WRN inhibitors

Abstract

This disclosure relates to compounds of formula I:(I) and pharmaceutically acceptable salts thereof, and compositions thereof, as well as methods for treating cancer, including those comprising WRN proteins. In another aspect, the present invention provides a method for treating cancer in a subject, more particularly, wherein the cancer is characterized by high-frequency microsatellite instability (MSI-H) or mismatch repair mechanism deficiency (dMMR), and comprises the step of administering to the subject a therapeutically effective amount of a compound of formula I of the present invention. TIFF2026522310000521.tif25164

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 63 / 507,014 filed 8 June 2023; U.S. Provisional Application No. 63 / 519,746 filed 15 August 2023; U.S. Provisional Application No. 63 / 586,952 filed 29 September 2023; U.S. Provisional Application No. 63 / 613,647 filed 21 December 2023; U.S. Provisional Application No. 63 / 566,038 filed 15 March 2024; and U.S. Provisional Application No. 63 / 639,457 filed 26 April 2024, each of which is incorporated herein by reference in its 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 407274-78WRP5_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-frequency 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 compared to chemotherapy. 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] Provides two rings BC, linker L, R 4 And ring A is 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, the biring ring BC is one of the following: [ka] Selected from, [ka] This represents the bonding point to ring A, Ring B is one or two R independently selected from H, halogen, CN, OH, C1-C6 aliphatic, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C3-C6 cycloalkoxy. 1b The C1-C6 aliphatic, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy and C3-C6 cycloalkoxy are each independently and optionally substituted with 1-5 halogens, OH, CN, C1-C6 alkyl or C3-C6 cycloalkyl groups. Ring A is, A 4-7 member saturated or partially unsaturated divalent monocyclic carbocyclylene or a 4-7 member saturated or partially unsaturated divalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 1-4 heteroatoms plus 0 or 1 nitrogen atom); or 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). And, Ring A is a set of 0 to 4 independently selected R Bis substituted by a substituent, -L- is -C(O)-, -S(O)-, -S(O)2- and [Chemical Formula] is a linker selected from R 1a is a 5- to 6-membered heteroaryl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted by 1 to 3 groups independently selected from halogen, C1-C6 aliphatic, C3-C6 cycloalkyl, halo C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, and further substituted by 0 to 3 independently selected R B a 5- to 6-membered heteroaryl further substituted by a 4- to 7-membered saturated or partially unsaturated heterocyclyl (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted by 1 or 2 groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR, and further substituted by 0 to 3 independently selected R B a 4- to 7-membered saturated or partially unsaturated heterocyclyl further substituted by a 4- to 12-membered saturated or partially unsaturated bicyclic ring system, fused, bridged, or spirocyclic, selected from carbocyclyl or 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 B a 4- to 12-membered saturated or partially unsaturated bicyclic ring system, and H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, CN, -OR, -OR 10 -NR 10 R 11 -C(O)NR 10 R 11 -CH2NR10 R 11 or -SO2R 12 (The C1-C6 aliphatic, C3-C7 cycloalkyl or C1-C6 alkylene-O-C1-C6 alkyl groups are 0-5 independently selected R B (Replaced by) Select from, Alternatively, R on an adjacent atom of ring B 1a and one R 1b This means that together with the adjacent ring B atom to which they are bonded, they form a fused cyclic group on ring B, selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the fused cyclic group on ring B has 0-3 independently selected R B It has been replaced by, R 2 C(R C )2C(O)N(R)R 2A And, R 2A The substituents are phenyl or pyridyl, which are optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 aliphatic atoms, halo-C1-C4 alkyl atoms, C3-C6 cycloalkyl atoms, halo-C3-C6 cycloalkyl atoms, -OH, -CN, C1-C4 alkoxy atoms, halo-C1-C4 alkoxy atoms, and -SF5 atoms, wherein two substituents on adjacent atoms of phenyl or pyridyl combine with the adjacent atoms to form a 4-7 membered carbocyclyl condensed to phenyl or pyridyl, and two substituents on adjacent atoms of phenyl or pyridyl combine with the adjacent atoms to form a 4-7 membered heterocyclyl condensed to phenyl or pyridyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the condensed 4-7 membered carbocyclyl or condensed 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogens, or R2A 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 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, 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. R 4 is a 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 B Substituted by, and optionally, two adjacent atoms of the phenyl or first 5-6 membered heteroaryl have two substituents, which together with the adjacent atoms form a cyclic group selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is condensed on the phenyl or first 5-6 membered heteroaryl, and the condensed cyclic group has 0-3 independently selected R B It is replaced by, or R 4These are C1-C4 aliphatic, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each substituted with 0-3 groups independently selected from halogens, -CN, -OH, C1-C4 alkyl groups, C1-C4 alkoxy groups, optionally substituted 5-6 membered heterocyclyl groups, and optionally substituted 5-6 membered heterocyclyloxy groups. R 10 R is H, C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), excluding H. 10 Each of these is one or two independently selected R B It is replaced as needed, R 11 is either H, C1-C6 aliphatic or C3-C6 cycloalkyl, or R 10 and R 11 Together with the nitrogen atom to which they are bonded, they form a 5-6 membered ring which may be substituted as needed with one, two, or three substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxys, and halo-C1-C4 alkoxys. R 12 R is a C1-C6 aliphatic, C3-C6 cycloalkyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), 12 Each of these is optionally substituted with one or two groups independently selected from halogens, C1-C6 aliphatic groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, and C3-C6 cycloalkoxy groups. R BThese 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, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, and C3 Each instance is independently selected from the group consisting of ~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, O(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 C The R is independently selected from hydrogen, -CH3, or -CH2CH3 each time it appears, or two R C Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. 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 cyclic group selected from a 4-7 member saturated ring, a 4-7 member partially unsaturated ring, or a 5-6 member heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which are substituted as needed, and the cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0017] 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.

[0018] In one embodiment, the present disclosure relates to a compound of formula I' or a pharmaceutically acceptable salt thereof: [ka] Provide (In the formula, the biring ring BC is one of the following: [ka] Selected from, [ka] This represents the bonding point to ring A, R 1b Each group is independently selected from H, halogen, CN, OH, C1-C6 aliphatic, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C3-C6 cycloalkoxy, and each of the C1-C6 aliphatic, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C3-C6 cycloalkoxy groups is independently and optionally substituted with 1 to 5 halogens, OH, CN, C1-C6 alkyl, or C3-C6 cycloalkyl groups, and z is 0, 1, or 2. Ring A is, A 4-7 member saturated or partially unsaturated divalent monocyclic carbocyclylene or a 4-7 member saturated or partially unsaturated divalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 1-4 heteroatoms plus 0 or 1 nitrogen atom); or 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). And, Ring A is a set of 0 to 4 independently selected R B Substituting with substituents, -L- is -C(O)-, -S(O)-, -S(O)2- and [ka] A linker selected from, R 1a teeth, 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 halogens, C1-C6 aliphatic groups, C3-C6 cycloalkyl groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, and C3-C6 cycloalkoxy groups, wherein 0-3 independently selected R B Further substitutions are made by 5-6 member heteroaryls, A 4-7 member saturated or partially unsaturated 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 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR, and which has 0-3 independently selected R B A 4-7 member saturated or partially unsaturated heterocycline, further substituted by A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system, selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R B A 4-12 member saturated or partially unsaturated bicyclic ring system that is substituted by, and H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, CN, -OR, -OR 10 , -NR 10 R 11 -C(O)NR 10 R 11 -CH2NR 10 R 11 or -SO2R 12 (The C1-C6 aliphatic, C3-C7 cycloalkyl or C1-C6 alkylene-O-C1-C6 alkyl groups are 0-5 independently selected R B (Replaced by) Select from, Alternatively, R on an adjacent atom of ring B 1a and one R 1b This means that together with the adjacent ring B atom to which they are bonded, they form a fused cyclic group on ring B, selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the fused cyclic group on ring B has 0-3 independently selected R B It has been replaced by, R 2 C(R C )2C(O)N(R)R 2A , C(R C )2C(R C )2C(O)N(R)R 2A , C(R C )2C(R C)2N(R)C(O)N(R)R 2A and C(R C )2C(R C )2N(R)C(O)R 2A Selected from, R 2A The 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 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 -S F5 is optionally substituted with one, two, or three substituents independently selected from F5, where two substituents on adjacent atoms of phenyl or pyridyl optionally form a 4- to 7-membered carbocycline condensed to phenyl or pyridyl, where two substituents on adjacent atoms of phenyl or pyridyl optionally form a 4- to 7-membered heterocycline condensed to phenyl or pyridyl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the condensed 4- to 7-membered carbocycline or condensed 4- to 7-membered heterocycline is substituted with 0 to 5 independently selected halogens, where two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridging ring, condensed ring, or spirocyclic ring are as follows: • 3- to 7-membered saturated or partially unsaturated carbocyclyls, which are substituted as needed, and · A 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted forms an optionally formed cyclic group selected from, or R 2A is 2-benzimidazolyl, 2-naphthyl or 3-quinolinyl, each of which is optionally substituted by one, two or three substituents independently selected from halogen, C 1~4 alkyl and -OH, R 3 is hydrogen, C1-C4 aliphatic, C3-C5 cycloalkyl, C1-C4 alkoxy, -NHR 3A , -N(R 3A )2 or C1-C4 alkylthio, each of which other than hydrogen is optionally substituted by -OH, one to five independently selected halogens, OR, -C(O)NR 10 R 11 or N(R)C(O)R, R 3A is each independently selected from C1-C4 alkyl, R 4 is phenyl or a first 5- to 6-membered heteroaryl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said phenyl or first 5- to 6-membered heteroaryl being substituted by 0 to 5 R B and optionally, two adjacent atoms of said phenyl or first 5- to 6-membered heteroaryl have two substituents, and these two substituents together with said adjacent atoms form a 4- to 7-membered carbocyclyl, 4- to 7-membered heterocyclyl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or second 5- to 6-membered heteroaryl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to the phenyl or first 5- to 6-membered heteroaryl, said fused cyclic group being substituted by 0 to 3 independently selected R B or R 4is C1-C4 aliphatic, C1-C4 alkoxy or C3-C6 cycloalkyl, each of which is independently substituted by 0-3 groups selected from halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclyl and optionally substituted 5-6 membered heterocyclyloxy, R 10 is H, C1-C6 aliphatic, halo C1-C6 alkyl, C3-C6 cycloalkyl, halo C3-C6 cycloalkyl, -C(O)C1-C6 alkyl or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), and R excluding H 10 are each optionally substituted by one or two independently selected R B as appropriate, R 11 is H, C1-C6 aliphatic or C3-C6 cycloalkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached, optionally form a 5-6 membered ring substituted by one, two or three substituents independently selected from halogen, -OH, -CN, C1-C4 alkoxy and halo C1-C4 alkoxy, R 12 is C1-C6 aliphatic, C3-C6 cycloalkyl or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), and R 12 are each optionally substituted by one or two groups independently selected from halogen, C1-C6 aliphatic, halo C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and C3-C6 cycloalkoxy, R BThese 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, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, and C3 Each instance is independently selected from the group consisting of ~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, O(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 C The R is independently selected from hydrogen, -CH3, or -CH2CH3 each time it appears, or two R C Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. 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 cyclic group selected from a 4-7 member saturated ring, a 4-7 member partially unsaturated ring, or a 5-6 member heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which are substituted as needed, and the cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0019] 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.

[0020] In one embodiment, the present disclosure relates to a compound of formula I'' or a pharmaceutically acceptable salt thereof: [ka] Provide (In the formula, the biring ring BC is one of the following: [ka] Selected from, [ka] This represents the bonding point to ring A, R 1b Each group is independently selected from H, halogen, CN, OH, C1-C6 aliphatic, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C3-C6 cycloalkoxy, and each of the C1-C6 aliphatic, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C3-C6 cycloalkoxy groups is independently and optionally substituted with 1 to 5 halogens, OH, CN, C1-C6 alkyl, or C3-C6 cycloalkyl groups, and z is 0, 1, or 2. Ring A is, A 4-7 member saturated or partially unsaturated divalent monocyclic carbocyclylene or a 4-7 member saturated or partially unsaturated divalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 1-4 heteroatoms plus 0 or 1 nitrogen atom); or 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). And, Ring A is a set of 0 to 4 independently selected R B Substituting with substituents, -L- is -C(O)-, -S(O)-, -S(O)2- and [ka] A linker selected from, R 1a teeth, 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 halogens, C1-C6 aliphatic groups, C3-C6 cycloalkyl groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, and C3-C6 cycloalkoxy groups, wherein 0-3 independently selected R B Further substitutions are made by 5-6 member heteroaryls, A 4-7 member saturated or partially unsaturated 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 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR, and which has 0-3 independently selected R B A 4-7 member saturated or partially unsaturated heterocycline, further substituted by A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system, selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R B A 4-12 member saturated or partially unsaturated bicyclic ring system that is substituted by, and H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, CN, -OR, -OR 10 , -NR 10 R 11 -C(O)NR 10 R 11 -CH2NR 10 R 11 or -SO2R 12 (The C1-C6 aliphatic, C3-C7 cycloalkyl or C1-C6 alkylene-O-C1-C6 alkyl groups are 0-5 independently selected R B (Replaced by) Select from, Alternatively, R on an adjacent atom of ring B 1a and one R 1b This means that together with the adjacent ring B atom to which they are bonded, they form a fused cyclic group on ring B, selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the fused cyclic group on ring B has 0-3 independently selected R B It has been replaced by, R 2 C(R C )2C(O)N(R)R 2A , C(R C )2C(R C )2C(O)N(R)R 2A , C(R C )2C(R C)2N(R)C(O)N(R)R 2A and C(R C )2C(R C )2N(R)C(O)R 2A Selected from, R 2A The 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 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 -S F5 is optionally substituted with one, two, or three substituents independently selected from F5, where two substituents on adjacent atoms of phenyl or pyridyl optionally form a 4- to 7-membered carbocycline condensed to phenyl or pyridyl, where two substituents on adjacent atoms of phenyl or pyridyl optionally form a 4- to 7-membered heterocycline condensed to phenyl or pyridyl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the condensed 4- to 7-membered carbocycline or condensed 4- to 7-membered heterocycline is substituted with 0 to 5 independently selected halogens, where two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridging ring, condensed ring, or spirocyclic ring are as follows: • 3- to 7-membered saturated or partially unsaturated carbocyclyls, which are substituted as needed, and • A 4-7 member saturated or partially unsaturated heterocycline having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be substituted as needed. A cyclic group selected from may be formed as needed, 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 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, 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. R 4 is a 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 B Substituted by, and optionally, two adjacent atoms of the phenyl or first 5-6 membered heteroaryl have two substituents, which together with the adjacent atoms form a cyclic group selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is condensed on the phenyl or first 5-6 membered heteroaryl, and the condensed cyclic group has 0-3 independently selected R B It is replaced by, or R 4These are C1-C4 aliphatic, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each substituted with 0-3 groups independently selected from halogens, -CN, -OH, C1-C4 alkyl groups, C1-C4 alkoxy groups, optionally substituted 5-6 membered heterocyclyl groups, and optionally substituted 5-6 membered heterocyclyloxy groups. R 10 R is H, C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), excluding H. 10 Each of these is one or two independently selected R B It is replaced as needed, R 11 is either H, C1-C6 aliphatic or C3-C6 cycloalkyl, or R 10 and R 11 Together with the nitrogen atom to which they are bonded, they form a 5-6 membered ring which may be substituted as needed with one, two, or three substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxys, and halo-C1-C4 alkoxys. R 12 R is a C1-C6 aliphatic, C3-C6 cycloalkyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), 12 Each of these is optionally substituted with one or two groups independently selected from halogens, C1-C6 aliphatic groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, and C3-C6 cycloalkoxy groups. R BThese 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, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, and C3 Each instance is independently selected from the group consisting of ~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, O(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 C The R is independently selected from hydrogen, -CH3, or -CH2CH3 each time it appears, or two R C Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. 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 cyclic group selected from a 4-7 member saturated ring, a 4-7 member partially unsaturated ring, or a 5-6 member heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which are substituted as needed, and the cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0021] 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:

[0022] 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.

[0023] Throughout this specification, and in the examples or claims, the compound structures shown include representations at certain stereocenters, where “or1” is intended to encompass the compound in its pure form as stereochemistry, in which case the stereochemistry at the stereocenter marked “or1” is either the stereochemistry shown in the schematic diagram, or the marked stereocenter has the opposite configuration to that shown in the schematic diagram. In structures having stereocenters with the same label such as “or1”, the relative stereochemistry between the two stereocenters with the label is as illustrated, as in Examples I-39 and I-40. [ka] A stereocenter marked with "abs" is intended to encompass a substance in which the marked stereocenter is of the stereochemistry shown in the schematic diagram. A stereocenter marked with "&1" or "and1" indicates that the compound substance has a mixture of R and S configuration stereoisomers with respect to the marked stereocenter, and that the compound substances are in the same relative configuration with respect to each other if they share the same labeling such as "and1" or "&1" as in Example I-34.

[0024] Throughout this specification and in the examples or claims, compound structures that include the notation "or1" at a particular stereocenter, include other notations that are absolute at a particular stereocenter, and indicate "S" are intended to encompass mixtures of pure compounds as stereochemistry, in which case the stereochemistry at the stereocenter marked "or1" is either the stereochemistry shown in the schematic diagram, or the marked "or1" stereocenter has the opposite stereoconfiguration to that shown in the schematic diagram, and the stereocenter marked "S" is absolute, as in Example (I-122): 2-(2-((1R * ,5S *As shown, it is as follows: )-2-azabicyclo[3.1.0]hexane-2-yl)-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide. [ka]

[0025] 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.

[0026] 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.

[0027] 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)

[0028] 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).

[0029] 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.

[0030] 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.

[0031] 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).

[0032] As used herein, the term "unsaturated" means that a part of it has one or more unsaturated units.

[0033] The term "cubanyl" refers to the substituents of cubane shown below. [ka]

[0034] In this specification, the substituent -Me refers to a methyl group, -CH3.

[0035] 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.

[0036] 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.

[0037] 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]

[0038] Carbocyclylene may be saturated, as in the example shown above, or partially unsaturated, as in the example shown below. [ka]

[0039] 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]

[0040] 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]

[0041] 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]

[0042] 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]

[0043] 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]

[0044] 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.

[0045] 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]

[0046] Further examples below show a carbocyclyl moiety condensed to ring E 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 on ring E." Therefore, "ring E" 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 E. Any further fused rings resulting from the substituents of ring E are described as "fused to ring E". 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 E (not shown), and are subject to the same interpretation. [ka]

[0047] 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.

[0048] The term "halogen" refers to F, Cl, Br, or I.

[0049] 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.

[0050] 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.

[0051] As used herein, the terms “heterocyclic,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are interchangeable 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. The partially unsaturated 7-10 member bicyclic heterocyclic moieties may include aryl or heteroaryl rings fused to a non-aromatic ring. For example, the 7-10 member bicyclic heterocyclic moieties may include the bicyclic heterocyclies shown below: [ka] When used to refer to ring atoms in a heterocyclic ring, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 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).

