Aza-tricyclic derivative, and preparation method therefor and use thereof

Abstract

The present invention relates to an aza-tricyclic derivative, a preparation method therefor, and a use of a pharmaceutical composition containing the derivative in medicine. Specifically, the present invention relates to an aza-tricyclic derivative represented by general formula (I), a preparation method therefor, a pharmaceutically acceptable salt thereof, and a use thereof as a therapeutic agent, in particular as a WRN inhibitor, wherein the definition of each substituent in general formula (I) is the same as the definition in the description.

Description

Azatricyclic derivatives, processes for their preparation and uses thereof

[0001] Cross-reference to related applications

[0002] This application claims priority to the invention patent applications filed with the China National Intellectual Property Office on May 24, 2024, entitled “Azatricyclic derivatives, processes for their preparation and uses thereof”, application number CN202410651957.6, and filed with the China National Intellectual Property Office on January 23, 2025, entitled “Azatricyclic derivatives, processes for their preparation and uses thereof”, application number CN202510111452.5, the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present application relates to azatricyclic derivatives, processes for their preparation and pharmaceutical compositions containing the derivatives and their use as therapeutic agents, in particular as WRN inhibitors. BACKGROUND

[0004] WRN in humans is composed of 1432 amino acid residues, and contains five important components from N-terminal to C-terminal, including exonuclease domain, ATPase domain, RecQ C-terminal domain, helicase / ribonuclease D C-terminal domain and nuclear localization signal. Among the five human RecQ helicases, WRN is the only one with 3'→5' exonuclease activity, which is achieved by the specific activation of its N-terminal exonuclease domain by Ku70 / 80 complex bound to the DNA terminus. The ATPase domain is the largest and most conserved component in the RecQ helicase family, which acts as an ATP-dependent DNA translocation module by binding and hydrolyzing ATP. The RecQ C-terminal domain is the main site of DNA binding and catalyzes the unwinding of DNA double strands. Therefore, the ATPase domain and the RecQ C-terminal domain together constitute the core of the WRN helicase. WRN is a DNA helicase with multiple enzyme activities that can bind to DNA and other proteins. This makes the enzyme play an important role in maintaining genomic integrity and stability, including participating in DNA damage repair, replication and transcription, and maintaining telomere and heterochromatin stability.

[0005] Synthetic lethality refers to the phenomenon that two non-lethal genes are simultaneously inhibited (the inhibited forms include genetic defects such as gene mutation, gene silencing, and / or molecular perturbations such as gene expression knockdown, drug inhibition) and lead to cell death. Using this mechanism, a specific mutation in cancer is found, and its “synthetic lethal partner” is found and inhibited, thereby specifically killing cancer cells with the mutation.

[0006] WRN is a "synthetic lethal partner" of high microsatellite instability (MSI-H), a hypermutable state caused by frequent insertion and / or deletion mutations in regions of nucleotide repeats due to defects in DNA mismatch repair (MMR), which is commonly seen in cancers such as endometrial cancer (31%), colorectal cancer (25%) and gastric cancer (19%). In MSI-H cancer cells, thymine / adenine dinucleotide (TA) repeats are highly unstable and undergo massive amplification, forming non-B DNA secondary structures (e.g. cruciform and G-quadruplex) that require WRN-specific unwinding for replication. In the absence of WRN, these DNA secondary structures are cleaved by the MUS81-EME1-SLX4 endonuclease complex, leading to extensive DNA end resection, depletion of replication protein A (RPA), chromosomal fragmentation and cell death. Moreover, in tumor models with MMR defects, loss of WRN leads to activation of multiple DNA damage signaling markers, inducing cell cycle arrest and apoptosis, and thereby inhibiting tumor cell proliferation. Recent studies have shown that WRN small molecule inhibitors can specifically cause tumor regression in MSI-H tumor models, but have no effect on microsatellite stable (MSS) tumor models. Therefore, small molecule chemicals that can inhibit WRN helicase activity are expected to be a new method for effectively treating MSI-H cancers.

[0007] There is no drug on the market for WRN target inhibitors. Tumors still lack effective treatment drugs, which are seriously threatening human health, and there is still a huge unmet clinical need. SUMMARY

[0008] To solve the above technical problems, the present application provides aza-tricyclic derivative represented by general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0009] wherein:

[0010] W is selected from N and CH;

[0011] L is selected from -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, and -NR g C(=O)-;

[0012] R g is selected from the group consisting of a hydrogen atom and C 1-6 alkyl;

[0013] is a single or double bond as necessary to exhibit the normal valency state for each atom;

[0014] Q is selected from the group consisting of C, N and CR d ;

[0015] R d is selected from the group consisting of a hydrogen atom, a deuterium atom, a hydroxyl group, a cyano group, a halogen and a methoxy group;

[0016] or, R d together with the carbon atom to which it is attached and one adjacent carbon atom thereof forms a ring C (to form the structure ), ring C is selected from the group consisting of C 3-6 cycloalkyl and 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains 1, 2 or 3 N, O or S(=O) r ; wherein said C 3-6 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted by 1, 2 or 3 R BB ;

[0017] is a single or double bond or is absent (to form a 5-membered ring) as necessary to exhibit the normal valency state for each atom;

[0018] provided that:

[0019] when is a double bond, K is CH and J is C;

[0020] when is a single bond, K is selected from the group consisting of -(CR dd R ee ) y - and -NH-, J is N, CH or CD; y is selected from the group consisting of 1 and 2;

[0021] R dd , R ee are the same or different, each independently selected from the group consisting of a hydrogen atom, a deuterium atom, C 1-6 alkyl and C 1-6 haloalkyl;

[0022] or R dd , R ee together with the same carbon atom to which they are attached form -C(=O)-, C 3-6cycloalkyl or 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains 1, 2 or 3 N, O or S(=0) r ; wherein said C 3-6 ycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with 1, 2 or 3 R BB substituents;

[0023] or, R dd is a hydrogen atom or absent, R ee and the carbon atom to which it is attached and one of its adjacent carbon atoms together form a ring C (to form the structure ), ring C is selected from C 3-6 ycloalkyl or 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains 1, 2 or 3 N, O or S(=0) r ; wherein said C 3-6 ycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with 1, 2 or 3 R BB substituents;

[0024] R c are the same or different, each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group and a C 1-6 haloalkyl group;

[0025] or, two R c together with the same carbon atom to which they are attached form a -C(=0)-, C 3-6 ycloalkyl or 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains 1, 2 or 3 N, O or S(=0) r ; wherein said C 3-6 ycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with 1, 2 or 3 R BB substituents;

[0026] R BB is selected from a deuterium atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group and a halogen;

[0027] or, two R BB together with the same carbon atom to which they are attached form a C 3-4 ycloalkyl or 3-4 membered heterocyclyl, wherein said 3-4 membered heterocyclyl contains 1, 2 or 3 N, O or S(=0) r ;

[0028] or, two R BB together with the adjacent two carbon atoms to which they are attached form a C 3-4cycloalkyl or 3-4 membered heterocyclyl, wherein said 3-4 membered heterocyclyl contains 1, 2 or 3 N, O or S(=O) r ;

[0029] R 1 selected from the group consisting of alkyl, alkenyl, alkynyl, -NR 15 R 16 , alkoxy, alkylthio, wherein said alkyl, alkoxy or alkylthio is optionally further substituted by 1, 2 or 3 substituents selected from the group consisting of R A , said alkenyl or alkynyl is at least substituted by 1, 2 or 3 substituents selected from the group consisting of R AA ;

[0030] R AA selected from the group consisting of halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl and fused ring; wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl or fused ring is optionally further substituted by 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxy and cyano; with the proviso that said heterocyclyl is not morpholinyl;

[0031] R 15 , R 16 are each independently selected from the group consisting of hydrogen atom, deuterium atom, C 1-6 alkyl and aryl, wherein said C 1-6 alkyl or aryl is optionally further substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy and cyano;

[0032] Ring A is:

[0033] C 3-8 saturated monocycloalkyl, C 7-8 partially unsaturated monocycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl, wherein said spirocycloalkyl, fused cycloalkyl or bridged cycloalkyl contains 0 or 1 double bond; or 4-membered monocyclic heterocyclyl, 7-8 membered monocyclic heterocyclyl, spiroheterocyclyl or fused heterocyclyl, wherein said monocyclic heterocyclyl, spiroheterocyclyl or fused heterocyclyl contains 0 or 1 double bond, with the proviso that any one ring constituting said spiroheterocyclyl is not cyclopropane, wherein said monocyclic heterocyclyl is optionally further bridged by C 1-2 alkylene to form a bridged heterocyclyl; or bicyclic aryl, bicyclic heteroaryl or bicyclic fused ring;

[0034] is selected from the group consisting of single bond and double bond as required to exhibit the normal valency for each atom thereof;

[0035] provided that: U is CR bb when selected from a double bond, and ring B is selected from cycloalkyl, heterocyclyl and fused ring groups;

[0036] U is selected from -O-, -N(R e )- and -S- when selected from a single bond, and ring B is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl and fused ring groups;

[0037] R bb is selected from a hydrogen atom and C 1-6 1-6 alkyl;

[0038] R e is selected from a hydrogen atom and C 1-6 1-6 alkyl;

[0039] R A are the same or different, each independently selected from a deuterium atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -SF5, -OR 5 , -OC(=O)R 5 , -C(=O)R 5 , -C(=O)OR 5 , -N(R 6 )C(=O)R 7 , -N(R 6 )C(=O)OR 7 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -S(=O) r NR 6 R 7 and -S(=O) r R 5 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more substituents selected from a deuterium atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -OR 8 , =O, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -NR 9 R 10 , -C(=O)NR 9 R 10 , -S(=O)2NR 9 R 10-N(R 9 )C(=O)R 10 -N(R 9 )C(=O)OR 10 -N(R A )C(=O)N(R cc )2;

[0040] or two R A together with the carbon atom to which they are attached form a -C(=O)-, -C(=S)- or -C(=NR cc );

[0041] R cc is selected from the group consisting of hydrogen atom, hydroxyl group and C 1-6 alkyl group;

[0042] R 2 is selected from the group consisting of hydrogen atom, deuterium atom, halogen, C 1-6 alkyl group, C 1-6 hydroxyalkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, -OR 5 , -S(=O) r R 5 or -NR 6 R 7 ;

[0043] or two R 2 together with the carbon atom to which they are attached form a -C(=O)- or cyclopropyl group;

[0044] or two R 2 together with the adjacent carbon atoms to which they are attached form a C 3-6 cycloalkyl group or a 3-8 membered heterocyclyl group, wherein said 3-8 membered heterocyclyl group contains 1, 2 or 3 N, O or S(=O) r ; wherein said C 3-6 cycloalkyl group or 3-8 membered heterocyclyl group is optionally further substituted with 1, 2 or 3 R BB ;

[0045] R 3 is selected from the group consisting of hydrogen atom, C 1-6 alkyl group, amino group, hydroxylamino group, aryl group, heteroaryl group and a bicyclic fused ring, wherein said bicyclic fused ring is preferably a fused ring consisting of a monocyclic aryl group or a monocyclic heteroaryl group and a monocyclic heterocyclyl group or a monocyclic cycloalkyl group, wherein said C 1-6 alkyl group, aryl group, heteroaryl group or bicyclic fused ring is optionally further substituted with 1, 2 or 3 R B ;

[0046] R Bthe same or different, are each independently selected from the group consisting of a deuterium atom, an alkyl group, a hydroxy group, a halogen, a nitro group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -SF5, -OR 5 , -OC(=O)R 5 , -C(=O)R 5 , -C(=O)OR 5 , -N(R 6 )C(=O)R 7 , -N(R 6 )C(=O)OR 7 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -S(=O) r NR 6 R 7 and -S(=O) r R 5 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with 1, 2 or 3 substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , =O, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -NR 9 R 10 , -C(=O)NR 9 R 10 , -S(=O)2NR 9 R 10 , -N(R 9 )C(=O)R 10 and -N(R 9 )C(=O)OR 10 ;

[0047] R 13 , R 14 are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a C 1-6 alkyl group and a C 1-6 alkoxy group, or R 13 , R 14 together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl group, wherein said C 3-6 cycloalkyl group is optionally further substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy and cyano;

[0048] R 4selected from the group consisting of aryl, heteroaryl and bicyclic fused rings, wherein the bicyclic fused rings are preferably fused rings consisting of a monocyclic aryl or monocyclic heteroaryl and a monocyclic heterocyclyl or monocyclic cycloalkyl, wherein the aryl, heteroaryl or bicyclic fused rings are optionally further substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium atom, halogen, hydroxyl, cyano, -SF5, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkenyl, C 1-6 alkynyl, -NR 6 R 7 , -C(=O)R 5 and -S(=O) r R 5 , wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkenyl, C 1-6 alkynyl is optionally further substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium atom, hydroxyl, halogen and C 3-6 cycloalkyl;

[0049] R 5 are each independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally further substituted by one or more substituents selected from the group consisting of deuterium atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -NR 9 R 10 , -C(=O)NR 9 R 10 , -S(=O)2NR 9 R 10 and -N(R 9 )C(=O)R 10 ;

[0050] R 6 and R 7 are each independently selected from the group consisting of hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl can optionally be further substituted by 1, 2 or 3 substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(=O)R 8 , -C(=O)OR 8-OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 and -N(R 9 )C(=O)R 10 ;

[0051] or, R 6 and R 7 , together with the atom to which they are attached, form a 4-8 membered heterocyclyl containing 1, 2 or 3 N, O or S(=O) r ; wherein said 4-8 membered heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -NR 9 R 10 , -C(=O)NR 9 R 10 , -S(=O)2NR 9 R 10 and -N(R 9 )C(=O)R 10 ;

[0052] R 8 , R 9 and R 10 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an amine group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group can optionally be further substituted by 1, 2 or 3 substituents selected from the group consisting of hydroxy, halogen, nitro, amine, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy and carboxylate;

[0053] p is 0, 1, 2, 3 or 4;

[0054] m is 0, 1, 2, 3, 4 or 5;

[0055] n is 0, 1, 2, 3, 4, 5 or 6;

[0056] q is 0, 1, 2, 3 or 4;

[0057] r is each independently 0, 1 or 2.

