WO2013137479A1 - Decahydroquinoxaline derivatives and analogs thereof - Google Patents

Decahydroquinoxaline derivatives and analogs thereof Download PDF

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Publication number
WO2013137479A1
WO2013137479A1 PCT/JP2013/057923 JP2013057923W WO2013137479A1 WO 2013137479 A1 WO2013137479 A1 WO 2013137479A1 JP 2013057923 W JP2013057923 W JP 2013057923W WO 2013137479 A1 WO2013137479 A1 WO 2013137479A1
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group
lower alkyl
disorder
alkyl group
nmr
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PCT/JP2013/057923
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French (fr)
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Tomoichi Shinohara
Hirofumi Sasaki
Kuninori Tai
Nobuaki Ito
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Otsuka Pharmaceutical Co., Ltd.
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Priority to JP2014543711A priority Critical patent/JP6415982B2/en
Publication of WO2013137479A1 publication Critical patent/WO2013137479A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/499—Spiro-condensed pyrazines or piperazines
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
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    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel heterocyclic compound.
  • drugs previously used in the treatment of depression selectively inhibit the reuptake of norepinephrine or serotonin.
  • examples of such drugs include imipramine (first- generation antidepressant), maprotiline (second-generation antidepressant), selective serotonin reuptake inhibitors (SSRIs, third-generation antidepressants) typified by fluoxetine, and serotonin and/or norepinephrine reuptake inhibitors (SNRIs, fourth-generation antidepressants) typified by venlafaxine (S. Miura, Japanese Journal of Clinical Psychopharmacology, 2000, 3: 311-318).
  • An object of the present invention is to provide a drug that has a wide therapeutic spectrum and can exert sufficient therapeutic effects in a short period, compared with
  • the present inventors have conducted diligent studies to attain the object and have consequently found that a heterocyclic compound represented by the general formula (1) shown below can be used in the production of the desired drug.
  • the present invention has been completed based on these findings.
  • the present invention provides a heterocyclic compound or a salt thereof or a medicament comprising the same according to any one of Items 1 to 21 shown below, a pharmaceutical composition comprising the compound or an use of the compounds, a method for treating or preventing diseases or a methods for producing the compounds.
  • Item 1 A medicament comprising a heterocyclic compound represented by the general formula (1) or a salt thereof:
  • n represents an integer of 1 or 2;
  • X represents -O- or -CH 2 -;
  • R 1 represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a protecting group, or a tri-lower alkylsilyloxy-lower alkyl group;
  • R 2 and R 3 which are the same or different, each independently represent hydrogen or a lower alkyl group; or R 2 and R 3 are bonded to form a cyclo-C3-C8 alkyl group; and
  • R 4 represents an aromatic group or a heterocyclic group, wherein
  • aromatic or heterocyclic group may have one or more arbitrary substituent(s).
  • Item 2 The medicament according to item 1, comprising comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, wherein
  • R 4 represents any of
  • aromatic or heterocyclic groups may have one or more substituent(s) selected from 1-1) a halogen atom,
  • pyrazolyl group which may have a lower alkyl group(s)
  • thiazolyl group which may have a lower alkyl group(s),
  • pyrimidyl group which may have a lower alkyl group(s),
  • Item 3 The medicament according to item 2, comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, wherein
  • R 4 represents any of
  • aromatic or heterocyclic groups may have 1 to 4 substituent(s) selected from
  • Item 4 The medicament according to item 3, comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, wherein
  • R 1 represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a benzyl group, or a tri-lower alkylsilyloxy-lower alkyl group;
  • R 4 represents any of
  • aromatic or heterocyclic groups may have 1 to 4 substituent(s) selected from
  • thiazolyl group which may have 1 lower alkyl group
  • pyrimidyl group which may have 1 lower alkyl group
  • R 1 represents hydrogen
  • R 2 and R 3 which are the same or different, each independently represent a lower alkyl group; or R 2 and R 3 are bonded to form a cyclo-C3-C8 alkyl group; and
  • R 4 represents any of
  • aromatic or heterocyclic groups may have 1 to 2 substituent(s) selected from
  • Item 6 The medicament according to item 5, comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, which is selected from
  • Item 7 A pharmaceutical composition comprising a heterocyclic compound represented by the general formula (1) or a salt thereof according to item 1 as an active ingredient and a pharmaceutically acceptable carrier.
  • neurotransmission of serotonin, norepinephrine or dopamine comprising as an active ingredient a heterocyclic compound of general formula (1) or a salt thereof according to item 1.
  • Item 9 a prophylactic and/or therapeutic agent according to item 8, wherein the disorder is selected from the group consisting of depression, depression status caused by adjustment0 disorder, anxiety caused by adjustment disorder, anxiety caused by various diseases, generalized anxiety disorder, phobia, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, acute stress disorder, hypochondria, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorder, obesity, chemical dependence, pain, fibromyalgia, Alzheimer's disease, memory deficit, Parkinson's disease, restless leg syndrome, endocrine disorder, vasospasm, cerebellar ataxia, gastrointestinal disorder, negative syndrome of schizophrenia, premenstrual syndrome, stress urinary incontinence, Tourette's disorder, attention deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, impulse control disorder, trichotillomania, kleptomania, gambling disorder, cluster headache, migraine, chronic
  • paroxysmal hemicrania chronic fatigue syndrome, precocious ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome and headache.
  • Item 10 a prophylactic and/or therapeutic agent according to item 9, wherein the depression is selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymic disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; hypomelancholia; recurrent brief depressive disorder; refractory depression; chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; depression caused by various physical diseases such as Cushing('s) syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea- galactorrhea syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, brain infarct ⁇ brain hemorrhage subarachnoid hemorrhage, diabetes millitus, virus infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc.; presenile depression; senile depression; depression in children and adolescents; depression induced by drugs
  • a prophylactic and/or therapeutic agent according to item 9, wherein the anxiety caused by various diseases is selected from the group consisting of anxiety caused by head injury, brain infection, inner ear impairment, cardiac failure, cardiac dysrhythmia,
  • hyperadrenalism hyperthyroidism
  • asthma chronic obstructive pulmonary disease
  • a heterocyclic compound or a salt thereof selected from the group consisting of the following compounds:
  • Item 15 A medicament comprising the heterocyclic compound or a salt thereof according to Item 13 or 14.
  • Item 16 A pharmaceutical composition comprising a heterocyclic compound or a salt thereof according to Item 13 or 14 as an active ingredient and a pharmaceutically acceptable carrier.
  • Item 17 A prophylactic and/or therapeutic agent for disorders caused by reduced neurotransmission of serotonin, norepinephrine or dopamine, comprising as an active ingredient a heterocyclic compound of general formula (1) or a salt thereof according to Item 13 or 14.
  • Item 18 A prophylactic and/or therapeutic agent according to Item 17, wherein the disorder is selected from the group consisting of depression, depression status caused by adjustment disorder, anxiety caused by adjustment disorder, anxiety caused by various diseases, generalized anxiety disorder, phobia, obsessive-compulsive disorder, panic disorder,
  • posttraumatic stress disorder acute stress disorder, hypochondria, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorder, obesity, chemical dependence, pain, fibromyalgia, Alzheimer's disease, memory deficit, Parkinson's disease, restless leg syndrome, endocrine disorder, vasospasm, cerebellar ataxia, gastrointestinal disorder, negative syndrome of schizophrenia, premenstrual syndrome, stress urinary incontinence, Tourette's disorder, attention deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, impulse control disorder, trichotillomania, kleptomania, gambling disorder, cluster headache, migraine, chronic paroxysmal hemicrania, chronic fatigue syndrome, precocious ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome and headache.
  • ADHD attention deficit hyperactivity disorder
  • Item 20 A prophylactic and/or therapeutic agent according to Item 18, wherein the anxiety caused by various diseases is selected from the group consisting of anxiety caused by head injury, brain infection, inner ear impairment, cardiac failure, arrhythmia, hyperadrenalism, hyperthyroidism, asthma and chronic obstructive pulmonary disease.
  • Item 21 A prophylactic and/or therapeutic agent according to Item 18, wherein the pain is selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic cervical syndrome, spinal cord injury pain, trigeminal neuralgia, diabetic neuropathy.
  • lower means a group having 1 to 6 (preferably 1 to 4, more preferably 1 to 3) carbon atoms, unless otherwise specified.
  • a heterocyclic ring group includes saturated or unsaturated monocyclic or polycyclic heterocyclic rings comprising at least one hetero atoms selected from an oxygen atom(s), a sulfur atom(s) and nitrogen atom(s). More preferably, it includes the following heterocyclic ring:
  • 3 to 8 unsaturated-membered, preferably 5 or 6-membered heteromonocyclic ring containing 1 to 4 nitrogen atoms for example, pyrrolyl , pyrroliny, imidazolyl, pyrazolyl, pyridyl groups and N-oxide thereof, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1, 2, 4- triazolyl, lH-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl gourps etc.), tetrazolyl group (e.g., 1H- tetrazolyl, 2H-tetrazolyl groups, etc.), dihydrotriazinyl (e.g., 4, 5-dihydro-l, 2, 4-triazinyl, 2, 5- dihydro-1, 2, 4-triazinyl groups) groups, etc. can be mentioned.
  • imidazolyl e.
  • 3 to 8-membered, preferably 5 or 6-membered unsaturated heteromonocyclic ring containing 1 to 4 nitrogen atoms for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, pyperazinyl groups, etc. can be mentioned.
  • pyrrolidinyl group can be mentioned.
  • indolyl dihydroindolyl, (e.g., 2, 3-dihydro-lH- dihydroindolyl group, etc.), iso indolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl (e.g., 3, 4-dihydro-lH-isoquinolyl group, etc.), tetrahydroquinolyl, tetrahydroisoquinolyl (e.g., 1, 2, 3, 4-tetrahydro-lH-isoquinolyl, 5, 6, 7, 8-tetrahydroisoquinolyl groups, etc.), carbostyril, dihydrocarbostyril (e.g., 3, 4-dihydrocarbostyril group, etc.), indazolyl, be
  • quinolyl isoquinolyl, quinoxalinyl, indolyl, indazolyl, pyrrolopyridyl, tetrahydroquinolyl, carbazolyl, indolinyl, quinazolyl, phthalazinyl, tetrahydrobenzodiazepinyl, or tetrahydrobenzoazepinyl groups, etc.
  • quinolyl isoquinolyl, quinoxalinyl, indolyl, indazolyl, pyrrolopyridyl, tetrahydroquinolyl, carbazolyl, indolinyl, quinazolyl, phthalazinyl, tetrahydrobenzodiazepinyl, or tetrahydrobenzoazepinyl groups, etc.
  • quinolyl isoquinolyl, quinoxalinyl, indolyl, indazolyl, pyrrolopyridyl, te
  • 3 to 8 membered, preferably 5 or 6 membered unsaturated heteromono ring containing 1 to 2 oxygen atoms, for example, furyl group, etc. can be mentioned.
  • dihydrobenzodioxepinyl groups etc.
  • benzofuryl, benzodioxynyl, benzodioxolyl, dihydrobenzofuryl, dihydrobenzodioxepinyl, dihydrobenzodioxsepinylyl, chromenyl, or chromanyl groups can be mentioned.
  • 3 to 8-membered, preferably 5 or 6-membered unsaturated heteromonocyclic ring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazoyl, 1, 2, 5-oxadiazoyl groups, etc.) groups, etc.
  • oxazolyl, oxadiazolyl groups can be mentioned.
  • 3 to 8-membered, preferably 5 or 6-membered saturated heteromonocyclic ring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, morpholinyl group, etc. can be mentioned.
  • benzoxazdiazolyl, benzisoxazolyl, furopyridyl (e.g., furo[2, 3-b] pyridyl, furo[3, 2-c]pyridyl groups, etc.), dihydrobenzoxadinyl groups, etc. can be mentioned.
  • furopyridyl e.g., furo[2, 3-b] pyridyl, furo[3, 2-c]pyridyl groups, etc.
  • dihydrobenzoxadinyl groups e.g., benzoxazolyl, dihydrobenzoxadinyl groups.
  • 3 to 8-membered, preferably 5 or 6-membered unsaturated heteromonocyclic ring containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms for example, thiazolyl, 1, 2-thiazolyl, thiazolynyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1, 2, 3- thiadiazolyl groups, etc.) groups, etc.
  • thiazolyl group can be mentioned.
  • 3 to 8-membered, preferably, 5 or 6-membered saturated heteromonocyclic ring containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolydinyl group, etc, can be mentioned.
  • 3 to 8-membered, preferably, 5 or 6-membered unsaturated heteromonocyclic ring containing 1 sulfur atom, for example, thienyl group, etc. can be mentioned.
  • dihydroimidazothiazolyl e.g., 2, 3-dihydroimidazo[2, 1-b] thiazolyl group, etc.
  • thienopyradinyl e.g., thieno[2, 3-b] pyradinyl group, etc.
  • groups, etc. can be mentioned.
  • thienopyridyl or benzothiazolyl groups can be mentioned.
  • the above heterocyclic ring can be substituted by one or more optional substituents.
  • aromatic ring it includes, for example, C 6- i4 aryl groups can be mentioned.
  • the preferable examples of the aryl groups are a phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenyl, indenyl groups. Among them, phenyl, naphtyl, anthryl, phenanthryl groups are preferable.
  • the aryl groups can be partially saturated. As the partially unsaturated aryl groups are, for example, dihydroindenyl, fluorenyl, dihydroacenaphthylenyl,
  • heterocyclic rings can be substituted by one or more optional substituents.
  • saturated hydrocarbon group it includes, for example, lower alkyl, cyclo C3- C8 alkyl groups, etc.
  • an unsaturated hydrocarbon group it includes, for example, lower alkenyl, lower alkynyl, phenyl groups, etc.
  • X 0, S, Se, Te, NH, NR.
  • the characteristic group it includes, for example, carboxy, carbamoyl, cyano, hydroxy, amino groups, etc.
  • the optional substituents are the above heterocyclic rings, aromatic ring groups, saturated hydrocarbon groups, unsaturated hydrocarbon groups, characteristic groups, etc.
  • Examples of the lower alkyl group can include linear or branched alkyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms), unless otherwise specified. More specifically, it includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, l-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2,2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, and 3-methylpentyl groups, etc.
  • Examples of a lower alkoxy group can include linear or branched alkoxy groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms), unless otherwise specified. More specifically, it includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert- butoxy, sec-butoxy, n-pentyloxy, 1-ethylpropoxy, isopentyloxy, neopentyloxy, n-hexyloxy, 1,2,2- trimethylpropoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, isohexyloxy, and 3-methylpentyloxy groups, etc.
  • halogen atom examples include fluorine, chlorine, bromine, and iodine atoms, unless otherwise specified.
  • halogen-substituted lower alkyl group can include the lower alkyl groups exemplified above which are substituted by 1 to 7 (more preferably 1 to 3) halogen atoms, unless otherwise specified. More specifically, it includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2- chloroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl,
  • heptafluoroisopropyl 3-chloropropyl, 2-chloropropyl, 3-bromopropyl, 4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl, 5,5,5-trifluoropentyl, 5- chloropentyl, 6,6,6-trifluorohexyl, 6-chlorohexyl, and perfluorohexyl groups, etc.
  • halogen-substituted lower alkoxy group can include the lower alkoxy groups exemplified above which are substituted by 1 to 7 (preferably 1 to 3) halogen atoms, unless otherwise specified. More specifically, it includes fluoromethoxy,
  • difluoromethoxy trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, pentafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, 3-chloropropoxy, 2-chloropropoxy, 3- bromopropoxy, 4,4,4-trifluorobutoxy, 4,4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy, 4- bromobutoxy, 2-chlorobutoxy, 5,5,5-trifluoropentyloxy, 5-chloropentyloxy, 6,6,6- trifluorohexyloxy, 6-chlorohexyloxy, and perfluorohe
  • Examples of a cyclo-C3-C8 alkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, etc., unless otherwise specified.
  • Examples of a lower alkanoyl group can include linear or branched alkanoyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms), unless otherwise specified. More specifically, it includes formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert- butylcarbonyl, and hexanoyl groups, etc.
  • Examples of a lower alkylthio group can include thio groups which are substituted by linear or branched alkyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms), unless otherwise specified. More specifically, it includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio, n-pentylthio, 1-ethylpropylthio, isopentylthio, neopentylthio, n-hexylthio, 1,2,2-trimethylpropylthio, 3,3- dimethylbutylthio, 2-ethylbutylthio, isohexylthio, and 3-methylpentylthio groups, etc.
  • Examples of a lower alkenyl group can include linear or branched alkenyl groups having 1 to 3 double bonds and 2 to 6 carbon atoms (preferably 2 to 4 carbon atoms), unless otherwise specified, and the lower alkenyl group encompasses both trans and cis forms.
  • it includes vinyl, 1-propenyl, 2-propenyl, 1 -methyl- 1-propenyl, 2-methyl-l- propenyl, 2-methyl-2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3- pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-yl, 2-hexenyl, 1-hexenyl, 5- hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-l-propenyl, 2-ethyl-l-propenyl, 1,3,5-hexatrienyl, 1,3-hexadienyl, and 1,4-hexadienyl groups, etc.
  • Examples of a hydroxy-lower alkyl group can include the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) which have 1 to 5, preferably 1 to 3 hydroxy groups, unless otherwise specified.
  • it includes hydroxymethyl, 2-hydroxyethyl, 2- hydroxypropyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3,4- dihydroxybutyl, l,l-dimethyl-2-hydroxyethyl, 5 -hydroxy pentyl, 6-hydroxyhexyl, 3,3-dimethyl- 3-hydroxypropyl, 2-methyl-3-hydroxypropyl, 2,3,4-trihydroxybutyl, and perhydroxyhexyl groups, etc.
  • Examples of a lower alkylamino group can include amino groups having 1 to 2 of the lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 (more preferably 1 to 4, even more preferably 1 to 3) carbon atoms) exemplified above, unless otherwise specified. More specifically, it includes methylamino, dimethylamino, diethylamino, and diisopropylamino groups, etc.
  • Examples of a lower alkylsulfamoyl group can include sulfamoyl groups having 1 to 2 of the lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 (more preferably 1 to 4, even more preferably 1 to 3) carbon atoms) exemplified above, unless otherwise specified. More specifically, it includes methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, and ethylmethylsulfamoyl groups, etc.
  • Atri-lower alkylsilyl group can be exemplified by silyl groups which are substituted by 3 linear or branched alkyl groups having 1 to 6 carbon atoms, such as
  • Examples of a tri(lower alkyl)silyloxy-lower alkyl group can include tri(lower alkyl)silyloxy-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)), unless otherwise specified.
  • it includes trimethylsilyloxymethyl, 1- (or 2-)trimethylsilyloxyethyl, 1- (or 2- or 3-)trimethylsilyloxypropyl, triethylsilyloxymethyl, 1- (or 2-)triethylsilyloxyethyl, 1- (or 2- or 3-)triethylsilyloxypropyl, triisopropylsilyloxymethyl, 1- (or 2-)triisopropylsilyloxyethyl, and 1- (or 2- or 3- )triisopropylsilyloxypropyl groups, etc.
  • Examples of a phenoxy-lower alkyl group can include the lower alkyl groups
  • Examples of a phenyl-lower alkoxy group can include the lower alkoxy groups (preferably linear or branched alkoxy groups having 1 to 6 (more preferably 1 to 4, even more preferably 1 to 3) carbon atoms) exemplified above which have 1 to 3, preferably 1 phenyl group, unless otherwise specified. More specifically, it includes benzyloxy, 2-phenylethoxy, 1- phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1, 1- dimethyl-2-phenylethoxy, and 2-methyl-3-phenylpropoxy groups, etc.
  • lower alkoxy groups preferably linear or branched alkoxy groups having 1 to 6 (more preferably 1 to 4, even more preferably 1 to 3) carbon atoms
  • it includes benzyloxy, 2-phenylethoxy, 1- phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylp
  • Examples of a phenyl-lower alkenyl group can include the lower alkenyl groups
  • Examples of a lower alkylamino-lower alkyl group can include lower alkyl groups which have 1 to 2 of the lower alkylamino groups exemplified above, unless otherwise specified. More specifically, it includes methylaminomethyl, ethylaminomethyl,
  • Examples of a lower alkylamino-lower alkoxy group can include lower alkoxy groups which have 1 to 2 of the lower alkylamino groups exemplified above, unless otherwise specified. More specifically, it includes methylaminomethoxy, ethylaminomethoxy,
  • dimethylaminomethoxy 1- (or 2-)dimethylaminoethoxy, 1- (or 2- or 3-)dimethylaminopropoxy, diisopropylaminomethoxy, 1- (or 2-)diethylaminoethoxy, and bis(dimethylamino)methoxy groups, etc.
  • Examples of a dihydrobenzodioxinyl group include 2,3- dihydrobenzo[b][l,4]dioxinyl, 3,4-dihydrobenzo[c][l,2]dioxinyl, and 2,4-dihydrobenzo[d][l,3] dioxinyl groups, etc.
  • Examples of an imidazolyl-lower alkyl group can include the lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 (more preferably 1 to 4) carbon atoms) exemplified above which have 1 to 3, preferably 1 imidazolyl group. More specifically, it includes 1- (or 2- or 4- or 5-)imidazolylmethyl, 1- (or 2-) ⁇ 1- (or 2- or 4- or 5-)imidazolyl ⁇ ethyl, and 1- (or 2- or 3-) ⁇ l- (or 2- or 4- or 5-)imidazolyl ⁇ propyl groups, etc.
  • a dihydroindenyl group includes (1-, 2-, 4-, or 5-)-l,2-dihydroindenyl groups, etc.
  • a dihydroquinolyl group includes 1,2-dihydroquinolyl, 3,4-dihydroquinolyl, 1,4- dihydroquinolyl, 4a,8a-dihydroquinolyl, 5,6-dihydroquinolyl, 7,8-dihydroquinolyl, and 5,8- dihydroquinolyl groups, etc.
  • a fluorenyl group includes lH-fluorenyl, 2H-fluorenyl, 3H-fluorenyl, 4aH- fluorenyl, 5H-fluorenyl, 6H-fluorenyl, 7H-fluorenyl, 8H-fluorenyl, 8aH-fluorenyl, and 9H- fluorenyl groups, etc.
  • a dihydrobenzofuryl group includes 2,3-dihydro-(2-, 3-, 4-, 5-, 6-, or 7-)benzofuryl groups, etc.
  • a dihydrobenzoxazinyl group includes (2-, 3-, 4-, 5-, 6-, 7-, or 8-)3,4-dihydro-2H- benzo[b][1.4]oxazinyl and (1-, 2-, 4-, 5-, 6-, 7-, or 8-)2,4-dihydro-lH-benzo[d][1.3]oxazinyl groups, etc.
  • Atetrahydrobenzodiazepinyl group includes (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-) 2,3,4,5-tetrahydro-lH-benzo[b][l ,4]diazepinyl and (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-)2,3,4,5- tetrahydro-lH-benzo[e][1.4]diazepinyl groups, etc.
  • Examples of a tetrahydrobenzodiazepinyl group can include (1-, 2-, 3-, 4-, 5-, 6-,
  • a dihydrobenzodioxepinyl group includes 3,4-dihydro-2H-l,5-benzodioxepinyl, 4,5-dihydro-3H-l,2-benzodioxepinyl, and 3,5-dihydro-2H-l,4-benzodioxepinyl groups, etc.
  • Examples of a pyrrolidinyl group which may have an oxo group(s) include pyrrolidinyl group which may have 1 to 2 (preferably 1) oxo groups, unless otherwise specified. More specifically, it includes (1-, 2-, or 3-)pyrrolidinyl, (2- or 3-)oxo-l-pyrrolidinyl, (3-, 4-, or 5-)oxo-2-pyrrolidinyl, and (2-, 4-, or 5-)oxo-3-pyrrolidinyl groups, etc.
  • Examples of an oxadiazolyl group which may have a lower alkyl group(s) can include oxadiazolyl group which may have 1 to 2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. More specifically, it includes 5-methyl-l,3,4- oxadiazolyl, 5-ethyl-l,3,4-oxadiazolyl, 5-propyl-l,3,4-oxadiazolyl, 5-butyl-l,3,4-oxadiazolyl, 5- pentyl-l,3,4-oxadiazolyl, and 5-hexyl-l,3,4-oxadiazolyl groups, etc.
  • Examples of a pyrazolyl group which may have a lower alkyl group(s) can include pyrazolyl group which may have 1 to 2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. More specifically, it includes 1 -methyl- 1H- pyrazolyl, 1 -ethyl- IH-pyrazolyl, 1 -propyl- IH-pyrazolyl, 1-isopropyl-lH-pyrazolyl, 1-butyl-lH- pyrazolyl, 1-tert-butyl-lH-pyrazolyl, and 1,3-dimethyl-lH-pyrazolyl groups, etc.
  • Examples of a thiazolyl group which may have a lower alkyl group(s) can include thiazolyl group which may have 1 to 2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. More specifically, it includes 2-methylthiazolyl, 2- ethylthiazolyl, 2-propylthiazolyl, 2-isopropylthiazolyl, 2-butylthiazolyl, 2-tert-butylthiazolyl, and 2,5-dimethylthiazolyl groups, etc.
  • Examples of a pyrimidyl group which may have a lower alkyl group(s) can include pyrimidyl group which may have 1 to 2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. More specifically, it includes 2- methylpyrimidyl, 2-ethylpyrimidyl, 2-propylpyrimidyl, 2-isopropylpyrimidyl, 2-butylpyrimidyl, 2-tert-butylpyrimidyl, and 2,4-dimethylpyrimidyl groups, etc.
  • Examples of a pyridazinyl group which may have a lower alkyl group(s) can include pyridazinyl group which may have 1 to 2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. More specifically, it includes 3- methylpyridazinyl, 3-ethylpyridazinyl, 3-propylpyridazinyl, 3-isopropylpyridazinyl, 3- butylpyridazinyl, 3-tert-butylpyridazinyl, and 3,4-dimethylpyridazinyl groups, etc.
  • Examples of a pyridazinyloxy group which may have a lower alkyl group(s) can include oxy group which is substituted by pyridazinyl which may have 1 to 2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. More specifically, it includes 6-methylpyridazinyl-3-yloxy and 4-methylpyridazinyl-3-yloxy groups, etc.
  • Examples of a pyrrolidinyl-lower alkoxy group can include lower alkoxy groups (preferably linear or branched alkoxy groups having 1 to 6 (more preferably 1 to 4, even more preferably 1 to 3) carbon atoms) exemplified above which have 1 to 3, preferably 1 pyrrolidinyl group, unless otherwise specified. Specific examples thereof include (1-, 2-, or 3-)
  • pyrrolidinylmethoxy 2-[(l-, 2-, or 3-)pyrrolidinyl]ethoxy, 1-[(1-, 2-, or 3-)pyrrolidinyl]ethoxy, 3- [(1-, 2-, or 3-)pyrrolidinyl]propoxy, 4-[(l-, 2-, or 3-)pyrrolidinyl]butoxy, 5-[(l-, 2-, or 3-) pyrrolidinyl]pentyloxy, 6-[(l-, 2-, or 3-)pyrrolidinyl]hexyloxy, l,l-dimethyl-2-[(l-, 2-, or 3-) pyrrolidinyl]ethoxy, and 2-methyl-3-[(l-, 2-, or 3-)pyrrolidinyl]propoxy groups, etc.
  • Examples of a protecting group include protecting groups routinely used, such as substituted or unsubstituted lower alkanoyl [e.g., formyl, acetyl, propionyl, and trifluoroacetyl], phthaloyl, lower alkoxycarbonyl [e.g., tertiary butoxycarbonyl and tertiary amyloxycarbonyl], substituted or unsubstituted aralkyloxycarbonyl [e.g., benzyloxycarbonyl and p- nitrobenzyloxycarbonyl], 9-fiuorenylmethoxycarbonyl, substituted or unsubstituted
  • lower alkanoyl e.g., formyl, acetyl, propionyl, and trifluoroacetyl
  • phthaloyl lower alkoxycarbonyl [e.g., tertiary butoxycarbonyl and tertiary amyloxycarbon
  • arenesulfonyl e.g., benzenesulfonyl and tosyl
  • nitrophenylsulfenyl e.g., benzenesulfonyl and tosyl
  • aralkyl e.g., trityl and benzyl
  • lower alkylsilyl groups e.g., triisopropylsilyl
  • Examples of a phenyl-lower alkyl group can include the lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 (more preferably 1 to 4 carbon atoms) exemplified above which have 1 to 3, preferably 1 phenyl group, unless otherwise specified. More specifically, it includes benzyl, phenethyl, 3-phenylpropyl, benzhydryl, trityl, 4- phenylbutyl, 5-phenylpentyl, and 6-phenylhexyl groups, etc.
  • lower alkyl groups preferably linear or branched alkyl groups having 1 to 6 (more preferably 1 to 4 carbon atoms) exemplified above which have 1 to 3, preferably 1 phenyl group, unless otherwise specified. More specifically, it includes benzyl, phenethyl, 3-phenylpropyl, benzhydryl, trityl, 4- phenylbutyl, 5-phenylpent
  • Examples of a morpholinyl-lower alkyl group can include the lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 carbon atoms) exemplified above which have 1 to 2 (preferably 1) morpholinyl groups, unless otherwise specified.
  • Examples of a pyrrolidinyl -lower alkyl group can include the lower alkyl groups exemplified above which have 1 to 3 (preferably 1) pyrrolidinyl groups, unless otherwise specified. More specifically, it includes (1-, 2-, or 3-) pyrrolidinylmethyl, 2-[(l-, 2- or 3-) pyrrolidinyl]ethyl,.l-[(l-, 2- or 3-)] pyrrolidinyl]ethyl, 3-[(l-, 2- or 3-)] pyrrolidinyl]propyl, 4- [(1-, 2- or 3-)] pyrrolidinyl]butyl, 5-[(l-, 2- or 3-)] pyrrolidinyl]pentyl, 6-[(l-, 2- or 3-)] pyrrolidinyl]hexyl, 1, l-dimethyl-2-[(l-, 2- or 3-)] pyrrolidinyl] ethyl, and
  • Examples of a piperidyl-lower alkyl group can include the lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 carbon atoms) exemplified above which have 1 to 2 (preferably 1) piperidyl groups, unless otherwise specified.
  • piperidylmethyl 2-[(l-, 2-, 3- or 4-)piperidyl]ethyl, 1- [(1-, 2-, 3- or 4-)piperidyl]ethyl, 3-[(l-, 2-, 3- or 4-)piperidyl]propyl, 4-[(l-, 2-, 3- or 4- )piperidyl]butyl, l, l-dimethyl-2-[(l-, 2-, 3- or 4-)piperidyl] ethyl, 5-[(l-, 2-, 3- or 4- )piperidyl]pentyl, 6-[(l-, 2-, 3- or 4-)piperidyl]hexyl, 1-[(1-, 2-, 3- or 4-)piperidyl]isopropyl, and 2-methyl-3-[(l-, 2-, 3- or 4-)piperidyl]propyl groups, etc.
  • Examples of a lower alkoxycarbonyl group can include linear or branched alkoxy groups having preferably 1 to 6 carbon atoms and having a lower alkoxycarbonyl moiety as exemplified above. More specifically, it includes methoxycarbonyl, ethoxycarbonyl, n- propxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert- butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxycarbonyl, n- hexyloxycarbonyl, isohexyloxycarbonyl, 3 -methyl pentyloxycarbonyl groups, etc.
  • Examples of a piperazinyl group which may have a lower alkyl group(s) include piperazinyl groups which may have 1 to 2 (preferably 1) lower alkyl groups, unless otherwise specified. More specifically, it includes 2-methylpiperazinyl, 4-methylpiperazinyl, 2- ethylpiperazinyl, 2-propylpiperazinyl, 2-isopropylpiperazinyl, 2-butylpiperazinyl, 2-tert butylpiperazinyl, and 2, 4-dimethylpiperazinyl groups, etc.
  • Examples of a piperazinyl-lower alkyl group which may have a lower alkyl group(s) include piperazinyl groups exemplified above which may have 1 to 2 (preferably 1) lower alkyl groups, unless otherwise specified. More specifically, it includes l-(4- methylpiperazinyl)methyl, l-(2-methyl piperazinyl)methyl, 2-(l -methyl piperazinyl)ethyl, 3-(l- methyl piperazinyl)propyl, 4-(l -methyl piperazinyl)butyl groups, etc.
  • Examples of a phenyl group which may have a lower alkoxy group(s) include phenyl groups exemplified above which may have 1 to 2 (preferably 1) lower alkoxy groups, unless otherwise specified. More specifically, it includes 4-methoxyphenyl, 4-ethoxyphenyl, 4- propoxyphenyl, 4-isopropylphenyl, 4-butoxyphenyl, 4-tert butoxyphenyl groups, etc. can be mentioned.
  • a phenoxy group exemplified above which may have a halogen atom(s) include phenoxy groups which may have 1 to 4 (preferably 1) halogen atoms, unless otherwise specified. More specifically, it includes 4-fluorophenoxy, 3, 4-difluorophenoxy, 3, 4, 5-trifluorophenoxy, and 3-chloro-4,5-difluorophenoxy groups, etc.
  • a tetrahydroquinolyl group includes, for example, 1, 2, 3, 4- tetrahydroquinolyl, 5, 6, 7, 8-tetrahydroquinolyl, 4a, 5, 8, 8a-tetrahydroquinolyl, 3, 4, 4a, 8a-tetrahydroquinolyl, 4a, 5, 8, 8a-tetrahydroquinolyl, and 4a, 5, 6, 7- tetrahydroquinolyl groups, etc.
  • a dihydroacenaphthylenyl group includes, for example, 1, 2- dihydroacenaphthylenyl, 2a 1 , 3 -dihydroacenaphthylenyl, 5, 6- dihydroacenaphthylenyl, 3, 7- dihydroacenaphthylenyl, 2a 1 , 6-dihydroacenaphthylenyl, 1, 2a 1 -dihydroacenaphthylenyl, and 6, 8a-dihydroacenaphthylenyl groups, etc. More preferably , it is 1, 2-dihydroacenaphthylenyl group can be mentioned.
  • Atetrahydronaphthyl group includes, for example, 1, 2, 3, 4-tetrahydronaphthyl, 1, 2, 3, 5-tetrahydronaphthyl, and 5, 6, 7, 8-tetrahydronaphthyl, 2, 3, 7, 8-tetrahydronaphthyl groups, etc. can be mentioned.
  • a dihydroquinazolinyl group includes, for example, 1, 2-dihydroquinazolinyl, 3, 4-dihydroquinazolinyl, 4a, 5-dihydroquinazolinyl, 5, 6-dihydroquinazolinyl, 6, 7- dihydroquinazolinyl, 7,8-dihydroquinazolinyl, 8,8a-dihydroquinazolinyl, and 4a, 8a- dihydroquinazolinyl groups, etc. can be mentioned.
  • the heterocyclic compound represented by the general formula (1) can be produced by various methods.
  • the heterocyclic compound represented by the general formula (1) is produced by methods represented by the reaction formulas shown below. Reaction Formula- 1
  • the leaving group represented by Xi can be exemplified by halogen atoms, lower alkanesulfonyloxy groups, arylsulfonyloxy groups, aralkylsulfonyloxy groups, trihalomethanesulfonyloxy groups, sulfonio groups, and
  • toluenesulfoxy groups Preferable examples of the leaving groups for the present reaction include halogen atoms.
  • halogen atoms represented by Xi can include fluorine, chlorine, bromine, and iodine atoms.
  • the lower alkanesulfonyloxy groups represented by Xi can be exemplified specifically by linear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms, such as methanesulfonyloxy, ethanesulfonyloxy, n-propanesulfonyloxy, isopropanesulfonyloxy, n- butanesulfonyloxy, tert-butanesulfonyloxy, n-pentanesulfonyloxy, and n-hexanesulfonyloxy groups.
  • arylsulfonyloxy groups represented by Xi can include:
  • phenylsulfonyloxy groups which may have 1 to 3 groups selected from the group consisting of linear or branched alkyl groups having 1 to 6 carbon atoms, linear or branched alkoxy groups having 1 to 6 carbon atoms, nitro groups, and halogen atoms as substituents on the phenyl ring; and naphthylsulfonyloxy groups.
  • the phenylsulfonyloxy groups which may have the substituents can be exemplified specifically by phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2- nitrophenylsulfonyloxy, and 3-chlorophenylsulfonyloxy groups.
  • the naphthylsulfonyloxy groups can be exemplified specifically by a-naphthylsulfonyloxy and ⁇ -naphthylsulfonyloxy groups.
  • Examples of the aralkylsulfonyloxy groups represented by Xi can include: linear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms, which are substituted by a phenyl group which may have 1 to 3 groups selected from the group consisting of linear or branched alkyl groups having 1 to 6 carbon atoms, linear or branched alkoxy groups having 1 to 6 carbon atoms, nitro groups, and halogen atoms as substituents on the phenyl ring; and linear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms, which are substituted by a naphthyl group.
  • alkanesulfonyloxy groups which are substituted by the phenyl group can be exemplified specifically by benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4- phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4- nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, and 3-chlorobenzylsulfonyloxy.
  • alkanesulfonyloxy groups which are substituted by the naphthyl group can be exemplified specifically by a-naphthylmethylsulfonyloxy and ⁇ -naphthylmethylsulfonyloxy groups.
  • the perhaloalkanesulfonyloxy groups represented by X t can be exemplified specifically by trifluoromethanesulfonyloxy groups.
  • Examples of the sulfonio groups represented by Xi can specifically include dimethylsulfonio, diethylsulfonio, dipropylsulfonio, di-(2-cyanoethyl)sulfonio, di-(2- nitroethyl)sulfonio, di-(aminoethyl)sulfonio, di-(2-methylaminoethyl)sulfonio, di-(2- dimethylaminoethyl)sulfonio, di-(2-hydroxyethyl)sulfonio, di-(3-hydroxypropyl)sulfonio, di-(2- methoxyethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2- carboxyethyl)sulf
  • a compound represented by the general formula (2) and the compound represented by the general formula (3) can be reacted in the presence of a palladium catalyst in the presence or absence of a basic compound without or in an inert solvent to thereby produce the compound (1).
  • the inert solvent can include, for example: water; ether solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; lower alcohol solvents such as methanol, ethanol, and isopropanol; ketone solvents such as acetone and methyl ethyl ketone; and polar solvents such as N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile.
  • ether solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether
  • aromatic hydrocarbon solvents such as benz
  • the palladium compound used in the present reaction is not particularly limited.
  • tetravalent palladium catalysts such as sodium hexachloropalladium (IV) acid tetrahydrate and potassium hexachloropalladium (IV) acid
  • divalent palladium catalysts such as palladium (II) chloride, palladium (II) bromide, palladium (II) acetate, palladium (II) acetylacetonate, dichIorobis(benzonitrile)palladium (II), dichlorobis(acetonitrile)palladium (II), dichlorobis(triphenylphosphine)palladium (II), dichlorotetraammine palladium (II),
  • the amount of the palladium catalyst used is not particularly limited and usually ranges from 0.000001 to 20 mol in terms of palladium with respect to 1 mol of the compound of the general formula (2). More preferably, the amount of the palladium compound used ranges from 0.0001 to 5 mol in terms of palladium with respect to 1 mol of the compound of the general formula (2).
  • the present reaction proceeds advantageously in the presence of an appropriate ligand.
  • an appropriate ligand for example, 2,2'-bis(diphenylphosphino)-l, -binaphthyl (BINAP), tri-o- tolylphosphine, bis(diphenylphosphino)ferrocene, triphenylphosphine, tri-t-butylphosphine, tricyclohexylphosphine, and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) can be used as the ligand for the palladium catalyst.
  • These ligands are used alone or as a mixture of two or more of them.
  • the tertiary phosphine may be prepared in a complex form in advance and added thereto.
  • the complex can include tri-t- butylphosphonium tetrafluoroborate and tri-t-butylphosphonium tetraphenylborate.
  • the ratio between the palladium catalyst and the ligand used is not particularly limited.
  • the amount of the ligand used is approximately 0.1 to 100 mol, preferably
  • Inorganic and organic bases known in the art can be used widely as the basic compound.
  • Examples of the inorganic bases can include: alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate; alkali metals such as sodium and potassium; phosphates such as sodium phosphate and potassium phosphate; amides such as sodium amide; and alkali metal hydrides such as sodium hydride and potassium hydride.
  • alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate
  • alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate
  • alkali metals such as sodium and potassium
  • phosphates such as sodium
  • organic bases can include: alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, and potassium t-butoxide; and amines such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,
  • alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, and potassium t-butoxide
  • amines such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,
  • basic compounds are used alone or as a mixture of two or more of them. More preferable examples of the basic compound used in the present reaction include alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate, and sodium t-butoxide.
  • the amount of the basic compound used is usually 0.5 to 10 mol, preferably 0.5 to 6 mol, with respect to 1 mol of the compound of the general formula (2).
  • the ratio between the compound of the general formula (2) and the compound of the general formula (3) used in the Reaction Formula- 1 may be at least 1 mol, preferably approximately 1 to 5 mol of the latter compound with respect to 1 mol of the former compound.
  • the reaction can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure.
  • inert gas such as nitrogen or argon
  • the present reaction is usually performed under temperature conditions involving room temperature to 200°C, preferably room temperature to 150°C, and generally completed in approximately 1 to 30 hours. It is also achieved by heating at 100 to 200°C for 5 minutes to 1 hour using a microwave reactor.
  • reaction product After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of interest.
  • the compound represented by the general formula (2) used as a starting material in the Reaction Formula- 1 is produced from compounds known in the art, for example, by methods represented by Reaction Formulas-3 and 4 shown below.
  • the compound represented by the general formula (3) is an easily obtainable compound known in the art or a compound easily produced by a method known in the art.
  • R 2 , R 3 , R 4 , X, 1, m, and n are defined as above; and R la represents a protecting group.
  • Examples of the protecting group include the protecting groups exemplified above.
  • the compound represented by the general formula (lb) can be produced by subjecting a compound represented by the general formula (la) to the elimination reaction of the protecting group.
  • a method routinely used such as hydrolysis or hydrogenolysis can be applied to the elimination reaction of the protecting group.
  • the present reaction is usually performed in a solvent routinely used that does not adversely affect the reaction.
  • the solvent include: water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; ether solvents such as tetrahydrofuran, dioxane, diethyl ether, dimethoxy ethane, and diglyme; ester solvents such as methyl acetate and ethyl acetate; aprotic polar solvents such as acetonitrile, ⁇ , ⁇ -dimethylformamide, dimethyl sulfoxide, and N- methylpyrrolidone; halogenated hydrocarbon solvents such as methylene chloride and ethylene chloride; and other organic solvents.
  • the hydrolysis is preferably performed in the presence of a base or an acid (including Lewis acids).
  • Inorganic and organic bases known in the art can be used widely as the base.
  • the inorganic bases include alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., magnesium and calcium), and hydrides, carbonates, or bicarbonates thereof.
  • the organic bases include trialkylamines (e.g., trimethylamine and triethylamine), picoline, and l,5-diazabicyclo[4.3.0]non-5-ene.
  • Organic and inorganic acids known in the art can be used widely as the acid.
  • the organic acids include: fatty acids such as formic acid, acetic acid, and propionic acid; and trihaloacetic acids such as trichloroacetic acid and trifluoroacetic acid.
  • the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, and hydrogen bromide.
  • the Lewis acids include boron trifluoride-ether complexes, boron tribromide, aluminum chloride, and ferric chloride.
  • the reaction is preferably performed in the presence of a cation scavenger (e.g., anisole and phenol).
  • a cation scavenger e.g., anisole and phenol.
  • the amount of the base or the acid used is not particularly limited as long as it is an amount necessary for hydrolysis.
  • the reaction temperature is usually 0 to 120°C, preferably room temperature to
  • reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 12 hours, more preferably 1 to 8 hours.
  • Hydrogenolysis methods known in the art can be applied widely to the hydrogenolysis. Examples of such hydrogenolysis methods include chemical reduction and catalytic reduction.
  • Preferable reducing agents used in chemical reduction are the combinations of hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium
  • borohydride and sodium cyanoborohydride
  • metals e.g., tin, zinc, and iron
  • metal compounds e.g., chromium chloride and chromium acetate
  • organic or inorganic acids e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, and hydrobromic acid.
  • platinum catalysts e.g., platinum plates, platinum sponge, platinum black, colloidal platinum, platinum oxide, and platinum wires
  • palladium catalysts e.g., palladium sponge, palladium black, palladium oxide, palladium-carbon, palladium/barium sulfate, and palladium/barium carbonate
  • nickel catalysts e.g., reduced nickel, nickel oxide, and Raney nickel
  • cobalt catalysts e.g., reduced cobalt and Raney cobalt
  • iron catalysts e.g., reduced iron
  • the amount of the reducing agent used in chemical reduction or the catalyst used in catalytic reduction is not particularly limited and may be an amount usually used.
  • the reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure.
  • the reaction temperature is usually 0 to 120°C, preferably room temperature to 100°C, more preferably room temperature to 80°C.
  • the reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 10 hours, more preferably 30 minutes to 4 hours.
  • reaction product After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of the general formula (lb) of interest.
  • the deprotection reaction of the protecting group is not limited to the reaction conditions described above.
  • reaction described in T.W. Green, P.G.M. Wuts, "Protective Groups in Organic Synthesis", 4th ed., or John Wiley & Sons; New York, 1991, P. 309 can also be applied to the present reaction step.
  • the compound represented by the general formula (2) is a novel compound, which is useful as an intermediate for the compound represented by the general formula (1), as described above.
  • the compound of the general formula (2) is produced according to, for example,
  • R 1 , R 2 , R 3 , X, I, m, and n are defined as above.
  • the compound represented by the general formula (2a) is produced by subjecting a compound represented by the general formula (4) and a compound represented by the general formula (5) to cyclization reaction to form a compound represented by the general formula (6) (Step A), which is then reduced (Step B).
  • reaction between the compound represented by the general formula (4) and the compound represented by the general formula (5) can be performed in the presence or absence of a base without or in an inert solvent.
  • the inert solvent can include, for example: water; ethers such as dioxane, tetrahydroiuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile.
  • ethers such as dioxane, tetrahydroiuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • lower alcohols such as methanol
  • Basic compounds known in the art can be used widely. Examples thereof can include: alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metals such as sodium and potassium; other inorganic bases such as sodium amide, sodium hydride, and potassium hydride; alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; and other organic bases such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,
  • DBN dimethylaniline
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • DABCO l,4-diazabicyclo[2.2.2]octane
  • the amount of the basic compound used is usually 0.5 to 10 mol, preferably 0.5 to 6 mol, with respect to the compound of the general formula (4).
  • the reaction can be performed by adding, if necessary, alkali metal iodide (e.g., potassium iodide and sodium iodide) as a reaction promoter.
  • alkali metal iodide e.g., potassium iodide and sodium iodide
  • the ratio between the compound of the general formula (4) and the compound of the general formula (5) used in the reaction formula may be usually at least 0.5 mol, preferably approximately 0.5 to 5 mol of the latter compound with respect to 1 mol of the former compound.
  • the reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure.
  • the reaction is usually performed under temperature conditions involving 0°C to
  • 200°C preferably room temperature to 150°C, and generally completed in approximately 1 to 30 hours.
  • the compound of the general formula (4) and the compound of the general formula (5) used as starting materials in the Step A are easily obtainable compounds known in the art or compounds easily produced by a method known in the art.
  • the compound represented by the general formula (2a) can be produced by subjecting the compound represented by the general formula (6) to reduction reaction without or in an inert solvent.
  • Examples of such reduction methods include chemical reduction and catalytic reduction.
  • the inert solvent can include: water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol methyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
  • ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol methyl ether, and ethylene glycol dimethyl ether
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • lower alcohols such as methanol, ethanol, and isopropanol
  • ketones such as acetone and methyl
  • Preferable reducing agents used in chemical reduction are the combinations of hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, boron hydride, sodium borohydride, and sodium cyanoborohydride), metals (e.g., tin, zinc, and iron), or metal compounds (e.g., chromium chloride and chromium acetate) with organic or inorganic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, and hydrobromic acid).
  • hydrides e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, boron hydride, sodium borohydride, and sodium cyanoborohydride
  • metals e.g., tin, zinc, and iron
  • metal compounds e.g., chromium chloride and
  • platinum catalysts e.g., platinum plates, platinum sponge, platinum black, colloidal platinum, platinum oxide, and platinum wires
  • palladium catalysts e.g., palladium sponge, palladium black, palladium oxide, palladium-carbon, palladium/barium sulfate, and palladium/barium carbonate
  • nickel catalysts e.g., reduced nickel, nickel oxide, and Raney nickel
  • cobalt catalysts e.g., reduced cobalt and Raney cobalt
  • iron catalysts e.g., reduced iron
  • the amount of the reducing agent used in chemical reduction or the catalyst used in catalytic reduction is not particularly limited and may be an amount usually used.
  • the reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure.
  • the reaction temperature is usually 0 to 120°C, preferably room temperature to 100°C, more preferably room temperature to 80°C.
  • the reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 10 hours, more preferably 30 minutes to 4 hours.
  • reaction product After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of the general formula (2a) of interest.
  • R 1 , R 2 , R 3 , X, 1, m, and n are defined as above.
  • the compound represented by the general formula (2b) is produced by subjecting the compound represented by the general formula (4) and a compound represented by the general formula (7) to cyclization reaction to form a compound represented by the general formula (8) (Step C), which is then reduced (Step D).
  • the reaction conditions are the same reaction conditions as in the Reaction Formula-3.
  • R 1 , R 2 , R 3 , R 4 , 1, m, n, and X are defined as above; and Y and Z, which are the same or different, each independently represent a leaving group.
  • Examples of the leaving groups represented by Y and Z in the general formula (9) include the leaving groups exemplified above.
  • the compound represented by the general formula (2) can be produced by subjecting the compound represented by the general formula (4) and a compound represented by the general formula (9) to cyclization reaction.
  • the cyclization reaction is usually performed in the presence or absence of a basic compound.
  • the present reaction is usually performed in a solvent routinely used that does not adversely affect the reaction.
  • the solvent include : water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; ether solvents such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and diglyme; ester solvents such as methyl acetate and ethyl acetate; aprotic polar solvents such as acetonitrile, ⁇ , ⁇ -dimethylformamide, dimethyl sulfoxide, and N- methylpyrrolidone; halogenated hydrocarbon solvents such as methylene chloride and ethylene chloride; and other organic solvents.
  • a transition metal catalyst and a ligand may be used in this reaction.
  • the transition metal include ruthenium chloride, dichlorotris(triphenylphosphine)ruthenium, dibromotris(triphenylphosphine)ruthenium, dihydridotetrakis(triphenylphosphine)ruthenium, ( ⁇ 4 -cyclooctadiene)( ⁇ 6 -cyclooctatriene)ruthenium, dichlorotricarbonylruthenium dimers, dodecacarbonyltriruthenium, ( -pentamethylcyclopentadienyl)chloro(ri 4 - cyclooctatriene)ruthenium, palladium acetate, palladium chloride,
  • ligand examples include: unidentate phosphine ligands typified by trimethylphosphine, triethylphosphine, tri-n-propylphosphine, tri-i-propylphosphine, tri-n- butylphosphine, tri-t-butylphosphine, tricyclohexylphosphine, triphenylphosphine, and tri(o- tolyl)phosphine; bidentate phosphine ligands typified by l,2-bis(diphenylphosphino)ethane, 1,3- bis(diphenylphosphino)propane, l,4-bis(diphenylphosphino)butane, and 1,2- (diethylphosphino)ethane; and phosphite ligands typified by triethyl phosphite, tributyl phosphite, triphen
  • This reaction may be performed in the presence of a base.
  • Inorganic and organic bases known in the art can be used widely as the base.
  • the inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate), alkali metal lower alkoxides (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., sodium hydride and potassium hydride).
  • alkali metals e.g., sodium and potassium
  • alkali metal bicarbonates e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate
  • organic bases examples include trialkylamines (e.g., trimethylamine, triethylamine, and N-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N- methylmorpholine, l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • TBN l,5-diazabicyclo[4.3.0]non-5-ene
  • DABCO l,4-diazabicyclo[2.2.2]octane
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • the amount of the base used is usually 0.1 to 10
  • the reaction can also be performed in the presence of a mixture of an oxidizing agent and a reducing agent.
  • oxidizing agent examples include manganese dioxide, chromic acid, lead tetraacetate, silver oxide, copper oxide, halogen acid, dimethyl sulfoxide (Swern oxidation), organic peroxides, and oxygen.
  • a method such as electrode oxidation may be used.
  • borohydride reagents such as sodium borohydride
  • aluminum hydride reagents such as lithium aluminum hydride.
  • the ratio between the compound of the general formula (9) and the compound of the general formula (4) used in the reaction formula is usually at least 1 mol, preferably approximately 1 to 5 mol of the former compound with respect to 1 mol of the latter compound.
  • the reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure.
  • the reaction temperature is not particularly limited.
  • the reaction is usually performed under cooling, at room temperature, or under heating.
  • the reaction is preferably performed under temperature conditions involving room temperature to 100°C, for 30 minutes to 30 hours, preferably 30 minutes to 5 hours.
  • reaction product After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of the general formula (2) of interest.
  • Examples of preferable salts of the compound of the general formula (1) include pharmacologically acceptable salts, for example: metal salts such as alkali metal salts (e.g., sodium salt and potassium salt) and alkaline earth metal salts (e.g., calcium salt and magnesium salt); ammonium salt; salts of inorganic bases such as alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, and cesium carbonate), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), and alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide); salts of organic bases such as tri-(lower) alkylamine (e.g., trimethylamine, triethylamine, and N-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylamin
  • solvate e.g., a hydrate or an ethanolate
  • solvate e.g., a hydrate or an ethanolate
  • the solvate include hydrates.
  • Each compound of interest obtained according to each of the reaction formulas can be isolated and purified from the reaction mixture, for example, by separating, after cooling, the reaction mixture into a crude reaction product by isolation procedures such as filtration, concentration, and extraction and subjecting the crude reaction product to usual purification procedures such as column chromatography and recrystallization.
  • the compound represented by the general formula (1) of the present invention also encompasses isomers such as geometric isomers, stereoisomers, and optical isomers, of course.
  • Various isomers can be isolated by a standard method using difference in physicochemical properties among the isomers.
  • racemic compounds can be converted to sterically pure isomers by a general optical resolution method [e.g., method involving conversion to diastereomeric salts with a general optically active acid (tartaric acid, etc.) and subsequent optical resolution].
  • Diastereomeric mixtures can be separated by, for example, fractional crystallization or chromatography.
  • Optically active compounds can also be produced using appropriate optically active starting materials.
  • the present invention also encompasses isotope-labeled compounds which are the same as the compound represented by the general formula (1) except that one or more atom(s) is substituted by one or more atoms(s) having a particular atomic mass or mass number.
  • Examples of the isotope that can be incorporated in the compound of the present invention include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 18 F, and 36 C1.
  • These particular isotope-labeled compounds of the present invention containing any of the isotopes and/or other isotopes of other atoms, for example, radioisotope (e.g., 3 H and 14 C)-incorporated compounds are useful in assay for the distribution of drugs and/or substrates in tissues. Tritiated (i.e., 3 H) and carbon-14 (i.e., I4 C) isotopes are particularly preferable because of their easy preparation and detectability.
  • the isotope-labeled compounds of the present invention can be prepared generally by substituting an unlabeled reagent by an easily obtainable isotope-labeled reagent by a method disclosed in the reaction formulas and/or Examples below.
  • a pharmaceutical preparation comprising the compound of the present invention as an active ingredient will be described.
  • the pharmaceutical preparation is obtained by making the compound of the present invention into usual dosage forms of pharmaceutical preparations and prepared using a diluent and/or an excipient usually used, such as fillers, extenders, binders, humectants, disintegrants, surfactants, and lubricants.
  • a diluent and/or an excipient usually used such as fillers, extenders, binders, humectants, disintegrants, surfactants, and lubricants.
  • Such a pharmaceutical preparation can be selected from among various forms according to a therapeutic purpose. Typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions, suspensions, etc.).
  • Carries known in the art for use for forming a tablet form can be used widely examples thereof include: excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions,
  • disintegrants such as dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cacao butter, and hydrogenated oil; absorption promoters such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol.
  • disintegrants such as dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters,
  • the tablets can be coated, if necessary, with a usual coating material to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film- coated tablets, and bilayer or multilayer tablets.
  • Carries known in the art for use for forming a pill form can be used widely.
  • excipients such as glucose, lactose, starch, cacao butter, hydrogenated plant oil, kaolin, and talc
  • binders such as gum arabic powder, powdered tragacanth, gelatin, and ethanol
  • disintegrants such as laminaran and agar.
  • Carries known in the art for use for forming a suppository form can be used widely.
  • examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, and semisynthetic glyceride.
  • solutions, emulsions, and suspensions are preferably sterile and isotonic with blood.
  • suspensions can be used widely.
  • examples thereof include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.
  • the pharmaceutical preparation may contain common salt, glucose, or glycerin in an amount sufficient for preparing an isotonic solution and may contain usual solubilizers, buffers, soothing agents, and the like, and if necessary, coloring agents, preservatives, perfumes, flavoring agents, sweetening agents, and the like, and/or other drugs.
  • the amount of the compound of the present invention contained in the pharmaceutical preparation is not particularly limited and can be selected appropriately from within a wide range.
  • the compound of the present invention is usually contained in an amount of preferably approximately 1 to 70% by weight in the pharmaceutical preparation.
  • a method for administering the pharmaceutical preparation according to the present invention is not particularly limited.
  • the pharmaceutical preparation is administered by a method according to various dosage forms, the age, sex, and disease state of a patient, and other conditions.
  • tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered.
  • injections can be administered through an intravenous route alone or as a mixture with a usual replacement fluid such as glucose or amino acid or can be administered alone through intramuscular, intradermal, hypodermic, or intraperitoneal route, if necessary.
  • Suppositories are rectally administered.
  • the dose of the pharmaceutical preparation may be selected appropriately according to use, the age, sex, and disease state of a patient, and other conditions.
  • the pharmaceutical preparation is usually administered once or several times a day at a daily dose of approximately 0.001 to 100 mg, preferably approximately 0.001 to 50 mg, per kg of body weight.
  • the dose varies depending on various conditions. Thus, in some cases, a dose smaller than this range suffices. In other cases, a dose exceeding this range is required.
  • a heterocyclic compound of the present invention has reuptake inhibitory effects on 1, 2, or 3 monoamines (serotonin, norepinephrine, and dopamine).
  • the heterocyclic compound of the present invention has remarkably strong uptake inhibitory activity in in-vitro or ex-vivo tests on any one, any two, or all of the 3 monoamines, compared with existing compounds having monoamine uptake inhibitory activity. Moreover, the heterocyclic compound of the present invention exhibits remarkably strong activity in brain microdialysis study against increase in any one, any two, or all of the 3 monoamines, compared with existing compounds having monoamine uptake inhibitory activity.
  • the heterocyclic compound of the present invention has a wide therapeutic spectrum, compared with antidepressants known in the art.
  • the heterocyclic compound of the present invention exerts sufficient therapeutic effects even in short-term administration.
  • the heterocyclic compound of the present invention has excellent bioavailability, weak inhibitory activity on metabolic enzymes in the liver, few side effects, and excellent safety.
  • the heterocyclic compound of the present invention is excellent in transfer into the brain.
  • the heterocyclic compound of the present invention also exerts strong activity in a mouse forced swimming test used in depression screening. Moreover, the heterocyclic compound of the present invention also exerts strong activity in a rat forced swimming test used in depression screening. Moreover, the heterocyclic compound of the present invention also exerts strong activity in a reserpine-induced hypothermia test used in depression screening.
  • the heterocyclic compound of the present invention exerts strong activity in a marble burying behavior test of anxiety or stress disease model mice and in fear-conditioned stress models.
  • the heterocyclic compound of the present invention has reuptake inhibitory effects on 1, 2, or 3 monoamines (serotonin, norepinephrine, and dopamine) and is therefore effective for treating various disorders associated with the reduced neurotransmission of serotonin, norepinephrine, or dopamine.
  • Such disorders include depression (e.g.: major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymic disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; hypomelancholia; recurrent brief depressive disorder; refractory depression/chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; depression caused by various physical diseases such as Cushing syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactorrhea syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, brain infarct, brain hemorrhage, subarachnoid hemorrhage, diabetes mellitus, virus infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, and cancer, etc.; presenile depression; senile depression; depression in children and adolescents; depression induced by drugs such as interferon, etc.); depression status caused by adjustment disorder, anxiety caused by adjustment
  • phobia e.g., agoraphobia, social fear, simple phobia, social phobia, social anxiety disorder, ereuthrophobia, anthrophobia, acrophobia, odontophobia, trypanophobia, specific phobia, simple phobia, animal phobia, claustrophobia, nyctophobia and phobic anxiety
  • obsessive-compulsive disorder panic disorder, posttraumatic stress disorder, acute stress syndrome, hypochondriasis disorder, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependence (e.g., addition to alcohol, cocaine, heroin
  • paroxysmal hemicrania chronic fatigue syndrome, precocious ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome and headache (associated with angiopathy).
  • Lithium aluminum hydride (541 mg, 14.3 mmol) was added to an anhydrous dioxane (40 mL) solution of cis-3,3-dimethyloctahydrocyclopentapyrazin-2-one (2.00 g, 11.9 mmol) with stirring at room temperature, and the mixture was gradually heated and stirred for 10 minutes under reflux. The reaction mixture was cooled to ice temperature. Then, sodium sulfate decahydrate was added thereto in small portions until no hydrogen gas was generated. Then, the mixture was stirred at room temperature for 1 hour. Insoluble matter was filtered through celite, and the filtrate was concentrated.
  • Trans-cyclohexane-l,2-diamine (3.00 g, 26.3 mmol) was diluted with ethanol (15 ml). To the solution, bromoethyl acetate (6.12 mL, 55.2 mmol) was added dropwise with ice- cooling, and the mixture was then stirred overnight at room temperature.

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Abstract

A heterocyclic compound represented by the general formula (1) or a salt thereof: wherein m, l, and n respectively represent an integer of 1 or 2; X represents -O- or -CH2-; R1 represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a protecting group, or a tri-lower alkylsilyloxy-lower alkyl group; R2 and R3, which are the same or different, each independently represent hydrogen or a lower alkyl group; or R2 and R3 are bonded to form a cyclo-C3-C8 alkyl group; and R4 represents an aromatic group or a heterocyclic group, wherein the aromatic or heterocyclic group may have one or more arbitrary substituent(s).