[0052] 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.

[0053] "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.

[0054] As used herein, "heterocyclyloxy" refers to an -OR group in which R is a heterocyclyl. Non-limiting examples are shown below. [ka]

[0055] 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.

[0056] 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.

[0057] 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) 0~4 O(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) 0~4OS(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) 0~4 OP(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.

[0058] 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) 0~2 NR ● 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.

[0059] 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. 1~6Selected 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.

[0060] 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.

[0061] 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. 1~6 An 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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:

[0067] In one embodiment, the present disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof: [ka] Provide (In the formula, the biring ring BC is one of the following: [ka] Selected from, [ka] This represents the bonding point to ring A, Ring B is one or two R independently selected from H, halogen, CN, OH, C1-C6 aliphatic, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C3-C6 cycloalkoxy. 1b The C1-C6 aliphatic, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy and C3-C6 cycloalkoxy are each independently and optionally substituted with 1-5 halogens, OH, CN, C1-C6 alkyl or C3-C6 cycloalkyl groups. Ring A is, A 4-7 member saturated or partially unsaturated divalent monocyclic carbocyclylene or a 4-7 member saturated or partially unsaturated divalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 1-4 heteroatoms plus 0 or 1 nitrogen atom); or 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). And, Ring A is a set of 0 to 4 independently selected R B Substituting with substituents, -L- is -C(O)-, -S(O)-, -S(O)2- and [ka] A linker selected from, R 1a teeth, 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 halogens, C1-C6 aliphatic groups, C3-C6 cycloalkyl groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, and C3-C6 cycloalkoxy groups, wherein 0-3 independently selected R B Further substitutions are made by 5-6 member heteroaryls, A 4-7 member saturated or partially unsaturated 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 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR, and which has 0-3 independently selected R B A 4-7 member saturated or partially unsaturated heterocycline, further substituted by A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system, selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R BA 4-12 member saturated or partially unsaturated bicyclic ring system that is substituted by, and H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, CN, -OR, -OR 10 , -NR 10 R 11 -C(O)NR 10 R 11 -CH2NR 10 R 11 or -SO2R 12 (The C1-C6 aliphatic, C3-C7 cycloalkyl or C1-C6 alkylene-O-C1-C6 alkyl groups are 0-5 independently selected R B (Replaced by) Select from, Alternatively, R on an adjacent atom of ring B 1a and one R 1b This means that together with the adjacent ring B atom to which they are bonded, they form a fused cyclic group on ring B, selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the fused cyclic group on ring B has 0-3 independently selected R B It has been replaced by, R 2 C(R C )2C(O)N(R)R 2A And, R 2AThe substituents are phenyl or pyridyl, which are optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 aliphatic atoms, halo-C1-C4 alkyl atoms, C3-C6 cycloalkyl atoms, halo-C3-C6 cycloalkyl atoms, -OH, -CN, C1-C4 alkoxy atoms, halo-C1-C4 alkoxy atoms, and -SF5 atoms, wherein two substituents on adjacent atoms of phenyl or pyridyl combine with the adjacent atoms to form a 4-7 membered carbocyclyl condensed to phenyl or pyridyl, and two substituents on adjacent atoms of phenyl or pyridyl combine with the adjacent atoms to form a 4-7 membered heterocyclyl condensed to phenyl or pyridyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the condensed 4-7 membered carbocyclyl or condensed 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 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 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, 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. R 4 is a 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 BSubstituted by, and optionally, two adjacent atoms of the phenyl or first 5-6 membered heteroaryl have two substituents, which together with the adjacent atoms form a cyclic group selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is condensed on the phenyl or first 5-6 membered heteroaryl, and the condensed cyclic group has 0-3 independently selected R B It is replaced by, or R 4 These are C1-C4 aliphatic, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each substituted with 0-3 groups independently selected from halogens, -CN, -OH, C1-C4 alkyl groups, C1-C4 alkoxy groups, optionally substituted 5-6 membered heterocyclyl groups, and optionally substituted 5-6 membered heterocyclyloxy groups. R 10 R is H, C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), excluding H. 10 Each of these is one or two independently selected R B It is replaced as needed, R 11 is either H, C1-C6 aliphatic or C3-C6 cycloalkyl, or R 10 and R 11 Together with the nitrogen atom to which they are bonded, they form a 5-6 membered ring which may be substituted as needed with one, two, or three substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxys, and halo-C1-C4 alkoxys. R 12R is a C1-C6 aliphatic, C3-C6 cycloalkyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), 12 Each of these is optionally substituted with one or two groups independently selected from halogens, C1-C6 aliphatic groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, and C3-C6 cycloalkoxy groups. R B 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, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, and C3 Each instance is independently selected from the group consisting of ~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, O(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 C The R is independently selected from hydrogen, -CH3, or -CH2CH3 each time it appears, or two R C Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. Each R is independently substituted with hydrogen or, if necessary, C. 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, together with the same atom, form a cyclic group selected from a 4-7 member saturated ring, a 4-7 member partially unsaturated ring, or a 5-6 member heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which are substituted as needed, and the cyclic group has 0-3 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, the biring ring BC is one of the following: [ka] [ka] Selected from, [ka] This represents the bonding point to ring A, R 1bEach group is independently selected from H, halogen, CN, OH, C1-C6 aliphatic, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C3-C6 cycloalkoxy, and each of the C1-C6 aliphatic, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C3-C6 cycloalkoxy groups is independently and optionally substituted with 1 to 5 halogens, OH, CN, C1-C6 alkyl, or C3-C6 cycloalkyl groups, and z is 0, 1, or 2. Ring A is, A 4-7 member saturated or partially unsaturated divalent monocyclic carbocyclylene or a 4-7 member saturated or partially unsaturated divalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 1-4 heteroatoms plus 0 or 1 nitrogen atom); or 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). And, Ring A is a set of 0 to 4 independently selected R B Substituting with substituents, -L- is -C(O)-, -S(O)-, -S(O)2- and [ka] A linker selected from, R 1a teeth, 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 halogens, C1-C6 aliphatic groups, C3-C6 cycloalkyl groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, and C3-C6 cycloalkoxy groups, wherein 0-3 independently selected R B Further substitutions are made by 5-6 member heteroaryls, A 4-7 member saturated or partially unsaturated 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 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR, and which has 0-3 independently selected R B A 4-7 member saturated or partially unsaturated heterocycline, further substituted by A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system, selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R B A 4-12 member saturated or partially unsaturated bicyclic ring system that is substituted by, and H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, CN, -OR, -OR 10 , -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 B (Replaced by) Select from, Alternatively, R on an adjacent atom of ring B1a and one R 1b This means that together with the adjacent ring B atom to which they are bonded, they form a fused cyclic group on ring B, selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the fused cyclic group on ring B has 0-3 independently selected R B It has been replaced by, R 2 C(R C )2C(O)N(R)R 2A , C(R C )2C(R C )2C(O)N(R)R 2A , C(R C )2C(R C )2N(R)C(O)N(R)R 2A and C(R C )2C(R C )2N(R)C(O)R 2A Selected from, 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 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 -S F5 is optionally substituted with one, two, or three substituents independently selected from F5, where two substituents on adjacent atoms of phenyl or pyridyl optionally form a 4- to 7-membered carbocycline condensed to phenyl or pyridyl, where two substituents on adjacent atoms of phenyl or pyridyl optionally form a 4- to 7-membered heterocycline condensed to phenyl or pyridyl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the condensed 4- to 7-membered carbocycline or condensed 4- to 7-membered heterocycline is substituted with 0 to 5 independently selected halogens, where two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridging ring, condensed 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. A cyclic group selected from may be formed as needed, or R 2AThese 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 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, 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. R 4 is a 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 B Substituted by, and optionally, two adjacent atoms of the phenyl or first 5-6 membered heteroaryl have two substituents, which together with the adjacent atoms form a cyclic group selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is condensed on the phenyl or first 5-6 membered heteroaryl, and the condensed cyclic group has 0-3 independently selected R B It is replaced by, or R 4These are C1-C4 aliphatic, C1-C4 alkoxy, or C3-C6 cycloalkyl groups, each substituted with 0-3 groups independently selected from halogens, -CN, -OH, C1-C4 alkyl groups, C1-C4 alkoxy groups, optionally substituted 5-6 membered heterocyclyl groups, and optionally substituted 5-6 membered heterocyclyloxy groups. R 10 R is H, C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), excluding H. 10 Each of these is one or two independently selected R B It is replaced as needed, R 11 is either H, C1-C6 aliphatic or C3-C6 cycloalkyl, or R 10 and R 11 Together with the nitrogen atom to which they are bonded, they form a 5-6 membered ring which may be substituted as needed with one, two, or three substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxys, and halo-C1-C4 alkoxys. R 12 R is a C1-C6 aliphatic, C3-C6 cycloalkyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), 12 Each of these is optionally substituted with one or two groups independently selected from halogens, C1-C6 aliphatic groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, and C3-C6 cycloalkoxy groups. R BThese 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, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, and C3 Each instance is independently selected from the group consisting of ~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, O(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 C The R is independently selected from hydrogen, -CH3, or -CH2CH3 each time it appears, or two R C Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. 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 cyclic group selected from a 4-7 member saturated ring, a 4-7 member partially unsaturated ring, or a 5-6 member heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which are substituted as needed, and the cyclic group has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0069] In some embodiments, ring A is a 4-7 member saturated or partially unsaturated divalent monocyclic carbocyclylene or a 4-7 member saturated or partially unsaturated divalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, plus 1-4 heteroatoms plus 0 or 1 nitrogen atom). In some embodiments, ring A is a 4-7 member saturated or partially unsaturated divalent monocyclic carbocyclylene, in which case ring A has 0-4 independently selected R B It is substituted with substituents. In some embodiments, ring A is a 4- to 7-membered saturated or partially unsaturated divalent monocyclic heterocyclene (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 1 to 4 heteroatoms plus 0 or 1 nitrogen atom), and ring A has 0 to 4 independently selected R B It is substituted with substituents.

[0070] In some embodiments, ring A is a 4-12 member saturated or partially unsaturated divalent bicyclic ring system that is condensed, bridged, or spirocyclic, selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 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 carbocyclylene, in which case ring A is 0-4 independently selected R BSubstitutings 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 B It is substituted with substituents.

[0071] 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.

[0072] In some embodiments, ring A is [ka] That is the case.

[0073] In some embodiments, ring A is [ka] That is the case.

[0074] In some embodiments, ring A is [ka] That is the case.

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

[0076] In some embodiments, ring A is selected from one of the substituents in Table 1 or Table 1a.

[0077] As generally stated above, L is -C(O)-, -S(O)-, -S(O)2- and [ka] It is a linker selected from among them.

[0078] In some embodiments, the linker L is -C(O)-.

[0079] In some embodiments, the linker L is -S(O)-.

[0080] In some embodiments, the linker L is -S(O)2-.

[0081] In some embodiments, the linker L is [ka] That is the case.

[0082] In some embodiments, the linker L is selected from one of the substituents in Table 1 or Table 1a.

[0083] As generally stated above, R 1a The following can be selected: a) 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 halogens, C1-C6 aliphatic groups, C3-C6 cycloalkyl groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, and C3-C6 cycloalkoxy groups, wherein 0-3 independently selected R B Further substitutions are made by 5-6 member heteroaryls, A 4-7 member saturated or partially unsaturated 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 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR, and which has 0-3 independently selected R B A 4-7 member saturated or partially unsaturated heterocycline, further substituted by A condensed, bridged, or spirocyclic, 4-12 member saturated or partially unsaturated bicyclic ring system, selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclyl or heterocyclyl comprises 0-3 independently selected R B A 4-12 member saturated or partially unsaturated bicyclic ring system that is substituted by, and H, halogen, C1-C6 aliphatic, C3-C7 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, CN, -OR, -OR 10 , -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 B (Replaced by) Alternatively, R on an adjacent atom of ring B 1a and one R 1bThis means that together with the adjacent ring B atom to which they are bonded, they form a fused cyclic group on ring B, selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the fused cyclic group on ring B has 0-3 independently selected R B It has been replaced by [this].

[0084] In some embodiments, R 1a 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 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy, wherein the 5-6 membered heteroaryl has 0-3 independently selected R B It is further replaced by R. In some embodiments, 1a This is a 4-6 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 Azetidinyls, which are aliphatic, -OR, or optionally substituted with one or two independently selected halogens, and pyrrolidinyls, which are optionally substituted with one or two independently selected halogens, with 0 to 2 R elements independently selected from these. B It is substituted with a group. In some embodiments, R 1a 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 1~4Azetidinyls, which are aliphatic, -OR, or optionally substituted with one or two independently selected halogens, and pyrrolidinyls, which are optionally substituted with one or two independently selected halogens, with 0 to 2 R elements independently selected from these. B It is substituted with a group. In some embodiments, R 1a R is a carbocykyl with 3 to 7 members, which is substituted as needed. In some embodiments, R 1a is a C2-C4 alkenyl which is substituted as needed. In some embodiments, R 1a R is a cyclopropyl-substituted C2-C4 alkenyl. In some embodiments, R 1a These are methyl-substituted C2-C4 alkenyl compounds.

[0085] In some embodiments, R 1a R is a 6-membered partially unsaturated heterocycline (having one oxygen atom). In some embodiments, R 1a R is a 4-membered saturated heterocycline (having one oxygen atom). In some embodiments, R 1a 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 B It is further substituted by R B C is replaced as needed. 1~6 It is an aliphatic group. In some embodiments, R 1a 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 B It is further substituted by R B C is replaced as needed. 1~6It is an aliphatic group. In some embodiments, R 1a -NR 10 R 11 And R 10 R is a 5-6 membered heteroaryl (having one or two nitrogen atoms) which is optionally substituted with one or two groups independently selected from halogens, CH3, OCH3, C3-C6 cycloalkyl and C3-C6 cycloalkoxy, and 11 is H or CH3. In some embodiments, R 1a -CH2NR 10 R 11 And R 10 R is a 5-6 membered heteroaryl (having one or two nitrogen atoms) which is optionally substituted with one or two groups independently selected from halogens, CH3, OCH3, C3-C6 cycloalkyl and C3-C6 cycloalkoxy, and 11 is H or CH3. In some embodiments, R 1a is a C2-C4 alkene, and the alkene is optionally substituted with OCH3 or one, two, or three fluorine atoms. In some embodiments, R 1a The C2-C4 alkyne is, and the alkyne is optionally substituted with OCH3 or one, two, or three fluorine atoms. In some embodiments, R 1a is -SO2R 12 And R 12 R is selected from a 5-6 membered heteroaryl having 1-2 nitrogen heteroatoms, which may be optionally substituted with CH3, or one or two groups independently selected from a halogen and CH3. In some embodiments, R 1a is a cyclopropyl which is optionally substituted with 1-2 fluorine atoms. In some embodiments, R 1a is a C1-C6 alkyl group which is optionally substituted with OH or 1-2 fluorine atoms. In some embodiments, R 1a is -C(O)NR 10 R 11 And R 10 is H or CH3, and R11 It is either H or CH3.

[0086] In some embodiments, R 1a 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 3 independently selected R B It is further replaced as needed by R. In some embodiments, 1a 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 1a is a 5-membered heteroaryl (having 2 nitrogen atoms) 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, wherein the 5-membered heteroaryl has 0-1 R B It is further replaced as needed by R B These are hydroxyl-substituted C1-C4 alkyl groups.

[0087] In some embodiments, R 1a is 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 B It is further replaced as needed.

[0088] In some embodiments, R 1aIt is substituted with C1-C4 alkoxys and has 0-2 R B It is a pyridyl that has been further substituted by [another compound].

[0089] In some embodiments, R 1a 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 B It is further replaced by [this].

[0090] In some embodiments, R 1a The first element is selected from groups a to d: a) 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 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, and which has 0-3 independently selected R B Further substitutions are made by 5-6 member heteroaryls, A 4-7 member saturated or partially unsaturated 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, C3-C6 cycloalkoxy, and -OR, and which has 0-3 independently selected R B A 4-7 member saturated or partially unsaturated heterocycline, further substituted by A 4-12 member saturated or partially unsaturated divalent bicyclic ring system, which is condensed, bridged, or spirocyclic, selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclylene or heterocyclylene comprises 0-3 independently selected R BA 4-12 member saturated or partially unsaturated divalent bicyclic ring system substituted by, and H, halogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C1-C6 alkyl-O-C1-C6 alkyl, CN, -OR, -NR 10 R 11 -C(O)NR 10 R 11 -CH2NR 10 R 11 , -SO2R 12 (C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl or C1-C6 alkylene-O-C1-C6 alkyl are 0-5 independently selected R B (May be replaced by...)

[0091] In some embodiments, R 1a is a 4-7 member saturated or partially unsaturated 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 the 4-7 member saturated or partially unsaturated heterocycline is 0-3 independently selected R B It is further replaced by [this].

[0092] In some embodiments, R 1a 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 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, wherein the 5-6 membered heteroaryl has 0-3 independently selected R B It is further replaced by [this].

[0093] In some embodiments, R 1a teeth, [ka] Selected from the group consisting of, * indicates a bond point to ring B.

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

[0095] In some embodiments, R 1a teeth, [ka] [ka] That is the case.

[0096] In some embodiments, R 1a teeth, [ka] That is the case.

[0097] In some embodiments, R 1a teeth, [ka] That is the case.

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

[0099] In some embodiments, R 1a teeth, [ka] That is the case.

[0100] As generally stated above, R 1b Each of these is independently selected from H, halogen, CN, OH, C1-C6 aliphatic, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C3-C6 cycloalkoxy, and each of the C1-C6 aliphatic, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkylene-O-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and C3-C6 cycloalkoxy is independently and optionally substituted with 1 to 5 halogens, OH, CN, C1-C6 alkyl, or C3-C6 cycloalkyl.

[0101] In some embodiments, R on adjacent atoms of ring B 1a and one R 1b This means that together with the adjacent ring B atom to which they are bonded, they form a fused cyclic group on ring B, selected from phenyl, a 5-6 membered heteroaryl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 4-7 membered saturated or partially unsaturated carbocyclyl, or a 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the fused cyclic group on ring B has 0-3 independently selected R B It has been replaced by [this].

[0102] In some embodiments, R on adjacent atoms of ring B 1a and one R 1b This means that together with the adjacent ring B atom to which they are bonded, they form a phenyl fused cyclic group on ring B, and the fused cyclic group on ring B consists of 0 to 3 independently selected R B It is replaced by R on an adjacent atom of ring B. In some embodiments, R on an adjacent atom of ring B 1a and one R 1bThese, together with the adjacent ring B atoms to which they are bonded, form a cyclic group condensed on ring B, which is a 5-6 member heteroaryl group (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the cyclic group condensed on ring B has 0-3 independently selected R B It is replaced by R on an adjacent atom of ring B. In some embodiments, R on an adjacent atom of ring B 1a and one R 1b These, together with the adjacent ring B atoms to which they are bonded, form a condensed cyclic group on ring B, which is a 4-7 member saturated or partially unsaturated carbocyclyl, and the condensed cyclic group on ring B consists of 0-3 independently selected R B It is replaced by R on an adjacent atom of ring B. In some embodiments, R on an adjacent atom of ring B 1a and one R 1b These, together with the adjacent ring B atoms to which they are bonded, form a fused cyclic group on ring B, which is a 4-7 member saturated or partially unsaturated heterocycline (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the fused cyclic group on ring B has 0-3 independently selected R B It has been replaced by [this].