[0058] In a preferred embodiment of the present application, a compound according to formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein is a single bond; Q is selected from N and CR d

[0059] R d is selected from a hydrogen atom, or R d together with the carbon atom to which it is attached and the adjacent carbon atom thereof forms a ring C (to form a structure ), ring C is selected from C 3-6 cycloalkyl and 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains one or more N, O or S(=O) r ; wherein said C 3-6 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with 1, 2 or 3 R BB ;

[0060] K, J, R c , R BB , r and q are as defined in formula (I).

[0061] In a preferred embodiment of the present application, a compound according to formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein is a single bond, K is CR dd R ee , J is N, CH or CD;

[0062] R dd is selected from a hydrogen atom and a deuterium atom; R ee is selected from a hydrogen atom and a deuterium atom;

[0063] or, R dd is selected from nothing or a hydrogen atom, R ee together with the carbon atom to which it is attached and the adjacent carbon atom thereof forms a ring C (to form a structure ), ring C is selected from C 3-6 cycloalkyl and 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains one, two or three N, O or S(=O) r ; wherein said C 3-6 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with 1, 2 or 3 R BB ;

[0064] Q, R c , R BB , r and q are as defined in formula (I).

[0065] ​In a preferred embodiment of the present application, a compound of general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of:

[0066] wherein: each ring C is independently selected from C 3-6 cycloalkyl and 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains 1, 2 or 3 N, O or S(=O) r ;

[0067] R BB is independently selected from the group consisting of a hydrogen atom, a deuterium atom, a methyl group and a fluorine atom;

[0068] R c is independently selected from the group consisting of a hydrogen atom, a deuterium atom, a methyl group and a fluorine atom; 1-6 alkyl and C 1-6 haloalkyl;

[0069] R d , R dd , R ee is independently selected from the group consisting of a hydrogen atom and a deuterium atom;

[0070] n is 0, 1, 2, 3, 4, 5 or 6;

[0071] t is 0, 1 or 2;

[0072] q is 0, 1, 2, 3 or 4;

[0073] r is 0, 1 or 2.

[0074] In a preferred embodiment of the present application, a compound of general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein ring C is selected from cyclopropyl and cyclobutyl;

[0075] t is 0;

[0076] R dd , R ee is independently selected from the group consisting of a hydrogen atom and a deuterium atom;

[0077] R c is selected from the group consisting of a hydrogen atom, a deuterium atom and a methyl group;

[0078] R d is selected from the group consisting of a hydrogen atom and a deuterium atom;

[0079] n is 0, 1, 2, 3, 4, 5 or 6;

[0080] q is 0, 1 or 2.

[0081] In a preferred embodiment of the present application, a compound according to formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, is a compound according to formula (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof: is selected from the group consisting of:

[0082] In a preferred embodiment of the present application, a compound according to formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, is a compound according to formula (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

[0083] wherein: W, R 1 , R 2 , R 3 , R 4 or p are as defined in formula (I).

[0084] In a preferred embodiment of the present application, a compound according to formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, is a compound according to formula (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

[0085] wherein: W, R 1 , R 2 , R 3 , R 4 or p are as defined in formula (I).

[0086] In a preferred embodiment of the present application, a compound according to formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from a hydrogen atom or a methyl group.

[0087] In a preferred embodiment of the present application, a compound according to formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, is a compound according to formula (IV-1) or (IV-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

[0088] wherein: W, R 1 , R 3 , R 4 are as defined in formula (I).

[0089] In a preferred embodiment of the present application, a compound according to formula (IV-1) or (IV-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, is a compound according to formula (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

[0090] wherein: W, R 1 , R 3 , R 4 are as defined in (IV-1) or (IV-2).

[0091] In a preferred embodiment of the application, a compound of general formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, -NR 15 R 16 and C 1-6 alkenyl, wherein said C 1-6 alkyl is optionally further substituted with 1, 2 or 3 halogen, wherein said C 1-6 alkenyl is substituted with at least 1, 2 or 3 substituents selected from R AA ;

[0092] R AA is selected from halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl and fused rings; wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl or fused rings are optionally further substituted with 1, 2 or 3 substituents selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, halogen, hydroxy and cyano; with the proviso that said heterocyclyl is not morpholinyl;

[0093] R 15 is selected from a hydrogen atom;

[0094] R 16 is selected from C 1-6 alkyl and aryl, wherein said C 1-6 alkyl or aryl are optionally further substituted with 1, 2 or 3 halogen.

[0095] In a preferred embodiment of the application, a compound of general formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from wherein ring A is selected from C 3-8 saturated monocycloalkyl, C 7-8partially unsaturated monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl, bridged cycloalkyl, 4-membered monocyclic heterocyclyl, 7-8 membered monocyclic heterocyclyl, spiroheterocyclyl, bicyclic heteroaryl and bicyclic fused ring, wherein said spirocycloalkyl, fused cycloalkyl, bridged cycloalkyl, 4-membered monocyclic heterocyclyl, 7-8 membered monocyclic heterocyclyl or spiroheterocyclyl contains 0 or 1 double bond, provided that none of the rings constituting said spiroheterocyclyl is cyclopropane;

[0096] R A selected from the group consisting of deuterium atom, halogen, hydroxyl, methyl, deuterated methyl, methoxy, NR 6 R 7 and -C(=O)NR 6 R 7 ; or, two R A together with the same carbon atom to which they are attached form a -C(=O) or -C(=NR cc );

[0097] R cc selected from the group consisting of hydroxyl and methoxy;

[0098] R 6 , R 7 selected from the group consisting of hydrogen atom;

[0099] m is 0, 1, 2, 3, 4 or 5;

[0100] In a preferred embodiment of the present application, a compound of general formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of wherein is selected from the group consisting of double bond, U is CR bb , ring B is selected from the group consisting of cycloalkyl and heterocyclyl;

[0101] R bb selected from the group consisting of hydrogen atom and methyl;

[0102] R A selected from the group consisting of deuterium atom, halogen, hydroxyl, methyl, methoxy, NR 6 R 7 and -C(=O)NR 6 R 7 ; R 6 , R 7 selected from the group consisting of hydrogen atom;

[0103] m is 0 or 1.

[0104] In a preferred embodiment of the present application, a compound according to formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from wherein is selected from a single bond, U is selected from O, and ring B is selected from aryl or heteroaryl;

[0105] m is 0.

[0106] In a preferred embodiment of the present application, a compound according to formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from

[0107] In a preferred embodiment of the present application, a compound according to formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl and 8-10 membered bicyclic fused rings, wherein the 8-10 membered bicyclic fused rings are preferably fused rings consisting of a monocyclic heteroaryl and a monocyclic heterocyclyl, and wherein the 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl or 8-10 membered bicyclic fused rings are optionally further substituted by one or more substituents selected from deuterium, hydroxy, halogen, alkyl, alkylthio, alkoxy, haloalkyl, hydroxyalkyl and haloalkoxy.

[0108] In a preferred embodiment of the present application, a compound according to formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from

[0109] In a preferred embodiment of the present application, a compound according to formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from

[0110] wherein X is selected from N and CH;

[0111] R17 selected from the group consisting of a hydrogen atom, halogen, hydroxyl, cyano, -SF5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkenyl, C 5 alkynyl, -C(=O)R r and -S(=O) 5 R 1-6 alkyl or C 1-6 haloalkyl, C

[0112] R 18 selected from the group consisting of a hydrogen atom, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and -C(=O)R 5 ;

[0113] R 19 selected from the group consisting of a hydrogen atom, hydroxyl, cyano, halogen, methyl and methoxy;

[0114] R 20 selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl or C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0115] R 5 are each independently selected from the group consisting of a hydrogen atom and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally further substituted with 1, 2 or 3 deuterium atoms or halogen;

[0116] r is 0, 1 or 2.

[0117] In a preferred embodiment of the present application, a compound of general formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of:

[0118] In a preferred embodiment of the present application, a compound of general formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) is selected from the group consisting of: In a preferred embodiment of the present application, a compound of general formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) is selected from the group consisting of:

[0119] or stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

[0120] Note: If there is a discrepancy between the structure drawn and the name given for the structure, the structure drawn is considered correct.

[0121] Further, the present application provides a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0122] The present application provides the use of a compound of formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a WRN inhibitor.

[0123] The present application also provides the use of a compound of formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for the treatment of a WRN-mediated disease, wherein the WRN-mediated disease is preferably a microsatellite instability-high (MSI-H) cancer; wherein the WRN-mediated disease is selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, renal clear cell carcinoma, ovarian serous cystadenocarcinoma, cholangiocarcinoma, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, cutaneous melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia or glioma, preferably colorectal cancer, gastric cancer and endometrial cancer.

[0124] The present application further provides the use of a compound of formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for the treatment of a microsatellite instability-high (MSI-H) cancer.

[0125] This invention provides the use of compounds of general formula (I), (II), (III), (IV-1), (IV-2), (V-1) or (V-2) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for treating colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, clear cell renal cell carcinoma, ovarian serous cystadenocarcinoma, bile duct carcinoma, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, melanoma of the skin, squamous cell carcinoma of the lung, prostate cancer, lung adenocarcinoma, transitional cell carcinoma of the bladder, pediatric neuroblastoma, chronic lymphocytic leukemia or glioma, preferably in the preparation of medicaments for treating colorectal cancer, gastric cancer or endometrial cancer.

[0126] Detailed description of the invention

[0127] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0128] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 and C1-C4 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0129] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. C2-C4 alkenyl groups are preferred. Alkenyl groups may be optionally substituted or unsubstituted.

[0130] "Alkyne group" refers to an aliphatic hydrocarbon group containing a single carbon-carbon triple bond, which can be straight-chain or branched. C2-C is preferred. 10 The alkynyl group is preferred, more preferably C2-C6 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be substituted or unsubstituted.

[0131] "Cycloalkyl" refers to non-aromatic cyclic alkyl groups in which one or more ring-forming atoms are carbon atoms, the rings contain 0, 1 or multiple double bonds, and include monocyclic, polycyclic, fused, bridged, and spiro rings, preferably having 3 to 7 membered monocyclic or 5 to 18 membered bicyclic or tricyclic rings.

[0132] Examples of "monocycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl,

[0133] Monocycloalkyl groups can be substituted or unsubstituted.

[0134] "Spiroalkyl" refers to 5 to 18 membered polycyclic groups having two or more cyclic structures sharing a single carbon atom (termed a spiro atom) between the rings, the rings contain 0, 1 or multiple double bonds, but no ring has a fully conjugated system of π electrons, preferably 6 to 14 membered, more preferably 7 to 10 membered. Spiroalkyl groups are classified as mono-, bi- or polycycloalkyl groups depending on the number of spiro atoms shared between the rings, preferably mono- and bi-spiroalkyl groups, preferably 4 / 5, 4 / 4, 4 / 6, 3 / 6, 5 / 5 or 5 / 6 membered. Non-limiting examples of "spiroalkyl" groups include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl, Spiroalkyl groups can be substituted or unsubstituted.

[0135] "Fused cycloalkyl" refers to 5 to 18 membered polycyclic groups having two or more cyclic structures sharing a pair of carbon atoms between the rings, one or more rings can contain 0, 1 or multiple double bonds, but no ring has a fully conjugated system of π electrons, preferably 6 to 14 membered, more preferably 6 to 10 membered. Fused cycloalkyl groups are classified as bicyclic, tricyclic, tetracyclic or polycyclic depending on the number of rings, preferably bicyclic or tricyclic, more preferably 3 / 5, 5 / 5 or 5 / 6 bicyclic fused cycloalkyl groups. Non-limiting examples of "fused cycloalkyl" groups include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decalinyl, tetradecahydrophenanthryl, Fused cycloalkyl groups can be substituted or unsubstituted.

[0136] "bridged cycloalkyl" refers to a fully carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two non-directly connected carbon atoms with each other, one or more rings can contain 0, 1 or multiple double bonds, but none of the rings has a fully conjugated π-electron aromatic system, preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, The bridged cycloalkyl group can be substituted or unsubstituted.

[0137] "Heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably in the present application and refer to non-aromatic heterocyclic groups in which 1 or 2 or 3 ring-forming atoms are selected from nitrogen, oxygen and S(O) r (in which r is selected from 0, 1 and 2) heteroatoms, containing 0, 1 or multiple double bonds in the ring, including monocyclic, polycyclic, fused, bridged and spirocyclic, preferably having 3 to 8 membered monocyclic or 5 to 18 membered bicyclic or tricyclic, which can contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur.

[0138] The heterocyclyl group can be substituted or unsubstituted.

