Tricyclic compounds and uses thereof

Abstract

The present invention provides compounds having formula (I): wherein R1, R2, R3, x, R4, R5, y, R, M, W, L, V, T, Y, J, K and A are as described herein, or pharmaceutically acceptable salts thereof, therapeutic uses of the compounds, uses of the compounds as research type chemicals, pharmaceutical compositions and combinations comprising the compounds, and processes for preparing the compounds of the invention. # imgabs0 #

Description

Technical Field

[0001] The present invention provides tricyclic heterocyclic compounds, such as 5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine compounds and their analogs and derivatives, their use for inhibiting Werner syndrome RecQ DNA helicase (WRN), and methods of treating diseases using said compounds, particularly their use in treating cancer, and particularly in treating cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), including colorectal cancer, gastric cancer, and endometrial cancer. The present invention also provides the use of said compounds as research chemicals, intermediate compounds, combinations, methods, and formulations. Background Art

[0002] Loss of 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 in 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 WRN-dependent mechanism 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 an effective amount of a WRN inhibitor. The present invention also provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, which compounds are useful for treating cancer, particularly cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). Compounds that bind to and / or inhibit WRN are also provided and thus can be used as research chemicals, such as chemical probes and as tool compounds. For example, such uses can be for studying WRN-related diseases or high MSI disorders. Various embodiments of the present invention are described herein.

[0004] In some aspects, provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0005]

[0006] Among them

[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 a linker selected from -C(O)-, -S(O)-, -S(O) 2 -, and ;

[0011] Y is N, C, or CH;

[0012] 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 is a single bond, Y is an unsubstituted carbon or a carbon substituted with OH or F;

[0013] When Y is N, is a single bond;

[0014] means that K is connected to the adjacent atom via a single bond or a double bond;

[0015] Wherein:

[0016] When is a double bond, is a single bond, K is CH, J is C, and A is a linker selected from -C(O)-, -S(O)-, -S(O) 2 -, and ;

[0017] Or

[0018] When is a single bond, K is selected from -CH 2 -, -CH 2 CH 2 -, -NH-, and a bond (to form a 5-membered ring: ), J is N, and A is a linker selected from -C(O)-, -S(O)-, -S(O) 2 -, and ;

[0019] Or

[0020] When is a single bond, K is -CH 2 -, J is CH, and A is selected from -S(O)-, -S(O) 2 -, and connector;

[0021] y is 0, 1, 2, 3 or 4;

[0022] R 5 is independently selected from:

[0023] ·-(C 1- C 4 )alkyl,

[0024] ·-(C 3- C 5 )cycloalkyl,

[0025] · and wherein two R 5 substituents on the same ring carbon atom together with the carbon atom to which they are attached can be joined to form a (C 3- C 4 )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,

[0026] · when is a carbon-nitrogen single bond, the R 5 substituents on K and on the adjacent carbon atom can be joined to form a ring C:

[0027]

[0028] wherein ring C is a fused (C 3 -C 6 )cycloalkyl ring, a fused (C 3 -C 6 )heterocyclic ring or a fused benzene ring, wherein the fused (C 3 -C 6 )heterocyclic ring contains a ring carbon atom and a ring heteroatom selected from O, N and S,

[0029] and wherein when ring C is a fused (C 3 -C 6 )cycloalkyl ring, the fused (C 3 -C 6 )cycloalkyl ring is unsubstituted or substituted with 1 or 2 R 40 groups, wherein the R 40 is selected from:

[0030] ·(C 1- C 2 )alkyl, wherein each (C 1- C 2 )alkyl is independently unsubstituted or substituted with OH or 1, 2 or 3 halogen atoms,

[0031] · halogen, especially F,

[0032] · or two Rs on the same ring carbon atom 40 substituents together with the carbon atoms to which they are attached may be linked to form a (C 3- C 4 ) 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;

[0033] · 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;

[0034] · when is a carbon-carbon single bond, Y is N and is a single bond, and A is a linker selected from -S(O)-, -S(O) 2 -, and Rs on K and on adjacent carbon atoms 5 substituents may be linked to form ring C:

[0035]

[0036] wherein ring C is a fused (C 3 -C 6 ) cycloalkyl ring, a fused (C 3 -C 6 ) heterocyclic ring or a fused benzene ring, wherein the fused (C 3 -C 6 ) heterocyclic ring contains ring carbon atoms and one ring heteroatom selected from O, N, and S,

[0037] and wherein when ring C is a fused (C 3 -C 6 ) cycloalkyl ring, the fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted with 1 or 2 R 40 groups, wherein the R 40 is selected from:

[0038] · (C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) alkyl is independently unsubstituted or substituted with OH or 1, 2, or 3 halogens,

[0039] · halogen, especially F,

[0040] · or two Rs on the same ring carbon atom 40 substituents together with the carbon atoms to which they are attached may be linked to form a (C3- C 4 ) cycloalkyl spiro or 3- or 4-membered heterocyclic spiro, wherein the heterocyclic spiro contains a ring carbon atom and a ring heteroatom selected from O, N, and S;

[0041] · or two Rs on adjacent carbon atoms 40 substituents are joined together with the carbon atoms to which they are attached to form a fused cyclopropyl ring;

[0042] · and wherein when K is -CH 2 - and J is N, two Rs 5 substituents may be joined to form a (C 1 -C 3 ) alkylene bridge or heteroalkylene bridge, wherein the heteroalkylene bridge is a heteroatom selected from N and O or is -CH 2 -O-CH 2 -;

[0043] R 1 is:

[0044] 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 Rs 33 substituents, wherein R 33 is halo, and wherein the cycloalkenyl or halo-substituted cycloalkenyl is substituted by 0, 1, or 2 Rs 15 substituents,

[0045] or R 1 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, preferably 1 or 2 Rs 33 substituents, wherein 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 substituents,

[0046] 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 Fs,

[0047] or the heterocyclic group or halogen-substituted heterocyclic group has two substituents at the same ring carbon atom, which are linked to form a cyclopropyl spiro ring,

[0048] or the heterocyclic group or halogen-substituted heterocyclic group is fused with a (C 3 -C 5 ) heterocyclic alkyl ring, wherein the (C 3 -C 5 ) heterocyclic alkyl ring contains ring carbon atoms and one ring O atom;

[0049] or R 1 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, preferably wherein the total number of ring S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1,

[0050] 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 halogen and (C 1 -C 4 ) alkyl, wherein the (C 1 -C 4 ) alkyl is unsubstituted or substituted by 1, 2 or 3 halogens,

[0051] or R 1 is a phenyl group, wherein the phenyl group is unsubstituted or substituted by 1, 2, 3 or 4, preferably 1 or 2 R 33 , wherein R 33 is halogen, and wherein the phenyl group or halogen-substituted phenyl group is substituted by 0, 1 or 2 R 15 substituents,

[0052] or R 1 is a (C 2 -C 4 ) alkynyl group or a (C 2 -C 4 ) alkenyl group, wherein the (C 2 -C 4 ) alkynyl group and the (C 2 -C 4 ) alkenyl group are unsubstituted or substituted by (C 1 -C 4 ) alkyl-O-C(O)- or morpholinyl;

[0053] R 15 、R 16 、R17 、R 18 、R 19 、R 20 、R 22 and R 23 are each independently selected from:

[0054] · halo

[0055] · (C 1- C 4 )alkyl - O - which is unsubstituted or substituted with 1, 2 or 3 halos

[0056] · (C 1 -C 2 )alkyl which is unsubstituted or substituted with OH, -O-(C 1 -C 4 )alkyl or 1, 2 or 3 halos

[0057] · HOC(O)-(CH 2 ) n -,

[0058] · H 3 C - C(O)(CH 2 ) n -,

[0059] · (C 1 -C 4 )alkyl - O - C(O)(CH 2 ) n ,

[0060] · =O

[0061] · 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

[0062] · R 25 (R 24 )N -, wherein R 24 is H or (C 1 -C 4 )alkyl which is unsubstituted or substituted with 1, 2 or 3 halos, R 25 is H or (C 1 -C 4 )alkyl which is unsubstituted or substituted with 1, 2 or 3 halos

[0063] · OH

[0064] where n is 0, 1 or 2.

[0065] R 2 is the following moiety:

[0066]

[0067] R 6 Selected from:

[0068] · H,

[0069] · Halo,

[0070] · Unsubstituted or substituted by 1, 2 or 3 halos of (C 1 -C 4 ) alkyl,

[0071] · Unsubstituted or substituted by 1, 2 or 3 halos of (C 3 -C 5 ) cycloalkyl,

[0072] · Unsubstituted or substituted by 1, 2 or 3 halos of -O-(C 1 -C 4 ) alkyl,

[0073] · OH, and

[0074] · CN;

[0075] R 8 Selected from H, halo, and unsubstituted or substituted by 1, 2 or 3 halos of (C 1 -C 4 ) alkyl,

[0076] R 9 Selected from H, O-CH 3 , OH, CN, CH 3 and halo;

[0077] R 28 Selected from:

[0078] · SF 5 ,

[0079] · H,

[0080] · -C(O)H,

[0081] · Halo,

[0082] · Unsubstituted or substituted by 1, 2 or 3 halos of (C 1 -C 4 ) alkyl,

[0083] · (C 1 -C 4 ) alkynyl,

[0084] · (C 1 -C 4Alkenyl,

[0085] · (C 3 -C 5 ) cycloalkyl, unsubstituted or substituted with 1, 2 or 3 halogens, and

[0086] · OCF 3 ;

[0087] X is selected from C-R 7 and N, where R 7 is H or halogen, or R 7 can, together with R 28 or R 6 and the atoms to which they are attached, form a fused (C 4 -C 6 ) cycloalkyl ring, where the fused (C 4 -C 6 ) cycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 halogens,

[0088] Or

[0089] R 2 is selected from:

[0090]

[0091] where

[0092] R 31 is selected from H, halogen and CH 3 ,

[0093] R 32 is selected from H, halogen and CH 3 ,

[0094] R 3 is selected from:

[0095] · halogen, and

[0096] · (C 1 -C 4 ) alkyl, unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen and OH,

[0097] · Or two R 3 substituents on the same ring carbon atom can, together with the carbon atom to which they are attached, form a cyclopropyl ring;

[0098] x is 0, 1 or 2;

[0099] R 4 is selected from:

[0100] -(C 1 -C 4)alkyl;

[0101] -heteroaryl 1, wherein the heteroaryl 1 is a 5- or 6-membered fully unsaturated monocyclic ring containing ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S;

[0102] -heteroaryl 2, wherein the 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 the heteroatoms can be in one or both rings;

[0103] -phenyl;

[0104] wherein heteroaryl 1, heteroaryl 2, and phenyl are each independently substituted with 1, 2, or 3 substituents 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:

[0105] ·H,

[0106] ·halo,

[0107] ·(C 1 -C 4 )alkyl unsubstituted or substituted with 1, 2, or 3 halo substituents,

[0108] ·(C 1 -C 2 )alkyl substituted with -O-(C 1 -C 2 )alkyl or OH,

[0109] ·-S-(C 1 -C 3 )alkyl,

[0110] ·-O-(C 1 -C 4 )alkyl unsubstituted or substituted with 1, 2, or 3 halo substituents,

[0111] ·OH,

[0112] ·(C 3 -C 5 )cycloalkyl, wherein the (C 3 -C 5) The cycloalkyl group is unsubstituted or substituted with 1 or 2 halogens,

[0113] ·-O-(C 3 -C 5 ) cycloalkyl,

[0114] ·-NR 34 R 35 , where R 34 and R 35 are independently selected from:

[0115] o H,

[0116] o (C 1 -C 4 ) alkyl, where the (C 1 -C 4 ) alkyl is unsubstituted or substituted with OH or -O(C 1 -C 2 ) alkyl;

[0117] o and 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 CH 3 ;

[0118] ·CN,

[0119] ·-(C 2 -C 4 ) alkenyl,

[0120] ·-(C 2 -C 4 ) alkynyl,

[0121] ·=O

[0122] ·-C(O)H, and

[0123] ·-C(O)(C 1 -C 4 ) alkyl;

[0124] And * indicates the point of attachment.

[0125] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention and one or more pharmaceutically acceptable carriers.

[0126] In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising a compound of formula (I) of the present invention and one or more therapeutic active agents.

[0127] On the other hand, the present invention provides a compound of the present invention having formula (I) for use as a medicament, in particular for the treatment of disorders or diseases that can be treated by WRN inhibition.

[0128] On the other hand, the present invention provides a compound of the present invention having formula (I) for the treatment of cancer, in particular wherein the cancer is characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

[0129] On the other hand, 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 having formula (I).

[0130] On the other hand, 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 having formula (I).

[0131] On the other hand, the present invention provides the use of a compound of the present invention having formula (I) in the preparation of a medicament for the treatment of disorders or diseases that can be treated by WRN inhibition.

[0132] On the other hand, the present invention provides a compound of the present invention having formula (I) for use as a research chemical, for example as a chemical probe or as a tool compound.

[0133] On the other hand, the present invention provides a solid form, method or intermediate as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0134] Figure 1 Shows the X-ray powder diffraction pattern of the compound of Example 18A.

[0135] Figure 2 Shows the efficacy of Example 18A against SW48 colorectal xenografts in Crl:NU(NCr)-Foxn1 nu mice.

[0136] Figure 3 Shows the efficacy of Example 18A against SW48 colorectal xenografts in Crl:NU(NCr)-Foxn1 nu mice.

[0137] Figure 4 Shows the efficacy of Example 21A against SW48 colorectal xenografts in Crl:NU(NCr)-Foxn1 nu mice.

[0138] Figure 5 shows the tolerance of Example 21A to SW48 colorectal xenografts in Crl:NU(NCr)-Foxn1 nu mice.

[0139] Figure 6 shows the X-ray powder diffraction pattern of the compound of Example 21A. Detailed Description

[0140] Accordingly, the present invention provides a compound having the formula (I):

[0141]

[0142] wherein R 1 , R 2 , R 3 , x, Y, K, J, R 4 , R 5 and A are as described in the Summary of the Invention above.

[0143] Unless otherwise specified, the term "compounds of the present invention" or "compound having the formula (I)" refers to one or more compounds having the formula (I), sub-formulas thereof, exemplary compounds and their salts, as well as all zwitterions, stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), and inherently formed moieties, and combinations or mixtures of the foregoing aspects thereof.

[0144] Various (enumerated) embodiments of the present invention are described herein. It should be recognized that the features specified in each embodiment may be combined with other specified features to provide additional embodiments of the present invention.

[0145] Example 1. A compound having the formula (I) or a pharmaceutically acceptable salt thereof, as described above.

[0146] Example 2. The compound having the formula (I) or a pharmaceutically acceptable salt thereof according to Example 1, wherein when R 1 is a ring, then:

[0147] · Each R 1 ring atom adjacent to the R 1 ring atom connecting the remainder of the molecule to the R 1 ring is independently unsubstituted or substituted only by halo, particularly, independently unsubstituted or substituted by one F substituent, and

[0148] · Preferably, said R 1 ring is bonded to the adjacent R 1 ring nitrogen atom or double bond via the R 1 ring carbon atom of the ring and is connected to the rest of the molecule. 1 ring carbon atom of the ring and is connected to the rest of the molecule.

[0149] Example 3. A compound of formula (I) according to Example 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is:

[0150] 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, wherein R 33 is halo, and wherein the cycloalkenyl or halo-substituted cycloalkenyl is substituted by 0, 1 or 2 R 15 substituents,

[0151] or R 1 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, especially 1 or 2 R 33 substituents, wherein 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 substituents,

[0152] or R 1 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 substituents, wherein R 21 and R 30 are independently selected from halo and (C 1 -C 4)alkyl, wherein the (C 1 -C 4 )alkyl is unsubstituted or substituted with 1, 2 or 3 halogens,

[0153] and R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 are each independently selected from:

[0154] ·halogen

[0155] ·(C 1- C 4 )alkyl-O- that is unsubstituted or substituted with 1, 2 or 3 halogens;

[0156] ·(C 1 -C 2 )alkyl that is unsubstituted or substituted with OH, -O-(C 1 -C 4 )alkyl or 1, 2 or 3 halogens,

[0157] ·HOC(O)-(CH 2 ) n -,

[0158] ·H 3 C-C(O)(CH 2 ) n -,

[0159] ·(C 1 -C 4 )alkyl-O-C(O)(CH 2 ) n ,

[0160] ·=O

[0161] ·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 with 1 or 2 Fs,

[0162] ·R 25 (R 24 )N-, wherein R 24 is H or (C 1 -C 4 )alkyl that is unsubstituted or substituted with 1, 2 or 3 halogens, R 25 is H or (C 1 -C 4)alkyl

[0163] ·OH

[0164] wherein n is 0, 1 or 2.

[0165] Example 4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1, 2 or 3, wherein R 1 is:

[0166] 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 or 2 R 33 substituents, wherein R 33 is halo, preferably F, and wherein the cycloalkenyl or halo-substituted cycloalkenyl is substituted by 0 or 1 R 15 substituent, preferably 1 substituent, wherein R 15 is selected from:

[0167] a) (C 1- C 2 )alkyl-O- unsubstituted or substituted by 1, 2 or 3 halo;

[0168] b) (C 1 -C 2 )alkyl unsubstituted or substituted by 1, 2 or 3 halo,

[0169] c) HOC(O)-(CH 2 ) n -,

[0170] d) H 3 C-C(O)(CH 2 ) n -,

[0171] e) H 3 C-O-C(O)(CH 2 ) n ,

[0172] f) =O, and

[0173] g) R 25 (R 24 )N-, H, wherein R 24 is H or (C 1 -C 2 )alkyl unsubstituted or substituted by 1, 2 or 3 halo, R 25 is H or (C 1 -C 2 )alkyl unsubstituted or substituted by 1, 2 or 3 halo,

[0174] n is 0 or 1,

[0175] wherein

[0176] · For 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 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

[0177] · The cycloalkenyl or halogen-substituted cycloalkenyl is double-bonded to an adjacent R 1 ring carbon atom of the R 1 ring carbon atom is connected to the rest of the compound;

[0178] or R 1 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 substituent independently selected from R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 , where the R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 are independently selected from:

[0179] a) (C 1- C 4 )alkyl-O- unsubstituted or substituted by 1, 2, or 3 halogens;

[0180] b) (C 1 -C 2 )alkyl unsubstituted or substituted by OH, -O-(C 1 -C 4 )alkyl or 1, 2, or 3 halogens,

[0181] c) HOC(O)-(CH 2 ) n -,

[0182] d) H 3 C-C(O)(CH 2 ) n -,

[0183] e) H 3 C-O-C(O)(CH 2 ) n ,

[0184] f) =O

[0185] g) R 25 (R 24 )N-, where R 24 is H, unsubstituted or (C 1 -C 2 )alkyl substituted with 1, 2 or 3 halogen atoms, R 25 is H, unsubstituted or (C 1 -C 2 )alkyl substituted with 1, 2 or 3 halogen atoms,

[0186] h) OH

[0187] where n is 0 or 1,

[0188] and wherein:

[0189] · 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

[0190] · The heterocyclic group is connected to the rest of the compound via an R 1 ring nitrogen atom or an R 1 ring carbon atom double-bonded to an adjacent ring atom;

[0191] Or R 1 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 , where R 21 and R 30Independently selected from (C 1 -C 2 ) alkyl, and said (C 1 -C 2 ) alkyl is unsubstituted or substituted with 1, 2 or 3 halo, and wherein preferably said alkyl or haloalkyl substituent is not present in the R group that is attached to the rest of the molecule 1 R adjacent to the ring atom 1 The alkyl or haloalkyl substituent is located on a ring atom and, more preferably, when the heteroaryl group is a 6-membered ring, is located in the para position of the ring relative to the rest of the molecule.

[0192] Embodiment 5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 4, wherein R 1 Selected from:

[0193]

[0194] Alternatively, 0-2 R in each of the above sections 33 Substituents,

[0195] R 33 It is F;

[0196] R 15 is halo, azetidinyl or pyrrolidinyl, wherein the azetidinyl and pyrrolidinyl are attached to the rest of the molecule via an N atom and are unsubstituted or substituted with 1 or 2 F;

[0197] R 16 YesR 25 (R 24 )N-, where R 24 is H or (C 1 -C 2 ) alkyl, R 25 is H or is unsubstituted or substituted by 1, 2 or 3 halogen, especially F (C 1 -C 2 )alkyl;

[0198] R 17 It is halogenated;

[0199] R 18 It is halogenated;

[0200] R 19 It is halogenated;

[0201] R 20 It is halogenated;

[0202] R 21 Yes (C 1 -C 2 )alkyl;

[0203] R 22 and R 23 each independently selected from:

[0204] · (C 1 -C 4 ) alkyl, unsubstituted or substituted with 1, 2 or 3 halogens

[0205] · HOC(O)-(CH 2 ) n -

[0206] · H 3 C-C(O)(CH 2 ) n -

[0207] · (H 3 C) 3 C-O-C(O)(CH 2 ) n -

[0208] · where n is 0, 1 or 2

[0209] and

[0210] R 30 is CH 3 .

[0211] Example 6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 5, wherein R 1 is selected from:

[0212]

[0213] R 15 is F;

[0214] R 16 is R 25 (R 24 )N-

[0215] R 17 is F;

[0216] R 18 is F;

[0217] R 19 is F;

[0218] R 20 is F;

[0219] R 21 is CH 3 ;

[0220] R22 is CF 3 , CHF 2 CH 2 , HOC(O)-CH 2 -, H 3 C-C(O)-, (H 3 C) 3 C-O-C(O)-;

[0221] R 23 is CF 3 , CHF 2 CH 2 -, (H 3 C) 3 C-O-C(O)-;

[0222] R 24 is CH 3 ; and

[0223] R 25 is CHF 2 CH 2 -.

[0224] Example 7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 6, wherein R 1 is selected from:

[0225]

[0226] Example 8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Example 7, wherein R 1 is selected from:

[0227]

[0228] Example 9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Example 8, wherein R 1 is selected from:

[0229]

[0230] Example 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Example 9, wherein R 1 is:

[0231]

[0232] Example 11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 10, wherein R 2 is the following moiety:

[0233]

[0234] R 6 Selected from:

[0235] · H,

[0236] · halo,

[0237] · unsubstituted or substituted with 1, 2 or 3 halos of (C 1 -C 4 ) alkyl,

[0238] · unsubstituted or substituted with 1, 2 or 3 halos of (C 3 -C 5 ) cycloalkyl,

[0239] · unsubstituted or substituted with 1, 2 or 3 halos of -O-(C 1 -C 4 ) alkyl,

[0240] · OH, and

[0241] · CN;

[0242] R 8 Selected from H, halo, and unsubstituted or substituted with 1, 2 or 3 halos of (C 1 -C 4 ) alkyl,

[0243] R 9 Selected from H, O-CH 3 , OH, CN, CH 3 and halo;

[0244] R 28 Selected from:

[0245] · SF 5 ,

[0246] · H,

[0247] · -C(O)H,

[0248] · halo,

[0249] · unsubstituted or substituted with 1, 2 or 3 halos of (C 1 -C 4 ) alkyl,

[0250] · (C 1 -C 4 ) alkynyl,

[0251] · (C 1 -C 4 ) alkenyl,

[0252] · (C 3 -C 5 ) cycloalkyl, unsubstituted or substituted with 1, 2 or 3 halogens, and

[0253] · OCF 3 ;

[0254] and X is selected from C-R 7 and N, where R 7 is H or halogen.

[0255] Example 12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 11, wherein R 2 is the following moiety:

[0256]

[0257] wherein

[0258] R 6 is selected from H, halogen, (C 1 -C 4 ) alkyl, unsubstituted or substituted with 1, 2 or 3 halogens;

[0259] R 8 is selected from H, halogen, (C 1 -C 4 ) alkyl, unsubstituted or substituted with 1, 2 or 3 halogens;

[0260] R 9 is selected from H, O-CH 3 , OH, CN, CH 3 and halogen;

[0261] R 28 is selected from SF 5 , halogen, C(O)H and (C 1 -C 4 ) alkyl, unsubstituted or substituted with 1, 2 or 3 halogens,

[0262] X is selected from C-R 7 and N; and

[0263] R 7 is selected from H and halogen.

[0264] Example 13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 12, wherein R 2 is the following moiety:

[0265]

[0266] R 6 is selected from H, Cl, CH 3 , F, and Br;

[0267] R 8 is selected from H, Cl, F, and CF 3 ;

[0268] R 9 is selected from H, CH 3 and Cl;

[0269] R 28 is selected from CF 3 , CF 2 H, -CH 2 CH 3 , Cl, SF 5 , Br, and -C(O)H;

[0270] X is selected from C-R 7 and N; and

[0271] R 7 is selected from H and F.

[0272] Example 14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1-13, wherein the following moiety:

[0273]

[0274] is selected from:

[0275]

[0276] Example 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Example 14, wherein the following moiety:

[0277]

[0278] is selected from:

[0279]

[0280] Example 16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Example 15, wherein the following moiety:

[0281]

[0282] is selected from:

[0283]

[0284] Example 17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Example 16, wherein the following moiety:

[0285]

[0286] is selected from:

[0287]

[0288] Example 18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 17, wherein x is 0 or 1. In particular, x is 1.

[0289] Example 19. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 18, wherein R 3 is an unsubstituted or substituted (C 1 -C 4 ) alkyl group substituted with 1, 2 or 3 substituents independently selected from halo and OH.

[0290] Example 20. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 19, wherein R 3 is an unsubstituted or substituted (C 1 -C 2 ) alkyl group substituted with 1, 2 or 3 substituents independently selected from halo and OH, preferably R 3 is -CH 2 CH 3 or CH 3 , more preferably CH 3 .

[0291] Example 21. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 20, wherein R 3 is CH 3 .

[0292] Example 22. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 21, wherein R 3 is located at the position shown in Formula 1i:

[0293]

[0294] Example 23. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 22, wherein Y is N and is Y connected by a single bond.

[0295] Example 24. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 23, wherein is K linked by a single bond, and K is selected from -CH 2 -, -CH 2 CH 2 -, -NH- and a bond (to form a 5-membered ring: ), J is N, and A is a linker selected from -C(O)-, -S(O)-, -S(O) 2 - and .

[0296] Example 25. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 24, wherein is K linked by a single bond, K is -CH 2 -, J is N, and A is a linker selected from -C(O)-, -S(O)-, -S(O) 2 - and .

[0297] Example 26. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 25, wherein A is a linker selected from -C(O)- and -S(O) 2 -, preferably -C(O)-.

[0298] Example 27. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 26, wherein R 5 are independently selected from:

[0299] · -(C 1- C 4 )alkyl, preferably methyl,

[0300] · and wherein two R 5 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- C 4 ) 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,

[0301] · When is a carbon-nitrogen single bond, the R 5 substituents on K and on the adjacent carbon atom may be linked to form a ring C:

[0302]

[0303] wherein ring C is a fused (C 3 -C6 ) a cycloalkyl ring, especially a fused cyclobutyl ring, fused (C 3 -C 6 ) a heterocyclic ring or a fused benzene ring, wherein the fused (C 3 -C 6 ) heterocyclic ring contains ring carbon atoms and a ring heteroatom selected from O, N, and S,

[0304] and wherein when ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, the fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted with 1 or 2 R 40 groups, wherein the R 40 is selected from:

[0305] · (C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) alkyl is independently unsubstituted or substituted with OH or 1, 2, or 3 halogens,

[0306] · halogen, especially F,

[0307] · or two R 40 substituents on the same ring carbon atom together with the carbon atom to which they are attached can be joined to form a (C 3- C 4 ) 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;

[0308] · or 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;

[0309] · and wherein when K is -CH 2 - and J is N, two R 5 substituents can be joined to form a (C 1 -C 3 ) alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is a heteroatom selected from N and O or is -CH 2 -O-CH 2 -.

[0310] Example 28. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 27, wherein R 5 is independently selected from:

[0311] ·-(C 1- C 4 ) alkyl, preferably methyl,

[0312] ·When is a carbon-nitrogen single bond, the R on K and the adjacent carbon atom 5 substituents can be linked to form a ring C:

[0313]

[0314] wherein ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, or a fused (C 3 -C 6 ) heterocyclic ring, wherein the fused (C 3 -C 6 ) heterocyclic ring contains a ring carbon atom and a ring heteroatom selected from O, N, and S,

[0315] and wherein when ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, the fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted with 1 or 2 R 40 groups, wherein the R 40 is selected from:

[0316] ·(C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) alkyl is independently unsubstituted or substituted with OH or 1, 2, or 3 halogens,

[0317] ·Halogen, especially F,

[0318] ·Or two R 40 substituents on the same ring carbon atom together with the carbon atom to which they are attached can be linked to form a (C 3- C 4 ) 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;

[0319] ·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;

[0320] ·And wherein when K is -CH 2 - and J is N, two R 5 substituents can be linked to form a (C1 -C 3 ) An alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is a heteroatom selected from N and O or is -CH 2 -O-CH 2 -.

