New heterocyclic compounds reducing the TASL protein level

Abstract

The present invention relates 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 use in treatment or prevention of an autoimmune disorder or inflammatory condition. The compound of formula (I) has been demonstrated to reduce the TASL protein level.

Description

[0001] New heterocyclic compounds reducing the TASL protein level

[0002] Field of the Invention

[0003] The present invention relates a compound of formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof. The present invention further relates to a pharmaceutical composition comprising the compound of formula (l)and at leastone pharmaceutically acceptable carrier. The compounds of formula (I) are useful as medicaments, for use in treatment or prevention of an autoimmune disorder or inflammatory condition, in particular an autoimmune disorder being systemic lupus erythematosus, or an inflammatory condition selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-dependent inflammation. Preferably, the autoimmune disorder to be treated with the compound of form ula (I) is a disorder associated with SLC15 peptide transporter. The compound of formula (I) has been demonstrated to reduce the TASL protein level.

[0004] Background of the Invention

[0005] Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoim- mune and inflammatory disorders. Recognition of pathogen-derived nucleic acids by pattern recognition receptors is essential to mount protective innate immune responses (E. Bartok, G. Hartmann, Immune Sensing Mechanisms that Discriminate Self from Altered Self and Foreign Nucleic Acids. Immunity 53, 54-77 (2020); A. Ablasser, Z. J. Chen, cGAS in action: Expanding roles in immunity and inflammation. Science 363, (2019); N. A. Lind, V. E. Rael, K. Pestal, B. Liu, G. M. Barton, Regulation of the nucleic acid -sensing Toll-like receptors. Nat Rev Immunol 22, 224-235 (2022)). Despite tight regulatory mechanisms, aberrant activation of these pathways by endogenous ligands or muta- tions in key regulatory components lead to excessive responses that are causatively linked to several 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 269, 60-75 (2016); Y. J. Crow, D. B. Stetson, The type I interferonopathies: 10 years on. Nat Rev Immunol 22, 471 -483 (2022)). In particular, sensing of nucleic acids by en- dolysosomal TLRs is thoughtto have a critical role in the pathogenesis of systemic lupus erythematosus (SLE) and related autoimmune diseases as well as inflammatory disorders (G. J. Brown et al., TLR7 gain -of -function genetic variation causes human lupus. Nature 605, 349-356 (2022); S. Fillatreau, B. Manfroi, T. Domer, Toll-like receptor sig- nalling in B cells during systemic lupus erythematosus. Nat Rev Rheumatol 17, 98-108 (2021 ); G. C. Tsokos, M. S. Lo, P. Costa Reis, K. E. Sullivan, New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol 12, 716-730 (2016)). Both human genetic and mouse studies have unequivocally identified the lyso- somal solute carrier SLC15A4 and transcription factor IRF5 as components essential for mediating disease develop- ment downstream of TLRs (T. Ban, G. R. Sato, T. Tamura, Regulation and role of the transcription factor IRF5 in in- nate immune responsesand systemic lupus erythematosus. Int Immunol 30, 529-536 (2018); J. Bentham et al., Ge- netic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet 47, 1457-1464 (2015); A. L. Blasius et al., Slc15a4, AP-3, and Herman- sky-Pudlaksyndrome proteins are required for Toll-like receptorsignaling in plasmacytoid dendritic cells (pDC). Proc Natl Acad Sci U S A 107, 19973-19978 (2010); T. Kobayashi et al., The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity 41 , 375-388 (2014); R. R. Graham et al., A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet 38, 550-555 (2006); A. Katewa et al., The peptide sym porter SLC15a4 is essential for the development of systemic lupus erythematosus in murine models. PLoS One 16, e0244439 (2021 ); H . Alm uttaqi, I. A. Udalova, Advances and challenges in targeting IRF5, a key regu- lator of inflammation. FEBS J 286, 1624-1637 (2019); S. Song et al., Inhibition of IRF5 hyperactivation protects from lupus onset and severity. J Clin Invest 130, 6700-6717 (2020); T. Ban et al., Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease. Nat Commun 12, 4379 (2021 ), Z. Wang et al., An autoimmune pleiotropicSNP modulates IRF5 alternative promoter usage through ZBTB3 -mediated chromatin looping. Nat Com- mun 14, 3430 (2023)). TASL, encoded by an SLE-associated gene previously known as CXorf21 , is a SLC15A4 in- teractor essential for IRF5 activation (Bentham et al., 2015; L. X. Heinz et al., TASL is the SLC15A4 -associated adaptor for IRF5 activation by TLR7-9. Nature 581 , 316-322 (2020); C. A. Odhams et al., Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in System ic Lupus Erythematosus. Nat Commun 10, 2164 (2019), Zhang et al, SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL. Nat Commun 42(8), 1 12916 (2023)). Through a C-terminal pLxlS motif, TASL acts as signaling adaptor medi- ating recruitment of IRF5, in analogy to the key immune adaptors MAVS, STING and TRIF for IRF3 (Heinz et al., 2020; S. Liu et al., Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activa- tion. Science 347, aaa2630 (2015)). Thus, TASL represents the a central element in a pathway in which each compo- nent is associated with autoimmune disorders, in particularSLE, providing an unusually strong case and rationale for therapeutic intervention. Interfering with SLC15A4-TASL complex formation has been shown to abolish TLR-induced IRF5 activation, suggesting that this pathway can be targeted with high specificity in order to treat diseases linked thereto.

[0006] Here we describe the identification of compounds, which interfere with the signaling from TLR (in particular TLR7 / 8) to IRF5, and as a result, interfere with IRF5 activation. More specifically, these compounds interfere with the assem- bly of the SLC15A4-TASL module, leading to efficient degradation of TASL and ablation of IRF5 activation. Conse- quently, these compounds block endolysosomal TLR-induced responses in disease-relevant human immune cells.

[0007] Objects and Summary of the Invention

[0008] The present inventors have demonstrated that targeting of an endolysosomal signaling complex by a compound inhibits a disease- (in particular an SLE-) associated proinflammatory pathway. The present inventors have found that chemical intervention with the compound of formula (I) leads to efficient degradation of TASL. Without wishing to be bound by theory, the present inventors have demonstrated that TASL is regulated by proteostatic interaction with SLC15A4. Accordingly, interfering with complex formation alone has been shown to lead to efficient degradation of TASL. Accordingly, the present invention is based at least in part on the discovery that exploiting this property may be advantageous for chemical targeting of TASL.

[0009] Accordingly, the present invention provides a SLC15A4 binder, which disrupts the SLC15A4-TASL complex, thus interfering with TASL levels and as a consequence interfering with IRF5 activation.

[0010] The invention will be summarized in the following embodiments. In a first embodiment, the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, wherein:

[0011] R1is thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or phenyl, each optionally substituted with one or more RS1; wherein each RS1is independently selected from -Hal, C1-6 alkyl, C1-6 haloalkyl, -cycloalkyl, O(C1-6 alkyl), and -O(C1-6 haloalkyl);

[0012] R2is H; is a moiety selected from wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein

[0013] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2; and

[0014] L2is wherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, (C1-6 alkylene)OH, -OH, O( C1-2 alkyl), or -O( C1-2 haloal- kyi); and wherein

[0015] RL1is absent or C1-2 alkylene;

[0016] R12is absent or C1-2 alkylene;

[0017] R13is absent or C1-2 alkylene; and wherein each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, and -(C2-3 alkylene)-O-heteroaryl, each optionally substituted with one or more RS3; pro- vided that not both R3are -H; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), N(C1-6 al kyl)(C1-6 alkyl), C1-6 alkyl, C1-6 haloalkyl, (C1-6 alkylene)CN, (C1-6 alkylene)OH, (C1-6 alkylene)NH(C1-6 alkyl), (C1-6 alkylene)N(C1-6 al- kyl )(C1-6 alkyl), O(Cie alkyl), O(C1-6 haloalkyl), (C1-6 alkylene)O(C1-6alkyl), (C1-6 alkylene)S(C1-6alkyl), -CO(C1-6 alkyl), CO(cycloalkyl), CO(heterocycloalkyl), -COOH, -COO(C1-6 alkyl), CONH2, CONH(C16 alkyl), -CO-N(C1-6 alkyl)(C1-6 al- kyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), S(O)2-(C1-6 alkyl), S(O)2-NH2, S(O)2-NH(C1-6 alkyl), S(O)2-N(CI-6 alkyl)(C1-6 alkyl), NH-S(0)2-(C1-6 alkyl), N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(Co-3alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(Co-3alkylene)-heterocycloalkyl, -(C0-3 alkylene)-aryl, and (C0-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -O-, and wherein the cycloalkyl moiety in said -(Co- 3 alkylene)- cycloalkyl. the heterocycloalkyl moiety in said -(Co-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(C0-3 alkylene)- aryl, and the heteroaryl moiety in said -(C0-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, O(C1-2 alkyl), and O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a heterocycloalkyl ring formed by two R3to- gether with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused heteroaryl ring; and wherein

[0018] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6alkyl), -(C2-6 alkylene)-N(C1-6 al- kyl)(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 al- kylene)-O-heterocycloalkyl, (C13 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, or -(C2-3 alkylene)- O-heteroaryl, wherein in said alkylene moiety of said (C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C1-3 alkylene)-aryl, and (C1-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by CHOH-, or -CH(CH2OH)-, and wherein the cycloalkyl moiety in said -(Co- 3 alkylene)-cycloalkyl or -(C2-3 alkylene)-O-cycloalkyl, the heterocycloalkyl moiety in said (Co-3 alkylene)-heterocycloalkyl or-(C2-3alkylene)-O-heterocycloalkyl, the aryl moi- ety in said -(C1-3 alkylene)-aryl or(C23 alkylene)-O-aryl, and the heteroaryl moiety in said -(C1-3 alkylene)-heteroaryl or -(C2-3 alkylene)-O-heteroaryl, are each optionally substituted with one or more groups each independently selected from -Hal, Ci.2alkyl, C1-2 haloalkyl, and O( C1-2 alkyl);

[0019] X1is CH or N;

[0020] X2is CH or N;

[0021] Y1is CRY1or N;

[0022] Y2is CRY2or N;

[0023] Y3is CRY3or N; and

[0024] Y4is CRY4or N; wherein RY1, RYZ, RY3, and RY4are each independently selected from H, CN, Hal, OH, C1-6 alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), O(C1-6haloalkyl), and (C1-6 alkylene)-O(C1-6 alkyl); provided that if X1and X2are both CH, at least one of Y1, Y2, Y3, and Y4is N; and provided that not more than three of X1, X2, Y1, Y2, Y3, and Y4are N; and provided that if A is

[0025] R13is absent,

[0026] R4is H, and

[0027] X2is N, then one of X1, Y1, Y2, Y3, and Y4is also N.

[0028] In a preferred embodiment, R1is wherein the dashed line marks the connection to the remainder of the molecule.

[0029] In a preferred embodiment, RS1is -Hal, Cvs alkyl or O(C1-6 alkyl).

[0030] In a more preferred embodiment, R1is 4-ethoxyphenyl, 6-ethoxypyridin-3-yl, 5-ethoxypyridin-2-yl, or5-fluoropyridin-2- yi.

[0031] In another preferred embodiment, R1is wherein the dashed line marks the connection to the remainder of the molecule.

[0032] In another preferred embodiment, RS1is C1-6 alkyl or -O(C1-6 alkyl).

[0033] In another more preferred embodiment, R1is 4-ethoxyphenyl.

[0034] In a preferred embodiment,

[0035] X1is CH or N;

[0036] X2is CH or N;

[0037] Y1is CRY1or N;

[0038] Y2is CRY2or N;

[0039] Y3is CRY3or N; and

[0040] Y4is CRY4or N; wherein at least one of Y1, Y2, Y3, and Y4does not represent N or CH; and wherein RY1, RYZ, RY3, and RY4are each independently selected from -H, -CN, -Hal, C1-6 alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl).

[0041] In a more preferred embodiment, the compound of formula (I) is a compound of formula (la), (lb), (Ic), or (Id):

[0042] In a more preferred embodiment,

[0043] RY1is -H;

[0044] RY2is -H, -Cl, or -F;

[0045] RY3is -H, -Cl, or -F; and

[0046] RY4is -H, -Cl, or -F.

[0047] In a preferred embodiment, A is

[0048] R3

[0049] R3. wherein the wavy line marks the connection to the remainder of the molecule; and wherein

[0050] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -0(0-2 alkyl), or -O(C1-2 haloalkyl); and wherein

[0051] RL1is absent; and

[0052] R1-2is absent or Ci alkylene; and wherein each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, and -(C2-3 alkylene)-O-heteroaryl, each optionally substituted with one or more RS3; pro- vided that not both R3are -H; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-CN, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl),

[0053] -(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkyl), -O(C1-6 alkyl), -O(C1-6 haloalkyl), -(C1-6 alkylene)-O(C1-6 alkyl), -(C1-6 al- kylene)-S(C1-6 alkyl), - -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COO(C1-6 al- kyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(Ci-Salkyl), -N(CI-Balkyl)-CO(C1-6 al- kyl), -S(O)2-(C1-6 alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)(C1-6 alkyl), -NH-S(O)2-(C1-6 al- kyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)- heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -O-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(Co-3 alkylene)-aryl, and the heteroaryl moiety in said -(C0-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, -O(C1-2 alkyl), and -O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a heterocycloalkyl ring formed by two R3to- gether with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused heteroaryl ring.

[0054] In a preferred embodiment, each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-(3-to 7-membered cycloalkyl), -(C2-3 alkylene)- O-(3- to 7-membered cycloalkyl), -(Co-3 alkylene)-( 3- to 7-membered heterocycloalkyl), -(C2-3 alkylene)-O-(3- to 7- membered heterocycloalkyl), -(C1-3 alkylene)-phenyl, -(C2-3 alkylene)-O-phenyl, -(C1-3 alkylene)-(5- or 6-membered heteroaryl), and -(C2-3 alkylene)-O-(5- or 6-membered heteroaryl), each optionally substituted with one or more RS3, wherein the aforementioned heterocycloalkyl and heteroaryl rings independently comprise one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non -oxi- dized; provided that not both R3are -H; or the two R3together with the nitrogen atom to which they are attached form a 3 - to 7-membered heterocycloalkyl ring, optionally substituted with one or more RS3, and optionally comprising in addition to the nitrogen atom one or more, same or different heteroatoms selected from O, N, or S, wherein said N - and / or S-atoms are independently oxidized or non-oxidized; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-CN, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl), -(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkyl), -O(C1-6 alkyl), -O(C1-6 haloalkyl), -(C1-6 alkylene)-O(C1-6 alkyl), -(C1-6 alkylene)-S(C1-6alkyl), -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COO(C1-6 al- kyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 al- kyl), -S(O)2-(C1-6 alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)(Ci-Balkyl), -NH-S(O)2-(C1-6 al- kyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(C0-3 alkylene)-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3- to 7-mem- bered heterocycloalkyl), -(C0-3 alkylene)-phenyl, and -(Co-3 alkylene)-(5- or 6-membered heteroaryl), wherein the aforementioned heterocycloalkyl and heteroaryl rings independently comprise one or more, same or different het- eroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, wherein in said alkylene moiety of said -(C0-3 alkylene)-(3- to 7-membered cycloalkyl), -(Co-3 alkylene)-(3- to 7-mem- bered heterocycloalkyl), -(C0-3 alkylene)-phenyl, and -(C0-3 alkylene)-(5- or 6-membered heteroaryl) one -CH2- group if present is optionally replaced by -O-, and wherein the 3- to 7-membered cycloalkyl moiety in said -(C0-3 alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(Co-3 alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(Co-3 alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0-3 alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each inde- pendently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, -O(C1-2 alkyl), and -O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a 3- to 7-membered heterocycloalkyl ring formed by two R3together with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused 5- or 6-membered heteroaryl ring, which comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized.

[0055] In a more preferred embodiment, each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C1-3 al- kylene)-phenyl, and -(C1.3 alkylene)-(5- or 6-membered heteroaryl), each optionally substituted with one or more RS3, wherein the aforementioned heterocycloalkyl and heteroaryl rings independently comprise one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxi- dized; or the two R3together with the nitrogen atom to which they are attached form a 3 - to 7-membered heterocycloalkyl ring, optionally substituted with one or more RS3, and optionally comprising in addition to the nitrogen atom one or more, same or different heteroatoms selected from O, N, or S, wherein said N - and / or S-atoms are independently oxidized or non-oxidized.

[0056] In a preferred embodiment,

[0057] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2.

[0058] In another preferred embodiment,

[0059] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2. In a more preferred embodiment,

[0060] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R12.

[0061] In another preferred embodiment, A is

[0062] -RL3 - 1_2 -R4 wherein the wavy line marks the connection to the remainder of the molecule; and wherein

[0063] L2is wherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1.6 alkylene)-OH, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl); and wherein

[0064] RL3is absent or Ci alkylene; and wherein

[0065] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6alkyl), -(C2-6 alkylene)-N(C1-6 al- kyl )(C1-6 alkyl), -(C0.3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 al- kylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3alkylene)-O-aryl, -(C1-3 alkylenej-heteroaryl, or-(C2-3 alkylene)- O-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0.3 alkylene)-heterocycloalkyl, -(C1-3 alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl or -(C2-3 alkylene)-O-cycloalkyl, the heterocycloalkyl moiety in said -(C0.3 alkylene)-heterocycloalkyl or -(C2-3 alkylene)-O-heterocycloalkyl, the aryl moiety in said -(C1-3 alkylene)-aryl or -(C2-3 alkylene)-O-aryl, and the heteroaryl moiety in said -(C1-3 alkylene)-het- eroaryl or -(C2-3 alkylene)-O-heteroaryl, are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl).

[0066] In a preferred embodiment,

[0067] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(Ci-Balkyl), -(C2-6 alkylene)-N(C1-6 al- kyl)(C1-6 alkyl), -(C0-3 alkylene)-(3- to 7-membered cycloalkyl), -(C2-3 alkylene)-O-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C2-3 alkylene)-O-(3- to 7-membered heterocycloalkyl), -(C1-3 alkylene)-phenyl, -(C2-3 alkylene)-O-phenyl, -(C1-3 alkylene)-(5- or 6-membered heteroaryl), or -(C2-3 alkylene)- O-(5- or 6-membered heteroaryl), wherein the aforementioned heterocycloalkyl and heteroaryl rings independently com prise one or more, same or different heteroatoms selected from O, N, or S, wherein said N - and / or S-atoms are independently oxidized or non-oxidized, wherein in said alkylene moiety of said -(Co-3 alkylene)-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3-to 7-membered heterocycloalkyl), -(C1-3alkylene)-phenyl, and -(C1-3 alkylene)-(5- or e- membered heteroaryl) one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the 3- to 7-membered cycloalkyl moiety in said -(C0-3 alkylene)-(3-to 7-membered cycloalkyl) or -(C2-3 alkylene)-O-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(Co-3 alkylene)-(3- to 7-membered heterocycloalkyl) or -(C2-3 alkylene)-O-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C1-3 alkylene)-phenyl or -(C2-3 alkylene)-O-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C1-3 alkylene)-(5- or 6-membered heteroaryl) or -(C2-3 alkylene)-O-(5- or 6-membered heteroaryl), are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl).

[0068] In a more preferred embodiment,

[0069] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6 alkyl), -(Co-3 alkylene)-(3- to 7-mem- bered cycloalkyl), -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C1-3 alkylene)-phenyl, or -(C1-3 alkylene)-(5- or 6-membered heteroaryl), wherein the aforementioned heterocycloalkyl and heteroaryl rings independently com- prise one or more, same or different heteroatoms selected from O, N, or S, wherein said N - and / or S-atoms are inde- pendently oxidized or non-oxidized, wherein in said alkylene moiety of said -(Co-3 alkylene)-(3- to 7-membered cyclo- alkyl), -(Co-3 alkylene)-(3-to 7-membered heterocycloalkyl), -(C1-3 alkylene)-phenyl, and -(C1-3 alkylene)-(5- ore-mem- bered heteroaryl) one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the 3- to 7-membered cycloalkyl moiety in said -(C0-3 alkylene)-(3- to 7-membered cycloalkyl) the 3- to 7-membered hetero- cycloalkyl moiety in said -(C0-3 alkylene)-(3-to 7-membered heterocycloalkyl), the phenyl in said -(C1-3 alkylene)-phe- nyl, and the 5- or 6-membered heteroaryl moiety in said -(C1-3 alkylene)-(5- or 6-membered heteroaryl), are each op- tionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl).

[0070] In a preferred embodiment,

[0071] L2is wherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4; and

[0072] R1-3is absent. In a particularly preferred embodiment, the compound of formula (I) is a compound selected from the following com- pounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

[0073] In a particularly preferred embodiment, the com pound of formula (I) is a compound selected from the following com- pounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

[0074]

[0075] In a particularly preferred embodiment, the com pound of formula (I) is a compound selected from the following com-

[0076] 5 pounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

[0077]

[0078] In another embodiment, the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, wherein:

[0079] R1is thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or phenyl, each optionally substituted with one or more RS1; wherein each RS1is independently selected from -Hal, C1-6 alkyl, C1-6 haloalkyl, -cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl);

[0080] R2is H;

[0081] A is a moiety selected from

[0082] R3

[0083] - RL3- L2- R4wherein the wavy line in each case marks the connection to the remainder of the molecule; wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2; and

[0084] L2is wherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, (C1-6 alkyleneJOH, -OH, O(C1-2 alkyl), or -O(C1-2 haloal- kyi); and wherein

[0085] RL1is absent or C1-2 alkylene;

[0086] R12is absent or C1-2 alkylene;

[0087] R13is absent or C1-2 alkylene; and wherein each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, and -(C2-3 alkylene)-O-heteroaryl, each optionally substituted with one or more RS3; pro- vided that not both R3are -H; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), N(C1-6 al kyl)(Ci-g alkyl), C1-6 alkyl, C1-6 haloalkyl, (C1-6 alkylene)CN, (Cvs alkyleneJOH, (C1-6 alkylene)NH(C1-6 alkyl), (C1-6 alkylene)N(C1-6 al- kyl)(C1-6 alkyl), 0(C1-6 alkyl), O(C1-6 haloalkyl), (C1-6 alkylene)O(C1-6alkyl), (C1-6 alkylene)S(C1-6alkyl), -CO(C1-6 alkyl), CO(cycloalkyl), CO(heterocycloalkyl), -COOH, -COO(C1-6 alkyl), CONH2, CONH(Cie alkyl), -CO-N(C1-6 alkyl)(C1-6 al- kyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), S(O)2-(C1-6 alkyl), S(O)2-NH2, S(O)2-NH(C1-6 alkyl), S(O)2-N(CI-6 alkyl)(C1-6 alkyl), NH-S(0)2-(C1-6 alkyl), N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(Co-3 alkylene)-aryl, and (Co-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -O-, and wherein the cycloalkyl moiety in said -(Co- 3 alkylene)- cycloalkyl. the heterocycloalkyl moiety in said -(Co-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(C0-3 alkylene)- aryl, and the heteroaryl moiety in said -(C0-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, O(C1-2 alkyl), and O(Ci-2haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a heterocycloalkyl ring formed by two R3to- gether with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused heteroaryl ring; and wherein

[0088] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6alkyl), -(C2-6 alkylene)-N(C1-6 al- kyl)(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 al- kylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, or-(C2-3 alkylene)- O-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C1-3 alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the cycloalkyl moiety in said -(Co- 3 alkylene)-cycloalkyl or -(C2-3 alkylene)-O-cycloalkyl, the heterocycloalkyl moiety in said -(Co-3 alkylene)-heterocycloalkyl or -(C2-3 alkylene)-O-heterocycloalkyl, the aryl moiety in said -(C1-3 alkylene)-aryl or -(C2-3 alkylene)-O-aryl, and the heteroaryl moiety in said -(C1-3 alkylene)-het- eroaryl or -(C2-3 alkylene)-O-heteroaryl, are each optionally substituted with one or more groups each independently selected from -Hal, Cv2alkyl, Cv2haloalkyl, and -O(Ci.2alkyl);

[0089] X1is CH or N;

[0090] X2is CH or N;

[0091] Y1is CRY1or N;

[0092] Y2is CRY2or N;

[0093] Y3is CRY3or N; and

[0094] Y4is CRY4or N; wherein RY1, RYZ, RY3, and RY4are each independently selected from -H, -CN, -Hal, -OH, Cvs alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), O(-C1-6 haloalkyl), and -(C1-6 alkylene)-O(C1-6alkyl); provided that if X1and X2are both CH, at least one of Y1, Y2, Y3, and Y4is N; and provided that not more than three of X1, X2, Y1, Y2, Y3, and Y4are N; and provided that if A is then X2is N, and X1, Y1, Y2, Y3, and Y4are all different from N; and provided that if A is

[0095] R13is absent,

[0096] R4is H, and

[0097] X2is N, then one of X1, Y1, Y2, Y3, and Y4is also N.

[0098] In a preferred embodiment, R1is wherein the dashed line marks the connection to the remainder of the molecule.

[0099] In another preferred embodiment, RS1is C1-6 alkyl or -O(C1-6 alkyl).

[0100] In a particularly preferred embodiment R1is 4-ethoxyphenyl.

[0101] In another preferred embodiment,

[0102] X1is CH or N;

[0103] X2is CH or N;

[0104] Y1is CRY1or N;

[0105] Y2is CRY2or N;

[0106] Y3is CRY3or N; and

[0107] Y4is CRY4or N; wherein at least one of Y1, Y2, Y3, and Y4does not represent N or CH; and wherein RY1, RY2, RY3, and RY4are each independently selected from -H, -CN, -Hal, C1-6 alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl).

[0108] In another preferred embodiment, the compound of formula (I) is a compound of formula (la), (lb), (Ic), or (Id):

[0109]

[0110] In another preferred embodiment,

[0111] RY1is -H;

[0112] RY2is -H, -Cl, or -F;

[0113] RY3is -H, -Cl, or -F; and

[0114] RY4is -H, -Cl, or -F.

[0115] In another preferred embodiment

[0116] A is

[0117] R3

[0118] - RL1— L1— RL2— l /

[0119] R3. wherein the wavy line marks the connection to the remainder of the molecule; wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl); and wherein

[0120] RL1is absent; and

[0121] R12is absent or Ci alkylene; and wherein each R3is independently selected from -H, C1.5 alkyl, -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl,

[0122] -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, and -(C2-3 alkylene)-O-heteroaryl, each optionally substituted with one or more RS3; pro- vided that not both R3are -H; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-CN, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl),

[0123] -(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkyl), -O(C 1-6 al kyl ), -O(C1-6 haloalkyl), -(C1-6 alkylene)-O(C1-6alkyl), -(C-i-o al- kylene)-S(C1-6 alkyl), -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COOH, -COO(Ci-g al- kyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 al- kyl), -S(O)2-(C1-6 alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)(C1-6 alkyl), -NH-S(O)2-(C1-6 al- kyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)- heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -O-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(Co-3 alkylene)-aryl, and the heteroaryl moiety in said

[0124] -(C0-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1.2 alkyl, C1.2 haloalkyl, -O(C1-2 alkyl), and -O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a heterocycloalkyl ring formed by two R3to- gether with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused heteroaryl ring.

[0125] In one more preferred embodiment, L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2.

[0126] In another more preferred embodiment,

[0127] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2.

[0128] In another preferred embodiment

[0129] A is

[0130] - RL3— L2- R4wherein the wavy line marks the connection to the remainder of the molecule; and wherein Lzis wherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -0(0-2 alkyl), or -O(C1-2 haloalkyl); and wherein

[0131] R13is absent or Ci alkylene; and wherein

[0132] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6alkyl), -(C2-6 alkylene)-N(C1-6 al- kyl)(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 al- kylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, or-(C2-3 alkylene)- O-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C1.3 alkylene)-aryl, and -(C1.3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl or -(C2-3 alkylene)-O-cycloalkyl, the heterocycloalkyl moiety in said -(Co-3 alkylene)-heterocycloalkyl or -(C2-3 alkylene)-O-heterocycloalkyl, the aryl moiety in said -(C1-3 alkylene)-aryl or -(C2-3 alkylene)-O-aryl, and the heteroaryl moiety in said -(C1-3 alkylene)-het- eroaryl or -(C2-3 alkylene)-O-heteroaryl, are each optionally substituted with one or more groups each independently selected from -Hal, C1.2 alkyl, C1.2 haloalkyl, and -O(C1-2alkyl).

[0133] In a more preferred embodiment,

[0134] L2is wherein the dashed line in each case marks the connection to R1-3, and the wavy line in each case marks the connec- tion to R4; and

[0135] R13is absent.

[0136] In another preferred embodiment, each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C1-3 alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl, each optionally substituted with one or more RS3; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3.

[0137] In a particularly preferred embodiment, one R3is -H or C1.5 alkyl, and the other R3is -(Co-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C1-3 alkylene)- phenyl, or -(C1-3 alkylene)-(5- or 6-membered heteroaryl), each optionally substituted with one or more RS3, wherein the heterocycloalkyl and heteroaryl rings independently comprise one or more ring heteroatoms independently se- lected from O, S and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if pre- sent) may optionally be oxidized; or the two R3together with the nitrogen atom to which they are attached form a 3 - to 7-membered heterocycloalkyl ring, optionally substituted with one or more RS3, wherein the heterocycloalkyl ring comprises one or more ring het- eroatoms 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 ; wherein RS3is independently selected from -CN, -Hal, -OH, C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-OH, -O(C1-6al- kyl), and -O(C1-6 haloalkyl).

[0138] In another preferred embodiment,

[0139] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6 alkyl), -(C0-3 alkylene)-heterocycloal- kyl, -(C1-3 alkylene)-aryl, or-(C1-3 alkylenej-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-hetero- cycloalkyl, -(C1-3 alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(C1-3 alkylene)-aryl and the heteroaryl moiety in said -(C1-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 al- kyl).

[0140] In a particularly preferred embodiment,

[0141] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C0-1 alkylene)-(3- to 7-membered heterocycloalkyl), -(Ci alkylene)-phenyl, or -(Ci alkylene)-(5- or 6-membered heteroaryl), wherein in said alkylene moiety of said -(C0-1 alkylene)-(3- to 7-membered heterocycloalkyl), -(Ci alkylene)-phenyl, and -(Ci alkylene)-(5- or 6-membered heteroaryl), one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the heterocy- cloalkyl moiety in said -(C0-1 alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(Ci alkylene)-phenyl and the heteroaryl moiety in said -(Ci alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2alkyl); and wherein the heterocycloalkyl and heteroaryl rings independently comprise one or more ring heteroatoms independently se- lected from O, S and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if pre- sent) may optionally be oxidized. In a particularly preferred embodiment, the compound of formula (I) is a compound selected from the following com- pounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

[0142] In a particularly preferred embodiment, the com pound of formula (I) is a compound selected from the following com- pounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

[0143]

[0144] In a second embodiment, the present invention relates to a pharmaceutical composition comprising the compound of formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier.

[0145] In a third embodiment, the present invention relates to the compound of formula (I) or a stereoisomer, tautomer, N- oxide, pharmaceutically acceptable saltorsolvate thereof , or to the pharmaceutical composition of the present inven- tion for use as a medicament.

[0146] Without wishing to be bound by theory, the present inventors have demonstrated that, as TASL level is regulated by its interaction with SLC15A4,the treatment with the com pounds of formula (I) leads to efficient degradation of TASL.

[0147] It is known to the skilled person and apparent from the literature that SLC15A4 and / or TASL play a crucial role in autoimmune disorders (including SLE)and inflammatory disorders (including inflammatory bowel disease (IBD), pso- riasis, and endosomal TLR-dependent inflammation).

[0148] Accordingly, there is a body of evidence based on genome wide association studies (GWAS) of SLE in human cells indicating the role SLC15A4 in this disorder. Bentham et al. (Bentham etal, (2015)) identified the genetic association of SLC15A4 and TASL (referenced therein as CXorf21 ) with SLE in a cohort of European ancestry. He CF and coworkers (He et al, (2010)) identified the genetic association of SLC15A4 with SLE-related discoid rash in a Chi- nese Han population. Langefeld and coworkers (Langefeld et al. Transancestral mapping and genetic load in sys- temic lupus erythematosus. Nat Com mun, 8, 16021 (2017)) identified the genetic association of SLC15A4 with SLE in a cohort of European ancestry.

[0149] Further, there is additional evidence of the role of TASL in the pathogenesis of SLE based on genetic studies in hu- man cells. Odhams et al. (Odhams etal (2019)) proposed that genetic variants of TASL (CXorf21 ) associated with SLE lead to increased TASL expression in an interferon- and sex-specific manner and hence suggest a potential ex- planation.

