%).

[0374] The sodium salt was prepared similarly to the general procedure. LC-MS:Rt=0.91 min;MS m / z[M+H-Boc] + 715.4 / 717 .4, m / z [MH] - 713.1 / 715.1; UPLC-MS 1

[0375] Based on an understanding of potency and structure-activity relationships, the stereochemistry of Example 4A was chosen as (7R,9R). and assigned it.

[0376] Example 4B: (7S,9S)—N-(2-chloro-6-(trifluoromethyl)pyridine -3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5- Hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methylpyrimidine Thiyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4] Triazolo[1,5-a]pyrimidine-9-carboxamide [ka] Step 1: (7S,9S)-6-(4-(5-benzyloxy-6-methylpyrimidine-4 -carbonyl)piperazin-1-yl)-N-(2-chloro-6-(trifluoromethyl )pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl Thiyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4] Triazolo[1,5-a]pyrimidine-9-carboxamide (7S,9S)-N-(2-chloro-6-(trifluoromethyl) )pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl 5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolidone 1,2-c,1,2,4-triazolo[1,5-a]pyrimidine-9-carboxamide amide (intermediate E2) (122 mg, 198 μmol) and 5-(benzyloxy)-6- Methylpyrimidine-4-carboxylic acid (Intermediate U) (48.0 mg, 196 μmol) DIPEA (180 μL, 1.03 mmol) was added, and the reaction mixture was stirred at room temperature for 2 minutes. The mixture was stirred, and then HATU (82.0 mg, 216 μmol) was added, and the reaction mixture was stirred at room temperature. The mixture was stirred for 13 minutes. The reaction mixture was diluted with water (3 mL) and sonicated. The resulting suspension The mixture was stirred for 1 hour. The mixture was filtered and dried to give the title compound as an off-white solid. The compound (104 mg, purity 85%, yield: 53%) was obtained. LC-MS:Rt=1.10 min;MS m / z[M+H-Boc] + 805.5 / 807 .6, m / z [MH] - 803.2 / 805.2; UPLC-MS 1

[0377] Step 2: (7S,9S)—N-(2-chloro-6-(trifluoromethyl)pyridine-3 -yl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydro ((6-methyl-4-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl -5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]tri Azolo[1,5-a]pyrimidine-9-carboxamide (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4- (carbonyl)piperazin-1-yl)-N-(2-chloro-6-(trifluoromethyl)piperazin-1-yl)- Lysin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl -5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]tri Azolo[1,5-a]pyrimidine-9-carboxamide (104 mg, 129 μmol) was dissolved in TFA (1.00 mL, 13.0 mmol) and stirred at 55° C. for 5.5 hours. The reaction mixture was evaporated and the crude product was purified by reverse phase preparative HPLC (RP-HPLC acidic 1:15 min). The product was purified by 20-50% B. The product-containing fractions were combined and lyophilized. The resulting powder (TFA solvate) was redissolved in DCM (5 mL) and solid NaHCO3 (50. 0 mg) was added. The suspension was kept at room temperature for 20 min, filtered and concentrated under reduced pressure to give a colorless The title compound was obtained as a solid (51.0 mg, purity 99%, yield: 50%). LC-MS:Rt=0.91 min;MS m / z[M+H-Boc] + 715.4 / 717 .4, m / z [MH] - 713.1 / 715.1; UPLC-MS 1

[0378] Example 5A: (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl )-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-hydroxy -2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazine-1-yl (I)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][ 1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide [ka] Step 1: (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-methoxymethyl) cis-2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazine-1- (yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c] [1,2,4]Triazolo[1,5-a]pyrimidine-9-carboxamide (7R,9R)-N-(2-chloro-4-(trifluoromethyl) )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (intermediate H4) (155 mg, 268 μmol), 7-(methoxymethoxy)-2,3-dihydriodide Furo[3,2-c]pyridine-6-carboxylic acid (intermediate Z) (60.4 mg, 268 μL) To a stirred solution of 23 mol) and HATU (122 mg, 322 μmol) was added DIPEA (23 4 μL, 1.34 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 2 minutes. The reaction mixture was diluted with EtOAc and water, extracted twice with EtOAc, and the combined organic layers were washed with Na The crude product was purified by column chromatography (Redi Separation column: 12g silica, eluent: DCM: DCM / MeOH (8 / 2) 100:0 The product-containing fractions were combined, concentrated under reduced pressure, and dried under high vacuum. Drying gave the title compound (164 mg, purity 96%, yield: 75%). LC-MS: Rt=1.03 min; MS m / z [M+H] + 785.5 / 787.5m / z[MH] - 783.4 / 784.7; UPLC-MS 1 LC-MS: Rt=5.04 min; MS m / z [M+H] + 785.5 / 787.5m / z[MH] - 783.3 / 785.3; UPLC-MS 2

[0379] Step 2: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-hydroxy-2 ,3-Dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl) -7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1, 2,4]Triazolo[1,5-a]pyrimidine-9-carboxamide (7R,9R)-N-(2-chloro-4-(trifluoromethyl)methyl)propanol in EtOH (1.5 mL) methyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4- (7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carbohydrate (1-(2-methyl-4-pyridinyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydro- Dropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxylate Ruboxamide (164 mg, 201 μmol), and EtOH (1.50 mL, 1.88 The reaction mixture was stirred at room temperature for 14 hours in 1.25M HCl (2.2 mmol). Diluted with aqueous NaHCO3, extracted twice with DCM, and the combined organic layers were dried over Na2SO4 The crude product was purified by reverse phase preparative HPLC (RP-HPLC acidic 1:20 The title compound (117 mg, purity 8.0%) was purified by HPLC using a 20-75% B column in 1 min to give the title compound (117 mg, purity 8.0%) as a white solid. 100%, yield: 79%).

[0380] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=0.94 min; MS m / z [M+H] + 741.6 / 743.6m / z[MH] - 739.4 / 741.4; UPLC-MS 1 LC-MS: Rt = 4.75 min; MS m / z [M+H] + 741.5 / 743.5m / z[MH] - 739.5 / 741.4; UPLC-MS 2

[0381] Based on an understanding of potency and structure-activity relationships, the stereochemistry of Example 5A was chosen as (7R,9R). and assigned it.

[0382] Example 5B: (7S,9S)—N-(2-chloro-4-(trifluoromethyl)phenyl )-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-hydroxy -2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazine-1-yl (I)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][ 1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide [ka] Step 1: (7S,9S)—N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-methoxymethyl) cis-2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazine-1- (yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c] [1,2,4]Triazolo[1,5-a]pyrimidine-9-carboxamide (7S,9S)-N-(2-chloro-4-(trifluoromethyl) )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (intermediate Form H3) (150 mg, 260 μmol), 7-(methoxymethoxy)-2,3-dihydriodide Furo[3,2-c]pyridine-6-carboxylic acid (intermediate Z) (58.4 mg, 260 μL) To a stirred solution of 22 mol) and HATU (118 mg, 311 μmol) was added DIPEA (22 7 μL, 1.30 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 2 minutes. The reaction mixture was diluted with EtOAc and water, extracted twice with EtOAc, and the combined organic layers were washed with Na The crude product was purified by column chromatography (Redi Separation column: 24g silica, eluent: DCM: DCM / MeOH (8 / 2) 100:0 The product-containing fractions were combined, concentrated under reduced pressure, and dried under high vacuum. Drying gave the title compound (155 mg, purity 95%, yield: 72%). LC-MS: Rt=1.02 min; MS m / z [M+H] + 785.5 / 787.5m / z[MH] - 783.3 / 785.3; UPLC-MS 1 LC-MS: Rt = 5.05 min; MS m / z [M+H] + 785.6 / 787.5m / z[MH] - 783.4 / 785.3; UPLC-MS 2

[0383] Step 2: (7S,9S)—N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-hydroxy-2 ,3-Dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl) -7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1, 2,4]Triazolo[1,5-a]pyrimidine-9-carboxamide (7S,9S)-N-(2-chloro-4-(trifluoromethyl)methyl)propanol in EtOH (1.5 mL) methyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4- (7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carbohydrate (1-(2-methyl-4-pyridinyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydro- Dropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxylate Ruboxamide (155 mg, 188 μmol), and EtOH (1.50 mL, 1.88 The reaction mixture was stirred at room temperature for 14 hours in 1.25M HCl (2.2 mmol). Diluted with aqueous NaHCO3, extracted twice with DCM, and the combined organic layers were dried over Na2SO4 The crude product was purified by reverse phase preparative HPLC (RP-HPLC acidic 1:25 The title compound (111 mg, purity 9%) was obtained as a white solid. 9%, yield: 79%).