[0321] Example 29. A compound of formula (I) according to any one of Examples 1 to 28 or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected from:

[0322] · -(C 1- C 2 ) alkyl, preferably methyl, and

[0323] · When is a carbon-nitrogen single bond, the R 5 substituents on K and on the adjacent carbon atom can be linked to form ring C:

[0324]

[0325] wherein ring C is a fused (C 3 -C 4 ) cycloalkyl ring, especially a fused cyclobutyl ring, and the fused (C 3 -C 4 ) cycloalkyl ring, especially a fused cyclobutyl ring, is unsubstituted or substituted with 1 or 2 R 40 groups as described in Example 28.

[0326] Example 30. A compound of formula (I) according to any one of Examples 1 to 29 or a pharmaceutically acceptable salt thereof, wherein y is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0327] Example 31. A compound of formula (I) according to any one of Examples 1 to 30 or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected from:

[0328] · CH 3 , and y is 1 or 2, and

[0329] · When is a carbon-nitrogen single bond, the R 5 substituents on K and on the adjacent carbon atom can be linked to form ring C:

[0330]

[0331] wherein ring C is a fused cyclobutyl ring.

[0332] Example 32. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, wherein the compound of formula (I) comprises the following moieties:

[0333]

[0334]

[0335] In particular

[0336] A:

[0337] Even more particularly

[0338] Or B:

[0339] Or C:

[0340]

[0341] Or wherein the linker -C(O)- is replaced by the alternative linker -S(O)-, -S(O) 2 - and as defined in claim 1.

[0342] Example 33. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 32, wherein R 4 is selected from:

[0343] -(C 1 -C 4 )alkyl;

[0344] - heteroaryl1, wherein said heteroaryl1 is a 5- or 6-membered fully unsaturated monocyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, and the total number of ring S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1;

[0345] - heteroaryl2, wherein said heteroaryl2 is a 9- or 10-membered fused bicyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, 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, and the total number of ring S atoms does not exceed 1, the total number of ring O atoms does not exceed 1, and in particular, the ring attached to the remainder of the molecule via linker -A- is fully unsaturated;

[0346] - phenyl;

[0347] wherein heteroaryl 1, heteroaryl 2, and phenyl are each independently substituted with 1, 2, or 3 substituents selected from R 10 , R 11 , R 12 , R 13 , and R 14 , where R 10 , R 11 , R 12 , R 13 , and R 14 are each independently selected from:

[0348] · H,

[0349] · halo

[0350] · (C 1 -C 4 )alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents

[0351] · (C 1 -C 2 )alkyl substituted with -O-(C 1 -C 2 )alkyl or OH

[0352] · -S-(C 1 -C 3 )alkyl

[0353] · -O-(C 1 -C 4 )alkyl, unsubstituted or substituted with 1, 2, or 3 halo substituents

[0354] · OH

[0355] · (C 3 -C 5 )cycloalkyl, where the (C 3 -C 5 )cycloalkyl is unsubstituted or substituted with 1 or 2 halo substituents

[0356] · -O-(C 3 -C 5 )cycloalkyl

[0357] · -NR 34 R 35 , where R 34 and R 35 are independently selected from:

[0358] o H,

[0359] o (C 1 -C 4 )alkyl, where the (C 1-C 4 ) The alkyl group is unsubstituted or substituted by OH or -O(C 1 -C 2 ) alkyl group;

[0360] 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 CH 3 substituted;

[0361] ·CN,

[0362] ·-(C 2 -C 4 ) alkenyl;

[0363] ·-(C 2 -C 4 ) alkynyl;

[0364] ·=O

[0365] ·-C(O)H, and

[0366] ·-C(O)(C 1 -C 4 ) alkyl;

[0367] Provided that there is an OH substituent on heteroaryl 1, heteroaryl 2 and phenyl, and the remaining R 10 , R 11 , R 12 , R 13 and R 14 are as defined herein.

[0368] Example 34. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 33, wherein R 4 is selected from:

[0369] -(C 1 -C 4 ) alkyl, especially -CH 3 ;

[0370] -heteroaryl 1; and

[0371] -heteroaryl 2;

[0372] -phenyl;

[0373] wherein heteroaryl 1, heteroaryl 2 and phenyl are each independently substituted by 1, 2 or 3 substituents selected from R 10 , R 11 , R 12 , R 13and R 14 is substituted by a substituent of R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from:

[0374] · H,

[0375] · halo

[0376] · (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents

[0377] · (C 1 -C 2 ) alkyl substituted by -O-(C 1 -C 2 ) alkyl or OH

[0378] · -S-(C 1 -C 3 ) alkyl

[0379] · -O-(C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents

[0380] · OH

[0381] · (C 3 -C 5 ) cycloalkyl, wherein the (C 3 -C 5 ) cycloalkyl is unsubstituted or substituted by 1 or 2 halo substituents

[0382] · -O-(C 3 -C 5 ) cycloalkyl

[0383] · -NR 34 R 35 , wherein R 34 and R 35 are independently selected from:

[0384] o H,

[0385] o (C 1 -C 4 ) alkyl, wherein the (C 1 -C 4 ) alkyl is unsubstituted or substituted by OH or -O(C 1 -C 2 ) alkyl

[0386] o and wherein R 34 and R 35 may together with the atoms to which they are attached form an azetidine, pyrrolidinyl or piperidine ring, wherein said azetidine, pyrrolidinyl and piperidine are unsubstituted or substituted with CH 3 substituents;

[0387] ·CN,

[0388] ·-(C 2 -C 4 ) alkenyl,

[0389] ·-(C 2 -C 4 ) alkynyl,

[0390] ·=O

[0391] ·-C(O)H, and

[0392] ·-C(O)(C 1 -C 4 ) alkyl;

[0393] provided that:

[0394] - There is an OH substituent on heteroaryl 1, heteroaryl 2 and phenyl, and relative to the position where R 4 is linked to linker -A-, said OH is in the ortho position of the R 4 ring,

[0395] or

[0396] - There is an =O substituent on heteroaryl 1 and heteroaryl 2,

[0397] and the remaining R 10 , R 11 , R 12 , R 13 and R 14 are as defined herein.

[0398] Example 35. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 34, wherein R 4 is selected from:

[0399] -(C 1 -C 4 ) alkyl, especially -CH 3 ;

[0400] - heteroaryl 1; and

[0401] - heteroaryl 2;

[0402] - phenyl;

[0403] wherein each of heteroaryl 1, heteroaryl 2 and phenyl is independently substituted with 1, 2 or 3 substituents 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: OH, ═O, H, F, Cl and CH 3 , provided that:

[0404] - there is one OH substituent on heteroaryl 1, heteroaryl 2 and phenyl, and relative to the position where R 4 is linked to linker - A, the OH is in the ortho position of the R 4 ring, and the remaining substituents are selected from H, F, Cl and CH 3 ,

[0405] or

[0406] - there is one ═O substituent on heteroaryl 1 and heteroaryl 2, and the remaining substituents are selected from H, F, Cl and CH 3 .

[0407] Example 36. A compound of formula (I) according to any one of Examples 1 to 35 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from CH 3 , heteroaryl 1 and heteroaryl 2, and the substituents are as defined above. In particular, heteroaryl 1 contains only ring carbon atoms and one or two nitrogen atoms. More particularly, heteroaryl 1 is pyridyl or pyrimidinyl.

[0408] Example 37. A compound of formula (I) according to any one of Examples 1 to 36 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:

[0409] -(C 1 -C 4 )alkyl, especially CH 3 ;

[0410]

[0411] wherein

[0412] R 10 , R 11 , R 12 , R 13 and R 14Independently selected from:

[0413] · H,

[0414] · Halo,

[0415] · (C 1 -C 4 ) alkyl which is unsubstituted or substituted with 1, 2 or 3 halo substituents,

[0416] · (C 1 -C 2 ) alkyl substituted with -O-(C 1 -C 2 ) alkyl or OH,

[0417] · -S-(C 1 -C 3 ) alkyl,

[0418] · -O-(C 1 -C 4 ) alkyl which is unsubstituted or substituted with 1, 2 or 3 halo substituents,

[0419] · (C 3 -C 5 ) cycloalkyl, wherein the (C 3 -C 5 ) cycloalkyl is unsubstituted or substituted with 1 or 2 halo substituents,

[0420] · -O-(C 3 -C 5 ) cycloalkyl,

[0421] · -NR 34 R 35 , wherein R 34 and R 35 are independently selected from:

[0422] o H,

[0423] o (C 1 -C 4 ) alkyl, wherein the (C 1 -C 4 ) alkyl is unsubstituted or substituted with OH or -O(C 1 -C 2 ) alkyl,

[0424] 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 with CH 3 ;

[0425] · CN,

[0426] · -(C 2 -C 4 ) alkenyl,

[0427] · -(C 2 -C 4 ) alkynyl,

[0428] · -C(O)H, and

[0429] · -C(O)(C 1 -C 4 ) alkyl.

[0430] Example 38. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 37, wherein R 4 is selected from:

[0431]

[0432] wherein

[0433] R 10 is selected from H, halo, (C 1 -C 2 ) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents, -O-(C 1 -C 2 ) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents;

[0434] R 11 is selected from H, halo, (C 1 -C 2 ) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents;

[0435] R 12 is selected from H, halo, (C 1 -C 2 ) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents;

[0436] R 13 is selected from H, -S-CH 3 , halo, (C 1 -C 2 ) alkyl unsubstituted or substituted with 1, 2 or 3 halo substituents; and

[0437] R 14 is selected from H, halo, (C 1 -C 2)Alkyl, O-(C which is unsubstituted or substituted by 1, 2 or 3 halogen substituents 1 -C 2 )alkyl, and cyclopropyl.

[0438] Example 39. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 38, wherein R 4 is selected from:

[0439]

[0440] wherein

[0441] R 10 is selected from H, F, Cl, CH 3 and OCF 3 ;

[0442] R 11 is selected from H, F, Cl and CH 3 ;

[0443] R 12 is selected from H, F, Cl and CH 3 ;

[0444] R 13 is selected from H, F, Cl, -S-CH 3 and CH 3 ; and

[0445] R 14 is selected from H, F, Cl, CH 3 , -CH 2 CH 3 , cyclopropyl, -OCHF 2 , OCF 3 .

[0446] In particular, at least one of the substituents R 10 , R 11 and R 12 is H.

[0447] In particular, at least one of the substituents R 13 and R 14 is H.

[0448] Example 40. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 39, wherein R 4 is selected from:

[0449]

[0450] Example 41. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 40, wherein R 4 is selected from:

[0451] -CH 3 ,

[0452] Example 42. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 41, wherein R 4 is selected from:

[0453] In particular

[0454] Example 43. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 42, wherein the compound of formula (I) has the stereochemistry shown in formula (I'):

[0455]

[0456] In particular, the compound of formula (I) is a compound of formula (I"):

[0457]

[0458] More particularly, the compound has the stereochemistry of formula (I'''):

[0459]

[0460] Example 44. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, wherein formula (I) is formula 1a:

[0461]

[0462] (Preferably, formula (I) is formula 1a).

[0463] In a particular embodiment, a compound of formula 1a' is provided:

[0464]

[0465] Example 45. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, wherein formula (I) is formula 1b:

[0466]

[0467] or 1b':

[0468]

[0469] Example 46. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, wherein formula (I) is formula 1c:

[0470]

[0471] or 1c':

[0472]

[0473] Example 47. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, wherein formula (I) is formula 1d:

[0474]

[0475] or 1d':

[0476]

[0477] Example 48. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, wherein formula (I) is formula 1e:

[0478]

[0479] or 1e':

[0480]

[0481] Example 49. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, wherein formula (I) is formula 1f:

[0482]

[0483] or 1f':

[0484]

[0485] Example 50. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 44, wherein formula (I) is formula 1g:

[0486]

[0487] More preferably, formula (I) is formula 1g.

[0488] There is also provided a compound of formula (I), which is formula 1g':

[0489]

[0490] Example 51. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 44 and 50, wherein formula (I) is formula 1h:

[0491]

[0492] Most preferably, formula (I) is formula 1h.

[0493] There is also provided a compound of formula (I), which is formula 1h':

[0494]

[0495] Example 52. A compound of formula 1g or 1g' or a pharmaceutically acceptable salt thereof according to Example 50,

[0496]

[0497] wherein R 1 is selected from:

[0498]

[0499]

[0500] R 15 is F;

[0501] R 16 is R 25 (R 24 )N-;

[0502] R 17 is F;

[0503] R 18 is F;

[0504] R 19 is F;

[0505] R 20 is F;

[0506] R 21 is CH 3 ;

[0507] R 22 is CF 3 、CHF 2 CH 2 、HOC(O)-CH 2 -、H 3 C-C(O)-、(H3 C) 3 C-O-C(O)-;

[0508] R 23 is CF 3 、CHF 2 CH 2 -, (H 3 C) 3 C-O-C(O)-;

[0509] R 24 is CH 3 ; and

[0510] R 25 is CHF 2 CH 2 -;

[0511] R 2 is the following moiety:

[0512]

[0513] wherein

[0514] R 6 is selected from H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents of (C 1 -C 4 )alkyl;

[0515] R 8 is selected from H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents of (C 1 -C 4 )alkyl;

[0516] R 9 is selected from H, O-CH 3 , OH, CN, CH 3 and halo;

[0517] R 28 is selected from SF 5 , halo, unsubstituted or substituted with 1, 2 or 3 halo substituents of (C 1 -C 4 )alkyl, and -C(O)H;

[0518] X is selected from C-R 7 and N; and

[0519] R 7 is selected from H and halo;

[0520] R 3 is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo and OH of (C 1 -C4 ) alkyl;

[0521] x is 0 or 1;

[0522] Y is CH or N, especially N;

[0523] y is 0, 1 or 2;

[0524] R 5 is selected from CH 3 ;

[0525] or in the following part:

[0526]

[0527] two R substituents on adjacent carbon atoms 5 are connected to form a ring C:

[0528]

[0529] - wherein the ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, and the fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted by 1 or 2 R 40 groups, wherein the R 40 is selected from:

[0530] · (C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) alkyl is independently unsubstituted or substituted by OH or 1, 2 or 3 halogen atoms,

[0531] · halogen, especially F,

[0532] · or two R 40 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- C 4 ) 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;

[0533] · or two R 40 substituents on adjacent carbon atoms are connected together with the carbon atoms to which they are attached to form a fused cyclopropyl ring;

[0534] and especially

[0535] R 4Selected from:

[0536] CH 3 、

[0537]

[0538] In particular

[0539] Especially

[0540]

[0541] Wherein

[0542] R 10 is selected from H, halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents, -O-(C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents;

[0543] R 11 is selected from H, halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents;

[0544] R 12 is selected from H, halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents;

[0545] R 13 is selected from H, -S-CH 3 , halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents; and

[0546] R 14 is selected from H, halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents, O-(C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents, and cyclopropyl.

[0547] In particular, formula 1g is formula 1g* or formula 1g**.

[0548] Example 53. A compound having formula 1h or 1h' according to Example 51 or a pharmaceutically acceptable salt thereof,

[0549]

[0550] Wherein:

[0551] R 1 is selected from:

[0552]

[0553] R 2 is selected from:

[0554]

[0555] R 3 is CH 3 ;

[0556] x is 0 or 1;

[0557] R 4 is selected from:

[0558] -CH 3 ,

[0559]

[0560] y is 0 or 1;

[0561] R 5 is selected from CH 3 ;

[0562] or a part thereof:

[0563]

[0564] is

[0565]

[0566] Example 54. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Example 1, wherein the compound is selected from:

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576] Example 55. A compound of formula (I) according to Example 1, wherein the compound is

[0577]

[0578] Example 56. A compound of formula (I) according to any one of Examples 1 to 44, 50, 51, 52, 53, 54 or 55, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof

[0579]

[0580] Example 57. A compound of formula (I) according to any one of Examples 1 to 44, 50, 51, 52, 53, 54 or 55, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof

[0581]

[0582] Example 58. A compound of formula (1b) according to any one of Examples 1 to 43 or 45, or a pharmaceutically acceptable salt thereof,

[0583]

[0584] wherein R 1 is selected from:

[0585]

[0586]

[0587] R 15 is F;

[0588] R 16 is R 25 (R 24 )N-;

[0589] R 17 is F;

[0590] R 18 is F;

[0591] R 19 is F;

[0592] R 20 is F;

[0593] R 21 is CH 3 ;

[0594] R 22 is CF 3 、CHF 2 CH 2 、HOC(O)-CH 2 -、H 3 C-C(O)-、(H 3 C) 3 C-O-C(O)-;

[0595] R 23 is CF 3 、CHF 2 CH 2 -、(H 3 C) 3 C-O-C(O)-;

[0596] R 24 is CH 3 ; and

[0597] R 25 is CHF 2 CH 2 -;

[0598] R 2 is the following part:

[0599]

[0600] wherein

[0601] R 6 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halos of (C 1 -C 4 )alkyl;

[0602] R 8 is selected from H, halo, unsubstituted or substituted with 1, 2 or 3 halos of (C 1 -C 4 )alkyl;

[0603] R 9 is selected from H, O-CH 3 , OH, CN, CH 3 and halo;

[0604] R 28 is selected from SF 5 , halo, unsubstituted or substituted with 1, 2 or 3 halos of (C 1 -C 4 )alkyl, and -C(O)H;

[0605] X is selected from C-R 7 and N; and

[0606] R 7 is selected from H and halo;

[0607] R 3 is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo and OH of (C 1 -C 4 )alkyl;

[0608] x is 0 or 1;

[0609] Part:

[0610]

[0611] As described in Example 1, or in particular

[0612]

[0613] y is 0 or 1;

[0614] R 5 is selected from CH 3 ;

[0615] or in the following part:

[0616]

[0617] Two R 5 substituents on adjacent carbon atoms are linked to form ring C:

[0618]

[0619] - Wherein ring C is a fused (C 3 -C6 ) a cycloalkyl ring, especially a fused cyclobutyl ring, and said fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted by 1 or 2 R 40 groups, wherein said R 40 is selected from:

[0620] · (C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) alkyl is independently unsubstituted or substituted by OH or 1, 2 or 3 halogens,

[0621] · halogen, especially F,

[0622] · or two R 40 substituents on the same ring carbon atom together with the carbon atom to which they are attached can be linked to form a (C 3- C 4 ) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein said heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N and S;

[0623] · 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;

[0624] and especially

[0625]

[0626] R 4 is selected from:

[0627] CH 3 ,

[0628]

[0629] especially

[0630] especially

[0631]

[0632] wherein

[0633] R 10 is selected from H, halogen, (C 1 -C 2 ) alkyl unsubstituted or substituted by 1, 2 or 3 halogen substituents, -O-(C 1 -C 2)alkyl;

[0634] R 11 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo substituents (C 1 -C 2 )alkyl;

[0635] R 12 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo substituents (C 1 -C 2 )alkyl;

[0636] R 13 is selected from H, -S-CH 3 , halo, unsubstituted or substituted by 1, 2 or 3 halo substituents (C 1 -C 2 )alkyl; and

[0637] R 14 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo substituents (C 1 -C 2 )alkyl, unsubstituted or substituted by 1, 2 or 3 halo substituents O-(C 1 -C 2 )alkyl, and cyclopropyl.

[0638] Example 59. A compound of formula (1b) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43 or 45 or 58,

[0639]

[0640] wherein:

[0641] R 1 is selected from:

[0642]

[0643] R 2 is selected from:

[0644]

[0645] R 3 is CH 3 ;

[0646] x is 0 or 1;

[0647] R 4 is selected from:

[0648] -CH 3 、

[0649] Part:

[0650]

[0651] is:

[0652]

[0653] y is 0 or 1;

[0654] R 5 is selected from CH 3 ;

[0655] or where the part is

[0656]

[0657] Example 60. A compound of formula (1c) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43 or 46,

[0658]

[0659] wherein R 1 is selected from:

[0660]

[0661]

[0662] R 15 is F;

[0663] R 16 is R 25 (R 24 )N-;

[0664] R 17 is F;

[0665] R 18 is F;

[0666] R 19 is F;

[0667] R 20 is F;

[0668] R 21 is CH 3 ;

[0669] R 22 is CF 3 、CHF 2 CH 2 、HOC(O)-CH 2 -、H 3C-C(O)-, (H 3 C) 3 C-O-C(O)-;

[0670] R 23 is CF 3 、CHF 2 CH 2 -, (H 3 C) 3 C-O-C(O)-;

[0671] R 24 is CH 3 ; and

[0672] R 25 is CHF 2 CH 2 -;

[0673] R 2 is the following moiety:

[0674]

[0675] wherein

[0676] R 6 is selected from H, halo, unsubstituted or substituted with 1, 2 or 3 halo of (C 1 -C 4 )alkyl;

[0677] R 8 is selected from H, halo, unsubstituted or substituted with 1, 2 or 3 halo of (C 1 -C 4 )alkyl;

[0678] R 9 is selected from H, O-CH 3 , OH, CN, CH 3 and halo;

[0679] R 28 is selected from SF 5 , halo, unsubstituted or substituted with 1, 2 or 3 halo of (C 1 -C 4 )alkyl, and -C(O)H;

[0680] X is selected from C-R 7 and N; and

[0681] R 7 is selected from H and halo;

[0682] R 3 is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo and OH of (C1 -C 4 ) alkyl;

[0683] x is 0 or 1;

[0684] Part:

[0685]

[0686] As described in Example 1, or in particular

[0687]

[0688] y is 0 or 1;

[0689] R 5 Selected from CH 3 ;

[0690] Or in the following part:

[0691]

[0692] Two R on adjacent carbon atoms 5 Substituents are connected to form ring C:

[0693]

[0694] - Wherein ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, and the fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted by 1 or 2 R 40 Groups, wherein the R 40 Selected from:

[0695] · (C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) alkyl is independently unsubstituted or substituted by OH or 1, 2 or 3 halogens,

[0696] · Halogen, especially F,

[0697] · Or two R on the same ring carbon atom 40 Substituents together with the carbon atom to which they are attached can be connected to form a (C 3- C 4 ) 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;

[0698] · Or two R on adjacent carbon atoms40 The substituents are attached to the carbon atoms to which they are attached to form a fused cyclopropyl ring;

[0699] and in particular

[0700]

[0701] R 4 is selected from:

[0702] CH 3 、

[0703]

[0704] in particular

[0705] especially

[0706]

[0707] wherein

[0708] R 10 is selected from H, halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents, -O-(C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents;

[0709] R 11 is selected from H, halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents;

[0710] R 12 is selected from H, halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents;

[0711] R 13 is selected from H, -S-CH 3 , halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents; and

[0712] R 14 is selected from H, halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents, O-(C 1 -C2 ) an alkyl group, and a cyclopropyl group.

[0713] Example 61. A compound of formula (1c) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43 or 46 or 60,

[0714]

[0715] wherein:

[0716] R 1 is selected from:

[0717]

[0718] R 2 is selected from:

[0719]

[0720] R 3 is CH 3 ;

[0721] x is 0 or 1;

[0722] R 4 is selected from:

[0723] -CH 3 ,

[0724] a moiety:

[0725]

[0726] is:

[0727]

[0728] y is 0 or 1;

[0729] R 5 is selected from CH 3 ;

[0730] or wherein the moiety is

[0731]

[0732] Example 62. A compound of formula (1d) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43 or 47,

[0733]

[0734] wherein R 1 is selected from:

[0735]

[0736]

[0737] R 15 is F;

[0738] R 16 is R 25 (R 24 )N-;

[0739] R 17 is F;

[0740] R 18 is F;

[0741] R 19 is F;

[0742] R 20 is F;

[0743] R 21 is CH 3 ;

[0744] R 22 is CF 3 、CHF 2 CH 2 、HOC(O)-CH 2 -、H 3 C-C(O)-、(H 3 C) 3 C-O-C(O)-;

[0745] R 23 is CF 3 、CHF 2 CH 2 -、(H 3 C) 3 C-O-C(O)-;

[0746] R 24 is CH 3 ; and

[0747] R 25 is CHF 2 CH 2 -;

[0748] R 2 is the following part:

[0749]

[0750] wherein

[0751] R 6Selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo substituents of (C 1 -C 4 ) alkyl;

[0752] R 8 Selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo substituents of (C 1 -C 4 ) alkyl;

[0753] R 9 Selected from H, O-CH 3 , OH, CN, CH 3 and halo;

[0754] R 28 Selected from SF 5 , halo, unsubstituted or substituted by 1, 2 or 3 halo substituents of (C 1 -C 4 ) alkyl, and -C(O)H;

[0755] X is selected from C-R 7 and N; and

[0756] R 7 is selected from H and halo;

[0757] R 3 is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo and OH of (C 1 -C 4 ) alkyl;

[0758] x is 0 or 1;

[0759] Part:

[0760]

[0761] As described in Example 1, or in particular

[0762]

[0763] y is 0 or 1;

[0764] R 5 is selected from CH 3 ;

[0765] Or in the following part:

[0766]

[0767] Two R 5 substituents on adjacent carbon atoms are linked to form a ring C:

[0768]

[0769] - wherein ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, and said fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted with 1 or 2 R 40 groups, wherein said R 40 is selected from:

[0770] · (C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) alkyl is independently unsubstituted or substituted with OH or 1, 2 or 3 halogens,

[0771] · halogen, especially F,

[0772] · or two R 40 substituents on the same ring carbon atom together with the carbon atom to which they are attached can be linked to form a (C 3- C 4 ) cycloalkyl spiro ring or a 3 - or 4 - membered heterocyclic spiro ring, wherein said heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N and S;

[0773] · 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;

[0774] and especially

[0775]

[0776] R 4 is selected from:

[0777] CH 3 、

[0778]

[0779] especially

[0780] especially

[0781]

[0782] wherein

[0783] R 10 is selected from H, halogen, (C 1 -C2 ) an alkyl group, unsubstituted or substituted with 1, 2 or 3 halo substituents, -O-(C 1 -C 2 ) alkyl;

[0784] R 11 is selected from H, halo, (C 1 -C 2 ) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents;

[0785] R 12 is selected from H, halo, (C 1 -C 2 ) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents;

[0786] R 13 is selected from H, -S-CH 3 , halo, (C 1 -C 2 ) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents; and

[0787] R 14 is selected from H, halo, (C 1 -C 2 ) alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents, O-(C 1 -C 2 ) alkyl, and cyclopropyl.

[0788] Example 63. A compound of formula (1d) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43 or 47 or 62,

[0789]

[0790] wherein:

[0791] R 1 is selected from:

[0792]

[0793] R 2 is selected from:

[0794]

[0795] R 3 is CH 3 ;

[0796] x is 0 or 1;

[0797] R 4 is selected from:

[0798] -CH 3 、

[0799] Part:

[0800]

[0801] is:

[0802]

[0803] y is 0 or 1;

[0804] R 5 is selected from CH 3 ;

[0805] or wherein the part is

[0806]

[0807] Example 64. A compound of formula (1e) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43 or 48,

[0808]

[0809] wherein R 1 is selected from:

[0810]

[0811]

[0812] R 15 is F;

[0813] R 16 is R 25 (R 24 )N-;

[0814] R 17 is F;

[0815] R 18 is F;

[0816] R 19 is F;

[0817] R 20 is F;

[0818] R 21 is CH 3 ;

[0819] R 22 is CF 3, CHF 2 CH 2 , HOC(O)-CH 2 -, H 3 C-C(O)-, (H 3 C) 3 C-O-C(O)-;

[0820] R 23 is CF 3 , CHF 2 CH 2 -, (H 3 C) 3 C-O-C(O)-;

[0821] R 24 is CH 3 ; and

[0822] R 25 is CHF 2 CH 2 -;

[0823] R 2 is the following part:

[0824]

[0825] wherein

[0826] R 6 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halos of (C 1 -C 4 )alkyl;

[0827] R 8 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halos of (C 1 -C 4 )alkyl;

[0828] R 9 is selected from H, O-CH 3 , OH, CN, CH 3 and halo;

[0829] R 28 is selected from SF 5 , halo, unsubstituted or substituted by 1, 2 or 3 halos of (C 1 -C 4 )alkyl, and -C(O)H;

[0830] X is selected from C-R 7 and N; and

[0831] R 7 is selected from H and halo;

[0832] R 3 is an unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo and OH (C 1 -C 4 ) alkyl;

[0833] x is 0 or 1;

[0834] Part:

[0835]

[0836] As described in Example 1, or in particular

[0837]

[0838] y is 0 or 1;

[0839] R 5 is selected from CH 3 ;

[0840] Or in the following part:

[0841]

[0842] Two R 5 substituents on adjacent carbon atoms are linked to form a ring C:

[0843]

[0844] - Wherein the ring C is a fused (C 3 -C 6 ) cycloalkyl ring, in particular a fused cyclobutyl ring, and the fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted by 1 or 2 R 40 groups, wherein the R 40 is selected from:

[0845] · (C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) alkyl is independently unsubstituted or substituted by OH or 1, 2 or 3 halo,

[0846] · Halo, especially F,

[0847] · 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- C 4)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;

[0848] · Or wherein 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;

[0849] And in particular

[0850]

[0851] R 4 is selected from:

[0852] CH 3 ,

[0853]

[0854] In particular

[0855] Especially

[0856]

[0857] Wherein

[0858] R 10 is selected from H, halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2, or 3 halo substituents, -O-(C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2, or 3 halo substituents;

[0859] R 11 is selected from H, halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2, or 3 halo substituents;

[0860] R 12 is selected from H, halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2, or 3 halo substituents;

[0861] R 13 is selected from H, -S-CH 3 , halo, (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2, or 3 halo substituents; And

[0862] R 14Selected from H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents of (C 1 -C 2 )alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents of O-(C 1 -C 2 )alkyl, and cyclopropyl.

