Oxazolopyridine-7(4H)-one WRN inhibitor

Abstract

This disclosure relates to compounds based on oxazolopyridine-7(4H)-one comprising the compound of formula (I):(formula (I)), pharmaceutically acceptable salts thereof, and compositions thereof, as well as methods for treating cancer, including those comprising WRN protein. In another embodiment, the present invention provides pharmaceutical compositions comprising the compound of formula I of the present invention and one or more pharmaceutically acceptable carriers. In another embodiment, the present invention provides combinations, in particular pharmaceutical combinations comprising the compound of formula I of the present invention and one or more therapeutic agents. TIFF2026521488000210.tif26168

Description

[Technical Field]

[0001] Related applications This application claims priority and benefit to U.S. Provisional Application No. 63 / 507,362 filed 9 June 2023; U.S. Provisional Application No. 63 / 518,298 filed 8 August 2023; and U.S. Provisional Application No. 63 / 613,651 filed 21 December 2023, the contents of each of these, which are incorporated herein by reference in their entirety.

[0002] Field of Invention The present invention provides bicyclic compounds and compositions for inhibiting Werner syndrome RecQ DNA helicase (WRN), the use thereof, methods for using the compounds, and methods for treating diseases using the compounds, in particular for treating cancer, especially cancers characterized by high frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), including colorectal cancer, gastric cancer, and endometrial cancer. The present invention also provides the use of the compounds as research chemicals, intermediates, combinations, processes, and formulations. Sequence List This application includes a sequence listing submitted via EFS in .xml format, which is incorporated herein by reference. A copy of ST.26 made on 8 June 2023 is named 407274-80WRP3_ST26.xml and has a size of 8,751 bytes. [Background technology]

[0003] background Loss of DNA mismatch repair mechanisms is a common initiation event in the development of cancer, occurring in 10–30% of colorectal cancers, endometrial cancers, ovarian cancers, and gastric cancers (Aaltonen, LA et al. Clues to the pathogenesis of familial colorectal cancer, Science 260, 812-816 (1993), Bonneville R et al., Landscape of Microsatellite Instability Across 39 Cancer Types. JCO Precis Oncol. 1: PO.17.00073 (2017)). Cancers lacking mismatch repair mechanisms (dMMR) exhibit high mutational loads and high frequency of deletion and insertion events in repetitive DNA regions, a phenotype known as microsatellite instability (MSI). Treatment for high microsatellite instability (MSI-H) cancers has advanced, and pembrolizumab (anti-PD1) treatment has recently been approved as a first-line treatment for MSI-H-dMMR metastatic colorectal cancer (CRC) after demonstrating significantly longer progression-free survival than chemotherapy when received as a first-line therapy for these cancers. However, there remains a significant unmet medical need for pembrolizumab in CRC and other MSI-H indications (Andre T., et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med 383(23):22072218 (2020)).Using 398 cell lines from the Cancer Cell Line Encyclopedia (CCLE), several large-scale functional genomics screenings across a large panel of cell lines, including Novartis (McDonald ER et al., Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening. Cell 170(3):577-592 (2017)), identified Werner syndrome RecQ helicase (WRN) as selectively required for the survival of cell lines with mismatch repair deficiencies that have become MSI-H (Behan, FM et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 568, 511-516 (2019), Chan, EM et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 568, 551-556 (2019). Kategaya, L., Perumal, SK, Hager, JH & Belmont, LD. Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability. iScience 13, 488-497 (2019). Lieb, S. et al. Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells. eLife 8, e43333 (2019). WRN is synthetically lethal in MSI cancer.In the MSI-H cancer model, WRN depletion leads to antiproliferative effects, activation of multiple DNA damage signaling markers, cell cycle arrest, and induction of apoptosis, whereas this is not the case in cancer cells with intact MMR pathways (or known as microsatellite stability or MSS). The antiproliferative effect of WRN depletion cannot be rescued by helicase-deficient WRN constructs, demonstrating that WRN helicase activity is necessary for MSI-H survival. These findings indicate that in MSI cancer, WRN helicases provide DNA repair and maintenance functions essential for cell survival. Recently, the WRN-dependent mechanism has been elucidated. Dinucleotide TA repeats have been shown to be selectively unstable and undergo large-scale expansion in MSI cells. These expanded TA repeats form secondary DNA structures that require WRN helicase for unwinding (van Wietmarschen, N. et al. Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature 586, 292-298, 2020). In the absence of WRN (or when WRN helicase is inhibited), expanded TA repeats in MSI cells undergo nuclease cleavage and chromosomal disruption. Therefore, inhibiting WRN helicase is an attractive strategy for treating MSI-H cancers. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Aaltonen, LA et al. Clues to the pathogenesis of familial colorectal cancer, Science 260, 812-816 (1993) [Non-Patent Document 2] Bonneville R et al., Landscape of Microsatellite Instability Across 39 Cancer Types. JCO Precis Oncol. 1: PO.17.00073 (2017) [Non-Patent Document 3] Andre T., et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med 383(23):22072218 (2020) [Non-Patent Document 4] McDonald ER et al., Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening. Cell 170(3):577-592 (2017) [Non-Patent Document 5] Behan, FM et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 568, 511-516 (2019) [Non-Patent Document 6] Chan, EM et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 568, 551-556 (2019) [Non-Patent Document 7] Kategaya, L., Perumal, SK, Hager, JH & Belmont, LD Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability. iScience 13, 488-497 (2019) [Non-Patent Document 8] Lieb, S. et al. Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells. eLife 8, e43333 (2019) [Non-Patent Document 9] van Wietmarschen, N. et al. Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature 586, 292-298, 2020 [Overview of the Initiative] [Means for solving the problem]

[0005] overview Novel treatments and therapies remain needed for the treatment of cancers, particularly those characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), including colorectal cancer, gastric cancer, or endometrial cancer. The present invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, wherein the compounds are inhibitors of Werner syndrome RecQ DNA helicase (WRN). The present invention further provides methods for treating, preventing or improving a disease or condition, comprising the step of administering an effective amount of a WRN inhibitor to a subject in need thereof. The present invention also provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, wherein the compounds are useful for the treatment of cancers, particularly those characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). Compounds that bind to and / or inhibit WRN and are therefore useful as research chemicals, for example, as chemical probes and tool compounds, are also provided. Various embodiments of the present invention are described herein.

[0006] In one embodiment, the present disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof: [ka] ), R 1 , R 2 , R 3 , R 4 Y, Z, -L- and ring A are as described and defined herein.

[0007] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I and one or more pharmaceutically acceptable carriers.

[0008] In another aspect, the present invention provides combinations, in particular pharmaceutical combinations comprising a compound of formula I of the present invention and one or more therapeutic agents.

[0009] In another aspect, the present invention provides compounds of formula I for pharmaceutical use, in particular for the treatment of disorders or diseases that can be treated by WRN inhibition.

[0010] In another aspect, the present invention provides compounds of formula I for use in the treatment of cancer, particularly compounds in which the cancer is characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair mechanism deficiency (dMMR).

[0011] In another aspect, the present invention provides a method for treating a disorder or disease that can be treated by WRN inhibition in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula I of the present invention.

[0012] In another aspect, the present invention provides a method for treating cancer in a subject, more particularly, the cancer being characterized by high frequency microsatellite instability (MSI-H) or mismatch repair mechanism deficiency (dMMR), and comprising the step of administering a therapeutically effective amount of a compound of Formula I of the present invention to the subject.

[0013] In another aspect, the present invention provides the use of compounds of formula I in the manufacture of pharmaceuticals for the treatment of disorders or diseases that can be treated by WRN inhibition.

[0014] In another embodiment, the present invention provides compounds of formula I for use as research chemicals, for example, as chemical probes or tool compounds.

[0015] In another embodiment, the present invention provides a solid form, process, or intermediate described herein. [Modes for carrying out the invention]

[0016] Detailed description 1. General description of a specific embodiment of the present invention: In one embodiment, the present disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof: [ka] Provide (In the formula, ring A is defined as follows: a) A 4-7 member saturated or partially unsaturated divalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated divalent bicyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). This represents, Ring A is a set of 0 to 4 independently selected R A Substituting with substituents, Y and Z are selected from N and O, respectively, such that Y is N and Z is O, or Y is O and Z is N. [ka] represents a single or double bond, and the 5-membered ring containing Z and Y is aromatic. L is -C(O)-, -S(O)-, -S(O)2- and [ka] A linker selected from, R 1 is, group a)~e): a) A 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with 1-3 groups independently selected from halogens, C1-C6 alkyls, halo-C1-C6 alkyls, C3-C6 cycloalkyls, C1-C6 alkoxys, and C3-C6 cycloalkoxys, wherein 0-3 independently selected R AA 5- to 6-membered monocyclic heteroaryl further substituted by b) A 9- to 10-membered bicyclic heteroaryl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted by one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, and further substituted by 0 to 3 independently selected R A A 9- to 10-membered bicyclic heteroaryl further substituted by c) A 4- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted by one or two groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR, and further substituted by 0 to 3 independently selected R A A 4- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl further substituted by d) A 4- to 12-membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic, selected from carbocyclyl and heterocyclyl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl is substituted by 0 to 3 independently selected R A A 4- to 12-membered saturated or partially unsaturated bicyclic ring system, and e) H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, -CN, -OR, -NR 10 R 11 -C(O)NR 10 R 11 -CH2NR 10 R 11 -SO2R 12 wherein C1-C6 aliphatic, C3-C7 cycloalkyl, or C1-C6 alkylene-O-C1-C6 alkyl is substituted by 0 to 5 independently selected R A as such substituted Select one of the following: R 10 This includes H, C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, or R A A 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted by one or two groups independently selected from the above, R 11 is either H, C1-C6 aliphatic or C3-C6 cycloalkyl, or R 10 and R 11 These may combine to form a 5-6 membered ring which is optionally substituted with one, two, or three substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxys, and halo-C1-C4 alkoxys. R 12 This is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, or halogen, C1-C6 aliphatic, halo-C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups. R AThese include optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, and halo-C1-C6 Each instance is independently selected from the group consisting of alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, C1-C6 alkylene-O-C1-C6 alkyl, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, and -N(R)S(O)2R. R 2 C(R B )2C(O)N(R)R 2A And, R B The elements are independently selected from hydrogen, -CH3, and -CH2CH3 for each occurrence, or two Rs. B Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. R 2AThese are phenyl or pyridyl, each optionally substituted with one, two or three substituents independently selected from halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy and -SF5, or two substituents on adjacent atoms of phenyl or pyridyl together with the adjacent atom to form a 4-7 membered carbocyclyl condensed to phenyl or pyridyl, or two substituents on adjacent atoms of phenyl or pyridyl together with the adjacent atom to form a 4-7 membered heterocyclyl condensed to phenyl or pyridyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), and the 4-7 membered carbocyclyl or 4-7 membered heterocyclyl is optionally substituted with 0-5 independently selected halogens, or R 2A These are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, and -OH groups. R 3 These are hydrogen, C1-C4 aliphatic, C3-C5 cycloalkyl, C1-C4 alkoxy, and -NHR 3A , -N(R 3A )2 or C1-C4 alkylthio, which, apart from hydrogen, each contain -OH, 1-5 independently selected halogens, -OR, -C(O)NR 10 R 11 Alternatively, it may be replaced as needed by N(R)C(O)R. R 3A Each of these is independently selected from C1-C4 alkyl groups as it appears. R 4 is a phenyl or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the phenyl or 5-6 membered heteroaryl has 0-5 R ASubstituting with or two substituents on adjacent atoms of the phenyl or 5-6 membered heteroaryl together with the adjacent atoms to form a 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on the phenyl or 5-6 membered heteroaryl, the 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl having 0-3 R A It is replaced by, or R 4 These are C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each independently selected from halogens, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclyl groups, and optionally substituted 5-6 membered heterocyclyloxy groups. Each R is independently substituted with hydrogen or, if necessary, C. 1~6 An aliphatic group, optionally substituted phenyl, optionally substituted 3-7 member saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 member saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or optionally substituted 5-6 member heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or Two R groups on the same atom, together with the same atom, form a 4- to 7-membered saturated ring, a 4- to 7-membered partially unsaturated ring, or a 5- to 6-membered heteroaryl ring (the 4- to 7-membered saturated ring and the 4- to 7-membered partially unsaturated ring have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 6-membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0017] To clarify, the above [ka] This represents a single bond or a double bond, and when Y is O, [ka] teeth [ka] And if Y is N, [ka] teeth [ka] And if Z is O, [ka] teeth [ka] And if Z is N, [ka] teeth [ka] It is understood that this is the case.

[0018] In another aspect, the present invention provides a method for treating a disorder or disease that can be treated by WRN inhibition in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof.

[0019] In another embodiment, the present disclosure relates to a compound of formula I' or a pharmaceutically acceptable salt thereof: [ka] Provided, R 4The answer is selected from one of a), b), and c): a) R 4 teeth, [ka] Ring B is selected from the group consisting of the following: * represents the connection point to L in equation I, R 4A , R 4B , R 4C , R 4D , R 4E and R 4F Any substituent present on ring E selected from the following is hydrogen; halogen; -OH; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; C1~C4 alkoxy; haloC1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; haloC1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4A and R 4B These intervening atoms bond together to form a 4-7 member optionally substituted carbocyryl, 4-7 member optionally substituted heterocyclyl, or 5-6 member optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring E, R 4C , R 4D , R 4E and R 4F Any substituent present on ring E selected from the following is hydrogen; halogen; -OH; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; halo C1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo C1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R4B and R 4C These intervening atoms bond together to form a 4-7 member optionally substituted carbocyryl, 4-7 member optionally substituted heterocyclyl, or 5-6 member optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring E, R 4A , R 4D , R 4E and R 4F Any substituent present on ring E selected from the following is hydrogen; halogen; -OH; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; halo C1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo C1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4C and R 4D These intervening atoms bond together to form a 4-7 member optionally substituted carbocyryl, 4-7 member optionally substituted heterocyclyl, or 5-6 member optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring E, R 4A , R 4B , R 4E and R 4F Any substituent present on ring E selected from the following is hydrogen; halogen; -OH; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; halo C1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo C1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4E is a halogen or -OH, and R 4A , R4B and R 4C and R 4D are each independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo C1-C4 alkyl; C1-C3 alkyl substituted by -OH, -OCH3 or -OCH2CH3; halo C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 or R 4E and R 4A are joined together with the intervening atoms to form a 5- to 6-membered optionally substituted heteroaryl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur) fused to ring E, and R 4B R 4C and R 4D are each independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo C1-C4 alkyl; C1-C3 alkyl substituted by -OH, -OCH3 or -OCH2CH3; halo C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 or R 4F and R 4A are joined together with the intervening atoms to form a 5- to 6-membered optionally substituted heteroaryl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur) fused to ring E, and R 4B and R 4C are each independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo C1-C4 alkyl; C1-C3 alkyl substituted by -OH, -OCH3 or -OCH2CH3; halo C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 are each independently selected, R13 Each of these is independently selected from C1-C4 alkyl groups, which are optionally substituted with hydrogen and -OH, -OCH3, or -OCH2CH3. R 14 Is it hydrogen, or NR 13 R 14 This forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, wherein the heterocyclic ring is optionally substituted with -CH3; or b) R 4 This is a 5-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein the heteroaryl is substituted with 0 to 4 groups independently selected from halogens, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl and C1-C4 alkoxy, or c) R 4 These are C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each of which is substituted with 0-3 groups independently selected from halogens, -CN, -OH, C1-C4 alkyl groups, C1-C4 alkoxy groups, optionally substituted 5-6 member heterocyclines, and optionally substituted 5-6 member heterocyclyloxy groups.

[0020] In another embodiment, the present invention provides a method for treating a disorder or disease in a subject that can be treated by WRN inhibition, comprising the step of administering to the subject a therapeutically effective amount of the compound of formula I' of the present invention or a pharmaceutically acceptable salt thereof.

[0021] In one embodiment, the present disclosure relates to a compound of formula I'' or a pharmaceutically acceptable salt thereof: [ka] Provide (In the formula, ring A is defined as follows: a) A 4-7 member saturated or partially unsaturated divalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated divalent bicyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). This represents, Ring A is a set of 0 to 4 independently selected R A Substituting with substituents, Y and Z are selected from N and O, respectively, such that Y is N and Z is O, or Y is O and Z is N. [ka] represents a single or double bond, and the 5-membered ring containing Z and Y is aromatic. L is -C(O)-, -S(O)-, -S(O)2- and [ka] A linker selected from, R 1 is, group a)~e): a) A 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with 1-3 groups independently selected from halogens, C1-C6 alkyls, halo-C1-C6 alkyls, C3-C6 cycloalkyls, C1-C6 alkoxys, and C3-C6 cycloalkoxys, wherein 0-3 independently selected R A Further substitutions are made by 5-6 member monocyclic heteroaryls, b) A 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein 0-3 independently selected R A Further substitutions are made by 9-10 member bicyclic heteroaryls, c) A 4-7 member saturated or partially unsaturated monocyclic heterocycline (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, and -OR, wherein 0-3 independently selected R A A 4-7 member saturated or partially unsaturated monocyclic heterocycline, further substituted by d) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system selected from carbocyclyls and heterocyclyls (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R A A 4-12 member saturated or partially unsaturated bicyclic ring system that is substituted by, and e) H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene -O-C1-C6 alkyl, -CN, -OR, -NR 10 R 11 -C(O)NR 10 R 11 -CH2NR 10 R 11 , -SO2R 12 The C1-C6 aliphatic, C3-C7 cycloalkyl, or C1-C6 alkylene-O-C1-C6 alkyl groups are 0-5 independently selected R A things that are replaced by Select one of the following: R10 This includes H, C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, or R A A 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted by one or two groups independently selected from the above, R 11 is either H, C1-C6 aliphatic or C3-C6 cycloalkyl, or R 10 and R 11 These may combine to form a 5-6 membered ring which is optionally substituted with one, two, or three substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxys, and halo-C1-C4 alkoxys. R 12 This is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, or halogen, C1-C6 aliphatic, halo-C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups. R AThese include optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, and halo-C1-C6 Each instance is independently selected from the group consisting of alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, C1-C6 alkylene-O-C1-C6 alkyl, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, and -N(R)S(O)2R. R 2 C(R B )2C(O)N(R)R 2A , C(R B )2C(R B )2C(O)N(R)R 2A , C(R B )2C(R B )2N(R)C(O)N(R)R 2A and C(R B )2C(R B )2N(R)C(O)R 2A Selected from, R B The elements are independently selected from hydrogen, -CH3, and -CH2CH3 for each occurrence, or two Rs. B Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. R 2AThe elements are phenyl, pyridyl, cubanyl, a 4- to 8-membered saturated or partially unsaturated monocyclic ring, a 5, 6, 7, 8, 9, 10, 11, or 12-membered saturated or partially unsaturated bridged ring, fused ring, or spirocyclic ring, wherein the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged ring, fused ring, or spirocyclic ring, contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound contains phenyl, pyridyl, cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated crosslinked ring, condensed ring, or spirocyclic ring, and the phenyl, pyridyl, cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated crosslinked ring, condensed ring, or spirocyclic ring is a halogen, C1-C4 aliphatic, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy and -SF5 are each optionally substituted with one, two, or three substituents independently selected from -SF5, or two substituents on an adjacent atom of phenyl or pyridyl, together with the adjacent atom, form a 4-7 membered carbocycline condensed to phenyl or pyridyl, or two substituents on an adjacent atom of phenyl or pyridyl, together with the adjacent atom, form a 4-7 membered heterocycline condensed to phenyl or pyridyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the 4-7 membered carbocycline or 4-7 membered heterocycline is substituted with 0-5 independently selected halogens, and two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridging ring, fused ring, or spirocyclic ring, are as follows: • 3- to 7-membered saturated or partially unsaturated carbocyclyls, which are substituted as needed, and • 4-7 member saturated or partially unsaturated heterocyclines having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which are substituted as needed. They form a cyclic group selected from, or R 2AThese are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, and -OH groups. R 3 These are hydrogen, C1-C4 aliphatic, C3-C5 cycloalkyl, C1-C4 alkoxy, and -NHR 3A , -N(R 3A )2 or C1-C4 alkylthio, which, apart from hydrogen, each contain -OH, 1-5 independently selected halogens, -OR, -C(O)NR 10 R 11 Alternatively, it may be replaced as needed by N(R)C(O)R. R 3A Each of these is independently selected from C1-C4 alkyl groups as it appears. R 4 is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6 membered heteroaryl has 0-5 R A Substituted by, or two substituents on adjacent atoms of the phenyl or the first 5-6 membered heteroaryl, together with the adjacent atoms, form a 4-7 membered carbocyclyl, 4-7 membered heterocyclyl or second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur) condensed on the phenyl or the first 5-6 membered heteroaryl, and the 4-7 membered carbocyclyl, 4-7 membered heterocyclyl or second 5-6 membered heteroaryl has 0-3 R A It is replaced by, or R 4These are C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each independently selected from halogens, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclyl groups, and optionally substituted 5-6 membered heterocyclyloxy groups. Each R is independently substituted with hydrogen or, if necessary, C. 1~6 An aliphatic group, optionally substituted phenyl, optionally substituted 3-7 member saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 member saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or optionally substituted 5-6 member heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or Two R groups on the same atom, together with the same atom, form a 4- to 7-membered saturated ring, a 4- to 7-membered partially unsaturated ring, or a 5- to 6-membered heteroaryl ring (the 4- to 7-membered saturated ring and the 4- to 7-membered partially unsaturated ring have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 6-membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0022] In another aspect, the present invention provides a method for treating a disorder or disease that can be treated by WRN inhibition in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula I'' of the present invention or a pharmaceutically acceptable salt thereof. 2. Compounds and Definitions:

[0023] The compounds of the present invention include those generally described herein, and are further exemplified by the classes, subclasses, and species disclosed herein. Where used herein, unless otherwise specified, the following definitions shall apply. For the purposes of the present invention, chemical elements are defined as those in the Handbook of Chemistry and Physics, 75 th The elements are identified according to the CAS version of the periodic table in Ed. Furthermore, the general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 th This is listed in Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001.

[0024] The terms “aliphatic” or “aliphatic group,” as used herein, mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic (also referred herein as “carbocyclic,” “alicyclic,” or “cycloalkyl”) having a single bond site to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet another embodiment, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another embodiment, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, “alicyclic” (or “carbocyclic” or “cycloalkyl”) refers to monocyclic C3-C6 hydrocarbons that are fully saturated or contain one or more unsaturated units but are not aromatic, and which have a single bond site to the rest of the molecule. Preferred aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0025] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system having at least one bridge, i.e., a saturated or partially unsaturated carbocyclic or heterocyclic ring system. As defined by IUPAC, a “bridge” is one or more unbranched chains or valence bonds of atoms connecting two bridgeheads, and a “bridgehead” is any skeletal atom of a ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, unless otherwise specified, a bridged bicyclic group has 5 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the bridged bicyclic group is optionally substituted with one or more substituents shown with respect to the aliphatic group. Further or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. The term “alkyl” refers to a linear or branched saturated C 1~12 This refers to an aliphatic group. In certain cases, alkyl refers to a linear or branched saturated carbon group. 1~8 Aliphatic groups or linear or branched saturated carbon atoms 1~6 This refers to an aliphatic group. The term "lower alkyl" refers to a linear or branched C group. 1~4 This refers to an alkyl group.

[0026] Examples of lower alkyl groups include methyl (-CH3), ethyl (-CH2CH3), propyl, isopropyl (2-propyl, iPr, as specified herein), i Pr and i-Pr are interchangeable terms), butyl, isobutyl (in this specification, 2-butyl, iBu, i Bu and i-Bu are interchangeable terms) and tert-butyl (in this specification, 2-methyl-2-butyl, tBu, t (Also referred to interchangeably as Bu and t-Bu)

[0027] The term "alkenyl" refers to a linear or branched partially unsaturated carbon atom containing at least one unsaturated carbon-carbon double bond. 2~12 This refers to an aliphatic group. In certain cases, an alkenyl is a linear or branched partially unsaturated carbon group containing at least one unsaturated carbon-carbon double bond. 2~8 or C2~6 This refers to an aliphatic group. The term "lower alkenyl" refers to a linear or branched partially unsaturated carbon atom containing at least one unsaturated carbon-carbon double bond. 2~4 This refers to an aliphatic group. Alkenyl groups include both cis (Z) and trans (E) positional isomers. Exemplary lower alkenyl groups are vinyl, allyl, 2-propenyl, and butenyl isomers (-CH2CH2CH=CH2, -CH2CH=CHCH3, and -CH=CHCH2CH3).

[0028] The term "alkynyl" refers to a linear or branched partially unsaturated carbon chain containing at least one unsaturated carbon-carbon triple bond. 2~12 This refers to an aliphatic group. In certain cases, an alkynyl is a linear or branched partially unsaturated carbon group containing at least one unsaturated carbon triple bond. 2~8 or C 2~6 This refers to an aliphatic group. The term "lower alkynyl" refers to a linear or branched partially unsaturated carbon atom containing at least one unsaturated carbon triple bond. 2~4 This refers to an aliphatic group. Exemplary lower alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

[0029] The term "haloalkyl" refers to a linear or branched alkyl group substituted with one or more halogen atoms. The term "lower haloalkyl" refers to a linear or branched C alkyl group substituted with one or more halogen atoms. 1~4 This refers to an alkyl group.

[0030] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidation form of nitrogen, sulfur, phosphorus, or silicon; any basic nitrogen or quaternized form of a heterocyclic ring, e.g., N (such as 3,4-dihydro-2H-pyrrolyl), NH (such as pyrrolidinyl), or NR) + This means (including N-substituted pyrrolidinyls).

[0031] As used herein, the term "unsaturated" means that a part of it has one or more unsaturated units.

[0032] As used herein, the term "saturated or unsaturated, linear or branched divalent C" refers to a saturated or unsaturated, linear or branched divalent C. 1~8 (or C 1~6 "C1-C6 hydrocarbon chains" refers to divalent alkylene, alkenylene, and alkynylene chains, which are either linear or branched, as defined herein.

[0033] As used herein, the term “divalent” to describe cyclic (and acyclic) groups refers, for example, to divalent carbocyclylenes, phenylenes, heterocyclenes, and heteroarylenes, which are the divalent moieties of carbocyclic, phenyl, heterocyclic, and heteroaryl groups as described herein. Non-limiting examples include: [ka] It includes.

[0034] As used herein, "carbocyclylene" refers to a carbocyclic or cycloalkyl moiety that is divalent (i.e., bonded to the rest of the compound at two different points) as described above. Non-limiting examples include cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, as shown below. [ka]

[0035] Carbocyclylene may be saturated, as in the example shown above, or partially unsaturated, as in the example shown below. [ka]

[0036] Carbocyclylenes may be polycyclic, for example, bicyclic or tricyclic. Such polycyclic carbocyclylene systems may be saturated or partially unsaturated (it should be understood that a polycyclic ring system in which one ring of a bicyclic system is aromatic but the whole is not aromatic can still fit within the definition of carbocyclylene). The rings may form bridging, condensation, or spiro systems. Non-limiting examples are shown below. [ka]

[0037] As used herein, "heterocyclylene" refers to a heterocyclic or heterocyclyl moiety that is divalent (i.e., bonded to the rest of the compound at two different points) as described above, and may be saturated or partially unsaturated. Non-limiting examples include those shown below. Heterocyclylene is understood to include bicyclic heterocyclylene systems. Non-limiting examples of bicyclic heterocyclylene moieties are also shown below, and the bicyclic system may be spirocyclic, condensed, or cross-linked, and may be saturated or partially unsaturated. [ka]

[0038] As used herein, "phenylene" refers to the phenyl moiety that is divalent (i.e., bonded to the rest of the compound at two different points) as described above. An example is shown below. [ka]

[0039] As used herein, "arylene" refers to a monocyclic or polycyclic aryl (i.e., phenyl or polycyclic aryl) moiety that is divalent (i.e., bonded to the rest of the compound at two different points) as described above, and the arylene group does not contain a heteroatom. An example is shown below. [ka]

[0040] As used herein, "heteroarylene" refers to a monocyclic or polycyclic aryl ring system containing at least one heteroatom, the ring system being divalent as described above (i.e., bonded to the rest of the compound at two different points). An example is shown below. [ka]

[0041] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n - where n is a positive integer, preferably 1-6, 1-4, 1-3, 1-2, or 2-3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Preferred substituents include those listed below with respect to substituted aliphatic groups.

[0042] Another phenyl, aryl, heteroaryl, carbocyryl, or heterocyclyl, for example, “phenyl or pyridyl” “carbocyryl (or heterocyclyl, aryl, phenyl, or heteroaryl),” as used herein, may be referred to as “partially unsaturated,” meaning that the aforementioned other ring “carbocyryl (or heterocyclyl, aryl, phenyl, or heteroaryl)” does not require further unsaturation beyond the carbon-carbon bonds shared with the fused ring (i.e., “phenyl or pyridyl”). These are exemplified below. [ka]

[0043] Further examples below show a carbocyclyl moiety condensed to ring B as defined in the embodiments herein. The carbocyclyl does not require the explicit descriptor “partially unsaturated” to describe it, because it shares two carbons with the condensed aromatic pyridine. Such wording is used herein, for example, as shown in the image below, “R 4A and R 4B It is used to describe systems such that "these intervening atoms join together to form a 4-7 membered carbocyclyl condensed into ring B." Therefore, "ring B" is its substituent (i.e., R 4A and R 4B This can refer to a monocyclic ring (i.e., pyridine and its substituents that do not form fused rings) that does not contain any further fused rings resulting from the substituents of ring B. Any further fused rings resulting from the substituents of ring B are described as "fused to ring B". Similarly, R 4A and R 4B These intervening atoms join together to form a 4-7 membered carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B (not shown), and are subject to the same interpretation. [ka]

[0044] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Preferred substituents include those listed below with respect to substituted aliphatic groups.

