2-phenoxy-1-(4-(alkylsulfonyl)piperidine-1-yl)ethane-1-one and 3-phenyl-1-(4-(alkylsulfonyl)piperidine-1-yl)prop-2-en-1-one derivatives as GPR183 antagonists for the treatment of chronic pain

Abstract

This disclosure relates to compounds of formula I (wherein X and R1-R4, n and m have the meanings set forth herein) and pharmaceutically acceptable salts thereof. Compounds of formula I exhibit GPR183 antagonist activity and are therefore useful in the treatment or prevention of disorders, conditions or diseases for which GPR183 antagonists have been shown to be useful, such as chronic pain, e.g., osteoarthritis, chronic low back pain, neuropathic pain, and immune system disorders, e.g., inflammatory bowel diseases such as colitis and Crohn's disease, multiple sclerosis, rheumatoid arthritis, inflammatory lung diseases, e.g., asthma, and psoriasis. TIFF2026522963000085.tif2570

Description

[Technical Field]

[0001] This disclosure relates to novel pharmaceutically active compounds, pharmaceutical compositions containing them, and their use as GPR183 antagonists. [Background technology]

[0002] G protein-coupled receptor 183 (GPR183), also known as Epstein-Barr virus-inducible G protein-coupled receptor 2 (EBI2), belongs to the G protein-coupled receptor (GPCR) superfamily, which consists of transmembrane proteins involved in a wide range of signaling pathways and physiological functions. Because approximately 30% of drugs in clinical use function as agonists, antagonists, or modulators of GPCRs, GPCRs are important targets for pharmacological interventions. GPR183 is one of the genes most highly expressed (more than 200-fold) in Burkitt lymphoma cells infected with Epstein-Barr virus (Non-Patent Literature 1). Following the de-orphanization of GPR183 by identifying 7α,25-dihydroxycholesterol as a potent and selective endogenous agonist of the receptor (Non-Patent Literature 2), the involvement of this receptor and ligand in cellular function and physiological processes has been more extensively studied and elucidated.

[0003] In cells, GPR183 is G i It has been shown that it binds to cAMP, inhibits ERK, and activates ERK (Non-Patent Literature 3). Ligand-induced or structural GPR183 internalization is independent of β-arrestin, while GPR183-mediated migration is dependent on β-arrestin binding (Non-Patent Literature 4).

[0004] GPR183-G is formed with its endogenous agonist, 7α,25-OHC. i The cryo-electron microscopy structures of the signaling complex and the inactive GPR183 receptor bound to the inverse agonist GSK682753A have been revealed. The oxysterol binding site and Gα iMutations within the interface weakened G protein signaling and inhibited oxysterol-mediated cell migration. This suggests that G protein signaling is directly involved in the oxysterol GPR183 pathway (Non-Patent Literature 5).

[0005] GPR183 is most abundantly expressed in immune cells and immune tissues, with the highest expression levels in B lymphocytes, followed by T lymphocytes and NK cells, and the lowest in monocytes. The lungs and gastrointestinal tract also show relatively high expression levels (Non-Patent Literature 6). This expression pattern, along with the finding that 7α,25-OHC and related oxysterols act as chemotactic factors for GPR183-expressing immune cells, inducing cell mailing in vitro and in vivo (Non-Patent Literature 2), suggests the potential for receptor targeting for immunological indications and diseases.

[0006] Acute intrathecal administration of 7α,25-OHC, a GPR183 ligand, induced dose-dependent allodynia in naive mice, demonstrating the involvement of GPR183 in pain perception. GPR183 expression was upregulated in the dorsal spinal cord after chronic compression injury (CCI) (Non-Patent Literature 7). Overexpression of the CH25H enzyme, which metabolizes cholesterol to the GPR183 agonist 7α,25-OHC, has been detected in the cartilage of human osteoarthritis patients (Non-Patent Literature 8). GPR183 expression in the central nervous system in human astrocytes (Non-Patent Literature 9) and microglia (Non-Patent Literature 10), as well as upregulation of the GPR183 receptor and induction of allodynia by endogenous GPR183 agonists in rodents, suggest the potential for improvement with GPR183 antagonists in pain indications.

[0007] Several compounds that modulate the activity of the GPR183 protein are known in the art. Patent Document 1 describes several heterocyclic compounds as GPR183 inhibitors. GPR183 antagonists for pain treatment are disclosed in Patent Document 2. Patent Document 3 describes spirocyclic EBI2 modulators, and Patent Document 4 describes amide derivatives as EBI2 modulators. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2023 / 066190 [Patent Document 2] U.S. Patent Application Publication No. 2021 / 0122750 [Patent Document 3] International Publication No. 2015 / 048567 [Patent Document 4] International Publication No. 2015 / 048570 [Non-patent literature]

[0009] [Non-Patent Document 1] Birkenbach et al., 1993 [Non-Patent Document 2] Hannedouche et al., 2011 [Non-Patent Document 3] Benned-Jensen et al., 2011 [Non-Patent Document 4] Kjaer et al., 2023 [Non-Patent Document 5] Chen et al., 2022 [Non-Patent Document 6] Rosenkilde et al. 2006 [Non-Patent Document 7] Braden et al., 2020 [Non-Patent Document 8] Choi et al., 2019 [Non-Patent Document 9] Rutowska et al., 2012 [Non-Patent Document 10] Hsiao et al., 2019 [Overview of the Initiative]

[0010] The object of this disclosure is to provide novel pharmacologically active compounds that act as antagonists to the GPR183 receptor. Furthermore, the object of this disclosure is to provide further compounds to be used as GPR183 antagonists in the treatment of diseases and conditions that are alleviated by inhibition of the GPR183 receptor, such as chronic pain, e.g., osteoarthritis, chronic low back pain, neuropathic pain, and immune system disorders, e.g., inflammatory bowel diseases such as colitis and Crohn's disease, multiple sclerosis, rheumatoid arthritis, inflammatory lung diseases such as asthma, and psoriasis. In addition, pharmaceutical compositions comprising the compounds disclosed herein are also provided.

[0011] The novel GPR183 antagonists described herein have improved physicochemical properties and a more desirable pharmacokinetic profile. [Modes for carrying out the invention]

