Bicyclic heterocycles and their use as WRN inhibitors

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein R1, R2, R3, R4, R5, R26, R27, R, M, L, W, T, V, Y, K, J, A and y are as described in the invention, therapeutic use, research use and methods for manufacturing the compounds of the invention. The invention further provides a combination of a pharmacologically active agent and a pharmaceutical composition. # imgabs0 #

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 diseases using the compounds, particularly in the treatment of cancer, and particularly in the treatment of cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) (including colorectal cancer, gastric cancer or endometrial cancer), their use as research chemicals, and the synthesis of the compounds, intermediates, formulations and combinations. Background Art

[0002] Deficiency in DNA mismatch repair is a common initiating event in cancer development, occurring in 10%-30% of colorectal, endometrial, ovarian, and gastric cancers (Aaltonen, L.A. 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 caused by loss of mismatch repair (MMR) capacity have a high mutational burden and frequent deletion and insertion events in repetitive DNA sequences, a phenotype known as microsatellite instability (MSI). Although progress has been made in the treatment of high microsatellite instability (MSI-H) cancers, and pembrolizumab (anti-PD1) treatment has been shown to significantly prolong progression-free survival compared to chemotherapy when used as first-line treatment for MSI-H-dMMR metastatic colorectal cancer, leading to the recent approval of pembrolizumab as first-line treatment for these cancers, there remains a significant unmet medical need in CRC and other MSI-H indications (André 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 in a large number of cell lines, including a screen by Novartis AG against 398 cell lines in the Cancer Cell Line Encyclopedia (CCLE) (McDonald E.R. et al., Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening. Cell 170(3):577-592 (2017)) have identified Werner syndrome RecQ helicase (WRN) as selectively essential for the survival of cell lines with defective mismatch repair that have become MSI-H (Behan, F.M. et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 568, 511-516 (2019); Chan, E.M. et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 568, 551-556 (2019); Kategaya, L., Perumal, S.K., Hager, J.H. and Belmont, L.D. Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability. iScience 13, 488-497 (2019); Lieb, S. et al. Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells. eLife 8, e43333 (2019)). WRN is synthetically lethal with MSI cancers.Depletion of WRN results in anti-proliferative effects and activation of multiple DNA damage signaling markers, induces cell cycle arrest and apoptosis in MMR cancer models, but does not induce cell cycle arrest and apoptosis in cancer cells with an intact MMR pathway. These findings suggest that WRN provides a DNA repair and maintenance function that is essential for cell survival in MSI cancers. Recently, the mechanism of WRN dependence has been elucidated. It has been proposed that dinucleotide TA repeats are selectively unstable and undergo large-scale amplification in MSI cells. These amplified TA repeats form secondary DNA structures that require unwinding by the WRN helicase (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 inhibition of the WRN helicase), the amplified TA repeats in MSI cells undergo nuclease cleavage and chromosomal breaks. Thus, inhibition of the WRN helicase is an attractive strategy for treating mismatch repair-deficient cancers. SUMMARY OF THE INVENTION

[0003] There remains a need for new treatments and therapies for treating cancer, and particularly for treating cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), including colorectal cancer, gastric cancer or endometrial cancer. The present invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, which compounds are inhibitors of Werner syndrome RecQ DNA helicase (WRN). The present invention further provides methods of treating, preventing or ameliorating a disease or disorder, which methods comprise 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:

[0005]

[0006] wherein

[0007] R, M, W, L, V and T are independently selected from C, CH and N,

[0008] to form sub-formulas 1a, 1b, 1c, 1d, 1e and 1f:

[0009]

[0010] A is linker-C(O)-;

[0011] Y is N, C or CH;

[0012] y is 0, 1, 2, 3 or 4;

[0013] Y means that when Y is CH, Y is connected to the adjacent carbon atom via a single bond, or when Y is C, Y is connected to the adjacent atom via a double bond, and when Y is a single bond, Y is an unsubstituted or OH- or F-substituted carbon;

[0014] When Y is N, Y is a single bond;

[0015] K means that K is connected to the adjacent atom via a single bond or a double bond;

[0016] Wherein:

[0017] When K is a double bond, Y is a single bond, K is CH and J is C,

[0018] Or

[0019] When K is a single bond, K is selected from -CH2-, -CH2CH2-, -NH- and a bond (to form a 5-membered ring: ), and J is N;

[0020] R5 is independently selected from:

[0021] · -(C 1- C4) alkyl,

[0022] · -(C 3- C5) cycloalkyl,

[0023] · And two R5 substituents on the same ring carbon atom together with the carbon atom to which they are attached can be connected to form a (C 3- C4) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N and S,

[0024] · When K J is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom can be connected to form a ring C:

[0025]

[0026] wherein ring C is a fused (C3-C6) cycloalkyl ring, a fused (C3-C6) heterocyclic ring or a fused benzene ring, wherein the fused (C3-C6) heterocyclic ring contains ring carbon atoms and one ring heteroatom selected from O, N and S,

[0027] and wherein when ring C is a fused (C3-C6) cycloalkyl ring, the fused (C3-C6) cycloalkyl ring is unsubstituted or substituted with 1 or 2 R 40 groups, wherein the R 40 is selected from:

[0028] · (C 1- C2)alkyl, wherein each (C 1- C2)alkyl is independently unsubstituted or substituted with OH or 1, 2 or 3 halogens,

[0029] · halogen, especially F,

[0030] · or two R 40 substituents on the same ring carbon atom together with the carbon atom to which they are attached may be linked to form a (C 3- C4)cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains ring carbon atoms and one ring heteroatom selected from O, N and S;

[0031] · or two R 40 substituents on adjacent carbon atoms are linked together with the carbon atoms to which they are attached to form a fused cyclopropyl ring;

[0032] · and wherein when K is -CH2- and J is N, two R5 substituents may be linked to form a (C1-C3) alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is a heteroatom selected from N and O or is -CH2-O-CH2-;

[0033] R1 is:

[0034] cycloalkenyl, wherein the cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms, and the cycloalkenyl is unsubstituted or substituted with 1, 2, 3 or 4, preferably 1 or 2 R 33 substituents, wherein R 33 is halogen, and wherein the cycloalkenyl or halogen-substituted cycloalkenyl is substituted with 0, 1 or 2 R 15 substituents, or the cycloalkenyl or halogen-substituted cycloalkenyl has 2 substituents on the same ring carbon atom that are linked to form an oxetane spiro ring,

[0035] Or R1 is a heterocyclic group, wherein the heterocyclic group is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O, and S, and wherein the heterocyclic group is unbridged or bridged, and the bridge is 1 or 2 carbon atoms, and wherein the heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4, preferably 1 or 2, R 33 substituents, where R 33 is halo, and wherein the heterocyclic group or halo-substituted heterocyclic group is substituted by 0, 1, or 2 substituents independently selected from R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 ;

[0036] Or the heterocyclic group or halo-substituted heterocyclic group is fused to a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted or substituted by 1, 2, or 3 F;

[0037] Or the heterocyclic group or halo-substituted heterocyclic group has 2 substituents on the same ring carbon atom that forms a cyclopropyl spiro ring or a tetrahydrofuran spiro ring;

[0038] Or the heterocyclic group or halo-substituted heterocyclic group is fused to a (C3-C5) heterocycloalkyl ring, wherein the (C3-C5) heterocycloalkyl ring contains ring carbon atoms and 1 ring O atom;

[0039] Or R1 is a heteroaryl, wherein the 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, preferably wherein the total number of ring S atoms does not exceed 1, and preferably the total number of ring O atoms does not exceed 1,

[0040] and wherein the heteroaryl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from R 21 and R 30 , where R 21 and R 30 are independently selected from halo and (C1-C4) alkyl, wherein the (C1-C4) alkyl is unsubstituted or substituted by 1, 2, or 3 halo;

[0041] Or R1 is a phenyl, wherein the phenyl is unsubstituted or substituted by 1, 2, 3, or 4, preferably 1 or 2, R 33 substituents, where R 33 is halo, and wherein the phenyl or halo-substituted phenyl is substituted by 0, 1, or 2 R 15 substituents;

[0042] Or R1 is a (C2-C4) alkynyl or (C2-C4) alkenyl group, wherein the (C2-C4) alkynyl and (C2-C4) alkenyl groups are unsubstituted or substituted with (C1-C4) alkyl-O-C(O)- or morpholinyl;

[0043] R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 are each independently selected from:

[0044] · Halo

[0045] · Unsubstituted or substituted with 1, 2 or 3 halos of (C 1- C4) alkyl-O-(CH2) n ;

[0046] · Unsubstituted or substituted with OH, -O-(C1-C2) alkyl or 1, 2 or 3 halos of (C1-C4) alkyl,

[0047] · HOC(O)-(CH2) n -,

[0048] · (C1-C4) alkyl-C(O)(CH2) n -

[0049] · (E)-cyclooct-4-en-1-yl-O-C(O)-

[0050] · (C1-C4) alkyl-O-C(O)(CH2) n

[0051] · =O

[0052] · Azetidinyl or pyrrolidinyl, wherein the azetidinyl and pyrrolidinyl are attached to the rest of the molecule via the N atom and are each unsubstituted or substituted with 1 or 2 Fs,

[0053] · R 25 (R 24 )N-(CH2) n wherein R 24 is H or unsubstituted or substituted with 1, 2 or 3 halos of (C1-C4) alkyl, and R 25 is:

[0054] οH

[0055] ο (C1-C4) alkyl - C(O)(CH2) n -, where the (C1-C4) alkyl of the (C1-C4) alkyl - C(O)(CH2) n - is unsubstituted or substituted with halo or -N3,

[0056] ο (C1-C4) alkyl - O - C(O)(CH2) n- ,

[0057] ο (C1-C4) alkyl that is unsubstituted or substituted with 1, 2, or 3 halo, or

[0058] ο (E)-cyclooct-4-en-1-yl - O - C(O)-,

[0059] ·OH

[0060] where n is 0, 1, or 2,

[0061] R 26 is CH3, H, or deuterium;

[0062] R 27 is CH3, H, or deuterium;

[0063] Or R 26 and R 27 together with the carbon atom to which they are attached form a cyclopropyl ring;

[0064] R2 is the following moiety:

[0065]

[0066] R6 is selected from:

[0067] ·H,

[0068] ·halo,

[0069] ·(C1-C4) alkyl that is unsubstituted or substituted with 1, 2, or 3 halo,

[0070] ·(C3-C5) cycloalkyl that is unsubstituted or substituted with 1, 2, or 3 halo,

[0071] ·-O-(C1-C4) alkyl that is unsubstituted or substituted with 1, 2, or 3 halo,

[0072] ·OH, and

[0073] ·CN;

[0074] R8 is selected from H, halo, and (C1-C4) alkyl that is unsubstituted or substituted with 1, 2, or 3 halo,

[0075] R9 is selected from H, O-CH3, OH, CN, CH3, and halogen;

[0076] R 28 is selected from:

[0077] · SF5,

[0078] · H,

[0079] · -C(O)H,

[0080] · halogen,

[0081] · (C1-C4) alkyl which is unsubstituted or substituted by 1, 2, or 3 halogens,

[0082] · (C1-C4) alkynyl,

[0083] · (C1-C4) alkenyl,

[0084] · (C3-C5) cycloalkyl which is unsubstituted or substituted by 1, 2, or 3 halogens, and

[0085] · OCF3;

[0086] X is selected from C-R7 and N, where R7 is H, CF3, or halogen, or R7 can be linked with R 28 or R6 together with the atoms to which they are attached form a fused (C4-C6) cycloalkyl ring, where the fused (C4-C6) cycloalkyl ring is unsubstituted or substituted by 1, 2, or 3 halogens,

[0087] or

[0088] R2 is selected from:

[0089]

[0090] where

[0091] R 31 is selected from H, halogen, and CH3,

[0092] R 32 is selected from H, halogen, and CH3,

[0093] R3 is:

[0094] · cyclopropyl,

[0095] · O-CH3,

[0096] · N(CH3)2,

[0097] · S-CH3,

[0098] ·(C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo and OH;

[0099] R4 is selected from:

[0100] -(C1-C4) alkyl which is unsubstituted or substituted by NH2;

[0101] -O-CH2 phenyl;

[0102] -O-CH2CH2 phenyl;

[0103] -NH-NH-C(O)-CF3;

[0104] -heteroaryl 1, wherein the heteroaryl 1 is a 5-membered 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;

[0105] -heteroaryl 2, wherein the heteroaryl 2 is a 9-membered 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, and wherein both rings are fully unsaturated, or one ring is fully unsaturated and the other is saturated or partially unsaturated, and wherein the heteroatoms may be in one or both rings;

[0106] -phenyl;

[0107] -heterocyclic group 2, wherein the heterocyclic group 2 is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S;

[0108] and

[0109]

[0110] wherein heteroaryl 1, heteroaryl 2 and phenyl are each substituted by 1, 2 or 3 substituents independently selected from R 10 、R 11 、R 12 、R 13 and R 14 wherein R 10 、R 11 、R 12 、R 13 and R 14 are each independently selected from:

[0111] ·H,

[0112] ·halo,

[0113] ·(C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents,

[0114] · (C1-C2) alkyl substituted by -O-(C1-C2) alkyl or OH,

[0115] · -S-(C1-C3) alkyl,

[0116] · -O-(C1-C4) alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents,

[0117] · OH,

[0118] · (C3-C5) cycloalkyl, wherein said (C3-C5) cycloalkyl is unsubstituted or substituted by 1 or 2 halo substituents,

[0119] · -O-(C3-C5) cycloalkyl,

[0120] · -NR 34 R 35 , wherein R 34 and R 35 are independently selected from:

[0121] οH,

[0122] ο (C1-C4) alkyl, wherein said (C1-C4) alkyl is unsubstituted or substituted by OH or -O(C1-C2) alkyl,

[0123] ο and wherein R 34 and R 35 may together with the atoms to which they are attached form an azetidine, pyrrolidine or piperidine ring, wherein said azetidine, pyrrolidine and piperidine are unsubstituted or substituted by CH3;

[0124] · CN,

[0125] · -(C2-C4) alkenyl,

[0126] · -(C2-C4) alkynyl,

[0127] · =O

[0128] · -C(O)H, and

[0129] · -C(O)(C1-C4) alkyl;

[0130] provided that R4 is not:

[0131]

[0132] wherein

[0133] R 10 、R 11 、R 12 、R 13 and R14 Independently selected from:

[0134] · H,

[0135] · halo,

[0136] · (C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents,

[0137] · (C1-C2)alkyl substituted with -O-(C1-C2)alkyl or OH,

[0138] · -S-(C1-C3)alkyl,

[0139] · -O-(C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents,

[0140] · OH,

[0141] · (C3-C5)cycloalkyl, wherein the (C3-C5)cycloalkyl is unsubstituted or substituted with 1 or 2 halo substituents,

[0142] · -O-(C3-C5)cycloalkyl,

[0143] · -NR 34 R 35 , wherein R 34 and R 35 are independently selected from:

[0144] οH,

[0145] ο(C1-C4)alkyl, wherein the (C1-C4)alkyl is unsubstituted or substituted with OH or -O(C1-C2)alkyl,

[0146] οand wherein R 34 and R 35 may together with the atoms to which they are attached form an azetidine, pyrrolidine or piperidine ring, wherein the azetidine, pyrrolidine and piperidine are unsubstituted or substituted with CH3;

[0147] · CN,

[0148] · -(C2-C4)alkenyl,

[0149] · -(C2-C4)alkynyl,

[0150] · -C(O)H, and

[0151] · -C(O)(C1-C4)alkyl;

[0152] And

[0153] * represents the point of attachment.

[0154] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable carriers.

[0155] In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, which comprises a compound of the present invention and one or more therapeutic active agents.

[0156] In another aspect, the present invention provides a compound of the present invention for use as a medicament, particularly for the treatment of disorders or diseases that can be treated by WRN inhibition.

[0157] In another aspect, the present invention provides a compound of the present invention for the treatment of cancer, particularly wherein the cancer is characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

[0158] 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, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention.

[0159] In another aspect, the present invention provides a method for treating cancer in a subject, more particularly wherein the cancer is characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention.

[0160] In another aspect, the present invention provides the use of a compound of the present invention in the preparation of a medicament for the treatment of a disorder or disease that can be treated by WRN inhibition.

[0161] In another aspect, the present invention provides the research use of a compound of the present invention. Detailed Description

[0162] Accordingly, the present invention provides a compound having the formula (I):

[0163]

[0164] wherein 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.

[0165] Unless otherwise indicated, the term "compound of the invention" refers to compounds having formula (I), compounds having sub-formulas thereof and exemplary compounds, and salts thereof, as well as all zwitterions, stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions) and inherently formed moieties.

[0166] Various (enumerated) embodiments of the invention are described herein. It should be recognized that the features specified in each embodiment can be combined with other specified features to provide additional embodiments of the invention.

[0167] Example 1. A compound having formula (I) or a pharmaceutically acceptable salt thereof, as described above.

[0168] Example 2. The compound having formula (I) or a pharmaceutically acceptable salt thereof according to Example 1, wherein when R1 is a ring, then:

[0169] · Each R1 ring atom adjacent to the R1 ring atom connecting the R1 ring to the remainder of the molecule is independently unsubstituted or substituted only by halo, particularly independently unsubstituted or substituted by one F substituent, and

[0170] · Preferably, the R1 ring is connected to the remainder of the molecule via an R1 ring nitrogen atom or an R1 ring carbon atom double-bonded to an adjacent R1 ring atom.

[0171] Example 3. The compound having formula (I) or a pharmaceutically acceptable salt thereof according to Example 1 or 2, wherein R1 is:

[0172] cycloalkenyl, wherein the cycloalkenyl is a partially unsaturated monocyclic moiety containing 5 or 6 ring carbon atoms, and the cycloalkenyl is unsubstituted or substituted by 1, 2, 3 or 4, preferably 1 or 2 R 33 substituents, where R 33 is halo, and wherein the cycloalkenyl or halo-substituted cycloalkenyl is substituted by 0, 1 or 2 R 15 substituents, preferably 1 substituent, or the cycloalkenyl or halo-substituted cycloalkenyl has 2 substituents on the same ring carbon atom that forms an oxetanyl spiro ring,

[0173] or R1 is a heterocyclic group, wherein the heterocyclic group is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, NH, O and S, and wherein the heterocyclic group is unbridged or bridged, and the bridge is 1 or 2 carbon atoms, and wherein the heterocyclic group is unsubstituted or substituted by 1, 2, 3 or 4, such as 1, 2 or 3, particularly 1 or 2 R 33 substituents, where R 33is halogenated, and wherein the heterocyclic group or halogenated heterocyclic group is substituted with 0, 1 or 2 substituents independently selected from R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 , preferably 0 or 1 substituent,

[0174] or the heterocyclic group or halogenated heterocyclic group is fused to a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted or substituted with 1, 2 or 3 Fs,

[0175] or the heterocyclic group or halogenated heterocyclic group has 2 substituents on the same ring carbon atom that forms a tetrahydrofuranyl spiro ring,

[0176] or R1 is a heteroaryl, wherein the 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 the heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R 21 and R 30 , wherein R 21 and R 30 are independently selected from halogenated and (C1-C4) alkyl, wherein the (C1-C4) alkyl is unsubstituted or substituted with 1, 2 or 3 halogenated groups,

[0177] or R1 is a phenyl, wherein the phenyl is unsubstituted or substituted with 1, 2, 3 or 4, preferably 1 or 2 R 33 substituents, wherein R 33 is halogenated, and wherein the phenyl or halogenated phenyl is substituted with 0 or 1 R 15 substituent,

[0178] or R1 is an unsubstituted or (C1-C4) alkyl-O-C(O)-substituted (C2-C4) alkynyl;

[0179] and R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 are each independently selected from:

[0180] · halogenated

[0181] · Unsubstituted or substituted with 1, 2 or 3 halogens, (C 1- C4)alkyl-O-(CH2) n ;

[0182] · Unsubstituted or substituted with OH, -O-(C1-C2)alkyl or 1, 2 or 3 halogens, (C1-C4)alkyl,

[0183] · HOC(O)-(CH2) n -,

[0184] · H3C-C(O)(CH2) n -,

[0185] · (C1-C4)alkyl-O-C(O)(CH2) n ,

[0186] · =O

[0187] · Azetidinyl or pyrrolidinyl, wherein the azetidinyl and pyrrolidinyl are attached to the remainder of the molecule via an N atom and are each unsubstituted or substituted with 1 or 2 Fs,

[0188] · R 25 (R 24 )N-(CH2) n , wherein R 24 is H or unsubstituted or substituted with 1, 2 or 3 halogens, (C1-C2)alkyl, R 25 is H, unsubstituted or substituted with 1, 2 or 3 halogens, (C1-C4)alkyl-C(O)-, (C1-C4)alkyl-O-C(O)-, or (C1-C4)alkyl,

[0189] · OH

[0190] wherein n is 0, 1 or 2,

[0191] Example 4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1, 2 or 3, wherein R1 is:

[0192] Cycloalkenyl, wherein the cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms and the cycloalkenyl is unsubstituted or substituted with 1 or 2 R 33 substituents, wherein R 33 is halogen, preferably F, and wherein the cycloalkenyl or halogen-substituted cycloalkenyl is substituted with 0 or 1 R 15 substituent, wherein R 15 is selected from:

[0193] a) Unsubstituted or substituted with 1, 2 or 3 halogens, (C 1-C2) alkyl-O-;

[0194] b) (C1-C2)alkyl, unsubstituted or substituted by 1, 2 or 3 halo;

[0195] c) HOC(O)-(CH2) n -

[0196] d) H3C-C(O)(CH2) n -

[0197] e) H3C-O-C(O)(CH2) n ,

[0198] f) =O, and

[0199] g) R 25 (R 24 )N-, H, where R 24 is H or (C1-C2)alkyl, unsubstituted or substituted by 1, 2 or 3 halo, R 25 is H or (C1-C2)alkyl, unsubstituted or substituted by 1, 2 or 3 halo,

[0200] n is 0 or 1,

[0201] where

[0202] · the R 15 substituents a) to g) of the cycloalkenyl or halo-substituted cycloalkenyl are not present on a ring atom adjacent to the ring atom connecting the cycloalkenyl or halo-substituted cycloalkenyl to the remainder of the molecule, and preferably, the cycloalkenyl or halo-substituted cycloalkenyl is a 6-membered ring, where 1 R 15 substituent is in the ring para position relative to the remainder of the molecule; and

[0203] · the cycloalkenyl or halo-substituted cycloalkenyl is attached to the remainder of the compound via a R1 ring carbon atom double-bonded to an adjacent R1 ring carbon atom;

[0204] or R1 is a heterocyclic group, where the heterocyclic group is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, NH, O and S, and where the heterocyclic group is unbridged or bridged, and the bridge is 1 or 2 carbon atoms, where the heterocyclic group is unsubstituted or substituted by 1 or 2 R 33 substituents, where R 33 is halo, preferably F, and where the heterocyclic group or halo-substituted heterocyclic group is substituted by 0 or 1 independently selected from R 15 , R 16 , R 17 , R 18 , R19 and R 20 and R 22 and R 23 are substituted by substituents of R 15 and R 16 and R 17 and R 18 and R 19 and R 20 and R 22 and R 23 are independently selected from:

[0205] a) (C 1- C4) alkyl-O- which is unsubstituted or substituted by 1, 2 or 3 halogen atoms;

[0206] b) (C1-C4) alkyl which is unsubstituted or substituted by OH, -O-(C1-C2) alkyl or 1, 2 or 3 halogen atoms,

[0207] c) HOC(O)-(CH2) n -,

[0208] d) H3C-C(O)(CH2) n -,

[0209] e) H3C-O-C(O)(CH2) n ,

[0210] f) =O

[0211] g) R 25 (R 24 )N-, where R 24 is H, (C1-C2) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, R 25 is H, (C1-C2) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms,

[0212] h) OH

[0213] where n is 0 or 1,

[0214] and wherein:

[0215] · The substituents a) to h) of the heterocyclic group or halogen-substituted heterocyclic group are not present on the ring atoms adjacent to the ring atoms connecting the rest of the molecule to the heterocyclic group or halogen-substituted heterocyclic group, and preferably, when the heterocyclic group or halogen-substituted heterocyclic group is a 6-membered ring, it has 0 or 1 substituent selected from a) to h), which is in the meta or para position, preferably the para position, relative to the rest of the molecule; and

[0216] · The heterocyclic group is attached to the remainder of the compound via an R1 ring nitrogen atom or an R1 ring carbon atom double-bonded to an adjacent ring atom;

[0217] Or R1 is heteroaryl, wherein the 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 the heteroaryl is unsubstituted or substituted by 1 or 2 substituents independently selected from R 21 and R 30 , wherein R 21 and R 30 are independently selected from (C1-C2) alkyl, and the (C1-C2) alkyl is unsubstituted or substituted by 1, 2 or 3 halogens, and wherein preferably, the alkyl or haloalkyl substituent is not present on the R1 ring atom adjacent to the R1 ring atom connecting the heteroaryl to the remainder of the molecule, and more preferably, when the heteroaryl is a 6-membered ring, the alkyl or haloalkyl substituent is in the ring para position relative to the remainder of the molecule.

[0218] Example 5. A compound of formula (I) according to any one of Examples 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from:

[0219]

[0220]

[0221] Alternatively, there are 0-2 R 33 substituents in each of the above parts,

[0222] R 33 is F;

[0223] R 15 is:

[0224] · Halo,

[0225] · R 25 (R 24 )N-(CH2) n , wherein R 24 is H or CH3 unsubstituted or substituted by 1, 2 or 3 halogens, R 25 is H, (C1-C4) alkyl-C(O)-, (C1-C4) alkyl-O-C(O)-, or (C1-C4) alkyl unsubstituted or substituted by 1, 2 or 3 halogens, or

[0226] · Azetidinyl or pyrrolidinyl, wherein the azetidinyl and pyrrolidinyl are linked to the remainder of the molecule via an N atom and are unsubstituted or substituted with 1 or 2 F atoms,

[0227] 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 which is unsubstituted or substituted with 1, 2 or 3 halogen atoms, especially F atoms;

[0228] R 17 is halogenated;

[0229] R 18 is halogenated;

[0230] R 19 is:

[0231] · halogenated

[0232] · (C1-C4) alkyl which is unsubstituted or substituted with 1, 2 or 3 halogen atoms,

[0233] · (C1-C4) alkyl-O-(CH2) n -;

[0234] R 20 is halogenated;

[0235] R 21 is (C1-C2) alkyl which is unsubstituted or substituted with 1, 2 or 3 F atoms;

[0236] R 22 and R 23 are each independently selected from:

[0237] · (C1-C4) alkyl which is unsubstituted or substituted with 1, 2 or 3 halogen atoms,

[0238] · (C1-C4) alkyl-O-(CH2) n -

[0239] · HOC(O)-(CH2) n -

[0240] · H3C-C(O)(CH2) n -

[0241] · (H3C)3C-O-C(O)(CH2) n -;

[0242] · where n is 0, 1 or 2;

[0243] and

[0244] R 30 is CH3.

[0245] Example 6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 5, wherein R1 is selected from:

[0246]

[0247] R 15 is F;

[0248] R 16 is R 25 (R 24 )N-;

[0249] R 17 is F;

[0250] R 18 is F;

[0251] R 19 is F;

[0252] R 20 is F;

[0253] R 21 is CH3;

[0254] R 22 is CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, (H3C)3C-O-C(O)-;

[0255] R 23 is CF3, CHF2CH2-, (H3C)3C-O-C(O)-;

[0256] R 24 is CH3; and

[0257] R 25 is CHF2CH2-.

[0258] Example 7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 6, wherein R1 is selected from:

[0259]

[0260]

[0261] Example 8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 7, wherein R1 is selected from:

[0262]

[0263] Example 9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 8, wherein R1 is selected from:

[0264]

[0265] Example 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 9, wherein R1:

[0266]

[0267] Example 11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 10, wherein R2 is the following moiety:

[0268]

[0269] wherein

[0270] R6 is selected from H, halo, (C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo;

[0271] R8 is selected from H, halo, (C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo;

[0272] R9 is selected from H, O-CH3, OH, CN, CH3 and halo;

[0273] R 28 is selected from SF5, halo, (C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo, and -C(O)H;

[0274] X is selected from C-R7 and N; and

[0275] R7 is selected from H and halo.

[0276] Example 12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 11, wherein R2 is the following moiety:

[0277]

[0278] R6 is selected from H, Cl, CH3, F and Br;

[0279] R8 is selected from H, Cl, F and CF3;

[0280] R9 is selected from H, CH3 and Cl;

[0281] R28 Selected from CF3, CF2H, -CH2CH3, Cl, SF5, Br, and -C(O)H;

[0282] X is selected from C-R7 and N; and

[0283] R7 is selected from H and F.

[0284] Example 13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 12, wherein R 28 is selected from CF3, CHF2, Cl, -CH2CH3, CH3, SF5, and Br.