[0863] Example 65. A compound of formula (1e) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43 or 48 or 64,

[0864]

[0865] wherein:

[0866] R 1 is selected from:

[0867]

[0868] R 2 is selected from:

[0869]

[0870] R 3 is CH 3 ;

[0871] x is 0 or 1;

[0872] R 4 is selected from:

[0873] -CH 3 、

[0874] moieties:

[0875]

[0876] is:

[0877]

[0878] y is 0 or 1;

[0879] R 5 is selected from CH 3 ;

[0880] or where the moiety is

[0881]

[0882] Example 66. A compound of formula (1f) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43 or 49,

[0883]

[0884] wherein R 1 is selected from:

[0885]

[0886]

[0887] R 15 is F;

[0888] R 16 is R 25 (R 24 )N-;

[0889] R 17 is F;

[0890] R 18 is F;

[0891] R 19 is F;

[0892] R 20 is F;

[0893] R 21 is CH 3 ;

[0894] R 22 is CF 3 、CHF 2 CH 2 、HOC(O)-CH 2 -、H 3 C-C(O)-、(H 3 C) 3 C-O-C(O)-;

[0895] R 23 is CF 3 、CHF 2 CH 2 -、(H 3 C) 3 C-O-C(O)-;

[0896] R 24 is CH 3 ; and

[0897] R 25 is CHF 2 CH 2 -;

[0898] R 2 is the following part:

[0899]

[0900] wherein

[0901] R 6 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo substituents of (C 1 -C 4 ) alkyl;

[0902] R 8 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo substituents of (C 1 -C 4 ) alkyl;

[0903] R 9 is selected from H, O-CH 3 , OH, CN, CH 3 and halo;

[0904] R 28 is selected from SF 5 , halo, unsubstituted or substituted by 1, 2 or 3 halo substituents of (C 1 -C 4 ) alkyl, and -C(O)H;

[0905] X is selected from C-R 7 and N; and

[0906] R 7 is selected from H and halo;

[0907] R 3 is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo and OH of (C 1 -C 4 ) alkyl;

[0908] x is 0 or 1;

[0909] part:

[0910]

[0911] as described in Example 1, or in particular

[0912]

[0913] y is 0 or 1;

[0914] R 5 is selected from CH 3 ;

[0915] or in the following parts:

[0916]

[0917] two Rs on adjacent carbon atoms 5 substituents are linked to form ring C:

[0918]

[0919] -wherein ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, and said fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted by 1 or 2 Rs 40 groups, wherein said R 40 is selected from:

[0920] · (C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) alkyl is independently unsubstituted or substituted by OH or 1, 2 or 3 halogens,

[0921] · halogen, especially F,

[0922] · or two Rs on the same ring carbon atom 40 substituents together with the carbon atom to which they are attached can be linked to form a (C 3- C 4 ) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein said heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N and S;

[0923] · 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;

[0924] and especially

[0925]

[0926] R 4 is selected from:

[0927] CH 3 ,

[0928]

[0929] especially

[0930] in particular

[0931]

[0932] wherein

[0933] R 10 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo substituents (C 1 -C 2 )alkyl, unsubstituted or substituted by 1, 2 or 3 halo substituents -O-(C 1 -C 2 )alkyl;

[0934] R 11 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo substituents (C 1 -C 2 )alkyl;

[0935] R 12 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo substituents (C 1 -C 2 )alkyl;

[0936] R 13 is selected from H, -S-CH 3 , halo, unsubstituted or substituted by 1, 2 or 3 halo substituents (C 1 -C 2 )alkyl; and

[0937] R 14 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo substituents (C 1 -C 2 )alkyl, unsubstituted or substituted by 1, 2 or 3 halo substituents O-(C 1 -C 2 )alkyl, and cyclopropyl.

[0938] Example 67. A compound of formula (1f) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43 or 49 or 66,

[0939]

[0940] wherein:

[0941] R 1 is selected from:

[0942]

[0943] R 2 is selected from:

[0944]

[0945] R 3 is CH 3 ;

[0946] x is 0 or 1;

[0947] R 4 is selected from:

[0948] -CH 3 ,

[0949] part:

[0950]

[0951] is:

[0952]

[0953] y is 0 or 1;

[0954] R 5 is selected from CH 3 ;

[0955] or in which the part is

[0956]

[0957] Example 68. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 67, wherein the compound is selected from:

[0958]

[0959]

[0960] Example 69. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 - 68, wherein the compound contains R in a non - zwitterionic form 4 part.

[0961] Example 70. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 - 68, wherein the compound contains R in a zwitterionic form 4 part.

[0962] Example 71. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 - 68, wherein the compound contains an R 4 part that is a mixture of zwitterionic and non - zwitterionic forms.

[0963] Example 72. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1-68, wherein R 4 moiety is as shown below, and the R 4 moiety is present in the non-zwitterionic form (d) or (e):

[0964]

[0965] Example 73. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1-68, wherein R 4 moiety is as shown below, and the R 4 moiety is present in a zwitterionic form selected from:

[0966]

[0967] Example 74. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1-68, wherein the R 4 moiety is present as a mixture of the zwitterionic forms (a) and (b) according to Example 72.

[0968] Example 75. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1-74, wherein the R 4 moiety is present as a mixture of:

[0969] · the non-zwitterionic form (e) and the zwitterionic form (a) or (b),

[0970] or

[0971] · the non-zwitterionic form (e) and the zwitterionic forms (a) and (b)

[0972] and

[0973] Example 76. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1-74, wherein the R 4 moiety is in the zwitterionic form (c):

[0974]

[0975] Example 77. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1-74, wherein the R 4 moiety is present as a mixture of the zwitterionic form (c) and the non-zwitterionic form (d):

[0976]

[0977] Example 78. A compound of formula (I) according to any one of Examples 1 to 44, 50, 51, 52, 53, 54, 55 or 56, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide:

[0978] In the non-zwitterionic form:

[0979]

[0980] Or in the zwitterionic form:

[0981]

[0982] Or in the zwitterionic form:

[0983]

[0984] Or a mixture of any two or three of said forms.

[0985] Example 79. A compound of formula (I) according to any one of Examples 1 to 44, 50, 51, 52, 53, 54, 55 or 57, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide:

[0986] In the non-zwitterionic form

[0987]

[0988] Or in the zwitterionic form:

[0989]

[0990] Or in the zwitterionic form:

[0991]

[0992] or a mixture of any two or three of said forms.

[0993] Example 80. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 1 - 79, in crystalline form.

[0994] Example 81. A compound of formula (I) according to any one of Examples 1 to 44, 50, 51, 52, 53, 54, 55 or 56 or 78, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, in crystalline form.

[0995] Example 82. A compound of formula (I) according to any one of Examples 1 to 44, 50, 51, 52, 53, 54, 55 or 57 or 79, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, in crystalline form.

[0996] Example 83. A compound of formula (I) according to any one of Examples 80 to 82, wherein the compound is in substantially pure form.

[0997] Example 84. A compound of formula (I) according to Example 1, wherein

[0998] · The crystalline form according to Example 81 is characterized by an X-ray powder diffraction pattern that includes 4 or more 2θ values selected from the group consisting of: 8.6 ± 0.2, 11.2 ± 0.2, 13.0 ± 0.2, 14.9 ± 0.2, 15.5 ± 0.2, 17.9 ± 0.2, 19.4 ± 0.2, 22.0 ± 0.2, 24.3 ± 0.2, 26.0 ± 0.2, 28.2 ± 0.2, 29.1 ± 0.2 and 29.7 ± 0.2 at a temperature of about 22 °C, and

[0999] · The crystalline form according to Example 82 is characterized by the following X-ray powder diffraction pattern, which contains 4 or more 2θ values selected from the group consisting of: 5.77±0.2, 6.67±0.2, 10.54±0.2, 12.36±0.2, 12.90±0.2, 13.02±0.2, 14.83±0.2, 15.27±0.2, 15.65±0.2, 15.99±0.2, 17.34±0.2, 18.52±0.2, 19.18±0.2, 20.04±0.2, 21.17±0.2, 21.47±0.2, 21.86±0.2, 22.96±0.2, 23.18±0.2 and 23.9±0.2 at a temperature of about 22 °C.

[1000] Example 85. A compound having the formula (I) according to Example 1, wherein

[1001] · The crystalline form according to Example 81 is characterized by the following X-ray powder diffraction pattern, which contains 5 or more 2θ values selected from the group consisting of: 8.6±0.2, 11.2±0.2, 13.0±0.2, 14.9±0.2, 15.5±0.2, 17.9±0.2, 19.4±0.2, 22.0±0.2, 24.3±0.2, 26.0±0.2, 28.2±0.2, 29.1±0.2 and 29.7±0.2 at a temperature of about 22 °C, and

[1002] · The crystalline form according to Example 82 is characterized by the following X-ray powder diffraction pattern, which contains 5 or more 2θ values selected from the group consisting of: 5.77±0.2, 6.67±0.2, 10.54±0.2, 12.36±0.2, 12.90±0.2, 13.02±0.2, 14.83±0.2, 15.27±0.2, 15.65±0.2, 15.99±0.2, 17.34±0.2, 18.52±0.2, 19.18±0.2, 20.04±0.2, 21.17±0.2, 21.47±0.2, 21.86±0.2, 22.96±0.2, 23.18±0.2 and 23.9±0.2 at a temperature of about 22 °C.

[1003] Example 86. A compound having the formula (I) according to Example 1, wherein

[1004] · The crystalline form according to Example 81 is characterized by the following X-ray diffraction pattern, which is substantially the same as the Figure 1 X-ray powder diffraction pattern shown in.

[1005] The crystalline form according to Example 82 is characterized by an X-ray diffraction pattern that is Figure 6 The X-ray powder diffraction patterns shown in are substantially the same.

[1006] Embodiment 87. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-79 and 83, wherein the compound is in an amorphous form.

[1007] Embodiment 88. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-83, wherein the compound is a sodium salt.

[1008] In one embodiment, there is provided a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein when R 1 When is a ring, then:

[1009] ·With the R 1 The ring connects the rest of the molecule to R 1 Each adjacent R 1 The ring atoms are independently unsubstituted or substituted only with halo, in particular, independently unsubstituted or substituted with one F substituent, and

[1010] Preferably, the R 1 Ring via R 1 Ring nitrogen atom or double bonded to adjacent R 1 Ring atom R 1 The ring carbon atoms are attached to the rest of the molecule.

[1011] In particular, R 1 yes:

[1012] 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 Substitution, where R 33 is halogenated, and wherein the cycloalkenyl or halogenated cycloalkenyl is substituted by 0, 1 or 2 R 15 Substituent substitution,

[1013] or R 1 is a heterocyclyl, wherein the heterocyclyl is a 5-membered or 6-membered fully saturated or partially unsaturated radical comprising ring carbon atoms and 1 or 2 ring heteroatoms independently selected from N, NH, O and S, and wherein the heterocyclyl is unbridged or bridged and the bridge is 1 or 2 carbon atoms, wherein the heterocyclyl is unsubstituted or substituted by 1, 2, 3 or 4, preferably 1 or 2 R 33 Substitution, where R 33is halogenated, and wherein said heterocyclic group or halogenated 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 ,

[1014] or R 1 is heteroaryl, wherein said heteroaryl is a 5- or 6-membered fully unsaturated monocyclic group containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, preferably 1 or 2 ring heteroatoms, wherein the total number of ring S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1, wherein said heteroaryl 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 halogenated and (C 1 -C 4 )alkyl, wherein said (C 1 -C 4 )alkyl is unsubstituted or substituted by 1, 2 or 3 halogenated substituents,

[1015] and R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 are each independently selected from:

[1016] · halogenated

[1017] · (C 1- C 4 )alkyl-O- which is unsubstituted or substituted by 1, 2 or 3 halogenated substituents;

[1018] · (C 1 -C 2 )alkyl which is unsubstituted or substituted by OH, -O-(C 1 -C 4 )alkyl or 1, 2 or 3 halogenated substituents,

[1019] · HOC(O)-(CH 2 ) n -,

[1020] · H 3 C-C(O)(CH 2 )n -,

[1021] ·(C 1 -C 4 )alkyl - O - C(O)(CH 2 ) n ,

[1022] ·═O

[1023] ·azetidinyl or pyrrolidinyl, wherein said azetidinyl and pyrrolidinyl are linked to the remainder of the molecule via an N atom and are each unsubstituted or substituted by 1 or 2 Fs,

[1024] ·R 25 (R 24 )N -, wherein R 24 is H or (C 1 -C 4 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens, R 25 is H or (C 1 -C 4 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens,

[1025] ·OH

[1026] wherein n is 0, 1 or 2.

[1027] More particularly, R 1 is:

[1028] cycloalkenyl, wherein said cycloalkenyl is a partially unsaturated monocyclic ring containing 5 or 6 ring carbon atoms and said cycloalkenyl is unsubstituted or substituted by 1 or 2 R 33 wherein R 33 is halogen, preferably F, and wherein said cycloalkenyl or halogen - substituted cycloalkenyl is substituted by 0 or 1 R 15 substituent, preferably 1 substituent, wherein R 15 is selected from:

[1029] h) (C 1- C 2 )alkyl - O - which is unsubstituted or substituted by 1, 2 or 3 halogens;

[1030] i) (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens,

[1031] j) HOC(O)-(CH 2 ) n -,

[1032] k) H 3C-C(O)(CH 2 ) n -,

[1033] l)H 3 C-O-C(O)(CH 2 ) n ,

[1034] m)=O, and

[1035] n)R 25 (R 24 )N-, H, where R 24 is H or an unsubstituted or 1-, 2- or 3-halogen-substituted (C 1 -C 2 )alkyl, R 25 is H or an unsubstituted or 1-, 2- or 3-halogen-substituted (C 1 -C 2 )alkyl,

[1036] n is 0 or 1,

[1037] where

[1038] · 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 ring para position relative to the rest of the molecule; and

[1039] · the cycloalkenyl or halogen-substituted cycloalkenyl is bonded via a double bond to the R 1 ring carbon atom of the adjacent R 1 ring carbon atom to connect to the rest of the compound;

[1040] or R 1 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 , R22 and R 23 is substituted by substituents of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 and R 23 are independently selected from:

[1041] i) (C 1- C 4 ) alkyl - O - which is unsubstituted or substituted by 1, 2 or 3 halogens;

[1042] j) (C 1 - C 2 ) alkyl which is unsubstituted or substituted by OH, - O - (C 1 - C 4 ) alkyl or 1, 2 or 3 halogens,

[1043] k) HOC(O)-(CH 2 ) n -,

[1044] l) H 3 C - C(O)(CH 2 ) n (R

[1045] m) H 3 C - O - C(O)(CH 2 ) n (R

[1046] n) = O

[1047] o) R 25 (R 24 ) N - where R 24 is H, (C 1 - C 2 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens, R 25 is H, (C 1 - C 2 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens,

[1048] p) OH

[1049] where n is 0 or 1,

[1050] and where:

[1051] · 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 at the meta or para position, preferably the para position, relative to the rest of the molecule; and

[1052] · The heterocyclic group is connected to the rest of the compound via R 1 ring nitrogen atom or an R 1 ring carbon atom double-bonded to an adjacent ring atom;

[1053] Or R 1 is a heteroaryl group, where 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, with the total number of ring S atoms not exceeding 1 and the total number of ring O atoms not exceeding 1, and the heteroaryl group is unsubstituted or substituted by 1 or 2 substituents independently selected from R 21 and R 30 , where R 21 and R 30 are independently selected from (C 1 -C 2 )alkyl, and the (C 1 -C 2 )alkyl is unsubstituted or substituted by 1, 2, or 3 halogens, and preferably, the alkyl or haloalkyl substituent is not present on the R 1 ring atoms adjacent to the R 1 ring atoms connecting the heteroaryl group to the rest of the molecule, and more preferably, when the heteroaryl group is a 6-membered ring, the alkyl or haloalkyl substituent is located at the ring para position relative to the rest of the molecule.

[1054] More particularly, R 1 is selected from:

[1055]

[1056]

[1057] R 33 is F;

[1058] R 15 is halo, azetidinyl, or pyrrolidinyl, where the azetidinyl and pyrrolidinyl are connected to the rest of the molecule via the N atom and are unsubstituted or substituted by 1 or 2 F;

[1059] R 16 is R 25 (R 24)N-, where R 24 is H or (C 1 -C 2 )alkyl, R 25 is H or an unsubstituted or 1-, 2- or 3-halogenated, especially F-substituted (C 1 -C 2 )alkyl;

[1060] R 17 is halogenated;

[1061] R 18 is halogenated;

[1062] R 19 is halogenated;

[1063] R 20 is halogenated;

[1064] R 21 is (C 1 -C 2 )alkyl;

[1065] R 22 and R 23 are each independently selected from:

[1066] ·an unsubstituted or 1-, 2- or 3-halogenated (C 1 -C 4 )alkyl,

[1067] ·HOC(O)-(CH 2 ) n -,

[1068] ·H 3 C-C(O)(CH 2 ) n -,

[1069] ·(H 3 C) 3 C-O-C(O)(CH 2 ) n -;

[1070] ·where n is 0, 1 or 2;

[1071] and

[1072] R 30 is CH 3 .

[1073] In a specific embodiment, R 1 is selected from:

[1074]

[1075]

[1076] R 15 is F;

[1077] R 16 is R 25 (R 24 )N-;

[1078] R 17 is F;

[1079] R 18 is F;

[1080] R 19 is F;

[1081] R 20 is F;

[1082] R 21 is CH 3 ;

[1083] R 22 is CF 3 、CHF 2 CH 2 、HOC(O)-CH 2 -、H 3 C-C(O)-、(H 3 C) 3 C-O-C(O)-;

[1084] R 23 is CF 3 、CHF 2 CH 2 -、(H 3 C) 3 C-O-C(O)-;

[1085] R 24 is CH 3 ; and

[1086] R 25 is CHF 2 CH 2 -.

[1087] In another embodiment, R 1 is selected from:

[1088]

[1089] In particular Especially More particularly

[1090]

[1091] In another embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 is one of the following moieties:

[1092]

[1093] R 6 is selected from:

[1094] · H,

[1095] · halo,

[1096] · (C 1 -C 4 )alkyl which is unsubstituted or substituted with 1, 2 or 3 halo,

[1097] · (C 3 -C 5 )cycloalkyl which is unsubstituted or substituted with 1, 2 or 3 halo,

[1098] · -O-(C 1 -C 4 )alkyl which is unsubstituted or substituted with 1, 2 or 3 halo,

[1099] · OH, and

[1100] · CN;

[1101] R 8 is selected from H, halo, and (C 1 -C 4 )alkyl which is unsubstituted or substituted with 1, 2 or 3 halo,

[1102] R 9 is selected from H, O-CH 3 , OH, CN, CH 3 and halo;

[1103] R 28 is selected from:

[1104] · SF 5 ,

[1105] · H,

[1106] · -C(O)H,

[1107] · halo,

[1108] · (C 1 -C 4 )alkyl which is unsubstituted or substituted with 1, 2 or 3 halo,

[1109] ·(C 1 -C 4 ) alkynyl,

[1110] ·(C 1 -C 4 ) alkenyl,

[1111] · (C 3 -C 5 ) cycloalkyl which is unsubstituted or substituted by 1, 2 or 3 halogens, and

[1112] · OCF 3 ;

[1113] And X is selected from C-R 7 and N, where R 7 is H or halogen.

[1114] In particular, R 2 is the following moiety:

[1115]

[1116] where

[1117] R 6 is selected from H, halogen, (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens;

[1118] R 8 is selected from H, halogen, (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens;

[1119] R 9 is selected from H, O-CH 3 , OH, CN, CH 3 and halogen;

[1120] R 28 is selected from SF 5 , halogen, C(O)H and (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens,

[1121] X is selected from C-R 7 and N; and

[1122] R 7 is selected from H and halogen.

[1123] More particularly, R 2 is the following moiety:

[1124]

[1125] R 6 selected from H, Cl, CH 3 , F, and Br;

[1126] R 8 selected from H, Cl, F, and CF 3 ;

[1127] R 9 selected from H, CH 3 and Cl;

[1128] R 28 selected from CF 3 、CF 2 H, -CH 2 CH 3 、Cl, SF 5 、Br, and -C(O)H;

[1129] X is selected from C-R 7 and N; and

[1130] R 7 is selected from H and F.

[1131] In one embodiment, moiety:

[1132]

[1133] is selected from:

[1134]

[1135] In particular

[1136]

[1137] More particularly

[1138]

[1139] Especially

[1140] In another embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein x is 0 or 1, especially 1.

[1141] In another embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo and OH, (C 1 -C4 ) An alkyl group, in particular, R 3 is an unsubstituted or substituted (C 1 -C 2 ) alkyl group with 1, 2 or 3 substituents independently selected from halo and OH, preferably R 3 is -CH 2 CH 3 or CH 3 , more preferably CH 3 .

[1142] In another embodiment, R 3 is located at the position shown in Formula 1i:

[1143]

[1144] In another embodiment, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is N, and is Y connected by a single bond. In particular,

[1145] wherein is K connected by a single bond, and K is selected from -CH 2 -, -CH 2 CH 2 -, -NH- and a bond (to form a 5-membered ring: ), J is N, and A is a linker selected from -C(O)-, -S(O)-, -S(O) 2 - and . More particularly, is K connected by a single bond, K is -CH 2 (-), J is N, and A is a linker selected from -C(O)-, -S(O)-, -S(O) 2 - and .

[1146] In one embodiment, A is a linker selected from -C(O)- and -S(O) 2 -, preferably -C(O)-.

[1147] In one embodiment, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound of Formula (I) has the stereochemistry shown in Formula (I’):

[1148]

[1149] When the compound of Formula (I) is a compound of Formula (I”):

[1150]

[1151] In particular, the compound has the stereochemistry of formula (I”’)

[1152]

[1153] In another embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected from:

[1154] · -(C 1- C 4 ) alkyl, preferably methyl,

[1155] · and wherein two R 5 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- C 4 ) 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,

[1156] · When is a carbon-nitrogen single bond, the R 5 substituents on K and on the adjacent carbon atom may be joined to form a ring C:

[1157]

[1158] wherein ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, a fused (C 3 -C 6 ) heterocyclic ring or a fused benzene ring, wherein the fused (C 3 -C 6 ) heterocyclic ring contains a ring carbon atom and a ring heteroatom selected from O, N, and S,

[1159] and wherein when ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, the fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted with 1 or 2 R 40 groups, wherein the R 40 is selected from:

[1160] · (C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) alkyl is independently unsubstituted or substituted with OH or 1, 2, or 3 halogens,

[1161] ·Halogenated, especially F,

[1162] ·or two Rs on the same ring carbon atom 40 substituents together with the carbon atom to which they are attached may be linked to form a (C 3- C 4 ) 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;

[1163] ·or two Rs on adjacent carbon atoms 40 substituents are linked together with the carbon atom to which they are attached to form a fused cyclopropyl ring;

[1164] ·and wherein when K is -CH 2 - and J is N, two Rs 5 substituents may be linked to form a (C 1 -C 3 ) alkylene bridge or a heteroalkylene bridge, wherein the heteroalkylene bridge is a heteroatom selected from N and O or is -CH 2 -O-CH 2 -.

[1165] In particular, R 5 independently selected from:

[1166] ·-(C 1- C 4 ) alkyl, preferably methyl,

[1167] ·when is a carbon-nitrogen single bond, the Rs on K and the adjacent carbon atom 5 substituents may be linked to form ring C:

[1168]

[1169] wherein ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, or a fused (C 3 -C 6 ) heterocyclic ring, wherein the fused (C 3 -C 6 ) heterocyclic ring contains a ring carbon atom and a ring heteroatom selected from O, N, and S,

[1170] and wherein when ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, the fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted with 1 or 2 Rs40 Group substitution, wherein said R 40 is selected from:

[1171] · (C 1- C 2 )alkyl, wherein each (C 1- C 2 )alkyl is independently unsubstituted or substituted by OH or one, two or three halogens,

[1172] · halogen, especially F,

[1173] · 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- C 4 ) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, wherein said heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N and S;

[1174] · 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;

[1175] · and wherein when K is -CH 2 - and J is N, two R 5 substituents may be linked to form a (C 1 -C 3 ) alkylene bridge or a heteroalkylene bridge, wherein said heteroalkylene bridge is a heteroatom selected from N and O or is -CH 2 -O-CH 2 -.

[1176] More particularly, R 5 is independently selected from:

[1177] · -(C 1- C 2 )alkyl, preferably methyl, and

[1178] · when is a carbon-nitrogen single bond, the R 5 substituents on K and on the adjacent carbon atom may be linked to form ring C:

[1179]

[1180] wherein ring C is a fused (C 3 -C 4 ) cycloalkyl ring, especially a fused cyclobutyl ring, and said fused (C 3 -C 4)The cycloalkyl ring, especially the fused cyclobutyl ring, is unsubstituted or substituted with 1 or 2 R groups as described in Example 28. 40 The group is substituted.

[1181] In one embodiment, y is 0, 1, 2, or 3, preferably 0, 1, or 2.

[1182] In a preferred embodiment, R 5 independently selected from:

[1183] ·CH 3 and y is 1 or 2, and

[1184] ·When is a carbon-nitrogen single bond, the R substituents on K and the adjacent carbon atoms can be linked to form ring C: 5 The substituent can form ring C:

[1185]

[1186] wherein ring C is a fused cyclobutyl ring.

[1187] In another embodiment, the compound having formula (I) includes the following moieties:

[1188]

[1189] or

[1190]

[1191] especially

[1192] A:

[1193] more particularly

[1194] or B: or C:

[1195]

[1196]

[1197] or where the linker -C(O)- is replaced by an alternative linker -S(O)-, -S(O) 2 - and substituted as defined in claim 1.

[1198] In another embodiment, there is provided a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 selected from:

[1199] -(C 1-C 4 ) alkyl;

[1200] - heteroaryl 1, wherein said heteroaryl 1 is a 5 - or 6 - membered fully unsaturated monocyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, and the total number of ring S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1;

[1201] - 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 can be in one or both rings, and the total number of ring S atoms does not exceed 1, the total number of ring O atoms does not exceed 1, and in particular, the ring connected to the rest of the molecule via linker - A - is fully unsaturated;

[1202] - phenyl;

[1203] 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:

[1204] · H,

[1205] · halo,

[1206] · (C 1 - C 4 ) alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents,

[1207] · (C 1 - C 2 ) alkyl substituted by - O - (C 1 - C 2 ) alkyl or OH,

[1208] · - S - (C 1 - C 3 ) alkyl,

[1209] · - O - (C 1 - C 4 ) alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents,

[1210] ·OH,

[1211] ·(C 3 -C 5 ) cycloalkyl, wherein the (C 3 -C 5 ) cycloalkyl is unsubstituted or substituted with 1 or 2 halogens,

[1212] ·-O-(C 3 -C 5 ) cycloalkyl,

[1213] ·-NR 34 R 35 , wherein R 34 and R 35 are independently selected from:

[1214] o H,

[1215] o (C 1 -C 4 ) alkyl, wherein the (C 1 -C 4 ) alkyl is unsubstituted or substituted with OH or -O(C 1 -C 2 ) alkyl,

[1216] 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 the azetidine, pyrrolidine and piperidine are unsubstituted or substituted with CH 3 ;

[1217] ·CN,

[1218] ·-(C 2 -C 4 ) alkenyl,

[1219] ·-(C 2 -C 4 ) alkynyl,

[1220] ·=O

[1221] ·-C(O)H, and

[1222] ·-C(O)(C 1 -C 4 ) alkyl;

[1223] provided that there is an OH substituent on heteroaryl 1, heteroaryl 2 and phenyl, and the remaining R 10 , R 11 , R 12 , R 13and R 14 As defined herein, in particular, the conditions are that:

[1224] - There is an OH substituent on heteroaryl 1, heteroaryl 2 and phenyl, and relative to R 4 The position connected to linker - A, the OH is located at the ortho - position of the R 4 ring,

[1225] or

[1226] - There is an ═O substituent on heteroaryl 1 and heteroaryl 2,

[1227] and the remaining Rs 10 、R 11 、R 12 、R 13 and R 14 are as defined herein.