[0012] This disclosure is based on General Formula I: [ka] (In the formula, The dotted line [----] represents a single or double bond; X is O, CH2, or CH, where if X is O or CH2, the dotted line represents a single bond; if X is CH, the dotted line represents a double bond; R1 is halogen, halo (C 1-3 ) alkyl or halo(C 1-3 ) is an alkoxy; R2 is a halogen; Alternatively, R1 and R2 bond to adjacent carbohydrate atoms, forming a fused 2,2-difluoro-1,3-dioxolane ring together with those carbohydrate atoms; R3 is hydrogen; R4 is (C 2-6 )alkyl, halo(C 1-3 )alkyl, (C 1-3 )alkoxy(C 1-6 )alkyl, (C 3-6 )cycloalkyl, 6-membered heterocyclyl, heterocyclyl(C 1-3 )alkyl, NHR5 or NR6R7, wherein the (C 3-6 )cycloalkyl or heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from hydroxy, (C 1-3 )alkyl and (C 1-3 )alkoxy; R5 is hydrogen, (C 2-6 )alkyl, (C 1-3 )alkoxy(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 3-6 )cycloalkyl(C 1-3 )alkyl, or heterocyclyl(C 1-3 )alkyl, wherein the (C 3-6 )cycloalkyl or heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from hydroxy, (C 1-3 )alkyl and phenyl(C 1-3 )alkyl; R6 and R7 together with the nitrogen atom to which they are attached form a pyrrolidine ring, wherein the pyrrolidine ring is substituted with one or two substituents independently selected from (C 1-3 )alkyl, hydroxy(C 1-6 )alkyl and heterocyclyl; n is an integer selected from 0, 1 or 2; m is an integer selected from 1 or 2) relates to a novel compound having or a pharmaceutically acceptable salt thereof, provided that the compound is 2-(4-chlorophenoxy)-1-(4-(ethylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-fluorophenoxy)-1-(4-(isobutylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-(isobutylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(2,4-dichlorophenoxy)-1-(4-(ethylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(2,4-dichlorophenoxy)-1-(4-(isobutylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-fluorophenoxy)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 2-(2,4-dichlorophenoxy)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 3-(4-chlorophenyl)-1-(4-(ethylsulfonyl)piperidine-1-yl)prop-2-en-1-one, 1-(4-(ethylsulfonyl)piperidine-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one, 3-(4-chlorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)prop-2-en-1-one, 3-(2,4-dichlorophenyl)-1-(4-(ethylsulfonyl)piperidine-1-yl)prop-2-en-1-one, 3-(4-bromophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(3,4-dichlorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(3-chloro-4-fluorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(4-chloro-3-fluorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(2,4-dichlorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(4-chlorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, 1-(4-(isobutylsulfonyl)piperidine-1-yl)-3-(4-(trifluoromethyl)phenyl)propan-1-one, 3-(4-bromophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 3-(3-chloro-4-fluorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 3-(3,4-dichlorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 3-(2,4-dichlorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 3-(4-chloro-3-fluorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)-3-(4-(trifluoromethyl)phenyl)propan-1-one, 1-(4-(ethylsulfonyl)piperidine-1-yl)-3-(4-fluorophenyl)propan-1-one, 1-(3-(4-chlorophenyl)propanoyl)piperidine-4-sulfonamide, or 1-(3-(4-fluorophenyl)propanoyl)piperidine-4-sulfonamide isn't it.

[0013] In one embodiment, the present disclosure relates to a compound of formula I, The dotted line [----] represents a single or double bond; X is O, CH2, or CH, where if X is O or CH2, the dotted line represents a single bond; if X is CH, the dotted line represents a double bond; R1 is halogen, halo (C 1-3 ) alkyl or halo(C 1-3 ) is an alkoxy; R2 is a halogen; R3 is hydrogen; R4 is (C 2-6 )alkyl, halo(C 1-3 ) alkyl, (C 1-3 )alkoxy(C 1-6 ) Alkyl, heterocyclyl (C 1-3 ) alkyl, NHR5 or NR6R7, where the heterocyclyl is unsubstituted or hydroxy, and (C 1-3 ) Substituted with one or more substituents independently selected from alkyl; R5 is (C 2-6 ) alkyl, (C 1-3 )alkoxy(C 1-6 ) alkyl, hydroxy(C 1-6 ) alkyl, (C 3-6 )Cycloalkyl, (C 3-6 )Cycloalkyl(C 1-3 ) alkyl, or heterocyclyl (C 1-3 ) is alkyl, and here, the (C 3-6 )Cycloalkyl or heterocyclyl is either unsubstituted or hydroxy, and (C 1-3 ) Substituted with one or more substituents independently selected from alkyl; R6 and R7, together with the nitrogen atom to which they are bonded, form a pyrrolidine ring, where the pyrrolidine ring is (C 1-3 ) Substituted with one or two substituents independently selected from alkyl and heterocyclyl groups; n is an integer selected from 0, 1, or 2; m is an integer selected from 1 or 2. The present invention relates to the compound or a pharmaceutically acceptable salt thereof, provided that the compound is 2-(4-chlorophenoxy)-1-(4-(ethylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-fluorophenoxy)-1-(4-(isobutylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-(isobutylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(2,4-dichlorophenoxy)-1-(4-(ethylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(2,4-dichlorophenoxy)-1-(4-(isobutylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-fluorophenoxy)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 2-(2,4-dichlorophenoxy)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 3-(4-chlorophenyl)-1-(4-(ethylsulfonyl)piperidine-1-yl)prop-2-en-1-one, 1-(4-(ethylsulfonyl)piperidine-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one, 3-(4-chlorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)prop-2-en-1-one, 3-(2,4-dichlorophenyl)-1-(4-(ethylsulfonyl)piperidine-1-yl)prop-2-en-1-one, 3-(4-bromophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(3,4-dichlorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(3-chloro-4-fluorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(4-chloro-3-fluorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(2,4-dichlorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(4-chlorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, 1-(4-(isobutylsulfonyl)piperidine-1-yl)-3-(4-(trifluoromethyl)phenyl)propan-1-one, 3-(4-bromophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 3-(3-chloro-4-fluorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 3-(3,4-dichlorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 3-(2,4-dichlorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 3-(4-chloro-3-fluorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)-3-(4-(trifluoromethyl)phenyl)propan-1-one, or 1-(4-(ethylsulfonyl)piperidine-1-yl)-3-(4-fluorophenyl)propan-1-one, isn't it.

[0014] In one embodiment, the present disclosure relates to a compound of formula I, X is O; R1 is a halogen; R3 is hydrogen; R4 is (C 3-6 ) alkyl, (C 1-3 )alkoxy(C 2-6 ) Alkyl, heterocyclyl (C 1-3 ) alkyl, or NHR5, where the heterocyclyl is unsubstituted; R5 is (C 1-3 )alkoxy(C 2-6 ) alkyl, hydroxy(C 3-6 ) alkyl, (C 3-6 )Cycloalkyl(C 1-3 ) alkyl, or heterocyclyl (C 1-3 ) is alkyl, and here, the (C 3-6 )Cycloalkyl or heterocyclyl is either unsubstituted or hydroxy and (C 1-2 ) is substituted with one substituent independently selected from alkyl; n is 0; m is 2. This relates to compounds or their pharmaceutically acceptable salts.

[0015] In one embodiment, the present disclosure relates to a compound of formula I, X is CH; R1 is a halogen; R3 is hydrogen; R4 is (C 3-6 ) alkyl, (C 1-3 )alkoxy(C 2-6 ) Alkyl, heterocyclyl (C 1-3 ) alkyl, or NHR5, where the heterocyclyl is unsubstituted; R5 is (C 1-3 )alkoxy(C 2-6 ) alkyl, hydroxy(C 3-6 ) alkyl, (C 3-6 )Cycloalkyl(C 1-3) alkyl, or heterocyclyl (C 1-3 ) is alkyl, and here, the (C 3-6 )Cycloalkyl or heterocyclyl is either unsubstituted or hydroxy and (C 1-2 ) is substituted with one substituent independently selected from alkyl; n is 0; m is 1 This relates to compounds or their pharmaceutically acceptable salts.

[0016] In one embodiment, the present disclosure relates to a compound of formula I, wherein X is O.

[0017] In one embodiment, the present disclosure relates to a compound of formula I, wherein X is CH2.

[0018] In one embodiment, the present disclosure relates to a compound of formula I, wherein X is CH.

[0019] In one embodiment, the present disclosure relates to a compound of formula I, wherein the heterocyclyl is the following group: [ka] This relates to a compound that is one of the following.

[0020] In one embodiment, the present disclosure relates to a compound of formula I, wherein the heterocyclyl is the following group: [ka] (Here, the atoms marked with an asterisk (*) are bonded to the parent molecule.) This relates to a compound that is one of the following.