Description

DESCRIPTION
DECAHYDROQUINOXALINE DERIVATIVES AND ANALOGS THEREOF
TECHNICAL FIELD
[0001]
The present invention relates to a novel heterocyclic compound.
BACKGROUND ART
[0002]
Three monoamines known as serotonin, norepinephrine, and dopamine function as neurotransmitters in vivo. Therefore, drugs having inhibitory effects on the reuptake of these monoamines have been used widely as therapeutic drugs for diseases associated with the central or peripheral nervous system.
[0003]
Most of drugs previously used in the treatment of depression selectively inhibit the reuptake of norepinephrine or serotonin. Examples of such drugs include imipramine (first- generation antidepressant), maprotiline (second-generation antidepressant), selective serotonin reuptake inhibitors (SSRIs, third-generation antidepressants) typified by fluoxetine, and serotonin and/or norepinephrine reuptake inhibitors (SNRIs, fourth-generation antidepressants) typified by venlafaxine (S. Miura, Japanese Journal of Clinical Psychopharmacology, 2000, 3: 311-318).
[0004]
However, all of these drugs require a period as long as 3 weeks or longer for exerting their therapeutic effects and, in addition, fail to exert sufficient therapeutic effects on approximately 30% of patients with depression (Phil Skolnick, European Journal of
Pharmacology, 1999, 375: 31-40).
DISCLOSURE OF INVENTION
[0005]
An object of the present invention is to provide a drug that has a wide therapeutic spectrum and can exert sufficient therapeutic effects in a short period, compared with
antidepressants known in the art.
[0006]
The present inventors have conducted diligent studies to attain the object and have consequently found that a heterocyclic compound represented by the general formula (1) shown below can be used in the production of the desired drug. The present invention has been completed based on these findings.
[0007]
The present invention provides a heterocyclic compound or a salt thereof or a medicament comprising the same according to any one of Items 1 to 21 shown below, a pharmaceutical composition comprising the compound or an use of the compounds, a method for treating or preventing diseases or a methods for producing the compounds.
Item 1. A medicament comprising a heterocyclic compound represented by the general formula (1) or a salt thereof:
Figure imgf000003_0001
wherein m, 1, and n respectively represent an integer of 1 or 2; X represents -O- or -CH2-;
R1 represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a protecting group, or a tri-lower alkylsilyloxy-lower alkyl group;
R2 and R3, which are the same or different, each independently represent hydrogen or a lower alkyl group; or R2 and R3 are bonded to form a cyclo-C3-C8 alkyl group; and
R4 represents an aromatic group or a heterocyclic group, wherein
the aromatic or heterocyclic group may have one or more arbitrary substituent(s).
Item 2. The medicament according to item 1, comprising comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, wherein
R4 represents any of
(1) a phenyl group,
(2) an indolyl group,
(3) a benzothienyl group,
(4) a naphthyl group,
(5) a benzofuryl group,
(6) a quinolyl group,
(7) an isoquinolyl group, 8) a pyridyl group,
9) a thienyl group,
0) a dihydrobenzoxazinyl group,
11) a dihydrobenzodioxinyl group,
(12) a dihydroquinolyl group,
(13) a chromanyl group,
(14) a quinoxalinyl group,
(15) a dihydroindenyl group,
(16) a dihydrobenzofuryl group, 17) a benzodioxolyl group,
(18) an indazolyl group,
19) a benzothiazolyl group,
(20) an indolinyl group,
21) a thienopyridyl group,
(22) a tetrahydrobenzazepinyl group,
(23) a tetrahydrobenzodiazepinyl group,
(24) a dihydrobenzodioxepinyl group,
(25) a fluorenyl group,
(26) a pyridazinyl group,
(27) a tetrahydroquinolyl group,
(28) a carbazolyl group,
(29) a phenanthryl group,
(30) a dihydroacenaphthylenyl group,
(31) a pyrrolopyridyl group,
(32) an anthryl group,
(33) a benzodioxinyl group,
(34) a pyrrolidinyl group,
(35) a pyrazolyl group,
(36) an oxadiazolyl group,
(37) a pyrimidinyl group,
(38) a tetrahydronaphthyl group,
(39) a dihydroquinazolinyl group,
(40) a benzoxazolyl group,
(41 ) a thiazolyl group, 42) a quinazolinyl group,
43) a phthalazinyl group,
44) a pyrazinyl group, and
45) a chromenyl group, wherein
these aromatic or heterocyclic groups may have one or more substituent(s) selected from 1-1) a halogen atom,
1-2) a lower alkyl group,
1-3) a lower alkanoyl group,
1-4) a halogen-substituted lower alkyl group,
1-5) a halogen-substituted lower alkoxy group,
1-6) a cyano group,
1-7) a lower alkoxy group,
1-8) a lower alkylthio group,
1-9) an imidazolyl group,
1-10 a tri-lower alkylsilyl group,
1-11 an oxadiazolyl group which may have a lower alkyl group(s),
1-12 a pyrrolidinyl group which may have an oxo group(s),
1-13 a phenyl group which may have a lower alkoxy group(s),
1-14 a lower alkylamino-lower alkyl group,
1-15 an oxo group,
1-16 a pyrazolyl group which may have a lower alkyl group(s),
1-17 a thienyl group,
1-18 a furyl group,
1-19 a thiazolyl group which may have a lower alkyl group(s),
1-20 a lower alkylamino group,
1-21 a pyrimidyl group which may have a lower alkyl group(s),
1-22 a phenyl-lower alkenyl group,
1-23 a phenoxy group which may have a halogen atom(s),
1-24 a phenoxy-lower alkyl group,
1-25 a pyrrolidinyl-lower alkoxy group,
1-26 a lower alkylsulfamoyl group,
1-27 a pyridazinyloxy group which may have a lower alkyl group(s),
1-28 a phenyl-lower alkyl group,
1-29 a lower alkylamino-lower alkoxy group, (1-30) an imidazolyl-lower alkyl group,
(1-31) a phenyl-lower alkoxy group,
(1-32) a hydroxy group,
(1-33) a lower alkoxy carbonyl group,
(1-34) a hydroxy-lower alkyl group,
(1-35) an oxazolyl group,
( 1 -36) a piperidyl group,
(1-37) a pyrrolyl group,
(1-38) a morpholinyl-lower alkyl group,
(1-39) a piperazinyl-lower alkyl group which may have a lower alkyl group(s),
(1-40) a piperidyl- lower alkyl group,
(1-41) a pyrrolidinyl-lower alkyl group,
(1-42) a morpholinyl group, and
(1-43) a piperazinyl group which may have a lower alkyl group(s).
Item 3. The medicament according to item 2, comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, wherein
R4 represents any of
(1) a phenyl group,
(2) an indolyl group,
(3) a benzothienyl group,
(4) a naphthyl group,
(5) a benzofuryl group,
(6) a quinolyl group,
(7) an isoquinolyl group,
(8) a pyridyl group,
(9) a thienyl group,
(10) a dihydrobenzoxazinyl group,
(11) a dihydrobenzodioxinyl group,
(12) a dihydroquinolyl group,
(13) a chromanyl group,
(14) a quinoxalinyl group,
(15) a dihydroindenyl group,
(16) a dihydrobenzofuryl group,
(17) a benzodioxolyl group, (18) an indazolyl group,
( 19) a benzothiazoly 1 group,
(20) an indolinyl group,
(21) a thienopyridyl group,
(22) a tetrahydrobenzazepinyl group,
(23) atetrahydrobenzodiazepinyl group,
(24) a dihydrobenzodioxepinyl group,
(25) a fluorenyl group,
(26) a pyridazinyl group,
(27) a tetrahydroquinolyl group,
(28) a carbazolyl group,
(29) a phenanthryl group,
(30) a dihydroacenaphthylenyl group,
(31) a pyrrolopyridyl group,
(32) an anthryl group,
(33) a benzodioxinyl group,
(34) a pyrrolidinyl group,
(35) a pyrazolyl group,
(36) an oxadiazolyl group,
(37) a pyrimidinyl group,
(38) a tetrahydronaphthyl group,
(39) a dihydroquinazolinyl group,
(40) a benzoxazolyl group,
(41) a thiazolyl group,
(42) a quinazolinyl group,
(43) a phthalazinyl group,
(44) a pyrazinyl group, and
(45) a chromenyl group, wherein
these aromatic or heterocyclic groups may have 1 to 4 substituent(s) selected from
( 1 - 1 ) a halogen atom,
(1-2) a lower alkyl group,
(1-3) a lower alkanoyl group,
(1-4) a halogen-substituted lower alkyl group,
(1-5) a halogen-substituted lower alkoxy group, (1-6) a cyano group,
(1-7) a lower alkoxy group,
(1-8) a lower alkylthio group,
(1-9) an imidazolyl group,
(1-10) a tri-lower alkylsilyl group,
(1-11) an oxadiazolyl group which may have 1 lower alkyl group,
(1-12) a pyrrolidinyl group which may have 1 oxo group,
(1-13) a phenyl group which may have 1 lower alkoxy group,
(1-1 ) a lower alkylamino-lower alkyl group,
(1-15) an oxo group,
(1-16) a pyrazolyl group which may have 1 lower alkyl group,
(1-17) a thienyl group,
(1-18) a furyl group,
(1-19) a thiazolyl group which may have 1 lower alkyl group,
(1-20) a lower alkylamino group,
(1-21) a pyrimidyl group which may have 1 lower alkyl group,
(1-22) a phenyl-lower alkenyl group,
(1-23) a phenoxy group which may have 1 halogen atom,
(1-24) a phenoxy-lower alkyl group,
(1-25) a pyrrolidinyi-lower alkoxy group,
(1-26) a lower alkylsulfamoyl group,
(1-27) a pyridazinyloxy group which may have 1 lower alkyl group,
( 1 -28) a phenyl-lower alkyl group,
(1-29) a lower alkylamino-lower alkoxy group,
(1-30) an imidazolyl-lower alkyl group,
(1-31) a phenyl-lower alkoxy group,
(1-32) a hydroxy group,
(1-33) a lower alkoxycarbonyl group,
(1-34) a hydroxy-lower alkyl group,
(1-35) an oxazolyl group,
(1-36) a piperidyl group,
(1-37) a pyrrolyl group,
(1-38) a morpholinyl-lower alkyl group,
(1-39) a piperazinyl-lower alkyl group which may have 1 lower alkyl group, (1-40) a piperidyl-lower alkyl group,
(1-41) a pyrrolidinyl-lower alkyl group,
(1-42) a morpholinyl group, and '
(1-43) a piperazinyl group which may have 1 lower alkyl group.
Item 4. The medicament according to item 3, comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, wherein
m represents 2; 1 and n respectively represent an integer of 1; X represents -CH2-;
R1 represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a benzyl group, or a tri-lower alkylsilyloxy-lower alkyl group; and
R4 represents any of
(1) a phenyl group,
(2) an indolyl group,
(4) a naphthyl group,
(5) a benzofuryl group, and
(31) a pyrrolopyridyl group, wherein
these aromatic or heterocyclic groups may have 1 to 4 substituent(s) selected from
( 1 - 1 ) a halogen atom,
(1-2) a lower alkyl group,
(1-3) a lower alkanoyl group,
(1-4) a halogen-substituted lower alkyl group,
(1-5) a halogen-substituted lower alkoxy group,
(1-6) a cyano group,
( 1 -7) a lower alkoxy group,
(1-8) a lower alkylthio group,
(1-9) an imidazolyl group,
( 1 - 10) a tri-lower alkylsilyl group,
(1-11) an oxadiazolyl group which may have 1 lower alkyl group,
(1-12) a pyrrolidinyl group which may have 1 oxo group,
(1-13) a phenyl group which may have 1 lower alkoxy group,
(l-14) a lower alkylamino-lower alkyl group,
(1-15) an oxo group,
(1-16) a pyrazolyl group which may have 1 lower alkyl group,
( 1 - 17) a thienyl group,
(1-18) a furyl group, -
1-19 a thiazolyl group which may have 1 lower alkyl group,
1-20 a lower alkylamino group,
1-21 a pyrimidyl group which may have 1 lower alkyl group,
1-22 a phenyl-lower alkenyl group,
1-23 a phenoxy group which may have 1 halogen atom,
1-24 a phenoxy-lower alkyl group,
1-25 a pyrrolidinyl-lower alkoxy group,
1-26 a lower alkylsulfamoyl group,
1-27 a pyridazinyloxy group which may have 1 lower alkyl group,
1-28 a phenyl-lower alkyl group,
1-29 a lower alkylamino-lower alkoxy group,
1-30 an imidazoly -lower alkyl group,
1-31 a phenyl-lower alkoxy group,
1-32 a hydroxy group,
1-34 a hydroxy-lower alkyl group,
1-35 an oxazolyl group,
1-36 a piperidyl group,
1-37 a pyrrolyl group,
1-38 a morpholinyl-lower alkyl group,
1-39 a piperazinyl-lower alkyl group which may have a lower alkyl group(s),
1-40 a piperidyl-lower alkyl group,
1-41 a pyrrolidinyl-lower alkyl group,
1-42 a morpholinyl group, and
1-43 a piperazinyl group which may have 1 lower alkyl group.
ic 5 The medicament according to item 4, comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, wherein
R1 represents hydrogen;
R2 and R3, which are the same or different, each independently represent a lower alkyl group; or R2 and R3 are bonded to form a cyclo-C3-C8 alkyl group; and
R4 represents any of
(1) a phenyl group,
(2) an indolyl group,
(4) a naphthyl group,
(5) a benzofuryl group, and (31) a pyrrolopyridyl group, wherein
these aromatic or heterocyclic groups may have 1 to 2 substituent(s) selected from
( 1 - 1 ) a halogen atom,
(1-2) a lower alkyl group,
5 (1-5) a halogen-substituted lower alkoxy group,
(1-6) a cyano group, and
(1-7) a lower alkoxy group.
Item 6. The medicament according to item 5, comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, which is selected from
0 (4aS,8aR)-l-(4-chlorophenyl)-3,3-dimethyldecahydroquinoxaline
2-chloro-4-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-l(2H)-yl)benzonitrile
(4aS,8aR)-l-(3-chloro-4-fluorophenyl)-3,3-dimethyldecahydroquinoxaline
(4aS,8aR)-l-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline
5-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-l(2H)-yl)-l-methyl-lH-indole-2-carbonitrile^5 (4a'R,8a'S)-4'-(7-methoxybenzofuran-4-yl)octahydro- H-spiro[cyclobutane-l,2'-quinoxaline]
(4aS,8aR)-l-(6,7-difluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline
5- ((4aS, 8aS)-3 ,3 -dimethyloctahydroquinoxalin- 1 (2H)-yl)- lH-indole-2-carbonitrile
(4aS, 8a/?)- 1 -(7-chloro-2,3 -dihydro- li/-inden-4-yl)-3,3 -dimethyldecahydroquinoxaline
6- ((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-l(2H)-yl)-2-naphthonitrile
Q (4aS,8aS)-3,3-dimethyl-l-(lH-pyrrolo[2,3-&]pyridin-4-yl)decahydroquinoxaline ancj
(4aS,,8aS)-l-(4-(difluoromethoxy)-3-fluorophenyl)-3,3-dimethyldecahydroquinoxaline
Item 7. A pharmaceutical composition comprising a heterocyclic compound represented by the general formula (1) or a salt thereof according to item 1 as an active ingredient and a pharmaceutically acceptable carrier.
5 Item 8. A prophylactic and/or therapeutic agent for disorders caused by reduced
neurotransmission of serotonin, norepinephrine or dopamine, comprising as an active ingredient a heterocyclic compound of general formula (1) or a salt thereof according to item 1.
Item 9. a prophylactic and/or therapeutic agent according to item 8, wherein the disorder is selected from the group consisting of depression, depression status caused by adjustment0 disorder, anxiety caused by adjustment disorder, anxiety caused by various diseases, generalized anxiety disorder, phobia, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, acute stress disorder, hypochondria, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorder, obesity, chemical dependence, pain, fibromyalgia, Alzheimer's disease, memory deficit, Parkinson's disease, restless leg syndrome, endocrine disorder, vasospasm, cerebellar ataxia, gastrointestinal disorder, negative syndrome of schizophrenia, premenstrual syndrome, stress urinary incontinence, Tourette's disorder, attention deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, impulse control disorder, trichotillomania, kleptomania, gambling disorder, cluster headache, migraine, chronic
paroxysmal hemicrania, chronic fatigue syndrome, precocious ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome and headache.
Item 10. a prophylactic and/or therapeutic agent according to item 9, wherein the depression is selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymic disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; hypomelancholia; recurrent brief depressive disorder; refractory depression; chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; depression caused by various physical diseases such as Cushing('s) syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea- galactorrhea syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, brain infarct^ brain hemorrhage subarachnoid hemorrhage, diabetes millitus, virus infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc.; presenile depression; senile depression; depression in children and adolescents; depression induced by drugs such as interferon, etc.
Item 11. A prophylactic and/or therapeutic agent according to item 9, wherein the anxiety caused by various diseases is selected from the group consisting of anxiety caused by head injury, brain infection, inner ear impairment, cardiac failure, cardiac dysrhythmia,
hyperadrenalism, hyperthyroidism, asthma and chronic obstructive pulmonary disease.
Item 12. A prophylactic and/or therapeutic agent according to item 9, wherein the pain is selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic cervical syndrome, spinal cord injury pain, trigeminal neuralgia, diabetic neuropathy.
Item 13. A heterocyclic compound or a salt thereof selected from the group consisting of the following compounds:
Figure imgf000013_0001
[Table 1-2]
Figure imgf000014_0001
[Table 1-3]
Figure imgf000015_0001
[Table 1-4]
Figure imgf000016_0001
[Table 1-5]
Figure imgf000017_0001
[Table 1-6]
Figure imgf000018_0001
[Table 1-7]
Figure imgf000019_0001
Item 14. A heterocyclic compound or a salt thereof selected from the group consisting of the following compounds:
[Table 1-8]
Figure imgf000019_0002
[Table 1-9]
Figure imgf000020_0001
Item 15. A medicament comprising the heterocyclic compound or a salt thereof according to Item 13 or 14.
Item 16. A pharmaceutical composition comprising a heterocyclic compound or a salt thereof according to Item 13 or 14 as an active ingredient and a pharmaceutically acceptable carrier.
Item 17. A prophylactic and/or therapeutic agent for disorders caused by reduced neurotransmission of serotonin, norepinephrine or dopamine, comprising as an active ingredient a heterocyclic compound of general formula (1) or a salt thereof according to Item 13 or 14. Item 18. A prophylactic and/or therapeutic agent according to Item 17, wherein the disorder is selected from the group consisting of depression, depression status caused by adjustment disorder, anxiety caused by adjustment disorder, anxiety caused by various diseases, generalized anxiety disorder, phobia, obsessive-compulsive disorder, panic disorder,
posttraumatic stress disorder, acute stress disorder, hypochondria, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorder, obesity, chemical dependence, pain, fibromyalgia, Alzheimer's disease, memory deficit, Parkinson's disease, restless leg syndrome, endocrine disorder, vasospasm, cerebellar ataxia, gastrointestinal disorder, negative syndrome of schizophrenia, premenstrual syndrome, stress urinary incontinence, Tourette's disorder, attention deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, impulse control disorder, trichotillomania, kleptomania, gambling disorder, cluster headache, migraine, chronic paroxysmal hemicrania, chronic fatigue syndrome, precocious ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome and headache. 19. A prophylactic and/or therapeutic agent according to claim 18, wherein the depression is selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymic disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; hypomelancholia; recurrent brief depressive disorder; refractory depression; chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; depression caused by various physical diseases such as Cushing('s) syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea- galactorrhea syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, brain infarct^ brain hemorrhage^ subarachnoid hemorrhage, diabetes millitus, virus infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc.; presenile depression; senile depression; depression in children and adolescents; depression induced by drugs such as interferon, etc.
Item 20. A prophylactic and/or therapeutic agent according to Item 18, wherein the anxiety caused by various diseases is selected from the group consisting of anxiety caused by head injury, brain infection, inner ear impairment, cardiac failure, arrhythmia, hyperadrenalism, hyperthyroidism, asthma and chronic obstructive pulmonary disease. Item 21. A prophylactic and/or therapeutic agent according to Item 18, wherein the pain is selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic cervical syndrome, spinal cord injury pain, trigeminal neuralgia, diabetic neuropathy.
[Embodiment to Carry Out the Invention]
[0008]
Each group shown in the general formula is specifically as shown below.
The term "lower" means a group having 1 to 6 (preferably 1 to 4, more preferably 1 to 3) carbon atoms, unless otherwise specified.
[0009]
A heterocyclic ring group includes saturated or unsaturated monocyclic or polycyclic heterocyclic rings comprising at least one hetero atoms selected from an oxygen atom(s), a sulfur atom(s) and nitrogen atom(s). More preferably, it includes the following heterocyclic ring:
[0010]
3 to 8 unsaturated-membered, preferably 5 or 6-membered heteromonocyclic ring containing 1 to 4 nitrogen atoms, for example, pyrrolyl , pyrroliny, imidazolyl, pyrazolyl, pyridyl groups and N-oxide thereof, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1, 2, 4- triazolyl, lH-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl gourps etc.), tetrazolyl group (e.g., 1H- tetrazolyl, 2H-tetrazolyl groups, etc.), dihydrotriazinyl (e.g., 4, 5-dihydro-l, 2, 4-triazinyl, 2, 5- dihydro-1, 2, 4-triazinyl groups) groups, etc. can be mentioned. Preferably, imidazolyl, pyridazinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl groups, etc. can be mentioned.
[0011]
3 to 8-membered, preferably 5 or 6-membered unsaturated heteromonocyclic ring containing 1 to 4 nitrogen atoms, for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, pyperazinyl groups, etc. can be mentioned. Preferably, pyrrolidinyl group can be mentioned.
[0012]
7 to 12-membered partially saturated or unsaturated condensed hetero ring group containing 1 to 5 nitrogen atoms, for example, indolyl, dihydroindolyl, (e.g., 2, 3-dihydro-lH- dihydroindolyl group, etc.), iso indolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl (e.g., 3, 4-dihydro-lH-isoquinolyl group, etc.), tetrahydroquinolyl, tetrahydroisoquinolyl (e.g., 1, 2, 3, 4-tetrahydro-lH-isoquinolyl, 5, 6, 7, 8-tetrahydroisoquinolyl groups, etc.), carbostyril, dihydrocarbostyril (e.g., 3, 4-dihydrocarbostyril group, etc.), indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[l, 5-b]pyridazinyl group, etc.), dihydrotriazolopyridazinyl, imidazopyridyl (e.g., imidazo[l, 2-a]pyridyl group, etc.), naphthyridyl, cinnolinyl, quinoxalinyl, pyrazolopyridyl (e.g., pyrazolo[2, 3-a]pyridyl group, etc.), pyrrolopyridyl, carbazolyl, Indolinyl, tetrahydrobenzodiazepinyl, tetrahydrobenzoazepinyl, quinazolinyl, phthalazinyl groups, etc. can be mentioned. Preferably, quinolyl, isoquinolyl, quinoxalinyl, indolyl, indazolyl, pyrrolopyridyl, tetrahydroquinolyl, carbazolyl, indolinyl, quinazolyl, phthalazinyl, tetrahydrobenzodiazepinyl, or tetrahydrobenzoazepinyl groups, etc. can be mentioned.
[0013]
3 to 8 membered, preferably 5 or 6 membered unsaturated heteromono ring containing 1 to 2 oxygen atoms, for example, furyl group, etc. can be mentioned.
[0014]
7 to 12-membered partially saturated or unsaturated condensed hetero ring group containing 1 to 3 oxygen atoms, for example, benzofuryl, dihydrobenzofuyl (e.g., 2, 3- dihydrobenzo [b] furyl group, etc.), chromanyl, benzodioxanyl (e.g., 1,4-benzodioxanyl group, etc.), dihydrobenzoxadinyl (e.g, 2, 3-dihydrobenzo-l,4-oxadinyl), benzodioxolyl (e.g., benzo[l„3] dioxolyl group, etc.), benzodioxynyl, dihydrobenzodioxynyl,
dihydrobenzodioxepinyl groups, etc. can be mentioned. Preferably, benzofuryl, benzodioxynyl, benzodioxolyl, dihydrobenzofuryl, dihydrobenzodioxepinyl, dihydrobenzodioxsepinylyl, chromenyl, or chromanyl groups can be mentioned.
[0015]
3 to 8-membered, preferably 5 or 6-membered unsaturated heteromonocyclic ring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazoyl, 1, 2, 5-oxadiazoyl groups, etc.) groups, etc. can be mentioned. Preferably, oxazolyl, oxadiazolyl groups can be mentioned.
[0016]
3 to 8-membered, preferably 5 or 6-membered saturated heteromonocyclic ring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, morpholinyl group, etc. can be mentioned.
[0017]
7 to 12-membered partially saturated or unsaturated condensed hetero ring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazoly,
benzoxazdiazolyl, benzisoxazolyl, furopyridyl (e.g., furo[2, 3-b] pyridyl, furo[3, 2-c]pyridyl groups, etc.), dihydrobenzoxadinyl groups, etc. can be mentioned. Preferably, benzoxazolyl, dihydrobenzoxadinyl groups can be mentioned.
[0018]
3 to 8-membered, preferably 5 or 6-membered unsaturated heteromonocyclic ring containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, 1, 2-thiazolyl, thiazolynyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1, 2, 3- thiadiazolyl groups, etc.) groups, etc. can be mentioned. Preferably, thiazolyl group can be mentioned.
[0019]
3 to 8-membered, preferably, 5 or 6-membered saturated heteromonocyclic ring containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolydinyl group, etc, can be mentioned.
[0020]
3 to 8-membered, preferably, 5 or 6-membered unsaturated heteromonocyclic ring containing 1 sulfur atom, for example, thienyl group, etc. can be mentioned.
[0021]
7 to 12-membered unsaturated condensed hetero ring containing 1 to 3 sulfur atoms, for example, benzothienyl group (e.g., benzo [b] thienyl group, etc.), etc. can be mentioned.
[0022]
7 to 12-membered partially saturated or unsaturated condensed hetero ring group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl, benzothadiazolyl, thienopyridyl (e.g., thieno[2, 3-b] pyridyl, thieno[2, 3-c] pyridyl, thieno[3, 2- c]pyridyl groups, etc.), imidazothiazolyl (e.g., imidazo[2, 1-b] thiazolyl group, etc.),
dihydroimidazothiazolyl (e.g., 2, 3-dihydroimidazo[2, 1-b] thiazolyl group, etc.), thienopyradinyl (e.g., thieno[2, 3-b] pyradinyl group, etc.), groups, etc. can be mentioned. Preferably, thienopyridyl or benzothiazolyl groups can be mentioned.
[0023]
The above heterocyclic ring can be substituted by one or more optional substituents.
[0024]
As an aromatic ring, it includes, for example, C6-i4 aryl groups can be mentioned. The preferable examples of the aryl groups are a phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenyl, indenyl groups. Among them, phenyl, naphtyl, anthryl, phenanthryl groups are preferable. The aryl groups can be partially saturated. As the partially unsaturated aryl groups are, for example, dihydroindenyl, fluorenyl, dihydroacenaphthylenyl,
tetrahydronaphthyl groups. Here, the above heterocyclic rings can be substituted by one or more optional substituents.
[0025]
As a saturated hydrocarbon group, it includes, for example, lower alkyl, cyclo C3- C8 alkyl groups, etc.
[0026]
As an unsaturated hydrocarbon group, it includes, for example, lower alkenyl, lower alkynyl, phenyl groups, etc.
[0027]
A characteristic group is a generic term used to refer to groups bind directly to a mother structure other than a carbon-carbon binding (atoms or atomic groups other than hydrogen), and -C≡N and >C=X (X=0, S, Se, Te, NH, NR). As the characteristic group, it includes, for example, carboxy, carbamoyl, cyano, hydroxy, amino groups, etc.
[0028]
The optional substituents are the above heterocyclic rings, aromatic ring groups, saturated hydrocarbon groups, unsaturated hydrocarbon groups, characteristic groups, etc.
Preferably, the substituents (1-1) to (1-43) described in item 2 above can be mentioned.
[0029]
Examples of the lower alkyl group can include linear or branched alkyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms), unless otherwise specified. More specifically, it includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, l-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2,2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, and 3-methylpentyl groups, etc.
[0030]
Examples of a lower alkoxy group can include linear or branched alkoxy groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms), unless otherwise specified. More specifically, it includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert- butoxy, sec-butoxy, n-pentyloxy, 1-ethylpropoxy, isopentyloxy, neopentyloxy, n-hexyloxy, 1,2,2- trimethylpropoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, isohexyloxy, and 3-methylpentyloxy groups, etc.
[0031]
Examples of a halogen atom include fluorine, chlorine, bromine, and iodine atoms, unless otherwise specified.
[0032]
Examples of a halogen-substituted lower alkyl group can include the lower alkyl groups exemplified above which are substituted by 1 to 7 (more preferably 1 to 3) halogen atoms, unless otherwise specified. More specifically, it includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2- chloroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl,
heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl, 4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl, 5,5,5-trifluoropentyl, 5- chloropentyl, 6,6,6-trifluorohexyl, 6-chlorohexyl, and perfluorohexyl groups, etc.
[0033]
Examples of a halogen-substituted lower alkoxy group can include the lower alkoxy groups exemplified above which are substituted by 1 to 7 (preferably 1 to 3) halogen atoms, unless otherwise specified. More specifically, it includes fluoromethoxy,
difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, pentafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, 3-chloropropoxy, 2-chloropropoxy, 3- bromopropoxy, 4,4,4-trifluorobutoxy, 4,4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy, 4- bromobutoxy, 2-chlorobutoxy, 5,5,5-trifluoropentyloxy, 5-chloropentyloxy, 6,6,6- trifluorohexyloxy, 6-chlorohexyloxy, and perfluorohexyloxy groups, etc.
[0034]
Examples of a cyclo-C3-C8 alkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, etc., unless otherwise specified.
[0035]
Examples of a lower alkanoyl group can include linear or branched alkanoyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms), unless otherwise specified. More specifically, it includes formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert- butylcarbonyl, and hexanoyl groups, etc.
[0036]
Examples of a lower alkylthio group can include thio groups which are substituted by linear or branched alkyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms), unless otherwise specified. More specifically, it includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio, n-pentylthio, 1-ethylpropylthio, isopentylthio, neopentylthio, n-hexylthio, 1,2,2-trimethylpropylthio, 3,3- dimethylbutylthio, 2-ethylbutylthio, isohexylthio, and 3-methylpentylthio groups, etc.
[0037]
Examples of a lower alkenyl group can include linear or branched alkenyl groups having 1 to 3 double bonds and 2 to 6 carbon atoms (preferably 2 to 4 carbon atoms), unless otherwise specified, and the lower alkenyl group encompasses both trans and cis forms. More specifically, it includes vinyl, 1-propenyl, 2-propenyl, 1 -methyl- 1-propenyl, 2-methyl-l- propenyl, 2-methyl-2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3- pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-yl, 2-hexenyl, 1-hexenyl, 5- hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-l-propenyl, 2-ethyl-l-propenyl, 1,3,5-hexatrienyl, 1,3-hexadienyl, and 1,4-hexadienyl groups, etc.
[0038]
Examples of a hydroxy-lower alkyl group can include the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) which have 1 to 5, preferably 1 to 3 hydroxy groups, unless otherwise specified. More specifically, it includes hydroxymethyl, 2-hydroxyethyl, 2- hydroxypropyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3,4- dihydroxybutyl, l,l-dimethyl-2-hydroxyethyl, 5 -hydroxy pentyl, 6-hydroxyhexyl, 3,3-dimethyl- 3-hydroxypropyl, 2-methyl-3-hydroxypropyl, 2,3,4-trihydroxybutyl, and perhydroxyhexyl groups, etc.
[0039]
Examples of a lower alkylamino group can include amino groups having 1 to 2 of the lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 (more preferably 1 to 4, even more preferably 1 to 3) carbon atoms) exemplified above, unless otherwise specified. More specifically, it includes methylamino, dimethylamino, diethylamino, and diisopropylamino groups, etc.
[0040]
Examples of a lower alkylsulfamoyl group can include sulfamoyl groups having 1 to 2 of the lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 (more preferably 1 to 4, even more preferably 1 to 3) carbon atoms) exemplified above, unless otherwise specified. More specifically, it includes methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, and ethylmethylsulfamoyl groups, etc.
[0041] Atri-lower alkylsilyl group can be exemplified by silyl groups which are substituted by 3 linear or branched alkyl groups having 1 to 6 carbon atoms, such as
triisopropylsilyl, tert-butyldimethylsilyl, trimethylsilyl, n-butylethylmethylsilyl, tert- butyldipropylsilyl, n-pentyldiethylsilyl, and n-hexyl-n-propylmethylsilyl groups, etc.
[0042]
Examples of a tri(lower alkyl)silyloxy-lower alkyl group can include tri(lower alkyl)silyloxy-lower alkyl groups whose lower alkyl moiety is any of the lower alkyl groups exemplified above (preferably, linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)), unless otherwise specified. More specifically, it includes trimethylsilyloxymethyl, 1- (or 2-)trimethylsilyloxyethyl, 1- (or 2- or 3-)trimethylsilyloxypropyl, triethylsilyloxymethyl, 1- (or 2-)triethylsilyloxyethyl, 1- (or 2- or 3-)triethylsilyloxypropyl, triisopropylsilyloxymethyl, 1- (or 2-)triisopropylsilyloxyethyl, and 1- (or 2- or 3- )triisopropylsilyloxypropyl groups, etc.
[0043]
Examples of a phenoxy-lower alkyl group can include the lower alkyl groups
(preferably linear or branched alkyl groups having 1 to 6 (more preferably 1 to 4, even more preferably 1 to 3) carbon atoms) exemplified above which have 1 to 3, preferably 1 phenoxy group, unless otherwise specified. More specifically, it includes phenoxymethyl, 1- phenoxy ethyl, 2-phenoxy ethyl, 3-phenoxypropyl, 2-phenoxypropyl, 4-phenoxybutyl, 5- phenoxypentyl, 4-phenoxypentyl, 6-phenoxyhexyl, 2-methyl-3-phenoxypropyl, and 1, 1- dimethyl-2-phenoxyethyl groups, etc.
[0044]
Examples of a phenyl-lower alkoxy group can include the lower alkoxy groups (preferably linear or branched alkoxy groups having 1 to 6 (more preferably 1 to 4, even more preferably 1 to 3) carbon atoms) exemplified above which have 1 to 3, preferably 1 phenyl group, unless otherwise specified. More specifically, it includes benzyloxy, 2-phenylethoxy, 1- phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1, 1- dimethyl-2-phenylethoxy, and 2-methyl-3-phenylpropoxy groups, etc.
[0045]
Examples of a phenyl-lower alkenyl group can include the lower alkenyl groups
(preferably linear or branched alkenyl groups having 2 to 6 (more preferably 2 to 4) carbon atoms) exemplified above which have 1 to 3, preferably 1 phenyl group, unless otherwise specified. More specifically, it includes styryl, 3-phenyl-2-propenyl (commonly called cirmamyl), 4-phenyl-2-butenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 5-phenyl-3-pentenyl, 6-phenyl-5-hexenyl, 6-phenyl-4-hexenyl, 6-phenyl-3-hexenyl, 4-phenyl-l,3-butadienyl, and 6- phenyl-l,3,5-hexatrienyl groups, etc.
[0046]
Examples of a lower alkylamino-lower alkyl group can include lower alkyl groups which have 1 to 2 of the lower alkylamino groups exemplified above, unless otherwise specified. More specifically, it includes methylaminomethyl, ethylaminomethyl,
dimethylamino methyl, 1- (or 2-)dimethylaminoethyl, 1- (or 2- or 3-)dimethylaminopropyl, diisopropylaminomethyl, 1- (or 2-)diethylaminoethyl, and bis(dimethylamino)methyl groups, etc.
[0047]
Examples of a lower alkylamino-lower alkoxy group can include lower alkoxy groups which have 1 to 2 of the lower alkylamino groups exemplified above, unless otherwise specified. More specifically, it includes methylaminomethoxy, ethylaminomethoxy,
dimethylaminomethoxy, 1- (or 2-)dimethylaminoethoxy, 1- (or 2- or 3-)dimethylaminopropoxy, diisopropylaminomethoxy, 1- (or 2-)diethylaminoethoxy, and bis(dimethylamino)methoxy groups, etc.
[0048]
Examples of a dihydrobenzodioxinyl group include 2,3- dihydrobenzo[b][l,4]dioxinyl, 3,4-dihydrobenzo[c][l,2]dioxinyl, and 2,4-dihydrobenzo[d][l,3] dioxinyl groups, etc.
[0049]
Examples of an imidazolyl-lower alkyl group can include the lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 (more preferably 1 to 4) carbon atoms) exemplified above which have 1 to 3, preferably 1 imidazolyl group. More specifically, it includes 1- (or 2- or 4- or 5-)imidazolylmethyl, 1- (or 2-){ 1- (or 2- or 4- or 5-)imidazolyl} ethyl, and 1- (or 2- or 3-){ l- (or 2- or 4- or 5-)imidazolyl}propyl groups, etc.
[0050]
A dihydroindenyl group includes (1-, 2-, 4-, or 5-)-l,2-dihydroindenyl groups, etc.
[0051]
A dihydroquinolyl group includes 1,2-dihydroquinolyl, 3,4-dihydroquinolyl, 1,4- dihydroquinolyl, 4a,8a-dihydroquinolyl, 5,6-dihydroquinolyl, 7,8-dihydroquinolyl, and 5,8- dihydroquinolyl groups, etc.
[0052]
A fluorenyl group includes lH-fluorenyl, 2H-fluorenyl, 3H-fluorenyl, 4aH- fluorenyl, 5H-fluorenyl, 6H-fluorenyl, 7H-fluorenyl, 8H-fluorenyl, 8aH-fluorenyl, and 9H- fluorenyl groups, etc.
[0053]
A dihydrobenzofuryl group includes 2,3-dihydro-(2-, 3-, 4-, 5-, 6-, or 7-)benzofuryl groups, etc.
[0054]
A dihydrobenzoxazinyl group includes (2-, 3-, 4-, 5-, 6-, 7-, or 8-)3,4-dihydro-2H- benzo[b][1.4]oxazinyl and (1-, 2-, 4-, 5-, 6-, 7-, or 8-)2,4-dihydro-lH-benzo[d][1.3]oxazinyl groups, etc.
[0055]
Atetrahydrobenzodiazepinyl group includes (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-) 2,3,4,5-tetrahydro-lH-benzo[b][l ,4]diazepinyl and (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-)2,3,4,5- tetrahydro-lH-benzo[e][1.4]diazepinyl groups, etc.
[0056]
Examples of a tetrahydrobenzodiazepinyl group can include (1-, 2-, 3-, 4-, 5-, 6-,
7-, 8-, or 9-)2,3,4,5-tetrahydro-lH-benzo[b][1.4]diazepinyl and (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-)2,3,4,5-tetrahydro-lH-benzo[e][1.4]diazepinyl groups, etc.
[0057]
A dihydrobenzodioxepinyl group includes 3,4-dihydro-2H-l,5-benzodioxepinyl, 4,5-dihydro-3H-l,2-benzodioxepinyl, and 3,5-dihydro-2H-l,4-benzodioxepinyl groups, etc.
[0058]
Examples of a pyrrolidinyl group which may have an oxo group(s) include pyrrolidinyl group which may have 1 to 2 (preferably 1) oxo groups, unless otherwise specified. More specifically, it includes (1-, 2-, or 3-)pyrrolidinyl, (2- or 3-)oxo-l-pyrrolidinyl, (3-, 4-, or 5-)oxo-2-pyrrolidinyl, and (2-, 4-, or 5-)oxo-3-pyrrolidinyl groups, etc.
[0059]
Examples of an oxadiazolyl group which may have a lower alkyl group(s) can include oxadiazolyl group which may have 1 to 2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. More specifically, it includes 5-methyl-l,3,4- oxadiazolyl, 5-ethyl-l,3,4-oxadiazolyl, 5-propyl-l,3,4-oxadiazolyl, 5-butyl-l,3,4-oxadiazolyl, 5- pentyl-l,3,4-oxadiazolyl, and 5-hexyl-l,3,4-oxadiazolyl groups, etc.
[0060]
Examples of a pyrazolyl group which may have a lower alkyl group(s) can include pyrazolyl group which may have 1 to 2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. More specifically, it includes 1 -methyl- 1H- pyrazolyl, 1 -ethyl- IH-pyrazolyl, 1 -propyl- IH-pyrazolyl, 1-isopropyl-lH-pyrazolyl, 1-butyl-lH- pyrazolyl, 1-tert-butyl-lH-pyrazolyl, and 1,3-dimethyl-lH-pyrazolyl groups, etc.
[0061]
Examples of a thiazolyl group which may have a lower alkyl group(s) can include thiazolyl group which may have 1 to 2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. More specifically, it includes 2-methylthiazolyl, 2- ethylthiazolyl, 2-propylthiazolyl, 2-isopropylthiazolyl, 2-butylthiazolyl, 2-tert-butylthiazolyl, and 2,5-dimethylthiazolyl groups, etc.
[0062]
Examples of a pyrimidyl group which may have a lower alkyl group(s) can include pyrimidyl group which may have 1 to 2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. More specifically, it includes 2- methylpyrimidyl, 2-ethylpyrimidyl, 2-propylpyrimidyl, 2-isopropylpyrimidyl, 2-butylpyrimidyl, 2-tert-butylpyrimidyl, and 2,4-dimethylpyrimidyl groups, etc.
[0063]
Examples of a pyridazinyl group which may have a lower alkyl group(s) can include pyridazinyl group which may have 1 to 2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. More specifically, it includes 3- methylpyridazinyl, 3-ethylpyridazinyl, 3-propylpyridazinyl, 3-isopropylpyridazinyl, 3- butylpyridazinyl, 3-tert-butylpyridazinyl, and 3,4-dimethylpyridazinyl groups, etc.
[0064]
Examples of a pyridazinyloxy group which may have a lower alkyl group(s) can include oxy group which is substituted by pyridazinyl which may have 1 to 2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. More specifically, it includes 6-methylpyridazinyl-3-yloxy and 4-methylpyridazinyl-3-yloxy groups, etc.
[0065]
Examples of a pyrrolidinyl-lower alkoxy group can include lower alkoxy groups (preferably linear or branched alkoxy groups having 1 to 6 (more preferably 1 to 4, even more preferably 1 to 3) carbon atoms) exemplified above which have 1 to 3, preferably 1 pyrrolidinyl group, unless otherwise specified. Specific examples thereof include (1-, 2-, or 3-)
pyrrolidinylmethoxy, 2-[(l-, 2-, or 3-)pyrrolidinyl]ethoxy, 1-[(1-, 2-, or 3-)pyrrolidinyl]ethoxy, 3- [(1-, 2-, or 3-)pyrrolidinyl]propoxy, 4-[(l-, 2-, or 3-)pyrrolidinyl]butoxy, 5-[(l-, 2-, or 3-) pyrrolidinyl]pentyloxy, 6-[(l-, 2-, or 3-)pyrrolidinyl]hexyloxy, l,l-dimethyl-2-[(l-, 2-, or 3-) pyrrolidinyl]ethoxy, and 2-methyl-3-[(l-, 2-, or 3-)pyrrolidinyl]propoxy groups, etc.
[0066]
Examples of a protecting group include protecting groups routinely used, such as substituted or unsubstituted lower alkanoyl [e.g., formyl, acetyl, propionyl, and trifluoroacetyl], phthaloyl, lower alkoxycarbonyl [e.g., tertiary butoxycarbonyl and tertiary amyloxycarbonyl], substituted or unsubstituted aralkyloxycarbonyl [e.g., benzyloxycarbonyl and p- nitrobenzyloxycarbonyl], 9-fiuorenylmethoxycarbonyl, substituted or unsubstituted
arenesulfonyl [e.g., benzenesulfonyl and tosyl], nitrophenylsulfenyl, aralkyl [e.g., trityl and benzyl], and lower alkylsilyl groups [e.g., triisopropylsilyl].
[0067]
Examples of a phenyl-lower alkyl group can include the lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 (more preferably 1 to 4 carbon atoms) exemplified above which have 1 to 3, preferably 1 phenyl group, unless otherwise specified. More specifically, it includes benzyl, phenethyl, 3-phenylpropyl, benzhydryl, trityl, 4- phenylbutyl, 5-phenylpentyl, and 6-phenylhexyl groups, etc.
[0068]
Examples of a morpholinyl-lower alkyl group can include the lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 carbon atoms) exemplified above which have 1 to 2 (preferably 1) morpholinyl groups, unless otherwise specified. More specifically, it includes 2-morpholinyl methyl, 3 -morpholinyl methyl, 4-morpholinyl methyl, 2- (2-morpholinyl)ethyl, 2-(3-morpholinyl)ethyl, 2-(4-morpholinyl)ethyl), l-(2-morpholinyl)ethyl, l-(3-morpholinyl)ethyl, l-(4-morpholinyl)ethyl, 3-(2-morpholinyl)propyl, 3-(3- morpholinyl)propyl, 3-(4-morpholinyl)propyl, 4-(2-morpholinyl)butyl, 4-(3-morpholinyl)butyl, 4-(4-morpholinyl)butyl, 5-(2-morpholinyl)pentyl, 5-(3-morpholinyl)pentyl, 5-(4- morpholinyl)pentyl, 6-(2- morpholinyl)hexyl, 6-(3- mo holinyl)hexyl, 6-(4- morpholinyl)hexyl, 3-methyl-3-(2-nu^holinyl)propyl, 3-methyl-3-(3- morpholinyl)propyl, 1, l-dimethyl-2-(2- nK^holinyl)ethyl, l,l-dimethyl-2-(3- mo holinyl)ethyl, and l,l-dimethyl-2-(4- moφholinyl)ethyl groups, etc.
[0069]
Examples of a pyrrolidinyl -lower alkyl group can include the lower alkyl groups exemplified above which have 1 to 3 (preferably 1) pyrrolidinyl groups, unless otherwise specified. More specifically, it includes (1-, 2-, or 3-) pyrrolidinylmethyl, 2-[(l-, 2- or 3-) pyrrolidinyl]ethyl,.l-[(l-, 2- or 3-)] pyrrolidinyl]ethyl, 3-[(l-, 2- or 3-)] pyrrolidinyl]propyl, 4- [(1-, 2- or 3-)] pyrrolidinyl]butyl, 5-[(l-, 2- or 3-)] pyrrolidinyl]pentyl, 6-[(l-, 2- or 3-)] pyrrolidinyl]hexyl, 1, l-dimethyl-2-[(l-, 2- or 3-)] pyrrolidinyl] ethyl, and 2-methyl-3-[(l-, 2- or
3-)] pyrrolidinyl]propyl groups, etc.
[0070]
Examples of a piperidyl-lower alkyl group can include the lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 carbon atoms) exemplified above which have 1 to 2 (preferably 1) piperidyl groups, unless otherwise specified. More specifically, it includes (1-, 2-, 3- or 4-) piperidylmethyl, 2-[(l-, 2-, 3- or 4-)piperidyl]ethyl, 1- [(1-, 2-, 3- or 4-)piperidyl]ethyl, 3-[(l-, 2-, 3- or 4-)piperidyl]propyl, 4-[(l-, 2-, 3- or 4- )piperidyl]butyl, l, l-dimethyl-2-[(l-, 2-, 3- or 4-)piperidyl] ethyl, 5-[(l-, 2-, 3- or 4- )piperidyl]pentyl, 6-[(l-, 2-, 3- or 4-)piperidyl]hexyl, 1-[(1-, 2-, 3- or 4-)piperidyl]isopropyl, and 2-methyl-3-[(l-, 2-, 3- or 4-)piperidyl]propyl groups, etc.
[0071]
Examples of a lower alkoxycarbonyl group can include linear or branched alkoxy groups having preferably 1 to 6 carbon atoms and having a lower alkoxycarbonyl moiety as exemplified above. More specifically, it includes methoxycarbonyl, ethoxycarbonyl, n- propxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert- butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxycarbonyl, n- hexyloxycarbonyl, isohexyloxycarbonyl, 3 -methyl pentyloxycarbonyl groups, etc.
[0072]
Examples of a piperazinyl group which may have a lower alkyl group(s) include piperazinyl groups which may have 1 to 2 (preferably 1) lower alkyl groups, unless otherwise specified. More specifically, it includes 2-methylpiperazinyl, 4-methylpiperazinyl, 2- ethylpiperazinyl, 2-propylpiperazinyl, 2-isopropylpiperazinyl, 2-butylpiperazinyl, 2-tert butylpiperazinyl, and 2, 4-dimethylpiperazinyl groups, etc.
[0073]
Examples of a piperazinyl-lower alkyl group which may have a lower alkyl group(s) include piperazinyl groups exemplified above which may have 1 to 2 (preferably 1) lower alkyl groups, unless otherwise specified. More specifically, it includes l-(4- methylpiperazinyl)methyl, l-(2-methyl piperazinyl)methyl, 2-(l -methyl piperazinyl)ethyl, 3-(l- methyl piperazinyl)propyl, 4-(l -methyl piperazinyl)butyl groups, etc.
[0074]
Examples of a phenyl group which may have a lower alkoxy group(s) include phenyl groups exemplified above which may have 1 to 2 (preferably 1) lower alkoxy groups, unless otherwise specified. More specifically, it includes 4-methoxyphenyl, 4-ethoxyphenyl, 4- propoxyphenyl, 4-isopropylphenyl, 4-butoxyphenyl, 4-tert butoxyphenyl groups, etc. can be mentioned As a phenoxy group exemplified above which may have a halogen atom(s) include phenoxy groups which may have 1 to 4 (preferably 1) halogen atoms, unless otherwise specified. More specifically, it includes 4-fluorophenoxy, 3, 4-difluorophenoxy, 3, 4, 5-trifluorophenoxy, and 3-chloro-4,5-difluorophenoxy groups, etc.
[0075]
A tetrahydroquinolyl group includes, for example, 1, 2, 3, 4- tetrahydroquinolyl, 5, 6, 7, 8-tetrahydroquinolyl, 4a, 5, 8, 8a-tetrahydroquinolyl, 3, 4, 4a, 8a-tetrahydroquinolyl, 4a, 5, 8, 8a-tetrahydroquinolyl, and 4a, 5, 6, 7- tetrahydroquinolyl groups, etc.
[0076]
A dihydroacenaphthylenyl group includes, for example, 1, 2- dihydroacenaphthylenyl, 2a1, 3 -dihydroacenaphthylenyl, 5, 6- dihydroacenaphthylenyl, 3, 7- dihydroacenaphthylenyl, 2a1, 6-dihydroacenaphthylenyl, 1, 2a1 -dihydroacenaphthylenyl, and 6, 8a-dihydroacenaphthylenyl groups, etc. More preferably , it is 1, 2-dihydroacenaphthylenyl group can be mentioned.
[0077]
Atetrahydronaphthyl group includes, for example, 1, 2, 3, 4-tetrahydronaphthyl, 1, 2, 3, 5-tetrahydronaphthyl, and 5, 6, 7, 8-tetrahydronaphthyl, 2, 3, 7, 8-tetrahydronaphthyl groups, etc. can be mentioned.
[0078]
A dihydroquinazolinyl group includes, for example, 1, 2-dihydroquinazolinyl, 3, 4-dihydroquinazolinyl, 4a, 5-dihydroquinazolinyl, 5, 6-dihydroquinazolinyl, 6, 7- dihydroquinazolinyl, 7,8-dihydroquinazolinyl, 8,8a-dihydroquinazolinyl, and 4a, 8a- dihydroquinazolinyl groups, etc. can be mentioned.
[0079]
The heterocyclic compound represented by the general formula (1) can be produced by various methods. As an example, the heterocyclic compound represented by the general formula (1) is produced by methods represented by the reaction formulas shown below. Reaction Formula- 1
Figure imgf000035_0001
(2)
(1)
wherein 1, R2, R3, R4, X, 1, m, and n are defined as above; and Xi represents a leaving group.
[0080]
In the general formula (3), the leaving group represented by Xi can be exemplified by halogen atoms, lower alkanesulfonyloxy groups, arylsulfonyloxy groups, aralkylsulfonyloxy groups, trihalomethanesulfonyloxy groups, sulfonio groups, and
toluenesulfoxy groups. Preferable examples of the leaving groups for the present reaction include halogen atoms.
[0081]
Examples of the halogen atoms represented by Xi can include fluorine, chlorine, bromine, and iodine atoms.
[0082]
The lower alkanesulfonyloxy groups represented by Xi can be exemplified specifically by linear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms, such as methanesulfonyloxy, ethanesulfonyloxy, n-propanesulfonyloxy, isopropanesulfonyloxy, n- butanesulfonyloxy, tert-butanesulfonyloxy, n-pentanesulfonyloxy, and n-hexanesulfonyloxy groups.
[0083]
Examples of the arylsulfonyloxy groups represented by Xi can include:
phenylsulfonyloxy groups which may have 1 to 3 groups selected from the group consisting of linear or branched alkyl groups having 1 to 6 carbon atoms, linear or branched alkoxy groups having 1 to 6 carbon atoms, nitro groups, and halogen atoms as substituents on the phenyl ring; and naphthylsulfonyloxy groups. The phenylsulfonyloxy groups which may have the substituents can be exemplified specifically by phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2- nitrophenylsulfonyloxy, and 3-chlorophenylsulfonyloxy groups. The naphthylsulfonyloxy groups can be exemplified specifically by a-naphthylsulfonyloxy and β-naphthylsulfonyloxy groups.
[0084]
Examples of the aralkylsulfonyloxy groups represented by Xi can include: linear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms, which are substituted by a phenyl group which may have 1 to 3 groups selected from the group consisting of linear or branched alkyl groups having 1 to 6 carbon atoms, linear or branched alkoxy groups having 1 to 6 carbon atoms, nitro groups, and halogen atoms as substituents on the phenyl ring; and linear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms, which are substituted by a naphthyl group. The alkanesulfonyloxy groups which are substituted by the phenyl group can be exemplified specifically by benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4- phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4- nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, and 3-chlorobenzylsulfonyloxy. The alkanesulfonyloxy groups which are substituted by the naphthyl group can be exemplified specifically by a-naphthylmethylsulfonyloxy and β-naphthylmethylsulfonyloxy groups.
[0085]
The perhaloalkanesulfonyloxy groups represented by Xt can be exemplified specifically by trifluoromethanesulfonyloxy groups.
[0086]
Examples of the sulfonio groups represented by Xi can specifically include dimethylsulfonio, diethylsulfonio, dipropylsulfonio, di-(2-cyanoethyl)sulfonio, di-(2- nitroethyl)sulfonio, di-(aminoethyl)sulfonio, di-(2-methylaminoethyl)sulfonio, di-(2- dimethylaminoethyl)sulfonio, di-(2-hydroxyethyl)sulfonio, di-(3-hydroxypropyl)sulfonio, di-(2- methoxyethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2- carboxyethyl)sulfonio, and di-(2-methoxycarbonylethyl)sulfonio, and diphenylsulfonio groups.
[0087]
A compound represented by the general formula (2) and the compound represented by the general formula (3) can be reacted in the presence of a palladium catalyst in the presence or absence of a basic compound without or in an inert solvent to thereby produce the compound (1).
[0088]
Examples of the inert solvent can include, for example: water; ether solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; lower alcohol solvents such as methanol, ethanol, and isopropanol; ketone solvents such as acetone and methyl ethyl ketone; and polar solvents such as N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. These inert solvents are used alone or as a mixture of two or more of them.
[0089]
The palladium compound used in the present reaction is not particularly limited.
Examples thereof include: tetravalent palladium catalysts such as sodium hexachloropalladium (IV) acid tetrahydrate and potassium hexachloropalladium (IV) acid; divalent palladium catalysts such as palladium (II) chloride, palladium (II) bromide, palladium (II) acetate, palladium (II) acetylacetonate, dichIorobis(benzonitrile)palladium (II), dichlorobis(acetonitrile)palladium (II), dichlorobis(triphenylphosphine)palladium (II), dichlorotetraammine palladium (II),
dichloro(cycloocta-l,5-diene)palladium (II), and palladium (II) trifluoroacetate Ι, - bis(diphenylphosphino)ferrocenedichloropalladium (Il)-dichloromethane complex; and zerovalent palladium catalysts such as tris(dibenzylideneacetone)dipalladium (0),
tris(dibenzylideneacetone)dipalladium (O)-chloroform complex, and
tetrakis(triphenylphosphine)palladium (0). These palladium compounds are used alone or as a mixture of two or more of them.
[0090]
In the present reaction, the amount of the palladium catalyst used is not particularly limited and usually ranges from 0.000001 to 20 mol in terms of palladium with respect to 1 mol of the compound of the general formula (2). More preferably, the amount of the palladium compound used ranges from 0.0001 to 5 mol in terms of palladium with respect to 1 mol of the compound of the general formula (2).
[0091]
The present reaction proceeds advantageously in the presence of an appropriate ligand. For example, 2,2'-bis(diphenylphosphino)-l, -binaphthyl (BINAP), tri-o- tolylphosphine, bis(diphenylphosphino)ferrocene, triphenylphosphine, tri-t-butylphosphine, tricyclohexylphosphine, and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) can be used as the ligand for the palladium catalyst. These ligands are used alone or as a mixture of two or more of them.
[0092]
Furthermore, in the present invention, the tertiary phosphine may be prepared in a complex form in advance and added thereto. Examples of the complex can include tri-t- butylphosphonium tetrafluoroborate and tri-t-butylphosphonium tetraphenylborate.
[0093] The ratio between the palladium catalyst and the ligand used is not particularly limited. The amount of the ligand used is approximately 0.1 to 100 mol, preferably
approximately 0.5 to 15 mol, with respect to 1 mol of the palladium catalyst.
[0094]
Inorganic and organic bases known in the art can be used widely as the basic compound.
[0095]
Examples of the inorganic bases can include: alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate; alkali metals such as sodium and potassium; phosphates such as sodium phosphate and potassium phosphate; amides such as sodium amide; and alkali metal hydrides such as sodium hydride and potassium hydride.
[0096]
Examples of the organic bases can include: alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, and potassium t-butoxide; and amines such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,
trimethylamine, dimethylaniline, N-methylmorpholine, l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and l,4-diazabicyclo[2.2.2]octane (DABCO).
[0097]
These basic compounds are used alone or as a mixture of two or more of them. More preferable examples of the basic compound used in the present reaction include alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate, and sodium t-butoxide.
[0098]
The amount of the basic compound used is usually 0.5 to 10 mol, preferably 0.5 to 6 mol, with respect to 1 mol of the compound of the general formula (2).
[0099]
The ratio between the compound of the general formula (2) and the compound of the general formula (3) used in the Reaction Formula- 1 may be at least 1 mol, preferably approximately 1 to 5 mol of the latter compound with respect to 1 mol of the former compound.
[0100] The reaction can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure.
[0101]
The present reaction is usually performed under temperature conditions involving room temperature to 200°C, preferably room temperature to 150°C, and generally completed in approximately 1 to 30 hours. It is also achieved by heating at 100 to 200°C for 5 minutes to 1 hour using a microwave reactor.
[0102]
After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of interest.
[0103]
The compound represented by the general formula (2) used as a starting material in the Reaction Formula- 1 is produced from compounds known in the art, for example, by methods represented by Reaction Formulas-3 and 4 shown below. The compound represented by the general formula (3) is an easily obtainable compound known in the art or a compound easily produced by a method known in the art.
Reaction Formula-2
Figure imgf000039_0001
wherein R2, R3, R4, X, 1, m, and n are defined as above; and Rla represents a protecting group.
[0104]
Examples of the protecting group include the protecting groups exemplified above.
[0105]
The compound represented by the general formula (lb) can be produced by subjecting a compound represented by the general formula (la) to the elimination reaction of the protecting group.
[0106]
A method routinely used such as hydrolysis or hydrogenolysis can be applied to the elimination reaction of the protecting group.
[0107]
The present reaction is usually performed in a solvent routinely used that does not adversely affect the reaction. Examples of the solvent include: water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; ether solvents such as tetrahydrofuran, dioxane, diethyl ether, dimethoxy ethane, and diglyme; ester solvents such as methyl acetate and ethyl acetate; aprotic polar solvents such as acetonitrile, Ν,Ν-dimethylformamide, dimethyl sulfoxide, and N- methylpyrrolidone; halogenated hydrocarbon solvents such as methylene chloride and ethylene chloride; and other organic solvents.
[0108]
(i) Hydrolysis:
[0109]
The hydrolysis is preferably performed in the presence of a base or an acid (including Lewis acids).
[0110]
Inorganic and organic bases known in the art can be used widely as the base.
Preferable examples of the inorganic bases include alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., magnesium and calcium), and hydrides, carbonates, or bicarbonates thereof. Preferable examples of the organic bases include trialkylamines (e.g., trimethylamine and triethylamine), picoline, and l,5-diazabicyclo[4.3.0]non-5-ene.
[0111]
Organic and inorganic acids known in the art can be used widely as the acid. Preferable examples of the organic acids include: fatty acids such as formic acid, acetic acid, and propionic acid; and trihaloacetic acids such as trichloroacetic acid and trifluoroacetic acid.
Preferable examples of the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, and hydrogen bromide. Examples of the Lewis acids include boron trifluoride-ether complexes, boron tribromide, aluminum chloride, and ferric chloride.
[0112]
When trihaloacetic acid or Lewis acid is used as the acid, the reaction is preferably performed in the presence of a cation scavenger (e.g., anisole and phenol). [0113]
The amount of the base or the acid used is not particularly limited as long as it is an amount necessary for hydrolysis.
[0114]
The reaction temperature is usually 0 to 120°C, preferably room temperature to
100°C, more preferably room temperature to 80°C. The reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 12 hours, more preferably 1 to 8 hours.
[0115]
(ii) Hydrogenolysis:
Hydrogenolysis methods known in the art can be applied widely to the hydrogenolysis. Examples of such hydrogenolysis methods include chemical reduction and catalytic reduction.
[0116]
Preferable reducing agents used in chemical reduction are the combinations of hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium
borohydride, and sodium cyanoborohydride), metals (e.g., tin, zinc, and iron), or metal compounds (e.g., chromium chloride and chromium acetate) with organic or inorganic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, and hydrobromic acid).
[0117]
Preferable catalysts used in catalytic reduction are platinum catalysts (e.g., platinum plates, platinum sponge, platinum black, colloidal platinum, platinum oxide, and platinum wires), palladium catalysts (e.g., palladium sponge, palladium black, palladium oxide, palladium-carbon, palladium/barium sulfate, and palladium/barium carbonate), nickel catalysts (e.g., reduced nickel, nickel oxide, and Raney nickel), cobalt catalysts (e.g., reduced cobalt and Raney cobalt), iron catalysts (e.g., reduced iron), etc.