[0103] As generally stated above, R 2 C(R C )2C(O)N(R)R 2A In some embodiments, R 2 C(R C )2C(R C )2C(O)N(R)R 2A In some embodiments, R 2 C(R C )2C(R C )2N(R)C(O)N(R)R 2A In some embodiments, R 2 C(R C )2C(R C )2N(R)C(O)R 2A In some embodiments, R 2 CH2C(O)N(H)R 2A In some embodiments, R 2CH2CH2C(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 C )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 C )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 C )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.

[0104] In some embodiments, R 2 teeth, [ka] [ka] That is the case.

[0105] In some embodiments, R 2 teeth, [ka] That is the case.

[0106] In some embodiments, R 2 teeth, [ka] That is the case.

[0107] In some embodiments, R 2 teeth, [ka] That is the case.

[0108] In some embodiments, R 2 This is selected from one of the substituents in Table 1 or Table 1a.

[0109] As generally stated above, R 2AThe compound is 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. Halogens, pyridyls, cubanyls, saturated or partially unsaturated monocyclic rings, or saturated or partially unsaturated crosslinked rings, condensed rings, or spirocyclic rings are 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 (haloC3-C6cycla The rings are optionally substituted with one, two, or three substituents independently selected from lkoxy) and -SF5, where two substituents on adjacent atoms of phenyl or pyridyl optionally form a 4- to 7-membered carbocycline condensed to phenyl or pyridyl, where two substituents on adjacent atoms of phenyl or pyridyl optionally form a 4- to 7-membered heterocycline condensed to phenyl or pyridyl (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the condensed 4- to 7-membered carbocycline or condensed 4- to 7-membered heterocycline is substituted with 0 to 5 independently selected halogens, where two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridging ring, condensed ring, or spirocyclic ring are: • 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. A cyclic group selected from may be formed as needed, or R 2AThese 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.

[0110] 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.

[0111] In some embodiments, R 2A This 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 optional substituents on adjacent atoms of phenyl, together with their intervening atoms, form a 4-7 membered carbocycline condensed on phenyl, and two optional substituents on adjacent atoms of phenyl, together with their intervening atoms, form a 4-7 membered heterocycline condensed on phenyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0112] 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.

[0113] 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 optional substituents on adjacent atoms of the pyridyl, together with their intervening atoms, form a 4-7 membered carbocyryl condensed to the pyridyl, and two optional substituents on adjacent atoms of the pyridyl, together with their intervening atoms, form a 4-7 membered heterocyclyl condensed to the pyridyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0114] 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.

[0115] 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, a saturated or partially unsaturated crosslinked ring, condensed ring, or spirocyclic ring may be 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 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, and halo-C1-C4 alkyls.

[0116] In some embodiments, R 2A The is a saturated or partially unsaturated crosslinking ring, a 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 crosslinking 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 ring is a saturated or partially unsaturated condensed ring, a 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 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.

[0118] In some embodiments, R 2A The 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.

[0119] 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 2AR 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.

[0120] 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 element is independently selected from H, 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.

[0121] 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.

[0122] 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 1~4 It is a 2-naphthyl which is optionally substituted with alkyl and one, two, or three substituents independently selected from -OH. In some embodiments, R 2A is halogen, C 1~4 It is a 3-quinolinyl molecule optionally substituted with one, two, or three substituents independently selected from the alkyl and -OH groups.

[0123] In some embodiments, R 2A This is a phenyl compound containing a -CF3 substituent, or a pyridyl compound containing a -CF3 substituent.

[0124] 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.

[0125] In some embodiments, R 2A This is selected from one of the substituents in Table 1 or Table 1a.

[0126] As generally stated above, R 3 These are hydrogen, C1-C4 alkyl, 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 substituted with N(R)C(O)R as needed.

[0127] 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 3is 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.

[0128] In some embodiments, R 3 This is selected from one of the substituents in Table 1 or Table 1a.

[0129] 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 R is propyl. In some embodiments, 3A It is butyl.

[0130] In some embodiments, R 3A This is selected from one of the substituents in Table 1 or Table 1a.

[0131] In some embodiments, R 4 The answer is selected from one of a), b), and c): a)R 4 teeth, [ka] A ring E selected from the group consisting of, In the formula, * is the connection point to L, R 4A , R 4B , R 4C , R 4D , R 4E and R 4FAny substituent present on ring E selected from the following is hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkoxy; 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 4A and R 4B These intervening atoms bond together, forming 0 to 3 independently selected R atoms. B A 4-7 member carbocyclyl substituted by, 0-3 independently selected R B A 4-7 member heterocycline substituted by, or 0-3 independently selected R B It forms a 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is fused to ring E, R 4C , R 4D , R 4E and R 4F Any substituent present on ring E 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 bond together, forming 0 to 3 independently selected R atoms. B A 4-7 member carbocyclyl substituted by, 0-3 independently selected R B A 4-7 member heterocycline substituted by, or 0-3 independently selected R BIt forms a 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is fused to ring E, R 4A , R 4D , R 4E and R 4F Any substituent present on ring E 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 bond together, forming 0 to 3 independently selected R atoms. B A 4-7 member carbocyclyl substituted by, 0-3 independently selected R B A 4-7 member heterocycline substituted by, or 0-3 independently selected R B It forms a 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is fused to ring E, R 4A , R 4B , R 4E and R 4F Any substituent present on ring E 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 R4D 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 bond together, forming 0 to 3 independently selected R atoms. B It forms a 5-6 member optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is condensed on ring E, 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 bond together, forming 0 to 3 independently selected R atoms. B It forms a 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is fused to ring E, R 4B and R 4C 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 14Each 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 R 13 and R 14 These, together with the nitrogen atoms to which they are bonded, form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, wherein the heterocyclic ring is optionally substituted with -CH3; or 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; 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.

[0132] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or I''. R 4A , R 4C and R 4DThese 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 bond together, forming 0 to 3 independently selected R atoms. B A 4-7 member carbocyclyl substituted by, 0-3 independently selected R B A 4-7 member heterocycline substituted by, or 0-3 independently selected R B It forms a 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is fused to ring E, R 4A 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 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, and NR 13 R 14 These combine to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, the heterocyclic ring being optionally substituted with -CH3. R 14 Is it hydrogen, or R 13 and R 14These, together with the nitrogen atoms to which they are bonded, form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, and the heterocyclic ring is optionally substituted with -CH3.

[0133] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or 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 instance is independently selected from C1-C4 alkyl groups, which are substituted as needed with hydrogen, or -OH, -OCH3, or -OCH2CH3, or NR 13 R 14 These combine to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, the heterocyclic ring being optionally substituted with -CH3. R 14 Is it hydrogen, or R 13 and R 14 These, together with the nitrogen atoms to which they are bonded, form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, and the heterocyclic ring is optionally substituted with -CH3, or R 4The 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.

[0134] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or 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 instance is independently selected from C1-C4 alkyl groups, which are substituted as needed with hydrogen, or -OH, -OCH3, or -OCH2CH3, or NR 13 R 14 These combine to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, the heterocyclic ring being optionally substituted with -CH3. R 14 It is hydrogen.

[0135] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or I''. R 4A , R 4C and R 4D These are independently selected from hydrogen, halogens, and C1-C4 alkyl groups.

[0136] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or 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 bond together to form a 4-7 membered carbocykyl or heterocyclyl or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring E, R 4C 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 is, or R 4B and R 4C These intervening atoms bond together, forming 0 to 3 independently selected R atoms. B A 4-7 member carbocyclyl substituted by, 0-3 independently selected R B A 4-7 member heterocycline substituted by, or 0-3 independently selected R B It forms a 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is fused to ring E, R 4A 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 Selected from, R 13 Each instance is independently selected from C1-C4 alkyl groups, which are substituted as needed with hydrogen, or -OH, -OCH3, or -OCH2CH3, or NR 13 R 14 These combine to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, the heterocyclic ring being optionally substituted with -CH3. R 14 It is hydrogen.

[0137] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or I''. R 4A and R 4BThese intervening atoms bond together to form a 4-7 membered carbocyrill, a 4-7 membered heterocyclyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring E. R 4C It is hydrogen.

[0138] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or 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 into ring E. R 4C It is hydrogen.

[0139] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or 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 4BThese intervening atoms bond together to form a 4-7 membered carbocyrill, a 4-7 membered heterocyclyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring E, R 4D 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 instance is independently selected from C1-C4 alkyl groups, which are substituted as needed with hydrogen, or -OH, -OCH3, or -OCH2CH3, or NR 13 R 14 These combine to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, the heterocyclic ring being optionally substituted with -CH3. R 14 H is H.

[0140] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or I''. R 4A and R 4D These are hydrogen atoms, R 4B These are C1-C4 alkyl groups.

[0141] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or I''. R 4A 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 Each is independently selected from, R 13 Each instance is independently selected from C1-C4 alkyl groups, which are substituted as needed with hydrogen, or -OH, -OCH3, or -OCH2CH3, or NR 13 R 14 These combine to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, the heterocyclic ring being optionally substituted with -CH3. R 14 H is H.

[0142] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or I''. R 4A and R 4C The elements are independently selected from hydrogen and C1-C4 alkyl groups.

[0143] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or I''. R 4A , R 4B , R 4C , R 4D and 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 bond together to form a 4-7 membered carbocyrill, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring E, 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 bond together to form a 4-7 membered carbocyrill, a 4-7 membered heterocyclyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) condensed on ring E, R 4A , R 4B and R 4EThese 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 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 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 E, 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 instance is independently selected from C1-C4 alkyl groups, which are substituted as needed with hydrogen, or -OH, -OCH3, or -OCH2CH3, or NR 13 R 14These combine to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, the heterocyclic ring being optionally substituted with -CH3. R 14 H is H.

[0144] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or I''. R 4A , R 4B , R 4C , R 4D and R 4E These are independently selected from hydrogen; halogens; C1-C4 alkyls; and C1-C4 alkoxys, or R 4C and R 4D These intervening atoms bond together to form a 4-7 membered heterocycline (having 1-3 nitrogen atoms) condensed on ring E, R 4A , R 4B and R 4E Each of them is hydrogen.

[0145] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or I''. R 4F 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 E, R 4B and R 4CThese 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 instance is independently selected from C1-C4 alkyl groups, which are substituted as needed with hydrogen, or -OH, -OCH3, or -OCH2CH3, or NR 13 R 14 These combine to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, the heterocyclic ring being optionally substituted with -CH3. R 14 H is H.

[0146] In some embodiments, R 4 The ring E has the following structure: [ka] And, * represents the linking point to the linker L that is bonded to ring A in formulas I, I', or 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 E, R 4B and R 4C Each of them is hydrogen.

[0147] In some embodiments, R 4is a 5-member heteroaryl (having one heteroatom independently selected from nitrogen, oxygen and sulfur, and 0, 1, 2 or 3 additional ring nitrogen atoms), and said heteroaryl is substituted by 0 to 4 groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, halo C1-C4 alkyl, C3-C6 cycloalkyl and C1-C4 alkoxy.

[0148] In some embodiments, R 4 is a 5-member heteroaryl (having one heteroatom independently selected from nitrogen, oxygen and sulfur, and 0, 1, 2 or 3 additional ring nitrogen atoms), and said heteroaryl is substituted by 0 to 4 groups independently selected from OH, -CH3, -CHF2, cyclopropyl and -OCH3.

[0149] In some embodiments, R 4 is C1-C4 alkyl, C1-C4 alkoxy or C3-C6 cycloalkyl, each of which is substituted by 0 to 3 groups independently selected from halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5- to 6-member heterocyclyl and optionally substituted 5- to 6-member heterocyclyloxy. In some embodiments, R 4 is C1-C4 alkyl substituted by 0 to 3 independently selected halogen, -CN, -OH, C1-C4 alkyl and C1-C4 alkoxy. In some embodiments, R 4 is C1-C4 alkoxy substituted by 0 to 3 independently selected halogen, -CN, -OH, C1-C4 alkyl and C1-C4 alkoxy. In some embodiments, R 4 is C3-C6 cycloalkyl substituted by 0 to 3 independently selected halogen, -CN, -OH, C1-C4 alkyl and C1-C4 alkoxy.

[0150] In some embodiments, R 4is isoxazolyl substituted by -OH or C1-C4 alkoxy.

[0151] In some embodiments, R 4 is a 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen and sulfur, and 0, 1, 2 or 3 additional ring nitrogen atoms) selected from the group consisting of thiophenyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and the heteroaryl is substituted by 0-4 groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, halo C1-C4 alkyl, C3-C6 cycloalkyl and C1-C4 alkoxy.

[0152] In some embodiments, R 4 is

Chemical formula

[0153] In some embodiments, R 4 teeth, [ka] [ka] That is the case.

[0154] In some embodiments, R 4 teeth, [ka] That is the case.

[0155] In some embodiments, R 4 These are as shown in Table 1 or Table 1a for the substituents.

[0156] As generally stated above, R 10 R is H, C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), excluding H. 10Each of these is one or two independently selected R B It is replaced as needed.

[0157] In some embodiments, R 10 is H. In some embodiments, R 10 R is a C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), 10 Each of these is one or two independently selected R B It is replaced as needed by R. In some embodiments, 10 R is C1-C6 aliphatic, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, or -C(O)C1-C6 alkyl, 10 Each of these is one or two independently selected R B It is replaced as needed by R. In some embodiments, 10 R is a 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), 10 This involves one or two independently selected R B It is replaced as needed.

[0158] In some embodiments, R 10 These are as shown in Table 1 or Table 1a for the substituents.

[0159] As generally stated above, R 11 is either H, C1-C6 aliphatic or C3-C6 cycloalkyl, or R 10 and R 11 These, together with the nitrogen atom to which they are bonded, form a 5-6 membered ring which may be optionally substituted with one, two, or three substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxys, and halo-C1-C4 alkoxys.

[0160] In some embodiments, R 11 is H, C1-C6 aliphatic or C3-C6 cycloalkyl. In some embodiments, R 11 is H. In some embodiments, R 11 These are C1-C6 aliphatic. In some embodiments, R 11 is a C3-C6 cycloalkyl group. In some embodiments, R 10 and R 11 Together with the nitrogen atom to which they are bonded, they form a 5-6 membered ring which may be optionally substituted with one, two, or three substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxys, and halo-C1-C4 alkoxys.

[0161] In some embodiments, R 11 These are as shown in Table 1 or Table 1a for the substituents.

[0162] As generally stated above, R 12 R is a C1-C6 aliphatic, C3-C6 cycloalkyl, or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), 12 Each of these groups is optionally substituted with one or two groups independently selected from halogens, C1-C6 aliphatic groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, and C3-C6 cycloalkoxy groups.

[0163] In some embodiments, R 12 is a C1-C6 aliphatic element, which is optionally substituted with one or two groups independently selected from halogens, C1-C6 aliphatic elements, halo-C1-C6 alkyl elements, C1-C6 alkoxy elements, C3-C6 cycloalkyl elements, and C3-C6 cycloalkoxy elements. In some embodiments, R 12is a C1-C6 aliphatic element, which is optionally substituted with one or two groups independently selected from halogens, C1-C6 aliphatic elements, halo-C1-C6 alkyl elements, C1-C6 alkoxy elements, C3-C6 cycloalkyl elements, and C3-C6 cycloalkoxy elements. In some embodiments, R 12 is a C3-C6 cycloalkyl group, which is optionally substituted with one or two groups independently selected from halogens, C1-C6 aliphatic groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, and C3-C6 cycloalkoxy groups. In some embodiments, R 12 It 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 halogens, C1-C6 aliphatic groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, and C3-C6 cycloalkoxy groups.

[0164] As generally stated above, R BThese 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, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, and C3 Each occurrence is independently selected from the group consisting of ~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, O(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.

[0165] In some embodiments, R B 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 B R is selected independently from halogens for each occurrence. In some embodiments, R B is selected independently from -OR for each occurrence. In some embodiments, R B C is replaced as needed. 1~6 Each aliphatic group is independently selected upon its appearance.

[0166] In some embodiments, R B This is selected from one of the substituents in Table 1 or Table 1a.

[0167] As generally stated above, R Cis independently selected for each occurrence from hydrogen, -CH3, and -CH2CH3, or two Rs C together with the carbon to which they are attached form a cyclopropyl ring. In some embodiments, R C is independently selected for each occurrence from hydrogen, -CH3, and -CH2CH3. In some embodiments, R C is hydrogen. In some embodiments, R C one of is -CH3 and the other of R C is hydrogen. In some embodiments, two Rs C together with the carbon to which they are attached form a cyclopropyl ring.

[0168] In some embodiments, R C is as selected from one of the substituents in Table 1 or Table 1a.

[0169] As generally described above, each R is independently hydrogen, or a C 1~6 aliphatic group optionally substituted with, phenyl optionally substituted with, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring optionally substituted with, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with, or a 5- to 6-membered heteroaryl ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with, or two R groups on the same atom together with the same atom form a cyclic group selected from a 4- to 7-membered saturated ring, a 4- to 7-membered partially unsaturated ring, or a 5- to 6-membered heteroaryl ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the cyclic group has 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0170] In some embodiments, each R is hydrogen. In some embodiments, each R is independently a C 1~6The 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).

[0171] In some embodiments, two R groups on the same atom, together with the same atom, form a cyclic group selected from a 4- to 7-membered saturated ring, a 4- to 7-membered partially unsaturated ring, or a 5- to 6-membered heteroaryl ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is optionally substituted, and the cyclic group has 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen or C 1~6 It is alkyl.

[0172] In some embodiments, R is selected from one or more substituents in Table 1 or Table 1a.

[0173] In some embodiments, the compound of formula I is the compound of formulas IIa to IIs: [ka] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , z, ring A, R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0174] In some embodiments, the compound of formula I is the compound of formula IIa' to formula IIs': [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , ring A, R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0175] In some embodiments, the compound of formula I is the compound of formulas IIa to IIs: [ka] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , z, ring A, 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.

[0176] In some embodiments, the compound of formula I is the compound of formula IIa' to formula IIs': [ka] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , ring A, 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.

[0177] In some embodiments, the compound of formula I is the compound of formulas IIa to IIs: [ka] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , z, 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.

[0178] In some embodiments, the compound of formula I is the compound of formula IIa' to formula IIs': [ka] [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 2 , R 3 and R 4Both when used alone and in combination, it is as defined herein, and ring A is, [ka] Selected from, R 2a teeth, [ka] Selected from.

[0179] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-a: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0180] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-b: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0181] In some embodiments, the compound of formula I, I', or I'' is the compound of III-c: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0182] In some embodiments, compounds of formula I, I', or I'' are compounds of formula III-d: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0183] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-e: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0184] In some embodiments, the compounds of formula I, I', or I'' are the compounds of formula III-f: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0185] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-g: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0186] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-h: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0187] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-i: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0188] In some embodiments, compounds of formula I, I', or I'' are compounds of formula III-j: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0189] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-k: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0190] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-l: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0191] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-m: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4Both when used alone and in combination, it is as defined herein.