[0021] In one embodiment, the present disclosure relates to a compound of formula I, 2-(3,4-dichlorophenoxy)-1-(4-(isopropylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-(difluoromethyl)phenoxy)-1-(4-(isopropylsulfonyl)piperidine-1-yl)ethane-1-one, 1-(4-((2-(1H-pyrazol-5-yl)ethyl)sulfonyl)piperidine-1-yl)-2-(4-chlorophenoxy)ethane-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-(2-ethoxyethyl)piperidine-4-sulfonamide, 2-(4-chlorophenoxy)-1-(4-(pentan-3-ylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(3,4-difluorophenoxy)-1-(4-(isopropylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-((difluoromethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-(isopropylsulfonyl)piperidine-1-yl)ethane-1-one, 1-(4-(isopropylsulfonyl)piperidine-1-yl)-2-(4-(trifluoromethoxy)phenoxy)ethane-1-one, 2-(4-chloro-3-fluorophenoxy)-1-(4-(isopropylsulfonyl)piperidine-1-yl)ethane-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, N-butyl-1-(2-(4-chlorophenoxy)acetyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-(4-hydroxy-4-methylpentyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-(3-hydroxy-3-methylbutyl)piperidine-4-sulfonamide, 2-(4-chlorophenoxy)-1-(4-((2,2-dimethylpyrrolidine-1-yl)sulfonyl)piperidine-1-yl)ethane-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-cyclopropylpiperidine-4-sulfonamide, 2-(4-chlorophenoxy)-1-(4-((3-methoxypropyl)sulfonyl)piperidine-1-yl)ethane-1-one, 1-(4-(sec-butylsulfonyl)piperidine-1-yl)-2-(4-chlorophenoxy)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-((2-(tetrahydrofuran-2-yl)ethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-(2-hydroxy-2-methylbutyl)piperidine-4-sulfonamide, N-((1H-pyrazol-5-yl)methyl)-1-(2-(4-chlorophenoxy)acetyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-(isoxazol-3-ylmethyl)piperidine-4-sulfonamide, (R)-1-(4-((3-(1H-pyrazol-5-yl)pyrrolidine-1-yl)sulfonyl)piperidine-1-yl)-2-(4-chlorophenoxy)ethane-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-((1-hydroxycyclobutyl)methyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-((1-methyl-1H-pyrazol-3-yl)methyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-((1-ethyl-1H-pyrazol-3-yl)methyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-(pyridazine-3-ylmethyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-((1-hydroxycyclopentyl)methyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-(3-methoxypropyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-(pyrazine-2-ylmethyl)piperidine-4-sulfonamide, 2-(4-chlorophenoxy)-1-(4-(propylsulfonyl)piperidine-1-yl)ethane-1-one, 1-(4-(isopropylsulfonyl)piperidine-1-yl)-2-(4-(trifluoromethyl)phenoxy)ethane-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-(2-hydroxy-2-methylpropyl)piperidine-4-sulfonamide, 1-(3-(4-chlorophenyl)propanoyl)-N-(3-methoxypropyl)piperidine-4-sulfonamide, (E)-3-(4-chlorophenyl)-1-(4-(isopropylsulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acryloyl)-N-((1-ethyl-1H-pyrazol-3-yl)methyl)piperidine-4-sulfonamide, (E)-1-(3-(4-chlorophenyl)acryloyl)-N-((1-ethyl-1H-pyrazol-3-yl)methyl)piperidine-4-sulfonamide, (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(isopropylsulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-1-(3-(4-chlorophenyl)acryloyl)-N-(2-hydroxy-2-methylpropyl)piperidine-4-sulfonamide, (E)-3-(4-bromophenyl)-1-(4-((3-methoxypropyl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acryloyl)-N-(3-hydroxy-3-methylbutyl)piperidine-4-sulfonamide, (E)-1-(3-(4-chlorophenyl)acryloyl)-N-(3-hydroxy-3-methylbutyl)piperidine-4-sulfonamide, (R,E)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acryloyl)-N-((tetrahydrofuran-2-yl)methyl)piperidine-4-sulfonamide, (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-((3-(2-hydroxypropan-2-yl)pyrrolidine-1-yl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-1-(3-(4-chlorophenyl)acryloyl)-N-(2-ethoxyethyl)piperidine-4-sulfonamide, (E)-1-(4-((2-(1H-pyrazol-1-yl)ethyl)sulfonyl)piperidine-1-yl)-3-(4-chlorophenyl)prop-2-en-1-one, (E)-N-(2-(1H-pyrazol-1-yl)ethyl)-1-(3-(4-chlorophenyl)acryloyl)piperidine-4-sulfonamide, (R,E)-3-(4-chlorophenyl)-1-(4-((3-(2-hydroxypropan-2-yl)pyrrolidine-1-yl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, (R,E)-1-(3-(4-chlorophenyl)acryloyl)-N-((tetrahydrofuran-2-yl)methyl)piperidine-4-sulfonamide, (E)-N-((1-benzyl-1H-pyrazol-3-yl)methyl)-1-(3-(4-chlorophenyl)acryloyl)piperidine-4-sulfonamide, (E)-N-(3-methoxypropyl)-1-(3-(4-(trifluoromethyl)phenyl)acryloyl)piperidine-4-sulfonamide, (E)-1-(3-(4-chlorophenyl)acryloyl)-N-(3-methoxypropyl)piperidine-4-sulfonamide, (E)-3-(4-chlorophenyl)-1-(4-(propylsulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-3-(4-chlorophenyl)-1-(4-((difluoromethyl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-3-(4-chlorophenyl)-1-(4-(cyclobutylsulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-3-(4-chlorophenyl)-1-(4-((2-methoxypyrimidine-5-yl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, 1-(4-((2-(1H-pyrazol-1-yl)ethyl)sulfonyl)piperidine-1-yl)-2-(4-chlorophenoxy)ethane-1-one, N-((1-benzyl-1H-pyrazol-3-yl)methyl)-1-(2-(4-chlorophenoxy)acetyl)piperidine-4-sulfonamide, (E)-1-(3-(4-chlorophenyl)acryloyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-((3-methoxypropyl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-3-(4-chlorophenyl)-1-(4-((3-methoxypropyl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-N-((1H-pyrazol-5-yl)methyl)-1-(3-(4-chlorophenyl)acryloyl)piperidine-4-sulfonamide, or (E)-1-(3-(4-chlorophenyl)acryloyl)piperidine-4-sulfonamide This relates to a compound or a pharmaceutically acceptable salt thereof.

[0022] In one embodiment, the present disclosure relates to a compound of formula I, [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0023] In one embodiment, the present disclosure relates to a compound of formula I, [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0024] In one embodiment, the present disclosure relates to a compound of formula I, [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0025] In one embodiment, the present disclosure relates to a compound of formula I, [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0026] In one embodiment, the present disclosure relates to a compound of formula I, [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0027] In one embodiment, the present disclosure relates to a compound of formula I, [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0028] In one embodiment, the present disclosure relates to a compound of formula I, [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0029] In one embodiment, the present disclosure relates to a compound of formula I, [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0030] In one embodiment, the present disclosure relates to a compound of formula I, [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0031] In one embodiment, the present disclosure relates to a compound of formula I, [ka] This relates to a compound or a pharmaceutically acceptable salt thereof.

[0032] Unless otherwise specified, the terms used herein have the meanings set forth below.

[0033] As used in the following definitions, the term "at least one" means one or more. For example, the term "at least one fluorine" means one or more fluorines, e.g., three, two, or one fluorine.

[0034] In this specification, the term "hydroxy" as used by itself or as part of another group means the -OH group.

[0035] In this specification, the terms "halo" or "halogen" as used by themselves or as part of another group mean fluorine, chlorine, bromine, or iodine.

[0036] In this specification, the term "(C)" is used by itself or as part of another group. 1-2 "Alkyl" refers to a saturated hydrocarbon group having a straight or branched chain portion containing one or two carbon atoms. (C 1-2 Typical examples of alkyl groups include methyl and ethyl.

[0037] In this specification, the term "(C)" is used by itself or as part of another group. 1-3 (C) alkyl refers to a saturated hydrocarbon group having a linear or branched chain portion containing one, two, or three carbon atoms. 1-3 Typical examples of alkyl groups include methyl, ethyl, n-propyl, and isopropyl.