[0150] There is further evidence in mouse models indicating the importance of TASL / SLC15A4 in the development of SLE. Baccala and coworkers (Baccala et al. Essential requirement for IRF8 and SLC15A4 implicates pDCs in the patho- genesis of lupus. PNAS, 110, 2940, (2013)) identified a protective role for SLC15A4 deficiency in the development of SLE in a mouse model using the C57BL / 6-Fas(lpr) strain. Kobayashi and coworkers (Kobayashi et al. (2014)) show that SLC15A4-deficiency is protective in two models of SLE (pristane-induced and C57BL / 6lpr / lpr mice) and that SLC15A4 is required in B cells for endosomal TLRfunction. Pollard and coworkers (Pollard et al. Induction of Sys- temic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN. J Immunol, 199, 3739, (2017)) found thatSLC15A4-deficiency is protective in a mercury-induced model of SLE. Katewa and coworkers (Katewa et al. (2021 )) describe a protective role for SLC15A4 in pristane-induced and NZB / W F1 murine genetic models of SLE and TASL-deficiency protects from auto- immunity in several mouse SLE models (Drobek, A. et al. The TLR7 / 9 adaptors TASL and TASL2 mediate IRF5-de- pendent antiviral responses and autoimmunity in mouse. Nat. Commun. 16, 967 (2025); Lau, L. etal. An essential role for TASL in mouse autoimmune pathogenesis and Toll-like receptor signaling. Nat. Commun. 16, 968 (2025)).

[0151] Accordingly, the com pounds of the present invention are considered useful in the treatmentor prevention of autoim- mune disorders, in particular SLE.

[0152] It can befurtherassumed based on the role of SLC15A4 and / orTASL in IRF5 activation, that the com pounds of the present invention will be useful in the treatment or prevention of autoimmune disorders, preferably selected from SLE, lupus nephritis, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, polymyositis / dermatomyositis, primary biliary cirrhosis, multiple sclerosis, oral ulcers, periodontitis, Behcet’s disease, inflammatory bowel disease, psoriasis, myasthenia gravis, and ankylosing spondylitis (Wang et al. (2023), Bentham et al. 2015), Katewa et al. (2021 )).

[0153] There is further a body of evidence based on genetic studies indicating the role of SLC15A4 and / or TASL in proin- flammatory cytokine production (such as IL-6) and inflammation. Heinz and coworkers (Heinz et al. (2020)) have shown an essential role of SLC15A4-TASL and their relationship in human cell linesand prim ary cells for endosomal TLR function.

[0154] There is furtherevidence based on studies in mouse models indicating the role of SLC15A4 and / or TASL in inflam- matory conditions. Blasius and coworkers (Blasius et al. (2010)) identified SLC15A4 as essential component in endo- somal TLRfunction in pDCs. Sasawatari and coworkers (Sasawatari et al. The solute carrier family 15A4 regulates TLR9 and NOD1 functions in the innate immune system and promotes colitis in mice. Gastroenterology, 140, 1513, (2011 )) have found SLC15A4-deficiency to impair CpG-induced production of proinflam matory cytokines from den- dritic cells. Furthermore, SLC15A4-deficiency was found to be protective in a mouse model of IBD. SLC15A4-defi- cient mice also showed defective cytokine production upon activation of the NOD -like receptor NOD1 . Blasius and coworkers (Blasius et al. Slc15a4, a gene required for pDC sensing of TLR ligands, is required to control persistent viral infection. PLoS Pathog 8, e1002915 (2012)) suggested an important role for SLC15A4 in pDCs in controlling viral persistence, as evidenced in a model of LCMV infection. Nakamura and coworkers (Nakamura etal. Endosomes are specialized platforms for bacterial sensing and NOD2 signalling, Nature, 509, 240, (2014)) proposed a role for SLC15A4 in the activation of NOD2 at the lysosome. Of note, NOD2 mutations are linked to IBD. Dosenovic and coworkers (Dosenovic et al. Slc15a4 function is required for intact class switch recombination to lgG2c in response to TLR9 stimulation. Immunol Cell Biol, 93, 136, (2015)) find defective endosomal TLRfunction in pDCs, splenic eDCs and B cells. Furthermore, production of antibodies elicited by a CpGA-adjuvanted vaccine is impaired in SLC15A4 mice. Griffith and coworkers (Griffith et al. A requirement for slc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice, Sci Rep 8, 14451 (2018)) describe a requirement for SLC15A4 in imiquimod -in- duced systemic inflam mation and psoriasiform inflammation in mice. Lopez-Haber and coworkers (Lopez-Haber et al. The phagosomal solute transporter SLC15A4 promotes inflammasome activity via mTORCI signaling and autophagy restraint in dendritic cells, EMBO J, 41 , e111161 (2022)) describe a contribution of SLC15A4 in inflammasome acti- vation via mTORCI signaling pathways.

[0155] It can be further assumed, based on the role of SLC15A4 and / or TASL in IRF5 activation, that the compounds of the present invention will be useful in the treatmentor prevention of inflammatory condition, preferably selected from inflammatory bowel disease, psoriasiform dermatitis, endosomal TLR-dependent inflammation, ulcerative colitis, Crohn’s disease, endosomal TLR-induced hyperinflammation, macrophage activation syndrome, allergic airway in- flammation, and sarcoidosis, preferably wherein the inflammatory condition is selected from inflammatory bowel dis- ease, psoriasiform dermatitis, and endosomal TLR-dependent inflammation. Accordingly, the com pounds of the present invention are useful in treatmentor prevention of an inflammatory condi- tion.

[0156] Thus, in a fourth embodiment, the present invention relates to the compound of formula (I) or a stereoisomer, tauto- mer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or to the pharmaceutical composition of the pre- sent invention for use in treatment or prevention of an autoimmune disorder or inflammatory condition. In one pre- ferred embodiment, the com pound of formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or to the pharmaceutical composition of the present invention for use in treatment or preven- tion of an autoimmune disorder. In another preferred embodiment, the compound of formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or to the pharmaceutical composition of the present invention for use in treatment or prevention of an inflammatory condition.

[0157] In a fifth embodiment, the present invention relates to use of the compound of formula (I) or a stereoisomer, tauto- mer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of the present invention in the manufacture of a medicamentfortreatmentorprevention of an autoimmune disorderorinflammatory condition.

[0158] In a sixth embodiment, the present invention relates to a method of treatment of an autoimmune disorder or inflam- matory condition, the method comprising administering the compound of formula (I) or a stereoisomer, tautomer, N - oxide, pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of the present inven- tion, to the subject in need thereof. It is to be understood that a therapeutically effective amount of the compound of formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or the pharma- ceutical composition of the present invention, is to be administered.

[0159] The autoimmune disorder is preferably selected from systemic lupus erythematosus, rheumatoid arthritis, sclero- derma, Sjogren’s syndrome, polymyositis / dermatomyositis, primary biliary cirrhosis, multiple sclerosis, oral ulcers, periodontitis, BehQet’s disease, myasthenia gravis, and ankylosing spondylitis. More preferably the autoimmune dis- order is systemic lupus erythematosus.

[0160] The inflammatory condition is preferably selected from inflammatory bowel disease, psoriasiform dermatitis, endo- somal TLR-dependent inflammation, ulcerative colitis, Crohn’s disease, endosomal TLR-induced hyperinflammation, macrophage activation syndrome, allergic airway inflammation, and sarcoidosis. More preferably, the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-dependent in- flammation.

[0161] Thus, in a seventh embodiment, the present invention relates to the compound of formula (I) or a stereoisomer, tau- tomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or to the pharmaceutical composition of the pre- sent invention for use in treatment or prevention of an autoimmune disorder or inflammatory condition, wherein the autoimmune disorder is selected from systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, polymyositis / dermatomyositis, primary biliary cirrhosis, multiple sclerosis, oral ulcers, periodontitis, Behcet’s disease, myasthenia gravis, and ankylosing spondylitis, preferably wherein the autoimmune disorder is sys- temiclupuserythematosus. orwherein the inflammatory condition is selected from inflammatory bowel disease, pso- riasiform dermatitis, endosomal TLR-dependent inflammation, ulcerative colitis, Crohn’s disease, endosomal TLR- induced hyperinflammation, macrophage activation syndrome, allergic airway inflammation, and sarcoidosis, prefera- bly wherein the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and en- dosomal TLR-dependent inflammation.

[0162] It is to be noted that the com pounds of the invention have been shown by the present inventors to reduce the TASL protein level suggesting binding to the SLC15 peptide transporter (i.e., SLC15A4). Accordingly and preferably, it is expected that the therapeutic effect of the compound of formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceu- tically acceptable salt or solvate thereof is based on the binding of SLC15 peptide transporter (i.e., SLC15A4), which in turn reduces the TASL protein level. Accordingly, in one embodimentthe present invention relates to the com- pound of formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of the present invention for use in the treatment or prevention of an autoimmune disor- der, wherein said compound orsaid pharmaceutical composition binds the SLC15 peptide transporter. Given the abil- ity of the compound of the presentinvention, or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, to bind the SLC15 peptide transporter, said compound is particularly useful in the treatment of the autoimmune disorder, wherein the autoimmune disorder is a disorderassociated with SLC15 peptide transporter. Ac- cordingly, the present invention in one embodiment relates to the compound of formula (I) or a stereoisomer, tauto- mer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of the present invention for use in the treatment or prevention of an autoimmune disorder, wherein the autoimmune disorder is a disorder associated with SLC15 peptide transporter.

[0163] Thus, in an eighth embodiment, the present invention relates to the compound of formula (I) or a stereoisomer, tau- tomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or to the pharmaceutical composition of the pre- sent invention for use in treatment or prevention of an autoimmune disorder or inflammatory condition , wherein the autoimmune disorder is a disorder associated with SLC15 peptide transporter, and / or wherein said compound or said pharmaceutical composition reduces the TASL protein level.

[0164] The compounds provided according to the present invention are also useful in treatment or prevention of other lu- pus diseases such as cutaneous or neonatal lupus erythematosus.

[0165] Definitions

[0166] The following definitions apply th roughoutthe present specification and the claims, unless specifically indicated oth- erwise.

[0167] The term “hydrogen” is herein used to referto protium , deuterium and / ortritium , preferably to protium . Accordingly, the term “non-hydrogen atom” refers to any atom that is not hydrogen, i.e. that is not protium , deuterium or tritium .

[0168] The term “hydrocarbon group” refers to a group consisting of carbon atoms and hydrogen atoms.

[0169] The term “alicyclic” is used in connection with cyclic groups and denotes that the corresponding cyclic group is non-aromatic.

[0170] As used herein, the term “alkyl” refers to a monovalentsaturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linearor branched. Accordingly, an “alkyl” group does not com prise any carbon -to-carbon double bond or any carbon-to-carbon triple bond. A “C1.5 alkyl” denotes 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 defined otherwise, the term “alkyl” preferably refers to C 1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.

[0171] As used herein, the term “alkenyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be lin- ear or branched and com prises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not com- prise any carbon-to-carbon triple bond. The term “C2-5 alkenyl” denotes an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1 -en-1 -yl, prop-1 -en-2-yl, or prop-2 -en-1 -yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1 -yl or buta-1 ,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term “alkenyl” preferably refers to C2-4 alkenyl.

[0172] As used herein, the term “alkynyl” refers to a monovalentunsaturated acyclic hydrocarbon group which may be lin- ear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. The term “C2-5 alkynyl” denotes an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless de- fined otherwise, the term “alkynyl” preferably refers to C2-4 alkynyl.

[0173] As used herein, the term “alkylene” refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linearorbranched. A “C1-5 alkylene” denotes an alkylene group having 1 to 5 carbon atoms, and the term “C0-3 alkylene” indicates thata covalentbond (corresponding to the option “Co alkylene”) or a C1-3 alkylene is present. Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), pro- pylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)-, or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2- CH2-CH2-). Unless defined otherwise, the term “alkylene” preferably refers to C 1-4 alkylene (including, in particular, linear C1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.

[0174] As used herein, the term “carbocyclyl” refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. Unless defined otherwise, “carbocyclyl" preferably refers to aryl, cycloalkyl or cycloalkenyl.

[0175] As used herein, the term “heterocyclyl” refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and / orfused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, orfour) ring 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 furtherwherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom -containing ring comprised in said 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 orfour N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at leastone carbon ring atom (which may option- ally be oxidized) in the corresponding heteroatom-containing ring. Unless defined otherwise, “heterocyclyl” preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.

[0176] As used herein, the term “aryl" refers to an aromatic hydrocarbon ring group, including monocyclicaromaticringsas well as bridged ring and / orfused ring systems containing at leastone aromatic ring (e g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Aryl” may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1 ,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1 H indenyl), an- thracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless defined otherwise, an “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

[0177] As used herein, the term “heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / orfused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at leastone of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, orfour) ring 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 furtherwherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom -containing ring comprised in said 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 orfour N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at leastone carbon ring atom (which may option- ally be oxidized) in the corresponding heteroatom -containing ring. “Heteroaryl” may, e.g., refer to thienyl (i.e., thio- phenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1 -benzopyranyl or 4H-1 -benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl , or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H -indolyl), isoindolyl, indazolyl, in- dolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, 0-carbolinyl, phenanthridinyl. acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 ,10]phenanthrolinyl, [1 ,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e g., 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl (i.e., furazanyl), or 1 ,3,4-oxadiazolyl), thiadiazolyl (e.g., 1 ,2,4-thiadiazolyl, 1 ,2,5- thiadiazolyl, or 1 ,3,4-thiad iazolyl), phenoxazinyl, pyrazolo[1 ,5-a]pyrim idinyl (e.g., pyrazolo[1 ,5-a]pyrim idin-3-yl),

[0178] 1 .2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thi- ophenyl (i.e., benzothienyl), triazolyl (e.g., 1 H-1 ,2,3-triazolyl, 2H-1 ,2,3-triazolyl, 1 H-1 ,2,4-triazolyl, or 4H-1 ,2,4-tria- zolyl), benzotriazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1 ,2 ,3-triazi nyl , 1 ,2 ,4-triazi nyl , or 1 ,3 ,5-triazi nyl ), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1 ,3-dihydrofuro[3,4-c]pyridinyl), imid- azopyridinyl (e.g., imidazo[1 ,2-a]pyrid inyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothieno- pyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1 ,3-benzodioxolyl, benzodioxanyl (e g.,

[0179] 1 .3-benzodioxanyl or 1 ,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term "heteroaryl” preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring 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 carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring 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 oxi- dized, and wherein one or more carbon ring atoms are optionally oxidized.

[0180] As used herein, the term “cycloalkyl” refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkyl” may, e.g., referto cyclopropyl, cyclo- butyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless defined other- wise, “cycloalkyl” preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl (i.e. 3- to 7- membered cycloalkyl). A particularly preferred “cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).

[0181] As used herein, the term “cycloalkylene” refers to a cycloalkanediyl group, i.e. a divalent saturated cyclic hydrocar- bon group. A “Cs cycloalkylene” denotes a cyclohexanediyl group, preferably a cyclohexane-1 ,4-diyl group. In other words, “Cg cycloalkylene” preferably refers to a cyclohexane unit which is attached to the remainder of the molecule at positions 1 and 4 of the cyclohexane ring. Unless defined otherwise, the term “cycloalkylene” preferably refers to C3-6 cycloalkylene (including, in particular, Ce cycloalkylene).

[0182] As used herein, the term “heterocycloalkyl” refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and / orfused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring 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 exam pie, each heteroatom -containing ring comprised in said saturated 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 corresponding heteroatom - containing ring is 1 to 4 and that there is at leastone carbon ring atom (which may optionally be oxidized) in the cor- responding heteroatom-containing ring. “Heterocycloalkyl” may, e.g., referto aziridinyl. azetidinyl, pyrrol idinyl, imidaz- olidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1 ,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., m orpholin -4-yl), thiomorphol inyl (e.g., thiomorpholin -4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1 ,3-dioxolanyl, tetrahydropyranyl, 1 ,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tet- rahydrothiophenyl (i .e., thiolanyl), 1 ,3-d ithiolanyl, thianyl , 1 ,1 -dioxothianyl, thiepanyl, decahydroquinolinyl, decahydroi- soquinol inyl, or2-oxa-5-aza-bicyclo[2.2.1 ]hept-5-yl. Unless defined otherwise, “heterocycloalkyl” preferably refers to a 3 to 1 1 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring het- eroatoms 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 ormore carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkyl” refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring 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 car- bon ring atoms are optionally oxidized.

[0183] As used herein, the term “halogen” or “Hal” refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I).

[0184] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are pref- erably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. “Haloalkyl” may, e.g., refer 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.

[0185] The terms “bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or con- tradicted by context.

[0186] As used herein, the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent. Whenever the term “optional”, “optionally” or “may” is used, the present invention specifically re- lates to both possibilities, i.e., that the corresponding feature is present er, alternatively, that the corresponding fea- ture is absent. For example, the expression “X is optionally substituted with Y’ (or “X may be substituted with Y’) means that X is either substituted with Y or is unsubstituted. Likewise, if a componentof a composition is indicated to be “optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

[0187] The term "substituted", as used herein, means that a hydrogen atom bonded to a designated atom is replaced with a specified substituent, provided thatthe substitution results in a stable or chemicallyfeasible compound. Unless oth- erwise indicated, a substituted atom may have one or more substituents and each substituent is independently se- lected.

[0188] The term "substitutable", when used in reference to a designated atom, means that attached to the atom is a hydro- gen, which can be replaced with a suitable substituent.

[0189] Various groups are referred to as being “optionally substituted" in this specification. Generally, these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maxi- mum numberof substituents is limited by the numberof attachment sites available on the substituted moiety. Unless defined otherwise, the “optionally substituted” groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted.

[0190] A skilled person will appreciate that the substituent groups comprised in the compounds of the present invention may be attached to the remainder of the respective compound via a number of different positions of the correspond- ing specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated in the examples.

[0191] As used herein, unless explicitly indicated otherwise or contradicted by context, the terms “a”, “an” and “the” are used interchangeably with “one or more” and “at least one”. Thus, for example, a composition comprising “a” com- pound of formula (I) can be interpreted as referring to a composition comprising “one or more” com pounds of formula (I). It is to be understood that wherever numerical ranges are provided / disclosed herein, all values and subranges en- compassed by the respective numerical range are meant to be encompassed within the scope of the invention. Ac- cordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, as well as each subrange encompassed by a numerical range disclosed herein.

[0192] As used herein, the term “about” preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and in particularto the exact numerical value indicated. If the term “about” is used in connection with the endpoints of a range, it preferably refers to the range from the lower endpoint -10% of its indi- cated numerical value to the upper end point +10% of its indicated numerical value, more preferably to the range from of the lower endpoint -5% to the upper endpoint +5%, and even more preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint.

[0193] As used herein, the term “comprising” (or “com prise”, “comprises", “contain”, “contains”, or “containing”), unless ex- plicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia”, i.e., “containing, among further optional elements, ...”. In addition thereto, this term also includes the narrower mean Ings of “consisting essentially of” and “consisting of”. For example, the term “A comprising B and C” has the meaning of “A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C” and the meaning of “A consisting of B and C” (i.e., no other components than B and C are comprised in A).

[0194] The “treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or dis- ease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only). The “treatment” of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject / patient suf- fering from the disorderordisease. Accordingly, the “treatment” of a disorderordisease may also refer to an amelio- ration of the disorderordisease, which may, e.g., lead to a halt in the progression of the disorder or disease or a de- lay in the progression of the disorderor disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject / patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above). The treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).

[0195] The term “prevention” of a disorder or disease, as used herein, is also well known in the art. For example, a pa- tient / subjectsuspected of being prone to sufferfrom a disorderordisease may particularly benefit from a prevention of the disorder or disease. The subject / patient may have a susceptibility or predisposition for a disorder or disease, including butnot limited to hereditary predisposition. Such a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators. It is to be understood that a disorderor disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the pa- tient / subject (for example, the patient / subject does not show any clinical or pathological symptoms). Thus, the term “prevention” com prises the use of a compound of the present invention before any clinical and / or pathological symp- toms are diagnosed or determined or can be diagnosed or determined by the attending physician (or attendant veteri- narian).

[0196] Detailed Description

[0197] The invention will be described in detail in the following.

[0198] As indicated above, the present invention relates in one embodiment to a compound of formula (I) or a stereoisomer, tautomer, N -oxide, pharmaceutically acceptable salt or solvate thereof, wherein the substituents are as defined above. Preferred embodiments of the substituents will be described in detail in the following. It is to be understood that each preferred embodimentis relevanton its own as well as in combination with other preferred em- bodiments. Furthermore, it is to be understood that the preferred embodiments in each case also apply to the stereoi- somers, tautomers, N-oxides, pharmaceutically acceptable salts and solvates of the compounds of the invention. ln one embodiment of the invention,

[0199] R1is thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or phenyl, each optionally substituted with one or more RS1; wherein each RS1is independently selected from -Hal, C1-6 alkyl, C1-6 haloalkyl, -cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl).

[0200] Preferably, each RS1is independently selected from -Hal, C-I-B alkyl, C1-6 haloalkyl, -(3- to 7-membered cycloal- kyl), -O(C1-6 alkyl), and -O(C1-6 haloalkyl).

[0201] In a preferred embodiment,

[0202] R1is pyridinyl, pyrimidinyl, or phenyl, each optionally substituted with one or more RS1; wherein each RS1is independently selected from -Hal, C-I-B alkyl, C1-6 haloalkyl, -cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl).

[0203] Preferably, each RS1is independently selected from -Hal, C-I-B alkyl, C-I-B haloalkyl, -(3- to 7-membered cycloal- kyl), -O(C1-6 alkyl), and -O(C-I-B haloalkyl).

[0204] In a preferred embodiment, in connection with the above definitions of R1, each RS1is independently selected from -Hal, C1-6 alkyl, C-I-B haloalkyl, and -O(C-I-B alkyl).

[0205] In a more preferred embodiment, in connection with the above definitions of R1, each RS1is independently selected from -Hal, C1-6 alkyl, and -O(C1-6 alkyl).

[0206] In an even more preferred embodiment, each RS1is independently selected from C1-6 alkyl and -O(C1-6 alkyl). wherein the dashed line marks the connection to the remainder of the molecule; and wherein RS1is selected from -Hal, C1-6 alkyl, CVB haloalkyl, -cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). Prefera- bly, RS1is C1-6 alkyl and -O(C1-6 alkyl).

[0207] Thus, in one especially preferred embodiment, the compound of formula (I) is a compound of formula (I -R1-1 ), (l-R1-2), or (l-R1-3):

[0208]

[0209] In another preferred embodiment, R1is wherein the dashed line marks the connection to the remainder of the molecule; and wherein RS1is selected from -Hal, C1-6 alkyl, C1-6 haloalkyl, -(3- to 7-membered cycloalkyl), -O(C1-6 alkyl), and -O(C1-6 haloalkyl). Preferably, RS1is -Hal, C1-6 alkyl or -0(0-6 alkyl).

[0210] In a particularly preferred embodiment, R1is 4-ethoxyphenyl, 6-ethoxypyridin-3-yl, 5-ethoxypyridin-2-yl, or 5-fluoro- pyridin-2-yl.

[0211] In another preferred embodiment, R1is wherein the dashed line marks the connection to the remainder of the molecule, and wherein RS1is selected from -Hal, C1-6 alkyl, C1-6 haloalkyl, -cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). Prefera- bly, RS1is C1-6 alkyl and -O(C1-6 alkyl).

[0212] Thus, in one particularly preferred embodiment, the compound of formula (I) is a compound of formula (l-R1-1 ) or (l-R1-2): Especially preferred are compounds of formula (l-R1-1 ). In a particularly preferred embodiment, R1is 4-ethoxy- phenyl. Such compounds of formula (I) will be referred to as compounds of formula (l-R1-1 *) hereinafter:

[0213] In one embodiment of the invention, R2is H.

[0214] In one embodiment of the invention,

[0215] X1is CH or N;

[0216] X2is CH or N;

[0217] Y1is CRY1or N;

[0218] Y2is CRY2or N;

[0219] Y3is CRY3or N; and

[0220] Y4is CRY4or N; wherein RY1, RY2, RY3, and RY4are each independently selected from -H, -CN, -Hal, -OH, Ci-a alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), -O(C1-6 haloalkyl), and -(C1-6 alkylene)-O(C1-6alkyl); provided that if X1and X2are both CH, at least one of Y1, Y2, Y3, and Y4is N; and provided that not more than three of X1, X2, Y1, Y2, Y3, and Y4are N.

[0221] In one preferred embodiment,

[0222] X1is CH or N;

[0223] X2is CH or N;

[0224] Y1is CRY1or N;

[0225] Y2is CRY2or N;

[0226] Y3is CRY3or N; and

[0227] Y4is CRY4or N; wherein at least one of Y1, Y2, Y3, and Y4does not represent N or CH; and wherein RY1, RY2, RY3, and RY4are each independently selected from -H, -CN, -Hal, C1-6 alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl).

[0228] In another preferred embodiment, the compound of formula (I) is a compound of formula (la), (lb), (Ic), or (Id):

[0229] In another preferred embodiment,

[0230] RY1is -H;

[0231] RY2is -H, -Cl, or -F;

[0232] RY3is -H, -Cl, or -F; and

[0233] RY4is -H, -Cl, or -F.

[0234] Thus, in another preferred embodiment, the com pound of formula (I) is a compound of formula (la), (lb), (Ic), or (Id), wherein

[0235] RY1is -H;

[0236] RY2is -H, -Cl, or -F;

[0237] RY3is -H, -Cl, or -F; and

[0238] RY4is -H, -Cl, or -F.

[0239] In one especially preferred embodiment, the compound of formula (I) is a compound of formula (la). In another es- pecially preferred embodiment, the com pound of formula (I) is a compound of formula (lb). In another especially pre- ferred embodiment, the compound of formula (I) is a compound of formula (Ic). In another especially preferred em- bodiment, the compound of formula (I) is a compound of formula (Id). In connection with these especially preferred embodiments, it is further preferred that RY1is -H;

[0240] RY2is -H, -Cl, or -F;

[0241] RY3is -H, -Cl, or -F; and

[0242] RY4is -H, -Cl, or -F.

[0243] In connection with the above-mentioned compounds of formula (la), (lb), (Ic), or (Id), R1is as defined above. It is particularly preferred that R1is wherein the dashed line marks the connection to the remainder of the molecule, and wherein RS1is selected from -Hal, C1-6 alkyl, C1-6 haloalkyl, -cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). Prefera- bly, RS1is C1-6 alkyl and -O(C1-6 alkyl). Particularly preferably, RS1is ethoxy.

[0244] Such compounds are referred to as compounds of formula (la-R1-1 ), (la-R1-2), (lb-R1-1 ), (lb-R1-2), (lc-R1-1 ), (Ic-R1-

[0245] 2), (ld-R1-1 ), and (ld-R1-2), respectively:

[0246]

[0247] In connection with the compounds of formula (la-R1-1 ), (la-R1-2), (lb-R1-1 ), (lb-R1-2), (lc-R1-1 ), (lc-R1-2), (ld-R1-1 ), and (ld-R1-2), it is further preferred that RY1is -H;

[0248] RY2is -H, -Cl, or -F; RY3is -H, -Cl, or -F; and

[0249] RY4is -H, -Cl, or -F.

[0250] In one embodiment of the invention, which applies to compounds of formula (I), and preferably also to compounds of formula (l-R1-1 ), (l-R1-2), (la), (lb), (Ic), and (Id) as well as to compounds of formula (la-R1-1 ), (la-R1-2), (lb-R1-1 ), (lb-R1-2), (lc-R1-1 ), (lc-R1-2), (ld-R1-1 ), and (ld-R1-2),

[0251] A is a moiety selected from

[0252] R3

[0253] R3and . - RL3- L2- R4wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein

[0254] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2; and

[0255] L2is wherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -O(C1-2 alkyl), or

[0256] -O(C1-2 haloalkyl); and wherein

[0257] RL1is absent or C1-2 alkylene;

[0258] R12is absent or C1-2 alkylene;

[0259] R13is absent or C1-2 alkylene; and wherein each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl,

[0260] -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, and -(C2-3 alkylene)-O-heteroaryl, each optionally substituted with one or more RS3; pro- vided that not both R3are -H; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl),

[0261] C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-CN, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl),

[0262] -(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkyl), -O(C1-6alkyl), -O(C1-6 haloalkyl), -(C1-6 alkylene)-O(C1-6alkyl), -(C-i-o al- kylene)-S(C1-6 alkyl), -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COOH, -COO(C1-6 al- kyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 al kyl )(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 al- kyl), -S(O)2-(C1-6 alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)(C-i-Balkyl), -NH-S(O)2-(C1-6 al- kyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)- heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -O-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl, the heterocycloalkyl moiety in said -(Co-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(Co-3 alkylene)-aryl, and the heteroaryl moiety in said -(Co-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, -O(C1-2 alkyl), and -O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a heterocycloalkyl ring formed by two R3to- gether with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused heteroaryl ring; and wherein

[0263] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6alkyl), -(C2-6 alkylene)-N(Ci-g al- kyl)(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 al- kylene)-O-heterocycloalkyl, -(C1.3 alkylene)-aryl, -(C2-3alkylene)-O-aryl, -(C1.3 alkylene)-heteroaryl, or-(C2-3 alkylene)- O-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C1-3 alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl or -(C2-3 alkylene)-O-cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl or -(C2-3 alkylene)-O-heterocycloalkyl, the aryl moiety in said -(C1-3 alkylene)-aryl or -(C2-3 alkylene)-O-aryl, and the heteroaryl moiety in said -(C1-3 alkylene)-het- eroaryl or -(C2-3 alkylene)-O-heteroaryl, are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl).

[0264] In connection with the above definitions of R3, RS3, and R4, cycloalkyl preferably refers to C3-7 cycloalkyl (i.e. 3- to 7- membered cycloalkyl), heterocycloalkyl preferably refers to a 3- to 7-membered heterocycloalkyl ring comprising one or more ring 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, aryl preferably refers to phenyl, and het- eroaryl preferably refers to a 5- or 6-membered heteroaryl ring comprising one or more ring heteroatoms inde- pendently selected from O, S and N, wherein the one or more S ring atoms (if present) and / or one or more N ring at- oms (if present) may optionally be oxidized.

[0265] Thus, -(C0-3 alkylene)-cycloalkyl is preferably -(C0-3 alkylene)-(C3-z cycloalkyl), -(C0-3 alkylene)-heterocycloalkyl is preferably -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(Co-3alkylene)-aryl is preferably -(C0-3 alkylene)-phe- nyl, and -(C0-3 alkylene)-heteroaryl is preferably -(C0-3 al kylene)-(5- or 6-membered heteroaryl), wherein the heterocy- cloalkyl and heteroaryl rings independently comprise one ormore ring 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.

[0266] Further, -(C1-3 alkylene)-aryl is preferably -(C1-3 alkylene)-phenyl, and -(C1-3 alkylene)-heteroaryl is preferably -(C1-3 alkylene)-(5- or 6-membered heteroaryl), wherein the heterocycloalkyl and heteroaryl rings independently com- prise one or more ring 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.

[0267] Similarly, -(C2-3 alkylene)-O-cycloalkyl is preferably -(C2-3 alkylene)-O-(C3-? cycloalkyl), -(C2-3 alkylene)-O-heterocy- cloalkyl is preferably -(C2-3 alkylene)-O-(3- to 7-membered heterocycloalkyl), -(C2-3 alkylene)-O-aryl is preferably -(C2-3 alkylene)-O-phenyl, and -(C2-3 alkylene)-O-heteroaryl is preferably -(C2-3 alkylene)-O-(5- or 6-membered het- eroaryl), wherein the heterocycloalkyl and heteroaryl rings independently comprise one or more ring heteroatoms in- dependently 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.

[0268] In connection with the substituents R3, R4, and RS3, it is preferred that the selection of these substituents does not result in a heteroatom , e.g., an oxygen or nitrogen atom , or halogen atom directly attached to a carbon atom , which is directly attached to the nitrogen atom contained in the A moiety. Further, in connection with the substituents Rx, it is preferred that the selection of this substituent does not result in a heteroatom, e.g., an oxygen or nitrogen atom, or a halogen atom directly attached to a carbon atom, which is di- rectly attached to the nitrogen atom contained in the A moiety or directly attached to the nitrogen atom of the amido group of the remainder of the molecule.