[0285] Example 14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 13, wherein R 28 is selected from CF3, Cl, and SF5, especially CF3.

[0286] Example 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 14, wherein X is CR7.

[0287] Example 16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 15, wherein R7 is H.

[0288] Example 17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 16, wherein R6 is H, F, Cl, or CH3.

[0289] Example 18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 17, wherein R6 is Cl.

[0290] Example 19. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 18, wherein R8 is F, CF3, or H.

[0291] Example 20. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 19, wherein R8 is H.

[0292] Example 21. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 20, wherein R9 is H.

[0293] Example 22. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 21, wherein R2 is selected from:

[0294]

[0295] Example 23. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 22, wherein R3 is an unsubstituted (C1-C4) alkyl or an (C1-C4) alkyl substituted with 1, 2 or 3 substituents independently selected from halo and OH.

[0296] Example 24. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 23, wherein R3 is an unsubstituted (C1-C2) alkyl or an (C1-C2) alkyl substituted with 1, 2 or 3 substituents independently selected from halo, OH, preferably -CH2CH3 or CH3, more preferably -CH2CH3.

[0297] Example 25. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 24, wherein R3 is selected from -CH3, -CH2CH3, -CH(CH3)2, and cyclopropyl.

[0298] Example 26. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 25, wherein R3 is -CH3 or -CH2-CH3.

[0299] Example 27. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 26, wherein R 26 is H.

[0300] Example 28. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 27, wherein R 27 is H.

[0301] Example 29. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 28, wherein R4 is selected from:

[0302] CH3,

[0303]

[0304] - heteroaryl1, wherein the heteroaryl1 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;

[0305] -Hetaryl 2, wherein said Hetaryl 2 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, and wherein both rings are completely unsaturated, or one ring is completely unsaturated and the other is saturated or partially unsaturated, and wherein said heteroatoms may be in one or both rings;

[0306] -phenyl; or

[0307] -heterocyclic group 2, wherein said heterocyclic group 2 is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S;

[0308] wherein Hetaryl 1, Hetaryl 2, phenyl, and the moieties selected from:

[0309]

[0310] are each independently substituted with 1, 2 or 3 substituents, particularly 1 or 2 substituents, selected from R 10 、R 11 、R 12 、R 13 and R 14 wherein each R 10 、R 11 、R 12 、R 13 and R 14 is independently selected from:

[0311] ·H,

[0312] ·halo,

[0313] ·(C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents,

[0314] ·(C1-C2)alkyl substituted with -O-(C1-C2)alkyl or OH,

[0315] ·-S-(C1-C3)alkyl,

[0316] ·-O-(C1-C4)alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents,

[0317] ·OH,

[0318] ·(C3-C5)cycloalkyl, wherein said (C3-C5)cycloalkyl is unsubstituted or substituted with 1 or 2 halo,

[0319] ·-O-(C3-C5)cycloalkyl,

[0320] ·-NR 34 R35 , wherein R 34 and R 35 are independently selected from:

[0321] οH,

[0322] ο (C1-C4) alkyl, wherein the (C1-C4) alkyl is unsubstituted or substituted by OH or -O(C1-C2) alkyl,

[0323] ο and wherein R 34 and R 35 may be joined together with the atoms to which they are attached to form an azetidine, pyrrolidine or piperidine ring, wherein the azetidine, pyrrolidine and piperidine are unsubstituted or substituted by CH3;

[0324] ·CN,

[0325] ·-(C2-C4) alkenyl,

[0326] ·-(C2-C4) alkynyl,

[0327] ·=O

[0328] ·-C(O)H, and

[0329] ·-C(O)(C1-C4) alkyl;

[0330] Example 30. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 29, wherein R4 is as described in Example 1 and other examples herein, provided that at least one of the OH, CN, =O, or NH2 substituents is present on each heteroaryl 1, heteroaryl 2, phenyl, on,

[0331] and the remaining R 10 , R 11 , R 12 , R 13 and R 14 are as defined herein.

[0332] Example 31. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 30, wherein R4 is as described in Example 1 and other examples herein, provided that one OH substituent is present on each heteroaryl 1, heteroaryl 2, phenyl, on,

[0333] and the remaining R 10 , R 11 , R 12 , R 13 and R 14As defined herein.

[0334] Example 32. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, wherein R4 is as described in Example 1 and other examples herein, provided that one OH substituent is present on each heteroaryl 1, heteroaryl 2, phenyl, 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 R 13 and R 14 are as defined herein.

[0335] Example 33. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 32, wherein R4 is as described in Example 1 and other examples herein, and each R 10 R 11 R 12 R 13 and R 14 is independently selected from:

[0336] · H,

[0337] · halo (preferably F),

[0338] · (C1-C2)alkyl (preferably CH3), the (C1-C2)alkyl being unsubstituted or substituted with 1, 2 or 3 halos,

[0339] · =O,

[0340] · CN,

[0341] · NH2, and

[0342] · -O-(C1-C2)alkyl unsubstituted or substituted with 1, 2 or 3 halos.

[0343] Example 34. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 33, wherein R4 is selected from:

[0344]

[0345]

[0346] Example 35. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 34, wherein Y is N and Y is Y connected by a single bond.

[0347] Example 36. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 35, wherein K is K linked by a single bond, and K is selected from -CH2-, -CH2CH2-, -NH- and a bond (to form a 5-membered ring: ), and J is N.

[0348] Example 37. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 36, wherein K is K linked by a single bond, K is -CH2- and J is N.

[0349] Example 38. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 37, wherein R5 is independently selected from:

[0350] · -(C 1- C4)alkyl, preferably methyl,

[0351] · and wherein two R5 substituents on the same ring carbon atom together with the carbon atom to which they are attached may be linked to form a (C 3- C4)cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N and S,

[0352] · when K J is a carbon-nitrogen single bond, the R5 substituents on K and on the adjacent carbon atom may be linked to form a ring C:

[0353]

[0354] wherein ring C is a fused (C3-C6)cycloalkyl ring, especially a fused cyclobutyl ring, a fused (C3-C6)heterocyclic ring or a fused benzene ring, wherein the fused (C3-C6)heterocyclic ring contains a ring carbon atom and a ring heteroatom selected from O, N and S,

[0355] and wherein when ring C is a fused (C3-C6)cycloalkyl ring, especially a fused cyclobutyl ring, the fused (C3-C6)cycloalkyl ring is unsubstituted or substituted with 1 or 2 R 40 groups, wherein the R 40 is selected from:

[0356] · (C 1- C2)alkyl, wherein each (C 1- C2)alkyl is independently unsubstituted or substituted with OH or 1, 2 or 3 halogens,

[0357] · Halo, especially F,

[0358] · Or two Rs on the same ring carbon atom 40 Substituents together with the carbon atoms to which they are attached can be linked to form a (C 3- C4) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains ring carbon atoms and a ring heteroatom selected from O, N, and S;

[0359] · Or two Rs on adjacent carbon atoms 40 Substituents are linked together with the carbon atoms to which they are attached to form a fused cyclopropyl ring;

[0360] · And wherein when K is -CH2- and J is N, two R5 substituents can be linked to form a (C1-C3) alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is a heteroatom selected from N and O or is -CH2-O-CH2-.

[0361] Example 39. A compound of formula (I) according to any one of Examples 1 to 38 or a pharmaceutically acceptable salt thereof, wherein R5 is independently selected from:

[0362] · -(C 1- C4) alkyl, preferably methyl,

[0363] · When K J is a carbon-nitrogen single bond, the R5 substituents on K and on the adjacent carbon atom can be linked to form ring C:

[0364]

[0365] wherein ring C is a fused (C3-C6) cycloalkyl ring, especially a fused cyclobutyl ring, or a fused (C3-C6) heterocyclic ring, wherein the fused (C3-C6) heterocyclic ring contains ring carbon atoms and a ring heteroatom selected from O, N, and S,

[0366] And wherein when ring C is a fused (C3-C6) cycloalkyl ring, especially a fused cyclobutyl ring, the fused (C3-C6) cycloalkyl ring is unsubstituted or substituted with 1 or 2 Rs 40 groups, wherein the R 40 is selected from:

[0367] · (C 1- C2) alkyl, wherein each (C 1- C2) alkyl is independently unsubstituted or substituted with OH or 1, 2, or 3 halos,

[0368] · Halo, especially F,

[0369] · Or two Rs on the same ring carbon atom 40 The substituents together with the carbon atoms to which they are attached can be linked to form a (C 3- C4) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N, and S;

[0370] · Or two Rs on adjacent carbon atoms 40 The substituents are linked together with the carbon atoms to which they are attached to form a fused cyclopropyl ring;

[0371] · And when K is -CH2- and J is N, two R5 substituents can be linked to form a (C1-C3) alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is a heteroatom selected from N and O or is -CH2-O-CH2-.

[0372] Example 40. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 39, wherein R5 is independently selected from:

[0373] · -(C 1- C2) alkyl, preferably methyl, and

[0374] · When K J is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom can be linked to form a ring C:

[0375]

[0376] wherein ring C is a fused (C3-C4) cycloalkyl ring, especially a fused cyclobutyl ring, and the fused (C3-C4) cycloalkyl ring, especially the fused cyclobutyl ring, is unsubstituted or is substituted with 1 or 2 Rs as described in the examples herein 40 groups.

[0377] Example 41. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 40, wherein y is 0, 1, 2, or 3, preferably 0, 1, or 2.

[0378] Example 42. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 41, wherein y is 0.

[0379] Example 43. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 42, wherein R5 is independently selected from:

[0380] · CH3, and y is 1 or 2, and

[0381] · When K When J is a carbon-nitrogen single bond, the R5 substituents on K and on the adjacent carbon atoms can be linked to form ring C:

[0382]

[0383] wherein ring C is a fused cyclobutyl ring.

[0384] Example 44. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, wherein the compound of formula (I) comprises the following moiety:

[0385]

[0386] or

[0387]

[0388] In particular

[0389] A:

[0390] More particularly

[0391] or B:

[0392] or C:

[0393]

[0394] Example 45. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 44, wherein the compound of formula (I) comprises the following moiety:

[0395]

[0396] Example 46. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45, wherein formula (I) is formula 1a, wherein A is -C(O)-:

[0397]

[0398] (Preferably, formula (I) is formula 1a)

[0399] Example 47. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45, wherein formula (I) is formula 1b, wherein A is -C(O)-:

[0400]

[0401] Example 48. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45, wherein formula (I) is formula 1c, wherein A is -C(O)-:

[0402]

[0403] Example 49. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45, wherein formula (I) is formula 1d, wherein A is -C(O)-:

[0404]

[0405] Example 50. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45, wherein formula (I) is formula 1e, wherein A is -C(O)-:

[0406]

[0407] Example 51. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45, wherein formula (I) is formula 1f, wherein A is -C(O)-:

[0408]

[0409] Example 52. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45, wherein formula (I) is formula 1g:

[0410]

[0411] More preferably, formula (I) is formula 1g.

[0412] Example 53. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45, wherein formula (I) is formula 1h:

[0413]

[0414] Most preferably, formula (I) is formula 1h.

[0415] Example 54. A compound of formula (1a) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 46, wherein A is -C(O)-:

[0416]

[0417] wherein

[0418] Y is N, C or CH;

[0419] Y means that when Y is CH, Y is attached to the adjacent carbon atom via a single bond, or when Y is C, Y is attached to the adjacent atom via a double bond;

[0420] y is 0, 1, 2 or 3;

[0421] K is K attached by a single bond, K is -CH2- and J is N;

[0422] R5 is independently selected from:

[0423] · -(C 1- C4)alkyl, preferably methyl,

[0424] · and two R5 substituents on the same ring carbon atom together with the carbon atom to which they are attached may be joined to form a (C 3- C4)cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N and S,

[0425] · when K J is a carbon-nitrogen single bond, the R5 substituents on K and on the adjacent carbon atom may be joined to form a ring C:

[0426]

[0427] wherein ring C is a fused (C3-C6)cycloalkyl ring, especially a fused cyclobutyl ring, a fused (C3-C6)heterocyclic ring or a fused benzene ring, wherein the fused (C3-C6)heterocyclic ring contains a ring carbon atom and a ring heteroatom selected from O, N and S,

[0428] and wherein when ring C is a fused (C3-C6)cycloalkyl ring, especially a fused cyclobutyl ring, the fused (C3-C6)cycloalkyl ring is unsubstituted or substituted by 1 or 2 R 40 groups, wherein the R 40 is selected from:

[0429] · (C 1- C2)alkyl, wherein each (C 1- C2)alkyl is independently unsubstituted or substituted by OH or 1, 2 or 3 halo,

[0430] · halo, especially F,

[0431] · or two R 40 substituents on the same ring carbon atom together with the carbon atom to which they are attached may be joined to form a (C 3-C4) a cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N, and S;

[0432] · Or where two R 40 substituents on adjacent carbon atoms are joined together with the carbon atoms to which they are attached to form a fused cyclopropyl ring;

[0433] · And where when K is -CH2- and J is N, two R5 substituents can be joined to form a (C1-C3) alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is a heteroatom selected from N and O or is -CH2-O-CH2-;

[0434] R1 is selected from:

[0435]

[0436]

[0437] Alternatively, there are 0-2 R 33 substituents in each of the above moieties,

[0438] R 33 is F;

[0439] R 15 is:

[0440] · Halo-substituted,

[0441] · R 25 (R 24 )N-(CH2) n , where R 24 is H or CH3 unsubstituted or substituted with 1, 2, or 3 halo-substituents, and R 25 is H, (C1-C4) alkyl-C(O)-, (C1-C4) alkyl-O-C(O)-, or (C1-C4) alkyl unsubstituted or substituted with 1, 2, or 3 halo-substituents, or

[0442] · Azetidinyl or pyrrolidinyl, wherein the azetidinyl and pyrrolidinyl are attached to the remainder of the molecule via an N atom and are unsubstituted or substituted with 1 or 2 F;

[0443] 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-substituents, especially F;

[0444] R17 is halogenated;

[0445] R 18 is halogenated;

[0446] R 19 is:

[0447] · halogenated

[0448] · (C1-C4) alkyl, unsubstituted or substituted by 1, 2 or 3 halogenated groups,

[0449] · (C1-C4) alkyl-O-(CH2) n -;

[0450] R 20 is halogenated;

[0451] R 21 is (C1-C2) alkyl, unsubstituted or substituted by 1, 2 or 3 F groups;

[0452] R 22 and R 23 each independently selected from:

[0453] · (C1-C4) alkyl, unsubstituted or substituted by 1, 2 or 3 halogenated groups,

[0454] · (C1-C4) alkyl-O-(CH2) n -

[0455] · HOC(O)-(CH2) n -

[0456] · H3C-C(O)(CH2) n -

[0457] · (H3C)3C-O-C(O)(CH2) n -;

[0458] · where n is 0, 1 or 2;

[0459] and

[0460] R 30 is CH3;

[0461] R2 is the following moiety:

[0462]

[0463] where

[0464] R6 is selected from H, halogenated, (C1-C4) alkyl, unsubstituted or substituted by 1, 2 or 3 halogenated groups;

[0465] R8 is selected from H, halo, unsubstituted or (C1-C4)alkyl substituted by 1, 2 or 3 halo;

[0466] R9 is selected from H, O-CH3, OH, CN, CH3 and halo;

[0467] R 28 Selected from SF5, halo, (C1-C4)alkyl which is unsubstituted or substituted by 1, 2 or 3 halo, and -C(O)H;

[0468] X is selected from C-R7 and N; and

[0469] R7 is selected from H and halo;

[0470] R3 is selected from -CH3, -CH2CH3, -CH(CH3)2, and cyclopropyl, in particular -CH3, and -CH2CH3;

[0471] R 26 It is H;

[0472] R 26 It is H;

[0473] R4 is selected from:

[0474] Unsubstituted or substituted with NH2 -(C1-C4)alkyl, -O-(CH2) 1-2 -phenyl, -NH-NH-C(O)-CF3,

[0475] -heteroaryl1, wherein said heteroaryl1 is a 5- or 6-membered fully unsaturated monocyclic ring comprising ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S;

[0476] -heteroaryl2, wherein the heteroaryl2 is a 9- or 10-membered fused bicyclic ring comprising ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, and wherein both rings are fully unsaturated, or one ring is fully unsaturated and the other is saturated or partially unsaturated, and wherein the heteroatoms may be in one or both rings;

[0477] -phenyl;

[0478] - heterocyclyl2, wherein said heterocyclyl2 is a 5- or 6-membered fully saturated or partially unsaturated group comprising ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S;

[0479] wherein heteroaryl1, heteroaryl2 and phenyl are each substituted by 1, 2 or 3 independently selected from R 10 , R 11 , R 12 , R 13 and R 14is substituted by substituents, where R 10 、R 11 、R 12 、R 13 and R 14 are each independently selected from:

[0480] · H,

[0481] · halo

[0482] · (C1-C4)alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents

[0483] · (C1-C2)alkyl substituted by -O-(C1-C2)alkyl or OH

[0484] · -S-(C1-C3)alkyl

[0485] · -O-(C1-C4)alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents

[0486] · OH

[0487] · (C3-C5)cycloalkyl, where the (C3-C5)cycloalkyl is unsubstituted or substituted by 1 or 2 halo substituents

[0488] · -O-(C3-C5)cycloalkyl

[0489] · -NR 34 R 35 ,where R 34 and R 35 are independently selected from:

[0490] οH

[0491] ο(C1-C4)alkyl, where the (C1-C4)alkyl is unsubstituted or substituted by OH or -O(C1-C2)alkyl

[0492] οand where R 34 and R 35 may together with the atoms to which they are attached form an azetidine, pyrrolidine or piperidine ring, where the azetidine, pyrrolidine and piperidine are unsubstituted or substituted by CH3;

[0493] · CN

[0494] · -(C2-C4)alkenyl

[0495] · -(C2-C4)alkynyl

[0496] · =O

[0497] · -C(O)H, and

[0498] · -C(O)(C1-C4) alkyl;

[0499] provided that R4 is not:

[0500]

[0501] wherein

[0502] R 10 、R 11 、R 12 、R 13 and R 14 are independently selected from:

[0503] · H,

[0504] · halo,

[0505] · (C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents,

[0506] · (C1-C2) alkyl substituted with -O-(C1-C2) alkyl or OH,

[0507] · -S-(C1-C3) alkyl,

[0508] · -O-(C1-C4) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents,

[0509] · OH,

[0510] · (C3-C5) cycloalkyl, wherein the (C3-C5) cycloalkyl is unsubstituted or substituted with 1 or 2 halo,

[0511] · -O-(C3-C5) cycloalkyl,

[0512] · -NR 34 R 35 wherein R 34 and R 35 are independently selected from:

[0513] οH,

[0514] ο (C1-C4) alkyl, wherein the (C1-C4) alkyl is unsubstituted or substituted with OH or -O(C1-C2) alkyl,

[0515] ο and wherein R 34 and R 35 may together with the atoms to which they are attached form an azetidine, pyrrolidine or piperidine ring, wherein the azetidine, pyrrolidine and piperidine are unsubstituted or substituted with CH3;

[0516] · CN,

[0517] · -(C2-C4) alkenyl,

[0518] · -(C2-C4) alkynyl,

[0519] · -C(O)H, and

[0520] · -C(O)(C1-C4) alkyl;

[0521] And

[0522] * represents the attachment point.

[0523] In particular, R4 is as described in any one of the examples. For example, R4 is selected from:

[0524] CH3,

[0525]

[0526] - heteroaryl1, wherein the heteroaryl1 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;

[0527] - heteroaryl2, wherein the heteroaryl2 is a 9-membered 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, and wherein both rings are fully unsaturated, or one ring is fully unsaturated and the other is saturated or partially unsaturated, and wherein the heteroatoms can be in one or both rings;

[0528] - phenyl; or

[0529] - heterocyclic2, wherein the heterocyclic2 is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S;

[0530] Wherein heteroaryl1, heteroaryl2, phenyl, and the part selected from:

[0531]

[0532] Each is independently selected from R 10 、R 11 、R 12 、R 13 And R 14 Of 1, 2 or 3 substituents, in particular 1 or 2 substituents, wherein each R 10 、R 11 、R 12 、R 13 And R 14 Is independently selected from:

[0533] ·H,

[0534] ·halo,

[0535] ·(C1-C4)alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents,

[0536] ·(C1-C2)alkyl substituted by -O-(C1-C2)alkyl or OH,

[0537] ·-S-(C1-C3)alkyl,

[0538] ·-O-(C1-C4)alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents,

[0539] ·OH,

[0540] ·(C3-C5)cycloalkyl, wherein the (C3-C5)cycloalkyl is unsubstituted or substituted by 1 or 2 halo substituents,

[0541] ·-O-(C3-C5)cycloalkyl,

[0542] ·-NR 34 R 35 wherein R 34 and R 35 are independently selected from:

[0543] οH,

[0544] ο(C1-C4)alkyl, wherein the (C1-C4)alkyl is unsubstituted or substituted by OH or -O(C1-C2)alkyl,

[0545] οand wherein R 34 and R 35 may together with the atoms to which they are attached form an azetidine, pyrrolidine or piperidine ring, wherein the azetidine, pyrrolidine and piperidine are unsubstituted or substituted by CH3;

[0546] ·CN,

[0547] ·-(C2-C4)alkenyl,

[0548] ·-(C2-C4)alkynyl,

[0549] ·=O

[0550] ·-C(O)H, and

[0551] ·-C(O)(C1-C4)alkyl.

[0552] More particularly, R1 is selected from:

[0553]

[0554] Example 55. A compound of formula (1b) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45 or 47, wherein A is -C(O)-:

[0555]

[0556] and wherein R1, R2, R3, R4, R5, R 26 、R 27 、Y, K, J, and y are as defined in Example 54.

[0557] Example 56. A compound of formula (1c) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45 or 48, wherein A is -C(O)-:

[0558]

[0559] and wherein R1, R2, R3, R4, R5, R 26 、R 27 、Y, K, J, and y are as defined in Example 54.

[0560] Example 57. A compound of formula (1d) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45 or 49, wherein A is -C(O)-:

[0561]

[0562] and wherein R1, R2, R3, R4, R5, R 26 、R 27 、Y, K, J, and y are as defined in Example 54.

[0563] Example 58. A compound of formula (1e) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45 or 50, wherein A is -C(O)-:

[0564]

[0565] and wherein R1, R2, R3, R4, R5, R 26 、R 27 、Y, K, J, and y are as defined in Example 54.

[0566] Example 59. A compound of formula (1f) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45 or 51, wherein A is -C(O)-:

[0567]

[0568] and wherein R1, R2, R3, R4, R5, R 26 , R 27 , Y, K, J, and y are as defined in Example 54.

[0569] Example 60. A compound of formula (1g) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45 or 54, wherein formula I or 1a is formula 1g:

[0570]

[0571] wherein R1, R2, R3, R4, R5, R 26 , R 27 , Y and y are as defined in Example 54.

[0572] Example 61. A compound of formula (1h) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45, 54 or 60, wherein formula I or 1a or 1g is formula 1h:

[0573]

[0574] wherein R1, R2, R3, R4, R5, R 26 , R 27 and y are as defined in Example 54.

[0575] Example 62. A compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from the compound structures exemplified herein.

[0576] Example 63. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 - 62, wherein the compound is in a non - zwitterionic form.

[0577] Example 64. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 - 62, wherein the compound is in a zwitterionic form.

[0578] Example 65. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 - 62, wherein the compound is a mixture of zwitterionic and non - zwitterionic forms.

[0579] Example 66. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 - 62, wherein the compound is a sodium salt.

[0580] Example 67. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1-62, wherein the compound is in amorphous form. For example, the compound is the sodium salt in amorphous form.

[0581] Example 68. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1-62, in crystalline form.

[0582] Example 69. A compound of formula (I) according to any one of Examples 1-62, wherein the compound is in substantially pure form.

[0583] Example 70. A combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 62, and one or more additional therapeutic active agents.

[0584] Example 71. The combination according to Example 70, wherein the additional therapeutic active agent is an anti-cancer agent.

[0585] Example 72. The combination according to Example 70 or 71, wherein the additional therapeutic active agent is a chemotherapeutic agent.

[0586] Example 73. The combination according to Example 72, wherein the additional therapeutic active agent is a chemotherapeutic agent selected from: anastrozole bicalutamide bleomycin sulfate busulfan busulfan injection capecitabine N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin carmustine chlorambucil cisplatin cladribine cyclophosphamide ( or ), cytarabine, cytosine arabinoside (Cytosar- ), cytarabine liposome injection dacarbazine (DTIC- ), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride daunorubicin citrate liposome injection dexamethasone, docetaxel doxorubicin hydrochloride etoposide fludarabine phosphate 5-fluorouracil flutamide Tizacrine, Gemcitabine (difluorodeoxycytidine), Hydroxycarbamide Idarubicin Ifosfamide Irinotecan L - Asparaginase Calcium Folinate, Melphalan 6 - Mercaptopurine Methotrexate Mitoxantrone Gemtuzumab, Paclitaxel phoenix (Yttrium - 90 / MX - DTPA), Pentostatin, Polybis - 20 Copolymer with Carmustine Implant Tamoxifen Citrate Teniposide 6 - Thioguanine, Thiotepa, Tirapazamine Topotecan Hydrochloride for Injection Vinblastine Vincristine and Vinorelbine Especially irinotecan.

[0587] Example 74. The combination according to Example 71, wherein the additional therapeutic agent is a PD - 1 inhibitor.

[0588] Example 75. The combination according to Example 70 or 71, wherein the additional therapeutic agent is an anti - PD - 1 antibody molecule.

[0589] Example 76. The combination according to Example 75, wherein the additional therapeutic agent is a PD - 1 inhibitor selected from the following: PDR001 (Novartis AG), Nivolumab (Bristol - Myers Squibb Company), Pembrolizumab (Merck & Co., Inc.), Pitolisant (CureTech Ltd.), MEDI0680 (MedImmune Limited), Cemiplimab (REGN2810, Regeneron Pharmaceuticals, Inc.), Dostarlimab (TSR - 042, Tesaro, Inc.), PF - 06801591 (Pfizer Inc.), Tislelizumab (BGB - A317, BeiGene, Ltd.), BGB - 108 (BeiGene, Ltd.), INCSHR1210 (Incyte Corporation), Batrilizumab (AGEN2035, Agenus Inc.), Sintilimab (Innovent Biologics, Inc.), Toripalimab (Shanghai Junshi Biosciences Co., Ltd.), Camrelizumab (Jiangsu Hengrui Medicine Co., Ltd.), and AMP - 224 (Amplimmune, Inc.), especially PDR001, Pembrolizumab or Tislelizumab, more especially Tislelizumab.

[0590] Example 77. A pharmaceutical composition comprising a compound of formula (I) according to any one of Examples 1 to 62 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0591] Example 78. A compound of formula (I) according to Examples 1 - 62 or a pharmaceutically acceptable salt thereof for use as a medicament.

[0592] Example 79. A compound of formula (I) according to Examples 1 - 62 or a pharmaceutically acceptable salt thereof for use according to Example 78, wherein the use is for the treatment of a disease treatable by WRN inhibition.

[0593] Example 80. A compound of formula (I) according to Examples 1 - 62 or a pharmaceutically acceptable salt thereof for use according to Example 78, wherein the use is for the treatment of cancer.

[0594] Example 81. A compound of formula (I) according to Examples 1 - 62 or a pharmaceutically acceptable salt thereof for use according to Example 80, wherein the cancer is characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR).

[0595] Example 82. A compound of formula (I) according to Examples 1 - 62 or a pharmaceutically acceptable salt thereof for use according to Example 81, wherein the cancer characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR) is selected from colorectal cancer, gastric cancer, and endometrial cancer, adrenocortical carcinoma, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer, and ovarian cancer.

[0596] Example 83. A compound of formula (I) according to Examples 1 - 62 or a pharmaceutically acceptable salt thereof for use according to Example 82, wherein the cancer characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR) is selected from colorectal cancer, gastric cancer, and endometrial cancer.

[0597] Example 84. A compound of formula (I) according to Examples 1 - 62 or a pharmaceutically acceptable salt thereof for use according to Example 81, wherein the cancer characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR) is selected from endometrial carcinoma of uterine corpus, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, carcinosarcoma of uterus, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, and serous cystadenocarcinoma of ovary.

[0598] Example 85. A method of 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 in Examples 1-62 or a pharmaceutically acceptable salt thereof.

[0599] Example 86. 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 in Examples 1-62 or a pharmaceutically acceptable salt thereof.

[0600] Example 87. A method of treating a disorder or disease in a subject that is treatable by WRN inhibition, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described in Examples 1-62 or a pharmaceutically acceptable salt thereof.

[0601] Example 88. 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 in Examples 1-62 or a pharmaceutically acceptable salt thereof.

[0602] Example 89. A method of treating cancer in a subject, the method comprising administering a compound of formula (I) as described in Examples 1-62 or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR).