[0118]
When these acids used in chemical reduction are in a liquid state, they can also be used as solvents.
[0119]
The amount of the reducing agent used in chemical reduction or the catalyst used in catalytic reduction is not particularly limited and may be an amount usually used.
[0120]
The reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure.
[0121]
The reaction temperature is usually 0 to 120°C, preferably room temperature to 100°C, more preferably room temperature to 80°C. The reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 10 hours, more preferably 30 minutes to 4 hours.
[0122]
After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of the general formula (lb) of interest.
[0123]
The deprotection reaction of the protecting group is not limited to the reaction conditions described above. For example, reaction described in T.W. Green, P.G.M. Wuts, "Protective Groups in Organic Synthesis", 4th ed., or John Wiley & Sons; New York, 1991, P. 309 can also be applied to the present reaction step.
[0124]
The compound represented by the general formula (2) is a novel compound, which is useful as an intermediate for the compound represented by the general formula (1), as described above.
[0125]
The compound of the general formula (2) is produced according to, for example,
Reaction Formulas-3, 4, or 5 shown below.
[0126]
Hereinafter, each reaction formula will be described.
Reaction Formula-3
Figure imgf000043_0001
Step B (reduction)
Figure imgf000043_0002
wherein R1, R2, R3, X, I, m, and n are defined as above.
[0127]
The compound represented by the general formula (2a) is produced by subjecting a compound represented by the general formula (4) and a compound represented by the general formula (5) to cyclization reaction to form a compound represented by the general formula (6) (Step A), which is then reduced (Step B).
[0128]
Step A
The reaction between the compound represented by the general formula (4) and the compound represented by the general formula (5) can be performed in the presence or absence of a base without or in an inert solvent.
[0129]
Examples of the inert solvent can include, for example: water; ethers such as dioxane, tetrahydroiuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. [0130]
Basic compounds known in the art can be used widely. Examples thereof can include: alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metals such as sodium and potassium; other inorganic bases such as sodium amide, sodium hydride, and potassium hydride; alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; and other organic bases such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,
trimethylamine, dimethylaniline, N-methylmorpholine, l,5-diazacyclo[4.3.0]non-5-ene (DBN), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and l,4-diazabicyclo[2.2.2]octane (DABCO).
[0131]
These basic compounds are used alone or as a mixture of two or more of them.
[0132]
The amount of the basic compound used is usually 0.5 to 10 mol, preferably 0.5 to 6 mol, with respect to the compound of the general formula (4).
[0133]
The reaction can be performed by adding, if necessary, alkali metal iodide (e.g., potassium iodide and sodium iodide) as a reaction promoter.
[0134]
The ratio between the compound of the general formula (4) and the compound of the general formula (5) used in the reaction formula may be usually at least 0.5 mol, preferably approximately 0.5 to 5 mol of the latter compound with respect to 1 mol of the former compound.
[0135]
The reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure.
[0136]
The reaction is usually performed under temperature conditions involving 0°C to
200°C, preferably room temperature to 150°C, and generally completed in approximately 1 to 30 hours.
[0137]
The compound of the general formula (4) and the compound of the general formula (5) used as starting materials in the Step A are easily obtainable compounds known in the art or compounds easily produced by a method known in the art.
[0138]
Step B
The compound represented by the general formula (2a) can be produced by subjecting the compound represented by the general formula (6) to reduction reaction without or in an inert solvent.
[0139]
Examples of such reduction methods include chemical reduction and catalytic reduction.
[0140]
Examples of the inert solvent can include: water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol methyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
hexamethylphosphoric triamide, and acetonitrile.
[0141]
Preferable reducing agents used in chemical reduction are the combinations of hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, boron hydride, sodium borohydride, and sodium cyanoborohydride), metals (e.g., tin, zinc, and iron), or metal compounds (e.g., chromium chloride and chromium acetate) with organic or inorganic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, and hydrobromic acid).
[0142]
Preferable catalysts used in catalytic reduction are platinum catalysts (e.g., platinum plates, platinum sponge, platinum black, colloidal platinum, platinum oxide, and platinum wires), palladium catalysts (e.g., palladium sponge, palladium black, palladium oxide, palladium-carbon, palladium/barium sulfate, and palladium/barium carbonate), nickel catalysts (e.g., reduced nickel, nickel oxide, and Raney nickel), cobalt catalysts (e.g., reduced cobalt and Raney cobalt), iron catalysts (e.g., reduced iron), etc.
[0143]
When these acids used in chemical reduction are in a liquid state, they can also be used as solvents. [0144]
The amount of the reducing agent used in chemical reduction or the catalyst used in catalytic reduction is not particularly limited and may be an amount usually used.
[0145]
The reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure.
[0146]
The reaction temperature is usually 0 to 120°C, preferably room temperature to 100°C, more preferably room temperature to 80°C. The reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 10 hours, more preferably 30 minutes to 4 hours.
[0147]
After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of the general formula (2a) of interest.
[0148]
Reaction Formula-4
Figure imgf000046_0001
Step D (reduction)
Figure imgf000046_0002
wherein R1, R2, R3, X, 1, m, and n are defined as above.
[0149]
The compound represented by the general formula (2b) is produced by subjecting the compound represented by the general formula (4) and a compound represented by the general formula (7) to cyclization reaction to form a compound represented by the general formula (8) (Step C), which is then reduced (Step D). The reaction conditions are the same reaction conditions as in the Reaction Formula-3.
[0150]
Reaction Formula- 5
Figure imgf000047_0001
wherein R1, R2, R3, R4, 1, m, n, and X are defined as above; and Y and Z, which are the same or different, each independently represent a leaving group.
[0151]
Examples of the leaving groups represented by Y and Z in the general formula (9) include the leaving groups exemplified above.
[0152]
Step E
The compound represented by the general formula (2) can be produced by subjecting the compound represented by the general formula (4) and a compound represented by the general formula (9) to cyclization reaction. The cyclization reaction is usually performed in the presence or absence of a basic compound.
[0153]
The present reaction is usually performed in a solvent routinely used that does not adversely affect the reaction. Examples of the solvent include : water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; ether solvents such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and diglyme; ester solvents such as methyl acetate and ethyl acetate; aprotic polar solvents such as acetonitrile, Ν,Ν-dimethylformamide, dimethyl sulfoxide, and N- methylpyrrolidone; halogenated hydrocarbon solvents such as methylene chloride and ethylene chloride; and other organic solvents.
[0154]
A transition metal catalyst and a ligand may be used in this reaction. Examples of the transition metal include ruthenium chloride, dichlorotris(triphenylphosphine)ruthenium, dibromotris(triphenylphosphine)ruthenium, dihydridotetrakis(triphenylphosphine)ruthenium, (η4-cyclooctadiene)(η6-cyclooctatriene)ruthenium, dichlorotricarbonylruthenium dimers, dodecacarbonyltriruthenium, ( -pentamethylcyclopentadienyl)chloro(ri4- cyclooctatriene)ruthenium, palladium acetate, palladium chloride,
dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium,
bis(dibenzylideneacetone)palladium, rhodium chloride, chlorotris(triphenylphosphine)rhodium, hydridocarbonyltris(triphenylphosphine)rhodium, hydridotris(triphenylphosphine)rhodium, di-μ- chlorotetracarbonyldirhodium, chlorocarbonylbis(triphenylphosphine)iridium, (η5- pentamethylcyclopentadienyl)dichloroiridium dimers, nickel tetrakis(triphenylphosphine), dicobaltoctacarbonyl, and (rj5-cyclopentadienyl)dicarbonylcobalt.
[0155]
Examples of the ligand include: unidentate phosphine ligands typified by trimethylphosphine, triethylphosphine, tri-n-propylphosphine, tri-i-propylphosphine, tri-n- butylphosphine, tri-t-butylphosphine, tricyclohexylphosphine, triphenylphosphine, and tri(o- tolyl)phosphine; bidentate phosphine ligands typified by l,2-bis(diphenylphosphino)ethane, 1,3- bis(diphenylphosphino)propane, l,4-bis(diphenylphosphino)butane, and 1,2- (diethylphosphino)ethane; and phosphite ligands typified by triethyl phosphite, tributyl phosphite, triphenyl phosphite, and tri(o-tolyl) phosphite.
[0156]
This reaction may be performed in the presence of a base. Inorganic and organic bases known in the art can be used widely as the base. Examples of the inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate), alkali metal lower alkoxides (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., sodium hydride and potassium hydride). Examples of the organic bases include trialkylamines (e.g., trimethylamine, triethylamine, and N-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N- methylmorpholine, l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When these bases are in a liquid state, they can also be used as solvents. These bases are used alone or as a mixture of two or more of them. The amount of the base used is usually 0.1 to 10 mol, preferably 0.1 to 3 mol, with respect to 1 mol of the compound of the general formula (7).
[0157]
The reaction can also be performed in the presence of a mixture of an oxidizing agent and a reducing agent.
[0158]
Examples of the oxidizing agent include manganese dioxide, chromic acid, lead tetraacetate, silver oxide, copper oxide, halogen acid, dimethyl sulfoxide (Swern oxidation), organic peroxides, and oxygen. A method such as electrode oxidation may be used.
[0159]
Examples of the reducing agent include borohydride reagents such as sodium borohydride and aluminum hydride reagents such as lithium aluminum hydride.
[0160]
The ratio between the compound of the general formula (9) and the compound of the general formula (4) used in the reaction formula is usually at least 1 mol, preferably approximately 1 to 5 mol of the former compound with respect to 1 mol of the latter compound.
[0161]
The reaction of the present invention can be performed in an atmosphere of inert gas such as nitrogen or argon under the atmospheric pressure or can be performed under increased pressure.
[0162]
The reaction temperature is not particularly limited. The reaction is usually performed under cooling, at room temperature, or under heating. The reaction is preferably performed under temperature conditions involving room temperature to 100°C, for 30 minutes to 30 hours, preferably 30 minutes to 5 hours.
[0163]
After the completion of the reaction, the reaction product can be treated by a standard method to obtain the compound of the general formula (2) of interest.
[0164]
Examples of preferable salts of the compound of the general formula (1) include pharmacologically acceptable salts, for example: metal salts such as alkali metal salts (e.g., sodium salt and potassium salt) and alkaline earth metal salts (e.g., calcium salt and magnesium salt); ammonium salt; salts of inorganic bases such as alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, and cesium carbonate), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), and alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide); salts of organic bases such as tri-(lower) alkylamine (e.g., trimethylamine, triethylamine, and N-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower) alkyl-morpholine (e.g., N- methylmorpholine), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo [5.4.0]undec-7- ene (DBU), and 1,4-diazabicyclo [2.2.2] octane (DABCO); inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and organic acid salts such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p- toluenesulfonate, and glutamate.
[0165]
Moreover, compounds in a form of a solvate (e.g., a hydrate or an ethanolate) added to the raw material or the compound of interest shown in each reaction formula are also included in each general formula. Preferable examples of the solvate include hydrates.
[0166]
Each compound of interest obtained according to each of the reaction formulas can be isolated and purified from the reaction mixture, for example, by separating, after cooling, the reaction mixture into a crude reaction product by isolation procedures such as filtration, concentration, and extraction and subjecting the crude reaction product to usual purification procedures such as column chromatography and recrystallization.
[0167]
The compound represented by the general formula (1) of the present invention also encompasses isomers such as geometric isomers, stereoisomers, and optical isomers, of course.
[0168]
Various isomers can be isolated by a standard method using difference in physicochemical properties among the isomers. For example, racemic compounds can be converted to sterically pure isomers by a general optical resolution method [e.g., method involving conversion to diastereomeric salts with a general optically active acid (tartaric acid, etc.) and subsequent optical resolution]. Diastereomeric mixtures can be separated by, for example, fractional crystallization or chromatography. Optically active compounds can also be produced using appropriate optically active starting materials.
[0169]
The present invention also encompasses isotope-labeled compounds which are the same as the compound represented by the general formula (1) except that one or more atom(s) is substituted by one or more atoms(s) having a particular atomic mass or mass number.
Examples of the isotope that can be incorporated in the compound of the present invention include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine isotopes such as 2H, 3H, 13C, 14C, 15N, 180, 170, 18F, and 36C1. These particular isotope-labeled compounds of the present invention containing any of the isotopes and/or other isotopes of other atoms, for example, radioisotope (e.g., 3H and 14C)-incorporated compounds, are useful in assay for the distribution of drugs and/or substrates in tissues. Tritiated (i.e., 3H) and carbon-14 (i.e., I4C) isotopes are particularly preferable because of their easy preparation and detectability.
Furthermore, substitution by heavier isotopes such as heavy hydrogen (i.e., 2H) can be expected to bring about particular therapeutic advantages attributed to improved metabolic stability, for example, increased in-vivo half-life, or reduced necessary doses. The isotope-labeled compounds of the present invention can be prepared generally by substituting an unlabeled reagent by an easily obtainable isotope-labeled reagent by a method disclosed in the reaction formulas and/or Examples below.
[0170]
A pharmaceutical preparation comprising the compound of the present invention as an active ingredient will be described.
[0171]
The pharmaceutical preparation is obtained by making the compound of the present invention into usual dosage forms of pharmaceutical preparations and prepared using a diluent and/or an excipient usually used, such as fillers, extenders, binders, humectants, disintegrants, surfactants, and lubricants.
[0172]
Such a pharmaceutical preparation can be selected from among various forms according to a therapeutic purpose. Typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions, suspensions, etc.).
[0173] Carries known in the art for use for forming a tablet form can be used widely Examples thereof include: excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions,
carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinyl pyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cacao butter, and hydrogenated oil; absorption promoters such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol.
[0174]
Furthermore, the tablets can be coated, if necessary, with a usual coating material to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film- coated tablets, and bilayer or multilayer tablets.
[0175]
Carries known in the art for use for forming a pill form can be used widely.
Examples thereof include: excipients such as glucose, lactose, starch, cacao butter, hydrogenated plant oil, kaolin, and talc; binders such as gum arabic powder, powdered tragacanth, gelatin, and ethanol; and disintegrants such as laminaran and agar.
[0176]
Carries known in the art for use for forming a suppository form can be used widely. Examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, and semisynthetic glyceride.
[0177]
When the compound represented by the general formula (1) is prepared as injections, solutions, emulsions, and suspensions are preferably sterile and isotonic with blood. Diluents known in the art for use for forming forms of these solutions, emulsions, and
suspensions can be used widely. Examples thereof include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, the pharmaceutical preparation may contain common salt, glucose, or glycerin in an amount sufficient for preparing an isotonic solution and may contain usual solubilizers, buffers, soothing agents, and the like, and if necessary, coloring agents, preservatives, perfumes, flavoring agents, sweetening agents, and the like, and/or other drugs.
[0178]
The amount of the compound of the present invention contained in the pharmaceutical preparation is not particularly limited and can be selected appropriately from within a wide range. The compound of the present invention is usually contained in an amount of preferably approximately 1 to 70% by weight in the pharmaceutical preparation.
[0179]
A method for administering the pharmaceutical preparation according to the present invention is not particularly limited. The pharmaceutical preparation is administered by a method according to various dosage forms, the age, sex, and disease state of a patient, and other conditions. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered. Moreover, injections can be administered through an intravenous route alone or as a mixture with a usual replacement fluid such as glucose or amino acid or can be administered alone through intramuscular, intradermal, hypodermic, or intraperitoneal route, if necessary. Suppositories are rectally administered.
[0180]
The dose of the pharmaceutical preparation may be selected appropriately according to use, the age, sex, and disease state of a patient, and other conditions. The pharmaceutical preparation is usually administered once or several times a day at a daily dose of approximately 0.001 to 100 mg, preferably approximately 0.001 to 50 mg, per kg of body weight.
[0181]
The dose varies depending on various conditions. Thus, in some cases, a dose smaller than this range suffices. In other cases, a dose exceeding this range is required.
[0182]
A heterocyclic compound of the present invention has reuptake inhibitory effects on 1, 2, or 3 monoamines (serotonin, norepinephrine, and dopamine).
[0183]
The heterocyclic compound of the present invention has remarkably strong uptake inhibitory activity in in-vitro or ex-vivo tests on any one, any two, or all of the 3 monoamines, compared with existing compounds having monoamine uptake inhibitory activity. Moreover, the heterocyclic compound of the present invention exhibits remarkably strong activity in brain microdialysis study against increase in any one, any two, or all of the 3 monoamines, compared with existing compounds having monoamine uptake inhibitory activity. [0184]
The heterocyclic compound of the present invention has a wide therapeutic spectrum, compared with antidepressants known in the art.
[0185]
The heterocyclic compound of the present invention exerts sufficient therapeutic effects even in short-term administration.
[0186]
The heterocyclic compound of the present invention has excellent bioavailability, weak inhibitory activity on metabolic enzymes in the liver, few side effects, and excellent safety.
[0187]
The heterocyclic compound of the present invention is excellent in transfer into the brain.
[0188]
The heterocyclic compound of the present invention also exerts strong activity in a mouse forced swimming test used in depression screening. Moreover, the heterocyclic compound of the present invention also exerts strong activity in a rat forced swimming test used in depression screening. Moreover, the heterocyclic compound of the present invention also exerts strong activity in a reserpine-induced hypothermia test used in depression screening.
[0189]
The heterocyclic compound of the present invention exerts strong activity in a marble burying behavior test of anxiety or stress disease model mice and in fear-conditioned stress models.
[0190]
The heterocyclic compound of the present invention has reuptake inhibitory effects on 1, 2, or 3 monoamines (serotonin, norepinephrine, and dopamine) and is therefore effective for treating various disorders associated with the reduced neurotransmission of serotonin, norepinephrine, or dopamine.
[0191]
Such disorders include depression (e.g.: major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymic disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; hypomelancholia; recurrent brief depressive disorder; refractory depression/chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; depression caused by various physical diseases such as Cushing syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactorrhea syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, brain infarct, brain hemorrhage, subarachnoid hemorrhage, diabetes mellitus, virus infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, and cancer, etc.; presenile depression; senile depression; depression in children and adolescents; depression induced by drugs such as interferon, etc.); depression status caused by adjustment disorder, anxiety caused by adjustment disorder, anxiety caused by various diseases [e.g.. nerve disorders (head injury, brain infection, and inner ear impairment); cardiovascular disorders (cardiac failure and arrhythmia); endocrine disorders (hyperadrenalism and hyperthyroidism); and respiratory disorders (asthma and chronic obstructive pulmonary disease)], generalized anxiety disorder, phobia (e.g., agoraphobia, social fear, simple phobia, social phobia, social anxiety disorder, ereuthrophobia, anthrophobia, acrophobia, odontophobia, trypanophobia, specific phobia, simple phobia, animal phobia, claustrophobia, nyctophobia and phobic anxiety), obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, acute stress syndrome, hypochondriasis disorder, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependence (e.g., addition to alcohol, cocaine, heroin, phenobarbital, nicotine, and benzodiazepines), pain (e.g., chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic cervical syndrome, spinal cord injury (SCI) pain, trigeminal neuralgia, diabetic neuropathy), fibromyalgia (FMS), Alzheimer's disease, memory deficit (e.g., dementia, amnestic disorder, and age-related cognitive decline (ARCD)), Parkinson's disease (e.g., non-motor/ psychotic symptoms, dementia in Parkinson disease, neuroleptic-induced Parkinson's syndrome, and tardive dyskinesia), restless leg diseases, endocrine disorders (e.g., hyperprolactinemia), vasospasm (particularly, in the cerebral vasculature), cerebellar ataxia, gastrointestinal disorders (which encompass changes in secretion and motility), negative syndromes of schizophrenia, premenstrual syndrome, stress urinary incontinence, Tourette's Disorder, attention deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, impulse control disorder, trichotillomania, kleptomania, gambling disorder, cluster headache, migraine, chronic
paroxysmal hemicrania, chronic fatigue syndrome, precocious ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome and headache (associated with angiopathy).
Examples
[0192]
Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, and Pharmacological Tests. The chemical structures of racemic bodies and optically active forms are indicated, for example, as shown below.
Racemic body
Relative confi uration
Figure imgf000056_0001
Optically active form
Absolute confi uration
Figure imgf000056_0002
[0193]
Reference Example 1
Production of cis-3,3-dimethyloctahydrocyclopentapyrazin-2-one
Relative configuration
Figure imgf000056_0003
90% acetone cyanohydrin (9.79 g, 104 mmol) was added to an aqueous (100 mL) solution of cis-cyclopentane-l,2-diamine (9.88 g, 98.6 mmol) at room temperature, and the mixture was stirred under reflux for 16 hours. The solvent was removed from the reaction mixture under reduced pressure, followed by azeotropy with ethanol. The obtained residue was purified by silica gel column chromatography (methylene chloride/methanol=l/10) to obtain cis- 3,3-dimethyloctahydrocyclopentapyrazin-2-one (5.00 g, 30%) in a white powder form.
1H-NMR(CDCl3)5ppm : 1.20(1 H,brs),1.34(3 H,s),1.39(3 H,s), 1.40-2.20(6 H,m),3.50-3.70(2 H,m),5.89(l H,brs).
[0194]
Compounds of Reference Examples 2 to 12 shown below were produced in the same way as in Reference Example 1 using appropriate starting materials.
[0195]
Reference Example 2
Trans-3 , 3 -dimethyloctahydrocyclopentapyrazin-2-one
Relative configuration
Figure imgf000057_0001
1H-NMR(CDCl3)5ppm . 1.26-1.55(9 H,m),l .75-2.00(4 H,m),2.85-3.02(1 H,m),3.05-3.20(1
H,m),6.02(l H,brs).
[0196]
Reference Example 3
Cis-3,3-dimethylhexahydrofuro[3,4-b]pyrazin-2-one
Relative configuration
Figure imgf000057_0002
1H-NMR(CDCl3)6ppm : 1.37(3H,s),1.40(3H,s), 1.50-1.85(lH,br),3.73-4.10(6H,m),6.02-
6.22(lH,br).
[0197]
Reference Example 4
Trans-3,3-dimethylhexahydrofliro[3,4-b]pyrazin-2-one
Relative configuration
Figure imgf000057_0003
1H- MR(CDCl3)5ppm : 1.38-1.43 (IH, br), 1.44 (3H, s), 1.47 (3H, s), 3.38-3.52 (IH, m), 3.52-
3.65 (3H, m), 4.00-4.14 (2H, m), 6.28-6.45 (IH, br).
[0198]
Reference Example 5
(4aS,8aS)-3,3-dimethyloctahydroquinoxalin-2-one Absolute configuration
Figure imgf000058_0001
1H-NMR(CDCl3)5ppm : 1.14-1.37 (6H, m), 1.38 (3H, s), 1.42 (3H, s), 1.69 (IH, brs), 1.74-1.84 (2H, m), 2.57-2.65 (IH, m), 2.96-3.04 (IH, m), 5.61(lH,s)
[0199]
Reference Example 6
(4aR, 8aR)-3 , 3 -dimethyloctahydroquinoxalin-2-one
Absolute configuration
Figure imgf000058_0002
1H- MR(CDCl3)6ppm : 1.14-1.37 (6H, m), 1.38 (3H, s), 1.42 (3H, s), 1.63 (IH, brs), 1.73-1.83
(2H, m), 2.57-2.66 (IH, m), 2.95-3.04 (IH, m), 5.55 (lH,s)
[0200]
Reference Example 7
Trans-3 , 3 -diethy loctahydroquinoxalin-2-one
Rel ive configuration
Figure imgf000058_0003
1H-NMR(CDCl3)5ppm : 0.92 (3H, t, J = 7.5 Hz), 0.93 (3H ,t, J = 7.3 Hz), 1.13-1.49 (7H, m),
1.60-1.99 (6H, m), 2.55-2.60 (IH, m), 2.91-3.00 (IH, m), 5.69(1H, brs)
[0201]
Reference Example 8
Trans-octahydro- 1 'H-spiro[cyclobutane- 1 ,2'-quinoxalin]-3'-one
Relative configuration
Figure imgf000058_0004
1H-NMR(CDCl3)5ppm : 1.14-1.46 (4H, m), 1.70-2.17 (9H, m), 2.43-2.52 (IH, m), 2.55-2.66 (IH, m), 2.78-2.88 (IH, m), 2.97-3.06 (IH, m), 5.65 (IH, brs)
[0202]
Reference Example 9
Cis-octahydro-rH-spiro[cyclobutane-l,2'-quinoxalin]-3'-one
Relative configuration
Figure imgf000059_0001
1H-NMR(CDCl3)5ppm : 1.1-1.3 ( IH, m ), 1.35-2.15 ( 12H, m ), 2.5-2.6 ( IH, m ), 2.75-2.85 ( lH, m ), 3.15-3.3 ( 2H, m ), 5.65( lH, br ).
[0203]
Reference Example 10
Trans-octahydro- 1 Ή-spirofcyclohexane- 1 ,2'-quinoxalin]-3'-one
Rel ive configuration
Figure imgf000059_0002
1H- MR(CDCl3)5ppm : 1.18-1.88 (18H, m), 2.03-2.13 (IH, m), 2.47-2.58 (IH, m), 2.92-3.00 (IH, m), 5.59 (IH, s)
[0204]
Reference Example 11
Cis-3,3-dimethyldecahydrocycloheptapyrazin-2-one
Relativ configuration
Figure imgf000059_0003
1H-NMR(CDCl3)6ppm : 1.12-2.00 (16 H, m), 2.03-2.20 (IH, m), 3.35-3.55 (2H, m ), 5.88 (IH, brs).
[0205]
Reference Example 12
Trans-3 , 3 -dimethyl decahydrocycloheptapyrazin-2-one Relative configuration
Figure imgf000060_0001
1H-NMR(CDCl3)5ppm : 1.35 (3H, s), 1.39 (3H, s), 1.42-1.90 (11H, m), 2.73-2.85 (1H, m), 3.13-
3.26 (lH, m), 5.51 (1H, brs).
[0206]
Reference Example 13
Production of cis-4,4-dimethyloctahydrocyclopenta[b][l,4]diazepin-2-one
Relative configuration
Figure imgf000060_0002
A toluene (200 mL) suspension of cis-cyclopentane-l,2-diamine (19.7 g, 197 mmol) and 3 -methyl -2-butenoic acid (19.7 g, 197 mmol) was stirred under reflux for 24 hours under azeotropic conditions using a Dean-Stark apparatus. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and the deposited crystal was collected by filtration. The obtained crystal was washed with ether and then dried to obtain cis- 4,4-dimethyloctahydrocyclopenta[b][l,4]diazepin-2-one (8.60 g, 24%) in a light brown powder form.
1H-NMR(CDCl3)5ppm : 1.10-1.56 (10 H, m), 1.65-1.80 (1 H, m), 2.02-2.30 (3 H, m), 2.60(1 H, d, J = 12.8 Hz), 3.18-3.37 (1 H, m), 3.68-3.85 (1 H, m), 5.73(lH,brs).
[0207]
Compounds of Reference Examples 14 and 15 below were produced in the same way as in Reference Example 13 using appropriate starting materials.
[0208]
Reference Example 14
(5aS,9aS)-4,4-dimethyldecahydro[b][l,4]diazepin-2-one
Absolute configuration
Figure imgf000060_0003
1H-NMR(CDCl3)5ppm : 1.00-1.45 (11H, m), 1.63-1.83 (3H, m), 1.83-2.00 (IH, m), 2.31-2.43
(IH, m), 2.65-2.81 (2H, m), 3.00-3.16 (IH, m), 5.54-5.90 (IH, br).
[0209]
Reference Example 15
(5aR,9aR)-4,4-dimethyldecahydro[b][l,4]diazepin-2-one
Absolute confi uration
Figure imgf000061_0001
1H-NMR(CDCl3)6ppm : 1.02-1.36 (11H, m), 1.64-1.83 (3H, m), 1.83-1.97 (IH, m), 2.37 (IH, dd, J = 2.4, 13.9 Hz), 2.66-2.81 (2H, m), 3.01-3.15 (IH, m), 5.75-5.92 (IH, brs).
[0210]
Reference Example 16
Production of cis-2,2-dimethyloctahydro-lH-cyclopenta[b]pyrazine
Relative configuration
Figure imgf000061_0002
Lithium aluminum hydride (541 mg, 14.3 mmol) was added to an anhydrous dioxane (40 mL) solution of cis-3,3-dimethyloctahydrocyclopentapyrazin-2-one (2.00 g, 11.9 mmol) with stirring at room temperature, and the mixture was gradually heated and stirred for 10 minutes under reflux. The reaction mixture was cooled to ice temperature. Then, sodium sulfate decahydrate was added thereto in small portions until no hydrogen gas was generated. Then, the mixture was stirred at room temperature for 1 hour. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=l/10) to obtain cis-2,2- dimethyloctahydro-lH-cyclopenta[b]pyrazine (1.67 g, 91%) in a pale yellow oil form.
1H-NMR(CDCl3)5ppm : 1.04 (3 H, s), 1.16 (3 H, s), 1.28-2.02 (8 H, m), 2.37 (1 H, d, J = 12.9
Hz), 2.70 (1 H, d, J = 12.9 Hz), 3.00-3.15 (1 H, m), 3.15-3.32 (1 H, m).
[0211]
Compounds of Reference Examples 17 to 34 below were produced in the same way as in Reference Example 16 using appropriate starting materials.
[0212] Reference Example 17
Trans-2,2-dimethyloctahydro-lH-cyclopenta[b]pyrazine
Relative configuration
Figure imgf000062_0001
1H-NMR(CDCl3)6ppm : 1.08 (3H, s), 1.19-1.92 (HH, m), 2.15-2.30 (1H, m), 2.55-2.74 (2H, m), 2.77 (1H, d, J = 12.2 Hz).
[0213]
Reference Example 18
Cis-2,2-dimethyldecahydrocyclopenta[b][l,4]diazepine
Relative configuration
Figure imgf000062_0002
1H-NMR(CDCl3)5ppm : 1.11 (3H, s), 1.14 (3H, s), 1.15-1.45 (6H, m), 1.55-1.67 (1H, m), 1.67- 1.77 (lH, m), 1.97-2.12 (2H, m), 2.68-2.80 (1H, m), 2.98-3.11 (2H, m), 3.16-3.28 (1H, m).
[0214]
Reference Example 19
Cis-2,2-dimethyloctahydrofuro[3,4-b]pyrazine
Relative configuration
Figure imgf000062_0003
1H- MR(CDCl3)6ppm : 1.08 (3H, s), 1.18 (3H, s), 1.40-1.80 (2H, br), 2.41(1H, d, J = 13.2 Hz), 2.69 (1H, d, J = 13.2 Hz), 3.33-3.43 (1H, m), 3.43-3.55 (lH, m), 3.63-3.72 (1H, m), 3.75-3.96 (3H, m).
[0215]
Reference Example 20
Trans-2,2-dimethyloctahydrofuro[3,4-b]pyrazine Relative confi uration
Figure imgf000063_0001
1H-NMR(CDCl3)5ppm : 1.13 (3H, s), 1.30 (3H, s), 1.44-1.65 (2H, m), 2.64-2.78 (2H, m), 2.83 (1H, d, J = 12.2 Hz), 3.11-3.22 (IH, m), 3.46 (1H, dd, J = 7.3, 10.5 Hz), 3.55 (IH, dd, J = 7.4, 10.5 Hz), 3.94 (IH, t, J = 7.1 Hz), 4.00 (IH, t, J = 7.2 Hz).
[0216]
Reference Example 21
Cis-2,2-dimethyldecahydro- lH-benzo[b][ 1 ,4]diazepine
Relative configuration
Figure imgf000063_0002
1H-NMR(CDCl3)6ppm : 1.08 (3H, s), 1.13 (3H, s), 1.18-1.84 (12H, m), 2.65-2.93 (3H, m), 3.14-
3.22 (IH, m).
[0217]
Reference Example 22
(5aS,9aS)-2,2-dimethyldecahydro-lH-benzo[b][l,4]diazepine
Absolute configuration
Figure imgf000063_0003
1H-NMR(CDCl3)6ppm : 1.00-1.35 (11H, m), 1.50-1.85 (7H, m), 2.20-2.31 (IH, m), 2.31-2.43
(lH,m), 2.79-2.90 (IH, m), 2.90-3.04 (IH, m).
[0218]
Reference Example 23
(5aR,9aR)-2,2-dimethyldecahydro-lH-benzo[b][l,4]diazepine Absolute configuration
Figure imgf000064_0001
^NMRtCDC^Sppm : 1.00-1.35 (11H, m), 1.50-1.85 (7H, m), 2.20-2.31 (IH, m), 2.31-2.43
(IH, m), 2.79-2.90 (IH, m), 2.90-3.04 (IH, m).
[0219]
Reference Example 24
Cis-2,2-dimethyldecahydroquinoxaline
Relative configuration
Figure imgf000064_0002
1H- MR(CDCl3)5ppm : 1.06 (3H, s), 1.19 (3H, s), 1.20-1.40 (5H, m), 1.53-1.60 (3H, m), 1.70- 1.77 (IH, m), 1.92-2.15 (IH, m), 2.36 (IH, d, J = 12.7 Hz), 2.66-2.72 (IH, m), 2.72 (IH, d, J = 12.7 Hz), 3.16-3.28 (IH, m).
[0220]
Reference Example 25
Trans-2,2-dimethyldecahydroquinoxaline
Relative configuration
Figure imgf000064_0003
1H-NMR(CDCl3)5ppm : 1.05 (3H, s), 1.08-1.74 (10H, m), 1.23 (3H, s), 2.02-2.12 (IH, m), 2.40- 2.50 (IH, m), 2.60 (IH, d, J = 12.1 Hz), 2.73 (IH, d, J = 12.1 Hz).
[0221]
Reference Example 26
(4aS,8aS)-2,2-dimethyldecahydroquinoxaline
Absolute configuration
Figure imgf000064_0004
1H-NMR(CDCl3)5ppm : 1.01-1.43 (6H, m), 1.05 (3H, s), 1.23 (3H, s), 1.58-1.63 (IH, m), 1.68- 1.74 (3H, m), 2.03-2.19 (IH, m), 2.40-2.49 (IH, m), 2.60 (IH, d, J = 12.1 Hz), 2.73 (IH, d, J = 12.1 Hz).
[0222]
Reference Example 27
(4aR,8aR)-2,2-dimethyldecahydroquinoxaline
Absolute configuration
Figure imgf000065_0001
1H- MR(CDCl3)5ppm : 1.05 (3H, s), 1.09-1.56 (6H, m), 1.23 (3H, s), 1.58-1.63 (IH, m), 1.66- 1.75 (3H, m), 2.03-2.12 (IH, m), 2.41-2.50 (IH, m), 2.61 (IH, d, J = 12.1 Hz), 2.75 (IH, d, J - 12.1 Hz).
[0223]
Reference Example 28
Trans-2,2-diethyldecahydroquinoxaline
Relative configuration
Figure imgf000065_0002
lH-NMR(CDCl3)6ppm : 0.79 (3H, t, J = 7.5 Hz), 0.81 (3H, t, J = 7.5 Hz), 0.86-1.02 (IH, m), 1.08-1.40 (8H, m), 1.47-1.60 (2H, m), 1.67-1.87 (3H, m), 2.06-2.15 (IH, m), 2.33-2.42 (IH, 2.57 (IH, d, J = 12.1 Hz), 2.81 (IH, d, J = 12.1 Hz).
[0224]
Reference Example 29
Trans-octahydro- 1 Ή-spirofcyclobutane- 1 ,2'-quinoxaline]
Relative configuration
Figure imgf000065_0003
MS (M-r-l) 181
Reference Example 30 Cis-octahydro- 1 'H-spiro[cyclobutane- 1 ,2'-quinoxaline]
Relative confi uration
Figure imgf000066_0001
MS (M+1) 181 [0226]
Reference Example 31
Trans-octahydro- 1 'H-spiro[cyclopentane- 1 ,2'-quinoxaline]
Relative confi uration
Figure imgf000066_0002
1H-NMR(CDCl3)5ppm : 1.10-1.97 (18H, m), 2.10-2.21 (IH, m), 2.29-2.38 (IH, m), 2.71 (IH, d, J = 12.2 Hz), 2.76 (IH, d, J = 12.2 Hz).
[0227]
Reference Example 32
Trans-octahydro- 1 Ή-spirofcyclohexane- 1 ,2'-quinoxaline]
Figure imgf000066_0003
1H-NMR(CDCl3)5ppm : 1.12-1.76 (20H, m), 2.12-2.20 (IH, m), 2.44-2.53 (IH, m), 2.55 (IH, d, J = 12.2 Hz), 2.98 (IH, d, J = 12.2 Hz).
[0228]
Reference Example 33
Cis-2,2-dimethyldecahydro-lH-cyclohepta[b]pyrazine Relative configuration
Figure imgf000067_0001
1H-NMR(CDCl3)5ppm : 1.00-2.02 (18H, m), 2.42 (1H, d, J
Hz), 2.75-2.86 (1H, m), 3.13-3.25 (1H, m).
[0229]
Reference Example 34
Trans-2,2-dimethyldecahydro-lH-cyclohepta[b]pyrazine
Figure imgf000067_0002
1H-N R(CDCl3)6ppm : 1.05 (3H, s), 1.21 (3H, s), 1.23-1.80 (12H, m), 2.09-2.20 (1H, m), 2.46-
2.60 (2H, m), 2.68 (1H, d, J = 11.8 Hz).
[0230]
Reference Example 35
Production of (2RS,4aSR,8aSR)-2-ethyldecahydroquinoxaline
Relative confi uration
Figure imgf000067_0003
Dichloro(pentamethylcyclopentadienyl)iridium (III) dimer (70 mg, 0.090 mmol) and sodium bicarbonate (73 mg, 0.87 mmol) were added to an aqueous (20 mL) solution of trans-cyclohexane-l,2-diamine (2.00 g, 17.5 mmol) and (±)-l,2-butanediol (1.69 mL, 18.4 mmol) with stirring at room temperature. Degassing and argon substitution were repeated 3 times, and the mixture was then stirred for 24 hours under reflux. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (methylene chloride/methanol) to obtain (2R*,4aS*,8aS*)-2- ethyldecahydroquinoxaline (2.03 g, yield: 69%) in a yellow solid form. 1H-NMR(CDCl3)5ppm : 0.92 (3H, t, J = 7.5 Hz), 1.10-1.60 (7H, m), 1.64-1.83 (5H, m), 2.16- 2.31 (2H, m), 2.44 (IH, dd, J = 11.5, 10.4 Hz), 2.58-2.67 (1H, m), 3.02 (1H, dd, J = 11.5, 2.7 Hz).
[0231]
Reference Example 36
Production of (4aS,8aS)-l-benzyldecahydroquinoxaline
Figure imgf000068_0001
Benzaldehyde (3.05 mL, 30.0 mmol) was added to a methanol (300 mL) solution of (lS,2S)-cyclohexane-l,2-diamine (3.43 g, 30.0 mmol) with stirring at room temperature, and the mixture was stirred overnight at the same temperature. The reaction mixture was cooled to 0°C. Sodium borohydride (2.27 g, 60.0 mmol) was added thereto, and the mixture was stirred at 0°C for 2 hours. To the reaction mixture, water (30 mL) was added, and the product was extracted twice with methylene chloride (50 mL). The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to obtain (lS,2S)-N-benzylcyclohexane-l,2-diamine (cas no. 207450-11-1) (2.95 g, yield: 48%) in a pale yellow oil form.
[0232]
The obtained (lS,2S)-N-benzylcyclohexane-l,2-diamine (2.90 g, 14.2 mmol) was dissolved in methylene chloride (284 nL). To the solution, 60% sodium hydride (1.99 g, 49.7 mmol) was added with ice-cooling and stirring in a nitrogen atmosphere. After 5 minutes, (2- bromoethyl)diphenylsulfonium trifluoromethanesulfonate (6.92 g, 15.6 mmol) was added to the reaction mixture with ice-cooling and stirring, and the mixture was stirred overnight at room temperature. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added dropwise in small portions, and the product was then extracted twice with methylene chloride (100 mL). The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane) to obtain (4aS,8aS)-l- benzyldecahydroquinoxaline (2.28 g, 70%) in a light brown solid form.
1H-NMR(CDCl3)6ppm : 1.05-1.4 ( 4H, m ), 1.50 ( IH, br ), 1.6-1.9 ( 4H, m ), 2.05-2.2 ( IH, m ), 2.2-2.3 ( IH, m ), 2.4-2.5 ( IH, m ), 2.65-2.75 ( IH, m ), 2.8-2.95 ( 2H, m ), 3.14 ( IH, d, J = 13.4Hz ), 4.11 ( IH, d, J = 13.4Hz ), 7.15-7.4 ( 5H, m ).
[0233]
Compounds of Reference Examples 37 to 39 below were produced in the same way as in Reference Example 36 using appropriate starting materials.
[0234]
Reference Example 37
(4aR, 8aR)- 1 -benzyldecahydroquinoxaline
Absolute configuration
Figure imgf000069_0001
1H-NMR(CDCl3)5ppm : 1.05-1.4 ( 4H, m ), 1.50 ( IH, br ), 1.6-1.9 ( 4H, m ), 2.05-2.2 ( IH, 2.2-2.3 ( IH, m ), 2.4-2.5 ( IH, m ), 2.65-2.75 ( IH, m ), 2.8-2.95 ( 2H, m ), 3.13 ( IH, d, J = 13.4Hz ), 4.11 ( lH, d, J = 13.4Hz ), 7.15-7.4 ( 5H, m ).
[0235]
Reference Example 38
Cis-decahydroquinoxaline-l-carboxylic acid tert-butyl ester
Relative configuration
Figure imgf000069_0002
1H- MR(CDCl3)5ppm : 1.05-1.15 ( IH, m ), 1.2-1.75 ( 19H, m ), 1.75-1.85 ( IH, m ), 1.85-2.2
( IH, m ), 3.70 ( IH, br ), 4.83( IH, br ).
[0236]
Reference Example 39
Cis- 1 -benzyldecahydroquinoxaline Relative confi uration
Figure imgf000070_0001
1H-NMR(CDCl3)5ppm : 1.0-2.0 ( 10H, m ), 2.2-2.4 ( 1H, m ), 2.45-2.7 ( 2H, m ), 2.75-3.1 ( 2H, m ), 3.63 ( 2H, br ), 7.05-7.45 ( 5H, m ).
[0237]
Reference Example 40
Production of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline
Absolute confi uration
Figure imgf000070_0002
[0238]
Reference Example 41
(4aS,8aR)-2,2-dimethyldecahydroquinoxaline
Absolute configuration
Figure imgf000070_0003
(-)-dibenzoyl-L-tartaric acid monohydrate (13.8 g, 36.7 mmol) in ethanol (140 mL) was added to an ethanol (140 mL) solution of cis-2,2-dimethyldecahydroquinoxaline (13.7 g, 81.4 mmol) with stirring at room temperature. The reaction mixture was stirred for 30 minutes under reflux and cooled to room temperature, and the deposited white crystal was then collected by filtration. The obtained crystal was washed with ethanol (20 mL) and then dried to obtain a white solid <1> (13.1 g). The filtrate and washes obtained in obtaining the solid <1> were concentrated under reduced pressure. The obtained residue was dissolved in ethanol (100 mL). To the solution, an ethanol (130 mL) solution of (+)-dibenzoyl-D-tartaric acid (13.1 g, 36.6 mmol) was added with stirring at room temperature, and the deposited crystal was collected by filtration. The obtained crystal was washed with ethanol (20 mL) and then dried to obtain a light brown solid <2> (16.6 g).
[0239]
A methanol (130 mL)/water (10 mL) suspension of the solid <1> was stirred for
30 minutes under reflux. Then, the reaction mixture was cooled to room temperature, and the deposited crystal was collected by filtration. The deposited crystal was washed with methanol (10 mL) and then dried to obtain (4aR,8aS)-2,2-dimethyldecahydroquinoxaline dibenzoyl-L- tartrate (11.4 g, 21.6 mmol) in a white solid form (the absolute configuration of cis-2.2- dimethyldecahydroquinoxaline was determined by the X-ray crystallographic analysis of the white solid). This solid was dissolved in a 1 N aqueous sodium hydroxide solution (44 mL), and the product was extracted with ether (100 mL) three times and with methylene chloride (100 mL) three times. The extracted organic layers were combined, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain (4aR,8aS)-2,2- dimethyldecahydroquinoxaline (3.44 g, yield: 25%) in a white solid form.
1H- MR (CDC13) 5ppm : 1.06 ( 3H, s ), 1.20 ( 3H, s ), 1.2-1.4 ( 4H, m ), 1.45-1.95 ( 5H, m ), 1.95-2.15 ( 1H, m ), 2.36 ( 1H, d, J = 12.7Hz ), 2.65-2.75 ( 2H, m ), 3.15-3.25 ( 1H, m ).
[0240]
A methanol (130 mL)/water (10 mL) suspension of the solid <2> was stirred for 1 hour under reflux. Then, the reaction mixture was cooled to room temperature, and the deposited crystal was collected by filtration. The deposited crystal was washed with methanol (10 mL) and then dried to obtain (4aS,8aR)-2,2-dimethyldecahydroquinoxaline dibenzoyl-D- tartrate (16.0 g, 30.4 mmol) in a white solid form. This solid was dissolved in a 1 N aqueous sodium hydroxide solution (65 mL), and the product was extracted with methylene chloride (100 mL) three times. The extracted organic layers were combined, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain (4aS,8aR)-2,2- dimethyldecahydroquinoxaline (4.63 g, yield: 34%) in a light brown solid form.
1H-NMR(CDCl3)6ppm : 1.06 ( 3H, s ), 1.19 ( 3H, s ), 1.2-1.45 ( 5H, m ), 1.45-1.65 ( 3H, m ), 1.65-1.8 ( 1H, m ), 1.95-2.15 ( 1H, m ), 2.36 ( 1H, d, J = 12.7Hz ), 2.6-2.8 ( 2H, m ), 3.15-3.25 ( 1H, m ).
[0241]
Compounds of Reference Examples 42 to 45 below were produced in the same way as in Reference Examples 40 and 41 using appropriate starting materials.
[0242] Reference Example 42
(4a'R,8a'S)-octahydro- 1 'H-spiro[cyclobutane- 1 ,2'-quinoxaline]
Absolute configuration
Figure imgf000072_0001
MS (MH- l) 181
Ή-NMR (CDC13) 6ppm : 1.20-2.20 (16H, m), 2.69 (IH, d, J = 12.4 Hz), 2.72-2.82 (IH, m), 2.87-3.02 (2H, m).
[0243]
Reference Example 43
(4a'S,8a'R)-octahydro- 1 Ή-spirofcyclobutane- 1 ,2'-quinoxaline]
Absolute configuration
Figure imgf000072_0002
MS (M+ 1) 181
'H-NMR (CDCI3) 6ppm : 1.20-2.20 (16H, m), 2.68 (IH, d, J = 12.5 Hz), 2.72-2.82 (IH, m), 2.87-3.02 (2H, m).
[0244]
Reference Example 44
(4aR,8aS)-l-benzyldecahydroquinoxaline
Absolute confi uration
Figure imgf000072_0003
1H-NMR(CDCl3)5ppm : 1.0-1.25 ( IH, m ), 1.25-1.65 ( 5H, m ), 1.65-2.05 ( 3H, m ), 2.2-2.4 ( IH, m ), 2.45-2.7 ( 2H, m ), 2.75-3.1 ( 3H, m ), 3.63 ( 2H, br ), 7.15-7.4 ( 5H, m ).
[0245]
Reference Example 45
(4aS,8aR)-l-benzyldecahydroquinoxaline Absolute configuration
Figure imgf000073_0001
1H- MR(CDCl3)5ppm :' 1.05-1.25 ( 1H, m ), 1.25-1.65 ( 5H, m ), 1.65-2.05 ( 3H, m ), 2.2-2.4
( 1H, m ), 2.5-2.7 ( 2H, m ), 2.75-3.1 ( 3H, m ), 3.63 ( 2H, br ), 7.15-7.4 ( 5H, m ).
[0246]
Reference Example 46
Production of (trans-3-oxodecahydroquinoxalin-l-yl)acetic acid ethyl ester
Relative configuration
Figure imgf000073_0002
Trans-cyclohexane-l,2-diamine (3.00 g, 26.3 mmol) was diluted with ethanol (15 ml). To the solution, bromoethyl acetate (6.12 mL, 55.2 mmol) was added dropwise with ice- cooling, and the mixture was then stirred overnight at room temperature.
[0247]
To the reaction solution, water was added, and the mixture was stirred. The product was extracted with methylene chloride. The organic layer was washed with saturated saline and dried over magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (methylene chloride/methanol) to obtain (trans-3-oxodecahydroquinoxalin-l- yl)acetic acid ethyl ester (2.35 g, yield: 74.4%) in an orange particulate solid form.
1H-NMR(CDCl3)6ppm : 1.13-1.41 (4H, m), 1.28 (3H, t, J = 7.1 Hz), 1.72-1.97 (4H, m), 2.59- 2.67 (1H, m), 3.06-3.13 (1H, m), 3.35 (1H, d, J = 17.4 Hz), 3.48 (1H, d, J = 16.8 Hz), 3.52 (1H, d, J = 17.4 Hz), 3.60 (1H, d, J = 16.8 Hz), 4.17 (2H, q, J = 7.1 Hz), 6.79 (1H, brs).
[0248]
[Reference Example 47] Production of 2-(trans-decahydroquinoxalin- 1 -y l)ethanol Relative configuration
H
Figure imgf000074_0001
Lithium aluminum hydride (1.00 g, 26.4 mmol) was suspended in anhydrous dioxane (40 ml). To the suspension, an anhydrous dioxane (10 ml) solution of (trans-3- oxodecahydroquinoxalin-l-yl)acetic acid ethyl ester (2.35 g, 9.78 mmol) was added dropwise with stirring at room temperature, and the mixture was then stirred under reflux for 10 minutes. The reaction mixture was cooled on ice, and sodium sulfate decahydrate was added thereto in small portions until no gas was generated. This mixture was filtered through celite and washed with methylene chloride, and the filtrate was then concentrated under reduced pressure to obtain 2-(trans-decahydroquinoxalin-l-yl)ethanol (1.74 g, yield: 97%) in a brown oil form.
1H-NMR(CDCl3)5ppm : 0.95-1.11 (1H, m), 1.15-1.44 (3H, m), 1.68-1.80 (5H, m), 1.85-1.94 (1H, m), 2.05-2.44 (4H, m), 2.87-2.97 (3H, m), 3.04-3.16 (1H, m), 3.46-3.54 (1H, m), 3.60-3.69 (1H, m).
[0249]
Reference Example 48
Production of trans- 1 -[2-(tert-butyldimethylsilyloxy)ethyl]decahydroquinoxaline
Relative configuration
Figure imgf000074_0002
Triethylamine (4.61 mL, 33.0 mmol) and subsequently tert-butyldimethylsilyl chloride (4.27 g, 28.3 mmol) were added to a methylene chloride (40 mL) solution of 2-(trans- decahydroquinoxalin-l-yl)ethanol (1.74 g, 9.44 mmol) with ice-cooling and stirring, and the mixture was stirred Overnight at room temperature. To the reaction mixture, water (100 mL) was added to terminate the reaction. The product was extracted with methylene chloride (100 mL). The organic layer was washed with water twice and with saturated saline once, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride/methanol) to obtain trans- 1- [2-(tert-butyldimethylsilyloxy)ethyl]decahydroquinoxaline (2.00 g, yield: 71%) in a light brown oil form.
1H-NMR(CDCl3)5ppm : 0.06 (6H, s), 0.89 (9H, s), 0.98-1.36 (4H, m), 1.65-1.79 (4H, m), 1.85- 1.95 (1H, m), 2.08-2.14 (1H, m), 2.24-2.39 (1H, m), 2.45-2.61 (2H, m) ,2.79-3.03 (4H, m), 3.62- 3.80 (2H, m).
[0250]
Compounds of Reference Examples 50 and 51 below were produced in the same way as in Reference Example 1 using appropriate starting materials.
[0251]
Reference Example 50
(4a'S,8a'S)-octahydro-rH-spiro[cyclobutane-l,2'-quinoxalin]-3'-one
Absolute configuration
Figure imgf000075_0001
1H-NMR (CDC13) 5ppm : 0.99-1.38 (4H, m), 1.55-1.78 (5H, m), 1.78-1.94 (3H, m), 2.21-2.33
(2H, m), 2.48-2.59 (1H, m), 2.63 (1H, brs), 2.76-2.87 (1H, m), 7.36 (1H, s).
[0252]
Reference Example 51
(4a'R,8a'R)-octahydro- 1 'H-spiro[cyclobutane- 1 ,2'-quinoxalin]-3 -one
Figure imgf000075_0002
1H- MR (CDC13) 5ppm : 0.97-1.36 (4H, m), 1.55-1.77 (5H, m), 1.77-1.92 (3H, m), 2.20-2.32
(2H, m), 2.47-2.57 (1H, m), 2.63 (1H, brs), 2.76-2.86 (1H, m), 7.36 (1H, s).
[0253]
Compounds of Reference Examples 52 and 53 below were produced in the same way as in Reference Example 16 using appropriate starting materials.
[0254]
Reference Example 52
(4a'S,8a'S)-octahydro- 1 'H-spiro[cyclobutane- 1 ,2'-quinoxaline] Absolute configuration
Figure imgf000076_0001
Ή-NMR (CDC13) 6ppm : 1.05-1.90 (15H, m), 2.15-2.30 (3H, m), 2.69 (1H, dd, J = 1.5, 12.2 Hz), 3.01 (1H, d,
J = 12.2 Hz).
[0255]
Reference Example 53
(4a'R,8a'R)-octahydro- 1 'H-spiro[cyclobutane- 1 ,2'-quinoxaline]
Absolute configuration
Figure imgf000076_0002
Ή-NMR (CDCI3) 5ppm : 1.05-1.91 (15H, m), 2.15-2.30 (3H, m), 2.69 (1H, d, J = 12.2 Hz), 3.01 (1H, d, J =
12.2 Hz).
[0256]
Reference Example 54
Production of (4aS,8aR)-tert-butyl 4-benzyldecahydroquinoxaline-l-carboxylate
Absolute configuration
Figure imgf000076_0003
Di-tert-butyl dicarbonate (1.70 g, 7.79 mmol) was added to a MeOH (16 solution of (4aR,8aS)-l-benzyldecahydroquinoxaline (1.63 g, 7.08 mmol), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was then purified by basic silica gel column chromatography (Hex-AcOEt) to obtain (4aS,8aR)-teit-butyl 4-benzyldecahydroquinoxaline-l-carboxylate (2.38 g, yield: quantitative) in a colorless oil form. 1H-NMR (CDCI3) 6ppm : 1.26-1.66 (14H, m), 1.79-1.96 (2H, m), 2.14-2.33 (2H, m), 2.40-2.45 (1H, m), 2.66 (1H, brs), 2.86 (1H, d, J = 13.2 Hz), 3.03 (1H, brs), 3.50-4.10 (2H, br), 4.16 (1H, d, J = 13.2 Hz), 7.21- 7.36 (5H, m).
[0257]
A compound of Reference Example 55 below was produced in the same way as in Reference Example 54 using appropriate starting materials.
[0258]
Reference Example 55
(4aR,8aS)-tert-butyl 4-benzyldecahydroquinoxaline- 1 -carboxylate
Absolute configuration
Figure imgf000077_0001
Ή-NMR (CDC13) Sppm : 1.26-1.66 (14H, m), 1.79-1.96 (2H, m), 2.14-2.33 (2H, m), 2.40-2.45 (1H, m), 2.65 (1H, brs), 2.86 (1H, d, J = 13.2 Hz), 3.03 (1H, brs), 3.51-4.10 (2H, br), 4.16 (1H, d, J = 13.2 Hz), 7.21-7.36 (5H, m).
[0259]
Reference Example 56
Production process of (4aS, 8aR)-tert-butyl decahy droquinoxaline- 1 -carboxylate
Absolute configuration
Figure imgf000077_0002
Pearlman's catalyst (0.24 g) was added to an EtOH (25 ml) solution of (4aS,8aR)- tert-butyl 4-benzyldecahydroquinoxaline- 1 -carboxylate (2.4 g, 7.26 mmol). This suspension was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was filtered through celite, and the residue was washed with EtOH. Then, the filtrate was concentrated under reduced pressure to obtain (4aS, 8aR)-tert-butyl decahy droquinoxaline- 1 -carboxylate (1.67 g, yield: 96%) in a colorless oil form.
Ή-NMR (CDCI3) 5ppm : 1.16-1.53 (14H, m), 1.53-1.82 (3H, m), 1.83-2.00 (1H, m), 2.68-2.83 (1H, m), 2.85-
3.10 (3H, m), 3.65-4.06 (2H, m).
[0260]
A compound of Reference Example 57 below was produced in the same way as in Reference Example 56 using appropriate starting materials.
[0261] Reference Example 57
(4aR, 8aS)-tert-butyl decahydroquinoxaline- 1 -carboxylate
Absolute configuration
Figure imgf000078_0001
[0262]
Reference Example 58
Production process of cis tert-butyl 4-(4-chlorophenyl)decahydroquinoxaline-l -carboxylate Relative configuration
Figure imgf000078_0002
A toluene (4 ml) suspension of cis tert-butyl decahydroquinoxaline- 1 -carboxylate
(240 mg, 0.999 mmol), l-bromo-4-chlorobenzene (211 mg, 1.10 mmol), Pd(OAc)2 (11.2 mg, 0.0499 mmol), t-Bu3P.HBF4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgS04 was further added thereto, and the mixture was stirred. Insoluble matter was filtered through celite, and the celite layer was washed with AcOEt (5 mlx2). Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a white solid (87 mg, yield: 25%).
'H-NMR (CDC13) 5ppm : 1.10-1.40 (4H, m), 1.40-1.52 (10H, m), 1.63-1.71 (1H, m), 1.73-1.82 (1H, m), 2.15- 2.28 (1H, m), 2.74 (1H, dt, J = 3.6, 11.8 Hz), 2.90-2.97 (1H, m), 3.05-3.11 (1H, m), 3.27 (1H, dt, J = 3.4, 12.6 Hz), 3.77-3.86 (1H, m), 4.01-4.10 (1H, m), 7.08-7.13 (2H, m), 7.25-7.30 (2H, m).
[0263] Compounds of Reference Examples 59 to 63 below were produced in the same way as in Reference Example 35 using appropriate starting materials.
[0264]
Reference Example 59
(4aS,8aS)-decahydroquinoxaline
Absolute configuration
Figure imgf000079_0001
1H-NMR (CDC13) 6ppm : 1.12-1.58 (6H, m), 1.62-1.78 (4H, m), 2.20-2.29 (2H, m), 2.82-3.02 (4H, m).
[0265]
Reference Example 60
(4aR,8aR)-decahydroquinoxaline
Absolute configuration
Figure imgf000079_0002
1H-NMR (CDC13) 5ppm : 1.14-1.27 (2H,m ), 1.27-1.57(4H, m), 1.62-1.79 (4H, m), 2.19-2.30(2H, m), 2.83-3.03(4H, m).
[0266]
Reference Example 61
(2R,4aS,8aS)-2-methyldecahydroquinoxaline
Absolute configuration
Figure imgf000079_0003
1H-NMR (CDCI3) 5ppm :1.02 (3H, d, J = 6.3 Hz), 1.11-1.51 (6H, m), 1.62-1.79 (4H, m), 2.14- 2.22 (1H, m), 2.24-2.33 (1H, m), 2.44 (1H, dd, J = 10.2, 11.7 Hz), 2.81-2.91 (1H, m), 2.94 (1H, dd, J = 2.9, 11.7 Hz).
[0267]
Reference Example 62
(2S,4aR,8aR)-2-methyldecahydroquinoxaline Absolute configuration
Figure imgf000080_0001
1H-NMR (CDC13) 5ppm : 1.02 (3H, d, J = 6.3 Hz), 1.10-1.49 (6H, m), 1.62-1.80 (4H, m), 2.14- 2.22 (1H, m), 2.24-2.33 (1H, m), 2.44 (1H, dd, J = 10.3, 11.7 Hz), 2.80-2.91 (1H, m), 2.94 (1H, dd, J = 2.9, 11.7 Hz).
[0268]
Reference Example 63
(2R,4aS,8aS)-2-ethyldecahydroquinoxaline
Absolute configuration
Figure imgf000080_0002
1H-NMR (CDC13) 6ppm : 0.92 ( 3H, t, J = 7.5 Hz ), 1.1-1.55 ( 8H, m ), 1.6-1.8 ( 4H, m ), 2.14- 2.32 ( 2H, m ), 2.39-2.5 ( 1H, m ), 2.57-2.68 ( 1H, m ), 3.01 ( 1H, dd, J = 2.6, 11.6 Hz ).
[0269]
Example 1
Production of (4aR,8aS)-3,3-dimethyl-l-(l-(triisopropylsilyl)-lH-indol-6- yl)decahydroquinoxaline
Absolute configuration
Figure imgf000080_0003
A toluene (8 mL) suspension of (4aS,8aR)-2,2-dimethyldecahydroquinoxaline
(337 mg, 2.00 mmol), 6-bromo-l-(triisopropylsilyl)-lH-indole (846 mg, 2.40 mmol), sodium tert-butoxide (269 mg, 2.80 mmol), palladium (II) acetate (22.5 mg, 0.0902 mmol), and tri-tert- butylphosphine tetrafluoroborate (29.1 mg, 0.101 mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. The reaction mixture was cooled to room temperature. Then, water (0.5 mL) and ethyl acetate (10 mL) were added thereto, and the mixture was stirred, followed by addition of magnesium sulfate. Insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by H-silica gel column chromatography (n-hexane: ethyl acetate) to obtain colorless, amorphous (4aR,8aS)-3,3- dimethyl-l-(l-(triisopropylsilyl)-lH-indol-6-yl)decahydroquinoxaline (0.75 g, yield: 85%). 1H-NMR(CDCl3)6ppm : 1.1-1.2 ( 18H, m ), 1.21 ( 3H, s ), 1.29 ( 3H ,s ), 1.3-1.55( 5H, m ), 1.55- 1.8 ( 7H, m ), 2.79 ( 1H, d, J = 11.6Hz ), 2.91 ( 1H, d, J = 11.6Hz ), 3.45-3.6 ( 2H, m ), 6.49 ( 1H, dd, J - 0.7, 3.2Hz ), 6.82 ( 1H, dd, J = 2.0, 8.6Hz ), 6.93 ( 1H, s ), 7.08 ( 1H, d, J = 3.2Hz ), 7.45 ( 1H, d, J = 8.6Hz ).
