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] SOLGATE GMBH

[0002] Our ref.: S13485WO

[0003] NEW HETEROCYCLIC COMPOUNDS REDUCING THE TASL PROTEIN LEVEL FIELD OF THE INVENTION

[0004] The present invention relates to 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 (I) and at least one 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 formula (I) is a disorder associated with SLC15 peptide transporter. The compound of formula (I) has been demonstrated to reduce the TASL protein level.

[0005] BACKGROUND OF THE INVENTION

[0006] Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune 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 mutations 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 acidsensing 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 endolysosomal TLRs is thought to 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. Dorner, Toll-like receptor signalling 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 lysosomal solute carrier SLC15A4 and transcription factor IRF5 as components essential for mediating disease development downstream of TLRs (T. Ban, G. R. Sato, T. Tamura, Regulation and role of the transcription factor IRF5 in innate immune responses and systemic lupus erythematosus. Int Immunol 30, 529-536 (2018); J. Bentham et al., Genetic 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 Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling 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 symporter SLC15a4 is essential for the development of systemic lupus erythematosus in murine models. PLoS One 16, e0244439 (2021); H. Almuttaqi, I. A. Udalova, Advances and challenges in targeting IRF5, a key regulator of inflammation. FEBS J 286, 1624-1637 (2019); S. Song et al., Inhibition of IRF5 hyperactivation protects from lupus onset and severity. J ClinInvest 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 pleiotropic SNP modulates IRF5 alternative promoter usage through ZBTB3-mediated chromatin looping. Nat Commun 14, 3430 (2023)). TASL, encoded by an SLE-associated gene previously known as CXorf21, is a SLC15A4 interactor 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 Systemic 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), 112916 (2023)). Through a C-terminal pLxlS motif, TASL acts as signaling adaptor mediating 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 activation. Science 347, aaa2630 (2015)). Thus, TASL represents a central element in a pathway in which each component is associated with autoimmune disorders, in particular SLE, 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. 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 assembly of the SLC15A4-TASL module, leading to efficient degradation of TASL and ablation of IRF5 activation. Consequently, these compounds block endolysosomal TLR-induced responses in disease-relevant human immune cells.

[0007] 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.

[0011] In a first embodiment, the present invention relates to a compound of formula (I)

[0012]

[0013] 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, C1-6alkyl, C1-6haloalkyl, -S(C1-6alkyl), C3-7cycloalkyl, -S(C1-6alkyl), O(-C1-6alkyl), and -O(C1-6haloalkyl);

[0014] R2is H;

[0015] A is

[0016] R3A

[0017] I - RL1— L1- RL2— l /

[0018] ?

[0019]

[0020] \

[0021] R3B.

[0022] wherein the wavy line in each case marks the connection to the remainder of the molecule;

[0023] and wherein

[0024] L1is

[0025]

[0026] wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2;

[0027] and wherein

[0028] p in each case independently is 1 or 2;

[0029] q in each case independently is 0, 1, 2, or 3;

[0030] each Rxis independently -S(O)2-(C1-6alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6alkyl), -S(O)2-N(C1-6alkyl)(C1-6alkyl), -(C1-6alkylene)-O(C1-6alkyl), -O-(C1-6alkylene)-O(C1-6alkyl), 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -0-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -CN, C-|.2alkyl, C-|.2haloalkyl, -0(0^2 alkyl), and -0(0^2 haloalkyl), and 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; each Rzis independently -Hal, -CN, C1-2alkyl, C1-2haloalkyl, -(C1-6alkylene)-OH, -OH, -O(C1-2alkyl), -O(C1-2haloalkyl), -S(O)2-(C1-6alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6alkyl), -S(O)2-N(C1-6alkyl)(C1-6alkyl), -(C1-6alkylene)-O(C1-6alkyl), -O-(C1-6alkylene)-O(C1-6alkyl), 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl), and 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;

[0031] Z1is CH2, CHRZ, C(RZ)2, NRN, O, S, S(=O), or S(=O)2;

[0032] wherein

[0033] RNis -H, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, -CO(C1-6alkyl), -CO(C1-6haloalkyl), -S(O)2-(C1-6alkyl), -S(O)2-(C1-6haloalkyl) -(C1-2alkylene)-(3- to 7-membered cycloalkyl), -( C1-2alkylene)-(3- to 7-membered heterocycloalkyl), -( C0-2alkylene)-phenyl, -( C0-2alkylene)-(5- or 6-membered aryl), or -( C0-2alkylene)-(5- or 6-membered heteroaryl), wherein the aforementioned heterocycloalkyl and heteroaryl rings independently comprise one or more, same ordifferent heteroatoms selected from O, N, or S, wherein said N- and / or S-atoms are independently oxidized or nonoxidized, wherein the 3- to 7-membered cycloalkyl moiety in said -( C1-2alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -( C1-2alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -( C0-2alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0-2alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2alkyl, C1-2haloalkyl;

[0034] and wherein

[0035] RL1is absent or Ci-2alkylene;

[0036] RL2is absent or C1.2alkylene; and

[0037] wherein

[0038] R3Aand R3Bare each independently selected from -H, C1-5alkyl, -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C2-3alkylene)-O-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C2-3alkylene)-O-(3- to 7-membered heterocycloalkyl), -(C1-3alkylene)-phenyl, -(C2-3alkylene)-O-phenyl, -(C1-3alkylene)-(5- or 6-membered) heteroaryl, and -(C2-3alkylene)-O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3, and 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;

[0039] provided that not both R3Aand R3Bare -H;

[0040] or R3Aand R3Btogether with the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more, same or different substituents RS3;

[0041] wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), C1-6alkyl, C1-6haloalkyl, -(C1-6alkylene)-CN, -(C1-6alkylene)-OH, -(C1-6alkylene)-NH(C1-6alkyl), -(C1-6alkylene)-N(C1-6alkyl)(C1-6alkyl), -O(C1-6alkyl), -O(C1-6haloalkyl), -(C1-6alkylene)-O(C1-6alkyl), -(C1-6alkylene)-S(C1-6alkyl), -CO(C1-6alkyl), -CO(3- to 7-membered cycloalkyl), -CO(3- to 7-membered heterocycloalkyl), -COOH, -COO(C1-6alkyl), -CO-NH2, -CO-NH(C1-6alkyl), -CO-N(C1-6alkyl)(C1-6alkyl), -NH-CO(C1-6alkyl), -N(C1-6alkyl)-CO(C1-6alkyl), -S(O)2-(C1-6alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6alkyl), -S(O)2-N(C1-6alkyl)(C1-6alkyl), -NH-S(O)2-(C1-6alkyl), -N(C1-6alkyl)-S(O)2-(C1-6alkyl), -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3alkylene)-phenyl, and -(C0-3alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3-to 7-membered heterocycloalkyl), -(C0-3alkylene)-phenyl, and -(C0-3alkylene)-(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 -(C0-3alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(C0-3alkylene)-(3-to 7-membered heterocycloalkyl), the phenyl in said -(C0-3alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0-3alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl);

[0042] or two RS3attached to the same carbon atom form =O; or, if attached to a heterocycloalkyl ring formed by R3Aand R3Btogether 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;

[0043] X1is CH or N;

[0044] X2is CH or N;

[0045] Y1is CRY1or N;

[0046] Y2is CRY2or N;Y3is CRY3or N; and

[0047] Y4is CRY4or N;

[0048] wherein RY1, RY2, RY3, and RY4are each independently selected from -H, -CN, -Hal, -OH, C1-6alkyl, C1-6haloalkyl, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), -O(C1-6alkyl), -O(C1-6haloalkyl), and -(C1-6alkylene)-O(C1-6alkyl); provided that if X1and X2are both CH, at least one of Y1, Y2, Y3, and Y4is N; and

[0049] provided that not more than three of X1, X2, Y1, Y2, Y3, and Y4are N.

[0050] In a preferred embodiment, R1is

[0051]

[0052] wherein the dashed line marks the connection to the remainder of the molecule.

[0053] In another preferred embodiment,

[0054] RS1is -F, C1-6alkyl or -O(C1-6alkyl).

[0055] In another preferred embodiment,

[0056] R1is 4-ethoxyphenyl.

[0057] In another preferred embodiment,

[0058] X1is CH or N;

[0059] X2is CH or N;

[0060] Y1is CH;

[0061] Y2is N, CH, CCI, or CF;

[0062] Y3is CH, CCI, or CF; and

[0063] Y4is CH;

[0064] provided that not both of X1and X2are CH.

[0065] In another preferred embodiment,

[0066] X1is CH;

[0067] X2is N;

[0068] Y1is CH;

[0069] Y2is CH or CF;

[0070] Y3is CH or CF; and

[0071] Y4is CH;

[0072] or

[0073] X1is CH;

[0074] X2is N;

[0075] Y1is CH;

[0076] Y2is N;

[0077] Y3is CH or CF; and

[0078] Y4is CH;

[0079] or

[0080] X1is N;

[0081] X2is N;

[0082] Y1is CH;Y2is CH or CF;

[0083] Y3is CH or CF; and

[0084] Y4is CH.

[0085] In another preferred embodiment

[0086] A is

[0087] R3A

[0088] 1 - RL1— L1- RL2— l /

[0089] ?

[0090]

[0091] \

[0092] R3B

[0093] wherein the wavy line marks the connection to the remainder of the molecule;

[0094] and wherein

[0095] L1is

[0096] (RX)P, (RX)P, (RX)P, (RX)P,

[0097]

[0098] , or - wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2;

[0099] and wherein

[0100] p in each case independently is 1 or 2;

[0101] q in each case independently is 0, 1, or 2;

[0102] each Rxis independently -S(O)2-(C1-6alkyl), -(C1-6alkylene)-O(C1-6alkyl), -O-(C1-6alkylene)-O(C1-6alkyl), -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -CN, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl), and 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;

[0103] each Rzis independently -Hal, -CN, C1-2alkyl, C1-2haloalkyl, -(C1-6alkylene)-OH, -OH, -O(C1-2alkyl), -O(C1-2haloalkyl), -S(O)2-(C1-6alkyl), -(C1-6alkylene)-O(C1-6alkyl), -O-(C1-6alkylene)-O(C1-6alkyl), -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl), and 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; and

[0104] Z1is CH2, CHF, CF2, CHOH, CHOCH3, O, S(=O), or S(=O)2;

[0105] and wherein

[0106] RL1is absent; and

[0107] RL2is absent;and wherein

[0108] R3Aand R3Bare each independently selected from -H, C1-3alkyl, -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C1-3alkylene)-phenyl, and -(C1-3alkylene)-(5- or 6-membered) heteroaryl, 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, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3;

[0109] provided that not both R3Aand R3Bare -H;

[0110] or R3Aand R3Btogether with the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more, same or different substituents RS3;

[0111] wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), C1-6alkyl, C1-6haloalkyl, -(C1-6alkylene)-OH, -(C1-6alkylene)-NH(C1-6alkyl), -(C1-6alkylene)-N(C1-6alkyl)(C1-6alkyl), -O(C1-6alkyl), -O(C1-6haloalkyl), -(C1-6alkylene)-O(C1-6alkyl), -CO(C1-6alkyl), -CO(3- to 7-membered cycloalkyl), -CO(3- to 7-membered heterocycloalkyl), -COOH, -COO(C1-6alkyl), -CO-NH2, -CO-NH(C1-6alkyl), -CO-N(C1-6alkyl)(C1-6alkyl), -S(O)2-(C1-6alkyl), -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3alkylene)-phenyl, and -(C0-3alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3alkylene)-phenyl, and -(C0-3alkylene)-(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 -(C0-3alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C0-3alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0-3alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl).

[0112] In another preferred embodiment

[0113] L1is

[0114]

[0115] wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2; and wherein p, q, Rx, and Rzare as defined in the preceding embodiments.

[0116] In a more preferred embodiment,

[0117] R3Ais -H or C1.2alkyl, which is unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -OCH3, -CO(CH3), and -S(O)2-(CH3); and

[0118] R3Bis selected from -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C1-3alkylene)-phenyl, and -(C1-3alkylene)-(5- or 6-membered) heteroaryl, 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, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3;

[0119] wherein each RS3is independently selected from -CN, -Hal, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), -O(C1-6haloalkyl), -(C1-6alkylene)-O(C1-6alkyl), -S(O)2-(C1-6alkyl), -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3alkylene)-phenyl, and -(C0-3alkylene)-(5- or 6-memberedheteroaryl), 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, wherein in said alkylene moiety of said -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3alkylene)-phenyl, and -(C0-3alkylene)-(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 -(C0-3alkylene)-(3-to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C0-3alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0-3alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl).

[0120] In a particularly preferred embodiment, the compound of formula (I) is a compound selected from the following compounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

[0121] F

[0122]

[0123]

[0124]

[0125] In another particularly preferred embodiment, the compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0126]

[0127] In another particularly preferred embodiment, the compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0128]

[0129] In another particularly preferred embodiment, the compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0130]

[0131] In another particularly preferred embodiment, the compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0132]

[0133] in another particularly preferred embodiment, the compound of formula (I) is the following compound or a pharmaceutically acceptable salt or solvate thereof:

[0134]

[0135] In another particularly preferred embodiment, the compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0136]

[0137] In another particularly preferred embodiment, the compound of formula (I) is the following compound or a pharma-ceutically acceptable salt thereof:

[0138]

[0139] in another particularly preferred embodiment, the compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:F

[0140]

[0141] In another particularly preferred embodiment, the compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0142]

[0143] In another particularly preferred embodiment, the compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0144]

[0145] 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.

[0146] In a third embodiment, the present invention relates to 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 as a medicament.

[0147] 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 compounds of formula (I) leads to efficient degradation of TASL.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), psoriasis, 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 et al, (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 Chinese Han population. Langefeld and coworkers (Langefeld et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun, 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 human cells. Odhams et al. (Odhams et al (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 explanation.

[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 pathogenesis 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 TLR function. Pollard and coworkers (Pollard et al. Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN. J Immunol, 199, 3739, (2017)) found that SLC15A4-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 autoimmunity in several mouse SLE models (Drobek, A. et al. The TLR7 / 9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse. Nat. Commun. 16, 967 (2025); Lau, L. et al. An essential role for TASL in mouse autoimmune pathogenesis and Toll-like receptor signaling. Nat. Commun. 16, 968 (2025)).

[0151] Accordingly, the compounds of the present invention are considered useful in the treatment or prevention of autoimmune disorders, in particular SLE.

[0152] 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 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, Behget’s disease, inflammatory bowel disease, psoriasis, myasthenia gravis, and ankylosing spondylitis (Wang et al. (2023), Bentham et al. 2015), Katewa et al. (2021 )). There is further a body of evidence based on genetic studies indicating the role of SLC15A4 and / or TASL in proinflammatory 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 lines and primary cells for endosomal TLR function.

[0153] There is further evidence based on studies in mouse models indicating the role of SLC15A4 and / or TASL in inflammatory conditions. Blasius and coworkers (Blasius et al. (2010)) identified SLC15A4 as essential component in endosomal TLR function 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 proinflammatory cytokines from dendritic cells. Furthermore, SLC15A4-deficiency was found to be protective in a mouse model of IBD.

[0154] SLC15A4-deficient 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 et al. 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 TLR function 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-induced systemic inflammation and psoriasiform inflammation in mice. Lopez-Haber and coworkers (Lopez-Haber et al. The phagosomal solute transporter SLC15A4 promotes inflammasome activity via mTORC1 signaling and autophagy restraint in dendritic cells, EMBO J, 41, e111161 (2022)) describe a contribution of SLC15A4 in inflammasome activation via mTORC1 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 treatment or 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 inflammation, and sarcoidosis, preferably wherein the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-dependent inflammation.

[0156] Accordingly, the compounds of the present invention are useful in treatment or prevention of an inflammatory condition.

[0157] Thus, in a fourth embodiment, the present invention relates to 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 autoimmune disorder or inflammatory condition. In one 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 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.

[0158] In a fifth embodiment, the present invention relates to use of the compound of formula (I) or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of the present invention in the manufacture of a medicament for treatment or prevention of an autoimmune disorder or inflammatory condition.

[0159] In a sixth embodiment, the present invention relates to a method of treatment of an autoimmune disorder or inflammatory 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 invention, 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 pharmaceutical composition of the present invention, is to be administered.

[0160] The autoimmune disorder is preferably selected from systemic lupus erythematosus, rheumatoid arthritis, scleroderma, 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 disorder is systemic lupus erythematosus.

[0161] The inflammatory condition is preferably selected from inflammatory bowel disease, psoriasiform dermatitis, endosomal TLR-dependent inflammation, ulcerative colitis, Crohn’s disease, endosomal TLR-inducedhyperinflammation, 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 inflammation.

[0162] Thus, in a seventh embodiment, the present invention relates to 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 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, Behget’s disease, myasthenia gravis, and ankylosing spondylitis, preferably wherein the autoimmune disorder is systemic lupus erythematosus, or wherein the inflammatory condition is 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 inflammation, and sarcoidosis, preferably wherein the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-dependent inflammation.

[0163] It is to be noted that the compounds 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, pharmaceutically 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 embodiment the present invention relates to the compound 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 disorder, wherein said compound or said pharmaceutical composition binds the SLC15 peptide transporter. Given the ability of the compound of the present invention, 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 disorder associated with SLC15 peptide transporter. Accordingly, the present invention in one embodiment relates to the compound 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 disorder, wherein the autoimmune disorder is a disorder associated with SLC15 peptide transporter.

[0164] Thus, in an eighth embodiment, the present invention relates to 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 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.

[0165] The compounds provided according to the present invention are also useful in treatment or prevention of other lupus diseases such as cutaneous or neonatal lupus erythematosus.

[0166] DEFINITIONS

[0167] The following definitions apply throughout the present specification and the claims, unless specifically indicated otherwise.

[0168] The term “hydrogen” is herein used to refer to protium, deuterium and / or tritium, 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. 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.As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise 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 tertbutyl). Unless defined otherwise, the term “alkyl” preferably refers to C1.4alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.

[0170] As used herein, the term “alkylene” refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched. A “C1.5 alkylene” denotes an alkylene group having 1 to 5 carbon atoms, and the term “C0.3 alkylene” indicates that a covalent bond (corresponding to the option “C0alkylene”) or a 0^3 alkylene is present. Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)-, or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). Unless defined otherwise, the term “alkylene” preferably refers to C1.4alkylene (including, in particular, linear C1.4alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.

[0171] As used herein, the term “carbocyclyl” or “carbocycle” 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, or cycloalkyl.

[0172] As used herein, the term "alkoxy” refers to an alkyl group which is bonded to the remainder of the molecule via an oxygen atom. For example, a group “-O(Ci_6alkyl)” may also be referred to as Ci_6alkoxy group and refers to an alkyl group having 1 to 6 carbon atoms being bonded to the remainder of the molecule via an oxygen atom. Exemplary alkoxy groups are methoxy, ethoxy, isopropoxy, tert-butoxy. Preferred alkoxy groups are “-O(C1.2alkyl)” groups, i.e., methoxy, or ethoxy.

[0173] As used herein, the term “heterocyclyl” refers to a 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 comprises 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, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein 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 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 least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. Unless defined otherwise, “heterocyclyl” preferably refers to heteroaryl, or heterocycloalkyl.

[0174] As used herein, the term “aryl” refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one 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., 1H indenyl), anthracenyl, 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.

[0175] As used herein, the term “heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one 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), wherein said aromatic ring group comprisesone 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 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 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 least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl), 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., 1H-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, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, p-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-thiadiazolyl), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidin-3-yl), 1,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1 H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1 H-1,2,4-triazolyl, or4H- 1.2.4-triazolyl), benzotriazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2, 3-dihydrofuro[2,3-c]pyridinyl or 1,3-dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g., imidazo[1,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1,3-benzodioxolyl, benzodioxanyl (e.g., 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 oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

[0176] 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., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless defined otherwise, “cycloalkyl” preferably refers to a C3.n cycloalkyl, and more preferably refers to a C3.7cycloalkyl. A particularly preferred “cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).

[0177] As used herein, the term “heterocycloalkyl” refers to a saturated 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), 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 example, 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 heteroatomcontaining ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkyl” may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1,3-dithiolanyl, thianyl, 1, 1 -dioxothianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless defined otherwise, “heterocycloalkyl” preferably refers to a 3 to 11 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 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; 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 carbon ring atoms are optionally oxidized.

[0178] As used herein, the term “halogen” or “Hal” or “-Hal” refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I). 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 preferably 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.

[0179] The terms “bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.

[0180] 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 relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature 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 component of 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.

[0181] The term "substituted", as used herein, means that a hydrogen atom bonded to a designated atom is replaced with a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents, and each substituent is independently selected.

[0182] The term "substitutable", when used in reference to a designated atom, means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent.

[0183] 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 maximum number of substituents is limited by the number of 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.

[0184] 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 thecorresponding specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated in the examples.

[0185] 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” compound of formula (I) can be interpreted as referring to a composition comprising “one or more” compounds of formula (I).

[0186] It is to be understood that wherever numerical ranges are provided / disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, 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.

[0187] 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 particular to 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 indicated numerical value to the upper endpoint +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.

[0188] As used herein, the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly 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 meanings 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).

[0189] The “treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (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 suffering from the disorder or disease. Accordingly, the “treatment” of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or 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).

[0190] The term “prevention” of a disorder or disease, as used herein, is also well known in the art. For example, a patient / subject suspected of being prone to suffer from a disorder or disease 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 but not 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 disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (for example, the patient / subject does not show any clinical or pathological symptoms). Thus, the term “prevention” comprises the use of a compound of the present invention before any clinical and / or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician (or attendant veterinarian).DETAILED DESCRIPTION

[0191] The invention will be described in detail in the following.

[0192] As indicated above, the present invention relates in one embodiment to a compound of formula (I)

[0193] R2

[0194] N\

[0195] A

[0196]

[0197] R

[0198] 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 embodiment is relevant on its own as well as in combination with other preferred embodiments. Furthermore, it is to be understood that the preferred embodiments in each case also apply to the stereoisomers, tautomers, N-oxides, pharmaceutically acceptable salts and solvates of the compounds of the invention.

[0199] In one embodiment of the invention,

[0200] R1is thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or phenyl, each optionally substituted with one or more RS1; wherein each RS1is independently selected from -Hal, C1-6alkyl, C1-6haloalkyl, -S(C1-6alkyl), C3-7cycloalkyl, -O(C1-6alkyl), and -O(C1-6haloalkyl).

[0201] In a preferred embodiment,

[0202] R1is pyridinyl, or phenyl, each optionally substituted with one or more RS1;

[0203] wherein each RS1is independently selected from -Hal, C1-6alkyl, C1-6haloalkyl, -S(C1-6alkyl), C3-7cycloalkyl, -O(C1-6alkyl), and -O(C1-6haloalkyl).

[0204] In another preferred embodiment R1is,

[0205]

[0206] wherein the dashed line marks the connection to the remainder of the molecule and RS1is as defined above or hereinafter.

[0207] In a preferred embodiment, in connection with the above definitions of R1,

[0208] each RS1is independently selected from -Hal, C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl).

[0209] In an even more preferred embodiment,

[0210] each RS1is independently selected from -F, C1-6alkyl or -O(C1-6alkyl).

[0211] In an even more preferred embodiment,

[0212] each RS1is independently selected from -F, C1-3alkyl or -O(C1-3alkyl).

[0213] In another preferred embodiment, R1is

[0214]

[0215] wherein the dashed line marks the connection to the remainder of the molecule; andwherein RS1is selected from -Hal, C1-6alkyl, C1-6haloalkyl, -S(C1-6alkyl), C3-7cycloalkyl, -O(C1-6alkyl), and -O(C1-6haloalkyl),

[0216] preferably

[0217] each RS1is independently selected from -Hal, C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl),

[0218] even more preferably

[0219] each RS1is independently selected from -F, C1-6alkyl or -O(C1-6alkyl), and

[0220] most preferably

[0221] each RS1is independently selected from -F, C1-3alkyl or -O(C1-3alkyl).

[0222] In an even more particularly preferred embodiment, RS1is -O(C2-alkyl), in other words RS1is ethoxy.

[0223] Thus, in one especially preferred embodiment, the compound of formula (I) is a compound of formula (l-R1-1), or (I- R1-2):

[0224]

[0225] Especially preferred are compounds of formula (l-R1-1).

[0226] In a particularly preferred embodiment, the compound of formula (I) is a compound of formula (l-R1-1), wherein RS1is ethoxy.

[0227] Accordingly, in a particularly preferred embodiment, R1is 4-ethoxyphenyl.

[0228] Such compounds of formula (I) will be referred to as compounds of formula (l-R1-1 *) hereinafter:

[0229]

[0230] In one embodiment of the invention,

[0231] R2is H.

[0232] In one embodiment of the invention,

[0233] X1is CH or N;

[0234] X2is CH or N;

[0235] Y1is CRY1or N;

[0236] Y2is CRY2or N;

[0237] Y3is CRY3or N; andY4is CRY4or N;

[0238] wherein RY1, RY2, RY3, and RY4are each independently selected from -H, -CN, -Hal, -OH, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), -O(C1-6haloalkyl), and -(C1-6alkylene)-O(C1-6alkyl);

[0239] provided that if X1and X2are both CH, at least one of Y1, Y2, Y3, and Y4is N; and

[0240] provided that not more than three of X1, X2, Y1, Y2, Y3, and Y4are N.

