Novel heterocyclic compounds binding to slc15a4

Abstract

The present invention relates to a compound of Formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof. The compounds of Formula (I) are useful as medicaments for the treatment or prevention of autoimmune disorders or inflammatory conditions. The compounds of Formula (I) have been shown to inhibit SLC15 peptide transporter-TASL assembly by binding to SLC15 peptide transporters.

Description

Technical Field

[0001] This invention relates to a compound of formula (I) or its stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts, or solvates. The invention also relates to a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable carrier. The compound of formula (I) can be used as a medicine for treating or preventing autoimmune diseases or inflammatory conditions, wherein, in particular, the autoimmune disease is systemic lupus erythematosus, or the inflammatory condition is selected from inflammatory bowel disease, psoriatic dermatitis, and endosomal TLR-dependent inflammation. Preferably, the autoimmune disease to be treated by the compound of formula (I) is a disease associated with the SLC15 peptide transporter. The compound of formula (I) has been shown to bind to the SLC15 peptide transporter. Background Technology

[0002] Dysregulation of pathogen recognition pathways in the innate immune system is associated with a variety of autoimmune and inflammatory diseases. Pattern recognition receptors' recognition of pathogen-derived nucleic acids is crucial for initiating protective innate immune responses (E. Bartok, G. Hartmann, Immune Sensing Mechanisms that Discriminate Self from Altered Self and Foreign Nucleic Acids). Immunity Volume 53, pp. 54-77 (2020); A. Ablasser, ZJ Chen, cGAS in action: Expanding roles in immunity and inflammation. Science , Vol. 363, (2019); NA Lind, VE Rael, K. Pestal, B. Liu, GM Barton, Regulation of the nucleic acid-sensing Toll-likereceptors., Nat Rev Immunol(Volume 22: pp. 224-235, 2022). Despite the existence of tight regulatory mechanisms, abnormal activation of these pathways caused by mutations in endogenous ligands or key regulatory elements can still lead to excessive responses, which are directly associated with various autoimmune and inflammatory conditions (K. Pelka, T. Shibata, K. Miyake, E. Latz, Nucleic acid-sensing TLRs and autoimmunity: novel insights from structural and cell biology). Immunol Rev Volume 269: pp. 60-75 (2016); YJ Crow, DB Stetson, The type I interferonopathies: 10 years on. Nat Rev Immunol Volume 22: pp. 471-483, 2022). In particular, endolysosomal TLR recognition of nucleic acids is considered to play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE) and related autoimmune diseases and inflammatory conditions (GJ Brown et al., TLR7 gain-of-function genetic variation causes human lupus). Nature Volume 605: pp. 349-356 (2022); S. Fillatreau, B. Manfroi, T. Dorner, Toll-like receptor signaling in B cells during systemic lupuserythematosus. Nat Rev Rheumatol , Volume 17: Pages 98-108 (2021); GC Tsokos, MS Lo, P. Costa Reis, KE Sullivan, New insights into the immunopathogenesis of systemic lupus erythematosus., Nat Rev RheumatolVolume 12: pp. 716-730 (2016)). Human genetics and mouse studies have clearly established that the lysosomal carrier SLC15A4 and transcription factor IRF5 are essential components downstream of TLR-mediated disease development (T. Ban, GR Sato, T. Tamura, Regulation and role of the transcription factor IRF5 in innate immune responses and systemiclupus erythematosus). Int Immunol , Volume 30: Pages 529-536 (2018); J. Bentham et al., Genetic association analyzes implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus., Nat Genet Volume 47, pp. 1457-1464 (2015); AL Blasius et al., Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells (pDC). Proc Natl Acad Sci USA Volume 107, pp. 19973-19978 (2010); T. Kobayashi et al., The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity , Vol. 41, pp. 375-388 (2014); RR Graham et al., Acommon haplotype of interferon regulatory factor 5 (IRF5) regulates splicingand expression and is associated with increased risk of systemic lupuserythematosus., Nat Genet Volume 38, pp. 550-555 (2006); A. Katewa et al., The peptidesymporter SLC15a4 is essential for the development of systemic lupuserythematosus in murine models. PLoS One , Volume 16, e0244439 (2021); H. Almuttaqi, I.A. Udalova, Advances and challenges in targeting IRF5, a key regulator of inflammation., FEBS J Volume 286, pp. 1624-1637 (2019); S. Song et al., Inhibition of IRF5 hyperactivation protects from lupus onset and severity. J Clin Invest Volume 130, pp. 6700-6717 (2020); T. Ban et al., Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease. Nat Commun Volume 12: Page 4379 (2021); Z. Wang et al., An autoimmune pleiotropic SNP modulates IRF5 alternative promoter usage through ZBTB3-mediated chromatin looping. Nat Commun Volume 14: Page 3430 (2023)). The recently discovered protein TASL (encoded by an SLE-associated gene previously known as CXorf21) is an SLC15A4 interactor essential for IRF5 activation (Bentham et al., 2015; LX Heinz et al., TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9). NatureVolume 581: pp. 316-322 (2020); CA Odhams et al., Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus. Nat Commun Volume 10: Page 2164 (2019); Zhang et al., SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL. Nat Commun Volume 42 (Issue 8): 112916 (2023)). TASL protein acts as a signal adaptor protein through the C-terminal pLxIS motif, mediating the recruitment of IRF5. This mechanism is similar to that of key immune adaptor proteins MAVS, STING, and TRIF in recruiting IRF3. (Heinz et al., 2020; S. Liu et al., Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation.) Science (Vol. 347, aaa2630, 2015). Therefore, TASL represents the fourth core element of the pathway, whose components are associated with autoimmune diseases, particularly SLE, providing a strong basis and principle for therapeutic intervention. Previous studies have shown that interfering with the formation of the SLC15A4-TASL complex completely blocks TLR-induced IRF5 activation, suggesting that this pathway can be specifically targeted to treat related diseases.

[0003] Here, we describe the identification of a series of compounds that interfere with signaling from TLRs (particularly TLR7 / 8) to IRF5, thereby disrupting IRF5 activation. More specifically, these compounds interfere with the assembly of the SLC15A4-TASL module, leading to efficient degradation of TASL and complete blockade of IRF5 activation. Therefore, these compounds block the lysosomal TLR-induced response in disease-associated human immune cells.

[0004] Purpose and Overview of the Invention

[0005] The inventors have demonstrated the inhibition of disease-associated pro-inflammatory pathways, particularly SLE, by targeting the lysosomal signaling complex with compounds. The inventors have also found that chemical intervention with compounds of formula (I) leads to efficient degradation of TASL. Not wishing to be bound by theory, the inventors have demonstrated that TASL is regulated through protein homeostasis interactions with SLC15A4. Therefore, previous studies have shown that simply interfering with complex formation leads to efficient degradation of TASL. Thus, the present invention is based at least in part on the finding that utilizing this property may be advantageous for the chemical targeting of TASL.

[0006] Therefore, the present invention provides an SLC15A4 conjugate that disrupts the SLC15A4-TASL complex, thereby interfering with TASL levels and consequently interfering with IRF5 activation.

[0007] The present invention will be summarized in the following embodiments.

[0008] In the first embodiment, the present invention relates to a compound of formula (I). (I) Or its stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts or solvates, wherein: R 1 For one or more R S1 Substituted phenyl; Each R S1 Independently selected from -Hal, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cycloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -NH-CO(C 1-6 Alkyl); or two R S1 Together they form fused heterocyclic alkyl or heteroaryl moieties; A is selected from the following: and ; In each case, the wavy line marks the connection to the rest of the molecule; And among them: R 2 C 2-4 Alkylene or C6 cycloalkylene, each optionally surrounded by one or more R S2 replace; Each R S2 Independently selected from -OH, -F, and -CH3; or two R S2 Together they form = O; Each R3 Independently selected from -H, C 1-5 Alkyl, -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 (alkylene)-heteroaryl, each optionally bound by one or more R S3 Replacement; the condition is two Rs 3 Not both -H; Or these two Rs 3 Together with the nitrogen atoms to which they are attached, they form a heterocyclic alkyl ring, which is optionally bounded by one or more R atoms. S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-NH(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 Alkyl), -O (C1-6 alkyl), -O (C 1-6 Halogenated alkyl), -(C 1-6 alkylene)-O(C 1-6 alkyl), -S(C 1-6 alkyl), -S(C1-6 haloalkyl), -(C 1-6 alkylene)-S(C 1-6 Alkyl), -COH, -CO(C 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -COOH, -COO (C 1-6 Alkyl), -CO-NH2, -CO-NH (C1-6 alkyl), -CO-N (C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO(C 1-6 Alkyl), -S(O)2-(C 1-6 Alkyl), -S(O)2-NH2, -S(O)2-NH(C 1-6Alkyl), -S(O)2-N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -N(C) 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Haloalkyl, -O(C) 1-2 alkyl) and -O(C 1-2 (halogenated alkyl); Or two R atoms bonded to the same carbon atom S3 Formation = O; or if connected by two R 3 On the heterocyclic alkyl ring formed together with the nitrogen atoms they are attached to, there are two R... S3 Together with the two adjacent atoms to which they are attached, they form a fused heteroaryl ring; R 4 Does not exist or is C 1-4 Alkylene; R 5 -H, -Hal, -OH, C 1-6 Alkyl or -O(C) 1-6 alkyl); R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-O(C1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 -(C0-3 alkylene)-heterocyclic alkyl, -(C0-3 alkylene)-aryl or -(C0-3 alkylene)-aryl 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups); X 1 For CH or N; X 2 For CH or N; Y 1 For CR Y1 Or N; Y 2 For CR Y2 Or N; Y 3 For CR Y3 Or N; Y 4 For CR Y4 Or N; Among them, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6alkyl); The condition is if X 1 and X 2 If both are CH, then Y 1 Y 2 Y 3 and Y 4 At least one of them is N; and The condition is if X 2 If N, then X 1 Y 1 Y 2 Y 3 and Y 4 One of them is also N; and The condition is X 1 X 2 Y 1 Y 2 Y 3 and Y 4 No more than two of them are N.

[0009] Combining the above definitions, especially R 3 R S3 and R 6 Definition, Cycloalkyl preferably refers to C 3-7 cycloalkyl, Heterocyclic alkyl groups preferably refer to 3- to 7-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl ring comprises one or more cyclic heteroatoms independently selected from O, S, and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized. The aryl group preferably refers to a phenyl group, and The heteroaryl preferably refers to a (5- or 6-membered heteroaryl) ring, wherein the heteroaryl ring comprises one or more cyclic heteroatoms independently selected from O, S and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized.

[0010] In a preferred embodiment, the present invention relates to a compound of formula (I). (I) Or its stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts or solvates, wherein: R 1 For one or more R S1 Substituted phenyl; Each R S1 Independently selected from -Hal, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cycloalkyl, -O(C)1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -NH-CO(C 1-6 Alkyl); or two R S1 Together they form fused heterocyclic alkyl or heteroaryl moieties; A is selected from the following: and ; In each case, the wavy line marks the connection to the rest of the molecule; And among them: R 2 C 2-4 Alkylene or C6 cycloalkylene, each optionally surrounded by one or more R S2 replace; Each R S2 Independently selected from -OH, -F, and -CH3; or two R S2 Together they form = O; Each R 3 Independently selected from -H, C 1-5 Alkyl, -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 (alkylene)-heteroaryl, each optionally bound by one or more R S3 Replacement; the condition is two Rs 3 Not both -H; Or these two Rs 3 Together with the nitrogen atoms to which they are attached, they form a heterocyclic alkyl ring, which is optionally bounded by one or more R atoms. S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-NH(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 Alkyl), -O (C1-6 alkyl), -O (C 1-6 Halogenated alkyl), -(C1-6 alkylene)-O(C 1-6 alkyl), -S(C 1-6 alkyl), -S(C1-6 haloalkyl), -(C 1-6 alkylene)-S(C 1-6 Alkyl), -COH, -CO(C 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -COOH, -COO (C 1-6 Alkyl), -CO-NH2, -CO-NH (C1-6 alkyl), -CO-N (C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO(C 1-6 Alkyl), -S(O)2-(C 1-6 Alkyl), -S(O)2-NH2, -S(O)2-NH(C 1-6 Alkyl), -S(O)2-N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -N(C) 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Haloalkyl, -O(C) 1-2 alkyl) and -O(C 1-2 (halogenated alkyl); Or two R atoms bonded to the same carbon atom S3 Formation = O; or if connected by two R 3 On the heterocyclic alkyl ring formed together with the nitrogen atoms they are attached to, there are two R... S3 Together with the two adjacent atoms to which they are attached, they form a fused heteroaryl ring; R 4 Does not exist or is C 1-4 Alkylene; R 5 -Hal, -OH, C 1-6 Alkyl or -O(C) 1-6 alkyl); R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-O(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 -(C0-3 alkylene)-heterocyclic alkyl, -(C0-3 alkylene)-aryl or -(C0-3 alkylene)-aryl 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups); X 1 For CH or N; X 2 For CH or N; Y 1 For CRY1 Or N; Y 2 For CR Y2 Or N; Y 3 For CR Y3 Or N; Y 4 For CR Y4 Or N; Among them, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6 alkyl); The condition is if X 1 and X 2 If both are CH, then Y 1 Y 2 Y 3 and Y 4 At least one of them is N; and The condition is if X 2 If N, then X 1 Y 1 Y 2 Y 3 and Y 4 One of them is also N; and The condition is X 1 X 2 Y 1 Y 2 Y 3 and Y 4 No more than two of them are N.

[0011] In a preferred embodiment of the compound of formula (I), R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6 alkyl).

[0012] In a preferred embodiment, the compound of formula (I) is a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), or (If). (Ia) (Ib) (Ic), (Id) (Ie) (If); Preferred formula (Ia) ), (Ib ), (Ic ), (Id ), (Ie ) or (If ) compounds (Ia ), (Ib ), (Ic ), (Id ), (Ie ), (If ).

[0013] In another preferred embodiment, the compound of formula (I) is a compound of formula (Ia), (Ib), (Ic), (Id), or (Ie). (Ia) (Ib) (Ic), (Id) (Ie).

[0014] In a more preferred embodiment, the compound of formula (I) is a compound of formula (Ia), (Ib), (Ic), (Id), or (Ie). (Ia) (Ib) (Ic), (Id) (Ie); Among them, R Y1 R Y2 R Y3 and R Y4Each is independently selected from -H, -CN, -Hal, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6 alkyl).

[0015] In a more preferred embodiment, the compound of formula (I) is a compound of formula (Ia), (Ib) or (Ic). (Ia) (Ib) (Ic).

[0016] In a more preferred embodiment, the compound of formula (I) is of formula (Ia) ), (Ib ) or (Ic ) compounds (Ia ), (Ib ), (Ic ).

[0017] In a particularly preferred embodiment, the compound of formula (I) is of formula (Ia) ) compounds (Ia ).

[0018] In a particularly preferred embodiment, the compound of formula (I) is of formula (Ib) ) compounds (Ib ).

[0019] In a particularly preferred embodiment, the compound of formula (I) is of formula (Ic) ) compounds (Ic ).

[0020] In another preferred embodiment, R 1 For -O(C 1-6 Alkyl-substituted phenyl groups.

[0021] In a more preferred embodiment, R 1 It is 4-ethoxyphenyl.

[0022] In another preferred embodiment, part A is , in R 2 It is a C2-alkylene or C3-alkylene.

[0023] In another preferred embodiment, part A is , in Each R 3 Independently selected from -H, C 1-5 Alkyl, -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 (alkylene)-heteroaryl, each optionally bound by one or more R S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, NH2, -NH(C) 1-6 alkyl), -N(C1-6 alkyl)(C 1-6 Alkyl), C1-6 alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -O(C 1-6 Alkyl), -(C1-6 alkylene)-O-(C 1-6 alkyl), -CO(C) 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -CO-NH2, -CO-NH (C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO(C 1-6 alkyl) and -S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 -(C0-3-alkylene)-aryl and -(C0-3-alkylene)-heteroaryl, wherein in the -(C0-3-alkylene)-heteroaryl 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups); Or two R atoms bonded to the same carbon atom S3 Formation = O.

[0024] In another preferred embodiment, part A is , in These two Rs 3 Together with the nitrogen atoms to which they are attached, they form a heterocyclic alkyl ring, which is optionally bounded by one or more R atoms. S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, NH2, -NH(C) 1-6 alkyl), -N(C1-6 alkyl)(C 1-6 Alkyl), C1-6 alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -O(C 1-6 Alkyl), -(C1-6 alkylene)-O-(C 1-6 alkyl), -CO(C) 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -CO-NH2, -CO-NH (C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO(C 1-6 Alkyl), -S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 -(C0-3-alkylene)-aryl and -(C0-3-alkylene)-heteroaryl, wherein in the -(C0-3-alkylene)-heteroaryl 0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups); Or two R atoms bonded to the same carbon atom S3 Formation = O; or two Rs S3 Together with the two adjacent atoms to which they are attached, they form a fused heteroaryl ring.

[0025] In another preferred embodiment, part A is .

[0026] In a particularly preferred embodiment, the compound is a compound selected from the group consisting of, or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof: , , , , , , , , , , , , , , , , , , , , .

[0027] In another particularly preferred embodiment, the compound is a compound selected from the group consisting of, or stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts, or solvates thereof: , , , , , , , , , .

[0028] In another particularly preferred embodiment, the compound is a compound selected from the group consisting of, or stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts, or solvates thereof: , , , , , , , , , , , , , .

[0029] In a second embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier.

[0030] In a third embodiment, the present invention relates to a compound of formula (I) of the present invention or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, which is used as a drug.

[0031] In a fourth embodiment, the present invention relates to a compound of formula (I) of the present invention or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for the treatment or prevention of autoimmune diseases or inflammatory conditions.

[0032] In a fifth embodiment, the present invention relates to the use of a compound of formula (I) of the present invention or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of autoimmune diseases or inflammatory conditions.

[0033] In a sixth embodiment, the present invention relates to a method for treating an autoimmune disease or inflammatory condition, the method comprising administering to a subject in need a compound of formula (I) of the present invention or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate, or a pharmaceutical composition thereof. It should be understood that a therapeutically effective amount of a compound of formula (I) of the present invention or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate, or a pharmaceutical composition thereof will be administered. Attached Figure Description

[0034] Figure 1 Example of TCG report molecular detection data, showing TASL-EmGFP (top) and mCherry (bottom) signals after compound treatment (Example Ic-8 in this example, which was used at three different concentrations as shown).

[0035] Figure 2 The binding of probe 1 to SLC15A4 was measured, as described in the NanoBRET assay outlined in Biological Example 2 of this paper.

[0036] definition

[0037] Unless otherwise specified, the following definitions apply throughout this specification and the claims.

[0038] The term “hydrogen” is used herein to refer to protium, deuterium, and / or tritium, preferably protium. Therefore, the term “non-hydrogen atom” refers to any atom that is not hydrogen, i.e., any atom that is not protium, deuterium, or tritium.

[0039] The term "hydrocarbon group" refers to a group composed of carbon and hydrogen atoms.

[0040] The term "alicyclic" is used in conjunction with a cyclic group and indicates that the corresponding cyclic group is non-aromatic.

[0041] As used herein, the term "alkyl" refers to a monovalent, saturated, acyclic (i.e., non-cyclic) hydrocarbon group that can be straight-chain or branched. Therefore, an "alkyl" group does not contain any carbon-carbon double or triple bonds. 1-5 "alkyl" refers to an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless otherwise defined, the term "alkyl" preferably refers to C14.1-4 Alkyl, more preferably methyl or ethyl, and even more preferably methyl.

[0042] As used herein, the term "alkenyl" refers to a monovalent unsaturated acyclic hydrocarbon group, which may be straight-chain or branched, and contains one or more (e.g., one or two) carbon-carbon double bonds, but no carbon-carbon triple bonds. The term "C" refers to... 2-5 "Alkenyl" refers to an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are vinyl, propenyl (e.g., propyl-1-en-1-yl, propyl-1-en-2-yl, or propyl-2-en-1-yl), butenyl, butadienyl (e.g., buten-1,3-dien-1-yl or buten-1,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprene). Unless otherwise defined, the term "alkenyl" preferably refers to C 2-4 Alkenyl group.

[0043] As used herein, the term "alkynyl" refers to a monovalent unsaturated acyclic hydrocarbon group that can be straight-chain or branched and contains one or more (e.g., one or two) carbon-carbon triple bonds and optionally one or more (e.g., one or two) carbon-carbon double bonds. The term "C..." 2-5 "Alynyl" refers to an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propynyl), or butynyl. Unless otherwise defined, the term "alkynyl" preferably refers to C... 2-4 Alkyne group.

