Piperidine derivatives useful as GPR183 antagonists

Abstract

The disclosure relates to compounds of formula I, wherein A, B, and R1 have the meaning given in the specification, and pharmaceutically acceptable salts thereof. The compounds of formula (I) exhibit GPR183 antagonistic activity and are thus useful in the treatment or prevention of disorder, condition, or disease where GRP183 antagonist is indicated to be useful.

Description

[0001]

[0002] NEW PHARMACEUTICAL COMPOUNDS

[0003] FIELD OF THE INVENTION

[0004] The present disclosure relates to novel pharmacologically active compounds as well as to pharmaceutical compositions comprising them and to their use as GPR183 antagonists.

[0005] BACKGROUND OF THE INVENTION

[0006] G protein-coupled receptor 183 (GPR183) also known as Epstein-Barr virus-induced G-protein coupled receptor 2 (EBE) belongs to the G-protein coupled receptor (GPCR) superfamily of cellular integral membrane proteins involved in a broad range of signaling pathways and physiological functions. GPCRs are important targets for pharmaceutical intervention as approximately 30 % of medicines in clinical use function as agonists, antagonists or modulators of the GPCRs. GPR183 is one of the most up-regulated genes (>200 fold) in Epstein-Barr virus-infected Burkitt lymphoma cells. Following deorphanization of GPR183 by identifying 7 a, 25- dihydroxycholesterol as a potent and selective endogenous agonist of the receptor, the involvement of the receptor and ligand in cellular functions and physiological processes have been more extensively studied and revealed.

[0007] Intracellularly GPR183 has been shown to couple to Gi and inhibition of cyclic AMP and activation of ERK. Ligand-induced or constitutive GPR183 internalization is independent of P-arrestin whereas migration mediated by GPR183 is dependent on p- arrestin coupling.

[0008] The cryo-EM structures of GPR183-Gi signalling complex with its endogenous agonist 7a,25-OHC and that of an inactive GPR183 receptor bound to the inverse agonist GSK682753A have been revealed. Mutations within the oxysterol binding site and the Gai interface attenuated G protein signalling and abolished oxysterol- mediated cell migration indicating that G protein signalling is directly involved in the oxy sterol GPR183 pathway.

[0009] GPR183 has been shown to be most abundantly expressed by immune cells and tissue, with highest expression in B-lymphocytes, followed by T lymphocytes, NK- cells and lowest in monocytes. The lungs and the gastrointestinal tract also show comparably high expression levels. The expression pattern and the finding that 7a,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing GPR183 by directing cell migration in vitro and in vivo implicates a possibility for targeting the receptor for immunological indications and disorders.

[0010] Involvement of GPR183 in pain perception has been shown as acute intrathecal injection of the GPR183 ligand, 7a,25-OHC in naive mice induced dose-dependent allodynia. GPR183 expression was upregulated in the dorsal spinal cord after chronic constriction injury (CCI). Overexpression of the CH25H enzyme, that metabolizes cholesterol to the GPR183 agonist 7a,25-OHC, has been detected in the cartilage of human osteoarthritis patients. GPR183 expression in the central nervous system in human astrocytes and microglia, as well as the upregulation of GPR183 receptor and induction of allodynia by the endogenous GPR183 agonist in rodents implicates a potential for amelioration by GPR183 antagonists in pain indications.

[0011] Some compounds modulating the activity of GPR183 protein are known in the art. W02023066190 describes some heterocyclic compounds as GBR183 inhibitors. GPR183 antagonists for the treatment of pain are disclosed in US20210122750. WO2015048567 describes some spirocyclic EBI2 modulators, and WO2015048570 describes amide derivatives as EBI2 modulators.

[0012] SUMMARY OF THE INVENTION

[0013] An object of the present disclosure is to provide novel pharmacologically active compounds that act as antagonist to GPR183 receptor. Accordingly, an object of the present disclosure is to provide further compounds to be used as GPR183 antagonist in the treatment of diseases and conditions such as, but not limited to, chronic pain e.g. osteoarthritis, chronic low back pain, neuropathic pain and immune system diseases e.g. inflammatory bowel diseases e.g. Colitis and Chron's diseases, multiple sclerosis, rheumatoid arthritis, inflammatory pulmonary diseases e.g. asthma and psoriasis ameliorated by inhibition of GPR183 receptors. Furthermore, the pharmaceutical compositions comprising the presently disclosed compounds are also provided.

[0014] The novel GPR183 antagonists of the present disclosure have improved physicochemical properties and a more desirable pharmacokinetic profde.

[0015] DETAILED DESCRIPTION OF THE INVENTION

[0016] The present disclosure relates to novel compounds having the general formula I, wherein;

[0017] A is 9 to 10 membered fused bicyclic heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S;

[0018] Ri is hydrogen, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, halo(Ci- 3)alkyl, halo(Ci-3)alkoxy, (C3-e)cycloalkyl, or cyano, wherein said (C3-e)cycloalkyl is unsubstituted or substituted with 1 to 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci- 3)alkyl, and heteroaryl;

[0019] B is CH2R2, CHR3R4, NHRs, or NR6R7;

[0020] R2 is (C2-5)alkyl, halo(Ci-3)alkyl, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-5)alkyl, (C3- e)cycloalkyl, (C3-e)cycloalkyl(Ci-3)alkyl, heterocyclyl, heterocyclyl(Ci-3)alkyl, heteroaryl, heteroaryl(Ci-3)alkyl, or (Rs)2N-(Ci-3)alkyl, wherein said (C3-e)cycloalkyl, heterocyclyl, or heteroaryl as such or as part of another group is unsubstituted or substituted with 1 to 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-3)alkyl, and heteroaryl;

[0021] R3 is halogen, or (Ci-3)alkyl;

[0022] R4 is halogen, or (Ci-3)alkyl; or Rs and R4 form, together with the carbon atom to which they are attached, a (C3- e)cycloalkyl ring, heterocyclyl, or heteroaryl, wherein said (C3-e)cycloalkyl, heterocyclyl, or heteroaryl as such or as part of another group is unsubstituted or substituted with 1 to 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-3)alkyl, and heteroaryl; Rs is (C2-e)alkyl, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-e)alkyl, (C3-e)cycloalkyl, phenyl, phenyl(Ci-3)alkyl, bridged bicyclo(C5-s)alkyl, (C3-e)cycloalkyl(Ci-3)alkyl, heterocyclyl, heterocyclyl(Ci-3)alkyl, heteroaryl, heteroaryl(Ci-3)alkyl, (Ci-3)alkyl- NH(C=O)-(Ci-3)alkyl, or di(Ci-3)alkylphosphoryl(Ci-3)alkyl, wherein said (C3- e)cycloalkyl, phenyl, bridged bicyclo(C5-s)alkyl), heterocyclyl, or heteroaryl as such or as part of another group is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, (Ci- 3)alkoxy(Ci-3)alkyl, hydroxy(Ci-3)alkyl, and heteroaryl, and wherein said heteroaryl is unsubstituted or substituted with one substituent being (Ci-3)alkyl;

[0023] Re is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl;

[0024] R7 is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl;

[0025] Rs is (Ci-3)alkyl; or Re and R7 form, together with the nitrogen atom to which they are attached, heterocyclyl, bridged heterocyclyl, or heteroaryl wherein said heterocyclyl, bridged heterocyclyl, or heteroaryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from hydroxy, (Ci-3)alkyl, hydroxy(Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, (Ci-3)alkyl-NH-(C=O)-, (Ci-3)alkyl-(C=O)-NH-, oxo, and heteroaryl; or a pharmaceutically acceptable salt thereof; with the provisos that when Re and R7 form a pyrrolidinyl or piperidinyl ring, said ring is not unsubstituted;

[0026] R2 is not furanyl; when R3 and R4 form a heteroaryl, said heteroaryl is not 1 -methyl- lH-imidazol-2-yl, or 4-methyl-4H-l,2,4-triazol-3-yl; compound is not

[0027] (5 -fluorobenzo [b]thiophen-2-yl)(4-(( 1 -methylimidazolidin-2-yl)sulfonyl)piperidin- 1 - yl)methanone,

[0028] (5 -fluorobenzo [b]thiophen-2-yl)(4-((4-methyl- 1 ,2,4-triazolidin-3 - yl)sulfonyl)piperidin- 1 -yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(2-methylquinolin-8-yl)methanone, (5-fluorobenzo[b]thiophen-2-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone, (lH-indol-5-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone, (4-(isobutylsulfonyl)piperidin- 1 -yl)(quinolin-2-yl)methanone, (lH-indol-3-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone,

[0029] (4-(isobutylsulfonyl)piperidin-l-yl)(4-methylquinolin-6-yl)methanone,

[0030] ( lH-indol-2-yl)(4-(isobutylsulfonyl)piperidin- 1 -yl)methanone, benzofuran-2-yl(4-(isobutylsulfonyl)piperidin- 1 -yl)methanone, ( lH-indol-6-yl)(4-(isobutylsulfonyl)piperidin- 1 -yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(7-methoxybenzofuran-2-yl)methanone, (4-(isobutylsulfonyl)piperidin- 1 -yl)(6-methoxy- lH-indol-2-yl)methanone, 2-(7 -methoxybenzofuran-2-yl)-4-((4-methyl- 1 ,2,4-triazolidin-3 - yl)sulfonyl)piperidine- 1 -carbaldehyde,

[0031] (2-methylbenzo [d]thiazol-6-yl)(4-(( 1 -methylimidazolidin-2-yl)sulfonyl)piperidin- 1 - yl)methanone, benzo [d]thiazol-2-yl(4-(( 1 -methylimidazolidin-2-yl)sulfonyl)piperidin- 1 - yl)methanone, (2-ethylbenzo[d]thiazol-6-yl)(4-((4-methyl-l,2,4-triazolidin-3-yl)sulfonyl)piperidin- l-yl)methanone,

[0032] (4-(( 1 -methylimidazolidin-2-yl)sulfonyl)piperidin- 1 -yl)(quinoxalin-2-yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(quinoxalin-6-yl)methanone, (4-(isobutylsulfonyl)piperidin- 1 -yl)(7-methoxybenzofuran-2-yl)methanone, benzo [d]thiazol-2-yl(4-(isobutylsulfonyl)piperidin- 1 -yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(2-methylbenzo[d]thiazol-6-yl)methanone, (lH-benzo[d]imidazol-6-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone, (6-fluoro- lH-indazol-3-yl)(4-(isobutylsulfonyl)piperidin- 1 -yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(2-methylimidazo[l,2-a]pyridin-3-yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(quinoxalin-2-yl)methanone,

[0033] (2-ethylbenzo[d]thiazol-6-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone, or (4-(isobutylsulfonyl)piperidin- 1 -yl)(6-methoxy- lH-indol-2-yl)methanone .

[0034] In one embodiment the present disclosure relates to compounds of formula I, wherein;

[0035] A is 9 to 10 membered fused bicyclic heteroaryl containing 1 heteroatom independently selected from N, O, and S;

[0036] Ri is hydrogen, halogen, (Ci-3)alkyl, (Ci-3)alkoxy(Ci-3)alkyl, halo(Ci-3)alkyl, halo(Ci- 3)alkoxy, (C3-e)cycloalkyl, or cyano, wherein said (C3-e)cycloalkyl is unsubstituted or substituted with 1 to 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, and hydroxy(Ci-3)alkyl;

[0037] B is CH2R2, CHR3R4, NHRs, orNReR?;

[0038] R2 is (C2-5)alkyl, halo(Ci-3)alkyl, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-5)alkyl, (C3- e)cycloalkyl, (C3-e)cycloalkyl(Ci-3)alkyl, heterocyclyl, heterocyclyl(Ci-3)alkyl, or (Rs)2N-(Ci-3)alkyl, wherein said (C3-e)cycloalkyl, or heterocyclyl as such or as part of another group is unsubstituted or substituted with 1 to 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-3)alkyl, and heteroaryl;

[0039] R3 is halogen, or (Ci-3)alkyl;

[0040] R4 is halogen, or (Ci-3)alkyl; or R3 and R4 form, together with the carbon atom to which they are attached, a (C3- e)cycloalkyl ring, or heterocyclyl, wherein said (C3-e)cycloalkyl, or heterocyclyl as such or as part of another group is unsubstituted or substituted with 1 to 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkyl, (Ci- 3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-3)alkyl, and heteroaryl;

[0041] R5 is (C2-e)alkyl, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-e)alkyl, (C3-e)cycloalkyl, phenyl, phenyl(Ci-3)alkyl, bridged bicyclo(C5-s)alkyl, (C3-e)cycloalkyl(Ci-3)alkyl, heterocyclyl, heterocyclyl(Ci-3)alkyl, heteroaryl, heteroaryl(Ci-3)alkyl, (Ci-3)alkyl- NH(C=O)-(Ci-3)alkyl, or di(Ci-3)alkylphosphoryl(Ci-3)alkyl, wherein said (C3- e)cycloalkyl, phenyl, bridged bicyclo(C5-s)alkyl), heterocyclyl, or heteroaryl as such or as part of another group is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, (Ci-