[0269] Thus, in a preferred embodiment, if R3or R4are -(C2-3 alkylene)-O-cycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C2-3 alkylene)-O-aryl,or-(C2-3 alkylene)-O-heteroaryl, it is preferred that the oxygen atom contained in these groups is not directly attached to a carbon atom, which is directly attached to the nitrogen atom contained in the A moiety.

[0270] Further, in a preferred embodiment, if R3or R4represent a group, wherein -CH2- is replaced by CH(OH), it is pre- ferred that the CH(OH) group is not directly attached to the nitrogen atom contained in the A moiety.

[0271] In another preferred embodiment, if RS3is -Hal, -OH, -NH2, -NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), or a group, wherein -CH2- is replaced by -O-, it is preferred that the halogen, nitrogen, or oxygen atom of these RS3substituents is not directly attached to a carbon atom, which is directly attached to the nitrogen atom contained in the A moiety.

[0272] In another preferred embodiment, if two RS3attached to the same carbon atom form =O, it is preferred thatthe =0 is not attached to a carbon atom, which is directly attached to the nitrogen atom contained in the A moiety.

[0273] In a preferred embodiment, if a substituent Rxis present at L1or L2, it is preferred that -Hal, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl) are not directly attached to a carbon atom, which is directly attached to a nitrogen atom of the A- moiety, or to a carbon atom, which is directly attached to the nitrogen atom of the amido group of the remainder of the molecule.

[0274] In one preferred embodiment, A is

[0275] R3

[0276] - RL1— L1— RL2~ l /

[0277] R3. wherein the wavy line marks the connection to the remainder of the molecule; and wherein

[0278] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1.2 alkyl, C1.2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl); and wherein

[0279] RL1is absent; and

[0280] R12is absent or Ci alkylene; and wherein each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl,

[0281] -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C-i-3 alkylene)-heteroaryl, and -(C2-3 alkylene)-O-heteroaryl, each optionally substituted with one or more RS3; pro- vided that not both R3are -H; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-CN, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl),

[0282] -(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkyl), -O(C1-6 alkyl), -O(C1-6 haloalkyl), -(C1-6 alkylene)-O(C1-6 alkyl), -(C1-6 al- kylene)-S(C1-6 alkyl), - -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COO(C1-6 al- kyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 al kyl )(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 al- kyl), -S(O)2-(C1-6 alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)(Ci-Balkyl), -NH-S(O)2-(C1-6 al- kyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)- heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -O-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(Co-3 alkylene)-aryl, and the heteroaryl moiety in said

[0283] -(C0-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, -O(C1-2 alkyl), and -O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a heterocycloalkyl ring formed by two R3to- gether with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused heteroaryl ring.

[0284] In a preferred embodiment, each R3is independently selected from -H, C1.5 alkyl, -(C0.3 alkylene)-(3-to 7-membered cycloalkyl), -(C2.3 alkylene)- O-(3- to 7-membered cycloalkyl), -(Co-3 alkylene)-( 3- to 7-membered heterocycloalkyl), -(C2-3 alkylene)-O-(3- to 7- membered heterocycloalkyl), -(C1-3 alkylene)-phenyl, -(C2-3 alkylene)-O-phenyl, -(C1-3 alkylene)-(5- or 6-membered heteroaryl), and -(C2-3 alkylene)-O-(5- or 6-membered heteroaryl), each optionally substituted with one or more RS3, wherein the aforementioned heterocycloalkyl and heteroaryl rings independently comprise one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non -oxi- dized; provided that not both R3are -H; or the two R3together with the nitrogen atom to which they are attached form a 3 - to 7-membered heterocycloalkyl ring, optionally substituted with one or more RS3, and optionally comprising in addition to the nitrogen atom one or more, same or different heteroatoms selected from O, N, or S, wherein said N - and / or S-atoms are independently oxidized or non-oxidized; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(Ci-Balkyl), C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-CN, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl),

[0285] -(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkyl), -O(C1-6 alkyl), -O(C1-6 haloalkyl), -(C1-6 alkylene)-O(C1-6 alkyl), -(C1-6 al- kylene)-S(C1-6 alkyl), -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COO(C1-6 alkyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(Ci.6alkyl), -S(O)2-(C1-6 al- kyl), -S(O)2-NH2, -S(O)2-NH(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)(C1-6 alkyl), -NH-S(O)2-(CI.6 alkyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(Co-3 alkylene)-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(Co-3 alkylene)-phenyl, and

[0286] -(C0-3 alkylene)-(5- or 6-membered heteroaryl), wherein the aforementioned heterocycloalkyl and heteroaryl rings in- dependently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, wherein in said alkylene moiety of said -(Co-3 alkylene)-(3- to 7- membered cycloalkyl), -(Co-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3 alkylene)-phenyl, and -(C0-3 alkylene)-(5-or6-membered heteroaryl) one -CH2- group if present is optionally replaced by -O-, and wherein the 3- to 7-membered cycloalkyl moiety in said -(C0-3 alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said

[0287] -(C0-3 alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(Co-3 alkylene)-(5- or 6-membered het- eroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, -O(C1-2 alkyl), and -O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a 3- to 7-membered heterocycloalkyl ring formed by two R3together with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused 5- or 6-membered heteroaryl ring, which comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized.

[0288] In a more preferred embodiment, each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C1-3 al- kylene)-phenyl,and -(C1-3 alkylene)-(5- or 6-membered heteroaryl), each optionally substituted with one or more RS3, wherein the aforementioned heterocycloalkyl and heteroaryl rings independently comprise one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non -oxi- dized; provided that not both R3are -H; or the two R3together with the nitrogen atom to which they are attached form a 3 - to 7-membered heterocycloalkyl ring, optionally substituted with one or more RS3, and optionally comprising in addition to the nitrogen atom one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized.

[0289] In an even more preferred embodiment, each R3is independently selected from a group selected from the connection to the nitrogen atom of the remainder of the molecule, i.e. the nitrogen atom to which the two R3are attached; provided that not both R3are -H; or the two R3together with the nitrogen atom to which they are attached form a group selected from wherein the wavy line in each case marks the connection to the remainderof the molecule , i.e. to R1-2, if present, or to L1, if R12is absent.

[0290] Preferably, if one R3is -H or -CH3, then the other R3is n to the nitrogen atom of the remainder of the molecule, i.e. the nitrogen atom to which the two R3are attached.

[0291] In one preferred embodiment,

[0292] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2.

[0293] In another preferred embodiment,

[0294] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2.

[0295] In a more preferred embodiment,

[0296] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R12.

[0297] In an even more preferred embodiment,

[0298] A is selected from wherein the wavy line marks the connection to the remainder of the molecule.

[0299] In another preferred embodiment, A is wherein the wavy line marks the connection to the remainder of the molecule; and wherein

[0300] L2is wherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1.6 alkylene)-OH, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl); and wherein

[0301] R13is absent or Ci alkylene; and wherein

[0302] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6alkyl), -(C2-6 alkylene)-N(C1-6 al- kyl )(C1-6 alkyl), -(C0.3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 al- kylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, or-(C2-3 alkylene)- O-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0.3 alkylene)-heterocycloalkyl, -(C1-3 alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl or -(C2-3 alkylene)-O-cycloalkyl, the heterocycloalkyl moiety in said -(C0.3 alkylene)-heterocycloalkyl or -(C2-3 alkylene)-O-heterocycloalkyl, the aryl moiety in said -(C1-3 alkylene)-aryl or -(C2-3 alkylene)-O-aryl, and the heteroaryl moiety in said -(C1-3 alkylene)-het- eroaryl or -(C2-3 alkylene)-O-heteroaryl, are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl).

[0303] In a preferred embodiment,

[0304] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(Ci-Balkyl), -(C2-6 alkylene)-N(C1-6 al- kyl)(C1-6 alkyl), -(C0-3 alkylene)-(3- to 7-membered cycloalkyl), -(C2-3 alkylene)-O-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C2-3 alkylene)-O-(3- to 7-membered heterocycloalkyl), -(C1-3 alkylene)-phenyl, -(C2-3 alkylene)-O-phenyl, -(C1-3 alkylene)-(5- or 6-membered heteroaryl), or -(C2-3 alkylene)- O-(5- or 6-membered heteroaryl), wherein the aforementioned heterocycloalkyl and heteroaryl rings independently com prise one or more, same or different heteroatoms selected from O, N, or S, wherein said N - and / or S-atoms are independently oxidized or non-oxidized, wherein in said alkylene moiety of said -(Co-3 alkylene)-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3-to 7-membered heterocycloalkyl), -(C1-3alkylene)-phenyl, and -(C1-3 alkylene)-(5- or e- membered heteroaryl) one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the 3- to 7-membered cycloalkyl moiety in said -(C0-3 alkylene)-(3-to 7-membered cycloalkyl) or -(C2-3 alkylene)-O-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(Co-3 alkylene)-(3- to 7-membered heterocycloalkyl) or -(C2-3 alkylene)-O-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C1-3 alkylene)-phenyl or -(C2-3 alkylene)-O-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C1-3 alkylene)-(5- or 6-membered heteroaryl) or -(C2-3 alkylene)-O-(5- or 6-membered heteroaryl), are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl).

[0305] In a more preferred embodiment,

[0306] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6 alkyl), -(Co-3 alkylene)-(3- to 7-mem- bered cycloalkyl), -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C1-3 alkylene)-phenyl, or -(C1-3 alkylene)-(5- or 6-membered heteroaryl), wherein the aforementioned heterocycloalkyl and heteroaryl rings independently com- prise one or more, same or different heteroatoms selected from O, N, or S, wherein said N - and / or S-atoms are inde- pendently oxidized or non-oxidized, wherein in said alkylene moiety of said -(Co-3 alkylene)-(3- to 7-membered cyclo- alkyl), -(Co-3 alkylene)-(3-to 7-membered heterocycloalkyl), -(C1-3 alkylene)-phenyl, and -(C1-3 alkylene)-(5- ore-mem- bered heteroaryl) one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the 3- to 7-membered cycloalkyl moiety in said -(C0-3 alkylene)-(3- to 7-membered cycloalkyl) the 3- to 7-membered hetero- cycloalkyl moiety in said -(C0-3 alkylene)-(3-to 7-membered heterocycloalkyl), the phenyl in said -(C1-3 alkylene)-phe- nyl, and the 5- or 6-membered heteroaryl moiety in said -(C1-3 alkylene)-(5- or 6-membered heteroaryl), are each op- tionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl).

[0307] In an even more preferred embodiment, each R4is independently selected from a group selected from wherein the wavy line in each case marks the connection to the nitrogen atom of L2. In a preferred embodiment,

[0308] L2is wherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4; and

[0309] R13is absent.

[0310] wherein the wavy line marks the connection to the remainder of the molecule.

[0311] In one embodiment of the invention, which applies to compounds of formula (I), and preferably also to compounds of formula (l-R1-1 ), (l-R1-2), (la), (lb), (Ic), and (Id) as well as to compounds of formula (la-R1-1 ), (la-R1-2), (lb-R1-1 ), (lb-R1-2), (lc-R1-1 ), (lc-R1-2), (ld-R1-1 ), and (ld-R1-2),

[0312] A is a moiety selected from wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein

[0313] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2; and

[0314] Lzis wherein the dashed line in each case marks the connection to R1-3, and the wavy line in each case marks the connection to R4; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1.2 alkyl, C1.2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -O(C1-2 alkyl), or

[0315] -O(C1-2 haloalkyl); and wherein

[0316] RL1is absent or C1-2 alkylene;

[0317] R1-2is absent or C1-2 alkylene;

[0318] R13is absent or C1-2 alkylene; and wherein each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, and -(C2-3 alkylene)-O-heteroaryl, each optionally substituted with one or more RS3; pro- vided that not both R3are -H; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(CI.Balkyl), -N(C1-6 alkyl)(C1-6 alkyl), C1-6 alkyl, C1-6 haloalkyl, -(Ci-Balkylene)-CN, -(Ci-Balkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl),

[0319] -(C1-6 alkylene)-N(C1-6 al kyl )(Ci-Balkyl), -O(C 1-6 al kyl ), -O(Ci-Bhaloalkyl), -(Ci-Balkylene)-O(C1-6alkyl), -(Ci-Bal- kylene)-S(C1-6 alkyl), -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COOH, -COO(C1-6 al- kyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 al kyl )(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 al- kyl), -S(O)2-(C1-6 alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)(Ci-Balkyl), -NH-S(O)2-(CI-Bal- kyl), -N(C1-6 alkyl)-S(O)2-(Ci-Balkyl), -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)- heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -O-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(Co-3 alkylene)-aryl, and the heteroaryl moiety in said -(C0-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, -O(C1-2 alkyl), and -O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a heterocycloalkyl ring formed by two R3to- gether with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused heteroaryl ring; and wherein

[0320] R4is -H, Ci-Balkyl, Ci-Bhaloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6alkyl), -(C2-6 alkylene)-N(Ci-Bal- kyl)(Ci-Balkyl), -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 al- kylene)-O-heterocycloalkyl, -(C1.3 alkylene)-aryl, -(C2-3alkylene)-O-aryl, -(C1.3 alkylene)-heteroaryl, or-(C2-3 alkylene)- O-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C1.3 alkylene)-aryl, and -(C1.3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the cycloalkyl moiety in said -(Co- 3 alkylene)-cycloalkyl or -(C2-3 alkylene)-O-cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl or -(C2-3 alkylene)-O-heterocycloalkyl, the aryl moiety in said -(C1.3 alkylene)-aryl or -(C2-3 alkylene)-O-aryl, and the heteroaryl moiety in said -(C1.3 alkylene)-het- eroaryl or -(C2-3 alkylene)-O-heteroaryl, are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2alkyl). In connection with the above definitions of R3, RS3, and R4, cycloalkyl preferably refers to C3-7 cycloalkyl, heterocy- cloalkyl preferably refers to a 3- to 7-membered heterocycloalkyl ring comprising one or more ring heteroatoms inde- pendently selected from O, S and N, wherein the one or more S ring atoms (if present) and / or one or more N ring at- oms (if present) may optionally be oxidized , aryl preferably refers to phenyl, and heteroaryl preferably refers to a 5- or 6-membered heteroaryl ring comprising one or more ring heteroatoms independently selected from O, S and N, wherein the one or more S ring atoms (if present) and / orone or more N ring atoms (if present) may optionally be oxi- dized.

[0321] Thus, -(C0-3 alkylene)-cycloalkyl is preferably -(Co- 3 alkylene)-(C3-z cycloalkyl), -(C0-3 alkylene)-heterocycloalkyl is preferably -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(Co-3alkylene)-aryl is preferably -(C0-3 alkylene)-phe- nyl, and -(C0-3 alkylene)-heteroaryl is preferably -(C0-3 al kylene)-(5- or 6-membered heteroaryl), wherein the heterocy- cloalkyl and heteroaryl rings independently comprise one ormore ring heteroatoms independently selected from O, S and N, wherein the one or more S ring atoms (if present) and / orone or more N ring atoms (if present) may optionally be oxidized.

[0322] Further, -(C1-3 alkylene)-aryl is preferably -(C1-3 alkylene)-phenyl, and -(C1-3 alkylene)-heteroaryl is preferably -(C1-3 alkylene)-(5- or 6-membered heteroaryl), wherein the heterocycloalkyl and heteroaryl rings independently com- prise one or more ring 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.

[0323] Similarly, -(C2-3 alkylene)-O-cycloalkyl is preferably -(C2-3 alkylene)-O-(C3.? cycloalkyl), -(C2-3 alkylene)-O-heterocy- cloalkyl is preferably -(C2-3 alkylene)-O-(3- to 7-membered heterocycloalkyl), -(C2-3 alkylene)-O-aryl is preferably -(C2-3 alkylene)-O-phenyl, and -(C2-3 alkylene)-O-heteroaryl is preferably -(C2-3 alkylene)-O-(5- or 6-membered het- eroaryl), wherein the heterocycloalkyl and heteroaryl rings independently comprise one or more ring heteroatoms in- dependently 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.

[0324] In connection with the substituents R3, R4, and RS3, it is preferred that the selection of these substituents does not result in a heteroatom , e.g., an oxygen or nitrogen atom , or halogen atom directly attached to a carbon atom , which is directly attached to the nitrogen atom contained in the A moiety.

[0325] Further, in connection with the substituents Rx, it is preferred that the selection of this substituent does not result in a heteroatom, e.g., an oxygen or nitrogen atom , or a halogen atom directly attached to a carbon atom , which is di- rectly attached to the nitrogen atom contained in the A moiety or directly attached to the nitrogen atom of the amido group of the remainder of the molecule.

[0326] Thus, in a preferred embodiment, if R3or R4are -(C2-3 alkylene)-O-cycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C2-3 alkylene)-O-aryl, or-(C2-3 alkylene)-O-heteroaryl, it is preferred that the oxygen atom contained in these groups is not directly attached to a carbon atom , which is directly attached to the nitrogen atom contained in the A moiety.

[0327] Further, in a preferred embodiment, if R3or R4represent a group, wherein -CH2- is replaced by CH(OH), it is pre- ferred that the CH(OH) group is not directly attached to the nitrogen atom contained in the A moiety.

[0328] In another preferred embodiment, if RS3is -Hal, -OH, -NH2, -NH(C1-6 alkyl), N(Ci-a alkyl)(C1-6 alkyl), or a group, wherein -CH2- is replaced by -O-, it is preferred that the halogen, nitrogen, or oxygen atom of these RS3substituents is not directly attached to a carbon atom , which is directly attached to the nitrogen atom contained in the A moiety.

[0329] In another preferred embodiment, if two RS3attached to the same carbon atom form =0, it is preferred that the =0 is not attached to a carbon atom, which is directly attached to the nitrogen atom contained in the A moiety.

[0330] In a preferred embodiment, if a substituent Rxis present at L1or L2, it is preferred that -Hal, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl) are not directly attached to a carbon atom , which is directly attached to a nitrogen atom of the A- moiety, or to a carbon atom , which is directly attached to the nitrogen atom of the amido group of the remainder of the molecule. In one preferred embodiment, which applies to com pounds of formula (I), and preferably also to compounds of for- mula (l-R1-1 ), (l-R1-2), (la), (lb), (Ic), and (Id) as well as to compounds of formula (la-R1-1 ), (la-R1-2), (lb-R1-1 ), (lb-R1-2), (lc-R1-1 ), (lc-R1-2), (ld-R1-1 ), and (ld-R1-2), A is wherein the wavy line marks the connection to the remainder of the molecule and the variables are as defined above and hereinafter. Said A-moiety is hereinafter referred to as A1 .

[0331] Compounds of formula (I), wherein A is the above moiety A1 , are referred to as compounds of formula (I-A1 ):

[0332] In a more preferred embodiment, A is

[0333] R3

[0334] - RL1— L1— RL2— NZ

[0335] R3. wherein the wavy line marks the connection to the remainder of the molecule; and wherein

[0336] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl); and wherein

[0337] RL1is absent; and

[0338] R12is absent or Ci alkylene; and wherein each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl,

[0339] -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, and -(C2-3 alkylene)-O-heteroaryl, each optionally substituted with one or more RS3; pro- vided that not both R3are -H; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(Ci-Balkyl), C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-CN, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl),

[0340] -(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkyl), -O(C1-6 alkyl), -O(C1-6 haloalkyl), -(C1-6 alkylene)-O(C1-6 alkyl), -(C1-6 al- kylene)-S(C1-6 alkyl), - -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COO(C1-6 al- kyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 al kyl )(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 al- kyl), -S(O)2-(C1-6 alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)(Ci-Balkyl), -NH-S(O)2-(CI-6 al- kyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)- heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -O-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(Co-3 alkylene)-aryl, and the heteroaryl moiety in said

[0341] -(C0-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, -O(C1-2 alkyl), and -O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a heterocycloalkyl ring formed by two R3to- gether with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused heteroaryl ring.

[0342] In connection with L1it is preferred that p is 0 or 1 ; and

[0343] Rx, if present, is -Hal, -OH, C1-2 alkyl, C1-2 haloalkyl, or 0(0-2 alkyl).

[0344] If Rxis present and represents -Hal, -OH, or -O(C1-2 alkyl), it is preferred that it is not directly attached to a carbon atom , which is directly attached to a nitrogen atom of the A-moiety, or to a carbon atom, which is directly attached to the nitrogen atom of the amido group of the remainder of the molecule.

[0345] It is even more preferred that p is 0, i.e. Rxis absent.

[0346] Thus, in one preferred embodiment,

[0347] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2.

[0348] In another preferred embodiment,

[0349] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R12.

[0350] As indicated above, RL1is preferably absent.

[0351] R12is preferably absent or Ci alkylene. In one embodiment, RL2is absent. In one embodiment, R1-2is Ci alkylene.

[0352] In view of the above, the moiety A, if it is a moiety A1 , is preferably selected from the following moieties: wherein the wavy line in each case marks the connection to the remainder of the molecule.

[0353] In one preferred embodiment, the moiety A, if it is a moiety A1 , is selected from the following moieties:

[0354] In one preferred embodiment, the moiety A, if it is a moiety A1 , is selected from the following moieties:

[0355] In one preferred embodiment, the moiety A, if it is a moiety A1 , is selected from the following moieties:

[0356] In one preferred embodiment, the moiety A, if it is a moiety A1 , is selected from the following moieties:

[0357] In connection with the above A1 moieties, it is preferred that each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C1-3 alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl, each optionally substituted with one or more RS3; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3.

[0358] Preferably RS3is independently selected from -CN, -Hal, -OH, C1.6 alkyl, C1.6 haloalkyl, -(C1.6 al- kylene)-OH, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). It is even more preferred that RS3is independently selected from -Hal and -OH.

[0359] In a preferred embodiment, each R3is independently selected from -H, C1.5 alkyl, -(Co-3 alkylene)-(3- to 7-mem- bered heterocycloalkyl), -(C1-3 alkylene)-phenyl, and -(C1-3 alkylene)-(5- or 6-membered heteroaryl), each optionally substituted with one or more RS3, wherein the heterocycloalkyl and heteroaryl rings independently comprise one or more ring 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 ; or the two R3together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring, optionally substituted with one or more RS3, wherein the heterocycloalkyl ring comprises one or more ring het- eroatoms 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.

[0360] In this connection, it is particularly preferred that RS3is independently selected from -CN, -Hal, -OH, C1-6 alkyl, C-i-6 haloalkyl, -(Cvs alkylene)-OH, -O(C1-6alkyl), and -O(C1-6 haloalkyl). It is even more preferred that RS3is inde- pendently selected from -Hal and -OH.

[0361] In one embodiment, it is preferred that one R3is -H or C1-5 alkyl, and the other R3is -(Co-3 alkylene)-heterocycloal- kyl, -(C1-3 alkylene)-aryl, or -(C1-3 alkylene)-heteroaryl, each optionally substituted with one or more RS3, or the two R3togetherwith the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring, optionally substituted with one or more RS3.

[0362] In this connection, it is particularly preferred that RS3is independently selected from -CN, -Hal, -OH, C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-OH, -O(C1-6alkyl), and -O(C1-6 haloalkyl). It is even more preferred that RS3is inde- pendently selected from -Hal and -OH.

[0363] In a preferred embodiment, one R3is -H or C1.5 alkyl, and the otherR3is -(Co-3 alkylene)-(3-to 7-membered hetero- cycloalkyl), -(C1-3 alkylene)-phenyl, or-(C1-3 alkylene)-(5- or 6-membered heteroaryl), each optionally substituted with one or more RS3, wherein the heterocycloalkyl and heteroaryl rings independentlycomprise one or more ring heteroa- toms 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; or the two R3together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring, optionally substituted with one or more RS3, wherein the heterocycloalkyl ring comprises one or more ring het- eroatoms 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.

[0364] In this connection, it is particularly preferred that RS3is independently selected from -CN, -Hal, -OH, C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-OH, -O(C1-6alkyl), and -O(C1-6 haloalkyl). It is even more preferred that RS3is inde- pendently selected from -Hal and -OH.

[0365] It is even more preferred that one R3is -H or Ci alkyl, and the other R3is -(Ci alkylene)-aryl, or -(Ci alkylene)-het- eroaryl, each optionally substituted with one or more RS3, or the two R3togetherwith the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with one or more RS3.

[0366] In this connection, it is particularly preferred that RS3is independently selected from -CN, -Hal, -OH, C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-OH, -O(C1-6alkyl), and -O(C1-6 haloalkyl). It is even more preferred that RS3is inde- pendently selected from -Hal and -OH.

[0367] It is yet even more preferred that one R3is -H or Ci alkyl, and the other R3is -(Ci alkylene)-phenyl, or -(Ci al- kylene)-^- or 6-membered heteroaryl), each optionally substituted with one or more RS3, wherein the heterocycloalkyl and heteroaryl rings independentlycomprise one ormore ring heteroatoms independently selected from O, S and N, wherein the one or more S ring atoms (if present) and / orone or more N ring atoms (if present) may optionally be oxi- dized; or the two R3together with the nitrogen atom to which they are attached form a 5 - or 6-membered heterocycloalkyl ring, optionally substituted with one or more RS3, wherein the heterocycloalkyl ring comprises one or more ring het- eroatoms 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. In this connection, it is particularly preferred that RS3is independently selected from -CN, -Hal, -OH, C-i-g alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-OH, -O(C1-6alkyl), and -O(C1-6 haloalkyl). It is even more preferred that RS3is inde- pendently selected from -Hal and -OH.

[0368] It is yet even more preferred thatone R3is -H or Ci alkyl, and the other R3is benzyl or pyridinylmethyl, each option- ally substituted with one or more RS3, or the two R3together with the nitrogen atom to which they are attached form a pyrrolidine ring, optionally substi- tuted with one or more RS3.

[0369] In this connection, it is particularly preferred that RS3is independently selected from -CN, -Hal, -OH, C1-6 alkyl, C-i-6 haloalkyl, -(Cvs alkylene)-OH, -O(C1-6alkyl), and -O(C1-6 haloalkyl). It is even more preferred that RS3is inde- pendently selected from -Hal and -OH.

[0370] In one preferred embodiment, which applies to com pounds offormula (I), and preferably also to compounds of for- mula (l-R1-1 ), (l-R1-2), (la), (lb), (Ic), and (Id) as well as to compounds of formula (la-R1-1 ), (la-R1-2), (lb-R1-1 ), (Ib-R1- wherein the wavy line marks the connection to the remainder of the molecule and the variables are as defined above and hereinafter. Said A-moiety is hereinafter referred to as A2.

[0371] Compounds of formula (I), wherein A is the above moiety A2, are referred to as compounds of formula (I-A2):

[0372] In a more preferred embodiment, A is wherein the wavy line marks the connection to the remainder of the molecule; and wherein

[0373] L2is wherein the dashed line in each case marks the connection to R1-3, and the wavy line in each case marks the connection to R4; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl); and wherein

[0374] R13is absent or Ci alkylene; and wherein

[0375] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(Ci-Balkyl), -(C2-6 alkylene)-N(C1-6 al- kyl)(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 al- kylene)-O-heterocycloalkyl, -(C1.3 alkylene)-aryl, -(C2-3alkylene)-O-aryl, -(C1.3 alkylene)-heteroaryl, or-(C2-3 alkylene)- O-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(Co- 3 alkylene)-heterocycloalkyl, -(C1-3 alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the cycloalkyl moiety in said -(Co- 3 alkylene)-cycloalkyl or -(C2-3 alkylene)-O-cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl or -(C2-3 alkylene)-O-heterocycloalkyl, the aryl moiety in said -(C1.3 alkylene)-aryl or -(C2-3 alkylene)-O-aryl, and the heteroaryl moiety in said -(C1.3 alkylene)-het- eroaryl or -(C2-3 alkylene)-O-heteroaryl, are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2alkyl).

[0376] In connection with Lz, it is to be understood that the optionally present Rxsubstituent(s) can be present at any posi- tion of the L2group, i.e. in case of bridged, fused, or spiro rings, the Rxsubstituent(s) may be present at each ring as well as at the bridge. However, it is preferred that, if Rxis -Hal, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl), Rxis not di- rectly attached to a carbon atom , which is directly attached to a nitrogen atom of the A-moiety, or to a carbon atom , which is directly attached to the nitrogen atom of the amido group of the remainder of the molecule.

[0377] In connection with L2, it is preferred that p is 0 or 1 ; and

[0378] Rx, if present, is -Hal, -OH, C1-2 alkyl, C1-2 haloalkyl, or -O(C1-2 alkyl).

[0379] If Rxis present and represents -Hal, -OH, or -O(C1-2 alkyl), it is preferred that it is not directly attached to a carbon atom , which is directly attached to a nitrogen atom of the A-moiety, or to a carbon atom, which is directly attached to the nitrogen atom of the amido group of the remainder of the molecule.

[0380] It is even more preferred that p is 0, i.e. that the optional Rxsubstituent is absent.

[0381] In one particularly preferred embodiment,

[0382] L2is wherein the dashed line in each case marks the connection to R1-3, and the wavy line in each case marks the connection to R4.

[0383] As indicated above, RL3is preferably absentorCi alkylene. In one embodiment, RL3is absent. In one embodiment, R13is Ci alkylene.

[0384] In connection with Lzbeing it is preferred that RL3is absent.

[0385] In view of the above, the moiety A, if it is a moiety A2, is preferably selected from the following moieties: wherein the wavy line marks the connection to the remainder of the molecule.

[0386] Preferably, the moiety A, if it is a moiety A2, is selected from the following moieties:

[0387] In connection with the above A2 moieties, it is preferred that

[0388] R4is -H, C-i-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-0(C1-6alkyl), -(Co-3 alkylene)-heterocycloal- kyl, -(C1-3 alkylene)-aryl, or-(C1-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-hetero- cycloalkyl, -(C1.3 alkylene)-aryl, and -(C1.3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(C1-3 alkylene)-aryl and the heteroaryl moiety in said -(C1-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -0(C1-2 al- kyi).

[0389] In a more preferred embodiment, R4is -H, C-i-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6 alkyl), -(C0-3 alkylene)-(3- to 7-mem- bered heterocycloalkyl), -(C1-3 alkylene)-phenyl, or -(C1-3 alkylene)-(5- or 6-membered heteroaryl), wherein in said alkylene moiety of said -(Co-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C1-3 alkylene)-phenyl, and -(C1-3 al- kylene)-(5- or 6-membered heteroaryl), one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)- , and wherein the heterocycloalkyl moiety in said -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C1-3 alkylene)-phenyl and the heteroaryl moiety in said -(C1-3 al kylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl); and wherein the heterocycloalkyl and heteroaryl rings independently comprise one or more ring 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.

[0390] In another preferred embodiment,

[0391] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C0-1 alkylene)-heterocycloalkyl, -(Ci alkylene)-aryl, or -(Ci alkylene)-heteroaryl, wherein in said alkylene moiety of said -(C0-1 alkylene)-heterocycloalkyl, -(Ci alkylene)-aryl, and -(Ci alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the heterocycloalkyl moiety in said -(C0-1 alkylene)-heterocycloalkyl, the aryl moiety in said -(Ci alkylene)-aryl and the heteroaryl moiety in said -(Ci alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1.2 alkyl, C1.2 haloalkyl, and -O(C1-2 alkyl).

[0392] In a more preferred embodiment,

[0393] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C0-1 alkylene)-(3- to 7-membered heterocycloalkyl), -(Ci alkylene)-phenyl, or -(Ci alkylene)-(5- or 6-membered heteroaryl), wherein in said alkylene moiety of said -(C0-1 alkylene)-(3- to 7-membered heterocycloalkyl), -(Ci alkylene)-phenyl, and -(Ci alkylene)-(5- or 6-membered heteroaryl), one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the heterocy- cloalkyl moiety in said -(C0-1 alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(Ci alkylene)-phenyl and the heteroaryl moiety in said -(Ci alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1.2 alkyl, C1-2 haloalkyl, and -O(C1-2alkyl); and wherein the heterocycloalkyl and heteroaryl rings independently comprise one or more ring heteroatoms independently se- lected from O, S and N, wherein the one or more S ring atoms (if present) and / or one or more N ring atoms (if pre- sent) may optionally be oxidized.

[0394] In another preferred embodiment,

[0395] R4is -H, C1-6 alkyl, -(C2-6 alkylene)-OH, -(C0-1 alkylene)-heterocycloalkyl, or -(Ci alkylene)-aryl, wherein in said alkylene moiety of said -(C0-1 alkylene)-heterocycloalkyl, or-(Ci alkylene)-aryl, one -CH2- group if present is optionally replaced by - -CH(CH2OH)-, and wherein the heterocycloalkyl moiety in said -(C0-1 alkylene)-heterocycloalkyl, and the aryl moiety in said -(Ci alkylene)-aryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2alkyl).

