TREX2 1,2,4-triazole-3-thion inhibitor used in the treatment of psoriasis, atopic dermatitis, or ichthyosis.

Abstract

The present invention relates to a compound of formula (I) for the treatment or prevention of pathological conditions associated with increased expression and activity of TREX2, wherein A1 is a group of formula (II), and A2 is a ring system consisting of one or two rings, where each ring is a saturated ring, a partially saturated ring, or an unsaturated ring, and is composed of N, O, S, C, NR p CR z , and C(R z ) has 5 or 6 ring members selected from the group consisting of 2, and A3 is X7-(X8) n The present invention provides a compound in which X1 represents CR1 or N, X2 represents CR2 or N, X3 represents CR3 or N, X4 represents CR4 or N, X5 represents CR5 or N, X6 represents CR6 or N, X7 represents CR7 or N, and X8 represents CR8 or N, where one, two, or three of X1 to X8 are N, and n is an integer selected from 0 or 1. The present invention also provides a compound of formula (Ibis), as well as pharmaceutical compositions containing the same and methods for preparing them. TIFF2026517359000192.tif39170

Description

[Technical Field]

[0001] The present invention provides compounds suitable as TREX2 inhibitors, as well as methods for producing them, pharmaceutical compositions, and their use in the treatment of inflammation of the skin and mucous membranes. [Background technology]

[0002] Throughout the lifespan of a cell, DNA replication, repair, recombination, and degradation are essential tasks. Several proteins are involved in these processes, among which 3'-5'-exonucleases play a crucial role.

[0003] 3-prime repair exonuclease 2 (TREX2) is homologous to TREX1 and is a non-processive 3'-5' exonuclease that shares similar biochemical characteristics. The preferred substrate for both proteins is DNA rather than RNA, and can be single-stranded DNA (ssDNA) or double-stranded DNA (dsDNA) (Non-Patent Literature 1). However, TREX1 and TREX2 exhibit different tissue expression profiles and biological functions. TREX1 is universally expressed and plays an anti-inflammatory role (Non-Patent Literature 2, Non-Patent Literature 3), while TREX2 shows limited expression in squamous epithelial tissues such as skin, specifically in keratinocytes, where it plays a pro-inflammatory role (Non-Patent Literature 4, Non-Patent Literature 5). In particular, TREX2 promotes DNA degradation and further cell death in damaged and stressed keratinocytes, thus shaping skin physiology by promoting skin inflammation in psoriasis (Non-Patent Literature 5). Trex2 knockout mice are viable and do not show significant differences in growth, survival, lymphocyte development, or spontaneous tumor incidence compared to their wild-type mice (Non-Patent Literature 4), which supports the important role of TREX2 in keratinocytes under threat rather than basal conditions.

[0004] The importance of the exonuclease TREX2 in skin homeostasis becomes apparent when its expression is abnormal. For example, TREX2 is overexpressed in psoriasis (Non-Patent Literature 5). Consistently, in mouse models of psoriasis with imiquimod-induced or IL-23-induced inflammation, Trex2 knockout mice have been found to show a significant reduction in signs of psoriatic inflammation, such as erythema or epidermal thickening (Non-Patent Literature 5). Furthermore, a decrease in the transcription of inflammation-related genes such as IL-23 and TNF-α, and inhibition of keratinocyte apoptosis were observed (Non-Patent Literature 5). In fact, dying keratinocyte cells release various signals that contribute to inducing and amplifying skin inflammation (Non-Patent Literature 6). Overall, the data indicate that TREX2 plays a crucial role in promoting the inflammatory psoriasis phenotype, highlighting this keratinocyte-specific exonuclease as a novel therapeutic target for psoriasis.

[0005] Furthermore, analysis of available transcriptome data revealed increased TREX2 expression in at least two other chronic inflammatory skin diseases, including ichthyosis (Non-Patent Documents 7 and 8) and atopic dermatitis (Non-Patent Document 9). Importantly, a significant Spearman correlation was observed between TREX2 expression and atopic dermatitis severity scores (Non-Patent Document 10). These expression data also highlight TREX2 as a potential target for ichthyosis and atopic dermatitis.

[0006] Regarding the role of TREX2 in cancer, upregulation of TREX2 in colorectal cancer has been associated with decreased survival rates (Non-Patent Literature 11). On the other hand, transcriptome analysis revealed that TREX2 expression increased in the K562 leukemia cell lineage after treatment with nilotinib, a BCR-ABL tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (GSE19567).

[0007] Until now, TREX2 has been considered more as a prognostic or diagnostic marker than as a therapeutic target for managing the aforementioned diseases. Furthermore, the TREX2 protein has been used as a tool to improve the efficiency of CRISPR / Cas9 editing (Non-Patent Literature 12).

[0008] In light of the above, there is a need to provide a molecule that can effectively inhibit TREX2 activity in a pathological environment and provide therapeutic benefits. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Mazur & Perrino, 2001 [Non-Patent Document 2] Morita et al., 2004 [Non-Patent Document 3] Gall et al., 2012 [Non-Patent Document 4] Parra et al., 2009 [Non-Patent Document 5] Manils et al., 2016 [Non-Patent Document 6] Pasparakis et al., 2014 [Non-Patent Document 7] Krieg et al., 2020 [Non-Patent Document 8] Kim et al., 2022 [Non-Patent Document 9] Esaki et al., 2015 [Non-Patent Document 10] Tsoi et al., 2019 [Non-Patent Document 11] Song et al., 2022 [Non-Patent Document 12] Yin et al., 2022 [Overview of the project]

[0010] The inventors have found that 1,2,4-triazole-3-thione compounds exhibit potent TREX2 inhibitory activity when substituted with a ring system at positions 4 and 5.

[0011] As shown below, the efficacy of compounds constituting part of the present invention in effectively and selectively inhibiting TREX2 against recombinant TREX2 protein and recombinant TREX1 protein was determined. The data are shown in Tables 1 and 2 below.

[0012] On the other hand, the compounds tested in this invention showed efficacy in inhibiting TREX2 exonuclease activity, and as shown in Table 1 below, the compound with the highest efficacy had an IC50 at less than 30 μM and close to 1 μM. 50 It was found to show a value.

[0013] On the other hand, the inventors demonstrated that these compounds are more selective in inhibiting TREX2 exonuclease than TREX1 exonuclease. As shown in Table 2 below, the IC2 of the most potent TREX2 inhibitors against TREX1 50 The value exceeds 100 μM, and the IC for TREX2 50 The value was approximately 100 times higher. This means that at doses in which the compound of the present invention inhibits TREX2, no significant effect would occur against TREX1. Therefore, the compound of the present invention is not only potent but also selective for TREX2 rather than TREX1.

[0014] As explained above, TREX2 and TREX1 are homologous proteins exhibiting similar biochemical and enzymatic properties, but these two exonucleases play different biological roles and exhibit different tissue expression patterns. In particular, TREX2, which is specifically expressed in keratinocytes, functions to promote skin inflammation, while TREX1, which is universally expressed across all cell types and tissues, has a broad range of anti-inflammatory functions.

[0015] The above in vitro findings regarding the efficacy of the compounds as TREX2 inhibitors were also confirmed in vivo in well-established mouse models of psoriasis, where the compounds of the present invention were administered orally, topically, or intraperitoneally. In all cases tested, a significant improvement in disease state (reduction of psoriasis-induced inflammation) was detected. In fact, all in vivo tested compounds of the present invention reduced psoriatic inflammation associated with TREX2 overexpression and subsequent increased activity. The specificity is supported by the absence of anti-inflammatory effects of the compounds in the absence of TREX2 (Trex2-deficient mice).

[0016] The data presented below also demonstrates their suitability as pharmacological agents, as they do not exhibit widespread cytotoxicity.

[0017] In view of the above, in a first embodiment, the present invention (1.1) is used in the treatment of pathological conditions associated with increased TREX2 expression, formula (I): [ka] (In the formula, A1 is equation (II): [ka] It is the basis of this formula, A3 is X7-(X8) n This represents, X1 represents CR1 or N, X2 represents CR2 or N, X3 represents CR3 or N, X4 represents CR4 or N, X5 represents CR5 or N, X6 represents CR6 or N, X7 represents CR7 or N, and X8 represents CR8 or N, provided that one, two, or three of X1 to X8 are N. n is an integer selected from 0 or 1. R1~R8 are independently substituted with hydrogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10Alkenyl, optionally substituted with one or more Z substituents, of (C2-C 10 Alkynyl, halogen, OR9, COOR 10 , and C(R x )2, NR y , O, or S, selected from the group consisting of cycloalkyl having 3 to 7 ring members, provided that at least one or two of these ring members are heteroatoms, or alternatively, R3 and R4, together with X3 and X4 to which they are attached, form a partially saturated or aromatic ring having 5 or 6 ring members, optionally substituted with one or more Z substituents, or alternatively, R4 and R5, together with X4 and X5 to which they are attached, form a partially saturated or aromatic ring having 5 or 6 ring members, optionally substituted with one or more Z substituents, or alternatively, R5 and R, together with X5 and X6 to which they are attached, form a partially saturated or aromatic ring having 5 or 6 ring members, optionally substituted with one or more Z substituents, or alternatively, R9 and R 10 are independently hydrogen, (C1-C 10 )alkyl optionally substituted with one or more Z substituents, (C2-C 10 )alkenyl optionally substituted with one or more Z substituents, (C2-C 10 )alkynyl; C(R x )2, NR y , O, or S, cycloalkyl having 3 to 7 ring members, C(O)R 11 , or NR 12 R 13 selected from R 11 is hydrogen, (C1-C 10 )alkyl optionally substituted with one or more Z substituents, (C2-C 10 )alkenyl optionally substituted with one or more Z substituents, (C2-C 10 )alkynyl; C(R x )2, NR yCycloalkyl groups having 3 to 7 ring members selected from O, or S, or N, O, S, and CR w Selected from the group consisting of, an aryl having 5 or 6 ring members, R x and R w These are, independently, hydrogen, C(O)R 14 , C(O)OR 15 , NR 16 R 17 , OR 18 , optionally substituted with one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from Alkinnil, R y , R 12 , R 13 , R 16 , and R 17 These are, independently, hydrogen, C(O)R 19 , C(O)OR 20 , optionally substituted with one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from Alkinnil, R 14 and R 19 These are independently hydrogen, NH2, and NHR. 21 , optionally substituted with one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, one or more OH groups, halogen, (C1~C 10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10 )Alkinyl, -O-(C1~C 10 ) alkyl, (C1~C 10) Haloalkyl, or -O-(C1~C 10 ) (C3-C7) cycloalkyls substituted with haloalkyls, or N, O, S, and CR t Selected from the group consisting of, an aryl having 5 or 6 ring members, R 15 and R 20 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, one or more OH groups, halogen, (C1~C 10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10 )Alkinyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from (C3-C7) cycloalkyl groups substituted with haloalkyl groups, R 18 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, one or more OH groups, halogen, (C1~C 10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10 )Alkinyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from (C3-C7) cycloalkyl groups substituted with haloalkyl groups, R 21 (C1~C) is a hydrogen atom substituted with one or more Z substituents. 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10Alkenyl, (C2 - C 10 ) alkynyl, optionally substituted with one or more OH, halogen, (C1 - C 10 ) alkyl, (C2 - C 10 ) alkenyl, (C2 - C 10 ) alkynyl, or -O-(C1 - C 10 ) alkyl-substituted (C3 - C7) cycloalkyl, or aryl having 5 or 6 ring members selected from the group consisting of N, O, S, and CR s , wherein R s is hydrogen, OH, halogen, (C1 - C 10 ) alkyl, -O-(C1 - C 10 ) alkyl, (C1 - C 10 ) haloalkyl, -O-(C1 - C 10 ) haloalkyl, (C2 - C 10 ) alkenyl, or (C2 - C 10 ) alkynyl, selected from R t is hydrogen, OH, halogen, (C1 - C 10 ) alkyl optionally substituted with one or more Z substituents, (C2 - C 10 ) alkenyl optionally substituted with one or more Z substituents, (C2 - C 10 ) alkynyl optionally substituted with one or more Z substituents, -O-(C1 - C 10 ) alkyl optionally substituted with one or more OH, halogen, (C1 - C 10 ) alkyl, (C2 - C 10 ) alkenyl, (C2 - C 10 ) alkynyl, -O-(C1 - C 10 ) alkyl, (C1 - C 10 ) haloalkyl, or -O-(C1 - C 10 ) haloalkyl-substituted (C3 - C7) cycloalkyl, or aryl having 5 or 6 ring members selected from the group consisting of N, O, S, and CR v , wherein R v is hydrogen, OH, halogen, (C1 - C 10 ) alkyl, -O-(C1 - C 10) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, L is -(CH2) p Selected from the group consisting of - and -C(O)-, m is the entire number selected from 0 or 1. p is the total number selected from 1 to 10, especially 1 to 5, and especially 1 to 2. A2 is a ring system consisting of one or two rings, where, Each ring is either saturated, partially saturated, or unsaturated, and is composed of N, O, S, C, or NR. p CR z , and C(R z ) Having 5 or 6 ring members selected from the group consisting of 2, When a ring system consists of two rings, these rings are either fused or isolated, and R p (C1~C) is a hydrogen atom substituted with one or more Z substituents. 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, (C3-C7) cycloalkyl substituted with one or more Z substituents, or N, O, S, and CR d Selected from the group consisting of aryls having 5 or 6 ring members, where R d OH, halogen, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, R z is hydrogen, halogen, O(CH2) a R 22, C(O)R 23 , optionally substituted with one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, SO2NR 24 R 25 ;C(R b )2, NR c A cycloalkyl ring having 3 to 7 ring members selected from O, or S, or N, O, S, and CR e Selected from the group consisting of aryls having 5 or 6 ring members, where R e Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, a is an integer representing 0 or 1. R 22 , R 23 , and R b These are independently substituted with hydrogen, halogen, OH, and optionally one or more Z substituents (C1~C 10 ) Alkyl, NR 37 R 38 , optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, -O-(C1~C) substituted with one or more Z substituents 10 )alkyl;C(R' b )2, NR' c A cycloalkyl ring having 3 to 7 ring members selected from O, or S, or N, O, S, and CR f Selected from the group consisting of aryls having 5 or 6 ring members, where R f Hydrogen, OH, halogens, (C1~C 10)alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, R 24 , R 25 , R b , R c , R 37 , R 38 , and R' c These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, (C3-C7) cycloalkyl, optionally substituted with one or more Z substituents; N, O, S, and CR g Selected from the group consisting of aryls having 5 or 6 ring members, where R g Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, Z is (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenil, (C2~C 10 ) Alkynyl, halogen, OR 26 COOR 27 , arbitrarily one or more OH, halogen, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenil, (C2~C 10 ) Alkinyl, COOR 28 NH2, or NHR 29 (C3~C7) cycloalkyl groups substituted with (C3~C7), optionally one or more OH groups, halogens, NH2, NHR 30 , (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenil, (C2~C 10 ) Alkinyl, or COOR 31 A aryl substituted with, and optionally one or more OH, halogen, NH2, NHR 32 , (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenil, (C2~C 10 ) Alkinyl, or COOR 33 Selected from the group consisting of heteroaryls substituted with, R 26 ~R 28 and R 31 ~R 33 Independently, hydrogen, (C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, and (C2~C 10 ) Selected from Alkinnil, R 29 , R 30 , and R 32 Independently, hydrogen, (C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10The present invention provides compounds (selected from alkynyls) or pharmaceutically acceptable salts or solvates thereof.

[0018] This embodiment can be clearly expressed as the use of the compound of formula (I) defined above in the manufacture of a pharmaceutical product for treating a pathological condition associated with the overexpression of TREX2. This embodiment can also be clearly expressed as a method for treating a pathological condition associated with the overexpression of TREX2, comprising the step of administering a therapeutically effective amount of the compound of formula (I) defined above to a subject in need of treatment.

[0019] In a second embodiment, the present invention (1.2) is of formula (Ibis): [ka] (In the formula, A 1bis Equation (IVbis): [ka] It is the basis of, and in the formula, (i) R3, R5~R7 are independently substituted with hydrogen, halogen, OH, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, OR9, COOR 10 , and C(R x )2, NR y It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from cycloalkyl rings that are heteroatoms, and R'4 is substituted with hydrogen, F, Cl, OH, or one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, OR9, COOR 10, and C(R x )2, NR y It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from cycloalkyl rings that are heteroatoms, or alternatively, (ii) R3 and R'4 condense to form an aromatic ring system with the carbon atoms to which they are attached, and R5, R6, and R7 are independently substituted with hydrogen, a halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from or alternative to alkinyl, (iii) X5 is CR5, where R5 and R6 condense to form an aromatic ring system with the carbon atoms to which they are attached, and R3 and R7 are independently substituted with hydrogen, a halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from alkynyl groups, and R'4 is substituted with hydrogen, F, Cl, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from Alkinnil, The present invention provides compounds of A2, L, and m (as defined in the first embodiment of the present invention) or pharmaceutically acceptable salts or solvates thereof.

[0020] In a third aspect, the present invention (1.3) provides a pharmaceutical composition comprising a therapeutically effective amount of a compound defined in a second aspect of the present invention and one or more pharmaceutically acceptable additives or carriers.

[0021] In a fourth embodiment, the present invention (1.4) provides compounds defined in the second embodiment of the present invention for use in therapeutic or biotechnological applications as research tools.

[0022] For example, the TREX2 protein is used as a tool to improve the efficiency of CRISPR / Cas9 editing. The TREX2 exonuclease promotes DNA end trimming, avoiding precise ligation and perfect DNA repair. In this context, TREX2 inhibition allowed for precise control of TREX2 activity in this biotechnology assay.

[0023] In a fifth embodiment, the present invention (1.5) provides a kit comprising means for determining TREX2 activity together with a compound defined in the first or second embodiment of the present invention.

[0024] In a final embodiment, the present invention (1.6) provides an in vitro method for inhibiting the activity of TREX2 in an isolated sample of a subject, comprising the step of contacting the isolated sample with any of the compounds of formula (I), formula (Ibis), or pharmaceutically acceptable salts or solvates thereof as defined in the first and second embodiments of the present invention.

[0025] Alternatively, apart from the embodiments described above, the present invention relates to the following further alternative embodiments:

[0026] In an alternative first embodiment (2.1), the present invention is used in the treatment or prevention of diseases caused by increased TREX2 expression, preferably selected from the group consisting of psoriasis, atopic dermatitis, and ichthyosis, comprising formula (I): [ka] (In the formula, A1 is either equation (III) or equation (IV) [ka] This is expressed as follows, where X5 represents N or CR5, and R3 to R7 are as defined below, or A1 is the formula: [ka] It is expressed as follows, where K is defined below: R3~R7 are independently substituted with hydrogen and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, halogen, OR9, COOR 10 , and C(R x )2, NR y It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from the group consisting of heteroatoms cycloalkyl groups, or alternatively, R3 and R4, together with X3 and X4 to which they are attached, form a partially saturated or aromatic ring having 5 or 6 ring members optionally substituted with one or more Z substituents, or alternatively, R4 and R5, together with X4 and X5 to which they are attached, form a partially saturated or aromatic ring having 5 or 6 ring members optionally substituted with one or more Z substituents, or alternatively, R5 and R6, together with X5 and X6 to which they are attached, form a partially saturated or aromatic ring having 5 or 6 ring members optionally substituted with one or more Z substituents, or alternatively, R9 and R 10 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl; C(R x )2, NR yCycloalkyl groups having 3 to 7 ring members selected from O or S, C(O)R 11 , or NR 12 R 13 Selected from, R 11 (C1~C) is a hydrogen atom substituted with one or more Z substituents. 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl; C(R x )2, NR y Cycloalkyl groups having 3 to 7 ring members selected from O, or S, or N, O, S, and CR w Selected from the group consisting of, an aryl having 5 or 6 ring members, R x and R w These are, independently, hydrogen, C(O)R 14 , C(O)OR 15 , NR 16 R 17 , OR 18 , optionally substituted with one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from Alkinnil, R y , R 12 , R 13 , R 16 , and R 17 These are, independently, hydrogen, C(O)R 19 , C(O)OR 20 , optionally substituted with one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from Alkinnil, R 14 and R 19 These are independently hydrogen, NH2, and NHR.21 , optionally substituted with one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, one or more OH groups, halogen, (C1~C 10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10 )Alkinyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) (C3-C7) cycloalkyls substituted with haloalkyls, or N, O, S, and CR t Selected from the group consisting of, an aryl having 5 or 6 ring members, R 15 and R 20 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, one or more OH groups, halogen, (C1~C 10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10 )Alkinyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from (C3-C7) cycloalkyl groups substituted with haloalkyl groups, R 18 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, one or more OH groups, halogen, (C1~C 10 ) Alkyl, (C2~C 10) Alkenil, (C2~C 10 )Alkinyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from (C3-C7) cycloalkyl groups substituted with haloalkyl groups, R 21 (C1~C) is a hydrogen atom substituted with one or more Z substituents. 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, one or more OH groups, halogen, (C1~C 10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10 )Alkinyl, or -O-(C1~C 10 )Cycloalkyl (C3-C7) substituted with alkyl, or N, O, S, and CR s Selected from the group consisting of aryls having 5 or 6 ring members, where R s Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, R t (C1~C) is substituted with hydrogen, OH, halogen, or one or more Z substituents. 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, -O-(C1~C) substituted with one or more Z substituents 10 )alkyl, one or more OH groups, halogen, (C1~C 10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10)Alkinyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) (C3-C7) cycloalkyls substituted with haloalkyls, or N, O, S, and CR v Selected from the group consisting of aryls having 5 or 6 ring members, where R v Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, K is hydrogen, halogen, (C1~C 10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10 )Alkinyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Haloalkyl; N, O, S, and CR v One or more aryls having 5 or 6 ring members are selected from the group consisting of R, where R v Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenil, or (C2~C 10 ) Alkinyl, or C(R x )2, NR y It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are heteroatoms, optionally (C1~C 10 Selected from cycloalkyls substituted with one or more Z substituents such as )alkyl or C(O)(C1~C4)alkyl, where Rx and R y This is as specified above, and L is -(CH2) p Selected from the group consisting of - and -C(O)-, m is the total number selected from 0 or 1. p is the total number selected from 1 to 10, especially 1 to 5, and especially 1 to 2. A2 is given by the following formula: [ka] A ring having any of the following rings: [ka] It is one of the following: During the ceremony, X9 is NR 34 , O, S, or CR z16 This represents, X 10 , NR 35 , O, S, or CR z17 This represents, X 11 , NR 36 , O, S, or CR z18 This represents, R z1 ~R z18 These are independently substituted with hydrogen, halogens, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 )Alkinyl, -O-(C1~C 10 ) Haloalkyl, (C1~C 10 ) Haloalkyl, O(CH2)R 22 , C(O)R 23 SO2NR 24 R 25 , OH, NR 24 R 25 ;N, O, S, and CR e Selected from the group consisting of , R is selected from aryls containing o-aryls such as phenoxy or benzyloxy having 5 or 6 ring members, where Re Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Haloalkyl, or NH, O, S, and C(R b ) Selected from cycloalkyls having 5 or 6 ring members selected from 2, R 22 ~R 25 , and R b These are independently hydrogen, halogen, OH, NR 37 R 38 , optionally substituted with one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, -O-(C1~C) substituted with one or more Z substituents 10 ) alkyl, C(R' b )2, NR' c A cycloalkyl ring having 3 to 7 ring members selected from O, or S, or N, O, S, and CR f Selected from the group consisting of aryls having 5 or 6 ring members, where R f Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, R 37 , R 38 , R' b , and R' c These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, (C3-C7) cycloalkyl, optionally substituted with one or more Z substituents; N, O, S, and CR g Selected from the group consisting of aryls having 5 or 6 ring members, where R g Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, R 34 , R 35 , and R 36 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) alkenyl and (C2~C) optionally substituted with one or more Z substituents 10 The present invention provides compounds (selected from alkynyls) or pharmaceutically acceptable salts or solvates thereof.

[0027] In a preferred embodiment of an alternative first aspect of the present invention, A1 is formula (III) or formula (IV) [ka] (wherein X5 represents N or CR5, and R3 to R7 are as defined in claim 1)

[0028] In another preferred embodiment of the alternative first aspect of the present invention, A1 may be optionally combined with any of the previously defined embodiments of the alternative first aspect of the present invention, where A1 is formula (III) or formula (IV) [ka] (wherein X5 represents CR5, and R3 to R7 are as defined in claim 1)

[0029] In another preferred embodiment of the alternative first aspect of the present invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the present invention, A1 is represented by formula (III), and R3~R6 are substituted with hydrogen, halogen, or one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, or -O-(C1~C) substituted with one or more Z substituents. 10 ) Selected from alkyl groups, and in particular, R3~R6 are hydrogen atoms.

[0030] In another preferred embodiment of the alternative first aspect of the present invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the present invention, A1 is represented by formula (IV), and R3~R7 are independently substituted with hydrogen, halogen, OH, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from or alternative to alkinyl, R3 and R4 condense to form an aromatic ring system with the carbon atoms to which they are attached, and R5, R6, and R7 are independently substituted with hydrogen, halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from or alternative to alkinyl, X5 is CR5, R5 and R6 are condensed to form an aromatic ring system with the carbon atoms to which they are attached, and R3, R4 and R7 are independently substituted with hydrogen, halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from Alkinyl.

[0031] In another preferred embodiment of the alternative first aspect of the present invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the present invention, A1 is represented by formula (III) or formula (IV), and A2 is represented by formula (V), formula (VI), formula (VII), or formula (VIII): [ka] (In the formula, X9 is NR 34 , O, S, or CR z16 This represents, X 10 , NR 35 , O, S, or CR z17 This represents, X 11 , NR 36 , O, S, or CR z18 This represents, R z1 ~R z18 These are independently substituted with hydrogen, halogens, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, O(CH2) a R 22 , C(O)R 23 SO2NR 24 R 25 ;N, O, S, and CR e An aryl having 5 or 6 ring members selected from the group consisting of (where R eHydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from haloalkyls), or NH, O, S, and C(R b ) Selected from cycloalkyls having 5 or 6 ring members selected from 2, R 22 ~R 25 , and R b This is as set forth in any one of the preceding claims, and, R 34 , R 35 , and R 36 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) alkenyl and (C2~C) optionally substituted with one or more Z substituents 10 It is an aryl ring (selected from alkynyls).

[0032] In another preferred embodiment of the alternative first aspect of the present invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the present invention, A1 is represented by formula (III) or (IV), and A2 is represented by formula (V), and Rz1 to Rz5 are substituted with hydrogen, and optionally one or more Z substituents (C1 to C 10 ) Alkyl, O(CH2) a R 22 , C6 aryl, halogen, COOH, or C(O)(C1~C 10 ) Selected from alkyl, and R 22 (C1~C) is substituted with one or more Z substituents as arbitrary. 10 ) Represents alkyl or C6 aryl, or alternatively, A2 is represented by equation (VI), and Rz6 to Rz8 are the same, and in particular these are hydrogen, or alternatively, A2 is expressed by equation (VII), and Rz9~Rz 12These are independently hydrogen, halogen, SO2NH2, or NH, O, S, and C(R b Selected from cycloalkyl groups having 5 or 6 ring members selected from )2, particularly Rz9~Rz 11 It is hydrogen, and Rz 12 These are hydrogen, halogens, SO2NH2, or NH, O, S, and C(R b ) Selected from cycloalkyl groups having 5 or 6 ring members selected from 2, or alternatively, A2 is expressed by equation (VIII), and X9, X 10 , and X 10 These are the same, and in particular these are CH, or alternatively, X9 and X 11 These are the same, and in particular, these are O.