[0044] As used herein, the term "alkylene" refers to an alkyl dienyllium group, which can be a straight-chain or branched divalent saturated acyclic hydrocarbon group. "C" 1-5 "alkylene" refers to an alkylene group having 1 to 5 carbon atoms, and the term "C" is used to indicate that the alkylene group has 1 to 5 carbon atoms. 0-3 "alkylene" indicates the presence of a covalent bond (corresponding to option "C0 alkylene") or C 1-3 Alkylene. Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)- or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). Unless otherwise defined, the term "alkylene" preferably refers to a C1-4 alkylene (particularly including straight-chain C1-4 alkylenes), more preferably to methylene or ethylene, and even more preferably to methylene.

[0045] As used herein, the term "carbocyclic" refers to a hydrocarbon cyclic group, including monocyclic, bridged, spirocyclic, and / or fused ring systems (which may consist of, for example, two or three rings), wherein the cyclic group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic), or aromatic. Unless otherwise defined, "carbocyclic" preferably refers to an aryl, cycloalkyl, or cycloalkenyl group.

[0046] As used herein, the term "heterocyclic group" refers to a cyclic group, including monocyclic and bridged, spirocyclic and / or fused ring systems (which may consist of, for example, two or three rings), wherein the cyclic group contains one or more (e.g., one, two, three or four) cyclic heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein the cyclic group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring included in the cyclic group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the respective heteroatom-containing ring is 1 to 4, and at least one carbocyclic atom (which may optionally be oxidized) is present in the respective heteroatom-containing ring. Unless otherwise defined, "heterocyclic group" preferably refers to a heteroaryl, heterocyclic alkyl, or heterocyclic alkenyl group.

[0047] As used herein, the term "aryl" refers to an aromatic hydrocarbon cyclic group, including monocyclic aromatic rings and bridged and / or fused ring systems containing at least one aromatic ring (e.g., a ring system consisting of two or three fused rings, wherein at least one of these fused rings is aromatic; or a bridged ring system consisting of two or three rings, wherein at least one of these bridged rings is aromatic). "Aryl" may, for example, refer to phenyl, naphthyl, dihydronaphthyl (i.e., 1,2-dihydronaphthyl), tetrahydronaphthyl (i.e., 1,2,3,4-tetrahydronaphthyl), indenyl, indenyl (e.g., 1H-indenyl), anthracene, phenanthryl, 9H-fluorenyl, or azulel. Unless otherwise defined, "aryl" preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably phenyl or naphthyl, and most preferably phenyl.

[0048] As used herein, the term "heteroaryl" refers to an aromatic ring group, including monocyclic aromatic rings and bridged and / or fused ring systems containing at least one aromatic ring (e.g., a ring system consisting of two or three fused rings, wherein at least one of these fused rings is aromatic; or a bridged ring system consisting of two or three rings, wherein at least one of these bridged rings is aromatic), wherein the aromatic ring group comprises one or more (e.g., one, two, three or four) cyclic heteroatoms, which are preferably independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the aromatic ring group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the respective heteroatom-containing ring is 1 to 4, and at least one carbon ring atom (which may optionally be oxidized) is present in the respective heteroatom-containing ring."Heteroaryl" can refer to, for example, thiophene, benzo[b]thiophene, naphtho[2,3-b]thiophene, thianyl, furanyl, benzofuranyl, isobenzofuranyl, benzodihydropyranyl, benzopyranyl (e.g., 2H-1-benzopyranyl or 4H-1-benzopyranyl), isobenzopyranyl (e.g., 1H-2-benzopyranyl), chromonel, xanthonyl, phenoxathiol, pyrroleyl (e.g., 1H-pyrroleyl), imidazolyl, pyrazolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indoleyl (e.g., 3H-indoleyl), isoindoleyl, indazoleyl, indoleyl... Azinyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphthidyl, quinoxalinyl, cyclolinyl, pteridinyl, carbazoyl, β-carbazoyl, phenanthridineyl, acridineyl, naphthalene-intercalated diazoxide, phenanthrolinyl (e.g., [1,10]phenanthrolinyl, [1,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazoyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (i.e., furazonyl) or 1,3,4-oxadiazolyl), thiadiazoyl (e.g., 1,2,4-thiadiazoyl, 1,2,5-thiadiazoyl or 1,3,4-thiadiazoyl) ), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidin-3-yl), 1,2-benzisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzo[b]thiophene (i.e., benzothiophene), triazolyl (e.g., 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl or 4H-1,2,4-triazolyl), benzotriazolyl, 1H-tetrazole, 2H-tetrazole, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazolyl), benzotriazolyl, 1H-tetrazole, 2H-tetrazole, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl), -triazinyl), furano[2,3-c]pyridyl, dihydrofuranopyridyl (e.g., 2,3-dihydrofurano[2,3-c]pyridyl or 1,3-dihydrofurano[3,4-c]pyridyl), imidazopyridyl (e.g., imidazo[1,2-a]pyridyl or imidazo[3,2-a]pyridyl), quinazolinyl, thienopyridyl, tetrahydrothienopyridyl (e.g., 4,5,6,7-tetrahydrothienopyridyl), dibenzofuranyl, 1,3-benzodioxolanecycloyl, benzodioxane (e.g., 1,3-benzodioxane or 1,4-benzodioxane), or coumarinyl.Unless otherwise defined, the term "heteroaryl" preferably refers to a 5- to 14-membered (more preferably 5- to 10-membered) monocyclic or fused-ring system comprising one or more (e.g., one, two, three, or four) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbide ring atoms are optionally oxidized; even more preferably, "heteroaryl" refers to a 5- or 6-membered monocyclic ring comprising one or more (e.g., one, two, or three) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbide ring atoms are optionally oxidized.

[0049] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon cyclic group, including monocyclic and bridged, spirocyclic, and / or fused ring systems (which may consist of, for example, two or three rings; for example, a fused ring system consisting of, for example, two or three fused rings). "Cycloalkyl" may, for example, refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl, or adamantyl. Unless otherwise defined, "cycloalkyl" preferably refers to C3- 11 Cycloalkyl, more preferably, refers to C3-7 cycloalkyl. Particularly preferred “cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).

[0050] As used herein, the term "cycloalkylene" refers to a cycloalkane dienyllium group, i.e., a divalent saturated cycloalkyl group. "C6 cycloalkylene" refers to a cyclohexane dienyllium group, preferably cyclohexane-1,4-diyl. In other words, "C6 cycloalkylene" preferably refers to a cyclohexane unit attached to the remainder of the molecule at positions 1 and 4 of the cyclohexane ring. Unless otherwise defined, the term "cycloalkylene" preferably refers to C3-6 cycloalkylene groups (particularly including C6 cycloalkylene groups).

[0051] As used herein, the term "heterocyclic alkyl" refers to a saturated cyclic group, including monocyclic and bridged, spirocyclic, and / or fused-ring systems (which may consist of, for example, two or three rings; e.g., fused-ring systems consisting of, for example, two or three fused rings), wherein the cyclic group contains one or more (e.g., one, two, three, or four) cyclic heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the saturated cyclic group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the respective heteroatom-containing ring is 1 to 4, and at least one carbon ring atom (which may optionally be oxidized) is present in the respective heteroatom-containing ring. "Heterocyclic alkyl" can refer to, for example, azirropropylalkyl, azirrobutylalkyl, pyrrolidinyl, imidazoalkyl, pyrazolylalkyl, piperidinyl, piperazinyl, azirroheptylalkyl, diazirroheptylalkyl (e.g., 1,4-diazaheptanyl), oxazolylalkyl, isoxazolylalkyl, thiazoalkyl, isothiazolylalkyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazirroheptylalkyl, and oxazirropropylalkyl. alkyl, oxetane, tetrahydrofuranyl, 1,3-dioxolane, tetrahydropyranyl, 1,4-dioxahexacyclone, oxetane, thioheptanyl, thioheptanyl, thioheptanyl, thioheptanyl, tetrahydrothiophene (i.e., thioheptanyl), 1,3-dithioheptanyl, thioheptanyl, 1,1-dioxothioheptanyl, thioheptanyl, decahydroquinolinyl, decahydroisoquinolinyl or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Unless otherwise defined, “heterocyclic alkyl” preferably refers to a 3- to 11-membered saturated cyclic group that is a monocyclic or fused-ring system (e.g., a fused-ring system consisting of two fused rings), wherein the cyclic group comprises one or more (e.g., one, two, three, or four) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbide ring atoms are optionally oxidized; more preferably, “heterocyclic alkyl” refers to a 5- to 7-membered saturated monocyclic group that comprises one or more (e.g., one, two, or three) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbide ring atoms are optionally oxidized.

[0052] As used herein, the term "halogen" or "Hal" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

[0053] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (preferably one to six, more preferably one to three) halogen atoms, which are independently selected from fluorine, chlorine, bromine, and iodine, and preferably all fluorine atoms. It should be understood that the maximum number of halogen atoms is limited by the number of available linking sites, and therefore depends on the number of carbon atoms contained in the alkyl portion of the haloalkyl group. "Haloalkyl" can refer, for example, to -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A particularly preferred "haloalkyl" group is -CF3.

[0054] Unless otherwise explicitly stated or the context contradicts it, the terms “bond” and “covalent bond” are used synonymously in this document.

[0055] As used herein, the terms “optional,” “optionally,” and “may” indicate that the indicated feature may be present, but may also be absent. Whenever the terms “optional,” “optionally,” or “may” are used, the invention specifically relates to two possibilities: the corresponding feature is present, or alternatively, the corresponding feature is absent. For example, the statement “X is optionally substituted by Y” (or “X may be substituted by Y”) means that X is substituted by Y or not substituted. Similarly, if a component of the composition is indicated as “optional,” the invention specifically relates to two possibilities: the corresponding component is present (included in the composition) or the corresponding component is not present in the composition.

[0056] As used herein, the term "substituted" means that a hydrogen atom bonded to a specified atom is replaced by a specified substituent, provided that the substitution produces a stable or chemically viable compound. Unless otherwise specified, the substituted atom may have one or more substituents, and each substituent is chosen independently.

[0057] When used with respect to a specific atom, the term "substitutable" means that the atom is attached to hydrogen, which can be replaced by a suitable substituent.

[0058] In this specification, various groups are referred to as "optionally substituted". Typically, these groups may have one or more substituents, for example, one, two, three, or four substituents. It should be understood that the maximum number of substituents is limited by the number of available linking sites on the substituted portion. Unless otherwise defined, "optionally substituted" groups mentioned in this specification preferably have no more than two substituents, and may particularly have only one substituent. Furthermore, unless otherwise defined, it is preferable that there are no optional substituents, i.e., the corresponding group is unsubstituted.

[0059] Those skilled in the art will understand that substituents contained in the compounds of the present invention can be linked to the remainder of the respective compound via a number of different positions of the respective specific substituent group. Unless otherwise defined, preferred positions of the various specific substituents are shown in the examples.

[0060] As used herein, unless otherwise expressly stated or the context contradicts, the terms “a,” “an,” and “the” are used interchangeably with “one or more” and “at least one.” Thus, for example, a composition comprising a compound of “a” formula (I) may be understood to mean a composition comprising “one or more” compounds of formula (I).

[0061] It should be understood that regardless of which numerical range is provided / disclosed herein, all values ​​and subranges covered by the corresponding numerical range are intended to be covered within the scope of this invention. Therefore, this invention specifically and individually relates to each value falling within the numerical range disclosed herein, and each subrange covered by the numerical range disclosed herein.

[0062] As used herein, the term "about" preferably refers to ±10% of the indicated value, more preferably ±5% of the indicated value, and particularly to the exact indicated value. If the term "about" is used in conjunction with the endpoints of a range, it preferably refers to the range from -10% of the lower endpoint of its indicated value to +10% of the upper endpoint of its indicated value, more preferably the range from -5% of the lower endpoint to +5% of the upper endpoint, and even more preferably the range defined by the exact values ​​of the lower and upper endpoints.

[0063] As used herein, unless otherwise expressly stated or the context contradicts, the term "comprising" (or "including" or "containing") has the meaning of "particularly containing," that is, "containing, among other optional elements...". In addition, the term also includes the narrower meanings of "consistently composed of" and "composed of". For example, the term "A comprises B and C" means "A particularly contains B and C," where A may contain additional optional elements (e.g., also covers "A contains B, C, and D"), but the term also includes the meanings of "A is substantially composed of B and C" and "A is composed of B and C" (i.e., A does not contain any components other than B and C).

[0064] "Treatment" of a symptom or disease can, for example, result in the cessation of the progression of the symptom or disease (e.g., symptoms do not worsen) or a delay in the progression of the symptom or disease (in cases where the cessation of progression is only temporary). "Treatment" of a symptom or disease can also result in partial remission (e.g., symptom improvement) or complete remission (e.g., symptom disappearance) in a subject / patient suffering from the symptom or disease. Therefore, "treatment" of a symptom or disease can also refer to improvement of the symptom or disease, which can, for example, result in the cessation of the progression of the symptom or disease or a delay in the progression of the symptom or disease. Relapse may occur after such partial or complete remission. It should be understood that a subject / patient may experience a wide range of responses to treatment (such as the exemplary responses described above). Treatment of a symptom or disease may include, in particular, curative treatment (preferably resulting in complete remission and ultimately curing the symptom or disease) and palliative treatment (including symptom relief).

[0065] As used herein, the term "prevention" of a condition or disease is also well known in the art. For example, patients / subjects suspected of being susceptible to a condition or disease may particularly benefit from prevention of that condition or disease. Subjects / patients may have a susceptibility or predisposition to a condition or disease, including but not limited to a genetic predisposition. This predisposition can be determined by standard methods or assays using, for example, genetic markers or phenotypic indicators. It should be understood that the condition or disease to be prevented according to the present invention has not yet been diagnosed or cannot be diagnosed in the patient / subject (e.g., the patient / subject does not exhibit any clinical or pathological symptoms). Therefore, the term "prevention" includes the use of the compounds of the present invention prior to the diagnosis or determination of any clinical and / or pathological symptoms by or by an attending physician (or practicing veterinarian). Detailed Implementation

[0066] The present invention will be described in detail below.

[0067] As described above, in one embodiment, the present invention relates to compounds of formula (I). (I) Or its stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts, or solvates, wherein the substituents are as defined above. Preferred embodiments of the substituents will be described in detail below. It should be understood that each preferred embodiment is relevant on its own and in combination with other preferred embodiments. Furthermore, it should be understood that in each case, the preferred embodiments also apply to the stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts, and solvates of the compounds of the present invention.

[0068] In one embodiment of the compound of formula (I), X 1 For CH or N; X 2 For CH or N; Y 1 For CR Y1 Or N; Y 2 For CR Y2 Or N; Y 3 For CR Y3 Or N; Y 4 For CR Y4 Or N; Among them, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6 alkyl); The condition is if X 1 and X 2 If both are CH, then Y 1 Y 2 Y 3 and Y 4 At least one of them is N; and The condition is if X 2 If N, then X 1 Y 1 Y 2 Y 3 and Y 4 One of them is also N; and The condition is X 1 X 2 Y 1 Y2 Y 3 and Y 4 No more than two of them are N.

[0069] In a preferred embodiment, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, and -C. 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl groups).

[0070] In a more preferred embodiment, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -Hal, C1 alkyl, C1 haloalkyl, -O (C1 alkyl) and -O (C1 haloalkyl).

[0071] In one or even a more preferred embodiment, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -Hal, C1 alkyl, and C1 haloalkyl.

[0072] In a particularly preferred embodiment, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -Cl, -F, and -CH3.

[0073] In another implementation scheme, X 1 For CH or N; X 2 For CH or N; Y 1 For CR Y1 ; Y 2 For CR Y2 Or N; Y 3 For CR Y3 Or N; Y 4 For CR Y4 Or N; Among them, R Y1 R Y2 R Y3 and RY4 Each is independently selected from -H, -CN, -Hal, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6 alkyl); The condition is if X 1 and X 2 If both are CH, then Y 1 Y 2 Y 3 and Y 4 At least one of them is N; and The condition is if X 2 If N, then X 1 Y 1 Y 2 Y 3 and Y 4 One of them is also N; and The condition is X 1 X 2 Y 1 Y 2 Y 3 and Y 4 No more than two of them are N.

[0074] In a preferred embodiment, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6 alkyl).

[0075] In a preferred embodiment, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, and -C. 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl groups).

[0076] In a more preferred embodiment, RY1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -Hal, C1 alkyl, C1 haloalkyl, -O (C1 alkyl) and -O (C1 haloalkyl).

[0077] In one or even a more preferred embodiment, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -Hal, C1 alkyl, and C1 haloalkyl.

[0078] In a particularly preferred embodiment, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -Cl, -F, and -CH3.

[0079] In one embodiment, the compound of formula (I) is a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), or (If). (Ia) (Ib) (Ic), (Id) (Ie) (If).

[0080] In a preferred embodiment, the compound of formula (I) is a compound of formula (Ia), (Ib), (Ic), (Id), or (Ie).

[0081] Similarly, for compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If), R Y1 R Y2 R Y3 and R Y4 If present, each is independently selected from -H, -CN, -Hal, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 (alkylene)-O (C1-6 alkyl). Preferably, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, -OH, and C.1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6 alkyl).

[0082] In a preferred embodiment, R Y1 R Y2 R Y3 and R Y4 If they exist, they are each independently selected from -H, -CN, -Hal, and -C. 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl groups).

[0083] In a more preferred embodiment, R Y1 R Y2 R Y3 and R Y4 If present, each is independently selected from -H, -Hal, C1 alkyl, C1 haloalkyl, -O(C1 alkyl) and -O(C1 haloalkyl).

[0084] In one or even a more preferred embodiment, R Y1 R Y2 R Y3 and R Y4 If present, each is independently selected from -H, -Hal, C1 alkyl, and C1 haloalkyl.

[0085] In a particularly preferred embodiment, R Y1 R Y2 R Y3 and R Y4 If present, it is independently selected from -H, -Cl, -F, and -CH3.

[0086] In one embodiment, the compound of formula (I) is a compound of formula (Ia), (Ib) or (Ic).

[0087] Particularly preferred, R Y1 and R Y4 If it exists, it is -H.

[0088] Therefore, in one embodiment, the compound of formula (I) is of formula (Ia) ), (Ib ), (Ic ), (Id ), (Ie ) or (If ) compounds (Ia ), (Ib ), (Ic ), (Id ), (Ie ), (If ).

[0089] In a preferred embodiment, the compound of formula (I) is of formula (Ia) ), (Ib ) or (Ic ) compounds (Ia ), (Ib ), (Ic ).

[0090] In a preferred embodiment, the compound of formula (I) is of formula (Ia) ) compounds (Ia ).

[0091] In another preferred embodiment, the compound of formula (I) is of formula (Ib) ) compounds (Ib ).

[0092] In another preferred embodiment, the compound of formula (I) is of formula (Ic) ) compounds (Ic ).

[0093] Regarding formula (Ia) ), (Ib ), (Ic ), (Id ), (Ie ) and (If Compounds of R Y2 and R Y3 If present, each is independently selected from -H, -CN, -Hal, -OH, -NH2, C1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 (alkylene)-O (C1-6 alkyl). Preferably, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6 alkyl).

[0094] In a preferred embodiment, R Y2 and R Y3 If they exist, they are each independently selected from -H, -CN, -Hal, and -C. 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl groups).

[0095] In a more preferred embodiment, R Y2 and R Y3 If present, each is independently selected from -H, -Hal, C1 alkyl, C1 haloalkyl, -O(C1 alkyl) and -O(C1 haloalkyl).

[0096] In one or even a more preferred embodiment, R Y2 and R Y3 If present, each is independently selected from -H, -Hal, C1 alkyl, and C1 haloalkyl.

[0097] In a particularly preferred embodiment, R Y2 and R Y3 If present, it is independently selected from -H, -Cl, -F, and -CH3.

[0098] In some particularly preferred embodiments, R Y2 and R Y3 If it exists, it is -H.

[0099] In some other particularly preferred embodiments, R Y2 If it exists, it is -H, and R Y3 If present, it is -Cl, -F, or -CH3.

[0100] Where R Y2 and R Y3 The formula for -H (Ia) Compounds of formula (Ia) will be called compounds of formula (Ia) Compounds of HH).

[0101] Where R Y2 -H and R Y3 The formula for -Cl (Ia) Compounds of formula (Ia) will be called compounds of formula (Ia) Compounds of HCl.

[0102] Where R Y2 -H and R Y3 The expression for -F (Ia) Compounds of formula (Ia) will be called compounds of formula (Ia) Compounds of HF.

[0103] Where R Y2 -H and R Y3 The formula for -CH3 (Ia) Compounds of formula (Ia) will be called compounds of formula (Ia) Compounds containing HCH3).

[0104] Where R Y2 and R Y3 The formula for -H (Ib) Compounds of formula (Ib) will be called compounds of formula (Ib) Compounds of HH).

