WO2019040106A2 - Composés, sels associés et méthodes pour le traitement de maladies - Google Patents

Composés, sels associés et méthodes pour le traitement de maladies Download PDF

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WO2019040106A2
WO2019040106A2 PCT/US2018/000353 US2018000353W WO2019040106A2 WO 2019040106 A2 WO2019040106 A2 WO 2019040106A2 US 2018000353 W US2018000353 W US 2018000353W WO 2019040106 A2 WO2019040106 A2 WO 2019040106A2
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Prior art keywords
methyl
fluorophenyl
phenyl
methylpropoxy
urea
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PCT/US2018/000353
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WO2019040106A3 (fr
Inventor
Ethan S. Burstein
Roger Olsson
Karl Erik Jansson
Niklas Patrik SKÖLD
Larisa Yudina WAHLSTRÖM
Henrik Von Wachenfeldt
Magnus Gustav Wilhelm BERGNER
Klaus DREISCH
Kyrylo POPOV
Oleksnadr KOVALENKO
Per Tomas Klingstedt
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Acadia Pharmaceuticals Inc.
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Publication of WO2019040106A2 publication Critical patent/WO2019040106A2/fr
Publication of WO2019040106A3 publication Critical patent/WO2019040106A3/fr

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    • 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
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • Serotonin or 5-hydroxytryptamine plays a significant role in the functioning of the mammalian body.
  • 5-HT is an important neurotransmitter and neuromodulator that is implicated in such diverse behaviors and responses as sleeping, eating, locomotion, perceiving pain, learning and memory, sexual behavior, controlling body temperature and blood pressure.
  • serotonin plays an important role in the control systems of the afferent peripheral nociceptors (Moulignier, Rev. Neurol. 150:3-15, (1994)).
  • Peripheral functions in the cardiovascular, hematological and gastrointestinal systems have also been ascribed to 5-HT.
  • 5-HT has been found to mediate a variety of contractile, secretory, and electrophysiologic effects including vascular and nonvascular smooth muscle contraction, and platelet aggregation.
  • the 5-HT2A receptor subtype (also referred to as subclass) is widely yet discretely expressed in the human brain, including many cortical, limbic, and forebrain regions postulated to be involved in the modulation of higher cognitive and affective functions. This receptor subtype is also expressed on mature platelets where it mediates, in part, platelet aggregation, one of the initial steps in the process of vascular thrombosis.
  • Serotonin receptors are members of a large human gene family of membrane-spanning proteins that function as transducers of intercellular
  • GPCRs G-protein coupled receptors
  • G-proteins G-protein coupled receptors
  • second messenger molecules such as cyclic AMP, inositol phosphates, and diacylglycerol.
  • At least 14 genetically distinct 5-HT receptor subtypes have been identified and assigned to one of seven families (5-HT1-7). Each subtype displays a unique distribution, preference for various ligands, and functional correlate(s).
  • Serotonin may be an important component in various types of pathological conditions such as certain psychiatric disorders (depression, aggressiveness, panic attacks, obsessive compulsive disorders, psychosis, schizophrenia, suicidal tendency), certain
  • Serotonin receptors are members of a large human gene family of membrane-spanning proteins that function as transducers of intercellular communication. They exist on the surface of various cell types, including neurons and platelets, where, upon their activation by either their endogenous ligand serotonin or exogenously administered drugs, they change their conformational structure and subsequently interact with downstream mediators of cellular signaling.
  • GPCRs G-protein coupled receptors
  • G- proteins guanine nucleotide binding proteins
  • cyclic AMP guanine nucleotide binding proteins
  • diacylglycerol second messenger molecules
  • the 5-HT2A receptor subtype (also referred to as subclass) is widely yet discretely expressed in the human brain, including many cortical, limbic, and forebrain regions postulated to be involved in the modulation of higher cognitive and affective functions. This receptor subtype is also expressed on mature platelets where it mediates, in part, platelet aggregation, one of the initial steps in the process of vascular thrombosis.
  • Antipsychotic drugs have been shown to interact with a large number of central monoaminergic neurotransmitter receptors, including dopaminergic, serotonergic, adrenergic, muscarinic, and histaminergic receptors. It is likely that the therapeutic and adverse effects of these drugs are mediated by distinct receptor subtypes. The high degree of genetic and pharmacological homology between these receptor subtypes has hampered the development of subtype-selective compounds, as well as the determination of the normal physiologic or pathophysiologic role of any particular receptor subtype. Thus there is a need to develop drugs that are selective for individual receptor classes and subclasses amongst
  • the prevailing llicuiy fui Hie mechanism of action of antipsychotic drugs involves antagonism of dopamine D2 receptors.
  • antagonism of dopamine D2 receptors also mediates the extrapyramidal side effects as well as some additional undesired effects of antipsychotic therapies such as a worsening of depression symptoms, anhedonia and impairment of cognitive processes.
  • Antagonism of 5-HT2A receptors is an alternate molecular mechanism for drugs with antipsychotic efficacy, possibly through antagonism of heightened or exaggerated signal transduction through serotonergic systems. 5-HT2A antagonists are therefore good candidates for treating psychosis without extrapyramidal side effects or other undesired effects associated with blockade of dopamine D 2 receptors.
  • GPCRs such as the 5-HT2A receptor have been assumed to exist in a quiescent state unless activated by the binding of an agonist (a drug that activates a receptor).
  • an agonist a drug that activates a receptor
  • GPCR monoamine receptors including serotonin receptors
  • inverse agonists Both agonists and inverse agonists possess intrinsic activity at a receptor, in that they alone can activate or inactivate these molecules, respectively.
  • classic or neutral antagonists compete against agonists and inverse agonists for access to the receptor, but do not possess the intrinsic ability to inhibit elevated basal or constitutive receptor responses.
  • n are independently an integer selected from the group consisting of 0, 1, 2, and 3;
  • p is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6;
  • q is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
  • r is an integer selected from the group consisting of 0, 1, 2, and 3;
  • haloalkyl unsubstituted or substituted Ci -6 hydroxyalkyl, unsubstituted or substituted Ci -6 aminoalkyl, unsubstituted or substituted Ci-6 alkenyl, unsubstituted or substituted Ci-6 alkoxy, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted C 3-6 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
  • R 2 , R2a, R2b, R2c and R 2 a are independently selected from the group consisting of hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, unsubstituted or substituted Ci -6 alkyl, unsubstituted or substituted Ci -6 haloalkyl, unsubstituted or substituted Ci -6
  • R 3 is selected from hydrogen, deuterium, hydroxyl, -OD, unsubstituted or substituted Ci -6 alkyl, unsubstituted or substituted Ci -6 haloalkyl, unsubstituted or substituted Ci -6 hydroxyalkyl, unsubstituted or substituted Ci -6 alkenyl, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted C 3-6 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
  • R 4a , R 4 b, R 5 a, Rsb, R 5 c, Rsd, R9a and R are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted 0 -6 alkyl;
  • R 6 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted Ci-4 alkyl, and substituted or unsubstituted Ci-4 alkoxy, substituted or unsubstituted aryl;
  • R 7 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C alkyl, and substituted or unsubstituted Ci-4 alkoxy;
  • R 8 is absent, or selected from the group consisting of hydrogen, deuterium, cyano, hydroxyl, -OD, substituted or unsubstituted C alkyl, substituted or unsubstituted C alkenyl, substituted or unsubstituted C 3- cycloalkyl, and substituted or unsubstituted C alkoxy;
  • Rio and Rn independently are selected from the group consisting of hydrogen, amino, unsubstituted or substituted Ci -6 alkyl;
  • A is selected from the group consisting of
  • E is N or CH
  • B is a ring system selected from the group consisting of substituted or unsubstituted 4- 12 membered heteroalicyclic ring systems;
  • X is O or S.
  • Some embodiments disclosed herein relate to a method for treating a disease in a patient comprising administering to the patient an effective amount of a compound, pharmaceutically acceptable salt, polymorph or stereoisomer of a compound according to Formula (I), wherein the disease is selected from the group consisting of Abnormal hormonal activity, Alzheimer's disease, Alzheimer's disease dementia, Alzheimer's disease psychosis, Addiction (alcohol, cocaine, methamphetamine, nicotine and opioid), Addison's disease, ADHD, Alzheimer's disease psychosis, Affective disorders, Aggressiveness, Agitation, Akathisia, Alcohol addiction, Alcohol withdrawal, Amenorrhea, Amyotrophic lateral sclerosis, Anhedonia, Anorexia, Anti-NMDAR encephalitis, Anxiety, Appetite disorders, Asthma, Autism, Behavioral disorders, Behavioral disturbances associated with dementia, Binge eating disorder associated with impulse control disorder (ICD), Bipolar disorder, Blindness, Borderline disorder, Borderline personality disorder
  • Hypertension Hypersexuality associated with ICD, Hypotension, Hypoglutamateriga disorders, Impulse control disorder, Idiopathic thrombocytopenic purpura, Impotence, Incontinence, Increased intraocular pressure, Infertility, Inflammatory pain, Insomnia, Ischemia, Ischemic stroke, Lewy body disease (LBD), Learning disorders, Libido
  • methamphetamine addiction Migraine, mild cognitive impairment (MCI), Motor tics, Multi- infarct dementia, Multiple sclerosis, Multiplex development disorder, Myocardial infarction, Myoclonus, Neuropathic pain, Neurodegenerative disorder, Neuropsychiatric disease, Nicotine addiction, Non motor symptoms of Parkinson's disease selected from dementia, depression, apathy, hallucinations, dribbling saliva (sialorrhea), constipation, pain, genitourinary problems and sleep disorders, Obsessive compulsive disorder, On off phenomena, Opioid addiction, Osteoporosis, Pancreatis, Panic attacks, Parkinson's disease, Parkinson's disease dementia, Parkinson's disease psychosis, Periodic limb movement during sleep (PLMS), Peripheral vascular disease, Pituitary tumor, Postherpetic neuralgia, Progressive Supranucelar Palsy, Prion disease including Creutzfeld-Jakob disease (CJD), Gerstmann-
  • Prolactinoma, Pseudobulbar affect PBA
  • Psychomotor slowing Psychimotor slowing
  • Psychosis Psychimotor slowing
  • Psychosis Psychimotor slowing
  • Psychosis Psychimotor slowing
  • Psychosis Psychimotor slowing
  • Psychoses secondary to neurodegenerative disorders
  • Psychosomatic disorders Psychitic depression
  • Post-traumatic stress disorder PTSD
  • Raynaud's disease Reflex sympathetic dystrophy
  • Restless legs syndrome Retinal disease
  • Schizoaffective disorders Schizophrenia
  • negative symptoms of schizophrenia cognitive impairment associated with schizophrenia
  • Sepsis Serotonin syndrome
  • Sexual dysfunction sexual dysfunction associated with antidepressant use
  • Sleep apnea Sleep disorders
  • Sleep maintenance insomnia social anxiety disorder, Spinal injury, Spinocerebellar Atrophy, Suicidal tendency, Thrombosis, Thrombotic stroke, Thrombotic thrombocytopenic purpura, Tinnitus, Tiredness, Tourette
  • any "R" group(s) such as, without limitation, Ri , R2. 3, R4,
  • R 5 , R 6 , R 7; R 8 , R9, and R 10 represent substituents that can be attached to the indicated atom.