[0603] Example 90. The method according to Example 89, wherein the cancer characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR) is selected from colorectal cancer, gastric cancer, and endometrial cancer, adrenocortical carcinoma, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer, and ovarian cancer.

[0604] Example 91. The method according to Example 90, wherein the cancer characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR) is selected from colorectal cancer, gastric cancer, and endometrial cancer.

[0605] Example 92. The method according to Example 89, wherein the cancer characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR) is selected from endometrial carcinoma of the uterine corpus, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, carcinosarcoma of the uterus, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, and serous cystadenocarcinoma of the ovary.

[0606] Use of a compound according to any one of Examples 1 to 62 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.

[0607] Use of a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof according to Example 93, wherein the cancer is characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR).

[0608] Example 95. Use of a compound according to any one of Examples 1 to 62 or a salt thereof as a research chemical, chemical probe or tool compound.

[0609] Example 96. A method for preparing a compound according to any one of Examples 1 to 62 or a pharmaceutically acceptable salt thereof.

[0610] Example 97. An intermediate compound as defined herein.

[0611] Also provided herein are compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof,

[0612] and in particular, when R1 is a ring, then:

[0613] · Each R1 ring atom adjacent to the R1 ring atom connecting the R1 ring to the remainder of the molecule is independently unsubstituted or substituted only by halo, in particular, independently unsubstituted or substituted by one F substituent, and

[0614] · Preferably, the R1 ring is connected to the remainder of the molecule via an R1 ring nitrogen atom or an R1 ring carbon atom double-bonded to an adjacent R1 ring atom.

[0615] More particularly, R1 is:

[0616] cycloalkenyl, wherein the cycloalkenyl is a partially unsaturated monocyclic moiety containing 5 or 6 ring carbon atoms, and the cycloalkenyl is unsubstituted or substituted by 1, 2, 3 or 4, preferably 1 or 2 R 33 substituents, where R 33 is halo, and wherein the cycloalkenyl or halo-substituted cycloalkenyl is substituted by 0, 1 or 2 R 15 substituents, preferably 1 substituent, or the cycloalkenyl or halo-substituted cycloalkenyl has 2 substituents on the same ring carbon atom that forms an oxetanyl spiro ring,

[0617] or R1 is a heterocyclic group, wherein the heterocyclic group is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, NH, O and S, and wherein the heterocyclic group is unbridged or bridged, and the bridge is 1 or 2 carbon atoms, wherein the heterocyclic group is unsubstituted or substituted by 1, 2, 3 or 4, such as 1, 2 or 3, especially 1 or 2 R 33 substituents, where R 33is halogenated, and wherein said heterocyclic group or halogenated substituted heterocyclic group is substituted with 0, 1 or 2 substituents independently selected from R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 substituents, preferably 0 or 1 substituent,

[0618] or said heterocyclic group or halogenated substituted heterocyclic group is fused to a cyclopropyl ring, wherein said cyclopropyl ring is unsubstituted or substituted with 1, 2 or 3 Fs,

[0619] or said heterocyclic group or halogenated substituted heterocyclic group has 2 substituents on the same ring carbon atom that forms a tetrahydrofuranyl spiro ring,

[0620] or R1 is a 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 substituted with 1, 2 or 3 substituents independently selected from R 21 and R 30 wherein R 21 and R 30 are independently selected from halogenated and (C1 - C4) alkyl, wherein said (C1 - C4) alkyl is unsubstituted or substituted with 1, 2 or 3 halogenated substituents,

[0621] or R1 is a phenyl, wherein said phenyl is unsubstituted or substituted with 1, 2, 3 or 4, preferably 1 or 2 R 33 substituents, wherein R 33 is halogenated, and wherein said phenyl or halogenated substituted phenyl is substituted with 0 or 1 R 15 substituent,

[0622] or R1 is an unsubstituted or (C1 - C4) alkyl - O - C(O) - substituted (C2 - C4) alkynyl;

[0623] and R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 are each independently selected from:

[0624] · halogenated

[0625] · Unsubstituted or substituted with 1, 2 or 3 halogens, (C 1- C4)alkyl-O-(CH2) n ;

[0626] · Unsubstituted or substituted with OH, -O-(C1-C2)alkyl or 1, 2 or 3 halogens, (C1-C4)alkyl,

[0627] · HOC(O)-(CH2) n -,

[0628] · H3C-C(O)(CH2) n -,

[0629] · (C1-C4)alkyl-O-C(O)(CH2) n ,

[0630] · =O

[0631] · Azetidinyl or pyrrolidinyl, wherein the azetidinyl and pyrrolidinyl are attached to the remainder of the molecule via the N atom and are each unsubstituted or substituted with 1 or 2 Fs,

[0632] · R 25 (R 24 )N-(CH2) n , where R 24 is H or unsubstituted or substituted with 1, 2 or 3 halogens, (C1-C2)alkyl, R 25 is H, unsubstituted or substituted with 1, 2 or 3 halogens, (C1-C4)alkyl-C(O)-, (C1-C4)alkyl-O-C(O)-, or (C1-C4)alkyl,

[0633] · OH

[0634] where n is 0, 1 or 2,

[0635] Even more particularly, R1 is:

[0636] Cycloalkenyl, wherein the cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms and the cycloalkenyl is unsubstituted or substituted with 1 or 2 R 33 substituents, where R 33 is halogen, preferably F, and wherein the cycloalkenyl or halogen-substituted cycloalkenyl is substituted with 0 or 1 R 15 substituent, where R 15 is selected from:

[0637] h) Unsubstituted or substituted with 1, 2 or 3 halogens, (C 1- C2)alkyl-O-;

[0638] i) (C1-C2) alkyl, unsubstituted or substituted by 1, 2 or 3 halogens,

[0639] j) HOC(O)-(CH2) n -,

[0640] k) H3C-C(O)(CH2) n -,

[0641] l) H3C-O-C(O)(CH2) n ,

[0642] m) =O, and

[0643] n) R 25 (R 24 )N-, H, where R 24 is H or (C1-C2) alkyl, unsubstituted or substituted by 1, 2 or 3 halogens, R 25 is H or (C1-C2) alkyl, unsubstituted or substituted by 1, 2 or 3 halogens,

[0644] n is 0 or 1,

[0645] where

[0646] · the R 15 substituents a) to g) of the cycloalkenyl or halogen-substituted cycloalkenyl are not present on the ring atoms adjacent to the ring atoms connecting the cycloalkenyl or halogen-substituted cycloalkenyl to the rest of the molecule, and preferably, the cycloalkenyl or halogen-substituted cycloalkenyl is a 6-membered ring, where 1 R 15 substituent is in the para position of the ring relative to the rest of the molecule; and

[0647] · the cycloalkenyl or halogen-substituted cycloalkenyl is connected to the rest of the compound via the R1 ring carbon atom double-bonded to the adjacent R1 ring carbon atom;

[0648] Or R1 is a heterocyclic group, where the heterocyclic group is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, NH, O and S, and where the heterocyclic group is unbridged or bridged, and the bridge is 1 or 2 carbon atoms, where the heterocyclic group is unsubstituted or substituted by 1 or 2 R 33 substituents, where R 33 is halogen, preferably F, and where the heterocyclic group or halogen-substituted heterocyclic group is substituted by 0 or 1 independently selected from R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22and R 23 is substituted by substituents of, where said R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 are independently selected from:

[0649] i) (C 1- C4) alkyl-O- which is unsubstituted or substituted by 1, 2 or 3 halo;

[0650] j) (C1-C4) alkyl which is unsubstituted or substituted by OH, -O-(C1-C2) alkyl or 1, 2 or 3 halo,

[0651] k) HOC(O)-(CH2) n -,

[0652] l) H3C-C(O)(CH2) n -,

[0653] m) H3C-O-C(O)(CH2) n ,

[0654] n) =O

[0655] o) R 25 (R 24 )N-, where R 24 is H, (C1-C2) alkyl which is unsubstituted or substituted by 1, 2 or 3 halo, R 25 is H, (C1-C2) alkyl which is unsubstituted or substituted by 1, 2 or 3 halo,

[0656] p) OH

[0657] where n is 0 or 1,

[0658] and wherein:

[0659] · The substituents a) to h) of the heterocyclic group or halo-substituted heterocyclic group are not present on the ring atoms adjacent to the ring atoms connecting the heterocyclic group or halo-substituted heterocyclic group to the rest of the molecule, and preferably, when the heterocyclic group or halo-substituted heterocyclic group is a 6-membered ring, it has 0 or 1 substituent selected from a) to h), located at the meta or para position, preferably the para position, relative to the rest of the molecule; and

[0660] · The heterocyclic group is connected to the rest of the compound via an R1 ring nitrogen atom or an R1 ring carbon atom double-bonded to an adjacent ring atom;

[0661] Alternatively, R1 is a heteroaryl, wherein the 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 the heteroaryl is unsubstituted or substituted by 1 or 2 substituents independently selected from R 21 and R 30 wherein R 21 and R 30 are independently selected from (C1-C2) alkyl, and the (C1-C2) alkyl is unsubstituted or substituted by 1, 2, or 3 halogens, and wherein preferably, the alkyl or haloalkyl substituent is not present on the R1 ring atom adjacent to the R1 ring atom connecting the heteroaryl to the remainder of the molecule, and more preferably, when the heteroaryl is a 6-membered ring, the alkyl or haloalkyl substituent is in the ring para position relative to the remainder of the molecule.

[0662] In particular, R1 is selected from:

[0663]

[0664]

[0665] Alternatively, there are 0-2 R 33 substituents in each of the above parts,

[0666] R 33 is F;

[0667] R 15 is:

[0668] · halo,

[0669] · R 25 (R 24 )N-(CH2) n wherein R 24 is H or CH3 unsubstituted or substituted by 1, 2, or 3 halogens, R 25 is H, (C1-C4) alkyl-C(O)-, (C1-C4) alkyl-O-C(O)-, or (C1-C4) alkyl unsubstituted or substituted by 1, 2, or 3 halogens, or

[0670] · azetidinyl or pyrrolidinyl, wherein the azetidinyl and pyrrolidinyl are connected to the remainder of the molecule via the N atom and are unsubstituted or substituted by 1 or 2 F;

[0671] R 16 is R 25 (R 24 )N-, wherein R 24 is H or (C1-C2) alkyl, R25 is H or a (C1-C2)alkyl group which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, especially F;

[0672] R 17 is halogen;

[0673] R 18 is halogen;

[0674] R 19 is:

[0675] · halogen

[0676] · a (C1-C4)alkyl group which is unsubstituted or substituted by 1, 2 or 3 halogen atoms,

[0677] · (C1-C4)alkyl-O-(CH2) n -;

[0678] R 20 is halogen;

[0679] R 21 is a (C1-C2)alkyl group which is unsubstituted or substituted by 1, 2 or 3 F atoms;

[0680] R 22 and R 23 are each independently selected from:

[0681] · a (C1-C4)alkyl group which is unsubstituted or substituted by 1, 2 or 3 halogen atoms,

[0682] · (C1-C4)alkyl-O-(CH2) n -

[0683] · HOC(O)-(CH2) n -

[0684] · H3C-C(O)(CH2) n -

[0685] · (H3C)3C-O-C(O)(CH2) n -;

[0686] · where n is 0, 1 or 2;

[0687] and

[0688] R 30 is CH3.

[0689] R1 is preferably selected from:

[0690]

[0691] R 15It is F;

[0692] R 16 It is R 25 (R 24 )N-;

[0693] R 17 It is F;

[0694] R 18 It is F;

[0695] R 19 It is F;

[0696] R 20 It is F;

[0697] R 21 It is CH3;

[0698] R 22 It is CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, (H3C)3C-O-C(O)-;

[0699] R 23 It is CF3, CHF2CH2-, (H3C)3C-O-C(O)-;

[0700] R 24 It is CH3; and

[0701] R 25 It is CHF2CH2-.

[0702] In particular, R1 is selected from:

[0703]

[0704]

[0705] More preferably, R1 is selected from:

[0706]

[0707] In particular

[0708]

[0709] More preferably

[0710]

[0711] In particular, R2 is the following moiety:

[0712]

[0713] wherein

[0714] R6 is selected from H, halogen, (C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens;

[0715] R8 is selected from H, halogen, (C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens;

[0716] R9 is selected from H, O-CH3, OH, CN, CH3 and halogen;

[0717] R 28 is selected from SF5, halogen, (C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens, and -C(O)H;

[0718] X is selected from C-R7 and N; and

[0719] R7 is selected from H and halogen.

[0720] More particularly, R2 is the following moiety:

[0721]

[0722] R6 is selected from H, Cl, CH3, F and Br;

[0723] R8 is selected from H, Cl, F and CF3;

[0724] R9 is selected from H, CH3 and Cl;

[0725] R 28 is selected from CF3, CF2H, -CH2CH3, Cl, SF5, Br and -C(O)H;

[0726] X is selected from C-R7 and N; and

[0727] R7 is selected from H and F.

[0728] Particularly, R 28 is selected from CF3, CHF2, Cl, -CH2CH3, CH3, SF5 and Br. More particularly, R 28 is selected from CF3, Cl and SF5, particularly CF3.

[0729] Particularly, X is CR7. More particularly, R7 is H.

[0730] Particularly, R6 is H, F, Cl or CH3. More particularly, R6 is Cl.

[0731] Particularly, R8 is F, CF3 or H. More particularly, R8 is H.

[0732] Particularly, R9 is H.

[0733] In particular, R2 is selected from

[0734]

[0735]

[0736] In particular, R3 is an unsubstituted (C1-C4) alkyl or an (C1-C4) alkyl substituted with 1, 2 or 3 substituents independently selected from halo and OH, or R3 is selected from -CH3, -CH2CH3, -CH(CH3)2, and cyclopropyl. More particularly, R3 is an unsubstituted (C1-C2) alkyl or an (C1-C2) alkyl substituted with 1, 2 or 3 substituents independently selected from halo and OH, preferably -CH2CH3 or CH3, more preferably -CH2CH3.

[0737] In particular, R 26 is H.

[0738] In particular, R 27 is H.

[0739] In particular, R4 is selected from:

[0740] CH3,

[0741]

[0742] - heteroaryl 1, wherein said heteroaryl 1 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;

[0743] - heteroaryl 2, wherein said heteroaryl 2 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, and wherein both rings are fully unsaturated, or one ring is fully unsaturated and the other is saturated or partially unsaturated, and wherein said heteroatoms may be in one or both rings;

[0744] - phenyl; or

[0745] - heterocyclic group 2, wherein said heterocyclic group 2 is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S;

[0746] wherein heteroaryl 1, heteroaryl 2, phenyl, and the moieties selected from:

[0747]

[0748] are each independently selected from R 10 、R 11 、R 12 、R 13 and R14 is substituted with 1, 2 or 3 substituents, in particular 1 or 2 substituents, where each R 10 , R 11 , R 12 , R 13 and R 14 is independently selected from:

[0749] · H,

[0750] · halo

[0751] · (C1-C4)alkyl which is unsubstituted or substituted with 1, 2 or 3 halo substituents

[0752] · (C1-C2)alkyl substituted with -O-(C1-C2)alkyl or OH

[0753] · -S-(C1-C3)alkyl

[0754] · -O-(C1-C4)alkyl which is unsubstituted or substituted with 1, 2 or 3 halo substituents

[0755] · OH

[0756] · (C3-C5)cycloalkyl, where the (C3-C5)cycloalkyl is unsubstituted or substituted with 1 or 2 halo

[0757] · -O-(C3-C5)cycloalkyl

[0758] · -NR 34 R 35 , where R 34 and R 35 is independently selected from:

[0759] οH

[0760] ο(C1-C4)alkyl, where the (C1-C4)alkyl is unsubstituted or substituted with OH or -O(C1-C2)alkyl

[0761] οand where R 34 and R 35 can together with the atoms to which they are attached form an azetidine, pyrrolidine or piperidine ring, where the azetidine, pyrrolidine and piperidine are unsubstituted or substituted with CH3;

[0762] · CN

[0763] · -(C2-C4)alkenyl

[0764] · -(C2-C4)alkynyl

[0765] · =O

[0766] · -C(O)H, and

[0767] · -C(O)(C1-C4)alkyl;

[0768] More particularly, R4 is as described in Example 1 and other examples herein, provided that at least one of the OH, CN, =O, or NH2 substituents is present on each heteroaryl 1, heteroaryl 2, phenyl, on,

[0769] and the remaining R 10 、R 11 、R 12 、R 13 and R 14 are as defined herein.

[0770] Even more particularly, R4 is as described in Example 1 and other examples herein, provided that one OH substituent is present on each heteroaryl 1, heteroaryl 2, phenyl, on,

[0771] and the remaining R 10 、R 11 、R 12 、R 13 and R 14 are as defined herein.

[0772] In another embodiment, R4 is as described herein, provided that one OH substituent is present on each heteroaryl 1, heteroaryl 2, phenyl, on, and relative to the position where R4 is linked to the linker -C(O)-, the OH substituent is in the ortho position of the R4 ring, and the remaining R 10 、R 11 、R 12 、R 13 and R 14 are as defined herein.

[0773] More particularly, R4 is as described herein, and each R 10 、R 11 、R 12 、R 13 and R 14 is independently selected from:

[0774] · H,

[0775] · halo (preferably F),

[0776] · (C1-C2)alkyl (preferably CH3), said (C1-C2)alkyl being unsubstituted or substituted with 1, 2, or 3 halos,

[0777] ·=O,

[0778] ·CN,

[0779] ·NH2, and

[0780] · -O-(C1-C2)alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens.

[0781] More particularly, R4 is selected from:

[0782]

[0783] Particularly, Y is N and Y is Y connected by a single bond.

[0784] Particularly, K is K connected by a single bond, and K is selected from -CH2-, -CH2CH2-, -NH- and a bond (to form a 5-membered ring: ), and J is N. More particularly, K is K connected by a single bond, K is -CH2- and J is N.

[0785] Particularly, R5 is independently selected from:

[0786] · -(C 1- C4)alkyl, preferably methyl,

[0787] · and two R5 substituents on the same ring carbon atom together with the carbon atom to which they are attached can be connected to form a (C 3- C4)cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N and S,

[0788] · When K J is a carbon-nitrogen single bond, the R5 substituents on K and the adjacent carbon atom can be connected to form ring C:

[0789]

[0790] wherein ring C is a fused (C3-C6)cycloalkyl ring, particularly a fused cyclobutyl ring, a fused (C3-C6)heterocyclic ring or a fused benzene ring, wherein the fused (C3-C6)heterocyclic ring contains a ring carbon atom and a ring heteroatom selected from O, N and S,

[0791] and wherein when ring C is a fused (C3-C6)cycloalkyl ring, particularly a fused cyclobutyl ring, the fused (C3-C6)cycloalkyl ring is unsubstituted or substituted by 1 or 2 R 40 groups, wherein the R 40 is selected from:

[0792] · (C 1- C2) alkyl, wherein each (C 1- C2) alkyl is independently unsubstituted or substituted by OH or one, two or three halogens,

[0793] · halogen, especially F,

[0794] · or two R 40 substituents on the same ring carbon atom together with the carbon atom to which they are attached may be linked to form a (C 3- C4) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N and S;

[0795] · or two R 40 substituents on adjacent carbon atoms are linked together with the carbon atoms to which they are attached to form a fused cyclopropyl ring;

[0796] · and wherein when K is -CH2- and J is N, two R5 substituents may be linked to form a (C1-C3) alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is a heteroatom selected from N and O or is -CH2-O-CH2-.

[0797] More particularly, R5 is independently selected from:

[0798] · -(C 1- C4) alkyl, preferably methyl,

[0799] · when K J is a carbon-nitrogen single bond, the R5 substituents on K and on the adjacent carbon atom may be linked to form a ring C:

[0800]

[0801] wherein ring C is a fused (C3-C6) cycloalkyl ring, especially a fused cyclobutyl ring, or a fused (C3-C6) heterocyclic ring, wherein the fused (C3-C6) heterocyclic ring contains a ring carbon atom and a ring heteroatom selected from O, N and S,

[0802] and wherein when ring C is a fused (C3-C6) cycloalkyl ring, especially a fused cyclobutyl ring, the fused (C3-C6) cycloalkyl ring is unsubstituted or substituted by one or two R 40 groups, wherein the R 40 is selected from:

[0803] · (C 1- C2) alkyl, wherein each (C 1- C2) alkyl is independently unsubstituted or substituted by OH or one, two or three halogens,

[0804] · halogenated, especially F,

[0805] · or two Rs on the same ring carbon atom 40 substituents together with the carbon atoms to which they are attached can be linked to form a (C 3- C4) cycloalkyl spiro ring or a 3- or 4-membered heteroalkyl spiro ring, wherein the heteroalkyl spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N, and S;

[0806] · or two Rs on adjacent carbon atoms 40 substituents are linked together with the carbon atoms to which they are attached to form a fused cyclopropyl ring;

[0807] · and wherein when K is -CH2- and J is N, two R5 substituents can be linked to form a (C1-C3) alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is a heteroatom selected from N and O or is -CH2-O-CH2-.

[0808] Even more particularly, R5 is independently selected from:

[0809] · -(C 1- C2) alkyl, preferably methyl, and

[0810] · when K J is a carbon-nitrogen single bond, the R5 substituents on K and on the adjacent carbon atom can be linked to form ring C:

[0811]

[0812] wherein ring C is a fused (C3-C4) cycloalkyl ring, especially a fused cyclobutyl ring, and the fused (C3-C4) cycloalkyl ring, especially the fused cyclobutyl ring, is unsubstituted or is substituted with 1 or 2 Rs as described in the examples herein 40 groups.

[0813] Particularly, y is 0, 1, 2, or 3, preferably 0, 1, or 2.

[0814] More particularly, R5 is independently selected from:

[0815] · CH3, and y is 1 or 2, and

[0816] · when K J is a carbon-nitrogen single bond, the R5 substituents on K and on the adjacent carbon atom can be linked to form ring C:

[0817]

[0818] wherein ring C is a fused cyclobutyl ring.

[0819] In particular, the compounds of formula (I) include the following moieties:

[0820]

[0821] or

[0822]

[0823] In particular

[0824] A:

[0825] More particularly

[0826] or B:

[0827] or C:

[0828]

[0829] More particularly, the compounds of formula (I) include the following moieties:

[0830]

[0831]

[0832] Form

[0833] Depending on the choice of starting materials and procedures, the compounds can exist in possible stereoisomeric forms or as mixtures thereof (e.g., as pure optical isomers or as mixtures of stereoisomers such as racemates and mixtures of diastereoisomers), depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, mixtures of diastereoisomers, and optically pure forms. The optically active (R)- and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents can be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents can have a cis or trans configuration. All tautomeric forms are also included.

[0834] As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds of the 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 invention and are generally not biologically or otherwise undesirable. In many cases, due to the presence of amino and / or carboxyl groups or similar groups, the compounds of the invention are capable of forming acid salts and / or base salts.

[0835] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

[0836] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0837] 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.

[0838] Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.

[0839] 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, these salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0840] Organic bases from which salts can be derived include, for example, primary amines, secondary amines, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0841] In another aspect, the present invention provides the compounds of the present invention in the form of: acetate, ascorbate, adipate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, mucate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / monohydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or cinchophenate.

[0842] Except for the deuteration explicitly described in formula (I), any formula given herein is intended to represent both the unlabeled form and the isotopically labeled form of the compound. Isotopically labeled compounds have the structures depicted by the formulas given herein, except that one or more atoms are replaced by atoms having the selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen. For example, the present invention includes deuterated forms of the exemplary compounds disclosed herein. In the compounds having formula (I), for example, one or more H atoms on the ring:

[0843]

[0844] can be replaced by deuterium, and for example, one or more atoms on the R1 moiety can be replaced by deuterium:

[0845]

[0846] Furthermore, the incorporation of certain isotopes, particularly deuterium (i.e., 2Compounds in which one or more hydrogen atoms are replaced by deuterium (i.e., H or D) can offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements or improved therapeutic index or tolerance. It should be understood that in this context deuterium is considered a substituent of the compounds of the invention. The concentration of deuterium can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance of the specified isotope and its natural abundance. If a substituent in a compound of the invention is indicated as deuterium, such a compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each specified deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) or at least 6633.3 (99.5% deuterium incorporation) for each specified deuterium atom. It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0847] Other examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 I. Thus, it should be understood that the invention includes compounds incorporating one or more of any of the above isotopes, including, for example, radioactive isotopes such as 3 H and 14 C, or those incorporating non-radioactive isotopes such as 2 H and 13 C. Such isotopically labeled compounds can be used in metabolic studies (with 14 C), reaction kinetics studies (with, for example, 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)), including determination of drug or substrate tissue distribution, or for radioactive treatment of patients. In particular, 18Compounds labeled with F or a label may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the attached examples and preparations, using appropriate isotopically labeled reagents in place of the unlabeled reagents previously used.

[0848] Definitions

[0849] 'Compounds of the present invention' or 'compounds having formula (I)' or 'compounds having formula 1a', etc. include their zwitterions, their non-zwitterionic (non-charged forms), or pharmaceutically acceptable salts of said zwitterionic or non-zwitterionic forms.

[0850] 'Zwitterion' or 'zwitterionic form' means a compound containing both a positively charged and a negatively charged functional group.

[0851] Unless otherwise specified, halo means fluoro, chloro or bromo, particularly fluoro or chloro.

[0852] Alkyl and alkoxy groups containing the required number of carbon atoms can be straight-chain or branched. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[0853] '=O' means an oxo substituent.

[0854] When R1 is a substituted or unsubstituted cycloalkenyl, said cycloalkenyl includes, but is not limited to, cyclohexenyl, particularly groups such as cyclohex-1-en-1-yl, etc.

[0855] When R1 is a substituted or unsubstituted heterocyclic group, said heterocyclic group includes, but is not limited to, 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, tetrahydropyridyl (such as 1,4,5,6-tetrahydropyridin-3-yl and 1,2,3,6-tetrahydropyridin-4-yl) and dihydropyridyl (such as 3,6-dihydropyridyl), etc.

[0856] When R1 is a heteroaryl, the 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 independently selected from N, O and S, preferably 1 or 2 ring heteroatoms, preferably where 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 a substituted or unsubstituted heteroaryl, the heteroaryl includes but is not limited to pyridyl, especially pyridin-3-yl and other substituted or unsubstituted groups.

[0857] - 'Heteroaryl 1' is a 5- or 6-membered fully unsaturated (including aromatic) monocyclic group 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, the heteroaryl 1 contains only ring carbon atoms and one or two nitrogen atoms. Heteroaryl 1 includes but is not limited to pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, isothiazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, triazolyl and pyrazinyl, especially pyridyl, pyrimidinyl and triazolyl.

[0858] - 'Heteroaryl 2', where the heteroaryl 2 is a 9- or 10-membered fused bicyclic group containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, and where both rings are fully unsaturated (including aromatic), or one ring is fully unsaturated (including aromatic) and the other is saturated or partially unsaturated, and where the heteroatoms can be in one or both rings. 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 connected to the rest of the molecule via linker -A- is fully unsaturated. Heteroaryl 2 includes but is not limited to benzofuryl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolopyridyl, imidazopyridyl, pyrazolopyridyl, isoindolyl, indazolyl, purinyl, indolinyl, imidazopyridyl, pyrazolopyridyl, pyrrolopyridazinyl, pyrrolopyridyl, imidazopyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyrimidinopyrimidinyl, pyrazinopyrazinyl, hydropyranopyridyl (especially hydrofuranylpyridyl, especially dihydrofuranylpyridyl), and imidazopyridyl.

[0859] The present invention includes all tautomeric forms of the compounds having formula (I). For example, when heteroaryl 1 and heteroaryl 2 are substituted with =O, they can form tautomers, for example, as follows:

[0860]

[0861] 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 and include, but are not limited to, colorectal cancer, gastric cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, ovarian cancer, etc.

[0862] The terms "tumor" and "cancer" are used interchangeably herein, e.g., both terms include solid and liquid, such as disseminated or circulating tumors. As used herein, the term "cancer" or "tumor" includes pre-malignant as well as malignant cancers and tumors.

[0863] As used herein, a 'WRN inhibitor' or 'WRN helicase inhibitor' means a compound that inhibits Werner syndrome RecQ DNA helicase (WRN). The term "WRN" as used herein refers to the protein of Werner syndrome RecQ DNA helicase. The term "WRN" includes mutants, fragments, variants, isoforms, and homologs of full-length wild-type WRN. In one embodiment, the protein is encoded by the WRN gene (Entrez Gene ID 7486; Ensembl ID ENSG00000165392). Exemplary WRN sequences are available in the Uniprot database under accession number Q14191.

[0864] A 'WRN-mediated disease or disorder' includes a disease or disorder that is treated by WRN inhibition, such as cancer. In particular, this can include cancers characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR).

[0865] 'Microsatellite unstable cancer', 'high microsatellite instability cancer', 'high microsatellite cancer', and 'high MSI cancer', 'MSI hi ' and 'MSI-H' are used interchangeably herein and describe cancers having a high number of alterations in the length of simple repetitive genomic sequences within microsatellites.