[0241] In another embodiment,

[0242] RY1is -H;

[0243] RY2is -H, -Cl, or -F;

[0244] RY3is -H, -Cl, or -F; and

[0245] RY4is -H, or -F.

[0246] Thus, in one preferred embodiment,

[0247] X1is CH or N;

[0248] X2is CH or N;

[0249] Y1is CH;

[0250] Y2is N, CH, CCI, or CF;

[0251] Y3is CH, CCI, or CF; and

[0252] Y4is CH;

[0253] provided that not both of X1and X2are CH.

[0254] In another preferred embodiment,

[0255] X1is CH or N;

[0256] X2is CH or N;

[0257] Y1is CH;

[0258] Y2is N, CH, or CF;

[0259] Y3is CH, or CF; and

[0260] Y4is CH;

[0261] In another preferred embodiment,

[0262] X1is CH;

[0263] X2is N;

[0264] Y1is CH;

[0265] Y2is CH or CF;

[0266] Y3is CH or CF; and

[0267] Y4is CH;

[0268] or

[0269] X1is CH;

[0270] X2is N;

[0271] Y1is CH;

[0272] Y2is N;

[0273] Y3is CH or CF; and

[0274] Y4is CH;

[0275] or

[0276] X1is N;

[0277] X2is N;

[0278] Y1is CH;

[0279] Y2is CH or CF;

[0280] Y3is CH or CF; and

[0281] Y4is CH.In another preferred embodiment, the compound of formula (I) is a compound of formula (la), (lb), or (Ic):

[0282] wh

[0283]

[0284] erein RY2is H or F; and RY3is H or F;

[0285]

[0286] wherein RY3is H or F; or

[0287] whe

[0288]

[0289] rein RY2is H or F; and RY3is H or F.

[0290] In one especially preferred embodiment, the compound of formula (I) is a compound of formula (la). In another especially preferred embodiment, the compound of formula (I) is a compound of formula (lb). In another especially preferred embodiment, the compound of formula (I) is a compound of formula (Ic).

[0291] In one especially preferred embodiment, the compound of formula (I) is a compound of formula (la) or (Ic).

[0292] In connection with the above-mentioned compounds of formula (la), (lb), or (Ic), R1is as defined above. It is particularly preferred that R1is

[0293]

[0294] wherein the dashed line marks the connection to the remainder of the molecule, and

[0295] wherein RS1is selected from -Hal, C1-6alkyl, C1-6haloalkyl, -S(C1-6alkyl), C3-7cycloalkyl, -O(C1-6alkyl), and -O(C1-6haloalkyl). Preferably, RS1is -F, C1-3alkyl or -O(C1-3alkyl). Particularly preferably, RS1is ethoxy.

[0296] Such compounds are referred to as compounds of formula (la-R1-1), (la-R1-2), (lb-R1-1), (lb-R1-2), (lc-R1-1), and (lc-R1-2), respectively:

[0297]

[0298] In connection with the compounds of formula (la-R1-1), (la-R1-2), (lc-R1-1), and (lc-R1-2), it is further preferred that RY2is -H, or -F; and

[0299] RY3is -H, or -F.

[0300] In connection with the compounds of formula (lb-R1-1), (lb-R1-2), it is further preferred that

[0301] RY3is -H, or -F.

[0302] In one preferred embodiment the compound of formula (I) is a compound of formula (la-R1-1 ), (la-R1-2), or (lc-R1-1), wherein in connection with the compounds of formula (la-R1-1), (la-R1-2), and (lc-R1-1), it is further preferred that RY2is -H; and

[0303] RY3is -H, or -F.

[0304] 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), and (Ic), as well as to compounds of formula (la-R1-1), (la-R1-2), (lb-R1-1), (Ib-R1-2), (lc-R1-1 ), and (lc-R1-2),

[0305] A is

[0306] R3A

[0307] I - RL1— L1- RL2— l /

[0308] ?

[0309]

[0310] \

[0311] R3B.

[0312] wherein the wavy line in each case marks the connection to the remainder of the molecule;

[0313] and wherein

[0314] L1is

[0315]

[0316] wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2;

[0317] and wherein

[0318] p in each case independently is 1 or 2;

[0319] q in each case independently is 0, 1, 2, or 3;

[0320] each Rxis independently -S(O)2-(C1-6alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6alkyl), -S(O)2-N(C1-6alkyl)(C1-6alkyl), -(C1-6alkylene)-O(C1-6alkyl), -O-(C1-6alkylene)-O(C1-6alkyl), 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -0-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -CN, C1.2alkyl, C1.2haloalkyl, -O(C1.2alkyl), and -O(C1.2haloalkyl), and 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; each Rzis independently -Hal, -CN, C1.2alkyl, C1.2haloalkyl, -(C-|.6alkylene)-OH, -OH, -O(C1.2alkyl), -O(C1.2haloalkyl), -S(O)2-(C1-6alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6alkyl), -S(O)2-N(C1-6alkyl)(C1-6alkyl), -(C-^ alkylene)-O(Ci_6alkyl), -O-fC^g alkylene)-O(C-|_6alkyl), 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -0-(3- to 7-membered cycloalkyl), -0-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, C1.2alkyl, C1.2haloalkyl, -O(C1.2alkyl), and -O(C1.2haloalkyl), and 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;

[0321] Z1is CH2, CHRZ, C(RZ)2, NRN, O, S, S(=O), or S(=O)2;

[0322] wherein

[0323] RNis -H, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, -CO(C1-6alkyl), -CO(C1-6haloalkyl), -S(O)2-(C1-6alkyl), -S(O)2-(C1-6haloalkyl), -(C1-2alkylene)-(3- to 7-membered cycloalkyl), -( C1-2alkylene)-(3-to 7-membered heterocycloalkyl), -( C0-2alkylene)-phenyl, -( C0-2alkylene)-(5- or 6-membered aryl), or -( C0-2alkylene)-(5- or 6-membered heteroaryl), 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 nonoxidized, wherein the 3- to 7-membered cycloalkyl moiety in said -( C1.2alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -( C1.2alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -( C0-2 alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(Co-2 alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1.2alkyl, C1.2haloalkyl;

[0324] and wherein

[0325] RL1is absent or C1.2alkylene;

[0326] RL2is absent or C1.2alkylene; and

[0327] wherein

[0328] R3Aand R3Bare each independently selected from -H, C1-5alkyl, -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C2-3alkylene)-O-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C2-3alkylene)-O-(3- to 7-membered heterocycloalkyl), -(C1-3alkylene)-phenyl, -(C2-3alkylene)-O-phenyl, -(C1-3alkylene)-(5- or 6-membered) heteroaryl, and -(C2-3alkylene)-O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3, and 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;provided that not both R3Aand R3Bare -H;

[0329] or R3Aand R3Btogether with the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more, same or different substituents RS3;

[0330] wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NHfC^g alkyl), -NfC^g alkyl)(C-|_6alkyl), C-|.g alkyl, C-i-e haloalkyl, -(C-|.6alkylene)-CN, -(C-|.6alkylene)-OH, -(C-|.6alkyleneJ-NHfC^g alkyl), -(C^g alkyleneJ-NfC^g alkyl)(C-|.g alkyl), -OfC^g alkyl), -OfC^g haloalkyl), -(C^g alkylene)-O(C-|.g alkyl), -(C-i.g alkylene)-S(C-|.g alkyl), -COfC^g alkyl), -CO(3- to 7-membered cycloalkyl), -CO(3- to 7-membered heterocycloalkyl), -COOH, -COOfC^g alkyl), -CO-NH2, -CO-NHfC-i-g alkyl), -CO-N(Ci.g alkyi c^g alkyl), -NH-CO(Ci.g alkyl), -NfC-i.g alkylJ-COfC^g alkyl), -S(O)2-(C-i-g alkyl), -S(O)2-NH2, -S(O)2-NH(Ci.g alkyl), -S(O)2-N(Ci.g alkyi c^g alkyl), -NH-S(O)2-(C1-6alkyl), -NfC-i.g alkyl)-S(O)2-(C-|.g alkyl), -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3alkylene)-phenyl, and -(C0-3alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3-to 7-membered heterocycloalkyl), -(C0-3alkylene)-phenyl, and -(C0-3alkylene)-(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 -(C0-3alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(C0-3alkylene)-(3-to 7-membered heterocycloalkyl), the phenyl in said -(C0-3alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0-3alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl);

[0331] or two RS3attached to the same carbon atom form =O; or, if attached to a heterocycloalkyl ring formed by R3Aand R3Btogether 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.

[0332] As indicated above in connection with R3A, R3B, and RS3, cycloalkyl preferably refers to C3.7cycloalkyl, 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 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 / or one or more N ring atoms (if present) may optionally be oxidized.

[0333] In connection with the substituents R3A, R3B, 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.

[0334] 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 directly 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.

[0335] In a more preferred embodiment, A is

[0336] R3A

[0337] - RL1— L1— RL2— l /

[0338]

[0339] R3B.

[0340] wherein the wavy line marks the connection to the remainder of the molecule;

[0341] and wherein

[0342]

[0343] , or - wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2;

[0344] and wherein

[0345] p in each case independently is 1 or 2;

[0346] q in each case independently is 0, 1, or 2;

[0347] each Rxis independently -S(O)2-(Ci-6 alkyl), -(Ci_6alkylene)-O(C1.6alkyl), -O-(C1-6alkylene)-O(C1-6alkyl), -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or-0-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -CN, C-|.2alkyl, C-|.2haloalkyl, -0(0^2 alkyl), and -0(0^2 haloalkyl), and 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;

[0348] each Rzis independently -Hal, -CN, C1-2alkyl, C1-2haloalkyl, -(C1-6alkylene)-OH, -OH, -O(C1-2alkyl), -O(C1-2haloalkyl), -S(O)2-(C1-6alkyl), -(C1-6alkylene)-O(C1-6alkyl), -O-(C1-6alkylene)-O(C1-6alkyl), -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl), and 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; and

[0349] Z1is CH2, CHF, CF2, CHOH, CHOCH3, O, S(=O), or S(=O)2;

[0350] and wherein

[0351] RL1is absent; and

[0352] RL2is absent;

[0353] and wherein

[0354] R3Aand R3Bare each independently selected from -H, C1-3alkyl, -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C1-3alkylene)-phenyl, and -(C1-3alkylene)-(5- or 6-membered) heteroaryl, 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, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3;

[0355] provided that not both R3Aand R3Bare -H;

[0356] or R3Aand R3Btogether with the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more, same or different substituents RS3;

[0357] wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), C1-6alkyl, C1-6haloalkyl, -(C1-6alkylene)-OH, -(C1-6alkylene)-NH(C1-6alkyl), -(C1-6alkylene)-N(C1-6alkyl)(C1-6alkyl),-O(C1-6alkyl), -O(C1-6haloalkyl), -(C1-6alkylene)-O(C1-6alkyl), -CO(C1-6alkyl), -CO(3- to 7-membered cycloalkyl), -CO(3- to 7-membered heterocycloalkyl), -COOH, -COO(C1-6alkyl), -CO-NH2, -CO-NH(C1-6alkyl), -CO-N(C1-6alkyl)(C1-6alkyl), -S(O)2-(C1-6alkyl), -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3alkylene)-phenyl, and -(C0-3alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3alkylene)-phenyl, and -(C0-3alkylene)-(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 -(C0-3alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C0-3alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0-3alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl).

[0358] In another preferred embodiment,

[0359] L1is

[0360]

[0361] (Rx)p. (Rx)p. (Rx)p, or (RX)P,

[0362] wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2. In this connection, it is to be understood that Rz, Rx, p and q are as defined above and hereinafter. In one embodiment with regard to the above L1, it is preferred that q is 0, i.e. Rzis absent.

[0363] In another preferred embodiment,

[0364] L1is

[0365]

[0366] , or - wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2. In this connection, it is to be understood that Z1, Rzand q are as defined above and hereinafter. In one embodiment with regard to the above L1, it is preferred that Z1is O.

[0367] In a more preferred embodiment,

[0368] L1is

[0369]

[0370] wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2; and wherein p, q, Rx, and Rzare as defined above and hereinafter.

[0371] In an even more preferred embodiment,

[0372] L1is

[0373]

[0374] < (RX)P

[0375] wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2; and wherein p, q, Rx, and Rzare as defined above and hereinafter.

[0376] In connection with the above L1moieties, it is particularly preferred that

[0377] if L1is

[0378] (RX)p. (RX)p, (RX)p, or (RX)P,

[0379] R

[0380]

[0381] 3Ais H.

[0382] In connection with the above definitions of L1, it is preferred that

[0383] p in each case independently is 1 or 2;

[0384] q in each case independently is 0, 1, 2, or 3;

[0385] each Rxis independently -S(O)2-(C1-6alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6alkyl), -S(O)2-N(CI_6alkyi c^e alkyl), -(C-pg alkylene)-O(Ci.6alkyl), -O-(C-|.6alkylene)-O(Ci.6alkyl), 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -0-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -CN, Cp2alkyl, Cp2haloalkyl, -O(C1.2alkyl), and -O(C1.2haloalkyl), and 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; each Rzis independently -Hal, -CN, C1-2alkyl, C1-2haloalkyl, -(C1-6alkylene)-OH, -OH, -O(C1-2alkyl), -O(C1-2haloalkyl), -S(O)2-(C1-6alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6alkyl), -S(O)2-N(C1-6alkyl)(C1-6alkyl), -(C1-6alkylene)-O(C1-6alkyl), -O-(C1-6alkylene)-O(C1-6alkyl), 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl), and 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;

[0386] Z1is CH2, CHRZ, C(RZ)2, NRN, O, S, S(=O), or S(=O)2;

[0387] wherein

[0388] RNis -H, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, -CO(C1-6alkyl), -CO(C1-6haloalkyl), -S(O)2-(C1-6alkyl), -S(O)2-(C1-6haloalkyl), -(C1-2alkylene)-(3- to 7-membered cycloalkyl), -( C1-2alkylene)-(3-to 7-membered heterocycloalkyl), -( C0-2alkylene)-phenyl, -( C0-2alkylene)-(5- or 6-membered aryl), or -( C0-2alkylene)-(5- or 6-membered heteroaryl), 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 nonoxidized, wherein the 3- to 7-membered cycloalkyl moiety in said -( C1-2alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -( C1-2alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -( C0-2alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0-2alkylene)-(5- or 6-memberedheteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1.2alkyl, C1.2 haloalkyl.

[0389] In connection with L1, it is more preferred that,

[0390] p in each case independently is 1 or 2;

[0391] q in each case independently is 0, 1, or 2;

[0392] each Rxis independently -S(O)2-(C1.6alkyl), -(C-|.g alkyleneJ-OfC^e alkyl), -O-fC^g alkyleneJ-OfC^e alkyl), -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or-0-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -CN, C-|.2alkyl, C-|.2haloalkyl, -0(0^2 alkyl), and -0(0^2 haloalkyl), and 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;

[0393] each Rzis independently -Hal, -CN, C1.2alkyl, C1.2haloalkyl, -(C-|.6alkylene)-OH, -OH, -0(0^2 alkyl), -0(0^2 haloalkyl), -S(O)2-(C1.6alkyl), -(C-|.6alkylene)-O(Ci.6alkyl), -O-fC^g alkylene)-O(Ci.6alkyl), -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, C1.2alkyl, C1.2haloalkyl, -0(0^2 alkyl), and -0(0^2 haloalkyl), and 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; and

[0394] Z1is CH2, CHF, CF2, CHOH, CHOCH3, O, S(=O), or S(=O)2.

[0395] In connection with the above definitions of L1and the moiety A comprising the same, in one embodiment, it is preferred that p in each case is 1, or 2. It is even more preferred that p in each case is 1.

[0396] In another embodiment, it is even more preferred that q in each case is 0, i.e. Rzis absent.

[0397] In one embodiment,

[0398] RL1is absent or C1.2alkylene; and

[0399] RL2is absent or C1.2alkylene.

[0400] In a preferred embodiment,

[0401] RL1is absent; and

[0402] RL2is absent or C1.2alkylene.

[0403] As indicated above, RL1is preferably absent.

[0404] RL2is preferably absent or C1alkylene. In one embodiment, RL2is absent. In one embodiment, RL2is C1alkylene. In a particularly preferred embodiment,

[0405] RL1is absent; and

[0406] RL2is absent.

[0407] In a more preferred embodiment,

[0408] L1is

[0409]

[0410] wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connec-tion to RL2; and

[0411] wherein p in each case is 1, q in each case is 0, i.e. Rzis absent;

[0412] Rxis -S(O)2-(Ci-6 alkyl), -(Ci_6alkylene)-O(Ci.6alkyl), -O-fC^g alkylene)-O(Ci.6alkyl), -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -0-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -CN, C-|.2alkyl, C1.2haloalkyl, -O(C1.2alkyl), and -O(C1.2haloalkyl), and 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;

[0413] RL1is absent; and

[0414] RL2is absent.

[0415] In this connection, it is preferred that Rxis -O-fC^g alkylene)-O(Ci.6alkyl) or -0-(3- to 7-membered heterocycloalkyl), in particular -O-(C-|.3alkyleneJ-OfC^g alkyl), e.g. -O-(C2alkylene)-O(C1alkyl).

[0416] In view of the above, the moiety A, is preferably selected from the following moieties:

[0417]

[0418] wherein the wavy line in each case marks the connection to the remainder of the molecule; and

[0419] wherein it is particularly preferred that q is 1 or 0, i.e. that Rzis absent; and p is 1.

[0420] In one preferred embodiment, the moiety A, is selected from the following moieties:

[0421]

[0422] wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein it is particularly preferred that q is 0, i.e. Rzis absent, and p is 1.

[0423] In one preferred embodiment, the moiety A, is selected from the following moieties:

[0424]

[0425] wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein it is particularly preferred that q is 0, i.e. Rzis absent, and p is 1.

[0426] In one preferred embodiment, the moiety A, is selected from the following moieties:

[0427]

[0428] wherein the wavy line in each case marks the connection to the remainder of the molecule, and

[0429] wherein it is particularly preferred that q is 1 or 0, more preferably q is 0, i.e. that Rzis absent.

[0430] Thus, in view of the above, the moiety A, is more preferably selected from the following moieties:

[0431]

[0432] wherein the wavy line in each case marks the connection to the remainder of the molecule; and

[0433] wherein it is particularly preferred that p is 1, i.e. the cyclopentyl linker is substituted with one Rx, wherein Rxis as defined above or hereinafter.

[0434] In one embodiment,

[0435] Z1is CH2, CHRZ, C(RZ)2, NRN, O, S, S(=O), or S(=O)2.

[0436] In connection with the above embodiment, it is to be understood that Rzand RNare as defined above or hereinafter.

[0437] In a preferred embodiment,

[0438] Z1is CH2, CHF, CF2, CHOH, CHOCH3, O, S(=O), or S(=O)2.

[0439] In an even more preferred embodiment,

[0440] Z1is CH2, O, S(=O), or S(=O)2.

[0441] In a yet even more preferred embodiment,

[0442] Z1is CH2or O.

[0443] In a particularly preferred embodiment,In connection with the above definitions of Z1,

[0444] RNis -H, C-i-6 alkyl, Ci_6haloalkyl, C3.7cycloalkyl, -COfC^g alkyl), -COfC^g haloalkyl), -S(O)2-(C1.6alkyl), -S(O)2-(C-|_6haloalkyl), -(Ci.2alkylene)-(3- to 7-membered cycloalkyl), -( C1.2alkylene)-(3-to 7-membered heterocycloalkyl), -( Co-2alkylene)-phenyl, -( C0.2alkylene)-(5- or 6-membered aryl), or -( C0.2alkylene)-(5- or 6-membered heteroaryl), 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 nonoxidized, wherein the 3- to 7-membered cycloalkyl moiety in said -( C1.2alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -( C1.2alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -( C0.2alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0.2alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1.2alkyl, Ci.2haloalkyl.

[0445] In connection with the above definitions of Z1,

[0446] RNis preferably -H, C-|.6alkyl, C-|.6haloalkyl, C3.7cycloalkyl, -COfC^g alkyl), -COfC^g haloalkyl), -S(O)2-(C1.6alkyl), or -S(O)2-(C1.6haloalkyl).

[0447] In one preferred embodiment, the moiety A, is selected from the following moieties:

[0448]

[0449] wherein the wavy line in each case marks the connection to the remainder of the molecule.

[0450] In one particularly preferred embodiment, the moiety A, is selected from the following moieties:

[0451]

[0452] , or

[0453] wherein the wavy line in each case marks the connection to the remainder of the molecule.

[0454] In this connection, it is preferred that Rxis -O-fC^g alkylene)-O(Ci.6alkyl) or -0-(3- to 7-membered heterocycloalkyl), in particular -O-(Ci.3alkylene)-O(Ci.3alkyl), e.g. -O-(C2alkylene)-O(C1alkyl).

[0455] In connection with the above A moieties, it is preferred that

[0456] R3Aand R3Bare each independently selected from -H, C-,.5 alkyl, -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C2.3alkylene)-O-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), -(C2.3alkylene)-O-(3- to 7-membered heterocycloalkyl), -(Ci.3alkylene)-phenyl, -(C2.3alkylene)-O-phenyl, -(Ci.3alkylene)-(5- or e-membered) heteroaryl, and -(C2.3alkylene)-O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3, and 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;

[0457] provided that not both R3Aand R3Bare -H;or R3Aand R3Btogether with the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more, same or different substituents RS3;

[0458] wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NHfC^g alkyl), -NfC^g alkyl)(C-|_6alkyl), Ci_6alkyl, C-i-6 haloalkyl, -(C-|.g alkylene)-CN, -(C-|.g alkylene)-OH, -(C-|.g alkyleneJ-NHfC^e alkyl), -(C-|.g alkyleneJ-NfC^e alkyl)(C-|.6alkyl), -O(C-|.g alkyl), -O(C-|.g haloalkyl), -(C-|.6alkylene)-O(C-|.6alkyl), -(C-i.g alkylene)-S(C-|.6alkyl), -CO(C-|.g alkyl), -CO(3- to 7-membered cycloalkyl), -CO(3- to 7-membered heterocycloalkyl), -COOH, -COOfC^g alkyl), -CO-NH2, -CO-NH(CI-6alkyl), -CO-N(Ci.ealkyl)(Ci.6alkyl), -NH-CO(Ci.ealkyl), -N(Ci.ealkyl)-CO(Ci.6alkyl), -S(O)2-(C-i-6 alkyl), -S(O)2-NH2, -S(O)2-NH(Ci.g alkyl), -S(O)2-N(Ci.g alkyi c^g alkyl), -NH-S(O)2-(C1-6alkyl), -NfC-i.g alkyl)-S(O)2-(C-|.6alkyl), -(C0.3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3 alkylene)-(3- to 7-membered heterocycloalkyl), -(Co-3 alkylene)-phenyl, and -(C0.3 alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0.3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3 alkylene)-(3-to 7-membered 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 -(C0.3 alkylene)-(3-to 7-membered heterocycloalkyl), the phenyl in said -(C0.3 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 independently selected from -Hal, C-|.2alkyl, C-|.2haloalkyl, -0(0^2 alkyl), and -0(0^2 haloalkyl);

[0459] or two RS3attached to the same carbon atom form =O; or, if attached to a heterocycloalkyl ring formed by R3Aand R3Btogether 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.

[0460] It is even more preferred that

[0461] R3Aand R3Bare each independently selected from -H, C1.3 alkyl, -(C0.3 alkylene)-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C-i.3 alkylene)-phenyl, and -(C-i.3 alkylene)-(5- or 6-membered) heteroaryl, 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, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3;

[0462] provided that not both R3Aand R3Bare -H;

[0463] or R3Aand R3Btogether with the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more, same or different substituents RS3;

[0464] wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NHfC^g alkyl), -NfC^g alkyl)(C-|.6alkyl), C-i.g alkyl, C-i-6 haloalkyl, -(C-|.g alkylene)-OH, -(C-|.g alkyleneJ-NHfC^g alkyl), -(C-|.g alkyleneJ-NfC^g alkyl)(C-|_6alkyl), -0(0^6 alkyl), -O(C-|.g haloalkyl), -(C-|.6alkylene)-O(C-|.g alkyl), -COfC^g alkyl), -CO(3- to 7-membered cycloalkyl), -CO(3- to 7-membered heterocycloalkyl), -COOH, -COOfC^ alkyl), -CO-NH2, -CO-NHfC-i.g alkyl), -CO-N(Ci.g alkyl)(C-|_g alkyl), -S(O)2-(C1.6alkyl), -(C0.3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.3alkylene)-phenyl, and -(C0.3 alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0.3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3 alkylene)-(3- to 7-membered 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 -(C0.3 alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C0.3 alkylene)-phenyl, and the 5- or 6-membered heteroarylmoiety in said -(C0.3 alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1.2alkyl, C1.2haloalkyl, -0(0^2 alkyl), and -0(0^2 haloalkyl).