[0396] It is especially preferred that

[0397] R4is H, Ci-C2-alkyl, -(C1-6 alkylene)-OH, oxetanyl, benzyl, p-fluorobenzyl, or

[0398] Particularly preferred com pounds of formula (I) are selected from the following compounds or a stereoisomer, tauto- mer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

[0399] In a particularly preferred embodiment, the compound of formula (I) is a compound selected from the following com- pounds:

[0400]

[0401] In a particularly preferred embodiment, the compound of formula (I) is a compound selected from the following com-

[0402] 5 pounds:

[0403]

[0404] In another particularly preferred embodiment, the com pound of formula (I) is a compound selected from the follow-

[0405] 5 ing compounds:

[0406] 5

[0407] In another particularly preferred embodiment, the compound offormula (I) is a compound selected from the follow- ing compounds:

[0408]

[0409] The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of formula (I) which maybe formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protona- tion, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; am monium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrim ethylammonium salts, benzyltriethylammo- nium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for ex- ample: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihy- drogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclo- pentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesul- fonate (esylate),2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidicamino acid salts such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts of the com- pounds of formula (I) include s hydrochloride salt, a hydrobrom ide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt. A particularly preferred pharmaceutically accepta- ble salt of the compound of formula (I) is a hydrochloride salt. Accordingly, it is preferred that the compound of for- mula (I), including any one of the specific com pounds of formula (I) described herein, is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, or a phosphate salt, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt. The present invention also specifically relates to the compound of formula (I), including anyone of the specific com- pounds of formula (I) described herein, in non-salt form .

[0410] Moreover, the scope of the invention embraces the compounds of formula (I) in any solvated form , including, e.g., solvates with water (i.e., as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crys- talline forms (i.e., polymorphs), of the compounds offormula (l) are also encompassed within the scope of the inven- tion. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of the com- pounds of the formula (I) are likewise embraced by the invention.

[0411] Furthermore, the com pounds of formula (I) may exist in the form of different stereoisomers (including, e g., geomet- ric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, prototropic tautomers, such as keto / enol tautomers or th ione / th lol tautomers). All such stereoisomers or tautomers of the com- pounds of formula (I) are contemplated as being part of the present invention, either in admixture or in pure or sub- stantially pure form . As for stereoisomers, the invention embraces the isolated optical isomers of the compounds ac- cording to the invention as well as any mixtures thereof (including, in particular, racemic mixtures / racemates). The racemates can be resolved (i.e., separated) by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomericderivatives. orseparation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystalli- zation. The present invention further encompasses any tautomers of the compounds of formula (I). It will be under- stood that some com pounds may exhibit tautomerism . In such cases, the formulae provided herein expressly depict onlyone of the possible tautomericforms. The formulae and chemical names as provided herein are intended to en- compass anytautomericform ofthe corresponding compound and not to be lim ited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.

[0412] Furthermore, the com pounds of formula (I) may exist in the form of N -oxides, i.e. in a form with at least one tertiary nitrogen atom being oxidized to an N-oxide moiety.

[0413] The scope of the invention also embraces com pounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e.,ZH; also re- ferred to as "D”). Accordingly, the invention also embraces com pounds of formula (I) which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol -% hydrogen-1 (1H) and about 0.0156 mol-% deuterium (ZH or D). The content of deuterium in one or more hydrogen positions in the com pounds of formula (I) can be increased using deuteration techniques known in the art. For example, a compound of formula (I) or a reac- tant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H / D exchange reaction using, e g., heavy water (D2O). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(1 1 -12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861 -5868, 2014. The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compound of formula (I) is not enriched in deuterium . Accordingly, the presence of naturally occur- ring hydrogen atoms or1H hydrogen atoms in the compounds of formula (I) is preferred.

[0414] The present invention also embraces com pounds of formula (I), in which one or more atoms are replaced by a posi- tron-emitting isotope of the corresponding atom , such as, e.g.,18F,11C,13N,150,76Br,77Br,1ZOI and / or1Z4I. Such com- pounds can be used as tracers, trackers or imaging probes in positron emission tomography (PET). The invention thus includes (i) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are re- placed by18F atoms, (ii) com pounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by11C atoms, (ill) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen at- oms) are replaced by13N atoms, (iv) com pounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxy- gen atoms) are replaced by15O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e g., all bromine atoms) are replaced by76Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by77Br atoms, (vii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by120l atoms, and (viii) com pounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by124l atoms. In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by specific isotopes.

[0415] The compounds provided herein may be administered as compounds perse or may be formulated as medica- ments. The medicaments / pharmaceutical compositions may optionally comprise one or more pharmaceutically ac- ceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigmen ts, stabilizers, preservatives, antioxidants, and / or solubility enhancers.

[0416] The pharmaceutical compositions may comprise one ormore solubility enhancers, such as, e.g., polyethylene gly- col), including poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tylox- apol, polysorbate 80, macrogol-15-hydroxystearate (e g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, leci- thin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a-cyclodextrin, p-cyclodextrin, y-cyclodextrin, hydroxyethyl-P-cyclodextrin, hydroxypropyl-P-cyclodextrin, hydroxy- ethyl-y-cyclodextrin, hydroxypropyl-y-cyclodextrin. dihydroxypropyl-p-cyclodextrin. sulfobutylether-p-cyclodextrin, sul- fobutylether-y-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-P-cyclodextrin, diglucosyl-P-cyclodextrin, maltosyl-a- cyclodextrin, maltosyl-P-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-P-cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-p-cyclodextrin, methyl-p-cyclodextrin, a carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypro- pylcellulose, polyvinylpyrrolidone, a vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0417] The pharm aceutical compositions may also com prise one or m ore preservatives, particularly one or m ore antim icro- bial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2 -ethoxyethanol, m-cresol, chlorocresol (e.g., 2- chloro-3-methyl-phenol or4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoicacid (or a pharmaceutically acceptable saltthereof), sorbic acid (or a pharmaceutically acceptable saltthereof), chlorhexidine, thimerosal, or any combination thereof.

[0418] The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in “Remington: The Science and Practice of Pharmacy”, Pharmaceutical Press, 22ndedition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, in- travenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administra- tion. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitu- tion, dispersible powders and granules, medicated gums, chewing tablets and effervescenttablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for re- constitution. Emulsions are a preferred dosage form forparenteral administration. Dosage forms for rectal and vagi- nal administration include suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and insufflation, forexample bya metered inhaler. Dosage formsfortopical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.

[0419] The compounds of formula (I) or the above described pharmaceutical com positions com prising a compound of for- mula (I) may be administered to a subject by any convenient route of administration, whether system ically / peripher- allyor at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as a n ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e g., using injec- tion techniques or infusion techniques, and including, for exam pie, by injection, e.g., subcutaneous, intradermal, intra- muscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intra- peritoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for ex- am pie, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aero- sol, e.g., through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including in- travitreal or intracameral), rectal, or vaginal administration.

[0420] If said compounds or pharmaceutical compositions are administered parenterally, then examples of such admin- istration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intra u- reth rally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and / or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (prefera- bly to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations understerile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0421] Said compoundsorpharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

[0422] The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), so- dium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvi- nylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be in- cluded. Solid com positions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols. For aqueous suspen- sions and / or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0423] For oral administration, the compoundsorpharmaceutical compositions are preferably administered by oral inges- tion, particularly by swallowing. The compounds or pharmaceutical compositions can thus be administered to pass through the mouth into the gastrointestinal tract, which can also be referred to as “oral -gastrointestinal” administra- tion.

[0424] Alternatively, said compoundsorpharmaceutical compositionscan be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting pow- der. The compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch.

[0425] Said compoundsorpharmaceutical compositions may also be administered by sustained release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include, e.g., polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(-)-3-hydroxy- butyric acid. Sustained-release pharmaceutical compositions also include liposomally entrapped compounds. The present invention thus also relates to liposomes containing a compound of the invention.

[0426] Said compoundsorpharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocularroute. For ophthalmicuse, they can 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 pre- servative such as a benzalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

[0427] It is also envisaged to prepare dry powderformulationsof the compounds of formula (I) for pulmonary administra- tion, particularly inhalation. Such dry powders may be prepared by spray drying under conditions which result in a substantiallyamorphousglassyora substantially crystalline bioactive powder. Accordingly, dry powders of the com- pounds of the present invention can be made according to an emulsification / spray drying process.

[0428] For topical application to the skin, said com pounds or pharmaceutical compositionscan be formulated as a suitable ointmentcontaining the 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 can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.

[0429] The present invention thus relates to the compoundsorthe pharmaceutical compositions provided herein, wherein the corresponding compound orpharmaceutical composition is to be administered by any one of: an oral route; topi- cal route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniquesorinfusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticu- lar, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, in- cluding by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracam eral route; rectal route; or vaginal route. Preferred routes of administration are oral administration or parenteral administration . For each of the compounds or pharmaceutical com positions provided herein, it is particularly preferred that the respective compound orpharmaceutical composition is to be administered orally (particularly by oral ingestion).

[0430] Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specificdose level and frequencyof dosageforany particularindividual subjectmay be varied and will depend upon a variety of factors including the activity of the specific com pound employed, the metabolic stability and length of ac- tion of that com pound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excre- tion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.

[0431] A proposed, yet non-limiting dose of the compounds according to the invention for oral administration to a human (of 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 maybe administered, e.g., 1 to 3 times per day. The unit dose may also be administered 1 to 7 times per week, e.g., with not more than one administration perday. It will be appreciated that it may be neces- sary to make routine variations to the dosage depending on the age and weight of the patient / subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

[0432] The therapeutic use of the compounds of the present invention will be described in the following.

[0433] In one embodiment, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0434] Without wishing to be bound by theory, the present inventors have demonstrated that, as TASL level is regulated by its interaction with SLC15A4,the treatment with the com pounds of formula (I) leads to efficient degradation of TASL.

[0435] It is known to the skilled person and apparent from the literature that SLC15A4 and / or TASL play a crucial role in autoimmune disorders (including SLE)and inflammatory disorders (including inflammatory bowel disease (IBD), pso- riasis, and endosomal TLR-dependent inflammation).

[0436] Accordingly, there is a body of evidence based on genome wide association studies (GWAS) of SLE in human cells indicating the role SLC15A4 in this disorder. Bentham et al. (Bentham etal, (2015)) identified the genetic association of SLC15A4 and TASL (referenced therein as CXorf21 ) with SLE in a cohort of European ancestry. He OF and coworkers (He et al, (2010)) identified the genetic association of SLC15A4 with SLE-related discoid rash in a Chi- n nese Han population. Langefeld and coworkers (Langefeld et al. Transancestral mapping and genetic load in sys- temic lupus erythematosus. Nat Com mun, 8, 16021 (2017)) identified the genetic association of SLC15A4 with SLE in a cohort of European ancestry.

[0437] Further, there is additional evidence of the role of TASL in the pathogenesis of SLE based on genetic studies in hu- man cells. Odhams et al. (Odhams etal (2019)) proposed that genetic variants of TASL (CXorf21 ) associated with SLE lead to increased TASL expression in an interferon- and sex-specific manner and hence suggest a potential ex- planation.

[0438] There is further evidence in mouse models indicating the importance of TASL / SLC15A4 in the development of SLE. Baccala and coworkers (Baccala et al. Essential requirement for IRF8 and SLC15A4 implicates pDCs in the patho- genesis of lupus. PNAS, 110, 2940, (2013)) identified a protective role for SLC15A4 deficiency in the development of SLE in a mouse model using the C57BL / 6-Fas(lpr) strain. Kobayashi and coworkers (Kobayashi et al. (2014)) show that SLC15A4-deficiency is protective in two models of SLE (pristane-induced and C57BL / 6lpr / lpr mice) and that SLC15A4 is required in B cells for endosomal TLRfunction. Pollard and coworkers (Pollard et al. Induction of Sys- temic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN. J Immunol, 199, 3739, (2017)) found thatSLC15A4-deficiency is protective in a mercury-induced model of SLE. Katewa and coworkers (Katewa et al. (2021 )) describe a protective role for SLC15A4 in pristane-induced and NZB / W F1 murine genetic models of SLE and TASL -deficiency protects from auto- immunity in several mouse SLE models (Drobek, A. et al. The TLR7 / 9 adaptors TASL and TASL2 mediate IRF5-de- pendent antiviral responses and autoimmunity in mouse. Nat. Commun. 16, 967 (2025); Lau, L. etal. An essential role for TASL in mouse autoimmune pathogenesis and Toll-like receptor signaling. Nat. Commun. 16, 968 (2025)).

[0439] Accordingly, the com pounds of the present invention are considered useful in the treatmentor prevention of autoim- mune disorders, in particular SLE.

[0440] It can befurtherassumed based on the role of SLC15A4 and / orTASL in IRF5 activation, that the com pounds of the present invention will be useful in the treatment or prevention of autoimmune disorders, preferably selected from SLE, lupus nephritis, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, polymyositis / dermatomyositis, primary biliary cirrhosis, m ultiple sclerosis, oral ulcers, periodontitis, Behcet’s disease, inflammatory bowel disease, psoriasis, myasthenia gravis, and ankylosing spondylitis (Wang et al. (2023), Bentham et al. 2015), Katewa et al. (2021 )).

[0441] There is further a body of evidence based on genetic studies indicating the role of SLC15A4 and / or TASL in proin- flammatory cytokine production (such as IL-6) and inflammation. Heinz and coworkers (Heinz et al. (2020)) have shown an essential role of SLC15A4-TASL and their relationship in human cell linesand primary cells for endosomal TLR function.

[0442] There is furtherevidence based on studies in mouse models indicating the role of SLC15A4 and / or TASL in inflam- matory conditions. Blasius and coworkers (Blasius et al. (2010)) identified SLC15A4 as essential component in endo- somal TLRfunction in pDCs. Sasawatari and coworkers (Sasawatari etal. The solute carrierfamily 15A4 regulates TLR9 and NOD1 functions in the innate immune system and promotes colitis in mice. Gastroenterology, 140, 1513, (2011 )) have found SLC15A4-deficiency to impair CpG-induced production of proinflam matory cytokines from den- dritic cells. Furthermore, SLC15A4-deficiency was found to be protective in a mouse model of IBD. SLC15A4 -defi- cient mice also showed defective cytokine production upon activation of the NOD-like receptor NOD1 . Blasius and coworkers (Blasius et al. Slc15a4, a gene required for pDC sensing of TLR ligands, is required to control persistent viral infection. PLoS Pathog 8, e1002915 (2012)) suggested an important role for SLC15A4 in pDCs in controlling viral persistence, as evidenced in a model of LCMV infection. Nakamura and coworkers (Nakamura etal. Endosomes are specialized platforms for bacterial sensing and NOD2 signalling, Nature, 509, 240, (2014)) proposed a role for SLC15A4 in the activation of NOD2 at the lysosome. Of note, NOD2 mutations are linked to IBD. Dosenovic and coworkers (Dosenovicet ai. Slc15a4 function is required for intact class switch recombination to lgG2c in response to TLR9 stimulation. Immunol Cell Biol, 93, 136, (2015)) find defective endosomal TLRfunction in pDCs, splenic eDCs and B cells. Furthermore, production of antibodies elicited by a CpGA-adjuvanted vaccine is impaired in SLC15A4 mice. Griffith and coworkers (Griffith et al. A requirementforslc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice, Sci Rep 8, 14451 (2018)) describe a requirement for SLC15A4 in imiquimod -in- duced systemic inflam mation and psoriasiform inflammation in mice. Lopez-Haber and coworkers (Lopez-Haber et al. The phagosomal solute transporterSLCI 5A4 promotes inflammasome activity via mTORCI signaling and autophagy restraint in dendriticcells, EMBO J, 41 , e111161 (2022)) describe a contribution of SLC15A4 in inflammasome acti- vation via mTORCI signaling pathways.

[0443] It can be further assumed, based on the role of SLC15A4 and / or TASL in IRF5 activation, that the compounds of the present invention will be useful in the treatmentor prevention of inflammatory condition, preferably selected from inflammatory bowel disease, psoriasiform dermatitis, endosomal TLR-dependent inflammation, ulcerative colitis, Crohn’s disease, endosom al TLR-induced hyperinflammation, macrophage activation syndrome, allergic airway in- flammation, and sarcoidosis, preferably wherein the inflammatory condition is selected from inflammatory bowel dis- ease, psoriasiform dermatitis, and endosomal TLR-dependent inflammation.

[0444] Accordingly, the com pounds of the present invention are useful in treatmentor prevention of an inflammatory condi- tion.

[0445] Thus, in one embodiment, the present invention relates to the compound of formula (I) or its pharmaceutically ac- ceptable salt, or the pharmaceutical composition of the present invention, for use in treatment or prevention of an au- toimmune disorderoran inflammatory condition. In one embodiment, the present invention relates to the compound of formula (I) or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention, for use in treatment or prevention of an autoimmune disorder. In one embodiment, the present invention relates to the compound of formula (I) or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention, for use in treatmentor prevention of an inflammatory condition.

[0446] The autoimmune disorder is preferably selected from systemic lupus erythematosus, rheumatoid arthritis, sclero- derma, Sjogren’s syndrome, polymyositis / dermatomyositis, primary biliary cirrhosis, multiple sclerosis, oral ulcers, periodontitis, Behget’s disease, myasthenia gravis, and ankylosing spondylitis. More preferably the autoimmune dis- order is systemic lupus erythematosus.

[0447] The inflammatory condition is preferably selected from inflammatory bowel disease, psoriasiform dermatitis, endo- somal TLR-dependent inflammation, ulcerative colitis, Crohn's disease, endosomal TLR-induced hyperinflammation, macrophage activation syndrome, allergic airway inflammation, and sarcoidosis. More preferably, the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-dependent in- flammation.

[0448] In one embodiment, the present invention relates to use of the compound of formula (I) or its pharmaceutically ac- ceptable salt, or the pharmaceutical composition of the presentinvention, in the manufacture of a medicamentforuse in the treatmentor prevention of an autoimmune disorderoran inflammatory condition. In one embodiment, the pre- sent invention relates to use of the compound of formula (I) or its pharmaceutically acceptable salt, or the pharma- ceutical composition of the presentinvention, in the manufacture of a medicamentfor use in the treatment or preven- tion of an autoimmune disorder. In one embodiment, the present invention relates to use of the compound of formula (I) or its pharmaceutically acceptable salt, orthe pharmaceutical composition of the present invention, in the manu- facture of a medicamentfor use in the treatment or prevention of an inflammatory condition.

[0449] In one embodiment, the present invention relates to the method of treating an autoimmune disorder, the method comprising administering the compound of formula (I) or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention, to a subject in need thereof. It is to be understood that said compound or its salt or said pharmaceutical composition is to be administered in a therapeutically effective amount, preferably as de- scribed herein.

[0450] In one embodiment, the present invention relates to the method of treating an inflammatory condition, the method comprising administering the compound of formula (I) or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention, to a subject in need thereof. It is to be understood that said compound or its salt or said pharmaceutical composition is to be administered in a therapeutically effective amount, preferably as de- scribed herein.

[0451] It is to be noted that the compound of formula (I) or its salt has been shown by the present inventors to inhibit SLC15 peptide transporter (i.e., SLC15A4). Accordingly and preferably, it is expected that the therapeutic effect of the compound of formula (I) or its salt is based on the inhibition of SLC15 peptide transporter (i.e., SLC15A4). Ac- cordingly, in one embodiment the present invention relates to the compound of formula (I) or its salt, or the pharma- ceutical composition of the present invention for use in the treatment or prevention of an autoimmune disorder, wherein said compound or said pharmaceutical composition inhibits SLC15 peptide transporter. Given the ability of the compound of the present invention, or its salt, to inhibit the SLC15 peptide transporter, said compound is particu- larly useful in the treatment of the autoimmune disorder, wherein the autoimmune disorder is a disorder associated with SLC15 peptide transporter. Accordingly, the present invention in one embodiment relates to the compound of formula (I) or its salt, or the pharmaceutical composition of the present invention wherein said compound or said pharmaceutical composition for use in the treatment or prevention of an autoimmune disorder, wherein the autoim- mune disorder is a disorder associated with SLC15 peptide transporter.

[0452] The compounds provided in the present invention are also useful in treatmentor prevention of other lupus diseases such as cutaneous or neonatal lupus erythematosus.

[0453] The invention will be illustrated in the following examples, which however are not to be construed as limiting.

[0454] Examples

[0455] List of abbreviations:

[0456] Methods:

[0457] HPLC-MS Methods:

[0458] Method 1 :

[0459] Instrument - Shimadzu Prominance HPLC attached with API 2000 Mass Spectrometer from Applied Biosystems.

[0460] Ionisation method: Electrospray

[0461] UV Wavelength range (nm): 220 and 260

[0462] Solvent A: 10 mM Ammonium Acetate in Water and Solvent B: Acetonitrile

[0463] Flow rate: 1 .2 ml / min mobile phase: from 90 % [10 mM Ammonium Acetate in Water] and 10 % [Acetonitrile] to 70% [10 mM Ammonium

[0464] Acetate in Water] and 30% [Acetonitrile] in 1.50 min, further 10% [10 mM Ammonium Acetate in Water] and 90% [Acetonitrile] in 3.00 min, held this mobile phase composition up to 4.00 min and finally back to initial condition in 5.00 min.

[0465] Type of column: Xbridge C18 (4.6 x 50 mm, 5 micron)

[0466] Mass conditions:

[0467] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source

[0468] Declustering Potential: 50 V

[0469] Mass range: 200-1700 amu

[0470] Scan type: Q1

[0471] Polarity: + / -ve

[0472] Ion Source: Turbo spray

[0473] Ion spray voltage: +5500 for +ve mode and -4500 for -ve mode

[0474] Method 1a:

[0475] Instrument - Shimadzu Prominance HPLC attached with API 2000 Mass Spectrometer from Applied Biosystems.

[0476] Ionisation method: Electrospray

[0477] UV Wavelength range (nm): 220 and 260

[0478] Solvent A: 10 mM Ammonium Acetate in Water and Solvent B: Acetonitrile

[0479] Flow rate: 1 .0 ml / min mobile phase: 95 % [10 mM Ammonium Acetate in Water] and 5 % [Acetonitrile] held for 1 .50 min, then 50% [10 mM Ammonium Acetate in Water] and 50% [Acetonitrile] in 7.00 min, further 10% [10 mM Ammonium Acetate in Water] and 90% [Acetonitrile] in 10.00 min, held this mobile phase composition up to 11.00 min and finally back to initial condition in 12.00 min.

[0480] Type of column: Xbridge C18 (4.6 x 50 mm, 5 micron)

[0481] Mass conditions:

[0482] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source

[0483] Declustering Potential: 50 V

[0484] Mass range: 100-1200 amu

[0485] Scan type: Q1

[0486] Polarity: + / -ve

[0487] Ion Source: Turbo spray

[0488] Ion spray voltage: +5500 for +ve mode and -4500 for -ve mode

[0489] Mass Source temperature: 200 °C. Method 1 b:

[0490] Instrument - Shimadzu Prominance HPLC attached with API 2000 Mass Spectrometer from Applied Biosystems.

[0491] Ionisation method: Electrospray

[0492] UV Wavelength range (nm): 220 and 260

[0493] Solvent A: 10 m M Ammonium Acetate in Water and Solvent B: Acetonitrile

[0494] Flow rate: 1 .2 ml / min mobile phase: from 50 % [10 mM Ammonium Acetate in Water] and 50 % [Acetonitrile] to 5% [10 m M Ammonium Acetate in Water] and 95% [Acetonitrile] in 1 .50 min, held this mobile phase composition up to 4.00 min and finally back to initial condition in 5.00 min.

[0495] Type of column: Xbridge C18 (4.6 x 50 mm , 5 micron)

[0496] Mass conditions:

[0497] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source Declustering Potential: 50 V

[0498] Mass range: 100-1300 amu

[0499] Scan type: Q1

[0500] Polarity: + / -ve

[0501] Ion Source: Turbo spray

[0502] Ion spray voltage: +5500 for +ve mode and -4500 for -ve mode

[0503] Mass Source temperature: 200 °C.

[0504] Method 2:

[0505] Waters Acquity H Class UPLC attached with Waters SQD 2 mass spectrometer.

[0506] Ionisation method: Electro spray

[0507] Capillary (kV) 3.50, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow

[0508] (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0509] Mass range:100 to 900 Da

[0510] DAD Wavelength range (nm): 200 to 400

[0511] Solvent A: 5 mM NFUOAc in water and Solvent B: 5 mM NFUOAc in ACN: Water (90:10)

[0512] Flow rate: 1 .20 ml / min

[0513] (mobile phase: 95% [5 m M NH4OAC in water] and 5% [5 mM NFUOAc in ACN: Water (90:10)] held for 0.75 min, then 85% [5 m M NH4OAC in water] and 15% [5 mM NH4OAc in ACN: Water (90:10)] in 1 .25 min further30% [5 mM NH4OAc in water] and 70% [5 mM NH4OAC in ACN: Water (90:10)] in 2.50 min, and finally 2% [5 mM NH4OAC in water] and 98% [5 m M NH4OAC in ACN: Water (90:10)] in 3.75 min, held this mobile phase com position up to 4.25 min and finally back to initial condition in 4.50 min and held this composition up to 5.10 min).

[0514] Column Used: Xbridge C18 column (3.5 pm, 50 x 3 mm)

[0515] Column Temperature: 40 °C.

[0516] Method 3:

[0517] Waters Acquity H Class UPLC attached with Waters QDA mass spectrometer.

[0518] Ionisation method: Electro spray

[0519] Capillary (kV) 0.80, Cone (V) 15.00, Source Temperature (°C) 120, Probe Temperature (°C)600, Mass range:100 to 900 Da

[0520] DAD Wavelength range (nm): 200 to 400

[0521] Solvent A: 0.05% Formic acid in water and Solvent B: 0.05% HCOOH in ACN: Water (90:10)

[0522] Flow rate: 0.6 ml / min

[0523] (mobile phase: 95% [0.05% HCOOH in water] and 5% [0.05% HCOOH in ACN: Water (90:10)] held for 0.75 min, then to 75% [0.05% HCOOH in water] and 25% [0.05% HCOOH in ACN: Water (90:10) ] in 1 .5 min, furtherto 5% [0.05% HCOOH in water] and 95% [0.05% HCOOH inACN: Water (90:10) ] in 3.00 min, held this mobile phase composition up to 4.00 min and finally back to initial condition in 4.50 min and held this composition up to 5.10 min).

[0524] Column Used: Waters Acquity UPLC BEH C18 (2.1 x 50 mm, 1.7 micron)

[0525] Column Temperature: 45 °C.

[0526] Mass Source temperature: 200 °C.

[0527] Method 4:

[0528] Waters Acquity H Class UPLC attached with Waters QDA mass spectrometer.

[0529] Ionisation method: Electro spray Capillary (kV) 0.80, Cone (V) 15.00, Source Temperature (°C) 120, Probe Temperature (°C) 600, Mass range:100 to 900 Da

[0530] DAD Wavelength range (nm): 200 to 400

[0531] Solvent A: 0.05% TFA in water and Solvent B: ACN

[0532] Flow rate: 1 .00 ml / min

[0533] (mobile phase: 98% [0.05% TFA in water] and 2% [ACN] held for 1 .00 min, then 40% [0.05% TFA in water] and 60% [ACN] in 4.50 min and finally 5% [0.05% TFA in water] and 95% [ACN] in 9.50 min, held this mobile phase composi- tion up to 13.00 min and finally back to initial condition in 14.00 min and held this composition up to 15.00 min).

[0534] Column Used: Luna Omega Polar C18 column (3 pm, 100 x 4.6 mm)

[0535] Column Temperature: 40 °C.

[0536] Method 5:

[0537] Waters Acquity H Class UPLC attached with Waters QDA mass spectrometer.

[0538] Ionisation method: Electro spray

[0539] Capillary (kV) 0.80, Cone (V) 15.00, Source Temperature (°C) 120, Probe Temperature (°C) 600, Mass range:100 to 900 Da

[0540] DAD Wavelength range (nm): 200 to 400

[0541] Solvent A: 0.05% TFA in water and Solvent B: ACN

[0542] Flow rate: 0.40 ml / min

[0543] (mobile phase: 98% [0.05% TFA in water] and 2% [ACN] to 90% [0.05% TFA in water] and 10% [ACN] in 1 .50 min, then 60% [0.05% TFA in water] and 40% [ACN] in 18.00 min and finally 5% [0.05% TFA in water] and 95% [ACN] in 19.00 min, held this mobile phase composition up to 20.00 min and finally back to initial condition in 22.00 min and held this composition up to 25.00 min).

[0544] Column Used: Acquity BEH C18 column (1 .8 pm, 100 x 2.7mm) Column Temperature: 40 °C.

[0545] Method 6:

[0546] Waters Acquity UPLC attached with Waters ZQ mass spectrometer.

[0547] Ionisation method: Electro spray

[0548] Capillary (kV) 3.50, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow

[0549] (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0550] Mass range:100 to 900 Da

[0551] DAD Wavelength range (nm): 200 to 400

[0552] Solvent A: 5 mM NH4OAc in water and Solvent B: 5 mM NH4OAc in ACN: Water (90:10)

[0553] Flow rate: 1 .20 ml / min

[0554] (mobile phase: 95% [5 m M NFUOAc in water] and 5% [5 mM NFUOAc in ACN: Water (90:10)] held for 0.75 min, then to 70% [5 mM NH4OAC in water] and 30% [5 mM NH4OAC in ACN: Water (90:10) ] in 1 .00 min, and finally 2% [5 mM NH4OAC in water] and 98% [5 mM NH4OAC in ACN: Water (90:10) ] in 2.00 min, held this mobile phase com position up to 2.50 min and finally back to initial condition in 2.75 min and held this composition up to 3.0 min).

[0555] Column Used: Xbridge C18 column (3.5 pm, 50 x 3 mm)

[0556] Column Temperature: Ambient

[0557] Method 7:

[0558] Water Acquity UPLC attached with Waters ZQ micromass mass spectrometer.

[0559] Ionisation method: Electro spray

[0560] Capillary (kV) 3.50, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow

[0561] (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0562] Mass range:100 to 900 Da

[0563] DAD Wavelength range (nm): 200 to 400

[0564] Solvent A: 0.05% Formic acid in water and Solvent B: 0.05% HCOOH in ACN: Water (90:10)

[0565] Flow rate: 1 .0 ml / min (mobile phase: 98% [0.05% HCOOH in water] and 2% [0.05% HCOOH in ACN: Water (90:10)] held for 0.75 min, then 90% [0.05% HCOOH in water] and 10% [0.05% HCOOH in ACN: Water (90:10) ] in 1.0 min, further to 2% [0.05% HCOOH in water] and 98% [0.05% HCOOH in ACN: Water (90:10) ] in 2.00 min, held this mobile phase com position up to 2.25 min and finally back to initial condition in 2.90 min and held this composition up to 3.00 min).

[0566] Column Used: YMC-TRIART C18 (2.1 x 33 mm, 3.0 micron)

[0567] Column Temperature: Ambient

[0568] Method 8:

[0569] Waters Acquity H Class UPLC attached with Waters SQD 2 mass spectrometer.

[0570] Ionisation method: Electro spray

[0571] Capillary (kV) 3.00, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas

[0572] Flow (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0573] Mass range:100 to 900 Da

[0574] DAD Wavelength range (nm): 200 to 400

[0575] Solvent A: 5 mM NH4OAC in water and Solvent B: 5 mM NH4OAC in ACN: Water (90:10)

[0576] Flow rate: 1 .00 ml / min

[0577] (mobile phase: 98% [5 m M NH4OAC in water] and 2% [5 mM NH4OAC in ACN: Water (90:10)] held for 1 .00 min, then 50% [5 m M NH4OAC in water] and 50% [5 m M NH4OAC in ACN: Water (90:10) ] in 5.00 min and finally 2% [5 mM NH4OAC in water] and 98% [5 mM NH4OAC in ACN: Water (90:10) ] in 8.00 min, held this mobile phase composition up to 10.00 min and finally back to initial condition in 1 1 .00 min and held this composition up to 12.00 min).

[0578] Column Used: Xbridge C18 column (3.5 pm, 50 x 3 mm) Column Temperature: 40°C.

[0579] Method 9:

[0580] Water Acquity H Class UPLC attached with Waters SQD 2 mass spectrometer.