[0866] The MSI-H or dMMR tumor status of a patient can be determined using, for example, a polymerase chain reaction (PCR) assay for the MSI-H status or an immunohistochemistry (IHC) assay for dMMR. Methods for differentiating MSI-H or dMMR tumor status are described, for example, in Ryan et al. Crit Rev Oncol Hematol. [Critical Reviews in Oncology / Hematology] 2017;116:38-57; Dietmaier and Hofstadter. Lab Invest [Laboratory Investigation] 2001, 81:1453-1456; and Kawakami et al. Curr Treat Options Oncol. [Current Treatment Options in Oncology] 2015;16(7):30.

[0867] Microsatellite instability is particularly seen in colorectal cancer, gastric cancer, and endometrial cancer, and also in adrenocortical carcinoma, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer, and ovarian cancer. Examples of high microsatellite cancers include endometrial carcinoma of the uterine corpus, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, and ovarian serous cystadenocarcinoma.

[0868] Cancers with "deficient mismatch repair" (dMMR) or "dMMR signature" include cancer types associated with documented mutations or epigenetic silencing of MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, and PMS1, microsatellite fragile sites, or other gene inactivation mechanisms, including but not limited to lung cancer, breast cancer, renal cancer, colorectal cancer, ovarian cancer, prostate cancer, upper respiratory and digestive 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 "deficient" mismatch repair have a significantly reduced (e.g., at least about 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction) amount of mismatch repair. In some cases, cells or cancers with deficient mismatch repair do not perform mismatch repair.

[0869] As used herein, the terms "synthetic lethality" and "synthetic lethal" are used to refer to a decrease in cell viability and / or a decrease in cell proliferation rate caused by a combination of mutations in two or more genes or by a method (e.g., RNA interference or protein function inhibition) that results in loss of function (but not by loss of function of only one of these genes).

[0870] The term "pharmaceutical composition" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof in a form suitable for oral or parenteral administration, and at least one pharmaceutically acceptable carrier.

[0871] 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, sweetening agents, 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 Edition, Pharmaceutical Press, 2013, pp. 1049 - 1070).

[0872] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit a biological or medical response in a subject (e.g., a decrease or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of a disorder, slowing or delaying of disease progression, or prevention of a disease, etc.).

[0873] 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, effectively: (1) at least partially alleviates, prevents, and / or improves (i) a disorder or disease mediated by WRN, or (ii) associated with WRN activity, or (iii) characterized by the activity (normal or abnormal) of WRN; or (2) reduces or inhibits the activity of WRN.

[0874] In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a cell, or tissue, or acellular biomaterial, or medium, effectively reduces or inhibits, at least in part, the activity of WRN or reduces the level of WRN protein.

[0875] As used herein, the term "subject" refers to a primate (e.g., a human (male or female)), dog, rabbit, guinea pig, pig, rat, and mouse. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.

[0876] As used herein, the term "inhibit (inhibit, inhibition, or inhibiting)" refers to a reduction or inhibition of a given disorder, symptom, or condition, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0877] As used herein, the term "treat", "treating", or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of its clinical symptoms); or reducing or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those physical parameters or biomarkers that may not be discernible to the patient.

[0878] As used herein, the term "prevent", "preventing", or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0879] As used herein, a subject is "in need of" treatment if the subject would benefit biologically, medically, or in terms of quality of life from the treatment.

[0880] As used herein, the terms "a / an", "the", and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context.

[0881] 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, the following describes suitable methods and materials. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the invention and does not pose a limitation on the scope of the invention as otherwise claimed.

[0882] Isomeric form

[0883] Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the present invention may exist in racemic or enantiomerically enriched form, e.g., in (R)-, (S)-, or (R,S)-configurations. In certain embodiments, each asymmetric atom has an (R)- or (S)-configuration with at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. If possible, substituents on atoms with unsaturated double bonds may exist in cis-(Z)- or trans-(E)-forms.

[0884] Accordingly, as used herein, the compounds of the present invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, e.g., as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[0885] Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates based on the physicochemical differences of the components, e.g., by chromatography and / or fractional crystallization.

[0886] The racemates of any resulting compounds or intermediates of the present invention can be resolved into optically active enantiomers by known methods, e.g., by separating the diastereomeric salts obtained with an optically active acid or base and liberating the optically active acidic or basic compound. In particular, therefore, the basic moiety can be used to resolve the compounds of the present invention into their optical enantiomers, e.g., by fractional crystallization of the salts formed with an optically active acid such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic compounds or racemic intermediates of the present invention can also be resolved by chiral chromatography (e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent).

[0887] The compounds of the present invention, i.e., the compounds of formula (I) containing groups capable of acting as hydrogen bond donors and / or acceptors, are capable of forming co-crystals with suitable co-crystal formers. These co-crystals can be prepared from the compounds of formula (I) by known co-crystallization procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting the compounds of formula (I) with a co-crystal former in solution under crystallization conditions and separating the co-crystals thus formed. Suitable co-crystal formers include those described in WO 2004 / 078163. Accordingly, the present invention further provides co-crystals comprising the compounds of formula (I).

[0888] In addition, the compounds of the present invention (including their salts) can also be obtained in their hydrate form or include other solvents used for their crystallization. The compounds of the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); thus, the present invention is intended to include both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and are known to be harmless to recipients, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0889] Formulations

[0890] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical compositions can be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, percutaneous or topical administration), and rectal administration, particularly oral administration. Topical administration can also involve inhalation or intranasal application. The pharmaceutical compositions of the present invention can be made in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories), or in liquid form (including but not limited to solutions, suspensions or emulsions). Tablets can be film-coated or enteric-coated according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising the active ingredient and one or more of the following:

[0891] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0892] b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, also comprising

[0893] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; when needed

[0894] d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and

[0895] e) adsorbents, colorants, flavorants and sweeteners.

[0896] Compounds 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).

[0897] Solid dispersion technology has been used to improve the dissolution characteristics 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. April 30, 2009, pp. 234-246).

[0898] Typical methods for solubilizing compounds for parenteral administration are to optimize the pH or use co-solvents (such as PEG300, PEG400, propylene glycol, or ethanol). If these methods are not feasible for some reason, surfactants (such as 80 or Cremophor ) can be considered. Cyclodextrins are established as safe solubilizers. Compounds with high solubility in natural oils (such as propofol) can be dissolved in parenteral fat emulsions.

[0899] There are also provided pharmaceutical compositions comprising a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0900] Use

[0901] The compounds of the invention in free form or in the form of a pharmaceutically acceptable salt exhibit valuable pharmacological properties, e.g., WRN inhibitory properties, as indicated, for example, in the in vitro tests provided herein, and are thus indicated for use in therapy or as research chemicals, e.g., laboratory research chemicals, such as chemical probes or as tool compounds.

[0902] 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, such as a tool compound or a chemical probe, particularly for the study of WRN or for example high MSI 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, such as a tool compound or a chemical probe, particularly for the study of WRN or for example high MSI cancers.

[0903] There is also provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for the treatment of cancer. Cancers that can be treated by WRN inhibition include cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). In particular, a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof can be used for the treatment of cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

[0904] There is also provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for use as a medicament. In particular, the uses are:

[0905] · for the treatment of diseases treatable by WRN inhibition,

[0906] · for the treatment of cancer,

[0907] · for the treatment of cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR),

[0908] · for the treatment of cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (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,

[0909] · for the treatment of cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), which cancers are selected from colorectal cancer, gastric cancer, prostate cancer and endometrial cancer, or

[0910] · for the treatment of cancer, wherein the cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) are selected from uterine corpus endometrial cancer, colon adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, prostate cancer and ovarian serous cystadenocarcinoma.

[0911] There is also provided the following method:

[0912] · Modulating the WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof,

[0913] · Inhibiting WRN in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof,

[0914] · 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,

[0915] · 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,

[0916] · Treating cancer in a subject, the method comprising administering a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR). In particular, cancers characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR) are selected from colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer, and ovarian cancer. More particularly, cancers characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR) are selected from colorectal cancer, gastric cancer, prostate cancer, and endometrial cancer. Examples include endometrial carcinoma of the uterine corpus, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical cancer, carcinosarcoma of the uterus, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, prostate cancer, and serous cystadenocarcinoma of the ovary.

[0917] There is also provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof:

[0918] · Use in therapy,

[0919] · Use in the preparation of a medicament,

[0920] · Use in the preparation of a medicament for treating cancer. In particular, the cancer is characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR),

[0921] · Use in the preparation of a medicament for treating a disease that can be treated by WRN inhibition,

[0922] In particular, the cancer is characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR), such as colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer, and ovarian cancer, particularly colorectal cancer, gastric cancer, prostate cancer, or endometrial cancer or corpus endometrial cancer, colon adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical cancer, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal cancer, breast cancer, renal clear cell carcinoma, and ovarian serous cystadenocarcinoma.

[0923] In some embodiments, the subject has or is identified as having a microsatellite instability (MSI-H) cancer, such as a reference control, such as 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 other MSI-H cancer. In some embodiments, the subject has colorectal cancer (CRC), endometrial cancer, or gastric cancer that has or is identified as having microsatellite instability (MSI-H), such as a reference control, such as a normal subject. Such identification techniques are known in the art.

[0924] Dosage form

[0925] The pharmaceutical composition or combination of the present invention can be, for example, in unit dosage form with about 1 - 1000 mg of one or more active ingredients for a subject of about 50 - 70 kg.

[0926] Combination

[0927] "Combination" refers to a fixed combination in the form of a single dosage unit, or to combination administration, where the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered independently at the same time or separately within a time interval with a combination partner (e.g., another drug as explained below, also referred to as a "therapeutic agent" or "co-agent"), especially in cases where these time intervals allow the combination partner to exhibit a cooperative (e.g., synergistic) effect. The individual components may be packaged in a kit or separately. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration. As used herein, the terms "co-administer" or "combination administration" etc. are meant to encompass the administration of the selected combination partners to a single subject in need (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or simultaneously. As used herein, the term "drug combination" means a product resulting from the mixing or combination of more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that the therapeutic agents (e.g., the compound of the present invention and the combination partner) are administered to a patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" means that the therapeutic agents (e.g., the compound of the present invention and the combination partner) are administered to a patient as separate entities simultaneously, in parallel, or sequentially (without a specific time limit), where such administration provides therapeutically effective levels of both compounds in the patient. The latter also applies to cocktail therapies, e.g., the administration of three or more therapeutic agents.

[0928] The combinations described herein may include a compound of formula (I) and one or more additional therapeutic agents, e.g., one or more anti-cancer agents, cytotoxic or cytostatic agents, hormonal therapies, vaccines, and / or other immunotherapies. In other embodiments, the combination is further co-administered or used in combination with other therapeutic modalities, including surgery, radiation, cryosurgery, and / or hyperthermia. Such combination therapies may advantageously use lower doses of the administered therapeutic agents, thereby avoiding possible toxicities or complications associated with the treatment.

[0929] Additional therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids, which have therapeutic activity or enhance therapeutic activity when co-administered with the compounds disclosed herein to a patient.

[0930] In one embodiment, the additional therapeutic active agent is a chemotherapeutic agent. General chemotherapeutic agents contemplated for combination therapy include anastrozole bicalutamide bleomycin sulfate busulfan busulfan injection capecitabine N4-Pentyloxycarbonyl-5-deoxy-5-fluorocytidine, Carboplatin Carmustine Chlorambucil Cisplatin Cladribine Cyclophosphamide ( or ), Cytarabine, Cytosine arabinoside (Cytosar- ), Liposomal cytarabine injection Dacarbazine (DTIC- ), Dactinomycin (Actinomycin D, Cosmegan), Daunorubicin hydrochloride Liposomal daunorubicin citrate injection Dexamethasone, Docetaxel Doxorubicin hydrochloride Etoposide Fludarabine phosphate 5-Fluorouracil Flutamide Tezacitibine, Gemcitabine (difluorodeoxycitidine), Hydroxyurea Idarubicin Ifosfamide Irinotecan L-Asparaginase Calcium folinate, Melphalan 6-Mercaptopurine Methotrexate Mitoxantrone (mitoxantrone) Gemtuzumab (mylotarg), Paclitaxel Phoenix (Yttrium90 / MX-DTPA), Pentostatin, Polifeprosan 20 with carmustine implant Tamoxifen citrate Teniposide 6-Thioguanine, Thiotepa (thiotepa), Tirapazamine (tirapazamine) Topotecan hydrochloride for injection Vinblastine Vincristine and Vinorelbine

[0931] In another embodiment, the additional therapeutic agent is an anti-cancer agent.

[0932] Particularly interesting combination partners for combination with the compounds of the invention include fluorouracil (5-FU) and irinotecan

[0933] In another embodiment, the additional therapeutic active agent is the chemotherapeutic agent irinotecan

[0934] In another embodiment, the additional therapeutic 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 inhibitor of PD-1 or PD-L1 is an antibody molecule against PD-1 or PD-L1. In another embodiment, the additional therapeutic active agent is an anti-PD-1 antibody molecule

[0935] In another embodiment, the PD-1 inhibitors are selected from PDR001 (Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co), pidilizumab (CureTech), MEDI0680 (Medimmune), cemiplimab (REGN2810, Regeneron), dostarlimab (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

[0936] In a further embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US2015 / 0210769, published July 30, 2015, entitled "Antibody Molecules to PD-1 and Uses Thereof", which is incorporated herein by reference in its entirety

[0937] In another embodiment, a combination is provided that includes a compound of formula (I) or a pharmaceutically acceptable salt thereof, a chemotherapeutic agent, and a PD-1 inhibitor.

[0938] In particular, the chemotherapeutic agent and the PD-1 inhibitor are selected from those described above.

[0939] More particularly, the chemotherapeutic agent is irinotecan 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 per week. In some embodiments, tislelizumab is administered IV at 300 mg on day 1 of each 28-day cycle. In some embodiments, tislelizumab may be administered at 500 mg once every four (4) weeks.

[0940] In another embodiment, the anti-PD-1 antibody molecule (e.g., tislelizumab) comprises a heavy chain and / or a light chain, VH, VL, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 as follows:

[0941]

[0942]

[0943] In some embodiments, the PD-1 inhibitor comprises the HCDR and LCDR of tislelizumab as shown in SEQ ID NOs:7-12.

[0944] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a steady dose between about 100 mg and about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 100 mg and about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 100 mg and about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 100 mg and about 300 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 100 mg and about 200 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 200 mg and about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 200 mg and about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 200 mg and about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 200 mg and about 300 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 300 mg and about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 300 mg and about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 300 mg and about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 400 mg and about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 400 mg and about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 500 mg and about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 600 mg and about 700 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 700 mg and about 800 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 800 mg and about 900 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 900 mg and about 1000 mg.

[0945] In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered at a stable dose of about 100 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 700 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 800 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 900 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 1000 mg.

[0946] In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered once every ten weeks. In some embodiments, the PD-1 inhibitor is administered once every nine weeks. In some embodiments, the PD-1 inhibitor is administered once every eight weeks. In some embodiments, the PD-1 inhibitor is administered once every seven weeks. In some embodiments, the PD-1 inhibitor is administered once every six weeks. In some embodiments, the PD-1 inhibitor is administered once every five weeks. In some embodiments, the PD-1 inhibitor is administered once every four weeks. In some embodiments, the PD-1 inhibitor is administered once every three weeks. In some embodiments, the PD-1 inhibitor is administered once every two weeks. In some embodiments, the PD-1 inhibitor is administered once a week.

[0947] In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered intravenously.

[0948] In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered over a period of about 20 minutes to 40 minutes (e.g., about 30 minutes). In some embodiments, the PD-1 inhibitor is administered over a period of about 30 minutes. In some embodiments, the PD-1 inhibitor is administered over a period of about one hour. In some embodiments, the PD-1 inhibitor is administered over a period of about two hours. In some embodiments, the PD-1 inhibitor is administered over a period of about three hours. In some embodiments, the PD-1 inhibitor is administered over a period of about four hours. In some embodiments, the PD-1 inhibitor is administered over a period of about five hours. In some embodiments, the PD-1 inhibitor is administered over a period of about six hours.

[0949] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered intravenously at a dose between about 300 mg and about 500 mg (e.g., about 400 mg) once every four weeks. In some embodiments, the PD-1 inhibitor is administered intravenously at a dose between about 200 mg and 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.

[0950] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered intravenously at a dose between about 300 mg and about 500 mg (e.g., about 400 mg) over a period of about 20 minutes to about 40 minutes (e.g., about 30 minutes) once every two weeks. In some embodiments, the PD-1 inhibitor is administered intravenously at a dose between about 200 mg and about 400 mg (e.g., about 300 mg) over a period of about 20 minutes to about 40 minutes (e.g., about 30 minutes) once every three weeks.

[0951] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 100 mg per week. For example, if a patient is given a 10-week dose, 1000 mg of the PD-1 inhibitor (e.g., tislelizumab) can be given. If a 9-week dose is given, 900 mg of the PD-1 inhibitor (e.g., tislelizumab) can be given. If an 8-week dose is given, 800 mg of the PD-1 inhibitor (e.g., tislelizumab) can be given. If a 7-week dose is given, 700 mg of the PD-1 inhibitor (e.g., tislelizumab) can be given. If a 6-week dose is given, 600 mg of the PD-1 inhibitor (e.g., tislelizumab) can be given. If a 5-week dose is given, 500 mg of the PD-1 inhibitor (e.g., tislelizumab) can be given. If a 4-week dose is given, 400 mg of the PD-1 inhibitor (e.g., tislelizumab) can be given. If a 3-week dose is given, 300 mg of the PD-1 inhibitor (e.g., tislelizumab) can be given. If a 2-week dose is given, 200 mg of the PD-1 inhibitor (e.g., tislelizumab) can be given. If a 1-week dose is given, 100 mg of the PD-1 inhibitor (e.g., tislelizumab) can be given.

[0952] For example, if an anti-PD-1 antibody (such as tislelizumab) is used, it can be administered once every three weeks as an intravenous infusion at a dose of 200 mg. Alternatively, tislelizumab can be administered once every four weeks as an intravenous infusion at a dose of 300 mg. If an anti-PD-1 antibody (such as tislelizumab) is used, it can be administered once every three weeks as an intravenous infusion at a dose of 300 mg. Alternatively, tislelizumab can be administered once every four weeks as an intravenous infusion at a dose of 400 mg.

[0953] The structure of the active compound identified by number, common name or trade name can be taken from the actual version of the standard compendium "The Merck Index" or from a database (e.g., international patents (such as IMS World Publications)). The above compounds that can be used in combination with the compounds of the present invention can be prepared and administered as described in the art (such as in the documents cited above).

[0954] In one embodiment, the present invention provides a product comprising a compound of the present invention and at least one other therapeutic agent for simultaneous, separate or sequential use in therapy as a combined preparation. In one embodiment, the therapy is for treating a WRN-mediated disease or disorder. The product provided as a combined preparation includes a composition that jointly contains the compound of the present invention and one or more other therapeutic agents in the same pharmaceutical composition, or contains the compound of the present invention and one or more other therapeutic agents in separate forms (e.g., in the form of a kit).

[0955] In one embodiment, the present invention provides a pharmaceutical composition that contains a compound of the present invention and one or more additional therapeutic agents. Optionally, the pharmaceutical composition may contain a pharmaceutically acceptable carrier as described above.

[0956] In one embodiment, the present invention provides a kit that contains two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition contains a compound of the present invention. In one embodiment, the kit contains means for separately retaining the compositions, such as containers, separate bottles, or separate foil pouches. Examples of such kits are blister packs, such as those typically used for packaging tablets, capsules, etc.

[0957] The kit of the present invention can be used to administer different dosage forms (e.g., oral and parenteral), to administer the separate compositions at different dosing intervals, or to titrate the separate compositions relative to each other. To aid compliance, the kit of the present invention typically contains administration instructions.

[0958] In the combination therapies of the present invention, the compounds of the present invention and other therapeutic agents can be produced and / or formulated by the same or different manufacturers. Additionally, the compounds of the present invention and other therapeutic agents can be combined to form a combination therapy: (i) before the combination product is released to physicians (e.g., in the case of a kit containing the compounds of the present invention and other therapeutic agents); (ii) shortly before administration, by the physician himself / herself (or under the guidance of the physician); (iii) in the patient himself / herself, e.g., during sequential administration of the compounds of the present invention and other therapeutic agents.

[0959] Accordingly, the present invention provides the use of the compounds of the present invention for the treatment of WRN-mediated diseases or disorders, wherein a medicament is prepared for co-administration with another therapeutic agent. The present invention also provides the use of another therapeutic agent for the treatment of WRN-mediated diseases or disorders, wherein the medicament is co-administered with the compounds of the present invention.

[0960] The present invention also provides the compounds of the present invention for use in the treatment of WRN-mediated diseases or disorders, wherein the compounds of the present invention are prepared for co-administration with another therapeutic agent. The present invention also provides another therapeutic agent for use in the treatment of WRN-mediated diseases or disorders, wherein the other therapeutic agent is prepared for co-administration with the compounds of the present invention. The present invention also provides the compounds of the present invention for use in the treatment of WRN-mediated diseases or disorders, wherein the compounds of the present invention are co-administered with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method for the treatment of WRN-mediated diseases or disorders, wherein the other therapeutic agent is co-administered with the compounds of the present invention.

[0961] The present invention also provides the use of the compounds of the present invention for the treatment of WRN-mediated diseases or disorders, wherein the patient has been previously treated (e.g., within 24 hours) with another therapeutic agent. The present invention also provides the use of another therapeutic agent for the treatment of WRN-mediated diseases or disorders, wherein the patient has been previously treated (e.g., within 24 hours) with the compounds of the present invention.

[0962] Biological Assays and Data

[0963] The activity of the compounds according to the present invention can be evaluated by the following in vitro methods.

[0964] Materials and Methods

[0965] Molecular biology and virus production. DNA encoding human Werner helicase (UniProt Q14191, WRN, amino acids S2 - S1432) was designed as four DNA strings, which were codon - optimized for expression in Escherichia coli. These strings were either ordered from GeneArt (Life Technologies, Regensburg, Germany) or made with overlapping oligonucleotides by sub - cloning.

[0966] Using the FlashBac Ultra system (Oxford Expression Technologies, 100302), according to the manufacturer's instructions, baculovirus was produced from the expression plasmid pLAF1202 (SEQ ID NO:1) encoding His - ZZ - 3C - WRN (aaN517 - P1238, encoded by nucleotides 578 - 2743 in the sequence) using 540 ng of plasmid DNA, 5.4 μg of Flashbac Ultra DNA and 5.4 μL of Lipofectin for transfection (Life Technologies, 18292 - 011). After incubation for 5 hours, the solution was diluted with 500 μL of TC100 medium (Life Technologies, 13055 - 025) and incubated at 27 °C for 7 days.

[0967] Cells were harvested by centrifugation at 800 x g for 10 minutes, and the supernatant containing the virus was transferred to a new sterile tube. For the first virus amplification, 500 μL of the virus was added to 25 mL of SF9 cells at a density of one million cells / mL and incubated at 27 °C (200 rpm) for 5 days. Cell viability, density and diameter were measured, and the virus was harvested by centrifugation at 3000 rpm for 15 minutes after signs of infection.

[0968] Baculovirus - infected insect cells (BIIC) were produced as described by Wasilko et al., 2009, DOI:10.1016 / j.pep.2009.01.002.

[0969] Briefly, in a conical flask, 100 mL of ESF921 medium (Expression Systems - 96 - 001 - 01, supplemented with 0.5X streptomycin / penicillin) containing 100 million SF9 cells (one million cells / mL) was infected with 300 million baculovirus particles of each construct (estimated MOI = 3) and incubated at 27 °C at 130 rpm for 24 hours. The infected cells were transferred to 50 mL tubes and harvested by centrifugation at 100 x g for 10 minutes at room temperature.

[0970] Resuspend the cells to 10 million / mL in ESF921 (0.5X streptomycin / penicillin) medium containing BSA (final 10 mg / mL) and 10% DMSO. Transfer 500 μL aliquots of the cells to 1.8 mL cryotubes and freeze overnight at -80 °C in a Nunc Cryo 1 °C freezing container.

[0971] SEQ ID NO:1

[0972]

[0973] Protein expression and purification

[0974] An aliquot of BIIC of the Werner helicase protein His-ZZ-3C-WRN (aa N517 - P1238, pLAF1202) was diluted 1 / 100 into ESF921 medium and further diluted 1 / 100 into an expression / production flask with Sf21 cells (1 million cells / mL) in 1 L of ESF921 medium and incubated for 96 h (27 °C, 130 rpm) for protein expression.

[0975] The WRN protein was purified using the following protocol. The cell pellet was 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). The cells were lysed in three passes through a homogenizer (Avestin, Emulsiflex C3) at 800 - 1000 bar. The lysed sample was centrifuged at 48000 x g for 40 minutes (Sorvall RC5B, SS - 34 rotor) and the supernatant was passed through a 0.45 μm filter.

[0976] The lysate was loaded onto On a HisTrap Crude FF 5 mL column (GE Healthcare) on a Pure 25 chromatography system (GE Healthcare). Contaminating proteins were washed away with buffer A and the bound proteins were eluted with a linear gradient from 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, internally generated) was added to the eluted protein. The N-terminal purification tag was cleaved off by the protease during overnight dialysis at 5 °C against 2 L of buffer (50 mM Tris pH 7.0, 150 mM NaCl, 1 mM TCEP, 10% glycerol, 0.02% CHAPS). 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 the equilibration buffer. The bound target protein was eluted with a linear gradient of the same buffer containing 1 M sodium chloride over 20 column volumes 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. Finally, the purified protein was aliquoted and frozen on dry ice. The purity, quantity, and characteristics of the protein were determined by RP-HPLC and LC-MS.

[0977] In Vitro Enzymatic Activity Assay of WRN Helicase

[0978] An ATPase assay was established to measure the DNA-dependent ATP hydrolysis activity of the WRN helicase. This assay was also used to evaluate the inhibitory properties of the compounds of the present invention on the DNA-dependent WRN ATPase activity.

[0979] The core helicase motif of the WRN protein (aa N517 - P1238) was generated for this assay (protein production as described above). A 45 - oligonucleotide sequence called "FLAP26" as described by Brosh et al., 2009, DOI:10.1074 / jbc.M111446200 (TTTTTTTTTTTTTTTTTTTTTCCAAGTAAAACGACGGCCAGTGC; SEQ ID NO:2) was purchased from IDT (Integrated DNA Technologies, Leuven, Belgium) and used as the single - stranded DNA substrate. The ADP - Glo assay kit (Promega, Madison, Wisconsin) allows quantification of ADP produced in the ATP hydrolysis reaction for setting up this assay.

[0980] Time - course experiments were first performed to determine the optimal enzymatic 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 μM ATP in the following assay buffer: 30 mM Tris pH 7.5, 2 mM MgCl2, 0.02% BSA, 50 mM NaCl, 0.1% pluronic F127 prepared in DNase - free water.

[0981] To evaluate the inhibitory properties of the compounds of the present invention, serial dilutions (10 semi - log dilutions from a 10 mM DMSO solution) were prepared in DMSO. In a 384 - well low - volume assay plate (Greiner, #784075), 50 nanoliters of each concentration was pre - incubated with 2.5 microliters of 20 nM WRN helicase protein in assay buffer with 600 μM ATP for 3 hours. Control wells included a "high control" (no inhibition) which contained DMSO without the test compound; and a "low control" (maximal inhibition) which contained buffer without protein. The reaction was started by adding 2.5 microliters of 0.4 nM FLAP26 and incubated at room temperature for 30 minutes. The reaction was terminated by adding 5 microliters of the first ADP - Glo reagent and incubated for one hour to remove excess ATP. Subsequently, 10 microliters of the ATP detection reagent was added and incubated for another hour before reading. Luminescence output was recorded using a Tecan 1000 reader with a 5 - minute delay before reading. Each concentration of the compound was tested in duplicate in the assay plate.

[0982] The method described by Formenko et al., 2006, DOI: 10.1016 / j.cmpb.2006.01.008 was used for data analysis with in-house developed software (the undisclosed Novartis AG Helios software application, Novartis Institutes for BioMedical Research). After normalizing the activity values of the wells to % inhibition (% inhibition = [(high control - sample) / (high control - low control)] x 100), IC 50 fits were performed from duplicate assays on each plate according to [4]. Data analysis can also be performed using commercially available software designed to derive IC 50 values using 4-parameter fitting (e.g., GraphPad Prism, XLfit). The reported IC 50 values are the geometric mean of at least 2 independent replicates.

[0983] Method for detecting the effect on cell proliferation

[0984] The colon cancer cell lines SW48 (RRID:CVCL_1724), HCT 116 (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.