[0105] Where R Y2 -H and R Y3 The formula for -Cl (Ib) Compounds of formula (Ib) will be called compounds of formula (Ib) Compounds of HCl.

[0106] Where R Y2 -H and R Y3 The expression for -F (Ib) Compounds of formula (Ib) will be called compounds of formula (Ib) Compounds of HF.

[0107] Where R Y2 -H and R Y3 The formula for -CH3 (Ib) Compounds of formula (Ib) will be called compounds of formula (Ib) Compounds containing HCH3).

[0108] Where R Y3 The formula for -H (Ic) Compounds of formula (Ic) will be called compounds of formula (Ic) Compounds of H).

[0109] Where R Y3 The formula for -Cl (Ic) Compounds of formula (Ic) will be called compounds of formula (Ic) Compounds of Cl).

[0110] Where R Y3 The expression for -F (Ic) Compounds of formula (Ic) will be called compounds of formula (Ic) Compounds of F).

[0111] Where R Y3 The formula for -CH3 (Ic) Compounds of formula (Ic) will be called compounds of formula (Ic) Compounds containing CH3).

[0112] Regarding compounds of formula (I), and regarding compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie) or (If), and regarding formula (Ia) ), (Ib ), (Ic ), (Id ), (Ie ) or (If Compounds of formula (Ia) ), (Ib ) or (Ic Compounds of formula (Ia) HH), (Ia) HCl), (Ia HF), (Ia) HCH3), (Ib HH), (Ib HCl), (Ib) HF), (Ib HCH3), (Ic H), (Ic Cl), (Ic F), (Ic Compounds containing CH3), regarding the substituent R 1 The following preferred embodiments of A are applicable.

[0113] In one implementation, R 1 For one or more R S1 Substituted phenyl; Each R S1 Independently selected from -Hal, C 1-6 Alkyl, C1-6 Halogenated alkyl, cycloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -NH-CO(C 1-6 Alkyl); or two R S1 Together they form fused heterocyclic alkyl or heteroaryl moieties.

[0114] In a preferred embodiment, R 1 For being an R S1 Substituted phenyl, wherein R S1 Selected from -Hal, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl groups).

[0115] In a more preferred embodiment, R 1 For -O(C 1-6 Alkyl-substituted phenyl groups.

[0116] In one or even a more preferred embodiment, R 1 It is a phenyl group that has been substituted with an ethoxy group.

[0117] In a more preferred embodiment, R 1 It is 4-ethoxyphenyl.

[0118] In one implementation, Part A is , The wavy line marks the connection to the rest of the molecule; And among them: R 2 C 2-4 Alkylene or C6 cycloalkylene, each optionally surrounded by one or more R S2 replace; Each R S2 Independently selected from -OH, -F, and -CH3; or two R S2 Together they form = O; Each R 3 Independently selected from -H, C 1-5 Alkyl, -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 (alkylene)-heteroaryl, each optionally bound by one or more R S3 Replacement; the condition is two Rs 3 Not both -H; Or these two Rs 3 Together with the nitrogen atoms to which they are attached, they form a heterocyclic alkyl ring, which is optionally bounded by one or more R atoms. S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-NH(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 Alkyl), -O (C1-6 alkyl), -O (C 1-6 Halogenated alkyl), -(C 1-6 alkylene)-O(C 1-6 alkyl), -S(C 1-6 alkyl), -S(C1-6 haloalkyl), -(C 1-6 alkylene)-S(C 1-6 Alkyl), -COH, -CO(C 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -COOH, -COO (C 1-6 Alkyl), -CO-NH2, -CO-NH (C1-6 alkyl), -CO-N (C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO(C 1-6 Alkyl), -S(O)2-(C 1-6 Alkyl), -S(O)2-NH2, -S(O)2-NH(C 1-6 Alkyl), -S(O)2-N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -N(C) 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Haloalkyl, -O(C) 1-2 alkyl) and -O(C 1-2 (halogenated alkyl); Or two R atoms bonded to the same carbon atom S3 Formation = O; or if connected by two R 3 On the heterocyclic alkyl ring formed together with the nitrogen atoms they are attached to, there are two R... S3 Together with the two adjacent atoms to which they are attached, they form a fused heteroaryl ring.

[0119] Combining the above definitions, especially R 3 and R S3 Definition, Cycloalkyl preferably refers to C 3-7 cycloalkyl, Heterocyclic alkyl groups preferably refer to 3- to 7-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl ring comprises one or more cyclic heteroatoms independently selected from O, S, and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized. The aryl group preferably refers to a phenyl group, and The heteroaryl preferably refers to a (5- or 6-membered heteroaryl) ring, wherein the heteroaryl ring comprises one or more cyclic heteroatoms independently selected from O, S and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized.

[0120] Therefore, -(C 0-3 (alkylene)-cycloalkyl is preferably -(C 0-3 alkylene)-(C 3-7 cycloalkyl), -(C0-3 (alkylene)-heterocyclic alkyl is preferably -(C 0-3 alkylene)-(3 to 7-membered heterocyclic alkyl),-(C 0-3 (alkylene)-aryl is preferably -(C 0-3 alkylene)-phenyl, and -(C 0-3 (alkylene)-heteroaryl is preferably -(C 0-3 (alkylene)-(5 or 6-membered heteroaryl), wherein the heterocyclic alkyl and heteroaryl rings independently comprise one or more cyclic heteroatoms independently selected from O, S and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized.

[0121] Regarding the substituent R 3 and R S3 Preferably, the selection of these substituents does not result in the direct attachment of heteroatoms (e.g., oxygen or nitrogen atoms) or halogen atoms to carbon atoms that are directly attached to nitrogen atoms contained in part A.

[0122] Therefore, in a preferred embodiment, if R S3 -Hal, -OH, -NH2, -NH(C) 1-6 Alkyl), N(C) 1-6 Alkyl)(C 1-6 Alkyl groups or groups in which -CH2- is replaced by O are preferred. S3 The halogen, nitrogen, or oxygen atom of the substituent is not directly bonded to the carbon atom, which is directly bonded to the nitrogen atom contained in part A.

[0123] In another preferred embodiment, if two R atoms are bonded to the same carbon atom S3 If the =O is formed, it is preferable that the =O is not connected to a carbon atom, and that the carbon atom is directly connected to the nitrogen atom contained in part A.

[0124] Regarding Part A, regarding R 2 and R 3 The following preferred implementation schemes are applicable.

[0125] In a preferred embodiment R 2 It is a C2-alkylene or C3-alkylene.

[0126] In a particularly preferred embodiment R 2 It is a C2 alkylene group.

[0127] In another particularly preferred embodiment, R 2 It is a C3 alkylene group.

[0128] In a preferred embodiment Each R 3 Independently selected from -H, C 1-5 Alkyl, -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 (alkylene)-heteroaryl, each optionally bound by one or more R S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C1-6 alkyl)(C 1-6 Alkyl), C1-6 alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -O(C 1-6 Alkyl), -(C1-6 alkylene)-O-(C 1-6 alkyl), -CO(C) 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -CO-NH2, -CO-NH (C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO(C 1-6 Alkyl), -S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups); Or two R atoms bonded to the same carbon atom S3 Formation = O.

[0129] In a more preferred embodiment, Each R 3 Independently selected from -H, C 1-5 Alkyl, -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 (alkylene)-heteroaryl, each optionally bound by one or more R S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, C1-6 alkyl, C 1-6 Halogenated alkyl groups and -O(C) 1-6 alkyl).

[0130] In one or even a more preferred embodiment, Each R 3 Independently selected from -H, C 1-5 Alkyl, -(C 0-3 alkylene)-(C 3-7 cycloalkyl), -(C 0-3 alkylene)-(3 to 7-membered heterocyclic alkyl), -(C 0-3 alkylene)-phenyl and -(C 0-3 (alkylene)-(5 or 6-membered heteroaryl), each optionally bound by one or more R S3 Substitution, wherein the heterocyclic alkyl and heteroaryl rings independently comprise one or more cyclic heteroatoms independently selected from O, S and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, C1-6 alkyl, C 1-6 Halogenated alkyl groups and -O(C) 1-6 alkyl).

[0131] With the two Rs mentioned above 3 The particularly preferred A portion related to the definition is selected from the following groups: , , , , , , , and ; The wavy line marks the connection to the rest of the molecule; m is 0, 1, or 2; n is 0, 1, or 2; And among them, the aforementioned R 2 and R S3 The definition applies.

[0132] Specifically, regarding part A above, the preferred option is...

[0133] R 2 It is a C2-alkylene or C3-alkylene; and

[0134] Each R S3 Independently selected from -CN, -Hal, -OH, NH2, C1-6 alkyl, C 1-6 Halogenated alkyl groups and -O(C) 1-6 alkyl).

[0135] With the two Rs mentioned above 3 The particularly preferred A portion, as defined in the definition, is selected from the following groups: (A-1) (A-2) (A-3) and (A-4); The wavy line marks the connection to the rest of the molecule; And among them, the aforementioned R 2 The definition applies.

[0136] Specifically, regarding part A above, the preferred option is...

[0137] R 2 It is a C2-alkylene or C3-alkylene.

[0138] If R 2 If it is a C2 alkylene group, then the above A portion is referred to as A-1-C2, A-2-C2, A-3-C2, and A-4-C2.

[0139] If R 2 If it is a C3 alkylene group, then the above A part is referred to as A-1-C3, A-2-C3, A-3-C3 and A-4-C3.

[0140] In another preferred embodiment, These two Rs 3 Together with the nitrogen atoms to which they are attached, they form a heterocyclic alkyl ring, which is optionally bounded by one or more R atoms. S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C1-6 alkyl)(C 1-6 Alkyl), C1-6 alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -O(C 1-6 Alkyl), -(C1-6 alkylene)-O-(C 1-6 alkyl), -CO(C) 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -CO-NH2, -CO-NH (C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO(C 1-6 Alkyl), -S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups); Or two R atoms bonded to the same carbon atom S3 Formation = O; or two Rs S3Together with the two adjacent atoms to which they are attached, they form a fused heteroaryl ring.

[0141] In a more preferred embodiment, These two Rs 3 Together with the nitrogen atoms to which they are attached, they form a heterocyclic alkyl ring, which is optionally bounded by one or more R atoms. S3 replace; These two Rs 3 Together with the nitrogen atoms to which they are attached, they form a heterocyclic alkyl ring, which is optionally bounded by one or more R atoms. S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, C1-6 alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups).

[0142] In a more preferred embodiment, These two Rs 3 Together with the nitrogen atoms to which they are attached, they form 3 to 7-membered heterocyclic alkyl rings, which are optionally connected by one or more R atoms. S3 Substitution, wherein the heterocyclic alkyl group comprises one or more cyclic heteroatoms independently selected from O, S and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized; Each RS3 Independently selected from -CN, -Hal, -OH, -NH2, C1-6 alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -(C 0-3 alkylene)-(C 3-7 cycloalkyl), -(C 0-3 alkylene)-(3 to 7-membered heterocyclic alkyl), -(C 0-3 alkylene)-phenyl and -(C 0-3 Alkylene-(5 or 6-membered heteroaryl), wherein the heterocyclic alkyl and heteroaryl rings independently comprise one or more cyclic heteroatoms independently selected from O, S, and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and wherein in the -(C 0-3 alkylene)-(C 3-7 cycloalkyl), -(C 0-3 alkylene)-(3 to 7-membered heterocyclic alkyl), -(C 0-3 alkylene)-phenyl and -(C 0-3 In the alkylene moiety of (alkylene)-(5 or 6-membered heteroaryl), if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 alkylene)-(C 3-7 The cycloalkyl moiety in the cycloalkyl group, the -(C 0-3 The heterocyclic alkyl moiety in (alkylene)-(3 to 7-membered heterocyclic alkyl), the -(C 0-3 The aryl moiety in the alkylene-phenyl group and the -(C 0-3 In the alkylene group (5 or 6-membered heteroaryl), the heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups).

[0143] With the two Rs mentioned above 3 The particularly preferred A portion related to the definition is selected from the following groups: , , , and ; The wavy line marks the connection to the rest of the molecule; n is 0, 1, or 2; And among them, the aforementioned R 2 and R S3 The definition applies.

[0144] Specifically, regarding part A above, the preferred option is...

[0145] R 2 It is a C2-alkylene or C3-alkylene; and

[0146] Each R S3 Independently selected from -CN, -Hal, -OH, NH2, C1-6 alkyl, C 1-6 Haloalkyl, -O(C1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 -(C0-3-alkylene)-aryl and -(C0-3-alkylene)-heteroaryl, wherein in the -(C0-3-alkylene)-heteroaryl 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups).

[0147] With the above R 3 The particularly preferred A portion, as defined in the definition, is selected from the following groups: (A-5) (A-6) (A-7) (A-8) (A-9) (A-10) (A-11) and (A-12); The wavy line marks the connection to the rest of the molecule; And among them, the aforementioned R 2 The definition applies.

[0148] Specifically, regarding part A above, the preferred option is...

[0149] R 2 It is a C2-alkylene or C3-alkylene.

[0150] If R 2 If it is a C2 alkylene group, then the above A part is called A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2 and A-12-C2.

[0151] If R 2 If it is a C3 alkylene group, then the above A part is called A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3 and A-12-C3.

[0152] In summary, in a preferred embodiment, A is selected from the following: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0153] In a particularly preferred embodiment, the A portion is selected from A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, and A-12-C2.

[0154] In another particularly preferred embodiment, the A portion is selected from A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0155] The present invention particularly prefers formula (Ia) HH), (Ia) HCl), (Ia HF), (Ia) HCH3), (Ib HH), (Ib HCl), (Ib) HF), (Ib HCH3), (Ic H), (Ic Cl), (Ic F), (Ic Compounds of CH3), wherein R 1 It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0156] In one embodiment, the compound of formula (I) is of formula (Ia) Compounds of HH), wherein R 1 It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0157] In another embodiment, the compound of formula (I) is of formula (Ia) Compounds of HCl, wherein R 1 It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0158] In another embodiment, the compound of formula (I) is of formula (Ia) Compounds of HF, wherein R 1It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0159] In another embodiment, the compound of formula (I) is of formula (Ia) Compounds of HCH3), wherein R 1 It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0160] In one embodiment, the compound of formula (I) is of formula (Ib) Compounds of HH), wherein R 1 It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0161] In another embodiment, the compound of formula (I) is of formula (Ib) Compounds of HCl, wherein R 1It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0162] In another embodiment, the compound of formula (I) is of formula (Ib) Compounds of HF, wherein R 1 It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0163] In another embodiment, the compound of formula (I) is of formula (Ib) Compounds of HCH3), wherein R 1 It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0164] In one embodiment, the compound of formula (I) is of formula (Ic) Compounds of H), wherein R 1It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0165] In another embodiment, the compound of formula (I) is of formula (Ic) Compounds of Cl), wherein R 1 It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0166] In another embodiment, the compound of formula (I) is of formula (Ic) Compound F), wherein R 1 It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0167] In another embodiment, the compound of formula (I) is of formula (Ic) Compounds of CH3), wherein R 1It is 4-ethoxyphenyl, and A is selected from the following parts: A-1-C2, A-2-C2, A-3-C2, A-4-C2, A-5-C2, A-6-C2, A-7-C2, A-8-C2, A-9-C2, A-10-C2, A-11-C2, A-12-C2, A-1-C3, A-2-C3, A-3-C3, A-4-C3, A-5-C3, A-6-C3, A-7-C3, A-8-C3, A-9-C3, A-10-C3, A-11-C3, and A-12-C3.

[0168] In yet another implementation, Part A is... , The wavy line marks the connection to the rest of the molecule; And among them: R 4 Does not exist or is C 1-4 Alkylene; R 5 -H, -Hal, -OH, C 1-6 Alkyl or -O(C) 1-6 alkyl); R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-O(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl or -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups).

[0169] Regarding the substituent R 6 Preferably, the selection of the substituent does not allow a heteroatom (e.g., an oxygen or nitrogen atom) or a halogen atom to be directly bonded to a carbon atom that is directly bonded to a nitrogen atom contained in part A; and does not allow a heteroatom (e.g., an oxygen atom) to be directly bonded to a nitrogen atom contained in part A.

[0170] Therefore, in a preferred embodiment, if R 6 For -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-O(C 1-6 alkyl) or -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 Alkyl), then -(C) is preferred. 2-6 alkylene)-OH, -(C 2-6 alkylene)-O(C 1-6 alkyl) or -(C 2-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 alkyl).

[0171] Furthermore, in a preferred embodiment, if R 6 In the case of a group in which -CH2- is replaced by -O-, it is preferred that the oxygen atom is not directly bonded to the carbon atom, but is directly bonded to the nitrogen atom contained in part A; and is not directly bonded to the nitrogen atom contained in part A.

[0172] In yet another implementation, Part A is... , The wavy line marks the connection to the rest of the molecule; And among them: R 4 Does not exist or is C 1-4 Alkylene; R 5 -Hal, -OH, C 1-6 Alkyl or -O(C) 1-6 alkyl); R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, -(C1-6 alkylene)-OH, -(C 1-6 alkylene)-O(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 -(C0-3 alkylene)-heterocyclic alkyl, -(C0-3 alkylene)-aryl or -(C0-3 alkylene)-aryl 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups).

[0173] In a preferred embodiment R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl or -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups).

[0174] In a more preferred embodiment, R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 0-3 alkylene)-(C 3-7 cycloalkyl), -(C 0-3 alkylene)-(3 to 7-membered heterocyclic alkyl), -(C 0-3 alkylene)-phenyl or -(C 0-3 Alkylene-(5 or 6-membered heteroaryl), wherein the heterocyclic alkyl and heteroaryl rings independently comprise one or more cyclic heteroatoms independently selected from O, S, and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and wherein in the -(C 0-3 alkylene)-(C 3-7 cycloalkyl), -(C 0-3 alkylene)-(3 to 7-membered heterocyclic alkyl), -(C 0-3 alkylene)-phenyl and -(C 0-3 In the alkylene moiety of (alkylene)-(5 or 6-membered heteroaryl), if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 alkylene)-(C 3-7 The cycloalkyl moiety in the cycloalkyl group, the -(C 0-3 The heterocyclic alkyl moiety in (alkylene)-(3 to 7-membered heterocyclic alkyl), the -(C 0-3 The aryl moiety in the alkylene-phenyl group and the -(C 0-3 In the alkylene group (5 or 6-membered heteroaryl), the heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups).

[0175] In another preferred embodiment, part A is ; The wavy line marks the connection to the rest of the molecule; And among them: R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-O(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 -(C0-3 alkylene)-heterocyclic alkyl, -(C0-3 alkylene)-aryl or -(C0-3 alkylene)-aryl 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups).

[0176] Preferably, R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl or -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in the (alkylene)-heterocyclic alkyl group, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 In the alkylene-heteroaryl group, each heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups).

[0177] More preferably, R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 0-3 alkylene)-(C 3-7 cycloalkyl), -(C 0-3 alkylene)-(3 to 7-membered heterocyclic alkyl), -(C 0-3 alkylene)-phenyl or -(C 0-3 Alkylene-(5 or 6-membered heteroaryl), wherein the heterocyclic alkyl and heteroaryl rings independently comprise one or more cyclic heteroatoms independently selected from O, S, and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and wherein in the -(C 0-3 alkylene)-(C 3-7 cycloalkyl), -(C 0-3 alkylene)-(3 to 7-membered heterocyclic alkyl), -(C 0-3 alkylene)-phenyl and -(C 0-3 In the alkylene moiety of (alkylene)-(5 or 6-membered heteroaryl), if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 alkylene)-(C 3-7 The cycloalkyl moiety in the cycloalkyl group, the -(C 0-3 The heterocyclic alkyl moiety in (alkylene)-(3 to 7-membered heterocyclic alkyl), the -(C 0-3 The aryl moiety in the alkylene-phenyl group and the -(C 0-3 In the alkylene group (5 or 6-membered heteroaryl), the heteroaryl moiety is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups).

[0178] Particularly preferred compounds of formula (I) are selected from the following compounds or their stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts or solvates: , , , , , , , , , , , , , , , , , , , , .

[0179] Further preferred compounds of formula (I) are selected from the following compounds or their stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts or solvates: , , , , , , , , , .

[0180] Further preferred compounds of formula (I) are selected from the following compounds or their stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts or solvates: , , , , , , , , , , , , , .