[0033] In another preferred embodiment of the alternative first aspect of the present invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the present invention, R3~R7 are independently substituted with hydrogen and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, F, Cl, OR9, COOR 10 , or C(R x )2, NR y It has 3 to 7 ring members selected from O or S, however at least one or two of these ring members are selected from heteroatoms, specifically cycloalkyl groups. R3~R7 are independently substituted with hydrogen and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Selected from alkynyl, F, or Cl, in particular, R3~R7 are independently substituted with hydrogen and optionally one or more Z substituents (C1~C 10) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, OR9, COOR 10 , or C(R x )2, NR y It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from cycloalkyl heteroatoms.

[0034] In another preferred embodiment of the alternative first aspect of the present invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is [01-001] 4-(benzo[d][1,3]dioxol-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-002] 5-(quinoline-2-yl)-4-(4-(trifluoromethyl)phenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-003] 4-(4-chlorophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-004] 5-(quinoline-2-yl)-4-(p-tolyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-005] 4-(3-bromophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-006] 4-benzyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-007] 4-phenyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-008] 1-(4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenyl)ethane-1-one, [01-009] 4-(4-phenoxybenzyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-010] 4-(4-methoxy-2-methylphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-011] 4-(4-methoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-012] 4-([1,1'-biphenyl]-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-013] 4-(4-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-014] 5-(quinoline-2-yl)-4-(thiophene-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-015] 4-(4-phenoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-016] 4-(3-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-017] 4-(2,3-dihydro-1H-inden-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-018] 4-(6-chloropyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-019] 4-(6-(piperazine-1-yl)pyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-020] Phenyl(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone, [01-021] (4-chlorophenyl) (3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone, [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-023] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-024] 4-(benzo[d][1,3]dioxol-5-yl)-5-(5-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-025] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-026] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-(trifluoromethoxy)benzyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-027] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,3-dihydro-1H-inden-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-028] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-phenoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-029] 4-(4-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-030] 4-(3-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-031] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-methoxy-2-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-032] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-033] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-(pyrrolidine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-034] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, [01-035] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, [01-036] (3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)(phenyl)methanone, [01-037] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[2,1-a]isoquinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-038] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-039] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyrazine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, N-(4,6-dimethylpyrimidine-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, N-(4-methoxy-1,2,5-thiadiazole-3-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, 3-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, 4-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-thione, 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-hydroxyquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [1-050] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-methylquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-051] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-bromoimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-052] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-053] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(1-methyl-1H-pyrazole-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-054] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,2-diphenylethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-055] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(3-morpholinopropyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-056] 3-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, [01-057] 3-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzamide, [01-058] 5-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-2-methoxybenzoic acid, [01-059] 5-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-2-methoxybenzamide, [01-060] 4-(4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenoxy)picolinic acid, [01-061] 4-(4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenoxy)-N-methylpicolinamide, [01-062] 4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-063] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-chloropyridine-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-064] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-065] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(4-methylpiperazine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-066] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(piperazine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-067] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-morpholinopyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-068] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-chloropyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-069] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(piperazine-1-yl)pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-070] 1-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)propan-1-one, [01-071](3aR,4R,6aS)-4-(5-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-5-oxopentyl)tetrahydro-1H-thieno[3,4-d]imidazole-2(3H)-one, [01-072] 1-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-3-(5,5-difluoro-7-(1H-pyrrole-2-yl)-5H-5λ 4 ,6λ 4 -Dipyrololo[1,2-c:2',1'-f][1,3,2]diazavorinin-3-yl)propan-1-one, [01-073]4-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-N-(4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ 4 ,5λ 4 -Dipyrrolo[1,2-c:2',1'-f][1,3,2]diazavorinin-10-yl)phenyl)-4-oxobutanamide, and all pharmaceutically acceptable salts or solvates thereof, in particular their sodium salts, Selected from the group consisting of

[0035] In another preferred embodiment of the alternative first aspect of the present invention, optionally in combination with any of the previously defined embodiments of the alternative first aspect of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is [01-001] 4-(benzo[d][1,3]dioxol-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-058] 5-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-2-methoxybenzoic acid, [01-060] 4-(4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenoxy)picolinic acid, N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, and all pharmaceutically acceptable salts or solvates thereof, in particular their sodium salts, Selected from the group consisting of

[0036] A specific alternative embodiment of the present invention (2.2) refers to a compound of formula I as defined in the alternative first embodiment of the present invention, used in therapeutic applications, optionally in combination with any of the previously defined embodiments of the alternative first embodiment of the present invention, provided that this compound is: [01-001] 4-(benzo[d][1,3]dioxol-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-008] 1-(4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenyl)ethane-1-one, N-(4,6-dimethylpyrimidine-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, and, N-(4-methoxy-1,2,5-thiadiazole-3-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, None of the compounds in this group are selected.

[0037] On the other hand, the present invention further refers to an alternative second embodiment (2.3) of the present invention, in which the present invention is optionally combined with any of the previously defined embodiments of the alternative first embodiment of the present invention, in particular a compound of formula I as defined in the alternative first embodiment of the present invention, provided that such a compound of formula I includes the following compounds: [01-001] 4-(benzo[d][1,3]dioxol-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-008] 1-(4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenyl)ethane-1-one, N-(4,6-dimethylpyrimidine-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, N-(4-methoxy-1,2,5-thiadiazole-3-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, [01-003] 4-(4-chlorophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-006] 4-benzyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-011] 4-(4-methoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-062] 4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, 3-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, 4-(4-((1H-1,2,4-triazole-1-yl)methyl)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, and, 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-hydroxyquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, None of the above are included.

[0038] In a preferred embodiment of an alternative second aspect of the present invention, the compound is of formula (Ibis): [ka] (In the formula, A 1bis Equation (IVbis): [ka] It is the basis of, and in the formula, (i) R3, R5~R7 are independently substituted with hydrogen, halogen, OH, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, OR9, COOR 10 , and C(R x )2, NR y It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from cycloalkyl rings that are heteroatoms, and R'4 is substituted with hydrogen, F, Cl, OH, or one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, OR9, COOR 10 , and C(R x )2, NR y It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from cycloalkyl rings that are heteroatoms, or alternatively, (ii) R3 and R'4 condense to form an aromatic ring system with the carbon atoms to which they are attached, and R5, R6, and R7 are independently substituted with hydrogen, a halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from or alternative to alkinyl, (iii) X5 is CR5, where R5 and R6 condense to form an aromatic ring system with the carbon atoms to which they are attached, and R3 and R7 are independently substituted with hydrogen, a halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from alkynyl groups, and R'4 is substituted with hydrogen, F, Cl, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from Alkinnil, A2 is represented by formula (V), formula (VI), formula (VII), or formula (VIII) as defined in claim 6 or 7, and L and m are compounds of the compound (as defined in claim 1) or pharmaceutically acceptable salts or solvates thereof.

[0039] In another preferred embodiment of an alternative second aspect of the present invention, the compound is [01-002] 5-(quinoline-2-yl)-4-(4-(trifluoromethyl)phenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-004] 5-(quinoline-2-yl)-4-(p-tolyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-005] 4-(3-bromophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-007] 4-phenyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-009] 4-(4-phenoxybenzyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-010] 4-(4-methoxy-2-methylphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-012] 4-([1,1'-biphenyl]-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-013] 4-(4-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-014] 5-(quinoline-2-yl)-4-(thiophene-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-015] 4-(4-phenoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-016] 4-(3-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-017] 4-(2,3-dihydro-1H-inden-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-018] 4-(6-chloropyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-019] 4-(6-(piperazine-1-yl)pyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-020] Phenyl(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone, [01-021] (4-chlorophenyl) (3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone, [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-023] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-024] 4-(benzo[d][1,3]dioxol-5-yl)-5-(5-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-025] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-026] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-(trifluoromethoxy)benzyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-027] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,3-dihydro-1H-inden-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-028] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-phenoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-029] 4-(4-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-030] 4-(3-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-031] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-methoxy-2-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-032] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-033] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-(pyrrolidine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-034] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, [01-035] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, [01-036] (3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)(phenyl)methanone, [01-037] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[2,1-a]isoquinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-038] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-039] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyrazine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-040] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-methylquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-050] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-methylquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-051] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-bromoimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-052] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-053] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(1-methyl-1H-pyrazole-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-054] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,2-diphenylethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-055] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(3-morpholinopropyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-056] 3-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, [01-057] 3-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzamide, [01-058] 5-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-2-methoxybenzoic acid, [01-059] 5-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-2-methoxybenzamide, [01-060] 4-(4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenoxy)picolinic acid, [01-061] 4-(4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenoxy)-N-methylpicolinamide, [01-063] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-chloropyridine-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-064] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-065] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(4-methylpiperazine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-066] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(piperazine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-067] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-morpholinopyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-068] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-chloropyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-069] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(piperazine-1-yl)pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-070] 1-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)propan-1-one, [01-071](3aR,4R,6aS)-4-(5-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-5-oxopentyl)tetrahydro-1H-thieno[3,4-d]imidazole-2(3H)-one, [01-072] 1-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-3-(5,5-difluoro-7-(1H-pyrrole-2-yl)-5H-5λ 4 ,6λ 4 -Dipyrololo[1,2-c:2',1'-f][1,3,2]diazavorinin-3-yl)propan-1-one, [01-073]4-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-N-(4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ 4 ,5λ 4 -Dipyrrolo[1,2-c:2',1'-f][1,3,2]diazavorinin-10-yl)phenyl)-4-oxobutanamide, and all pharmaceutically acceptable salts or solvates thereof, in particular their sodium salts, Selected from the group consisting of

[0040] In an alternative third embodiment, the present invention (2.4) provides a pharmaceutical composition comprising a therapeutically effective amount of a compound defined in an alternative second embodiment of the present invention and one or more pharmaceutically acceptable additives or carriers.

[0041] In an alternative fourth embodiment, the present invention (2.5) provides compounds defined in an alternative second embodiment of the present invention for use in therapeutic or biotechnological applications as research tools.

[0042] In an alternative fifth embodiment, the present invention (2.6) provides a kit comprising means for determining TREX2 activity together with a compound specified in an alternative first embodiment or an alternative second embodiment of the present invention.

[0043] In a final alternative embodiment, the present invention (2.7) provides an in vitro method for inhibiting the activity of TREX2 in an isolated sample of a subject, comprising the step of contacting the isolated sample with any of the compounds of formula (I), formula (Ibis), or pharmaceutically acceptable salts or solvates thereof as defined in the alternative first and alternative second embodiments of the present invention. [Brief explanation of the drawing]

[0044] [Figure 1]This figure illustrates the efficacy and selectivity of compounds 01-001 and 01-022 in inhibiting TREX2 exonuclease activity more than TREX1 exonuclease activity. The IC50s of compounds 01-001 (triangle) and 01-022 (rhombic) for TREX2(A) exonuclease activity and TREX1(B) exonuclease activity were measured in vitro at the indicated compound concentrations or vehicle (V) using recombinant MBP-TREX2 protein isoforms and recombinant MBP-TREX1 protein isoforms, and a 3000 bp dsDNA fragment as a substrate. MBP was included as a negative control for exonuclease activity. Representative concentration-response assays and calculated IC50s for each compound are shown. The top section shows DNA electrophoresis, and the bottom section shows the concentration-response curve indicating the DNA remaining at the indicated concentration ([C]). The amount of DNA relative to the negative control is shown in arbitrary units (AU). Compounds 01-001 and 01-022 inhibited TREX2 exonuclease activity in a concentration-dependent manner, but did not inhibit TREX1 exonuclease activity. The IC50 values ​​(over 100 μM) for TREX1 of compounds 01-001 and 01-022 were approximately 100 times higher than the IC50 values ​​for TREX2 (0.9 μM to 1.2 μM for 0-001 and 01-022, respectively). [Figure 2]This figure shows the activity of the compound 01-045 in reducing IL-23-induced psoriasis inflammation in wild-type (wt) (solid circle) mice and Trex2-deficient (dotted square) mice. Intraperitoneal (ip) treatment with 01-045 resulted in a significant reduction in IL-23-induced otitis in wt mice, reaching the levels observed in Trex2 knockout mice (Trex2- / -). The left and right ears of the mice were treated intradermally once daily with either IL-23 or PBS, respectively. Mice were treated once daily with 01-045 (3 mg / kg) (white circles and squares) or vehicle (V, black circles and squares) one day after the start of IL-23 treatment. Arrows indicate compound administration. The increase in ear thickness relative to PBS caused by IL-23 (Δ) (expressed in millimeters (mm)) (Y axis) is shown along time (expressed in days (days)) (X axis). Mean ± SEM of at least 5 mice per group. Analysis of significant differences between untreated and compound-treated mice: Two-way ANOVA with Sidac multiple comparison tests, ****p<0.0001, compound-treated mice vs. untreated wt mice. [Figure 3] This figure illustrates the efficacy of the 01-001 compound in reducing IL-23-induced psoriasis inflammation. (A) Intraperitoneal (ip) and (B) gastric (ig) treatment with 01-001 significantly reduced IL-23-induced otitis. The left and right ears of mice were treated intradermally once daily with either IL-23 or PBS, respectively. Two days after the start of IL-23 treatment, the mice were treated once daily with 01-001 (white triangles) at 3 mg / kg (ip) (A) and 20 mg / kg (ig) (B) respectively, or with a vehicle (V, black triangles). Arrows indicate compound administration. The increase in ear thickness relative to PBS induced by IL-23 (expressed in millimeters (mm)) (Y-axis) is shown along time (expressed in days (days)) (X-axis). Mean ± SEM of at least 5 mice per group. Analysis of statistical significance: Two-way ANOVA using Sidaq's multiple comparison test, *p<0.05, **p<0.01, ****p<0.0001. [Figure 4]This figure illustrates the efficacy of 01-022 in reducing IL-23-induced psoriatic inflammation. (A) Intragastric (ig) and (B) topical 01-022 treatment induced significant reduction in IL-23-induced otitis. The left and right ears of mice were treated intradermally once daily with IL-23 or PBS, respectively. Two days after the start of IL-23 treatment, mice were treated twice daily with 01-022 (diamond) or vehicle (V, black circle) at 5 mg / kg (a), 20 mg / kg (b), and 50 mg / kg (c), and once daily with 200 nmol (e) of 01-022 (diamond). Arrows indicate compound administration. The increase in ear thickness relative to PBS induced by IL-23 (expressed in millimeters (mm)) (Y axis) is shown along time (expressed in days (days)) (X axis). Mean ± SEM of at least 5 mice per group. Statistical significance analysis: Two-way ANOVA with Dunnett (A) or Sidac (B) multiple comparison tests, ***p<0.001, ****p<0.0001. [Figure 5] This figure illustrates the efficacy of 01-022 in reducing MC903-induced atopic dermatitis inflammation. (A, B) Topical treatment with 01-022 causes significant reduction in MC903-induced ear inflammation. The left and right ears of mice were treated topically once daily with either MC903 or ethanol, respectively. The ears of the mice were treated once daily with 01-022 (200 nmol) (rhomboid) 8 days after the start of MC903 treatment. Arrows indicate compound administration. (A) The increase in ear thickness induced by MC903 compared to ethanol (expressed in millimeters (mm)) (Y axis) is shown along time (X axis), and (B) the increase in ear thickness on day 12 compared to day 8 (expressed in millimeters (mm)) is shown. (C) Number of scratching episodes over 10 minutes on day 12 in the left ear treated with MC903. Mean ± SEM of 10 mice per group. Analysis of statistical significance: Two-way ANOVA using Sidac's multiple comparison test (A) and unpaired two-tailed Student t-tests (B, C), *p<0.05, ***p<0.001, ****p<0.0001. [Modes for carrying out the invention]

[0045] Terms not specifically defined herein should be given the meaning that a person skilled in the art would assign in light of the disclosure and context. However, where used herein, unless otherwise specified, the following terms shall have the meanings indicated and the following rules shall be observed.

[0046] Throughout this specification and its accompanying clauses, the phrase “comprise” and its variations such as “comprises” and “comprising” should be interpreted inclusively. That is, these phrases are intended to convey that, to the extent the context allows, other elements or integers not specifically listed may be included. The phrase “comprise” also includes the term “consists of.”

[0047] For the purposes of this invention, any range shown includes both the lower and upper limits of that range.

[0048] Please note that the following sections relate only to the first through fifth embodiments, which include the final embodiments of the invention as clearly specified in the summary of the invention, and not to any of the alternative embodiments, which include the alternative final embodiments of the invention as clearly specified in the summary of the invention.

[0049] Sections relating to the first through fifth embodiments, including the final embodiment specified in the summary of the invention (see embodiments 1.1 to 1.6 of the summary of the invention).

[0050] In a first embodiment, the present invention provides the use of a compound of formula (I) in the treatment of diseases caused by increased expression and activity of TREX2.

[0051] In the context of this invention, the term "pathological condition caused by increased TREX2 expression" refers to any pathological condition in which overexpression (i.e., overactivity) of TREX2 is observed compared to a reference value obtained from a control population. In one embodiment, the control population is a healthy population. In another embodiment, the level of TREX2 is determined in isolated tissue or cell samples from the subject. In one embodiment, the RNA level is determined. Analysis of TREX2 RNA expression can be performed using any routine protocol with commercially available reagents, such as those used by Manils et al. (Non-Patent Literature 5).

[0052] In the context of this invention, the term "subject" includes all animals, including domesticated mammals and humans. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0053] Throughout this specification, the term “treatment” includes, but is not limited to, the relief, reduction, or elimination of one or more symptoms of a condition; reduction of the severity of the condition; stabilization of the condition (i.e., preventing exacerbation); delay or slowing of its progression; relief or improvement of the condition; and remission (whether whole or in part).

[0054] As used in the present invention, the term "prevention" refers to preventing the onset of pathological conditions in patients who are predisposed but do not yet exhibit symptoms of the disease.

[0055] As used herein, the term “animal” refers to a vertebrate. Such animals include both domesticated animals, such as livestock, laboratory animals, and domestic pets, and non-domesticated animals, such as wild animals. In one embodiment, the animal is a vertebrate. In a particular embodiment, the animal is a domesticated mammal or a human.

[0056] In the context of this invention, the term "alkyl" refers to a linear or branched hydrocarbon chain group that is unsaturated and attached to the remainder of the molecule by a single bond. Typical alkyl groups have 1 to about 10, 1 to about 8, or 1 to about 6 carbon atoms, and include, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, and n-pentyl. When substituted with a cycloalkyl group, the alkyl group corresponds to a "cycloalkylalkyl" group such as cyclopropylmethyl. When substituted with an aryl group, the alkyl group corresponds to an "arylalkyl" group such as benzyl, benzhydryl, or phenethyl. When substituted with a heterocyclyl group, the alkyl group corresponds to a "heterocyclylalkyl" group.

[0057] In the context of the present invention, the term "alkenyl" refers to a linear or branched hydrocarbon chain group comprising at least two carbon atoms and at least one C=C double bond, with the remainder of the molecule attached by single bonds. Typical alkenyl groups have 2 to about 10, 2 to about 8, or 2 to about 6 carbon atoms. In certain embodiments, the alkenyl group is vinyl, 1-methylethenyl, 1-propenyl, 2-propenyl, or butenyl.

[0058] In the context of the present invention, the term "alkynyl" refers to a linear or branched hydrocarbon chain group containing one or more C≡C triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.

[0059] When an alkenyl or alkynyl is bonded to a nitrogen atom (forming a substituted amine), the bond is formed via a carbon atom that does not form a double or triple bond.

[0060] In the context of this invention, the term "halogen" refers to bromo, chloro, iodine, or fluoro.

[0061] In the context of the present invention, the term "haloalkyl" refers to a non-unsaturated linear or branched hydrocarbon chain group in which one or more hydrogen atoms are replaced by halogens. Exemplary, non-limiting examples of haloalkyls include chloromethyl, trifluoromethyl, and 1-chloro-2-fluoroethyl.

[0062] In the context of the present invention, unless otherwise specified, the term "cycloalkyl" refers to a saturated hydrocarbon ring. Exemplary, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl.

[0063] In the context of the present invention, the term "heteroaryl" refers to a monocyclic carbon ring having five or six ring members, of which one, two, or three are heteroatoms, particularly selected from N, O, or S.

[0064] In the context of this invention, the term "salt" should be understood as any form of the compound used in accordance with this invention, in which case the compound is in ionic form, charged and coupled with a counterion (cation or anion), or dissolved. This definition also includes quaternary ammonium salts and complexes of the active molecule with other molecules and ions, particularly complexes formed by ionic interactions. This definition includes physiologically acceptable salts in particular, and this term should be understood as equivalent to "pharmacologically acceptable salt" or "pharmaceutically acceptable salt."

[0065] In the context of the present invention, the term “pharmaceutically acceptable salt” means any salt that is physiologically acceptable (usually meaning non-toxic, particularly as a result of counterions) when used in a manner appropriate to the treatment applied or used in humans and / or mammals. These physiologically acceptable salts may be formed with cations or bases and, in the context of the present invention, are understood to be salts formed with at least one compound used in accordance with the present invention, usually an acid such as an anion (deprotonated), and, when used particularly in humans and / or mammals, preferably at least one inorganic physiologically acceptable cation. This includes salts with alkali metals and alkaline earth metals, as well as salts with ammonium cations (NH4 + Salts formed with (mono)sodium or (di)sodium, (mono)potassium or (di)potassium, magnesium, or calcium are particularly preferred. These physiologically acceptable salts may also be formed with anions or acids, and in the context of the present invention, are understood to be salts formed with at least one compound used in accordance with the present invention, usually a cation, for example, protonated at nitrogen, and, in particular when used for humans and / or mammals, at least one physiologically acceptable anion. Specifically, in the context of the present invention, particularly when used for humans and / or mammals, salts formed with physiologically acceptable acids, i.e., salts of certain active compounds with physiologically acceptable organic or inorganic acids. Examples of this type of salt are salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, or citric acid.

[0066] In the context of the present invention, the term "solvate" should be understood to mean any form of compound, particularly hydrates and alcolates such as methanelates, in which the compound according to the present invention is bonded to another molecule (usually a polar solvent) by a non-covalent bond. The preferred solvate is the hydrate.

[0067] Any compound of formula (I) referred to herein is intended to represent not only such specific compound but also certain variants or forms. In particular, the compounds referred to herein may have chiral centers and therefore exist in various enantiomer or diastereomer forms. Thus, any compound of formula (I) referred to herein is intended to represent one of the following: a racemate, one or more enantiomer forms, one or more diastereomer forms, or a mixture thereof. Similarly, stereoisomerism or geometric isomerism with respect to double bonds is also possible, and therefore, in some cases, the molecule may exist as an (E)-isomer or (Z)-isomer (trans and cis isomer). If a molecule contains several double bonds, each double bond will have its own stereoisomerism, which may be the same as or different from the stereoisomerism of the other double bonds in the molecule. Furthermore, the compounds referred to herein may exist as atropoisomers. All stereoisomers, including enantiomers, diastereomers, geometric isomers, and atropoisomers of the compounds referred to herein, as well as mixtures thereof, are considered to be within the scope of the present invention.

[0068] Furthermore, any compound of formula (I) referred to herein may exist as a tautomer. Specifically, the term tautomer refers to one of two or more structural isomers of a compound that exists in equilibrium and can be readily converted from one isomeric form to another.

[0069] In one embodiment of the first aspect of the present invention, one or two of X1 to X8 represent N. In particular, one of X1 to X8 represents N, and in particular X7 represents N.

[0070] In another embodiment of the first aspect of the present invention, in any combination of the above or below embodiments, n is 1 and one of X1 to X8 represents N.

[0071] In another embodiment of the first aspect of the present invention, A1 may be optionally combined with any of the embodiments described above or below, with respect to formula (III): [ka] (wherein R3 to R6 are as defined in the first embodiment of the present invention)

[0072] In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments described above or below, A1 is represented by formula (III), and R3 to R6 are substituted with hydrogen, halogen, or optionally one or more Z substituents (C1 to C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, or -O-(C1~C) substituted with one or more Z substituents. 10 ) Selected from alkyl groups.

[0073] In another embodiment of the first aspect of the present invention, in any combination with the above or below embodiments, A1 is represented by formula (III) and R3 to R6 are the same. In another embodiment of the first aspect of the present invention, in any combination with the above or below embodiments, A1 is represented by formula (III) and R3 to R6 are hydrogen.

[0074] In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments described above or below, the compound of formula (I) is a compound in which n is 0 and two or three of X1 to X7 represent N.

[0075] In another embodiment of the first aspect of the present invention, A1 may be optionally combined with any of the embodiments described above or below, with respect to formula (IV): [ka] (In the formula, X5 represents N or CR5, and R3 to R7 are as defined above.)

[0076] In another embodiment of the first aspect of the present invention, A1 is represented by formula (IV), and, optionally in combination with any of the embodiments described above or below, R3~R7 are independently substituted with hydrogen, halogen, OH, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from or alternative to alkinyl, R3 and R4 condense to form an aromatic ring system with the carbon atoms to which they are attached, and R5, R6, and R7 are independently substituted with hydrogen, halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from or alternative to alkinyl, X5 is CR5, R5 and R6 are condensed to form an aromatic ring system with the carbon atoms to which they are attached, and R3, R4 and R7 are independently substituted with hydrogen, halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from Alkinyl.

[0077] In another embodiment of the first aspect of the present invention, in any combination with the embodiments described above or below, A2 consists of a single ring, particularly a six-membered aromatic ring, where the ring members are as defined in the first aspect of the present invention.

[0078] In another embodiment of the first aspect of the present invention, A2 may be optionally combined with any of the embodiments described above or below, with formula (V), formula (VI), formula (VII), or formula (VIII): [ka] (In the formula, X9 is NR 34 , O, S, or CR z16 This represents, X 10 , NR 35 , O, S, or CR z17 This represents, X 11 , NR 36 , O, S, or CR z18 This represents, R z1 ~R z18 These are independently substituted with hydrogen, halogens, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, O(CH2) a R 22 , C(O)R 23 SO2NR 24 R 25 ;N, O, S, and CR e An aryl having 5 or 6 ring members selected from the group consisting of (where R e Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from haloalkyls), or NH, O, S, and C(R b) Selected from cycloalkyls having 5 or 6 ring members selected from 2, R 22 ~R 25 , and R b This is as defined in one of the earlier embodiments, and, R 34 , R 35 , and R 36 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) alkenyl and (C2~C) optionally substituted with one or more Z substituents 10 It is an aryl ring (selected from alkynyls).

[0079] In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments described above or below, A2 is represented by formula (V) and R z1 ~R z18 These are independently hydrogen, halogens, (C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, O(CH2) a R 22 , C(O)R 23 ;NH, O, S, and C(R b ) Cycloalkyls having 5 or 6 ring members selected from 2, as well as N, O, S, and CR e Selected from the group consisting of aryls having 5 or 6 ring members, where R e Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from haloalkyl groups.

[0080] In another embodiment of the first aspect of the present invention, R may be optionally combined with any of the embodiments described above or below. 22 and R 23(C1~C) is substituted with H and optionally one or more Z substituents. 10 ) Selected from alkyl groups.

[0081] In another embodiment of the first aspect of the present invention, R may be optionally combined with any of the embodiments described above or below. 24 and R 25 These are independently hydrogen; NH, O, S, and C(R) b ) Cycloalkyls having 5 or 6 ring members selected from 2, as well as N, O, S, and CR g Selected from the group consisting of aryls having 5 or 6 ring members, where R g Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from haloalkyl groups.

[0082] In another embodiment of the first aspect of the present invention, R may be optionally combined with any of the embodiments described above or below. 24 and R 25 One is H, and the other is H;NH, O, S, and C(R b ) Cycloalkyls having 5 or 6 ring members selected from 2, as well as N, O, S, and CR g Selected from the group consisting of aryls having 5 or 6 ring members, where R g Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from haloalkyl groups.