  • a non-limiting list of R groups includes but is not limited to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl. If two "R" groups are covalently bonded to the same atom or to adjacent atoms, then they may be "taken together" or “combined” as defined herein to form a cycloalkyl, aryl, heteroaryl or heteroalicyclyl group.
  • Ra and Rb of anNR a Rb group are indicated to be “taken together” or “combined”, it means that they are covalently bonded to one another at their terminal atoms to form a ring that includes the nitrogen:
  • the substituent(s) (which may be present one or more times, such as 1, 2, 3 or 4 times) are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfiny
  • trihalomethanesulfonamido, and amino including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • substituent on a group is deemed to be "substituted," the substituent itself is substituted with one or more of the indicated substituents.
  • substituted it is meant that one or more hydrogen atoms on the referenced substituent may be replaced with a group(s) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido,
  • C m to C Intel refers to the number of carbon atoms in the relevant group. That is, the group can contain from “m” to "n", inclusive, carbon atoms.
  • a "Ci to C 6 alkyl” group refers to all alkyl groups having from 1 to 6 carbons, that is, CH 3 -, CH 3 CH 2 -,
  • alkyl refers to a straight or branched hydrocarbon chain group that is fully saturated (no double or triple bonds).
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms, such as "Ci -6 ".
  • the alkyl group could also be a lower alkyl having 1 to 4 carbon atoms.
  • the alkyl group of the compounds may be designated as "C1-C4 alkyl,” “Ci-4 alkyl” or similar designations.
  • C1-C4 alkyl or "C 1-4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like. When substituted, the substituent group(s) is(are) one or more group(s) individually and
  • trihalomethanesulfonamido, and amino including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • the term “optionally”, for example “optionally deuterated” means that group may be unsubstituted or substituted with one or more of the indicated substituents, e.g. one or more hydrogen(s) may be replaced by one or more deuterium(s).
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. If more than one double bond is present, the double bonds may be conjugated or not conjugated.
  • the alkenyl group may have 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as “2 to 20" refers to each integer in the given range; e.g., "2 to 20 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc. , up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term
  • alkenyl where no numerical range is designated.
  • the substiruent group(s) is(are) one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, mercapto, alkylthio, cyano, halogen, nitro, haloalkyl, haloalkoxy, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • the alkynyl group may have 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as “2 to 20” refers to each integer in the given range; e.g., "2 to 20 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term
  • alkynyl where no numerical range is designated).
  • An alkynyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkenyl group substitution.
  • hetero refers to heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur.
  • heteroalkyl refers to a straight or branched alkyl group consisting of the stated number of carbon atoms, where one or more carbon atom(s), such as 1, 2, 3 or 4 carbon atom(s), and the associated hydrogen atom(s) have been independently replaced with the same or different heteroatoms selected from nitrogen, oxygen and sulfur.
  • the carbon atom(s) being replace may be in the middle or at the end of the alkyl group.
  • heteroalkyl include, but are not limited to, -S-alkyl, -O-alkyl, -NH-alkyl, -alkylene-O-alkyl, etc
  • aryl refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent atoms) that have a fully delocalized pi-electron system.
  • aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted.
  • hydrogen atoms are replaced by substiruent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O- carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,
  • substituents on an aryl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system), in which at least one of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • Examples of monocyclic "heteroaryl” include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazole, oxadiazole, and triazine.
  • heteroaryl examples include, but are not limited to, quinoline, isoquinoline, quinazoline, quinoxaline, indole, purines, benzofuran, benzolhiophene, benzopyranones (e.g. coumarin, chromone, and isocoumarin).
  • a heteroaryl may be substituted.
  • substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, tri
  • substituents on a heteroaryl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.
  • an "aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group.
  • the alkylene and aryl group of an aralkyl may be substituted. Examples include but are not limited to benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl.
  • the alkylene group is a lower alkylene group.
  • a “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group.
  • the alkylene and heteroaryl group of heteroaralkyl may be substituted. Examples include but are not limited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, pyrazolylalkyl and imidazolylalkyl, and their substituted as well as benzo-fused analogs.
  • the alkylene group is a lower alkylene group.
  • alkylene is a straight-chained tethering group, forming bonds to connect molecular fragments via their terminal carbon atoms.
  • the alkylene may have 1 to 20 carbon atoms.
  • the alkylene may also be a medium size alkylene having 1 to 10 carbon atoms, such as ' ⁇ - ⁇ "
  • the alkylene could also be a lower alkylene having 1 to 4 carbon atoms.
  • the alkylene may be designated as "Ci-C 4 alkylene", "Ci-4 alkylene” or similar designations.
  • Non-limiting examples include, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (- CH 2 CH 2 CH 2 -), and butylene (-(CH 2 ) 4 -) groups.
  • methylene ethylene
  • ethylene -CH 2 CH 2 -
  • propylene - CH 2 CH 2 CH 2 -
  • butylene -(CH 2 ) 4 -
  • heteroalkylene by itself or in combination with another term refers to an alkylene group consisting of the stated number of carbon atoms in which one or more of the carbon atoms, such as 1 , 2, 3 or 4 carbon atom(s), are independently replaced with the same or different heteroatoms selected from oxygen, sulfur and nitrogen.
  • heteroalkylene examples include, but not limited to -CH2-O-, -CH 2 -CH 2 -0-, -CH 2 -CH 2 -CH 2 -0-, - CH 2 -NH-, -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -NH-, -CH 2 -CH 2 - NH-CH2-, -O-CH 2 -CH 2 -O-CH 2 - CH2-O-, -0-CH 2 -CH 2 -0-CH 2 -CH 2 -, and the like.
  • arylalkylidene refers to an alkylidene group in which either R' or R" is an aryl group. An alkylidene group may be substituted.
  • alkoxy refers to the group -OR wherein R is an alkyl, e.g. methoxy, ethoxy, n-propoxy, cyclopropoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy and the like. An alkoxy may be substituted.
  • alkylthio refers to the formula -SR wherein R is an alkyl is defined as above, e.g. methylmercapto, ethylmercapto, n-propylmercapto, 1- methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec- butylmercapto, tert-butylmercapto, and the like.
  • An alkylthio may be substituted.
  • aryloxy and arylthio refers to RO- and RS-, in which R is an aryl as defined above, e.g., phenoxy, naphthalenyloxy, azulenyloxy, anthracenyloxy, naphthalenylthio, phenylthio and the like. Both an aryloxy and arylthio may be substituted.
  • alkenyloxy refers to the formula -OR wherein R is an alkenyl as defined above, e.g., vinyloxy, propenyloxy, n-bufenyloxy, iso-butenyloxy, sec- pentenyloxy, tert-pentenyloxy, and the like.
  • the alkenyloxy may be substituted.
  • acyl refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted.
  • cycloalkyl refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion.
  • Cycloalkyl groups may range from C 3 to Cio, such as from C 3 to C 6 .
  • a cycloalkyl group may be unsubstituted or substituted.
  • Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated.
  • substituents on a cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including an aryl and a heteroaryl.
  • cycloalkenyl refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be "aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro-connected fashion. Cycloalkenyl groups may range from C 3 to Oo, such as from C 3 to C 8 or from C 5 to Cio.
  • C 3-8 cycloalkenyl includes C 4-8 cycloalkenyl, C 5-8 cycloalkenyl or C 6-8 cycloalkenyl.
  • a cycloalkenyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated. When substituted, substituents on a cycloalkenyl group may form an aromatic ring fused to the cycloalkenyl group, including an aryl and a heteroaryl.
  • cycloalkynyl refers to a cycloalkyl group that contains one or more triple bonds in the ring. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkynyl groups may range from C 8 to C12. A cycloalkynyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated. When substituted, substituents on a cycloalkynyl group may form an aromatic ring fused to the cycloalkynyl group, including an aryl and a heteroaryl.
  • heteroalicyclic or “heteroalicyclyl” refers to a 3- to 18 membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • heteroalicyclic or heteroalicyclyl refers to a 3- to 18 membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • heteroalicyclyl groups may range from C 2 to Cio, in some embodiments it may range from C 2 to C 9 , and in other embodiments it may range from C 2 to C 8 .
  • the "heteroalicyclic” or “heteroalicyclyl” may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be joined together in a fused, bridged or spiro-connected fashion; and the nitrogen, carbon and sulfur atoms in the "heteroalicyclic” or “heteroalicyclyl” may be oxidized; the nitrogen may be quaternized; and the rings may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system throughout all the rings, examples are 2H-benzo[b][l,4]oxazin-3(4H)-one, 3,4-dihydroquinolin-2(lH)-one, 1,2,3,4- tetrahydroquinoline, 3,4
  • the substituent(s) may be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido
  • heteroalicyclic or “heteroalicyclyl” include but are not limited to, azepinyl, dioxolanyl, imidazolinyl, morpholinyl, oxetanyl, furanyl, oxiranyl, piperidinyl N-Oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyranyl, 4-piperidonyl, pyrazolidinyl, 2- oxopyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone.
  • a "fused bicyclic ring” refers to a ring system where the two rings share two adjacent atoms. The two rings share one covalent bond.
  • An example of a fused bicyclic ring is decalin.
  • a "spiro bicyclic ring” refers to a bicyclic ring wherein the two rings share one atom.
  • a "bridged ring system” refers to a ring system where two rings share three or more atoms.
  • the two bridgehead atoms are separated by a bridge containing at least one atom, a specific example is norbornane, also known as bicyclo[2.2.1]heptane.
  • the structure of bicyclo[2.2.1]heptane is shown below also indicating the bridgehead atoms
  • a "(cycloalkyl)alkyl” is a cycloalkyl group connected, as a substituent, via an alkylene group.
  • the alkylene and cycloalkyl of a (cycloalkyl)alkyl may be substituted.