[0384] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=0.93 min; MS m / z [M+H] + 741.6 / 743.4m / z[MH] - 739.4 / 741.4; UPLC-MS 1 LC-MS: Rt=4.67 min; MS m / z [M+H] + 741.6 / 743.6m / z[MH] - 739.4 / 741.3; UPLC-MS 2

[0385] Example 6A: (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl )-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro- 3-hydroxypicolinoyl)piperazin-1-yl)-7-methyl-5-oxo-5, 7,8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a ]pyrimidine-9-carboxamide [ka] Step 1: (7R,9R)-6-(4-(3-(benzyloxy)-4-fluoropicolino) (2-chloro-4-(trifluoromethyl)phenyl)-N-(2-chloro-4-(trifluoromethyl)phenyl)- -2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo- 5,7,8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5 -a]pyrimidine-9-carboxamide (7R,9R)-N-(2-chloro-4-(trifluoromethyl) )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (intermediate Form H4) (155 mg, 268 μmol), 3-(benzyloxy)-4-fluoropicoate Phosphoric acid (intermediate W) (66.3 mg, 268 μmol) and HATU (122 mg, 32 To a stirred solution of 2 μmol of PEG-400 (234 μL, 1.34 mmol) was added DIPEA (234 μL, 1.34 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 minutes. The reaction mixture was diluted with EtOAc and water and diluted with Et0Ac. It was extracted twice with tOAc and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: 12 g silica, eluent D The product was purified by DMSO / MeOH (8 / 2) 100:0 to 50:50. The fractions were combined, concentrated under reduced pressure and dried under HV to give the title compound (211 mg, purity 94%, yield: 92%). LC-MS: Rt=1.23 min; MS m / z [M+H] + 807.6 / 809.5m / z[MH] - 805.4 / 807.4; UPLC-MS 1 LC-MS: Rt=6.19 min; MS m / z [M+H] + 807.5 / 809.5m / z[MH] - 805.6 / 807.4; UPLC-MS 2

[0386] Step 2: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro-3- Hydroxypicolinoyl)piperazin-1-yl)-7-methyl-5-oxo-5,7, 8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pi Rimidine-9-carboxamide (7R,9R)-6-(4-(3-( benzyloxy)-4-fluoropicolinoyl)piperazin-1-yl)-N-(2-chlorobenzyloxy) 2-(3,6-dihydro-4-(trifluoromethyl)phenyl)-4H-pyran -4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (21 The mixture (0 mg, 245 μmol) was stirred at 50° C. for 14 hours. The reaction mixture was diluted with DCM and NaH Diluted with aqueous CO3, extracted twice with DCM, and the combined organic layers were dried over Na2SO4 The crude product was purified by reverse phase preparative HPLC (RP-HPLC acid 1:20 min). 20-75% B) to give the title compound (96.0 mg, purity 10%) as a white solid. 0%, yield: 55%).

[0387] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=1.02 min; MS m / z [M+H] + 717.5 / 719.5m / z[MH] - 715.3 / 717.3; UPLC-MS 1 LC-MS: Rt=5.04 min; MS m / z [M+H] + 717.5 / 719.5m / z[MH] - 715.3 / 717.3; UPLC-MS 2

[0388] Based on an understanding of potency and structure-activity relationships, the stereochemistry of Example 6A was chosen as (7R,9R). and assigned it.

[0389] Example 6B: (7S,9S)—N-(2-chloro-4-(trifluoromethyl)phenyl )-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro- 3-hydroxypicolinoyl)piperazin-1-yl)-7-methyl-5-oxo-5, 7,8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a ]pyrimidine-9-carboxamide [ka] Step 1: (7S,9S)-6-(4-(3-(benzyloxy)-4-fluoropicolino) (2-chloro-4-(trifluoromethyl)phenyl)-N-(2-chloro-4-(trifluoromethyl)phenyl)- -2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo- 5,7,8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5 -a]pyrimidine-9-carboxamide (7S,9S)-N-(2-chloro-4-(trifluoromethyl) )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (intermediate Form H3) (150 mg, 260 μmol), 3-(benzyloxy)-4-fluoropicoate Phosphoric acid (intermediate W) (64.2 mg, 260 μmol) and HATU (118 mg, 31 To a stirred solution of 1 μmol of PEG-100 (DIPEA) was added at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, diluted with EtOAc and water, and Extracted twice with EtOAc, the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure The crude product was purified by column chromatography (RediSep column: 12 g silica, eluent The product was purified using DCM:DCM / MeOH (8 / 2) 100:0 to 50:50. The containing fractions were combined, concentrated under reduced pressure and dried under HV to give the title compound (159 mg, pure). The purity was 92% and the yield was 70%. LC-MS: Rt=1.22 min; MS m / z [M+H] + 807.5 / 809.5m / z[MH] - 805.4 / 807.4; UPLC-MS 1 LC-MS: Rt=6.09 min; MS m / z [M+H] + 807.5 / 809.5m / z[MH] - 805.4 / 807.4; UPLC-MS 2

[0390] Step 2: (7S,9S)—N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro-3- Hydroxypicolinoyl)piperazin-1-yl)-7-methyl-5-oxo-5,7, 8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pi Rimidine-9-carboxamide (7S,9S)-6-(4-(3-( benzyloxy)-4-fluoropicolinoyl)piperazin-1-yl)-N-(2-chlorobenzyloxy) 2-(3,6-dihydro-4-(trifluoromethyl)phenyl)-4H-pyran -4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (15 The mixture (9 mg, 181 μmol) was stirred at 50° C. for 14 hours. The reaction mixture was diluted with DCM and NaH Diluted with aqueous CO3, extracted twice with DCM, and the combined organic layers were dried over Na2SO4 The crude product was purified by reverse phase preparative HPLC (RP-HPLC acid 1:20 min). 20-75% B) to give the title compound (77.0 mg, purity 98%) as a white solid. %, yield: 58%).

[0391] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=1.02 min; MS m / z [M+H] + 716.9 / 718.9m / z[MH] - 715.3 / 717.4; UPLC-MS 1 LC-MS: Rt=5.06 min; MS m / z [M+H] + 716.9 / 718.8m / z[MH] - 715.4 / 717.3; UPLC-MS 2

[0392] Example 7: (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl) -2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-6-(4-(1- Methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carbohydrate Nyl)piperazin-1-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1 ,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide [ka] 1-Methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3- The carboxylic acid (20.9 mg, 138 μmol) was dissolved in DCM (1.4 ml) at room temperature under argon. L). Acetone (21.9 mg, 152 μmol) was added and the reaction mixture was stirred at room temperature for 1.75 h. (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2 -(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(pyran-4-yl)- Perazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2, 4]triazolo[1,5-a]pyrimidine-9-carboxamide (intermediate H4) (40. 0 mg, 69.0 μmol) was added, followed by DIPEA (61.0 μL, 346 μmol) l) was added and the resulting brown solution was stirred at room temperature for 1 hour. Water (3 mL) and saturated Na Aqueous HCO3 (2 mL) was added and the reaction mixture was kept at room temperature overnight. Extract with M (4 x 20 mL), wash the combined organic layers with water (5 mL) and dry on a phase separator. The crude product was purified by reverse phase chromatography to give an orange solid (66.0 mg). Purification was performed by preparative HPLC (RP-HPLC acidic 1: 15-85% B in 20 min). The product-containing fractions were combined, the ACN was removed under reduced pressure, and the aqueous residue was salted with saturated aqueous NaHCO3. The combined organic layers were dried in a phase separator and extracted with DCM (4 x 20 mL). Concentration under reduced pressure gave the title compound (35.8 mg, purity 99%, yield: 73%) as a white solid. %) was obtained.

[0393] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt = 0.99 min; MS m / z [M+H] + 703.6 / 705.6m / z[MH] - 701.3 / 703.3; UPLC-MS 1 LC-MS: Rt = 4.89 min; MS m / z [M+H] + 703.1 / 705.1m / z[MH] - 701.3 / 703.3; UPLC-MS 2

[0394] Example 8 (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro-3- Hydroxy-6-methylpicolinoyl)piperazin-1-yl)-7-methyl-5-ox so-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1 ,5-a]pyrimidine-9-carboxamide [ka] Step 1: (7R,9R)-6-(4-(3-(benzyloxy)-4-fluoro-6-methyl)- (2-chloro-4-(trifluoromethyl)picolinoyl)piperazin-1-yl)-N-( ... 2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl- 5-Oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triaconazole Zolo[1,5-a]pyrimidine-9-carboxamide (7R,9R)-N-(2-chloro-4-(trifluoromethyl) )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (intermediate Form H4) (155 mg, 268 μmol), 3-(benzyloxy)-4-fluoro-6 -methylpicolinic acid (Intermediate V) (80.0 mg, 268 μmol) and HATU (12 To a stirred solution of 2 mg (322 μmol) of DIPEA (234 μL, 1.34 mmol) was added at room temperature and the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with EtOAc and water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and The crude product was purified by column chromatography (RediSep column: silica 12 g The eluent was DCM:DCM / MeOH (8 / 2) 100:0 to 50:50. The product-containing fractions were combined, concentrated under reduced pressure, and dried under high vacuum to give a white foam. The title compound (220 mg, purity 92%, yield: 92%) was obtained. LC-MS: Rt=1.28 min; MS m / z [M+H] + 821.6 / 823.6m / z[MH] - 819.5 / 821.4; UPLC-MS 1 LC-MS: Rt=6.43 min; MS m / z [M+H] + 821.5 / 823.6m / z[MH] - 819.6 / 821.6; UPLC-MS 2

[0395] Step 2: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro-3- Hydroxy-6-methylpicolinoyl)piperazin-1-yl)-7-methyl-5-ox so-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1 ,5-a]pyrimidine-9-carboxamide (7R,9R)-6-(4-(3-( benzyloxy)-4-fluoro-6-methylpicolinoyl)piperazin-1-yl)- N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro- 2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyran Triazolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide The reaction mixture was stirred at 50° C. for 40 hours. The mixture was diluted with M and aqueous NaHCO3, extracted twice with DCM, and the combined organic layers were washed with Na2SO The crude product was purified by column chromatography (RediSep Column: 24g of silica, eluent: DCM: DCM / MeOH (8 / 2) 100:0-50 The product-containing fractions were combined, concentrated under reduced pressure, and dried under high vacuum. This gave the title compound (150 mg, purity 100%, yield: 83%) as a white solid.