[0042] 3)alkoxy(Ci-3)alkyl, hydroxy(Ci-3)alkyl, and heteroaryl, and wherein said heteroaryl is unsubstituted or substituted with one substituent being (Ci-3)alkyl;

[0043] Re is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl;

[0044] R? is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl;

[0045] Rs is (Ci-3)alkyl; or Re and R? form, together with the nitrogen atom to which they are attached, heterocyclyl, bridged heterocyclyl, or heteroaryl wherein said heterocyclyl, bridged heterocyclyl, or heteroaryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from hydroxy, (Ci-3)alkyl, hydroxy(Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, (Ci-3)alkyl-NH-(C=O)-, (Ci-3)alkyl-(C=O)-NH-, oxo, and heteroaryl; or a pharmaceutically acceptable salt thereof; with the proviso that the compound is not

[0046] (5 -fluorobenzo [b]thiophen-2-yl)(4-(( 1 -methylimidazolidin-2-yl)sulfonyl)piperidin- 1 - yl)methanone,

[0047] (5 -fluorobenzo [b]thiophen-2-yl)(4-((4-methyl- 1 ,2,4-triazolidin-3 - yl)sulfonyl)piperidin- 1 -yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(2-methylquinolin-8-yl)methanone, (5-fluorobenzo[b]thiophen-2-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone, (lH-indol-5-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone, (4-(isobutylsulfonyl)piperidin- 1 -yl)(quinolin-2-yl)methanone, (lH-indol-3-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(4-methylquinolin-6-yl)methanone, ( lH-indol-2-yl)(4-(isobutylsulfonyl)piperidin- 1 -yl)methanone, benzofuran-2-yl(4-(isobutylsulfonyl)piperidin- 1 -yl)methanone, or (lH-indol-6-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone.

[0048] In one embodiment the present disclosure relates to compounds of formula I, wherein ring A is any one of the following groups:

[0049] wherein atom marked with * is bonded to the parent molecular moiety.

[0050] In one embodiment the present disclosure relates to compounds of formula I, wherein ring A is any one of the following groups: wherein atom marked with * is bonded to the parent molecular moiety; and

[0051] Ri is halogen, (Ci-3)alkyl, halo(Ci-3)alkyl, halo(Ci-3)alkoxy, (C3-e)cycloalkyl, or cyano.

[0052] In one embodiment the present disclosure relates to compounds of formula I, wherein;

[0053] A is 9 to 10 membered fused bicyclic heteroaryl containing 1 heteroatom independently selected from N, O, and S;

[0054] Ri is hydrogen, halogen, (Ci-3)alkyl, halo(Ci-3)alkyl, halo(Ci-3)alkoxy, (C3- e)cycloalkyl, or cyano, wherein said (C3-e)cycloalkyl is unsubstituted;

[0055] B is CH2R2, CHR3R4, NHR5, or NR6R7;

[0056] R2 is (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-5)alkyl, (C3-e)cycloalkyl, heterocyclyl, heteroaryl(Ci-3)alkyl, or (Rs)2N-(Ci-3)alkyl, wherein said (C3-e)cycloalkyl, or heteroaryl as such or as part of another group is unsubstituted;

[0057] R3 is halogen, or (Ci-3)alkyl;

[0058] R4 is halogen, or (Ci-3)alkyl; or R3 and R4 form, together with the carbon atom to which they are attached, a (C3- e)cycloalkyl ring, or heterocyclyl, wherein said (C3-e)cycloalkyl or heterocyclyl as such or as part of another group is unsubstituted;

[0059] Rs is (C2-e)alkyl, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-e)alkyl, (C3-e)cycloalkyl, phenyl, phenyl(Ci-3)alkyl, bridged bicyclo(C5-s)alkyl, (C3-e)cycloalkyl(Ci-3)alkyl, heterocyclyl, heterocyclyl(Ci-3)alkyl, heteroaryl(Ci-3)alkyl, (Ci-3)alkyl-NH(C=O)- (Ci-3)alkyl, or di(Ci-3)alkylphosphoryl(Ci-3)alkyl, wherein said phenyl, bridged bicyclo(C5-s)alkyl, or heterocyclyl as such or as part of another group is unsubstituted, said heteroaryl as such or as part of another group is unsubstituted or substituted with 1 substituent being (Ci-3)alkyl, said (C3-e)cycloalkyl as such or as part of another group is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkoxy, and heteroaryl, and wherein said heteroaryl is unsubstituted or substituted with one substituent being (Ci- 3)alkyl;

[0060] Re is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl;

[0061] R7 is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl;

[0062] Rs is (Ci-3)alkyl; or Re and R7 form, together with the nitrogen atom to which they are attached, pyrrolidinyl, piperidinyl, morpholinyl, bicyclic heterocyclyl, or bridged heterocyclyl wherein said morpholinyl or bridged heterocyclyl is unsubstitued, said bicyclic heterocyclyl is unsubstituted or substituted with 1 substituent being oxo, said pyrrolidinyl, or piperidinyl is substituted with 1 or 2 substituent(s) independently selected from hydroxy, (Ci-3)alkyl, hydroxy(Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkyl-NH- (C=O)-, (Ci-3)alkyl-(C=O)-NH-, and heteroaryl; or a pharmaceutically acceptable salt thereof.

[0063] In one embodiment the present disclosure relates to compounds of formula I, wherein B is CH2R2, or CHR3R4.

[0064] In one embodiment the present disclosure relates to compounds of formula I wherein B is CH2R2.

[0065] In one embodiment the present disclosure relates to compounds of formula I, wherein B is CHR3R4

[0066] In one embodiment the present disclosure relates to compounds of formula I, wherein;

[0067] A is 9 to 10 membered fused bicyclic heteroaryl containing 1 heteroatom independently selected from N, O, and S;

[0068] Ri is hydrogen, halogen, (Ci-3)alkyl, halo(Ci-3)alkyl, halo(Ci-3)alkoxy, (C3- e)cycloalkyl, or cyano, wherein said (C3-e)cycloalkyl is unsubstituted;

[0069] B is CH2R2, or CHR3R4;

[0070] R2 is (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-5)alkyl, (C3-e)cycloalkyl, heterocyclyl, heteroaryl(Ci-3)alkyl, or (Rs)2N-(Ci-3)alkyl, wherein said (C3-e)cycloalkyl, or heteroaryl as such or as part of another group is unsubstituted;

[0071] R3 is halogen, or (Ci-3)alkyl;

[0072] R4 is halogen, or (Ci-3)alkyl; or R3 and R4 form, together with the carbon atom to which they are attached, a (C3- e)cycloalkyl ring, or heterocyclyl, wherein said (C3-e)cycloalkyl or heterocyclyl as such or as part of another group is unsubstituted; and

[0073] Rs is (Ci-3)alkyl; or a pharmaceutically acceptable salt thereof.

[0074] In one embodiment the present disclosure relates to compounds of formula I, wherein B is NHRs, or NR6R7.

[0075] In one embodiment the present disclosure relates to compounds of formula I, wherein B is NHRs.

[0076] In one embodiment the present disclosure relates to compounds of formula I, wherein B is NReR?.

[0077] In one embodiment the present disclosure relates to compounds of formula I, wherein;

[0078] A is 9 to 10 membered fused bicyclic heteroaryl containing 1 heteroatom independently selected from N, O, and S;

[0079] Ri is hydrogen, halogen, (Ci-3)alkyl, halo(Ci-3)alkyl, halo(Ci-3)alkoxy, (C3- e)cycloalkyl, or cyano, wherein said (C3-e)cycloalkyl is unsubstituted;

[0080] B is NHRs. or NReR

[0081] R5 is (C2-e)alkyl, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-e)alkyl, (C3-e)cycloalkyl, phenyl, phenyl(Ci-3)alkyl, bridged bicyclo(C5-s)alkyl, (C3-e)cycloalkyl(Ci-3)alkyl, heterocyclyl, heterocyclyl(Ci-3)alkyl, heteroaryl(Ci-3)alkyl, (Ci-3)alkyl-NH(C=O)- (Ci-3)alkyl, or di(Ci-3)alkylphosphoryl(Ci-3)alkyl, wherein said phenyl, bridged bicyclo(C5-s)alkyl, or heterocyclyl as such or as part of another group is unsubstituted, said heteroaryl as such or as part of another group is unsubstituted or substituted with 1 substituent being (Ci-3)alkyl, said (C3-e)cycloalkyl as such or as part of another group is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkoxy, and heteroaryl, and wherein said heteroaryl is unsubstituted or substituted with one substituent being (Ci- 3)alkyl;

[0082] Re is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl;

[0083] R7 is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl; or Re and R7 form, together with the nitrogen atom to which they are attached, pyrrolidinyl, piperidinyl, morpholinyl, bicyclic heterocyclyl, or bridged heterocyclyl wherein said morpholinyl or bridged heterocyclyl is unsubstitued, said bicyclic heterocyclyl is unsubstituted or substituted with 1 substituent being oxo, said pyrrolidinyl, or piperidinyl is substituted with 1 or 2 substituent(s) independently selected from hydroxy, (Ci-3)alkyl, hydroxy(Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkyl-NH-

[0084] (C=O)-, (Ci-3)alkyl-(C=O)-NH-, and heteroaryl; or a pharmaceutically acceptable salt thereof.

[0085] In one embodiment the present disclosure relates to compounds of formula I, wherein

[0086] Ri is hydrogen, halogen, or halo(Ci-3)alkyl;

[0087] B is NHRs:

[0088] R5 is (C2-e)alkyl, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-e)alkyl, (C3-6)cycloalkyl, or (C3- 6)cycloalkyl(Ci-3)alkyl, wherein said (C3-6)cycloalkyl as such or as part of another group is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from hydroxy, (Ci-3)alkoxy, or heteroaryl, and wherein said heteroaryl is unsubstituted or substituted with one substituent being (Ci-3)alkyl; or a pharmaceutically acceptable salt thereof.

[0089] In one embodiment the present disclosure relates to compounds of formula I, wherein the compound is;

[0090] 1 -( lH-indole-2-carbonyl)-N-phenylpiperidine-4-sulfonamide, l-(6-chlorobenzo[b]thiophene-2-carbonyl)-N-((l-hydroxycyclopropyl)methyl)- piperidine-4-sulfonamide, (S)-l-(5-chloro-lH-indole-2-carbonyl)-N-((tetrahydrofuran-2-yl)methyl)piperidine- 4-sulfonamide, (R)-l-(5-chloro-lH-indole-2-carbonyl)-N-((tetrahydrofuran-2-yl)methyl)piperidine- 4-sulfonamide, (7-chloroquinolin-3-yl)(4-((difluoromethyl)sulfonyl)piperidin-l-yl)methanone, (5-chloro-lH-indol-2-yl)(4-(((tetrahydrofuran-2-yl)methyl)sulfonyl)piperidin-l- yl)methanone,

[0091] 1 -(5-chloro- lH-indole-2-carbonyl)-N-(( 1 -methyl- lH-pyrazol-3-yl)methyl)- piperidine-4-sulfonamide,

[0092] (5 -chloro- lH-indol-2-yl)(4-((4-hydroxypiperidin- 1 -yl)sulfonyl)piperidin- 1 - yl)methanone, trans- 1 -(5-chloro- lH-indole-2-carbonyl)-N-(2 -hydroxy cyclopentyl)piperidine-4- sulfonamide, cis-l-(5-chloro-lH-indole-2-carbonyl)-N-(2-hydroxycyclopentyl)piperidine-4- sulfonamide,

[0093] (4-((2-(lH-pyrazol-5-yl)ethyl)sulfonyl)piperidin-l-yl)(7-chloroquinolin-3- yl)methanone,

[0094] (4-((6-azabicyclo[3.1.0]hexan-6-yl)sulfonyl)piperidin-l-yl)(5-chloro-lH-indol-2- yl)methanone,

[0095] (R)-(7-chloroquinolin-3-yl)(4-((3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)sulfonyl)- piperidin- 1 -yl)methanone,

[0096] (S)-(7-chloroquinolin-3-yl)(4-((3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)sulfonyl)- piperidin- 1 -yl)methanone,

[0097] 1 -(7 -chloroquinoline-3 -carbonyl)-N-( 1 -( 1 -methyl- lH-pyrazol-3 -yl)cyclopropyl)- piperidine-4-sulfonamide,

[0098] 1 -(7 -chloroquinoline-3 -carbonyl)-N-(( 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)- piperidine-4-sulfonamide,