[0139] Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, azetidinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidinyl,

[0140] "Spiroheterocyclyl" refers to a polycyclic group of 5 to 18 members, containing two or more cyclic structures, and sharing one atom between the single rings with each other, containing 0, 1 or multiple double bonds in the ring, but none of the rings has a fully conjugated π-electron aromatic system, in which 1, 2 or 3 ring atoms are selected from nitrogen, oxygen or S(O) rheteroatoms, the remainder of the ring atoms being carbon. Preferably 6- to 14- membered, more preferably 7- to 10-membered. Spiroheterocyclyl groups are classified as mono-, bi- or polyspiroheterocyclyl groups, preferably mono- and bi- spiroheterocyclyl groups, according to the number of spiro atoms shared between rings. More preferably 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 5-, 5 / 6- or 6 / 6- membered monospiroheterocyclyl groups. Non-limiting examples of "spiroheterocyclyl" groups include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7- azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0141] "Fused heterocyclyl" means a polycyclic group containing two or more cyclic structures sharing a pair of atoms with one another, 1, 2 or 3 rings can contain 0, 1 or multiple double bonds, but no ring has a fully conjugated pi-electron system, wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen or S(O) r heteroatoms, the remainder of the ring atoms being carbon. Preferably 6- to 14- membered, more preferably 7- to 10-membered. According to the number of rings making up the fused heterocyclyl group, it can be a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl group, preferably bicyclic or tricyclic, more preferably 5 / 5- or 5 / 6- bicyclic fused heterocyclyl groups. Non-limiting examples of "fused heterocyclyl" groups include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-lH-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][l,4]dioxine,

[0142] "Bridged heterocyclyl" means a polycyclic group containing two or more cyclic structures sharing two non-adjacent atoms with one another, 1, 2 or 3 rings can contain 0, 1 or multiple double bonds, but no ring has a fully conjugated pi-electron system, wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen or S(O) r heteroatoms, the remainder of the ring atoms being carbon. Preferably 6- to 14- membered, more preferably 7- to 10-membered. According to the number of rings making up the fused heterocyclyl group, it can be a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl group, preferably bicyclic or tricyclic, more preferably 5 / 5- or 5 / 6- bicyclic fused heterocyclyl groups. Non-limiting examples of "fused heterocyclyl" groups include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-lH-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][l,4]dioxine,

[0143] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0144] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 (1, 2, 3 or 4) atoms selected from nitrogen, oxygen and sulfur. Examples of "heteroaryl" compounds include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indoleyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridyl, pyridine- 2(1H)-keto, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyrimidin-2(1H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl

[0145] The heteroaryl group can be substituted or unsubstituted.

[0146] A "fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms, wherein at least one ring has a fully conjugated π electron aromatic system, and one, two, or three rings may contain zero, one, or more double bonds, but at least one ring does not have a fully conjugated π electron aromatic system, wherein the ring atoms are selected from zero, one, or more nitrogen, oxygen, or S(O). rheteroatoms selected from O, N, or S, and the remaining ring atoms are carbon. The fused ring preferably comprises a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of aryl or heteroaryl with monocyclic heterocyclyl or monocyclic cycloalkyl. Preferably, the fused ring is 6 to 14 membered, more preferably 8 to 10 membered. Examples of "fused rings" include, but are not limited to:

[0147] "Alkoxy" refers to a radical of the formula (alkyl-O-). Alkyl is as defined above. Preferably, the alkoxy group is C1-C6alkoxy. Examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, and the like.

[0148] "Alkylthio" refers to a radical of the formula (alkyl-S-). Alkyl is as defined above. Preferably, the alkylthio group is C1-C6alkylthio. Examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, t-butylthio, and the like.

[0149] "Nitro" refers to the -NO2group.

[0150] "Hydroxy" refers to the -OH group.

[0151] "Halo" refers to fluoro, chloro, bromo, and iodo.

[0152] "Amino" refers to -NH2.

[0153] "Hydroxylamino" refers to -NHOH.

[0154] "Cyano" refers to -CN.

[0155] "Benzyl" refers to -CH2-phenyl.

[0156] "Carboxy" refers to -C(=O)OH.

[0157] "Carboxylate" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.

[0158] "Hydroxyalkyl" refers to an alkyl group as defined above wherein the alkyl group is substituted with a hydroxyl group.

[0159] "Aminoalkyl" refers to an alkyl group as defined above wherein the alkyl group is substituted with an amino group.

[0160] "Haloalkyl" refers to an alkyl group as defined above wherein the alkyl group is substituted with a halo group.

[0161] "Haloalkoxy" refers to an alkoxy group as defined above wherein the alkoxy group is substituted with a halo group.

[0162] In the present text, for groups which involve alkyl groups, such as hydroxyalkyl, haloalkyl, haloalkoxy, alkoxy and alkylthio, among others, C1-C6corresponding groups are preferred, or C1-C4corresponding groups, such as C1-C6alkyl, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6alkoxy and C1-C6alkylthio.

[0163] "DMSO" means dimethyl sulfoxide.

[0164] "BOC" means tert-butoxycarbonyl.

[0165] "Bn" means benzyl.

[0166] "THP" means 2-tetrahydropyranyl.

[0167] "TFA" means trifluoroacetic acid.

[0168] "Ts" means p-toluenesulfonyl.

[0169] "Bn" means benzyl.

[0170] "SEM" means (trimethylsilyl)ethoxymethyl.

[0171] A "leaving group", or leaving group, is an atom or functional group that departs from a larger molecule in a chemical reaction, a term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant that is attacked by the nucleophile is called the substrate, and the atom or group that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Groups that can readily accept electrons and bear a negative charge well are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the more readily the leaving group departs from other molecules. This is because the smaller the pKa of its conjugate acid, the greater the tendency of the corresponding leaving group to exist as an anion (or a neutral leaving group) without bonding to other atoms. Common leaving groups include, but are not limited to, halogen, methylsulfonyl, -OTs, or -OH.

[0172] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1, 2, or 3, of a group are independently of one another replaced by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by the person skilled in the art without undue effort. For example, an amino group with a free hydrogen or a hydroxyl group can not be stable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0173] "substituted" or "substituted" as used herein, means that a group can be substituted with one or two or three or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =0, OR 5 -C(=O)R 5 -C(=O)OR 5 -NHC(=O)R 5 -NHC(=O)OR 5 -NR 6 R 7 -C(=O)NR 6 R 7 -CH2NHC(=O)OR 5 -CH2NR 6 R 7 -S(O) r R 5 ;

[0174] R 5 each independently is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally further substituted with one, two or three substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 and -NR 9 C(=O)R 10 ;

[0175] R 6 and R 7 each independently is selected from the group consisting of a hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one, two or three substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -C(=O)R 8 -C(=O)OR8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 and -NR 9 C(=O)R 10 substituted;

[0176] or, R 6 and R 7 together with the atom to which they are attached form a 4-8 membered heterocyclyl group, wherein the 4-8 membered heterocyclyl group contains one or more N, O, or S(O)r, and said 4-8 membered heterocyclyl group is optionally further substituted with 1, 2, or 3 substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 and -NR 9 C(=O)R 10 substituted;

[0177] R 8 , R 9 and R 10 are each independently selected from the group consisting of a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with 1, 2, or 3 substituents selected from the group consisting of hydroxy, halo, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, and carboxylate;

[0178] r are each independently 0, 1, or 2.

[0179] Herein, a wavy line indicates the position at which a group is attached to a compound.

[0180] The compounds of the present application can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present application, including but not limited to, diastereomeric, enantiomeric, and atropisomeric forms, and geometric (conformational) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of the present application.

[0181] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., diastereomeric, enantiomeric, and atropisomeric, and geometric (conformational) isomeric) forms of the structure; for example, where a structure is depicted exclusively in one of its isomeric forms, it is intended to also include other isomeric forms of that structure. Individual stereoisomers of compounds of the application can be prepared by using stereoselective synthesis or by resolution of mixtures of enantiomers or non-enantiomeric isomers. Some of the compounds can exist in zwitterionic forms and are within the scope of the present application.

[0182] "Pharmaceutically acceptable salts" means salts of the compounds of this application that are physiologically tolerated and suitable for medical use. The pharmaceutically acceptable salts of the compounds of Formula (I) can be metal salts, amine salts with suitable acids.

[0183] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or physiologically acceptable salts or prodrugs thereof with other chemical components, such as physiologically pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism and to facilitate absorption of the active ingredient. DETAILED DESCRIPTION

[0184] The following examples are intended to further describe the present application but are not intended to limit the scope of the present application.

[0185] Examples

[0186] The examples below provide preparations of representative compounds of Formula (I) and related structural identification data. It must be understood that the examples below are intended to illustrate the present application and are not intended to limit the present application. 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are reported in ppm using tetramethylsilane as internal standard (0.00 ppm). 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are reported in ppm using tetramethylsilane as internal standard (0.00 ppm).

[0187] Mass spectra were recorded on a LC / MS instrument and ionization can be ESI or APCI.

[0188] Thin layer chromatography silica gel plates were Yantai Huanghai HSG F254 or Qingdao GF254 silica gel plates. The silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.2 mm in thickness, and the silica gel plates used for thin layer chromatography separation and purification of products were 0.4 mm to 0.5 mm in thickness.

[0189] The column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0190] In the following examples, all temperatures are in degrees Celsius, unless otherwise indicated, and all starting materials and reagents are commercially available or synthesized according to known procedures unless otherwise indicated, and are used without further purification unless otherwise indicated, and the commercial suppliers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzhan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0191] CD3OD: deuterated methanol.

[0192] CDCl3: deuterated chloroform.

[0193] DMSO-d6: deuterated dimethyl sulfoxide.

[0194] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a volume of about 1 L.

[0195] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0196] The compounds are purified by silica gel column chromatography and reverse phase column chromatography, and the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile system. The volume ratio of the solvents is different according to the polarity of the compounds, and a small amount of acidic or basic reagent can also be added for adjustment, such as acetic acid or triethylamine.

[0197] Example 1

[0198] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0199] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0200] First step

[0201] tert-butyl 4-(2-bromo-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0202] 4-(2-bromo-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-5-oxo-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0203] To a solution of tert-butyl 4-(9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 1c (170 mg, 194.48 µmol, prepared according to published patent “WO2024079623”) in N,N-dimethylformamide (5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36.90 mg, 194.48 µmol), 1-hydroxybenzotriazole (12.26 mg, 194.48 µmol) and N,N- dimethylformamide (0.5 mL). The reaction mixture was stirred at room temperature for 40 min, then 2-chloro-4-(trifluoromethyl)aniline 1b (35.91 mg, 194.48 µmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: system B) to give tert-butyl 4-(2-chloro-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 1d (170 mg, 194.48 µmol, 100% yield).

[0204] MS m / z (ESI): 618.1 [M-56+1]

[0205] Second step

[0206] tert-butyl 4-(9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0207] tert-butyl 4-(9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0208] A mixture of tert-butyl 4-(2-bromo-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 1c (700 mg, 1.04 mmol), 2-(cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1d (299.51 mg, 1.35 mmol, commercially available), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (84.07 mg, 103.72 µmol), sodium carbonate (329.80 mg, 3.11 mmol) in a mixture of 1,4-dioxane (20 mL) and water (3 mL) was purged with argon for three times, and then the reaction mixture was heated to 85 °C for 16 h. The reaction mixture was cooled to room temperature, and then water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: system B) to give tert-butyl 4-(9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 1e (270 mg, 37.72% yield).

[0209] MS m / z (ESI): 634.3 [M-56+1]

[0210] Third Step

[0211] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0212] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0213] To a solution of tert-butyl 4-(9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 1e (650 mg, 941.82 μmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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 1f (556 mg), which was used directly in the next step. MS m / z (ESI): 590.2 [M+1]

[0214] Fourth Step

[0215] 6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0216] 6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0217] To a solution of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1g (345.23 mg, 1.41 mmol, commercial), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (361.28 mg, 1.88 mmol), 1-hydroxybenzotriazole (254.65 mg, 1.88 mmol), N,N-dimethylformamide (5 mL) was added N,N-dimethylformamide (5 mL) at room temperature, and the mixture was stirred at room temperature for 40 min. Then a solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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 1f (556 mg, 942.31 µmol) in N,N-dimethylformamide (5 mL) was added, and the mixture was stirred at room temperature for 18 h. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: system B) to give 6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide 1h (370 mg) in 48.10% yield.

[0218] MS m / z (ESI): 816.3 [M+1]

[0219] Fifth step

[0220] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0221] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0222] Trifluoroacetic acid (12 mL) was added to a solution of 6-(4-(5-(benzyloxy)-6- methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2- (cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide 1h (600 mg, 735.05 pmol) in dichloromethane (3 mL) at room temperature, and the reaction was stirred at 30 °C for 24 h. The reaction was concentrated under reduced pressure, and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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 1 (380 mg) in 71.19% yield.

[0223] MS m / z (ESI): 726.3 [M+1]

[0224] Example 1A & Example 1B & Example 1C & Example 1D

[0225] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0226] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0227] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0228] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0229] (7S,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0230] (7S,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0231] (7R,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0232] (7R,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0233] First step

[0234] tert-butyl 4-(2-bromo-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0235] 4-(2-bromo-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0236] Phosphorus oxychloride (369.96 mg, 2.41 mmol, 224.90 μL) was added to a solution of 2-bromo-6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxylic acid 1a (400 mg, 804.28 μmol), 2-chloro-4-(trifluoromethyl)aniline 1b (235.94 mg, 1.21 mmol), pyridine (636.18 mg, 8.04 mmol) in dichloromethane (7 mL) under argon atmosphere at room temperature. The reaction was stirred for 18 h. Water (30 mL) was added to the reaction mixture. The mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: system B) to give tert-butyl 4-(2-bromo-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 1c (410 mg) in 75.53% yield.