[0581] Ionisation method: Electro spray

[0582] Capillary (kV) 3.50, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow

[0583] (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0584] Mass range:100 to 900 Da

[0585] DAD Wavelength range (nm): 200 to 400

[0586] Solvent A: 0.05% Formic acid in water and Solvent B: 0.05% HCOOH in ACN: Water (90:10)

[0587] Flow rate: 0.8 ml / min

[0588] (mobile phase: 95% [0.05% HCOOH in water] and 5% [0.05% HCOOH in ACN: Water (90:10)] held for 0.75 min, then to 75% [0.05% HCOOH in water] and 25% [0.05% HCOOH in ACN: Water (90:10) ] in 1 .5 min, furtherto 5% [0.05% HCOOH in water] and 95% [0.05% HCOOH in ACN: Water (90:10) ] in 3.00 min, held this mobile phase composition up to 4.00 min and finally back to initial condition in 4.50 min and held this composition up to 5.10 min).

[0589] Column Used: Waters Acquity UPLC BEH C8 (2.1 x 50 mm, 1.7 micron)

[0590] Column Temperature: 45 °C.

[0591] Method 10:

[0592] Water Acquity H Class UPLC attached with Waters SQD 2 mass spectrometer.

[0593] Ionisation method: Electro spray

[0594] Capillary (kV) 3.50, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow

[0595] (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0596] Mass range:100 to 900 Da

[0597] DAD Wavelength range (nm): 200 to 400

[0598] Solvent A: 0.05% Formic acid in water and Solvent B: 0.05% HCOOH in ACN: Water (90:10)

[0599] Flow rate: 0.7 ml / min

[0600] (mobile phase: 95% [0.05% HCOOH in water] and 5% [0.05% HCOOH in ACN: Water (90:10)] held for 1 .00 min, then 50% [0.05% HCOOH in water] and 50% [0.05% HCOOH in ACN: Water (90:10) ] in 5.00 min, further to 10% [0.05% HCOOH in water] and 90% [0.05% HCOOH in ACN: Water (90:10) ] in 8.00 min, held this mobile phase composition up to 10.00 min and finally back to initial condition in 1 1 .50 min and held this composition up to 12.00 min).

[0601] Column Used: Waters Acquity UPLC BEH C18 (2.1 x 50 mm , 1.7 micron) Column Temperature: 45 °C. Method 11 :

[0602] Waters Acquity UPLC attached with Waters ZQ mass spectrometer.

[0603] Ionisation method: Electro spray

[0604] Capillary (kV) 3.50, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow

[0605] (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750 Mass range:100 to 900 Da

[0606] DAD Wavelength range (nm): 200 to 400

[0607] Solvent A: 0.05% HCOOH in water and Solvent B: 0.05% HCOOH in ACN: Water (90:10)

[0608] Flow rate: 1 .00 ml / min

[0609] (mobile phase: 95% [0.05% HCOOH in water] and 5% [: 0.05% HCOOH in ACN: Water (90:10) ] held for 0.75 min, then to 70% [0.05% HCOOH in water] and 30% [: 0.05% HCOOH in ACN: Water (90:10) ] in 1.00 min, and finally 2%

[0610] [0.05% HCOOH in water] and 98% [: 0.05% HCOOH in ACN: Water (90:10) ] in 2.00 min, held this mobile phase composition up to 2.50 min and finally back to initial condition in 2.75 min and held this composition up to 3.0 min). Column Used: YMC Triart C18 column (3 pm , 33 x 2.1 mm)

[0611] Column Temperature: Ambient

[0612] Method 12:

[0613] Instrument - Shimadzu Prominance HPLC attached with API 2000 Mass Spectrometer from Applied Biosystems.lonisation method: Electrospray

[0614] UV Wavelength range (nm): 220 and 260 Solvent A: 10 mM Ammonium Acetate in Water and Solvent B: Acetonitrile

[0615] Flow rate: 1 .2 ml / min mobile phase: from 90 % [10 mM Ammonium Acetate in Water] and 10 % [Acetonitrile] to 70% [10 mM Ammonium

[0616] Acetate in Water] and 30% [Acetonitrile] in 1.50 min, further 10% [10 mM Ammonium Acetate in Water] and 90% [Acetonitrile] in 3.00 min, held this mobile phase composition up to 4.00 min and finally back to initial condition in 5.00 min.

[0617] Type of column: Shimpack GIST C18 (4.6 x 50 mm, 5 micron) Mass conditions:

[0618] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source

[0619] Declustering Potential: 50 V

[0620] Mass range: 100-1200 amu

[0621] Scan type: Q1 Polarity: + / -ve

[0622] Ion Source: Turbo spray

[0623] Ion spray voltage: +5500 for +ve mode and -4500 for -ve mode

[0624] Mass Source temperature: 200 °C. Method 13:

[0625] Instrument - Shimadzu Prominance HPLC attached with API 2000 Mass Spectrometer from Applied Biosystems.

[0626] Ionisation method: Electrospray

[0627] UV Wavelength range (nm): 220 and 260

[0628] Solvent A: 10 mM Ammonium Acetate in Water and Solvent B: Acetonitrile Flow rate: 1.2 ml / min mobile phase: from 90 % [10 mM Ammonium Acetate in Water] and 10 % [Acetonitrile] to 70% [10 mM Ammonium Acetate in Water] and 30% [Acetonitrile] in 1.50 min, further 10% [10 mM Ammonium Acetate in Water] and 90% [Acetonitrile] in 3.00 min, held this mobile phase composition up to 4.00 min and finally back to initial condition in 5.00 min.

[0629] Type of column: Shimadzu C18 (4.6 x 50 mm, 5 micron)

[0630] Mass conditions:

[0631] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source

[0632] Declustering Potential: 50 V

[0633] Mass range: 100-1200 amu

[0634] Scan type: Q1

[0635] Polarity: + / -ve

[0636] Ion Source: Turbo spray

[0637] Ion spray voltage: +5500 for +ve mode and -4500 for -ve mode

[0638] Mass Source temperature: 200 deg C.

[0639] Method S1

[0640] Instrument - Agilent 1260 Infinity II + 6125C SQ

[0641] Ionisation method: Electrospray

[0642] UV Wavelength range (nm): 190 and 400

[0643] Solvent A: Water + 0.1 % Formic acid B: Acetonitrile + 0.1 % Formic acid

[0644] Flow rate: 0.6 ml / min

[0645] Mobile phase: 90% [Water + 0.1 % Formic acid] and 10% [Acetonitrile + 0.1 % Formic acid] for 1 .00 min, then gradient to 10% [Water + 0.1 % Formic acid ] and 90% [Acetonitrile + 0.1 % Formic acid] over 4.00 min and further 10% [Water + 0.1 % Formic acid ] and 90% [Acetonitrile + 0.1 % Formic acid] for 2.00 min.

[0646] Type of column: ZORBAX RRHT StableBond C18, 2.1 x 50 mm, 1 .8 pm, 600 bar. 80 A

[0647] Mass conditions:

[0648] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source.

[0649] Declustering Potential: 135 V

[0650] Mass range: 50-1500 m / z

[0651] Scan type: Q1

[0652] Polarity: + / -ve

[0653] Ion Source: Turbo spray

[0654] Ion spray voltage: +4000 for +ve mode and -4000 for -ve mode

[0655] Mass Source temperature: 300 °C.

[0656] Method S2

[0657] Instrument - Agilent 1260 Infinity II + 6125C SQ Ionisation method: Electrospray

[0658] UV Wavelength range (nm): 190 and 400

[0659] Solvent A: Water + 0.1 % Formic acid B: Acetonitrile + 0.1 % Formic acid

[0660] Flow rate: 0.6 ml / min

[0661] Mobile phase: 90% [Water + 0.1 % Formic acid ] and 10% [Acetonitrile + 0.1 % Formic acid] for 1 .00 min, then gradi- ent to 10% [Water + 0.1 % Formic acid ] and 90% [Acetonitrile + 0.1 % Formic acid] over 6.00 min and further 10% [Water + 0.1 % Formic acid ] and 90% [Acetonitrile + 0.1 % Formic acid] for 3.00 min.

[0662] Type of column: ZORBAX RRHT StableBond C18, 2.1 x 50 mm, 1 .8 pm, 600 bar. 80 A

[0663] Mass conditions:

[0664] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source.

[0665] Declustering Potential: 135 V

[0666] Mass range: 50-1500 m / z

[0667] Scan type: Q1

[0668] Polarity: + / -ve

[0669] Ion Source: Turbo spray

[0670] Ion spray voltage: +4000 for +ve mode and -4000 for -ve mode

[0671] Mass Source temperature: 300 °C.

[0672] Method S3

[0673] Instrument - Agilent 1260 Infinity II + 6125C SQ

[0674] Ionisation method: Electrospray

[0675] UV Wavelength range (nm): 190 and 400

[0676] Solvent A: Water + 0.1 % Formic acid B: Acetonitrile + 0.1 % Formic acid

[0677] Flow rate: 0.6 ml / min

[0678] Mobile phase: 90% [Water + 0.1 % Formic acid ] and 10% [Acetonitrile + 0.1 % Formic acid] for 1 .00 min, then gradi- ent to 10% [Water + 0.1 % Formic acid ] and 90% [Acetonitrile + 0.1 % Formic acid] over 11 .00 min and further 10% [Water + 0.1 % Formic acid ] and 90% [Acetonitrile + 0.1 % Formic acid] for 3.00 min.

[0679] Type of column: ZORBAX RRHT StableBond C18, 2.1 x 50 mm, 1 .8 pm, 600 bar. 80 A Mass conditions:

[0680] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source.

[0681] Declustering Potential: 135 V

[0682] Mass range: 50-1500 m / z

[0683] Scan type: Q1

[0684] Polarity: + / -ve

[0685] Ion Source: Turbo spray ton spray voltage: +4000 for +ve mode and -4000 for -ve mode

[0686] Mass Source temperature: 300 °C.

[0687] Method S4

[0688] Instrument - Agilent 1260 Infinity II + 6125C SQ

[0689] Ionisation method: Electrospray

[0690] UV Wavelength range (nm): 190 and 400

[0691] Solvent A: Water + 0.1 % Formic acid B: Acetonitrile + 0.1 % Formic acid

[0692] Flow rate: 0.6 ml / min

[0693] Mobile phase: 85% [Water + 0.1 % Formic acid ] and 15% [Acetonitrile + 0.1 % Formic acid] for 1 .00 min, then gradi- ent to 10% [Water + 0.1 % Formicacid ] and 90% [Acetonitrile + 0.1 % Formic acid] over 4.50 min, further 10% [Water + 0.1 % Formicacid ] and 90% [Acetonitrile + 0.1 % Formicacid] forO.50 min, then gradient back to starting composi- tion over 1 .00 min

[0694] Type of column: ZORBAX RRHT StableBond C18, 2.1 x 50 mm, 1 .8 pm, 600 bar. 80 A

[0695] Mass conditions:

[0696] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source.

[0697] Declustering Potential: 135 V

[0698] Mass range: 50-1500 m / z

[0699] Scan type: Q1

[0700] Polarity: + / -ve

[0701] Ion Source: Turbo spray

[0702] Ion spray voltage: +4000 for +ve mode and -4000 for -ve mode

[0703] Mass Source temperature: 300 °C.

[0704] Method S5

[0705] Instrument - Agilent 1260 Infinity II + 6125C SQ

[0706] Ionisation method: Electrospray UV Wavelength range (nm): 190 and 400

[0707] Solvent A: Water + 0.1 % Formic acid B: Acetonitrile + 0.1 % Formic acid

[0708] Flow rate: 0.6 ml / min

[0709] Mobile phase: 85% [Water + 0.1 % Formic acid ] and 15% [Acetonitrile + 0.1 % Formic acid] for 0.10 min, then gradi- ent to 90% [Water + 0.1 % Formic acid ] and 10% [Acetonitrile + 0.1 % Formic acid] over O.90 min, then gradient to 10% [Water + 0.1 % Formic acid ] and 90% [Acetonitrile + 0.1 % Formic acid] for 21 .00 min and further 10% [Water + 0.1 % Formic acid ] and 90% [Acetonitrile + 0.1 % Formic acid] for 3.00 min

[0710] Type of column: ZORBAX RRHT StableBond C18, 2.1 x 50 mm, 1.8 pm, 600 bar. 80 A

[0711] Mass conditions:

[0712] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source.

[0713] Declustering Potential: 135 V

[0714] Mass range: 50-1900 m / z

[0715] Scan type: Q1

[0716] Polarity: + / -ve

[0717] Ion Source: Turbo spray

[0718] Ion spray voltage: +4000 for +ve mode and -4000 for -ve mode Mass Source temperature: 300 °C.

[0719] RP Preparative HPLC Methods:

[0720] Method N

[0721] Preparative HPLC was done on Waters auto purification instrument. Column name: KINETEX,EVO-C18,100-A(212X 250 MM,5p) operating at am bient temperature and flow rate of 16 mL / min. Mobile phase: A=Acetonitrile: Metha- nol(50:50), B = 20mM Ammonium Bicarbonate in water; Gradient Profile: Mobile phase initial composition of 40% A and 60% B, then 50% A and 50% B in 4.5 min, then to 66% A and 34% B in 15.5 min., then to 100% A and 0% B in 16.5 min., held this composition up to 19 min. for column washing, then returned to initial composition in 19.5 min. and held till 22 min.

[0722] Preparative chiral SFC Methods:

[0723] Preparative chiral SFC Methods A:

[0724] Chiral separation was done on Agilent 1200 series instrument. Column name: CHIRALCEL OD-H (250 X 20 mm) 5p. Operating at ambienttemperature and flow rate is 18.0 mL / min. Mobile phase was mixture of 80% Hexane, 20% EtOH, held this isocratic mixture run up to 27 min with wavelength of 300 nm.

[0725] Preparative chiral SFC Methods I: SFC Prep Purification is running on Waters SFC 80 instruments equipped with Waters 2489 UV / Visible Detector by using I CELLULOSE Z (30 mm x 250 mm), 5p Column operating at 35°C temperature, maintaining flow rate of 70 ml / min, using 55% CO2 in super critical state & 45% of 0.2% Methanolic ammonia in MeOH as Mobile phase. Run this isocratic mixture upto 15.0 minutes and also maintained the isobaric condition of 100 bar at 230 nm wavelength. SFC Prep Conditions

[0726] Analytical chiral SFC methods:

[0727] Analytical chiral SFC method 1 : Instrument: Thar SFC Investigator; Column: I Cellulose Z (4.6 x 150 mm), 5 pm, Mobile phase: 60% CO2 + 40% of (0.3% IP amine in Methanol); Flow: 3 mL / min; % of Co-solvent: 40%; ABPR: 1500 psi; T: 35 °C.

[0728] Analytical chiral SFC method 2: Instrument: Thar SFC Investigator; Column: C AMYLOSE A (4.6 x 250 mm), 5 pm, Mobile phase: 50% CO2 + 50% of (0.3% Methanolic NH3 in ACN: Methanol (1 : 1 )); Flow: 5 mL / min; % of Co-solvent 50%; ABPR:100 bar; T: 35 °C.

[0729] Analytical chiral SFC method 3: Instrument: Thar SFC Investigator; Column: I Cellulose Z (4.6 x 250 mm), 5 pm, Mobile phase: 65% CO2 + 35% of (0.3% Methanolic NH3 in ACN: Methanol (1 :1 )); Flow: 3 mL / min; % of Co-solvent 35%; ABPR:100 bar; T: 35 °C.

[0730] Analytical chiral SFC method 4: Instrument: Acquity UPC2; Column: Chiralpak IK (4.6 x 250 mm), 5 pm, Mobile phase: 60% CO2 + 40% of (0.3% IP amine in Methanol); Flow: 4 mL / min; % of Co-solvent: 40%; ABPR: 1500 psi; T: 35 °C.

[0731] Analytical chiral SFC method 5: Instrument: Acquity UPC2; Column: I Cellulose Z (4.6 x 150 mm), 5 pm, Mobile phase: 60% CO2 + 40% of (0.3% IP amine in Methanol); Flow: 3 mL / min; % of Co-solvent: 40%; ABPR: 1500 psi; T: 35 °C.

[0732] Analytical chiral SFC method 6: Instrument: Acquity UPC2; Column: I Cellulose Z (4.6 x 150 mm), 5 pm, Mobile phase: 60% CO2 + 40% of (0.3% IP amine in ACN: Methanol (1 :1 )); Flow: 3 mL / min; % of Co-solvent: 40%; ABPR: 1500 psi; T: 35 °C.

[0733] Analytical chiral SFC method 7: Instrument: Acquity UPC2; Column: I Cellulose Z (4.6 x 150 mm), 5 pm, Mobile phase: 60% CO2 + 40% of (0.2% IP amine in Methanol); Flow: 3 mL / min; % of Co-solvent: 40%; ABPR: 1500 psi; T: 35 °C.

[0734] Analytical chiral SFC method 8: Instrument: Acquity UPC2; Column: (R, R) Whelk 0-1 (4.6 x 150 mm), 3.5 pm, Mobile phase: 70% CO2 + 30% (0.2% IP amine in Methanol); Flow: 3 mL / min; % of Co-solvent: 30%; ABPR: 1500 psi; T: 35 °C. Analytical chiral SFC method 9: Instrument: Acquity UPC2; Column: Cellulose SC (4.6 x 250 mm), 5 pm , Mobile phase: 50% CO2 + 50% of (0.2% IP amine in Methanol); Flow: 3 mL / m in; % of Co-solvent: 50%; ABPR: 1500 psi; T: 35 °C.

[0735] Analytical chiral SFC method: Instrument: Acquity UPC2; Column: Chiralpak IG (4.6 x 250 mm), 5 pm , Mobile phase: 50% CO2 + 50% of (0.2% IP amine in ACN: MeOH (1 :1 )); Flow: 3 m L / min; % of Co-solvent: 50%; ABPR: 1500 psi; T: 35 °C.

[0736] Analytical chiral SFC method 11 : Instrument: Thar SFC Investigator; Column: (R, R) Whelk 0-1 (4.6 x 150 mm), 5 pm , Mobile phase: 75% CO2 + 25% of (0.3% IP amine in IPA); Flow: 3 g / min; % of Co-solvent: 25%; ABPR: 100 bar; T: 35 °C.

[0737] Analytical chiral SFC method 12: Instrument: Thar SFC Investigator; Column: I Cellulose Z (4.6 x 150 mm), 5 pm, Mobile phase: 60% CO2 + 40% of (0.3% IP amine in ACN: IPA (1 :1 )); Flow: 3 m L / min; % of Co-solvent: 40%; ABPR: 1500 psi; T: 35 °C.

[0738] Analytical chiral SFC method 13: Instrument: Thar SFC Investigator; Column: (R, R) Whelk 0-1 (4.6 x 150 mm), 5 pm , Mobile phase: 75% CO2 + 25% of (0.3% Methanolic NH3 in ACN: MeOH (1 :1 )); Flow: 3 g / min; % of Co-solvent: 25%; ABPR: 100 bar; T: 35 °C.

[0739] Analytical chiral SFC method 14: Instrument: Acquity UPC2; Column: Chiralpak IC (4.6 x 250 mm), 5 pm , Mobile phase: 60% CO2 + 40% of (0.3% IP amine in Methanol); Flow: 3 mL / min; % of Co-solvent: 40%; ABPR: 1500 psi; T: 35 °C.

[0740] Analytical chiral normal phase HPLC:

[0741] Analytical chiral normal phase HPLC Method-1 :

[0742] Chiral NP Method: Chiral separation was done on Agilent 1200 series instrument. Column name: CHIRALPAK IG (250 X 4.6 mm),5p. Operating at ambienttemperature and flow rate is 1.0 mL / min. Mobile phase was mixture of 50% Hex- ane, 25% Ethyl Acetate, 25% EtOH and 0.1 % IP Amine held this isocratic mixture run up to 30 min with wavelength of 272 nm .

[0743] Preparation examples:

[0744] Compounds of the structure (I) can be prepared by a synthesis sequence depicted in the following Schemes 1 -8.

[0745]

[0746] Scheme 1 : Synthesis of intermediates M-3: Intermediates M-3a can be obtained starting from various 3-chloroiso- quinoline-1 -carboxylic acid esters and boronic acids of the formular R1B(OH)2 under Suzuki reaction conditions (method A) or othertransition metal catalyzed coupling reactions to give intermediates M-2a. Saponification of inter- mediates M-2a gives access to intermediates M-3a. Intermediates M-3b can be obtained by reaction of anilines M-4 with aldehydes K2, BF3THF complexand pyruvic acid (method B, J. Org. Chem., 2023, 88, 12816 - 12820). Alterna- tively intermediates M-3b can be obtained by reaction of anilines M-4 with aldehydes K-2, BF3THF complex and ethyl pyruvate (method C, J. Org. Chem., 2023, 88, 12816 - 12820) to obtain intermediates M-2b which are con- verted to intermediates M-3bby saponification. Additional intermediates M-3b can be obtained by reacting isatins M- 5 with K-4and KOH in a condensation reaction (Method D). Intermediates M-6 can be deprotonated using n-BuLi at lowtemperatures in THF and treated with diethyl oxalate (method E) to obtain intermediates M-7. Intermediates M-7 can be reacted with a ketone intermediate K-3 in a condensation reaction (method F) to obtain intermediates M-3c. Isatins M-5 can be acylated with differentacid chlorides K-4 in pyridine to obtain intermediates M-8. Intermediates M- 8 can be reacted with NH4OAC in ethanol at high temperatures (method G) to obtain intermediates M-3d.

[0747] Scheme 2: Synthesis of intermediates B-4a, B-5a and B-4b: Intermediates B-4 can be obtained by mesylation or making the chloride of alcohol B-1 to obtain intermediates B-2 which are reacted with amines B-6 in a substitution reaction to obtain intermediates B-3. The Boc-protected intermediates B-3 can deprotected to obtain intermediates B-4. Boc-protected intermediates B-1 can be deprotected to obtain intermediates B-5a. Ketones E-1 can be sub- jected to a reductive amination reaction with amines B-6 to obtain intermediates E-2. Deprotection of E-2 gives inter- mediates B-4b. Additional amines B-4 and B-5 can be obtained in analogous manner.

[0748]

[0749] PG = Boc or Cbz

[0750] Scheme 3: Synthesis of com pounds (I): Compound of the formula (I) can be obtained by am ide coupling of carboxylic acid intermediates M-3 with amines of the amine intermediates B-4 and E-3. Additional compounds (I) can be ob- tained by amide coupling of M-3 with amines D-1 followed by cleavage of the protecting group. Additional compounds (I) can be obtained from compounds (I) with at least one R3= H by subjecting them to a reductive amination oralkyla- tion reactions with the corresponding aldehydes, ketones, or chlorides, bromides, mesylates or other alkylating rea- gents respectively.

[0751] am for

[0752] D'2n - 1 or 2 D-3 n = 1 or 2 O n = 1 or 2

[0753] Scheme 4: Synthesis of compounds (I): Compounds (I) can be obtained by reacting intermediates M-3 in an ami- dation reaction with amines B-5 to obtain alcohol intermediates M-10 followed by conversion of intermediates M-10 into chlorides, bromides, tosylates, or mesylates M-11 and subsequent reaction of intermediates M-11 with an amine B-6 to obtain com pounds (I). Additional com pounds (I) can be obtained via a sequence starting from carboxylic acids M-3 and performing an amidation with amines B-8 to obtain intermediates M-12. Intermediates M-12 can be depro- tected to obtain aldehyde intermediates M-13 which can be subjected to a reductive amination reaction with amines B-6 to obtain com pounds (I). Additional com pounds (I) can be obtained by reacting intermediates M-3 with amines B- 7 in amidation reactions to obtain intermediates M-14 which can be subjected to reductive amination with amines B-6 to obtain compounds (I). Com pounds (I) can also be obtained via am ide formation of intermediates M-3 with amines D-1ato obtain intermediates D-2 which can be deprotected to obtain amine intermediates D-3. The amine intermedi- ates D-3 can be converted to compounds (I) with one R3= H via reductive amination with the corresponding alde- hydes or ketones. Optionally these com pounds (I) can be objected to another reductive amination to obtain additional com pounds (I). Another way of making compounds (I) is reacting intermediates M-15 with amines B-4b in amidation reactions following a Suzuki reactions of intermediates M-16 with boronic acids K-1 (method H).

[0754]

[0755] Scheme d: Synthesis of compounds (I): Compounds (I) can be obtained in a sequence starting from carboxylic acid intermediates M-3 which can be reacted with amines B-10, B-11 , B-12, B-13, or B-14 in an amidation reaction to ob- tain intermediates M-17, M-19, M-21 , M-23, or M-25 respectively. Subsequently intermediates M-17, M-19, M-21 , M- 23, or M-25 can be deprotected to obtain compounds (I). Compounds with R4= H can be reacted with the corre- sponding aldehydes or ketones in reductive amination reactions to obtain compounds (I), or to alkylation reactions with the corresponding chlorides, bromides, mesylates, tosylates, or othersuitable alkylation reagents to obtain com- pounds (I). Compounds (I) can be further modified to obtain additional compounds (I) e.g. reduction of an ester group in R4 to the corresponding alcohol. epoxide opening

[0756] Scheme 6: Additional compounds (I) can be obtained by reacting intermediates M-3 with amines B-15 in an ami- dation reaction to obtain intermediates M-27. Intermediates M-27 are epoxidized to obtain intermediates M-28. Com- pounds (I) can be obtained by opening the epoxide intermediates M-28 with an amine B-6. Additional compounds (I) can be obtained by reacting selected compounds (I) (if one R3in (I) is a hydrogen) with an aldehyde or ketone in a reductive amination reaction.

[0757] epoxide opening

[0758] Scheme 7: Additional compounds (I) can be obtained by reacting intermediates M-3 with amines B-16 in an ami- dation reaction to obtain intermediates M-29. Intermediates M-29 are epoxidized to obtain intermediates M-30. Com- pounds (I) can be obtained by opening the epoxide in intermediates M-30 with an amine B-6. Additional compounds (I) can be obtained by reacting selected com pounds (I) (if one R3in (I) is a hydrogen) with an aldehyde or ketone in a reductive amination reaction.

[0759] Scheme 8: Additional compounds (I) can be obtained in a sequence by starting with epoxide intermediates M-30 which can be opened by applying suitable reactions with nucleophiles (alcohols, thiols, nitrile, Grignard reagents, etc.) to introduce a R4and obtain alcohols M-31 . Alcohol intermediates M-31 are oxidized to the corresponding ke- tones M-32 which are reacted with amines B-6 in a reductive amination reaction to obtain compounds (I). Synthesis of methyl 3-(4-ethoxyphenyl)isoquinoline-1 -carboxylate (M-2a-1 ):

[0760] To a stirred solution of methyl 3-chloroisoquinoline-1 -carboxylate (M-1 a) (1 .0 g, 4.52 mmol) in a mixture of dioxane: H2O (4:1 ) (8.0 mL),was added K3PO4 (2.88 g, 13.57 mmol). The mixture was purged with argon for 10 min. (4 -Ethox- yphenyl) boronic acid (0.9 g, 5.43 mmol) and PdCl2(dtbpf) (0.29 g, 0.45 mmol) were added under argon atmosphere and the mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to ambient temperature, diluted with a mixture of water (10 m L) and EtOAc (20 m L). The layers separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulfate, solvents concentrated under reduced pres- sure and the residue was purified by Com biflash chromatography (eluted with 10-20% EtOAc-hexanes) to afford me- thyl 3-(4-ethoxyphenyl) isoquinoline-1 -carboxylate (M-2a-1 ).

[0761] HPLC-MS (Method 1 ): Rt = 3.93 min; Observed m / z: [M+H]+= 307.9.

[0762] Additional compounds M-2a are available in an analogous manner using different intermediates M-1 and boronic ac- ids K-1 as starting materials. The crude products are purified by chromatography if necessary.

[0763] Synthesis of 3-(4-ethoxyphenyl)isoquinoline-1 -carboxylic acid (M-3a-1 ):

[0764] To a stirred solution of methyl 3-(4-ethoxyphenyl) isoquinoline-1 -carboxylate (M-2a-1 ) (500 mg, 1 .63 mmol) in THF:MeOH:H2O (7:3:2) (10.0 mL), was added LIOH H2O (205 mg, 4.88 mmol) and stirred for 16 h at room tempera- ture. The reaction was diluted with water, washed with ethyl acetate, aqueous layeracidified to pH 6 using 1 N aque- ous HCI at 0°C. The product was extracted with 10% MeOH in DCM (3 x 10 m L). The combined organic layer was dried over anhydrous sodium sulfate and solvents were evaporated under reduced pressure to afford 3 -(4-ethoxy- phenyl) isoquinoline-1 -carboxylic acid (M-3a-1 ).

[0765] HPLC-MS (Method 2): Rt = 2.09 min; Observed m / z: [M+H]+= 294.2.

[0766] Additional intermediates M-3a are available in an analogous manner using different intermediates M-2 as starting ma- terials. The crude products are purified by chromatography if necessary. Synthesis of ethyl 7-chloro-2-(4-ethoxyphenyl)-6-fluoroquinoline-4-carboxylate (M-2b-1 ):

[0767] To a solution of M-4a (1 .48 g, 10.2 mmol) in 20 mL acetonitrile were added 4-ethoxybenzaldehyde (K-2a, 1 .71 g, 11 .4 mmol) and BF3THF (397 mg, 2.84 mmol) at room temperature. The reaction mixture was heated to 65 °C and stirred for 10 min. To the resulting solution, ethyl pyruvate (660 mg, 5.68 mmol) in 15 mL acetonitrile was added drop- wise over 3 h. After the addition stirring was continued for24 h at 65 °C. The reaction mixture was evaporated to dry- ness, redissolved in 100 mL DCM and washed with saturated aqueous NaHCOa (3 times). The organic phase was dried over MgSO4, filtered and the solvents were evaporated. Purification of the crude material was done by column chromatography on 80 g silica with cyclohexane-DCM gradient to afford M-2b-1.

[0768] Additional intermediates M-2bare available in an analogous manner using different intermediates M-4and aldehydes K-2 as starting materials. The crude products are purified by chromatography if necessary (Table Ex1 ). Table Ex1 : Synthesis of ethyl 7-chloro-2-(4-ethoxyphenyl)-6-fluoroquinoline-4-carboxylic acid (M-3b-1 ):

[0769] The ester intermediate M-2b-1 (1 .56 g, 4.17 mmol) was dissolved in 100 mLTHF / water (2 / 1 , v / v) followed by addition of aqueous 50% NaOH (1 mL). The mixture was stirred for 18 hours. THF was evaporated under reduced pressure, and aqueous 37% HCI was added dropwise under stirring to acidify the mixture until a precipitate was formed. The resulting precipitate was collected by filtration, washed with cold water, and diethyl ether, and dried under vacuum to give intermediate M-3b-1. Additional intermediates M-3 are available in an analogous manner using different intermediates M-2 as starting ma- terials. The crude products are purified by chromatography if necessary (Table Ex 2).

[0770] Table Ex 2:

[0771] Synthesis of ethyl 2-(4-ethoxyphenyl)-8-(trifluoromethyl)quinoline-4-carboxylic acid (M-3b-4):

[0772] To a solution of aniline M-4d (1 .64 g, 10.2 mmol) in 20 mL acetonitrile were added 4 -ethoxybenzaldehyde (K-2a, 1 .71 g, 11 .4 mmol) and BF3THF (397 mg, 2.84 mmol) at room temperature. The reaction mixture was heated to 65 °C and stirred for 10 min at the same temperature. To the resulting solution, pyruvic acid (500 mg, 5.68 mmol) in 15 mL of acetonitrile was added dropwise over 3 h, and after the addition, stirring was continued for 24 h at 65 °C. After cool- ing the reaction mixture to room temperature, brine was added, and extraction was performed with EtOAc (150 mL). The combined organic layer was washed with brine, dried over MgSCX filtered and evaporated in vacuo till dryness. The resulting crude material was purified by column chromatography on 80 g silica column with DCM / MeOH gradient to yield M-3b-4.

[0773] Additional intermediates M-3b are available in an analogous manner using different intermediates M-4 and K-2 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 3). Table Ex 3:

[0774] Synthesis of methyl 7-chloro-2-(4-ethoxyphenyl) quinoline-4-carboxylic acid (M-3b-7): Potassium hydroxide (1 .85 g, 33.04 mmol) was added to a mixture of 6-chloro-2,3-dihydro-1 H-indole-2, 3-dione (M- 5a) (2 g, 11 .01 mmol), and 1-(4-ethoxyphenyl)ethan-1-one (K-3a) (2.17 g, 13.21 mmol) in EtOH (20 mL) and the re- action mixture was heated to 80 °C and stirred at the same temperature for 24 h. The reaction mixture was concen- trated in vacuo and taken up in water and washed with ethyl acetate. The layers were separated, and the water phase was acidified to pH 1 using 1 N aq. solution of HCI to give a precipitate. The solid was filtered and washed with ice-cold water. The solid was dried under vacuum to afford 7-chloro-2-(4-ethoxyphenyl) quinoline-4-carboxylic acid (M-3d-7) which was used in the next step without further purification.