  • Examples include but are not limited cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl,
  • the alkylene group is a lower alkylene group.
  • a "(cycloalkenyl)alkyP' is a cycloalkenyl group connected, as a substituent, via an alkylene group.
  • the alkylene and cycloalkenyl of a (cycloalkenyl)alkyl may be substituted.
  • the alkylene group is a lower alkylene group.
  • a "(cycloalkynyl)alkyl” is a cycloalkynyl group connected, as a substituent, via an alkylene group.
  • the alkylene and cycloalkynyl of a (cycloalkynyl)alkyl may be substituted.
  • the alkylene. group is a lower alkylene group.
  • halo or halogen refers to F (fluoro), CI (chloro), Br
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and l-chloro-2-fiuoromethyl, 2- fluoroisobutyl. A haloalkyl may be substituted.
  • haloalkoxy refers to a RO-group in which R is a haloalkyl group.
  • groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and 1-chloro-l-fluoromethoxy, 2-fluoroisobutyoxy.
  • a haloalkoxy may be substituted.
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein.
  • An O-carboxy may be substituted.
  • a C-carboxy may be substituted.
  • a "trihalomethanesulfonyl” group refers to an "X 3 CSO 2 -" group" wherein X is a halogen.
  • a "nitro” group refers to a "-NO 2 " group.
  • a "cyano" group refers to a "-CN” group.
  • a "cyanato” group refers to an "-OCN” group.
  • An "isocyanato” group refers to a "-NCO” group.
  • a "thiocyanato" group refers to a "-SCN” group.
  • a "hydroxy” group or "hydroxyl” group refers to an "-OH” group.
  • An "isothiocyanato" group refers to an " -NCS” group.
  • a sulfinyl may be substituted.
  • a “sulfonyl” group refers to an “SO 2 R” group in which R can be the same as defined with respect to O-carboxy. A sulfonyl may be substituted.
  • S-sulfonamido refers to a "-S0 2 NRARB” group in which RA and
  • RB independently of each other can be the same as defined with respect to the R group as defined for O-carboxy, or combined to form a ring system selected from the group consisting of substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • a S-sulfonamido may be substituted.
  • An "N-sulfonamido" group refers to a "RS0 2 N(R A )-" group in which R and
  • RA independently of each other can be the same as defined with respect to the R group as defined for O-carboxy.
  • An N-sulfonamido may be substituted.
  • a "trihalomethanesulfonamido" group refers to an "X 3 CS0 2 N(R)-" group with
  • X as halogen and R can be the same as defined with respect to O-carboxy.
  • trihalomethanesulfonamido may be substituted.
  • a C-amido may be substituted.
  • a lower alkoxyalkyl refers to an alkoxy group connected via a lower alkylene group.
  • a lower alkoxyalkyl may be substituted.
  • amine refers to "RNH 2 " (a primary amine), “R 2 NH” (a secondary amine), “R 3 N” (a tertiary amine). An amino group may be substituted.
  • An aminoalkyl refers to an amino group connected via a lower alkylene group.
  • An aminoalkyl may be substituted.
  • 0 zero
  • -(CH 2 ) s -C2 -6 alkyl wherein S can be "0” means that the -(CH 2 )- is absent and the remaining group is -C 2-6 alkyl
  • another illustrative example is whenever “r” is “0",then the -(CR9 a R9b)- group is absent and a bond is connecting "E" to ring system "B”.
  • Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well-known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enatiomerically pure or be stereoisomeric mixtures.
  • compounds provided herein may be scalemic mixtures.
  • each double bond may independently be E or Z or a mixture thereof.
  • all tautomeric forms are also intended to be included.
  • tautomer and “tautomeric” refer to alternate forms of a compound disclosed herein that differ in the position of a proton.
  • isotopes may be present in the compounds described herein.
  • Each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen- 2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • methyl includes -CH 3 , - CD 3 , -CH 2 D etc.
  • pharmaceutically acceptable salt refers to a salt of a compound that does not abrogate the biological activity and properties of the compound.
  • Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base.
  • Base-formed salts include, without limitation, ammonium salt ( H 4 + ); alkali metal, such as, without limitation, sodium or potassium, salts; alkaline earth, such as, without limitation, calcium or magnesium, salts; salts of organic bases such as, without limitation, dicyclohexylamine, piperidine, piperazine, methylpiperazine, N-methyl-D-glucamine, diethylamine, ethylenediamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, without limitation, arginine and lysine.
  • alkali metal such as, without limitation, sodium or potassium
  • alkaline earth such as, without limitation, calcium or magnesium
  • salts of organic bases such as, without limitation, dicyclohexylamine, piperidine, piperazine, methylpiperazine, N-methyl-D-glucamine, diethylamine, ethylenediamine, tris(hydroxymethyl)methylamine
  • salts with the amino group of amino acids
  • Useful acid-based salts include, without limitation, acetates, adipates, aspartates, ascorbates, benzoates, butyrates, caprate, caproate, caprylate, camsylates, citrates, decanoates, formates, fumarates, gluconates, glutarate, glycolates, hexanoates, laurates, lactates, maleates, nitrates, oleates, oxalates, octanoates, propanoates, palmitates, phosphates, sebacates, succinates, stearates, sulfates, sulfonates, such as methanesulfonates, ethanesulfonates, p-toluenesulfonates, salicylates, tartrates, and tosylates.
  • solvates and hydrates are complexes of a compound with one or more solvent of water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
  • a “prodrug” refers to a compound that may not be
  • the prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have better solubility than the active parent drug in pharmaceutical compositions.
  • prodrug a compound disclosed herein, which is administered as an ester (the "prodrug") to facilitate absorption through a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to a carboxylic acid (the active entity) once inside the cell where water-solubility is beneficial.
  • prodrug a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized in vivo to release the active parent compound.
  • prodrugs relates to formation of a basic nitrogen comprising the piperidyl group of Formula (I), wherein the basic nitrogen may be formed by the metabolic cleavage of a group attached to the nitrogen of the piperidyl group, forming a basic nitrogen, e.g. as shown in Formula A.
  • Particular examples are acyl and tosyl groups attached to the nitrogen.
  • Anti-drug refers to a compound or composition acting against or opposing illicit drugs or their use. Compounds of the present application may act as anti-drugs.
  • to "modulate" the activity of a receptor means either to activate it, i.e., to increase its cellular function over the base level measured in the particular environment in which it is found, or deactivate it, i.e., decrease its cellular function to less than the measured base level in the environment in which it is found and/or render it unable to perform its cellular function at all, even in the presence of a natural binding partner.
  • a natural binding partner is an endogenous molecule that is an agonist for the receptor.
  • An "agonist” is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor).
  • partial agonist refers to a compound that has an affinity for a receptor but, unlike an agonist, when bound to the receptor it elicits only a fractional degree of the pharmacological response normally associated with the receptor even if a large number of receptors are occupied by the compound.
  • An "inverse agonist” is defined as a compound, which reduces, or suppresses the basal activity of a receptor, such that the compound is not technically an antagonist but, rather, is an agonist with negative intrinsic activity.
  • antagonist refers to a compound that binds to a receptor to form a complex that does not give rise to any response, as if the receptor was unoccupied.
  • An antagonist attenuates the action of an agonist on a receptor.
  • An antagonist may bind reversibly or irreversibly, effectively eliminating the activity of the receptor permanently or at least until the antagonist is metabolized or dissociates or is otherwise removed by a physical or biological process.
  • a "subject” refers to an animal that is the object of treatment, observation or experiment.
  • Animal includes cold- and warm-blooded vertebrates and invertebrates such as birds, fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • a "patient” refers to a subject that is being treated by a medical professional such as an M.D. or a D.V.M. to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.
  • a “carrier” refers to a compound that facilitates the
  • DMSO dimethyl sulfoxide
  • a "diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
  • an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • a “diluent” is a type of excipient.
  • a "receptor” is intended to include any molecule present inside or on the surface of a cell that may affect cellular physiology when it is inhibited or stimulated by a ligand.
  • a receptor comprises an extracellular domain with ligand-binding properties, a transmembrane domain that anchors the receptor in the cell membrane, and a cytoplasmic domain that generates a cellular signal in response to ligand binding ("signal transduction").
  • a receptor also includes any intracellular molecule that in response to ligation generates a signal.
  • a receptor also includes any molecule having the characteristic structure of a receptor, but with no identifiable ligand.
  • a receptor includes a truncated, modified, mutated receptor, or any molecule comprising partial or all of the sequences of a receptor.
  • Ligand is intended to include any substance that interacts with a receptor.
  • “Selective” or “selectivity” is defined as a compound's ability to generate a desired response from a particular receptor type, subtype, class or subclass while generating less or little response from other receptor types.
  • “Selective” or “selectivity” of one or more particular subtypes of a compound means a compound's ability to increase the activity of the subtypes while causing less, little or no increase in the activity of other subtypes.
  • Selectivity of a compound between receptor targets may for example be determined by the ratio of potencies or affinities for those targets. For example, a compound is said to be 10-fold selectivity for Target 1 over Target 2 if said compound has a pKi of 10 nM for Target 1 and 100 nM for Target 2. Said compound is therefore 10-fold more potent at Target 1, i.e. it is 10- fold selective for Target 1.
  • IC50 refers to an amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response.
  • the IC50 can be determined using an assay.
  • the assay may be an R-SAT® assay as described herein but is not limited to an RSAT assay.
  • EC50 refers to an amount, concentration or dosage of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound, in an assay that measures such response such as but not limited to R-SAT® assay described herein.
  • pKi refers to the negative logarithm of the Ki, the equilibrium dissociation constant of an antagonist-receptor complex measured in a functional antagonist or radioligand binding assay, e.g. R-SAT® assay as described herein.
  • coadministration refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo. Coadministration means the simultaneous delivery of separate agents; the simultaneous delivery of a mixture of agents; as well as the delivery of one agent followed by delivery of a second agent or additional agents. Agents that are coadministered are typically intended to work in conjunction with each other.
  • an effective amount means an amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or palliation of the symptoms of the disease being treated.
  • prevent/preventing should not be construed to mean that a condition and/or a disease never might occur again after use of a compound or
  • compositions according to embodiments disclosed herein to achieve prevention.
  • the term should neither be construed to mean that a condition not might occur, at least to some extent, after such use to prevent said condition. Rather,
  • prevent/preventing is intended to mean that the condition to be prevented, if occurring despite such use, will be less severe than without such use.