[0099] (R)-(7 -chloroquinolin-3 -yl)(4-((3 -methoxypyrrolidin- 1 -yl)sulfonyl)piperidin- 1 - yl)methanone,

[0100] 7-(( 1 -(7 -chloroquinoline-3 -carbonyl)piperidin-4-yl)sulfonyl)-2,7- diazaspiro [4.4] nonan- 1 -one, l-(5-cyclopropylbenzo[b]thiophene-2-carbonyl)-N,N-dimethylpiperidine-4- sulfonamide,

[0101] N-(bicyclo[l .1. l]pentan-l-yl)-l-(5-fluoro-lH-indole-2-carbonyl)piperidine-4- sulfonamide,

[0102] (R)-l-(5-methyl-lH-indole-2-carbonyl)-N-((tetrahydrofuran-2-yl)methyl)piperidine- 4-sulfonamide,

[0103] (S)-l-(5-methyl-lH-indole-2-carbonyl)-N-((tetrahydrofuran-2-yl)methyl)piperidine- 4-sulfonamide,

[0104] N-(bicyclo[ 1.1. l]pentan- 1 -yl)- 1 -( lH-indole-2-carbonyl)piperidine-4-sulfonamide, (5-chloro-lH-indol-2-yl)(4-(isopropylsulfonyl)piperidin-l-yl)methanone, (5-chloro-lH-indol-2-yl)(4-((difluoromethyl)sulfonyl)piperidin-l-yl)methanone, l-(5-chloro-lH-indole-2-carbonyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide,

[0105] N-benzyl- 1 -( lH-indole-2-carbonyl)piperidine-4-sulfonamide, (4-(isopropylsulfonyl)piperidin-l-yl)(5-(trifluoromethyl)-lH-indol-2-yl)methanone, (4-((difluoromethyl)sulfonyl)piperidin-l-yl)(5-fluoro-lH-indol-2-yl)methanone, (4-((difluoromethyl)sulfonyl)piperidin- 1 -yl)(5-(trifluoromethyl)- lH-indol-2- yl)methanone, (4-((difluoromethyl)sulfonyl)piperidin-l-yl)(5-(trifluoromethoxy)-lH-indol-2- yl)methanone, (4-(isopropylsulfonyl)piperidin- 1 -yl)(5-(trifluoromethoxy)- lH-indol-2- yl)methanone, N-(2-methoxyethyl)-l-(5-(trifluoromethoxy)-lH-indole-2-carbonyl)piperidine-4- sulfonamide, l-(6-chlorobenzo[b]thiophene-2-carbonyl)-N-(2-methoxyethyl)piperidine-4- sulfonamide, l-(5-cyanobenzo[b]thiophene-2-carbonyl)-N-(2-methoxyethyl)piperidine-4- sulfonamide,

[0106] N-(2-methoxyethyl)-l-(5-(trifluoromethyl)-lH-indole-2-carbonyl)piperidine-4- sulfonamide,

[0107] (5 -chloro- lH-indol-2-yl)(4-((2-methoxyethyl)sulfonyl)piperidin-l-yl)methanone, N-(2-methoxyethyl)-N-methyl-l-(5-methyl-lH-indole-2-carbonyl)piperidine-4- sulfonamide, (4-((difluoromethyl)sulfonyl)piperidin-l-yl)(quinolin-6-yl)methanone, l-(6-cyanobenzo[b]thiophene-2-carbonyl)-N-(2-methoxyethyl)piperidine-4- sulfonamide,

[0108] N-( 1 -methoxypropan-2-yl)- 1 -(5-methyl- lH-indole-2-carbonyl)piperidine-4- sulfonamide, (6-chlorobenzo[b]thiophen-2-yl)(4-((2-methoxyethyl)sulfonyl)piperidin-l- yl)methanone, l-(6-chlorobenzo [b]thiophene-2-carbonyl)-N-(2 -hydroxy-2 -methylpropyl)piperidine- 4-sulfonamide, l-(6-chlorobenzo [b]thiophene-2-carbonyl)-N-(2 -hydroxy-2 -methylbutyl)piperidine- 4-sulfonamide,

[0109] 1-(7-chloroquinoline-3-carbonyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, N-(2-methoxyethyl)-l-(7-(trifluoromethyl)quinoline-3-carbonyl)piperidine-4- sulfonamide,

[0110] N-(2-methoxyethyl)-l-(2-(trifluoromethyl)quinoline-6-carbonyl)piperidine-4- sulfonamide, (4-((difluoromethyl)sulfonyl)piperidin-l-yl)(7-(trifluoromethyl)quinolin-3- yl)methanone,

[0111] (7-chloroquinolin-3 -yl)(4-(isopropylsulfonyl)piperidin- 1 -yl)methanone,

[0112] 2-((l-(5-chloro-lH-indole-2-carbonyl)piperidine)-4-sulfonamido)-N- methylacetamide,

[0113] N -(2-( IH-pyrazol- 1 -yl)ethyl)- 1 -(5-chloro- lH-indole-2-carbonyl)piperidine-4- sulfonamide, (4-(isopropylsulfonyl)piperidin- 1 -yl)(7-(trifluoromethyl)quinolin-3 -yl)methanone, l-(7-chloroquinoline-3-carbonyl)-N-(2-hydroxy-2-methylpropyl)piperidine-4- sulfonamide, (7-chloroquinolin-3-yl)(4-((3-methoxypropyl)sulfonyl)piperidin-l-yl)methanone, (S)-(4-((3 -( lH-pyrazol-5 -yl)pyrrolidin- 1 -yl)sulfonyl)piperidin- 1 -y 1) ( 5 -chloro- 1H- indol-2-yl)methanone,

[0114] (R)-(4-((3-( lH-pyrazol-5 -yl)pyrrolidin- 1 -yl)sulfonyl)piperidin- 1 -y 1) (5 -chloro- 1H- indol-2-yl)methanone, l-(5-chloro-lH-indole-2-carbonyl)-N-(2-hydroxy-2-methylpropyl)piperidine-4- sulfonamide, (4-((difluoromethyl)sulfonyl)piperidin-l-yl)(2-(trifluoromethyl)quinolin-6- yl)methanone,

[0115] (4-(isopropylsulfonyl)piperidin-l-yl)(2-(trifluoromethyl)quinolin-6-yl)methanone, N -(( lH-pyrazol-5 -yl)methyl)- 1 -(7-chloroquinoline-3 -carbonyl)piperidine-4- sulfonamide,

[0116] (5-chloro-lH-indol-2-yl)(4-((l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6- yl)sulfonyl)piperidin- 1 -yl)methanone,

[0117] (S)-(5-chloro- lH-indol-2-yl)(4-((3-hydroxypyrrolidin- 1 -yl)sulfonyl)piperidin- 1 - yl)methanone,

[0118] (R)-(5-chloro- lH-indol-2-yl)(4-((3-hydroxypyrrolidin- 1 -yl)sulfonyl)piperidin- 1 - yl)methanone, l-(7-chloroquinoline-3-carbonyl)-N-(isoxazol-3-ylmethyl)piperidine-4-sulfonamide, l-(7-chloroquinoline-3-carbonyl)-N-((l-methyl-lH-pyrazol-3-yl)methyl)piperidine-

[0119] 4-sulfonamide, l-(5-chloro-lH-indole-2-carbonyl)-N-(isoxazol-3-yhnethyl)piperidine-4- sulfonamide, l-(5-chloro-lH-indole-2-carbonyl)-N-(pyridazin-3-yhnethyl)piperidine-4- sulfonamide, l-(7-chloroquinoline-3-carbonyl)-N-((l-ethyl-lH-pyrazol-3-yl)methyl)piperidine-4- sulfonamide, l-(7-chloroquinoline-3-carbonyl)-N-(2-ethoxyethyl)piperidine-4-sulfonamide, (7-chloroquinolin-3-yl)(4-((3-hydroxy-3-methylpyrrolidin-l-yl)sulfonyl)piperidin-l- yl)methanone, l-(7-chloroquinoline-3-carbonyl)-N-((l-hydroxycyclopentyl)methyl)piperidine-4- sulfonamide, l-(7-chloroquinoline-3-carbonyl)-N-(pyridazin-3-yhnethyl)piperidine-4- sulfonamide,

[0120] (7-chloroquinolin-3 -yl)(4-(pentan-3 -ylsulfonyl)piperidin- 1 -yl)methanone, l-(7-chloroquinoline-3-carbonyl)-N-(3-methoxypropyl)piperidine-4-sulfonamide, (4-((3-methoxypropyl)sulfonyl)piperidin-l-yl)(2-(trifluoromethyl)quinolin-6- yl)methanone,

[0121] (5-chloro-lH-indol-2-yl)(4-((cyclopropylmethyl)sulfonyl)piperidin-l-yl)methanone, (5-chloro-lH-indol-2-yl)(4-(oxetan-3-ylsulfonyl)piperidin-l-yl)methanone, (5 -chloro- lH-indol-2-yl)(4-((3 -(dimethylamino)propyl)sulfonyl)piperidin- 1 - yl)methanone,

[0122] (5 -chloro- lH-indol-2-yl)(4-(cyclobutylsulfonyl)piperidin- 1 -yl)methanone, 1 -(7 -chloroquinoline-3 -carbonyl)-N-(3 -hydroxy-3 -methylbutyl)piperidine-4- sulfonamide, l-(7-chloroquinoline-3-carbonyl)-N-(4-hydroxy-4-methylpentyl)piperidine-4- sulfonamide, l-(5-chloro-lH-indole-2-carbonyl)-N-cyclopropylpiperidine-4-sulfonamide, l-(7-chloroquinoline-3-carbonyl)-N-cyclopropylpiperidine-4-sulfonamide, N-(l-((l-(5-chloro-lH-indole-2-carbonyl)piperidin-4-yl)sulfonyl)pyrrolidin-3- yl)acetamide, l-(7-chloroquinoline-3-carbonyl)-N-((l-hydroxycyclopropyl)methyl)piperidine-4- sulfonamide,

[0123] N-((lH-indazol-4-yl)methyl)-l-(7-chloroquinoline-3-carbonyl)piperidine-4- sulfonamide,

[0124] (5 -chloro- lH-indol-2-yl)(4-((3 -hydroxy-3 -methylbutyl)sulfonyl)piperidin-l- yl)methanone,

[0125] 1 -(5-chloro- lH-indole-2-carbonyl)-N-( 1 -hydroxypropan-2-yl)piperidine-4- sulfonamide,

[0126] N-butyl-l-(5-chloro-lH-indole-2-carbonyl)piperidine-4-sulfonamide, l-(5-chloro-lH-indole-2-carbonyl)-N-(3,3-difluorocyclobutyl)piperidine-4- sulfonamide, l-(5-methyl-lH-indole-2-carbonyl)-N-(tetrahydrofuran-3-yl)piperidine-4- sulfonamide, l-(7-chloroindolizine-2-carbonyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, (7-chloroindolizin-2-yl)(4-(isopropylsulfonyl)piperidin-l-yl)methanone, (5-chloro-lH-indol-2-yl)(4-(morpholinosulfonyl)piperidin-l-yl)methanone, (5-chloro-lH-indol-2-yl)(4-(pentan-3-ylsulfonyl)piperidin-l-yl)methanone, l-(7-chloroquinoline-3-carbonyl)-N-(pyrazin-2-ylmethyl)piperidine-4-sulfonamide, ( lH-indol-2-yl)(4-(isopropylsulfonyl)piperidin- 1 -yl)methanone,

[0127] N,N-dimethyl-l-(6-methylbenzofuran-2-carbonyl)piperidine-4-sulfonamide, l-(lH-indole-2-carbonyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, N-(2-methoxyethyl)-l-(5-methyl-lH-indole-2-carbonyl)piperidine-4-sulfonamide, l-(5-fluoro-lH-indole-2-carbonyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, (4-((difluoromethyl)sulfonyl)piperidin- 1 -yl)(6-methyl- lH-indol-2-yl)methanone, l-(5-chloro-lH-indole-2-carbonyl)-N-(oxetan-3-yl)piperidine-4-sulfonamide, (4-((2-azabicyclo[2.1. l]hexan-2-yl)sulfonyl)piperidin-l-yl)(5-methyl-lH-indol-2- yl)methanone, l-(5-chloro-lH-indole-2-carbonyl)-N-(3-methoxycyclobutyl)piperidine-4- sulfonamide,

[0128] (6-chloro- lH-indol-2-yl)(4-(isopropylsulfonyl)piperidin- 1 -yl)methanone, (6-fluoro-lH-indol-2-yl)(4-(isopropylsulfonyl)piperidin-l-yl)methanone,

[0129] 1 -(( 1 -(5-chloro- lH-indole-2-carbonyl)piperidin-4-yl)sulfonyl)-N-methylpiperidine- 4-carboxamide,

[0130] (5 -chloro- lH-indol-2-yl)(4-((3-methoxypropyl)sulfonyl)piperidin-l-yl)methanone, (6-chlorobenzo[b]thiophen-2-yl)(4-((3-methoxypropyl)sulfonyl)piperidin-l- yl)methanone, l-(5-chloro-lH-indole-2-carbonyl)-N-(2-(dimethylphosphoryl)ethyl)piperidine-4- sulfonamide,

[0131] N,N-dimethyl-l-(6-methylbenzo[b]thiophene-2-carbonyl)piperidine-4-sulfonamide, l-(5-chloro-lH-indole-2-carbonyl)-N,N-dimethylpiperidine-4-sulfonamide, N,N-dimethyl-l-(5-methylbenzofuran-2-carbonyl)piperidine-4-sulfonamide, N,N-dimethyl-l-(6-(trifluoromethyl)benzo[b]thiophene-2-carbonyl)piperidine-4- sulfonamide,

[0132] N,N-dimethyl-l-(5-(trifluoromethoxy)benzo[b]thiophene-2-carbonyl)piperidine-4- sulfonamide, l-(6-chlorobenzo[b]thiophene-2-carbonyl)-N,N-dimethylpiperidine-4-sulfonamide, (4-((difluoromethyl)sulfonyl)piperidin- 1 -yl)( lH-indol-2-yl)methanone, l-(5-chloro-lH-indole-2-carbonyl)-N-(2-methoxyethyl)-N-methylpiperidine-4- sulfonamide, or l-(5-chloro-lH-indole-2-carbonyl)-N,N-bis(2-methoxyethyl)piperidine-4- sulfonamide; or a pharmaceutically acceptable salt thereof.