[0396] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=1.06 min; MS m / z [M+H] + 731.5 / 733.5m / z[MH] - 729.3 / 731.3; UPLC-MS 1 LC-MS: Rt=5.25 min; MS m / z [M+H] + 731.6 / 733.5m / z[MH] - 729.3 / 731.4; UPLC-MS 2

[0397] Example 9: (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl) -2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(6-hydroxyisothiazolinone) Midazo[1,2-a]pyridine-5-carbonyl)piperazin-1-yl)-7-methyl -5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]tri Azolo[1,5-a]pyrimidine-9-carboxamide [ka] Step 1: (7R,9R)-6-(4-(6-benzyloxy)imidazo[1,2-a] Pyridine-5-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)pyridine (fluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7- Methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4 ]triazolo[1,5-a]pyrimidine-9-carboxamide (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-( 3,6-Dihydro-2H-pyran-4-yl)-7-ethyl-5-oxo-6-(pipera) Zin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4] Triazo[1,5-a]pyromidine-9-carboxamide (intermediate H4) (71.1 mg , 123 μmol) and 6-(benzyloxy)imidazo[1,2-a]pyridine-5- The carboxylic acid (intermediate AA) (33.0 mg, 123 μmol) was added under argon at room temperature. HATU (56.1 mg, 148 μmol) and DIPEA (107 μL, 615 μmol) was added and the reaction mixture was stirred at room temperature for 45 min. The reaction was then quenched with water (10 mL). The reaction mixture was diluted with EtOAc (3× The mixture was extracted with 50 mL of water and washed with 3 x 10 mL of water and 2 x 10 mL of brine. The combined organic layers were dried on a phase separator over Na2SO4 and concentrated under reduced pressure to give a brown oil. The crude product was purified by reverse phase preparative HPLC (RP-HPLC acid 1:20 The product-containing fractions were combined and purified with saturated aqueous NaHCO3. The solution was basified, the ACN was removed under reduced pressure, and the aqueous residue was extracted with DCM (4 x 20 mL). The combined organic layers were dried on a phase separator and concentrated under reduced pressure to give a pale pink solid. As a result, the title compound (63.0 mg, purity 99%, yield: 61%) was obtained. LC-MS: Rt=1.04 min; MS m / z [M+H] + 828.3 / 830.4m / z[MH] - 826.3 / 828.3; UPLC-MS 1

[0398] Step 2: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(6-hydroxyimino) Dazo[1,2-a]pyridine-5-carbonyl)piperazin-1-yl)-7-methyl- 5-Oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triaconazole Zolo[1,5-a]pyrimidine-9-carboxamide (7R,9R)-6-(4-(6-(benzyloxy)imidazo[1,2-a]pyridin N-(2-chloro-4-(trifluoro-5-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl) ... methyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl -5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]tri Azolo[1,5-a]pyrimidine-9-carboxamide (61.5 mg, 74.0 μmol l) was mixed with TFA (1.00 mL, 13.0 mmol), and the reaction mixture was heated at 50°C. The mixture was stirred for 52.5 hours and then at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and The brown solid residue was extracted with DCM (4 x 50 mL) and saturated NaHCO The mixture was extracted with 3 aqueous solution (15 mL) and brine (15 mL). The combined organic layers were separated using a phase separator. The crude product was dried at 47°C and concentrated under reduced pressure to give a light brown solid (77.0 mg). The mixture was adsorbed onto Isolute and subjected to column chromatography (RediSep column: silica 1 2g, purified with eluent DCM:DCM / MeOH (8 / 2) 100:0 to 20:80 The product-containing fractions were combined and concentrated under reduced pressure to give the product as a beige solid. The title compound was obtained (35.4 mg, purity 100%, yield: 65%).

[0399] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=0.88 min; MS m / z [M+H] + 738.6 / 740.7m / z[MH] - 736.4 / 738.3; UPLC-MS 1 LC-MS: Rt=4.35 min; MS m / z [M+H] + 738.2 / 740.2m / z[MH] - 736.3 / 738.2; UPLC-MS 2

[0400] Example 10 (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl) -2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(3-hydroxy- 2-methylisonicotinoyl)piperazin-1-yl)-7-methyl-5-oxo-5, 7,8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a ]pyrimidine-9-carboxamide [ka] 3-Hydroxy-2-methylisonicotinic acid (41.4 mg, 208 μmol) was added to The 1-chloro-N,N,2-trimethylpropanediol was dissolved in DCM (2 mL) at room temperature under pressure. Lop-1-en-1-amine (32.8 mg, 228 μmol) was added and the reaction mixture The mixture was stirred at room temperature for 2.25 hours. (7R,9R)-N-(2-chloro-4-(trifluoromethyl)-2-methyl-2-oxo ...oxo-2-methyl (3,6-dihydro-2H-pyran-4-yl)-7-methyl 5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo [1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide Intermediate H4 (60.0 mg, 104 μmol) and DIPEA (91.0 μL, 5 19 μmol) was added and the reaction mixture was stirred at room temperature for 4 days. mL) and saturated aqueous NaHCO3 (2 mL), and quenched with DCM (4 x 20 mL). The combined organic layers were washed with water (5 mL), dried on a phase separator, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (RP-HPLC) to give a brown oil (126 mg). C Acid 1: 20-80% B in 20 min. The product-containing fractions were combined and saturated. The aqueous residue was basified with aqueous NaHCO3, the ACN was removed under reduced pressure, and the aqueous residue was diluted with DCM (4 × 2 The combined organic layers were washed with water, dried on a phase separator, and concentrated under reduced pressure. The title compound was obtained as a white solid (37.0 mg, purity 100%, yield: 50%). .

[0401] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=0.95 min; MS m / z [M+H] + 713.5 / 715.5m / z[MH]- 711.2 / 713.2; UPLC-MS 1

[0402] Example 11 (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl) -2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(3-hydroxypyran-4-yl) ... Corinoyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetramethyl Lahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9 -Carboxamide [ka] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-( 3,6-Dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(pipera) Zin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4] Triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H4) (79.0 m g, 137 μmol) was dissolved in DCM (1.4 mL) under argon at 0°C. roxypicolinoyl chloride (Intermediate X) (36.6 mg, 232 μmol) was added, Subsequently, DIPEA (120 μL, 683 μmol) was added slowly. The mixture was stirred at room temperature for 1.75 hours to give 3-hydroxypicolinoyl chloride (Intermediate X) (15. 0 mg, 95.0 μmol) was added again and the reaction mixture was stirred at room temperature for 4.5 hours. The mixture was quenched with water (3 mL) and saturated aqueous NaHCO3 (3 mL) and diluted with DCM (4 The combined organic layers were dried on a phase separator and concentrated under reduced pressure to give a brown A colored solid (117 mg) was obtained. The crude product was purified by reverse phase preparative HPLC (RP-HPLC Acid 1: Purification was performed by 10-70% B in 20 min. The product-containing fractions were combined and purified with saturated NaHCO. 3 in water, the ACN was removed under reduced pressure, and the aqueous residue was diluted with DCM (4 × 15 mL). The aqueous layer was extracted twice with EtOAc. The organic layer was dried in a phase separator and concentrated under reduced pressure. The title compound (57.0 mg, purity 100%, yield: 60%) was obtained as a beige solid. %) was obtained.

[0403] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt = 1.01 min; MS m / z [M+H] + 699.5 / 701.3m / z[MH] - 697.1 / 699.1; UPLC-MS 1 LC-MS: Rt = 5.08 min; MS m / z [M+H] + 699.2 / 701.2 m / z[MH] - 697.2 / 699.2; UPLC-MS 2

[0404] Example 12 (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl) -2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(2-fluoro-3 -hydroxyisonicotinoyl)piperazin-1-yl)-7-methyl-5-oxo-5 ,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a] Pyrimidine-9-carboxamide [ka] 2-Fluoro-3-hydroisonicotinic acid (54.4 mg, 346 μmol) was dissolved in argon. The resulting mixture was dissolved in DCM (3.5 mL) at room temperature under reduced pressure. Prop-1-en-1-amine (54.4 mg, 346 μmol) was added to the reaction mixture. The mixture was stirred at room temperature for 2.25 hours. (7R,9R)-N-(2-chloro-4-(trifluoromethyl)-2,4-difluoromethanesulfonyl ... (3,6-dihydro-2H-pyran-4-yl)-7-methyl- 5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolidone 1,2-c,1,2,4-triazolo[1,5-a]pyrimidine-9-carboxamide The amide (Intermediate H4) (100 mg, 173 μmol) was added, followed by DIPEA (15 1 μL, 865 μmol) was added. The reaction mixture was stirred at room temperature for 50 minutes. The mixture was quenched with water (3 mL) and saturated aqueous NaHCO3 (3 mL) and diluted with DCM (4 x 2 The combined organic layers were dried on a phase separator and concentrated under reduced pressure to give a brown An oil (174 mg) was obtained. The crude product was purified by reverse phase preparative HPLC (RP-HPLC acidic 1:2 The product-containing fractions were combined and purified by saturated NaHCO3 The aqueous solution was basified with HCl, the ACN was removed under reduced pressure, and the aqueous residue was extracted with DCM (4 x 50 mL). The combined organic layers were washed with water, dried on a phase separator and concentrated under reduced pressure to give a white solid. The title compound (59.4 mg, purity 100%, yield: 48%) was obtained as a solid.