[0045] The term "cubanyl" refers to the substituents of cubane shown below. [ka]

[0046] The term "halogen" refers to F, Cl, Br, or I.

[0047] When used alone or as part of a larger term, such as in "aralkyl," "aralkoxy," or "aryloxyalkyl," the term "aryl" refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, where at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, which may have one or more substituents. Similarly, the scope of the term "aryl" also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthoimidyl, phenantridinyl, or tetrahydronaphthyl, as used herein.

[0048] Used alone or as part of a larger term, such as "heteroaryl" or "heteroarcoxy," the terms "heteroaryl" and "heteroar-" refer to a group having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms, and having 6, 10, or 14 π electrons shared in the cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl groups include, non-limitingly, pyrazinyl, pyrazolyl, pyridadinyl, pyridyl, pyrimidinyl, triazinyl, thienyl, furanil, pyrrolyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl), 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-” also, as used herein, include a group in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, in which case, unless otherwise specified, the radical or bond site is located on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused.Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, indolidinyl, isoindolin-1-only, 1,2-dihydro-3H-pyrrolo[3,4-c]pyridinyl-3-onyl, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl-1-onyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyro This includes r[1,2-b]pyridazinyl, pyrroro[1,2-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxadinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which include a ring that is substituted as needed. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are substituted independently as needed.

[0049] As used herein, the terms “heterocyclic,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to stable 5-7 member monocyclic-heterocyclic moieties or 7-10 member bicyclic-heterocyclic moieties that are either saturated or partially unsaturated and have one or more, preferably 1-4, heteroatoms as defined above, in addition to carbon atoms. When used in reference to the ring atoms of a heterocyclic ring, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (such as 3,4-dihydro-2H-pyrrolyl), NH (such as pyrrolidinyl), or + It may also be an NR (such as an N-substituted pyrrolidinyl).

[0050] Heterocyclic rings can be bonded to their pendant group at any heteroatom or carbon atom, resulting in a stable structure, and any of the ring atoms can be substituted as needed. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocyclic,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl. The heterocyclyl group may be monocyclic or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, where the alkyl moiety and heterocyclyl moiety are substituted independently as needed.

[0051] "Arirene" or "heteroarirene" (i.e., phenylene) as used herein means any divalent aryl or heterocyclyl described herein, which is a bisradical substituted at each of the two substitutable positions of the ring system described in detail above.

[0052] As used herein, "heterocyclyloxy" refers to an -OR group in which R is a heterocyclyl. Non-limiting examples are shown below. [ka]

[0053] As used herein, the term “partially unsaturated” refers to a ring portion containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated sites, but is not intended to include aryl or heteroaryl moies as defined herein.

[0054] As described herein, the compounds of the present invention may contain “optionally substituted” moieties. Generally, the term “substituted” means that one or more hydrogens of the designated moiety are replaced by preferred substituents, whether preceded by the term “optionally.” Unless otherwise specified, the “optionally substituted” group may have preferred substituents at each of its substituted positions, and the substituents may be the same or different at any position if more than one position in any given structure is substituted by more than one substituent selected from the designated group. The substituent combinations envisioned by the present invention preferably result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, means a compound that remains substantially unchanged when subjected to conditions that enable its generation, detection, and, in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0055] A suitable monovalent substituent on the substitutable carbon atom of the group "substituted as needed" is, independently, a halogen;-(CH2) 0~4 B(OR°)2;-(CH2) 0~4 R°;-(CH2) 0~4 OR°;-O(CH2) 0~4 R o ;-O-(CH2) 0~4 C(O)OR°;-(CH2) 0~4 CH(OR°)2;-(CH2) 0~4 SR°;R° may be substituted -(CH2) 0~4 It may be substituted with Ph;R°-(CH2) 0~4O(CH2) 0~1 It may be substituted with Ph;R° - CH=CHPh;R° - (CH2) 0~4 O(CH2) 0~1 -Pyridyl;-NO2;-CN;-N3;-(CH2) 0~4 N(R°)2;-(CH2) 0~4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0~4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0~4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-N(R°)C(NR°)N(R°)2;-(CH2) 0~4 C(O)R°;-C(S)R°;-(CH2) 0~4 C(O)OR°;-(CH2) 0~4 C(O)SR°;-(CH2) 0~4 C(O)OSiR°3;-(CH2) 0~4 OC(O)R°;-OC(O)(CH2) 0~4 SR°;-(CH2) 0~4 SC(O)R°;-(CH2) 0~4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°;-(CH2) 0~4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0~4 SSR°;-(CH2) 0~4 S(O)2R°;-(CH2) 0~4 S(O)2OR°;-(CH2) 0~4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0~4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-(CH2) 0~4 P(O)2R°;-(CH2) 0~4 P(O)R°2;-(CH2) 0~4 OP(O)R°2;-(CH2) 0~4OP(O)(OR°)2;-SiR°3,-(linear or branched C 1~4 Alkylene)ON(R°)2; or -(linear or branched C 1~4 The alkylene is C(O)ON(R°)2, where R° may be substituted as defined below, independently of hydrogen and C. 1~6 Aliphatic, -SO2-C 1~4 Aliphatic (i.e., -SO2CH3)-CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5-6 member heteroaryl ring), or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, even if defined above, two independently occurring R° atoms, together with their intervening atoms, form a 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0056] Suitable monovalent substituents on R° (or rings formed by two independently occurring R° atoms joining together with the intervening atom) are, independently, halogens, -(CH2) 0~2 R ● ,-(HaroR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 Ure ● ,-(CH2) 0~2 CH(OR ● )2;-O(HaroR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● ,-(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● ,-(CH2) 0~2 SR ● ,-(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● ,-(CH2) 0~2NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3, -C(O)SR ● ,-(linear or branched C 1~4 Alkylene)C(O)OR ● or -SSR ● And R ● Each of these is either unsubstituted, or, if preceded by "halo", substituted by only one or more halogens, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 A 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from Ph, nitrogen, oxygen, or sulfur. Preferred divalent substituents on the saturated carbon atom of R° include =O and =S.

[0057] Suitable divalent substituents on saturated carbon atoms of "substituted as needed" groups, including R°, (or rings formed by two independently occurring R° atoms joining with the intervening atom) are: =O, =S, =NNR * 2. =NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2)) 2~3 O- or -S(C(R * 2)) 2~3 S- is included and R appears independently. * These are hydrogen and C, which may be substituted as defined below. 1~6 Selected from unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having aliphatic or 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents bonded to the substituted carbon in the vicinal of the "optionally substituted" group include -O(CR * 2) 2~3 O- is included and R appears independently. *These are hydrogen and C, which may be substituted as defined below. 1~6 Selected from an aliphatic, or unsubstituted, 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0058] R * Suitable substituents on the aliphatic group include halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● Contains 2 or -NO2, R ● Each of these is either unsubstituted, or, if preceded by "halo", substituted by only one or more halogens, independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0059] A suitable substituent on the substituted nitrogen of the group "substituted as needed" is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2. -C(NH)NR † 2 or -N(R † )S(O)2R † R † Each of these independently consists of hydrogen, and C which may be substituted as defined below. 1~6An unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from aliphatic, unsubstituted-OPh, or nitrogen, oxygen, or sulfur, or, even if defined above, two independently occurring R † These, together with the intervening atoms, form unsubstituted 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0060] R † Suitable substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● It is 2 or -NO2, R ● Each of these is either unsubstituted, or, if preceded by "halo", substituted by only one or more halogens, independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0061] As used herein, the term “pharmaceutically acceptable salt” means a salt that, within reasonable limits of medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that is commensurate with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al., in J. Pharmaceutical Sciences, 1977, 66, 1-19, describe pharmaceutically acceptable salts in detail. pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids, as well as inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed by using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate. This includes lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and others.

[0062] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C1~4 Alkyl)4 salts are included. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, which are formed using counterions such as halide ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions, where appropriate.

[0063] Unless otherwise specified, the structures illustrated herein represent all isomers of the structure (e.g., enantiomers, diastereomers, and geometric isomers (or stereoisomers)), such as the R and S configurations with respect to each chiral center, the Z and E double bond isomers, the Z and E stereostructural isomers, and R a (or M) and S a It is also intended that the (or P) atrop isomers be included. Thus, single stereochemical isomers of the compound, as well as enantiomers, diastereomers, and geometric isomers (or stereostructures) are within the scope of the invention. Unless otherwise specified, all tautomer forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise specified, the structures illustrated herein are also intended to include compounds that differ only in the presence of one or more isotopic enriched atoms. For example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, including carbon substitution with carbon-enriched carbon, fall within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. In certain embodiments, ring A of the provided compound may be substituted with one or more deuterium atoms.

[0064] The structures shown represent relative stereoconfigurations unless otherwise indicated as absolute configurations. This invention intends to focus on individual enantiomers and racemic mixtures. 3. Description of exemplary embodiments:

[0065] In one embodiment, the present disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof: [ka] Provide (In the formula, ring A is, a) A 4-7 member saturated or partially unsaturated divalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated divalent bicyclic ring system selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). This represents, Ring A is a set of 0 to 4 independently selected R A Substituting with substituents, Y and Z are selected from N and O, respectively, such that Y is N and Z is O, or Y is O and Z is N. [ka] represents a single or double bond, and the 5-membered ring containing Z and Y is aromatic. L is -C(O)-, -S(O)-, -S(O)2- and [ka] A linker selected from, R 1 is, group a)~e): a) A 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with 1-3 groups independently selected from halogens, C1-C6 alkyls, halo-C1-C6 alkyls, C3-C6 cycloalkyls, C1-C6 alkoxys, and C3-C6 cycloalkoxys, wherein 0-3 independently selected R A Further substitutions are made by 5-6 member monocyclic heteroaryls, b) A 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein 0-3 independently selected R A Further substitutions are made by 9-10 member bicyclic heteroaryls, c) A 4-7 member saturated or partially unsaturated monocyclic heterocycline (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, and -OR, wherein 0-3 independently selected R A A 4-7 member saturated or partially unsaturated monocyclic heterocycline, further substituted by d) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system selected from carbocyclyls and heterocyclyls (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R A A 4-12 member saturated or partially unsaturated bicyclic ring system that is substituted by, and e) H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene -O-C1-C6 alkyl, -CN, -OR, -NR 10 R11 -C(O)NR 10 R 11 -CH2NR 10 R 11 , -SO2R 12 The C1-C6 aliphatic, C3-C7 cycloalkyl, or C1-C6 alkylene-O-C1-C6 alkyl groups are 0-5 independently selected R A things that are replaced by Select one of the following: R 10 This includes H, C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, or R A A 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted by one or two groups independently selected from the above, R 11 is either H, C1-C6 aliphatic or C3-C6 cycloalkyl, or R 10 and R 11 These may combine to form a 5-6 membered ring which is optionally substituted with one, two, or three substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxys, and halo-C1-C4 alkoxys. R 12 This is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, or halogen, C1-C6 aliphatic, halo-C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups. R AThese include optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, and halo-C1-C6 Each instance is independently selected from the group consisting of alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, C1-C6 alkylene-O-C1-C6 alkyl, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, and -N(R)S(O)2R. R 2 C(R B )2C(O)N(R)R 2A And, R B The elements are independently selected from hydrogen, -CH3, and -CH2CH3 for each occurrence, or two Rs. B Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. R 2AThese are phenyl or pyridyl, each optionally substituted with one, two or three substituents independently selected from halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy and -SF5, or two substituents on adjacent atoms of phenyl or pyridyl together with the adjacent atom to form a 4-7 membered carbocyclyl condensed to phenyl or pyridyl, or two substituents on adjacent atoms of phenyl or pyridyl together with the adjacent atom to form a 4-7 membered heterocyclyl condensed to phenyl or pyridyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), and the 4-7 membered carbocyclyl or 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogens, or R 2A These are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, and -OH groups. R 3 These are hydrogen, C1-C4 aliphatic, C3-C5 cycloalkyl, C1-C4 alkoxy, and -NHR 3A , -N(R 3A )2 or C1-C4 alkylthio, which, apart from hydrogen, each contain -OH, 1-5 independently selected halogens, -OR, -C(O)NR 10 R 11 Alternatively, it may be replaced as needed by N(R)C(O)R. R 3A Each of these is independently selected from C1-C4 alkyl groups as it appears. R 4 is a phenyl or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the phenyl or 5-6 membered heteroaryl has 0-5 R ASubstituting with or two substituents on adjacent atoms of the phenyl or 5-6 membered heteroaryl together with the adjacent atoms to form a 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on the phenyl or 5-6 membered heteroaryl, the 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl having 0-3 R A It is replaced by, or R 4 These are C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each independently selected from halogens, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclyl groups, and optionally substituted 5-6 membered heterocyclyloxy groups. Each R is independently substituted with hydrogen or, if necessary, C. 1~6 An aliphatic group, optionally substituted phenyl, optionally substituted 3-7 member saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 member saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or optionally substituted 5-6 member heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or Two R groups on the same atom, together with the same atom, form a 4- to 7-membered saturated ring, a 4- to 7-membered partially unsaturated ring, or a 5- to 6-membered heteroaryl ring (the 4- to 7-membered saturated ring and the 4- to 7-membered partially unsaturated ring have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 6-membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0066] In one embodiment, this disclosure relates to Formula I xCompounds of or pharmaceutically acceptable salts thereof: [ka] Provide (In the formula, ring A is, a) A 4-7 member saturated or partially unsaturated divalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated divalent bicyclic ring system selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). This represents, Ring A is a set of 0 to 4 independently selected R A Substituting with substituents, Y and Z are selected from N and O, respectively, such that Y is N and Z is O, or Y is O and Z is N. [ka] represents a single or double bond, and the 5-membered ring containing Z and Y is aromatic. R 1 is, group a)~e): a) A 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with 1-3 groups independently selected from halogens, C1-C6 alkyls, halo-C1-C6 alkyls, C3-C6 cycloalkyls, C1-C6 alkoxys, and C3-C6 cycloalkoxys, wherein 0-3 independently selected R A Further substitutions are made by 5-6 member monocyclic heteroaryls, b) A 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein 0-3 independently selected R A Further substitutions are made by 9-10 member bicyclic heteroaryls, c) A 4-7 member saturated or partially unsaturated monocyclic heterocycline (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, and -OR, wherein 0-3 independently selected R A A 4-7 member saturated or partially unsaturated monocyclic heterocycline, further substituted by d) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system selected from carbocyclyls and heterocyclyls (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R A A 4-12 member saturated or partially unsaturated bicyclic ring system that is substituted by, and e) H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene -O-C1-C6 alkyl, -CN, -OR, -NR 10 R 11 -C(O)NR 10 R 11 -CH2NR 10 R 11 , -SO2R 12 The C1-C6 aliphatic, C3-C7 cycloalkyl, or C1-C6 alkylene-O-C1-C6 alkyl groups are 0-5 independently selected R A things that are replaced by Select one of the following: R10 This includes H, C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, or R A A 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted by one or two groups independently selected from the above, R 11 is either H, C1-C6 aliphatic or C3-C6 cycloalkyl, or R 10 and R 11 These may combine to form a 5-6 membered ring which is optionally substituted with one, two, or three substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxys, and halo-C1-C4 alkoxys. R 12 This is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, or halogen, C1-C6 aliphatic, halo-C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups. R AThese include optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, and halo-C1-C6 Each instance is independently selected from the group consisting of alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, C1-C6 alkylene-O-C1-C6 alkyl, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, and -N(R)S(O)2R. R 2 C(R B )2C(O)N(R)R 2A And, R B The elements are independently selected from hydrogen, -CH3, and -CH2CH3 for each occurrence, or two Rs. B Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. R 2AThese are phenyl or pyridyl, each optionally substituted with one, two or three substituents independently selected from halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy and -SF5, or two substituents on adjacent atoms of phenyl or pyridyl together with the adjacent atom to form a 4-7 membered carbocyclyl condensed to phenyl or pyridyl, or two substituents on adjacent atoms of phenyl or pyridyl together with the adjacent atom to form a 4-7 membered heterocyclyl condensed to phenyl or pyridyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), and the 4-7 membered carbocyclyl or 4-7 membered heterocyclyl is optionally substituted with 0-5 independently selected halogens, or R 2A These are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, and -OH groups. R 3 These are hydrogen, C1-C4 aliphatic, C3-C5 cycloalkyl, C1-C4 alkoxy, and -NHR 3A , -N(R 3A )2 or C1-C4 alkylthio, which, apart from hydrogen, each contain -OH, 1-5 independently selected halogens, -OR, -C(O)NR 10 R 11 Alternatively, it may be replaced as needed by N(R)C(O)R. R 3A Each of these is independently selected from C1-C4 alkyl groups as it appears. R 4 is a phenyl or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the phenyl or 5-6 membered heteroaryl has 0-5 R ASubstituting with or two substituents on adjacent atoms of the phenyl or 5-6 membered heteroaryl together with the adjacent atoms to form a 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on the phenyl or 5-6 membered heteroaryl, the 4-7 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl having 0-3 R A It is replaced by, or R 4 These are C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each independently selected from halogens, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclyl groups, and optionally substituted 5-6 membered heterocyclyloxy groups. Each R is independently substituted with hydrogen or, if necessary, C. 1~6 An aliphatic group, optionally substituted phenyl, optionally substituted 3-7 member saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 member saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or optionally substituted 5-6 member heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or Two R groups on the same atom, together with the same atom, form a 4- to 7-membered saturated ring, a 4- to 7-membered partially unsaturated ring, or a 5- to 6-membered heteroaryl ring (the 4- to 7-membered saturated ring and the 4- to 7-membered partially unsaturated ring have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 6-membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0067] In one embodiment, this disclosure relates to Formula I yCompounds of or pharmaceutically acceptable salts thereof: [ka] Provide (In the formula, ring A is, a) A 4-7 member saturated or partially unsaturated divalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated divalent bicyclic ring system selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). This represents, Ring A is a set of 0 to 4 independently selected R A Substituting with substituents, Y and Z are selected from N and O, respectively, such that Y is N and Z is O, or Y is O and Z is N. [ka] represents a single or double bond, and the 5-membered ring containing Z and Y is aromatic. R 1 is, group a)~e): a) A 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with 1-3 groups independently selected from halogens, C1-C6 alkyls, halo-C1-C6 alkyls, C3-C6 cycloalkyls, C1-C6 alkoxys, and C3-C6 cycloalkoxys, wherein 0-3 independently selected R A Further substitutions are made by 5-6 member monocyclic heteroaryls, b) A 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein 0-3 independently selected R A Further substitutions are made by 9-10 member bicyclic heteroaryls, c) A 4-7 member saturated or partially unsaturated monocyclic heterocycline (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, and -OR, wherein 0-3 independently selected R A A 4-7 member saturated or partially unsaturated monocyclic heterocycline, further substituted by d) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system selected from carbocyclyls and heterocyclyls (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R A A 4-12 member saturated or partially unsaturated bicyclic ring system that is substituted by, and e) H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene -O-C1-C6 alkyl, -CN, -OR, -NR 10 R 11 -C(O)NR 10 R 11 -CH2NR 10 R 11 , -SO2R 12 The C1-C6 aliphatic, C3-C7 cycloalkyl, or C1-C6 alkylene-O-C1-C6 alkyl groups are 0-5 independently selected R A things that are replaced by Select one of the following: R10 This includes H, C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, or R A A 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted by one or two groups independently selected from the above, R 11 is either H, C1-C6 aliphatic or C3-C6 cycloalkyl, or R 10 and R 11 These may combine to form a 5-6 membered ring which is optionally substituted with one, two, or three substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxys, and halo-C1-C4 alkoxys. R 12 This is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, or halogen, C1-C6 aliphatic, halo-C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups. R AThese include optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, and halo-C1-C6 Each instance is independently selected from the group consisting of alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, C1-C6 alkylene-O-C1-C6 alkyl, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, and -N(R)S(O)2R. R 2 C(R B )2C(O)N(R)R 2A , C(R B )2C(R B )2C(O)N(R)R 2A , C(R B )2C(R B )2N(R)C(O)N(R)R 2A and C(R B )2C(R B )2N(R)C(O)R 2A Selected from, R B The elements are independently selected from hydrogen, -CH3, and -CH2CH3 for each occurrence, or two Rs. B Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. R 2AThe elements are phenyl, pyridyl, cubanyl, a 4- to 8-membered saturated or partially unsaturated monocyclic ring, a 5, 6, 7, 8, 9, 10, 11, or 12-membered saturated or partially unsaturated bridged ring, fused ring, or spirocyclic ring, wherein the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged ring, fused ring, or spirocyclic ring, contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compounds contain phenyl, pyridyl, cubanyl, saturated or partially unsaturated monocyclic rings, or saturated or partially unsaturated crosslinked rings, condensed rings, or spirocyclic rings, and include halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and The ring is substituted as needed by one, two, or three substituents independently selected from bi-SF5, or two substituents on an adjacent atom of phenyl or pyridyl, together with the adjacent atom, form a 4- to 7-membered carbocycline condensed to phenyl or pyridyl, or two substituents on an adjacent atom of phenyl or pyridyl, together with the adjacent atom, form a 4- to 7-membered heterocycline condensed to phenyl or pyridyl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the 4- to 7-membered carbocycline or 4- to 7-membered heterocycline is substituted by 0 to 5 independently selected halogens, and two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridging ring, fused ring, or spirocyclic ring, are as follows: • 3- to 7-membered saturated or partially unsaturated carbocyclyls, which are substituted as needed, and • 4-7 member saturated or partially unsaturated heterocyclines having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which are substituted as needed. They form a cyclic group selected from, or R 2AThese are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, and -OH groups. R 3 These are hydrogen, C1-C4 aliphatic, C3-C5 cycloalkyl, C1-C4 alkoxy, and -NHR 3A , -N(R 3A )2 or C1-C4 alkylthio, which, apart from hydrogen, each contain -OH, 1-5 independently selected halogens, -OR, -C(O)NR 10 R 11 Alternatively, it may be replaced as needed by N(R)C(O)R. R 3A Each of these is independently selected from C1-C4 alkyl groups as it appears. R 4 is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6 membered heteroaryl has 0-5 R A Substituted by, or two substituents on adjacent atoms of the phenyl or the first 5-6 membered heteroaryl, together with the adjacent atoms, form a 4-7 membered carbocyclyl, 4-7 membered heterocyclyl or second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur) condensed on the phenyl or the first 5-6 membered heteroaryl, and the 4-7 membered carbocyclyl, 4-7 membered heterocyclyl or second 5-6 membered heteroaryl has 0-3 R A It is replaced by, or R 4These are C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each independently selected from halogens, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclyl groups, and optionally substituted 5-6 membered heterocyclyloxy groups. Each R is independently substituted with hydrogen or, if necessary, C. 1~6 An aliphatic group, optionally substituted phenyl, optionally substituted 3-7 member saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 member saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or optionally substituted 5-6 member heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or Two R groups on the same atom, together with the same atom, form a 4- to 7-membered saturated ring, a 4- to 7-membered partially unsaturated ring, or a 5- to 6-membered heteroaryl ring (the 4- to 7-membered saturated ring and the 4- to 7-membered partially unsaturated ring have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 6-membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0068] In one embodiment, the present disclosure relates to a compound of formula I'' or a pharmaceutically acceptable salt thereof: [ka] Provide (In the formula, ring A is defined as follows: a) A 4-7 member saturated or partially unsaturated divalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated divalent bicyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). This represents, Ring A is a set of 0 to 4 independently selected R A Substituting with substituents, Y and Z are selected from N and O, respectively, such that Y is N and Z is O, or Y is O and Z is N. [ka] represents a single or double bond, and the 5-membered ring containing Z and Y is aromatic. L is -C(O)-, -S(O)-, -S(O)2- and [ka] A linker selected from, R 1 is, group a)~e): a) A 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with 1-3 groups independently selected from halogens, C1-C6 alkyls, halo-C1-C6 alkyls, C3-C6 cycloalkyls, C1-C6 alkoxys, and C3-C6 cycloalkoxys, wherein 0-3 independently selected R A Further substitutions are made by 5-6 member monocyclic heteroaryls, b) A 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein 0-3 independently selected R A Further substitutions are made by 9-10 member bicyclic heteroaryls, c) A 4-7 member saturated or partially unsaturated monocyclic heterocycline (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, and -OR, wherein 0-3 independently selected R A A 4-7 member saturated or partially unsaturated monocyclic heterocycline, further substituted by d) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system selected from carbocyclyls and heterocyclyls (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R A A 4-12 member saturated or partially unsaturated bicyclic ring system that is substituted by, and e) H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene -O-C1-C6 alkyl, -CN, -OR, -NR 10 R 11 -C(O)NR 10 R 11 -CH2NR 10 R 11 , -SO2R 12 The C1-C6 aliphatic, C3-C7 cycloalkyl, or C1-C6 alkylene-O-C1-C6 alkyl groups are 0-5 independently selected R A things that are replaced by Select one of the following: R 10 This includes H, C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, or R A A 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted by one or two groups independently selected from the above, R11 is either H, C1-C6 aliphatic or C3-C6 cycloalkyl, or R 10 and R 11 These may combine to form a 5-6 membered ring which is optionally substituted with one, two, or three substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxys, and halo-C1-C4 alkoxys. R 12 This is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, or halogen, C1-C6 aliphatic, halo-C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups. R A These include optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, and halo-C1-C6 Each instance is independently selected from the group consisting of alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, C1-C6 alkylene-O-C1-C6 alkyl, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, and -N(R)S(O)2R. R 2 C(RB )2C(O)N(R)R 2A , C(R B )2C(R B )2C(O)N(R)R 2A , C(R B )2C(R B )2N(R)C(O)N(R)R 2A and C(R B )2C(R B )2N(R)C(O)R 2A Selected from, R B The elements are independently selected from hydrogen, -CH3, and -CH2CH3 for each occurrence, or two Rs. B Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. R 2AThe elements are phenyl, pyridyl, cubanyl, a 4- to 8-membered saturated or partially unsaturated monocyclic ring, a 5, 6, 7, 8, 9, 10, 11, or 12-membered saturated or partially unsaturated bridged ring, fused ring, or spirocyclic ring, wherein the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged ring, fused ring, or spirocyclic ring, contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound contains phenyl, pyridyl, cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated crosslinked ring, condensed ring, or spirocyclic ring, and the phenyl, pyridyl, cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated crosslinked ring, condensed ring, or spirocyclic ring is a halogen, C1-C4 aliphatic, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy and -SF5 are each optionally substituted with one, two, or three substituents independently selected from -SF5, or two substituents on an adjacent atom of phenyl or pyridyl, together with the adjacent atom, form a 4-7 membered carbocycline condensed to phenyl or pyridyl, or two substituents on an adjacent atom of phenyl or pyridyl, together with the adjacent atom, form a 4-7 membered heterocycline condensed to phenyl or pyridyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the 4-7 membered carbocycline or 4-7 membered heterocycline is substituted with 0-5 independently selected halogens, and two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridging ring, fused ring, or spirocyclic ring, are as follows: • 3- to 7-membered saturated or partially unsaturated carbocyclyls, which are substituted as needed, and • 4-7 member saturated or partially unsaturated heterocyclines having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which are substituted as needed. They form a cyclic group selected from, or R 2AThese are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, and -OH groups. R 3 These are hydrogen, C1-C4 aliphatic, C3-C5 cycloalkyl, C1-C4 alkoxy, and -NHR 3A , -N(R 3A )2 or C1-C4 alkylthio, which, apart from hydrogen, each contain -OH, 1-5 independently selected halogens, -OR, -C(O)NR 10 R 11 Alternatively, it may be replaced as needed by N(R)C(O)R. R 3A Each of these is independently selected from C1-C4 alkyl groups as it appears. R 4 is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6 membered heteroaryl has 0-5 R A Substituted by, or two substituents on adjacent atoms of the phenyl or the first 5-6 membered heteroaryl, together with the adjacent atoms, form a 4-7 membered carbocyclyl, 4-7 membered heterocyclyl or second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur) condensed on the phenyl or the first 5-6 membered heteroaryl, and the 4-7 membered carbocyclyl, 4-7 membered heterocyclyl or second 5-6 membered heteroaryl has 0-3 R A It is replaced by, or R 4These are C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each independently selected from halogens, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclyl groups, and optionally substituted 5-6 membered heterocyclyloxy groups. Each R is independently substituted with hydrogen or, if necessary, C. 1~6 An aliphatic group, optionally substituted phenyl, optionally substituted 3-7 member saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 member saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or optionally substituted 5-6 member heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or Two R groups on the same atom, together with the same atom, form a 4- to 7-membered saturated ring, a 4- to 7-membered partially unsaturated ring, or a 5- to 6-membered heteroaryl ring (the 4- to 7-membered saturated ring and the 4- to 7-membered partially unsaturated ring have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 6-membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0069] In one embodiment, the present invention relates to formulas I, I', I x , I y Or provides a compound of I'', R 4 The answer is selected from one of a), b), and c): a) R 4 teeth, [ka] A ring B selected from the group consisting of s, * represents expressions I, I', and I x , I y or a connection point to L in I'', R 4A, R 4B , R 4C , R 4D , R 4E and R 4F Any substituent present on ring B selected from the following is hydrogen; halogen; -OH; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; C1~C4 alkoxy; haloC1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; haloC1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4A and R 4B These intervening atoms bond together to form a 4-7 member optionally substituted carbocyryl, 4-7 member optionally substituted heterocyclyl, or 5-6 member optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, and R 4C , R 4D , R 4E and R 4F Any substituent present on ring B selected from the following is hydrogen; halogen; -OH; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; halo C1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo C1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4B and R 4C These intervening atoms join together to form a 4-7 member optionally substituted carbocyryl, 4-7 member optionally substituted heterocyclyl, or 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, R 4A , R 4D , R4E and R 4F Any substituent present on ring B selected from the following is hydrogen; halogen; -OH; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; halo C1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo C1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4C and R 4D These intervening atoms join together to form a 4-7 member optionally substituted carbocyryl, 4-7 member optionally substituted heterocyclyl, or 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, R 4A , R 4B , R 4E and R 4F Any substituent present on ring B selected from the following is hydrogen; halogen; -OH; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; halo C1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo C1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4E is a halogen or -OH, and R 4A , R 4B , R 4C and R 4D These include hydrogen; halogens; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14They are either selected independently from each other, or R 4E and R 4A These intervening atoms join together to form a 5-6 member, optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, and R 4B , R 4C and R 4D These include hydrogen; halogen; -OH; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; haloC1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; haloC1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4F and R 4A These intervening atoms join together to form a 5-6 member, optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, and R 4B , R 4C and R 4D Any substituent present on ring B selected from the following is hydrogen; halogen; -OH; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; halo C1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo C1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 Each is independently selected from, R 13 Each of these is independently selected from C1-C4 alkyl groups, which are optionally substituted with hydrogen and -OH, -OCH3, or -OCH2CH3. R 14 Is it hydrogen, or NR 13 R 14This forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, wherein the heterocyclic ring is optionally substituted with -CH3; or b) R 4 This is a 5-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein the heteroaryl is substituted with 0 to 4 groups independently selected from halogens, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl and C1-C4 alkoxy, or c) R 4 These are C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each of which is substituted with 0-3 groups independently selected from halogens, -CN, -OH, C1-C4 alkyl groups, C1-C4 alkoxy groups, optionally substituted 5-6 member heterocyclines, and optionally substituted 5-6 member heterocyclyloxy groups.