[0192] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-n: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0193] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-o: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0194] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-p: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0195] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-q: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0196] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-r: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0197] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-s: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0198] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-a: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R3 and R 4 Both when used alone and in combination, it is as defined herein, and R 2a teeth, [ka] Selected from.

[0199] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-b: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0200] In some embodiments, the compound of formula I, I', or I'' is the compound of III-c: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0201] In some embodiments, compounds of formula I, I', or I'' are compounds of formula III-d: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0202] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-e: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0203] In some embodiments, the compounds of formula I, I', or I'' are the compounds of formula III-f: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0204] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-g: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0205] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-h: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0206] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-i: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0207] In some embodiments, compounds of formula I, I', or I'' are compounds of formula III-j: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0208] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-k: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0209] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-p: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0210] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-q: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0211] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-r: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , R 2 , R3 and R 4 Both when used alone and in combination, it is as defined herein, and R 2a teeth, [ka] Selected from.

[0212] In some embodiments, the compound of formula I, I', or I'' is the compound of formula III-s: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1a , R 1b , 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.

[0213] In some embodiments, the compound of formula I, I', or I'' is the compound of formula IV-a to IV-h: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R B , R 2 , R 3 Ring A, Linker L and R 4 Both when used alone and in combination, it is as defined herein.

[0214] In some embodiments, the compound of formula I, I', or I'' is the compound of formula Va: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R B , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0215] In some embodiments, the compound of formula I, I', or I'' is the compound of formula Vb: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R B , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0216] In some embodiments, compounds of formula I, I', or I'' are compounds of formula Vc: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R B , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0217] In some embodiments, compounds of formula I, I', or I'' are compounds of formula Vd: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R B , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0218] In some embodiments, compounds of formula I, I', or I'' are compounds of formula Ve: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R B , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0219] In some embodiments, the compound of formula I, I', or I'' is the compound of formula Vf: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R B , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0220] In some embodiments, compounds of formula I, I', or I'' are compounds of formula Vg: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R B , R 2 , R 3 and R 4 Both when used alone and in combination, it is as defined herein.

[0221] In some embodiments, the compound of formula I, I', or I'' is the compound of formula Vh: [ka] or a pharmaceutically acceptable salt thereof, In the formula, R B , R 2 , R 3 and R 4Both when used alone and in combination, it is as defined herein.

[0222] In some embodiments, the compound of formula I, I', or I'' is selected from one of those illustrated in Table 1 or Table 1a, or from pharmaceutically acceptable salts thereof. Table 1 or Table 1a identifies the compounds by their IUPAC names, and Table 2 or Table 2a lists the same compounds and shows their chemical structures. If there is any difference between the name of a compound in Table 1 or Table 1a and the structure of the same compound in Table 2 or Table 2a, the compound structure in Table 2 or Table 2a shall prevail and identify the compound corresponding to each individual compound number (I-#) in Table 1 or Table 1a. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1a-1 Table 1a-2 Table 1a-3 Table 1a-4 Table 1a-5 Table 1a-6 [Table 1a-7] [Table 1a-8] 4. Use of pharmaceutical compositions, treatment methods, and compounds

[0223] 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., aluminum magnesium 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.

[0224] 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.

[0225] Pharmaceutical compositions comprising compounds of formula I, I', or I'' described herein, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers are also provided. use

[0226] The compounds of formula I, I', or I'' of the present invention, in free form or in pharmaceutically acceptable salt form, exhibit beneficial pharmacological properties, such as WRN inhibitory properties, as demonstrated by the in vitro tests presented in the following section, and are therefore suitable for therapeutic or research use, such as chemical probes and tool compounds.

[0227] Compounds of formula I, I', or 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, I', or I'' described herein as research chemicals, for example, tool compounds or chemical probes, particularly for research on WRN, is provided.

[0228] Compounds of formula I, I', or 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, I', or 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).

[0229] Compounds of formula I, I', or 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, carcinosarcoma of the uterus, 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.

[0230] 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, I', or 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, I', or 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, I', or 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, I', or 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, I', or I'' as 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) include colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, and cervical cancer. Cancers selected from esophageal cancer, breast cancer, kidney cancer, and ovarian cancer. More specifically, cancers characterized by high frequency of 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.

[0231] The use of compounds of formula I, I', or 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.

[0232] 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

[0233] 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.

[0234] Any of the formulas shown herein is intended to represent an unlabeled form of the compound and an isotope-labeled form, in addition to the deuteration specifically claimed in formula I, I', or I''. The isotope-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.

[0235] 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.

[0236] 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.

[0237] "The compound of the present invention" or "the compound of formula I, I' or I''" includes its zwitterion, its non-zwitterion (uncharged form), or a pharmaceutically acceptable salt thereof of the said zwitterion or non-zwitterion form. "Zwitterion" or "zwitterion form" means a compound containing both positively and negatively charged functional groups.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] "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).

[0242] "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 large number of changes in the length of single repeat genomic sequences within microsatellites.

[0243] 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).

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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).

[0248] 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.

[0249] The term "therapeutic dose" of the compound of the present invention refers to an 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] As used herein, if an object is expected to benefit from a procedure biologically, medically, or in terms of quality of life, such object "needs" such procedure.

[0257] 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.

[0258] "May be joined" means either joined or not joined.

[0259] "May be replaced by Deuterium" means that it is either replaced by Deuterium or not replaced by Deuterium.

[0260] 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

[0261] 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, where possible, exist in cis-(Z)- or trans-(E)- form.

[0262] 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 (antagonists), racemates, or mixtures thereof.

[0263] 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.

[0264] 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.

[0265] Compounds of the present invention, i.e., compounds of formula I, I', or 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, I', or I'' by known cocrystal-forming procedures. Such procedures include contact between compounds of formula I, I', or I'' and a cocrystal-forming agent 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 comprising compounds of formula I, I', or I''.

[0266] 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.

[0267] 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

[0268] 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

[0269] "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, I', or 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 via the same route of administration or simultaneously. The term “pharmaceutical combination,” as used herein, means a product obtained by mixing or combining one or more therapeutic agents, and includes both immobilized and unimmobilized combinations of therapeutic agents. The term “immobilized combination” means that both the therapeutic agent, e.g., the compound of the present invention and the combination partner, are administered simultaneously to the patient in the form of a single entity or a single dose.

[0270] 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.

[0271] The combinations described herein may include compounds of formula I, I', or 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.

[0272] Also provided are combinations comprising compounds of formula I, I', or I'' as described herein, or pharmaceutically acceptable salts thereof as described herein, and 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 include: • Anti-cancer drugs, · Chemotherapy, 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 (registered trademark), cladribine (Leustatin (registered trademark)), cyclophosphamide (Cytoxan (registered trademark) or Neosar (registered trademark)), cytarabine, cytosine arabinoside (Cytosar-U (registered trademark)), cytarabine liposomal injection (DepoCyt (registered trademark)), dacarbazine (DTIC-Dome (registered trademark)), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine (registered trademark)), and daunorubicin triphosphate. • 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 (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) PD-1 inhibitors selected from AMP-224 (Amplimmune), penprimab (Akeso Biopharma Inc.), zimbererimab (Arcus Biosciences Inc.), and prorugolimab (Biocad Ltd), • Spartalizumab, or • Tithrelizumab (BGB-A317, Beigene).

[0273] In further embodiments, the additional therapeutic activator is the chemotherapy drug irinotecan (Camptosar®).

[0274] 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.

[0275] 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".

[0276] In another embodiment, a compound of formula I, I', or I'' or a pharmaceutically acceptable salt thereof is provided, along with a combination of chemotherapy and a PD-1 inhibitor. In particular, the chemotherapy and PD-1 inhibitor are selected from those described above. In some embodiments, the PD-1 inhibitor is pembrolizumab, nivolumab, semiprimab, dostallimab, or retifanlimab.

[0277] 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.

[0278] 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, I', or I'' and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of the present invention and the other therapeutic agent(s) in individual forms, for example, in the form of a kit.

[0279] 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.

[0280] The kits 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 kits of the present invention typically include instructions for administration.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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

[0285] 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 attached synthesis scheme. Scheme 1 [ka] [ka] Scheme 2 [ka] Scheme 3 [ka] Ring G: A phenyl, pyridyl, or 5-6 membered aromatic ring, a 4-7 membered saturated or partially unsaturated carbon ring, or a 4-7 membered saturated or partially unsaturated heterocycle, as may be substituted. Scheme 4 [ka] [ka] Scheme 5 [ka] Scheme 6 [ka] Scheme 7 [ka] [ka]

[0286] R within the genus 2 The synthesis of a representative intermediate-6 can be prepared as shown in Scheme 8 below. Substituted anilines such as L can be used in the amide coupling in the above scheme. Alternatively, L can be used to produce a substrate suitable for nucleophilic substitution to generate the compounds of this disclosure, and intermediate-6 can be obtained as shown below. Scheme 8 [ka]

[0287] Those skilled in the art will be able to adapt such a synthetic procedure to synthesize the compounds of the present disclosure to obtain variously substituted compounds of formula I, I', or I''. [Examples]

[0288] 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.

[0289] List of abbreviations: NCS: N-chlorosuccinimide THF: Tetrahydrofuran LiOH-H2O: Lithium hydroxide monohydrate (COCl)2: Oxalyl chloride DIEA: N,N-diisopropylethylamine NBS: N-bromosuccinimide TsOH-H2O:4-Methylbenzenesulfonic acid monohydrate TsOH: 4-methylbenzenesulfonic acid H3PO4: Phosphate EtOH: Ethanol TFA: Trifluoroacetic acid Boc2O: Di-tert-butyl dicarbonate POCl3: Phosphoryl Chloride HCl: Hydrochloric acid EDCI: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride ppm: parts per million LCMS: Liquid Chromatography Mass Spectrometry HPLC: High-Performance Liquid Chromatography NMR: nuclear magnetic resonance CDCl3: Deuterated chloroform H2O: Water DCM: Dichloromethane MeOH: methanol DMF: N,N-dimethylformamide æ:ethyl acetate PE: Petroleum ether Na2SO4: Sodium sulfate Broad s: singlet d: doublet t: triplet m: Multiplet q: Quartet DQ: Quartet's Doublet PPh3: Triphenylphosphine LDA: Lithium diisopropylamide ACN: Acetonitrile NH4HCO3: Ammonium bicarbonate eq: equivalent N: Regulation aq.: water-based M: Molar concentration Boc:tert-butyloxycarbonyl FA: Formic acid Et3N: Triethylamine NaOH: Sodium hydroxide N2: Nitrogen Pd(dppf)Cl2:bis(diphenylphosphin)ferrocene]dichloropalladium(II) complex K3PO4: Tripotassium phosphate NH4Cl: Ammonium chloride pH: Hydrogen ion concentration index TLC: Thin-layer chromatography CuCN: Copper(I) cyanide DMA: Dimethylacetamide NaIO4: Sodium periodate NaHCO3: Sodium bicarbonate NaBH4: Sodium borohydride K3PO4: Anhydrous Tripotassium Phosphate Cs2CO3: Dicecium Carbonate CuI: Copper(I) iodide Pd(PPh3)2Cl2: Dichloropalladium triphenylphosphan Rose Bengal: Dipotassium 4,5,6,7-Tetrachloro-2',4',5',7'-Tetraiodo-3-Oxospiro[2-Benzofuran-1,9'-Xanthene]-3',6'-Diolate Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0) NaH: Sodium hydride K2OsO4-2H2O: Potassium (VI) osmite dihydrate DAST: Diethylaminosulfur trifluoride LiOH: Lithium hydroxide K2CO3: Potassium carbonate, anhydrous Pd(dppf)Cl2-CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane O2: Oxygen DMSO: Dimethyl sulfoxide LED: Light-emitting diode Broad s: singlet d: doublet t: triplet m: Multiplet q: Quartet h: time PPh3: Triphenylphosphine LDA: Lithium diisopropylamide ACN: Acetonitrile NH4HCO3: Ammonium bicarbonate eq: equivalent N: Regulation aq: water-based M: Molar concentration Boc:tert-butyloxycarbonyl FA: Formic acid Et3N: Triethylamine NaOH: Sodium hydroxide N2: Nitrogen Pd(dppf)Cl2:Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex pH: Hydrogen ion concentration index Co(acac)2: Cobalt(II) acetylacetonate Na2S: Sodium sulfide NH3: Ammonia CO: Carbon monoxide t-BuOK: Potassium t-butoxide NaBH(OAc)3: Sodium triacetoxyborohydride SFC: Supercritical Fluid Chromatography PMB: 4-Methoxybenzyl CD3OD: Deuterated methanol MeMgBr: Methylmagnesium bromide HBr: Hydrobromic Acid HI: Hydroiodic acid N2: Nitrogen DMSO-d6: Deuterated Dimethyl Sulfoxide P2S5: Diphosphorus pentasulfide DMAP: 4-dimethylaminopyridine NMP: N-methylpyrrolidone DEA: Diethylamine BOP: (Benzotriazol1yloxy)tris(dimethylamino)phosphonium hexafluorophosphate KI: Potassium iodide MTBE: Methyl tert-butyl ether (Example 1) Synthesis of the Compounds Disclosed

[0290] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-1) [ka]

[0291] Step 1: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0292] To a solution of pyridine (2 mL) containing 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (27 mg, 0.17 mmol, 1.1 equivalents), EDCI (33 mg, 0.17 mmol, 1.1 equivalents) was added, and the mixture was stirred at room temperature for 0.5 hours. Next, N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-3-methyl-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide hydrochloride (intermediate-2, prepared according to the general method of the scheme above) (80 mg, 0.16 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and then diluted with H2O (10 mL). The resulting mixture was adjusted to pH 5 with a 1N HCl aqueous solution and extracted by DCM (10 mL x 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, H2O (10 mmol / L NH4HCO3)-ACN) to obtain the title compound.

[0293] 1 H NMR (400MHz, CDCl3) δ ppm 11.82 (br s, 1H), 8.65 (s, 1H), 8.59 (s, 1H), 8.49 (d, 1H), 8.42 (s, 1H), 7.64 (s, 1H), 7.55 (br d, 1H), 5.75 - 5.51 (m, 1H), 5.38 (br s, 2H), 4.79 (br d, 1H), 4.16 - 3.93 (m, 2H), 3.63 - 3.47 (m, 1H), 3.29 (br d, 2H), 3.10 (br d, 1H), 2.92 - 2.74 (m, 2H), 2.71 (s, 3H), 2.57 (s, 3H), 1.36 (t, 3H).

[0294] LCMS:645.4[M+H] + .

[0295] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-3-methyl-7-(4-(1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-2) [ka]

[0296] Step 1. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-3-methyl-7-(4-(1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0297] A solution of 1-methyl-1H-pyrazole-4-carboxylic acid was reacted according to the procedure described for I-1, and then post-treatment was performed.

[0298] LCMS:617.2[M+H] + .

[0299] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-3) [ka]

[0300] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(3-hydroxypicolinoyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0301] A solution of 3-hydroxypicolinic acid was reacted according to the procedure described for I-1, and then post-treatment was performed.

[0302] LCMS:630.2[M+H] + .

[0303] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(3-hydroxy-2-methoxyisonicotinoyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-4) [ka]

[0304] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(3-hydroxy-2-methoxyisonicotinoyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0305] A solution of 3-hydroxy-2-methoxyisonicotinic acid was reacted according to the procedure described for I-1, and then post-treatment was performed.

[0306] LCMS:660.4[M+H] + .

[0307] Synthesis of 2-(7-(4-acetylpiperazine-1-yl)-6-ethyl-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide(I-5) [ka]

[0308] Step 1. Synthesis of 2-(7-(4-acetylpiperazine-1-yl)-6-ethyl-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0309] Acetic acid was reacted with I-1 according to the procedure described, followed by workup.

[0310] LCMS:551.2[M+H] + .

[0311] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(4-hydroxy-2-methoxynicotinoyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-6) [ka]

[0312] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(3-hydroxy-2-methoxyisonicotinoyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0313] A solution of 4-hydroxy-2-methoxypyridine-3-carboxylic acid (intermediate-101) was reacted according to the procedure described for I-1 and then workd up.

[0314] LCMS:660.2[M+H] + .

[0315] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridine-4-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-7) [ka]

[0316] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridine-4-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0317] To a solution of pyridine (0.5 mL) containing 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (44 mg, 0.29 mmol, 8.0 equivalents), EDCI (55 mg, 0.29 mmol, 8.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 0.5 hours. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-(2-methoxypyridine-4-yl)-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide hydrochloride (intermediate-5) (23 mg, 36 μmol, 1.0 equivalent) was added to the mixture, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0318] LCMS:738.2[M+H] + .

[0319] 1H NMR (400 MHz, CDCl3) δ ppm 11.79 (br s, 1H), 9.08 (s, 1H), 8.65 (s, 1H), 8.59 (s, 1H), 8.50 (d, 1H), 8.32 (d, 1H), 7.69 - 7.63 (m, 2H), 7.54 (br d, 1H), 7.45 (s, 1H), 5.59 (br s, 1H), 5.42 (br s, 2H), 4.79 (br s, 1H), 4.08 - 3.96 (m, 5H), 3.54 (br s, 1H), 3.31 (br s, 2H), 3.11 (br s, 1H), 2.84 (br d, 2H), 2.58 (s, 3H), 1.39 (br t, 3H).

[0320] Synthesis of (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxo-2-(propa-1-en-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (I-8): I-8 was synthesized from intermediate-3 according to the chemistry outlined in scheme 4.

[0321] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxo-2-(propa-1-en-2-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (Synthesis of I-9: I-9 was synthesized from intermediate-3 according to the chemistry outlined in scheme 4.

[0322] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclopropyl-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (I-10): I-10 was synthesized from intermediate-3 according to the chemistry outlined in Scheme 4.

[0323] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxo-2-(propa-1-in-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-11) [ka]

[0324] Step 1: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxo-2-(propa-1-in-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0325] To a solution of pyridine (1 mL) containing N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-8-oxo-7-(piperazin-1-yl)-2-(propa-1-in-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamidotrifluoroacetate (intermediate-20) (33 mg, 62 μmol, 1.0 equivalent) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (19 mg, 0.12 mmol, 2.0 equivalents), EDCI (24 mg, 0.12 mmol, 2.0 equivalents) was added, and the resulting mixture was stirred at 40°C for 15 hours. The mixture was quenched with H2O (10 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 the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0326] LCMS:669.4[M+H] + .

[0327] 1 H NMR (400 MHz, CDCl3) δ ppm 12.05 (s, 1H), 8.67 - 8.59 (m, 3H), 8.51 (br d, 1H), 7.67 (s, 1H), 7.56 (br d, 1H), 5.73 - 5.51 (m, 1H), 5.37 (br d, 2H), 4.88 - 4.67 (m, 1H), 4.07 - 3.95 (m, 2H), 3.62 - 3.44 (m, 1H), 3.37 - 3.22 (m, 2H), 3.17 - 3.04 (m, 1H), 2.90 - 2.73 (m, 2H), 2.60 (s, 3H), 2.15 (s, 3H), 1.39 (br t, 3H).