[0083] In another embodiment of the first aspect of the present invention, in any combination with the embodiments described above or below, A2 is represented by formula (VI), and Rz6 to Rz8 are the same, and in particular these are hydrogen.

[0084] In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments described above or below, A2 is represented by formula (VIII), and X9, X 10 , and X 10 These are the same, and in particular these are CH, or alternatively, X9 and X 11 These are the same, and in particular, these are O.

[0085] In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments described above or below, A2 is represented by formula (VII) and Rz9~Rz 12 These are independently hydrogen, halogen, SO2NH2, or NH, O, S, and C(R b Selected from cycloalkyl groups having 5 or 6 ring members selected from )2, in particular Rz9~Rz 11 It is hydrogen, and Rz 12 These are hydrogen, halogens, SO2NH2, or NH, O, S, and C(R b Selected from cycloalkyl groups having 5 or 6 ring members, selected from 2.

[0086] In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments described above or below, A2 is represented by formula (V) and R z1 ~R z5 (C1~C) is a hydrogen atom substituted with one or more Z substituents. 10 ) Alkyl, O(CH2) a R 22 , C6 aryl, halogen, COOH, and C(O)(C1~C 10 ) Selected from alkyl, and R 22 (C1~C) is substituted with one or more Z substituents as arbitrary. 10 ) Represents alkyl or C6 aryl.

[0087] In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments described above or below, R1 to R8 are independently substituted with hydrogen, or optionally with one or more Z substituents (C1 to C 10) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, F, Cl, OR9, COOR 10 , and C(R x )2, NR y It has 3 to 7 ring members selected from , O, or S, wherein at least one or two of these ring members are selected from cycloalkyl heteroatoms, and in particular these are substituted with hydrogen, and optionally one or more Z substituents (C1-C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Selected from alkynyl, F, and Cl. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments described above or below, R1 to R8 are independently substituted with hydrogen, optionally one or more Z substituents (C1 to C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, OR9, COOR 10 , and C(R x )2, NR y It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from cycloalkyl heteroatoms.

[0088] In another embodiment of the first aspect of the present invention, Z is a halogen, optionally in combination with any of the embodiments described above or below.

[0089] In another embodiment of the first aspect of the present invention, the compound may be optionally combined with any of the embodiments described above or below, [01-001] 4-(benzo[d][1,3]dioxol-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-002] 5-(quinoline-2-yl)-4-(4-(trifluoromethyl)phenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-003] 4-(4-chlorophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-004] 5-(quinoline-2-yl)-4-(p-tolyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-005] 4-(3-bromophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-006] 4-benzyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-007] 4-phenyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-008] 1-(4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenyl)ethane-1-one, [01-009] 4-(4-phenoxybenzyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-010] 4-(4-methoxy-2-methylphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-011] 4-(4-methoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-012] 4-([1,1'-biphenyl]-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-013] 4-(4-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-014] 5-(quinoline-2-yl)-4-(thiophene-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-015] 4-(4-phenoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-016] 4-(3-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-017] 4-(2,3-dihydro-1H-inden-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-018] 4-(6-chloropyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-019] 4-(6-(piperazine-1-yl)pyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-020] Phenyl(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone, [01-021] (4-chlorophenyl) (3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone, [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-023] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-024] 4-(benzo[d][1,3]dioxol-5-yl)-5-(5-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-025] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-026] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-(trifluoromethoxy)benzyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-027] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,3-dihydro-1H-inden-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-028] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-phenoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-029] 4-(4-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-030] 4-(3-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-031] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-methoxy-2-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-032] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-033] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-(pyrrolidine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-034] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, [01-035] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, [01-036] (3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)(phenyl)methanone, [01-037] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[2,1-a]isoquinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-038] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, and, [01-039] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyrazine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, N-(4,6-dimethylpyrimidine-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, N-(4-methoxy-1,2,5-thiadiazole-3-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, 3-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, 4-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-thione, 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-hydroxyquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, and all pharmaceutically acceptable salts or solvates thereof, in particular their sodium salts, Selected from the group consisting of

[0090] In another embodiment of the first aspect of the present invention, the compound may be optionally combined with any of the embodiments described above or below, [01-001] 4-(benzo[d][1,3]dioxol-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-003] 4-(4-chlorophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, and all pharmaceutically acceptable salts or solvates thereof, in particular their sodium salts, Selected from the group consisting of

[0091] In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments described above or below, the pathological condition associated with increased TREX2 expression is an inflammatory condition of the skin or mucous membrane. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments described above or below, the condition is selected from psoriasis, atopic dermatitis, or ichthyosis.

[0092] In a second embodiment, the present invention provides compounds of formula (Ibis), pharmaceutically acceptable salts or solvates thereof.

[0093] All embodiments described above with respect to A2, A3, X1, X2, X3, X5, X6, L, and m in the first aspect of the present invention are also embodiments of compounds in the second aspect of the present invention.

[0094] In another embodiment of a second aspect of the present invention, A may be optionally combined with any of the embodiments described above or below. 1bis It is represented by formula (IVbis), and R3 to R7 are independently substituted with hydrogen, halogen, and optionally one or more Z substituents (C1 to C 10 ) Selected from alkyl groups.

[0095] In another embodiment of the second aspect of the present invention, in any combination with any of the embodiments described above or below, A2 consists of a single ring, in particular a six-membered aromatic ring, where the ring members are as defined in the first aspect of the present invention.

[0096] In another embodiment of a second aspect of the present invention, A2 may be optionally combined with any of the embodiments described above or below, with formula (V), formula (VI), formula (VII), or formula (VIII): [ka] (In the formula, X9 is NR 34 , O, S, or CR z16 This represents, X 10 , NR 35 , O, S, or CR z17 This represents, X 11 , NR 36 , O, S, or CR z18 This represents, R z1 ~R z18 These are independently substituted with hydrogen, halogens, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, O(CH2) a R 22 , C(O)R 23 SO2NR 24 R 25 ;N, O, S, and CR e An aryl having 5 or 6 ring members selected from the group consisting of (where R e Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from haloalkyls), or NH, O, S, and C(R b ) Selected from cycloalkyls having 5 or 6 ring members selected from 2, R 22 ~R 25 , and R b This is as defined in one of the earlier embodiments, and, R 34 , R 35 , and R 36 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) alkenyl and (C2~C) optionally substituted with one or more Z substituents 10 It is an aryl ring (selected from alkynyls).

[0097] In another embodiment of a second aspect of the present invention, in combination with any of the embodiments described above or below, A2 is represented by formula (V) and R z1 ~R z18 These are independently hydrogen, halogens, (C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, O(CH2) a R 22 , C(O)R 23 ;NH, O, S, and C(R b ) Cycloalkyls having 5 or 6 ring members selected from 2, as well as N, O, S, and CR e Selected from the group consisting of aryls having 5 or 6 ring members, where R e Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from haloalkyl groups.

[0098] In another embodiment of a second aspect of the present invention, R may be optionally combined with any of the embodiments described above or below. 22 and R 23 (C1~C) is substituted with H and optionally one or more Z substituents. 10 ) Selected from alkyl groups.

[0099] In another embodiment of a second aspect of the present invention, R may be optionally combined with any of the embodiments described above or below. 24 and R 25 These are independently hydrogen; NH, O, S, and C(R) b ) Cycloalkyls having 5 or 6 ring members selected from 2, as well as N, O, S, and CR g Selected from the group consisting of aryls having 5 or 6 ring members, where R g Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from haloalkyl groups.

[0100] In another embodiment of a second aspect of the present invention, R may be optionally combined with any of the embodiments described above or below. 24 and R 25 One is H, and the other is H;NH, O, S, and C(R b ) Cycloalkyls having 5 or 6 ring members selected from 2, as well as N, O, S, and CR g Selected from the group consisting of aryls having 5 or 6 ring members, where R g Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from haloalkyl groups.

[0101] In another embodiment of a second aspect of the present invention, in combination with any of the embodiments described above or below, A2 is represented by formula (VI), and Rz6 to Rz8 are the same, and in particular these are hydrogen.

[0102] In another embodiment of a second aspect of the present invention, in combination with any of the embodiments described above or below, A2 is represented by formula (VIII), and X9, X 10 , and X 10 These are the same, and in particular these are CH, or alternatively, X9 and X 11 These are the same, and in particular, these are O.

[0103] In another embodiment of a second aspect of the present invention, A2 is represented by formula (VII) and R is optionally combined with any of the embodiments described above or below. z9 ~R z12 These are independently hydrogen, halogen, SO2NH2, or NH, O, S, and C(R b) Selected from cycloalkyls having 5 or 6 ring members selected from 2, in particular, R z9 ~R z11 is hydrogen, and R z12 These are hydrogen, halogens, SO2NH2, or NH, O, S, and C(R b Selected from cycloalkyl groups having 5 or 6 ring members, selected from 2.

[0104] In another embodiment of a second aspect of the present invention, optionally in combination with any of the embodiments described above or below, R1-R3, R'4, and R5-R8 are independently substituted with hydrogen, optionally with one or more Z substituents (C1-C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, OR9, COOR 10 , and C(R x )2, NR y It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from the group consisting of heteroatom cycloalkyl rings.

[0105] In another embodiment of a second aspect of the present invention, the compound of formula (Ibis) is [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-023] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-024] 4-(benzo[d][1,3]dioxol-5-yl)-5-(5-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-025] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-026] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-(trifluoromethoxy)benzyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-027] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,3-dihydro-1H-inden-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-028] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-phenoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-029] 4-(4-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-030] 4-(3-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-031] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-methoxy-2-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-032] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-033] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-(pyrrolidine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-034] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, [01-035] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, [01-036] (3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)(phenyl)methanone, [01-037] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[2,1-a]isoquinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-038] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, and, [01-039] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyrazine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, and all pharmaceutically acceptable salts or solvates thereof, in particular their sodium salts, Selected from the group consisting of

[0106] In a third embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound (Ibis) or (I') of the present invention as defined above, or a pharmaceutically active salt thereof.

[0107] A "therapeutic effective dose" is understood to be the amount of a compound (or compound) that, when administered, is sufficient to prevent the development of one or more symptoms of the disease being treated, or to alleviate one or more symptoms of that disease to some extent.

[0108] The precise therapeutic dose of the component(s), as well as the amount of the compound(s) of the present invention, may depend on several variable factors. Some of these include the route of administration, the time of drug release (e.g., immediate release or sustained release), the administration schedule, the severity of the condition, and the patient's condition.

[0109] Pharmaceutical compositions can be prepared in liquid, semi-solid, or solid dosage forms, such as injectable solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, dressings, suppositories, ointments, creams, lotions, gels, emulsions, or aerosols, or in multi-particle forms, such as pills or granules, which can be compressed into tablets, poured into capsules, suspended in liquids, or administered as is.

[0110] These compositions can be prepared using conventional means, devices, methods, or processes known in the art.

[0111] pharmaceutically acceptable adjuvants, vehicles, or additives that can be used in such compositions are adjuvants, vehicles, or additives that are known to those skilled in the art or are commonly used in the preparation of therapeutic compositions, and these may be selected from the group consisting of, for example, additives, fillers, solvents, diluents, surfactants, colorants, preservatives, disintegrants, lubricants, lubricants, flavoring agents, or binders.

[0112] The term "pharmaceutically acceptable" applies to pharmaceutically acceptable materials, compositions, or vehicles. Each component must be pharmaceutically acceptable in the sense that it is compatible with other components of the pharmaceutical composition. Furthermore, each component must be suitable for use in contact with human tissues or organs without excessive toxicity, irritation, allergic response, immunogenicity, or causing other problems or complications, and must be commensurate with a reasonable benefit-to-risk ratio in animals, especially humans.

[0113] The selection of physiologically compatible adjuvants or the number of adjuvants used depends on the administration method of the pharmaceutical composition, i.e., oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal, ear, or intratympanic administration. Preparations in the form of tablets, sugar-coated pills, capsules, granules, pills, drops, especially ear drops, juices, or syrups are preferably suitable for oral administration, while liquids, suspensions, easily reconstituted dry preparations, or sprays are also preferably suitable for parenteral, topical, or inhalation administration. The compounds of the present invention used in the pharmaceutical compositions according to the present invention are preparations suitable for transdermal administration, either in depot preparations, in dissolved form, or in dressings, or, as appropriate, with the addition of other active ingredients that promote skin penetration. Preparations that are orally or transdermally administered may also release each compound of the present invention in a delayed form.

[0114] For example, when administered orally in tablet or capsule form, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, or sorbitol. When administered orally in liquid form, the oral drug component can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, or water. Furthermore, suitable binders, lubricants, disintegrants, and colorants can be incorporated into the mixture as desired or required. Suitable binders include natural sugars such as starch, gelatin, glucose, or β-lactose, natural and synthetic gums such as corn sweetener, acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, and wax. Lubricants used in these dosage forms include sodium oleate, sodium stearate, and magnesium stearate. Examples of disintegrants, though not limited to them, include starch, methylcellulose, agar, bentonite, and xanthan gum.

[0115] Gelatin capsules contain an active ingredient and a powdered carrier such as lactose, starch, cellulose derivatives, magnesium stearate, or stearic acid. Compressed tablets can be made using similar diluents. Both tablets and capsules can be manufactured as sustained-release products, providing continuous release of the drug over several hours. Compressed tablets may be coated with sugar or film to mask any unpleasant tastes and protect the tablets from the air, or they may be enterically coated to selectively disintegrate in the gastrointestinal tract.

[0116] Liquid dosage forms for oral administration may contain colorants and flavorings to improve patient acceptance.

[0117] The dosage of the pharmaceutical composition administered will naturally vary depending on the intended use and known factors such as the recipient's age, health condition, and weight, the nature and severity of symptoms, any concomitant treatments, the frequency of treatment, and the desired effect. The recipient may be any type of mammal, but is preferably human.

[0118] Please note that the following sections relate only to alternative embodiments, including alternative final embodiments of the invention that are clearly specified in the summary of the invention.

[0119] Sections relating to the first to fifth alternative embodiments, including the final alternative embodiment specified and defined in the summary of the invention (see embodiments 2.1 to 2.7 of the summary of the invention).

[0120] In a first alternative embodiment, the present invention provides the use of a compound of formula (I) as defined in an alternative first embodiment of the present invention in the treatment of diseases caused by increased expression and activity of TREX2.

[0121] In the context of this invention, the term "pathological condition caused by increased TREX2 expression" refers to any pathological condition in which overexpression (i.e., overactivity) of TREX2 is observed compared to a reference value obtained from a control population. In one embodiment, the control population is a healthy population. In another embodiment, the level of TREX2 is determined in isolated tissue or cell samples from the subject. In one embodiment, the RNA level is determined. Analysis of TREX2 RNA expression can be performed using any routine protocol with commercially available reagents, such as those used by Manils et al. (Non-Patent Literature 5).

[0122] In the context of this invention, the term "subject" includes all animals, including domesticated mammals and humans. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0123] Throughout this specification, the term “treatment” includes, but is not limited to, the relief, reduction, or elimination of one or more symptoms of a condition; reduction of the severity of the condition; stabilization of the condition (i.e., preventing exacerbation); delay or slowing of its progression; relief or improvement of the condition; and remission (whether whole or in part).

[0124] As used in the present invention, the term "prevention" refers to preventing the onset of pathological conditions in patients who are predisposed but do not yet exhibit symptoms of the disease.

[0125] As used herein, the term “animal” refers to a vertebrate. Such animals include both domesticated animals, such as livestock, laboratory animals, and domestic pets, and non-domesticated animals, such as wild animals. In one embodiment, the animal is a vertebrate. In a particular embodiment, the animal is a domesticated mammal or a human.

[0126] In the context of this invention, the term "alkyl" refers to a linear or branched hydrocarbon chain group that is unsaturated and attached to the remainder of the molecule by a single bond. Typical alkyl groups have 1 to about 10, 1 to about 8, or 1 to about 6 carbon atoms, and include, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, and n-pentyl. When substituted with a cycloalkyl group, the alkyl group corresponds to a "cycloalkylalkyl" group such as cyclopropylmethyl. When substituted with an aryl group, the alkyl group corresponds to an "arylalkyl" group such as benzyl, benzhydryl, or phenethyl. When substituted with a heterocyclyl group, the alkyl group corresponds to a "heterocyclylalkyl" group.

[0127] In the context of the present invention, the term "alkenyl" refers to a linear or branched hydrocarbon chain group comprising at least two carbon atoms and at least one C=C double bond, with the remainder of the molecule attached by single bonds. Typical alkenyl groups have 2 to about 10, 2 to about 8, or 2 to about 6 carbon atoms. In certain embodiments, the alkenyl group is vinyl, 1-methylethenyl, 1-propenyl, 2-propenyl, or butenyl.

[0128] In the context of the present invention, the term "alkynyl" refers to a linear or branched hydrocarbon chain group containing one or more C≡C triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.

[0129] When an alkenyl or alkynyl is bonded to a nitrogen atom (forming a substituted amine), the bond is formed via a carbon atom that does not form a double or triple bond.

[0130] In the context of this invention, the term "halogen" refers to bromo, chloro, iodine, or fluoro.

[0131] In the context of the present invention, the term "haloalkyl" refers to a non-unsaturated linear or branched hydrocarbon chain group in which one or more hydrogen atoms are replaced by halogens. Exemplary, non-limiting examples of haloalkyls include chloromethyl, trifluoromethyl, and 1-chloro-2-fluoroethyl.

[0132] In the context of the present invention, unless otherwise specified, the term "cycloalkyl" refers to a saturated hydrocarbon ring. Exemplary, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl.

[0133] In the context of the present invention, the term "heteroaryl" refers to a monocyclic carbon ring having five or six ring members, of which one, two, or three are heteroatoms, particularly selected from N, O, or S.

[0134] In the context of this invention, the term "salt" should be understood as any form of the compound used in accordance with this invention, in which case the compound is in ionic form, charged and coupled with a counterion (cation or anion), or dissolved. This definition also includes quaternary ammonium salts and complexes of the active molecule with other molecules and ions, particularly complexes formed by ionic interactions. This definition includes physiologically acceptable salts in particular, and this term should be understood as equivalent to "pharmacologically acceptable salt" or "pharmaceutically acceptable salt."

[0135] In the context of the present invention, the term “pharmaceutically acceptable salt” means any salt that is physiologically acceptable (usually meaning non-toxic, particularly as a result of counterions) when used in a manner appropriate to the treatment applied or used in humans and / or mammals. These physiologically acceptable salts may be formed with cations or bases and, in the context of the present invention, are understood to be salts formed with at least one compound used in accordance with the present invention, usually an acid such as an anion (deprotonated), and, when used particularly in humans and / or mammals, preferably at least one inorganic physiologically acceptable cation. This includes salts with alkali metals and alkaline earth metals, as well as salts with ammonium cations (NH4 +Salts formed with (mono)sodium or (di)sodium, (mono)potassium or (di)potassium, magnesium, or calcium are particularly preferred. These physiologically acceptable salts may also be formed with anions or acids, and in the context of the present invention, are understood to be salts formed with at least one compound used in accordance with the present invention, usually a cation, for example, protonated at nitrogen, and, in particular when used for humans and / or mammals, at least one physiologically acceptable anion. Specifically, in the context of the present invention, particularly when used for humans and / or mammals, salts formed with physiologically acceptable acids, i.e., salts of certain active compounds with physiologically acceptable organic or inorganic acids. Examples of this type of salt are salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, or citric acid.

[0136] In the context of the present invention, the term "solvate" should be understood to mean any form of compound, particularly hydrates and alcolates such as methanelates, in which the compound according to the present invention is bonded to another molecule (usually a polar solvent) by a non-covalent bond. The preferred solvate is the hydrate.

[0137] Any compound of formula (I) as defined in the alternative first or alternative second embodiment of the present invention as referred to herein is intended to represent not only such specific compounds but also certain variant forms or shapes. In particular, the compounds referred to herein may have chiral centers and therefore exist in various enantiomer or diastereomer forms. Accordingly, any compound of formula (I) as defined in the alternative first or alternative second embodiment of the present invention as referred to herein is intended to represent one of the following: a racemate, one or more enantiomer forms, one or more diastereomer forms, and mixtures thereof. Similarly, stereoisomerism or geometric isomerism with respect to double bonds is also possible, and therefore, in some cases, the molecule may exist as an (E)-isomer or (Z)-isomer (trans isomer and cis isomer). If a molecule contains several double bonds, each double bond will have its own stereoisomerism, which may be the same as or different from the stereoisomerism of the other double bonds in the molecule. Furthermore, the compounds referred to herein may exist as atropoisomers. All stereoisomers, including enantiomers, diastereomers, geometric isomers, and atropoisomers of the compounds referred to herein, as well as mixtures thereof, are considered to be within the scope of the present invention.

[0138] Furthermore, any compound of formula (I) as defined in the alternative first or alternative second embodiment of the present invention as referred to herein may exist as a tautomer. Specifically, the term tautomer refers to one of two or more structural isomers of a compound that exist in equilibrium and can be readily converted from one isomeric form to another.

[0139] In one embodiment of an alternative first aspect of the present invention, optionally in combination with any of the embodiments described above or below, the pathological condition associated with increased TREX2 expression is an inflammatory condition of the skin or mucous membrane. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments described above or below, the condition is selected from psoriasis, atopic dermatitis, or ichthyosis.

[0140] On the other hand, in relation to an alternative third embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds or pharmaceutically active salts thereof defined in the alternative second embodiment of the present invention as defined above.

[0141] A "therapeutic effective dose" is understood to be the amount of a compound (or compound) that, when administered, is sufficient to prevent the development of one or more symptoms of the disease being treated, or to alleviate one or more symptoms of that disease to some extent.

[0142] The precise therapeutic dose of the component(s), as well as the amount of the compound(s) of the present invention, may depend on several variable factors. Some of these include the route of administration, the time of drug release (e.g., immediate release or sustained release), the administration schedule, the severity of the condition, and the patient's condition.

[0143] Pharmaceutical compositions can be prepared in liquid, semi-solid, or solid dosage forms, such as injectable solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, dressings, suppositories, ointments, creams, lotions, gels, emulsions, or aerosols, or in multi-particle forms, such as pills or granules, which may be compressed into tablets, poured into capsules, suspended in liquids, or administered as is.

[0144] These compositions can be prepared using conventional means, devices, methods, or processes known in the art.

[0145] pharmaceutically acceptable adjuvants, vehicles, or additives that can be used in such compositions are adjuvants, vehicles, or additives that are known to those skilled in the art or are commonly used in the preparation of therapeutic compositions, and these may be selected from the group consisting of, for example, additives, fillers, solvents, diluents, surfactants, colorants, preservatives, disintegrants, lubricants, lubricants, flavoring agents, or binders.

[0146] The term "pharmaceutically acceptable" applies to pharmaceutically acceptable materials, compositions, or vehicles. Each component must be pharmaceutically acceptable in the sense that it is compatible with other components of the pharmaceutical composition. Furthermore, each component must be suitable for use in contact with human tissues or organs without excessive toxicity, irritation, allergic response, immunogenicity, or causing other problems or complications, and must be commensurate with a reasonable benefit-to-risk ratio in animals, especially humans.

[0147] The selection of physiologically compatible adjuvants or the number of adjuvants used depends on the administration method of the pharmaceutical composition, i.e., oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal, ear, or intratympanic administration. Preparations in the form of tablets, sugar-coated pills, capsules, granules, pills, drops, especially ear drops, juices, or syrups are preferably suitable for oral administration, while liquids, suspensions, easily reconstituted dry preparations, or sprays are also preferably suitable for parenteral, topical, or inhalation administration. The compounds of the present invention used in the pharmaceutical compositions according to the present invention are preparations suitable for transdermal administration, either in depot preparations, in dissolved form, or in dressings, or, as appropriate, with the addition of other active ingredients that promote skin penetration. Preparations that are orally or transdermally administered may also release each compound of the present invention in a delayed form.

[0148] For example, when administered orally in tablet or capsule form, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, or sorbitol. When administered orally in liquid form, the oral drug component can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, or water. Furthermore, suitable binders, lubricants, disintegrants, and colorants can be incorporated into the mixture as desired or required. Suitable binders include natural sugars such as starch, gelatin, glucose, or β-lactose, natural and synthetic gums such as corn sweetener, acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, and wax. Lubricants used in these dosage forms include sodium oleate, sodium stearate, and magnesium stearate. Examples of disintegrants, though not limited to them, include starch, methylcellulose, agar, bentonite, and xanthan gum.

[0149] Gelatin capsules contain an active ingredient and a powdered carrier such as lactose, starch, cellulose derivatives, magnesium stearate, or stearic acid. Compressed tablets can be made using similar diluents. Both tablets and capsules can be manufactured as sustained-release products, providing continuous release of the drug over several hours. Compressed tablets may be coated with sugar or film to mask any unpleasant tastes and protect the tablets from the air, or they may be enterically coated to selectively disintegrate in the gastrointestinal tract.

[0150] Liquid dosage forms for oral administration may contain colorants and flavorings to improve patient acceptance.

[0151] The dosage of the pharmaceutical composition administered will naturally vary depending on the intended use and known factors such as the recipient's age, health condition, and weight, the nature and severity of symptoms, any concomitant treatments, the frequency of treatment, and the desired effect. The recipient may be any type of mammal, but is preferably human.

[0152] Finally, according to another aspect of the present invention, a compound of the present invention comprising the compounds defined in the first to second aspects of the present invention, and the compounds defined in the alternative first to alternative second aspects of the present invention, is given formula (IX) [ka] It can be prepared by cyclizing N-carbonylaminothiourea (wherein L, m, A1, and A2 are as defined above).

[0153] There is a well-known method for cyclizing N-carbonylaminothiourea of ​​formula (IX), for example, by adding a base.

[0154] N-carbonylaminothiourea can also be obtained using well-known synthetic routes. Exemplary, non-limiting examples are given below.

[0155] Other objects, advantages, or features of the present invention will be apparent to those skilled in the art, partly from the specification and partly from the practice of the invention. The following examples are illustrative and not intended to limit the invention. [Examples]

[0156] Chemical substances and chemical synthesis 1.General information All chemicals were purchased from commercial suppliers and used as received unless otherwise specified. Microwave irradiation reactions were performed using a Biotage Initiator Classic. Column chromatography was performed on commercially available silica gel. Flash column chromatography was performed using an Isolera Prime (Biotage) with dual UV detection via pre-packed normal-phase or reverse-phase (4g, 12g, and 24g) plates. Thin-layer chromatography was performed using pre-coated Merck silica gel 60 F254 plates and visualized under 254nm and 365nm UV light.

[0157] 1 ¹H NMR spectra were recorded using a 400 MHz or 600 MHz NMR spectrometer. Chemical shifts were reported in ppm(δ) as s (singular), d (double), t (triply), dd (double double), m (multiple lines), etc. The residual solvent signal was used as a reference. HPLC-MS spectra were performed as follows:

[0158] 1) Using an Agilent 1260 Infinity II:Poroshell 120 EC-C15 (4.6 mm × 50 mm, 2.7 μm), gradient elution was performed at 40°C with mobile phase A (H2O + 0.05% formic acid) and mobile phase B (ACN + 0.05% formic acid) at a flow rate of 0.6 mL / min. The DAD detector was set to 254 nm or 220 nm, the injection volume was 5 μL, and the oven temperature was 40°C.

[0159] 2) Using a Waters 2795 Alliance ZORBOX Extended-C181 (2.1 mm × 50 mm, 3.5 μm) at 35°C, gradient elution was performed with mobile phase A (H2O + 0.05% formic acid) and mobile phase B (ACN + 0.05% formic acid) at a flow rate of 0.7 mL / min. The DAD detector was set to the range of 210 nm to 600 nm, and the injection volume was 5 μL.

