Bicyclic heterocycles and their use as WRN inhibitors

Abstract

The present invention relates to a compound of formula (I): [Formula 1] TIFF2025539085000315.tif31170 (in the formula, R1, R2, R3, R4, R5, R 26 , R 27 , R, M, L, W, T, V, Y, K, J, A, and y are as described in the Summary of the Invention), or pharmaceutically acceptable salts thereof, therapeutic uses, research uses, and methods for making the compounds of the invention. The invention further provides combination pharmacologically active agents and pharmaceutical compositions.

Description

[Technical Field]

[0001] The present invention provides bicyclic heterocyclic compounds, their use for inhibiting Werner syndrome RecQ DNA helicase (WRN), and methods of treating disease using said compounds, particularly their use in the treatment of cancer, particularly cancers characterized as microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), including colorectal, gastric or endometrial cancer, their use as research chemicals, syntheses, intermediates, formulations and combinations of said compounds. [Background technology]

[0002] Loss of DNA mismatch repair (MMR) is a common initiating event in cancer development, occurring in 10–30% of colorectal, endometrial, ovarian, 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 that have lost mismatch repair (MMR) capability have high mutation burdens and frequent deletion and insertion events in repetitive DNA tracts, a phenotype known as microsatellite instability (MSI). While progress has been made in the treatment of microsatellite instability-high (MSI-H) cancers, with pembrolizumab (anti-PD1) recently approved as first-line therapy for MSI-H-dMMR metastatic colorectal cancer after it was demonstrated to result in significantly longer progression-free survival compared with chemotherapy, significant unmet medical needs remain 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):2207-2218(2020)).Several large-scale functional genomics screens across large panels of cell lines, including Novartis using 398 cell lines from the Cancer Cell Line Encyclopedia (CCLE) (McDonald ER et al., Project DRIVEA Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening. Cell 170(3):577-592 (2017)), have identified the Werner syndrome RecQ helicase (WRN) as being selectively required for survival of cell lines with defective mismatch repair function 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. eLife8, e43333 (2019). WRN is synthetically lethal in MSI cancers.Depletion of WRN leads to antiproliferative effects, activating multiple DNA damage signaling markers, inducing cell cycle arrest, and apoptosis in MMR cancer models, but not in cancer cells with an intact MMR pathway. These findings indicate that WRN provides DNA repair and maintenance functions essential for cell survival in MSI cancers. Recently, the mechanism of WRN dependence has been elucidated. Dinucleotide TA repeats have been shown to be selectively unstable and undergo large-scale expansions 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 chromosome breakage. Therefore, inhibiting WRN helicase is an attractive strategy for treating mismatch repair-deficient cancers. Summary of the Invention

[0003] There remains a need for new therapies and treatments for cancer, particularly cancers characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR), including colorectal, gastric, 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 ameliorating a disease or condition, comprising administering to a subject in need thereof an effective amount of a WRN inhibitor. The present invention further provides WRN inhibitor compounds as research chemicals. Various embodiments of the present invention are described herein.

[0004] In certain aspects, provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof: [ka] (In the formula, R, M, W, L, V and T are independently selected from C, CH and N; Let sub-formulas 1a, 1b, 1c, 1d, 1e and 1f be of the form: [ka] A is a linker that is -C(O)-; Y is N, C or CH; y is 0, 1, 2, 3 or 4; Y [ka] means that when Y is CH, it is connected to the adjacent carbon atom via a single bond, or when Y is C, it is connected to the adjacent atom via a double bond; [ka] is a single bond, then Y is unsubstituted or substituted by OH or F; If Y is N, then Y [ka] is a single bond; K [ka] means that K is connected to the adjacent carbon atom via a single or double bond; where: K [ka] If is a double bond, Y [ka] is a single bond, K is CH and J is C, or or K [ka] is a single bond, K is -CH2-, -CH2CH2-, -NH- and a bond (5-membered ring: [ka] and J is N; R5 is independent, -(C 1~ C4) alkyl, -(C 3~ C5) cycloalkyl, where two R5 substituents on the same ring carbon atom, together with the carbon atom to which they are attached, form (C 3~ C4) may form a cycloalkylspiro ring or a 3- or 4-membered heterocyclylspiro ring, wherein the heterocyclylspiro ring contains ring carbon atoms and one ring heteroatom selected from O, N, and S; ·K [ka] When J is a carbon-nitrogen single bond, K and the R5 substituent on the adjacent carbon atom combine to form ring C: [ka] may be formed, wherein ring C is a fused (C3-C6) cycloalkyl ring, a fused (C3-C6) heterocyclyl ring, or a fused phenyl ring, wherein the fused (C3-C6) heterocyclyl ring contains ring carbon atoms and one ring heteroatom selected from O, N, and S; When ring C is a fused (C3-C6) cycloalkyl ring, the fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, wherein said R 40 teeth, ·(C 1~ C2) alkyl (wherein each (C 1~C2) alkyl is independently unsubstituted or substituted with OH or 1, 2, or 3 halo; Halo, especially F, Alternatively, where two R on the same ring carbon atom 40 The substituents, together with the carbon atoms to which they are attached, form a group called (C 3~ C4) may form a cycloalkyl spiro ring or a 3- or 4-membered heterocyclyl spiro ring, wherein the heterocyclyl spiro ring contains ring carbon atoms and one ring heteroatom selected from O, N, and S; Or, two R on adjacent carbon atoms 40 The substituents, together with the carbon atoms to which they are attached, form a fused cyclopropyl ring. Selected from; where K is -CH2- and J is N, two R5 substituents may be linked to form a (C1-C3) alkylene or heteroalkylene bridge, where the heteroalkylene bridge is one heteroatom selected from N and O or is -CH2-O-CH2-. Selected from; R1 is cycloalkenyl, wherein said cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms, said cycloalkenyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2, R 33 where R 33 is halo, and said cycloalkenyl or halo-substituted cycloalkenyl has 0, 1 or 2 R 15 substituted by a substituent, or said cycloalkenyl or halo-substituted cycloalkenyl has two substituents on the same ring carbon atom to which it is attached to form an oxetanyl spiro ring; Alternatively, R is heterocyclyl, wherein the heterocyclyl is a fully saturated or partially unsaturated 5- or 6-membered group comprising ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S, wherein the heterocyclyl is unbridged or bridged, the bridge being 1 or 2 carbon atoms, wherein the heterocyclyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2, R 33 where R 33 is halo, and said heterocyclyl or halo-substituted heterocyclyl is independently R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 or substituted by 0, 1 or 2 substituents selected from Alternatively, said heterocyclyl or halo-substituted heterocyclyl is fused to a cyclopropyl ring, wherein said cyclopropyl ring is unsubstituted or substituted with 1, 2 or 3 F; Alternatively, said heterocyclyl or halo-substituted heterocyclyl has two substituents at the same ring carbon atom which are joined to form a cyclopropyl spiro ring or a tetrahydrofuranyl spiro ring; Alternatively, the heterocyclyl or halo-substituted heterocyclyl is fused to a (C3-C5) heterocycloalkyl ring, wherein the (C3-C5) heterocycloalkyl ring contains ring carbon atoms and one ring O atom; or Alternatively, R1 is heteroaryl, wherein said heteroaryl is a 5- or 6-membered fully unsaturated monocyclic group containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, preferably 1 or 2 ring heteroatoms, and preferably the total number of ring S atoms does not exceed 1, and preferably the total number of ring O atoms does not exceed 1; and the heteroaryl is unsubstituted or R 21 and R 30 and is substituted by 1, 2, or 3 substituents independently selected from21 and R 30 is independently selected from halo and (C1-C4) alkyl, wherein said (C1-C4) alkyl is unsubstituted or substituted with 1, 2 or 3 halo; Alternatively, R1 is phenyl, wherein said phenyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2 R 33 where R 33 is halo, and said phenyl or halo-substituted phenyl is selected from 0, 1 or 2 R 15 Is substituted with a substituent, Alternatively, R1 is (C2-C4)alkynyl or (C2-C4)alkenyl, wherein said (C2-C4)alkynyl and (C2-C4)alkenyl are unsubstituted or substituted by (C1-C4)alkyl-OC(O)- or morpholinyl; Each R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 is, independently, Hello, unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C4) Alkyl-O-(CH2) n , (C1-C4)alkyl unsubstituted or substituted by OH, —O—(C1-C2)alkyl or 1, 2 or 3 halo, HOC(O)-(CH2) n -, (C1-C4) alkyl-C(O)(CH2) n -, (E)-cyclooct-4-en-1-yl-OC(O)-, (C1-C4) alkyl-OC(O)(CH2) n , =O azetidinyl or pyrrolidinyl, wherein said azetidinyl and pyrrolidinyl are linked to the rest of the molecule via an N atom and each is unsubstituted or substituted with one or two F, ·R 25 (R 24 )N-(CH2) n where R 24 is H or (C-C) alkyl unsubstituted or substituted with 1, 2 or 3 halo, and R 25 teeth, ohhh, o(C1-C4) alkyl-C(O)(CH2) n -, where (C1-C4) alkyl-C(O)(CH2) n - wherein said (C1-C4) alkyl is unsubstituted or substituted with halo or -N3; o(C1-C4) alkyl-OC(O)(CH2) n -, o (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, or o(E)-cyclooct-4-en-1-yl-OC(O)-, OH Selected from where n is 0, 1 or 2; R 26 is CH3, H or deuterium; R 27 is CH3, H or deuterium; Or, R 26 and R 27 together with the carbon atoms to which they are attached form a cyclopropyl ring; R2 is part: [ka] and R6 is ·H, Hello, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, (C3-C5)cycloalkyl unsubstituted or substituted by 1, 2 or 3 halo, -O-(C1-C4)alkyl, unsubstituted or substituted with 1, 2 or 3 halo; ·OH, and ·CN Selected from; R8 is selected from H, halo, and (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo; R9 is selected from H, O-CH3, OH, CN, CH3 and halo; R 28 teeth, SF5, H, ·-C(O)H, Hello, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, ·(C1-C4)alkynyl; (C1-C4) alkenyl, (C3-C5))cycloalkyl unsubstituted or substituted with 1, 2 or 3 halo, and Selected from OCF3; X is selected from C-R7 and N, where R7 is H, CF3, or halo, or R7 is R 28 or R6, together with the atoms to which they are attached, can form a fused (C4-C6)cycloalkyl ring, wherein said fused (C4-C6)cycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 halo, or R2 is [ka] (In the formula, R 31 is selected from H, halo, and CH3; R 32 is selected from H, halo and CH Selected from; R3 is Cyclopropyl, ·O-CH3, N(CH3)2, ·S-CH3, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo and OH; R4 is -(C1-C4)alkyl unsubstituted or substituted with NH2; -O-CH2phenyl; -O-CH2-CH2 and -CN; -NH-NH-C(O)-CF3; -Heteroaryl1, wherein said Heteroaryl1 is a 5- or 6-membered fully unsaturated monocyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S; -heteroaryl2, wherein said heteroaryl2 is a 9- or 10-membered fused bicyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein both rings are fully unsaturated or one ring is fully unsaturated and the other saturated or partially unsaturated, and said heteroatoms can be in one or both rings; -phenyl; -heterocyclyl2, wherein said heterocyclyl2 is a 5- or 6-membered fully saturated or partially unsaturated group consisting of ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S; and [ka] Here, heteroaryl 1, heteroaryl 2, and phenyl are each R 10 , R 11 , R 12 , R 13 and R 14 and wherein each R 10 , R 11 , R 12 , R 13 and R 14 teeth, ·H, Hello, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents, -O-(C1-C2)alkyl or (C1-C2)alkyl substituted by OH, -S-(C1-C3) alkyl, -O-(C1-C4)alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents; ·OH, (C3-C5)cycloalkyl (wherein said (C3-C5)cycloalkyl is unsubstituted or substituted with 1 or 2 halo), -(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent ohhh, o(C1-C4)alkyl, wherein said (C1-C4)alkyl is unsubstituted or substituted with OH or —O(C1-C2)alkyl; o and where R 34 and R 35 can be taken together with the atoms to which they are attached to form an azetidine, pyrrolidinyl, or piperidine ring, wherein said azetidine, pyrrolidinyl, and piperidine are unsubstituted or substituted with CH3. selected from ·CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, =O, -C(O)H, and -C(O)(C1-C4) alkyl are independently selected from; However, R4 is [ka] Instead, (In the formula, R 10 , R 11 , R 12 , R 13 and R 14 is, independently, ·H, Hello, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents, -O-(C1-C2)alkyl or (C1-C2)alkyl substituted by OH, -S-(C1-C3) alkyl, -O-(C1-C4)alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents; ·OH, (C3-C5)cycloalkyl (wherein said (C3-C5)cycloalkyl is unsubstituted or substituted with 1 or 2 halo), -(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent ohhh, o(C1-C4)alkyl, wherein said (C1-C4)alkyl is unsubstituted or substituted with OH or —O(C1-C2)alkyl; o and where R 34 and R 35 can be taken together with the atoms to which they are attached to form an azetidine, pyrrolidinyl, or piperidine ring, wherein said azetidine, pyrrolidinyl, and piperidine are unsubstituted or substituted with CH3. selected from ·CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -C(O)H, and -C(O)(C1-C4) alkyl are independently selected from; * indicates the point of attachment).

[0005] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and one or more pharmaceutically acceptable carriers.

[0006] In another aspect, the present invention provides combinations, particularly pharmaceutical combinations, comprising a compound of the present invention and one or more therapeutically active agents.

[0007] In another aspect, the present invention provides compounds of the present invention for use as a pharmaceutical, particularly for treating a disorder or disease that can be treated by WRN inhibition.

[0008] In another aspect, the present invention provides a compound of the invention for use in the treatment of cancer, particularly wherein the cancer is characterised by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR).

[0009] In another aspect, the present invention provides a method for treating a disorder or disease in a subject that can be treated by WRN inhibition, comprising administering to the subject a therapeutically effective amount of a compound of the present invention.

[0010] In another aspect, the invention provides a method of treating cancer in a subject, more particularly a method wherein the cancer is characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR), comprising administering to the subject a therapeutically effective amount of a compound of the invention.

[0011] In another aspect, the present invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a disorder or disease that can be treated by WRN inhibition.

[0012] In another embodiment, the present invention provides research uses of the compounds of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0013] Thus, the present invention provides compounds of formula (I): [ka] (In the formula, R1, R2, R3, R4, R5, R 26 , R 27 , R, M, L, W, T, V, Y, K, J, A, and y are as described in the Summary of the Invention above.

[0014] Unless otherwise specified, the term "compounds of the invention" or "compound of the invention" refers to compounds of Formula (I), subformulas thereof, and exemplified compounds, and salts thereof, as well as all diastereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitution), and inherently formed moieties.

[0015] Various (enumerated) embodiments of the present invention are described herein, and it will be recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

[0016] Embodiment 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as described above.

[0017] Embodiment 2. When R1 is a ring, each R ring atom adjacent to the R ring atom at which the R ring is attached to the remainder of the molecule is independently unsubstituted or substituted only with halo, and in particular is independently unsubstituted or substituted with one F substituent; and Preferably, the R1 ring is linked to the rest of the molecule via an R1 ring nitrogen atom or an R1 ring carbon atom that is double bonded to an adjacent R1 ring atom, According to embodiment 1, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0018] Embodiment 3. R1 is cycloalkenyl, wherein said cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms, said cycloalkenyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2, R 33 where R 33 is halo, and said cycloalkenyl or halo-substituted cycloalkenyl has 0, 1 or 2 R 15 substituted with a substituent, preferably one substituent, or said cycloalkenyl or halo-substituted cycloalkenyl having two substituents on the same ring carbon atom to which it is attached to form an oxetanyl spiro ring; Alternatively, R1 is heterocyclyl, wherein the heterocyclyl is a fully saturated or partially unsaturated 5- or 6-membered group comprising ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, NH, O and S, and wherein the heterocyclyl is unbridged or bridged, the bridge being 1 or 2 carbon atoms, and wherein the heterocyclyl is unsubstituted or has 1, 2, 3 or 4, e.g. 1, 2 or 3, especially 1 or 2, R 33 where R 33 is halo, and said heterocyclyl or halo-substituted heterocyclyl is independently R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 or substituted by 0, 1 or 2 substituents, preferably 0 or 1 substituents, selected from Alternatively, said heterocyclyl or halo-substituted heterocyclyl is fused to a cyclopropyl ring, wherein said cyclopropyl ring is unsubstituted or substituted with 1, 2 or 3 F; Alternatively, said heterocyclyl or halo-substituted heterocyclyl has two substituents at the same ring carbon atom which are joined to form a tetrahydrofuranyl spiro ring; Alternatively, R is heteroaryl, wherein said heteroaryl is a 5- or 6-membered fully unsaturated monocyclic group containing ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S, preferably 1 or 2 ring heteroatoms, wherein the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1, and wherein said heteroaryl is unsubstituted or is selected from R 21 and R 30 and is substituted by 1, 2, or 3 substituents independently selected from 21 and R 30 is independently selected from halo and (C1-C4) alkyl, wherein said (C1-C4) alkyl is unsubstituted or substituted with 1, 2 or 3 halo; Alternatively, R1 is phenyl, wherein said phenyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2 R 33 where R 33 is halo, and said phenyl or halo-substituted phenyl is substituted with zero or one R 15 Is substituted with a substituent, or R1 is (C2-C4)alkynyl unsubstituted or substituted with (C1-C4)alkyl-OC(O)-; And each R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 is, independently, Halo unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C4) Alkyl-O-(CH2) n , (C1-C4)alkyl unsubstituted or substituted by OH, —O—(C1-C2)alkyl or 1, 2 or 3 halo, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (C1-C4) alkyl-OC(O)(CH2) n , =O, azetidinyl or pyrrolidinyl, wherein said azetidinyl and pyrrolidinyl are linked to the rest of the molecule via an N atom and each is unsubstituted or substituted with one or two F, ·R 25 (R 24 )N-(CH2) n (where R 24 is H or (C-C) alkyl unsubstituted or substituted with 1, 2 or 3 halo, and R 25 is H, (C1-C4)alkyl-C(O)-, (C1-C4)alkyl-OC(O)-, or (C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo; OH Selected from 3. The compound of formula (I) according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2.

[0019] Embodiment 4. R1 is cycloalkenyl, wherein the cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms, and the cycloalkenyl is unsubstituted or contains one or two R 33 where R 33 is halo, preferably F, and said cycloalkenyl or halo-substituted cycloalkenyl is selected from the group consisting of 0 or 1 R 15 substituted by a substituent, where R 15 teeth, a) (C1-C2) alkyl-O—, unsubstituted or substituted with 1, 2 or 3 halo; b) (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 halo; c) HOC(O)-(CH2) n -, d) H3C-C(O)(CH2) n -, e) H3C-OC(O)(CH2) n , f) = O, and g)R 25 (R 24 )N-, H(where R 24 is H or (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 halo, and R 25 is H or (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 halo is selected from n is 0 or 1, where: R of the cycloalkenyl or halo-substituted cycloalkenyl 15 Substituents a) through g) are not present on the ring atom adjacent to the ring atom at which said cycloalkenyl or halo-substituted cycloalkenyl is attached to the remainder of the molecule, and preferably said cycloalkenyl or halo-substituted cycloalkenyl has one R in the ring para position relative to the remainder of the molecule. 15 a 6-membered ring having a substituent, and the cycloalkenyl or halo-substituted cycloalkenyl is linked to the remainder of the compound via an R1 ring carbon atom that is double-bonded to an adjacent R1 ring carbon atom; Alternatively, R is heterocyclyl, wherein the heterocyclyl is a fully saturated or partially unsaturated 5- or 6-membered group containing ring carbon atoms and one or two ring heteroatoms independently selected from N, NH, O, and S, and wherein the heterocyclyl is unbridged or bridged, the bridge being one or two carbon atoms, and wherein the heterocyclyl is unsubstituted or contains one or two R 33 where R 33 is halo, preferably F, and said heterocyclyl or halo-substituted heterocyclyl is independently R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23wherein R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 is, independently, a) unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C4) alkyl-O-, b) (C1-C4) alkyl unsubstituted or substituted with OH, —O—(C1-C2) alkyl or 1, 2 or 3 halo; c) HOC(O)-(CH2) n -, d) H3C-C(O)(CH2) n -, e) H3C-OC(O)(CH2) n , f)=O g)R 25 (R 24 )N-(where R 24 is H, (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 halo, and R 25 is H, (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 halo h)OH is selected from where n is 0 or 1, And here, the substituents a) to h) of said heterocyclyl or halo-substituted heterocyclyl are not present on the ring atom by which said heterocyclyl or halo-substituted heterocyclyl is attached to the remainder of the molecule, preferably if said heterocyclyl or halo-substituted heterocyclyl is a 6-membered ring it has 0 or 1 substituent selected from a) to h) in the meta or para position, preferably in the para position, relative to the remainder of the molecule; the heterocyclyl is linked to the remainder of the compound via an R1 ring nitrogen atom or an R1 ring carbon atom that is double-bonded to an adjacent ring atom; Alternatively, R is heteroaryl, wherein said heteroaryl is a 5- or 6-membered fully unsaturated monocyclic group containing ring carbon atoms and one or two ring heteroatoms independently selected from N, O and S, preferably N, wherein the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1, and wherein said heteroaryl is unsubstituted or R 21 and R 30 and is substituted by one or two substituents independently selected from 21 and R 30 are independently selected from (C1-C2)alkyl, said (C1-C2)alkyl being unsubstituted or substituted with 1, 2 or 3 halo, wherein preferably said alkyl or haloalkyl substituent is not present on the R1 ring atom adjacent to the R1 ring atom at which the heteroaryl is attached to the remainder of the molecule, and more preferably when the heteroaryl is a 6-membered ring, said alkyl or haloalkyl substituent is in the ring para position relative to the remainder of the molecule; A compound of formula (I) according to any one of embodiments 1, 2 or 3, or a pharmaceutically acceptable salt thereof.

[0020] Embodiment 5. R1 is [ka] Selected from; Alternatively, in each of the above moieties, 0 to 2 R 33 There is a substituent, R 33 is F; R 15 teeth, ·Halo; ·R 25 (R 24 )N-(CH2) n (where R 24 is H or CH3 unsubstituted or substituted with 1, 2 or 3 halo, R 25 is H, (C1-C4)alkyl-C(O)-, (C1-C4)alkyl-OC(O)-, or (C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo, or azetidinyl or pyrrolidinyl, where the azetidinyl and pyrrolidinyl are linked to the rest of the molecule via an N atom and are unsubstituted or substituted by one or two F, R 16 is R 25 (R 24 )N-, where R 24 is H or (C1-C2) alkyl, and R 25 is H or (C1-C2)alkyl unsubstituted or substituted with 1, 2 or 3 halo, especially F; R 17 is a halo; R 18 is a halo; R 19 teeth, Halo (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, (C1-C4) alkyl-O-(CH2) n - and; R 20 is a halo; R 21 is (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 F; R 22 and R 23 are each independently (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, (C1-C4) alkyl-O-(CH2) n -, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (H3C)3C-OC(O)(CH2) n -; where n is 0, 1, or 2 Selected from; R 30 is CH3, A compound of formula (I) according to any one of embodiments 1 to 4, or a pharmaceutically acceptable salt thereof.

[0021] Embodiment 6. R1 comprises: [ka] Selected from; R 15 is F; R 16 teeth, 25 (R 24 )N- and; R 17 is F; R 18 is F; R 19 is F; R 20 is F; R 21 is CH3; R 22 are CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, (H3C)3C-OC(O)-; R 23 are CF3, CHF2CH2-, (H3C)3C-OC(O)-; R 24 is CH3; and R 25 is CHF2CH2-, A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 5.

[0022] Embodiment 7. R1 is [ka] [ka] 7. The compound of formula (I) according to any one of embodiments 1 to 6, selected from:

[0023] Embodiment 8. R1 is [ka] 8. The compound of formula (I) according to any one of embodiments 1 to 7, selected from:

[0024] Embodiment 9. R1 is [ka] 9. The compound of formula (I) according to any one of embodiments 1 to 8, selected from:

[0025] Embodiment 10. R1 is [ka] 10. The compound of formula (I) according to any one of embodiments 1 to 9, wherein:

[0026] Embodiment 11. R2 is [ka] This is the part (In the formula, R6 is selected from H, halo, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo; R8 is selected from H, halo, and (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo; R9 is selected from H, O-CH3, OH, CN, CH3 and halo; R 28 is selected from SF5, halo, (C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo, and C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo; A compound of formula (I) according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof.

[0027] Embodiment 12. R2 is [ka] This is the part R6 is selected from H, Cl, CH3, F, and Br; R8 is selected from H, Cl, F, and CF3; R9 is selected from H, CH3, and Cl; R 28 is selected from CF3, CF2H, -CH2CH3, Cl, SF5, Br, and -C(O)H; X is selected from C-R7 and N; and 12. A compound of formula (I) according to any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from H and F.

[0028] Embodiment 13.R 28 13. The compound of formula (I) according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein is selected from CF3, CHF2, Cl, —CH2CH3, CH3, SF5 and Br.

[0029] Embodiment 14.R 28 14. The compound of formula (I) according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is selected from CF3, Cl and SF5, in particular CF3.

[0030] Embodiment 15. A compound of formula (I) according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein X is CR7.

[0031] Embodiment 16. A compound of formula (I) according to any one of embodiments 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R7 is H.

[0032] Embodiment 17. A compound of Formula (I) according to any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R6 is H, F, Cl, or CH3.

[0033] Embodiment 18. A compound of Formula (I) according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R6 is Cl.

[0034] Embodiment 19. A compound of formula (I) according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R8 is F, CF3, or H.

[0035] Embodiment 20. A compound of Formula (I) according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R8 is H.

[0036] Embodiment 21. A compound of formula (I) according to any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R9 is H.

[0037] Embodiment 22. R2 is [ka] 22. The compound of formula (I) according to any one of embodiments 1 to 21, selected from: or a pharmaceutically acceptable salt thereof.

[0038] Embodiment 23. A compound of formula (I) according to any of embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R3 is (C1-4)alkyl unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo and OH.

[0039] Embodiment 24. A compound of formula (I) according to any of embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R3 is (C1-C2)alkyl unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo and OH, preferably -CH2CH3 or CH3, more preferably -CH2CH3.

[0040] Embodiment 25. A compound of Formula (I) according to any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from -CH3, -CH2CH3, -CH(CH3)2, and cyclopropyl.

[0041] Embodiment 26. A compound of Formula (I) according to any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R3 is -CH3 or -CH2-CH3.

[0042] Embodiment 27.R 26 27. A compound of formula (I) according to any one of embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, wherein

[0043] Embodiment 28.R 27 28. A compound of formula (I) according to any one of embodiments 1 to 27, or a pharmaceutically acceptable salt thereof, wherein

[0044] Embodiment 29. R4 is CH3, [ka] -Heteroaryl1, wherein said Heteroaryl1 is a 5-membered fully unsaturated monocyclic ring consisting of ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S; -heteroaryl2, wherein said heteroaryl2 is a 9- or 10-membered fused bicyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein both rings are fully unsaturated or one ring is fully unsaturated and the other saturated or partially unsaturated, and said heteroatoms can be in one or both rings; -phenyl; or -heterocyclyl2, wherein said heterocyclyl2 is a 5- or 6-membered fully saturated or partially unsaturated group consisting of ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S; wherein heteroaryl 1, heteroaryl 2, phenyl, and [ka] each moiety selected from R 10 , R 11 , R12 , R 13 and R 14 and wherein each R 10 , R 11 , R 12 , R 13 and R 14 are each independently ·H, Hello, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents, -O-(C1-C2)alkyl or (C1-C2)alkyl substituted by OH, -S-(C1-C3) alkyl, -O-(C1-C4)alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents; ·OH, (C3-C5)cycloalkyl (wherein said (C3-C5)cycloalkyl is unsubstituted or substituted with 1 or 2 halo), -(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent ohhh, o(C1-C4)alkyl, wherein said (C1-C4)alkyl is unsubstituted or substituted with OH or —O(C1-C2)alkyl; o and where R 34 and R 35 can be taken together with the atoms to which they are attached to form an azetidine, pyrrolidinyl, or piperidine ring, wherein said azetidine, pyrrolidinyl, and piperidine are unsubstituted or substituted with CH3. selected from ·CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, =O, -C(O)H, and -C(O)(C1-C4) alkyl are independently selected from; A compound of formula (I) according to any one of embodiments 1 to 28, or a pharmaceutically acceptable salt thereof.

[0045] Embodiment 30. R4 is as described in embodiment 1 and other embodiments herein, except that at least one OH, CN, ═O, or NH2 substituent is selected from each of Heteroaryl1, Heteroaryl2, phenyl, [ka] The condition is that it exists above Remaining R 10 , R 11 , R 12 , R 13 and R 14 is as defined herein; The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of embodiments 1-29, which is a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0046] Embodiment 31. R4 is as described in embodiment 1 and other embodiments herein, except that one OH substituent is selected from each of Heteroaryl1, Heteroaryl2, phenyl, [ka] exists on Remaining R 10 , R 11 , R 12 , R 13 and R 14 is as defined herein; A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 30.

[0047] Embodiment 32. R4 is as described in embodiment 1 and other embodiments herein, except that one OH substituent is selected from each of Heteroaryl1, Heteroaryl2, phenyl, [ka] the OH substituent is in the ortho position of the R4 ring relative to the position connecting R4 to the linker -C(O)-, and the remaining R 10 , R 11 , R 12 , R 13 and R 14 is as defined herein; 32. A compound of formula (I) according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof.

[0048] Embodiment 33. R4 is as described in embodiment 1 and other embodiments herein, each R 10 , R 11 , R 12 , R 13 and R 14 but, ·H, Halo (preferably F), (C1-C2) alkyl (preferably CH3), wherein the (C1-C2) alkyl is unsubstituted or substituted with 1, 2 or 3 halo, =O, ·CN, NH2, and -O-(C1-C2)alkyl (unsubstituted or substituted with 1, 2 or 3 halo) 33. A compound of formula (I) according to any of embodiments 1-32, or a pharmaceutically acceptable salt thereof, independently selected from:

[0049] Embodiment 34. R4 is [ka] [ka] 34. The compound of formula (I) according to any one of embodiments 1 to 33, selected from: or a pharmaceutically acceptable salt thereof.

[0050] Embodiment 35. Y is N and Y [ka] is Y linked by a single bond; or a pharmaceutically acceptable salt thereof.

[0051] Embodiment 36.K [ka] is K connected by a single bond, and K is -CH2-, -CH2CH2-, -NH-, and a bond (5-membered ring: [ka] and J is N; or a pharmaceutically acceptable salt thereof.

[0052] Embodiment 37.K [ka] is K linked by a single bond, K is -CH2-, and J is N; or a pharmaceutically acceptable salt thereof.