[0133] In one embodiment the present disclosure relates to compounds of formula I, wherein the compound is

[0134] or a pharmaceutically acceptable salt thereof.

[0135] In one embodiment the present disclosure relates to compounds of formula I, wherein the compound is or a pharmaceutically acceptable salt thereof.

[0136] In one embodiment the present disclosure relates to compounds of formula I, wherein the compound is or a pharmaceutically acceptable salt thereof.

[0137] In one embodiment the present disclosure relates to compounds of formula I, wherein the compound is or a pharmaceutically acceptable salt thereof. In one embodiment the present disclosure relates to compounds of formula I, wherein the compound is

[0138] or a pharmaceutically acceptable salt thereof.

[0139] In one embodiment the present disclosure relates to compounds of formula I, wherein the compound is or a pharmaceutically acceptable salt thereof.

[0140] In one embodiment the present disclosure relates to compounds of formula I, wherein the compound is or a pharmaceutically acceptable salt thereof.

[0141] Unless otherwise specified, the terms employed herein have the meanings indicated below.

[0142] The term “at least one” employed in the meanings below refers to one or several. For example, the term “at least one fluorine” refers to one or several fluorines, for example three, two, or one fluorines.

[0143] The term “hydroxy”, as employed herein as such or as part of another group, refers to a -OH group.

[0144] The term “cyano”, as employed herein, refers to CN group.

[0145] The term “halo” or “halogen”, as employed herein as such or as part of another group, refers to fluorine, chlorine, bromine, or iodine.

[0146] The term “(Ci-3)alkyl”, as employed herein as such or as part of another group, refers to a saturated hydrocarbon group having a straight or branched moiety, containing 1, 2, or 3 carbon atom(s). Representative examples of (Ci-3)alkyl include methyl, ethyl, n-propyl, and isopropyl.

[0147] The term “(Ci-5)alkyl”, as employed herein as such or as part of another group, refers to a saturated hydrocarbon group having a straight or branched moiety, containing 1, 2, 3, 4, or 5 carbon atom(s). Representative examples of (Ci-5)alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tertbutyl, n-pentyl, iso-pentyl, and pentan-3 -yl.

[0148] The term “(Ci-6)alkyl”, as employed herein as such or as part of another group, refers to a saturated hydrocarbon group having a straight or branched moiety, containing 1,

[0149] 2, 3, 4, 5, or 6 carbon atom(s). Representative examples of (Ci-e)alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, pentan-3 -yl, and n-hexyl.

[0150] The term “(C2-5)alkyl”, as employed herein as such or as part of another group, refers to a saturated hydrocarbon group having a straight or branched moiety, containing 2,

[0151] 3, 4, or 5 carbon atom(s). Representative examples of (C2-5)alkyl include, but are not limited to, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n- pentyl, iso-pentyl, and pentan-3-yl.

[0152] The term “(C2-6)alkyl”, as employed herein as such or as part of another group, refers to a saturated hydrocarbon group having a straight or branched moiety, containing 2, 3, 4, 5 or 6 carbon atom(s). Representative examples of (C2-e)alkyl include, but are not limited to, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n- pentyl, iso-pentyl, pentan-3 -yl, and n-hexyl.

[0153] The term “(C3-6)alkyl”, as employed herein as such or as part of another group, refers to a saturated hydrocarbon group having a straight or branched moiety, containing 3,

[0154] 4, 5 or 6 carbon atom(s). Representative examples of (C3-e)alkyl include, but are not limited to, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso pentyl, pentan-3-yl, and n-hexyl.

[0155] The term “(Ci-3)alkoxy”, as employed herein as such or as part of another group, refers to an (Ci-3)alkyl group, as defined herein, bonded to an oxygen atom. Representative examples of (Ci-3)alkoxy include, but are not limited to, methoxy, ethoxy, and n-propoxy.

[0156] The term “(Ci-3)alkoxy(Ci-3)alkyl”, as employed herein, as such or as part of another group, refers to at least one (Ci-3)alkoxy group, as defined herein, bonded to an (Ci- 3)alkyl group, as defined herein. When there are several (Ci-3)alkoxy groups, the (Ci- 3)alkoxy groups can be attached to the same or different carbon atom and the (Ci- 3)alkoxy groups can be identical or different. Representative examples of (Ci- 3)alkoxy(Ci-3)alkyl include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl, 1 -methyl -2- propoxyethyl, 1 -methoxy- 1 -methylethyl, and 3 -methoxypropyl.

[0157] The term “hydroxy(Ci-6)alkyl” or “hydroxy(Ci-3)alkyl”, as employed herein as such or as part of another group, refers to at least one hydroxy group, as defined herein, bonded to an (Ci-e)alkyl or (Ci-3)alkyl group, as defined herein. When there are several hydroxy groups, the hydroxy groups can be attached to the same or different carbon atom. Representative examples ofhydroxy(Ci-6)alkyl or hydroxy(Ci-3)alkyl include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1 -hydroxyethyl, 3 -hydroxypropyl, 1 -hydroxypropyl, 1 -methyl- 1 -hydroxyethyl, 1 -methyl- 1- hydroxypropyl, 2 -hydroxy-2 -methylpropyl, 3 -hydroxy-3 -methylbutyl, 4-hydroxy-4- methylpentyl, and 2 -hydroxy-2 -methylbutyl.

[0158] The term “halo(Ci-3)alkyl”, as employed herein as such or as part of another group, refers to at least one halogen bonded to an (Ci-3)alkyl group, as defined herein. When there are several halogens, the halogens can be attached to the same or different carbon atom and the halogens can be identical or different. Representative examples of halo(Ci-3)alkyl include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 3 -bromopropyl, and 2-chloropropyl.

[0159] The term “halo(Ci-3)alkoxy”, as employed herein as such or as part of another group, refers to at least one halogen bonded to an (Ci-3)alkoxy group, as defined herein. When there are several halogens, the halogens can be attached to the same or different carbon atom and the halogens can be identical or different. Representative examples of halo(Ci-3)alkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 3- fluoropropoxy, and 3,3,3-trifluoropropoxy.

[0160] The term “di(Ci-3)alkylphosphoryl”, as employed herein as such or as part of another group, refers to two (Ci-3)alkyl groups, as defined herein, both appended to a P(=O) group.

[0161] The term “di(Ci-3)alkylphosphoryl(Ci-3)alkyl”, as employed herein as such or as part of another group, refers to a di(Ci-3)alkylphosphoryl group, as defined herein, bonded to an (Ci-3)alkyl group, as defined herein. The (Ci-3)alkyl groups can be identical or different. Representative examples of di(Ci-3)alkylphosphoryl(Ci-3)alkyl include, but are not limited to dimethylphosphorylethyl, dimethylphosphorylpropyl, and diethylphosphorylethyl.

[0162] The term “(C3-6)cycloalkyl”, as employed herein as such or as part of another group, refers to a saturated hydrocarbon group having cyclic moiety, containing 3, 4, 5, or 6 carbon atom(s). Representative examples of (C3-e)cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0163] The term “(C3-6)cycloalkyl(Ci-3)alkyl”, as employed herein, refers to a (C3-e)cyclo- alkyl group, as defined herein, bonded to an (Ci-3)alkyl group, as defined herein. Representative examples of (C3-e)cycloalkyl(Ci-3)alkyl include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, and cyclohexylethyl.

[0164] The term “phenyl(Ci-3)alkyl”, as employed herein, refers to a phenyl group bonded to an (Ci-3)alkyl group, as defined herein. Representative examples of phenyl(Ci- 3)alkyl include, but are not limited to, benzyl, phenylethyl, and phenylpropyl.

[0165] The term “bridged bicyclo(C5-8)alkyl”, as employed herein as such or as part of another group, refers to a saturated hydrocarbon group containing 5, 6, 7 or 8 carbon atom(s), having bicyclic moiety in which two non-adjacent carbon atoms are shared by both rings. The rings are connected by a bridge containing at least one atom. Representative examples of bridged bicyclo(C5-s)alkyl include, but are not limited to, bicyclo [l. l.l]pentanyl, bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl.

[0166] The term “heterocyclyl”, as employed herein as such or as part of another group, refers to a 4, 5, or 6 membered saturated or partially unsaturated monocyclic group containing 1, 2, or 3 ring heteroatom(s) each independently selected from N, O, and S, or to an 6, 7, 8, 9 or 10 membered saturated or partially unsaturated bicyclic group containing 1, 2 or 3 ring heteroatom(s) each independently selected from N, O, and S, wherein in the bicyclic ring system the rings can be fused sharing two adjacent ring atoms or the ring system can be spirocyclic sharing only one single atom. When the heterocyclyl group is an 6,7, 8, 9 or 10 membered partially unsaturated bicyclic group, one of the rings is optionally aromatic. Said heterocyclyl can be optionally substituted or unsubstituted. Unless otherwise noted, the heterocyclyl may be attached via any heteroatom or carbon atom of the ring, such that the result is a stable structure. Representative examples of heterocyclyl include, but are not limited to, imidazolidinyl, triazolidinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl morpholinyl, 6-azabicyclo[3.1.0]hexanyl, 2,7- diazaspiro[4.4]nonanyl, l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridinyl, and 2,3- dihydrobenzofuranyl .

[0167] The term “heteroaryl”, as employed herein as such or as part of another group, refers to a 5, 6 or 7 membered aromatic monocyclic group containing 1, 2, 3 or 4 ring heteroatom(s) each independently selected from N, O, and S or to an 8, 9 or 10 membered aromatic bicyclic group containing 1, 2, 3 or 4 ring heteroatom(s) each independently selected from N, O, and S. Said heteroaryl can be optionally substituted or unsubstituted. Unless otherwise noted, the heteroaryl may be attached via any heteroatom or carbon atom of the ring, such that the result is a stable structure. Representative examples of heteroaryl include, but are not limited to, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrrolyl, isoxazolyl, furanyl, thiophen- 1-yl, thiazolyl, phenylpiperidinyl, indoleyl, indazolyl, indolizinyl, benzothiophen-2-yl, benzofuranyl, and quinolinyl.

[0168] The term “heterocyclyl(Ci-3)alkyl”, as employed herein, refers to a heterocyclyl group, as defined herein, bonded to an (Ci-3)alkyl group, as defined herein. Representative examples of heterocyclyl(Ci-3)alkyl include, but are not limited to, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-ylethyl, tetrahydropyran-3-ylmethyl, and tetrahydropyran-3-ylethyl.

[0169] The term “heteroaryl(Ci-3)alkyl”, as employed herein, refers to a heteroaryl group, as defined herein, bonded to an (Ci-3)alkyl group, as defined herein. Representative examples of heterocyclyl(Ci-3)alkyl include, but are not limited to, pyrazol-3- ylmethyl, pyrazol-5-ylmethyl, pyrazol-5-ylethyl, pyrazol-l-ylethyl, l,2,4-triazol-3- ylmethyl, isoxazol-3-ylmethyl, pyridazin-3-ylmethyl, pyrazin-2-ylmethyl, and indazol-4-ylmethyl .