[0405] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt = 1.01 min; MS m / z [M+H] + 717.2 / 719.2m / z[MH] - 715.3 / 717.3; UPLC-MS 1

[0406] Example 13 (7R,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl) -2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxypyridine) Rimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7 ,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a] Pyrimidine-9-carboxamide [ka] Step 1: (7R,9R)-6-(4-(5-(benzyloxy)pyrimidine-4-carbo N-(2-chloro-4-(trifluoromethyl)phenyl)piperazin-1-yl -2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo- 5,7,8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5 -a]pyrimidine-9-carboxamide (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-( 3,6-Dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(pipera) Zin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4] Triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H4) (113 mg , 196 μmol) and 5-(benzyloxy)pyrimidine-4-carboxylic acid (47.3 mg, 205 μmol) were mixed in DMF (2.7 mL) under argon at room temperature. HATU (92.0 mg, 235 μmol) was added, followed by DIPEA (171 μL , 978 μmol) was added. The reaction mixture was stirred at room temperature for 1.75 hours. It was quenched with water (5 mL) and extracted with EtOAc (3×60 mL). Wash with water (2 x 25 mL) and brine (2 x 20 mL) and phase separate with Na2SO4. The crude product was dried over a separatory tube and concentrated under reduced pressure to give a light brown solid (182 mg). The product was purified by reverse-phase preparative HPLC (RP-HPLC acidic 1: 20-80% B in 20 min). The product-containing fractions were combined and lyophilized to give the title compound (64.0 mg) as a white solid. The product was obtained with a purity of 94% and a yield of 39%. LC-MS: Rt=1.13 min; MS m / z [M+H] + 790.5 / 792.5m / z[MH] - 788.4 / 790.4; UPLC-MS 1

[0407] Step 2: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxypyridine) 7-methyl-5-oxo-5,7-imidin-4-carbonyl)piperazin-1-yl)- 8,9-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pi Rimidine-9-carboxamide (7R,9R)-6-(4-(5-(benzyloxy)pyrimidine-4-carbonyl) Piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-Dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7 ,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a] Pyrimidine-9-carboxamide (64.4 mg, 81.0 μmol) was dissolved in TFA (1.9 0 mL, 24.5 mmol) and the reaction mixture was stirred at 50°C for 70 hours. The mixture was concentrated under reduced pressure, redissolved in DCM, concentrated again, and then dried under HV. The crude product was adsorbed onto Isolute and purified by filtration to give a light brown oil (61.5 mg). Column chromatography (RediSep column: silica 12g Gold, eluent D CM:DCM / MeOH (8 / 2) 100:0 to 20:80), and then S Further purification was carried out by FC (SFC1). The product-containing fractions were combined and concentrated under reduced pressure to give The title compound was obtained as a beige solid (28.4 mg, purity 100%, yield: 50%). Ta.

[0408] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=0.97 min; MS m / z [M+H] + 700.4 / 702.3m / z[MH] - 698.3 / 700.3; UPLC-MS 1 LC-MS: Rt = 4.91 min; MS m / z [M+H] + 700.3 / 702.2m / z[MH] - 698.2 / 700.2; UPLC-MS 2

[0409] Example 14A: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- -2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxybenzoyl) (6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5 -Oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazo 2-[1,5-a]pyrimidine-9-carboxamide [ka] Step 1: (7R,9R)-6-(4-(5-benzyloxy-6-methylpyrimidine-4 -carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo [1,5-a]pyrimidine-9-carboxamide (7R,9R)-N-(2-chloro-4-(trifluoromethyl) )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (intermediate Form H4) (155 mg, 268 μmol), 5-(benzyloxy)-6-methylpyrimidin azine-4-carboxylic acid (intermediate U) (65.5 mg, 268 μmol) and HATU (1 To a stirred solution of 22 mg, 322 μmol) of DIPEA (234 μL, 1.34 mmol) ) was added at room temperature, and the reaction mixture was stirred at room temperature for 10 minutes. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and reduced. The crude product was purified by column chromatography (RediSep column: silica 2 4g, purified with eluent DCM:DCM / MeOH (8 / 2) 100:0 to 50:50 The product-containing fractions were combined, concentrated under reduced pressure, and dried under high vacuum to give the title compound ( 211 mg, purity 91%, yield: 89% were obtained. LC-MS: Rt = 1.20 min; MS m / z [M+H] + 804.5 / 806.5m / z[MH] - 802.5 / 804.5; UPLC-MS 1 LC-MS: Rt=5.98 min; MS m / z [M+H] + 804.5 / 806.5m / z[MH] - 802.5 / 804.5; UPLC-MS 2

[0410] Step 2: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6 -methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo so-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1 ,5-a]pyrimidine-9-carboxamide (7R,9R)-6-(4-(5-benzyloxy)-6-methyl)-2-methyl-2-methyl-1H-pyridin-2-one in TFA (2 mL) 4-(2-chloro-4-( ... (trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl) -7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1, 2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (211 mg, 23 9 μmol) was stirred at 50° C. for 14 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with DCM and aqueous NaHCO3, extracted twice with DCM, and the combined organic layers were washed with water and The crude product was purified by column chromatography, washed with HCl and brine, dried over Na2SO4, and concentrated under reduced pressure. Chromatography (RediSep column: silica 24g, eluent DCM: DCM / Me OH (8 / 2) 100:0 to 50:50) to give a white solid (97.0 mg). This was further purified by reverse-phase preparative HPLC (RP-HPLC acidic 1: 5-95% B in 20 min). The product-containing fractions were combined, basified with saturated aqueous NaHCO3, and purified by Concentration under reduced pressure gave the title compound (107 mg, purity 100%, yield: 63%) as a white solid. obtained.

[0411] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=1.06 min; MS m / z [M+H] + 714.3 / 716.3m / z[MH] - 712.3 / 714.3; UPLC-MS 1 LC-MS: Rt=5.23 min; MS m / z [M+H] + 714.4 / 716.4m / z[MH] - 712.4 / 714.4; UPLC-MS 2 1H NMR(400MHz,DMSO-d6)δ 10.54-10.40(m,2H ),8.56(s,1H),8.03-7.86(m,2H),7.74(dd,J=8 .8,2.1Hz,1H),6.89-6.73(m,1H),5.53(dd,J=1 0.4,2.3Hz,1H),4.27-4.21(m,2H),3.86-3.66( m,3H),3.62-3.07(m,8H),3.03-2.96(m,2H),2. 53-2.47(m,2H)2.44(s,3H),2.16-2.08(m,1H), 1.41 (d, J = 7.3 Hz, 3H).

[0412] The stereochemistry of Example 14A was determined by single crystal X-ray diffraction and WRN co-crystal X-ray diffraction. Further, intermediate H4 was also assigned as (7R,9R).

[0413] Example 14B: (7S,9S)—N-(2-chloro-4-(trifluoromethyl)phenyl) -2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxybenzoyl) (6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5 -Oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazo 2-[1,5-a]pyrimidine-9-carboxamide [ka] Step 1: (7S,9S)-6-(4-(5-benzyloxy-6-methylpyrimidine-4 -carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo [1,5-a]pyrimidine-9-carboxamide (7S,9S)-N-(2-chloro-4-(trifluoromethyl) )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (intermediate Form H3) (160 mg, 277 μmol), 5-(benzyloxy)-6-methylpyrimidin azine-4-carboxylic acid (intermediate U) (67.6 mg, 277 μmol) and HATU (1 To a stirred solution of 26 mg, 332 μmol) of DIPEA (242 μL, 1.38 mmol) ) was added at room temperature, and the reaction mixture was stirred at room temperature for 10 minutes. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and reduced. The crude product was purified by column chromatography (RediSep column: silica 2 4g, purified with eluent DCM:DCM / MeOH (8 / 2) 100:0 to 50:50 The product-containing fractions were combined, concentrated under reduced pressure, and dried under high vacuum to give a white foam. This gave the title compound (135 mg, purity 100%, yield: 61%). LC-MS: Rt=1.21 min; MS m / z [M+H] + 804.5 / 806.5m / z[MH] - 802.5 / 804.5; UPLC-MS 1 LC-MS: Rt=5.92 min; MS m / z [M+H] + 804.5 / 806.5m / z[MH] - 802.5 / 804.6; UPLC-MS 2

[0414] Step 2: (7S,9S)—N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6 -methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo so-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1 ,5-a]pyrimidine-9-carboxamide (7S,9S)-6-(4-(5-benzyloxy)-6-methyl)-2-methyl-2-methyl-2-methyl-1 ... 1-(2-chloro-4-(methylpyrimidine-4-carbonyl)piperazin-1-yl)-N ... (trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)- 7-Methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2 ,4]Triazolo[1,5-a]pyrimidine-9-carboxamide (130 mg, 162 The reaction mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. Diluted with DCM and aqueous NaHCO3, extracted twice with DCM, and the combined organic layers were washed with water and The crude product was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography (RediSep column: silica 12g, eluent DCM: DCM / MeO The product-containing fractions were combined and purified by H (8 / 2) 100:0 to 50:50. Concentration under reduced pressure gave the title compound (97.0 mg, purity 100%, yield: 84%) as a white solid. ) was obtained.

[0415] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt=1.06 min; MS m / z [M+H] + 714.3 / 716.3m / z[MH] - 712.3 / 714.3; UPLC-MS 1 LC-MS: Rt=5.17 min; MS m / z [M+H] + 714.4 / 716.4m / z[MH] - 712.4 / 714.4; UPLC-MS 2

[0416] Example 14C: (7S,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl) -2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxybenzoyl) (6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5 -Oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazo 2-[1,5-a]pyrimidine-9-carboxamide [ka] Step 1: (7S,9R)-6-(4-(5-benzyloxy-6-methylpyrimidine-4 -carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo [1,5-a]pyrimidine-9-carboxamide (7S,9R)-N-(2-chloro-4-(trifluoromethyl) )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (intermediate Form H2) (495 mg, 771 μmol), 5-(benzyloxy)-6-methylpyrimidin azine-4-carboxylic acid (intermediate U) (188 mg, 771 μmol) and HATU (35 To a stirred solution of 2 mg (925 μmol) of DIPEA (673 μL, 3.85 mmol) was added at room temperature and the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with EtOAc and water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and The crude product was purified by column chromatography (RediSep column: silica 40 g The eluent was DCM:DCM / MeOH (8 / 2) 100:0 to 75:25. The product-containing fractions were combined and concentrated under reduced pressure to give the title compound (6) as a white foam. 18 mg, purity 88%, yield: 88% were obtained. LC-MS: Rt=1.17 min; MS m / z [M+H] + 804.3 / 806.3m / z[MH] - 802.3 / 804.3; UPLC-MS 1

[0417] Step 2: (7S,9R)—N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6 -methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo so-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1 ,5-a]pyrimidine-9-carboxamide (7S,9R)-6-(4-(5-( benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)- N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro- 2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyran Triazolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide The reaction mixture was stirred at room temperature for 72 hours. and diluted with aqueous NaHCO3, extracted twice with DCM, and the combined organic layers were washed with brine. The crude product was purified by column chromatography. (RediSep column: 40g silica, eluent: DCM: DCM / MeOH (8 / 2) The yellow solid was purified by reversed-phase preparative H PLC (RP-HPLC acidic 1: 15-80% B in 20 min), (RP-HPLC acidic 1 The product-containing fractions were combined and purified by saturated NaHC1C. The mixture was basified with aqueous O3, the ACN was removed under reduced pressure, and the resulting aqueous residue was extracted twice with DCM. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a white solid. The title compound was obtained (295 mg, purity 99%, yield: 61%). LC-MS: Rt=1.02 min; MS m / z [M+H] + 714.1 / 716.1m / z[MH] - 712.3 / 714.3; UPLC-MS 1 LC-MS: Rt = 5.01 min; MS m / z [M+H] + 714.1 / 716.1m / z[MH] - 712.3 / 714.3; UPLC-MS 2

[0418] Example 14C is more potent than 14D based on SAR and structural understanding, so its The stereochemistry was assigned as (7S,9R).