[0053] Embodiment 38.R5 is -(C1-C4) alkyl, preferably methyl, two R5 substituents on the same ring carbon atom may, together with the carbon atom to which they are attached, form a (C3-C4)cycloalkylspirocycle or a 3- or 4-membered heterocyclylspirocycle, wherein the heterocyclylspirocycle contains ring carbon atoms and one ring heteroatom selected from O, N and S; ·K [ka] When J is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom combine to form ring C: [ka] may be formed, wherein ring C is a fused (C3-C6) cycloalkyl ring, in particular a fused cyclobutyl ring, a fused (C3-C6) heterocyclyl ring or a fused phenyl ring, the fused (C3-C6) heterocyclyl ring containing ring carbon atoms and one ring heteroatom selected from O, N and S, and when ring C is a fused (C3-C6) cycloalkyl ring, in particular a fused cyclobutyl ring, said fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, and the R 40 but, (C1-C2)alkyl, where each (C1-C2)alkyl is independently unsubstituted or substituted with OH or 1, 2 or 3 halo; Halo, especially F, Or, two R on the same ring carbon atom 40 The substituents, together with the carbon atoms to which they are attached, may form a (C3-C4)cycloalkylspirocycle or a 3- or 4-membered heterocyclylspirocycle, wherein said heterocyclylspirocycle contains ring carbon atoms and one ring heteroatom selected from O, N, and S; Or, two R on adjacent carbon atoms 40 the substituents, together with the carbon atoms to which they are attached, form a fused cyclopropyl ring; and wherein, when K is -CH2- and J is N, the two R5 substituents may join to form a (C1-C3) alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is one heteroatom selected from N and O, or is -CH2-O-CH2-; A compound of formula (I) according to any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof.

[0054] Embodiment 39. R5 is -(C 1~ C4)) alkyl, preferably methyl; ·K [ka] When J is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom combine to form ring C: [ka] may be formed, wherein ring C is a fused (C3-C6) cycloalkyl ring, in particular a fused cyclobutyl ring, or a fused (C3-C6) heterocyclyl ring, the fused (C3-C6) heterocyclyl ring containing ring carbon atoms and one ring heteroatom selected from O, N and S, and when ring C is a fused (C3-C6) cycloalkyl ring, in particular a fused cyclobutyl ring, said fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, and the R 40 but, (C1-C2)alkyl, where each (C1-C2)alkyl is independently unsubstituted or substituted with OH or 1, 2 or 3 halo; Halo, especially F, Or, two R on the same ring carbon atom 40 The substituents, together with the carbon atoms to which they are attached, may form a (C3-C4)cycloalkylspirocycle or a 3- or 4-membered heterocyclylspirocycle, wherein said heterocyclylspirocycle contains ring carbon atoms and one ring heteroatom selected from O, N, and S; Or, two R on adjacent carbon atoms 40 the substituents, together with the carbon atoms to which they are attached, form a fused cyclopropyl ring; and when K is -CH2- and J is N, the two R5 substituents may be joined to form a (C1-C3) alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is one heteroatom selected from N and O, or is -CH2-O-CH2-; A compound of formula (I) according to any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof.

[0055] Embodiment 40.R5 is -(C1-C2) alkyl, preferably methyl, and ·K [ka] When J is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom combine to form ring C: [ka] wherein ring C is a fused (C-C) cycloalkyl ring, particularly a fused cyclobutyl ring, and said fused (C-C) cycloalkyl ring, particularly a fused cyclobutyl ring, is unsubstituted or contains one or two R 40 is substituted with a group. 40. A compound of formula (I) according to any of embodiments 1-39, or a pharmaceutically acceptable salt thereof, independently selected from:

[0056] Embodiment 41. A compound of formula (I) according to any one of embodiments 1 to 40, or a pharmaceutically acceptable salt thereof, wherein y is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0057] Embodiment 42. A compound of formula (I) according to any one of embodiments 1 to 41, or a pharmaceutically acceptable salt thereof, wherein y is 0.

[0058] Embodiment 43.R5 is CH3 and y is 1 or 2, and ·K [ka] When J is a carbon-nitrogen single bond, the R5 substituent on K and the R5 substituent on the adjacent carbon atom combine to form a ring C: [ka] wherein ring C is a fused cyclobutyl ring. 43. A compound of formula (I) according to any of embodiments 1-42, or a pharmaceutically acceptable salt thereof, independently selected from:

[0059] Embodiment 44. A compound of formula (I) [ka] especially, A: [ka] More specifically, [ka] Or B: [ka] or C: [ka] 44. A compound of formula (I) according to any one of embodiments 1 to 43, comprising a moiety which is: or a pharmaceutically acceptable salt thereof.

[0060] Embodiment 45. A compound of formula (I) [ka] 45. The compound of formula (I) according to any one of embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, comprising the moiety:

[0061] Embodiment 46. Formula (I) is Formula 1a and A is -C(O)-: [ka] is (Preferably, formula (I) is formula 1a), 46. ​​A compound of formula (I) according to any one of embodiments 1 to 45, or a pharmaceutically acceptable salt thereof.

[0062] Embodiment 47. Formula (I) is Formula 1b and A is -C(O)-: [ka] 46. ​​The compound of formula (I) according to any one of embodiments 1 to 45, wherein:

[0063] Embodiment 48. Formula (I) is Formula 1c and A is -C(O)-: [ka] 46. ​​The compound of formula (I) according to any one of embodiments 1 to 45, wherein:

[0064] Embodiment 49. Formula (I) is Formula 1d and A is -C(O)-: [ka] 46. ​​The compound of formula (I) according to any one of embodiments 1 to 45, wherein:

[0065] Embodiment 50. Formula (I) is Formula 1e and A is -C(O)-: [ka] 46. ​​The compound of formula (I) according to any one of embodiments 1 to 45, wherein:

[0066] Embodiment 51. Formula (I) is Formula 1f and A is -C(O)-: [ka] 46. ​​The compound of formula (I) according to any one of embodiments 1 to 45, wherein:

[0067] Embodiment 52. Formula (I) is a compound of formula 1g: [ka] 46. ​​The compound of formula (I) according to any one of embodiments 1 to 45, wherein: More preferably, formula (I) is formula 1g.

[0068] Embodiment 53. Formula (I) is Formula 1h: [ka] 46. ​​The compound of formula (I) according to any one of embodiments 1 to 45, wherein: Most preferably, formula (I) is formula 1h.

[0069] Embodiment 54. A is -C(O)-: [ka] and During the ceremony, Y is N, C or CH; Y [ka] means that when Y is CH, it is connected to the adjacent carbon atom via a single bond, or when Y is C, it is connected to the adjacent atom via a double bond, y is 0, 1, 2, or 3; K [ka] are linked by a single bond, K is -CH2-, and J is N; R5 is -(C1-C4) alkyl, preferably methyl, two R5 substituents on the same ring carbon atom may, together with the carbon atom to which they are attached, form a (C3-C4)cycloalkylspirocycle or a 3- or 4-membered heterocyclylspirocycle, wherein the heterocyclylspirocycle contains ring carbon atoms and one ring heteroatom selected from O, N and S; ·K [ka] When J is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom combine to form ring C: [ka] may be formed, wherein ring C is a fused (C3-C6) cycloalkyl ring, in particular a fused cyclobutyl ring, a fused (C3-C6) heterocyclyl ring or a fused phenyl ring, the fused (C3-C6) heterocyclyl ring containing ring carbon atoms and one ring heteroatom selected from O, N and S, and when ring C is a fused (C3-C6) cycloalkyl ring, in particular a fused cyclobutyl ring, said fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, and the R 40 but, (C1-C2)alkyl, where each (C1-C2)alkyl is independently unsubstituted or substituted with OH or 1, 2 or 3 halo; Halo, especially F, Or, two R on the same ring carbon atom 40 The substituents, together with the carbon atoms to which they are attached, may form a (C3-C4)cycloalkylspirocycle or a 3- or 4-membered heterocyclylspirocycle, wherein said heterocyclylspirocycle contains ring carbon atoms and one ring heteroatom selected from O, N, and S; Or, two R on adjacent carbon atoms 40 the substituents, together with the carbon atoms to which they are attached, form a fused cyclopropyl ring; where K is -CH2- and J is N, two R5 substituents may be linked to form a (C1-C3) alkylene or heteroalkylene bridge, where the heteroalkylene bridge is one heteroatom selected from N and O or is -CH2-O-CH2-. are independently selected from; R1, [ka] [ka] Selected from; Alternatively, in each of the above moieties, 0 to 2 R 33 There is a substituent, R 33 is F; R 15 teeth, ·Halo; ·R 25 (R 24 )N-(CH2) n (where R 24 is H or CH3 unsubstituted or substituted with 1, 2 or 3 halo, R 25 is H, (C1-C4)alkyl-C(O)-, (C1-C4)alkyl-OC(O)-, or (C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo, or azetidinyl or pyrrolidinyl, where the azetidinyl and pyrrolidinyl are linked to the rest of the molecule via an N atom and are unsubstituted or substituted by one or two F, R 16 is R 25 (R 24 )N-, where R 24 is H or (C1-C2) alkyl, and R 25 is H or (C1-C2)alkyl unsubstituted or substituted with 1, 2 or 3 halo, especially F; R 17 is a halo; R 18 is a halo; R 19 teeth, Halo (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, (C1-C4) alkyl-O-(CH2) n - and; R 20 is a halo; R 21 is (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 F; R 22 and R 23 are each independently (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, (C1-C4) alkyl-O-(CH2) n -, HOC(O)-(CH2) n -, H3C~C(O)(CH2) n -, (H3C)3C-OC(O)(CH2) n ; where n is 0, 1 or 2; R 30 is CH3; R2 is the part [ka] During the ceremony, R6 is selected from H, halo, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo; R8 is selected from H, halo, and (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo; R9 is selected from H, O-CH3, OH, CN, CH3 and halo; R 28 is selected from SF5, halo, (C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo, and C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo and; R3 is selected from -CH3, -CH2CH3, -CH(CH3)2, and cyclopropyl, in particular -CH3 and -CH2CH3; R 26 But H; R 26 But H; R4 is Unsubstituted or NH2, -O-(CH2) 1-2 -phenyl, -(C1-C4)alkyl substituted with -NH-NH-C(O)-CF3, -Heteroaryl1, wherein said Heteroaryl1 is a 5- or 6-membered fully unsaturated monocyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S; -heteroaryl2, wherein said heteroaryl2 is a 9- or 10-membered fused bicyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein both rings are fully unsaturated or one ring is fully unsaturated and the other saturated or partially unsaturated, and said heteroatoms can be in one or both rings; -phenyl; -heterocyclyl2, wherein said heterocyclyl2 is a 5- or 6-membered fully saturated or partially unsaturated group consisting of ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S; Here, heteroaryl 1, heteroaryl 2, and phenyl are each R 10 , R 11 , R 12 , R 13 and R 14 and wherein each R 10 , R 11 , R 12 , R 13 and R 14 teeth, H, ·Halo; (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents, -O-(C1-C2)alkyl or (C1-C2)alkyl substituted by OH, -S-(C1-C3) alkyl, -O-(C1-C4)alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents; ·OH, (C3-C5)cycloalkyl (wherein said (C3-C5)cycloalkyl is unsubstituted or substituted with 1 or 2 halo), -(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent ohhh, o(C1-C4)alkyl, wherein said (C1-C4)alkyl is unsubstituted or substituted with OH or —O(C1-C2)alkyl; o and where R 34 and R 35 can be taken together with the atoms to which they are attached to form an azetidine, pyrrolidinyl, or piperidine ring, wherein said azetidine, pyrrolidinyl, and piperidine are unsubstituted or substituted with CH3. selected from ·CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, =O, -C(O)H, and -C(O)(C1-C4) alkyl are independently selected from; However, R4 is [ka] Instead, (In the formula, R 10 , R 11 , R12 , R 13 and R 14 is, independently, H, ·Halo; (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents, -O-(C1-C2)alkyl or (C1-C2)alkyl substituted by OH, -S-(C1-C3) alkyl, -O-(C1-C4)alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents; ·OH, (C3-C5)cycloalkyl, wherein said (C3-C5)cycloalkyl is unsubstituted or substituted with one or two halo groups; -(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent ohhh, o(C1-C4)alkyl, wherein said (C1-C4)alkyl is unsubstituted or substituted with OH or —O(C1-C2)alkyl; o and where R 34 and R 35 can be taken together with the atoms to which they are attached to form an azetidine, pyrrolidinyl, or piperidine ring, wherein said azetidine, pyrrolidinyl, and piperidine are unsubstituted or substituted with CH3. selected from ·CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -C(O)H, and -C(O)(C1-C4) alkyl are independently selected from; * indicates the point of attachment).

[0070] In particular, R4 is as described in any of the embodiments herein. CH3, [ka] -Heteroaryl1, wherein said Heteroaryl1 is a 5-membered fully unsaturated monocyclic ring consisting of ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S; -heteroaryl2, wherein said heteroaryl2 is a 9- or 10-membered fused bicyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein both rings are fully unsaturated or one ring is fully unsaturated and the other saturated or partially unsaturated, and said heteroatoms can be in one or both rings; -phenyl; or -heterocyclyl2, wherein said heterocyclyl2 is a 5- or 6-membered fully saturated or partially unsaturated group consisting of ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S; wherein heteroaryl 1, heteroaryl 2, phenyl, and [ka] each moiety selected from R 10 , R 11 , R 12 , R 13 and R 14 and wherein each R 10 , R 11 , R 12 , R 13 and R 14 are each independently H, ·Halo; (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents, -O-(C1-C2)alkyl or (C1-C2)alkyl substituted by OH, -S-(C1-C3) alkyl, -O-(C1-C4)alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents; ·OH, (C3-C5)cycloalkyl, wherein said (C3-C5)cycloalkyl is unsubstituted or substituted with one or two halo groups; -(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent ohhh, o(C1-C4)alkyl, wherein said (C1-C4)alkyl is unsubstituted or substituted with OH or —O(C1-C2)alkyl; o and where R 34 and R 35 can be taken together with the atoms to which they are attached to form an azetidine, pyrrolidinyl, or piperidine ring, wherein said azetidine, pyrrolidinyl, and piperidine are unsubstituted or substituted with CH3. selected from ·CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, =O, -C(O)H, and -C(O)(C1-C4)alkyl.

[0071] More specifically, R1 is [ka] is selected from.

[0072] Embodiment 55. A is -C(O)-: [ka] wherein R1, R2, R3, R4, R5, R 26 , R 27 , Y, K, J, and y are as defined in embodiment 54; 48. A compound of formula (1b) according to any one of embodiments 1 to 45 or 47, or a pharmaceutically acceptable salt thereof.

[0073] Embodiment 56. A is -C(O)-: [ka] wherein R1, R2, R3, R4, R5, R 26 , R 27 , Y, K, J, and y are as defined in embodiment 54; 49. A compound of formula (1c) according to any one of embodiments 1 to 45 or 48, or a pharmaceutically acceptable salt thereof.

[0074] Embodiment 57. A is -C(O)-: [ka] wherein R1, R2, R3, R4, R5, R 26 , R 27 , Y, K, J, and y are as defined in embodiment 54; 50. A compound of formula (1d) according to any one of embodiments 1 to 45 or 49, or a pharmaceutically acceptable salt thereof.

[0075] Embodiment 58. A is -C(O)-: [ka] wherein R1, R2, R3, R4, R5, R 26 , R 27 , Y, K, J, and y are as defined in embodiment 54; A compound of formula (1e) according to any one of embodiments 1 to 45 or 50, or a pharmaceutically acceptable salt thereof.

[0076] Embodiment 59. A is -C(O)-: [ka] wherein R1, R2, R3, R4, R5, R 26 , R 27 , Y, K, J, and y are as defined in embodiment 54; A compound of formula (1f) according to any one of embodiments 1 to 45 or 51, or a pharmaceutically acceptable salt thereof.

[0077] Embodiment 60. Formula I or 1a is Formula 1g: [ka] And, In the formula, R1, R2, R3, R4, R5, R 26 , R 27 , Y and y are as defined in embodiment 54; A compound of formula (1g) according to any one of embodiments 1 to 45 or 54, or a pharmaceutically acceptable salt thereof.

[0078] Embodiment 61. Formula I or 1a or 1g is a compound of formula 1h: [ka] And, In the formula, R1, R2, R3, R4, R5, R 26 , R 27 and y is as defined in embodiment 54. A compound of formula (1h) according to any of embodiments 1 to 45, or 54 or 60, or a pharmaceutically acceptable salt thereof.

[0079] Embodiment 62. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the compound structures exemplified herein.

[0080] Embodiment 63. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 62, wherein the compound is in non-zwitterionic form.

[0081] Embodiment 64. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 62, wherein the compound is in zwitterionic form.

[0082] Embodiment 65. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 62, wherein the compound is a mixture of zwitterionic and non-zwitterionic forms.

[0083] Embodiment 66. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 62, wherein the compound is a sodium salt.

[0084] Embodiment 67. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 62, wherein the compound is in amorphous form. For example, the compound is a sodium salt in amorphous form.

[0085] Embodiment 68. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 62, in a crystalline form.

[0086] Embodiment 69. A compound of Formula (I) according to any one of embodiments 1 to 62, wherein the compound is in substantially pure form.

[0087] Embodiment 70. A combination comprising a compound of formula (I) as defined in any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof and one or more additional therapeutically active agents.

[0088] Embodiment 71. A combination according to embodiment 70, wherein the additional therapeutically active agent is an anti-cancer agent.

[0089] Embodiment 72. A combination according to embodiment 70 or 71, wherein the additional therapeutically active agent is chemotherapy.

[0090] Embodiment 73. The additional therapeutically active agent is 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 (L eukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), citrate Daunorubicin liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), Mylotarg, paclitaxel (Taxol®),The combination according to embodiment 72, wherein the chemotherapeutic agent is selected from Phoenix (Yttrium 90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®) and vinorelbine (Navelbine®), in particular irinotecan.

[0091] Embodiment 74. The combination according to embodiment 71, wherein the additional therapeutically active agent is a PD-1 inhibitor.

[0092] Embodiment 75. A combination according to embodiment 70 or 71, wherein the additional therapeutically active agent is an anti-PD-1 antibody molecule.

[0093] Embodiment 76. The additional therapeutically active agent is selected from the group consisting of PDR001 (Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co), pidilizumab (CureTech), MEDI0680 (Medimmune), cemiplimab (REGN2810, Regeneron), dostallimab (TSR-042, Tesaro), PF-06801591 (Pfizer), tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), balstilimab (AGEN2035, Agenus), sintilimab (InnoVent), toripalimab (Shanghai Junshi Bioscience), camrelizumab (Jiangsu Hengrui Medicine Co.), and AMP-224 (Amplimmune), in particular a PD-1 inhibitor selected from PDR001, pembrolizumab or tislelizumab, more particularly tislelizumab.

[0094] Embodiment 77. A pharmaceutical composition comprising a compound of formula (I), as defined in any one of embodiments 1 to 62, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0095] Embodiment 78. A compound of formula (I) as defined in any one of embodiments 1 to 62, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0096] Embodiment 79. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to embodiments 1 to 62, for use according to embodiment 78, wherein the use is for the treatment of a disease treated by WRN inhibition.

[0097] Embodiment 80. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to embodiments 1 to 62, for use according to embodiment 78, wherein the use is for the treatment of cancer.

[0098] Embodiment 81. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to embodiments 1 to 62, for use according to embodiment 80, wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

[0099] Embodiment 82. A compound of formula (I) as defined in embodiments 1 to 62, or a pharmaceutically acceptable salt thereof, for use according to embodiment 81, wherein the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal cancer, gastric cancer, and endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer, and ovarian cancer.

[0100] Embodiment 83. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to embodiments 1 to 62, for use according to embodiment 82, wherein the cancer characterized as microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal cancer, gastric cancer, and endometrial cancer.

[0101] Embodiment 84. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 62, for use according to embodiment 81, wherein the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from endometrial carcinoma of the uterus, colon adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma, renal clear cell carcinoma, and ovarian serous cystadenocarcinoma.

[0102] Embodiment 85. A method of modulating WRN activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to embodiments 1-62.

[0103] Embodiment 86. A method of inhibiting WRN in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to embodiments 1-62.

[0104] Embodiment 87. A method of treating a disorder or disease that can be treated by WRN inhibition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to embodiments 1-62.

[0105] Embodiment 88. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to embodiments 1 to 62.

[0106] Embodiment 89. A method of treating cancer in a subject, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to embodiments 1 to 62, wherein the cancer is characterized as microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR).

[0107] Embodiment 90. The method of embodiment 89, wherein the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal cancer, gastric cancer, and endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer, and ovarian cancer.

[0108] Embodiment 91. The method of embodiment 90, wherein the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal cancer, gastric cancer, and endometrial cancer.

[0109] Embodiment 92. The method of embodiment 89, wherein the cancer characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) is selected from endometrial carcinoma, colon adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, esophageal carcinoma, breast carcinoma, renal clear cell carcinoma, and ovarian serous cystadenocarcinoma.

[0110] Embodiment 93. Use of a compound according to any one of embodiments 1 to 62, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

[0111] Embodiment 94. The use of a compound according to any one of embodiments 1 to 62 or a pharmaceutically acceptable salt thereof according to claim 93, wherein the cancer is characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR).

[0112] Embodiment 95. Use of a compound according to any one of embodiments 1 to 62, or a salt thereof, as a research chemical, chemical probe, or tool compound.

[0113] Embodiment 96. A method for making a compound according to any one of Embodiments 1 to 62, or a pharmaceutically acceptable salt thereof.

[0114] Embodiment 97. An intermediate compound as defined herein.

[0115] Also provided is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: In particular, when R1 is a ring, each R ring atom adjacent to the R ring atom at which the R ring is attached to the remainder of the molecule is independently unsubstituted or substituted only with halo, and in particular is independently unsubstituted or substituted with one F substituent; and Preferably, the R1 ring is linked to the remainder of the molecule via an R1 ring nitrogen atom or an R1 ring carbon atom that is double bonded to an adjacent R1 ring atom.

[0116] More specifically, R1 is cycloalkenyl, wherein said cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms, said cycloalkenyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2, R 33 where R 33 is halo, and said cycloalkenyl or halo-substituted cycloalkenyl has 0, 1 or 2 R 15 substituted with a substituent, preferably one substituent, or said cycloalkenyl or halo-substituted cycloalkenyl having two substituents on the same ring carbon atom to which it is attached to form an oxetanyl spiro ring; Alternatively, R1 is heterocyclyl, wherein the heterocyclyl is a fully saturated or partially unsaturated 5- or 6-membered group comprising ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, NH, O and S, and wherein the heterocyclyl is unbridged or bridged, the bridge being 1 or 2 carbon atoms, and wherein the heterocyclyl is unsubstituted or has 1, 2, 3 or 4, e.g. 1, 2 or 3, especially 1 or 2, R 33 where R 33 is halo, and said heterocyclyl or halo-substituted heterocyclyl is independently R 15 , R 16 , R 17 , R 18 , R19 , R 20 , R 22 and R 23 or substituted by 0, 1 or 2 substituents, preferably 0 or 1 substituents, selected from Alternatively, said heterocyclyl or halo-substituted heterocyclyl is fused to a cyclopropyl ring, wherein said cyclopropyl ring is unsubstituted or substituted with 1, 2 or 3 F; Alternatively, said heterocyclyl or halo-substituted heterocyclyl has two substituents at the same ring carbon atom which are joined to form a tetrahydrofuranyl spiro ring; Alternatively, R is heteroaryl, wherein said heteroaryl is a 5- or 6-membered fully unsaturated monocyclic group containing ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S, preferably 1 or 2 ring heteroatoms, wherein the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1, and wherein said heteroaryl is unsubstituted or is selected from R 21 and R 30 and is substituted by 1, 2, or 3 substituents independently selected from 21 and R 30 is independently selected from halo and (C1-C4) alkyl, wherein said (C1-C4) alkyl is unsubstituted or substituted with 1, 2 or 3 halo; Alternatively, R1 is phenyl, wherein said phenyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2 R 33 where R 33 is halo, and said phenyl or halo-substituted phenyl is substituted with zero or one R 15 Is substituted with a substituent, or R1 is (C2-C4)alkynyl unsubstituted or substituted with (C1-C4)alkyl-OC(O)-; And each R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R22 and R 23 is, independently, Halo unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C4) Alkyl-O-(CH2) n , (C1-C4)alkyl unsubstituted or substituted by OH, —O—(C1-C2)alkyl or 1, 2 or 3 halo, HOC(O)-(CH2) n -, H3C~C(O)(CH2) n -, (C1-C4) alkyl-OC(O)(CH2) n , =O, azetidinyl or pyrrolidinyl, wherein said azetidinyl and pyrrolidinyl are linked to the rest of the molecule via an N atom and each is unsubstituted or substituted with one or two F, ·R 25 (R 24 )N-(CH2) n (where R 24 is H or (C-C) alkyl unsubstituted or substituted with 1, 2 or 3 halo, and R 25 is H, (C1-C4)alkyl-C(O)-, (C1-C4)alkyl-OC(O)-, or (C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo; OH is selected from Here, n is 0, 1 or 2. Even more specifically, R1 is cycloalkenyl, wherein the cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms, and the cycloalkenyl is unsubstituted or contains one or two R 33 where R 33 is halo, preferably F, and said cycloalkenyl or halo-substituted cycloalkenyl is selected from the group consisting of 0 or 1 R 15substituted by a substituent, where R 15 teeth, h) unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C2) alkyl-O-, i) (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 halo; j) HOC(O)-(CH2) n -, k) H3C-C(O)(CH2) n -, l) H3C-OC(O)(CH2) n , m)=O, and n)R 25 (R 24 )N-, H(where R 24 is H or (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 halo, and R 25 is H or (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 halo is selected from n is 0 or 1, During the ceremony, R of the cycloalkenyl or halo-substituted cycloalkenyl 15 Substituents a) through g) are not present on the ring atom adjacent to the ring atom at which said cycloalkenyl or halo-substituted cycloalkenyl is attached to the remainder of the molecule, and preferably said cycloalkenyl or halo-substituted cycloalkenyl has one R in the ring para position relative to the remainder of the molecule. 15 a 6-membered ring having a substituent, and the cycloalkenyl or halo-substituted cycloalkenyl is linked to the remainder of the compound via an R1 ring carbon atom that is double-bonded to an adjacent R1 ring carbon atom; Alternatively, R is heterocyclyl, wherein the heterocyclyl is a fully saturated or partially unsaturated 5- or 6-membered group containing ring carbon atoms and one or two ring heteroatoms independently selected from N, NH, O, and S, and wherein the heterocyclyl is unbridged or bridged, the bridge being one or two carbon atoms, and wherein the heterocyclyl is unsubstituted or contains one or two R 33 where R 33 is halo, preferably F, and said heterocyclyl or halo-substituted heterocyclyl is independently R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 wherein R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 is, independently, i) unsubstituted or substituted with 1, 2 or 3 halo (C 1~ C4) alkyl-O-, j) (C1-C4) alkyl unsubstituted or substituted with OH, —O—(C1-C2) alkyl or 1, 2 or 3 halo; k) HOC(O)-(CH2) n -, l) H3C-C(O)(CH2) n -, m) H3C-OC(O)(CH2) n , n)=O o)R 25 (R 24 )N-, H(where R 24 is H or (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 halo, and R 25is H or (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 halo; p)OH where n is 0 or 1, And here, the substituents a) to h) of said heterocyclyl or halo-substituted heterocyclyl are not present on the ring atom by which said heterocyclyl or halo-substituted heterocyclyl is attached to the remainder of the molecule, preferably if said heterocyclyl or halo-substituted heterocyclyl is a 6-membered ring it has 0 or 1 substituent selected from a) to h) in the meta or para position, preferably in the para position, relative to the remainder of the molecule; the heterocyclyl is linked to the remainder of the compound via an R1 ring nitrogen atom or an R1 ring carbon atom that is double-bonded to an adjacent ring atom; Alternatively, R is heteroaryl, wherein said heteroaryl is a 5- or 6-membered fully unsaturated monocyclic group containing ring carbon atoms and one or two ring heteroatoms independently selected from N, O and S, preferably N, wherein the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1, and wherein said heteroaryl is unsubstituted or R 21 and R 30 and is substituted by one or two substituents independently selected from 21 and R 30 are independently selected from (C1-C2)alkyl, said (C1-C2)alkyl being unsubstituted or substituted with 1, 2 or 3 halo, wherein preferably said alkyl or haloalkyl substituent is not present on the R1 ring atom adjacent to the R1 ring atom at which the heteroaryl is attached to the remainder of the molecule, and more preferably when the heteroaryl is a 6-membered ring, said alkyl or haloalkyl substituent is in the ring para position relative to the remainder of the molecule.

[0117] In particular, R1 is [ka] Selected from; Alternatively, in each of the above moieties, 0 to 2 R 33 There is a substituent, R 33 is F; R 15 teeth, ·Halo; ·R 25 (R 24 )N-(CH2) n (where R 24 is H or CH3 unsubstituted or substituted with 1, 2 or 3 halo, R 25 is H, (C1-C4)alkyl-C(O)-, (C1-C4)alkyl-OC(O)-, or (C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo, or azetidinyl or pyrrolidinyl, where the azetidinyl and pyrrolidinyl are linked to the rest of the molecule via an N atom and are unsubstituted or substituted by one or two F, R 16 is R 25 (R 24 )N-, where R 24 is H or (C1-C2) alkyl, and R 25 is H or (C1-C2)alkyl unsubstituted or substituted with 1, 2 or 3 halo, especially F; R 17 is a halo; R 18 is a halo; R 19 teeth, Halo (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, (C1-C4) alkyl-O-(CH2) n - and; R 20 is a halo; R 21 is (C1-C2) alkyl unsubstituted or substituted with 1, 2 or 3 F; R 22 and R 23 are each independently (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo, (C1-C4) alkyl-O-(CH2) n -, HOC(O)-(CH2) n -, H3C-C(O)(CH2) n -, (H3C)3C-OC(O)(CH2) n -Selected from; where n is 0, 1 or 2; R 30 is CH3.

[0118] R1 is preferably [ka] Selected from; R 15 is F; R 16 teeth, 25 (R 24 )N- and; R 17 is F; R 18 is F; R 19 is F; R 20 is F; R 21 is CH3; R 22 are CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, (H3C)3C-OC(O)-; R 23 are CF3, CHF2CH2-, (H3C)3C-OC(O)-; R 24 is CH3; and R 25 is CHF2CH2-.

[0119] In particular, R1 is [ka] [ka] is selected from.

[0120] More preferably, R1 is [ka] Selected from, in particular [ka] is selected from.

[0121] More preferably, [ka] is selected from.

[0122] In particular, R2 is the part: [ka] and During the ceremony, R6 is selected from H, halo, (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo; R8 is selected from H, halo, and (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo; R9 is selected from H, O-CH3, OH, CN, CH3 and halo; R 28 is selected from SF5, halo, (C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo, and C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo.

[0123] More specifically, R2 is the moiety: [ka] and R6 is selected from H, Cl, CH3, F, and Br; R8 is selected from H, Cl, F, and CF3; R9 is selected from H, CH3, and Cl; R 28 is selected from CF3, CF2H, -CH2CH3, Cl, SF5, Br, and -C(O)H; X is selected from C-R7 and N; and R7 is selected from H and F.

[0124] In particular, R 28 is selected from CF3, CHF2, Cl, —CH2CH3, CH3, SF5 and Br. More specifically, R 28 is selected from CF3, Cl and SF5, in particular CF3.

[0125] In particular, X is CR7. More particularly, R7 is H.

[0126] In particular, R6 is H, F, Cl or CH3. More particularly, R6 is Cl.

[0127] In particular, R8 is F, CF3 or H. More particularly, R8 is H.

[0128] In particular, R9 is H.

[0129] In particular, R2 is [ka] [ka] is selected from.

[0130] In particular, R3 is (C1-C4)alkyl unsubstituted or substituted with one, two, or three substituents independently selected from halo and OH, or R3 is selected from -CH3, -CH2CH3, -CH(CH3)2, and cyclopropyl. More particularly, R3 is (C1-C2)alkyl unsubstituted or substituted with one, two, or three substituents independently selected from halo and OH, preferably -CH2CH3 or CH3, and more preferably -CH2CH3.

