EP3535244A1 - Composés spiro en tant que modulateurs de s1p - Google Patents

Composés spiro en tant que modulateurs de s1p

Info

Publication number
EP3535244A1
EP3535244A1 EP17800433.9A EP17800433A EP3535244A1 EP 3535244 A1 EP3535244 A1 EP 3535244A1 EP 17800433 A EP17800433 A EP 17800433A EP 3535244 A1 EP3535244 A1 EP 3535244A1
Authority
EP
European Patent Office
Prior art keywords
azetidine
inden
dihydrospiro
oxy
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17800433.9A
Other languages
German (de)
English (en)
Inventor
Wilhelm Amberg
Jeroen VAN BERGEIJK
Herve Geneste
Wilfried Hornberger
Elizabeth Louise Van Der Kam
Udo Lange
Mario Mezler
Michael Ochse
Frank OELLIEN
Patrick WALLESER
Sean C Turner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Deutschland GmbH and Co KG
Original Assignee
AbbVie Deutschland GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AbbVie Deutschland GmbH and Co KG filed Critical AbbVie Deutschland GmbH and Co KG
Publication of EP3535244A1 publication Critical patent/EP3535244A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/12—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems

Definitions

  • the invention relates to spiro compounds with affinity to SIP receptors, pharmaceutical compositions comprising such compounds, the use of such compounds in the treatment or alleviation of diseases and disorders in which an SIP receptor is involved or in which modulation of the endogenous SIP signaling system via an SIP receptor is involved and the preparation of a medicament for treating or alleviating such diseases and disorders.
  • SIP Sphingosine-l-phosphate
  • SIP is part of the sphingolipid class of molecules. SIP is a bioactive sphingolipid that mediates a wide variety of cellular responses, such as proliferation, autophagy, blockade of apoptosis, cell
  • SIP is a modulator of APP processing via BACE1 regulation as well as lipid raft formation and can interact with ABC transporters thereby modulating cellular in- and efflux.
  • SIP can bind with members of the endothelial cell differentiation gene family (EDG receptors) of plasma membrane-localized G protein-coupled receptors. To date, five members of this family have been identified as SIP receptors in different cell types, SlPl (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6) and S1P5 (EDG-8).
  • EDG receptors endothelial cell differentiation gene family
  • EDG-3 endothelial cell differentiation gene family
  • SIP SlPl (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6) and S1P5 (EDG-8).
  • SIP can produce cytoskeletal re-arrangements in many cell types to regulate immune cell trafficking
  • SIP central nervous system
  • peripheral organ systems The above mentioned actions of SIP are mediated by interaction with its receptors. Therefore, SIP receptors are therapeutic targets for the treatment of, for example, neoplastic diseases, diseases of the central and peripheral nervous system, autoimmune disorders and tissue rejection in transplantation.
  • SIP is secreted by vascular endothelium and is present in blood at concentrations of 200-900 nanomolar and is bound by albumin and other plasma proteins. This provides both a stable reservoir in extracellular fluids and efficient delivery to high-affinity cell-surface receptors. SIP binds with low nanomolar affinity to the five receptors S1P1-5. In addition, platelets also contain SIP and may be locally released to cause e.g. vasoconstriction. The receptor subtypes S1P1, S1P2 and S1P3 are widely expressed and represent dominant receptors in the cardiovascular system. Further, S1P1 is also a receptor on lymphocytes.
  • S1P4 receptors are almost exclusively in the haematopoietic and lymphoid system.
  • S1P5 is primarily (though not exclusively) expressed in central nervous system (CNS; brain and spinal cord). Other tissues with S1P5 expression are skin and spleen. Moreover, S1P5 is expressed on NK cells.
  • CNS central nervous system
  • NK cells NK cells.
  • S1P5 expression is shown at the level of astrocytes, endothelial cells, glial cells, oligodendrocytes and to a lesser extent neurons.
  • the present invention relates to modulators of the S1P5 receptor, in particular agonists, and preferably to agonists with selectivity over S1P1, S1P3 and/or S1P4 receptors, in view of unwanted cardiovascular and/or peripheral immune- modulatory effects.
  • S1P5 agonists can be used in the treatment of cognitive disorders, in particular age-related cognitive decline.
  • evidence has shown an impact on amyloid 6 (protein) processing, ABC transporter expression, blood-brain-barrier integrity, neuro-inflammatory processes, and (sphingo)lipid content in the CNS.
  • AD Alzheimer's Disease
  • genes responsible for SIP degradation were strongly upregulated, including the phosphatidic acid phosphatase PPAP2A and SIP lyase genes, while genes for ceramide production (apoptotic sphingolipid) were upregulated (Katsel et al, 2007, Neurochem Res, 32, 845-856).
  • CSF cerebrospinal fluid
  • sphingolipdidosis disorders such as Niemann Pick Disease and Gauchers (Cutler et al, 2002, Ann Neurol, 52, 448-457; Haughey et al, 2004, Ann Neurol, 55, 257-267; Cutler et al, 2010, Neurol, 63, 636-630; Mielke et al, 2013, PLOS ONE, 8; Bras et al, 2008, FEBS Journal, 275, 5767-5773; Vidaurre et al, 2014, Brain, 137, 2271-2286; Fan et al, 2013, J Lipid Research, 54, 2800- 2814).
  • Modulating the activity of the S1P5 receptor in the central nervous system may be a therapeutic method for such neurodegenerative or cognitive disorders by shifting the ceramide/SlP balance towards SIP effects and away from ceramide- mediated cell death.
  • Soluble 6-amyloid (A6) oligomers are considered the proximate effectors of synaptic injury and neuronal death occurring in AD.
  • A6 induces increased ceramide levels and oxidative stress in neuronal cultures, leading to apoptosis and cell death.
  • SIP is a potent neuroprotective factor against this A6-induced damage, consistent with its role as ceramide's counterpart (Cutler et al, 2004, PNAS, 101, 2070-2075, Malaplate-Armand, 2006, Neurobiol. Dis, 23, 178-189).
  • A6 is also proinflammatory, inducing the migration of monocytes to sites of injury, and the S1P1, S1P3, S1P4, S1P5 agonist FTY720/Fingolimod inhibits such migration.
  • A6 is known to induce expression of S1P2 and S1P5, but not of S1P1, S1P3 and S1P4 (Kaneider et al, 2004, FASEB).
  • the actions of FTY720/FIngolimod and those expressed by monocytes suggest these effects are mediated by the S1P5 receptor.
  • the same applies to more recent findings that FTY720/Fingolimod is able to modulate A6-induced memory deficits (Fukumoto et al, 2014, Beh Brain Res, 268, 88-93).
  • SIP modulates action potentials in capsaicin-sensitive sensory neurons (Zhang et al, 2006, J Physiol, 575, 101-113) and SIP levels are known to be decreased in CSF in acute and inflammatory pain models (Coste et al, 2008, J Biol Chem, 283, 32442-32451).
  • S1P1, S1P3, S1P4, S1P5 receptor agonist S1P1, S1P3, S1P4, S1P5 receptor agonist
  • FTY720/Fingolimod is indeed able to reduce nociceptive behavior in neuropathic pain models (Coste et al, 2008, 12, 995-1004), while the selective S1P1 agonist SEW2817 fails to have an effect.