  • Embodiments disclosed herein relate to a compound according to Formula (I)
  • r is an integer selected from the group consisting of 0, 1 , 2, and 3;
  • Ci -6 hydroxyalkyl unsubstituted or substituted Ci -6 aminoalkyl, unsubstituted or substituted Ci -6 alkenyl, unsubstituted or substituted Ci- alkoxy,
  • R2, R2a, R2b, R2c and R2d are independently selected from the group consisting of hydrogen, deuterium, amino, hydroxyl, -OD, halogen, cyano, unsubstituted or substituted Ci -6 alkyl, unsubstituted or substituted Ci -6 haloalkyl, unsubstituted or substituted Ci -6 hydroxyalkyl, unsubstituted or substituted Ci -6 alkenyl, unsubstituted or substituted Ci -6 alkoxy,
  • R 3 is selected from hydrogen, deuterium, hydroxyl, -OD, unsubstituted or substituted Ci-6 alkyl, unsubstituted or substituted Ci-6 haloalkyl, unsubstituted or substituted Ci -6
  • R.4a, R4b, R 5 a, R 5 b, R 5 c, R 5 d, R9a and R% are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted Ci -6 alkyl;
  • R 6 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, - OD, cyano, substituted or unsubstituted C 1-4 alkyl, and substituted or unsubstituted C1-4 alkoxy, substituted or unsubstituted aryl;
  • R 7 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, - OD, cyano, substituted or unsubstituted C 1-4 alkyl, and substituted or unsubstituted C1-4 alkoxy;
  • R 8 is absent, or selected from the group consisting of hydrogen, deuterium, cyano, hydroxyl, - OD, substituted or unsubstituted C 1 -4 alkyl, substituted or unsubstituted C alkenyl, substituted or unsubstituted C 3 - 6 cycloalkyl, and substituted or unsubstituted Ci -4 alkoxy; Rio and Rn, independently are selected from the group consisting of hydrogen, amino, unsubstituted or substituted Ci -6 alkyl;
  • E is N or CH
  • B is a ring system selected from the group consisting of substituted or unsubstituted 4-12 membered heteroalicyclic ring systems;
  • X is O or S.
  • Some embodiments relate to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, stereoisomers, and deuterated analogues thereof, wherein A is substituted or unsubstituted 5 or 6 membered heteroaryl, e.g. substituted or unsubstituted oxadiazolyl or substituted or unsubstituted triazolyl, such as substituted or unsubstituted l,2,4-oxadiazol-5-yl, substituted or unsubstituted 1,2,4- oxadiazol-3-yl or substituted or unsubstituted triazolyl.
  • A is substituted or unsubstituted 5 or 6 membered heteroaryl, e.g. substituted or unsubstituted oxadiazolyl or substituted or unsubstituted triazolyl, such as substituted or unsubstituted l,2,4-oxadiazol-5-y
  • Some embodiments relate to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, stereoisomers, and deuterated analogues thereof, wherein ring system B has the formula: R 8
  • R 6a , R6b, R6c and R 6 d independently are absent or selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted CM alkyl, and substituted or unsubstituted Ci-4 alkoxy; and R 7a , R7b, 7c and R 7 d independently are absent or selected from the group consisting of, hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted Ci-4 alkyl, and substituted or unsubstituted C 1-4 alkoxy; R 8 is absent, or selected from the group consisting of hydrogen, cyano, hydroxyl, substituted or unsubstituted Ci ⁇ alkyl, substituted or unsubstituted Ci-t alkenyl, substituted or unsubstituted C -6 cycloalkyl, and substituted or unsubstituted Ci
  • r is 0 or 1, e.g. when the ring system B is selected from the group consisting of 4, 5, 6 or 7 membered ring comprising at least one nitrogen atom, as described hereinabove. In some embodiments r is 0.
  • Some embodiments relate to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, stereoisomers, and deuterated analogues thereof, wherein the ring system B is selected from the group consisting of
  • T, U, V, Y, Z are independently selected from the group consisting of -0-, -C-, and -N-; wherein when B is selected from
  • R 6a , R 6 b, R 6c and R 6 d independently are absent or selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted Ci ⁇ alkyl, and substituted or unsubstituted C1-4 alkoxy; and R 7a , R?
  • R7c and R 7 d independently are absent or selected from the group consisting of, hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted C 1-4 alkyl, and substituted or unsubstituted C alkoxy; and R 8 is absent, or selected from the group consisting of hydrogen, cyano, hydroxyl, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted Ci -4 alkenyl, substituted or unsubstituted C 3-6 cycloalkyl, and substituted or unsubstituted C1-4 alkoxy.
  • r is 0 or 1 . In some embodiments r is 1 .
  • T, U, Y, and Z are -C- (carbon atom).
  • R 6a , R 6 b, and R 6c independently are absent or selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted Ci-4 alkyl, and substituted or unsubstituted C alkoxy; and R 7a , R7t > , and R 7c independently are absent or selected from the group consisting of, hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted C1-4 alkyl, and substituted or unsubstituted O-4 alkoxy; R 8 is selected from the group consisting of hydrogen, cyano, hydroxyl, substituted or unsubstituted C alkyl, substituted or unsubstituted C1-4 alkenyl, substituted or unsubstituted C 3-6 cycloalkyl, and substituted or unsubstituted C alkoxy; and r is 1 ;
  • Some embodiments relate to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, stereoisomers, and deuterated analogues thereof, wherein the ring system B is selected from the group consisting of a bridged bicyclic ring system, wherein the two rings of the bridged bicyclic ring system share three or more atoms; a fused bicyclic ring system, wherein the two rings share two adjacent atoms; and a spiro bicyclic ring system, wherein the two rings share one atom and ring system, and wherein ring system B is heteroalicyclic.
  • the bicyclic ring system comprises at least one nitrogen atom.
  • the bicyclic ring system consist of one nitrogen atom as the only heteroatom.
  • Some embodiments relate to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, stereoisomers, and deuterated analogues thereof, wherein the bicyclic ring system is a ring system wherein at least one of the rings in ring system B is selected from the group consisting of a 4-membered ring, 5- membered ring or a 6-membered ring system, such as a 4-membered ring, 5 -membered ring or a 6-membered ring system comprising carbon atoms and one nitrogen atom.
  • Some embodiments relate to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, stereoisomers, and deuterated analogues thereof, wherein the bridged bicyclic ring system is a 6-12 membered bicyclic ring system comprising at least one nitrogen atom, such as a ring system consisting of carbon atoms and one nitrogen atom only.
  • Some embodiments relate to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, stereoisomers, and deuterated analogues thereof, wherein the ring system B is selected from the group consisting of
  • R 6A , R 6 b, R6c and R 6 d independently are absent or selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted Ci-4 alkyl, and substituted or unsubstituted C alkoxy;
  • R 7 a, R7t > , 7c and R 7 d independently are absent or selected from the group consisting of, hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted C 1-4 alkyl, and substituted or unsubstituted CM alkoxy;
  • R 8 is absent, or selected from the group consisting of hydrogen, cyano, -OH, substituted or unsubstituted Ci-4 alkyl, substituted or unsubstituted C alkenyl, substituted or unsubstituted C 3-6 cycloalkyl, and substituted or unsubstituted C
  • the ring system B is selected from the group consisting of
  • R 6a , R 6 t > , R6c and R 6 d independently are absent or selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted Ci-4 alkyl, and substituted or unsubstituted C alkoxy;
  • R 7a , R7b, R7c and R 7 a independently are absent or selected from the group consisting of, hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted C1-4 alkyl, and substituted or unsubstituted C1-4 alkoxy;
  • R 8 is absent, or selected from the group consisting of hydrogen, cyano, -OH, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted Ci-4 alkenyl, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted
  • Some embodiments relate to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, stereoisomers, and deuterated analogues thereof, wherein the ring system B is selected from the group consisting of
  • T, U, V, Y, and Z are independently selected from the group consisting of -0-, -C-, and -N-;
  • R 6 , R 6a , R.6b, R 6 c and R 6 independently are absent or selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted Ci-4 alkyl, and substituted or unsubstituted C1-4 alkoxy;
  • R 7 , R 7a , R7b, R7c and R 7 independently are absent or selected from the group consisting of, hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted CI alkyl, and substituted or unsubstituted Ci-4 alkoxy;
  • R 8a , Rsb and R 8 is absent, or selected from the group consisting of hydrogen, cyano, hydroxyl, substituted or unsubstituted Ci ⁇
  • T, U, V, Y, and Z are independently selected from the group consisting of -C- and -N-; or T, U, and Z are -C-; and V and Y are independently selected from the group consisting of -C- and -N-; or T, U, V, Y, and Z are -C-.
  • ring system B being a bicyclic ring system comprising one or more heteroatoms, and it is readily understood by those skilled in the art that the ring systems disclosed herein, such as hereinabove could be combined with other embodiments not explicitly disclosed in combination.
  • Some embodiments relate to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, stereoisomers, and deuterated analogues thereof, wherein the ring system B is selected from the group consisting of
  • T, U, V, W, Y, and Z are independently selected from the group consisting of -0-, -C-, and -N-;
  • R 6 is absent or selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, substituted or unsubstituted C 1-4 alkyl, and substituted or unsubstituted C 1-4 alkoxy;
  • R 7 is absent or selected from the group consisting of, hydrogen, deuterium, halogen, hydroxyl, -OD, substituted or unsubstituted C alkyl, and substituted or unsubstituted C alkoxy;
  • R 8 is absent, or selected from the group consisting of hydrogen, cyano, -OH, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C alkenyl, substituted or unsubstituted C 3-6 cycloalkyl, and substituted or unsubstituted C
  • Some embodiments relate to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, stereoisomers, and deuterated analogues thereof, wherein the ring system B
  • n q and p independently are 0 or 1.
  • ring system B may be selected from the group consisting of
  • R7a, R7b, R7c, R7d and R7e are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, -OD, substituted or unsubstituted C1-4 alkyl, and substituted or unsubstituted C1-4 alkoxy; and R 8 , is selected from the group consisting of hydrogen, cyano, hydroxyl, substituted or unsubstituted C alkyl, substituted or unsubstituted C alkenyl, substituted or unsubstituted C 3-6 cycloalkyl, and substituted or unsubstituted C1-4 alkoxy.
  • Some embodiments relate to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, stereoisomers, and deuterated analo ues thereof, wherein the ring system B has the following formula
  • R 6a , and R 6 b are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted C alkyl, and substituted or unsubstituted CM alkoxy, substituted or unsubstituted aryl;
  • R 7 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, oxo, -OD, cyano, substituted or unsubstituted CM alkyl, and substituted or unsubstituted CM alkoxy; when p is 0 then at least one of R 6a and R 6 b is not hydrogen.