[0181] The scope of this invention covers all pharmaceutically acceptable salt forms of compounds of formula (I), which can be formed, for example, by protonation of an inorganic or organic acid with a lone pair of electrons and readily protonated (such as an amino group), or in the form of a salt of an acid group (such as a carboxylic acid group) and a physiologically acceptable cation. Exemplary base addition salts include, for example: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts, such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine, meglumine, ethylenediamine, or choline salts; aralkylamine salts, such as N,N-dibenzylethylenediamine, benzylamine, or phenethylbenzylamine; heterocyclic aromatic amine salts, such as pyridine, methylpyridine, quinoline, or isoquinoline; quaternary ammonium salts, such as tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, benzyltriethylammonium, benzyltributylammonium, methyltrioctylammonium, or tetrabutylammonium; and basic amino acid salts, such as arginine, lysine, or histidine. Exemplary acid addition salts include, for example: inorganic acid salts, such as hydrobromide, hydroiodide, sulfate (e.g., sulfate or hydrogen sulfate), nitrate, phosphate (e.g., phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, perchlorate, borate, or thiocyanate; and organic acid salts, such as acetate, propionate, butyrate, valerate, hexanoate, heptate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, and tartrate. Malates, citrates, succinates, adipates, gluconates, glycolates, nicotinates, benzoates, salicylates, ascorbic acid salts, bis(hydroxynaphthyl) salts (sebate), camphorates, gluconate, or neopentanoates; sulfonates, such as methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates (hydroxyethyl sulfonate), benzenesulfonates, p-toluenesulfonates (toluenesulfonate), 2-naphthalenesulfonates (naphthalenesulfonate), 3-phenylsulfonates, or camphorsulfonates; glycerophosphates; and acidic amino acid salts, such as aspartate or glutamate. Preferred pharmaceutically acceptable salts of compounds of formula (I) include hydrochlorides, hydrobromides, methanesulfonates, sulfates, tartrates, fumarates, acetates, citrates, and phosphates. Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are hydrochlorides. Therefore, compounds of formula (I) are preferred, including any of the specific compounds of formula (I) described in this application, in the form of hydrochloride, hydrobromide, methanesulfonate, sulfate, tartrate, fumarate, acetate, citrate or phosphate, and compounds of formula (I) are particularly preferred in the form of hydrochloride.

[0182] The present invention also specifically relates to compounds of formula (I) in non-salt form, including any of the specific compounds of formula (I).

[0183] Furthermore, the scope of this invention covers any solvated form of compounds of formula (I), including, for example, solvates with water (i.e., hydrated forms) or solvates with organic solvents such as methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms of compounds of formula (I), including any amorphous or crystalline form (i.e., polymorphs), are also covered within the scope of this invention. It should be understood that such solvates and physical forms of pharmaceutically acceptable salts of compounds of formula (I) are also covered by this invention.

[0184] Furthermore, compounds of formula (I) may exist in the form of different isomers, particularly stereoisomers (including, for example, geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers (particularly including proton transfer tautomers, such as ketone / enol tautomers or thionone / thiol tautomers). All such isomers of compounds of formula (I), whether in mixture form, pure form or substantially pure form, are considered part of this invention. Regarding stereoisomers, this invention covers the isolated optical isomers of compounds according to the invention and any mixtures thereof (particularly including racemic mixtures / racemates). Racemates can be resolved (i.e., separated) by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can also be obtained from racemates by forming a salt with an optically active acid, followed by crystallization. This invention also includes any tautomers of compounds of formula (I). It should be understood that some compounds may exhibit tautomerism. In such cases, the structural formulas provided herein only explicitly illustrate one of the possible tautomer forms. The structural formulas and chemical names provided herein are intended to cover any tautomer form of the corresponding compound, and are not limited to the specific tautomer forms shown in the figures or identified by the compound name.

[0185] Furthermore, the compound of formula (I) can exist in the form of an N-oxide, that is, in the form in which at least one tertiary nitrogen atom is oxidized to an N-oxide moiety.

[0186] The scope of this invention also covers compounds of formula (I) in which one or more atoms are replaced by specific isotopes of the corresponding atoms. For example, this invention covers compounds in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by deuterium atoms (i.e., 2 H; also known as "D") is a substitute for formula (I). Therefore, the present invention also covers compounds of formula (I) enriched with deuterium. Naturally occurring hydrogen is a compound containing about 99.98 mol-% hydrogen-1 ( 1H) and approximately 0.0156 mol-% deuterium ( 2 A mixture of isotopes of H or D. The deuteration content at one or more hydrogen sites in a compound of formula (I) can be increased using deuteration techniques known in the art. For example, a compound of formula (I) or a reactant or precursor used to synthesize a compound of formula (I) can be subjected to an H / D exchange reaction using, for example, heavy water (D₂O). Other suitable deuteration techniques are described in: Atzrodt J et al. Bioorg Med Chem Volume 20 (Issue 18), pp. 5658-5667, 2012; William JS et al. Journal of Labeled Compounds and Radiopharmaceuticals Volume 53 (Issues 11-12), pp. 635-644, 2010; Modvig A et al. J Org Chem Volume 79, pp. 5861-5868, 2014. The content of deuterium can be determined, for example, using mass spectrometry or NMR spectroscopy. Unless otherwise specified, it is preferred that the compounds of formula (I) are not enriched in deuterium. Therefore, the compounds of formula (I) contain naturally occurring hydrogen atoms or 1 H hydrogen atoms are preferred.

[0187] The present invention also covers compounds of formula (I) in which one or more atoms are replaced by positron-emitting isotopes of the corresponding atoms, such as... 18 F, 11 C 13 N、 15 O、 76 Br、 77 Br、 120 I and / or 124 I. Such compounds can be used as tracers, tracking agents, or imaging probes in positron emission tomography (PET). Therefore, the present invention includes (i) one or more fluorine atoms (or, for example, all fluorine atoms) being... 18 Compounds of formula (I) in which one or more carbon atoms (or, for example, all carbon atoms) are replaced by F atoms. 11 Compounds of formula (I) in which C atoms are substituted, and (iii) in which one or more nitrogen atoms (or, for example, all nitrogen atoms) are... 13 Compounds of formula (I) in which the N atom is substituted, and (iv) wherein one or more oxygen atoms (or, for example, all oxygen atoms) are... 15 Compounds of formula (I) with O atoms substituted, and (v) wherein one or more bromine atoms (or, for example, all bromine atoms) are... 76 Compounds of formula (I) with Br atom substitution, (vi) wherein one or more bromine atoms (or, for example, all bromine atoms) are substituted. 77Compounds of formula (I) with Br atom substitution, (vii) wherein one or more iodine atoms (or, for example, all iodine atoms) are substituted. 120 Compounds of formula (I) in which one or more iodine atoms (or, for example, all iodine atoms) are substituted with an I atom, and (viii) compounds in which one or more iodine atoms (or, for example, all iodine atoms) are substituted with an I atom. 124 Compounds of formula (I) with I atoms substituted. Generally, it is preferred that no atoms in compounds of formula (I) are substituted by specific isotopes.

[0188] The compounds provided herein may be administered in their own form or formulated as pharmaceuticals. Pharmaceutical / pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubilizers.

[0189] The pharmaceutical composition may contain one or more solubilizers, such as polyethylene glycol (including polyethylene glycols with a molecular weight in the range of about 200 Da to about 5000 Da (e.g., PEG 200, PEG 300, PEG 400 or PEG 600)), ethylene glycol, propylene glycol, glycerin, nonionic surfactants, tylosap, polysorbate 80, polyethylene glycol-15-hydroxystearate (e.g., Kolliphor). ® HS 15, CAS 70142-34-6), phospholipids, lecithin, myristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearyl phosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl ether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin The following are considered as a whole: purine, disaccharidoyl-β-cyclodextrin, maltodextrin-α-cyclodextrin, maltodextrin-β-cyclodextrin, maltodextrin-γ-cyclodextrin, maltotrisyl-β-cyclodextrin, maltotrisyl-γ-cyclodextrin, disaccharidoyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyl sulfide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, or any combination thereof.

[0190] The pharmaceutical composition may also contain one or more preservatives, particularly one or more antimicrobial preservatives, such as benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methylphenol or 4-chloro-3-methylphenol), benzalkonium chloride, benzyl chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

[0191] Pharmaceutical compositions can be formulated using techniques known to those skilled in the art, such as those disclosed in "Remington: The Science and Practice of Pharmacy," Pharmaceutical Press, 22nd edition. Pharmaceutical compositions can be formulated into dosage forms for oral, parenteral (e.g., intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac), rectal, nasal, topical, aerosol, or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, pharmaceutical gums, chewable tablets, and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersants, and powders and granules for reconstitution. Emulsions are preferred dosage forms for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and oval forms. Dosage forms for nasal application can be administered via inhalation and blowing, such as through a metered-dose inhaler. Dosage forms for topical application include creams, gels, ointments, balms, patches, and transdermal delivery systems.

[0192] The compound of formula (I) or the pharmaceutical composition comprising the above-described compound (I) may be administered to the subject via any convenient route of administration, whether systemic / peripheral or at the site of desired action, including but not limited to one or more of the following: oral (e.g., in tablet, capsule or ingestible solution form), topical (e.g., transdermal, intranasal, ocular, oral, and sublingual), parenteral (e.g., using injection or infusion techniques, including, for example, by injection (e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrasheath, intraspinal, intracapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, or intrasternal injection), and by, for example, implanted receptacle (e.g., subcutaneous or intramuscular implantation), pulmonary (e.g., by inhalation or blowing therapy using, for example, an aerosol, such as oral or nasal), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or anterior chamber), rectal, or vaginal administration.

[0193] If the compound or pharmaceutical composition is to be administered parenterally, examples of such administration include one or more of the following: intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracardiac, intramuscular, or subcutaneous administration, and / or administration by means of an infusion technique. For parenterally administration, the compound is preferably used in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salt or glucose, to make the solution isotonic with blood. If necessary, the aqueous solution should be appropriately buffered (preferably to a pH of 3 to 9). The preparation of suitable parenteral formulations under sterile conditions can be readily accomplished using standard pharmaceutical techniques known to those skilled in the art.

[0194] The compound or pharmaceutical composition may also be administered orally in the form of tablets, capsules, oval forms, elixirs, solutions or suspensions, which may contain flavoring agents or coloring agents for immediate release, delayed release, modulated release, sustained release, pulsatile release or controlled release purposes.

[0195] Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, and glycine; disintegrants such as starch (preferably corn, potato, or cassava starch), sodium starch hydroxyacetate, croscarmellose sodium, and certain complex silicates; and granulation binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin, and gum arabic. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included. Similar types of solid compositions may also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, or high molecular weight polyethylene glycol. For aqueous suspensions and / or elixirs, the pharmaceutical preparation may be combined with various sweeteners or flavoring agents, colorants or dyes, emulsifiers and / or suspending agents, and diluents such as water, ethanol, propylene glycol, and glycerin, and combinations thereof.

[0196] For oral administration, the compound or pharmaceutical composition is preferably ingested orally, particularly by swallowing. Therefore, the compound or pharmaceutical composition can be administered via the oral cavity into the gastrointestinal tract, which may also be referred to as "oral-gastrointestinal" administration.

[0197] Alternatively, the compound or pharmaceutical composition may be administered in the form of a suppository or oval, or topically in the form of a gel, hydrogel, lotion, solution, cream, ointment, or powder. The compounds of the present invention may also be administered transdermally, for example, by using a skin patch.

[0198] The compound or pharmaceutical composition may also be administered via a sustained-release system. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of molded articles, such as membranes or microcapsules. Sustained-release matrices include, for example, copolymers of polylactide, L-glutamic acid, and γ-ethyl-L-glutamic acid, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(–)-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include compounds encapsulated in liposomes. Therefore, the present invention also relates to liposomes containing compounds of the present invention.

[0199] The compounds or pharmaceutical compositions may also be administered via the pulmonary, rectal, or ocular routes. For ophthalmic use, they may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline, optionally in combination with a preservative (such as benzalkonium chloride). Alternatively, they may be formulated in ointments (such as petrolatum).

[0200] It is also envisioned to prepare dry powder formulations of compounds of formula (I) for pulmonary administration, particularly inhalation. Such dry powder formulations can be prepared by spray drying under conditions that result in a substantially amorphous, glassy, ​​or substantially crystalline bioactive powder. Therefore, dry powder formulations of the compounds of the present invention can be prepared according to an emulsification / spray drying method.

[0201] For topical application to the skin, the compound or pharmaceutical composition may be formulated as a suitable ointment containing an active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, they may be formulated as a suitable lotion or cream suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, hexadecyl ester wax, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0202] Therefore, this invention relates to the compounds or pharmaceutical compositions provided herein, wherein the respective compounds or pharmaceutical compositions are administered via any of the following routes: oral administration; local administration, including transdermal, intranasal, ocular, buccal, or sublingual routes; parenteral administration using injection or infusion techniques, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrasheathal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, intrasternal, intravenous, intraurethral, ​​or intracranial routes; pulmonary administration, including inhalation or blowing therapy; gastrointestinal administration; intrauterine administration; intraocular administration; subcutaneous administration; ophthalmic administration, including intravitreal or intra-anterior chamber administration; rectal administration; or vaginal administration. Preferred routes of administration are oral or parenteral administration. For each of the compounds or pharmaceutical compositions provided herein, oral administration (particularly by oral ingestion) is particularly preferred.

[0203] Typically, the physician will determine the most suitable actual dose for the individual subject. The specific dose level and frequency for any particular individual subject can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, weight, general health condition, sex, diet, administration pattern and timing, excretion rate, drug combination, severity of the specific condition, and the individual subject's ongoing treatment.

[0204] The suggested, but not limiting, dosage of the compounds of the present invention for oral administration to a human (approximately 70 kg body weight) may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose. The unit dose may be administered, for example, 1 to 3 times daily. The unit dose may also be administered 1 to 7 times weekly, for example, no more than once daily. It should be understood that routine dosage adjustments may be necessary based on the patient / subject's age and weight, as well as the severity of the condition to be treated. The precise dosage and route of administration will ultimately be determined by the attending physician or veterinarian.

[0205] The therapeutic uses of the compounds of this invention will be described below.

[0206] In one embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used as a drug.

[0207] Without being bound by theory, the inventors have demonstrated that treatment with the compound of formula (I) results in efficient degradation of TASL, since TASL levels are regulated by their interaction with SLC15A4.

[0208] It is known to those skilled in the art and is evident from the literature that SLC15A4 and / or TASL play a key role in autoimmune diseases (including SLE) and inflammatory diseases (including inflammatory bowel disease (IBD), psoriasis and endosomal TLR-dependent inflammation).

[0209] Therefore, genome-wide association studies (GWAS) of SLE in human cells provide substantial evidence for the role of SLC15A4 in this condition. Bentham et al. (2015) identified the genetic association between SLC15A4 and TASL (referred to as CXorf21 in this study) and SLE in a cohort of European descent. He CF and colleagues (2010) identified the genetic association between SLC15A4 and SLE-associated discoid rash in the Han Chinese population. Langefeld and colleagues (Langefeld et al., Transancestral mapping and genetic load in systemiclupus erythematosus.) Nat Commun (Vol. 8, 16021 (2017)) identified the genetic association between SLC15A4 and SLE in a cohort of European populations.

[0210] Furthermore, based on genetic studies in human cells, there is additional evidence suggesting a role for TASL in the pathogenesis of SLE. Odhams et al. (Odhams et al. (2019)) proposed that SLE-associated genetic variants of TASL (CXorf21) lead to increased TASL expression in an interferon-specific and sex-specific manner, thus offering a potential explanation.

[0211] Further evidence in mouse models provides the importance of TASL / SLC15A4 in the development of SLE. (Baccala et al., Essential requirement for IRF8 and SLC15A4 implicates pDCs in the pathogenesis of lupus.) PNASVolume 110, page 2940, (2013) identified the protective effect of SLC15A4 deficiency in the development of SLE in a mouse model using the C57BL / 6-Fas(lpr) strain. Kobayashi et al. (Kobayashi et al., (2014)) showed that SLC15A4 deficiency had a protective effect in two SLE models (norphyrane-induced mice and C57BL / 6lpr / lpr mice) and that SLC15A4 is essential for endosome TLR function in B cells. Pollard et al. (Pollard et al., Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN.) J Immunol Volume 199, page 3739 (2017) found that SLC15A4 deficiency is protective in mercury-induced SLE models. Katewa et al. (Katewa et al., (2021)) described the protective effect of SLC15A4 in norphyton-induced SLE models and NZB / W F1 mouse genetic SLE models.

[0212] Therefore, the compounds of the present invention are considered to be useful for the treatment or prevention of autoimmune diseases, particularly SLE.

[0213] Based on the role of SLC15A4 and / or TASL in IRF5 activation, it can also be assumed that the compounds of the present invention can be used to treat or prevent autoimmune diseases, preferably selected from SLE, lupus nephritis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, polymyositis / dermatomyositis, primary biliary cirrhosis, multiple sclerosis, oral ulcers, periodontitis, Behçet's disease, inflammatory bowel disease, psoriasis, myasthenia gravis, and ankylosing spondylitis (Wang et al., (2023), Bentham et al., (2015), Katewa et al., (2021)).

[0214] Based on genetic studies, there is also substantial evidence to support the role of SLC15A4 and / or TASL in the production of pro-inflammatory cytokines (such as IL-6) and inflammation. Heinz et al. (Heinz et al., (2020)) have demonstrated the important role of SLC15A4-TASL and their role in endosome TLR function in human cell lines and primary cells.

[0215] Based on mouse model studies, further evidence exists regarding the role of SLC15A4 and / or TASL in inflammatory conditions. Blasius et al. (Blasius et al., (2010)) identified SLC15A4 as an essential component of endosome TLR function in pDCs. Sasawatari et al. (Sasawatari et al., The solute carrier family 15A4 regulates TLR9 and NOD1 functions in the innate immune system and promotes scolitis in mice.) Gastroenterology Volume 140, page 1513 (2011) found that SLC15A4 deficiency impairs the production of pro-inflammatory cytokines by dendritic cells induced by CpG. Furthermore, studies have shown that SLC15A4 deficiency is protective in an IBD mouse model. SLC15A4-deficient mice also exhibited defective cytokine production after activation of the NOD-like receptor NOD1. Blasius et al. (Slc15a4, a gene required for pDC sensing of TLR ligands, is required to control persistent viral infection.) PLoS Pathog Volume 8, e1002915 (2012) demonstrates the important role of SLC15A4 in controlling persistent infection of pDC, as demonstrated in models of LCMV infection. Nakamura et al. (Nakamura et al., Endosomes are specialized platforms for bacterial sensing and NOD2 signaling, Nature Volume 509, page 240 (2014) proposed the role of SLC15A4 in activating NOD2 in lysosomes. Notably, NOD2 mutations are associated with IBD. Dosenovic et al. (Dosenovic et al., Slc15a4 function is required for intact class switch recombination to IgG2c in response to TLR9 stimulation.) Immunol Cell Biol(Volume 93: Page 136, 2015) found defects in the endosome TLR function of pDCs, splenic cDCs, and B cells. Furthermore, antibody production induced by CpGA adjuvant vaccines was impaired in SLC15A4 mice. Griffith et al. (Griffith et al., A requirement for slc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice, Sci Rep Volume 8, 14451 (2018) describes SLC15A4 as being required for imiquimod-induced systemic inflammation and psoriasis-like inflammation in mice. Lopéz-Haber et al. (Lopéz-Haber et al., The phagosomal solute transporter SLC15A4 promotes inflammasome activity via mTORC1 signaling and autophagy restraintin dendritic cells) describes SLC15A4 as being required for imiquimod-induced systemic inflammation and psoriasis-like inflammation in mice. EMBO J Volume 41, e111161 (2022) describes the contribution of SLC15A4 to inflammasome activation via the mTORC1 signaling pathway.

[0216] Based on the role of SLC15A4 and / or TASL in IRF5 activation, it can also be assumed that the compounds of the present invention can be used to treat or prevent inflammatory conditions, preferably selected from inflammatory bowel disease, psoriasis-like dermatitis, endosome TLR-dependent inflammation, ulcerative colitis, Crohn's disease, endosome TLR-induced hyperinflammatory, macrophage activation syndrome, allergic airway inflammation, and sarcoidosis, preferably wherein the inflammatory condition is selected from inflammatory bowel disease, psoriasis-like dermatitis, and endosome TLR-dependent inflammation.

[0217] Therefore, the compounds of the present invention can be used to treat or prevent inflammatory conditions.

[0218] Therefore, in one embodiment, the present invention relates to a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment or prevention of autoimmune diseases or inflammatory conditions. In one embodiment, the present invention relates to a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment or prevention of autoimmune diseases. In one embodiment, the present invention relates to a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment or prevention of inflammatory conditions.

[0219] The autoimmune disease is preferably selected from systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjögren's syndrome, polymyositis / dermatomyositis, primary biliary cirrhosis, multiple sclerosis, oral ulcers, periodontitis, Behcet's disease, myasthenia gravis, and ankylosing spondylitis. More preferably, the autoimmune disease is systemic lupus erythematosus.