[0170] The term ’’bridged heterocyclyl”, as employed herein as such or as part of another group, refers to a bicyclic heterocyclyl, as defined herein, where two or more nonadj acent atoms within the ring structure are connected by one or more atoms, forming a bridge. Representative examples of bridged heterocyclyl include, but are not limited to, 2-azabicyclo[2.1.1]hexan-2-yl, and l,4-diazabicyclo[2.2.2]octan-4-yl.

[0171] The term “optionally substituted” means that the specific group is unsubstituted or substituted with one or more substituents. The substitution is meant to occur at any valency-allowed position on the compound, including the atom that is bonded to the parent molecular moiety, such that the result is a stable structure.

[0172] The abbreviation “GPR183” refers to G protein-coupled receptor 183, also known as EBI2 (Epstein-Barr virus-induced G-protein coupled receptor 2).

[0173] The expression “compounds of the present disclosure”, as employed herein, refers to the compounds of formula I, and the pharmaceutically acceptable salts thereof.

[0174] The “pharmaceutically acceptable salts” according to the present disclosure include therapeutically active, non-toxic, base and acid salt forms, which the compounds of formula I are able to form with both organic and inorganic bases and acids. Representative examples of pharmaceutically acceptable base addition salt forms, for example, metal or amine salts, include, but are not limited to, ammonium salts, lithium, sodium, potassium, calcium, magnesium, aluminum and zinc salts, salts with organic bases, such as N-methyl-D-glucamine, hydrabamine salts and salts with amino acids, such as arginine, lysine, and the like. Representative examples of pharmaceutically acceptable acid addition salts include, but are not limited to, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates, acetates, oxalates, fumarates, and succinates.

[0175] The present disclosure includes all the possible geometric isomers, for example cis and trans isomers, of the compounds of formula I, as well as all the possible optical isomers, such as diastereomers and enantiomers, of the compound of formula I. Furthermore, the present disclosure includes all the individual isomers and any mixtures thereof, such as racemic mixture. The individual isomers may be obtained using the corresponding isomeric forms of the starting materials or they may be separated after the preparation of the end compound according to conventional separation methods. For the separation of optical isomers, such as enantiomers, from the mixture thereof, conventional resolution methods, for example fractional crystallization or preparative chiral chromatography, may be used.

[0176] The following general abbreviations are used: NaOH = sodium hydroxide, EtOH = ethanol, Boc = tert-butyloxycarbonyl protecting group, H2O2 = hydrogen peroxide, MeOH = methanol, MeCN = acetonitrile, EtOAc = ethyl acetate, HATU = (1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro phosphate), DIPEA = N,N-disopropylethylamine, DMF = N,N- dimethylformamide, TEA = triethylamine, DCM = dichloromethane, HC1 = hydrochloric acid, NaHSCh = sodium bisulfite, H2O = water, DMSO-d6 = deuterated dimethyl sulfoxide, NaHCCh = sodiumbicarbonate, CO2 = carbon dioxide, NaCl = sodium chloride, KC1 = potassium chloride, MgCh = magnesium chloride, CaCh = calcium chloride, THF = tetrahydrofuran, DMSO = dimethyl sulfoxide, tBu = tertbutane, HEPES = 2-[4-(2-hydroxyethyl)piperazin-l-yl]ethanesulfonic acid, RT = room temperature, h = hour, eq = equivalent, aq = aqueous,1H NMR = proton nuclear magnetic resonance, s = singlet, d = doublet, t = triplet, m = multiplet, br s = broad singlet, br d = broad douplet, LC-MS = liquid chromatography - mass spectrometry, H = proton, M = molarity, SM = starting material, Int = intermediate, MHz = megahertz, mmol = millimole, g = gram, mg = milligram, ml= milliliter, pl = microliter, mM = millimolar, and pM = micromolar, and nM = nanomolar.

[0177] The present disclosure will be explained in more detail by the following examples. The examples are meant for illustrating purposes only and do not limit the scope of the invention defined in the claims. Various modifications and embodiments can be made without departing from the spirit and scope thereof. It will be appreciated that where typical or preferred experimental conditions (i.e., reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. The synthetic routes described below are meant to illustrate the preparation of the compounds of formula I and the preparation is by no means limited thereto, that is, there are also other possible synthetic methods which are within the general knowledge of a person skilled in the art.

[0178] The compounds of formula I may be converted, if desired, into their pharmaceutically acceptable salt form using methods known in the art.

[0179] 1H NMR spectra of the products were measured by a Bruker Avance III HD 400 MHz or Bruker Avance NEO 600 MHz NMR instruments. LC-MS analyses were performed using a Waters Acquity UPLC / MS with a Q detector.

[0180] The starting materials used in the processes herein are either commercially available or can be prepared via general synthetic routes.

[0181] The procedures for preparing the compounds of formula (I) are detailed below including the synthesis of various intermediates involved in process of preparing the compounds according to the present disclosure.

[0182] Preparation of the compounds of the present disclosure

[0183] General route 1 :

[0184] O

[0185] General route 2:

[0186] General procedures for sulfones:

[0187] Oxone or

[0188] General procedure A:

[0189] A mixture of tert-butyl 4-mercaptopiperidine-l -carboxylate (1 eq), alkyl halide (1- 1.1 eq), and 2 M NaOH (aq., 1-1.2 eq) in EtOH (0.2-0.5 M) was stirred (RT - 70°C) until the starting material was consumed. The product sulfide was obtained by acqueous work-up. Optionally the crude product was purified by column chromatography .

[0190] Following compounds were synthesized using General procedure A:

[0191] General procedure B 1 :

[0192] Sulfide (1 eq) was dissolved in MeOH- H2O (2: 1 - 1 : 1, 50-200 mM) and the solution was cooled in an ice bath. Oxone® (2.2 eq) was added. The resulting mixture was stirred (0 °C - RT) until the starting material was consumed. The product sulfone was obtained by acqueous work-up. Optionally the crude product was purified by column chromatograpy.

[0193] Following compounds were synthesized using General procedure Bl:

[0194] General procedure B2:

[0195] Sulfide (1 eq) and ammonium heptamolybdate tetrahydrate (0.03 eq) were dissolved in MeCN (100-400 mM) and the solution was cooled in an ice bath. H2O2 (30-50 % aq., 6 eq) was added drop wise. The resulting mixture was stirred (0°C - RT) until the starting material was consumed. The product sulfone was obtained by acqueous work-up (incl. NaHSCf wash). Optionally the crude product was purified by column chromatograpy.

[0196] Following compounds were synthesized using General procedure B2:

[0197] General procedure for sulfonamides

[0198] General Procedure C: A flask was charged with amine (or its salt) (1-1.5 eq.), TEA (2-3 eq.) or DIPEA (1.4-3eq.) and DCM or DMF (0.4-0.8 M). Then l-Boc-4-piperidinesulfonyl chloride (1 eq.) was added. Reaction was stirred at rt until completion. Mixture was diluted with DCM, washed with 1 M HC1, sat. NaHCCh . Organic phase was evaporated to dryness. Product was used as such or optionally purified by column chromatography. Following compounds were synthesized using General procedure C:

[0199]

[0200]

[0201] Deprotection

[0202] X = SO2R or SO2NR2X = SO2R or SO2N R2

[0203] General procedure D: The boc protected amine (1 eq) was dissolved in EtOAc (0.2 - 0.6 M). 3.7 - 4.3 M HCI in dioxane (8 - 10 eq) was added to the solution and the mixture was stirred in room temperature untill the starting material was consumed. The product HCI salt was filtered and washed with EtOAc or diethyl ether.

[0204] General procedure D2: The boc protected amine (1 eq) was dissolved in DCM (0. 1 - 0.6 M). Trifluoroacetic acid (8-10 eq) was added to the solution and the mixture was stirred in room temperature until the starting material was consumed. The reaction mixture was evaporated to dryness. Toluene was added to the residue and evaporated to dryness yielding the product TFA salt.

[0205] Following compounds were synthesized using General procedure D:

[0206]

[0207]

[0208]

[0209]

[0210]

[0211] Procedure for Int-123: tert-butyl 4-(N-(2-methoxyethyl)-N-methylsulfamoyl)- piperidine- 1 -carboxylate

[0212] A round bottomed flask was charged with tert-butyl 4-(N-(2-methoxyethyl)- sulfamoyl)piperidine- 1 -carboxylate (Int-53, 380 mg), cesium carbonate (576 mg) and dry DMSO (3.8 mL). Then iodomethane (0.11 mL) was added and reaction was stirred for 5 h. Reaction mixture was diluted with EtOAc (15 mL) and water (15 mL). Phases were separated and organic phase was evaporated onto celite. Reverse phase chromatography (Cl 8) gave 282 mg of tert-butyl 4-(N-(2-methoxyethyl)-N- methylsulfamoyl)piperidine-l -carboxylate as clear oil.

[0213] 'HNMR (400MHz, DMSO-de) 5: 4.02 (br d, 2H), 3.50-3.37 (m, 3H), 3.34-3.30 (m, 2H), 3.27 (s, 3H), 2.87 (s, 3H), 2.85-2.63 (m, 2H), 1.92 (br d, 2H), 1.50-1.35 (s, 11H); MS: m / z 281.3 [M-tBu+2H]+.

[0214] Procedure for Int-124: tert-butyl 4-((3-(methylcarbamoyl)pyrrolidin-l-yl)sulfonyl)- piperidine- 1 -carboxylate

[0215] Step 1: tert-butyl 4-((3-(methoxycarbonyl)pyrrolidin-l-yl)sulfonyl)piperidine-l- carboxylate

[0216] Synthesized using General procedure C from methyl pyrrolidine -3 -carboxylate (0.27 g), tert-butyl 4-(chlorosulfonyl)piperidine-l -carboxylate (0.50 g), and TEA (0.74 ml) in DCM (8 ml) giving 0.52 g of tert-butyl 4-((3 -(methoxy carbonyl)pyrrolidin-l- yl)sulfonyl)piperidine- 1 -carboxylate .

[0217] 'HNMR (400MHz, DMSO-de) 5: 4.02 (br d, 2H), 3.65 (s, 3H), 3.57-3.33 (m, 5H), 3.29-3.20 (m, 1H), 2.76 (br s, 2H), 2.21-2.01 (m, 2H), 1.98-1.89 (m, 2H), 1.52-1.37 (m, 11H). MS: m / z 375.3 [M-H]'.

[0218] Step 2: l-((l-(tert-butoxycarbonyl)piperidin-4-yl)sulfonyl)pyrrolidine-3-carboxylic acid

[0219] A round bottomed flask was charged with tert-butyl 4-((3- (methoxycarbonyl)pyrrolidin-l-yl)sulfonyl)piperidine-l -carboxylate (0.52 g), THF (4 ml), and water (2 ml). Lithium hydroxide monohydrate (0.17 g ) was added, and the mixture was stirred for 3 days at RT. The mixture was acidified with 1 M HC1 and extracted with EtOAc giving 0.47 g of l-((l-(tert-butoxycarbonyl)piperidin-4- yl)sulfonyl)pyrrolidine-3-carboxylic acid.

[0220] 'HNMR (400MHz, DMSO-de) 5: 12.56 (br s, 1H), 4.08-3.95 (m, 2H), 3.55-3.25 (m, 5H), 3.18-3.08 (m, 1H), 2.76 (br s, 2H), 2.19-2.00 (m, 2H), 1.98-1.89 (m, 2H), 1.52- 1.42 (m, 2H), 1.40 (s, 9H). MS: m / z 307.2 [M-t-Bu+H]+.

[0221] Step 3: tert-butyl 4-((3-(methylcarbamoyl)pyrrolidin-l-yl)sulfonyl)piperidine-l- carboxylate

[0222] A round bottomed flask was charged with l-((l-(tert-butoxycarbonyl)piperidin-4- yl)sulfonyl)pyrrolidine-3-carboxylic acid (0.47 g), methylamine hydrochloride (0.26 g), HATU (0.59 g), and DMF (5 ml). DIPEA was added and the resulting mixture was stirred for 18 h at RT. The mixture was diluted with EtOAc and washed with water, 1 M HC1, sat. NaHCCh solution, water, and brine. The organic phase was dried and evaporated giving 0.26 g of tert-butyl 4-((3-(methylcarbamoyl)pyrrolidin- 1 -yl)sulfonyl)piperidine- 1 -carboxylate.

[0223] 'HNMR (400MHz, DMSO-de) 5: 7.94 (q, 1H), 4.09-3.96 (m, 1H), 3.53-3.27 (m, 5H, overlapping water signal), 3.03-2.89 (m, 1H), 2.76 (br s, 2H), 2.59 (d, 3H), 2.11-1.90 (m, 5H), 1.52-1.42 (m, 2H), 1.40 (s, 9H). MS: m / z 2162 [M-Boc+H]+.