[0465] In a preferred embodiment,

[0466] R3Ais H or C1.2alkyl, which is unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -OCH3, -CO(CH3), and -S(O)2-(CH3); and

[0467] R3Bis selected from -(C0.3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3 alkylene)-(3- to 7-membered heterocycloalkyl), -(0^3 alkylene)-phenyl, and -(C-|.3alkylene)-(5- or 6-membered) heteroaryl, 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, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3;

[0468] wherein each RS3is independently selected from -CN, -Hal, Ci_6alkyl, Ci_6haloalkyl, -O(C-|.6alkyl), -O(C-|.6haloalkyl), -(C-|.6alkylene)-O(Ci.6alkyl), -S(O)2-(C1.6alkyl), -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.3alkylene)-phenyl, and -(C0.3alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3- to 7-membered 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 -(C0.3alkylene)-(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 -(C0.3 alkylene)-phenyl, and the 5- or e-membered heteroaryl moiety in said -(C0.3alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1.2alkyl, C1.2haloalkyl, -0(0^2 alkyl), and -0(0^2 haloalkyl).

[0469] In an especially preferred embodiment,

[0470] R3Ais -H or C1-2alkyl, which is unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -OCH3, and -S(O)2-(CH3); and

[0471] R3Bis selected from phenyl, benzyl, -(ethylene)-phenyl, -(methylene)-thiophenyl or -(methylene)-pyridinyl, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3.

[0472] In another especially preferred embodiment,

[0473] R3Ais -H or C1.2alkyl, which is unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -OCH3, and -S(O)2-(CH3); and

[0474] R3Bis cyclobutyl, benzyl, or-(methylene)-pyridinyl, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3.

[0475] Thus, with the above-mentioned definitions of cycloalkyl heterocycloalkyl in combination with the definitions of R3Aand R3B, in a preferred embodiment, if R3Aor R3Bare -(C2.3alkylene)-0-cycloalkyl, -(C2.3alkylene)-O-heterocycloalkyl, -(C2.3alkylene)-O-aryl, or -(C2.3alkylene)-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.

[0476] Further, in a preferred embodiment, if R3Aor R3Brepresent a group, wherein -CH2- is replaced by CH(OH), it is preferred that the CH(OH) group is not directly attached to the nitrogen atom contained in the A moiety.In another preferred embodiment, if RS3is -Hal, -OH, -NH2, -NH(CI.6alkyl), NfC^g alkyl)(Ci_6alkyl), 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. In another preferred embodiment, if two RS3attached to the same carbon atom form =O, it is preferred that the =O is not attached to a carbon atom, which is directly attached to the nitrogen atom contained in the A moiety.

[0477] In a preferred embodiment, if a substituent Rxis present at L1, it is preferred that -Hal, -OH, -O(C1.2alkyl), or -O(C1.2haloalkyl) 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.

[0478] In one embodiment, each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NHfC^g alkyl), -NfC^g alkyl)(Ci.6alkyl), C-i.g alkyl, C-|.6haloalkyl, -(C-i.g alkylene)-CN, -(C-i.g alkylene)-OH, -(Ci.6alkyleneJ-NHfC^g alkyl), -(0-i.g alkyleneJ-NfC^g alkyl)(Ci.6alkyl), -OfC^g alkyl), -OfC^g haloalkyl), -(C-i.g alkylene)-O(C-|.g alkyl), -(C^g alkylene)-S(C-|_6alkyl), -COfC^g alkyl), -CO(3- to 7-membered cycloalkyl), -CO(3- to 7-membered heterocycloalkyl), -COOH, -000(0-1.6 alkyl), -CO-NH2, -CO-NHfC-i.g alkyl), -CO-NfC-i-g alkyi c^e alkyl), -NH-COfC-i.g alkyl), -NfC-i.g alkylJ-COfC-i-e alkyl), -S(O)2-(C1-6alkyl), -S(O)2-NH2, -S(O)2-NH(C.|.6 alkyl), -SfO^-NfC^e alkylJfC^e alkyl), -NH-S(O)2-(C-i-e alkyl), -NfC^e alkyl)-S(O)2-(C1.6alkyl), -(C0-3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.3alkylene)-phenyl, and -(C0.3alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.3alkylene)-phenyl, and -(C0.3alkylene)-(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 -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C0.3alkylene)-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 independently selected from -Hal, C1.2alkyl, C1.2haloalkyl, -O(C1.2alkyl), and -O(C1.2haloalkyl);

[0479] or two RS3attached to the same carbon atom form =O; or, if attached to a heterocycloalkyl ring formed by R3Aand R3Btogether 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.

[0480] Preferably each RS3is independently selected from

[0481] -CN, -Hal, -OH, -NH2, -NHfC-i.g alkyl), -NfC-i.g alkyi c^e alkyl), C-i-g alkyl, C-i.g haloalkyl, -(C-i-g alkylene)-OH, -(C-i-g alkyleneJ-NHfC^e alkyl), -(Ci.6alkyleneJ-NfC^e alkyl)(C-|_6 alkyl), -O(Ci.6alkyl), -O(Ci.6haloalkyl), -(Ci.6alkylene)-O(Ci.6 alkyl), -COfC^g alkyl), -CO(3- to 7-membered cycloalkyl), -CO(3- to 7-membered heterocycloalkyl), -COOH, -COO(C-|.6 alkyl), -CO-NH2, -CO-NHfC-i.g alkyl), -CO-NfC-i.g alkyi c^e alkyl), -S(O)2-(C1-6alkyl), -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3 alkylene)-phenyl, and -(C0-3 alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0-3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.3alkylene)-phenyl, and -(C0.3alkylene)-(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 -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C0.3alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0.3alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1.2alkyl, C1.2haloalkyl, -O(C1.2alkyl), and -O(C1.2haloalkyl).Even more preferably each RS3is independently selected from -CN, -Hal, Ci_6alkyl, Ci_6haloalkyl, -O(C-|.6alkyl), -0(0^6 haloalkyl), -(C-i.g alkylene)-O(Ci.6alkyl), -S(O)2-(C1.6alkyl), -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.3 alkylene)-phenyl, and -(C0.3 alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3- to 7-membered 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 -(C0.3alkylene)-(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 -(C0.3 alkylene)-phenyl, and the 5- or e-membered heteroaryl moiety in said -(C0.3alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1.2alkyl, C1.2haloalkyl, -0(0^2 alkyl), and -0(0^2 haloalkyl).

[0482] Most preferably each RS3is independently selected from -F, -Cl, -Br, or -OH.

[0483] In another preferred embodiment,

[0484] R3Ais -H or C1-2alkyl, which is unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -OCH3, and -S(O)2-(CH3); and

[0485] R3Bis cyclobutyl, benzyl or -(methylene)-pyridinyl, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more substituents RS3, wherein RS3is independently selected from -F, -Cl, -Br, or -OH, preferably RS3is -F.

[0486] In another preferred embodiment,

[0487] R3Ais -H or C1-2alkyl, which is unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -OCH3, and -S(O)2-(CH3); and

[0488] R3Bis benzyl or -(methylene)-pyridinyl, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more substituents RS3, wherein RS3is independently selected from -F, -Cl, -Br, or -OH, preferably RS3is -F.

[0489] In another preferred embodiment,

[0490] R3Ais -H or -CH3; and

[0491] R3Bis benzyl or -(methylene)-pyridinyl, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more substituents RS3, wherein RS3is -F.

[0492] In another preferred embodiment,

[0493] R3Ais -H or -CH3; and

[0494] R3Bis benzyl or -(methylene)-pyridinyl, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more substituents RS3, wherein RS3is -F.

[0495] In one especially preferred embodiment, the present invention relates to a compound of formula (I), in particular a compound of formula (la), (lb), or (Ic), wherein

[0496] RY2is -H;

[0497] RY3is -H, or -F;

[0498] the moiety A, is selected from the following moieties:

[0499]

[0500] ; wherein the wavy line in each case marks the connection to the remainder of the molecule;

[0501] R1is

[0502]

[0503] wherein the dashed line marks the connection to the remainder of the molecule; and

[0504] wherein RS1is -O(C2-alkyl), in other words RS1is ethoxy;

[0505] R3Ais -H or Ci.2alkyl, which is unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -OCH3, and -S(O)2-(CH3); and

[0506] R3Bis phenyl, benzyl, -(ethylene)-phenyl, -(methylene)-thiophenyl or -(methylene)-pyridinyl, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3,

[0507] wherein RS3is independently selected from -F, -Cl, -Br, or -OH.

[0508] In this connection, it is preferred that Rxis -O-fC^g alkylene)-O(C1.6alkyl) or -0-(3- to 7-membered heterocycloalkyl), in particular -O-fC^s alkyleneJ-OfC^g alkyl), e.g. -O-(C2alkylene)-O(C1alkyl).

[0509] In another especially preferred embodiment, the present invention relates to a compound of formula (I), in particular a compound of formula (la), (lb), or (Ic), wherein

[0510] RY2is -H;

[0511] RY3is -H, or -F;

[0512] the moiety A, is selected from the following moieties:

[0513]

[0514] , or; wherein the wavy line in each case marks the connection to the remainder of the molecule;

[0515] R1is

[0516]

[0517] wherein the dashed line marks the connection to the remainder of the molecule; and

[0518] wherein RS1is -O(C2-alkyl), in other words RS1is ethoxy;

[0519] R3Ais -H or Ci.2alkyl, which is unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -OCH3, and -S(O)2-(CH3); and

[0520] R3Bis selected from benzyl, or-(methylene)-pyridinyl, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more substituents RS3,

[0521] wherein RS3is -F.

[0522] In this connection, it is preferred that Rxis -O-fC^g alkylene)-O(Ci.6alkyl) or -0-(3- to 7-membered heterocycloalkyl), in particular -O-fC^s alkylene)-O(Cg_3alkyl), e.g. -O-(C2alkylene)-O(C1alkyl).In one embodiment of the invention, the compound of formula (I) is not the following compound:

[0523]

[0524] In one embodiment the compound of formula (I) is selected from the following compounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

[0525]

[0526] F

[0527]

[0528]

[0529]

[0530]

[0531]

[0532] Particularly preferred compounds of formula (I) are selected from the following compounds or a stereoisomer, 5 tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

[0533]

[0534]

[0535]

[0536] In a particularly preferred embodiment, the compound of formula (I) is a compound selected from the following 5 compounds or a pharmaceutically acceptable salt thereof:

[0537]

[0538]

[0539] In one embodiment, a particularly preferred compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0540]

[0541] In another embodiment, a particularly preferred compound of formula (I) is the following compound or a pharmaceu-tically acceptable salt thereof:

[0542]

[0543] In another embodiment, a particularly preferred compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0544] xNH

[0545]

[0546] In another embodiment, a particularly preferred compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0547]

[0548] In another embodiment, a particularly preferred compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0549]

[0550] In another embodiment, a particularly preferred compound of formula (I) is the following compound or a pharmaceu-tically acceptable salt thereof:

[0551]

[0552] In another embodiment, a particularly preferred compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0553]

[0554] In another embodiment, a particularly preferred compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0555]

[0556] In another embodiment, a particularly preferred compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0557]

[0558] In another embodiment, a particularly preferred compound of formula (I) is the following compound or a pharmaceutically acceptable salt thereof:

[0559]

[0560] The scope of the invention embraces all pharmaceutically acceptable salt forms ofthe compounds of formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, 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; ammonium 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, benzyltrimethylammonium salts, benzyltriethylammonium 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 example: 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 dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, 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), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts ofthe compounds of formula (I) include a hydrochloride salt, a hydrobromide 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 acceptable salt ofthe compound of formula (I) is a hydrochloride salt. Accordingly, it is preferred that the compound of formula (I), including any one ofthe specific compounds 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.

[0561] The present invention also specifically relates to the compound of formula (I), including any one ofthe specific compounds of formula (I) described herein, in non-salt form.

[0562] Moreover, the scope ofthe 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 crystalline forms (i.e., polymorphs), ofthe compounds of formula (I) are also encompassed within the scope oftheinvention. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of the compounds of the formula (I) are likewise embraced by the invention.

[0563] Furthermore, the compounds of formula (I) may exist in the form of different stereoisomers (including, e.g., geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, prototropic tautomers, such as keto / enol tautomers or thione / thiol tautomers). All such stereoisomers or tautomers of the compounds of formula (I) are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces the isolated optical isomers of the compounds according 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 diastereomeric derivatives, or separation 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 crystallization. The present invention further encompasses any tautomers of the compounds of formula (I). It will be understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms. The formulae and chemical names as provided herein are intended to encompass any tautomeric form of the corresponding compound and not to be limited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.

[0564] Furthermore, the compounds 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.

[0565] The scope of the invention also embraces compounds 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.,2H; also referred to as “D”). Accordingly, the invention also embraces compounds 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 (2H or D). The content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art. For example, a compound of formula (I) or a reactant or precursor 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(11-12), 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 occurring hydrogen atoms or1H hydrogen atoms in the compounds of formula (I) is preferred.

[0566] The present invention also embraces compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g.,18F,11C,13N,15O,76Br,77Br,120I and / or124I. Such compounds 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 replaced by18F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by11C atoms, (iii) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by13N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen 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 by120I atoms, and (viii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by124I atoms. In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by specific isotopes.The compounds provided herein may be administered as compounds perse or may be formulated as medicaments. The medicaments / pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubility enhancers.

[0567] The pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), 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, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a-cyclodextrin, p-cyclodextrin, y-cyclodextrin, hydroxyethyl-p-cyclodextrin, hydroxypropyl-p-cyclodextrin, hydroxyethyl-y-cyclodextrin, hydroxypropyl-y-cyclodextrin, dihydroxypropyl-p-cyclodextrin, sulfobutylether-p-cyclodextrin, sulfobutylether-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, hydroxypropylcellulose, polyvinylpyrrolidone, a vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0568] The pharmaceutical compositions may also comprise one or more preservatives, particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

[0569] 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, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration. 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 reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.

[0570] The compounds of formula (I) or the above described pharmaceutical compositions comprising a compound of formula (I) may be administered to a subject by any convenient route of administration, whether systemically / peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, or vaginal administration.

[0571] If said compounds or pharmaceutical compositions are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly,intraurethrally, 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 (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Said compounds or pharmaceutical 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.

[0572] 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), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions 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 suspensions 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.

[0573] For oral administration, the compounds or pharmaceutical compositions are preferably administered by oral ingestion, 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” administration.

[0574] Alternatively, said compounds or pharmaceutical compositions can 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 powder. The compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch.

[0575] Said compounds or pharmaceutical 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-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include liposomally entrapped compounds. The present invention thus also relates to liposomes containing a compound of the invention.

[0576] Said compounds or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route. For ophthalmic use, 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 preservative such as a benzalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

[0577] It is also envisaged to prepare dry powder formulations of the compounds of formula (I) for pulmonary administration, particularly inhalation. Such dry powders may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be made according to an emulsification / spray drying process.

[0578] For topical application to the skin, said compounds or pharmaceutical compositions can be formulated as a suitable ointment containing 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 ormore of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.

[0579] The present invention thus relates to the compounds or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route. Preferred routes of administration are oral administration or parenteral administration. For each of the compounds or pharmaceutical compositions provided herein, it is particularly preferred that the respective compound or pharmaceutical composition is to be administered orally (particularly by oral ingestion).

[0580] Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy. 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 may be 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 per day. It will be appreciated that it may be necessary 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.

[0581] The therapeutic use of the compounds of the present invention will be described in the following.

[0582] In one embodiment, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0583] 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 compounds of formula (I) leads to efficient degradation of TASL. 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), psoriasis, and endosomal TLR-dependent inflammation).

[0584] 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 et al, (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 Chinese Han population. Langefeld and coworkers (Langefeld et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun, 8, 16021(2017)) identified the genetic association of SLC15A4 with SLE in a cohort of European ancestry.

[0585] Further, there is additional evidence of the role of TASL in the pathogenesis of SLE based on genetic studies in human cells. Odhams et al. (Odhams et al (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 explanation.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 pathogenesis 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 TLR function. Pollard and coworkers (Pollard et al. Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN. J Immunol, 199, 3739, (2017)) found that SLC15A4-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 autoimmunity in several mouse SLE models (Drobek, A. et al. The TLR7 / 9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse. Nat. Commun. 16, 967 (2025); Lau, L. et al. An essential role for TASL in mouse autoimmune pathogenesis and Toll-like receptor signaling. Nat. Commun. 16, 968 (2025)).

[0586] Accordingly, the compounds of the present invention are considered useful in the treatment or prevention of autoimmune disorders, in particular SLE.

[0587] 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 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, Behget’s disease, inflammatory bowel disease, psoriasis, myasthenia gravis, and ankylosing spondylitis (Wang et al. (2023), Bentham et al. 2015), Katewa et al. (2021 )). There is further a body of evidence based on genetic studies indicating the role of SLC15A4 and / or TASL in proinflammatory 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 lines and primary cells for endosomal TLR function.

[0588] There is further evidence based on studies in mouse models indicating the role of SLC15A4 and / or TASL in inflammatory conditions. Blasius and coworkers (Blasius et al. (2010)) identified SLC15A4 as essential component in endosomal TLR function 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 proinflammatory cytokines from dendritic cells. Furthermore, SLC15A4-deficiency was found to be protective in a mouse model of IBD.

[0589] SLC15A4-deficient 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 et al. 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 TLR function 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-induced systemic inflammation and psoriasiform inflammation in mice. Lopez-Haber and coworkers (Lopez-Haber et al. The phagosomal solute transporter SLC15A4 promotes inflammasome activity via mTORC1 signaling and autophagy restraint in dendritic cells, EMBO J, 41, e111161 (2022)) describe a contribution of SLC15A4 in inflammasome activation via mTORC1 signaling pathways.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 treatment or 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 inflammation, and sarcoidosis, preferably wherein the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-dependent inflammation.

[0590] Accordingly, the compounds of the present invention are useful in treatment or prevention of an inflammatory condition.

[0591] Thus, 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 or an 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 treatment or prevention of an inflammatory condition.

[0592] The autoimmune disorder is preferably selected from systemic lupus erythematosus, rheumatoid arthritis, scleroderma, 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 disorder is systemic lupus erythematosus.

[0593] The inflammatory condition is 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 inflammation, and sarcoidosis. More preferably, the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-dependent inflammation.

[0594] Thus, in one embodiment, the present invention relates to 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 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, Behget’s disease, myasthenia gravis, and ankylosing spondylitis, preferably wherein the autoimmune disorder is systemic lupus erythematosus, or wherein the inflammatory condition is 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 inflammation, and sarcoidosis, preferably wherein the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-dependent inflammation.

[0595] In a preferred embodiment, the present invention relates to 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 systemic lupus erythematosus, inflammatory bowel disease, psoriasiform dermatitis, or endosomal TLR-dependent inflammation.

[0596] In a more preferred embodiment, the present invention relates to 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 systemic lupus erythematosus.

[0597] In another more preferred embodiment, the present invention relates to 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 inflammatory bowel disease.In another more preferred embodiment, the present invention relates to 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 psoriasiform dermatitis.

[0598] In another more preferred embodiment, the present invention relates to 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 endosomal TLR-dependent inflammation.

[0599] In one embodiment, the present invention relates to use of the compound of formula (I) or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention, in the manufacture of a medicament for use in the treatment or prevention of an autoimmune disorder or an inflammatory condition. In one embodiment, the present invention relates to use of the compound of formula (I) or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention, in the manufacture of a medicament for use in the treatment or prevention of an autoimmune disorder. In one embodiment, the present invention relates to use of the compound of formula (I) or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention, in the manufacture of a medicament for use in the treatment or prevention of an inflammatory condition.

[0600] 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 described herein.

[0601] 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 described herein.

[0602] 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).

[0603] Accordingly, in one embodiment the present invention relates to the compound of formula (I) or its salt, or the pharmaceutical 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 particularly 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 autoimmune disorder is a disorder associated with SLC15 peptide transporter.

[0604] The compounds provided in the present invention are also useful in treatment or prevention of other lupus diseases such as cutaneous or neonatal lupus erythematosus.

[0605] The invention will be illustrated in the following examples, which however are not to be construed as limiting.EXAMPLES

[0606] List of abbreviations:

[0607] ACN acetonitrile

[0608] Cbz benzyloxy carbonyl

[0609] DCM dichloromethane

[0610] DCE dichloroethane

[0611] DIPEA N, N-diisopropylethylamine

[0612] DMAc dimethylacetamide

[0613] DMSO dimethyl sulfoxide

[0614] DMF dimethylformamide

[0615] DMP Dess-Martin periodinane

[0616] dppf [1,1 -bis(diphenylphosphino)ferrocene] dtbpf [1,1 '-bis (di- tert -butylphosphino)ferrocene] ELSD Evaporative light scattering detector

[0617] EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimid EDC-HCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimid - hydrochloride

[0618] HATU hexafluorophosphate azabenzotriazole tetramethyl uronium

[0619] HPLC High-performance liquid chromatography HPLC-MS high-performance liquid chromatography - mass spectrometry

[0620] IPA isopropylamine

[0621] LS-MS liquid chromatography-mass spectrometry Ms mesylate

[0622] MS mass spectrometry

[0623] rac racemic

[0624] PdCI2(dtbpf) 1,1-Bis-(di-tert.-butylphosphino-)ferrocen- palladiumdichloride

[0625] PG protecting group

[0626] prep. preparative

[0627] RP reverse phase

[0628] RT room temperature

[0629] TCFH chloro-N, N, N', N'-tetramethylformamidinium hexafluorophosphate

[0630] THF tetrahydrofuran

[0631] n-BuLi n-butyllithium

[0632] Boc tert-butoxycarbonyl

[0633] Bn Benzyl

[0634] Ts tosyl

[0635] T3P propanephosphonic acid anhydride

[0636] MeOH methanol

[0637] HOBT hydroxybenzotri azole

[0638]

[0639] DMAP 4-dimethylaminopyridine

[0640]

[0641] Methods:

[0642] HPLC-MS Methods:

[0643] Method 1:

[0644] Instrument - Shimadzu Prominance HPLC attached with API 2000 Mass Spectrometer from Applied Biosystems. Ionisation method: Electrospray

[0645] UV Wavelength range (nm): 220 and 260

[0646] Solvent A: 10 mM Ammonium Acetate in Water and Solvent B: Acetonitrile

[0647] Flow rate: 1.2 mL / min

[0648] 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.

[0649] TIME (min) MODULE %A (10 mM % B (Acetonitrile)

[0650] Ammonium

[0651] Acetate in

[0652] Water)

[0653] 0.01 Pumps 90 10

[0654] 1.50 Pumps 70 30

[0655] 3.00 Pumps 10 90

[0656] 4.00 Pumps 10 90

[0657] 5.00 Pumps 90 10

[0658] 5.10 System Controller Stop

[0659]

[0660] Type of column: Xbridge C18 (4.6 x 50 mm, 5 micron)

[0661] Mass conditions:

[0662] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source Declustering Potential: 50 V

[0663] Mass range: 200-1700 amu

[0664] Scan type: Q1

[0665] Polarity: + / -ve

[0666] Ion Source: Turbo spray

[0667] Ion spray voltage: +5500 for +ve mode and -4500 for -ve mode

[0668] Method 2:

[0669] Waters Acquity H Class UPLC attached with Waters SQD 2 mass spectrometer.

[0670] Ionisation method: Electro spray

[0671] Capillary (kV) 3.50, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0672] Mass range: 100 to 900 DaDAD Wavelength range (nm): 200 to 400

[0673] Solvent A: 5 mM NH4OAc in water and Solvent B: 5 mM NH4OAc in ACN: Water (90:10)

[0674] Flow rate: 1.20 mL / min

[0675] (mobile phase: 95% [5 mM NH4OAc in water] and 5% [5 mM NH4OAc in ACN: Water (90:10)] held for 0.75 min, then 85% [5 mM NH4OAC in water] and 15% [5 mM NH4OAc in ACN: Water (90: 10)] in 1.25 min further 30% [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 mM NH4OAC in ACN: Water (90:10)] in 3.75 min, held this mobile phase composition up to 4.25 min and finally back to initial condition in 4.50 min and held this composition up to 5.10 min).

[0676] TIME (min) Flow Rate (mL / min) %A (5 mM NH4OAC % B (5 mM NH4OAC in ACN: Water in water) (90:10))

[0677] 0.00 1.20 95 5

[0678] 0.75 1.20 95 5

[0679] 1.25 1.20 85 15

[0680] 2.50 1.20 30 70

[0681] 3.75 1.20 2 98

[0682] 4.25 1.20 2 98

[0683] 4.50 1.20 95 5

[0684] 5.10 1.20 95 5

[0685]

[0686] Column Used: Xbridge C18 column (3.5 µm, 50 x 3 mm)

[0687] Column Temperature: 40 °C.

[0688] Method 3:

[0689] Waters Acquity H Class UPLC attached with Waters QDA mass spectrometer.

[0690] Ionisation method: Electro spray

[0691] Capillary (kV) 0.80, Cone (V) 15.00, Source Temperature (°C) 120, Probe Temperature (°C) 600, Mass range:100 to 900 Da

[0692] DAD Wavelength range (nm): 200 to 400

[0693] Solvent A: 0.05% Formic acid in water and Solvent B: 0.05% HCOOH in ACN: Water (90:10)

[0694] Flow rate: 0.6 mL / min

[0695] (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, further to 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).