[0328] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-methoxy-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-12) [ka]

[0329] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-methoxy-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0330] To a 1 mL solution of pyridine containing 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (22 mg, 0.15 mmol, 3.0 equivalents), EDCI (28 mg, 0.15 mmol, 3.0 equivalents) was added and the mixture was stirred at room temperature for 0.5 hours. Next, a 1 mL solution of pyridine containing N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-methoxy-3-methyl-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide hydrochloride (intermediate-16) (26 mg, 48 μmol, 1.0 equivalent) was added, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated and then purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0331] LCMS:675.0[M+H] + .

[0332] 1 H NMR (400 MHz, CDCl3) δ ppm 11.88 (s, 1H), 8.58 (s, 1H), 8.51 (d, 1H), 8.36 (s, 1H), 7.63 (s, 1H), 7.55 (br d, 1H), 5.63 - 5.48 (m, 1H), 5.37 (br s, 2H), 4.86 - 4.69 (m, 1H), 4.17 (s, 3H), 4.09 - 3.98 (m, 2H), 3.60 - 3.46 (m, 1H), 3.33 - 3.20 (m, 2H), 3.16 - 3.03 (m, 1H), 2.91 - 2.70 (m, 2H), 2.61 (s, 3H), 2.57 (s, 3H), 1.34 (br t, 3H).

[0333] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(difluoromethyl)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-13) [ka]

[0334] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(difluoromethyl)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0335] To a solution of pyridine (0.5 mL) containing 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (21 mg, 134 μmol, 6.0 equivalents), EDCI (26 mg, 134 μmol, 6.0 equivalents) was added and the mixture was stirred at room temperature for 0.5 hours. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(difluoromethyl)-6-ethyl-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide hydrochloride (intermediate-19) (13 mg, 22 μmol, 1.0 equivalent) was added to the mixture and the reaction was stirred at 30°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (water (0.1% FA)-ACN) to obtain the title compound.

[0336] LCMS:681.2[M+H] + .

[0337] 1H NMR (400MHz, CDCl3) δ ppm 11.81 (br s, 1H), 9.00 (s, 1H), 8.60 (s, 1H), 8.52 - 8.44 (m, 2H), 7.68 (s, 1H), 7.55 (br d, 1H), 7.08 - 6.77 (m, 1H), 5.62 (br d, 1H), 5.40 (br s, 2H), 4.80 (br d, 1H), 3.98 (br t, 2H), 3.53 (br s, 1H), 3.31 (br s, 2H), 3.18 - 2.98 (m, 1H), 2.83 (m, 2H), 2.58 (s, 3H), 1.39 (t, 3H).

[0338] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-14) [ka]

[0339] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0340] To a solution of 2-(2-bromo-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (intermediate-21) (20 mg, 28 μmol, 1.0 equivalent) in 1,4-dioxane (0.5 mL), dimethylamine hydrochloride (11 mg, 0.14 mmol, 5.0 equivalents) and DIEA (22 mg, 0.17 mmol, 6.0 equivalents) were added. The resulting mixture was stirred at 100°C for 1 hour and then concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0341] LCMS:674.4[M+H] + .

[0342] 1 H NMR (400 MHz, CDCl3) δ ppm 11.91 (s, 1H), 8.58 (s, 2H), 8.54 (d, 1H), 8.20 (s, 1H), 7.61 (d, 1H), 7.53 (dd, 1H), 5.53 (br dd, 1H), 5.31 (br s, 2H), 4.84 - 4.68 (m, 1H), 4.05 (dt, 2H), 3.60 - 3.44 (m, 1H), 3.27 (s, 6H), 3.24 (br s, 2H), 3.15 - 3.00 (m, 1H), 2.88 - 2.67 (m, 2H), 2.56 (s, 3H), 1.34 (t, 3H).

[0343] Synthesis of (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2-ethoxyvinyl)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-15) [ka]

[0344] Step 1. Synthesis of (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2-ethoxyvinyl)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0345] To a solution of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (22 mg, 0.14 mmol, 4.0 equivalents) in pyridine (0.5 mL), EDCI (27 mg, 0.14 mmol, 4.0 equivalents) and (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(2-ethoxyvinyl)-6-ethyl-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamidotrifluoroacetate (intermediate-26) (20 mg, 35 μmol, 1.0 equivalent) were added. The resulting mixture was stirred at 40°C for 1 hour and then concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0346] LCMS:701.4[M+H] + .

[0347] 1H NMR (400 MHz, CDCl3) δ ppm 11.88 (s, 1H), 8.68 (s, 1H), 8.59 (s, 1H), 8.52 (d, 1H), 8.41 (s, 1H), 7.87 (d, 1H), 7.63 (s, 1H), 7.54 (br d, 1H), 6.02 (d, 1H), 5.64 - 5.50 (m, 1H), 5.42 - 5.23 (m, 2H), 4.84 - 4.72 (m, 1H), 4.08 - 3.94 (m, 4H), 3.59 - 3.45 (m, 1H), 3.33 - 3.23 (m, 2H), 3.16 - 3.03 (m, 1H), 2.89 - 2.72 (m, 2H), 2.57 (s, 3H), 1.36 (dt, 6H).

[0348] Synthesis of rac-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-methoxy-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (racemic mixture, trans(I-16)) [ka]

[0349] Step 1. Synthesis of rac-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-methoxy-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (racemic mixture, trans).

[0350] To a solution of rac-2-(7-(2,5-diazabicyclo[4.2.0]octan-2-yl)-6-ethyl-2-methoxy-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide hydrochloride (racemic mixture, trans) (intermediate-29) (45 mg, 80 μmol, 1.0 equivalent) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (15 mg, 95 μmol, 1.2 equivalents) in pyridine (1 mL), EDCI (46 mg, 0.24 mmol, 3.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (0.25 mL), THF (0.25 mL), and H2O (0.5 mL). A 0.5 mL, 1 M aqueous solution of LiOH was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0351] LCMS:701.4[M+H] + .

[0352] 1 H NMR (400 MHz, CDCl3) δ 8.61 (br s, 1H), 8.51 (d, 1H), 8.26 (br s, 1H), 7.62 (s, 1H), 7.54 (br d, 1H), 5.42 - 5.28 (m, 3H), 5.03 - 4.24 (m, 2H), 4.20 (s, 3H), 4.05 - 3.57 (m, 2H), 3.37 (br d, 2H), 3.25 - 3.13 (m, 1H), 2.62 (s, 3H), 2.55 (s, 3H), 2.38 - 1.94 (m, 2H), 1.52 - 1.39 (m, 2H), 1.34 (br t, 3H).

[0353] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclopropyl-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-17) [ka]

[0354] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-cyclopropyl-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0355] To a mixture of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-(2-cyclopropyl-6-ethyl-3-methyl-8-oxo-7-piperazine-1-yl-pyrido[2,3-b]pyrazine-5-yl)acetamide hydrochloride (intermediate-30) (37 mg, 67 μmol, 1.0 equivalent) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (21 mg, 0.14 mmol, 2.0 equivalents) in pyridine (1 mL), EDCI (26 mg, 0.14 mmol, 2.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with H2O (10 mL) and extracted with ELISA (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The title compound was obtained by purifying the residue by reverse-phase HPLC (C18 column, H2O (10 mmol / L NH4HCO3)-ACN).

[0356] LCMS:685.2[M+H] + .

[0357] 1H NMR (400 MHz, CDCl3) δ ppm 11.67 (br s, 1H), 8.58 (s, 1H), 8.51 (d, 1H), 8.43 (s, 1H), 7.63 (d, 1H), 7.55 (br d, 1H), 5.65 - 5.43 (m, 1H), 5.36 (br s, 2H), 4.76 (br dd, 1H), 4.02 (dt, 2H), 3.62 - 3.39 (m, 1H), 3.34 - 3.19 (m, 2H), 3.18 - 2.96 (m, 1H), 2.89 - 2.71 (m, 5H), 2.57 (s, 3H), 2.24 - 2.16 (m, 1H), 1.37 - 1.30 (m, 5H), 1.10 (br dd, 2H).

[0358] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxo-2-vinylpyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-18) [ka]

[0359] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxo-2-vinylpyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0360] To a solution of 2-(2-bromo-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4(trifluoromethyl)phenyl)acetamide (intermediate-23) (40 mg, 55 μmol, 1.0 equivalent) and potassium trifluoro(vinyl)borate (7 mg, 55 μmol, 1.0 equivalent) in dioxane (4 mL) and H2O (0.8 mL), Pd(dppf)Cl2 (4 mg, 6 μmol, 0.1 equivalent) and K3PO4 (23 mg, 0.11 mmol, 2.0 equivalent) were added. The reaction mixture was degassed and purged with N2 three times, and then stirred at 80°C for 1 hour under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with ELISA (10 mL x 2). The combined organic layers were washed with brine (7.5 mL x 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0361] LCMS:671.2[M+H] + .

[0362] 1 H NMR (400 MHz, CDCl3) δ ppm 11.81 (s, 1H), 8.59 (s, 1H), 8.51 (d, 1H), 8.39 (br s, 1H), 7.63 (s, 1H), 7.55 (br d, 1H), 7.09 - 6.99 (m, 1H), 6.74 (d, 1H), 5.73 (d, 1H), 5.64 - 5.53 (m, 1H), 5.36 (br d, 2H), 4.87 - 4.70 (m, 1H), 4.08 - 3.96 (m, 2H), 3.60 - 3.46 (m, 1H), 3.34 - 3.22 (m, 2H), 3.16 - 3.04 (m, 1H), 2.95 - 2.77 (m, 2H), 2.75 (s, 3H), 2.58 (s, 3H), 1.39 - 1.34 (m, 3H).

[0363] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-chloro-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-19) [ka]

[0364] Step 1: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-chloro-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0365] To a solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-chloro-6-ethyl-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide hydrochloride (intermediate-31) (390 mg, 737 μmol, 1.0 equivalent) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (227 mg, 1.47 mmol, 2.0 equivalents) in pyridine (5 mL), EDCI (282 mg, 1.47 mmol, 2.0 equivalents) was added, and the resulting mixture was stirred at 40°C for 15 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0366] LCMS:665.4[M+H] + .

[0367] 1H NMR (400 MHz, CDCl3) δ 11.83 (s, 1H), 8.62 (d, 2H), 8.52 - 8.42 (m, 2H), 7.69 (d, 1H), 7.56 (d, 1H), 5.69 - 5.57 (m, 1H), 5.39 (br s, 2H), 4.88 - 4.73 (m, 1H), 4.08 - 3.93 (m, 2H), 3.62 - 3.48 (m, 1H), 3.30 (br d, 2H), 3.17 - 3.04 (m, 1H), 2.91 - 2.72 (m, 2H), 2.59 (s, 3H), 1.39 (t, 3H).

[0368] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(methylamino)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-20) [ka]

[0369] Step 1: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(methylamino)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0370] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-((4-methoxybenzyl)(methyl)amino)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (intermediate-32) (15 mg, 19 μmol, 1.0 equivalent) was dissolved in TFA (0.5 mL) and then stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0371] LCMS:660.4[M+H] + .

[0372] 1 H NMR (400 MHz, CDCl3) δ ppm 8.99 (s, 1H), 8.60 (s, 1H), 8.40 (br d, 1H), 8.22 (s, 1H), 7.64 (s, 1H), 7.50 (br d, 1H), 5.70 - 5.32 (m, 3H), 4.85 - 4.65 (m, 1H), 4.02 - 3.75 (m, 2H), 3.61 - 3.41 (m, 1H), 3.27 (br s, 2H), 3.13 - 2.97 (m, 4H), 2.87 - 2.72 (m, 2H), 2.58 (s, 3H), 1.35 (br t, 3H).

[0373] Synthesis of (E)N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxo-2-(propa-1-en-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-21) [ka]

[0374] Step 1. Synthesis of (E)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxo-2-(propa-1-en-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0375] To a solution of 2-(2-bromo-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (intermediate-23) (50 mg, 69 μmol, 1.0 equivalent) and (E)-propa-1-en-1-ylboronic acid (6 mg, 69 μmol, 1.0 equivalent) in 1,4-dioxane (1 mL) and H2O (0.2 mL), Pd(dppf)Cl2-CH2Cl2 (6 mg, 7 μmol, 0.1 equivalent) and K3PO4 (29 mg, 0.14 mmol, 2.0 equivalent) were added, and the resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The reaction mixture was quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with RINKAN (50 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, H2O (10 mmol / L NH4HCO3)-ACN) to obtain the title compound.

[0376] LCMS:685.2[M+H] + .

[0377] 1H NMR (400 MHz, CDCl3) δ ppm 11.68 (br s, 1H), 8.60 (s, 1H), 8.52 (br d, 1H), 8.47 (br s, 1H), 7.63 (s, 1H), 7.56 (br d, 1H), 7.37 - 7.30 (m, 1H), 6.69 (br d, 1H), 5.73 - 5.51 (m, 1H), 5.37 (br s, 2H), 4.91 - 4.67 (m, 1H), 4.11 - 3.92 (m, 2H), 3.65 - 3.45 (m, 1H), 3.36 - 3.23 (m, 2H), 3.19 - 3.02 (m, 1H), 2.91 - 2.76 (m, 2H), 2.73 (s, 3H), 2.59 (s, 3H), 2.01 (br d, 3H), 1.37 (br t, 3H).

[0378] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-hydroxypropan-2-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-22) [ka]

[0379] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(2-hydroxypropan-2-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0380] To a solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxo-2-(propa-1-en-2-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-23) (30 mg, 44 μmol, 1 equivalent) in THF (1 mL), phenylsilane (9 mg, 88 μmol, 2.0 equivalents) and bis[(Z)-1-methyl-3-oxobuta-1-enoxy]cobalt (1 mg, 2 μmol, 0.05 equivalents) were added. The resulting mixture was stirred at room temperature under an O2 atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure and then purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0381] LCMS:703.4[M+H] + .

[0382] 1 H NMR (400 MHz, CDCl3) δ ppm 8.58 (s, 1H), 8.48 (br d, 1H), 8.42 - 8.24 (m, 1H), 7.65 (s, 1H), 7.55 (br d, 1H), 7.49 - 7.28 (m, 1H), 5.75 - 5.50 (m, 1H), 5.48 - 5.13 (m, 2H), 5.12 - 4.84 (m, 1H), 4.83 - 4.59 (m, 1H), 4.32 - 3.76 (m, 2H), 3.62 - 3.39 (m, 1H), 3.38 - 3.18 (m, 2H), 3.18 - 2.98 (m, 1H), 2.97 - 2.82 (m, 3H), 2.81 - 2.70 (m, 1H), 2.57 (s, 3H), 1.70 (br s, 6H), 1.36 (br t, 3H).

[0383] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxo-2-(propa-1-en-2-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-23) [ka]

[0384] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxo-2-(propa-1-en-2-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0385] To a solution of 2-(2-bromo-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (intermediate-23) (50 mg, 69 μmol, 1.0 equivalent) and potassium trifluoro(propa-1-en-2-yl)borate (11 mg, 76 μmol, 1.1 equivalents) in 1,4-dioxane (1 mL) and H2O (0.2 mL), Pd(dppf)Cl2 (5 mg, 7 μmol, 0.1 equivalent) and K3PO4 (29 mg, 0.14 mmol, 2.0 equivalents) were added. The resulting mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with H2O (10 mL), and extracted with RINKAN (5 mL x 3). The combined organic layer was washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0386] LCMS:685.4[M+H] +.

[0387] 1 H NMR (400 MHz, CDCl3) δ ppm 11.79 (br s, 1H), 8.58 (s, 1H), 8.49 (br d, 2H), 7.63 (s, 1H), 7.55 (br d 1H), 5.69 - 5.50 (m, 2H), 5.49 - 5.28 (m, 2H), 5.22 (s, 1H), 4.89 - 4.65 (m, 1H), 4.12 - 3.87 (m, 2H), 3.63 - 3.41 (m, 1H), 3.40 - 3.18 (m, 2H), 3.17 - 2.99 (m, 1H), 2.98 - 2.76 (m, 2H), 2.74 (s, 3H), 2.57 (s, 3H), 2.24 (s, 3H), 1.42 - 1.28 (m, 3H).

[0388] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-hydroxy-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-24) [ka]

[0389] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-hydroxy-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0390] To a solution of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (29 mg, 0.16 mmol, 4.0 equivalents) in pyridine (0.5 mL), EDCI (32 mg, 0.16 mmol, 4.0 equivalents) was added, and the mixture was stirred at room temperature for 0.5 hours. Next, N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-hydroxy-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide hydrochloride (intermediate-34) (21 mg, 41 μmol, 1.0 equivalent) was added at room temperature, and the reaction mixture was stirred at 40 °C for 16 hours. The reaction mixture was concentrated under reduced pressure, and then purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0391] LCMS:647.1[M+H] + .

[0392] 1 H NMR (400 MHz, CHCl3) δ 11.65 (br s, 1H), 8.60 (s, 1H), 8.50 (d, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 7.70 (s, 1H), 7.57 (br d, 1H), 5.59 - 5.44 (m, 1H), 5.36 (br s, 2H), 4.90 - 4.73 (m, 1H), 4.01 (br t, 2H), 3.59 - 3.41 (m, 1H), 3.32 - 3.19 (m, 2H), 3.14 - 3.02 (m, 1H), 2.90 - 2.71 (m, 2H), 2.58 (s, 3H), 1.35 (br t, 3H).

[0393] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(hydroxymethyl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-25) [ka]

[0394] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(hydroxymethyl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0395] To a solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-(hydroxymethyl)-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamidotrifluoroacetate (intermediate-35) (40 mg, 76 μmol, 1.0 equivalent) in pyridine (0.8 mL), EDCI (44 mg, 0.23 mmol, 3.0 equivalents) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (40 mg, 0.23 mmol, 3.0 equivalents) were added. The mixture was stirred at 40°C for 16 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (water (0.1% FA)-ACN) to obtain the title compound.

[0396] LCMS:661.1[M+H] + .

[0397] 1 1H NMR (400 MHz, CDCl3) δ ppm 8.86 (br d, 1H), 8.80 (s, 1H), 8.58 (s, 1H), 8.43 (br d, 1H), 7.63 (s, 1H), 7.51 (br d, 1H), 5.55 - 5.39 (m, 3H), 5.00 (s, 2H), 4.77 - 4.70 (m, 1H), 4.04 - 3.92 (m, 2H), 3.55 - 3.46 (m, 1H), 3.29 (br s, 2H), 3.10 - 3.04 (m, 1H), 2.85 - 2.75 (m, 2H), 2.56 (s, 3H), 1.36 (br t, 3H).

[0398] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(difluoromethoxy)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-26) [ka]

[0399] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(difluoromethoxy)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0400] To a solution of pyridine (0.5 mL) containing 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (18 mg, 0.10 mmol, 4.0 equivalents), EDCI (19 mg, 0.10 mmol, 4.0 equivalents) was added, and the mixture was stirred at room temperature for 0.5 hours. Next, N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(difluoromethoxy)-6-ethyl-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide hydrochloride (intermediate-36) (14 mg, 25 μmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0401] LCMS:697.1[M+H] + .