[0070] As generally stated above, ring A is, a) A 4-7 member saturated or partially unsaturated divalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated divalent bicyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). This represents, Ring A is a set of 0 to 4 independently selected R A It is substituted with substituents.

[0071] In some embodiments, ring A is a 4-7 member saturated or partially unsaturated divalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), in which case ring A is 0-4 independently selected R A It is substituted with substituents. In some embodiments, ring A is a 4- to 7-membered saturated or partially unsaturated divalent monocyclic carbocrylene, in which case ring A is 0 to 4 independently selected R A It is substituted with substituents. In some embodiments, ring A is a 4-7 member saturated or partially unsaturated divalent monocyclic heterocyclene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), in which case ring A is 0-4 independently selected R A It is substituted with substituents.

[0072] In some embodiments, ring A is a condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated divalent bicyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), in which case ring A is 0-4 independently selected R A Substitutings are present. In some embodiments, ring A is a 4-12 member saturated or partially unsaturated divalent bicyclic ring system that is condensed, bridged, or spirocyclic and is a carbocyclylene, in which case ring A is composed of 0-4 independently selected R A Substitutings are present. In some embodiments, ring A is a 4-12 member saturated or partially unsaturated divalent bicyclic ring system that is condensed, bridged, or spirocyclic and is a heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), in which case ring A has 0-4 independently selected R A It is substituted with substituents.

[0073] In some embodiments, ring A is a 4- to 12-membered saturated or partially unsaturated divalent bicyclic ring system containing two fused rings. In some embodiments, ring A is a 4- to 12-membered saturated or partially unsaturated divalent bicyclic ring system containing a spirocyclic ring system. In some embodiments, ring A is a 4- to 12-membered saturated or partially unsaturated divalent bicyclic ring system containing a bridging ring system.

[0074] In some embodiments, ring A is [ka] Selected from, ring A is 0 to 4 independently selected R A It is substituted with substituents.

[0075] In some embodiments, ring A is [ka] That is the case.

[0076] In some embodiments, ring A is [ka] That is the case.

[0077] In some embodiments, ring A is [ka] That is the case.

[0078] In some embodiments, ring A is selected from one of the substituents in Table 1, Table 1a, or Table 1b.

[0079] As generally stated above, R 1 is, group a)~e): a) A 5-6 membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with 1-3 groups independently selected from halogens, C1-C6 alkyls, halo-C1-C6 alkyls, C3-C6 cycloalkyls, C1-C6 alkoxys, and C3-C6 cycloalkoxys, wherein 0-3 independently selected R A Further substitutions are made by 5-6 member monocyclic heteroaryls, b) A 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein 0-3 independently selected R A Further substitutions are made by 9-10 member bicyclic heteroaryls, c) A 4-7 member saturated or partially unsaturated monocyclic heterocycline (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, and -OR, wherein 0-3 independently selected R A A 4-7 member saturated or partially unsaturated monocyclic heterocycline, further substituted by d) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system selected from carbocyclyls and heterocyclyls (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R A A 4-12 member saturated or partially unsaturated bicyclic ring system that is substituted by, and e) H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene -O-C1-C6 alkyl, -CN, -OR, -NR 10 R11 -C(O)NR 10 R 11 -CH2NR 10 R 11 , -SO2R 12 The C1-C6 aliphatic, C3-C7 cycloalkyl, or C1-C6 alkylene-O-C1-C6 alkyl groups are 0-5 independently selected R A things that are replaced by Selected from.

[0080] In some embodiments, R 1 This is a 5-6 member monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy, and the 5-6 member monocyclic heteroaryl is 0-2 independently selected R A It is further replaced by R. In some embodiments, 1 This is a 4-membered or 6-membered saturated or partially unsaturated monocyclic heterocycline (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heterocycline is substituted with halogens, oxo, -NR2, and optionally C 1~4 Substituted with 0 to 2 groups independently selected from aliphatic, -OR, azetidinyls optionally substituted with one or two independently selected halogens, and pyrrolidinyls optionally substituted with one or two independently selected halogens. In some embodiments, R 1 This is a 6-8 member saturated or partially unsaturated bridged bicyclic heterocycline (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heterocycline is substituted with halogens, oxo, -NR2, and optionally C 1~4Substituted with 0 to 2 groups independently selected from aliphatic, -OR, azetidinyls optionally substituted with one or two independently selected halogens, and pyrrolidinyls optionally substituted with one or two independently selected halogens. In some embodiments, R 1 R is a carbocykyl with 3 to 7 members, which is substituted as needed. In some embodiments, R 1 is a C2-C4 alkenyl which is substituted as needed. In some embodiments, R 1 R is a cyclopropyl-substituted C2-C4 alkenyl. In some embodiments, R 1 It is a methyl-substituted C2 alkenyl.

[0081] In some embodiments, R 1 R is a 6-membered partially unsaturated heterocycline (having one oxygen atom). In some embodiments, R 1 is a 6-membered heteroaryl (having one nitrogen atom), and the heteroaryl may optionally be substituted with one or two groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy, and the heteroaryl has 0-1 R A It is further substituted by R A C is replaced as needed. 1~6 It is an aliphatic group. In some embodiments, R 1 is a 6-membered heteroaryl (having 2 nitrogen atoms), the heteroaryl may optionally be substituted with one or two groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and C3-C6 cycloalkoxy, the heteroaryl has 0-1 R A It is further substituted by R A C is replaced as needed. 1~6 It is an aliphatic group.

[0082] In some embodiments, R 1is a 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, wherein the 9-10 membered bicyclic heteroaryl has 0-3 independently selected R A It is further replaced by [this].

[0083] In some embodiments, R 1 is a 5-membered heteroaryl (having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1 to C6 alkyl, C1 to C6 alkoxy, C3 to C6 cycloalkyl, and C3 to C6 cycloalkoxy, wherein the 5-membered heteroaryl has 0 to 2 independently selected R A It is further replaced as needed by R. In some embodiments, 1 R is a five-membered heteroaryl (having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy. In some embodiments, R 1 is a 5-membered heteroaryl (having 2 nitrogen atoms) substituted with one or two groups independently selected from C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy, wherein the 5-membered heteroaryl has 0-1 R A It is further replaced as needed by R A These are hydroxyl-substituted C1-C4 alkyl groups.

[0084] In some embodiments, R 1is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one group from among C1-C6 alkoxy or C3-C6 cycloalkyl, and the 5-6 membered heteroaryl has 0-3 independently selected R A It is further replaced as needed.

[0085] In some embodiments, R 1 It is substituted with C1-C4 alkoxys and has 0-2 R A This is a pyridyl that is further substituted by substituents.

[0086] In some embodiments, R 1 This is a 5-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 additional ring nitrogen atom), wherein the 5-membered heteroaryl is optionally substituted with a C1-C6 alkyl or C3-C5 cycloalkyl, and has 0-2 R A It is further substituted with substituents.

[0087] In some embodiments, R 1 teeth, c) A 5-6 member saturated or partially unsaturated heterocycline (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is substituted with halogens, oxo, -NR2, or optionally C 1~4 Heterocyclines substituted with 0-2 groups independently selected from aliphatic, -OR, azetidinyls optionally substituted with one or two independently selected halogens, and pyrrolidinyls optionally substituted with one or two independently selected halogens; or d) A 6-8 member saturated or partially unsaturated bridged bicyclic heterocycline (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is substituted with halogens, oxo, -NR2, and optionally C 1~4Heterocyclines substituted with 0-2 groups independently selected from aliphatic, -OR, azetidinyls optionally substituted with one or two independently selected halogens, and pyrrolidinyls optionally substituted with one or two independently selected halogens. That is the case.

[0088] In some embodiments, R 1 This is a 5-6 member saturated or partially unsaturated heterocycline (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heterocycline is substituted with halogens, oxo, -NR2, or optionally C 1~4 Substituted with 0 to 2 groups independently selected from aliphatic, -OR, azetidinyl groups optionally substituted with one or two independently selected halogens, and pyrrolidinyl groups optionally substituted with one or two independently selected halogens.

[0089] In some embodiments, R 1 is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with one group selected from C1-C6 alkoxy and C3-C6 cycloalkyl, wherein the 5-6 membered heteroaryl has 0-3 independently selected R A It is further replaced by [this].

[0090] In some embodiments, R 1 teeth, [ka] [ka] That is the case.

[0091] In some embodiments, R 1 teeth, [ka] That is the case.

[0092] In some embodiments, R 1 teeth, [ka] That is the case.

[0093] In some embodiments, R 1 teeth, [ka] That is the case.

[0094] In some embodiments, R 1 teeth, [ka] That is the case.

[0095] In some embodiments, R 1 This is selected from one of the substituents in Table 1, Table 1a, or Table 1b.

[0096] As generally stated above, R AThese include optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, and halo-C1-C6 alkyl. Each instance is independently selected from the group consisting of lucoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, C1-C6 alkylene-O-C1-C6 alkyl, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, and -N(R)S(O)2R.

[0097] In some embodiments, R A C is a halogen, -OR, or substituted as needed. 1~6 Each instance is independently selected from the group consisting of aliphatic groups. In some embodiments, R A R is selected independently from halogens for each occurrence. In some embodiments, R A is selected independently from -OR for each occurrence. In some embodiments, R A R is a 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is substituted as needed. In some embodiments, R A R is a C3-C6 cycloalkyl that is substituted as needed. In some embodiments, A C is replaced as needed. 1~6 Each aliphatic group is independently selected upon its appearance.

[0098] In some embodiments, R A This is selected from one of the substituents in Table 1, Table 1a, or Table 1b.

[0099] As generally stated above, R 2 C(R B )2C(O)N(R)R 2A , C(R B )2C(R B )2C(O)N(R)R 2A , C(R B )2C(R B )2N(R)C(O)N(R)R 2A or C(R B )2C(R B )2N(R)C(O)R 2A In some embodiments, R 2 C(R B )2C(O)N(R)R 2A In some embodiments, R 2 C(R B )2C(R B )2C(O)N(R)R 2A In some embodiments, R 2 C(R B )2C(R B )2N(R)C(O)N(R)R 2A In some embodiments, R 2 C(R B )2C(R B )2N(R)C(O)R 2A In some embodiments, R 2 CH2C(O)N(H)R 2A In some embodiments, R 2 CH2CH2C(O)N(H)R 2A In some embodiments, R 2 CH2CH2N(R)C(O)N(R)R 2A In some embodiments, R 2 CH2CH2N(H)C(O)R 2A In some embodiments, R 2 C(R B)2C(O)N(H)R 2A And R 2A R is a phenyl or bicyclo[1.1.1]pentyl which is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyls, or halo-C1-C4 alkyls. In some embodiments, R 2 C(R B )2C(O)N(H)R 2A And R 2A R is a phenyl molecule that is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyl groups, or halo-C1-C4 alkyl groups. In some embodiments, R 2 C(R B )2C(O)N(H)R 2A And R 2A This is a bicyclo[1.1.1]pentyl which is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyls, or halo-C1-C4 alkyls.

[0100] In some embodiments, R 2 teeth, [ka] [ka] That is the case.

[0101] In some embodiments, R 2 teeth, [ka] That is the case.

[0102] In some embodiments, R 2 teeth, [ka] That is the case.

[0103] In some embodiments, R2 teeth, [ka] That is the case.

[0104] In some embodiments, R 2 This is selected from one of the substituents in Table 1, Table 1a, or Table 1b.

[0105] As generally stated above, R B The elements are independently selected from hydrogen, -CH3, and -CH2CH3 for each occurrence, or two Rs. B These, together with the carbon atoms to which they are bonded, form a cyclopropyl ring. In some embodiments, R B R is independently selected from hydrogen, -CH3, and -CH2CH3 for each occurrence. In some embodiments, R B is hydrogen. In some embodiments, two R B These, together with the carbon atoms to which they are bonded, form a cyclopropyl ring.

[0106] In some embodiments, R B This is selected from one of the substituents in Table 1, Table 1a, or Table 1b.

[0107] As generally stated above, R 2AThe elements are phenyl, pyridyl, cubanyl, a 4- to 8-membered saturated or partially unsaturated monocyclic ring, a 5, 6, 7, 8, 9, 10, 11, or 12-membered saturated or partially unsaturated bridged ring, fused ring, or spirocyclic ring, wherein the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged ring, fused ring, or spirocyclic ring, contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compounds contain phenyl, pyridyl, cubanyl, saturated or partially unsaturated monocyclic rings, or saturated or partially unsaturated crosslinked rings, condensed rings, or spirocyclic rings, and include halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and The ring is substituted as needed by one, two, or three substituents independently selected from bi-SF5, or two substituents on an adjacent atom of phenyl or pyridyl, together with the adjacent atom, form a 4- to 7-membered carbocycline condensed to phenyl or pyridyl, or two substituents on an adjacent atom of phenyl or pyridyl, together with the adjacent atom, form a 4- to 7-membered heterocycline condensed to phenyl or pyridyl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the 4- to 7-membered carbocycline or 4- to 7-membered heterocycline is substituted by 0 to 5 independently selected halogens, and two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridging ring, fused ring, or spirocyclic ring, are as follows: • 4- to 7-membered saturated or partially unsaturated carbocyclyls, which are substituted as needed, and • 3-7 member saturated or partially unsaturated heterocyclines having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which are optionally substituted. They form a cyclic group selected from, or R 2AThese are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, and -OH groups.

[0108] In some embodiments, there are 1 to 6 individual cases in which two substituents on the same first, second, third, fourth, fifth, or sixth atom of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging ring, fused ring, or spirocyclic ring form 1 to 6 of the cyclic groups. In some embodiments, there is one case in which two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging ring, fused ring, or spirocyclic ring form one of the cyclic groups. In some embodiments, there are two individual cases in which two substituents on the same first and second atoms of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging ring, fused ring, or spirocyclic ring form both of the cyclic groups. In some embodiments, there are three individual cases in which two substituents on the same first, second, and third atoms of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging ring, fused ring, or spirocyclic ring form three of the cyclic groups. In some embodiments, there are four individual cases in which two substituents on the same first, second, third, and fourth atoms of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging ring, fused ring, or spirocyclic ring form four of the cyclic groups. In some embodiments, there are five individual cases in which two substituents on the same first, second, third, fourth, and fifth atoms of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging ring, fused ring, or spirocyclic ring form five of the cyclic groups. In some embodiments, there are six individual cases in which two substituents on the same first, second, third, fourth, fifth, and sixth atoms of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging ring, fused ring, or spirocyclic ring form six of the cyclic groups.

[0109] In some embodiments, R 2A The molecule is a phenyl molecule optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyls, halo-C1-C4 alkyls, C3-C6 cycloalkyls, halo-C3-C6 cycloalkyls, -OH, -CN, C1-C4 alkoxys, halo-C1-C4 alkoxys, and -SF5, wherein two substituents on adjacent atoms of the phenyl molecule, together with the adjacent atoms, form a 4-7 membered carbocycline condensed on the phenyl molecule, and two substituents on adjacent atoms of the phenyl molecule, together with the adjacent atoms, form a 4-7 membered heterocycline condensed on the phenyl molecule (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0110] In some embodiments, R 2A R is a phenyl molecule that is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyl groups, halo-C1-C4 alkyl groups, C3-C6 cycloalkyl groups, halo-C3-C6 cycloalkyl groups, -OH groups, -CN groups, C1-C4 alkoxy groups, halo-C1-C4 alkoxy groups, and -SF5 groups. In some embodiments, R 2A R is a phenyl molecule that is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyl groups, and halo-C1-C4 alkyl groups. In some embodiments, R 2A R is a phenyl which is optionally substituted with a halogen, a C1-C4 alkyl, and a halo-C1-C4 alkyl. In some embodiments, R 2A R is a phenyl molecule optionally substituted with two substituents independently selected from halogens, C1-C4 alkyl groups, and halo-C1-C4 alkyl groups. In some embodiments, R 2A This is a phenyl compound that is optionally substituted with three substituents independently selected from halogens, C1-C4 alkyl groups, and halo-C1-C4 alkyl groups.

[0111] In some embodiments, R 2AThe pyridyl is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyls, halo-C1-C4 alkyls, C3-C6 cycloalkyls, halo-C3-C6 cycloalkyls, -OH, -CN, C1-C4 alkoxys, halo-C1-C4 alkoxys, and -SF5, wherein two substituents on adjacent atoms of the pyridyl combine with the adjacent atoms to form a 4-7 membered carbocyclyl condensed to the pyridyl, and two substituents on adjacent atoms of the pyridyl combine with the adjacent atoms to form a 4-7 membered heterocyclyl condensed to the pyridyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0112] In some embodiments, R 2A is a pyridyl which is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyls, halo-C1-C4 alkyls, C3-C6 cycloalkyls, halo-C3-C6 cycloalkyls, -OH, -CN, C1-C4 alkoxys, halo-C1-C4 alkoxys, and -SF5. In some embodiments, R 2A is a pyridyl which is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyls, and halo-C1-C4 alkyls. In some embodiments, R 2A is a pyridyl which is optionally substituted with a halogen, a C1-C4 alkyl or a halo-C1-C4 alkyl. In some embodiments, R 2A is a pyridyl which is optionally substituted with two substituents independently selected from halogens, C1-C4 alkyls, and halo-C1-C4 alkyls. In some embodiments, R 2A It is a pyridyl which is optionally substituted with three substituents independently selected from halogens, C1-C4 alkyls, and halo-C1-C4 alkyls.

[0113] In some embodiments, R 2AThe compound is a cubenyl, a 4- to 8-membered saturated or partially unsaturated monocyclic ring, a 5, 6, 7, 8, 9, 10, 11, or 12-membered saturated or partially unsaturated bridged ring, fused ring, or spirocyclic ring, wherein the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged ring, fused ring, or spirocyclic ring, contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the cubenyl, partially unsaturated monocyclic ring, and Alternatively, saturated or partially unsaturated crosslinked rings, condensed rings, or spirocyclic rings are optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and -SF5.

[0114] In some embodiments, R 2A R is a bicyclo[1.1.1]pentyl which is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyls, and halo-C1-C4 alkyls. In some embodiments, R 2A R is a bicyclo[2.2.2]octyl which is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyls, and halo-C1-C4 alkyls. In some embodiments, R 2A R is a bicyclo[3.1.0]pentyl which is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyls, and halo-C1-C4 alkyls. In some embodiments, R 2A is a cubenyl which is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyls, and halo-C1-C4 alkyls. In some embodiments, R 2AThis is 2-oxabicyclo[2.1.1]hexane-4-yl, which is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyls, and halo-C1-C4 alkyls.

[0115] In some embodiments, R 2A The is a saturated or partially unsaturated crosslinked 5, 6, 7, 8, 9, 10, 11, or 12-membered ring, which contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the crosslinked ring is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and -SF5.

[0116] In some embodiments, R 2A The fused ring is a saturated or partially unsaturated condensed 5, 6, 7, 8, 9, 10, 11, or 12-membered ring containing 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the condensed ring is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and -SF5.

[0117] In some embodiments, R 2AThe 5, 6, 7, 8, 9, 10, 11, or 12-membered ring of a saturated or partially unsaturated spirocyclic structure, which contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the spirocyclic ring is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and -SF5.

[0118] In some embodiments, R 2A is a bicyclo[1.1.1]pentyl which is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and -SF5. In some embodiments, R 2A R is a bicyclo[1.1.1]pentyl which is optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyls, and halo-C1-C4 alkyls. In some embodiments, R 2A R is bicyclo[1.1.1]pentyl, which is optionally substituted with a halogen, C1-C4 alkyl, or haloC1-C4 alkyl. In some embodiments, R 2A R is a bicyclo[1.1.1]pentyl which is optionally substituted with two substituents independently selected from halogens, C1-C4 alkyls, and halo-C1-C4 alkyls. In some embodiments, R 2A This is a bicyclo[1.1.1]pentyl which is optionally substituted with three substituents independently selected from halogens, C1-C4 alkyls, and halo-C1-C4 alkyls.

[0119] In some embodiments, R 2A teeth, [ka] A ring F selected from the group consisting of, where x, y, and q are independently selected from 1, 2, or 3, and Y 1 O, NR 15 , CHR 15 or CR 15 R 15 Selected independently from, R 15 The following are independently selected from halogens, C1-C4 aliphatic, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and -SF5.

[0120] In some embodiments, R 2A The structure is as follows: [ka] It is a ring F of R 15 The elements are selected from halogens, C1-C4 aliphatic elements, halo-C1-C4 alkyl elements, C3-C6 cycloalkyl elements, halo-C3-C6 cycloalkyl elements, -OH elements, -CN elements, C1-C4 alkoxy elements, halo-C1-C4 alkoxy elements, C3-C6 cycloalkoxy elements, halo-C3-C6 cycloalkoxy elements, and -SF5 elements.

[0121] In some embodiments, R 2A These are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are halogens, C, respectively. 1~4 It is optionally substituted with one, two, or three substituents independently selected from alkyl and -OH groups. In some embodiments, R 2A is halogen, C 1~4 It is 2-benzimidazolyl, optionally substituted with one, two, or three substituents independently selected from alkyl and -OH. In some embodiments, R 2A is halogen, C 1~4It is a 3-quinolinyl molecule optionally substituted with one, two, or three substituents independently selected from the alkyl and -OH groups.

[0122] In some embodiments, R 2A This is a phenyl compound containing a -CF3 substituent, or a pyridyl compound containing a -CF3 substituent.

[0123] In some embodiments, R 2A This is bicyclo[1.1.1]pentyl containing the -CF3 substituent, or bicyclo[1.1.1]pentyl containing the -CHF2 substituent.

[0124] In some embodiments, R 2A This is selected from one of the substituents in Table 1, Table 1a, or Table 1b.

[0125] As generally stated above, R 3 These are hydrogen, C1-C4 aliphatic, C3-C5 cycloalkyl, C1-C4 alkoxy, and -NHR 3A , -N(R 3A )2 or C1-C4 alkylthio, which, apart from hydrogen, are optionally substituted with -OH, 1-5 independently selected halogens, or C1-C4 alkoxys.

[0126] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a C1-C4 alkyl group which is optionally substituted with -OH, 1-5 independently selected halogens, or C1-C4 alkoxy groups. In some embodiments, R 3 is a C1-C4 alkyl group. In some embodiments, R 3 is -CH2CH3. In some embodiments, R 3 is -CH3. In some embodiments, R 3 -OH, 1 to 5 independently selected halogens or C1 to C4 alkoxys as needed, C3 to C5 cycloalkyl, C1 to C4 alkoxy, -NHR 3A, -N(R 3A )2 or C1-C4 alkylthio. In some embodiments, R 3 R is a C3-C5 cycloalkyl group which is optionally substituted with -OH, 1-5 independently selected halogens, or C1-C4 alkoxy groups. In some embodiments, R 3 is a C1-C4 alkoxy which is optionally substituted with -OH, 1-5 independently selected halogens, or C1-C4 alkoxys. In some embodiments, R 3 -OH, -NHR which may be substituted as needed with 1 to 5 independently selected halogens or C1 to C4 alkoxys. 3A In some embodiments, R 3 -N(R) is optionally substituted with -OH, 1 to 5 independently selected halogens or C1 to C4 alkoxys. 3A )2. In some embodiments, R 3 is a C1-C4 alkylthio which is optionally substituted with -OH, 1-5 independently selected halogens or C1-C4 alkoxys. In some embodiments, R 3 The group is selected from the group consisting of C1-C4 alkyl and C3-C5 cycloalkyl groups.

[0127] In some embodiments, R 3 This is selected from one of the substituents in Table 1, Table 1a, or Table 1b.

[0128] As generally stated above, R 3A Each of these is independently selected from C1-C4 alkyl groups for each occurrence. In some embodiments, R 3A is -CH3. In some embodiments, R 3A is -CH2CH3. In some embodiments, R 3A is propyl. In some embodiments, R 3A It is butyl.

[0129] In some embodiments, R 3AThis is selected from one of the substituents in Table 1, Table 1a, or Table 1b.

[0130] As generally stated above, L is -C(O)-, -S(O)-, -S(O)2- and [ka] It is a linker selected from among them.

[0131] In some embodiments, the linker L is -C(O)-.

[0132] In some embodiments, the linker L is -S(O)-.

[0133] In some embodiments, the linker L is -S(O)2-.

[0134] In some embodiments, the linker L is [ka] That is the case.

[0135] In some embodiments, the linker L is selected from one of the substituents in Table 1, Table 1a, or Table 1b.

[0136] As generally stated above, R 4 The answer is selected from one of a), b), and c): a) R 4 teeth, [ka] Ring B is selected from the group consisting of the following: * represents the linkage point to the linker L bonded to ring A in formula I, R 4A , R 4B , R 4C , R 4D , R 4E and R 4FAny substituent present on ring B selected from the following is hydrogen; halogen; -OH; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; C1~C4 alkoxy; haloC1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; haloC1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4A and R 4B These intervening atoms bond together to form a 4-7 member optionally substituted carbocyryl, 4-7 member optionally substituted heterocyclyl, or 5-6 member optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, and R 4C , R 4D , R 4E and R 4F Any substituent present on ring B selected from the following is: hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4B and R 4C These intervening atoms join together to form a 4-7 member optionally substituted carbocyryl, 4-7 member optionally substituted heterocyclyl, or 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, R 4A , R 4D , R 4E and R 4FAny substituent present on ring B selected from the following is: hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4C and R 4D These intervening atoms join together to form a 4-7 member optionally substituted carbocyryl, 4-7 member optionally substituted heterocyclyl, or 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, R 4A , R 4B , R 4E and R 4F Any substituent present on ring B selected from the following is: hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4E is a halogen or -OH, and R 4A , R 4B , R 4C and R 4D These include hydrogen; halogens; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4E and R4A These intervening atoms join together to form a 5-6 member, optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, and R 4B , R 4C and R 4D These include hydrogen; halogens; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4F and R 4A These intervening atoms join together to form a 5-6 member, optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, and R 4B , R 4C and R 4D Any substituent present on ring B selected from the following is: hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 Each is independently selected from, R 13 Each of these is independently selected from C1-C4 alkyl groups, which are optionally substituted with hydrogen and -OH, -OCH3, or -OCH2CH3. R 14 Is it hydrogen, or NR 13 R 14 This forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, wherein the heterocyclic ring is optionally substituted with -CH3; or b) R4 This is a 5-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein the heteroaryl is substituted with 0 to 4 groups independently selected from halogens, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl and C1-C4 alkoxy, or c) R 4 These are C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each of which is substituted with 0-3 groups independently selected from halogens, -CN, -OH, C1-C4 alkyl groups, C1-C4 alkoxy groups, optionally substituted 5-6 member heterocyclines, and optionally substituted 5-6 member heterocyclyloxy groups.