[0696] TIME (min) Flow Rate (mL / min) %A (0.05% HCOOH % B (0.05% HCOOH in ACN: Water in water) (90:10))

[0697] 0.00 0.60 95 5

[0698] 0.75 0.60 95 5

[0699] 1.50 0.60 75 25

[0700] 3.00 0.60 5 95

[0701] 4.00 0.60 5 95

[0702] 4.50 0.60 95 5

[0703]

[0704] 5.10 0.60 95 5

[0705]

[0706] Column Used: Waters Acquity UPLC BEH C18 (2.1 x 50 mm, 1.7 micron)

[0707] Column Temperature: 45 °C.

[0708] Mass Source temperature: 200 °C.

[0709] Method 4:

[0710] Waters Acquity H Class UPLC atached with Waters QDA mass spectrometer.

[0711] Ionisation method: Electro spray

[0712] Capillary (kV) 0.80, Cone (V) 15.00, Source Temperature (°C) 120, Probe Temperature (°C) 600, Mass range: 100 to 900 Da

[0713] DAD Wavelength range (nm): 200 to 400

[0714] Solvent A: 0.05% TFA in water and Solvent B: ACN

[0715] Flow rate: 1.00 mL / min

[0716] (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 composition up to 13.00 min and finally back to initial condition in 14.00 min and held this composition up to 15.00 min).

[0717] TIME (min) Flow Rate (mL / min) %A (0.05% TFA % B (ACN)

[0718] in water)

[0719] 0.00 1.00 98 2

[0720] 1.00 1.00 98 2

[0721] 4.50 1.00 40 60

[0722] 9.50 1.00 5 95

[0723] 13.00 1.00 5 95

[0724] 14.00 1.00 98 2

[0725] 15.00 1.00 98 2

[0726]

[0727] Column Used: Luna Omega Polar C18 column (3 pm, 100 x 4.6 mm)

[0728] Column Temperature: 40 °C.

[0729] Method 5:

[0730] Waters Acquity H Class UPLC atached with Waters QDA mass spectrometer.

[0731] Ionisation method: Electro spray

[0732] Capillary (kV) 0.80, Cone (V) 15.00, Source Temperature (°C) 120, Probe Temperature (°C) 600, Mass range: 100 to 900 Da

[0733] DAD Wavelength range (nm): 200 to 400

[0734] Solvent A: 0.05% TFA in water and Solvent B: ACN

[0735] Flow rate: 0.40 mL / min

[0736] (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] in19.00 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).

[0737] TIME (min) Flow Rate (mL / min) %A (0.05% TFA % B (ACN)

[0738] in water)

[0739] 0.00 0.40 98 2

[0740] 1.50 0.40 90 10

[0741] 18.00 0.40 60 40

[0742] 19.00 0.40 5 95

[0743] 20.00 0.40 5 95

[0744] 22.00 0.40 98 2

[0745] 25.00 0.40 98 2

[0746]

[0747] Column Used: Acquity BEH C18 column (1.8 µm, 100 x 2.7 mm)

[0748] Column Temperature: 40 °C.

[0749] Method 6:

[0750] Waters Acquity UPLC attached with Waters ZQ mass spectrometer.

[0751] Ionisation method: Electro spray

[0752] Capillary (kV) 3.50, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0753] Mass range: 100 to 900 Da

[0754] DAD Wavelength range (nm): 200 to 400

[0755] Solvent A: 5 mM NH4OAc in water and Solvent B: 5 mM NH4OAc in ACN: Water (90: 10)

[0756] Flow rate: 1.20 mL / min

[0757] (mobile phase: 95% [5 mM NH4OAc in water] and 5% [5 mM NH4OAc 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 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).

[0758] TIME (min) Flow Rate %A % B (5 mM NH4OAC in ACN:

[0759] (mL / min) (5 mM NH4OAC in water) Water (90: 10))

[0760] 0.00 1.20 95 5

[0761] 0.75 1.20 95 5

[0762] 1.00 1.20 70 30

[0763] 2.00 1.20 2 98

[0764] 2.50 1.20 2 98

[0765] 2.75 1.20 95 5

[0766] 3.00 1.20 95 5

[0767]

[0768] Column Used: Xbridge C18 column (3.5 µm, 50 x 3 mm)

[0769] Column Temperature: AmbientMethod 7:

[0770] Water Acquity UPLC attached with Waters ZQ micromass mass spectrometer.

[0771] Ionisation method: Electro spray

[0772] Capillary (kV) 3.50, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0773] Mass range: 100 to 900 Da

[0774] DAD Wavelength range (nm): 200 to 400

[0775] Solvent A: 0.05% Formic acid in water and Solvent B: 0.05% HCOOH in ACN: Water (90:10)

[0776] Flow rate: 1.0 mL / min

[0777] (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 composition up to 2.25 min and finally back to initial condition in 2.90 min and held this composition up to 3.00 min).

[0778] TIME Flow Rate %A (0.05% HCOOH in % B (0.05% HCOOH in ACN:

[0779] (min) (mL / min) water) Water (90:10))

[0780] 0.00 1.0 90 10

[0781] 0.75 1.0 90 10

[0782] 1.00 1.0 50 50

[0783] 2.00 1.0 2 98

[0784] 2.25 1.0 2 98

[0785] 2.90 1.0 90 10

[0786] 3.00 1.0 90 10

[0787]

[0788] Column Used: YMC-TRIART C18 (2.1 x 33 mm, 3.0 micron)

[0789] Column Temperature: Ambient

[0790] Method 8:

[0791] Waters Acquity H Class UPLC attached with Waters SQD 2 mass spectrometer.

[0792] Ionisation method: Electro spray

[0793] Capillary (kV) 3.00, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0794] Mass range: 100 to 900 Da

[0795] DAD Wavelength range (nm): 200 to 400

[0796] Solvent A: 5 mM NH4OAc in water and Solvent B: 5 mM NH4OAc in ACN: Water (90:10)

[0797] Flow rate: 1.00 mL / min

[0798] (mobile phase: 98% [5 mM NH4OAc in water] and 2% [5 mM NH4OAc in ACN: Water (90:10)] held for 1.00 min, then 50% [5 mM NH4OAC in water] and 50% [5 mM 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 11.00 min and held this composition up to 12.00 min).

[0799] TIME (min) Flow Rate (mL / min) %A (5 mM NH4OAC in % B (5 mM NH4OAC in water) ACN: Water (90:10)) 0.00 1.00 98 2

[0800]

[0801] 1.00 1.00 98 2 5.00 1.00 50 50

[0802] 8.00 1.00 2 98

[0803] 10.00 1.00 2 98

[0804] 11.00 1.00 98 2

[0805] 12.00 1.00 98 2

[0806]

[0807] Column Used: Xbridge C18 column (3.5 µm, 50 x 3 mm)

[0808] Column Temperature: 40 °C.

[0809] Method 9:

[0810] Water Acquity H Class UPLC attached with Waters SQD 2 mass spectrometer.

[0811] Ionisation method: Electro spray

[0812] Capillary (kV) 3.50, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0813] Mass range: 100 to 900 Da

[0814] DAD Wavelength range (nm): 200 to 400

[0815] Solvent A: 0.05% Formic acid in water and Solvent B: 0.05% HCOOH in ACN: Water (90:10)

[0816] Flow rate: 0.8 mL / min

[0817] (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, further to 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).

[0818] TIME (min) Flow Rate (mL / min) %A (0.05% HCOOH in % B (0.05% HCOOH in ACN:

[0819] water) Water (90:10))

[0820] 0.00 0.80 95 5

[0821] 0.75 0.80 95 5

[0822] 1.50 0.80 75 25

[0823] 3.00 0.80 5 95

[0824] 4.00 0.80 5 95

[0825] 4.50 0.80 95 5

[0826] 5.10 0.80 95 5

[0827]

[0828] Column Used: Waters Acquity UPLC BEH C8 (2.1 x 50 mm, 1.7 micron)

[0829] Column Temperature: 45 °C.

[0830] Method 10:

[0831] Water Acquity H Class UPLC attached with Waters SQD 2 mass spectrometer.

[0832] Ionisation method: Electro spray

[0833] Capillary (kV) 3.50, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0834] Mass range: 100 to 900 DaDAD Wavelength range (nm): 200 to 400

[0835] Solvent A: 0.05% Formic acid in water and Solvent B: 0.05% HCOOH in ACN: Water (90:10)

[0836] Flow rate: 0.7 mL / min

[0837] (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 11.50 min and held this composition up to 12.00 min).

[0838] TIME (min) Flow Rate (mL / min) %A (0.05% HCOOH in % B (0.05% HCOOH in ACN:

[0839] water) Water (90: 10))

[0840] 0.00 0.70 95 5

[0841] 1.00 0.70 95 5

[0842] 5.00 0.70 50 50

[0843] 8.00 0.70 10 90

[0844] 10.00 0.70 10 90

[0845] 11.50 0.70 95 5

[0846] 12.00 0.70 95 5

[0847]

[0848] Column Used: Waters Acquity UPLC BEH C18 (2.1 x 50 mm, 1.7 micron)

[0849] Column Temperature: 45 °C.

[0850] Method 11:

[0851] Waters Acquity UPLC attached with Waters ZQ mass spectrometer.

[0852] Ionisation method: Electro spray

[0853] Capillary (kV) 3.50, Cone (V) 25.00, Source Temperature (°C) 150, Desolvation Temperature (°C) 400, Cone Gas Flow (L / Hr) -50, Desolvation Gas Flow (L / Hr) -750

[0854] Mass range: 100 to 900 Da

[0855] DAD Wavelength range (nm): 200 to 400

[0856] Solvent A: 0.05% HCOOH in water and Solvent B: 0.05% HCOOH in ACN: Water (90:10)

[0857] Flow rate: 1.00 mL / min

[0858] (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% [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).

[0859] TIME (min) Flow Rate (mL / min) %A 0.05% HCOOH in % B (0.05% HCOOH in ACN:

[0860] water) Water (90: 10) )

[0861] 0.00 1.00 95 5

[0862] 0.75 1.00 95 5

[0863] 1.00 1.00 70 30

[0864] 2.00 1.00 2 98

[0865] 2.50 1.00 2 98

[0866] 2.75 1.00 95 5

[0867] 3.00 1.00 95 5

[0868]

[0869] Column Used: YMC Triart C18 column (3 µm, 33 x 2.1 mm)Column Temperature: Ambient

[0870] Method-12:

[0871] Instrument -Shimadzu Prominance HPLC attached with API 2000 Mass Spectrometer from Applied Biosystems. Ionisation method: Electrospray

[0872] UV Wavelength range (nm): 220 and 260

[0873] Solvent A: 10 mM Ammonium Acetate in Water and Solvent B: Acetonitrile

[0874] Flow rate: 1.2 mL / min

[0875] 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.

[0876] TIME MODULE %A (10 mM Ammonium Acetate in % B (Acetonitrile) Water)

[0877] 0.01 Pumps 90 10

[0878] 1.50 Pumps 70 30

[0879] 3.00 Pumps 10 90

[0880] 4.00 Pumps 10 90

[0881] 5.00 Pumps 90 10

[0882] 5.10 System Controller Stop

[0883]

[0884] Type of column: Shimpack GIST C18 (4.6 x 50 mm, 5 micron)

[0885] Mass conditions:

[0886] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source Declustering Potential: 50 V

[0887] Mass range: 100-1200 amu

[0888] Scan type: Q1

[0889] Polarity: + / -ve

[0890] Ion Source: Turbo spray

[0891] Ion spray voltage: +5500 for +ve mode and -4500 for -ve mode

[0892] Mass Source temperature: 200 °C.

[0893] Method 13:

[0894] Instrument - Shimadzu Prominance HPLC attached with API 2000 Mass Spectrometer from Applied Biosystems.

[0895] Ionisation method: Electrospray

[0896] UV Wavelength range (nm): 220 and 260

[0897] Solvent A: 10 mM Ammonium Acetate in Water and Solvent B: Acetonitrile

[0898] Flow rate: 1.2 mL / min

[0899] 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.

[0900] TIME MODULE %A (10 mM Ammonium Acetate in % B (Acetonitrile)

[0901] Water)

[0902] 0.01 Pumps 90 10

[0903]

[0904] 1.50 Pumps 70 30

[0905] 3.00 Pumps 10 90

[0906] 4.00 Pumps 10 90

[0907] 5.00 Pumps 90 10

[0908] 5.10 System Stop

[0909] Controller

[0910]

[0911] Type of column: Shimadzu C18 (4.6 x 50 mm, 5 micron)

[0912] Mass conditions:

[0913] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source Declustering Potential: 50 V

[0914] Mass range: 100-1200 amu

[0915] Scan type: Q1

[0916] Polarity: + / -ve

[0917] Ion Source: Turbo spray

[0918] Ion spray voltage: +5500 for +ve mode and -4500 for -ve mode

[0919] Mass Source temperature: 200 deg C.

[0920] Method S1

[0921] Instrument- Agilent 1260 Infinity II + 6125C SQ

[0922] Ionisation method: Electrospray

[0923] UV Wavelength range (nm): 190 and 400

[0924] Solvent A: Water + 0.1 % Formic acid B: Acetonitrile + 0.1 % Formic acid

[0925] Flow rate: 0.6 mL / min

[0926] 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.

[0927] TIME MODULE %A (Water + 1% Formic % B (Acetonitrile + 1%

[0928] acid) Formic acid)

[0929] 0.01 Pumps 90 10

[0930] 1.00 Pumps 90 10

[0931] 5.00 Pumps 10 90

[0932] 7.00 Pumps 10 90

[0933] 7.01 System Controller Stop

[0934]

[0935] Type of column: ZORBAX RRHT StableBond C18, 2.1 x 50 mm, 1.8 µm, 600 bar. 80 Å

[0936] Mass conditions:

[0937] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source.

[0938] Declustering Potential: 135 V

[0939] Mass range: 50-1500 m / z

[0940] Scan type: Q1

[0941] Polarity: + / -ve

[0942] Ion Source: Turbo spray

[0943] Ion spray voltage: +4000 for +ve mode and -4000 for -ve modeMass Source temperature: 300 °C.

[0944] Method S2

[0945] Instrument- Agilent 1260 Infinity II + 6125C SQ

[0946] Ionisation method: Electrospray

[0947] UV Wavelength range (nm): 190 and 400

[0948] Solvent A: Water + 0.1 % Formic acid B: Acetonitrile + 0.1 % Formic acid

[0949] Flow rate: 0.6 mL / min

[0950] 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 6.00 min and further 10% [Water + 0.1% Formic acid] and 90% [Acetonitrile + 0.1% Formic acid] for 3.00 min.

[0951] TIME MODULE %A (Water + 1% Formic % B (Acetonitrile + 1%

[0952] acid) Formic acid)

[0953] 0.01 Pumps 90 10

[0954] 1.00 Pumps 90 10

[0955] 7.00 Pumps 10 90

[0956] 10.00 Pumps 10 90

[0957] 10.01 System Controller Stop

[0958]

[0959] Type of column: ZORBAX RRHT StableBond C18, 2.1 x 50 mm, 1.8 µm, 600 bar. 80 Å

[0960] Mass conditions:

[0961] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source.

[0962] Declustering Potential: 135 V

[0963] Mass range: 50-1500 m / z

[0964] Scan type: Q1

[0965] Polarity: + / -ve

[0966] Ion Source: Turbo spray

[0967] Ion spray voltage: +4000 for +ve mode and -4000 for -ve mode

[0968] Mass Source temperature: 300 °C.

[0969] Method S3

[0970] Instrument- Agilent 1260 Infinity II + 6125C SQ

[0971] Ionisation method: Electrospray

[0972] UV Wavelength range (nm): 190 and 400

[0973] Solvent A: Water + 0.1 % Formic acid B: Acetonitrile + 0.1 % Formic acid

[0974] Flow rate: 0.6 mL / min

[0975] 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 11.00 min and further 10% [Water + 0.1% Formic acid] and 90% [Acetonitrile + 0.1% Formic acid] for 3.00 min.

[0976] TIME MODULE %A (Water + 1% Formic % B (Acetonitrile + 1%

[0977] acid) Formic acid)

[0978] 0.01 Pumps 90 10

[0979] 1.00 Pumps 90 30

[0980] 12.00 Pumps 10 90

[0981]

[0982] 15.00 Pumps 10 90

[0983] 15.01 System Controller Stop

[0984]

[0985] Type of column: ZORBAX RRHT StableBond C18, 2.1 x 50 mm, 1.8 μm, 600 bar. 80 Å

[0986] Mass conditions:

[0987] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source.

[0988] Declustering Potential: 135 V

[0989] Mass range: 50-1500 m / z

[0990] Scan type: Q1

[0991] Polarity: + / -ve

[0992] Ion Source: Turbo spray

[0993] Ion spray voltage: +4000 for +ve mode and -4000 for -ve mode

[0994] Mass Source temperature: 300 °C.

[0995] Method S4

[0996] Instrument- Agilent 1260 Infinity II + 6125C SQ

[0997] Ionisation method: Electrospray

[0998] UV Wavelength range (nm): 190 and 400

[0999] Solvent A: Water + 0.1 % Formic acid B: Acetonitrile + 0.1 % Formic acid

[1000] Flow rate: 0.6 mL / min

[1001] Mobile phase: 85% [Water + 0.1% Formic acid] and 15% [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 4.50 min, further 10% [Water + 0.1% Formic acid] and 90% [Acetonitrile + 0.1% Formic acid] for 0.50 min, then gradient back to starting composition over 1.00 min

[1002] TIME MODULE %A (Water + 0.1% Formic % B (Acetonitrile + 0.1%

[1003] acid) Formic acid)

[1004] 0.01 Pumps 85 15

[1005] 1.00 Pumps 85 15

[1006] 5.50 Pumps 10 90

[1007] 6.00 Pumps 10 90

[1008] 7.00 Pumps 85 15

[1009] 7.01 System Controller Stop

[1010]

[1011] Type of column: ZORBAX RRHT StableBond C18, 2.1 x 50 mm, 1.8 µm, 600 bar. 80 Å

[1012] Mass conditions:

[1013] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source.

[1014] Declustering Potential: 135 V

[1015] Mass range: 50-1500 m / z

[1016] Scan type: Q1

[1017] Polarity: + / -ve

[1018] Ion Source: Turbo spray

[1019] Ion spray voltage: +4000 for +ve mode and -4000 for -ve mode

[1020] Mass Source temperature: 300 °C.Method S5

[1021] Instrument- Agilent 1260 Infinity II + 6125C SQ

[1022] Ionisation method: Electrospray

[1023] UV Wavelength range (nm): 190 and 400

[1024] Solvent A: Water + 0.1 % Formic acid B: Acetonitrile + 0.1 % Formic acid

[1025] Flow rate: 0.6 mL / min

[1026] Mobile phase: 85% [Water + 0.1% Formic acid] and 15% [Acetonitrile + 0.1% Formic acid] for 0.10 min, then gradient to 90% [Water + 0.1% Formic acid] and 10% [Acetonitrile + 0.1% Formic acid] over 0.90 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

[1027] TIME MODULE %A (Water + 0.1% Formic % B (Acetonitrile + 0.1%

[1028] acid) Formic acid)

[1029] 0.00 Pumps 85 15

[1030] 0.10 Pumps 85 15

[1031] 1.00 Pumps 90 10

[1032] 22.00 Pumps 10 90

[1033] 25.00 Pumps 10 90

[1034] 25.01 System Controller Stop

[1035]

[1036] Type of column: ZORBAX RRHT StableBond C18, 2.1 x 50 mm, 1.8 µm, 600 bar. 80 Å

[1037] Mass conditions:

[1038] Ionization technique: ESI (Electron Spray Ionization) using API (Atmospheric pressure Ionization) source.

[1039] Declustering Potential: 135 V

[1040] Mass range: 50-1900 m / z

[1041] Scan type: Q1

[1042] Polarity: + / -ve

[1043] Ion Source: Turbo spray

[1044] Ion spray voltage: +4000 for +ve mode and -4000 for -ve mode

[1045] Mass Source temperature: 300 °C.

[1046] RP Preparative HPLC Methods:

[1047] RP preparative HPLC Method-A:

[1048] Preparative HPLC was done on Waters auto purification instrument. Column name: LONG-YMC, C18(20 X 250 MM), 5 pm operating at ambient temperature and flow rate of 16 mL / min. Mobile phase: A=Acetonitrile, B = 20mM Ammonium Bicarbonate in water; Gradient Profile: Mobile phase initial composition of 30% A and 70% B, then 35% A and 65% B in 3 min, then to 75% A and 25% B in 24.0 min., then to 100% A and 0% B in 24.50 min., held this composition up to 27.0 min. for column washing, then returned to initial composition in 27.50 min. and held till 30 min.

[1049] RP preparative HPLC Method-B:

[1050] Preparative HPLC was done on Waters auto purification instrument. Column name: LONG- XTERRA, C18(50 X 100 MM),10MICRON operating at ambient temperature and flow rate of 16mL / min. Mobile phase: A=Acetonitrile, B = 20 mM Ammonium Bicarbonate in water; Gradient Profile: Mobile phase initial composition of 10% A and 90% B, then10% A and 90% B in 4 min, then to 44% A and 56% B in 17.0 min., then to 100% A and 0% B in 18.00 min., held this composition up to 20.50 min. for column washing, then returned to initial composition in 21.00 min. and held till 23 min.

[1051] RP preparative HPLC Method-C:

[1052] Preparative HPLC was done on Waters auto purification instrument. Column name: LUNA, EVO-C18,100-A(21.2 X 250 MM), 5 MICRON operating at ambient temperature and flow rate of 16mL / min. Mobile phase: A=Acetonitrile, B = 20mM Ammonium Bicarbonate in water; Gradient Profile: Mobile phase initial composition of 15% A and 85% B, then 15% A and 85% B in 4 min, then to 40% A and 60% B in 15.50 min., then to 100% A and 0% B in 16.50 min., held this composition up to 19.50 min. for column washing, then returned to initial composition in 20.00 min. and held till 22 min.

[1053] RP preparative HPLC Method-D:

[1054] Preparative HPLC was done on Waters auto purification instrument. Column name: Xbridge C18 (50 x 19 mm, 5p) operating at ambient temperature and flow rate of 20 mL / min. Mobile phase: A = 20mM Ammonium Bicarbonate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then 75% A and 25% B in 1 min, then to 20% A and 80% B in 14 min., then to 5% A and 95% B in 15 min., held this composition up to 17 min. for column washing, then returned to initial composition in 17 min. and held till 18 min.

[1055] RP preparative HPLC Method-E:

[1056] Preparative HPLC was done on Waters auto purification instrument. Column name: YMC-Actus C18 (250 x 20 mm, 5p) operating at ambient temperature and flow rate of 16 mL / min. Mobile phase: A = 20mM Ammonium Bicarbonate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 30% A and 70% B, then 10% A and 90% B in 3 min, then to 5% A and 95% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min.

[1057] RP preparative HPLC Method-F:

[1058] Preparative HPLC was done on Waters auto purification instrument. Column name: Xbridge C18 (50 x 19 mm, 5p) operating at ambient temperature and flow rate of 16 mL / min. Mobile phase: A = 20mM Ammonium Bicarbonate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 60% A and 40% B, then 40% A and 60% B in 1 min, then to 20% A and 80% B in 14 min., then to 5% A and 95% B in 15 min., held this composition up to 16 min. for column washing, then returned to initial composition in 17 min. and held till 18 min.

[1059] RP preparative HPLC Method-G:

[1060] Preparative HPLC was done on Waters auto purification instrument. Column name: Gemini C18 (250 x 21.2 mm, 5p) operating at ambient temperature and flow rate of 16 mL / min. Mobile phase: A = 20 mM Ammonium Bicarbonate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 60% A and 40% B, then 35% A and 65% B in 3 min, then to 20% A and 80% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min.

[1061] RP preparative HPLC Method-H:

[1062] Preparative HPLC was done on Waters auto purification instrument. Column name: - Hydrosphere C18 (250 x 20 mm, 5p) operating at ambient temperature and flow rate of 16.0 mL / min. Mobile phase: A= 10 mM Ammonium acetate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 65% A and 35% B, then to 30% A and 70% B in 22 min, then to 0% A and 100% B in 23 min., held this composition up to 25 min. for column washing, then returned to initial composition in 26 min. and held till 28 mins.RP preparative HPLC Method-O:

[1063] Preparative HPLC was done on Waters auto purification instrument. Column name: Chromcore polar C18 (250 x 21.2 mm, 5p) operating at ambient temperature and flow rate of 16 mL / min. Mobile phase: A = 20 mM Ammonium Bicarbonate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 60% A and 40% B, then 25% A and 75% B in 3 min, then to 10% A and 90% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min.

[1064] Analytical chiral SFC Methods:

[1065] 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.

[1066] Analytical chiral SFC Method 2: Instrument: Thar SFC Investigator; Column: C AMYLOSE A (4.6 * 250 mm), 5 pm, Mobile phase: 50% CO2 + 50% of (0.3% Methanolic NH3in ACN: Methanol (1: 1)); Flow: 5 mL / min; % of Co-solvent: 50%; ABPR: 100 bar; T: 35 °C.