  • R 6a and R 6 b are not hydrogen or deuterium; or one of R 6a and R 6 b is selected from halogen, CM alkyl and aryl, such as R 6 b is halogen and R 6a is hydrogen, or R 6 b is fluoro and R 6a is hydrogen
  • R 6 b is halogen
  • R 8a , Rsb and R 8 independently are absent, or selected from the group consisting hydrogen, -CF 3 , - CHF 2 , -CF2CF 3 , -OCF 3 , -OCF 2 CF 3 and -OCHF 2 .
  • R 8a , R 8 b and R 8 independently are absent or hydrogen,
  • R la , Rib, and Ri c are hydrogen
  • Rid is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, methyl, -CD 3 , methoxy, -OCD 3 , -OCF3 and -CF 3 , such as hydrogen or fluoro.
  • Ri is selected from the group consisting of halogen, amino, methyl, -CD 3 , ethyl, -CD 2 CD 3 , optionally deuterated n-propyl, optionally deuterated iso-propyl, optionally deuterated n-butyl, optionally deuterated iso-butyl, optionally deuterated n-pentyl, optionally deuterated 2-methyl-butyl, optionally deuterated n-hexyl, optionally deuterated 2-methyl-pentyl, methoxy, -OCD 3 , optionally deuterated ethoxy, optionally deuterated n-propoxy, optionally deuterated isopropoxy, optionally deuterated n- butoxy, optionally deuterated iso-butoxy, optionally deuterated pentyl-oxy, optionally deuterated 4-methyl-butoxy, optionally deuterated hexyl-oxy, optionally deuterated 4- methylpent
  • Ri is fluoro
  • Ri a , Rib, and Ri c are hydrogen
  • Rid is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, methyl, - CD 3 , methoxy, -OCD3, -OCF3 and -CF3, such as hydrogen or fluoro.
  • Ri is fluoro
  • Rid is hydrogen or fluoro
  • R , Rib, and Ri c are hydrogen.
  • R 2 , R 2a , R2b, R2c and R 2 d independently are selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, C 1-6 haloalkoxy, C3-4 cycloalkyl, C3-4 cycloalkyl-Ci-3 alkyl and deuterated analogues thereof; or R 2 and R 2 b, taken together with the phenyl ring they attach to and the atoms to which they are attached form a bicyclic fused ring system.
  • R 2a , R 2c , R2d, and R3 ⁇ 4 independently are selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, methyl, -CD 3 , methoxy, - OCD 3 ,-OCF 3 and -CF 3 .
  • R 2a , R 2 c and R3 ⁇ 4 are hydrogen
  • R 2 d is hydrogen, fluoro or hydroxyl, for example R 2a , R 2c , R2b and R 2 d are hydrogen.
  • R 2 is selected from the group consisting of halogen, cyano, methyl, -CD3, ethyl, -CD 2 CD3, optionally deuterated n-propyl, optionally deuterated iso-propyl, optionally deuterated n-butyl, optionally deuterated iso-butyl, optionally deuterated n-pentyl, optionally deuterated 2-methyl-butyl, optionally deuterated n-hexyl, optionally deuterated 2-methyl-pentyl, optionally deuterated methoxy, optionally deuterated ethoxy, optionally deuterated n-propoxy, optionally deuterated isopropoxy, optionally deuterated allyloxy, optionally deuterated prop-2-yn-l-yloxy, optionally deuterated n-butoxy, optionally deuterated iso-butoxy, optionally deuterated tert-butoxy, optionally deuterated pentyl-
  • R 2 may be selected from methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, prop-2-yn-l-yloxy, n- butoxy, iso-butoxy, tert-butoxy, pentyl-oxy, 4-methyl-butoxy, hexyl-oxy, 4-methylpentoxy, cyclopropyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxy,
  • R3 is selected from the group consisting of hydrogen, deuterium, hydroxyl, -OD, substituted or unsubstituted Ci -6 alkyl, substituted or unsubstituted Ci -6 alkoxy, substituted or unsubstituted -(CH 2 )s-C3-6 cycloalkyl, substituted or unsubstituted -(CH 2 ) s -C 2- 5 heteroalicyclyl, substituted or unsubstituted -(CH 2 ) s -C 2-5 heteroaryl, and substituted or unsubstituted -(CH 2 ) s -Cs-6 aryl, wherein each s is selected from the group consisting of 0, 1, 2 and 3.
  • R 4a , i b , R 5 a, R 5 b, R 5 c and R 5 d when present, are independently hydrogen or methyl.
  • R 4a , R4b, R 5 a, R 5 b, 5 c and R 5 d are hydrogen when said R-group is present.
  • R 6, R 6a , R6b, R6c, R6d, and R 6e independently are absent or selected from the group consisting of hydrogen, deuterium, halogen, and substituted or unsubstituted Ci -4 alkyl.
  • R 6 is hydrogen or fiuoro
  • R 6a , R 6 b, R6c, Red, and R 6e independently are absent or selected from the group consisting of hydrogen, fiuoro, methyl and methoxy.
  • Additional examples are R 6a , 6b, R6c, R 6 d, and R 6e are independently selected from the group consisting of from fiuoro, methyl and methoxy, and the others are hydrogen or absent.
  • R 7 , R 7a , R7b, R7c, R7d and R 7e independently are absent or selected from the group consisting of hydrogen, deuterium, halogen, methyl and methoxy. In many embodiments R7, R7 a , R7b, R7c, R 7 d and R 7e are absent.
  • R 6 e.g. R 6 b
  • one R 6 is fluoro or hydrogen and any other R 6 are absent or hydrogen
  • p is zero, i.e. no R 7 group is present.
  • R 8 R 8a , and R 8 b independently are absent or selected from the group consisting of hydrogen, halogen, methyl, ethyl, propyl, methoxy, ethoxy, Ci -2 - haloalkyl, and Ci -2- haloalkoxy; such as hydrogen, -CF 3 , -CHF 2 , -CF2CF3 -OCF 3 , -OCF2CF3 and -OCHF2.
  • R 8 is hydrogen.
  • R 8 (when present) is hydrogen, R 6 hydrogen or fluoro, and no R7 group is present irrespectively of which heteroalicyclic ring system B disclosed herein is selected.
  • R 8 is hydrogen, R 6 hydrogen or fluoro, and no R7 group is present irrespectively of which heteroalicyclic ring system B disclosed herein is selected.
  • Examples are ring system B selected from 4, 5, 6 or 7 membered rings comprising at least one nitrogen atom (e.g.
  • heteroalicyclic ring system such as a 4-7 membered ring system, and provided that when B is a substituted or unsubstituted piperidyl-4-yl or unsubstituted 1 -phenylmethyl pyrrolidin-3-yl R 6 b is not hydrogen); bridged heteroalicyclic bicyclic ring system, wherein the two rings share three or more atoms, comprising at least one nitrogen atom; fused heteroalicyclic bicyclic ring system, wherein the two rings share two adjacent atoms, a spiro heteroalicyclic bicyclic ring system, wherein the two rings share one atom, comprising at least one nitrogen atom.
  • E is N (i.e. a nitrogen atom).
  • r is 0 or 1
  • m and n independently are selected from 0 and 1 , such as m is 1 and n is 0 or 1 ; and/or p and q independently are selected from 0 and 1.
  • R , Rib, and Ri c are hydrogen Rid is hydrogen or fluoro; Ri is fluoro; R 2a , 2b, R2c are and R 2 d are hydrogen; and R 2 is selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, prop-2-yn-l -yloxy, n-butoxy, iso-butoxy, tert-butoxy, pentyl-oxy, 4-methyl-butoxy, hexyl-oxy, 4-methylpentoxy, cyclopropyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxy, cyclobutylmethoxy,
  • Some embodiments disclosed herein relate to a method for treating a disease in a patient comprising administering to the patient an effective amount of a compound, pharmaceutically acceptable salt, polymorph or stereoisomer of a compound according to Formulas (I), wherein the disease is selected from the group consisting of Abnormal hormonal activity, Alzheimer's disease, Addiction (alcohol, nicotine and opioid), Addison's disease, ADHD, Alzheimer's disease psychosis, Affective disorders, Aggressiveness, Agitation, Akathisia, Alcohol addiction, Alcohol withdrawal, Amenorrhea, Amyotrophic lateral sclerosis, Anorexia, Anxiety, Appetite disorders, Asthma, Autism, Behavioral disorders, Behavioral disturbances associated with dementia, Binge eating disorder associated with impulse control disorder (ICD), Bipolar disorder, Blindness, Borderline disorder, Borderline personality disorder, Bradykinesia, Bulimia, Buying associated with ICD, Cardiac arrhythmia, Cerebral vascular accidents, Charles Bonne
  • Fibromyalgia Frailty, Friedrich's Ataxia, Frontotemperal Dementia, Gambling associated with ICD, Galactorrhea, General anxiety disorder, Glaucoma, Hair loss or thinning,
  • Hypertension Hypersexuality associated with ICD, Hypotension, Hypoglutamateriga disorders, Impulse control disorder, Idiopathic thrombocytopenic purpura, Impotence, Incontinence, Increased intraocular pressure, Infertility, Inflammatory pain, Insomnia, Ischemia, Ischemic stroke, Lewy body disease (LBD), Learning disorders, Libido
  • Thrombotic thrombocytopenic purpura Tinnitus, Tiredness, Tourette's syndrome, Transient insomnia, Traumatic brain injury, Treatment-resistant depression, Tremor, Vaginal dryness, Vasospasm Wakefulness, Hallucinations associated with Parkinson's disease, Delusions associated with Parkinson's disease; cancer, Pancreatic cancer, Hypoactive sexual desire disorder, and Liver fibrosis.
  • Suitable routes of administration of compounds of Formula (I) may, for example, include oral, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • the compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • compositions of the present invention may be any pharmaceutical compositions of the present invention.
  • compositions for use as described herein thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the acrive compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • the crude material was purified by HPLC, eluting with 5-25% acetonitrile in water (containing 0.1 % trifluoroacetic acid) to afford (7R,8aR)-N-[(4-fluorophenyl)methyl]-octahydroindolizin-7-amine (50 mg, faster eluting compound) and (7S,8aR)-N-[(4-fluorophenyl)methyl]-octahydroindolizin-7-amine (30 mg, slower eluting compound).