[0237] MS m / z (ESI): 618.1 [M-56+H]

[0238] Second step

[0239] tert-butyl 4-(9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0240] tert-butyl 4-(9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0241] To a solution of tert-butyl 4-(9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 1c (570 mg, 844.57 µmol), 2-(cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1d (243.89 mg, 1.10 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (68.46 mg, 84.46 µmol), sodium carbonate (268.55 mg, 2.53 mmol) in 1,4-dioxane (20 mL) and water (3 mL) was purged with argon for three times, then the reaction mixture was heated to 80 °C for 6 h. The reaction was monitored to be complete. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: system B) to give tert-butyl 4-(9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate 1e (500 mg, 85.78 % yield).

[0242] MS m / z (ESI): 634.3 [M-56+1]

[0243] Third step

[0244] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0245] N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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

[0246] Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl 4-(9-((2-chloro-4- (trifluoromethyl)phenyl)carbamoyl)-2-(cyclohept-l-en-l-yl)-7-methyl-5-oxo-5,7,8,9- tetrahydropyrrolo[l,2-c][l,2,4]triazolo[l,5-a]pyrimidin-6-yl)piperazine-l-carboxylate le (500 mg, 724.48 pmol) in dichloromethane (12 mL) at room temperature and the reaction was stirred at room temperature for 40 min. The reaction was monitored to be complete and concentrated under reduced pressure to give N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(cyclohept-l-en-l-yl)-7-methyl-5-oxo-6-(piperazin-l-yl)-5,7,8,9- tetrahydropyrrolo[l,2-c][l,2,4]triazolo[l,5-a]pyrimidine-9-carboxamide If (427 mg) in 99.89% yield.

[0247] MS m / z (ESI): 590.2 [M + 1]

[0248] Fourth Step

[0249] 6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0250] 6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0251] To a solution of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1g (265.13 mg, 1.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (277.46 mg, 1.45 mmol), 1-hydroxybenzotriazole (195.57 mg, 1.45 mmol), N,N- diisopropylethylamine (467.64 mg, 3.62 mmol) in N,N-dimethylformamide (10 mL) was added N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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 1f (427 mg, 723.68 µmol) in N,N-dimethylformamide (10 mL) and the reaction was stirred at room temperature for 18 h. The reaction was monitored to be complete. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: system B) to give 6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide 1h (510 mg) in 86.34% yield.

[0252] MS m / z (ESI): 816.3 [M+1]

[0253] Fifth step

[0254] Trifluoroacetic acid (10 mL) was added to a solution of 6-(4-(5-(benzyloxy)-6- methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2- (cyclohept-1-en-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide 1h (510 mg, 624.79 pmol) in dichloromethane (2 mL) at room temperature and the reaction was stirred at 30 °C for 24 h. The reaction was concentrated under reduced pressure and then separated by preparative liquid chromatography (Waters 3767 / Qda separation column: SunFire Sunfire C18, 19*250mm, 10um; mobile phase A: 0.1% formic acid in water, B: acetonitrile; flow rate: 20 mL / min) to give diastereoisomer 1-peak1 (shorter retention time: RT = 11.224 min) and 1-peak2 (longer retention time: RT = 11.419 min).

[0255] 1-peak1 was subjected to SFC resolution (resolution system: Waters SFC 150; chiral separation column: DAICEL CHIRAL (250*30mm; 10pm); mobile phase A: supercritical CO2 / mobile phase B: ethanol (+0.1% 7.0 mol / L ammonia ethanol) / A:B = 50:50; flow rate: 140 mL / min; column temperature: room temperature; back pressure: 140 bar; cycle time: 10.0 min) to give 1C (62 mg, shorter retention time, RT = 1.056 min) in 13% yield; and 1D (11 mg, longer retention time, RT = 2.695 min) in 2% yield.

[0256] 1C was characterized as follows:

[0257] SFC RT = 1.056 min (system: Waters UPCC (CA-352); chiral separation column: DAICEL CHIRAL (100*3.0mm; 3.0pm); mobile phase A: supercritical CO2 / mobile phase B: ethanol (0.1% diethylamine) / A:B = 60:40; flow rate: 1.5 mL / min; column temperature: 35 °C; back pressure: 1800 psi; run time: 8.00 min); ee = 100%

[0258] MS m / z (ESI): 726.2 [M+1]

[0259] 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.23 (s, 1H), 8.58 (s, 1H), 7.98 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.03 (t, J = 6.8 Hz, 1H), 5.59 (dd, J = 8.5, 5.4 Hz, 1H), 3.71 (q, J = 7.1 Hz, 1H), 2.75 - 2.65 (m, 2H), 2.65 - 2.55 (m, 1H), 2.44 (s, 3H), 2.42 - 2.35 (m, 1H), 2.35 - 2.25 (m, 2H), 1.85 - 1.73 (m, 2H), 1.60 - 1.40 (m, 7H).

[0260] 1D characterization as follows:

[0261] SFC RT = 2.695 min (System: Waters UPC C (CA-352); Chiral separation column: DAICEL CHIRAL (100 x 3.0 mm; 3.0 pm); mobile phase A: supercritical CO2 / mobile phase B: ethanol (0.1% diethylamine) / A:B = 60:40; flow rate: 1.5 mL / min; column temperature: 35 °C; back pressure: 1800 psi; run time: 8.00 min); ee = 95%

[0262] MS m / z (ESI): 726.2 [M+1]

[0263] 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 10.02 (br s, 1H), 8.56 (s, 1H), 7.98 (d, J 1.4 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.74 (dd, J = 8.6 & 1.3 Hz, 1H), 7.03 (t, J = 6.8 Hz, 1H), 5.59 (dd, J = 8.5, 5.4 Hz, 1H), 3.71 (q, J = 7.1 Hz, 1H), 2.77 - 2.69 (m, 2H), 2.64 - 2.54 (m, 1H), 2.44 (s, 3H), 2.42 - 2.35 (m, 1H), 2.35 - 2.24 (m, 2H), 1.85 - 1.73 (m, 2H), 1.58 - 1.44 (m, 7H).

[0264] 1-peak2 SFC resolution (System: Waters SFC 150; Chiral separation column: DAICEL (250 x 30 mm; 10 pm); mobile phase A: supercritical CO2 / mobile phase B: ethanol (+0.1% 7.0 mol / L ammonia ethanol) / A:B = 60:40; flow rate: 140 mL / min; column temperature: room temperature; back pressure: 140 bar; cycle time: 10.0 min) to give 1B (11 mg, shorter retention time, RT = 2.297 min), 2% yield, and 1A (12 mg, longer retention time, RT = 4.601 min), 2% yield.

[0265] 1B was characterized as follows:

[0266] SFC RT = 2.297 min (System: Waters UPC^ (CA-352); Chiral separation column: DAICEL CHIRAL (100 x 3.0 mm; 3.0 pm); mobile phase A: supercritical CO2 / mobile phase B: ethanol (0.1% diethylamine) / A:B = 70:30; flow rate: 1.5 mL / min; column temperature: 35 °C; back pressure: 1800 psi; run time: 8.00 min); ee = 100%

[0267] MS m / z (ESI): 726.2 [M+1]

[0268] 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 10.23 (s, 1H), 8.58 (s, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.75 (dd, J = 8.6 & 1.7 Hz, 1H), 7.05 (t, J = 6.7 Hz, 1H), 5.51 (dd, J = 10.3 & 1.7 Hz, 1H), 3.73 - 3.69 (m, 1H), 3.02 - 2.94 (m, 1H), 2.80 - 2.70 (m, 2H), 2.44 (s, 3H), 2.35 - 2.25 (m, 2H), 2.16 - 2.07 (m, 1H), 1.85 - 1.73 (m, 2H), 1.58 - 1.43 (m, 4H), 1.40 (d, J = 7.2 Hz, 3H).

[0269] 1A was characterized as follows:

[0270] SFC RT = 4.601 min (System: Waters UPC^ (CA-352); Chiral separation column: DAICEL CHIRAL (100 x 3.0 mm; 3.0 pm); mobile phase A: Supercritical CO2 / mobile phase B: ethanol (0.1% diethylamine) / A:B = 70:30; flow rate: 1.5 mL / min; column temperature: 35 °C; back pressure: 1800 psi; run time: 8.00 min); ee = 100%

[0271] MS m / z (ESI): 726.2 [M+1]

[0272] 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 10.23 (s, 1H), 8.58 (s, 1H), 7.99 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.05 (t, J = 6.7 Hz, 1H), 5.51 (d, J = 10.3 Hz, 1H), 3.73-3.69 (m, 1H), 3.02 - 2.94 (m, 1H), 2.80 - 2.70 (m, 2H), 2.44 (s, 3H), 2.35 - 2.25 (m, 2H), 2.16-2.07 (m, 1H), 1.85 - 1.73 (m, 2H), 1.58 - 1.43 (m, 4H), 1.40 (d, J = 7.2 Hz, 3H).

[0273] The following compound configurations were determined with reference to patent application publication WO2024079623 (compound configurations of Examples 2-6 below are determined in the same manner):

[0274] 1A is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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;

[0275] 1B is (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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;

[0276] 1C is (7S,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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;

[0277] 1D is (7R,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(cyclohept-1-en-1-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.

[0278] Example 2A & Example 2B

[0279] (7R,9R)-N-(2-chloro-4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0280] (7R,9R)-N-(2-chloro-4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0281] (7S,9S)-N-(2-chloro-4-(pentafluoro-λ 6- sulfaneyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0282] (7S,9S)-N-(2-chloro-4-(pentafluoro-λ 6 - sulfaneyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0283] First step

[0284] 2-chloro-4-(pentafluoro-λ 6 - sulfaneyl)aniline

[0285] 2-chloro-4-(pentafluoro-λ 6 - sulfaneyl)aniline

[0286] To 4-(pentafluoro-λ 6 - sulfaneyl)aniline 2a (5.12 g, 23.36 mmol, commercial), N-chlorosuccinimide (3.74 g, 28.03 mmol) were added in acetonitrile (10 mL) and stirred at 60 °C for 16 h. The reaction was monitored to be complete. The resulting residue was purified by silica gel column chromatography (eluent: system A) to give 2-chloro-4-(pentafluoro-λ 6 - sulfaneyl)aniline 2b (4.46 g) in 75.28% yield.

[0287] MS m / z (ESI): 254.0 [M+1]

[0288] Second step

[0289] tert-butyl 4-(2-bromo-9-((2-chloro-4-(pentafluoro-λ 6tert-butyl 4-((7S,9S)-9-((2-chloro-4-(pentafluoro-λ

[0290] tert-butyl 4-((7S,9S)-9-((2-chloro-4-(pentafluoro-λ 6 tert-butyl 4-((7S,9S)-9-((2-chloro-4-(pentafluoro-λ

[0291] tert-butyl 4-((7S,9S)-9-((2-chloro-4-(pentafluoro-λ 6 tert-butyl 4-((7S,9S)-9-((2-chloro-4-(pentafluoro-λ 6 tert-butyl 4-((7S,9S)-9-((2-chloro-4-(pentafluoro-λ

[0292] Step 3

[0293] tert-butyl 4-((7S,9S)-9-((2-chloro-4-(pentafluoro-λ 6tert-butyl 4-((7R,9R)-9-((2-chloro-4-(pentafluoro-λ 6 tert-butyl 4-((7R,9R)-9-((2-chloro-4-(pentafluoro-λ

[0294] tert-butyl 4-((7R,9R)-9-((2-chloro-4-(pentafluoro-λ 6 tert-butyl 4-((7R,9R)-9-((2-chloro-4-(pentafluoro-λ 6 tert-butyl 4-((7R,9R)-9-((2-chloro-4-(pentafluoro-λ

[0295] tert-butyl 4-((7R,9R)-9-((2-chloro-4-(pentafluoro-λ 64,4,5,5-Tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 2c (920 mg, 1.26 mmol), 4,4,5,5-tetramethyl-2-(2,5,6,7-tetrahydrooxaza-3-yl)-1,3,2-dioxoborazine Cyclopentane 2d (421.94 mg, 1.88 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (101.75 mg, 125.52 μmol), and sodium carbonate (399.12 mg, 3.77 mmol) were dissolved in 1,4-dioxane / water (10 mL / 1 mL) solution, purged three times with argon gas, and reacted at 80 °C for 2 hours. After monitoring the reaction to completion, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain two components, 2e-peak1 and 2e-peak2. The component 2 (2e-peak2), which has a longer retention time, was identified as the target component, 4-((7S,9S)-9-((2-chloro-4-(pentafluoro-λ)). 6 -Thioalkyl)phenyl)carbamoyl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxoheptan-3-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester and 4-((7R,9R)-9-((2-chloro-4-(pentafluoro-λ) 6 A mixture of thioalkyl)phenyl)carbamoyl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxetaneheptan-3-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester, 2e-peak2 (240 mg, one group of enantiomers), 25.49% yield, was used for subsequent reactions.

[0296] MS m / z(ESI): 694.1 [M-56+1]

[0297] Step 4

[0298] (7S,9S)-N-(2-chloro-4-(pentafluoro-λ 6(7S,9S)-N-(2-chloro-4-(pentafluoro-λ 6 (7S,9S)-N-(2-chloro-4-(pentafluoro-λ

[0299] (7S,9S)-N-(2-chloro-4-(pentafluoro-λ 6 (7S,9S)-N-(2-chloro-4-(pentafluoro-λ 6 (7S,9S)-N-(2-chloro-4-(pentafluoro-λ

[0300] (7S,9S)-N-(2-chloro-4-(pentafluoro-λ 6 (7S,9S)-N-(2-chloro-4-(pentafluoro-λ 6mixture of (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(pentafluoro-λ

[0301] MS m / z (ESI): 650.2 [M+1]

[0302] Fifth step

[0303] (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-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-(pentafluoro-λ 6 -sulfaneyl)phenyl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0304] (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-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-(pentafluoro-λ6 - sulfanyl)phenyl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-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- (pentafluoro-λ6- sulfanyl)phenyl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide as a mixture 2g (220 mg, one group of enantiomers), yield 78.46%.