[1067] 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 NH3in ACN: Methanol (1:1)); Flow: 3 mL / min; % of Co-solvent: 35%; ABPR: 100 bar; T: 35 °C.

[1068] 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.

[1069] Analytical chiral SFC Method 5: Instrument: Acquity UPC2; Column: I Cellulose Z (4.6 * 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.

[1070] Analytical chiral SFC Method 6: Instrument: Acquity UPC2; Column: I Cellulose Z (4.6 * 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.

[1071] Analytical chiral SFC Method 7: Instrument: Acquity UPC2; Column: I Cellulose Z (4.6 * 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.

[1072] Analytical chiral SFC Method 8: 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.

[1073] Analytical chiral SFC Method 9: 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 / min; % of Co-solvent: 50%; ABPR: 1500 psi; T: 35 °C. Analytical chiral SFC Method 10: 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 mL / min; % of Co-solvent: 50%; ABPR: 1500 psi; T: 35 °C.

[1074] 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.

[1075] 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 mL / min; % of Co-solvent: 40%; ABPR: 1500 psi; T: 35 °C.

[1076] 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.Analytical chiral SFC Method 14: Instrument: Acquity UPC2; Column: Chiralpak IC (4.6 x 250 mm), 5 μm, 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.

[1077] Analytical chiral SFC Method 30: Instrument: Acquity UPC2; Column: Chiralpak IC (4.6 * 250 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.

[1078] Analytical Chiral NP Methods:

[1079] Analytical Chiral NP Method 1

[1080] Chiral NP Method: Chiral separation was done on Agilent 1200 series instrument. Column name: CHIRALPAK IG (250 X 4.6 mm),5p. Operating at ambient temperature and flow rate is 1.0 mL / min. Mobile phase was mixture of 50% hexane, 25% EtOAc, 25% EtOH and 0.1% IP Amine held this isocratic mixture run up to 30 min with wavelength of 272 nm.

[1081] Preparative chiral SFC methods:

[1082] Preparative chiral SFC method G:

[1083] SFC PREP Purification has been completed on Waters SFC 150 instrument equipped with Waters 2489 UV / Visible Detector by using l-Cellulose-Z (30.0 mm x 250.0 mm), 5p Column operating at 35°C temperature, maintaining flow rate of 100 mL / min, using 60% CO2in super critical state & 40% of 0.2% (7(M) Ammonia in Methanol) in Methanol as Mobile phase. This isocratic mixture is running up to 10.0 min, also maintaining the isobaric condition of 100 bar at 257 nm wavelength.

[1084] SFC Prep Conditions

[1085] □

[1086] System Waters SFC-150

[1087] Column l-Cellulose-Z (30.0 mm x 250.0 mm), 5p

[1088] Flow | 100 mL / min

[1089] Mobile Phase 60% CO2+ 40% of 0.2% (7N Ammonia in Methanol) in Methanol ABPR 100 bar

[1090] Temperature | 35°C

[1091] UV I 257 nm

[1092] Diluent MeOH + DCM

[1093] Loading | 1.87 mg / 5.50 Mins

[1094] Sample concentration 7.50 mg / mL

[1095]

[1096] Preparative chiral SFC method H:

[1097] SFC Prep Purification of CR720-23828-78-P1 was performed on Waters SFC PREP 150 instruments equipped with Waters 2489 UV / Visible Detector by using (R. R) Whelk-O1(30 mm x 250 mm ), 5p Column operating at 35 °C, maintaining flow rate of 120 mL / min, using 65% CO2 in super critical state & 35% of 0.2% 7(M)Methanolic Ammoniain Methanol as Mobile phase. Run this isocratic mixture up to 22 min, and also maintained the isobaric condition of 100 bar at 230 nm wavelength.

[1098] SFC Prep Conditions

[1099] System Waters SFC PREP 150

[1100] Column (R. R) Whelk-O1 (30 mm x 250 mm), 5p

[1101] Flow 120 mL / min

[1102] Mobile Phase 65% CO2 + 35% of 0.2% 7(M)Methanolic Ammonia in Methanol

[1103] ABPR 100 bar

[1104] Temperature 35 °C

[1105] UV 230nm

[1106] Diluent MeOH+ DCM

[1107] Loading |1.75 mg / 5.6 Mins

[1108] Sample concentration 11.67mg / mL

[1109]

[1110] Preparative chiral SFC method L:

[1111] SFC Prep Purification of CR720-24580-67-P1(34 mg) is running on Waters SFC 150 instruments equipped with Waters 2489 UV / Visible Detector by using CHIRALPAK IG (30 mm x 250 mm ), 5p Column operating at 35°C temperature, maintaining flow rate of 140 mL / min, using 60% CO2 in super critical state & 40% of 0.2% (7M Ammonia in Methanol) in ACN: MeOH(1:1) as Mobile phase. Run this isocratic mixture up to 20.0 min and also maintained the isobaric condition of 110 bar at 272 nm wavelength

[1112] SFC Prep Conditions

[1113] System SFC-150

[1114] Column CHIRALPAK IG (30 mm x 250 mm), 5p

[1115] Flow 140 mL / min

[1116] Mobile Phase 60% CO2 +40% of 0.2% (7M Ammonia in Methanol) in ACN: MeOH (1:1) ABPR 1110 Bar

[1117] Temperature 35 °C

[1118] UV 272 nm

[1119] Diluent | MeOH + DCM

[1120] Loading 1.49 mg / 9 Mins

[1121] Sample concentration 13.6 mg / mL

[1122]

[1123] Preparative chiral SFC method Ab:

[1124] SFC Prep Purification of CR720-24046-65-P1 (T. N-162) (~6.5 mg) is currently running on Pic Solutions 175 instrument equipped with Knauer 40D UV / Visible Detector by using I CELLULOSE Z (30.0 mm x 250 mm ), 5p Column operating at 35°C temperature, maintaining flow rate of 140 mL / min, using 75% CO2in super critical state & 25% of 0.2%Methanolic Ammonia in Acetonitrile / Isopropanol (1:1) as Mobile phase. This isocratic mixture is running up to 26.0 min and also maintained the isobaric condition of 120 bar at 275 nm wavelength.

[1125] SFC Prep Conditions

[1126] System Pic Solutions 175

[1127] Column I CELLULOSE Z (30.0 mm x 250 mm), 5p

[1128] Flow 140 mL / min

[1129] Mobile Phase 75% CO2+ 25% of 0.2% Methanolic Ammonia in Acetonitrile / Isopropanol (1:1) ABPR 120 Bar

[1130] Temperature 35°C

[1131] UV 275 nm

[1132] Diluent MeOH

[1133] Loading 1.04mg / 10 Mins

[1134] Sample concentration 6.5 mg / mL

[1135]

[1136] Preparation examples:

[1137] Compounds of the structure (I) can be prepared by a synthesis sequence depicted in the following Schemes 1-4.

[1138] M-3

[1139] method D

[1140]

[1141] M-6 M-7 M-1Scheme 1: Intermediates M-1 a can be obtained by reaction of anilines M-2 with aldehydes K-1, BF3THF complex and pyruvic acid (method A, J. Org. Chem., 2023, 88, 12816 - 12820). Additional intermediates M-1a can be obtained by reacting isatins M-3 with K-2 and KOH in a condensation reaction (Method B).

[1142] Isatins M-3 can be acylated with different acid chlorides K-3 in pyridine to obtain intermediates M-5. Intermediates M-5 can be reacted with NH4OAc in ethanol at high temperatures (method G) to obtain quinazoline intermediates M-1b. Intermediates M-6 can be deprotonated using n-BuLi at low temperatures in THF and treated with diethyl oxalate (method D) to obtain intermediates M-7. Intermediates M-7 can be reacted with a ketone intermediate K-2 in a condensation reaction (method E) to obtain different intermediates M-1.

[1143] reductive aldehyde or amination ketone

[1144]

[1145] if one R3= H I

[1146] Scheme 2: Synthesis of compounds (I): Compounds (I) can be obtained by reacting intermediates M-1 in an amidation reaction with amines A-1 to obtain intermediates M-8 followed by cleavage of the Boc group to obtain intermediates M-9 as the free base or a salt depending on the deprotection method and purification. M-9 can be converted to compounds (I) by a reductive amination as shown in Scheme 2 or by alkylation or related reactions. Additional compounds (I) can be obtained via a sequence starting from ketone intermediates A-2 and performing a reductive amination reaction with an amine A-3 to obtain intermediates A-4. Intermediates A-4 can be converted to amine intermediates A-5 by cleaving the Boc protecting group which gives the free bases of salts of A-5 depending on synthesis method and purification. Amines A-5 can be reacted with acid intermediates M-1 in an amidation reaction to obtain compounds (I). 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.H2N

[1147] amide formation M-1 M-10 M-11 epoxide opening

[1148]

[1149] ,3A

[1150]

[1151] Scheme 3: Additional compounds I can be obtained by reacting intermediates M-1 with amines A-6 in an amidation reaction to obtain intermediates M-10. Intermediates M-10 can be epoxidized to obtain intermediates M-11.

[1152] Compounds I can be obtained by opening the epoxide in intermediates M-11 with an amine A-3. 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.

[1153] M-12 M-13 epoxide opening

[1154]

[1155] I M-15 M-14 Scheme 4: Additional compounds I can be obtained in a sequence starting with reacting intermediates M-1 with amines A-7 in an amidation reaction to obtain intermediates M-12. Intermediates M-12 are epoxidized to obtain intermediates M-13. The epoxides in intermediates M-13 can be opened by applying suitable reactions withnucleophiles (alcohols, thiols, nitrile, Grignard reagents, etc.) to introduce Rxand obtain alcohols M-14. Alcohol intermediates M-14 are oxidized to the corresponding ketones M-15 which are reacted with amines A-3 in a reductive amination reaction to obtain compounds I.

[1156] Synthesis of ethyl 2-(4-ethoxyphenyl)-8-(trifluoromethyl)quinoline-4-carboxylic acid (M-1a-2):

[1157] o 7 \—° ~n \ — / /

[1158] ° M / \b) Z X — / z

[1159] M T / b T _ _

[1160] / T _

[1161] To a solution of aniline M-2a (1.64 g, 10.2 mmfo cl) in 20 mL acetonitrile were added 4-ethoxybenzaldehyde (K-1a, 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, 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 cooling 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 MgSO4, 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-1a-2.

[1162] Additional intermediates M-1a are available in an analogous manner using different intermediates M-2 and K-1 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 1).

[1163] Table Ex 1:

[1164] # Structure HPLC tret

[1165] [M+H]+Method [min]

[1166] M-1a-2 6 5.84 362.0

[1167] M-1a-3 6 5.30 312.0

[1168] M-1a-4 6 4.79 312.0

[1169]

[1170] Synthesis of methyl 7-chloro-2-(4-ethoxyphenyl) quinoline-4-carboxylic acid (M-1a-5):

[1171] J k?

[1172] Xj ° /

[1173] Potassium hydroxide (1.85 g, 33.04 S m rmol) was added to a mixture of 6-chloro-2,3-dihydro-1 / 7-indole-2, 3-dione (M-3a) (2 g, 11.01 mmol), and 1-(4-ethoxyphenyl)ethan-1-one (K-2-1) (2.17 g, 13.21 mmol) in EtOH (20 mL) and the reaction mixture was heated at 80 °C for 24 h. The reaction mixture was concentrated in vacuo and taken up in water and washed with ethyl acetate. The layers were° s reparated, 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-1a-5) which was used in the next step without further purification.

[1174] Additional intermediates M-1a are available in an analogous manner using different intermediates M-3a and K-2 as starting materials. The crude product Os are purified by chromatography if necessary (Table Ex 2).

[1175] Table Ex 2:

[1176] HPLC

[1177] # S itructure tret [min] [M+H]+

[1178] Method

[1179] ,0

[1180] HO-^

[1181] M-1a-5 1 2.95 326.2

[1182] _

[1183] cr

[1184] M-1a-6 6 4.64 294.1

[1185] M-1a-7 1 2.56 295.1

[1186]

[1187]

[1188] Synthesis of methyl 1-(4-ethoxybenzoyl) indoline-2, 3-dione (M-5-1):

[1189]

[1190] M-5-1

[1191] An oven dried two neck 100 mL round botom flask was charged isatin (M-3a) (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 (0.68 mL, 4.42 mmol) was added dropwise. Upon completion of addition, the reaction mixture was slowly allowed to warm to room temperature and heated at 60 °C afterwards. The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled (ice-bath) and neutralized by addition 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 layer was washed with brine, dried over sodium sulfate, concentrated followed by azeotropic distillation with toluene to afford 1-(4-ethoxybenzoyl) indoline-2, 3-dione (M-5-1) which was used in the next step without further purification.

[1192] Additional intermediates M-5 are available in an analogous manner using different intermediates M-3 and / or different acid chlorides K-3 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 3).Table Ex 3:

[1193] HPLC

[1194] # Structure tret [min] [M+H]+

[1195] Method

[1196] O

[1197] M-5-1 n.a. n.a. n.a.

[1198] oz

[1199] O

[1200] jTx >°

[1201] M-5-2 z~~v=:on.a. n.a. n.a.

[1202] of

[1203]

[1204] Synthesis of 2-(4-ethoxyphenyl) quinazoline-4-carboxylic acid (M-1b-1):

[1205] NH4OAc, EtOH

[1206]

[1207] 1-(4-ethoxybenzoyl) indoline-2, 3-dione (M-5-1) (500 mg, 1.69 mmol) was added to an oven dried sealed tube. Ammonium acetate (1.3 g, 16.93 mmol) was added followed by anhydrous ethanol (5 mL). The reaction mixture was heated in a pre-heated oil bath at 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 under cooling (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 combi-flash chromatography using 0-20% MeOH in DCM as eluent to afford 2-(4-ethoxyphenyl) quinazoline-4-carboxylic acid (M-1b-1).

[1208] Additional compounds in table M-1 are available in an analogous manner using different intermediates M-5 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 4).Table Ex 4:

[1209] HPLC

[1210] # Structure tret [min] [M+H]+

[1211] Method

[1212] M-1b-1 3 2.70 295.2

[1213] ,0

[1214] HO— / '

[1215] M-1b-2 3 2.13 313.2

[1216] ft

[1217] F

[1218]

[1219] Synthesis of methyl 2-(4-ethoxyphenvh-1,6-naphthyridine-4-carboxylic acid

[1220]

[1221] 0

[1222]

[1223] M-7-1 / ^ oT

[1224] 1

[1225] To a stirred solution of ethyl 2-[4-(2,2-dimethylpropanamido) pyridin-3-yl]-2-oxoacetate (M-7-1) (600 mg, 2.16 mmol) in EtOH: H2O (4:1) (20 mL), was added KOH (483 mg, 8.63 mmol) and refluxed for2h. 1-(4-ethoxyphenyl) ethan-1-one (K-2-1) (743 mg, 4.52 mmol) was added and the reaction mixture was refluxed for an additional 16 h. The reaction mixture was concentrated under vacuum. Water was added and the mixture was washed with EtOAc and the phases were separated. The aqueous layer was acidified to pH 6 by addition of 2 N aqueous HCI solution at ice bath temperature. The resulting precipitate was filtered and dried under vacuum to afford 2-(4-ethoxyphenyl)-1,6-naphthyridine-4-carboxylic acid (M-1c-1).

[1226] Additional intermediates M-1 are available in an analogous manner using different intermediates M-7 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 5).

[1227] Table Ex 5:

[1228] HPLC

[1229] # Structure tret [min] [M+H]+

[1230] Method

[1231] , O

[1232] HO— / '

[1233] 1 2.48 295.3

[1234]

[1235]

[1236] Synthesis of tert-b Cuty / \ O^l I r ((1S.3 / ?)-3-(2-(4-ethoxyphenyl)quinoline-4-carboxamido)cvclohexyl)carbamate (M-8a-1):

[1237] Q'u.

[1238] 0

[1239] To a stirred solution of 2-(4-ethoxyphenyl) quinoline-4-carboxylic acid (M-1a-1) (350 mg, 1.19 mmol) in DMF (10 mL) was added DIPEA (1.04 mL, 5.97 mmol), EDC HCI (572.76 mg, 2.98 mmol), HOBt (241.63 mg, 1.79 mmol) and stirred for 30 min at 0 °C. tert-butyl ((1S,3R)-3-aminocyclohexyl)carbamate (A-1-1) (306.86 mg, 1.43 mmol) was added and stirred for 16 h at room temperature. The reaction was diluted with ice cold water(100 mL), extracted with ethyl acetate (3 x 25 mL). The combined organic layer was washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash column chromatography to afford tert-butyl ((1S,3R)-3-(2-(4-ethoxyphenyl) quinoline-4-carboxamido) cyclohexyl) carbamate (M-8a-1).

[1240] Additional intermediates M-8 are available in an analogous manner using different intermediates M-1 and A-1 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 6).

[1241] Table Ex 6:

[1242] # Structure HPLC

[1243] Let [min] [M+H]+Method

[1244] M-8a-1 1 3.70 490.3

[1245]

[1246] O= /

[1247] NH

[1248] M-8a-2 1 3.65 490.4

[1249] C / ^ O\ I,o

[1250] H rN-^

[1251] C\^ ° °Y _

[1252] 0

[1253] °^ /

[1254] M-8a-3 1 4.09 490.1

[1255] 0) C

[1256] ATx O

[1257] J J o / o / 11

[1258] M-8a-4 1 3.73 508.5

[1259] M-8b-1 1 2.25 491.3

[1260]

[1261] M-8c-1 1 3.53 491.2 r / o i

[1262] °

[1263] Ss r r

[1264] ° r

[1265] M-8a-5 3 3.20 491.3 ) o C

[1266] KJ T C Ol

[1267] o o1

[1268] M-8a-6 7 2.29 509.3

[1269] M-8c-2 12 3.53 492.1

[1270]

[1271] Synthesis of A / -((1 / ?,3S)-3-aminocvclohexyl)-2-(4-ethoxyphenyl) quinoline-4-carboxamide hydrochloride (M-9a-1)

[1272]

[1273] M-8a-1

[1274] To a stirred solution of tert-butyl tert-butyl((1S,3R)-3-(2-(4-ethoxyphenyl) quinoline-4-carboxamido) cyclohexyl) carbamate (M-8a-1) (375 mg, 0.77 mmol) in 1,4-dioxan (3 mL), was added 4 M HCI in dioxane (5 mL) at 0 °C and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was evaporated to dryness, triturated with n-pentane to afford A / -((1R,3S)-3-aminocyclohexyl)-2-(4-ethoxyphenyl) quinoline-4-carboxamide hydrochloride (M-9a-1).

[1275] Additional intermediates M-9 are available in an analogous manner using different intermediates M-8 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 7).

[1276] Table Ex 7:

[1277] # Structure HPLC

[1278] tret [min] [M+H]+Method

[1279] SNH2. HCI

[1280] , O

[1281] M-9a-1 HN- / ' 1 2.95 390.2

[1282] Vy 'NV- / o _

[1283] NH2. HCI

[1284] M-9a-2 HN- / ' 1 2.97 390.5

[1285] / A

[1286] Vy 'N°\ _

[1287]

[1288] ^^NH2. HCI

[1289] M-9a-3 HN— / 1 2.99 390.1

[1290] V# 'N\=== / ° _

[1291] SNH2HCI

[1292] yO

[1293] M-9a-4 HN— / 1 3.12 408.4

[1294] FSNH2HCI

[1295] ,o

[1296] M-9b-1 HN— / 1 1.31 391.4

[1297] ^ )=N

[1298] VJ / Nv== / °\ _

[1299] XNH2HCI

[1300] yO

[1301] M-9c-1 HN- / 1 3.09 391.3

[1302] N / =\ / V 'V- rs

[1303] S\__jZ~~N V— / O

[1304] XNH2HCI

[1305] , O

[1306] M-9a-5 HN- / 3 1.63 391.3

[1307] / ===( \ / ~~N

[1308]

[1309] SNH2HCI

[1310] ,o

[1311] M-9a-6 HN-^ 12 1.22 409.4

[1312] / =:==\

[1313] FSNH2HCI

[1314] M-9c-2 HN— 1 2.87 392.2

[1315]

[1316] Synthesis of A / -((1R.3S)-3-(benzylamino)cvclohexyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (1-1)

[1317]

[1318] MgSO4(78.88 mg, 0.66 mmol), Et3N (0.14 mL, 0.99 mmol) and A / -[(1R,3S)-3-aminocyclohexyl]-2-(4-ethoxyphenyl) quinoline-4-carboxamide hydrochloride (M-9a-1) (140 mg, 0.33 mmol) were added to a solution of benzaldehyde (34.88 mg, 0.33 mmol) in DCE (5 mL) at room temperature and stirred for 24 h under an N2atmosphere. The reaction mixture was filtered through cartridge, and the filtrate was evaporated under reduced pressure. The residue was diluted with MeOH (5 mL). NaBH4(24.98 mg, 0.66 mmol) was added portion wise at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with aqueous, saturated NH4CI solution (2 mL). The solvents were removed under vacuum, and the residue was diluted with water (2 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and filtrate concentrated under reduced pressure. The crude residue was purified by RP Prep-HPLC to afford A / -((1R,3S)-3-(benzyl amino) cyclohexyl)-2-(4-ethoxyphenyl) quinoline-4-carboxamide (1-1).

[1319] Additional compounds I are available in an analogous manner using different intermediates M-9 as starting materials. The crude products are purified by chromatography if necessary. If mixtures of stereoisomers are obtained from the reaction they can be separated to obtain pure stereoisomers by means of preparative chiral chromatography like chiral SFC (Table Ex 8).

[1320] Table Ex 8:# Structure HPLC tret

[1321] [M+H]+Method [min]

[1322] sNH

[1323] HN- / '

[1324] 1-1 2 2.76 480.4

[1325] _

[1326] A / -((1R,3S)-3-(benzylamino)cyclohexyl)-2-(4- ethoxyphenyl)quinoline-4-carboxamide

[1327] NH

[1328] z0

[1329] HN— #

[1330] I-2 2 2.70 480.4

[1331] _

[1332] A / -((1S,3R)-3-(benzylamino)cyclohexyl)-2-(4- ethoxyphenyl)quinoline-4-carboxamide

[1333] I-3 2 2.70 480.4

[1334] ■',0

[1335] HN~Y

[1336] _

[1337]

[1338] A / -((1R,3 / ?)-3-(benzylamino)cyclohexyl)-2-(4- ethoxyphenyl)quinoline-4-carboxamide

[1339] F

[1340] ^0

[1341] SNH

[1342] ,o

[1343] HN- / '

[1344] -4 2 3.01 516.3

[1345] N\=-= / ' _

[1346] F

[1347] 2-(4-ethoxyphenyl)-7-fluoro-A / -((1R,3S)-3-((4- fluorobenzyl)amino)cyclohexyl)quinoline-4- carboxamide

[1348] xNH

[1349] HN—

[1350] -5 2 2.86 494.6

[1351] 2-(4-ethoxyphenyl)-A / -((1R,3S)-3- (phenethylamino)cyclohexyl)quinoline-4- carboxamide

[1352]

[1353] F

[1354] 0

[1355] SNH

[1356] yO

[1357] HN— / '

[1358] -6 2 2.83 498.3

[1359] VJ / Nv= / °\ _

[1360] 2-(4-ethoxyphenyl)-A / -((1R,3S)-3-((4- fluorobenzyl)amino)cyclohexyl)quinoline-4- carboxamide

[1361] SNH

[1362] yO

[1363] HN— ■ /

[1364] -7 2 2.93 498.3 v== / ~ o

[1365] F

[1366] A / -((1R,3S)-3-(benzylamino)cyclohexyl)-2-(4- ethoxyphenyl)-7-fluoroquinoline-4-carboxamide

[1367] F

[1368] 0

[1369] SNH

[1370] -8 2 2.72 498.3 yO

[1371] HN- / '

[1372]

[1373] 2-(4-ethoxyphenyl)-A / -(( 1 R,3S)-3-(((5-fluoropyridin- 2-yl)methyl)amino)cyclohexyl)quinoline-4- carboxamide

[1374] ^0

[1375] SNH

[1376] HN- / '

[1377] -9 ^_ / =N 2 3.10 481.3

[1378] °\ _

[1379] A / -((1R,3S)-3-(benzylamino)cyclohexyl)-2-(4- ethoxyphenyl)quinazoline-4-carboxamide

[1380] F

[1381] 0

[1382] \ F

[1383] xNH

[1384] zO

[1385] HN-^

[1386] -10 2 2.99 516.3

[1387] A / -((1R,3S)-3-((2,4- difluorobenzyl)amino)cyclohexyl)-2-(4- ethoxyphenyl)quinoline-4-carboxamide

[1388]

[1389] x^0

[1390] NH

[1391] HN-^

[1392] -11 2 2.49 48

[1393] \=== / V-r» 1.4

[1394] _

[1395] A / -((1R,3S)-3-(benzylamino)cyclohexyl)-2-(4- ethoxyphenyl)-1,6-naphthyridine-4-carboxamide

[1396] F

[1397] KNH

[1398] zO

[1399] HN~Y

[1400] -12 9 2.29 500.3

[1401] / z===< \ / r~'N

[1402] 2-(6-ethoxypyridin-3-yl)-A / -((1R,3S)-3-(((5- fluoropyridin-2- yl)methyl)amino)cyclohexyl)quinoline-4- carboxamide

[1403] F

[1404] 0

[1405] SNH

[1406] -13 9 2.31 518.4 zO

[1407] HN- / '

[1408] z^~N

[1409] F

[1410]

[1411] 2-(6-ethoxypyridin-3-yl)-7-fluoro-A / -((1R,3S)-3-(((5- fluoropyridin-2- yl)methyl)amino)cyclohexyl)quinoline-4- carboxamide

[1412] F

[1413] o

[1414] xNH

[1415] HN- / '

[1416] -14 2 2.47 500.4

[1417] N / =\ -z — V 'V- \~_y ~ o _

[1418] 2-(4-ethoxyphenyl)-A / -((1R,3S)-3-(((5-fluoropyridin- 2-yl)methyl)amino)cyclohexyl)-1,6-naphthyridine-4- carboxamide

[1419] F

[1420] o

[1421] xNH

[1422] zO

[1423] HN- / '

[1424] -15 2 2.37 501.4

[1425] / =:==<:^\ / r~N

[1426] ^ / ~~N V== / ~O _

[1427] 2-(6-ethoxypyridin-3-yl)-A / -((1R,3S)-3-(((5- fluoropyridin-2-yl)methyl)amino)cyclohexyl)-1,6- naphthyridine-4-carboxamide

[1428]

[1429] Synthesis of A / -((1R.3S)-3-(benzyl(methyl)amino)cvclohexyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (1-16):

[1430]

[1431] To a stirred solution of A / -[(1R,3S)-3-(benzyl amino) cyclohexyl]-2-(4-ethoxyphenyl) quinoline-4-carboxamide (1-1) (150 mg, 0.31 mmol) in MeOH (5 mL) was added formaldehyde (18.78 mg, 0.63 mmol), AcOH (27 uL, 0.47 mmol) and NaBH3CN (39.41 mg, 0.63 mmol) at room temperature and stirred for 16 h under N2atmosphere. The reaction mixture was cooled to 0 °C, quenched with aqueous, saturated NH4CI (2 mL). MeOH was evaporated to dryness, diluted with water (5 mL), extracted with ethyl acetate (2x 10 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by RP Prep-HPLC to afford A / -[(1R,3S)-3-[benzyl(methyl) amino] cyclohexyl]-2-(4-ethoxyphenyl) quinoline-4-carboxamide (I-16).