[0137] In some embodiments, R 4 Ring B has the following structure: [ka] And, * represents the linkage point to the linker L bonded to ring A in formula I, R 4A , R 4C and R 4D These include hydrogen; halogens; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4C and R 4D These intervening atoms join together to form a 4-7 membered carbocyryl or 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, R 4AThis refers to hydrogen; halogen; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; haloC1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; haloC1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; or NR 13 R 14 And, R 13 Each of these is independently selected from C1-C4 alkyl groups, which are optionally substituted with hydrogen and -OH, -OCH3, or -OCH2CH3. R 14 Is it hydrogen, or NR 13 R 14 This forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, and the heterocyclic ring is optionally substituted with -CH3.

[0138] In some embodiments, R 4 Ring B has the following structure: [ka] And, * represents the linkage point to the linker L bonded to ring A in formula I, R 4A These are -OCH3, -OCH2CH3, or -OCHF2. R 4C and R 4D These include hydrogen; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; halo C1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo C1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 Each is independently selected from, R 13 Each of these is independently selected from C1-C4 alkyl groups, which are optionally substituted with hydrogen and -OH, -OCH3, or -OCH2CH3. R 14Is it hydrogen, or NR 13 R 14 This forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, wherein the heterocyclic ring is optionally substituted with -CH3; or R 4 The compound is a 5-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein the heteroaryl is substituted with 0 to 4 substituents independently selected from halogens, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy.

[0139] In some embodiments, R 4 Ring B has the following structure: [ka] And, * represents the linkage point to the linker L bonded to ring A in formula I, R 4A These are -OCH3, -OCH2CH3, or -OCHF2. R 4C and R 4D These include hydrogen; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; halo C1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo C1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 Each is independently selected from, R 13 Each of these is independently selected from C1-C4 alkyl groups, which are optionally substituted with hydrogen and -OH, -OCH3, or -OCH2CH3. R 14 Is it hydrogen, or NR 13 R 14This forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, and the heterocyclic ring is optionally substituted with -CH3.

[0140] In some embodiments, R 4 Ring B has the following structure: [ka] And, * represents the linkage point to the linker L bonded to ring A in formula I, R 4A , R 4C and R 4D These are independently selected from hydrogen, halogens, and C1-C4 alkyl groups.

[0141] In some embodiments, R 4 Ring B has the following structure: [ka] And, * represents the linkage point to the linker L bonded to ring A in formula I, R 4A , R 4B and R 4C These include hydrogen; halogens; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; C1~C4 alkoxy; haloC1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; haloC1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4A and R 4B These intervening atoms join together to form a 4-7 membered carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, and R 4CThis refers to hydrogen; halogen; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; haloC1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; haloC1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; or NR 13 R 14 is it, or R 4B and R 4C These intervening atoms join together to form a 4-7 membered carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, and R 4A This refers to hydrogen; halogen; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; haloC1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; haloC1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; or NR 13 R 14 And, R 13 Each of these is independently selected from C1-C4 alkyl groups, which are optionally substituted with hydrogen and -OH, -OCH3, or -OCH2CH3. R 14 Is it hydrogen, or NR 13 R 14 This forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, and the heterocyclic ring is optionally substituted with -CH3.

[0142] In some embodiments, R 4 Ring B has the following structure: [ka] And, * represents the linkage point to the linker L bonded to ring A in formula I, R 4A and R 4BThese intervening atoms join together to form a 4-7 membered carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B. R 4C It is hydrogen.

[0143] In some embodiments, R 4 Ring B has the following structure: [ka] And, * represents the linkage point to the linker L bonded to ring A in formula I, R 4A and R 4B These atoms join together with the intervening atoms to form a 5-membered heterocycline (containing one oxygen atom) condensed in ring B. R 4C It is hydrogen.

[0144] In some embodiments, R 4 Ring B has the following structure: [ka] And, * represents the linkage point to the linker L bonded to ring A in formula I, R 4A , R 4B and R 4D These include hydrogen; halogens; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; C1~C4 alkoxy; haloC1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; haloC1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4A and R 4Bcombines and joins with those intervening atoms to form a 4- to 7-membered carbocyclic or heterocyclic ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to ring B, and R 4D is hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo C1-C4 alkyl; C1-C3 alkyl substituted by -OH, -OCH3 or -OCH2CH3; halo C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; or NR 13 R 14 where R 13 is independently selected, on each occurrence, from hydrogen and C1-C4 alkyl optionally substituted by -OH, -OCH3 or -OCH2CH3, R 14 is hydrogen or NR 13 R 14 forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl and piperidinyl, said heterocyclic ring being optionally substituted by -CH3.

[0145] In some embodiments, R 4 is ring B of the following structure:

Chemical formula

[0146] In some embodiments, R 4 is ring B of the following structure:

Chemical formula

[0147] In some embodiments, R 4 Ring B has the following structure: [ka] And, * represents the linkage point to the linker L bonded to ring A in formula I, R 4A and R 4C The elements are independently selected from hydrogen and C1-C4 alkyl groups.

[0148] In some embodiments, R 4 Ring B has the following structure: [ka] And, * represents the linkage point to the linker L bonded to ring A in formula I, R 4A , R 4B , R 4C , R 4Dand R 4E These include hydrogen; halogens; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; C1~C4 alkoxy; haloC1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; haloC1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4A and R 4B These intervening atoms join together to form a 4-7 membered carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, and R 4C , R 4D and R 4E These include hydrogen; halogens; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4C and R 4D These intervening atoms join together to form a 4-7 membered carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, and R 4A , R 4B and R 4E These include hydrogen; halogens; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4Eis a halogen or -OH, and R 4A , R 4B , R 4C and R 4D These include hydrogen; halogens; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4E and R 4A These intervening atoms join together to form a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, R 4B , R 4C and R 4D These include hydrogen; halogens; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 Each is independently selected from, R 13 Each of these is independently selected from C1-C4 alkyl groups, which are optionally substituted with hydrogen and -OH, -OCH3, or -OCH2CH3. R 14 Is it hydrogen, or NR 13 R 14 This forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, and the heterocyclic ring is optionally substituted with -CH3.

[0149] In some embodiments, R 4 Ring B has the following structure: [ka] and * is a bonding point to linker L bonded to ring A in formula I, R 4A , R 4B , R 4C , R 4D and R 4E are each independently selected from hydrogen; halogen; C1-C4 alkyl; and C1-C4 alkoxy, or R 4C and R 4D bond together with the intervening atoms to form a 4- to 7-membered heterocyclyl (having 1 to 3 nitrogen atoms) fused to ring B, and R 4A , R 4B and R 4E are each hydrogen.

[0150] In some embodiments, R 4 is ring B of the following structure:

Chemical formula

[0151] In some embodiments, R 4 Ring B has the following structure: [ka] And, * represents the linkage point to the linker L bonded to ring A in formula I, R 4F and R 4A These intervening atoms bond together to form a 5-6 member heteroaryl (having 1-2 nitrogen atoms) condensed on ring B, R 4B and R 4C Each of them is hydrogen.

[0152] In some embodiments, R 4 Ring B has the following structure: [ka] And, * represents the linkage point to the linker L bonded to ring A in formula I, R 4A , R 4C , R 4D and R 4F These include hydrogen; halogens; -CN; C1~C4 alkyl; C2~C4 alkenyl; C2~C4 alkynyl; C1~C4 alkoxy; haloC1~C4 alkyl; C1~C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; haloC1~C4 alkoxy; C3~C6 cycloalkyl; C3~C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4C and R 4DThese intervening atoms join together to form a 4-7 member optionally substituted carbocyryl or optionally substituted heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, R 4A and R 4F These include hydrogen; halogens; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 They are either selected independently from each other, or R 4F and R 4A These intervening atoms join together to form a 5-6 member, optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, and R 4C and R 4D These include hydrogen; halogens; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 Each is independently selected from, R 13 Each of these is independently selected from C1-C4 alkyl groups, which are optionally substituted with hydrogen and -OH, -OCH3, or -OCH2CH3. R 14 Is it hydrogen, or NR 13 R 14 These may combine with the N to which they are bound to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, the heterocyclic ring being optionally substituted with -CH3.

[0153] In some embodiments, R 4 This is a 5-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein the heteroaryl is substituted with 0 to 4 groups independently selected from halogens, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy.

[0154] In some embodiments, R 4 The compound is a five-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein the heteroaryl is substituted with 0 to 4 groups independently selected from OH, -CH3, -CHF2, cyclopropyl, and -OCH3.

[0155] In some embodiments, R 4 The C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl groups are each substituted with 0-3 groups independently selected from halogens, -CN, -OH, C1-C4 alkyl groups, C1-C4 alkoxy groups, optionally substituted 5-6 member heterocyclines, and optionally substituted 5-6 member heterocyclyloxy groups. In some embodiments, R 4 is a C1-C4 alkyl substituted with 0-3 independently selected halogens, -CN, -OH, C1-C4 alkyls, and C1-C4 alkoxys. In some embodiments, R 4 R is a C1-C4 alkoxy substituted with 0-3 independently selected halogens, -CN, -OH, C1-C4 alkyls, and C1-C4 alkoxys. In some embodiments, R 4 These are C3-C6 cycloalkyls substituted with 0-3 independently selected halogens, -CN, -OH, C1-C4 alkyls, and C1-C4 alkoxys.

[0156] In some embodiments, R 4It is an isoxazolyl substituted with -OH or C1-C4 alkoxy.

[0157] In some embodiments, R 4 This is a five-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional ring nitrogen atoms) selected from the group consisting of imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl, wherein the heteroaryl is substituted with 0 to 4 groups independently selected from halogens, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy.

[0158] In some embodiments, R 4 teeth, [ka] [ka] That is the case.

[0159] In some embodiments, R 4 teeth, [ka] [ka] That is the case.

[0160] In some embodiments, R 4 These are as shown in Table 1, Table 1a, or Table 1b for substituents.

[0161] As generally stated above, each R is independently a hydrogen atom, or a C atom as needed. 1~6An aliphatic group, optionally substituted phenyl, optionally substituted 3-7 member saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 member saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or optionally substituted 5-6 member heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or two R groups on the same atom may combine with the same atom to form optionally substituted 4-7 member saturated ring, 4-7 member partially unsaturated ring, or 5-6 member heteroaryl ring (the 4-7 member saturated ring and the 4-7 member partially unsaturated ring have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5-6 member heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0162] In some embodiments, R is independently hydrogen, or C as needed. 1~6 The components are an aliphatic group, optionally substituted phenyl, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring, optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or optionally substituted 5- to 6-membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0163] In some embodiments, two R groups on the same atom combine with the same atom to form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring (the 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0164] In some embodiments, R is independently hydrogen or C 1~6 It is an alkyl group. In some embodiments, R is hydrogen.

[0165] In some embodiments, R is selected from one or more substituents in Table 1, Table 1a, or Table 1b.

[0166] In some embodiments, the compound of formula I is a compound of formula Ia or formula Ib or a pharmaceutically acceptable salt thereof: [ka] In the formula, rings A and R 1 , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0167] In some embodiments, the compound of formula I is a compound of formula Ia or formula Ib or a pharmaceutically acceptable salt thereof: [ka] And, In the formula, rings A, R 1 , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein, and R 2a teeth, [ka] Selected from.

[0168] In some embodiments, the compound of formula I is a compound of formula Ia or formula Ib or a pharmaceutically acceptable salt thereof: [ka] And, In the formula, R 1 , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein, and ring A is, [ka] Selected from, R 2a teeth, [ka] Selected from.

[0169] In some embodiments, the compound of formula I is a compound of formula II-a, formula II-b, or formula II-c, or a pharmaceutically acceptable salt thereof: [ka] And, In the formula, ring A, linker L, R 2 , R 3 , Y, Z and R 4 Both when used alone and in combination, it is as defined herein.

[0170] In some embodiments, the compound of formula I is a compound of formula II-d, formula II-e, or formula II-f, or a pharmaceutically acceptable salt thereof: [ka] And, In the formula, rings A, R 2 , R 3 , Y, Z and R 4 Both when used alone and in combination, it is as defined herein.

[0171] In some embodiments, the compound of formula I is a compound of formula III-a, formula III-b, or formula III-c, or a pharmaceutically acceptable salt thereof: [ka] [ka] And, In the formula, rings A, R 1 , R2 , Y, Z and R 3 Both when used alone and in combination, it is as defined herein. X is CH, CR 7 or N, R 5 is -OH or halogen, R 6 is halogen, C 1~4 Alkyl or C 1~4 It is an alkoxy, R 7 These are, independently, hydrogen, halogen, and C. 1~4 Alkyl or C 1~4 It is an alkoxy, R 8 C 1~4 It is alkyl, R 9 In each of the cases where there are 0 to 2, independently, hydrogen or C 1~4 It is alkyl. In some embodiments: X is either CH or N. R 5 is -OH or fluoro, R 6 It is fluoro, -CH3 or -OCH3, R 7 Each of these is independently hydrogen, fluoro, -CH3, or -OCH3. R 8 It is -CH3, R 9 In each case, it is independently hydrogen or -CH3.

[0172] In some embodiments, the compound of formula I is a compound of formula IV-a, formula IV-b, or formula IV-c, or a pharmaceutically acceptable salt thereof: [ka] And, In the formula, rings A, R 2 , Y, Z and R 3 Both when used alone and in combination, it is as defined herein. R 5 is -OH or halogen, R 6 is halogen, C 1~4 Alkyl or C 1~4 It is an alkoxy. In some embodiments: R 5 is -OH or fluoro, R 6 It is fluoro, -CH3, or -OCH3.

[0173] In some embodiments, the compound of formula I is a compound of formula Va, formula Vb, or formula Vc, or a pharmaceutically acceptable salt thereof: [ka] And, In the formula, rings A, R 2 , Y, Z and R 3 Both when used alone and in combination, it is as defined herein. X is CH, CR 7 or N, R 7 These are, independently, hydrogen, halogen, and C. 1~4 Alkyl or C 1~4 It is an alkoxy. In some embodiments, X is CH or N, and R 7 These are hydrogen, fluoro, -CH3, or -OCH3.

[0174] In some embodiments, the compound of formula I is a compound of formula VI-a, formula VI-b, or formula VI-c, or a pharmaceutically acceptable salt thereof: [ka] And, In the formula, rings A, R 2 , Y, Z and R 3 Both when used alone and in combination, it is as defined herein. R 8 C 1~4 It is alkyl, R 9 In each of the cases where there are 0 to 2, independently, hydrogen or C 1~4It is alkyl. In some embodiments: R 8 It is -CH3, and R 9 In each case, it is independently hydrogen or -CH3.

[0175] In some embodiments, the compound of formula I is the compound of formula VII-a or VII-b, or a pharmaceutically acceptable salt thereof: [ka] And in the formula, R 1 , R 2 , R 3 , R A and R 4 Both when used alone and in combination, it is as defined herein.

[0176] In some embodiments, the compound of formula I is the compound of formula VII-a or VII-b, or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , R A and R 4 Both when used alone and in combination, it is as defined herein, and R 2a teeth, [ka] Selected from.

[0177] In some embodiments, the compound of formula I is a compound of formula VII-c, formula VII-d, or formula VII-e, or a pharmaceutically acceptable salt thereof: [ka] And, In the formula, R 2 , R 3 , Y, Z and R 4 Both when used alone and in combination, it is as defined herein.

[0178] In some embodiments, the compound of formula I is a compound of formula VIII-a, VIII-b, or VIII-c, or a pharmaceutically acceptable salt thereof: [ka] And, In the formula, R 1 , R 2 , Y, Z and R 3 Both when used alone and in combination, it is as defined herein. X is CH, CR 7 or N, R 5 is -OH or halogen, R 6 is halogen, C 1~4 Alkyl or C 1~4 It is an alkoxy, R 7 These are, independently, hydrogen, halogen, and C. 1~4 Alkyl or C 1~4 It is an alkoxy, R 8 C 1~4 It is alkyl, R 9 In each of the cases where there are 0 to 2, independently, hydrogen or C 1~4 It is alkyl. In some embodiments: X is either CH or N. R 5 is -OH or fluoro, R 6 It is fluoro, -CH3 or -OCH3, R 7 Each of these is independently hydrogen, fluoro, -CH3, or -OCH3. R 8 It is -CH3, R 9 In each case, it is independently hydrogen or -CH3.

[0179] In some embodiments, the compound of formula I is a compound of formula IX-a, formula IX-b, or formula IX-c, or a pharmaceutically acceptable salt thereof: [ka] And, In the formula, Y, Z, R 2 and R 3 Both when used alone and in combination, it is as defined herein. R 5 is -OH or halogen, R 6 is halogen, C 1~4 Alkyl or C 1~4 It is an alkoxy. In some embodiments: R 5 is -OH or fluoro, R 6 It is fluoro, -CH3, or -OCH3.

[0180] In some embodiments, the compound of formula I is a compound of formula Xa, formula Xb, or formula Xc or a pharmaceutically acceptable salt thereof: [ka] [ka] And, In the formula, Y, Z, R 2 and R 3 Both when used alone and in combination, it is as defined herein. X is CH, CR 7 or N, R 7 These are, independently, hydrogen, halogen, and C. 1~4 Alkyl or C 1~4 It is an alkoxy.

[0181] In some embodiments: X is CH or N, and R 7 Each of these is independently hydrogen, fluoro, -CH3, or -OCH3.

[0182] In some embodiments, the compound of formula I is a compound of formula XI-a, formula XI-b, or formula XI-c, or a pharmaceutically acceptable salt thereof: [ka] And, In the formula, Y, Z, R 2 and R 3 Both when used alone and in combination, it is as defined herein. R 8 C 1~4 It is alkyl, R 9 In each of the cases where there are 0 to 2, independently, hydrogen or C 1~4 It is alkyl. In some embodiments: R 8 It is -CH3, and R 9 In each case, it is independently hydrogen or -CH3.

[0183] In some embodiments, the compound of formula I is a compound of formula XII-a, formula XII-b, or formula XII-c, or a pharmaceutically acceptable salt thereof: [ka] And, R 2 C(R B )2C(O)NHR 2A And, R B Each of these is independently selected from hydrogen and -CH3, R 2A These are phenyl, pyridyl, or bicyclo[1.1.1]pentyl, which are, respectively, optionally substituted with one, two, or three substituents independently selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, and -SF5, or R 2A These are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are halogens, C, respectively.1~4 They are optionally substituted with one, two, or three substituents independently selected from alkyl and -OH groups. R 3 These are C1-C4 alkyl, C3-C5 cycloalkyl, or C1-C4 alkoxy groups, each of which may be substituted as needed with -OH, 1-3 independently selected halogens, or C1-C4 alkoxy groups. R 7 These are, independently, hydrogen, halogen, and C. 1~4 Alkyl or C 1~4 It is an alkoxy.

[0184] In some embodiments, the compound of formula I is a compound of formula XII-d, formula XII-e, or formula XII-f, or a pharmaceutically acceptable salt thereof: [ka] And, R 2 C(R B )2C(O)NHR 2A And, R B Each of these is independently selected from hydrogen and -CH3, R 2A These are phenyl, pyridyl, or bicyclo[1.1.1]pentyl, which are, respectively, optionally substituted with one, two, or three substituents independently selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, and -SF5, or R 2A These are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are halogens, C, respectively. 1~4 They are optionally substituted with one, two, or three substituents independently selected from alkyl and -OH groups. R 3These are C1-C4 alkyl, C3-C5 cycloalkyl, or C1-C4 alkoxy groups, each of which may be substituted as needed with -OH, 1-3 independently selected halogens, or C1-C4 alkoxy groups. R 7 These are, independently, hydrogen, halogen, and C. 1~4 Alkyl or C 1~4 It is an alkoxy.

[0185] In some embodiments, the compound of formula I is selected from one of those illustrated in Table 1, Table 1a, or Table 1b, or from pharmaceutically acceptable salts thereof. Table 1, Table 1a, or Table 1b identifies the compounds by their IUPAC names, and Table 2, Table 2a, or Table 2b lists the same compounds or shows their chemical structures. If there is any difference between the name of a compound in Table 1, Table 1a, or Table 1b and the structure of the same compound in Table 2, Table 2a, or Table 2b, the compound structure in Table 2, Table 2a, or Table 2b takes precedence, identifying the compound corresponding to each individual compound number (I-#) in Table 1, Table 1a, or Table 1b. [Table 1] [Table 1a-1] [Table 1a-2] [Table 1a-3] [Table 1a-4] [Table 1a-5] [Table 1a-6] [Table 1a-7] [Table 1a-8] [Table 1a-9] [Table 1a-10] [Table 1b-1] [Table 1b-2] [Table 1b-3] [Table 1b-4] [Table 1b-5] [Table 1b-6] [Table 1b-7] [Table 1b-8] 4. Use of pharmaceutical compositions, treatment methods, and compounds

[0186] In another embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition may be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration, particularly for oral administration. Topical administration may also relate to inhalation or intranasal administration. The pharmaceutical composition of the present invention may be prepared in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets may be film-coated or enterically coated according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with one or more of the following: a) Diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine b) In the case of tablets, other lubricants may be used, such as silica, talc, stearic acid, its magnesium or calcium salt, and / or polyethylene glycol. c) If desired, a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone. d) Tablet decomposition materials, such as starch, agar, alginic acid or its sodium salt, or foaming mixtures; and e) Absorbents, colorants, flavorings, and sweeteners.

[0187] Typical methods for dissolving compounds for parenteral administration include pH optimization or the use of a co-solvent (e.g., PEG300, PEG400, propylene glycol, or ethanol). If these methods are not feasible for any reason, the use of surfactants may be considered (e.g., Tween® 80 or Cremophor EL®). Cyclodextrins are established as safe solubilizers. Compounds with high solubility in natural oils may dissolve in parenteral lipid emulsions.

[0188] Pharmaceutical compositions comprising a compound of formula I described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers are also provided. use

[0189] Compounds of Formula I of the present invention, in free form or pharmaceutically acceptable salt form, exhibit beneficial pharmacological properties, such as WRN inhibitory properties, as demonstrated by in vitro tests presented in the following section, and are therefore suitable for therapeutic or research use, such as chemical probes and tool compounds.

[0190] Compounds of formula I described herein are also provided. These compounds can be used as research chemicals, including the added biotin moiety, for example, tool compounds or chemical probes, particularly for research on WRN. In another embodiment, the use of compounds of formula I described herein as research chemicals, for example, tool compounds or chemical probes, particularly for research on WRN, is provided.

[0191] Compounds of formula I described herein or pharmaceutically acceptable salts thereof are also provided for use in the treatment of cancer. Cancers that can be treated by WRN inhibition include cancers characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). In particular, compounds of formula I described herein or pharmaceutically acceptable salts thereof may be useful in the treatment of cancers characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

[0192] Compounds of formula I described herein or pharmaceutically acceptable salts thereof are also provided for use as pharmaceuticals. In particular, such use is for the following: • Treatment of diseases treated by WRN inhibition Cancer treatment, Treatment of cancer characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), Treatment of cancers characterized by high frequency of microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), such as colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, and ovarian cancer. Treatment of cancers characterized by high frequency of microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), selected from colorectal cancer, gastric cancer, prostate cancer, and endometrial cancer, or Treatment of cancers characterized by high frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), selected from endometrial carcinoma of the uterine body, adenocarcinoma of the colon, adenocarcinoma of the stomach, adenocarcinoma of the rectum, adrenal cortical carcinoma, uterine carcinosarcoma, squamous cell carcinoma of the cervix, adenocarcinoma of the uterine cavity, esophageal cancer, breast cancer, clear cell carcinoma of the kidney, prostate cancer, and serous cystadenocarcinoma of the ovary.

[0193] The following methods are also provided: A method for modulating WRN activity in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula I described herein or a pharmaceutically acceptable salt thereof. A method for inhibiting WRN in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula I described herein or a pharmaceutically acceptable salt thereof. A method for treating a disorder or disease in a subject that can be treated by WRN inhibition, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula I described herein or a pharmaceutically acceptable salt thereof. A method for treating cancer in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula I described herein or a pharmaceutically acceptable salt thereof. A method for treating cancer in a subject, comprising the step of administering a compound of Formula I described herein, wherein the cancer is characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). In particular, cancers characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) are selected from colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, and ovarian cancer. More specifically, cancers characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) are selected from colorectal cancer, gastric cancer, prostate cancer, and endometrial cancer. Examples include endometrial cancer of the uterine body, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, intracervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, prostate cancer, and ovarian serous cystadenocarcinoma.

[0194] The use of compounds of formula I described herein or pharmaceutically acceptable salts thereof is also provided below: · treatment; • Manufacturing of pharmaceuticals, • Manufacturing of pharmaceuticals for the treatment of cancer. In particular, said cancer is characterized by high frequency microsatellite instability (MSI-H) or mismatch repair mechanism deficiency (dMMR). • Manufacture of pharmaceuticals for the treatment of diseases that can be treated by WRN inhibition. In this case, cancers are particularly characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), such as colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, and ovarian cancer, in particular colorectal cancer, gastric cancer, prostate cancer, or endometrial cancer, or endometrial cancer of the uterine body, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical cancer, uterine carcinosarcoma, cervical squamous cell carcinoma, intracervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, and ovarian serous cystadenocarcinoma.

[0195] In some embodiments, subjects are identified as having or possessing microsatellite instability-H cancer, for example, with reference to a control, e.g., a normal subject. In one embodiment, subjects have MSI-H advanced solid tumors, colorectal cancer (CRC), endometrial cancer, uterine cancer, gastric cancer, or other MSI-H cancers. In some embodiments, subjects have colorectal (CRC) cancer, endometrial cancer, or gastric cancer, and these cancers are identified as having or possessing microsatellite instability (MSI-H), for example, with reference to a control, e.g., a normal subject. Such identification techniques are known in the art. form

[0196] Depending on the selection of starting materials and procedures, compounds can exist in one form of any possible stereoisomer, or as a mixture thereof, for example, as a pure optical isomer, or as a mixture of stereoisomers such as a racemate and a mixture of diastereoisomers, depending on the number of chiral carbon atoms. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, mixtures of diastereoisomers, and optically pure forms. Optically active (R)- and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents, or they can be divided using conventional techniques. If the compound contains a double bond, the substituent may have an E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. It is also intended to include all tautomer forms.

[0197] Any of the formulas shown herein are intended to represent the unlabeled and isotopically labeled forms of the compound, in addition to the deuteration specifically claimed in Formula I. The isotopically labeled compound has the structure illustrated by the formulas shown herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen.

[0198] Furthermore, the incorporation of certain isotopes, particularly deuterium (i.e., 2H or D), may result in certain therapeutic benefits, such as greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, or improved therapeutic index or tolerability. In this context, deuterium is understood to be a substituent of the compound of the present invention. The concentration of deuterium can be defined by the isotopic enrichment factor. The term “isotopic enrichment factor,” as used herein, means the ratio between the abundance of an isotope and the natural abundance of a specified isotope. When the substituent in the compound of the present invention is represented as deuterium, such a compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), 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), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom. It should be understood that the term "isotope enrichment factor" can be applied to any isotope in the same way as described for deuterium.

[0199] Other examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 3H, 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, 123I, 124I, and 125I, respectively. Therefore, it should be understood that the present invention includes compounds incorporating one or more of the above-mentioned isotopes, including, for example, radioactive isotopes such as 3H and 14C, or compounds in which non-radioactive isotopes such as 2H and 13C are present. Such isotope-labeled compounds are useful for metabolic studies (using 14C), reaction kinetic studies (e.g., using 2H or 3H), detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) (including drug or substrate tissue distribution assays), or for radioactive treatment of patients. In particular, 18F or labeled compounds may be especially desirable for PET or SPECT studies. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by using a suitable isotope-labeling reagent instead of previously used unlabeled reagents, in a process similar to that described in the attached examples and preparations.

[0200] "The compound of the present invention" or "the compound of formula I" includes its zwitterion, its non-zwitterion (uncharged form), or a pharmaceutically acceptable salt of the said zwitterion or non-zwitterion form. "Zwitterion" or "zwitterion form" means a compound containing both positively and negatively charged functional groups.

[0201] The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or to other parts of the body through the bloodstream and lymphatic system. Examples of various cancers described herein, but not limited to, include colorectal cancer, gastric cancer, endometrial cancer, prostate cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, and ovarian cancer.

[0202] The terms “tumor” and “cancer” are used interchangeably herein, and both terms, for example, encompass solid and liquid tumors, such as diffuse tumors or circulating tumors. Where used herein, the terms “cancer” or “tumor” include precancerous as well as malignant cancers and tumors.

[0203] As used herein, “WRN inhibitor” or “WRN helicase inhibitor” means a compound that inhibits Werner syndrome RecQ DNA helicase (WRN). As used herein, the term “WRN” means the protein of Werner syndrome RecQ DNA helicase. The term “WRN” includes mutants, fragments, variants, isoforms, and homologs of full-length wild-type WRN. In one embodiment, the protein is encoded by the WRN gene (Entrez gene ID 7486; Ensembl ID ENSG00000165392). An exemplary WRN sequence is available in the Uniprot database under deposit number Q14191.