[1228] In certain embodiments, R 4 is selected from:

[1229] -(C 1 -C 4 )alkyl, especially -CH 3 ;

[1230] - heteroaryl 1; and

[1231] - heteroaryl 2;

[1232] - phenyl;

[1233] 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: OH, ═O, H, F, Cl and CH 3 , provided that:

[1234] - There is an OH substituent on heteroaryl 1, heteroaryl 2 and phenyl, and relative to R 4 The position connected to linker - A, the OH is located at the ortho - position of the R 4 ring, and the remaining substituents are selected from H, F, Cl and CH 3 ,

[1235] or

[1236] - There is a =O substituent on heteroaryl 1 and heteroaryl 2, and the remaining substituents are selected from H, F, Cl, and CH 3 .

[1237] More particularly, R 4 is selected from CH 3 , heteroaryl 1, and heteroaryl 2, and the substituents are as defined above. In particular, the heteroaryl 1 contains only ring carbon atoms and one or two nitrogen atoms. Preferably, the heteroaryl 1 is pyridyl or pyrimidinyl.

[1238] In one embodiment, R 4 is selected from:[[]]

[1239] -(C 1 -C 4 )alkyl, especially CH 3 ;

[1240]

[1241] wherein

[1242] R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from:[[]]

[1243] · H,

[1244] · halo

[1245] · (C 1 -C 4 )alkyl unsubstituted or substituted with 1, 2, or 3 halo substituents

[1246] · (C 1 -C 2 )alkyl substituted with -O-(C 1 -C 2 )alkyl or OH

[1247] · -S-(C 1 -C 3 )alkyl

[1248] · -O-(C 1 -C 4 )alkyl unsubstituted or substituted with 1, 2, or 3 halo substituents

[1249] · (C 3 -C 5 )cycloalkyl, wherein the (C 3 -C 5 )cycloalkyl is unsubstituted or substituted with 1 or 2 halo substituents

[1250] ·-O-(C 3 -C 5 ) cycloalkyl,

[1251] ·-NR 34 R 35 , where R 34 and R 35 are independently selected from:

[1252] o H,

[1253] o(C 1 -C 4 ) alkyl, where the (C 1 -C 4 ) alkyl is unsubstituted or substituted by OH or -O(C 1 -C 2 ) alkyl;

[1254] o and where R 34 and R 35 can be joined together with the atoms to which they are attached to form an azetidine, pyrrolidine or piperidine ring, where the azetidine, pyrrolidine and piperidine are unsubstituted or substituted by CH 3 substituted;

[1255] ·CN,

[1256] ·-(C 2 -C 4 ) alkenyl,

[1257] ·-(C 2 -C 4 ) alkynyl,

[1258] ·-C(O)H, and

[1259] ·-C(O)(C 1 -C 4 ) alkyl.

[1260] Preferably, R 4 is selected from:

[1261]

[1262] where

[1263] R 10 is selected from H, halo, (C 1 -C 2 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents, -O-(C 1 -C 2 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halo substituents;

[1264] R 11 is selected from H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents of (C 1 -C 2 )alkyl;

[1265] R 12 is selected from H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents of (C 1 -C 2 )alkyl;

[1266] R 13 is selected from H, -S-CH 3 , halo, unsubstituted or substituted with 1, 2 or 3 halo substituents of (C 1 -C 2 )alkyl; and

[1267] R 14 is selected from H, halo, unsubstituted or substituted with 1, 2 or 3 halo substituents of (C 1 -C 2 )alkyl, unsubstituted or substituted with 1, 2 or 3 halo substituents of O-(C 1 -C 2 )alkyl, and cyclopropyl.

[1268] In particular, R 4 is selected from:

[1269]

[1270] wherein

[1271] R 10 is selected from H, F, Cl, CH 3 and OCF 3 ;

[1272] R 11 is selected from H, F, Cl and CH 3 ;

[1273] R 12 is selected from H, F, Cl and CH 3 ;

[1274] R 13 is selected from H, F, Cl, -S-CH 3 and CH 3 ; and

[1275] R 14 is selected from H, F, Cl, CH 3 , -CH 2 CH 3, cyclopropyl, -OCHF 2 , OCF 3 。

[1276] In particular, at least one of the substituents R 10 , R 11 and R 12 is H.

[1277] In particular, at least one of the substituents R 13 and R 14 is H.

[1278] In another embodiment, R 4 is selected from:

[1279] -CH 3 ,

[1280] In particular

[1281] -CH 3 ,

[1282] Preferably, R 4 is selected from:

[1283] In particular

[1284] In other embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein formula (I) is

[1285] Formula 1a:

[1286] 1a, in particular, 1a is 1a':

[1287] or formula 1b:

[1288] 1b, in particular, 1b is 1b':

[1289] or formula 1c:

[1290] 1c, in particular, 1c is 1c':

[1291] or formula 1d:

[1292] In particular, 1d is 1d': or formula 1e:

[1293] 1e, and in particular, 1e is 1e': or formula 1f:

[1294] 1f, and in particular, 1f is 1f': or formula 1g:

[1295] 1g, and in particular, 1g is 1g': or formula 1h:

[1296] 1h, and in particular, 1h is 1h':

[1297] In one embodiment, there is provided a compound having formula (I), in particular formula (I'):

[1298] In particular

[1299] (more particularly I''': ),

[1300] or a pharmaceutically acceptable salt thereof,

[1301] wherein

[1302] R, M, W, L, V, and T are independently selected from C, CH, and N,

[1303] to form 1a, 1b, 1c, 1d, 1e, and 1f as shown herein, in particular 1a', 1b', 1c', 1d', 1e', and 1f', in particular 1a', more particularly 1h' or 1g', as described herein,

[1304] A is linker - C(O)-;

[1305] Y is N, C, or CH;

[1306] 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 is a single bond, Y is unsubstituted or substituted with OH or F;

[1307] When Y is N, is a single bond;

[1308] means that K is connected to the adjacent atom via a single bond or a double bond;

[1309] wherein:

[1310] When When it is a double bond, it is a single bond, K is CH, J is C, and A is linker - C(O)-;

[1311] Or

[1312] When is a single bond, K is selected from -CH 2 -, -CH 2 CH 2 -, -NH- and a bond (to form a 5 - membered ring: ), J is N, and A is linker - C(O)- (in particular, K is -CH 2 -, and J is N);

[1313] y is 0, 1, 2, 3 or 4;

[1314] R 5 is independently selected from:

[1315] · -(C 1- C 4 )alkyl,

[1316] · -(C 3- C 5 )cycloalkyl,

[1317] · And two R 5 substituents on the same ring carbon atom together with the carbon atom to which they are attached can be joined to form a (C 3- C 4 )cycloalkyl spiro ring or a 3 - or 4 - membered heterocyclic spiro ring, where the heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N and S,

[1318] · When is a carbon - nitrogen single bond, the R 5 substituents on K and on the adjacent carbon atom can be joined to form a ring C:

[1319]

[1320] where ring C is a fused (C 3 -C 6 )cycloalkyl ring (preferably cyclobutyl), a fused (C 3 -C 6 )heterocyclic ring or a fused benzene ring, where the fused (C 3 -C 6 )heterocyclic ring contains a ring carbon atom and a ring heteroatom selected from O, N and S,

[1321] And where when ring C is a fused (C 3 -C 6 )cycloalkyl ring, the fused (C3 -C 6 ) The cycloalkyl ring is unsubstituted or substituted by 1 or 2 R 40 groups, where the R 40 is selected from:

[1322] · (C 1- C 2 ) alkyl, where each (C 1- C 2 ) alkyl is independently unsubstituted or substituted by OH or 1, 2 or 3 halogens,

[1323] · halogen, especially F,

[1324] · or two R 40 substituents on the same ring carbon atom together with the carbon atom to which they are attached can be linked to form a (C 3- C 4 ) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, where the heterocyclic spiro ring contains a ring carbon atom and a ring heteroatom selected from O, N and S;

[1325] · 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;

[1326] · and where when K is -CH 2 - and J is N, two R 5 substituents can be linked to form a (C 1 -C 3 ) alkylene bridge or a heteroalkylene bridge, where the heteroalkylene bridge is a heteroatom selected from N and O or is -CH 2 -O-CH 2 -;

[1327] R 1 is:

[1328] cycloalkenyl, where 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 halogen, and where the cycloalkenyl or halogen-substituted cycloalkenyl is substituted by 0, 1 or 2 R 15 substituents,

[1329] or R 1is 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, 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 ;

[1330] or the heterocyclic group or the halo-substituted heterocyclic group is fused to a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted or substituted by 1, 2, or 3 F;

[1331] or the heterocyclic group or the halo-substituted heterocyclic group has 2 substituents at the same ring carbon atom, which are linked to form a cyclopropyl spiro ring;

[1332] or the heterocyclic group or the halo-substituted heterocyclic group is fused to a (C 3 -C 5 ) heterocycloalkyl ring, wherein the (C 3 -C 5 ) heterocycloalkyl ring contains ring carbon atoms and 1 ring O atom;

[1333] or R 1 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, preferably wherein the total number of ring S atoms does not exceed 1 and the total number of ring O atoms does not exceed 1,

[1334] and wherein the heteroaryl group 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 (C 1 -C 4 ) alkyl, wherein the (C 1 -C 4 ) alkyl is unsubstituted or substituted by 1, 2, or 3 halo;

[1335] or R 1is phenyl, wherein the phenyl is unsubstituted or substituted by 1, 2, 3 or 4, preferably 1 or 2, R 33 substituents, wherein R 33 is halo, and wherein the phenyl or halo-substituted phenyl is substituted by 0, 1 or 2 R 15 substituents;

[1336] R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 are each independently selected from:

[1337] · halo

[1338] · (C 1- C 4 )alkyl-O- which is unsubstituted or substituted by 1, 2 or 3 halo

[1339] · (C 1 -C 2 )alkyl which is unsubstituted or substituted by OH, -O-(C 1 -C 4 )alkyl or 1, 2 or 3 halo

[1340] · HOC(O)-(CH 2 ) n -

[1341] · H 3 C-C(O)(CH 2 ) n -

[1342] · (C 1 -C 4 )alkyl-O-C(O)(CH 2 ) n -

[1343] · =O

[1344] · 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 by 1 or 2 F

[1345] · R 25 (R 24 )N-, wherein R 24 is H or (C 1 -C 4 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halo, R 25is H or an unsubstituted or halo-substituted (C 1 -C 4 )alkyl,

[1346] ·OH

[1347] where n is 0, 1 or 2,

[1348] provided that when R 1 is a ring, then:

[1349] · each R 1 ring atom adjacent to the R 1 ring atom connecting the rest of the molecule to the R 1 ring is independently unsubstituted or substituted only by halo, in particular, independently unsubstituted or substituted by one F substituent, and

[1350] · the R 1 ring is attached to the rest of the molecule via the R 1 ring nitrogen atom or a double bond to an adjacent R 1 ring atom of the R 1 ring carbon atom;

[1351] R 2 is the following moiety:

[1352]

[1353] R 6 is selected from:

[1354] · H,

[1355] · halo,

[1356] · an unsubstituted or halo-substituted (C 1 -C 4 )alkyl,

[1357] · an unsubstituted or halo-substituted (C 3 -C 5 )cycloalkyl,

[1358] · an unsubstituted or halo-substituted -O-(C 1 -C 4 )alkyl,

[1359] · OH, and

[1360] · CN;

[1361] R 8 is selected from H, halo, and an unsubstituted or halo-substituted (C 1 -C4 ) alkyl

[1362] R 9 selected from H, O-CH 3 , OH, CN, CH 3 and halo;

[1363] R 28 is selected from:

[1364] · SF 5 ,

[1365] · H,

[1366] · -C(O)H,

[1367] · halo,

[1368] · (C 1 -C 4 ) alkyl,

[1369] · (C 1 -C 4 ) alkynyl,

[1370] · (C 1 -C 4 ) alkenyl,

[1371] · (C 3 -C 5 ) cycloalkyl, and

[1372] · OCF 3 ;

[1373] X is selected from C-R 7 and N, where R 7 is H or halo, or R 7 can together with R 28 or R 6 and the atoms to which they are attached form a fused (C 4 -C 6 ) cycloalkyl ring, where the fused (C 4 -C 6 ) cycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 halos,

[1374] or

[1375] R 2 is selected from:

[1376]

[1377] wherein

[1378] R 31 Selected from H, halo, and CH 3 ,

[1379] R 32 Selected from H, halo, and CH 3 ,

[1380] R 3 Selected from:

[1381] · halo, and

[1382] · (C 1 -C 4 )alkyl which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from halo and OH,

[1383] · or two R 3 substituents on the same ring carbon atom may be joined with the carbon atom to which they are attached to form a cyclopropyl ring;

[1384] x is 0, 1, or 2;

[1385] R 4 Selected from:

[1386] -(C 1 -C 4 )alkyl;

[1387] - heteroaryl1, wherein the heteroaryl1 is a 5- or 6-membered fully unsaturated monocyclic ring containing ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S;

[1388] - 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;

[1389] - phenyl;

[1390] wherein heteroaryl1, heteroaryl2, 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:

[1391] · H,

[1392] · halogenated,

[1393] · (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogenated substituents,

[1394] · (C 1 -C 2 ) alkyl which is substituted by -O-(C 1 -C 2 ) alkyl or OH,

[1395] · -S-(C 1 -C 3 ) alkyl,

[1396] · -O-(C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogenated substituents,

[1397] · OH,

[1398] · (C 3 -C 5 ) cycloalkyl, wherein the (C 3 -C 5 ) cycloalkyl is unsubstituted or substituted by 1 or 2 halogenated substituents,

[1399] · -O-(C 3 -C 5 ) cycloalkyl,

[1400] · -NR 34 R 35 , wherein R 34 and R 35 are independently selected from:

[1401] o H,

[1402] o (C 1 -C 4 ) alkyl, wherein the (C 1 -C 4 ) alkyl is unsubstituted or substituted by OH or -O(C 1 -C 2 ) alkyl,

[1403] 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 the azetidine, pyrrolidine and piperidine are unsubstituted or substituted by CH 3 ;

[1404] ·CN,

[1405] ·-(C 2 -C 4 )alkenyl,

[1406] ·-(C 2 -C 4 )alkynyl,

[1407] ·=O

[1408] ·-C(O)H, and

[1409] ·-C(O)(C 1 -C 4 )alkyl;

[1410] Provided that:

[1411] -There is an OH substituent on heteroaryl 1, heteroaryl 2 and phenyl, and relative to the position where it is linked to linker -A-, the OH is in the ortho position of the R 4 ring, 4 or

[1412] -There is an =O substituent on heteroaryl 1 and heteroaryl 2,

[1413] and the remaining R

[1414] , R 10 , R 11 , R 12 , R 13 and R 14 are as defined herein,

[1415] and * indicates the attachment point. Specific embodiments of the compounds having formula (I), particularly formula (I') or (I'''), are described herein.

[1416] In one embodiment, there is provided a compound having formula (1g) or a pharmaceutically acceptable salt thereof:

[1417]

[1418] Wherein R 1 is selected from:

[1419]

[1420] R 15 is F;

[1421] R 16 is R 25 (R 24 )N-;

[1422] R 17 is F;

[1423] R 18 is F;

[1424] R 19 is F;

[1425] R 20 is F;

[1426] R 21 is CH 3 ;

[1427] R 22 is CF 3 、CHF 2 CH 2 、HOC(O)-CH 2 -、H 3 C-C(O)-、(H 3 C) 3 C-O-C(O)-;

[1428] R 23 is CF 3 、CHF 2 CH 2 -、(H 3 C) 3 C-O-C(O)-;

[1429] R 24 is CH 3 ; and

[1430] R 25 is CHF 2 CH 2 -;

[1431] R 2 is the following part:

[1432]

[1433] wherein

[1434] R 6 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo of (C 1 -C 4 )alkyl;

[1435] R 8 is selected from H, halo, unsubstituted or substituted by 1, 2 or 3 halo of (C 1 -C 4 )alkyl;

[1436] R 9 is selected from H, O-CH 3 、OH、CN、CH3 and halogenation;

[1437] R 28 is selected from SF 5 , halogenated, unsubstituted or substituted with 1, 2 or 3 halogen atoms of (C 1 -C 4 ) alkyl, and -C(O)H;

[1438] X is selected from C-R 7 and N; and

[1439] R 7 is selected from H and halogenated;

[1440] R 3 is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogenated and OH of (C 1 -C 4 ) alkyl;

[1441] x is 0 or 1;

[1442] Y is CH or N, especially N;

[1443] y is 0, 1 or 2;

[1444] R 5 is selected from CH 3 ;

[1445] or in the following part:

[1446]

[1447] two R 5 substituents on adjacent carbon atoms are connected to form a ring C:

[1448]

[1449] - wherein the ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, and the fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted with 1 or 2 R 40 groups, wherein the R 40 is selected from:

[1450] · (C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) alkyl is independently unsubstituted or substituted with OH or 1, 2 or 3 halogen atoms,

[1451] · halogenated, especially F,

[1452] · or two Rs on the same ring carbon atom 40 The substituents together with the carbon atoms to which they are attached may be linked to form a (C 3- C 4 ) 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;

[1453] · 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;

[1454] And ring C is in particular

[1455] R 4 Selected from:

[1456] CH 3 ,

[1457]

[1458]

[1459] In particular

[1460] Especially

[1461]

[1462] Wherein

[1463] R 10 Selected from H, halo, (C 1 -C 2 ) alkyl which is unsubstituted or substituted by 1, 2, or 3 halo substituents, -O-(C 1 -C 2 ) alkyl which is unsubstituted or substituted by 1, 2, or 3 halo substituents;

[1464] R 11 Selected from H, halo, (C 1 -C 2 ) alkyl which is unsubstituted or substituted by 1, 2, or 3 halo substituents;

[1465] R 12 Selected from H, halo, (C 1 -C 2 ) alkyl which is unsubstituted or substituted by 1, 2, or 3 halo substituents;

[1466] R 13 Selected from H, -S-CH3 , halogenated, unsubstituted or substituted with 1, 2 or 3 halogenated substituents, (C 1 -C 2 ) alkyl; and

[1467] R 14 is selected from H, halogenated, unsubstituted or substituted with 1, 2 or 3 halogenated substituents, (C 1 -C 2 ) alkyl, unsubstituted or substituted with 1, 2 or 3 halogenated substituents, O-(C 1 -C 2 ) alkyl, and cyclopropyl.

[1468] In particular, R 1 , R 2 , R 3 , x, R 5 , y, Y and R 4 are as described in the examples herein.

[1469] In another embodiment, there is provided a compound of formula (1h) or a pharmaceutically acceptable salt thereof:

[1470]

[1471] wherein:

[1472] R 1 is selected from:

[1473]

[1474] R 2 is selected from:

[1475]

[1476] R 3 is CH 3 ;

[1477] x is 0 or 1;

[1478] R 4 is selected from:

[1479] -CH 3 ,

[1480]

[1481] y is 0 or 1;

[1482] R 5 is selected from CH 3 ;

[1483] or a part thereof:

[1484]

[1485] Yes

[1486]

[1487] In particular, R 1 、R 2 、R 3 、x、R 5 、y and R 4 as described in the examples herein.

[1488] There is also provided an intermediate compound or a salt thereof for use in the chemical synthesis of a compound having formula (I) as described herein.

[1489] In another aspect, there is provided a method or method step for synthesizing a compound having formula (I) as described herein.

[1490] For example, in one embodiment of the present invention, there is provided

[1491] an intermediate compound having formula FN2:

[1492]

[1493] wherein Y, R 1 、R 2 、R 3 、x、R 5 and y are as defined herein.

[1494] For example, intermediate compound N2:

[1495] Intermediate N2 or

[1496] intermediate Q.

[1497] In another embodiment of the present invention, there is provided an intermediate compound having formula FM:

[1498]

[1499] wherein Y, R 1 、R 2 、R 3 、x、R 5 and y are as defined herein, and PG is any suitable protecting group including BOC (tert-butoxycarbonyl). Such suitable protecting groups are known to those skilled in the art.

[1500] For example, there are provided intermediate compounds M1, M2, M3, M4 or QPG:

[1501]

[1502] Intermediate QPG.

[1503] In another embodiment of the present invention, an intermediate compound having the formula FL is provided:

[1504]

[1505] wherein Y, R 3 , x, R 5 and y are as defined herein, wherein Z’ is OH or O-C(CH 3 ) 3 . PG is any suitable protecting group, including BOC (tert-butoxycarbonyl). Such suitable protecting groups are known to those skilled in the art.

[1506] For example, intermediate compound L is provided:

[1507] Intermediate L.

[1508] In another embodiment of the present invention, an intermediate compound having the following formula is provided:

[1509]

[1510] wherein Y, R 1 , R 3 , x, R 5 and y are as defined herein, Z’ is OH or O-C(CH 3 ) 3 , and Z” is H or PG, wherein PG is any suitable protecting group, including BOC (tert-butoxycarbonyl). Suitable protecting groups are known to those skilled in the art.

[1511] For example, intermediate compound LB is provided:

[1512] Intermediate LB,

[1513] or intermediate Q4:

[1514] (Intermediate Q Step 4)

[1515] or intermediate Q5:

[1516] (Intermediate Q Step 5).

[1517] In another embodiment, intermediate compound U is provided:

[1518] Intermediate U

[1519] In another embodiment of the present invention, an intermediate compound having formula FQ is provided:

[1520] wherein R 1 , R 3 and x are as defined herein, and Z’ is OH or O-C(CH 3 ) 3 . For example, intermediate compounds Q3.1, Q3.2, Q3.3 or Q3.4 are provided;

[1521]

[1522] In another aspect, the present invention is as claimed or as described herein.

[1523] Formulation

[1524] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for a particular route 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:

[1525] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[1526] b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, also comprising

[1527] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; when needed

[1528] d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and

[1529] e) adsorbents, colorants, flavorants and sweeteners.

[1530] 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).

[1531] Solid dispersion technology has been used to improve the dissolution properties and bioavailability of orally administered drugs (Dhirendra K et al.: ‘Solid dispersions: A review’, Pakistan Journal of Pharmaceutical Sciences, Faculty of Pharmacy, University of Karachi, Pakistan, Vol. 22, No. 2, April 30, 2009, pp. 234-246).

[1532] 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 Tween 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.

[1533] 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.

[1534] Use

[1535] The compounds of formula (I) of the invention in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, such as WRN inhibitory properties, for example, as shown by the in vitro and in vivo tests provided in the following sections, and are thus indicated for use in therapy or as research chemicals, such as chemical probes and tool compounds.

[1536] In another aspect of the present invention, there is provided a compound of formula (I) or a salt thereof as described herein for use as a research chemical, such as a tool compound or a chemical probe, particularly for the study of WRN. In another embodiment, there is provided the use of a compound of formula (I) or a salt thereof as described herein as a research chemical, such as a tool compound or a chemical probe, particularly for the study of WRN.

[1537] There is also provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein 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) or a pharmaceutically acceptable salt thereof as described herein can be used for the treatment of cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

[1538] There is also provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for use as a medicament. In particular, the uses are:

[1539] · for the treatment of diseases treatable by WRN inhibition,

[1540] · for the treatment of cancer,

[1541] · for the treatment of cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR),

[1542] · 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, renal cancer and ovarian cancer,

[1543] · for the treatment of cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) selected from colorectal cancer, gastric cancer, prostate cancer and endometrial cancer, or

[1544] · for the treatment of cancer, wherein cancers characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) are selected from uterine corpus endometrial carcinoma, 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.

[1545] There is also provided the following method:

[1546] · Modulating the WRN activity of 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,

[1547] · Inhibiting the WRN of 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,

[1548] · 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 herein or a pharmaceutically acceptable salt thereof,

[1549] · 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,

[1550] · 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.

[1551] There is also provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof:

[1552] · Use in therapy,

[1553] · Use in the preparation of a medicament,

[1554] · 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),

[1555] · Use in the preparation of a medicament for treating a disease treatable by WRN inhibition,

[1556] 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, especially 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.

[1557] 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.

[1558] Form

[1559] 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 embrace 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.

[1560] As used herein, the term "salt(s)" refers to acid addition salts or base addition salts of the compounds of the present invention. "Salt" particularly includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and are generally not biologically or otherwise undesirable. In many cases, due to the presence of amino and / or carboxyl groups or groups similar thereto, the compounds of the present invention are capable of forming acid salts and / or base salts.

[1561] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

[1562] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[1563] 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.

[1564] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[1565] 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.

[1566] In certain embodiments, sodium salts of the compounds described herein are provided.

[1567] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[1568] 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, hydroxyethylsulfonate, 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, sulfosalicylic acid, sulfate, tartrate, toluenesulfonate, triphenylacetate, trifluoroacetate, or cinchophenate.

[1569] Any formula given herein is intended to represent both the unlabeled form and the isotopically labeled form of a compound. An isotopically labeled compound has the structure described by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Isotopes that can be incorporated into the compounds of the invention include, for example, isotopes of hydrogen. For example, the invention includes deuterated forms of the exemplary compounds disclosed herein.

[1570] For example, one or more H atoms on a ring:

[1571]

[1572] can be replaced by deuterium,

[1573] or one or more atoms on an R 1 moiety can be replaced by deuterium:

[1574]

[1575] In addition, incorporation of certain isotopes, particularly deuterium (i.e., 2 H or D) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index or tolerability. It should be understood that deuterium is considered a substituent of the compounds of the invention in this context. The concentration of deuterium can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio of the isotopic abundance of the indicated isotope to its natural abundance. If a substituent in a compound of the invention is indicated as deuterium, then such a compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation on each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom. It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[1576] 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. Accordingly, it is to be understood that the present invention includes compounds incorporating one or more of any of the foregoing 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 the tissue distribution of a drug or a substrate, or for radioisotope treatment of patients. In particular, 18 F or labeled compounds 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 accompanying examples and preparations, using appropriate isotopically labeled reagents in place of the unlabeled reagents previously employed.

[1577] Definitions

[1578] '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.

[1579] 'Zwitterion' or 'zwitterionic form' means a compound containing both a positively charged and a negatively charged functional group.

[1580] For example, compounds having formula (I) as described herein can include the following forms, where R 4 is in zwitterionic form (c) or non-zwitterionic form (d),

[1581] or mixtures thereof.

[1582] Compounds having formula (I) as described herein can also include the following forms, where R 4 is in zwitterionic form (a) or (b) or non-zwitterionic form (e),

[1583]

[1584] or mixtures of two of them, or mixtures of all three of them.

[1585] "Halogen" means fluorine, chlorine or bromine, particularly fluorine or chlorine.

[1586] Alkyl and alkoxy groups containing the required number of carbon atoms can be straight-chain or branched-chain. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[1587] ‘=O’ means an oxo substituent.

[1588] When R 1 is a substituted or unsubstituted cycloalkenyl group, said cycloalkenyl group includes, but is not limited to, cyclohexenyl, particularly groups such as cyclohex-1-en-1-yl, etc.

[1589] When R 1 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.

[1590] When R 1 is a heteroaryl group, said heteroaryl group is a 5-membered or 6-membered fully unsaturated (which includes 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 R 1 is a substituted or unsubstituted heteroaryl group, said heteroaryl group includes, but is not limited to, pyridyl, particularly substituted or unsubstituted groups such as pyridin-3-yl, etc.

[1591] - 'Heteroaryl 1' is a 5- or 6-membered fully unsaturated (including aromatic) monocyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. Preferably, the total number of ring S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1. In particular, 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.

[1592] - 'Heteroaryl 2', wherein the 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 (including aromatic), or one ring is fully unsaturated (including aromatic) and the other is saturated or partially unsaturated, and wherein 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, particularly dihydrofuranylpyridyl), and imidazopyridyl.

[1593] The present invention includes all tautomeric forms of the compounds having formula (I).

[1594] For example, when heteroaryl 1 and heteroaryl 2 are substituted by =O, they can form tautomers, for example, as follows:

[1595]

[1596] The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or to other parts of the body through the bloodstream and lymphatic system. Examples of various cancers are described herein and include but are not limited to colorectal cancer, gastric cancer, endometrial cancer, prostate cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, ovarian cancer, etc.

[1597] The terms "tumor" and "cancer" are used interchangeably herein, e.g., both terms include solid and liquid, e.g., disseminated or circulating tumors. As used herein, the term "cancer" or "tumor" includes pre-malignant as well as malignant cancers and tumors.

[1598] As used herein, a 'WRN inhibitor' or 'WRN helicase inhibitor' means a compound that inhibits Werner syndrome RecQ DNA helicase (WRN). As used herein, the term "WRN" 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 can be obtained in the Uniprot database under accession number Q14191.

[1599] 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).

[1600] '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 repeat genomic sequences within microsatellites.

[1601] A patient's MSI-H or dMMR tumor status can be determined using, e.g., a polymerase chain reaction (PCR) assay for MSI-H status or an immunohistochemistry (IHC) assay for dMMR. Methods for differentiating MSI-H or dMMR tumor status are described, e.g., 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.

[1602] 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, prostate cancer, and ovarian cancer. Examples of high microsatellite cancers include endometrial carcinoma of the uterine body, 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.

[1603] Cancers with "deficient mismatch repair" (dMMR) or "dMMR signature" include cancer types associated with documented MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, and PMS1 mutations or epigenetic silencing, 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.