[1432] Additional compounds I are available in an analogous manner using different compounds I (with R3B= H) and suitable aldehydes or ketones as starting materials. The crude products are purified by chromatography if necessary. If mixtures of stereoisomers are obtained from the reaction, they can be separated to obtain pure stereoisomers by means of preparative chiral chromatography like chiral SFC (Table Ex 9).

[1433] Table Ex 9:

[1434] # Structure HPLC tret

[1435] [M+H]+Method [min]

[1436] xN— -

[1437] HN— #

[1438] 1-16 2 3.12 494.4

[1439] A / -((1R,3S)-3-(benzyl(methyl)amino)cyclohexyl)-2- (4-ethoxyphenyl)quinoline-4-carboxamide

[1440]

[1441] ,0

[1442] HN- / '

[1443] -17 2 3.02 494.4

[1444] V^ / N\==z / 0 _

[1445] A / -((1R,3 / ?)-3-(benzyl(methyl)amino)cyclohexyl)-2- (4-ethoxyphenyl)quinoline-4-carboxamide

[1446] N—

[1447] ,0

[1448] HN— /

[1449] -18 2 3.06 494.4

[1450] _

[1451] A / -((1S,3R)-3-(benzyl(methyl)amino)cyclohexyl)-2- (4-ethoxyphenyl)quinoline-4-carboxamide

[1452] -19 2 3.33 538.6

[1453] ,o

[1454] HN- / '

[1455] _

[1456]

[1457] A / -((1R,3S)-3-(benzyl(2- methoxyethyl)amino)cyclohexyl)-2-(4- ethoxyphenyl)quinoline-4-carboxamide

[1458] I-20 2 3.08 586.3

[1459] A / -((1R,3S)-3-(benzyl(2- (methylsulfonyl)ethyl)amino)cyclohexyl)-2-(4- ethoxyphenyl)quinoline-4-carboxamide

[1460] 0 / 0=

[1461] nn5-aS°

[1462] 0N^°

[1463] - HN-^

[1464] 1-21 2 3.08 536.5

[1465] N\===Z °\ _

[1466] A / -((1R,3S)-3-(benzyl(oxetan-3- yl)amino)cyclohexyl)-2-(4-ethoxyphenyl)quinoline- 4-carboxamide

[1467]

[1468]

[1469] Synthesis of tert-butyl ((1 / ?.3S)-3-((3.3-difluorocvclobutyl)amino)cvclohexyl)carbamate (A-4-1a) and tert-butyl ((1 / ?.3 / ?)-3-((3.3-difluorocvclobutyl)amino)cvclohexyl)carbamate (A-4-1b):

[1470] A-3-1

[1471]

[1472] To a stirred solution of tert-butyl (R)-(3-oxocyclohexyl)carbamate (A-2-1) (150 mg, 0.7 mmol) in DCE (5 mL), TEA (0.3 mL, 2.11 mmol) was added followed by 3,3-difluorocyclobutan-1-amine (75.33 mg, 0.7 mmol), MgSO4(174.42 mg, 1.41 mmol) and the reaction mixture was stirred at 25 °C for 1 h. After 1 h, NMe4BH(OAc)3(369.95 mg, 1.41 mmol) was added in portions at 0-5 °C and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with aqueous saturated NH4CI solution. The solvents were removed under vacuum, and the residue was diluted with water (5 mL) and extracted with 5% MeOH in DCM (3 x 5 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and filtrate was concentrated under vacuum to afford a mixture of tert-butyl ((1 R,3S)-3-((3,3-difluorocyclobutyl)amino)cyclohexyl)carbamate (A-4-1a) and tert-butyl ((1R,3R)-3-((3,3-difluorocyclobutyl)amino)cyclohexyl)carbamate (A-4-1b) (150 mg, crude) which was used in the next step without further purification.

[1473] Additional intermediates A-4 are available in an analogous manner using different intermediates A-2 and / or A-3 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 10).Table Ex 10:

[1474] # Structure HPLC

[1475] Let [min] [M+H]+Method

[1476] A-4-1a and

[1477] 1 (ELSD) 3.23 304.9

[1478] A-4-1b

[1479]

[1480] Synthesis of (1S,3 / ?)-A / 1-(3,3-difluorocvclobutyl)cyclohexane-1,3-diamine hydrochloride (A-5-1a) and (1R,3 / ?)-A / 1-(3,3-difluorocvclobutyl)cvclohexane-1,3-diamine hydrochloride (A-5-1b):

[1481] I

[1482] +O

[1483] I

[1484] i y yy^

[1485]

[1486] 1 o

[1487] A-4-1a A-4-1b

[1488] To a stirred solution of a crude mixture of tert-butyl ((1R,3S)-3-((3,3-difluorocyclobutyl)amino)cyclohexyl)carbamate (A-4-1a) and tert-butyl ((1R,3R)-3-((3,3-difluorocyclobutyl)amino)cyclohexyl)carbamate (A-4-1b) (180 mg, 0.59 mmol) in 1,4-dioxane (5 mL), HCI (4 M in dioxane) (0.2 mL) was added dropwise at 0 °C under inert atmosphere and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to afford a mixture of (1S,3R)-A / 1-(3,3-difluorocyclobutyl)cyclohexane-1,3-diamine hydrochloride (A-5-1a) and (1R.3R)-A / 1-(3,3-difluorocyclobutyl)cyclohexane-1,3-diamine hydrochloride (A-5-1b) (130 mg, crude) which was used in the next step without further purification.

[1489] Additional intermediates A-5 are available in an analogous manner using different intermediates A-4 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 11).

[1490] Table Ex 11:

[1491] # Structure HPLC

[1492] tret [min] [M+H]+

[1493] Method

[1494]

[1495]

[1496] Synthesis of A / -(HR.3S)-3-((3.3-difluorocvclobutyl)amino)cvclohexyl)-2-(4-ethoxyphenyl)ciuinoline-4-carboxamide fl- 23) and A / -(HR.3R)-3-((3.3-difluorocvclobutyl)amino)cvclohexyl)-2-(4-ethoxyphenyl)ciuinoline-4-carboxamide fl-24):

[1497]

[1498] To a stirred solution of 2-(4-ethoxyphenyl) quinoline-4-carboxylic acid (M-1a-1) (300 mg, 1.02 mmol) and a crude mixture of (1S,3R)-A / 1-(3,3-difluorocyclobutyl)cyclohexane-1,3-diamine hydrochloride (A-5-1a) and (1R,3R)-A / 1-(3,3-difluorocyclobutyl)cyclohexane-1,3-diamine hydrochloride (A-5-1b) (209mg, 1.02 mmol) in DMF (5.0 mL), DIPEA (0.54 mL, 3.07 mmol) was added followed by EDC HCI (490.17 mg, 2.56 mmol), HOBt (207.3 mg, 1.53 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with excess ice-cold water and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by RP preparative HPLC to afford A / -((1R,3S)-3-((3,3-difluorocyclobutyl)amino)cyclohexyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (I-23) and A / -((1R,3R)-3-((3,3-difluorocyclobutyl)amino)cyclohexyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (I-24).

[1499] Additional compounds I are available in an analogous manner using different intermediates M-1 and / or A-5 as starting materials. The crude products are purified by chromatography if necessary. If mixtures of stereoisomers are obtained from the reaction they can be separated to obtain pure stereoisomers by means of preparative chiral chromatography like chiral SFC (Table Ex 12).

[1500] Table Ex 12:

[1501] # Structure HPLC tret

[1502] [M+H]+Method [min]

[1503]

[1504] XNH

[1505] HN- - {

[1506] I-23

[1507] 2 2.90 480.3

[1508] A / -((1R,3S)-3-((3,3- difluorocyclobutyl)amino)cyclohexyl)-2-(4- ethoxyphenyl)quinoline-4-carboxamide

[1509] oNH

[1510] HN-- / '

[1511] I-24

[1512] 2 2.95 480.3 VzZN\== / ° _

[1513] A / -((1R,3R)-3-((3,3- difluorocyclobutyl)amino)cyclohexyl)-2-(4- ethoxyphenyl)quinoline-4-carboxamide

[1514]

[1515] Synthesis of tert-butyl (5-(benzylamino) tetrahvdro-2 / 7-pyran-3-yl) carbamate (A-4-2):

[1516]

[1517] To a stirred solution tert-butyl (5-oxotetrahydro-2 / 7-pyran-3-yl) carbamate (A-2-2, 240 mg, 1.11 mmol) and benzyl amine (A-3-2) (119.48 mg, 1.11 mmol) in MeOH (5 mL), acetic acid (6 uL, 0.11 mmol) was added followed by NaBH3CN(70.07 mg, 1.11 mmol) and the reaction mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction mixture was quenched with saturated aqueous NH4CI solution, concentrated under reduced pressure to remove MeOH and then it was extracted with 10% MeOH in DCM (2x 20 mLJ. The combined organic layer was washed with brine (2 x 15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford tertbutyl (5-(benzylamino)tetrahydro-2 / 7-pyran-3-yl)carbamate (A-4-2) as a mixture of four stereoisomers (two pairs of enantiomers).

[1518] Additional intermediates A-4 are available in an analogous manner using different intermediates A-2 and / or A-3 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 13).

[1519] Table Ex 13:

[1520] # Structure HPLC tret

[1521] [M+H]+Method [min]

[1522] 2.98 & 307.1 &

[1523] A-4-2 I J 0 1

[1524] 0 3.12 306.9 Mixture of 4 stereoisomers

[1525] N l I " 3.02 & 326.2 &

[1526] A-4-3 1 ) O 10

[1527] O 3.11 326.2 Mixture of 4 stereoisomers

[1528]

[1529] Synthesis of A / 3-benzyltetrahvdro-2 / 7-pyran-3,5-diamine 2,2,2-trifluoroacetate (A-5-2):

[1530] TFA, DCM

[1531] Mixture of 4 stereoisomers

[1532]

[1533] A-4-2

[1534] A-5-2

[1535] To a stirred solution tert-butyl (5-(benzylamino) tetrahydro-2 / 7-pyran-3-yl) carbamate (A-4-2, 200 mg, 0.65 mmol, mixture of 4 stereoisomers) in DCM (6 mL), TFA (3 mL) was added dropwise at 0 °C under argon atmosphere and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to afford A / 3-benzyltetrahydro-2 / 7-pyran-3,5-diamine 2,2,2-trifluoroacetate. (A-5-2) as a mixture of 4 stereoisomers (two sets of enantiomers).

[1536] Additional intermediates A-5 are available in an analogous manner using different intermediates A-4 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 14).

[1537] Table Ex 14:

[1538] # Structure HPLC tret

[1539] [M+H]+Method [min]

[1540]

[1541] ys / NH2TFA

[1542] 1.68 & 207.2 &

[1543] A-5-2 1

[1544] 1.86 207.3 Mixture of 4 stereoisomers

[1545] F\>^

[1546] I N^-^NH2TFA

[1547] 1.20 & 226.0 &

[1548] A-5 -3 1

[1549] 1.39 226.2 Mixture of 4 stereoisomers

[1550]

[1551] Synthesis of / 'ac-A / -((3S.5F?)-5-(benzylamino)tetrahvdro-2 / 7-pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide fl- 25) and / 'ac-A / -((3S,5S)-5-(benzylamino)tetrahvdro-2 / 7-pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (I-26):

[1552] Mixture of 4 stereoisomers

[1553]

[1554] To a stirred solution of 2-(4-ethoxyphenyl)quinoline-4-carboxylic acid (M-1a-1) (200 mg, 0.68 mmol) and N3-benzyltetrahydro-2 / 7-pyran-3,5-diamine 2,2,2-trifluoroacetate (A-5-2) (168.79 mg, 0.82 mmol, mixture of 4 stereoisomers) in DMF (5 mL), triethylamine (0.38 mL, 2.73 mmol) was added followed by HATU (311.12 mg, 0.82 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice water, extracted with ethyl acetate (2 x 25 mLJ. The combined organic layer was washed with aqueous, saturated NaHCO3solution(2 x 20 mL) followed by brine (2 x 15 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford the crude product, which was purified by RP Prep HPLC to afford the pure product as two isomers: Rac-A / -((3S,5 / ?)-5-(benzylamino)tetrahydro-2 / 7-pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (I-25) and Rac-A / -((3S,5S)-5-(benzylamino)tetrahydro-2 / 7-pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (I-26).

[1555] Additional compounds I are available in an analogous manner using different intermediates M-1 and / or A-5 as starting materials. The crude products are purified by chromatography and the enantiomers can be separated by chiral SFC or other chital separation methods (Table Ex 15).

[1556] Table Ex15:

[1557] # Structure

[1558] HPLC Method [M+H]+

[1559] [min]

[1560]

[1561] ^0

[1562] SNH

[1563] ',o

[1564] HN- / '

[1565] -25 V# ~N\==Z / ° _ 2 2.87 482.6

[1566] Racemate

[1567] Stereochemistry tentatively assigned

[1568] Rac-A / -((3S,5R)-5-(benzylamino)tetrahydro- 2 / 7-pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4- carboxamide

[1569] ^0

[1570] NH

[1571] °Z)

[1572] HN- / '

[1573] -26 Vz / ny==z °Y _ 2 3.01 482.6

[1574] Racemate

[1575] Stereochemistry tentatively assigned

[1576] Rac -A / -((3S,5S)-5-(benzylamino)tetrahydro- 2 / 7-pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4- carboxamide

[1577]

[1578] SNH

[1579] OQ

[1580] 2 2.74 482.5 HN-

[1581] -27

[1582] Stereochemistry tentatively assigned

[1583] A / -((3S,5R)-5-(benzylamino)tetrahydro-2 / 7- Analytical

[1584] pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4- Chiral SFC 5.17 - carboxamide Method-1

[1585] ^0

[1586] NH

[1587] oz\

[1588] 2 2.76 482.5,0

[1589] HN-^

[1590] -28

[1591] (=== / °\ _

[1592] Stereochemistry tentatively assigned

[1593] A / -((3R,5S)-5-(benzylamino)tetrahydro-2 / 7- Analytical

[1594] pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4- Chiral SFC 3.94 carboxamide Method-1

[1595] F

[1596] O

[1597] xNH

[1598] -29

[1599] 8 5.48 501.3 HN-^

[1600] _

[1601] Racemate

[1602] Stereochemistry tentatively assigned

[1603]

[1604] Rac-2-(4-ethoxyphenyl)-A / -((3S,5R)-5-(((5- fluoropyridin-2-yl)methyl)amino)tetrahydro-2 / 7- pyran-3-yl)quinoline-4-carboxamide

[1605] F

[1606] o

[1607] NH

[1608] q / )

[1609] HN-^

[1610] I-30

[1611] VJ / N2 2.66 501.3 v== / °\ _

[1612] Racemate

[1613] Stereochemistry tentatively assigned

[1614] Rac-2-(4-ethoxyphenyl)-A / -((3S,5S)-5-(((5- fluoropyridin-2-yl)methyl)amino)tetrahydro-2 / 7- pyran-3-yl)quinoline-4-carboxamide

[1615] F

[1616] o

[1617] SNH

[1618] 9 2.26 501.3 HN- / '

[1619] 1-31

[1620] Stereochemistry tentatively assigned

[1621] 2-(4-ethoxyphenyl)- / V-((3S,5R)-5-(((5- Analytical

[1622] fluoropyridin-2-yl)methyl)amino)tetrahydro-2 / 7- chiral SFC 9.35 - pyran-3-yl)quinoline-4-carboxamide method-12

[1623]

[1624] F

[1625] o

[1626] SNH

[1627] <0

[1628] ',o

[1629] HN— ■ {

[1630] -32 _ 2 2.78 519.5

[1631] F

[1632] Racemate

[1633] Stereochemistry tentatively assigned

[1634] Rac-2-(4-ethoxyphenyl)-A / -((3S,5R)-5-(((5- fluoropyridin-2-yl)methyl)amino)tetrahydro-2 / 7- pyran-3-yl)quinoline-4-carboxamide

[1635] F

[1636] o

[1637] NH

[1638] c> \

[1639] ',o

[1640] HN— Z'

[1641] -33

[1642] 2 2.86 519.5 F

[1643] Racemate

[1644] Stereochemistry tentatively assigned

[1645] Rac-2-(4-ethoxyphenyl)-A / -((3S,5S)-5-(((5- fluoropyridin-2-yl)methyl)amino)tetrahydro-2 / 7- pyran-3-yl)quinoline-4-carboxamide

[1646]

[1647] F

[1648] o

[1649] SNHOQ 2 2.86 519.5

[1650] HN-^

[1651] I-34

[1652] F

[1653] Stereochemistry tentatively assigned

[1654] 2-(4-ethoxyphenyl)-7-fluoro-A / -((3S,5R)-5-(((5- Analytical

[1655] fluoropyridin-2-yl)methyl)amino)tetrahydro-2 / 7- Chiral SFC 4.04 - pyran-3-yl)quinoline-4-carboxamide Method-30

[1656]

[1657] Synthesis of / 'ac-A / -(3,6-dihvdro-2 / 7-pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-10-1):

[1658]

[1659] Racemate

[1660] To a stirred solution of 2-(4-ethoxyphenyl) quinoline-4-carboxylic acid (M-1a-1) (260 mg, 0.885 mmol) and 3,6-dihydro-2 / 7-pyran-3-amine hydrochloride (A-6-1) (100 mg, 0.738 mmol) in DMF (5.0 mL), DIPEA (0.3 mL) was added followed by EDC (170 mg, 0.885 mmol), HOBt (120 mg, 0.885 mmol) and the reaction mixture was stirred at room temperature for 16h. The reaction mixture was diluted with excess ice-cold water and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography to obtain rac-A / -(3,6-dihydro-2 / 7-pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-10-1).

[1661] Additional intermediates M-10 are available in an analogous manner using different intermediates M-1 and / or A-6 as starting materials. The crude products are purified by chromatography if necessary (Table Ex 16).

[1662] Table Ex 16:# Structure HPLC tret

[1663] [M+H]+Method [min]

[1664] 03

[1665] / O

[1666] HN— ■

[1667] M-10-1 S2 5.94 375.2

[1668] _

[1669] Racemate

[1670]

[1671] Synthesis of rac-A / -((1R,5R,6S)-3,7-dioxabicvclo[4.1.01heptan-5-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-11-1 aland rac-A / -(HS.5R.6R)-3.7-dioxabicvclof4.1.01heptan-5-yl)-2-(4-ethoxyphenyl)ciuinoline-4-carboxamide (M-11-

[1672]

[1673] ibl

[1674] Step 1:

[1675]

[1676] Racemate To a stirred solution of A / -(3,6-dihydro-2 / 7-pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (280 mg, 0.748 mmol) in DCM was added 3-chlorobenzoperoxoic acid (368 mg, 1.496 mmol, 70% Wt) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (30 mL) and washed with saturated aqueous NHCO3solution and water. The organic phase was dried over MgSO4, filtered and the solvents were removed under reduced pressure. The resulting crude product was purified by column chromatography to afford a mixture of rac-4-(((1R,5R,6S)-3,7-dioxabicyclo[4.1.0]heptan-5-yl)carbamoyl)-2-(4-ethoxyphenyl)quinoline 1-oxide and rac-4-(((1S,5R,6R)-3,7-dioxabicyclo[4.1.0]heptan-5-yl)carbamoyl)-2-(4-ethoxyphenyl)quinoline 1-oxide which was used in the next step without further purification.

[1677] Additional precursors to intermediates M-11 are available in an analogous manner using different intermediates M-10 as starting materials (Table Ex 17). In the case that no oxidation of a core nitrogen occurs this step directly leads to intermediates M-11 (Table Ex 18) and no step 2 (reduction) is needed. The crude products are purified by chromatography if necessary

[1678] Table Ex 17:

[1679] # Structure HPLC tret

[1680] [M+H]+Method [min]

[1681]

[1682]

[1683] To a stirred solution of mixture of rac-4-(((1 / ?,5 / ?,6S)-3,7-dioxabicyclo[4.1.0]heptan-5-yl)carbamoyl)-2-(4-ethoxyphenyl)quinoline 1 -oxide and rac-4-(((1S,5 / ?,6 / ?)-3,7-dioxabicyclo[4.1.0]heptan-5-yl)carbamoyl)-2-(4-ethoxyphenyl)quinoline 1-oxide (250 mg, 0.615 mmol) in DMF (5 mL) was added diboron tetrahydroxide (551 mg, 6.15 mmol) at room temperature and the mixture was stirred at the same temperature for 3 h. The reaction mixture was diluted with DCM (50 mL) and washed with saturated aqueous NHCO3solution and water. The organic phase was dried over MgSO4, filtered and the solvents were removed under reduced pressure. The resulting crude product was purified by column chromatography to afford a mixture of rac-A / -((1R,5 / ?,6S)-3,7-dioxabicyclo[4.1.0]heptan-5-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-11-1a)and rac-A / -((1S,5R,6R)-3,7-dioxabicyclo[4.1.0]heptan-5-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-11 -1 b) which was used in the next step without further purification. Additional intermediates M-11 (Table Ex 18) are available in an analogous manner using different intermediates M-10 as starting materials. The crude products are purified by chromatography if necessary

[1684] Table Ex 18:

[1685] # Structure HPLC tret

[1686] [M+H]+Method [min]

[1687]

[1688]

[1689] / ?ac-A / -((3 / ?.4 / ?.5S)-5-(benzylamino)-4-hvdroxytetrahvdro-2 / 7-pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide £!z35X

[1690]

[1691] not isolated

[1692] To a stirred solution of a mixture of rac-A / -((1R,5 / ?,6S)-3,7-dioxabicyclo[4.1.0]heptan-5-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-11-1a) and rac-A / -((1S,5 / ?,6 / ?)-3,7-dioxabicyclo[4.1.0]heptan-5-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-11-1b) (26 mg, 0.067 mmol) in MeOH (5 mL) was added benzylamine (71 mg, 0.67 mmol). The mixture was heated to 70 °C and stirred at the same temperature for 24 h. The reaction mixture was diluted with DCM (50 mL) and washed with saturated aqueous NHCO3solution and water. The organic phase was dried over MgSO4, filtered and the solvents were removed under reduced pressure. The resulting crude product was purified by column chromatography to afford Rac-A / -((3 / ?,4 / ?,5S)-5-(benzylamino)-4-hydroxytetrahydro-2 / 7-pyran-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (I-35) (Other isomers were not isolated in sufficient amounts). Additional compounds I are available in an analogous manner using different intermediates M-11 and other suitable amines as starting materials. The crude products are purified by chromatography, and the enantiomers can be separated by chiral SFC or other chital separation methods (Table Ex 19).