[0204] "WRN-mediated diseases or conditions" include diseases or conditions treated by WRN inhibition, such as cancer. In particular, this may include cancers characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

[0205] "Microsatellite instability cancer," "high frequency microsatellite instability cancer," "high frequency microsatellite cancer," and "high frequency MSI cancer," "MSIhi," and "MSI-H" are used interchangeably as used herein to describe cancers with a high number of changes in the length of single repeat genomic sequences within microsatellites.

[0206] Determining a patient's MSI-H or dMMR tumor status can be done, for example, using polymerase chain reaction (PCR) testing for MSI-H status or immunohistochemistry (IHC) testing for dMMR status. Methods for identifying MSI-H or dMMR tumor status are described, for example, Ryan et al. Crit Rev Oncol Hematol. 2017; 116:38-57; Dietmaier and Hofstadter. Lab Invest 2001, 81:1453-1456; and Kawakami et al. Curr Treat Options Oncol. 2015; 16(7): 30).

[0207] Microsatellite instability is particularly seen in colorectal cancer, gastric cancer, and endometrial cancer, but can also be seen in adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, prostate cancer, and ovarian cancer. Examples of high-frequency microsatellite cancers include endometrial cancer of the uterine body, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical cancer, uterine carcinosarcoma, cervical squamous cell carcinoma, intracervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, and ovarian serous cystadenocarcinoma.

[0208] Cancers with “mismatch repair deficiency” (dMMR) or “dMMR characteristics” include, but are not limited to, cancers of the lung, chest, kidney, colon, ovary, prostate, upper respiratory tract, gastrointestinal tract, stomach, endometrium, liver, pancreas, hematopoietic and lymphocyte tissues, skin, thyroid, pleura, autonomic ganglia, central nervous system, soft tissue, pediatric rhabdoid sarcoma, melanoma, and other cancers, including cancer types associated with demonstrated MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, and PMS1 mutations or epigenetic silencing, microsatellite vulnerable sites, or other gene inactivation mechanisms. Cells or cancers with “mismatch repair deficiency” have a significantly reduced amount of mismatch repair mechanism (e.g., at least about 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction). In some cases, cells or cancers with mismatch repair deficiency do not perform mismatch repair.

[0209] As used herein, the term “pharmaceutical composition” means the compound of the present invention or a pharmaceutically acceptable salt thereof, coupled with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

[0210] As used herein, the term “pharmaceutically acceptable carrier” means a substance useful for the preparation or use of a pharmaceutical composition and which would be considered publicly known to those skilled in the art, including, for example, suitable diluents, solvents, dispersions, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption retarders, salts, drug stabilizers, binders, additives, disintegrants, lubricants, wetting agents, sweeteners, flavorings, dyes, and combinations thereof (see, for example, Remington, The Science and Practice of Pharmacy, 22nd Ed. Pharmaceutical Press, 2013, pp. 1049–1070).

[0211] The terms "synthetic lethal" and "synthetically lethal" are used to refer to a decrease in cell viability and / or cell proliferation rate caused by a combination of mutations or techniques (e.g., RNA interference or protein dysfunction) that result in loss of function in two or more genes, but not by loss of function in just one of those genes.

[0212] The term "therapeutic dose" of the compound of the present invention refers to the amount of the compound that causes a target biological or medical response, such as a decrease or inhibition of enzyme or protein activity, or that improves symptoms, alleviates a condition, slows or delays disease progression, or prevents a disease. In some embodiments, the method of the present invention involves administering a therapeutic dose of the compound specified herein.

[0213] In one embodiment, the term “therapeutic dose” means an amount of the compound of the present invention that, when administered to a subject, is effective in at least partially alleviating, preventing and / or improving a condition, disorder or disease mediated by WRN, or (ii) related to WRN activity, or (iii) characterized by (normal or abnormal) WRN activity, or (2) reducing or inhibiting WRN activity.

[0214] In another embodiment, the term “therapeutic dose” refers to an amount of the compound of the present invention that, when administered to cells or tissues or noncellular biomaterials or culture media, is effective in at least partially reducing or inhibiting WRN activity or reducing WRN protein levels.

[0215] As used herein, the term “subject” refers to primates (e.g., male or female humans), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate, a rat, or a mouse. In yet other embodiments, the subject is a human.

[0216] As used herein, the terms “inhibit,” “inhibit,” or “to inhibit” refer to the reduction or suppression of a given condition, symptom, disorder, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0217] As used herein, the terms “to treat,” “to treat,” or “treatment” any disease or disorder mean to reduce or improve the disease or disorder (i.e., to slow or stop the onset of the disease or at least one of its clinical symptoms), or to reduce or improve at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be recognized by the patient.

[0218] As used herein, the terms “prevent,” “prevent,” or “prevent” any disease or disorder refer to preventive measures for a disease or disorder, or delays the onset or progression of a disease or disorder.

[0219] As used herein, if a subject is expected to benefit from a procedure biologically, medically, or in terms of quality of life, such subject "needs" such procedure.

[0220] As used herein, the terms “a,” “an,” “the,” and similar terms used in the context of the present invention (in particular, in the context of the claims) should be interpreted as encompassing both singular and plural nouns, unless otherwise specifically indicated herein or unless explicitly contradicted by the context.

[0221] "May be joined" means either joined or not joined.

[0222] "May be replaced by Deuterium" means that it is either replaced by Deuterium or not replaced by Deuterium.

[0223] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention pertains. Similar or equivalent methods and materials to those described herein may be used in carrying out or testing the present invention, but preferred methods and materials are described below. Furthermore, the materials, methods and examples are merely illustrative and not intended to be limiting. All methods described herein may be carried out in any preferred order, unless otherwise specifically indicated herein or unless it is clearly inconsistent with the context. The use of any examples or illustrative phrases presented herein (e.g., "etc.") is intended solely to better illustrate the present invention and not to limit the scope of the claimed invention in particular. isomorphic form

[0224] Any of the chiral atoms (e.g., carbon) of the compounds of the present invention may exist in a racemic state or enriched with enantiomers, for example, in (R)-, (S)-, or (R,S)- configurations. In certain embodiments, each chiral atom has an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% in the (R)- or (S)- configuration. Substituents on atoms having unsaturated double bonds may, if possible, exist in cis-(Z)- or trans-(E)- form.

[0225] Therefore, as used herein, the compounds of the present invention may exist in one of the possible stereoisomers, rotational isomers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antiseptics), racemates, or mixtures thereof.

[0226] Any of the resulting stereoisomerized mixtures can be separated, for example, by chromatography and / or fractional crystallization, into pure or substantially pure geometric or optical isomers, diastereomers, or racemates, based on the physicochemical differences of their constituents.

[0227] Any racemic mixture of the compound or intermediate of the present invention can be divided into optical counterparts by known methods, for example, by separating its diastereomer salt obtained using an optically active acid or base and liberating the optically active acidic or basic compound. In particular, the compound of the present invention can be divided into optical counterparts by fractional crystallization of the salt formed with an optically active acid, for example, tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-thuloyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid, using the basic moiety. The racemic compound or racemic intermediate of the present invention can also be divided by chiral chromatography, for example, by high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0228] Compounds of the present invention, i.e., compounds of formula I, containing groups capable of acting as hydrogen bond donors and / or acceptors, may be able to form cocrystals with suitable cocrystal-forming agents. These cocrystals can be prepared from compounds of formula I by known cocrystal-forming procedures. Such procedures include contact between compounds of formula I and cocrystal-forming agents in solution under grinding, heating, co-sublimation, eutectic, or crystallization conditions, and isolation of the cocrystals formed thereby. Suitable cocrystal-forming agents include those described in WO2004 / 078163. Accordingly, the present invention further provides cocrystals containing compounds of formula I.

[0229] Furthermore, the compounds of the present invention may also include their salts, be obtained in the form of their hydrates, or include other solvents used for their crystallization.

[0230] The compounds of the present invention may necessarily or intentionally form solvates with pharmaceutically acceptable solvents (including water), and therefore the present invention is intended to encompass both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of the compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are commonly used in the pharmaceutical field and are known to be harmless to recipients, such as water and ethanol. The term "hydrate" refers to a complex in which the solvent molecule is water. Dosage form

[0231] The pharmaceutical composition or combination of the present invention may, for example, be administered in a unit dose of approximately 1 to 1000 mg of active ingredients (multiple ingredients are possible) to a target weighing approximately 50 to 70 kg. Combinations

[0232] "Combination" refers to either a fixed combination or a combination administration in a single-dose unit form, in which case the compound of formula I or a pharmaceutically acceptable salt thereof, and the combination partner (e.g., another drug described below, also referred to as "therapeutic agent" or "co-agent") may be administered simultaneously, independently, or individually within a time interval (particularly if such a time interval allows the combination partner to exhibit a synergistic effect). A single component may be packaged in a kit or individually. Before administration, one or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose. As used herein, terms such as "co-administration" or "combination administration" are intended to encompass the administration of a selected combination partner to a single subject (e.g., a patient) that requires it, and are intended to include treatment regimens in which the drugs do not necessarily need to be administered by the same route of administration or simultaneously. As used herein, the term "pharmaceutical combination" means a product obtained by mixing or combining one or more therapeutic agents, and includes both fixed and unfixed combinations of therapeutic agents. The term "fixed combination" means that both the therapeutic agent, for example, the compound and the combination partner of the present invention, are administered to the patient simultaneously in the form of a single entity or a single dose.

[0233] The term "non-fixed combination" means that both the therapeutic agent, e.g., the compound of the present invention and its combination partner, are administered to the patient as separate entities, simultaneously, concurrently, or sequentially, without any specified time limit, in which case such administration provides the patient's body with therapeutically effective levels of both compounds. The latter also applies to cocktail therapies, e.g., the administration of three or more therapeutic agents.

[0234] The combinations described herein may include the compound of Formula I and one or more additional therapeutic agents, such as one or more anticancer agents, cytotoxic agents or cell proliferation inhibitors, hormonal treatments, vaccines and / or other immunotherapies. In other embodiments, the combinations may be further administered or used in combination with modalities of other therapeutic procedures, including surgery, radiation, cryosurgery and / or hyperthermia. Such combination therapies are advantageous because they utilize lower doses of the therapeutic agents administered, thus avoiding potential toxicity or complications associated with the procedure.

[0235] Also provided are compounds of formula I as described herein or pharmaceutically acceptable salts thereof as described herein, and combinations comprising one or more additional therapeutic agents. The additional therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids, which are therapeutically active or, when administered to a patient in combination with the compounds of this disclosure, enhance therapeutic activity. In particular, the additional therapeutic agents are: • Anti-cancer drugs, · Chemotherapy, • Liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin (Registered Trademark)), Tezacitibin, Gemcitabine (Difluorodeoxycytidine), Hydroxyurea (Hydrea®), Idarubicin (Idamycin®), Ifosfamide (IFEX0), Irinotecan (Camptosar®), L-Asparaginase (ELSPAR®), Leucovorin Calcium, Melphalan (Alkeran®), 6-Mercaptopurine (Purin ethol(registered trademark)), methotrexate (Folex(registered trademark)), mitoxantrone (Novantrone(registered trademark)), Mylotarg, paclitaxel (Taxol(registered trademark)), Phoenix (yttrium 90 / MX-DTPA), pentostatin, polyfeprosan 20 with carmustine implant (Gliadel(registered trademark)), tamoxifen citrate (Nolvadex(registered trademark)), teniposide (Vumon(registered trademark)), 6-thioguanine, thiotepa, tirapazamine (Tirazone(registered trademark)), topotecan hydrochloride for injection (Hycamptin(registered trademark)), vinblastine (Velban(registered trademark)), vincristine (Oncovin(registered trademark)) and vinorelbine (Navelbine(registered trademark)), especially fluorouracil (5-FU) and irinotecan (Camptosar(registered trademark)), • PD-1 inhibitors, · Anti-PD-1 antibody molecule, • Spartalizumab, or • Tithrelizumab (BGB-A317, Beigene).

[0236] In a particular embodiment, additional therapeutic agents include: Anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin ( A chemotherapeutic agent selected from Platinol®, cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposomal injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin triphosphate, or • Spartalizumab (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pizilizumab (CureTech), MED10680 (Medimmune), Semiprimab (REGN2810, Regeneron), Dostallimab (TSR-042, Tesaro), PF-06801591 (Pfizer), Tisrelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), Valstilimab (AGEN2035, Agenus), Scintilimab (InnoVent), Tripalimab (Shanghai Junshi Bioscience), Camrelizumab (Jiangsu Hengrui Medicine) A PD-1 inhibitor selected from AMP-224 (Amplimmune), penprimab (Akeso Biopharma Inc.), zimbererimab (Arcus Biosciences Inc.), and prorugolimab (Biocad Ltd). In further embodiments, an additional therapeutic activator is the chemotherapy drug irinotecan (Camptosar®).

[0237] In another embodiment, the additional therapeutic agent is a PD-1 inhibitor, for example, a human PD-1 inhibitor. In another embodiment, the immunomodulator is a PD-L1 inhibitor, for example, a human PD-L1 inhibitor. In one embodiment, the PD-1 or PD-L1 inhibitor is an antibody molecule against PD-1 or PD-L1. In another embodiment, the additional therapeutic agent is an anti-PD-1 antibody molecule.

[0238] In further embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US2015 / 0210769, published on July 30, 2015, with the title of the invention, "Antibody Molecules to PD-1 and Uses Thereof".

[0239] In other embodiments, compounds of formula I or pharmaceutically acceptable salts thereof and combinations of chemotherapy and PD-1 inhibitors are provided. In particular, the chemotherapy and PD-1 inhibitor are selected from those described above. In some embodiments, the PD-1 inhibitor (e.g., tislerizumab) is administered in a flat dose between about 100 mg and about 600 mg. In some embodiments, the PD-1 inhibitor is administered in a dose between about 100 mg and about 500 mg. In some embodiments, the PD-1 inhibitor is administered in a dose between about 100 mg and about 400 mg. In some embodiments, the PD-1 inhibitor is administered in a dose between about 100 mg and about 300 mg. In some embodiments, the PD-1 inhibitor is administered in a dose between about 100 mg and about 200 mg. In some embodiments, the PD-1 inhibitor is administered in a dose between about 200 mg and about 600 mg. In some embodiments, the PD-1 inhibitor is administered in a dose between about 200 mg and about 500 mg. In some embodiments, the PD-1 inhibitor is administered in doses between approximately 200 mg and approximately 400 mg. In some embodiments, the PD-1 inhibitor is administered in doses between approximately 200 mg and approximately 300 mg. In some embodiments, the PD-1 inhibitor is administered in doses between approximately 300 mg and approximately 600 mg. In some embodiments, the PD-1 inhibitor is administered in doses between approximately 300 mg and approximately 500 mg. In some embodiments, the PD-1 inhibitor is administered in doses between approximately 300 mg and approximately 400 mg. In some embodiments, the PD-1 inhibitor is administered in doses between approximately 400 mg and approximately 600 mg. In some embodiments, the PD-1 inhibitor is administered in doses between approximately 400 mg and approximately 500 mg. In some embodiments, the PD-1 inhibitor is administered in doses between approximately 500 mg and approximately 600 mg. In some embodiments, the PD-1 inhibitor is administered in doses between approximately 600 mg and approximately 700 mg. In some embodiments, the PD-1 inhibitor is administered in a dose between approximately 700 mg and approximately 800 mg. In some embodiments, the PD-1 inhibitor is administered in a dose between approximately 800 mg and approximately 900 mg. In some embodiments, the PD-1 inhibitor is administered in a dose between approximately 900 mg and approximately 1000 mg.

[0240] In some embodiments, the PD-1 inhibitor (e.g., tislerizumab) is administered in a flat dose of approximately 100 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of approximately 200 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of approximately 300 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of approximately 400 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of approximately 500 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of approximately 600 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of approximately 700 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of approximately 800 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of approximately 900 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of approximately 1000 mg.

[0241] In some embodiments, the PD-1 inhibitor (e.g., tislerizumab) is administered once every 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 7 weeks. In some embodiments, the PD-1 inhibitor is administered once every 6 weeks. In some embodiments, the PD-1 inhibitor is administered once every 5 weeks. In some embodiments, the PD-1 inhibitor is administered once every 4 weeks. In some embodiments, the PD-1 inhibitor is administered once every 3 weeks. In some embodiments, the PD-1 inhibitor is administered once every 2 weeks. In some embodiments, the PD-1 inhibitor is administered once a week.

[0242] In some embodiments, the PD-1 inhibitor (e.g., tislerizumab) is administered intravenously.

[0243] In some embodiments, the PD-1 inhibitor (e.g., tislerizumab) is administered over a period of approximately 20 to 40 minutes (e.g., approximately 30 minutes). In some embodiments, the PD-1 inhibitor is administered over a period of approximately 30 minutes. In some embodiments, the PD-1 inhibitor is administered over a period of approximately 1 hour. In some embodiments, the PD-1 inhibitor is administered over a period of approximately 2 hours. In some embodiments, the PD-1 inhibitor is administered over a period of approximately 3 hours. In some embodiments, the PD-1 inhibitor is administered over a period of approximately 4 hours. In some embodiments, the PD-1 inhibitor is administered over a period of approximately 5 hours. In some embodiments, the PD-1 inhibitor is administered over a period of approximately 6 hours.

[0244] In some embodiments, the PD-1 inhibitor (e.g., tislerizumab) is administered intravenously once every four weeks in a dose between approximately 300 mg and approximately 500 mg (e.g., approximately 400 mg). In some embodiments, the PD-1 inhibitor is administered intravenously once every three weeks in a dose between approximately 200 mg and approximately 400 mg (e.g., approximately 300 mg). In some embodiments, tislerizumab is administered once every four weeks in a dose of 400 mg. In some embodiments, tislerizumab is administered once every three weeks in a dose of 300 mg.

[0245] In some embodiments, a PD-1 inhibitor (e.g., tislerizumab) is administered intravenously once every two weeks over a period of approximately 20 to 40 minutes (e.g., approximately 30 minutes) in a dose between approximately 300 mg and approximately 500 mg (e.g., approximately 400 mg). In some embodiments, a PD-1 inhibitor is administered intravenously once every three weeks over a period of approximately 20 to 40 minutes (e.g., approximately 30 minutes) in a dose between approximately 200 mg and approximately 400 mg (e.g., approximately 300 mg).

[0246] In some embodiments, the PD-1 inhibitor (e.g., tislerizumab) is administered in doses of approximately 100 mg per week. For example, if a patient is given a 10-week dose, the PD-1 inhibitor (e.g., tislerizumab) may be administered in 1000 mg doses. If a 9-week dose is given, the PD-1 inhibitor (e.g., tislerizumab) may be administered in 900 mg doses. If an 8-week dose is given, the PD-1 inhibitor (e.g., tislerizumab) may be administered in 800 mg doses. If a 7-week dose is given, the PD-1 inhibitor (e.g., tislerizumab) may be administered in 700 mg doses. If a 6-week dose is given, the PD-1 inhibitor (e.g., tislerizumab) may be administered in 600 mg doses. If a 5-week dose is given, the PD-1 inhibitor (e.g., tislerizumab) may be administered in 500 mg doses. If a 4-week dose is given, the PD-1 inhibitor (e.g., tislerizumab) may be administered at 400 mg. If a 3-week dose is given, the PD-1 inhibitor (e.g., tislerizumab) may be administered at 300 mg. If a 2-week dose is given, the PD-1 inhibitor (e.g., tislerizumab) may be administered at 200 mg. If a 1-week dose is given, the PD-1 inhibitor (e.g., tislerizumab) may be administered at 100 mg.

[0247] For example, when an anti-PD-1 antibody such as tislerizumab is used, it may be administered as an intravenous infusion of 200 mg once every three weeks. Alternatively, tislerizumab may be administered as an intravenous infusion of 300 mg once every four weeks. When an anti-PD-1 antibody such as tislerizumab is used, it may be administered as an intravenous infusion of 300 mg once every three weeks. Alternatively, tislerizumab may be administered as an intravenous infusion of 400 mg once every four weeks.

[0248] The above-mentioned compounds, which can be used in combination with the compounds of the present invention, can be prepared and administered as described in the art, such as in the documents cited above.

[0249] In one embodiment, the present invention provides a product comprising the compound of the present invention and at least one other therapeutic agent as a combination preparation for simultaneous, individual, or sequential use in treatment. In one embodiment, the treatment is the treatment of a disease or condition mediated by WRN. The product provided as a combination preparation comprises a composition containing the compound of formula I and other therapeutic agents together in the same pharmaceutical composition, or in individual forms, for example, in the form of a kit, comprising the compound of the present invention and other therapeutic agents.

[0250] In one embodiment, the present invention provides a kit comprising two or more individual pharmaceutical compositions, at least one of which contains a compound of the present invention. In one embodiment, the kit comprises means for individually holding the compositions, such as containers, divided bottles, or divided foil packets. An example of such a kit is blister packaging, which is commonly used for packaging tablets, capsules, and the like.

[0251] The kit of the present invention may be used to administer different dosage forms (e.g., oral and parenteral), to administer individual compositions at different dosing intervals, or to set the dosages of individual compositions relative to each other. To assist in medication adherence, the kit of the present invention typically includes instructions for administration.

[0252] In the combination therapy of the present invention, the compound of the present invention and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the present invention and other therapeutic agents may be put together in combination therapy: (i) before the combination product is sold to a physician (for example, in the case of a kit containing the compound of the present invention and other therapeutic agents), (ii) immediately before administration, by the physician himself (or under the guidance of the physician), or (iii) between the sequential administrations of the compound of the present invention and other therapeutic agents, for example, by the patient himself.

[0253] Accordingly, the present invention provides a use of the compound of the present invention for treating a disease or condition mediated by WRN, wherein the pharmacopoeia is prepared for administration with another therapeutic agent. The present invention also provides a use of another therapeutic agent for treating a disease or condition mediated by WRN, wherein the pharmacopoeia is administered together with the compound of the present invention.

[0254] The present invention also provides a compound of the present invention for use in treating a disease or condition mediated by WRN, wherein the compound of the present invention is prepared for administration with another therapeutic agent. The present invention also provides another therapeutic agent for use in treating a disease or condition mediated by WRN, wherein the other therapeutic agent is prepared for administration with the compound of the present invention. The present invention also provides a compound of the present invention for use in treating a disease or condition mediated by WRN, wherein the compound of the present invention is administered together with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by WRN, wherein the other therapeutic agent is administered together with the compound of the present invention.

[0255] The present invention also provides the use of the compounds of the present invention for treating a disease or condition mediated by WRN, wherein the patient has previously been treated with another therapeutic agent (e.g., within 24 hours). The present invention also provides the use of another therapeutic agent for treating a disease or condition mediated by WRN, wherein the patient has previously been treated with the compounds of the present invention (e.g., within 24 hours). 5. General synthesis methods for producing the compounds of this disclosure

[0256] The compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying synthesis scheme.

[0257] Referring to Scheme 1, Acyl 2 chloride (this is the R of this compound) 1 3 can be produced by amide synthesis achieved by coupling (containing substituents) with primary amine 1. 5 is obtained by intramolecular cyclization of 3 to form oxazole 4 (the portion containing X and Y of this compound) and subsequent amine protection. Butane-2one is reacted with the ester of 5 in the presence of a strong base to obtain 6, which is subsequently brominated at the α-keto position to obtain 7. The bromine is replaced by a nucleophilic ring A surrogate (protected piperidine in step 7) to produce 10. 10 can undergo intramolecular cyclization to produce the oxazolo[5,4-b]pyridine-7(4H)-one core of this compound in intermediate 11. Substituent R 2 R 2 The nucleophilic substitution of surrogate 12 introduces it into the core of 11, and 13 can be obtained. Deprotection of 13 and R 4 Compounds of the present disclosure, such as I-2, can be obtained by amide coupling using surrogate 15.

[0258] Using similar chemistry as described in Scheme 1, the intermediates and compounds of the present disclosure described below can be formed. A person skilled in the art can skillfully use alternative protecting group strategies and transition metal cross-coupling (see Step 1) within the scope of their skills to transform substituents (e.g., R) from Scheme 1 to the intermediate in Scheme 2. 1 , R 2 , R 4 The order in which ring A) is introduced can be easily changed. General synthetic methods for producing the [5,4-b]pyridine-4(7H) intermediates of this disclosure, such as scheme 1:11. [ka] [ka] Scheme 2: General synthetic method for producing the [4,5-b]pyridine-4(7H) compounds of this disclosure [ka] [ka] [ka]

[0259] Those skilled in the art will be able to adapt such a synthetic procedure to synthesize the compounds of the present disclosure to obtain various substituted compounds of formula I. [Examples]

[0260] As shown in the following examples, in certain exemplary embodiments, the compounds are prepared according to the procedures provided herein. While the methods illustrate the synthesis of certain compounds in this disclosure, it will be understood that these methods and other methods known to those skilled in the art can be applied to all compounds described herein, as well as their respective subclasses and species. List of abbreviations: H2O: Water ACN: Acetonitrile THF: Tetrahydrofuran FA: Formic acid Na2SO4: Sodium sulfate æ:ethyl acetate HCl: Hydrochloric acid DCM: Dichloromethane pH: Hydrogen ion concentration index (Boc2)O:di-tert-butyl dicarbonate POCl3: Phosphorus oxychloride EDCI: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride LCMS: Liquid Chromatography-Mass Spectrometry HPLC: High-Performance Liquid Chromatography NH4Cl: Ammonium chloride K3PO4: Tripotassium phosphate TFA: Trifluoroacetic acid NBS: N-bromosuccinimide DIEA: N,N-diisopropylethylamine Pd(dppf)2Cl2-CH2Cl2:1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex TsOH: 4-methylbenzenesulfonic acid DMSO-d6: Deuterated Dimethyl Sulfoxide NMP:N-methyl-2-pyrrolidone DBU:1,8-Diazabicyclo[5.4.0]Undeca-7-En LiHMDS: Lithium hexamethyldisilazide Preparative TLC: Preparative Thin-Layer Chromatography s: singlet m: Multiplet d: doublet DQ: Quartet's Doublet t: triplet Broad N: Regulation eq: equivalent M: Molar concentration PE: Petroleum ether aq: water-based SOCl2: Thionyl Chloride MTBE: Methyl tert-butyl ether KI: Potassium iodide PMB-Cl: 4-methoxybenzyl chloride t-BuOK: Potassium t-butoxide Cs2CO3: Cesium Carbonate DMF: N,N-dimethylformamide N2: Nitrogen POCl3: Phosphoryl chloride Na2SO4: Sodium sulfate CDCl3: Deuterated chloroform CD3OD: Deuterated methanol (Example 1) Synthesis of the Compounds Disclosed

[0261] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[4,5-b]pyridine-4(7H)-yl)acetamide(I-1) [ka]

[0262] Intermediate-3 and the other intermediates in the following synthesis procedure can be synthesized as described below.

[0263] Step 12. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[4,5-b]pyridine-4(7H)-yl)acetamide

[0264] N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-6-piperazine-1-yloxazolo[4,5-b]pyridine-4-yl]acetamide (18 mg, 29 μmol, 1 equivalent, HCl salt) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (7 mg, 43 μmol, 1.5 equivalents) were dissolved in pyridine (0.4 mL) and EDCI (11 mg, 57 μmol, 2 equivalents) was added. The mixture was stirred at 25 °C for 4 hours. The reaction mixture was quenched with H₂O (10 mL). It was then extracted with ELISA (10 mL × 3). The combined organic phase was washed with brine (15 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue. When the residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1), the title compound was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.82 (s, 1H), 8.58 (s, 1H), 8.51 (d, 1H), 8.47 (s, 1H), 8.34 (d, 1H), 7.63 (d, 1H), 7.60 (d, 1H), 7.55 (d, 1H), 7.49 (s, 1H), 5.69 - 5.55 (m, 1H), 5.24 (s, 2H), 4.84 - 4.74 (m, 1H), 4.06 - 4.02 (m, 2H), 4.00 (s, 3H), 3.51 - 3.53 (m, 1H), 3.22 - 3.18 (q, 2H), 3.06- 3.02 (m, 1H), 2.91 - 2.73 (m, 2H), 2.57 (s, 3H), 1.32 (t, 3H).LCMS:727.2[M+H] + .

[0265] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[5,4-b]pyridine-4(7H)-yl)acetamide(I-2) [ka]

[0266] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[5,4-b]pyridine-4(7H)-yl)acetamide

[0267] To a pyridine (0.5 mL) solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-6-(piperazine-1-yl)oxazolo[5,4-b]pyridine-4(7H)-yl)acetamide hydrochloride (intermediate-9) (45 mg, 72 μmol, 1 equivalent) and sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate (intermediate-10) (71 mg, 0.36 mmol, 5 equivalents), EDCI (55 mg, 0.29 mmol, 4 equivalents) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 5:1) to obtain the title compound.

[0268] 1 H-NMR (400 MHz, CD3OD) δ ppm 8.27 (d, 1H), 8.14 (d, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.67 - 7.52 (m, 2H), 7.39 (s, 1H), 5-66 - 5.24 (m, 2H), 4.66 - 4.65 (m, 2H), 3.95 (s, 3H), 3.92 - 3.70 (m, 2H), 3.53 - 3.38 (m, 1H), 3.15 (q, 2H), 3.10 - 3.02 (m, 1H), 2.90 - 2.79 (m, 1H), 2.75 - 2.62 (m, 1H), 2.40 (s, 3H), 1.29 (t, 3H).

[0269] LCMS:727.3[M+H] + .