[0038] In this specification, the term "(C)" is used by itself or as part of another group. 1-6 "Alkyl" refers to a saturated hydrocarbon group having a straight or branched chain portion containing one, two, three, four, five, or six carbon atoms. (C 1-6 Typical examples of alkyl groups 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.

[0039] In this specification, the term "(C)" is used by itself or as part of another group. 2-6 (C) alkyl refers to a saturated hydrocarbon group having a straight or branched chain portion containing 2, 3, 4, 5, or 6 carbon atoms. 2-6 Typical examples of alkyl groups 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.

[0040] In this specification, the term "(C)" is used by itself or as part of another group. 3-6 (C) alkyl refers to a saturated hydrocarbon group having a straight or branched chain portion containing 3, 4, 5, or 6 carbon atoms. 3-6 Typical examples of alkyl groups 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.

[0041] In this specification, the term "(C)" is used by itself or as part of another group. 1-3 )alkoxy" is a compound bonded to an oxygen atom, as defined herein (C 1-3 ) means alkyl group. (C 1-3 Typical examples of alkoxys include, but are not limited to, methoxy, ethoxy, and n-propoxy.

[0042] In this specification, the term "(C)" is used by itself or as part of another group. 3-6 )Cycloalkyl means a saturated hydrocarbon group having a cyclic portion containing 3, 4, 5, or 6 carbon atoms. (C 3-6 Typical examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0043] As used herein, either by itself or as part of another group, the term "heterocyclyl" means a 5- or 6-membered saturated, partially saturated, or aromatic monocyclic group containing one or two ring heteroatoms each independently selected from N and O. The heterocyclyl may optionally be substituted or unsubstituted. Unless otherwise specified, a 5- or 6-membered heterocyclyl can be attached via any heteroatom or carbon atom of the ring such that the resulting structure is stable. Representative examples of heterocyclyl include, but are not limited to, pyrrolidinyl, piperidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, and isoxazolyl.

[0044] As used herein, either by itself or as part of another group, the term "halo(C 1-3 )alkyl" means at least one halogen attached to an (C 1-3 )alkyl group as defined herein. When there are multiple halogens, they may be attached to the same or different carbon atoms, and they may be the same or different. Representative examples of halo(C 1-3 )alkyl include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 3-bromopropyl, and 2-chloropropyl.

[0045] As used herein, either by itself or as part of another group, the term "halo(C 1-3 )alkoxy" means at least one halogen attached to an (C 1-3 )alkoxy group as defined herein. When there are multiple halogens, they may be attached to the same or different carbon atoms, and they may be the same or different. Halo(C 1-3Representative examples of alkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 3-fluoropropyl, and 3,3,3-trifluoropropyl.

[0046] As used herein, the term “(C 1-3 )alkoxy(C 1-6 )alkyl” or “(C 1-3 )alkoxy(C 2-6 )alkyl” means an (C 1-6 )alkyl group as defined herein or at least one (C 2-6 )alkoxy group as defined herein attached to an (C 1-3 )alkyl group. When there are multiple (C 1-3 )alkoxy groups, those (C 1-3 )alkoxy groups may be attached to the same or different carbon atoms, and those (C 1-3 )alkoxy groups may be the same or different. Representative examples of (C 1-3 )alkoxy(C 1-6 )alkyl or (C 1-3 )alkoxy(C 2-6 )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, 3-methoxypropyl, and 4-methoxybutyl.

[0047] As used herein, the term “hydroxy(C 1-6 )alkyl” or “hydroxy(C 3-6 )alkyl” means an (C 1-6 )alkyl group as defined herein or (C 3-6) means at least one hydroxyl group as defined herein, bonded to an alkyl group. If there are multiple hydroxyl groups, those hydroxyl groups may be bonded to the same or different carbon atoms. Hydroxyl (C 1-6 ) alkyl or hydroxy(C 3-6 Typical examples of alkyl groups 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.

[0048] The term "(C)" as used herein 3-6 )Cycloalkyl(C 1-3 )alkyl" is defined herein as (C 1-3 ) bonded to an alkyl group, as defined herein (C 3-6 ) means cycloalkyl. (C 3-6 )Cycloalkyl(C 1-3 Typical examples of alkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, and cyclohexylethyl.

[0049] The term "heterocycline (C)" as used herein 1-3 )alkyl" is defined herein as (C 1-3 ) Means a heterocyclyl as defined herein, bonded to an alkyl group. Heterocyclyl (C 1-3Typical examples of alkyl groups include, but are not limited to, pyrazol-3-ylmethyl, pyrazine-2-ylmethyl, pyridazine-3-ylmethyl, pyrazol-5-ylethyl, pyrazol-1-ylethyl, tetrahydropyran-3-ylmethyl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-ylethyl, and isoxazol-3-ylmethyl.

[0050] The term "phenyl(C)" as used herein 1-3 )alkyl" is defined herein as (C 1-3 ) This refers to a phenyl group bonded to an alkyl group. Phenyl(C 1-3 Typical examples of alkyl groups include, but are not limited to, benzyl, phenylethyl, and phenylpropyl.

[0051] As used herein in relation to various residues, the term "substituted" refers to halogens, hydroxyls, (C) unless otherwise specified. 1-2 ) alkyl, (C 1-3 ) alkyl, heterocyclyl, and phenyl(C) 1-3 ) refers to alkyl substituents. Unless otherwise specified, the substituted group may contain 1 to 3, preferably 1 or 2 of the above substituents. Substitution means that it occurs at any position permitted by the valence of the compound, including an atom that is bonded to the parent molecule so as to result in a stable structure. The term "optionally substituted" means that a particular group is either unsubstituted or substituted with one or more substituents.

[0052] The abbreviation "GPR183" stands for G protein-coupled receptor 183, also known as EBI2 (Epstein-Barr virus-induced G protein-coupled receptor 2).

[0053] As used herein, the term "compounds of the disclosure" means the compounds of formula I and their pharmaceutically acceptable salts.

[0054] The “pharmaceutically acceptable salts” as relating to this disclosure include therapeutically active and non-toxic base salts and acid salts in which the compound of formula I can form with organic and inorganic bases, as well as organic and inorganic acids. Typical examples of pharmaceutically acceptable base addition salt forms, such as metal salts or amine salts, include, but are not limited to, ammonium salts, lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, and zinc salts, salts with organic bases such as N-methyl-D-glucamine, hydravamin salts, and salts with amino acids such as arginine and lysine. Typical examples of pharmaceutically acceptable acid addition salts include, but are not limited to, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methanesulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbicates, acetates, oxalates, fumarates, and succinates.

[0055] This disclosure includes all possible geometric isomers of the compound of formula I, e.g., cis and trans isomers, as well as all possible optical isomers of the compound of formula I, such as diastereomers and enantiomers. Furthermore, this disclosure includes all individual isomers and any mixtures thereof, racemic mixtures, etc. Individual isomers may be obtained using the corresponding isomeric forms of the starting materials, or they may be separated after the preparation of the final compound according to conventional separation methods. Conventional separation methods, such as fractional crystallization or preparative chiral chromatography, may be used to separate optical isomers, such as enantiomers, from their mixtures.