  • Intermediate 22 and intermediate 23 were purified from intermediate 21 by chiral chromatography using a Daicel IA column eluting with petroleum-ether (boiling point 40-65 °C): ethanol: methanol with ratio 95: 2.5: 2.5 modified with diethylamine 0,1% to give tert- butyl (3S,4R)-3-fluoro-4- ⁇ [(4-fluorophenyl)methyl] amino ⁇ piperidine-l -carboxylate as the faster eluting enantiomer and tert-butyl (3R,4S)-3-fluoro-4- ⁇ [(4- fluorophenyl)methyl] amino ⁇ piperidine-l -carboxylate as the slower eluting enantiomer.
  • the compound was prepared in analogy with intermediate 20 using tert-butyl 4- oxo-2-(trifluoromethyl)piperidine-l-carboxylate and 4-fluorobenzylamine. Methanol was used as solvent.
  • Tetrabutylammonium iodide (3.7 g, 10 mmol), potassium carbonate (55.2 g, 400 mmol) and isobutyl bromide (27 ml, 250 mmol) were added to 4-hydroxybenzonitrile (11.9 g, 100 mmol) in dimethylformamide (100 ml). The mixture was heated to 70 °C. After 18 hours, the mixture was cooled to ambient temperature, diluted with water (150 ml) and extracted with diethyl ether (2 x 400 ml). The organic phase was washed with water (3 x 200 ml), dried (sodium sulfate), filtered and concentrated to give the desired intermediate (17.2 g, 98 %).
  • Example 1 (3R,4S)-3-fluoro-N-[(4-fluorophenyl)methyl]-l-methyl-N-(3- ⁇ [4-(2- methylpropoxy)phenyl]methyl ⁇ -l,2,4-oxadiazol-5-yl)piperidin-4-amine; trifluoroacetic acid and (3S,4R)-3-fluoro-N-[(4-fluorophenyl)methyl]-l -methyl-N-(3- ⁇ [4-(2- methylpropoxy)phenyl]methyl ⁇ -l,2,4-oxadiazol-5-yl)piperidin-4-amine; trifluoroacetic acid
  • Lithium alumimumhydride (7.6 g, 200 mmol) is suspended in diethylether (dry, 150 ml) and a solution of 2-[4-(2-methylpropoxy)phenyl]acetonitrile (17.0 g, 97 mmol) in diethyl ether (dry, 100 ml), is added dropwise under nitrogen. The reaction mixture is then refluxed for 18 h. The reaction mixture is quenched by very slow addition of water (8 ml), aqueous sodium hydroxide solution (15%, 8 ml) and water (24 ml). The suspension is filtered and the residue is rinsed with diethylether (100 ml).
  • Example 2 tert-butyl 4- ⁇ [( ' 4-fluorophenyl)methyl J(!3- ⁇ [4-(2- methylpropoxy)phenyl]methyl ⁇ -l,2,4-oxadiazol-5-yl)amino ⁇ piperidine-l-carboxylate (2a); N-[(4-fluorophenyl)methyl]-N-(3- ⁇ [4-(2-methylpropoxy)phenyl]methyl ⁇ -l,2,4-oxadiazol-5- yl)piperidin-4-amine (2b); and N-[(4-fluorophenyl)methyl]-l-methyl-N-(3- ⁇ [4-(2- methylpropoxy)phenyl]methyl ⁇ -l,2,4-oxadiazol-5-yl)piperidin-4-amine (2c)
  • tert-butyl 4- ⁇ [(4-fluorophenyl)methyl](3- ⁇ [4-(2-methylpropoxy)phenyl]methyl ⁇ - l,2,4-oxadiazol-5-yl)amino ⁇ piperidine-l-carboxylate (690 mg, 1.28 mmol) is stirred in dichloromethane (20 ml)/ TFA (4 ml) over night. The solvent is evaporated and the residue freeze dried from acetonitrile / water. The title compound is an off-white powder as a TFA salt), 600 mg (85 %).
  • Example 5 tert-Butyl 4- ⁇ [(4-fluorophenyl)methyl](5- ⁇ [4-(2-methylpropoxy)- phenyl]methyl ⁇ -4H-l,2,4-triazol-3-yl)amino ⁇ piperidine-l-carboxylate (5a); N-[(4- fluorophenyl)methyl]-N-(5- ⁇ [4-(2-methylpropoxy)phenyl]methyl ⁇ -4H-l,2,4-triazol-3- yl)piperidin-4-amine (5b); N-[(4-fluorophenyl)methyl]-l -methyl -N-(5- ⁇ [4-(2- methylpropoxy)phenyl]methyl ⁇ -4H-l,2,4-triazol-3-yl)piperidin-4-amine (5c); and 3-(4- ⁇ [(4- fluorophenyl)methyl](5- ⁇ [4-(2-methylpropoxy)phenyl]methyl ⁇ ⁇ [4-(
  • the aqueous phase was washed with dichloromethane (20 ml) and the combined organic phase was washed with 20% brine (2 x 20 ml), dried over Na 2 S04, concentrated and was purified by column chromatography using silica gel, eluting with ethylacetate:methanol 1 :0.2 to ethylacetate:methanol:triethyl amine 1 :0.2:0.02 to get the product as free base (321 mg, 55.2%).
  • reaction suspension was filtered to remove silica and the silica gel was washed with 3 ml acetonitrile.
  • the combined acetonitrile solution was concentrated and the product was purified by preparative HPLC with 40 to 90% acetonitrile in water (containing 0.1 % TFA) to get 24.1 mg (68%) as a TFA salt.
  • Example 6 (3S,4R)-3-fluoro-N-[(4-fluorophenyl)methyl]-N- ⁇ 3-[(4- methoxyphenyl)methyl]-l,2,4-oxadiazol-5-yl ⁇ piperidin-4-amine; trifluoroacetic acid and (3 R,4S)-3 -fluoro-N- [(4-fluorophenyl)methyl] -N- ⁇ 3 -[(4-methoxyphenyl)methyl] - 1 ,2,4- oxadiazol-5-yl ⁇ piperidin-4-amine; trifluoroacetic acid
  • Example 7 (3S,4R)-3-fluoro-N-[(4-fluorophenyl)methyl]-N- ⁇ 3-[(4- methoxyphenyl)methyl]-l,2,4-oxadiazol-5-yl ⁇ -l-methylpiperidin-4-amine hydrochloride and (3R,4S)-3-fluoro-N-[(4-fluorophenyl)methyl]-N- ⁇ 3-[(4-methoxyphenyl)methyl]-l,2,4- oxadiazol-5-yl ⁇ -l -methylpiperidin-4-amine hydrochloride
  • Example 8 3-(4- ⁇ [(4-fluorophenyl)methyl](5- ⁇ [4-(2- methylpropoxy)phenyl]methyl ⁇ -4H-l,2,4-triazol-3-yl)amino ⁇ piperidin-l-yl)propanoic acid; trifluoroacetic acid (8)
  • the water phase was extracted with dichloromethane (20 ml) and the combined organic phases were washed with brine (2x20 ml), dried over sodium sulfate, filtered, and concentrated.
  • the crude material was purified by column chromatography using silicon dioxide gel, eluting with 9-17 % methanol in dichloromethane to afford the desired intermediate (321 mg, 55 %).
  • Example 9 N-[(4-fluorophenyl)methyl]-N- ⁇ 1 -methyl-3-[4-(2-methylpropoxy)- phenyl]-lH-l,2,4-triazol-5-yl ⁇ piperidin-4-amine; trifluoroacetic acid (9)
  • Example 10 N-[(4-fluorophenyl)methyl]-N- ⁇ 5-[4-(2-methylpropoxy)phenyl]-4H- l,2,4-triazol-3-yl ⁇ piperidin-4-amine; trifluoroacetic acid (10)
  • Example 11 methyl 3-(4- ⁇ [(4-fluorophenyl)methyl]( ⁇ 5-[4-(2-methylpropoxy)- phenyl]-4H-l ,2,4-triazol-3-yl ⁇ )amino ⁇ piperidin-l-yl)propanoate; trifluoroacetic acid (11)
  • Example 12 3-(4- ⁇ [(4-fluorophenyl)methyl]( ⁇ 5-[4-(2-methylpropoxy)phenyl]- 4H-l ,2,4-triazol-3-yl ⁇ )amino ⁇ piperidin-l-yl)propanoic acid; trifluoroacetic acid (12)
  • Example 13 3-(4- ⁇ [(4-fluorophenyl)methyl]( ⁇ 5-[4-(2-methylpropoxy)phenyl]- 4H-l,2,4-triazol-3-yl ⁇ )amino ⁇ piperidin-l-yl)propanamide; trifluoroacetic acid (13)
  • Example 14 N-[(4-fluorophenyl)methyl]-N- ⁇ [(3R)-l-methylpyrrolidin-3- yl]methyl ⁇ -2-[4-(propan-2-yloxy)phenyl]acetamide; trifluoroacetic acid (14)
  • dichloromethane 500 ⁇ was added to a solution of tert-butyl (3S)-3-( ⁇ [(4- fluorophenyl)methyl] amino ⁇ methyl)pyrrolidine-l-carboxylate (50 mg, 162 ⁇ ) and diisopropylethylamine (45.8 ⁇ , 324 ⁇ ) in dichloromethane (500 ⁇ ). After 1 hour of stirring at ambient temperature the mixture was concentrated. The crude material was purified by column chromatography using silica gel, eluting with 25-50% ethyl acetate in petroleum ether to afford the title compound (77.2 mg, 98%).
  • Example 15 N-[(4-fluorophenyl)methyl]-N- ⁇ [(3S)-l-methylpyrrolidin-3- yl]methyl ⁇ -2-[4-(propan-2-yloxy)phenyl]acetamide; trifluoroacetic acid (15)
  • Example 16 3 -[(4-fluorophenyl)methyl] - 1 - ⁇ [4-(2-methylpropoxy)phenyl]- methyl ⁇ -3- ⁇ [(3R)-l-methylpyrrolidin-3-yl]methyl ⁇ urea (16)
  • Formaldehyde (37% aqueous, 17.3 ⁇ , 232 ⁇ ) and sodium triacetoxyborohydride (65.6 mg, 310 ⁇ ) were added. After 30 minutes of stirring at ambient temperature more formaldehyde (37% aqueous, 17.3 ⁇ , 232 ⁇ ) was added. After additionally 1 hour more sodium triacetoxyborohydride (65.6 mg, 310 ⁇ ) was added. The resulting mixture was stirred for 30 minutes before it was cooled to -20 °C and stored overnight. The mixture was heated to ambient temperature, diluted with sodium hydroxide (1 M, 5 ml) and extracted with dichloromethane (2 x 5 ml). The organic phase was dried using a phase separator and concentrated.