[0985] SW48, SNU-407, and DLD1-WRN-KO cells were cultured in growth medium consisting of RPMI-1640 (Amimed, catalog number 1-41F22-I), 2 mM L-glutamine (Amimed, catalog number 5-10K50), 10 mM HEPES (Gibco, catalog number 15630-056), 1 mM sodium pyruvate (Amimed, catalog number 5-60F00-H), 1X penicillin-streptomycin (Amimed, catalog number 4-01F00-H), and 10% fetal bovine serum (Amimed, catalog number 2-01F30-G, lot number 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 in a humidified 5% CO2 incubator at 37°C.

[0986] After filtration through a Steriflip-NY 20-μm filter (Millipore, catalog number SCNY00020), trypsinized cells were seeded at 2,000 (SW48) or 1,500 (SNU-407, DLD1-WRN-KO, HCT 116) cells / well in 100 μL of growth medium in white clear-bottom 96-well plates (Costar, catalog number 3903). Three replicate plates were prepared for each compound treatment condition. In addition, one plate (referred to as “day 0”) was prepared to quantify the number of live cells at the time of compound addition. After incubation overnight at 37°C in a humidified 5% CO2 atmosphere, eight 3-fold serial dilutions of a given compound stock solution (obtained at a concentration of 10 mM in DMSO and stored at 4°C) were directly dispensed into each triplicate assay plate using an HP 300D non-contact digital dispenser (TECAN). In all wells, the final concentration of DMSO was normalized to 0.1%. At 96 h after compound addition, cell ATP levels were evaluated as a surrogate for cell viability after addition of 50 μL of CellTiterGlo (Promega, catalog number G7573) reagent and luminescence quantification was performed on an MPLEX multimode plate reader (TECAN) after incubation at room temperature for 10 min. On the day of compound addition, the number of live cells in the “day 0” plate was quantified in the same manner.

[0987] For data analysis, prior to further calculations, the measured background signal determined in wells containing medium but no cells was subtracted from all other data points. The extent of growth inhibition and potential cell killing was evaluated by comparing the ATP levels in compound-treated cells (measured using CellTiterGlo (Promega)) to the ATP levels present at the time of compound addition. To this end, the following conditional concept was programmatically applied in HELIOS, an in-house software that applies a multi-step decision tree to achieve optimal concentration-response curve fitting (Gubler et al., SLASD DOI: 10.1177 / 2472555217752140) to calculate the growth percentage (%G) for each compound-treated well: %G = ((T - V0) / V0)) * 100 when T < V0; and %G = ((T - V0) / (V - V0)))*100 when T ≥ V0; where V0 is the viability level at the time of compound addition, and V and T represent the vehicle control viability level and the compound-treated viability level, respectively, at the end of compound incubation. 100%, 0%, and -100% represent no growth inhibition, growth arrest, and complete cell kill, respectively. Conventionally, the compound concentration resulting in half-maximal growth inhibition (GI50) and the residual cell viability at the highest tested compound concentration (data (cmax), expressed as a percentage) were calculated. Data analysis can also be performed using commercially available software designed to derive IC50 values using 4-parameter fitting (e.g., GraphPad Prism, XLfit). The reported GI 50 values are the geometric mean of at least 2 independent replicates.

[0988] The following table shows the IC 50 data in the WRN ATPase assay and the GI 50 data in the proliferation assays using the SW48 and DLD1-WRN-KO cell lines for the compounds of the present invention. For example, Example 11 is a WRN ATPase inhibitor with a biochemical IC 50 of 0.05 μM, a proliferation GI 50 of 0.06 μM in SW48, and greater than 10 μM in the DLD1 WRN-KO cell line.

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996] The data is the geometric mean of at least two repeated measurements.

[0997] Preparation of Compounds

[0998] The compounds of the present invention can be prepared as described in the following examples. The examples are intended to illustrate the invention and should not be construed as limiting it.

[0999] Instrumental Methods

[1000] Microwave: Unless otherwise stated, all microwave reactions were carried out in a Biotage initiator or an Anton Paar monowave 450, irradiated at 0 - 400 W by a magnetron at 2.45 GHz with the processing capacity of Robot Eight / Robot Sixty / Robottwentyfour.

[1001] UPLC - MS method: Using Waters Acquity UPLC with a Waters SQ detector, unless otherwise stated.

[1002] UPLC - MS method: Using Waters Acquity UPLC with a Waters SQ detector, unless otherwise stated.

[1003] UPLC-MS 1

[1004]

[1005]

[1006] UPLC-MS 3

[1007]

[1008] UPLC-MS 4

[1009]

[1010] UPLC-MS 7

[1011]

[1012]

[1013] UPLC-MS 8

[1014]

[1015] UPLC-MS 10

[1016]

[1017] UPLC-MS 11

[1018]

[1019] UPLC-MS 12

[1020]

[1021] UPLC-MS 15

[1022]

[1023] UPLC-MS 17

[1024]

[1025] UPLC-MS 18

[1026]

[1027]

[1028] HPLC method:

[1029] HPLC 1

[1030]

[1031] HPLC 4

[1032]

[1033] HPLC 5

[1034]

[1035]

[1036] HPLC 6

[1037]

[1038] Preparative Methods

[1039] Column chromatography:

[1040] Unless otherwise specified, column chromatography was performed on silica gel using a pre-packed column (described in detail below) or on a glass column according to standard flash chromatography.

[1041] System 1 Teledyne ISCO, CombiFlash Rf, CombiFlash Rf+

[1042] System 2 Biotage Isolera

[1043] Column Pre-packed RediSep Rf column, or SNAP column

[1044] Sample adsorption On Isolute, or on silica gel, or as a solution

[1045] Supercritical fluid chromatography (SFC):

[1046] Purification was completed on a Waters preparative SFC-100-MS system equipped with the latest ABSYS, Waters 2998 photodiode array detector and Waters MS single quadrupole detector.

[1047] SFC 8

[1048] Instrument: WATERS SFC 100 with the latest ABSYS

[1049] Mobile phase: A: CO2, B: MeOH

[1050] Flow rate: 150 mL / min MeOH + 30 mL / min CO2, a constant flow rate of 180 mL / min

[1051] Column: 100 x 30 Reprosil NH2 100A 3μm

[1052] Temperature: 50 °C

[1053] Back pressure: 100 bar

[1054] Detection UV: 210 - 400 nm

[1055] Gradient: 16% B to 24% B in 4 min

[1056] Reverse phase HPLC:

[1057] Acidic RP-HPLC 1

[1058]

[1059] Preparation of Compounds

[1060] The following examples are intended to illustrate the invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. Unless otherwise mentioned, all evaporations are carried out under reduced pressure, typically between about 15 mmHg and 100 mmHg (= 20 - 133 mbar). The abbreviations used are those conventional in the art.

[1061] All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents and catalysts used for synthesizing the compounds of the present invention are commercially available or can be produced by organic synthesis methods known to those of ordinary skill in the art. In addition, the compounds of the present invention can be produced by organic synthesis methods known to those of ordinary skill in the art, as shown in the following examples.

[1062] The structures of all end products, intermediates and starting materials are confirmed by standard analytical spectroscopic features (e.g., MS, IR, NMR). The absolute stereochemistry of representative examples of the preferred (most active) isomers has been determined by analyzing the X-ray crystal structure of the complex in which each compound binds to WRN or by analyzing the small molecule X-ray crystal structure of the precursor or final compound.

[1063] Amines synthesized via acid deprotection of Boc precursors are generally obtained in the form of HCl or TFA salts. The corresponding free base can be isolated by partitioning between DCM and aq sat NaHCO3, as described for intermediate D.

[1064] General Conditions

[1065] Using electrospray, chemical and electron impact ionization methods, mass spectra were obtained on an LC-MS system using a series of instruments configured as follows: Waters Acquity UPLC with a Waters SQ detector, Shimadzu NEXERA UPLC PDA with a Shimadzu LCMS2020 as the MSD, Agilent1200HPLC PDA with an AB Sciex API2000 TQ as the MSD, and Agilent 1200HPLC PDA with an AB Sciex API3200 QTRAP as the MSD. [M+H] + Refers to the protonated molecular ion of a chemical species.

[1066] NMR spectra were recorded using a Bruker Ultrashield TM 400 (400 MHz), Bruker Ultrashield TM400Plus (400 MHz), Bruker Ultrashield TM 600 (600 MHz) and Bruker Ascend TM The 400 (400 MHz) spectrometer was run, with or without tetramethylsilane as an internal standard. Chemical shifts (δ values) were reported in ppm downfield from tetramethylsilane, and the spectral splitting patterns were designated as: singlet (s), doublet (d), triplet (t), multiplet, unresolved or more overlapping signals (m), broad signal (br). Solvents are given in parentheses.

[1067] Celite: Celite R (Celite Corporation) = diatomaceous earth-based filter aid

[1068] Phase separator: Biotage-Isolute phase separator - (part number: 120 - 1906 - D, for 15 mL; part number: 120 - 1908 - F, for 70 mL; and part number: 120 - 1909 - J, for 150 mL)

[1069] Thiol: SiliCYCLE thiol metal scavenger - (part number: R51030B, loading: 1.31 mmol / g, particle size: 40 - 63 μm)

[1070] Si - Thiol: Biotage thiol metal scavenger - (part number: 9180 - 0100, loading: 1.3 mmol / g)

[1071] PL - BnSH MP - resin: Agilent thiol metal scavenger - (part number: PL3582 - 6689, 2.2 mmol / g 100A 150 - 1 kg)

[1072] Si - TMT: Biotage thiol metal scavenger - (part number: 9538) - 301: Alfa Aesar thiol metal scavenger (part number: 45902)

[1073] PL - HCO3 MP SPE column (500 mg / 6 mL) - (part number: PL3540 - C603)

[1074] PL - HCO3 MP SPE column (100 mg / 6 mL) - (part number: PL3540 - A603)

[1075] Preparation of Sodium Salts

[1076] The compound can be suspended in tert-butanol and 0.1 M NaOH (1 equivalent) is added. The mixture can be stirred / sonicated at room temperature. If the suspension turns into a clear solution, it is lyophilized. If the suspension remains turbid, water can be added and the resulting solution is lyophilized. If no change occurs, up to a total of 2 equivalents of 0.1 M NaOH is added until a clear solution is observed, and then it is lyophilized. If the NMR of the resulting solid still contains tert-butanol, the solid is dissolved in a small amount of water and lyophilized again.

[1077] Abbreviations

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084] Preparation of Final Compounds

[1085] Scheme 1 Preparation of the final compound (Route I)

[1086]

[1087] Route I

[1088] 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

[1089]

[1090] 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). At 0 °C, 2-bromo-N-(4-(trifluoromethyl)phenyl)acetamide (450 mg, 1.60 mmol) and DIPEA (760 μmol, 4.35 mmol) were added. The RM was stirred at room temperature for 12 h. Water was added and the resulting solid was filtered off. The crude product was purified by column chromatography (Combiflash column: 12 g, eluent DCM:MeOH 100:0 to 95:5). The fractions containing the product were combined, concentrated and dried under HV to give the title compound.

[1091] LC-MS: Rt = 1.50 min; MS m / z [M+H] + 579.2; UPLC-MS 11

[1092] Examples 2 to 10 were prepared using a method similar to Example 1, using methods known to the skilled chemist in the art and using starting materials in the public domain. Examples 7 to 10 were analyzed from the crude reaction mixture.

[1093]

[1094]

[1095]

[1096] Scheme 2 Preparation of the final compound (Routes II, III)

[1097]

[1098] Route II

[1099] 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-dihydrofuro[3,2-c]pyridin-6-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)-yl)acetamide

[1100]

[1101] Step 1N-(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

[1102] To a beige suspension of 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 the addition of HATU (61.3 mg, 161 μmol). The reaction mixture (RM) was stirred at room temperature for 30 minutes. The RM was diluted with water and extracted three times with DCM. The combined organic phases were dried over 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 afford the title compound.

[1103] LC-MS: Rt = 1.04 min; MS m / z [M+H] + 773.6 / 775.6, m / z [M-H] - 771.5 / 773.6; UPLC-MS1

[1104] 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

[1105] 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 anhydrous EtOH (1.94 mL) was added HCl 1.25 M 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 in Et2O. The resulting pale yellow suspension was filtered. The filter cake was washed with Et2O and dried to give a beige solid. The filtrate was concentrated under vacuum to give a light brown residue. The filter cake was dissolved in MeOH and filtered through a PL-HCO3 MP SPE column. The filtrate was concentrated under reduced pressure to give a beige solid. The crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 5% to 100% B in 20 min). The fractions containing the product were combined, basified with aq sat NaHCO3, extracted twice with DCM, dried over a phase separator and concentrated under reduced pressure to give the title compound.

[1106] LC-MS: Rt = 0.93 min; MS m / z [M+H] + 729.5 / 731.5, m / z [M-H] - 727.5 / 729.4; UPLC-MS1

[1107] Examples 12 to 34 were prepared using a method similar to Example 11, using methods known to a skilled chemist in the art and using starting materials in the public domain.

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116] Route III

[1117] 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

[1118]

[1119] To a deep 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). The RM was stirred for 5 minutes and then 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 room temperature for 5 h. The RM was diluted with DCM and washed with water. The aqueous phase was extracted once with DCM. The combined organic phases were dried over a phase separator, concentrated under reduced pressure and dried under HV. The crude product was purified by column chromatography (RediSep column: silica 4 g, eluent DCM:DCM / MeOH (9 / 1) 100:0 to 0:100). The fractions containing the product were combined, concentrated and dried under HV to afford the title compound.

[1120] LC-MS: Rt = 1.02 min; MS m / z [M+H] + 678.1, m / z [M-H] - 676.1; UPLC-MS 3

[1121] 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

[1122]

[1123] A solution of 3-hydroxyisonicotinic acid (53.8 mg, 386 μmol) in DCM (4 mL) was cooled to 0 °C. Then 1-chloro-N,N,2-trimethyl-1-propenylamine (56.0 μL, 425 μmol) was added and the RM was stirred at room temperature for 2 h. The solution was cooled to 0 °C again 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 room temperature for 1 h. The RM was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried over 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.

[1124] LC-MS: Rt = 0.95 min; MS m / z [M+H] + 639.4, m / z [M-H] - 637.3; UPLC-MS 4

[1125] Examples 37 to 68 were prepared using methods similar to Examples 35 and 36, using methods known to a skilled chemist in the art and starting materials in the public domain.

[1126]

[1127]

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134]

[1135]

[1136] Scheme 3Preparation of the final compound containing R4 N-acetyl-piperazine (Routes IV, V)

[1137]

[1138] Route IV

[1139] 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

[1140]

[1141] 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 Et3N (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 room temperature for 2.5 days and then at 50 °C for 4 h. The RM was purified by reversed-phase preparative HPLC (acidic RP-HPLC 1: 28% to 58% B in 20 min). The fractions containing the product were combined and basified with a small amount of saturated aqueous NaHCO3. The ACN was removed under reduced pressure and the resulting solid was filtered off, washed with water and dried under HV to give the title compound as a white solid.

[1142] LC-MS: Rt = 0.93 min; MS m / z [M+H] + 560.4, m / z [M-H] - 558.4; UPLC-MS 8

[1143] Examples 70 to 103 were prepared using a method similar to Example 69, using methods known to a skilled chemist in the art and starting materials in the public domain.

[1144]

[1145]

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152]

[1153]

[1154] Route V

[1155] 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

[1156]

[1157] 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), Pd X-Phos G3 (28.1 mg, 33.0 μmol) and K3PO4 1 M aqueous solution (2.00 mL, 2.00 mmol) were mixed in dioxane (1 mL) and stirred at 65 °C for 1 hour. Water, saturated NaHCO3 aqueous solution and DCM were added. The aqueous layer was washed twice with DCM. The combined organic phases were dried over a phase separator and concentrated under reduced pressure. The residue was dissolved in DCM. Then 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: silica 40 g, eluent DCM:DCM / MeOH (9 / 1) 100:0 to 0:100) to give the title compound.

[1158] LC-MS: Rt = 0.92 min; MS m / z [M+H] + 562.5, m / z [M-H] - 560.5; UPLC-MS 8

[1159] Examples 105 to 135 were prepared using a method similar to that of Example 104, using methods known to a skilled chemist in the art and starting materials in the public domain.

[1160]

[1161]

[1162]

[1163]

[1164]

[1165]

[1166]

[1167]

[1168]

[1169] Scheme 4 Preparation of the final compound containing R4 piperidine (Route VI)

[1170]

[1171] Route VI

[1172] 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

[1173]

[1174] 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 room temperature for 1 hour. The RM was concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC (RP-HPLC acidic 1:20 min 5% to 100% B), then purified by preparative chiral HPLC (Instrument: Sepiatec prep SFC-100; Column: LUX Amylose-1 (Chiralpak AD), 250 mm x 30 mm 5 μm; Eluent: A: 37% IPA + 0.1% NH3, B: 63% scCO2; Flow rate: 80.0 mL / min; Detection: UV; Injection volume: 2.3 mL; Gradient: Isocratic, A: 37%, B: 63%; Column oven temperature: 40 °C; BPR: 120 bar) to give the title compound.

[1175] LC-MS: Rt = 1.01 min; MS m / z [M+H] + 673.4, m / z [M-H] - 671.4; UPLC-MS 8

[1176] Examples 137 to 146 were prepared using a method similar to Example 136, using methods known to a skilled chemist in the art and starting materials in the public domain. In some cases, the order of steps was changed.

[1177]

[1178]

[1179]

[1180]

[1181] Scheme 4 Preparation of the final compound containing R4 piperazine (Route VII)

[1182]

[1183] 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

[1184]

[1185] Under argon, 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). Et3N (34.4 μL, 248 μmol) was added, followed by acetic anhydride (9.30 mg, 91.0 μmol). The reaction mixture (RM) was stirred at room temperature for 2 h. Et3N (30.0 μL, 216 μmol) and acetic anhydride (9.30 mg, 91.0 μmol) were added again, and the RM was stirred at room temperature for 2.25 h. The RM was diluted with DCM and washed with saturated aqueous NH4Cl and water. The organic phase was dried over a phase separator and concentrated under reduced pressure. The crude product was purified by SFC (SFC 8). The fractions containing the product were combined, concentrated under reduced pressure and dried under HV to give the title compound as a white solid.

[1186] LC-MS: Rt = 0.97 min; MS m / z [M+H]+ 586.4, m / z [M-H]- 584.3; UPLC-MS 4

[1187] Examples 148 to 166 were prepared using a method similar to that of Example 147, using methods known to a skilled chemist in the art and starting materials in the public domain.

[1188]

[1189]

[1190]

[1191]

[1192]

[1193]

[1194] Intermediate

[1195] Intermediate A2-(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

[1196]

[1197] 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

[1198]

[1199] Dissolve 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) in DMF (50 mL), and stir the RM at 80 °C for 2 h. Cool the RM to room temperature, dilute with DCM, and extract the organic phase with saturated aqueous NaHCO3 and brine, dry over Na2SO4 and concentrate under reduced pressure. Purify the crude product by column chromatography (eluent heptane:EtOAc / MeOH (9 / 1) 100:0 to 30:70). Combine the fractions containing the product and concentrate under reduced pressure, then crystallize from TBME to obtain the title compound.

[1200] LC-MS: Rt = 1.15 min; MS m / z [M+H] + 614.0, m / z [M-H] - 612.0; UPLC-MS 4

[1201] 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

[1202]

[1203] Dissolve 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-dioxaborolane (3.95 g, 18.8 mmol), K3PO4 1.5 N (20.9 mL, 31.3 mmol) and XPhos Pd G3 (1.06 g, 1.25 mmol) in 1,4-dioxane (50 mL). Stir the RM at 90 °C for 1 h and after cooling, dilute with EtOAc. Wash the organic phase with saturated aqueous NaHCO3 and brine, dry over Na2SO4 and concentrate under reduced pressure. Dissolve the substance in DCM / MeOH (1:1) and add Si-Thiol (258 mg). After stirring for 30 min, filter the mixture and concentrate. Crystallize the crude product from DCM and TBME to afford the title compound.

[1204] LC-MS: Rt = 1.13 min; MS m / z [M+H] + 618.2, m / z [M-H] - 616.1; UPLC-MS 4

[1205] 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

[1206]

[1207] Dissolve 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) in DCM (50 mL) and add TFA (22.3 mL, 289 mmol). Stir the RM at room temperature for 1 h and then concentrate under reduced pressure. Add and remove toluene again and repeat the process. Dissolve the residue in EtOAc and wash with saturated aqueous NaHCO3 and brine. During extraction, the product crystallizes, collect the solid and dry to afford the title compound.

[1208] LC-MS: Rt = 0.84 min; MS m / z [M+H] + 518.2, m / z [M-H] - 516.0; UPLC-MS 4

[1209] 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

[1210]

[1211] Step 1 2-bromo-5-cyclopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one

[1212]

[1213] 5-bromo-4H-1,2,4-triazol-3-amine (5.00 g, 29.1 mmol) and ethyl 3-cyclopropyl-3-oxopropionate (6.83 g, 43.7 mmol) were mixed in 1-butanol (40 mL). H3PO4 (8.40 g, 72.9 mmol) was added and the reaction mixture (RM) was stirred at 100 °C for 20 h. Ethyl 3-cyclopropyl-3-oxopropionate (1.00 g, 6.40 mmol) was added and the RM was stirred at 100 °C for 22.5 h. Ethyl 3-cyclopropyl-3-oxopropionate (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 filter cake was washed with a small amount of EtOH and the filtrate was concentrated under reduced pressure. The filter cake was washed with hot EtOH and the filtrate was concentrated under reduced pressure. Both the filter cake and the filtrate contained the product, so the two were combined again and concentrated under reduced pressure. The resulting oil was left to stand at room temperature over the weekend. The crystallized solid was filtered out and washed with Et2O 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 of silica, eluent DCM:MeOH 100:0 to 85:15). The fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a white solid (923 mg, 99% purity, yield: 12%). The mother liquor was concentrated, adsorbed onto Isolute and purified by column chromatography (silica gel column: 120 g of silica, eluent DCM:MeOH 100:0 to 85:15). The fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a beige solid (1.14 g, 99% purity, yield: 15%).

[1214] Total: 2.06 g, 99% purity, yield: 27%).

[1215] LC-MS: Rt = 0.50 min; MS m / z [M+H] + 255.0 / 257.0, m / z [M-H] - 252.9 / 254.9; UPLC-MS4

[1216] 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

[1217]

[1218] 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 the RM was stirred at room temperature. The resin disintegrated. The suspension was filtered and the cake was washed with water. The cake (1.78 g) was suspended in DCM and MeOH and filtered out. Then it was washed and dried under Hv to give the title compound as a beige solid (829 mg, 85% purity, yield: 33%).

[1219] LC-MS: Rt = 1.03 min; MS m / z [M+H] + 456.1 / 458.1, m / z [M-H] - 453.9 / 455.9; UPLC-MS4

[1220] 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

[1221]

[1222] 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-dioxaborolane (926 mg, 4.41 mmol) and Pd X-Phos G3 (124 mg, 147 μmol) were mixed in dioxane (15 mL), and 1 M K3PO4 in water (8.81 mL, 8.81 mmol) was added. The RM was evacuated and backfilled with argon several times, 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 over a phase separator and concentrated under reduced pressure. The aqueous layer was a suspension, which was filtered. The aqueous layer was extracted three times with DCM, dried over a phase separator and concentrated under reduced pressure. All the organics were combined with the filter cake and suspended in hot EtOH (500 mL). Then it was filtered, the filter cake was dissolved in warm ACN, and Si-Thiol (2.00 g) was added. The mixture was stirred at 45 °C for 5 min, then filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a grey solid (650 mg, 99% purity, yield: 48%). The mother liquor was mixed with Si-Thiol (2.00 g) and stirred at 45 °C for 5 min, then filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a bright brown solid (610 mg, 79% purity, yield: 36%).

[1223] Total: 1.26 g, 89% purity, yield: 84%.

[1224] LC-MS: Rt = 0.98 min; MS m / z [M+H] + 460.3, m / z [M-H] - 458.3; UPLC-MS 4

[1225] 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

[1226]

[1227] 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 left to stand at room temperature 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 room temperature and left to stand at room temperature 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 through a phase separator and concentrated under reduced pressure. The brown solid residue was mixed with hexane and the suspension was filtered. The filter cake was mixed with hexane again and filtered again. The filter cake was dried under HV to give the title compound as a light brown solid (508 mg, 74% purity, yield: 53%).

[1228] LC-MS: Rt = 1.04 min; MS m / z [M+H] + 538.1 / 540.1, m / z [M-H] - 536.2 / 538.2; UPLC-MS4

[1229] 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

[1230]

[1231] 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 and left standing overnight at room temperature, and then it was combined with another batch. The RM was extracted with EtOAc (3 x 80 mL), saturated aqueous NaHCO3 (2 x 30 mL), and water (2 x 30 mL). The organic layer was washed with 1 N HCl (4 x 25 mL) and water (2 x 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 filter cake was washed thoroughly 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 column: silica 24 g, eluent DCM:MeOH / Et3N (95 / 5) 90:10 to 50:50), the fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a solid (97.0 mg, 87% purity, yield: 21%).

[1232] LC-MS: Rt = 0.86 min; MS m / z [M+H] + 544.3, m / z [M-H] - 542.3; UPLC-MS 3

[1233] 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

[1234]

[1235] ​ 2-Bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one

[1236]

[1237] 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%).

[1238] ​ 2-Bromo-6-iodo-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one

[1239]

[1240] Under nitrogen, 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. Acetic acid (29.1 mL) was added, followed by NIS (2.16 g, 9.61 mmol). The RM was stirred at 60 °C for 1 h. The RM was cooled to room temperature. The solid was filtered off and washed 3 times with EtOH. The solid was dried under Hv to give the title compound (2.76 g, 95% purity, yield: 89%).

[1241] LC-MS: Rt = 0.56 min; MS m / z [M+H] + 354.9 / 356.9, m / z [M-H] - 353.0 / 355.0; UPLC-MS8

[1242] ​ 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

[1243]

[1244] Palladium G3-tricyclohexylphosphine (183 mg, 282 μmol), i.e., palladium(II) [(tricyclohexylphosphine)-2-(2-aminobiphenyl)] methanesulfonate, was purged with nitrogen. 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) were added, followed by K3PO4 1.5 M in water (5.63 mL, 8.45 mmol). The RM was stirred at 70 °C for 1 h. 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. The 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. 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 column: silica 40 g, eluent DCM:DCM / MeOH (8 / 2) 100:0 to 50:50) to afford the title compound as a white powder (734 mg, 90% pure, yield: 57%).

[1245] LC-MS: Rt = 0.86 min; MS m / z [M-H] - 408.2 / 410.2; UPLC-MS 14

[1246] ​ 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

[1247]

[1248] Under N2 atmosphere, PtO2 (40.6 mg, 179 μmol) was added 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). The flask was purged with hydrogen for 2 minutes. The reaction mixture (RM) was stirred at room temperature for 2 hours. PtO2 (66.0 mg, 291 μmol) was added and the RM was stirred at room temperature for 2 hours. PtO2 (103 mg, 454 μmol) was added and the RM was stirred at room temperature overnight. PtO2 (122 mg, 543 μmol) was added and the RM was stirred at room temperature. The RM was filtered through a pad of diatomaceous earth. The crude product was purified by column chromatography (silica column: silica 12 g, eluent DCM:DCM / MeOH (8 / 2) from 100:0 to 50:50) to give the title compound (580 mg, 80% pure, yield: 63%).

[1249] LC-MS: Rt = 0.89 min; MS m / z [M+H] + 412.2 / 414.2, m / z [M-H] -

[1250] 410.3 / 412.3; UPLC-MS 8

[1251] ​ 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

[1252]

[1253] 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 N2 atmosphere, DMF (1.4 mL) and K3PO4 1 M in water (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-dioxaborolane (60.0 mg, 286 μmol) were added and the RM was stirred for 3 h to afford the title compound as the RM.

[1254] LC-MS: Rt = 1.25 min; MS m / z [M+H] + 416.3, m / z [M-H] - 414.4; UPLC-MS 8

[1255] ​ 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

[1256]

[1257] 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, 2-bromo-N-(4-(trifluoromethyl)phenyl)acetamide (397 mg, 1.41 mmol) was added. 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 through a phase separator and concentrated under reduced pressure. The mixture was treated with Si TMT. The solvent was removed, the residue was adsorbed onto Isolute and purified by column chromatography (silica column: silica 24 g, eluent DCM:DCM / MeOH (8 / 2) 100:0 to 70:30), and then purified in 5 portions by reverse-phase preparative HPLC (5x RP-HPLC acidic 1: 20% to 95% B in 20 min) to give the title compound (185 mg, 60% pure, yield: 18%).

[1258] LC-MS: Rt = 1.18 min; MS m / z [M+H] + 617.4, m / z [M-H] - 615.5; UPLC-MS 8

[1259] ​ 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

[1260]

[1261] To 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 tert-butyl ester (145 mg, 198 μmol), TFA (306 μL, 3.97 mmol) in DCM (2 mL) was added. The RM was stirred at room temperature for 1 h. DCM was added and the crude product was washed with NaOH solution. The aqueous layer was washed with EtOAc. The organic layer was dried through a phase separator and concentrated under reduced pressure to give the title compound (130 mg, 79% purity, quantitative).