[0056] The following common abbreviations are used: NaOH = sodium hydroxide, EtOH = ethanol, Boc = tert-butyloxycarbonyl protecting group, H2O2 = hydrogen peroxide, MeOH = methanol, MeCN = acetonitrile, siRNA = ethyl acetate, HATU = (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), DIPEA = N,N-diisopropylethylamine, DMF = N,N-dimethylformamide, TEA = triethylamine, DCM = dichloromethane, HCl = hydrochloric acid, NaHSO3 = sodium bisulfite, H2O = water DAST = diethylamino trifluoride sulfur, DMSO-d6 = deuterated dimethyl sulfoxide, LiOH = lithium hydroxide, NaHCO3 = sodium bicarbonate, CO2 = carbon dioxide, NaCl = sodium chloride, KCl = potassium chloride, MgCl2 = magnesium chloride, CaCl2 = calcium chloride, THF = tetrahydrofuran, K2CO3 = potassium carbonate, CuI = copper(I) iodide, N2 = dinitrogen, DMSO = dimethyl sulfoxide, KOtBu = potassium tert-butoxide, HEPES = 2-[4-(2-hydroxyethyl)piperazine-1-yl]ethanesulfonic acid, RT = room temperature, h = time, eq = equivalent weight, aq = aqueous solution. 1 ¹H NMR = Proton Nuclear Magnetic Resonance, s = Singlet, d = Doublet, t = Triplet, m = Multiplet, br s = Broad Singlet, br d = Broad Doublet, LC-MS = Liquid Chromatography-Mass Spectrometry, H = Proton, M = Molar Concentration, SM = Starting Material, Int = Intermediate, MHz = Megahertz, mmol = Millimole, g = Gram, mg = Milligram, ml = Milliliter, and mM = Millimolar.

[0057] The present disclosure will be illustrated in more detail by the following examples. These examples are for illustrative purposes only and do not limit the scope of the invention as defined in the claims. Various modifications and embodiments are possible without departing from its spirit and scope. Where typical or preferred experimental conditions (i.e., reaction temperature, time, number of moles of reagents, solvent, etc.) are given, it will be understood that other experimental conditions may also be used unless otherwise noted. Optimal reaction conditions may vary depending on the specific reactants and solvents used, but such conditions can be determined by those skilled in the art using standard optimization procedures. The synthetic routes described below are for illustrating the preparation of the compound of formula I, but are by no means limited thereto, i.e., other possible synthetic methods exist within the scope of the general knowledge of those skilled in the art.

[0058] The compound of formula I can, if necessary, be converted to a pharmaceutically acceptable salt form using methods known in the art.

[0059] Products 1 ¹H NMR spectra were measured using a Bruker Avance III HD 400 MHz or Bruker Avance NEO 600 MHz NMR spectrometer. LC-MS analysis was performed using a Waters Acquity UPLC / MS equipped with a Q detector.

[0060] The starting materials used in the processes described herein are either commercially available or can be produced by common synthetic routes.

[0061] The procedure for producing the compound of formula I, including the synthesis of various intermediates involved in the process of producing the compound according to this disclosure, is described in detail below.

[0062] Manufacturing of the Compounds Disclosed General Route 1: [ka]

[0063] General Route 2: [ka]

[0064] General procedure for sulfones [ka]

[0065] General Procedure A A mixture of tert-butyl 4-mercaptopiperidine-1-carboxylate (1 eq), alkyl halide (1-1.3 eq), and 2M NaOH (aqueous solution, 1-1.3 eq) in EtOH (0.2-0.5 M) was stirred until the starting materials were consumed (RT ~60°C). The resulting sulfide was obtained by aqueous workup. Optionally, the crude product was purified by column chromatography.

[0066] The following compounds were synthesized using general procedure A: TIFF2026522963000018.tif232156 TIFF2026522963000019.tif133156

[0067] Instructions for Int-9: [ka] A microwave reaction vial was filled with 5-iodo-2-methoxypyrimidine (195 mg, 0.79 mmol, 1.2 eq), tert-butyl 4-mercaptopiperidine-1-carboxylate (0.15 g, 0.66 mmol, 1.0 eq), K2CO3 (181 mg, 1.31 mmol, 2 eq), 1,4-diazabicyclo[2.2.2]octane (7.4 mg, 0.066 mmol, 0.1 eq), CuI (6.3 mg, 0.033 mmol, 0.05 eq), and dried MeCN (3.5 ml). N2 was passed through the resulting mixture for 5 minutes, and the vial was sealed. The vial was heated in a microwave reactor at 120°C for 12 hours. The reaction mixture was diluted with EtOAC and washed with water and brine. The organic phase was dried and evaporated. The crude product was purified by column chromatography to obtain 107 mg of tert-butyl 4-((2-methoxypyrimidine-5-yl)thio)piperidine-1-carboxylate. 1 H NMR (400MHz, DMSO-d6) δ: 8.67 (s, 2H), 3.93 (s, 3H), 3.86-3.78 (m, 2H), 3.25-3.16 (m, 1H), 2.93-2.73 (m, 2H), 1.85-1.77 (m, 2H), 1.37 (s, 9H), 1.33-1.21 (m, 2H). MS: m / z 270.1 [Mt-Bu+H] + .

[0068] General procedure B1: One eq of sulfide was dissolved in MeOH-H2O (2:1 to 1:1, 50 to 200 mM), and the solution was cooled in an ice bath. Oxon® (2.2 eq) was added. The resulting mixture was stirred until the starting material was consumed (0°C-RT). The resulting sulfone was obtained by aqueous workup. Optionally, the crude product was purified by column chromatography.

[0069] The following compounds were synthesized using general procedure B1: TIFF2026522963000021.tif182156

[0070] General procedure B2: 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% aqueous solution, 6 eq) was added dropwise. The resulting mixture was stirred until the starting materials were consumed (0°C). The generated sulfone was obtained by aqueous workup (including NaHSO3 washing). Optionally, the crude product was purified by column chromatography.

[0071] The following compounds were synthesized using general procedure B2: TIFF2026522963000022.tif184156 TIFF2026522963000023.tif185156

[0072] General procedure for sulfonamides [ka]

[0073] General procedure C: A flask was packed with amine (or its salt) (1–1.1 eq), TEA (2–3 eq) or DIPEA (3 eq), and DCM or DMF (0.5–0.8 M). Then, 1-Boc-4-piperidinesulfonyl chloride (1 eq) was added. The mixture was stirred at room temperature until the reaction was complete. The mixture was diluted with DCM and washed with 1 M HCl and saturated NaHCO3. The organic phase was evaporated to dryness. The product was used directly or optionally purified by column chromatography.

[0074] The following compounds were synthesized using general procedure C: TIFF2026522963000025.tif229156 TIFF2026522963000026.tif218156 TIFF2026522963000027.tif205156 TIFF2026522963000028.tif220156 TIFF2026522963000029.tif227156

[0075] Deprotection [ka]

[0076] General procedure D: BOC-protected amine (1 eq) was dissolved in phenyl (0.3–0.6 M). 3.7–4.3 M HCl (8–10 eq) in dioxane was added to the solution, and the mixture was stirred at room temperature until the starting material was consumed. The resulting HCl salt was filtered and washed with phenyl or diethyl ether.

[0077] The following compounds were synthesized using general procedure D: TIFF2026522963000031.tif224156 TIFF2026522963000032.tif233156 TIFF2026522963000033.tif229156 TIFF2026522963000034.tif241156 TIFF2026522963000035.tif233156 TIFF2026522963000036.tif237156 TIFF2026522963000037.tif228156 TIFF2026522963000038.tif57156

[0078] Instructions for Int-68: 1.59 g, 1 eq of tert-butyl 4-(N-(4-hydroxy-4-methylpentyl)sulfamoyl)piperidine-1-carboxylate (Int-20) was dissolved in 10 ml of dichloromethane. 10 eq of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature until the starting material was consumed (2-3 hours). The volatile components were evaporated to obtain a viscous oily substance. 20 ml of water and 2 M HCl (2 eq) were added to the crude product, and the solution was freeze-dried to obtain an oily solid. This substance was recrystallized with MeOH / methyl tert-butyl ether to obtain a white solid of 4-((2,2-dimethylpyrrolidine-1-yl)sulfonyl)piperidine,HCl (0.91 g, 80% purity), which was used in the next step. TIFF2026522963000039.tif55156

[0079] Instructions for Int-69: [ka]

[0080] 2-(4-(difluoromethyl)phenoxy)ethyl acetate 253 mg, 1.22 mmol of 2-(4-formylphenoxy)ethyl acetate was dissolved in 10 ml of DCM. 0.48 ml, 3.65 mmol of DAST was added at 0°C. The resulting mixture was stirred overnight at RT for 15 minutes at 0°C. The addition of DAST (0.48 ml, 3.65 mmol) and stirring were repeated twice. After aqueous workup, 217 mg of 2-(4-(difluoromethyl)phenoxy)ethyl acetate was obtained. 1 H NMR (400MHz, DMSO-d6) δ: 7.54-7.48 (m, 2H), 7.08-7.03 (m, 2H), 6.96 (t, 1H), 4.85 (s, 2H), 4.18 (q, 2H), 1.22 (t, 3H).