[0220] The inflammatory condition is preferably selected from inflammatory bowel disease, psoriatic dermatitis, endosomal TLR-dependent inflammation, ulcerative colitis, Crohn's disease, endosomal TLR-induced hyperinflammatory, macrophage activation syndrome, allergic airway inflammation, and sarcoidosis. More preferably, the inflammatory condition is selected from inflammatory bowel disease, psoriatic dermatitis, and endosomal TLR-dependent inflammation.

[0221] In one embodiment, the present invention relates to the use of a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating or preventing autoimmune diseases or inflammatory conditions. In one embodiment, the present invention relates to the use of a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating or preventing autoimmune diseases. In one embodiment, the present invention relates to the use of a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating or preventing inflammatory conditions.

[0222] In one embodiment, the present invention relates to a method for treating an autoimmune disease, the method comprising administering to a subject in need a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. It should be understood that the compound or its salt, or the pharmaceutical composition, is administered in a therapeutically effective amount, preferably as described herein.

[0223] In one embodiment, the present invention relates to a method for treating an inflammatory condition, the method comprising administering to a subject in need a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. It should be understood that the compound or its salt, or the pharmaceutical composition, is administered in a therapeutically effective amount, preferably as described herein.

[0224] It should be noted that the inventors have demonstrated that compounds of formula (I) or salts thereof inhibit SLC15 peptide transporter (i.e., SLC15A4)-TASL assembly by binding to the SLC15 peptide transporter. Therefore, and preferably, the therapeutic effect of compounds of formula (I) or salts thereof is expected to be based on inhibiting SLC15 peptide transporter (i.e., SLC15A4)-TASL assembly by binding to the SLC15 peptide transporter. Thus, in one embodiment, the present invention relates to compounds of formula (I) or salts thereof, or pharmaceutical compositions thereof, for the treatment or prevention of autoimmune diseases, wherein the compound or pharmaceutical composition inhibits SLC15 peptide transporter-TASL assembly. Given the ability of the compounds of the present invention or salts thereof to inhibit SLC15 peptide transporter-TASL assembly, the compounds are particularly useful in the treatment of autoimmune diseases, wherein the autoimmune diseases are related to the SLC15 peptide transporter. Therefore, in one embodiment, the present invention relates to a compound of formula (I) of the present invention or a salt thereof, or a pharmaceutical composition thereof, wherein the compound or the pharmaceutical composition is used to treat or prevent an autoimmune disease, wherein the autoimmune disease is a disease associated with the SLC15 peptide transporter.

[0225] The compounds provided by this invention can also be used to treat or prevent other lupus diseases, such as cutaneous or neonatal lupus erythematosus.

[0226] The present invention will be described in the following embodiments, but these embodiments should not be construed as limiting.

[0227] Example

[0228] List of Abbreviations:

[0229] method: HPLC method: Method A: Instruments: Shimadzu Prominance HPLC, coupled with Applied Biosystems API 2000 mass spectrometer.

[0230] Ionization method: Electrospray

[0231] UV wavelength range (nm): 220 and 260

[0232] Solvent A: 10mM ammonium acetate aqueous solution; Solvent B: Acetonitrile

[0233] Flow rate: 1.2 ml / min

[0234] Mobile phase: The mobile phase was changed from 90% [10mM ammonium acetate aqueous solution] and 10% [acetonitrile] to 70% [10mM ammonium acetate aqueous solution] and 30% [acetonitrile] within 1.50 min; then changed to 10% [10mM ammonium acetate aqueous solution] and 90% [acetonitrile] within 3.00 min, and this mobile phase composition was maintained until 4.00 min; finally, the mobile phase was restored to the initial conditions within 5.00 min.

[0235]

[0236] Column type: Xbridge C18 (4.6×50mm, 5 microns)

[0237] Mass spectrometry conditions: Ionization technology: ESI (electrospray ionization) using API (atmospheric pressure ionization) sources.

[0238] De-clustering voltage: 50V

[0239] Quality range: 200-1700 amu

[0240] Scan type: Q1

[0241] Polarity: + / -ve

[0242] Ion source: Turbo spray

[0243] Ion spray voltage: +5500V for +VE mode, -4500V for -VE mode

[0244] Mass spectrometry ion source temperature: 200℃.

[0245] Method B: Instrument: Waters Acquity H Class UPLC, coupled with a Waters SQD 2 mass spectrometer.

[0246] Ionization method: Electrospray

[0247] Capillary voltage (kV): 3.50; Cone voltage (V): 25.00; Ion source temperature (°C): 150; Desolventizing temperature (°C): 400; Cone gas flow rate (L / Hr): -50; Desolventizing gas flow rate (L / Hr): -750

[0248] Quality range: 100 to 900 Da

[0249] DAD wavelength range (nm): 200 to 400

[0250] Solvent A: 5mM NH4OAc aqueous solution; Solvent B: 5mM NH4OAc ACN:water (90:10) solution

[0251] Flow rate: 1.20 ml / min

[0252] (Mobile phase: 95% [5mM NH4OAc aqueous solution] and 5% [5mM NH4OAc in ACN:water (90:10) solution] maintained for 0.75 min; then changed to 85% [5mM NH4OAc aqueous solution] and 15% [5mM NH4OAc in ACN:water (90:10) solution] within 1.25 min; then changed to 70% [5mM NH4OAc aqueous solution] and 30% [5mM NH4OAc in ACN:water (90:10) solution] within 2.50 min; then changed to 2% [5mM NH4OAc aqueous solution] and 98% [5mM NH4OAc in ACN:water (90:10) solution] within 3.75 min, maintained this mobile phase composition for 4.25 min; finally restored to the initial conditions within 4.50 min, and maintained this composition for 5.10 min).

[0253] Time and flow rate (ml / min) %A (5mM NH4OAc aqueous solution) %B (5mM NH4OAc in ACN:water (90:10) solution).

[0254]

[0255] Column used: Xbridge C18 column (3.5μm, 50×3mm)

[0256] Column temperature: 40℃.

[0257] Method C: Instrumentation: Water Acquity H Class UPLC coupled with a Waters SQD 2 mass spectrometer.

[0258] Ionization method: Electrospray

[0259] Capillary voltage (kV): 3.50; Cone voltage (V): 25.00; Ion source temperature (°C): 150; Desolventizing temperature (°C): 400; Cone gas flow rate (L / Hr): -50; Desolventizing gas flow rate (L / Hr): -750

[0260] Quality range: 100 to 900 Da

[0261] DAD wavelength range (nm): 200 to 400

[0262] Solvent A: 0.05% formic acid aqueous solution; Solvent B: 0.05% HCOOH in ACN:water (90:10) solution

[0263] Flow rate: 0.8 mL / min

[0264] (Mobile phase: 95% [0.05% HCOOH aqueous solution] and 5% [0.05% HCOOH in ACN:water (90:10) solution] maintained for 0.75 min; then changed to 75% [0.05% HCOOH aqueous solution] and 25% [0.05% HCOOH in ACN:water (90:10) solution] within 1.5 min; then changed to 5% [0.05% HCOOH aqueous solution] and 95% [0.05% HCOOH in ACN:water (90:10) solution] within 3.00 min, and maintained this mobile phase composition for 4.00 min; finally, returned to the initial conditions within 4.50 min, and maintained this composition for 5.10 min).

[0265]

[0266] Column used: Waters Acquity UPLC BEH C8 (2.1 × 50 mm, 1.7 μm)

[0267] Column temperature: 45℃.

[0268] Method D: Instrumentation: Water Acquity H Class UPLC coupled with a Waters SQD 2 mass spectrometer.

[0269] Ionization method: Electrospray

[0270] Capillary voltage (kV): 3.50; Cone voltage (V): 25.00; Ion source temperature (°C): 150; Desolventizing temperature (°C): 400; Cone gas flow rate (L / Hr): -50; Desolventizing gas flow rate (L / Hr): -750

[0271] Quality range: 100 to 900 Da

[0272] DAD wavelength range (nm): 200 to 400

[0273] Solvent A: 0.05% formic acid aqueous solution; Solvent B: 0.05% HCOOH in ACN:water (90:10) solution

[0274] Flow rate: 0.8 mL / min

[0275] (Mobile phase: 95% [0.05% HCOOH aqueous solution] and 5% [0.05% HCOOH in ACN:water (90:10) solution] maintained for 1.00 min; then changed to 50% [0.05% HCOOH aqueous solution] and 50% [0.05% HCOOH in ACN:water (90:10) solution] within 5.00 min; then changed to 10% [0.05% HCOOH aqueous solution] and 90% [0.05% HCOOH in ACN:water (90:10) solution] within 8.00 min, and maintained this mobile phase composition for 10.00 min; finally, returned to the initial conditions within 11.50 min, and maintained this composition for 12.00 min).

[0276]

[0277] Column used: Waters Acquity UPLC BEH C8 (2.1 × 50 mm, 1.7 μm)

[0278] Column temperature: 45℃.

[0279] Method E: Instruments: Shimadzu Prominence HPLC, coupled with Applied Biosystems API 2000 mass spectrometer.

[0280] Ionization method: Electrospray

[0281] UV wavelength range (nm): 220 and 260

[0282] Solvent A: 10mM ammonium acetate aqueous solution; Solvent B: Acetonitrile

[0283] Flow rate: 1.2 mL / min

[0284] Mobile phase: The mobile phase was changed from 50% [10mM ammonium acetate aqueous solution] and 50% [acetonitrile] to 5% [10mM ammonium acetate aqueous solution] and 95% [acetonitrile] within 1.50 min, and this mobile phase composition was maintained until 4.00 min; finally, the mobile phase was restored to the initial conditions within 5.00 min.

[0285]

[0286] Column type: Xbridge C18 (4.6×50mm, 5 microns)

[0287] Mass spectrometry conditions: Ionization technology: ESI (electrospray ionization) using an API (atmospheric pressure ionization) source. De-clustering voltage: 50V Quality range: 200-1700 amu Scan type: Q1 Polarity: + / -ve Ion source: Turbo spray Ion spray voltage: +5500V for +VE mode, -4500V for -VE mode Mass spectrometry ion source temperature: 200℃.

[0288] Method F: Instruments: Shimadzu Prominance HPLC, coupled with Applied Biosystems API 2000 mass spectrometer.

[0289] Ionization method: Electrospray

[0290] UV wavelength range (nm): 220 and 260

[0291] Solvent A: 10mM ammonium acetate aqueous solution; Solvent B: Acetonitrile

[0292] Flow rate: 1.0 ml / min

[0293] Mobile phase: 95% [10mM ammonium acetate aqueous solution] and 5.00% [acetonitrile] maintained for 0.75 min; then changed to 50% [10mM ammonium acetate aqueous solution] and 50% [acetonitrile] within 5.00 min; then changed to 5% [10mM ammonium acetate aqueous solution] and 95% [acetonitrile] within 9.00 min, maintaining this mobile phase composition until 10.00 min; finally, restored to the initial conditions within 11.00 min, and maintained the initial composition until 12.00 min.

[0294]

[0295] Column type: Xbridge C18 (4.6×100mm, 5 microns)

[0296] Mass spectrometry conditions: Ionization technology: ESI (electrospray ionization) using an API (atmospheric pressure ionization) source. De-clustering voltage: 50V Quality range: 200-1700 amu Scan type: Q1 Polarity: + / -ve Ion source: Turbo spray Ion spray voltage: +5500V for +VE mode, -4500V for -VE mode Mass spectrometry ion source temperature: 200℃.

[0297] Method G: Instrument: Waters Acquity H Class UPLC, coupled with a Waters SQD 2 mass spectrometer.

[0298] Ionization method: Electrospray

[0299] Capillary voltage (kV): 3.50; Cone voltage (V): 25.00; Ion source temperature (°C): 150; Desolventizing temperature (°C): 400; Cone gas flow rate (L / Hr): -50; Desolventizing gas flow rate (L / Hr): -750

[0300] Quality range: 100 to 900 Da

[0301] DAD wavelength range (nm): 200 to 400

[0302] Solvent A: 5mM NH4OAc aqueous solution; Solvent B: 5mM NH4OAc ACN:water (90:10) solution

[0303] Flow rate: 1.00 ml / min

[0304] (Mobile phase: 98% [5mM NH4OAc aqueous solution] and 2% [5mM NH4OAc in ACN:water (90:10) solution] maintained for 1.00 min; then changed to 50% [5mM NH4OAc aqueous solution] and 50% [5mM NH4OAc in ACN:water (90:10) solution] within 5.00 min; finally changed to 2% [5mM NH4OAc aqueous solution] and 98% [5mM NH4OAc in ACN:water (90:10) solution] within 8.00 min, maintained this mobile phase composition for 10.00 min, and finally restored to the initial conditions within 12.00 min, maintained this composition for 12.10 min).

[0305]

[0306] Column used: Xbridge C18 column (3.5μm, 50×3mm)

[0307] Column temperature: 40℃.

[0308] Method H: Instrument: Waters Acquity H Class UPLC, coupled with a Waters QDA mass spectrometer.

[0309] Ionization method: Electrospray

[0310] Capillary voltage (kV): 0.80; Taper voltage (V): 15.00; Ion source temperature (°C): 120; Probe temperature (°C): 600; Mass range: 100 to 900 Da

[0311] DAD wavelength range (nm): 200 to 400

[0312] Solvent A: 0.05% formic acid aqueous solution; Solvent B: ACN

[0313] Flow rate: 1.00 ml / min

[0314] (Mobile phase: 98% [0.05% aqueous formic acid] and 2% [ACN] maintained for 1.00 min; then changed to 40% [0.05% aqueous formic acid] and 60% [ACN] within 4.50 min; changed to 5% [0.05% aqueous formic acid] and 95% [ACN] within 9.50 min, and maintained this mobile phase composition for 13.00 min; finally, returned to the initial conditions within 14.00 min, and maintained this composition for 15.00 min).

[0315]

[0316] Column used: Luna Omega Polar C18 column (3.5μm, 100×4.6mm)

[0317] Column temperature: 40℃.

[0318] Method J: Instrument: Agilent 1260 Infinity II + 6125C SQ Ionization method: Electrospray UV wavelength range (nm): 190 and 400 Solvent A: Water + 0.1% formic acid; Solvent B: Acetonitrile + 0.1% formic acid Flow rate: 0.6 ml / min Mobile phase: 90% [water + 0.1% formic acid] and 10% [acetonitrile + 0.1% formic acid] were maintained constant for 5.00 min; then changed to 10% [water + 0.1% formic acid] and 90% [acetonitrile + 0.1% formic acid], and maintained for 2.00 min.

[0319]

[0320] Column type: ZORBAX RRHT StableBond C18, 2.1 × 50 mm, 1.8 μm, 600 bar. 80 Å

[0321] Mass spectrometry conditions: Ionization technology: ESI (electrospray ionization) using API (atmospheric pressure ionization) sources.

[0322] De-clustering voltage: 135V

[0323] Mass range: 50-1500 m / z

[0324] Scan type: Q1

[0325] Polarity: + / -ve

[0326] Ion source: Turbo spray

[0327] Ion spray voltage: +4000 for +VE mode, -4000 for -VE mode

[0328] Mass spectrometry ion source temperature: 300℃.

[0329] Method K: Waters Acquity H Class UPLC, coupled with a Waters QDA mass spectrometer.

[0330] Ionization method: Electrospray

[0331] Capillary voltage (kV): 0.80; Taper voltage (V): 15.00; Ion source temperature (°C): 120; Probe temperature (°C): 600; Mass range: 100 to 900 Da

[0332] DAD wavelength range (nm): 200 to 400

[0333] Solvent A: 0.05% formic acid aqueous solution; Solvent B: 0.05% HCOOH in ACN:water (90:10) solution

[0334] Flow rate: 0.6 ml / min

[0335] (Mobile phase: 95% [0.05% HCOOH aqueous solution] and 5% [0.05% HCOOH in ACN:water (90:10) solution] maintained for 0.75 min; then changed to 75% [0.05% HCOOH aqueous solution] and 25% [0.05% HCOOH in ACN:water (90:10) solution] within 1.5 min; then changed to 5% [0.05% HCOOH aqueous solution] and 95% [0.05% HCOOH in ACN:water (90:10) solution] within 3.00 min, and maintained this mobile phase composition for 4.00 min; finally, returned to the initial conditions within 4.50 min, and maintained this composition for 5.10 min).

[0336]

[0337] Column used: Waters Acquity UPLC BEH C18 (2.1 × 50 mm, 1.7 micrometers)

[0338] Column temperature: 45℃.

[0339] Mass spectrometry ion source temperature: 200℃.

[0340] Method L: Waters Acquity H Class UPLC, coupled with a Waters QDA mass spectrometer.

[0341] Ionization method: Electrospray

[0342] Capillary voltage (kV): 0.80; Taper voltage (V): 15.00; Ion source temperature (°C): 120; Probe temperature (°C): 600; Mass range: 100 to 900 Da

[0343] DAD wavelength range (nm): 200 to 400

[0344] Solvent A: 0.05% TFA aqueous solution; Solvent B: ACN

[0345] Flow rate: 0.40 ml / min

[0346] (Mobile phase: changed from 98% [0.05% TFA aqueous solution] and 2% [ACN] to 90% [0.05% TFA aqueous solution] and 10% [ACN] within 1.50 min; then changed to 60% [0.05% TFA aqueous solution] and 40% [ACN] within 18.00 min; changed to 5% [0.05% TFA aqueous solution] and 95% [ACN] within 19.00 min, and maintained this mobile phase composition until 20.00 min; finally, returned to the initial conditions within 22.00 min, and maintained this composition until 25.00 min).

[0347]

[0348] Column used: Acquity BEH C18 column (1.8μm, 100×2.7mm)

[0349] Column temperature: 40℃.

[0350] HPLC method: Method M: Reversed-phase HPLC was performed on an Agilent 1200 series instrument equipped with a diode array detector. Column: X bridge C18 (5 μm, 100 mm × 4.6 mm); flow rate: 1.0 mL / min. Two mobile phases were used: mobile phase A: acetonitrile; mobile phase C: 10 mM ammonium acetate aqueous solution; and gradient conditions were run using them: mobile phase A: 2% [acetonitrile] and mobile phase B: 98% [10 mM ammonium acetate aqueous solution] for 0.01 min; 2% [acetonitrile] and 98% [10 mM ammonium acetate aqueous solution] for 1.50 min; then 35% [acetonitrile] and 65% [10 mM ammonium acetate aqueous solution] for 4.5 min; 95% [acetonitrile] and 5% [10 mM ammonium acetate aqueous solution] for 11 min, maintaining this composition for 13 min for column washing; then reverting to the initial composition within 14 min and maintaining this composition for 18.0 min (total run time 18.0 min). Diluent: DMSO. Use an injection volume of 2.0 μl.

[0351] Method N: Reversed-phase HPLC was performed on an Agilent 1260 Infinity 2 series instrument equipped with a diode array detector. Column: ACQUITY UPLC BEH C18 (1.7 μm, 100 × 2.1 mm); Flow rate: 0.4 mL / min. Two mobile phases were used: Mobile phase A: acetonitrile; Mobile phase C: 0.1% TFA aqueous solution; and gradient conditions were run using them: Mobile phase A: 2% [acetonitrile] and mobile phase C: 98% [0.1% TFA aqueous solution] maintained for 0.00 min; maintained with 10% [acetonitrile] and 90% [0.1% TFA aqueous solution] maintained for 1.50 min; then maintained with 40% [acetonitrile] and 60% [0.1% TFA aqueous solution] maintained for 18 min; maintained with 95% [acetonitrile] and 5% [0.1% TFA aqueous solution] maintained for 19 min, maintaining this composition for 20 min for column washing; then restored to the initial composition within 22 min and maintained this composition for 28 min (total run time 28 min). Diluent: DMSO. 3 μl injection volume was used.

[0352] Normal-phase preparative HPLC methods: Method - Preparation A: Chiral separation was performed on an Agilent 1200 series instrument. Column name: CHIRALCEL OD-H (250×20mm), 5μm. Operation at room temperature, flow rate: 18.0 mL / min. Mobile phase: a mixture of 80% hexane and 20% EtOH, isocratic elution, runtime: 27 min, detection wavelength: 300 nm.

[0353] Preparation example: Compounds of structure (I) can be prepared by the synthetic sequence shown in schemes 1-3 below.

[0354]

[0355] Option 1: Synthesis of intermediate M-3

[0356] Scheme 2: Synthesis of compound (I) based on amide formation

[0357] Option 3: Synthesis of compound (I) based on amide formation and reductive amination (amine B-4, particularly amino groups with optional R) S2 The unit between the acetal / ketal groups of the substituents provides the R of part A of the compound of formula (I). 2 Group.

[0358] Compound (I) can be prepared from intermediate M-1, which can be converted into different intermediates M-2 via Suzuki coupling using substituted phenylboronic acid (Method A). Alternatively, intermediate M-2 can be obtained using another coupling reaction suitable for introducing substituted phenyl groups. Different carboxylic acid intermediates M-3a can be obtained by saponification of intermediate M-2.