[0419] Example 14D: (7R,9S)—N-(2-chloro-4-(trifluoromethyl)phenyl) -2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxybenzoyl) (6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5 -Oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazo 2-[1,5-a]pyrimidine-9-carboxamide [ka]

[0420] Step 1: (7R,9S)-6-(4-(5-benzyloxy-6-methylpyrimidine-4 -carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo [1,5-a]pyrimidine-9-carboxamide (7R,9S)-N-(2-chloro-4-(trifluoromethyl) )phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5- Oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (intermediate Form H1) (466 mg, 806 μmol), 5-(benzyloxy)-6-methylpyrimidin azine-4-carboxylic acid (intermediate U) (197 mg, 806 μmol) and HATU (36 To a stirred solution of 1000 mg of PEG-100 (8 mg, 967 μmol), DIPEA (704 μL, 4.03 mmol) was added at room temperature and the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with EtOAc and water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and The crude product was purified by column chromatography (RediSep column: silica 40 g The eluent was DCM:DCM / MeOH (8 / 2) 100:0 to 50:50. The product-containing fractions were combined and concentrated under reduced pressure to give the title compound (618) as a white foam. mg, purity 90%, yield: 86%). LC-MS: Rt=1.17 min; MS m / z [M+H] + 804.4 / 806.4m / z[MH] - 802.3 / 804.3; UPLC-MS 1

[0421] Step 2: (7R,9S)—N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6 -methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo so-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1 ,5-a]pyrimidine-9-carboxamide (7R,9S)-6-(4-(5-( benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)- N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro- 2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyran Triazolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide The reaction mixture was stirred at 50° C. for 14 hours. Dilute with M and aqueous NaHCO3, extract twice with DCM, and then add the combined organic layers with brine. The crude product was purified by column chromatography. RediSep column: 40 g silica, eluent: DCM: DCM / MeOH (8 / 2 ) 100:0 to 50:50) to give a yellow solid, which was separated into two batches and separated by reverse phase preparative The product was purified by HPLC (RP-HPLC acidic 1: 15-80% B in 20 min). The containing fractions were combined, basified with saturated aqueous NaHCO3, and the ACN was removed under reduced pressure to give The resulting aqueous residue was extracted twice with DCM. The combined organic layers were dried over Na2SO4 and reduced Concentration under reduced pressure gave the title compound (283 mg, purity 96%, yield: 55%) as a white solid. obtained. LC-MS: Rt=1.02 min; MS m / z [M+H] + 714.3 / 716.3m / z[MH] - 712.3 / 714.3; UPLC-MS 1 LC-MS: Rt = 5.05 min; MS m / z [M+H] + 714.2 / 716.2m / z[MH] - 712.2 / 714.2; UPLC-MS 2

[0422] Example 15A: (7R,9R)-2-(3,6-dihydro-2H-pyran-4-yl)- 6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-methyl-N- (2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-5,7,8,9- Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine -9-carboxamide [ka] (7R,9R)-2-(3,6-dihydro-2H-pyran-4- yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5- Oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (intermediate A colorless solution of compound K4 (25.0 mg, 40.0 μmol) was added to DIPEA (35 0.0 μL, 198 μmol) was added, followed by 3-hydroxypicolinoyl chloride (medium Compound X (9.37 mg, 59.0 μmol) was added. The reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was extracted with water (10 mL) and TBME (10 mL). The aqueous layer was washed with water (15 mL) and brine (15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 45 °C. Concentration gave a brown solid (49.5 mg). The crude product was purified by reverse phase preparative HPLC (RP-HPLC). The product was purified by PLC acid 1:5-100% B in 20 min. The product-containing fractions were combined and purified. The ACN was removed under reduced pressure. The aqueous residue was basified with saturated aqueous NaHCO3 and diluted with DCM ( The combined organic layers were dried over anhydrous Na2SO4, filtered, and Concentration under reduced pressure gave the title compound (17.0 mg, purity 98%, yield: 62%) as a white solid. ) was obtained.

[0423] The sodium salt was prepared similarly to the general procedure. LC-MS: Rt = 1.00 min; MS m / z [M+H] + 679.5, m / z [MH ] - 677.5; UPLC-MS 1 LC-MS: Rt=4.78 min; MS m / z + 679.6, m / z [MH] - 677 .5;UPLC-MS 2

[0424] The stereochemistry of Example 15A was determined by single crystal X-ray diffraction and WRN co-crystal X-ray diffraction. Further, intermediate H4 was also assigned as (7R,9R).

[0425] Example 15B: (7S,9S)-2-(3,6-dihydro-2H-pyran-4-yl)- 6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-methyl-N- (2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-5,7,8,9- Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine -9-carboxamide [ka] (7S,9S)-2-(3,6-dihydro-2H-pyran-4- yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5- Oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2 -c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (intermediate A colorless solution of compound K3 (23.0 mg, 36.0 μmol) was added to DIPEA (32 0.0 μL, 182 μmol) was added, followed by 3-hydroxypicolinoyl chloride (medium Compound X (8.62 mg, 55.0 μmol) was added. The reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was extracted with water (10 mL) and TBME (10 mL). The aqueous layer was washed with water (15 mL) and brine (15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 45 °C. Concentration gave a light brown solid (30.1 mg). The crude product was purified by reverse phase preparative HPLC (RP- The product was purified by HPLC (5-100% B in 20 min). The product-containing fractions were combined. The ACN was removed under reduced pressure. The aqueous residue was basified with saturated aqueous NaHCO3 and diluted with DCM. (3×15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and Concentration under reduced pressure gave the title compound (9.50 mg, purity 87%, yield: 33%) as a white solid. %) was obtained. LC-MS: Rt = 1.00 min; MS m / z [M+H] + 679.6, m / z [MH ] - 677.5; UPLC-MS 1 LC-MS: Rt = 4.79 min; MS m / z [M+H] + 679.6, m / z [MH ] - 677.5; UPLC-MS 2

[0426] Example 15C: (7S,9R)-2-(3,6-dihydro-2H-pyran-4-yl)- 6-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-7-methyl-N- (2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-5,7,8,9- Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine -9-carboxamide [ka] (7S,9R)-2-(3,6-dihydro-2H-pyran-4) in DCM (50 mL) -yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5 -oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1, 2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (medium A colorless solution of intermediate complex K1 (24.0 mg, 40.0 μmol) was added to DIPEA (3 5.0 μL, 202 μmol) was added, followed by 3-hydroxypicolinoyl...