[0131] In particular, R 26 is H.

[0132] In particular, R 27 is H.

[0133] In particular, R4 is CH3, [ka] -Heteroaryl1, wherein said Heteroaryl1 is a 5-membered fully unsaturated monocyclic ring consisting of ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S; -heteroaryl2, wherein said heteroaryl2 is a 9- or 10-membered fused bicyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein both rings are fully unsaturated or one ring is fully unsaturated and the other saturated or partially unsaturated, and said heteroatoms can be in one or both rings; -phenyl; or -heterocyclyl2, wherein said heterocyclyl2 is a 5- or 6-membered fully saturated or partially unsaturated group consisting of ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S; wherein heteroaryl 1, heteroaryl 2, phenyl, and [ka] each moiety selected from R10 , R 11 , R 12 , R 13 and R 14 and wherein each R 10 , R 11 , R 12 , R 13 and R 14 are each independently ·H, ·Halo; (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents, -O-(C1-C2)alkyl or (C1-C2)alkyl substituted by OH, -S-(C1-C3) alkyl, -O-(C1-C4)alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents; ·OH, (C3-C5)cycloalkyl (wherein said (C3-C5)cycloalkyl is unsubstituted or substituted with 1 or 2 halo), -(C3-C5)cycloalkyl, -NR 34 R 35 (where R 34 and R 35 is independent ohhh, o(C1-C4)alkyl, wherein said (C1-C4)alkyl is unsubstituted or substituted with OH or —O(C1-C2)alkyl; o and where R 34 and R 35 can be taken together with the atoms to which they are attached to form an azetidine, pyrrolidinyl, or piperidine ring, wherein said azetidine, pyrrolidinyl, and piperidine are unsubstituted or substituted with CH3. selected from ·CN, -(C2-C4)alkenyl, -(C2-C4)alkynyl, =O, -C(O)H, and -C(O)(C1-C4) alkyl are independently selected from

[0134] More specifically, R4 is as described in embodiment 1 and other embodiments herein, except that at least one OH, CN, =O, or NH2 substituent is selected from each of Heteroaryl1, Heteroaryl2, phenyl, [ka] exists on Remaining R 10 , R 11 , R 12 , R 13 and R 14 is as defined herein.

[0135] Even more specifically, R4 is as described in embodiment 1 and other embodiments herein, except that one OH substituent is selected from each of Heteroaryl1, Heteroaryl2, phenyl, [ka] exists on Remaining R 10 , R 11 , R 12 , R 13 and R 14 is as defined herein.

[0136] In another embodiment, R4 is as described herein, except that one OH substituent is selected from each of Heteroaryl1, Heteroaryl2, phenyl, [ka] and the OH substituent is in the ortho position of the R4 ring relative to the position connecting R4 to the linker -C(O)-, and the remaining R 10 , R 11 , R 12 , R13 and R 14 is as defined herein.

[0137] More specifically, R4 is as described herein, and each R 10 , R 11 , R 12 , R 13 and R 14 are each independently H, Halo (preferably F), (C1-C2) alkyl (preferably CH3), wherein the (C1-C2) alkyl is unsubstituted or substituted with 1, 2 or 3 halo, =O, ·CN, NH2, and -O-(C1-C2)alkyl (unsubstituted or substituted with 1, 2 or 3 halo) is selected from.

[0138] More specifically, R4 is [ka] -NH-NH-C(O)-CF3, and [ka] is selected from.

[0139] In particular, Y is N and N, and Y [ka] is a Y linked by a single bond.

[0140] In particular, K [ka] is K connected by a single bond, and K is -CH2-, -CH2CH2-, -NH-, and a bond (5-membered ring: [ka] and J is N. More specifically, K [ka] are Ks linked by a single bond, K is -CH2-, and J is N.

[0141] In particular, R5 -(C1-C4) alkyl, preferably methyl, two R5 substituents on the same ring carbon atom may, together with the carbon atom to which they are attached, form a (C3-C4)cycloalkylspirocycle or a 3- or 4-membered heterocyclylspirocycle, wherein the heterocyclylspirocycle contains ring carbon atoms and one ring heteroatom selected from O, N and S; ·K [ka] When J is a carbon-nitrogen single bond, the R5 substituent on K and the R5 substituent on the adjacent carbon atom combine to form a ring C: [ka] may be formed, wherein ring C is a fused (C3-C6) cycloalkyl ring, in particular a fused cyclobutyl ring, a fused (C3-C6) heterocyclyl ring or a fused phenyl ring, the fused (C3-C6) heterocyclyl ring containing ring carbon atoms and one ring heteroatom selected from O, N and S, and when ring C is a fused (C3-C6) cycloalkyl ring, in particular a fused cyclobutyl ring, said fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, and the R 40 but, (C1-C2)alkyl, where each (C1-C2)alkyl is independently unsubstituted or substituted with OH or 1, 2 or 3 halo; Halo, especially F, Or, two R on the same ring carbon atom 40 The substituents, together with the carbon atoms to which they are attached, may form a (C3-C4)cycloalkylspirocycle or a 3- or 4-membered heterocyclylspirocycle, wherein said heterocyclylspirocycle contains ring carbon atoms and one ring heteroatom selected from O, N, and S; Or, two R on adjacent carbon atoms 40 the substituents, together with the carbon atoms to which they are attached, form a fused cyclopropyl ring; and when K is -CH2- and J is N, the two R5 substituents may be joined to form a (C1-C3) alkylene bridge or a heteroalkylene bridge, where the heteroalkylene bridge is one heteroatom selected from N and O, or is -CH2-O-CH2-.

[0142] More specifically, R5 is independently -(C1-C4) alkyl, preferably methyl, ·K [ka] When J is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom combine to form ring C: [ka] may be formed, wherein ring C is a fused (C3-C6) cycloalkyl ring, in particular a fused cyclobutyl ring, or a fused (C3-C6) heterocyclyl ring, the fused (C3-C6) heterocyclyl ring containing ring carbon atoms and one ring heteroatom selected from O, N and S, and when ring C is a fused (C3-C6) cycloalkyl ring, in particular a fused cyclobutyl ring, said fused (C3-C6) cycloalkyl ring is unsubstituted or contains one or two R 40 group, and the R 40 but, (C1-C2)alkyl, where each (C1-C2)alkyl is independently unsubstituted or substituted with OH or 1, 2 or 3 halo; Halo, especially F, Or, two R on the same ring carbon atom 40 The substituents, together with the carbon atoms to which they are attached, may form a (C3-C4)cycloalkylspirocycle or a 3- or 4-membered heterocyclylspirocycle, wherein said heterocyclylspirocycle contains ring carbon atoms and one ring heteroatom selected from O, N, and S; Or, two R on adjacent carbon atoms 40 the substituents, together with the carbon atoms to which they are attached, form a fused cyclopropyl ring; and when K is -CH2- and J is N, the two R5 substituents may be joined to form a (C1-C3) alkylene bridge or a heteroalkylene bridge, where the heteroalkylene bridge is one heteroatom selected from N and O, or is -CH2-O-CH2-.

[0143] Even more specifically, R5 is independently -(C1-C2) alkyl, preferably methyl, and ·K [ka] When J is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom combine to form ring C: [ka] wherein ring C is a fused (C-C) cycloalkyl ring, particularly a fused cyclobutyl ring, and said fused (C-C) cycloalkyl ring, particularly a fused cyclobutyl ring, is unsubstituted or contains one or two R 40 substituted with a group is selected from.

[0144] In particular, y is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0145] More specifically, R5 is independently CH3 and y is 1 or 2, and ·K [ka] When J is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom combine to form ring C: [ka] may be formed (wherein ring C is a fused cyclobutyl ring) is selected from.

[0146] In particular, compounds of formula (I) comprise the moiety: [ka] especially, A: [ka] More specifically, [ka] Or B: [ka] or C: [ka] Includes:

[0147] More specifically, the compounds of formula (I) comprise the moiety: [ka] Includes:

[0148] form Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible stereoisomers or as a mixture thereof, e.g., as pure optical isomers or as stereoisomeric mixtures, such as racemic and diastereoisomeric mixtures, depending on the number of asymmetric carbon atoms. The present disclosure is intended to include all such possible stereoisomers, including racemic mixtures, diastereoisomeric mixtures, and optically pure forms. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents or separated using conventional techniques. When the compounds contain double bonds, the substituent may be in the E- or Z-configuration. When the compounds contain a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0149] As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of a compound of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and that are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0150] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0151] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0152] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0153] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0154] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0155] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0156] In another aspect, the present invention provides an anti-inflammatory agent comprising an anti-inflammatory agent selected from the group consisting of acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobiolate, and the like. and the like. In some embodiments, the compounds of the present invention are provided in the form of a salt of the following: phosphate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate.

[0157] Any formula given herein is intended to represent the unlabeled form of the compound as well as the isotopically labeled form, in addition to the deuteration specifically required by formula (I). Isotopically labeled compounds have the structure depicted by the formula given herein, except that one or more atoms are replaced with atoms having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present invention include, for example, hydrogen isotopes. For example, the present invention includes deuterated forms of the exemplary compounds disclosed herein. In the compounds of formula (I), for example, one or more H atoms present on the ring: [ka] may be substituted with deuterium, for example, one or more atoms of the R moiety may be deuterium: [ka] may be substituted with.

[0158] Additionally, certain isotopes, particularly deuterium (i.e. 2Incorporation of H or D) may result in certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements, or improved therapeutic index or tolerability. It is understood that deuterium in this context is considered a substituent of the compounds of the present invention. The concentration of deuterium can be defined by the isotopic enrichment factor. The term "isotopic enrichment factor," as used herein, refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the invention is designated as deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom 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). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in a manner similar to that described for deuterium.

[0159] Other examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 Therefore, the present invention includes, for example, 3 H and 14 Radioactive isotopes such as C, or 2 H and 13It should be understood that the term "isotopically labeled compounds" includes compounds incorporating one or more of any of the foregoing isotopes, including those in which non-radioactive isotopes such as HCl, ... 14 C), reaction rate tests (e.g. 2 H or 3 H), 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 radiation treatment of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention may generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying Examples and Preparations, substituting appropriate isotopically labeled reagents for previously used non-labeled reagents.

[0160] definition A "compound of the invention" or "compound of Formula (I)" or "compound of Formula 1a" and the like includes the zwitterion, the non-zwitterion (uncharged form), or a pharmaceutically acceptable salt of said zwitterion or non-zwitterionic form.

[0161] "Zwitterion" or "zwitterionic form" refers to a compound that contains both positively charged and negatively charged functional groups.

[0162] Halo means fluoro, chloro or bromo, especially fluoro or chloro, unless otherwise stated.

[0163] The alkyl and alkoxy groups containing the required number of carbon atoms can be unbranched or branched. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, and t-butoxy.

[0164] "=O" means an oxo substituent.

[0165] When R1 is substituted or unsubstituted cycloalkenyl, said cycloalkenyl includes, but is not limited to, groups such as cyclohexenyl, particularly cyclohex-1-en-1-yl.

[0166] When R1 is a substituted or unsubstituted heterocyclyl, the heterocyclyl includes, but is not limited to, groups such as morpholinyl, piperidinyl, pyrrolidinyl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 5,6-dihydro-1,4-dioxin-2-yl, dihydropyranyl, particularly 3,4-dihydro-2H-pyran-6-yl, 5,6-dihydro-2H-pyran-3-yl and 3,6-dihydro-2H-pyran-4-yl, piperazinyl, tetrahydropyridinyl, such as 1,4,5,6-tetrahydropyridin-3-yl and 1,2,3,6-tetrahydropyridin-4-yl, and dihydropyridinyl, such as 3,6-dihydropyridinyl.

[0167] When R1 is heteroaryl, said heteroaryl is a 5- or 6-membered fully unsaturated (including aromatic) monocyclic group containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms, preferably 1 or 2 ring heteroatoms, independently selected from N, O and S, and preferably the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1. When R1 is substituted or unsubstituted heteroaryl, said heteroaryl includes, but is not limited to, substituted or unsubstituted groups such as pyridinyl, particularly pyridin-3-yl. "Heteroaryl 1" is a 5- or 6-membered fully unsaturated (including aromatic) monocyclic ring containing ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S. Preferably, the total number of ring S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1. In particular, said heteroaryl 1 contains only ring carbon atoms and 1 or 2 nitrogen atoms. Heteroaryl 1 includes, but is not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, isothiazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, triazolyl, and pyrazinyl, especially pyridyl, pyrimidinyl, and triazolyl. - "heteroaryl2", wherein said heteroaryl2 is a 9- or 10-membered fused bicyclic ring containing ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S, wherein both rings are fully unsaturated (including aromatic), or one ring is fully unsaturated (including aromatic) and the other is saturated or partially unsaturated, and the heteroatoms can be in one or both rings.

[0168] Preferably, the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1. In particular, the ring that is connected to the rest of the molecule via the linker -A- is fully unsaturated. Heteroaryl 2 includes, but is not limited to, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolopyridinyl, imidazopyridinyl, pyrazololpyridinyl, isoindolyl, indazolyl, purinyl, indolinyl, imidazopyridinyl, pyrazolopyridinyl, pyrrolopyridazinyl, pyrrolopyridinyl, imidazopyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyrimidopyrimidinyl, pyrazinopyrazinyl, hydropyranopyridinyl, particularly hydrofuropyridinyl (particularly dihydrofuropyridinyl), and imidazopyridinyl.

[0169] The present invention includes all tautomeric forms of compounds of formula (I). For example, when Heteroaryl 1 and Heteroaryl 2 are substituted with ═O, they may form tautomers such as: [ka]

[0170] The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein, including, but not limited to, colon cancer, gastric cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, ovarian cancer, etc.

[0171] The terms "tumor" and "cancer" are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors. As used herein, the term "cancer" or "tumor" includes pre-cancerous and malignant cancers and tumors.

[0172] As used herein, a "WRN inhibitor" or "WRN helicase inhibitor" refers to a compound that inhibits Werner syndrome RecQ DNA helicase (WRN). As used herein, the term "WRN" refers to the Werner syndrome RecQ DNA helicase protein. 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 from the Uniprot database under accession number Q14191.

[0173] A "WRN-mediated disease or condition" includes diseases or conditions, such as cancer, that are treated by WRN inhibition. In particular, this can include cancers characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR).

[0174] As used herein, the terms "microsatellite unstable cancer", "microsatellite unstable high cancer", "microsatellite high cancer", and "MSI high cancer", "MSI hi " and "MSI-H" are used interchangeably to describe cancers that have multiple alterations within the length of simple repeat genomic sequences within microsatellites.

[0175] Determining a patient's MSI-H or dMMR tumor status can be performed, for example, using a polymerase chain reaction (PCR) test for MSI-H status or an immunohistochemistry (IHC) test for dMMR. Methods for identifying MSI-H or dMMR tumor status are described, for example, in 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).

[0176] Microsatellite instability can also be found in colorectal, gastric, and endometrial cancers, particularly adrenocortical carcinoma, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer, and ovarian cancer. Examples of frequent microsatellite cancers include endometrial cancer of the uterine corpus, colon adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, prostate cancer, and ovarian serous cystadenocarcinoma.

[0177] Cancers with "defective mismatch repair" (dMMR) or "dMMR signature" include cancers associated with reported mutations or epigenetic silencing of MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, and PMS1, microsatellite instability, or other gene inactivation mechanisms, including, but not limited to, lung cancer, breast cancer, kidney cancer, colorectal cancer, ovarian cancer, prostate cancer, upper aerodigestive tract cancer, gastric cancer, endometrial cancer, liver cancer, pancreatic cancer, hematopoietic and lymphoid tissue cancer, skin cancer, thyroid cancer, pleural cancer, autonomic ganglion cancer, central nervous system cancer, soft tissue cancer, pediatric rhabdoid sarcoma, melanoma, and other cancers. Cells or cancers with "defective" mismatch repair have a significant reduction in mismatch repair (e.g., at least about 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction). In some cases, cells or cancers with defective mismatch repair function do not perform mismatch repair.

[0178] As used herein, the terms "synthetic lethal" and "synthetic lethal" are used to refer to a reduction in cell viability and / or a reduction in cell proliferation rate caused by a combination of mutations or approaches that result in loss of function in two or more genes (e.g., RNA interference or protein function inhibition), but not by loss of function of only one of those genes.

[0179] The term "pharmaceutical composition" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof combined with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

[0180] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, e.g., Remington The Science and Practice of Pharmacy, 22nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0181] The term "therapeutically effective amount" of a compound of the invention refers to that amount of a compound of the invention that will elicit a biological or medical response in a subject, e.g., a reduction or inhibition of enzyme or protein activity, or that will ameliorate symptoms, reduce pathology, slow or delay disease progression, or prevent disease.

[0182] In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, prevent, and / or ameliorate a condition, or a disorder or disease (i) mediated by WRN, or (ii) associated with WRN activity, or (iii) characterized by WRN activity (normal or abnormal), or (2) reduce or inhibit the activity of WRN.

[0183] In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a cell, or tissue, or non-cellular biological material, or culture medium, is effective to at least partially reduce or inhibit the activity of WRN or reduce WRN protein levels.

[0184] As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0185] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0186] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or halting the onset of the disease or at least one clinical symptom thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible to the patient.

[0187] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or the delay in the onset or progression of the disease or disorder.

[0188] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0189] As used herein, the words "a," "an," "the," and similar terms used in connection with the present invention (particularly in connection with the claims) are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0190] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Furthermore, the materials, methods, and examples are illustrative only and not limiting. Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. The use of any examples or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the invention and does not otherwise limit the scope of the claimed invention.

[0191] Isomers Any asymmetric atom (e.g., carbon, or the like) of the compounds of the present invention may be present in a racemic form or enriched in one enantiomer, for example, in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has an enantiomeric 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 at atoms having unsaturated double bonds may, where possible, be present in cis-(Z)- or trans-(E)-form.

[0192] Thus, as used herein, a compound of the invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as a substantially pure geometric (cis or trans) stereoisomer, diastereomer, optical isomer (enantiomer), racemate, or mixtures thereof.

[0193] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, on the basis of the physical chemical differences of the constituent components, for example, by chromatography and / or fractional recrystallization.

[0194] Any resulting racemic forms of the compounds or intermediates of the present invention can be resolved into their optical antipodes by known methods, for example, by separating their diastereomeric salts obtained with optically active acids or bases, and liberating the optically active acidic or basic compounds. In particular, compounds of the present invention can be resolved into their optical antipodes by, for example, fractional crystallization of salts formed with optically active acids (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid) using basic moieties in this way. Racemic compounds or racemic intermediates of the present invention can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0195] The compounds of the present invention, i.e., compounds of formula (I) containing groups capable of acting as donors and / or acceptors for hydrogen bonds, can form co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of formula (I) by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting a compound of formula (I) in solution with a co-crystal former under crystallization conditions and isolating the co-crystal formed thereby. Suitable co-crystal formers include those described in WO 2004 / 078163. Accordingly, the present invention further provides co-crystals comprising compounds of formula (I).

[0196] Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or can include other solvents used in their crystallization. The compounds of the present invention may inherently or intentionally form solvates with pharmaceutically acceptable solvents (including water), and therefore the present invention encompasses both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of the compounds of the present invention (including their pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field that are known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0197] formulation In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition may be formulated for a specific route of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal, or topical administration), and rectal administration. Topical administration may also be suitable for inhalation or intranasal administration. The pharmaceutical composition of the present invention may be comprised of a solid formulation (e.g., but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or a liquid formulation (e.g., but not limited to, solutions, suspensions, or emulsions). Tablets may be film-coated or enteric-coated according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient in combination with one or more of the following: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; in the case of tablets also c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; optionally, d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavorings and sweeteners.

[0198] Compounds intended for parenteral or oral administration can be solubilized using a variety of methods, including nanosuspensions, solid dispersions, and liposomes (van Hoogevest P., Xiangli L., and Alfred F. “Drug delivery strategies for poorly water-soluble drugs: The industrial perspective,” Expert Opinion on Drug Delivery 2011, 8(11), 1481-1500).

[0199] Solid dispersion technology has been used to improve the dissolution properties and bioavailability of orally administered drugs (Dhirendra K et al: 'Solid dispersions: A review', Pakistan Journal of Pharmaceutical Sciences, Faculty of Pharmacy, University of Karachi, Pakistan, vol. 22, no. 2, 30 April 2000, pages 234-246).

[0200] Common methods for solubilizing compounds for parenteral administration are pH optimization or the use of cosolvents (e.g., PEG300, PEG400, propylene glycol, or ethanol). If these approaches are not feasible for some reason, the use of surfactants can be considered (e.g., Tween® 80 or Cremophor EL®). Cyclodextrins have been established as safe solubilizing agents. Compounds with high solubility in natural oils (e.g., propofol) can be solubilized in parenteral fat emulsions.

[0201] Also provided are pharmaceutical compositions comprising a compound of Formula (I) described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0202] use The compounds of the invention, in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g., WRN inhibitory properties, as demonstrated in in vitro tests such as those provided herein, and are therefore indicated for use in therapy or as research chemicals, e.g., laboratory research chemicals, as chemical probes or as tool compounds.

[0203] In another aspect of the present invention, there is provided a compound of formula (I) as described herein, or a salt thereof, which can be used as a research chemical, e.g., a tool compound or chemical probe, particularly for the study of WRN or, e.g., MSI-high cancers. In another embodiment, there is provided the use of a compound of formula (I) as described herein, or a salt thereof, as a research chemical, e.g., a tool compound or chemical probe, particularly for the study of WRN or, e.g., MSI-high cancers.

[0204] Also provided is a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for use in treating cancer. Cancers that can be treated by WRN inhibition include cancers characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR). In particular, a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, can be useful in treating cancers characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR).

[0205] There is also provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. In particular, said use comprises For the treatment of diseases treated by WRN inhibition, For the treatment of cancer, For the treatment of cancers characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR), For the treatment of cancers characterized by microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), such as colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, renal, and ovarian cancers, for the treatment of cancers characterized by microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), selected from colorectal cancer, gastric cancer, prostate cancer, and endometrial cancer; or for the treatment of cancer, wherein the cancer characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) is selected from endometrial carcinoma of the uterine corpus, colon adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, esophageal carcinoma, breast cancer, renal clear cell carcinoma, prostate cancer, and ovarian serous cystadenocarcinoma. is.

[0206] The following methods are also provided: a method for modulating WRN activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof; a method of inhibiting WRN in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof; a method of treating a disorder or disease in a subject that can be treated by WRN inhibition, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof; a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof; A method of treating cancer in a subject, comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein the cancer is characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR). In particular, the cancer characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) is selected from colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical carcinoma, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, and ovarian cancer. More particularly, the cancer characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) is selected from colorectal cancer, gastric cancer, prostate cancer, and endometrial cancer. Examples include endometrial carcinoma of the uterine corpus, colon adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, esophageal carcinoma, breast carcinoma, renal clear cell carcinoma, prostate carcinoma, and ovarian serous cystadenocarcinoma.

[0207] A compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof: In treatment, In pharmaceutical manufacturing, in the manufacture of a medicament for the treatment of cancer, in particular cancers characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR), In the manufacture of a medicament for the treatment of a disease that can be treated by inhibition of WRN, Use, In particular, the cancer is characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR), such as colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical carcinoma, 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 corpus, colon adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, and ovarian serous cystadenocarcinoma. Uses are also provided.

[0208] In some embodiments, the subject has or has been diagnosed as having a microsatellite instability (MSI-H) cancer, e.g., compared to a control, e.g., a normal subject. In one embodiment, the subject has an MSI-H advanced solid tumor, colorectal cancer (CRC), endometrial cancer, uterine cancer, gastric cancer, or another MSI-H cancer. In some embodiments, the subject has colorectal cancer (CRC), endometrial cancer, or gastric cancer, which has or has been diagnosed as having microsatellite instability (MSI-H), e.g., compared to a control, e.g., a normal subject. Such diagnostic techniques are known in the art.

[0209] Dosage form The pharmaceutical composition or combination of the present invention may be, for example, in a unit dosage of about 1 to 1000 mg of active ingredient for a subject of about 50 to 70 kg.

[0210] combination "Combination" refers to a fixed combination in one unit dosage form, or to combined administration in which a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a combination partner (e.g., another drug, as described below, also referred to as a "therapeutic agent" or "adjuvant") are administered simultaneously and independently, or may be administered separately within a time interval (particularly when these time intervals allow the combination partners to exhibit a cooperative, e.g., synergistic, effect). The single components may be packaged as a kit or packaged individually. One or both of the components (e.g., powder or liquid) may be reconstituted or diluted to the desired dosage before administration. The terms "co-administration" or "administration in combination," or the like, as used herein, are meant to encompass the administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include therapeutic regimens in which the agents need not necessarily be administered by the same route of administration or at the same time. The term "pharmaceutical combination," as used herein, refers to a product resulting from the mixing or combining of multiple therapeutic agents, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that the therapeutic agents (e.g., a compound of the invention and a combination partner) are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the therapeutic agents (e.g., a compound of the invention and a combination partner) are both administered to a patient as separate entities simultaneously, concurrently, or sequentially with no specific time limit, such administration resulting in therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy (e.g., the administration of three or more therapeutic agents).

[0211] The combinations described herein may include a compound of Formula (I) and one or more additional therapeutic agents, such as one or more anti-cancer agents, cytotoxic or cytostatic agents, hormone therapy, vaccines, and / or other immunotherapies. In other embodiments, the combination is further administered or used in conjunction with other therapeutic modalities, including surgery, radiation, cryosurgery, and / or hyperthermia. Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thereby avoiding potential toxicities or complications associated with the treatments.

[0212] The additional therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with a compound of the present disclosure.

[0213] In one embodiment, the additional therapeutically active agent is a chemotherapeutic agent. Common chemotherapeutic agents contemplated for use in combination therapy include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), injectable busulfan (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carboplatin (Calplatin®), cyclosporine ... cisplatin (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), injectable cytarabine liposome (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (ActinomycinD, Cosmegan), daunorubicin hydrochloride (Cerubidine®), injectable daunorubicin citrate liposome (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluridan-2-one (Fludara®), fluoxetine ... Fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leukotriene (Lupe®), thiazolinone (Thiazolinone ... These include Covorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), Mylotarg, paclitaxel (Taxol®), Phoenix (Yttrium-90 / MX-DTPA), pentostatin, polifeprosan 20 (Gliadel®) including carmustine implant, tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0214] In another embodiment, the additional therapeutically active agent is an anti-cancer agent.

[0215] Combination partners of particular interest for combination with the compounds of the present invention include fluorouracil (5-FU) and irinotecan (Camptosar®).

[0216] In a further embodiment, the additional therapeutically active agent is the chemotherapy irinotecan (Camptosar®).

[0217] In another embodiment, the additional therapeutically active agent is an inhibitor of PD-1, e.g., human PD-1. In another embodiment, the immunomodulator is an inhibitor of PD-L1, e.g., human PD-L1. In one embodiment, the PD-1 or PD-L1 inhibitor is an antibody molecule directed against PD-1 or PD-L1. In another embodiment, the additional therapeutically active agent is an anti-PD-1 antibody molecule.

[0218] In another embodiment, the PD-1 inhibitor is selected from the group consisting of PDR001 (Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co), pidilizumab (CureTech), MEDI0680 (Medimmune), cemiplimab (REGN2810, Regeneron), dostallimab (TSR-042, Tesaro), PF-06801591 (Pfizer), tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), balstilimab (AGEN2035, Agenus), sintilimab (InnoVent), toripalimab (Shanghai Junshi Bioscience), camrelizumab (Jiangsu Hengrui Medicine Co.), and AMP-224 (Amplimmune), particularly PDR001 or tislelizumab.

[0219] In a further embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule described in U.S. Patent Application Publication No. 2015 / 0210769, entitled "Antibody Molecules to PD-1 and Uses Thereof," published July 30, 2015, which is incorporated by reference in its entirety.

[0220] In another embodiment, there is provided a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a chemotherapeutic agent, and a PD-1 inhibitor.

[0221] In particular, the chemotherapy and PD-1 inhibitor are selected from those mentioned above.

[0222] More specifically, the chemotherapeutic agent is irinotecan (Camptosar®) and the PD-1 inhibitor is PDR001 or tislelizumab. Tislelizumab may have a heavy chain of SEQ ID NO: 3 and a light chain of SEQ ID NO: 4. In some embodiments, the anti-PD-1 antibody is administered at 100 mg / week. In some embodiments, tislelizumab is administered at 300 mg IV on day 1 of each 28-day cycle. In some embodiments, tislelizumab may be administered at 500 mg once every four weeks.

[0223] In another embodiment, the anti-PD-1 antibody molecule, e.g., tislelizumab, comprises the following heavy and / or light chain: VH, VL, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3.

[0224] [Table 1]

[0225] In some embodiments, the PD-1 inhibitor comprises the HCDR and LCDR of tislelizumab set forth in SEQ ID NOs: 7-12.

[0226] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered in a flat dose of about 100 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of about 100 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of about 100 mg to about 400 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of about 100 mg to about 300 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of about 100 mg to about 200 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of about 200 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of about 200 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of about 200 mg to about 400 mg. In some embodiments, the PD-1 inhibitor is administered in a dose of about 200 mg to about 300 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg to about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 400 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 400 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 500 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 600 mg to about 700 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 700 mg to about 800 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 800 mg to about 900 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 900 mg to about 1000 mg.

[0227] The PD-1 inhibitor (e.g., tislelizumab) is administered at a flat dose of about 100 mg. The PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 200 mg. The PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 300 mg. The PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 400 mg. The PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 500 mg. The PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 600 mg. The PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 700 mg. The PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 800 mg. The PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 900 mg. The PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 1000 mg.

[0228] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered once every 10 weeks. In some embodiments, the PD-1 inhibitor is administered once every 9 weeks. In some embodiments, the PD-1 inhibitor is administered once every 8 weeks. In some embodiments, the PD-1 inhibitor is administered once every 7 weeks. In some embodiments, the PD-1 inhibitor is administered once every 6 weeks. In some embodiments, the PD-1 inhibitor is administered once every 5 weeks. In some embodiments, the PD-1 inhibitor is administered once every 4 weeks. In some embodiments, the PD-1 inhibitor is administered once every 3 weeks. In some embodiments, the PD-1 inhibitor is administered once every 2 weeks. In some embodiments, the PD-1 inhibitor is administered once every week.

[0229] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered intravenously.

[0230] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered over about 20 to 40 minutes (e.g., about 30 minutes). In some embodiments, the PD-1 inhibitor is administered over about 30 minutes. In some embodiments, the PD-1 inhibitor is administered over about 1 hour. In some embodiments, the PD-1 inhibitor is administered over about 2 hours. In some embodiments, the PD-1 inhibitor is administered over about 3 hours. In some embodiments, the PD-1 inhibitor is administered over about 4 hours. In some embodiments, the PD-1 inhibitor is administered over about 5 hours. In some embodiments, the PD-1 inhibitor is administered over about 6 hours.

[0231] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered intravenously at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every four weeks. In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered intravenously at a dose of about 200 mg to about 400 mg (e.g., about 300 mg) once every three weeks. In some embodiments, tislelizumab is administered at a dose of 400 mg once every four weeks. In some embodiments, tislelizumab is administered at a dose of 300 mg once every three weeks.