[0270] Synthesis of 2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[4,5-b]pyridine-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide(I-3) [ka]

[0271] Step 5. Synthesis of 2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[4,5-b]pyridine-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide

[0272] EDCI (79 mg, 412 μmol, 3 equivalents) was added to a pyridine (1 mL) solution of 2-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-6-piperazine-1-yl-oxazolo[4,5-b]pyridine-4-yl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]acetamide hydrochloride (intermediate-15) (80 mg, 137 μmol, 1 equivalent) and 5-hydroxy-6-methylpyrimidine-4-carboxylate sodium (intermediate-10) (54 mg, 274 μmol, 2 equivalents). The mixture was stirred at 25°C for 4 hours. H2O (10 mL) was added to the reaction mixture. The mixture was then extracted with ELISA (10 mL × 3). The combined organic phases were washed with brine (15 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1) to obtain the title compound.

[0273] 1H NMR (400 MHz, CDCl3) δ ppm 11.82 (s, 1H), 8.57 (s, 1H), 8.31 (d, 1H), 7.54 (d, 1H), 7.43 (s, 1H), 6.81 (s, 1H), 5.63 - 5.60 (m, 1H), 5.00 (s, 2H), 4.84 - 4.73 (m, 1H), 4.04 (q, 2H), 3.99 (s, 3H), 3.55 - 3.42 (m, 1H), 3.04 - 3.02 (m, 3H), 2.89 - 2.75 (m, 2H), 2.57 (s, 3H), 2.34 (s, 6H), 1.26 (t, 3H).

[0274] LCMS:683.2[M+H] + .

[0275] Synthesis of 2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[5,4-b]pyridine-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide(I-4) [ka]

[0276] Step 3. Synthesis of 2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[5,4-b]pyridine-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide

[0277] To a pyridine (0.2 mL) solution of 2-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-6-piperazine-1-yl-oxazolo[5,4-b]pyridine-4-yl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]acetamide hydrochloride (intermediate-13) (20 mg, 34 μmol, 1 equivalent) and 5-hydroxy-6-methylpyrimidine-4-carboxylate sodium (intermediate-10) (34 mg, 172 μmol, 5 equivalents), EDCI (26 mg, 137 μmol, 4 equivalents) was added. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, MeOH / DCM = 10:1) to obtain the title compound.

[0278] 1 H NMR (400 MHz, CD3OD) δ ppm 8.29 (d, 1H), 8.14 (s, 1H), 7.57 (d, 1H), 7.40 (s, 1H), 5.07 (s, 2H), 4.66 - 4.63 (m, 1H), 3.97 (s, 3H), 3.94 - 3.79 (m, 2H), 3.72 - 3.59 (m, 1H), 3.48 - 3.44 (m, 1H), 3.19 - 3.08 (m, 1H), 3.04 (q, 2H), 2.-86 - 2.82 (m, 1H), 2.70 - 2.66 (m, 1H), 2.42 (s, 3H), 2.32 (s, 6H), 1.24 (t, 3H).

[0279] LCMS:683.3[M+H] + . [Table 2-1] [Table 2-2]

[0280] As can be recognized by those skilled in the art, the compounds in Table 2a can be obtained from intermediate 1 (ethyl 2,4-diiodooxazole-5-carboxylate). [Table 2a-1] [Table 2a-2] [Table 2a-3] [Table 2a-4] [Table 2a-5] [Table 2a-6] [Table 2a-7] [Table 2a-8] [Table 2a-9] [Table 2a-10] [Table 2a-11] [Table 2a-12] [Table 2a-13] [Table 2a-14] [Table 2a-15] [Table 2a-16] [Table 2a-17] [Table 2a-18] [Table 2a-19] [Table 2a-20]

[0281] As can be recognized by those skilled in the art, the compounds in Table 2b can be obtained by one or more of the common synthetic routes described herein and / or by methods known to those skilled in the art. [Table 2b-1] [Table 2b-2] [Table 2b-3] [Table 2b-4] [Table 2b-5] [Table 2b-6] [Table 2b-7] [Table 2b-8] [Table 2b-9] [Table 2b-10] [Table 2b-11] [Table 2b-12] [Table 2b-13] [Table 2b-14] [Table 2b-15] [Table 2b-16] LCMS method LCMS 1 Equipment Shimadzu LCMS-2020 Stationary phase Kinetex EVO C18 2.1×30mm, 5μm Mode two-component gradient Mobile phase A: 0.025% NH3·H2O (v / v) in water Mobile phase B: Acetonitrile Gradient: B from 5% to 95% in 0.8 minutes, B to 95% in 0.42 minutes, B from 95% to 5% in 0.01 minutes, B to 5% in 0.35 minutes. Flow rate 1.5mL / min Column temperature: 40°C Column: 2.1 × 30 mm, 5 μm LCMS 2 Equipment Shimadzu LCMS-2020 Stationary phase HALO C 18 3.0 x 30 mm, 5 μm Mode two-component gradient Mobile phase A: 0.0375% TFA (v / v) in water Mobile phase B: 0.01875% TFA (v / v) in acetonitrile gradient [Table 5] Flow rate 1.5mL / min Column temperature 50℃ Column HALO C 18 3.0 x 30 mm, 5 μm LCMS 3 Equipment Agilent HPLC-1290 Stationary phase HALO C18 100×4.6mm, 2.7μm Mode two-component gradient Mobile phase A H2O+0.05%TFA Mobile phase B: Acetonitrile + 0.05% TFA Gradient: Increase B from 10% to 95% over 6 minutes, then maintain B at 95% for 2 minutes. Flow rate 1.5mL / min Column temperature: 40°C Column: 100 × 4.6 mm, 2.7 μm

[0282] Intermediate-1: Ethyl 2,4-diiodoxazole-5-carboxylate [ka] Step 1. Synthesis of ethyl 2,4-diiodoxazole-5-carboxylate (intermediate 1)

[0283] To a solution of ethyl oxazole-5-carboxylate (10.00 g, 70.86 mmol, 1 equivalent) in THF (100 mL), LiHMDS (1 M, 248.01 mL, 3.5 equivalents) was added at -30°C, and the mixture was stirred at -30°C for 1 hour. Next, I2 (53.95 g, 212.58 mmol, 3 equivalents) was added to the mixture, and the mixture was stirred at 25°C for 15 hours. The mixture was poured into H2O (500 mL). Next, it was extracted with RINKAN (200 mL x 3). The organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (RINKAN / PE eluent), and trituration with EtOH (10 mL) yielded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.30 (q, 2H), 1.30 (t, 3H).LCMS:394.0[M+H] + .

[0284] Intermediate 2: tert-butyl 4-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-4,7-dihydrooxazolo[4,5-b]pyridine-6-yl)piperazine-1-carboxylate [ka] Step 1. Synthesis of ethyl 4-iodo-2-(2-methoxypyridine-4-yl)oxazole-5-carboxylate

[0285] To a solution of ethyl 2,4-diiodoxazole-5-carboxylate (4.90 g, 12.47 mmol, 1 equivalent), (2-methoxy-4-pyridyl)boronic acid (1.91 g, 12.47 mmol, 1 equivalent), and K2CO3 (3.45 g, 24.94 mmol, 2 equivalents) in dioxane (100 mL) and H2O (20 mL), Pd(dppf)Cl2 (913 mg, 1.25 mmol, 0.1 equivalent) was added. The mixture was degassed, purged three times with N2, and then stirred at 60°C for 16 hours under an N2 atmosphere. The mixture was poured into H2O (200 mL) and extracted with SiO2 (100 mL x 3). The organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (using siRNA / PE as the eluent), and recrystallized with EtOH (50 mL), yielding the title compound as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm 8.32 (d, 1H), 7.54 (d, 1H), 7.43 (s, 1H), 4.46 (q, 2H), 4.00 (s, 3H), 1.46 (t, 3H).

[0286] LCMS:375.1[M+H] + . Step 2. Synthesis of ethyl 4-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazole-5-carboxylate

[0287] To a 20 mL solution of ethyl 4-iodo-2-(2-methoxy-4-pyridyl)oxazole-5-carboxylate (1.00 g, 2.67 mmol, 1 equivalent) and 1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methaneamine (1.03 g, 4.01 mmol, 1.5 equivalents), Pd(OAc)2 (60 mg, 267 μmol, 0.1 equivalent), Xantphos (155 mg, 267 μmol, 0.1 equivalent), and Cs2CO3 (1.31 g, 4.01 mmol, 1.5 equivalents) were added. The mixture was degassed, purged three times with N2, and stirred at 110°C for 12 hours under an N2 atmosphere. It was then quenched with H2O (150 mL), and the mixture was extracted with ELISA (150 mL x 3). The combined organic phases were washed with brine (150 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (using siRNA / PE as the eluent), yielding the title compound as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, 1H), 7.53 (d, 1H), 7.42 (s, 1H), 7.19 (d, 4H), 6.86 (d, 4H), 4.77 (s, 4H), 4.31 (q, 2H), 4.02 (s, 3H), 3.81 (s, 6H), 1.33 (t, 3H).

[0288] LCMS:504.3[M+H] + . Step 3. Synthesis of 4-(bis(4-methoxybenzyl)amino)-N-methoxy-2-(2-methoxypyridine-4-yl)-N-methyloxazole-5-carboxamide

[0289] A mixture of ethyl 4-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4-pyridyl)oxazole-5-carboxylate (500 mg, 993 μmol, 1 equivalent) and N-methoxymethanamine hydrochloride (484 mg, 4.96 mmol, 5.0 equivalents) in THF (12 mL) was mixed with LiHMDS (1 M, 7.94 mL, 8 equivalents) at 0°C under an N2 atmosphere, and the mixture was stirred at 0°C under an N2 atmosphere for 1 hour. The reaction mixture was quenched at 0°C with saturated NH4Cl aqueous solution (50 mL). Next, the mixture was extracted with RINKAN (50 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound as a yellow gum-like substance, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ ppm 8.28 (d, 1H), 7.47 (d, 1H), 7.32 (s, 1H), 7.18 (d, 4H), 6.83 (d, 4H), 4.66 (s, 4H), 4.00 (s, 3H), 3.79 (s, 6H), 3.74 (s, 3H), 3.20 (s, 3H).

[0290] LCMS:519.2[M+H] + . Step 4. Synthesis of 1-(4-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazole-5-yl)pentan-1,3-dione

[0291] A mixture of butan-2-one (556 mg, 7.71 mmol, 690 μL, 5.0 equivalents) and 4-[bis[(4-methoxyphenyl)methyl]amino]-N-methoxy-2-(2-methoxy-4-pyridyl)-N-methyl-oxazole-5-carboxamide (800 mg, 1.54 mmol, 1 equivalent) in THF (8 mL) was mixed with LiHMDS (1 M, 7.71 mL, 5.0 equivalents) at 0°C under an N2 atmosphere. The mixture was stirred at 60°C for 1 hour. The reaction mixture was quenched at 0°C with saturated NH4Cl aqueous solution (100 mL). The mixture was then extracted with ELISA (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. When the residue was purified by flash silica gel chromatography (using SiO / PE as the eluent), the title compound was obtained as a yellow, gum-like substance.

[0292] LCMS:530.2[M+H] + . Step 5. Synthesis of 1-(4-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazol-5-yl)-2-bromopentan-1,3-dione

[0293] To a mixture of 1-[4-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4-pyridyl)oxazole-5-yl]pentan-1,3-dione (320 mg, 604 μmol, 1 equivalent) in DCM (10 mL), NBS (86 mg, 483 μmol, 0.8 equivalents) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. Next, TsOH.H2O (21 mg, 121 μmol, 0.2 equivalents) was added to the mixture, and the mixture was stirred for a further 1 hour at 25°C. The reaction mixture was quenched with H2O (20 mL) at 25°C. Next, the mixture was extracted with DCM (15 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound as a yellow oily substance, which was used directly in the next step without purification.

[0294] LCMS:608.1[M+H] + . Step 6. Synthesis of tert-butyl 4-(1-(4-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazole-5-yl)-1,3-dioxopentan-2-yl)piperazine-1-carboxylate

[0295] To a solution of tert-butylpiperazine-1-carboxylate (107 mg, 575 μmol, 1 equivalent) in THF (7 mL), DIEA (149 mg, 1.15 mmol, 200 μL, 2 equivalents) and 1-[4-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4-pyridyl)oxazole-5-yl]-2-bromopentan-1,3-dione (350 mg, 575 μmol, 1 equivalent) were added. The mixture was stirred at 25°C for 16 hours. It was quenched with H2O (30 mL) and then extracted with ELISA (30 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (using SiO / PE as the eluent) to obtain the title compound as a yellow oily substance.

[0296] LCMS:714.3[M+H] + . Step 7. Synthesis of 5-ethyl-2-(2-methoxypyridine-4-yl)-6-(piperazine-1-yl)oxazolo[4,5-b]pyridine-7(4H)-one

[0297] A solution of tert-butyl 4-[1-[4-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4-pyridyl)oxazole-5-carbonyl]-2-oxo-butyl]piperazine-1-carboxylate (300 mg, 420 μmol, 1 equivalent) in TFA (6 mL) was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool naturally to room temperature and concentrated under reduced pressure to obtain the title compound as a yellow oily substance, which was used directly in the next step without purification.

[0298] LCMS:356.1[M+H] + . Step 8. Synthesis of tert-butyl 4-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-4,7-dihydrooxazolo[4,5-b]pyridine-6-yl)piperazine-1-carboxylate

[0299] To a 5 mL solution of 5-ethyl-2-(2-methoxy-4-pyridyl)-6-piperazin-1-yl-4H-oxazolo[4,5-b]pyridine-7-one (150 mg, 422 μmol, 1 equivalent) in DCM (5 mL), DIEA (55 mg, 422 μmol, 74 μL, 1 equivalent) and (Boc)2O (184 mg, 844 μmol, 194 μL, 2 equivalents) were added at 0 °C. The mixture was stirred at 0 °C for 1 hour. Next, the reaction mixture was diluted with H2O (20 mL). The mixture was then extracted with DCM (15 mL x 3). The combined organic phase was washed with brine (15 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by flash silica gel chromatography (ethyl / PE eluent) to obtain the title compound as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm 8.26 (s, 1H), 7.52 (d, 1H), 7.39 (s, 1H), 4.16 - 4.01 (m, 2H), 3.94 (s, 3H), 3.91 - 3.80 (m, 2H), 3.02 - 2.93 (m, 4H), 2.66 (q, 2H), 1.50 (s, 9H), 1.35 (t, 3H).

[0300] LCMS: 456.2[M+H] + .

[0301] Intermediate 3: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-6-(piperazine-1-yl)oxazolo[4,5-b]pyridine-4(7H)-yl)acetamide hydrochloride [ka] Step 1. Synthesis of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-4,7-dihydrooxazolo[4,5-b]pyridine-6-yl)piperazine-1-carboxylate

[0302] To a solution of tert-butyl 4-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-4H-oxazolo[4,5-b]pyridine-6-yl]piperazine-1-carboxylate (80 mg, 176 μmol, 1 equivalent) in DMF (2 mL), DIEA (68 mg, 527 μmol, 92 μL, 3 equivalents) and N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (intermediate-12) (83 mg, 228 μmol, 1.3 equivalents) were added. The mixture was stirred at 60°C for 1 hour. The reaction mixture was cooled to 25°C and quenched with H2O (20 mL). It was then extracted with ELISA (15 mL x 3). The combined organic phase was washed with brine (15 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by flash silica gel chromatography (using siRNA / PE as the eluent) to obtain the title compound as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm 8.53 (d, 1H), 8.43 (s, 1H), 8.35 (d, 1H), 7.65 - 7.60 (m, 2H), 7.58 - 7.54 (m, 1H), 7.51 (s, 1H), 5.23 (s, 2H), 4.19 - 4.05 (m, 2H), 4.01 (s, 3H), 3.97 - 3.86 (m, 2H), 3.14 (q, 2H), 3.13 - 3.11 (m, 2H), 2.69 - 2.65 (m, 2H), 1.51 (s, 9H), 1.30 (t, 3H).

[0303] LCMS:691.3[M+H] + .

[0304] Step 2. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-6-(piperazine-1-yl)oxazolo[4,5-b]pyridine-4(7H)-yl)acetamide hydrochloride

[0305] To a solution of tert-butyl 4-[4-[2-[2-chloro-4-(trifluoromethyl)anilino]-2-oxo-ethyl]-5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-oxazolo[4,5-b]pyridine-6-yl]piperazine-1-carboxylate (20 mg, 29 μmol, 1 equivalent) in DCM (0.4 mL), HCl / dioxane (4 M, 0.40 mL, 55 equivalents) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound as a yellow solid, which was used directly in the next step without purification.

[0306] LCMS:591.2[M+H] + .

[0307] Intermediate 4: 7-hydroxy-2,3-dihydrofl[3,2-c]pyridine-6-carboxylic acid [ka]

[0308] Step 1. Synthesis of methyl 3-(bromomethyl)furan-2-carboxylate

[0309] To a solution of methyl 3-methylfuran-2-carboxylate (5.00 g, 35.7 mmol, 1.00 equivalent) in CCl4 (50.0 mL), NBS (6.68 g, 37.5 mmol, 1.05 equivalent) and AIBN (2.35 g, 14.3 mmol, 0.40 equivalent) were added at room temperature. The mixture was degassed three times with N2 and stirred at 50°C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using siRNA / PE as the eluent) to obtain the title compound.

[0310] LCMS:219 / 221[M+H] + .

[0311] Step 2. Synthesis of methyl 3-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamide)methyl)furan-2-carboxylate

[0312] Methyl 2-(4-methylbenzenesulfonamide) acetate (5.23 g, 21.5 mmol, 1.00 equivalent) was added to a solution of methyl 3-(bromomethyl)furan-2-carboxylate (4.70 g, 21.5 mmol, 1.00 equivalent) and K2CO3 (5.93 g, 43.0 mmol, 2.00 equivalent) in ACN (47.0 mL), and the mixture was stirred at room temperature for 16 hours. The reaction product was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica column chromatography (eluent: siRNA / PE) to obtain the title compound. LCMS: 382[M+H] + .

[0313] Step 3. Synthesis of methyl 7-hydroxyfluoro[3,2-c]pyridine-6-carboxylate

[0314] To a solution of methyl 3-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamide)methyl)furan-2-carboxylate (1.80 g, 4.72 mmol, 1.00 equivalent) in THF (18.0 mL), a 1 M LiHMDS solution (14.2 mL, 14.2 mmol, 3.00 equivalent) in THF was added dropwise at -78°C under an N2 atmosphere. After addition, the reaction mixture was warmed to 0°C and stirred under an N2 atmosphere for 5 hours. A saturated aqueous NH4Cl solution was added to the reaction mixture, and the aqueous phase was extracted with SiO4. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (SiO4 / PE eluent) to obtain the title compound.

[0315] LCMS:194[M+H] + .

[0316] Step 4. Synthesis of methyl 7-hydroxy-2,3-dihydrofl[3,2-c]pyridine-6-carboxylate

[0317] A mixture of methyl 7-hydroxyfluoro[3,2-c]pyridine-6-carboxylate (760 mg, 3.93 mmol, 1.00 equivalent) in MeOH (10.0 mL) was mixed with Pd / C (152 mg, 20%). The mixture was degassed and purged with H2 gas (40 psi). It was then stirred at 50°C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using DCM / MeOH as the eluent) to obtain the title compound.

[0318] LCMS:196[M+H] + .

[0319] Step 5. Synthesis of 7-hydroxy-2,3-dihydrofl[2,3-c]pyridine-6-carboxylic acid

[0320] A mixture of methyl 7-hydroxy-2,3-dihydrofl[3,2-c]pyridine-6-carboxylate (680 mg, 3.48 mmol, 1.00 equivalent) in H2O (3.00 mL) and MeOH (3.00 mL) was mixed with NaOH (557 mg, 13.9 mmol, 4.00 equivalent) at room temperature, and the resulting mixture was stirred at 60°C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O and acidified with 3N HCl. The precipitated solid was collected by filtration and dried to obtain the title compound, which was used directly in the next step without further purification.

[0321] LCMS:182[M+H] + .

[0322] Intermediate-5: 4-hydroxy-2,3-dihydrofl[2,3-c]pyridine-5-carboxylic acid [ka]

[0323] Step 1. Synthesis of methyl 2-(bromomethyl)furan-3-carboxylate

[0324] To a stirred solution of methyl 2-methylfuran-3-carboxylate (10.0 g, 71.4 mmol, 1.00 equivalent) in CCl4 (55.0 mL), NBS (15.2 g, 85.6 mmol, 1.20 equivalent) and AIBN (586 mg, 3.57 mmol, 0.05 equivalent) were added at room temperature. The resulting mixture was degassed three times with N2 and stirred overnight at 50°C under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using  / PE as the eluent) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.86 (d, 1H), 6.80 (d, 1H), 4.95 (s, 2H), 3.82 (s, 3H).

[0325] Step 2. Synthesis of methyl 2-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamide)methyl)furan-3-carboxylate

[0326] To a stirred solution of methyl 2-(bromomethyl)furan-3-carboxylate (12.0 g, 54.8 mmol, 1.00 equivalent) and methyl 2-(4-methylbenzenesulfonamide) acetate (13.3 g, 54.8 mmol, 1.00 equivalent) in ACN (100 mL), K2CO3 (15.1 g, 110 mmol, 2.00 equivalent) was added at room temperature. The resulting mixture was degassed three times with N2 and then stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using siRNA / PE as the eluent) to obtain the title compound.

[0327] LCMS:382.1[M+H] + .

[0328] Step 3. Synthesis of methyl 4-hydroxyfl[2,3-c]pyridine-5-carboxylate

[0329] A 1M solution of methyl 2-([N-(2-methoxy-2-oxoethyl)4-methylbenzenesulfonamide]methylfuran-3-carboxylate (9.00 g, 23.6 mmol, 1.00 equivalent) in THF (50.0 mL) was prepared in THF under N2 conditions at -78°C. LiHMDS solution (70.0 mL, 70.0 mmol, 3.00 equivalents) was added. The resulting mixture was stirred under N2 at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution at 0°C and diluted with H2O (200 mL). The resulting mixture was extracted with siRNA (2 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (siRNA / PE eluent) to obtain the crude product, which was then purified by trituration with PE (250 mL) to obtain the title compound. LCMS: 194.0 [M + H] + .

[0330] Step 4. Synthesis of methyl 4-hydroxy-2,3-dihydrofl[2,3-c]pyridine-5-carboxylate

[0331] To a solution of methyl 4-hydroxyfluoro[2,3-c]pyridine-5-carboxylate (1.00 g, 5.18 mmol, 1.00 equivalent) in AcOH (1.00 mL) and MeOH (10.0 mL), Pd / C (1.65 g, 10%) was added. The mixture was degassed three times with H2, and then stirred under H2 at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (C18 column, H2O (10 mmol / L NH4HCO3)-ACN) to obtain the title compound.

[0332] LCMS: 195.9 [M+H] + .

[0333] Step 5. Synthesis of 4-hydroxy-2,3-dihydrofl[2,3-c]pyridine-5-carboxylic acid

[0334] To a stirred solution of methyl 4-hydroxy-2H,3H-flu[2,3-c]pyridine-5-carboxylate (300 mg, 1.54 mmol, 1.00 equivalent) in MeOH (3.00 mL), NaOH (246 mg, 6.15 mmol, 4.00 equivalent) and H2O (3.00 mL) were added at room temperature. The reaction mixture was stirred overnight at 60°C. The mixture was acidified to pH=3 with 1N HCl. The resulting mixture was extracted with RINKAN (3 × 15 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound, which was used directly in the next step without further purification.

[0335] LCMS:181.9[M+H] + .

[0336] Intermediate-11: Methyl 5-methoxy-6-methylpyrimidine-4-carboxylate

[0337] Intermediate -6: 5-hydroxy-6-methylpyrimidine-4-carboxylic acid [ka]

[0338] Step 1: Synthesis of 4-chloro-5-methoxy-6-methylpyrimidine

[0339] To a mixture of 4,6-dichloro-5-methoxypyrimidine (30.00 g, 167.6 mmol, 1.0 equivalent) in THF (300 mL), a 3M MeMgBr solution in diethyl ether (61.45 mL, 184.4 mmol, 1.1 equivalents) was added dropwise at 0°C, and the mixture was stirred at 5°C for 1 hour. The resulting mixture was poured into H2O (200 mL) and extracted with SiO (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by flash silica gel chromatography (SiO / PE eluent) to obtain the title compound.

[0340] LCMS:159.1[M+H] + .

[0341] Step 2: Synthesis of methyl 5-methoxy-6-methylpyrimidine-4-carboxylate (intermediate-11)

[0342] To a mixture of 4-chloro-5-methoxy-6-methylpyrimidine (22.00 g, 138.7 mmol, 1.0 equivalent) in MeOH (250 mL), Pd(dppf)Cl2-CH2Cl2 (6.80 g, 8.32 mmol, 0.06 equivalent) and TEA (28.1 g, 278 mmol, 2.0 equivalent) were added. The reaction mixture was purged with CO (50 psi) and stirred overnight at 50°C. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using siRNA / PE as the eluent) to obtain the title compound.

[0343] LCMS:183.1[M+H] + .

[0344] Step 3: Synthesis of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid

[0345] A mixture of methyl 5-methoxy-6-methylpyrimidine-4-carboxylate (16.00 g, 87.83 mmol, 1.0 equivalent) in aqueous HBr solution (68.5 mL, 68%) was stirred overnight at 50°C. Next, aqueous HI solution (67.2 mL, 56%) was added and the mixture was stirred at 50°C for 6 hours. The reaction mixture was cooled to room temperature, made basic to pH 9 with 50% aqueous NaOH solution at 0°C, and then adjusted to pH 7 with 2 M aqueous HCl solution at 0°C. The mixture was filtered, and the filter cake was dried under vacuum to obtain the title compound, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ ppm 15.96 - 15.12 (m, 1H), 8.37 (s, 1H), 2.34 (s, 3H).

[0346] LCMS:155.1[M+H] + .

[0347] Intermediate-7: 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazole-4-yl)-2-bromopentan-1,3-dione [ka]

[0348] Step 1. Synthesis of 2-methoxyisonicotinoyl chloride

[0349] To a solution of 2-methoxypyridine-4-carboxylic acid (60.00 g, 391.8 mmol, 1 equivalent) in toluene (500 mL), SOCl2 (140 g, 1.18 mol, 85.4 mL, 3 equivalents) was added at 20 °C, and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, washed with DCM (25 ml x 2), and the combined filtrate was concentrated under reduced pressure to obtain the title compound, which was used directly in the next step without purification.

[0350] Step 2. Synthesis of ethyl 2-cyano-2-(2-methoxyisonicotinamide)acetate

[0351] To a solution of ethylamino(cyano)acetate 4-methylbenzenesulfonate (40.61 g, 135.2 mmol, 1 equivalent) in pyridine (70 mL) and DCM (100 mL), 23.20 g, 135.2 mmol, 1 equivalent of 2-methoxypyridine-4-carbonyl chloride in DCM (40 mL) was added at 0°C. The mixture was stirred at 40°C for 1 hour. The reaction mixture was quenched with H2O (100 mL) and extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (EtOH / DCM eluent) to obtain the title compound.

[0352] LCMS:264.1[M+H] + .

[0353] Step 3. Synthesis of ethyl 5-amino-2-(2-methoxypyridine-4-yl)oxazole-4-carboxylate

[0354] Ethyl 2-cyano-2-[(2-methoxypyridine-4-carbonyl)amino]acetate (18.00 g, 68.38 mmol, 1 equivalent) was mixed with TFA (125 g, 1.09 mol, 81.3 mL, 16 equivalents). The mixture was stirred at 40°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with EtOH (40 ml) at 0°C for 5 minutes, filtered, and the filter cake was washed with EtOH (20 ml x 2) and MTBE (20 ml). The mixture was then dried under reduced pressure to obtain the title compound.

[0355] 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.26 (d, 1H), 7.67 (s, 2H), 7.31 (d, 1H), 7.01 (s, 1H), 4.24 (q, 2H), 3.90 (s, 3H), 1.28 (t, 3H).

[0356] LCMS:264.0[M+H] + .

[0357] Step 4. Synthesis of ethyl 5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazole-4-carboxylate

[0358] To a solution of ethyl 5-amino-2-(2-methoxy-4-pyridyl)oxazole-4-carboxylate (5.00 g, 19.0 mmol, 1 equivalent) in DMF (50 mL), Cs2CO3 (27.85 g, 85.47 mmol, 4.5 equivalents), KI (315 mg, 1.90 mmol, 0.1 equivalent), and 4-methoxybenzyl chloride (8.92 g, 57.0 mmol, 7.73 mL, 3 equivalents) were added. The reaction mixture was stirred at 110°C for 1 hour. The reaction mixture was poured into H2O (300 mL) and extracted with RINKAN (150 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The title compound was obtained by purifying the residue by flash silica gel chromatography (using SiO / PE as the eluent) and reverse-phase HPLC (C18 column, water (FA)-ACN).

[0359] 1 H-NMR (400 MHz, CDCl3) δ ppm 8.20 (d, 1H), 7.39 (d 1H), 7.22 - 7.14 (m, 5H), 6.87 (d, 4H), 4.70 (s, 4H), 4.38 (q, 2H), 3.96 (s, 3H), 3.81 (s, 6H), 1.39 (t, 3H).

[0360] LCMS:504.2[M+H] + .