Claims

1. A compound of formula (I) 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; 【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】 When is a single bond, Y is a carbon atom that is unsubstituted or substituted by OH or F. can be; If Y is N, 【Transformation 6】 is a single bond; 【Transformation 7】 means that K is connected to the adjacent 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: y is 0, 1, 2, 3 or 4; 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 are attached to the carbon atom to which they are attached. Together with ３～ C ４ ) a cycloalkylspiro ring or a 3- or 4-membered heterocyclic may form a heterocyclylspiro ring, wherein the heterocyclylspiro ring is and one ring heteroatom selected from O, N, and S), ・ 【Chemistry 16】 When is a carbon-nitrogen single bond, R on K and the adjacent carbon atom ５ The substituent is bonded to ring C. It may be formed: 【Chemistry 17】 Here, ring C is fused (C ３ ~C ６ ) cycloalkyl ring, fused (C ３ ~C ６ ) Heterogeneity a chlorine ring or a fused phenyl ring, ３ ~C ６ ) heterocyclyl ring contains ring carbon atoms and one ring heteroatom selected from O, N and S; Ring C is fused (C ３ ~C ６ ) cycloalkyl ring, the fused (C ３ ~C ６ ) Shi The chloroalkyl ring is unsubstituted or contains one or two R ４０ is substituted with a group, Here, the above R ４０ teeth, ・ (C １～ C ２ ) alkyl (wherein each (C １～ C ２ ) alkyl is independently non- substituted or substituted with OH or 1, 2 or 3 halo); ・Halo, especially F, or where two R on the same ring carbon atom ４０ The substituents are Together with the carbon atom present, (C ３～ C ４ ) a cycloalkyl spiro ring or 3 or 4 and optionally form a membered heterocyclyl spiro ring, wherein said heterocyclyl spiro ring is containing ring carbon atoms and one ring heteroatom selected from O, N, and S), Alternatively, two R on adjacent carbon atoms ４０ The substituents are attached to the carbon atoms to which they are attached. Together with the atom, forms a fused cyclopropyl ring Selected from: ・ [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 bonded Ring C may be formed by: 【Chemistry 21】 Here, ring C is fused (C ３ ~C ６ ) cycloalkyl ring, fused (C ３ ~C ６ ) Heterogeneity a chlorine ring or a fused phenyl ring, ３ ~C ６ ) heterocyclyl ring contains ring carbon atoms and one ring heteroatom selected from O, N and S; Ring C is fused (C ３ ~C ６ ) cycloalkyl ring, the fused (C ３ ~C ６ ) Shi The chloroalkyl ring is unsubstituted or contains one or two R ４０ is substituted with a group, Here, the above R ４０ teeth, ・ (C １～ C ２ ) alkyl (wherein each (C １～ C ２ ) alkyl is independently non- substituted or substituted with OH or 1, 2 or 3 halo); ・Halo, especially F, or where two R on the same ring carbon atom ４０ The substituents are Together with the carbon atom present, (C ３～ C ４ ) a cycloalkyl spiro ring or 3 or 4 may form a membered heterocyclyl spiro ring, wherein the heterocyclyl spiro ring is containing ring carbon atoms and one ring heteroatom selected from O, N, and S), Alternatively, where two R on adjacent carbon atoms ４０ Substituents are the groups to which they are attached. together with the carbon atom adjacent to it to form a fused cyclopropyl ring Selected from: ・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 heteroalkylene bridge is one heteroatom selected from N and O, or -CH ２ -O-CH ２ -), Selected from: 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 is replaced by So, 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, 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 1, 2, 3 or 4, preferably 1 or 2, R ３３ Place where R ３３ is halo, and the heterocyclyl or halo-substituted hetero Cyclyl is independently R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２２ and R ２３ or substituted by 0, 1 or 2 substituents selected from 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. Has it been replaced? 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 ) Heterosyc wherein the (C ３ ~C ５ ) The heterocycloalkyl ring is a ring containing carbon atoms 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 two ring heteroatoms, and preferably a 5- or 6-membered fully unsaturated monocyclic group containing the total number of S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1; The heteroaryl is unsubstituted or R ２１ and R ３０ 1 independently selected from , substituted by 2 or 3 substituents, where R ２１ and R ３０ is independent And halo and (C １ ~C ４ ) alkyl, wherein said (C １ ~C ４ ) Al The alkyl is unsubstituted or substituted by 1, 2 or 3 halo; Or, R １ is phenyl, wherein said phenyl is unsubstituted or 1, 2, 3 or four, preferably one or two R ３３ where R ３３ teeth halo, and said phenyl or halo-substituted phenyl is selected from 0, 1 or 2 R １５ Substituted with a substituent Is it being done? 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, ・Haro unsubstituted or substituted with 1, 2 or 3 halo (C １～ C ４ )a Rukill-O-, unsubstituted or OH, —O—(C １ ~C ２ ) alkyl or 1, 2 or 3 substituted with halo (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 are connected to the rest of the molecule through an atom, and each is unsubstituted or one or substituted with two F's), ・R ２５ (R ２４ ) N-(where R ２４ is H or unsubstituted or 1, 2 or substituted with 3 halo groups (C １ ~C ４ ) alkyl, and R ２５ is H or unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl) ・OH is selected from wherein n is 0, 1 or 2; R ２ is a part 【Chemistry 22】 and R ６ teeth, ・H, ・Halo, unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ )a Rukill-O-, unsubstituted or substituted with 1, 2 or 3 halo (C ３ ~C ５ ) Shi chloroalkyl, -O-(C) is unsubstituted or substituted with 1, 2 or 3 halo １ ~C ４ ) alkyl, OH, and ・CN Selected from: R ８ is H, halo, and is 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 )a Lukil, ・ (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 ) can form a cycloalkyl ring, wherein the fused (C ４ -C ６ ) Cycloa The alkyl ring is unsubstituted or substituted with 1, 2 or 3 halo; or R ２ teeth, 【Chemistry 23】 is selected from where: R ３１ is H, halo and CH ３ is selected from R ３２ is H, halo and CH ３ is selected from R ３ teeth, Halo, and unsubstituted or containing 1, 2 or 3 substituents independently selected from halo and OH; is substituted with a substituent (C １ ~C ４ ) alkyl, Or, two R on the same ring carbon atom ３ The substituents are bonded to the carbon atoms to which they are attached. may be taken together to form a cyclopropyl ring Selected from: x is 0, 1 or 2; R ４ teeth, -(C １ ~C ４ ) alkyl, Heteroaryl 1, wherein said heteroaryl 1 is a heteroaryl consisting of ring carbon atoms and N, O and S; and 1, 2, 3, or 4 independently selected ring heteroatoms. is a monocyclic ring of Heteroaryl 2, wherein said heteroaryl 2 is a heteroaryl consisting of ring carbon atoms and N, O and S; and 9- or 10-membered fused bicyclic rings containing 1, 2, 3, or 4 independently selected ring heteroatoms. rings, both rings being fully unsaturated, or one ring being fully unsaturated and the other being saturated. or partially unsaturated, and the heteroatoms can be in one or both rings; -phenyl Selected from: Here, heteroaryl 1, heteroaryl 2, and phenyl are each R １０ , R １１ , R １２ , R １３ and R １４ and substituted by 1, 2 or 3 substituents independently selected from where each 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 )a Lukil, -S-(C １ ~C ３ ) alkyl, -O-(C) is unsubstituted or substituted with 1, 2 or 3 halo substituents １ ~C ４ ) alkyl, ・OH, ・ (C ３ ~C ５ ) cycloalkyl (wherein the above (C ３ ~C ５ ) Cycloalkyl is not substituted or substituted with 1 or 2 halo); -O-(C ３ ~C ５ ) cycloalkyl, -NR ３４ R ３５ (where R ３４ and R ３５ is independent o H, o (C １ ~C ４ ) alkyl (wherein the above (C １ ~C ４ ) alkyl is unsubstituted or OH 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. can form an azetidine, pyrrolidinyl or piperidine ring, Zetidine, pyrrolidinyl and piperidine are unsubstituted or CH ３ is replaced by selected from ・CN, - (C ２ ~C ４ ) alkenyl, - (C ２ ~C ４ ) alkynyl, ・=O、 -C(O)H, and -C(O)(C １ ~C ４ ) alkyl Selected from: * indicates point of attachment].

2. The compound of formula (I) has the formula 1a: 【Chemistry 24】 2. The compound of formula (I) according to claim 1, wherein:

3. R １ teeth, cycloalkenyl, wherein the cycloalkenyl has 5 or 6 ring carbon atoms; and a partially unsaturated monocyclic ring containing 1 or 2 R ３３ where R ３３ is halo, preferably F The cycloalkenyl or halo-substituted cycloalkenyl is 0 or 1 R １５ substituent, preference Preferably, it is substituted with one substituent, where R １５ teeth, a) unsubstituted or substituted with 1, 2 or 3 halo (C １～ C ２ )a Rukill-O-, b) unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ２ )a Lukil, c)HOC(O)-(CH ２ ) ｎ -、 d)H ３ C-C(O)(CH ２ ) ｎ -、 e)H ３ C-O-C(O)(CH ２ ) ｎ 、 f) = O, and g) R ２５ (R ２４ ) N-, H (where R ２４ is H or unsubstituted or 1, 2 or substituted with three halo (C １ ~C ２ ) alkyl, and R ２５ Is H or non-place or substituted with 1, 2 or 3 halo (C １ ~C ２ ) alkyl) is selected from n is 0 or 1; where: R of the cycloalkenyl or halo-substituted cycloalkenyl １５ The substituents a) to g) are wherein said cycloalkenyl or halo-substituted cycloalkenyl is attached to the remainder of the molecule. and preferably said cycloalkenyl or halo-substituted Cycloalkenyl has one R in the ring para position relative to the rest of the molecule. １５ having a substituent is a six-membered ring, The cycloalkenyl or halo-substituted cycloalkenyl is not an adjacent R １ ring carbon atoms R double bonded to １ is linked to the remainder of the compound via a ring carbon atom; Or, R １ 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 Ha halo , preferably 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 selected from or substituted by one substituent, wherein R １５ , R １６ , R １７ , R １ ８ , R １９ , R ２０ , R ２２ and R ２３ is, independently, a) unsubstituted or substituted with 1, 2 or 3 halo (C １～ C ４ )a Rukill-O-, b) unsubstituted or OH, —O—(C １ ~C ２ ) alkyl or 1, 2 or 3 substituted with halo (C １ ~C ４ ) alkyl, c)HOC(O)-(CH ２ ) ｎ -、 d)H ３ C-C(O)(CH ２ ) ｎ -、 e)H ３ C-O-C(O)(CH ２ ) ｎ 、 f) = O, g) R ２５ (R ２４ ) N-(where R ２４ is H, unsubstituted or 1, 2 or substituted with three halo (C １ ~C ２ ) alkyl, and R ２５ is H, unsubstituted or is substituted with 1, 2 or 3 halo (C １ -C ２ ) alkyl), h) OH is selected from where n is 0 or 1, where: The substituents a) to h) of the heterocyclyl or halo-substituted heterocyclyl are No halo-substituted heterocyclyl or halo-substituted heterocyclyl is present on the ring atom that is attached to the remainder of the molecule. Preferably, when the heterocyclyl or halo-substituted heterocyclyl is a 6-membered ring, It is in the meta or para position, preferably the para position, relative to the rest of the molecule, selected from a) to h). has 0 or 1 substituent selected from the group consisting of: The heterocyclyl may be attached to the rest of the compound by R １ Ring nitrogen atom or adjacent R double bonded to the ring atom １ are linked via a ring carbon atom; Or, R １ is heteroaryl, wherein said heteroaryl is a heteroaryl having a ring carbon atom and a 5, including 1 or 2 ring heteroatoms independently selected from N, O and S, preferably N or a 6-membered fully unsaturated monocyclic group, wherein the total number of ring S atoms does not exceed 1 and the number of ring O atoms is the total number does not exceed 1, wherein said heteroaryl is unsubstituted or ２１ and R ３０ and is substituted by one or two substituents independently selected from ２ １ and R ３０ (C １ ~C ２ ) alkyl, wherein (C １ ~C ２ ) Al Halo is unsubstituted or substituted with 1, 2 or 3 halo, wherein preferred Alternatively, the alkyl or haloalkyl substituent may be a heteroaryl group that is bonded to the remainder of the molecule. Matching R １ R adjacent to the ring atom １ Preferably, no ring atoms are present, and more preferably, heteroaryl When the ring is six-membered, the alkyl or haloalkyl substituent is in the ring para position relative to the rest of the molecule. Located in 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R １ teeth, 【Chemistry 25】 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 each unsubstituted. or substituted by 1 or 2 F; 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. Replaced (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 )a Rukill-O-, ・ HOC(O)-(H ２ ) ｎ -、 ・ H ３ C-C(O)(CH ２ ) ｎ -、 ・ (H ３ C) ３ C-O-C(O)(CH ２ ) ｎ -; where n is 0, 1 or 2 Selected from: 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 26】 The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, selected from Acceptable salt.