[0232] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered intravenously over about 20 to about 40 minutes (e.g., about 30 minutes) at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every two weeks. In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered intravenously over about 20 to about 40 minutes (e.g., about 30 minutes) at a dose of about 200 mg to about 400 mg (e.g., about 300 mg) once every three weeks.

[0233] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 100 mg / week. For example, if a patient is administered a 10-week dose, the PD-1 inhibitor (e.g., tislelizumab) can be administered at 1000 mg. If a 9-week dose is administered, the PD-1 inhibitor (e.g., tislelizumab) can be administered at 900 mg. If an 8-week dose is administered, the PD-1 inhibitor (e.g., tislelizumab) can be administered at 800 mg. If a 7-week dose is administered, the PD-1 inhibitor (e.g., tislelizumab) can be administered at 700 mg. If a 6-week dose is administered, the PD-1 inhibitor (e.g., tislelizumab) can be administered at 600 mg. If a 5-week dose is administered, the PD-1 inhibitor (e.g., tislelizumab) can be administered at 500 mg. If a 4-weekly dose is administered, the PD-1 inhibitor (e.g., tislelizumab) can be administered at 400 mg. If a 3-weekly dose is administered, the PD-1 inhibitor (e.g., tislelizumab) can be administered at 300 mg. If a 2-weekly dose is administered, the PD-1 inhibitor (e.g., tislelizumab) can be administered at 200 mg. If a 1-weekly dose is administered, the PD-1 inhibitor (e.g., tislelizumab) can be administered at 100 mg.

[0234] For example, when using an anti-PD-1 antibody such as tislelizumab, it can be administered at a dose of 200 mg as an intravenous infusion once every three weeks. Alternatively, it can be administered at a dose of 300 mg as an intravenous infusion once every four weeks. When using an anti-PD-1 antibody such as tislelizumab, it can be administered at a dose of 300 mg as an intravenous infusion once every three weeks. Alternatively, it can be administered at a dose of 400 mg as an intravenous infusion once every four weeks.

[0235] The structures of the active compounds, identified by code numbers, generic names or trade names, can be obtained from the current edition of the standard compendium "The Merck Index" or from databases such as Patents International (e.g., IMS World Publications). The above-mentioned compounds that can be used in combination with the compounds of the present disclosure can be prepared and administered as described in the art, for example, in the documents cited above.

[0236] In one embodiment, the present invention provides a product comprising a compound of the present invention and at least one other therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy. In one embodiment, the therapy is treatment of a disease or condition mediated by WRN. Products provided as combined preparations include compositions comprising a compound of the present invention and another therapeutic agent together in the same pharmaceutical composition, or compositions comprising a compound of the present invention and another therapeutic agent in separate forms, e.g., in the form of a kit.

[0237] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. Optionally, the pharmaceutical composition may include a pharmaceutically acceptable carrier as described herein.

[0238] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention. In one embodiment, the kit comprises a means for retaining the compositions separately, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack, such as those commonly used for packaging tablets, capsules, and the like.

[0239] The kits of the invention can be used to administer different dosage forms, e.g., oral and parenteral, to administer the separate compositions at different dosage intervals, or to titrate the separate compositions together. To aid in compliance, the kits of the invention typically include directions for administration.

[0240] In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the present invention and the other therapeutic agent may be combined into a combination therapy (i) prior to delivery of the combination product to the physician (e.g., in the case of a kit containing the compound of the present invention and the other therapeutic agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; or (iii) in the patient himself, for example, during sequential administration of the compound of the present invention and the other therapeutic agent.

[0241] Thus, the present invention provides the use of a compound of the present invention for treating a disease or condition mediated by WRN, wherein the medicament is prepared for administration with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating a disease or condition mediated by WRN, wherein the medicament is administered with a compound of the present invention.

[0242] The present invention also provides a compound of the present invention for use in the treatment of 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 a second therapeutic agent for use in the treatment of a disease or condition mediated by WRN, wherein the second therapeutic agent is prepared for administration with a compound of the present invention. The present invention also provides a compound of the present invention for use in the treatment of a disease or condition mediated by WRN, wherein the compound of the present invention is administered for administration with another therapeutic agent. The present invention also provides a second therapeutic agent for use in the treatment of a disease or condition mediated by WRN, wherein the second therapeutic agent is administered with a compound of the present invention.

[0243] The invention also provides the use of a compound of the invention for treating a disease or condition mediated by WRN, wherein the patient has been previously treated (e.g., within 24 hours) with another therapeutic agent. The invention also provides the use of a compound of the invention for treating a disease or condition mediated by WRN, wherein the patient has been previously treated (e.g., within 24 hours) with another therapeutic agent.

[0244] Biological Assays and Data The activity of the compounds of the present invention may be assessed by the following in vitro methods.

[0245] Materials and Methods Molecular biology and virus production. DNA encoding human Werner helicase (UniProt Q14191, WRN, amino acids S2-S1432) was engineered as four codon-optimized DNA strings for expression in Escherichia coli (E. coli). Strings were ordered from GeneArt (LifeTechnologies, Regensburg, Germany) or prepared by subcloning overlapping oligonucleotides.

[0246] Baculovirus from expression plasmid pLAF1202 (SEQ ID NO: 1) encoding His-ZZ-3C-WRN (aa N517-P1238, encoded by nucleotides 578-2743 in the sequence) was generated for transfection using the FlashBac Ultra system (Oxford Expression Technologies 100302) with 540 ng of plasmid DNA, 5.4 μg of FlashBac Ultra DNA, and 5.4 microliters of Lipofectin (Life Technologies 18292-011) according to the manufacturer's instructions. After 5 hours of incubation, the solution was diluted with 500 microliters of TC100 medium (Life Technologies 13055-025) and incubated at 27°C for 7 days.

[0247] Cells were harvested by centrifugation at 800 × g for 10 minutes, and the virus-containing supernatant was transferred to a new sterile tube. For initial viral amplification, 500 microliters of virus was added to 25 mL of SF9 cells at 1 million cells / mL and incubated at 27°C (200 rpm) for 5 days. Cell viability, density, and diameter were measured, and virus showing signs of infection was harvested by centrifugation at 3000 rpm for 15 minutes.

[0248] Baculovirus-infected insect cells (BIIC) were generated as described in Wasilko et al, 2009, DOI:10.1016 / j.pep.2009.01.002.

[0249] Briefly, 100 million SF9 cells (1 million cells / mL) in 100 mL of ESF921 medium (Expression System-96-001-01, supplemented with 0.5x streptomycin / penicillin) were infected with 300 million baculovirus particles of each construct (estimated MOI = 3) in an Erlenmeyer flask and incubated at 27°C and 130 rpm for 24 h. Infected cells were transferred to a 50 mL tube and harvested by centrifugation at 100 x g for 10 min at RT.

[0250] Cells were resuspended at 10 million / mL in ESF921 (0.5x streptomycin / penicillin) medium containing BSA (final 10 mg / mL) and 10% DMSO. 500 μL aliquots of cells were transferred to 1.8 mL cryotubes and frozen overnight at -80°C in a Nunc Cryo 1°C freezing container. SEQ ID NO: 1 [ka] [ka] [ka]

[0251] Protein expression and purification A BIIC aliquot for the Werner helicase protein His-ZZ-3C-WRN (aa N517-P1238, pLAF1202) was diluted 1 / 100 in ESF921 medium and further diluted 1 / 100 into an expression / production flask containing Sf21 cells (1 million cells / mL) in 1 L of ESF921 medium and incubated for 96 hours (27°C, 130 rpm) for protein expression.

[0252] WRN protein was purified using the following protocol. Cell pellets were thawed and resuspended in 80 mL of buffer A (50 mM Tris, 300 mM NaCl, 20 mM imidazole, 1 mM TCEP, 10% glycerol, pH 7.8) supplemented with Turbonuclease (final concentration 40 units / mL, Merck) and cOmplete protease inhibitor tablets (1 tablet / 50 mL, Roche). Cells were lysed by passing three times through a homogenizer (Avestin, Emulsiflex C3) at 800-1000 bar. The lysed sample was centrifuged at 48,000 × g for 40 min (Sorvall RC5B, SS-34 rotor), and the supernatant was passed through a 0.45 μm filter.

[0253] The lysate was loaded onto a 5 mL His-Trap crude FF column (GE Healthcare) attached to an AeKTA Pure 25 chromatography system (GE Healthcare). Contaminating proteins were washed off with buffer A, and bound proteins were eluted with a linear gradient over 10 column volumes to 100% buffer B (50 mM Tris, 300 mM NaCl, 300 mM imidazole, 1 mM TCEP, 10% glycerol, pH 7.8). 1% (w / w) HRV 3C protease (His-MBP tagged, produced in-house) was added to the eluted protein. The N-terminal purification tag was cleaved by the protease during overnight dialysis against 2 L of buffer (50 mM Tris pH 7.0, 150 mM NaCl, 1 mM TCEP, 10% glycerol, 0.02% CHAPS) at 5°C. The protein solution was then carefully diluted by adding two volumes of 20 mM Tris pH 7.0, 10% glycerol, 0.02% CHAPS. The slightly turbid protein solution was passed through a 0.45 μm filter. The cleaved protein was loaded onto a Resource S 6 mL column (GE Healthcare) pre-equilibrated with 20 mM Tris, 20 mM NaCl, 1 mM TCEP, 10% glycerol, pH 7.0. The cleaved tag and contaminating proteins were washed away with equilibration buffer. The bound target protein was eluted with a linear gradient over 20 column volumes of the same buffer containing 1 M sodium chloride and then injected onto a HiLoad 16 / 600 Superdex 75 pg column (GE Healthcare) pre-equilibrated with 50 mM Tris pH 7.4, 300 mM NaCl, 10% glycerol. Fractions containing pure protein were identified by SDS-PAGE and pooled. The purified protein was finally divided into aliquots and frozen on dry ice. Protein purity, quantity, and identity were determined by RP-HPLC and LC-MS.

[0254] In vitro enzyme activity assay for WRN helicase An ATPase assay was set up to measure the DNA-dependent ATP hydrolysis activity of WRN helicase, and this assay was also used to evaluate the inhibitory properties of the compounds of the present invention against DNA-dependent WRN ATPase activity.

[0255] The core helicase motif of the WRN protein (aa N517-P1238) was generated for this assay (protein was generated as described above). The 45-nucleotide oligonucleotide sequence (TTTTTTTTTTTTTTTTTTTTTTCCAAGTAAAACGACGGCCAGTGC; SEQ ID NO: 2) designated "FLAP26," described in Brosh et al., 2009, DOI: 10.1074 / jbc.M111446200, was purchased from IDT (Integrated DNA Technologies, Leuven, Belgium) and used as a single-stranded DNA substrate. The ADP-Glo ​​assay kit (Promega, Madison, WI), which allows for quantification of ADP generated in the ATP hydrolysis reaction, was used to set up this assay.

[0256] A time course experiment was first performed to determine the best enzyme assay conditions (including buffer conditions, reaction time, and concentrations of protein, ATP, and DNA substrate). A typical reaction consisted of 10 nM WRN protein, 0.2 nM FLAP26, and 300 micromolar ATP in the following assay buffer: 30 mM Tris pH 7.5, 2 mM MgCl, 0.02% BSA, 50 mM NaCl, 0.1% pluronic F127 (prepared in DNAse-free water).

[0257] To evaluate the inhibitory properties of compounds of the present invention, serial dilutions were prepared in DMSO (10 half-log dilutions from a 10 mM DMSO solution). Fifty nanoliters of each concentration was preincubated for 3 hours in assay buffer containing 600 micromolar ATP in a 384-well small-volume assay plate (Greiner #784075) containing 2.5 microliters of 20 nM WRN helicase protein. Control wells included a "high control" (no inhibition) containing DMSO without test compound and a "low control" (maximum inhibition) containing buffer without protein. The reaction was initiated by the addition of 2.5 microliters of FLAP26 at 0.4 nM and incubated for 30 minutes at room temperature. The reaction was stopped by the addition of 5 microliters of the first ADP-Glo ​​reagent and incubated for 1 hour to remove excess ATP. Subsequently, 10 microliters of ATP detection reagent was added and incubated for an additional hour before reading. Luminescence output was recorded using a Tecan 1000 reader with a 5-minute delay before reading. Each concentration of compound was tested in duplicate on the assay plate.

[0258] Data analysis was performed using in-house developed software (Novartis Helios software application, Novartis Institutes for BioMedical Research, unpublished) using the method described by Formenko et al., 2006, DOI: 10.1016 / j.cmpb.2006.01.008. After normalizing well activity values ​​to % inhibition (% inhibition = [(high control - sample) / (high control - low control)] x 100), IC values ​​were calculated from duplicate measurements on each plate according to [4]. 50 Data analysis was also performed using a four-parameter fit (e.g., GraphPad Prism, XLfit) to determine the IC 50 This can be done using commercially available software designed to derive the reported IC values. 50 Values ​​are the geometric means of at least two independent replicates.

[0259] Methods for detecting effects on cell proliferation The colon cancer cell lines SW48 (RRID: CVCL_1724), HCT116 (RRID: CVCL_0291), and SNU-407 (RRID: CVCL_5058) were obtained from ATCC. The WRN knockdown-insensitive colon cancer cell line DLD-1 (RRID: CVCL_0248) was obtained from the Korean Cell Line Bank (KCLB) and used to generate derivatives in which the endogenous WRN gene copy was knocked out by CRISPR-mediated editing using standard CRISPR methods. The resulting cell line, DLD1-WRN-KO, was used to evaluate potential off-target compound effects.

[0260] SW48, SNU-407, and DLD1-WRN-KO cells were cultured in growth medium consisting of RPMI-1640 (Amimed catalog no. 1-41F22-I), 2 mM L-glutamine (Amimed catalog no. 5-10K50), 10 mM HEPES (Gibco catalog no. 15630-056), 1 mM sodium pyruvate (Amimed catalog no. 5-60F00-H), 1× penicillin-streptomycin (Amimed catalog no. 4-01F00-H), and 10% fetal bovine serum (Amimed catalog no. 2-01F30-G, lot no. LB11566P). HCT 116 cells were cultured in growth medium consisting of McCoys 5A (Amimed catalog number 1-18F01-I), 2 mM L-glutamine (Amimed catalog number 5-10K50), 1x penicillin-streptomycin (Amimed catalog number 4-01F00-H), and 10% fetal bovine serum (Amimed catalog number 2-01F30-G, lot number LB11566P). All cells were maintained at 37°C in a humidified 5% CO2 incubator.

[0261] After filtration through a Steriflip-NY 20 μm filter (Millipore catalog no. SCNY00020), trypsinized cells were seeded into white, clear-bottom 96-well plates (Costar catalog no. 3903) at 2,000 (SW48) or 1,500 (SNU-407, DLD1-WRN-KO, HCT 116) cells / well in 100 microliters of growth medium. Three replicate plates were prepared for each compound treatment condition. Additionally, one plate (designated "day 0") was prepared for quantitating viable cell numbers at the time of compound addition. After overnight incubation at 37°C in a humidified 5% CO2 atmosphere, eight three-fold serial dilutions of a given compound stock (obtained at a concentration of 10 mM in DMSO and stored at 4°C) were dispensed directly into each of the triplicate assay plates using an HP 300D non-contact digital dispenser (TECAN). The final concentration of DMSO was normalized to 0.1% in all wells. Ninety-six hours after compound addition, cellular ATP levels, as a surrogate for cell viability, were assessed after the addition of 50 microliters of CellTiterGlo (Promega catalog number G7573) reagent, and luminescence was quantified on an MPLEX multimode plate reader (TECAN) after a 10-minute incubation at room temperature. The number of viable cells in the "day 0" plate was similarly quantified on the day of compound addition.

[0262] For data analysis, the assay background signal determined in wells containing medium but no cells was subtracted from all data points prior to further calculations. The degree of growth inhibition and potential cell death were evaluated by comparing the ATP levels (measured using CellTiterGlo, Promega) in compound-treated cells to those present at the time of compound addition. For this purpose, the following conditional concepts were programmatically applied in HELIOS. HELIOS is in-house software that applies a multi-step decision tree to reach an optimal fit of the concentration-response curve (Gubler et al, SLAS DOI: 10.1177 / 2472555217752140), and calculates the growth % (G%) of each well treated with a compound: G% = ((T - V0) / V0)) * 100 (when T < V0), G% = ((T - V0) / (V - V0)))*100 (when T ≥ V0) (where V0 is the survival rate level at the time of compound addition, and V and T are the vehicle control survival level and compound-treated survival level, respectively, at the end of compound incubation). 100%, 0%, and -100% indicate, respectively, the absence of growth inhibition, growth arrest, and complete cell death. The compound concentration (GI50) that results in 50% growth inhibition and the residual cell survival rate (data (cmax), expressed as a percentage) at the highest concentration of the test compound were routinely calculated. Data analysis can also be performed using commercially available software designed to derive IC50 values using a 4-parameter fit (e.g., GraphPad Prism, XL Fit). The reported GI 50 values are the geometric mean of at least two independent replicates.

[0263] The following table shows the IC 50 data in the WRN ATPase assay for the compounds of the present invention, and the GI 50 data in the growth assay using the SW48 and DLD1-WRN-KO cell lines. For example, Example 11 shows a biochemical IC 50 of 0.05 μM and a growth GI 50is a WRN ATPase inhibitor with a concentration of 0.06 μM in SW48 and ≥10 μM in DLD1 WRN-KO cell lines.

[0264] [Table 2]

[0265] [Table 3]

[0266] [Table 4]

[0267] [Table 5]

[0268] [Table 6]

[0269] Data are geometric means from at least two replicate determinations.

[0270] Preparation of compounds The compounds of the present disclosure can be prepared as described in the following examples, which are intended to illustrate the invention and should not be construed as limiting the invention.

[0271] device Microwave: All microwave reactions were carried out in a Biotage Initiator or Anton Paar monowave 450 irradiating from a 2.45 GHz magnetron with a Robot Eight / Robot Sixty / Robot Twentyfour processing capacity at 0-400 W unless otherwise specified.

[0272] UPLC-MS Method: A Waters Acquity UPLC equipped with a Waters SQ detector is used unless otherwise specified.

[0273] UPLC-MS Method: A Waters Acquity UPLC equipped with a Waters SQ detector is used unless otherwise specified.

[0274] UPLC-MS 1: Column CORTECS (trademark) C18+2.7μm, Column dimensions: 2.1 x 50 mm Column temperature: 80°C Eluent A: Water + 4.76% isopropanol + 0.05% FA + 3.75mM AA B: Isopropanol + 0.05% FA Flow rate 1.0mL / min Gradient: 1 to 50% B in 1.4 min, 50 to 98% B in 0.3 min

[0275] UPLC-MS 3: Column: ACQUITY UPLC® BEH C18 1.7 μm Column dimensions: 2.1 x 50 mm Column temperature: 80℃ Eluent A: Water + 4.76% isopropanol + 0.05% FA + 3.75mM AA B: Isopropanol + 0.05% FA Flow rate 0.6mL / min Gradient: 1 to 98% B in 1.7 min

[0276] UPLC-MS 4: Column: ACQUITY UPLC® BEH C18 1.7 μm Column dimensions: 2.1 x 50 mm Column temperature: 80°C Eluent A: Water + 0.05% FA + 3.75mM AA B: Isopropanol + 0.05% FA Flow rate 0.6 / 0.7mL / min Gradient: 5 to 98% B in 1.7 min

[0277] UPLC-MS 7: Column: Acquity UPLC® HSS T3 1.8 μm Column dimensions: 2.1 x 50 mm Column temperature: 60°C Eluent A: Water + 0.05% formic acid + 3.75 mM ammonium acetate B: Acetonitrile + 0.04% FA Flow rate 1.0mL / min Gradient: 2 to 98% B in 1.4 min

[0278] UPLC-MS 8: Column: Acquity UPLC® HSS T3 1.8 μm Column dimensions: 2.1 x 50 mm Column temperature: 60°C Eluent A: Water + 0.05% formic acid + 3.75 mM ammonium acetate B: Acetonitrile + 0.04% FA Flow rate 1.0mL / min Gradient: 5 to 98% B in 1.4 min

[0279] UPLC-MS 10: Column CORTECS (trademark) C18+2.7μm, Column dimensions: 2.1 x 50 mm Column temperature: 80°C Eluent A: Water + 0.05% FA + 3.75mM AA B: Isopropanol + 0.05% FA Flow rate 1.0mL / min Gradient: 1% to 98% B in 1.4 minutes

[0280] UPLC-MS 11: Equipment: Shimadzu NEXERA UPLC PDA with Shimadzu LCMS 2020 as MSD Column: Mercury MS Synergi C12 2.5μm Column dimensions: 20 x 4.0 mm Column temperature: 40°C Eluent A: Water + 0.1% FA B: Acetonitrile Flow rate 2.0mL / min Gradient Time / %B: 0.01 / 5, 0.5 / 5, 1.0 / 95, 1.5 / 95, 2.0 / 5, 3.0 / 5

[0281] UPLC-MS 12: Instrumentation: Agilent 1200 HPLC PDA with AB Sciex API2000 TQ as MSD Column: Mercury MS Synergi C12 2.5μm Column dimensions: 20 x 4.0 mm Column temperature: 30°C Eluent A: Water + 0.1% FA B: Acetonitrile Flow rate 2.0mL / min Gradient Time / %B: 0.01 / 30, 0.5 / 30, 1.0 / 95, 2.4 / 95, 2.5 / 30, 3.0 / 30

[0282] UPLC-MS 15: Column: Acquity UPLC® HSS T3 1.8 μm Column dimensions: 2.1 x 50 mm Column temperature: 50°C Eluent A: Water + 0.05% formic acid + 3.75 mM ammonium acetate B: Acetonitrile + 0.04% FA Flow rate 1.0mL / min Gradient: 5 to 98% B in 1.4 min

[0283] UPLC-MS 17: Column: ACQUITY UPLC® BEH C18 1.7 μm Column dimensions: 2.1 x 100 mm Column temperature: 80°C Eluent A: Water + 4.76% isopropanol + 0.05% FA + 3.75mM AA B: Isopropanol + 0.05% FA Flow rate 0.4mL / min Gradient: 1 to 60% B in 8.4 min, 60 to 98% B in 1.0 min

[0284] UPLC-MS 18: Column: ACQUITY UPLC® BEH C18 1.7 μm Column dimensions: 2.1 x 50 mm Column temperature: 60°C Eluent A: Water + 0.05% FA + 3.75mM AA B: Acetonitrile + 0.04% FA Flow rate 1.0mL / min Gradient: 2 to 98% B in 0.8 min

[0285] HPLC Method: HPLC 1: Instruments: Agilent 1100 series with PDA detector Column: Kinetex C-18, 5 μm Column dimensions: 150 x 4.6 mm Column temperature: 40°C Eluent A: Water + 0.01% TFA B: Acetonitrile Flow rate 1.0mL / min Gradient Time / B: 0 / 30, 2 / 40, 5 / 90, 8 / 100, 10 / 100, 11 / 30, 12 / 30

[0286] HPLC 4: Instrument Agilent 1260 Column: Agilent Poroshell 120 EC-C18, 2.7 μm Column dimensions: 4.6 x 50 mm Column temperature: 40°C Eluent A: Water + 0.1% TFA B: Acetonitrile + 0.1% TFA Flow rate 1.2mL / min Gradient: 5%B to 95%B in 5 minutes, hold for 2 minutes

[0287] HPLC 5: Instrument Agilent 1260 HPLC Column: InertSustain C18, 5 μm Column dimensions: 4.6 x 150 mm Column temperature: 30°C Eluent A: Water + 5mmol(NH4)2CO3 B: Acetonitrile Flow rate 1.0mL / min Gradient: 10%B to 90%B in 8 minutes, hold for 2 minutes

[0288] HPLC 6: Instrument: Agilent 1260 infinity series HPLC system with DAD / ELSD Column: Atlantis dC18, 5 μm Column dimensions: 4.6 x 250 mm Column temperature: 25°C Eluent A: Water + 0.1% TFA B: Acetonitrile Flow rate 1.0mL / min Gradient: 10%B to 100%B in 15 minutes, hold for 5 minutes

[0289] Adjustment method: Column chromatography: Column chromatography was carried out on silica gel using prepacked columns as detailed below, or using glass columns according to standard flash chromatography techniques, unless otherwise stated. System 1 TeledyneISCO, CombiFlash Rf, CombiFlash Rf+ System 2 Biotage Isolera Column: Pre-packed RediSep Rf cartridge or SNAP cartridge Isolute or adsorb the sample onto silica gel, or add it as a solution.

[0290] Supercritical Fluid Chromatography (SFC) Purification was performed on a Waters preparative SFC-100-MS system with ABSYS updates, equipped with a Waters 2998 photodiode array detector and a Waters MS single quadrupole detector.

[0291] SFC 8: Equipment: WATERS SFC 100 with ABSYS update Mobile phase: A: CO2, B: MeOH Flow rate: 150mL / min MeOH+30mL / min CO2, constant flow rate of 180mL / min Column: 100 x 30 Reprosil NH2100A 3 μm Temperature: 50℃ Back pressure: 100bar Detection UV: 210~400nm Gradient: 16%B to 24%B in 4 minutes

[0292] Reverse phase HPLC: RP-HPLC acidic 1: System Gilson Column: Waters SunFire Prep C18 OBD (100 mm x 30 mm), 5 μm Eluent A: Water + 0.1% TFA, B: Acetonitrile Flow rate 40mL / min

[0293] Preparation of compounds The following examples are intended to illustrate the present invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporations are carried out under reduced pressure, typically at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). Abbreviations used are conventional in the art.

[0294] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art. Additionally, the compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art, as shown in the examples below.

[0295] The structure of all final products, intermediates, and starting materials is confirmed by standard analytical spectroscopic characteristics, such as MS, IR, or NMR. The absolute stereochemistry of representative examples of the preferred (most active) isomers has been determined by analysis of the X-ray crystal structure of a complex of the respective compound bound to WRN or by small molecule X-ray crystal structures of precursors or final compounds.

[0296] Amines synthesized by acidic deprotection of the Boc precursor were often obtained as HCl or TFA salts. The corresponding free bases can be isolated by partitioning between DCM and saturated aqueous NaHCO3, as described for intermediate D.

[0297] General conditions: Mass spectra were acquired on LC-MS systems using electrospray, chemical, and electron impact ionization methods from various instruments with the following configurations: Waters Acquity UPLC with a Waters SQ detector, Shimadzu NEXERA UPLC PDA with a Shimadzu LCMS 2020 as the MSD, Agilent 1200 HPLC PDA with an AB Sciex API 2000 TQ as the MSD, and Agilent 1200 HPLC PDA with an AB Sciex API 3200 QTRAP as the MSD. [M+H] + refers to the protonated molecular ion of a chemical species.

[0298] NMR spectra were performed using Bruker Ultrashield™ 400 (400 MHz), Bruker Ultrashield™ 400 Plus (400 MHz), Bruker Ultrashield™ 600 (600 MHz), and Bruker Ascend™ 400 (400 MHz) spectrometers, all with and without tetramethylsilane as an internal standard. Chemical shifts (d values) are reported in ppm downfield from tetramethylsilane, and spectral splitting patterns are designated as singlets (s), doublets (d), triplets (t), multiplets, unresolved or further overlapping signals (m), or broad signals (br). Solvents are indicated in parentheses.

[0299] Celite:Celite R (Celite Corporation) = Filter aid based on diatomaceous earth Phase separator: Biotage Isolute Phase Separator (Part Number: 120-1906-D (15 mL), Part Number: 120-1908-F (70 mL), and Part Number: 120-1909-J (150 mL)) SiliaMetS® Thiol: SiliCYCLE Thiol Metal Scavenger (Part Number: R51030B, Loading: 1.31 mmol / g, Particle Size: 40-63 μm) ISOLUTE® Si-Thiol: Biotage thiol metal scavenger (Part Number: 9180-0100, Loading: 1.3 mmol / g) PL-BnSH MP Resin: Agilent thiol metal scavenger (Part Number: PL3582-6689, 2.2 mmol / g 100A, 150-1 kg) ISOLUTE® Si-TMT: Biotage Thiol Metal Scavenger (Part Number: 9538) Smopex®-301: Alfa Aesar thiol metal scavenger (Part Number: 45902) PL-HCO3MP SPE Cartridge (500mg / 6mL) - (Part Number: PL3540-C603) PL-HCO3MP SPE Cartridge (100mg / 6mL) - (Part Number: PL3540-A603)

[0300] Sodium salt formation: This compound can be suspended in tert-butanol and 0.1M NaOH (1 equivalent) can be added. The mixture can be stirred / sonicated at room temperature. Once the suspension becomes a clear solution, it can be lyophilized. If the suspension is still cloudy, water can be added and lyophilized. If there is no change, add 0.1M NaOH up to a total of 2 equivalents until a clear solution is observed and lyophilize. If the NMR of the resulting solid still contains tert-butanol, dissolve the solid in a small amount of water and lyophilize again.

[0301] Abbreviation

[0302] [Table 7]

[0303] [Table 8]

[0304] [Table 9]

[0305] [Table 10]

[0306] [Table 11]

[0307] Preparation of final compounds Scheme 1: Preparation of final compounds (Route I) [ka] Route I Example 1: 2-(6-(4-acetylpiperazin-1-yl)-2-(3-fluoropiperidin-1-yl)-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] 6-(4-Acetylpiperazin-1-yl)-2-(3-fluoropiperidin-1-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (Intermediate F) (550 mg, 1.45 mmol) was suspended in DMF (10 mL). 2-Bromo-N-(4-(trifluoromethyl)phenyl)acetamide (450 mg, 1.60 mmol) and DIPEA (760 μmol, 4.35 mmol) were added at 0 °C. The RM was stirred at RT for 12 h. Water was added and the resulting solid was filtered. The crude product was purified by column chromatography (Combiflash column: 12 g, eluent DCM:MeOH 100:0 to 95:5). The product-containing fractions were combined, concentrated, and dried under high vacuum to give the title compound. LC-MS: Rt = 1.50 min; MS m / z [M+H] + 579.2;UPLC-MS11

[0308] Examples 2-10 were prepared in a manner similar to Example 1, using methods known to those skilled in the art and using known starting materials. For Examples 7-10, the crude reaction mixtures were analyzed.

[0309] [Table 12]

[0310] [Table 13]

[0311] [Table 14]

[0312] [Table 15]

[0313] Scheme 2: Preparation of final compounds (Routes II, III) [ka] Route II Example 11: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(7-hydroxy-2,3-dihydrofluoro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] Step 1: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide To a suspension of beige N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (Intermediate D) (80.0 mg, 134 μmol) and 7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylic acid (Intermediate P) (36.8 mg, 141 μmol) in DMF (1.34 mL) was added DIPEA (117 μL, 671 μmol), followed by HATU (61.3 mg, 161 μmol). The RM was stirred at room temperature for 30 min. The RM was diluted with water and extracted three times with DCM. The combined organic phase was dried on a phase separator and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica 4 g, eluent DCM: DCM / MeOH (8 / 2) 100:0 to 10:90) to give the title compound. LC-MS: Rt = 1.04 min; MS m / z [M+H] + 773.6 / 775.6, m / z [MH] - 771.5 / 773.6; UPLC-MS1

[0314] Step 2: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine 6-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide To a pale yellow solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide (88.0 mg, 97.0 μmol) in absolute EtOH (1.94 mL) was added 1.25 M hydrochloric acid in EtOH (155 μL, 193 μmol). The RM was stirred at room temperature for 7 days. The RM was concentrated to dryness under vacuum. The residue was triturated with EtO. The resulting pale yellow suspension was filtered. The cake was washed with EtO and dried to give a beige solid. The filtrate was concentrated in vacuo to give a light brown residue. The cake was dissolved in MeOH and filtered through a PL-HCO3MP SPE cartridge. The filtrate was concentrated under reduced pressure to give a beige solid. The crude product was purified by reverse-phase preparative HPLC (RP-HPLC acidic 1: 5-100% B in 20 min). The product-containing fractions were combined, basified with saturated aqueous NaHCO3, extracted twice with DCM, dried over a phase separator, and concentrated under reduced pressure to give the title compound. LC-MS: Rt = 0.93 min; MS m / z [M+H] + 729.5 / 731.5, m / z [MH] - 727.5 / 729.4; UPLC-MS1

[0315] Examples 12-34 were prepared in a manner analogous to Example 11 using methods and known starting materials known to those skilled in the art.