[1604] As used herein, the term "pharmaceutical composition" refers to a compound of the invention or a pharmaceutically acceptable salt thereof in a form suitable for oral or parenteral administration and at least one pharmaceutically acceptable carrier.

[1605] As used herein, the term "pharmaceutically acceptable carrier" refers to substances useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, e.g., Remington The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press, 2013, pp. 1049 - 1070).

[1606] The terms "synthetic lethality" and "synthetic lethal" are used to refer to a reduction in cell viability and / or a reduction in the rate of cell proliferation 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).

[1607] The term "therapeutically effective amount" of a compound of the present invention refers to the amount of a compound of the present invention that will elicit a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity, or an improvement in symptoms, alleviation of a disorder, slowing or delaying of disease progression, or prevention of a disease, etc.).

[1608] In one embodiment, the term "therapeutically effective amount" refers to the 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.

[1609] In another embodiment, the term "therapeutically effective amount" refers to the 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 the activity of WRN or reduces the level of WRN protein by at least a portion.

[1610] 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, rat, or mouse. In still other embodiments, the subject is a human.

[1611] 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.

[1612] As used herein, the term "treat (treat, treating, or treatment)" of any disease or disorder refers to alleviating or improving the disease or disorder (i.e., slowing or halting the development of the disease or at least one of its clinical symptoms); or reducing or improving at least one physical parameter or biomarker associated with the disease or disorder, including those physical parameters or biomarkers that may not be distinguishable to the patient.

[1613] As used herein, the term "prevent (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.

[1614] As used herein, a subject is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from the treatment.

[1615] 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.

[1616] ‘May combine’ means combine or not combine.

[1617] ‘May be replaced by deuterium’ means be replaced by deuterium or not be replaced by deuterium.

[1618] 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 limit the scope of the invention claimed otherwise.

[1619] Isomeric form

[1620] Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the present invention can exist in racemic or enantiomerically enriched form, e.g., (R)-, (S)-, or (R,S)-configurations. In certain embodiments, each asymmetric atom has an (R)- or (S)-configuration with an enantiomeric excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. Substituents on atoms having unsaturated double bonds can exist in cis-(Z)- or trans-(E)-forms, if possible.

[1621] Accordingly, as used herein, the compounds of the invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereoisomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[1622] Any resulting mixture of stereoisomers may be separated into the pure or substantially pure geometric or optical isomers, diastereoisomers, racemates, based on the physicochemical differences of the components, e.g., by chromatography and / or fractional crystallization.

[1623] The racemates of any resulting compounds or intermediates of the invention may be resolved into the optically active enantiomers by known methods, e.g., by separation of the diastereoisomeric salts thereof obtained with an optically active acid or base, and liberation of the optically active acidic or basic compound. In particular, therefore, the compounds of the invention may be resolved into their optical enantiomers by means of a basic moiety, 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 invention may also be resolved by chiral chromatography (e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent).

[1624] The compounds of the 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 may 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 the 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 invention further provides co-crystals comprising the compounds of formula (I).

[1625] In addition, the compounds of the invention (including their salts) may also be obtained in their hydrate form, or include other solvents used for their crystallization. The compounds of the invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); accordingly, the invention is intended to include both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of the invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art and are known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[1626] Dosage Forms

[1627] The pharmaceutical composition or combination of the present invention may be, for example, in unit dosage form having from about 1 to 1000 mg of one or more active ingredients for a subject of about 50 - 70 kg.

[1628] Combination

[1629] "Combination" means a fixed combination in the form of a single dosage unit, or combination administration, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and a combination partner (e.g., another drug as explained below, also referred to as a "therapeutic agent" or "co - agent") may be administered independently at the same time or separately at intervals of time, especially when 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 cover the administration of the selected combination partners to a single subject (e.g., a patient) in need, 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 simultaneously, in parallel or sequentially (without a specific time limit) as separate entities, wherein 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.

[1630] 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.

[1631] Combinations are also provided, which comprise a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof as described herein and one or more additional therapeutic active agents. The additional therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments or nucleic acids, which have therapeutic activity or enhance therapeutic activity when administered to a patient in combination with the compounds disclosed herein. In particular, the additional therapeutic active agents are:

[1632] · anti-cancer agents,

[1633] · chemotherapeutic agents,

[1634] · chemotherapeutic agents selected from: anastrozole bicalutamide bleomycin sulfate busulfan busulfan injection capecitabine N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin carmustine chlorambucil cisplatin cladribine cyclophosphamide cytarabine, cytosine arabinoside (Cytosar- )), cytarabine liposomal injection dacarbazine (DTIC- ), actinomycin D (Cosmegan), daunorubicin hydrochloride daunorubicin citrate liposomal injection dexamethasone, docetaxel doxorubicin hydrochloride etoposide fludarabine phosphate 5-fluorouracil flutamide tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea idarubicin ifosfamide irinotecan L-asparaginase calcium folinate, melphalan 6-mercaptopurine methotrexate mitoxantrone gemtuzumab (mylotarg), paclitaxel Yttrium 90 / MX-DTPA, pentostatin, polylactic-polyglycolic acid copolymer carmustine implant Tamoxifen citrate Teniposide 6-Thioguanine, thiotepa, tirapazamine Topotecan hydrochloride for injection Vinblastine Vincristine and Vinorelbine Especially fluorouracil (5-FU) and irinotecan

[1635] · PD-1 inhibitor,

[1636] · Anti-PD-1 antibody molecule, or

[1637] · PD-1 inhibitors selected from: PDR001 (Novartis AG), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co), pidilizumab (CureTech Ltd.), MEDI0680 (Medimmune), cemiplimab (REGN2810, Regeneron Pharmaceuticals), dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), tislelizumab (BGB-A317, BeiGene), BGB-108 (BeiGene), INCSHR1210 (Incyte), balstilimab (AGEN2035, Agenus), sintilimab (Innovent Biologics), toripalimab (Shanghai Junshi Biosciences Co., Ltd.), camrelizumab (Jiangsu Hengrui Medicine Co., Ltd.), and AMP-224 (Amplimmune), pamiparlimab (Akeso Biopharma Inc), zapalisimab (Arcus Biosciences) and Prolgolimab (Biocad Ltd.), especially PDR001, more especially tislelizumab (BGB-A317, BeiGene).

[1638] In another embodiment, the additional therapeutic agent is the chemotherapeutic agent irinotecan

[1639] In another embodiment, the additional therapeutic 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 agent is an anti-PD-1 antibody molecule.

[1640] In a further embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule, such as that described in US2015 / 0210769, entitled "Antibody Molecules to PD-1 and Uses Thereof" published on July 30, 2015 (which is incorporated herein by reference in its entirety).

[1641] In another embodiment, a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a chemotherapeutic agent, and a PD-1 inhibitor is provided. In particular, the chemotherapeutic agent and the PD-1 inhibitor are selected from those described above. 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.

[1642] In another embodiment, the anti-PD-1 antibody molecule (e.g., tislelizumab) comprises the following heavy and / or light chains, VH, VL, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3:

[1643]

[1644]

[1645] In some embodiments, the PD-1 inhibitor comprises the HCDR and LCDR of tislelizumab as shown in SEQ ID NO:7-12.

[1646] 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.

[1647] 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.

[1648] 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.

[1649] In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered intravenously.

[1650] In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered over a period of about 20 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.

[1651] 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.

[1652] 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.

[1653] 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.

[1654] 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.

[1655] 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 (e.g., 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 (e.g., in the literature cited above).

[1656] In one embodiment, the present invention provides a product comprising a compound of formula (I) of the present invention and at least one other therapeutic agent as a combination preparation for use simultaneously, separately or sequentially in therapy. In one embodiment, the therapy is for treating a WRN-mediated disease or disorder. The product provided as a combination preparation includes a composition comprising the compound of formula (I) and one or more other therapeutic agents together in the same pharmaceutical composition, or comprising the compound of the present invention and one or more other therapeutic agents in separate forms (e.g., in a kit form).

[1657] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition contains a compound of formula (I) of the present invention. In one embodiment, the kit comprises means for separately retaining the compositions, such as containers, separate bottles, or separate foil pouches. An example of such a kit is a blister pack, such as is typically used for packaging tablets, capsules, etc.

[1658] The kits of the present invention can be used to administer different dosage forms (e.g., oral and parenteral), to administer the separate compositions at different dosage intervals, or to titrate the separate compositions relative to each other. To aid compliance, the kits of the present invention typically contain administration instructions.

[1659] In the combination therapies of the present invention, the compounds of formula (I) of the present invention and other therapeutic agents can be produced and / or formulated by the same or different manufacturers. In addition, 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 (or under the guidance of the physician); (iii) in the patient himself, for example, during the sequential administration of the compounds of the present invention and other therapeutic agents.

[1660] Accordingly, the present invention provides the use of the compounds of formula (I) of the present invention for the treatment of diseases or disorders mediated by WRN, wherein a medicament is prepared for administration together with another therapeutic agent. The present invention also provides the use of another therapeutic agent for the treatment of diseases or disorders mediated by WRN, wherein the medicament is administered together with the compounds of formula (I) of the present invention.

[1661] The present invention also provides the compounds of formula (I) of the present invention for use in the treatment of diseases or disorders mediated by WRN, wherein the compounds of formula (I) of the present invention are prepared for administration together with another therapeutic agent. The present invention also provides another therapeutic agent for use in the treatment of diseases or disorders mediated by WRN, wherein the other therapeutic agent is prepared for administration together with the compounds of the present invention. The present invention also provides the compounds of formula (I) of the present invention for use in the treatment of diseases or disorders mediated by WRN, wherein the compounds of the present invention are administered together with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method for the treatment of diseases or disorders mediated by WRN, wherein the other therapeutic agent is administered together with the compounds of formula (I) of the present invention.

[1662] The present invention also provides the use of the compounds of formula (I) of the present invention for the treatment of diseases or disorders mediated by WRN, 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 diseases or disorders mediated by WRN, wherein the patient has been previously treated (e.g., within 24 hours) with the compounds of the present invention.

[1663] Biological Assays and Data

[1664] The activity of the compounds according to the present invention can be evaluated by the following in vitro and in vivo methods.

[1665] Materials and Methods

[1666] 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 subcloning overlapping oligonucleotides.

[1667] 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 (aa N517 - 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.

[1668] 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 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.

[1669] Baculovirus-infected insect cells (BIIC) were produced as described by Wasilko et al., 2009, DOI: 10.1016 / j.pep.2009.01.002.

[1670] 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.

[1671] 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.

[1672] SEQ ID NO:1

[1673]

[1674] Protein expression and purification

[1675] 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.

[1676] 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.

[1677] The lysate was loaded onto a column mounted on 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 proteins. The N-terminal purification tag was cleaved off by the protease during overnight dialysis against 2 L of buffer (50 mM Tris pH 7.0, 150 mM NaCl, 1 mM TCEP, 10% glycerol, 0.02% CHAPS) at 5 °C. The protein solution was then carefully diluted by adding two volumes of 20 mM Tris pH 7.0, 10% glycerol, 0.02% CHAPS. The slightly turbid protein solution was passed through a 0.45 μm filter. The cleaved protein was loaded onto a Resource S 6 mL column (GE Healthcare) pre-equilibrated with 20 mM Tris, 20 mM NaCl, 1 mM TCEP, 10% glycerol (pH 7.0). The cleaved tag and contaminating proteins were washed away with 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.

[1678] In vitro enzymatic activity assay of WRN helicase

[1679] An ATPase assay was set up 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 DNA-dependent WRN ATPase activity.

[1680] 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 a single - stranded DNA substrate. The ADP - Glo assay kit (Promega, Madison, WI) allows quantification of ADP generated in the ATP hydrolysis reaction for setting up this assay.

[1681] 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 MgCl 2 , 0.02% BSA, 50 mM NaCl, 0.1% pluronic F127 prepared in DNase - free water.

[1682] To evaluate the inhibitory properties of the compounds of the present invention, serial dilutions were prepared in DMSO (10 semi - logarithmic dilutions from a 10 mM DMSO solution). 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" (maximum 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. Thereafter, 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.

[1683] The method described by Formenko et al., 2006, DOI: 10.1016 / j.cmpb.2006.01.008 was used, and data analysis was performed using 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 yield 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.

[1684] Methods for detecting effects on cell proliferation

[1685] 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 was 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.

[1686] 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). At 37 °C, all cells were maintained in a humidified 5% CO 2 incubator.

[1687] 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. At 37 °C in a humidified 5% CO 2 atmosphere, after overnight incubation, 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%. Ninety-six hours 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 a 10-minute incubation at room temperature. On the day of compound addition, the number of live cells in the "Day 0" plate was quantified in the same manner.

[1688] 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 degree of growth inhibition and potential cell killing was evaluated by comparing the ATP levels in compound-treated cells (measured using CellTiterGlo (Promega)) with 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 an optimal concentration-response curve fit (Gubler et al., SLASD DOI: 10.1177 / 2472555217752140) to calculate the percentage growth (%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 that results in half-maximal growth inhibition (GI50) and the residual cell viability at the highest tested compound concentration (data (cmax), expressed as a percentage) are calculated. Data analysis can also be performed using commercially available software that is 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.

[1689] Efficacy of WRN inhibitors against subcutaneous SW48 colorectal xenografts

[1690] Experiments were conducted in female Crl:NU(NCr)-Foxn1 nu -homozygous nude mice (Charles River). Animals were housed in Allentown XJ cages (IVC, up to 6 mice per cage) under optimized hygienic conditions, with free access to food and water, and a 12h:12h light:dark cycle. Animals were allowed to acclimatize to the new environment for at least 1 week prior to participating in the experimental design. The studies described herein were conducted in accordance with license 1975 approved by the Basel Cantonal Veterinary Office.

[1691] By subcutaneous inoculation of human colorectal cancer SW48 cells (in HBSS, 5 x 10 in 100 μL 6cells / animal) to establish tumors. SW48 human colorectal cancer cells were obtained from ATCC. The cells were cultured at 37 °C in a 5% CO 2 atmosphere in RPMI-1640 medium (Bio Concept, #1-41F01-I) supplemented with 10% FCS (Bio Concept, #2-01F30-I), 2 mM L-glutamine (Bio Concept, #5-10K50-H), 1 mM sodium pyruvate (Bio Concept, #5-60F00-H), and 10 mM HEPES (Bio Concept, #5-31F00-H). To establish SW48 xenografts, cells were harvested and resuspended in HBSS (Sigma, #H6648), and then 100 μL containing 5 million cells was subcutaneously injected into the right flank of animals anesthetized with isoflurane. Tumor size expressed in mm 3 was calculated according to the formula: (L x W2 x π / 6); where W = the width of the tumor and L = the length of the tumor. As a measure of efficacy, the %T / C value was calculated at the end of the experiment according to the formula:

[1692] (Δ Tumor volume 处理的 / Δ Tumor volume 对照 ) * 100

[1693] Tumor regression was calculated according to the formula:

[1694] -(Δ Tumor volume 处理的 / Tumor volume 处理开始时 ) * 100

[1695] where Δ Tumor volume represents the average tumor volume on the evaluation day minus the average tumor volume at the start of the experiment.

[1696] The amorphous sodium salt of the test compound (corrected with the salt factor) was dissolved in a 20% w / v aqueous solution of 2-hydroxypropyl-β-cyclodextrin (HPBCD). Starting from the highest concentration solution at the highest dose in the study, a series of concentrations were prepared by serial dilution.

[1697] Treatment started approximately two weeks after tumor cell inoculation when the average volume of the xenografts reached approximately 200 mm 3 . Based on tumor volume, tumor-bearing animals were randomly divided into experimental groups of 6 animals each, and treatment was started. The compound was administered orally (p.o.) once daily (qd) at 1, 3, 5, or 10 mg / kg (Example 18A) and 0.1, 0.3, 1, 3 mg / kg (Example 21A). In addition, each study included a control group treated once daily with vehicle (20% 2-hydroxypropyl-β-cyclodextrin). Tumor volume and body weight were measured twice a week until the end of the study.

[1698] In the study evaluating the efficacy of Example 18A, tumors in the vehicle-treated group grew approximately linearly from about 200 to 1,100 mm 3 and decreased on day 32 after injection ( Figure 1 ) due to the termination of animals with large tumor masses. During the entire treatment period, vehicle-treated animals gained up to 9% in body weight at the start of treatment ( Figure 2 ). After an initial weight loss (not exceeding 14% in individual animals within the first 10 days of treatment), the animals began to gain weight, reaching 18% of their starting body weight ( Figure 2 ). A dose-dependent anti-tumor effect was observed ( Figure 1 ). At the 1 mg / kg dose level, a slight tumor growth delay was observed, and on day 32 of the study (day 14 of treatment), %T / C reached 22%. Administration at doses of 3, 5, and 10 mg / kg produced significant anti-tumor activity, with maximum regressions of 71% on day 49 of the study (day 31 of treatment), 83% on day 49 of the study (day 31 of treatment), and 91% on day 63 of the study (day 45 of treatment), respectively. Recurrence was observed in all treatment groups, and the time of recurrence was dose-dependent ( Figure 1 ). After day 90 of the study, the sudden decrease in the mean tumor volume observed in the 3 and 5 mg / kg treatment groups was the result of the termination of animals with large tumor masses ( Figure 1 ).

[1699] In the study evaluating the efficacy of Example 21A, tumors in the vehicle-treated group grew approximately linearly from about 200 to 1,000 mm 3 and decreased on day 29 after injection ( Figure 3 ) due to the termination of animals with large tumor masses. During the entire treatment period, vehicle-treated animals gained up to 11% in body weight at the start of treatment ( Figure 4 ). Example 21A was well tolerated throughout the study, and in individual cases, the weight loss of individual animals was minimal, not exceeding 15% ( Figure 4 ). The weight loss observed in the study was not dose-dependent and may be unrelated to the treatment. A dose-dependent anti-tumor effect was observed ( Figure 3)。At the 0.1 mg / kg dose level, tumor growth delay was observed, and %T / C reached 50% from day 25 to day 29 of the study (day 10 to day 14 of treatment). At a dose of 0.3 mg / kg, after an initial arrest (%T / C reached 0% on day 29 of the study, i.e., day 14 of treatment), tumor regrowth occurred on day 36 post-inoculation. Administration at doses of 1 and 3 mg / kg produced significant anti-tumor activity, with 75% and 99% maximum regression on day 52 (day 37 of treatment) and day 85 (day 70 of treatment) of the study, respectively. During treatment, no recurrence was observed in three animals treated with Example 21A at 1 mg / kg and in the entire group treated at 3 mg / kg. The sudden decrease in the average tumor volume observed in the groups treated at 0.3 and 1 mg / kg after day 81 and day 102 of the study, respectively, was the result of termination of animals with large tumor masses ( Figure 1 )。

[1700] 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.

[1701] For example, Example 1A is a WRN ATPase inhibitor with a biochemical IC 50 of 0.02 μM, a proliferation GI 50 of 0.04 μM in SW48, and greater than 10 μM in the DLD1 WRN-KO cell line.

[1702]

[1703]

[1704]

[1705] Except for the biochemical data of Examples 1D and 22B, the data are geometric means of at least two replicate assays.

[1706] On the other hand, the present invention provides compounds having formula (I), which can be used as research chemicals, such as tool compounds or chemical probes. In particular, such use is for experiments related to WRN inhibition or MSI-high cancers.

[1707] Preparation of Compounds

[1708] 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 thereof.

[1709] Instrumental Methods

[1710] X-ray powder diffraction instrument and method Figure 1 :

[1711]

[1712] X-ray powder diffraction instrument and method, Figure 6 :

[1713]

[1714] For the compound sample of Example 21A with a relatively high crystallinity, the following alternative instrumental method was used:

[1715]

[1716] This alternative method produced the following peaks:

[1717] Angle d Rel. 5.78 15.28 67.6％ 6.66 13.26 14.8％ 10.54 8.39 24.4％ 11.55 7.66 21.6％ 11.99 7.38 22.4％ 12.33 7.17 59.6％ 12.90 6.86 38.2％ 13.02 6.80 51.5％ 13.83 6.40 13.5％ 14.80 5.98 48.3％ 15.27 5.80 48.3％ 15.65 5.66 62.1％ 16.00 5.54 19.7％ 16.58 5.34 16.3％ 17.33 5.11 64.5％ 18.50 4.79 24.7％ 19.18 4.62 71.0％ 20.03 4.43 83.3％ 21.16 4.19 25.2％ 21.47 4.14 82.2％ 21.85 4.06 39.0％ 22.36 3.97 24.7％ 22.92 3.88 63.2％ 23.17 3.84 88.6％ 23.90 3.72 100.0％

[1718] UPLC-MS Methods:

[1719] Use Waters Acquity UPLC with a Waters SQ detector, unless otherwise specified. UPLC-MS1:

[1720]

[1721] UPLC-MS2:

[1722]

[1723]

[1724] UPLC-MS 3:

[1725] UPLC-MS 4:

[1726] UPLC-MS 5:

[1727]

[1728]

[1729] UPLC-MS 6:

[1730] UPLC-MS 7:

[1731] UPLC-MS 8:

[1732] UPLC-MS 9:

[1733]

[1734]

[1735] UPLC-MS10:

[1736] HPLC Methods:

[1737] HPLC 1:

[1738] HPLC 2:

[1739]

[1740]

[1741] Chiral HPLC Methods:

[1742] C-HPLC 1:

[1743] Instrument: Analytical SFC-MS Waters UPC 2

[1744] Injection: 5 μL

[1745] Mobile phase: A: 45% MeOH + 0.1% NH 3 , B: 55% scCO 2

[1746] Flow rate: 3 mL / min

[1747] Column: Chiralpak AD (4.6 mm x 100 mm 5 μm)

[1748] Detection UV: DAD

[1749] Gradient: Isocratic, A: 45%, B: 55%

[1750] Column oven temperature: 40 °C

[1751] BPR: 1800 psi

[1752] C-HPLC 2:

[1753] Instrument: Analytical SFC-MS Waters UPC 2

[1754] Injection: 5 μL

[1755] Mobile phase: A: 45% IPA + 0.1% NH 3 , B: 55% scCO 2

[1756] Flow rate: 3 mL / min

[1757] Column: Chiralpak IB (4.6 mm x 100 mm 5 μm)

[1758] Detection UV: DAD

[1759] Gradient: Isocratic, A: 45%, B: 55%

[1760] Column oven temperature: 40 °C

[1761] BPR: 1800 psi

[1762] C-HPLC 3:

[1763] Instrument: Analytical SFC-MS Waters UPC 2

[1764] Injection: 5 μL

[1765] Mobile phase: A: 45% MeOH + 0.1% NH 3 , B: 55% scCO 2

[1766] Flow rate: 3 mL / min

[1767] Column: Chiralpak IB-N (4.6 mm x 100 mm 5 μm)

[1768] Detection UV: DAD

[1769] Gradient: Isocratic, A: 45%, B: 55%

[1770] Column oven temperature: 40 °C

[1771] BPR: 1800 psi

[1772] C-HPLC 4:

[1773] Instrument: Analytical SFC-MS Waters UPC 2

[1774] Injection: 5 μL

[1775] Mobile phase: A: 40% MeOH + 0.1% NH 3 , B: 60% scCO 2

[1776] Flow rate: 3 mL / min

[1777] Column: Chiralpak IB-N (4.6 mm x 100 mm 5 μm)

[1778] Detection UV: DAD

[1779] Gradient: Isocratic, A: 40%, B: 60%

[1780] Column oven temperature: 40 °C

[1781] BPR: 1800 psi

[1782] C-HPLC 5:

[1783] Instrument: Analytical SFC-MS Waters UPC 2

[1784] Injection: 5 μL

[1785] Mobile phase: A: 55% MeOH + 0.05% NH 3 , B: 45% scCO 2

[1786] Flow rate: 3 mL / min

[1787] Column: Chiralpak IB (4.6 mm x 100 mm 5 μm)

[1788] Detection UV: DAD

[1789] Gradient: Isocratic, A: 55%, B: 45%

[1790] Column oven temperature: 40 °C

[1791] BPR: 1800 psi

[1792] C-HPLC 6:

[1793] Instrument: Ultimate3000

[1794] Injection: 4 μL

[1795] Mobile phase: A: 40% heptane containing DEA, B: 60% EtOH containing DEA;

[1796] Flow rate: 0.420 mL / min

[1797] Column: Chiralpak IG-3 (3.0 mm x 100 mm 3 μm)

[1798] Detection UV: 240 nm

[1799] Gradient: Isocratic, A: 40%, B: 60%

[1800] Column oven temperature: 25 °C

[1801] BPR: 1800 psi

[1802] C-HPLC 7:

[1803] Instrument: Analytical SFC-MS Waters UPC 2

[1804] Injection volume: 5 μL

[1805] Mobile phase: A: 40% MeOH + 0.1% NH 3 , B: 60% scCO 2

[1806] Flow rate: 3 mL / min

[1807] Column: Chiralpak IC (4.6 mm x 100 mm 5 μm)

[1808] Detection UV: DAD

[1809] Gradient: Isocratic, A: 40%, B: 60%

[1810] Column oven temperature: 40 °C

[1811] BPR: 1800 psi

[1812] C-HPLC 8:

[1813] Instrument: Analytical SFC-MS Waters UPC 2

[1814] Injection volume: 5 μL

[1815] Mobile phase: A: 45% MeOH + 0.1% NH 3 , B: 55% scCO 2

[1816] Flow rate: 3 mL / min

[1817] Column: Chiralpak IB-N (4.6 mm x 100 mm 5 μm)

[1818] UV detection: DAD

[1819] Gradient: isocratic, A: 45%, B: 55%

[1820] Column oven temperature: 40 °C

[1821] BPR: 1800 psi

[1822] C-HPLC 9:

[1823] Instrument: Analytical SFC-MS Waters UPC 2

[1824] Injection volume: 5 μL

[1825] Mobile phase: A: 25% MeOH + 0.1% NH 3 , B: 75% scCO 2

[1826] Flow rate: 3 mL / min

[1827] Column: Chiralpak IB (4.6 mm x 100 mm 5 μm)

[1828] UV detection: DAD

[1829] Gradient: isocratic, A: 25%, B: 75%

[1830] Column oven temperature: 40 °C

[1831] BPR: 1800 psi

[1832] C-HPLC 10:

[1833] Instrument: Analytical SFC-MS Waters UPC 2

[1834] Injection volume: 5 μL

[1835] Mobile phase: A: 40% MeOH + 0.1% NH 3 , B: 60% scCO 2

[1836] Flow rate: 3 mL / min

[1837] Column: Chiralpak IB (4.6 mm x 100 mm 5 μm)

[1838] UV detection: DAD

[1839] Gradient: isocratic, A: 40%, B: 60%

[1840] Column oven temperature: 40 °C

[1841] BPR: 1800 psi

[1842] C-HPLC 11:

[1843] Instrument: Analytical SFC-MS Waters UPC 2

[1844] Injection volume: 5 μL

[1845] Mobile phase: A: 35% MeOH + 0.025% NH 3 , B: 65% scCO 2

[1846] Flow rate: 3 mL / min

[1847] Column: Chiralpak IB-N (4.6 mm x 100 mm 5 μm)

[1848] UV detection: DAD

[1849] Gradient: Isocratic, A: 35%, B: 65%

[1850] Column oven temperature: 40 °C

[1851] BPR: 1800 psi

[1852] C-HPLC 12:

[1853] Instrument: Analytical SFC-MS Waters UPC 2

[1854] Injection volume: 5 μL

[1855] Mobile phase: A: 20% MeOH + 0.05% NH 3 , B: 80% scCO 2

[1856] Flow rate: 3 mL / min

[1857] Column: Chiralpak AD (4.6 mm x 100 mm 5 μm)

[1858] UV detection: DAD

[1859] Gradient: Isocratic, A: 20%, B: 80%

[1860] Column oven temperature: 40 °C

[1861] BPR: 1800 psi

[1862] C-HPLC 13:

[1863] Instrument: Analytical SFC-MS Waters UPC 2

[1864] Injection: 5 μL

[1865] Mobile phase: A: 50% MeOH + 0.1% NH 3 , B: 50% scCO 2

[1866] Flow rate: 3 mL / min

[1867] Column: Chiralpak IB-N (4.6 mm x 100 mm 5 μm)

[1868] Detection UV: DAD

[1869] Gradient: Isocratic, A: 50%, B: 50%

[1870] Column oven temperature: 40 °C

[1871] BPR: 1800 psi

[1872] C-HPLC 14:

[1873] Instrument: Analytical SFC-MS Waters UPC 2

[1874] Injection: 5 μL

[1875] Mobile phase: A: 10% MeOH + 0.05% NH 3 , B: 90% scCO 2

[1876] Flow rate: 3 mL / min

[1877] Column: Chiralpak IG (4.6 mm x 100 mm 5 μm)

[1878] Detection UV: DAD

[1879] Gradient: Isocratic, A: 10%, B: 90%

[1880] Column oven temperature: 40 °C

[1881] BPR: 1800 psi

[1882] Preparative Methods:

[1883] Column Chromatography:

[1884] Unless otherwise specified, column chromatography is carried out on silica gel using pre-packed columns (described in detail below) or using glass columns according to standard flash chromatography.