[0775] Additional intermediates M-3b are available in an analogous manner using different intermediates M-5 and K-3 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 4).

[0776] Table Ex 4:

[0777] Synthesis of 2,7-dichloroquinoline-4-carboxylate: 6-chloro-2,3-dihydro-1 H-indole-2, 3-dione (1 .5 g, 8.261 mmol) and malonic acid (2.58 g, 24.783 mmol) were dissolved in AcOH (75 mL). Then reaction mixture was stirred at reflux for 16 h. The reaction mixture was evaporated under vacuum and the residue was diluted with water (15 m L). The generated solid was filtered. The sloid was transferred to aqueous NaHCOa solution. The basic aqueous part was cooled to 0 °C and acidified with 2 N aqueous HCI solu- tion to pH -1 . The precipitate was filtered and washed with cold water. The solid was dried under vacuum to afford 7 - chloro-2-hydroxyquinoline-4-carboxylic acid.

[0778] Table Ex 4a:

[0779] Synthesis of Preparation of 2-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyrimidine:

[0780] 1.

[0781] Preparation of reagent 2-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyrimidine:

[0782] A mixture of 5-bromo-2-ethoxypyrimidine (1 .3 g, 6.403 mmol), bis(pinacolato)diboron (3.25 g, 12.806 mmol), freshly dried potassium acetate (1.8 g, 19.208 mmol), and Pd(dppf)Cl2 DCM (209 mg, 0.256 mmol) in dioxane (48 m L) was degassed with nitrogen and heated to 100 °C for 16h . Solvents were evaporated under vacuum . The residue was treated with brine (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 2-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl) pyrimidine the crude was used in the next step without purification.

[0783] LC-MS (Method-1 ): Rt = 3.36 min; Calculated: m / z = 250.15, Observed: [M+H]+= 251 .2.

[0784] Preparation of ethyl 7-chloro-2-(2-ethoxypyrimidin-5-yl) quinoline-4-carboxylate:

[0785] To a de-gassed solution of ethyl 2,7-dichloroquinoline-4-carboxylate (100 mg, 0.37 mmol) in dioxane : water (4:1 ) (5 m L) were added 2-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (93 mg, 0.37 mmol), K3PO4 (157 mg, 0.74 mmol) and Pd-1 18 (19 mg, 0.03 mmol). The reaction mixture was again degassed for 10 minutes and stirred at 80°C for 1 h. The reaction mixture was diluted with EtOAc (15 mL) and water (5 mL). The organic layer was separated and dried over anhydrous sodium sulfate, filtered and evaporated. The crude residue was purified by com bi -flash col- umn chromatography (30% EtOAc in hexanes as eluent) to afford ethyl 7-chloro-2-(2-ethoxypyrimidin-5-yl) quinoline- 4-carboxylate.

[0786] Table Ex 4b:

[0787] Synthesis of Preparation of 7-chloro-2-(2-ethoxypyrimidin-5-yl) quinoline-4-carboxylic acid (M-3b-15):

[0788] To a stirred solution of ethyl 7-chloro-2-(2-ethoxypyrimidin-5-yl)quinoline-4-carboxylate (400 mg, 1.118 mmol) in THF (10 mL) was added KOSiMea (286 mg, 2.236 mmol). The reaction mixture was stirred at room temperature for 2 h.The reaction mixture was neutralized with 2 N aqueous HCI and evaporated under vacuum to afford 7-chloro-2-(2-ethoxy- pyrim idin-5-yl) quinoline-4-carboxylic acid (M-3b-15). The crude was used in the next step without purification.

[0789] Table Ex 4c: Synthesis of methyl 2-(4-ethoxyphenyl)-1 ,6-naphthyridine-4-carboxylic acid (M-3c-1 ):

[0790] M-7

[0791] To a stirred solution of ethyl 2-[4-(2,2-dimethylpropanamido) pyridin-3-yl]-2-oxoacetate (600 mg, 2.16 mmol) in EtOH:H2O (4:1 ) (20 mL), was added KOH (483 mg, 8.63 mmol) and refluxed for 2 h. 1 -(4-ethoxyphenyl) ethan-1-one (K-3a) (743 mg, 4.52 mmol) was added and the reaction mixture was refluxed for an additional 16 h. The reaction mixture was concentrated undervacuum. Water was added and the mixture was washed with EtOAc and the phases were separated. The aqueous layerwas acidified to pH 6 by addition of 2 N aqueous HCI solution at ice bath temper- ature. The resulting precipitate was filtered and dried under vacuum to afford 2 -(4-ethoxyphenyl)-1 ,6-naphthyridine-4- carboxylic acid (M-3c-1).

[0792] Additional intermediates M-3c are available in an analogous manner using different intermediates M-7 and K-3 as starting materials. The crude products are purified by chromatography if necessary. (Table Ex 5).

[0793] Table Ex 5:

[0794] Synthesis of methyl 1 -(4-ethoxybenzovh indoline-2, 3-dione (M-8a):

[0795] An oven dried two neck 100 mL round bottom flask was charged with a magnetic stirring bar and isatin (M-5a, 500 mg, 3.4 mmol). 7.5 mL of anhydrous pyridine was added under nitrogen atmosphere and the reaction mixture was cooled in an ice-bath.4-Ethyoxybenzoyl chloride (K-4a, 0.68 mL, 4.42 mmol) was added drop-wise. Upon completion of addition, the reaction mixture was slowly allowed to warm to room temperature and heated to 60 °C afterwards.

[0796] The reaction mixture was stirred at 60 °C for2h. The reaction mixture was cooled (ice -bath) and neutralized by addi- tion of 1 N aqueous HCI to pH - 7. Water was added to the mixture, the phases were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layerwas washed with brine, dried over sodium sulfate, concentrated followed by azeotropic distillation with toluene to afford 1-(4-ethoxybenzoyl) indoline-2, 3-dione (M-8a) which was used in the next step without further purification.

[0797] Additional intermediates M-8 are available in an analogous manner using differentintermediates M-5 and / or different acid chlorides K-4 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 6).

[0798] Table Ex 6:

[0799] Synthesis of 2-(4-ethoxyphenyl) guinazoline-4-carboxylic acid (M-3d-1 ): N H4OAC, EtOH

[0800] M-3d-1

[0801] 1-(4-ethoxybenzoyl) indoline-2, 3-dione (M-8a)(500 mg, 1 .69 mmol)wasadded to an oven dried sealed tube. Ammo- nium acetate (1 .3 g, 16.93 mmol) was added followed by anhydrous ethanol (5 mL). The reaction mixture was heated in a pre-heated oil bath to 100 °C under vigorous stirring and stirred at this temperature for 16 h. The organic solvent was evaporated, and the solid residue was dissolved in water. The aqueous layer was acidified (pH ~ 5) by addition of 1 N aqueous HCI undercooling (ice-bath)and extracted with a mixture of 20% isopropanol in DCM. The combined organic layer was washed with brine, dried over sodium sulfate, concentrated, and the residue was purified by com bi - flash chromatography using 0-20% MeOH in DCM as eluent to afford 2-(4-ethoxyphenyl) quinazoline-4-carboxylic acid (M-3d-1 ).

[0802] Additional compounds in table M-3d are available in an analogous manner using differentintermediates M-8 as start- ing materials. The crude products are purified by chromatography if necessary (Table Ex 7). Table Ex 7:

[0803] Synthesis of 2-(6-ethoxypyridin-3-yl)quinazoline-4-carboxylic acid (M-3d-5):

[0804] To a stirred solution of 2-chloroquinazoline-4-carboxylic acid (130 mg, 0.62 mmol) and (6-ethoxypyridin-3-yl) boronic acid (104.06, 0.62 mmol) in dioxane (7 m L) and water (1 mL), K3PO4 (132.12 mg, 0.62 mmol) was added to the reaction mixture and deoxygenated by purging with nitrogen for five minutes. PdCl2(dtbpf) (40.57 mg, 0.06 mmol) was added to the reaction mixture and stirred at 100 °C for 16h . The reaction mixture was filtered over celite, and the filtrate was concentrated under vacuum . The residue was diluted with water (5m L) and washed with ether (2 x 5m L). The aqueous layer was acidified using aqueous 1 N HCI to pH~2-3. The product was extracted with 10% MeOH in DCM (3 x 10 mL). The combined organic layer was washed with brine (2 x 1 OmL), dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under vacuum to afford 2-(6-ethoxypyridin-3-yl) quinazoline-4-carboxylic acid.

[0805] Additional compounds in table M-3d are available in an analogous manner using different chlorides or boronic acids as starting materials. The crude products are purified by chromatography if necessary (Table Ex 7c).

[0806] Table Ex 7c:

[0807] Preparation of 2-(5-fluoropyridin-2-yl) quinazolin-4(3H)-one:

[0808] To a stirred solution of 2-amino-4-fluorobenzamide (2.0 g, 14.68 mmol) in DMAc (20 mL), were added 5-fluoropico- linaldehyde (1 .83 g, 14.68 mmol) and NaHSOa (764 mg, 7.34 mmol). The resulting solution was stirred overnight at 150°C. The reaction mixture was cooled to 25°C. The resulting solution was slowly diluted with water (100 mL). The resultantsolids were collected by filtration. The solid was washed with water (2 x 20 mL) and ether (20 mL).The solid was dried under vacuum to afford 2-(5-fluoropyridin-2-yl) quinazolin-4(3H)-one.

[0809] Table Ex 7d:

[0810] Preparation of 4-chloro-2-(5-fluoropyridin-2-vh guinazoline:

[0811] A suspension of 2-(5-fluoropyridin-2-yl) quinazolin-4(3H)-one (1 .2 g,4.97 mmol) in POCI3 (20 mL) was added N, N- diethyl aniline (0.3 mL, 0.17 mmol). The resulting solution was stirred for 16 h at 120°C. The reaction mixture was concentrated under vacuum. The residue was dissolved in 30 m L of dichloromethane. The resulting mixture was neu- tralized with NH4OH solution. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The crude compound was purified by combi-flash column chromatography (50% EtOAc in hexanes as eluent) to afford 4-chloro-2-(5-fluoropyridin-2-yl) quinazoline.

[0812] Table Ex 7e:

[0813] Preparation of 4-(1-ethoxyvinyl)-2-(5-fluoropyridin-2-yl) quinazoline:

[0814] Cl Tributyl(1-ethoxyvinyl)stannane,

[0815] To a stirred and de-gassed solution of 4-chloro-2-(5-fluoropyridin-2-yl) quinazoline (650 mg, 2.50 mmol) in toluene (30 mL) were added tributyl(1 -ethoxyethenyl) stannane (904 mg, 2.50 mmol) and Pd(dppf)2Cl2DCM (204 mg, 0.25 mmol) under nitrogen. The reaction mixture was stirred at 110°C for 16 h. After completion of the reaction, reaction mixture was quenched with KF solution (50 mL) and extracted with ethyl acetate (2 x 75 mL). Organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under vacuum . The resi- due was purified by combi-flash column chromatography (50% EtOAc in hexanes as eluent) to afford 4-(1 -ethoxyvi- nyl)-2-(5-fluoropyridin-2-yl) quinazoline.

[0816] Table Ex 7f:

[0817] Preparation of ethyl 2-(5-fluoropyridin-2-yl) quinazoline-4-carboxylate (M-2d-1 ):

[0818] To a stirred solution of 4-(1 -ethoxyvinyl)-2-(5-fluoropyridin-2-yl) quinazoline (500 mg,1 .69 mmol) in dioxane (10 mL) was added a solution of NalO4 (724 mg, 3.3 mmol) and KMnO4 (50 mg, 0.34 mmol) in water (5 mL) was added under ice cold conditions. The reaction mixture was stirred at room tern perature for 16h. After completion of the reaction, as confirmed by LC-MS, the reaction mixture was filtered through celite. The reaction mixture was diluted with water (20 m L) and extracted with EtOAc (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and filtrate was evaporated under vacuum . The crude residue was purified by com bi -flash column chromatog- raphy (50% EtOAc in hexanes as to 10% MeOH in DCM as eluent) to afford ethyl 2-(5-fluoropyridin-2-yl) quinazoline- 4-carboxylate (M-2d-1 ).

[0819] Additional intermediates M-2 are available in an analogous mannerfollowing the same sequence using different alde- hydes and amides (according to the preparation of 2 -(5-fl uoropyridin-2-yl) quinazolin-4(3H)-one and consecutive steps) as starting materials. The crude products are purified by chromatography if necessary (Table Ex 7g).

[0820] Table Ex 7g:

[0821] Synthesis of ((1 r,3 / ')-3-((tert-butoxycarbonyl)amino)cvclobutyl)methyl methanesulfonate (B-2a): CH

[0822] B-1a2CI2B-2a

[0823] To a stirred solution of tert-butyl ((1 r,3 / j-3-(hydroxym ethyl) cyclobutyl) carbamate (B-1a) (300 mg, 1 .49 mmol) in CH2CI2 (4 mL), was added EtaN (0.62 mL, 4.47 mmol) and the mixture was cooled to 0 °C. MsCI (0.18 mL, 2.24 mmol) was added drop wise and stirred for 2 h at room temperature. The reaction mixture was diluted with CH2CI2 (10 mL) and washed with water (2 x 5 mL) and brine (2 x 5m L). The organic layer was dried over sodium sulphate, filtered, and concentrated underreduced pressure to afford ((1 r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutyl) methyl methane sulfonate (B-2a) which was used as the crude product for the next step and can be purified by chromatog- raphy if necessary.

[0824] Additional intermediates B-1 are available in an analogous manner using different intermediates B-2 as starting ma- terials. The crude products are purified by chromatography if necessary (Table Ex 8)

[0825] Table Ex 8:

[0826] Synthesis of N1-benzyl- / V1-methylcyclobutane-1 ,3-diamine (B-4b-1) Step 1 : The tert-butyl (3-oxocyclobutyl)carbamate (E-1a, 1 g, 1 equiv., 5 mmol)and W-methyl-1-phenylmethanamine (0.7 g, 1 .1 equiv., 6 mmol)were dissolved in DCM (5 mL)and sodium triacetoxyborohydride (2 g, 2 equiv., 0.01 mol), acetic acid (0.2 g, 0.2 mL, 0.5 equiv., 3 mmol) were added. The reaction was stirred at 20 °C for 2 h. The reaction mixture was washed with saturated NaHCOs aq. twice, dried over Mg2SO4, filtered and the solvent was evaporated. The crude product was purified by column chromatography to obtain tert-butyl (3-(benzyl(methyl)amino)cyclobu- tyl)carbamate (E-2a). Additional intermediates E-2 are available in an analogous manner using different intermediates E-1 and different amines of theformula HN(R3)2 as starting materials. The crude productsare purified by chromatography if necessary (Table Ex 9).

[0827] Table Ex 9:

[0828] Step 2: tert-Butyl (3-(benzyl(methyl)amino)cyclobutyl)carbamate (1 .95 g, 6.71 mmol) was dissolved in DCM (5 mL) and HCI in 1 ,4-dioxane (9 g, 10 Eq, 0.07 mol) was added. The reaction was stirred at 20 °C for 2 h. The precipitate was filtered and dried in vacuo to afford N1-benzyl-N1-methylcyclobutane-1 ,3-diamine (B-4b-1) as HCI salt. Which was directly used in the next step.

[0829] Additional intermediates B-4b are available in an analogous manner using different intermediates E-2 as starting ma- terial. The crude products are used directly in the next step (Table Ex 10).

[0830] Table Ex 10:

[0831] Synthesis of tert-butyl ((1r,3r)-3-((benzyl(methyl)amino)methyl)cvclobutyl)carbamate (B-3a): To a stirred solution of ((1 r,3r)-3-((tert-butoxycarbonyl) amino) cyclobutyl) methyl methane sulfonate (B-2a) (360 mg, 1 .29 mmol) and benzyl(methyl)amine (156 mg, 1 .29 mmol), in acetonitrile (4.0 mL), was added K2CO3 (494 mg, 3.87 mmol), KI (213 mg, 1 .29 mmol) and the mixture was stirred for 16 h at 80 °C. The solvents were removed under vac- uum and the residue was diluted with water (20 mL). The product was extracted with EtOAc (2 x 25 mL). The com- bined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford tert-butyl ((1r,3r)-3-((benzyl (methyl) amino) methyl) cyclobutyl) carbamate (B-3a) which was used in the next step without purification and can be purified by chromatography if necessary.

[0832] Additional intermediates B-3 are available in an analogous manner using different intermediates B-2 and different secondaryor primaryamines as starting materials. The crude products are purified by chromatography if necessary (Table Ex 11 )

[0833] Table Ex 11 :

[0834] Synthesis of tert-butyl (1r,3r)-3-((benzyl(methyl)amino)methyl)cvclobutan-1-amine (B-4a-1):

[0835] To a stirred solution of tert-butyl((1r,3 / j-3-((benzyl(m ethyl) ami no) methyl) cyclobutyl) carbamate (B-3a) (371 mg, 1 .22 mmol) in CH2CI2 (5.0 mL), was added TFA (0.47 mL, 6.09 mmol) at 0 °C and stirred for 16 h at room temperature.

[0836] The reaction mixture was evaporated to dryness, and the residue was triturated with pentane to afford (1 r,3r)-3-((ben- zyl(m ethyl) amino) methyl) cyclobutan-1 -amine (B-4a) as TFA salt which was used in the next step without purifica- tion.

[0837] Additional intermediates B-4 are available in an analogous manner using different intermediates B-3 as starting ma- terials. The crude products are purified by chromatography if necessary (Table Ex 12)

[0838] Table Ex 12:

[0839] Synthesis of tert-butyl (1 R.4R,5R)-5-amino-2-azabicvclo(2.2.11heDtane-2-carboxylate (B-13a)

[0840] Step 1 :

[0841] To tert-butyl (1 R,4R)-5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (250 mg) were added benzyl amine (300 mg) and 30 m L DCM. To the resulting solution was added 500 mg sodium triacetoxyborohydride under stirring, and the reaction mixture was left stirring for 18 h. The resulting suspension was washed 2 times with saturated aqueous Na- HCOa, the phases were separated and the organic phase wasdried over MgSCU, filtered, and the solvents were evap- orated. The residue was purified by column chromatography to obtain tert-butyl (1 R,4R,5R)-5-(benzylamino)-2-azabi- cyclo[2.2.1]heptane-2-carboxylate.

[0842] Step 2:

[0843] Tert-butyl (1 R, 4R,5R)-5-(benzylamino)-2-azabicyclo[2.2.1 ]heptane-2 -carboxylate (292 mg) was placed in a 20 m L vial followed by the addition of 15 mL of MeOH, finally 200 mg of 10% Pd / C were added. A balloon with hydrogen was installed on top and the suspension was stirred for 3 h at am blent temperature. The reaction mixture was filtered and evaporated till dryness to obtain (1 R,4R,5R)-5-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate (B-13a)

[0844] Additional intermediates B-13 are available in an analogous manner using different corresponding ketones as starting materials (Table Ex 13):

[0845] Table Ex 13:

[0846] Synthesis of A / -((1r,3r)-3-((benzyl(methyl)amino)methyl)cvclobutyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (lb-1): lb-1

[0847] 2-(4-Ethoxyphenyl)quinoline-4-carboxylicacid (M-3b-8, 110 mg, 0.38 mmol) was dissolved in DMF (4.0 mL)followed by addition of EtsN (0.26 mL, 1 .87 mmol) and HATU (171 mg, 0.45 mmol). The mixture was stirred for 15 min. (1r,3r)-3-((Benzyl(methyl) amino) methyl) cyclobutan-1-amine (B-4a, 114 mg, 0.56 mmol) was added and the mixture was stirred for 16 h at room temperature. The reaction mixture was purified by RP preparative HPLC to af- ford N-((1 r,3r)-3-((benzyl(methyl) amino) methyl) cyclobutyl)-2-(4-ethoxyphenyl) quinoline-4-carboxamide (lb-1 ). Additional compounds I are available in an analogous manner using intermediates M-3 and different amines B-4 or other amines as starting materials. The crude products are purified by chromatography if necessary (Table Ex 14).

[0848] Table Ex 14: Synthesis of A / -((1r,3r)-3-((benzyl (methyl) amino) methyl) cyclobutyl)-7-chloro-2-(4-ethoxyphenyl) quinazoline-4-car- boxamide (Id-1): 7-Chloro-2-(4-ethoxyphenyl) quinazoline-4-carboxylic acid (M-3d-1 , 110 mg, 0.34 mmol) was dissolved in pyridine (4.0 mL)and T3P (50% w / w in EtOAc) (1.064 g, 1.67 mmol)wasadded. The mixture was stirred for 15 min. (1 r,3r)-3- ((benzyl(m ethyl) amino) methyl) cyclobutan-1 -amine (B-4a, 102 mg, 0.50 mmol) was added and the mixture was stirred for 16 h at room temperature. Pyridine was evaporated to dryness under vacuum and co -distilled with toluene. The residue was purified by RP preparative HPLCto afford N-((1r,3r)-3-((benzyl (methyl) amino) methyl) cyclobutyl)- 7-chloro-2-(4-ethoxyphenyl)quinazoline-4-carboxamide Id-1.

[0849] Additional com pounds (I) are available in an analogous manner using intermediates M-3 and different am Ines B-4 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 15). Table Ex 15: Synthesis of ((1 r,3r)-3-aminocvclobutyl)) methanol hydrochloride (B-5a):

[0850] To a stirred solution of tert-butyl((1 r,3r)-3-(hydroxymethyl) cyclobutyl) carbamate (B-1a, 600 mg, 2.98 mmol) in 1 ,4- dioxane (3.0 mL), was added 4 M HCI in dioxane (5.0 mL) at 0 °C and the mixture was stirred for 16 h. The reaction mixture was evaporated to dryness to afford ((1 r,3r)-3-aminocyclobutyl) methanol hydrochloride (B-5a) which was used in next step without further purification.

[0851] Additional intermediates B-5 are available in an analogous manner using alternative intermediates B-1 starting mate- rials. (Table Ex 16).

[0852] Table Ex 16:

[0853] Synthesis of 2-(4-ethoxyphenyl)-A / -((1r,3r)-3-(hvdroxymethyl) cvclobutyl) quinoline-4-carboxamide (M-10b-1):

[0854] To a stirred solution of 2-(4-ethoxyphenyl)quinoline-4-carboxylicacid (M-3b-8, 300 mg, 1 .02 mmol) in DMF (4.0 mL), was added DIPEA (0.71 mL, 5.11 mmol), EDC (317 mg, 2.05 mmol), HOBt(345 mg, 2.56 mmol) and the mixture was stirred for 15 min. ((1 r,3r)-3-Aminocyclobutyl) methanol hydrochloride (B-5a, 141 mg, 1 .02 mmol) was added and the mixture was stirred for 16 h at room temperature. The reaction mixture was purified by combi-flash column chroma- tography to afford 2-(4-ethoxyphenyl)-N-((1r,3r)-3-(hydroxymethyl) cyclobutyl) quinoline-4-carboxamide (M-10b-1).

[0855] Additional intermediates M-10 are available in an analogous manner using different amines M-3 and different inter- mediate amines B-5 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 17). Table Ex 17: Synthesis of A / -((1r,3r)-3-(chloromethyl) cvclobutyl)-2-(4-ethoxyphenyl) quinoline-4-carboxamide (M-11 b-1):

[0856] To a stirred solution of 2-(4-ethoxyphenyl)-A / -((1 r,3r)-3-(hydroxymethyl) cyclobutyl) quinoline-4-carboxam ide (M-10b- 1 , 200 mg, 0.531 mmol) in DCE (6.0 mL),was added SOCI2 (0.19 mL, 2.65 mmol) at 0 °C. The mixture was heated to

[0857] 70 °C and stirred at the same temperature for 16 h. The reaction mixture was evaporated to dryness, diluted with CH2CI2 (5 m L) and neutralized with saturated aqueous NaHCOs at 0 °C. The aqueous layer was extracted with CH2CI2 (2 x 10 mL). The combined organic layer was dried over sodium sulphate, and concentrated under reduced pressure to afford A / -((1r,3r)-3-(chloromethyl) cyclobutyl)-2-(4-ethoxy phenyl) quinoline-4-carboxamide (M-11b-1) which was used without further purification in the next step.

[0858] Additional intermediates M-10 are available in an analogous manner using different intermediates M-11 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 18).

[0859] Table Ex 18:

[0860] Synthesis of 2-(4-ethoxyphenyl)-N-((1 r,3r)-3-(((R)-3-fluoropyrrolidin-1-yl) methyl) cvclobutyl)quinoline-4-carboxamide

[0861] To a stirred solution of N-((1r,3r)-3-(chloromethyl) cyclobutyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-11 b-1 , 170 mg, 0.40 mmol) in acetonitrile (5.0 mL), was added DIPEA (0.49 mL, 2.85 mmol), KI (202 mg, 1 .22 mmol) and (3R)-3-fluoropyrrolidine hydrochloride (153 mg, 1 .22 mmol). The mixture was stirred for 48 h at 110 °C. The reaction was filtered through a Celite bed and washed with acetonitrile. The filtrate was evaporated to dryness and the residue was purified by RP preparative HPLC to afford 2-(4-ethoxyphenyl)-A / -((1r,3r)-3-(((R)-3-fluoropyrrolidin-1-yl) methyl) cyclobutyl) quinoline-4-carboxamide (lb-7).

[0862] Additional compounds I are available in an analogous manner using different intermediates M-11 and amines B-6 as starting materials. Alternatively, a 1 :1 mixture of dioxane and NMP can be used as the solvent and reaction can be heated in a sealed tube to 100 °C. The crude products are purified by chromatography if necessary (Table Ex 19).

[0863] Table Ex 19:

[0864] Synthesis of (1 -((2-(4-ethoxyphenyl)quinoline-4-carboxamido)methyl)cvclopropyl)methyl methanesulfonate (M-11 b-4)

[0865] To a cooled (0 °C) solution of 2-(4-ethoxyphenyl)-N-((1-(hydroxymethyl)cyclopropyl)methyl)quinoline-4-carboxamide (M-10b-4, 0.2 g, 1 equiv., 0.5 mmol) and triethylamine (0.08 g, 0.1 m L, 1 .5 equiv., 0.8 mmol) in DCM (5 m L) was added methanesulfonyl chloride (0.1 g, 0.08 mL, 2 equiv., 1 mmol). The reaction was maintained at O °C during the first hour, followed by warming to room temperature, under vigorous stirring and nitrogen atmosphere for 3 h. The mixture was extracted with dichloromethane (3 x 30 mL) and the combined organic extracts were washed with a 10% aqueous hydrochloric acid solution, brine, dried over sodium sulfate and evaporated. The crude product was used withoutfurtherpurification forthe next step. (1 -((2-(4-Ethoxyphenyl)quinoline-4-carboxamido)methyl)cyclopropyl)me- thyl methanesulfonate (M-11 b-4). No HPLC / MS data was obtained since the intermediate was prone to hydrolysis.

[0866] Additional intermediates M-11 are available in an analogous manner using different intermediates M-10 as starting materials and are used as the crude products in the next step.

[0867] Synthesis of (R)-2-(4-ethoxyphenyl)-A / -((1 -((3-fluoropyrrolidin-1 -yl)methyl)cvclopropyl)methyl)quinoline-4-carboxamide

[0868] (lb-18)

[0869] (1 -((2-(4-ethoxyphenyl)quinoline-4-carboxamido)methyl)cyclopropyl)methyl methanesulfonate (M-11 b-4, 50 mg, 1 equiv., 0.1 1 mmol) and DIPEA (28 mg, 38 μL, 2 equiv., 0.22 mmol) in acetonitirle (2 m L). The mixture was allowed to stir at 20 °C for 10 min. (R)-3-fluoropyrrolidine hydrochloride (17 mg, 1 .2 equiv., 0.13 mmol) in acetonitrile (0.5 mL) was added. The mixture was then heated to 80 °Cand stirred for 16 h at the same temperature. The reaction mixture was cooled to RT, filtered, and concentrated to yield the crude product. This was dissolved in EtOAc (25 mL) and ex- tracted with 1 M HCI (4 x 15 mL). The aqueous layers were combined and made basic by addition of aqueous NaOH solution (2 mL, 20 M). The aqueous layer was extracted with dichloromethane (2 x 25 mL), the organic layers were combined, dried overNa2SO4, filtered, and concentrated. The crude reaction mixture was purified by column chroma- tography to furnish (R)-2-(4-ethoxyphenyl)- / V-((1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methyl)quinoline-4-car- boxamide (lb-18)

[0870] Additional compounds I are available in an analogous manner using different intermediates M-11 and amines of the formula B-6 as starting materials and are purified by chromatography (Table Ex 20).

[0871] Table Ex 20:

[0872] Synthesis of 2-(4-ethoxyphenyl)-N-(3-oxocvclobutyl) quinoline-4-carboxamide (M-14b-1 ): To a stirred solution of 2-(4-ethoxyphenyl) quinoline-4-carboxylic acid (M-3b-8) (2.0 g, 6.80 mmol) in DMF (20 mL) was added EtsN (4.7 mL, 34.08 mmol), HATU (3.01 g, 8.10 mmol). The mixture was stirred for60 min. 3-aminocyclo- butan-1-one hydrochloride (B-7a) (1 .0 g, 8.20 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture slowly poured into excess ice -water, extracted with EtOAc (2 x 20 mL). The combined or- ganic layer was washed several times with chilled brine, dried over sodium sulphate, filtered, concentrated under re- duced pressure. The crude residue was purified by com bi -flash column chromatography eluting with 70% ethyl ace- tate in hexanes to afford 2-(4-ethoxyphenyl)-N-(3-oxocyclobutyl) quinoline-4-carboxamide (M-14b-1).

[0873] Additional intermediates M-14 are available in an analogous manner using different intermediates M-3 and B-7 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 21 ).

[0874] Table Ex 21 :

[0875] Synthesis of (S)-3-(4-ethoxyphenyl)-A / -(3-(3-hvdroxypyrrolidin-1-yl)cvclobutyl)isoquinoline-1 -carboxamide (l-a3) The 3-(4-ethoxyphenyl)-A / -(3-oxocyclobutyl)isoquinoline-1 -carboxamide (M-14a-1, 25 mg, 1 equiv., 69 μmol) and (S)- pyrrolidin-3-ol (6 mg, 1 equiv., 69 μmol) were dissolved in DCM (5 mL) and sodium triacetoxyborohydride (15 mg, 1 equiv., 69 μmol), acetic acid (4.2 mg, 4.0 μL, 1 equiv., 69 μmol) were added. The reaction was stirred at 20 °C for 2 h. The reaction mixture was washed with saturated NaHCOa aq. twice, dried over Mg2SO4, filtered, and the solvent evaporated. The crude product was purified by column chromatography yielding (S)-3-(4-ethoxyphenyl)-N-(3-(3-hy- droxypyrrolidin-1 -yl)cyclobutyl)isoquinoline-1 -carboxamide (la-3).

[0876] Additional compounds I are available in an analogous manner using different intermediates M-14 and B-6 as starting materials. The crude products, potentially as a mixture of diastereomers, are purified by chromatography if necessary (Table Ex 22).

[0877] Table Ex 22:

[0878]

[0879]

[0880]

[0881] Synthesis of A / -((1s,3s)-3-(benzyl(methyl)amino)cvclobutyl)-2-chloroquinoline-4-carboxamide and A / -((1r,3r)-3-(ben- zyl(methvnamino)cvclobutyl)-2-chloroquinoline-4-carboxamide (M-16a and M-16b):

[0882] M-15a

[0883] M-16a M-16b The 2-chloroquinoline-4-carboxylicacid hydro chloride (M-15a HCI,400 mg, 1 equiv., 1 .64 mmol) and EDC (314 mg, 1 Equiv., 1 .64 mmol) were dissolved in DCM (5 mL) and HOBt (125 mg, 0.5 equiv., 819 μmol), and amine B-4b-1 (249 mg, 0.8 equiv.1 .21 .mmol) were added. The reaction was stirred at 20 °C for 2 h. The reaction mixture was washed with saturated NaHCOs aq. twice, dried over Mag2SO4, filtered and the solvent was evaporated under re- duced pressure. The crude product was purified by column chromatography (EtOAc / MeOH, gradient 100-50%) to afford two diastereomers: N-((1 r,3r)-3-(benzyl(methyl)amino)cyclobutyl)-2-chloroquinoline-4-carboxamide (M-16b) and N-((1 s,3s)-3-(benzyl(methyl)amino)cyclobutyl)-2-chloroquinoline-4-carboxamide (M-16a).