6. R １ teeth, 【Chemistry 27】 The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from Acceptable salt.

7. R ２ Here is the part: 【Chemistry 28】 and where: R ６ is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl; R ８ is H, halo, 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 is SF ５ , halo, C(O)H, and unsubstituted or substituted with 1, 2 or 3 halo groups. (C １ ~C ４ ) alkyl; X is C-R ７ and N; and R ７ is selected from H and 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 29】 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. portion: 【Transformation 30】 teeth, 【Chemistry 31】 The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from Acceptable salt.

10. portion: 【Chemistry 32】 teeth, 【Transformation 33】 The compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, selected from Acceptable salt.

11. The compound of formula (I) or its derivatives according to any one of claims 1 to 10, wherein x is 0 or 1. Pharmaceutically acceptable salts.

12. R ３ is unsubstituted or contains 1, 2 or 3 independently selected from halo and OH (C １ ~C ２ 12. The method according to claim 1, wherein the aryl group is alkyl. A compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

13. R ３ is CH ３ The compound of formula (I) according to any one of claims 1 to 12, Pharmaceutically acceptable salts.

14. Y is N; 【Transformation 34】 is Y linked by a single bond, ) or a pharmaceutically acceptable salt thereof. 【Request Item 15】 【Chemistry 35】 is K linked by a single bond, and K is -CH ２ -, J is N, and A -C(O)-, -S(O)-, -S(O) ２ - and 【Transformation 36】 The compound of formula (I) according to any one of claims 1 to 14, wherein the linker is selected from is a pharmaceutically acceptable salt thereof.

16. A compound of formula (I) according to any one of claims 1 to 15, wherein A is a -C(O)- linker. or a pharmaceutically acceptable salt thereof.

17. R ５ is, independently, - (C １～ C ４ )) alkyl, preferably methyl, where two R on the same ring carbon atom ５ Substituents are attached to the carbon atom to which they are attached. Together with ３～ C ４ ) a cycloalkylspiro ring or a 3- or 4-membered heterocyclic may form a heterocyclylspiro ring, wherein the heterocyclylspiro ring is and one ring heteroatom selected from O, N, and S), ・ 【Chemistry 37】 When is a carbon-nitrogen single bond, R on K and the adjacent carbon atom ５ The substituent is bonded to ring C. It may be formed: 【Chemistry 38】 Here, ring C is fused (C ３ ~C ６ ) cycloalkyl rings, especially fused cyclobutyl rings, fused Combined (C ３ ~C ６ ) heterocyclyl ring or fused phenyl ring, wherein the fused (C ３ ~C ６ A heterocyclyl ring is a ring consisting of ring carbon atoms and one ring hetero selected from O, N, and S. containing a molybdenum atom, Ring C is fused (C ３ ~C ６ ) When the ring is a cycloalkyl ring, particularly a fused cyclobutyl ring, The condensation reaction (C ３ ~C ６ ) The cycloalkyl ring is unsubstituted or contains one or two R ４０ group, wherein the R ４０ teeth, ・ (C １～ C ２ ) alkyl (wherein each (C １～ C ２ ) alkyl is independently a non-substituted or substituted with OH or 1, 2 or 3 halo), ・Halo, especially F, or where two R on the same ring carbon atom ４０ Substituents are the groups to which they are attached. Together with the carbon atom (C ３～ C ４ ) a cycloalkylspiro ring or a 3- or 4-membered A heterocyclylspiro ring may be formed (wherein the heterocyclylspiro ring is a ring containing carbon ring atoms and one ring heteroatom selected from O, N, and S); Alternatively, two R on adjacent carbon atoms ４０ Substituents are attached to the carbon together with the atoms to form a fused cyclopropyl ring Selected from: ・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 heteroalkylene bridge is one heteroatom selected from N and O, or -CH ２ -O-CH ２ - is) A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, selected from Acceptable salts.

18. R ５ is, independently, - (C １～ C ２ ) alkyl, preferably methyl, and ・ 【Chemistry 39】 When is a carbon-nitrogen single bond, R on K and the adjacent carbon atom ５ The substituent is bonded to ring C. It may be formed: 【Chemistry 40】 Here, ring C is fused (C ３ ~C ４ ) a cycloalkyl ring, especially a fused cyclobutyl ring. and the condensation (C ３ ~C ４ ) The cycloalkyl ring, especially the fused cyclobutyl ring, is unsubstituted. or one or two R ４０ group, wherein the R ４０ teeth, ・ (C １～ C ２ ) alkyl (wherein each (C １～ C ２ ) alkyl is independently non- substituted or substituted with OH or 1, 2 or 3 halo); ・Halo, especially F, or where two R on the same ring carbon atom ４０ The substituents are Together with the carbon atom present, (C ３～ C ４ ) a cycloalkyl spiro ring or 3 or 4 may form a membered heterocyclyl spiro ring, wherein the heterocyclyl spiro ring is containing ring carbon atoms and one ring heteroatom selected from O, N, and S), Alternatively, two R on adjacent carbon atoms ４０ The substituents are attached to the carbon atoms to which they are attached. Together with the atom, forms a fused cyclopropyl ring Selected from A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, selected from Acceptable salts.

19. R ５ is, independently, ・CH ３ , y is 1 or 2, and ・ 【Chemistry 41】 When is a carbon-nitrogen single bond, R on K and the adjacent carbon atom ５ The substituent is bonded to ring C. It may be formed: 【Chemistry 42】 wherein ring C is a fused cyclobutyl ring A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, selected from Acceptable salts.

20. The compound of formula (I) comprises the moiety: 【Chemistry 43】 20. A compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, comprising: Salt that can be used.

21. A compound of formula (I) according to any one of claims 1 to 20, wherein y is 0, 1 or 2; and pharmaceutically acceptable salts thereof.

22. R ４ teeth, -(C １ ~C ４ ) alkyl, Heteroaryl 1, wherein said heteroaryl 1 is selected from the group consisting of ring carbon atoms and N, O and S. and 1, 2, 3 or 4 ring heteroatoms independently selected from the group consisting of: monocyclic rings, wherein the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1; - heteroaryl 2 (wherein said heteroaryl 2 is selected from the group consisting of ring carbon atoms and N, O and S) and 1, 2, 3 or 4 ring heteroatoms independently selected from cyclic rings, both rings being fully unsaturated, or one ring being fully unsaturated and the other saturated; The heteroatoms may be present in one or both rings, and the ring S The total number of ring O atoms does not exceed 1, and the total number of ring O atoms does not exceed 1, in particular via the linker -A- the ring connecting it to the rest of the molecule is fully unsaturated); -phenyl Selected from: Here, heteroaryl 1, heteroaryl 2, and phenyl are each R １０ , R １１ , R １２ , R １３ and R １４ and substituted by 1, 2 or 3 substituents independently selected from where each 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 )a Lukil, -S-(C １ ~C ３ ) alkyl, -O-(C) is unsubstituted or substituted with 1, 2 or 3 halo substituents １ ~C ４ ) alkyl, ・OH, ・ (C ３ ~C ５ ) cycloalkyl (wherein the above (C ３ ~C ５ ) Cycloalkyl is a substituent. or substituted with 1 or 2 halo), -O-(C ３ ~C ５ ) cycloalkyl, -NR ３４ R ３５ (where R ３４ and R ３５ is independent o H, o (C １ ~C ４ ) alkyl (wherein the above (C １ ~C ４ ) alkyl is unsubstituted or OH 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. can form an azetidine, pyrrolidinyl or piperidine ring, Zetidine, pyrrolidinyl and piperidine are unsubstituted or CH ３ is replaced by selected from ・CN, - (C ２ ~C ４ ) alkenyl, - (C ２ ~C ４ ) alkynyl, ・=O、 -C(O)H, and -C(O)(C １ ~C ４ ) alkyl Selected from: However, one OH substituent is present on Heteroaryl 1, Heteroaryl 2 and Phenyl. And the remaining R １０ , R １１ , R １２ , R １３ and R １４ is as defined herein That is, A compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof.

23. R ４ teeth, -(C １ ~C ４ ) alkyl, especially —CH ３ , heteroaryl 1, and heteroaryl 2, -phenyl Selected from: Here, heteroaryl 1, heteroaryl 2, and phenyl are each R １０ , R １１ , R １２ , R １３ and R １４ and substituted by 1, 2 or 3 substituents independently selected from where each 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 )a Lukil, -S-(C １ ~C ３ ) alkyl, -O-(C) is unsubstituted or substituted with 1, 2 or 3 halo substituents １ ~C ４ ) alkyl, ・OH, ・ (C ３ ~C ５ ) cycloalkyl (wherein the above (C ３ ~C ５ ) Cycloalkyl is a substituent. or substituted with 1 or 2 halo), -O-(C ３ ~C ５ ) cycloalkyl, -NR ３４ R ３５ (where R ３４ and R ３５ is independent o H, o (C １ ~C ４ ) alkyl (wherein the above (C １ ~C ４ ) alkyl is unsubstituted or OH 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. can form an azetidine, pyrrolidinyl or piperidine ring, Zetidine, pyrrolidinyl and piperidine are unsubstituted or CH ３ is replaced by selected from ・CN, - (C ２ ~C ４ ) alkenyl, - (C ２ ~C ４ ) alkynyl, ・=O、 -C(O)H, and -C(O)(C １ ~C ４ ) alkyl Selected from: however, - one OH substituent is present on heteroaryl 1, heteroaryl 2 and phenyl , wherein the OH is R ４ R ４ Is it in the ortho position of the ring? 、 or one =0 substituent is present on heteroaryl 1 and heteroaryl 2, The remaining R １０ , R １１ , R １２ , R １３ and R １４ is defined as herein A compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof.