[1885]

[1886] Supercritical Fluid Chromatography (SFC):

[1887] 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.

[1888] SFC 1:

[1889] Instrument: WATERS SFC 100 with the latest ABSYS

[1890] Mobile phase: A: CO 2 , B: MeOH

[1891] Flow rate: 150 mL / min MeOH + 30 mL / min CO 2 , a constant flow of 180 mL / min

[1892] Column: 250 x 30 Reprospher PEI 100A 5um

[1893] Temperature: 50 °C

[1894] Back pressure: 100 bar

[1895] Detection UV: 210 - 400 nm

[1896] Gradient: 23% B to 31% B in 7 min

[1897] Reverse Phase HPLC:

[1898] Basic RP-HPLC 1:

[1899]

[1900] Acidic RP-HPLC 1:

[1901]

[1902] Acidic RP-HPLC 2:

[1903]

[1904] Acidic RP-HPLC 3:

[1905]

[1906] Preparation of Compounds

[1907] The following examples are intended to illustrate the invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. All evaporations are carried out under reduced pressure, typically between about 15 mmHg and 100 mmHg (= 20 - 133 mbar), if not otherwise mentioned. The abbreviations used are those conventional in the art.

[1908] 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.

[1909] 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 of each compound with WRN or by analyzing the small molecule X-ray crystal structure of the precursor or final compound.

[1910] 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 separated by partitioning between DCM and aq sat NaHCO 3 as described for intermediate C.

[1911] General Conditions:

[1912] Mass spectra are obtained on an LC-MS system using electrospray, chemical, and electron impact ionization methods with a series of instruments configured as follows: Waters Acquity UPLC with a Waters SQ detector, analytical SFC-MS WatersUPC 2 and Agilent 1260 HPLC. [M + H] + refers to the protonated molecular ion of a chemical species. [M - H] - refers to the deprotonated molecular ion of a chemical species.

[1913] NMR spectra are recorded using a Bruker Ultrashield TM 400 (400 MHz) and a Bruker Ultrashield TMThe 600 (600 MHz) spectrometer was run with and 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 (m), unresolved or more overlapping signals (m), broad signal (br). Solvents are given in parentheses.

[1914] 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)

[1915] Thiol: SiliCYCLE thiol metal scavenger - (part number: R51030B, loading: 1.31 mmol / g, particle size: 40 - 63 μm)

[1916] Si - TMT: Biotage thiol metal scavenger - (part number: 9538 - 0100, loading: 0.49 mmol / g).

[1917] Preparation of Sodium Salts:

[1918] The compound was suspended in tert - butanol. 0.1 M NaOH (1 eq) was added. The mixture was stirred / sonicated at room temperature. If the suspension became a clear solution, it was lyophilized. If the suspension remained turbid, water was added and the resulting solution was lyophilized. If no change occurred, up to a total of 2 eq of 0.1 M NaOH was added until a clear solution was observed, and then it was lyophilized. If the NMR of the resulting solid still contained tert - butanol, the solid was dissolved in a small amount of water and lyophilized again. The final sodium salt was obtained as a colorless powder. XRPD confirmed the amorphous state.

[1919] Abbreviations

[1920]

[1921]

[1922]

[1923]

[1924]

[1925] Preparation of Final Compounds

[1926] Example 1A: (7R,9R)-6-(4-(4-chloro-3-hydroxypyridine-1-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and Example 1B: (7S,9S)-6-(4-(4-chloro-3-hydroxypyridine-1-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and Example 1C: (7S,9R)-6-(4-(4-chloro-3-hydroxypyridine-1-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and Example 1D: (7R,9S)-6-(4-(4-chloro-3-hydroxypyridine-1-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1927]

[1928] N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate C) (707 mg, 1.22 mmol), 4-chloro-3-hydroxypyridinecarboxylic acid (232 mg, 1.34 mmol) and HATU (486 mg, 1.28 mmol) were mixed with DCM (15 mL) and cooled to 0 °C. Then DIPEA (531 μL, 3.04 mmol) was added and the mixture was stirred at room temperature for 2 days. Water (10 mL), aq sat NaHCO 3 (10 mL) and DCM (10 mL) were added. The aqueous layer was washed with DCM (2 x 10 mL). The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative ISCO (RediSep column: C18 50 g gold, eluent: water + 0.1% TFA:ACN 95:5 to 0:100, 20 min). The fractions containing the product were combined and washed with aq sat NaHCO3 Alkalinize, extract twice with DCM, dry over a phase separator and concentrate under reduced pressure. Further purify the residue in three parts by reversed-phase preparative HPLC (acidic RP-HPLC 1: 20% to 80% B in 20 min, hold at 45% for 3 min, and hold at 55% for 3 min), (acidic RP-HPLC 1: 35% to 75% B in 19 min, hold at 45% for 2 min, and hold at 55% for 3 min), and (acidic RP-HPLC 1: 35% to 75% B in 16 min, hold at 50% for 3 min). Combine all fractions containing the first elution peak with purity > 90% and use aq sat NaHCO 3 Alkalinize, extract twice with DCM, dry over a phase separator and concentrate under reduced pressure. Combine all fractions containing the second elution peak with purity > 90% and use aq sat NaHCO 3 Alkalinize, extract twice with DCM, dry over a phase separator and concentrate under reduced pressure. Combine all other fractions containing the first elution peak and / or the second elution peak and use aq sat NaHCO 3 Alkalinize, extract twice with DCM, dry over a phase separator, concentrate under reduced pressure and purify by reversed-phase preparative HPLC (basic RP-HPLC 1: 20% to 80% B in 20 min). Combine all fractions containing the first elution peak with purity > 90% and use aq sat NaHCO 3 Alkalinize, extract twice with DCM, dry over a phase separator, concentrate under reduced pressure and combine with the first batch. Combine all fractions containing the second elution peak with purity > 90% and use aq sat NaHCO 3 Alkalinize, extract twice with DCM, dry over a phase separator, concentrate under reduced pressure and combine with the first batch.

[1929] Purify the first elution peak (racemate of 2 enantiomers - 180 mg) by preparative chiral SFC (instrument: Sepiatec prep SFC-100; column: LUX Amylose-1 (Chiralpak-AD), 250 mm x 30 mm 5 μm; eluent: A: 45% MeOH + 0.1% NH 3 , B: 55% scCO 2 ; flow rate: 80.0 mL / min; detection: UV; injection volume: 1 mL; gradient: isocratic, A: 45%, B: 55%; column oven temperature: 40 °C; BPR: 105 bar).

[1930] Example 1C:(7S,9R)-6-(4-(4-chloro-3-hydroxypyridinecarbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1931] First eluting stereoisomer from chiral separation: 75.0 mg, 99% pure, yield: 8%

[1932] LC-MS: Rt = 1.05 min; MS m / z [M+H] + 736.5 / 738.5, m / z [M-H] - 734.3 / 736.3; UPLC-MS1

[1933] Chiral HPLC (C-HPLC 1): Rt = 1.08 min, 99.5% ee

[1934] Example 1D: (7R,9S)-6-(4-(4-chloro-3-hydroxypyridinecarbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1935] Second eluting stereoisomer from chiral separation: 80.0 mg, 99% pure, yield: 9%

[1936] LC-MS: Rt = 1.07 min; MS m / z [M+H] + 736.5 / 738.4, m / z [M-H] - 734.2 / 736.2; UPLC-MS1

[1937] Chiral HPLC (C-HPLC 1): Rt = 1.84 min, 99.5% ee

[1938] The second eluting peak (racemate of 2 enantiomers - 152 mg) was passed through preparative chiral SFC (instrument: Sepiatec prep SFC-100; column: LUX Amylose-1 (Chiralpak AD), 250 mm x 30 mm 5 μm; eluent: A: 48% MeOH + 0.1% NH 3 , B: 52% scCO 2; Flow rate: 85.0 mL / min; Detection: UV; Injection volume: 2.5 mL; Gradient: Isocratic, A: 48%, B: 52%; Column oven temperature: 40 °C; BPR: 100 bar) Purification.

[1939] Example 1B: (7S,9S)-6-(4-(4-Chloro-3-hydroxypyridinecarbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1940] First eluted stereoisomer of chiral separation: 65.0 mg, 99% pure, Yield: 7%

[1941] Sodium salt was prepared analogously to the general procedure.

[1942] LC-MS: Rt = 1.07 min; MS m / z [M+H] + 736.5 / 738.6, m / z [M-H] - 734.3 / 736.3; UPLC-MS1

[1943] Chiral HPLC (C-HPLC 1): Rt = 1.02 min, 99.5% ee

[1944] Example 1A: (7R,9R)-6-(4-(4-Chloro-3-hydroxypyridinecarbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1945] Second eluted stereoisomer of chiral separation: 72.0 mg, 95% pure, Yield: 7.5%

[1946] Sodium salt was prepared analogously to the general procedure.

[1947] LC-MS: Rt = 1.07 min; MS m / z [M+H] + 736.4 / 738.5, m / z [M-H] - 734.3 / 736.4; UPLC-MS1

[1948] Chiral HPLC (C-HPLC 1): Rt = 1.80 min, 99.5% ee

[1949] The stereochemistry of Examples 1A and 1C was assigned as (7R,9R) and (7S,9R), respectively, based on their potency and understanding of the structure-activity relationship.

[1950] Example 2A: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and Example 2B: (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and Example 2C: (7S,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and Example 2D: (7R,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1951]

[1952] Step 1:(7R,9S)-6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and (7S,9R)-6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and (7S,9S)-6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and (7R,9R)-6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1953] N-(2-Chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate C) (650 mg, 1.12 mmol), 5-(Benzyloxy)-6-methylpyrimidine-4-carboxylic acid (Intermediate U) (301 mg, 1.23 mmol) and HATU (447 mg, 1.18 mmol) were mixed in DCM (20 mL) and cooled to 0 °C. Then DIPEA (489 μL, 2.80 mmol) was added. The mixture was stirred at room temperature for 1.5 h. Water (10 mL), aq sat NaHCO 3(10 mL) and DCM (10 mL). The aqueous layer was washed with DCM (2 x 10 mL). The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude product was purified in 6 portions by reverse-phase preparative HPLC (acidic RP-HPLC 1: 25% to 85% B in 20 min, held at 65% for 1 min), (acidic RP-HPLC 1: 40% to 75% B in 20 min), (acidic RP-HPLC 1: 40% to 70% B in 18 min, held at 60% for 1 min), (acidic RP-HPLC 1: 48% to 63% B in 17 min), (acidic RP-HPLC 1: 48% to 61% B in 17 min), and (acidic RP-HPLC 1: 45% to 60% B in 15 min, held at 50% for 2 min). All fractions containing the first elution peak were combined, basified with aq sat NaHCO 3 and extracted twice with DCM, dried over a phase separator, and concentrated under reduced pressure to give a racemic mixture of (7R,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and (7S,9R)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide.

[1954] LC-MS: Rt = 1.14 min; MS m / z [M+H] + 807.6 / 809.6, m / z [M-H] - 805.5 / 807.4; UPLC-MS1

[1955] All fractions containing the second elution peak were combined, basified with aq sat NaHCO 3Alkalinize, extract twice with DCM, dry over a phase separator and concentrate under reduced pressure to obtain a racemic mixture of (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and (7R,9R)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide.

[1956] LC-MS: Rt = 1.16 min; MS m / z [M+H] + 807.5 / 809.5, m / z [M-H] -

[1957] 805.3 / 807.2; UPLC-MS1

[1958] Step 2a: (7R,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and (7S,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1959] The racemic mixture (first elution peak) (325 mg, 403 μmol) of (7R,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and (7S,9R)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide was dissolved in DCM (5 mL), and TFA (5.00 mL, 64.9 mmol) was added. The mixture was stirred at 60 °C overnight. The mixture was concentrated under reduced pressure. The crude product was purified in two parts by reverse-phase preparative HPLC (acidic RP-HPLC 1: 20% to 80% B in 20 min, held at 40% for 1 min, and held at 50% for 2 min) and (acidic RP-HPLC 1: 25% to 75% B). The fractions containing the product were combined, basified with aq sat NaHCO 3 and extracted twice with DCM, dried over a phase separator and concentrated under reduced pressure.

[1960] The racemate (224 mg, 95% pure) was purified by preparative chiral SFC (instrument: Sepiatec prep SFC-100; column: Chiralpak IB-N 250 mm x 30 mm 5 μm; eluents: A: 45% IPA + 0.1% NH 3 3, B: 55% scCO 2 2; flow rate: 80.0 mL / min; detection: UV; injection volume: 1.1 mL; gradient: isocratic, A: 45%, B: 52%; column oven temperature: 40 °C; BPR: 110 bar).

[1961] First Eluted Stereoisomer: (7R,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1962] 99.0 mg, 96% pure, yield: 33%

[1963] LC-MS: Rt = 0.98 min; MS m / z [M+H] + 717.6 / 719.6, m / z [M-H] - 715.4 / 717.4; UPLC-MS1

[1964] LC-MS: Rt = 4.86 min; MS m / z [M+H] + 717.5 / 719.6, m / z [M-H] - 715.4 / 717.4; UPLC-MS2

[1965] Chiral HPLC (C-HPLC 2): Rt = 1.51 min, 99.5% ee

[1966] Second Eluted Stereoisomer: (7S,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1967] 90.0 mg, 100% pure, yield: 31%

[1968] LC-MS: Rt = 0.99 min; MS m / z [M+H] + 717.6 / 719.7, m / z [M-H] - 715.2 / 717.3; UPLC-MS1

[1969] LC-MS: Rt = 4.90 min; MS m / z [M+H] + 717.5 / 719.5, m / z [M-H] - 715.5 / 717.4; UPLC-MS2

[1970] Chiral HPLC (C-HPLC 2): Rt = 2.07 min, 97.2% ee

[1971] Step 2b:(7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1972] The racemic mixture (second elution peak) (359 mg, 414 μmol) of (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and (7R,9R)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide was dissolved in DCM (5 mL), and TFA (5.00 mL, 64.9 mmol) was added. The mixture was stirred overnight at 60 °C. The mixture was concentrated under reduced pressure. The crude product was purified in two parts by reverse-phase preparative HPLC (basic RP-HPLC 1: 25% to 75% B in 20 min) and (basic RP-HPLC 2: 20% to 65% B in 20 min). The fractions containing the product were combined, extracted twice with DCM, dried over a phase separator and concentrated under reduced pressure.

[1973] The racemate (236 mg) was purified by preparative chiral HPLC (instrument: Waters Prep SFC100-MS; column: Chiralpak IB-N 250 mm x 30 mm 5 μm; eluent: A: 45% MeOH + 0.1% NH 3 , B: 55% scCO 2 ; flow rate: 80.0 mL / min; detection: DAD; injection volume: 1 mL; gradient: isocratic, A: 45%, B: 55%; column oven temperature: 40 °C; BPR: 120 bar).

[1974] First Eluted Stereoisomer:(7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1975] 62.2 mg, 87% pure

[1976] The first eluted stereoisomer was purified by reverse-phase preparative HPLC (acidic RP-HPLC 2: 5% to 100% B in 30 min). The fractions containing the product were combined, basified with aq sat NaHCO 3 and extracted twice with DCM, dried over a phase separator and concentrated under reduced pressure to give the title compound (47.8 mg, 99% pure, yield: 16%).

[1977] The sodium salt was prepared analogously to the general procedure.

[1978] LC-MS: Rt = 1.01 min; MS m / z [M+H] + 717.5 / 719.5, m / z [M-H] - 715.3 / 717.4; UPLC-MS1

[1979] Chiral HPLC (C-HPLC 3): Rt = 1.00 min, 97.5% ee

[1980] Second Eluted Stereoisomer: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1981] 41.3 mg, 100% pure, yield: 14%

[1982] The sodium salt was prepared analogously to the general procedure.

[1983] LC-MS: Rt = 1.00 min; MS m / z [M+H] + 717.6 / 719.6, m / z [M-H] - 715.5 / 717.4; UPLC-MS1

[1984] Chiral HPLC (C-HPLC 3): Rt = 3.21 min, 99.5% ee

[1985] The stereochemistry of Examples 2A and 2C was assigned as (7R,9R) and (7S,9R), respectively, based on their potencies and understanding of the structure-activity relationship.

[1986] Example 3A: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(4-fluoro-3-hydroxy-6-methylpyridine-1-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and Example 3B: (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(4-fluoro-3-hydroxy-6-methylpyridine-1-carbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1987]

[1988] Step 1: (7S,9S)-6-(4-(3-(benzyloxy)-4-fluoro-6-methylpyridine-1-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and (7R,9R)-6-(4-(3-(benzyloxy)-4-fluoro-6-methylpyridine-1-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1989] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate D) (483 mg, 695 μmol), (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate D) (483 mg, 695 μmol), 3-(benzyloxy)-4-fluoro-6-methylpicolinic acid (Intermediate V) (232 mg, 888 μmol) and an enantiomeric mixture of HATU (277 mg, 730 μmol) were mixed in DCM (5 mL) and DIPEA (350 μL, 2.00 mmol) was added. The white suspension turned into a light yellow solution and was stirred at room temperature for 1 hour. Water (10 mL), aq sat NaHCO 3 (10 mL) and DCM (10 mL) were added. The aqueous layer was washed with DCM (2 x 10 mL). The combined organic layers were dried over a phase separator and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 2: 35% to 65% B in 20 min). The fractions containing the product were combined, basified with aq sat NaHCO 3 and extracted twice with DCM, dried over a phase separator and concentrated under reduced pressure to give the title compound.

[1990] The racemate (434 mg) was purified by preparative chiral HPLC (instrument: Waters Prep SFC100-MS; column: Chiralpak IB-N 250 mm x 30 mm 5 μm; eluent: A: 40% MeOH + 0.1% NH 3 , B: 60% scCO 2 ; flow rate: 80.0 mL / min; detection: DAD; injection volume: 1.3 mL; gradient: isocratic, A: 40%, B: 60%; BPR: 120 bar).

[1991] First Eluted Stereoisomer: (7S,9S)-6-(4-(3-(Benzyloxy)-4-fluoro-6-methylpyridinecarbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1992] 181 mg, 99% pure, yield: 31%

[1993] LC-MS: Rt = 1.25 min; MS m / z [M+H] + 824.5 / 826.3, m / z [M-H] - 822.1 / 824.1; UPLC-MS1

[1994] LC-MS: Rt = 6.29 min; MS m / z [M+H] + 824.3 / 826.3, m / z [M-H] - 822.3 / 824.2; UPLC-MS2

[1995] Chiral HPLC (C-HPLC 4): Rt = 0.92 min, 99% ee

[1996] Second Eluted Stereoisomer: (7R,9R)-6-(4-(3-(Benzyloxy)-4-fluoro-6-methylpyridinecarbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[1997] 175 mg, 99% pure, yield: 30%

[1998] LC-MS: Rt = 1.25 min; MS m / z [M+H] + 824.4 / 826.5, m / z [M-H] - 822.1 / 824.1; UPLC-MS1

[1999] LC-MS: Rt = 6.29 min; MS m / z [M+H] + 824.3 / 826.3, m / z [M-H] - 822.3 / 824.2; UPLC-MS2

[2000] Chiral HPLC (C-HPLC 4): Rt = 3.13 min, 99% ee

[2001] Step 2a: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(4-fluoro-3-hydroxy-6-methylpyridinecarbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2002] (7R,9R)-6-(4-(3-(Benzyloxy)-4-fluoro-6-methylpyridinecarbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (second eluting stereoisomer) (175 mg, 212 μmol) was dissolved in DCM (5 mL). TFA (5.00 mL, 64.9 mmol) was added. The mixture was stirred at 60 °C for 2.5 days. The mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 10% to 90% B in 20 min). The fractions containing the product were combined, basified with aq sat NaHCO 3 and extracted twice with DCM, dried over a phase separator and concentrated under reduced pressure to give the title compound (115 mg, 99% pure, yield: 73%).

[2003] The sodium salt was prepared analogously to the general procedure.

[2004] LC-MS: Rt = 1.03 min; MS m / z [M+H] + 734.5 / 735.8, m / z [M-H] - 732.1 / 734.1; UPLC-MS1

[2005] Step 2b: (7S,9S)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-6-(4-(4-fluoro-3-hydroxy-6-methylpyridinecarbonyl)piperazin-1-yl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2006] (7S,9S)-6-(4-(3-(Benzyloxy)-4-fluoro-6-methylpyridinecarbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-morpholino-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (first eluting stereoisomer) (181 mg, 219 μmol) was dissolved in DCM (5 mL). TFA (5.00 mL, 64.9 mmol) was added. The mixture was stirred at 60 °C for 1.5 days. The mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 10% to 90% B in 20 min). The fractions containing the product were combined, basified with aq sat NaHCO 3Alkalinized, extracted twice with DCM, dried through a phase separator and concentrated under reduced pressure to give the title compound (111 mg, 99% pure, yield: 68%).

[2007] The sodium salt was prepared analogously to the general procedure.

[2008] LC-MS: Rt = 1.03 min; MS m / z [M+H] + 734.5 / 735.8, m / z [M-H] - 732.1 / 734.1; UPLC-MS1

[2009] The stereochemistry of Example 3A was assigned as (7R,9R) based on potency and understanding of the structure-activity relationship.

[2010] Example 4A: (7R,9R)-N-(2-Chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2011]

[2012] Step 1: (7R,9R)-6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2013] To (7R,9R)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate E1) (127 mg, 206 μmol) and 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (Intermediate U) (50.4 mg, 206 μmol) in DMF (1 mL) was added DIPEA (180 μL, 1.03 mmol). The RM was stirred at room temperature for 2 minutes, then HATU (86.0 mg, 227 μmol) was added and the RM was stirred at room temperature for 13 minutes. The RM was diluted with water (3 mL) and sonicated. The resulting suspension was stirred for 1 hour. The mixture was filtered and dried to give the title compound as a colorless solid (114 mg, 90% pure, yield: 62%).

[2014] LC-MS: Rt = 1.08 min; MS m / z [M+H-Boc] + 805.5 / 807.5, m / z [M-H] - 803.4 / 805.4; UPLC-MS1

[2015] Step 2: (7R,9R)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2016] (7R,9R)-6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (114 mg, 142 μmol) was dissolved in TFA (1.00 mL, 13.0 mmol) and stirred at 55 °C for 5.5 hours. The RM was evaporated and the crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 20% to 50% B in 15 min). The fractions containing the product were combined and lyophilized. The resulting powder (TFA solvate) was redissolved in DCM (5 mL) and solid NaHCO 3(50.0 mg). The suspension was kept at room temperature for 20 minutes, filtered and evaporated under reduced pressure to give the title compound as a colorless solid (62.0 mg, 99% pure, yield: 61%).

[2017] The sodium salt was prepared analogously to the general procedure.

[2018] LC-MS: Rt = 0.91 min; MS m / z [M + H - Boc] + 715.4 / 717.4, m / z [M - H] - 713.1 / 715.1; UPLC-MS1

[2019] The stereochemistry of Example 4A was assigned as (7R,9R) based on its potency and understanding of the structure-activity relationship.

[2020] Example 4B: (7S,9S)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2021]

[2022] Step 1: (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2023] To (7S,9S)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate E2) (122 mg, 198 μmol) and 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (Intermediate U) (48.0 mg, 196 μmol) in DMF (1 mL) was added DIPEA (180 μL, 1.03 mmol). The RM was stirred at room temperature for 2 minutes, then HATU (82.0 mg, 216 μmol) was added and the RM was stirred at room temperature for 13 minutes. The RM was diluted with water (3 mL) and sonicated. The resulting suspension was stirred for 1 hour. The mixture was filtered and dried to give the title compound as an off-white solid (104 mg, 85% pure, yield: 53%).

[2024] LC-MS: Rt = 1.10 min; MS m / z [M+H-Boc] + 805.5 / 807.6, m / z [M-H] - 803.2 / 805.2; UPLC-MS1

[2025] Step 2: (7S,9S)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2026] (7S,9S)-6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (104 mg, 129 μmol) was dissolved in TFA (1.00 mL, 13.0 mmol) and stirred at 55 °C for 5.5 hours. The RM was evaporated and the crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 20% to 50% B in 15 min). The fractions containing the product were combined and lyophilized. The resulting powder (TFA solvate) was redissolved in DCM (5 mL) and solid NaHCO 3(50.0 mg). The suspension was kept at room temperature for 20 minutes, filtered and concentrated under reduced pressure to give the title compound as a colorless solid (51.0 mg, 99% pure, yield: 50%).

[2027] LC-MS: Rt = 0.91 min; MS m / z [M+H-Boc] + 715.4 / 717.4, m / z [M-H] - 713.1 / 715.1; UPLC-MS1

[2028] Example 5A: (7R,9R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2029]

[2030] Step 1: (7R,9R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2031] At room temperature, DIPEA (234 μL, 1.34 mmol) was added to a stirred solution of (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H4) (155 mg, 268 μmol), 7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylic acid (Intermediate Z) (60.4 mg, 268 μmol) and HATU (122 mg, 322 μmol) in DMF (2 mL), and the reaction mixture (RM) was stirred at room temperature for 2 minutes. The RM was diluted with EtOAc and water, extracted twice with EtOAc, and the combined organic layers were passed through Na 2 SO 4Dry and concentrate under reduced pressure. Purify the crude product by column chromatography (RediSep column: silica 12 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 50:50). Combine the fractions containing the product, concentrate under reduced pressure and dry under HV to give the title compound (164 mg, 96% pure, yield: 75%).

[2032] LC-MS: Rt = 1.03 min; MS m / z [M+H] + 785.5 / 787.5, m / z [M-H] - 783.4 / 784.7; UPLC-MS1

[2033] LC-MS: Rt = 5.04 min; MS m / z [M+H] + 785.5 / 787.5, m / z [M-H] - 783.3 / 785.3; UPLC-MS2

[2034] Step 2: (7R,9R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2035] At room temperature, stir (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (164 mg, 201 μmol) in EtOH (1.5 mL) and 1.25 M HCl in EtOH (1.50 mL, 1.88 mmol) for 14 h. Dilute the RM with DCM and aq NaHCO 3 and extract twice with DCM. Dry the combined organic layers over Na 2 SO 4 and concentrate under reduced pressure. Purify the crude product by reverse-phase preparative HPLC (acidic RP-HPLC 1: 20% to 75% B in 20 min) to give the title compound as a white solid (117 mg, 100% pure, yield: 79%).

[2036] Sodium salts were prepared analogously to the general procedure.

[2037] LC-MS: Rt = 0.94 min; MS m / z [M+H] + 741.6 / 743.6, m / z [M-H] - 739.4 / 741.4; UPLC-MS1

[2038] LC-MS: Rt = 4.75 min; MS m / z [M+H] + 741.5 / 743.5, m / z [M-H] - 739.5 / 741.4; UPLC-MS2

[2039] The stereochemistry of Example 5A was assigned as (7R,9R) based on its potency and understanding of the structure-activity relationship.

[2040] Example 5B: (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2041]

[2042] Step 1: (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2043] At room temperature, DIPEA (227 μL, 1.30 mmol) was added to a stirred solution of (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H3) (150 mg, 260 μmol), 7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carboxylic acid (Intermediate Z) (58.4 mg, 260 μmol) and HATU (118 mg, 311 μmol) in DMF (2 mL), and the RM was stirred at room temperature for 2 minutes. The RM was diluted with EtOAc and water, extracted twice with EtOAc, and the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica 24 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 50:50). The fractions containing the product were combined, concentrated under reduced pressure and dried under HV to give the title compound (155 mg, 95% pure, yield: 72%).

[2044] LC-MS: Rt = 1.02 min; MS m / z [M+H] + 785.5 / 787.5, m / z [M-H] - 783.3 / 785.3; UPLC-MS1

[2045] LC-MS: Rt = 5.05 min; MS m / z [M+H] + 785.6 / 787.5, m / z [M-H] - 783.4 / 785.3; UPLC-MS2

[2046] Step 2: (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-hydroxy-2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2047] At room temperature, (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(7-(methoxymethoxy)-2,3-dihydrofuro[3,2-c]pyridine-6-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (155 mg, 188 μmol) in EtOH (1.5 mL) and 1.25 M HCl in EtOH (1.50 mL, 1.88 mmol) were stirred for 14 h. The RM was diluted with DCM and aq NaHCO 3 and extracted twice with DCM, and the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 5% to 95% B in 25 min) to afford the title compound as a white solid (111 mg, 99% pure, yield: 79%).

[2048] The sodium salt was prepared analogously to the general procedure.