[0402] 1H NMR (400 MHz, CDCl3) δ ppm 11.75 (br s, 1H), 8.59 (s, 1H), 8.48 (d, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 7.75 (t, 1H), 7.67 (d, 1H), 7.55 (d, 1H), 5.59 (d, 1H), 5.38 (s, 2H), 4.77 (s, 1H), 4.06 - 3.89 (m, 2H), 3.52 (s, 1H), 3.28 (s, 2H), 3.10 (s, 1H), 2.92 - 2.68 (m, 2H), 2.57 (s, 3H), 1.37 (t, 3H).

[0403] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxo-2-(2-oxopyrrolidine-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-27) [ka]

[0404] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxo-2-(2-oxopyrrolidine-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0405] To a solution of pyridine (0.5 mL) containing 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (34 mg, 0.22 mmol, 5.0 equivalents), EDCI (42 mg, 0.22 mmol, 5.0 equivalents) was added, and the mixture was stirred at room temperature for 0.5 hours. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-8-oxo-2-(2-oxopyrrolidine-1-yl)-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide hydrochloride (intermediate-37) (27 mg, 44 μmol, 1.0 equivalent) was added to the mixture, and the reaction mixture was stirred at 30°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (water (0.1% FA)-ACN) to obtain the title compound.

[0406] LCMS:714.2[M+H] + .

[0407] 1 H NMR (400MHz, CDCl3) δ ppm 11.79 (br s, 1H), 9.88 (s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 8.51 (d, 1H), 7.64 (s, 1H), 7.53 (d, 1H), 5.57 (br s, 1H), 5.37 (br s, 2H), 4.77 (br s, 1H), 4.28 (t, 2H), 4.08 - 3.96 (m, 2H), 3.61 - 3.45 (m, 1H), 3.32 (br d, 2H), 3.11 (br s, 1H), 2.82 (br d, 2H), 2.73 (t, 2H), 2.57 (s, 3H), 2.23 (m, 2H), 1.38 (t, 3H).

[0408] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(difluoromethyl)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-28) [ka]

[0409] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(difluoromethyl)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0410] To a solution of pyridine (1 mL) containing 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (69 mg, 0.45 mmol, 5.0 equivalents), EDCI (77 mg, 0.40 mmol, 4.5 equivalents) was added, and the resulting mixture was stirred at room temperature for 0.5 hours. Next, N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(difluoromethyl)-6-ethyl-3-methyl-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide hydrochloride (intermediate-39) (50 mg, 89 μmol, 1.0 equivalent) was added, and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and then purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0411] LCMS:695.1[M+H] + .

[0412] 1H NMR (400 MHz, CDCl3) δ 11.84 (s, 1H), 8.60 (s, 1H), 8.47 (d, 1H), 8.30 (s, 1H), 7.68 (d, 1H), 7.59 - 7.52 (m, 1H), 7.12 - 6.79 (m, 1H), 5.68 - 5.53 (m, 1H), 5.44 - 5.31 (m, 2H), 4.90 - 4.72 (m, 1H), 4.05 - 3.93 (m, 2H), 3.59 - 3.46 (m, 1H), 3.33 - 3.21 (m, 2H), 3.17 - 3.05 (m, 1H), 2.87 (s, 3H), 2.85 - 2.73 (m, 2H), 2.57 (s, 3H), 1.39 - 1.35 (m, 3H).

[0413] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-29) [ka]

[0414] Step 1. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0415] DIEA (54 mg, 0.41 mmol, 6.0 equivalents) was added to a solution of 2-(2-bromo-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-3-methyl-8-oxopyrid[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (50 mg, 69 μmol, 1.0 equivalent) and dimethylamine hydrochloride (41 mg, 0.35 mmol, 5.0 equivalents) in 1,4-dioxane (1 mL), and the resulting mixture was stirred at 100 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and then purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0416] LCMS:688.2[M+H] + .

[0417] 1 H NMR (400 MHz, CDCl3) δ 8.78 - 8.66 (m, 1H), 8.61 (s, 1H), 8.40 (br d, 1H), 7.65 (s, 1H), 7.53 (br d, 1H), 5.57 (br s, 3H), 4.86 - 4.73 (m, 1H), 3.97 (br t, 2H), 3.60 - 3.46 (m, 1H), 3.32 (br d, 2H), 3.09 (s, 7H), 2.94 - 2.78 (m, 2H), 2.72 (s, 3H), 2.58 (s, 3H), 1.36 (t, 3H).

[0418] Synthesis of 2-(2-acetamido-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide(I-31) [ka]

[0419] Step 1. Synthesis of 2-(2-acetamido-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0420] To a solution of pyridine (1 mL) containing 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (45 mg, 0.29 mmol, 4.0 equivalents), EDCI (56 mg, 0.29 mmol, 4.0 equivalents) and 2-(2-acetamido-6-ethyl-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamidotrifluoroacetate (intermediate-51) (40 mg, 72 μmol, 1.0 equivalent) were added, and the resulting mixture was stirred overnight at 40°C. The reaction mixture was concentrated under reduced pressure and then purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0421] LCMS:688.3[M+H] + .

[0422] 1 H NMR (400 MHz, CDCl3) δ ppm 9.66 (s, 1H), 9.29 - 9.04 (m, 1H), 8.74 - 8.61 (m, 1H), 8.59 (s, 1H), 8.48 (d, 1H), 7.65 (d, 1H), 7.58 - 7.48 (m, 1H), 5.64 - 5.47 (m, 1H), 5.46 - 5.19 (m, 2H), 4.88 - 4.66 (m, 1H), 4.06 - 3.88 (m, 2H), 3.51 (br t, 1H), 3.38 - 3.24 (m, 2H), 3.10 (br d, 1H), 2.87 - 2.73 (m, 2H), 2.56 (s, 3H), 2.26 (s, 3H), 1.37 (br t, 3H).

[0423] Synthesis of rac-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (racemic mixture, trans, I-34) [ka]

[0424] Step 1: Synthesis of rac-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (racemic mixture, trans)

[0425] EDCI (54 mg, 0.28 mmol, 2.0 equivalents) was added to a mixture of rac-2-(7-(2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(dimethylamino)-6-ethyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamidetrifluoroacetate (racemic mixture, trans) (intermediate-45) (80 mg, 0.14 mmol, 1.0 equivalent) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (44 mg, 0.28 mmol, 2.0 equivalents) in pyridine (2 mL). The mixture was stirred at room temperature for 1 hour, and then quenched with H2O (100 mL). The resulting mixture was extracted with ELISA (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0426] LCMS:700.4[M+H] + .

[0427] 1 HNMR: (400 MHz, CDCl3) δ ppm 12.71 (s, 1H), 8.61 (br s, 1H), 8.54 (d, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 7.60 (s, 1H), 7.53 (br d, 1H), 5.78 - 4.87 (m, 3H), 4.57 - 4.10 (m, 2H), 4.02 - 3.53 (m, 2H), 3.37 (br d, 2H), 3.29 (s, 6H), 3.21 - 3.11 (m, 1H), 2.61 - 1.95 (m, 5H), 1.57 - 1.38 (m, 2H), 1.34 (br t, 3H).

[0428] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclobutylidenemethyl)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-38) [ka]

[0429] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(cyclobutylidenemethyl)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0430] To a solution of 2-(2-bromo-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (intermediate-21) (30 mg, 42 μmol, 1.0 equivalent) and 2-(cyclobutylidenemethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8 mg, 42 μmol, 1.0 equivalent) in 1,4-dioxane (0.5 mL) and H2O (0.1 mL), Pd(dppf)Cl2 (3 mg, 4 μmol, 0.1 equivalent) and K3PO4 (18 mg, 85 μmol, 2.0 equivalent) were added. The resulting mixture was stirred at 80°C for 1 hour and then concentrated under vacuum. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0431] LCMS:697.2[M+H] + .

[0432] 1 H NMR (400 MHz, CDCl3) δ ppm 8.70 (br s, 1H), 8.58 (s, 1H), 8.55 - 8.49 (m, 2H), 7.63 (d, 1H), 7.54 (br d, 1H), 6.47 (br s, 1H), 5.64 - 5.51 (m, 1H), 5.34 (br s, 2H), 4.86 - 4.72 (m, 1H), 4.11 - 3.96 (m, 2H), 3.60 - 3.44 (m, 1H), 3.38 - 3.20 (m, 4H), 3.17 - 3.05 (m, 1H), 2.98 (br t, 2H), 2.89 - 2.71 (m, 2H), 2.57 (s, 3H), 2.18 (q, 2H), 1.36 (br t, 3H).

[0433] Acquisition of first and second elutes by chiral separation of rac-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (racemic mixture, trans, I-34); stereoisomer 1 and stereoisomer 2; (I-39 and I-40)

[0434] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (single stereoisomer, first eluted compound as stereoisomer 1, trans) (I-39); and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (single stereoisomer, second eluted compound as stereoisomer 2, trans) (I-40) [ka]

[0435] rac-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrid[2,3-b]pyrazine-5(8H)-yl)acetamide (racemic mixture, trans) was subjected to chiral SFC (SFC preparative method: Equipment: Waters 80Q preparative SFC system; Column: Daicel Chiralpak OD column, 250×25mm) The title compound was obtained by separation using the following method: ID, 10 μm particle size; mobile phase A: CO2, mobile phase B: EtOH (0.1% saturated aqueous NH3); isocratic elution: 35% phase B in supercritical CO2; flow rate: 70 g / min; retention time: peak 1: 5.40 min, peak 2: 7.86 min; back pressure: 100 bar to maintain CO2 in a supercritical flow; wavelength: 220 nm).

[0436] SFC analysis method: [Table 5]

[0437] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide, single isomer, first eluted stereoisomer as stereoisomer 1, retention time (SFC analysis method): 2.09 min.

[0438] LCMS:700.4[M+H] + .

[0439] 1HNMR: (400 MHz, CDCl3) δ ppm 8.61 (br s, 1H), 8.55 (d, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 7.60 (d, 1H), 7.54 (br d, 1H), 5.64 - 4.97 (m, 3H), 4.52 - 4.18 (m, 2H), 4.02 - 3.73 (m, 2H), 3.37 (br d, 2H), 3.29 (s, 6H), 3.23 - 3.11 (m, 1H), 2.68 - 1.87 (m, 5H), 1.43 (br d, 2H), 1.34 (t, 3H).

[0440] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide, single stereoisomer, second eluted stereoisomer as stereoisomer 2, retention time (SFC analysis method): 2.30 min.

[0441] LCMS:700.4[M+H] + .

[0442] 1 HNMR: (400 MHz, CDCl3) δ ppm 8.60 (br s, 1H), 8.54 (d, 1H), 8.45 (br s, 1H), 8.22 (s, 1H), 7.60 (s, 1H), 7.53 (br d, 1H), 5.58 - 4.91 (m, 3H), 4.51 - 4.19 (m, 2H), 4.03 - 3.64 (m, 2H), 3.37 (br d, 2H), 3.29 (s, 6H), 3.19-3.17 (m, 1H), 2.64 - 2.58 (m, 1H), 2.55 (s, 3H), 2.33 - 2.23 (m, 1H), 1.71 - 1.62 (m, 1H), 1.43 - 1.37 (m, 1H), 1.34 (t, 3H).

[0443] Synthesis of 5-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N,N-dimethyl-8-oxo-5,8-dihydropyrido[2,3-b]pyrazine-2-carboxamide (I-48) [ka]

[0444] Step 1. 5-[2-[2-chloro-4-(trifluoromethyl)anilino]-2-oxo-ethyl]-6-ethyl-7-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl]-N,N-dimethyl-8-oxopyrido[2,3-b]pyrazine-2-carboxamide

[0445] To a solution of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (22 mg, 0.14 μmol, 2.0 equivalents) in pyridine (1 mL), EDCI (27 mg, 0.14 mmol, 2.0 equivalents) and 5-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-6-ethyl-N,N-dimethyl-8-oxo-7-(piperazin-1-yl)-5,8-dihydropyrido[2,3-b]pyrazine-2-carboxamide hydrochloride (intermediate-50) (40 mg, 71 μmol, 1.0 equivalent) were added. The mixture was stirred at 40°C for 1 hour and then concentrated under vacuum. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0446] LCMS:702.2[M+H] + .

[0447] 1H NMR (400 MHz, CDCl3) δ ppm 9.18 (s, 1H), 8.93 - 8.65 (m, 1H), 8.58 (s, 1H), 8.45 (br d, 1H), 7.67 (s, 1H), 7.53 (br d, 1H), 5.69 - 5.51 (m, 1H), 5.50 - 5.30 (m, 2H), 4.90 - 4.66 (m, 1H), 3.99 (br t, 2H), 3.59 - 3.46 (m, 1H), 3.39 (s, 3H), 3.35 - 3.24 (m, 2H), 3.18 (s, 3H), 3.12 - 3.03 (m, 1H), 2.95 - 2.74 (m, 2H), 2.57 (s, 3H), 1.38 (br t, 3H).

[0448] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(morpholinomethyl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-49) [ka]

[0449] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(morpholinomethyl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0450] To a solution of pyridine (1 mL) containing 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (31 mg, 0.20 μmol, 2.0 equivalents), EDCI (39 mg, 0.20 mmol, 2.0 equivalents) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-(morpholinomethyl)-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]pyrazine-5(8H)-yl)acetamide hydrochloride (intermediate-49) (60 mg, 0.10 μmol, 1.0 equivalent) were added. The mixture was stirred at 40°C for 1 hour and then concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0451] LCMS:730.2[M+H] + .

[0452] 1 H NMR (400 MHz, CDCl3) δ ppm 8.87 (s, 1H), 8.84 (br s, 1H), 8.58 (s, 1H), 8.48 (d, 1H), 7.64 (d, 1H), 7.53 (br d, 1H), 5.56 (br d, 1H), 5.42 (br s, 2H), 4.82 - 4.69 (m, 1H), 4.10 - 3.94 (m, 2H), 3.90 (s, 2H), 3.77 - 3.65 (m, 4H), 3.50 (br d, 1H), 3.30 (br d, 2H), 3.09 (br s, 1H), 2.91 - 2.72 (m, 2H), 2.68 - 2.44 (m, 7H), 1.36 (t, 3H).

[0453] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(7-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-methyl-5-oxopyrido[2,3-b]thieno[3,2-e]pyrazine-8(5H)-yl)acetamide(I-61) [ka]

[0454] Step 1. Synthesis of tert-butyl4-(8-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-7-ethyl-2-methyl-5-oxo-5,8-dihydropyrido[2,3-b]thieno[3,2-e]pyrazine-6-yl)piperazine-1-carboxylate

[0455] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(7-ethyl-2-methyl-5-oxo-6-(piperazin-1-yl)pyrido[2,3-b]thieno[3,2-e]pyrazine-8(5H)-yl)acetamide hydrochloride (intermediate-48) (27 mg, 45 μmol, 1 equivalent) and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (intermediate-13) (27 mg, 0.14 mmol, 3 equivalents) were dissolved in pyridine (0.5 mL) and EDCI (26 mg, 0.14 mmol, 3 equivalents) were added. The mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO2, MeOH / DCM eluent) and reverse-phase HPLC (C18 column, water (FA)-ACN) to obtain the title compound.

[0456] 1 H NMR (400 MHz, CD3OD) δ ppm 8.57 (s, 1H), 8.09 (d, 1H), 7.83 (s, 1H), 7.61 (d, 1H), 7.39 - 7.31 (m, 1H), 5.68 (s, 2H), 4.82 - 4.68 (m, 2H), 4.64 - 4.57 (m, 1H), 4.19 - 4.07 (m, 1H), 3.97 (q, 2H), 3.54 - 3.42 (m, 1H), 3.23 - 3.12 (m, 1H), 3.01 - 2.89 (m, 1H), 2.86 - 2.77 (m, 1H), 2.74 (s, 3H), 2.55 (s, 3H), 1.40 (t, 3H).

[0457] LCMS:701.2[M+H] + .

[0458] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-methyl-8-oxopyrido[2,3-b]thiazolo[4,5-e]pyrazine-5(8H)-yl)acetamide(I-95) [ka]

[0459] Step 15. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-methyl-8-oxopyrido[2,3-b]thiazolo[4,5-e]pyrazine-5(8H)-yl)acetamide

[0460] To a 1 mL solution of pyridine containing N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-methyl-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]thiazolo[4,5-e]pyrazine-5(8H)-yl)acetamidetrifluoroacetate (intermediate-54) (21 mg, 31 μmol, 1 equivalent) and sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate (intermediate-55) (25 mg, 0.13 mmol, 4 equivalents), EDCI (24 mg, 0.13 mmol, 4 equivalents) was added, and the mixture was stirred at 25°C for 14 hours. Next, sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate (6 mg, 31 μmol, 1 equivalent) and EDCI (6 mg, 31 μmol, 1 equivalent) were added at 60°C, and the reaction mixture was stirred at 60°C for 1 hour. This process of adding sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate (6 mg, 31 μmol, 1 equivalent) and EDCI (6 mg, 31 μmol, 1 equivalent) and stirring at 60°C for 1 hour was repeated five times. The reaction mixture was concentrated to obtain a residue. The residue was purified by preparative TLC (using SiO2, MeOH / DCM as the eluent) to obtain the title compound.

[0461] 1 H NMR (400 MHz, CD3OD) δ ppm 8.54 (s, 1H), 8.07 (d, 1H), 7.80 (d, 1H), 7.58 (m, 1H), 5.69 (s, 2H), 4.12 - 4.09 (m, 1H), 3.96 - 3.90 (m, 2H), 3.54 - 3.40 (m, 1H), 3.36 - 3.32 (m, 2H), 3.21 - 3.11 (m, 1H), 3.01 - 2.85 (m, 5H), 2.82 - 2.73 (m, 1H), 2.52 (s, 3H), 1.38 (t, 3H).

[0462] LCMS:702.3[M+H] + .

[0463] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(dimethylamino)-2-ethyl-7-fluoro-3-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-4-oxo-1,5-naphthyridine-1(4H)-yl)acetamide (I-109) [ka]

[0464] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(dimethylamino)-2-ethyl-7-fluoro-3-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-4-oxo-1,5-naphthyridine-1(4H)-yl)acetamide

[0465] N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[6-(dimethylamino)-2-ethyl-7-fluoro-4-oxo-3-piperazine-1-yl-1,5-naphthyridine-1-yl]acetamide hydrochloride (intermediate-57) (14 mg, 23 μmol, 1 equivalent) and 5-hydroxy-6-methylpyrimidine-4-carboxylate sodium (intermediate-55) (23 mg, 118 μmol, 5 equivalents) were dissolved in pyridine (0.4 mL) and EDCI (18 mg, 95 μmol, 4 equivalents) was added. The mixture was stirred at 20°C for 2 hours. Brine (15 mL) was added to the reaction mixture, and the mixture was extracted with ELISA (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH) to obtain the title compound.