[0270]
Example 2
Production of (4aR,8aS)-l-(lH-indol-6-yl)-3,3-dimethyldecahydroquinoxaline
Absolute confi uration
Figure imgf000081_0001
Tetra-n-butyl ammonium fluoride (1 M in THF) (3.41 mL, 3.41 mol) was added to a tetrahydrofuran (15 mL) solution of (4aR,8aS)-3,3-dimethyl-l-(l-(triisopropylsilyl)-lH- indol-6-yl)decahydroquinoxaline (0.750 g, 1.71 mmol) with stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction mixture under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (ethyl acetate hexane) to obtain a white solid. The obtained solid was recrystallized from diisopropyl ether/hexane to obtain (4aR,8aS)-l-(lH-indol-6-yl)-3,3- dimethyldecahydroquinoxaline (305 mg, yield: 63%).
1H-NMR(CDCl3)5ppm : 1.0-1.55 ( llH, m ), 1.55-1.85 ( 4H, m ), 2.79 ( 1H, d, J = 11.6Hz ), 2.94 ( 1H, d, J = 11.6Hz ), 3.45-3.55 ( 1H, m ), 3.6-3.75 ( 1H, m ), 6.35-6.5 ( 1H, m ), 6.79( 1H, s ), 6.86 ( 1H, dd, J = 2.1, 8.7Hz ), 7.03 ( 1H, dd, J = 2.7, 2.7Hz ), 7.47 ( 1H, d, J = 8.6Hz ), 7.92 ( lH, br ).
[0271]
Example 3
Production of (4aS,8aS)-l-(4-chlorophenyl)decahydroquinoxaline Absolute confi uration
Figure imgf000082_0001
1-chloroethyl chloroformate (229 ί, 2.10 mmol) was added to a methylene chloride (6.5 mL) solution of (4aS,8aS)-l-benzyl-4-(4-chlorophenyl)decahydroquinoxaline (0.650 g, 1.91 mmol) with ice-cooling and stirring. The mixture was stirred at room
temperature for 15 hours, and the reaction mixture was then concentrated under reduced pressure. The obtained residue was dissolved in methanol (6.5 mL), and this solution was stirred for 1 hour under reflux. The solvent was distilled off from the reaction mixture. To the obtained residue, acetone (5 mL) was added, and the mixture was stirred. The deposited crystal was collected by filtration. The obtained crystal was washed with acetone (1 mL) and then dried to obtain (4aS,8aS)-l-(4-chlorophenyl)decahydroquinoxaline (253 mg, yield: 53%) in a white powder form.
1H- MR( DMSO-d6 )6ppm : 0.85-1.05 ( lH, m ), 1.1-1.4 ( 2H, m ), 1.4-1.65 ( 3H, m ), 1.65-1.8 ( 1H, m ), 1.9-2.05 ( 1H, m ), 2.8-3.0 ( 2H, m ), 3.05-3.2 ( 3H, m ), 3.2-3.5 ( 1H, m ), 7.1-7.2 ( 2H, m ), 7.35-7.45 ( 2H, m ), 9.2-9.65 ( 2H, m ).
[0272]
Example 4
Production of cis-4-(benzo[b]thiophen-5-yl)- 1 ,2,2-trimethyldecahydroquinoxaline hydrochloride
Figure imgf000082_0002
A 37% aqueous formaldehyde solution (0.81 mL, 9.9 mmol) was added to a methanol (10 mL) solution of cis-l-(benzo[b]thiophen-5-yl)-3,3-dimethyldecahydroquinoxaline (298 mg, 0.992 mmol) with stirring at room temperature. After 30 minutes, sodium
cyanoborohydride (311 mg, 4.96 mmol) and acetic acid (0.30 mL) were added to the reaction solution at room temperature, and the mixture was stirred overnight. The solvent was distilled off from the reaction mixture under reduced pressure. Then, a saturated aqueous solution of sodium bicarbonate (50 mL) was added thereto, followed by extraction with ethyl acetate (50 mL) twice. The organic layer was washed with water twice and with saturated saline once, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanols 0:1) to obtain a brown oil. 4 N hydrochloric acid/ethyl acetate (0.6 mL) was added to an ethanol solution of the obtained oil with stirring at room temperature, and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain cis-4-(benzo[b]thiophen-5-yl)-l,2,2-trimethyldecahydroquinoxaline hydrochloride (258 mg, yield: 74%) in a white powder form.
1H-NMR(CDCl3)5ppm : 1.17-1.34 (IH, m), 1.37-1.74 (2H, m), 1.47 (3H, s), 1.87-2.04 (IH, m),
I.90 (3H, s), 2.20-2.30 (IH, m), 2.39-2.54 (IH, m), 2.64-2.88 (2H, m), 2.75 (3H, d, J = 4.9 Hz), 3.12 (IH, d, J = 13.2 Hz), 3.69-3.74 (IH, m), 3.85-3.93 (IH, m), 3.87 (Hi d, J = 13.2 Hz), 7.01 (IH, dd, J - 8.8, 2.3 Hz), 7.21-7.32 (2H, m), 7.44 (IH, d, J = 5.4 Hz), 7.75 (IH, d, J = 8.8 Hz),
II.20 (IH, brs).
[0273]
Example 5
Production of 2-(trans-4-(naphthalen-2-yl)decahydroquinoxalin-l-yl)ethanol dihydrochloride Relative confi uration
Figure imgf000083_0001
Tetra-n-butyl ammonium fluoride (1 M in THF) (2.1 mL, 2.1 mmol) was added to a THF (10 mL) solution of trans- l-(2-(tert-butyldimethylsilyloxy)ethyl)-4-(naphthalen-2- yl)decahydroquinoxaline (820 mg, 1.93 mmol) with stirring at room temperature, and the mixture was stirred overnight. To the reaction mixture, ethyl acetate was added, and the resultant mixture was washed with water twice and with saturated saline once, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride :methanol=10: 1) to obtain a colorless, amorphous solid (534 mg). A 319 mg aliquot of the obtained solid was dissolved in ethanol. To the solution, 4 N hydrochloric acid/ethyl acetate (1.0 mL) was added with stirring at room temperature, and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain 2-(trans-4- (naphthalen-2-yl)decahydroquinoxalin-l-yl)ethanol dihydrochloride (365 mg, yield: 49%) in a white powder form.
1H-NMR(CDCl3)6ppm : 1.23-1.76 (4H, m), 1.86-2.08 (3H, m) ,2.43-2.48 (IH, m), 3.18-3.25 (IH, m), 3.72-3.77 (2H, m), 3.93-3.98 (IH, m), 3.93-4.78 (IH, br), 4.08-4.20 (2H, m), 4.39-4.55 (IH, m), 4.57-4.78 (2H, m), 4.97-5.06 (IH, m), 7.61-7.68 (3H, m), 7.81-8.07 (3H, m), 8.17-8.69 (IH, br), 12.73 (IH, brs), 14.91 (IH, brs).
[0274]
Example 77
Production of (4aS,8aR)-l-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline
Absolute configuration
Figure imgf000084_0001
A toluene (4 ml) suspension of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 4-bromo-7-fluorobenzofuran (258 mg, 1.20 mmol), Pd(OAc)2 (11.2 mg, 0.0499 mmol), t-Bu3RHBF4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 4 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgS04 was further added thereto, and the mixture was stirred. Insoluble matter was filtered, and the residue was washed with AcOEt (5 mlx2). Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex- AcOEt) to obtain a colorless oil (167 mg). This oil was crystallized from hexane (1 mL) to obtain (4aS,8aR)-l-(7-fluorobenzofuran-4-yl)-3,3- dimethyldecahydroquinoxaline (107 mg, yield: 35%) in a white powder form.
1H- MR ( CDC13 ) 6ppm : 1.0-1.45 ( llH, m ), 1.6-1.8 ( 3H, m ), 1.8-1.95 ( IH, m ), 2.70 ( IH, d, J = 11.3Hz ), 3.04 ( IH, d, J = 11.3Hz ), 3.50 ( 1H, ddd, J = 3.8, 3.8, 12.1Hz ), 3.55-3.65 ( IH, m ), 6.47 ( 1H, dd, J = 3.4, 8.6Hz ), 6.84 ( 1H, dd, J = 2.5, 2.5Hz ), 6.89 ( IH, dd, J = 8.6, 10.4Hz ), 7.60 ( IH, d, J = 2.2Hz ).
[0275]
Example 106
Production of (4aS,8aR)-l-(4-chlorophenyl)-3,3-dimethyldecahydroquinoxaline hydrochloride Absolute configuration
Figure imgf000085_0001
Atoluene (10 ml) suspension of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline
(252 mg, 1.50 mmol), l-bromo-4-chlorobenzene (345 mg, 1.80 mmol), Pd(OAc)2 (16.8 mg, 0.0748 mmol), t-Bu3P.HBF4 (21.8 mg, 0.0751 mmol), and NaOt-Bu (202 mg, 2.10 mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgS04 was further added thereto, and the mixture was stirred. Then, insoluble matter was filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (Hex- AcOEt). The obtained oil was dissolved in 1 N HCl-EtOH (3 mL), and the solvent was distilled off under reduced pressure. The deposited crystal was recrystallized from ethanol/acetone to obtain (4aS,8aR)-l-(4-chlorophenyl)-3,3-dimethyldecahydroquinoxaline hydrochloride (262 mg, yield: 55%) in a white powder form.
1H-NMR ( DMSO-d6 ) 5ppm : 1.2-1.45 ( 6H, m ), 1.51 ( 3H, s ), 1.6-2.1 ( 5H, m ), 2.93 ( IH, d, J = 13.6Hz ), 3.40 ( IH, d, J = 13.8Hz ), 3.65-3.85 ( IH, m ), 3.9-4.1 ( IH, m ), 6.8-7.05 ( 2H, m ), 7.1-7.35 ( 2H, m ), 8.14 ( IH, br ), 9.77 ( IH, br ).
[0276]
Example 112
Production of (4aS, 8aR)- 1 -(3 -chloro-4-fluoropheny l)-3 , 3 -dimethy ldecahydroquinoxaline hydrochloride bsolute configuration
Figure imgf000086_0001
A toluene (10 ml) suspension of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline
(168 mg, 0.998 mmol), 4-bromo-2-chloro-l-fluorobenzene (251 mg, 1.20 mmol), Pd(OAc)2 (11.2 mg, 0.0500 mmol), t-Bu3P.HBF4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgS04 was further added thereto, and the mixture was stirred. Then, insoluble matter was filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (Hex- AcOEt). The obtained oil was dissolved in 1 N HCl-EtOH (3 mL), and ethanol was distilled off under reduced pressure. The deposited crystal was recrystallized from ethanol/acetone to obtain (4aS,8aR)-l- (3-chloro-4-fluorophenyl)-3,3-dimethyldecahydroquinoxaline hydrochloride (153 mg, yield: 46%) in a white powder form.
1H-NMR ( DMSO-de ) 6ppm : 1.15-1.45 ( 6H, m ), 1.51 ( 3H, s ), 1.6-1.9 ( 4H, m ), 1.9-2.05 ( 1H, m ), 2.94 ( 1H, d, J = 13.5Hz ), 3.3-3.45 ( lH, m ), 3.65-3.8 ( 1H, m ), 3.95-4.1 ( 1H, m ), 6.85-7.0 ( 1H, m ), 7.12 ( 1H, dd, J = 3.0, 6.2Hz ), 7.25 ( 1H, dd, J = 9.1, 9. lHz ), 8.13 ( 1H, br ), 9.86 ( 1H, br ).
[0277]
Example 150
Production of 5 -((4aR, 8aS)-3 , 3 -dimethyldecahydroquinoxalin- 1 -yl)- 1 -methyl- 1 H-indole-2- carbonitrile
Absolute configuration
Figure imgf000086_0002
A toluene (4 ml) suspension of (4aS,8aR)-2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 5-bromo-l -methyl- lH-indole-2-carbonitrile (259 mg, 1.10 mmol), Pd(OAc)2 (11.2 mg, 0.0499 mmol), t-Bu3P.HBF4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 4 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgS04 was further added thereto, and the mixture was stirred. Insoluble matter was filtered through celite, and the residue was washed with CH2Cl2:MeOH (3 : 1) (5 mLx2). Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex- AcOEt) to obtain a colorless oil. This oil was crystallized from hexane (1 mL) to obtain 5-((4aR,8aS)-3,3- dimethyldecahydroquinoxalin-l-yl)-l -methyl- lH-indole-2-carbonitrile (148 mg, yield: 46%) in a pale yellow powder form.
1H- MR ( CDC13 ) 5ppm : 0.7-2.3 ( 15H, m ), 2.7-3.2 ( 2H, m ), 3.5-3.8 ( 2H, m ), 3.85 ( 3H, s ),
6.95-7.05 ( 2H, m ), 7.15-7.3 ( 2H, m ).
[0278]
Example 237
Production of (4aS,8aS)-l-(3-chloro-4-cyanophenyl)-3,3-dimethyldecahydroquinoxaline hydrochloride
Absolute configuration
Figure imgf000087_0001
A toluene (10 ml) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline
(400 mg, 2.38 mmol), 4-bromo-2-chlorobenzonitrile (669 mg, 3.09 mmol), Pd(OAc)2 (53 mg, 0.24 mmol), t-Bu3P.HBF4 (70 mg, 0.24 mmol), and t-BuONa (320 mg, 3.33 mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled. Then, insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (CH2Cl2 MeOH) to obtain an orange amorphous solid. This amorphous solid was dissolved in ethyl acetate (5 mL). A crystal deposited by the addition of 4 N HC1/ AcOEt (0.6 mL) was collected by filtration and dried under reduced pressure to obtain (4aS,8aS)-l-(3-chloro-4-cyanophenyl)-3,3- dimethyldecahydroquinoxaline hydrochloride (304 mgm, 48%) in a pale orange powder form. 1H-NMR ( CDC13 ) 6ppm : 1.05-1.20 (1H, m), 1.23-1.44 (2H, m), 1.54-2.10 (4H, m), 1.63 (3H, s), 1.68 (3H, s), 2.35-2.40 (1H, m), 2.89 (1H, d, J = 12.7 Hz), 3.19 (2H, br), 3.34 (1H, d, J = 12.7 Hz), 7.06 (1H, dd, J = 8.4, 2.0 Hz), 7.20 (1H, d, J = 2.0 Hz), 7.61 (1H, d, J = 8.4 Hz), 9.62 (1H, brs), 9.90 (1H, br)
[0279]
Example 579
Production of (4a'R,8a'S)-4'-(7-methoxybenzofuran-4-yl)octahydro- 1 'H-spiro[cyclobutane- 1 ,2 - quinoxaline]
Absolute configuration
Figure imgf000088_0001
Atoluene (4 ml) suspension of (4a'R,8a'S)-octahydro-rH-spiro[cyclobutane-l,2'-quinoxaline] (180 mg, 0.998 mmol), 4-bromo-7-methoxybenzofuran (250 mg, 1.10 mmol), Pd(OAc)2 (11.2 mg, 0.0499 mmol), t-Bu3PHBF4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 4 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgS04 was further added thereto, and the mixture was stirred. Insoluble matter was filtered, and the residue was washed with AcOEt (5 mLx2). Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex- AcOEt) to obtain a colorless amorphous solid. This solid was crystallized from hexane (1 mL) to obtain (4a'R,8a'S)-4'-(7-methoxybenzofuran-4-yl)octahydro- rH-spiro[cyclobutane-l,2'-quinoxaline] (107 mg, yield: 35%) in a white powder form.
1H-NMR ( CDC13 ) 6ppm : 0.95-1.1 ( 2H, m ), 1.3-1.4 ( 1H, m ), 1,4-2.1 ( 11H, m ), 2.25-2.4 ( 1H, m ), 3.01 ( 1H, d, J = 11.0Hz ), 3.17 ( 1H, d, J = 11.1Hz ), 3.40 ( 1H, br ), 3.45-3.5 ( 1H, m ), 3.97 ( 3H, s ), 6.58 ( 1H, d, J = 8.4Hz ), 6.70 ( 1H, d, J = 8.4Hz ), 6.80 ( IH, d, J = 2.1Hz ), 7.58 ( lH, d, J - 2.1Hz ).
[0280]
Example 580
Production of (4aS,8aR)-l-(6,7-difluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline hydrochloride Absolute configuration
Figure imgf000089_0001
A toluene (6 ml) suspension of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline (252 mg, 1.50 mmol), 4-bromo-6,7-difluorobenzofuran (384 mg, 1.65 mmol), Pd(OAc)2 (16.8 mg, 0.0748 mmol), t-Bu3P.HBF4 (21.8 mg, 0.0751 mmol), and NaOt-Bu (202 mg, 2.10 mmol) was stirred for 3 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgS04 was further added thereto, and the mixture was stirred. Then, insoluble matter was filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (Hex- AcOEt) to obtain a pale yellow oil (193 mg). This oil was dissolved in ethanol (2 mL). To the solution, 1 N HCl-EtOH (1.2 mL) was added, and the mixture was stirred. The deposited crystal was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to obtain (4aS,8aR)-l-(6,7-difluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline hydrochloride (167 mg, yield: 31%) in a white powder form.
1H-NMR ( DMSO-d6 ) 6ppm : 1.01-1.17 ( 2FL m ), 1.34-1.44 ( ILL m ), 1.48 ( 3H, s ), 1.52 ( 3H, s ), 1.59-2.07 ( 5H, m ), 3.00 ( 1H, d, J = 13.0Hz ), 3.28 ( 1H, d, J = 13.2Hz ), 3.75-3.9 ( 1H, m ), 4.0-4.15 ( 1H, m ), 6.83 ( 1H, dd, J = 5.9, 13.5Hz ), 7.36 ( 1H ,dd, J = 2.6, 2.6Hz ), 8.0-8.2 ( 2H, m ), 9.7-9.9 ( lH, m ).
[0281]
Example 581
Production of (4aS,8aS)-l-(2-cyano-l-(triisopropylsilyl)-lH-indol-5-yl) 3,3- dimethyldecahydroquinoxaline ion
Figure imgf000090_0001
A toluene (5 ml) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 5-bromo-l-(triisopropylsilyl)-lH-indole-2-carbonitrile (493 mg, 1.31 mmol), Pd(OAc)2 (13.3 mg, 0.0594 mmol), tBu3P.HBF4 (17.2 mg, 0.0594 mmol), and t-BuONa (137 mg, 1.43 mmol) was stirred at 100°C for 4 hours in a nitrogen atmosphere. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane) to obtain (4aS,8aS)-l-(2-cyano-l- (triisopropylsilyl)-lH-indol-5-yl) 3,3-dimethyldecahydroquinoxaline (430 mg, 78%) in a white amorphous solid form.
1H-NMR (CDC13) 6ppm : 0.75-1.38 (26H, m), 1.41 (3H, s), 1.54-1.77 (4H, m), 2.01 (3H, quintet, J = 7.5 Hz), 2.25-2.32 (1H, m), 2.65 (lH, d, J = 11.2 Hz), 2.75-2.85 (2H, m), 7.11 (1H, dd, J = 2.0, 9.1 Hz), 7.32 (1H, d, J = 2.0 Hz), 7.33 (1H, d, J = 0.5 Hz), 7.50 (1H, d, J = 9.1 Hz).
[0282]
Example 582
Production of (4aS,8aS)-l-(2-cyano-lH-indol-5-yl) 3,3-dimethyldecahydroquinoxaline
Absolute configuration
Figure imgf000090_0002
Tetrabutylammonium fluoride (1 M THF solution, 0.73 mL, 0.73 mmol) was added to an anhydrous tetrahydrofuran (5 mL) solution of (4aS,8aS)-l-(2-cyano-l-
(triisopropylsilyl)-lH-indol-5-yl) 3,3-dimethyldecahydroquinoxaline (170 mg, 0.366 mmol) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane=l/10-»l/l). The solvent was removed under reduced pressure. The obtained residue was recrystallized from ethyl acetate/n- hexane to obtain (4aS,8aS)-l-(2-cyano-lH-indol-5-yl) 3,3-dimethyldecahydroquinoxaline (30 mg, yield: 27%) in a white powder form.
1H-NMR (DMSO-d6) 5ppm : 0.82-1.00 (4H, m), 1.08-1.34 (6H, m), 1.42-1.67 (5H, m), 2.19- 2.27 (1H, m), 2.55 (1H, d, J = 10.9 Hz), 2.59-2.69 (2H, m), 7.11 (1H, dd, J = 1.8, 8.8 Hz), 7.26 (1H, d, J = 0.8 Hz), 7.32 (1H, d, J = 1.8 Hz), 7.36 (1H, d, J = 8.8 Hz) 12.25 (1H, brs).
[0283]
Example 583
Production of (4aS,8aR)-l-(7-chloro-2,3-dihydro-lH-inden-4-yl)-3,3- dimethyldecahydroquinoxaline
Absolute configuration
Figure imgf000091_0001
A toluene (1 mL) solution of bis(tri-tert-butylphosphine)palladium (25.6 mg,
0.0501 mmol) was added to a toluene (4 ml) suspension of (4aR,8aS)-2,2- dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 4-bromo-7-chloro-2,3-dihydro-lH-indene (255 mg, 1.10 mmol), and NaOt-Bu (135 mg, 1.40 mmol), and the mixture was stirred for 4 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgS04 was further added thereto, and the mixture was stirred. Insoluble matter was filtered through celite, and the residue was washed with AcOEt (5 mLx2). Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a white solid (167 mg). This solid was recrystallized from ethanol/water to obtain (4aS,8aR)-l-(7-chloro-2,3-dihydro-lH-inden-4- yl)-3,3-dimethyldecahydroquinoxaline (136 mg, yield: 43%) in a white powder form.
1H-NMR ( CDC13 ) 5ppm : 0.97-1.12 ( 3H, m ), 1.16 ( 3H, s ), 1.27 ( 3H, s ), 1.31-1.44 ( 2H, m ), 1.45-1.76 ( 3H, m ), 1.78-1.92 ( 1H, m ), 1.94-2.06 ( 1H, m ), 2.12-2.23 ( 1H, m ), 2.51 ( Hi d, J = 11.2Hz ), 2.85-3.05 ( 5H, m ), 3.1-3.2 ( 1H, m ), 3.45-3.55 ( 1H, m ), 6.58 ( 1H, d, J = 8.4Hz ), 7.03 ( 1H, d, J = 8.4Hz ).
[0284] Example 584
Production of (4aS, 8aS)- 1 -(6-cyanonaphthalen-2-yl)-3 ,3 -dimethyldecahydroquinoxaline dihydrochloride
Absolute configuration
Figure imgf000092_0001
A toluene (5 mL) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 6-bromo-2-naphthonitrile (303 mg, 1.31 mmol), Pd(OAc)2 (13.3 mg, 0.0594 mmol), tBu3P.HBF4 (17.2 mg, 0.0594 mmol), and t-BuONa (137 mg, 1.43 mmol) was stirred at 100°C for 4 hours. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane). The solvent was removed under reduced pressure. The obtained residue was dissolved in ethyl acetate. To this solution, 1 N hydrochloric acid-ethanol was added, and the deposited crystal was collected by filtration. The obtained crystal was dried under reduced pressure to obtain (4aS,8aS)-l-(6-cyanonaphthalen-2-yl)-3, 3 -dimethyldecahydroquinoxaline dihydrochloride (303 mg, yield: 65%) in a white powder form.
1H-NMR (DMSO-d6) 5ppm : 1.10-1.50 (6H, m), 1.56-1.90 (7H, m), 2.00-2.14 (1H, m), 3.08- 3.45 (4H, m), 4.68-5.32 (1H, br), 7.45 (1H, dd, J = 2.0, 8.9 Hz), 7.64 (1H, d, J = 1.8 Hz), 7.73 (1H, dd, J = 1.6, 8.6 Hz), 8.00 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.49 (1H, s), 9.10- 9.28 (1H, br), 10.04-10.28 (1H, br).
[0285]
Example 585
Production of (4aS,8aS)-3,3-dimethyl-l-(l-(triisopropylsilyl)-lH-pyrrolo[2,3-b]pyridin-4- yl)decahydroquinoxaline
Figure imgf000093_0001
A toluene (5 mL) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline
(200 mg, 1.19 mmol), 4-bromo-l-(triisopropylsilyl)-lH-pyrrolo[2,3-b]pyridine (462 mg, 1.31 mmol), Pd(OAc)2 (13.3 mg, 0.0594 mmol), tBu3P.HBF4 (17.2 mg, 0.0594 mmol), and t-BuONa (137 mg, 1.43 mmol) was stirred at 100°C for 4 hours in a nitrogen atmosphere. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane) to obtain (4aS,8aS)-3,3- dimethyl-l-(l-(triisopropylsilyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline (439 mg, 84%) in a white amorphous solid form.
1H-NMR (CDC13) 6ppm : 0.95-1.20 (22H, m), 1.36-1.45 (3H, m), 1.52 (3H, s), 1.65-1.92 (7H, m), 2.11-2.20 (1H, m), 2.57-2.67 (2H, m), 2.83-2.95 (1H, m), 3.26- (1H, d, J = 11.7 Hz), 6.55 (1H, d, J = 3.5 Hz), 6.63 (1H, d, J = 5.3 Hz), 7.18 (1H, d, J = 3.5 Hz), 8.12 (1H, d, J = 5.3 Hz).
[0286]
Example 586
Production of (4aS,8aS)-3,3-dimethyl-l-(lH-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline fumarate
Absolute configuration
Figure imgf000093_0002
Tetrabutylammonium fluoride (1 M THF solution, 1.95 mL, 1.95 mmol) was added to an anhydrous tetrahydrofuran (5 mL) solution of (4aS,8aS)-3,3-dimethyl-l-(l- (triisopropylsilyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline (430 mg, 0.976 nmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane=l/10-»l/l) to obtain a product (370 mg, 1.30 mmol) in an oil form. This oil was dissolved in ethanol (5 mL). To this solution, an ethanol (5 mL) solution of fumaric acid (151 mg) was added, and ethanol was removed under reduced pressure. The obtained solid was recrystallized from ethanol/ethyl acetate to obtain (4aS,8aS)-3,3- dimethyl- l-(lH-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline fumarate (246 mg, yield: 63%) in a white powder form.
1H-NMR (DMSO-de) 5ppm : 0.94-1.09 (1H, m), 1.20 (3H, s), 1.26-1.55 (7H, m), 1.68-1.78 (1H, m), 1.85-2.04 (2H, m), 2.81-2.93 (1H, m), 2.95-3.23 (3H, m), 6.36-6.42 (1H, m), 6.49 (2H, s), 6.71 (1H, d, J = 5.2 Hz), 7.32-7.38 (1H, m), 8.09 (1H, d, J = 5.2 Hz), 8.50-11.20 (1H, br), 11.59 (1H, s).
[0287]
Example 587
Production of (4aS, 8aS)- 1 -(4-(difiuoromethoxy)-3 -fluorophenyl)-3 , 3 - dimethyldecahydroquinoxaline dihydrochloride
A on
Figure imgf000094_0001
A toluene (5 mL) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 4-bromo-l-difluoromethoxy-2-fluorobenzene (315 mg, 1.31 mmol),
Pd(OAc)2 (13.3 mg, 0.0594 mmol), tBu3P.HBF4 (17.2 mg, 0.0594 mmol), and t-BuONa (137 mg, 1.43 mmol) was stirred at 100°C for 4 hours. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane). The solvent was removed under reduced pressure. The obtained residue was dissolved in ethyl acetate. To this solution, 1 N hydrochloric acid-ethanol was added, and the deposited crystal was collected by filtration. The obtained crystal was dried under reduced pressure to obtain (4aS,8aS)-l-(4-difluoromethoxy-3-fluorophenyl)-3,3- dimethyldecahydroquinoxaline dihydrochloride (193 mg, yield: 40%) in a white powder form.
1H-NMR (DMSO-d6) 6ppm : 1.01-1.39 (6H, m), 1.49-1.67 (6H, m), 1.67-1.77 (1H, m), 1.96-2.05 (1H, m), 2.81-2.95 (2H, m), 3.02 (1H, d, J = 12.5 Hz), 3.10-3.23 (1H, m), 4.30-4.80 (1H, br), 6.96-7.01 (1H, m), 7.02 (0.25H, s), 7.17 (1H, dd, J = 2.5, 12.1 Hz), 7.20 (0.5H, s), 7.33 (1H, t, J
= 8.9 Hz), 7.39 (0.25H, s), 9.04-9.21 (1H, m), 9.70-9.85 (1H, m).
[0288]
Example 1677
Production of (4aS,8aS)-3,3-dimethyl-l-(3-chloro-4-trifluoromethylphenyl)decahydroquinoxali ne dihydrochloride
n
Figure imgf000095_0001
A toluene (5 mL) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline
(200 mg, 1.19 mmol), 4-bromo-2-chloro-l-trifluoromethylbenzene (370 mg, 1.43 mmol), sodium tert-butoxide (137 mg, 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol), and tri-tert- butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) was stirred for 4 hours at 100 °C in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to obtain pale yellow oil. 1 N hydrochloric acid/ethyl acetate (5.0 mL) was added to an ethanol solution of the obtained oil with stirring at room temperature, and, after sufficient stirring, the mixed solution was concentrated under reduced pressure. The obtained oil was added with an appropriate amount of ethanol/ethyl acetate and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain (4aS,8aS)-3,3-dimethyl-l-(3-chloro-4- trifluoromethylphenyl)decahydroquinoxaline dihydrochloride (348 mg, yield: 70%) in a white powder form.
Example 1680
Production of (4aS,8aS)-l-(4-ethynylphenyl)-3,3-dimethyldecahydroquinoxaline oxalate
A on
Figure imgf000095_0002
Atetrahydrofuran (5 mL) solution of (4aS,8aS)-3,3-dimethyl-l-(4- trimethylsilylethynylphenyl)-decahydroquinoxaline (320mg, 0.940mmol) was added with 1N- tetrabutylammonium fluoride/ tetrahydrofuran solution (1.88mL) with stirring at room
temperature and stirred overnight. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by H-silica gel column chromatography (n-hexane: ethyl acetate) to obtain pale yellow oil. An ethanol solution (5 ml) of oxalic acid (84.6 mg) was added to an ethanol solution of the obtained oil with stirring at room temperature, and, after sufficient stirring, the mixed solution was concentrated under reduced pressure. The obtained oil was added with an appropriate amount of ethanol/ethyl acetate and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain (4aS,8aS)-l-ethynylphenyl-3,3-dimethyldecahydroquinoxaline oxalate (187mg, yield: 55%) in a white powder form.
Example 1687
Production of (4aS,8aS)-3,3-dimethyl-l-(3-chloro-4-cyclopropoxyphenyl)decahydroquinoxalin e dihydrochloride
A on
Figure imgf000096_0001
A toluene (5 mL) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline
(200 mg, 1.19 mmol), 4-bromo-2-chloro-l-cyclopropoxybenzene (324 mg, 1.31 mmol), sodium tert-butoxide (137 mg, 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol), and tri-tert- butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) was stirred for 4 hours at 100 °C in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to obtain pale yellow oil. 1 N hydrochloric acid/ethyl acetate (5.0 mL) was added to an ethanol solution of the obtained oil with stirring at room temperature, and, after sufficient stirring, the mixed solution was concentrated under reduced pressure. The obtained oil was added with an appropriate amount of ethanol/ethyl acetate and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain (4aS,8aS)-3,3-dimethyl-l-(3-chloro-4- cyclopropoxyphenyl)decahydroquinoxaline dihydrochloride (334 mg, yield: 69%) in a white powder form. Example 1693
Production of (4aS,8aS)-3,3-dimethyl- 1 -(3-chloro-5-fluoro-4-methoxyphenyl)decahydroquinox aline dihydrochloride
n
Figure imgf000097_0001
A toluene (5 mL) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline
(200mg, 1.19mmol), 5-bromo-l-chloro-3-fluoro-2-methoxybenzene (342mg, 1.43mmol), sodium tert-butoxide (137 mg, 1.43 mmol), palladium (Π) acetate (21.3 mg, 0.0951 mmol), and tri-tert- butylphosphine tetrafiuoroborate (27.6 mg, 0.0951 mmol) was stirred for 4 hours at 100 °C in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to obtain pale yellow oil. 1 N hydrochloric acid/ethyl acetate (5.0 mL) was added to an ethanol solution of the obtained oil with stirring at room temperature, and, after sufficient stirring, the mixed solution was concentrated under reduced pressure. The obtained oil was added with an appropriate amount of ethanol/ethyl acetate and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain (4aS,8aS)-3,3-dimethyl-l-(3-chloro-5-fiuoro-4- methoxyphenyl)decahydroquinoxaline dihydrochloride (320mg, yield: 67%) in a white powder form.
Example 1695
Production of (4aS,8aS)-l-(4-difluoromethoxy-3-difluoromethylphenyl)-3,3-dimethyldecahydr oquinoxaline dihydrochloride
Absolute configuration
Figure imgf000097_0002
A toluene (5 mL) suspension of (4aS,8aS)-2,2- dimethyldecahydroquinoxaline (200mg, 1.19mmol), 4-bromo-l-difluoromethoxy-2- difluoromethylbenzene (357mg, 1.31 mmol), sodium tert-butoxide (137 mg, 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol), and tri-tert-butylphosphine tetrafiuoroborate (27.6 mg, 0.0951 mmol) was stirred for 4 hours at 100 °C in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by NH- silica gel column chromatography (n-hexane: ethyl acetate) to obtain pale yellow oil. 1 N hydrochloric acid/ethyl acetate (5.0 mL) was added to an ethanol solution of the obtained oil with stirring at room temperature, and, after sufficient stirring, the mixed solution was concentrated under reduced pressure. The obtained oil was added with an appropriate amount of ethanol/ethyl acetate and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain (4aS,8aS)-l-(4-difluoromethoxy-3-difluoromethylphenyl-3,3-dimethyldecahydroquinoxaline dihydrochloride (281 mg, yield: 54%) in a white powder form.
Example 1696
Production of (4aS,8aS)- l-(3-chloro-4-difluoromethoxy-5-fluorophenyl)-3,3-dimethyldecahydr oquinoxaline dihydrochloride
Absolute configuration
Figure imgf000098_0001
A toluene (5 mL) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline (200mg, 1.19mmol), 5-bromo-l-chloro-2-difluoromethoxy-3-fluorobenzene (360mg, 1.31mmol), sodium tert-butoxide (137 mg, 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol), and tri-tert-butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) was stirred for 4 hours at 100 °C in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n- hexane:ethyl acetate) to obtain pale yellow oil. 1 N hydrochloric acid/ethyl acetate (5.0 mL) was added to an ethanol solution of the obtained oil with stirring at room temperature, and, after sufficient stirring, the mixed solution was concentrated under reduced pressure. The obtained oil was added with an appropriate amount of ethanol/ethyl acetate and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain (4aS,8aS)-l-(3-chloro-4-difluoromethoxy-5-fluorophenyl)-3,3- dimethyldecahydroquinoxaline dihydrochloride (120mg, yield: 23%) in a white powder form. Example 1697 Production of (4aS,8aS)-l-(4-(l, l-difluorethoxy)phenyl)-3,3-dimethyldecahydroquinoxaline di hydrochloride
Absolute configuration
Figure imgf000099_0001
A toluene (5 mL) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline (200mg, 1.19mmol), l-bromo-4-(l, l-difluoroethoxy)benzene (310mg, 1.31mmol), sodium tert- butoxide (137 mg, 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol), and tri-tert- butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) was stirred for 4 hours at 100 °C in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to obtain pale yellow oil. 1 N hydrochloric acid/ethyl acetate (5.0 mL) was added to an ethanol solution of the obtained oil with stirring at room temperature, and, after sufficient stirring, the mixed solution was concentrated under reduced pressure. The obtained oil was added with an appropriate amount of ethanol/ethyl acetate and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain (4aS,8aS)-l-(4-(l, l-difluorethoxy)phenyl)-3,3-dimethyldecahydroquinoxaline dihydrochloride(342mg, yield: 72%) in a white powder form
Example 1698
Production of (4aS,8aS)-l-(3-chloro-4-trifluoromethoxyphenyl)-3,3-dimethyldecahydroquinoxa line dihydrochloride
Absolute configuration
Figure imgf000099_0002
A toluene (5 mL) suspension of (4aS,8aS)-2,2- dimethyldecahydroquinoxaline(200mg, 1.19mmol), 4-bromo-2-chloro-l- trifluoromethoxybenzene (393 mg, 1.43 mmol), sodium tert-butoxide (137 mg, 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol), and tri-tert-butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) was stirred for 4 hours at 100 °C in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by H-silica gel column chromatography (n-hexane:ethyl acetate) to obtain pale yellow oil. 1 N hydrochloric acid/ethyl acetate (5.0 mL) was added to an ethanol solution of the obtained oil with stirring at room temperature, and, after sufficient stirring, the mixed solution was concentrated under reduced pressure. The obtained oil was added with an appropriate amount of ethanol/ethyl acetate and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain (4aS , 8aS)- 1 -(3 -chloro-4-trifluoromethoxypheny l)-3 , 3 -dimethyldecahydroquinoxaline dihydrochloride (308 mg, yield: 59%) in a white powder form.
Example 1731
Production of (4aR,8aR)-l-(4-difluoromethoxy-3-(difluoromethyl)phenyl)-3,3-dimethyldecahy droquinoxaline dihydrochloride
A ion
Figure imgf000100_0001
A toluene (5 mL) suspension of (4aR,8aR)-2,2- dimethyldecahydroquinoxaline(200mg, 1.19mmol) 4-bromo- 1 -difluoromethoxy-2- difluoromethylbenzene(357mg, 1.31mmol), sodium tert-butoxide (137 mg, 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol), and tri-tert-butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) was stirred for 4 hours at 100 °C in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane:ethyl acetate) to obtain pale yellow oil. 1 N hydrochloric acid/ethyl acetate (5.0 mL) was added to an ethanol solution of the obtained oil with stirring at room temperature, and, after sufficient stirring, the mixed solution was concentrated under reduced pressure. The obtained oil was added with an appropriate amount of ethanol/ethyl acetate and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain (4aS,8aS)-l-(4-difluoromethoxy-3-(difluoromethyl)phenyl)-3,3-dimethyldecahydroquinoxaline dihydrochloride (225 mg, yield: 44%) in a white powder form.
Example 1740 Production of (3R,4aS,8aS)-l-(3-chloro-4-difluoromethoxy-5-fluorophenyl)-3-methyldecahydr oquinoxaline oxalate
Absolute configuration
Figure imgf000101_0001
A toluene (5 mL) suspension of (2R,4aS,8aS)-2-methyldecahydroquinoxaline (300mg, 1.94mmol), 5-bromo-l-chloro-2-difluoromethoxy-3-fluorobenzene(589mg,2.14mmol), sodium tert-butoxide (137 mg, 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol), and tri-tert-butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) was stirred for 4 hours at 100 °C in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n- hexane:ethyl acetate) to obtain pale yellow oil. An ethanol solution (5 ml) of oxalic acid (61 mg) was added to an ethanol solution of the obtained oil with stirring at room temperature, and, after sufficient stirring, the mixed solution was concentrated under reduced pressure. The obtained oil was added with an appropriate amount of ethanol/ethyl acetate and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain (3R,4aS,8aS)-l-(3-chloro-4-difluoromethoxy-5- fluorophenyl)-3-methyldecahydroquinoxaline oxalate (52 mg, yield: 6%) in a white powder form. Example 1741
Production of (3R,4aS,8aS)-l-(3-fluoro-4-difluoromethoxyphenyl)-3-methyldecahydroquinoxal ine oxalate
A n
Figure imgf000101_0002
A toluene (5 mL) suspension of (2R,4aS,8aS)-2-methyldecahydroquinoxaline (300mg, 1.94mmol)> 4-bromo-2-fiuoro-l-trifiuoromethoxybenzene (554mg, 2.14mmol), sodium tert-butoxide (137 mg, 1.43 mmol), palladium (Π) acetate (21.3 mg, 0.0951 mmol), and tri-tert- butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) was stirred for 4 hours at 100 °C in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane:ethyl acetate) to obtain pale yellow oil. An ethanol solution (5 ml) of oxalic acid (67 mg) was added to an ethanol solution of the obtained oil with stirring at room temperature, and, after sufficient stirring, the mixed solution was concentrated under reduced pressure. The obtained oil was added with an appropriate amount of ethanol/ethyl acetate and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain (3R,4aS,8aS)-l-(3-fluoro-4-difluoromethoxyphenyl)-3- methyldecahydroquinoxaline oxalate (240 mg, yield. 29%) in a white powder form.
Compounds of Examples 6 to 76, 78 to 105, 107 to 111, 113 to 149, 151 to 236,
238 to 578, 588 to 1656, 1657 to 1676, 1678 to 1679, 1681 to 1686, 1688 to 1692, 1694, 1699 to 1730, 1732 to 1739, 1742 to 1750 shown in tables below were produced in the same way as in the Examples using corresponding appropriate starting materials. In these tables, for example, the produced compounds have physical properties such as a crystalline form, m.p. (melting point), salt, 1H-NMR, and MS (mass spectrum).
289] Table 1-8
Relative configuration
Figure imgf000103_0001
Example X R* 1H-NMR Salt
1H-NMR (DMSO-dB) Sppm : 1.39 (3H, s), 1.49 (3H, s), 1.56-220 <β H, m), 3.04 (1H, d, J = 13.3
Hydrochloride β -CHj- Hz), 3.61 (1H, d, J = 13.3 Hz), 3.75-3.90 (1H, m), 4.40-4.55 (1 H, m), 7.17-7.30 (2 H, m),
7.33-7.48 (2 H, m), 7.65-7.83 (3 H, m), 8.35-6.60 (1 H, brm), 9.70-9.95 (1 H, brm).
1H-NMR (D SO-d6) 8ppm : 1.39 (3H, s), 1.48 (3H, 8), 1.55-219 (6H, m), 3.01 (1H, d, J = 13.2
13.2 HZ). 3.70-3.87 (1H, m). 4.28-4.45 (1H, m), 7.17 (1H, dd, J = 22, 9.0
-CHr Hydrochloride
Figure imgf000103_0002
5.4 Hz), 7.37 (1 H, d, J = 22 Hz), 7.67 (1H, d, J = 5.4 Hz), 7.81 (1H, J = B.9
Hz), 8.42-8.65 (1H, br), 9.80-10.05 (1H, br).
1H-NMR (DMSO-dB) Bppm : 1.42 (3H, s), 1.49 (3H, s), 3.07 (1H, d, J = 13.4 Hz), 3.53 (1H, d, J
= 13.4 Hz), 3.72 (1H, t, J = 8.8 Hz), 3.90-4.17 (4H, m), 4.79-4.94 {1H, m), 7.19 (1H, dd, J = 2.4, Hydrochloride 8.9 Hz), 7.30 (1H, dd, J = 0.5, 5.4 Hz), 7.41 (1H, d, J = 24 Hz), 7.69 (1H, d, J = 54 Hz), 7.83
(1Ή d, J = 8.9 Hz) 8.60-8.85 ( H, br), 10.41-10.65 (1H, br).
1H-NMR (DMSO-d6) δρρΓτί : 1.33 (3H, 6), 1.44 (3H, s), 1.55-2.19 (6H, m), 292 (1H, d, J = 13.5
-CHr Hz) 348 (iH, d, J = 13.5 Hz), 366-3.82 (1H, m), 4.20-4.35 (1H, m), 6.98 (2H, d, J = 9.0 Hz), Hydrochloride
723 (2H, d. J = 9.0 Hz), 8.40-8.86 (1H, br), 9.75-10.05 (1H, br).
CI 1H- MR (DMSO-dB) δρ τη ·.1.32 (3H, 8), 1.43 (3H, S), 1.55-2 5 (6H, m), 293 (1H, d, J = 13.6 tO -CHr Hz), 3.58 (1H, d, J = 13:6 Hz), 3.65-3.82 (1H, m), 4.20-4.40 (1H, m), 6.97 {1H, dd, J = 29, 9.0 Hydrochloride
Hz), 7.19 (1H, 0, J = 29 Hz), 7.40 (1H, d, J = 9.0 Hz), 8.40-8.52 (1H, br), 970-9.95 (1H, br)
1H-NMR (DMSO-d6) Sppm : 1.34 (3H, s), 1.44 (3H, s), 2.99 (1H, d, J = 13.8 Hz), 3.60-3.73 (2H,
CI
11 -o- m), 3.85-4.11 (4H, m), 4.71-4.90 (IH, m), 6.95-7.08 (1H, m), 7.20-7.30 (1H, m), 7.42 (1H, d, J Hydrochloride
CI 9.0 Hz), B.60-8.89 (1H, br), 10.20-10.61 (1H, br).
[0290]
Table 2
Figure imgf000104_0001
Example X NMR Salt
1H-NM (D SO<)e) Oppm : 1.30-1.60 (4H, m), 1.60 (3H, 6), 1.85-205 (4H, m), 2.05-223 (1H.
12 -CHj- m), 282-296 (IK m), 3.06-3.25 (1H, m), 3.25-3.45 (2H, m), 40O6.25 (1H, br), 7.29 (1H, dd, J Dlrr drochloride
9.33-9.67 (1H, br), 3.73-10.08 flH, bl),
(3H, s), 1.65-207 (5H. m), 294 (1H, d, J =
(1H, dd, J = 1.7, 8.7 Hz), 7.42 (1H, d, J = Dihyrirochlaride 5.4 Hz), 7.93 (1H, d, J = 8.7 Hz), 9.403.70
s). 290 (1H, d. J = 12.7 Hz), 3.34 (1H, d, J
4.O0-4.10 (1H, m), 4.11-4.28 (1H, m),
14 O rjihydroohloride
(1H, d, J = 5.4 Hz), 7.62 (1H, d, J = 21
Hz), 9.68-10.08 (1H, bf), 10.0B-10.30 (1H, br).
(3H, e), 1.65-1.88 βΗ, m), 1.88-210 (2H,
m).4.03-4.70 (1H, br), 7.09 (1H,
IS -CHr Dihydrochlorlde
(1H, d, J = 8.7 Hz), 9.28-9.59 (1H,
Figure imgf000104_0002
1.53 (3H, s), 1.63-204 (5H, m), 282 ( H, d, J =
16 -CHr 26 Hz), 328-3.36 (1H, m), 4.35-5.05 (1H, br), Dihydrochlorlde
Figure imgf000104_0003
(1H, br), 9.75-10.02 <1H, br).
1H-NMR (DMSO-d8) Oppm : 1.46 (3H, B), 1.64 (3H, s), 2.89 (1H, d, J = 12.9 Hz), 3.47-3.66 (3H,
m), 3.81-3.97 f2H, m), 4.01-4.15 (1H, m), 4.3+4.45 (1H, m), 7.26 (1H, dd, J - 23, 8.8 Hz),
17 -O- Hydrochloride
7.38-7.44 (1H, m), 7.44-7.50 (1H, m), 7.50-7.54 (1H, m), 7.80-7.87 (2H, m), 7.89 (1H, d, J = 8.1
HZ), 9.84-10.04 (1H, br), 10.04-1O.20 (1H. br).
[0291]
Table 3
Relative configuration
Figure imgf000104_0004
Example NMR Salt
1H-NMR(DMSCW6) o"ppm (80¾) : 1.40 (3 H, S), 1.43-1.70 (5 H, m).1.72- .92 (2 H, m), 1.95-223
(4H, m), 3.39-3.52(2 H, m), 3.B5-4.02 (1 H, br), 4.02-4.14(1 H, m), 5.64-6.00 (1 H, br), 7.31-7.38 (1 Dlhydrochloride H. m), 7.38-7.47 (2 H, m), 7.50-7.57 (1 H, m), 7.72-7.85 (3 H, m),8.44-8.80 (1 H, br), 9.04-9.40 (1 H, br).
1H-NMR (DMSOd8) δρρΓπ (80¾) : 1.31-1.51 (5H, m), 1.54 (3H, s), 1.63-1.76 (2H, m), 1.87-2.12
(3H, rn), 2.12-223 (1 H, m), 3.22-3.44 (2H, m), 3.85-4.02 (2H, m), 5.00-5.90 (1H, br), 7.33 (1H, d, J = Dihydrochlorlde 8.6 Hz), 7.36 (1H, d, J = 5.4 Hz), 7.70 (1H, d, J = 5.4 Hz), 7.77 (1H, 8), 7.89 (1H, d. J = 8.6 Hz),
8.25-8.74 (1H, br), 9.00-S.54 (1H. br).
1H- MR (DMSOd8) Oppm : 1.34 (3H, s), 1.39-1.55 (5H, m), 1.67-1.90 (3H, m), 1.90-2.16 (3H, m),
Dihydrochlorlde 3.17-3.38 (2H, m), 3.7&4.02 (2H. m), 7.10-7.20 (2H, m). 7.25-7.37 (2H, m), 7.37-7.90 (1H, br),
Figure imgf000104_0005
8.45-8.69 (1H, br), 8.89-9.19 (1H, br). [0292] Table 4
Relative configuration
Figure imgf000105_0001
Example R4 NMR Salt
1H-NMR (DMSO-dB) tf ppm (80¾) : 1.43 (3H, e), 1.47 pH, e), 1.51-1.65 (1H, m), 1.72-1.90 (3H, m),
21 1.93-2.09 (2H, m), 2.12-229 (2H, m), 3.69-3.80 (1H, m), 3.81-3.92 (1H, m), 3.96-4.11 (1H, m), 4.11-4.70 DlhydracWorlde
9.49-9.58 (1H, br).
Figure imgf000105_0002
(1H, br).
1H- MR (DMSrXB) Sppm (80¾) : 1.44 (6H. S), 1.47-1.64 (1H, m), 1.67-1.84 (3H, m), 1.86-213 PH,
23 m), 2.14-2.30 {1H, m), 3.60-3.80 |2H, m), 3.92-4.07 (1H, m), 5.80-6.70 (1H, br), 7.04 (1H, d, J = 8.9 Hz), Dihydrochlorlde
7.2B (1H, d, J = 8.9 Hz), 9.40-9.75 (2H, br).
[0293] Table 5
Relative configuration
Figure imgf000105_0003
Example R' R4 NMR Salt
1H-NMR (DMSO) Bppm : 1.29-1.57 pH, m), 1.46 (3H, s), 1.57 (3H, e), 1.69-1.91 (4H, m),
^γ^γ^»» 1.98-2.09 (1H, m), 3.07 (1H, d, J = 13.5 Hz), 3.51 (1H, d, J = 13.5 Hz), 3.73-3.92 (1H, m), HydracWoride ^ ^ 4.11-4.30 (1H, m), 7.18 (1H, d, J = 2.2 Hz), 7.22-7.28 (1H, m), 7.36-7,43 (2H, m), 7.68-7.B0
(3H, m), 8.02-8.31 (1H, m), 9.62-9.91 (1H, br)
1H-NMR (CDCI3) 6ppm . 1.21-1.36 (1H, m), 1.40-1.53 (1H, m), 1.48 (3H, s), 1.58-1.77 (2H,
- ^^^ m), 1.93 PH, s), 1.98-205 (1H, m), 218-234 (1H, m), 2.37-2.58 (1H, m), 2.67-2.88 (1H, rrt),
25 -CHj i jT J 2.82 (3H, d, J = 4.S Hz), 3.26 (1H, d, J = 13.4 Hz), 3.64-3.77 (1H, m), 3.91 (1H, d, J = 13.4 Hydrochloride
Hz), 3.97-404 (1H, m), 7.07-7.09 (1H, m), 7.17-7.22 (1H, m), 7.30-7.35 {1H, m), 7.40-7.48
(1H, m), 7.66-7.83 (3H, m), 11.27 (1H, brs)
. 1.2-1.5 ( 6H, m ), 1.57 ( 3H, & ), 1.6-1.95 ( 4H, m ), 1.95-2.15
H, d, J = 13.4Hz ), 3.75-3.9 ( H, m ), 4.05-4.2
28 41 2.5, 8.9Hz ), 7.1-7.2 ( 2H, m ), 7.38 ( 1H, dd, J = Dihydrochlorlde
Figure imgf000105_0004
1H, d, J = 9.1Hz), 6.05-8.3 ( 1H, m ), 9.75-10.06
( 7H, m ), 1.7-2.1
27 -H m), 4.1-4.3 ( 1H, Hydroch|or|de
, 7.74 ( H, d, J =
Figure imgf000105_0005
1H-NMR (CDCI3) Sppm : 1.18-1.28 (1H, m), 1.38-1.50 (2H, m), 1.66 (3H, s), 1.72-2.00 (2H,
= 12.8 Hz), 3.43 (1 H, d, J
28 = 8.8, 2.2 Hz), 7.21-7.25 Hydrochloride
Figure imgf000106_0001
(1H, br), 9.99-10.37 (1H,
br)
1.37-1.74 (2H, m), 1.47 (3H, s), 1.87-2.04 (1H,
d, J = 4.9
29 13.2 Hz), Hydrochloride d, J = 8.8
Figure imgf000106_0002
MR (CDCI3) Bppm : 1.11-1.33 (1H, m), 1.36-1.54 (2H, m), 1.65 (3H, 1.72-2.00 (2H,
.90 (3H, s), 2.07-2.29 (1H, m), 2.34-2.60 (2H, m), 3.08 (1H, d, J = 13.2 Hz), 3.42 (1H, d, J
30 Hydrochloride
Figure imgf000106_0003
2 Hz), 3.76-4.02 (2H, m), 7.02 (1H, dd, J = 8.7, 2.2 Hz), 7.17-7.31 (3H ,m), 7.70 (1H, d, J
= 8.7 HZ), 8.64-9.00 (1H, br), 10.08-10.37 (1H, br)
m), 1.38-1.74 (3H, m), 1.46 (3H, s), 1.90 (3H, e),
H, m), 2.81 (3H, d, J =
3.3 Hz), 3.89-3.99 (1H, Hydrochloride
Figure imgf000106_0004
= 8.7 Hz), 11.04-11.44
(1H, br)
( 2H, m ), 1.25-1.45 ( H, m ), 1.53 ( 6H, β ), 1.6-1.7
= 2.8Hz ), 3.48 ( 1H, d, J =
32 H, dd, J = 7.7, 7.7Hz ), 748 Hydrochloride
Figure imgf000106_0005
5.4Hz ), 8.17 { 1H, br ), 9.78
Figure imgf000106_0006
[0294]
Table 6
Relative configuration
Figure imgf000106_0007
1 H-NMR ( CDCI3 ) Bppm : 1.13 ( 18H, d, J = 7.5Hz ), 1.21 ( 3H, s ), 1.25-1.3 ( 5H, m ), 1.35-1.45 CH3 ( 2H, m ), 1.53 ( 1H, br ), 1.6-1.8 ( 7H, m ), 2.80 ( 1H, d, J = 11.7Hz), 293 ( 1H, d, J = 11.5Hz), 36 H3C^Si- CH3 3.45-3.55 C 1H, m ), 3.55-3.65 ( 1H, m ), 6.48 ( 1H, d, J = 2.6Hz), 6.85 ( 1H, dd, J = 2.4, 9.0Hz),
7.02 ( 1H, d, J = 2.4Hz ), 7.16 ( 1H, d, J = 3.2Hz ), 7.36 ( 1H, d, J = 9.1Hz ).
1H- R ( CDCI3 ) Bppm : 1.1-1.2 ( 18H, m ), 1.21 ( 3H, s ), 1.25-1.3 ( H, m ), 1.3-1.85 ( 11H,
36 m ), 279 ( 1H, d, J = 11.6Hz), 2.91 ( 1 H, d, J = 11.6Hz), 3.45-3.65 ( 2H, m ), 6.45-6.5 { 1H, m ),
6.82 ( 1H, dd, J = 2.0, 8.6Hz), 6.93 ( 1H, s ), 7.08 ( 1 H, d, J = 3.2Hz), 7.45 ( 1H, d, J = 8.6Hz ).
Figure imgf000106_0008
[0295] Table 7
Figure imgf000107_0001
Example R1 R* NMR Salt
( 3H. m ), 1.21 ( 3H, s ). 1.25-1.45 ( 6H,
), 3.11 ( 1H,
37 -H dd, J = 0.9,
Figure imgf000107_0002
dd, J = 7.7,
7.7Hz ), 7 14 ( 1H, dd, J = 2.8, 2.8Hz), 8.18 ( H, br).
1H-NMR ( CDCI3 ) Bppm : 1.0-1.15 ( 5H, m ), 1.19 ( 3H, s ), 1.2-1.5 ( 3H, m),
1.6- .7 C H, m), 2.0-2.3 { 5H, rn ), 2.76 ( 1H, d, J = 11.5Hz), 3.05-3.15 ( H, m ), 3.38 ( 1H, d, J = 11.4Hz ), 3.8-3.9 ( 1H, m ), 6.49 ( 1 H, d, J = 7.4Hz ),
6.55-6.6 ( 1H, ), 6.99 ( H, d, J - 7.4Hz ), 7.07 ( 1H, dd, J =7.8, 7.8Hz),
7.13 ( 1 H, dd, J = 2.8, 2.8Hz ), 8. 1 ( 1H, br ).
1 H-NMR ( CDCI3 ) Bppm : 1.0-1.85 ( 15H, m ), 2.82 ( 1H, d, J = 11.5Hz ), 2.88
11H, d, J = 11.5Hz ), 3.45-3.55 ( 1H, m ), 3.55-3.65 ( 1H, m ), 6.4-6.45 ( 1H, m ), 6.95 ( H, dd, J = 2.3, 8.8Hz ), 7.04 ( 1H, d, J = 2.2Hz ), 7.13 ( H, dd, J =
2.8, 2.8Hz ), 7.25-7.3 ( 1H, m ), 7.98 ( H, br ).
1 H-NMR ( CDCI3 ) Bppm : 1.06 ( 3H, 9), 1.1-1.55 ( BH, m ), 1.6-1.75 ( 1H, m ),
1.95-2.15 ( 2H, m ), 2.18 ( 3H, s }, 2.80 ( 1H, d, J = 11.4Hz ), 2.95-3.0 ( 1H, m ), 3,10 ( 1H, d, J = 11.4Hz ), 3.55-3.7 ( 1H, m ), 6.35-6.45 ( 1H, m ), 6.94
Figure imgf000107_0003
( 1H, dd, J = 2.3, 8.8Hz ), 7.03 { 1H, d, J = 2.0Hz ), 7.12 ( H, dd, J = 2.8,
2.8Hz ), 7.2-7.3 ( 1 H, m ), 7.94 ( 1 H, br ).
1 H-NMR ( DMSO-d6 ) Bppm : 1.0-1.4 { 9H, m ), 1.4-1.9 ( 5H, m ), 2.82 ( 1H, d,
H J = 11 ,9HZ ), Z95 ( 1H. d, J = 12.0Hz ). 3.0-4.5 { 4H, m ), 6.25 ( 1H, dd, J =
41 -fl N Hemltumarate
2.4, 2.4Hz ), 6.47 ( 1H, s ), 6.7-6.8 ( 2H, m ), 7.10 ( 1H, dd, J = 2.7, 2.7Hz ),
= 9.3Hz ), 10.65 ( 1H, s ).
Bppm : 0.95-1.5 ( 11H, m ), 1.55-1.7 ( 1 H, m ), 1.85-2.1
), 2.65-4.2 ( 6H, m ), 6.2-6.25 ( 1H, m ), 6.60 ( 2H, s ), Fumarate 1H, dd, J = 2.4, 3.0Hz ), 7.33 ( H, d, J = 8.5Hz ), 10.60
Figure imgf000107_0004
1 H-NMR ( DMSO-46 ) Bppm : 0.95-1.4 ( 9H, rn ), 1.45-1.9 ( 5H, m ), 2.88 ( 2H, dd, J = 12.3, 15.1Hz ), 3.5-3.6 ( H, m ), 3.6-3.75 { 4H, m ), 6.24 ( 1H, dd, J =
43 - N Hemifumarate
0.6, 3.0Hz ), 6.47 ( 1H, s ), 6.85-7.0 ( 2H, m ), 7.18 { 1H, d, J = 3.0Hz ), 7,27
CH
1.1-1.4 ( 9H, m ), 1.4-1.9 ( 6H, m ), 2.85 ( 1H. d,
= 12.1Hz ), 3.5-3.6 ( 1H, m ), 3.69 ( 3H, s ), Fumarate d, J = 3.1Hz ), 6.49 ( 2H, β ), 6.7-6.85 ( 2H, m ),
Figure imgf000107_0005
( H, d, J = B.6Hz).
1 H-NMR ( OMSO-d6 ) Bppm : 1.0-1.3 ( 2H, m ), 1.3-1.45 ( 7H, m ), 1.5-1.95
( 5H, m ), 2.9-3.1 ( 2H, m ), 3.71 ( H, br ), 3.8-3.95 ( 1H, rn ), 3.98 ( 3H, s ),
45 -H 3/2 Fumarate
6.54 ( 3H, s ), 7.04 ( 1H, s ), 7.27 ( 1H, dd, J = 1,9, 9.2Hz ), 7.51 ( H, d, J =
Figure imgf000107_0006
9.1Hz ), 7.83 ( H, s ), 10.6 ( H, br ).
1 H-NMR ( DMSCX16 ) Bppm : 1.1-1.35 ( 2H, m ), 1.35-1.45 ( 4H, m ), 1.50
46 -H
Figure imgf000107_0007
( 1H. br), 9.83 ( 1H, br). [0296]
Table 8
n
Figure imgf000108_0001
Example R R9 R' NMR Salt
1 H-NMR (DMSO-d6) Bppm : 1.1-1.35 (2H, m ), 1.35-1.5 (4H, m ), 1.53 (3H, s),
1.6-1.95 ( H, m ), 1.95-2.15 ( 1H, m ), 2.94 ( 1H, d, J = 13.3Hz), 3.24 ( H, d, J = Dihydrochloride
47 -H -H
13.2Hz), 3.65-3.85 ( 1H, m ), 3.85-4.0 ( 1H, m), 5.30 ( 1H, br ), 6.9-7.0 ( 2H, m ),
7.0-7.1 ( 2H, m ), 8.0-8.35 ( 1H, m ), 10.03 ( 1H, d, J = 10.5Hz ).
1 H-NMR ( DMSO-d6 ) Bppm : 1.2-1.35 ( 6H. m ), 1.52 ( 3H, s ), .6-1.95 ( H, m ),
1.95-2.15 { 1H, m ), 2.93 ( 1H, d, J= 13.5Hz), 3.36 ( 1H, d, J = 13.5Hz), 3.65-3.8 Hydrochloride
48 -H -H -H -H
( 1H, m ), 3.9-4.1 ( 1H, m ), 6.6*B (. 1H, ), 6.9-7.1 ( 1H, m ), 7.25 ( H, dd, J =
9.5, .19.7HZ), 8.0-6.4 [ 1H, m), 10.02 ( 1H, d, J = 11.3Hz).