[0160] 2. General Procedures and Characteristic Data The final triazole 1 and its corresponding sodium salt 1-Na were obtained using the following synthetic route. [ka]

[0161] 2.1. Synthesis of esters and the 6 compounds produced [ka] P01A: A 0.2 M solution of carboxylic acid 7 in dry methanol was prepared in a two-necked flask equipped with a condenser. Thionyl chloride (3 equivalents) was added dropwise, and the mixture was stirred at 60°C for 6 hours. The solvent was then evaporated, and the remaining solid was dissolved in water. The mixture was carefully neutralized with aqueous sodium bicarbonate and extracted three times with dichloromethane. The combined organic phase was dried over magnesium sulfate and condensed to obtain the title compound 6.

[0162] [ka] P01B: In a Schlenk tube, a suspension of α-aminoazine 8 in DCM was heated at 60°C for 5 to 24 hours. The reaction mixture was cooled, and the intermediate was filtered in solid form. In a second Schlenk tube, the obtained intermediate was resuspended in ethanol, the tube was sealed, and the mixture was refluxed for 4 to 24 hours. The mixture was then condensed, and the residue was carefully basicized to pH 8 with an aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic phase was dried over magnesium sulfate and condensed. The resulting solid was purified on silica or recrystallized from ethanol to obtain the title compound 6.

[0163] [ka] [06-001] Methylquinoline-2-carboxylate (3.21 g, 95%) relative to 2-quinaldic acid, according to P01A.

[0164] [ka] [06-002] Ethylimidazo[1,2-a]isoquinoline-2-carboxylate (320 mg, 30%) relative to 1-aminoisoquinoline, according to P01B. 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.66 - 8.61 (m, 1H), 8.44 (d, J = 7.3 Hz, 1H), 8.03 - 7.96 (m, 1H), 7.84 - 7.75 (m, 2H), 7.54 (d, J = 7.2 Hz, 1H), 4.40 (q, J = 7.1 Hz, 4H), 1.37 (t, J = 7.1 Hz, 3H).

[0165] [ka] [06-003] Ethylimidazo[1,2-a]quinoline-2-carboxylate (228 mg, 27%) relative to 2-aminoquinoline, according to P01B. LC-MS (ES) m / z = 406 [M+H] + .

[0166] [ka] [06-004] Ethylimidazo[1,2-a]pyrazine-2-carboxylate (370 mg, 18%) relative to 2-aminopyrazine, according to P01B. 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (dd, J = 1.5, 0.6 Hz, 1H), 8.69 (d, J = 0.7 Hz, 1H), 8.59 (dd, J = 4.7, 1.6 Hz, 1H), 7.98 (d, J = 4.6 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). LC-MS (ES) m / z = 192 [M+H] + .

[0167] [ka] [06-005] Methyl 2-methylquinoline-4-carboxylate (403 mg, 80%) according to P01A for 2-methylquinoline-4-carboxylic acid. 1 H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 4.04 (s, 3H), 2.80 (s, 3H).

[0168] 2.2. Synthesis of Hydrazide 4 [ka] P02A: A 0.8 M solution of ester 6 in ethanol was mixed with hydrazine monohydrate (40 equivalents, 80% solution). The reaction mixture was refluxed for 5 to 12 hours. After confirmation of the completion of the reaction by TLC, the ethanol was removed under vacuum. The remaining solution was poured into ice water, the resulting precipitate was filtered, and freeze-dried to obtain the title compound 4.

[0169] P02B: In a pressure tube, hydrazine monohydrate (4 equivalents, 80% solution) was added to a 0.8 M solution of ester 6 in ethanol. The tube was sealed and the reaction mixture was heated at 120°C for 12 to 24 hours. After confirmation of the completion of the reaction by TLC, the ethanol was partially removed under vacuum, the resulting precipitate was filtered, and washed with cold ethanol or cold ether to obtain the title compound 4.

[0170] [ka] [04-001] Quinoline-2-carbohydrazide (2.02g, 67%, P02A applied to 06-001). LC-MS (ES) m / z = 188.28 [M+H] + .

[0171] [ka] [04-002]Imidazo[2,1-a]isoquinoline-2-carbohydrazide (63 mg, 67%, P02B applied to 06-002).

[0172] [ka] [04-003]Imidazo[1,2-a]Quinoline-2-Carbohydrazide (98 mg, 52%, P02B applied to 06-003). LC-MS (ES) m / z = 227 [M+H] + .

[0173] [ka] [04-004]Imidazo[1,2-a]pyrazine-2-carbohydrazide (46 mg, 50%, P02B applied to 06-004). LC-MS (ES) m / z = 178 [M+H] + .

[0174] [ka] [04-005] 2-Methylquinoline-4-carbohydrazide (0.184 g (45%) was obtained by applying a modified version of P02A to 06-005 and irradiating the reaction mixture in a microwave reactor at 80°C for 45 minutes): LC-MS (ES) m / z = 202.23 [M+H] + .

[0175] [ka] [04-006] 6-bromoimidazo[1,2-a]pyridine-2-carbozide (a modified version of P02B was applied to ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate, the reaction mixture was refluxed overnight, the formed solid was filtered and washed with ethanol to obtain 0.164 g (69%)).

[0176] [ka] [04-007]7-bromoimidazo[1,2-a]pyridine-2-carbozide (a modified version of P02B was applied to ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate, the reaction mixture was refluxed for 4 hours, the formed solid was filtered and washed with ethanol to obtain 0.398 g (93%)).

[0177] 2.3 Synthesis of Isothiocyanate 3 [ka] P03: A solution of sodium bicarbonate (3 equivalents) in water (12 mL) was added to amine 5 (1 equivalent) in a mixture of chloroform (12 mL) and water (12 mL). Thiophosgene (1.05 equivalents) was added dropwise at 0°C. The two-phase solution was stirred at room temperature for 1 hour, or stirred until completion of the reaction was confirmed by TLC. The two phases were separated. The combined organic layers were washed with brine, dried over Na2SO4, and condensed under reduced pressure to obtain the title compound 3.

[0178] [ka] [03-001] 3-Isothiocyanatobenzamide (318 mg, 61%, P03 applied to 3-aminobenzamide). 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (bs, 1H), 7.88 (t, J = 1.6 Hz, 1H), 7.85 (dt, J = 7.4, 1.5 Hz, 1H), 7.60 - 7.51 (m, 3H).

[0179] [ka] [03-002] 5-Isothiocyanato-2-methoxybenzamide (260 mg, 52%, P03 applied to 5-amino-2-methoxybenzamide). 1 H NMR (400 MHz, DMSO-d6) δ 7.76 - 7.64 (m, 2H), 7.56 (dd, J = 8.8, 2.8 Hz, 1H), 7.20 (d, J = 8.9 Hz, 1H), 3.91 (s, 3H).

[0180] [ka] [03-003] 4-(4-isothiocyanatophenoxy)-N-methylpicolinamide (561 mg, 86%, P03 applied to 4-(4-aminophenoxy)-N-methylpicolinamide). 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (q, J = 4.7 Hz, 1H), 8.54 (d, J = 5.6 Hz, 1H), 7.59 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 2.5 Hz, 1H), 7.32 (d, J = 8.9 Hz, 2H), 7.20 (dd, J = 5.6, 2.6 Hz, 1H), 2.79 (d, J = 4.9 Hz, 3H).

[0181] 2.4 Synthesis of intermediate carbothioamide 2 [ka] P04: In a Carousel® tube, equimolar amounts of isothiocyanate 3 and hydrazide 4 were suspended in ethanol (typically 0.1 M), the tube was sealed, and the mixture was refluxed for 2 to 16 hours. Once the consumption of the starting materials was confirmed, the tube was cooled to room temperature or 0°C, the formed precipitate was filtered, washed with a small amount of cold ethanol, and dried to obtain intermediate 2. If no precipitate formed, the solvent was evaporated, and the crude material was used directly after trituration with cold ether or cold pentane.

[0182] Typical examples include HPLC-MS and / or 1 The characteristics were identified using 1H NMR.

[0183] [ka] [02-001]N-(benzo[d][1,3]dioxol-5-yl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (120 mg, 65%) from 04-001 and isothiocyanate benzo[d][1,3]dioxol.

[0184] [ka] [02-002] 2-(quinoline-2-carbonyl)-N-(4-(trifluoromethyl)phenyl)hydrazine-1-carbothioamide (116 mg, 59%) from 04-001 and 1-isothiocyanato-4-(trifluoromethyl)benzene. LC-MS (ES) m / z = 391 [M+H] + .

[0185] [ka] [02-003] N-(4-chlorophenyl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (101 mg, 57%) from 04-001 and 1-chloro-4-isothiocyanatobenzene.

[0186] [ka] [02-004] 2-(quinoline-2-carbonyl)-N-(p-tolyl)hydrazine-1-carbothioamide (78 mg, 46%) from 04-001 and 1-isothiocyanato-4-methylbenzene.

[0187] [ka] [02-005] N-(3-bromophenyl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (134 mg, 67%) from 04-001 and 1-bromo-3-isothiocyanatobenzene. LC-MS (ES) m / z = 385 [M+H] + .

[0188] [ka] [02-006] N-benzyl-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (148 mg, 88%) from 04-001 and (isothiocyanatomethyl)benzene.

[0189] [ka] [02-007] N-phenyl-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (107 mg, 66%) from 04-001 and isothiocyanatebenzene.

[0190] [ka] [02-008] N-(4-acetylphenyl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (from 04-001 and 1-(4-isothiocyanatophenyl)ethane-1-one), 118 mg, 65%. LC-MS (ES) m / z = 365 [M+H] + .

[0191] [ka] [02-009] N-(4-phenoxybenzyl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (166 mg, 77%) from 04-001 and 1-(isothiocyanatomethyl)-4-phenoxybenzene.

[0192] [ka] [02-010] N-(4-methoxy-2-methylphenyl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (159 mg, 88%) from 04-001 and 1-isothiocyanato-4-methoxy-2-methylbenzene. LC-MS (ES) m / z = 367 [M+H] +

[0193] [ka] [02-011] N-(4-methoxyphenyl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (109 mg, 61%) from 04-001 and 1-isothiocyanato-4-methoxybenzene.

[0194] [ka] [02-012]N-([1,1'-biphenyl]-3-yl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (273 mg, 98%) from 04-001 and 3-isothiocyanate-1,1'-biphenyl. LC-MS (ES) m / z = 399 [M+H] + .

[0195] [ka] [02-013] N-(4-(benzyloxy)phenyl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (201 mg, 93%) from 04-001 and 1-(benzyloxy)-4-isothiocyanatobenzene. LC-MS (ES) m / z = 339 [M+H] +

[0196] [ka] [02-014] 161 mg, 94% from 2-(quinoline-2-carbonyl)-N-(thiophene-2-ylmethyl)hydrazine-1-carbothioamide (04-001 and 2-(4-isothiocyanatobenzyl)thiophene). 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.58 (s, 1H), 8.68 (s, J = 30.0 Hz, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.6 Hz, 2H), 8.09 (d, J = 8.2 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 5.0 Hz, 1H), 7.01 (s, 1H), 6.96 - 6.90 (m, 1H), 4.86 (d, J = 5.8 Hz, 2H).

[0197] [ka] [02-015] N-(4-phenoxyphenyl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (290 mg, 64%) from 04-001 and 1-isothiocyanato-4-phenoxybenzene. LC-MS (ES) m / z = 415 [M+H] + .

[0198] [ka] [02-016] N-(3-(benzyloxy)phenyl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (360 mg, 84%) from 04-001 and 1-(benzyloxy)-3-isothiocyanatobenzene). LC-MS (ES) m / z = 429 [M+H] + .

[0199] [ka] [02-017] N-(2,3-dihydro-1H-inden-5-yl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (292 mg, 81%) from 04-001 and 5-isothiocyanate-2,3-dihydro-1H-inden. LC-MS (ES) m / z = 363 [M+H] + .

[0200] [ka] [02-018] N-(6-chloropyridine-3-yl)-2-(quinoline-2-carbonyl)hydrazine-1-carbothioamide (176 mg, 70%) from 04-001 and 2-chloro-5-isothiocyanatopyridine. LC-MS (ES) m / z = 358 [M+H] + .

[0201] [ka] [02-020] N-(2-(quinoline-2-carbonyl)hydrazine-1-carbonothioyl)benzamide (248 mg, 71%) from 04-001 and benzoyl isothiocyanate. 1H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 11.98 (s, 1H), 11.48 (s, 1H), 8.67 (d, J = 8.5 Hz, 1H), 8.25 - 8.11 (m, 3H), 8.02 (d, J = 7.8 Hz, 2H), 7.93 (t, J = 7.6 Hz, 1H), 7.79 (t, J = 7.5 Hz, 1H), 7.69 (t, J = 7.4 Hz, 1H), 7.60 - 7.52 (m, 2H). LC-MS (ES) m / z = 351 [M+H] + .

[0202] [ka] [02-021] 4-Chloro-N-(2-(quinoline-2-carbonyl)hydrazine-1-carbonothioyl)benzamide (275 mg, 72%) from 04-001 and 4-chlorobenzoyl isothiocyanate. LC-MS (ES) m / z = 385 [M+H] + .

[0203] [ka] [02-022]N-(benzo[d][1,3]dioxol-5-yl)-2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbothioamide (345 mg, 89%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and isothiocyanate benzo[d][1,3]dioxol. LC-MS (ES) m / z = 390 [M+H] + .

[0204] [ka] [02-023]N-(benzo[d][1,3]dioxol-5-yl)-2-(imidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbothioamide (230 mg, 77%) from imidazo[1,2-a]pyridine-2-carbohydrazide and isothiocyanate benzo[d][1,3]dioxol. LC-MS (ES) m / z = 356 [M+H] + .

[0205] [ka] [02-024]N-(benzo[d][1,3]dioxol-5-yl)-2-(5-methylimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbothioamide (249 mg, 81%) from 5-methylimidazo[1,2-a]pyridine-2-carbohydrazide and isothiocyanate benzo[d][1,3]dioxol. LC-MS (ES) m / z = 370 [M+H] + .

[0206] [ka] [02-025]N-(benzo[d][1,3]dioxol-5-yl)-2-(7-methylimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbothioamide (143 mg, 61%) from 7-methylimidazo[1,2-a]pyridine-2-carbohydrazide and isothiocyanatebenzo[d][1,3]dioxol.

[0207] [ka] [02-026] 2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)-N-(4-(trifluoromethoxy)benzyl)hydrazine-1-carbothioamide (210 mg, 65%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 1-(isothiocyanatomethyl)-4-(trifluoromethoxy)benzene.

[0208] [ka] [02-027] 2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)-N-(2,3-dihydro-1H-inden-5-yl)hydrazine-1-carbothioamide (162 mg, 88%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 5-isothiocyanate-2,3-dihydro-1H-inden.

[0209] [ka] [02-028] 2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)-N-(4-phenoxyphenyl)hydrazine-1-carbothioamide (167 mg, 80%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 1-isothiocyanate-4-phenoxybenzene.

[0210] [ka] [02-029] N-(4-(benzyloxy)phenyl)-2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbothioamide (199 mg, 92%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 1-(benzyloxy)-4-isothiocyanatobenzene.

[0211] [ka] [02-030] N-(3-(benzyloxy)phenyl)-2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbothioamide (187 mg, 88%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 1-(benzyloxy)-3-isothiocyanatobenzene.

[0212] [ka] [02-031] 2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)-N-(4-methoxy-2-methylphenyl)hydrazine-1-carbothioamide (159 mg, 86%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 1-isothiocyanate-4-methoxy-2-methylbenzene.

[0213] [ka] [02-032] 2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)-N-(6-chloropyridine-3-yl)hydrazine-1-carbothioamide (172 mg, 63%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 2-chloro-5-isothiocyanatopyridine.

[0214] [ka] [02-034] 4-(2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbothioamide)benzoic acid (332 mg, 89%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 4-isothiocyanatebenzoic acid. LC-MS (ES) m / z = 390 [M+H] + .

[0215] [ka] [02-035] 2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)-N-(4-sulfamoylphenyl)hydrazine-1-carbothioamide (343 mg, 85%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 4-isothiocyanatobenzenesulfonamide. LC-MS (ES) m / z = 425 [M+H] + .

[0216] [ka] [02-036] N-(2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbonothioyl)benzamide (174 mg, 63%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohazide and benzoyl isothiocyanate. 1 H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 11.91 (s, 1H), 10.90 (s, 1H), 8.65 (dd, J = 7.3, 0.7 Hz, 1H), 8.60 (d, J = 0.6 Hz, 1H), 8.01 - 7.97 (m, 2H), 7.91 - 7.88 (m, 1H), 7.71 - 7.64 (m, 1H), 7.54 (dd, J = 10.6, 4.8 Hz, 2H), 7.14 (dd, J = 7.3, 2.1 Hz, 1H). LC-MS (ES) m / z = 374 [M+H] + .

[0217] [ka] [02-037]N-(benzo[d][1,3]dioxol-5-yl)-2-(imidazo[2,1-a]isoquinoline-2-carbonyl)hydrazine-1-carbothioamide (53 mg, 69%) from 04-002 and isothiocyanatebenzo[d][1,3]dioxol.

[0218] [ka] [02-038]N-(benzo[d][1,3]dioxol-5-yl)-2-(imidazo[1,2-a]quinoline-2-carbonyl)hydrazine-1-carbothioamide (72 mg, 63%) from 04-003 and isothiocyanate benzo[d][1,3]dioxol.

[0219] [ka] [02-039]N-(benzo[d][1,3]dioxol-5-yl)-2-(imidazo[1,2-a]pyrazine-2-carbonyl)hydrazine-1-carbothioamide (46 mg, 65%) from 04-004 and isothiocyanate benzo[d][1,3]dioxol.

[0220] [ka] [02-040]N-(benzo[d][1,3]dioxol-5-yl)-2-(2-methylquinoline-4-carbonyl)hydrazine-1-carbothioamide (82 mg, 64%) from 04-005 and isothiocyanate benzo[d][1,3]dioxol. LC-MS (ES) m / z = 381 [M+H] + .

[0221] [ka] [02-041] N-(3,4-dimethoxybenzyl)-2-(quinoline-2-carbonyl)hydrazine-1-carboxamide (183 mg, 69%, condensed with 04-001 and 4-(isocyanatomethyl)-1,2-dimethoxybenzene by applying P04). LC-MS (ES) m / z = 382 [M+H] + .

[0222] [ka] [02-042]N-(benzo[d][1,3]dioxol-5-yl)-2-(6-bromoimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbothioamide (65 mg, 54%) from 04-006 and isothiocyanate benzo[d][1,3]dioxol. LC-MS (ES) m / z = 435 [M+H] + .

[0223] [ka] [02-043]N-(benzo[d][1,3]dioxol-5-yl)-2-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbothioamide (152 mg, 89%) from 04-007 and isothiocyanate benzo[d][1,3]dioxol.

[0224] [ka] [02-044] 2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)-N-(thiophen-2-ylmethyl)hydrazine-1-carbothioamide (152 mg, 87%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 2-(isothiocyanatomethyl)thiophene.

[0225] [ka] [02-045] 2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)-N-(1-methyl-1H-pyrazole-3-yl)hydrazine-1-carbothioamide (198 mg, 94%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 3-isothiocyanato-1-methyl-1H-pyrazole. 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.90 (s, 1H), 10.64 (s, 1H), 8.65 (dd, J = 7.3, 0.8 Hz, 1H), 8.53 (d, J = 0.7 Hz, 1H), 7.87 (s, 1H), 7.67 (s, 1H), 7.12 (dd, J = 7.3, 2.1 Hz, 1H), 5.96 (s, 1H), 3.80 (s, 4H).

[0226] [ka] [02-046] 177 mg, 79% of 2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)-N-(2,2-diphenylethyl)hydrazine-1-carbothioamide (7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and (2-isothiocyanatoethane-1,1-diyl)dibenzene). 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.42 (bs, 1H), 8.64 (dd, J = 7.3, 0.9 Hz, 1H), 8.46 (d, J = 0.8 Hz, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.32 - 7.08 (m, 11H), 4.49 (d, J = 8.1 Hz, 1H), 4.07 (t, J = 6.5 Hz, 2H).

[0227] [ka] [02-047] 2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)-N-(3-morpholinopropyl)hydrazine-1-carbothioamide (155 mg, 82%) from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 4-(3-isothiocyanatopropyl)morpholine. 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.30 (s, 1H), 8.65 (dd, J = 7.3, 0.9 Hz, 1H), 8.50 (d, J = 0.8 Hz, 1H), 7.92 (s, 1H), 7.78 (dd, J = 1.9, 1.0 Hz, 1H), 7.10 (dd, J = 7.3, 2.1 Hz, 1H), 3.51 - 3.40 (m, 6H), 2.32 - 2.22 (m, 6H), 1.64 (p, J = 7.0 Hz, 2H).

[0228] [ka] [02-048] 3-(2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbothioamide)benzamide (188 mg quantitatively from 7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 03-001). 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.81 (s, 2H), 8.66 (dd, J = 7.3, 0.9 Hz, 1H), 8.52 (s, 1H), 7.95 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.63 (dt, J = 7.8, 1.3 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.11 (dd, J = 7.3, 2.1 Hz, 1H).

[0229] [ka] [02-049] 5-(2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbothioamide)-2-methoxybenzamide (7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 03-002, 108 mg, 68%). 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.70 (s, 2H), 8.66 (dd, J = 7.3, 0.9 Hz, 1H), 8.52 (d, J = 0.8 Hz, 1H), 7.80 (d, J = 2.4 Hz, 2H), 7.67 - 7.60 (m, 2H), 7.52 (s, 1H), 7.14 - 7.05 (m, 2H), 3.89 (s, 3H).

[0230] [ka] [02-050] 4-(4-(2-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)hydrazine-1-carbothioamide)phenoxy)-N-methylpicolinamide (7-chloroimidazo[1,2-a]pyridine-2-carbohydrazide and 03-003, 182 mg, 77%). 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.81 (bs, 2H), 8.76 (q, J = 4.7 Hz, 1H), 8.66 (dd, J = 7.3, 0.9 Hz, 1H), 8.55 - 8.49 (m, 2H), 7.81 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 2.6 Hz, 1H), 7.22 - 7.09 (m, 4H), 2.78 (d, J = 4.8 Hz, 3H).

[0231] [ka] [02-051]N-(benzo[d][1,3]dioxol-5-yl)-2-nicotinoylhydrazine-1-carbothioamide (68 mg, 43%) derived from nicotinohydrazide and isothiocyanate benzo[d][1,3]dioxol.

[0232] [ka] [02-052]N-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroisonicotinoyl)hydrazine-1-carbothioamide (342 mg, 98%) from 2-chloroisonicotinohydrazide and isothiocyanate benzo[d][1,3]dioxol. LC-MS (ES) m / z = 351 [M+H] + .

[0233] [ka] [02-053]N-(benzo[d][1,3]dioxol-5-yl)-2-(6-chloronicotinoyl)hydrazine-1-carbothioamide (316 mg, 90%) from 6-chloronicotinohydrazide and isothiocyanate benzo[d][1,3]dioxol. LC-MS (ES) m / z = 352 [M+H] + .

[0234] [ka] [02-054] N-(benzo[d][1,3]dioxol-5-yl)-2-(6-chloropicolinoyl)hydrazine-1-carbothioamide (795 mg, 78%) derived from 6-chloropicolinohydrazide and isothiocyanate benzo[d][1,3]dioxol. 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.72 (s, 1H), 9.64 (s, 1H), 8.15 - 7.96 (m, 2H), 7.77 (dd, J = 7.6, 1.3 Hz, 1H), 7.04 (s, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.01 (s, 2H). LC-MS (ES) m / z = 351 [M+H] + .

[0235] 2.5 Synthesis of Triazole 1 and Related Compounds [ka] P05: In a Carousel™ tube, compound 2 (1 equivalent) was suspended in an aqueous NaOH solution (typically 1 M, 20-40 equivalents). After three vacuum-argon cycles, the tube was sealed and the mixture was refluxed for 6-24 hours. Once consumption of the starting material was confirmed by HPLC-MS or TLC, the tube was cooled to room temperature and the pH was adjusted to 3 using an aqueous HCl solution (typically 1 M). The resulting precipitate was filtered, washed with a very small amount of cold water, and lyophilized to obtain title compound 1. If a highly lipophilic intermediate was present, up to 5% (vol / vol) of ethanol was added to the reaction mixture.

[0236] P06: In a Carousel™ tube, compound 2 (1 equivalent) was suspended in a 10% Na2CO3 aqueous solution (typically 20 to 40 equivalents). After three vacuum-argon cycles, the tube was sealed and the mixture was refluxed for 6 to 24 hours. Once consumption of the starting material was confirmed by HPLC-MS or TLC, the tube was cooled to room temperature and the pH was adjusted to 3 using an aqueous HCl solution (typically 2M, with stirring). The resulting precipitate was filtered, washed with a very small amount of cold water, and freeze-dried to obtain title compound 1.

[0237] P07: Compound 2 was suspended in glacial acetic acid (typically 70 to 100 equivalents) in a pressure tube. The tube was sealed and the mixture was stirred at 160°C for 6 to 24 hours. Once the consumption of the starting material was confirmed by HPLC-MS, the tube was cooled to room temperature. The formed precipitate was filtered, washed with cold water, and freeze-dried to obtain the title compound 1.

[0238] P08: To improve the solubility of compound 1, these were converted to the corresponding sodium salt 1-Na as follows: In a Falcon tube, 5 mg to 10 mg of compound 1 was dissolved in a minimum amount of acetonitrile (typically 2 mL to 3 mL), and 1 equivalent of NaOH (in aqueous solution form) was added. The solution was then diluted with water to obtain a 1:9 acetonitrile:water solution. The solution was then freeze-dried to obtain the sodium salt 1-Na in quantitative yield. Typical examples are shown by LC-MS or 1 Characterized by 1H NMR.

[0239] [ka] [01-001] 4-(benzo[d][1,3]dioxol-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (197 mg, 78%, P05 applied to intermediate 02-001): 1 H NMR (400 MHz, DMSO-d6) δ 14.29 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 5.3 Hz, 2H), 7.73 (d, J = 7.4 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.10 - 6.91 (m, 2H), 6.82 (d, J = 8.1 Hz, 1H), 6.13 (s, 2H). LC-MS (ES) m / z = 349 [M+H] + .

[0240] [01-001-Na] Sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.61 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.48 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.53 (dd, J = 8.2, 2.0 Hz, 1H), 6.08 (s, 2H). LC-MS (ES) m / z = 349 [M-Na+H] + .

[0241] [ka] [01-002] 5-(quinoline-2-yl)-4-(4-(trifluoromethyl)phenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (33g, 86%, P06 applied to intermediate 02-002): 1 H NMR (400 MHz, DMSO-d6) δ 14.46 (s, 1H), 8.49 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.69 (dd, J = 13.8, 7.1 Hz, 3H), 7.61 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H). LC-MS (ES) m / z = 342 [M+H] + .

[0242] [01-002-Na] Sodium 3-(quinoline-2-yl)-5-thioxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1,2,4-triazole-1-oid. 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.2 Hz, 1H). LC-MS (ES) m / z = 342 [M-Na+H] + .

[0243] [ka] [01-003] 4-(4-chlorophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (53 mg, 70%, P05 applied to intermediate 02-003): 1 H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 8.45 (d, J = 8.6 Hz, 1H), 8.08 (t, J = 10.8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H). LC-MS (ES) m / z = 339 [M+H] + .