[0224] General procedure E: A flask was charged with acid (1.0 eq.), amine salt (1.0-1.2 eq), HATU (1.0-1.5 eq.), DMF or EtOAc (0.2-1.2 M). Then DIPEA or TEA (3-6 eq.) was added and mixture was stirred at rt until completion. Reaction was diluted with EtOAc and water or sat. NaHCO Phases were separated and organic phase was evaporated. Residue was purified with column chromatography to give amide coupling product. Following compounds were synthesized using General procedure E

[0225] General procedure F:

[0226] Amine or amine salt (1 eq), the carboxylic acid (1 eq) and triethylamine (3-5 eq) was weighed into a vial and dry DMF (0.1-0.5 M) was added. The mixture was flushed with nitrogen. 1-Propanephosphonic acid cyclic anhydride 50% in DMF (1.5-3 eq) was added dropwise. The mixture was stirred at room temperature until the starting material was consumed. The crude product was obtained by aqueous work-up. Optionally the residue was purified with column chromatography to give amide coupling product. Following compounds were synthesized using General procedure F:

[0227] Procedure for compound 123: l-(5-chloro-lH-indole-2-carbonyl)-N-(2- methoxyethyl)-N-methylpiperidine-4-sulfonamide A round botomed flask was charged with l-(5-chloro-lH-indole-2-carbonyl)-N-(2- methoxyethyl)piperidine-4-sulfonamide (Example 29, 55 mg), cesium carbonate (67 mg) and dry DMSO (1 ml). Then iodomethane (10 pl) was added and reaction was stirred for 2.5 h. Reaction mixture was diluted with EtOAc (5 ml) and water (5 ml). Phases were separated and organic phase was evaporated onto celite. Reverse phase chromatography (Cl 8) gave 15 mg of l-(5-chloro-lH-indole-2-carbonyl)-N-(2- methoxyethyl)-N-methylpiperidine-4-sulfonamide as white powder.

[0228] 'H NMR (400MHz, DMSO-de) 5: 11.82 (s, 1H), 7.66 (d, 1H), 7.43 (d, 1H), 7.19 (dd, 1H), 6.80 (br s, 1H), 4.50 (br d, 2H), 3.60 (t, 1H), 3.47 (t, 2H), 3.43-3.39 (m, 2H), 3.28 (s, 3H), 3.24-2.93 (m, 2H), 2.90 (s, 3H), 2.05 (br d, 2H), 1.72-1.54 (m, 2H); MS: m / z 414.3 [M+H]+.

[0229] Procedure for compound 124: l-(5-chloro-lH-indole-2-carbonyl)-N,N-bis(2- methoxyethyl)piperidine-4-sulfonamide

[0230] A round bottomed flask was charged with l-(5-chloro-lH-indole-2-carbonyl)-N-(2- methoxyethyl)piperidine-4-sulfonamide (Example 29, 100 mg), cesium carbonate (98 mg) and dry DMSO (1 ml). Then l-bromo-2 -methoxyethane (26 pl) was added and reaction was stirred for 4 h. Reaction mixture was diluted with EtOAc (5 ml) and water (5 ml). Phases were separated and organic phase was evaporated onto celite. Reverse phase chromatography (C18) gave 32 mg of l-(5-chloro-lH-indole-2- carbonyl)-N,N-bis(2-methoxyethyl)piperidine-4-sulfonamide as white powder. 'HNMR (400MHz, DMSO-de) 5: 11.80 (s, 1H), 7.66 (d, 1H), 7.43 (d, 1H), 7.19 (dd, 1H), 6.81 (s, 1H), 4.60-4.44 (m, 2H), 3.60 (tt, 1H), 3.51-3.44 (m, 4H), 3.44-3.38 (m, 4H), 3.28 (s, 6H), 3.21-2.87 (m, 2H), 2.13-1.99 (m, 2H), 1.73-1.51 (m, 2H); MS: m / z 458.2 [M+H]+.

[0231] As already mentioned hereinbefore, the compounds of formula I show interesting pharmacological properties, namely they exhibit antagonistic activity for GPR183 receptor. Said properties are demonstrated with the pharmacological test presented below.

[0232] EXPERIMENT 1: In vitro pharmacology

[0233] Human THP-1 monocyte-like cell line (ATCC) endogenously expressing human GPR183 receptors were used to study GPR183 pharmacology in vitro. Cells were maintained at 37°C in a 5 % CO2 95 % air atmosphere in RPMI-1640 medium (ATCC) supplemented with 10 % foetal bovine serum and 0.05 mM 2- mercaptoethanol .

[0234] Cells in suspension plated at a density of 22500 cells / well in 384-well plates were incubated with Calcium 6 Assay reagent (Molecular Devices, CA, USA) and compounds in the concentration range 0.04 nM - 1 pM diluted in Ringer buffer for 90 minutes at 37°C in the dark. Ringer buffer consisted of (in mM): 143 NaCl, 4 KC1, 1.2 MgCh, 1 CaCh, 5 glucose, 10 HEPES and (pH 7.4 adjusted with 1.0 M NaOH). IpM 7a25-dihydroxysterol was used as agonist and changes in intracellular calcium were monitored using FLIPRtetra (Molecular Devices, CA, USA) and displayed using Screen Works software. The samples were excited at 470-495 nm and emission was detected at 515-575 nm. All experiments were performed at 37°C. Baseline fluorescence minimum was subtracted from maximum for the calculation of in vitro antagonism pharmacology. The IC50 values were determined using a four- parameter logistic fit model (ActivityBase XE). The results are shown in Table 1.

[0235] Table 1. GPR183 antagonistic activity in vitro.

[0236] EXPERIMENT 2: In vivo efficacy

[0237] The efficacy of GPR183 antagonist compounds can be studied in a preclinical in vivo mono-iodoacetate (MIA) model of osteoarthritis pain in rats according to the method described by Combe et al., in Neuroscience Letters, 370 (2004).

[0238] The compounds of formula I exhibit GPR183 antagonistic activity. The present disclosure thus provides compounds for use as a medicament. Compounds for use in the treatment of disorder, condition, or disease where a GPR183 antagonist is indicated to be useful are also provided. Furthermore, a method for the treatment of disorder, condition, or disease where a GPR183 antagonist is indicated to be useful is provided. In said method an effective amount of at least one compound of formula I is administered to a mammal, such as human, in need of such treatment. The use of the compounds of formula I for the manufacture of a medicament for the treatment of disorder, condition, or disease where a GPR183 antagonist is indicated to be useful is also provided.

[0239] In one embodiment of the invention the aforementioned disorder, condition or disease where a GPR183 antagonist is indicated to be useful is chronic pain e.g. osteoarthritis, chronic low back pain, neuropathic pain and immune system diseases e.g. inflammatory bowel diseases e.g. Colitis and Chron's diseases, multiple sclerosis, rheumatoid arthritis, or inflammatory pulmonary diseases e.g. asthma and psoriasis ameliorated by inhibition of GPR183 receptors.

[0240] The compounds of the present disclosure can be administered, for example, enterally, topically, or parenterally by means of any pharmaceutical formulation useful for said administration and comprising at least one active compound of formula I in pharmaceutically acceptable and effective amounts together with pharmaceutically acceptable diluents, carriers and / or excipients known in the art. The manufacture of such pharmaceutical formulations is known in the art.

[0241] The therapeutic dose to be given to a subject in need of the treatment will vary depending on the compound being administered, the species, the age and the sex of the subject being treated, the particular condition being treated, as well as the route and method of administration, and is easily determined by a person skilled in the art. Accordingly, the typical dosage for oral administration is from 10 ng / kg to 100 mg / kg per day, and for parenteral administration from 1 ng / kg to 10 mg / kg for an adult mammal.

[0242] The compounds of the present disclosure are given to the subject as such or in combination with one or more other active ingredients, each in its own composition or some or all of the active ingredients combined in a single composition, and / or suitable pharmaceutical excipients. Suitable pharmaceutical excipients include conventionally used excipients and formulation aids, such as fdlers, binders, disintegrating agents, lubricants, solvents, gel forming agents, emulsifiers, stabilizers, colorants and / or preservatives.

[0243] The compounds of the present disclosure are formulated into dosage forms using commonly known pharmaceutical manufacturing methods. The dosage forms can be, for example, tablets, capsules, granules, suppositories, emulsions, suspensions or solutions. Depending on the route of administration and the galenic form, the amount of the active ingredient in a formulation can typically vary between 0.01 % and 100

[0244] % by weight.

[0245] A person skilled in the art will appreciate that the embodiments described herein can be modified without departing from the inventive concept. A person skilled in the art also understands that the present disclosure is not limited to the particular embodiments disclosed but is intended to also cover modifications of the embodiments that are within the scope of the present disclosure.

Claims

1. wherein;A is 9 to 10 membered fused bicyclic heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S;Ri is hydrogen, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, halo(Ci- 3)alkyl, halo(Ci-3)alkoxy, (C3-e)cycloalkyl, or cyano, wherein said (C3-e)cycloalkyl is unsubstituted or substituted with 1 to 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci- 3)alkyl, and heteroaryl;B is CH2R2, CHR3R4, NHRs, or NR6R7;R2 is (C2-5)alkyl, halo(Ci-3)alkyl, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-5)alkyl, (C3- e)cycloalkyl, (C3-e)cycloalkyl(Ci-3)alkyl, heterocyclyl, heterocyclyl(Ci-3)alkyl, heteroaryl, heteroaryl(Ci-3)alkyl, or (Rs)2N-(Ci-3)alkyl, wherein said (C3-e)cycloalkyl, heterocyclyl, or heteroaryl as such or as part of another group is unsubstituted or substituted with 1 to 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-3)alkyl, and heteroaryl;R3 is halogen, or (Ci-3)alkyl;R4 is halogen, or (Ci-3)alkyl; or R3 and R4 form, together with the carbon atom to which they are attached, a (C3- e)cycloalkyl ring, heterocyclyl, or heteroaryl, wherein said (C3-e)cycloalkyl, heterocyclyl, or heteroaryl as such or as part of another group is unsubstituted or substituted with 1 to 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-3)alkyl, and heteroaryl;R5 is (C2-e)alkyl, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-e)alkyl, (C3-e)cycloalkyl,phenyl, phenyl(Ci-3)alkyl, bridged bicyclo(C5-8)alkyl, (C3-6)cycloalkyl(Ci-3)alkyl, heterocyclyl, heterocyclyl(Ci-3)alkyl, heteroaryl, heteroaryl(Ci-3)alkyl, (Ci-3)alkyl- NH(C=O)-(Ci-3)alkyl, or di(Ci-3)alkylphosphoryl(Ci-3)alkyl, wherein said (C3- 6)cycloalkyl, phenyl, bridged bicyclo(C5-8)alkyl), heterocyclyl, or heteroaryl as such or as part of another group is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkyl, (Ci-3)alkoxy, (Ci- 3)alkoxy(Ci-3)alkyl, hydroxy(Ci-3)alkyl, and heteroaryl, and wherein said heteroaryl is unsubstituted or substituted with one substituent being (Ci-3)alkyl;Re is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl;R7 is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl;Rs is (Ci-3)alkyl; or Re and R7 form, together with the nitrogen atom to which they are attached, heterocyclyl, bridged heterocyclyl, or heteroaryl wherein said heterocyclyl, bridged heterocyclyl, or heteroaryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from hydroxy, (Ci-3)alkyl, hydroxy(Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkoxy(Ci-3)alkyl, (Ci-3)alkyl-NH-(C=O)-, (Ci-3)alkyl-(C=O)-NH-, oxo, and heteroaryl; or a pharmaceutically acceptable salt thereof; with the provisos that when Re and R7 form a pyrrolidinyl or piperidinyl ring, said ring is not unsubstituted;R2 is not furanyl; when R3 and R4 form a heteroaryl, said heteroaryl is not 1 -methyl- lH-imidazol-2-yl, or 4-methyl-4H-l,2,4-triazol-3-yl; compound is not (5-fluorobenzo[b]thiophen-2-yl)(4-((l-methylimidazolidin-2- yl)sulfonyl)piperidin- 1 -yl)methanone,(5 -fluorobenzo [b]thiophen-2-yl)(4-((4-methyl- 1 ,2,4-triazolidin-3 - yl)sulfonyl)piperidin- 1 -yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(2-methylquinolin-8-yl)methanone, (5-fluorobenzo[b]thiophen-2-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone, (lH-indol-5-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone, (4-(isobutylsulfonyl)piperidin- 1 -yl)(quinolin-2-yl)methanone,( I H-indol-3-yl)(4-(isobutylsiilfonyl)pipcridin-l-yl)mcthanonc. (4-(isobutylsulfonyl)piperidin-l-yl)(4-methylquinolin-6-yl)methanone, ( lH-indol-2-yl)(4-(isobutylsulfonyl)piperidin- 1 -yl)methanone, benzofuran-2-yl(4-(isobutylsulfonyl)piperidin- 1 -yl)methanone, ( lH-indol-6-yl)(4-(isobutylsulfonyl)piperidin- 1 -yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(7-methoxybenzofuran-2-yl)methanone, (4-(isobutylsulfonyl)piperidin- 1 -yl)(6-methoxy- lH-indol-2-yl)methanone, 2-(7 -methoxybenzofuran-2-yl)-4-((4-methyl- 1 ,2,4-triazolidin-3 - yl)sulfonyl)piperidine- 1 -carbaldehyde, (2-methylbenzo [d]thiazol-6-yl)(4-(( 1 -methylimidazolidin-2-yl)sulfonyl)piperidin- 1 - yl)methanone, benzo [d]thiazol-2-yl(4-(( 1 -methylimidazolidin-2-yl)sulfonyl)piperidin- 1 - yl)methanone, (2-ethylbenzo[d]thiazol-6-yl)(4-((4-methyl-l,2,4-triazolidin-3-yl)sulfonyl)piperidin- l-yl)methanone,(4-(( 1 -methylimidazolidin-2-yl)sulfonyl)piperidin- 1 -yl)(quinoxalin-2-yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(quinoxalin-6-yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(7-methoxybenzofuran-2-yl)methanone, benzo [d]thiazol-2-yl(4-(isobutylsulfonyl)piperidin- 1 -yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(2-methylbenzo[d]thiazol-6-yl)methanone, (lH-benzo[d]imidazol-6-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone, (6-fluoro- lH-indazol-3-yl)(4-(isobutylsulfonyl)piperidin- 1 -yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(2-methylimidazo[l,2-a]pyridin-3-yl)methanone, (4-(isobutylsulfonyl)piperidin-l-yl)(quinoxalin-2-yl)methanone, (2-ethylbenzo[d]thiazol-6-yl)(4-(isobutylsulfonyl)piperidin-l-yl)methanone, or (4-(isobutylsulfonyl)piperidin- 1 -yl)(6-methoxy- lH-indol-2-yl)methanone .