  • the effects can be contributed to effects on the S1P5 receptor.
  • potent and selective agents that are agonists of the S1P5 receptor will be beneficial for the treatment of cognitive disorders
  • SlP5-selective ligands would be beneficial for these diseases by not engaging the S1P1, S1P3 and/or S1P4 receptor ensuring a lack of peripheral immune suppression and cardiovascular side-effects.
  • WO 2012/004373 describes SIP receptor modulators containing a fused heterocyclic core. This fused heterocyclic core structurally differs from the compounds of the present invention in the size and position of the rings
  • WO 2012/004378 also describes SIP receptor modulators containing a core comprising a fused bicyclic ring structure. These compounds structurally differ from the compounds of the present invention in the position of the ring structures relative to each other, resulting in differences in overall three-dimensional configuration of the chemical structure. Other differences are in the size of the ring structures and the heteroatoms present in the ring structure.
  • S1P5 receptor modulators in particular agonists, preferably to agonists with selectivity over in particular S1P1, S1P3 and/or S1P4 receptors to avoid unwanted cardiovascular and/or immunomodulatory effects. It is a further object of the invention to provide a method for treatment or alleviation of a variety of CNS disorders, such as cognitive disorders, in particular age-related cognitive decline.
  • the invention therefor provides a compound of formula (I):
  • X is CH 2 or O
  • n and n are independently 0 or 1;
  • Rl is selected from the group consisting of -(Cl-4)alkylene-R2, -(C3- 6)cycloalkylene-R2, -(Cl-3)alkylene-(C3-6)cycloalkylene-R2 and -(C3- 6)cycloalkylene-(Cl-3)alkylene-R2, wherein the (Cl-4)alkylene is optionally substituted with up to 3 carbon atoms, with (CH2)2 to form a cyclopropyl moiety or with (CH2)3 to form a cyclobutyl moiety and wherein R2 is selected from the group consisting of -COOH, -OH, -OPO3H2, -PO3H2, -COO(Cl-4)alkyl and tetrazol-5-yl;
  • L is attached to atom 1, 2, 3 or 4 and is a group -W-(CH2)p-T- wherein:
  • halogen atom independently selected from the group consisting of a halogen atom, hydroxy, (Cl-4)alkyl optionally substituted with one or more halogen atoms, and (Cl- 4)alkoxy optionally substituted with one or more halogen atoms;
  • p is 0 or an integer from 1 to 4.
  • R3 is selected from the group consisting of(C3-6)cycloalkyl, (C4-6)cycloalkenyl, phenyl, biphenyl, naphthyl, a monocyclic heterocycle and a 8-10 membered fused bicyclic group, each optionally substituted with one or more substituents
  • R4 is absent or selected from the group consisting of a halogen atom, (Cl-4)alkyl optionally substituted with one or more halogen atoms, and (Cl-4)alkoxy optionally substituted with one or more halogen atoms.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary.
  • the invention provides a method of treatment or alleviation of a disease or disorder in which an SIP receptor is involved or in which modulation of the endogenous SIP signaling system via an SIP receptor is involved, preferably S1P5, comprising administering to a patient in need thereof a compound according to the invention or a pharmaceutically acceptable salt thereof.
  • the invention provides a use of a compound according to the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or alleviation of a disease or disorder in which an SIP receptor is involved or in which modulation of the endogenous SIP signaling system via an SIP receptor is involved, preferably S1P5 receptor.
  • the invention provides a compound according to the invention or a pharmaceutically acceptable salt thereof for use in therapy.
  • the invention provides a compound according to the invention or a pharmaceutically acceptable salt thereof for use in the treatment or alleviation of a disease or disorder in which an SIP receptor is involved or in which modulation of the endogenous SIP signaling system via an SIP receptor is involved, preferably S1P5.
  • the compounds of the invention are modulators of the SIP receptor, in particular of the S1P5 receptor. More specifically, the compounds of the invention are S1P5 receptor agonists.
  • pharmaceutically acceptable salts are in particular suitable for agonizing S1P5 in a subject suffering from a disorder in which modulation of S1P5 activity and the subsequent ceramide/SlP axis is beneficial.
  • Administration of such compound to a subject is preferably such that S1P5 activity in the subject is altered and treatment is achieved.
  • the compounds of the present invention are particularly suitable to treat or alleviate diseases and disorder s in which an SIP receptor is involved or in which modulation of the endogenous SIP signaling system via an SIP receptor is involved.
  • the compounds of the present invention are suitable to treat or alleviate a disorder or disorder selected from the group consisting of Alzheimer's Disease (AD) and associated dementia's, amyloid 6-associated disorders, Mild Cognitive Impairment (MCI), Parkinson's Disease (PD), Lewy Body Dementia (LBD), Progressive Supranuclear Palsy (PSP), Cerebral Palsy (CP), Amyotrophic Lateral Sclerosis (ALS), Frontal Temporal Lobe Dementia (FTLD), multiple sclerosis, Huntington's Disease, neurological symptoms of sphingolipidosis disorders, a lysosomal storage disorder including Tay Sachs Disease, Sandhoff Disease, Fabry's Disease, Krabbe Disease, Gaucher's Disease, Niemann Pick A, B or C, and Batten's Disease, stroke, HIV-associated Dementia (HAD), HIV-associate Neurocognitive Disorder (HAND), HIV-associated neuropathy, schizophrenia, cognitive deficits in Schizophrenia, an attention deficit disorder including
  • CIPN depression, treatment-resistant depression, Creutzfeld- Jakob Disease and other Prion-related Disorders, Down's Syndrome, autism, age-related cognitive decline or memory impairment, cognitive deficits associated with diabetes, dementia, dementia associated with Down's Syndrome, cognitive deficits in psychiatric disorders, dementia associated with Lewy Body pathology, diminished CNS function associated with traumatic brain injury, Pick's Disease, spinal cord injury, a demyelinating disorder, a disorder of basal ganglia and AIDS-associated dementia.
  • the compounds of the invention are further suitable to treat or alleviate a disease with a neuro-inflammatory component, in particular a disease or disorder selected from the group consisting of Psoriasis type 1 and type 2, atopic dermatitis, dermatitis scleroderma, insulin- dependent diabetes mellitus, ulcerative colitis, atherosclerosis, sepsis syndrome, septic shock, Dengue hemorrhagic fever, Dengue, atopic allergy, HIV/AIDS, barrier-integrity associated lung diseases, leukemia, contact dermatitis, encephalomyelitis, Epstein Barr virus infection and other virus infections requiring cell-cell fusion.
