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US-12617777-B2 - GPR84 antagonists and uses thereof

US12617777B2US 12617777 B2US12617777 B2US 12617777B2US-12617777-B2

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of GPR84, and the treatment of GPR84-mediated disorders.

Inventors

  • Shaun Abbott
  • Nadia Michel NASSER
  • Mylène De Léséleuc
  • Julien Martel
  • Elyse Bourque
  • Jeremy Green
  • Alexandre Larivée
  • Jean-Benoìt GIGUÈRE
  • Elodie LANDAGARAY
  • Claudio Sturino

Assignees

  • Liminal Biosciences Limited

Dates

Publication Date
20260505
Application Date
20220202

Claims (20)

  1. 1 . A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or pyridyl; Ring B together with (R 3 ) n is one of the following: R 1 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with p instances of R 4 ; each instance of R 2 , R 4 , and R 5 is independently hydrogen, deuterium, R z , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —CF 2 R, —CF 3 , —CR 2 (CN), —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —C(S)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)NR 2 , —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —N═S(O)R 2 , —S(NR) (O)R, —N(R)S(O)R, —N(R)CN, —Si(OR)R 2 , —SiR 3 , —P(O)(R)NR 2 , —P(O)(R)OR, or —P(O)R 2 ; each instance of R z is independently a C 1-3 aliphatic; R 3 is hydrogen; L 1 is a covalent bond; L 2 is a covalent bond; L 3 is X is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bridged or spiro cyclic, bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R 5 ; each instance of R is independently hydrogen or C 1-3 aliphatic; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and q is 0, 1, 2, or 3.
  2. 2 . The compound of claim 1 , wherein the compound is any one of formulae I-a, I-b-1, I-b-2, or I-b-3: or a pharmaceutically acceptable salt thereof.
  3. 3 . The compound of claim 1 , wherein the Ring A is phenyl.
  4. 4 . The compound of claim 1 , wherein Ring A and its R 2 substituents is
  5. 5 . The compound of claim 1 , wherein Ring B and its R 3 substituents is
  6. 6 . The compound of claim 1 , wherein Ring B and its R 3 substituents is
  7. 7 . The compound of claim 1 , wherein R 1 is a 4 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur which is substituted with p instances of R 4 .
  8. 8 . The compound of claim 1 , wherein R 1 and its R 4 substituents is
  9. 9 . The compound of claim 1 , wherein Ring A is pyridyl; Ring B together with (R 3 ) n is each instance of R 2 , R 4 , and R 5 is independently hydrogen, deuterium, R z , halogen, —CN, —NO 2 , —OR, —SR, or —NR 2 ; X is a 4-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur wherein said ring is substituted with q instances of R 5 ; n is 0 or 1; p is 0, 1, or 2; and q is 0, 1, or 2.
  10. 10 . The compound of claim 9 , wherein X is a 5-7 membered saturated monocyclic heterocyclic ring having 1 or 2 oxygen atoms, wherein said ring is substituted with q instances of R 5 .
  11. 11 . The compound of claim 1 , wherein each instance of R 2 and R 5 is independently hydrogen, deuterium, R z , halogen, —CN, —NO 2 , —OR, —SR, or —NR 2 ; m is 0, 1, or 2; n is 0 or 1; p is 0, 1, or 2; and q is 0, 1, or 2.
  12. 12 . The compound of claim 1 , wherein X is a 5-7 membered saturated monocyclic heterocyclic ring having 1 or 2 oxygen atoms, wherein said ring is substituted with q instances of R 5 .
  13. 13 . The compound of claim 1 , wherein the compound is of either one of formulae I-ii-1 or I-ii-2: or a pharmaceutically acceptable salt thereof, wherein R 2′ is an R 2 .
  14. 14 . The compound of claim 1 , wherein the compound is of either one of formulae I-jj-1 or I-jj-2: or a pharmaceutically acceptable salt thereof.
  15. 15 . The compound of claim 1 , wherein the compound is of either one of formulae I-kk-1 or I-kk-2: or a pharmaceutically acceptable salt thereof, wherein R 2′ is an R 2 .
  16. 16 . The compound of claim 1 , wherein the compound is of either one of formulae I-II-1 or I-11-2: or a pharmaceutically acceptable salt thereof.
  17. 17 . A compound selected from the following or a pharmaceutically acceptable salt thereof: Com- pound Structure I-75 I-111 I-112 I-114 I-128 I-129 I-142 I-153 I-157 I-158 I-170 I-183 I-184 I-202 I-213 I-223 I-253 I-254 I-255 I-256 I-260 I-263 I-264 I-271 I-279 I-280 I-376 I-377 I-378 I-379 I-380 I-381 I-384 I-385 I-386 I-387 I-388 I-390 I-409 I-421 I-422 I-428 I-431 I-436 I-437 I-439 I-442 I-445 I-446 I-447 I-448 I-449 I-450 I-461 I-463 I-470 I-471 I-472 I-477 I-484 I-485 I-486 I-487 I-495 I-499 I-500 I-501 I-506 I-507 I-508 I-519 I-520 I-524 I-529 I-544 I-555 I-584 I-585 I-588 I-589 I-595 I-600 I-609 I-614 I-618 I-626 I-630 I-641 I-654 I-664 I-665 I-667 I-677 I-678 I-685 I-687 I-694 I-696 I-706 I-707 I-710 I-711 I-726 I-728 I-729 I-730 I-735 I-740 I-748 I-754 I-755 I-765 I-776 I-784 I-786 I-796 I-800 I-801 I-804 I-805 I-807 I-809 I-816 I-860 I-863 I-864
  18. 18 . A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  19. 19 . A method of inhibiting GPR84 in a biological sample comprising contacting the sample with the compound of claim 1 or a pharmaceutically acceptable salt thereof.
  20. 20 . A method of treating a GPR84-mediated disorder, disease, or condition in a patient comprising administering to said patient in need thereof the compound of claim 1 .