[2049] LC-MS: Rt = 0.93 min; MS m / z [M+H] + 741.6 / 743.4, m / z [M-H] - 739.4 / 741.4; UPLC-MS1

[2050] LC-MS: Rt = 4.67 min; MS m / z [M+H] + 741.6 / 743.6, m / z [M-H] - 739.4 / 741.3; UPLC-MS2

[2051] Example 6A: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro-3-hydroxypyridinecarbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2052]

[2053] Step 1:(7R,9R)-6-(4-(3-(Benzyloxy)-4-fluoropicolinoyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2054] At room temperature, DIPEA (234 μL, 1.34 mmol) was added to a stirred solution of (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H4) (155 mg, 268 μmol), 3-(benzyloxy)-4-fluoropicolinic acid (Intermediate W) (66.3 mg, 268 μmol), and HATU (122 mg, 322 μmol) in DMF (2 mL), and the reaction mixture (RM) was stirred at room temperature for 3 minutes. The RM was diluted with EtOAc and water, extracted twice with EtOAc, and the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica 12 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 50:50). The fractions containing the product were combined, concentrated under reduced pressure, and dried under high vacuum to give the title compound (211 mg, 94% pure, yield: 92%).

[2055] LC-MS: Rt = 1.23 min; MS m / z [M+H] + 807.6 / 809.5, m / z [M-H] - 805.4 / 807.4; UPLC-MS1

[2056] LC-MS: Rt = 6.19 min; MS m / z [M+H] + 807.5 / 809.5, m / z [M-H] - 805.6 / 807.4; UPLC-MS2

[2057] Step 2:(7R,9R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro-3-hydroxypyridine-1-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2058] (7R,9R)-6-(4-(3-(Benzyloxy)-4-fluoropyridine-1-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (210 mg, 245 μmol) in TFA (2.00 mL, 26.0 mmol) was stirred at 50 °C for 14 h. The RM was diluted with DCM and aq NaHCO 3 and extracted twice with DCM, and the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 20% to 75% B in 20 min) to give the title compound as a white solid (96.0 mg, 100% pure, yield: 55%).

[2059] The sodium salt was prepared analogously to the general procedure.

[2060] LC-MS: Rt = 1.02 min; MS m / z [M+H] + 717.5 / 719.5, m / z [M-H] - 715.3 / 717.3; UPLC-MS1

[2061] LC-MS: Rt = 5.04 min; MS m / z [M+H] + 717.5 / 719.5, m / z [M-H] - 715.3 / 717.3; UPLC-MS2

[2062] The stereochemistry of Example 6A was assigned as (7R,9R) based on its potency and understanding of the structure-activity relationship.

[2063] Example 6B:(7S,9S)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro-3-hydroxypyridine-1-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2064]

[2065] Step 1: (7S,9S)-6-(4-(3-(Benzyloxy)-4-fluoropyridine-1-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2066] At room temperature, DIPEA (227 μL, 1.30 mmol) was added to a stirred solution of (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H3) (150 mg, 260 μmol), 3-(benzyloxy)-4-fluoropicolinic acid (Intermediate W) (64.2 mg, 260 μmol), and HATU (118 mg, 311 μmol) in DMF (2 mL), and the reaction mixture (RM) was stirred at room temperature for 10 minutes. The RM was diluted with EtOAc and water, extracted twice with EtOAc, and the combined organic layers were dried over Na 2 SO 4 dried and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica gel 12 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 50:50). The fractions containing the product were combined, concentrated under reduced pressure, and dried under high vacuum to give the title compound (159 mg, 92% pure, yield: 70%).

[2067] LC-MS: Rt = 1.22 min; MS m / z [M+H] + 807.5 / 809.5, m / z [M-H] - 805.4 / 807.4; UPLC-MS1

[2068] LC-MS: Rt = 6.09 min; MS m / z [M+H] +807.5 / 809.5, m / z [M-H] - 805.4 / 807.4; UPLC-MS2

[2069] Step 2: (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro-3-hydroxypyridinecarbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2070] (7S,9S)-6-(4-(3-(benzyloxy)-4-fluoropyridinecarbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (159 mg, 181 μmol) in TFA (2.00 mL, 26.0 mmol) was stirred at 50 °C for 14 h. The RM was diluted with DCM and aq NaHCO 3 diluted, extracted twice with DCM, and the combined organic layers were dried over Na 2 SO 4 dried and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 20% to 75% B in 20 min) to give the title compound as a white solid (77.0 mg, 98% pure, yield: 58%).

[2071] The sodium salt was prepared analogously to the general procedure.

[2072] LC-MS: Rt = 1.02 min; MS m / z [M+H] + 716.9 / 718.9, m / z [M-H] - 715.3 / 717.4; UPLC-MS1

[2073] LC-MS: Rt = 5.06 min; MS m / z [M+H] + 716.9 / 718.8, m / z [M-H] - 715.4 / 717.3; UPLC-MS2

[2074] Example 7:(7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-6-(4-(1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carbonyl)piperazin-1-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2075]

[2076] At room temperature, under argon, 1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid (20.9 mg, 138 μmol) was suspended in DCM (1.4 mL). 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (21.9 mg, 152 μmol) was added and the RM was stirred at room temperature for 1.75 h. (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H4) (40.0 mg, 69.0 μmol) was added, then DIPEA (61.0 μL, 346 μmol) was added, and the resulting brown solution was stirred at room temperature for 1 h. Water (3 mL) and aq sat NaHCO 3 (2 mL) were added and the RM was kept at room temperature overnight. The RM was extracted with DCM (4 x 20 mL), and the combined organic layers were washed with water (5 mL), dried over a phase separator, and concentrated under reduced pressure to give an orange solid (66.0 mg). The crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 15% to 85% B in 20 min). The fractions containing the product were combined, ACN was removed under reduced pressure, and the aqueous residue was basified with aq sat NaHCO 3 and extracted with DCM (4 x 20 mL). The combined organic layers were dried over a phase separator and concentrated under reduced pressure to give the title compound as a white solid (35.8 mg, 99% pure, yield: 73%).

[2077] The sodium salt was prepared analogously to the general procedure.

[2078] LC-MS: Rt = 0.99 min; MS m / z [M+H] + 703.6 / 705.6, m / z [M-H] - 701.3 / 703.3; UPLC-MS1

[2079] LC-MS: Rt = 4.89 min; MS m / z [M+H] + 703.1 / 705.1, m / z [M-H] - 701.3 / 703.3; UPLC-MS2

[2080] Example 8: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro-3-hydroxy-6-methylpyridinecarbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2081]

[2082] Step 1: (7R,9R)-6-(4-(3-(benzyloxy)-4-fluoro-6-methylpyridinecarbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2083] At room temperature, DIPEA (234 μL, 1.34 mmol) was added to a stirred solution of (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H4) (155 mg, 268 μmol), 3-(benzyloxy)-4-fluoro-6-methylpyridinecarboxylic acid (Intermediate V) (80.0 mg, 268 μmol) and HATU (122 mg, 322 μmol) in DMF (2 mL), and the reaction mixture (RM) was stirred at room temperature for 5 minutes. The RM was diluted with EtOAc and water, extracted twice with EtOAc, and the combined organic layers were dried over Na 2 SO 4 dried and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica 12 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 50:50). The fractions containing the product were combined, concentrated under reduced pressure and dried under HV to give the title compound as a white foam (220 mg, 92% pure, yield: 92%).

[2084] LC-MS: Rt = 1.28 min; MS m / z [M+H] + 821.6 / 823.6, m / z [M-H] - 819.5 / 821.4; UPLC-MS1

[2085] LC-MS: Rt = 6.43 min; MS m / z [M+H] + 821.5 / 823.6, m / z [M-H] - 819.6 / 821.6; UPLC-MS2

[2086] Step 2: (7R,9R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro-3-hydroxy-6-methylpyridine-1-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2087] (7R,9R)-6-(4-(3-(Benzyloxy)-4-fluoro-6-methylpyridine-1-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (220 mg, 246 μmol) in TFA (2.00 mL, 26.0 mmol) was stirred at 50 °C for 40 h. The RM was diluted with DCM and aq NaHCO 3 and extracted twice with DCM, and the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica 24 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 50:50). The fractions containing the product were combined, concentrated under reduced pressure and dried under HV to give the title compound as a white solid (150 mg, 100% pure, yield: 83%).

[2088] The sodium salt was prepared analogously to the general procedure.

[2089] LC-MS: Rt = 1.06 min; MS m / z [M+H] + 731.5 / 733.5, m / z [M-H] - 729.3 / 731.3; UPLC-MS1

[2090] LC-MS: Rt = 5.25 min; MS m / z [M+H] + 731.6 / 733.5, m / z [M-H] - 729.3 / 731.4; UPLC-MS2

[2091] Example 9: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(6-hydroxyimidazo[1,2-a]pyridine-5-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2092]

[2093] Step 1: (7R,9R)-6-(4-(6-(benzyloxy)imidazo[1,2-a]pyridine-5-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2094] At room temperature, under argon, (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H4) (71.1 mg, 123 μmol) and 6-(benzyloxy)imidazo[1,2-a]pyridine-5-carboxylic acid (Intermediate AA) (33.0 mg, 123 μmol) were mixed in DMF (1.5 mL). HATU (56.1 mg, 148 μmol) and DIPEA (107 μL, 615 μmol) were added and the reaction mixture (RM) was stirred at room temperature for 45 minutes. Then it was quenched with water (10 mL). The RM was extracted with EtOAc (3 x 50 mL), washed with water (3 x 10 mL) and brine (2 x 10 mL). The combined organic layers were dried over Na 2 SO 4 dried and concentrated under reduced pressure to give a brown oil (161 mg). The crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC1: 20% to 80% B in 20 min). The fractions containing the product were combined and washed with aq sat NaHCO 3Alkalinization, removal of ACN under reduced pressure and extraction of the aqueous residue with DCM (4 x 20 mL). The combined organic layers were dried over a phase separator and concentrated under reduced pressure to give the title compound as a light pink solid (63.0 mg, 99% pure, yield: 61%).

[2095] LC-MS: Rt = 1.04 min; MS m / z [M+H] + 828.3 / 830.4, m / z [M-H] - 826.3 / 828.3; UPLC-MS1

[2096] Step 2: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(6-hydroxyimidazo[1,2-a]pyridine-5-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2097] (7R,9R)-6-(4-(6-(Benzyloxy)imidazo[1,2-a]pyridine-5-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (61.5 mg, 74.0 μmol) was mixed with TFA (1.00 mL, 13.0 mmol) and the reaction mixture was stirred at 50 °C for 52.5 h and then at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and dried under high vacuum. The brown solid residue was extracted with DCM (4 x 50 mL) and washed with aq sat NaHCO 3 (15 mL) and brine (15 mL). The combined organic layers were dried over a phase separator and concentrated under reduced pressure to give a light brown solid (77.0 mg). The crude product was adsorbed onto Isolute and purified by column chromatography (RediSep column: silica 12 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 20:80). The fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a light beige solid (35.4 mg, 100% pure, yield: 65%).

[2098] The sodium salt was prepared analogously to the general procedure.

[2099] LC-MS: Rt = 0.88 min; MS m / z [M+H] +738.6 / 740.7, m / z [M-H] - 736.4 / 738.3; UPLC-MS1

[2100] LC-MS: Rt = 4.35 min; MS m / z [M+H] + 738.2 / 740.2, m / z [M-H] - 736.3 / 738.2; UPLC-MS2

[2101] Example 10: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(3-hydroxy-2-methylisonicotinoyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2102]

[2103] At room temperature, 3-hydroxy-2-methylisonicotinic acid (41.4 mg, 208 μmol) was dissolved in DCM (2 mL) under argon. 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (32.8 mg, 228 μmol) was added and the RM was stirred at room temperature for 2.25 h. (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H4) (60.0 mg, 104 μmol) and DIPEA (91.0 μL, 519 μmol) were added and the RM was stirred at room temperature for 4 days. The RM was quenched with water (2 mL) and aq sat NaHCO 3 (2 mL) and extracted with DCM (4 x 20 mL). The combined organic layers were washed with water (5 mL), dried over a phase separator and concentrated under reduced pressure to give a brown oil (126 mg). The crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 20% to 80% B in 20 min). The fractions containing the product were combined, basified with aq satNaHCO 3 The title compound as a white solid (37.0 mg, 100% pure, yield: 50%) was obtained by evaporating the ACN under reduced pressure and extracting the residue aqueous solution with DCM (4 x 20 mL). The combined organic layers were washed with water, dried over a phase separator and concentrated under reduced pressure.

[2104] The sodium salt was prepared analogously to the general procedure.

[2105] LC-MS: Rt = 0.95 min; MS m / z [M+H] + 713.5 / 715.5, m / z [M-H] - 711.2 / 713.2; UPLC-MS1

[2106] Example 11: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(3-hydroxypyridine-1-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2107]

[2108] At 0 °C and under argon, (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H4) (79.0 mg, 137 μmol) was dissolved in DCM (1.4 mL). 3-Hydroxypyridine-1-carbonyl chloride (Intermediate X) (36.6 mg, 232 μmol) was added, followed by slow addition of DIPEA (120 μL, 683 μmol). The reaction mixture was stirred at room temperature for 1.75 h, 3-Hydroxypyridine-1-carbonyl chloride (Intermediate X) (15.0 mg, 95.0 μmol) was added again, and the reaction mixture was stirred at room temperature for 4.5 h. The reaction mixture was quenched with water (3 mL) and aq sat NaHCO 3 (3 mL) and extracted with DCM (4 x 15 mL). The combined organic layers were dried over a phase separator and concentrated under reduced pressure to give a brown solid (117 mg). The crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 10% to 70% B in 20 min). The fractions containing the product were combined, basified with aq sat NaHCO 3 and ACN was removed under reduced pressure. The aqueous residue was extracted with DCM (4 x 15 mL). The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over a phase separator and concentrated under reduced pressure to give the title compound as a beige solid (57.0 mg, 100% pure, yield: 60%).

[2109] The sodium salt was prepared analogously to the general procedure.

[2110] LC-MS: Rt = 1.01 min; MS m / z [M+H] + 699.5 / 701.3, m / z [M-H] - 697.1 / 699.1; UPLC-MS1

[2111] LC-MS: Rt = 5.08 min; MS m / z [M+H] + 699.2 / 701.2, m / z [M-H] - 697.2 / 699.2; UPLC-MS2

[2112] Example 12: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(2-fluoro-3-hydroxyisonicotinoyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2113]

[2114] At room temperature, 2-fluoro-3-hydroxyisonicotinic acid (54.4 mg, 346 μmol) was dissolved in DCM (3.5 mL) under argon. 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (54.4 mg, 346 μmol) was added and the reaction mixture (RM) was stirred at room temperature for 2.25 h. (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H4) (100 mg, 173 μmol) was added, then DIPEA (151 μL, 865 μmol). The RM was stirred at room temperature for 50 min. The RM was quenched with water (3 mL) and aq sat NaHCO 3 (3 mL) and extracted with DCM (4 x 20 mL). The combined organic layers were dried over a phase separator and concentrated under reduced pressure to give a brown oil (174 mg). The crude product was purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 15% to 85% B in 20 min). The fractions containing the product were combined and washed with aq sat NaHCO 3Alkalinization, removal of ACN under reduced pressure and extraction of the residual aqueous solution with DCM (4 x 50 mL). The combined organic layers were washed with water, dried through a phase separator and concentrated under reduced pressure to afford the title compound as a white solid (59.4 mg, 100% pure, yield: 48%).

[2115] The sodium salt was prepared analogously to the general procedure.

[2116] LC-MS: Rt = 1.01 min; MS m / z [M+H] + 717.2 / 719.2, m / z [M-H] - 715.3 / 717.3; UPLC-MS1

[2117] Example 13: (7R,9R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxypyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2118]

[2119] Step 1: (7R,9R)-6-(4-(5-(Benzyloxy)pyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2120] At room temperature, under argon, (7R,9R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H4) (113 mg, 196 μmol) and 5-(benzyloxy)pyrimidine-4-carboxylic acid (47.3 mg, 205 μmol) were mixed in DMF (2.7 mL). HATU (92.0 mg, 235 μmol) was added, followed by DIPEA (171 μL, 978 μmol). The reaction mixture was stirred at room temperature for 1.75 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with water (2 x 25 mL) and brine (2 x 20 mL), dried through a phase separator with Na 2SO 4 Dry and concentrate under reduced pressure to obtain a bright brown solid (182 mg). Purify the crude product by reverse-phase preparative HPLC (acidic RP-HPLC 1: 20% to 80% B in 20 min). Combine the fractions containing the product and lyophilize to obtain the title compound as a white solid (64.0 mg, 94% pure, yield: 39%).

[2121] LC-MS: Rt = 1.13 min; MS m / z [M+H] + 790.5 / 792.5, m / z [M-H] - 788.4 / 790.4; UPLC-MS1

[2122] Step 2: (7R,9R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxypyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2123] Dissolve (7R,9R)-6-(4-(5-(Benzyloxy)pyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (64.4 mg, 81.0 μmol) in TFA (1.90 mL, 24.5 mmol) and stir the RM at 50 °C for 70 h. Concentrate the RM under reduced pressure, redissolve in DCM and concentrate again, then dry under HV to obtain a bright brown oil (61.5 mg). Adsorb the crude product onto Isolute and purify by column chromatography (RediSep column: silica 12 g gold, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 20:80), then further purify by SFC (SFC 1). Combine the fractions containing the product and concentrate under reduced pressure to obtain the title compound as a beige solid (28.4 mg, 100% pure, yield: 50%).

[2124] Prepare the sodium salt analogously to the general procedure.

[2125] LC-MS: Rt = 0.97 min; MS m / z [M+H] + 700.4 / 702.3, m / z [M-H] - 698.3 / 700.3; UPLC-MS1

[2126] LC-MS: Rt = 4.91 min; MS m / z [M+H] + 700.3 / 702.2, m / z [M-H] - 698.2 / 700.2; UPLC-MS2

[2127] Example 14A: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2128]

[2129] Step 1: (7R,9R)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2130] At room temperature, DIPEA (234 μL, 1.34 mmol) was added to a stirred solution of (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H4) (155 mg, 268 μmol), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (Intermediate U) (65.5 mg, 268 μmol) and HATU (122 mg, 322 μmol) in DMF (2 mL), and the reaction mixture (RM) was stirred at room temperature for 10 minutes. The RM was diluted with EtOAc and water, extracted twice with EtOAc, and the combined organic layers were dried over Na 2 SO 4 dried and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica gel 24 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 50:50). The fractions containing the product were combined, concentrated under reduced pressure and dried under HV to give the title compound (211 mg, 91% pure, yield: 89%).

[2131] LC-MS: Rt = 1.20 min; MS m / z [M+H] + 804.5 / 806.5, m / z [M-H] - 802.5 / 804.5; UPLC-MS1

[2132] LC-MS: Rt = 5.98 min; MS m / z [M+H] + 804.5 / 806.5, m / z [M-H] - 802.5 / 804.5; UPLC-MS2

[2133] Step 2: (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2134] (7R,9R)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (211 mg, 239 μmol) in TFA (2 mL) was stirred at 50 °C for 14 h. The RM was concentrated under reduced pressure. The RM was diluted with DCM and aq NaHCO 3 and extracted twice with DCM, and the combined organic layers were washed with water and brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica 24 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 50:50) to afford a white solid (97.0 mg), which was further purified by reverse-phase preparative HPLC (acidic RP-HPLC 1: 5% to 95% B in 20 min). The fractions containing the product were combined, basified with aq sat NaHCO 3 and concentrated under reduced pressure to give the title compound as a white solid (107 mg, 100% pure, yield: 63%).

[2135] The sodium salt was prepared analogously to the general procedure.

[2136] LC-MS: Rt = 1.06 min; MS m / z [M+H] + 714.3 / 716.3, m / z [M-H] - 712.3 / 714.3; UPLC-MS1

[2137] LC-MS: Rt = 5.23 min; MS m / z [M+H] + 714.4 / 716.4, m / z [M-H] - 712.4 / 714.4; UPLC-MS2

[2138] 1H NMR (400 MHz, DMSO-d6) δ 10.54 - 10.40 (m, 2H), 8.56 (s, 1H), 8.03 - 7.86 (m, 2H), 7.74 (dd, J = 8.8, 2.1 Hz, 1H), 6.89 - 6.73 (m, 1H), 5.53 (dd, J = 10.4, 2.3 Hz, 1H), 4.27 - 4.21 (m, 2H), 3.86 - 3.66 (m, 3H), 3.62 - 3.07 (m, 8H), 3.03 - 2.96 (m, 2H), 2.53 - 2.47 (m, 2H) 2.44 (s, 3H), 2.16 - 2.08 (m, 1H), 1.41 (d, J = 7.3 Hz, 3H).

[2139] The stereochemistry of Example 14A was determined by single crystal X-ray diffraction and WRN co-crystal X-ray diffraction. By extension, Intermediate H4 was also assigned as (7R,9R).

[2140] Example 14B: (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2141]

[2142] Step 1: (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2143] At room temperature, DIPEA (242 μL, 1.38 mmol) was added to a stirred solution of (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H3) (160 mg, 277 μmol), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (Intermediate U) (67.6 mg, 277 μmol) and HATU (126 mg, 332 μmol) in DMF (2 mL), and the RM was stirred at room temperature for 10 minutes. The RM was diluted with EtOAc and water, extracted twice with EtOAc, and the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica 24 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 50:50). The fractions containing the product were combined, concentrated under reduced pressure and dried under HV to give the title compound as a white foam (135 mg, 100% pure, yield: 61%).

[2144] LC-MS: Rt = 1.21 min; MS m / z [M+H] + 804.5 / 806.5, m / z [M-H] - 802.5 / 804.5; UPLC-MS1

[2145] LC-MS: Rt = 5.92 min; MS m / z [M+H] + 804.5 / 806.5, m / z [M-H] - 802.5 / 804.6; UPLC-MS2

[2146] Step 2: (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2147] (7S,9S)-6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (130 mg, 162 μmol) in TFA (2 mL) was stirred at 50 °C for 4 h. The RM was concentrated under reduced pressure. The RM was diluted with DCM and aq NaHCO 3 and extracted twice with DCM, and the combined organic layers were washed with water and brine, and dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica 12 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 50:50). The fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a white solid (97.0 mg, 100% pure, yield: 84%).

[2148] The sodium salt was prepared analogously to the general procedure.

[2149] LC-MS: Rt = 1.06 min; MS m / z [M+H] + 714.3 / 716.3, m / z [M-H] - 712.3 / 714.3; UPLC-MS1

[2150] LC-MS: Rt = 5.17 min; MS m / z [M+H] + 714.4 / 716.4, m / z [M-H] - 712.4 / 714.4; UPLC-MS2

[2151] Example 14C: (7S,9R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2152]

[2153] Step 1:(7S,9R)-6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2154] At room temperature, DIPEA (673 μL, 3.85 mmol) was added to a stirred solution of (7S,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H2) (495 mg, 771 μmol), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (Intermediate U) (188 mg, 771 μmol), and HATU (352 mg, 925 μmol) in DMF (6 mL), and the reaction mixture (RM) was stirred at room temperature for 5 minutes. The RM was diluted with EtOAc and water, extracted twice with EtOAc, and the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica 40 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 75:25). The fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a white foam (618 mg, 88% pure, yield: 88%).

[2155] LC-MS: Rt = 1.17 min; MS m / z [M+H] + 804.3 / 806.3, m / z [M-H] - 802.3 / 804.3; UPLC-MS1

[2156] Step 2: (7S,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2157] (7S,9R)-6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (618 mg, 676 μmol) in TFA (6.00 mL, 78.0 mmol) was stirred at room temperature for 72 h. The RM was diluted with DCM and aq NaHCO 3 and extracted twice with DCM, and the combined organic layers were washed with brine and dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica 40 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 50:50) to afford a yellow solid, which was purified in two parts by reverse-phase preparative HPLC (acidic RP-HPLC 1: 15% to 80% B in 20 min), (acidic RP-HPLC 1: 15% to 80% B in 20 min). The fractions containing the product were combined, basified with aq sat NaHCO 3 and ACN was removed under reduced pressure and the resulting aqueous residue was extracted twice with DCM. The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to afford the title compound as a white solid (295 mg, 99% pure, yield: 61%).

[2158] LC-MS: Rt = 1.02 min; MS m / z [M+H] + 714.1 / 716.1, m / z [M-H] - 712.3 / 714.3; UPLC-MS1

[2159] LC-MS: Rt = 5.01 min; MS m / z [M+H] + 714.1 / 716.1, m / z [M-H] - 712.3 / 714.3; UPLC-MS2

[2160] The stereochemistry of Example 14C was assigned as (7S,9R) due to its SAR-based potency being higher than 14D and structural understanding.

[2161] Example 14D:(7R,9S)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2162]

[2163] Step 1: (7R,9S)-6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2164] At room temperature, DIPEA (704 μL, 4.03 μmol) was added to a stirred solution of (7R,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate H1) (466 mg, 806 μmol), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (Intermediate U) (197 mg, 806 μmol) and HATU (368 mg, 967 μmol) in DMF (5 mL), and the reaction mixture (RM) was stirred at room temperature for 5 minutes. The RM was diluted with EtOAc and water, extracted twice with EtOAc, and the combined organic layers were dried over Na 2 SO 4 2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica gel 40 g, eluent: DCM:DCM / MeOH (8 / 2) from 100:0 to 50:50). The fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a white foam (618 mg, 90% pure, yield: 86%).

[2165] LC-MS: Rt = 1.17 min; MS m / z [M+H] + 804.4 / 806.4, m / z [M-H] - 802.3 / 804.3; UPLC-MS1

[2166] Step 2:(7R,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2167] (7R,9S)-6-(4-(5-(Benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (618 mg, 692 μmol) in TFA (6.00 mL, 78.0 mmol) was stirred at 50 °C for 14 h. The RM was diluted with DCM and aq NaHCO 3 and extracted twice with DCM, and the combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography (RediSep column: silica 40 g, eluent: DCM:DCM / MeOH (8 / 2) 100:0 to 50:50) to afford a yellow solid, which was purified in 2 parts by reverse phase preparative HPLC (acidic RP-HPLC 1: 15% to 80% B in 20 min). The fractions containing the product were combined, basified with aq satNaHCO 3 , ACN was removed under reduced pressure and the resulting aqueous residue was extracted twice with DCM. The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to give the title compound as a white solid (283 mg, 96% pure, yield: 55%).

[2168] LC-MS: Rt = 1.02 min; MS m / z [M+H] + 714.3 / 716.3, m / z [M-H] - 712.3 / 714.3; UPLC-MS1

[2169] LC-MS: Rt = 5.05 min; MS m / z [M+H] + 714.2 / 716.2, m / z [M-H] -

[2170] 712.2 / 714.2; UPLC-MS2

[2171] Example 15A: (7R,9R)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(3-hydroxypyridine-1-carbonyl)piperazin-1-yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2172]

[2173] At room temperature, to a colorless solution of (7R,9R)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate K4) (25.0 mg, 40.0 μmol) in DCM (2 mL) was added DIPEA (35.0 μL, 198 μmol), and then 3-hydroxypyridine-1-carbonyl chloride (Intermediate X) (9.37 mg, 59.0 μmol) was added. The RM was stirred at room temperature for 3.5 h. The RM was extracted with water (10 mL) and TBME (10 mL). The organic layer was washed with water (15 mL) and brine (15 mL). The aqueous layer was washed with TBME (2 x 15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure at 45 °C to give a brown solid (49.5 mg). 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 and the ACN was removed under reduced pressure. The aqueous residue was basified with aqsat NaHCO 3 and extracted with DCM (3 x 15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure to give the title compound as a white solid (17.0 mg, 98% pure, yield: 62%).

[2174] The sodium salt was prepared analogously to the general procedure.

[2175] LC-MS: Rt = 1.00 min; MS m / z [M+H] + 679.5, m / z [M-H] - 677.5; UPLC-MS1

[2176] LC-MS: Rt = 4.78 min; MS m / z [M+H]+ 679.6, m / z [M-H] - 677.5; UPLC-MS2

[2177] The stereochemistry of Example 15A was determined by single crystal X-ray diffraction and WRN co-crystal X-ray diffraction. By extension, Intermediate K4 was also assigned as (7R,9R).

[2178] Example 15B: (7S,9S)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(3-hydroxypyridinecarbonyl)piperazin-1-yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2179]

[2180] At room temperature, DIPEA (32.0 μL, 182 μmol) was added to a colorless solution of (7S,9S)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate K3) (23.0 mg, 36.0 μmol) in DCM (2 mL), and then 3-hydroxypyridinecarbonyl chloride (Intermediate X) (8.62 mg, 55.0 μmol) was added. The RM was stirred at room temperature for 3.5 h. The RM was extracted with water (10 mL) and TBME (10 mL). The organic layer was washed with water (15 mL) and brine (15 mL). The aqueous layer was washed with TBME (2 x 15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure at 45 °C to give a light brown solid (30.1 mg). 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 and the ACN was removed under reduced pressure. The aqueous residue was basified with aqsat NaHCO 3 and extracted with DCM (3 x 15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure to give the title compound as a white solid (9.50 mg, 87% pure, yield: 33%).