[0316] [Table 16]

[0317] [Table 17]

[0318] [Table 18]

[0319] [Table 19]

[0320] [Table 20]

[0321] [Table 21]

[0322] [Table 22]

[0323] [Table 23]

[0324] Route III Example 35: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(6-hydroxypyrazolo[1,5-a]pyridine-7-carbonyl)piperazin-1-yl)-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] To a dark purple suspension of 6-hydroxypyrazolo[1,5-a]pyridine-7-carboxylic acid (Intermediate O) (16.5 mg, 85.0 μmol) in DCM (386 μL) was added HATU (44.1 mg, 116 μmol), followed by DIPEA (40.5 μL, 232 μmol). After stirring the RM for 5 min, 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (Intermediate A) (40.0 mg, 77.0 μmol) was added. The RM was stirred at RT for 5 h. The reaction mixture was diluted with DCM and washed with water. The aqueous phase was extracted once with DCM. The combined organic phases were dried on a phase separator, concentrated under reduced pressure, and dried under high vacuum. The crude product was purified by column chromatography (RediSep column: 4 g silica, eluent DCM:DCM / MeOH (9:1) 100:0 to 0:100). The product-containing fractions were combined, concentrated, and dried under high vacuum to give the title compound. LC-MS: Rt = 1.02 min; MS m / z [M+H] + 678.1, m / z [MH] - 676.1;UPLC-MS3

[0325] Example 36: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(3-hydroxyisonicotinoyl)piperazin-1-yl)-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] A solution of 3-hydroxyisonicotinic acid (53.8 mg, 386 μmol) in DCM (4 mL) was cooled to 0° C. Next, 1-chloro-N,N,2-trimethyl-1-propenylamine (56.0 μL, 425 μmol) was added, and the RM was stirred at RT for 2 h. The solution was again cooled to 0° C., and DIPEA (169 μL, 966 μmol) was added, followed by 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (Intermediate A) (100 mg, 193 μmol). The RM was stirred at RT for 1 h. The RM was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried on a phase separator and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC (RP-HPLC acidic 15:20 to 50% B in 7 min, 50 to 100% B in 0.2 min) to give the title compound after lyophilization. LC-MS: Rt = 0.95 min; MS m / z [M+H] + 639.4, m / z [MH] - 637.3;UPLC-MS4

[0326] Examples 37-68 were made in a manner analogous to Examples 35 and 36 using methods and known starting materials known to those skilled in the art.

[0327] [Table 24]

[0328] [Table 25]

[0329] [Table 26]

[0330] [Table 27]

[0331] [Table 28]

[0332] [Table 29]

[0333] [Table 30]

[0334] [Table 31]

[0335] [Table 32]

[0336] [Table 33]

[0337] [Table 34]

[0338] Scheme 3: Preparation of final compounds containing R4 N-acetyl-piperazine (Routes IV, V) [ka]

[0339] Route IV Example 69: 2-(6-(4-acetylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] To a solution of 2-(6-(4-acetylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetic acid (Intermediate H) (64.0 mg, 98.0 μmol) and 4-aminobenzotrifluoride (15.0 μL, 117 μmol) in DMF (500 μL) was added EtN (54.0 μL, 391 μmol) and T3P 50% in DMF (116 μL, 195 μmol). The brown solution mixture was stirred at room temperature for 4.5 h. 4-Aminobenzotrifluoride (15.0 μL, 117 μmol), T3P 50% in DMF (116 μL, 195 μmol), and Et3N (54.0 μL, 391 μmol) were added, and the RM was stirred at RT for 2.5 days and then at 50 °C for 4 h. The RM was purified by reverse-phase preparative HPLC (RP-HPLC acidic 1:28 to 58% B in 20 min). The product-containing fractions were combined and salted out with a small amount of saturated NaHCO3. The ACN was evaporated under reduced pressure, and the resulting solid was filtered, washed with water, and dried under high vacuum to give the title compound as a white solid. LC-MS: Rt = 0.93 min; MS m / z [M+H] + 560.4, m / z [MH] - 558.4;UPLC-MS8

[0340] Examples 70-103 were made in an analogous manner to Example 69 using methods and known starting materials known to those skilled in the art.

[0341] [Table 35]

[0342] Table 36

[0343] Table 37

[0344] Table 38

[0345] Table 39

[0346] Table 40

[0347] Table 41

[0348] Table 42

[0349] Table 43

[0350] Table 44

[0351] Table 45

[0352] Table 46

[0353] Route V Example 104: 2-(6-(4-acetylpiperazin-1-yl)-2-(5,6-dihydro-1,4-dioxin-2-yl)-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] 2-(6-(4-Acetylpiperazin-1-yl)-2-bromo-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (Intermediate G) (370 mg, 665 μmol), 2-(5,6-dihydro-1,4-dioxin-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (169 mg, 798 μmol), PdX-PhosG3 (28.1 mg, 33.0 μmol), and 1M aqueous KPO4 (2.00 mL, 2.00 mmol) were mixed in dioxane (1 mL) and stirred at 65 °C for 1 h. Water, saturated aqueous NaHCO3, and DCM were added. The aqueous layer was washed twice with DCM. The combined organic phase was dried on a phase separator and concentrated under reduced pressure. The residue was dissolved in DCM. Then, Isolute® Si-Thiol was added. The mixture was stirred at room temperature for 1 hour. Then, it was filtered. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel column: 40 g silica, eluent DCM: DCM / MeOH (9 / 1) 100:0 to 0:100) to obtain the title compound. LC-MS: Rt = 0.92 min; MS m / z [M+H] + 562.5, m / z [MH] - 560.5;UPLC-MS8

[0354] Examples 105-135 were prepared in a manner analogous to Example 104 using methods and known starting materials known to those skilled in the art.

[0355] Table 47

[0356] Table 48

[0357] Table 49

[0358] Table 50

[0359] Table 51

[0360] Table 52

[0361] Table 53

[0362] Table 54

[0363] Table 55

[0364] Table 56

[0365] Table 57

[0366] Scheme 4: Preparation of final compounds containing R4 piperidine (Route VI) [ka]

[0367] Route VI Example 136: 2-(6-(1-(3,6-difluoro-2-hydroxybenzoyl)piperidin-4-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] 3,6-Difluoro-2-hydroxybenzoic acid (31.0 mg, 178 μmol) was dissolved in DCM (100 μL) and mixed with 1-chloro-N,N,2-trimethyl-1-propenylamine (17.7 μL, 134 μmol). The RM was stirred at room temperature for 30 minutes. DIPEA (46.7 μL, 267 μmol) was added, followed by 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-6-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (Intermediate C) (46.0 mg, 89.0 μmol). The RM was stirred at RT for 1 hour. The RM was concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC (RP-HPLC acidic 1:5 to 100% B in 20 min) and then by preparative chiral HPLC (apparatus: Sepiatec prep SFC-100; column: LUX Amylose-1 (Chiralpak AD), 250 mm × 30 mm 5 μm; eluent: A: 37% IPA + 0.1% NH, B: 63% scCO; flow rate: 80.0 mL / min; detection: UV; injection volume: 2.3 mL; gradient: isocratic A: 37%, B: 63%; oven temperature: 40 °C; BPR: 120 bar) to give the title compound. LC-MS: Rt = 1.01 min; MS m / z [M+H] + 673.4, m / z [MH] - 671.4;UPLC-MS8

[0368] Examples 137-146 were made in a manner analogous to Example 136, using methods and known starting materials known to those skilled in the art, and in certain cases the order of steps was changed.

[0369] [Table 58]

[0370] [Table 59]

[0371] [Table 60]

[0372] [Table 61]

[0373] Scheme 4: Preparation of R4 piperazine-containing final compounds (Route VII) [ka]

[0374] Example 147: 2-(6-(4-acetylpiperazin-1-yl)-5-cyclopropyl-2-(3,6-dihydro-2H-pyran-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] 2-(5-Cyclopropyl-2-(3,6-dihydro-2H-pyran-4-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (Intermediate B) (45.0 mg, 83.0 μmol) was dissolved in THF (1.65 mL) under argon. EtN (34.4 μL, 248 μmol) was added, followed by acetic anhydride (9.30 mg, 91.0 μmol). The RM was stirred at RT for 2 h. EtN (30.0 μL, 216 μmol) and acetic anhydride (9.30 mg, 91.0 μmol) were added again, and the RM was stirred at RT for 2.25 h. The RM was diluted with DCM and washed with saturated aqueous NHCl and water. The organic phase was dried on a phase separator and concentrated under reduced pressure. The crude product was purified by SFC (SFC 8). The product-containing fractions were combined, concentrated under reduced pressure, and dried under high vacuum to give the title compound as a white solid. LC-MS:Rt=0.97min;MSm / z[M+H]+586.4, m / z[MH]-584.3;UPLC-MS4

[0375] Examples 148-166 were prepared in an analogous manner to Example 147 using methods and known starting materials known to those skilled in the art.

[0376] [Table 62]

[0377] [Table 63]

[0378] [Table 64]

[0379] [Table 65]

[0380] [Table 66]

[0381] [Table 67]

[0382] [Table 68]

[0383] Intermediates Intermediate A: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] Step 1: tert-butyl 4-(2-bromo-5-methyl-7-oxo-4-(2-oxo-2-((4-(trifluoromethyl)phenyl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] tert-Butyl 4-(2-bromo-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (Intermediate J) (7.38 g, 17.9 mmol), 2-bromo-N-(4-(trifluoromethyl)phenyl)acetamide (6.04 g, 21.4 mmol), and DIPEA (9.36 mL, 53.6 mmol) were dissolved in DMF (50 mL) and the RM was stirred at 80 °C for 2 h. The RM was cooled to room temperature, diluted with DCM, and the organic phase was extracted with saturated aqueous NaHCO and brine, dried over NaSO, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: heptane: EtOAc / MeOH (9 / 1) 100:0 to 30:70). The product-containing fractions were combined, concentrated under reduced pressure, and then crystallized from TBME to give the title compound. LC-MS: Rt = 1.15 min; MS m / z [M+H] + 614.0, m / z [MH] - 612.0;UPLC-MS4

[0384] Step 2: tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-4-(2-oxo-2-((4-(trifluoromethyl)phenyl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] tert-Butyl 4-(2-bromo-5-methyl-7-oxo-4-(2-oxo-2-((4-(trifluoromethyl)phenyl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (7.70 g, 12.5 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (3.95 g, 18.8 mmol), 1.5 N KPO (20.9 mL, 31.3 mmol), and XPhos Pd G (1.06 g, 1.25 mmol) were dissolved in 1,4-dioxane (50 mL). The RM was stirred at 90 °C for 1 h, cooled, and diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated under reduced pressure. This material was dissolved in DCM / MeOH (1:1) and ISOLUTE® Si-thiol (258 mg) was added. After stirring for 30 minutes, the mixture was filtered and concentrated. The crude product was crystallized from DCM and TBME to give the title compound. LC-MS: Rt = 1.13 min; MS m / z [M+H] + 618.2, m / z [MH] - 616.1;UPLC-MS4

[0385] Step 3: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] tert-Butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-4-(2-oxo-2-((4-(trifluoromethyl)phenyl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (5.95 g, 9.63 mmol) was dissolved in DCM (50 mL) and TFA (22.3 mL, 289 mmol) was added. The RM was stirred at room temperature for 1 h and then concentrated under reduced pressure. Toluene was added and removed again, and the procedure was repeated. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 and brine. During extraction, the product crystallized; the solids were collected and dried to give the title compound. LC-MS: Rt = 0.84 min; MS m / z [M+H] + 518.2, m / z [MH] - 516.0;UPLC-MS4

[0386] Intermediate B: 2-(5-cyclopropyl-2-(3,6-dihydro-2H-pyran-4-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] Step 1: 2-Bromo-5-cyclopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one [ka] 5-Bromo-4H-1,2,4-triazol-3-amine (5.00 g, 29.1 mmol) and ethyl 3-cyclopropyl-3-oxopropanoate (6.83 g, 43.7 mmol) were mixed in 1-butanol (40 mL). H3PO4 (8.40 g, 72.9 mmol) was added, and the RM was stirred at 100 °C for 20 h. Ethyl 3-cyclopropyl-3-oxopropanoate (1.00 g, 6.40 mmol) was added, and the RM was stirred at 100 °C for 22.5 h. Ethyl 3-cyclopropyl-3-oxopropanoate (1.00 g, 6.40 mmol) was added, and the RM was stirred at 100 °C for 23.5 h. The RM was cooled to room temperature, and the yellow suspension was filtered. The cake was washed with a small amount of EtOH, and the filtrate was concentrated under reduced pressure. The cake was washed with hot EtOH, and the filtrate was concentrated under reduced pressure. Both the cake and the product-containing filtrate were recombined and concentrated under reduced pressure. The resulting oil was left at room temperature over the weekend. The crystallized solid was filtered off and washed with EtO to give a white solid (2.62 g). The crude product was adsorbed onto Isolute and purified by column chromatography (silica gel column: 40 g silica, eluent DCM:MeOH 100:0 to 85:15). The product-containing fractions were combined and concentrated under reduced pressure to give the title compound (923 mg, 99% purity, 12% yield) as a white solid. The mother liquor was concentrated, adsorbed onto Isolute, and purified by column chromatography (silica gel column: 120 g silica, eluent DCM:MeOH 100:0 to 85:15). The product-containing fractions were combined and concentrated under reduced pressure to give the title compound (1.14 g, 99% purity, 15% yield) as a beige solid. Total: 2.06g, purity 99%, yield: 27%). LC-MS: Rt = 0.50 min; MS m / z [M+H] + 255.0 / 257.0, m / z [MH] - 252.9 / 254.9; UPLC-MS4

[0387] Step 2: 2-(2-bromo-5-cyclopropyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] 2-Bromo-5-cyclopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (1.19 g, 4.67 mmol) and 2-bromo-N-(4-(trifluoromethyl)phenyl)acetamide (1.73 g, 5.84 mmol) were mixed in DMF (12 mL). DIPEA (2.50 mL, 14.0 mmol) was added and the RM was stirred at 65° C. for 6 h and then at room temperature overnight. Water was added and stirring of the RM was continued at room temperature. The resin collapsed. The suspension was filtered and the cake was washed with water. The cake (1.78 g) was suspended in DCM and MeOH and filtered off. It was then washed and dried under high vacuum to give the title compound (829 mg, 85% purity, 33% yield) as a beige solid. LC-MS: Rt = 1.03 min; MS m / z [M+H] + 456.1 / 458.1, m / z [MH] - 453.9 / 455.9; UPLC-MS4

[0388] Step 3: 2-(5-cyclopropyl-2-(3,6-dihydro-2H-pyran-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] 2-(2-Bromo-5-cyclopropyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (1.34 g, 2.94 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (926 mg, 4.41 mmol), and Pd X-Phos G3 (124 mg, 147 μmol) were mixed in dioxane (15 mL) and 1 M aqueous KPO (8.81 mL, 8.81 mmol) was added. The RM was evacuated and backfilled with argon several times and then stirred at 90 °C for 1.5 h. The RM was cooled to room temperature. The RM was extracted with EtOAc (3 x 70 mL) and water (2 x 20 mL). The organic layer was dried through a phase separator and concentrated under reduced pressure. The aqueous layer was a suspension and was filtered. The aqueous layer was extracted three times with DCM, dried through a phase separator, and concentrated under reduced pressure. All organics were combined with the cake and suspended in hot EtOH (500 mL). This was then filtered, and the cake was dissolved in warm ACN, and Si-thiol (2.00 g) was added. The mixture was stirred at 45 °C for 5 min and filtered. The filtrate was concentrated under reduced pressure to give the title compound (650 mg, 99% purity, 48% yield) as a gray solid. The mother liquor was mixed with Si-thiol (2.00 g), stirred at 45 °C for 5 min, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (610 mg, 79% purity, 36% yield) as a light brown solid. Total: 1.26g, purity 89%, yield: 84%. LC-MS: Rt = 0.98 min; MS m / z [M+H] + 460.3, m / z [MH] - 458.3;UPLC-MS4

[0389] Step 4: 2-(6-bromo-5-cyclopropyl-2-(3,6-dihydro-2H-pyran-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] 2-(5-Cyclopropyl-2-(3,6-dihydro-2H-pyran-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (610 mg, 1.33 mmol) and NBS (295 mg, 1.66 mmol) were mixed in DMF (28 mL). The RM was stirred at 60 °C for 5.5 h and then allowed to stand at RT for 2 days. NBS (125 mg, 703 μmol) was added, and the RM was stirred at 60 °C for 5 h. NBS (50 mg, 281 μmol) was added, and the RM was stirred at 60 °C for 1.5 h. It was then cooled to RT and allowed to stand overnight. The RM was diluted with DCM and saturated aqueous NaHCO3. Most of the DMF was removed under reduced pressure. The solid residue was extracted with EtOAc (3 x 40 mL), water (2 x 20 mL), and brine (25 mL). The organic layer was dried on a phase separator and concentrated under reduced pressure. The brown solid residue was mixed with hexane, and the suspension was filtered. The cake was mixed again with hexane and filtered again. The cake was dried under high vacuum to give the title compound (508 mg, purity 74%, yield: 53%) as a light brown solid. LC-MS: Rt = 1.04 min; MS m / z [M+H] + 538.1 / 540.1, m / z [MH] - 536.2 / 538.2; UPLC-MS4

[0390] Step 5: 2-(5-cyclopropyl-2-(3,6-dihydro-2H-pyran-4-yl)-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] 2-(6-Bromo-5-cyclopropyl-2-(3,6-dihydro-2H-pyran-4-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (548 mg, 743 μmol) and piperazine (2.50 g, 29.0 mmol) were mixed with DMSO (5 mL), and the RM was stirred at 140 °C under argon for 5 h. The RM was cooled to room temperature, allowed to stand at room temperature overnight, and then combined with another batch. The RM was extracted with EtOAc (3 × 80 mL), saturated aqueous NaHCO (2 × 30 mL), and water (2 × 30 mL). The organic layer was washed with 1 N HCl (4 × 25 mL) and water (2 × 20 mL). The organic layer was concentrated slightly and extracted twice with 1 N HCl. The combined aqueous layers were basified with solid NaHCO3 and extracted three times with EtOAc. The organic layer was dried over a phase separator and concentrated under reduced pressure. The solid residue was suspended in DCM and MeOH and filtered. The cake was washed well with DCM, and the filtrate was concentrated to give a light brown solid (254 mg). The crude product was adsorbed onto Isolute and purified by column chromatography (silica gel column: 24 g silica, eluent DCM:MeOH / Et3N (95 / 5) 90:10 to 50:50). The product-containing fractions were combined and concentrated under reduced pressure to give the title compound (97.0 mg, 87% purity, 21% yield) as a solid. LC-MS: Rt = 0.86 min; MS m / z [M+H] + 544.3, m / z [MH] - 542.3; UPLC-MS3

[0391] Intermediate C: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-6-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] Step 1: 2-Bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one [ka] To a solution of 3-bromo-1H-1,2,4-triazol-5-amine (Intermediate R) (60.0 g, 60.6 mmol) in AcOH (380 mL) was added ethyl 3-oxobutanoate (86.6 g, 66.6 mmol). The RM was stirred at 80 °C overnight. The mixture was filtered and washed with AcOH (160 mL). The wet filter cake was dried to give the title compound (80.0 g, 80%).

[0392] Step 2: 2-Bromo-6-iodo-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one [ka] 2-Bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (2.00 g, 8.73 μmol) was added to a flame-dried flask under nitrogen. Acetic acid (29.1 mL) was added, followed by NIS (2.16 g, 9.61 mmol). The reaction mixture was stirred at 60° C. for 1 hour. The RM was cooled to room temperature. The solid was filtered off and washed three times with EtOH. The solid was dried under high vacuum to give the title compound (2.76 g, 95% purity, 89% yield). LC-MS: Rt = 0.56 min; MS m / z [M+H] + 354.9 / 356.9, m / z [MH] - 353.0 / 355.0; UPLC-MS8

[0393] Step 3: tert-butyl 4-(2-bromo-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] Palladium G3-tricyclohexylphosphine: [(tricyclohexylphosphine)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (183 mg, 282 μmol) was purged with nitrogen. A solution of 2-bromo-6-iodo-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (1.00 g, 2.82 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (894 mg, 2.89 mmol) in n-butanol (100 μL) was added, followed by the addition of 1.5MKPO aqueous solution (5.63 mL, 8.45 mmol). The reaction mixture was stirred at 70 °C for 1 hour. tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (50.0 mg, 162 μmol) was added, and the RM was stirred at 70 °C overnight. N-Butanol was removed under reduced pressure. EtOAc was added, and the mixture was washed with NH₄Cl. The organic layer was dried through a phase separator. ISOLUTE® Si-TMT (6.50 g, 2.82 mmol) was added, and the mixture was stirred at 40 °C for 1 h. The solid was filtered off and washed with EtOAc. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel column: 40 g silica, eluent DCM:DCM / MeOH (8 / 2) 100:0 to 50:50) to give the title compound (734 mg, purity 90%, yield: 57%) as a white powder. LC-MS: Rt = 0.86 min; MS m / z [M−H] - 408.2 / 410.2; UPLC-MS14

[0394] Step 4: tert-butyl 4-(2-bromo-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(2-bromo-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (734 mg, 1.79 mmol) in MeOH (10 mL) was added PtO (40.6 mg, 179 μmol) under a N atmosphere. The flask was purged with hydrogen for 2 minutes. The RM was stirred at RT for 2 hours. PtO (66.0 mg, 291 μmol) was added, and the RM was stirred at RT for 2 hours. PtO (103 mg, 454 μmol) was added, and the RM was stirred at RT overnight. PtO (122 mg, 543 μmol) was added, and the RM was stirred at RT. The RM was filtered through a pad of Celite. The crude product was purified by column chromatography (silica gel column: silica 12 g, eluent DCM:DCM / MeOH (8 / 2) 100:0 to 50:50) to obtain the title compound (580 mg, purity 80%, yield: 63%). LC-MS: Rt = 0.89 min; MS m / z [M+H] + 412.2 / 414.2, m / z [MH] - 410.3 / 412.3; UPLC-MS8

[0395] Step 5: tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperidine-1-carboxylate [ka] tert-Butyl 4-(2-bromo-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperidine-1-carboxylate (580 mg, 1.41 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (443 mg, 2.11 mmol), and X-Phos Pd G3 (71.4 mg, 84.0 μmol) were mixed. Under a N2 atmosphere, DMF (1.4 mL) and an aqueous 1MK3PO4 solution (2.81 mL, 1.82 mmol) were added. The RM was stirred at 80 °C for 1 h. X-Phos Pd G3 (10.0 mg, 11.8 μmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (60.0 mg, 286 μmol) were added and the RM was stirred for 3 h to give the title compound as RM. LC-MS: Rt = 1.25 min; MS m / z [M+H] + 416.3, m / z [MH] - 414.4;UPLC-MS8

[0396] Step 6: tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-4-(2-oxo-2-((4-(trifluoromethyl)phenyl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperidine-1-carboxylate [ka] To the RM containing tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperidine-1-carboxylate was added 2-bromo-N-(4-(trifluoromethyl)phenyl)acetamide (397 mg, 1.41 mmol). The RM was stirred at 80° C. for 40 min. 2-Bromo-N-(4-(trifluoromethyl)phenyl)acetamide (88.0 mg, 313 μmol) was added and the RM was stirred at 80° C. for 30 min. Most of the DMF was removed under reduced pressure. EtOAc was added and the mixture was washed with NaHCO3. The organic layer was dried on a phase separator and concentrated under reduced pressure. The mixture was treated with Si TMT. The solvent was removed and the residue was adsorbed onto Isolute and purified by column chromatography (silica gel column: 24 g silica, eluent DCM:DCM / MeOH (8 / 2) 100:0 to 70:30) and then purified in five batches by reverse-phase preparative HPLC (5 × RP-HPLC acidic 1:20 to 95% B in 20 min) to give the title compound (185 mg, purity 60%, yield: 18%). LC-MS: Rt = 1.18 min; MS m / z [M+H] + 617.4, m / z [MH] - 615.5;UPLC-MS8

[0397] Step 7: 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-6-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] To tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-4-(2-oxo-2-((4-(trifluoromethyl)phenyl)amino)ethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperidine-1-carboxylate (145 mg, 198 μmol) was added TFA (306 μL, 3.97 mmol) in DCM (2 mL). The RM was stirred at RT for 1 h. DCM was added and the crude product was washed with NaOH solution. The aqueous layer was extracted with EtOAc. The organic layer was dried over a phase separator and concentrated under reduced pressure to give the title compound (130 mg, 79% purity, quantitative). LC-MS: Rt = 0.74 min; MS m / z [M+H] + 517.3, m / z [MH] - 515.4;UPLC-MS8

[0398] Intermediate D: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] Step 1: tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] 3-Bromo-1H-1,2,4-triazol-5-amine (Intermediate R) (82.6 g, 507 mmol) and tert-butyl 4-(1-methoxy-1,3-dioxopentan-2-yl)piperazine-1-carboxylate (Intermediate N) (175 g, 557 mmol) were mixed in EtOH (465 mL). H3PO4 (49.7 g, 507 mmol) was added. The mixture was stirred under nitrogen at 80 °C for 12 h. The mixture was concentrated in vacuo to remove EtOH, then quenched by the addition of saturated aqueous NaHCO3 (1 L) and extracted with DCM (3 × 1 L). The combined organic layers were washed with brine (3 × 1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica column, eluent DCM:MeOH 1:0 to 10:1). The product-containing fractions were combined and concentrated under reduced pressure to give the title compound as a yellow solid. LC-MS:Rt=0.91min;MSm / z[M+H-Boc] + 327.1 / 329.1, m / z [M+H] + 427.2 / 429.2, m / z [MH] - 425.2 / 427.2; UPLC-MS1 LC-MS:Rt=4.53 min;MSm / z[M+H-Boc] + 327.1 / 329.1, m / z [MH] - 425.2 / 427.2; UPLC-MS2 1 H NMR(400MHz,DMSO-d6)δ 13.27(s,1H),3.91(m,2H),3.31(m,2H),2.88(m,2H),2.75(m,2H),2.61(m,2H),1.42(s,9H),1.17(t,J=7.4Hz,3H)

[0399] Step 2: tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-(2-bromo-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (15.0 g, 35.1 mmol) in 1,4-dioxane (150 mL) and water (50 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (11.1 g, 52.7 mmol) and Na2CO3 (7.44 g, 70.2 mmol). The RM was degassed with nitrogen for 15 min. Pd(dppf)Cl2·DCM (1.43 g, 1.76 mmol) was added, and the RM was stirred at 100 °C for 14 h. Water (300 mL) was added and the RM was extracted with 10% MeOH in DCM (2 × 500 mL). The organic layer was washed with brine (300 mL), dried over NaSO, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel column: 40 g silica, eluent DCM:MeOH 100:0 to 97:3). The product-containing fractions were combined, concentrated in vacuo, and dried under high vacuum to give the title compound. LC-MS: Rt = 0.96 min; MS m / z [M+H] + 431.4, m / z [MH] - 429.3;UPLC-MS3 1 H NMR(400MHz,DMSO-d6)δ 13.00(s,br,1H),6.81(m,1H),4.28(m,2H),3.92(m,2H),3.82(m,2H),3.37(m,2H),2 .89(m,2H),2.76(m,2H),2.62(m,2H),2.51(m,2H),1.43(s,9H),1.19(t,J=7.3Hz,3H)

[0400] Step 3: tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] tert-Butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (6.50 g, 15.1 mmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (Intermediate S) (6.04 g, 16.6 mmol) were mixed in DMF (72 mL) at 0 °C. DIPEA (7.91 mL, 45.3 mmol) was added and the RM was stirred at 45 °C for 3.5 h. The RM was cooled to room temperature. Water (70 ml) was added and the suspension was stirred at room temperature overnight. The suspension was sonicated for 25 min and filtered. The cake was washed with a small amount of water and dried. The filtrate was filtered again. The second filtrate was extracted with EtOAc (2 × 400 mL), washed with brine (2 × 50 mL), dried through a phase separator, and concentrated under reduced pressure. The second cake was adsorbed onto Isolute and purified by column chromatography (RediSep column: 220 g silica, eluent: DCM:DCM / MeOH (1:1) 100:0 to 80:20). Fractions containing pure product were combined and concentrated under reduced pressure. The beige solid foam was dissolved in EtO, and the resulting crystals were sonicated. The suspension was left overnight, filtered, washed with a small amount of EtO, and dried under high vacuum to give cake 1 as a white solid. Fractions containing impurities were combined and concentrated under reduced pressure. They were then combined with the concentrated organic layer from the extraction and purified again by column chromatography (RediSep column: 120 g silica Gold, eluent: DCM:DCM / MeOH (1 / 1) 100:0 to 85:15). The product-containing fractions were combined, concentrated under reduced pressure, and dried under HV. The beige solid foam was crystallized from EtO to give cake 2 as a white solid. Cake 1 and cake 2 were combined to give the title compound. LC-MS:Rt=1.33 min;MSm / z[M+H-Boc] + 566.0 / 568.0, m / z[M+H] + 666.0 / 668.0, m / z [MH] - 664.1 / 666.1; UPLC-MS1

[0401] Step 4: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] tert-Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (6.41 g, 9.62 mmol) was dissolved in DCM (70 mL) and TFA (11.1 mL, 144 mmol) was added. The RM was stirred at RT for 1 h. The RM was concentrated under reduced pressure. The residue was dissolved in DCM and concentrated again under reduced pressure. This was done three times. The resulting oil was dried under high vacuum to give a pale rose solid foam. The foam was suspended in EtO and sonicated. The suspension was filtered, washed with Et2O and dried under HV to give the title compound as a white solid. LC-MS: Rt = 0.78 min; MS m / z [M+H] + 566.4 / 568.4, m / z [MH] - 564.2 / 566.2; UPLC-MS1

[0402] Intermediate D: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] Step 1: tert-butyl 4-(3-amino-6-ethyl-2-imino-4-oxo-1,2,3,4-tetrahydropyrimidin-5-yl)piperazine-1-carboxylate [ka] Hydrazinecarboximidamide·HCl (35.0 g, 317 mmol) was added to EtOH (400 mL), followed by aqueous tetrabutylammonium hydroxide (40 wt % in water) (206 g, 318 mmol). The mixture was stirred at 55°C for 80 minutes. tert-Butyl 4-(1-methoxy-1,3-dioxopentan-2-yl)piperazine-1-carboxylate (Intermediate N) (50.0 g, 159 mmol) was added. The mixture was stirred at reflux for 6 hours and then cooled to room temperature. The solvent was removed under vacuum until 1 / 4 of the solvent volume remained. The resulting suspension was stirred for 1-2 hours and then filtered. The cake was dried under vacuum to give the title compound as a white solid. MS m / z[M+H] + 339.2