[0081] Int-69:2-(4-(difluoromethyl)phenoxy)acetic acid 2-(4-(difluoromethyl)phenoxy)ethyl acetate (215 mg, 0.93 mmol) was dissolved in THF (1.5 ml). LiOH·H2O (58.8 mg, 1.40 mmol) and H2O (0.5 ml) were added, and the mixture was stirred overnight in RT. The mixture was acidified with 1 M HCl and extracted with SiO to obtain 207 mg of 2-(4-(difluoromethyl)phenoxy)acetic acid. 1 H NMR (400MHz, DMSO-d6) δ: 12.72 (br s, 1H), 7.53-7.48 (m, 1H), 7.06-7.00 (m, 2H), 6.96 (t, 1H), 4.75 (s, 2H). MS: m / z 201.2 [MH]-.

[0082] General procedure E: A flask was packed with acid (1.0 eq), amine salt (1.0–1.2 eq), HATU (1.2–1.5 eq), and DMF (0.2–0.3 M). Next, DIPEA (5 eq) was added, and the mixture was stirred at room temperature until the reaction was complete. The reaction was diluted with RINKAN and water or saturated NaHCO3. The phases were separated, and the organic phase was evaporated. The residue was purified by column chromatography to obtain the amide coupling product.

[0083] General procedure for compounds 10 and 11: 4-(isopropylsulfonyl)piperidine, HCl (1 eq), carboxylic acid (1 eq), and triethylamine (5 eq) were weighed into a vial, and dry DMF (0.2-0.3 M) was added. The mixture was purged with nitrogen. 50% 1-propanephosphonic acid cyclic anhydride (1.5-3 eq) was added dropwise to the DMF. The mixture was stirred at room temperature until the starting materials were consumed. The product was obtained by aqueous workup.

[0084] The following compounds were synthesized using general procedure E: TIFF2026522963000041.tif189156 TIFF2026522963000042.tif169156 TIFF2026522963000043.tif230156 TIFF2026522963000044.tif204156 TIFF2026522963000045.tif214156 TIFF2026522963000046.tif226156 TIFF2026522963000047.tif222156 TIFF2026522963000048.tif173156 TIFF2026522963000049.tif174156 TIFF2026522963000050.tif178156 TIFF2026522963000051.tif184156 TIFF2026522963000052.tif173156 TIFF2026522963000053.tif184156 TIFF2026522963000054.tif164156 JPEG2026522963000055.jpg228156 TIFF2026522963000056.tif246156 TIFF2026522963000057.tif226156 TIFF2026522963000058.tif169156 TIFF2026522963000059.tif189156 TIFF2026522963000060.tif226156 TIFF2026522963000061.tif177156 TIFF2026522963000062.tif234156 TIFF2026522963000063.tif210156 TIFF2026522963000064.tif230156 TIFF2026522963000065.tif234156 TIFF2026522963000066.tif73156

[0085] General procedure for compounds 65 and 66: (E)-N-((1-benzyl-1H-pyrazol-3-yl)methyl)-1-(3-(4-chlorophenyl)acryloyl)piperidine-4-sulfonamide (52) (21 mg, 1 eq) was dissolved in 0.3 ml of DMSO and cooled in an ice bath. KOtBu (1 M in THF, 0.295 ml, 7 eq) was added. Oxygen was passed through the solution for 10 minutes. The reaction was stopped with 10% aqueous citric acid solution and extracted with ELISA. The volatile components were evaporated to obtain a solid. The crude product was purified by column chromatography to obtain (E)-N-((1H-pyrazol-5-yl)methyl)-1-(3-(4-chlorophenyl)acryloyl)piperidine-4-sulfonamide (65) or (E)-1-(3-(4-chlorophenyl)acryloyl)piperidine-4-sulfonamide (66). TIFF2026522963000067.tif131156

[0086] As mentioned above, the compound of formula I exhibits interesting pharmacological properties, specifically antagonist activity against the GPR183 receptor. These properties are demonstrated by the pharmacological tests described below.

[0087] Experiment 1: In vitro pharmacology The pharmacology of GPR183 in vitro was studied using a human THP-1 monocyte-like cell line (ATCC) that endogenously expresses the human GPR183 receptor. The cells were maintained at 37°C in a 5% CO2 95% air atmosphere in RPMI-1640 medium (ATCC) supplemented with 10% fetal bovine serum and 0.05 mM 2-mercaptoethanol.

[0088] Suspended cells seeded at a density of 22,500 cells / well in 384-well plates were incubated with Calcium 6 assay reagent (Molecular Devices, CA, USA) and compounds diluted in Ringer buffer at concentrations of 0.04 nM to 1 μM for 90 minutes at 37°C in the dark. Ringer buffer composition (mM): 143 NaCl, 4 KCl, 1.2 MgCl2, 1 CaCl2, 5 glucose, 10 HEPES and (adjusted with 1.0 M NaOH to pH 7.4). Intracellular calcium changes were monitored using FLIPRtetra (Molecular Devices, CA, USA) with 1 μM 7α,25-dihydroxysterol as an agonist and displayed in ScreenWorks software. Samples were excited at 470–495 nm and luminescence was detected at 515–575 nm. All experiments were performed at 37°C. In vitro antagonistic pharmacology was calculated by subtracting the minimum baseline fluorescence value from the maximum value. The IC50 value was determined using a four-parameter logistic fit model (ActivityBase XE). The results are shown in Table 1.

[0089] [Table 1] TIFF2026522963000069.tif243156 TIFF2026522963000070.tif248156 TIFF2026522963000071.tif248156 TIFF2026522963000072.tif33156

[0090] Experiment 2: In vitro efficacy The efficacy of GPR183 antagonist compounds can be investigated in a nonclinical in vivo monoiodoacetic acid (MIA) model of osteoarthritis pain in rats, following the method described by Combe et al. in Neuroscience Letters, 370 (2004).

[0091] Compounds of formula I exhibit GPR183 antagonist activity. Therefore, this disclosure provides compounds for use as pharmaceuticals. Compounds for use in the treatment of disorders, conditions, or diseases for which GPR183 antagonists are indicated as useful are also provided. Furthermore, methods for treating disorders, conditions, or diseases for which GPR183 antagonists are indicated as useful are also provided. In such methods, an effective amount of at least one compound of formula I is administered to a mammal, such as a human, in need of treatment. The use of compounds of formula I in the manufacture of pharmaceuticals for the treatment of disorders, conditions, or diseases for which GPR183 antagonists are indicated as useful is also provided.

[0092] In one embodiment, the aforementioned disorders, conditions, or diseases for which a GPR183 antagonist is shown to be useful are chronic pain, e.g., osteoarthritis, chronic low back pain, neuropathic pain, and immune system disorders, e.g., inflammatory bowel disease, e.g., colitis and Crohn's disease, multiple sclerosis, rheumatoid arthritis, or inflammatory lung diseases, e.g., asthma and psoriasis, which are improved by inhibition of the GPR183 receptor.

[0093] The compounds of this disclosure may be administered, for example, enterally, topically, or parenterally, by any pharmaceutical formulation comprising at least one active compound of formula I in a useful and pharmaceutically acceptable amount together with a pharmaceutically acceptable diluent, carrier, and / or excipient known in the art. The manufacture of such pharmaceutical formulations is known in the art.