[1262] LC-MS: Rt = 0.74 min; MS m / z [M+H] + 517.3, m / z [M-H] - 515.4; UPLC-MS 8

[1263] ​ 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

[1264]

[1265] ​ 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

[1266]

[1267] 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 at 80 °C under nitrogen for 12 h. The mixture was concentrated in vacuo to remove EtOH, then quenched by addition of saturated aqueous NaHCO3 (1 L) and extracted with DCM (3 x 1 L). The combined organic layers were washed with brine (3 x 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 fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a yellow solid.

[1268] LC-MS: Rt = 0.91 min; MS m / z [M+H-Boc] + 327.1 / 329.1, m / z [M+H] + 427.2 / 429.2, m / z [M-H] - 425.2 / 427.2; UPLC-MS 1

[1269] LC-MS: Rt = 4.53 min; MS m / z [M+H-Boc] + 327.1 / 329.1, m / z [M-H]- 425.2 / 427.2; UPLC-MS 2

[1270] 1 H NMR (400 MHz, 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 = 7.4 Hz, 3H)

[1271] ​ 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

[1272]

[1273] 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-dioxaborolane (11.1 g, 52.7 mmol) and Na2CO3 (7.44 g, 70.2 mmol). The RM was degassed with nitrogen for 15 minutes. Pd(dppf)Cl2.DCM (1.43 g, 1.76 mmol) was added and the RM was stirred at 100 °C for 14 hours. Water (300 mL) was added and the RM was extracted with 10% MeOH in DCM (2 x 500 mL). The organic layer was washed with brine (300 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel column: silica 40 g, eluent DCM:MeOH 100:0 to 97:3). The fractions containing the product were combined, concentrated in vacuo and dried under HV to give the title compound.

[1274] LC-MS: Rt = 0.96 min; MS m / z [M+H] + 431.4, m / z [M-H] - 429.3; UPLC-MS 3

[1275] 11H NMR (400 MHz, 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 = 7.3 Hz, 3H)

[1276] ​ 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

[1277]

[1278] At 0 °C, 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). 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 filter cake was washed with a small amount of water and dried. The filtrate was filtered again. The second filtrate was extracted with EtOAc (2 x 400 mL), washed with brine (2 x 50 mL), dried over a phase separator and concentrated under reduced pressure. The 2 filter cakes were adsorbed onto Isolute and purified by column chromatography (RediSep column: silica 220 g, eluent: DCM:DCM / MeOH (1 / 1) 100:0 to 80:20). The pure fractions containing the product were combined and concentrated under reduced pressure. The beige solid foam was dissolved in Et2O and the resulting crystals were sonicated. The suspension was left standing overnight, filtered, washed with a small amount of Et2O and dried under HV to give Filter Cake 1 as a white solid. The impure fractions were combined and concentrated under reduced pressure. Then they were combined with the concentrated organic layer from the extraction and purified again by column chromatography (RediSep column: silica 120 g Gold, eluent DCM:DCM / MeOH (1 / 1) 100:0 to 85:15). The fractions containing the product were combined, concentrated under reduced pressure and dried under HV. The beige solid foam was crystallized from Et2O to give Filter Cake 2 as a white solid. Filter Cake 1 and Filter Cake 2 were combined to give the title compound.

[1279] LC-MS: Rt = 1.33 min; MS m / z [M+H-Boc] + 566.0 / 568.0, m / z [M+H] + 666.0 / 668.0, m / z [M-H] - 664.1 / 666.1; UPLC-MS 1

[1280] ​ 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

[1281]

[1282] Dissolve 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) in DCM (70 mL), and add TFA (11.1 mL, 144 mmol). Stir the RM at room temperature for 1 h. Concentrate the RM under reduced pressure. Dissolve the residue in DCM and concentrate again under reduced pressure. This is done three times. Dry the resulting oil under HV to obtain a light rose solid foam. Suspend the foam in Et2O and sonicate. Filter the suspension, wash with Et2O and dry under HV to obtain the title compound as a white solid.

[1283] LC-MS: Rt = 0.78 min; MS m / z [M+H] + 566.4 / 568.4, m / z [M-H] - 564.2 / 566.2; UPLC-MS1

[1284] ​ 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

[1285]

[1286] ​ tert-butyl 4-(3-amino-6-ethyl-2-imino-4-oxo-1,2,3,4-tetrahydropyrimidin-5-yl)piperazine-1-carboxylate

[1287]

[1288] Mix hydrazinecarboximidamide.HCl (35.0 g, 317 mmol) with EtOH (400 mL), and then with aqueous tetrabutylammonium hydroxide (40 wt%, in water) (206 g, 318 mmol). Stir the mixture at 55 °C for 80 min. Add tert-butyl 4-(1-methoxy-1,3-dioxopentan-2-yl)piperazine-1-carboxylate (Intermediate N) (50.0 g, 159 mmol). Stir the mixture at reflux for 6 h, then cool to room temperature. Remove the solvent in vacuo until 1A solvent volume of 1 / 4. The resulting suspension was stirred for 1 - 2 hours and then filtered. The filter cake was dried under vacuum to obtain the title compound as a white solid.

[1289] MS m / z [M + H] + 339.2

[1290] ​ 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

[1291]

[1292] A solution of 3,6-dihydro-2H-pyran-4-carbaldehyde (intermediate Q) (20.0 g, 178 mmol) in NMP and a solution of 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), followed by FeCl3 (48 g, 297 mmol). The black solution was heated to 50 °C in the open air and stirred for 48 hours. The black 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 filter cake was added to acetone (400 mL) and stirred at room temperature for 4 hours. The suspension was filtered and washed with acetone (100 mL). The filter cake was added to EtOH (400 mL) and heated to 70 °C and stirred for 4 hours. Then the mixture was cooled to room temperature, filtered and washed with EtOH (100 mL) to obtain the title compound as a brown solid.

[1293] MS m / z [M + H] + 430.2

[1294] ​ 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

[1295]

[1296] 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 mmol) 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 room temperature overnight. The suspension was sonicated for 10 min, filtered and washed with water. The filter cake was dried under HV, mixed with Et2O and sonicated for 5 min. The suspension was stirred under reflux, filtered and the solid was washed with Et2O. A second batch of solid precipitate was filtered from the filtrate. The two filter cakes were combined to give the title compound as a beige solid.

[1297] LC-MS: Rt = 1.16 min; MS m / z [M+H-Boc] + 445.4, UPLC-MS 1

[1298] ​ : 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

[1299]

[1300] 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 Et2O (3 x 70 mL) and water (3 x 15 mL). The aqueous layer was cooled to 0 °C and 4 M HCl (1.87 mL, 7.50 mmol) was added until pH 3. The resulting suspension was extracted with EtOAc (3 x 200 mL), twice with brine and then twice with EtOAc. The combined organic layers were eluted through a phase separator and concentrated under reduced pressure to give the title compound as a bright brown solid.

[1301] LC-MS: Rt = 0.76 min; MS m / z [M+H-Boc]+ 389.5, m / z [M-H] - 487.2; UPLC-MS 1

[1302] ​ 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

[1303]

[1304] Dissolve 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) in EtOAc (50 mL) and Et3N (4.77 mL, 34.4 mmol). Add 2-chloro-4-(trifluoromethyl)aniline (1.68 g, 8.60 mmol) and T3P 50% in DMF (10.2 mL, 17.2 mmol), and stir the RM at room temperature for 1 hour. Adsorb the RM onto Isolute and purify by column chromatography (RediSep column: silica 120 g, eluent cyclohexane:EtOAc 100:0 to 20:80). Combine and concentrate the fractions containing the product to obtain the title compound.

[1305] LC-MS: Rt = 1.35 min; MS m / z [M+H-Boc] + 566.3 / 568.3, m / z [M-H] - 664.4 / 666.4; UPLC-MS 1

[1306] ​ 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

[1307]

[1308] To a solution of 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) in DCM (50 mL) was added TFA (8.36 mL, 109 mmol), and the RM was stirred at room temperature 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 over a phase separator and concentrated under reduced pressure to give the title compound.

[1309] LC-MS: Rt = 0.79 min; MS m / z [M+H] + 566.3 / 568.3, m / z [M-H] - 564.4 / 566.4; UPLC-MS1

[1310] ​ : 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

[1311]

[1312] ​ tert-butyl 4-(5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[1313]

[1314] 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) were heated in AcOH (139 mL, 2.43 mol) 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 cooled 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.

[1315] LC-MS: Rt = 0.79 min; MS m / z [M+H] + 335.5, m / z [M-H]- 333.4; UPLC-MS 8

[1316] ​ 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

[1317]

[1318] The flask was flame-dried under reduced pressure and backfilled with argon. 4-(5-Methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester (5.00 g, 14.7 mmol) was suspended in anhydrous THF (14.7 mL). At room temperature, a solution of zinc chloride-2,2,6,6-tetramethylpiperidine lithium chloride complex (35.9 mL, 32.2 mmol) was added dropwise to the white suspension at a rate of 1 mL / min. The RM was stirred for 1.5 h. Then it was stored in the refrigerator overnight under argon. The next morning, it was stirred at room temperature for 4 h. Under argon, 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. The RM was stirred at room temperature for 68.5 h. The reaction was partitioned between THF (100 mL) and 5N aqueous NH4Cl solution (100 mL). The aqueous layer was back-extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with 10% aqueous Na2S2O3 solution (150 mL), brine (150 mL), and dried over a phase separator. The solvent was collected and treated with Si-TMT (36.6 g, 17.6 mmol). The suspension was stirred at 40 °C for 1 h and filtered through a celite pad. The volatiles were removed under pressure. The residue was adsorbed onto Isolute and purified by column chromatography ( EcoFlex silica column 330 g, eluent DCM:MeOH 100:0 to 95:5). The fractions containing the product were combined and concentrated to give the title compound as an off-white solid.

[1319] LC-MS: Rt = 0.89 min; MS m / z [M+H] + 417.3, m / z [M-H] - 415.2; UPLC-MS 8

[1320] ​6-(4-Acetylpiperazin-1-yl)-2-(3-fluoropiperidin-1-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one

[1321] ​ : 3-(3-Fluoropiperidin-1-yl)-1H-1,2,4-triazol-5-amine

[1322]

[1323] Suspend 3-fluoropiperidine hydrochloride (1.00 g, 7.30 mmol) in ACN (5 mL). Add dimethyl cyanodithioiminocarbonate (1.07 g, 7.30 mmol) and DIPEA (1.27 mL, 7.30 mmol) and stir the RM at 80 °C for 14 h. Add hydrazine hydrate (11.6 mL, 7.30 mmol) and stir the RM at 80 °C for 14 h. Concentrate the RM under reduced pressure. Add water and extract it with 10% MeOH in DCM. Dry the organic phase over Na2SO4 and concentrate it under reduced pressure to give the title compound.

[1324] ​ : 6-(4-Acetylpiperazin-1-yl)-2-(3-fluoropiperidin-1-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one

[1325]

[1326] Suspend 3-(3-fluoropiperidin-1-yl)-1H-1,2,4-triazol-5-amine (800 mg, 4.32 mmol) in EtOH (25 mL). Add ethyl 2-(4-acetylpiperazin-1-yl)-3-oxobutyrate (Intermediate L) (1.45 g, 5.62 mmol) and acetic acid (200 μL, 3.49 mmol) and stir the RM at 100 °C for 12 h. Concentrate the RM under reduced pressure. Purify the crude product by column chromatography (Combiflash column: 12 g, eluent DCM:MeOH 100:0 to 95:5). Combine the fractions containing the product, concentrate it under HV and dry it to give the title compound.

[1327] ​ 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

[1328]

[1329] ​ 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

[1330] 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 dropwise TFA (3.7 g, 32.4 mmol). The RM was stirred at 40 °C for 5 h. The RM was concentrated under reduced pressure to afford the title compound as a brown residue.

[1331] LC-MS: Rt = 0.42 min; MS m / z [M+H] + 413.2; UPLC-MS 8

[1332] ​ : 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), T3P 50% in EtOAc (3.95 mL, 6.63 mmol) and Et3N (1.85 mL, 13.3 mmol) were mixed in DCM (5 mL) and stirred at room temperature 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 filter cake was dried under HV.

[1333] LC-MS: Rt = 0.97 min; MS m / z [M+H] + 556.4, m / z; UPLC-MS 8

[1334] ​ 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

[1335]

[1336] ​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

[1337]

[1338] 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) (200 mg, 426 μmol), 3,6-dihydro-2H-pyran-4-ylboronic acid pinacol ester (112 mg, 533 μmol) and X-Phos G3 (18.0 mg, 21.0 μmol) were introduced into an MW vial, which was then purged with argon / vacuumed several times. DMF (3 mL) and K3PO4 1 M in water (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 NaHCO3. The combined organic phases were dried over 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 afford the title compound.

[1339] LC-MS: Rt = 0.88 min; MS m / z [M+H] + 473.4, m / z [M-H] - 471.4; UPLC-MS 8

[1340] ​ 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

[1341]

[1342] TFA (604 μL, 7.84 mmol) was added dropwise 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). The RM was stirred at room temperature for 20.5 h. The RM was concentrated under reduced pressure to afford the title compound as a viscous brown residue.

[1343] LC-MS: Rt = 0.47 min; MS m / z [M+H] + 417.3, m / z [M-H] - 415.4; UPLC-MS 8

[1344] ​ 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

[1345]

[1346] 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). K2CO3 (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 x 25 mL) and three times with DCM (3 x 150 mL). The combined organic phases were dried over 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 afford the title compound as a beige solid.

[1347] LC-MS: Rt = 0.90 min; MS m / z [M+H] + 469.2 / 471.2, m / z [M-H] - 467.1 / 469.1; UPLC-MS8

[1348] ​ 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

[1349]

[1350] 3-Bromo-1H-1,2,4-triazol-5-amine (Intermediate R) (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 H3PO4 (2.97 g, 25.8 mmol) were mixed in EtOH (25 mL) and stirred under reflux for 18 h. RM was cooled to room temperature, DIPEA (12.9 mL, 73.6 mmol) and Boc2O (1.71 mL, 7.36 mmol) were added, and RM was stirred at room temperature for 1 h. RM was quenched with aqueous NH4Cl, diluted with DCM, extracted twice with DCM, dried over Na2SO4, concentrated, and dried. The crude product was crystallized from DCM and TBME to afford the title compound.

[1351] LC-MS: Rt = 0.87 min; MS m / z [M+H] + 413.1, m / z [M-H] - 411.0; UPLC-MS 4

[1352] ​ 6-(4-Acetylpiperazin-1-yl)-2-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one

[1353]

[1354] 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. RM was cooled to room temperature and crystallized. Water (200 mL) was added and the mixture was stirred at room temperature for 2 h. The solid was filtered off and the white powder was dried at 30 °C under HV to afford the title compound.

[1355] LC-MS: Rt = 0.53 min; MS m / z [M+H] + 355.1 / 357.1, m / z [M-H] - 353.0 / 355.1; UPLC-MS8

[1356] ​ Ethyl 2-(4-acetylpiperazin-1-yl)-3-oxobutanoate

[1357]

[1358] To a yellow solution of 1-acetylpiperazine (105 g, 808 mmol) in toluene (808 mL) was added ethyl 2-chloroacetoacetate (58.8 mL, 404 mmol). The solution was stirred at 100 °C for 2 h. The RM was filtered through hyflo and the residue was washed with toluene. The filtrate was evaporated. The brown oil was stirred in 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: silica 330 g, eluent EtOAc). The fractions containing the product were combined, concentrated under HV and dried to afford the title compound.

[1359] LC-MS: Rt = 0.60 / 0.87 min; MS m / z [M+H] + 257.2, m / z [M-H] - 255.1; UPLC-MS 8

[1360] ​ tert-Butyl 4-(1-ethoxy-1,3-dioxobutan-2-yl)piperazine-1-carboxylate

[1361]

[1362] At room temperature, K2CO3 (223 g, 1.61 mol) was added to a stirred solution of tert-butyl piperazine-1-carboxylate (150 g, 805 mmol) in ACN (1.5 L), and the resulting mixture was stirred for 15 minutes. Then ethyl 2-chloro-3-oxobutyrate (112 mL, 809 mmol) was added slowly at the same temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a celite pad. The celite pad was washed with EtOAc (2 L). The combined organic layers were concentrated under reduced pressure to give a crude residue. 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 fractions containing the product 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. Then it was purified again by column chromatography (silica gel, 60 - 120 mesh, eluent petroleum ether:EtOAc 100:0 to 85:15). The pure fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a liquid. The two liquids were mixed, dissolved in DCM and concentrated under reduced pressure to give the title compound as a brown liquid. The liquid was dissolved in DCM again and concentrated under reduced pressure. This process was repeated three times, and then dried under vacuum to give the title compound as a brown liquid.

[1363] HPLC: Rt = 11.763 min; HPLC 6

[1364] ​ tert-Butyl 4-(1-methoxy-1,3-dioxopentan-2-yl)piperazine-1-carboxylate

[1365] ​ Methyl 2-chloro-3-oxopentanoate

[1366]

[1367] At room temperature, SO2Cl2 (14.0 kg, 104 mol) was added to a solution of methyl 3-oxopentanoate (10.4 kg, 80.0 mol) in DCM (67 L) over 2.5 hours. The reaction was warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM (20 L) and washed with water (10 L) and brine (10 L), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a light yellow liquid.

[1368] 11H NMR (400 MHz, CDCl3-d) δ 4.65 (s, 1H), 3.68 (s, 3H), 2.59 (m, 2H), 0.96 (t, 3H)

[1369] ​ tert-Butyl 4-(1-methoxy-1,3-dioxopentan-2-yl)piperazine-1-carboxylate

[1370]

[1371] Et3N (22.3 L, 161 mol) was added to a solution of methyl 2-chloro-3-oxopentanoate (12.1 kg, 53.7 mol) in anhydrous ACN (53 L) over 1.5 h, and then tert-butyl piperazine-1-carboxylate (10.0 kg, 53.7 mol) in ACN (50 L) was added dropwise over 2.5 h. The reaction was stirred at 60 °C for 16 h. The RM was filtered and washed with EtOAc (10 L). Then the filtrate was concentrated under reduced pressure, the residue was dissolved in EtOAc (45 L) and washed with water (45 L), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica column 150 mm x 800 mm x 70 mm, eluent: heptane:EtOAc 100:0 to 90:10) to give the title compound.

[1372] HPLC: Rt = 3.681 / 5.513 min; HPLC 4

[1373] ​ 6-Hydroxypyrazolo[1,5-a]pyridine-7-carboxylic acid

[1374]

[1375] ​ : 5-Bromoimidazo[1,2-a]pyridin-6-ol

[1376]

[1377] The flask was flame-dried under vacuum and backfilled with argon. The argon-flushed dry flask was charged with 5-bromo-6-methoxyimidazo[1,2-a]pyridine (1.00 g, 4.18 mmol) and anhydrous DCM (14 mL). 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 warmed to room temperature. The RM was stirred at room temperature for 18 h. The RM was cooled to -78 °C, and then anhydrous MeOH (3.42 mL, 84.0 mmol) was added slowly. The RM was concentrated to dryness. MeOH (5 mL) was added, and then Et2O (100 mL) was added. 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 afford the title compound as a pink powder (1.19 g, 98% pure, yield: 95%).

[1378] LC-MS: Rt = 0.23 min; MS m / z [M+H] + 213.2 / 215.2, MS m / z [M-H] - 210.9 / 212.9; UPLC-MS 7

[1379] ​ : 6-(Benzyloxy)-5-bromoimidazo[1,2-a]pyridine

[1380]

[1381] The flask was flame-dried under vacuum and backfilled with argon. The argon-flushed dry 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 room temperature 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 x 25 mL). The organic layers were combined, washed with brine (50 mL), and dried over a phase separator. The solvent was reduced to dryness to afford a light brown oil (668 mg). The crude product was purified by normal phase chromatography ( FlashPure ID HP silica column 24 g, eluent: heptane:EtOAc 100:0 to 15:85). The fractions containing the product were combined and concentrated to afford the title compound as a beige powder (94.6 mg, 98% pure, yield: 8%).

[1382] LC-MS: Rt = 0.80 min; MS m / z [M+H] + 303.1 / 305.1; UPLC-MS 1

[1383] ​ Ethyl 6-(benzyloxy)imidazo[1,2-a]pyridine-5-carboxylate

[1384]

[1385] Charge the reactor with 6-(benzyloxy)-5-bromoimidazo[1,2-a]pyridine (94.0 mg, 304 μmol), PdCl2(dppf).DCM adduct (12.4 mg, 15.0 μmol), Et3N (128 μL, 912 μmol) and anhydrous EtOH (10 mL). The autoclave is subjected to three cycles of evacuation-backfilling with argon. Subsequently, it is filled with 20 bar of CO at room temperature and then heated at 80 °C for 20 h. Introduce PdCl2(dppf).DCM adduct (12.4 mg, 15.0 μmol) and Et3N (128 μL, 912 μmol), and heat the RM at 90 °C for 20 h. Charge Si-TMT (62.0 mg, 30.0 μmol) into the mixture and stir it at room temperature. Filter the mixture through a pad of diatomaceous earth. Remove the volatiles under pressure to give a yellowish-brown solid (175 mg). Charge the yellowish-brown solid (175 mg) from the previous step and K2CO3 (42.4 mg, 304 μmol) into an argon-flushed dry vial. Suspend the contents in anhydrous DMF (2 mL) and introduce (bromomethyl)benzene (26.0 μL, 213 μmol). Seal the vial and allow the resulting mixture to react at room temperature for 16 h. Introduce (bromomethyl)benzene (13.0 μL, 106 μmol) and stir the RM at room temperature for 22.5 h. Partition the reaction between water (10 mL) and EtOAc (5 mL). Collect the organic layer and back-extract the aqueous layer with EtOAc (3 x 5 mL). Combine the organic layers, wash with brine (20 mL) and dry over a phase separator. Reduce the solvent to dryness to give a light brown oil (107 mg). Adsorb the crude product onto Isolute and purify by normal-phase chromatography ( FlashPure ID HP silica column 12 g, eluent: heptane:EtOAc 100:0 to 0:100). Combine and concentrate the fractions containing the product to give the title compound as a beige solid (37.3 mg, 98% pure, yield: 41%).

[1386] LC-MS: Rt = 0.79 min; MS m / z [M+H] +297.4; UPLC-MS 1

[1387] ​ : 6-(Benzyloxy)imidazo[1,2-a]pyridine-5-carboxylic acid

[1388]

[1389] 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 NaOH in water (119 μL, 119 μmol). The resulting mixture was stirred at room temperature for 23.5 h. 1 M NaOH in water (11.9 mL, 119 μmol) was added, and the RM was stirred at room temperature for 21.5 h. The RM was frozen in a dry ice / acetone mixture and lyophilized to give the title compound as a white powder (33.7 mg, 98% pure, yield: 95%).

[1390] LC-MS: Rt = 0.56 min; MS m / z [M+H] + 269.3, MS m / z [M-H] - 267.1; UPLC-MS 10

[1391] ​ 6-Hydroxypyrazolo[1,5-a]pyridine-7-carboxylic acid

[1392]

[1393] 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 MeOH / THF 1:1 (evacuated and purged with argon several times) was added Pd-C (5 mg, 4.70 μmol). 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).

[1394] LC-MS: Rt = 0.49 min; MS m / z [M+H] + 179.0; UPLC-MS 1

[1395] ​ 7-(Methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylic acid

[1396]

[1397] ​ : 6-Bromofuro[3,2-c]pyridin-7-ol

[1398]

[1399] The flask was flame-dried under vacuum and backfilled with argon. The argon-purged dry 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 RM was cooled to -78 °C, and then 1 M BBr3 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 RM 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, and then Et2O (150 mL) was added. 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 as a white solid (4.58 g, 98% pure, yield: 73%).

[1400] LC-MS: Rt = 0.36 min; MS m / z [M+H] + 214.0 / 216.0, m / z [M-H] - 212.1 / 214.0; UPLC-MS1

[1401] ​ Ethyl 7-hydroxyfuro[3,2-c]pyridine-6-carboxylate

[1402]

[1403] The reactor was charged with 6-bromofuro[3,2-c]pyridin-7-ol (4.58 g, 15.3 mmol), PdCl2(dppf).DCM (624 mg, 764 μmol), Et3N (8.60 mL, 61.1 mmol) and anhydrous EtOH (50 mL). The autoclave was subjected to three cycles of evacuation-backfilling with argon. Subsequently, it was filled with 10 bar of CO at room temperature and then heated at 80 °C for 24 h. Si-TMT (15.6 g, 7.64 mmol) was introduced, and the suspension was stirred at 40 °C for 1 h. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The residue was adsorbed onto Isolute and purified by normal-phase chromatography ( FlashPure ID HP silica column 120 g, eluent: heptane:DCM / MeOH (8:2) 100:0 to 20:80) for purification. The fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a brown solid (2.06 g, 98% pure, yield: 64%).

[1404] LC-MS: Rt = 0.54 min; MS m / z [M+H] + 208.2; UPLC-MS 1

[1405] ​ Ethyl 7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylate

[1406]

[1407] Charge a reactor with a solution of Pd-C 10 wt% (518 mg, 487 μmol) and ethyl 7-hydroxyfuro[3,2-c]pyridine-6-carboxylate (2.06 g, 9.74 mmol) in anhydrous EtOH (32.5 mL). The autoclave was subjected to three cycles of evacuation-backfilling with nitrogen. Subsequently, it was filled with 5 bar of hydrogen (20.0 mg, 9.74 mmol) at room temperature and stirred for 5 days. The RM was filtered through a Celite pad. 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 chromatography ( FlashPure ID HP silica column 80 g, eluent: DCM:DCM / MeOH (8:2) 100:0 to 70:30) for purification. The fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a white powder (1.37 g, 98% pure, yield: 66%).

[1408] LC-MS: Rt = 0.38 min; MS m / z [M+H] + 210.2; UPLC-MS 1

[1409] ​ Ethyl 7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylate

[1410]

[1411] 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) (previously purged with argon / vacuumed), DIPEA (1.38 mL, 7.84 mmol) was added. 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). The dark orange reaction mixture (RM) was stirred at 0 °C for 1.5 h, the ice bath was removed, and the resulting RM was stirred at room temperature for 3.25 h. The RM was quenched with aqueous NaHCO3 (100 mL). The aqueous layer was extracted twice with DCM. The combined organic layers were dried through a phase separator, concentrated and dried under high vacuum. The residue was adsorbed onto Isolute and purified by normal-phase chromatography (RediSep column: silica 40 g, eluent: heptane:EtOAc 100:0 to 10:90). The fractions containing the product were combined and concentrated to give the title compound as a white solid (1.19 g, 73% pure, yield: 66%).

[1412] LC-MS: Rt = 0.48 min; MS m / z [M+H] + 254.2; UPLC-MS 1

[1413] ​ : 7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylic acid

[1414]

[1415] 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), 1 M NaOH in water (4.60 mL, 4.60 mmol) was added. The resulting colorless reaction mixture (RM) was stirred at room temperature for 73 h. The white suspension was filtered. The filter 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 vacuum to give the title compound as the sodium salt (871 mg, 95% pure, yield: 97%).

[1416] LC-MS: Rt = 0.25 min; MS m / z [M+H] + 226.3; UPLC-MS 10

[1417] ​ 3,6-dihydro-2H-pyran-4-carbaldehyde

[1418]

[1419] According to the reference: Org. Lett. [Organic Letters] 2014, 16, 4142 - 4145.

[1420] At 5 °C, NaCN (15.4 g, 315 mmol) was added to a mixture of tetrahydro - 4H - pyran - 4 - one (30.0 g, 300 mmol) and water (300 mL), and then NaHSO4 was added until pH = 4 - 5 was reached. The reaction was stirred at 10 °C for 1 hour, then NaCl (17.5 g, 300 mmol) was added at 25 °C, and then 2 - MeTHF was added. 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 changed to toluene (300 mL) to obtain 4 - hydroxytetrahydro - 2H - pyran - 4 - carbonitrile. Pyridine (48.5 mL, 599 mmol) was added at 65 °C, and then POCl3 (27.9 mL, 300 mmol) was added slowly. The RM 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 obtain 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, then 4M 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. Then the organic solution was concentrated under reduced pressure to obtain the title compound as a solution in toluene (unstable when concentrated).

[1421] 1H NMR (400 MHz, DMSO - d6) δ 9.46 (s, 1H), 7.05 (m, 1H), 4.33 (m, 2H), 3.69 (m, 2H), 2.16 (m, 2H).