[0244] [01-003-Na] Sodium 4-(4-chlorophenyl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.0 Hz, 1H), 7.47 (t, J = 7.0 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.23 - 7.16 (m, 3H). LC-MS (ES) m / z = 339 [M-Na+H] + .

[0245] [ka] [01-004] 5-(quinoline-2-yl)-4-(p-tolyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (56 mg, 69%, P05 applied to intermediate 02-004): 1¹H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 2.38 (s, 3H), indicating loss of mobile protons. LC-MS (ES) m / z = 319 [M+H] + .

[0246] [01-004-Na]Sodium 3-(quinoline-2-yl)-5-thioxo-4-(p-tolyl)-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 319 [M-Na+H] +

[0247] [ka] [01-005] 4-(3-bromophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (48 mg, 46%, P05 applied to intermediate 02-005): 1 H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.77 - 7.69 (m, 3H), 7.62 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.42 (dt, J = 8.0, 1.4 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H). LC-MS (ES) m / z = 385 [M+H] + .

[0248] [01-005-Na] Sodium 4-(3-bromophenyl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 385 [M-Na+H] + .

[0249] [ka] [01-006] 4-benzyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (62 mg, 66%, P05 applied to intermediate 02-006): 1 H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 4.3 Hz, 1H), 8.01 (d, J = 3.3 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.3 Hz, 2H), 7.22 (t, J = 7.5 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 6.04 (s, 2H). LC-MS (ES) m / z = 319 [M+H] + .

[0250] [01-006-Na] Sodium 4-benzyl-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (dt, J = 13.1, 6.7 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.53 (t, J = 8.9 Hz, 1H), 7.32 - 7.26 (m, 2H), 7.18 - 7.11 (m, 2H), 7.06 (t, J = 6.9 Hz, 1H), 6.02 (s, 2H). LC-MS (ES) m / z = 319 [M-Na+H] + .

[0251] [ka] [01-007] 4-phenyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (51 mg, 72%, P05 applied to intermediate 02-007): 1 H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1H), 8.46 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.4 Hz, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.53 - 7.40 (m, 3H), 7.39 - 7.34 (m, 2H), 7.29 (d, J = 8.3 Hz, 1H). LC-MS (ES) m / z = 305 [M+H] + .

[0252] [01-007-Na] Sodium 4-phenyl-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 6.9 Hz, 1H), 7.40 - 7.29 (m, 3H), 7.20 - 7.10 (m, 3H). LC-MS (ES) m / z = 305 [M-Na+H] + .

[0253] [ka] [01-008] 1-(4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenyl)ethane-1-one (37 mg, 43%, apply P06 to intermediate 02-008): 1 H NMR (400 MHz, DMSO-d6) δ 14.43 (s, 1H), 8.47 (d, J = 8.7 Hz, 1H), 8.11 - 8.00 (m, 3H), 7.97 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.0 Hz, 1H), 7.59 (dd, J = 15.3, 8.3 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 1H), 2.65 (s, J = 37.2 Hz, 3H). LC-MS (ES) m / z = 347 [M+H] + .

[0254] [ka] [01-009] 4-(4-phenoxybenzyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (44 mg, 57%, P05 applied to intermediate 02-009): 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 8.51 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 8.06 (t, J = 7.6 Hz, 2H), 7.85 (t, J = 7.8 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.37 - 7.29 (m, 4H), 7.09 (t, J = 7.3 Hz, 1H), 6.92 - 6.81 (m, 4H), 6.02 (s, 2H). LC-MS (ES) m / z = 411 [M+H] + .

[0255] [01-009-Na] Sodium 4-(4-phenoxybenzyl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 8.7 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.0 Hz, 1H), 7.53 (t, J = 7.3 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.33 - 7.25 (m, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.8 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 6.00 (s, 2H). LC-MS (ES) m / z = 411 [M-Na+H] + .

[0256] [ka] [01-010] 4-(4-methoxy-2-methylphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (51 mg, 67%, P05 applied to intermediate 02-010). 1H NMR (400 MHz, DMSO-d6) δ 14.33 (s, 1H), 8.47 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 2.7 Hz, 1H), 6.81 (dd, J = 8.6, 2.8 Hz, 1H), 3.81 (s, J = 5.4 Hz, 3H), 2.06 (s, 3H). LC-MS (ES) m / z = 349 [M+H] + .

[0257] [01-010-Na] Sodium 4-(4-methoxy-2-methylphenyl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.86 - 6.79 (m, 2H), 6.72 (dd, J = 8.5, 2.8 Hz, 1H), 3.79 (s, 3H), 1.91 (s, 3H). LC-MS (ES) m / z = 349 [M-Na+H] + .

[0258] [ka] [01-011] 4-(4-methoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (50 mg, 88%, P05 applied to intermediate 02-011).1 H NMR (400 MHz, DMSO-d6) δ 14.30 (s, 1H), 8.46 (d, J = 8.6 Hz, 1H), 8.01 - 7.93 (m, 2H), 7.73 (t, J = 7.3 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H). LC-MS (ES) m / z = 335 [M+H] + .

[0259] [01-011-Na] Sodium 4-(4-methoxyphenyl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 335 [M-Na+H] + .

[0260] [ka] [01-012] 4-([1,1'-biphenyl]-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (70 mg, 92%, P05 applied to intermediate 02-012). 1 H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 8.01 - 7.93 (m, 1H), 7.86 - 7.80 (m, 1H), 7.75 (t, J = 1.8 Hz, 1H), 7.70 - 7.54 (m, 5H), 7.44 (t, J = 7.5 Hz, 2H), 7.40 - 7.33 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H). LC-MS (ES) m / z = 381 [M+H] + .

[0261] [01-012-Na] Sodium 4-([1,1'-biphenyl]-3-yl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 381 [M-Na+H] + .

[0262] [ka] [01-013] 4-(4-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (44 mg, 55%, P05 applied to intermediate 02-013). 1 H NMR (400 MHz, DMSO-d6) δ 14.29 (s, 1H), 8.45 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.49 (d, J = 7.1 Hz, 2H), 7.42 (t, J = 7.1 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 5.20 (s, 2H). LC-MS (ES) m / z = 411 [M+H] + .

[0263] [01-013-Na] Sodium 4-(4-(benzyloxy)phenyl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 411 [M-Na+H] + .

[0264] [ka] [01-014] 5-(quinoline-2-yl)-4-(thiophene-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (55 mg, 73%, P05 applied to intermediate 02-014). 1 H NMR (400 MHz, DMSO-d6) δ 14.34 (s, 1H), 8.56 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 5.0 Hz, 1H), 7.24 (d, J = 3.1 Hz, 1H), 6.93 - 6.83 (m, 1H), 6.25 (s, 2H). LC-MS (ES) m / z = 325 [M+H] + .

[0265] [01-014-Na]Sodium 3-(quinoline-2-yl)-4-(thiophene-2-ylmethyl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 325 [M-Na+H] + .

[0266] [ka] [01-015] 4-(4-phenoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (34 mg, 44%, P05 applied to intermediate 02-015): 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.68 (t, J = 7.0 Hz, 1H), 7.52 (t, J = 7.0 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.7 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H), 7.07 (dd, J = 8.6, 0.9 Hz, 2H), 7.04 (d, J = 8.8 (Hz, 2H). The mobile proton signal is lost. LC-MS (ES) m / z = 397 [M+H] + .

[0267] [01-015-Na] Sodium 4-(4-phenoxyphenyl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 397 [M-Na+H] + .

[0268] [ka] [01-016] 4-(3-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (27 mg, 37%, P05 applied to intermediate 02-016). 1H NMR (400 MHz, DMSO-d6) δ 14.29 (s, 1H), 8.43 (d, J = 8.6 Hz, 1H), 8.02 - 7.93 (m, 2H), 7.69 (t, J = 6.9 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.40 - 7.34 (m, 3H), 7.33 - 7.24 (m, 4H), 7.13 (dd, J = 8.2, 2.2 Hz, 1H), 7.06 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 5.07 (d, J = 12.9Hz, 2H). LC-MS (ES) m / z = 411 [M+H] + .

[0269] [01-016-Na] Sodium 4-(3-(benzyloxy)phenyl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 411 [M-Na+H] + .

[0270] [ka] [01-017] 4-(2,3-dihydro-1H-inden-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (46 mg, 60%, P05 applied to intermediate 02-017). 1H NMR (400 MHz, DMSO-d6) δ 14.29 (s, 1H), 8.45 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 2.90 (dt, J = 23.2, 7.2 Hz, 4H), 2.16 - 2.01 (m, 2H). LC-MS (ES) m / z = 345 [M+H] + .

[0271] [01-017-Na] Sodium 4-(2,3-dihydro-1H-inden-5-yl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 345 [M-Na+H] + .

[0272] [ka] [01-018] 4-(6-chloropyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (43 mg, 35%, P06 applied to intermediate 02-018). 1 H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 8.58 - 8.46 (m, 2H), 8.13 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.83 - 7.70 (m, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H). LC-MS (ES) m / z = 340 [M+H] + .

[0273] [01-018-Na]Sodium 4-(6-chloropyridine-3-yl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 340 [M-Na+H] + .

[0274] [ka] [01-019] 4-(6-(piperazin-1-yl)pyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione: In a pressure tube, a solution of compound 01-018 (30 mg, 1 equivalent) and piperazine (38 mg, 5 equivalents) in dioxane (8.8 mL, 0.1 M) was stirred at 100°C for 60 hours. The solvent was evaporated, and the crude product was purified by reverse-phase chromatography (water:acetonitrile gradient, both containing 0.07% TFA) to obtain the title compound (8 mg, 23%). LC-MS (ES) m / z = 390 [M+H] + .

[0275] [ka] [01-020] Phenyl(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone (46 mg, 68%, isolated as acetate by applying P07 to intermediate 02-020). 1H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H), 11.98 (s, 1H), 8.58 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 7.6 Hz, 2H), 8.13 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.70 (t, J = 8.6 Hz, 2H), 7.60 (t, J = 7.6 Hz, 2H), 1.91 (s, 3H). LC-MS (ES) m / z = 333 [M+H] + .

[0276] [ka] [01-021] (4-chlorophenyl) (3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone (25 mg, 33%, P07 applied to intermediate 02-021). 1 H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 8.59 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 8.6 Hz, 2H), 8.13 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.76 - 7.60 (m, 3H). LC-MS (ES) m / z = 367 [M+H] + .

[0277] [01-021-Na] Sodium 4-(4-chlorobenzoyl)-3-(quinoline-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 367 [M-Na+H] + .

[0278] [ka] [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (811 mg, 87%, P05 applied to intermediate 02-022). 1 H NMR (400 MHz, DMSO-d6) δ 14.07 (s, 1H), 8.58 (d, J = 7.3 Hz, 1H), 7.74 (d, J = 2.1 Hz, 1H), 7.64 (s, 1H), 7.08 - 6.96 (m, 3H), 6.84 (dd, J = 8.2, 2.1 Hz, 1H), 6.16 (s, 2H). LC-MS (ES) m / z = 372[M+H] + .

[0279] [01-022-Na] Sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 7.2 Hz, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 6.92 (dd, J = 7.3, 2.1 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 1.9 Hz, 1H), 6.54 (dd, J = 8.2, 2.0 Hz, 1H), 6.08 (s, 2H). LC-MS (ES) m / z = 372 [M-Na+H] + .

[0280] [ka] [01-023] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (51 mg, 45%, P05 applied to intermediate 02-023). 1 H NMR (400 MHz, DMSO-d6) δ 14.27 (s, 1H), 8.67 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.62 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.15 - 7.04 (m, 3H), 6.91 (dd, J = 8.0, 1.9 Hz, 1H), 6.18 (s, 2H). LC-MS (ES) m / z = 338 [M+H] + .

[0281] [01-023-Na] Sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(imidazo[1,2-a]pyridine-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (dt, J = 6.8, 1.2 Hz, 1H), 7.53 (s, 1H), 7.48 - 7.39 (m, 1H), 7.17 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.82 (td, J = 6.8, 1.2 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.54 (dd, J = 8.2, 2.0 Hz, 1H), 6.07 (s, 2H). LC-MS (ES) m / z = 338 [M-Na+H] + .

[0282] [ka] [01-024] 4-(benzo[d][1,3]dioxol-5-yl)-5-(5-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (66 mg, 57%, P05 applied to intermediate 02-024). 1 ¹H NMR (400 MHz, DMSO-d6) δ 14.19 (s, 1H), 7.57 (s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 9.2, 6.8 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 7.1 Hz, 1H), 6.88 (dd, J = 8.2, 2.1 Hz, 1H), 6.15 (s, 2H), 2.49 (s, overlaps with solvent peak). LC-MS (ES) m / z = 352 [M+H] + .

[0283] [01-024-Na] Sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(5-methylimidazo[1,2-a]pyridine-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1 ¹H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 0.7 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.15 (dd, J = 9.1, 6.8 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 6.8 Hz, 1H), 6.56 (dd, J = 8.2, 2.0 Hz, 1H), 6.06 (s, 2H). The methyl signal overlaps with the solvent peak. LC-MS (ES) m / z = 352 [M-Na+H] + .

[0284] [ka] [01-025] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (49 mg, 64%, P05 applied to intermediate 02-025). 1 H NMR (400 MHz, DMSO-d6) δ 14.24 (s, 1H), 8.54 (d, J = 7.1 Hz, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 7.09 (d, J = 3.3 Hz, 1H), 7.07 (d, J = 3.1 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.90 (dd, J = 8.3, 2.0 Hz, 1H), 6.18 (s, 2H), 2.40 (s, J = 27.6 Hz, 3H). LC-MS (ES) m / z = 352 [M-Na+H] + .

[0285] [01-025-Na] Sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(7-methylimidazo[1,2-a]pyridine-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 7.0 Hz, 1H), 7.42 (s, 1H), 7.23 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.78 (s, 1H), 6.68 (dd, J = 6.9, 1.6 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.08 (s, 2H), 2.30 (s, 3H). LC-MS (ES) m / z = 352 [M-Na+H] + .

[0286] [ka] [01-026] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-(trifluoromethoxy)benzyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (210 mg, 66%, P05 applied to intermediate 02-026). 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 7.2 Hz, 1H), 8.23 ​​(s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.00 (dd, J = 7.2, 2.1 Hz, 1H), 5.79 (s, J = 14.9 Hz, 2H). LC-MS (ES) m / z = 426 [M+H] + .

[0287] [ka] [01-027] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,3-dihydro-1H-inden-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (55 mg, 72%, P05 applied to intermediate 02-027). 1 H NMR (400 MHz, DMSO-d6) δ 14.10 (s, 1H), 8.56 (d, J = 7.3 Hz, 1H), 7.73 (s, 1H), 7.59 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.24 (s, 1H), 7.10 (d, J = 6.5 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 2.98 - 2.84 (m, 4H), 2.14 - 2.03 (m, 2H).

[0288] [01-027-Na] Sodium 3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,3-dihydro-1H-inden-5-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 11H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 7.3, 0.8 Hz, 1H), 7.60 (dd, J = 1.4, 0.8 Hz, 1H), 7.48 (d, J = 0.7 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.05 (s, 1H), 6.90 (dd, J = 7.3, 2.1 Hz, 1H), 6.85 (dd, J = 7.8, 1.9 Hz, 1H), 2.87 (dt, J = 11.1, 7.4 Hz, 4H), 2.13 - 1.97 (m, 2H).

[0289] [Chemical formula] [01-028] 5-(7-Chloroimidazo[1,2-a]pyridin-2-yl)-4-(4-phenoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (43 mg, 56%, applying P05 to Intermediate 02-028). 1 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.44 (dd, J = 14.6, 7.6 Hz, 2H), 7.22 - 7.13 (m, 3H), 7.09 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 6.8 Hz, 1H). The mobile proton signal is lost, which is highly likely to have been exchanged with accidental H2O in the solvent.

[0290] [01-028-Na] Sodium 3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-4-(4-phenoxyphenyl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-ide. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 7.2, 0.8 Hz, 1H), 7.64 (d, J = 0.7 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.20 - 7.13 (m, 3H), 7.08 (dd, J = 8.7, 1.1 Hz, 2H), 7.00 - 6.95 (m, 2H), 6.93 (dd, J = 7.2, 2.1 Hz, 1H).

[0291] [ka] [01-029] 4-(4-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (29 mg, 38%, P05 applied to intermediate 02-029). 1 H NMR (400 MHz, DMSO-d6) δ 14.09 (s, 1H), 8.56 (d, J = 7.2 Hz, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.50 (d, J = 7.2 Hz, 2H), 7.46 - 7.39 (m, 2H), 7.37 (d, J = 7.3 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.9 Hz, 2H), 7.02 (dd, J = 7.2, 1.9 Hz, 1H), 5.17 (s, 2H).

[0292] [01-029-Na] Sodium 4-(4-(benzyloxy)phenyl)-3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 7.3, 0.8 Hz, 1H), 7.58 (dd, J = 1.4, 0.8 Hz, 1H), 7.52 (d, J = 0.7 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.45 - 7.30 (m, 3H), 7.11 - 7.04 (m, 2H), 7.02 - 6.95 (m, 2H), 6.91 (dd, J = 7.3, 2.1 Hz, 1H), 5.12 (s, 2H).

[0293] [ka] [01-030] 4-(3-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (47g, 61%, P05 applied to intermediate 02-030). 1 ¹H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 7.2 Hz, 1H), 7.64 (s, 1H), 7.56 (s, 1H), 7.44 - 7.20 (m, 6H), 7.10 (d, J = 8.5 Hz, 1H), 7.04 - 6.93 (m, 2H), 6.87 (d, J = 7.7 Hz, 1H), 5.07 (s, 2H). The mobile proton signal is lost, which is likely due to accidental replacement with H₂O in the solvent.

[0294] [01-030-Na] Sodium 4-(3-(benzyloxy)phenyl)-3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.54 (s, 1H), 7.41 (d, J = 6.9 Hz, 2H), 7.37 - 7.31 (m, 2H), 7.30 - 7.22 (m, 2H), 6.98 (dd, J = 8.0, 2.1 Hz, 1H), 6.91 (dd, J = 7.3, 2.1 Hz, 1H), 6.88 - 6.84 (m, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.05 (s, 2H).

[0295] [ka] [01-031] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-methoxy-2-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (49 mg, 64%, P05 applied to intermediate 02-031). 1 H NMR (400 MHz, DMSO-d6) δ 14.13 (s, 1H), 8.56 (d, J = 7.4 Hz, 1H), 7.72 (s, 1H), 7.45 (s, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.03 - 6.97 (m, 2H), 6.91 (dd, J = 8.6, 2.4 Hz, 1H), 3.83 (s, 3H), 2.00 (s, 3H).

[0296] [01-031-Na] Sodium 3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-methoxy-2-methylphenyl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 11H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J = 7.3, 0.7 Hz, 1H), 7.58 (dd, J = 1.4, 0.8 Hz, 1H), 7.20 (d, J = 0.6 Hz, 1H), 6.90 - 6.84 (m, 3H), 6.78 (dd, J = 8.6, 2.7 Hz, 1H), 3.79 (s, 3H), 1.91 (s, 3H).

[0297]

Chem.

[0298] [01-032-Na] Sodium 3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-4-(6-chloropyridin-3-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-ide.

[0299]

Chem.

[0300] [ka] [01-034] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid (48 mg, 63%, P05 applied to intermediate 02-034). 1H NMR (400 MHz, DMSO-d6) δ 14.22 (s, 1H), 13.24 (s, 1H), 8.56 (dd, J = 7.3, 0.7 Hz, 1H), 8.07 (d, J = 8.6 Hz, 2H), 7.86 (d, J = 0.6 Hz, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.02 (dd, J = 7.3, 2.1 Hz, 1H). LC-MS (ES) m / z = 372 [M+H] + .

[0301] [01-034-Na] Disodium 4-(4-carboxylatophenyl)-3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid (apply modified P08 to compound 01-034 using 2 equivalents of NaOH). 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J = 7.3, 0.8 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.60 (dd, J = 1.4, 0.8 Hz, 1H), 7.42 (d, J = 0.7 Hz, 1H), 7.06 - 7.00 (m, 2H), 6.88 (dd, J = 7.3, 2.1 Hz, 1H). LC-MS (ES) m / z = 372 [M-2Na+H] + .

[0302] [ka] [01-035] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide (84 mg, 88%, P05 applied to intermediate 02-035). 1H NMR (400 MHz, DMSO-d6) δ 14.27 (s, 1H), 8.59 (d, J = 7.2 Hz, 1H), 8.07 (s, 1H), 7.90 (dd, J = 24.5, 5.3 Hz, 2H), 7.64 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.52 (s, 2H), 7.05 (dd, J = 7.3, 2.1 Hz, 1H). LC-MS (ES) m / z = 407 [M+H] + .

[0303] [01-035-Na] Sodium 3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-sulfamoylphenyl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 7.3, 0.7 Hz, 1H), 7.76 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 6.92 (dd, J = 7.2, 2.1 Hz, 1H). LC-MS (ES) m / z = 407 [M-Na+H] + .

[0304] [ka] [01-036] (3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)(phenyl)methanone (21 mg, 37%, isolated with trace amounts of acetic acid by applying P07 to intermediate 02-036). 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.66 (dd, J = 7.3, 0.6 Hz, 1H), 8.64 (d, J = 0.5 Hz, 1H), 8.18 - 8.12 (m, 2H), 7.89 (d, J = 2.1 Hz, 1H), 7.68 (t, J = 7.4 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.12 (dd, J = 7.3, 2.1 Hz, 1H). LC-MS (ES) m / z = 356 [M+H] + .

[0305] [01-036-Na]Sodium 4-benzoyl-3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 356 [M-Na+H] + .

[0306] [ka] [01-037] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[2,1-a]isoquinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (13 mg, 34%, apply P05 to intermediate 02-037). 1 H NMR (400 MHz, DMSO-d6) δ 14.05 (s, 1H), 8.36 - 8.30 (m, 2H), 7.89 - 7.85 (m, 1H), 7.72 - 7.63 (m, 2H), 7.62 (s, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 2.1 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.91 (dd, J = 8.2, 2.1 Hz, 1H), 6.17 (s, J = 9.7 Hz, 2H). LC-MS (ES) m / z = 388 [M+H] + .

[0307] [ka] [01-038] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (22 mg, 46%, apply P05 to intermediate 02-038). 1 H NMR (400 MHz, DMSO-d6) δ 14.11 (s, 1H), 8.66 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.99 (dd, J = 7.9, 1.2 Hz, 1H), 7.78 - 7.68 (m, 2H), 7.60 - 7.53 (m, 1H), 7.47 (d, J = 9.6 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.85 (dd, J = 8.2, 2.1 Hz, 1H), 6.14 (s, 2H). LC-MS (ES) m / z = 388 [M+H] + .

[0308] [ka] [01-039] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyrazine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (11 mg, 34%, apply P05 to intermediate 02-039). 1H NMR (400 MHz, DMSO-d6) δ 14.16 (s, 1H), 9.06 (d, J = 0.9 Hz, 1H), 8.59 (dd, J = 4.6, 1.6 Hz, 1H), 7.90 (t, J = 5.1 Hz, 1H), 7.85 (d, J = 0.7 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.86 (dd, J = 8.2, 2.1 Hz, 1H), 6.16 (s, 2H). LC-MS (ES) m / z = 339 [M+H] + .

[0309] [ka] [01-040] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-methylquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (28 mg, 37%, P05 applied to intermediate 02-040). 1 H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.74 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.66 - 7.42 (m, 2H), 7.05 (d, J = 2.0 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.75 (dd, J = 8.3, 2.0 Hz, 1H), 6.01 (s, 2H), 2.60 (s, 3H). LC-MS (ES) m / z = 363 [M+H] + .

[0310] [ka] [01-050] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-methylquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (17 mg, 59%, apply P05 to intermediate 02-042). 1 H NMR (400 MHz, DMSO-d6) δ 14.08 (s, 1H), 8.92 (dd, J = 1.9, 0.9 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.41 (dd, J = 9.7, 1.9 Hz, 1H), 7.07 - 7.03 (m, 2H), 6.85 (dd, J = 8.2, 2.1 Hz, 1H), 6.16 (s, 2H). LC-MS (ES) m / z = 417 [M+H] + .

[0311] [01-050-Na] Sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(6-bromoimidazo[1,2-a]pyridine-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (dd, J = 2.0, 0.9 Hz, 1H), 7.50 (d, J = 0.7 Hz, 1H), 7.43 (dt, J = 9.7, 0.8 Hz, 1H), 7.27 (dd, J = 9.6, 2.0 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.53 (dd, J = 8.2, 2.0 Hz, 1H), 6.08 (s, 2H). LC-MS (ES) m / z = 417 [M-Na+H] + .

[0312] [ka] [01-051] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-bromoimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (32 mg, 71%, P05 applied to intermediate 02-043). 1 H NMR (400 MHz, DMSO-d6) δ 14.07 (s, 1H), 8.52 (dd, J = 7.3, 0.9 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 0.8 Hz, 1H), 7.10 (dd, J = 7.2, 2.0 Hz, 1H), 7.06 - 7.00 (m, 2H), 6.84 (dd, J = 8.2, 2.1 Hz, 1H), 6.16 (s, 2H). LC-MS (ES) m / z = 417 [M+H] + .

[0313] [ka] [01-052] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (29 mg, 61%, P05 applied to intermediate 02-044). LC-MS (ES) m / z = 407 [M+H] + .

[0314] [01-052-Na] Sodium 3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(thiophen-2-ylmethyl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, J = 7.2, 0.8 Hz, 1H), 8.24 (s, 1H), 7.83 (dt, J = 2.1, 0.8 Hz, 1H), 7.19 (dd, J = 5.1, 1.3 Hz, 1H), 7.07 (dd, J = 3.5, 1.3 Hz, 1H), 7.03 (dd, J = 7.2, 2.1 Hz, 1H), 6.78 (dd, J = 5.1, 3.4 Hz, 1H), 5.94 (s, 2H). LC-MS (ES) m / z = 407 [M-Na+H] + .

[0315] [ka] [01-053] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(1-methyl-1H-pyrazole-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (43 mg, 78%, P05 applied to intermediate 02-045). 1 H NMR (400 MHz, DMSO-d6) δ 14.17 (s, 1H), 8.61 (dd, J = 7.3, 0.9 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.56 (s, 1H), 7.08 (dd, J = 7.3, 2.2 Hz, 1H), 6.45 (d, J = 2.3 Hz, 1H), 3.93 (s, 3H). LC-MS (ES) m / z = 363 [M+H] + .

[0316] [ka] [01-054] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,2-diphenylethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (66 mg, 86%, P05 applied to intermediate 02-046). 1¹H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 7.2, 0.9 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.88 (s, 1H), 7.11 - 6.99 (m, 11H), 5.22 (d, J = 8.0 Hz, 2H), 4.79 (t, J = 8.0 Hz, 1H). The mobile proton signal is lost, which is likely due to accidental replacement with H₂O in the solvent. LC-MS (ES) m / z = 432 [M+H] + .

[0317] [ka] [01-055] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(3-morpholinopropyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (36 mg, 47%, P05 relative to intermediate 02-047; title compound isolated as HCl salt). 1 H NMR (400 MHz, DMSO-d6) δ 14.07 (s, 1H), 10.59 (s, 1H), 8.68 (dd, J = 7.3, 0.8 Hz, 1H), 8.60 (d, J = 0.8 Hz, 1H), 7.93 (dt, J = 2.2, 0.8 Hz, 1H), 7.16 (dd, J = 7.3, 2.1 Hz, 1H), 4.52 (t, J = 7.2 Hz, 2H), 3.99 - 3.91 (m, 3H), 3.73 (t, J = 12.1 Hz, 2H), 3.28 - 3.18 (m, 3H), 3.14 - 3.01 (m, 3H), 2.26 (p, J = 7.3 Hz, 3H). One methylene signal overlaps with the residual peak of the solvent water. LC-MS (ES) m / z = 380 [M+H] + .