[0361] Step 5. Synthesis of 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazol-4-yl)-3-hydroxypenta-2-en-1-one

[0362] To a solution of butan-2-one (752 mg, 10.4 mmol, 933 μL, 2.5 equivalents) in THF (10 mL), LiHMDS (1 M in THF, 10.43 mL, 2.5 equivalents) was added at 0°C under an N2 atmosphere. The reaction mixture was stirred at 25°C for 0.5 hours. Next, ethyl 5-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4-pyridyl)oxazole-4-carboxylate (2.10 g, 4.17 mmol, 1 equivalent) dissolved in THF (10 mL) was added to the mixture. The reaction mixture was stirred at 60°C for 1 hour under an N2 atmosphere. The reaction mixture was poured into a saturated NH4Cl solution (200 mL) and extracted with RINKAN (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The title compound was obtained by purifying the residue by flash silica gel chromatography (using siRNA / PE as the eluent).

[0363] LCMS:530.2[M+H] + .

[0364] Step 6. Synthesis of 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazol-4-yl)-2-bromopentan-1,3-dione

[0365] To a 10 mL solution of 1-[5-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4-pyridyl)oxazol-4-yl]-3-hydroxypenta-2-en-1-one (1.00 g, 1.89 mmol, 1 equivalent) in DCM (10 mL), NBS (269 mg, 1.51 mmol, 0.8 equivalents) was added at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into H₂O (100 mL) and extracted with DCM (60 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound, which was used directly in the next step without purification.

[0366] LCMS:610.1[M+H] + .

[0367] Intermediate-8: 2-(6-(4-(tert-butoxycarbonyl)piperazine-1-yl)-5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[5,4-b]pyridine-4(7H)-yl)acetic acid [ka]

[0368] Step 1. Synthesis of tert-butyl 4-(1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazole-4-yl)-1,3-dioxopentan-2-yl)piperazine-1-carboxylate

[0369] 1-[5-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4-pyridyl)oxazol-4-yl]-2-bromopentan-1,3-dione (intermediate-7) (700 mg, 1.15 mmol, 1 equivalent) and tert-butylpiperazine-1-carboxylate (214 mg, 1.15 mmol, 1 equivalent) were dissolved in THF (7 mL), to which DIEA (298 mg, 2.30 mmol, 401 μL, 2 equivalents) was added. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was poured into H₂O (100 mL) and extracted with SiO (60 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (SiO / PE eluent) to obtain the title compound.

[0370] 1 H-NMR (400 MHz, CDCl3) δ ppm 8.22 (d, 1H), 7.26 (d, 1H), 7.17 (d, 4H), 7.06 (s, 1H), 6.88 (d, 4H), 5.28 (s, 1H), 4.97 - 4.86 (m, 2H), 4.84 - 4.70 (m, 2H), 3.98 (s, 3H), 3.81 (s, 6H), 3.48 - 3.44 (m, 4H), 2.90 - 2.54 (m, 6H), 1.44 (s, 9H), 1.10 (t, 3H).

[0371] LCMS:714.3[M+H] + .

[0372] Step 2. Synthesis of 1-(5-((4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazole-4-yl)-2-(piperazine-1-yl)pentan-1,3-dionetrifluoroacetate

[0373] A solution of tert-butyl 4-[1-[5-[bis[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4-pyridyl)oxazole-4-carbonyl]-2-oxo-butyl]piperazine-1-carboxylate (700 mg, 981 μmol, 1 equivalent) in TFA (7 mL) was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the title compound, which was used directly in the next step without purification.

[0374] LCMS:494.2[M+H] + .

[0375] Step 3. Synthesis of tert-butyl 4-(1-(5-((4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazole-4-yl)-1,3-dioxopentan-2-yl)piperazine-1-carboxylate

[0376] To a 6 mL solution of DCM containing 1-(5-((4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazole-4-yl)-2-(piperazine-1-yl)pentan-1,3-dionetrifluoroacetate (590 mg, 971 μmol, 1 equivalent), DIEA (377 mg, 2.91 mmol, 507 μL, 3 equivalents) and Boc2O (254 mg, 1.17 mmol, 267 μL, 1.2 equivalents) were added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into H2O (50 mL) and extracted by DCM (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethylethanol / PE eluent) to obtain the title compound.

[0377] 1H-NMR (400 MHz, CDCl3) δ ppm 8.23 ​​(d, 1H), 7.76 (s, 1H), 7.36 - 7.28 (m, 2H), 7.14 (s, 1H), 6.92 (d, 2H), 5.00 (s, 1H), 4.62 (d, 2H), 3.99 (s, 3H), 3.82 (s, 3H), 3.45 - 3.49 (m, 4H), 2.79 - 2.47 (m, 6H), 1.43 (s, 9H), 1.10 (t, 3H).

[0378] LCMS: 594.3[M+H] + .

[0379] Step 4. Synthesis of tert-butyl 4-(1-(5-((2-(tert-butoxy)-2-oxoethyl)(4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazole-4-yl)-1,3-dioxopentan-2-yl)piperazine-1-carboxylate

[0380] To a solution of tert-butyl 4-(1-(5-((4-methoxybenzyl)amino)-2-(2-methoxypyridine-4-yl)oxazole-4-yl)-1,3-dioxopentan-2-yl)piperazine-1-carboxylate (460 mg, 775 μmol, 1 equivalent) and tert-butyl 2-bromoacetate (151 mg, 775 μmol, 114 μL, 1 equivalent) in THF (4.6 mL), t-BuOK (348 mg, 3.10 mmol, 4 equivalents) was added. The reaction mixture was stirred at 50°C for 0.5 hours. Next, a second batch of tert-butyl 2-bromoacetate (151 mg, 775 μmol, 114 μL, 1 equivalent) was added to the mixture. The reaction mixture was stirred for a further 0.5 hours at 50°C. Next, the third batch of tert-butyl 2-bromoacetate (151 mg, 775 μmol, 114 μL, 1 equivalent) was added to the mixture, and the mixture was stirred at 50°C for a further 0.5 hours. The reaction mixture was diluted with H2O (50 mL) and extracted using DCM (40 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using siRNA / PE as the eluent) to obtain the title compound.

[0381] 1 H-NMR (400 MHz, CDCl3) δ ppm 8.23 ​​(d, 1H), 7.29 (s, 1H), 7.25 (d, 2H), 7.09 (s, 1H), 6.90 (d, 2H), 5.28 (s, 2H), 4.85 (s, 1H), 4.58 - 4.29 (m, 2H), 3.98 (s, 3H), 3.82 (s, 3H), 3.48 - 3.44 (m, 4H), 2.76 - 2.69 (m, 4H), 2.55 (q, 2H) ,1.44 (s, 9H), 1.42 (s, 9H), 1.09 (t, 3H).

[0382] LCMS:708.4[M+H] + .

[0383] Step 5. Synthesis of trifluoroacetate of 2-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-6-(piperazine-1-yl)oxazolo[5,4-b]pyridine-4(7H)-yl)acetic acid

[0384] A solution of tert-butyl 4-[1-[5-[(2-tert-butoxy-2-oxo-ethyl)-[(4-methoxyphenyl)methyl]amino]-2-(2-methoxy-4-pyridyl)oxazole-4-carbonyl]-2-oxo-butyl]piperazine-1-carboxylate (400 mg, 565 μmol, 1 equivalent) in TFA (4 mL) was stirred at 120 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound, which was used directly in the next step without purification.

[0385] LCMS:414.1[M+H] + .

[0386] Step 6. Synthesis of 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[5,4-b]pyridine-4(7H)-yl)acetic acid

[0387] To a solution of trifluoroacetate salt of 2-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-6-(piperazin-1-yl)oxazolo[5,4-b]pyridine-4(7H)-yl)acetic acid (290 mg, 550 μmol, 1 equivalent) in DCM (3 mL), DIEA (355 mg, 2.75 mmol, 479 μL, 5 equivalents) and (Boc)2O (180 mg, 825 μmol, 190 μL, 1.5 equivalents) were added. The reaction mixture was stirred at 25°C for 0.5 hours. The reaction mixture was poured into H2O (3 mL) and extracted with DCM (4 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (using MeOH / DCM as the eluent) to obtain the title compound.

[0388] LCMS:514.1[M+H] + .

[0389] Intermediate-9: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-6-(piperazine-1-yl)oxazolo[5,4-b]pyridine-4(7H)-yl)acetamide hydrochloride [ka]

[0390] Step 1. Synthesis of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-4,7-dihydrooxazolo[5,4-b]pyridine-6-yl)piperazine-1-carboxylate

[0391] 2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-oxazolo[5,4-b]pyridine-4-yl]acetic acid (80 mg, 0.16 mmol, 1 equivalent) and 2-chloro-4-(trifluoromethyl)aniline (40 mg, 0.20 mmol, 28 μL, 1.3 equivalents) were mixed in pyridine (0.8 mL) and POCl3 (36 mg, 0.23 mmol, 22 μL, 1.5 equivalents) at 0°C. The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The title compound was obtained by purifying the residue by reverse-phase HPLC (C18 column, water (FA)-ACN).

[0392] LCMS:691.3[M+H] + .

[0393] Step 2. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-6-(piperazine-1-yl)oxazolo[5,4-b]pyridine-4(7H)-yl)acetamide hydrochloride

[0394] A solution of tert-butyl 4-[4-[2-[2-chloro-4-(trifluoromethyl)anilino]-2-oxo-ethyl]-5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-oxazolo[5,4-b]pyridine-6-yl]piperazine-1-carboxylate (50 mg, 72 μmol, 1 equivalent) in HCl / 1,4-dioxane (2 M, 0.5 mL) was stirred at 25 °C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound, which was used directly in the next step without purification.

[0395] LCMS:591.2[M+H] + .

[0396] Intermediate -10:5-hydroxy-6-methylpyrimidine-4-carboxylate sodium [ka]

[0397] Step 3. Synthesis of 5-hydroxy-6-methylpyrimidine-4-carboxylate sodium

[0398] To a solution of methyl 5-methoxy-6-methylpyrimidine-4-carboxylate (intermediate-11) (210 g, 1.15 mol, 1 equivalent), HBr (850 mL) was added at 20°C. After the addition, the mixture was stirred at 50°C for 16 hours, and then HI (600 mL) was added at 50°C. The resulting mixture was stirred at 50°C for 6 hours. The reaction mixture was filtered. The filtrate was adjusted to pH 8-9 with an aqueous solution of NaOH (30% in water) at 0-5°C. The mixture was filtered, and the filter cake was dried under reduced pressure to obtain the title compound, which was used directly in the next step without further purification.

[0399] 1 H NMR (400 MHz, CD3OD) δ ppm 8.47 (s, 1H), 2.48 (s, 3H).

[0400] Intermediate-12: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide [ka]

[0401] Step 1. Synthesis of 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0402] To a 200 mL solution of DCM containing 2-chloro-4-(trifluoromethyl)aniline (19.1 g, 97.7 mmol, 1.0 equivalent) and TEA (19.76 g, 195.3 mmol, 2.0 equivalents), a 50 mL solution of DCM containing 2-chloroacetyl chloride (11.03 g, 97.7 mmol, 1.0 equivalent) was added dropwise at 0°C. After addition, the resulting mixture was warmed to room temperature and stirred overnight at room temperature. The reaction mixture was purified by column chromatography using silica gel (with siRNA / PE as the eluent) to obtain the title compound.

[0403] LCMS: 273.9[M+H] + .

[0404] Step 2. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide

[0405] To a solution of 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (7.70 g, 28.3 mmol, 1.0 equivalent) in acetone (60 mL), KI (5.17 g, 31.1 mmol, 1.1 equivalent) was added, and the resulting mixture was stirred at 60°C for 2 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum to obtain the title compound, which was used in the next step without further purification.

[0406] LCMS:363.9[M+H] + .

[0407] Intermediate-13: 2-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-6-(piperazine-1-yl)oxazolo[5,4-b]pyridine-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide hydrochloride [ka]

[0408] Step 1. Synthesis of tert-butyl4-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-4-(2-oxo-2-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)amino)ethyl)-4,7-dihydrooxazolo[5,4-b]pyridine-6-yl)piperazine-1-carboxylate

[0409] To a mixture of 2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-oxazolo[5,4-b]pyridine-4-yl]acetic acid (intermediate-8) (50 mg, 97 μmol, 1 equivalent) and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (37 mg, 195 μmol, 2 equivalents) in DMF (0.5 mL), HATU (74 mg, 195 μmol, 2 equivalents) and DIEA (38 mg, 292 μmol, 51 μL, 3 equivalents) were added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with ELISA (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (using DCM / MeOH as the eluent) to obtain the title compound.

[0410] LCMS:647.3[M+H] + .

[0411] Step 2. Synthesis of 2-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-6-(piperazine-1-yl)oxazolo[5,4-b]pyridine-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide hydrochloride

[0412] A solution of tert-butyl 4-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-4-[2-oxo-2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]ethyl]oxazolo[5,4-b]pyridine-6-yl]piperazine-1-carboxylate (25 mg, 39 μmol, 1 equivalent) in HCl / 1,4-dioxane (2 M, 0.2 mL) was stirred at 25 °C for 0.5 hours. The reaction mixture was directly concentrated under reduced pressure to obtain the title compound, which was used in the next step without further purification.

[0413] LCMS: 547.3[M+H] + .

[0414] Intermediate-14: 2-(6-(4-(tert-butoxycarbonyl)piperazine-1-yl)-5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[4,5-b]pyridine-4(7H)-yl)acetic acid

[0415] Intermediate-15: 2-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-6-(piperazine-1-yl)oxazolo[4,5-b]pyridine-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide hydrochloride [ka] [ka]

[0416] Step 1. Synthesis of tert-butyl 4-(4-(2-ethoxy-2-oxoethyl)-5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-4,7-dihydrooxazolo[4,5-b]pyridine-6-yl)piperazine-1-carboxylate

[0417] To a solution of tert-butyl 4-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-4H-oxazolo[4,5-b]pyridine-6-yl]piperazine-1-carboxylate (intermediate-2) (1.00 g, 2.20 mmol, 1 equivalent) and 2-ethyl bromoacetate (440 mg, 2.63 mmol, 292 μL, 1.2 equivalents) in dioxane (10 mL), DIEA (851 mg, 6.59 mmol, 1.15 mL, 3 equivalents) was added. The mixture was stirred at 100 °C for 0.5 hours. The reaction mixture was diluted with H₂O (200 mL) and extracted with ELISA (250 mL x 2). The combined organic phase was washed with brine (100 mL x 1), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue. The title compound was obtained by purifying the residue by silica gel chromatography (using SiO / PE as the eluent).

[0418] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, 1H), 7.60 (d, 1H), 7.37 (s, 1H), 5.23 (s, 2H), 4.21 (q, 2H), 3.94 - 3.85 (m, 5H), 3.63 (q, 2H), 2.95 - 2.58 (m, 4H), 2.59 - 2.56 (m, 2H), 1.43 (s, 9H), 1.23 (t, 3H), 1.11 (t, 3H).

[0419] LCMS: 542.2[M+H] + .

[0420] Step 2. Synthesis of 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[4,5-b]pyridine-4(7H)-yl)acetic acid

[0421] To a solution of tert-butyl 4-[4-(2-ethoxy-2-oxo-ethyl)-5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-oxazolo[4,5-b]pyridine-6-yl]piperazine-1-carboxylate (180 mg, 332 μmol, 1 equivalent) in EtOH (2 mL), THF (2 mL), and H2O (2 mL), LiOH.H2O (21 mg, 499 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 0.5 hours. The pH of the mixture was adjusted to approximately 4 by dropwise addition of HCl (1 M) at 25°C, and the mixture was extracted with ELISA (5 mL x 3). The combined organic phase was washed with brine (15 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound, which was used directly in the next step without further purification.

[0422] LCMS:514.2[M+H] + .

[0423] Step 3. Synthesis of tert-butyl4-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-4-(2-oxo-2-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)amino)ethyl)-4,7-dihydrooxazolo[4,5-b]pyridine-6-yl)piperazine-1-carboxylate

[0424] To a solution of 2-[6-(4-tert-butoxycarbonylpiperazin-1-yl)-5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-oxazolo[4,5-b]pyridine-4-yl]acetic acid (intermediate-14) (180 mg, 294 μmol, 1 equivalent) and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (110 mg, 589 μmol, 2 equivalents) in DMF (2 mL), DIEA (114 mg, 883 μmol, 154 μL, 3 equivalents) and HATU (224 mg, 589 μmol, 2 equivalents) were added. The mixture was stirred at 25°C for 1 hour. H2O (15 mL) was added to the reaction mixture. The mixture was then extracted with ELISA (15 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (using siRNA / PE as the eluent) to obtain the title compound.

[0425] LCMS:647.3[M+H] +

[0426] Step 4. Synthesis of 2-(5-ethyl-2-(2-methoxypyridine-4-yl)-7-oxo-6-(piperazine-1-yl)oxazolo[4,5-b]pyridine-4(7H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide hydrochloride

[0427] A solution of tert-butyl 4-[5-ethyl-2-(2-methoxy-4-pyridyl)-7-oxo-4-[2-oxo-2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]ethyl]oxazolo[4,5-b]pyridine-6-yl]piperazine-1-carboxylate (180 mg, 278 μmol, 1 equivalent) in HCl / dioxane (2 M, 3.6 mL, 26 equivalents) was stirred at 25°C for 0.2 hours. The mixture was concentrated directly under vacuum to obtain the title compound, which was used directly in the next step without further purification.

[0428] LCMS: 547.2[M+H] + . (Example 2) WRN(BV08)ADP-Glo ​​Assay Protocol

[0429] Bovine skin gelatin (BSG), dimethyl sulfoxide (DMSO), Pluronic F-127, and tris(2-carboxyethyl)phosphine hydrochloride solution (TCEP) were purchased from Sigma-Aldrich (St. Louis, MO) at the highest possible purity. Bicin buffer solution was purchased from Alfa Aesar (Tewksbury, MA), and compound NSC-617145 was purchased from Tocris (Minneapolis, MN). DNA double helixes were synthesized at BGI (Shenzhen, China) and consisted of strand 1 with sequence 5'-GCACTGGCCGTCGTTTTACGGTCG-3' (SEQ ID NO: 1) and strand 2 with sequence 5'-TCCAAGTAAAACGACGGCCAGTGC-3' (SEQ ID NO: 2). The DNA strands were annealed by heating to 95°C for 5 minutes and then slowly cooling to room temperature. Using a LabCyte Echo 550 (Agilent; Santa Clara, CA), the compound in 100% DMSO (0.1 μl) was spotted onto a 384-well white polystyrene Optiplate-384 (Perkin Elmer; Waltham, MA) assay plate. For maximum signal control, DMSO (0.1 μl) was added to rows A-H of column 12 and rows I-P of column 24. For minimum signal control (100% inhibition), compound NSC-617145 (0.1 μl) was added to rows I-P of column 12 and rows A-H of column 24. The compound / DMSO mixture was pre-incubated at 25°C for 15 minutes in assay buffer containing 20 mM bicin (pH=7.5), 1 mM MgCl2, 10 mM KCl, 0.1% Pluronic F-127, 0.005% BSG, and 1 mM TCEP, along with 5 μl of 2× WRN (BV08) prepared as described below. The reaction was initiated by adding the 2× substrate mixture to 5 μl of assay buffer and incubated at 25°C for 60 minutes. The final concentrations of the assay components were 0.15 nM WRN, 5 μM ATP, and 0.1 nM DNA double strand. The final DMSO concentration was 1%, and the reference compound concentration (NSC-617145) used as the minimum signal control was 20 μM.The reaction was stopped as instructed by adding the ADP-Glo ​​kit component (Promega; Madison, WI), and the relative luminescence unit (RLU) was read using an Envision 2104 (Perkin Elmer; Waltham, MA). Calculation of % inhibition: %INH=(RLU MAX-RLU sample) / (RLU MAX-RLU MIN))×100 In the formula, RLU = relative luminescence unit, sample = signal in the sample well, and MIN and MAX are the minimum and maximum signal references, respectively. 4-parameter IC 50 Fitted type: Y = Bottom + (Top - Bottom) / (Slope of 1 + (IC50 / X)^Hill) In the formula, top and bottom are usually variable, but in the three-parameter fitting, they may be fixed to 100 or 0, respectively. Y is the % inhibition and X is the compound concentration. WRN protein synthesis

[0430] Molecular biology and virogenesis. DNA encoding human Werner helicase (Uniprot Q14191, amino acids 517-1235 including the L1074F point mutation) was generated by codon optimization for E. coli expression and subcloned into a pFastBac vector with a TEV-cleavable 8xHis tag (WRN-BV08). Baculoviruses derived from the expression plasmid WRN-BV08 were generated by transfection and amplification according to the manufacturer's instructions.

[0431] Gene sequence of WRN-BV08[pFastBac1-WRN-(517-1235 L1074F)-TEV-8His] (Sequence ID 3)

[0432] Protein sequence of WRN-BV08[pFastBac1-WRN-(517-1235 L1074F)-TEV-8His] (SEQ ID NO: 4) MNEGEEDDDKDFLWPAPNEEQVTCLKMYFGHSSFKPVQWKVIHSVLEERRDNVAVMATGYGKSLCFQYPPVYVGKIGLVISPLISLMEDQVLQLKMSNIPACFLGSAQSENVLTDIKLGKYRIVYVTPEYCSGNMGLLQQLEADIGITLIAVDEAHCISEWGHDFRDSFRKLGSLKTALPMVP IVALTATASSSIREDIVRCLNLRNPQITCTGFDRPNLYLEVRRKTGNILQDLQPFLVKTSSHWEFEGPTIIYCPSRKMTQQVTGELRKLNLSCGTYHAGMSFSTRKDIHHRFVRDEIQCVIATIAFGMGINKADIRQVIHYGAPKDMESYYQEIGRAGRDGLQSSCHVLWAPADINLNRHLLTE IRNEKFRLYKLKMMAKMEKYLHSSRCRRQIILSHFEDKQVQKASLGIMGTEKCCDNCRSRLDHCYSMDDSEDTSWDFGPQAFKLLSAVDILGEKFGIGLPILFLRGSNSQRLADQYRRHSLFGTGKDQTESWWKAFSRQLITEGFLVEVSRYNKFMKICALTKKGRNWLHKANTESQSLILQAN EELCPKKFLLPSSKTVSSGTKEHCYNQVPVELSTEKKSNLEKLYSYKPCDKISSGSNISKKSIMVQSPEKAYSSSQPVISAQEQETQIVLYGKLVEARQKHANKMDVPPAILATNKILVDMAKMRPTTVENVKRIDGVSEGKAAMLAPLLEVIKHFCQTNSVQTDLFSSENLYFQGHHHHHHHH

[0433] Sf9 cells grown in SF900II medium were infected with 1:200 WRN-BV08P2 virus and incubated at 27°C for 72 hours for protein expression. WRN proteins were purified using the following protocol: The cell pellet was thawed and resuspended in Buffer A (50 mM Tris, pH 7.5, 500 mM NaCl, 1 mM TCEP, 10% glycerol) supplemented with 0.5% CHAPS, 1 mM PMSF, 1 μg / ml leupeptin, 1 μg / ml pepstatin, Pierce Universal nuclease, and a cocktail tablet. The clarified lysate was loaded onto a Ni Sepharose® Excel column, washed with Buffer A, and the bound proteins were eluted using Buffer A supplemented with 300 mM imidazole. The eluted proteins were dialyzed against Buffer A and digested overnight at 4°C using a His-tagged TEV (1:5 ratio). After adding ZnCl2 to the sample at a final concentration of 15 μM, the sample was loaded onto a second Ni Sepharose® Excel column. Untagged WRN proteins were eluted from the column with buffer A supplemented with 20 mM imidazole, dialyzed overnight in buffer B (50 mM Tris, pH 7.5, 1 mM TCEP, 10% glycerol) supplemented with 150 mM NaCl, and loaded onto a heparin column. Proteins were eluted using a stepwise gradient of buffer B supplemented with 150 mM, 200 mM, 300 mM, and 500 mM NaCl. The WRN-containing fractions were pooled and concentrated, then loaded into buffer C (20 mM HEPES, pH 7.5, 250 mM NaCl, 0.25 mM TCEP, 2.5% glycerol) using a HiLoad 16 / 600 Superdex® 200 pg column (GE Healthcare) for size exclusion chromatography.

[0434] ICs obtained for the test compound 50 The results are shown in Table 3 below. IC 50 Compounds with a concentration of less than or equal to 0.005 μM are denoted as "A". 50 Compounds with a concentration higher than 0.005 μM and less than or equal to 0.05 μM are denoted as "B".50 Compounds with a concentration higher than 0.05 μM and less than or equal to 0.1 μM are denoted as "C". 50 Compounds with a concentration higher than 0.1 μM or equal to 0.5 μM are denoted as "D". [Table 3] (Example 3) A method for determining the effect of p21 induction on cells.

[0435] Colon cancer cell lineage HCT116 was obtained from ATCC and cultured in McCoy's 5A medium (Gibco 16600108) maintained at 37°C under 5% CO2, supplemented with 10% FBS (Transgene FS201-02) and 100 units / mL of penicillin-streptomycin (Gibco 15140122). On the day of seeding, 2,000 cells in 30 μL of culture medium per well were plate-cultured in a poly-D-lysine 384-well black clear plate (Biocoat 356663) and incubated overnight at 37°C under 5% CO2. The following day, the compounds were serially diluted in DMSO to obtain a total of 11 test concentrations. The typical starting concentration of each compound was 10 μM after a 2-fold dilution. Next, 150 nL of diluted compound was added in a double chain to the assay plate using Echo 655 (Labcyte). The plate was centrifuged at 500 RPM for 1 minute, and then incubated at 37°C for 24 hours under 5% CO2. After 24 hours, the medium was removed, and the cells were fixed by adding 40 μL of 4% paraformaldehyde solution to each well and incubated at room temperature for 20 minutes. Next, the plate was washed four times using a microplate washer with 100 μL of washing buffer per well (PBS containing 0.1% Tween®-20). Then, 30 μL of ice-cold methanol was added to each well, and the plate was incubated at -20°C for 10 minutes. The plates were washed four times using a microplate washer with 100 μL of washing buffer per well, then 30 μL of blocking buffer per well (Intercept PBS blocking buffer (LI-COR927-70001), containing 0.05% Tween®-20) was added, and the plates were incubated at room temperature for 2 hours with shaking.Next, 20 μL of primary antibody solution ((1:1000 diluted p21 Waf1 / CIP(12D1) rabbit mAb (Cell Signaling Technologies 2947) and 1:2000 diluted GAPDH(D4C6R) mouse mAb (Cell Signaling Technologies 97166) in blocking buffer) was added to each test well, and the plate was left overnight at 4°C. The following day, the plate was washed five times for 5 minutes each time with 100 μL of washing buffer per well using a microplate washer. Next, 20 μL of secondary antibody (1:2000 dilution in blocking buffer of IRDye 680CW goat anti-mouse IgG(H+L) (LI-COR 926-68070) and 1:2000 dilution in blocking buffer of IRDye 800CW goat anti-rabbit IgG(H+L) (LI-COR 926-32211)) was added to each well, and the plates were stored at room temperature in the dark for 2 hours with shaking. Then, using a microplate washer, the plates were washed four times with 100 μL of washing buffer per well. Finally, the p21 signal and GAPDH signal were read and quantified at 800 nm and 700 nm, respectively, using a LI-COR Odyssey CLx imaging system. Each plate contained either a DMSO control (low control) or an internal reference WRN inhibitor (high control). For quantification, the 800nm / 700nm ratio was calculated for each well to obtain the p21 induction factor, and then the activation rate for each compound well was calculated as follows: ((100 × (ratio of compound wells - ratio of low control) / (ratio of high control - ratio of low control)). The EC50 values ​​for each compound were generated after fitting a nonlinear regression curve using commercially available software.