[1693] Table Ex 19:

[1694] # Structure HPLC tret

[1695] [M+H]+Method [min]

[1696]

[1697]

[1698] Synthesis of A / -(cvclopent-3-en-1-vh-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-12-1)

[1699] 0

[1700]

[1701] VJ M-12-1

[1702] To a stirred solution of

[1703] f 2-(4-ethoxyphenyl) quinoline-4-carboxylic acid (M-1a-1) (250 mg, 0.85 mmol) in DCM (5 mL) was added EDC HCI (245.09 mg, 1.28 mmol), HOBt (57.53 mg, 0.43 mmol) and stirred for 5 min. Cyclopent-3-en-1-amine hydrochloride (A-7-1) (101.93 mg, 0.85 mmol) and DIPEA (0.15 mL, 0.85 mmol) were added. The reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3solution (2 x 5 mL). The organic layer was dried over anhydrous Na2SO4, filtered and filtrate concentrated under vacuum. The residue was purified by combi-flash column chromatography to afford A / -(cyclopent-3-en-1-yl)-2-(4-ethoxyphenyl) quinoline-4-carboxamide (M-12-1).

[1704] Additional intermediates M-12 (Table Ex 20) are available in an analogous manner using different intermediates M-1 and / or A-7 as starting materials. The crude products are purified by chromatography if necessary

[1705] Table Ex 20:

[1706] # Structure HPLC tret

[1707] [M+H]+Method [min]

[1708] M-12-1 1 3.60 359.2

[1709]

[1710] O — r- /

[1711]

[1712] Of

[1713] Synthesis of A / -((1 / ?.3s.5S)-6-oxabicvclor3.1.01hexan-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-13-1):

[1714] O

[1715] ° r

[1716]

[1717] To a stirred solution of A / -(cyclopent-3-en-1-yl)-2-(4-ethoxyphenyl) quinoline-4-carboxamide (M-12-1) (450 mg, 1.25 mmol) in DCM (30 mL) was added m-CPBA (433.29 mg, 2.51 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The mixture was washed with saturated aqueous NaHCO3solution (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 A / -((1R,3s,5S)-6-oxabicyclo[3.1.0]hexan-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-13-1). Additional intermediates M-13 (Table Ex 21) are available in an analogous manner using different intermediates M-12 as starting materials. The crude products are purified by chromatography if necessary.

[1718] Table Ex 21:

[1719] # Structure HPLC tret

[1720] [M+H]+Method [min]

[1721] M-13-1 1 3.37 375.1

[1722] - HN— Z'

[1723] M-13-2 1 1.54 393.3

[1724] FZ

[1725]

[1726] Synthesis of: Rac-2-(4-ethoxyphenyl)-A / -((1S.3S.4S)-3-hvdroxy-4-(2-methoxyethoxy)cvclopentyl)ciuinoline-4-carboxamide (M-14a)

[1727]

[1728] To a stirred solution of A / -((1R,3S,5S)-6-oxabicyclo[3.1.0]hexan-3-yl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (M-13-1) (200 mg, 0.53 mmol) in 2-methoxy ethanol (5 mL) was added NaH (60% w / w) (42 mg, 1.07 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with DCM (20 mL), cooled on ice-water bath and treated with aqueous NH4CI solution (10 mL). The layers were separated, the organic layer was washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by combi-flash column chromatography to afford rac-2-(4-ethoxyphenyl)-A / -((1S,3S,4S)-3-hydroxy-4-(2-methoxyethoxy)cyclopentyl)quinoline-4-carboxamide (M-14-1).

[1729] Additional intermediates M-14 (Table Ex 22) are available in an analogous manner using different intermediates M-13 and / or other suitable nucleophiles to open epoxides (e.g. other alcohols) as starting materials. The crude products are purified by chromatography if necessary

[1730] Table Ex 22:

[1731] # Structure HPLC tret

[1732] [M+H]+Method [min]

[1733] OH

[1734] - yO

[1735] HN-^

[1736] M-14-1 1 7.37 451.2

[1737] Racemate

[1738] OH

[1739] O-J

[1740] M-14-2 HN-^ S4 4.61 449.3

[1741] Racemate N «= / ® _

[1742]

[1743]

[1744] Synthesis of / 'ac-2-(4-ethoxyphenyl)-A / -((1R,3S)-3-(2-methoxyethoxy)-4-oxocvclopentyl)quinoline-4-carboxamide (F)

[1745]

[1746] Racemate Racemate

[1747] M-14-1 M-15-1

[1748] To a mixture of rac-2-(4-ethoxyphenyl)-A / -((1S,3S,4S)-3-hydroxy-4-(2-methoxyethoxy)cyclopentyl)quinoline-4-carboxamide (M-14-1) (170 mg, 0.38 mmol) in DCM (10 mL), DMP (240.06 mg, 0.57 mmol) was added. The reaction was stirred at 20 °C for 18 h. The reaction mixture was successively washed with mixture of aq. NaHCO3and 5% sodium thiosulfate solution (4 x 10 mL), brine (2 x 10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by combi-flash column chromatography to afford rac-2-(4-ethoxyphenyl)-A / -((1R,3S)-3-(2-methoxyethoxy)-4-oxocyclopentyl)quinoline-4-carboxamide (M-15-1).

[1749] Additional intermediates M-15 (Table Ex 23) are available in an analogous manner using different intermediates M-14 and / or other suitable nucleophiles to open epoxides (e.g. other alcohols) as starting materials. The crude products are purified by chromatography if necessary

[1750] Table Ex 23:

[1751] # Structure HPLC tret

[1752] [M+H]+Method [min]

[1753] O

[1754] M-15-1 HN- / ' 1 3.40 449.0

[1755] 22^ ^ _

[1756] Racemate

[1757]

[1758]

[1759] Synthesis of A / -((1S.3R.4S)-3-(benzylamino)-4-(2-methoxyethoxy)cvclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (1-36) and A / -((1R,3S,4R)-3-(benzylamino)-4-(2-methoxyethoxy)cvclopentyl)-2-(4-

[1760]

[1761] To a stirred solution rac-2-(4-ethoxyphenyl)-A / -((1R,3S)-3-(2-methoxyethoxy)-4-oxocyclopentyl)quinoline-4-carboxamide (M-15-1) in DCM (10 mL) benzyl amine (28.67 mg, 0.27 mmol), Na(OAc)3BH (113.41 mg, 0.54 mmol) was added portion wise at ice bat temperature. The reaction was stirred at 20 °C for 16 h. The reaction was washed with saturated, aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under vacuum. The crude residue was purified first by RP preparative HPLC to afford Rac-A / -((1S,3R,4S)-3-(benzylamino)-4-(2-methoxyethoxy)cyclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide, followed by chiral SFC to afford A / -((1S,3R,4S)-3-(benzylamino)-4-(2-methoxyethoxy)cyclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide(1-36) and A / -((1R,3S,4R)-3-(benzylamino)-4-(2-methoxyethoxy)cyclopentyl)-2-(4-ethoxyphenyl)quinoline-4-carboxamide (I-37).

[1762] Additional compounds I are available in an analogous manner using different intermediates M-15 and other suitable amines as starting materials (Table Ex 24). The crude products are purified by chromatography and the enantiomers can be separated by chiral SFC or other chiral separation methods. Examples: I-36, I-37: Preparative chiral SFC method H.

[1763] Table Ex 24:

[1764] # Structure HPLC tret

[1765] [M+H]+Method [min]

[1766] 2 2.84 540.6 0

[1767] I-36

[1768] o'

[1769] A / -((1S,3R,4S)-3-(benzylamino)-4-(2- Analytical methoxyethoxy)cyclopentyl)-2-(4- chiral SFC 4.56 -

[1770] ethoxyphenyl)quinoline-4-carboxamide method-11

[1771] ?

[1772] NH

[1773] 2 2.83 540.6

[1774] \,0

[1775] HN-^

[1776] I-37

[1777] \=== / '

[1778] A / -((1R,3S,4R)-3-(benzylamino)-4-(2- Analytical methoxyethoxy)cyclopentyl)-2-(4- Chiral SFC 4.10 - ethoxyphenyl)quinoline-4-carboxamide Method-11

[1779]

[1780] o

[1781] \H

[1782] ' / O

[1783] HN—

[1784] I-38 S3 5.77 541.4

[1785] Racemate N V== / ~<“\ _

[1786] Rac-2-(4-ethoxyphenyl)-A / -((1S,3S,4R)-3-(2- methoxyethoxy)-4-((pyridin-4- ylmethyl)amino)cyclopentyl)quinoline-4- carboxamide

[1787] \^N

[1788] NHXO^°"-Q

[1789] '', O

[1790] HN- / '

[1791] I-39 S3 6.86 541.4

[1792] Racemate \ _

[1793] Rac-2-(4-ethoxyphenyl)-A / -((1S,3S,4R)-3-(2- methoxyethoxy)-4-((pyridin-2- ylmethyl)amino)cyclopentyl)quinoline-4- carboxamide

[1794] \H

[1795] I-49 2 2.63 541.5

[1796] HN-^

[1797] Vj / NV== / °\ _

[1798]

[1799] 2-(4-ethoxyphenyl)-A / -((1S,3S,4R)-3-(2- Analytical methoxyethoxy)-4-((pyridin-2- chiral SFC 4.18 - ylmethyl)amino)cyclopentyl)quinoline-4- Method 31 carboxamide

[1800] NH

[1801] o-J yy

[1802] ■' / O

[1803] HN- / '

[1804] I-40 S1 4.98 552.3

[1805] Racemate N X^y \ _

[1806] Rac-2-(4-ethoxyphenyl)-A / -((1S,3S,4R)-3-(oxetan- 3-yloxy)-4-(phenethylamino)cyclopentyl)quinoline- 4-carboxamide

[1807] HN- / '

[1808] 1-41 S1 5.26 554.4

[1809] RacemateNX= / ~<^

[1810] Rac-2-(4-ethoxyphenyl)-A / -((1S,3S,4R)-3-(2- methoxyethoxy)-4- (phenethylamino)cyclopentyl)quinoline-4- carboxamide

[1811]

[1812] XNH

[1813] ■',o

[1814] HN- / '

[1815] I-42 S1 4.91 546.3

[1816] Racemate v=== / ~O _

[1817] Rac-2-(4-ethoxyphenyl)-A / -((1S,3S,4R)-3-(2- methoxyethoxy)-4-((thiophen-2- ylmethyl)amino)cyclopentyl)quinoline-4- carboxamide

[1818] ^?s

[1819] NH

[1820] o-V

[1821] ',o

[1822] HN-- / '

[1823] I-43 S1 4.68 544.3

[1824] Racemate y _

[1825] Rac-2-(4-ethoxyphenyl)-A / -((1S,3S,4R)-3-(oxetan- 3-yloxy)-4-((thiophen-2- ylmethyl)amino)cyclopentyl)quinoline-4- carboxamide

[1826] NH

[1827] I-44 S1 4.81 - °-7 L_y

[1828] ' zO

[1829] HN- / '

[1830] RacemateNV== / ~<^ _

[1831]

[1832] Rac-2-(4-ethoxyphenyl)-A / -((1S,3S,4R)-3-(oxetan- 3-yloxy)-4-((2-(pyridin-2- yl)ethyl)amino)cyclopentyl)quinoline-4- carboxamide

[1833] NH

[1834] ,^.0,,, J"

[1835] ',o

[1836] I-45 HN~Y 10 4.76 538.4

[1837] RacemateN«= / \ _

[1838] Rac-A / -((1S,3R,4S)-3-(benzylamino)-4-(oxetan-3- yloxy)cyclopentyl)-2-(4-ethoxyphenyl)quinoline-4- carboxamide

[1839] XNH

[1840] *,0

[1841] HN-~Y

[1842] I-46 3 2.34 559.3

[1843] Racemate

[1844] FZ

[1845] Minor isomer

[1846] Rac-2-(4-ethoxyphenyl)-7-fluoro-N-((1R,3R,4R)-3- (2-methoxyethoxy)-4-((pyridin-2- ylmethyl)amino)cyclopentyl)quinoline-4- carboxamide

[1847]

[1848] VN

[1849] \H

[1850] ' o HN- / '

[1851] -47 3 2.34 559.3

[1852] — ^7~A—

[1853] Racemate O '== / _

[1854] F

[1855] Rac-2-(4-ethoxyphenyl)-N-((1S,3S,4R)-3-(2-methoxyethoxy)-4-((pyridin-2-ylmethyl)amino)cyclopentyl)quinoline-4-carboxamide

[1856] 0

[1857] ° r

[1858] 2 2.66 559.4

[1859] -48

[1860] 2-(4-ethoxyphenyl)-A / -((1S,3S,4R)-3-(2- Analytical methoxyethoxy)-4-((pyridin-2- Chiral SFC 4.39 - ylmethyl)amino)cyclopentyl)quinoline-4- Method-10

[1861] carboxamide

[1862]

[1863] Biological data

[1864] Biological example 1: TASL proteostasis by TASL-EmGFP-P2A-mCherry (TGC) reporter

[1865] The TGC reporter construct encodes C-terminally EmGFP-tagged TASL followed by the P2A self-cleaving peptide and mCherry (SEQ ID NO:01), enabling constitutive expression of both ORFs from the same promoter. The measurement of EmGFP to mCherry fluorescence ratio allows the monitoring of TASL-EmGFP intracellular levels by microscopy imaging.

[1866] HEK-293T cells stably overexpressing the TGC reporter and N-terminally 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 separate genomic integration of a lentiviral construct carrying the HA-SLC15A4 sequence. 2k cells per well were seeded in Dulbecco's Modified Eagle Medium (DMEM; Gibco, cat. #11965092) with 10 % fetal bovine serum (FBS; Fisher Scientific, cat. #11550356) and 1 % Pen-Strep (Sigma-Aldrich, cat. #P4333) in 384-well plates precoated with poly-D-ly-sine (Rewity, cat. #6007718). Right after seeding, compounds were added over a 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 48 h of incubation at 37 °C and 5 % of CO2, Hoechst 33342 dye (Fisher Scientific, cat. #62249) was added at a final concentration of 5 pM. Each plate was spun down and then incubated for 10 min 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 min at RT and then two washing steps with Dulbecco’s Phosphate Buffered Saline (PBS; Sigma-Aldrich, cat. #D8537) were performed. Finally, 30 pL of PBS was added to the wells and the plates were sealed and stored at 4 °C until being imaged.

[1867] Microscopy images were acquired on an Operetta CLS High Content Analysis System with a 20X water objective (1.0 NA) using Harmony 5.1 software (PerkinElmer / Rewity). Exposure settings for Hoechst, mCherry, and EmGFP channels 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 regions on Hoechst and EmGFP / mCherry 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 per field are reported in Table BiolEx-1.

[1868] The assay of the present example allows for the 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).

[1869] Table BiolEx-1:

[1870] Example EmGFP / mCherry ratio EmGFP / mCherry ratio EmGFP / mCherry ratio reduction reduction at 1.1 pM reduction at 4 pM at 14 pM

[1871] 1-1 +++ +++ +

[1872] I-2 + ++ NA

[1873] I-3 ++ +++ ++

[1874] I-4 +++ +++ NA

[1875] I-5 +++ ++ ++

[1876] I-6 +++ ++ +

[1877]

[1878] I-7 +++ +++ NA I-8 +++ +++ +++ I-9 +++ +++ + 1-10 +++ ++ ++ 1-11 +++ +++ NA 1-12 ++ ++ ++ 1-13 ++ +++ + 1-14 ++ ++ ++ 1-15 ++ ++ +++ 1-16 +++ +++ ++ 1-17 ++ ++ +++ 1-18 + ++ +++ 1-19 + ++ ++ I-20 ++ ++ ++ 1-21 + ++ ++ I-22 + + + I-23 + ++ ++ I-24 + # + # + I-25 ++ +++ +++ I-26 + ++ +++ I-27 ++ ++ ++ I-28 + # + # + I-29 ++ ++ ++ I-30 + + + 1-31 ++ ++ ++ I-32 ++ ++ ++ I-33 + + ++ I-34 ++ ++ ++ I-35 ++ ++ ++ I-36 +++ +++ ++ I-37 + # + ++ I-38 + ++ ++ I-39 ++ ++ +++ I-40 ++ +++ +++ 1-41 ++ +++ +++ I-42 ++ ++ ++ I-43 ++ ++ ++ I-44 ++ ++ NA I-45 + ++ ++ I-46 + + ++ I-47 ++ ++ +++ I-48 ++ ++ + I-49 ++ ++ +

[1879]

[1880] The ratios were defined as follows in Table BiolEx-1:

[1881] +++: EmGFP / mCherry ratio between 0 and 0.4

[1882] ++: EmGFP / mCherry ratio between 0.41 and 0.7

[1883] +: EmGFP / mCherry ratio between 0.71 and 0.99

[1884] #: Compounds close to the threshold of 1

[1885] Wherein “between” is defined as including the endpoints of the given range.

[1886] Biological example 2: Enzyme-linked immunosorbent assay (ELISA)

[1887] IRF5 activation downstream of the SLC15A4 / TASL signalling complex results in the production and secretion of proinflammatory cytokines, including interleukin-6 (IL-6) and tumor-necrosis factor alpha (TNFa) (Heinz et al. 2020, Takaoka et al. 2005). Cytokine production can be monitored by ELISA, an assay well known to the skilled person.

[1888] Peripheral blood mononuclear cells (PBMCs), B cells, monocytes, or plasmacytoid dendritic cells (pDCs) from healthy human donors are purified from whole blood by density centrifugation (Ficoll-Paque, Fisher Scientific, cat.

[1889] #11768538), followed by magnetic bead isolation for B cells, monocytes, and pDCs. PBMCs are frozen in FBS (Fisher Scientific, cat. #11550356) plus 10 % DMSO (as freezing media) until further use, whereas B cells, monocytes, and pDCs are used freshly, directly after isolation. For compound treatment, all cells are incubated in Roswell Park Memorial Institute 1640 media (RPMI; Gibco, cat. #12004997) containing 10 % FBS. 100k-200k cells per well are seeded in transparent or black 96-well plates (Corning Costar, Fisher Scientific, cat. #10687551; Corning Costar, Sigma Aldrich, cat. #CLS3904-100EA), compounds are added at a serial concentration in technical triplicates, and plates are incubated at 37 °C and 5 % of CO2 for 48 h. 18-20 h before readout, the cells are stimulated with 5 pg / mL Resiquimod (R848; MedChem Express, cat. #HY-13740) or CpG-B (ODN2006, synthesized by IDT). At the end of the stimulation period, plates are spun down at 250 g for 5 min and supernatants are collected and analyzed for IL-6 and TNFa cytokine levels by ELISA (Invitrogen, cat. #88-7066-88 and #88-7346-88) according to the manufacturer’s instructions. For IFNa ELISA (Invitrogen, cat. # BMS216), cells are treated with compounds for 3-6 h followed by 14 h of stimulation with R848 or CpG-B.

[1890] Treatment of PBMCs, B cells, monocytes, and pDCs with compounds, which are able to interfere with the SLC15A4 / TASL complex (thus interfering with the pathway that would ultimately result in IRF5 activation, which leads to cytokine production), is expected to result in reduced cytokine production.

[1891] This was confirmed for PBMCs as follows:

[1892] PBMCs from healthy human donors were purified from whole blood by density centrifugation (Ficoll-Paque, Fisher Scientific, cat. #11768538) and frozen in FBS (Fisher Scientific, cat. #11550356) plus 10 % DMSO (as freezing media) until further use. For compound treatment, the PBMCs were incubated in RPMI (Gibco, cat. #12004997) containing 10 % FBS. 100k-200k cells per well were seeded in transparent or black 96-well plates (Corning Costar, Fisher Scientific, cat. #10687551; Corning Costar, Sigma Aldrich, cat. #CLS3904-100EA), compounds were added at a serial concentration in technical triplicates, and plates were incubated at 37 °C and 5 % of CO2 for 48 h. 18-20 h before readout, the cells were stimulated with 5 pg / mL R848 (MedChem Express, cat. #HY-13740). At the end of the stimulation period, plates were spun down at 250 g for 5 min and supernatants were collected and analyzed for TNFa cytokine levels by ELISA (Invitrogen, cat. #88-7066-88 and #88-7346-88) according to the manufacturer’s instructions.

[1893] The results for the examples at the indicated concentrations as given using PBMCs stimulated with R848 are shown in Table BiolEx-2.Table BiolEx-2:

[1894] TNFa reduction at TNFa reduction at TNFa reduction at Example 0.0038 pM 0.023 pM 0.138 pM 1-1 +++ +++

[1895] I-2 + +

[1896] I-3 ++ +++

[1897] I-4 +++ +++

[1898] I-5 +++ +++

[1899] I-6 +++ +++

[1900] I-7 +++ +++

[1901] I-8 +++ +++

[1902] I-9 +++ +++

[1903] 1-10 ++ ++

[1904] 1-11 +++ +++

[1905] 1-12 +++ +++

[1906] 1-13 +++ +++

[1907] 1-14 + ++

[1908] 1-15 ++ +++

[1909] 1-16 +++ +++

[1910] 1-17 + ++

[1911] 1-18 + ++

[1912] 1-19 + +

[1913] I-20 ++ ++

[1914] 1-21 + ++

[1915] I-22 + ++

[1916] I-23 + ++

[1917] I-24 + +

[1918] I-25 +++ +++

[1919] I-26 + ++

[1920] I-27 +++ +++

[1921] I-28 + +

[1922] I-29 ++ +++

[1923] I-30 + +

[1924] 1-31 ++ ++

[1925] I-32 ++ +++

[1926] I-33 + +

[1927] I-34 ++ +++

[1928] I-35 +++ +++

[1929]

[1930] I-36 +++ +++

[1931] I-37 + +

[1932] I-38 + +

[1933] I-39 +++ +++

[1934] I-40 ++ +++

[1935] 1-41 ++ +++

[1936] I-42 ++ +++

[1937] I-43 + ++

[1938] I-44 ++ +++

[1939] I-45 + ++

[1940] I-46 + ++

[1941] I-47 +++ +++

[1942] I-48 +++ +++

[1943] I-49 +++ +++

[1944]

[1945] The TNFa reduction was defined as follows in Table BiolEx-2:

[1946] +++: Normalized TNFa concentration compared to DMSO treatment between 0 and 0.4

[1947] ++: Normalized TNFa concentration compared to DMSO treatment between 0.41 and 0.7

[1948] +: Normalized TNFa concentration compared to DMSO treatment between 0.71 and 0.99

[1949] Wherein “between” is defined as including the endpoints of the given range.

[1950] THP1 cells (CLS, cat. #300356) are cultured in transparent or black 96-well plates (Corning Costar, Fisher Scientific, cat. #10687551; Corning Costar, Sigma Aldrich, cat. #CLS3904-100EA) in RPMI 1640 media (Gibco, cat.

[1951] #12004997) containing 10 % FBS (Fisher Scientific, cat. #11550356), 1 % Pen-Strep (Gibco cat. #15070063), 1 mM sodium pyruvate (Gibco, cat. #11360070), 2 mM L-Glutamine (Gibco, cat. #A2916801), and 25 mM HEPES (Gibco, cat. #11560496). 100k THP1 cells per well were seeded and treated with a serial concentration of compounds in technical triplicates. Plates are incubated at 37 °C and 5 % of CO2 for 48 h. 18-20 h before readout, the cells are stimulated with 5 pg / mL R848 (MedChem Express, cat. #HY-13740). At the end of the stimulation period, plates are spun down at 250 g for 5 min and supernatants are collected and analyzed for TNFa and IL-6 cytokine levels by ELISA (Invitrogen, cat. #88-7346-88 and #88-7066-88) according to the manufacturer’s instructions.

[1952] Treatment of THP1 cells with compounds is expected to result in reduced cytokine production.

[1953] 100k THP1-Dual hTLR9 cells (Invivogen, cat. #thpd-htlr9) per well are seeded in transparent or black 96-well 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), 2 mM L-Glutamine (Gibco, cat. #A2916801), and 25 mM HEPES (Gibco, cat. #11560496). These cells are treated with a serial concentration of compounds in technical triplicates and incubated for 48 h in 37 °C and 5 % of CO2. 18-20 h before readout, the cells are stimulated with 3-5 pM CpG-B (ODN2006, synthesized by IDT). At the end of the stimulation period, plates are spun down at 250 g for 5 min and supernatants are collected and analyzed for TNFa and IL-6 cytokine levels by ELISA (Invitrogen, cat. #88-7346-88 and #88-7066-88) according to the manufacturer’s instructions.

[1954] Treatment of THP1-Dual hTLR9 cells with compounds is expected to result in reduced cytokine production.Biological example 3: TNF-a Detection using the HTRF method

[1955] 200k THP1 cells (ATCC, cat. #TIB-202) per well are cultured in 96-well plates (Falcon, cat. #351172) in RPMI 1640 (ATCC, cat. #30-2001 ) containing 10 % HI FBS (Gibco, cat. #10082147) and 1X Pen-Strep (Gibco, cat. #15140122) and are treated with the compounds and concentrations thereof as indicated in Table BiolEx-2 below for 48 h. In the last 18-20 h, cells are stimulated with 5 pg / mL R848 (MedChem Express, cat. #HY-13740). At the end of the stimulation period, supernatants are collected and analyzed for TNFa cytokine levels using a Human TNFa Detection Kit (Revvity, cat. #2HTNFAPEG) using the HTRF (Homogeneous Time-Resolved Fluorescence) method in 384-well plates (Revvity, cat. #6008280) in technical triplicates, according to the manufacturer’s instructions.