[0884] Additional intermediates M-16 are available in an analogous manner using different intermediates M-15 and B-4 as starting materials. The crude products are purified by chromatography if necessary. If mixtures of stereoisomers are obtained, they are separated by chromatography using chiral columns if necessary (Table Ex 23).

[0885] Table Ex 23: Synthesis of A / -((1 s,3s)-3-(benzyl(methyl)amino)cvclobutyl)-2-(5-methylthiophen-2-yl)ciuinoline-4-carboxamide (Ib- 371

[0886] M-16a A / -((1 s,3s)-3-(Benzyl(methyl)amino)cyclobutyl)-2-chloroquinoline-4-carboxamide (M-16a, 40 mg, 1 equiv., 0.11 mmol), 4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-1 ,3,2-dioxaborolane (28 mg, 1 .2 equiv., 0.13 mmol) were weighed into a 50 mL Schlenk tube. Then Pd(dppf)Ch (0.02 g, 0.01 equiv., 0.03 mmol) and potassium carbonate (0.7 g, 2 equiv., 5 mmol) were added. The powder mixture was suspended in 1 ,4-dioxane (10 mL) and H2O (2.5 mL) and degassed with bubbling through argon. The reaction mixture was heated to 90 °C and stirred at the same tempera- ture for 18 h. The reaction mixture was diluted with 50 mL ethyl acetate and washed with water (2 x 50 mL), brine (50 mL), and the organic phase was concentrated under vacuum. The crude product was purified via column chromatog- raphy(gradient DCM / MeOH (0 to 95)) to afford N-((1s,3s)-3-(benzyl(methyl)amino)cyclobutyl)-2-(5-methylthiophen-2- yl)quinoline-4-carboxamide (lb-37). Additional com pounds (I) are available in an analogous manner using different intermediates M-16 and boronic acids K-2 or the corresponding 4,4,5,5-tetramethyl-dioxaborolanes as starting materials. The crude products are purified by chromatography if necessary (Table Ex 24).

[0887] Table Ex 24:

[0888] Synthesis of A / -((1s.3s)-3-((benzyl(methyl)amino)methyl)cvclobutyl)-5.7-dichloro-2-(4-ethoxyphenyl)quinoline-4-car- boxamide (lb-40):

[0889] The 5,7-dichloro-2-(4-ethoxyphenyl)quinoline-4-carboxylicacid (M-3b-3, 25 mg, 1 equiv., 69 μmol) and EDC (26 mg, 2 equiv., 0.14 mmol) and HOBt (5.3 mg, 0.5 equiv., 35 μmol) were dissolved in DCM (5 mL) and stirred for 5 min then (1 s,3s)-3-((benzyl(methyl)amino)methyl)cyclobutan-1-amine, 2HCI (B-4a-22HCI, 21 mg, 1.1 equiv., 76 μmol), and DIPEA (8.9 mg, 12 μL, 1 Equiv., 69 μmol) were added. The reaction mixture was stirred at 20 °C for 2 h. The re- action mixture was washed with saturated NaHCOaaq. twice, dried over MgzSCU, filtered and the solvent was evapo- rated under reduced pressure. The crude product was purified by column chromatography to give A / -((1s,3s)-3-((ben- zyl(methyl)amino)methyl)cyclobutyl)-5,7-dichloro-2-(4-ethoxyphenyl)quinoline-4-carboxamide (lb-40).

[0890] Additional com pounds (I) are available in an analogous manner using different intermediates M-3 and B-4 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 25).

[0891] Table Ex 25:

[0892] Synthesis of tert-butyl ((1 F?,3S)-3-(2-(4-ethoxyphenyl)quinoline-4-carboxamido)cvclopentyl)carbamate (D-2b-1 ):

[0893] D-2b-1 To a stirred solution of 2-(4-ethoxyphenyl) quinoline-4-carboxylicacid (M-3b-8) (300 mg, 1 .02 mmol) in DMF (5.0 mL) was added DIPEA (0.88 m L, 5.10 mmol), EDC-HCI (491 mg, 2.54 mmol), HOBt (207mg, 1 .52 mmol) and tert-butyl ((1 R,3S)-3-aminocyclopentyl)carbamate (D-1 a-2) (224 mg, 1 .12 mmol) and the mixture was stirred at room tempera- ture for 16 h. The reaction was diluted with chilled water (25 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine (3 x 20 mL), dried over sodiu m sulphate, filtered, and concentrated under reduced pressure. The crude residue was purified by combi-flash chromatography to afford ((1 R,3S)-3-(2-(4- ethoxyphenyl)quinoline-4-carboxamido)cyclopentyl)carbamate (D-2b-1 ).

[0894] Additional intermediates D-2, M-27 or M-29 are available in an analogous manner using different intermediates M-3 and amines D-1 , B-15 or B-16 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 26).

[0895] Table Ex 26:

[0896]

[0897] Synthesis of tert-butyl N-[(1 S,3R)-3-[2-(4-ethoxyphenyl) quinoline-4-amido] cyclopentyll carbamate (D-3b-1 ): To a stirred solution of ((1 R,3S)-3-(2-(4-ethoxyphenyl)quinoline-4-carboxamido)cyclopentyl)carbamate (D-2b-1) (280 mg, 0.59 mmol) in 1 ,4-dioxane (5.0 mL), was added HCI in dioxane (2.0 mL) at 0 °C and the mixture was stirred for 16 h at room temperature. The reaction mixture was evaporated to dryness, triturated with pentane to afford N- ((1 S,3R)-3-aminocyclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (D-3b1) as hydrochloride salt which was used in the next step without further purification.

[0898] Additional intermediates D-3 are available in an analogous manner using different intermediates D-2 starting materi- als. The crude products are purified by chromatography if necessary (Table Ex 27).

[0899] Table Ex 27:

[0900] Synthesis of S,3f?)-3-(benzylamino)cvclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (lb-47):

[0901] D-3b-1 lb-47 To a stirred solution of A / -((1 S,3R)-3-aminocyclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide hydrochloride (D- 3b-1 , 100 mg, 0.24 mmol) in DCE (5.0 mL), was added TEA (0.14 mL, 0.97 mmol) and the mixture was stirred for 60 min. MgSO4 (58 mg, 0.49 mmol) and benzaldehyde (28 mg, 0.27 mmol) were added and the mixture was stirred at room temperature for 16 h under N 2 atmosphere. The reaction was filtered, and the solvent was evaporated to dry- ness. The residue was re-dissolved in MeOH (5.0 mL) and NaBH4 (17 mg, 0.43 mmol) was added at 0 °C and the mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C and quenched with satu- rated aqueous NH4CI solution (20 mL). MeOH was evaporated and the mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layerwas dried over sodium sulphate and concen- trated underreduced pressure to obtain the crude productwhich was purified byRP Prep-HPLCto afford A / -((1 S,3R)- 3-(benzylamino)cyclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (lb-47).

[0902] Additional com pounds (I) are available in an analogous manner using intermediates D-3 and the corresponding alde- hydes or ketones as starting materials. The crude products are purified by chromatography if necessary (Table Ex 28).

[0903] Table Ex 28:

[0904] Synthesis of S,3R)-3-(benzyl(methyl)amino)cvclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (lb-49):

[0905] AcOH, NaBH3CN, MeOH lb-49

[0906] To a stirred solution of A / -((1 S,3R)-3-(benzylamino)cyclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (lb-47) (80.0 mg, 0.17 mmol) in MeOH (5.0 mL)was added formaldehyde (15 mg, 0.51 mmol), AcOH (0.02 mL, 0.26 mmol) and NaBH3CN (22 mg, 0.35 mmol) at room temperature. The mixture was stirred for 16 h under N 2 atmosphere. The reaction mixture was cooled to 0 °C and quenched by addition of saturated aqueous NH4CI solution (5.0 mL). MeOH was evaporated to dryness and the residue was diluted with water (5 mL). The mixture was extracted with ethyl ace- tate (3 x 5 mL) and the combined organic layer was dried over sodium sulphate, concentrated under reduced pres- sure to get the crude product. The crude product was purified by RP Prep-HPLC to afford A / -((1 S,3R)-3-(benzyl(me- thyl)amino)cyclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (lb-49).

[0907] Additional compounds (I) are available in an analogous manner using compounds (I) (one R3= H) and the corre- sponding aldehydes or ketones as starting materials. The crude products are purified by chromatography if neces- sary (Table Ex 29).

[0908] Table Ex 29: Synthesis of A / -((1 F?,3s,5S)-6-oxabicvclo[3.1 .01hexan-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-30-1 ):

[0909] To a stirred solution of N-(cyclopent-3-en-1-yl)-2-(4-ethoxyphenyl) quinoline-4-carboxamide (M-29-1 ) (450 mg, 1.25 mmol) in DCM (30 mL) was added mCPBA (433.29 mg, 2.51 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was successively washed with saturated aqueous NaHCQj solution (2 x 10 mL), water (10 mL)and brine (2 x 10 mL).The organic layer was dried over anhydrous sodium sulfate, filtered and filtrated concentrated under vacuum. The residue was purified by combi-flash column chromatography (80% EtOAc in hexanes as eluent) to afford N-((1 R,3s,5S)-6-oxabicyclo [3.1 .0] hexan-3-yl)-2-(4-ethoxyphenyl)quino- line-4-carboxamide (M-30-1). Additional intermediates M-28 and M-30 are available in an analogous mannerby using different intermediates M-27 or M-29 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 30).

[0910] Table Ex 30:

[0911] Synthesis of rac-2-(4-ethoxyphenyl)-N-((1 S,3S,4S)-3-hvdroxy-4-methoxycvclopentyl)quinoline-4-carboxamide (M-31 - 1 ):

[0912] To a stirred solution of N-((1 R,3s,5S)-6-oxabicyclo [3.1 .0] hexan-3-yl)-2-(4-ethoxyphenyl) quinoline-4-carboxamide (M- 30-1 ) (375 mg, 1 mmol) in MeOH (10 m L) was added 25% NaOMe solution in MeOH (2.2 mL, 10.02 mmol). The reaction mixture was stirred at 60 °C for 16 h. After the completion, solvents were evaporated under vacuum . The residue was diluted with DCM (20 ml_) and washed with water (2 x 10 mL), brine (I O m L). The organic layerwas dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under vacuum. The residue was purified by com bi -flash column chromatography to afford rac-2-(4-ethoxyphenyl)-A / -((1 S,3S,4S)-3-hydroxy-4-methoxycyclopentyl) quinoline-4- carboxamide (M-31 -1 )

[0913] Additional intermediates M-31 are available in an analogous manner by using different intermediates M-30 and / or differentalcohols orothersuitable nucleophiles as starting materials. The crude products are purified by chromatog- raphy if necessary (Table Ex 30a).

[0914] Table Ex 30a:

[0915] Synthesis of rac-2-(4-ethoxyphenyl)- / V-((1 R,3S)-3-methoxy-4-oxocvclopentyl)quinoline-4-carboxamide (M-32-1 )

[0916] To a mixture of rac-2-(4-ethoxyphenyl)-A / -((1 S,3S,4S)-3-hydroxy-4-methoxycyclopentyl) quinoline-4-carboxamide (M- 31 -1 ) in DCM (10 mL) was added BMP (203.5 mg, 0.48 mmol). The reaction was stirred at room temperature for 18 h. The reaction was washed with 1 :1 mixture of saturated aqueous NaHCOa and 10% aqueous sodium thiosulfate solution (3 x 10 mL), brine (2 x 10 mL). The organic layer was dried over anhydrous NazSCU, filtered and the filtrated was concentrated undervacuum . The residue was purified by combi-flash column chromatography (eluting with 50% EtOAc in hexanes) to afford rac-2-(4-ethoxyphenyl)-N-((1 S,3S)-3-methoxy-4-oxocyclopentyl) quinoline-4-carbox- amide (M-32-1 ). Additional intermediates M-32 are available in an analogous manner by using different intermediates M-31 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 30 b).

[0917] Table Ex 30b: Synthesis of A / -((1 S,3R,4S)-3-(benzylamino)-4-methoxycvclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (Ib-

[0918] 114)and A / -((1 R,3S,4R)-3-(benzylamino)-4-methoxycvclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (lb-115):

[0919] To a stirred solution of rac-2-(4-ethoxyphenyl)-N-((1S,3S)-3-methoxy-4-oxocyclopentyl)quinoline-4-carboxamide (M- 32-1) (140 mg, 0.35 mmol) inDCM (10 mL) was successively added benzyl amine (55.63 mg, 0.52 mmol) and Na(OAc)aBH (146.72 mg , 0.69 mmol) at ice-bath temperature. The reaction was stirred at room temperature for 2 h. The reaction mixture was washed with aqueous NaHCOa solution (2 x 5 mL). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated undervacuum. The crude residue was first purified by RP prepara- tive HPLC to obtain the racemic product (rac-lb-114) which was followed by chiral SFC to afford N-((1 S,3R,4S)-3- (benzylamino)-4-methoxycyclopentyl)-2-(4-ethoxyphenyl) quinoline-4-carboxamide (lb-114) and A / -((1 R,3S,4R)-3- (benzylamino)-4-methoxycyclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (lb-115).

[0920] Additional com pounds (I) are available in an analogous manner using different Intermediates M-32 and / or amines B- 6 as starting materials as racemates or after chiral separation as pure enantiomers (Table Ex 30c).

[0921] Table Ex 30c:

[0922] Synthesis of rac- / V-((1 S,3R,4R)-3-(benzylamino)-4-hvdroxycvclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide

[0923] (lb-116): lb-116

[0924] Racemate A solution of N-((1 R,3S,5S)-6-oxabicyclo[3.1 .0]hexan-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxam ide (M-30-1 ) (50 mg, 0,134 mmol) and phenylmethamine (14 mg, 0.134 mmol) in MeOH was heated to 60 °C and stirred at the same temperature for 18 hours. The solvent amount was reduced under reduced pressure and the residue was purified by column chromatography to afford Synthesis of rac-N-((1 S,3R,4R)-3-(benzylamino)-4-hydroxycyclopentyl)-2-(4-ethox- yphenyl)quinoline-4-carboxam ide (lb-116).

[0925] Additional com pounds (I) are available in an analogous manner using different epoxide intermediates M-30 or M-28 and / or amines B-6 as starting materials. Racemic mixtures can be separated by means of chiral SFC separation if necessary. (Table Ex 30d).

[0926] Table Ex 30d:

[0927]

[0928] Synthesis of tert-butyl (3aR,5s,6aS)-5-(2-(4-ethoxyphenyl)quinoline-4-carboxamido)hexahvdrocvclopenta[c1pyrrole-

[0929] 2(1H)-carboxylate (M-17a)

[0930] The 2-(4-ethoxyphenyl)quinoline-4-carboxylicacid (M-3b-8, 100 mg, 1 equiv., 341 μmol) and EDC (131 mg, 2 equiv., 682 μmol), HOBt (26.1 mg, 0.5 equiv., 170 μmol) were dissolved in DCM (5 mL) and stirred for 5 min. Then tert-butyl (3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1 H)-carboxylate (B-10a, 77.2 mg, 1 equiv., 341 μmol), and DIPEA (44.1 mg, 1 equiv., 341 μmol) were added. The reaction mixture was stirred at 20 °C for2 h. The reaction mix- ture was washed with saturated aq. NaHCOa twice, dried over Mg2SO4, filtered and the solvent was evaporated. The crude product was purified by column chromatography.

[0931] Additional intermediates M-17, M-19, M-21 , M-23 or M-25 are available in an analogous manner by using different intermediates M-3 and the corresponding amines B-10, B-11, B-12, B-13 or B-15 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 30e).

[0932] Table Ex 30e:

[0933] Synthesis of 2-(4-ethoxyphenyl)-N-((3af?,5s,6aS)-octahvdrocvclopenta[clpyrrol-5-yl)quinoline-4-carboxamide (lb-52) Tert-butyl (3aR,5s,6aS)-5-(2-(4-ethoxyphenyl)quinoline-4-carboxamido)hexahydrocyclopenta[c]pyrrole-2(1H)-carbox- ylate (M-17a, 204 mg, 1 equiv., 407 μmol) was dissolved in DCM and HCI in 1 ,4-dioxane (507 mg, 482 μL, 10 equiv., 4.07 mmol) was added. The reaction was stirred at 20 °C for 2 h. Then DCM was evaporated, the solid precipitated by addition of Et2O, filtered and dried in vacuo to afford 2-(4-ethoxyphenyl)-A / -((3aR,5s,6aS)-octahydrocyclo- penta[c]pyrrol-5-yl)quinoline-4-carboxamide (lb-52)as bis-HCI salt. The product can be purified by chromatography if necessary. Additional compounds(l) are available in an analogous manner using different Intermediates M-17, M-19, M-21 , M- 23 or M-25 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 31 ).

[0934] Table Ex 31 :

[0935] Synthesis of 2-(4-ethoxyphenyl)- / \ / -((3aR,5r,6aS)-2-(oxetan-3-yl)octahvdrocvclopentarclpyrrol-5-yl)quinazoline-4-car- boxamide (Id-12)

[0936] 2-(4-Ethoxyphenyl)-N-((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)quinazoline-4-carboxamide (Id-9, 25 mg, 1 equiv., 62 μmol)and oxetan-3-one (18 mg, 4 equiv., 0.25 mmol) were dissolved in DCM (5 mL), and acetic acid (0.19 mg, 0.18 μL, 0.05 equiv., 3.1 pm ol), sodium triacetoxyborohydride (26 mg, 1 equiv., 0.12 mmol) were added. The re- action was stirred at 20 °C for 2 h. The reaction mixture was washed with saturated NaHCOa aq. twice, dried over Mg2SO4, filtered and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography to yield 2-(4-ethoxyphenyl)-N-((3aR,5r,6aS)-2-(oxetan-3-yl)octahydrocyclopenta[c]pyrrol-5- yl)quinazoline-4-carboxamide (Id-12)

[0937] Additional com pounds (I) are available in an analogous manner using different compounds (I) (R4= H) and the corre- sponding ketones or aldehydes as starting materials. The crude products are purified by chromatography if neces- sary (Table Ex 32).

[0938] Table Ex 32:

[0939] Synthesis of 2-(4-ethoxyphenvD- / \ / -((3af?,5s,6aS)-2-(2-hydroxyethyl)octahvdrocvclopenta[clpyrrol-5-yl)quinazoline-4- carboxamide (lb-129):

[0940] To a stirred solution ofel-2-(6-ethoxypyridin-3-yl)-N-((3aR,5s, 6aS)-octahydrocyclopenta [c]pyrrol-5-yl) quinoline-4-car- boxamide hydrochloride (lb-161 ) (100 mg, 0.23 mmol) in ACN (5 mL) in a seal tube was added 2-iodoethan-1 -ol (47.01 mg, 0.27 mmol) and DIPEA (0.12 mL , 0.68 mmol) and stirred for 16 h at 90 °C. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP Prep HPLC to afford 2-(4-ethoxyphenyl)-N-((3aR,5s,6aS)- 2-(2-hydroxyethyl)octahydrocyclopenta[c]pyrrol-5-yl)quinazoline-4-carboxamide (lb-129)

[0941] Additional com pounds (I) are available in an analogous manner using different compounds (I) (R4= H) and the corre- sponding suitable alkyl halides (e.g. 2-bromoethan-1 -ol). Alternatively, dioxane can be used as a solvent. The crude products are purified by chromatography if necessary (Table Ex 32b).

[0942] Table Ex 32b:

[0943] Synthesis of Rac-2-(6-ethoxypyridin-3-yl)-A / -((3aR,5S,6aS)-2-((R)-1-hvdroxypropan-2-yl)octahvdrocvclopenta[c1pyr- rol-5-yl)quinoline-4-carboxamide (lb-150):

[0944] To a stirred solution of 2-(6-ethoxypyridin-3-yl)-A / -((3aR,5s,6aS)-octahydrocyclopenta [c] pyrrol-5-yl) quinoline-4-car- boxamide hydrochloride (lb-161 ) (100 mg, 0.25 mmol) in MeOH (5.0 mL) was added 1-hydroxypropan-2-one (27.61 mg, 0.37 mmol), AcOH (0.1 mL)and MgSO4 (61 .62 mg, 0.5 mmol) and stirred for 1 h. NaBHaCN (31 .3 mg, 0.5 mmol) was added at 0 °C and stirred for 16 h at room temperature. The reaction was filtered through a cartridge, evaporated under reduced pressure, and the residue was purified by RP Prep-HPLC to afford the racemate of 2-(6-ethoxypyridin- 3-yl)-A / -((3aR,5S,6aS)-2-((R)-1-hydroxypropan-2-yl) octahydrocyclopenta [c] pyrrol-5-yl) quinoline-4-carboxamide (lb- 150) Additional com pounds (I) are available in an analogous manner using different compounds (I) (R4= H) and the corre- sponding suitable ketones or aldehydes. The crude products are purified by chromatography if necessary (Table Ex 32c). Stereoisomers can be separated by preparative chiral chromatography (e.g. prep, chiral SFC) or other methods for chiral separation.

[0945] Table Ex 32c:

[0946] Synthesis ot A / -((3aR,5S,6aS)-2-((R)-1 -cvclopropyl-2-hvdroxyethyl)octahvdrocvclopenta[c1pyrrol-5-yl)-2-(6-ethoxypyri- din-3-yl)quinoline-4-carboxamide (lb-154) and / V-((3aR,5S,6aS)-2-((R)-1 -cvclopropyl-2-hvdroxyethyl)octahvdrocvclo- pentato1pyrrol-5-yl)-2-(6-ethoxypyridin-3-yl)quinoline-4-carboxamide (lb-155):

[0947] Step 1 :

[0948] To a stirred solution of rel-2-(6-ethoxypyridin-3-yl)-N-((3aR, 5s, 6aS)-octahydrocyclopenta [c] pyrrol-5-yl) quinoline-4- carboxam ide hydrochloride (lb-161 ) (200 mg, 0.46 mmol) in ACN (10 mL) was added ethyl 2-bromo-2-cyclopropy- lacetate (113.21 mg, 0.55 mmol) and DIPEA (0.24 mL, 1 .37 mmol) and stirred for 16 h at 100°C. The reaction was diluted with water (10 mL), extracted with ethyl acetate (2x 10 m L). The combined organic layer was washed with brine (2 x 10 mL), dried over anhydrous sodium sulphate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash column chromatography (eluted with 65% EtOAc in hexanes) to afford ethyl 2-cyclopropyl-2-((3aR, 5s, 6aS)-5-(2-(6-ethoxypyridin-3-yl) quinoline-4-carboxamido) hexahydrocyclopenta [c] pyrrol- 2(1 H)-yl) acetate (lb-162) as the racemate.

[0949] Additional com pounds (I) are available in an analogous manner using different compounds (I) (R4= H) and the corre- sponding alkyl halides. The crude products are purified by chromatography if necessary (Table Ex 32b). Stereoiso- mers can be separated by preparative chiral chromatography (e.g. prep, chiral SFC) or other methods for chiral sepa- ration if necessary.

[0950] Table 32d

[0951] Step 2:

[0952] To a stirred solution of ethyl 2-cyclopropyl-2-((3aR, 5s, 6aS)-5-(2-(6-ethoxypyridin-3-yl) quinoline-4-carboxamido) hex- ahydrocyclopenta [c] pyrrol-2(1 H)-yl) acetate (1-162) (100 mg, 0.19 mmol) in anhydrous TH F (6 mL), was added LiBH4 (2 (M) in THF) (0.19 m L, 0.38 mmol) at0°C and stirred at room temperature for 48 h. After which time, the reaction was cooled to 0°C, slowly added to aqueous saturated NH4CI solution (10 mL), kept at 0°C and stirred for 30 minutes. The solvents were evaporated under vacuum, the residue was diluted with water (10 m L) and extracted with EtOAc (3 x 10 m L). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum . The residue was purified by RP preparative HPLC to afford A / -((3aR, 5s, 6aS)-2-(1 -cyclopropyl-2-hydroxyethyl) octahydrocyclopenta[c] pyrrol-5-yl)-2-(6-ethoxypyridin-3-yl) quinoline-4-carboxamide (lb-153) which was separated into its enantiomers lb-154 and lb-155 by chiral preparative SFC.

[0953] Additional com pounds (I) are available in an analogous manner using different compounds (I) with an ester group in R4. The crude products are purified bychromatography if necessary (Table Ex32e). Stereoisomers can be separated by preparative chiral chromatography (e.g. prep, chiral SFC) or other methods for chiral separation if necessary.

[0954] Table 32e

[0955] Synthesis of 2-(4-ethoxyphenyl)- / \ / -((3aR.5s.6aS)-2-(oxetan-2-ylmethyl)octahvdrocvclopentarc1pyrrol-5-yl)quinoline-4- carboxamide (lb-159):

[0956]

[0957] Mixture of 2 stereoisomers

[0958] To a stirred solution of2-(4-ethoxyphenyl)- / V-((3aR, 5s, 6aS)-octahydrocyclopenta [c] pyrrol-5-yl)quinoline-4-carbox- amide hydrochloride (lb-52) (100 mg, 0.152 mmol) in acetonitrile (3 m L) in a seal tube was added oxetan-2-ylm ethyl 4- methyl benzene- 1 -sulfonate (60.4 mg, 0.25 mmol), DIPEA (89 μL, 0.76 mmol).The reaction mixture was stirred at80°C for 16 h. The reaction mixture was filtered and diluted with excess ice-cold water, extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with brine, dried over anhydrous NajSCX and concentrated under re- duced pressure. The residue was purified by RP preparative HPLC to afford 2-(4-ethoxyphenyl)-N-((3aR,5s,6aS)-2- (oxetan-2-ylmethyl)octahydrocyclopenta[c]pyrrol-5-yl)quinoline-4-carboxamide (lb-159). Additional com pounds (I) are available in an analogous manner using different compounds (I) (R4= H) and the corre- sponding tosylates as starting materials. The crude products are purified by chromatography if necessary (Table Ex 32f ).

[0959] Table Ex 32f:

[0960] Synthesis of 2-(4-ethoxyphenyl)-A / -((3aR.5r.6aS)-2-(2-hvdroxy-2-methylpropyl)octahvdrocvclopenta[c1pyrrol-5- yl)quinazoline-4-carboxamide (Id-16)

[0961] The 2-(4-ethoxyphenyl)-A / -((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)quinazoline-4-carboxamide (Id-9, 25 mg, 1 equiv., 62 μmol) and potassium carbonate (13 mg, 1 .5 equiv., 93 μmol) were dissolved in MeOH (5 mL) and 2,2-di- methyloxirane (27 mg, 6 Eq, 0.37 mmol) was added. The reaction mixture was heated to 50 °C and was stirred at 50 °C for 12 h. To the reaction mixture was added saturated NaHCOa aq. and EtOAc. The phases were separated, and the organic layer was washed with saturated NaHCOa aq., dried over MgaSO^ filtered and solvent evaporated under reduced pressure. The crude product was purified by column chromatography to obtain 2-(4-ethoxyphenyl)-N- ((3aR,5r,6aS)-2-(2-hydroxy-2-methylpropyl)octahydrocyclopenta[c]pyrrol-5-yl)quinazoline-4-carboxamide (Id-16).

[0962] Additional com pounds (I) are available in an analogous manner using different compounds (I) (R4= H) and the corre- sponding epoxides as starting materials. The crude products are purified by chromatography if necessary (Table Ex 33).

[0963] Table Ex 33:

[0964] Biological data

[0965] Biological example 1 : TASL proteostasis by TASL-EmGFP-P2A-m Cherry (TGC) reporter

[0966] The TGC reporter construct encodes C-term inally EmGFP-tagged TASL followed by the P2A self-cleaving peptide and m Cherry (SEQ ID NO:01 ), enabling constitutive expression of both ORFs from the same promoter. The measure- mentof EmGFP to mCherry fluorescence ratio allows the monitoring of TASL-EmGFP intracellular levels by micros- copy imaging.

[0967] 2k HEK-293T cells stably overexpressing the TGC reporter and N -term inally HA-tagged SLC15A4 (SEQ ID NO:02) were generated by genomic integration of a lentiviral construct carrying the sequence of the TGC reporter and a sep- arate genomic integration of a lentiviral construct carrying the HA-SLC15A4 sequence. The cells were seeded in DMEM media with 10% FBS (Gibco # 1 1965092, Fisher Scientific, cat. #1 1550356) and 1 % Pen -Strep (Sigma-AI- drich cat. #P4333) in 384-well plates (Perkin Elmer, cat. #8693-22361 ) previously coated with poly-lysine (Sigma- Aldrich, cat. #P6282). Right after seeding, compounds were added overa concentration range using a Tecan D300e Digital Dispenser, with specific concentrations indicated in Table BiolEx-1 below. 1 % DMSO was used as negative control to normalize the data per plate. Each compound was measured in two independent biological replicates and each replica had three technical measurements. After 48h of incubation at 37 degrees and 5% of CO2, Hoechst 33342 dye (Fisher Scientific, cat. #62249) was added at 5 pM final . Each plate was spun down and then incubated for 10 minutes at room temperature (RT) protected from light. Next, media was removed and 2% Paraformaldehyde (PFA) was added to the cells. The plate was incubated again for 20 minutes at RT and then two washing steps with Dulbecco’s Phosphate Buffered Saline (PBS, Sigma-Aldrich, cat.# D8537)were performed. Finally, 30pl of PBS was added to the wells and the plates were sealed and stored at 4 degrees until being imaged.

[0968] Microscopy images were acquired on Operetta CLS High Content Analysis System with a 20x water objective (1 .0 NA) using Harmony 5.1 software (PerkinElmer / Revvity). Exposure settings for Hoechst, mCherry and EmGFP chan- nels were adjusted to avoid image saturation. Following acquisition, images were subjected to analysis via an analy- sis / segmentation sequence implemented on Harmony 5.1 . The latter involved identifying cell nuclei and cytosolic re- gions, on Hoechst and Em GFP / m Cherry channels, respectively. Total cell fluorescent intensity values were derived for both EmGFP and mCherry channels in a population of cells excluding image artifacts and outliers, such as false positive cells and debris. Averaged EmGFP / mCherry ratios perfield are reported in Table BiolEx-1 .

[0969] The assay of the present exam pie allows forthe monitoring of changes in protein levels of TASL upon compound treatment, with active compounds being able to reduce the EmGFP / mCherry ratio (a ratio of 0 is understood as no detectable TASL protein).

[0970] Table BiolEx-1 : > > >> > > > > > > lb-15

[0971] > > > >> > > > >> >

[0972] The ratios were defined as follows in Table BiolEx-1 :

[0973] +++: Em GFP / m Cherry ratio between 0 and 0.4

[0974] ++: EmGFP / mCherry ratio between 0.41 and 0.7

[0975] +: EmGFP / mCherry ratio between 0.71 and 0.99.

[0976] Biological example 2: Enzyme-linked immunosorbent assay (ELISA)

[0977] IRF5 activation downstream of the SLC15A4 / TASL signalling complex results in the production and secretion of pro- inflammatory cytokines including interleukin-6 (IL-6) and tumor-necrosis factor alpha ( TNFa) (Heinz et al. 2020, Ta- kaoka et al, 2005). Cytokine production can be monitored by ELISA, an assay well known to the skilled person.

[0978] Peripheral Blood Mononuclear Cells (PBMCs) or isolated B cells, monocytes, plasmacytoid dendritic cells (pDCs) from healthy human donors were purified from whole blood by density centrifugation (Ficoll -Paque, Fisher Scientific, cat. #1 1768538), followed by magnetic bead isolation when it comes to the differentcell types. PBMCs were frozen in Fetal Bovine Serum (FBS, Fisher Scientific, cat. #11550356) plus 10% DMSO (as freezing media) until further use, whereas the different cell types were used freshly prepared. For com pound treatment, PBMCs were thawed in or cell types incubated in RPMI 1640 media (Gibco cat. #12004997) containing 10% FBS and counted. 100k-200k cells per well were seeded in 96-well transparent or black plates (Corning Costar, Fisher Scientific, cat. #10687551 ; Corning Costar, Sigma Aldrich, cat. #CLS3904-100EA) and com pounds were added ata serial concentration in technical trip- licates (Table BiolEx-2 provides the results at specific concentrations as indicated), and plates were incubated at 37 degrees and 5% of CO2 for48h. 18-20h before readout, cells were stimulated with 5pg / m L Resiquimod (R848, Med- Chem Express, cat. #HY-13740) or CpG-B (ODN2006, synthesized by IDT). At the end of the stimulation period, plates were spun down at 250g for5 minutes and supernatants were collected and analyzed for IL-6 and TNFa cyto- kine levels by ELISA (Invitrogen, cat. #88-7066-88 and 88-7346-88) according to manufacturer’s instructions. For IFNa ELISA (Invitrogen, cat. # BMS216), cells were treated with compounds for 3-6h following by 14h of stimulation with R848 or CpG-B.