  • a neuro-inflammatory component in particular a disease or disorder selected from the group consisting of Psoriasis type 1 and type 2, atopic dermatitis, dermatitis scleroderma, insulin- dependent diabetes mellitus, ulcerative colitis, atherosclerosis, sepsis syndrome, septic shock, Dengue hemorrhagic fever
  • n is 0 or 1.
  • the nitrogen containing ring preferably is a 4- membered or 6-membered ring. Hence, preferably m and n are both 0 or both 1. In one embodiment, m and n are both 1 and the compound has the formula (lb):
  • X is O. In a preferred embodiment, X is CH2.
  • L is attached to one of the atoms numbered 1, 2, 3 or 4.
  • the group L-R3 is attached to one of the carbon atoms numbered 2 or 3.
  • formula (I is preferably selected from formula (Ic) and formula (Id) :
  • formula (I) is selected from formula (Ie) and
  • a compound of the invention is a compound of formula (Ie).
  • L is a group -W-(CH2)p-T- wherein:
  • p is 0 or an integer from 1 to 4.
  • T is -O- or -0-(Cl-4)alkyl-, preferably -O- or -O-CH2-, if W is selected from the group consisting of -O- and optionally substituted -phenyl, -(C3-7)cycloalkyl-, -pyridyl-, -thienyl- or -thiazolyl-. Otherwise, i.e.
  • T is preferably absent.
  • Rl is selected from the group consisting of -(Cl-4)alkylene-R2, -(C3- 6)cycloalkylene-R2, -(Cl-3)alkylene-(C3-6)cycloalkylene-R2 and -(C3-
  • Rl is -(Cl-3)alkylene-R2 or -
  • (C3-6)cycloalkylene-R2 wherein the (Cl-3)alkylene is optionally substituted with up to two CH3 groups, with (CH2)2 to form a cyclopropyl moiety or with (CH2)3 to form a cyclobutyl moiety.
  • Rl is selected from the group consisting of -
  • Rl is selected from the group consisting of -l,3-cyclobutylene-R2 and -(Cl-3)alkylene-R2, wherein the (Cl)alkyl is unsubstituted and the (C2)alkyl and the (C3)alkyl are substituted with up to two CH3 groups, with (CH2)2 to form a cyclopropyl moiety or with (CH2)3 to form a cyclobutyl moiety.
  • Rl is selected from the group consisting of -CH2-R2, -C2-alkylene-R2 wherein the C2-alkylene is substituted with up to two CH3 groups, with (CH2)2 to form a cyclopropyl moiety or with (CH2)3 to form a cyclobutyl moiety, -C3-alkylene-R2 wherein the alkylene is substituted with one CH3 group, and -(C3-6)cycloalkylene-R2.
  • Rl is -CH2-R2, ⁇ — ⁇ or -1,3- cyclobutylene-R2, wherein R2 is COOH.
  • R2 is selected from the group consisting of -COOH, -OH, -OPO3H2, - PO3H2, -COO(Cl-4)alkyl and tetrazol-5-yl.
  • R2 is preferably selected from the group consisting of -OH, -COOH and -COO(Cl-4)alkyl.
  • R2 is -COOH.
  • R3 is selected from the group consisting of (C3-6)cycloalkyl, (C4- 6)cycloalkenyl, phenyl, biphenyl, naphthyl, a monocyclic heterocycle and a 8-10 membered fused bicyclic group, each optionally substituted with one or more substituents independently selected from the group consisting of:
  • R3 is selected from the group consisting of (C3-6)cycloalkyl, (C4-6)cycloalkenyl, phenyl, a monocyclic heterocycle and a 8-10 membered fused bicyclic group, each optionally substituted with one or more substituents, preferably 1 to 3 substituents, independently selected from the group consisting of:
  • R3 is selected from the group consisting of: o (C3-6)cycloalkyl, preferably cyclohexyl, optionally substituted with (Cl- 4)alkyl;
  • o monocyclic heterocycle preferably oxanyl or pyridyl, most preferably pyridyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of:
  • o 8-10 membered fused bicyclic group preferably 2,3-dihydrobenzofuranyl, or indanyl, optionally substituted with one or two halogen atoms;
  • o phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of:
  • R3 is selected from the group consisting of:
  • R3 is pyridyl, optionally substituted with 1 or 2 substituents independelty selected from the group consisting of halogen, cyano, (Cl 4)alkyl optionally substituted with one or more fluoro atoms, (Cl 4)alkoxy optionally substituted with one or more fluoro atoms or with (C3-6)cycloalkyl, (C3-
  • cycloalkyl optionally substituted with (Cl-4)alkyl, (Cl-4)alkoxy or a halogen atom.
  • Such optionally substituted pyridyl is further preferably attached to the cyclic core via linker -O-CH2-, whereby the -CH2- is attached to R3.
  • R4 is absent or is attached to atom 1, 2, 3 or 4 and selected from the group consisting of a halogen atom, (Cl-4)alkyl optionally substituted with one or more halogen atoms, and (Cl-4)alkoxy optionally substituted with one or more halogen atoms.
  • R4 is absent or a halogen atom.
  • R4 is absent.
  • Further particularly preferred compounds of the invention are compounds of formula (I), preferably formula (Ic) or (Id) , or pharmaceutically acceptable saltsthereof, wherein
  • X is CH 2 or O
  • n and n are both 0 or both 1, preferably both 0;
  • Rl is selected from the group consisting of -CH2-R2, -C2-alkyli wherein the C2-alkylene is substituted with up to two carbon atoms, with (CH2)2 to form a cyclopropyl moiety or with (CH2)3 to form a cyclobutyl moiety, and -(C3- 6)cycloalkylene-R2, wherein R2 is selected from the group consisting of -COOH, - OH, -OPO3H2, -PO3H2, -COO(Cl-4)alkyl and tetrazol-5-yl, preferably from the group consisting of -OH, -COOH and -COO(Cl-4)alkyl;
  • L is attached to atom 1, 2, 3 or 4, preferably to atom 2 or 3, and is a group -W-(CH2)p-T- wherein:
  • p is 0, or an integer from 1 to 4 and
  • T is absent or selected from the group consisting of -O- and -0-(Cl-
  • R3 is selected from the group consisting of (C3-6)cycloalkyl, (C4-
  • R4 is absent or selected from the group consisting of a halogen atom, (Cl-4)alkyl optionally substituted with one or more halogen atoms, and (Cl- 4)alkoxy optionally substituted with one or more halogen atoms.
  • X is CH 2 or O
  • Rl is selected from the group consisting of -CH2-R2, -C2-alkylene-R2 wherein the C2-alkylene is substituted with up to two carbon atoms, with (CH2)2 to form a cyclopropyl moiety or with (CH2)3 to form a cyclobutyl moiety, -C3-alkylene- R2 wherein the 3alkylene is substituted with one carbon atom, and -(C3- 6)cycloalkylene-R2, wherein R2 is selected from the group consisting of -COOH, - OH, -OPO3H2, -PO3H2, -COO(Cl-4)alkyl and tetrazol-5-yl, preferably from the group consisting of -OH, -COOH and -COO(Cl-4)alkyl;
  • L is a group -W-(CH2)p-T- wherein:
  • p is 0, or an integer from 1 to 4 and
  • T is absent or selected from the group consisting of -O- and -0-(Cl-
  • R3 is selected from the group consisting of:
  • o monocyclic heterocycle preferably oxanyl or pyridyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of:
  • o 8-10 membered fused bicyclic group preferably 2,3-dihydrobenzofuranyl, indanyl, indoly or 1,3-dioxaindanyl, optionally substituted with one or two halogen atoms;
  • R4 is absent.
  • X is CH 2 or O;
  • Rl is selected from the group consisting of -CH2-R2, -CH2-C(CH3)-CH2- R2, and -l,3-cyclobutylene-R2, wherein R2 is selected from the group consisting of - OH, -COOH and -COO(Cl-4)alkyl, and preferably is -OH or -COOH, more preferably -COOH;
  • L is selected from the group consisting of -(C2-4)alkyl-, -0-, -0-(Cl-
  • R3 is selected from the group consisting of:
  • o monocyclic heterocycle preferably oxanyl or pyridyl, optionally substituted with one or two substituents independently selected from the group consisting of:
  • o 8-10 membered fused bicyclic group preferably 2, 3-dihydrobenzofuranyl, indanyl, indoly or 1,3-dioxaindanyl, optionally substituted with one or two halogen atoms;
  • X is CH 2 or O
  • Rl is selected from the group consisting of -CH2-R2, -CH2-C(CH3)-CH2-
  • R2 is selected from the group consisting of -OH, -COOH and -COO(Cl-4)alkyl, and preferably is -OH or -COOH, more preferably -COOH;
  • L is -0-(Cl-3)alkyl-, preferably -O-CH2-;
  • R3 is a monocyclic heterocycle, preferably oxanyl or pyridyl, optionally substituted with one or two substituents independently selected from the group consisting of
  • R4 is absent.
  • X is CH 2 ;
  • n and n are both 0 or both 1, preferably both 0;
  • Rl is selected from the group consisting of -l,3-cyclobutylene-R2 and - (Ci-3)alkylene-R2 wherein the (Cl)alkylene is unsubstituted, and the (C2)-alkylene and the (C3)-alkylene ares substituted with up to two carbon atoms, with (CH2)2 to form a cyclopropyl moiety or with (CH2)3 to form a cyclobutyl moiety, wherein R2 is selected from the group consisting of -COOH, -OH, -OPO3H2, -PO3H2, -COO(Cl-
  • L is attached to atom 2 or 3, and is a group -W-(CH2)p-T- wherein:
  • p is 0, or an integer from 1 to 4 and
  • T is absent or selected from the group consisting of -O- and -0-(Cl-
  • R3 is selected from the group consisting of:
  • o monocyclic heterocycle preferably oxanyl or pyridyl, optionally
  • o 8-10 membered fused bicyclic group preferably preferably 2,3- dihydrobenzofuranyl, indanyl, indoly or 1,3-dioxaindanyl, optionally substituted with one or two halogen atoms;
  • o phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of:
  • R4 is absent or selected from the group consisting of a halogen atom, (Cl-4)alkyl optionally substituted with one or more halogen atoms, and (Cl- 4)alkoxy optionally substituted with one or more halogen atoms.
  • Particularly preferred compounds depicted in table 1 are compounds having a EC50 for the S1P5 receptor of 100 nM or less, as shown in table 1, i.e. compounds having an S1P5 EC50 range A or B in table 1. Such compounds having an EC50 for the S1P5 receptor of 100 nM or less further preferably have an EC50 for at least one of the SlPl receptor, the S1P3 receptor and the S1P4 receptor of more than 1 ⁇ .
  • a preferred embodiment having an S1P5 EC50 of 100 nM or less (indicated with range A or B in table 1) and EC50 of more than 1 ⁇ for at least one of the SlPl receptor, the S1P3 receptor and the S1P4 receptor.
  • Further particularly preferred compounds depicted in table 1 are compounds having a EC50 for the S1P5 receptor of 10 nM or less, as shown in table 1, i.e. compounds having an S1P5 EC50 range A in table 1.
  • a preferred compound according to the invention is selected from the group consisting of:
  • Such compounds having an EC50 for the S1P5 receptor of lOnM or less further preferably have an EC50 for at least one of the SlPl receptor, the S1P3 receptor and the S1P4 receptor of more than 1 ⁇ .
  • a preferred compound according to the invention is selected from the group consisting of:
  • a compound of the invention has a EC50 for the S1P5 receptor of 10 nM or less, i.e. compounds having an S1P5 EC50 range A in table 1, and an EC50 of more than 1 ⁇ for the S1P1 receptor.
  • a preferred compound according to the invention is selected from the group consisting of:
  • a compound of the invention has a EC50 for the S1P5 receptor of 10 nM or less, i.e. compounds having an S1P5 EC50 range A in table 1, and a EC50 of more than 1 ⁇ for the S1P3 receptor.
  • a preferred compound according to the invention is selected from the group consisting of:
  • a compound of the invention has a
  • a preferred compound according to the invention is selected from the group consisting of:
  • a preferred compound according to the invention is selected from the group consisting of:
  • halogen or "a halogen atom” refers to fluoro, chloro, bromo, or iodo. Preferred halogen atoms are fluoro and chloro.
  • (Cx-y)alkyl refers to a branched or unbranched alkyl group having x-y carbon atoms.
  • (Cl-4)alkyl means a branched or unbranched alkyl group having 1-4 carbon atoms, for example methyl, ethyl, propyl, isopropyl or butyl.
  • (Cl-2) alkyl refers to an alkyl group having 1 or 2 carbon atoms. Preferred alkyl groups are methyl and ethyl.
  • (Cx-y)alkoxy refers to an alkoxy group having x-y carbon atoms, wherein the alkyl moiety is as defined above.
  • (Cl-4)alkoxy means an alkoxy group having a (Cl-4)-alkyl moiety. Examples of alkoxy groups are methoxy, ethoxy, and -0-CH(CH3)-CF3.
  • (Cx-y)alkylene refers to a branched or unbranched saturated alkylene group having x-y carbon atoms.
  • (Cl-4)alkylene means a saturated alkylene group having 1-4 carbon atoms, for example methylene, (CH 2 ) 3 -CHCH 3 -, -C(CH 3 ) 2 -, -CHCH3CH2-.
  • Rl as -(Cl-4)alkylene-R2
  • one or more carbon atoms in the alkylene group may independently be substituted with (CH2)2 to form a cyclopropyl moiety, for instance to form an Rl group — or with (CH2)3 to form a cyclobutyl moiety.
  • a dashed line in a partial structure such as ⁇ — ⁇ means that the partial structure is attached to the remainder of the structure at the site of the dashed line. For instance if Rl is — 1 , the compound of
  • (Cx-y)alkenyl means a branched or unbranched alkenyl group having x-y carbon atoms, wherein the double bond may be present at various positions in the group. Examples are ethenyl, propenyl, 1- butenyl, 2-butenyl.
  • (C2-4)alkenyl means a branched or unbranched alkenyl group having 2-4 carbon atoms.
  • (Cx-y)alkynyl refers to a branched or unbranched alkynyl group having x-y carbon atoms, wherein the triple bond may be present at different positions in the group, for example ethynyl, propanyl, 1- butynyl, 2-butynyl.
  • (C2-4)alkynyl refers to a branched or unbranched alkynyl group having 2-4 carbon atoms.
  • (Cx-y)cycloalkyl refers to a cyclic alkyl group having x-y carbon atoms.
  • (C3-6)cycloalkyl refers to a cyclic alkyl group having 3-6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • a preferred (C3-8)cycloalkyl in the definition of R3 is cyclopentyl, cyclohexyl or cycloheptyl, more preferably cyclohexyl.
  • (Cx-y)cycloalkoxy means an alkoxy as defined above wherein the alkyl moiety is a Cx-y-cycloalkyl, e.g.
  • (Cx-y)cycloalkenyl means a cyclic alkenyl group having x-y carbon atoms.
  • (C4-6)cycloalkenyl means a cyclic alkenyl group having 4-6 carbon atoms and comprising one or two double bonds, for example cyclohexenyl.
  • a cycloalkenyl as used herein has one carbon-carbon double bond, e.g. cyclobutene, cyclopentene, cyclohexene and cycloheptene.
  • (Cx-y)cycloalkylene means a saturated cyclic group having x-y carbon atoms.
  • (C3-7)cycloalkylene means a saturated cyclic group having 3-7 carbon atoms, e.g. cyclobutylene,
  • 8-10 membered fused bicyclic group for R3 means a fused ring system of two ring structures together having 8-10 atoms.
  • the rings can be either aromatic or non-aromatic ring structures, preferably the fused bicyclic group contains at least one aromatic ring.