[1422] ​ 3 - bromo - 1H - 1,2,4 - triazol - 5 - amine

[1423] ​ 3,5 - dibromo - 1 - (methoxymethyl) - 1H - 1,2,4 - triazole

[1424]

[1425] At 10 °C, 3,5-dibromo-1H-1,2,4-triazole (4.00 kg, 17.6 mol) was added to a solution of NaH (846 g, 21.2 mol, 60%) in DMF (12 L). The resulting solution was stirred at 10 °C for 1 hour. Subsequently, at 20 °C, chloromethyl methyl ether (1.70 kg, 21.2 mol) was added dropwise. The mixture was stirred at room temperature overnight. The reaction was quenched with H2O (20 L). The resulting solution was extracted with TBME (2 x 7 L). The combined organic layers were washed with 10% NaCl (2 x 7 L), dried over Na2SO4 and concentrated under reduced pressure at 40 °C. The residue was triturated with heptane (3 L) to afford the title compound as a white solid.

[1426] HPLC: Rt = 3.042 min; HPLC 4

[1427] ​ 3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-amine

[1428]

[1429] At room temperature, 3,5-dibromo-1-(methoxymethyl)-1H-1,2,4-triazole (800 g, 2.78 mol) was dissolved in 25% NH3 . H2O (2.89 L, 16.3 mol) and MeOH (80 mL). The mixture was stirred at 120 °C for 18 hours. The mixture was cooled to 5 - 10 °C and the solid was collected by filtration and washed with water (200 mL). The filter cake was dried under vacuum at 60 °C to afford the title compound as a white solid.

[1430] HPLC: Rt = 1.701 min; HPLC 4

[1431] ​ 3-Bromo-1H-1,2,4-triazol-5-amine

[1432]

[1433] At room temperature, HBr (4.39 kg, 21.7 mol) was added 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). The mixture was stirred at 100 °C for 18 hours. The mixture was adjusted to pH = 7.0 - 7.5 with 10% NaOH at 20 - 30 °C and extracted with EtOAc (10 x 3 L). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure at 50 °C to afford the title compound as a white solid.

[1434] HPLC: Rt = 0.702 min; HPLC 4

[1435] HPLC: Rt = 1.902 min; HPLC 5

[1436] ​ 3-Bromo-1H-1,2,4-triazol-5-amine

[1437]

[1438] At 0 °C, over 1.5 h, a solution of NaNO2 (313 g, 4.54 mol) in water (782 mL) was added dropwise to a solution of 1H-1,2,4-triazole-3,5-diamine (300 g, 3.03 mol) in HBr / H2O (2.4 L). The reaction was warmed to room temperature and stirred for 1 h. The reaction was stirred at 100 °C for 16 h. The RM was cooled to room temperature, filtered, and the pH of the mixture (66 combined batches) was adjusted to 4 by adding 10% NaOH. The mixture was extracted with EtOAc (2 x 55 L), dried over Na2SO4 and filtered. The organic phase was concentrated under reduced pressure to give the title compound. The pH of the aqueous phase was adjusted to 7 - 7.5 with 10% NaOH. It was then extracted with EtOAc (10 x 35 L), dried over Na2SO4 and filtered. The organic phase was concentrated under reduced pressure to give the title compound.

[1439] HPLC: Rt = 1.933 min; HPLC 5

[1440] ​ : N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide

[1441] ​ 2-Chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide

[1442]

[1443] At 0 °C, 2-chloro-4-(trifluoromethyl)aniline (18.5 g, 95.0 mmol) was dissolved in DCM (180 mL). A solution of 2-chloroacetyl chloride (10.7 g, 95.0 mmol) in DCM (40 mL) was added dropwise over 15 min. After maintaining at 0 °C for 30 min, the RM was warmed to room temperature. The white suspension was stirred overnight at room temperature. The suspension was filtered and washed with DCM. The filtrate was concentrated under reduced pressure and dried under HV to give the title compound as a white solid.

[1444] LC-MS: Rt = 1.14 min; MS m / z [M-H] -270.1 / 272.1 / 274.0; UPLC-MS 1

[1445] ​ N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide

[1446]

[1447] Dissolve 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (15.8 g, 58.2 mmol) in acetone (215 mL), add KI (10.6 g, 64.0 mmol), and stir the RM under reflux for 2.25 h. Cool the RM to room temperature and filter the suspension. Wash the cake with acetone and DCM. Concentrate the filtrate under reduced pressure and dry under HV to obtain the title compound.

[1448] LC-MS: Rt = 1.13 min; MS m / z [M-H] - 362.0 / 364.0; UPLC-MS 1

[1449] ​

[1450] Methods for preparing compounds of formula 1b, 1c, 1d, 1e and 1f are provided. Unless otherwise stated, the groups of the method schemes are defined as in the examples and preferred options herein. The synthetic methods can be modified to prepare variants under formula (I) according to procedures known to the skilled chemist.

[1451] ​

[1452]

[1453] A method for preparing a compound of formula AAK (Scheme XI) is provided, the method comprising steps a, b, c, d, e, f, g, h, i and j. It should be understood that the order of method steps a, b, c, d, e, f, g, h, i and j can be varied as required to optimize the synthesis. The compound of formula AAK can be obtained via coupling reaction step j by reacting a compound of formula AAJ with compound AAZ (wherein R4 is as defined above). The coupling reaction can be amide formation. The coupling reaction step can be carried out using, for example, HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) or Ghosez reagent (1-chloro-N,N,2-trimethylpropenylamine), preferably in a one- or two-step procedure. Alternatively, other alternative amide coupling methods are known in the art. For examples of amide bond formation, see Mantalbetti, C.A.G.N and Falque, V., Amide bond formation and peptide coupling, Tetrahedron, 2005, 61(46), pp. 10827-10852 and references cited therein.

[1454] A compound of formula AAJ can be prepared, including step i of deprotecting PG from a compound of formula AAI (wherein PG represents a suitable protecting group, preferably a BOC group, and wherein the other substituents are as defined above). There are many known methods for deprotecting the BOC group. The deprotection step can be carried out using, for example, TFA or HCl, in a solvent (such as dichloromethane or dioxane).

[1455] A compound of formula AAI can be prepared, including step h starting from a compound of formula AAH, wherein R 50represents halo, especially bromo, and wherein PG represents a suitable protecting group (e.g., BOC group), and other substituents are as defined above. Step h can be a nucleophilic aromatic substitution reaction and can be carried out by combining a compound having the formula AAH with an amine (e.g., tert-butyl piperazine-1-carboxylate or alternatively piperazine). A stoichiometric excess of the amine can be used, preferably 2 to 50 molar equivalents of the amine in an organic solvent (e.g., DMSO or NMP). The reaction is preferably stirred at a temperature of about 80 - 140 °C and can be carried out in a capped test tube. An alternative method for step h can use Buchwald-Hartwig conditions with an amine (e.g., tert-butyl piperazine-1-carboxylate), a ligand (such as Brettphos or RuPhos, or a hybrid of RuPhos and a palladium catalyst such as RuPhos Pd G1, RuPhos Pd G4 or [PdCl(allyl)]2) in an organic solvent (such as dioxane or THF) in the presence of a base (such as K2CO3 or Cs2CO3 or tert-BuONa). The reaction is preferably stirred at a temperature of about 80 °C - 120 °C. The reaction is preferably carried out under an inert gas (such as nitrogen or argon). Alternatively, other alternative Buchwald-Hartwig coupling methods are known in the art. For examples of methods, see B. T. Ingoglia et al., Biaryl monophosphine ligands in palladium-catalyzed C-N coupling: An updated User's guide, Tetrahedron, 2019, 75(32), pp. 4199 - 4211 and the references cited therein.

[1456] A compound having the formula AAH can be prepared, including step g, wherein a compound having the formula AAG (wherein the substituents are as defined herein) is halogenated. Step g can be carried out using a halogenating reagent (such as N-bromosuccinimide or N-iodosuccinimide) in a solvent (e.g., DMF or acetonitrile). The reaction is preferably stirred at a temperature of about 20 °C - 80 °C.

[1457] A compound having the formula AAG can be prepared, including step f, wherein a compound having the formula AAF (wherein the substituents are as defined herein) is alkylated by reaction with a compound having the formula AAY (wherein R 50 represents halo, especially bromo, iodo or chloro, and other substituents are as defined above). Step f can be carried out in a solvent (e.g., DMF or dioxane) in the presence of a base (such as K2CO3 or N,N-diisopropylethylamine). The reaction is preferably stirred at a temperature of about 20 °C - 80 °C.

[1458] Compounds of formula AAF can be prepared, including step e starting from compounds of formula AAE, where R 51 represents H or methoxy and the other substituents are as defined above. Many methods for cleaving benzyl or p-methoxybenzyl 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 stoichiometric excess), in a solvent (such as dichloromethane or dioxane), and preferably stirred at a temperature of about 20 °C - 80 °C. An alternative method for step e can use hydrogenation conditions in the presence of a hydrogen atmosphere and a catalyst (such as Pd / C or palladium hydroxide / C). The reaction is preferably stirred at a temperature of about 20 - 50 °C in an organic solvent (such as ethanol or methanol).

[1459] Compounds of formula AAE can be prepared, including step d starting from compounds of formula AAD, where R 50 represents halo, especially bromo, and the other substituents are as defined above. Step d involves reacting 2 - 10 molar equivalents of an alcohol (such as benzyl alcohol or p-methoxybenzyl alcohol) with 2 - 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 °C - 40 °C (preferably 20 °C) for about 10 - 60 minutes. Then the compound of formula AAD is added and stirring is continued at a temperature of about 20 °C - 100 °C (preferably 20 °C - 60 °C). The reaction is preferably carried out under an inert gas (such as nitrogen or argon). An example method is described on page 574 of WO 2021 / 222522, 2021, A1.

[1460] Compounds of formula AAD (where R 50 represents halo, especially bromo or iodo, and the other substituents are as defined herein) can be prepared, including step c starting from compounds of formula AAC. Step c involves reacting a compound of formula AAC with a base (such as LiTMP (lithium tetramethylpiperidine) or LDA (lithium diisopropylamide)) with stirring, in a solvent (such as THF), at a temperature of about -78 °C to 20 °C, under an inert gas (such as nitrogen or argon). After stirring for an appropriate 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 reagents are known in the art.

[1461] Compounds of formula AAC (wherein R1 and R3 are as defined above) can be prepared, including step b starting from compounds of formula AAB. Step b can be a Suzuki or Negishi or Stille or Kumada cross-coupling reaction and includes reacting a compound of formula AAB with R3n-MX (wherein R3 is as defined above, n is 1, 2, 3 or 4, and MX represents, for example, B(OH)2, BPin (Pin represents boronic acid pinacol ester), BF3K, B(MIDA), Sn, Zn, Mg-halide). Example Negishi cross-coupling conditions include reacting a compound of formula AAD with an alkyl zincate (such as dimethyl zinc or diethyl zinc, preferably in stoichiometric excess, such as 2-10 molar equivalents) in the presence of a catalyst (such as PdCl2(dppf) or Pd(PPh3)4), in a suitable solvent (such as THF), at a temperature of about 20-120 °C (preferably 20-80 °C), under an inert gas (such as nitrogen or argon).

[1462] Compounds of formula AAB (wherein R1 is as defined above) can be prepared, including step a starting from compound AAA. Step a can be a Suzuki or Negishi or Stille or Kumada cross-coupling reaction and includes reacting a compound of formula AAA with R1n-MX (wherein R1 is as defined above, n is 1, 2, 3 or 4, and MX represents, for example, B(OH)2, BPin (Pin represents boronic acid pinacol ester), BF3K, Sn, Zn, Mg-halide). Example Suzuki cross-coupling conditions include reacting a compound of formula AAA 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 mixture (such as DMF, THF or dioxane or water), at a temperature of about 20-120 °C (preferably 20-80 °C), under an inert gas (such as nitrogen or argon). An example method is described on page 32 of CN 112707908A.

[1463] Compounds of formula AAA can be prepared according to the method described on page 31 of CN 112707908 A.

[1464] ​

[1465]

[1466] Alternatively, compounds of formula AAK can be prepared according to the route shown in Scheme XII, which comprises steps k, L, m, zd, za, zh, ze, zj, and zf. Conditions similar to those described for steps d, a, h, e, j, and f of Scheme XI above can be used to carry out the methods comprising steps zd, za, zh, ze, zj, and zf for preparing compounds of formula AAP, AAQ, AAR, AAS, and AAT. It should be understood that the order of method steps k, L, m, zd, za, zh, ze, zj, and zf can be varied as needed to optimize the synthesis.

[1467] Compounds of formula AAO (wherein R 50 represents halogen, especially bromine or chlorine, and the other substituents are as defined above) can be prepared, including step m starting from a compound of formula AAN. Step m comprises reacting a compound of formula AAN with a stoichiometric excess (e.g., 2 - 10 molar equivalents) of a halogenating reagent such as PCl5 or PBr3 in a sealed tube at a temperature of about 200 °C - 270 °C (preferably 250 °C - 270 °C) for about 1 - 10 hours. An exemplary method is described in J. Org. Chem. [Journal of Organic Chemistry], Vol. 39, No. 15, 1974, p. 2146.

[1468] Compounds of formula AAN (wherein R3 is as defined above) can be prepared, including step L starting from a compound of formula AAM. Step L comprises reacting a 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 °C - 100 °C. Then the product of this reaction is reacted with tert-butyl nitrite in the presence of CuBr2 in a solvent such as acetonitrile at a temperature of about 20 °C - 50 °C. An exemplary method is described on page 31 of CN112707908A.

[1469] Compounds of formula AAM (wherein R3 is as defined above) can be prepared, including step k starting from AAL. Step k comprises 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.

[1470] Compounds of formula AAL (wherein R3 is as defined above) are commercially available or their preparation methods are known in the art.

[1471] ​

[1472]

[1473] Compounds having formula 1d can be prepared by methods similar to those described herein according to the exemplary routes shown in Scheme XIII. Methods similar to those for a skilled chemist in the art can be adjusted accordingly. It should be understood that the order of the method steps shown in Scheme XIII can be changed as needed to optimize the synthesis.

[1474] ​

[1475]

[1476] Compounds having formula 1e can be prepared by methods similar to those described herein according to the exemplary routes shown in Scheme XIV. Methods similar to those for a skilled chemist in the art can be adjusted accordingly. It should be understood that the order of the method steps shown in Scheme XIV can be changed as needed to optimize the synthesis.

[1477] ​

[1478]

[1479] ​

[1480]

[1481] A method for preparing a compound having formula BBN (Scheme XV), which comprises steps ba, bc, bd, be, bf, bg, bh, bj, bk, bL, bm, ye or yi, and yj. It should be understood that the order of steps ba, bc, bd, be, bf, bg, bh, bj, bk, bL, bm, ye or yi, and yj can be changed as needed to optimize the synthesis. The compound having formula BBN can be obtained via the coupling reaction step yj by reacting a compound having formula BBM (wherein the substituents are as defined above) with compound AAZ (where R4 is as defined above) using a method similar to that described herein.

[1482] A compound having formula BBM (wherein the substituents are as defined above) can be prepared by deprotecting a compound having formula BBL (where PG represents a suitable protecting group such as BOC or p-methoxybenzyl or benzyl, and the other substituents are as defined above), including step ye or step yi, which uses a method similar to that described in step e or step i of Scheme XI.

[1483] Compounds of formula BBL can be prepared, including step bL starting from compound BBK (wherein the substituents are as defined above) and compound BBX or compound BBW (wherein PG is as defined above and LG is represented by halo (especially iodine or bromine) or OH or OMs (methanesulfonate) or OTs (p-toluenesulfonate) or OTf (trifluoromethanesulfonate) or B(OH)2, BPin (Pin represents 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 or K2CO3 or DBU or NaOtBu or phosphazene base P2-Et). A stoichiometric excess (preferably 2 to 50 molar equivalents) of BBX can be used in an organic solvent (such as DMF or NMP). The reaction is preferably stirred at a temperature of about 80 °C - 150 °C and can be carried out in a capped test tube. An alternative method for step bL can use an Ullmann-type reaction. Exemplary Ullmann-type cross-coupling conditions include reacting the compound of formula BBK with compound 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 (preferably 2 to 50 molar equivalents) of BBX can be used. An alternative method for step bL can include using Buchwald-Hartwig conditions, reacting the compound of formula BBK with compound BBW using a method similar to that described in step h (Scheme XI) for example. The product of the reaction between the compound of formula BBK and the compound of formula BBW can optionally be hydrogenated using methods known in the art to obtain a compound of formula BBL (wherein the piperidine ring is saturated). Alternative cross-coupling conditions are known in the art; for examples of methods, see De Meijere et al., Metal-Catalyzed Cross-Coupling Reactions, Wiley, 2014 and the references cited therein.

[1484] Compounds of formula BBK can be prepared, including step bk starting from a compound of formula BBJ (substituents as defined above). Step bk includes reacting the compound of formula BBJ with a stoichiometric excess (such as 3 to 5 molar equivalents) of L-methionine in a solvent (such as methanesulfonic acid) at a temperature of about 20 - 80 °C.

[1485] Compounds of formula BBJ can be prepared, including step bj starting from compounds of formula BBI (wherein the substituents are as defined above). Step bj includes reacting a compound of formula BBI with a stoichiometric excess (e.g., 3 - 5 molar equivalents) of R2-NH2 (where R2 is as defined above) in the presence of a stoichiometric excess of trimethylaluminum (e.g., 3 - 5 molar equivalents), in a solvent (such as toluene), at a temperature of about 20 - 80 °C.

[1486] Compounds of formula BBI can be prepared, including step bi starting from compounds of formula BBH (wherein the substituents are as defined above). Step bj includes reacting a compound of formula BBH with a stoichiometric excess (e.g., 20 - 100 molar equivalents) of gaseous hydrogen chloride in ethanol, at a temperature of about 20 - 100 °C, preferably in a sealed tube.

[1487] Compounds of formula BBH can be prepared, including step bh starting from compounds of formula BBG (wherein the substituents are as defined above). Step bh includes reacting a compound of formula BBH with a stoichiometric excess (e.g., 3 - 5 molar equivalents) of potassium fluoride in water, in the presence of an additional solvent (such as DMF or methanol), at a temperature of about 20 - 100 °C (preferably 60 - 100 °C).

[1488] Compounds of formula BBG can be prepared, including step bg starting from compounds of formula BBF (where R 50 is represented by halo (especially iodine or bromine), and the other substituents are as defined above). Step bg includes reacting a compound of formula BBF with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole in the presence of a catalyst (such as XPhos PdG3) and a base (such as potassium carbonate), in a suitable solvent (such as DMF), at a temperature of about 20 - 120 °C (preferably 60 - 100 °C), under an inert gas (such as nitrogen or argon).

[1489] Compounds of formula BBF can be prepared, including step bf starting from compounds of formula BBE (wherein the substituents are as defined above). Step bf includes reacting a compound of formula BBE with a base (such as sodium hydride) at a temperature of about 0 - 20 °C, in a solvent (such as DMF), under an inert gas (such as nitrogen or argon) for about 5 - 30 minutes. Then 1-(bromomethyl)-4-methoxybenzene is added, and the reaction is stirred at a temperature of about 0 - 20 °C.

[1490] Compounds of formula BBE can be prepared, including step be, in which a compound of formula BBD (wherein the substituents are as defined above) is halogenated. Step be can be carried out using a halogenating reagent (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 °C - 80 °C.

[1491] Compounds of formula BBD can be prepared, including step bd starting from a compound of formula BBC (wherein the substituents are as defined above). Step bd includes reacting a compound of formula BBC with a compound of formula BBY (wherein R1 is as defined above) in a solvent (such as DMF or toluene or dioxane) at a temperature of about 80 °C - 150 °C. An alternative method for step bd can include reacting a compound of formula BBC with a compound of formula BBZ (wherein R1 is as defined above) in a solvent (such as dichloroethane or DMF or toluene or dioxane) at a temperature of about 0 - 20 °C. A base, such as triethylamine, can be added. Then the reaction is stirred at a temperature of about 80 °C - 150 °C.

[1492] Compounds of formula BBC can be prepared, including step bc starting from a compound of formula BBB (wherein the substituents are as defined above). Step bc includes reacting a compound of formula BBB with a stoichiometric excess (such as 2 to 5 molar equivalents) of hydrazine hydrate in a solvent (such as ethanol). The reaction is preferably stirred at a temperature of about 60 °C - 100 °C.

[1493] Compounds of formula BBB can be prepared, including step ba starting from a compound of formula BBA or BBAA (wherein the substituents are as defined above). Compounds of formula BBA or BBAA are commercially available or their preparation methods are known in the art. Step ba includes 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 °C - 120 °C.

[1494] ​

[1495]

[1496] Compounds having the 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 should be understood that the order of steps ca, cb, cc, cd, ce, cf, xg, xh, xi, xj, xk, xe or xi, and xj can be changed as needed to optimize the synthesis. Conditions similar to those described for steps bf, bg, bh, bi, e, i, and j of Schemes XI and XV above can be used to carry out the methods including steps xg, xh, xi, xj, xk, xe or xi, and xj for preparing compounds having the formulas CCG, CCH, CCI, CCJ, CCL, CCM, and CCN.

[1497] Compounds having the formula CCK can be prepared, including step xj starting from a compound having the formula CCJ (wherein the substituents are as defined above). Step xj includes reacting a compound having the formula CCJ with di-tert-butyl dicarbonate or p-methoxybenzyl bromide or benzyl bromide in the presence of a base (such as triethylamine), in a solvent (such as dichloromethane or dioxane), at a temperature of about 0 - 20 °C.

[1498] Compounds having the formula CCF (wherein PG represents a suitable protecting group, such as BOC or p-methoxybenzyl or benzyl, and the other substituents are as defined above) can be prepared, including step ce starting from a compound having the formula CCE (wherein the substituents are as defined above). Step ce includes reacting a compound having the formula CCE with Echavarren's 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. [Organic Letters] 2013, 15, 11, 2616 - 2619. An alternative method for preparing compounds having the formula CCF includes reacting a compound having the formula CCE with a base (such as sodium hydride) in a solvent (such as DMF or THF or dioxane), at a temperature of about 60 °C - 140 °C (preferably 80 °C - 120 °C), in a sealed tube, under an inert gas (such as nitrogen or argon).

[1499] Compounds of formula CCE can be prepared, including step cd starting from compound CCD (wherein the substituents are as defined above). Step cd includes reacting a compound of formula CCD with a compound of formula CCY or CCZ (wherein PG represents a suitable protecting group such as BOC or p-methoxybenzyl or benzyl) in the presence of a base (such as triethylamine or N-ethyl-N,N-diisopropylamine), in a solvent (such as THF or dioxane or DMF), at a temperature of about 20 - 140 °C (preferably 60 - 120 °C). Compounds of formula CCY or CCZ are commercially available or their preparation methods are known in the art.

[1500] Compounds of formula CCD can be prepared, including step cc starting from compound CCC (wherein PG2 represents a protecting group such as MOM (methoxymethyl) or SEM ((trimethylsilyl)ethoxymethyl), and the other substituents are as defined above). Step cc includes 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 °C - 60 °C). Alternative methods for deprotecting the SEM or MOM group are known in the art.

[1501] Compounds of formula CCC can be prepared, including step cb starting from a compound of formula CCB (wherein the substituents are as defined above). Step cb can be a Sonogashira reaction, which reacts a compound of formula CCB with a compound of formula CCX (wherein R3 is as defined above) in the presence of a catalyst (such as Pd(PPh3)4 and a copper catalyst such as copper(I) iodide) and a base (such as triethylamine or lithium carbonate), in a solvent (such as dioxane or DMF or acetonitrile, THF), at a temperature of about 20 - 120 °C (preferably 80 - 120 °C), under an inert gas (such as nitrogen or argon). Step cb can alternatively be a Suzuki or Stille cross-coupling reaction, including reacting a compound of formula CCB with a compound of formula CCW (wherein MX2 represents B(OH)2, BPin (Pin represents boronic acid pinacol ester), BF3K, B(MIDA), tributyltin, and R3 is as defined above). Methods for the Sonogashira reaction, Suzuki reaction or Stille reaction are known in the art. For examples of methods, see Molnar et al., Palladium-Catalyzed Coupling Reactions, Wiley, 2013 and the references cited therein.

[1502] Compounds of formula CCB can be prepared, including step ca starting from a compound of formula CCA (wherein the substituents are as defined above). Step a can be a Suzuki cross-coupling reaction and includes reacting a compound of formula CCA with R1n -MX (wherein R1 is as defined above, n is 1, 2, 3 or 4, and MX represents, for example, B(OH)2, BPin (Pin represents pinacol borate), BF3K). Exemplary Suzuki cross-coupling conditions include reacting a compound having the 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 mixture (such as DMF, THF or 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 having the formula CCA are commercially available or their preparation methods are known in the art.

[1503] ​

[1504]

[1505] ​

[1506]

[1507] Compounds having the 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 should be understood that the order of steps da, db, dc, dd, de, df, dg, dh, di, dj, dk, dL or dM, and dn can be changed as needed to optimize the synthesis. Methods for preparing compounds having the formula DDF, DDG, DDH, DDI, DDJ, DDK, DDL, DDM and DDN, which include steps de, df, dg, dh, di, dj, dk, dL, dM and dn, including an optional hydrogenation step, such as step dk, can be carried out using conditions similar to those described herein.

[1508] Compounds having the formula DDE (wherein R 50 represents halogen, especially bromine or iodine, and other substituents are as defined above) can be prepared, including step dd starting from a compound having the formula DDD (wherein the substituents are as defined above). Step dd can be carried out using a halogenating reagent (such as N-bromosuccinimide or N-iodosuccinimide) in a solvent (such as DMF or acetonitrile or acetic acid). The reaction is preferably stirred at a temperature of about 20 °C - 110 °C.

[1509] Compounds of formula DDD (wherein the substituents are as defined above) can be prepared, including step dc starting from compounds of formula DDC (wherein the substituents are as defined above). Step dc can be carried out under conditions similar to those described for step a of Scheme XI above.

[1510] Compounds of formula DDC (wherein the substituents are as defined above) can be prepared, including step db starting from compounds of formula DDB (wherein the substituents are as defined above). Step db involves reacting a compound of formula DDB with a stoichiometric excess (e.g., 3 - 100 molar equivalents, especially 10 - 20 molar equivalents) of an ammonium salt (such as ammonium acetate) in a solvent (such as acetic acid) at a temperature of about 60 - 130 °C (preferably 80 - 120 °C).

[1511] Compounds of formula DDB (wherein the substituents are as defined above) can be prepared, including step da starting from compounds of formula DDA. Step da involves reacting a compound of formula DDA with a compound of formula DDZ (wherein R 50 represents halogen, especially chlorine or bromine, and the other substituents are as defined above) in the presence of a base (such as potassium carbonate), in a solvent (such as acetone or acetonitrile), at a temperature of about 0 - 50 °C (preferably 0 - 20 °C). Compounds of formula DDZ are commercially available or their preparation methods are known in the art.

[1512] "Protecting group":

[1513] In the above methods, functional groups that are present in the starting materials and are not intended to participate in the reaction are present in protected form (if required), and the protecting groups present are removed, whereby the starting material compound may also be present in the form of a salt, provided that there is a salt-forming group and the reaction can be carried out in the form of a salt. In a further process step, if required, functional groups of the starting compound that should not participate in the reaction may be present in unprotected form or may be protected, for example by one or more protecting groups. The protecting groups are then removed in whole or in part according to one of the known methods. Protecting groups and the manner in which they are introduced and removed are described, for example, in the following documents: "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973; "Methoden der organischen Chemie", Houben-Weyl, 4th Edition, Volume 15 / 1, Georg-Thieme-Verlag, Stuttgart 1974; and Theodora W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York 1981. Protecting groups are characterized in that they can be removed easily, i.e., without undesired side reactions, for example by solvolysis, reduction, photolysis or alternatively under physiological conditions.

[1514] The invention further encompasses any variant of the method of the invention, in which the intermediate products obtainable at any stage are used as starting materials and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure enantiomers.

[1515] The compounds and intermediates of the invention can also be converted into one another according to methods generally known to those skilled in the art.

[1516] The intermediates and end products can be worked up and / or purified according to standard methods, for example using chromatography, distribution methods, (re)crystallization, etc.

[1517] The following generally applies to all methods mentioned before and below in this text. All of the above method steps can be carried out as follows: under reaction conditions known to those skilled in the art (including those specifically mentioned), in the absence or usually in the presence of a solvent or diluent, including, for example, a solvent or diluent that is inert to the reagents used and dissolves the reagents; in the absence or presence of a catalyst, condensing agent or neutralizing agent, such as an ion exchanger, such as a cation exchanger, for example in the H+ form; depending on the nature of the reaction and / or the nature of the reactants at reduced, normal or elevated temperatures, for example in the temperature range from about -100 °C to about 190 °C, including, for example, from about -80 °C to about 150 °C, such as from -80 °C to -60 °C, at room temperature, from -20 °C to 40 °C or at the reflux temperature; at atmospheric pressure or in a closed vessel, under pressure where appropriate; and / or in an inert atmosphere (e.g., under an argon or nitrogen atmosphere).

