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EP-4739656-A1 - 2-PHENOXY-1-(4-(ALKYLSULFONYL)PIPERIDIN-1-YL)ETHAN-1-ONE AND 3-PHENYL-1-(4-(ALKYLSULFONYL)PIPERIDIN-1-YL)PROP-2-EN-1-ONE DERIVATIVES AS GPR183 ANTAGONISTS FOR THE TREATMENT OF CHRONIC PAIN

EP4739656A1EP 4739656 A1EP4739656 A1EP 4739656A1EP-4739656-A1

Abstract

The disclosure relates to compounds of formula I, wherein X, and R 1 -R 4 , n, and m have the meaning given in the specification, and pharmaceutically acceptable salts thereof. The compounds of formula I exhibit GPR 183 antagonistic activity and are thus useful in the treatment or prevention of disorder, condition, or disease where GRP183 antagonist is indicated to be useful, such as e.g. 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.

Inventors

  • AHLMARK, MARKO
  • HAIKARAINEN, ANSSI
  • KOIVISTO, ARI-PEKKA
  • KUMPULAINEN, Esa
  • SAHARI, Aleksi
  • TURKU, Ainoleena
  • VÄISÄNEN, Emilia

Assignees

  • Orion Corporation

Dates

Publication Date
20260513
Application Date
20240704

Claims (20)