2. The compound according to claim 1, wherein A is any one of the following groups:wherein atom marked with * is bonded to the parent molecular moiety.

3. The compound according to any one of claims 1 or 2, wherein A is any one of the following groups:wherein atom marked with * is bonded to the parent molecular moiety; andRi is halogen, (Ci-3)alkyl, halo(Ci-3)alkyl, halo(Ci-3)alkoxy, (C3-e)cycloalkyl, or cyano.

4. The compound according to any one of claims 1 to 3, wherein; B is CH2R2, CHR3R4, NHRs, or NR6R7;R2 is (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-5)alkyl, (C3-e)cycloalkyl, heterocyclyl,heteroaryl(Ci-3)alkyl, or (Rs)2N-(Ci-3)alkyl, wherein said (C3-6)cycloalkyl, or heteroaryl as such or as part of another group is unsubstituted;R3 is halogen, or (Ci-3)alkyl;R4 is halogen, or (Ci-3)alkyl; or R3 and R4 form, together with the carbon atom to which they are attached, a (C3- e)cycloalkyl ring, or heterocyclyl, wherein said (C3-e)cycloalkyl or heterocyclyl as such or as part of another group is unsubstituted;R5 is (C2-e)alkyl, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-e)alkyl, (C3-e)cycloalkyl, phenyl, phenyl(Ci-3)alkyl, bridged bicyclo(C5-s)alkyl, (C3-e)cycloalkyl(Ci-3)alkyl, heterocyclyl, heterocyclyl(Ci-3)alkyl, heteroaryl(Ci-3)alkyl, (Ci-3)alkyl-NH(C=O)- (Ci-3)alkyl, or di(Ci-3)alkylphosphoryl(Ci-3)alkyl, wherein said phenyl, bridged bicyclo(C5-s)alkyl, or heterocyclyl as such or as part of another group is unsubstituted, said heteroaryl as such or as part of another group is unsubstituted or substituted with 1 substituent being (Ci-3)alkyl, said (C3-e)cycloalkyl as such or as part of another group is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkoxy, and heteroaryl, and wherein said heteroaryl is unsubstituted or substituted with one substituent being (Ci- 3)alkyl;Re is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl;R7 is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl;Rs is (Ci-3)alkyl; or Re and R7 form, together with the nitrogen atom to which they are attached, pyrrolidinyl, piperidinyl, morpholinyl, bicyclic heterocyclyl, or bridged heterocyclyl, wherein said morpholinyl or bridged heterocyclyl is unsubstitued, said bicyclic heterocyclyl is unsubstituted or substituted with 1 substituent being oxo, said pyrrolidinyl, or piperidinyl is substituted with 1 or 2 substituent(s) independently selected from hydroxy, (Ci-3)alkyl, hydroxy(Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkyl-NH- (C=O)-, (Ci-3)alkyl-(C=O)-NH-, and heteroaryl; or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 4, wherein B is CH2R2, orCHR3R4.

6. The compound according to claim 4 wherein;R2 is (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-5)alkyl, (C3-e)cycloalkyl, heterocyclyl, heteroaryl(Ci-3)alkyl, or (Rs)2N-(Ci-3)alkyl, wherein said (C3-e)cycloalkyl, or heteroaryl as such or as part of another group is unsubstituted;R3 is halogen, or (Ci-3)alkyl;R4 is halogen, or (Ci-3)alkyl; or R3 and R4 form, together with the carbon atom to which they are attached, a (C3- e)cycloalkyl ring, or heterocyclyl, wherein said (C3-e)cycloalkyl or heterocyclyl as such or as part of another group is unsubstituted; and Rs is (Ci-3)alkyl; or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 4, wherein B is NHR5, or NR6R7.

8. The compound according to claim 7, wherein;R5 is (C2-e)alkyl, (Ci-3)alkoxy(Ci-3)alkyl, hydroxy(Ci-e)alkyl, (C3-e)cycloalkyl, phenyl, phenyl(Ci-3)alkyl, bridged bicyclo(C5-s)alkyl, (C3-e)cycloalkyl(Ci-3)alkyl, heterocyclyl, heterocyclyl(Ci-3)alkyl, heteroaryl(Ci-3)alkyl, (Ci-3)alkyl-NH(C=O)- (Ci-3)alkyl, or di(Ci-3)alkylphosphoryl(Ci-3)alkyl, wherein said phenyl, bridged bicyclo(C5-s)alkyl, or heterocyclyl as such or as part of another group is unsubstituted, said heteroaryl as such or as part of another group is unsubstituted or substituted with 1 substituent being (Ci-3)alkyl, said (C3-e)cycloalkyl as such or as part of another group is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from hydroxy, halogen, (Ci-3)alkoxy, and heteroaryl, and wherein said heteroaryl is unsubstituted or substituted with one substituent being (Ci- 3)alkyl;Re is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl;R7 is (Ci-3)alkyl, or (Ci-3)alkoxy(Ci-3)alkyl; or Re and R7 form, together with the nitrogen atom to which they are attached, pyrrolidinyl, piperidinyl, morpholinyl, bicyclic heterocyclyl, or bridged heterocyclyl wherein said morpholinyl or bridged heterocyclyl is unsubstitued, said bicyclicheterocyclyl is unsubstituted or substituted with 1 substituent being oxo, said pyrrolidinyl, or piperidinyl is substituted with 1 or 2 substituent(s) independently selected from hydroxy, (Ci-3)alkyl, hydroxy(Ci-3)alkyl, (Ci-3)alkoxy, (Ci-3)alkyl-NH- (C=O)-, (Ci-3)alkyl-(C=O)-NH-, and heteroaryl; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, wherein the compound is; 1 -( lH-indole-2-carbonyl)-N-phenylpiperidine-4-sulfonamide, l-(6-chlorobenzo[b]thiophene-2-carbonyl)-N-((l-hydroxycyclopropyl)methyl)- piperidine-4-sulfonamide, (S)-l-(5-chloro-lH-indole-2-carbonyl)-N-((tetrahydrofuran-2-yl)methyl)piperidine- 4-sulfonamide, (R)-l-(5-chloro-lH-indole-2-carbonyl)-N-((tetrahydrofuran-2-yl)methyl)piperidine- 4-sulfonamide, (7-chloroquinolin-3-yl)(4-((difluoromethyl)sulfonyl)piperidin-l-yl)methanone, (5-chloro-lH-indol-2-yl)(4-(((tetrahydrofuran-2-yl)methyl)sulfonyl)piperidin-l- yl)methanone,1 -(5-chloro- lH-indole-2-carbonyl)-N-(( 1 -methyl- lH-pyrazol-3-yl)methyl)- piperidine-4-sulfonamide,(5 -chloro- lH-indol-2-yl)(4-((4-hydroxypiperidin- 1 -yl)sulfonyl)piperidin- 1 - yl)methanone, trans- 1 -(5-chloro- lH-indole-2-carbonyl)-N-(2 -hydroxy cyclopentyl)piperidine-4- sulfonamide, cis-l-(5-chloro-lH-indole-2-carbonyl)-N-(2-hydroxycyclopentyl)piperidine-4- sulfonamide, (4-((2-(lH-pyrazol-5-yl)ethyl)sulfonyl)piperidin-l-yl)(7-chloroquinolin-3- yl)methanone, (4-((6-azabicyclo[3.1.0]hexan-6-yl)sulfonyl)piperidin-l-yl)(5-chloro-lH-indol-2- yl)methanone,(R)-(7-chloroquinolin-3-yl)(4-((3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)sulfonyl)- piperidin- 1 -yl)methanone,(S)-(7-chloroquinolin-3-yl)(4-((3-(2-hydroxypropan-2-yl)pyrrolidin-l-yl)sulfonyl)-piperidin- 1 -yl)methanone,1 -(7 -chloroquinoline-3 -carbonyl)-N-( 1 -( 1 -methyl- lH-pyrazol-3 -yl)cyclopropyl)- piperidine-4-sulfonamide,1 -(7 -chloroquinoline-3 -carbonyl)-N-(( 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)- piperidine-4-sulfonamide,(R)-(7 -chloroquinolin-3 -yl)(4-((3 -methoxypyrrolidin- 1 -yl)sulfonyl)piperidin- 1 - yl)methanone,7-(( 1 -(7 -chloroquinoline-3 -carbonyl)piperidin-4-yl)sulfonyl)-2,7- diazaspiro [4.4] nonan- 1 -one, l-(5-cyclopropylbenzo[b]thiophene-2-carbonyl)-N,N-dimethylpiperidine-4- sulfonamide,N-(bicyclo[l .

1. l]pentan-l-yl)-l-(5-fluoro-lH-indole-2-carbonyl)piperidine-4- sulfonamide,(R)-l-(5-methyl-lH-indole-2-carbonyl)-N-((tetrahydrofuran-2-yl)methyl)piperidine- 4-sulfonamide,(S)-l-(5-methyl-lH-indole-2-carbonyl)-N-((tetrahydrofuran-2-yl)methyl)piperidine- 4-sulfonamide,N-(bicyclo[ 1.