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application Ser. No. 63/144,720, filed Feb. 2, 2021; the contents of which are hereby incorporated by reference. TECHNICAL FIELD OF THE INVENTION The present invention relates to compounds and methods useful for antagonizing G-protein coupled receptor 84 (GPR84). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION The G-protein coupled receptor 84 (GPR84), also known as EX33, GPCR4, and G protein-coupled receptor 84, is a medium chain fatty acid receptor mainly expressed in immune cells and upregulated under inflammatory conditions. GPR84 was isolated and characterized from human B cells (Wittenberger et al. 2001. J. Mol. Biol. 307, 799-813) as the result of an expressed sequence tag data mining strategy, and also using a degenerate primer reverse transcriptase-polymerase chain reaction (RT-PCR) approach aimed to identify novel chemokine receptors expressed in neutrophils (Yousefi S et al. 2001. J. Leukoc. Biol. 69, 1045-1052). GPR84 remained an orphan GPCR until the identification of medium-chain Free Fatty Acids (FFAs) with carbon chain lengths of 9-14 as ligands for this receptor (Wang J et al. 2006. J. Biol. Chem. 281, 34457-34464). GPR84 was described to be activated by capric acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) with potencies of 5 μM, 9 μM and 11 μM, respectively. Three small molecules were also described to have some GPR84 agonist activity: 3,3′-diindolylmethane (DIM) (Wang et al. 2006), embelin (Hakak Y et al. 2007. WO2007027661 (A2)) and 6-n-octylaminouracil (6-OAU) (Suzuki M et al. 2013. J. Biol. Chem. 288, 10684-10691). GPR84 has been shown to be expressed in immune cells at least but not limited to polymorphonuclear leukocytes (PMN), neutrophils, monocytes, T cells and B cells. (Hakak et al. 2007; Venkataraman C, Kuo F. 2005. Immunol. Lett. 101, 144-153; Wang et al. 2006; Yousefi et al. 2001). Higher levels of GPR84 were measured in neutrophils and eosinophils than in T-cells and B-cells. GPR84 expression was demonstrated in tissues that may play a role in the propagation of the inflammatory response such as lung, spleen, bone marrow. For example, in a recent review, du Bois reported the current status of therapies for lung interstitial diseases, such as idiopathic pulmonary fibrosis (IPF). There are almost 300 distinct injurious or inflammatory causes of interstitial lung disease that can result in diffuse lung scarring, and the initial stages of the IPF pathology are very likely to involve inflammation (du Bois R M. 2010. Nat. Rev. Drug Discov. 9, 129-140), and combination therapies involving anti-inflammatory treatment could be advantageously used. The expression of GPR84 was highly up-regulated in monocytes/macrophages upon LPS stimulation (Wang et al. 2006). GPR84 knock-out (KO) mice are viable and indistinguishable from wild-type littermate controls (Venkataraman & Kuo 2005). The proliferation of T and B cells in response to various mitogens is reported to be normal in GPR84-deficient mice (Venkataraman & Kuo 2005). T helper 2 (Th2) differentiated T cells from GPR84 KO mice secreted higher levels of IL4, IL5, IL13, the 3 major Th2 cytokines, compared to wild-type littermate controls. In contrast, the production of the Th1 cytokine, INFγ, was similar in Th1 differentiated T cells from GPR84 KO mice and wild-type littermate (Venkataraman & Kuo 2005). In addition, capric acid, undecanoic acid and lauric acid dose dependently increased the secretion of interleukin-12 p40 subunit (IL-12 p40) from RAW264.7 murine macrophage-like cells stimulated with LPS. The pro-inflammatory cytokine IL-12 plays a pivotal role in promoting cell-mediated immunity to eradicate pathogens by inducing and maintaining T helper 1 (Th1) responses and inhibiting T helper 2 (Th2) responses. Medium-chain FFAs, through their direct actions on GPR84, may affect Th1/Th2 balance. Berry et al. identified a whole-blood 393-gene transcriptional signature for active tuberculosis (TB) (Berry M P R et al. 2010. Nature 466, 973-977). GPR84 was part of this whole-blood 393-gene transcriptional signature for active TB indicating a potential role for GPR84 in infectious diseases. GPR84 expression was also described in microglia, the primary immune effector cells of the central nervous system (CNS) of myeloid-monocytic origin (Bouchard C et al. 2007. Glia 55, 790-800). As observed in peripheral immune cells, GPR84 expression in microglia was highly inducible under inflammatory conditions such as TNFα and IL1 treatment but also notably endotoxemia and experimental autoimmune encephalomyelitis (EAE), suggesting a role in neuroinflammatory processes. Those results suggest that GPR84 would be up-regulated in CNS not only during endo