[1956] Treatment of THP1 cells with compounds is expected to result in reduced cytokine production.In particular, the present invention relates to the following items:

[1957] 1. A compound of formula (I)

[1958]

[1959] or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, wherein

[1960] R1is thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or phenyl, each optionally substituted with one or more RS1; wherein each RS1is independently selected from -Hal, Ci.6alkyl, Ci.6haloalkyl, -S(Ci.6alkyl), C3.7cycloalkyl, -OfC^g alkyl), and -O(C-|.g haloalkyl);

[1961] R2

[1962]

[1963] is H;

[1964] A is

[1965] R3A

[1966] 1 RL1— L1RL2— N

[1967] ?

[1968]

[1969] \

[1970] R3B.

[1971] wherein the wavy line in each case marks the connection to the remainder of the molecule;

[1972] and wherein

[1973] L1is

[1974]

[1975] wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2;

[1976] and wherein

[1977] p in each case independently is 1 or 2;

[1978] q in each case independently is 0, 1, 2, or 3;

[1979] each Rxis independently -S(O)2-(C1-6alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6alkyl), -S(O)2-N(CI_6alkyi c^e alkyl), -(C1-6alkylene)-O(C1-6alkyl), -O-(C1-6alkylene)-O(C1-6alkyl), 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -0-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -CN, C1.2alkyl, C1.2haloalkyl, -O(C1.2alkyl), and -O(C1.2haloalkyl), and 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;

[1980] each Rzis independently -Hal, -CN, C1.2alkyl, C1.2haloalkyl, -(Ci.6alkylene)-OH, -OH, -O(C1.2alkyl), -O(C1.2haloalkyl), -S(O)2-(C1-6alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6alkyl), -S(O)2-N(C1-6alkyl)(C1-6alkyl), -(C-^ alkylene)-O(C.|.6alkyl), -O-fC^g alkylene)-O(C-|.6alkyl), 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -0-(3- to 7-membered cycloalkyl), -0-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is in-dependently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl), and 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;

[1981] Z1is CH2, CHRZ, C(RZ)2, NRN, O, S, S(=O), or S(=O)2;

[1982] wherein

[1983] RNis -H, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, -CO(C1-6alkyl), -CO(C1-6haloalkyl), -S(O)2-(C1-6alkyl), or -S(O)2-(C1-6haloalkyl), -(C1-2alkylene)-(3- to 7-membered cycloalkyl), -(C1-2alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-2alkylene)-phenyl, -(C0-2alkylene)-(5- or 6-membered heteroaryl), or -( C0.2alkylene)-(5- or 6-membered heteroaryl), 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, wherein the 3- to 7-membered cycloalkyl moiety in said -(C1-2alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(C1-2alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C0-2alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0-2alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2alkyl, C1-2haloalkyl;

[1984] and wherein

[1985] RL1is absent or Ci-2alkylene;

[1986] RL2is absent or Ci_2alkylene; and

[1987] wherein

[1988] R3Aand R3Bare each independently selected from -H, C1-5alkyl, -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C2-3alkylene)-O-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C2-3alkylene)-O-(3- to 7-membered heterocycloalkyl), -(C1-3alkylene)-phenyl, -(C2-3alkylene)-O-phenyl, -(C1-3alkylene)-(5- or 6-membered) heteroaryl, and -(C2.3 alkylene)-O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3, and 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;

[1989] provided that not both R3Aand R3Bare -H;

[1990] or R3Aand R3Btogether with the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more, same or different substituents RS3;

[1991] wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), C1-6alkyl, C1-6haloalkyl, -(C1-6alkylene)-CN, -(C1-6alkylene)-OH, -(C1-6alkylene)-NH(C1-6alkyl), -(C1-6alkylene)-N(C1-6alkyl)(C1-6alkyl), -O(C1-6alkyl), -O(C1-6haloalkyl), -(C1-6alkylene)-O(C1-6alkyl), -(C1-6alkylene)-S(C1-6alkyl), -CO(C1-6alkyl), -CO(3- to 7-membered cycloalkyl), -CO(3- to 7-membered heterocycloalkyl), -COOH, -COO(C1-6alkyl), -CO-NH2, -CO-NH(C1-6alkyl), -CO-N(C1-6alkyl)(C1-6alkyl), -NH-CO(C1-6alkyl), -N(C1-6alkyl)-CO(C1-6alkyl), -S(O)2-(C1-6alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6alkyl), -S(O)2-N(C1-6alkyl)(C1-6alkyl), -NH-S(O)2-(C1-6alkyl), -N(C1-6alkyl)-S(O)2-(C1-6alkyl), -(C0.3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3 alkylene)-phenyl, and -(C0.3alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0-3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.3alky-lene)-phenyl, and -(C0.3alkylene)-(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 -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(CQ.3 alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0.3alkylene)-(5- or 6-memberedheteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1.2alkyl, C-i-2 haloalkyl, -O(C1.2alkyl), and -O(C1.2haloalkyl);

[1992] or two RS3attached to the same carbon atom form =O; or, if attached to a heterocycloalkyl ring formed by R3Aand R3Btogether 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;

[1993] X1is CH or N;

[1994] X2is CH or N;

[1995] Y1is CRY1or N;

[1996] Y2is CRY2or N;

[1997] Y3is CRY3or N; and

[1998] Y4is CRY4or N;

[1999] wherein RY1, RY2, RY3, and RY4are each independently selected from -H, -CN, -Hal, -OH, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), -O(C1-6haloalkyl), and -(C1-6alkylene)-O(C1-6alkyl);

[2000] provided that if X1and X2are both CH, at least one of Y1, Y2, Y3, and Y4is N; and

[2001] provided that not more than three of X1, X2, Y1, Y2, Y3, and Y4are N.

[2002] 2. The compound of item 1, wherein R1is

[2003]

[2004] wherein the dashed line marks the connection to the remainder of the molecule.

[2005] 3. The compound of item 1 or 2, wherein RS1is -F, C1-6alkyl or -O(C1-6alkyl).

[2006] 4. The compound of any one of items 1 to 3, wherein R1is 4-ethoxyphenyl.

[2007] 5. The compound of any one of items 1 to 4, wherein

[2008] X1is CH or N;

[2009] X2is CH or N;

[2010] Y1is CH;

[2011] Y2is N, CH, CCI, or CF;

[2012] Y3is CH, CCI, or CF; and

[2013] Y4is CH;

[2014] provided that not both of X1and X2are CH.

[2015] 6. The compound of any one of items 1 to 5, wherein

[2016] X1is CH;

[2017] X2is N;

[2018] Y1is CH;

[2019] Y2is CH or CF;

[2020] Y3is CH or CF; and

[2021] Y4is CH;

[2022] or

[2023] X1is CH;

[2024] X2is N;Y1is CH;

[2025] Y2is N;

[2026] Y3is CH or CF; and

[2027] Y4is CH;

[2028] or

[2029] X1is N;

[2030] X2is N;

[2031] Y1is CH;

[2032] Y2is CH or CF;

[2033] Y3is CH or CF; and

[2034] Y4is CH.

[2035] 7. The compound of any one of items 1 to 6, wherein A is

[2036] R3A

[2037] 1 - RL1— L1- RL2— N

[2038] ?

[2039]

[2040] \

[2041] R3B

[2042] wherein the wavy line marks the connection to the remainder of the molecule;

[2043] and wherein

[2044] L1is

[2045] (RX)P, (RX)P, (RX)P, (RX)P,

[2046]

[2047] , or - wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2;

[2048] and wherein

[2049] p in each case independently is 1 or 2;

[2050] q in each case independently is 0, 1, or 2;

[2051] each Rxis independently -S(O)2-(C1.6alkyl), -(Ci_6alkylene)-O(C1.6alkyl), -O-(C1-6alkylene)-O(C1-6alkyl), -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or-0-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -CN, C1.2alkyl, C1.2haloalkyl, -0(0^2 alkyl), and -0(0^2 haloalkyl), and 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;

[2052] each Rzis independently -Hal, -CN, C1-2alkyl, C1-2haloalkyl, -(C1-6alkylene)-OH, -OH, -O(C1-2alkyl), -O(C1-2haloalkyl), -S(O)2-(C1-6alkyl), -(C1-6alkylene)-O(C1-6alkyl), -O-(C1-6alkylene)-O(C1-6alkyl), -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl), and 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; and

[2053] Z1is CH2, CHF, CF2, CHOH, CHOCH3, O, S(=O), or S(=O)2;

[2054] and wherein

[2055] RL1is absent; and

[2056] RL2is absent;

[2057] and wherein

[2058] R3Aand R3Bare each independently selected from -H, C-i.3 alkyl, -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C1.3 alkylene)-phenyl, and -(C1.3 alkylene)-(5- or 6-membered) heteroaryl, 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, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3;

[2059] provided that not both R3Aand R3Bare -H;

[2060] or R3Aand R3Btogether with the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more, same or different substituents RS3;

[2061] wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), C1-6alkyl, C1-6haloalkyl, -(C1-6alkylene)-OH, -(C1-6alkylene)-NH(C1-6alkyl), -(C1-6alkylene)-N(C1-6alkyl)(C1-6alkyl), -O(C1-6alkyl), -O(C1-6haloalkyl), -(C1-6alkylene)-O(C1-6alkyl), -CO(C1-6alkyl), -CO(3- to 7-membered cycloalkyl), -CO(3- to 7-membered heterocycloalkyl), -COOH, -COO(C1-6alkyl), -CO-NH2, -CO-NH(C1-6alkyl), -CO-N(C1-6alkyl)(C1-6alkyl), -S(O)2-(C1-6alkyl), -(C0.3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.3alkylene)-phenyl, and -(C0.3 alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0.3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3 alkylene)-(3-to 7-membered heterocycloalkyl), -(CQ.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-mem-bered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(C0.3 alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C0.3 alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0-3alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl).

[2062] 8. The compound of any one of items 1 to 7, wherein

[2063] L1is

[2064]

[2065] , or - wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the con-nection to RL2; and wherein p, q, Rx, and Rzare as defined in the preceding items.

[2066] 9. The compound of any one of items 1 to 8, wherein

[2067] R3Ais -H or C1.2alkyl, which is unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -OCH3, -CO(CH3), and -S(O)2-(CH3); andR3Bis selected from -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C1-3alkylene)-phenyl, and -(C1-3alkylene)-(5- or 6-membered) heteroaryl, 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, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3;

[2068] wherein each RS3is independently selected from -CN, -Hal, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), -O(C1-6haloalkyl), -(C1-6alkylene)-O(C1-6alkyl), -S(O)2-(C1-6alkyl), -(C0-3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.3alkylene)-phenyl, and -(C0.3alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3alkylene)-phenyl, and -(C0-3alkylene)-(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 -(C0-3alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(C0-3alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C0-3alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0-3alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl).

[2069] 10. The compound of any one of items 1 to 9, wherein the compound is a compound selected from the following compounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

[2070] F

[2071]

[2072]

[2073] NH

[2074]

[2075] 11. A pharmaceutical composition comprising the compound of any one of items 1 to 10 and at least one pharmaceutically acceptable carrier.

[2076] 12. The compound of any one of items 1 to 10 or the pharmaceutical composition of item 11 for use as a medicament.

[2077] 13. The compound of any one of items 1 to 10 or the pharmaceutical composition of item 11 for use in the treatment or prevention of an autoimmune disorder or inflammatory condition.

[2078] 14. The compound for use or the pharmaceutical composition for use of item 13, 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, Behget’s disease, myasthenia gravis, and ankylosing spondylitis, preferably wherein the autoimmune disorder is systemic lupus erythematosus, or wherein the inflammatory condition is 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 inflammation, and sarcoidosis, preferably wherein the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-de-pendent inflammation.

[2079] 15. The compound for use or the pharmaceutical composition for use of any of items 13 to 14, 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.

Claims

CLAIMS1. A compound of formula (I)or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, whereinR1is thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or phenyl, each optionally substituted with one or more RS1; wherein each RS1is independently selected from -Hal, Ci_6alkyl, Ci_6haloalkyl, -S(Ci.6alkyl), C3.7cycloalkyl, -O(Ci.6alkyl), and -O(C-|.6haloalkyl);R2is H;A isR3A| - RL1— L1- RL2— N?\R3B.wherein 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 RL2;and whereinp in each case independently is 1 or 2;q in each case independently is 0, 1, 2, or 3;each Rxis independently -S(O)2-(C1-6alkyl), -S(O)2-NH2, -S(O)2-NH(C1-6alkyl), -S(O)2-N(C1-6alkyl)(C1-6alkyl), -(C1-6alkylene)-O(C1-6alkyl), -O-(C1-6alkylene)-O(C1-6alkyl), 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -O-(3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -CN, C1-2alkyl, C1-2haloalkyl, -O(C1-2alkyl), and -O(C1-2haloalkyl), and 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;each Rzis independently -Hal, -CN, Ci.2alkyl, Ci.2haloalkyl, -(C-i.g alkylene)-OH, -OH, -O(Ci.2alkyl), -0(0^2 haloalkyl), -SfOHC^B alkyl), -S(O)2-NH2, -S(O)2-NH(Ci.g alkyl), -S(O)2-N(C.|.6alkyl)(Ci.6alkyl), -(C-i.g alkylene)-O(C-|_6alkyl), -O-(C-|.g alkylene)-O(C-|_6alkyl), 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -O-(3- to 7-membered cycloalkyl), -O-(3- to 7- membered heterocycloalkyl), -O-phenyl, or-0-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, C-|.2alkyl, C-|.2haloalkyl, -0(0^2 alkyl), and -0(0^2 haloalkyl), and 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;Z1is CH2, CHRZ, C(RZ)2, NRN, O, S, S(=O), or S(=O)2;whereinRNis -H, C-i-6 alkyl, Ci_6haloalkyl, C3.7cycloalkyl, -COfC^g alkyl), -COfC^g haloalkyl), -S(O)2-(Ci.6alkyl), or haloalkyl), -(C1.2alkylene)-(3- to 7-membered cycloalkyl), -( C1.2alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.2alkylene)-phenyl, -(C0.2alkylene)-(5- or 6-membered aryl), or -(C0.2alkylene)-(5- or e- membered heteroaryl), 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, wherein the 3- to 7-membered cycloalkyl moiety in said -(Ci_2alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(Ci_2alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -( C0.2alkylene)-phenyl, and the 5- or e- membered heteroaryl moiety in said -(C0.2alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, Ci_2alkyl, Ci_2haloalkyl; and whereinRL1is absent or Ci-2alkylene;RL2is absent or 0^2 alkylene;and whereinR3Aand R3Bare each independently selected from -H, C-,.5 alkyl, -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C2.3alkylene)-O-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), -(C2.3alkylene)-O-(3- to 7-membered heterocycloalkyl), -(Ci.3alkylene)-phenyl, -(C2.3alkylene)-O-phenyl, -(Ci.3alkylene)-(5- or e-membered) heteroaryl, and -(C2.3alkylene)-O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3, and 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;provided that not both R3Aand R3Bare -H;or R3Aand R3Btogether with the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more, same or different substituents RS3;wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NHfC^g alkyl), -NfC^g alkyl )(C-|_6alkyl), C-i.g alkyl, C-i-e haloalkyl, -(C-|.6alkylene)-CN, -(C-|.6alkylene)-OH, -(C-|.6alkyleneJ-NHfC^g alkyl), -(C^g alkyleneJ-NfC^g alkyl)(Ci.g alkyl), -©(C^g alkyl), -OfC^g haloalkyl), -(C^g alkylene)-O(Ci.6alkyl), -(C-i.g alkylene)-S(Ci.6alkyl), -COfC^g alkyl), -CO(3- to 7-membered cycloalkyl), -CO(3- to 7-membered heterocycloalkyl), -COOH, -COOfC^g alkyl), -CO-NH2, -CO-NHfC-i-g alkyl), -CO-N(Ci.g alkyi c^g alkyl), -NH-CO(Ci.g alkyl), -NfC-i.g alkylJ-COfC^g alkyl), -S(O)2-(C-i-g alkyl), -S(O)2-NH2, -S(O)2-NH(C1.g alkyl), -S(O)2-N(C1.g alkyi c^g alkyl), -NH-S(O)2-(C1.g alkyl), -NfC-i.g alkyl)-S(O)2-(Ci.g alkyl), -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0-3 alkylene)-phenyl, and -(C0.3alkylene)-(5- or 6-membered heteroaryl), wherein the aforementioned heterocycloalkyl and heteroaryl rings independently comprise one or more, same or different heteroatoms selectedfrom O, N, or S, wherein said N- and / or S-atoms are independently oxidized or non-oxidized, wherein in said alkylene moiety of said -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3-to 7-membered 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 -(C0.3alkylene)-(3-to 7-membered heterocycloalkyl), the phenyl in said -(C0.3alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0.3alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1.2alkyl, C1.2haloalkyl, -O(C1.2alkyl), and -O(C1.2haloalkyl);or two RS3attached to the same carbon atom form =O; or, if attached to a heterocycloalkyl ring formed by R3Aand R3Btogether 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;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_6alkyl, Ci_6haloalkyl, -0(0^6 alkyl), -O(C-|.6haloalkyl), and -(C-|.6alkyleneJ-OfC^g alkyl);provided that if X1and X2are both CH, at least one of Y1, Y2, Y3, and Y4is N; andprovided that not more than three of X1, X2, Y1, Y2, Y3, and Y4are 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 -F, C-i.g alkyl or -OfC^g alkyl), preferably ethoxy.

4. The compound of any one of claims 1 to 3, wherein R1is 4-ethoxyphenyl.

5. The compound of any one of claims 1 to 4, whereinX1is CH or N;X2is CH or N;Y1is CH;Y2is N, CH, CCI, or CF;Y3is CH, CCI, or CF; andY4is CH;provided that not both of X1and X2are CH.

6. The compound of any one of claims 1 to 5, whereinX1is CH;X2is N;Y1is CH;Y2is CH or CF;Y3is CH or CF; andY4is CH;orX1is CH;X2is N;Y1is CH;Y2is N;Y3is CH or CF; andY4is CH;orX1is N;X2is N;Y1is CH;Y2is CH or CF;Y3is CH or CF; andY4is CH.

7. The compound of any one of claims 1 to 6, wherein A isR3A- RL1— L1- RL2— l / R3Bwherein the wavy line marks the connection to the remainder of the molecule;and whereinL1is, or - wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2;and whereinp in each case independently is 1 or 2;q in each case independently is 0, 1, or 2;each Rxis independently -S(O)2-(C1.6alkyl), -(C-i.g alkylene)-O(Ci.6alkyl), -O-fC^g alkylene)-O(Ci.6alkyl), -O- (3- to 7-membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -O-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -CN, C1.2alkyl, Ci.2haloalkyl, -O(C1.2alkyl), and -O(C1.2haloalkyl), and wherein the aforementioned heterocycloalkyland 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;each Rzis independently -Hal, -CN, C-|_2alkyl, C-|_2haloalkyl, -(Ci.6alkylene)-OH, -OH, -O(Cp2alkyl), -O(Cp2haloalkyl), -S(O)2-(C1.6alkyl), -(Ci.6alkylene)-O(C-|_6alkyl), -O-(Cp6alkylene)-O(C-|_6alkyl), -O-(3- to 7- membered cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -O-phenyl, or -0-(5- or 6-membered heteroaryl), wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents selected from -Hal, Ci_2alkyl, C1.2haloalkyl, -O(C1.2alkyl), and -O(C1.2haloalkyl), and 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; andZ1is CH2, CHF, CF2, CHOH, CHOCH3, O, S(=O), or S(=O)2;and whereinRL1is absent; andRL2is absent;and whereinR3Aand R3Bare each independently selected from -H, C1.3 alkyl, -(C0.3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C-|.3alkylene)-phenyl, and -(Cp3alkylene)-(5- or 6-membered) heteroaryl, 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, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3;provided that not both R3Aand R3Bare -H;or R3Aand R3Btogether with the nitrogen atom to which they are attached form a heterocycloalkyl ring, optionally substituted with one or more, same or different substituents RS3;wherein each RS3is independently selected from -CN, -Hal, -OH, -NH2, -NH(Cp6alkyl), -N(Cp6alkyl )(C-|_6alkyl), Ci_6alkyl, C-i-e haloalkyl, -(Cpg alkylene)-OH, -(Cpg alkylene)-NH(C-|.6alkyl), -(Cpg alkylene)-N(C-|.6alkyl)(Ci_6alkyl), -OfCpg alkyl), -O(C-|.6haloalkyl), -(Cpg alkylene)-O(C-|.6alkyl), -CO(C-|.6alkyl), -CO(3- to 7-membered cycloalkyl), -CO(3- to 7-membered heterocycloalkyl), -COOH, -COO(Ci.6alkyl), -CO-NH2, -CO-NH(Ci.ealkyl), -CO-N(Ci.ealkyl)(Cp6alkyl), -S(O)2-(C1-6alkyl), -(C0.3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3 alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.3alkylene)-phenyl, and -(C0.3alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.3alkylene)-phenyl, and -(C0.3alkylene)-(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 -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C0.3alkylene)-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 independently selected from -Hal, Cp2alkyl, Cp2haloalkyl, -O(Cp2alkyl), and -O(Cp2haloalkyl).

8. The compound of any one of claims 1 to 7, whereinL1is'< (RX)P, or -wherein the dashed line in each case marks the connection to RL1, and the wavy line in each case marks the connection to RL2; and wherein p, q, Rx, and Rzare as defined in the preceding claims.

9. The compound of any one of claims 1 to 8, whereinR3Ais -H or C1-2alkyl, which is unsubstituted or substituted with one or more, same or different substituents selected from -Hal, -OCH3, -CO(CH3), and -S(O)2-(CH3); andR3Bis selected from -(C0.3 alkylene)-(3- to 7-membered cycloalkyl), -(C0.3 alkylene)-(3- to 7-membered heterocycloalkyl), -(0^3 alkylene)-phenyl, and -(C-|.3alkylene)-(5- or 6-membered) heteroaryl, 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, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents RS3;wherein each RS3is independently selected from -CN, -Hal, Ci_6alkyl, Ci_6haloalkyl, -O(C-|_6alkyl), -O(C-|.6haloalkyl), -(C-i-e alkylene)-O(Ci.6alkyl), -S(O)2-(C1.6alkyl), -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), -(C0.3alkylene)-phenyl, and -(C0.3alkylene)-(5- or 6-membered heteroaryl), 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, wherein in said alkylene moiety of said -(C0.3alkylene)-(3- to 7-membered cycloalkyl), -(C0.3alkylene)-(3- to 7-membered 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 -(C0.3alkylene)-(3- to 7-membered cycloalkyl), the 3- to 7-membered heterocycloalkyl moiety in said -(C0.3alkylene)-(3- to 7-membered heterocycloalkyl), the phenyl in said -(C0.3 alkylene)-phenyl, and the 5- or 6-membered heteroaryl moiety in said -(C0.3alkylene)-(5- or 6-membered heteroaryl) are each optionally substituted with one or more groups each independently selected from -Hal, C1.2alkyl, C1.2haloalkyl, -0(0^2 alkyl), and -0(0^2 haloalkyl).

10. The compound of any one of claims 1 to 9, wherein the compound is a compound selected from the following compounds or a stereoisomer, tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

11. The compound of any one of claims 1 to 9, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof:

12. The compound of any one of claims 1 to 9, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof:

13. The compound of any one of claims 1 to 9, wherein the compound is the following compound or a pharmaceuti-cally acceptable salt thereof:SNH14. The compound of any one of claims 1 to 9, wherein the compound is the following compound or a pharmaceuti-cally acceptable salt thereof:

15. The compound of any one of claims 1 to 9, wherein the compound is the following compound or a pharmaceuti-cally acceptable salt thereof:

16. The compound of any one of claims 1 to 9, wherein the compound is the following compound or a pharmaceuti-cally acceptable salt thereof:

17. The compound of any one of claims 1 to 9, wherein the compound is the following compound or a pharmaceuti-cally acceptable salt thereof:

18. The compound of any one of claims 1 to 9, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof:

19. The compound of any one of claims 1 to 9, wherein the compound is the following compound or a pharmaceuti-cally acceptable salt thereof:

20. The compound of any one of claims 1 to 9, wherein the compound is the following compound or a pharmaceutically acceptable salt thereof:

21. A pharmaceutical composition comprising the compound of any one of claims 1 to 20 and at least one pharmaceutically acceptable carrier.

22. The compound of any one of claims 1 to 20 or the pharmaceutical composition of claim 21 for use as a medicament.

23. The compound of any one of claims 1 to 20 or the pharmaceutical composition of claim 21 for use in the treatment or prevention of an autoimmune disorder or inflammatory condition.

24. The compound for use or the pharmaceutical composition for use of claim 23, 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, Behget’s disease, myasthenia gravis, and ankylosing spondylitis, preferably wherein the autoimmune disorder is systemic lupus erythematosus, or wherein the inflammatory condition is 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 inflammation, and sarcoidosis, preferably wherein the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-dependent inflammation.

25. The compound for use or the pharmaceutical composition for use of any of claims 23 to 24, 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.

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