  • Example 17 3-[(4-fluorophenyl)methyl]-l - ⁇ [4-(2- methylpropoxy)phenyl]methyl ⁇ -3 - ⁇ [(3 S)- 1 -methylpyrrolidin-3 -yl] methyl ⁇ urea;
  • Example 18 N-[(4-fluorophenyl)methyl]-N-[(l-methylazetidin-3-yl)methyl]-2-[4- (2-methylpropoxy)phenyl]acetamide; trifluoroacetic acid (18)
  • Example 19 (scheme 6): N-[(4-fluorophenyl)methyl]-N- ⁇ [(5R)-3-methyl-l ,3- oxazinan-5-yl]methyl ⁇ -2-[4-(2-methylpropoxy)phenyl]acetamide; trifluoroacetic acid (19a); and N-[(4-fluorophenyl)methyl]-N- ⁇ [(5S)-3-methyl-l,3-oxazinan-5-yl]methyl ⁇ -2-[4-(2- methylpropoxy)phenyl]acetamide; trifluoroacetic acid (19b)
  • N-[2-(aminomethyl)-3-hydroxypropyl]-N-[(4-fluorophenyl)methyl]-2-[4-(2- methylpropoxy)phenacetamide (7mg, 17 ⁇ ⁇ ) was dissolved in tetrahydrofuran (1 ml).
  • Formaldehyde (37% aqueous, 1.78 ⁇ , 23.9 ⁇ ) and sodium triacetoxyborohydride (6.75 mg, 31.8 ⁇ ) were added. After 15 minutes of stirring at ambient temperature more formaldehyde (37% aqueous, 1.78 ⁇ , 23.9 ⁇ ) was added. After 2 hours more sodium triacetoxyborohydride (6.75 mg, 31.8 ⁇ ) was added.
  • Example 20 N-[(4-fluorophenyl)methyl]-N- ⁇ [(2R)-1 -methylpyrrolidin-2- yl]methyl ⁇ -2-[4-(propan-2-yloxy)phenyl]-acetamide; trifiuoroacetic acid (20)
  • Example 21 N-[(4-fluorophenyl)methyl]-2-[4-(2-methylpropoxy)phenyl]-N- ⁇ [(2R)-l-methylpyrrolidin-2-yl]methyl ⁇ -acetamide; trifluoroacetic acid (21)
  • Example 23 N-[(4-fluorophenyl)methyl]-2-(4-methoxyphenyl)-N- ⁇ [(2S)-l- methylpyrrolidin-2-yl]methyl ⁇ acetamide; trifluoroacetic acid (23)
  • Example 24 3-[(4-fluorophenyl)methyl]-l- ⁇ [4-(2-methylpropoxy)phenyl]- methyl ⁇ -3- ⁇ [(2S)-pyrrolidin-2-yl]methyl ⁇ urea; trifluoroacetic acid (24a) and 3-[(4- fluorophenyl)methyl] - 1 - ⁇ [4-(2-methylpropoxy)phenyl]methyl ⁇ -3 - ⁇ [(2S)- 1 -methylpyrrolidin- 2-yl]methyl ⁇ urea; trifluoroacetic acid (24b)
  • Example 25 3-[(4-fluorophenyl)methyl]-l-[(4-methoxyphenyl)methyl]-3- ⁇ [(2S)- l-methylpyrrolidin-2-yl]methyl ⁇ -urea; trifluoroacetic acid (25)
  • Example 26 3-[(4-fluorophenyl)methyl]-l- ⁇ [4-(2-methylpropoxy)phenyl]- methyl ⁇ -3- ⁇ [(2R)-l-methylpyrrolidin-2-yl]methyl ⁇ urea; trifluoroacetic acid (26)
  • Example 27 3-[(4-fluorophenyl)methyl]-3- ⁇ [(2R)-l-methylpyrrolidin-2- yl]methyl ⁇ -l- ⁇ [4-(propan-2-yloxy)phenyl]-methyl ⁇ urea; trifluoroacetic acid (27)
  • Example 28 N-[(4-fluorophenyl)methyl]-N-[(lR,3r,5S)-8-methyl-8-azabicyclo- [3.2.1]octan-3-yl]-2-[4-(2-methylpropoxy)phenyl]acetamide; trifluoroacetic acid (28)
  • dichloromethane (1 ml) was added to (lR,3r,5S)-N-[(4-fluorophenyl)methyl]-8-methyl-8- azabicyclo[3.2.1]octan-3-amine (25 mg, 101 ⁇ ) and triethylamine (28.1 ⁇ , 201 ⁇ ). After 1 hour of stirring at ambient temperature water (1 ml) was added. The organic phase was separated. The aqueous phase was extracted with dichloromethane (1 ml). The combined organic phase was dried using a phase separator and concentrated.
  • Example 29 N-[(4-fluorophenyl)methyl]-N-[(lR,3s,5S)-8-methyl-8-azabicyclo- [3.2.1]octan-3-yl]-2-[4-(2-methylpropoxy)phenyl]acetamide; trifluoroacetic acid (29)
  • Example 30 N-[(4-fluorophenyl)methyl]-2-(4-methoxyphenyl)-N-[(lR,3r,5S)-8- methyl-8-azabicyclo[3.2.1]octan-3-yl]acetamide; trifluoroacetic acid (30)
  • Example 31 N-[(4-fluorophenyl)methyl]-2-(4-methoxyphenyl)-N-[(lR,3s,5S)-8- methyl-8-azabicyclo[3.2.1]octan-3-yl]acetamide; trifluoroacetic acid (31)
  • Example 32 2-(4-methoxyphenyl)-N-[(lR,3r,5S)-8-methyl-8- azabicyclo[3.2.1]octan-3-yl]-N-[(4-methylphenyl)methyl]acetamide; trifluoroacetic acid (32)
  • Example 33 2-(4-methoxyphenyl)-N-[(lR,3s,5S)-8-methyl-8-azabicyclo- [3.2.1]octan-3-yl]-N-[(4-methylphenyl)methyl]acetamide; trifluoroacetic acid (33)
  • Example 34 N-[(lR,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]-N-[(4- methylphenyl)methyl]-2-[4-(2-methylpropoxy)phenyl]acetamide; trifluoroacetic acid (34)
  • Example 35 N-[(lR,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]-N-[(4- methylphenyl)methyl]-2-[4-(2-methylpropoxy)phenyl]acetamide; trifluoroacetic acid (35)
  • Example 36 l-[(4-fluorophenyl)methyl]-l-[(lR,4S,6S)-2-methyl-2-azabicyclo- [2.2.1]heptan-6-yl]-3- ⁇ [4-(2-methylpropoxy)phenyl]methyl ⁇ urea; trifluoroacetic acid (36a) and l-[(4-fluorophenyl)methyl]-l-[(l S,4R,6R)-2-methyl-2-azabicycl-o[2.2.1]heptan-6-yl]-3- ⁇ [4-(2-methylpropoxy)phenyl]methyl ⁇ urea; trifluoroacetic acid (36b)
  • Example 37 N-[(4-fluorophenyl)methyl]-N-[(lR,4S,6S)-2-methyl-2-azabicyclo- [2.2.1]heptan-6-yl]-2-[4-(propan-2-yloxy)phenyl]acetamide; trifluoroacetic acid (37a) and N- [(4-fluorophenyl)methyl]-N-[(lS,4R,6R)-2-methyl-2-azabicyclo[2.2.1]heptan-6-yl]-2-[4- (propan-2-yloxy)phenyl]acetamide; trifluoroacetic acid (37b)
  • Example 38 3- ⁇ l-azabicyclo[2.2.2]octan-4-yl ⁇ -3-[(4-fluorophenyl)methyl]-l- ⁇ [4- (2-methylpropoxy)phenyl]methyl ⁇ urea hydrochloride (38)
  • Example 39 2-(4-methoxyphenyl)-N-[(lR,3S,5S)-8-methyl-8- azabicyclo[3.2.1]octan-3-yl]-N-[(4-methylphenyl)methyl]acetamide; oxalic acid (39a) and 2- (4-methoxyphenyl)-N-[(lR,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]-N-[(4- methylphenyl)methyl]acetamide; oxalic acid (39b)
  • Example 40 N-[(4-fluorophenyl)methyl]-2-[4-(propan-2-yloxy)phenyl]-N- [(lR,5S,6r)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl]acetamide; trifluoroacetic acid (40a) and N-[(4-fluorophenyl)methyl]-2-[4-(propan-2-yloxy)phenyl]-N-[(lR,5S,6s)-3-methyl-3- azabicyclo[3.1.1]heptan-6 yl]acetamide; trifluoroacetic acid (40b) [00451 ] tert-butyl ( 1 R,5 S,6r)-6- ⁇ [(4-fluorophenyl)methyl] amino ⁇ -3 - azabicyclo[3.1.1]heptane-3-carboxylate and tert-butyl (lR,5S)-3-methyl
  • Example 41 3-[(4-fluorophenyl)methyl]-l- ⁇ [4-(propan-2-yloxy)phenyl]methyl ⁇ -
  • Example 42 N-[(4-fluorophenyl)methyl]-2-[4-(propan-2-yloxy)phenyl]-N- [(lR,5S,9s)-7-methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl]acetamide; trifluoroacetic acid (42)
  • Example 43 N-[(4-fluorophenyl)methyl]-2-[4-(propan-2-yloxy)phenyl]-N- [(1 R,5S,9r)-7-methyl-3-oxa-7-azabicyclo[3.3.1 ]nonan-9-yl]acetamide; trifluoroacetic acid (43)
  • Example 44 3-[(4-fluorophenyl)methyl]-l- ⁇ [4-(2-methylpropoxy)phenyl]- methyl ⁇ -3-[(lR,5S,9r)-7-methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl]urea; trifluoroacetic acid (44a) and 3-[(4-fluorophenyl)methyl]-l- ⁇ [4-(2-methylpropoxy)phenyl]methyl ⁇ -3- [(lR,5S,9s)-7-methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl]urea; trifluoroacetic acid (44b)
  • the compound was prepared as a 1 :1 mixture of diastereomers in analogy with example 41 using 7-methyl-(lR,5S,9r)-9- ⁇ [(4-fluorophenyl)methyl]amino ⁇ -3-oxa-7- azabicyclo[3.3.1]nonane and 7-methyl-(lR,5S,9s)-9- ⁇ [(4-fluorophenyl)methyl]amino ⁇ -3- oxa-7-azabicyclo[3.3.1]nonane (undefined mixture) and l-(isocyanatomethyl)-4-(2- methylpropoxy)benzene. Yield: 22.3 mg, 61%.