1 H-NMR ( DMSO-d8 ) Bppm : 1.25-1.6 ( 9H, m ), 1.6-2.05 ( 5H, m ), 295 ( 1H, d,
-H -F J = 14.0Hz ), 3.56 ( H, d, J = 13.9HZ ), 3.6-3.75 ( 1H, m ), 4.0-4.15 ( 1H, m ), Hydrochloride
49 -H
6.35-6.55 ( 1 H, m ), 6.5-6.75 ( 2H, m ), 8.05-8.4 { 1H, m ), 9.65-10.2 ( 1H, m ).
1 H-NMR ( DMSO-d6 ) Bppm : 1.2-1.45 ( 6H, m ), 1.50 ( 3H, ε ), 1.6-1.9 ( 4H, m ),
1.9-2.05 ( 1H, m ), 2.90 ( 1H, d. J = 13.7Hz ), 3.42 ( 1H, d, J = 13.7Hz), 3.6-3.7S
-H -H -OCHi -H Hydrochloride
60
( 1H, m ), 3.78 ( 3H, ), 3.9-4.05 ( 1H, m ), 6.65-6.8 ( 2H, m ), 8.17 ( 1H, br ), 9.86
(1H, br ).
1 H-NMR ( DMSO-d6 ) Bppm : 0.96 [ 3H, s ), 1.05-1.2 ( 4H, m ), 1.2-1.5 { 4H, m ),
3/2 Fumarate
51 -CHj -F -OCH, -H 1.55-1.75 ( 1H, m ), 1.85-2.1 ( 2H, m ), 216 ( 3H, s ), 2.75-2.9 ( 2H, m ), 3.12
( 1H, d, J = 124Hz ), 3.65-3.85 ( 4H, m ), 6.55-6.65 ( 5H, m >.
1 H-NMR { DMSO-dS ) Bppm : 1.2-1.45 ( 6H, m ), 1.51 { 3H, s ), 1.6-2.05 ( 5H, m ),
2.94{ 1H, d, J = 13.7Hz), 3.48 ( 1H, d, J = 14.0Hz), 3.65-3.8 ( 1H. m ), 4.0-4.15
62 -H -H -CI -H Hydrochloride
( 1H, m), 6.77 ( 1H, dd, J = 1.5, 7.8HZ ), 6.90 ( 1H, dd, J = 2.3, 8.4HZ ), 6.95-7.0
( 1H, m ), 7.21 C 1 H, dd, J = 8.1, 8.1Hz ), 8.14 ( 1H, br ), 9.55-10.0 ( 1 H, m ).
1 H-NMR ( DMSO-d6 ) Bppm : 0.97 ( 3H, s ), 1,05-1.2 (4H, m ), 1.2-1.5 ( H, m ),
1.6-1.75 ( 1H, m ), .9-2.1 ( 2H, m ), 2.15 ( 3H, s ), 2.65-5.05 ( 6H, m ), 6.61 ( 2H, Fumarate
Figure imgf000108_0002
s ), 6.66 ( 1H, dd, J = 1.2, 7.8Hz ), 6.75-6.9 ( 2H, m ), 7.15 ( 1H, dd, J = 8.1,
8.1Hz).
1 H-NMR ( DMSO-de ) Bppm : 1.15-1.45 ( 6H, m ), 1.52 (3H, s ), 1.6-2.1 (5H, m ),
2.93 ( 1H, d, J = 13.6Hz ), 3.39 [ 1 H, d, J = 13.9Hz ), 3.65-3.8 ( 1H, m ), 3.9-4.1
54 -CI -H Hydrochloride
( 1 H, m ), 6.9-7.0 ( 2H, m ), 7.15-7.3 (, 2H, m ), 7.95-8.4 ( 1 H, m ), 9.65-10.1 ( 1H, m ).
1 H-NMR ( DMSO-d6 ) Bppm : 0.99 ( 3H, s ), 1.05-1.5 ( 8H, m ), 1.55-1.75 ( 1H,
Fumarate
55 -CH, -CI -H -H m ), 1.85-2.1 ( 2H, m ), 2.17 ( 3H, s ), 2.8- 95 ( 2H, m ), 3.12 ( 1H, d, J =
123Hz ), 3.7-3.85 ( 1 H, m ), 6.61 ( 2H, s ), 6.8-6.9 (2H, m ), 7.1-7.2 ( 2H, m ).
1 H-NMR (DMSO) Bppm : 1.21-1.62 (2H, m), 1.38 (3H, s), 1.53 (3H, s),
1.67-2.09 (6H, m), 2.95 (1H, d, J = 13.6 Hz), 3.48 (1H, d, J = 13.6 Hz), 3,70-3.74 Hydrochloride
56 -H -H -CI ■a -H -H
(1H, m), 4.04^1.10 (1H, m), 6.95 (1H, dd, J = 8.7, 2.6 Hz), 7.17 (1H, d, J = 2.6
H2), 7.40 (1H, d. J = 8.7 Hz), 8.03-8.52 (1 H, br).9.77-10.21 (1H, br) 1 H-NMR (CDCI3) Bppm : 1.23-1.72 (4H, m), 1.42 (3H, s), 1.89 (3H, 8), 2.01-2.11
(1H, m), 2.20-2.28 (1H, m), 2.37-2.S5 (1H, m), 268-2.83 (1H, m), 2.79 (3H, d, J =
57 -CHj -H -CI -a -H -H 4.8 Hz), 3.09 (1 H, d, J = 13.5 Hz), 3.54-3.65 (1H, m), 3.76-3.83 ( H, m), 3.78 (1 H, Hydrochloride d, J = 13.5 Hz), 6.88 (1H, dd, J = 9.0, 2.9 Hz), 6.92 (1H, d, J = 29 Hz), 7.30 (1H, d, J = 9.0 HZ), 11 48 (1 H, fS)
1 H-NMR (DMSO) Bppm : 1.24-1.57 (3H, m), 1.37 (3H, s), 1.52 (3H, s),
1.64-1.81 (4H, m), 1.87-2.01 (1H, m), 2.92 (1H, d, J = 13.1 Hz), 3.45 ( H, d, J =
58 -H -H -CI -H -H Hydrochloride
13.1 Hz), 3.65-3.79 (1H, m), 3.90-4.06 (1H, m), 6.89-6.94 (1H, m), 7.08-7.11 (1H, m), 7.20-7.27 (1K m), 7.90-8.21 ( H, br), 9.55-9.81 (1H, br)
[0297]
Table 9
Absolute configuration
Figure imgf000109_0001
Example R NMR Salt
1 H-NMR ( CDCI3 ) 5ppm : 1.15-1.35 ( 8H, m ), 1.35-1.85 ( 7H, m), 2.82 ( 1H, d, J = 11.7Hz),
χχχ 3.05 ( H, d, J = 11.8Hz), 3.45-3.55 ( H, m ), 3.7-3.6 ( 1H, m ), 3.B8 ( 3H, s ), Θ.97 [ 1H, d, J
C, H3 ' = 2.4Hz ), 7.0-7.1 ( 2H, m ), 7.22-7.29 ( 1H, m ), 7.55 { 1H, d, J = 8.8Hz ), 7.61 ( H, d, J =
9.0ΗΖ).
1 H-NMR (CDCI3 ) Bppm : 1.15-1.3 ( 8H, m ), 1.3-1.5 ( 6H, m ), 1.65-1.85 ( 4H, m ), 2.82 ( 1H,
d,J = 11.7Hz), 3.04 ( 1H, d, J = 11.7Hz), 3.45-3.55 ( 1 H, m ), 3.7-3.8 ( H, m), 4.11 (2H, q, J
60 -H XXX OC2H5 = 7.0Hz ), 6.96 ( 1H, d, J = 2.4Hz ), 7.03 ( 1H, d, J = 2.4Hz ), 7.06 ( 1H, dd, J = 2.5, 8.8Hz ),
7.2-7.3 C 1 H, m ), 7.55 ( 1H, d, J = 8.9Hz ), 7.59 ( 1H, d, J = 9.0Hz ).
1 H-NMR { DMSO-d6 ) Oppm : 1.25- .5 ( 6H, m ), 1.56 ( 3H, s ), 1.65-21 ( 5H, m ), 3.06 { 1 H,
d, J = 13.4Hz), 3.48 ( 1H, d, J = 13.4Hz ), 3.8-3.9 ( 1H, m ), 4.1-4.2 ( 1H, m ), 4.42 ( 1H, br ), Dihydrochloride
Figure imgf000109_0002
7.24 ( 1H, d, J = 22Hz), 7.31 ( 1H, ddd, J = 4.5, 12.8, 12.8Hz), 7.47 ( 1H, dd, J = 23, 9.2Hz),
( 1H, m ), 9.75-9.95 ( 1H, m ).
Figure imgf000109_0003
[0298]
Figure imgf000110_0001
[0299] Table 11
Example R1
Figure imgf000111_0001
( 1H, m }.
( 11H, m ), 1.55-1.75 [ 1H, m ), 1.85-21 ( 2H,
6.61 ( 2H, s ), 7.10 ( 1H, dd, J = 2.4, 9.0Hz ),
70 -CH» Fumarate
J = 0.5, 5.4Hz ), 7.62 ( 1H, d, J = 5.4Hz ), 7.75
6H, m ), 1.54 ( 3H, s ), 1.6-2.1 ( 5H, m ), 3.03
.6Hz ), 3.7-3.9 ( 1H, m ), 4.0-4.2 ( 1 H, m ), 7.14
71 -H Hydrochloride
Figure imgf000111_0002
= 2.2, 8.9Hz), 7.27 ( 1H, d, J = 5.4Hz ), 7.4-7.55 ( 2H, m ), 7.71 ( 1H, d, J =
8.8Hz ), 8.14 ( H, br ), 9.84 ( 1H, br ).
£ DMSO-d6 ) Oppm : 0.95-1.2 ( 2H, m ), 1.3-1.45 ( 1H, m ), 1.45-1.7 ( 7H, m ),
, 1.9-22 ( 2H, m), 291 ( 1H, d, J = 12.8Hz), 3.48 ( 1H, d, J = 12.9Hz),
72 -H ), 7.01 { 1H, d, J = 7.5HZ ), 7.34 ( 1H, dd, J = 7.7, 7.7Hz), 7.48 ( 1H, d, Hydrochloride
Figure imgf000111_0003
( 1H, d. J = 7.7HZ ), 7.76 ( 1H, d, J = 5.4Hz ), 8.24 ( 1H, br ), 9.94 ( 1H,
br). '
[0300] Table 12
Absolute configuration
Figure imgf000112_0001
( 2H, m ), 1.35-1.5 ( 4H, m ), 1.54 ( 3H, s ), 1.6-1.95
1HZ ), 3.75-3.9 ( 1H,
74 -H = 2.5, 9.0Hz ), 7.13 Dihydrochlorlde
Figure imgf000112_0002
8.11 ( 1H, br ), 9.91
( 1H, br ).
1H-IMMR ( DMSO-d6 ) oppm : 1.15-1.5 ( 6H, m ), 1.55 ( 3H, s ), 1.6-1.95 ( 4H, m ), 1.85-2.15
( 1H, m ), 3.01 [ 1H, d, J = 13.4Hz ), 3.36 ( 1H, d, J = 13.1Hz ), 3.7-3.85 ( H, m ), 3.95-4.05
75 -H Dihydrochlorlde
Figure imgf000112_0003
( 1H, m ), 4.50 ( 1H, br ), 6.80 [ 1 H, d, J = 2.1Hz), 6.98 ( 1H, dd, J = 1.9, 6.7Hz), 7.13 { H, s ),
), 8.20 ( 1H. br ), 9.85-10.2 ( 1H, m ).
3H,
),
Hydrochloride dd,
1H,
1H,
8.6,
3H,
2H,
7.14 ( 1H, d, J = d, J
Figure imgf000112_0004
1 H-NMR ( OMSO-de ) 8ppm : 0.95-1.1 (2H, m ), 1.3-1.4 ( 1H, m ), 1.51 ( 3H, s ), 1.52 ( 3H,
Figure imgf000112_0005
[0301]
Table 13
Absolute configuration
Figure imgf000113_0001
Example R' R* NMR Salt
1H-NMR ( COCI3 ) 8ppm : 1.1-1.2 ( 20H, m ), 1.20 ( 3H, ), 1.3-1.45 ( 8H, ), 1.55-1.8 ( 6H, m ), 1.8-2.0 ( 1H, m ), 2.83 ( 1H, d, J = 11.5Hz), 3.11 ( 1H, d, J = 11.5Hz ), 3.6-3.7 ( 1H, m ),
82 -H Y N'? X ?HH-,3 3.7-3.8 ( 1H, m ), 6.50 ( 1H, d, J = 7.4HZ ). 6.64 ( 1H, d, J = 3.1Hz ), 7.00 ( 1 H, dd, J = 7.9,
3.2Hz).
5H, m ), J =
Figure imgf000113_0002
1H-NMR ( CDCI3 ) 6ppm : 1.1-1.2 ( 1BH, m ), 1.21 ( 3H, 9 ), 1.29 ( 3H, s ), 1.3-1.5 ( 5H, m ), 1.55-1.8 ( 7H, m ), 2.79 ( 1H, d, J = 11.6Hz), 2.91 ( 1H, d, J = 11.6Hz ), 3.45-3.6 (2H, m ), 6.48 ( 1H, d, J = 3.2Hz ), 6.82 ( 1H, dd, J = 2.0, 8.6Hz), 6.93 ( 1H, ), 7.08 ( 1H, d, J = 3.2Hz ), 7.45 (1H, d, J = 8.6Hz).
[0302]
Table 14
Absolute configuration
Figure imgf000113_0003
Example R* R* NMR Salt
), 1.5-1.8 , 3.6-3.75 6.95-7.05 , br).
m ), 2.93 , 8.8Hz ), Fumarate
Figure imgf000113_0004
1H-NMR (CDCI3 ) Sppm : 1.05-1.85 ( 15H, m ), 2.79 ( 1H, d, J = 11.6Hz), 2.94 ( 1H, d, J = 11.6Hz ), 3.45-3.55 ( 1H, m ), 3.6-3.75 ( 1H, m ), 6.35-6.45 ( 1H, m ), 6.79 ( 1H, ε ), 6.86
87 -H
( 1H, dd, J = 2.1, 8.7Hz), 7.03 ( 1H, dd, J = 2.4, 3.2Hz), 7.47 ( 1H, d, J = 8.7Hz ), 7.89 ( 1H, br). [0303]
Table 15
Example R MR Salt
2H, m ), 1.25-1.4 ( 4H, m ), 1.40 ( 3H, s ),
), 3.21 ( 1 H, d, J = 12.2Hz ), 3.74 ( 3H,
-H Fumarate
BHZ ), 6.5-6.55 ( 3H, m ), 6.95-7.05 ( 2H, m ),
Figure imgf000114_0001
1H-NMR ( DMSO-d6 ) Oppm : 1.0-1.2 ( 2H, m ), 1.32 ( 7H, bs ), 1.45-1.65 ( 6H, m ),
89 -H N 2.85-2.95 ( 2H, m ), 3.63 ( 1H, br ), 3.65-3.8 ( H, m ), 6.24 ( 1H, dd, J- 0.6, 3.0Hz ), 6,50 Fumarate
), 7.28 ( 1H, d, J = 8.6Hz ).
Figure imgf000114_0002
[0304]
Table 16
ration
Figure imgf000114_0003
Example R* R* NMR Salt
1H-NMR ( DMSO-d6 ) Sppm : 1.1-1.4 ( 8H, m ), 1.45-1.75 ( 4H, m ), 1.8-1.95 ( 1H, m ),
S. 2.80 ( 1H, d, J = 12.3Hz), 3.20 ( 1H, d, J = 12.3Hz), 3.4-3.5 ( 1H, m), 3.8-39 ( 1H, m),
92 -ti Hemiftimarate
6.51 ( 1H, ), 7.20 ( 1H, dd, J = 2.5, 9.1ΗΖ ), 7.51 { 1H, d, J = 24Hz ), 7.85 ( 1H, d, J =
), 1.50 d, J = Hydrochloride H, d, J
Figure imgf000114_0004
( 2H, m ), 1.3-1.5 { 4H, m ), 1.53 { 3H, s ), 1.6-1.9
7.4Hz ), 2.93 ( 1H, d.
94 -H ( 1H, m ), 6.70 ( 1H, Dirtydrochtoride
Figure imgf000114_0005
), 7.8-8.4 ( 2H, m ),
8.85-10.2 ( 1H, m ).
1H-NMR ( D SO-d6 ) Sppm : 1.1-1.3 ( 2H, m ), 1.35-1.5 {4H, m ), 1.51 ( 3H, a ), 1.6-1.9
( 4H, m ), 2.0-2.1 ( 1H, m ), 2.95 ( 1H, d, J = 13.0Hz ), 3.02 ( 1H, d, J = , 13.0Hz ), 3.11 □[hydrochloride
95 -H 0 ( 2H, t, J = 8.8Hz), 3.7-3.85 ( 2H, m ), 4.44 ( 2H, t, J = 8.6Hz ), 4.7-5.5 ( 1H, m ), 6.6-6.7
( 2H, m ), 6.85-6.95 ( 1H, m ), 8.09 ( 1H, br ), 9.94 ( 1H, br ). [0305]
Table 17
Absolute configuration
Figure imgf000115_0001
Example ' R» NMR Salt
1H-NMR ( DMSO-d6 ) oppm : 1.1-1.25 ( 2H, m ), 1.35-1.45 ( 1H. m ), 1.46
( 3H, s ), 1.49 ( 3H, s ), 1.6-1.85 ( 3H, m ), 1.85-2.05 ( 2H, m ), 2.93 ( 1 H, d,
96 -H -H -H +1 J = 13.1Hz ), 3.27 ( 1H, d, J = 13.2Hz ), 3.55-3.65 ( 1H, m ), 3.8-3.9 ( H, Hydrochloride m ), 6.95-7.05 ( 1H, m ), 7.05-7.2 ( 3H, m ), 8.0-8.2 ( 1H, m ). 9.55-9.75
( 1H, m ).
1H-NMR ( DMSOde ) oppm : 1.1-1.35 ( 2H, m ), 1.35-1.45 ( 4H, m ), 1.53
( 3H, s ), 1.6-1.95 ( 4H, m ), 1.95-2.15 ( 1 H, m ), 294 ( H, d, J = 13.3Hz ).
97 -H -H -H -H 3.24 ( 1H, d, J = 13.3Hz ), 3.65-3.85 ( 1H, m ), 3.85-4.0 ( 1 H, m ), 4.2-5.8 Dlhydroctiloride
( 1H, m ), 8.85-7.0 ( 2H, m ), 7.0-7.1 ( 2H, m ), 8.19 ( 1H, br ), 10.05 ( 1H, r ).
1H- R ( DMSO-d6 ) Oppm : .2-1.35 ( 2H, m ), 1.35-1.45 ( 4H, m ), 1.52
( 3H, s ). 1.6-1.9 ( H, m ), 2.0-2.1 ( 1H, m ), 2.90 ( 1H, d, J = 13.3Hz), 3.22
-OCHj -H ( H, d, J = 13.2Hz ), 3.85-3.8 ( 4H, m ), 3.85-3.95 ( 1H, m ), 66-8.7 ( H, Dlhydrochloride m ), 6.89 ( 1H, d¾ J = 2.9, 14.7Hz ), 7.02 ( 1H, dd, J = 9.5, 9.5Hz ),
8.05-8.25 ( 1 H. m ), 9.94 ( H, br ).
1H-NMR ( DMSO-d6 ) Bppm : 1.2-1.45 ( 6H. m ), 1.55 ( 3H, s ), 1.6-1.95
( 4H, m ), 2.0-2.15 ( 1H, m ), 2.95 ( 1H, d, J = 13.2Hz ), 3.24 ( 1H, d, J =
Dihydrochlortde
-H -H -OCHj 13.2Hz ), 3.7-3.8 ( H, m ), 3.82 ( 3H, s ), 3.9-4.0 ( H, m ), 6.4-6.5 ( H,
m ), 6.70 ( 1H, dd, J = 2.8, 7.6Hz ), 7.03 ( 1H, dd, J = 8.9, 11.3Hz ), 8.0
( 1H, br ), 8.15-8.35 ( 1H, m ), 10.0-10.15 ( 1H, m ).
1H-NMR ( DMSOd6 ) Oppm : 1.15-1.3 ( 2H. m ), 1.35-1.45 ( 1H, m ), 1.46
( 3H, s ), 1.50 ( 3H, s ), 1.6-1.65 ( 3H, m ), 1.9-2.05 ( 2H, m ), 3.00 ( 1H, d, J
Hydrochloride
100 -H -F = 13.2Hz ), 3.28 ( 1H, d, J = 13.2Hz ), 3.6-3.7 ( 1H, m ), 3.8-3.9 { 1H, m ),
6.85-8.95 ( H, m ), 6.95-7.05 ( H, m ), 7.05-7.15 ( 1H, m ), 8.05-8.35 ( 1H, m ), 9.7-9.9 (, 1H, m ).
1H-NMR ( DMSO-dfi ) 6ppm : 1.05-1.4 ( 9H, m ), 1.4-1.9 ( 5H, m ), 2.72
(01 -F -H ( 1H, d, J = 12.5Hz ), 2.8-4.6 ( 8H, m ), 6.54 ( 2H, ), 6.6-6.7 ( 1H, m ), Fumarate
6.85-7.0 [ 1H, m ), 7.20 ( 1 H, dd, J = 9.5, 19.9Hz ).
1H- MR ( DMSO-d6 ) 8ppm : 1.25-1.5 ( 6H, m ), 1.51 ( 3H, S ), 1.65-2.1
( 5H, m ), 2.92 ( H, d, J = 13.8Hz ), 3.46 ( 1H, d, J = 13.8ΗΖ ), 3.65-3.75
102 Hydrochloride
( 1H, m ), 4.0-4.1 ( 1H, m >, 6.8-6.95 ( 2H, m ), 8.15-8.35 ( 1H, m ),
9.85-10.1 ( 1H, m ).
1H-NMR ( DMSO-d6 ) 6ppm : 1.25-1.55 ( 9H, m ), 1.6-1.85 ( 4H, m ),
1.85-2.05 ( 1H, m ), 2.90 ( H, d, J = 13.8Hz ), 3.43 ( 1H, d, J = 12.8Hz ),
103 -OCHj -H Hydrochloride
3.65-3.75 ( 1H, m ), 3.78 ( 3H, s ), 3.95-4.05 ( 1H, m ), 8.6-6.8 ( 2H, m ),
8.06 ( 1H, br), 9.57 ( 1H, br).
1H-NMR ( OMSO-d6 ) appm : 1.0-1.2 ( 2H, m ), 1.3-1.4 ( 1H, m ), 1.48 ( 3H, s ), 1.50 ( 3H, s ), 1.6-1.85 ( 3H, m ), 1.85-2.1 ( 2H, m ). 2.74 ( 1H, d. J =
104 -H -CI -H -H -H 12.8Hz ), 3.41 ( 1H, d, J = 13.1Hz ), 3.5-3.6 ( 1H, m ), 3.8-3.9 ( 1H, m ), Hydrochloride
7.05-7.15 ( 1H, m ), 7.17 ( 1H, dd, J = 1.4, 8.0HZ ), 7.25-7.35 ( 1H, m ), 7.44
< 1H, d, J = 1.5, 7.9Hz ), 8.02 ( 1H, br), 9.63 ( 1H, br). 1 H-NMR ( D SO-cffi ) Oppm : 1.15-1.45 ( 6H, m ), 1.51 ( 3H, B ), 1.5-1.9
( 4H, m ), 1.95-2.1 ( 1H, m ), 2.92 ( H, d, J = 13.3Hz ), 3.20 ( 1H, d, J =
-CI -OCH, □(hydrochloride
13.1Hz ), 3.7-3.8 ( 4H, m ), 3.9-4.0 ( 1H, m ), 5.9 ( 1H, br ), 6.88 ( 1H, dd, J
= 29, 9.1HZ), 7.0-7.05 [ 1H, m), Θ.11 ( 1H, br ), 9.90 ( 1H, be).
1 H-NMR ( DMSO-d6 ) Sppm : 1.2-1.45 ( 6H, m ), 1.51 ( 3H, s ), 1.8-2.1
{ 5H, m ), 2.93 ( 1 H, d, J = 13.6Hz ), 3.40 ( 1H, d, J = 13.8Hz ), 3.65-3.85
-H -H -H -H Hydrochloride
( 1H. m ), 3.9-4.1 ( 1H, in ), 6.8-7.05 { 2H, m ), 7.1-7.35 (2H, m ), 8.14 ( H, br), 9.77 ( 1H, br).
1 H-NMR ( DMSO-d8 ) Bppm : 0.98 ( 3H, s ), 1.05-1.2 ( 4H, m ), 1.2-1.45
-CHj -H -H -a Ή ( 4H, m ), 1.55-1.75 ( H, m ), 1.85-21 ( 2H, m ), 216 ( 3H, s ), 2.65-4.2 Fumarate
( H, m ), 6.61 ( 2H, β ). 6.8-6.9 ( 2H, m ), 7.1 -7.2 ( 2H, m ), 12.8 ( 2H, br ).
1 H-NMR ( DMSO-d6 ) Bppm : 1.2-1.5 ( 6H, m ), 1.5-1.6 ( 3H, m ), 1.6-1.85
{ 4H, m ), 2.0-2.1 ( 1H, m ), 2.95 ( 1H, d, J = 13.5Hz ), 3.3-3.5 ( H, m ),
-H -H -OCHj -a -H 3.7-3.8 ( 1H, m ), 3.84 ( 3H, 8 ), 4.0-4.1 ( 1H, m ), 6.52 ( 1 H, dd, J = 2.6, Hydrochloride
8.9Hz ), 6.63 ( 1H, d, J = 2.8H2 ), 7,19 ( 1H, d, J = 8.8Hz- ), 8.19 ( 1H, br ),
9.75-10.1 ( 1H, m).
1 H-NMR t DMSO 16 ) 6ppm : 1.05-1.25 ( 2H, m ), 1.35-1.45 ( 1H, m ), .47
( 3H, 8 ), 1.49 ( 3H, s ), 1.6-1.85 ( 3H. m ), 1.85-205 ( 2H, m ), 2.76 ( 1 H, d,
Hydrochloride
-H -ci -a -H -H -H J = 12.8Hz), 3.42 ( 1H, d, J = 13.0Hz ), 3.5-3.6 ( 1H, m ), 3.8-3.9 ( 1H, m ),
7.18 ( H, dd, J = 1.6, 7.9Hz ), 7.31 ( 1H, dd, J = 8.0, B.OHz ), 7.37 ( 1H, dd,
J = 1.5, 8.0HZ ), 8.01 ( 1H, br'), 9.5-9.7 ( 1H, m ).
1H-NMR ( DMSO-d6 ) Bppm : 1.2-1.45 ( 6H, m ), 1.52 ( 3H, s ), 1.6-2.15
( 5H, m ), 2.95 ( 1H, d, J = 13.7Hz), 3.49 ( 1H, d, J = 13.4Hz), 3.6-3.8 ( H,
-H -H -a Hydrochloride m ), 3.95-4.15 ( 1H, m ), 6.95 ( H, dd, J = 2.6, 9.1 Hz ), 7.05-7.25 ( 1 H, m ),
7.40 ( 1H, d, J = 9.0Hz ), 7.95-8.4 ( 1H, m ), 9.6-10.15 ( H, m ).
1 H-NMR ( OMSO-d6 ) Bppm : 0.96 ( 3H, s ), 1.05-1.2 ( 4H, m ), 1.2-1.5
( 4H, m ), 1.6-1.75 ( 1H, m ), 1.85-2.05 ( 2H, m ), 214 ( 3H, S |, 2.75-2.95 3/2 Fumarate
-CH. -CI -a ( 2H, m ), 3.17 { 1H, d, J = 12.4Hz ), 3.7-3.9 ( 1H, m ), 8.62 ( 3H, s ), 6.87
( 1H, dd, J = 2.9, 9.1 Hz ), 7.04 ( 1H, d, J = 2.9Hz ), 7.33 ( 1H, d, J = 9.0Hz),
11.0 ( 3H, br).
1 H-NMR ( DMSO-d6 ) Oppm : 1.15-1.45 ( 6H, m ), 1.51 ( 3H, s ), 1.6-1.9
{ 4H, m ), 1.9-2.05 ( 1H, ), 2.01 ( H, d, J = 8.2Hz ), 3.3-3.45 ( H, m ), Hydrochloride
-H -CI -H -H
3.65-3.B ( 1 H, m ), 3.95-4.1 ( 1 H, m ), 6.85-7.0 ( 1 H, m ), 7.12 ( H, dd, J =
3.0, 6.2ΗΖ ), 7.25 ( H, dd, J = 9.1, 9.1HZ ), 8.13 < 1 H, br ), 9.86 ( 1H, br ).
1 H-NMR ( DMSO-d6 ) Bppm : 1.2-1.45 ( 6H, m ), 1.51 ( 3H, s ), 1.6-2.1
( 5H, m ), 2.94 ( 1H, d, J = 13.7HZ ), 3.50 ( 1H, d, J = 13.6Hz ), 365-3.8
-H -a -H -H ( 1 H, w ), 3.95-4.15 ( H, m ), 6.B0 ( 1 H, dd, J = 2.6, 9.1Hz ), 7.01 ( 1 H, dd, Hydrochloride
J = 2.7, 3.4Hz ), 7.34 ( H. dd, J = 9.0, 9.0Hz ), 8.22 ( 1H, br ), 9.90 ( 1H, br).
[0306]
Table 18
Absolute configuration
Figure imgf000117_0001
Example R' NMR Salt
1H-NMR ( C0CI3 ) βρριπ : 1.15-1.35 ( 8H, m ), 1.35-1.85 ( 7H, m ), 2.82 ( 1H, d. J = 11.7Hz ), 3.05 ( 1H, d, J = 11.7Hz ), 3.45-3.55 ( 1H, m ), 3.7-3.8 ( 1H, m ), 3.88 ( 3H, s ),
114 -H
CH3 6.97 ( 1H, d, J = 2.3H2 ), 7.03 ( 1 H, d, J = 2.4ΗΖ ), 7.06 ( 1 H, dd, J = 2.6, 88Hz ), 7.26 ( 1H,
dd, J = 2.5, 9.0Hz ), 7.55 ( 1H, d, J = 8.8Hz }, 7.61 ( 1 H, d, J = 9.0Hz ).
1H-NMR ( CDCI3 ) eppm : 1.05 ( 3H, s ), 1.15-1.5 ( 8H, m ), 1.65-1.8 ( 1H, m ), 2.0-2.15 ( 2H, m ), 2.18 ( 3H, ), 29-3.0 ( 2H, rfl ), 3.09 ( 1H, d, J = 11.7ΗΖ), 3.7-3.8 ( 1H, m ), 3.88
115 -CH3
OCH, ( 3H, s ), 8.95 ( 1 H, d, J = 2.4Hz ), 7.0-7.1 ( 2H, m ), 7.15-7.3 C 1 H, m ), 7.55 ( 1H, d, J =
8.7HZ ), 7.59 ( 1H, d, J = 9.1Hz).
1H-NMR ( CDCI3 ) Bppm : 1.15-1.3 ( 8H, m ), 1.3-1.85 ( 10H, m ), 2.82 ( 1 H, d, J = 11.7Hz ), 3.04 ( 1H, d, J = 11.7Hz ), 3.45-3.55 ( 1H, m ), 3.7-3.8 ( 1H, m ), 4.11 ( 2H, q, J = 7.0Hz ),
116 -H XXX OC2H5 8.96 ( 1H, d, J = 24Hz ), 7.03 ( 1H, d, J = 2.4Hz ), 7.08 ( 1 H, dd, J = 2.5, 8.8Hz ), 7.2-7.3
( 1 H, m ), 7.55 ( 1 H, d, J = 8.9Hz ), 759 ( 1H, d, J = 9.0Hz ).
1H-NMR ( D SO-d6 ) Opprn : .25- .5 ( 6H, m ), 1.57 ( 3H, s ), 1.85-2.15 ( SH, m ), 3.06
.9 ( 1H, m ), 4.15-4.25 ( 1H, m ), 5.02
117 -H 4.5, 12.8, 2.8Hz ), 7.47 ( 1H, dd, J = Dlhydrachloride
Figure imgf000117_0002
( 2H, m ), 8.15-8.3 ( H, m ), 9.9-10.0
( 1H, m ).
( 1H, m ), 1.45-1.7 ( 7H, m ),
Figure imgf000117_0003
[0307] Table 19
Figure imgf000118_0001
[0308]
Table 20
Absolute configuration
Figure imgf000119_0001
Example R R* NMR Salt
Difumarate
Figure imgf000119_0002
: 1.2-1.35 ( 2H, m ), 1.35-1.5 ( 4H, m ), 1.54 ( 3H, s ), 1.6-2.1
15 ( 1H,
128 Hydrochloride z), 7.68
).
2H, m ),
127 24 ( 1H, Fumarate
Figure imgf000119_0003
8.9Hz).
1H- MR ( DMSO-d6 ) Bppm : 1.2-1.5 ( 6H, m ), 1.53 ( 3H, s ), 1.8-2.05 ( 5H, m ), 3.03
( 1H, d, J = 13.5Hz), 3.44( 1H, d, J = 13.5Hz), 3.75-3.9 ( 1H, m ), 4.0-4.15 ( H, m ), 7.14
128 Hydrochloride
Figure imgf000119_0004
( 1H, dd, J = 2.2, 8.8Hz ), 7.27 ( 1H, d, J = 5.4Hz), 7.44 ( 1H, d, J = 5.4Hz ), 7.48 ( 1 H, d, J
= 1.8Hz), 7.71 ( H, d, J = 8.8Hz), 7.95-8.2 ( 1H, m ), 9.55-9.8 ( 1H, m ).
: 1.25-1.5 ( 6H, m ), 1.61 ( 3H, 6 ), 1.65-1.9 ( 3H, m ),
( 1H, d, J = 13.9Hz), 3.58 ( 1H, d, J =
129 15 ( H, dd, J = 2.3, 8.9Hz ), 7.28 ( 1H, Hydrochloride
Figure imgf000119_0005
d, J = 1.9Hz), 772 ( 1H, d, J = 8.8Hz ),
9.42 ( 1H, br ).
1H-NMR ( OMSO-dB ) Bppm : 0.95-1.2 ( 2H, m ), 1.3-1.45 ( 1H, m ), 1.53 ( 6H, s ),
1.55-1.7 ( 1H, m ), 1.7-1.9 ( 2H, m ), 1.9-2.15 ( 2H, m ), 2.92 ( H, d, J = 12.9Hz ), 3.48
130 ( H, d, J = 12.8Hz ), 3.75-4.0 ( 2H, m ), 7.02 ( H, d, J = 7.6Hz ), 7.35 ( 1H dd, J = 7.7, Hydrochloride
Figure imgf000119_0006
7.7Hz ), 7.48 ( 1H, d, J = 5.4Hz ), 7.81 ( 1H, d, J = 7.9Hz ), 7.76 ( 1 H, d, J = 5.4Hz ), 8.1B
( 1H, br), 9.81 ( 1H, br).
[0309]
Table 21 n
Figure imgf000120_0001
Example R NMR Salt
1 H-NMR DMSO-tffi o m : 0.95-1.15 ( 2H, m ), 1.3-1.45 ( 1H, m ), 1.52 ( 3H, s ), 1.54
, J = 13.0ΗΖ ), 3.30 ( 1H, d, J = 13.4Hz ), 3.75-3.9
131 -H Hydrochloride
1H, m ), 7.1-7.25 ( 3H, m ), 7.94 ( 1H d, J = 2.2Hz ),
( 2H, m ), 1.3-1.4 { 1H, m ), 1.43 ( 3H, s ), 1.55-1.9 d, J = 4.7Hz}, 3.21 ( 1H. d, J = 13.3Hz), 3.55 ( 1H,
132 -CH3 Hydrochloride
-6.75 ( 1H, m ), 7.15-7.25 (3H, m ), 7.95 ( 1H, d, J =
Figure imgf000120_0002
m ), 1.35-1.5 ( 4H, m ), 1.55 { 3H, s ). 1.6-1.95
3.75-3.9
133 -K 9.0Hz ), Dlhydroehlor!de
Figure imgf000120_0003
1H, br),
9.99 ( 1H, br).
1 H-NMR ( DMSO-d8 ) Spprn : 1.2-1.5 { 6H, m ), 1.56 ( 3H, s ), 1.6-2.0 ( 4H, m ), 2.0-2.15
Q ( 1H, m ), 3.01 ( 1H, d, J = 13.4Hz ), 3.35 ( 1H, d, J = 13.3Hz ), 3.85-3.85 ( 1H, m ),
134 -H Dihydrochloride
3.95-4.15 ( 1H, m ), 6.75-6.85 { 1H, m ), 698 ( 1H, dd, J = 2.1, 8.7Hz), 7.13 ( 1H, s ), 7.47
( 1H, m ), 10.0-10.2 ( 1H, m ).
( 3H,
( 1H,
135 -H Hydrochloride
7.21
Figure imgf000120_0004
m ).
1 H-NMR ( CDCI3 ) δρρτη : 1.0-1.45 ( 11H, m ), 1.6-1.8 ( 3H, m ), 1.8-1.95 ( H, m ), 2.70
( 1H. d, J = 11.3Hz ), 3.04 ( 1H, d, J = 11.4Hz), 3.45-3.55 ( 1H, m ), 3.55-3.65 ( 1H, m ),
6.47 ( 1H, dd, J = 3.4, 8.6Hz ), 6.84 ( 1H, dd, J = 2.5, 2.5Hz ), 6.89 ( 1H, dd, J = 8.6,
Figure imgf000120_0005
2.1Hz ).
), 1.20 { 3H, s ), 1.25-1.45 ( 6H, m ), 1.6-1.8
11.5Hz ), 3.05 { 1H, d, J = 11.4Hz ), 3.55-3.65
, d, J = 2.2HZ ), 7.14 ( 1H, d, J = 8.4Hz ), 7.61
Figure imgf000120_0006
1 H-NMR ( OMSO-d6 ) Spprn : 0.95-1.1 ( 2H, m ), 1.3-1.4 ( 1 H, m ). 1.51 ( 3H, s ), 1.53 { 3H.
), 1.6-1.7 { 1H, m ), 1.7-2.0 ( 3H, m ), 2.O-2.05 ( 1H, m ), 239 ( 3H, ), 2.95 ( 1H, d, J =
138 -tf 12.8Hz ), 3.28 ( 1H, d, J = 12.9Hz ), 3.7-3.8 ( 1H, m ), 4.0-4.15 ( 1H, m), 6.61 ( 1H, d, J = Hydrochloride
Figure imgf000120_0007
7.9Hz ), 6.99 C 1H, d, J = 8.1Hz ), 7.20 ( 1H, d, J = 2.2Hz ), 7.95 ( 1H, d, J = 22Hz ),
8.0-8.15 C 1H, m ), 9.57-9.95 ( 1H, m ).
1 H-NMR ( DMSO-06 ) flppm : 0.9-1.1 ( 2H, m ), 1.3-1.4 ( 1H, m ), 1.52 ( 6H, s ), 1.55-1.65
( 3H, m ), 1.95-21 ( 1H, m ), 2.86 ( H, J, J = 12.8Hz), 3.27 ( H, d, J =
4.15 ( 1H, m ), 6.61 ( 1H, d, J = 8.4Hz ), 6.79 Hydrochloride
139 -H H, m ), 3.87 ( 3H, s ), 4.0- 7.21 < 1H, d, J = 2.2Hz ), 7.95 ( 1H, d, J = 21Hz), 7.95-8.15 ( 1H, m ),
Figure imgf000120_0008
1 H-NMR ( DMSO-d6 } Oppm : 1.05-1.25 ( 2H, m ), 1.35-1.45 ( 1H, m ), 1.50 ( 3H, s), 1.54
( 3H, s), 1.6-1 9 ( 3H, m ), 1.9-2.1 [ 2H. m ), 3.17 { H, d, J = 13.1Hz), 3.29 ( 1H, d, J =
Hydrochloride
140 -H 13.2Hz ), 3.9-1.0 ( 1H, m ), 4.0-4.1 ( 1H, m ), 6.80 ( 1H, dd, J = 4.4, 8.7Hz), 6.98 ( 1H, dd, J
Figure imgf000120_0009
= 8.9, 8.9Hz ), 7.06 ( 1H, d, J = 2.2Hz ), 8.06 ( 1H, d, J = 2.2Hz ), 8.1-8.3 ( 1H, m ),
9.75-9.95 ( 1H, m ). [0310]
Table 22
Figure imgf000121_0001
1H-NMR ( COCI3 ) Bppm . .13 ( 18H, d, J = 7.5Hz ), 1.21 ( 3H, B ), 1.28 ( 3H, β ), 1.3-1.8 { 5H, N CH3 m ), 1.6-1.8 ( 7H, m ), 2.80 ( 1 H, d, J = 11.7Hz), 293 ( 1H, d, J = 11.6Hz), 3.45-3.55 { 1H, m ),
142 -H HaCy-Si-ScHg 3.55-3.65 ( 1H, m ), 6.48 ( 1H, dd, J = 0.7, 3.1Hz), 6.85 ( 1H, dd, J = 2.4, 9.0Hz), 7.02 ( 1H, .d, J
= 2.3Hz), 7.16 ( 1H, d, J = 3.1Hz ), 7.36 ( 1H, d, J = 9.0Hz ).
[0311]
Table 23
Figure imgf000122_0001
Example * R* NMR Salt
1H-NMR ( CDCI3 ) 5ppm : 0.9-1.15 ( 2H, m ), 1.21 ( 3H, s ), 1.25-1.45 ( 5H, m ),
J =
143 -H H,
Figure imgf000122_0002
2.6,
2.8Hz), 8.16 ( 1H, br).
1H-NMR ( DMSO-d6 ) 6ppm : 1.0-1.25 ( 2H, tn ), 1.33 ( 7H, bs ), 1.45-1.9 ( 5H, m ),
144 -H 2.8-3.0 ( 2H, m ), 3.0-4.05 ( 5H, m ), 6.2-6.3 < 1H, m ), 6.50 ( 2H, s ), 6.86 ( 1 H, dd, J = Fumarate
Figure imgf000122_0003
2.2, 8.8HZ ), 6.95 ( 1H, d, J = 1.9HZ ), 7.15-7.3 ( 2H. m ), 10.79 ( H, s ).
), 1.25-1.4 ( 4H, m ), 1.42 ( 3H, s ).
( H, d, J = 12.3Hz ), 3.74 ( 3H, s ),
145 -H Fumarate
.5-6.55 (3H, m ), 6.95-7.05 ( 2H, m),
Figure imgf000122_0004
1H-NMR ( CDCI3 ) 6ppm : 1.0-1.5 ( 11H, m ), 1.6-1.7 ( 1H, m ), 2.05-2.3 ( 5H, m ), 2.75 ( 1H, d, J = 11.4Hz ), 3.05-3.15 ( 1H, m ), 3.38 ( 1H, d, J = 11.5Hz ), 3.75 { 3H, s ), 3.8-3.9 ( 1H, m ), 8.45-6.55 ( 2H, m ), 6.92 ( H, d, J = 8.2Hz ), 6.96 ( 1H, d, J = 3.1 Hz ),
Figure imgf000122_0005
7.10 ( 1H, dd, J = 0.7, 3.1Hz ).
1H-NMR ( DMSO-d6 ) δρρτη ; 1.0-1.2 ( 2H, m ), 1.33 ( 7H, ba ), 1.45-185 ( 6H, m ),
147 -H N 2.85-2.95 { 2H, m ), 3.64 ( 1H, lar), 3.7-3.8 ( 4H, m ), 6.24 ( 1H, dd, J = 0.7, 3.0Hz ), 6.51 Fumarate
CH3 ( 2H, s ), 6.9-7.0 ( 2H, m ), 7.19 ( H, d, J = 3.0Hz ), 7.28 ( 1H, d, J = 8.6Hz J.
1H-NMR ( DMSO-d6 ) Sppm : 1.05-1.3 ( 2H, m ), 1.3-1.45 ( 7H, m ), 1.5-1.9 ( 5H, m ), 2.93 ( 1H, d, J = 12.3Hz ), 3.09 ( 1H, d, J = 12.4Hz ), 3.65 ( 1H, br ), 3.70 ( 3H, s ),
148 -H Fumarate
3.8-3.95 ( 1H, m ), 6.25 ( 1H, d, J = 3.0Hz ). 6.51 ( 2H, s ), 6.75-6.85 ( 2H, m ), 7.09
Figure imgf000122_0006
( 1 H, d, J = 3.1 Hz ), 7.36 ( 1 H, d, J = 9.2Hz ).
2.0-2.15 H, d, J = 1.8Hz ),
Figure imgf000122_0007
H-N R ( CDCI3 ) Sppm : 0.7-2.3 ( 15H, m ), 2.7-3.2 ( 2H, m ), 3.5-3.8 ( 2H, m ), 3.85
CN
150 -H ( 3H, s), 6.95-7.05 ( 2H, m ), 7.15-7.3 ( 2H, m ).
[0312]
Table 24
on
Figure imgf000123_0001
Example R' NMR Salt
Figure imgf000123_0002
), 9.02 ( 1H, s ).
( DMSO-d8 ) 6ppm : 1.0-1.2 ( 2H, m ), 1.3-1.45 ( H, m ), 1.48 ( 3H, s), 1.50
1.55-1.7 ( H, m ), 1.7-2.15 ( 6H. ni >, 2.7-2.95 ( 5H, m ), 3,28 ( 1H, d, J =
152 -H Hydrochloride
3.35-3.45 ( 1H, m ), 38-3.9 ( 1H, m ), 6.68 ( 1H, d, J = 7.8Hz ), 6.90 ( 1 H, d, J
Figure imgf000123_0003
.7.05 ( H, dd, J = 7.6, 7.6Hz), 7.95-8.2 ( 1H. m ), 9.7-9.95 ( 1H, m ).
1.35-1.5 ( 4H. m ), 1.53 ( 3H, s ),
153 -H □(hydrochloride
Figure imgf000123_0004
( 1H, br), 8.0-8.3 ( 1H, m ), 9.9-10.1 ( H, m ).
) 8ppm : 1.1-1.3 { 2H, m ), 1.35-1.5 ( 4H, m ), 1.52 ( 3H, s ),
1 ( 1H, m ), 295 ( 1H, d, J = 13.0Hz ), 3.02 ( 1H, d, J = ,
154 -H Dihydrochlorlde
Figure imgf000123_0005
8.6Hz ), 3.7-3.85 ( 2H, m ), 4.44 ( 2H, t, J - 8.6Hz ).5.S6 ( 1 H,
br ), 6.6-6.7 ( 2H, m ), 8.85-6.95 ( 1H, m ), 8.0-8.25 ( 1H, m ), 9.9-10.2 ( H, m ).
[0313]
Table 25
A solute configuration
Figure imgf000124_0001
Example R* R* R* NMR Salt
1H-NMR ( DMSO-tffi ) Oppm : 1.1-1.25 ( 2H, m ), 1.3-1.45 ( 1H, m ), 1.46
{ 3H, ), 1.45 ( 3H, ), 1.65-1.85 ( 3H, m ), .85-Z05 ( 2H, m ), 2.93 ( 1 H, Hydrochloride
156 -H -H -H -H
d, J = 13.0Hz), 3.27 ( H, d, J = 13.1Hz ), 3.55-3.65 { H, m ), 3.8-3.9 ( 1H, m ), 6.95-7.05 ( 1H, m ), 7.05-7.2 ( 3H, m ), 8.03 ( 1H, br ), 9.66 ( 1H, br ).
1H- MR ( D SO-de ) oppm : 1.15-1.45 ( 6H, m ), 1.52 ( 3H, s ), 1.6-2.15
( 5H, m ), 2.94 ( 1H, d, J = 13.3Hz ), 3.25 ( 1H, d, J = 13.1Hz ), 3.35-3.4
156 -H -F -H +i DihydrochlorldB
( 3H, m ), 6.85-7.0 ( 2H, m ), 7.0-7.1 ( 2H, m ), 8.16 ( 1H, br ), 9.94 ( 1H, br ).
1H-NMR ( DMSO-d6 ) Bppm : 0.9Θ ( 3H, s ), 1.0-1.1 ( 1H, m ), 1.16 ( 3H, s), 1.2-1.45 ( 4H, m ), 1.55-1.7 ( H, m), 1.85-2.05 ( 2H, s ), 2.15 ( 3H, s ),
157 -CHa -H -H -F H Fumarate
2.35-4.55 ( 4H, m ), 6.59 ( 2H, S }, 6.8-6.9 ( 2H, m ), 6.9-7.05 (2H, m ), 12.9
(2H, br).
1H-NMR ( DMSO-d6 ) oppm : 1.2-1.35 ( 2H, m ), 1.35-1.45 ( 4H, m ), 1.51
( 3H, β >, 1.6-1.9 ( 4H, m ), 1.95-2.1 ( 1H, m ), 2.90 ( 1H, d, J = 13.4Hz ),
158 -H -H -F -OCHj -H -H 3.22 ( 1H, d, J = 133Hz ), 3.65-3.8 ( 4H, m ), 3.85-3.95 ( 1H, m ), 6.6-67 Hydrochloride
( H, m ), 6.89 ( 1H, dd, J = 2.9, 14.7Hz ), 7.02 ( H, dd, J = 9.5. 9.5Hz ),
8.12 { H, m ), 9.90 ( 1H, br ).
1H-NMR ( D SO-d6 ) 5ppm : 1.2-1.5 ( 6H, m ), 1.54 ( 3H, s ), 1.6-1.95
( 4H, m ), 2.0-2.15 ( 1H, m ), 2.95 ( 1H, d, J = 13.3Hz ), 3.24 ( 1H, d, J =
159 -H -H -OCH, -H 13.2Hz ), 3.7-3.8 ( 1H, m ), 3.82 ( 3H, s ), 3.9-4.05 ( 1H, m ), 6.4-6.5 ( 1H, Hydrochloride m ), 6.70 ( 1 H, dd, J = 2.8. 7.6Hz ), 7.03 ( 1H, dd, J = 8.9, 11.3Hz ), 7.75
( 1H, br ), 8.15-8.35 { 1H. m ), 10.0-10.15 ( 1H, m ).
1H-NMR ( DMSad6 ) appm : 1.15-1.3 ( 2H, m ), 1.35-1.45 ( 1H, m ), 1.46
( 3H, 8 ), 1.50 ( 3H, 8), 1.6-1.85 ( H, m ), 1.9-2.05 (3H, m ), 3.00 ( H, d, J
(60 -F -F -H = 13.2Hz ), 3.28 ( 1H, d, J = 13.4Hz ), 3.6-3.7 ( H, m ), 3.8-3.9 ( 1H, m ), Hydrochloride
6.85-6.95 ( 1H, m ), 6.95-7.05 ( 1H, m ), 7.05-7.15 ( 1H, m ), 8.1-8.3 ( 1H, m ), 9.7-9.9 ( 1H. m ).
1H-NMR ( DMSO-d6 ) βρρτη : 1.2-1.5 ( 6H, m ), 1.52 ( 3H, s ), 1.6-2.15
( 5H, m ), 2.93 ( 1H, d. J = 13.5Hz ). 3.2-3.45 ( 1H, m ), 3.6S-3.8 ( H, m ),
161 -H -H -4H +i Hydrochloride
3.9-4.1 ( 1H, m ), 6.85-6.8 ( 1H, m ), 6.95-7.1 ( H, m ), 7.25 ( 1H, dd, J =
9.4, 19.8Hz ), 6.0-8.35 ( 1H, m ), 9.75-10.1 ( 1H, m ).
1H-NMR ( D SO-d5 ) Oppm . 0.97 ( 3H. s ), 1.05-1.2 ( 4H, m ), 1.2-1.45
( 4H, m ), 1.6-1.75 { 1H, m ), 1.85-2.05 ( 2H, 8 ), 2.14 ( 3H, s ). 2.65-4.05
162 -CHs -H -F -F -H -H Fumarate
( 4H, m ), 6.55«.7 ( 3H, m ), 6.8-6.Θ5 ( 1H, m ), 7.18 ( H, dd, J = 9.5,
20.0Hz ), 13.0 ( 2H, br ). 1H-N R ( DMSC~d6 ) 8ppm : 1.25-1.5 { 6H, m ), 1.50 ( 3H, s ), 1.65-1.9
( 4H, m ), 1.95-2.05 ( H, m ), 2.92 ( 1 H, d, J = 13.8Hz ), 3.47 ( 1 H, d, J =
183 -H -H -F -H Hydrochloride
13.8Hz ), 3.65-3.8 ( 1H, m ), 4.0-4.1 ( 1H, m ), 8.8-6.95 ( 2H, m ), 6.1-8.3
( 1H, m ). 9.75-9.95 ( 1H, m ).
( 6H, m ), 1.50 ( 3H, s ), 1.6-1.9
), 3.42 ( 1H, d, J = Hydrochloride
Figure imgf000125_0001
( 1H, m }, 6.6-6.85
( 2H, m), 8.16 ( 1H, br ), 9.85 ( 1H, br).
1H-NMR ( DMSO-dB ) Bppm : 1.0-1.2 ( 2H, m ), 1.3-1.45 ( 1H, m ), 1.49
( 3H, s ), 1.51 ( 3H, s ), 1.6-1.85 ( 3H, m ), 1.9-2.1 ( 2H, m ), 2.73 ( 1 H, d, J Hydrochloride
165 -H -CI -H -H -H -H = 12.8Hz ), 3.41 ( 1H, d, J = 12.8Hz ), 3.45-3.55 ( 1 H, m ), 3.75-3.9 ( 1H,
m ), 7.05-7.15 ( 1H, m ), 7.17 ( 1H, dd, J = 1.4, 8.0Hz ), 7.25-7.35 ( 1H, m ),
7.44 ( 1H, d, J = 1.5, 8.0Hz), 8.09 ( H, br ), 9.7-9.9 ( H, m ).
1H-NMR { DMSO-d6 ) Bppm : 1.15-1,45 ( 6H, m ), 1.52 ( 3H, s ), 1.6-1.9
( 4H, m ), 2.0-2.1 ( 1H, m ), 2.92 ( 1H, d, J = 13.2Hz ). 3.19 ( 1H, d, J =
166 -H -a -CCHj Dihydrochloride
13.1Hz ), 3.7-3.8 ( 4H, m ), 3.85-3.95 ( 1H, m ), 5.9 ( 1H, br ), 6.88 ( 1H. dd,
J = 2.9, 9.0HZ), 7.0-7.05 ( H, m ), 8.15 ( H, br), 10.00 ( 1H, br ).
1H-NMR ( DMSO-dB ) Bppm : 1.2-1.45 ( 6H, m ), 1.51 ( 3H, S ), 1.6-2.1
( 5H, m ), 2.93 ( H, d, J = 13.7Hz), 3.2-3.5 ( 1H, m ), 3.65-3.85 { 1H, m ),
167 -H -a -H Hydrochloride
3.9-4.1 ( 1H, m ), 6.98 ( 2H, d, J = 9.0Hz ), 7.24 ( 2H, d, J = 8.9Hz), 8.14
( 1H, br), 9.45-10.0 ( 1H, m ).
1H-NMR ( DMSO-oB ) Bppm : 0.97 ( 3H, s ), 1.05-1.2 ( 4H, m ), 1.2-1.45
168 -CHi +1 -H -CI -H -H ( 4H, m ), 1.6-1.75 ( 1H, m ), 1.85-2.05 ( 2H, m ). 2.14 ( 3H, 8 ), 2.85-4.35 Fumarate
( 4H, m ), 6.61 ( 2H, s ), 6.8-69 ( 2H, m ), 7.1-7.2 ( 2H, m ), 129 ( 2H, br ).
1H-NMR ( DMSO-d6 ) Bppm : 1.05-1.25 ( 2H, m ), 1.35-1.45 ( 1H, m ), 1.47
( 3H, 9 ), 1.49 ( 3H, s ), 1.6-1.85 [ 3H, m ), 1.9-2.05 ( 2H, m ), 2.76 ( H, d, J
Hydrochloride
169 -H -CI -a -H -H -H = 12.8Hz ), 3.42 ( 1H, d, J = 13.0Hz ), 3.5-3.6 ( H, m ), 3.8-3.9 [ 1H, m ),
.18 ( 1H, dd, J = 1.6, 7.9Hz), 7.31 ( 1H, dd, J = 6.0, B.OHz ), 7.37 ( 1H, dd,
J = 1.5, 8.0Hz), 8.02 ( H, br), 9.61 [ 1H, br).
H- MR ( DMSO-d6 ) Bppm : 1.2-1.45 ( 6H, m ), 1.51 ( 3H, s ), 1.6-2.1
( 5H, m ), 2.95 ( 1H, d, J = 13.7Hz ), 3.49 ( 1H, d, J = 13.7Hz ), 3.65-3.8 Hydrochloride
170 -H -a -CI -H -H
( H, m ), 4.0-4.15 ( 1H, m ), 6.95 ( 1H, dd, J = 3.0, 9.1 Hz), 7.18 ( H, d, J =
2.9Hz ), 7.40 ( H, d, J = 9.0Hz ), 7.95-8.35 ( 1 H, m ), 9.6-10.05 ( 1H, m ).
1H-NMR { DMSO-d6 ) Bppm : 0.95 ( 3H, s ), 1.05-1.2 ( 4H, m ), 1.2-1.5
( H, m ), 1.55-1.75 ( H, m , 1.85-2.05 (.2H, m ), 2.13 ( 3H, s ), Z75-23 3/2 Fumarate
171 -CHj -ci -a -H -H ( 2H, m ), 3.17 ( H, d, J = 12.4Hz ), 3.75-3.85 ( H, m ), 6.62 ( 3H, s ), 6.87
( 1H, dd, J = 2.9, 9.1Hz ), 7.04 ( 1H, d, J = 29Hz), 7.33 ( H. d, J = 9.0Hz),
11.0 ( 3H, br ).
1H-NMR ( DMSO-d6 ) Bppm : 1.1-1.45 ( 6H, m ), 1.50 ( 3H, S ). 1.6-1.9
( 4H, m ), 1.9-2.1 ( 1H. s ), 2,00 { 1H, d, J = 8.2Hz ), 3.25-3.45 ( 1H, m ),
72 -CI -H Hydrochloride
3.65-3.85 ( 1H, m ).3.9-4.1 ( 1 H, m ), 6.85-7.0 [ 1H, m ), 7.12 ( 1H, dd, J =
3.0, 6.3Hz ), 7.25 ( 1H, dd, J = 9.1, 9.1Hz), 8.12 (1H, br), 9.82 ( 1H, br ).
1H-NMR ( DMSO-d6 ) Bppm : 1.2-1.45 [ 6H, m ), 1.50 ( 3H, s ), 1.8-2.1
( 5H, m ), 2.94 ( H, d, J = 13.8Hz ), 3.51 ( 1H, d, J = 13.9Hz ), 3.65-3.85
Hydrochloride
173 -H -F -a -H -H ( 1H, m), 3.95-4.15 (1H, m), 6.80 ( 1H, dd, J = 2.5, 8.9Hz), 7.01 ( 1H, dd,
J = 28, 13.4Hz), 7.34 ( 1 H, dd, J = 9.0, 9.0Hz ), 8.16 ( 1H, br ), 9.77 ( 1H, br).
1H-NMR { DMSO-d6 ) Bppm : 1.2-1.5 ( 6H, m ), 1.53 ( 3H, s ), 1.65-1.95
( 4H, m ), 1.95-2.1 ( 1H, m ), 2.95 ( 1H, d, J = 13.5HZ ), 3.3-3.45 ( H, m ), Hydrochloride
174 -H -H -CCHj -CI -H 3.7-3.8 ( H, m ), 3.84 ( 3H, s ), 4.0-4.1 ( 1H, m ), 6.52 ( 1 H, dd, J = 2.7,
B.9HZ ), 6.63 ( 1 H, d, J = 2.6Hz ), 7.19 ( H, d, J = 8.8Hz ), 8.18 ( 1H, br ),
9.88 ( 1H, br ). [0314]
Table 26
Relative configuration
Figure imgf000126_0001
Example 1 NMR Salt
1H-NMR (CDCI3) 8ppm : 1.04-1.21 (1H, m), 1.25-1.46 (2H, m), 1.64-1.88 (3H, m), 1.67
(3H, s), 1.77 (3H, s), 2.00-2.12 (1H, m), 2.34-2.40 (1H, m), 288 (1H, d, J = 12.5 Hz), t75 -H Hydrochloride
Figure imgf000126_0002
3.13-3,29 (2H, m), 3.42 (1H, d, J = 12.5 Hz), 7.29-7.34 (1H, m), 7.41-7.51 (2H, m), 7.60
( H, s), 7.77-7.82 (3H, m).9.51 {1H, bre), 9.79 (1H, brs)
(2H, in), 1.58-1.81 (3H, m), 1.65
Hz),
178 -H Hz), Hydrochloride
9.46
Figure imgf000126_0003
1H-NMR (DMSO) 8ppm : 0.92-1.37 (3H, m), 1.27 (3H, 8), 1.40-1.60 (3H, m), 1.52 (3H, s),
1.60-1.75 (1H, m), 1.80-1.90 (1H, m), 2.60-2.73 (1H, m), 2.78 (1H, d, J = 121 Hz), 2.97
177 (1H, d, J = 12.1 Hz), 3.00-3.12 (1H, m), 3.13-3.89 (3H, br), 3.76 (3H, s), 6.36 {1H, d, J = Fumarate
Figure imgf000126_0004
3.0 Hz), 6.50 (2H, s), 6.94 (1H, dd, J = 8.6, 1.6 Hz), 7.28 (1H, d, J = 1.8 Hz), 7.30 (1H, d, J
. = 3.0 Hz), 7.36 (1 H, d, J = 8.6 Hz)
1H-NMR (CDCI3) 5ppm : 0.97-1.09 (1H, m), 1.23-1.38 (2H, m), 1.52-1.68 (3H, m), 1.63
a
, (3H, s), 1.66 (3H. e), 1.92-2.05 (1H, m), 2.29-2.36 (1H, m), 2.73 (1H, d, J = 12.4 Hz), Hydrochloride
178 -H XX 2.9+3.03 (1H, m), 3.11-3.22 (1H, m), 3.28 (1H, d, J = 12.4 Hz), 7.02 (1 H, dd, J = 8.5, 2.4
■ci
Hz), 7.25 (1H, d, J = 2.4 Hz), 7.39 (1H, d, J = 8.5 Hz), 9.50 ( H, brs), 9.78 (1H, bre)
[0315]
Table 27
Figure imgf000127_0001
Example R1 R* NMR Salt
1H-NMR (CDCI3) δρρτπ : 1.26-2.30 (8H. m), 1.79 (3H, s), 2.17 (3H, s). 251-2.57 (1H,
Dihydrochloride
179 -H m), 3.36 (1H, d, J = 13.2 Hz), 3.90-4.30 (2H, m), 4.08 (1H, d, J = 13.2 Hz), 7.56-7.69 (2H,
Figure imgf000127_0002
m), 7.83-8.01 (4H, m), 8.50 (1H, bra), 10.07 (1H, brs), 10.26 (1H, bre)
(1H, m), 1.42-1,76 (4H, m), 1.76 (3H, s), 1.91-1.93
2.85 (3H, d, J = 4.9 Hz), 3.49
Figure imgf000127_0003
13.6 Hz), 4.95-5.05 (1H, m),
7.55-7.67 (2H, m), 7.8S-6.Q5 (4H, m), 8.95 (1H, br), 13.17 (1H. brs)
1H-N R (D SO-d6) 5ppm: 0.94-1.25 (2H, m), 1.25-1.45 (5H, m), 1.45-1.55 (1H, m),
1.55-1.80 (5H, m), 1.95-2.10 (1H, m), 2.82 (1H, d, J = 12.4 Hz), 2.97-3.11 (2H, m), Hydrochloride 3.36-3.51 (1H, m), 7.40 (1H, d, J = 7.3 Hz), 7.50-7.59 (3H, m), 7.79 (1H, d, J = 8.2 Hz),
7.89-7.98 ( H, m), 8.42-8.48 (1H, m), 8.97-9.24 (1H, br), 9.50-9.80 (1H, br).