[0305] Triazolo[1,5-a]pyrimidine-9-carboxamide

[0306] To a solution of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1g (117.23 mg, 479.95 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122.68 mg, 639.94 μmol), 1-hydroxybenzotriazole (86.47 mg, 639.94 μmol), N,N- diisopropylethylamine (206.76 mg, 1.60 mmol) in N,N-dimethylformamide (3 mL) was added a solution of 2f (208 mg, 319.97 μmol) in N,N-dimethylformamide (3 mL) at room temperature. The reaction was stirred at room temperature for 18 hours. The reaction was monitored to completion. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: system B) to give (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-N-(2-chloro-4-(pentafluoro-λ 6 - sulfanyl)phenyl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-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- (pentafluoro-λ6- sulfanyl)phenyl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide as a mixture 2g (220 mg, one group of enantiomers), yield 78.46%. 6 - sulfanyl)phenyl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-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- (pentafluoro-λ6- sulfanyl)phenyl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide as a mixture 2g (220 mg, one group of enantiomers), yield 78.46%.

[0307] MS m / z (ESI): 876.2 [M+1]

[0308] Sixth step

[0309] (7S,9S)-N-(2-chloro-4-(pentafluoro-λ 6(7S,9S)-N-(2-chloro-4-(pentafluoro-λ

[0310] (7S,9S)-N-(2-chloro-4-(pentafluoro-λ 6 (7S,9S)-N-(2-chloro-4-(pentafluoro-λ

[0311] (7S,9S)-N-(2-chloro-4-(pentafluoro-λ 6 (7S,9S)-N-(2-chloro-4-(pentafluoro-λ

[0312] (7S,9S)-N-(2-chloro-4-(pentafluoro-λ 6 (7S,9S)-N-(2-chloro-4-(pentafluoro-λ

[0313] Trifluoroacetic acid (5 mL) was added to a solution of 2 g (220 mg, 251.06 pmol) in dichloromethane (1 mL) at room temperature and the reaction was left to proceed at room temperature for 18 hours. The reaction was monitored to be complete and concentrated under reduced pressure. After separation by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% trifluoroacetic acid + water, mobile phase B: acetonitrile) and lyophilization, a chiral separation was performed (system: Waters SFC 150; chiral separation column: DAICEL CHIRALPAK® IC (250 x 30 mm; 10 pm); mobile phase A: supercritical CO2 / mobile phase B: ethanol (+0.1% 7.0 mol / L ammonia ethanol) / A:B = 45:55; flow rate: 145 mL / min; column temperature: room temperature; back pressure: 100 bar; cycle time: 7 min) to give 2B (64 mg, RT = 1.511 min) in 31% yield and 2A (74 mg, RT = 3.097 min) in 36% yield. (250 x 30 mm; 10 pm); mobile phase A: supercritical CO2 / mobile phase B: ethanol (+0.1% 7.0 mol / L ammonia ethanol) / A:B = 45:55; flow rate: 145 mL / min; column temperature: room temperature; back pressure: 100 bar; cycle time: 7 min) to give 2B (64 mg, RT = 1.511 min) in 31% yield and 2A (74 mg, RT = 3.097 min) in 36% yield.

[0314] 2B was characterized as follows:

[0315] MS m / z (ESI): 786.2 [M+1]

[0316] SFC: RT = 1.511 min (system: Waters UPCC (CA-352); chiral separation column: DAICEL CHIRALPAK® IC (100 x 3.0 mm; 3.0 pm); mobile phase A: supercritical CO2 / mobile phase B: ethanol (0.1% diethylamine) / A:B = 60:40; flow rate: 1.5 mL / min; column temperature: 35 °C; back pressure: 1800 psi; run time: 8.00 min); ee = 100%

[0317] 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (br s, 1H), 8.43 (s, 1H), 8.16 (d, J = 2.3 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.92 (dd, J = 9.0 & 2.2 Hz, 1H), 7.00 (t, J = 5.6 Hz, 1H), 5.53 (dd, J = 10.2 & 1.1 Hz, 1H), 4.62 (s, 2H), 3.83 (t, J = 5.5 Hz, 2H), 3.75 - 3.63 (m, 1H), 3.05 - 2.90 (m, 1H), 2.48 - 2.41 (m, 2H), 2.40 (s, 3H), 2.11 (d, J = 13.4 Hz, 1H), 1.88 - 1.72 (s, 2H), 1.39 (d, J = 7.0 Hz, 3H).​

[0318] 2A was characterized as follows:

[0319] MS m / z (ESI): 786.2 [M+1]

[0320] SFC: RT = 3.097 min (System: Waters UPC C (CA-352); Chiral separation column: DAICEL CHIRAL (100 x 3.0 mm; 3.0 pm); mobile phase A: Supercritical CO2 / mobile phase B: Ethanol (0.1% diethylamine) / A:B = 60:40; flow rate: 1.5 mL / min; column temperature: 35 °C; back pressure: 1800 psi; run time: 8.00 min); ee = 95%

[0321] 1 H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 10.27 (br s, 1H), 8.57 (s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.93 (dd, J = 9.1 & 2.3 Hz, 1H), 7.00 (t, J = 5.6 Hz, 1H), 5.53 (dd, J = 10.2 & 1.2 Hz, 1H), 4.63 (s, 2H), 3.83 (t, J = 5.6 Hz, 2H), 3.77 - 3.63 (m, 1H), 3.02 - 2.90 (m, 1H), 2.47 - 2.41 (m, 2H), 2.44 (s, 3H), 2.11 (d, J = 13.7 Hz, 1H), 1.90 - 1.74 (s, 2H), 1.40 (d, J = 7.1 Hz, 3H).

[0322] 2B is (7S,9S)-N-(2-chloro-4-(pentafluoro-lambda 6 - sulfanyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin- 1 -yl)-7-methyl-5-oxo-2-(2,5,6,7-tetrahydrooxepin-3-yl)-5,7,8,9-tetrahy dropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide;

[0323] 2A is (7R,9R)-N-(2-chloro-4-(pentafluoro-lambda 6(7R,9R)-2-(cyclohept-1-en-1-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ

[0324] Example 3A & Example 3B

[0325] (7R,9R)-2-(cyclohept-1-en-1-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0326] (7R,9R)-2-(cyclohept-1-en-1-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0327] (7R,9R)-2-(cyclohept-1-en-1-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0328] (7R,9R)-2-(cyclohept-1-en-1-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0329] First step

[0330] tert-butyl 4-(2-bromo-7-methyl-5-oxo-9-((4-(pentafluoro-λ 6 -5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0331] tert-butyl 4-(2-bromo-7-methyl-5-oxo-9-((4-(pentafluoro-λ 6 -5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0332] tert-butyl 4-(2-bromo-7-methyl-5-oxo-9-((4-(pentafluoro-λ 6 -5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide 6 -5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0333] MS m / z (ESI): 642.1 [M-56+1]

[0334] second step

[0335] tert-butyl 4-((7S,9S)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-9-((4-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate and tert-butyl 4-((7R,9R)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-9-((4-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0336] 4-((7S,9S)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-9-((4-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate and 4-((7R,9R)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-9-((4-(pentafluoro-λ 6 -sulfaneyl)phenyl)carbamoyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0337] tert-butyl 4-((7S,9S)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-9-((4-(pentafluoro-λ 6-tert-butyl 4-((7S,9S)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-9-((4- (pentafluoro-λ 6 -tert-butyl 4-((7S,9S)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-9-((4- (pentafluoro-λ 6 -tert-butyl 4-((7S,9S)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-9-((4- (pentafluoro-λ

[0338] MS m / z (ESI): 714.3 [M+1]

[0339] Step 3

[0340] (7S,9S)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6- sulfanyl)phenyl)-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide and (7R,9R)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro- λ 6 - sulfanyl)phenyl)-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide and (7R,9R)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro- λ

[0341] - sulfanyl)phenyl)-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide and (7R,9R)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro- λ 6 - sulfanyl)phenyl)-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide and (7R,9R)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro- λ 6 - sulfanyl)phenyl)-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide and (7R,9R)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro- λ

[0342] - sulfanyl)phenyl)-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide and (7R,9R)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro- λ 6 - sulfanyl)phenyl)-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide and (7R,9R)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro- λ 6 - sulfanyl)phenyl)-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide and (7R,9R)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro- λ

[0343] MS m / z (ESI): 614.2 [M+1]

[0344] Fourth Step

[0345] (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-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)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0346] (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-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)-2-(cyclohept-1-en-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0347] To a solution of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid 1g (128.36 mg, 525.55 μmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (134.33 mg, 700.73 μmol), 1-hydroxybenzotriazole (94.68 mg, 700.73 μmol) and N,N- diisopropylethylamine (226.41 mg, 1.75 mmol) in N,N-dimethylformamide (9 mL) was added a solution of 3c (215 mg, 350.37 μmol) in N,N-dimethylformamide (9 mL) at room temperature. The reaction was stirred at room temperature for 3 hours. The reaction was monitored to completion. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: system B) to give a mixture of (7S,9S)-6-(4-(5-(benzyloxy)-6-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-(cyclohept-l-en-l-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-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-l-yl)-2-(cyclohept-l-en-l-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide 3d (250 mg, one group of enantiomers) in 84.96% yield.

[0348] MS m / z (ESI): 840.3 [M+1]

[0349] Fifth step

[0350] (7S,9S)-2-(cyclohept-1-en-1-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0351] (7S,9S)-2-(cyclohept-1-en-1-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0352] (7R,9R)-2-(cyclohept-1-en-1-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0353] (7R,9R)-2-(cyclohept-1-en-1-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0354] Trifluoroacetic acid (4 mL) was added to a solution of 3d (250 mg, 297.66 pmol) in dichloromethane (1 mL) at room temperature and the reaction was left to proceed for 24 hours at room temperature. The reaction was monitored to be complete and concentrated under reduced pressure. After separation by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% trifluoroacetic acid + water, mobile phase B: acetonitrile), and lyophilization, chiral separation was performed (system: Waters SFC 150; chiral separation column: DAICEL Chiralpak® IC (250 x 25 mm; 10 pm); mobile phase A: supercritical CO2 / mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol) / A:B = 45:55; flow rate: 145 mL / min; column temperature: room temperature; back pressure: 100 bar; cycle time: 6 min), to give 3B (55 mg, RT = 0.844 min) in 24% yield and 3A (57 mg, RT = 4.598 min) in 26% yield. (250 x 25 mm; 10 pm); mobile phase A: supercritical CO2 / mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol) / A:B = 45:55; flow rate: 145 mL / min; column temperature: room temperature; back pressure: 100 bar; cycle time: 6 min), to give 3B (55 mg, RT = 0.844 min) in 24% yield and 3A (57 mg, RT = 4.598 min) in 26% yield.

[0355] 3B was characterized as follows:

[0356] MS m / z (ESI): 750.3 [M+1]

[0357] SFC: RT = 0.844 min (System: Waters UPC2 (CA-352); Chiral separation column: DAICEL CHIRAL (100 x 3.0 mm; 3.0 pm); mobile phase A: Supercritical CO2 / mobile phase B: methanol (0.1% diethylamine A) / A:B = 60:40; flow rate: 2.0 mL / min; column temperature: 35 °C; back pressure: 1800 psi; run time: 8.00 min); ee = 100%

[0358] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.16 (br s, 1H), 8.56 (s, 1H), 7.90 (d, J = 9.3 Hz, 2H), 7.80 (d, J = 8.9 Hz, 2H), 6.98 (t, J = 6.8 Hz, 1H), 5.31 (dd, J = 10.5 & 2.0 Hz, 1H), 3.71 - 3.62 (m, 1H), 3.05 - 2.90 (m, 1H), 2.80 - 2.68 (m, 2H), 2.44 (s, 3H), 2.32 - 2.20 (m, 2H), 2.09 (d, J = 12.0 Hz, 1H), 1.84 - 1.68 (m, 2H), 1.58 - 1.43 (m, 4H), 1.39 (d, J = 7.0 Hz, 3H).

[0359] 3A was characterized as follows:

[0360] MS m / z (ESI): 750.3 [M+1]

[0361] SFC: RT = 4.598 min (System: Waters UPC2 (CA-352); Chiral separation column: DAICEL CHIRAL (100 x 3.0 mm; 3.0 pm); mobile phase A: Supercritical CO2 / mobile phase B: methanol (0.1% diethylamine) / A:B = 60:40; flow rate: 2.0 mL / min; column temperature: 35 °C; back pressure: 1800 psi; run time: 8.00 min); ee = 100%

[0362] 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.23 (s, 1H), 8.58 (s, 1H), 7.90 (d, J = 9.2 Hz, 2H), 7.80 (d, J = 9.0 Hz, 2H), 6.98 (t, J = 6.6 Hz, 1H), 5.31 (dd, J = 10.2 & 1.6 Hz, 1H), 3.76 - 3.60 (m, 1H), 3.05 - 2.89 (m, 1H), 2.77 - 2.67 (m, 2H), 2.44 (s, 3H), 2.32 - 2.22 (m, 2H), 2.09 (d, J = 12.3 Hz, 1H), 1.85 - 1.70 (m, 2H), 1.58 - 1.43 (m, 4H), 1.39 (d, J = 7.1 Hz, 3H).