[0466] 1H NMR (400 MHz, CDCl3) δ ppm 12.30 - 11.04 (m, 1H), 9.02 (br s, 1H), 8.56 (s, 1H), 8.44 (d, 1H), 7.60 (s, 1H), 7.53 (d, 1H), 7.34 (d, 1H), 5.63 - 5.40 (m, 1H), 5.09 (s, 2H), 4.90 - 4.63 (m, 1H), 4.60 - 4.29 (m, 1H), 4.07 (q, 2H), 3.49 (s, 1H), 3.26 - 3.00 (m, 7H), 2.90 - 2.67 (m, 2H), 2.55 (s, 3H), 2.10 - 1.97 (m, 1H), 1.27 (t, 3H).

[0467] LCMS:691.3[M+H] + .

[0468] Synthesis of 2-(2-(dimethylamino)-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide(I-110) [ka]

[0469] Step 1. Synthesis of 2-(2-(dimethylamino)-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide

[0470] To a solution of 2-(2-(dimethylamino)-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetic acid (intermediate-62) (17 mg, 33 μmol, 1.0 equivalent) and 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine hydrochloride (12 mg, 65 μmol, 2.0 equivalents) in DMF (1 mL), HATU (25 mg, 65 μmol, 2.0 equivalents) and DIEA (13 mg, 98 μmol, 3.0 equivalents) were added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with H2O (10 mL) and extracted with SiO (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0471] LCMS:656.5[M+H] + .

[0472] 1 H NMR (400 MHz, CDCl3) δ ppm 12.60 (s, 1H), 8.74 - 8.49 (m, 1H), 8.32 (br s, 1H), 6.90 - 6.43 (m, 1H), 5.75 - 4.79 (m, 3H), 4.39 - 4.08 (m, 2H), 4.00 - 3.51 (m, 2H), 3.40 (br s, 1H), 3.31 (s, 6H), 3.28 - 3.22 (m, 1H), 3.13 (br s, 1H), 2.55 (s, 3H), 2.29 (s, 8H), 1.56 - 1.36 (m, 2H), 1.30 (br t, 3H).

[0473] Synthesis of 2-(2-(bis(methyl-d3)amino)-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide(I-101) [ka]

[0474] Step 1. Synthesis of 2-(2-(bis(methyl-d3)amino)-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0475] To a solution of 2-(2-bromo-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (intermediate-63) (40 mg, 54 μmol, 1.0 equivalent) in 1,4-dioxane (1 mL), DIEA (42 mg, 326 μmol, 6.0 equivalents) and bis(methyl-d3)amine hydrochloride (24 mg, 272 μmol, 5.0 equivalents) were added. The resulting mixture was stirred at 100°C for 1 hour and then concentrated under reduced pressure. The title compound was obtained by purifying the residue by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN).

[0476] LCMS:706.3[M+H] + .

[0477] 1 1H NMR (400 MHz, CDCl3) δ 12.68 (s, 1H), 8.61 (br s, 1H), 8.55 (d, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 7.60 (s, 1H), 7.54 (d, 1H), 5.80 - 4.89 (m, 3H), 4.54 - 4.14 (m, 2H), 4.06 - 3.56 (m, 2H), 3.47 - 3.27 (m, 2H), 3.25 - 3.00 (m, 1H), 2.61 - 1.94 (m, 5H), 1.50 - 1.39 (m, 2H), 1.34 (t, 3H).

[0478] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(7-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-3-(2-methylpropa-1-en-1-yl)-5-oxopyrido[3,2-e][1,2,4]triazine-8(5H)-yl)acetamide(I-111) [ka]

[0479] Step 1: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(7-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-3-(2-methylpropa-1-en-1-yl)-5-oxopyrido[3,2-e][1,2,4]triazine-8(5H)-yl)acetamide

[0480] To a 2 mL solution of pyridine containing 2-(6-((1S,6S)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-ethyl-3-(2-methylpropa-1-en-1-yl)-5-oxopyrido[3,2-e][1,2,4]triazine-8(5H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamidotrifluoroacetate (intermediate-69) (170 mg, 295 μmol, 1.0 equivalent) and sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate (intermediate-55) (91 mg, 590 μmol, 2.0 equivalents), EDCI (141 mg, 738 μmol, 2.5 equivalents) was added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated NH4Cl aqueous solution (10 mL) and then extracted with RINKAN (5 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0481] LCMS:712.2[M+H] + .

[0482] 1 H NMR (400 MHz, CDCl3) δ ppm 12.48 (m, 1H), 8.74 (s, 1H), 8.53 (s, 1H), 8.34 (d, 1H), 7.56 (s, 1H), 7.42 (d, 1H), 6.73 (s, 1H), 5.58 (s, 2H), 4.80 (d, 1H), 4.15 (s, 2H), 3.96 - 3.45 (m, 2H), 3.41 - 3.01 (m, 3H), 2.47 (s, 3H), 2.37 - 2.16 (m, 4H), 2.03 (s, 3H), 1.97 - 1.72 (m, 2H), 1.39 (s, 1H), 1.31 (t, 3H).

[0483] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(7-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-methyl-5-oxoflo[2,3-b]pyrido[3,2-e]pyrazine-8(5H)-yl)acetamide(I-112) [ka]

[0484] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(7-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-methyl-5-oxoflo[2,3-b]pyrido[3,2-e]pyrazine-8(5H)-yl)acetamide

[0485] To a solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(7-ethyl-2-methyl-5-oxo-6-(piperazine-1-yl)flo[2,3-b]pyrido[3,2-e]pyrazine-8(5H)-yl)acetamide hydrochloride (intermediate-72) (80 mg, 137 μmol, 1 equivalent) in pyridine (2 mL), EDCI (131 mg, 685 μmol, 5 equivalents) and sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate (intermediate-55) (120 mg, 685 μmol, 5 equivalents) were added. The mixture was stirred at 25°C for 12 hours. The mixture was poured into H2O (20 mL) and extracted by DCM (10 mL x 3). The combined organic layers were concentrated under vacuum to obtain the residue. The title compound was obtained by purifying the residue by reverse-phase HPLC (C18 column, water (10 mmol / L FA)-ACN).

[0486] 1H NMR (400 MHz, CD3OD) δ ppm 8.55 (s, 1H), 8.11 (d, 1H), 7.81 (d, 1H), 7.58 (d, 1H), 6.87 (s, 1H), 5.64 (s, 2H), 4.71- 4.68 (m, 1H), 4.18 - 4.05 (m, 1H), 3.95 - 3.93 (m, 2H), 3.53 - 3.40 (m, 1H), 3.30 - 3.29 (m, 2H), 3.21 - 3.09 (m, 1H), 3.00 - 2.87 (m, 1H), 2.82 - 2.73 (m, 1H), 2.61 (s, 3H), 2.52 (s, 3H), 1.37 (t, 3H).

[0487] LCMS:685.3[M+H] + .

[0488] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-methyl-8-oxopyrido[2,3-b]thieno[2,3-e]pyrazine-5(8H)-yl)acetamide(I-113) [ka]

[0489] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-methyl-8-oxopyrido[2,3-b]thieno[2,3-e]pyrazine-5(8H)-yl)acetamide

[0490] To a pyridine (0.5 mL) solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-methyl-8-oxo-7-(piperazin-1-yl)pyrido[2,3-b]thieno[2,3-e]pyrazine-5(8H)-yl)acetamide hydrochloride (intermediate-75) (22 mg, 37 μmol, 1 equivalent) and sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate (intermediate-55) (26 mg, 148 μmol, 4 equivalents), EDCI (25 mg, 129 μmol, 3.5 equivalents) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (5 mL x 2). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (SiO2, eluent: SiO2) to obtain the title compound.

[0491] 1 H NMR (400 MHz, CDCl3) δ ppm 8.73 (s, 1H), 8.60 (s, 1H), 8.52 (d, 1H), 7.61 (s, 1H), 7.54 (d, 1H), 7.18 (s, 1H), 5.60 (s, 1H), 5.42 (s, 2H), 4.82 - 4.79 (m, 1H), 4.06 - 4.01 (m, 2H), 3.58 - 3.50 (m, 1H), 3.36 - 3.35 (m, 2H), 3.19 - 3.06 (m, 1H), 2.89 - 2.80 (m, 3H), 2.77 (s, 3H), 2.58 (s, 3H), 1.39 (t, 3H).

[0492] LCMS:701.3[M+H] + .

[0493] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-methyl-8-oxopyrido[2,3-b]thiazolo[4,5-e]pyrazine-5(8H)-yl)acetamide(I-114) [ka]

[0494] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-methyl-8-oxopyrido[2,3-b]thiazolo[4,5-e]pyrazine-5(8H)-yl)acetamide

[0495] To a solution of 2-(7-((1S,6S)-2,5-diazabicyclo[4.2.0]octan-2-yl)-6-ethyl-2-methyl-8-oxopyrido[2,3-b]thiazolo[4,5-e]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamidotrifluoroacetate (intermediate-77) (80 mg, 113 μmol, 1 equivalent) in pyridine (2 mL), 5-hydroxy-6-methylpyrimidine-4-carboxylate sodium (intermediate-55) (112 mg, 662 μmol, 5.5 equivalents) and EDCI (109 mg, 565 μmol, 5 equivalents) were added. The mixture was stirred at 50°C for 12 hours. The mixture was concentrated under vacuum to obtain the residue. The title compound was obtained by purifying the residue by reverse-phase HPLC (C18 column, water (10 mmol / L FA)-ACN).

[0496] 1H NMR (400 MHz, CD3OD) δ ppm 8.57 (s, 1H), 8.08 (d, 1H), 7.82 (s, 1H), 7.60 (d, 1H), 5.67 (s, 2H), 4.82 - 4.69 (m, 1H), 4.22 - 4.02 (m, 1H), 3.84 - 3.59 (m, 3H), 3.57 - 3.34 (m, 3H), 2.98 (s, 3H), 2.52 (s, 3H), 1.83 - 1.62 (m, 2H), 1.58 - 1.44 (m, 2H), 1.39 (t, 3H).

[0497] LCMS:728.1[M+H] + .

[0498] Synthesis of 2-(7-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-methyl-5-oxopyrido[2,3-b]thieno[3,2-e]pyrazine-8(5H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide(I-115) [ka]

[0499] Step 1. Synthesis of 2-(7-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-methyl-5-oxopyrido[2,3-b]thieno[3,2-e]pyrazine-8(5H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide

[0500] EDCI (181 mg, 946 μmol, 5 equivalents) was added to a 3 mL solution of pyridine containing 2-(7-ethyl-2-methyl-5-oxo-6-(piperazin-1-yl)pyrido[2,3-b]thieno[3,2-e]pyrazine-8(5H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamidotrifluoroacetate (intermediate-83) (120 mg, 189 μmol, 1 equivalent) and sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate (intermediate-55) (155 mg, 880 μmol, 4.6 equivalents). The mixture was stirred at 60°C for 6 hours. The residue was obtained by direct concentration of the mixture under vacuum. The title compound was obtained by purifying the residue by silica gel chromatography (using SiO / PE as the eluent) and reverse-phase HPLC (C18 column, water (10 mmol / L FA)-ACN).

[0501] 1 H NMR (400 MHz, CD3OD) δ ppm 8.57 (s, 1H), 7.36 (s, 1H), 5.32 (s, 2H), 4.76 - 4.65 (m, 1H), 4.19 - 3.88 (m, 3H), 3.53 - 3.39 (m, 1H), 3.23 (q, 2H), 3.19 - 3.11 (m, 1H), 2.96 - 2.85 (m, 1H), 2.78 - 2.74 (m, 4H), 2.53 (s, 3H), 2.29 (s, 6H), 1.33 (t, 3H).

[0502] LCMS: 657.3[M+H] + .

[0503] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-1-methyl-8-oxo-1,2,3,8-tetrahydro-5H-pyrido[2,3-b]pyrrolo[2,3-e]pyrazine-5-yl)acetamide (I-116) [ka]

[0504] Step 1: Synthesis of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[11-ethyl-12-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl]-4-methyl-13-oxo-2,4,8,10-tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,7,11-tetraen-10-yl]acetamide

[0505] To a solution of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-(11-ethyl-4-methyl-13-oxo-12-piperazine-1-yl-2,4,8,10-tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,7,11-tetraen-10-yl)acetamidetrifluoroacetate (intermediate-86) (8 mg, 15 μmol, 1.0 equivalent) in DCM (2 mL), DIEA (8 mg, 58 μmol, 4.0 equivalent) and 5-hydroxy-6-methylpyrimidine-4-carbonyl chloride (intermediate-84) (12 mg, 73 μmol, 5.0 equivalent) were added. The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 2). The organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0506] 1H NMR (400 MHz, CDCl3) δ ppm 11.79 (s, 1H), 8.58 (s, 1H), 8.54 (d, 1H), 8.29 (s, 1H), 7.61 (s, 1H), 7.55 (d, 1H), 5.50 (s, 1H), 5.29 (s, 2H), 4.76 (d, 1H), 4.13 - 4.00 (m, 2H), 3.74 (t, 2H), 3.50 (s, 1H), 3.23 (t, 4H), 3.15 (s, 3H), 3.08 (s, 1H), 2.87 - 2.67 (m, 2H), 2.57 (s, 3H), 1.32 (t, 3H).

[0507] LCMS:686.5[M+H] + .

[0508] Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2-methylpiperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-98) and (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2-methylpiperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-99) [ka]

[0509] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2-methylpiperazine-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0510] To a solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(2-methylpiperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (intermediate-88) (175 mg, 317 μmol, 1.0 equivalent) in pyridine (3 mL), EDCI (365 mg, 1.90 mmol, 6.0 equivalents) and sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate (intermediate-55) (279 mg, 1.59 mmol, 5.0 equivalents) were added, and the resulting mixture was stirred overnight at 40°C. The reaction mixture was concentrated under reduced pressure and then purified by reverse-phase HPLC (water (0.1% FA-ACN)) to obtain the title compound.

[0511] Step 2. Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2-methylpiperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (single stereoisomer, first eluted compound) and (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2-methylpiperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide (single stereoisomer, second eluted compound)

[0512] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2-methylpiperazine-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide was subjected to chiral SFC (SFC preparative method: Equipment: Waters 80Q preparative SFC system; Column: DAIEL CHIRALCEL OX, 250×30mm) The title compound was obtained by separation using the following method: ID, 10 μm particle size; mobile phase A: CO2, mobile phase B: MeOH / ACN = 7 / 3 = 100% (0.1% NH3-H2O); isocratic elution: 50% phase B in supercritical CO2; flow rate: 80 g / min; retention time: peak 1: 3.23 min, peak 2: 4.59 min; back pressure: 100 bar to maintain CO2 in a supercritical flow; wavelength: 220 nm).

[0513] I-98

[0514] LCMS:688.2[M+H] + .

[0515] 1 H NMR (400 MHz, CDCl3) δ 8.58 (br s, 1H), 8.54 (d, 1H), 8.45 (br s, 1H), 8.20 (s, 1H), 7.60 (s, 1H), 7.53 (br d, 1H), 5.61 - 5.29 (m, 2H), 5.29 - 5.05 (m, 1H), 4.83 - 4.63 (m, 1H), 4.25 - 4.10 (m, 1H), 3.94 (dt, 1H), 3.60 - 3.50 (m, 1H), 3.26 (s, 6H), 3.07 (br dd, 2H), 2.92 - 2.60 (m, 2H), 2.56 (s, 3H), 1.33 (br t, 3H), 1.01 - 0.79 (m, 3H).

[0516] Retention time of analyzed chiral SFC: 0.919 minutes.

[0517] I-99

[0518] LCMS:688.2[M+H] + .

[0519] 1 H NMR (400 MHz, CDCl3) δ 8.58 (br s, 1H), 8.54 (d, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 7.60 (s, 1H), 7.53 (d, 1H), 5.62 - 5.33 (m, 2H), 5.30 - 5.11 (m, 1H), 4.82 - 4.68 (m, 1H), 4.24 - 4.11 (m, 1H), 3.94 (dt, 1H), 3.57 - 3.48 (m, 1H), 3.27 (s, 6H), 3.19 - 2.97 (m, 2H), 2.97 - 2.59 (m, 2H), 2.57 (s, 3H), 1.34 (br t, 3H), 0.98 - 0.83 (m, 3H).

[0520] Retention time of analyzed chiral SFC: 1.519 minutes.

[0521] Analytical SFC method:

[0522] Instrument: SHIMADZU LC-30Adsf; Column: Cellulose-4 50×4.6mm ID, 3μm; Mobile phase: Phase A is CO2 and Phase B is MeOH+ACN(0.05%DEA); Isocratic elution: 40% MeOH+ACN(0.05%DEA) in CO2; Flow rate: 3mL / min; Detector: PDA; Column temperature: 35℃; Back pressure: 100Bar.

[0523] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-((3-methoxycyclobutylidene)methyl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-117) [ka]

[0524] Step 1. Synthesis of N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[6-ethyl-7-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl]-2-[(3-methoxycyclobutylidene)methyl]-8-oxopyrido[2,3-b]pyrazine-5-yl]acetamide

[0525] 1,4-Dioxane (1 mL) and H2O (0.2 mL) containing 2-(2-bromo-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (intermediate-21) (50 mg, 70 μmol, 1.0 equivalent) and To a mixture of 2-((3-methoxycyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate-89) (16 mg, 70 μmol, 1.0 equivalent), Pd(dppf)Cl2.CH2Cl2 (17 mg, 21 μmol, 0.3 equivalent) and K3PO4 (45 mg, 211 μmol, 3.0 equivalent) were added, and the resulting mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and extracted with SiO (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by reverse-phase HPLC (water (0.1% FA)-ACN) to obtain the title compound.

[0526] LCMS:727.4[M+H] + .

[0527] 1 1H NMR (400 MHz, CDCl3) δ ppm 12.28 (s, 1H), 8.72 - 8.61 (m, 1H), 8.58 (s, 1H), 8.52 (br d, 2H), 7.64 (s, 1H), 7.54 (br d, 1H), 6.72 - 6.51 (m, 1H), 5.73 - 5.51 (m, 1H), 5.51 - 5.18 (m, 2H), 4.92 - 4.65 (m, 1H), 4.14 - 3.98 (m, 3H), 3.67 - 3.48 (m, 2H), 3.37 - 3.28 (m, 5H), 3.23 - 3.07 (m, 3H), 3.00 - 2.92 (m, 1H), 2.90 - 2.71 (m, 2H), 2.57 (s, 3H), 1.37 (br d, 3H).

[0528] Synthesis of 2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide(I-108) [ka]

[0529] Step 1. Synthesis of 2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide

[0530] To a mixture of 2-(2-(dimethylamino)-6-ethyl-7-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetic acid (intermediate-91) (20 mg, 40 μmol, 1.0 equivalent) and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (15 mg, 81 μmol, 2.0 equivalents) in DMF (1 mL), HATU (31 mg, 81 μmol, 2.0 equivalents) and DIEA (16 mg, 121 μmol, 3.0 equivalents) were added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with H2O (10 mL) and extracted with SiO (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA-ACN)) to obtain the title compound.

[0531] LCMS:630.3[M+H] + .