  • Preferred 8-10 membered fused bicyclic groups in the definition of R3 contain up to two heteroatoms, preferably O, S and/or N.
  • Preferred 8-10 membered bused bicyclic groups are indane, tetralin, benzofuran, isobenzofuran, dihydrobenzofuran, dihydroisobenzofuran,
  • benzimidazole dihydrobenzimidazole and tetrahydrobenzimidazole
  • benzoxazole dihydrobenzoxazole, tetrahydrobenzoxazole, benzisoxazole, dihydrobenzisoxazole and tetrahydrobenzisoxazole.
  • More preferred 8-10 membered fused bicyclic groups in the definition of R3 are indanyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzo[c]thiophenyl benzoxazolyl, 2,3-dihydrobenzofuranyl and 1,3-dioxaindanyl, more preferably indanyl, indolyl, 2,3-dihydrobenzofuranyl and 1,3-dioxaindanyl.
  • monocyclic heterocycle means a heteroatom- containing cyclic group.
  • the term “monocyclic heterocycle” encompasses monocyclic heteroaryl groups and non-aromatic heteromonocyclic groups.
  • Preferred monocyclic heterocycles are furanyl, thienyl, pyrrolyl, oxanyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, morpholinyl.
  • Particularly preferred monocyclic heterocycles in the definition of R3 are pyridyl, piperidyl, oxanyl, pyranyl, thianyl and thiopyranyl, more preferably pyridyl and oxanyl.
  • substituents indicate a group may be unsubstituted or substituted with the indicated number and type of the substituent(s).
  • substituents independently selected from means that if a group that is substituted with more than one substituent, these substituents may be the same or different from each other.
  • multiple variables are independently chosen from more than one definition, such as m and n in present formula (I) which can be 0 or 1, the term “independently” means that each variables may have the same or different definition as the other variable(s).
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the compound. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention.
  • the present invention encompasses all such isomeric forms of these compounds.
  • the independent syntheses of these diastereomers or their chromatographic separations may be achieved with any method known in the art, for instance as described in the Examples.
  • the absolute stereochemistry of a compound may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as chiral HPLC or SFC (Supercritical Fluid Chromatography) techniques. In the Examples, two suitable SFC methods are described.
  • Salts of compounds according to the invention are also provided. Such salts include, but are not limited to, acid addition salts and base addition salts.
  • pharmaceutically acceptable salt refers to those salts retain the pharmacological activity of the compounds and that are, within the scope of sound medical judgment, suitable for use in humans or animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art.
  • bases or acids can be prepared in situ when isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids, for instance by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble, or in a solvent such as water or an organic solvent which is then removed in vacuo or by freeze- drying, or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
  • pharmaceutically acceptable acids and bases include organic and inorganic acids such as acetic acid, trifluoroacetic acid, hydrochloric acid, and bases.
  • Compounds may exist as polymorphs and as such are intended to be included in the present invention.
  • the compounds of the invention may be prepared by methods known in the art and to a skilled person. Suitable methods to prepare the compounds are described in the experimental section of this description.
  • Compounds according to the invention are useful in counteracting diseases or disorders mediated by an SIP receptor, preferably S1P5. They are preferably mixed with pharmaceutically suitable auxiliaries, e.g. as described in the standard reference “Remington, The Science and Practice of Pharmacy” (21st edition, Lippincott Williams & Wilkins, 2005, see especially Part 5: Pharmaceutical Manufacturing).
  • the compounds together with pharmaceutically suitable auxiliaries may be compressed into solid dosage units, such as pills or tablets, or be processed into capsules or suppositories.
  • pharmaceutically suitable liquids the compounds can also be applied in the form of a solution, suspension or emulsion.
  • a pharmaceutical composition comprising a compound according to the invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent and/or excipient.
  • pharmaceutically acceptable it is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • any pharmaceutically suitable additive which does not interfere with the function of the active compounds can be used.
  • a pharmaceutical composition according to the invention is preferably suitable for human use.
  • suitable carriers comprise a solution, lactose, starch, cellulose derivatives and the like, or mixtures thereof.
  • said suitable carrier is a solution, for example saline.
  • excipients which can be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as
  • microcrystalline cellulose a disintegrating agent such as corn starch,
  • the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil.
  • a liquid carrier such as fatty oil.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compositions for intravenous administration may for example be solutions of the compounds of the invention in sterile isotonic aqueous buffer. Where necessary, the intravenous compositions may include for instance solubilizing agents, stabilizing agents and/or a local anesthetic to ease the pain at the site of the injection.
  • the compounds of the invention may be administered enterally or parenterally.
  • a pharmaceutical kit or kit of parts comprising one or more containers filled with one or more
  • compositions of the invention and optionally one or more pharmaceutically acceptable excipients as described herein.
  • Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the
  • a pharmaceutical kit or kit of parts comprises instructions for use.
  • the compounds of the invention are modulators of the SIP receptor, in particular of the S1P5 receptor. More specifically, the compounds of the invention are S1P5 receptor agonists.
  • the compounds are useful in the treatment or alleviation of diseases or disorders mediated by an SIP receptor, preferably S1P5.
  • the compounds of the present invention are particularly suitable to treat or alleviate diseases and disorder s in which an SIP receptor is involved or in which modulation of the endogenous SIP signaling system via an SIP receptor is involved, preferably S1P5.
  • a method of treatment or alleviation of a disease or disorder in which an SIP receptor is involved or in which modulation of the endogenous SIP signaling system via an SIP receptor is involved comprising administering to a patient in need thereof a compound according to the invention or a pharmaceutically acceptable salt thereof.
  • Said patient is preferably a human patient.