[0363] 3B is (7S,9S)-2-(cyclohepten-l-en-l-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-l-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-lambda 6 - sulfanyl)phenyl)-5,7,8,9-tetrahydropyrrolo[l,2-c][l,2,4]triazolo[l,5-a]pyrimidine-9- carboxamide;

[0364] 3A is (7R,9R)-2-(cyclohepten-l-en-l-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4- carbonyl)piperazin-l-yl)-7-methyl-5-oxo-N-(4-(pentafluoro-lambda 6 - sulfanyl)phenyl)-5,7,8,9-tetrahydropyrrolo[l,2-c][l,2,4]triazolo[l,5-a]pyrimidine-9- carboxamide.

[0365] Example 4A & Example 4B

[0366] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-(methyl-d3)-1H-indol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0367] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-(methyl-d3)-1H-indol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0368] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-(methyl-d3)-1H-indol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0369] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-(methyl-d3)-1H-indol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0370] Prepared according to the experimental procedure of Example 1B, 1A, SFC resolution conditions (System: K-Prep LAB100G; Chiral resolution column: DAICEL CHIRALPAK® AD-H (250 x 25 mm; 10 pm); Mobile phase: methanol (+ 0.1% 7.0 mol / L ammoniumcarbonate); Flow rate: 60 mL / min; Column temperature: room temperature; Cycle time: 4.5 min). (250 x 25 mm; 10 pm); Mobile phase: methanol (+ 0.1% 7.0 mol / L ammoniumcarbonate); Flow rate: 60 mL / min; Column temperature: room temperature; Cycle time: 4.5 min), to give 4B (25 mg, RT = 2.221 min) in 9% yield and 4A (32 mg, RT = 4.317 min) in 11% yield.

[0371] 4B was characterized as follows:

[0372] MS m / z (ESI): 764.3 [M+1]

[0373] SFC: RT = 2.221 min (System: Shimadzu LC-20AD; Chiral resolution column: DAICEL CHIRALPAK® AD-H (250 x 25 mm; 10 pm); Mobile phase: methanol (+ 0.1% 7.0 mol / L ammoniumcarbonate); Flow rate: 60 mL / min; Column temperature: room temperature; Cycle time: 4.5 min). (250 x 4.6 mm; 5 pm); mobile phase: methanol (0.1% diethylamine); flow rate: 1 mL / min; column temperature: 25 °C); ee = 100%.

[0374] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.24 (s, 1H), 8.59 (s, 1H), 8.31 (dd, J = 1.5 & 0.5 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.92 (dd, J = 8.6 & 1.5 Hz, 1H), 7.75 (dd, J = 9.0 & 1.6 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 6.55 (dd, J = 3.1 & 0.9 Hz, 1H), 5.62 (dd, J = 10.3 & 2.3 Hz, 1H), 3.83 - 3.68 (m, 1H), 3.07 - 2.96 (m, 1), 2.45 (s, 3H), 2.16 (d, J = 13.8 Hz, 1H), 1.44 (d, J = 7.2 Hz, 3H).

[0375] 4A was characterized as follows:

[0376] MS m / z (ESI): 764.3 [M+1]

[0377] SFC: RT = 4.317 min (System: Shimadzu LC-20AD; Chiral separation column: DAICEL CHIRAL (250 x 4.6 mm; 5 pm); mobile phase: methanol (0.1% diethylamine); flow rate: 1 mL / min; column temperature: 25 °C); ee = 100%.

[0378] 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.24 (s, 1H), 8.59 (s, 1H), 8.31 (dd, J = 1.5 & 0.5 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.92 (dd, J = 8.6 & 1.5 Hz, 1H), 7.75 (dd, J = 9.0 & 1.6 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 6.55 (dd, J = 3.1 & 0.9 Hz, 1H), 5.62 (dd, J = 10.3 & 2.3 Hz, 1H), 3.83 - 3.68 (m, 1H), 3.07 - 2.96 (m, 1), 2.45 (s, 3H), 2.16 (d, J = 13.8 Hz, 1H), 1.44 (d, J = 7.2 Hz, 3H).

[0379] 4B is (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-(methyl-d3)-1H-indol-5-yl)- 5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide;

[0380] 4A is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-(methyl-d3)-1H-indol-5-yl)- 5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide.

[0381] Example 5A & Example 5B

[0382] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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

[0383] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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

[0384] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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

[0385] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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

[0386] First step

[0387] tert-butyl 4-((7S,9S)-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(2,3-dihydrobenzofuran-5-yl)-7-methyl -5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate and tert-butyl 4-((7R,9R)-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(2,3-dihydrobenzofuran-5-yl)-7-methyl -5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0388] 4-((7S,9S)-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(2,3-dihydrobenzofuran-5-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester and 4-((7R,9R)-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(2,3-dihydrobenzofuran-5-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester

[0389] To a solution of 2-(2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane 5a (191 mg, 777.90 µmol, commercial) in 1,4-dioxane (10 mL) and water (2 mL) was added sodium carbonate (164.90 mg, 1.56 mol), 4-(2-bromo-9-((2-chloro-4- (trifluoromethyl)phenyl)carbamoyl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2- c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 1c (350 mg, 518.60 µmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (38.47 mg, 51.86 µmol). The mixture was stirred at 90 °C for 12 h under nitrogen atmosphere. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was separated and purified by column chromatography on silica gel (eluent: A system) to give two fractions 5b-peak1 and 5b-peak2, in which fraction 2 (5b-peak2) was a mixture of 4-((7S,9S)-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(2,3-dihydrobenzofuran-5-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester and 4-((7R,9R)-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-2-(2,3-dihydrobenzofuran-5-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester, 5b-peak2 (186 mg, one group of enantiomers), yield 36.99%.

[0390] MS m / z (ESI): 714.5 [M+1]

[0391] Second step

[0392] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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 and(7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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

[0393] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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 and(7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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

[0394] 5b-peak2 (100 mg, 140.03 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added at 0 °C. The reaction mixture was then stirred at 25 °C for 1 hour. After the reaction was complete, the pH of the reaction mixture was adjusted to 8–9 with sodium bicarbonate solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-yl)-7-methyl-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2] A mixture of [-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide and (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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, 5c (85 mg, one group of enantiomers), yield 98.86%.

[0395] MS m / z(ESI): 614.2 [M+1]

[0396] Step 3

[0397] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-yl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-c arbonyl)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

[0398] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-yl)-6-(4-(5-hydroxy-6-methylpyrimidin-4-carbonyl)piperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-9-carboxamide

[0399] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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

[0400] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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

[0401] To a solution of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid 5d (45.18 mg, 293.15 pmol, commercial) in N,N-dimethylformamide (2 mL) was added 1-hydroxybenzotriazole (39.61 mg, 293.15 pmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56.20 mg, 293.15 pmol) and N,N-diisopropylethylamine (56.72 mg, 439.73 pmol). The mixture was stirred at 25 °C for 10 min. Then 5c (90 mg, 146.58 pmol) was added and stirred at 30 °C for 16 h. After the reaction was completed, the mixture was purified by reverse phase column (eluent: D system) and then lyophilized. The residue was separated and purified by chiral preparation (instrument: Waters SFC 150, gradient column: DAICEL Chiralpak IC, 250 x 25 mm, 10 pm, flow rate: 60 mL / min, gradient: 60% supercritical CO2: 40% ethanol (+0.1% 7.0 mol / L ammonia ethanol); column temperature: room temperature) to give 5B (23 mg, RT = 1.697 min) in 20.97% yield and 5A (20 mg, RT = 3.202 min) in 18.24% yield. 250x25mm, 10pm, flow rate: 60mL / min, gradient: 60% supercritical CO2: 40% ethanol (+0.1% 7.0 mol / L ammonia ethanol); column temperature: room temperature) to give 5B (23 mg, RT = 1.697 min) in 20.97% yield and 5A (20 mg, RT = 3.202 min) in 18.24% yield.

[0402] 5B was characterized as follows:

[0403] MS m / z (ESI): 750.1 [M+1]

[0404] SFC: RT = 1.697 min (System: Waters UPC2 (CA-415); Chiral separation column: DAICEL CHIRAL SFC: RT = 1.697 min (System: Waters UPC2 (CA-415); Chiral separation column: DAICEL CHIRAL

[0405] 1 H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 10.23 (s, 1H), 8.58 (s, 1H), 8.00 - 7.94 (m, 3H), 7.85 (dd, J = 8.2 & 1.8 Hz, 1H), 7.75 (d, J = 8.6 & 1.7 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.59 (dd, J = 10.2 & 1.9 Hz, 1H), 4.60 (t, J = 8.8 Hz, 2H), 3.78 - 3.70 (m, 1H), 3.25 (t, J = 8.8 Hz, 4H), 3.07 - 2.96 (m, 2H), 2.45 (s, 3H), 2.18 - 2.11 (m, 1H), 1.43 (d, J = 7.2 Hz, 3H).

[0406] 5A was characterized as follows:

[0407] MS m / z (ESI): 750.1 [M+1]

[0408] SFC: RT = 1.697 min (System: Waters UPC2 (CA-415); Chiral separation column: DAICEL CHIRAL SFC: RT = 1.697 min (System: Waters UPC2 (CA-415); Chiral separation column: DAICEL CHIRAL

[0409] 1H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 10.23 (s, 1H), 8.58 (s, 1H), 8.00 - 7.94 (m, 3H), 7.85 (dd, J = 8.2 & 1.8 Hz, 1H), 7.75 (d, J = 8.6 & 1.7 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.59 (dd, J = 10.2 & 1.9 Hz, 1H), 4.60 (t, J = 8.8 Hz, 2H), 3.76 - 3.70 (m, 1H), 3.25 (t, J = 8.8 Hz, 4H), 3.08 - 2.97 (m, 2H), 2.45 (s, 3H), 2.18 - 2.11 (m, 1H), 1.43 (d, J = 7.2 Hz, 3H).

[0410] 5B is (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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;

[0411] 5A is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2,3-dihydrobenzofuran-5-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.

[0412] Example 6A & Example 6B

[0413] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0414] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0415] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0416] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0417] First step

[0418] tert-butyl 4-((7S,9S)-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)- 5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate and tert-butyl 4-((7R,9R)-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)- 5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylate

[0419] 4-((7S,9S)-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester and 4-((7R,9R)-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester

[0420] To the reaction solution of 4-(2-bromo-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester 1c (250.00 mg, 370.43 μmol) in 1,4-dioxane (15 mL) and water (2.5 mL) was added sodium carbonate (117.78 mg, 1.11 μmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 6a (191.23 mg, 740.85 μmol, commercially available) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (27.48 mg, 37.04 μmol). The mixture was stirred at 100 °C for 5 h under nitrogen atmosphere. After the reaction was completed, water (30 mL) was added to the reaction mixture, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel plate (eluent: A system) to separate and purify two components 6b-peak1 and 6b-peak2, wherein component 2 (6b-peak2) was the target component, which was a mixture of 4-((7S,9S)-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester and 4-((7R,9R)-9-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester, 6b-peak2 (50 mg, one group of enantiomers), yield 18.59%. MS m / z (ESI): 726.2 [M+1]

[0421] Second step

[0422] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-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(7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0423] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-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(7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0424] A mixture of 6b-peak2 (120 mg, 165.26 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added at 0 °C. Then the reaction mixture was stirred at 25 °C for 0.5 h. After the reaction was completed, the reaction mixture was adjusted to pH 8-9 with sodium bicarbonate solution, extracted with dichloromethane (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a mixture of (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-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 (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-6-(piperazin-1-yl)-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide 6c (100 mg, a group of enantiomers), yield 96.66%.

[0425] MS m / z (ESI): 626.1 [M+1]

[0426] Third step

[0427] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0428] (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0429] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0430] (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide

[0431] To a solution of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid 5d (36.46 mg, 239.60 pmol), 1-hydroxybenzotriazole (43.17 mg, 319.47 pmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61.24 mg, 319.47 pmol) and N,N- diisopropylethylamine (61.93 mg, 479.21 pmol) in N,N-dimethylformamide (2 mL) was stirred at 25 °C for 10 min. Then 6c (100 mg, 159.74 pmol) was added and stirred at 30 °C for 16 h. After the reaction was completed, the reaction mixture was purified by reverse phase column (eluent: D system) and then lyophilized, and purified by chiral preparation (instrument: Waters SFC 150, gradient column: DAICEL Chiralpak® AD-H 250 x 30 mm, 10 pm, flow rate: 150 mL / min, gradient: 50% supercritical CO2: 50% isopropanol (+0.1% 7.0 mol / L ammonia isopropanol), column temperature: room temperature) to give 6A (7.82 mg, SFC RT = 1.271 min) in a yield of 6.44% and 6B (8.28 mg, SFC RT = 3.654 min) in a yield of 6.82%. 250x30mm, 10pm, flow rate: 150 mL / min, gradient: 50% supercritical CO2: 50% isopropanol (+0.1% 7.0 mol / L ammonia isopropanol), column temperature: room temperature) to give 6A (7.82 mg, SFC RT = 1.271 min) in a yield of 6.44% and 6B (8.28 mg, SFC RT = 3.654 min) in a yield of 6.82%.

[0432] 6A was characterized as follows:

[0433] MS m / z (ESI): 762.1 [M+1]

[0434] SFC: RT = 1.271 min (System: Waters UPC2 (CA-415); Chiral separation column: DAICEL CHIRAL SFC: RT = 3.654 min (System: Waters UPC2 (CA-415); Chiral separation column: DAICEL CHIRAL

[0435] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.24 (s, 1H), 8.59 (s, 1H), 8.50 (s, 1H), 8.18 (d, J = 0.5 Hz, 1H), 8.16 - 8.12 (m, 1H), 8.02 - 7.96 (m, 2H), 7.79 - 7.72 (m, 2H), 5.63 (dd, J = 10.4 & 1.6 Hz, 1H), 4.08 (s, 3H), 3.82 - 3.68 (m, 1H), 3.10-2.97 (m, 2H), 2.45 (s, 3H), 2.19-2.15 (m, 1H), 1.44 (d, J = 7.2 Hz, 3H).