1. l]pentan- 1 -yl)- 1 -( lH-indole-2-carbonyl)piperidine-4-sulfonamide, (5-chloro-lH-indol-2-yl)(4-(isopropylsulfonyl)piperidin-l-yl)methanone, (5-chloro-lH-indol-2-yl)(4-((difluoromethyl)sulfonyl)piperidin-l-yl)methanone, l-(5-chloro-lH-indole-2-carbonyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, N-benzyl- 1 -( lH-indole-2-carbonyl)piperidine-4-sulfonamide, (4-(isopropylsulfonyl)piperidin-l-yl)(5-(trifluoromethyl)-lH-indol-2-yl)methanone, (4-((difluoromethyl)sulfonyl)piperidin-l-yl)(5-fluoro-lH-indol-2-yl)methanone, (4-((difluoromethyl)sulfonyl)piperidin- 1 -yl)(5-(trifluoromethyl)- lH-indol-2- yl)methanone, (4-((difluoromethyl)sulfonyl)piperidin-l-yl)(5-(trifluoromethoxy)-lH-indol-2- yl)methanone, (4-(isopropylsulfonyl)piperidin- 1 -yl)(5-(trifluoromethoxy)- lH-indol-2- yl)methanone, N-(2-methoxyethyl)-l-(5-(trifluoromethoxy)-lH-indole-2-carbonyl)piperidine-4-sulfonamide, l-(6-chlorobenzo[b]thiophene-2-carbonyl)-N-(2-methoxyethyl)piperidine-4- sulfonamide, l-(5-cyanobenzo[b]thiophene-2-carbonyl)-N-(2-methoxyethyl)piperidine-4- sulfonamide,N-(2-methoxyethyl)-l-(5-(trifluoromethyl)-lH-indole-2-carbonyl)piperidine-4- sulfonamide,(5 -chloro- lH-indol-2-yl)(4-((2-methoxyethyl)sulfonyl)piperidin-l-yl)methanone, N-(2-methoxyethyl)-N-methyl-l-(5-methyl-lH-indole-2-carbonyl)piperidine-4- sulfonamide, (4-((difluoromethyl)sulfonyl)piperidin-l-yl)(quinolin-6-yl)methanone, l-(6-cyanobenzo[b]thiophene-2-carbonyl)-N-(2-methoxyethyl)piperidine-4- sulfonamide,N-( 1 -methoxypropan-2-yl)- 1 -(5-methyl- lH-indole-2-carbonyl)piperidine-4- sulfonamide, (6-chlorobenzo[b]thiophen-2-yl)(4-((2-methoxyethyl)sulfonyl)piperidin-l- yl)methanone, l-(6-chlorobenzo [b]thiophene-2-carbonyl)-N-(2 -hydroxy-2 -methylpropyl)piperidine- 4-sulfonamide, l-(6-chlorobenzo [b]thiophene-2-carbonyl)-N-(2 -hydroxy-2 -methylbutyl)piperidine- 4-sulfonamide,1-(7-chloroquinoline-3-carbonyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, N-(2-methoxyethyl)-l-(7-(trifluoromethyl)quinoline-3-carbonyl)piperidine-4- sulfonamide,N-(2-methoxyethyl)-l-(2-(trifluoromethyl)quinoline-6-carbonyl)piperidine-4- sulfonamide, (4-((difluoromethyl)sulfonyl)piperidin-l-yl)(7-(trifluoromethyl)quinolin-3- yl)methanone, (7-chloroquinolin-3 -yl)(4-(isopropylsulfonyl)piperidin- 1 -yl)methanone,2-((l-(5-chloro-lH-indole-2-carbonyl)piperidine)-4-sulfonamido)-N- methylacetamide,N -(2-( IH-pyrazol- 1 -yl)ethyl)- 1 -(5-chloro- lH-indole-2-carbonyl)piperidine-4- sulfonamide, (4-(isopropylsulfonyl)piperidin- 1 -yl)(7-(trifluoromethyl)quinolin-3 -yl)methanone, l-(7-chloroquinoline-3-carbonyl)-N-(2-hydroxy-2-methylpropyl)piperidine-4- sulfonamide, (7-chloroquinolin-3-yl)(4-((3-methoxypropyl)sulfonyl)piperidin-l-yl)methanone, (S)-(4-((3 -( lH-pyrazol-5 -yl)pyrrolidin- 1 -yl)sulfonyl)piperidin- 1 -y 1) ( 5 -chloro- 1H- indol-2-yl)methanone,(R)-(4-((3-( lH-pyrazol-5 -yl)pyrrolidin- 1 -yl)sulfonyl)piperidin- 1 -y 1) (5 -chloro- 1H- indol-2-yl)methanone, l-(5-chloro-lH-indole-2-carbonyl)-N-(2-hydroxy-2-methylpropyl)piperidine-4- sulfonamide, (4-((difluoromethyl)sulfonyl)piperidin-l-yl)(2-(trifluoromethyl)quinolin-6- yl)methanone, (4-(isopropylsulfonyl)piperidin-l-yl)(2-(trifluoromethyl)quinolin-6-yl)methanone, N -(( lH-pyrazol-5 -yl)methyl)- 1 -(7-chloroquinoline-3 -carbonyl)piperidine-4- sulfonamide, (5-chloro-lH-indol-2-yl)(4-((l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6- yl)sulfonyl)piperidin- 1 -yl)methanone,(S)-(5-chloro- lH-indol-2-yl)(4-((3-hydroxypyrrolidin- 1 -yl)sulfonyl)piperidin- 1 - yl)methanone,(R)-(5-chloro- lH-indol-2-yl)(4-((3-hydroxypyrrolidin- 1 -yl)sulfonyl)piperidin- 1 - yl)methanone, l-(7-chloroquinoline-3-carbonyl)-N-(isoxazol-3-ylmethyl)piperidine-4-sulfonamide, l-(7-chloroquinoline-3-carbonyl)-N-((l-methyl-lH-pyrazol-3-yl)methyl)piperidine- 4-sulfonamide, l-(5-chloro-lH-indole-2-carbonyl)-N-(isoxazol-3-ylmethyl)piperidine-4- sulfonamide, l-(5-chloro-lH-indole-2-carbonyl)-N-(pyridazin-3-ylmethyl)piperidine-4- sulfonamide, l-(7-chloroquinoline-3-carbonyl)-N-((l-ethyl-lH-pyrazol-3-yl)methyl)piperidine-4-sulfonamide, l-(7-chloroquinoline-3-carbonyl)-N-(2-ethoxyethyl)piperidine-4-sulfonamide, (7-chloroquinolin-3-yl)(4-((3-hydroxy-3-methylpyrrolidin-l-yl)sulfonyl)piperidin-l- yl)methanone, l-(7-chloroquinoline-3-carbonyl)-N-((l-hydroxycyclopentyl)methyl)piperidine-4- sulfonamide, l-(7-chloroquinoline-3-carbonyl)-N-(pyridazin-3-yhnethyl)piperidine-4- sulfonamide,(7-chloroquinolin-3 -yl)(4-(pentan-3 -ylsulfonyl)piperidin- 1 -yl)methanone, l-(7-chloroquinoline-3-carbonyl)-N-(3-methoxypropyl)piperidine-4-sulfonamide, (4-((3-methoxypropyl)sulfonyl)piperidin-l-yl)(2-(trifluoromethyl)quinolin-6- yl)methanone,(5-chloro-lH-indol-2-yl)(4-((cyclopropylmethyl)sulfonyl)piperidin-l-yl)methanone, (5-chloro-lH-indol-2-yl)(4-(oxetan-3-ylsulfonyl)piperidin-l-yl)methanone, (5 -chloro- lH-indol-2-yl)(4-((3 -(dimethylamino)propyl)sulfonyl)piperidin- 1 - yl)methanone,(5 -chloro- lH-indol-2-yl)(4-(cyclobutylsulfonyl)piperidin- 1 -yl)methanone, 1 -(7 -chloroquinoline-3 -carbonyl)-N-(3 -hydroxy-3 -methylbutyl)piperidine-4- sulfonamide, l-(7-chloroquinoline-3-carbonyl)-N-(4-hydroxy-4-methylpentyl)piperidine-4- sulfonamide, l-(5-chloro-lH-indole-2-carbonyl)-N-cyclopropylpiperidine-4-sulfonamide, l-(7-chloroquinoline-3-carbonyl)-N-cyclopropylpiperidine-4-sulfonamide, N-(l-((l-(5-chloro-lH-indole-2-carbonyl)piperidin-4-yl)sulfonyl)pyrrolidin-3- yl)acetamide, l-(7-chloroquinoline-3-carbonyl)-N-((l-hydroxycyclopropyl)methyl)piperidine-4- sulfonamide,N-((lH-indazol-4-yl)methyl)-l-(7-chloroquinoline-3-carbonyl)piperidine-4- sulfonamide,(5 -chloro- lH-indol-2-yl)(4-((3 -hydroxy-3 -methylbutyl)sulfonyl)piperidin-l- yl)methanone,1 -(5-chloro- lH-indole-2-carbonyl)-N-( 1 -hydroxypropan-2-yl)piperidine-4- sulfonamide,N-butyl-l-(5-chloro-lH-indole-2-carbonyl)piperidine-4-sulfonamide, l-(5-chloro-lH-indole-2-carbonyl)-N-(3,3-difluorocyclobutyl)piperidine-4- sulfonamide, l-(5-methyl-lH-indole-2-carbonyl)-N-(tetrahydrofuran-3-yl)piperidine-4- sulfonamide, l-(7-chloroindolizine-2-carbonyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, (7-chloroindolizin-2-yl)(4-(isopropylsulfonyl)piperidin-l-yl)methanone, (5-chloro-lH-indol-2-yl)(4-(morpholinosulfonyl)piperidin-l-yl)methanone, (5-chloro-lH-indol-2-yl)(4-(pentan-3-ylsulfonyl)piperidin-l-yl)methanone, l-(7-chloroquinoline-3-carbonyl)-N-(pyrazin-2-ylmethyl)piperidine-4-sulfonamide, ( lH-indol-2-yl)(4-(isopropylsulfonyl)piperidin- 1 -yl)methanone,N,N-dimethyl-l-(6-methylbenzofuran-2-carbonyl)piperidine-4-sulfonamide, l-(lH-indole-2-carbonyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, N-(2-methoxyethyl)-l-(5-methyl-lH-indole-2-carbonyl)piperidine-4-sulfonamide, l-(5-fluoro-lH-indole-2-carbonyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, (4-((difluoromethyl)sulfonyl)piperidin- 1 -yl)(6-methyl- lH-indol-2-yl)methanone, l-(5-chloro-lH-indole-2-carbonyl)-N-(oxetan-3-yl)piperidine-4-sulfonamide, (4-((2-azabicyclo[2.

1. l]hexan-2-yl)sulfonyl)piperidin-l-yl)(5-methyl-lH-indol-2- yl)methanone, l-(5-chloro-lH-indole-2-carbonyl)-N-(3-methoxycyclobutyl)piperidine-4- sulfonamide,(6-chloro- lH-indol-2-yl)(4-(isopropylsulfonyl)piperidin- 1 -yl)methanone, (6-fluoro-lH-indol-2-yl)(4-(isopropylsulfonyl)piperidin-l-yl)methanone,1 -(( 1 -(5-chloro- lH-indole-2-carbonyl)piperidin-4-yl)sulfonyl)-N-methylpiperidine- 4-carboxamide,(5 -chloro- lH-indol-2-yl)(4-((3-methoxypropyl)sulfonyl)piperidin-l-yl)methanone, (6-chlorobenzo[b]thiophen-2-yl)(4-((3-methoxypropyl)sulfonyl)piperidin-l- yl)methanone, l-(5-chloro-lH-indole-2-carbonyl)-N-(2-(dimethylphosphoryl)ethyl)piperidine-4-sulfonamide,N,N-dimethyl-l-(6-methylbenzo[b]thiophene-2-carbonyl)piperidine-4-sulfonamide, l-(5-chloro-lH-indole-2-carbonyl)-N,N-dimethylpiperidine-4-sulfonamide, N,N-dimethyl-l-(5-methylbenzofuran-2-carbonyl)piperidine-4-sulfonamide, N,N-dimethyl-l-(6-(trifluoromethyl)benzo[b]thiophene-2-carbonyl)piperidine-4- sulfonamide,N,N-dimethyl-l-(5-(trifluoromethoxy)benzo[b]thiophene-2-carbonyl)piperidine-4- sulfonamide, l-(6-chlorobenzo[b]thiophene-2-carbonyl)-N,N-dimethylpiperidine-4-sulfonamide, (4-((difluoromethyl)sulfonyl)piperidin- 1 -yl)( lH-indol-2-yl)methanone, l-(5-chloro-lH-indole-2-carbonyl)-N-(2-methoxyethyl)-N-methylpiperidine-4- sulfonamide, or l-(5-chloro-lH-indole-2-carbonyl)-N,N-bis(2-methoxyethyl)piperidine-4- sulfonamide; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, wherein the compound is15. The compound according to claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof17. The compound according to any one of claims 1 to 16 for use as a medicament.

18. The compound according to any one of claims 1 to 17 for use in the treatment of a disorder, condition, or disease where a GPR183 antagonist is indicated to be useful.

19. The compound according to claim 18, wherein the disorder, condition, or disease is chronic pain e.g. osteoarthritis, chronic low back pain, neuropathic pain and immune system diseases e.g. inflammatory bowel diseases e.g. Colitis and Chron's diseases, multiple sclerosis, rheumatoid arthritis, inflammatory pulmonary diseases e.g. asthma and psoriasis ameliorated by inhibition of GPR183 receptors.

20. A method for the treatment of a disorder, condition, or disease where a GPR183 antagonist is indicated to be useful, which method comprises administering to a mammal in need of such treatment an effective amount of at least one compound according to claim 1.

21. The method according to claim 20, wherein the disorder, condition, or disease is chronic pain e.g. osteoarthritis, chronic low back pain, neuropathic pain and immune system diseases e.g. inflammatory bowel diseases e.g. Colitis and Chron's diseases, multiple sclerosis, rheumatoid arthritis, inflammatory pulmonary diseases e.g. asthma and psoriasis ameliorated by inhibition of GPR183 receptors.

22. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier, diluent and / or excipient.

23. The pharmaceutical composition according to claim 22 wherein the composition comprises further at least one other active ingredient.

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