24. R ４ teeth, -(C １ ~C ４） Alkyl, especially —CH ３、 【Chemistry 44】 is 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 )a Lukil, -S-(C １ ~C ３ ) alkyl, -O-(C) is unsubstituted or substituted with 1, 2 or 3 halo substituents １ ~C ４ ) alkyl, ・ (C ３ ~C ５ ) cycloalkyl (wherein the above (C ３ ~C ５ ) Cycloalkyl is a substituent. or substituted with 1 or 2 halo), -O-(C ３ ~C ５ ) cycloalkyl, -NR ３４ R ３５ (where R ３４ and R ３５ is independent o H, o (C １ ~C ４ ) alkyl (wherein the above (C １ ~C ４ ) alkyl is unsubstituted or OH 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. can form an azetidine, pyrrolidinyl or piperidine ring, Zetidine, pyrrolidinyl and piperidine are unsubstituted or CH ３ is 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: A compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

25. R ４ teeth, 【Chemistry 45】 is selected from where: R １０ is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents; There are (C １ ~C ２ ) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents; Substituted -O-(C １ ~C ２ ) alkyl; R １１ is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents; There are (C １ ~C ２ ) alkyl; R １２ is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents; There are (C １ ~C ２ ) alkyl; R １３ is H, -S-CH ３ , halo, unsubstituted or 1, 2 or 3 halo substituted group (C １ ~C ２ ) alkyl; R １４ is H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents; There are (C １ ~C ２ ) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents; The substituted O-(C １ ~C ２ ) alkyl, and cyclopropyl; A compound of formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

26. R ４ teeth, -CH ３ 、 【Chemistry 46】 A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, selected from Acceptable salts.

27. R ４ teeth, 【Chemistry 47】 ,especially 【Chemistry 48】 A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, selected from Acceptable salts.

28. The compound of formula (I) has the formula (I'): 【Chemistry 49】 A compound of formula (I) according to any one of claims 1 to 27, having the stereochemistry shown in Pharmaceutically acceptable salts.

29. The compound of formula I' has formula I"': [Transformation 50] A compound of formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, Salt that can be used.

30. Formula (I) may be a compound of formula 1g, 1g', 1g* or 1g**: 【Chemistry 51】 The compound of formula (I) according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, Salt.

31. Formula (I) may be represented by formula 1h or 1h': 【Chemistry 52】 The compound of formula (I) according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, Salt.

32. The compound is 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 2. The compound of formula (I) according to claim 1, selected from: or a pharmaceutically acceptable salt thereof.

33. The compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- (R)-4-(5-(3,6-dihydro-2H-pyran-4-yl)-6-( ... -hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazine-1- yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c] [1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide or its drug physiologically acceptable salts 【Chemistry 61】 2. The compound of formula (I) according to claim 1, wherein:

34. The compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 1S,6S)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)- 5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabis( Chloro[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9- Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine -9-carboxamide, or a pharmaceutically acceptable salt thereof 【Transformation 62】 2. The compound of formula (I) according to claim 1, wherein:

35. The compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- (R)-4-(5-(3,6-dihydro-2H-pyran-4-yl)-6-( ... -hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazine-1- yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c] [1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, Non-zwitterionic forms: 【Transformation 63】 or the zwitterionic form: 【Chemistry 64】 or the zwitterionic form: 【Transformation 65】 or a mixture of any two or three of the above forms 2. The compound of formula (I) according to claim 1, wherein:

36. The compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 1S,6S)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)- 5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabis( Chloro[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9- Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine -9-carboxamide, Non-zwitterionic form 【Chemical Formula 66】 or the zwitterionic form: 【Transformation 67】 or the zwitterionic form: 【Transformation 68】 or a mixture of any two or three of the above forms 2. The compound of formula (I) according to claim 1, wherein:

37. The compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- (R)-4-(5-(3,6-dihydro-2H-pyran-4-yl)-6-( ... -hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazine-1- yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c] In the crystalline form of [1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide A compound of formula (I) according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof. salt.

38. The compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 1S,6S)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)- 5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabis( Chloro[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9- Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine 37. The compound of formula (I) according to any one of claims 1 to 36, in the crystalline form of 9-carboxamide. The compound or a pharmaceutically acceptable salt thereof.

39. The compound of formula (I) according to any one of claims 1 to 36, wherein the compound is in amorphous form. or a pharmaceutically acceptable salt thereof.

40. The compound of formula (I) according to any one of claims 1 to 39 is a sodium salt. or a pharmaceutically acceptable salt thereof.

41. A compound of formula (I) according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof. A combination comprising a salt and one or more additional therapeutically active agents.

42. 42. The combination of claim 41, wherein the additional therapeutically active agent is an anti-cancer agent.

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

44. 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.

45. 42. The combination of claim 41, wherein the additional therapeutically active agent is a PD-1 inhibitor.

46. 42. The combination of claim 41, wherein the additional therapeutically active agent is an anti-PD-1 antibody molecule.

47. 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 46. ​​The combination of claim 45, wherein the PD-1 inhibitor is selected from tislelizumab 。

48. A compound of formula (I) according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the salt and one or more pharmaceutically acceptable carriers.

49. A compound of formula (I) according to any one of claims 1 to 40 for use as a medicament is a pharmaceutically acceptable salt thereof.

50. 50. The method of claim 49, wherein the use is for the treatment of a disease treated by WRN inhibition. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40 for use in Acceptable salts.

51. 51. The use of claim 49 or 50, wherein the use is for the treatment of cancer.

41. A compound of formula (I) according to any one of 1 to 40, or a pharmaceutically acceptable salt thereof.

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

51. The method of claim 50, characterized in that the nucleotide sequence of claim 1 is a nucleotide sequence of claim 10, characterized in that the nucleotide sequence of claim 10 is a nucleotide sequence of claim 11, characterized in that the nucleotide sequence of claim 10 is a nucleotide sequence of claim 12, characterized in that the nucleotide sequence of claim 10 is a nucleotide sequence of claim 13, characterized in that the nucleotide sequence of claim 10 is a nucleotide sequence of claim 14, characterized A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of the preceding claims.

53. 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, and ovarian cancer.

53. The method of claim 52, wherein the cancer is selected from cervical cancer, esophageal cancer, breast cancer, renal cancer, prostate cancer, and ovarian cancer. A compound of formula (I) according to any one of claims 1 to 40 or a pharmaceutical composition thereof for the above-mentioned uses. A physiologically acceptable salt.

54. 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 40 for the use according to claim 53 The compound or a pharmaceutically acceptable salt thereof.

55. 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 53. The method of claim 52, wherein the ovarian cancer is selected from ovarian serous cystadenocarcinoma and ovarian serous cystadenocarcinoma. Item 41. A compound of formula (I) according to any one of Items 1 to 40, or a pharmaceutically acceptable salt thereof.

56. 41. A method of modulating WRN activity in a subject, comprising administering to a subject a compound of formula (I) according to claims 1 to 40. or a pharmaceutically acceptable salt thereof to said subject.

57. A method of inhibiting WRN in a subject, comprising administering to a subject a compound of formula (I) according to claims 1 to 40 or administering to said subject a therapeutically effective amount of a pharmaceutically acceptable salt thereof.

58. Methods for treating disorders or diseases that can be treated by inhibiting WRN in a subject A method for the treatment of a patient having a condition where a compound of formula (I) according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof is administered. administering to said subject a therapeutically effective amount.

59. A method of treating cancer in a subject, comprising administering to a subject a compound of formula (I) according to claims 1 to 40 or a compound thereof administering to said subject a therapeutically effective amount of a pharmaceutically acceptable salt.

60. Therapeutic efficacy of the compounds of formula (I) according to claims 1 to 40, or pharmaceutically acceptable salts thereof.

1. A method of treating cancer in a subject, comprising administering an amount of characterized by satellite instability (MSI-H) or mismatch repair deficiency (dMMR) How to do it.

61. 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 61. The method of claim 60, wherein the cancer is selected from cervical cancer, esophageal cancer, breast cancer, renal cancer, and ovarian cancer. method.

62. Microsatellite instability-high (MSI-H) or mismatch repair deficiency (dM 6. The method of claim 5, wherein the cancer characterized by MR is selected from colon cancer, gastric cancer, and endometrial cancer.

1. The method according to claim 1.

63. 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 61. The method of claim 60, wherein the tumor is selected from ovarian serous cystadenocarcinoma and ovarian serous cystadenocarcinoma.

64. A compound according to any one of claims 1 to 40 or a drug thereof in the manufacture of a medicament for treating cancer. Use of biologically acceptable salts.

65. The cancer may be microsatellite instability-high (MSI-H) or mismatch repair-deficient. The compound according to any one of claims 1 to 40, characterized by a deficiency (dMMR) or a pharmaceutical composition thereof.

65. The use of a physiologically acceptable salt thereof according to claim 64.

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

41. A compound of formula (I) or a salt thereof according to any one of 1 to 40.

67. Any of claims 1 to 40 as research chemicals, e.g. tool compounds or chemical probes. Use of a compound of formula (I) or a salt thereof according to any one of claims 1 to 4.

68. A process for producing the compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof. Process.

69. An intermediate compound as described herein.

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