[0532] 1 1H NMR (400 MHz, CDCl3) δ ppm 12.07 (s, 1H), 8.58 (s, 1H), 8.23 ​​(s, 1H), 6.84 - 6.52 (m, 1H), 5.64 - 5.37 (m, 1H), 5.15 (br d, 2H), 4.86 - 4.60 (m, 1H), 4.06 - 3.87 (m, 2H), 3.62 - 3.42 (m, 1H), 3.24 (s, 6H), 3.18 - 3.04 (m, 3H), 2.87 - 2.75 (m, 2H), 2.57 (s, 3H), 2.29 (s, 6H), 1.28 (br t, 3H).

[0533] Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3-(dimethylamino)-7-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2-methylpiperazin-1-yl)-5-oxopyrido[3,2-e][1,2,4]triazine-8(5H)-yl)acetamide(I-118) [ka]

[0534] Step 1: Synthesis of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3-(dimethylamino)-7-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2-methylpiperazin-1-yl)-5-oxopyrido[3,2-e][1,2,4]triazine-8(5H)-yl)acetamide

[0535] To a pyridine (1 mL) solution of (S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3-(dimethylamino)-7-ethyl-6-(2-methylpiperazin-1-yl)-5-oxopyrido[3,2-e][1,2,4]triazine-8(5H)-yl)acetamidetrifluoroacetate (intermediate-95) (33 mg, 60 μmol, 1.0 equivalent) and 5-hydroxy-6-methylpyrimidine-4-carboxylate sodium (intermediate-55) (14 mg, 90 μmol, 1.5 equivalents), EDCI (23 mg, 119 μmol, 2.0 equivalents) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into a saturated NH4Cl aqueous solution (10 mL) and then extracted with ELISA (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0536] LCMS:689.4[M+H] + .

[0537] 1 H NMR (400 MHz, CDCl3) δ 8.56 - 8.44 (m, 2H), 8.42 (d, 1H), 7.57 (d, 1H), 7.44 (br d, 1H), 5.71 - 5.16 (m, 3H), 4.76 - 4.55 (m, 1H), 4.08 - 3.92 (m, 1H), 3.84 - 3.71 (m, 1H), 3.50 - 3.41 (m, 1H), 3.31 (s, 6H), 3.06 - 2.90 (m, 2H), 2.82 - 2.54 (m, 2H), 2.49 (s, 3H), 1.28 (br t, 3H), 0.93 - 0.75 (m, 3H).

[0538] Synthesis of 2-(2-(dimethylamino)-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide(I-129) [ka] [ka]

[0539] Step 10: Synthesis of 2-(2-(dimethylamino)-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[0540] To a solution of 2-(2-bromo-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-3-methyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide (intermediate-108) (80 mg, 109 μmol, 1.0 equivalent) and dimethylamine hydrochloride (89 mg, 1.09 mmol, 10.0 equivalents) in 1,4-dioxane (1 mL), DIEA (211 mg, 1.64 mmol, 15.0 equivalents) was added, and the resulting mixture was stirred at 100°C for 3 hours. The reaction mixture was concentrated under reduced pressure and then purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0541] LCMS:698.3[M+H] + .

[0542] 1 H NMR (400 MHz, CDCl3) δ 11.79 ( br s, 1H), 8.99 (s, 1H), 8.60 (s, 1H), 8.48 - 8.44 (t, 1H), 7.42 - 7.40 (d, 1H), 7.35 - 7.32 (d, 1H), 5.64 - 5.23 (m, 3H), 4.34 - 4.29 (m, 2H), 3.92 - 3.76 (m, 2H), 3.38 - 3.35 (m, 2H), 3.23 - 3.20 (m, 1H), 3.06 (s, 6H), 2.71 (s, 3H), 2.54 (s, 3H), 2.43 - 2.26 (m, 1H), 1.71 - 1.69 (m, 1H), 1.43 - 1.42 (m, 1H), 1.42 - 1.34 (m, 2H), 1.32 (t, 3H).

[0543] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2,3-dimethyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide(I-126) [ka]

[0544] Step 4: Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2,3-dimethyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)acetamide

[0545] To a 1.0 mL solution of pyridine containing 2-(7-((1S,6S)-2,5-diazabicyclo[4.2.0]octan-2-yl)-6-ethyl-2,3-dimethyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide hydrochloride (intermediate-110) (80 mg, 145.72 μmol, 1.0 equivalent) and sodium 5-hydroxy-6-methylpyrimidine-4-carboxylate (intermediate-55) (67 mg, 437 μmol, 3.0 equivalents), EDCI (140 mg, 728 μmol, 5 equivalents) was added, and the resulting mixture was stirred at 30°C for 3 hours. An aqueous solution of NaOH (1 M, 1 mL) was added to the reaction mixture, and it was stirred for 15 minutes. The resulting mixture was adjusted to pH=6 with HCl aqueous solution (1M) and extracted with SiO2 (10 mL x 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0546] LCMS:685.3[M+H]+ .

[0547] 1 H NMR (400 MHz, CDCl3) δ 11.72 (br s, 1H), 8.61 (s, 1H), 8.50 - 8.48 (d, 1H), 8.34 (s, 1H), 7.62 (s, 1H), 7.55 - 7.43 (d, 1H), 5.66 - 4.92 (m, 3H), 4.26 (s, 2H), 3.90 - 3.70 (m, 2H), 3.39 - 3.22 (m, 3H), 2.74 (s, 3H), 2.69 (s, 3H), 2.55 (s, 3H), 2.30 - 2.28 (m, 1H), 1.46 (br s, 2H), 1.37 - 1.33 (t, 3H), 1.32 - 1.26 (m, 1H).

[0548] Synthesis of 2-(2-(dimethylamino)-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide(I-121) [ka]

[0549] Step 4: Synthesis of 2-(2-(dimethylamino)-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide

[0550] To a 1 mL solution of DCM containing 2-(7-((1S,6S)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(dimethylamino)-6-ethyl-8-oxopyrido[2,3-b]pyrazine-5(8H)-yl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamidetrifluoroacetate (intermediate-114) (50 mg, 91 μmol, 1.0 equivalent), DIEA (94 mg, 731 μmol, 8.0 equivalents) and a 0.5 mL solution of DCM containing 5-hydroxy-6-methylpyrimidine-4-carbonyl chloride (intermediate-84) (79 mg, 457 μmol, 5.0 equivalents) were added, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was quenched with H2O (10 mL) and then extracted with DCM (10 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to obtain the title compound.

[0551] LCMS:684.3[M+H] + .

[0552] 1 H NMR (400 MHz, CDCl3) δ 12.01 (s, 1H), 8.71 (br s, 1H), 8.61 (br s, 1H), 8.47 (t, 1H), 8.23 ​​(s, 1H), 7.41 (br d, 1H), 7.34 (br d, 1H), 5.80 - 4.88 (m, 3H), 4.56 - 4.10 (m, 2H), 4.08 - 3.82 (m, 1H), 3.81 - 3.58 (m, 1H), 3.37 (br d, 2H), 3.29 (s, 6H), 3.25 - 3.14 (m, 1H), 2.55 (s, 3H), 1.45 (dt, 2H), 1.33 (br t, 4H), 1.26 (br s, 1H).

[0553] Synthesis of 2-(2-cyclopropyl-6-ethyl-7-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-dia...

Claims

1. One compound from formulas II-a to II-s: 【Chemical 301】 【Chemical 302】 or its pharmaceutically acceptable salt [In the formula, R １ａ (a) to (d) a) 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) optionally substituted with one or two groups independently selected from cycloalkoxy, wherein 0-3 independently selected R Ｂ Further substitutions are made by 5-6 member heteroaryls, b) a 4- to 6-membered saturated or partially unsaturated heterocyclyl having from 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted by halogen, oxo, NR ２ , optionally substituted C １～ C ４ aliphatic, -OR, azetidinyl optionally substituted by one or two independently selected halogens, and pyrrolidinyl optionally substituted by one or two independently selected halogens, and is substituted by 0 to 2 R Ｂ groups independently selected therefrom, heterocyclyl, c) A 6-8 member saturated or partially unsaturated bridged bicyclic heterocycline (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which contains halogens, oxo, and NR ２ C is replaced as needed. １～ C ４ Azetidinyls, which are aliphatic, -OR, or optionally substituted with one or two independently selected halogens, and pyrrolidinyls, which are optionally substituted with one or two independently selected halogens, with 0 to 2 R atoms independently selected from these. Ｂ Heterocyclines substituted with a group, and d) H, halogen, C １ ~C ６ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, 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 3-7 member carbocyclyl Selected from, the C １ ~C ６ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl or 3- to 7-membered carbocyclyl is used to select 0 to 3 independently chosen R Ｂ It has been replaced by, R １ｂ The groups are H, halogen, CN, OH, and C, respectively. １ ~C ６ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C １ ~C ６ Alkoxy, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkylene-OC １ ~C ６ Alkyl and C ３ ~C ６ Selected independently from cycloalkoxys, the C １ ~C ６ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C １ ~C ６ Alkoxy, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkylene-OC １ ~C ６ Alkyl and C ３ ~C ６ Cycloalkoxys are composed of 1 to 5 halogens, OH, CN, and C. １ ~C ６ Alkyl and C ３ ~C ６ Each element is independently substituted with a cycloalkyl group as needed, and z is 0, 1, or 2. Ring A is, A 4-7 member saturated or partially unsaturated divalent monocyclic carbocyclylene or a 4-7 member saturated or partially unsaturated divalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atom in addition to the 1-4 heteroatoms); or 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). And, Ring A consists of 0 to 4 independently selected R Ｂ Substituting with substituents, R ２ is C(R Ｃ ) ２ C(O)N(R)R ２Ａ And, R ２Ａ is phenyl or pyridyl, each of which is independently selected from one, two or three substituents selected from halogen, C １ to C ４ aliphatic, halo C １ to C ４ alkyl, C ３ to C ６ cycloalkyl, halo C ３ to C ６ cycloalkyl, -OH, -CN, C １ to C ４ alkoxy, halo C １ to C ４ alkoxy and -SF ５ and is optionally substituted by one, two or three substituents independently selected therefrom, and two substituents on adjacent atoms of said phenyl or pyridyl together with said adjacent atoms form a 4- to 7-membered carbocyclic ring fused to said phenyl or pyridyl, and two substituents on adjacent atoms of said phenyl or pyridyl together with said adjacent atoms form a 4- to 7-membered heterocyclic ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur) fused to said phenyl or pyridyl, and said fused 4- to 7-membered carbocyclic ring or fused 4- to 7-membered heterocyclic ring is substituted by 0 to 5 independently selected halogens or R ２Ａ These are 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, which are halogens, C, etc. １～４ 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 alkylthio, and these, other than hydrogen, are each optionally substituted by -OH, 1 to 5 independently selected halogens, OR, -C(O)NR １０ R １１ or N(R)C(O)R, R ３Ａ These are C １ ~C ４ Selected independently of alkyl, 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 Ｂ Substituted by, and optionally, two adjacent atoms of the phenyl or first 5-6 membered heteroaryl have two substituents, which together with the adjacent atoms form a cyclic group selected from a 4-7 membered carbocyclyl, a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is condensed to the phenyl or first 5-6 membered heteroaryl, and the condensed cyclic group has 0-3 independently selected R Ｂ It is replaced by, or R ４ C １ ~C ４ aliphatic, 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, 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 １ ~C ６ Alkyl or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), except for H, R １０ Each of these is one or two independently selected R Ｂ It is replaced as needed, R １１ H, C １ ~C ６ Aliphatic or C ３ ~C ６ It is either cycloalkyl or R １０ and R １１ Together with the nitrogen atom to which they are bonded, they form halogens, -OH, -CN, and C １ ~C ４ Alkoxy and Halo C １ ~C ４ It forms a 5-6 membered ring which is optionally substituted with one, two, or three substituents independently selected from the alkoxy, R １２ C １ ~C ６ aliphatic, C ３ ~C ６ A cycloalkyl or 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), R １２ These are halogen and C, respectively. 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 It is optionally substituted with one or two groups independently selected from the cycloalkoxy, R Ｂ 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 Faliphatic, Halo C １ ~C ６ Alkyl, C 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 Ｃ is hydrogen, -CH ３ or -CH ２ CH ３ Either they are independently selected from each occurrence, or two R Ｃ Together with the carbon atoms to which they are bonded, they form a cyclopropyl ring. 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 cyclic group selected from a 4- to 7-membered saturated ring, a 4- to 7-membered partially unsaturated ring, or a 5- to 6-membered heteroaryl ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which may be substituted as needed, and the 4- to 7-membered saturated ring or the 4- to 7-membered partially unsaturated ring has 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

2. The aforementioned compound is given by formula II-e: 【Chemical 303】 The compound or a pharmaceutically acceptable salt thereof according to claim 1.

3. The aforementioned compound is given by formula II-b: 【Chemical 304】 The compound or a pharmaceutically acceptable salt thereof according to claim 1.

4. The aforementioned compound is defined by formula II-c: 【Chemical 305】 The compound or a pharmaceutically acceptable salt thereof according to claim 1.

5. The aforementioned compound is given by formula II-d: 【Chemical 306】 The compound or a pharmaceutically acceptable salt thereof according to claim 1.

6. The aforementioned compound is defined by formula II-a: 【Chemical 307】 The compound or a pharmaceutically acceptable salt thereof according to claim 1.

7. The aforementioned compound is given by formula II-f: 【Chemical 308】 The compound or a pharmaceutically acceptable salt thereof according to claim 1.

8. The compound is of formula II-n or II-p: 【Chemical 309】 The compound or a pharmaceutically acceptable salt thereof according to claim 1.

9. R ４ but, 【Chemical 310】 A ring E selected from the group consisting of, * is the bond point to -C(O)-, R ４Ａ , R ４Ｂ , R ４Ｃ , R ４Ｄ , R ４Ｅ and R ４Ｆ Any substituent present on ring E selected from is hydrogen; halogen; -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 However, these intervening atoms bond together, forming 0 to 3 independently selected R atoms. Ｂ A 4-7 member carbocyclyl substituted by, 0-3 independently selected R Ｂ A 4-7 member heterocycline substituted by, or 0-3 independently selected R Ｂ It forms a 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is fused to ring E, R ４Ｃ , R ４Ｄ , R ４Ｅ and R ４Ｆ Any substituent present on ring E selected from 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 ４Ｂ and R ４Ｃ However, these intervening atoms bond together, forming 0 to 3 independently selected R atoms. Ｂ A 4-7 member carbocyclyl substituted by, 0-3 independently selected R Ｂ A 4-7 member heterocycline substituted by, or 0-3 independently selected R Ｂ It forms a 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is fused to ring E, R ４Ａ , R ４Ｄ , R ４Ｅ and R ４Ｆ Any substituent present on ring E selected from 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 ４Ｃ and R ４Ｄ However, these intervening atoms bond together, forming 0 to 3 independently selected R atoms. Ｂ A 4-7 member carbocyclyl substituted by, 0-3 independently selected R Ｂ A 4-7 member heterocycline substituted by, or 0-3 independently selected R Ｂ It forms a 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is fused to ring E, R ４Ａ , R ４Ｂ , R ４Ｅ and R ４Ｆ Any substituent present on ring E selected from 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 However, it is a halogen or -OH, and R ４Ａ , 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 They are either selected independently from each other, or R ４Ｅ and R ４Ａ However, these intervening atoms bond together, forming 0 to 3 independently selected R atoms. Ｂ It forms a 5-6 member optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is condensed on ring E, 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 They are either selected independently from each other, or R ４Ｆ and R ４Ａ However, these intervening atoms bond together, forming 0 to 3 independently selected R atoms. Ｂ It forms a 5-6 member heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) which is fused to ring E, R ４Ｂ and R ４Ｃ 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 Is it hydrogen, or R １３ and R １４ However, together with the nitrogen atom to which they are bonded, they form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, or piperidinyl, and the heterocyclic ring is -CH ３ It is replaced as needed by; 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 It is substituted with 0 to 4 groups independently selected from the alkoxy, or R ４ However, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy or C ３ ~C ６ These are cycloalkyl groups, and these 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 a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8.

10. R ４ but, 【Chemical 311】 A ring E selected from the group consisting of, * is the bond point to -C(O)-, 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, or -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 H, or NR １３ R １４ However, when combined, they form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, and the heterocyclic ring contains one or more -CH ３ Substituted as needed by the base, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8.

11. R ４ but, 【Chemical 312】 【Chemistry 313】 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8.

12. R ４ but, 【Chemical 314】 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8.

13. Ring A is 【Chemical Industry 315】 Selected from, Ring A is selected from 0 to 4 independently selected R Ｂ Substituting with substituents, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10.

14. Ring A, and the 0 to 4 independently selected R in which Ring A is substituted. Ｂ The substituent is 【Chemical 316】 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10.

15. Ring A is 【Chemical 317】 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10.

16. Ring A is 【Chemical 318】 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10.

17. R １ａ 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) optionally substituted with 1-3 groups selected from cycloalkyl, wherein the 5-6 membered heteroaryl is substituted with 0-3 independently selected R Ｂ It is further substituted by the R group. １ｂ However, H, halogen, C １ ~C ６ Alkyl, Halo C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy and Halo C １ ~C ６ A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, selected from alkoxys.

18. R １ａ However, the heterocycline is a 4-6 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. １～４ Azetidinyls, which are aliphatic, -OR, or optionally substituted with one or two independently selected halogens, and pyrrolidinyls, which are optionally substituted with one or two independently selected halogens, with 0 to 2 R atoms independently selected from these. Ｂ It is substituted with R １ｂ However, H, halogen, C １ ~C ６ Alkyl, Halo C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy and Halo C １ ~C ６ A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, selected from alkoxys.

19. R １ａ 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 C ３ ~C ７ It is a cycloalkyl, and the C １ ~C ６ Alkyl, C ２ ~C ４ Alken, C ２ ~C ４ Alkynes and C ３ ~C ７ Cycloalkyls 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 0 to 3 R values ​​selected independently of the alkoxy Ｂ It is substituted with R １ｂ However, H, halogen, C １ ~C ６ Alkyl, Halo C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy and Halo C １ ~C ６ A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, selected from alkoxys.

20. R １ａ but, 【Chemical 319】 【Chem.320】 A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following:

21. R ２Ａ However, -CF ３ Phenyl containing substituents, or -CF ３ A compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, comprising a substituted pyridyl.

22. R ２ but, 【Chemistry 321】 【Chemistry 322】 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 20.

23. R ２ but, 【Chemical 323】 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 20.

24. R ３ However, C １ ~C ４ Alkyl or C ３ ~C ５ A cycloalkyl compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23.

25. R ３ However, -OH, 1 to 5 independently selected halogens or C １ ~C ４ C is substituted with alkoxy as needed. １ ~C ４ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, which is alkyl.

26. R ３ C １ ~C ４ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, which is alkyl.

27. R ３ However, -CH ２ CH ３ The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23.

28. A compound selected from one of those listed in Table 1, Table 1a, Table 2, or Table 2a, or a pharmaceutically acceptable salt thereof.

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

30. 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 28.

31. 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 28.

32. 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 28.

33. 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 28.

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

35. The method according to claim 34, 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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