  • a compound according to the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or alleviation of a disease or disorder in which an SIP receptor is involved or in which modulation of the endogenous SIP signaling system via an SIP receptor is involved, preferably S1P5 receptor.
  • a compound according to the invention or a pharmaceutically acceptable salt thereof for use in therapy, preferably for use as a medicament.
  • Said diseases or disorder is preferably selected from the group consisting of Alzheimer's Disease (AD), multiple sclerosis, Huntington's Disease and Parkinson's Disease.
  • AD Alzheimer's Disease
  • multiple sclerosis Huntington's Disease
  • Parkinson's Disease a group consisting of Alzheimer's Disease (AD)
  • AD multiple sclerosis
  • Huntington's Disease a group consisting of Alzheimer's Disease (AD)
  • Parkinson's Disease a group consisting of diseases or disorder.
  • PS-Triphenylphosphine polystyrene-triphenylphosphine (resin-bound
  • Method B Mobile Phase: A: Water (10 mM NH4HCO3), B: ACN
  • the compounds were either characterized via proton-NMR in d6- dimethylsulfoxide,d-chloroform, d-methanol or d-pyridine on a 400 MHz (Bruker AVm 400) or 500 MHz NMR instrument (Bruker Avance 500 MHz with 5 mm BBFo-z-Grd) or a 600 MHz (Bruker Avance 600 MHz with 5 mm Cryoprobe CPTCI (1H-13C/15N z-Grd), and/or by mass spectrometry.
  • the magnetic nuclear resonance spectral properties refer to the chemical shifts ( ⁇ ) expressed in parts per million (ppm).
  • the relative area of the shifts in the 1H-NMR spectrum corresponds to the number of hydrogen atoms for a particular functional type in the molecule.
  • the nature of the shift, as regards multiplicity, is indicated as singlet (s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t), broad triplet (t br.), quartet (q), quintet (quint.) and multiplet (m).
  • SFC Supercritical Fluid Chromatography
  • Preparative separations were carried out on a Waters Prep lOOq SFC System, controlled by Waters MassLynx Software.
  • the system consists of an open bed injector/collector, a heated column compartment including a switch for 6 columns, a COi-booster pump, a pump module for modifier flow. Detection was done by UV and a quadrupole mass spectrometer (Waters Aquity QDa, ESI-ionization).
  • the gas liquid separator was driven with a make-up flow of 30 mL/min methanol.
  • the backpressure regulator was set to 120 bar and heated to 60°C. If not stated otherwise, the columns were 250 mm in length, 20 mm in diameter and packed with 5 ⁇ material. They were kept at 30°C during the separation. As mobile phase, a mixture of liquefied CO2 and organic modifier with additive was used as indicated for each sample. The flow rate was kept at 100 g/min.
  • R4 is H.
  • Appropriately substituted starting compound 1 can be used to prepare the corresponding substituted 3'H-spiro[azetidine-3,2'-benzofuran]-6'-ol.
  • R4-substituted 2,4-dihydroxybenzaldehyde derivatives can be converted to the corresponding parabenzyl ether derivatives with benzyl bromide under basic conditions.
  • Reaction with diethyl 2-bromomalonate under basic conditions gives the corresponding diethyl R4-substituted 6-(benzyloxy)-3-hydroxybenzofuran-2,2(3H)- dicarboxylate.
  • R4 is H.
  • Appropriately substituted starting compound 1 can be used to prepare the corresponding substituted l',3'-dihydrospiro[azetidine-3,2'-inden]-5'-ol.
  • R4- substituted 4-methoxy-l,2-dimethylbenzene can be dibrominated in the two benzylic positions to give the corresponding l,2-bis(bromomethyl)-4- methoxybenzene.
  • an R4- substituted 4-methoxyphthalate can be reduced (e.g.
  • LAH, AICI3 gives the corresponding l-benzyl-5'-methoxy-l',3'- dihydrospiro[azetidine-3,2'-indene] .
  • Demethylation e.g. ⁇ gives the
  • Rl-moieties can be introduced starting from the corresponding azetidines, wherein X is O or CH2 (see synthetic schemes 1 and 2), using alkylating or reductive amination conditions as depicted in scheme 4 above.
  • Rl-moiety contains an ester the corresponding acid can be obtained by saponification under basic (e.g. NaOH) or acidic (e.g. TFA) conditions.
  • Scheme 4 shows a number of routes starting from R4 substituted 3'H-spiro[azetidine-3,2'-benzofuran]-6'-ol or ,3'- dihydrospiro[azetidine-3,2'-inden]-5'-ol.
  • DIPEA DIPEA
  • R3-L-moieties can be introduced starting from the corresponding phenols via the corresponding nonaflates or triflates followed by Sonogashira reaction with an substituted alkyne or by the same protocol followed by hydrogenation which can yield the corresponding ethenyl derivative as shown in scheme 5.
  • R3-L-moieties that contain a phenyl ether can be obtained under alkylating conditions using the corresponding alkylhalide precursors or under Mitsunobu conditions using the corresponding alkyl alcohols.
  • the corresponding acid can be obtained by saponification under basic (e.g. NaOH) or acidic (e.g. TFA) conditions.
  • Scheme 5 shows a number of routes starting from R4 substituted 3 ⁇ - spiro[azetidine-3,2'-benzofuran]-6'-ol or l',3'-dihydrospiro[azetidine-3,2'-inden]-5'- ol. It is clear to a person skilled in the art that these routes are suitable to introduce R3-L-moieties in in the corresponding pyrrolidine- or piperidine- containing compounds as well.
  • the reaction mixture was diluted with CH2CI2 and washed 2x with sat. NH4CI- solution and lx with saturated NaCl.
  • the organic layer was dried over MgS04, filtered and evaporated.
  • the residue was purified using the Isco-Combiflash (12 g, 0-10% MeOH in CH2CI2, 30mL/min).
  • the reaction mixture was diluted with CH2CI2 and washed 2x with water and lx with saturated NaCl.
  • the organic layer was dried over a Chromabond PTS- cartridge and evaporated.
  • the residue was purified using the Isco-Combiflash (12 g, 0-10% MeOH in CH2CI2, 30mL/min).
  • the crude product contained some DMSO and was used in next step.
  • the reaction mixture was evaporated.
  • the residue was extracted with CH2CI2 and water. After phase separation with a Chromabond PTS-cartridge the organic layer was evaporated.
  • the residue was purified by using the Isco-Combiflash (4 g, 0-10% MeOH in CH2CI2, 18 mL/min)
  • reaction mixture was evaporated. The residue was dissolved in water and neutralized with 0.5 mL 2N HC1. The precipitate was filtered, washed with water and dried overnight at 40°C under vacuum.
  • Tetrakis(triphenylphosphine)palladium(0) (8 mg, 6.92 ⁇ ) was added. The mixture was stirred for 30 min at 100°C in the Biotage microwave. LC/MS showed conversion, but the main peak was the reactant. The mixture was stirred for further 30 min at 120°C in the Biotage micowave, LC/MS showed a better conversion rate. The reaction mixture was stirred for further 60 min at 120°C in the Biotage microwave.
  • the reaction mixture was evaporated.
  • the residue was dissolved in CH2CI2 and washed lx with water. After phase separation with a Chromabond PTS Cartridge the organic layer was evaporated.
  • the residue was purified using the Isco- Combiflash (4 g, 0-10% MeOH in CH2CI2).
  • the reaction mixture was evaporated.
  • the residue was dissolved in CH2CI2 and washed lx with water, after phase separation with a Chromabond PTS Cartridge the organic layer was evaporated.