  1. CLAIMS 1. A compound of formula I, wherein; the dotted line [- - - -] represents a single or a double bond; X is O, CH 2 or CH, provided that when X is O or CH 2 the dotted line is a single bond, and when X is CH the dotted line is a double bond; R 1 is halogen, halo(C 1-3 )alkyl or halo(C 1-3 )alkoxy; R 2 is halogen; or R1 and R2 attached to adjacent carbon ring atoms form, together with the carbon ring atoms a fused 2,2-difluoro-1,3-dioxolane ring; R 3 is hydrogen; R4 is (C2-6)alkyl, halo(C1-3)alkyl, (C1-3)alkoxy(C1-6)alkyl, (C3-6)cycloalkyl, 6- membered heterocyclyl, heterocyclyl(C1-3)alkyl, NHR5 or NR6R7, wherein said (C3- 6 )cycloalkyl or heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from hydroxy, (C1-3)alkyl and (C1-3)alkoxy; R5 is hydrogen, (C2-6)alkyl, (C1-3)alkoxy(C1-6)alkyl, hydroxy(C1-6)alkyl, (C3- 6 )cycloalkyl, (C 3-6 )cycloalkyl(C 1-3 )alkyl, or heterocyclyl(C 1-3 )alkyl, wherein said (C 3- 6 )cycloalkyl or heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from hydroxy, (C1-3)alkyl and phenyl(C1-3)alkyl; R6 and R7 form, together with the nitrogen atom to which they are attached, a pyrrolidine ring wherein said pyrrolidine ring is substituted with 1 or 2 substituents independently selected from (C1-3)alkyl, hydroxy(C1-6)alkyl and heterocyclyl; n is an integer selected from 0, 1 or 2; m is an integer selected from 1 or 2; or a pharmaceutically acceptable salt thereof; with the proviso that the compound is not 2-(4-chlorophenoxy)-1-(4-(ethylsulfonyl)piperidin-1-yl)ethan-1-one, 2-(4-fluorophenoxy)-1-(4-(isobutylsulfonyl)piperidin-1-yl)ethan-1-one, 2-(4-chlorophenoxy)-1-(4-(isobutylsulfonyl)piperidin-1-yl)ethan-1-one, 2-(2,4-dichlorophenoxy)-1-(4-(ethylsulfonyl)piperidin-1-yl)ethan-1-one, 2-(2,4-dichlorophenoxy)-1-(4-(isobutylsulfonyl)piperidin-1-yl)ethan-1-one, 2-(4-fluorophenoxy)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidin-1-yl)ethan-1-one, 2-(4-chlorophenoxy)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidin-1-yl)ethan-1-one, 2-(2,4-dichlorophenoxy)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidin-1-yl)ethan-1- one, 3-(4-chlorophenyl)-1-(4-(ethylsulfonyl)piperidin-1-yl)prop-2-en-1-one, 1-(4-(ethylsulfonyl)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one, 3-(4-chlorophenyl)-1-(4-(isobutylsulfonyl)piperidin-1-yl)prop-2-en-1-one, 3-(2,4-dichlorophenyl)-1-(4-(ethylsulfonyl)piperidin-1-yl)prop-2-en-1-one, 3-(4-bromophenyl)-1-(4-(isobutylsulfonyl)piperidin-1-yl)propan-1-one, 3-(3,4-dichlorophenyl)-1-(4-(isobutylsulfonyl)piperidin-1-yl)propan-1-one, 3-(3-chloro-4-fluorophenyl)-1-(4-(isobutylsulfonyl)piperidin-1-yl)propan-1-one, 3-(4-chloro-3-fluorophenyl)-1-(4-(isobutylsulfonyl)piperidin-1-yl)propan-1-one, 3-(2,4-dichlorophenyl)-1-(4-(isobutylsulfonyl)piperidin-1-yl)propan-1-one, 3-(4-chlorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidin-1-yl)prop-2-en-1-one, 1-(4-(isobutylsulfonyl)piperidin-1-yl)-3-(4-(trifluoromethyl)phenyl)propan-1-one, 3-(4-bromophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidin-1-yl)propan-1-one, 3-(3-chloro-4-fluorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidin-1-yl)propan- 1-one, 3-(3,4-dichlorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidin-1-yl)propan-1- one, 3-(2,4-dichlorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidin-1-yl)propan-1- one, 3-(4-chloro-3-fluorophenyl)-1-(4-((furan-2-ylmethyl)sulfonyl)piperidin-1-yl)propan- 1-one, 1-(4-((furan-2-ylmethyl)sulfonyl)piperidin-1-yl)-3-(4-(trifluoromethyl)phenyl)- propan-1-one, 1-(4-(ethylsulfonyl)piperidin-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.
  2. 2. The compound according to claim 1, wherein X is O; R 1 is halogen; R3 is hydrogen; R4 is (C3-6)alkyl, (C1-3)alkoxy(C2-6)alkyl, heterocyclyl(C1-3)alkyl, or NHR5, wherein said heterocyclyl is unsubstituted; R5 is (C1-3)alkoxy(C2-6)alkyl, hydroxy(C3-6)alkyl, (C3-6)cycloalkyl(C1-3)alkyl, or heterocyclyl(C1-3)alkyl, wherein said (C3-6)cycloalkyl or heterocyclyl is unsubstituted or substituted with one substituent independently selected from hydroxy and (C1-2)alkyl; n is 0; m is 2; or a pharmaceutically acceptable salt thereof.
  3. 3. The compound according to claim 1, wherein X is CH; R 1 is halogen; R3 is hydrogen; R4 is (C3-6)alkyl, (C1-3)alkoxy(C2-6)alkyl, heterocyclyl(C1-3)alkyl, or NHR5, wherein said heterocyclyl is unsubstituted; 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(C1-3)alkyl, wherein said (C3-6)cycloalkyl or heterocyclyl is unsubstituted or substituted with one substituent independently selected from hydroxy and (C 1-2 )alkyl; n is 0; m is 1; or a pharmaceutically acceptable salt thereof.
  4. 4. The compound according to any one of claims 1 to 3, wherein the heterocyclyl is any one of the following groups: .
  5. 5. The compound according to claim 1, wherein the compound is; 2-(3,4-dichlorophenoxy)-1-(4-(isopropylsulfonyl)piperidin-1-yl)ethan-1-one, 2-(4-chlorophenoxy)-1-(4-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)piperidin-1- yl)ethan-1-one, 2-(4-(difluoromethyl)phenoxy)-1-(4-(isopropylsulfonyl)piperidin-1-yl)ethan-1-one, 1-(4-((2-(1H-pyrazol-5-yl)ethyl)sulfonyl)piperidin-1-yl)-2-(4-chlorophenoxy)ethan- 1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-(2-ethoxyethyl)piperidine-4-sulfonamide, 2-(4-chlorophenoxy)-1-(4-(pentan-3-ylsulfonyl)piperidin-1-yl)ethan-1-one, 2-(3,4-difluorophenoxy)-1-(4-(isopropylsulfonyl)piperidin-1-yl)ethan-1-one, 2-(4-chlorophenoxy)-1-(4-((difluoromethyl)sulfonyl)piperidin-1-yl)ethan-1-one, 2-(4-chlorophenoxy)-1-(4-(isopropylsulfonyl)piperidin-1-yl)ethan-1-one, 1-(4-(isopropylsulfonyl)piperidin-1-yl)-2-(4-(trifluoromethoxy)phenoxy)ethan-1-one, 2-(4-chloro-3-fluorophenoxy)-1-(4-(isopropylsulfonyl)piperidin-1-yl)ethan-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-dimethylpyrrolidin-1-yl)sulfonyl)piperidin-1- yl)ethan-1-one, 1-(2-(4-chlorophenoxy)acetyl)-N-cyclopropylpiperidine-4-sulfonamide, 2-(4-chlorophenoxy)-1-(4-((3-methoxypropyl)sulfonyl)piperidin-1-yl)ethan-1-one, 1-(4-(sec-butylsulfonyl)piperidin-1-yl)-2-(4-chlorophenoxy)ethan-1-one, 2-(4-chlorophenoxy)-1-(4-((2-(tetrahydrofuran-2-yl)ethyl)sulfonyl)piperidin-1- yl)ethan-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)pyrrolidin-1-yl)sulfonyl)piperidin-1-yl)-2-(4- chlorophenoxy)ethan-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-(pyridazin-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-(pyrazin-2-ylmethyl)piperidine-4-sulfonamide, 2-(4-chlorophenoxy)-1-(4-(propylsulfonyl)piperidin-1-yl)ethan-1-one, 1-(4-(isopropylsulfonyl)piperidin-1-yl)-2-(4-(trifluoromethyl)phenoxy)ethan-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)piperidin-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)piperidin-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)piperidin-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)pyrrolidin-1-yl)sulfonyl)piperidin-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)piperidin-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)pyrrolidin-1- yl)sulfonyl)piperidin-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)piperidin-1-yl)prop-2-en-1-one, (E)-3-(4-chlorophenyl)-1-(4-((difluoromethyl)sulfonyl)piperidin-1-yl)prop-2-en-1- one, (E)-3-(4-chlorophenyl)-1-(4-(cyclobutylsulfonyl)piperidin-1-yl)prop-2-en-1-one, (E)-3-(4-chlorophenyl)-1-(4-((2-methoxypyrimidin-5-yl)sulfonyl)piperidin-1- yl)prop-2-en-1-one, 1-(4-((2-(1H-pyrazol-1-yl)ethyl)sulfonyl)piperidin-1-yl)-2-(4-chlorophenoxy)ethan- 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)- piperidin-1-yl)prop-2-en-1-one, (E)-3-(4-chlorophenyl)-1-(4-((3-methoxypropyl)sulfonyl)piperidin-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, or a pharmaceutically acceptable salt thereof.
  6. 6. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.
  7. 7. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.
  8. 8. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.
  9. 9. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.
  10. 10. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.
  11. 11. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.
  12. 12. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.
  13. 13. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.
  14. 14. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.
  15. 15. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.
  16. 16. The compound according to any one of claims 1 to 15 for use as a medicament.
  17. 17. The compound according to any one of claims 1 to 16 for use in the treatment of a disorder, condition, or disease where a GPR183 antagonist is indicated to be useful.
  18. 18. The compound according to claim 17, 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.
  19. 19. 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.
  20. 20. The method according to claim 19, 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.