1H-NMR (CDCI3) Bppm : 1.21-2.12 (8H, m), 1.77 (3H, a), 2.11 (3H. s), 249-2.55 (1H, m), 3.27 (1H, d, J = 13.1 Hz), 3.64-4.22 (3H, m), 3.94 {3H,s), 7.15-7.24 (2H, m), 7.68-7.85 ΟΆνύπκΜοΜβ
Figure imgf000127_0004
(3H, m), 8.25 (1H, bre), 10.04 (2H, brs)
1H- MR (CDCI3) 8ppm : 1.20-1.50 (2H, m), 1.63-2.28 (7H, m), 1.70 (3H, e), 1.95 (3H, e),
2.01 (3H, d, J = 4.9 Hz), 3.27 (1H, d, J = 13.2 Hz), 3.49-3.85 (1H, m>, 3.94 (3H, s),
(83 -CHj Dihydrochloride
OCH3 4.22-4.70 (2H, br), 7.14-7.25 {2H, m), 7.68-7.82 (3H, m), 7.97-8.60 (1H, br), 12.21 (1H,
bre)
1H-NMR (DMSO-d6) Bppm : 1.01-1.48 (6H, m), 1.48-1.85 (7H, m), 1.95-2.12 (1H, m),
Dihydrochloride
184 -H 2.88-3.33 (4H, m), 4.45-5.45 (1H, br), 7.30-7.48 (2H, m), 7.62-7.75 (2H, m), 7.89 (1H, d, J
= 8.8 HZ), 7.99 (1H, dd, J = 5.8, 9.1 Hz), 9.07-9.38 (1H, br), 9.60-9.68 (1H, br).
[0316]
Table 28
Absolute configuration
Figure imgf000128_0001
Example R1 NMR Salt
1H-NMR (CDCI3) Bppm : 0.96-1.07 f,1H, m), 1.25-1.33 (2H, m), 1.48-1.86 (3H, m), 1.65 (3H,
B), 1.85 (3H, 8), 1.95-2.12 (1H, m), 2.37-2.42 [1H, m), 288 (1H, d, J = 12.7 Hz), 3.20-3.35
Hydrochloride
185 -H (2H, m), 3.32 (1H, d, J = 127 Hz), 7.28 (1H, d, J = 7.7 Hz), 7.35 (1H, dd, J = 7.7, 7.7 Hz),
Figure imgf000128_0002
7.41 (1H, d, J = 5.5 Hz), 7.53 (1H, d, J = 5.5 Hz), 7.72 (1H, d, J = 7.7 Hz), 9.57 (1H, brs),
9.67 ( H, bre)
(3H, s), 247-2.54 (1H, m),
Figure imgf000128_0003
10.15 (2H, brs)
(3H, s), 1.84-2.21 (2H, m), 2.14 (3H, s),
m),
187 -CHj Dihydrochlorlde
Figure imgf000128_0004
5.5
Hz), 7.74-9.30 (2H, br), 7.97-8.10 (1H, m), 13.12 (1H, bra)
1H-NMR (COCI3) Bppm : 1.26-2.06 {8H, m), 1.75 (3H, a), 2,05 (3H, s), 2.46-2.52 (1H, m),
3.23 (1H, d, J = 13.4 Hz), 3.70-4.05 (2H, br), 3.66 (1H, d, J = 13.4 Hz), 7.36 (1H, d, J = 5.5
188 -H Dihydrochbride
Hz), 7.56 (1H, d, J = 5.5 Hz), 7.67 (1 H, brs), 7.89 (1H, d, J = 8.6 Hz), 8.38 (1H, bre), 10.03
(2H, brs)
1H-N R (CDCI3) Oppm : 1.18-1.35 (1H, rn), 1.39-1.53(1H, m), 1,55-1.75 (2H, m), 1.74(3H,
3), 1.84-1.86 (1H, m), 2.02-2.39 (4H, m), 2,08 (3H, S), 2.84 (3H, d, J = 4.9 Hz), 3.42 (1H, d,
189 -CH, Dihydrochlorlde
Figure imgf000128_0005
J = 13.5 Hz), 3.98-4.07 (1H, m), 4.56 (1H, d, J = 13.5 Hz), 4.76-4.84 (1H, m), 7.39 (1H, d, J
= 5.5 Hz), 7.63 (1H, d, J = 5.5 Hz), 7.90-7.99 (2H, m), B.7B0 (1 H, br), 13.05 (1H, brs)
1H- MR (DMSO-d6) Bppm : 0.95-1.48 (6H, m), 1.48-1.80 (7H, m), 1.90-2.O7 (1H, m),
Hydrochloride
190 -H 2.87-3.16 (3H, rn), 3.16-3.32 (1H, m), 7.23 ( H, d, J = 7.5 Hz), 7.40-7.52 (2H, m), 7.67-7.78
(2H, m), 8.92-9.22 (1H, br), 9.40-9.70 (1H, br).
[0317]
Table 29
Absolute configuration
Figure imgf000129_0001
Absolute configuration
Figure imgf000130_0001
NMR Salt
Figure imgf000130_0002
[0319]
Table 31
Absolute configuration
Figure imgf000130_0003
Example R* NMR Melting point (°C) Salt
-
Figure imgf000130_0004
7.39{1H, 8), e.10 (1H, Pre) Hemlfumarate
Fumarate
Fumarate
Figure imgf000131_0001
IH-NMR (DMSO-d6) Bppm : 0.90-1.63 (12H, m), 1.63-1.77 (1H, m), 1.82-1.99
(1H, m), 2.60-2.88 (2H, m), 2.91-3 4 (2H, m), 3.75 (3H, s), 3.80-5.30 (2H, br), Fumarate 6.36 (1H, d, J = 3.0 Hz), 6.48 (2H, s), 6.85 (1H, d, J = 8.4 Hz), 7.14 (1H, s), 7.27
Figure imgf000131_0002
(1H, d, J = 3.0 Hz), 7.46 (1H, d, J = 8.4 Hz), 8.76-10.00 (1H, br).
1H-NMR (D SO-d6) Bppm . 0.90-1.35 (10H, m), 1.40-1.55 (2H, m), 1.55-1.80
CH3 (1H, m), 2.02-216 (1H, m), 2.39 (3H, s), 2.55-2.80 (3H,m ), 2.90-3.08 (1H, m),
210 -CH. N Fumarate
3.15-4.70 C5H,m), 6.32-6.40 (1 H, m), 6.56 (2H, S), 6.85 (1H, dd, J = 1.5, 8.4 Hz),
7.14 (1H, s), 7.26 (1H, d, J = 3.1 Hz), 7.45 (1H, d, J = 8.4 Hz).
Fumarate
Figure imgf000131_0003
Dlhydrochloride
Dlhydrochloride
Figure imgf000131_0004
6.86 (1H, d, J = 8.2 Hz), 865-895 (1H, br), 3.22-9.52 (1H, br).
1H-NMR (DMSO) Bppm : 1.04-1.46 (4H, m), 1.35 (3H, s), 1.50-1.75 (4H, m),
1.59 (3H, B), 1.94-1.99 (1H, m), 282-2.92 (1H, m), 2.97 (1 H, d, J = 12.3 Hz),
216 -H 3.07 (1H, d, J = 12.3 Hz), 3.13-3.28 (1H, m), 7.28 (1H, dd, J = 8.5, 1.8 Hz), 7.81 Dlhydrochloride
Figure imgf000131_0005
(1H, d, J = 1.8 Hz), 8.12 (1H, d, J = 8.5 Hz), 8.85-9.05 (1H, br), 9.41 (1H, 8),
9.48-9.56 (1H, br) [0320]
Table 32
Absolute configuration
Figure imgf000132_0001
Example R' R4 NMR Melting point (°C) Salt
1H-NMR (DMSO-oS) δρρτη: 100-1.44 {6H, m), 1.50-1.79 (7H,
m), 1.96-2.08 (1H, m), 2.82-3.00 (2H, m), 3.00-3.25 (2H, m), 3.S1
217 -H (3H, S), 8.62 (1H, d, J = 9.5 Hz), 7.38-7.46 (1H, m), 7.48-7.58 Dihydrochlorlde
Figure imgf000132_0002
<2H, m), 7.91 (1H, d, J = 9.5 Hz), 7.98-B.62 (1H, br), 9.14-9.37
(1H, br), 9.65-9.88 (1H, br).
m), 1.09 (3H, m),
Figure imgf000132_0003
(1H, d, J= 8.5 Hz), 890 (1H, dd, J = 1.7, 4.2 Hz).
m), 1.22-1.48 (3H, m),
Hz),
219 -H Hz),
Figure imgf000132_0004
8.36
(1H, dd, J = .0, 8.4 Hz). 8.84 (1 H, d, J = 4.8 Hz).
1H-NNIR (CDCI3) 5ppm: 0.80-1.17 (5H, m), 1.21-1.50 (6H, m),
Hz),
220 -H , m),
Figure imgf000132_0005
(1H,
dd, J = 1.1, 8.3 Hz), 8.81 (1H, dd, J = 1.7, 4.2 Hz).
1H- MR (CDCI3) Bppm: 1.04-1.20 (4H, m), 1.20-1.48 (7H, m),
1.67-1.86 (3H, m), 1.98 (1H, dd, J = 3.0, 13.0), 2.61-2.70 (1H,
221 -H m). 2.82-2.95 (2H, m), 3.07 (1H, d, J = 12.0 Hz), 7.20 {1H, d, J =
N
1.8 Hz), 7.32 (1H, dd, J = 2.1, 8.8 HZ), 7.50 (1H, d, J = 5,8 Hz),
7.84 (1H, d, J = 8.8 Hz), 8.41 (1H, d, J = 5.8 Hz), 9.09 (1H, s).
[0321]
Table 33
Absolute configuration
Figure imgf000133_0001
Example R1 R5 R* NMR Salt
1H- MR (COC13) 6ppm : 1.21-1.36 (1H. m), 1.44-1.61 (2H, m), 1.68-2.00
(3H, m), 1.78 (3H, e), 2.09-2.33 (1H, m), 2.22 (3H, s), 2.51-2.55 (1H, m),
222 -H -H -H -F 3.42 (1H, d, J = 13.2 Hz), 3.92-4.12 (1H, m), 4.15 (1H, d, J = 13.2 Hz), Dihydrochloride
4.37-4.44 (1H, m), 7.22-7.27 (4H, m), 7.90-8.46 (1H, br), 9.90-10.18 (1H, m). 10.32-10.60 <1H, brs)
1H-NMR (CDCI3) Bppm : 0.90-1.10 (1H, m), 1.14-1.38 (2H. m), 1.40-1.75
(2H, m), 1.53 (3H, s), 1.59 (3H, e), 1.85-1.95 (1H, m), 2.01-2.23 (2H, m),
223 -CHj -H -H -H 272 (3H, d, J = 5.0 Hz), 2.75 (1H, d, J = 129 Hz), 2.87-3.06 (1H, m), Dihydroc loride
3.40-3.50 (1H, m), 3.80 (1H, d, J = 12.9 Hz), 6.98-7.04 (2H, m), 7,18-7.23
(2H, m), 12.10 (1H, brs)
1H-NMR (CDCI3) Bppm : 1.17-1.46 (3H, m), 1.53-1.74 (2H, m), 1.66 (3H, s), 1.79 (3H, 1.79 (1H, brs), 1.88-2.06 (1H, m), 2.24-2.46 (1H, m), 2.88
224 -H -H -F -F -H (1H, d, J = 12.5 Hz), 3.10-3.40 (2H, m), 3.43 (1H, d, J = 12.5 Hz), Hydrochloride
7.13-7.16 (2H, m), 7.20-7.28 (1H, m), 9.40-9,75 ( H, br), 9.76-10.08 (1H, br)
1H-NMR (COCI3) Bppm : 1.19-1.41 (3H, m), 1.61 (8H, brs), 1.80-2.02 (1H.
m), 2.04-2.24 (2H, m), 2.74 (3H, d, J = 5.0 Hz), 2.87 (1H. d, J = 12.8 Hz),
225 -CHj -F Hydrochloride
3.08-3.20 (1H, m), 3.62-3.78 (1H, m), 3.92 (1H, d, J = 12.8 Hz), 7.11-7.19
(2H, m), 7.27-7.32 (1H, m), 12.08 (1H, brs)
1H- MR (COCI3) Bppm : 1.13-1.42 (3H, m), 1.47-1.81 (3H, mj, 1.65 (3H,
S), 1.74 (3H, 8), 1.86-2.05 (1H, m), 2.32-2.38 (1H, m), 280 (1H, d, J = 12.5
226 -H -CI -H Hz), 3.07-3.16 (1H, m), 3.19-3.29 (1H, m), 3.36 (1H, d, J = 12.5 Hz), Hydrochloride
7.07-7.21 (2H, m), 7.34 (1H, dd, J = 6.5, 2.3 Hz), 9.56 (1H, bm), 9.82-9.88
(1H, br)
1H-NMR (DMSO-d8) Bppm : 1.00-1.45 (6H, m), 1 45-1.81 (7H, m),
1.81-2.10 (1H, m), 2.22 (3H, d, J = 1.5 Hz), 278-3.00 (2H, m), 3.00-3.27
227 -H -CH, Dihydrochloride
(2H, m), 4.10-4.98 (1H, br), 6.96-7.23 (3H, m), 9.00-9.40 (1H, br),
9.56-9.92 (1H, br).
1H-NVR (D SO-d6) S pp at 80 ¾: 1.00-1.43 (6H, m), 1.49-1.77 (7H, m), 1.97-2.08 (1H, m), 2.B1 (1H, d, J = 12.3 Hz), 2.84-2.93 (1H, m),
228 ■ -OCH, -H 3.04-3.16 (2H, m), 3.83 (3H, s), 4.30-4.57 (1H, br), 6.68-6.74 (1H, m), 6.86 Dihydrochloride
(1H, dd, J = 2.5, 7.9 Hz), 7.11 (1 H, dd, J = 8.6, 11.4 Hz), 8.94-9.25 (1H, br), 9.48-9.60 (1H, br).
1H-NMR (CDCI3) Bppm : 1.21-1.51 (2H, m), 1.62-1.97 (5H, m), 1.72 (3H, s), 2.03 PH, s), 2.29 (3H, 5), 2.44-2.49 (1H, m), 3.21 (1H, d, J = 12.9 Hz),
229 -H Hydrochloride
-CH3 -H -H
3.66-3.87 (2H, m), 3.21 (1H, d, J = 129 Hz), 7.25-7.31 (1H, m), 7.47-7.62
(2H, m), 10.00 (2H, bre) 1H-NMR (CDCI3) Bppm : 1.20-1.40 (3H, m), 1.48-1.75 (2H, m), 1.61 (3H, s). 1.64 (3H, s), 1.84-1.93 (1H, m), 2.11-2. 6 (2H, m), 2.26 (3H, d, J = 1.9
Hz), 273 (3H, d, J = 5.0 Hz), 2.90 (1 H, d, J = 12.9 Hz), 3.12-3.24 (1H, m), Hydrochloride 3.65-3.80 (1H, m), 3.82 (1H, d, J = 12.9 Hz), 7.09-7.21 (3H, m), 12.33 (1H, bra)
1H-NMR (CDCI3} δρρτη : 1.01-1.12 (1H, m), 1.20-1.39 (2H. m), 1.56-2.04
(4H, m), 1.63 (3H, s), .69 (3H, 2.31-2.36 (1H, m), 2.78 (1H, d, J = 12.4
Hz), 2.97-3.04 (1H, m), 3.13-3.24 (1H, m), 3.29 (1H, d, J = 12.4 Hz), Hydrochloride 6.91-7.01 (2H, m), 7.34 (1H, dd, J = 84, 8.3 Hz), 9.50 (1H, brs), 9.80 (1H, brs)
1H-NMR (COCO) δρρπι : 1.00-1.13 (1H, m), 1.17-1.40 (2H, m), 1.53 (3H, s), 1.60 (3H, s), 1.60-1.61 (3H, m), 1.90-1.94 f1H, m), 2.04-2.25 (1H, m),
Hydrochloride 272 (3H, d, J = 4.9 Hz), 2.78 (1H, d, J = 12.8 Hz), 2.92-3.04 (1H, m),
3.46-3.55 (1H, m), 3.81 (1H, d, J = 128 Hz), 7.00-7.06 <2H, m), 7.32-7.39
(1H, m), 12.26 (1H, brs)
1H- MR (OMSO-d6) 6ppm : 1.02-134 (3H, m), 133 (3H, s), 151 (3H, s),
154-173 (4H, m), 1.96-2.01 (1H, m), 2.76-2.83 (1H, m), 289 (1H, d, J = Dihydrochlorlde 12.5 Hz), 2.98 (1H, d, J = 12.5 Hz), 3.08-3.18 (1H, m), 3.87 (3H, s), 4.76
(1H, s), 6.86-6.96 (2H, m), 9.01-9.09 (1H, m), 9.70-9.75 (1H, m)
1H-NMR (DMSO-d6) δρρτη : 1.05-1.45 (6H, m), 145-180 (7H, m),
1.95-2.06 (1H, m), 2.70-2.90 (2H, m), 2.95-3.23 (2H, m), 3.81 (3H, s), Dihydrochlorlde 4.65-5.40 (1H, br), 8.88-7.08 (2H, m), 7.08-7.22 (1H, m), 8.90-9.25 (1H, br), 9.55-9.85 (1H, br).
1H-NMR (COC13) 6ppm : 105-113 (1H, m), 123-135 (2H, m), 1.50-178
(3H, m), 163 (3H, s), 1.71 (3H, s), 1.92-2.08 (1H, m), 2.31-2.36 (1H, m),
2.78 (1H, d, J = 12.7 Hz), 3.00-3.09 (1H, m), 3.15-3.26 (1H, m), 3.31 (1H, Hydrochloride d, J = 12.7 Hz), 7.07-7.10 (1H, m), 7.15-7.19 (2H, m), 7.23-7.29 (1H, m),
9.50 (1H, brs), 9.79 (1H, brs)
1H-NMR (CDC13) Sppm : 118-150 (2H, m), 160-181 (2H, m), 1.71 (3H, s), 191-2.30 (5H, m), 2.00 (3H, s), 2.80 (3H, d, J = 4.9 Hz), 3.32 (1H, d, J ^hydrochloride = 13.4 HZ), 3.81-3.94 <1R m), 4.42 (1H, d, J = 13.4 Hz), 4.61-4.70 (1H, m), 7.42-7.50 (2H, m), 7.97 (1H, brs), 8.13 (1H, brs), 13.7 {1H, brs)
1H-NMR (CDQ3) 6ppm : 105-120 (1H, m), 123-144 (2H, m), 1.54-2.10
(4H, m), 163 (3H, s), 1.88 (3H, s), 2.35-2.40 (1H, m), 2.89 (1H, d, J = 12.7 Hydrochloride Hz), 3.19 (2H, br), 3.34 (1H, d, J = 12.7 Hz), 7.06 (1H, dd, J = 8.4, 2.0 Hz),
7.20 (1H, d, J = 2.0 Hz), 7.81 (1H, d, J = 8.4 Hz), 9.62 (1H, brs), 9.90 (1H, br)
1H-NMR (CDCI3) Bppm : 101-115 (1H, m), 123-146 (2H, m), 150 (3H,
S), 161 (3H, s), 161-198 (3H, m), 2.09-2.27 (2H, m), 2.72 (3H, d, J = 4.9
Hydrochloride Hz), 2.87 (1H, d, J = 13.0 Hz), 2.91-3.03 (1H, m), 3.63-3.72 (1H, m), 3.84
(1H, d, J = 13.0 Hz), 7.14 (1H, dd, J = 8.4, 2.1 Hz), 7.26 (1H, d, J = 2.1
Hz), 7.62 (1H, d, J = 8.4 Hz), 12.38 (1H, brs)
1H-NMR (CDCI3) Sppm : 125-2.04 (7H, m), 1.75 (3H, s), 2.13 (3H,
2.40 (3H, s), 2.48-2.53 (1H, m), 3.33 (1H, d, J = 13.1 Hz), 3.88-3.92 (1H,
Hydrochloride m), 3.97 (1H, d, J= 13.1 Hz), 4.10-4.17 (1H, m), 7.36 (1H, d, J = 8. Hz),
7.78 (1H, d, J = 8.4 Hz), 8.00 (1H, s), 10.03-10.07 (1H, m), 10.20-10.30
I1H, rn) 1H-NMR (CDCI3) Bppm : 1.14-1.41 (3H, m), 1.47-1.74 (2H, m), 1 58 (3H,
s), 1.60 (3H s), 1.89-1.93 (1H, m), 2.10-2.22 (2H. m), 2.35 (3H, s), 2.72
Hydrochloride
240 -CHj -H -CI -CH3 (3H, d, J = 4.9 Hz), 2.83 (1H, d, J = 12.9 Hz), 3.0O-3.15 (1H, m), 3.45-3.67
(1H, m), 3.85 (1H, d, J = 12.9 Hz), 7.11-7.22 (2H, m), 7.32 (1H, s), 12.24
(1H, bm)
1H-NMR (DMSCXJ6) fi pm : 0.95-1.41 (6H, m), 1.41-1.60 (7H,m ),
1.88-2.05 (1H, m), 2.69-2.90 (2H, m), 2.93-3.05 (1H, m), 3.05-3.24
241 -H -CI -CCH, -H Dihydrochloride
(1H,m ), 3.83 (3H, S), 4.15-5.35 (1H, br}, 7.02-7.25 (3H, m), 8.87-9.18 (1H, br), 9.40-9.72 (1H, br).
1H- MR (COCI3) Sppm : 1.13-1.24 (1H, m), 1.25-1.36 (2H, m), 1.60-1.83
(3H, m), 1.64 (3H, s), 1.74 (3H, s), 1.B9-2.02 (1H, m), 2.32-2.37 (1H, m),
Hydrochloride
242 -H -H -CI -H -H 2.80 (1H, d, J = 12.5 Hz), 3.12-3.16 (1H, m), 3.22-3.29 (1H, m), 3.36 (1H,
d, J = 12.5 Hz), 7.19-7.22 (2H, m), 7.29-7.33 (2H, m), 9.52 (1H, brs), 9.81
(1H, bra)
1H-NMR (CDCI3) 6ppm : 1.02-1.40 (3H, m), 1.48-1.75 (2H, m), 1.61 (3H, s), 1.63 (3H, 8), 1.80-202 (1H, m), 2.11-216 (2H, m), 2.74 (3H, d, J = 5.0 Hydrochloride
243 -CH, -H -H -CI -H
HZ), 2.88 (1H, d, J = 129 Hz). 3.10-3.22 (1H, m), 3.66-3.78 (1H, m), 3.93
(1H, d, J = 12.9 Hz), 7.30-7.38 (4H, rrt), 12.28 (1H, brs)
1H-NMR (OMSO-d6) Bppm : 0.90-1.79 (13H. m), 1.78-1.95 (1H, m), 2.29
244 -H -H -CHa -CI -H -H (3H, s), 2.58-3.08 (4H, m), 3.10-4.30 (3H, br), 6.48 (2H, s), 6.89-7.00 (1H, Fumarate m), 7.07 (1 H, d, J = 2.3 Hz), 7.33 (1H, d, J = 8.5 Hz).
(7H, m),
Figure imgf000135_0001
7.37 (1H, d, J = 8.4 Hz), 8.90-9.19 (1H, br), 9.51-9.85 (1H, br).
1H-NMR (CDCI3) Oppm : 1.15-1.45 (3H, m), 1.58-1.81 (3H, m), 1.65 (3H,
B), 1.75 (3H, 8), 1.88-2.04 (1H, m), 2.32-2.38 (1H, m), 2.82 (1H, d, J = 12.6
Hydrochloride
246 -a -CI Hz), 3.12-3.31 (2H, m), 3.38 (1H, d, J = 12.6 Hz), 7.15 (1H, dd, J = 8.5, 2.3
Hz), 7.40 (1H, d, J = 2.3 Hz), 7.42 (1H, d, J = 8.5 Hz), 9.57 (1H, br), 9.82
(1H, br)
1H-NMR (CDCI3) Oppm : 1.23-1.49 (2H, m), 1.60-1.75 (2H, m), 1.69 (3H,
8), 1.91 (3H, 8), 1.91-2.15 (3H, m), 222-2.28 (1H, m), 279 (3H, d, J = 4.9
Hydrochloride
247 -CH, -a Hz), 3.23 (1H, d, J = 13.2 Hz), 3.64-3.76 (1H, m), 4.33 (1H, d, J = 13.2
Hz), 4.43-4.52 (1H, m), 7.56(1H, d, J = 8.7 Hz), 7.82 (1H, dd, J = 8.7, 2.3
Hz), 8.14 (1H, d, J = 2.3 Hz), 12.88 (1H, brs)
1H-NMR (DMSO-d6) Spprn : 1.02-1.50 (7H, m), 1.50-1.82 (6H, m),
Dihydrochloride
248 -H 1.96- 218 (1H, m), 2.60-3.60 (4H, m), 3.76 (3H, 8), 6.85-7.10 (2H, m),
7.10-7.6B(2H, m), 8.60-10.90 (3H, m).
1H-NMR (D SO-d6) tfppm at 80 °C: 1.00-1.43 (6H, m), 1.49-1.77 (7H, m), 1.97-2.08 (1H, m), 2.81 (1H, d, J = 123 Hz), 2.84-2.93 (1H, m),
Dihydrochlorlde
249 -H -H -OCHj 3.04-3.18 (2H, m), 3.83 (3H, e), 430-4.57 (1H, br), 6.66-6.74 (1H. m), 6.86
(1H, dd, J = 25, 7.9 Hz), 7.11 (1H, dd. J = 8.6, 11.4 Hz), 8.94-9.25 (1H, br), 9.49-9.80 (1H, br).
[0322]
Table 34
Abs n
Figure imgf000136_0001
Example R1 NMR Salt
1H-NMR (CQC13) Sppm '. 1.10-1.47 (3H, m), 1.48-2.16 (4H, m), 1.69 (3H, 6), 1.78 (3H, s),
Hydrochloride
250 -H 2.30-2.54 (1H, rn), 2.95 (1H, d, J = 12.5 Hz), 3.20-3.50 (2H, tor), 3.52 (1H, d, J = 12.5 Hz),
7.37-7.52 (2H, m), 7.60-8.00 (4H, m), 9.18-10.05 (2H, br)
1H-NMR (COCO) δρρτη : 1.20-1.35 (1H, m), 1.41-1.55 (1H, m), 1.59-1.82 (2H, m), 1.75 (3H, s), 1.91-2.01 (1H, m), 2.02-2.15 (2H, m), 2.14 (3H, s), 2.30-2.44 (2HP m), 2.85 (3H, d, J =
251 -CH, Dihydrochloride
Figure imgf000136_0002
4.8 Hz), 3.49 (1H, d, J = 13.5 Hz), 4.07-4.19 (1H, m), 4.66 (1H, d, J = 13.5 Hz), 492-5.01
8.87 {1H, br), 1311 (1H, brs)
Hydrochloride
Dihydrochloride
Figure imgf000136_0003
1H-NMR (CD CIS) Oppm : 1.20-2.05 (BH, m), 1.73 (3H, a), 2.00 (3H, s), 2.44-2.48 (1H, m),
254 -H 3.15 (1H, d, J = 10.7 Hz), 3.55-3.88 (3H, br), 7.38 (1 H, d, J = 5.5 Hz), 7.49-7.89 (1H, m), Dihydrochloride
7.55 (1H, d, J = 5.5 Hz), 7.92 (1H, d, J = 8.6 Hz), 8.14 (1H, bra), 9.94 (2H, brs)
[0323]
Table 35
Absolute configuration
Figure imgf000137_0001
Example R' R* NMR Salt
1H-NMR (DMSO-dB) oppm : 0.95-1.82 (13H, m), 1.97-2.12 (1H, m), 2.80-3.35 (4H, m),
265 -H 6.07-6.72 (1H, br), 6.72-7.20 (2H, m), 7.23-7.35 (1H, m), 7.35-753 (1H, m), 7.99 (1H, brs), Dihydfoc lorlda
Figure imgf000137_0002
280 -H Dihydrochloride
Figure imgf000137_0003
.2 Hz), 7.69 (1H,
J = 2.2 Hz), 8.97-9.26 (1 H, br), 9.45-9.82 (1 H, br).
[0324]
Table 36
Absolute configuration
Figure imgf000138_0001
Example R1 NMR Melting point ("C) Salt
209.8 -
281 -H . CN
N Fumarate
214.2
Dihydrochloride
Figure imgf000138_0002
1H-N R (CDa3) Bppm: 0.80-1.17 pH, m), 1.21-1.50 (6H, m), 1.61-1.88 (4H,
m), 242-2.50 (1H, m), 274 (1H, d, J = 11.4 Hz), 2.80-2.90 (1H, m), 2.96 (1H, d,
265 -H
J = 11.4 Hz), 7.31-7.39 (2H, m), 7.50 (1H, dd, J = 2.4, 9.0 Hz), 8.01 (1H, d, J =
9.0 Hz), 6.06 (1H, dd, J= 1.1, 8.3 Hz), 8.81 ( H, dd, J = 1.7, 4.2 Hz).
1H-NMR (CDCI3) Bppm: 1.04-1.20 (4H, m),' l.20-1.48 (7H, m), 1.67-1.86 (3H,
m), 1.96 (1H, dd, J = 3.0, 13.0), 261-2.70 (1H, m), 2.82-2.95 (2H, m), 3.07 (1H,
268 -H d, J = 12.0 Hz), 7.20 (1H, d, J = 1.8 Hz), 7.32 (1H, dd, J = 2.1, 8.8 Hz), 7.50
(1H, d, J = 5.8 Hz), 7.84 (1H, d, J = 8.8 Hz), 8.41 (1H, d, J = 5.8 Hz), 9.09 (1H,
[0325]
Table 37
Figure imgf000139_0001
Example R1 R5 R6 R7 R8 R9 NMR Salt
1 H-NMR (DMSO-d6) Sppm : 0.99-1.44 (6H, m), 1.44-1.80 (7H, m), 1.93-2.10
267 -H -H -H -F -H -H (1H, m), 2.75-299 (2H, m), 2.99-3.28 (2H,m ), 5.08-6.80 (1H, br), 7.10-7.33 -^hydrochloride
(4H, m), 8.96-9.42 (1H, br), 9.58-9.94 (1H, br).
1 H-NMR (DMSf d6) fippm at 80 °C. 1.00-1.43 (6H, m), 1.49-1.77 (7H, m),
1.97-2.08 (1H, m), 2.81 (1H, d, J = 123 Hz), 2.B4-293 [1H, m), 3.04-3.18
268 -H -H -OCHj -F -H -H (2H, m), 3.83 (3H, s), 4.30-4.57 (1H, br), 6.68-6.74 (1H, m), 6.86 (1H, <Jd, J = Dihydroehloride
2.5, 7.9 Hz), 7.11 (1H, dd, J = 8.6, 11.4 Hz), 8.94-9.25 (1H, br), 9.49-9.80
(1H, br).
1 H-NMR (CDCB) Bppm : 1.02-1.17 (1H, m), 1.25-1.44 (2H, m), 1.62-2.05
(4H, m), 1.63 (3H, s), 1.68 (3H, s), 235-241 (1H, m), 2.89 (1H, d, J = 12.8 Hydrochloride
269 -H . -H . -ci -CN -H -H
Hz), 3.20 (2H, br), 3.35 (1H, d, J = 12.8 Hz), 7.07 (1H, dd, J = 8.4, 2.0 Hz),
7.20 (1H, d, J = 20 Hz), 7.61 (1H, d, J = 8.4 Hz), 9.61 (1 H, bre), 9.89 (1H, br)
1 H-NMR (DMSO-d6) Bppm : 0.95-1.45 (6H, m), 1.45-1.80 (7H, m), 1.88-2.06
Dihydroehloride
270 -H -H -H -a -H -H (1H, m), 2.70-3.05 (3H, m), 3.08-3.28 [1H, m), 3.50-3.94 (1H, br), 7.13 (2H, d,
J = 8.7 Hz), 7.39 (2H, d, J = 8.7 Hz), 8.66-9.20 ( H, br), 9.20-9.80 (1 H, br).
1 H-NMR (DMSO-d6) Sppm : 1.00-1.45 (6H, m), 1.45-1.83 (7H, m), 1.90-208
<1H, m), 270-287 (1H, m), 2.87-3.08 (2H, m), 3.08-3.28 (1H, m), 3.85 (3H,
271 -H -H -OCH-, -a -H -H Hydrochloride s), 6.72 {1H, dd, J = 2.2, 8.4 Hz), 6.79 (1H, d, J = 22 Hz), 7.36 (1H, d, J = 8.4
Hz), 8.73-9.10 (1H, br), 9.34-9.70 (1 H, br).
1 H-NMR (CDCB) Bppm : 0.98-1.14 (1H, m), 1.26-1.39 (2H, m), 1.55-1.78
(3H, m), .62 (3H, B), 1.68 (3H, s), 1.92-2.05 (1 H, m), 2.30-2.35 (1 H, m), 273
272 -H -H * -a -H -H (1H, d, J = 12.5 Hz), 295-3.03 (1H, m), 3.11-3.23 (1H, m), 3.28 (1H, d, J = Hydrochloride
1 5 Hz), 7.20 (1H, dd, J = 8.5, 2.4 Hz), 7.25 (1H, d, J = 2.4 Hz), 7.39 (1H,
J = 8.5 Hz), 9.49 (1H, br), 9.79 (1H, br)
1 H-NMR (CDQ3) Bppm : 1.23-1.49 (2H, m), 1.60-1.74 (2H, m), 1.69 (3H, s),
1.87-2.15 (3H, m), 1.91 (3H, 8), 2.21-2.28 (1H, m), 2.78 (3H, d, J = 4.9 Hz),
Hydrochloride
273 -CHj -H -a ■a -H -H 3.22 (1H, d, J = 13.2 Hz), 3.63-3.75 (1H, m), 4.32 (1H, d, J = 13.2 Hz),
4.42-4.51 (1H, m), 7.56(1H, d, J = 8.7 Hz), 7.81 (1H, dd, J = 8.7, 20 Hz), 8.14
(1H, d, J = 20 Hz), 12.71 (1H, bre)
[0326]
Table 38
Absolute configuration
Figure imgf000140_0001
Example R2,Ra Salt
1H-NMR ( COCI3 ) Cppm : 1.25-1.7 ( 5H, m ), 1.75-1.9 ( 1H, m ), 2.05-2.2 ( 2H, m ). 2.3-2.4 ( 1H, m ), 2.6-2.7 [ 1H, m ), 2.8-2.9 ( 1H, m ), 2.92 ( 1H, d, J =
13.1Hz ), 3.0-3.15 ( 2H, m ), 3.65-3.75 ( 1H, m ), 4.20 ( 1H, d, J = 13.1Hz ),
Figure imgf000140_0002
6.7-6.8 ( 2H, m ), 7.1-7.2 ( 2H, m ), 7.2-7.3 ( H, m ), 7.3-7.4 ( H, m ).
: 1.2-1.4 ( 2H. m ), 1.4-1.5 ( H, m ), 1.5-1.95 ( H,
), 3.4-3.6 ( 2H. m ),
Dlhydrochloride ), 6.9-7.0 (2H, m ),
( 10H, m ), 2.3-2.6
1H, d, J = 13.4Hz ), Oihydrochloride 6.95-9.2 ( 1H, m ),
Figure imgf000140_0003
1H-NMR ( COC13 ) Bppm : 1.05-1.35 ( 3H, m ), 1.35-1.45 ( 1H, m ), 1.45-1.65
Figure imgf000140_0004
d, J = 9.1Hz).
( 10H, m ), 2.35-2.6
278 -(CH2)y
Figure imgf000140_0005
8.9Hz ), 8.9-9.1 ( 1H, m ), 11-125 ( 1H, m ).
[0327]
Table 39
Absolute configuration
Figure imgf000141_0001
Dihydrochloride
Figure imgf000141_0002
Dlhydrochlorlde
Figure imgf000141_0003
XXX OCH3
DIhydrachlorlde
Figure imgf000141_0004
[0328]
Table 40
n
Figure imgf000142_0001
Example ' R* R5 R* NMR Salt
1H-NMR (COCI3) 8ppm : 1.18-1.48 (2H, m), 1.62-208 {8H, m), 2.56-2.61
Oihydroehloride
284 -H -H -CHj (1H, m), 3.63-3.68 (1H, m), 4.23 (1H, brs), 4.67 {3H, bre), 7.61-8.26 (7H, m),
Figure imgf000142_0002
9.60-9.81 (1H, m), 11.36 (1H, br), 14.02 (1H, bre)
Bppm : 1.02-1.43 (3H, m), 130 (3H, d, J = 6.4 Hz),
1.95-2.20 (1H, m), 2.97-3.53 (6H, m), 7.26-7.46 (1H, br),
285 -H -H -CHj Dlhydrochloride
Figure imgf000142_0003
Hz), 7.69-8.00 (1H, br), 7.88 (1H, d, J = 5.4 Hz), 8.09 (1H,
d, J = 8.2 Hz), 9.28-10.12 (2H, br)
1H- MR (DMSOJBppm : 0.87-1.06 (1H, m), 1.17-1.35 (2H, m), 1.24(3H, d, J
a = 6.3 Hz), 1.41-1.84 (4H, m), .92-2.07 (1H, m), 2.88-3.08 (3H, m), 3.24 ( H,
286 -H -H -CHj Hydrochloride ci d, J = 124 Hz), 3.31-3.52 (1H, br), 7.16 (1H, dd, J = 8.6, 21 Hz), 7.40 (1 H, d,
J = 2.1 Hz), 7.60 (1H, d, J = 8.6 Hz), 9.02-9.33 (1H, br), 9.50-9.85 (1H, br)
1H-NMR (CDCI3) Bppm : 1,05 (3H, t, J = 7.3 Hz), 1.24-1.48 {2H, m),
.41 (1H, br), 243-2.76 (1H, m), 2.83-5.31 (5H, br), Hydrochloride .20 (1.3H, br), 11.04-11.78 (0.3H, br), 13.30-13.79
: 1.06 (3H, t, J = 7.6 Hz), 1.22-2.25 (10H, m),
(3H, s), 3.31-4.97 (4H, br), 7.36-8.02 {7H, m), Dihydrochloride
Figure imgf000142_0004
1H-NMR (CDCI3) Bppm : 0.80-247 (11H, m), 0.99 (3H, t, J = 7.4 Hz), 1.17
(3H, t, J = 7.3 Hz), 2.66-2.76 (1H, m), 286-3.18 (1H, br), 3.38-3.43 (1H, m),
Dihydrochloride
3.65- 4.01 (2H, m), 4.02-4.36 (1H, m), 7.54-7.61 (2H, m), 7.80-7.96 (5H, m),
9.37 (1H, bre).9.80-1049 (1H, br)
1H-NMR (CDa3) Bppm : 1.07 (3H, t, J = 7.5 Hz), 1:25-1.42 (2H, m),
1.48-1.85 (7H, m), 1.93-2.10 (2H, m), 2.16-2.40 (1H, m), 2.50-Z69 (1H, m), Dihydtochloiide
Figure imgf000142_0005
2.91-5.05 (4H, br), 7.33-8.76 (4H, br & m), 9.19-9.85 (1H, br), 11.09-11.67
(0.4H, br), 13.40-13.82 (0.6H, br)
1H-IMMR (CDC13) 5ppm : 0.80-2.44 (11H, m), 0.97 (3H, t, J = 7.4 Hz), 1.15
(3H, t, J = 7.4 Hz), 2.60-2.66 (1H, m), 2.78-3.09 (1H, m), 3.20-3.37 (1H. m),
Dlhydrochloride
291 -H -CjHs -¾Hs 3.45-4.16 (3H, m), 7.37 (1H, d, J = 5.4 Hz), 7.49-7.71 (1H, m), 7.55 (1H, d, J
Figure imgf000142_0006
" 5.4 Hz), 7.86-7.96 (1H, m), 8.01-8.47 (1H, br), 9.02-9.48 (1H, br),
9.69-10.18 (1H, br)
1H-NMR (CDCI3) Bppm : 1.07 (3H, t, J = 7.5 Hz), 1.23-1.50 (3H, m),
1.51-2.13 (8H m), 216-2.39 [1H, m), 2.50-2.71 (1H, m), 2.90-5.09 (4H, br), Dlhydrochloride
Figure imgf000142_0007
7.30-7.46 (1H, m), 7.46-8.33 (3H, br), 9.10-9.91 (1H, br), 10.95-11.65 (0.4H,
br), 13.37-ia92 {0.6H, br)
293 -H -CjHj -C2H5 Dlhydrochloride
Figure imgf000142_0008
9.66- 10.18 {1H, br) 1H-NM (CDCI3) Cppm : 0.87-2.38 (11H, m), 0.98 (3H, t, J = 7.4 Hz), 1.14
(3H, t, J = 7.2 HZ), 2.49-2.73 (1H, m), 2.73-3.11 (1H, m), 3.31-3.42 (1H, m),
294 -H -Oft -CjH, Dihydro Chloride
o 3.52-4.28 (3H, m), 6.82 (1H, d, J= 1.9 Hz), 7.54-7.68 (2H, m), 7.71 (1H, d, J
(1H, br), 9.75-10.34 {1H, br)
m),
11.1 Hydrochloride (1 H,
Figure imgf000143_0001
1H-NMR ( DMS0-d6 ) Oppm : 0.93 ( 3H, t, J = 7.3Hz ), 1.2-1.4 ( 2H, m ),
1.4-1.6 ( 3H, m ), 1.6-1.9 ( 6H, m ), 2.05-215 ( 1H, m ), 28-2.9 ( H, m ), 3.25 Hydrochloride
Figure imgf000143_0002
CI ( H, br ), 3.5-3.6 ( 2H, m ), 4.0-4.1 ( 1H, m ), 8.95-7.05 ( 2H, m ), 7.2-7.3 ( 2H
m ), 6.35-6.6 ( 1H, m ), 9.3-8.5 ( 1H, m ).
[0329]
Table 41
Rel n
Figure imgf000143_0003
Example R" NMR Salt
1H-NMR (CDCI3) Bppm : 0.08 (6H, s), 0.91 (9H, s), 1.04-1.35 (4H, rn), 1.53-1.80 (3H, m),
2.18-2.33 (2H, m), 2.60-2.76 (2H, m), 2.80-3.01 (3H, m), 3.09-3.13 (2H, m), 3.69-3.85 (2H,
Figure imgf000143_0004
m), 7.29-7.48 (3H, m), 7.52-7.53 (1H, m), 7.73-7.80 (3H, m)
, m),
(3H,
CHpH3 Hz),
Figure imgf000143_0005
Bppm : 0.07 (6H, s), 0.81-1.90 (3H, m), 0.90 (9H, s), 1.55-1.78 (4H, m),
2.46-2.54 (1H, m), 257-267 (1H, m), 2.72-282 (1H, m), 2.85-2.97 (4H,
0Η£Η3 m), 6.97 (1H, dd, J = 6.6, 2.4 Hz), 7.22 (1H, d, J = 24 Hz), 7.34 (1H, d, J
Figure imgf000143_0006
1H-NMR (CDCI3) δρρτπ : 1.25-1.53 (2H, m), 1.61-1.70 (1H, m), 1.74-1.80 (2H, m),
1.89-2.04 {2H, m), 238-2.43 (1H, m), 3.08-3.16 (1H, m), 3.53-3.59 (1H, m), 3.66-3.73 (1H,
300 -H Hydrochloride
Figure imgf000143_0007
m), 3.88-3.94 (1H, m), 4.06-4.14 (3H, m), 4.35-4.43 (2H, m), 4.61-4.78 (1H, m), 7.61 (1H, d,
J = 8.7 Hz), 7.71 (1H, d, J = 8.7 Hz), 8.00 (1H, brs), 12.52 (1H, bre)
[0330]
Table 42
Relative configuration
H H
CD
Example NMR Salt
1H-NMR (CDCI3) Bppm : 1.25-1.50 (2H, rn), 1.60-2.05 (5H, m), 2.35-270 (1H, m), 2.81-5.38 (6H, br),
301 Hydrochloride
Figure imgf000144_0001
br), 13.51-14.36 (0.55H, br)
302 , br), Dihydrochlorlde
303 Hydrochloride
Figure imgf000144_0002
[0331]
Table 43
Relative configuration
Figure imgf000144_0003
Example R1 * R¾ R» NMR Salt
1 H-NM { DMSO-d6 ) Bppm : 1.2-1.35 (2H, m ), 1.4-2.1 (10H, m ), 2.3-2.5 (2H, m ), 3.03 ( 1H, d, J = 13.2Hz ), 3.35-3.45 ( H, m ), 3.68 ( 1H, d, J = 13.4Hz ),
304 -H -<CHj)y Dihydrochlorlde
CI 3.9-4.0 ( 1H, m ), 4.35 ( 1H, br ), 6.95-7.05 ( 2H, m ), 7.2-7.3 ( 2H, m ), 8.9-9.1
( 1H, m ), 10.0-10.15 ( 1H, m ).
1H-NMR (COCO) Bppm : 1.20-1.58 (2H, m), 1.60-2.17 (10H, rri), 2.29-237 (1H, m), 2.46-2.87 (2H, m), 296-3.29 (1H, br), 3.33 (1H, d, J = 13.2 Hz), 3.60-398
305 -H -(CHj)«- Hydrochloride
(1H, br), 3.98-4.41 (2H, br), 7.56-7.60 (2H, m), 7.80-7.98 (4H, m), 8.11-8.71 (1H, br), 9.63-10.08 (1H, br), 10.13-10.87 (1H, br)
AH-NMR (CDCI3) 6 pm : 1.20-1.33 (1H, m), 1.40-2.0B (12H, m), 2.24-2.44 (2H, m), 2.58-2.69 (1H, m), 2.83 (3H, d, J = 4.8 Hz), 3.45 (1H, d, J = 13.4 Hz),
308 -CH3 -<CH2)«- Dihydrochlorlde
Figure imgf000144_0004
3.56-3.83 (1H, m), 3.874.14 (1H, m), 4.08 (1H, d, J = 13.4 Hz), 4.74-4.86 (1H,
m), 7.55-7.65 (2H, m). 7.88-8.03 (4H, m), 8.42-9.20 (1H, br), 13.33 (1H, brs)
307 H -(CHdf Dihydrochlorlde
Figure imgf000144_0005
(1H, d, J = 6.6 Hz), 8.12-8.19 (1H, br), 9.65-10.02 (1H, br), 10.29-10.83 (1H, br) 1H-NMR (CDCI3) Oppm : 1.20-1.36 (1H, m), 1.41-2.21 (12H, m), 2.29-Z37 (1H,
m), 2.49-2.58 (1H, m), 2.61-2.67 (1H, m), 3.07-3.30 ( H, br), 3.36 (1H, d, J = 13.1
308 Hz). 3.66-3.97 (1H, br), 3.98-4.32 (2H, br), 7.38 { H, d, J = 5.5 Hz), 7.59 (1H, d, J Dlhydrochlorlde
Figure imgf000145_0001
= 5.5 Hz), 7.67-7.90 (1H, br), 7.93 (1H, d, J = 8.6 Hz), 8.11-8.93 (1H, br),
9.56-10.03 (1H, br), 10.20-10.81 (1H, br)
1H-N R (CDCI3) Bppm : 0.91-1.13 (1H, m), 1.23-1.38 (2H, m), .46-2.12 (10H,
Cl m), 2.33-2.48 (3H, m), 276 (1H, d, J = 12.5 Hz), 2.94-3.12 (2H, m), 3.32 (1H, d, J
309 Hydrochloride
CI = 12.5 Hz), 7.03 (1 H, dd, J = 8.5,2.4 Hz), 7.28 (1H, d, J = 2.4 Hz), 7.39 (1 H, d, J =
8.5 Hz), 9.75 (2H, brs)
CI 1H- MR (DMSO) δρριτι : 0.96-2.27 (16H, m), 2.97-3.59 (4H, m), 7.10 (1H, d, J =
310 -(CH_)4- 8.7 Hz), 7.31 (1H, s), 7.78 (1H, d, J = 8.7 Hz), 8.93-9.28 (1H, br), 9.32-9.67 (1H, Hydrochloride
(CDCI3) Spprn : 1.18-2.19 (16H, m), 2.30-2.35 (1H, m), 2.47-252 (1H,
311 {1H, br), 3.44-3.67 (3H, m), 7.47-7.61 (3H, m), 7.83-7.89 (4H, m), 9.84 Hydrochloride
Figure imgf000145_0002
1H-NMR (CDCI3) Bppm : 0.89-1.01 (1H, m), 1.08-1.70 (15H, m), 1.86-1.90 (1H, m), 2.42-2.47 (1H, m), 2.64-2.73 (1H, m), 2.79 (1 H, d, J = 12.2 Hz), 3.00-3.08
312 (1H, m), 3.15 (1H, d, J = 12.2 Hz), 3.76 (3H, s), 3.47-4.70 (3H, br), 6.36 [1H, d, J Fumarate
CH3 = 3.0 Hz), 8.49 (2H, s), 6.93 (1H, dd, J = 8.6, 1.4 Hz), 7.27 (1 H, d, J = 1.4 Hz),
7.29 (1H, d, J = 3.0 Hz), 7.36 (1 H, d, J = 8.6 Hz)
1H-NMR (CDCI3) 6ppm ; 0.96-1.08 (1H, m), 1.23-1.45 (6H, m), 1.06-2.13 (8H,
•CI m), 2.20-2.25 (1H, m), 2.35-2.40 (1H, m), 2.62-2.67 (1H, m), 3.03-3.31 (4H, m),
313 -(CHjfe- Hydrochloride
CI 7.03 (1H, dd, J = 8.5, 2.4 Hz), 7.26 (1H, d, J = 2.4Hz), 7.40 (1H, d, J = 8.5 Hz),
9.49 {2H, brs)
[0332]
Table 44
Absolute configuration
Figure imgf000145_0003
Example R NMR Salt
1H-N R ( CDCI3 ) 6pprn : 0.9-1.1 ( 1H, m ), 1.15-1.4 ( 3H, m ), 1.55-1.7 ( 2H, m ), 1.75-1.85
( 1H, m ), 2.1-2.2 ( 1H, m ), 2.25-2.45 ( 2H, m ), 2.55-2.7 { H, m ), 2.7-2.8 ( 1H, m ), 2.85-2.95
314 ( 2H, m ), 3.21 ( 1H, d, J = 13.4Hz ), 4.18 ( 1H, d, J = 13.4Hz ), 7.05-7.1 ( 2H, m ), 7.2-7.35
(7H, m).
1H-NMR ( CD03 ) Bppm : 0.9-1.4 ( 4H, m ), 1.5-1.65 ( 2H, m ), 1.7-1.9 ( 2H, m ), 205-2.2
315 -H ( 1 H, m ), 2.32 ( 3H, s ), 2.45-26 ( 2H, m ), Z8-2.9 ( 1 H, m ), 29-3.1 ( 2H, m ), 7.0-7.1 ( 2H,
m ), 7.2-7.3 ( 2H, m ). [0333]
Table 45
Absolute configuration
Figure imgf000146_0001
Example R1 NMR Salt
1 H-NMR ( CDCB } Oppm .0.95-1.1 ( H, m ), .15-1.45 ( 3H, m ), 1.5-1.7 ( 2H, m ), 1.75-1.85
( 1H, m), 2.1-2.25 ( 1H, m ), 2.25-245 ( 2H, m), 2.55-2.7 ( 1H, m ), 2.7-2.8 ( 1H, m ), 285-3.0
318
H2C ( 2H, m ), 3.21 ( 1H, d, J = 13.3Hz), 4.18 { 1H, d, J = 13.4Hz), 7.0-7.1 ( 2H, m ), 7.2-7.35 ( 7H, m ).
1 H-NMR (, DMSCMJ6 ) 6ppm : 0.65-1.05 ( 1H, m ). 1.1-1.4 \ 2H, m ), 1.4-1.65 ( 3H, m ),
7 1.65-1.8 ( H, m ), 1.8-2.05 { H, m ), 2.8-3.0 ( 2H, m ), 3.0-3.2 ( 3H, m ), 3.2-3.5 ( H, m ), Hydrochloride
31
7.1-7.2 ( 2H, m 5, .35-7.45 { 2H, m >, 9.2-9.7 ( H, m ).
1 H-NMR ( COC13 ) Bppm 0.9-1.4 ( 4H, m ), 1.5- .65 ( 2H, m ), 1.7-1.9 ( 2H, m ), 2.05-2.2
318 -c¾ ( 1H, m 1, 2.32 ( 3H, β ), 2.45-2.6 ( 2H, m), 2.6-2.9 ( H, m ), 2.9-3.1 ( 2H, m ), 7.0-7.15 ( 2H,
m ), 7.2-7.3 ( 2H, m ).
[0334]
Table 46
Re
Figure imgf000146_0002
Example NMR Salt
1 H-NMR (DMSO-d6) Bppm : 1.35 (3H, e), 1.45-1.67 (6H, m), 1.67-2.00 (4H, m), 2.16-2.30
(2H, m), 230-2.43 (1H, m), 3.39-3.48 (1H, m), 3.62-3.72 (1H, m), 3.88-3.96 (1H, m),
319 Dihydrochlorlde
3.09-1.08 (1H, m), 6.05*75 (1H, br), 7.10 (1H, »), 7.20-7.25 (1H, m), 7.25-7.34 (1H, m),
7.33-7.40 (1H, m), 7.66-7.80 (3H, m), 6.22-8.35 (1H, br), 9.30-9.45 (1H, br).
1 H-NMR (DMS&d6) Sppm at 80 °C. 1.37-1.55 (5H, m), 1.55-1.70 (4H, m), 1.71-200 (4H, m), 2,19-2.40 (3H, m), 3.3W.50 (1H, m), 3.52-3.66 (1H, m), 3.84-3.97 (2H, m), 5.53-5.66
320 Dihydrochlorlde
(1H, br), 7.08 (1H, dd, J = 2.4, 8.9 Hz), 7.28 (1H, d, J = 5.4 Hz), 7.36 (1H, d, J = 2.4 Hz), 7.60
(1H, d, J = 5.4 Hz), 7.76 (1 H, d, J = 8.9 Hz), 6.07-6.40 (1H, br), 9.20-9.57 (1H, br).
1H-NMR (DMSO-d6) Bppm : 1.32 (3H, s), 1.43-1.61 (6H, m), 1.65-1.89 (4H, m), 207-2.17
(1H, m), 217-227 (1H, m), 227-240 (1H, m), 3.27-3.36 (1H, m), 3.40-3.55 (1H, m),
321 Dihydrochlorlde
Figure imgf000146_0003
3.79-3.90 (2H, m), 5.00-6.60 ( H, br), 6.84 (2H, d, J = 8.9 Hz), 7.19 (2H, d, J = 8.9 Hz),
8.19-6.35 (1H, br), 9.25-9.44 (1H, br).
1 H-NMR (DMSO-d6) Bppm : 1.32 (3H, 3), 1.40-1.63 (6H, m), 1.63-1.90 (4H, m), 2.07-2.25
CI (2H, m), 2.30-2.33 (1H, m), 3.27-3.38 (1H, m), 3.48-3.59 (1H, m), 3.78-3.66 (1H, m).
322 Dihydrochloride
3.86-3.95 (1H, m), 5.30-6.75 (1H, br), 6.83 (1H, d, J = 3.0, 9.1 Hz), 7.02 (1H, d, J = 3.0 Hz),
7.35 (1H, d, J = 9.1 Hz), 8.23-8.40 (1H, br), 9.22-9.45 (1H, br). [0335]
Table 47
Relative configuration
Figure imgf000147_0001
Example NMR Salt
1H-NMR (DMSO-d6) 8ppm : 1.39 (3H, s), 1.43-1.65 (7H, rn), 171-1.90 (4H, m), 1.93-2.06
Figure imgf000147_0002
[0336]
Table 48
Absolute configuration
Figure imgf000147_0003
Example NMR Salt
1H-NMR (DMSO-d6) rjppm : 1.35 (3H, s), 1.45-1.67 (6H, m), 1 67-2.00 {4H, m), 2.16-2.30
(2H, m), 2.30-2.43 (1H, m), 3.38-3.48 (1H, m), 3.62-3.72 (1H, m). 3.88-3.98 (1H, m),
Figure imgf000147_0004
3.09-4.08 (1H, m), 6.05-6.75 (1H, br), 7.10 (1H, 7.20-7.25 (1H, m), 7.25-7.34 (1H, m),
m), 8.22-B.35 (1H, 8.30-9.45 (1H, br).
1.37-1.55 (5H, m), 1.55-1.70 (4H, m), 1.71-2.00 (4H, m), 3.52-3.66 (1H, m), 3.84-3.97 (2H, m), 5.53-5.86
Figure imgf000147_0005
7.28 (1H, d, J = 5.4 Hz), 7.36 (1H, d, J = 2.4 Hz), 7.60
(1H, J = 5.4 Hz), 7.76 (1H, d, J = 8.9 Hz), 8.07-8.40 (1H, 9.20-9.57 (1H, br).
1H-NMR (DMSO-d6) 6ppm : 1.33-1.52 (10H, m), 1.64-1.82 (4H, m), 1.82-1.93 (1H, m),
329 2.30-2.40 (1H, m), 3.40-3.54 (2H, m), 3.54-370 (2H, m), 4.45-5.20 (1H, 6.66 (2H, d, J = DihydrooWoride
CI 9.0 Hz), 7.19 (2H, d, J = 9.0 Hz), 8.55-8.70 (1H, br), 8.75-6.92 (1H,
1H-NMR <DMSO-d6) Bppm : 1.32 (3H, s), 1.40-1.63 (6H, m), 1.63-1.90 (4H, m), 2.07-2.25
(2H, m), 230-2.33 (1H, m), 3.27-3.38 (1H, m), 3.48-3.59 (1H, m), 3.78-3.86 (1H, m),
Figure imgf000147_0006
3.86-3.95 (1H, m), 5.30-6.75 (1H, br), 6.83 (1H, d, J = 3.0, 9.1 Hz), 7.02 (1H, d, J = 3.0 Hz),
7.35 (1 H, d, J = 9.1 Hz), 8.23-8.40 (1 H, br), 9.22-9.45 (1H, br). [0337]
Table 49
Ab
Figure imgf000148_0001
Example NM Salt
1H- MR (DMSO-d6) Oppm : 1.35 (3H, s), 1.45-1.67 (6H, m). 1.67-200 (4H, m), 216-2.30
(2H, m), 2.30-2.43 (1H, m), 3.39-3.48 (1H, m), 3.62-3.72 (1H, m), 3.88-3.96 (1H, m),
331 □(hydrochloride
3.09-4.08 (1H, m), 6.05-6.75 (1H, br), 7.10 (1H, 8), 7.20-7.25 (1H, m), 7.25-7.34 (1H, m), 7.33-7.40 (1H, m), 7.66-7.80 (3H, m), 8.22-6.35 (1H, br), 9.30-9.45 (1H, br).
1H-NMR (D SO-de) S pm at 80 ¾: 1.37-1.55 (5H, m), 1.55-1.70 (4H, m), 1.71-2.00 (4H, m), 2.19-2.40 (3H, m), 3.35-3.50 (1H, m), 3.52-3.66 (1H, m), 3.84-3.97 (2H, m), 5.53-5.86
332 Dlhydrochloride
Figure imgf000148_0002
(1H, br), 7.06 (1H, dd, J = 2.4, 8.9 Hz), 7.28 (1H, d, J = 5.4 Hz), 7.36 (1H, d, J = 2.4 Hz), 7.60
d, J = 8.9 Hz), 8.07-8.40 (1H, br), 9.20-9.57 {1H, br).
m), 1.64-1.82 (4H, m), 1.82-1.93 (1H, m),
333 (2H, m), 4.45-5.20 (1H, br), 6.68 (2H, d, J = Dihydrochloiide
Figure imgf000148_0003
br), 8.75-8.92 (1H, br).
1H- MR (DMSO-dS) 5ppm : 1.32 (3H, s), 1.40-1.63 (6H, m), 1.83-1.90 (4H, m), 2.07-2.25
CI (2H, m), 230-2.33 (1H, m), 3.27-3.38 (1H, m), 3.48-3.59 {1H, m), 3.78-3.86 (1H, m),
334 ^hydrochloride
3.86-3.95 (1H, m), 5.30-6.75 (1H, br), 6.63 (1H, d, J = 3.0, 9.1 Hz), 7.02 (1H, d, J = 3.0 Hz),
7.35 ( H, d, J = 9.1 Hz), 8.23-8.40 ( H, br), 9.22-9.45 (1H, br).
[0338]
Table 50
Absolute configuration
Figure imgf000148_0004
8.80-9.00 (1H, br).
1H-NMR (DMSO-d6) Sppm at 80 ¾: 1.38-1.54 (10H, m), 1.69-2.02 (5H, m), 241-2.50 (1H,
336 m), 3.55-3.85 (4H, m), 4.97-5.80 [1H, br), 6.94-7.10 (1H, br), 7.18-7.40 (2H, m), 7.59 (1H, d, J Dlhydrochloride
Figure imgf000148_0005
= 5.4 Hz), 7.78 (1H, d, J = 8.9 Hz), 8.75-8.92 (1H, br), 8.92-9.30 (1H, br).