[0436] 6B was characterized as follows:

[0437] MS m / z (ESI): 762.1 [M+1]

[0438] SFC: RT = 3.654 min (System: Waters UPC2 (CA-415); Chiral separation column: DAICEL CHIRAL SFC: RT = 3.654 min (System: Waters UPC2 (CA-415); Chiral separation column: DAICEL CHIRAL

[0439] 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.18 (s, 1H), 8.14 (dd, J = 8.8 & 1.4 Hz, 1H), 8.02 - 7.96 (m, 2H), 7.79 - 7.72 (m, 2H), 5.63 (dd, J = 9.9 & 1.7 Hz, 1H), 4.08 (s, 3H), 3.79 - 3.69 (m, 1H), 3.11 - 2.97 (m, 2H), 2.43 (s, 3H), 2.21 - 2.13 (m, 1H), 1.44 (d, J = 7.2 Hz, 3H).

[0440] 6A is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)- 5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide;

[0441] 6B is (7S,9S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-methyl-2-(1-methyl-1H-indazol-5-yl)- 5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide.

[0442] Biological evaluation

[0443] Test 1, Test of the compound of the application on the inhibition of WRN enzyme activity (ATPase)

[0444] The following method was used to determine the degree of inhibition of the recombinant human WRN ATPase activity by the compounds of the application under in vitro conditions. This method uses the Promega ADP-Glo® Kinase Assay kit (Cat. No. V9102). The detailed experimental procedure can be found in the kit instructions. TM Kinase Assay kit (Cat. No. V9102). The detailed experimental procedure can be found in the kit instructions.

[0445] The experimental procedure is briefly described as follows: the test compound is first dissolved in DMSO to prepare a stock solution, and then gradient dilution is carried out using a reaction buffer (30 mM Tris, pH 7.5, 2 mM MgCl2, 50 mM NaCl, 0.02% BSA, 0.1% Pluronic F127), and the final concentration of the test compound in the reaction system ranges from 1000 nM to 0.004 nM; the WRN protein (purchased from BPS, item number 101264) is prepared using the reaction buffer, the substrate Flap26 (synthesized by Shanghai Jeery Bioengineering Co., Ltd. on commission, sequence 5'-TTTTTTTTTTTTTTTTTTTTTTCCAAGTAAAACGACGGCCAGTGC-3') and ATP working solution (from ADP-Glo TM Kinase Assay kit component V915A). The reaction is carried out in a 384-well microplate, first adding the compound and recombinant human WRN protein (final concentration 5 nM) to the well, and incubating at room temperature for 15 minutes, then adding the Flap solution (final concentration 0.1 nM) and ATP solution (final concentration 30 uM) to the reaction solution, and incubating at room temperature for 10 minutes. Then 5 uL of ADP-Glo Reagent is added to the reaction system, and incubated at room temperature for 40 minutes. Then 10 uL of Kinase Detection Reagent is added to the reaction system, and incubated at room temperature for 30 minutes. After incubation, the chemiluminescence intensity value of each well is measured on a luminometer in luminescence mode. The percentage inhibition of the compound at each concentration is calculated by comparing the luminescence intensity ratio with the control group (0.1% DMSO), and the IC 50 values of the compounds of the present application are obtained by nonlinear regression analysis of the compound concentration logarithm-inhibition rate using GraphPad Prism 9 software, as shown in Table 1.

[0446] The IC 50 values of the compounds of the present application are obtained by nonlinear regression analysis of the compound concentration logarithm-inhibition rate using GraphPad Prism 9 software, as shown in Table 1.

[0447] "AA" indicates that the IC 50 ≤1 nM; "A" indicates that the IC 50 <100 nM.

[0448] Table 1 IC 50

[0449] Conclusion: The compounds of the present application have good inhibitory effect on WRN enzyme activity (ATPase) with IC 50 <100 nM.

[0450] Test Example 2, Inhibition of SW48 Cell Proliferation Assay

[0451] The following method was used to determine the effect of the compounds of the present application on SW48 cell proliferation. SW48 cells (MSI-H cells) were purchased from the American Type Culture Collection and cultured in Leibovitz's L-15 (Gibco, Cat# 11415064) medium containing 10% fetal bovine serum, 100 U penicillin and 100 pg / mL streptomycin. Cell viability was determined by Luminescent Cell Viability Assay Kit (Promega, Cat# G7573).

[0452] The experimental procedure followed the kit instruction steps and was briefly described as follows: the test compounds were first dissolved in DMSO to prepare a 10 mM stock solution, then diluted with culture medium to prepare test samples, with the final concentration of the compounds ranging from 10,000 nM to 1.52 nM. Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate at a density of 500 cells per well, incubated overnight in a 37°C, air incubator, and then continued to be incubated for 120 hours after the addition of the test compounds. After the incubation was completed, 40 uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes, and then left to stand for 10 minutes, after which the luminescence value of each well of the sample was read on a microplate reader using the Luminescence mode. The percentage inhibition of the compounds at each concentration point was calculated by comparing the values with the control group (0.1% DMSO), and then the compound concentration versus inhibition rate was subjected to non-linear regression analysis in GraphPad Prism 9 software to obtain the IC 50 values of the compounds of the present application, see Table 2.

[0453] The IC 50 values of the compounds of the present application are represented by A,

[0454] “A” represents 1 nM < IC 50 < 100 nM.

[0455] Table 2 IC 50 data of the compounds of the present application on SW48 cell proliferation

[0456] Conclusion: The compounds of the present application have good inhibitory effect on SW48 cell proliferation with IC 50 < 100 nM.

[0457] Test Example 3, Inhibition of RL95-2 Cell Proliferation Assay

[0458] The following method was used to determine the effect of the compounds of the present application on the proliferation of RL95-2 cells. RL95-2 cells (MSI-H cells) were purchased from the Cell Resource Center of Shanghai Life Science Research Institute, Chinese Academy of Sciences and cultured in DMEM / F12 medium (Gibco, Cat. No. A4192001) containing 10% fetal bovine serum, 100 U of penicillin and 100 μg / mL of streptomycin. Cell viability was determined by Luminescent Cell Viability Assay kit (Promega, Cat. No. G7573).

[0459] The experimental method was operated according to the steps of the kit instructions, and the brief description is as follows: the test compound was first dissolved in DMSO to prepare a 10 mM stock solution, then diluted with culture medium to prepare test samples, and the final concentration of the compound ranged from 10000 nM to 1.52 nM. Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate at a density of 500 cells per well, incubated in a 37°C, 5% CO2 incubator overnight, and then incubated for another 120 hours after the addition of the test compound. After the incubation was completed, 50 uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes, and then incubated for 10 minutes. Then the luminescence value of each well was read on a microplate reader using the Luminescence mode. The percentage inhibition of the compound at each concentration point was calculated by comparing the values with the control group (0.1% DMSO), and then the compound concentration-log-inhibition was analyzed by non-linear regression analysis in GraphPad Prism 9 software to obtain the IC 50 value of the compound for inhibiting cell proliferation, as shown in Table 3.

[0460] The IC 50 value of the compound of the present application is represented by A,

[0461] “A” represents 1 nM < IC 50 <100 nM.

[0462] Table 3 IC 50 data of the compound of the present application for inhibiting the proliferation of RL95-2 cells

[0463] Conclusion: The compound of the present application has a good inhibitory effect on the IC 50 <100 nM for inhibiting the proliferation of RL95-2 cells.

[0464] Test Example 4, Determination of the Inhibition of the Proliferation of HCT116 Cells by the Compound of the Present Application

[0465] The following method was used to determine the effect of the compounds of the present application on the proliferation of HCT116 cells. HCT116 cells were purchased from the Cell Resource Center of Shanghai Life Science Research Institute, Chinese Academy of Sciences, and were cultured in McCoy's 5a medium containing 10% fetal bovine serum, 100 U of penicillin and 100 μg / mL of streptomycin. Cell viability was determined by luminescent cell viability assay kit (Promega, item number G7573).

[0466] The experimental method was operated according to the steps of the kit instructions, and a brief description is as follows: the test compound was first dissolved in DMSO to prepare a 10 mM stock solution, then diluted with culture medium to prepare test samples, and the final concentration of the compound ranged from 10000 nM to 1.52 nM. Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate at a density of 300 cells per well, incubated in a 37°C, 5% CO2 incubator overnight, and then incubated for another 120 hours after the addition of the test compound. After the incubation was completed, 50 uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes, and then incubated for 10 minutes. Then the luminescence value of each well was read on a microplate reader using the Luminescence mode. The percentage inhibition of the compound at each concentration point was calculated by comparing the values with the control group (0.1% DMSO), and then the compound concentration versus inhibition rate was subjected to nonlinear regression analysis in GraphPad Prism 9 software to obtain the IC 50 value of the compound for inhibiting cell proliferation, as shown in Table 4.

[0467] The IC 50 value of the compound of the present application is represented by A,

[0468] “A” represents 1 nM < IC 50 <100 nM.

[0469] Table 4 IC 50 data of the compound of the present application for inhibiting the proliferation of HCT116 cells

[0470] Conclusion: The compound of the present application has a good inhibitory effect on the IC 50 <100 nM.