[0359] Intermediate M-6 can be obtained by Suzuki coupling of intermediate M-4 and a substituted phenylboronic acid (Method B), or by alternative coupling reactions suitable for introducing a substituted phenyl group. Intermediate M-6 can be obtained by Negishi coupling to introduce a cyano group into intermediate M-6 (Method C) or by alternative methods. Intermediate M-6 can be hydrolyzed to the carboxylic acid derivative M-3b.

[0360] Intermediate M-7 can be used in THF at low temperatures. n -BuLi is deprotonated and then treated with diethyl oxalate (method D) to give intermediate M-8. Intermediate M-8 can be reacted with ketone intermediate K-1 via a condensation reaction (method E) to give intermediate M-3c.

[0361] Indigo M-9 can be acylated in pyridine with different acyl chlorides K-2 to give intermediate M-10. Intermediate M-10 can be reacted with an ethanolic solution of NH4OAc at high temperature (method F) to give intermediate M-3d.

[0362] Compound (I) can be prepared from different intermediates M-3 using the synthetic sequence shown in Scheme 2. Intermediate M-3 can be reacted with different amines B-1 or B-2 via amide coupling to give compound (I). Intermediate M-3 can also react with different amines B-3 containing protecting groups (e.g., Boc, Cbz, Bn) at the piperidine nitrogen to give intermediate M-11, which can be deprotected by a suitable method (method G) to give R. 6 = Compound of H (I). Then R 6 = H compound (I) can be further modified by: by using a suitable R 6 The R group is introduced by alkylation of -X (X = Hal, -OMs, -OTs, or related groups) (Method H) or by reductive amination with a suitable aldehyde or ketone (Method I). 6 (R) 6 (not H), thus obtaining another compound (I). Compound (I) can be further modified to obtain another compound (I) (e.g., by removing the protecting group or by introducing another substituent).

[0363] Other compounds (I) can be obtained through the following reaction sequence: first, intermediate M-3 reacts with amine B-4 to form an amide, yielding intermediate M-12. These intermediates are then hydrolyzed in either an acetal or a ketal to give the corresponding aldehyde or ketone, respectively (in R...). 2 The terminal carbon atom has a suitable substituent R S2 In the case of ketones: -CR S2 (OEt)2) Intermediate M-13 (Scheme 3). Intermediate M-13 can be converted into compound (I) by reductive amination with amine B-5 (method J).

[0364] R 2 = Cyclohexyl (optionally defined by one or more R S2 The substituted compound (I) can be obtained by reacting M-3 with 4-aminocyclohexane-1-one or with one or more R... S2 The substituted 4-aminocyclohexane-1-one derivative was amide-coupled and then reductively aminationed with amine B-5.

[0365] Synthesis of methyl 3-(4-ethoxyphenyl)isoquinoline-1-carboxylate (M-2a-1):

[0366] K3PO4 (2.88 g, 13.57 mmol) was added to a stirred solution of methyl 3-chloroisoquinoline-1-carboxylate (M-1a) (1.0 g, 4.52 mmol) in a mixture of dioxane:H2O (4:1) (8.0 mL). The mixture was purged with argon for 10 min. 4-ethoxyphenyl)boronic acid (0.9 g, 5.43 mmol) and PdCl2(dtbpf) (0.29 g, 0.45 mmol) were added under an argon atmosphere, and the mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature and diluted with a mixture of water (10 mL) and EtOAc (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by Combiflash chromatography (eluting with 10%-20% EtOAc-hexane) to obtain methyl 3-(4-ethoxyphenyl)isoquinoline-1-carboxylic acid (M-2a-1).

[0367] LC-MS (Method A): R t =3.93 min; Measured m / z: [M+H] + =307.9.

[0368] The other intermediate, M-2a, can be obtained in a similar manner, using intermediate M-1 and different boric acids as raw materials. If necessary, the crude product can be purified by chromatography (Table Ex1a).

[0369] Table Ex1a:

[0370] Synthesis of 3-(4-ethoxyphenyl)isoquinoline-1-carboxylic acid (M-3a):

[0371] LiOH·H2O (205 mg, 4.88 mmol) was added to a stirred solution of methyl 3-(4-ethoxyphenyl)isoquinoline-1-carboxylic acid (M-2a) (500 mg, 1.63 mmol) in THF:MeOH:H2O (7:3:2) (10.0 mL), and the mixture was stirred at room temperature for 16 h. The reactants were diluted with water, washed with ethyl acetate, and the aqueous layer was acidified to pH 6 at 0 °C using 1 N HCl aqueous solution. The product was extracted with 10% MeOH in DCM solution (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give 3-(4-ethoxyphenyl)isoquinoline-1-carboxylic acid (M-3a-1).

[0372] LC-MS (Method B): R t =2.09 min; Measured m / z: [M+H] + =294.2.

[0373] The other intermediate, M-3a, can be obtained in a similar manner, using intermediate M-2a and different boric acids as raw materials. If necessary, the crude product can be purified by chromatography (Table Ex1a).

[0374] Table Ex1b:

[0375] 3-(4-ethoxyphenyl)- N Synthesis of -(3-morpholinopropyl)isoquinoline-1-carboxamide (Ia-1):

[0376] DIPEA (0.18 mL, 1.02 mmol) was added to a DMF (3 mL) solution of methyl 3-(4-ethoxyphenyl)isoquinoline-1-carboxylic acid (M-3a-1) (100 mg, 0.34 mmol). The mixture was cooled to 0 °C and EDC-HCl (131 g, 0.68 mmol), HOBt (51 mg, 0.37 mmol), and 3-morpholinopropane-1-amine (73 mg, 0.51 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by preparative HPLC to give 3-(4-ethoxyphenyl)-N-[3-(morpholino-4-yl)propyl]isoquinoline-1-carboxamide (Ia-1).

[0377] The other compound Ia can be obtained in a similar manner, using intermediate M-3 and different amines B-1 as raw materials. If necessary, the crude product is purified by chromatography (Table Ex1).

[0378] Table Ex1:

[0379] N Synthesis of 3,3-diethoxypropyl)-3-(4-ethoxyphenyl)isoquinoline-1-carboxamide (M-12-1)

[0380] To a stirred solution of 3-(4-ethoxyphenyl)isoquinoline-1-carboxylic acid (M-3a-1) (1.5 g, 5.11 mmol) in DMF (15 mL), 3,3-diethoxypropane-1-amine (1.12 g, 7.67 mmol), Et3N (2.15 mL, 15.35 mmol), and HATU (2.33 g, 6.14 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was purified by combi-flash column chromatography to obtain... N -(3,3-diethoxypropyl)-3-(4-ethoxyphenyl)isoquinoline-1-carboxamide (M-12-1).

[0381] The other intermediate, M-12, can be obtained in a similar manner, using intermediate M-3 and a different amine B-4 as raw materials. If necessary, the crude product can be purified by chromatography (Table Ex2).

[0382] Table Ex2:

[0383] 3-(4-ethoxyphenyl)- N Synthesis of 3-(3-oxopropyl)isoquinoline-1-carboxamide (M-13-1):

[0384] An aqueous solution of HCl (2N) (1.4 mL) was added to a stirred solution of N-(3,3-diethoxypropyl)-3-(4-ethoxyphenyl)isoquinoline-1-carboxamide (M-12-1) (200.0 mg, 0.47 mmol) in a mixture of THF:H₂O (2:1, 3 mL), and the mixture was stirred at room temperature for 2 h. A saturated aqueous solution of NaHCO₃ was added to the reaction mixture, and the mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (2 × 20 mL). The organic layers were dried over anhydrous sodium sulfate and evaporated to give 3-(4-ethoxyphenyl)-N-(3-oxopropyl)isoquinoline-1-carboxamide (M-13-1).

[0385] LC-MS (Method C): R t =3.91 min. Measured m / z: [M+H] + =348.9.

[0386] The other intermediate, M-13, can be obtained in a similar manner using intermediate M-12 as a starting material. If necessary, the crude product can be purified by chromatography (Table Ex3).

[0387] Table Ex3

[0388] ( S )-3-(4-ethoxyphenyl)- N -(3-(3-fluoropyrrolidone-1-yl)propyl)isoquinoline-1-carboxamide (Ia-8) Synthesis:

[0389] To 3-(4-ethoxyphenyl)-N-(3-oxopropyl)isoquinoline-1-carboxamide (M-13-1) (80 mg, 0.230 mmol, 1.0 equivalent), ( S Anhydrous MgSO4 (42 mg, 0.345 mmol, 1.5 equivalents) was added to a stirred solution of 3-fluoropyrrolidine (31 mg, 0.345 mmol, 1.5 equivalents) and Et3N (2 equivalents) in DCE (2.5 mL), and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. Tetramethylammonium triacetoxyborohydride (121 mg, 0.460 mmol, 2.0 equivalents) was added, and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was filtered through diatomaceous earth, the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain (…). S )-3-(4-ethoxyphenyl)- N -(3-(3-fluoropyrrolidone-1-yl)propyl)isoquinoline-1-carboxamide (Ia-8).

[0390] LC-MS (Method B): R t =2.99 min. Measured m / z: [M+H] + =422.3

[0391] Other compounds (I) can be produced in a similar manner, using intermediate M-13 or compound Ia (R). 6 =H) and different amines B-5 were obtained as raw materials. If necessary, the crude product was purified by chromatography (Table Ex4).

[0392] Table Ex4:

[0393] The synthesis of 4-(3-(4-ethoxyphenyl)isoquinoline-1-carboxamido)piperidine-1-carboxylic acid tert-butyl ester (M-11a-1) become:

[0394] Add to a stirred solution of 15 mL of DMF containing 1.0 g (3.41 mmol) of 3-(4-ethoxyphenyl)isoquinoline-1-carboxylic acid (M-3a-1) N -(3-Dimethylaminopropyl)- N 4-Ethylcarbodiimide hydrochloride (784 mg, 4.09 mmol, 1.2 equivalents), 4-aminopiperidine-1-carboxylic acid tert-butyl ester (683 mg, 3.41 mmol, 1.0 equivalents), DIPEA (1.2 g, 10.2 mmol, 3.0 equivalents), and DMAP (83 mg, 0.68 mmol, 0.2 equivalents). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was purified by combi-flash column chromatography to give 4-(3-(4-ethoxyphenyl)isoquinoline-1-carboxamido)piperidine-1-carboxylic acid tert-butyl ester (M-11-1).

[0395] 3-(4-ethoxyphenyl)- N Synthesis of 1-(piperidin-4-yl)isoquinoline-1-carboxamide dihydrochloride (Ia-33):

[0396] 4-(3-(4-ethoxyphenyl)isoquinoline-1-carboxamido)piperidine-1-carboxylic acid tert-butyl ester (M-11a-1) (970 mg, 1.0 equivalent, 2.04 mmol) was dissolved in 3 mL of DCM. A dioxane solution of 4M HCl (10.19 mL, 40.76 mmol, 20 equivalents) was added. The reaction mixture was stirred at room temperature for 18 h. Another 5 mL of dioxane solution of 4M HCl was added, and the reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure to obtain 3-(4-ethoxyphenyl)- N -(piperidin-4-yl)isoquinoline-1-carboxamide dihydrochloride (Ia-33). It was purified by RP HPLC to obtain (Ia-33).

[0397] The other compound (I) can be obtained in a similar manner using intermediate M-11 or compound (I) with functional groups that are cleavable under these conditions. If necessary, the crude product is purified by chromatography (Table Ex5).

[0398] Table Ex5:

[0399] 3-(4-ethoxyphenyl)- N -(1-(2-hydroxyethyl)piperidin-4-yl)isoquinoline-1-carboxamide (Ia-37) become:

[0400] To 3-(4-ethoxyphenyl)- N To a 1 mL THF solution of 3-(piperidin-4-yl)isoquinoline-1-carboxamide hydrochloride (Ia-33) (50 mg, 0.13 mmol, 1.0 equivalence), 2-chloroethanol (11 mg, 0.13 mmol, 1.0 equivalence), NaI (20 mg, 0.13 mmol, 1.0 equivalence), and DIPEA (52 mg, 70 μL, 0.40 mmol, 3.0 equivalence) were added, and the reaction mixture was stirred at 50 °C for 18 h. Another portion of 2-chloroethanol (11 mg, 1.0 equivalence, 0.13 mmol) was added, and the reaction mixture was heated to 60 °C and stirred at the same temperature for 18 h. The reaction mixture was diluted with EtOAc (30 mL), washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography to give 3-(4-ethoxyphenyl)- N -(1-(2-hydroxyethyl)piperidin-4-yl)isoquinoline-1-carboxamide (Ia-37).

[0401] LC-MS (Method B): R t =2.44 min; Measured m / z: [M+H] + =420.3.

[0402] 3-(4-ethoxyphenyl)- N Synthesis of -(1,4-dioxaspiro[4.5]decane-8-yl)isoquinoline-1-carboxamide:

[0403] Add 3-(4-ethoxyphenyl)isoquinoline-1-carboxylic acid (1) (500 mg, 1.70 mmol) to a stirred solution of 3-(4-ethoxyphenyl)isoquinoline-1-carboxylic acid (1) in DMF (5 mL) (294 mg, 1.87 mmol) and EDC to a stirred solution of 3-(4-ethoxyphenyl)isoquinoline-1-carboxylic acid (1) (500 mg, 1.70 mmol) in DMF (5 mL). HCl (816 mg, 4.26 mmol), HOBt (345 mg, 2.55 mmol), and DIPEA (0.89 mL, 5.30 mmol) were added. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by column chromatography to give 3-(4-ethoxyphenyl)- N -(1,4-dioxaspiro[4.5]decane-8-yl)isoquinoline-1-carboxamide (LC-MS method A: R t =3.94 min; [M+H] + =432.9).

[0404] 3-(4-ethoxyphenyl)- N Synthesis of -(4-oxocyclohexyl)isoquinoline-1-carboxamide:

[0405] At 25℃, 3-(4-ethoxyphenyl)- N 1,4-Dioxaspiro[4.5]decane-8-yl)isoquinoline-1-carboxamide (100.0 mg, 0.23 mmol) was added to a stirred solution of THF:H2O (3 mL) with HCl (2N aqueous solution) (1.0 mL) and stirred at room temperature for 3 h. A saturated aqueous solution of NaHCO3 was added to the reaction mixture, which was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give 3-(4-ethoxyphenyl)- N -(4-oxocyclohexyl)isoquinoline-1-carboxamide (LC-MS method A: R) t =3.70 min; [M+H] + =389.1).

[0406] ( S )-3-(4-ethoxyphenyl)- N -(4-(3-hydroxypyrrolidin-1-yl)cyclohexyl)isoquinoline-1-carboxamide Synthesis of (Ia-51):

[0407] MgSO4 (37 mg, 0.306 mmol, 2.0 equivalent) and 3-(4-ethoxyphenyl)- N -(4-oxocyclohexyl)isoquinoline-1-carboxamide (60 mg, 0.153 mmol, 1.0 equivalent) was added to ( S The mixture was added to a DCE (3 mL) solution of pyrrolidine-3-ol (20 mg, 0.230 mmol, 1.5 equivalents) and triethylamine (46 mg, 0.459 mmol, 3.0 equivalents) and stirred for 1 hour under a N2 atmosphere. Tetramethylammonium triacetoxyborohydride (81 mg, 0.306 mmol, 2.0 equivalents) was added, and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered and evaporated. The crude compound was purified by preparative HPLC to give Ia-51, a mixture of cis and trans isomers.

[0408] Compound Ia-52, a mixture of cis and trans isomers, can be produced in a similar manner using 3-(4-ethoxyphenyl)- N -(4-oxocyclohexyl)isoquinoline-1-carboxamide and ( R 3-pyrrolidine-3-ol was used as a starting material for synthesis. The crude product was purified by preparative HPLC using RP (Table Ex5a). Other analogues can be obtained by using different carboxylic acids and different amines using the same method.

[0409] Table Ex5a:

[0410] Synthesis of 8-chloro-6-(4-ethoxyphenyl)isoquinoline (M-5-1):

[0411] In a dried, screw-capped 50 mL tube equipped with a magnetic stir bar, 6-bromo-8-chloroisoquinoline (M-4-1) (200 mg, 0.83 mmol), (4-ethoxyphenyl)boronic acid (179 mg, 1.08 mmol), and K3PO4 (352 mg, 1.66 mmol) were dissolved in 10 mL of dioxane:water (5:1). The reaction mixture was purged with N2 for 15 minutes. Under a nitrogen atmosphere, PdCl2(dtbpf) (54 mg, 0.08 mmol) was added to the reaction mixture. The reaction mixture was heated to 80 °C and stirred at that temperature for 5 h. 20 mL of ethyl acetate and 20 mL of water were added to the reaction mixture, and the phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by combi-flash column chromatography (using a 5% to 10% hexane solution of EtOAc) to give 8-chloro-6-(4-ethoxyphenyl)isoquinoline (M-5-1).

[0412] LC-MS (Method B): R t =3.17 min; Measured m / z: [M+H] + =284.1.

[0413] Synthesis of 6-(4-ethoxyphenyl)isoquinoline-8-carboxynitrile (M-6-1):

[0414] In a dried, sealed 50 mL tube equipped with a magnetic stir bar, 8-chloro-6-(4-ethoxyphenyl)isoquinoline (M-6-1) (390 mg, 1.37 mmol) and Zn(CN)₂ (403 mg, 3.43 mmol) were dissolved in 13 mL of anhydrous DMAc. The reaction mixture was purged with nitrogen for 15 minutes. Under a nitrogen atmosphere, Zn (90 mg, 1.37 mmol) and Pd(dppf)Cl₂ were added. For DCM, the reaction mixture was heated to 165 °C and stirred at this temperature for 16 h. 20 mL of ethyl acetate and 30 mL of water were added to the reaction mixture, and the phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice-cold brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by combi-flash chromatography (using a 15% to 20% hexane solution of EtOAc) to give 6-(4-ethoxyphenyl)isoquinoline-8-carboxynitrile (M-6-1).

[0415] LC-MS (Method C): R t =3.23 min. Measured m / z: [M+H] + =275.3.

[0416] Synthesis of 6-(4-ethoxyphenyl)isoquinoline-8-carboxylic acid (M-3b-1):

[0417] In a 100 mL round-bottom flask equipped with a magnetic stir bar, 6-(4-ethoxyphenyl)isoquinoline-8-carboxynitrile (M-6-1) (400 mg, 1.56 mmol) was added. A mixture of MeOH:H₂O (1:1, 15 mL) was added, followed by KOH (246 mg, 4.38 mmol). The reaction mixture was heated to reflux and stirred under reflux for 16 h. The solvent was removed under vacuum, and the residue was dissolved in 30 mL of water and washed with dichloromethane. The aqueous layer was cooled in an ice bath and acidified by adding 1 (N) HCl (pH approximately 5). The mixture was extracted with a mixture of 20% IPA and DCM solution. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 6-(4-ethoxyphenyl)isoquinoline-8-carboxylic acid (M-3b-1).

[0418] LCMS (Method B): R t =2.06 min. Measured m / z: [M+H] + =294.2.

[0419] Synthesis of 6-(4-ethoxyphenyl)-N-(3-morpholinopropyl)isoquinoline-8-carboxamide (Id-1):

[0420] In a dried 25 mL round-bottom flask equipped with a magnetic stir bar, 6-(4-ethoxyphenyl)isoquinoline-8-carboxylic acid (M-3b-1) (75 mg, 0.26 mmol, 1 equivalent) was dissolved in anhydrous DMF (10 mL / mmol) under a nitrogen atmosphere. HATU (0.65 mmol, 2.5 equivalent) was added in one step, followed by dropwise addition of DIPEA (1.3 mmol, 5 equivalent). The reaction mixture was stirred at room temperature for 5 minutes. 3-morpholinopropyl-1-aminoamine (0.39 mmol, 1.5 equivalent) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with a mixture of 10% MeOH in DCM (20 mL) and water (20 mL), and the phases were separated. The aqueous layer was extracted with 10% MeOH in DCM. The combined organic layers were washed with ice-cold brine, dried over sodium sulfate, concentrated, and purified by preparative HPLC to obtain [6-(4-ethoxyphenyl)-N-(3-morpholinopropyl)isoquinoline-8-carboxamide] (Id-1).

[0421] Other compounds, such as Id, can be obtained in a similar manner using intermediate M-3b and different amines B1 as raw materials (Table Ex6). If necessary, the crude product can be purified by chromatography.