[0094] The therapeutic dose to be administered to a subject requiring treatment varies depending on the compound being administered, the species, age, and sex of the subject being treated, the specific condition being treated, and the route and method of administration, and can be easily determined by those skilled in the art. Therefore, a typical oral dose for adult mammals is 10 ng / kg to 100 mg / kg per day, and a parenteral dose is 1 ng / kg to 10 mg / kg.

[0095] The compounds of this disclosure are administered to a subject either by themselves or in combination with one or more other active ingredients (each ingredient in a separate composition, or some or all of the active ingredients in a single composition), and / or with appropriate pharmaceutical excipients. Appropriate pharmaceutical excipients include conventionally used excipients and formulation aids, such as fillers, binders, disintegrants, lubricants, solvents, gelling agents, emulsifiers, stabilizers, colorants, and / or preservatives.

[0096] The compounds of this disclosure are formulated into dosage forms using well-known methods for manufacturing pharmaceuticals. These dosage forms include, for example, tablets, capsules, granules, suppositories, emulsions, suspensions, or solutions. Depending on the route of administration and the galenic form, the content of the active ingredient in the formulation can typically vary between 0.01% and 100% by weight.

[0097] Those skilled in the art will understand that the embodiments described herein can be modified without departing from the concept of the invention. Furthermore, those skilled in the art will understand that this disclosure is not limited to the embodiments specifically disclosed, but is intended to encompass modifications of embodiments that fall within the scope of this disclosure.

Claims

1. Equation I 【Chemistry 1】 (In the formula, The dotted line [----] indicates a single or double bond; X is O, CH 2 or CH, where X is O or CH 2 In this case, the dotted line represents a single bond, and when X is CH, the dotted line represents a double bond; R 1 is halogen, halo (C 1-3 ) alkyl or halo(C 1-3 ) is an alkoxy; R 2 It is a halogen; or R 1 and R 2 It bonds to an adjacent carbohydrate atom, forming a fused 2,2-difluoro-1,3-dioxolane ring together with the carbohydrate atom; R 3 is hydrogen; R 4 is, (C 2-6 ) alkyl, halo(C 1-3 ) alkyl, (C 1-3 ) Alkoxy (C 1-6 ) alkyl, (C 3-6 ) Cycloalkyl, 6-membered ring heterocyclyl, heterocyclyl (C 1-3 ) alkyl, NHR 5 or NR 6 R 7 And here, the (C 3-6 ) Cycloalkyl or heterocyclyl is either unsubstituted or hydroxy, (C 1-3 ) alkyl and (C 1-3 ) is substituted with one or more substituents independently selected from the alkoxy; R 5 is hydrogen, (C 2-6 ) alkyl, (C 1-3 ) Alkoxy (C 1-6 ) alkyl, hydroxy (C 1-6 ) alkyl, (C 3-6 ) Cycloalkyl, (C 3-6 ) Cycloalkyl (C 1-3 ) alkyl, or heterocyclyl (C 1-3 ) is alkyl, and here, the (C 3-6 ) Cycloalkyl or heterocyclyl is either unsubstituted or hydroxy, (C 1-3 ) Alkyl and phenyl (C 1-3 ) is substituted with one or more substituents independently selected from alkyl; R 6 and R 7 These, together with the nitrogen atom to which they are bonded, form a pyrrolidine ring, where the pyrrolidine ring is (C 1-3 ) alkyl, hydroxy (C 1-6 ) Substituted with one or two substituents independently selected from alkyl and heterocyclyl; n is an integer selected from 0, 1, or 2; m is an integer selected from 1 or 2. Compounds of or pharmaceutically acceptable salts thereof; However, the aforementioned compound is 2-(4-chlorophenoxy)-1-(4-(ethylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-fluorophenoxy)-1-(4-(isobutylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-(isobutylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(2,4-dichlorophenoxy)-1-(4-(ethylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(2,4-dichlorophenoxy)-1-(4-(isobutylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-fluorophenoxy)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 2-(2,4-dichlorophenoxy)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 3-(4-chlorophenyl)-1-(4-(ethylsulfonyl)piperidine-1-yl)prop-2-en-1-one, 1-(4-(ethylsulfonyl)piperidine-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one, 3-(4-chlorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)prop-2-en-1-one, 3-(2,4-dichlorophenyl)-1-(4-(ethylsulfonyl)piperidine-1-yl)prop-2-en-1-one, 3-(4-bromophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(3,4-dichlorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(3-chloro-4-fluorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(4-chloro-3-fluorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(2,4-dichlorophenyl)-1-(4-(isobutylsulfonyl)piperidine-1-yl)propan-1-one, 3-(4-chlorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, 1-(4-(isobutylsulfonyl)piperidine-1-yl)-3-(4-(trifluoromethyl)phenyl)propan-1-one, 3-(4-bromophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 3-(3-chloro-4-fluorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 3-(3,4-dichlorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 3-(2,4-dichlorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 3-(4-chloro-3-fluorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)propan-1-one, 1-(4-((furan-2-ylmethyl)sulfonyl)piperidine-1-yl)-3-(4-(trifluoromethyl)phenyl)propan-1-one, 1-(4-(ethylsulfonyl)piperidine-1-yl)-3-(4-fluorophenyl)propan-1-one, 1-(3-(4-chlorophenyl)propanoyl)piperidine-4-sulfonamide, or 1-(3-(4-fluorophenyl)propanoyl)piperidine-4-sulfonamide isn't it.

2. X is O; R 1 It is a halogen; R 3 is hydrogen; R 4 is, (C 3-6 ) alkyl, (C 1-3 ) Alkoxy (C 2-6 ) alkyl, heterocyclyl (C 1-3 ) alkyl, or NHR 5 And here, the heterocyclyl is not substituted; R 5 is, (C 1-3 ) Alkoxy (C 2-6 ) alkyl, hydroxy (C 3-6 ) alkyl, (C 3-6 ) Cycloalkyl (C 1-3 ) alkyl, or heterocyclyl (C 1-3 ) is alkyl, and here, the (C 3-6 ) Cycloalkyl or heterocyclyl is either unsubstituted or hydroxy and (C 1-2 ) is substituted with one substituent independently selected from alkyl; n is 0; The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 2.

3. X is CH; R 1 It is a halogen; R 3 is hydrogen; R 4 is, (C 3-6 ) alkyl, (C 1-3 ) Alkoxy (C 2-6 ) alkyl, heterocyclyl (C 1-3 ) alkyl, or NHR 5 And here, the heterocyclyl is not substituted; R 5 is, (C 1-3 ) Alkoxy (C 2-6 ) alkyl, hydroxy (C 3-6 ) alkyl, (C 3-6 ) Cycloalkyl (C 1-3 ) alkyl, or heterocyclyl (C 1-3 ) is alkyl, and here, the (C 3-6 ) Cycloalkyl or heterocyclyl is either unsubstituted or hydroxy and (C 1-2 ) is substituted with one substituent independently selected from alkyl; n is 0; The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 1.

4. Heterocyclines are based on the following groups: 【Chemistry 2】 The compound according to any one of claims 1 to 3, which is any one of the above.