[0979] Treatment of PBMCs with com pounds, which are able to the interfere with the SLC15A4 / TASL com plex (thus interfer- ing with the pathway that would ultimately result in IRF5 activation, which leads to cytokine production), is expected to result in reduced cytokine production. The results for the examples at the indicated concentrations as given using PBMCs stimulated with Resiquimod are shown in Table BiolEx-2a and BiolEx-2b below. Table BiolEx-2a:

[0980] Table BiolEx-2b:

[0981] The TNFa reduction was defined as follows in Table BiolEx-2a and -2b:

[0982] +++: Normalized TNFa concentration compared to DMSO treatment between 0 and 0.4

[0983] ++: Normalized TNFa concentration compared to DMSO treatment between 0.41 and 0.7

[0984] +: Normalized TNFa concentration compared to DMSO treatment between 0.71 and 0.99.

[0985] THP1 cells (CLS, cat. #300356) are cultured as 100k per well in 96-well transparent or black plates (Corning Costar, Fisher Scientific, cat. #10687551 ; Corning Costar, Sigma Aldrich, cat. #CLS3904-100EA) in RPMI 1640 media (Gibco cat. #12004997) containing 10% FBS (Fisher Scientific, cat. #11550356), 1 % Pen / strep (Gibco cat. #15070063), 1mM sodium pyruvate (Gibco, cat. #11360070), 2m M L-Glutamine (Gibco, cat. # A2916801 ) and 25m M HEPES (Gibco, cat. #11560496). THP1 -cells are treated with a serial concentration of compounds in technical triplicates. Plates are incubated at 37 degreesand 5% of CO2 for48h. 18-20h before readout, cells are stimulated with 5pg / mL Resiquimod (R848, MedChem Express, cat. #HY-13740). At the end of the stimulation period, plates are spun down at 250g for 5 minutes and supernatants are collected and analyzed for TN Fa and IL -6 cytokine levels by ELISA (Invi- trogen, cat. #88-7346-88 and #88-7066-88) according to manufacturer’s instructions.

[0986] Treatment of THP1 cells with compounds is expected to result in reduced cytokine production.

[0987] THP1-Dual hTLR9 Cells (Invivogen, cat. #thpd-htlr9) are seeded as 100k per well in 96-well transparent or black plates (Corning Costar, Fisher Scientific, cat. #10687551 ; Corning Costar, Sigma Aldrich, cat. #CLS3904-100EA) in RPMI 1640 media (Gibco cat. #12004997) containing 10% FBS (Fisher Scientific, cat. #11550356), 1 % Pen / strep (Gibco cat. #15070063), 2mM L-Glutamine (Gibco, cat. # A2916801 ) and 25mM HEPES (Gibco, cat. #11560496). These cells are treated with a serial concentration of compounds in technical triplicates and incubated for48h in 37 degreesand 5% of CO2. 18-20h before readout, cells are stimulated with 3-5pM CpG-B (ODN2006, synthesized by IDT). At the end of the stimulation period, plates are spun down at 250g for 5 minutes and supernatants are collected and analyzed forTNFa and IL-6 cytokine levels by ELISA (Invitrogen, cat. #88-7346-88 and #88-7066-88) according to manufacturer’s instructions.

[0988] Treatment of THP1 -Dual hTLR9 Cells with compounds is expected to result in reduced cytokine production.

[0989] Biological example 3: TNF-a Detection using HTRF method

[0990] 200k THP1 cells (ATCC, cat. #TIB-202) per well are cultured in 96-well plates (Falcon, Cat#351172) in RPM1 1640 (ATCC, Cat# 30-2001 ) + 10% HI FBS (Gibco, Cat# 10082147)+ 1X Penstrep (Gibco, Cat# 15140122) and treated with various concentrations of compounds for 48h. In the last 18-20h, cells are stimulated with 5pg / mL Resiquimod (R848, MedChem Express, cat. #HY-13740). At the end of the stimulation period, supernatants are collected and an- alyzed forTNFa cytokine levels by the Human TNFa detection Kit (Revvity, cat. # 2HTNFAPEG) with HTRF (Homo- geneous Time Resolved Fluorescence) method in 384-well (Revvity, Cat# 6008280) plates in technical triplicates, according to the manufacturer’s instructions. Treatmentof THP1 cells with compounds is expected to result in reduced cytokine production. The results for the ex- amples at the indicated concentrations are shown in Table BiolEx-3 below.

[0991] Table BiolEx-3:

[0992] The TNFa reduction was defined as follows in Table BiolEx-3:

[0993] +++: Normalized TNFa concentration compared to DMSO treatment between 0 and 0.4

[0994] ++: Normalized TNFa concentration compared to DMSO treatment between 0.41 and 0.7

[0995] +: Normalized TNFa concentration compared to DMSO treatment between 0.71 and 0.99.

[0996] In particular, the present invention relates to the following items:

[0997] 1. A compound of formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, wherein:

[0998] R1is thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or phenyl, each optionally substituted with one or more RS1; wherein each RS1is independently selected from -Hal, Cvs alkyl, Cvs haloalkyl, -cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl);

[0999] R2is H;

[1000] A is a moiety selected from R3

[1001] RL1— L1R iL2?— N /

[1002] R3and

[1003] - RL3- L2- R4wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein

[1004] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2; and

[1005] L2is wherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl); and wherein

[1006] RL1is absent or C1-2 alkylene;

[1007] R12is absent or C1-2 alkylene;

[1008] R13is absent or C1-2 alkylene; and wherein each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 al- kylene)-heteroaryl, and -(C2-3 alkylene)-O-heteroaryl, each optionally substituted with one or more RS3; provided that not both R3are -H; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(Ci-Balkyl), C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-CN, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl), -(C1-6 alkylene)-N(Ci-Balkyl)(C1-6 alkyl), -O(C1-6alkyl), -O(C1-6 haloalkyl), -(C1-6 alkylene)-O(C1-6alkyl), -(C1-6 alkylene)-S(C1-6 alkyl), -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COOH, -COO(C1-6 alkyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), -S(O)2-(C1-6 alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6 al- kyl), -S(O)2-N(CI-6 alkyl)(C1-6 alkyl), -NH-S(O)2-(C1-6 alkyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(Co-3alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(Co-3 alkylene)-cycloalkyl, -(Co-3 alkylene)-heterocycloalkyl, -(Co-3 alkylene)-aryl, and -(Co-3 alkylene)-het- eroaryl one -CH2- group if present is optionally replaced by -O-, and wherein the cycloalkyl moiety in said -(C0-3 al- kylene)-cycloalkyl, the heterocycloalkyl moiety in said -(Co-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(Co- 3 alkylene)-aryl, and the heteroaryl moiety in said -(Co-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, -O(C1-2 alkyl), and -O(Ci-2haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a heterocycloalkyl ring formed by two R3to- gether with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused heteroaryl ring; and wherein

[1009] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-o alkylene)-O(C1-6alkyl), -(C2-6 alkylene)-N(C1-6 al- kyl)(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 al- kylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, or-(C2-3 alkylene)- O-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C1-3 alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or - CH(CH2OH)-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl or -(C2.3 alkylene)-O-cycloalkyl, the heterocycloalkyl moiety in said -(Co-3 alkylene)-heterocycloalkyl or-(C2-3alkylene)-0-heterocycloalkyl, the aryl moiety in said -(C1-3 alkylene)-aryl or -(C2-3 alkylene)-O-aryl, and the heteroaryl moiety in said -(C1-3 alkylene)-heteroaryl or -(C2-3 alkylene)-O-heteroaryl, are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl);

[1010] X1is CH or N;

[1011] X2is CH or N;

[1012] Y1is CRY1or N;

[1013] Y2is CRY2or N;

[1014] Y3is CRY3or N; and

[1015] Y4is CRY4or N; wherein RY1, RYZ, RY3, and RY4are each independently selected from -H, -CN, -Hal, -OH, C1-6 alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), -O(C1-6 haloalkyl), and -(C1-6 alkylene)-O(C1-6 alkyl); provided that if X1and X2are both CH, at least one of Y1, Y2, Y3, and Y4is N; and provided that not more than three of X1, X2, Y1, Y2, Y3, and Y4are N; and provided that if A is

[1016] - RL3— L2- R4 then X2is N, and X1, Y1, Y2, Y3, and Y4are all different from N; and provided that if A is

[1017] 1 -RL3 - 1_2 -R4

[1018] L2is

[1019] R1-3is absent,

[1020] R4is H, and

[1021] X2is N, then one of X1, Y1, Y2, Y3, and Y4is also N.

[1022] 2. The compound of item 1 , wherein R1is wherein the dashed line marks the connection to the remainder of the molecule.

[1023] The compound of item 1 or 2, wherein RS1is C1-6 alkyl or -O(C1-6 alkyl).

[1024] The compound of any one of items 1 to 3, wherein R1is 4-ethoxyphenyl.

[1025] The compound of any one of items 1 to 4, wherein

[1026] X1is CH or N;

[1027] X2is CH or N;

[1028] Y1is CRY1or N;

[1029] Y2is CRY2or N;

[1030] Y3is CRY3or N; and

[1031] Y4is CRY4or N; wherein at least one of Y1, Y2, Y3, and Y4does not represent N or CH; and wherein RY1, RY2, RY3, and RY4are each independently selected from -H, -CN, -Hal, C1-6 alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), and -O(C1-6haloalkyl).

[1032] 6. The compound of any one of items 1 to 5, wherein the compound of formula (I) is a compound of formula (la), (lb), (Ic), or (Id):

[1033] 7. The compound of any one of items 1 to 6, wherein

[1034] RY1is -H;

[1035] RY2is -H, -Cl, or -F;

[1036] RY3is -H, -Cl, or -F; and

[1037] RY4is -H, -Cl, or -F.

[1038] 8. The compound of any one of items 1 to 7, wherein A is

[1039] R3

[1040] — RL1— L1— RL2— r /

[1041] R3. wherein the wavy line marks the connection to the remainder of the molecule; and wherein

[1042] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl); and wherein

[1043] RL1is absent; and

[1044] R12is absent or Ci alkylene; and wherein each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 al- kylene)-heteroaryl, and -(C2-3 alkylene)-O-heteroaryl, each optionally substituted with one or more RS3; provided that not both R3are -H; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)(C1-6 alkyl), C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-CN, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl), -(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkyl), -O(C1-6 alkyl), -O(C1-6 haloalkyl), -(C1-6 alkylene)-O(C1-6alkyl), -(C1.6 alkylene)-S(Ci-Balkyl), -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COO(C1-6 alkyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), -S(O)2-(C1-6 alkyl), -S(O)2-NH2]-S(O)2-NH(C1-6 al- kyl), -S(O)2-N(C1-6 alkyl)(C1-6 alkyl), -NH-S(O)2-(C1-6 alkyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(Co-3alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(Co-3 alkylene)-cycloalkyl, -(Co-3 alkylene)-heterocycloalkyl, -(Co-3 alkylene)-aryl, and -(Co-3 alkylene)-het- eroaryl one -CH2- group if present is optionally replaced by -O-, and wherein the cycloalkyl moiety in said -(C0-3 al- kylene)-cycloalkyl, the heterocycloalkyl moiety in said -(Co-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(C0-3 alkylene)-aryl, and the heteroaryl moiety in said -(Co-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, -O(C1-2 alkyl), and -O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a heterocycloalkyl ring formed by two R3to- gether with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused heteroaryl ring.

[1045] 9. The compound of item 8, wherein

[1046] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2.

[1047] 10. The compound of item 8, wherein

[1048] L1is wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R12.

[1049] 1 1 . The compound of any one of items 1 to 7, wherein A is

[1050] -RL3 - 1_2 -R4 wherein the wavy line marks the connection to the remainder of the molecule; and wherein

[1051] L2is

[1052] wherein the dashed line in each case marks the connection to R1-3, and the wavy line in each case marks the connection to R4; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl); and wherein

[1053] R1-3is absent or Ci alkylene; and wherein

[1054] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6alkyl), -(C2-6 alkylene)-N(Ci-g al- kyl)(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 al- kylene)-O-heterocycloalkyl, -(C1.3 alkylene)-aryl, -(C2-3alkylene)-O-aryl, -(C1.3 alkylene)-heteroaryl, or-(C2-3 alkylene)- O-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(Co- 3 alkylene)-heterocycloalkyl, -(C1-3 alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl or -(C2-3 alkylene)-O-cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl or -(C2-3 alkylene)-O-heterocycloalkyl, the aryl moiety in said -(C1-3 alkylene)-aryl or -(C2-3 alkylene)-O-aryl, and the heteroaryl moiety in said -(C1-3 alkylene)-het- eroaryl or -(C2-3 alkylene)-O-heteroaryl, are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl).

[1055] 12. The compound of item 1 1 , wherein

[1056] L2is wherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4; and

[1057] R13is absent.

[1058] 13. The compound of any one of items 1 to 10, wherein each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C1-3alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl, each optionally substituted with one or more RS3; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3.

[1059] 14. The compound of any one of items 1 to 7, 1 1 , or 12, wherein

[1060] R4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-0(C1-6alkyl), -(Co-3 alkylene)-heterocycloal- kyl, -(C1-3 alkylene)-aryl, or-(C1-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-hetero- cycloalkyl, -(C1-3 alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(C1-3 alkylene)-aryl and the heteroaryl moiety in said -(C1-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 al- kyl).

[1061] 15. The compound of anyone of items l to 14, wherein the com pound is a com pound selected from the following compounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

[1062]

[1063] 5 16. The compoundofanyoneofitemsl to 14, wherein the com pound is a com pound selected from the following compounds ora stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

[1064]

[1065] 17. A pharmaceutical composition comprising the compound of any one of items 1 to 16 and at least one pharma- ceutically acceptable carrier.

[1066] 18. The compound of any one of items 1 to 16 or the pharmaceutical composition of item 17 for use as a medica- ment.

[1067] 19. The compound of any one of items 1 to 16 or the pharmaceutical composition of item 17 for use in the treat- ment or prevention of an autoimmune disorder or inflammatory condition.

[1068] 20. The compound for use orthe pharmaceutical composition for use of item 19, wherein the autoimmune disor- der is selected from systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, polymyo- sitis / dermatomyositis, primary biliary cirrhosis, multiple sclerosis, oral ulcers, periodontitis, Behcet's disease, myas- thenia gravis, and ankylosing spondylitis, preferably wherein the autoimmune disorder is systemic lupus erythemato- sus, orwherein the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, en- dosomal TLR-dependentinflammation, ulcerative colitis, Crohn’s disease, endosomal TLR-induced hyperinflamma- tion, macrophage activation syndrome, allergic airway inflammation, and sarcoidosis, preferably wherein the inflam- matory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-depend- ent inflammation. 21 . The compound for use or the pharmaceutical composition for use of any of items 19 to 20, wherein the auto- immune disorder is a disorder associated with SLC15 peptide transporter, and / or wherein said compound or said pharmaceutical composition reduces the TASL protein level.

Claims

Claims1. A compound of formula (I)or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, wherein:R1is thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or phenyl, each optionally substituted with one or more RS1; wherein each RS1is independently selected from -Hal, C1-6 alkyl, C1-6 haloalkyl, -cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl);R2is H;A is a moiety selected fromR3RL1— L1RL2~ f / R3andRL3- L2- R4wherein the wavy line in each case marks the connection to the remainder of the molecule; and whereinL1iswherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R12; andL2iswherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4;and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -O(C1-2 alkyl), or-O(C1-2 haloalkyl); and whereinRL1is absent or C1-2 alkylene;R12is absent or C1-2 alkylene;R13is absent or C1-2 alkylene; and wherein each R3is independently selected from -H, C1.5 alkyl, -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, and -(C2-3 alkylene)-O-heteroaryl, each optionally substituted with one or more RS3; provided that not both R3are -H; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), C1-6 alkyl, C1-6 haloalkyl, -(C-i-o alkylene)-CN, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl), -(C1-6 al- kylene)-N(Ci-e al kyl )(C 1.5 alkyl), -0(C1-6 alkyl), -O(Ci 6 haloalkyl), -(C-i-o alkylene)-O(C1-6alkyl), -(C1-6 al- kylene)-S(Ci -Balkyl), -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COOH, -COO(C1-6 al- kyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 al- kyl), -S(O)2-(C1-6 alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6 alkyl), -S(O)2-N(C1-6 alkyl)(Ci-Balkyl), -NH-S(O)2-(C1-6 al- kyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)- heterocycloalkyl, -(C0-3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -O-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl, the heterocycloalkyl moiety in said -(Co- 3 alkylene)-heterocycloalkyl, the aryl moiety in said -(C0-3 alkylene)-aryl, and the heteroaryl moiety in said -(C0-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, -O(C1-2 alkyl), and -O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a heterocycloalkyl ring formed by two R3to- gether with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused heteroaryl ring; and whereinR4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6alkyl), -(C2-6 alkylene)-N(C1-6 al- kyl )(C1-6 alkyl), -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C2-3 al- kylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, or-(C2-3 alkylene)- O-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C1-3 alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl or -(C2-3 alkylene)-O-cycloalkyl, the heterocycloalkyl moiety in said -(Co-3 alkylene)-heterocycloalkyl or -(C2-3 alkylene)-O-heterocycloalkyl, the aryl moiety in said -(C1-3 alkylene)-aryl or -(C2-3 alkylene)-O-aryl, and the heteroaryl moiety in said -(C1-3 alkylene)-het- eroaryl or -(C2-3 alkylene)-O-heteroaryl, are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl);X1is CH or N;X2is CH or N;Y1is CRY1or N;Y2is CRY2or N;Y3is CRY3or N; andY4is CRY4or N; wherein RY1, RY2, RY3, and RY4are each independently selected from -H, -CN, -Hal, -OH, Ci-g alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), -O(C1-6 haloalkyl), and -(C1.6 alkylene)-O(C1-6 alkyl); provided that if X1and X2are both CH, at least one of Y1, Y2, Y3, and Y4is N; and provided that not more than three of X1, X2, Y1, Y2, Y3, and Y4are N; and provided that if A is- RL3- L2- R4L2isR13is absent,R4is H, andX2is N, then one of X1, Y1, Y2, Y3, and Y4is also N.

2. The compound of claim 1 , wherein R1iswherein the dashed line marks the connection to the remainder of the molecule.

3. The compound of claim 1 or 2, wherein RS1is -Hal, Cvs alkyl or -O(C1-6 alkyl).

4. The compound of any one of claims 1 to 3, wherein R1is 4-ethoxyphenyl, 6-ethoxypyridin-3-yl, 5-ethoxypyri- din-2-yl, or 5-fluoropyridin-2-yl.

5. The compound of claim 1 , wherein R1iswherein the dashed line marks the connection to the remainder of the molecule.

6. The compound of claim 1 or 5, wherein RS1is C1-6 alkyl or -O(C1-6 alkyl).

7. The compound of any one of claims 1 , 5, or 6, wherein R1is 4-ethoxyphenyl.

8. The compound of any one of claims 1 to 7, whereinX1is CH or N;X2is CH or N;Y1is CRY1or N;Y2is CRY2or N;Y3is CRY3or N; andY4is CRY4or N; wherein at least one of Y1, Y2, Y3, and Y4does not represent N or CH ; and wherein RY1, RY2, RY3, and RY4are each independently selected from -H, -CN, -Hal, C1-6 alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl).

9. The compound of any one of claims 1 to 8, wherein the compound of formula (I) is a compound of formula (la),(lb), (Ic), or (Id):

10. The compound of any one of claims 1 to 9, whereinRY1is -H;RY2is -H, -Cl, or -F;RY3is -H, -Cl, or -F; andRY4is -H, -Cl, or -F.1 1 . The compound of any one of claims 1 to 10, wherein A isR3- RL1— L1— RL2— l / R3. wherein the wavy line marks the connection to the remainder of the molecule; and whereinL1iswherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R12; and wherein p is O, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -0(0-2 alkyl), or -O(C1-2 haloalkyl); and whereinRL1is absent; andR1-2is absent or Ci alkylene; and wherein each R3is independently selected from -H, C1.5 alkyl, -(C0-3 alkylene)-cycloalkyl, -(C2-3 alkylene)-O-cycloalkyl,-(C0-3 alkylene)-heterocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 alkylene)-heteroaryl, and -(C2-3 alkylene)-O-heteroaryl, each optionally substituted with one or more RS3; pro- vided that not both R3are -H; or the two R3togetherwith the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally sub- stituted with one or more RS3; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-CN, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl),-(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkyl), -O(C1-6 alkyl), -O(C1-6 haloalkyl), -(C1-6 alkylene)-O(C1-6 alkyl), -(C1-6 al- kylene)-S(C1-6 alkyl), -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COO(C1-6 alkyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(Ci-Salkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), -S(O)2-(C1-6 al- kyl), -S(O)2-NH2, -S(O)2-NH(CI-6 alkyl), -S(O)2-N(C1-6 alkyl)(C1-6 alkyl), -NH-S(O)2-(C1-6 alkyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-heterocycloalkyl, -(C0-3 alkylene)-aryl, and-(C0-3 alkylene)-heteroaryl, wherein in said alkylene moiety of said -(Co-3 alkylene)-cycloalkyl, -(C0-3 alkylene)-hetero- cycloalkyl, -(Co- 3 alkylene)-aryl, and -(C0-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -O-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl, the heterocycloalkyl moiety in said-(C0-3 alkylene)-heterocycloalkyl, the aryl moiety in said -(Co-3 alkylene)-aryl, and the heteroaryl moiety in said-(C0-3 alkylene)-heteroaryl are each optionally substituted with one or more groups each independently selected from -Hal, C1.2 alkyl, C1.2 haloalkyl, -O(C1-2 alkyl), and -O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a heterocycloalkyl ring formed by two R3to- gether with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused heteroaryl ring.

12. The compound of any one of claims 1 to 1 1 , wherein each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-(3-to 7-membered cycloalkyl), -(C2-3 alkylene)- O-(3- to 7-membered cycloalkyl), -(Co-3 alkylene)-( 3- to 7-membered heterocycloalkyl), -(C2-3 alkylene)-O-(3- to 7- membered heterocycloalkyl), -(C1.3 alkylene)-phenyl, -(C2-3 alkylene)-O-phenyl, -(C1.3 alkylene)-(5- or 6-membered heteroaryl), and -(C2-3 alkylene)-O-(5- or 6-membered heteroaryl), each optionally substituted with one or more RS3, wherein the aforementioned heterocycloalkyl and heteroaryl rings independently comprise one or more, same or dif- ferent heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non -oxi- dized; provided that not both R3are -H;or the two R3together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring, optionally substituted with one or more RS3, and optionally comprising in addition to the nitrogen atom one or more, same or different heteroatoms selected from O, N, or S, wherein said N - and / or S-atoms are independently oxidized or non-oxidized; wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-CN, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-NH(C1-6 alkyl), -(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkyl), -O(C1-6 alkyl), -O(C1-6 haloalkyl), -(C1-6 alkylene)-O(C1-6 alkyl), -(C1-6 alkylene)-S(C1-6alkyl), -CO(C1-6 alkyl), -CO(cycloalkyl), -CO(heterocycloalkyl), -COO(C1-6 alkyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 al kyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), -S(O)2-(C1-6 alkyl), -S(O)2-NH2, -S(O)2-N H(CI-6 alkyl), -S(O)2-N(CI-6 alkyl)(C1-6 alkyl), -NH-S(O)2-(C1-6 alkyl), -N(C1-6 alkyl)-S(O)2-(C1-6 alkyl), -(Co-3 alkylene)-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3 alkylene)-phenyl, and -(C0-3 al kylene)-(5- or 6-membered heteroaryl), wherein the aforemen- tioned heterocycloalkyl and heteroaryl rings independentlycomprise one or more, same or different heteroatoms se- lected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, wherein in said alkylene moiety of said -(Co-3 alkylene)-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3- to 7-membered heterocy- cloalkyl), -(Co- 3 alkylene)-phenyl, and -(C0-3 al kylene)-(5- or 6-membered heteroaryl) one -CH2- group if present is op- tionally replaced by -O-, and wherein the 3- to 7-membered cycloalkyl moiety in said -(C0-3 alkylene)-(3- to 7-mem- bered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(C0-3 alkylene)-(3- to 7-membered heterocy- cloalkyl), the phenyl in said -(Co-3 alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(Co-s al- kylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, -O(C1-2 alkyl), and -O(C1-2 haloalkyl); or two RS3attached to the same carbon atom form =0; or, if attached to a 3- to 7-membered heterocycloalkyl ring formed by two R3together with the nitrogen atom to which they are attached, two RS3together with two neighboring atoms to which they are attached form a fused 5- or 6-membered heteroaryl ring, which comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized.

13. The compound of any one of claims 1 to 12, whereinL1iswherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R12.The compound of any one of claims 1 to 12, whereinL1iswherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R12.

15. The compound of any one of claims 1 to 12 or 14, whereinL1iswherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to R1-2.

16. The compound of any one of claims 1 to 10, wherein A iswherein the wavy line marks the connection to the remainder of the molecule; and whereinL2iswherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4; and wherein p is 0, 1 , or 2; and each Rxis independently -Hal, -CN, C1-2 alkyl, C1-2 haloalkyl, -(C1-6 alkylene)-OH, -OH, -O(C1-2 alkyl), or -O(C1-2 haloalkyl); and whereinR13is absent or Ci alkylene; and whereinR4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6alkyl),-(C2-6 alkylene)-N(C1-6alkyl)(C1-6alkyl), -(Co-3 alkylene)-cycloalkyl, -(C2-3alkylene)-O-cycloalkyl, -(Co-3alkylene)-heter- ocycloalkyl, -(C2-3 alkylene)-O-heterocycloalkyl, -(C1-3 alkylene)-aryl, -(C2-3 alkylene)-O-aryl, -(C1-3 alkylene)-het- eroaryl, or -(C2-3 alkylene)-O-heteroaryl, wherein in said alkylene moiety of said -(C0-3 alkylene)-cycloalkyl, -(C0-3 al- kylene)-heterocycloalkyl, -(C1-3alkylene)-aryl, and -(C1-3 alkylene)-heteroaryl one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the cycloalkyl moiety in said -(C0-3 alkylene)-cycloalkyl or-(C2-3 alkylene)-O-cycloalkyl, the heterocycloalkyl moiety in said -(C0-3 alkylene)-heterocycloalkyl or-(C2-3alkylene)-O- heterocycloalkyl, the aryl moiety in said -(C1-3 alkylene)-aryl or -(C2-3 alkylene)-O-aryl, and the heteroaryl moiety in said -(C1-3 alkylene)-heteroaryl or -(C2-3 alkylene)-O-heteroaryl, are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -0(0-2 alkyl).

17. The compound of any one of claims 1 to 10 or 16, whereinR4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6alkyl), -(C2-6 alkylene)-N(Ci-g al- kyl)(C1-6 alkyl), -(C0-3 alkylene)-(3- to 7-membered cycloalkyl), -(C2-3 alkylene)-O-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C2-3 alkylene)-O-(3- to 7-membered heterocycloalkyl), -(C1-3 alkylene)-phenyl, -(C2-3 alkylene)-O-phenyl, -(C1-3 alkylene)-(5- or 6-membered heteroaryl), or -(C2-3 alkylene)- O-(5- or 6-membered heteroaryl), wherein the aforementioned heterocycloalkyl and heteroaryl rings independently com prise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, wherein in said alkylene moiety of said -(C0-3 alkylene)-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3-to 7-membered heterocycloalkyl), -(C1-3alkylene)-phenyl, and -(C1-3 alkylene)-(5- or e- membered heteroaryl) one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH2OH)-, and wherein the 3- to 7-membered cycloalkyl moiety in said -(C0-3 alkylene)-(3-to 7-membered cycloalkyl) or -(C2-3 alkylene)-O-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(Co-3 alkylene)-(3- to 7-membered heterocycloalkyl) or-(C2-3 alkylene)-O-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C1-3 alkylene)-phenyl or -(C2-3 alkylene)-O-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C1-3 alkylene)-(5- or 6-membered heteroaryl) or -(C2-3 alkylene)-O-(5- or 6-membered heteroaryl), are each optionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl).

18. The compound of any one of claims 1 to 10, 16, or 17, whereinL2iswherein the dashed line in each case marks the connection to R13, and the wavy line in each case marks the connection to R4; andR13is absent.

19. The compound of any one of claims 1 to 15, wherein each R3is independently selected from -H, C1-5 alkyl, -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl),-(C1-3 alkylene)-phenyl, and -(C1-3 alkylene)-(5- or 6-membered heteroaryl), each optionally substituted with one or more RS3, wherein the aforementioned heterocycloalkyl and heteroaryl rings independently comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized; or the two R3together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring, optionally substituted with one or more RS3, and optionally comprising in addition to the nitrogen atom one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized.

20. The compound of any one of claims 1 to 10, 16, 17, or 18, whereinR4is -H, C1-6 alkyl, C1-6 haloalkyl, -(C2-6 alkylene)-OH, -(C2-6 alkylene)-O(C1-6 alkyl), -(Co-3 alkylene)-(3- to 7-mem- bered cycloalkyl), -(C0-3 alkylene)-(3-to 7-membered heterocycloalkyl), -(C1-3 alkylene)-phenyl, or -(C1-3 alkylene)-(5- or 6-membered heteroaryl), wherein the aforementioned heterocycloalkyl and heteroaryl rings independently com- prise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are inde-pendently oxidized or non-oxidized, wherein in said alkylene moiety of said -(Co- 3 alkylene)-(3- to 7-membered cyclo- alkyl), -(Co-3 alkylene)-(3-to 7-membered heterocycloalkyl), -(C1-3 alkylene)-phenyl, and -(C1-3 alkylene)-(5-or6-mem- bered heteroaryl) one -CH2- group if present is optionally replaced by -CHOH-, or -CH(CH20H)-, and wherein the 3- to 7-membered cycloalkyl moiety in said -(C0-3 alkylene)-(3- to 7-membered cycloalkyl) the 3- to 7-membered hetero- cycloalkyl moiety in said -(C0-3 alkylene)-(3-to 7-membered heterocycloalkyl), the phenyl in said -(C1-3 alkylene)-phe- nyl, and the 5- or 6-membered heteroaryl moiety in said -(C1-3 alkylene)-(5- or 6-membered heteroaryl), are each op- tionally substituted with one or more groups each independently selected from -Hal, C1-2 alkyl, C1-2 haloalkyl, and -O(C1-2 alkyl).

21. The compound of any one of claims 1 to 10, wherein the com pound is a com pound selected from the following compounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:5 22. The compound of any one of claims 1 to 10, wherein the com pound is a com pound selected from the following compounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

23. The compound of any one of claims 1 to 10, wherein the com pound is a com pound selected from the following compounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

24. A pharmaceutical composition comprising the compound of any one of claims 1 to 23 and at least one phar- maceutically acceptable carrier.

25. The compound of any one of claims 1 to 23 or the pharmaceutical composition of claim 24 for use as a medic- ament.

26. The compound of any one of claims 1 to 23 or the pharmaceutical composition of claim 24 for use in the treat- ment or prevention of an autoimmune disorder or inflammatory condition.

27. The compound foruse orthe pharmaceutical composition foruse of claim 26, wherein the autoimmune disor- der is selected from systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, polymyo- sitis / dermatomyositis, primary biliary cirrhosis, multiple sclerosis, oral ulcers, periodontitis, Behget’s disease, myas- thenia gravis, and ankylosing spondylitis, preferably wherein the autoimmune disorder is systemic lupus erythemato- sus, orwherein the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, en- dosomal TLR-dependentinflammation, ulcerative colitis, Crohn’s disease, endosomal TLR-induced hyperinflamma- tion, macrophage activation syndrome, allergic airway inflammation, and sarcoidosis, preferably wherein the inflam- matory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-depend- ent inflammation.

28. The compound foruse orthe pharmaceutical com position for use of any of claims 26 to 27, wherein the auto- immune disorder is a disorder associated with SLC15 peptide transporter, and / or wherein said compound or said pharmaceutical composition reduces the TASL protein level.

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