[0422] Table Ex6:

[0423] Synthesis of 2-(4-ethoxyphenyl)-1,8-naphthidine-4-carboxylic acid (M-3c-1):

[0424] To a stirred solution of ethyl 2-[2-(2,2-dimethylpropamido)pyridin-3-yl]-2-oxoethyl acetate (M-3c-1) (550 mg, 1.98 mmol) in ethanol (16 mL) and water (4 mL), KOH (465 mg, 8.30 mmol) was added, and the reaction mixture was refluxed for 2 h. Then, 1-(4-ethoxyphenyl)ethyl-1-one (K-1-1) (681 mg, 4.15 mmol, 2.1 equivalents) was added, and the mixture was refluxed for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc. The aqueous layer was cooled in an ice bath, and the pH was adjusted to approximately 5 by carefully adding an aqueous solution of 2(N) HCl. The aqueous phase was extracted with a mixture of 10% MeOH and DCM solution. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give 2-(4-ethoxyphenyl)-1,8-naphthidine-4-carboxylic acid (M-3c-1).

[0425] LC-MS (Method B): R t =1.76 min. Measured m / z: [M+H] + =295.1.

[0426] Synthesis of methyl 2-(4-ethoxyphenyl)-1,6-naphthyl-4-carboxylic acid (M-3c-4):

[0427] KOH (483 mg, 8.63 mmol) was added to a stirred solution of ethyl 2-[4-(2,2-dimethylpropamido)pyridin-3-yl]-2-oxoethyl acetate (M-8b-1) (600 mg, 2.16 mmol) in EtOH:H₂O (4:1) (20 mL) and refluxed for 2 h. 1-(4-ethoxyphenyl)ethyl-1-one (K-1-1) (743 mg, 4.52 mmol) was added, and the reaction mixture was refluxed again for 16 h. The reaction mixture was concentrated under vacuum. Water was added, and the mixture was washed with EtOAc to separate the phases. The aqueous phase was acidified to pH 6 by adding 2N HCl aqueous solution at an ice bath temperature. The resulting precipitate was filtered and dried under vacuum to give 2-(4-ethoxyphenyl)-1,6-naphthyl-4-carboxylic acid (M-3c-4).

[0428] LC-MS (Method A): R t =2.48 min. Measured m / z: [M+H] + =295.3.

[0429] methyl 2-(4-ethoxyphenyl)- N -[3-(morpholino-4-yl)propyl]-1,6-naphthyl-4-carboxamide (Ic-1) synthesis:

[0430] DIPEA (0.18 mL, 1.02 mmol) was added to a DMF (3 mL) solution of 2-(4-ethoxyphenyl)-1,6-naphthyl-4-carboxylic acid (M-3c-4) (100 mg, 0.34 mmol). The mixture was cooled to 0 °C and EDC-HCl (131 g, 0.68 mmol), HOBt (51 mg, 0.37 mmol), and 3-morpholinopropane-1-amine (73 mg, 0.51 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by preparative HPLC to give 2-(4-ethoxyphenyl)- N -[3-(morpholino-4-yl)propyl]-1,6-naphthidine-4-carboxamide (Ic-1).

[0431] The other compound Ia can be obtained in a similar manner, using intermediate M-3c and different amines B-1 as starting materials. If necessary, the crude product is purified by chromatography (Table Ex7).

[0432] Table Ex7:

[0433] Synthesis of methyl 2-(4-ethoxyphenyl)-1,7-naphthidine-4-carboxylic acid (M-3c-5):

[0434] Ethyl 2-oxo-2-(3-neoptiamidopyridin-4-yl)ethyl acetate (M-8c-1) (0.7 g, 2.52 mmol) was dissolved in a 4:1 mixture of EtOH and water (28 mL). The reaction mixture was heated to reflux under a nitrogen atmosphere and stirred under reflux for 2 h. 1-(4-ethoxyphenyl)ethyl-1-one (K-1-1) (868 mg, 5.29 mmol, 2.1 equivalents) was added, and the solution was refluxed again for 24 h. The solvent was removed under vacuum, and the residue was dissolved in 30 mL of water and washed with CH2Cl2. The aqueous phase was acidified by adding 1N HCl aqueous solution and extracted with a mixture of 20% IPA and DCM solution. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 2-(4-ethoxyphenyl)-1,7-naphthyl-4-carboxylic acid (M-3c-5).

[0435] LC-MS (Method C): R t =2.45 min. Measured m / z: [M+H] + =295.3.

[0436] The other compound, M-3c, can be obtained in a similar manner, using intermediate M-8c and / or different amines B-1 as starting materials. If necessary, the crude product can be purified by chromatography.

[0437] 2-(4-ethoxyphenyl)- N Synthesis of [-(3-morpholinopropyl)-1,7-naphthyl-4-carboxamide] (If-1):

[0438] Under a nitrogen atmosphere, 2-(4-ethoxyphenyl)-1,7-naphthyl-4-carboxylic acid (M-3c-5) (110 mg, 0.375 mmol, 1 equivalent) was dissolved in anhydrous DMF (4 mL). HATU (356 mg, 0.938 mmol, 2.5 equivalent) was added in a single addition, followed by dropwise addition of DIPEA (646 mg, 1.875 mmol, 5 equivalent), and the reaction mixture was stirred at room temperature for 5 min. 3-morpholinopropyl-1-amine (81 mg, 0.563 mmol, 1.5 equivalent) was added, and the reaction mixture was heated to 60 °C and stirred at this temperature for 16 h. A mixture of 10% MeOH in DCM (20 mL) was added to the reaction mixture. The resulting organic phase was washed with water. The aqueous layer was extracted with a mixture of 10% MeOH in DCM. The combined organic layers were washed with ice-cold brine, dried over sodium sulfate, concentrated, and the residue was purified by preparative HPLC using RP to obtain [2-(4-ethoxyphenyl)- N [-(3-morpholinopropyl)-1,7-naphthyl-4-carboxamide] (If-1).

[0439] Other compounds, such as If, can be obtained in a similar manner, using intermediate M-3 and different amines B1 as raw materials. If necessary, the crude product is purified by chromatography (Table Ex8).

[0440] Table Ex8:

[0441] Synthesis of methyl 1-(4-ethoxybenzoyl)dihydroindole-2,3-dione (M-10-1):

[0442] A magnetic stir bar and indigo (M-9-1) (500 mg, 3.4 mmol) were placed in a dried 100 mL double-necked round-bottom flask. 7.5 mL of anhydrous pyridine was added under a nitrogen atmosphere, and the reaction mixture was cooled in an ice bath. 4-ethoxybenzoyl chloride (0.68 mL, 4.42 mmol) was added dropwise. After the addition was complete, the reaction mixture was slowly brought to room temperature and then heated to 60 °C. The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled (in an ice bath) and neutralized to pH approximately 7 by adding 1 N HCl aqueous solution. Water was added to the mixture to separate the phases, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated, and then azeotropically distilled with toluene to give 1-(4-ethoxybenzoyl)dihydroindole-2,3-dione (M-10-1), which was used in the next step without further purification.

[0443] The other intermediate M-10 can be obtained in a similar manner, using different intermediates M-9 and / or different acyl chlorides K-2 as raw materials. If necessary, the crude product is purified by chromatography (Table Ex9).

[0444] Table Ex9:

[0445] Synthesis of 2-(4-ethoxyphenyl)quinazolin-4-carboxylic acid (M-3d-1):

[0446] 1-(4-ethoxybenzoyl)dihydroindole-2,3-dione (M-10-1) (500 mg, 1.69 mmol) was added to a dried, sealed tube. Ammonium acetate (1.3 g, 16.93 mmol) was added, followed by anhydrous ethanol (5 mL). The reaction mixture was heated in a preheated oil bath at 100 °C with vigorous stirring for 16 h. The organic solvent was evaporated, and the solid residue was dissolved in water. The aqueous layer was acidified (pH approximately 5) by adding 1 N HCl aqueous solution under cooling (ice bath) and extracted with a mixture of 20% isopropanol and DCM solution. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated, and the residue was purified by combi-flash chromatography using 0–20% MeOH DCM solution as eluent to give 2-(4-ethoxyphenyl)quinazoline-4-carboxylic acid (M-3d-1).

[0447] The other compounds in Table M-3d can be obtained in a similar manner, using different intermediates M-10 as raw materials. If necessary, the crude products are purified by chromatography (Table Ex10).

[0448] Table Ex10:

[0449] 2-(4-ethoxyphenyl)- N Synthesis of -(3-morpholinopropyl)quinazoline-4-carboxamide (Ib-1):

[0450] Under a nitrogen atmosphere, 2.5 mL of HPLC-grade acetonitrile containing 70 mg (0.24 mmol) of 2-(4-ethoxyphenyl)quinazolin-4-carboxylic acid (M-3d-1) was added sequentially to the stirred solution of acetonitrile (2.5 mL) containing hexafluorophosphate. N , N , N , N '-Tetramethylformamidinium salt (666 mg, 2.37 mmol, 10 equivalents) and 3-morpholinopropyl-1-amine (0.087 mL, 0.59 mmol). DIPEA (0.83 mL, 4.75 mmol, 20 equivalents) was added dropwise, and the resulting reaction mixture was stirred at 65 °C for 16 h. The reaction mixture was partitioned between a mixture of 10% MeOH in DCM (30 mL) and water (30 mL). The aqueous fraction was extracted with the mixture or a 10% MeOH in DCM solution (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give 2-(4-ethoxyphenyl)- N -(3-morpholinopropyl)quinazoline-4-carboxamide (Ib-1).

[0451] Other compounds, such as Ib, can be obtained in a similar manner using different carboxylic acid derivatives M-3d and / or different amines B-1 as starting materials. If necessary, the crude product is purified by chromatography (Table Ex11).

[0452] Table Ex11:

[0453] Synthesis of NanoBRET probe (probe 1): 2-(4-ethoxyphenyl)- N -(4-(4-(6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexyl Synthesis of acyl)piperazine-1-yl)butyl)quinoline-4-carboxamide (probe 1):

[0454] To 2-(4-ethoxyphenyl)- N HATU (57 mg, 0.15 mmol, 1.5 equivalent) was added to an anhydrous DMF (3 mL) solution of (4-(piperazin-1-yl)butyl)quinoline-4-carboxamide·2HCl (51 mg, 0.1 mmol, 1 equivalent), 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexanoic acid (44 mg, 0.15 mmol, 1.5 equivalent), and DIPEA (51 mg, 4 equivalent). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (35 mL) and then washed twice with a saturated aqueous solution of NaHCO3 (35 mL). The organic layer was washed with brine (40 mL), separated in a funnel, dried over MgSO4, filtered, and the solvent was evaporated. The crude product was purified by normal-phase chromatography using a pre-packed Chromabond column (25 g silica gel) and a gradient eluent (EtOAc / MeOH (1% Et3N)) to obtain 2-(4-ethoxyphenyl)- N -(4-(4-(6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexanoyl)piperazin-1-yl)butyl)quinoline-4-carboxamide (probe 1). Measured m / z: [M+H] + =709.5 Rt=7.13 (LC-MS method J)

[0455] To a solution of 4-(4-(2-(4-ethoxyphenyl)quinoline-4-carboxamido)butyl)piperazine-1-carboxylic acid tert-butyl ester (93 mg, 0.17 mmol), 1 mL of HCl (4N, dioxane solution) was added to 10 mL of dichloromethane, and the reaction mixture was stirred for 3 h, resulting in the formation of a white precipitate. The reaction mixture was concentrated to a smaller volume, 10 mL of diethyl ether was added, the precipitate was filtered off, and dried under vacuum to give 2-(4-ethoxyphenyl)- N-(4-(piperazin-1-yl)butyl)quinoline-4-carboxamide·2HCl (51 mg, 0.1 mmol).

[0456]

[0457] 2-(4-ethoxyphenyl)- cooled to 0°C N To a solution of 182 mg (182 mg, 0.5 mmol, 1 equivalent) in 5 mL of anhydrous dichloromethane, a solution of methanesulfonyl chloride (80 mg, 0.7 mmol, 1.4 equivalent) in 1 mL of anhydrous dichloromethane was added, followed by a solution of triethylamine (101 mg, 1 mmol, 2 equivalents) in 1 mL of anhydrous dichloromethane. The reaction mixture was stirred at 0 °C for 2 h. After conversion, the reaction mixture was filtered and evaporated to obtain crude 4-(2-(4-ethoxyphenyl)quinoline-4-carboxamido)butylmethanesulfonate in quantitative yield. The crude product was dissolved in 10 mL of acetonitrile, and piperazine-1-carboxylic acid tert-butyl ester (558 mg, 3 mmol, 6 equivalents) was added in a single addition, followed by potassium carbonate (276 mg, 2 mmol, 4 equivalents). The reaction mixture was stirred at 60 °C for 18 h and evaporated to dryness. The residue was diluted with DCM (50 mL) and then washed with an aqueous solution of NaHCO3. Wash twice with 35 mL of water. Wash the organic layer with 40 mL of brine, separate in a funnel, dry over MgSO4, filter, and evaporate. Purify the crude product by normal-phase chromatography using a pre-packed Chromabond column (25 g silica gel) and a gradient eluent (EtOAc / MeOH (1% Et3N)) to give 4-(4-(2-(4-ethoxyphenyl)quinoline-4-carboxamido)butyl)piperazine-1-carboxylic acid tert-butyl ester (93 mg, 0.17 mmol), a brown oil.

[0458]

[0459] HATU (450 mg, 1.18 mmol, 1.18 equivalent) was added to an anhydrous DMF (7 mL) solution of 2-(4-ethoxyphenyl)quinoline-4-carboxylic acid (293 mg, 1 mmol, 1 equivalent), 4-aminobut-1-ol (120 mg, 1.35 mmol, 1.35 equivalent), and DIPEA (258 mg, 2 equivalent), and the reaction mixture was stirred at 20 °C for 18 hours. The reaction mixture was diluted with DCM (35 mL) and then washed twice with an aqueous solution of NaHCO3 (35 mL). The organic layer was washed with brine (40 mL), separated in a funnel, dried over MgSO4, filtered, and evaporated. The crude product was purified by normal-phase chromatography using a pre-packed Chromabond column (25 g silica gel) and a gradient eluent (EtOAc / MeOH (1% Et3N)) to obtain 2-(4-ethoxyphenyl)-N-(4-hydroxybutyl)quinoline-4-carboxamide (321 mg, 0.88 mmol), which was a grayish-white powder.

[0460] Biological data

[0461] Biological Example 1: TASL protein homeostasis was detected using the TASL-EmGFP-P2A-mCherry (TGC) reporter molecule.

[0462] The TGC reporter molecule construct encodes a C-terminal EmGFP-tagged TASL, which is then linked to a P2A self-cleaving peptide and mCherry (SEQ ID NO: 01), enabling both ORFs to be constitutively expressed from the same promoter. Measurement of the EmGFP to mCherry fluorescence ratio allows for monitoring of intracellular TASL-EmGFP levels via microscopic imaging.

[0463] By integrating the genome of a lentiviral construct carrying the TGC reporter molecule sequence and independently integrating the genome of a lentiviral construct carrying the HA-SLC15A4 sequence, 2kJ HEK-293T cells stably overexpressing the TGC reporter molecule and SLC15A4 (SEQ ID NO: 02) with an N-terminal HA tag were generated. Cells were seeded in 384-well plates (Perkin Elmer, cat. #8693-22361) pre-coated with poly-L-lysine (Sigma-Aldrich, cat. #P6282) in DMEM medium containing 10% FBS (Gibco #11965092, Fisher Scientific, cat. #11550356) and 1% Pen-Strep (Sigma-Aldrich, cat. #P4333). Immediately after seeding, the compounds were added at final concentrations of 4 μM and 14 μM using a Tecan D300e digital dispensing system. 1% DMSO was used as a negative control to normalize the data for each plate. Two independent biological replicates were set up for each compound, with each replicate containing three technical measurements. After incubation at 37°C and 5% CO2 for 48 h, Hoechst 33342 dye (Fisher Scientific, cat.#62249) was added to a final concentration of 5 μM. Each plate was centrifuged and then incubated at room temperature (RT) for 10 min. The culture medium was then removed, and 2% paraformaldehyde (PFA) was added to the cells. The plates were incubated again at room temperature for 20 min, and then washed twice with DuPont phosphate-buffered saline (PBS, Sigma-Aldrich, cat.#D8537). Finally, 30 μl of PBS was added to the wells, the plates were sealed, and stored at 4°C until imaging.

[0464] Microscopic images were acquired using Harmony 5.1 software (PerkinElmer / Revvity) on an Operetta CLS high-content analysis system with a 20× water immersion objective (1.0 NA). Exposure settings for the Hoechst, mCherry, and EmGFP channels were adjusted to avoid image saturation. Following acquisition, the images were analyzed using an analysis / segmentation workflow implemented in Harmony 5.1. This workflow included identifying cell nuclei using the Hoechst channel and identifying cytoplasmic regions using the EmGFP / mCherry channels. Total cellular fluorescence intensity values ​​for the EmGFP and mCherry channels were extracted from the cell population after excluding image artifacts and outliers (such as false-positive cells and cell debris). The average EmGFP / mCherry ratio for each field of view is shown in Table BiolEx-1. Figure 1 An example of a microscope image obtained using the measurement of Example Ic-8 is shown.

[0465] The assay in this embodiment allows for monitoring changes in TASL protein levels after compound treatment, where the active compound reduces the EmGFP / mCherry ratio (a ratio of 0 indicates that TASL protein is not detected).

[0466] Table BiolEx-1:

[0467] The ratios are defined in the following table, BiolEx-1: +++: EmGFP / mCherry ratio between 0 and 0.4 ++: EmGFP / mCherry ratio between 0.41 and 0.7 +: The EmGFP / mCherry ratio is between 0.71 and 0.99.

[0468] Biological Example 2: NanoBRET binding assay

[0469] Using Gibson cloning, the GGGGS adapter (SEQ ID NO: 04) was inserted directly downstream of T358 (located in the loop region E353-T363), followed by the insertion of the full-length NanoLuc sequence (SEQ ID NO: 03). Additionally, the N-terminal region (amino acids 2-29) containing the lysosome-targeting LL motif of SLC15A4 was deleted. The full sequence of this construct is shown in SEQ ID NO: 05. Stable HAP1 cell lines overexpressing SLC15A4 were generated using lentiviral transduction. The parental HAP1 cell lines were obtained from HorizonDiscovery #C669.

[0470] For NanoBRET measurements (Machleidt et al., NanoBRET - A Novel BRET Platform for the Analysis of Protein–Protein Interactions, ACS Chem. Biol., 2015), HAP1 cells overexpressing the above construct were seeded at 60 kC cells / well in 96-well plates (Corning #CLS3904). 100 ml of IMDM medium (Gibco #12440053) containing 10% FBS (Fisher Scientific, cat.#11550356) and 1% Pen-Strep (Sigma-Aldrich, cat.#P4333) was added to each well. The day after seeding, the IMDM medium was replaced with 30 μl of OPTIMEM (Thermo Fisher, 31985062) containing Vivazine (1:200 dilution, Promega, #N2581), and the test compounds were added at final concentrations of 3 μM and 12.5 μM, respectively. The control wells were treated with a solution containing the same final concentration of DMSO as the highest concentration compound treatment group. The plates were incubated at 37°C and 5% CO2 for 1 h, and then measurements were performed on a Tecan Spark instrument covering two spectral ranges: 450–475 nm (Nanoluc (“donor” emission) and 520–545 nm (NBD (“acceptor”, 4-nitro-7-aminobenzofuran) emission), this measurement being a “acceptor-free” reading. Then, probe 1 (for the synthesis and structure of the fluorescent acceptor, see the above section on the synthesis of NanoBRET probe (probe 1)) was added at a final concentration of 20 μM, and the plates were incubated at 37°C and 5% CO2 for 10 min. The plates were then measured again as described above: measurements were performed on a Tecan Spark instrument covering two spectral ranges: 450–475 nm (Nanoluc emission) and 520–545 nm (NBD emission), this measurement being a “acceptor-positive” reading.

[0471] NanoBRET arbitrary units are calculated by dividing the number of electrons emitted by NBD by the number of electrons emitted by Nanoluc. For normalization purposes, the NBD / Nluc ratio obtained from the "acceptorless" readout is subtracted from the NBD / Nluc ratio obtained from the "acceptor-equipped" readout. The result is multiplied by 1000 to obtain the value in milliBRET units (mBU).

[0472] BRET mBU = (NBD / Nanoluc) There are receptors - (NBD / Nanoluc) Receptorless

[0473] Since probe 1 binds to SLC15A4, an increase in probe 1 concentration leads to an increase in the BRET signal, such as... Figure 2 As shown.

[0474] For a given compound, the BRET mBU was normalized against the DMSO reading, yielding results shown in Table BiolEx-2 below. Compounds that cause a decrease in BRET signal replace the fluorescent receptor (probe 1), thus binding SLC15A4 in a conformation that prevents TASL binding. TASL is predicted to bind to SLC15A4 in an inward conformation (Custodio et al., Molecular basis of TASL recruitment by PHT1). Nature Communications (2023).