[0403] Step 2: tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] A solution of 3,6-dihydro-2H-pyran-4-carbaldehyde (Intermediate Q) (20.0 g, 178 mmol) in NMP and tert-butyl 4-(3-amino-6-ethyl-2-imino-4-oxo-1,2,3,4-tetrahydropyrimidin-5-yl)piperazine-1-carboxylate (52.9 g, 149 mmol) in NMP (400 mL) was added, followed by FeCl3 (48 g, 297 mmol). The dark solution was heated to 50 °C open to air and stirred for 48 h. The dark RM was cooled to room temperature. Water (1.2 L) was added slowly (exothermic). The suspension was filtered and washed with water (400 mL). The resulting wet cake was added to acetone (400 mL) and stirred at room temperature for 4 h. The suspension was filtered and washed with acetone (100 mL). The cake was added to EtOH (400 mL) and heated to 70° C. and stirred for 4 h. The mixture was then cooled to room temperature and washed with EtOH (100 mL) to give the title compound as a brown solid. MS m / z[M+H] + 430.2

[0404] Step 3: tert-butyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] tert-Butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (3.00 g, 6.97 mol) and tert-butyl 2-bromoacetate (1.46 g, 7.32 mmol) were mixed in DMF (20 mL) under argon. DIPEA (3.65 mL, 20.9 mmol) was added, and the RM was stirred at 55 °C for 4.5 h. Water (50 mL) was added, and the RM was stirred at RT overnight. The suspension was sonicated for 10 min, filtered, and washed with water. The cake was dried under high vacuum, mixed with EtO, and sonicated for 5 min. The suspension was stirred at reflux, filtered, and the solid was washed with EtO. A second crop of solid precipitated from the filtrate after filtration. Both cakes were combined to give the title compound as a beige solid. LC-MS:Rt=1.16 min;MSm / z[M+H-Boc] + 445.4, UPLC-MS1

[0405] Step 4: 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetic acid [ka] tert-Butyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (2.75 g, 5.00 mmol) was dissolved in THF (50 mL) and MeOH (20 mL). 1 M NaOH (7.50 mL, 7.50 mmol) was added, and the RM was stirred at room temperature for 18.5 h. The solvent was removed, water was added, and the RM was extracted with EtO (3 × 70 mL) and water (3 × 15 mL). The aqueous layer was cooled to 0 °C, and 4 M HCl (1.87 mL, 7.50 mmol) was added until the pH reached 3. The resulting suspension was extracted with EtOAc (3 x 200 mL), washed twice with brine, then twice with EtOAc. The combined organic layers were passed through a phase separator and concentrated under reduced pressure to give the title compound as a light brown solid. LC-MS:Rt=0.76 min;MSm / z[M+H-Boc] + 389.5, m / z [MH] - 487.2;UPLC-MS1

[0406] Step 5: tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] 2-(6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetic acid (4.20 g, 8.60 mmol) was dissolved in EtOAc (50 mL) and EtN (4.77 mL, 34.4 mmol). 2-Chloro-4-(trifluoromethyl)aniline (1.68 g, 8.60 mmol) and 50% T3P in DMF (10.2 mL, 17.2 mmol) were added, and the RM was stirred at room temperature for 1 h. The RM was adsorbed onto Isolute and purified by column chromatography (RediSep column: silica 120 g, eluent cyclohexane:EtOAc 100:0 to 20:80). The product-containing fractions were combined and concentrated to give the title compound. LC-MS:Rt=1.35 min;MSm / z[M+H-Boc] + 566.3 / 568.3, m / z [MH] - 664.4 / 666.4; UPLC-MS1

[0407] Step 2: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-6-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide [ka] tert-Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (4.82 g, 7.24 mmol) was dissolved in DCM (50 mL), TFA (8.36 mL, 109 mmol) was added, and the RM was stirred at RT for 2 h. The RM was concentrated under reduced pressure. DCM was added, and the mixture was extracted with aqueous NaHCO3, adjusted to pH 10, extracted three times with DCM, dried on a phase separator, and concentrated under reduced pressure to give the title compound. LC-MS: Rt = 0.79 min; MS m / z [M+H] + 566.3 / 568.3, m / z [MH] - 564.4 / 566.4; UPLC-MS1

[0408] Intermediate E: tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] Step 1: tert-butyl 4-(5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] 4H-1,2,4-Triazol-3-amine (13.6 g, 162 mmol) and tert-butyl 4-(1-ethoxy-1,3-dioxobutan-2-yl)piperazine-1-carboxylate (Intermediate M) (50.9 g, 162 mmol) in AcOH (139 mL, 2.43 mol) were heated at 100° C. for 70 min. Most of the AcOH was removed in vacuo. The mixture was diluted with EtOH (100 mL) and heated at 88° C. for 18 h. The mixture was allowed to cool to room temperature and filtered. The solid was washed with EtOH (120 mL) and dried in vacuo at 50° C. overnight to give the title compound as an off-white solid. LC-MS: Rt = 0.79 min; MS m / z [M+H] + 335.5, m / z [MH] - 333.4; UPLC-MS8

[0409] Step 2: tert-butyl 4-(2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] The flask was flame dried under reduced pressure and backfilled with argon. tert-Butyl 4-(5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate (5.00 g, 14.7 mmol) was suspended in anhydrous THF (14.7 mL). To this white suspension, zinc chloro 2,2,6,6-tetramethylpiperidide lithium chloride complex solution (35.9 mL, 32.2 mmol) was added dropwise at 1 mL / min. The RM was stirred for 1.5 h. It was then stored overnight under argon in a freezer. The next morning, it was stirred at room temperature for 4 h. 4-Bromo-3,6-dihydro-2H-pyran (3.18 mL, 29.3 mmol), CPhos (392 mg, 879 μmol), and CPhos Pd G3 (746 mg, 879 μmol) were introduced under argon. The RM was stirred at RT for 68.5 h. The reaction was partitioned between THF (100 mL) and 5N aqueous NH4Cl (100 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with 10% aqueous Na2S2O3 (150 mL), brine (150 mL), and dried through a phase separator. The solvent was recovered and treated with ISOLUTE® Si-TMT (36.6 g, 17.6 mmol). The suspension was stirred at 40 °C for 1 h and filtered through a pad of Celite. Volatiles were removed under pressure. The residue was adsorbed onto Isolute and purified by column chromatography (330 g FlashPure EcoFlex silica cartridge, eluent DCM:MeOH 100:0 to 95:5). Product-containing fractions were combined and concentrated to give the title compound as an off-white solid. LC-MS: Rt = 0.89 min; MS m / z [M+H] + 417.3, m / z [MH] - 415.2;UPLC-MS8

[0410] Intermediate F: 6-(4-acetylpiperazin-1-yl)-2-(3-fluoropiperidin-1-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one Step 1: 3-(3-fluoropiperidin-1-yl)-1H-1,2,4-triazol-5-amine [ka] 3-Fluoropiperidine hydrochloride (1.00 g, 7.30 mmol) was suspended in ACN (5 mL). Dimethyl cyanocarbonimidodithioate (1.07 g, 7.30 mmol) and DIPEA (1.27 mL, 7.30 mmol) were added, and the RM was stirred at 80° C. for 14 h. Hydrazine hydrate (11.6 mL, 7.30 mmol) was added, and the RM was stirred at 80° C. for 14 h. The RM was concentrated under reduced pressure. Water was added, and extracted with 10% MeOH in DCM. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give the title compound.

[0411] Step 2: 6-(4-acetylpiperazin-1-yl)-2-(3-fluoropiperidin-1-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one [ka] 3-(3-Fluoropiperidin-1-yl)-1H-1,2,4-triazol-5-amine (800 mg, 4.32 mmol) was suspended in EtOH (25 mL). Ethyl 2-(4-acetylpiperazin-1-yl)-3-oxobutanoate (Intermediate L) (1.45 g, 5.62 mmol) and acetic acid (200 μL, 3.49 mmol) were added, and the RM was stirred at 100 °C for 12 h. The RM was concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: 12 g silica, eluent DCM:MeOH 100:0 to 95:5). The product-containing fractions were combined, concentrated, and dried under high vacuum to give the title compound.

[0412] Intermediate G: 2-(6-(4-acetylpiperazin-1-yl)-2-bromo-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide [ka] Step 1: 2-(6-(4-acetylpiperazin-1-yl)-2-bromo-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetic acid To a solution of tert-butyl 2-(6-(4-acetylpiperazin-1-yl)-2-bromo-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetate (Intermediate I) (1.5 g, 3.2 mmol) in DCM (5 mL) was added TFA (3.7 g, 32.4 mmol) dropwise. The RM was stirred at 40° C. for 5 h. The RM was concentrated under reduced pressure to give the title compound as a brown residue. LC-MS: Rt=0.42 min; MS m / z [M+H] + 413.2;UPLC-MS8

[0413] Step 2: 2-(6-(4-Acetylpiperazin-1-yl)-2-bromo-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetic acid (1.37 g, 3.32 mmol), 4-(trifluoromethyl)aniline (374 mg, 2.32 mmol), 50% T3P (3.95 mL, 6.63 mmol) in EtOAc, and Et3N (1.85 mL, 13.3 mmol) were mixed in DCM (5 mL) and stirred at RT for 3 h. Water, saturated aqueous NaHCO3, and DCM were added to the RM. The aqueous layer was washed twice with DCM. The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The mixture was suspended in MeOH and filtered. The cake was dried under high vacuum. LC-MS: Rt = 0.97 min; MS m / z [M+H] + 556.4, m / z; UPLC-MS8

[0414] Intermediate H: 2-(6-(4-acetylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetic acid [ka] Step 1: tert-Butyl 2-(6-(4-acetylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetate [ka] 2-(6-(4-acetylpiperazin-1-yl)-2-bromo-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)tert-butyl acetate (Intermediate I) (200 mg, 426 μmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (112 mg, 533 μmol), and X-PhosG3 (18.0 mg, 21.0 μmol) were placed in a MW vial and then purged / evacuated with argon several times. DMF (3 mL) and 1 M aqueous KPO solution (852 μL, 852 μmol) were added. The RM was stirred at 60 °C for 3.75 h. The RM was diluted with DCM and washed three times with saturated aqueous NaHCO. The combined organic phase was dried on a phase separator and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica 12 g, eluent DCM:DCM / MeOH (9 / 1) 100:0 to 50:50) to give the title compound. LC-MS: Rt = 0.88 min; MS m / z [M+H] + 473.4, m / z [MH] - 471.4; UPLC-MS8

[0415] Step 2: 2-(6-(4-acetylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetic acid [ka] To a solution of tert-butyl 2-(6-(4-acetylpiperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetate (195 mg, 392 μmol) in DCM (600 μL) was added TFA (604 μL, 7.84 mmol) dropwise. The RM was stirred at RT for 20.5 h. The RM was concentrated under reduced pressure to give the title compound as a sticky brown residue. LC-MS: Rt=0.47 min; MS m / z [M+H] + 417.3, m / z [MH] - 415.4;UPLC-MS8

[0416] Intermediate I: tert-butyl 2-(6-(4-acetylpiperazin-1-yl)-2-bromo-5-methyl-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetate [ka] 6-(4-Acetylpiperazin-1-yl)-2-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (Intermediate K) (3.25 g, 8.68 mmol) and tert-butyl 2-bromoacetate (1.90 g, 9.55 mmol) were mixed in DMF (20 mL). KCO (2.40 g, 17.4 mmol) was added, and the RM was stirred at 80 °C for 4.5 h. The RM was concentrated under reduced pressure. The residue was dissolved in DCM and extracted twice with water (2 × 25 mL) and three times with DCM (3 × 150 mL). The combined organic phase was dried on a phase separator and concentrated under reduced pressure. The crude product was adsorbed onto Isolute and purified by column chromatography (RediSep column: silica 120 g, eluent DCM:DCM / MeOH (9 / 1) 100:0 to 50:50) to give the title compound as a beige solid. LC-MS: Rt = 0.90 min; MS m / z [M+H] + 469.2 / 471.2, m / z [MH] - 467.1 / 469.1; UPLC-MS8

[0417] Intermediate J: tert-butyl 4-(2-bromo-5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate [ka] 3-Bromo-1H-1,2,4-triazol-5-amine (Intermediate ER) (4.00 g, 24.5 mmol), tert-butyl 4-(1-ethoxy-1,3-dioxobutan-2-yl)piperazine-1-carboxylate (Intermediate M) (8.49 g, 27.0 mmol), and HPO (2.97 g, 25.8 mmol) were mixed in EtOH (25 mL) and stirred at reflux for 18 h. The RM was cooled to room temperature, and DIPEA (12.9 mL, 73.6 mmol) and BocO (1.71 mL, 7.36 mmol) were added. The RM was stirred at room temperature for 1 h. The RM was quenched with aqueous NHCl, diluted with DCM, extracted twice with DCM, dried over NaSO, concentrated, and dried. The crude product was crystallized from DCM and TBME to give the title compound. LC-MS: Rt = 0.87 min; MS m / z [M+H] + 413.1, m / z [MH] - 411.0;UPLC-MS4

[0418] Intermediate K: 6-(4-acetylpiperazin-1-yl)-2-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one [ka] 5-Bromo-1H-1,2,4-triazol-3-amine (Intermediate R) (41.0 g, 239 mmol) and ethyl 2-(4-acetylpiperazin-1-yl)-3-oxobutanoate (Intermediate L) (68.1 g, 239 mmol) were suspended in AcOH (137 mL, 2.39 mol) and heated at 100° C. for 3 h. The RM was cooled to room temperature and allowed to crystallize. Water (200 mL) was added and the mixture was stirred at room temperature for 2 h. The solid was filtered, and the white powder was dried under vacuum at 30° C. to give the title compound. LC-MS: Rt=0.53 min; MS m / z [M+H] + 355.1 / 357.1, m / z [MH] - 353.0 / 355.1; UPLC-MS8

[0419] Intermediate L: Ethyl 2-(4-acetylpiperazin-1-yl)-3-oxobutanoate [ka] To a yellow solution of 1-acetylpiperazine (105 g, 808 mmol) in toluene (808 mL) was added ethyl 2-chloroacetatoacetate (58.8 mL, 404 mmol). The solution was stirred at 100° C. for 2 h. The RM was filtered over Hyflo and the residue was washed with toluene. The filtrate was evaporated. The brown oil was stirred with DCM (200 mL) for 1 h, filtered and the residue was washed with DCM. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: 330 g silica, eluent heptane; product-containing fractions were combined, concentrated and dried under high vacuum to give the title compound. LC-MS:Rt=0.60 / 0.87min;MSm / z[M+H] + 257.2, m / z [MH] - 255.1;UPLC-MS8

[0420] Intermediate M: tert-butyl 4-(1-ethoxy-1,3-dioxobutan-2-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl piperazine-1-carboxylate (150 g, 805 mmol) in ACN (1.5 L) was added K2CO3 (223 g, 1.61 mol) at room temperature, and the RM was stirred for 15 min. Then, ethyl 2-chloro-3-oxobutanoate (112 mL, 809 mmol) was added slowly at the same temperature. The resulting RM was stirred at room temperature for 16 h. The RM was filtered through a pad of Celite. The Celite pad was washed with EtOAc (2 L). The combined organic layers were concentrated under reduced pressure to give the crude product. The residue was dissolved in EtOAc (3 L), then washed with ice-cold water and brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product as a light brown liquid. The crude product was purified by column chromatography (silica gel, 60-120 mesh, eluent petroleum ether: EtOAc 100:0 to 85:15). The pure product-containing fractions were combined and concentrated under reduced pressure to give the title compound as a liquid. The impure fractions were combined and concentrated under reduced pressure. They were then purified by column chromatography (silica gel, 60-120 mesh, eluent petroleum ether: EtOAc 100:0 to 85:15). The pure product-containing fractions were combined and concentrated under reduced pressure to give the title compound as a liquid. Both liquids were mixed, dissolved in DCM, and concentrated under reduced pressure to give the title compound as a brown liquid. The liquid was redissolved in DCM and concentrated under reduced pressure. This process was repeated three times, then dried under vacuum to give the title compound as a brown liquid. HPLC:Rt=11.763min;HPLC6

[0421] Intermediate N: tert-butyl 4-(1-methoxy-1,3-dioxopentan-2-yl)piperazine-1-carboxylate Step 1: Methyl 2-chloro-3-oxopentanoate [ka] To a solution of methyl 3-oxopentanoate (10.4 kg, 80.0 mol) in DCM (67 L) was added SO2Cl2 (14.0 kg, 104 mol) at room temperature over 2.5 h. The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DCM (20 L), washed with water (10 L), brine (10 L), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as a pale yellow liquid. 1 H NMR(400MHz,CDCl3-d)δ 4.65(s,1H),3.68(s,3H),2.59(m,2H),0.96(t,3H)

[0422] Step 2: tert-butyl 4-(1-methoxy-1,3-dioxopentan-2-yl)piperazine-1-carboxylate [ka] To a solution of methyl 2-chloro-3-oxopentanoate (12.1 kg, 53.7 mol) in dry ACN (53 L) was added EtN (22.3 L, 161 mol) over 1.5 h, followed by the dropwise addition of tert-butyl piperazine-1-carboxylate (10.0 kg, 53.7 mol) in ACN (50 L) over 2.5 h. The reaction was stirred at 60 °C for 16 h. The reaction mixture was filtered and washed with EtOAc (10 L). The filtrate was then concentrated under reduced pressure, and the residue was dissolved in EtOAc (45 L), washed with water (45 L), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica column 150 mm × 800 mm × 70 mm, eluent heptane:EtOAc 100:0 to 90:10) to provide the title compound. HPLC: Rt=3.681 / 5.513 min; HPLC 4

[0423] Intermediate O: 6-Hydroxypyrazolo[1,5-a]pyridine-7-carboxylic acid [ka] Step 1: 5-Bromoimidazo[1,2-a]pyridin-6-ol [ka] The flask was flame dried in vacuo and backfilled with argon. 5-Bromo-6-methoxyimidazo[1,2-a]pyridine (1.00 g, 4.18 mmol) and anhydrous DCM (14 mL) were added to a dry, argon-purged flask. The resulting mixture was cooled to -78 °C, and then 1 M BBr3 in DCM (20.9 mL, 20.9 mmol) was added dropwise. After the addition was complete, the resulting dark brown suspension was allowed to warm to room temperature. The RM was stirred at RT for 18 h. The reaction mixture was cooled to -78 °C, and then anhydrous MeOH (3.42 mL, 84.0 mmol) was added slowly. The reaction mixture was concentrated to dryness. MeOH (5 mL) was added, followed by Et2O (100 mL). The brown suspension was sonicated, and the solid was filtered off. The solid was washed with Et2O (2 x 50 mL) and dried under vacuum to give the title compound as a pink powder (1.19 g, 98% purity, 95% yield). LC-MS: Rt = 0.23 min; MS m / z [M+H] + 213.2 / 215.2, MS m / z [MH] - 210.9 / 212.9; UPLC-MS7

[0424] Step 2: 6-(benzyloxy)-5-bromoimidazo[1,2-a]pyridine [ka] The flask was flame dried in vacuo and backfilled with argon. A dry, argon-flushed flask was charged with 5-bromoimidazo[1,2-a]pyridin-6-ol (1.19 g, 3.97 mmol) and potassium carbonate (1.66 g, 11.9 mmol). The contents were suspended in anhydrous DMF (9.92 mL), and the resulting mixture was treated with (bromomethyl)benzene (626 μL, 5.16 mmol). The RM was stirred at RT for 21 h. The reaction was partitioned between water (35 mL) and EtOAc (30 mL). The organic layer was collected, and the aqueous layer was back-extracted with EtOAc (3 × 25 mL). The organic layers were combined, washed with brine (50 mL), and dried using a phase separator. The solvent was reduced to dryness to give a brownish oil (668 mg). The crude product was purified by normal phase chromatography (Buchi® FlashPure ID HP silica cartridge 24 g, eluent heptane:EtOAc 100:0 to 15:85). The product-containing fractions were combined and concentrated to give the title compound (94.6 mg, 98% purity, 8% yield) as a beige powder. LC-MS: Rt = 0.80 min; MS m / z [M+H] + 303.1 / 305.1; UPLC-MS1

[0425] Step 3: Ethyl 6-(benzyloxy)imidazo[1,2-a]pyridine-5-carboxylate [ka] A reactor was charged with 6-(benzyloxy)-5-bromoimidazo[1,2-a]pyridine (94.0 mg, 304 μmol), PdCl(dppf).DCM adduct (12.4 mg, 15.0 μmol), EtN (128 μL, 912 μmol), and anhydrous EtOH (10 mL). The autoclave was evacuated and backfilled with argon three times. It was then charged with 20 bar of CO at room temperature and heated at 80 °C for 20 h. PdCl(dppf).DCM adduct (12.4 mg, 15.0 μmol) and EtN (128 μL, 912 μmol) were introduced, and the reaction mixture was heated at 90 °C for 20 h. ISOLUTE® Si-TMT (62.0 mg, 30.0 μmol) was introduced to the mixture, which was then left stirring at room temperature. The mixture was filtered through a pad of Celite. Volatiles were removed under pressure to give a tan solid (175 mg). A vial flushed with dry argon was charged with the tan solid (175 mg) from the previous step and K2CO3 (42.4 mg, 304 μmol). The contents were suspended in anhydrous DMF (2 mL), and (bromomethyl)benzene (26.0 μL, 213 μmol) was introduced. The vial was sealed, and the resulting mixture was allowed to react at room temperature for 16 hours. (Bromomethyl)benzene (13.0 μL, 106 μmol) was added, and the reaction mixture was stirred at room temperature for 22.5 hours. The reaction was partitioned between water (10 mL) and EtOAc (5 mL). The organic layer was collected, and the aqueous layer was back-extracted with EtOAc (3 × 5 mL). The organic layers were combined, washed with brine (20 mL), and dried using a phase separator. The solvent was reduced to dryness to give a brownish oil (107 mg). The crude product was adsorbed onto Isolute and purified by normal phase column chromatography (Buchi® FlashPure ID HP silica cartridge 12 g, eluent heptane: EtOAc 100:0 to 0:100). The product-containing fractions were combined and concentrated to give the title compound (37.3 mg, 98% purity, 41% yield) as a beige solid. LC-MS: Rt = 0.79 min; MS m / z [M+H] + 297.4;UPLC-MS1

[0426] Step 4: 6-(benzyloxy)imidazo[1,2-a]pyridine-5-carboxylic acid [ka] Ethyl 6-(benzyloxy)imidazo[1,2-a]pyridine-5-carboxylate (36.0 mg, 119 μmol) was dissolved in ACN (1.19 mL), and the mixture was treated with 1 M aqueous NaOH (119 μL, 119 μmol). The resulting solution was stirred at room temperature for 23.5 hours. 1 M aqueous NaOH (11.9 mL, 119 μmol) was added, and the reaction mixture was stirred at room temperature for 21.5 hours. The reaction mixture was frozen in a mixture of dry ice / acetone and lyophilized to give the title compound (33.7 mg, 98% purity, 95% yield) as a white powder. LC-MS: Rt = 0.56 min; MS m / z [M+H] + 269.3, MS m / z [MH] - 267.1;UPLC-MS10

[0427] Step 5: 6-Hydroxypyrazolo[1,5-a]pyridine-7-carboxylic acid [ka] To a purple / brown solution of 6-(benzyloxy)imidazo[1,2-a]pyridine-5-carboxylic acid (53 mg, 0.186 mmol) in 4 mL of 1:1 MeOH / THF was evacuated and purged with argon several times, and Pd—C (5 mg, 4.70 μmol) was added. The resulting dark green / black mixture was evacuated and purged with hydrogen several times, then stirred at 20°C for 1.5 h. The reaction mixture was filtered through a Millipore filter (PTFE membrane filter 0.2 μm), and the filtrate was concentrated and dried under vacuum (40°C) to give the title compound as a dark purple residue (36 mg, 0.186 mmol, 100% yield). LC-MS: Rt=0.49 min; MS m / z [M+H] + 179.0;UPLC-MS1

[0428] Intermediate P: 7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylic acid [ka] Step 1: 6-Bromofuro[3,2-c]pyridin-7-ol [ka] The flask was flame dried in vacuo and backfilled with argon. A dry, argon-flushed flask was charged with 6-bromo-7-methoxyfuro[3,2-c]pyridine (5.00 g, 20.8 mmol) and anhydrous DCM (69.4 mL). The reaction mixture was cooled to -78 °C, and then 1 M BBr in DCM (125 mL, 125 mmol) was added dropwise. After the addition was complete, the resulting yellow suspension was warmed to room temperature and stirred for 13.5 h. The reaction mixture was cooled to -78 °C, and then anhydrous MeOH (17.0 mL, 417 mmol) was added dropwise. The reaction was concentrated to dryness. MeOH (10 mL) was added, followed by EtO (150 mL). The brown suspension was sonicated and filtered. The solid was washed with Et2O (2 x 100 mL) and dried under vacuum at 40 °C overnight to give the title compound (4.58 g, 98% purity, 73% yield) as a white solid. LC-MS: Rt = 0.36 min; MS m / z [M+H] + 214.0 / 216.0, m / z [MH] - 212.1 / 214.0; UPLC-MS1

[0429] Step 2: Ethyl 7-hydroxyfuro[3,2-c]pyridine-6-carboxylate [ka] A reactor was charged with 6-bromofuro[3,2-c]pyridin-7-ol (4.58 g, 15.3 mmol) and PdCl(dppf). DCM (624 mg, 764 μmol), EtN (8.60 mL, 61.1 mmol), and anhydrous EtOH (50 mL) were added. The autoclave was evacuated and backfilled with argon three times. It was then charged with 10 bar of CO at room temperature and heated to 80°C for 24 hours. ISOLUTE® Si-TMT (15.6 g, 7.64 mmol) was added, and the suspension was stirred at 40°C for 1 hour. The mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was adsorbed onto Isolute and purified by normal-phase column chromatography (Buchi® FlashPure ID HP silica cartridge 120 g, eluent heptane:DCM / MeOH (8 / 2) 100:0 to 20:80). The product-containing fractions were combined and concentrated under reduced pressure to give the title compound (2.06 g, 98% purity, 64% yield) as a brown solid. LC-MS: Rt = 0.54 min; MS m / z [M+H] + 208.2;UPLC-MS1

[0430] Step 3: Ethyl 7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylate [ka] The reactor was charged with 10 wt% Pd-C (518 mg, 487 μmol) and a solution of ethyl 7-hydroxyfuro[3,2-c]pyridine-6-carboxylate (2.06 g, 9.74 mmol) in anhydrous EtOH (32.5 mL). The autoclave was evacuated and backfilled with nitrogen three times. It was then charged with 5 bar of hydrogen (20.0 mg, 9.74 mmol) at room temperature and stirred for 5 days. The reaction mixture was filtered through a pad of Celite. The cake was washed with EtOH (25 mL). The filtrate was concentrated under reduced pressure. The residue was adsorbed onto Isolute and purified by normal-phase column chromatography (80 g Buchi® FlashPure ID HP silica cartridge, eluent DCM:DCM / MeOH (8 / 2) 100:0 to 70:30). The product-containing fractions were combined and concentrated under reduced pressure to give the title compound as a white powder (1.37 g, 98% purity, 66% yield). LC-MS: Rt=0.38 min; MS m / z [M+H] + 210.2;UPLC-MS1

[0431] Step 4: Ethyl 7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylate [ka] To a colorless solution of ethyl 7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylate (1.12 g, 5.23 mmol) and DMAP (130 mg, 1.05 mmol) in anhydrous DCM (52.3 mL), which had been pre-purged / evacuated with argon, was added DIPEA (1.38 mL, 7.84 mmol). The colorless mixture was cooled to 0 °C, and then MOMCl (662 μL, 7.84 mmol) was added dropwise (the colorless solution gradually turned into a dark orange solution). This dark orange reaction mixture was stirred at 0 °C for 1.5 h, the ice bath was removed, and the resulting reaction mixture was stirred at room temperature for 3.25 h. The reaction mixture was quenched with aqueous NaHCO (100 mL). The aqueous layer was extracted twice with DCM. The combined organic layers were dried through a phase separator, concentrated, and dried under reduced pressure. The residue was adsorbed onto Isolute and purified by normal phase column chromatography (RediSep column: 40 g silica, eluent heptane: EtOAc 100:0 to 10:90). The product-containing fractions were combined and concentrated to give the title compound (1.19 g, 73% purity, 66% yield) as a white solid. LC-MS: Rt=0.48 min; MS m / z [M+H] + 254.2;UPLC-MS1

[0432] Step 5: 7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylic acid [ka] To a colorless solution of ethyl 7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylate (1.19 g, 3.42 mmol) in ACN (46 mL) was added 1 M aqueous NaOH (4.60 mL, 4.60 mmol). The resulting colorless reaction mixture was stirred at room temperature for 73 h. The white suspension was filtered. The cake was washed with a small amount of water and dried under vacuum. The filtrate was frozen and lyophilized. The resulting white solid was dissolved in water and extracted twice with DCM. The combined organic layers were dried through a phase separator, concentrated, and dried under reduced pressure to give the title compound (871 mg, 95% purity, 97% yield) as the sodium salt. LC-MS: Rt=0.25 min; MS m / z [M+H] + 226.3; UPLC-MS10

[0433] Intermediate Q: 3,6-dihydro-2H-pyran-4-carbaldehyde [ka] Reference: Org.Lett.2014,16,4142-4145.

[0434] To a mixture of tetrahydro-4H-pyran-4-one (30.0 g, 300 mmol) and water (300 mL), NaCN (15.4 g, 315 mmol) was added at 5 °C, followed by NaHSO4 until a pH of 4–5 was reached. The reaction was stirred at 10 °C for 1 h, and then NaCl (17.5 g, 300 mmol) was added at 25 °C, followed by 2-MeTHF. The organic layer was separated, and the aqueous layer was extracted twice with 2-MeTHF. The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure, and the solvent was switched to toluene (300 mL) to give 4-hydroxytetrahydro-2H-pyran-4-carbonitrile. Pyridine (48.5 mL, 599 mmol) was added at 65 °C, followed by the slow addition of POCl3 (27.9 mL, 300 mmol). The reaction mixture was stirred at 65°C for 1 hour, then cooled to room temperature, and water was added. The layers were separated, and the aqueous layer was extracted twice with toluene. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 3,6-dihydro-2H-pyran-4-carbonitrile. The residue was mixed with toluene (300 mL), and DIBAL-H (46.9 g, 330 mmol) was added at -10°C. The reaction was stirred at -10°C for 1 hour, after which 4 M HCl was added. The two layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine and dried over Na2SO4. The organic solution was then concentrated under reduced pressure to give the title compound as a solution in toluene (not stable upon concentration). 1H NMR(400MHz,DMSO-d6)δ 9.46(s,1H),7.05(m,1H),4.33(m,2H),3.69(m,2H),2.16(m,2H).