  • the residue was purified using the Isco- Combiflash (4 g, 0-10% MeOH in CH2CI2).
  • reaction mixture was evaporated. The residue was dissolved in water and neutralized with 0.25 mL 2n HCl. CH2CI2 was added, the mixture was stirred at RT for lh. After phase separation the organic layer was dried over MgSC , filtered and evaporated.
  • reaction mixture was evaporated.
  • the residue was dissolved in water and acidified with 2n HC1 (1 mL, pH-value 1-2).
  • the precipitate was filtered, washed lx with water, dried overnight under vacuum at 40°C.
  • Example 7 was prepared analogous to example 6:
  • reaction mixture was evaporated, the residue was dissolved in CH2CI2 and washed lx with sat. NH4Cl-solution, the phases were separated with a
  • Example 20 2,2,2-trifluoroacetic acid compound with 2-(5'-((2-chloro-6- (trifluoromethyl)benzyl)oxy)-l',3'-dihydrospiro[azetidine-3,2'-inden]-l-yl)acetic acid (1:1)
  • Example 23 2,2,2-trifluoroacetic acid compound with 2-(5'-((2,5- dichlorobenzyl)ox -l',3'-dihydrospiro[azetidine-3,2'-inden]-l-yl)acetic acid (1:1)
  • Example 24 2,2,2-trifluoroacetic acid compound with 2-(5'-((2-chloro-6- ethylbenzyl)oxy)-l',3'-dihydrospiro[azetidine-3,2'-inden]-l-yl)acetic acid (1:1)
  • Example 28 l-((5'-((2-chloro-6-ethylbenzyl)oxy)-l',3'-dihydrospiro[azetidine-3,2'- inden]-l-yl)methyl)cyclopropanecarboxylic acid
  • reaction mixture was evaporated, the residue was dissolved in CH2CI2 and washed lx with sat. NH4Cl-solution, the phases were separated with a
  • Examples 29 - 49 were prepared analogous to example 28: Example 29. l-((5'-(benzyloxy)-l',3'-dihydrospiro[azetidine-3,2'-inden]-l- yl)methyl)cyclopropanecarboxylic acid
  • Example 30 l-((5'-((2-fluoro-6-methoxybenzyl)oxy)-l',3'-dihydrospiro[azetidine- 3,2'-inden]-l-yl)methyl)cyclopropanecarboxylic acid compound with 2,2,2- trifluoroacetic ac
  • Example 31 l-((5'-((2-chloro-6-methoxybenzyl)oxy)-l',3'-dihydrospiro[azetidine- 3,2'-inden]-l-yl)methyl)cyclopropanecarboxylic acid compound with 2,2,2- trifluoroacetic acid (1:1)
  • Example 32 l-((5'-((2-chloro-4-ethoxybenzyl)oxy)-l',3'-dihydrospiro[azetidine-3,2'- inden] - 1 - yl) methyl) cycloprop anecarb oxylic acid
  • Example 39 l-((5'-((2,6-dimethylbenzyl)oxy)-l',3'-dihydrospiro[azetidine-3,2'- inden]-l-yl)methyl)cyclopropanecarboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1)
  • Example 40 l-((5'-((2-chloro-4-methoxybenzyl)oxy)-l',3'-dihydrospiro[azetidine- 3,2'-inden]-l-yl)methyl)cyclopropanecarboxylic acid
  • Example 41 l-((5'-((2-(trifluoromethyl)benzyl)oxy)-l',3'-dihydrospiro[azetidine- 3,2'-inden]-l-yl)methyl)cyclopropanecarboxylic acid compound with 2,2,2- trifluoroacetic acid (1:1)
  • Example 43 l-((5'-((5-fluoro-2-(trifluoromethyl)benzyl)oxy)-l',3'- dihydrospiro [azetidine- 3 , 2' -inden] - 1 -yl)methyl)cyclopropanecarboxylic acid compound with -trifluoroacetic acid (1:1)
  • Example 44 l-((5'-((2-chloro-6-cyclopropylbenzyl)oxy)-l',3'-dihydrospiro[azetidine- 3,2'-inden]-l-yl)methyl)cyclopropanecarboxylic acid compound with acetic acid (1:1)
  • Example 46 l-((5'-((2,6-dichlorobenzyl)oxy)-l',3'-dihydrospiro[azetidine-3,2'- inden] - 1 - yl) methyl) cycloprop anecarb oxylic acid
  • Example 47 l-((5'-((2-chloro-6-(trifluoromethyl)benzyl)oxy)-l',3'- dihydrospiro[azetidine-3,2'-inden]-l-yl)methyl)cyclopropanecarboxylic acid compound with -trifluoroacetic acid (1:1)
  • Example 48 l-((5'-((2-ethyl-6-fluorobenzyl)oxy)-l',3'-dihydrospiro[azetidine-3,2'- inden]-l-yl)methyl)cyclopropanecarboxylic acid
  • Example 50 l-((5'-(4-((3-fluorobenzyl)oxy)phenyl)-l',3'-dihydrospiro[azetidine-3,2'- in d - 1 - yl) methyl) cycloprop anecarb oxylic acid
  • the reaction mixture was diluted with CH2CI2 and washed 2x with sat. NH4CI- solution and lx with saturated sodium chloride solution.
  • the organic layer was dried over MgS04, filtered and evaporated.
  • the residue was purified using the Isco- Combiflash (12 g, 0-10% MeOH in CH2CI2, 30 mL/min).
  • Tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.075 mmol) was added.
  • the reaction mixture was stirred for 60 min at 120°C in the CEM microwave.
  • LC/MS showed product mass, the color of the reaction mixture changed during the reaction from yellow to black, reaction was stopped.
  • the reaction mixture was evaporated.
  • the residue was dissolved in CH2CI2 and washed 2x with water, lx with saturated sodium chloride solution, dried over MgS04, filtered and evaporated.
  • the residue was purified using the Isco- Combiflash (12 g, 0-10% MeOH in CH2CI2, 30 mL/min)
  • reaction mixture was filtered and the organic layer was evaporated.
  • Example 51 1 - ((5' - (4- (cyclohexylmethoxy)phenyl) - 1 ', 3' - dihydrospiro [azetidine- 3,2'-inden]-l-yl)methyl)cyclopropanecarboxylic acid
  • Example 54 l-((5'-phenethoxy-l',3'-dihydrospiro[azetidine-3,2'-inden]-l- yl)methyl)cyclopropanecarboxylic acid
  • the reaction mixture was evaporated, the residue was dissolved in ethyl acetate and washed 2x with sat. Nl Cl-solution, the organic layer was dried with MgS04, filtrated and evaporated.
  • the residue was purified using the Isco-Combiflash (40 g, 0-15% MeOH in CH2CI2, 40 mL/min).
  • the reaction mixture was evaporated.
  • the residue was dissolved in CH2CI2 and water. After phase separation with a Chromabond PTS-cartridge, the organic layer was evaporated.
  • the residue was purified using the Isco-Combiflash (4 g, 0-10%
  • reaction mixture was evaporated.
  • the residue was dissolved in water and neutralized with HCl (to pH value 7-8).
  • CH2CI2 was added.
  • the aqueous layer was extracted 2x with CH2CI2. After phase separation the combined organic layers were dried with MgSC , filtered and evaporated.
  • the reaction mixture was evaporated, the residue was dissolved in ethyl acetate and washed 2x with sat. NH4Cl-solution, the organic layer was dried with MgSC , filtrated and evaporated.
  • the residue was purified using the Isco-Combiflash (40 g, 0-15% MeOH in CH2CI2, 30 mL/min).
  • the reaction mixture was evaporated.
  • the residue was dissolved in CH2CI2 and water. After phase separation with a Chromabond PTS-cartridge, the organic layer was evaporated.
  • the residue was purified using the Isco-Combiflash (4 g, 0-10% MeOH in CH2CI2, 18 mL/min).
  • reaction mixture was evaporated.
  • the residue was dissolved in water and neutralized with 2N HCl to pH 7-8. Approx. 100 mL CH2CI2 and a small amount of MeOH were added. After phase separation the organic layer was dried over MgS04, filtered and evaporated.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés hétérocycliques de formule (I) en tant que modulateurs de SIP, des compositions pharmaceutiques les contenant, et leurs utilisations dans le traitement ou le soulagement des maladies ou des troubles induites par un récepteur SIP.
EP17800433.9A 2016-11-02 2017-11-02 Composés spiro en tant que modulateurs de s1p Withdrawn EP3535244A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN2016104349 2016-11-02
US201662434820P 2016-12-15 2016-12-15
PCT/EP2017/078043 WO2018083171A1 (fr) 2016-11-02 2017-11-02 Composés spiro en tant que modulateurs de s1p