Claims

A compound of general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof: wherein: W is selected from N and CH; L is selected from -C(=0)-, -C(=S)-, -S(=0)-, -S(=0)2-, and -NR g C(=O)-; R g selected from a hydrogen atom and C 1-6 alkyl; is selected from a single and a double bond as necessary to render each atom thereof a normal valence; Q is selected from C, N and CR d ; R d selected from a hydrogen atom, a deuterium atom, a hydroxyl group, a cyano group, a halogen and a methoxy group; or R d with the carbon atom to which it is attached and the carbon atom next to it, forms a ring C (to form the structure ), ring C is selected from C 3-6 cycloalkyl and 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains 1, 2, or 3 N, O, or S(=O) r ; wherein said C 3-6 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted by one or more R BB substituents; is a single, double or is absent (to form a 5-membered ring); provided that: When when K is CH, J is C; When K is selected from the group consisting of -O-, -S-, -S(O)-, -S(O)2-, -NH-, -NR dd R ee ) y - and -NH-, J is N, CH or CD; y is selected from 1 and 2; R dd , R ee are identical or different, each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a C 1-6 alkyl group and a C 1-6 haloalkyl group; or R dd , R ee together with the same carbon atom to which they are attached form a -C(=O)-, C 3-6 cycloalkyl or 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl contains 1, 2, or 3 N, O, or S(=O) r atoms; wherein the C 3-6 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted by 1, 2, or 3 R BB groups; or R dd is a hydrogen atom or is absent, R ee together with the carbon atom to which it is attached and the adjacent carbon atom thereof forms a ring C (to form a structure ), ring C is selected from C 3-6 cycloalkyl or 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains 1, 2, or 3 N, O, or S(=O) groups r ; wherein said C 3-6 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with 1, 2, or 3 R BB substituents; R c the same or different, each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group and a C 1-6 haloalkyl group; or two R c together with the same carbon atom to which they are attached form a -C(=O)-, C 3-6 cycloalkyl or 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains 1, 2, or 3 N, O, or S(=O) atoms r ; wherein said C 3-6 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted by 1, 2, or 3 R BB substituents; R BB selected from the group consisting of a deuterium atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and halogen; or two R BB with the same carbon atom to which they are attached form a C 3-4 cycloalkyl or 3-4 membered heterocyclyl, wherein said 3-4 membered heterocyclyl contains 1, 2 or 3 N, O or S(=O) r ; or two R BB with the two adjacent carbon atoms to which they are attached form a C 3-4 cycloalkyl or 3-4 membered heterocyclyl, wherein said 3-4 membered heterocyclyl contains 1, 2 or 3 N, O or S(=O) r ; R 1 selected from alkyl, alkenyl, alkynyl, -NR 15 R 16 , alkoxy, alkylthio, wherein said alkyl, alkoxy or alkylthio is optionally further substituted by 1, 2, or 3 substituents selected from R A , and said alkenyl or alkynyl is substituted by at least one or more substituents selected from R AA ; R AA selected from the group consisting of halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, and fused ring; wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, or fused ring is optionally further substituted with 1, 2, or 3 substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxyl, and cyano; provided that said heterocyclyl is not morpholinyl; R 15 , R 16 are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a C 1-6 alkyl group and an aryl group, wherein said C 1-6 alkyl or aryl group is optionally further substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy and cyano; ring A is selected from: C 3-8 saturated monocyclic alkyl, C 7-8 partially unsaturated monocyclic alkyl, spirocyclic alkyl, fused cyclic alkyl, or bridged cyclic alkyl, wherein said spirocycloalkyl, fused cycloalkyl or bridged cycloalkyl contains 0 or 1 double bond; A 4-membered monocyclic heterocyclic group, a 7-8-membered monocyclic heterocyclic group, a spirocyclic heterocyclic group, or a fused heterocyclic group, wherein the monocyclic heterocyclic group, spirocyclic heterocyclic group, or fused heterocyclic group contains 0 or 1 double bonds, provided that none of the rings constituting the spirocyclic group is cyclopropane, and wherein the monocyclic heterocyclic group is optionally further formed by two atoms on the ring that are not directly connected through a C-type bond. 1-2 Alkyl groups are linked to form bridged heterocyclic groups; bicyclic aryl, bicyclic heteroaryl or bicyclic fused ring; is selected from a single and a double bond as necessary; provided that: U is CR when selected from a double bond bb ring B is selected from the group consisting of cycloalkyl, heterocyclyl, and fused ring groups; U is selected from -O-, -N(R e )- and -S-, ring B is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl and fused ring groups; R bb selected from a hydrogen atom and C 1-6 alkyl; R e selected from a hydrogen atom and C 1-6 alkyl; R A the same or different, each independently selected from the group consisting of a deuterium atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -SF5, -OR 5 , -OC(=O)R 5 , -C(=O)R 5 , -C(=O)OR 5 , -N(R 6 )C(=O)R 7 , -N(R 6 )C(=O)OR 7 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -S(=O) r NR 6 R 7 and -S(=O) r R 5 , wherein said alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally further substituted with 1, 2 or 3 substituents selected from the group consisting of a deuterium atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -OR 8 , =O, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -NR 9 R 10 , -C(=O)NR 9 R 10 , -S(=O)2NR 9 R 10 , -N(R 9 )C(=O)R 10 and -N(R 9 )C(=O)OR 10 ; or two R A with the same carbon atom to which they are attached form a -C(=0), -C(=S) or -C(=NR cc ); R cc selected from a hydrogen atom, a hydroxy group and C 1-6 alkoxy group; R 2 selected from a hydrogen atom, a deuterium atom, a halogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -OR 5 , -S(=O) r R 5 and -NR 6 R 7 ; or two R 2 together with the same carbon atom to which they are attached form a -C(=O) or cyclopropyl; or two R 2 together with the two adjacent carbon atoms to which they are attached form a C 3-6 cycloalkyl or 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains 1, 2, or 3 N, O, or S(=O) atoms r ; wherein said C 3-6 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted by 1, 2, or 3 R BB substituents; R 3 selected from a hydrogen atom, C 1-6 alkyl, amino, hydroxylamino, aryl, heteroaryl or bicyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring consisting of a monocyclic aryl or monocyclic heteroaryl and a monocyclic heterocyclyl or monocyclic cycloalkyl, wherein the C 1-6 alkyl, aryl, heteroaryl or bicyclic fused ring are optionally further substituted by 1, 2 or 3 R B substituents; R B the same or different, each independently selected from the group consisting of a deuterium atom, alkyl, hydroxy, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -SF5, -OR 5 , -OC(=O)R 5 , -C(=O)R 5 , -C(=O)OR 5 , -N(R 6 )C(=O)R 7 , -N(R 6 )C(=O)OR 7 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -S(=O) r NR 6 R 7 and -S(=O) r R 5 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with 1, 2 or 3 substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , =O, -C(=O)R 8 , -C(=O)OR 8 , -OC(=O)R 8 , -NR 9 R 10 , -C(=O)NR 9 R 10 , -S(=O)2NR 9 R 10 , -N(R 9 )C(=O)R 10 and -N(R 9 )C(=O)OR 10 ; R 13 , R 14 each independently is selected from the group consisting of a hydrogen atom, a deuterium atom, a C 1-6 alkyl group and a C 1-6 alkoxy group, or R 13 , R 14 together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl group, wherein said C 3-6 cycloalkyl group is optionally further substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy and cyano; R 4 is selected from aryl, heteroaryl and bicyclic fused rings, wherein the bicyclic fused rings are preferably fused rings consisting of a monocyclic aryl or monocyclic heteroaryl and a monocyclic heterocyclyl or monocyclic cycloalkyl, wherein the aryl, heteroaryl or bicyclic fused rings are optionally further substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, -SF5, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkenyl, C 1-6 alkynyl, -NR 6 R 7 , -C(=O)R 5 and -S(=O) r R 5 , wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkenyl, C 1-6 alkynyl are optionally further substituted by 1, 2 or 3 substituents selected from the group consisting of a deuterium atom, hydroxyl, halogen or C 3-6 cycloalkyl; R 5 each independently is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with 1, 2, or 3 substituents selected from the group consisting of a deuterium atom, hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -C(=0)R 8 , -C(=0)OR 8 , -OC(=0)R 8 , -NR 9 R 10 , -C(=0)NR 9 R 10 , -S(=0)2NR 9 R 10 , and -N(R 9 )C(=0)R 10 ; R 6 and R 7 are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group can optionally be further substituted by 1, 2 or 3 substituents selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =0, -C(=0)R 8 , -C(=0)OR 8 , -OC(=0)R 8 , -NR 9 R 10 , -C(=0)NR 9 R 10 , -S(=0)2NR 9 R 10 and -N(R 9 )C(=0)R 10 ; Or, R 6 and R 7 The atoms bonded to them together form a structure containing one, two, or three N, O, or S atoms (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one, two or three of the following groups: hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 and -N(R) 9 )C(=O)R 10 The substituents are replaced; R 8 , R 9 and R 10 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an amine group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group can optionally be further substituted by 1, 2 or 3 substituents selected from the group consisting of a hydroxyl group, a halogen, a nitro group, an amine group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a carboxyl group and a carboxylate group; p is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3 or 4; and each r is independently 0, 1 or 2. The compound according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein is a single bond; Q is selected from N and CR d ; R d is selected from a hydrogen atom, or R d and the carbon atom to which it is attached and one carbon atom adjacent thereto form a ring C (to form a structure ), ring C is selected from C 3-6 cycloalkyl or 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains 1, 2, or 3 N, O, or S(=O) groups r ; wherein said C 3-6 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted by 1, 2, or 3 R BB substituents; K, J, R c K, J, R BB K, J, R K, J, R K, J, R K, J, R K, J, R K, J, R K, J, R K, J, R The compound according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein K is CR dd R ee J is N, CH or CD; R dd selected from a hydrogen atom and a deuterium atom; R ee selected from a hydrogen atom and a deuterium atom; or R is a hydrogen atom, or R dd is absent or a hydrogen atom, R ee with the carbon atom to which it is attached and the adjacent carbon atom thereof together form a ring C (to form a structure ), ring C is selected from C 3-6 cycloalkyl and 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains 1, 2, or 3 N, O, or S(=O) groups r ; wherein said C 3-6 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with one, two, or three R BB substituents; Q, R c Q, R BB Q, R Q, R Q, R Q, R Q, R Q, R Q, R Q, R Q, R Q, R Q, R Q, R The compound according to any one of claims 1-3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein selected from the group consisting of: wherein: each ring C is independently selected from C 3-6 cycloalkyl and 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl contains 1, 2, or 3 N, O, or S(=O) atoms r ; R BB each independently is selected from the group consisting of a deuterium atom, a methyl group, and a fluorine; R c each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group and a C 1-6 haloalkyl group R d , R dd , R ee are each independently selected from the group consisting of a hydrogen atom and a deuterium atom; n is 0, 1, 2, 3, 4, 5 or 6; t is 0, 1 or 2; q is 0, 1, 2, 3 or 4; r is 0, 1 or 2. The compound according to claim 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from cyclopropyl or cyclobutyl; t is 0; R dd , R ee are each independently selected from the group consisting of a hydrogen atom and a deuterium atom; R c selected from a hydrogen atom, a deuterium atom and a methyl group; R d selected from a hydrogen atom and a deuterium atom; n is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1 or 2. The compound according to claim 5, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein selected from the group consisting of: The compound according to any one of claims 1 to 6, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, is a compound according to general formula (II), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof: wherein: W, R 1 W, R 2 W, R 3 W, R 4 and p are as defined in claim 1. The compound according to any one of claims 1 to 6, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, is a compound according to general formula (III), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof: wherein: W, R 1 W, R 2 W, R 3 W, R 4 and p are as defined in claim 1. The compound according to any one of claims 1 to 8, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from a hydrogen atom and a methyl group. The compound according to claim 9, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, is a compound according to general formula (IV-1) or (IV-2), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof: wherein: W, R 1 W, R 3 W, R 4 are as defined in claim 1. The compound according to claim 10, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, is a compound according to general formula (V-1) or (V-2), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof: wherein: W, R 1 R 3 R 4 The definition is as described in claim 1. The compound according to any one of claims 1 to 11, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, -NR 15 R 16 or C 1-6 alkenyl, wherein said C 1-6 alkyl is optionally further substituted with 1, 2 or 3 halogens, wherein said C 1-6 alkenyl is substituted with at least 1, 2 or 3 substituents selected from R AA ; R AA selected from the group consisting of halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, and fused ring; wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, or fused ring is optionally further substituted with 1, 2, or 3 substituents selected from the group consisting of methyl, trifluoromethyl, methoxy, trifluoromethoxy, halogen, hydroxy, and cyano; with the proviso that said heterocyclyl is not morpholinyl; R 15 selected from a hydrogen atom; R 16 selected from C 1-6 alkyl and aryl, wherein said C 1-6 alkyl or aryl is optionally further substituted by 1, 2 or 3 halogen. The compound according to any one of claims 1-11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 selected from wherein ring A is selected from C 3-8 saturated monocyclic alkyl, C 7-8 partially unsaturated monocyclic alkyl, spirocyclic alkyl, fused cyclic alkyl, bridged cyclic alkyl, 4-membered monocyclic heterocyclyl, 7-8 membered monocyclic heterocyclyl, spiroheterocyclyl, bicyclic heteroaryl and bicyclic fused cyclic, wherein said spirocyclic alkyl, fused cyclic alkyl, bridged cyclic alkyl, 4-membered monocyclic heterocyclyl, 7-8 membered monocyclic heterocyclyl or spiroheterocyclyl contains 0 or 1 double bond, provided that, none of the rings comprising said spiroheterocyclyl is cyclopropane; R A selected from a deuterium atom, halogen, hydroxyl, methyl, deuterated methyl, methoxy, NR 6 R 7 and -C(=O)NR 6 R 7 ; or, two R A together with the same carbon atom to which they are attached form a -C(=O) or -C(=NR cc ); R cc selected from hydroxy and methoxy; R 6 , R 7 is selected from a hydrogen atom; m is 0, 1, 2, 3, 4 or 5. The compound according to any one of claims 1-11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from wherein selected from a double bond, U is CR bb ring B is selected from cycloalkyl and heterocyclyl; R bb selected from a hydrogen atom and a methyl group; R A selected from a deuterium atom, a halogen, a hydroxyl group, a methyl group, a methoxy group, NR 6 R 7 and -C(=O)NR 6 R 7 ; R 6 , R 7 is selected from a hydrogen atom; m is 0 or 1. The compound according to any one of claims 1-11, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from wherein is selected from a single bond, U is selected from O, and ring B is selected from aryl and heteroaryl; m is 0. The compound according to any one of claims 1-11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: The compound according to any one of claims 1 to 16, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl and 8-10 membered bicyclic fused ring, wherein the 8-10 membered bicyclic fused ring is preferably a fused ring consisting of a monocyclic heteroaryl and a monocyclic heterocyclyl, and wherein the 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl or 8-10 membered bicyclic fused ring is optionally further substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium atom, hydroxy, halogen, alkyl, alkylthio, alkoxy, haloalkyl, hydroxyalkyl and haloalkoxy. The compound according to claim 17, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of: The compound according to any one of claims 1-18, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4 selected from wherein X is selected from N and CH; R 17 selected from a hydrogen atom, a halogen, a hydroxyl, a cyano, -SF5, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkenyl, C 1-6 alkynyl, -C(=O)R 5 and -S(=O) r R 5 ; wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted with 1, 2 or 3 substituents selected from a deuterium atom, a hydroxyl, a halogen or a cyclopropyl; R 18 selected from a hydrogen atom, a halogen, a cyano group, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group, a C 3-6 halocycloalkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group and a -C(=O)R 5 ; R 19 selected from a hydrogen atom, a hydroxyl group, a cyano group, a halogen, a methyl group and a methoxy group; R 20 selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group and a C 1-6 haloalkoxy group; R 5 each independently is selected from the group consisting of a hydrogen atom and a C 1-6 alkyl group, wherein said C 1-6 alkyl group is optionally further substituted with 1, 2, or 3 deuterium atoms or halogens; r is 0, 1 or 2. The compound according to claim 19, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of: The compound according to any one of claims 1-20, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is: A pharmaceutical composition comprising a compound according to any one of claims 1-21, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Use of a compound according to any one of claims 1-21, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for the manufacture of a WRN inhibitor. Use of a compound according to any one of claims 1-21, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for the manufacture of a medicament for the treatment of a disease mediated by WRN; preferably, wherein said disease mediated by WRN is a microsatellite instability-high cancer. The use according to claim 24, wherein said microsatellite instability-high cancer is selected from colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, renal clear cell carcinoma, ovarian serous cystadenocarcinoma, cholangiocarcinoma, thymoma, liver cancer, head and neck squamous cell carcinoma, sarcoma, cutaneous melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia and glioma, preferably colorectal cancer, gastric cancer or endometrial cancer. Use of a compound according to any one of claims 1-21, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for the manufacture of a medicament for the treatment of a microsatellite instability-high cancer. Use of a compound according to any one of claims 1-21, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for the manufacture of a medicament for the treatment of a microsatellite instability-high cancer. Use according to claim 26, wherein the high microsatellite instability cancer is selected from the group consisting of colorectal cancer, gastric cancer, endometrial cancer, rectal adenocarcinoma, adrenocortical carcinoma, uterine sarcoma, cervical cancer, nephroblastoma, mesothelioma, esophageal cancer, breast cancer, renal clear cell carcinoma, ovarian serous cystadenocarcinoma, cholangiocarcinoma, thymoma, hepatocarcinoma, head and neck squamous cell carcinoma, sarcoma, cutaneous melanoma, lung squamous cell carcinoma, prostate cancer, lung adenocarcinoma, bladder transitional cell carcinoma, pediatric neuroblastoma, chronic lymphocytic leukemia and glioma, preferably colorectal cancer, gastric cancer or endometrial cancer.

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