[0318] [ka] [01-056] 3-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid (22 mg, 29%, P05 applied to intermediate 02-048). 1 H NMR (400 MHz, DMSO-d6) δ 14.20 (s, 1H), 13.26 (s, 1H), 8.55 (dd, J = 7.3, 0.8 Hz, 1H), 8.14 - 8.04 (m, 1H), 7.96 - 7.90 (m, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.70 - 7.60 (m, 3H), 7.02 (dd, J = 7.3, 2.1 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 168.6, 166.4, 145.9, 144.1, 134.9, 133.2, 132.0, 131.8, 131.4, 130.3, 129.7, 129.5, 128.4, 115.7, 114.4, 114.1. LC-MS (ES) m / z = 372 [M+H] + .

[0319] [ka] [01-057] 3-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzamide (39 mg, 58%, P06 applied to intermediate 02-048). 1 H NMR (400 MHz, DMSO-d6) δ 14.21 (s, 1H), 8.55 (dd, J = 7.3, 0.9 Hz, 1H), 8.13 - 8.02 (m, 2H), 7.97 - 7.75 (m, 2H), 7.71 - 7.41 (m, 4H), 7.02 (dt, J = 7.3, 1.7 Hz, 1H). LC-MS (ES) m / z = 371 [M+H] + .

[0320] [ka] [01-058] 5-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-2-methoxybenzoic acid (21 mg, 44%, P05 applied to intermediate 02-049). 1 ¹H NMR (400 MHz, DMSO-d6) δ 14.15 (s, 1H), 8.59 (dd, J = 7.3, 0.8 Hz, 1H), 7.77 (d, J = 0.7 Hz, 1H), 7.70 (dd, J = 2.0, 1.0 Hz, 1H), 7.66 (d, J = 2.7 Hz, 1H), 7.54 (dd, J = 8.8, 2.7 Hz, 1H), 7.26 (d, J = 9.0 Hz, 1H), 7.03 (dd, J = 7.3, 2.1 Hz, 1H), 3.90 (s, 3H). The mobile proton signal of the carboxylic acid was lost, which is likely due to accidental replacement with H₂O in the solvent. LC-MS (ES) m / z = 402 [M+H] + .

[0321] [ka] [01-059] 5-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-2-methoxybenzamide (31 mg, 65%, apply P06 to intermediate 02-049). 1H NMR (400 MHz, DMSO-d6) δ 14.13 (s, 1H), 8.56 (dd, J = 7.3, 0.8 Hz, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.74 - 7.62 (m, 4H), 7.51 (dd, J = 8.8, 2.8 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.01 (dd, J = 7.3, 2.1 Hz, 1H), 3.98 (s, 3H). LC-MS (ES) m / z = 401 [M+H] + .

[0322] [ka] [01-060] 4-(4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenoxy) picolinic acid (61 mg, 65%, P05 applied to intermediate 02-050). 1 H NMR (400 MHz, DMSO-d6) δ 14.20 (s, 1H), 8.68 (d, J = 5.7 Hz, 1H), 8.59 (dd, J = 7.3, 0.8 Hz, 1H), 7.87 (d, J = 0.7 Hz, 1H), 7.72 (dd, J = 2.0, 1.0 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.35 (dd, J = 5.7, 2.6 Hz, 1H), 7.05 (dd, J = 7.3, 2.1 Hz, 1H). The mobile proton signal of the carboxylic acid is lost, likely due to accidental replacement with H2O in the solvent. LC-MS (ES) m / z = 465 [M+H] + .

[0323] [ka] [01-061] 4-(4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenoxy)-N-methylpicolinamide (46 mg, 68%, P06 applied to intermediate 02-050). 1 H NMR (400 MHz, DMSO-d6) δ 14.19 (s, 1H), 8.83 (q, J = 4.8 Hz, 1H), 8.63 (dd, J = 7.3, 0.8 Hz, 1H), 8.59 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 0.8 Hz, 1H), 7.87 (dd, J = 2.1, 1.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 2.6 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.32 (dd, J = 5.6, 2.6 Hz, 1H), 7.05 (dd, J = 7.3, 2.1 Hz, 1H), 2.84 (d, J = 4.8 Hz, 3H). LC-MS (ES) m / z = 479 [M+H] + .

[0324] [ka] [01-062] 4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (36 mg, 76%, P05 applied to intermediate 02-051). 1H NMR (400 MHz, DMSO-d6) δ 14.19 (s, 1H), 8.61 (dd, J = 4.8, 1.7 Hz, 1H), 8.57 (d, J = 2.2 Hz, 1H), 7.73 (dt, J = 8.0, 2.0 Hz, 1H), 7.43 (dd, J = 7.9, 4.9 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.84 (dd, J = 8.3, 2.1 Hz, 1H), 6.13 (s, 2H). LC-MS (ES) m / z = 299 [M+H] + .

[0325] [01-062-Na] Sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(pyridine-3-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. 1 H NMR (400 MHz, DMSO-d6) 8.44 (dd, J = 2.3, 0.9 Hz, 1H), 8.41 (dd, J = 4.8, 1.7 Hz, 1H), 7.56 (dt, J = 8.0, 2.0 Hz, 1H), 7.29 (ddd, J = 8.0, 4.7, 0.9 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.51 (dd, J = 8.1, 2.1 Hz, 1H), 6.09 (s, 2H). LC-MS (ES) m / z = 299 [M-Na+H] + .

[0326] [ka] [01-063] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-chloropyridine-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (91 mg, 32%, apply P06 to intermediate 02-052). 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 7.41 (s, 1H), 7.28 (dd, J = 5.1, 1.5 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 8.3, 2.1 Hz, 1H), 6.16 (s, 2H). LC-MS (ES) m / z = 333 [M+H] + .

[0327] [01-063-Na]Sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(2-chloropyridine-4-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 333 [M-Na+H] + .

[0328] [ka] [01-064] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (82 mg, 66%, apply P06 to intermediate 02-053). 1 H NMR (400 MHz, DMSO-d6) δ 14.24 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 7.76 (dd, J = 8.4, 2.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.85 (dd, J = 8.2, 1.9 Hz, 1H), 6.14 (s, 2H). LC-MS (ES) m / z = 333 [M+H] + .

[0329] [01-064-Na] Sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(6-chloropyridin-3-yl)-5-thioxo-4,5-dihydro-1,2,4-triazol-1-ide. 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 8.4, 2.5 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.52 (dd, J = 8.1, 2.1 Hz, 1H), 6.10 (s, 2H). LC-MS (ES) m / z = 333 [M-Na+H] + .

[0330]

Chem.

[0331] [01-065-Na] Sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(6-(4-methylpiperazine-1-yl)pyridine-3-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid.

[0332] [ka] [01-066] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(piperazine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione. Under pressure in an argon-filled tube, a solution of compound 01-064 (30 mg, 1 equivalent) and piperazine (23 mg, 3 equivalents) in ethanol (1.3 mL) was stirred overnight under reflux. The solvent was evaporated, and the title compound (15 mg, 44%) was isolated by reverse-phase column chromatography (H2O:ACN). 1 ¹H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 2.4 Hz, 1H), 7.40 (dd, J = 9.0, 2.5 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.84 - 6.75 (m, 2H), 6.14 (s, 2H), 3.55 - 3.48 (m, 4H), 2.82 (t, J = 5.2 Hz, 4H). The mobile proton signal is lost, likely due to accidental replacement with H₂O in the solvent or overlap with the residual solvent peak. LC-MS (ES) m / z = 383 [M+H] + .

[0333] [01-066-Na]sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(6-(piperazine-1-yl)pyridine-3-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 383 [M-Na+H] + .

[0334] [ka] [01-067] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-morpholinopyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione. Under argon pressure, a solution of compound 01-064 (30 mg, 1 equivalent) and morpholine (0.8 mL, 15 equivalents) in dioxane (9 mL) was stirred under reflux for 48 hours. The solvent was evaporated, and the title compound (16 mg, 46%) was isolated by flash column chromatography (DCM:MeOH) through silica. 1 H NMR (400 MHz, DMSO-d6) δ 13.95 (s, 1H), 8.09 - 8.03 (m, 1H), 7.42 (dd, J = 9.0, 2.5 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.84 - 6.76 (m, 2H), 6.14 (s, 2H), 3.64 (dd, J = 5.8, 4.0 Hz, 4H), 3.48 (dd, J = 5.8, 4.1 Hz, 4H). LC-MS (ES) m / z = 384 [M+H] + .

[0335] [01-067-Na]Sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(6-morpholinopyridine-3-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 384 [M-Na+H] + .

[0336] [ka] [01-068] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-chloropyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion (175 mg, 74%, apply P06 to intermediate 02-054). 1H NMR (400 MHz, DMSO-d6) δ 14.27 (s, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.01 - 6.94 (m, 2H), 6.76 (dd, J = 8.2, 2.1 Hz, 1H), 6.11 (s, 2H). LC-MS (ES) m / z = 333 [M+H] + .

[0337] [01-068-Na]Sodium 4-(benzo[d][1,3]dioxol-5-yl)-3-(6-chloropyridine-2-yl)-5-thioxo-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 333 [M-Na+H] + .

[0338] [ka] [01-069] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(piperazine-1-yl)pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione. Under pressure in an argon-free tube, a solution of compound 01-068 (100 mg, 1 equivalent) and piperazine (130 mg, 5 equivalents) in dioxane (1.2 mL) was stirred under reflux for 48 hours. The solvent was evaporated, and the title compound (15 mg, 44%) was isolated by trituration in DCM and Et2O. 1H NMR (400 MHz, DMSO-d6) 7.60 (dd, J = 8.6, 7.4 Hz, 1H), 7.19 (d, J = 7.3 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 6.70 (dd, J = 8.2, 2.1 Hz, 1H), 6.10 (s, 2H), 2.98 (dd, J = 6.4, 3.7 Hz, 4H), 2.59 (dd, J = 6.2, 3.7 Hz, 4H). The mobile proton signal is lost, likely due to accidental replacement with H2O in the solvent or overlap with the residual solvent peak. LC-MS (ES) m / z = 383 [M+H] + .

[0339] [ka] [01-070] 1-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)propan-1-one. Compound 01-069 (50 mg, 1 equivalent) and propionic acid (12 mg, 1.2 equivalents) were dissolved in DMF:AcOEt:DMSO (10:10:11, 4.2 mL) and DIPEA (91 μL, 4 equivalents) was added under argon. After stirring at room temperature for 20 minutes, HATU (60 mg, 1.2 equivalents) was added. The mixture was stirred overnight at room temperature. The solution was then concentrated under reduced pressure and the title compound (19 mg, 33%) was isolated by reverse-phase flash chromatography (H2O:ACN). 1H NMR (400 MHz, DMSO-d6) δ 14.05 (s, 1H), 7.64 (dd, J = 8.6, 7.4 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 2.1 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 6.73 (dd, J = 8.3, 2.1 Hz, 1H), 6.12 (s, 2H), 3.09 (d, J = 39.0 Hz, 4H), 2.32 (q, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). The two methylene signals of piperazine are lost and overlap with the residual solvent peak. LC-MS (ES) m / z = 439 [M+H] + .

[0340] [ka] [01-071](3aR,4R,6aS)-4-(5-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-5-oxopentyl)tetrahydro-1H-thieno[3,4-d]imidazole-2(3H)-one. Compound 01-069 (35 mg, 1 equivalent) and biotin (26 mg, 1.2 equivalents) were dissolved in DMF:AcOEt:DMSO (10:10:11, 5.4 mL) and DIPEA (64 μL, 4 equivalents) was added under argon. After stirring at room temperature for 20 minutes, HATU (42 mg, 1.2 equivalents) was added. The mixture was stirred overnight at room temperature. Next, the solution was concentrated under reduced pressure, and the title compound (19 mg, 33%) was isolated by reverse-phase flash chromatography (H2O:ACN). 1H NMR (400 MHz, DMSO-d6) 14.03 (s, 1H), 7.68 - 7.60 (m, 1H), 7.23 (d, J = 7.4 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.94 (s, 1H), 6.83 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.43 (s, 1H), 6.36 (s, 1H), 6.12 (s, 2H), 4.31 (dd, J = 7.6, 5.1 Hz, 1H), 4.18 - 4.10 (m, 1H), 3.16 - 3.07 (m, 3H), 3.03 (s, 2H), 2.83 (dd, J = 12.4, 5.1 Hz, 1H), 2.62 - 2.52 (m, 3H), 2.37 - 2.27 (m, 3H), 1.72 - 0.68 (m, 9H). LC-MS (ES) m / z = 609 [M+H] + .

[0341] [ka] [01-072] 1-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-3-(5,5-difluoro-7-(1H-pyrrole-2-yl)-5H-5λ 4 ,6λ 4 -Dipyrrolo[1,2-c:2',1'-f][1,3,2]diazavorinin-3-yl)propan-1-one. A solution of compound 01-069 (4.5 mg, 1 equivalent) in DMF:DMSO (20:1 4.2 mL) was prepared in an amber vial under dark and argon conditions. DIPEA (91 mL, 4 equivalents) was added, and after 20 minutes, commercially available NanoBRET-590-SE (5.0 mg, 1 equivalent) was added. The mixture was stirred at room temperature for 1 hour. The solution was then diluted with 30 mL of water and lyophilized. The powder was washed with cold ether and dried to obtain the title compound (6.0 mg, 73%). LC-MS (ES) m / z = 695 [M+H]+ .

[0342] [ka] BODIPY-NH2 was prepared according to the reported procedure: "Nonperturbative Fluorogenic Labeling of Immunophilins Enables the Wash-free Detection of Immunosuppressants." M. Bertolini, L. Mendive-Tapia, O. Ghashghaei, A. Reese, C. Lochenie, AM Schoepf, M. Sintes, K. Tokarczyk, Z. Nare, AD Scott, SR Knight, AR Aithal, A. Sachdeva, R. Lavilla, M. Vendrell. ACS Central Sci. 2024. https: / / doi.org / 10.1021 / acscentsci.3c01590.

[0343] BODIPY-COOH: Succinic anhydride (15 mg, 1.1 equivalents) was dissolved in DCM (4 mL), and a solution of BODIPY-NH2 (50 mg, 1.000 equivalents) in DCM (4 mL) was added dropwise. The mixture was stirred overnight at room temperature. The solution was washed with brine and saturated NH4Cl solution. The organic phase was dried and evaporated to obtain the title adduct (58 mg, 89.6%). 1 H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 10.20 (s, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 6.17 (s, 2H), 2.65 - 2.57 (m, 2H), 2.58 - 2.49 (m, 3H), 2.44 (s, 6H), 1.40 (s, 6H).

[0344] [01-073]4-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-N-(4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ 4 ,5λ 4 -Dipyrrolo[1,2-c:2',1'-f][1,3,2]diazabolinin-10-yl)phenyl)-4-oxobutanamide. Compound 01-069 (32 mg, 1 equivalent) and BODIPY-COOH (44 mg, 1.2 equivalents) were dissolved in DMF DMSO (10:1, 9.0 mL) and DIPEA (58 μL, 4 equivalents) was added under argon. After stirring at room temperature for 20 minutes, HATU (38 mg, 1.2 equivalents) was added. The mixture was stirred at room temperature for 2 hours. The solution was then concentrated under reduced pressure. Water was added to the crude material and extracted three times with DCM. The combined organic layers were dried and evaporated and purified by flash chromatography through silica (DCM:MeOH) to obtain the title compound (26 mg, 39%). 1 H NMR (400 MHz, DMSO-d6) δ 14.08 (s, 1H), 10.21 (s, 1H), 7.80 (dd, J = 8.8, 2.3 Hz, 2H), 7.65 (dd, J = 8.6, 7.4 Hz, 1H), 7.30 - 7.21 (m, 3H), 7.01 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 2.1 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 6.74 (dd, J = 8.2, 2.1 Hz, 1H), 6.18 (s, 2H), 6.13 (s, 2H), 3.37 (m, 6H), 3.19 (s, 2H), 3.05 (s, 2H), 2.73 - 2.60 (m, 2H), 2.44 (s, 6H), 1.40 (s, 6H). LC-MS (ES) m / z = 805 [M+H] + .

[0345] 2.6. Synthesis of compounds involving modifications at the sulfur atom (for comparative purposes) [ka] [01-041] 4-(3,4-bimethoxybenzyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-one (19 mg, 20%, P05 applied to intermediate 02-041). 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.46 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.08 - 7.99 (m, 2H), 7.85 (t, J = 7.0 Hz, 1H), 7.68 (t, J = 7.0 Hz, 1H), 7.03 (s, 1H), 6.79 (s, 2H), 5.54 (s, 2H), 3.63 (s, 3H), 3.53 (s, 3H). LC-MS (ES) m / z = 363 [M+H] + .

[0346] [01-041-Na] Sodium 4-(3,4-dimethoxybenzyl)-5-oxo-3-(quinoline-2-yl)-4,5-dihydro-1,2,4-triazole-1-oid. LC-MS (ES) m / z = 363 [M-Na+H] + .

[0347] [ka] [01-042] 2-(4-(benzo[d][1,3]dioxol-5-yl)-5-(methylthio)-4H-1,2,4-triazole-3-yl)quinoline. Compound 01-001 (80 mg, 1 equivalent) and K2CO3 (39 mg, 2 equivalents) were suspended in dry DMF (1.3 mL, 0.175 M) in a Pyrex tube. Iodomethane (0.03 mL, 2 equivalents) was added dropwise. The mixture was stirred at room temperature for 2 hours. Once the consumption of the starting materials was confirmed, the mixture was quenched with 10 mL of water. This was then extracted with ethyl acetate (3 × 30 mL), and the combined organic layer was dried over magnesium sulfate, concentrated, and purified over silica (hexane-ethyl acetate (50%)) to obtain the title compound (46 mg, 55%). 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 7.3 Hz, 1H), 7.72 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.61 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 8.2, 2.1 Hz, 1H), 6.16 (s, 2H), 2.67 (s, 3H). LC-MS (ES) m / z = 363 [M+H] + .

[0348] [ka] [01-043] 2-(4-(benzo[d][1,3]dioxol-5-yl)-4H-1,2,4-triazole-3-yl)quinoline. Compound 01-001 (80 mg, 1 equivalent) and CuBr2 (8 mg, 15%) were suspended in DMSO (0.9 mL, 0.25 M) in a small Pyrex tube, and the mixture was stirred at 80°C for 1 hour. Once the consumption of the starting materials was confirmed, the tube was cooled to room temperature, and the mixture was quenched with 20 mL of water. This was then extracted with ethyl acetate (3 × 40 mL), and the combined organic layer was dried over magnesium sulfate, concentrated, and purified over silica (hexane-ethyl acetate (50% → 70%)) to obtain the title compound (36 mg, 49%). 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.50 (d, J = 8.5 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.17 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.94 (dd, J = 8.2, 1.8 Hz, 1H), 6.14 (s, 2H). LC-MS (ES) m / z = 317 [M+H] + .

[0349] 3. Purchased compounds [ka] [01-044] N-(4,6-dimethylpyrimidine-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide.

[0350] [ka] [01-045] N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide.

[0351] [ka] [01-046] N-(4-methoxy-1,2,5-thiadiazole-3-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide.

[0352] [ka] [01-047] 3-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid.

[0353] [ka] [01-048] 4-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-thione.

[0354] [ka] [01-049] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-hydroxyquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione.

[0355] Biochemical and biological tests 1. Generation of recombinant TREX2 protein and recombinant TREX1 protein Human and mouse TREX2 and TREX1 proteins were expressed as fusions with maltose-binding protein (MBP) in the pMAL-c2 plasmid (New England Biolabs). MBP, recombinant MBP-TREX2, and recombinant MBP-TREX1 proteins were induced with isopropyl-1-thio-β-D-galactopyranoside (0.3 mM), produced in Escherichia coli BL21, and affinity-purified using amylose resin according to the manufacturer's procedure (New England Biolabs). The expression and purification of recombinant MBP-TREX2 and recombinant MBP-TREX1, and their characterization of TREX2 and TREX1 exonuclease activity, have been previously reported (Manils et al., 2015, Hemphill & Perrino, 2019).

[0356] 2. Assays for TREX2 exonuclease activity and TREX1 exonuclease activity. Evaluation of the efficacy and selectivity of TREX2 inhibitors. Assays were performed to measure TREX2 exonuclease activity and TREX1 exonuclease activity, and the degradation of double-stranded DNA (dsDNA) by the purified MBP-TREX2 recombinant protein and MBP-TREX1 recombinant protein obtained as disclosed in the previous section was evaluated in the absence and presence of the TREX2 inhibitor.

[0357] In short, the compound was pre-incubated with the recombinant protein at the specified concentration in exonuclease reaction buffer (20 mM Tris-HCl (pH 7.4), 5 mM MgCl2, and 100 μg / ml bovine serum albumin) at room temperature for 15 minutes. The compound was dissolved in dimethyl sulfoxide (DMSO) and included as the vehicle (5% final concentration) for analysis. The reaction was then initiated by adding dsDNA (200 ng of dsDNA GFPpcDNA3 plasmid, 3000 bp long, digested with EcoRI). The reaction was carried out at 37°C for 15 minutes and terminated by adding 3× stop sample loading buffer (9 mM EDTA, 60 mM Tris-HCl (pH 8), 25% glycerol, 0.125% orange G). The reaction products were then subjected to agarose gel electrophoresis using SYBR Safe dye (Thermo Fisher Scientific®) to separate and visualize the DNA bands. The remaining DNA was quantified using Quantity One 1-D Analysis (Bio-Rad) software.

[0358] Recombinant proteins MBP-TREX2 and MBP-TREX1 were titrated, and assays were performed at concentrations (100 nM to 200 nM) of each isoform that exhibited similar degradation kinetics of dsDNA. MBP was used as a negative control. Compounds were tested at concentrations ranging from 1 μM to 100 μM to determine the inhibition of DNA degradation. 50 The range was determined. The most potent selected compound was further tested over a wide concentration range (0.03 μM to 100 μM) to determine IC50. 50 The value was calculated accurately.

[0359] 3. Animal models. Evaluation of the efficacy and specificity of TREX2 inhibitors in vivo. Trex2 knockout mouse (Trex2 - / -) has been previously described (Non-Patent Literature 4), and the specificity of the TREX2 inhibitor was tested in vivo using this mouse. Trex2 in C57BL / 6N background - / - Mice and wild-type (wt) mice were bred and reared at the Animal Facility of the University of Barcelona at the Bellvitge Campus, in accordance with the requirements of the Ethics Committee on Animal Use and Care of the University of Barcelona. All experiments were conducted with the authorization of the Catalan government.

[0360] To determine the in vivo efficacy of representative and most active series of TREX2 inhibitors for the treatment of psoriasis, a well-characterized mouse model of IL-23-induced psoriasis was used, as previously reported (Manils et al., 2015). Briefly, mice were intradermally (id) once daily into the left and right ears of either mouse interleukin-23 (IL-23) (Miltenyi, 0.5 μg in 10 μl of PBS) or PBS (10 μl), respectively. These compounds were administered intraperitoneally (ip), intragastricly (ig), or topically once or twice daily to 12-16 week old male and female mice, one or two days after the initiation of once-daily treatment with IL-23, as shown. The formulation vehicle used for intrapulmonary bypass (IP) was 10% DMSO and 90% (volume / volume) saline; for iliacid (IG) administration, it was 10% DMSO, 0.5% carboxymethylcellulose, and 90% saline; and for topical administration, it was 10% DMSO and 90% acetone. Ear thickness was measured using a digital caliper, and the increase in ear thickness caused by IL-23 was calculated relative to PBS.

[0361] To determine the in vivo efficacy of representative TREX2 inhibitors for the treatment of atopic dermatitis, a well-documented mouse model of MC903-induced atopic dermatitis was used (Moosbrugger-Martinz et al., 2017). Briefly, the left and right ears of mice were topically treated daily with either MC903 (1 nmol per ear, 10 μl dorsal and 10 μl ventral) or ethanol (99%) over an 11-day treatment period, following a sequence of 5 days of treatment, 2 days of interruption, and 4 days of treatment, respectively. TREX2 inhibitor compounds were administered topically once daily to female mice aged 16–20 weeks, 8 days after the initiation of MC903 treatment as shown. The formulation vehicle used for topical administration was 10% DMSO and 90% ethanol (indicated amount per ear, 10 μl dorsal and 10 μl ventral).

[0362] 4. Growth assay: Evaluation of cytotoxicity of TREX2 inhibitors Cytotoxicity studies of TREX2 inhibitors were conducted on various cell lines, including Hep-G2 cell lines (human hepatocellular carcinoma cells), SH-SY5Y cell lines (human neuroblastoma cells), HEK293 cell lines (human fetal kidney cells), and HaCaT cell lines (immortalized human keratinocyte cells). Growth assays were performed using Crystal Violet (Sigma-Aldrich) technology for Hep-G2 and SH-SY5Y cell lines, and alamarBlue® HS Cell Viability Reagent (Thermo Fisher) for HEK293 and HaCaT cell lines. In short, cells were seeded in sterile 96-well plates, and the compound dissolved in DMSO was added to the cells. For crystal violet staining, cells were stained with 0.1% crystal violet solution and incubated at room temperature for 15 minutes with shaking. The absorbance of the cell plates was measured at a wavelength of 595 nm (Tecan M1000 infinite Pro). In alamarBlue-based assays, alamarBlue® HS Cell Viability Reagent was directly added to cells in culture medium and incubated in a cell culture incubator at 37°C for 1 to 4 hours, avoiding direct light. The absorbance of the reagent was measured at 570 nm using 600 nm as the reference wavelength (POLARstar Omega) and normalized to the 600 nm value. In all experiments, a control containing DMSO in the same proportion as the dissolved compound was included. Growth inhibition (%) was expressed using the formula: Inhibition (%) = 100 - ((AO × 100) / AT) The calculation was performed based on the following formula: (wherein AO is the absorbance observed in the well containing the compound under study, and AT is the absorbance observed in the well containing the DMSO control).

[0363] The effect of the TREX2 inhibitor was evaluated at 100 μM and compared with the effect of cisplatin, a DNA synthesis inhibitor included as a positive control for cytotoxicity.

[0364] 5.Statistical analysis Statistical analysis was performed using GraphPad Prism™ 10. For multiple comparison post-hoc tests, unpaired t-tests and two-way ANOVA with Dunnett or Sidac multiple comparison tests were used, as shown. A p-value ≤ 0.05 was considered statistically significant.

[0365] Results and Discussion The inventors have developed a small molecule compound that inhibits TREX2 more effectively and selectively than TREX1.

[0366] Table 1 below shows the IC for TREX2 exonuclease inhibition of the compounds of the present invention. 50 The values ​​are shown. The most active compound has an IC5 concentration close to 1 μM. 50 The value was shown.

[0367] [Table 1]

[0368] Some of the compounds of the present invention were tested by their ability to inhibit TREX1. Table 2 below shows the IC for TREX1 exonuclease of the most potent TREX2 inhibitors. 50 The values ​​are shown. All the compounds tested were found to have lower efficacy (above 100 μM) in inhibiting TREX1 exonuclease activity, indicating that these compounds exhibit higher selectivity in inhibiting TREX2 exonuclease activity than in inhibiting TREX1 exonuclease activity.