[0435] Intermediate R: 3-bromo-1H-1,2,4-triazol-5-amine Step 1: 3,5-Dibromo-1-(methoxymethyl)-1H-1,2,4-triazole [ka] To a solution of NaH (846 g, 21.2 mol, 60%) in DMF (12 L) was added 3,5-dibromo-1H-1,2,4-triazole (4.00 kg, 17.6 mol) at 10 °C. The resulting solution was stirred at 10 °C for 1 h. Following this, chloro(methoxy)methane (1.70 kg, 21.2 mol) was added dropwise at 20 °C. The mixture was stirred at room temperature overnight. The reaction was quenched with HO (20 L). The resulting mixture was extracted with TBME (2 × 7 L). The combined organic layers were washed with 10% NaCl (2 × 7 L), dried over NaSO, and concentrated under reduced pressure at 40 °C. The residue was triturated with heptane (3 L) to give the title compound as a white solid. HPLC: Rt = 3.042 min; HPLC 4

[0436] Step 2: 3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-amine [ka] 3,5-Dibromo-1-(methoxymethyl)-1H-1,2,4-triazole (800 g, 2.78 mol) was dissolved in 25% NH . Dissolved in HO (2.89 L, 16.3 mol) and MeOH (80 mL) at RT. This mixture was stirred at 120 °C for 18 h. The mixture was cooled to 5-10 °C, and the solid was collected by filtration and washed with water (200 mL). The cake was dried under vacuum at 60 °C to give the title compound as a white solid. HPLC: Rt = 1.701 min; HPLC 4

[0437] Step 3: 3-Bromo-1H-1,2,4-triazol-5-amine [ka] To a solution of 3-bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-amine (329 g, 1.45 mol) in MeOH (1.5 L) was added HBr (4.39 kg, 21.7 mol) at room temperature. The mixture was stirred at 100 °C for 18 h. The mixture was adjusted to pH 7.0-7.5 with 10% NaOH at 20-30 °C and extracted with EtOAc (10 × 3 L). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure at 50 °C to give the title compound as a white solid. HPLC: Rt = 0.702 min; HPLC 4 HPLC: Rt=1.902 min; HPLC 5

[0438] Intermediate R: 3-bromo-1H-1,2,4-triazol-5-amine [ka] To a solution of 1H-1,2,4-triazole-3,5-diamine (300 g, 3.03 mol) in HBr / HO (2.4 L) was added NaNO (313 g, 4.54 mol) in water (782 mL) dropwise over 1.5 h at 0 °C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, filtered, and the pH of the mixture (66 batches combined) was adjusted to 4 by the addition of 10% NaOH. The mixture was extracted with EtOAc (2 × 55 L), dried over NaSO, and filtered. The organic phase was concentrated under reduced pressure to give the title compound. The pH of the aqueous layer was adjusted to 7-7.5 with 10% NaOH. It was then extracted with EtOAc (10 × 35 L), dried over NaSO, and filtered. The organic phase was concentrated under reduced pressure to give the title compound. HPLC: Rt = 1.933 min; HPLC 5

[0439] Intermediate S: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide Step 1: 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide [ka] 2-Chloro-4-(trifluoromethyl)aniline (18.5 g, 95.0 mmol) was dissolved in DCM (180 mL) at 0° C. A solution of 2-chloroacetyl chloride (10.7 g, 95.0 mmol) in DCM (40 mL) was added dropwise over 15 minutes. After 30 minutes at 0° C., the RM was allowed to warm to room temperature. The white suspension was stirred at room temperature overnight. The suspension was filtered and washed with DCM. The filtrate was concentrated under reduced pressure and dried under high vacuum to give the title compound as a white solid. LC-MS: Rt = 1.14 min; MS m / z [M−H] - 270.1 / 272.1 / 274.0; UPLC-MS1

[0440] Step 2: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide [ka] 2-Chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (15.8 g, 58.2 mmol) was dissolved in acetone (215 mL), KI (10.6 g, 64.0 mmol) was added, and the RM was stirred under reflux for 2.25 h. The RM was cooled to room temperature, and the suspension was filtered. The cake was washed with acetone and DCM. The filtrate was concentrated under reduced pressure and dried under high vacuum to give the title compound. LC-MS: Rt = 1.13 min; MS m / z [M−H] - 362.0 / 364.0; UPLC-MS1

[0441] Synthesis schemes for compounds of formula 1b, 1c, 1d, 1e and 1f Provided are processes for preparing compounds of formula 1b, 1c, 1d, 1e and 1f. Unless otherwise specified, the groups in the process schemes are as defined in the embodiments and preferences herein. The synthesis can be modified to prepare variants of formula (I) according to procedures known to those skilled in the art.

[0442] Scheme XI [ka] A method for preparing a compound of formula AAK (Scheme XI) is provided, comprising steps a, b, c, d, e, f, g, h, i, and j. It should be understood that the order of process steps a, b, c, d, e, f, g, h, i, and j can be varied to optimize the synthesis as needed. A compound of formula AAK can be obtained by reacting a compound of formula AAJ (wherein R4 is defined as above) with a compound AAZ via coupling reaction step j. The coupling reaction can be an amide formation. The coupling reaction step can be carried out preferably in one or two steps using, for example, HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) or Gause's reagent (1-chloro-N,N,2-trimethylpropenylamine). Alternatively, further alternative amide coupling methods are known in the art. For examples of amide bond formation, see Mantalbetti, CAGN and Falque, V., Amide bond formation and peptide coupling, Tetrahedron, 2005, 61(46), pp 10827-10852, and references cited therein.

[0443] A compound of formula AAJ can be prepared from a compound of formula AAI, where PG represents a suitable protecting group, preferably a BOC group, and the other substituents are as defined above, by deprotecting PG in step i. There are many known methods for deprotecting a BOC group. The deprotection step can be carried out, for example, using TFA or HCl in a solvent such as dichloromethane or dioxane.

[0444] A compound of formula AAI can be prepared by reacting a compound of formula AAH, where R 50The compound of formula (II) can be prepared by starting from a compound of formula (II) (wherein AAH represents halo, particularly bromo, and PG represents a suitable protecting group, e.g., a BOC group, and the other substituents are as defined above), including step h. Step h can be a nucleophilic aromatic substitution reaction, which can be carried out by combining a compound of formula (II) with an amine, e.g., tert-butyl piperazin-1-ylcarboxylate or piperazine. A stoichiometric excess of the amine, preferably 2 to 50 molar equivalents, can be used in an organic solvent, e.g., DMSO or NMP. The reaction can be carried out in a stirred, capped tube, preferably at a temperature of about 80 to 140°C. An alternative method for step h is to use Buchwald-Hartwig conditions, which involve the use of a ligand such as an amine, e.g., tert-butyl piperazin-1-ylcarboxylate, Brettphos, RuPhos, or RuPhos hybrid, and a palladium catalyst such as RuPhos Pd G1, RuPhos Pd G4, or [PdCl(allyl)]2 in the presence of a base such as K2CO3, Cs2CO3, or tert-BuONa in an organic solvent such as dioxane or THF. The reaction is preferably stirred at a temperature of about 80-120 °C. The reaction is preferably carried out under an inert gas such as nitrogen or argon. Alternatively, further alternative Buchwald-Hartwig coupling methods are known in the art; for example methods see B.T. Ingoglia et al. Biaryl monophosphine ligands in palladium-catalyzed CN coupling: An updated User's guide, Tetrahedron, 2019, 75(32), pp. 4199-4211, and references cited therein.

[0445] A compound of formula AAH can be prepared by halogenating a compound of formula AAG (wherein the substituents are as defined herein) in step g. Step g can be carried out using a halogenating agent such as N-bromosuccinimide or N-iodosuccinimide in a solvent such as DMF or acetonitrile. The reaction is preferably stirred at a temperature of about 20-80°C.

[0446] The compound of formula AAG can be prepared by reacting a compound of formula AAY, where R 50 The compounds of formula AAF can be prepared by reacting a methyl group with a methyl group containing 2-methyl-1-(2-methyl-2-propanol), wherein the substituents are as defined herein, in step f, the alkylation of a compound of formula AAF (wherein the substituents are as defined herein) with a methyl group containing 2-methyl-1-(2-methyl-2-propanol), wherein the substituents are as defined herein. Step f can be carried out in a solvent such as DMF or dioxane in the presence of a base such as KCO or N,N-diisopropylethylamine. The reaction is preferably stirred at a temperature of about 20-80°C.

[0447] The compound of formula AAF can be prepared by reacting a compound of formula AAE, where R 51 represents H or methoxy, and other substituents are as defined above). Many methods for cleaving benzyl or para-methoxybenzyl groups are known in the art. Step e can be carried out in the presence of an acid such as TFA or HCl or HBr, preferably in a stoichiometric excess, in a solvent such as dichloromethane or dioxane, and is preferably stirred at a temperature of about 20-80°C. In an alternative method for step e, hydrogenation conditions can be used in the presence of a hydrogen atmosphere and a catalyst such as Pd / C or palladium hydroxide / C. The reaction is preferably stirred in an organic solvent such as ethanol or methanol at a temperature of about 20-50°C.

[0448] Compounds of formula AAE can be prepared starting from compounds of formula AAD by including step d, wherein R 50represents halo, particularly bromine, and the other substituents are as defined above. Step d involves reacting 2 to 10 molar equivalents of an alcohol, such as benzyl alcohol or para-methoxybenzyl alcohol, with 2 to 5 molar equivalents of a base, such as sodium hydride, in an organic solvent, such as THF or dioxane, with stirring at a temperature of about 20 to 40°C, preferably 20°C, for about 10 to 60 minutes. A compound of formula AAD is then added, and stirring is continued at a temperature of about 20 to 100°C, preferably 20 to 60°C. The reaction is preferably carried out under an inert gas, such as nitrogen or argon. An exemplary method is described on page 574 of WO 2021 / 222522, 2021, A1.

[0449] A compound of formula AAD, where R 50 wherein represents halo, particularly bromo or iodo, and other substituents are as defined herein, can be prepared by starting with a compound of formula AAC, including step c. Step c involves reacting a compound of formula AAC with a base such as LiTMP (lithium tetramethylpiperidide) or LDA (lithium diisopropylamide) in a solvent such as THF under an inert gas such as nitrogen or argon at a temperature of about −78° C. to 20° C. with stirring. After stirring for an appropriate period of time, about 30 minutes to 3 hours, a halogenating reagent such as bromine or iodine is added at a temperature of about −78° C. to 20° C., and stirring is continued. Other suitable halogenating agents are known in the art.

[0450] A compound of formula AAC (wherein R and R are as defined above) can be prepared by step b starting from a compound of formula AAB. Step b can be a Suzuki, Negishi, Stille or Kumada cross-coupling reaction, which comprises reacting a compound of formula AAB with R-MX (wherein R is as defined above, n is 1, 2, 3 or 4, and MX represents, for example, B(OH), BPin (Pin represents a boronic acid pinacol ester), BFK, B(MIDA), Sn, Zn, Mg-Halo). An example of Negishi cross-coupling conditions involves reacting a compound of formula AAD with, preferably a stoichiometric excess, for example 2-10 molar equivalents, of an alkyl zincate, such as dimethyl zinc or diethyl zinc, in the presence of a catalyst such as PdCl(dppf) or Pd(PPh) under an inert gas such as nitrogen or argon at a temperature of about 20-120°C, preferably 20-80°C, in a suitable solvent such as THF.

[0451] A compound of formula AAB (wherein R1 is as defined above) can be prepared from compound AAA by step a. Step a can be a Suzuki, Negishi, Stille, or Kumada cross-coupling reaction, which involves reacting a compound of formula AAA with R1-MX (wherein R1 is as defined above, n is 1, 2, 3, or 4, and MX represents, for example, B(OH)2, BPin (wherein Pin represents a pinacol boronic acid ester), BF3K, Sn, Zn, or Mg-Halo). Exemplary Suzuki cross-coupling conditions include reacting a compound of formula AAA with R1-BPin in a suitable solvent mixture, such as DMF, THF, dioxane, or water, in the presence of a catalyst, such as PdCl2(dppf) or Pd(PPh3)4, and a base, such as K3PO4 or potassium carbonate, under an inert gas, such as nitrogen or argon, at a temperature of about 20-120°C, preferably 20-80°C. An exemplary method is described on page 32 of CN112707908A.

[0452] Compounds of formula AAA can be prepared according to the method described on page 31 of CN112707908A.

[0453] Scheme XII [ka] Alternatively, compounds of formula AAK can be prepared according to the route shown in Scheme XII, which includes steps k, L, m, zd, za, zh, ze, zj, and zf. The process for preparing compounds of formula AAP, AAQ, AAR, AAS, and AAT, which includes steps zd, za, zh, ze, zj, and zf, can be carried out using conditions similar to those described above for steps d, a, h, e, j, and f of Scheme XI. It is understood that the order of process steps k, L, m, zd, za, zh, ze, zj, and zf can be varied as needed to optimize the synthesis.

[0454] A compound of formula AAO, where R 50 wherein represents halo, particularly bromo or chloro, and other substituents are as defined above, can be prepared by step m starting from a compound of formula AAN. Step m involves reacting a compound of formula AAN in a stoichiometric excess, for example 2-10 molar equivalents, with a halogenating agent such as PCl5 or PBr3 in a sealed tube at a temperature of about 200-270°C, preferably 250-270°C, for about 1-10 hours. An exemplary method is described in J. Org. Chem., Vol. 39, No. 15, 1974, page 2146.

[0455] Compounds of formula AAN (wherein R3 is as defined above) can be prepared by step L starting from a compound of formula AAM. Step L involves reacting the compound of formula AAM with hydroxylamine in the presence of a base such as triethylamine and a solvent such as ethanol or methanol at a temperature of about 60-100°C. The product of this reaction is then reacted with tert-butyl nitrite in the presence of CuBr2 in a solvent such as acetonitrile at a temperature of about 20-50°C. An exemplary method is described on page 31 of CN112707908A.

[0456] Compounds of formula AAM, where R3 is as defined above, can be prepared starting from AAL, including step k, which involves reacting a compound of formula AAL with ethoxycarbonyl isothiocyanate in a solvent such as dichloromethane at a temperature of about 0-20° C. for 2-18 hours.

[0457] Compounds of formula AAL, where R3 is as defined above, are commercially available or methods for their preparation are known in the art.

[0458] Scheme XIII [ka] Compounds of formula 1d can be prepared according to the exemplary route shown in Scheme XIII using methods similar to those described herein.Similar methods can be adapted by chemists skilled in the art.It is understood that the order of the process steps shown in Scheme XIII can be changed as necessary to optimize synthesis.

[0459] Scheme XIV [ka] Compounds of formula 1e can be prepared according to the exemplary route shown in scheme XIV using methods similar to those described herein.Similar methods can be adapted by chemists skilled in the art.It is understood that the order of the process steps shown in scheme XIV can be changed as necessary to optimize synthesis.

[0460] Scheme XV [ka] Scheme XV (continued) [ka] The process for preparing a compound of formula BBN (Scheme XV) includes steps ba, bc, bd, be, bf, bg, bh, bj, bk, bL, bm, ye or yi, and yj. It is understood that the order of processes ba, bc, bd, be, bf, bg, bh, bj, bk, bL, bm, ye or yi and yj can be varied as necessary to optimize the synthesis. A compound of formula BBN can be obtained by reacting a compound of formula BBM (wherein the substituents are as defined above) with a compound AAZ (wherein R4 is as defined above) via coupling reaction step yj using methods similar to those described herein.

[0461] Compounds of formula BBM, where the substituents are as defined above, can be prepared by deprotecting a compound of formula BBL, where PG represents a suitable protecting group such as BOC or para-methoxybenzyl or benzyl, and the other substituents are as defined above, including step ye or step yi using methods similar to those described in step e or step i of Scheme XI.

[0462] The compound of formula BBL can be prepared by starting with compound BBK (where the substituents are as defined above) and using compound BBX or compound BBW (where PG is as defined above, and LG is halo, particularly iodo or bromo, or OH, or OM (methanesulfonate), OT (p-toluenesulfonate), or OTf (trifluoromethanesulfonate), or B(OH)2, BPin (Pin represents a boronic acid pinacol ester) BF3K). Step bL can be carried out by combining the compound of formula BBK with compound BBX in the presence of a base such as sodium hydride, K2CO3, DBU, NaOtBu, or the phosphazene base P2-Et. A stoichiometric excess of BBX, preferably 2 to 50 molar equivalents, can be used in an organic solvent such as DMF or NMP. The reaction can be carried out in a stirred, capped tube, preferably at a temperature of about 80 to 150 °C. An alternative method for step bL can use an Ullmann-type reaction. Examples of Ullmann-type cross-coupling conditions include reacting a compound of formula BBK with a compound of formula BBW in the presence of a catalyst such as copper(I) iodide, a ligand such as N-(2-cyanophenyl)pyridine-2-carboxamide or 4,7-dimethoxy-1,10-phenanthroline or N1,N2-dibenzylethane-1,2-diamine, and a base such as K3PO4 or K2CO3 in a suitable solvent mixture such as DMSO or DMF at a temperature of about 80-150 °C. A stoichiometric excess of BBX, preferably 2-50 molar equivalents, can be used. An alternative method for step bL can include reacting a compound of formula BBK with a compound of formula BBW using Buchwald-Hartwig conditions, for example, using a method similar to that described for step h (Scheme XI). The product of the reaction of a compound of formula BBK with a compound of formula BBW can optionally be hydrogenated using methods known in the art to provide a compound of formula BBL in which the piperidine ring is saturated.Alternative cross-coupling conditions are known in the art, for example methods see De Meijere et al. Metal-Catalyzed Cross-Coupling Reactions, Wiley, 2014, and references cited therein.

[0463] The compound of formula BBK can be prepared by step bk starting from a compound of formula BBJ, wherein the substituents are as defined above. Step bk comprises reacting the compound of formula BBJ with a stoichiometric excess of L-methionine, for example 3 to 5 molar equivalents of L-methionine, in a solvent such as methanesulfonic acid at a temperature of about 20 to 80° C.

[0464] The compound of formula BBJ can be prepared by step bj starting from a compound of formula BBI, where the substituents are as defined above. Step bj comprises reacting the compound of formula BBI with a stoichiometric excess of R2-NH2, where R2 is as defined above, e.g., 3 to 5 molar equivalents, and a stoichiometric excess of trimethylaluminum, e.g., 3 to 5 molar equivalents, in a solvent such as toluene at a temperature of about 20 to 80°C.

[0465] A compound of formula BBI can be prepared by step bi starting from a compound of formula BBH, where the substituents are as defined above. Step bj comprises reacting the compound of formula BBH with a stoichiometric excess of hydrogen chloride gas, e.g., 20-100 molar equivalents, in ethanol at about 20-100°C, preferably in a sealed tube.

[0466] The compound of formula BBH can be prepared by step bh starting from a compound of formula BBG, wherein the substituents are as defined above. Step bh comprises reacting the compound of formula BBH with a stoichiometric excess of potassium fluoride, for example 3-5 molar equivalents, in water or in the presence of an additional solvent such as DMF or methanol at a temperature of about 20-100°C, preferably 60-100°C.

[0467] The compound of formula BBG can be prepared by reacting a compound of formula BBF, where R 50 is represented by halo, particularly iodo or bromo, and other substituents are as defined above), step bg comprises reacting a compound of formula BBF with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole under an inert gas such as nitrogen or argon in a suitable solvent such as DMF in the presence of a catalyst such as XPhos Pd G3 and a base such as potassium carbonate at a temperature of about 20-120°C, preferably 60-100°C.

[0468] The compound of formula BBF can be prepared by step bf starting from a compound of formula BBE, wherein the substituents are as defined above. Step bf involves reacting the compound of formula BBE with a base such as sodium hydride under an inert gas such as nitrogen or argon in a solvent such as DMF at a temperature of about 0-20°C for about 5-30 minutes. 1-(Bromomethyl)-4-methoxybenzene is then added and the reaction is stirred at a temperature of about 0-20°C.

[0469] The compound of formula BBE can be prepared by halogenating a compound of formula BBD (wherein the substituents are defined as above) in step (be). Step (be) can be carried out using a halogenating agent such as N-bromosuccinimide or N-iodosuccinimide in a solvent such as DMF or acetonitrile. The reaction is preferably stirred at a temperature of about 20-80°C.

[0470] The compound of formula BBD can be prepared by step bd starting from a compound of formula BBC (wherein the substituents are as defined above). Step bd involves reacting a compound of formula BBC with a compound of formula BBY (wherein R1 is defined as above) in a solvent such as DMF, toluene, or dioxane at a temperature of about 80-150°C. An alternative method of step bd can involve reacting a compound of formula BBC with a compound of formula BBZ (wherein R1 is defined as above) in a solvent such as dichloroethane, DMF, toluene, or dioxane at a temperature of about 0-20°C. A base such as triethylamine may be added. The reaction is then stirred at a temperature of about 80-150°C.

[0471] The compound of formula BBC can be prepared by step bc starting from a compound of formula BBC (wherein the substituents are defined as above). Step bc involves reacting the compound of formula BBB with a stoichiometric excess of hydrazine hydrate, e.g., 2-5 molar equivalents, in a solvent such as ethanol. The reactants are preferably stirred at a temperature of about 60-100°C.

[0472] The compound of formula BBB can be prepared by step ba starting from a compound of formula BBA or BBAA, where the substituents are defined as above. Compounds of formula BBA or BBAA are commercially available, or their preparation is known in the art. Step ba involves reacting a compound of formula BBA or BBAA with P2S5 or Lawesson's reagent in a solvent such as dioxane or pyridine. The reaction is preferably stirred at a temperature of about 80-120°C.

[0473] Scheme XVI [ka] Compounds of formula CCN can be prepared according to the route shown in Scheme XVI, which includes steps ca, cb, cc, cd, ce, cf, xg, xh, xi, xj, xk, xe, or xi and xj. It is understood that the order of processes ca, cb, cc, cd, ce, cf, xg, xh, xi, xj, xk, xe, or xi and xj can be varied as necessary to optimize the synthesis. Methods including steps xg, xi, xj, xk, xe, or xi and xj for preparing compounds of formula CCG, CCH, CCI, CCJ, CCL, CCM, and CCN can be carried out using conditions similar to those described above for steps bf, bg, bh, bi, e, i, and j of Scheme XI and Scheme XV.

[0474] A compound of formula CCK can be prepared by step xj starting from a compound of formula CCJ, wherein the substituents are defined as above. Step xj comprises reacting a compound of formula CCJ with di-tert-butyl dicarboxylate or para-methoxybenzyl bromide or benzyl bromide in a solvent such as dichloromethane or dioxane in the presence of a base such as triethylamine at a temperature of about 0-20°C.

[0475] A compound of formula CCF, in which PG represents a suitable protecting group such as BOC or para-methoxybenzyl or benzyl, and the other substituents are as defined above, can be prepared by starting with a compound of formula CCE, in which the substituents are as defined above, in accordance with step ce. Step ce involves reacting the compound of formula CCE with an echavalene gold(I) catalyst in a solvent such as THF at a temperature of about 60-140°C, preferably 80-120°C, in a sealed tube. An exemplary method is described in Org. Lett. 2013, 15, 11, 2616-2619. An alternative method for preparing a compound of formula CCF involves reacting the compound of formula CCE with a base such as sodium hydride in a solvent such as DMF, THF, or dioxane in a sealed tube under an inert gas such as nitrogen or argon at a temperature of about 60-140°C, preferably 80-120°C.

[0476] The compound of formula CCE can be prepared by step cd starting from compound CCD (wherein the substituents are defined as above). Step cd comprises reacting the compound of formula CCD with a compound of formula CCY or CCZ (wherein PG represents a suitable protecting group such as BOC or para-methoxybenzyl or benzyl) in a solvent such as THF or dioxane or DMF in the presence of a base such as triethylamine or N-ethyl-N,N-diisopropylamine at a temperature of about 20-140°C, preferably 60-120°C. Compounds of formula CCY or CCZ are commercially available or methods for their preparation are known in the art.

[0477] Compounds of formula CCD can be prepared including step cc starting from compound CCC, where PG2 represents a protecting group such as MOM (methoxymethyl) or SEM (trimethylsilyl)ethoxymethyl, and the other substituents are as defined above. Step cc involves reacting a compound of formula CCC with an acid such as HCl or TFA in a solvent such as dioxane or dichloromethane at a temperature of about 0-80° C., preferably 20-60° C. Alternative methods for deprotecting the SEM or MOM group are known in the art.

[0478] A compound of formula CCC can be prepared by step cb starting from a compound of formula CCB (wherein the substituents are as defined above). Step cb can be a Sonogashira reaction in which a compound of formula CCB is reacted with a compound of formula CCX (wherein R3 is as defined above) under an inert gas atmosphere such as nitrogen or argon in a solvent such as dioxane, DMF, or acetonitrile (THF) in the presence of a catalyst such as Pd(PPh3)4, a copper catalyst such as copper(I) iodide, and a base such as triethylamine or lithium carbonate at a temperature of about 20-120°C, preferably 80-120°C. Step cb can alternatively be a Suzuki or Stille cross-coupling reaction, which involves reacting a compound of formula CCB with a compound of formula CCW, where MX2 represents B(OH)2, BPin (wherein Pin represents a pinacol boronic acid ester), BF3K, B(MIDA), or tributyltin, and R3 is as defined above. Methods for Sonogashira, Suzuki or Stille reactions are known in the art, for example methods see Molnar et al. Palladium-Catalyzed Coupling Reactions, Wiley, 2013, and references cited therein.

[0479] The compound of formula CCB can be prepared by step ca starting from a compound of formula CCA, where the substituents are as defined above. Step a can be a Suzuki cross-coupling reaction, in which the compound of formula CCA is reacted with R 1n-MX (wherein R1 is as defined above, n is 1, 2, 3, or 4, and MX represents, for example, B(OH)2, and BPin (Pin represents boric acid pinacol ester) BF3K). An example of Suzuki cross-coupling conditions includes reacting a compound of formula CCA with R1-BPin in the presence of a catalyst such as PdCl2(dppf) or Pd(PPh3)4 and a base such as K3PO4 or potassium carbonate in a suitable solvent such as DMF, THF, dioxane, or water at a temperature of about 20-120°C, preferably 60-120°C, under an inert gas such as nitrogen or argon. Compounds of formula CCA are commercially available, or methods for their preparation are known in the art.

[0480] Scheme XVII [ka] Scheme XVII (continued) [ka] Compounds of formula DDN can be prepared according to the route shown in Scheme XVII, which includes steps da, db, dc, dd, de, df, dg, dh, di, dj, dk, dL, or dM and dn. It is understood that the order of processes da, db, dc, dd, de, df, dg, dh, di, dj, dk, dL, or dM and dn can be varied as necessary to optimize the synthesis. Methods including steps de, df, dh, di, dj, dk, dL, dM, and dn for preparing compounds of formula DDF, DDG, DDH, DDI, DDJ, DDK, DDL, DDM, and DDN can be carried out using conditions similar to those described herein, including an optional hydrogenation step, such as step dk.

[0481] A compound of formula DDE, where R 50where DDD represents halo, particularly bromo or iodo, and the other substituents are as defined above, can be prepared by starting from a compound of formula DDD, where the substituents are as defined above, in step dd. Step dd can be carried out using a halogenating agent such as N-bromosuccinimide or N-iodosuccinimide in a solvent such as DMF, acetonitrile, or acetic acid. The reaction is preferably stirred at a temperature of about 20-110°C.

[0482] A compound of formula DDD, where the substituents are as defined above, can be prepared by step dc starting from a compound of formula DDC, where the substituents are as defined above. Step dc can be carried out using conditions similar to those described above for step a of Scheme XI.

[0483] A compound of formula DDC, wherein the substituents are as defined above, can be prepared by step db starting from a compound of formula DDB, wherein the substituents are as defined above. Step db comprises reacting the compound of formula DDB with a stoichiometric excess of an ammonium salt, such as ammonium acetate, for example 3 to 100 molar equivalents, particularly 10 to 20 molar equivalents, in a solvent such as acetic acid at a temperature of about 60 to 130°C, preferably 80 to 120°C.

[0484] The compound of formula DDB, wherein the substituents are as defined above, can be prepared by step da, starting from a compound of formula DDA, which comprises reacting the compound of formula DDA with a compound of formula DDZ, wherein R 50 represents halo, particularly chloro or bromo, and the other substituents are as defined above. Compounds of formula DDZ are commercially available or methods for their preparation are known in the art.

[0485] "Protecting group": In the above-mentioned method, functional groups present in the starting material and not intended to participate in the reaction are present in a protected form if necessary, and the existing protecting groups are cleaved, so that the starting compound can also be present in the form of a salt if a salt-forming group is present and the reaction in the form of a salt is possible.In an additional process step that is optionally carried out, functional groups of the starting compound that should not participate in the reaction can be present in an unprotected form or can be protected, for example, by one or more protecting groups.The protecting groups are then completely or partially removed according to one of known methods. Protecting groups and methods for their introduction and removal are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, and "Methoden der organischen Chemie", Houben-Weyl, 4th edition, Vol. 15 / 1, Georg-Thieme-Verlag, Stuttgart 1974, and Theodora W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York 1981. A characteristic of a protecting group is that it can be easily removed, i.e., without undergoing undesired secondary reactions such as solvolysis, reduction, photolysis, etc., or under physiological conditions.

[0486] The invention further includes any variation of this process in which an intermediate product obtained at any stage thereof is used as a starting material to carry out the remaining steps, or the starting material is formed in situ under the reaction conditions, or the reaction components are used in the form of their salts or are optically pure substances.

[0487] The compounds of the present invention and intermediates may also be converted into each other according to methods commonly known to those skilled in the art.

[0488] Intermediates and final products can be worked up and / or purified according to standard methods, eg using chromatographic methods, distribution methods, and (re-)crystallization.

[0489] The following applies generally to all processes mentioned hereinbefore and hereafter: Any of the process steps described above can be carried out under reaction conditions known per se (including those specifically mentioned), for example in the absence or customary presence of solvents or diluents, including those inert to and dissolving the reagents used, in the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, such as cation exchangers in the H+ form, at low, normal or elevated temperatures, depending on the nature of the reaction and / or reactants, for example in the temperature range of about -80°C to about 150°C, for example -80°C to -60°C, room temperature, -20°C to 40°C, or about -100°C to about 190°C, including reflux temperature, at atmospheric pressure or in a closed vessel, if appropriate under elevated pressure, and / or in an inert atmosphere, for example under an argon or nitrogen atmosphere.

[0490] At all reaction stages, the mixtures of isomers formed may be separated into individual isomers, e.g., diastereoisomers or enantiomers, or into any desired mixture of isomers, e.g., racemates or diastereomeric mixtures, e.g., in a manner analogous to the methods described herein.

[0491] Solvents from which suitable solvents may be selected for any particular reaction include those specifically mentioned, unless otherwise indicated in the process description, or, for example, water, esters such as lower alkyl-lower alkanoates, for example, ethyl acetate, ethers such as aliphatic ethers, for example, diethyl ether, or cyclic ethers, for example, tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, for example, benzene or toluene, alcohols, for example, methanol, ethanol, or 1- or 2-propanol, nitriles, for example, acetonitrile, halogenated hydrocarbons, for example, methylene chloride or chloroform, acid amides, for example, dimethylformamide or dimethylacetamide, bases, for example, heterocyclic nitrogen bases, for example, pyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, for example, lower alkanoic acid anhydrides, for example, acetic anhydride, cyclic, linear or branched hydrocarbons, for example, cyclohexane, hexane, or isopentane, methylcyclohexane, or mixtures of these solvents, for example, aqueous solutions. Such solvent mixtures may also be used in work-up, for example by chromatography or partitioning.