5. The compound, 2-(3,4-dichlorophenoxy)-1-(4-(isopropylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-(difluoromethyl)phenoxy)-1-(4-(isopropylsulfonyl)piperidine-1-yl)ethane-1-one, 1-(4-((2-(1H-pyrazol-5-yl)ethyl)sulfonyl)piperidine-1-yl)-2-(4-chlorophenoxy)ethane-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-(2-ethoxyethyl)piperidine-4-sulfonamide, 2-(4-chlorophenoxy)-1-(4-(pentan-3-ylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(3,4-difluorophenoxy)-1-(4-(isopropylsulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-((difluoromethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-(isopropylsulfonyl)piperidine-1-yl)ethane-1-one, 1-(4-(isopropylsulfonyl)piperidine-1-yl)-2-(4-(trifluoromethoxy)phenoxy)ethane-1-one, 2-(4-chloro-3-fluorophenoxy)-1-(4-(isopropylsulfonyl)piperidine-1-yl)ethane-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, N-butyl-1-(2-(4-chlorophenoxy)acetyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-(4-hydroxy-4-methylpentyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-(3-hydroxy-3-methylbutyl)piperidine-4-sulfonamide, 2-(4-chlorophenoxy)-1-(4-((2,2-dimethylpyrrolidine-1-yl)sulfonyl)piperidine-1-yl)ethane-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-cyclopropylpiperidine-4-sulfonamide, 2-(4-chlorophenoxy)-1-(4-((3-methoxypropyl)sulfonyl)piperidine-1-yl)ethane-1-one, 1-(4-(sec-butylsulfonyl)piperidine-1-yl)-2-(4-chlorophenoxy)ethane-1-one, 2-(4-chlorophenoxy)-1-(4-((2-(tetrahydrofuran-2-yl)ethyl)sulfonyl)piperidine-1-yl)ethane-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-(2-hydroxy-2-methylbutyl)piperidine-4-sulfonamide, N-((1H-pyrazol-5-yl)methyl)-1-(2-(4-chlorophenoxy)acetyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-(isoxazol-3-ylmethyl)piperidine-4-sulfonamide, (R)-1-(4-((3-(1H-pyrazol-5-yl)pyrrolidine-1-yl)sulfonyl)piperidine-1-yl)-2-(4-chlorophenoxy)ethane-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-((1-hydroxycyclobutyl)methyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-((1-methyl-1H-pyrazol-3-yl)methyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-((1-ethyl-1H-pyrazol-3-yl)methyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-(pyridazine-3-ylmethyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-((1-hydroxycyclopentyl)methyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-(3-methoxypropyl)piperidine-4-sulfonamide, 1-(2-(4-chlorophenoxy)acetyl)-N-(pyrazine-2-ylmethyl)piperidine-4-sulfonamide, 2-(4-chlorophenoxy)-1-(4-(propylsulfonyl)piperidine-1-yl)ethane-1-one, 1-(4-(isopropylsulfonyl)piperidine-1-yl)-2-(4-(trifluoromethyl)phenoxy)ethane-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-(2-hydroxy-2-methylpropyl)piperidine-4-sulfonamide, 1-(3-(4-chlorophenyl)propanoyl)-N-(3-methoxypropyl)piperidine-4-sulfonamide, (E)-3-(4-chlorophenyl)-1-(4-(isopropylsulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acryloyl)-N-((1-ethyl-1H-pyrazol-3-yl)methyl)piperidine-4-sulfonamide, (E)-1-(3-(4-chlorophenyl)acryloyl)-N-((1-ethyl-1H-pyrazol-3-yl)methyl)piperidine-4-sulfonamide, (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-(isopropylsulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-1-(3-(4-chlorophenyl)acryloyl)-N-(2-hydroxy-2-methylpropyl)piperidine-4-sulfonamide, (E)-3-(4-bromophenyl)-1-(4-((3-methoxypropyl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acryloyl)-N-(3-hydroxy-3-methylbutyl)piperidine-4-sulfonamide, (E)-1-(3-(4-chlorophenyl)acryloyl)-N-(3-hydroxy-3-methylbutyl)piperidine-4-sulfonamide, (R,E)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acryloyl)-N-((tetrahydrofuran-2-yl)methyl)piperidine-4-sulfonamide, (R,E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-((3-(2-hydroxypropan-2-yl)pyrrolidine-1-yl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-1-(3-(4-chlorophenyl)acryloyl)-N-(2-ethoxyethyl)piperidine-4-sulfonamide, (E)-1-(4-((2-(1H-pyrazol-1-yl)ethyl)sulfonyl)piperidine-1-yl)-3-(4-chlorophenyl)prop-2-en-1-one, (E)-N-(2-(1H-pyrazol-1-yl)ethyl)-1-(3-(4-chlorophenyl)acryloyl)piperidine-4-sulfonamide, (R,E)-3-(4-chlorophenyl)-1-(4-((3-(2-hydroxypropan-2-yl)pyrrolidine-1-yl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, (R,E)-1-(3-(4-chlorophenyl)acryloyl)-N-((tetrahydrofuran-2-yl)methyl)piperidine-4-sulfonamide, (E)-N-((1-benzyl-1H-pyrazol-3-yl)methyl)-1-(3-(4-chlorophenyl)acryloyl)piperidine-4-sulfonamide, (E)-N-(3-methoxypropyl)-1-(3-(4-(trifluoromethyl)phenyl)acryloyl)piperidine-4-sulfonamide, (E)-1-(3-(4-chlorophenyl)acryloyl)-N-(3-methoxypropyl)piperidine-4-sulfonamide, (E)-3-(4-chlorophenyl)-1-(4-(propylsulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-3-(4-chlorophenyl)-1-(4-((difluoromethyl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-3-(4-chlorophenyl)-1-(4-(cyclobutylsulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-3-(4-chlorophenyl)-1-(4-((2-methoxypyrimidine-5-yl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, 1-(4-((2-(1H-pyrazol-1-yl)ethyl)sulfonyl)piperidine-1-yl)-2-(4-chlorophenoxy)ethane-1-one, N-((1-benzyl-1H-pyrazol-3-yl)methyl)-1-(2-(4-chlorophenoxy)acetyl)piperidine-4-sulfonamide, (E)-1-(3-(4-chlorophenyl)acryloyl)-N-(2-methoxyethyl)piperidine-4-sulfonamide, (E)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-((3-methoxypropyl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-3-(4-chlorophenyl)-1-(4-((3-methoxypropyl)sulfonyl)piperidine-1-yl)prop-2-en-1-one, (E)-N-((1H-pyrazol-5-yl)methyl)-1-(3-(4-chlorophenyl)acryloyl)piperidine-4-sulfonamide, or (E)-1-(3-(4-chlorophenyl)acryloyl)piperidine-4-sulfonamide, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. The compound, 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. The compound, 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. The compound, 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. The compound, 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. The compound, 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. The compound, 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. The compound, 【Chemistry 9】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. The compound, 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. The compound, 【Chemistry 11】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. The compound, 【Chemistry 12】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. A compound according to any one of claims 1 to 15 for use as a pharmaceutical.

17. A compound according to any one of claims 1 to 16, for use in the treatment of a disorder, condition, or disease for which a GPR183 antagonist has been indicated to be useful.

18. The compound according to claim 17, wherein the disorder, condition, or disease is improved by inhibition of the GPR183 receptor, and is chronic pain, such as osteoarthritis, chronic low back pain, neuropathic pain, and immune system disorders, such as inflammatory bowel diseases such as colitis and Crohn's disease, multiple sclerosis, rheumatoid arthritis, inflammatory lung diseases, such as asthma, and psoriasis.

19. A method for treating a disorder, condition, or disease for which a GPR183 antagonist has been indicated as useful, comprising administering an effective amount of at least one compound according to claim 1 to a mammal in need of such treatment.

20. The method according to claim 19, wherein the disorder, condition, or disease is improved by inhibition of the GPR183 receptor, and is chronic pain, such as osteoarthritis, chronic low back pain, neuropathic pain, and immune system disorders, such as inflammatory bowel diseases such as colitis and Crohn's disease, multiple sclerosis, rheumatoid arthritis, inflammatory lung diseases, such as asthma, and psoriasis.

21. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 15, and a pharmaceutically acceptable carrier, diluent and / or excipient.

22. The pharmaceutical composition according to claim 21, wherein the composition further comprises at least one other active ingredient.

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