Description

NEW PHARMACEUTICAL COMPOUNDS FIELD OF THE INVENTION The present disclosure relates to novel pharmacologically active compounds as well as to pharmaceutical compositions comprising them and to their use as GPR183 antagonists. BACKGROUND OF THE INVENTION G protein‐coupled receptor 183 (GPR183) also known as Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) 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 (Birkenbach et al.,1993). Following deorphanization of GPR183 by identifying 7α,25-dihydroxycholesterol as a potent and selective endogenous agonist of the receptor (Hannedouche et al., 2011), the involvement of the receptor and ligand in cellular functions and physiological processes have been more extensively studied and revealed. Intracellularly GPR183 has been shown to couple to Gi and inhibition of cyclic AMP and activation of ERK (Benned-Jensen et al.,2011). Ligand-induced or constitutive GPR183 internalization is independent of β-arrestin whereas migration mediated by GPR183 is dependent on β-arrestin coupling (Kjær et al.,2023). The cryo-EM structures of GPR183-Gi signalling complex with its endogenous agonist 7α,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 Gαi interface attenuated G protein signalling and abolished oxysterol- mediated cell migration indicating that G protein signalling is directly involved in the oxysterol GPR183 pathway (Chen et al.,2022). 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 (Rosenkilde et al.2006). The expression pattern and the finding that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing GPR183 by directing cell migration in vitro and in vivo (Hannedouche et al., 2011) implicates a possibility for targeting the receptor for immunological indications and disorders. Involvement of GPR183 in pain perception has been shown as acute intrathecal injection of the GPR183 ligand, 7α,25-OHC in naive mice induced dose-dependent allodynia. GPR183 expression was upregulated in the dorsal spinal cord after chronic constriction injury (CCI) (Braden et al., 2020). Overexpression of the CH25H enzyme, that metabolizes cholesterol to the GPR183 agonist 7α,25-OHC, has been detected in the cartilage of human osteoarthritis patients (Choi et al., 2019). GPR183 expression in the central nervous system in human astrocytes (Rutowska et al., 2012) and microglia (Hsiao et al., 2019), 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. Some compounds modulating the activity of GPR183 protein are known in the art. WO2023066190 describes some heterocyclic compouds as GPR183 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. SUMMARY OF THE INVENTION 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. The novel GPR183 antagonists of the present disclosure have improved physicochemical properties and a more desirable pharmacokinetic profile. DETAILED DESCRIPTION OF THE INVENTION The present disclosure relates to novel compounds having the general formula I, wherein; the dotted line [- - - -] represents a single or a double bond; X is O, CH2 or CH, provided that when X is O or CH2 the dotted line is a single bond, and when X is CH the dotted line is a double bond; R1 is halogen, halo(C1-3)alkyl or halo(C1-3)alkoxy; R2 is ha