[0492] Sulfonimidamides and their synthesis are described in Chem. Eur. J. 2017, 23, 15189-15193 DOI: 10.1002 / chem.201703272.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, R, M, W, L, V and T are independently selected from C, CH and N; Forming sub-formulas 1a, 1b, 1c, 1d, 1e and 1f: 【Chemistry 2】 A is a linker that is —C(O)—; Y is N, C or CH; y is 0, 1, 2, 3 or 4; Y 【Transformation 3】 means that when Y is CH, it is connected to the adjacent carbon atom via a single bond, or when Y is C, it is connected to the adjacent atom via a double bond; 【Chemistry 4】 is a single bond, then Y is an unsubstituted carbon or is substituted by OH or F; If Y is N, then Y 【Transformation 5】 is a single bond; K 【Transformation 6】 means that K is connected to the adjacent atom via a single or double bond; where: K 【Transformation 7】 When Y is a double bond, 【Transformation 8】 is a single bond, K is CH, and J is C or K 【Chemistry 9】 is a single bond, K is -CH ２ -, -CH ２ CH ２ -, -NH- and a bond (5-membered ring: 【Chemistry 10】 and J is N; R ５ is, independently, ・-(C １～ C ４ ) alkyl, ・-(C ３～ C ５ ) cycloalkyl, and where two R on the same ring carbon atom ５ Substituents, together with the carbon atom to which they are attached, can be represented by (C ３～ C ４ ) may form a cycloalkylspiro ring or a 3- or 4-membered heterocyclylspiro ring, said heterocyclylspiro ring containing ring carbon atoms and one ring heteroatom selected from O, N and S; ・K 【Chemistry 11】 When J is a carbon-nitrogen single bond, R on K ５ The substituent and R on the adjacent carbon atom ５ The substituents are bonded to ring C: 【Chemistry 12】 may be formed, Here, ring C is fused (C ３ ~C ６ ) cycloalkyl ring, fused (C ３ ~C ６ ) heterocyclyl ring or fused phenyl ring, wherein the fused (C ３ ~C ６ ) heterocyclyl rings contain ring carbon atoms and one ring heteroatom selected from O, N, and S; Ring C is fused (C ３ ~C ６ ) cycloalkyl ring, the fused (C ３ ~C ６ ) The cycloalkyl ring is unsubstituted or contains one or two R ４０ group, wherein the R ４０ teeth, ・(C １～ C ２ ) alkyl, wherein each (C １～ C ２ ) alkyl is independently unsubstituted or substituted with OH or 1, 2 or 3 halo; (C １ ~C ２ ) alkyl ・Halo, especially F, Or two R on the same ring carbon atom ４０ The substituents, together with the carbon atoms to which they are attached, form a group such that (C ３ ~C ４ ) may form a cycloalkylspiro ring or a 3- or 4-membered heterocyclylspiro ring, wherein said heterocyclylspiro ring contains ring carbon atoms and one ring heteroatom selected from O, N and S; Or two R on adjacent carbon atoms ４０ the substituents, taken together with the carbon atoms to which they are attached, form a fused cyclopropyl ring; ・Here, K is -CH ２ - and when J is N, two R ５ The substituents are bonded to (C １ ~C ３ ) may form an alkylene bridge or a heteroalkylene bridge, wherein said heteroalkylene bridge is one heteroatom selected from N and O, or is —CH ２ -O-CH ２ -is, Selected from: R １ teeth, cycloalkenyl, wherein said cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms, said cycloalkenyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2, R ３３ where R ３３ is halo, and said cycloalkenyl or halo-substituted cycloalkenyl has 0, 1 or 2 R １５ or said cycloalkenyl or halo-substituted cycloalkenyl has two substituents on the same ring carbon atom to which it is attached to form an oxetanyl spiro ring; Or, R １ is heterocyclyl, wherein said heterocyclyl is a fully saturated or partially unsaturated 5- or 6-membered group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S, said heterocyclyl is unbridged or bridged, said bridge being 1 or 2 carbon atoms, wherein said heterocyclyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2, R ３３ where R ３３ is halo, and said heterocyclyl or halo-substituted heterocyclyl is independently R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２２ and R ２３ or substituted by 0, 1 or 2 substituents selected from Alternatively, said heterocyclyl or halo-substituted heterocyclyl is fused to a cyclopropyl ring, wherein said cyclopropyl ring is unsubstituted or substituted with 1, 2 or 3 F; Alternatively, said heterocyclyl or halo-substituted heterocyclyl has two substituents at the same ring carbon atom which are joined to form a cyclopropyl spiro ring or a tetrahydrofuranyl spiro ring; Alternatively, the heterocyclyl or halo-substituted heterocyclyl is (C ３ ~C ５ ) heterocycloalkyl ring, wherein the (C ３ ~C ５ ) heterocycloalkyl rings contain ring carbon atoms and one ring O atom, or Or, R １ is heteroaryl, wherein said heteroaryl is a 5- or 6-membered fully unsaturated monocyclic group containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, preferably 1 or 2 ring heteroatoms, and preferably the total number of ring S atoms does not exceed 1 and preferably the total number of ring O atoms does not exceed 1; and the heteroaryl is unsubstituted or R ２１ and R ３０ and is substituted by 1, 2, or 3 substituents independently selected from ２１ and R ３０ are independently halo and (C １ ~C ４ ) alkyl, wherein said (C １ ~C ４ ) alkyl is unsubstituted or substituted by 1, 2 or 3 halo; Or, R １ is phenyl, wherein said phenyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2, R ３３ where R ３３ is halo, and said phenyl or halo-substituted phenyl is selected from 0, 1 or 2 R １５ Is substituted with a substituent, Or, R １ is (C ２ ~C ４ ) alkynyl or (C ２ ~C ４ ) alkenyl, wherein the (C ２ ~C ４ ) alkynyl and (C ２ ~C ４ ) alkenyl is unsubstituted or (C １ ~C ４ ) substituted by alkyl-O—C(O)— or morpholinyl; Each R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２２ and R ２３ is, independently, ・Haro unsubstituted or substituted with 1, 2 or 3 halo (C １～ C ４ ) alkyl-O—(CH ２ ) ｎ , unsubstituted or OH, —O—(C １ ~C ２ ) alkyl or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, ・HOC(O)-(H ２ ) ｎ -、 ・(C １ -C ４ ) alkyl-C(O)(CH ２ ) ｎ -, (E)-cyclooct-4-en-1-yl-O—C(O)—, ・(C １ -C ４ ) alkyl-O—C(O)(CH ２ ) ｎ , ・=O, azetidinyl or pyrrolidinyl, which are linked to the rest of the molecule via an N atom and which are each unsubstituted or substituted with one or two F, ・R ２５ (R ２４ )N-(CH ２ ) ｎ where R ２４ is H or unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, and R ２５ teeth, ohhh, o (C １ ~C ４ ) alkyl-C(O)(CH ２ ) ｎ -, where (C １ -C ４ ) alkyl-C(O)(CH ２ ) ｎ - the above (C １ ~C ４ ) Alkyl is unsubstituted or is selected from halo and -N ３ is replaced by o (C １ ~C ４ ) alkyl-O—C(O)(CH ２ ) ｎ , o unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, or o(E)-cyclooct-4-en-1-yl-O—C(O)—, ・OH is selected from where n is 0, 1 or 2; R ２６ is CH ３ , H or deuterium; R ２７ is CH ３ , H or deuterium; Or, R ２６ and R ２７ together with the carbon atom to which they are attached form a cyclopropyl ring; R ２ is a part 【Chemistry 13】 and R ６ teeth, ・H, · Halo; unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, unsubstituted or substituted with 1, 2 or 3 halo (C ３ ~C ５ ) cycloalkyl, -O-(C １ ~C ４ ) alkyl, OH, and ・CN Selected from: R ８ is H, halo, and is unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl; R ９ is H, O-CH ３ , OH, CN, CH ３ and halo; R ２８ teeth, ・SF ５ 、 ・H, -C(O)H, · Halo; unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, ・(C １ ~C ４ ) alkynyl; ・(C １ ~C ４ ) alkenyl, unsubstituted or substituted with 1, 2 or 3 halo (C ３ ~C ５ ) cycloalkyl, and ・OCF ３ Selected from: X is C-R ７ and N, where R ７ is H, CF ３ , or halo, or R ７ is R ２８ Or R ６ , and together with the atoms to which they are attached form a condensed group (C ４ ~C ６ ) can form a cycloalkyl ring, wherein the fused (C ４ ~C ６ ) the cycloalkyl ring is unsubstituted or substituted with 1, 2, or 3 halo; or R ２ teeth, 【Chemistry 14】 is selected from During the ceremony, R ３１ is H, halo and CH ３ is selected from R ３２ is H, halo and CH ３ Selected from: R ３ teeth, cyclopropyl, ・O-CH ３ 、 ・N(CH ３ ) ２ 、 ・S-CH ３ 、 unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo and OH (C １ ~C ４ ) alkyl; R ４ teeth, unsubstituted or NH ２ (C １ ~C ４ ) alkyl; ・O-CH ２ Phenyl; -O-CH ２ CH ２ Phenyl; -NH-NH-C(O)-CF ３ ; Heteroaryl1, which is a 5- or 6-membered fully unsaturated monocyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S; heteroaryl2, which is a 9- or 10-membered fused bicyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein both rings are fully unsaturated or one ring is fully unsaturated and the other saturated or partially unsaturated, and said heteroatoms may be in one or both rings; -phenyl; heterocyclyl2, which is a 5- or 6-membered fully saturated or partially unsaturated group consisting of ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S; is selected from 【Chemistry 15】 Here, heteroaryl 1, heteroaryl 2, and phenyl are each R １０ , R １１ , R １２ , R １３ and R １４ and wherein each R １０ , R １１ , R １２ , R １３ and R １４ teeth, ・H, · Halo; unsubstituted or substituted with 1, 2 or 3 halo substituents (C １ ~C ４ ) alkyl, -O-(C １ ~C ２ ) substituted by alkyl or OH (C １ ~C ２ ) alkyl, -S-(C １ ~C ３ ) alkyl, -O-(C) is unsubstituted or substituted with 1, 2 or 3 halo substituents １ ~C ４ ) alkyl, ・OH, ・(C ３ ~C ５ ) cycloalkyl, unsubstituted or substituted with 1 or 2 halo; (C ３ ~C ５ ) cycloalkyl, -O-(C ３ ~C ５ ) cycloalkyl, ・-NR ３４ R ３５ where R ３４ and R ３５ is independent ohhh, o (C １ ~C ４ ) alkyl, unsubstituted or OH or —O(C １ ~C ２ ) alkyl-substituted, (C １ ~C ４ ) alkyl, o and where R ３４ and R ３５ can be taken together with the atoms to which they are attached to form an azetidine, pyrrolidinyl, or piperidine ring, wherein said azetidine, pyrrolidinyl, and piperidine are unsubstituted or ３ has been replaced by -NR ３４ R ３５ , ・CN, ・-(C ２ ~C ４ ) alkenyl, ・-(C ２ ~C ４ ) alkynyl, ・=O, -C(O)H, and -C(O)(C １ ~C ４ ) alkyl are independently selected from However, R ４ teeth, 【Chemistry 16】 Instead, in the formula, R １０ , R １１ , R １２ , R １３ and R １４ is, independently, ・H, · Halo; unsubstituted or substituted with 1, 2 or 3 halo substituents (C １ ~C ４ ) alkyl, -O-(C １ ~C ２ ) substituted by alkyl or OH (C １ ~C ２ ) alkyl, -S-(C １ ~C ３ ) alkyl, -O-(C) is unsubstituted or substituted with 1, 2 or 3 halo substituents １ ~C ４ ) alkyl, ・OH, ・(C ３ ~C ５ ) cycloalkyl, unsubstituted or substituted with 1 or 2 halo; (C ３ ~C ５ ) cycloalkyl, -O-(C ３ ~C ５ ) cycloalkyl, ・-NR ３４ R ３５ where R ３４ and R ３５ is independent, ohhh, o (C １ ~C ４ ) alkyl (wherein the above (C １ ~C ４ ) alkyl is unsubstituted or is selected from the group consisting of OH or —O(C １ ~C ２ ) alkyl-substituted), o and where R ３４ and R ３５ can be taken together with the atoms to which they are attached to form an azetidine, pyrrolidinyl, or piperidine ring, wherein said azetidine, pyrrolidinyl, and piperidine are unsubstituted or ３ is replaced by -NR ３４ R ３５ , ・CN, ・-(C ２ ~C ４ ) alkenyl, ・-(C ２ ~C ４ ) alkynyl, -C(O)H, and -C(O)(C １ ~C ４ ) alkyl are independently selected from A compound of formula (I) or a pharmaceutically acceptable salt thereof, where * indicates the point of attachment.

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

3. R １ teeth, cycloalkenyl, wherein said cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms, said cycloalkenyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2, R ３３ where R ３３ is halo, and said cycloalkenyl or halo-substituted cycloalkenyl has 0, 1 or 2 R １５ substituted with a substituent, preferably one substituent, or said cycloalkenyl or halo-substituted cycloalkenyl has two substituents on the same ring carbon atom to which it is attached to form an oxetanyl spiro ring; Or, R １ is heterocyclyl, wherein the heterocyclyl is a fully saturated or partially unsaturated 5- or 6-membered group comprising ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, NH, O and S, the heterocyclyl being unbridged or bridged, the bridge being 1 or 2 carbon atoms, wherein the heterocyclyl is unsubstituted or has 1, 2, 3 or 4, e.g. 1, 2 or 3, especially 1 or 2, R ３３ where R ３３ is halo, and said heterocyclyl or halo-substituted heterocyclyl is independently R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２２ and R ２３ or substituted by 0, 1 or 2 substituents, preferably 0 or 1 substituents, selected from Alternatively, said heterocyclyl or halo-substituted heterocyclyl is fused to a cyclopropyl ring, wherein said cyclopropyl ring is unsubstituted or substituted with 1, 2 or 3 F; Alternatively, said heterocyclyl or halo-substituted heterocyclyl has two substituents at the same ring carbon atom which are joined to form a tetrahydrofuranyl spiro ring; Or, R １ is heteroaryl, wherein said heteroaryl is a 5- or 6-membered fully unsaturated monocyclic group containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, preferably 1 or 2 ring heteroatoms, wherein the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1, and wherein said heteroaryl is unsubstituted or ２１ and R ３０ and is substituted by 1, 2, or 3 substituents independently selected from ２１ and R ３０ is halo and (C １ ~C ４ ) alkyl, wherein said (C １ ~C ４ ) alkyl is unsubstituted or substituted with 1, 2 or 3 halo; Or, R １ is phenyl, wherein said phenyl is unsubstituted or has 1, 2, 3 or 4, preferably 1 or 2, R ３３ where R ３３ is halo, and said phenyl or halo-substituted phenyl is selected from the group consisting of 0 or 1 R １５ Is substituted with a substituent, Or R １ is unsubstituted or (C １ ~C ４ ) alkyl-O—C(O)— substituted (C ２ ~C ４ ) alkynyl; And each R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２２ and R ２３ is, independently, ・Haro unsubstituted or substituted with 1, 2 or 3 halo (C １～ C ４ ) alkyl-O—(CH ２ ) ｎ , unsubstituted or OH, —O—(C １ ~C ２ ) alkyl or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, ・HOC(O)-(H ２ ) ｎ -、 ・H ３ C-C(O)(CH ２ ) ｎ -、 ・(C １ -C ４ ) alkyl-O—C(O)(CH ２ ) ｎ , ・=O, azetidinyl or pyrrolidinyl, which are linked to the rest of the molecule via an N atom and which are each unsubstituted or substituted with one or two F, ・R ２５ (R ２４ )N-(CH ２ ) ｎ where R ２４ is H, or is unsubstituted or substituted with 1, 2 or 3 halo (C １ -C ２ ) alkyl, and R ２５ is H, (C １ ~C ４ ) alkyl-C(O)-, (C １ ~C ４ ) alkyl-O—C(O)— or unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, R ２５ (R ２４ )N-(CH ２ ) ｎ , ・OH is selected from 3. A compound of formula (I) according to claim 1 or 2, wherein n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R １ teeth, cycloalkenyl, wherein said cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms, said cycloalkenyl is unsubstituted or has one or two R ３３ where R ３３ is halo, preferably F, and said cycloalkenyl or halo-substituted cycloalkenyl has zero or one R １５ is substituted by a substituent, where R １５ teeth, o) unsubstituted or substituted with 1, 2 or 3 halo (C １～ C ２ ) alkyl-O-, p) unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ２ ) alkyl, V)HOC(O)-(CH ２ ) ｎ -、 r)H ３ C-C(O)(CH ２ ) ｎ -、 s)H ３ C-O-C(O)(CH ２ ) ｎ 、 t)=O, and u)R ２５ (R ２４ ) N—, H, where R ２４ is H or unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ２ ) alkyl, and R ２５ is H or unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ２ ) alkyl, R ２５ (R ２４ ) N-, H is selected from n is 0 or 1; During the ceremony, The R of the cycloalkenyl or halo-substituted cycloalkenyl １５ Substituents a) through g) are not present on the ring atom adjacent to the ring atom at which said cycloalkenyl or halo-substituted cycloalkenyl is attached to the remainder of the molecule, and preferably said cycloalkenyl or halo-substituted cycloalkenyl has one R in the ring para position relative to the remainder of the molecule. １５ a substituted six-membered ring, and The cycloalkenyl or halo-substituted cycloalkenyl is not an adjacent R １ R double bonded to a ring carbon atom １ is linked to the remainder of the compound via a ring carbon atom; Or, R １ is heterocyclyl, wherein said heterocyclyl is a fully saturated or partially unsaturated 5- or 6-membered group containing ring carbon atoms and one or two ring heteroatoms independently selected from N, NH, O and S, said heterocyclyl is unbridged or bridged, said bridge being one or two carbon atoms, wherein said heterocyclyl is unsubstituted or is substituted with one or two R ３３ where R ３３ is halo, preferably F, and said heterocyclyl or halo-substituted heterocyclyl is independently R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２２ and R ２３ wherein R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２２ and R ２３ is, independently, q) unsubstituted or substituted with 1, 2 or 3 halo (C １～ C ４ ) alkyl-O-, r) unsubstituted or OH, —O—(C １ ~C ２ ) alkyl or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, s)HOC(O)-(CH ２ ) ｎ -、 t)H ３ C-C(O)(CH ２ ) ｎ -、 u)H ３ C-O-C(O)(CH ２ ) ｎ 、 v) = O w)R ２５ (R ２４ )N—, where R ２４ is H or unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ２ ) alkyl, and R ２５ is H or unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ２ ) alkyl, R ２５ (R ２４ ) N-, x) OH Selected from where n is 0 or 1, And here, - the substituents a) to h) of said heterocyclyl or halo-substituted heterocyclyl are not present on the ring atom where said heterocyclyl or halo-substituted heterocyclyl is attached to the remainder of the molecule, preferably when said heterocyclyl or halo-substituted heterocyclyl is a 6-membered ring it has 0 or 1 substituents selected from a) to h) in the meta or para position relative to the remainder of the molecule, preferably in the para position; The heterocyclyl is linked to the rest of the compound by R １ R double-bonded to a ring nitrogen atom or adjacent ring atom １ linked via a ring carbon atom; Or, R １ is heteroaryl, wherein said heteroaryl is a 5- or 6-membered fully unsaturated monocyclic group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S, preferably N, wherein the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1, and wherein said heteroaryl is unsubstituted or ２１ and R ３０ and is substituted by one or two substituents independently selected from ２１ and R ３０ (C １ ~C ２ ) alkyl, wherein (C １ ~C ２ ) alkyl is unsubstituted or substituted with 1, 2, or 3 halo, wherein preferably said alkyl or haloalkyl substituent is at least one of said R 1 to R 2 to R 3 to R 4 to R 5 to R 6 to R 7 to R 8 to R 9 to R 10 to R 11 to R 12 to R 13 to R 14 to R 15 to R 16 to R 17 to R 18 to R 19 to R 20 to R 21 １ The R adjacent to the ring atom １ 4. The compound of formula (I) according to claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, wherein no ring atom is present, and more preferably, when heteroaryl is a 6-membered ring, the alkyl or haloalkyl substituent is in the ring para position relative to the rest of the molecule.

5. R １ teeth, 【Chemistry 17】 Selected from: Alternatively, in each of the moieties above, 0 to 2 R ３３ There is a substituent, R ３３ is F; R １５ teeth, · Halo; ・R ２５ (R ２４ )N-(CH ２ ) ｎ where R ２４ is H or CH unsubstituted or substituted with 1, 2 or 3 halo ３ and R ２５ is H, (C １ ~C ４ ) alkyl-C(O)-, (C １ ~C ４ ) alkyl-O—C(O)— or unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, R ２５ (R ２４ )N-(CH ２ ) ｎ , or Azetidinyl or pyrrolidinyl, which is linked to the rest of the molecule via an N atom and is unsubstituted or substituted with one or two F. and R １６ is R ２５ (R ２４ ) N—, where R ２４ is H or (C １ ~C ２ ) alkyl, and R ２５ is H or unsubstituted or substituted with 1, 2 or 3 halo, especially F (C １ ~C ２ ) alkyl; R １７ is a halo; R １８ is a halo; R １９ teeth, ・Haro unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, ・(C １ ~C ４ ) alkyl-O—(CH ２ ) ｎ - and R ２０ is a halo; R ２１ is unsubstituted or substituted with 1, 2 or 3 F (C １ ~C ２ ) alkyl, R ２２ and R ２３ teeth, Each independently, unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, ・(C １ ~C ４ ) alkyl-O—(CH ２ ) ｎ -, ・HOC(O)-(H ２ ) ｎ -、 ・H ３ C-C(O)(CH ２ ) ｎ -、 ・(H ３ C) ３ C-O-C(O)(CH ２ ) ｎ - Selected from: where n is 0, 1 or 2; R ３０ is CH ３ That is, A compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

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

7. R １ teeth, 【Chemistry 19】 【Chemistry 20】 The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from:

8. R ２ Here is the part: 【Chemistry 21】 And, During the ceremony, R ６ is H, halo, unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl; R ８ is H, halo, and is unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl; R ９ is H, O-CH ３ , OH, CN, CH ３ and halo; R ２８ is SF ５ , halo, unsubstituted or substituted with 1, 2 or 3 halo (C １ ~C ４ ) alkyl, and C(O)H; X is C-R ７ and N; and R ７ is selected from H and halo; A compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. R ２ but, 【Chemistry 22】 Selected from: A compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. R ３ is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo and OH (C １ ~C ４ 10. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

11. R ４ teeth, CH ３ 、 【Chemistry 23】 Heteroaryl1, which is a 5-membered, fully unsaturated, monocyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S; heteroaryl2, which is a 9- or 10-membered fused bicyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein both rings are fully unsaturated or one ring is fully unsaturated and the other saturated or partially unsaturated, and said heteroatoms may be in one or both rings; -phenyl; or heterocyclyl2, which is a 5- or 6-membered fully saturated or partially unsaturated group consisting of ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S; is selected from wherein heteroaryl 1, heteroaryl 2, phenyl, and 【Chemistry 24】 each moiety selected from １０ , R １１ , R １２ , R １３ and R １４ and wherein each R １０ , R １１ , R １２ , R １３ and R １４ are each independently ・H, · Halo; unsubstituted or substituted with 1, 2 or 3 halo substituents (C １ ~C ４ ) alkyl, -O-(C １ ~C ２ ) substituted by alkyl or OH (C １ ~C ２ ) alkyl, -S-(C １ ~C ３ ) alkyl, -O-(C) is unsubstituted or substituted with 1, 2 or 3 halo substituents １ ~C ４ ) alkyl, ・OH, ・(C ３ ~C ５ ) cycloalkyl, unsubstituted or substituted with 1 or 2 halo; (C ３ ~C ５ ) cycloalkyl, -O-(C ３ ~C ５ ) cycloalkyl, ・-NR ３４ R ３５ and R ３４ and R ３５ is independent, ohhh, o (C １ ~C ４ ) alkyl (wherein the above (C １ ~C ４ ) alkyl is unsubstituted or is selected from the group consisting of OH or —O(C １ ~C ２ ) alkyl-substituted), o and where R ３４ and R ３５ can be taken together with the atoms to which they are attached to form an azetidine, pyrrolidinyl, or piperidine ring, wherein said azetidine, pyrrolidinyl, and piperidine are unsubstituted or ３ is replaced by -NR ３４ R ３５ , ・CN, ・-(C ２ ~C ４ ) alkenyl, ・-(C ２ ~C ４ ) alkynyl, ・=O, -C(O)H, and -C(O)(C １ ~C ４ ) alkyl The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, selected from:

12. R ４ at least one of OH, CN, ═O, or NH ２ The substituents are each heteroaryl 1, heteroaryl 2, phenyl, 【Chemistry 25】 as claimed in claim 1 or 11, provided that The remaining R １０ , R １１ , R １２ , R １３ and R １４ is defined as herein A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. R ４ but, 【Chemistry 26】 13. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from:

14. K 【Chemistry 27】 are connected by a single bond, and K is -CH ２ - and J is N, or a pharmaceutically acceptable salt thereof.

15. R ５ But independently, ・-(C １ ~C ４ ) alkyl, preferably methyl, and Two R on the same ring carbon atom ５ The substituents, together with the carbon atoms to which they are attached, form a group such that (C ３ ~C ４ ) may form a cycloalkylspiro ring or a 3- or 4-membered heterocyclylspiro ring, wherein said heterocyclylspiro ring contains ring carbon atoms and one ring heteroatom selected from O, N and S; ・K 【Chemistry 28】 When J is a carbon-nitrogen single bond, R on K and the adjacent carbon atom ５ The substituents are bonded to ring C: 【Chemistry 29】 may be formed, Here, ring C is fused (C ３ ~C ６ ) cycloalkyl rings, especially fused cyclobutyl rings, fused (C ３ ~C ６ ) heterocyclyl ring or fused phenyl ring, ３ ~C ６ ) heterocyclyl rings contain ring carbon atoms and one ring heteroatom selected from O, N, and S; Ring C is fused (C ３ ~C ６ ) cycloalkyl ring, particularly a fused cyclobutyl ring, ３ ~C ６ ) The cycloalkyl ring is unsubstituted or contains one or two R ４０ group, wherein the R ４０ teeth, ・(C １～ C ２ ) alkyl, wherein each (C １～ C ２ ) alkyl is independently unsubstituted or substituted with OH or 1, 2 or 3 halo; (C １ ~C ２ ) alkyl, ・Halo, especially F, Or two R on the same ring carbon atom ４０ The substituents, together with the carbon atoms to which they are attached, form a group such that (C ３ ~C ４ ) may form a cycloalkylspiro ring or a 3- or 4-membered heterocyclylspiro ring, wherein said heterocyclylspiro ring contains ring carbon atoms and one ring heteroatom selected from O, N and S; Or, two R on adjacent carbon atoms ４０ the substituents, together with the carbon atoms to which they are attached, form a fused cyclopropyl ring; Selected from: And K is -CH ２ -, and when J is N, two R ５ The substituents are bonded to (C １ ~C ３ ) may form an alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is one heteroatom selected from N and O, or is —CH ２ -O-CH ２ - is) The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, selected from:

16. R ５ But independently, ・-(C １ ~C ２ ) alkyl, preferably methyl, and ・K 【Transformation 30】 When J is a carbon-nitrogen single bond, R on K ５ The substituent and R on the adjacent carbon atom ５ The substituents are bonded to ring C: 【Chemistry 31】 Forming Here, ring C is fused (C ３ ~C ４ ) cycloalkyl rings, particularly fused cyclobutyl rings, ３ ~C ４ ) The cycloalkyl ring, particularly the fused cyclobutyl ring, is unsubstituted or contains one or two R ４０ substituted with a group, 16. The compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, selected from:

17. A compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein y is 0, 1, 2 or 3, preferably 0, 1 or 2.

18. The compound of formula (I) comprises the moiety: 【Chemistry 32】 In particular, A: 【Transformation 33】 More specifically, 【Transformation 34】 Or B: 【Chemistry 35】 or C: 【Transformation 36】 18. The compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, comprising:

19. Formula (I) is Formula 1a, and A is -C(O)-: 【Chemistry 37】 19. The compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:

20. A compound of formula (I) or a pharmaceutically acceptable salt thereof selected from the compounds exemplified herein.

21. A combination comprising a compound of formula (I) according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof and one or more additional therapeutically active agents.

22. 22. The combination of claim 21, wherein the additional therapeutically active agent is an anti-cancer agent.

23. Additional therapeutically active agents include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukera n (registered trademark)), cisplatin (Platinol (registered trademark)), cladribine (Leustatin (registered trademark)), cyclophosphamide (Cytoxan (registered trademark) or Neosar (registered trademark)), cytarabine, cytosine arabinoside (Cytosar-U (registered trademark)), cytarabine liposome injection (DepoCyt (registered trademark)), dacarbazine (DTIC-Dome (registered trademark)), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine (registered trademark)), daunorubicin citrate Rubicin liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (H ydrea (registered trademark)), idarubicin (Idamycin (registered trademark)), ifosfamide (IFEX (registered trademark)), irinotecan (Camptosar (registered trademark)), L-asparaginase (ELSPAR (registered trademark)), leucovorin calcium, melphalan (Alkeran (registered trademark)), 6-mercaptopurine (Purinethol (registered trademark)), methotrexate (Folex (registered trademark)), mitoxantrone (Novantrone (registered trademark)), Mylotarg, paclitaxel (Taxol (registered trademark)),22. The combination according to claim 21, wherein the chemotherapeutic agent is selected from Phoenix (Yttrium 90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®) and vinorelbine (Navelbine®), in particular irinotecan.

24. 22. The combination of claim 21, wherein the additional therapeutically active agent is a PD-1 inhibitor.

25. Additional therapeutically active agents include PDR001 (Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co.), and pembrolizumab (Merck & Co.). Co), pidilizumab (CureTech), MEDI0680 (Medimmune), cemiplimab (REGN2810, Regeneron), dostallimab (TSR-042, Tesaro), PF-06801591 (Pfizer), tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), balstilimab (AGEN2035, Agenus), sintilimab (InnoVent), toripalimab (Shanghai Junshi Bioscience), camrelizumab (Jiangsu Hengrui Medicine) Co.), and AMP-224 (Amplimmune), in particular PDR001, tislelizumab, and pembrolizumab, more particularly tislelizumab.

26. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

27. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 for use as a medicine.

28. 28. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, for the use according to claim 27, wherein the use is for the treatment of a disease treated by WRN inhibition.

29. 28. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, for the use according to claim 27, wherein said use is for the treatment of cancer.

30. 29. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, for use according to claim 29, wherein the cancer is characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR).

31. 31. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, for use according to claim 30, wherein the cancer characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) is selected from colorectal cancer, gastric cancer, and endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer, and ovarian cancer.

32. 32. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, for use according to claim 31, wherein the cancer characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) is selected from colorectal cancer, gastric cancer, and endometrial cancer.

33. 31. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, for use according to claim 30, wherein the cancer characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) is selected from endometrial carcinoma, colon adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, esophageal carcinoma, breast cancer, renal clear cell carcinoma, and ovarian serous cystadenocarcinoma.

34. 21. A method of modulating WRN activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

35. 21. A method of treating a disorder or disease that can be treated by inhibiting WRN in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

36. 21. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

37. 21. A method of treating cancer in a subject, comprising administering a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized by microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR).

38. 21. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

39. Use of a compound of formula (I) or a salt thereof according to any one of claims 1 to 20 as a research chemical, chemical probe or tool compound.

40. A process or intermediate as defined herein.

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