[0369] [Table 2]

[0370] From the above data, it can be concluded that the compounds of the present invention effectively and selectively inhibit TREX2. Among them, compounds 01-001 and 01-022 were found to exhibit the highest efficacy in inhibiting TREX2 exonuclease (approximately 1.2 μM and 0.9 μM IC2, respectively). 50(Figure 1). Furthermore, IC for TREX1 50 (Over 100μM) is the IC for TREX2 50 Because the values ​​are approximately 100 times higher, data demonstrate that these compounds are more selective in inhibiting TREX2 exonuclease than the closely related TREX1 exonuclease (Figure 1, Table 1 and Table 2).

[0371] Furthermore, analogues of TREX2 inhibitor compounds were tested to gain an initial understanding of their structure-activity relationships (SARs). This allowed us to determine the structural characteristics and essential scaffolding for TREX2 inhibition. Specifically, the loss of TREX2 inhibitory ability in compounds 01-041, 01-042, and 01-043—compounds in which sulfur is replaced by oxygen, methylated, or removed, respectively—indicates that the central ring is essential and that changes at the sulfur atom are not permissible.

[0372] Furthermore, wild-type (wt) mice and Trex2 knockout (Trex2 - / - An early proof-of-concept assay using an IL-23-induced psoriasis mouse model demonstrated the in vivo efficacy and specificity of IL-23 in reducing inflammation. As shown in Figure 2, when compounds 01-045 were administered intraperitoneally (ip) once daily at relatively low doses (3 mg / kg), IL-23-induced ear thickness in wt mice was reduced in IL-23-treated Trex2 - / - While the levels of mice decreased significantly to a level close to that of mice, the Trex2 - / - Since no effect was observed in mice, this supports the TREX2-dependent action of TREX2 inhibitors.

[0373] Consistently, it exhibits the highest in vitro potency in inhibiting TREX2 exonuclease activity (approximately 1.2 μM and 0.9 μM IC2, respectively). 50 ) and selectivity superior to TREX1 (IC 50TREX2 inhibitors 01-001 and 01-022 (Tables 1 and 2, Figure 1), which showed >100 μM levels, demonstrated efficacy in vivo by reducing IL-23-induced psoriatic inflammation in mice when administered intraperitoneally (ip), intragastricly (ig), or topically (Figures 3 and 4). Notably, dose-response assays (Figure 4) demonstrated that 01-022 was effective in reducing IL-23-induced psoriatic inflammation even when administered at a low dose of 5 mg / kg after 3 days of treatment (Figure 4A) and when administered topically (Figure 4B). In summary, TREX2 inhibitors demonstrated efficacy in reducing IL-23-induced inflammation through systemic, oral, and topical administration.

[0374] Furthermore, the TREX2 inhibitor 01-001 demonstrated in vivo efficacy in mice by reducing inflammation (Figures 5A and 5B) and itching (Figure 5C) in MC903-induced atopic dermatitis when administered topically.

[0375] On the other hand, cytotoxicity was evaluated to assess the suitability of some of the compounds of the present invention, particularly 01-001 and 01-022, as therapeutic agents (Table 3). In particular, the effects of 01-001 and 01-022 on cell proliferation were evaluated in several cell types, including the liver HEP-G2 cell lineage, the neuronal SH-SY5Y cell lineage, the kidney HEK293 cell lineage, and the keratinocyte HaCaT cell lineage. As shown in Table 3 below, the compounds 01-001-Na and 01-022-Na did not show significant cytotoxicity in any of the cell lines tested. Therefore, these data support the absence of cytotoxicity of TREX2 inhibitors and their suitability as therapeutic agents.

[0376] [Table 3]

[0377] In summary, the TREX2 inhibitor of the present invention potently, specifically, and selectively blocks TREX2 exonuclease activity, demonstrating efficacy in reducing IL-23-induced psoriasis inflammation without exhibiting cytotoxicity.

[0378] Further results The inventors have developed further small molecule compounds that inhibit TREX2 more effectively and selectively than TREX1.

[0379] These compounds are reproduced below in this specification: [ka]

[0380] Furthermore, the inventors have developed even more small molecule compounds that inhibit TREX2 more effectively and selectively than TREX1. These compounds are also reproduced below herein: [ka]

[0381] Table 4 below shows the IC for TREX2 exonuclease inhibition of further compounds of the present invention. 50 The values ​​are shown. The most active compound has an IC5 concentration close to 1 μM. 50 The value was shown.

[0382] [Table 4]

[0383] From the above data, it can be concluded that further compounds of the present invention effectively inhibit TREX2.

[0384] Some of the further compounds of the present invention were tested by their ability to inhibit TREX1. Table 5 below shows the IC for TREX1 exonuclease of the most potent TREX2 inhibitors. 50The values ​​are shown. All the compounds tested were found to have lower efficacy (100 μM or higher) in inhibiting TREX1 exonuclease activity, indicating that these compounds exhibit higher selectivity in inhibiting TREX2 exonuclease activity than in inhibiting TREX1 exonuclease activity.

[0385] [Table 5]

[0386] From the above data, it can be concluded that further compounds of the present invention are useful for the present invention because they effectively and selectively inhibit TREX2.

[0387] item For completeness, various aspects of the present invention are shown in the following numbered sections.

[0388] Item 1. Formula (I): Used in the treatment or prevention of pathological conditions associated with increased TREX2 expression: [ka] (In the formula, A1 is equation (II): [ka] It is the basis of this formula, A3 is X7-(X8) n This represents, X1 represents CR1 or N, X2 represents CR2 or N, X3 represents CR3 or N, X4 represents CR4 or N. X5 represents CR5 or N, X6 represents CR6 or N, X7 represents CR7 or N, X8 represents CR8 or N, However, one, two, or three of X1 to X8 are N. n is an integer selected from 0 or 1. R1~R8 are independently substituted with hydrogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, halogen, OR9, COOR 10 , and C(R x )2, NR y It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from the group consisting of heteroatoms cycloalkyl groups, or alternatively, R3 and R4, together with X3 and X4 to which they are attached, form a partially saturated or aromatic ring having 5 or 6 ring members optionally substituted with one or more Z substituents, or alternatively, R4 and R5, together with X4 and X5 to which they are attached, form a partially saturated or aromatic ring having 5 or 6 ring members optionally substituted with one or more Z substituents, or alternatively, R5 and R6, together with X5 and X6 to which they are attached, form a partially saturated or aromatic ring having 5 or 6 ring members optionally substituted with one or more Z substituents, or alternatively, R9 and R 10 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl; C(R x )2, NR y Cycloalkyl groups having 3 to 7 ring members selected from O or S, C(O)R 11 , or NR 12 R 13 Selected from, R 11 (C1~C) is a hydrogen atom substituted with one or more Z substituents. 10) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl; C(R x )2, NR y Cycloalkyl groups having 3 to 7 ring members selected from O, or S, or N, O, S, and CR w Selected from the group consisting of, an aryl having 5 or 6 ring members, R x and R w These are, independently, hydrogen, C(O)R 14 , C(O)OR 15 , NR 16 R 17 , OR 18 , optionally substituted with one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from Alkinnil, R y , R 12 , R 13 , R 16 , and R 17 These are, independently, hydrogen, C(O)R 19 , C(O)OR 20 , optionally substituted with one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from Alkinnil, R 14 and R 19 These are independently hydrogen, NH2, and NHR. 21 , optionally substituted with one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, one or more OH groups, halogen, (C1~C10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10 )Alkinyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) (C3-C7) cycloalkyls substituted with haloalkyls, or N, O, S, and CR t Selected from the group consisting of, an aryl having 5 or 6 ring members, R 15 and R 20 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, one or more OH groups, halogen, (C1~C 10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10 )Alkinyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from (C3-C7) cycloalkyl groups substituted with haloalkyl groups, R 18 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, one or more OH groups, halogen, (C1~C 10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10 )Alkinyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from (C3-C7) cycloalkyl groups substituted with haloalkyl groups, R21 (C1~C) is a hydrogen atom substituted with one or more Z substituents. 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, one or more OH groups, halogen, (C1~C 10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10 )Alkinyl, or -O-(C1~C 10 )Cycloalkyl (C3-C7) substituted with alkyl, or N, O, S, and CR s Selected from the group consisting of aryls having 5 or 6 ring members, where R s Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, R t (C1~C) is substituted with hydrogen, OH, halogen, or one or more Z substituents. 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, -O-(C1~C) substituted with one or more Z substituents 10 )alkyl, one or more OH groups, halogen, (C1~C 10 ) Alkyl, (C2~C 10 ) Alkenil, (C2~C 10 )Alkinyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) (C3-C7) cycloalkyls substituted with haloalkyls, or N, O, S, and CR vSelected from the group consisting of aryls having 5 or 6 ring members, where R v Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, L is -(CH2) p Selected from the group consisting of - and -C(O)-, m is the total number selected from 0 or 1. p is the total number selected from 1 to 10, especially 1 to 5, and especially 1 to 2. A2 is a ring system consisting of one or two rings, where, Each ring is either saturated, partially saturated, or unsaturated, and is composed of N, O, S, C, or NR. p CR z , and C(R z ) Having 5 or 6 ring members selected from the group consisting of 2, When a ring system consists of two rings, these rings are either fused or isolated, and R p (C1~C) is a hydrogen atom substituted with one or more Z substituents. 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, (C3-C7) cycloalkyl substituted with one or more Z substituents, or N, O, S, and CR d Selected from the group consisting of aryls having 5 or 6 ring members, where R d OH, halogen, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, R z is hydrogen, halogen, O(CH2) a R 22 , C(O)R 23 , optionally substituted with one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, SO2NR 24 R 25 ;C(R b )2, NR c A cycloalkyl ring having 3 to 7 ring members selected from O, or S, or N, O, S, and CR e Selected from the group consisting of aryls having 5 or 6 ring members, where R e Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, a is an integer representing 0 or 1. R 22 , R 23 , and R b These are independently substituted with hydrogen, halogen, OH, and optionally one or more Z substituents (C1~C 10 ) Alkyl, NR 37 R 38 , optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, -O-(C1~C) substituted with one or more Z substituents 10 )alkyl;C(R' b )2, NR' cA cycloalkyl ring having 3 to 7 ring members selected from O, or S, or N, O, S, and CR f Selected from the group consisting of aryls having 5 or 6 ring members, where R f Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, R 24 , R 25 , R b , R c , R 37 , R 38 , and R' c These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, (C3-C7) cycloalkyl, optionally substituted with one or more Z substituents; N, O, S, and CR g Selected from the group consisting of aryls having 5 or 6 ring members, where R g Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 ) Selected from Alkinnil, Z is (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenil, (C2~C10 ) Alkynyl, halogen, OR 26 COOR 27 , arbitrarily one or more OH, halogen, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenil, (C2~C 10 ) Alkinyl, COOR 28 NH2, or NHR 29 (C3~C7) cycloalkyl groups substituted with (C3~C7), optionally one or more OH groups, halogens, NH2, NHR 30 , (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenil, (C2~C 10 ) Alkinyl, or COOR 31 A aryl substituted with, and optionally one or more OH, halogen, NH2, NHR 32 , (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, -O-(C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenil, (C2~C 10 ) Alkinyl, or COOR 33 Selected from the group consisting of heteroaryls substituted with, R 26 ~R 28 and R 31 ~R 33 Independently, hydrogen, (C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, and (C2~C 10 ) Selected from Alkinnil, and, R 29 , R 30 , and R32 Independently, hydrogen, (C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, (C2~C 10 ) Alkenyl, or (C2~C 10 A compound of (selected from alkynyl) or a pharmaceutically acceptable salt or solvate thereof.

[0389] Item 2. One or two of X1 to X8 represent N, a compound of formula (I) as described in Item 1, or a pharmaceutically acceptable salt or solvate thereof.

[0390] Item 3.n is 1, and one of X1 to X8 represents N, a compound of formula (I) as described in any of the preceding items, or a pharmaceutically acceptable salt or solvate thereof.

[0391] Item 4.X7 represents N, a compound of formula (I) as described in any of the preceding items, or a pharmaceutically acceptable salt or solvate thereof.

[0392] Item 5.A1 is formula (III): [ka] A compound of formula (I) as described in any of the preceding items, represented by the formula (wherein R3 to R6 are as defined in item 1), or a pharmaceutically acceptable salt or solvate thereof.

[0393] Item 6. R3 to R6 are the same, the compound of formula (I) described in Item 5, or a pharmaceutically acceptable salt or solvate thereof.

[0394] Item 7. R3~R6 are substituted with hydrogen, halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkynyl, or -O-(C1~C) substituted with one or more Z substituents. 10A compound of formula (I) as described in either item 5 or 6, or a pharmaceutically acceptable salt or solvate thereof, selected from alkyl groups, in particular where R3 to R6 are hydrogen atoms.

[0395] Item 8. A compound of formula (I) as described in Item 1, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, and two or three of X1 to X7 represent N.

[0396] Item 9.A1 is formula (IV): [ka] A compound of formula (I) as described in either item 1 or 8, represented by (wherein X5 represents N or CR5, and R3 to R7 are as defined above), or a pharmaceutically acceptable salt or solvate thereof.

[0397] Item 10. R3~R7 are independently substituted with hydrogen, halogen, OH, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from or alternative to alkinyl, R3 and R4 condense to form an aromatic ring system with the carbon atoms to which they are attached, and R5, R6, and R7 are independently substituted with hydrogen, halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from or alternative to alkinyl, X5 is CR5, R5 and R6 are condensed to form an aromatic ring system with the carbon atoms to which they are attached, and R3, R4 and R7 are independently substituted with hydrogen, halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 A compound of formula (I) as described in item 9, selected from alkynyls, or a pharmaceutically acceptable salt or solvate thereof.

[0398] Item 11.A2 is a compound of formula (I) as described in any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, consisting of one ring, in particular a six-membered aromatic ring, where the ring members are as defined in Item 1.

[0399] Item 12.A2 is formula (V), formula (VI), formula (VII), or formula (VIII): [ka] (In the formula, X9 is NR 34 , O, S, or CR z16 This represents, X 10 , NR 35 , O, S, or CR z17 This represents, X 11 , NR 36 , O, S, or CR z18 This represents, R z1 ~R z18 These are independently substituted with hydrogen, halogens, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, O(CH2) a R 22 , C(O)R 23 SO2NR 24 R 25 ;N, O, S, and CR e An aryl having 5 or 6 ring members selected from the group consisting of (where R e Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) Selected from haloalkyls), or NH, O, S, and C(R b ) Selected from cycloalkyls having 5 or 6 ring members selected from 2, R 22 ~R 25 , and R b This is as stipulated in one of the preceding items, and, R 34 , R 35 , and R 36 These are independently substituted with hydrogen, and optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) alkenyl and (C2~C) optionally substituted with one or more Z substituents 10 A compound of formula (I) as described in item 11, or a pharmaceutically acceptable salt or solvate thereof, which is an aryl ring (selected from alkynyl).

[0400] Item 13.R z1 ~R z18 These are independently hydrogen, halogens, (C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, O(CH2) a R 22 , C(O)R 23 ;NH, O, S, and C(R b ) Cycloalkyls having 5 or 6 ring members selected from 2, as well as N, O, S, and CR e Selected from the group consisting of aryls having 5 or 6 ring members, where R e Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) A compound of formula (I) as described in item 12, selected from haloalkyls, or a pharmaceutically acceptable salt or solvate thereof.

[0401] Item 14.R 22 and R 23 (C1~C) is substituted with H and optionally one or more Z substituents. 10 A compound of formula (I) as described in either item 12 or 13, selected from alkyl groups, or a pharmaceutically acceptable salt or solvate thereof.

[0402] Item 15.R 24 and R 25 These are independently hydrogen; NH, O, S, and C(R) b ) Cycloalkyls having 5 or 6 ring members selected from 2, as well as N, O, S, and CR g Selected from the group consisting of aryls having 5 or 6 ring members, where R g Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) A compound of formula (I) as described in item 12, selected from haloalkyls, or a pharmaceutically acceptable salt or solvate thereof.

[0403] Item 16.R 24 and R 25 One of them is H, and the other is H;NH, O, S, and C(R b ) Cycloalkyls having 5 or 6 ring members selected from 2, as well as N, O, S, and CR g Selected from the group consisting of aryls having 5 or 6 ring members, where R g Hydrogen, OH, halogens, (C1~C 10 )alkyl, -O-(C1~C 10 ) alkyl, (C1~C 10 ) Haloalkyl, or -O-(C1~C 10 ) A compound of formula (I) as described in item 15, selected from haloalkyls, or a pharmaceutically acceptable salt or solvate thereof.

[0404] Item 17.A2 is a compound of formula (I) described in any of items 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, represented by formula (VI), where Rz6 to Rz8 are the same, and in particular these are hydrogen.

[0405] Item 18.A2 is expressed by formula (VIII), and X9, X 10 , and X 10 These are the same, and in particular these are CH, or alternatively, X9 and X 11 These are the same, and in particular, these are compounds of formula (I) as described in any of items 1 to 16, or pharmaceutically acceptable salts or solvates thereof.

[0406] Item 19.A2 is expressed by formula (VII), and Rz9~Rz 12 These are independently hydrogen, halogen, SO2NH2, or NH, O, S, and C(R b Selected from cycloalkyl groups having 5 or 6 ring members selected from )2, particularly Rz9~Rz 11 It is hydrogen, and Rz 12 These are hydrogen, halogens, SO2NH2, or NH, O, S, and C(R b A compound of formula (I) as described in any of items 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, selected from a cycloalkyl having five or six ring members selected from 2.

[0407] Item 20.A2 is represented by formula (V), and Rz1 to Rz5 are substituted with hydrogen, or optionally one or more Z substituents (C1 to C 10 ) Alkyl, O(CH2) a R 22 , C6 aryl, halogen, COOH, and C(O)(C1~C 10 ) Selected from alkyl, and R 22 (C1~C) is substituted with one or more Z substituents as arbitrary. 10 A compound of formula (I) as described in any of items 1 to 16, representing an alkyl or C6 aryl, or a pharmaceutically acceptable salt or solvate thereof.

[0408] Item 21. R1~R8 are independently substituted with hydrogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, F, Cl, OR9, COOR 10 , and C(R x )2, NR y It has 3 to 7 ring members selected from , O, or S, wherein at least one or two of these ring members are selected from cycloalkyl heteroatoms, and in particular these are substituted with hydrogen, and optionally one or more Z substituents (C1-C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) A compound of formula (I) as described in any of the preceding items, selected from alkynyl, F, and Cl, or a pharmaceutically acceptable salt or solvate thereof.

[0409] Item 22. R1~R8 are independently substituted with hydrogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, OR9, COOR 10 , and C(R x )2, NR y A compound of formula (I) as described in item 21, or a pharmaceutically acceptable salt or solvate thereof, having 3 to 7 ring members selected from , O, or S, wherein at least one or two of these ring members are selected from cycloalkyls, and at least one or two of these ring members are heteroatoms.

[0410] Item 23.Z is a halogen, a compound of formula (I) as described in any of the preceding items, or a pharmaceutically acceptable salt or solvate thereof.

[0411] Item 24. [01-001] 4-(benzo[d][1,3]dioxol-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-002] 5-(quinoline-2-yl)-4-(4-(trifluoromethyl)phenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-003] 4-(4-chlorophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-004] 5-(quinoline-2-yl)-4-(p-tolyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-005] 4-(3-bromophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-006] 4-benzyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-007] 4-phenyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-008] 1-(4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenyl)ethane-1-one, [01-009] 4-(4-phenoxybenzyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-010] 4-(4-methoxy-2-methylphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-011] 4-(4-methoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-012] 4-([1,1'-biphenyl]-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-013] 4-(4-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-014] 5-(quinoline-2-yl)-4-(thiophene-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-015] 4-(4-phenoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-016] 4-(3-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-017] 4-(2,3-dihydro-1H-inden-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-018] 4-(6-chloropyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-019] 4-(6-(piperazine-1-yl)pyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-020] Phenyl(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone, [01-021] (4-chlorophenyl) (3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone, [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-023] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-024] 4-(benzo[d][1,3]dioxol-5-yl)-5-(5-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-025] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-026] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-(trifluoromethoxy)benzyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-027] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,3-dihydro-1H-inden-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-028] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-phenoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-029] 4-(4-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-030] 4-(3-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-031] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-methoxy-2-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-032] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-033] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-(pyrrolidine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-034] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, [01-035] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, [01-036] (3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)(phenyl)methanone, [01-037] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[2,1-a]isoquinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-038] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, and, [01-039] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyrazine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, N-(4,6-dimethylpyrimidine-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, N-(4-methoxy-1,2,5-thiadiazole-3-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, 3-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, 4-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-thione, 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-hydroxyquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, and all pharmaceutically acceptable salts or solvates thereof, in particular their sodium salts, A compound of formula (I) used as described in any of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of the above.

[0412] Item 25. [01-001] 4-(benzo[d][1,3]dioxol-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-003] 4-(4-chlorophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, and all pharmaceutically acceptable salts or solvates thereof, in particular their sodium salts, A compound of formula (I) used as described in item 24, selected from the group consisting of the following.

[0413] Item 26. The pathological condition is an inflammatory condition of the skin or mucous membrane, and the compound of formula (I) used as described in any of the preceding items 1 to 25, or a pharmaceutically acceptable salt or solvate thereof.

[0414] Item 27. The condition is selected from psoriasis, atopic dermatitis, or ichthyosis, and is a compound of formula (I) used as described in any of the preceding items 1 to 26, or a pharmaceutically acceptable salt or solvate thereof.

[0415] Item 28. Formula (Ibis): [ka] (In the formula, A 1bis Equation (IVbis): [ka] It is the basis of, and in the formula, (i) R3, R5~R7 are independently substituted with hydrogen, halogen, OH, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, OR9, COOR 10 , and C(R x )2, NR y It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from cycloalkyl rings that are heteroatoms, and R'4 is substituted with hydrogen, F, Cl, OH, or one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, OR9, COOR 10, and C(R x )2, NR y It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from cycloalkyl rings that are heteroatoms, or alternatively, (ii) R3 and R'4 condense to form an aromatic ring system with the carbon atoms to which they are attached, and R5, R6, and R7 are independently substituted with hydrogen, a halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from or alternative to alkinyl, (iii) X5 is CR5, where R5 and R6 condense to form an aromatic ring system with the carbon atoms to which they are attached, and R3 and R7 are independently substituted with hydrogen, a halogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from alkynyl groups, and R'4 is substituted with hydrogen, F, Cl, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkenyl, or optionally substituted with one or more Z substituents (C2~C 10 ) Selected from Alkinnil, A2, L, m, R9, R 10 , R x , and R y A compound of (as defined in any of the preceding items) or a pharmaceutically acceptable salt or solvate thereof.

[0416] Item 29. R1~R3, R'4, and R5~R8 are independently substituted with hydrogen, or optionally one or more Z substituents (C1~C 10 ) alkyl, optionally substituted with one or more Z substituents (C2~C 10) Alkenyl, optionally substituted with one or more Z substituents (C2~C 10 ) Alkinyl, OR9, COOR 10 , and C(R x )2, NR y A compound of formula (Ibis) as described in item 28, or a pharmaceutically acceptable salt or solvate thereof, having 3 to 7 ring members selected from , O, or S, wherein at least one or two of these ring members are heteroatoms, selected from the group consisting of cycloalkyl rings.

[0417] Item 30. R1-R3, R'4, and R5-R8 are independently substituted with hydrogen and optionally one or more Z substituents (C1-C 10 A compound of formula (Ibis) as described in item 29, selected from the group consisting of alkyl groups, or a pharmaceutically acceptable salt or solvate thereof.

[0418] Item 31. [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-023] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-024] 4-(benzo[d][1,3]dioxol-5-yl)-5-(5-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-025] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-026] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-(trifluoromethoxy)benzyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-027] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,3-dihydro-1H-inden-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-028] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-phenoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-029] 4-(4-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-030] 4-(3-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-031] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-methoxy-2-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-032] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-033] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-(pyrrolidine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-034] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, [01-035] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, [01-036] (3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)(phenyl)methanone, [01-037] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[2,1-a]isoquinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-038] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, and, [01-039] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyrazine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, and all pharmaceutically acceptable salts or solvates thereof, in particular their sodium salts, A compound of any of the formulas (Ibis) from items 28 to 30, selected from the group consisting of the following.

[0419] Item 32. A pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds specified in the preceding items 28-32 and one or more pharmaceutically acceptable carriers or excipients.

[0420] Item 33. Compounds of formula (Ibis) as defined in any of Items 28-31, or pharmaceutically acceptable salts or solvates thereof, used in therapeutic, diagnostic, or research tools.

[0421] Item 34. A kit comprising a compound of formula (I), formula (Ibis), or a pharmaceutically acceptable salt or solvate thereof, as defined in any of the preceding items, along with means for determining the level of TREX2 protein expression.

[0422] Item 35. An in vitro method for inhibiting the activity of TREX2 in an isolated sample of a subject, comprising the step of contacting the isolated sample with a compound of formula (I), formula (Ibis), or a pharmaceutically acceptable salt or solvate thereof.