  • Example 45 N-[(4-fluorophenyl)methyl]-N-[(lR,4R,5R)-2-methyl-2-azabicyclo- [2.2.1]heptan-5-yl]-2-[4-(2-methylpropoxy)phenyl]acetamide; trifluoroacetic acid (45a) and N-[(4-fluorophenyl)methyl]-N-[(lS,4S,5S)-2-methyl-2-azabicyclo[2.2.1]heptan-5-yl]-2-[4- (2-methylpropoxy)phenyl]acetamide; trifluoroacetic acid (45b)
  • Example 46 3-[(4-fluorophenyl)methyl]-3-[(lR,4R,5R)-2-methyl-2-azabicyclo[2.2.1]heptan- 5-yl]-l- ⁇ [4-(2-methylpropoxy)phenyl]methyl ⁇ urea; trifluoroacetic acid (46a) and 3-[(4- fluorophenyl)methyl]-3-[(lS,4S,5S)-2-methyl-2-azabicyclo[2.2.1]heptan-5-yl]-l- ⁇ [4-(2- methylpropoxy)phenyl] methyl ⁇ urea; trifluoroacetic acid (46b)
  • Example 47 N- ⁇ [4-(dimethylamino)phenyl]methyl ⁇ -2-[4-(2- methylpropoxy)phenyl]-N-[(lR,5S,6r)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl]acetamide; bis(trifluoroacetic acid) (47)
  • Example 48 3-[(4-fluorophenyl)methyl]-3-[(lR,5S,6s)-3-methyl-3-azabicyclo- [3.1.0]hexan-6-yl]-l- ⁇ [4-(2-methylpropoxy)phenyl]methyl ⁇ urea; trifluoroacetic acid (48) [00483] (lR,5S,6s)-N-[(4-fluorophenyl)methyl]-3-methyl-3-azabicyclo[3.1.0]hexan-6- amine
  • N-Methyl-4-piperidone (9.88 g) in toluene (200 ml) was reacted with diallylamine (42.3 ml) in the presence of titanium tetrachloride (4.5 ml) at 20 °C for 20 hours.
  • the mixture was filtered and the filtrate was distilled (0.2 mbar, 90 °C) to give the enamine (oil, 12.6 g) which was chlorinated at - 50 °C with N-chlorosuccinimide (8.48 g) in dichloromethane (220 ml) for 2 hours.
  • diallylamine 3.07 g.
  • the diallylamine (2.42 g) was dissolved in dichloromethane (16 ml) and added slowly to a mixture of 1,3-dimethylbarbituric acid (6.36 g) and tetrakis(tri- phenylphosphine)palladium(O) (292 mg). After 5 hours stirring at 40 °C the mixture was evaporated and diethyl ether and potassium carbonate (6.0 g) were added. The mixture was stirred 1 hour, a small sample was taken out and diluted with water and showed pH> 10. The mixture was filtered and the solids were washed with diethyl ether.
  • the crude product was purified on a short silicon dioxide column using methanol as eluent to give 17 mg of a crystalline solid.
  • the solid was purified by HPLC, eluting with 40-80% acetonitrile in water (containing 0.1% trifluoroacetic acid) to afford the title compound (8 mg).
  • Example 49 l-[(4-fluorophenyl)methyl]-l-[(lR,5S,8r)-3-methyl-3- azabicyclo[3.2.1 ]octan-8-yl]-3- ⁇ [4-(2-methylpropoxy)phenyl]methyl ⁇ urea; trifluoroacetic acid (49)
  • Example 50 N-[(4-fluorophenyl)methyl]-N-[(lR,5S,8r)-3-methyl-3- azabicyclo[3.2.1 ]octan-8-yl]-2-[4-(2-methylpropoxy)phenyl]acetamide; trifluoroacetic acid (50)
  • Example 51 3-[(4-fluorophenyl)methyl]-l- ⁇ [4-(2-methylpropoxy)phenyl]met- hyl ⁇ -3-[(lR,5S,9s)-3-methyl-3-azabicyclo[3.3.1]nonan-9-yl]urea; trifluoroacetic acid (51)
  • Example 52 N-[(4-fluorophenyl)methyl]-2-[4-(2-methylpropoxy)phenyl]-N- [(lR,5S,9s)-3-methyl-3-azabicyclo[3.3.1]nonan-9-yl]acetamide; trifluoroacetic acid (52)
  • Example 53 3-[(4-fluorophenyl)methyl]-l- ⁇ [4-(2- methylpropoxy)phenyl]methyl ⁇ -3-[(lR,5S,9r)-3-methyl-3-azabicyclo[3.3.1]nonan-9-yl]urea; trifluoroacetic acid (53)
  • Example 54 3- ⁇ l-azatricyclor3.3.1.P, 7 ldecan-4-yl ⁇ -3-[(4-fluorophenyl)methyll- l- ⁇ [4-(propan-2-yloxy)phenyl]methyl ⁇ urea; trifluoroacetic acid (54)
  • Example 55 N-[(lR,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl]-N-[(4-fluorophenyl)- methyl]-2-[4-(2-methylpropoxy)phenyl]acetamide; trifluoroacetic acid (55)
  • Example 56 N-[(4-fluorophenyl)methyl]-2-[4-(2-methylpropoxy)phenyl]-N- [(lR,5S,9s)-3-azabicyclo[3.3.1]nonan-9-yl]acetamide; trifluoroacetic acid (56)
  • Example 57 3-[(lR,5S,8R)-3-azabicyclo[3.2.1]octan-8-yl]-3-[(4-fluorophenyl)- methyl]-l- ⁇ [4-(2-methylpropoxy)phenyl]methyl ⁇ urea; trifluoroacetic acid (57)
  • dichloromethane was added dropwise to tert-butyl (lR,5S,8r)-8- ⁇ [(4-fluorophenyl)methyl]- amino ⁇ -3-azabicyclo[3.2.1]octane-3-carboxylate (1 equivalent) in dichloromethane at room temperature. The mixture was stirred for 2.5 hours, then additional isocyanate (0.6
  • Example 58 3-[(4-fluorophenyl)methyl]-l- ⁇ [4-(2-methylpropoxy)phenyl]- methyl ⁇ -3-[(lR,5S,9s)-3-azabicyclo[3.3.1]nonan-9-yl]urea; trifluoroacetic acid (58)
  • Example 59 3-[(4-fluorophenyl)methyl]-l- ⁇ [4-(2-methylpropoxy)phenyl]- methyl ⁇ -3-[(lR,5S,9r)-3-azabicyclo[3.3.1]nonan-9-yl]urea; trifluoroacetic acid (59)
  • Example 61 3-[(3aR,5s,6aS)-2-methyl-octahydrocyclopenta[c]pyrrol-5-yl]-3-[(4- fluorophenyl)methyl]-l- ⁇ [4-(propan-2-yloxy)phenyl]methyl ⁇ urea; trifluoroacetic acid (61)
  • the intermediate was dissolved in dry dichloromethane (4.5 ml) and trifluoroacetic acid (1.5 ml) was added dropwise. After 60 minutes stirring the reaction mixture was concentrated, dried and dissolved in tetrahydrofuran (3 ml). To that solution formaldehyde (37% solution in water, 25.5 ⁇ ,, 342 ⁇ ) was added. After 15 minutes stirring sodium triacetoxyborohydride (72.6 mg, 342 ⁇ ). After 20 h stirring the reaction was concentrated and diluted with dichloromethane (15 ml) and sodium hydrogen carbonate (15 ml, aqueous, saturated). Phases were separated and the water phase was extracted with dichloromethane (2 x 15 ml).

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La présente invention concerne des composés selon les formules décrites dans la description, qui sont utiles pour le traitement de maladies.
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CN113214231A (zh) * 2020-01-21 2021-08-06 行远医药科技有限公司 5ht2a受体拮抗剂及其医疗应用
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CN113549006A (zh) * 2020-04-26 2021-10-26 江苏恩华药业股份有限公司 一种酰胺衍生物及其应用
WO2022017440A1 (fr) * 2020-07-22 2022-01-27 山东绿叶制药有限公司 Inhibiteur du récepteur 5-ht2a ou agoniste inverse, procédé de préparation associé, et application associée
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CN113214231B (zh) * 2020-01-21 2022-04-08 瀚远医药有限公司 5ht2a受体拮抗剂及其医疗应用
WO2021147818A1 (fr) * 2020-01-21 2021-07-29 瀚远医药有限公司 Antagoniste du récepteur 5-ht2a et son application dans le traitement de maladies du système nerveux central
CN113214231A (zh) * 2020-01-21 2021-08-06 行远医药科技有限公司 5ht2a受体拮抗剂及其医疗应用
CN113214289A (zh) * 2020-01-21 2021-08-06 瀚远医药有限公司 5-ht2a受体拮抗剂及其治疗中枢神经系统疾病的应用
CN113214289B (zh) * 2020-01-21 2022-10-28 瀚远医药有限公司 5-ht2a受体拮抗剂及其治疗中枢神经系统疾病的应用
CN113549006A (zh) * 2020-04-26 2021-10-26 江苏恩华药业股份有限公司 一种酰胺衍生物及其应用
CN113549006B (zh) * 2020-04-26 2023-07-21 江苏恩华药业股份有限公司 一种酰胺衍生物及其应用
WO2022017440A1 (fr) * 2020-07-22 2022-01-27 山东绿叶制药有限公司 Inhibiteur du récepteur 5-ht2a ou agoniste inverse, procédé de préparation associé, et application associée
CN113004207A (zh) * 2021-03-05 2021-06-22 中国医科大学 Plk4小分子抑制剂的化合物及其应用
CN113004207B (zh) * 2021-03-05 2023-10-17 中国医科大学 Plk4小分子抑制剂的化合物及其应用
WO2022192370A1 (fr) * 2021-03-10 2022-09-15 Jnana Therapeutics Inc. Inhibiteurs à petites molécules de la fonction de slc6a19 de mammifère
WO2024027800A1 (fr) * 2022-08-03 2024-02-08 嘉奥制药（石家庄）有限公司 Agoniste inverse du récepteur 5-ht2a, son procédé de préparation et son utilisation
WO2024059205A1 (fr) * 2022-09-14 2024-03-21 Jnana Therapeutics, Inc.. Traitement de la pcu avec des inhibiteurs pipéridines spiro-substitués et d'autres inhibiteurs pipéridines de la fonction slc6a19

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