[0436] The resulting EC obtained for the test compound 50 The results are shown in Table 4 below. EC 50 Compounds with a concentration of less than or equal to 0.50 μM are denoted as "A". EC 50 Compounds with a concentration higher than 0.50 μM and less than or equal to 2.00 μM are denoted as "B". EC 50Compounds with a concentration higher than 2.00 μM and less than or equal to 5.00 μM are denoted as "C". 50 Compounds with a concentration higher than 5.00 μM are denoted as "D". [Table 4]

Claims

1. Compounds of formula I'' or pharmaceutically acceptable salts thereof: 【Chemistry 128】 [In the formula, ring A is, a) A 4-7 member saturated or partially unsaturated divalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated divalent bicyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). This represents, Ring A consists of 0 to 4 independently selected R Ａ Substituting with substituents, Y and Z are selected from N and O, respectively, and either Y is N and Z is O, or Y is O and Z is N. 【Chemistry 129】 represents a single or double bond, and the five-membered ring containing Z and Y is aromatic. L is -C(O)-, -S(O)-, -S(O) ２ - and 【Chemistry 130】 A linker selected from, R １ (a) to (e) a) halogen, C １ ~C ６ alkyl, halo C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, C １ ~C ６ alkoxy and C ３ ~C ６ a 5- to 6-membered monocyclic heteroaryl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted by 1 to 3 groups independently selected from Ａ and further substituted by 0 to 3 independently selected R １ a 5- to 6-membered monocyclic heteroaryl, b) C １ ~C ６ aliphatic, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy and C ３ ~C ６ A 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with one or two groups independently selected from cycloalkoxy, wherein 0-3 independently selected R Ａ A 9-10 member bicyclic heteroaryl, further substituted by c) C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy and C ３ ~C ６ A 4- to 7-membered saturated or partially unsaturated monocyclic heterocycline (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with one or two groups independently selected from cycloalkoxy and -OR, wherein 0 to 3 independently selected R groups Ａ A 4-7 member saturated or partially unsaturated monocyclic heterocycline, further substituted by d) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system selected from carbocyclyls and heterocyclyls (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R Ａ A 4- to 12-membered saturated or partially unsaturated bicyclic ring system that is substituted by, and e) H, halogen, C １ ~C ６ aliphatic, C ３ ~C ７ Cycloalkyl, C １ ~C ６ Alkylene-OC １ ~C ６ Alkyl, -CN, -OR, -NR １０ R １１ , -C(O)NR １０ R １１ ien-CH ２ NR １０ R １１ , -SO ２ R １２ (C １ ~C ６ aliphatic, C ３ ~C ７ Cycloalkyl or C １ ~C ６ Alkylene-OC １ ~C ６ Alkyl is 0 to 5 independently selected R Ａ (Replaced by) One of the following will be selected: R １０ H, C １ ~C ６ Faliphatic, Halo C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, Halo C ３ ~C ６ Cycloalkyl, -C(O)C ３ ~C ６ Cycloalkyl, -C(O)C １ ~C ６ Alkyl or R Ａ A 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted by one or two groups independently selected from the above, R １１ H, C １ ~C ６ Aliphatic or C ３ ~C ６ It is either cycloalkyl or R １０ and R １１ These combine to form halogen, -OH, -CN, C １ ~C ４ Alkoxy and Halo C １ ~C ４ A 5-6 membered ring may be formed, optionally substituted with one, two, or three substituents independently selected from the alkoxy. R １２ is optionally substituted by one or two groups independently selected from C １ -C ６ aliphatic, C ３ -C ６ cycloalkyl or halogen, C １ -C ６ aliphatic, halo C １ -C ６ alkyl, C １ -C ６ alkoxy, C ３ -C ６ cycloalkyl and C ３ -C ６ cycloalkoxy, and is a 5- to 6-membered heteroaryl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted by one or two such groups R Ａ These include optionally substituted phenyl, optionally substituted 5-6 membered heteroaryls (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclines (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, and optionally substituted C １ ~C ６ Aliphatic, hydroxy-C １ ~C ６ Alkyl, Halo C １ ~C ６ Alkyl, substituted C as needed ３ ~C ６ Cycloalkyl, Halo C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, C ３ ~C ６ Cycloalkoxy, Halo C ３ ~C ６ Cycloalkoxy, C １ ~C ６ Alkylene-OC １ ~C ６ Alkyl, -CN, -NO ２ , oxo, -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -S(O)NR ２ , -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)C(NR)NR ２ , -N(R)S(O) ２ NR ２ , and -N(R)S(O) ２ Selected independently from the group consisting of R, R ２ C(R) Ｂ ) ２ C(O)N(R)R ２Ａ , C(R Ｂ ) ２ C(R Ｂ ) ２ C(O)N(R)R ２Ａ , C(R Ｂ ) ２ C(R Ｂ ) ２ N(R)C(O)N(R)R ２Ａ and C(R Ｂ ) ２ C(R Ｂ ) ２ N(R)C(O)R ２Ａ Selected from, R Ｂ is hydrogen, -CH ３ and -CH ２ CH ３ Either they are independently selected from each occurrence, or two R Ｂ Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. R ２Ａ The ring is a phenyl, pyridyl, cubanyl, a 4- to 8-membered saturated or partially unsaturated monocyclic ring, a 5, 6, 7, 8, 9, 10, 11, or 12-membered saturated or partially unsaturated bridged ring, condensed ring, or spirocyclic ring, wherein the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged ring, condensed ring, or spirocyclic ring, contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the phenyl, pyridyl, cubanyl, a saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged ring, condensed ring, or spirocyclic ring contains halogens, C １ ~C ４ Faliphatic, Halo C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, Halo C ３ ~C ６ Cycloalkyl, -OH, -CN, C １ ~C ４ Alkoxy, Halo C １ ~C ４ Alkoxy, C ３ ~C ６ Cycloalkoxy, Halo C ３ ~C ６ Cycloalkoxy and -SF ５ The rings are substituted as needed by one, two, or three substituents independently selected from each of the following: or two substituents on adjacent atoms of the phenyl or pyridyl ring, together with the adjacent atom, form a 4- to 7-membered carbocycline condensed to the phenyl or pyridyl ring; or two substituents on adjacent atoms of the phenyl or pyridyl ring, together with the adjacent atom, form a 4- to 7-membered heterocycline condensed to the phenyl or pyridyl ring (having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur); the 4- to 7-membered carbocycline or 4- to 7-membered heterocycline is substituted by 0 to 5 independently selected halogens; and two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridging ring, fused ring, or spirocyclic ring, are as follows: - Saturated or partially unsaturated carbocyrills of 3 to 7 members, which are substituted as needed, and - 4-7 member saturated or partially unsaturated heterocyclines having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted. They form a cyclic group selected from, or R ２Ａ These are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are halogens, C, etc. １ ~C ４ Faliphatic, Halo C １ ~C ４ They are optionally substituted with one, two, or three substituents independently selected from alkyl and -OH groups. R ３ is hydrogen, C １ ~C ４ aliphatic, C ３ ~C ５ Cycloalkyl, C １ ~C ４ Alkoxy, -NHR ３Ａ , -N(R ３Ａ ) ２ or C １ ~C ４ These are alkylthio groups, and apart from hydrogen, they each consist of -OH, 1 to 5 independently selected halogens, -OR, and -C(O)NR. １０ R １１ Alternatively, it may be replaced as needed with N(R)C(O)R. R ３Ａ These are C １ ~C ４ Each alkyl group is independently selected upon its appearance. R ４ is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6 membered heteroaryl has 0-5 R Ａ Substituting with or two substituents on adjacent atoms of the phenyl or the first 5-6 membered heteroaryl together with the adjacent atoms to form a 4-7 membered carbocyclyl, 4-7 membered heterocyclyl or second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur) condensed on the phenyl or the first 5-6 membered heteroaryl, the 4-7 membered carbocyclyl, 4-7 membered heterocyclyl or second 5-6 membered heteroaryl having 0-3 R Ａ It is replaced by, or R ４ C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy or C ３ ~C ６ These are cycloalkyl compounds, and these are halogen, -CN, -OH, oxo, and NH, respectively. ２ , C １ ~C ４ Alkyl, C １ ~C ４ Substituted with 0 to 3 groups independently selected from alkoxys, optionally substituted 5-6 membered heterocyclines, and optionally substituted 5-6 membered heterocyclyloxys, Each R is independently replaced by hydrogen, or C as needed. １～６ An aliphatic group, optionally substituted phenyl, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring, optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or optionally substituted 5- to 6-membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or Two R groups on the same atom, together with the same atom, form a 4- to 7-membered saturated ring, a 4- to 7-membered partially unsaturated ring, or a 5- to 6-membered heteroaryl ring, which may be substituted as needed (the 4- to 7-membered saturated ring and the 4- to 7-membered partially unsaturated ring have 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 6-membered heteroaryl ring has 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

2. Compounds of formula I or pharmaceutically acceptable salts thereof: 【Chemistry 131】 [In the formula, ring A is, a) A 4-7 member saturated or partially unsaturated divalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated divalent bicyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). This represents, Ring A consists of 0 to 4 independently selected R Ａ Substituting with substituents, Y and Z are selected from N and O, respectively, and either Y is N and Z is O, or Y is O and Z is N. 【Chemistry 132】 represents a single or double bond, and the five-membered ring containing Z and Y is aromatic. L is -C(O)-, -S(O)-, -S(O) ２ - and 【Chemistry 133】 A linker selected from, R １ (a) to (e) a) Halogen, C １ ~C ６ Alkyl, Halo C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy and C ３ ~C ６ A 5-6 member monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from cycloalkoxy, wherein 0-3 independently selected R Ａ Further substitutions are made by 5-6 member monocyclic heteroaryls, b) C １ ~C ６ aliphatic, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy and C ３ ~C ６ A 9-10 membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with one or two groups independently selected from cycloalkoxy, wherein 0-3 independently selected R Ａ A 9-10 member bicyclic heteroaryl, further substituted by c) C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy and C ３ ~C ６ A 4- to 7-membered saturated or partially unsaturated monocyclic heterocycline (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with one or two groups independently selected from cycloalkoxy and -OR, wherein 0 to 3 independently selected R groups Ａ A 4-7 member saturated or partially unsaturated monocyclic heterocycline, further substituted by d) A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system selected from carbocyclyls and heterocyclyls (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R Ａ A 4- to 12-membered saturated or partially unsaturated bicyclic ring system that is substituted by, and e) H, halogen, C １ ~C ６ aliphatic, C ３ ~C ７ Cycloalkyl, C １ ~C ６ Alkylene-OC １ ~C ６ Alkyl, -CN, -OR, -NR １０ R １１ , -C(O)NR １０ R １１ ien-CH ２ NR １０ R １１ , -SO ２ R １２ (C １ ~C ６ aliphatic, C ３ ~C ７ Cycloalkyl or C １ ~C ６ Alkylene-OC １ ~C ６ Alkyl is 0 to 5 independently selected R Ａ (Replaced by) One of the following will be selected: R １０ H, C １ ~C ６ Faliphatic, Halo C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, Halo C ３ ~C ６ Cycloalkyl, -C(O)C ３ ~C ６ Cycloalkyl, -C(O)C １ ~C ６ Alkyl or R Ａ A 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted by one or two groups independently selected from the above, R １１ H, C １ ~C ６ Aliphatic or C ３ ~C ６ It is either cycloalkyl or R １０ and R １１ These combine to form halogen, -OH, -CN, C １ ~C ４ Alkoxy and Halo C １ ~C ４ A 5-6 membered ring may be formed, optionally substituted with one, two, or three substituents independently selected from the alkoxy. R １２ C １ ~C ６ aliphatic, C ３ ~C ６ Cycloalkyl or halogen, C １ ~C ６ Faliphatic, Halo C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C ３ ~C ６ Cycloalkyl and C ３ ~C ６ A 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with one or two groups independently selected from the cycloalkoxy, R Ａ These include optionally substituted phenyl, optionally substituted 5-6 membered heteroaryls (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclines (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, and optionally substituted C １ ~C ６ Aliphatic, hydroxy-C １ ~C ６ Alkyl, Halo C １ ~C ６ Alkyl, substituted C as needed ３ ~C ６ Cycloalkyl, Halo C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, C ３ ~C ６ Cycloalkoxy, Halo C ３ ~C ６ Cycloalkoxy, C １ ~C ６ Alkylene-OC １ ~C ６ Alkyl, -CN, -NO ２ , oxo, -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -S(O)NR ２ , -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)C(NR)NR ２ , -N(R)S(O) ２ NR ２ , and -N(R)S(O) ２ Selected independently from the group consisting of R, R ２ C(R) Ｂ ) ２ C(O)N(R)R ２Ａ And, R Ｂ is hydrogen, -CH ３ and -CH ２ CH ３ Either they are independently selected from each occurrence, or two R Ｂ Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. R ２Ａ These are phenyl or pyridyl, which are halogens and C, respectively. １ ~C ４ Faliphatic, Halo C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, Halo C ３ ~C ６ Cycloalkyl, -OH, -CN, C １ ~C ４ Alkoxy, Halo C １ ~C ４ Alkoxy and -SF ５ The phenyl or pyridyl is optionally substituted with one, two, or three substituents independently selected from the phenyl or pyridyl, or two substituents on adjacent atoms of the phenyl or pyridyl combine with the adjacent atom to form a 4- to 7-membered carbocycline condensed with the phenyl or pyridyl, or two substituents on adjacent atoms of the phenyl or pyridyl combine with the adjacent atom to form a 4- to 7-membered heterocycline condensed with the phenyl or pyridyl (having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the 4- to 7-membered carbocycline or 4- to 7-membered heterocycline is substituted with 0 to 5 independently selected halogens, or R ２Ａ These are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are halogens, C, etc. １ ~C ４ Faliphatic, Halo C １ ~C ４ They are optionally substituted with one, two, or three substituents independently selected from alkyl and -OH groups. R ３ is hydrogen, C １ ~C ４ aliphatic, C ３ ~C ５ Cycloalkyl, C １ ~C ４ Alkoxy, -NHR ３Ａ , -N(R ３Ａ ) ２ or C １ ~C ４ These are alkylthio groups, and apart from hydrogen, they each consist of -OH, 1 to 5 independently selected halogens, -OR, and -C(O)NR. １０ R １１ Alternatively, it may be replaced as needed with N(R)C(O)R. R ３Ａ These are C １ ~C ４ Each alkyl group is independently selected upon its appearance. R ４ is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6 membered heteroaryl has 0-5 R Ａ Substituting with or two substituents on adjacent atoms of the phenyl or the first 5-6 membered heteroaryl together with the adjacent atoms to form a 4-7 membered carbocyclyl, 4-7 membered heterocyclyl or second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur) condensed on the phenyl or the first 5-6 membered heteroaryl, the 4-7 membered carbocyclyl, 4-7 membered heterocyclyl or second 5-6 membered heteroaryl having 0-3 R Ａ It is replaced by, or R ４ C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy or C ３ ~C ６ These are cycloalkyl compounds, and these are halogen, -CN, -OH, oxo, and NH, respectively. ２ , C １ ~C ４ Alkyl, C １ ~C ４ Substituted with 0 to 3 groups independently selected from alkoxys, optionally substituted 5-6 membered heterocyclines, and optionally substituted 5-6 membered heterocyclyloxys, Each R is independently replaced by hydrogen, or C as needed. １～６ An aliphatic group, optionally substituted phenyl, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring, optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or optionally substituted 5- to 6-membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or Two R groups on the same atom, together with the same atom, form a 4- to 7-membered saturated ring, a 4- to 7-membered partially unsaturated ring, or a 5- to 6-membered heteroaryl ring, which may be substituted as needed (the 4- to 7-membered saturated ring and the 4- to 7-membered partially unsaturated ring have 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 5- to 6-membered heteroaryl ring has 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

3. One of the following formulas: 【Chemistry 134】 [In the formula, R ４ The first option is selected from a), b), and c): a) R ４ teeth, 【Chemistry 135】 Ring B is selected from the group consisting of, * represents a bond point to L attached to ring A in formula I or I'', where L is -C(O)-. R ４Ａ , R ４Ｂ , R ４Ｃ , R ４Ｄ , R ４Ｅ and R ４Ｆ Any substituent present on ring B selected from the above is hydrogen; halogen; -OH; -CN; C １ ~C ４ Alkyl; C ２ ~C ４ Alkenyl; C ２ ~C ４ Alkinyl; C １ ~C ４ Alkoxy; Halo C １ ~C ４ Alkyl; -OH, -OCH ３ or -OCH ２ CH ３ C is replaced by １ ~C ３ Alkyl; Halo C １ ~C ４ Alkoxy; C ３ ~C ６ Cycloalkyl; C ３ ~C ６ Cycloalkoxy; and NR １３ R １４ They are either selected independently from each other, or R ４Ａ and R ４Ｂ These intervening atoms bond together to form a 4-7 member optionally substituted carbocyryl, 4-7 member optionally substituted heterocyclyl, or 5-6 member optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, R ４Ｃ , R ４Ｄ , R ４Ｅ and R ４Ｆ Any substituent present on ring B selected from the above is hydrogen; halogen; -OH; -CN; C １ ~C ４ Alkyl; C ２ ~C ４ Alkenyl; C ２ ~C ４ Alkinyl; Halo C １ ~C ４ Alkyl; -OH, -OCH ３ or -OCH ２ CH ３ C is replaced by １ ~C ３ Alkyl; Halo C １ ~C ４ Alkoxy; C ３ ~C ６ Cycloalkyl; C ３ ~C ６ Cycloalkoxy; and NR １３ R １４ They are either selected independently from each other, or R ４Ｂ and R ４Ｃ These intervening atoms bond together to form a 4-7 member optionally substituted carbocyryl, 4-7 member optionally substituted heterocyclyl, or 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, R ４Ａ , R ４Ｄ , R ４Ｅ and R ４Ｆ Any substituent present on ring B selected from the above is hydrogen; halogen; -OH; -CN; C １ ~C ４ Alkyl; C ２ ~C ４ Alkenyl; C ２ ~C ４ Alkinyl; Halo C １ ~C ４ Alkyl; -OH, -OCH ３ or -OCH ２ CH ３ C is replaced by １ ~C ３ Alkyl; Halo C １ ~C ４ Alkoxy; C ３ ~C ６ Cycloalkyl; C ３ ~C ６ Cycloalkoxy; and NR １３ R １４ They are either selected independently from each other, or R ４Ｃ and R ４Ｄ These intervening atoms bond together to form a 4-7 member optionally substituted carbocyryl, 4-7 member optionally substituted heterocyclyl, or 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, R ４Ａ , R ４Ｂ , R ４Ｅ and R ４Ｆ Any substituent present on ring B selected from the above is hydrogen; halogen; -OH; -CN; C １ ~C ４ Alkyl; C ２ ~C ４ Alkenyl; C ２ ~C ４ Alkinyl; Halo C １ ~C ４ Alkyl; -OH, -OCH ３ or -OCH ２ CH ３ C is replaced by １ ~C ３ Alkyl; Halo C １ ~C ４ Alkoxy; C ３ ~C ６ Cycloalkyl; C ３ ~C ６ Cycloalkoxy; and NR １３ R １４ They are either selected independently from each other, or R ４Ｅ is a halogen or -OH, and R ４Ａ , R ４Ｂ , R ４Ｃ and R ４Ｄ is hydrogen; halogen; -CN; C １ ~C ４ Alkyl; C ２ ~C ４ Alkenyl; C ２ ~C ４ Alkinyl; Halo C １ ~C ４ Alkyl; -OH, -OCH ３ or -OCH ２ CH ３ C is replaced by １ ~C ３ Alkyl; Halo C １ ~C ４ Alkoxy; C ３ ~C ６ Cycloalkyl; C ３ ~C ６ Cycloalkoxy; and NR １３ R １４ They are either selected independently from each other, or R ４Ｅ and R ４Ａ These intervening atoms join together to form a 5-6 membered, optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, R ４Ｂ , R ４Ｃ and R ４Ｄ is hydrogen; halogen; -OH; -CN; C １ ~C ４ Alkyl; C ２ ~C ４ Alkenyl; C ２ ~C ４ Alkinyl; Halo C １ ~C ４ Alkyl; -OH, -OCH ３ or -OCH ２ CH ３ C is replaced by １ ~C ３ Alkyl; Halo C １ ~C ４ Alkoxy; C ３ ~C ６ Cycloalkyl; C ３ ~C ６ Cycloalkoxy; and NR １３ R １４ They are either selected independently from each other, or R ４Ｆ and R ４Ａ These intervening atoms join together to form a 5-6 membered, optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring B, R ４Ｂ , R ４Ｃ and R ４Ｄ Any substituent present on ring B selected from the above is hydrogen; halogen; -OH; -CN; C １ ~C ４ Alkyl; C ２ ~C ４ Alkenyl; C ２ ~C ４ Alkinyl; Halo C １ ~C ４ Alkyl; -OH, -OCH ３ or -OCH ２ CH ３ C is replaced by １ ~C ３ Alkyl; Halo C １ ~C ４ Alkoxy; C ３ ~C ６ Cycloalkyl; C ３ ~C ６ Cycloalkoxy; and NR １３ R １４ Each is independently selected from, R １３ These are hydrogen, and -OH, -OCH ３ or -OCH ２ CH ３ Replace as needed with OC １ ~C ４ Each alkyl group is independently selected upon its appearance. R １４ is hydrogen, or NR １３ R １４ This forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, and the heterocyclic ring is -CH ３ It is replaced as needed by; or b) R ４ This is a five-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and zero, one, two, or three additional ring nitrogen atoms), wherein the heteroaryl is a halogen, -OH, -CN, C １ ~C ４ Alkyl, Halo C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl and C １ ~C ４ It is substituted with 0 to 4 groups independently selected from the alkoxy, or c) R ４ C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy or C ３ ~C ６ These are cycloalkyl compounds, and they are halogen, -CN, -OH, and C respectively. １ ~C ４ Alkyl, C １ ~C ４ [Substituted with 0 to 3 groups independently selected from alkoxys, optionally substituted 5-6 membered heterocyclines, and optionally substituted 5-6 membered heterocyclyloxys.] A compound or pharmaceutically acceptable salt thereof according to claim 1 or claim 2.

4. One of the following formulas: 【Transformation 136】 A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.

5. Ring A is 【Chemistry 137】 From which ring A is selected, and 0 to 4 independently selected R Ａ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, substituted with a substituent.

6. R １ However, halogen, C １ ~C ６ Alkyl, C ２ ~C ４ Alken, C ２ ~C ４ Alkyne, CN, -OR １０ , -NR １０ R １１ , -C(O)NR １０ R １１ ien-CH ２ NR １０ R １１ , -SO ２ R １２ Or a 3-7 membered carbocyclyl, C １ ~C ６ Alkyl, C ２ ~C ４ Alken, C ２ ~C ４ Alkynes and 3- to 7-membered carbocyclyls are halogens, C ３ ~C ６ Cycloalkyl, Halo C ３ ~C ６ Cycloalkyl, -OH, -CN, C １ ~C ４ Alkoxy and Halo C １ ~C ４ The compound according to any one of claims 1 to 5, which is substituted with 0 to 3 substituents independently selected from the alkoxy.

7. R １ However, halogen, C １ ~C ６ Alkyl, Halo C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy and C ３ ~C ６ A 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is optionally substituted with 1-3 groups independently selected from cycloalkyl, wherein the 5-6 membered heteroaryl is substituted with 0-3 independently selected R Ａ The compound according to any one of claims 1 to 5, further substituted by...

8. R １ However, C １ ~C ４ Substituted with alkoxy and containing 0 to 2 R Ａ The compound according to any one of claims 1 to 5, wherein the pyridyl is further substituted by...

9. R １ However, the five-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and zero or one additional ring nitrogen atom), and the five-membered heteroaryl is a halogen, C １ ~C ６ Alkyl, Halo C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy or C ３ ~C ６ Substituted with a cycloalkyl group, and containing 0 to 2 independently selected R groups. Ａ The compound according to any one of claims 1 to 5, further substituted by...

10. R １ but, c) A 5-6 member saturated or partially unsaturated heterocycline (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which contains halogens, oxo, -NR ２ C is replaced as needed. １ ~C ４ Heterocyclines substituted with 0 to 2 groups independently selected from aliphatic, -OR, azetidinyls optionally substituted with one or two independently selected halogens, and pyrrolidinyls optionally substituted with one or two independently selected halogens; or d) A 6-8 member saturated or partially unsaturated bridged bicyclic heterocycline (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein halogens, oxo, -NR ２ C is replaced as needed. １ ~C ４ Heterocyclines substituted with 0 to 2 groups independently selected from aliphatic, -OR, azetidinyls optionally substituted with one or two independently selected halogens, and pyrrolidinyls optionally substituted with one or two independently selected halogens. The compound according to any one of claims 1 to 5.

11. R １ However, the heterocycline is a 5-6 member saturated or partially unsaturated heterocycline (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the heterocycline is halogen, oxo, -NR ２ C is replaced as needed. １ ~C ４ The compound according to any one of claims 1 to 5, substituted with 0 to 2 groups independently selected from azetidinyl, which is aliphatic, -OR, or optionally substituted with one or two independently selected halogens, and pyrrolidinyl, which is optionally substituted with one or two independently selected halogens.

12. R １ but, 【Chemistry 138】 A compound according to any one of claims 1 to 5, selected from the group consisting of the above.

13. R ４ However, ring B has the following structure: 【Chemistry 139】 And, * represents the connection point to L in equation I, R ４Ａ However, hydrogen, halogens, -CH ３ ien-CH ２ CH ３ -F, -CF ２ H, -CF ３ , -OCH ３ , -OCF ３ , -OCH ２ CH ３ or -OCHF ２ And, R ４Ｂ , R ４Ｃ and R ４Ｄ However, hydrogen; halogen; -CN; C １ ~C ４ Alkyl; C ２ ~C ４ Alkenyl; C ２ ~C ４ Alkinyl; Halo C １ ~C ４ Alkyl; -OH, -OCH ３ or -OCH ２ CH ３ C is replaced by １ ~C ３ Alkyl; Halo C １ ~C ４ Alkoxy; C ３ ~C ６ Cycloalkyl; C ３ ~C ６ Cycloalkoxy; and NR １３ R １４ Each is independently selected from, R １３ However, hydrogen, and -OH, -OCH ３ or -OCH ２ CH ３ Replace as needed with OC １ ~C ４ Each alkyl group is independently selected upon its appearance. R １４ However, is it hydrogen, or R １３ and R １４ However, together with the nitrogen atoms to which they are bonded, they form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, and the heterocyclic ring is -CH ３ It is replaced as needed, or R ４ However, the heteroaryl is a five-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and zero, one, two, or three additional ring nitrogen atoms), and the heteroaryl is a halogen, -OH, -CN, C １ ~C ４ Alkyl, Halo C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl and C １ ~C ４ Substituted by 0 to 4 groups independently selected from the alkoxy, The compound according to any one of claims 1 to 12.

14. R ４ but, [Chemistry 140] And, * represents the connection point to L in equation I, R ４Ａ However, hydrogen, halogens, -CH ３ ien-CH ２ CH ３ -F, -CF ２ H, -CF ３ , -OCH ３ , -OCF ３ , -OCH ２ CH ３ or -OCHF ２ And, R ４Ｂ and R ４Ｃ However, hydrogen; -CN; C １ ~C ４ Alkyl; C ２ ~C ４ Alkenyl; C ２ ~C ４ Alkinyl; Halo C １ ~C ４ Alkyl; -OH, -OCH ３ or -OCH ２ CH ３ C is replaced by １ ~C ３ Alkyl; Halo C １ ~C ４ Alkoxy; C ３ ~C ６ Cycloalkyl; C ３ ~C ６ Cycloalkoxy; and NR １３ R １４ Each is independently selected from, R １３ However, hydrogen, and -OH, -OCH ３ or -OCH ２ CH ３ Replace as needed with OC １ ~C ４ Each alkyl group is independently selected upon its appearance. R １４ However, is it hydrogen, or R １３ and R １４ However, together with the nitrogen atoms to which they are bonded, they form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, and the heterocyclic ring is -CH ３ Replaced as needed by The compound according to any one of claims 1 to 12.

15. R ４ However, the heteroaryl is a five-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and zero, one, two, or three additional ring nitrogen atoms), and the heteroaryl is a halogen, -OH, -CN, C １ ~C ４ Alkyl, Halo C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl and C １ ~C ４ The compound according to any one of claims 1 to 12, which is substituted with 0 to 4 groups independently selected from the alkoxy.

16. R ４ The heteroaryl is a five-membered heteroaryl (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional ring nitrogen atoms) selected from the group consisting of imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl, wherein the heteroaryl is a halogen, -OH, -CN, C １ ~C ４ Alkyl, Halo C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl and C １ ~C ４ The compound according to any one of claims 1 to 12, which is substituted with 0 to 4 groups independently selected from the alkoxy.

17. R ４ However, -OH or C １ ~C ４ The compound according to claim 16, wherein the isoxazolyl is substituted with an alkoxy.

18. R ４ but, 【Chemistry 141】 【Chemistry 142】 The compound according to any one of claims 1 to 12.

19. R ２Ａ However, -CF ３ Phenyl containing substituents, or -CF ３ The compound according to any one of claims 1 to 18, wherein the pyridyl contains a substituent.

20. R ２ but, 【Chemistry 143】 The compound according to any one of claims 1 to 18.

21. R ２ but, 【Chemistry 144】 The compound according to claim 1, or any one of claims 3 to 18.

22. R ３ However, C １ ~C ４ Alkyl or C ３ ~C ５ A compound according to any one of claims 1 to 21, wherein it is a cycloalkyl compound.

23. Ring A, and the 0 to 4 independently selected R in which Ring A is substituted. Ａ The substituent is 【Chemistry 145】 A compound selected from any one of claims 1 to 3 and 6 to 22.

24. Ring A, and the 0 to 4 independently selected R in which Ring A is substituted. Ａ The substituent is 【Chemistry 146】 The compound according to any one of claims 1 to 3 and 6 to 22.

25. Ring A is 【Chemistry 147】 The compound according to any one of claims 1 to 3 and 5 to 22.

26. Ring A is 【Chemistry 148】 The compound according to any one of claims 1 to 3 and 5 to 22.

27. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridine-4-yl)-7-oxoxazolo[4,5-b]pyridine-4(7H)-yl)acetamide.

28. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, and one or more pharmaceutically acceptable carriers.

29. A method for treating cancer in a subject, wherein the cancer is characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), and the method comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27.

30. A method for modulating WRN activity in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27.

31. A method for treating a disorder or disease in a subject that can be treated by WRN inhibition, comprising the step of administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27.

32. A method for inhibiting WRN in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27.

33. The method according to claim 31, wherein the disorder or disease is a cancer characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair mechanism deficiency (dMMR).

34. The method according to claim 33, wherein the cancer characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair mechanism deficiency (dMMR) is selected from colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, and ovarian cancer.

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