1H- MR (DMSO-d6) δρρτη : 1.33-1.52 (10H, m), 1.64-1.82 (4H, m), 1.82-1.93 (1H, m),
337 2.30-2.40 (1H, m), 3.40-3.54 (2H, m), 3.54-3.70 (2H, m), 4.45-5.20 (1H, br), 6.66 (2H, d, J = DihydracMoride
9.0 Hz), 7.19 (2H, d, - = 9.0 Hz), 6.55-6.70 (1H, br), 8.75-8.92 (1H, br).
1H-NMR (DMSO-d6) 6ppm : 1.33-1.59 (10H, m), 1.61-1.90 (5H. m), 2.33-2.45 (1H, m),
338 3.45-3.56 (2H, m), 3.56-3.71 (2H, m), 5.05-β.ΟΟ (1H, br), 6.65 (1H, dd, J = 2.B, 9.1 Hz), 6.78 Oihydrochlortde
Figure imgf000148_0006
(1H, d, J = 2.8 Hz), 7.34 (1H, d, J = 9.1 Hz), 8.70-8.89 (1H, br), 9.00-9.15 (1H, br).
Figure imgf000149_0001
Example R* ' NM Salt
1H-NMR (DMSO-dS) Bppm : 1.39 (3H, s), 1.43-1.65 (7H, m), 1.71-1.90 (4H, m), 1.93-2.06 (1H, m),
339 T JL J 235-2.45 (1H, m), 3.60-3.79 (4H, m), 5.40-6.15 (1H, br), 6.90 (1H, a), 7.09-7.20 (2H, m), 7.30-7.40 ^hydrochloride
^*5^^ (1H, m), 7.65-7.72 (2H, m), 7.75 (1H, d, J = 9.0 Hz), 8.60-8.80 (1H, br), 8.80-9.00 (1H, br).
1H*IM (DMSO-dS) Sppmat 80 °C: 1.38-1.5 (10H, m), 1.89-2.02 (5H, m), 241-2.50 (1H,
340 jf ' ? m). 3.55-3.85 (4H, m), 4.97-5.80 {1H, br), 6.94-7.10 (1H, br), 7.1 B-7.40 (2H, m), 7.59 (1H, d, J = Olhydroch!orlde
® 5.4 Hz), 7.78 (1H, d, J = 8.9 Hz), 8.75-8.92 (1H, br), 8.92-9.30 (1H, br).
\^¾. 1H- MR (DMSO-d6) βρρτπ : 1.33-1.52 (10H, m), 1.64-1.82 (4H, m), 1.82-1.93 (1H, m),
341 JjL, 2.30-2.40 (1H, m), 3.40-3.54 (2H, m), 3.54-3.70 (2H, m), 4.45-5.20 (1H, br), 6.88 (2H, d, J = 9.0 Dihydrochlorido
Hz), 7.19 (2H, d, J = 9.0 Hz), 8.55-8.70 (1H, br), 8.75-8.92 (1H, br).
H-NMR (DMSO-<J6) 6ppm : 1.33-1.59 (10H, m), 1.61-1.90 (5H, m), 2.33-2.45 (1H, m),
342 3.45-3.56 (2H, m), 3.56-3.71 (2H, m), 5.05-6.00 (1H, br), 6.65 (1H, dd, J = 2.8, 9.1 Hz), 6.78 Dihydrochlorido
Figure imgf000149_0002
(1H, d, J = 2.8 Hz), 7.34 (1H, d, J = 9.1 Hz), 8.70-8.89 (1H, br), 9.00-9.15 (1H, br).
[0340]
Table 52
Relative configuration
Figure imgf000149_0003
Example R* NMR Salt
(2H, m), 2.94 (1H, d, J = 13.3), 3.51
343 Dlriydrochlorlde
Figure imgf000149_0004
(1H, br).
1H-NMR(DMSO-d6)6ppm : 1.10-1.38 (3H, m), 1.38-1.65 (8H, m), 1.65-1.92 (3H, m), 2.15-2.40 (2H, m), 289 (1H, d, J = 13.3 Hz), 3.37 (1H, d, J = 13.3 Hz), 3.77-3.95 (1H, m), 4.00-4.14 (1H,
344 ' Hydrochloride
Figure imgf000149_0005
m), 7.17 (1H, dd, J = 2.3, 8.9 Hz), 7.28-7.38 (2H, m), 7.68 (1H, d, J = 5.4 Hz), 7.83 (1H, d, J '
8.9 Hz), 8.44-8.74 (1H, br), 9.85^.90 (1H, br).
Figure imgf000149_0006
[0341]
Table 53
Relative configuration
Figure imgf000150_0001
CI 1H-NMR (DMSO-de) Sppm : 1.33 (3H, s), 1 36 (3H. s), 1.50-1 90 (9H, m), 2.07-2.28 (1H, m),
350 3.07 (1H, d, J = 14.2 Hz), 3.32-3.66 (3H, m), 6.88 (1H, dd, J = 2.8, 8.9 Hz), 7.09 (1H, d, J = 2.8 Hydrochloride
HZ), 7.43 (1H, d, J = 8.9 Hz), 8.70-8.92 (1H, br), 9.35-9.58 (1H, br).
2]
Table 54
Relative configuration
Figure imgf000151_0001
Example R5 R R7 MS(M+1 )
351 -H -H -H -H -H 245 352 -H -H -CH3 -H -H 259 353 -H -CH3 -H -H -H 259 354 -H -F -H -H -H 263 355 -H -H -CN -H -H 270
Figure imgf000151_0002
357 -H -CZH5 -H -H -H 273 358 -H -CH3 -H -CH3 -H 273 359 -H -H -CzH. -H -H 273 360 -H -OCH3 -H -H -H 275 361 -H -F -H -F -H 281 362 -H -CH3 -CN -H -H 284 363 -H -H -(CH2)2CH3 -H -H 287 364 -H -CH(CHj)2 -H -H -H 287 365 -H -H -CH(CH3)2 -H -H 287 366 -H -F -CN -H -H 288 -H -CN -H -F -H 288 -H -N(CH3)2 -H -H -H 288 -H -H . -N(CH3)2 -H -M 288 -H -OC2H5 -H -H -H 289 -H -CH3 -OCH3 -H -H 289 -H -H -OCHzCHj -H -H 289
Figure imgf000152_0001
-H -H -SCH3 -H -H 291
Figure imgf000152_0002
-H -F -H -CI -H 297 -H -F -F -F ■ -H 299 -H -H -C(CH3)3 -H -H 301 -H -CH3 -OCH3 -CH3 -H 303 -H •OCH(CH3)2 -H -H -H 303
Figure imgf000152_0003
-H -H -SCH2CH3 -H -H 305
-OCH3 -H -H -CI -H 309
Figure imgf000152_0004
-H -H <rN -H -H 311
INK -H -CF3 -H -H -H 313
-H -H -CF3 -H -H 313
-CI -H -CI -H -H 313
-H -CI -H -CI -H 313
-H -CF3 -CH3 -H -H 327
Figure imgf000153_0001
-H -H -OCF3 -H -H 329
-H -CF3 -H -F -H 331
Figure imgf000153_0002
-F -CF3 -H -H -H 331
-H -CF3 -F -H -H 331
-H -CF3 -OCH3 -H -H 343
-H -CF3 -CI -H -H 347
3]
Table 55
Relative configuration
Figure imgf000154_0001
ı54
Figure imgf000155_0001
44]
Table 56
Figure imgf000156_0001
Exam le R S( +1)
Figure imgf000156_0002
Figure imgf000157_0001

Figure imgf000158_0001
]
Figure imgf000159_0001
442 -H -OCH, -H -H -H 275
443 -OCH3 -H -H -H -H 275
444 -CH3 -H -H -H 277
445 -H -CHs -H -H 277
446 -F -H -H -CH3 -H 277
447 -H -F -CH3 -H -H 277
Figure imgf000160_0001
449 -H -H -F -H 281
450 -H -H -H 281
451 -H -CH3 -CN -H -H 284
452 -H -C(0)CH3 -H -H -H 287
453 -H -H -C(0)CH3 -H -H 287
454 -CH3 -H -Ch -CH, -H 287
455 -H -H -CH(CH3)2 -H -H 287
456 -H -CN -H -H 288
457 -H -F -CN -H -H 288 458 -H -CN -H -H 288
459 -H -N(CHj)2 -H -H -H 288
460 -H -H -N(CH3)2 -H -H 288
461 -CH3 -H -OCH3 -H -H 289
462 -H -CH3 -OCH3 -H -H 289
463 -H -CH3 -CH3 -H 291
464 -CH3 -CH3 -H -H 291
465 -H -H -SCH3 -H -H 291
466 -H -SCH3 -H -H -H 291
Figure imgf000161_0001
468 -CH3 -CI -H -H -H 293
469 -H -CH3 -CI -H -H 293
470 -H -CI -CH, -H -H 293
471 -CH3 -H -CI -H -H 293
472 -H -H -CI -H 297
473 -H -H -CI -H 297 474 -H -CI -H -H 297
475 -H -F -H 299
476 -H -H -(CH2) 3CH3 -H -H 301
477 -H -H -C(CH3) a -H -H 301
478 -H -H -CH2N(CH3)2 -H -H 302
479 -H -CH2N(CH3) 2 -H -H -H 302
480 -OCH{CH3) z -H -H -H -H 303
481 -H -CH3 -OCH3 -CH3 -H 303
482 -H -CI -CN -H -H 304
483 -H -OCH3 -H -OCH3 -H 305
484 -H -OCH, -OCHj -H -H 305
485 -OCH3 -H -H -OCH3 -H 305
486 -OCH* -F -H -H 311
487 -H -OCH3 -F -H 31 1
488 -OCH3 -H -F -H 311
489 -H -H -OCHFz -H -H 311
Figure imgf000163_0001
491 -H -H ) -H -H 311
492 -H Y U¾ -H -H -H 311
493 -H -H -H -H 311
494 -CF3 -H -H -H -H 313
495 -H -CF3 -H -H -H 313
496 -H -H -CF3 -H -H 313
497 -CI -H -CI -H -H 313
498 -H -CI -H -CI -H 313
Figure imgf000163_0002
500 -H -CHj -N(CH3)2 -CH3 -H 316
501 I J -H -H -H -H 321
Figure imgf000163_0003
504 -H . -CI -OC2Hs -H -H 323
Figure imgf000164_0001
509 -H -CF3 -CH, -H -H 327
Figure imgf000164_0002
14 -H -OCR -H -H -H 329 15 -OCF3 -H -H -H -H 329 6 -H -H -OCF3 -H -H 329 517 -H -CF3 -H -H 331
518 -H -CF, -F -H -H 331
519 -H -H -0(CHZ)2N(CH3)2
520 -H -OCH3 -OCH3 -OCH3 -H 335
H2
521 -H -H -H -H 335
Figure imgf000165_0001
526 -H -CFa -OCH3 -H -H 343
527 -H -H -0(CH2)5CH3 -H -H 345
528 -H -0(CH2) 3N(CH3)2
Figure imgf000165_0002
530 -H -CI -CF3 -H -H 347 531 -H -CF, -CI -H -H 347
532 -CI -CI -H -CI -H 347
Figure imgf000166_0001
537 -H -H -SOzN(CH3)z -H -H 352
Figure imgf000166_0002
541 -H -H -CH2N(i-Pr)2 -H
-H 358
542 -H -C -H -CF3 -H 381
Figure imgf000167_0001

Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
47]
Figure imgf000171_0001
[0348]
Table 63
Relative confi uration
Figure imgf000172_0001
Exam
R NMR Salt pie
1H-NMR ( DMSO-d6 ) 5ppm : 1.1-1.3 ( 2H,
m ), 1.3-1.45 ( 4H, m ), 1.52 ( 3H, s ), 1.6-1.9
( 4H, m ), 1.95-2.1 ( 1 H, m ), 2.93 ( 1 H, d, J =
588 13.1Hz ), 3.11 ( 1H, d, J = 13.3Hz ), 3.68 ( 3H, 2 Hydrochloride
OC > d, J = 0.6Hz ), 3.7-4.4 ( 3H, m ), 6.82 ( 2H, d, J
= 9.0Hz ), 6.89 ( 2H, d, J = 9.1Hz ), 8.09 ( 1 H,
br ), 9.83 ( 1H, br )
[0349]
Table 64
Absolute configuration
Figure imgf000172_0002
1H-NMR ( CDCI3 ) 6ppm : 1.03-1.12 ( 18H, m ), 1.12-1.32 ( 12H, m ), 1.32-1.65 ( 2H, m ), 1.66-1.84 ( 4H, m ), 2.82 ( 1H, d, J = 11.7Hz ), 3.08 ( 1H, d, J = 11.8Hz ), 3.47-3.53 ( 1H, m ),
591 3.73-3.81 ( 1H, m ), 3.88 ( 3H, s ), 5.17 ( 1H, d,
J = 11.0Hz ), 5.24 ( 1H, d, J = 11.0Hz ), 6.94
Figure imgf000173_0001
( 1H, d, J = 2.5Hz ), 7.16 ( 1H, d, J = 9.0Hz ),
7.31 ( 1H, dd, J = 2.5, 9.4Hz ), 7.58 ( 1H, d, J = 9.0Hz ), 8.12 ( 1H, d, J = 9.4Hz ).
1H-NMR ( CDCI3 ) δρρΓη : 1.14 ( 18H, d, J = 6.6Hz ), 1.19-1.35 ( 13H, m ), 1.35-1.65 ( 1H, m ), 1.65-1.84 ( 4H, m ), 2.83 ( 1H, d, J = 11.6Hz ), 3.04 ( 1H, d, J = 11.6Hz ), 3.5-3.6
592 ( 1H, m ), 3.7-3.8 ( 1H, m ), 3.87 ( 3H, s ), 4.93
Figure imgf000173_0002
( 2H, d, J = 1.0Hz ), 6.96 ( 1H, s ), 6.99 ( 1H, d,
J = 2.2Hz ), 7.21 ( 1 H, dd, J =2.4, 9.0Hz ), 7.59 ( 1 H, d, J = 9.0Hz ), 7.77 ( 1 H, s ).
[0350]
Table 65
Absolute configuration
Figure imgf000173_0003
Figure imgf000173_0004
1H-NMR ( CDCI3 ) δρριτι : 0.99 ( 1H, br), 1.15-
I.35 ( 8H, m ), 1.35-1.5 ( 2H, m ), 1.5-1.85 ( 4H, m ), 2.44 ( 1H, br ), 2.81 ( 1H, d, J =
II.7Hz ), 3.05 ( 1H, d, J = 11.8H ), 3.45-3.55 ( 1H, m ), 3.7-3.8 ( 1H, m ), 3.93 ( 3H, s ), 4.79 ( 2H, s ), 6.98 ( 1H, d, J = 2.4Hz ), 7.02 ( 1H,
Figure imgf000174_0001
S ), 7.21-7.28 ( 1H, m ), 7.54 ( 1H, s ), 7.60
(1H, d, J = 9.0Hz).
[0351]
Table 66
Absolute configuration
Figure imgf000174_0002
Figure imgf000174_0003
Figure imgf000175_0001
1H-NMR ( DMSO-d6 ) 5ppm : 1.26-1.52 ( 6H,
m ), 1.57 ( 3H, s ), 1.66-2.02 ( 4H, m ), 2.02- 2.12 ( 1H, m ), 3.07 ( 1H, d, J = 13.4Hz ), 3.51
608 ( 1H, d, J = 13.4Hz ), 3.65-3.9 ( 2H, m ), 4.15- 2 Hydrochloride
Figure imgf000176_0001
4.25 ( 1H, m ), 7.18 ( 1H, d, J = 2.2Hz ), 7.22- 7.3 ( 1H, m ), 7.35-7.47 ( 2H, m ), 7.65-7.85
( 3H, m ), 8.1-8.3 ( 1H, m ), 9.8-10.0 ( 1H, m ).
1H-NMR ( D SO-d6 ) 6ppm : 1.06-1.16 ( 1H,
m ), 1.16-1.39 ( 8H, m ), 1.46-1.78 ( 4H, m ),
1.78-1.93 ( 1H, m ), 2.81 ( 1H, d, J = 12.2Hz ),
2.9-4.0 ( 5H, m ), 4.30-4.42 ( 2H, m ), 6.27-6.58
609 1/2 Fumarate
( 2H, m ), 7.06 ( 1H, d, J = 2.1Hz ), 7.10 ( 1H,
Figure imgf000176_0002
dd, J = 2.6, 8.9Hz ), 7.26 ( 1H, d, J = 2.5Hz ),
7.35 ( 1H, dd, J = 2.6, 9.4Hz ), 7.61-7.68 ( 2H,
m).
1H-NMR ( DMSO-d6 ) 6ppm : 1.23-1.52 ( 6H,
m ), 1.59 ( 3H, s ), 1.64-2.03 ( 4H, m ), 2.03- 2.16 ( 1H, m ), 3.07 ( 1H, d, J = 13.3Hz ), 3.45
( 1H, d, J = 14.0Hz ), 3.75-3.85 ( 1H, m ), 3.95
610 ( 3H, s ), 4.1-4.2 ( 1H, m ), 4.77 ( 1H, br), 7.25 2 Hydrochloride
( 1H, d, J = 2.2Hz ), 7.46 ( 1H, s ), 7.58 ( 1H,
Figure imgf000176_0003
dd, J =2.4, 9.2Hz ), 7.81 ( 1H, d, J = 9.2Hz ),
8.23 ( 1H, s ), 8.25-8.4 ( 1H, m ), 10.13 ( 1H,
br).
H-NMR ( DMSO-d6 ) δρρπι : 1.12-1.20 ( 1H,
m ), 1.21-1.39 ( 8H, m ), 1.47-1.79 ( 4H, m ),
1.79-1.95 ( 1H, m ), 2.84 ( 1H, d, J = 12.3Hz ),
2.85-3.75 ( 5H, m ), 3.9-4.0 ( 1H, m ), 6.54
611 Fumarate
( 2H, s ), 7.12 ( 1H, d, J = 2.2Hz ), 7.34 ( 1H,
Figure imgf000176_0004
dd, J = 2.2, 8.7Hz ), 7.43 ( 1H, dd, J = 2.4,
9.2Hz ), 7.65-7.75 ( 2H, m ), 7.80 ( 1H, d, J =
2.1Hz). ■
1H-NMR ( DMSO-d6 ) δρρηι : 1.05-1.19 ( 1H,
m ), 1.19-1.40 ( 8H, m ), 1.46-1.80 ( 4H, m ),
612 1.80-1.96 ( 1H, m ), 2.83 ( 1H, d, J = 12.3Hz ), 1/2 Fumarate
2.9-4.3 ( 5H, m ), 6.51 ( 1H, S ), 7.05-7.45 ( 4H,
m ), 7.49 ( 1H, d, J = 2.3Hz ), 7.7-7.8 ( 2H, m ).
1H-NMR ( DMSO-d6 ) δρριη : 1.0-1.15 ( 2H,
m), 1.3-1.4 ( 1H, m ), 1.48 (3H, S ), 1.50 (3H,
S ), 1.55-1.65 ( 1H, m ), 1.7-1.8 (2H,m), 1.8- 2.0 ( 2H, m ), 2.25-2.35 ( 1H, m ), 2.4-2.5 ( 1H,
613 m ), 2.6-2.75 ( 2H, m ), 2.95-3.1 ( 2H, m ), 3.21 Hydrochloride
( 3H, s ), 3.3-3.5 ( 1H, m ), 3.78 ( 3H, s ), 3.85- 3.95 ( 1H, m ), 6.78 ( 1H, d, J = 8.9Hz ), 6.93
( 1H, d, J = 8.9Hz), 7.99 ( 1H, br), 9.64 ( 1H,
br).
1H-NMR ( DMSO-d6 ) 6ppm : 1.08-1.37 ( 9H,
m ), 1.42 ( 6H, s ), 1.47-1.85 ( 5H, m ), 2.76
( 1H, d, J = 12.4Hz), 2.95 ( 1H, d, J = 12.3Hz ),
614 3.53 ( 1H, br ), 3.63-3.73 ( 1H, m ), 4.74 ( 2H, Fumarate
Figure imgf000176_0005
s ), 6.52 ( 2H, s ), 6.58 ( 1H, d, J = 2.7Hz ),
6.65 ( 1H, d, J = 8.9Hz ), 6.76 ( 1H, dd, J = 2.8,
9.0Hz ).
[0352]
Table 67 Absolute configuration
Figure imgf000177_0001
Figure imgf000177_0002
Figure imgf000178_0001
[0353]
Table 68
Absolute configuration
Figure imgf000178_0002
Figure imgf000179_0001
[0354]
Table 69
Absolute configuration
Figure imgf000179_0002
Figure imgf000180_0001
( 1H, d, J = 8.5Hz), 8.22 ( 1H, br), 10.07 ( 1H, br).
Figure imgf000181_0001
[0355]
Table 70
Absolute configuration
Figure imgf000181_0002
Figure imgf000181_0003
1H-NMR (CDCI3) 5ppm : 1.11-1.19 ( 19H, m ),
H3C u 1.21 (3H, s), 1.23-1.32 ( 2H, m), 1.35 (3H,
V ¾_. s >■ 1-37-1.47 ( 2H, m ), 1.63-1.86 ( 6H, m ), fi-M N— < 3 1.90-2.04 ( 1H, m ), 3.04 (1H.d, J - 11.9Hz),
Y IY l ΓΗ 3.09 ( 1H, d, J = 12.0Hz), 3.55-3.65 ( 1H, m),
II J ΑΜ 3 3.8-3.9 (1H,m), 6.41 (1H,d, J = 7.5Hz), 7.05 H3C I3 ( 1H d j _ 85Hz j 716 ( 1H dd j _ 76
8.3Hz ), 8.26 ( 1H, d, J = 0.8Hz ).
Figure imgf000182_0001
[0356]
Table 71
Absolute configuration
Figure imgf000182_0002
Figure imgf000183_0001
[0357]
Table 72
Absolute configuration
Figure imgf000184_0001
Figure imgf000184_0002
Figure imgf000185_0001
[0358]
Table 73
Absolute configuration
Figure imgf000185_0002
Figure imgf000186_0001
[0359]
Table 74
Absolute configuration
Figure imgf000186_0002
Figure imgf000186_0003
Figure imgf000187_0001
[0360]
Table 75
Absolute configuration
(ffNiCH3
H ^4
Figure imgf000187_0002
Figure imgf000188_0001
[0361]
Table 76
Absolute configuration
Figure imgf000188_0002
e 1H-NMR ( DMSO-d6)
6ppm : 1.1-1.3 ( 2H,
m ), 1.35-1.45 ( 4H,
m), 1.52(3H, s), 1.6- 1.9 (4H, m ), 1.95-2.1
( 1H, m), 2.93 (1H, d,
J = 13.1Hz ), 3.10
687 -H -H -OCH3 -H -H 2 Hydrochloride
( 1H, d, J = 13.0Hz ),
3.68 ( 3H, s ), 3.7-3.9
( 2H, m ), 4.35-5.75
( 1H, m ), 6.75-6.85
( 2H, m ), 6.85-6.95
( 2H, m ), 8.11 ( 1H,
br),9.92 (1H, br).
1H-N R ( CDCI3 )
6ppm : 0.93-1.1 ( 2H,
m ), 1.17 ( 3H, s ),
1.31 ( 3H, s ), 1.35- 1.43 ( 2H, m ), 1.55- 1.75 ( 3H, m ), 1.78- 1.93 ( 1H, m ), 2.37
688 -CH3 -CI -H -H -H
(3H, s), 2.42 ( 1H, d,
J = 11.0Hz), 2.83-2.91
(1H, m), 3.10 (1H,d,
J = 11.0Hz ), 3.5-3.6
( 1H, m ), 6.79 ( 1H,
dd, J = 2.1, 7.1Hz ),
6.99-7.09 (2H,m).
1H-NMR ( DMSO-d6 )
5ppm : 1.0-1.17 ( 2H,
m), 1.3-1.43 (1H,m),
1.49 ( 3H, S ), 1.52
( 3H, s ), 1.56-1.68
( 1H, m ), 1.68-1.87
( 2H, m ), 1.87-2.1
( 2H, m ), 2.30 ( 3H,
s ), 2.62 ( 1H, d, J =
689 -CH3 -H -H -H -H Hydrochloride
12.6Hz ), 3.11-3.23
( 1H, m ), 3.25-3.45
( 1H, m ), 3.78-3.92
( 1H, m ), 6.92-7.04
( 2H, m ), 7.08-7.22
( 2H, m ), 8.03 ( 1H,
br ), 9.65-9.95 ( 1H,
m).
1H-NMR ( DMSO-d6 )
6ppm : 1.18-1.35 (2H,
m ), 1.35-1.48 ( 4H,
m ), 1.52 ( 3H, s ),
1.62-1.9 ( 4H, m ),
1.98-2.04 ( 1H, m ),
2.19 ( 3H, s ), 2.91
( 1H, d, J = 13.3Hz ),
690 -H -H -CH3 -H -H 3.25 ( 1H, d, J = 2 Hydrochloride
13.3Hz ), 3.7-3.8 ( 1H,
m ), 3.9-4.0 ( 1H, m ),
4.1-4.45 (1H,m), 6.8- 6.87 ( 2H, m ), 6.98- 7.07 ( 2H, m ), 8.05- 8.25 ( 1H, m ), 9.8- 10.05 ( 1H, m).
1H-NMR ( DMSO-d6 )
5ppm : 0.98-1.15 ( 2H,
m), 1.3-1.42 ( 1H, m ),
1.49 ( 3H, s ), 1.52
( 3H, s ), 1.55-1.67
( 1H, m ), 1.67-1.83
( 2H, m ), 1.83-2.008
( 2H, m ), 2.20 ( 3H,
s ), 2.22 ( 3H, s ), 2.59
691 -CH3 -CH3 -H -H -H ( 1H, d, J = 12.6Hz ), Hydrochloride
3.05-3.15 ( 1H, m ),
3.25-3.4 ( 1H, m ),
3.82-3.96 ( 1H, m ),
6.82 ( 1H, d, J =
7.8Hz), 6.91 (1H, d, J
= 7.4Hz ), 7.03 ( 1H,
dd, J = 7.7, 7.7Hz ),
7.98 ( 1H, br ), 9.65- 9.8 (1H, m).
1H-NMR ( DMSO-d6 )
5ppm : 1.22-1.47 (6H,
m ), 1.53 ( 3H, s ),
1.63-1.93 ( 4H, m ),
Figure imgf000190_0001
1H-NMR ( DMSO-d6 )
δρριη : 1.16-1.33 (2H,
m ), 1.36-1.45 ( 4H,
m ), 1.52 ( 3H, s ),
1.62-1.9 (4H,m), 2.0- 2.08 ( 1H, m ), 2.18
( 3H, d, J = 1.7Hz ),
2.93 ( 1H, d, J =
13.3Hz), 3.21 ( 1H, d,
693 -H -CH3 -H -H 2 Hydrochloride
J = 13.2Hz ), 3.7-3.8
(1H, m), 3.9-4.0 (1H,
m ), 4.15-4.55 ( 1H,
m ), 6.72-6.8 (1H,m),
6.81-6.89 ( 1H, m ),
6.97 ( 1H, dd, J = 9.1,
9.1Hz ), 8.05-8.25
( 1H, m ), 9.85-10.1
(1H,m).
1H-NMR "( D SO-d6 )
6ppm : 1.0-1.2 ( 2H,
m), 1.3-1.45 (1H,m),
1.49 ( 3H, s ), 1.51
( 3H, s ), 1.56-1.84
( 3H, m ), 1.84-2.06
( 2H, m ), 2.20 ( 3H, d,
J = 2.2Hz), 2.67 (1H,
d, J = 12.7Hz ), 3.15-
694 -CH3 -H -H -H Hydrochloride
3.25 ( 1H, m ), 3.29- 3.42 ( 1H, m ), 3.85- 4.0 ( 1H, m ), 6.83
( 1H, d, J = 8.0Hz ),
6.89 ( 1H, dd, J = 8.8,
8.8Hz ), 7.16 ( 1H, dd,
J = 7.9, 15.3Hz ), 8.02
( 1H, br ), 9.72 ( 1H,
br
1H-NMR ( DMSO-d6 )
6ppm : 1.25-1.46 (6H,
m ), 1.52 ( 3H, s ),
1.63-1.95 ( 4H, m ),
1.95- 2.1 ( 1H, m ),
2.95 ( 1H, d, J =
13.7Hz), 3.47 ( 1H, d,
J = 13.6Hz ), 3.7-3.8
695 -H -CI -H -H -H Hydrochloride
(1H, m), 4.0-4.1 (1H,
m), 6.77 ( 1H, dd, J =
1.4, 7.8Hz), 6.90 (1H,
d, J = 2.2, 8.4Hz ),
6.96- 7.01 ( 1H, m ),
7.21 ( 1H, dd, J = 8.1,
8.1Hz ), 8.17 ( 1H,
br), 9.85 (1H.br). 1H-NMR ( DMSO-d6 )
6ppm : 1.0-1.2 ( 2H,
m ), 1.3-1.4 ( 1H, m ),
1.48 ( 3H, s ), 1.51
( 3H, s ), 1.55-1.65
( 1H, m ), 1.65-1.85
( 2H, m ), 1.85-2.05
( 2H, m ), 2.13 ( 3H,
s ), 2.62 ( 1H, d, J = Hv(iroch|oridp
696 -CH3 -OCH3 -H 12.6Hz ), 3.1-3.2 (1H, Hydrochloride m ), 3.3-3.4 ( 1H, m ),
3.76 ( 3H, s ), 3.8-3.9
(1H, m), 6.61 (1H,d,
J = 7.9Hz ), 6.72 ( 1H,
d, J = 8.1Hz ), 7.10
( 1H, dd, J = 8.1,
8.1Hz ), 8.01 ( 1H,
br), 9.71 ( 1H, br).
1H-NMR ( DMSO-d6 )
δρρητι : 1.24-1.47 (6H,
m ), 1.51 ( 3H, s ),
1.63-1.91 ( 4H, m ),
1.91-2.08 ( 1H, m ),
2.20 ( 3H, s ), 2.91
( 1H, d, J = 13.5Hz ),
697 -H -CI -CH3 -H -H 3.23-3.42 ( 1H, m ), Hydrochloride
3.66-3.80 ( 1H, m ),
3.94-4.08 ( 1H, m ),
6.84 ( 1H, dd, J = 2.6,
8.5Hz), 6.97 ( 1H, d, J
= 2.6Hz), 7.16 (1H, d,
J = 8.6Hz), 8.12 ( 1H,
br), 9.82 (1H, br).
1H-NMR ( DMSO-d6 )
6ppm : 1.25-1.45 (6H,
m ), 1.51 ( 3H, s ),
1.65-1.9 (4H, m ), 2.0- 2.05 ( 1H, m ), 2.10
698 -H -F -CH3 -H -H Hydrochloride
Figure imgf000192_0001
m). 1H-NMR ( DMSO-d6 )
5ppm : 1.21-1.35 ( 2H,
m ), 1.35-1.48 ( 4H,
m ), 1.53 ( 3H, s ),
1.63-1.95 ( 4H, m ),
1.98-2.12 ( 1H, m ),
699 -H -H -OCHF2 -H -H 2.94 ( 1H, d, J = Hydrochloride
13.4Hz ), 3.32 ( 1H, d,
J = 13.3Hz ), 3.7-3.8
( 1 H, m ), 3.9-4.05
( 1H, m ), 6.85-7.26
( 5H, m ), 8.20 ( 1 H,
br ), 9.99 ( 1 H, br ).
1H-NMR ( DMSO-d6 )
6ppm : 1.25-1.49 ( 6H,
m ), 1.49-1.57 ( 3H,
m ), 1.65-1.95 ( 4H,
m ), 1.95-2.09 ( 1H,
m ), 2.96 ( 1H, d, J =
13.6Hz ), 3.39-3.48
700 -H -H -OCF3 -H -H Hydrochloride
( 1H, m ), 3.71-3.83
( 1H, m ), 3.98-4.09
( 1H, m ), 6.98-7.05
( 2H, m ), 7.16-7.24
( 2H, m ), 8.16 ( 1H,
br ), 9.65-10.1 ( 1H,
m
1H-NMR ( DMSO-d6 )
5ppm : 1.10 ( 3H, s )
1.15-1.25 ( 4H, m
1.25-1.45 ( 2H, m
1.45-1.7 ( 4H, m
1.85-2.0 ( 1H, m
2.76 ( 1H, d, J =
701 -H -CI -CN -H -H 1/2 Fumarate
12.8Hz ), 2.85-3.85
( 4H, m ), 3.85-3.95
( 1H, m ), 6.56 ( 1H,
s ), 6.94 ( 1H, dd, J =
2.5, 9.1Hz ), 7.09 ( 1H,
d, J = 2.4Hz ), 7.59
( 1H, d, J = 9.0Hz ).
1H-NMR ( DMSO-d6 )
5ppm : 1.25-1.5 ( 6H,
m ), 1.52 ( 3H ,s ),
1.65-2.1 ( 5H, m ),
2.97 ( 1 H, d, J =
13.8Hz ), 3.54 ( 1H, d,
J = 13.6Hz ), 3.65-3.8
702 -H -OCF3 -H -H ( 1H, m ), 4.0-4.15 Hydrochloride
( 1 H, m ), 6.81 ( 1 H,
dd, J = 2.2, 9.3Hz ),
7.05 ( 1 H, dd, J = 2.9,
14.4Hz ), 7.34 ( 1 H,
dd, J = 9.0, 9.0Hz ),
8.24 ( 1H, br ), 9.92
( 1H, br). 1H-NMR ( DMSO-d6 )
δρρσι : 1.10-1.37 ( 9H,
m ), 1.44-1.75 ( 4H,
m ), 1.75-1.90 ( 1H,
m ), 2.68 ( 1H, d, J =
12.4Hz ), 3.15 ( 1H, d,
703 -H -OCHF2 -H -H 1/2 Fumarate
J = 12.4Hz ), 3.25- 3.45 ( 1H, m ), 3.7-3.8
( 1H, m ), 6.51 ( 1 H,
m ), 6.67 ( 1H, d, J =
2.1 , 9.1Hz ), 6.81-7.24
( 3H, m )
1H-NMR ( DMS0-d6 )
δρριη : 1.07-1.36 ( 9H,
m ), 1.43-1.58 ( 1H,
m ), 1.58-1.72 ( 3H,
704 -H -CI -0CHF2 -H -H m ), 1.73-1.89 ( 1H, 1/2 Fumarate m ), 2.67 ( 1 H, d, J =
12.2Hz ), 3.0-3.7 ( 4H,
m ), 3.7-3.8 ( H, m ),
6.52 ( 1H, s ), 6.82- 7.24 ( 4H, m ).
1H-NMR ( DMSO-d6 )
5ppm : 1.15-1.41 ( 9H,
m ), 1.48-1.92 ( 5H,
m ), 2.75 ( 1 H, d, J =
12.7Hz ), 2.8-4.4 ( 6H,
705 -H -CHF2 m ), 6.46 ( 1 H, d, J = Fumarate
7.8Hz ), 6.54 ( 2H, s ),
6.62 ( 1H, s ), 6.76
( 1 H, dd, J = 2.1 ,
8.5Hz ), 7.0-7.4 ( 2H,
m ).
1H-NMR ( DMS0-d6 )
6ppm : 0.97-1.36 ( 9H,
m ), 1.43-1.73 ( 4H,
m ), 1.73-1.87 ( 1 H,
706 -H -OCHF2 -F -H -H m ), 2.67 ( 1 H, d, J = 1/2 Fumarate
12.1Hz ), 2.95-3.8
( 5H, m ), 6.52 ( 1H,
s ), 6.7-6.8 ( 2H, m ),
7.0-7.4 ( 2H, m ).
1H-NMR ( DMSO-d6 )
δρρηι : 1.11-1.37 ( 9H,
m ), 1.45-1.74 ( 4H,
m ), 1.77-1.91 ( 1 H,
m ), 2.69 ( 1H, d, J =
707 -H -OCHF2 -CI -H -H 1/2 Fumarate
12.3Hz ), 2.75-4.2
( 5H, m ), 6.52 ( 1H,
s ), 6.73-6.83 ( 2H,
m ), 7.03-7.43 ( 2H,
ml 1H-NMR ( DMSO-d6 )
6ppm : 1.06-1.21 (7H,
m ), 1.21-1.36 ( 2H,
m ), 1.41-1.70 ( 4H,
m ), 1.74-1.89 ( 1H,
-H -CN -OCHF2 -H -H m ), 2.68 ( 1H, d, J = 1/2 Fumarate
12.3Hz ), 2.9-3.75
( 4H, m ), 3.75-3.85
( 1H, m ), 6.54 ( 1H,
Figure imgf000195_0001
( 1H, m ), 3.80-4.27
( 4H, m ), 6.18-6.50
( 1H, m ), 6.90 ( 4H,
s), 8.0-8.25 ( H, m),
9.8-10.1 (1H, m).
1H-NMR ( DMSO-d6 )
6ppm : 1.20-1.46 (6H,
m ), 1.51 ( 3H, s ),
1.63-1.89 ( 4H m ),
1.92-2.08 ( 1H, m ),
2.91 ( 1H, d, J =
13.4Hz), 3.29 ( 1H, d,
J = 12.8Hz ), 3.67- 3.79 ( 1H, m ), 3.88-
712 -H -F -OCH2CF2 -H -H 4.01 ( 1H, m ), 4.20- Hydrochloride
4.33 ( 2H, m ), 6.18- 6.52 ( 1H, m ), 6.68
( 1H, dd, J = 1.8,
9.1Hz), 6.91 ( 1H, dd,
J = 2.9, 14.7Hz), 7.10
( 1H, dd, J = 9.5,
9.5Hz ), 8.0-8.2 ( 1H,
m ), 9.75-9.95 ( 1H,
m
1H-NMR ( DMSO-d6 )
5ppm : 1.06-1.16 ( 1H,
m ), 1.16-1.37 ( 8H,
m ), 1.45-1.88 ( 5H,
m ), 2.17 ( 3H, s ),
713 -H -CH3 -OCHCF2 -H -H ^ j oHz ) ^04 "( 1 H d= 1/2 Fumarate
J = 12.0Hz ), 3.1-3.9
( 4H, m ), 6.50 ( 1H,
s ), 6.71 ( 1H, dd, J =
3.0, 8.9Hz ), 6.75-7.16
(3H,m).
1H-NMR ( DMSO-d6 )
6ppm : 1.08-1.18 ( 1H,
m ), 1.18-1.27 ( 7H,
m ), 1.27-1.38 ( 1H,
m ), 1.44-1.60 ( 1H,
Figure imgf000196_0001
1 H-NMR ( DMSO-d6 )
6ppm : 0.94-1.14 ( 1H, m ), 1.14-1.15 ( 1H, m ), 1.18 ( 3H, s ), 1.26 ( 3H, s ), 1.28- 1.43 ( 2H, m ), 1.48 ( 1 H, br ), 1.61-1.73 ( 3H, m ), 1.76-1.90
7.5 -OCHCF2 -H -H -H -H ^^'.H ^
( 1H, d, J = 11.2Hz ), 3.45-3.6 ( 2H, m ), 6.55 ( 1 H, dd, J = 70.2, 81.4Hz ), 6.91 ( 1 H, dd, J = 1.4, 8.0Hz ), 6.93-6.99 ( 1H, m ), 7.07-7.18 ( 2H, m )
Absolute configuration
Figure imgf000197_0001
[0363]
Table 78 Absolute configuration
Figure imgf000198_0001
Figure imgf000198_0002
[0364]
Table 79
Absolute configuration
Figure imgf000198_0003
Figure imgf000199_0001
[0365]
Table 80
Absolute configuration
Figure imgf000199_0002
Exam
NMR Salt
1 H-NMR ( DMSO-d6 ) 6ppm : 0.9-1.05 ( 1H,
m ), 1.05-1.2 ( 1H, m ), 1.3-1.45 ( 1H, m ),
1.52 ( 3H, S ), 1.55-1.65 ( 4H, m ), 1.65-1.85
( 2H, m ), 1.85-2.05 ( 2H, m ), 2.73 ( 1H, d, J
= 12.5Hz ), 3.25-3.6 ( 2H, m ), 3.94 ( 3H, S ),
726 Hydrochloride
4.15-4.3 ( 1H, m ), 6.88 ( 1 H, d, J = 8.2Hz ),
7.06 ( 1H, d, J = 8.0Hz ), 7.5-7.55 ( 1H, m ),
7.55-7.6 ( 1 H, m ), 7.96 ( 1H, br ), 8.16 ( 1H,
Figure imgf000199_0003
dd, J = 1.0, 8.3Hz ), 8.24 ( 1H, d, J = 8.1Hz ),
9.4-9.6 ( 1H, m ).
Figure imgf000200_0001
Figure imgf000201_0001
9.8-10.1 (1H, m). 1H-NMR ( DMSO-d6 ) δρρηι : 1.06-1.17 ( 1H,
m ), 1.17- .39 ( 8H, m ), 1.46-1.79 ( 4H, m ),
1.79-1.92 ( 1H, m ), 2.82 ( 1H, d, J =
12.1Hz ), 2.9-4.2 ( 5H, m ), 4.30-4.41 ( 2H,
741 1/2 Fumarate m ), 6.27-6.59 ( 2H, m ), 7.06 ( 1H, d, J =
Figure imgf000202_0001
2.1Hz ), 7.10 ( 1H, dd, J = 2.6, 8.9Hz ), 7.26
( 1H, d, J = 2.5Hz ), 7.36 ( 1H, dd, J = 2.4,
9.2Hz), 7.60-7.68 (2H,m).
[0366]
Table 81
Absolute configuration
Figure imgf000202_0002
[0367]
Table 82
Absolute configuration
Figure imgf000202_0003
Exam
NMR Salt
Figure imgf000203_0001
Figure imgf000204_0001
[0368]
Table 83
Absolute configuration
Figure imgf000204_0002
Ex.am R4 NMR Salt pie 1H-NMR ( CDCI3 ) δρριπ : 1.02-1.17 ( 3H,
m ), 1.20 ( 3H, S ), 1.31 ( 3H, s ), 1.34-1.46
(2H, m ), 1.47-1.79 (3H, m), 1.81-1.95 ( 1H,
m ), 2.45 ( 3H, d, J = 1.0Hz ), 2.80 ( 1H, d, J =
756 11.5Hz ), 3.05 ( 1H, d, J = 11.5Hz ), 3.55-3.65
( 2H, m ), 6.39 ( 1 H, dd, J = 1.0, 1.OHz ), 6.56
Figure imgf000205_0001
( 1H, dd, J = 0.8, 7.7Hz ), 6.95-7.05 ( 1H, m ),
7.06 (1H, dd, J = 7.9, 7.9Hz).
1H-NMR ( DMSO-d6 ) 6ppm : 1.17-1.37 ( 2H,
m), 1.37-1.52 (4H, m), 1.56 (3H, s), 1.61- 1.73 ( 1H, m ), 1.73-1.99 ( 3H, m ), 2.00-2.15
( 1H, m ), 2.37 ( 3H, d, J = 0.9Hz ), 3.00 ( 1H,
d, J = 13.3Hz ), 3.28 ( 1H, d, J = 13.2Hz ),
757 2 Hydrochloride
3.7-3.85 ( 1H, m ), 3.95-4.1 ( 1H, m ), 4.92
Figure imgf000205_0002
( 1 H, br ), 6.40 ( 1 H, d, J = 0.8Hz ), 6.89 ( 1 H,
dd, J = 2.1, 8.6Hz ), 7.05 ( 1H, d, J = 1.5Hz),
Figure imgf000205_0003
Figure imgf000206_0001
[0369]
Table 84
Absolute configuration
Figure imgf000206_0002
Figure imgf000207_0001
Figure imgf000207_0002
Figure imgf000208_0001
Absolute configuration
Figure imgf000208_0002
Figure imgf000209_0001
[0371]
Table 86
Absolute configuration
Figure imgf000209_0002
Ex.
NMR Salt No.
1H-NMR ( CDCI3 ) δρρσι : 1.15-1.32 ( 9H,
m ), 1.33-1.50 ( 2H, m ), 1.64-1.88 ( 4H, m ),
2.82 ( 1H, d, J = 11.7Hz ), 3.03 ( 1H, d, J =
785 11.7Hz ), 3.46-3.54 ( 1H, m ), 3.71-3.79 ( 1H,
m ), 3.80 ( 3H, s ), 6.51 ( 1H, d, J = 1.7Hz ),
Figure imgf000209_0003
6.96 ( H, dd, J = 2.1, 9.0Hz ), 7.02 ( 1H, s ),
7.46 (1H, d, J = 9.0Hz).
1H-NMR ( DMSO-d6 ) 6ppm : 1.0-1.25 ( 2H,
m ), 1.25-1.4 ( 7H, m ), 1.45-1.9 ( 5H, m ),
2.94 ( 2H, s ), 3.36 ( 3H, br ), 3.66 ( 1H, br ),
786 Fumarate
3.7-3.8 ( 4H, m ), 6.29 ( 1H, d, J = 3.3Hz ),
6.54 ( 2H, s ), 7.39 ( 1H, d, J = 3.3Hz ), 7.43
( 1H, d, J = 2.2Hz ), 8.10 ( 1H, d, J = 2.5Hz ).
Figure imgf000210_0001
[0372]
Table 87
Absolute configuration
Figure imgf000210_0002
Exam
NMR Salt pie
1H-NMR ( DMSO-d6 ) 6ppm : 1.01-1.25 ( 2H,
m ), 1.32-1.42 ( 1H, m ), 1.46 ( 3H, s ), 1.48
(3H, s), 1.58-2.03 (6H, m ), 2.05-2.18 ( 1H,
790 m ), 2.70-2.93 ( 5H, m ), 3.24 ( 1H, d, J = Hydrochloride
12.9Hz ), 3.45-3.57 ( 1H, m ), 3.81-3.93 ( H,
m ), 6.53 ( 1H, d, J = 11.4Hz ), 6.70 ( 1H, d, J
= 8.4Hz), 8.02 ( 1H, br), 9.72 ( 1H, br). .
1H-NMR ( DMSO-d6 ) 6ppm : 0.90-1.21 ( 2H,
m ), 1.28-1.41 ( 1H, m ), 1.48 ( 6H, s ), 1.57- 1.67 ( 1H, m ), 1.67-2.06 ( 5H, m ), 2.08-2.21
( 1H, m ), 2.70 ( 1H, d, J = 12.4Hz ), 2.78-3.00
791 Hydrochloride
( 4H, m ), 3.22-3.42 ( 2H, m ), 3.77-3.92 ( H,
m ), 6.74 ( 1H, dd, J = 4.3, 8.6Hz ), 6.88 ( 1H,
Figure imgf000210_0003
dd, J = 8.6, 8.6Hz), 8.01 ( 1H, br), 9.73 ( 1H,
br).
Figure imgf000211_0001
[0373]
Table 88
Absolute configuration
Figure imgf000211_0002
Figure imgf000212_0001
[0374]
Table 89
Figure imgf000212_0002
Figure imgf000213_0001
[0375] Table 90 Absolute configuration
Figure imgf000214_0001
Exa
mple R5 R6 R7 R8 R9 NMR Salt
1H-NMR ( DMSO-d6 )
5ppm : 1.1-1.3 ( 2H, m ),
1.35-1.45 ( 4H, m ), 1.52
( 3H, s ), 1.6-1.9 ( 4H,
m ), 1.95-2.1 ( 1H, m ),
812 -H -H -OCH3 -H -H 93 < 1H.d, J = 13.1Hz ), 2 Hydroch,oride
3.68 ( 3H, s ), 3.7-3.9
(2H, m), 4.35-5.35 ( 1H,
m ), 6.75-6.85 ( 2H, m ),
6.85-6.95 ( 2H, m ), 8.09
(1H, br), 9.90 (1H, br).
1H-N R ( CDCI3 )
6ppm : 0.93-1.09 ( 3H,
m ), 1.16 ( 3H, s ), 1.23-
I.34 ( 4H, m ), 1.34-1.44
(2H, m), 1.44-1.75 (2H,
m ), 1.79-1.92 ( 1H, m ),
813 -CH3 -CI -H -H -H 2.37 ( 3H, s ), 2.41 ( 1H,
d, J = 11.0Hz), 2.83-2.91
(1H,m), 3.10 (1H,d, J =
II.1Hz ), 3.51-3.57 ( 1H,
m), 6.79 (1H, dd, J = 2.1,
7.1Hz ), 6.99-7.08 ( 2H,
m). ,
1H-NMR ( CDCI3 )
5ppm : 0.78-1.13 ( 3H,
m ), 1.16 ( 3H, s ), 1.28- 1.42 ( 5H, m ), 1.54-1.76
( 4H, m ), 1.81-1.95 ( 1H,
m ), 2.34 ( 3H, s ), 2.43
814 -CHS -H -H -H -H ( J^ ^ Hydrochloride
( 1H, d, J = 11.1Hz ),
3.47-3.58 ( 1H, m ), 6.88
( 1H, dd, J = 1.0, 7.9Hz),
6.91-6.97 ( 1H, m ), 7.07- 7.15 ( 1H, m ), 7.17 ( 1H,
dd, J = 0.7, 7.5Hz). 1 H-NMR ( DMSO-d6 )
6ppm : 1.16-1.33 ( 2H, m ), 1.34-1.48 ( 4H, m ), 1.49-1.56 ( 3H, m ), 1.61- 1.93 ( 4H, m ), 1.97-2.11
Figure imgf000215_0001
1H-NMR ( DMSO-d6 )
δρρ ι : 0.98-1.20 ( 2H,
m ), 1.3-1.43 ( 1H, m ),
1.50 ( 3H, s ), 1.51 ( 3H,
s ), 1.56-1.69 ( 1H, m ),
1.69-1.87 (2H, m).1.87-
2.08 ( 2H, m ), 2.20 ( 3H,
d, J = 2.3Hz), 2.67 ( 1H,
819 -CH3 -F -H -H -H d, J = 12.6Hz ), 3.15-3.25 Hydrochloride
(1H, m), 3.36 (1H, d, J =
12.8Hz ), 3.8-4.0 ( 1H,
m ), 6.83 ( 1H, d, J =
8.0Hz), 6.89 ( 1H, dd, J =
8.8, 8.8Hz ), 7.16 ( 1H,
dd, J = 7.9, 15.2Hz), 8.08
( 1H, br ), 9.7-10.0 ( 1H,
_JHi
1H-NMR ( DMSO-d6 )
Sppm : 1.14-1.41 ( 9Η,·
m ), 1.50-1.90 ( 5H, m ),
2.09 ( 3H, d, J =0.8Hz ),
820 -H -F -CH3 -H -H 3^19 ( IH' J = 1 8HZ )! F—
3.5-3.6 ( 1H, m ), 3.8-3.9
( 1H, m ), 6.52 (2H, s ),
6.60-6.71 ( 2H, m ), 7.05
(1H, dd, J = 8.9, 8.9Hz).
1H-NMR ( DMSO-d6 )
Figure imgf000216_0001
1H-N R ( DMSO-d6 )
δρρσι : 1.0-1.17 ( 2H, m ),
1.29-1.43 ( 1H, m ), 1.48
( 3H, s ), 1.51 ( 3H, s ),
1.56-2.05 ( 5H, m ), 2.12
(3H, s), 2.62 ( 1H, d, J =
12.6Hz ), 3.05-3.2 ( 1H,
823 -CH3 -OCH3 -H -H -H Hydrochloride m ), 3.3-3.4 ( 1H, m ),
3.76 ( 3H, S ), 3.85-3.95
(1H, m), 6.61 (1H, d, J =
7.9Hz ), 6.72 ( 1H, d, J =
8.2Hz), 7.10 (1H, dd, J =
8.1, 8.1Hz ), 7.99 ( 1H,
br), 9.5-9.8 (1H, m).
1H-NMR ( DMSO-d6 )
6ppm : 1.21-1.36 ( 2H,
m ), 1.36-1.46 ( 4H, m ),
1.52 ( 3H, s ), 1.63-1.92
(4H, m), 1.93-2.09 ( 1H,
824 -H -H -OCHF2 -H -H m ), 2.94 ( 1H, d, J = 2 Hydrochloride
13.4Hz), 3.33 ( 1H, d, J =
13.3Hz ), 3.5-4.4 ( 2H,
m ), 6.84-7.26 ( 5H, m ),
8.13 ( 1H, br), 9.84 ( 1H,
br).
1H-NMR ( DMSO-d6 )
5ppm : 1.26-1.48 ( 6H,
m ), 1.50 ( 3H, s ), 1.63- 1.92 ( 4H, m ), 1.92-2.06
(1H, m),2.96(1H, d, J =
825 -H -H -OCF3 -H -H 13.6Hz ), 3.44 ( 1H, d, J = Hydrochloride
13.5Hz ), 3.72-3.83 ( 1H,
m ), 3.98-4.09 ( 1H, m ),
6.96-7.07 ( 2H, m ), 7.15- 7.27 (2H, m ), 8.08 ( 1H,
br), 9.67(1 H, br).
1H-NMR ( DMSO-d6 )
5ppm : 1.10 ( 3H, s ),
1.15-1.25 (4H, m), 1.25- 1.45 ( 2H, m ), 1.45-1.75
( 4H, m ), 1.85-2.0 ( 1H,
m ), 2.75 ( 1H, d, J =
826 -H -CI -CN -H -H 1/2 Fumarate
13.0Hz ), 2.9-3.85 ( 4H,
m ), 3.85-3.95 ( 1H, m ),
6.56 ( 1H, s ), 6.94 ( 1H,
dd, J = 2.5, 9.1Hz ), 7.09
( 1H, d, J = 2.4Hz ), 7.59
(1H, d, J = 9.0Hz ).
1H-NMR ( DMSO-d6 )
6ppm : 1.28-1.46 ( 6H,
m ), 1.51 ( 3H ,s ), 1.63- 2.10 ( 5H, m ), 2.97 ( 1H,
d, J = 13.8Hz), 3.54 (1H,
d, J = 13.8Hz ), 3.65-3.8
827 -H -F -OCF3 -H -H Hydrochloride
( 1H, m ), 4.0-4.15 ( 1H,
m),6.81 (1H,dd, J = 2.2,
9.2Hz), 7.05 (1H, dd, J =
2.9, 14.4Hz ), 7.34 ( 1H,
dd, J = 9.2, 9.2Hz ), 8.22
(1H, br), 9.89(1 H, br). 1H-NMR ( DMSO-d6 )
6ppm : 1.09-1.37 ( 9H,
m ), 1.44-1.73 ( 4H, m ),
1.75-1.90 ( 1H, m ), 2.66
(1H, d, J = 12.1Hz), 3.0-
828 -H -F -OCHF2 -H -H 1/2 Fumarate
3.7 ( 4H, m ), 3.7-3.8
( 1H, m ), 6.52 ( 1H, m ),
6.67 ( 1H, d, J = 2.1,
9.3Hz ), 6.80-7.22 ( 3H,
1H-NMR ( D SO-d6 )
δρρπι : 1.08-1.37 ( 9H,
m ), 1.43-1.59 ( 1H, m ),
1.59-1.74 ( 3H, m ), 1.75-
829 -H -CI -OCHF2 -H -H 1/2 Fumarate
1.90 ( 1H, m ), 2.69 ( 1H,
d, J = 12.3Hz ), 2.8-4.2
( 5H, m ), 6.52 ( 1H, s ),
6.82-7.25 ( 4H, m ).
1H-NMR ( DMSO-d6 )
6ppm : 1.13-1.41 ( 9H,
m ), 1.46-1.93 ( 5H, m ),
2.75 (1H,d, J = 12.5Hz),
830 -H -OCHF2 -H -H -H 2.8-4.4 ( 6H, m ), 6.46 1/2 Fumarate
( 1H, d, J = 8.1Hz ), 6.54
( 2H, s ), 6.62 ( 1H, s ),
6.76 ( 1H, dd, J = 8.4Hz),
^ 7.0-7.4 (2H,m).
1H-NMR ( DMS0-d6 )
5ppm : 1.02-1.36 ( 9H,
m ), 1.44-1.59 ( 1H, m ),
1.59-1.74 ( 3H, m ), 1.74-
831 -H -OCHF2 -H -H 1/2 Fumarate
1.87 ( 1H, m ), 2.65-4.5
( 6H, m ), 6.52 ( 1H, s ),
6.7-6.8 ( 2H, m ), 7.0-7.4
(2H,m).
1H-NMR ( D SO-d6 )
6ppm : 1.10-1.38 ( 9H,
m ), 1.44-1.74 ( 4H, m ),
1.76-1.91 ( 1H, m ), 2.69
832 -H -OCHF2 -CI -H -H 1/2 Fumarate
( 1H, d, J = 12.3Hz ),
2.75-4.2 ( 5H, m ), 6.53
( 1H, s ), 6.75-6.85 ( 2H,
m), 7.05-7.45 ( 2H, m).
1H-NMR ( DMSO-d6 )
6ppm : 1.06-1.23 ( 7H,
m ), 1.23-1.37 ( 2H, m ),
1.43-1.74 (4H, m ), 1.75-
833 -H -CN -OCHF2 -H -H 1.89 ( 1H, m ), 2.69 ( 1H, 1/2 Fumarate d, J = 12.4Hz ), 2.9-3.75
( 4H, m ), 3.75-3.85 ( 1H,
m ), 6.53 ( 1H, s ), 7.00- 7.41 (4H, m).
1H-NMR ( DMSO-d6 )
5ppm : 1.1-1.4 ( 9H, m ),
1.44-1.76 (4H, m ), 1.76-
834 -H -OCHF2 -OCHF2 1.90 (1H,m), 2.69 (1H, 1/2 Fumarate d, J = 12.2Hz ), 2.8-4.25
( 5H, m ), 6.52 ( 1H, s ),
6.71-7.36 (5H, m). 1H-NMR ( DMSO-d6 )
6ppm : 1.08-1.23 ( 7H,
m ), 1.24-1.40 ( 2H, m ),
1.43-1.73 (4H, m ), 1.76-
835 -H -F -OCHF2 -F -H 1.91 ( 1H, m ), 2.67 ( 1H, 1/2 Fumarate d, J = 12.5Hz ), 2.8-4.2
( 5H, m ), 6.53 ( 1H, S ),
6.67-6.77 ( 2H, m ), 7.05
(1H, t, J = 72.9Hz).
1H-NMR ( D SO-d6 )
5ppm : 1.13-1.31 ( 2H,
m ), 1.32-1.47 ( 4H, m ),
1.53 ( 3H, s ), 1.61-1.90
( 4H m ), 1.97-2.12 ( 1H,
m ), 2.93 ( 1H, d, J =
836 -H -H -OCH2CHF2 -H -H 13.1Hz), 3.15 ( 1H, d, J = 2 Hydrochloride
13.1Hz ), 3.69-3.81 ( 1H,
m ), 3.83-3.93 ( 1H, m ),
4.10-4.46 ( 3H, m ), 6.12- 6.53 ( 1H, m ), 6.90 ( 4H,
s ), 8.0-8.25 ( 1H, m ),
9.9-10.1 (1H,m).
1H-NMR ( DMSO-d6 )
δρρπι : 1.20-1.46 ( 6H,
m ), 1.51 ( 3H, s ), 1.63- 1.91 ( 4H m ), 1.93-2.10
(1H, m),2.91 (1H, d, J =
13.4Hz), 3.29 ( 1H, d, J =
13.2Hz ), 3.67-3.80 ( 1H,
m ), 3.89-4.01 ( 1H, m ),
837 -H -F -OCH2CHF2 -H -H Hydrochloride
4.20-4.35 (2H, m ), 6.18- 6.51 ( 1H, m ), 6.68 ( 1H,
dd, J = 1.8, 9.1Hz ), 6.91
( 1H, dd, J = 2.9,
14.7Hz ), 7.10 ( 1H, dd, J
= 9.5, 9.5Hz ), 8.05-8.2
( 1H, m ), 9.75-9.95 ( 1H,
1H-NMR ( DMSO-d6 )
6ppm : 1.06-1.15 ( 1H,
m ), 1.15-1.38 ( 8H, m ),
I.42-1.88 ( 5H, m ), 2.17
(3H, s), 2.68 (1H, d, J =
838 -H -CH3 -OCHF2 -H -H 1/2 Fumarate
II.9Hz), 3.04 (1H, d, J =
12.1Hz ), 3.1-3.9 ( 4H,
m ), 6.50 ( 1H, s ), 6.71
( 1H, dd, J = 2.9, 8.9Hz),
6.75-7.16 (3H,m).
1H-NMR ( DMSO-d6 )
6ppm : 1.10-1.39 ( 9H,
m ), 1.45-1.90 ( 5H, m ),
2.72 (1H, d, J = 12.2Hz),
839 -H -OCH3 -OCHF2 -H -H 2.95-4.1 ( 8H, m ), 6.40 1/2 Fumarate
(1H, dd, J = 2.8, 8.9Hz ),
6.50 ( 1H, s ), 6.57 ( 1H,
d, J = 2.7Hz ), 6.63-7.03
(2H,m). 1H-NMR ( DMSO-d6 )
6ppm : 0.94-1.14 ( 1H,
m ), 1.14-1.17 ( 1H, m ),
1.18 ( 3H, s ), 1.26 ( 3H,
s ), 1.29-1.55 ( 3H, m ),
1.59-1.73 ( 3H, m ), 1.76- 1.90 ( 1H, m ), 2.49 ( 1H,
840 -OCHF2 -H -H -H -H
d, J = 11.2Hz ), 3.04 ( 1 H,
d, J = 11.2Hz ), 3.5-3.6
( 2H, m ), 6.55 ( 1H, dd, J
= 70.2, 81.4Hz ), 6.91
( 1H, dd, J = 1.4, 8.0Hz ),
6.93-6.99 ( 1H, m ), 7.07- 7.18 ( 2H, m )
[0376]
Table 91
Absolute configuration
Figure imgf000220_0001
Exam
R4 NMR Salt pie
1H-NMR ( DMSO-d6 ) 6ppm : 0.95-1.15 ( 2H,
m ), 1.35-1.45 ( 1H, m ), 1.51 ( 3H, s ), 1.56
to ( 3H, s ), 1.6-2.05 ( 5H, m ), 2.87 ( 1H, d, J = Hvdroch|oride
841 12.8Hz ), 3.3-3.4 ( 1H, m ), 3.65-3.75 ( 1H, Hydrochlonde m ), 4.1-4.2 ( 1H, m ), 7.05 ( 1 H, s ), 7.35-7.45
( 2H, m ), 7.9-8.1 ( 3H, m ), 9.5-9.7 ( 1H, m ).