Publications (1)

Publication Number Publication Date
EP3535244A1 true EP3535244A1 (fr) 2019-09-11

Family

ID=60382170

Family Applications (1)

Application Number Title Priority Date Filing Date
EP17800433.9A Withdrawn EP3535244A1 (fr) 2016-11-02 2017-11-02 Composés spiro en tant que modulateurs de s1p

Country Status (2)

Country Link
EP (1) EP3535244A1 (fr)
WO (1) WO2018083171A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020183307A1 (fr) * 2019-03-08 2020-09-17 The University Of Buea Dihydro-spiro[indoline-3:1'-isoquinoléin]-2-ones et leurs analogues et dérivés et méthodes de traitement du cancer et d'autres maladies
EP4116294A1 (fr) 2020-03-04 2023-01-11 Helioeast Pharmaceutical Co., Ltd. Composé benzo 2-azaspiro[4,4]nonane et son utilisation
WO2022117553A1 (fr) * 2020-12-01 2022-06-09 AbbVie Deutschland GmbH & Co. KG Dérivés d'amine spiro-cyclique utilisés en tant que modulateurs de s1p

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2439203B1 (fr) 2004-10-14 2014-11-19 AbbVie Deutschland GmbH & Co KG Composés aromatiques d'arylsulfonylmethyl ou arylsulfonamide pour le traitement des maladies concernant la modulation des récepteurs de dopamine D3
US20100317679A1 (en) * 2007-09-21 2010-12-16 Ligand Pharmaceuticals, Inc. Substituted aryl-fused spirocyclic amines
WO2009097567A1 (fr) * 2008-01-30 2009-08-06 Cephalon, Inc. Dérivés de pipéridine spirocyclique substitués en tant que ligands de récepteur d'histamine-3 (h3)
TW201643169A (zh) 2010-07-09 2016-12-16 艾伯維股份有限公司 作為s1p調節劑的螺-哌啶衍生物
TWI522361B (zh) 2010-07-09 2016-02-21 艾伯維公司 作為s1p調節劑的稠合雜環衍生物
UY34194A (es) 2011-07-15 2013-02-28 Astrazeneca Ab ?(3-(4-(espiroheterocíclico)metil)fenoxi)azetidin-1-il)(5-(fenil)-1,3,4-oxadiazol-2-il)metanona en el tratamiento de la obesidad?

Also Published As

Publication number Publication date
WO2018083171A1 (fr) 2018-05-11

Similar Documents

Publication Publication Date Title
AU2016378650B2 (en) Fused (hetero)cyclic compounds as S1P modulators
JP5139307B2 (ja) ナトリウムチャネルモジュレーターとしてのプロリンアミド誘導体
JP5139306B2 (ja) 電位依存性ナトリウムチャネルの調節因子としての第四級α−アミノカルボキサミド誘導体
SK361392A3 (en) Azaheterocyclylmethyl-chromans, method for producing them, their use and pharmaceutical composition containing same
WO2007091570A1 (fr) Inhibiteur de liaison de sphingosine-1-phosphate
JP2020502184A (ja) 疼痛および疼痛に関連する状態を処置するための新規なキノリンおよびイソキノリン誘導体
AU2016314973B2 (en) Fused heterocyclic compounds as S1P modulators
TW201321364A (zh) 苯基－３－氮雜－雙環［３．１．０］己－３－基－甲酮及其作為藥物之用途
EP2720546A1 (fr) Antagonistes du canal trpv4
WO2018083171A1 (fr) Composés spiro en tant que modulateurs de s1p
US20190300534A1 (en) Gabaergic ligands and their uses
CN114591352B (zh) 一种三唑并哒嗪类化合物及其应用
JP6483105B2 (ja) ピペラジン誘導体および医薬としてのその使用
JP6509321B2 (ja) 置換アザスピロ（４．５）デカン誘導体
JP6134654B2 (ja) 複素環化合物およびその用途
TWI756196B (zh) 用於治療藥物濫用和成癮之氧雜二氮雜螺環化合物
JP2009533441A (ja) ５‐ヒドロキシトリプタミン‐６リガンドとしての置換ジヒドロ［１，４］オキサジノ［２，３，４‐ｈｉ］インダゾール誘導体
WO2020210785A1 (fr) Composés agonistes du récepteur d3; procédés de préparation; intermédiaires de ceux-ci; et leurs procédés d'utilisation
CN113272315A (zh) 一类类固醇化合物及其用途
Calmes et al. Synthesis of enantiopure trans‐N‐Boc‐3‐aminobicyclo [2.2. 2] octane‐2‐carboxylic acids and their bicyclic 1, 3‐amino alcohol derivatives via the [4+ 2] cycloaddition of 1, 3‐cyclohexadiene to a chiral β‐nitroacrylate
KR20180036919A (ko) 3-에틸비사이클로[3.2.0]헵트-3-엔-6-온의 거울상이성질체의 분리
WO2023057414A1 (fr) Certaines octahydrofuro 3,4-b]pyrazines utilisées en tant que modulateurs du récepteur glp-1
US20200055817A1 (en) Spiro-compounds as sip modulators
EP3655392A1 (fr) Composés de quinoléine à substitution en positions 1, 2, 3 et 4 utilisés en tant que modulateurs de s1p
AU2018265615A1 (en) Substituted heterocyclic compounds as allosteric modulators of group II metabotropic glutamate receptors

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20190523

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20200707

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20201118