[1518] At all stages of the reaction, the mixture of isomers formed can be separated, for example, into the individual isomers, such as diastereomers or enantiomers, in a manner similar to the methods described above in this text, or into any desired mixture of isomers, such as a racemate or a mixture of diastereomers.

[1519] Unless otherwise stated in the description of the method, solvents that can be selected from those solvents applicable to any particular reaction include those specifically mentioned, or, for example, water; esters, such as lower alkyl-lower alkanoate esters, such as ethyl acetate; ethers, such as aliphatic ethers, such as diethyl ether, or cyclic ethers, such as tetrahydrofuran or dioxane; liquid aromatic hydrocarbons, such as benzene or toluene; alcohols, such as methanol, ethanol or 1- or 2-propanol; nitriles, such as acetonitrile; halogenated hydrocarbons, such as dichloromethane or chloroform; amides, such as dimethylformamide or dimethylacetamide; bases, such as heterocyclic nitrogen bases, such as pyridine or N-methylpyrrolidin-2-one; carboxylic anhydrides, such as lower alkanoic anhydrides, such as acetic anhydride; cyclic, straight-chain or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methylcyclohexane; or mixtures of these solvents, such as aqueous solutions. Such solvent mixtures can also be used for work-up, for example by chromatography or partitioning.

[1520] Sulfonylimide amide drugs and their synthesis are described in Chem. Eur. J. [European Chemical Journal] 2017, 23, 15189 - 15193 DOI: 10.1002 / chem.201703272.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R, M, W, L, V, and T are independently selected from C, CH, and N, to form sub-formulas 1a, 1b, 1c, 1d, 1e, and 1f: and A is linker-C(O)-; Y is N, C, or CH; y is 0, 1, 2, 3, or 4; Y means that when Y is CH, Y is connected to an adjacent carbon atom via a single bond, or when Y is C, Y is connected to an adjacent atom via a double bond, and when Y is a single bond, Y is an unsubstituted carbon or a carbon substituted with OH or F; When Y is N, Y is a single bond; K means that K is connected to an adjacent atom via a single bond or a double bond; wherein: When K is a double bond, Y is a single bond, K is CH and J is C, or When K is a single bond, K is selected from -CH2-, -CH2CH2-, -NH- and a bond (to form a 5-membered ring: ), and J is N; R5 is independently selected from: ·-(C 1- C4) alkyl, ·-(C 3- C5) cycloalkyl group, · And two R5 substituents on the same ring carbon atom, together with the carbon atom to which they are attached, may be joined to form a (C 3- C4) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N, and S, · When K is a carbon-nitrogen single bond, the R5 substituents on K and on the adjacent carbon atoms can be linked to form ring C: wherein ring C is a fused (C3-C6) cycloalkyl ring, a fused (C3-C6) heterocyclic ring, or a fused benzene ring, wherein the fused (C3-C6) heterocyclic ring contains ring carbon atoms and one ring heteroatom selected from O, N, and S, and wherein when ring C is a fused (C3-C6) cycloalkyl ring, said fused (C3-C6) cycloalkyl ring is unsubstituted or substituted with 1 or 2 R 40 groups, wherein said R 40 is selected from: ·(C 1- C2) alkyl, wherein each (C 1- C2) alkyl is independently unsubstituted or substituted with OH or one, two or three halogens, · halo, especially F, · Or two Rs on the same ring carbon atom 40 The substituents together with the carbon atoms to which they are attached can be linked to form a (C 3- C4) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N, and S; · or two Rs on adjacent carbon atoms are joined to the carbon atoms to which they are attached to form a fused cyclopropyl ring; 40 Substituents are joined to the carbon atoms to which they are attached to form a fused cyclopropyl ring; · and wherein when K is -CH2- and J is N, two R5 substituents may be linked to form a (C1-C3) alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is a heteroatom selected from N and O or is -CH2-O-CH2-; 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 substituted with 1, 2, 3 or 4, preferably 1 or 2, R 33 substituents, where R 33 is halo, and wherein the cycloalkenyl or halo-substituted cycloalkenyl is substituted with 0, 1 or 2 R 15 substituents, or the cycloalkenyl or halo-substituted cycloalkenyl has 2 substituents on the same ring carbon atom that form an oxetanyl spiro ring Alternatively, R1 is a heterocyclic group, wherein the heterocyclic group is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O, and S, and wherein the heterocyclic group is unbridged or bridged, and the bridge is 1 or 2 carbon atoms, and wherein the heterocyclic group is unsubstituted or substituted by 1, 2, 3, or 4, preferably 1 or 2, R 33 substituents, where R 33 is halo, and wherein the heterocyclic group or the halo-substituted heterocyclic group is substituted by 0, 1, or 2 substituents independently selected from R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 substituents, or the heterocyclic or halo-substituted heterocyclic is fused to a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted or substituted with 1, 2, or 3 Fs, or the heterocyclic or halo-substituted heterocyclic has 2 substituents on the same ring carbon atom that forms a cyclopropyl spiro ring or a tetrahydrofuran spiro ring, or the heterocyclic or halo-substituted heterocyclic is fused to a (C3-C5) heterocycloalkyl ring, wherein the (C3-C5) heterocycloalkyl ring contains ring carbon atoms and 1 ring O atom; or R1 is a heteroaryl, wherein the heteroaryl is a 5-membered 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, preferably wherein 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 wherein said heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R 21 and R 30 wherein R 21 and R 30 are independently selected from halo and (C1-C4)alkyl, wherein said (C1-C4)alkyl is unsubstituted or substituted with 1, 2 or 3 halo or R1 is phenyl, wherein said phenyl is unsubstituted or substituted with 1, 2, 3 or 4, preferably 1 or 2, R 33 substituents, where R 33 is halo, and wherein said phenyl or halo-substituted phenyl is substituted with 0, 1 or 2 R 15 substituents or R1 is a (C2-C4) alkynyl or a (C2-C4) alkenyl, wherein the (C2-C4) alkynyl and (C2-C4) alkenyl are unsubstituted or substituted with (C1-C4) alkyl-O-C(O)- or morpholinyl; R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 each independently selected from: · halo · An unsubstituted or C1, C2 or C3 halo-substituted (C 1- C4) alkyl - O - (CH2) n ; · unsubstituted or substituted with OH, -O-(C1-C2) alkyl, or (C1-C4) alkyl substituted with 1, 2, or 3 halos, ·HOC(O)-(CH2) n -, ·(C1-C4)alkyl-C(O)(CH2) n - · (E)-cyclooct-4-en-1-yl-O-C(O)-, ·(C1-C4)alkyl-O-C(O)(CH2) n , ·＝O · azetidinyl or pyrrolidinyl, wherein the azetidinyl and pyrrolidinyl are linked to the rest of the molecule via an N atom and are each unsubstituted or substituted with 1 or 2 Fs, ·R 25 (R 24 )N-(CH2) n , wherein R 24 is H or an unsubstituted or halo-substituted (C1-C4) alkyl group having 1, 2 or 3 halo substituents, and R 25 is: o H, o(C1-C4) alkyl-C(O)(CH2) n -, wherein the (C1-C4) alkyl of the (C1-C4) alkyl-C(O)(CH2) n - is unsubstituted or substituted with halogen or -N3, o(C1-C4)alkyl-O-C(O)(CH2) n , o unsubstituted or substituted with 1, 2, or 3 halos of (C1-C4) alkyl, or o (E)-cyclooct-4-en-1-yl-O-C(O)-, · OH wherein 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 the following moiety: R6 is selected from: ·H， · halo, · unsubstituted or substituted with 1, 2, or 3 halos of (C1-C4) alkyl, · unsubstituted or substituted with 1, 2, or 3 halos of (C3-C5) cycloalkyl, · unsubstituted or substituted with 1, 2, or 3 halos of -O-(C1-C4) alkyl, · OH, and · CN; R8 is selected from H, halo, and (C1-C4) alkyl unsubstituted or substituted with 1, 2, or 3 halos, R9 is selected from H, O-CH3, OH, CN, CH3, and halo; R 28 Selected from: · SF5, ·H， · -C(O)H, ·Halogenated, ·(C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogenated substituents, ·(C1-C4) alkynyl, ·(C1-C4) alkenyl, ·(C3-C5) cycloalkyl which is unsubstituted or substituted by 1, 2 or 3 halogenated substituents, and ·OCF3; X is selected from C-R7 and N, where R7 is H, CF3 or halo, or R7 may be joined to R 28 or R6 together with the atoms to which they are attached are joined to form a fused (C4-C6) cycloalkyl ring, where the fused (C4-C6) cycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 halo Or R2 is selected from: Wherein R 31 selected from H, halogen, and CH3, R 32 selected from H, halogen, and CH3 R3 is: ·Cyclopropyl, ·O-CH3, ·N(CH3)2, ·S-CH3, ·(C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogenated and OH; R4 is selected from: -(C1-C4) alkyl which is unsubstituted or substituted by NH2; -O-CH2 phenyl; -O-CH2CH2 phenyl; -NH-NH-C(O)-CF3; -Heteroaryl 1, wherein the heteroaryl 1 is a 5-membered 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; -Heteroaryl 2, wherein the heteroaryl 2 is a 9-membered 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, and wherein both rings are fully unsaturated, or one ring is fully unsaturated and the other is saturated or partially unsaturated, and wherein the heteroatoms can be in one or both rings; -Phenyl; -Heterocyclic group 2, wherein the heterocyclic group 2 is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S; And wherein heteroaryl 1, heteroaryl 2, and phenyl are each substituted with 1, 2, or 3 substituents independently selected from R 10 , R 11 , R 12 , R 13 , and R 14 , wherein R 10 , R 11 , R 12 , R 13 , and R 14 are each independently selected from: ·H， ·Halogenated, ·(C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogenated substituents, ·(C1-C2) alkyl substituted by -O-(C1-C2) alkyl or OH, ·-S-(C1-C3) alkyl, ·-O-(C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogenated substituents, ·OH, ·(C3-C5) cycloalkyl, wherein the (C3-C5) cycloalkyl is unsubstituted or substituted by 1 or 2 halogenated substituents, ·-O-(C3-C5) cycloalkyl, ·-NR 34 R 35 , where R 34 and R 35 are independently selected from: o H, o(C1-C4) alkyl, wherein the (C1-C4) alkyl is unsubstituted or substituted by OH or -O(C1-C2) alkyl, o and wherein R 34 and R 35 may be joined together with the atoms to which they are attached to form an azetidine, pyrrolidine or piperidine ring, wherein the azetidine, pyrrolidine and piperidine are unsubstituted or substituted by CH3; ·CN, ·-(C2-C4) alkenyl, ·-(C2-C4) alkynyl, ·＝O ·-C(O)H, and ·-C(O)(C1-C4) alkyl; Provided that R4 is not: Wherein R 10 , R 11 , R 12 , R 13 and R 14 Independently selected from: ·H， ·Halogenated, ·(C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogenated substituents, ·(C1-C2) alkyl substituted by -O-(C1-C2) alkyl or OH, ·-S-(C1-C3) alkyl, ·-O-(C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogenated substituents, ·OH, ·(C3-C5) cycloalkyl, wherein the (C3-C5) cycloalkyl is unsubstituted or substituted by 1 or 2 halogenated substituents, ·-O-(C3-C5) cycloalkyl, ·-NR 34 R 35 , wherein R 34 and R 35 are independently selected from: o H, o(C1-C4) alkyl, wherein the (C1-C4) alkyl is unsubstituted or substituted by OH or -O(C1-C2) alkyl, o and wherein R 34 and R 35 may together with the atoms to which they are attached form an azetidine, pyrrolidine or piperidine ring, wherein said azetidine, pyrrolidine and piperidine are unsubstituted or substituted by CH3; ·CN, · -(C2-C4) alkenyl, · -(C2-C4) alkynyl, · -C(O)H, and · -C(O)(C1-C4) alkyl; And * represents the attachment point.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein when R1 is a ring, then: · Each R1 ring atom adjacent to the R1 ring atom connecting the R1 ring to the rest of the molecule is independently unsubstituted or substituted only by halogen, in particular, independently unsubstituted or substituted by one F substituent, and · Preferably, the R1 ring is connected to the rest of the molecule via an R1 ring nitrogen atom or an R1 ring carbon atom double-bonded to an adjacent R1 ring atom.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein 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 substituted by 1, 2, 3 or 4, preferably 1 or 2, R 33 substituents, where R 33 is halo, and wherein the cycloalkenyl or halo-substituted cycloalkenyl is substituted by 0, 1 or 2 R 15 substituents, preferably 1 substituent, or the cycloalkenyl or halo-substituted cycloalkenyl has 2 substituents on the same ring carbon atom that forms an oxetanyl spiro ring Alternatively, R1 is a heterocyclic group, wherein the heterocyclic group is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, NH, O, and S, and wherein the heterocyclic group is unbridged or bridged, and the bridge is 1 or 2 carbon atoms, and wherein the heterocyclic group is unsubstituted or substituted with 1, 2, 3, or 4, for example 1, 2, or 3, especially 1 or 2, R 33 substituents, where R 33 is halogenated, and wherein the heterocyclic group or halogenated heterocyclic group is substituted with 0, 1, or 2 substituents independently selected from R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 substituents, preferably 0 or 1 substituent Or the heterocyclic group or halogen-substituted heterocyclic group is fused to a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted or substituted by 1, 2 or 3 Fs, Or the heterocyclic group or halogen-substituted heterocyclic group has 2 substituents on the same ring carbon atom that forms a tetrahydrofuranyl spiro ring, Alternatively, R1 is a heteroaryl group, wherein the heteroaryl group 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 the heteroaryl group is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from R 21 and R 30 wherein R 21 and R 30 are independently selected from halo and (C1-C4)alkyl, wherein the (C1-C4)alkyl is unsubstituted or substituted by 1, 2 or 3 halo or R1 is phenyl, where the phenyl is unsubstituted or substituted by 1, 2, 3 or 4, preferably 1 or 2, R 33 substituents, where R 33 is halo, and where the phenyl or halo-substituted phenyl is substituted by 0 or 1 R 15 substituent Or R1 is an unsubstituted or (C1-C4) alkyl-O-C(O)-substituted (C2-C4) alkynyl; And R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 are each independently selected from: · Halogen · unsubstituted or substituted by 1, 2 or 3 halogen atoms, (C 1- C4) alkyl - O - (CH2) n ; · Unsubstituted or substituted by OH, -O-(C1-C2) alkyl or a (C1-C4) alkyl substituted by 1, 2 or 3 halogens, ·HOC(O)-(CH2) n -, ·H3C-C(O)(CH2) n -, ·(C1-C4)alkyl-O-C(O)(CH2) n , ·＝O · Azetidinyl or pyrrolidinyl, wherein the azetidinyl and pyrrolidinyl are connected to the rest of the molecule via an N atom and are each unsubstituted or substituted by 1 or 2 Fs, ·R 25 (R 24 )N-(CH2) n , wherein R 24 is H or (C1-C2) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, and R 25 is H, (C1-C4) alkyl-C(O)-, (C1-C4) alkyl-O-C(O)-, or (C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, · OH Where n is 0, 1 or 2.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2 or 3, wherein R1 is: A cycloalkenyl group, wherein the cycloalkenyl group is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms, and the cycloalkenyl group is unsubstituted or substituted by 1 or 2 Rs 33 wherein R 33 is halo, preferably F, and wherein the cycloalkenyl group or the halo-substituted cycloalkenyl group is substituted by 0 or 1 R 15 substituent, wherein R 15 is selected from: o) (C which is unsubstituted or substituted by 1, 2 or 3 halogen atoms 1- C2) alkyl-O-; p) An unsubstituted or (C1-C2) alkyl substituted by 1, 2 or 3 halogens, q) HOC(O)-(CH2) n -, r)H3C-C(O)(CH2) n -, s)H3C-O-C(O)(CH2) n , t) =O, and u)R 25 (R 24 )N−,H, wherein R 24 is H or (C1-C2) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, R 25 is H or (C1-C2) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, n is 0 or 1, Where · The R of the cycloalkenyl or halogen-substituted cycloalkenyl 15 Substituents a) to g) are not present on the ring atoms adjacent to the ring atoms connecting the cycloalkenyl or halogen-substituted cycloalkenyl to the remainder of the molecule, and preferably, the cycloalkenyl or halogen-substituted cycloalkenyl is a 6-membered ring, wherein one R 15 substituent is in the ring para position relative to the remainder of the molecule; and · The cycloalkenyl or halogen-substituted cycloalkenyl is connected to the rest of the compound via an R1 ring carbon atom double-bonded to an adjacent R1 ring carbon atom; Alternatively, R1 is a heterocyclic group, wherein the heterocyclic group is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, NH, O, and S, and wherein the heterocyclic group is unbridged or bridged, and the bridge is 1 or 2 carbon atoms, and wherein the heterocyclic group is unsubstituted or substituted by 1 or 2 R 33 substituents, wherein R 33 is halo, preferably F, and wherein the heterocyclic group or the halo-substituted heterocyclic group is substituted by 0 or 1 substituent independently selected from R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 substituents, wherein the R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 are independently selected from: q) (C which is unsubstituted or substituted by 1, 2 or 3 halogens 1- C4) alkyl-O-; r) Unsubstituted or substituted by OH, -O-(C1-C2) alkyl or a (C1-C4) alkyl substituted by 1, 2 or 3 halogens, s)HOC(O)-(CH2) n -, t)H3C-C(O)(CH2) n -, u) H3C - O - C(O)(CH2) n , v) =O w)R 25 (R 24 )N-, where R 24 is H, unsubstituted or (C1-C2) alkyl substituted by 1, 2 or 3 halogens, R 25 is H, unsubstituted or (C1-C2) alkyl substituted by 1, 2 or 3 halogens, x) OH Where n is 0 or 1, And wherein: · The substituents a) to h) of the heterocyclic group or halogen-substituted heterocyclic group are not present on the ring atoms adjacent to the ring atoms connecting the heterocyclic group or halogen-substituted heterocyclic group to the rest of the molecule, and preferably, when the heterocyclic group or halogen-substituted heterocyclic group is a 6-membered ring, it has 0 or 1 substituent selected from a) to h), located meta or para, preferably para, relative to the rest of the molecule; and · The heterocyclic group is connected to the rest of the compound via an R1 ring nitrogen atom or an R1 ring carbon atom double-bonded to an adjacent ring atom; Alternatively, R1 is a heteroaryl group, wherein the heteroaryl group 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 the heteroaryl group is unsubstituted or substituted with 1 or 2 substituents independently selected from R 21 and R 30 , wherein R 21 and R 30 are independently selected from (C1-C2) alkyl groups, and the (C1-C2) alkyl groups are unsubstituted or substituted with 1, 2, or 3 halogens, and wherein preferably, the alkyl or haloalkyl substituents are not present on the R1 ring atoms adjacent to the R1 ring atom connecting the heteroaryl group to the remainder of the molecule, and more preferably, when the heteroaryl group is a 6-membered ring, the alkyl or haloalkyl substituents are in the ring para position relative to the remainder of the molecule.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1 is selected from: Alternatively, there are 0 - 2 Rs in each of the above parts 33 substituents R 33 is F; R 15 is: · Halogen, ·R 25 (R 24 )N-(CH2) n , wherein R 24 is H or CH3 which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, and R 25 is H, (C1-C4) alkyl-C(O)-, (C1-C4) alkyl-O-C(O)-, or (C1-C4) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, or · Azetidinyl or pyrrolidinyl, wherein the azetidinyl and pyrrolidinyl are connected to the rest of the molecule via an N atom and are unsubstituted or substituted with 1 or 2 F atoms, 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 which is unsubstituted or substituted by 1, 2 or 3 halogens, especially F; R 17 is halogenated; R 18 is halogenated; R 19 is: · Halo · (C1-C4)alkyl which is unsubstituted or substituted with 1, 2 or 3 halo substituents, ·(C1-C4)alkyl-O-(CH2) n -; R 20 is halogenated; R 21 is an unsubstituted or (C1-C2) alkyl group substituted with 1, 2 or 3 F atoms; R 22 and R 23 are each independently selected from: · (C1-C4)alkyl which is unsubstituted or substituted with 1, 2 or 3 halo substituents, ·(C1-C4) alkyl - O - (CH2) n - ·HOC(O)-(CH2) n -, ·H3C-C(O)(CH2) n -, ·(H3C)3C-O-C(O)(CH2) n -; · wherein n is 0, 1 or 2; and R 30 is CH3.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R1 is selected from: R 15 is F; R 16 is R 25 (R 24 )N-; R 17 is F; R 18 is F; R 19 is F; R 20 is F; R 21 is CH3; R 22 is CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, (H3C)3C-O-C(O)-; R 23 is CF3, CHF2CH2-, (H3C)3C-O-C(O)-; R 24 is CH3; and R 25 is CHF2CH2-.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R1 is selected from:

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R2 is the following moiety: wherein R6 is selected from H, halo, (C1-C4)alkyl which is unsubstituted or substituted with 1, 2 or 3 halo substituents; R8 is selected from H, halo, (C1-C4)alkyl which is unsubstituted or substituted with 1, 2 or 3 halo substituents; R9 is selected from H, O-CH3, OH, CN, CH3 and halo; R 28 selected from SF5, halogenated, unsubstituted or substituted with 1, 2 or 3 halogen atoms, (C1-C4) alkyl, and -C(O)H; X is selected from C-R7 and N; and R7 is selected from H and halo.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R2 is selected from 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R3 is (C1-C4)alkyl which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo and OH.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R4 is selected from: CH3, - heteroaryl1, wherein the heteroaryl1 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, wherein the 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, and wherein both rings are fully unsaturated, or one ring is fully unsaturated and the other is saturated or partially unsaturated, and wherein the heteroatoms may be in one or both rings; - phenyl; or - heterocyclic2, wherein the heterocyclic2 is a 5- or 6-membered fully saturated or partially unsaturated group containing ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, O and S; wherein heteroaryl1, heteroaryl2, phenyl, and moieties selected from the following: Each is independently selected from R 10 、R 11 、R 12 、R 13 and R 14 substituted by 1, 2 or 3 substituents, particularly 1 or 2 substituents, wherein each R 10 、R 11 、R 12 、R 13 and R 14 is independently selected from: ·H， · Halo, · (C1-C4)alkyl which is unsubstituted or substituted with 1, 2 or 3 halo substituents, · (C1-C2)alkyl substituted with -O-(C1-C2)alkyl or OH, · -S-(C1-C3)alkyl, · -O-(C1-C4)alkyl which is unsubstituted or substituted with 1, 2 or 3 halo substituents, · OH, · (C3-C5)cycloalkyl, wherein the (C3-C5)cycloalkyl is unsubstituted or substituted with 1 or 2 halo substituents, · -O-(C3-C5) cycloalkyl, ·-NR 34 R 35 , wherein R 34 and R 35 are independently selected from: o H, o (C1-C4) alkyl, wherein said (C1-C4) alkyl is unsubstituted or substituted by OH or -O(C1-C2) alkyl, o and wherein R 34 and R 35 may be joined together with the atoms to which they are attached to form an azetidine, pyrrolidine or piperidine ring, wherein said azetidine, pyrrolidine and piperidine are unsubstituted or substituted with CH3; · CN, · -(C2-C4) alkenyl, · -(C2-C4) alkynyl, ·＝O · -C(O)H, and · -C(O)(C1-C4) alkyl.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11, wherein R4 is as claimed in claim 1 or claim 11, provided that at least one of the OH, CN, ═O, or NH2 substituents is present on each heteroaryl 1, heteroaryl 2, phenyl, above, And the remaining Rs 10 s, Rs 11 s, Rs 12 s, Rs 13 s, and Rs 14 as defined herein.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R4 is selected from: CH3, -CH2NH2, -NH-NH-C(O)-CF3, and 14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein K is K connected by a single bond, K is -CH2- and J is N.

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R5 is independently selected from: ·-(C 1- C4) alkyl, preferably methyl, · and two R5 substituents on the same ring carbon atom, together with the carbon atom to which they are attached, may be joined to form a (C 3- C4) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N, and S, · When K is a carbon-nitrogen single bond, the R5 substituents on K and on the adjacent carbon atom can be linked to form ring C: wherein ring C is a fused (C3-C6) cycloalkyl ring, especially a fused cyclobutyl ring, a fused (C3-C6) heterocyclic ring or a fused benzene ring, wherein said fused (C3-C6) heterocyclic ring contains ring carbon atoms and one ring heteroatom selected from O, N and S, and wherein 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 substituted by 1 or 2 R 40 groups, wherein said R 40 is selected from: ·(C 1- C2) alkyl, wherein each (C 1- C2) alkyl is independently unsubstituted or substituted with OH or one, two or three halogens, · halogenated, especially F, · Or two Rs on the same ring carbon atom 40 The substituents together with the carbon atoms to which they are attached can be linked to form a (C 3- C4) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein the heterocyclic spiro ring contains ring carbon atoms and one ring heteroatom selected from O, N, and S; · or two Rs on adjacent carbon atoms are linked to the carbon atoms to which they are attached to form a fused cyclopropyl ring; 40 Substituents are linked to the carbon atoms to which they are attached to form a fused cyclopropyl ring; · and wherein when K is -CH2- and J is N, two R5 substituents may be linked to form a (C1-C3) alkylene bridge or a heteroalkylene bridge, wherein said heteroalkylene bridge is a heteroatom selected from N and O or -CH2-O-CH2-.

16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R5 is independently selected from: ·-(C 1- C2) alkyl, preferably methyl, and · When K is a carbon-nitrogen single bond, the R5 substituents on K and on the adjacent carbon atoms can be connected to form ring C: wherein ring C is a fused (C3-C4) cycloalkyl ring, especially a fused cyclobutyl ring, and said fused (C3-C4) cycloalkyl ring, especially a fused cyclobutyl ring, is unsubstituted or substituted by 1 or 2 R groups as described in the examples herein 40 groups.

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

18. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein the compound of formula (I) comprises the following moiety: especially A： More particularly Or B: or C:

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

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

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

22. The combination according to claim 21, wherein the additional therapeutic active agent is an anticancer agent.

23. The combination according to claim 21, wherein the additional therapeutic active agent is a chemotherapeutic agent selected from the following: anastrozole bicalutamide bleomycin sulfate busulfan busulfan injection capecitabine N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin carmustine chlorambucil cisplatin cladribine , cyclophosphamide ([ or ), cytarabine, cytosine arabinoside liposomal cytarabine injection dacarbazine actinomycin D (Cosmegan), daunorubicin hydrochloride liposomal daunorubicin citrate injection dexamethasone, docetaxel doxorubicin hydrochloride etoposide fludarabine phosphate 5-fluorouracil flutamide tegafur, gemcitabine (difluorodeoxycytidine), hydroxyurea idarubicin ifosfamide irinotecan L-asparaginase calcium folinate, melphalan 6-mercaptopurine methotrexate mitoxantrone gemtuzumab, paclitaxel phoenix (yttrium 90 / MX-DTPA), pentostatin, polylactide-coglycolide copolymer 20 containing carmustine implant tamoxifen citrate teniposide 6-thioguanine, thiotepa, tirapazamine topotecan hydrochloride for injection vinblastine vincristine and vinorelbine Especially irinotecan.

24. The combination according to claim 21, wherein the additional therapeutic active agent is a PD-1 inhibitor.

25. The combination according to claim 24, wherein the additional therapeutic agent is a PD-1 inhibitor selected from: PDR001 (Novartis AG), nivolumab (Bristol-Myers Squibb Company), pembrolizumab (Merck & Co., Inc.), pidilizumab (CureTech Ltd.), MEDI0680 (MedImmune Limited), cemiplimab (REGN2810, Regeneron Pharmaceuticals, Inc.), dostarlimab (TSR-042, Tesaro, Inc.), PF-06801591 (Pfizer Inc.), tislelizumab (BGB-A317, BeiGene, Ltd.), BGB-108 (BeiGene, Ltd.), INCSHR1210 (Incyte Corporation), balstilimab (AGEN2035, Agenus Inc.), sintilimab (Innovent Biologics, Inc.), toripalimab (Shanghai Junshi Biosciences Co., Ltd.), camrelizumab (Jiangsu Hengrui Medicine Co., Ltd.), and AMP-224 (Amplimmune, Inc.), particularly PDR001, tislelizumab, and pembrolizumab, and more particularly tislelizumab.

26. A pharmaceutical composition comprising a compound of formula (I) as claimed in 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) as claimed in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof for use as a medicament.

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

29. A compound of formula (I) as claimed in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof for use as claimed in claim 27, wherein the use is for the treatment of cancer.

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

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

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

33. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, for use as claimed in claim 30, wherein the cancers characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR) are selected from endometrial carcinoma of the uterine corpus, adenocarcinoma of the colon, adenocarcinoma of the stomach, adenocarcinoma of the rectum, adrenocortical carcinoma, carcinosarcoma of the uterus, squamous cell carcinoma of the cervix, endocervical adenocarcinoma, esophageal cancer, breast cancer, clear cell renal carcinoma, and serous cystadenocarcinoma of the ovary.

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

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

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

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

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

39. Use of the 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 method or intermediate as defined herein.

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