[2181] LC-MS: Rt = 1.00 min; MS m / z [M+H] + 679.6, m / z [M-H] - 677.5; UPLC-MS1

[2182] LC-MS: Rt = 4.79 min; MS m / z [M+H] + 679.6, m / z [M-H] - 677.5; UPLC-MS2

[2183] Example 15C: (7S,9R)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(3-hydroxypyridine-1-carbonyl)piperazin-1-yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2184]

[2185] At room temperature, to a colorless solution of (7S,9R)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate K1) (24.0 mg, 40.0 μmol) in DCM (50 mL) was added DIPEA (35.0 μL, 202 μmol), and then 3-hydroxypyridine-1-carbonyl chloride (Intermediate X) (9.55 mg, 61.0 μmol) was added. The RM was stirred at room temperature for 3.5 h. The RM was extracted with water (10 mL) and TBME (10 mL). The organic layer was washed with water (15 mL) and brine (15 mL). The aqueous layer was washed with TBME (2 x 15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure at 45 °C to give a brown solid (33.0 mg). The crude product was purified by column chromatography (RediSep column: silica 24 g, eluent: DCM:DCM / MeOH (9 / 1) 100:0 to 20:80). The fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a light brown solid (14.7 mg, 95% pure, yield: 51%).

[2186] LC-MS: Rt = 0.97 min; MS m / z [M+H] + 679.6, m / z [M-H]- 677.5; UPLC-MS1

[2187] LC-MS: Rt = 6.56 min; MS m / z [M+H] + 679.6, m / z [M-H] - 677.6; UPLC-MS2

[2188] The stereochemistry of Example 15C was assigned as (7S,9R) due to its potency and understanding of the structure-activity relationship.

[2189] Example 15D: (7R,9S)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(3-hydroxypyridinecarbonyl)piperazin-1-yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2190]

[2191] At room temperature, to a colorless solution of (7R,9S)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate K2) (24.0 mg, 40.0 μmol) in DCM (5 mL) was added DIPEA (35.0 mL, 202 μmol), and then 3-hydroxypyridinecarbonyl chloride (Intermediate X) (9.55 mg, 61.0 μmol) was added. The RM was stirred at room temperature for 3.5 hours. The RM was extracted with water (10 mL) and TBME (10 mL). The organic layer was washed with water (15 mL) and brine (15 mL). The aqueous layer was washed with TBME (2 x 15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure at 45 °C to give a brown solid (36.0 mg). The crude product was purified by column chromatography (RediSep column: silica 24 g, eluent: DCM:DCM / MeOH (9 / 1) 100:0 to 20:80). The fractions containing the product were combined and concentrated under reduced pressure to give the title compound as a light brown solid (13.5 mg, 96% pure, yield: 47%).

[2192] LC-MS: Rt = 0.97 min; MS m / z [M+H] +679.6, m / z [M-H] - 677.5; UPLC-MS1

[2193] LC-MS: Rt = 4.65 min; MS m / z [M+H] + 679.6, m / z [M-H] - 677.5; UPLC-MS2

[2194] Example 16: (7R,9R)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(4-(4-fluoro-3-hydroxypyridinecarbonyl)piperazin-1-yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2195]

[2196] Step 1: (7R,9R)-6-(4-(3-(benzyloxy)-4-fluoropyridinecarbonyl)piperazin-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[2197] At room temperature, to a stirred solution of (7R,9R)-2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-N-(2-methyl-4-(trifluoromethyl)phenyl)-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide (Intermediate K4) (175 mg, 311 μmol), 3-(benzyloxy)-4-fluoropicolinic acid (Intermediate W) (81.0 mg, 326 μmol), and HATU (142 mg, 373 μmol) in DMF (2 mL) was added DIPEA (313 μL, 1.79 mmol), and the RM was stirred at room temperature for 10 minutes. The RM was diluted with EtOAc and water, extracted twice with EtOAc, an...

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: A is a linker selected from -C(O)-, -S(O)-, -S(O) 2 -, and ; Y is N, C, or CH; 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 by 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, J is C, and A is a linker selected from -C(O)-, -S(O)-, -S(O) 2 -, and ; Or When K is a single bond, K is selected from -CH 2 -, -CH 2 CH 2 -, -NH- and a bond (to form a 5-membered ring: ), J is N, and A is a linker selected from -C(O)-, -S(O)-, -S(O) 2 - and ; Or When K is a single bond, K is -CH 2 -, J is CH, and A is a linker selected from -S(O)-, -S(O) 2 -, and ; y is 0, 1, 2, 3, or 4; R 5 independently selected from: ·-(C 1- C 4 )alkyl ·-(C 3- C 5 ) cycloalkyl group, · And two Rs on the same ring carbon atom 5 substituents together with the carbon atom to which they are attached can be joined to form a (C 3- C 4 ) 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 R 5 substituents on K and on the adjacent carbon atoms can be connected to form ring C: wherein ring C is a fused (C 3 -C 6 ) cycloalkyl ring, a fused (C 3 -C 6 ) heterocyclic ring or a fused benzene ring, wherein the fused (C 3 -C 6 ) heterocyclic ring contains ring carbon atoms and a ring heteroatom selected from O, N, and S, and wherein when ring C is a fused (C 3 -C 6 ) cycloalkyl ring, said fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted with 1 or 2 R 40 groups, wherein said R 40 is selected from: ·(C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) alkyl is independently unsubstituted or substituted by OH or one, two or three halogens, · Halo, especially F, · 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- C 4 ) cycloalkyl spiro ring or a 3- or 4-membered heterocyclic spiro ring, where 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 The substituents are joined to the carbon atoms to which they are attached to form a fused cyclopropyl ring; · When K is a carbon-carbon single bond, Y is N and Y is a single bond, and A is a linker selected from -S(O)-, -S(O) 2 -, and The R substituents on K and on the adjacent carbon atoms 5 can be linked to form ring C: wherein ring C is a fused (C 3 -C 6 ) cycloalkyl ring, a fused (C 3 -C 6 ) heterocyclic ring or a fused benzene ring, wherein the fused (C 3 -C 6 ) heterocyclic ring contains ring carbon atoms and a ring heteroatom selected from O, N and S, and wherein when ring C is a fused (C 3 -C 6 ) cycloalkyl ring, said fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted with 1 or 2 R 40 groups, wherein said R 40 is selected from: ·(C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) 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 Substituents together with the carbon atoms to which they are attached may be joined to form a (C 3- C 4 ) 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 -CH 2 - and J is N, two R 5 substituents may be joined to form a (C 1 -C 3 ) alkylene bridge or heteroalkylene bridge, wherein said heteroalkylene bridge is a heteroatom selected from N and O or is -CH 2 -O-CH 2 -; R 1 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, 2, 3 or 4, preferably 1 or 2, R 33 substituents, where R 33 is halo, and wherein the cycloalkenyl group or the halo-substituted cycloalkenyl group is substituted by 0, 1 or 2 R 15 substituents or R 1 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, preferably 1 or 2, R 33 substituents, wherein 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 substituents, Or the heterocyclic group or halo-substituted heterocyclic group is fused to a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted or substituted with 1, 2, or 3 F atoms, Or the heterocyclic group or halo-substituted heterocyclic group has 2 substituents at the same ring carbon atom, which are connected to form a cyclopropyl spiro ring, or the heterocyclic group or halogen-substituted heterocyclic group is fused with a (C 3 -C 5 ) heterocycloalkyl ring, wherein the (C 3 -C 5 ) heterocycloalkyl ring contains ring carbon atoms and one ring O atom; or R 1 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 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 (C 1 -C 4 )alkyl, wherein said (C 1 -C 4 )alkyl is unsubstituted or substituted with 1, 2 or 3 halo substituents or R 1 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, 1 or 2 R 15 substituents or R 1 is (C 2 -C 4 ) alkynyl or (C 2 -C 4 ) alkenyl, wherein the (C 2 -C 4 ) alkynyl and (C 2 -C 4 ) alkenyl are unsubstituted or substituted with (C 1 -C 4 ) 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 · (C 1- C 4 ) alkyl - O - that is unsubstituted or substituted by 1, 2, or 3 halogen atoms; · Unsubstituted or substituted by OH, -O-(C 1 -C 2 ) alkyl or (C 1 -C 4 ) alkyl substituted by 1, 2 or 3 halogens, ·HOC(O)-(CH 2 ) n -, ·H 3 C-C(O)(CH 2 ) n -, ·(C 1 -C 4 )alkyl - O - C(O)(CH 2 ) n , ·＝O · Azetidinyl or pyrrolidinyl, wherein the azetidinyl and pyrrolidinyl are connected to the rest of the molecule via an N atom and are each unsubstituted or substituted with 1 or 2 F atoms, ·R 25 (R 24 )N−, wherein R 24 is H or an unsubstituted or halo-substituted by 1, 2 or 3 (C 1 -C 4 ) alkyl group, R 25 is H or an unsubstituted or halo-substituted by 1, 2 or 3 (C 1 -C 4 ) alkyl group, · OH Where n is 0, 1, or 2, R 2 is the following part: R 6 Selected from: ·H， · Halo, · (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogens, · A (C 3 -C 5 ) cycloalkyl group that is unsubstituted or substituted with 1, 2, or 3 halogen atoms · -O-(C, unsubstituted or substituted by 1, 2 or 3 halogens 1 -C 4 )alkyl · OH, and · CN; R 8 selected from H, halogen, and (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms R 9 selected from H, O-CH 3 , OH, CN, CH 3 and halogenated; R 28 Selected from: ·SF 5 , ·H， · -C(O)H, · Halo, · (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, ·(C 1 -C 4 ) alkynyl group, ·(C 1 -C 4 ) alkenyl, · (C 3 -C 5 ) cycloalkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, and ·OCF 3 ; X is selected from C-R 7 and N, where R 7 is H or halo, or R 7 may together with R 28 or R 6 and the atoms to which they are attached form a fused (C 4 -C 6 ) cycloalkyl ring, wherein the fused (C 4 -C 6 ) cycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 halos, Or R 2 Selected from: Wherein R 31 selected from H, halogen, and CH 3 , R 32 selected from H, halogenated, and CH 3 , R 3 Selected from: · Halo, and · (C 1 -C 4 ) alkyl which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo and OH, · Or two Rs on the same ring carbon atom 3 substituents may together with the carbon atom to which they are attached form a cyclopropyl ring; x is 0, 1, or 2; R 4 Selected from: -(C 1 -C 4 ) alkyl; - Heteroaryl 1, wherein the heteroaryl 1 is a 5- or 6-membered fully unsaturated monocyclic ring containing ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S; - Heteroaryl 2, wherein the 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 the heteroatoms can be in one or both rings; - Phenyl; 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 , where R 10 , R 11 , R 12 , R 13 , and R 14 are each independently selected from: ·H， · Halo, · (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen substituents, · Substituted by -O-(C 1 -C 2 ) alkyl or OH-substituted (C 1 -C 2 ) alkyl, ·-S-(C 1 -C 3 )alkyl · -O-(C, unsubstituted or substituted by 1, 2 or 3 halogen substituents 1 -C 4 )alkyl · OH, ·(C 3 -C 5 ) cycloalkyl, wherein the (C 3 -C 5 ) cycloalkyl is unsubstituted or substituted by 1 or 2 halogens, ·-O-(C 3 -C 5 ) cycloalkyl group, ·-NR 34 R 35 , wherein R 34 and R 35 are independently selected from: o H, o(C 1 -C 4 ) alkyl, wherein the (C 1 -C 4 ) alkyl is unsubstituted or substituted with OH or -O(C 1 -C 2 ) 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, pyrrolidinyl or piperidine ring, wherein said azetidine, pyrrolidinyl and piperidine are unsubstituted or substituted by CH 3 substituted; · CN, ·-(C 2 -C 4 ) alkenyl, ·-(C 2 -C 4 ) alkynyl group, ·＝O · -C(O)H, and ·-C(O)(C 1 -C 4 )alkyl; And * indicates the point of attachment.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is formula 1a:

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 or claim 2, wherein R 1 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 or 2 R 33 substituents, where R 33 is halo, preferably F, and wherein the cycloalkenyl or halo-substituted cycloalkenyl is substituted by 0 or 1 R 15 substituent, preferably 1 substituent, where R 15 is selected from: a) (C 1- C 2 ) alkyl - O -; unsubstituted or substituted by 1, 2 or 3 halogen atoms b) (C 1 -C 2 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, c) HOC(O)-(CH 2 ) n -, d)H 3 C-C(O)(CH 2 ) n -, e)H 3 C-O-C(O)(CH 2 ) n , f) = O, and g) R 25 (R 24 )N-, H, where R 24 is H or (C 1 -C 2 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, R 25 is H or (C 1 -C 2 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, n is 0 or 1, Wherein · 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, where 1 R 15 substituent is in the ring para position relative to the remainder of the molecule; and · The cycloalkenyl or halo-substituted cycloalkenyl is bonded via a double bond to an adjacent R 1 R of the ring carbon atom 1 The ring carbon atom is connected to the remainder of the compound; or R 1 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 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 with 0 or 1 substituent independently selected from R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 and wherein the R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 and R 23 are independently selected from: a) (C 1- C 4 ) alkyl-O-; unsubstituted or substituted by 1, 2 or 3 halogen atoms b) unsubstituted or substituted by OH, -O-(C 1 -C 2 )alkyl or (C 1 -C 4 )alkyl substituted by 1, 2 or 3 halogens, c) HOC(O)-(CH 2 ) n -, d)H 3 C-C(O)(CH 2 ) n -, e)H 3 C-O-C(O)(CH 2 ) n , f) = O g) R 25 (R 24 )N−, wherein R 24 is H, unsubstituted or (C 1 -C 2 ) alkyl substituted by 1, 2 or 3 halogens, R 25 is H, unsubstituted or (C 1 -C 2 ) alkyl substituted by 1, 2 or 3 halogens, h) OH Where n is 0 or 1, And Wherein: · 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 atom 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 meta or para, preferably para, relative to the rest of the molecule; and · The heterocyclic group is attached via R 1 to a ring nitrogen atom or a double-bonded R to an adjacent ring atom 1 and the ring carbon atom is linked to the remainder of the compound; or R 1 is a heteroaryl group, wherein the heteroaryl group is a 5- or 6-membered fully unsaturated monocyclic radical comprising 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, wherein the heteroaryl group is unsubstituted or replaced by 1 or 2 ring heteroatoms independently selected from R 21 and R 30 Substituents, where R 21 and R 30 Independently selected from (C 1 -C 2 ) alkyl, and said (C 1 -C 2 ) alkyl is unsubstituted or substituted with 1, 2 or 3 halo, and wherein preferably said alkyl or haloalkyl substituent is not present in the R group that is attached to the rest of the molecule 1 The adjacent R 1 The alkyl or haloalkyl substituent is located on a ring atom and, more preferably, when the heteroaryl group is a 6-membered ring, is located in the para position of the ring relative to the rest of the molecule.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1, 2 or 3, wherein R 1 is selected from: R 33 is F; R 15 is halogenated, 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; R 16 is R 25 (R 24 )N-, where R 24 is H or (C 1 -C 2 )alkyl, and R 25 is H or (C 1 -C 2 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, especially F; R 17 is halogenated; R 18 is halogenated; R 19 is halogenated; R 20 is halogenated; R 21 is (C 1 -C 2 ) alkyl; R 22 and R 23 each independently selected from: · (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms, ·HOC(O)-(CH 2 ) n -, ·H 3 C-C(O)(CH 2 ) n -, ·(H 3 C) 3 C-O-C(O)(CH 2 ) n -; · Where n is 0, 1, or 2; And R 30 is CH 3 .

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, wherein R 1 is selected from:

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5, wherein R 1 is selected from:

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 2 is the following moiety: Wherein R 6 selected from H, halogen, unsubstituted or substituted by 1, 2 or 3 halogens of (C 1 -C 4 ) alkyl; R 8 Selected from H, halogen, unsubstituted or substituted by 1, 2 or 3 halogens of (C 1 -C 4 ) alkyl; R 9 selected from H, O-CH 3 , OH, CN, CH 3 and halogenated; R 28 selected from SF 5 , halogenated, C(O)H, and (C 1 -C 4 )alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen atoms; X is selected from C-R 7 and N; and R 7 Selected from H and halogen.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 2 is the following moiety: R 6 selected from H, Cl, CH 3 , F, and Br; R 8 selected from H, Cl, F, and CF 3 ; R 9 selected from H, CH 3 and Cl; R 28 Selected from CF 3 、CF 2 H, -CH 2 CH 3 、Cl, SF 5 、Br and -C(O)H; X is selected from C-R 7 and N; and R 7 Selected from H and F.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the moiety: Is selected from:

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the moiety: Is selected from:

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein x is 0 or 1.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11, wherein R 3 is an unsubstituted or substituted (C 1 -C 2 )alkyl group which is substituted by 1, 2 or 3 substituents independently selected from halo and OH.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12, wherein R 3 is CH 3 .

14. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 13, wherein Y is N and Y is Y linked by a single bond.

15. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14, wherein K is K linked by a single bond, K being -CH 2 -, J is N, and A is a linker selected from -C(O)-, -S(O)-, -S(O) 2 - and .

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

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R 5 is independently selected from: ·-(C 1- C 4 ) alkyl, preferably methyl, · and two Rs on the same ring carbon atom 5 substituents together with the carbon atoms to which they are attached can be joined to form a (C 3- C 4 ) 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 R 5 substituents on K and on the adjacent carbon atoms can be linked to form ring C: wherein ring C is a fused (C 3 -C 6 ) cycloalkyl ring, especially a fused cyclobutyl ring, a fused (C 3 -C 6 ) heterocyclic ring or a fused benzene ring, wherein the fused (C 3 -C 6 ) heterocyclic ring contains ring carbon atoms and a ring heteroatom selected from O, N and S, and wherein when the ring C is a fused (C 3 -C 6 ) cycloalkyl ring, in particular a fused cyclobutyl ring, the fused (C 3 -C 6 ) cycloalkyl ring is unsubstituted or substituted by 1 or 2 R 40 groups, wherein the R 40 is selected from: ·(C 1- C 2 ) alkyl, wherein each (C 1- C 2 ) 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 Substituents together with the carbon atoms to which they are attached may be joined to form a (C 3- C 4 ) 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 -CH 2 - and J is N, two R 5 substituents may be joined to form a (C 1 -C 3 ) alkylene bridge or heteroalkylene bridge, wherein said heteroalkylene bridge is a heteroatom selected from N and O or is -CH 2 -O-CH 2 -.

18. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 17, wherein R 5 is independently selected from: ·-(C 1- C 2 ) alkyl, preferably methyl, and · When K is a carbon-nitrogen single bond, the R 5 substituents on K and on the adjacent carbon atoms can be linked to form ring C: wherein ring C is a fused (C 3 -C 4 ) cycloalkyl ring, in particular a fused cyclobutyl ring, and said fused (C 3 -C 4 ) cycloalkyl ring, in particular a fused cyclobutyl ring, is unsubstituted or substituted by 1 or 2 R 40 groups, wherein said R 40 is selected from: ·(C 1- C 2 )alkyl, wherein each (C 1- C 2 )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 Substituents, together with the carbon atoms to which they are attached, may be joined to form a (C 3- C 4 ) 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.

19. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 18, wherein R 5 is independently selected from: ·CH 3 , and y is 1 or 2, and · When K is a carbon-nitrogen single bond, the R 5 substituents on K and on the adjacent carbon atoms may be linked to form ring C: where ring C is a fused cyclobutyl ring.

20. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein the compound of formula (I) comprises the following moiety:

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

22. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 21, wherein R 4 is selected from: -(C 1 -C 4 ) alkyl; - Heteroaryl 1, wherein the heteroaryl 1 is a 5- or 6-membered fully unsaturated monocyclic ring containing ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, and the total number of ring S atoms does not exceed 1, and the total number of ring O atoms does not exceed 1; - Heteroaryl 2, wherein the 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 the heteroatoms may be in one or both rings, and the total number of ring S atoms does not exceed 1, the total number of ring O atoms does not exceed 1, and in particular, the ring connected to the rest of the molecule via linker -A- is fully unsaturated; - Phenyl; 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 , where R 10 , R 11 , R 12 , R 13 , and R 14 are each independently selected from: ·H， ·Halogenated, · (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen substituents, · substituted by -O-(C 1 -C 2 ) alkyl or OH-substituted (C 1 -C 2 ) alkyl, ·-S-(C 1 -C 3 ) alkyl · -O-(C that is unsubstituted or substituted by 1, 2 or 3 halogen substituents 1 -C 4 )alkyl ·OH, ·(C 3 -C 5 ) cycloalkyl, wherein the (C 3 -C 5 ) cycloalkyl is unsubstituted or substituted with 1 or 2 halogens, ·-O-(C 3 -C 5 ) cycloalkyl group, ·-NR 34 R 35 , wherein R 34 and R 35 are independently selected from: o H, o(C 1 -C 4 ) alkyl, wherein the (C 1 -C 4 ) alkyl is unsubstituted or substituted with OH or -O(C 1 -C 2 ) 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 by CH 3 substituted; ·CN, ·-(C 2 -C 4 ) alkenyl, ·-(C 2 -C 4 ) alkynyl group, ·＝O ·-C(O)H, and ·-C(O)(C 1 -C 4 )alkyl; The condition is that there is an OH substituent on heteroaryl 1, heteroaryl 2 and phenyl, and the remaining R 10 , R 11 , R 12 , R 13 and R 14 are as defined herein.

23. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein R 4 is selected from: -(C 1 -C 4 )alkyl, especially -CH 3 ; - Heteroaryl 1; and - Heteroaryl 2; - Phenyl; 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: ·H， ·Halogenated, · (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen substituents, · substituted by -O-(C 1 -C 2 )alkyl or OH-substituted (C 1 -C 2 )alkyl, ·-S-(C 1 -C 3 ) alkyl · -O-(C which is unsubstituted or substituted by 1, 2 or 3 halogen substituents 1 -C 4 )alkyl ·OH, ·(C 3 -C 5 ) cycloalkyl, wherein the (C 3 -C 5 ) cycloalkyl is unsubstituted or substituted by 1 or 2 halogens, ·-O-(C 3 -C 5 ) cycloalkyl group, ·-NR 34 R 35 , where R 34 and R 35 are independently selected from: o H, o(C 1 -C 4 ) alkyl, wherein the (C 1 -C 4 ) alkyl is unsubstituted or substituted by OH or -O(C 1 -C 2 ) 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 by CH 3 substituted; ·CN, ·-(C 2 -C 4 ) alkenyl, ·-(C 2 -C 4 ) alkynyl group, ·＝O ·-C(O)H, and ·-C(O)(C 1 -C 4 )alkyl; Provided that: - There is an OH substituent on heteroaryl 1, heteroaryl 2 and phenyl, and relative to R 4 at the position connected to linker -A-, the OH is located at the ortho position of the R 4 ring Or - There is a =O substituent on heteroaryl 1 and heteroaryl 2, and the remaining R 10 , R 11 , R 12 , R 13 , and R 14 as defined herein.

24. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 23, wherein R 4 is selected from: -(C 1 -C 4 )alkyl, especially CH 3 ; wherein R 10 、R 11 、R 12 、R 13 and R 14 are independently selected from: ·H， ·Halogenated, · (C 1 -C 4 ) alkyl which is unsubstituted or substituted by 1, 2 or 3 halogen substituents, · substituted by -O-(C 1 -C 2 ) alkyl or OH-substituted (C 1 -C 2 ) alkyl, ·-S-(C 1 -C 3 ) alkyl · -O-(C that is unsubstituted or substituted by 1, 2 or 3 halogen substituents 1 -C 4 )alkyl ·(C 3 -C 5 ) cycloalkyl, wherein the (C 3 -C 5 ) cycloalkyl is unsubstituted or substituted with 1 or 2 halogens, ·-O-(C 3 -C 5 ) cycloalkyl group, ·-NR 34 R 35 , wherein R 34 and R 35 are independently selected from: o H, o(C 1 -C 4 ) alkyl, wherein the (C 1 -C 4 ) alkyl is unsubstituted or substituted by OH or -O(C 1 -C 2 ) 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 CH 3 substituted; ·CN, ·-(C 2 -C 4 ) alkenyl, ·-(C 2 -C 4 ) alkynyl group, ·-C(O)H, and ·-C(O)(C 1 -C 4 )alkyl 25. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein R 4 is selected from: wherein R 10 Selected from H, halogen, unsubstituted or substituted by 1, 2 or 3 halogen substituents of (C 1 -C 2 )alkyl, unsubstituted or substituted by 1, 2 or 3 halogen substituents of -O-(C 1 -C 2 )alkyl; R 11 Selected from H, halogen, unsubstituted or substituted by 1, 2 or 3 halogen substituents, (C 1 -C 2 ) alkyl; R 12 selected from H, halogen, unsubstituted or substituted by 1, 2 or 3 halogen substituents, (C 1 -C 2 ) alkyl; R 13 selected from H, -S-CH 3 , halogenated, unsubstituted or substituted by 1, 2 or 3 halogenated substituents, (C 1 -C 2 ) alkyl; and R 14 Selected from H, halogen, unsubstituted or substituted by 1, 2 or 3 halogen substituents, (C 1 -C 2 )alkyl, unsubstituted or substituted by 1, 2 or 3 halogen substituents, O-(C 1 -C 2 )alkyl, and cyclopropyl.

26. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 25, wherein R 4 is selected from: -CH 3 、 27. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 26, wherein R 4 is selected from: Especially 28. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, wherein the compound of formula (I) has the stereochemistry shown in formula (I’):

29. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, wherein the compound of formula I’ has formula I”’:

30. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein formula (I) is formula 1g, 1g’, 1g* or 1g**:

31. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein formula (I) is formula 1h or 1h’:

32. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from:

33. A compound of formula (I) according to claim 1, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof 34. The compound of formula (I) as claimed in claim 1, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof 35. The compound of formula (I) as claimed in claim 1, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide: in the non-zwitterionic form: or the zwitterionic form: or the zwitterionic form: or a mixture of any two or three of said forms.

36. The compound of formula (I) as claimed in claim 1, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide: in the non-zwitterionic form or the zwitterionic form: or the zwitterionic form: or a mixture of any two or three of said forms.

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

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

39. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of examples 1 - 36, wherein the compound is in amorphous form.

40. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of examples 1 - 39, wherein the compound is a sodium salt.

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

42. The combination as claimed in claim 41, wherein the additional therapeutic active agent is an anti-cancer agent.

43. The combination as claimed in claim 41, wherein the additional therapeutic active anti-cancer agent is a chemotherapeutic agent.

44. The combination according to claim 43, 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 with carmustine implant tamoxifen citrate teniposide 6-thioguanine, thiotepa, tirapazamine topotecan hydrochloride for injection vinblastine vincristine and vinorelbine Especially irinotecan.

45. The combination as claimed in claim 41, wherein the additional therapeutic active agent is a PD-1 inhibitor.

46. The combination as claimed in claim 41, wherein the additional therapeutic active agent is an anti-PD-1 antibody molecule.

47. The combination as claimed in claim 45, wherein the additional therapeutic active 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, LLC), 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 or tislelizumab.

49. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 40, and one or more pharmaceutically acceptable carriers.

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

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

51. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, for use as claimed in claim 49 or 50, wherein the use is for the treatment of cancer.

52. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, for use as claimed in claim 51, wherein the cancer is characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

53. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, for use as claimed in claim 52, wherein the cancer characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) is selected from colorectal cancer, gastric cancer, and endometrial cancer, adrenocortical carcinoma, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer, prostate cancer, and ovarian cancer.

54. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, for use as claimed in claim 53, wherein the cancer characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) is selected from colorectal cancer, gastric cancer, prostate cancer, and endometrial cancer.

55. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, for use as claimed in claim 52, wherein the cancer characterized by high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) is selected from prostate cancer, 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.

56. A method of modulating WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claims 1 - 40.

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

58. A method of treating a disorder or disease in a subject treatable by WRN inhibition, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claims 1 - 40.

59. 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) or a pharmaceutically acceptable salt thereof according to claims 1 - 40.

60. A method of treating cancer in a subject, the method comprising administering a compound of formula (I) as claimed in claims 1 - 40 or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR).

61. The method according to claim 60, wherein the cancer characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR) is selected from colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical carcinoma, uterine cancer, cervical cancer, esophageal cancer, breast cancer, renal cancer and ovarian cancer.

62. The method according to claim 61, 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.

63. The method according to claim 60, wherein the cancer characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR) is selected from prostate cancer, endometrial cancer 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.

64. Use of a compound as claimed in any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.

65. Use of a compound as claimed in any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof according to claim 64, wherein the cancer is characterized by high microsatellite instability (MSI-H) or defective mismatch repair (dMMR).

66. A compound of formula (I) as claimed in any one of claims 1 to 40 or a salt thereof for use as a research chemical, such as a tool compound or a chemical probe.

67. Use of a compound of formula (I) as claimed in any one of claims 1 to 40 or a salt thereof as a research chemical, such as a tool compound or a chemical probe.

68. A method for preparing a compound as claimed in any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof.

69. An intermediate compound as described herein.

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