[0423] Bibliographic References - Esaki H, Ewald DA, Ungar B, Rozenblit M, Zheng X, Xu H, Estrada YD, Peng X, Mitsui H, Litman T, Suarez-Farinas M, Krueger JG, Guttman-Yassky E. Identification of novel immune and barrier genes in atopic dermatitis by means of laser capture microdissection. J Allergy Clin Immunol. 2015 Jan;135(1):153-63. doi: 10.1016 / j.jaci.2014.10.037. - Gall A, Treuting P, Elkon KB, Loo YM, Gale M Jr, Barber GN, Stetson DB. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity. 2012 Jan 27;36(1):120-31. doi: 10.1016 / j.immuni.2011.11.018. - Hemphill WO, Perrino FW. Measuring TREX1 and TREX2 exonuclease activities. Methods Enzymol. 2019;625:109-133. doi: 10.1016 / bs.mie.2019.05.004. - Ko JH, Son MY, Zhou Q, Molnarova L, Song L, Mlcouskova J, Jekabsons A, Montagna C, Krejci L, Hasty P. TREX2 Exonuclease Causes Spontaneous Mutations and Stress-Induced Replication Fork Defects in Cells Expressing RAD51K133A. Cell Rep. 2020 Dec 22;33(12):108543. doi: 10.1016 / j.celrep.2020.108543. - Krieg P, Dick A, Latzko S, Rosenberger S, Meyer J, Crumrine D, Hielscher T, Elias PM, Rauh M, Schneider H. Conditional Alox12b Knockout: Degradation of the Corneocyte Lipid Envelope in a Mouse Model of Autosomal Recessive Congenital Ichthyoses. J Invest Dermatol. 2020 Jan;140(1):249-253.e6. doi: 10.1016 / j.jid.2019.06.134 - Manils J, Gomez D, Salla-Martret M, Fischer H, Fye JM, Marzo E, Marruecos L, Serrano I, Salgado R, Rodrigo JP, Garcia-Pedrero JM, Serafin AM, Canas X, Benito C, Toll A, Forcales SV, Perrino FW, Eckhart L, Soler C. Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis. Oncotarget. 2015 Sep 8;6(26):22375-96. doi: 10.18632 / oncotarget.4296. - Manils J, Casas E, Vina-Vilaseca A, Lopez-Cano M, Diez-Villanueva A, Gomez D, Marruecos L, Ferran M, Benito C, Perrino FW, Vavouri T, de Anta JM, Ciruela F, Soler C. The Exonuclease Trex2 Shapes Psoriatic Phenotype. J Invest Dermatol. 2016 Dec;136(12):2345-2355. doi: 10.1016 / j.jid.2016.05.122. - Mazur DJ, Perrino FW. Excision of 3' termini by the Trex1 and TREX2 3'-->5' exonucleases. Characterization of the recombinant proteins. J Biol Chem. 2001 May 18;276(20):17022-9. doi: 10.1074 / jbc.M100623200. - Moosbrugger-Martinz V, Schmuth M, Dubrac S. A Mouse Model for Atopic Dermatitis Using Topical Application of Vitamin D3 or of Its Analog MC903. Methods Mol Biol. 2017;1559:91-106. doi: 10.1007 / 978-1-4939-6786-5_8. - Morita M, Stamp G, Robins P, Dulic A, Rosewell I, Hrivnak G, Daly G, Lindahl T, Barnes DE. Gene-targeted mice lacking the Trex1 (DNase III) 3'-->5' DNA exonuclease develop inflammatory myocarditis. Mol Cell Biol. 2004 Aug;24(15):6719-27. doi: 10.1128 / MCB.24.15.6719-6727.2004. - Parra D, Manils J, Castellana B, Vina-Vilaseca A, Moran-Salvador E, Vazquez-Villoldo N, Tarancon G, Borras M, Sancho S, Benito C, Ortega S, Soler C. Increased Susceptibility to Skin Carcinogenesis in TREX2 Knockout Mice. Cancer Res. 2009 Aug 15;69(16):6676-84. doi: 10.1158 / 0008-5472.CAN-09-1208. - Pasparakis M, Haase I, Nestle FO. Mechanisms regulating skin immunity and inflammation. Nat Rev Immunol. 2014 May;14(5):289-301. doi: 10.1038 / nri3646. - Song D, Zhang D, Chen S, Wu J, Hao Q, Zhao L, Ren H, Du N. Identification and validation of prognosis-associated DNA repair gene signatures in colorectal cancer. Sci Rep. 2022 Apr 28;12(1):6946. doi: 10.1038 / s41598-022-10561-w. - Tsoi LC, Rodriguez E, Degenhardt F, Baurecht H, Wehkamp U, Volks N, Szymczak S, Swindell WR, Sarkar MK, Raja K, Shao S, Patrick M, Gao Y, Uppala R, Perez White BE, Getsios S, Harms PW, Maverakis E, Elder JT, Franke A, Gudjonsson JE, Weidinger S. Atopic Dermatitis Is an IL-13-Dominant Disease with Greater Molecular Heterogeneity Compared to Psoriasis. J Invest Dermatol. 2019 Jul;139(7):1480-1489. doi: 10.1016 / j.jid.2018.12.018. - Yin J, Lu R, Xin C, Wang Y, Ling X, Li D, Zhang W, Liu M, Xie W, Kong L, Si W, Wei P, Xiao B, Lee HY, Liu T, Hu J. Cas9 exo-endonuclease eliminates chromosomal translocations during genome editing. Nat Commun. 2022 Mar 8;13(1):1204. doi: 10.1038 / s41467-022-28900-w. Kim M, Mikhaylov D, Rangel SM, Pavel AB, He H, Renert-Yuval Y, Del Duca E, Malik K, Huynh T, Ibler E, Sun M, Zhang N, Estrada Y, Krueger J, Paller AS, Guttman-Yassky E. Transcriptomic Analysis of the Major Orphan Ichthyosis Subtypes Reveals Shared Immune and Barrier Signatures. J Invest Dermatol. 2022 Sep;142(9):2363-2374.e18. doi: 10.1016 / j.jid.2022.03.022.

Claims

1. Formula (I): For the treatment or prevention of psoriasis, atopic dermatitis, or ichthyosis: 【Chemistry 1】 (In the formula, A １ is equation (III) or equation (IV) 【Chemistry 2】 It is expressed as follows, and in this equation, X ５ is N or CR ５ Represents and R ３ ~R ７ This is as stipulated below, or, A １ The formula is: 【Transformation 3】 It is expressed as follows, where K is as defined below: R ３ to R ７ are independently selected from the group consisting of hydrogen, (C １ to C １０ )alkyl optionally substituted with one or more Z substituents, (C ２ to C １０ )alkenyl optionally substituted with one or more Z substituents, (C ２ to C １０ )alkynyl optionally substituted with one or more Z substituents, halogen, OR ９ , COOR １０ , and C(R ｘ ) ２ , NR ｙ , O, or S, and have 3 to 7 ring members, provided that at least one or two of these ring members are heteroatoms, and are selected from the group consisting of cycloalkyl, or alternatively, R ３ and R ４ These are attached to X ３ and X ４ Together with these, they form a partially saturated or aromatic ring having five or six ring members optionally substituted with one or more Z substituents, or alternatively, R ４ and R ５ These are attached to X ４ and X ５ Together with these, they form a partially saturated or aromatic ring having five or six ring members optionally substituted with one or more Z substituents, or alternatively, R ５ and R ６ These are attached to X ５ and X ６ Together with these, they form a partially saturated or aromatic ring having five or six ring members optionally substituted with one or more Z substituents, or alternatively, R ９ and R １０ These are independently hydrogen, and (C) which is substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkinyl, C(R ｘ ) ２ , NR ｙ Cycloalkyl groups having 3 to 7 ring members selected from O or S, C(O)R １１ , or NR １２ R １３ Selected from, R １１ (C) is substituted with hydrogen, or one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkinyl; C(R ｘ ) ２ , NR ｙ Cycloalkyl having 3 to 7 ring members selected from O, or S, or N, O, S, and CR ｗ Selected from the group consisting of, an aryl having five or six ring members, R ｘ and R ｗ These are, independently, hydrogen, C(O)R １４ , C(O)OR １５ , NR １６ R １７ , OR １８ , optionally substituted with one or more Z substituents (C １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, or optionally substituted with one or more Z substituents (C ２ ~C １０ ) Selected from Alkinnil, R ｙ , R １２ , R １３ , R １６ , and R １７ These are, independently, hydrogen, C(O)R １９ , C(O)OR ２０ , optionally substituted with one or more Z substituents (C １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, or optionally substituted with one or more Z substituents (C ２ ~C １０ ) Selected from Alkinnil, R １４ and R １９ are each independently hydrogen, NH ２ , NHR ２１ , optionally substituted with one or more Z substituents, (C １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents, (C ２ ~C １０ ) alkenyl, optionally substituted with one or more Z substituents, (C ２ ~C １０ ) alkynyl, optionally substituted with one or more OH, halogen, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, (C ２ ~C １０ ) alkynyl, -O-(C １ ~C １０ ) alkyl, (C １ ~C １０ ) haloalkyl, or -O-(C １ ~C １０ ) haloalkyl-substituted (C ３ ~C ７ ) cycloalkyl, or aryl having 5 or 6 ring members selected from the group consisting of N, O, S, and CR ｔ and are selected from, R １５ and R ２０ These are independently hydrogen, and (C) which is substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkynyl, one or more OH groups, halogen, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) Alkenil, (C ２ ~C １０ ) Alkinyl, -O-(C １ ~C １０ ) alkyl, (C １ ~C １０ ) Haloalkyl, or -O-(C １ ~C １０ ) Haloalkyl-substituted (C ３ ~C ７ ) Selected from cycloalkyl, R １８ These are independently hydrogen, and (C) which is substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkynyl, one or more OH groups, halogen, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) Alkenil, (C ２ ~C １０ ) Alkinyl, -O-(C １ ~C １０ ) alkyl, (C １ ~C １０ ) Haloalkyl, or -O-(C １ ~C １０ ) Haloalkyl-substituted (C ３ ~C ７ ) Selected from cycloalkyl, R ２１ (C) is substituted with hydrogen, or one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkynyl, one or more OH groups, halogen, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) Alkenil, (C ２ ~C １０ ) Alkinyl, or -O-(C １ ~C １０ ) alkyl-substituted (C ３ ~C ７ ) Cycloalkyl, or N, O, S, and CR ｓ Selected from the group consisting of aryls having 5 or 6 ring members, where R ｓ is hydrogen, OH, halogen, (C １ ~C １０ ) alkyl, -O-(C １ ~C １０ ) alkyl, (C １ ~C １０ ) Haloalkyl, -O-(C １ ~C １０ ) Haloalkyl, (C ２ ~C １０ ) Alkenil, or (C ２ ~C １０ ) Selected from Alkinnil, R ｔ (C) is substituted with hydrogen, OH, halogen, or one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkynyl, optionally substituted with one or more Z substituents -O-(C １ ~C １０ ) Alkyl, one or more OH groups, halogen, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) Alkenil, (C ２ ~C １０ ) Alkinyl, -O-(C １ ~C １０ ) alkyl, (C １ ~C １０ ) Haloalkyl, or -O-(C １ ~C １０ ) Haloalkyl-substituted (C ３ ~C ７ ) Cycloalkyl, or N, O, S, and CR ｖ Selected from the group consisting of aryls having 5 or 6 ring members, where R ｖ is hydrogen, OH, halogen, (C １ ~C １０ ) alkyl, -O-(C １ ~C １０ ) alkyl, (C １ ~C １０ ) Haloalkyl, -O-(C １ ~C １０ ) Haloalkyl, (C ２ ~C １０ ) Alkenil, or (C ２ ~C １０ ) Selected from Alkinnil, K is hydrogen, halogen, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) Alkenil, (C ２ ~C １０ ) Alkinyl, -O-(C １ ~C １０ ) alkyl, (C １ ~C １０ ) Haloalkyl, or -O-(C １ ~C １０ ) Haloalkyl; N, O, S, and CR ｖ One or more aryls having five or six ring members are selected from the group consisting of, where R ｖ is hydrogen, OH, halogen, (C １ ~C １０ ) alkyl, -O-(C １ ~C １０ ) alkyl, (C １ ~C １０ ) Haloalkyl, -O-(C １ ~C １０ ) Haloalkyl, (C ２ ~C １０ ) Alkenil, or (C ２ ~C １０ ) Alkinyl, or C(R ｘ ) ２ , NR ｙ It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are heteroatoms, optionally (C １ ~C １０ ) alkyl or C(O)(C １ ~C ４ ) Selected from cycloalkyls substituted with one or more Z substituents such as alkyl, where R ｘ and R ｙ As per the provisions above, L is -(CH ２ ) ｐ Selected from the group consisting of - and -C(O)-, m is the total number selected from 0 or 1. p is the total number selected from 1 to 10, especially 1 to 5, and especially 1 to 2. A ２ The formula is as follows: 【Chemistry 4】 A ring having any of the following: 【Transformation 5】 A ring selected from one of the following, During the ceremony, X ９ NR ３４ , O, S, or CR ｚ１６ This represents, X １０ NR ３５ , O, S, or CR ｚ１７ This represents, X １１ NR ３６ , O, S, or CR ｚ１８ This represents, R ｚ１ ~R ｚ１８ These are independently substituted with hydrogen, halogen, and (C) optionally substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkinyl, -O-(C １ ~C １０ ) Haloalkyl, (C １ ~C １０ ) Haloalkyl, O(CH ２ ) R ２２ , C(O)R ２３ SO ２ NR ２４ R ２５ OH, NR ２４ R ２５ ; N, O, S, and CR ｅ Selected from the group consisting of , R is selected from aryls containing o-aryls such as phenoxy or benzyloxy having 5 or 6 ring members, where R ｅ is hydrogen, OH, halogen, (C １ ~C １０ ) alkyl, -O-(C １ ~C １０ ) alkyl, (C １ ~C １０ ) Haloalkyl, or -O-(C １ ~C １０ ) Haloalkyl, or NH, O, S, and C(R ｂ ) ２ Selected from cycloalkyls having 5 or 6 ring members, R ２２ ~R ２５ , and R ｂ These are independently hydrogen, halogen, OH, NR ３７ R ３８ , optionally substituted with one or more Z substituents (C １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkynyl, optionally substituted with one or more Z substituents -O-(C １ ~C １０ ) alkyl, C(R' ｂ ) ２ NR' ｃ A cycloalkyl ring having 3 to 7 ring members selected from O or S, or N, O, S, and CR ｆ Selected from the group consisting of aryls having 5 or 6 ring members, where R ｆ is hydrogen, OH, halogen, (C １ ~C １０ ) alkyl, -O-(C １ ~C １０ ) alkyl, (C １ ~C １０ ) Haloalkyl, -O-(C １ ~C １０ ) Haloalkyl, (C ２ ~C １０ ) Alkenil, or (C ２ ~C １０ ) Selected from Alkinnil, R ３７ , R ３８ , R' ｂ , and R' ｃ These are independently hydrogen, and (C) which is substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkynyl, optionally substituted with one or more Z substituents (C ３ ~C ７ ) Cycloalkyl; N, O, S, and CR ｇ Selected from the group consisting of aryls having 5 or 6 ring members, where R ｇ is hydrogen, OH, halogen, (C １ ~C １０ ) alkyl, -O-(C １ ~C １０ ) alkyl, (C １ ~C １０ ) Haloalkyl, -O-(C １ ~C １０ ) Haloalkyl, (C ２ ~C １０ ) Alkenil, or (C ２ ~C １０ ) Selected from Alkinnil, R ３４ , R ３５ , and R ３６ These are independently hydrogen, and (C) which is substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) alkenyl and (C) optionally substituted with one or more Z substituents ２ ~C １０ A compound of (selected from alkynyl) or a pharmaceutically acceptable salt or solvate thereof.

2. A １ is formula (III) or formula (IV) 【Transformation 6】 (In the formula, X ５ is N or CR ５ Represents and R ３ ~R ７ A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof, represented as (as defined in claim 1).

3. A １ is formula (III) or formula (IV) 【Transformation 7】 (In the formula, X ５ CR ５ Represents and R ３ ~R ７ A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, represented as (as defined in claim 1).

4. A １ This is expressed by equation (III), and, R ３ ~R ６ (C) is substituted with hydrogen, halogen, or one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkynyl, or optionally substituted with one or more Z substituents -O-(C １ ~C １０ ) Selected from alkyl groups, especially R ３ ~R ６ The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

5. A １ It is expressed by equation (IV), and, R ３ ~R ７ These are independently substituted with hydrogen, halogen, OH, and optionally one or more Z substituents (C １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, or optionally substituted with one or more Z substituents (C ２ ~C １０ ) Selected from or alternative to alkinyl, R ３ and R ４ These condense to form an aromatic ring system with the carbon atoms to which they are attached, and R ５ , R ６ , and R ７ These are independently substituted with hydrogen, halogen, and (C) optionally substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, or optionally substituted with one or more Z substituents (C ２ ~C １０ ) Selected from or alternative to alkinyl, X ５ CR ５ And R ５ and R ６ These condense to form an aromatic ring system with the carbon atoms to which they are attached, and R ３ , R ４ , and R ７ These are independently substituted with hydrogen, halogen, and (C) optionally substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, or optionally substituted with one or more Z substituents (C ２ ~C １０ A compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, selected from alkynyls.

6. A １ This is as specified in any one of claims 2 to 5, and A ２ is formula (V), formula (VI), formula (VII), or formula (VIII): 【Transformation 8】 (In the formula, X ９ NR ３４ , O, S, or CR ｚ１６ This represents, X １０ NR ３５ , O, S, or CR ｚ１７ This represents, X １１ NR ３６ , O, S, or CR ｚ１８ This represents, R ｚ１ ~R ｚ１８ These are independently substituted with hydrogen, halogen, and (C) optionally substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkinyl, O(CH ２ ) ａ R ２２ , C(O)R ２３ SO ２ NR ２４ R ２５ ; N, O, S, and CR ｅ An aryl having five or six ring members selected from the group consisting of (where R ｅ is hydrogen, OH, halogen, (C １ ~C １０ ) alkyl, -O-(C １ ~C １０ ) alkyl, (C １ ~C １０ ) Haloalkyl, or -O-(C １ ~C １０ ) Selected from haloalkyls), or NH, O, S, and C (R ｂ ) ２ Selected from cycloalkyls having 5 or 6 ring members, R ２２ ~R ２５ , and R ｂ This is as defined in any one of claims 1 to 5, and, R ３４ , R ３５ , and R ３６ These are independently hydrogen, and (C) which is substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) alkenyl and (C) optionally substituted with one or more Z substituents ２ ~C １０ A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, which is an aryl ring (selected from alkynyl).

7. A １ This is as specified in any one of claims 2 to 5, and A ２ is expressed by equation (V), and Rz １ ~Rz ５ (C) is substituted with hydrogen, or optionally one or more Z substituents. １ ~C １０ ) alkyl, O(CH ２ ) ａ R ２２ , C ６ Aryl, halogen, COOH, or C(O)(C １ ~C １０ ) Selected from alkyl, and R ２２ (C) is substituted with one or more Z substituents. １ ~C １０ ) Alkyl, or C ６ Represents, or alternatively represents, A １ This is as specified in any one of claims 2 to 5, and A ２ is expressed by equation (VI), and Rz ６ ~Rz ８ These are the same, and in particular these are hydrogen, or alternatively, A １ This is as specified in any one of claims 2 to 5, and A ２ It is expressed by equation (VII), and Rz ９ ~Rz １２ These are, independently, hydrogen, halogen, and SO ２ NH ２ , or NH, O, S, and C(R ｂ ) ２ Selected from cycloalkyls having 5 or 6 ring members, particularly Rz ９ ~Rz １１ is hydrogen and Rz １２ These are hydrogen, halogens, and SO2. ２ NH ２ , or NH, O, S, and C(R ｂ ) ２ Selected from, or alternatively, from, a cycloalkyl having five or six ring members selected from, A １ This is as specified in any one of claims 2 to 5, and A ２ is expressed by equation (VIII), and X ９ , X １０ , and X １１ These are the same, and in particular these are CH, or alternatively, X ９ and X １１ These are the same, and in particular these are O, the compound of formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or solvate thereof.

8. R ３ ~R ７ These are independently hydrogen, and (C) which is substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkinyl, F, Cl, OR ９ COOR １０ , or C(R ｘ ) ２ , NR ｙ It has 3 to 7 ring members selected from O or S, however at least one or two of these ring members are selected from cycloalkyl heteroatoms, and in particular, R ３ ~R ７ These are independently hydrogen, and (C) which is substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Selected from alkynyl, F, or Cl, in particular, R ３ ~R ７ These are independently hydrogen, and (C) which is substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkinyl, OR ９ COOR １０ , or C(R ｘ ) ２ , NR ｙ A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, having 3 to 7 ring members selected from , O, or S, wherein at least one or two of these ring members are selected from cycloalkyl heteroatoms.

9. [01-001] 4-(benzo[d][1,3]dioxol-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-002] 5-(quinoline-2-yl)-4-(4-(trifluoromethyl)phenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-003] 4-(4-chlorophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-004] 5-(quinoline-2-yl)-4-(p-tolyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-005] 4-(3-bromophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-006] 4-benzyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-007] 4-phenyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-008] 1-(4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenyl)ethane-1-one, [01-009] 4-(4-phenoxybenzyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-010] 4-(4-methoxy-2-methylphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-011] 4-(4-methoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-012] 4-([1,1'-biphenyl]-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-013] 4-(4-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-014] 5-(quinoline-2-yl)-4-(thiophene-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-015] 4-(4-phenoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-016] 4-(3-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-017] 4-(2,3-dihydro-1H-inden-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-018] 4-(6-chloropyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-019] 4-(6-(piperazine-1-yl)pyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-020] Phenyl(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone, [01-021] (4-chlorophenyl) (3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone, [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-023] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-024] 4-(benzo[d][1,3]dioxol-5-yl)-5-(5-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-025] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-026] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-(trifluoromethoxy)benzyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-027] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,3-dihydro-1H-inden-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-028] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-phenoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-029] 4-(4-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-030] 4-(3-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-031] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-methoxy-2-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-032] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-033] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-(pyrrolidine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-034] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, [01-035] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, [01-036] (3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)(phenyl)methanone, [01-037] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[2,1-a]isoquinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-038] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, and [01-039] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyrazine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, N-(4,6-dimethylpyrimidine-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, N-(4-methoxy-1,2,5-thiadiazole-3-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, 3-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, 4-(4-((1H-1,2,4-triazole-1-yl)methyl)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thion, 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-hydroxyquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [1-050] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-methylquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-051] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-bromoimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-052] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-053] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(1-methyl-1H-pyrazole-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-054] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,2-diphenylethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-055] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(3-morpholinopropyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-056] 3-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, [01-057] 3-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzamide, [01-058] 5-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-2-methoxybenzoic acid, [01-059] 5-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-2-methoxybenzamide, [01-060] 4-(4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenoxy)picolinic acid, [01-061] 4-(4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenoxy)-N-methylpicolinamide, [01-062] 4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-063] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-chloropyridine-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-064] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-065] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(4-methylpiperazine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-066] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(piperazine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-067] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-morpholinopyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-068] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-chloropyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-069] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(piperazine-1-yl)pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-070] 1-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)propan-1-one, [01-071] (3aR, 4R, 6aS)-4-(5-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-5-oxopentyl)tetrahydro-1H-thieno[3,4-d]imidazole-2(3H)-one, [01-072] 1-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-3-(5,5-difluoro-7-(1H-pyrrole-2-yl)-5H-5λ ４ , 6λ ４ -Dipyrololo[1,2-c:2',1'-f][1,3,2]diazavorinin-3-yl)propan-1-one, [01-073] 4-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-N-(4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ ４ , 5λ ４ -Dipyrrolo[1,2-c:2',1'-f][1,3,2]diazabolinin-10-yl)phenyl)-4-oxobutanamide, and all pharmaceutically acceptable salts or solvates thereof, in particular their sodium salts, A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of the above.

10. [01-001] 4-(benzo[d][1,3]dioxol-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-058] 5-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-2-methoxybenzoic acid, [01-060] 4-(4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenoxy)picolinic acid, N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, and all pharmaceutically acceptable salts or solvates thereof, in particular their sodium salts, A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of the above.

11. A compound of formula I as defined in any one of claims 1 to 10 for therapeutic use (however, [01-001] 4-(benzo[d][1,3]dioxol-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-008] 1-(4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenyl)ethane-1-one, N-(4,6-dimethylpyrimidine-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, N-(5-ethyl-1,3,4-thiadiazole-2-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, and, N-(4-methoxy-1,2,5-thiadiazole-3-yl)-4-(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, (None of the following are selected from the list.)

12. Formula (Ibis): 【Chemistry 9】 (In the formula, A １ｂｉｓ The formula is (IVbis): 【Chemistry 10】 It is the basis of, and in the formula, (i) R ３ , R ５ ~R ７ These are independently substituted with hydrogen, halogen, OH, and optionally one or more Z substituents (C １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkinyl, OR ９ COOR １０ , and C(R ｘ ) ２ , NR ｙ It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from cycloalkyl rings that are heteroatoms, R' ４ (C) is substituted with hydrogen, F, Cl, OH, or one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkinyl, OR ９ COOR １０ , and C(R ｘ ) ２ , NR ｙ It has 3 to 7 ring members selected from O or S, wherein at least one or two of these ring members are selected from cycloalkyl rings that are heteroatoms, or alternatively, (ii) R ３ and R' ４ These condense to form an aromatic ring system with the carbon atoms to which they are attached, and R ５ , R ６ , and R ７ These are independently substituted with hydrogen, halogen, and (C) optionally substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, or optionally substituted with one or more Z substituents (C ２ ~C １０ ) Selected from or alternative to alkinyl, (iii)X ５ CR ５ And R ５ and R ６ These condense to form an aromatic ring system with the carbon atoms to which they are attached, R ３ and R ７ These are independently substituted with hydrogen, halogen, and (C) optionally substituted with one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, or optionally substituted with one or more Z substituents (C ２ ~C １０ ) Selected from Alkinnil and R' ４ (C) is substituted with hydrogen, F, Cl, and one or more Z substituents. １ ~C １０ ) alkyl, optionally substituted with one or more Z substituents (C ２ ~C １０ ) Alkenyl, or optionally substituted with one or more Z substituents (C ２ ~C １０ ) Selected from Alkinnil, A ２ is represented by formula (V), formula (VI), formula (VII), or formula (VIII) as defined in claim 6 or 7, and A compound of (where L and m are as defined in claim 1) or a pharmaceutically acceptable salt or solvate thereof.

13. [01-002] 5-(quinoline-2-yl)-4-(4-(trifluoromethyl)phenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-004] 5-(quinoline-2-yl)-4-(p-tolyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-005] 4-(3-bromophenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-007] 4-phenyl-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-009] 4-(4-phenoxybenzyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-010] 4-(4-methoxy-2-methylphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-012] 4-([1,1'-biphenyl]-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-013] 4-(4-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-014] 5-(quinoline-2-yl)-4-(thiophene-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-015] 4-(4-phenoxyphenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-016] 4-(3-(benzyloxy)phenyl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-017] 4-(2,3-dihydro-1H-inden-5-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-018] 4-(6-chloropyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-019] 4-(6-(piperazine-1-yl)pyridine-3-yl)-5-(quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-020] Phenyl(3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone, [01-021] (4-chlorophenyl) (3-(quinoline-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)methanone, [01-022] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-023] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-024] 4-(benzo[d][1,3]dioxol-5-yl)-5-(5-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-025] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-methylimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-026] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-(trifluoromethoxy)benzyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-027] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,3-dihydro-1H-inden-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-028] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-phenoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-029] 4-(4-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-030] 4-(3-(benzyloxy)phenyl)-5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-031] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(4-methoxy-2-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-032] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-033] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(6-(pyrrolidine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-034] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, [01-035] 4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzenesulfonamide, [01-036] (3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)(phenyl)methanone, [01-037] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[2,1-a]isoquinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-038] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]quinoline-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-039] 4-(benzo[d][1,3]dioxol-5-yl)-5-(imidazo[1,2-a]pyrazine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-040] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-methylquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-050] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-methylquinoline-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-051] 4-(benzo[d][1,3]dioxol-5-yl)-5-(7-bromoimidazo[1,2-a]pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-052] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-053] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(1-methyl-1H-pyrazole-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-054] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(2,2-diphenylethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-055] 5-(7-chloroimidazo[1,2-a]pyridine-2-yl)-4-(3-morpholinopropyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-056] 3-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzoic acid, [01-057] 3-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)benzamide, [01-058] 5-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-2-methoxybenzoic acid, [01-059] 5-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-2-methoxybenzamide, [01-060] 4-(4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenoxy)picolinic acid, [01-061] 4-(4-(3-(7-chloroimidazo[1,2-a]pyridine-2-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)phenoxy)-N-methylpicolinamide, [01-063] 4-(benzo[d][1,3]dioxol-5-yl)-5-(2-chloropyridine-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-064] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-chloropyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-065] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(4-methylpiperazine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-066] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(piperazine-1-yl)pyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-067] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-morpholinopyridine-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-068] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-chloropyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-069] 4-(benzo[d][1,3]dioxol-5-yl)-5-(6-(piperazine-1-yl)pyridine-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, [01-070] 1-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)propan-1-one, [01-071] (3aR, 4R, 6aS)-4-(5-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-5-oxopentyl)tetrahydro-1H-thieno[3,4-d]imidazole-2(3H)-one, [01-072] 1-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-3-(5,5-difluoro-7-(1H-pyrrole-2-yl)-5H-5λ ４ , 6λ ４ -Dipyrololo[1,2-c:2',1'-f][1,3,2]diazavorinin-3-yl)propan-1-one, [01-073] 4-(4-(6-(4-(benzo[d][1,3]dioxol-5-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)-N-(4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ ４ , 5λ ４ -Dipyrrolo[1,2-c:2',1'-f][1,3,2]diazabolinin-10-yl)phenyl)-4-oxobutanamide, and all pharmaceutically acceptable salts or solvates thereof, in particular their sodium salts, A compound selected from the group consisting of the following, as defined in any one of claims 1 to 10.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound specified in claim 12 or 13 or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or additives.

15. A compound as defined in claim 12 or 13, for use as a diagnostic or research tool.

16. An in vitro method for inhibiting the activity of TREX2 in an isolated sample of a subject, comprising the step of contacting the isolated sample with a compound specified in claim 12 or 13, or a pharmaceutically acceptable salt or solvate thereof.

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