[0475] Table BiolEx-2:

[0476] The normalized BRET signal is defined in the following table (BiolEx-2): +++: Normalized BRET signal between 0 and 0.6 ++: The normalized BRET signal is between 0.61 and 0.8. +: The normalized BRET signal is between 0.81 and 0.99.

[0477] Biological Example 3: Enzyme-linked immunosorbent assay (ELISA)

[0478] Activation of IRF5 downstream of the SLC15A4 / TASL signaling complex leads to the production and secretion of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) (Heinz et al., 2020; Takaoka et al., 2005). Cytokine production can be monitored by ELISA (an assay familiar to technicians).

[0479] Peripheral blood mononuclear cells (PBMCs) from healthy human donors were purified from whole blood by density centrifugation (Ficoll-Paque, Fisher Scientific, cat. #11768538), washed twice with PBS (Sigma-Aldrich, cat. #D8537), and frozen in fetal bovine serum (FBS, Fisher Scientific, cat. #11550356) containing 10% DMSO (as cryoprotectant) for later use. For compound processing, PBMCs were thawed and counted in RPMI 1640 medium (Gibco cat. #12004997) containing 10% FBS. 100k PBMCs were seeded per well into 96-well clear or black plates (Corning Costar, Fisher Scientific, cat.#10687551; Corning Costar, Sigma Aldrich, cat.#CLS3904-100EA), and compounds were added in concentration gradients from 50μM to 0.6nM, with three technical replicates for each concentration. The plates were incubated at 37°C and 5% CO2 for 48 h. Twenty h before plate reading, cells were stimulated with 5μg / mL rescismod (R848, MedChem Express, cat.#HY-13740). At the end of the stimulation period, the plates were centrifuged at 250g for 5 min, the supernatant was collected, and IL-6 and TNFα cytokine levels were analyzed by ELISA (Invitrogen, cat.#88-7066-88 and 88-7346-88) according to the manufacturer's instructions.

[0480] Treatment of PBMCs with compounds that interfere with the SLC15A4 / TASL complex (thus disrupting the pathway that ultimately leads to IRF5 activation and cytokine production) is expected to result in reduced cytokine production. IL-6 data from the test examples are shown in Table BiolEx-3 below, and TNFα data are shown in Table BiolEx-4 below.

[0481] Table BiolEx-3:

[0482] The degree of IL-6 reduction is defined in the following table by BiolEx-3: +++: Normalized IL-6 concentrations were between 0 and 0.4 compared to DMSO treatment. ++: Normalized IL-6 concentrations were between 0.41 and 0.7 compared to DMSO treatment. +: Normalized IL-6 concentrations were between 0.71 and 0.99 compared to DMSO treatment.

[0483] Table BiolEx-4:

[0484] The degree of IL-6 reduction is defined in the following table by BiolEx-3: +++: Compared to DMSO treatment, the normalized TNFα concentration was between 0 and 0.4. ++: Normalized TNFα concentrations were between 0.41 and 0.7 compared to DMSO treatment. +: Normalized TNFα concentrations were between 0.71 and 0.99 compared to DMSO treatment.

[0485] In particular, the present invention relates to the following items: 1. A compound of formula (I) (I) Or its stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts or solvates, wherein: R 1 For one or more R S1 Substituted phenyl; Each R S1 Independently selected from -Hal, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cycloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -NH-CO(C 1-6 Alkyl); or two R S1 Together they form fused heterocyclic alkyl or heteroaryl moieties; A is selected from the following: and ; In each case, the wavy line marks the connection to the rest of the molecule; And among them: R 2 C 2-4 Alkylene or C6 cycloalkylene, each optionally surrounded by one or more R S2 replace; Each R S2 Independently selected from -OH, -F, and -CH3; or two R S2 Together they form = O; Each R 3 Independently selected from -H, C 1-5 Alkyl, -(C 0-3 alkylene)-cycloalkyl, -(C 0-3alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 (alkylene)-heteroaryl, each optionally bound by one or more R S3 Replacement; the condition is two Rs 3 Not both -H; Or these two Rs 3 Together with the nitrogen atoms to which they are attached, they form a heterocyclic alkyl ring, which is optionally bounded by one or more R atoms. S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-NH(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 Alkyl), -O (C1-6 alkyl), -O (C 1-6 Halogenated alkyl), -(C 1-6 alkylene)-O(C 1-6 alkyl), -S(C 1-6 alkyl), -S(C1-6 haloalkyl), -(C 1-6 alkylene)-S(C 1-6 Alkyl), -COH, -CO(C 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -COOH, -COO (C 1-6 Alkyl), -CO-NH2, -CO-NH (C1-6 alkyl), -CO-N (C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO(C 1-6 Alkyl), -S(O)2-(C 1-6 Alkyl), -S(O)2-NH2, -S(O)2-NH(C 1-6 Alkyl), -S(O)2-N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -N(C)1-6 alkyl)-S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in (alkylene)-heterocyclic alkyl, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 The heteroaryl moiety in the (alkylene)-heteroaryl group is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Haloalkyl, -O(C) 1-2 alkyl) and -O(C 1-2 (halogenated alkyl); Or two R atoms bonded to the same carbon atom S3 Formation = O; or if connected by two R 3 On the heterocyclic alkyl ring formed together with the nitrogen atoms they are attached to, there are two R... S3 Together with the two adjacent atoms to which they are attached, they form a fused heteroaryl ring; R 4 Does not exist or is C 1-4 Alkylene; R 5 -Hal, -OH, C 1-6 Alkyl or -O(C) 1-6 alkyl); R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-O(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl or -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in (alkylene)-heterocyclic alkyl, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 The heteroaryl moiety in the (alkylene)-heteroaryl group is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups); X 1 For CH or N; X 2 For CH or N; Y 1 For CR Y1 Or N; Y 2 For CR Y2 Or N; Y 3 For CR Y3 Or N; Y 4 For CR Y4 Or N; Among them, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6 alkyl); The condition is if X 1 and X 2If both are CH, then Y 1 Y 2 Y 3 and Y 4 At least one of them is N; and The condition is if X 2 If N, then X 1 Y 1 Y 2 Y 3 and Y 4 One of them is also N; and The condition is X 1 X 2 Y 1 Y 2 Y 3 and Y 4 No more than two of them are N.

[0486] 2. The compound according to Project 1, wherein the compound of formula (I) is a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), or (If). (Ia) (Ib) (Ic), (Id) (Ie) (If); Preferred formula (Ia) ), (Ib ), (Ic ), (Id ), (Ie ) or (If ) compounds (Ia ), (Ib ), (Ic ), (Id ), (Ie ), (If ).

[0487] 3. The compound according to item 1 or 2, wherein the compound of formula (I) is of formula (Ia) ), (Ib ) or (Ic ) compounds (Ia ), (Ib ), (Ic ).

[0488] 4. The compound according to any one of items 1 to 3, wherein the compound of formula (I) is of formula (Ia) ) compounds (Ia ).

[0489] 5. The compound according to any one of items 1 to 3, wherein the compound of formula (I) is of formula (Ib) ) compounds (Ib ).

[0490] 6. The compound according to any one of items 1 to 3, wherein the compound of formula (I) is of formula (Ic) ) compounds (Ic ).

[0491] 7. The compound according to any one of items 1 to 6, wherein R 1 For -O(C 1-6 Alkyl-substituted phenyl groups.

[0492] 8. The compound according to any one of items 1 to 7, wherein R 1 It is 4-ethoxyphenyl.

[0493] 9. The compound according to any one of items 1 to 8, wherein portion A is , in R 2 It is a C2-alkylene or C3-alkylene.

[0494] 10. The compound according to any one of items 1 to 9, wherein portion A is , in Each R 3 Independently selected from -H, C 1-5 Alkyl, -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C0-3 (alkylene)-heteroaryl, each optionally bound by one or more R S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C1-6 alkyl)(C 1-6 Alkyl), C1-6 alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -O(C 1-6 Alkyl), -(C1-6 alkylene)-O-(C 1-6 alkyl), -CO(C) 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -CO-NH2, -CO-NH (C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO(C 1-6 Alkyl), -S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in (alkylene)-heterocyclic alkyl, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 The heteroaryl moiety in the (alkylene)-heteroaryl group is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups); Or two R atoms bonded to the same carbon atom S3 Formation = O.

[0495] 11. The compound according to any one of items 1 to 9, wherein portion A is , in These two Rs 3 Together with the nitrogen atoms to which they are attached, they form a heterocyclic alkyl ring, which is optionally bounded by one or more R atoms. S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C1-6 alkyl)(C 1-6 Alkyl), C1-6 alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -O(C 1-6 Alkyl), -(C1-6 alkylene)-O-(C 1-6 alkyl), -CO(C) 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -CO-NH2, -CO-NH (C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-CO(C 1-6 Alkyl), -S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in (alkylene)-heterocyclic alkyl, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 The heteroaryl moiety in the (alkylene)-heteroaryl group is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups); Or two R atoms bonded to the same carbon atom S3 Formation = O; or two Rs S3 Together with the two adjacent atoms to which they are attached, they form a fused heteroaryl ring.

[0496] 12. The compound according to any one of items 1 to 8, wherein portion A is .

[0497] 13. A compound according to any one of items 1 to 12, wherein the compound is a compound selected from the group consisting of, or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof: , , , , , , , , , , , , , , , , , , , , .

[0498] 14. A pharmaceutical composition comprising a compound according to any one of items 1 to 13 and at least one pharmaceutically acceptable carrier.

[0499] 15. The compound according to any one of items 1 to 13 or the pharmaceutical composition according to item 14, wherein the compound or the pharmaceutical composition is used as a medicine.

[0500] 16. The compound according to any one of items 1 to 13 or the pharmaceutical composition according to item 14, said compound or said pharmaceutical composition for the treatment or prevention of autoimmune diseases or inflammatory conditions.

[0501] 17. The compound or pharmaceutical composition for the use according to item 16, wherein the autoimmune condition is selected from systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjögren's syndrome, polymyositis / dermatomyositis, primary biliary cirrhosis, multiple sclerosis, oral ulcers, periodontitis, Behcet's disease, myasthenia gravis, and ankylosing spondylitis, preferably wherein the autoimmune condition is systemic lupus erythematosus, or wherein the inflammatory condition is selected from inflammatory bowel disease, psoriatic dermatitis, endosomal TLR-dependent inflammation, ulcerative colitis, Crohn's disease, endosomal TLR-induced hyperinflammatory, macrophage activation syndrome, allergic airway inflammation, and sarcoidosis, preferably wherein the inflammatory condition is selected from inflammatory bowel disease, psoriatic dermatitis, and endosomal TLR-dependent inflammation.

[0502] 18. The compound or pharmaceutical composition for the purpose according to item 16 or 17, wherein the autoimmune condition is a condition related to the SLC15 peptide transporter, and / or wherein the compound or pharmaceutical composition inhibits the SLC15 peptide transporter.

Claims

1. A compound of formula (I) (I) Or its stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts or solvates, wherein: R 1 For one or more R S1 Substituted phenyl; Each R S1 Independently selected from -Hal, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cycloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -NH-CO (C 1-6 Alkyl); or two R S1 Together they form fused heterocyclic alkyl or heteroaryl moieties; A is selected from the following: and ; In each case, the wavy line marks the connection to the rest of the molecule; And among them: R 2 C 2-4 Alkylene or C6 cycloalkylene, each optionally surrounded by one or more R S2 replace; Each R S2 Independently selected from -OH, -F, and -CH3; or two R S2 Together they form = O; Each R 3 Independently selected from -H, C 1-5 Alkyl, -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 (alkylene)-heteroaryl, each optionally surrounded by one or more R S3 Replacement; the condition is two Rs 3 Not both -H; Or these two Rs 3 Together with the nitrogen atoms to which they are attached, they form a heterocyclic alkyl ring, which is optionally bounded by one or more R atoms. S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-NH(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 Alkyl), -O (C1-6 alkyl), -O (C 1-6 Halogenated alkyl), -(C 1-6 alkylene)-O(C 1-6 alkyl), -S(C 1-6 alkyl), -S(C1-6 haloalkyl), -(C 1-6 alkylene)-S(C 1-6 Alkyl), -COH, -CO(C 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -COOH, -COO (C 1-6 Alkyl), -CO-NH2, -CO-NH (C1-6 alkyl), -CO-N (C 1-6 Alkyl)(C 1-6 Alkyl), -NH-CO(C 1-6 alkyl), -N(C) 1-6 alkyl)-CO(C 1-6 Alkyl), -S(O)2-(C 1-6 Alkyl), -S(O)2-NH2, -S(O)2-NH(C 1-6 Alkyl), -S(O)2-N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH-S(O)2-(C 1-6 alkyl), -N(C) 1-6 alkyl)-S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in (alkylene)-heterocyclic alkyl, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 The heteroaryl moiety in the (alkylene)-heteroaryl group is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Haloalkyl, -O(C) 1-2 alkyl) and -O(C 1-2 (halogenated alkyl); Or two R atoms bonded to the same carbon atom S3 Formation = O; or if connected by two R 3 On the heterocyclic alkyl ring formed together with the nitrogen atoms they are attached to, there are two R... S3 Together with the two adjacent atoms to which they are attached, they form a fused heteroaryl ring; R 4 Does not exist or is C 1-4 Alkylene; R 5 -H, -Hal, -OH, C 1-6 Alkyl or -O(C) 1-6 alkyl); R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-O(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 -(C0-3 alkylene)-heterocyclic alkyl, -(C0-3 alkylene)-aryl or -(C0-3 alkylene)-aryl 0-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in (alkylene)-heterocyclic alkyl, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 The heteroaryl moiety in the (alkylene)-heteroaryl group is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups); X 1 For CH or N; X 2 For CH or N; Y 1 For CR Y1 Or N; Y 2 For CR Y2 Or N; Y 3 For CR Y3 Or N; Y 4 For CR Y4 Or N; Among them, R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6 alkyl); The condition is if X 1 and X 2 If both are CH, then Y 1 Y 2 Y 3 and Y 4 At least one of them is N; and The condition is if X 2 If N, then X 1 Y 1 Y 2 Y 3 and Y 4 One of them is also N; and The condition is X 1 X 2 Y 1 Y 2 Y 3 and Y 4 No more than two of them are N.

2. The compound according to claim 1, wherein R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6 alkyl).

3. The compound according to claim 1 or 2, wherein the compound of formula (I) is a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), or (If). (Ia)、 (Ib)、 (Ic)、 (Id)、 (Ie)、 (If); Preferred formula (Ia) ), (Ib ), (Ic ), (Id ), (Ie ) or (If ) compounds (Ia )、 (Ib )、 (Ic )、 (Id )、 (Ie )、 (If )。 4. The compound according to any one of claims 1 to 3, wherein the compound of formula (I) is a compound of formula (Ia), (Ib), (Ic), (Id), or (Ie). (Ia)、 (Ib)、 (Ic)、 (Id)、 (Ie).

5. The compound according to any one of claims 1 to 4, wherein the compound of formula (I) is a compound of formula (Ia), (Ib), (Ic), (Id), or (Ie). (Ia)、 (Ib)、 (Ic)、 (Id)、 (Ie); Where R Y1 R Y2 R Y3 and R Y4 Each is independently selected from -H, -CN, -Hal, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl) and -(C 1-6 alkylene)-O(C 1-6 alkyl).

6. The compound according to any one of claims 1 to 5, wherein the compound of formula (I) is a compound of formula (Ia), (Ib) or (Ic). (Ia)、 (Ib)、 (Ic)。 7. The compound according to any one of claims 1 to 6, wherein the compound of formula (I) is of formula (Ia) ), (Ib ) or (Ic ) compounds (Ia )、 (Ib )、 (Ic )。 8. The compound according to any one of claims 1 to 7, wherein the compound of formula (I) is of formula (Ia) ) compounds (It )。 9. The compound according to any one of claims 1 to 7, wherein the compound of formula (I) is of formula (Ib) ) compounds (One ).

10. The compound according to any one of claims 1 to 7, wherein the compound of formula (I) is of formula (Ic) ) compounds (Ic )。 11. The compound according to any one of claims 1 to 10, wherein R 1 It is a phenyl group substituted with -O (C1-6 alkyl).

12. The compound according to any one of claims 1 to 11, wherein R 1 It is 4-ethoxyphenyl.

13. The compound according to any one of claims 1 to 12, wherein the A portion is ， in R 2 It is a C2-alkylene or C3-alkylene.

14. The compound according to any one of claims 1 to 13, wherein the A portion is ， in Each R 3 Independently selected from -H, C 1-5 Alkyl, -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 (alkylene)-heteroaryl, each optionally surrounded by one or more R S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, -NH(C 1-6 alkyl), -N(C1-6 alkyl)(C 1-6 Alkyl), C1-6 alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -O(C 1-6 Alkyl), -(C1-6 alkylene)-O-(C 1-6 alkyl), -CO(C) 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -CO-NH2, -CO-NH (C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH-CO(C 1-6 Alkyl), -S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(CO-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in (alkylene)-heterocyclic alkyl, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 The heteroaryl moiety in the (alkylene)-heteroaryl group is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups); Or two R atoms bonded to the same carbon atom S3 Formation = O.

15. The compound according to any one of claims 1 to 13, wherein portion A is ， in These two Rs 3 Together with the nitrogen atoms to which they are attached, they form a heterocyclic alkyl ring, which is optionally bounded by one or more R atoms. S3 replace; Each R S3 Independently selected from -CN, -Hal, -OH, -NH2, -NH(C 1-6 alkyl), -N(C1-6 alkyl)(C 1-6 Alkyl), C1-6 alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-OH, -O(C 1-6 Alkyl), -(C1-6 alkylene)-O-(C 1-6 alkyl), -CO(C) 1-6 Alkyl), -CO (cycloalkyl), -CO (heterocyclic alkyl), -CO-NH2, -CO-NH (C 1-6 Alkyl), -CO-N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH-CO(C 1-6 Alkyl), -S(O)2-(C 1-6 alkyl), -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(CO-3 alkylene)-heteroaryl, wherein in the -(C 0-3 alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocyclic alkyl, -(C 0-3 alkylene)-aryl and -(C 0-3 In the alkylene moiety of (alkylene)-heteroaryl, if a -CH2- group is present, the group is optionally replaced by -O-, and wherein the -(C 0-3 The cycloalkyl moiety in (alkylene)-cycloalkyl, the -(C 0-3 The heterocyclic alkyl moiety in (alkylene)-heterocyclic alkyl, the -(C 0-3 The aryl moiety in the alkylene-aryl group and the -(C 0-3 The heteroaryl moiety in the (alkylene)-heteroaryl group is optionally substituted by one or more groups, each of which is independently selected from -Hal, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -O (C1-2 alkyl groups); Or two R atoms bonded to the same carbon atom S3 Formation = O; or two Rs S3 Together with the two adjacent atoms to which they are attached, they form a fused heteroaryl ring.

16. The compound according to any one of claims 1 to 12, wherein the A portion is 。 17. The compound according to any one of claims 1 to 16, wherein the compound is a compound selected from the group consisting of, or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 18. The compound according to any one of claims 1 to 16, wherein the compound is a compound selected from the group consisting of, or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof: 、 、 、 、 、 、 、 、 、 。 19. The compound according to any one of claims 1 to 16, wherein the compound is a compound selected from the group consisting of, or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof: 、 、 、 、 、 、 、 、 、 、 、 、 、 。 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and at least one pharmaceutically acceptable carrier.

21. The compound according to any one of claims 1 to 19 or the pharmaceutical composition according to claim 20, wherein the compound or the pharmaceutical composition is used as a drug.

22. The compound according to any one of claims 1 to 19 or the pharmaceutical composition according to claim 20, wherein the compound or the pharmaceutical composition is used to treat or prevent autoimmune diseases or inflammatory conditions.

23. The compound or pharmaceutical composition for the use according to claim 22, wherein the autoimmune condition is selected from systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjögren's syndrome, polymyositis / dermatomyositis, primary biliary cirrhosis, multiple sclerosis, oral ulcers, periodontitis, Behcet's disease, myasthenia gravis, and ankylosing spondylitis, preferably wherein the autoimmune condition is systemic lupus erythematosus, or wherein the inflammatory condition is selected from inflammatory bowel disease, psoriatic dermatitis, endosomal TLR-dependent inflammation, ulcerative colitis, Crohn's disease, endosomal TLR-induced hyperinflammatory, macrophage activation syndrome, allergic airway inflammation, and sarcoidosis, preferably wherein the inflammatory condition is selected from inflammatory bowel disease, psoriatic dermatitis, and endosomal TLR-dependent inflammation.

24. The compound or pharmaceutical composition for the purpose according to any one of claims 21 to 23, wherein the autoimmune condition is a condition related to the SLC15 peptide transporter, and / or wherein the compound or pharmaceutical composition inhibits SLC15 peptide transporter-TASL assembly.

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