1H-NMR ( CDCI3 ) 6ppm : 0.89-1.18 ( 5H,
m ), 1.25-1.74 ( 9H, m ), 1.74-1.86 ( 1H, m ),
2.19 ( 3H, d, J = 0.9Hz ), 2.52 ( 1H, d, J =
842
11.2Hz ), 2.93 ( 1H, d, J = 11.2Hz ), 3.03-3.10
( 1H, m ), 3.47-3.52 ( 1H, m ), 6.35 ( 1H, d, J
= 3.3Hz ), 6.84-6.88 ( 1H, m ).
[0377]
Table 92
Relative configuration
Figure imgf000220_0002
1H-NMR (CDCI3)6ppm 1.13-1.24 (1 H, m),
1.25-1.36 (2H, m), 1.60-1.83 (3H, m), 1.64
(3H, s), 1.74 (3H, s), 1.89-2.02 (1H, m), 2.32-
843 2.37 (1H, m), 2.80 (1H, d, J = 12.5 Hz), 3.12- Hydrochloride
3.16 (1 H, m), 3.22-3.29 (1 H, m), 3.36 (1H, d, J
= 12.5 Hz), 7.19-7.22 (2H, m), 7.29-7.33 (2H,
m), 9.52 (1 H, brs), 9.81 (1H, brs)
1H-NMR (DMSO-d6) 5ppm : 1.00-1.98 (13H,
m), 1.98-2.28 (1H, br), 2.65-3.90 (4H, br),
844 2 Hydrochloride
4.18 (3H, s), 6.70-7.95 (3H, m), 8.22-8.60
Figure imgf000221_0001
(1 H, br), 8.80-11.33 (3H, brm).
[0378]
Table 93
Absolute configuration
Figure imgf000221_0002
Figure imgf000222_0001
Absolute confi uration
Figure imgf000222_0002
Figure imgf000222_0003
Figure imgf000223_0001
J = 9.1 Hz).
1H-NMR (DMSO-d6) 6ppm : 0.95-1.10 (1H,
m), 1.10-1.50 (9H, m), 1.53-1.73 (3H, m),
1.77-1.87 (1H, m), 2.58-2.70 (1H, m), 2.85
(2H, s), 2.89-3.00 (1H, m), 3.87 (3H, s), 4,61
855 1/2 Fumarate
(2H, s), 6.46 (1H, s), 7.20 (1H, dd, J = 2.0, 8.7
Figure imgf000223_0002
Hz), 7.22 (1 H, s), 7.46 (1H, d, J = 1.6 Hz),
7.73 (1H, d, J = 8.7 Hz), 7.79 (1 H, s). (3H not
found)
[0380]
Table 95
Absolute confi uration
Figure imgf000223_0003
Figure imgf000223_0004
Figure imgf000224_0001
Figure imgf000225_0001
[0381] Table 96 Absolute confi uration
Figure imgf000226_0001
[0382]
Table 97 Absolute confi uration
Figure imgf000227_0001
Figure imgf000228_0001
[0383]
Table 98
Absolute configuration
Figure imgf000228_0002
Figure imgf000229_0001
[0384]
Table 99
Absolute confi uration
Figure imgf000229_0002
1H-NMR (DMSO-d6) δρρηΐ : 0.91-1.08
(1H,m), 1.08-1.60 (11H, m), 1.61-1.72(1 H, m),
1.78-1.90 (1H, m), 2.60-2.71 (1H, m), 2.75
(1Hf d, J = 11.7 Hz), 2.90-3.05 (2H, m), 6.39
(1H, dd, J = 1.8, 3.4 Hz), 6.47 (1H, s), 7.42- 1/2 Fumarate 7.49 (1H,m ), 7.73 (1H, d, J = 2.0 Hz), 7.98
Figure imgf000230_0001
(1H, d, J = 2.2 Hz), 8.18-10.97 (2H, br), 11.59
(1H, s).
1H-NMR (DMS0-d6) 6ppm : 0.81-1.02 (4H,
m), 1.10-1.36 (6H, n), 1.36-2.05 (5H, m), 2.25- 2.35 (1H, m), 2.57 (1H, d, J = 11.0 Hz), 2.62-
898 2.70 (1H, m), 2.75 (1H, d, J = 11.0 Hz), 6.91
(1H, dd, J = 1.7, 8.6 Hz), 7.03 (1H, s), 7.27
Figure imgf000230_0002
(1H, d, J = 0.6 Hz), 7.55 (1H, d, J = 8.6 Hz)
11.93-12.33 (1H, br).
[0385]
Table 100
Absolute confi uration
Figure imgf000230_0003
[0386]
Table 101
Ab lute configuration
Figure imgf000230_0004
Figure imgf000231_0001
[0387]
Table 102
Absolute configuration
Figure imgf000231_0002
Figure imgf000232_0001
[0388]
Table 103
Absolute configuration
Figure imgf000232_0002
Exam
NMR Salt pie
1H-NMR (CDCI3) 6ppm : 0.92-1.06 (1 H, m),
1.09 (3H, s), 1.12-1.37 (3H, m), 1.40 (3H, s),
1.55-1.66 (2H, m), 1.66-1.78 (2H, m), 2.15-
912 2.25 (1H, m), 2.57-2.65 (1H, m), 2.69-2.83
ΌΗ (2H, m), 3.15-4.30 (2H, br), 6.72-6.79 (2H, m),
6.95-7.01 (2H, m).
Figure imgf000233_0001
[0389]
Table 104
Absolute configuration
Figure imgf000233_0002
Figure imgf000234_0001
δρρηι : 0.88-1.03 (1H, m),
1.10-1.25 (1H, m), 1.25- 1.40 (4H, m), 1.45-1.66
(6H, m), 1.67-1.89 (1H,
m), 1.92-2.03 (1H, m),
920 -CH3 -H -H 2.26 (3H, m), 2.65 (1H, d, Hydrochloride
J = 12.5 Hz), 2.80 (1H, d,
J = 12.5 Hz), 2.88-3.00
(1H, m), 3.15-3.28 (1H,
m), 7.06-7.17 (2H, m),
7.19-7.26 (2H, m), 9.04
(1H, brs), 9.58 (1H, brs).
1H-NMR (DMSO-d6)
6ppm : 0.87-1.02 (1H, m),
1.10-1.24 (1H, m), 1.24- 1.40 (4H, m), 1.40-1.64
(6H, m), 1.67-1.77 (1H,
m), 1.95-2.04 (1H, m),
2.21 (3H, s), 2.22 (3H, s),
921 -CH3 -CH3 -H -H -H Hydrochloride
2.59 (1H, d, J = 12.5 Hz),
2.82 (1H, d, J = 12.5 Hz),
2.86-2.95 (1H, m), 3.15- 3.37 (1H, m), 6.97-7.03
(2H, m), 7.07-1.15 (1H,
m), 9.11 (1H, brs), 9.65
(1H, brs).
1H-NMR (DMSO-d6)
5ppm : 1.22-1.65 (10H,
m), 1.65-1.84 (2H, m),
1.90-2.00 (1H, m), 2.10- 2.20 (1H, m), 3.38-3.61
(4H, m), 3.78 (1H, d, J =
922 -H -CN -H -H 2 Hydrochloride
14.5 Hz), 6.83 (1H, dd, J
= 2.3, 8.9 Hz), 6.97 (1H,
dd, J = 2.0, 13.7 Hz),
7.65 (1H, t, J = 8.5 Hz),
8.93-9.15 (1H, m), 9.51- 9.71 (1H, rn).
1H-NMR (DMSO-d6)
6ppm : 1.00-1.15 (1H, m),
1.15-1.41 (5H, m), 1.50- 1.67 (6H,m ), 1.67-1.77
(1H, m), 1.95-2.05 (1H,
m), 2.81-2.95 (2H, m),
923 -H -H -OCF3 -H -H 2 Hydrochloride
3.01 (1H, d, J = 12.5 Hz),
3.11-3.25 (1H, m), 5.42- 6.30 (1H, br), 7.20-7.27
(2H, m), 7.31-7.37 (2H,
m), 9.02-9.20 (1H, brm),
9.60-9.80 (1H, brm). 1H-NMR (D SO-d6)
6ppm : 1.04-1.20 (1H, m),
1.20-1.41 (5H, m), 1.49- 1.78 (7H, m), 1.96-2.06
(1H, m), 2.85-3.11 (3H,
924 -H m), 3.15-3.28 (1H, m), 2 Hydrochloride
5.10-6.60 (1H, br), 7.00- 7.15 (1H, m), 7.22-7.29
(1H, m), 7.47-7.54 (1H,
m), 9.09 (1H, brs), 9.71
(1H, brs).
1H-NMR (DMSO-d6)
6ppm : 0.98-1.11 (1H, m),
1.11-1.25 (1H, m), 1.25- 1.40 (4H, m), 1.48-1.65
(6H, m), 1.65-1.76 (1H,
m), 1.92-2.03 (1H, m),
2.75-2.90 (2H, m), 2.99
925 -H -H -OCHF2 -H -H 2 Hydrochloride
(1H, d, J = 12.8 Hz),
3.10-3.23 (1H, m), 4.85- 5.90 (1H, br), 7.01
(0.25H, s), 7.13-7.22
(4.5H, m), 7.38 (0.25H,
s), 9.06 (1H, brs), 9.63
(1H, brs).
1H-NMR (DMSO-d6)
δρριη : 1.02-1.42 (6H, m),
1.50-1.66 (6H, m), 1.66- 1.77 (1H, m), 1.95-2.05
(1H, m), 2.81-2.94 (2H,
m), 3.02 (1H, d, J = 12.5
Hz), 3.10-3.23 (1H, m),
926 -H -CI -OCHF2 -H -H 2 Hydrochloride
3.88-4.25 (1H, br), 7.15
(1H, dd, J = 2.6, 8.8 Hz),
7.24 (1H, t, J = 73.3 Hz),
7.32 (1H, d, J = 2.6 Hz),
7.34 (1H, d, J = 8.8 Hz),
9.05-9.22 (1H, m), 9.62- 9.80 (1H, m).
1H-NMR (DMSO-d6)
δρρΓΠ : 1.02-1.16 (1H, m),
1.16-1.41 (5H, m), 1.50- 1.67 (6H, m), 1.67-1.78
(1H, m), 1.96-2.06 (1H,
m), 2.84-2.97 (2H, m),
3.04 (1H, d, J = 12.5 Hz),
927 -H -OCHF2 -H -H -H 2 Hydrochloride
3.11-3.25 (1H, m), 6.89
(1H, s), 6.96 (1H, dd, J =
2.1, 8.1 Hz), 7.00 (1H, d,
J = 8.1 Hz), 7.27 (1H, t, J
= 74.1 Hz), 7.39 (1H, t, J
= 8.1 Hz), 8.30-9.30 (2H,
br), 9.69-9.89 (1H, br). 1H-NMR (DMSO-d6)
6ppm : 1.04-1.40 (6H, m),
1.50-1.69 (6H, m), 1.69- 1.79 (1H, m), 1.92-2.04
(1H,m), 2.78-2.89 (1H,
m), 2.89-3.06 (2H, m),
928 -H -OCHF2 -CI -H -H Hydrochloride
3.15-3.27 (1H, m), 7.01- 7.08 (2H, m), 7.32 (1 H, t,
J = 73,3 Hz), 7.54 (1H, d,
J = 8.4 Hz), 8.81-9.11
(1 H, m), 9.40-9.69 (1H,
JUL
1H-NMR (DMSO-d6)
6ppm : 1.00-1.40 (6H, m),
1.47-1.65 (6H, m), 1.67- 1.77 (1H, m), 1.90-2.00
(1H, m), 2.70-2.80 (1H,
m), 2.87 (1H, d, J = 12.5
Hz), 2.96 (1H, d, J = 12.5
929 -H -OCHF2 -H -H Hydrochloride
Hz), 3.10-3.24 (1H, m),
7.02-7.11 (2.25H, m),
7.27 (0.5H, s), 7.37 (1H,
dd, J = 8.8, 10.5 Hz),
7.46 (0.25H, s), 8.80-9.00
(1H, br), 9.39-9.58 (1H,
1H-NMR (DMSO-d6)
δρριτι : 1.03-1.15 (1 H, m),
1.17-1.41 (5H, m), 1.48- 1.82 (7H, m), 1.93-2.05
(1H, m), 2.82-2.91 (1 H,
m), 2.94 (1H, d, J = 12.7
Hz), 3.01 (1H, d, J = 12.7
930 -H -CN -OCHF2 -H -H Hz), 3.08-3.25 (1H, m), 2 Hydrochloride
4.00-4.60 (1H, br), 7.39
(1H, t, J= 72.6 Hz), 7.42
(1H, d, J = 8.9 Hz), 7.51
(1H, dd, J = 2.7, 9.0 Hz),
7.69 (1 H, d, J = 2.7 Hz),
8.90-9.10 (1H, br), 9.40- 9.65 (1H. br).
1 H-NMR (DMSO-d6)
δρρσι : 1.08-1.42 (6H, m),
1.42-1.80 (7H, m), 1.96- 2.07 (1H, m), 2.90-3.00
(1H, m), 3.05 (1 H, d, J =
13.0 Hz), 3.10 (1H, d, J =
931 -H -OCHF2 -H 2 Hydrochloride
13.0 Hz), 3.17-3.29 (1 H,
m), 3.55-3.85 (1H, br),
6.97-7.06 (2.25H, m),
7.19 (0.5H, s), 7.37
(0.25H, s), 8.90-9.07 (1 H,
br), 9.51-9.70 (1H, br). 1 H-NMR (DMSO-d6)
6ppm : 0.98-1.80 (13H,
m), 1.91-2.14 (1 H, m),
2.61-3.50 (4H, m), 4.20-
932 -H -H -OCH2CHF2 -H -H 4.40 (2H, m), 4.61-6.20 2 Hydrochloride
(1 H, br), 6.39 (1 H, tt, J =
3.4, 54.5 Hz), 6.85-7.65
(4H, brm), 8.84-10.20
(2H, br).
1 H-NMR (CDCI3) 6ppm :
0.95-1.09 (4H, m), 1 .15- 1.44 (7H, m), 1.57-1.78
(4H, m), 2.13-2.22 (1 H,
m), 2.56 (1 H, d, J =11.1
933 -H -OCH2CHF2 -H -H
Hz), 2.70-2.79 (2H, m),
4.21 (2H, dt, J = 4.2, 13.1
Hz), 6.08 (1 H, tt, J = 4.2,
55.1 Hz), 6.77-6.83 (1 H,
m), 6.84-6.95 (2H, m).
1 H-NMR (CDCI3) δρρηη :
0.93-1.10 (4H, m), 1.15- 1.41 (7H, m), 1.53-1.77
(4H, m), 2.14-2.23 (1 H,
m), 2.57 (1 H, d, J = 11.0
Hz), 2.68-2.79 (2H, m),
934 -H -CI -OCH2CHF2 -H -H
4.20 (2H, dt, J = 4.2, 13.0
Hz), 6.12 (1 H, tt, J = 4.2,
55.1 Hz), 6.87 (1 H, d, J =
8.7 Hz), 6.96 (1 H, dd, J =
2.5, 8.7 Hz), 7.13 (1H, d,
J = 2.5 Hz). ■
1 H-NMR (DMSO-d6)
δρρηι : 0.96-1.10 (1 H, m),
1.12-1.40 (5H, m), 1.47- 1.63 (6H, m), 1.67-1.76
(1 H, m), 1.90-2.01 (1 H,
m), 2.21 (3H, m), 2.70- 2.87 (2H, m), 2.96 (1 H, d,
935 -H -CH3 -OCHF2 -H -H 2 Hydrochloride
J = 12.1 Hz), 3.07-3.22
(1 H, m), 4.40-6.50 (1H,
br), 6.94 (0.25H, s), 6.97- 7.03 (1 H, m), 7.03-7.08
(1 H, m), 7.09-7.15 (1.5H,
m), 7.31 (0.25H, s), 9.01
(1H, brs), 9.56 (1 H, brs).
1H-NMR (DMSO-d6)
6ppm : 1.02-1.40 (6H, m),
1.50-1.79 (7H, m), 1.96- 2.06 (1 H, m), 2.78-2.95
(2H, m), 2.98-3.22
(2H,m), 3.82 (3H, s), 6.75
936 -H -OCH3 -OCHF2 -H -H 2 Hydrochloride
(1 H, d, J = 7.8 Hz), 6.80- 6.93 (1.25H, m), 7.01
(0.5H, s), 7.11-7.21
(1.25H, m), 7.21-7.75
(1 H, br), 9.14 (1 H, brs),
9.77 (1 H, brs).
[0390]
Table 105 Absolute configuration
Figure imgf000238_0001
[0391]
Table 106
absolute confi uration
Figure imgf000238_0002
Figure imgf000238_0003
1 H-NMR (CDCI3) 5ppm :0.75-1.42 (29H, m),
1.44 (3H, s), 1.58-1.83 (4H, m), 2.34-2.42 (1H, m), 2.68 (1H, d, J = 11.3 Hz), 2.78-2.87 (1H, m), 2.91 (1H, d, J = 11.3 Hz), 3.91 (3H, s), 5.19-5.27 (2H, m), 7.21 (1 H, d, J = 9.1 Hz), 7.29 (1H, d, J = 2.2, 9.1 Hz), 7.37 (1H, d, J =
Figure imgf000239_0001
2.1 Hz), 7.69 (1H, d, J = 9.0 Hz), 8.16 (1H, d,
J = 9.1 Hz).
1 H-NMR (CDCI3) 6ppm : 0.95-1.18 (23H, m),
I .18-1.40 (6H, m), 1.44 (3H, s), 1.57-1.77 (4H, m), 2.33-2.41 (1H, m), 2.71 (1H, d, J =
II .2 Hz), 2.77-2.85 (1H, m), 2.87 (1 H, d, J =
942 11.2 Hz), 3.89 (3H, s), 4.94 (2H, d, J = 1.0
Figure imgf000239_0002
Hz), 7.02 (1H, s), 7.22 (1 H, dd, J = 2.0, 8.6
Hz), 7.43 (1H, d, J = 1.8 Hz), 7.64 (1H, d, J = 8.6 Hz), 7.88 (1 H, s).
[0392]
Table 107
Absolute confi uration
Figure imgf000239_0003
8.8 Hz), 9.62 (1H. S).
1H-NMR (DMSO-d6) 5ppm : 0.90-1.10 (4H, m), 1.15-1.40 (6H, m), 1.51-1.75 (4H, m), 2.35-2.48 (1 H, m), 2.60-2.88 (3H, m), 2.96-
945 3.88 (1H, br), 7.23 (1H, d, J = 8.9 Hz), 7.34
(1H, dd, J = 2.1 , 9.0 Hz), 7.47 (1H, d, J = 2.0
Figure imgf000239_0004
Hz), 7.70 (1H, d, J = 8.9 Hz), 7.92 (1H, d, J =
9.0 Hz), 8.92-11.38 (1H, br).
Figure imgf000240_0001
[0393]
Table 108
Absolute confi uration
Figure imgf000240_0002
Figure imgf000241_0001
Figure imgf000241_0002
Figure imgf000242_0001
1H-NMR (CDCI3) δρρπΐ : 1.00-1.15 (4H, m),
1.20-1.70 (8H, m), 1.70-1.88 (3H, m), 2.39- 2.48 (1H, m), 2.70 (1H, d, J = 11.4 Hz), 2.79- 2.88 (1H, m), 2.93 (1H, d, J = 11.4 Hz), 4.29
966 (2H, dt, J = 4.2, 13.1 Hz), 6.15 (1H, tt, J = 4.1,
Figure imgf000243_0001
55.2 Hz), 7.03-7.11 (2H, m), 7.16 (1H, dd, J
= 2.1, 8.6 Hz), 7.33 (1H, d, J = 2.0 Hz), 7.65- 7.74 (2H, m).
1H-NMR (DMSO-d6) 5ppm : 0.91-1.05 (1H,
m), 1.07-1.36 (5H, m), 1.36-1.63 (12H, m),
1.63-1.74 (1H, m), 1.80-1.83 (1H, m), 2.50- 2.62 (1H, m), 2.71 (1H, d, J = 12.0 Hz), 2.86
967 Fumarate
(1H, d, J = 12.0 Hz), 2.92-3.02 (1H, m), 4.78
Figure imgf000243_0002
(2H, s), 6.48 (2H, s), 6.73 (1H, d, J = 8.6 Hz),
6.83 (1H, d, J = 2.3 Hz), 6.91 (1H, dd, J = 2.3,
8.6 Hz).9.52-11.33 (1H, br).
[0394]
Table 109
Absolute configuration
Figure imgf000243_0003
Exam
R4 NMR Salt pie.
1 H-NMR (DMSO-d6) 5ppm : 0.96-1.10 (1H,
m), 1.10-1.25 (1H, m), 1.26-1.41 (4H, m),
1.47-1.78 (7H, m), 1.94-2.05 (1H, m), 2.56
(3H, s), 2.84 (1H, d, J = 12.4 Hz), 2.90-3.02
968 Hydrochloride
(2H, m), 3.23-3.35 (1H, m), 7.15 (1H, d, J =
7.6 Hz), 7.22-7.33 (2H, m), 7.68 (1H, d, J =
Figure imgf000243_0004
7.9 Hz), 8.91-9.09 (1H, brm), 9.54-9.70 (1H,
brm).
1 H-NMR (DMSO-d6) δ ppm (80 °C): 1.03- 1.46 (6H, m), 1.50-1.79 (7H, m), 2.02-2.12
(1H, m), 2.53 (3H, s), 2.88 (1H, d, J = 12.4
969 Hydrochloride
Hz), 3.02-3.12 (1H, m), 3.12-3.27 (2H, m),
7.05 (1H, s), 7.13 (1H, d, J = 8.6 Hz), 7.62- 7.68 (2H, m), 9.25 (1H, brs), 9.75 (1H, brs).
1 H-NMR (DMSO-d6) 6ppm : 0.95-1.41 (6H,
m), 1.40-1.76 (7H, m), 1.96-2.05 (1H, m), 2.84
(1H, d, J = 12.4 Hz), 2.93-3.01 (1H, m), 3.04
970 (1H, d, J = 12.4 Hz), 3.28-3.44 (1H, m), 7.25 Hydrochloride
(2H, d, J = 7.0 Hz), 7.64 (1H, dd, J = 4.0, 5.3
Hz), 7.86 (1H, d, J = 5.3 Hz), 9.04-9.19 (1H,
Figure imgf000243_0005
brm), 9.63-9.75 (1H, brm).
Figure imgf000244_0001
Absolute onfiguration
Figure imgf000244_0002
Figure imgf000245_0001
[0396] Table 111
Absolute confi uration
Figure imgf000246_0001
[0397]
Table 112
Absolute confi uration
Figure imgf000247_0001
[0398]
Table 113
Absolute confi uration
Figure imgf000248_0001
[0399]
Table 114
Absolute configuration
Figure imgf000248_0002
1H-N R (DMSO-d6) 5ppm : 0.90-1.21 (2H,
m), 1.22-1.43 (4H, m), 1.43-1.80 (7H, m), 1.90-
1002 2.10 (1H, m), 2.58-3.40 (6H, m), 4.52 (2H, t, J 2 Hydrochloride
= 8.6 Hz), 5.35-6.40 (1H, br), 6.55-7.60 (3H,
Figure imgf000249_0001
m), 8.60-10.20 (2H, br).
1H-NMR (DMSO-d6) δρρηι : 0.98-1.13 (1H,
m), 1.13-1.40 (5H, m), 1.47-1.65 (6H, m), 1.65- 1.77 (1H, m), 1.91-2.06 (1 H, m), 2.74-2.90 (2H,
m), 2.99 (1H, d, J = 12.5 Hz), 3.08-3.21 (1H,
1003 2 Hydrochloride m), 4.05-5.00 (1H, br), 6.95 (1H, dd, J = 2.0,
Figure imgf000249_0002
8.6 Hz), 7.26 (1H, d, J = 2.0 Hz), 7.36 (1H, d, J
= 8.6 Hz), 8.94-9.20 (1H, br), 9.55-9.85 (1H,
bf
[0400]
Table 115
Absolute configuration
Figure imgf000249_0003
Figure imgf000250_0001
[0401]
Table 116
Absolute confi uration
Figure imgf000250_0002
Exam
R NMR Salt pie
1H-NMR (CDCI3) 6ppm : 0.92-1.06 (1H, m),
1.09 (3H, s), 1.12-1.39 (3H, m), 1.41 (3H, s),
1.55-1.66 (2H, m), 1.66-1.79 (2H, m), 2.17-
1011 2.25 (1H, m), 2.61 (1H, d, J = 11.3 Hz), 2.70-
ΌΗ 2.83 (2H, m), 3.53-4.70 (2H, br), 6.73-6.79 (2H,
m), 6.94-7.01 (2H, m).
1H-NMR (DMSO-d6) δρρηι : 0.82-1.00 (4H,
m), 1.09-1.35 (6H, m), 1.40-1.52 (1H, m), 1.52- 1.70 (4H, m), 2.15-2.25 (1H, m), 2.44-2.55 (1H,
1012
m), 2.55-2.64 (1H, m), 2.66 (1H, d, J = 12.2
Hz), 6.39-6.51 (3H, m), 6.99-7.09 (1H, m), 9.21
(1H,s).
1H-NMR (DMSO-d6) 6ppm : 0.90-1.03 (1H,
m), 1.05-1.53 (10H, m), 1.53-1.62 (1H, m),
1.62-1.74 (1H, m), 1.80-1.90 (1H,m ), 2.48- 2.59 (1H, m), 2.68 (1H, J = 11.8 Hz), 2.84 (1H,
1013 1/2 Fumarate d, J = 11.8 Hz), 2.90-3.01 (1H, m), 3.74 (3H, S),
Figure imgf000250_0003
4.45 (2H, s), 6.45 (1H, s), 6.86 (1H, d, J = 8.6
Hz), 6.94 (1H, dd, J = 2.5, 8.6 Hz), 7.15 (1H, d,
J = 2.5 Hz), 8.10-10.15 (1H, br).
Figure imgf000251_0001
[0402]
Table 117
Absolute configuration
Figure imgf000251_0002
Exam
NMR Salt pie 1 H-NMR (DMSO- d6) 5ppm : 0.88- 1.03 (1H, m), 1.10- 1.25 (1H, m), 1.25- 1.40 (4H, m), 1.45- 1.66 (6H, m), 1.67- 1.89 (1 H, m), 1.92-
2.03 (1H, m), 2.26
1019 -CH3 -H -H (3H, m), 2.65 (1 H, d, Hydrochloride
J = 12.5 Hz), 2.80
(1H, d, J = 12.5 Hz),
2.88-3.00 (1H, m),
3.15-3.28 (1H, m),
7.06-7.17 (2H, m),
7.19-7.26 (2H, m),
9.04 (1H, brs), 9.58
(1H, brs).
1 H-NMR (DMSO- d6) 6ppm : 0.89- 1.02 (1H, m), 1.09- 1.23 (1H, m), 1.24- 1.40 (4H, m), 1.40- 1.66 (6H, m), 1.67- 1.76 (1H, m), 1.93- 2.02 (1H, m), 2.21
1020 -CH3 -CH3 -H -H -H Hydrochloride
(3H, s), 2.22 (3H, s),
2.60 (1 H, d, J = 12.5
Hz), 2.76-2.95 (2H,
m), 3.15-3.35 (1H,
m),6.97-7.03 (2H,
m), 7.07-1.15 (1H,
m), 9.07 (1H, brs),
9.61 (1H, brs).
1 H-NMR (DMSO- d6) 6ppm : 1.21- 1.65 (10H, m), 1.65- 1.84 (2H, m), 1.90- 2.00 (1H, m), 2.10- 2.20 (1H, m), 3.38- 3.61 (3H, m), 3.78
1021 -H -CN (1H, d, J = 14.5 Hz), Fumarate
6.83 (1H, dd, J =
2.3, 8.9 Hz), 6.97
(1H, dd, J = 2.0,
13.7 Hz), 7.65 (1H,
t, J = 8.5 Hz), 8.93- 9.15 (1H, m), 9.51- 9.71 (1H, m). 1H-NMR (DMSO- d6) 6ppm : 1.00- 1.15 (1H, m), 1.15- 1.40 (5H, m), 1.50- 1.67 (6H,m ), 1.67- 1.77 (1H, m), 1.95- 2.05 (1H, m), 2.80-
1022 -H -H -OCF3 -H -H 2.95 (2H, m), 3.01 2 Hydrochloride
(1H, d, J = 12.4 Hz),
3.11-3.25 (1H, m),
5.15-5.32 (1 H, br),
7.20-7.27 (2H, m),
7.31-7.37 (2H, m),
9.10 (1 H, brs), 9.68
(1H, brm).
1H-NMR (DMSO- d6) 6ppm : 1.04- 1.20 (1H, m), 1.20- 1.41 (5H, m), 1.479- 1.78 (7H, m), 1.97- 2.07 (1 H, m), 2.86- 3.11 (3H, m), 3.15-
1023 -H -OCF3 -H -H 2 Hydrochloride
3.27 (1 H, m), 4.45- 6.85 (1H, br), 7.00- 7.16 (1H, m), 7.22- 7.29 (1H, m), 7.46- 7.55 (1 H, m), 9.12
(1 H, brs), 9.77 (1H,
brs).
1 H-NMR (DMSO- d6) 6ppm : 0.98- 1.40 (6H, m), 1.49- 1.77 (7H, m), 1.95- 2.06 (1H, m), 2.76- 2.95 (2H, m), 3.03
(1H, d, J = 12.3 Hz),
1024 -H -H -OCHF2 -H -H 2 Hydrochloride
3.10-3.23 (1H, m),
6.20-6.90 (1 H, br),
7.01 (0.25H, s),
7.13-7.23 (4.5H, m),
7.38 (0.25H, s), 9.17
(1H, brs), 9.74 (1H,
brm).
1 H-NMR (D SO- d6) 5ppm : 1.03-1.40
(6H, m), 1.50-1.67
(6H, m), 1.67-1.77
(1 H, m), 1.96-2.05
(1H, m), 2.81-2.95
(2H, m), 3.02 (1H, d,
J = 12.5 Hz), 3.10- 3.23 (1H, m), 3.88-
1025 -H -OCHF2 -H -H 2 Hydrochloride
4.20 (1H, br), 6.96- 7.01 (1 H, m), 7.02
(0.25H, S), 7.17 (1H,
dd, J = 2.5, 12.1
Hz), 7.20 (0.5H, s),
7.33 (1 H, t, J = 8.9
Hz), 7.39 (0.25H, s),
9.08-9.22 (1H, m),
9.70-9.88 (1H, m).
1 H-NMR (DMSO- d6) δρριτι : 1.02- 1.15 (1 H, m), 1.15- 1.41 (5H, m), 1.50- 1.67 (6H, m), 1.67- 1.78 (1H, m), 1.93-
2.04 (1H, m), 2.78- 2.95 (2H, m), 2.95- 3.06 (1H, m), 3.10-
1026 -H -CI -OCHF2 -H -H 2 Hydrochloride
3.25 (1H, m), 3.50-
4.05 (1H, br), 7.15
(1H, dd, J = 2.5, 8.8
Hz), 7.24 (1H, t, J =
73.3 Hz), 7.32 (1H,
d, J = 2.5 Hz), 7.34
(1H, d, J = 8.8 Hz),
8.90-9.20 (1 H, br),
9.44-9.75 (1H, br).
1 H-NMR (DMSO- d6) δρρηι : 1.01- 1.15 (1H, m), 1.15- 1.42 (5H, m), 1.50- 1.68 (6H, m), 1.68- 1.78 (1H, m), 1.96- 2.06 (1 H, m), 2.83- 2.96 (2H, m), 3.03
(1H, d, J = 12.7 Hz),
1027 -H -OCHF2 -H -H -H 3.10-3.25 (1H, m), 2 Hydrochloride
6.89 (1H, S), 6.96
(1H, dd, J = 2.1 , 8.1
Hz), 7.00 (1H, d, J =
8.1 Hz), 7.27 (1 H, t,
J = 74.1 Hz), 7.39
(1H, t, J = 8.1 Hz),
7.85-8.90 (1H, br),
9.00-9.25 (1 H, br),
9.65-9.85 (1 H, br). 1 H-NMR (DMSO- d6) δρριτι : 1.02- 1.41 (6H, m), 1.49- 1.80 (7H, m), 1.91-
2.07 (1H,m ), 2.78-
2.90 (1 H, m), 2.90- 3.05 (2H, m), 3.10-
1028 -H -OCHF2 -CI -H -H 3.27 (1 H, m), 3.90- 2 Hydrochloride
4.65 (1H, br), 7.01-
7.08 (2H, m), 7.32
(1 H, t, J = 73,3 Hz),
7.54 (1 H, d, J = 8.4
Hz), 8.85-9.10 (1H,
m), 9.39-9.70 (1H,
; ; m).
1 H-NMR (DMSO- d6) δρρρη : 1.00- 1.40 (6H, m), 1.47- 1.65 (6H, m), 1.67- 1.77 (1 H, m), 1.90-
2.00 (1H, m), 2.70-
2.80 (1H, m), 2.87
(1H, d, J = 12.5 Hz),
1029 -H . -OCHF2 -F -H -H 2.96 (1 H, d, J = 12.5 Hydrochloride
Hz), 3.10-3.24 (1H,
m), 7.02-7.11
(2.25H, m), 7.27
(0.5H, s), 7.37 (1 H,
dd, J = 8.8, 10.5
Hz), 7.46 (0.25H, s),
8.80-9.00 (1H, br),
9.39-9.58 (1H, br).
1 H-NMR (DMSO- d6) 6ppm : 1.02- 1.15 (1H, m), 1.17- 1.40 (5H, m), 1.48-
1.81 (7H, m), 1.93- 2.07 (1H, m), 2.82-
2.91 (1H, m), 2.94
(1 H, d, J = 12.6 Hz),
3.01 (1H, d, J = 12.6
1030 -H -CN -OCHF2 -H -H Hz), 3.08-3.25 (1H, 2 Hydrochloride m), 3.70-4.20 (1H,
br), 7.39 (1H, t, J=
72.6 Hz), 7.42 (1H,
d, J = 8.9 Hz), 7.51
(1H, dd, J = 2.7, 9.0
Hz), 7.69 (1H, d, J =
2.7 Hz), 8.90-9.10
(1H, br), 9.35-9.70
(1H, br). 1H-NMR (DMSO- d6) δρρπι : 1.08- 1.40 (6H, m), 1.43- 1.80 (7H, m), 1.95- 2.07 (1H, m), 2.88- 2.99 (1H, m), 3.05
(1H, d, J = 13.1 Hz),
1031 -H -F -OCHF2 -F -H 1£) ^"ύίθ H, 2 Hydrochloride m), ' 3.48-3.70 (1H!
br), 6.97-7.06
(2.25Η, m), 7.19
(0.5H, s), 7.37
(0.25H, s), 8.81-9.04
(1H, br), 9.45-9.65
(1 H, br).
1H-NMR (DMSO- d6) 6ppm : 0.98- 1.85 (13H, m), 1.90- 2.20 (1H, m), 2.60- 3.80 (4H, m), 4.20-
1032 -H -H -OCH2CHF2 -H -H 4.40 (2H, m), 4.40- 2 Hydrochloride
5.40 (1H, br), 6.38
(1H, tt, J = 3.4, 54.5
Hz), 6.85-7.70 (4H,
brm), 8.84-10.40
(2H, br).
1H-NMR (CDCI3)
δρρηι : 0.94-1.11
(4H, m), 1.14-1.41
(7H, m), 1.57-1.78
(4H, m), 2.13-2.22
(1H, m), 2.56 (1 H, d,
1033 -H -F OCH2CHF2 -H -H J = 11.1 Hz), 2.70-
2.79 (2H, m), 4.21
(2H, dt, J = 4.2, 13.1
Hz), 6.08 (1 H, tt, J =
4.2, 55.1 Hz), 6.77- 6.83 (1H, m), 6.83- 6.95 (2H, m).
1H-NMR (CDCI3)
5ppm : 0.93-1.11
(4H, m), 1.15-1.41
(7H, m), 1.55-1.77
(4H, m), 2.14-2.23
(1H, m), 2.57 (1H, d,
J = 11.0 Hz), 2.68-
1034 -H CI OCH2CHF2 -H -H 2.78 (2H, m), 4.20
(2H, dt, J = 4.2, 13.0
Hz), 6.12 (1 H, tt, J =
4.2, 55.1 Hz), 6.87
(1H, d, J = 8.7 Hz),
6.96 (1H, dd, J =
2.5, 8.7 Hz), 7.13
(1 H, d, J = 2.5 Hz). 1H-N R (DMSO- d6) 6ppm : 0.97- 1.10 (1H, m), 1.12- 1.40 (5H, m), 1.47- 1.63 (6H, m), 1.67- 1.76 (1H, m), 1.90- 2.01 (1H, m), 2.20
(3H, m), 2.70-2.80
(1H, m), 2.83 (1 H, d,
J = 12.3 Hz), 2.95
1035 -H -CH3 -OCHF2 -H -H (1 H, d, J = 12.3 Hz), 2 Hydrochloride
3.08-3.22 (1H, m),
4.60-5.40 (1H, br),
6.94 (0.25H, s), 6.99
(1H, dd, J = 2.5, 8.5
Hz), 7.05 (1H, d, J =
2.5 Hz), 7.09-7.15
(1.5H, m), 7.31
(0.25H, s), 8.85-9.01
(1 H, m), 9.40-9.55
(1H, m).
1H-NMR (DMSO- d6) 5ppm : 1.00- 1.40 (6H, m), 1.50- 1.80 (7H, m), 1.95-
2.06 (1H, m), 2.75- 2.94 (2H, m), 2.96-
3.07 (1H, m), 3.09- 3.22 (1H,m), 3.82
1036 -H -OCH3 -OCHF2 -H -H (3H, s), 6.08-6.65 2 Hydrochloride
(1 H, br), 6.73 (1H, d,
J = 8.2 Hz), 6.80- 6.89 (1.25H, m),
7.01 (0.5H, s), 7.14
(1H, d, J = 8.4 Hz),
7.19 (0.25H, s), 9.09
(1H, brs), 9.72 (1 H,
rs^
[0403]
Table 118
Absolute configuration
Figure imgf000257_0001
1H-NMR ( CDCI3 ) 5ppm : 0.95-1.15 ( 2H, m ),
1.3-1.4 ( 1H, m ), 1.4-2.1 ( 11H, m ), 2.25-2.4
( 1H, m ), 3.04 ( 1H, d, J = 11.1Hz ), 3.17 ( 1H,
1038 d, J = 10.9Hz ), 3.41 ( 1H, br ), 3.45-3.58 ( 1H, - m ), 6.54 ( 1H, dd, J = 3.3, 8.4Hz ), 6.82 ( 1H,
dd, J = 2.5, 2.5Hz ), 6.91 ( 1 H, dd, J = 8.6,
10.4Hz ), 7.59 ( 1 H, d, J = 2.1Hz ).
1H-NMR ( DMS0-d6 ) 6ppm : 0.95-1.5 ( 3H,
m ), 1.5-1.7 ( 2H, m ), 1.7-2.3 ( 6H, m ), 2.3-2.7
( 3H, m ), 3.0-3.4 ( 1 H, m ), 3.59 ( 2H, br ), 3.73
1039 Hydrochloride
( 1H, br ), 7.07 ( 1H, br ), 7.3-7.45 ( 1H, m ),
7.48 ( 1H, d, J = 5.4Hz ), 7.64 ( 1 H, br ), 7.75
Figure imgf000258_0001
( 1H, d, J = 5.4Hz ), 8.75-10.3 ( 2H, m ).
[0404]
Table 119
/ Absolute configuration
Figure imgf000258_0002
[0405]
Table 120 Relative confi uration
Figure imgf000259_0001
[0406]
Table 121
Absolute configuration
Figure imgf000259_0002
Exam
R4 NMR Salt pie
1 H-NMR ( DMSO-d6 ) 5ppm : 0.85-1.0 ( 1H,
m ), 1.12-1.40 ( 2H, m ), 1.42-1.63 ( 3H, m ),
1.65-1.78 ( 1 H, m ), 1.84-1.97 ( 3H, m ), 1.97- 2.06 ( 1H, m ).2.24-2.38 ( 2H, m ), 2.39-2.49
1045 2 Hydrochloride
( 1H, m ), 2.73-2.93 ( 2H, m ), 3.03 ( 1 H, d, J =
Figure imgf000259_0003
12.5Hz ), 3.23 ( 1H, d, J = 12.5Hz ), 3.6 ( 1H
br ), 7.15-7.25 ( 2H, m ), 7.37-7.46 ( 2H, m )
9.37 ( 1 H, br ), 9.87 ( 1 H, br).
1H-NMR ( CDCI3 ) 5ppm : 0.95-1.1 ( 1H, m )
1.15-1.45 ( 3H, m ), 1.45-1.95 ( 10H, m ), 2.45- 2.7 ( 3H, m ), 2.80 ( 1 H, dd, J = 1.7, 11.2Hz )
3.19 ( 1H, d, J = 11.1Hz ), 3.91 ( 3H, s ), 7.08-
Figure imgf000259_0004
7.15 ( 2H, m ), 7.29 ( 1 H, dd, J = 2.1, 8.7Hz )
7.45 ( 1H, d, J = 2.0Hz ), 7.63-7.71 ( 2H, m ).
1 H-NMR ( DMSO-d6 ) 6ppm : 0.85-1.1 ( 1H
m ), 1.1-1.45 ( 2H, m ), 1.45-1.65 ( 3H, m ).
1.65-1.8 ( 1H, m ), 1.8-2.0 ( 3H, m ), 2.0-2.15
( 1H, m ), 2.25-2.65 ( 3H, m ), 2.85-3.35 ( 2H,
1047 2 Hydrochloride m ), 3.6-4.35 ( 3H, m ), 6.9-7.2 ( 2H, m ), 7.31
Figure imgf000259_0005
( 1H, dd, J = 8.0, 8.0Hz ), 7.46 ( 1H, d, J =
8.2Hz ), 8.00 ( 1H, d, J = 1.6Hz ), 9.3-10.3
( 2H, m ).
Figure imgf000260_0001
Absolute configuration
Figure imgf000260_0002
Exam
NMR Salt pie
1H-NMR ( DMSO-d6 ) 5ppm : 0.85-1.05 ( H,
m ), 1.1-1.4 ( 2H, m ), 1.4-1.65 ( 3H, m ), 1.65- 1.8 ( 1H, m ), 1.8-2.0 ( 3H, m ), 2.0-2.1 ( 1H,
m ), 2.25-2.4 ( 2H, m ), 2.4-2.6 ( 1H, m ), 2.75-
1049 2 Hydrochloride
2.95 ( 2H, m ), 3.0-3.1 ( 1H, m ), 3.23 ( 1H, d, J
Figure imgf000260_0003
= 12.6Hz ), 3.5-4.0 ( 1H, m ), 7.15-7.25 ( 2H,
m ), 7.35-7.45 ( 2H, m ), 9.3-9.6 ( 1H, m ),
9.85-10.1 (1H, m).
1H-NMR ( CDCI3 ) 5ppm : 0.95-1.1 ( 1H, m ),
1.1-1.45 ( 3H, m ), 1.45-1.95 ( 10H, m ), 2.45- 2.7 ( 3H, m ), 2.80 ( H, dd, J = 1.7, 11.2Hz ),
1050 3.19 ( 1H, d, J = 11.2Hz ), 3.91 ( 3H, s ), 7.07- 7.15 ( 2H, m ), 7.29 ( 1H, dd, J = 2.1, 8.7Hz ),
7.45 ( 1 H, d, J = 2.0Hz ), 7.63-7.71 ( 2H, m ).
1H-NMR ( DMSO-d6 ) δρρηι : 0.85-1.1 ( 1H,
m), 1.1-1.4 (2H, m ), 1.4-1.65 ( 3H, m ), 1.65- 1.8 ( 1H, m ), 1.8-2.0 ( 3H, m ), 2.0-2.15 ( 1H,
1051 m ), 2.25-2.65 ( 3H, m ), 2.8-3.45 ( 2H, m ), 2 Hydrochloride
3.5-4.25 ( 3H, m ), 6.9-7.2 ( 2H, m ), 7.31 ( 1H,
dd, J = 8.0, 8.0Hz ), 7.46 ( 1H, d, J = 8.2Hz ),
8.00 ( 1 H, d, J = 1.8Hz ), 9.3-10.3 ( 2H, m ).
1H-NMR ( DMSO-d6 ) 6ppm : 0.8-0.95 ( 1H,
m ), 1.1-1.4 ( 3H, m ), 1.45-1.6 ( 2H, m ), 1.6- 1.7 ( 1H, m ), 1.7-1.9 ( 4H, m ), 2.0-2.15 ( 1H,
m ), 2.15-2.3 ( 1H, m ), 2.35-2.5 ( 1H, m ),
1052 1.5 Fumarate
2.65-2.85 ( 2H, m ), 2.85-3.0 ( 1H, m ), 3.13
( 1H, d, J = 11.7Hz ), 6.53 ( 3H, s ), 7.0-7.1
Figure imgf000260_0004
( 2H, m ), 7.18 ( 1H, dd, J = 8.6, 10.8Hz ), 8.07
(1H,d, J = 2.1Hz), 10.3(4H, br).
[0408]
Table 123 Relative configuration
Figure imgf000261_0001
1.33-1.72 ( 5H, m ), 1.72-1.91 ( 1H, m ), 1.92- 2.07 ( 1H, m ), 2.82-2.92 ( 1H, m ), 3.03-3.17
( 1 H, m ), 3.17-3.27 ( 1H, m ), 3.38 ( 1H, br ),
1057
3.42-3.52 ( 1H, m ), 3.52-3.61 ( 1H, m ), 6.85
( 1H, d, J = 7.6Hz ), 7.21-7.28 ( 1H, m ), 7.37
( 1 H, d, J = 5.5Hz ), 7.40-7.47 ( 1H, m ), 7.52
( 1H, d, J = 8.0Hz ).
1 H-NMR ( DMSO-d6 ) δρρηΐ : 1.26-1.42 ( 2H,
m ), 1.42-1.63 ( 2H, m ), 1.63-1.91 ( 3H, m ),
1.91-2.04 ( 1H, m ), 3.01-3.18 ( 2H, m ), 3.24- 3.42 ( 1H, m ), 3.47-3.55 ( 1H, m ), 3.55-3.65
1058 Hydrochloride
( H, m ), 4.06-4.19 ( 1H, m ), 6.95 ( 1H, dd, J
Figure imgf000261_0002
= 2.9, 9.0Hz ), 7.18 ( 1H, d, J = 2.9Hz ), 7.43
( 1H, d, J = 9.0Hz ). 9.00 ( 1H, br ), 9.62 ( 1H,
Figure imgf000262_0001
m ), 1.40-1.55 ( 1H, m ), 1.57-1.73 ( 2H, m ),
1.73-1.87 ( 2H, m ), 2.85-3.03 ( 3H, m ), 3.04-
1062 3.83 ( 4H, m ), 3.85-3.93 ( 1H, m ), 6.49 ( 1 H, 1/2 Fumarate s ), 7.09 ( 1H, dd, J = 2.2, 8.9Hz ), 7.25 ( 1H, d,
J = 5.3Hz ), 7.35-7.41 ( 2H, m ), 7.67 ( 1H, d, J
= 8.8Hz ).
[0409]
Table 124
uration
Figure imgf000262_0002
Exam
NMR Salt pie.
1H-NMR ( CDCI3 ) 6ppm : 1.23-1.43 ( 3H m ),
1.44-1.57 ( 1H, m ), 1.58-1.72 ( 1H, m ), 1.74- 1.84 ( 1H, m ), 2.08-2.27 ( 2H, m ), 2.33-2.42
Figure imgf000262_0003
Figure imgf000263_0001
[0410]
Table 125
Absolute configuration
Figure imgf000263_0002
[0411]
Table 126
Absolute configuration
Figure imgf000263_0003
Figure imgf000264_0001
[0412]
Table 127
Absolute configuration
Figure imgf000264_0002
[0413]
Table 128 Absolute configuration
Figure imgf000265_0001
[0414]
Table 129
Absolute configuration
Figure imgf000265_0002
1H-NMR (CDCI3) 6ppm : 0.95-1.09 (1H, m),
1.20-1.55 (4H, m), 1.55-1.63 (1H, m), 1.66- 1.86 (3H, m), 2.59-2.77 (2H, m), 2.81-3.01 (1H,
1075 m), 3.01-3.09 (1H, m), 3.18-3.30 (2H, m), 6.66- 6.71 (1H, m), 6.87 (1H, dd, J = 1.1 , 7.2 Hz),
7.10-7.21 (3H, m), 8.25 (1H, brs).
1H-NMR (CDCI3) δρρηι : 0.96-1.10 (1H, m),
1.10-1.43 (3H, m), 1.43-1.65 (3H, m), 1.65- 1.84 (2H, m), 2.42-2.53 (1H, m), 2.53-2.66 (1H,
1076 m), 2.97-3.12 (3H, m), 3.15-3.26 (1H, m), 6.51
(1H, dd, J = 1.0, 2.1 Hz), 7.06 (1H, dd, J = 2.0,
8.6 Hz), 7.17-7.23 (1H, m), 7.32 (1 H, d, J = 8.6
Hz), 7.44 ( H, d, J = 2.0 Hz), 8.36 (1H, brs).
1H-NMR (DMSO-d6) 6ppm : 0.81-0.96 (1 H, m), 1.06-1.35 (3H, m), 1.43-1.57 (2H, m), 1.58- 1.74 (2H, m), 2.01 (1H, brs), 2.30-2.41 (2H, m),
1077 2.75-2.97 (4H, m), 6.31-6.37 (1 H, m), 6.80 (1H,
dd, J = 1.8, 8.4 Hz), 7.10 (1H, s), 7.25 (1H, t, J
Figure imgf000266_0001
= 2.7 Hz), 7.41 (1H, d, J = 8.4 Hz), 10.89 (1 H,
1H-NMR (DMSO-d6) 6ppm : 0.85-0.98 (1 H, m), 1.12-1.35 (3H, m), 1.48-1.73 (4H, m), 2.17
(1H, brs), 2.32-2.50 (2H, m), 2.76-3.01 (4H, m),
1078 6.99-7.08 (2H, m), 7.20 (1H, dd, J = 2.1 , 8.7
Hz), 7.41 (1H, d, J = 1.8 Hz), 7.58 (1H, d, J =
Figure imgf000266_0002
8.8 Hz), 7.67 (1H, d, J = 8.8 Hz), 9.56 (1H,
brs).
[0415]
Table 130
Absolute configuration
Figure imgf000266_0003
Exam
NMR Salt pie
1H-NMR (CDCI3) 6ppm : 1.00-1.14 (1 H, m),
1.20-1.45 (3H, m), 1.45-1.60 (1H, m), 1.60- 1.68 (1 H, m), 1.68-1.85 (3H, m), 2.53-2.66 (2H, m), 2.95-3.10 (2H, m), 3.15-3.26 (2H, m), 7.33
(1H, dd, J = 2.1 , 8.8 Hz), 7.37-7.47 (2H, m),
7.51 (1H, d, J = 2.1 Hz), 7.74-7.82 (3H, m).
1H-NMR (CDCI3) δρρτη : 0.98-1.12 (1H, m),
1.17-1.82 (8H, m), 2.48-2.64 (2H, m), 2.95- 3.25 (4H, m), 3.90 (3H, s), 7.08-7.14 (2H, m),
7.31 (1H, dd, J = 2.1 , 8.7 Hz), 7.47 (1H, d, J =
Figure imgf000266_0004
2.0 Hz), 7.63-7.70 (2H, m).
Figure imgf000267_0001
7.97 (1H, d, J = 1.8 Hz). (2H not found)
[0416] Table 131
Absolute configuration
Figure imgf000268_0001
[0417]
Table 132
Absolute configuration
Figure imgf000268_0002
Exam
R4 NMR Salt pie.
Figure imgf000269_0001
brs).
[0418]
Table 133
Absolute configuration
Figure imgf000269_0002
Exam
R4 NMR Salt pie.
1H-NMR (CDCI3) 6ppm : 1.00-1.14 (1H, m),
1.20-1.45 (3H, m), 1.45-1.68 (2H, m), 1.68- 1.85 (3H, m), 2.53-2.66 (2H, m), 2.95-3.10 (2H, m), 3.15-3.26 (2H, m), 7.33 (1H, dd, J = 2.1,
Figure imgf000269_0003
8.8 Hz), 7.37-7.47 (2H, m), 7.51 (1H, d, J = 2.1
Hz), 7.74-7.82 (3H, m).
1H-NMR (CDCI3) 5ppm : 0.98-1.12 (1H, m),
1.17-1.45 (3H, m), 1.45-1.85 (5H, m), 2.49- 2.64 (2H, m), 2.95-3.25 (4H, m), 3.90 (3H, s),
7.08-7.14 (2H, m), 7.31 (1H, dd, J = 2.1 , 8.7
Figure imgf000269_0004
Hz), 7.47 (1H, d, J = 2.0 Hz), 7.63-7.70 (2H,
m).
Figure imgf000270_0001
[0419]
Table 134
Relative confi uration
Figure imgf000271_0001
[0420]
Table 134 Absolute configuration
Figure imgf000272_0001
[0421]
Table 135
Absolute configuration
Figure imgf000272_0002
Exam
R4 NMR Salt pie.
1 H-NMR (DMSO-d6) 6ppm : 0.85-0.99 (4H, m), 1.13-1.35 (3H, m), 1.49-1.75 (4H, m), 1.99
(1H, brs), 2.32-2.50 (3H, m), 2.92-3.02 (2H, m),
1 1 16 7.00-7.09 (2H, m), 7.19 (1 H, dd, J = 2.1 , 8.7
Hz), 7.41 (1 H, d, J = 1.8 Hz), 7.58 (1H, d, J =
Figure imgf000272_0003
8.8 Hz), 7.66 (1H, d, J = 8.8 Hz), 9.56 (1 H,
brs). 1H-NMR (DMSO-d6) δρρητΐ : 1.10-1.57 (7H,
m), 1.57-1.71 (2H, m), 1.71-1.82 (1 H, m), 2.11-
H— i 2.22 (1H,m ), 3.00-3.40 (6H, m), 7.22 (1H, t, J
1 1 17 V- = 7.4 Hz), 7.35-7.85 (4H, m), 8.09 (1H, d, J = 2 Hydrochloride
7.8 Hz), 8.37 (1H, brs), 9.96 (2H, brs), 11.61
(1H, brs).
H
Absolute confi uration
Figure imgf000273_0001
Exam
R4 NMR Salt pie.
1H-NMR (CDCI3) 5ppm : 0.98-1.11 (4H, m),
1.17-1.58 (4H, m), 1.58-1.85 (4H, m), 2.44- 2.53 (1H, m), 2.56-2.70 (2H, m), 3.12 (1H, dd,
11 18 J = 2.8, 11.2 Hz), 3.15-3.25 (1H, m), 3.90 (3H,
s), 7.08-7.16 (2H, m), 7.30 (1H, dd, J = 2.0, 8.7
Figure imgf000273_0002
Hz), 7.46 (1H, d, J = 2.0 Hz), 7.65 (1H, d, J =
4.8 Hz), 7.67 (1H, d, J = 4.9 Hz).
1H-NMR ( DMSO-d6 ) 6ppm : 0.95-1.05 ( 1H,
m ), 1.11 ( 3H, d, J = 6.3Hz ), 1.15-1.5 ( 3H,
m ), 1.5-1.6 ( 1H, m ), 1.65-1.75 ( 2H, m ),
1 1 19 1.85-1.95 ( 1H, m ), 2.65-2.85 ( 3H, m ), 2.85- 1/2 Fumarate
4.35 ( 4H, m ), 6.50 ( 1H, S ), 7.33 ( 1 H, dd, J =
Figure imgf000273_0003
2.1 , 8.7Hz ), 7.4-7.5 ( 2H, m ), 7.57 ( 1H, d, J =
1.8Hz ), 7.8-7.9 ( 3H, m ).
1 H-NMR (CDCI3) δρριη : 0.98-1.12 (4H, m),
1.18-1.48 (4H, m), 1.58-1.69 (1H, m), 1.69- 1.85 (3H, m), 2.46-2.54 (1H, m), 2.57 (1H, dd,
J = 10.2, 11.0 Hz), 2.62-2.70 (1H, m), 3.10-
1 120 3.25 (2H, m), 7.22 (1H, dt, J = 2.6, 8.8 Hz),
Figure imgf000273_0004
7.35 (1 H, dd, J = 1.8, 8.7 Hz), 7.40 (1 H, dd, J =
2.5, 9.9 Hz), 7.50 (1H, d, J = 1.9 Hz), 7.68-7.77
(2H, m).
[0423]
Table 137
Absolute configuration
Figure imgf000273_0005
Figure imgf000274_0001
[0424]
Table 138
Absolute configuration
Figure imgf000274_0002
Figure imgf000275_0001
[0425]
Table 139
Absolute configuration
Figure imgf000275_0002
Figure imgf000276_0001
8.15 (1 H, d, J = 7.7 Hz). (3H, not found)
[0426]
Table 140
Absolute configuration
Figure imgf000276_0002
E*Jf R4 NMR Salt pie
Figure imgf000277_0001
[0427]
Table 141
Absolute configuration
Figure imgf000277_0002
Exam
R NMR Salt pie
1H-NMR (CDCI3) 6ppm : 0.96-1.10 (4H, m),
1.13 (18H, d, J = 7.3 Hz), 1.19-1.50 (7H, m),
1.58-1.67 (1H, m), 1.68-1.84 (3H, m), 2.45- 2.53 (1H, m), 2.57 (1H, dd, J = 10.3, 11.0 Hz),
1141 2.62-2.70 (1H, m), 3.12 (1H, dd, J = 2.7, 11.2
Hz), 3.15-3.24 (1H, m), 7.09 (1H, dd, J = 2.4,
Figure imgf000277_0003
8.9 Hz), 7.17 (1H, d, J = 2.4 Hz), 7.27 (1H, dd,
J = 2.1, 8.7 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.59- 7.65 (2H, m).
1H-NMR (CDCI3) 6ppm : 0.94-1.12 (4H, m),
1.15-1.46 (4H, m), 1.57-1.68 (2H, m), 1.68- 1.85 (11H, m), 2.42-2.51 (1H, m), 2.59-2.70
(2H, m), 3.10 (1H, dd, J = 2.7, 11.2 Hz), 3.15-
1142 3.25 (1H, m), 7.29 (1H, dd, J = 2.2, 8.6 Hz),
7.30-7.37 (1H, m), 7.42-7.49 (1H, m), 7.76 (1H, d, J = 2.1 Hz), 7.93 (1H, d, J = 7.2 Hz), 8.21
Figure imgf000277_0004
(1H, d, J = 8.8 Hz), 8.29 (1H, d, J = 8.3 Hz). [0428]
Table 142
Absolute configuration
Figure imgf000278_0001
(1 H, brs).
[0429]
Table 143
Absolute configuration
Figure imgf000278_0002
1H-NMR ( DMSO-d6 ) 5ppm : 0.92-1.06 ( 1H,
m ), 1.11 ( 3H, d, J = 6.4Hz ), 1.16-1.51 ( 3H,
m ), 1.52-1.64 ( 1 H, m ), 1.64-1.78 ( 2H, m ),
1 146 1.82-1.94 ( 1H, m ), 2.65-2.85 ( 3H, m ), 2.85- 1/2 Fumarate
4.2 ( 4H, m ), 6.50 ( 1H, s ), 7.33 ( 1 H, dd, J =
Figure imgf000279_0001
2.1 , 8.7Hz ), 7.39-7.51 ( 2H, m ), 7.56 ( 1H, d,
J = 1.9Hz ), 7.80-7.89 ( 3H, m ).
1H-NMR (CDCI3) 6ppm : 0.98-1.12 (4H, m),
1.18-1.48 (4H, m), 1.60-1.69 (1H, m), 1.69- 1.85 (3H, m), 2.46-2.54 (1H, m), 2.57 (1H, dd,
J = 10.2, 11.0 Hz), 2.62-2.71 (1H, m), 3.10-
1 147 3.25 (2H, m), 7.22 (1H, dt, J = 2.6, 8.8 Hz),
Figure imgf000279_0002
7.35 (1H, dd, J = 1.8, 8.7 Hz), 7.40 (1H, dd, J =
2.5, 9.9 Hz), 7.50 (1H, d, J = 1.9 Hz), 7.68-7.77
(2H, m).
[0430]
Table 144
Absolute configuration
Figure imgf000279_0003
8.5 Hz).
1H-NMR (CDCI3) δρρητι : 0.86-1.02 (1H, m),
1.05 (3H, d, J = 6.4 Hz), 1.17-1.54 (4H, m),
1 ,54-1.63 (1H, m), 1.63-1.83 (3H, m), 2.39- 2.55 (1H, m), 2.55-2.65 (1H, m), 2.65-2.74 (1H,
1 149 m), 3.10 (1H, dd, J = 2.8, 11.4 Hz), 3.15-3.26
(1H, m), 7.12 (1H, dd, J = 0.7, 7.6 Hz), 7.30
Figure imgf000279_0004
(1H, t, J = 7.8 Hz), 7.35 (1H, d, J = 5.5 Hz),
7.57 (1H, d, J = 5.5 Hz), 7.64 (1H, d, J = 8.0
Hz).
1H-NMR (DMSO-d6) δρρσι : 0.90-1.04 (1H,
m), 1.10-1.35 (5H, m), 1.35-1.62 (3H, m), 1.64- 1.74 (1H, m), 1.84-1.95 (1H, m), 2.65-2.84 (3H,
m), 3.11 (1H, dd, J = 2.8, 11.8 Hz), 3.21-3.35
1 150 Fumarate
(1H, m), 6.49 (2H, s), 7.19 (1H, dd, J = 1.8, 8.5
Figure imgf000279_0005
Hz), 7.39 (1H, d, J = 5.4 Hz), 7.68 (1H, d, J =
5.4 Hz), 7.75 (1H, d, J = 1.8 Hz), 7.81 (1 H, d, J
= 8.5 Hz), 7.50-9.40 (1H, br).
[0431]
Table 145 Absolute configuration
Figure imgf000280_0001
Figure imgf000281_0001
[0432]
Table 146
Absolute configuration
Figure imgf000281_0002
Figure imgf000281_0003
1 H-NMR (DMSO-d6) δρρηη : 0.93-1.08 (1H,
m), 1.10-1.35 (5H, m), 1.401-1.60 (3H, m),
1.64-1.75 (1 H, m), 1.90-2.03 (1 H, m), 2.72- 3.00 (3H, m), 3.11 (1H, dd, J = 2.0, 12.0 Hz),
3.32-3.43 (1H, m), 3.85 (3H, s), 6.52 (2H, s),
1 163 Fumarate
7.15-7.23 (1H, m), 7.29 (1H, dd, J = 1.9, 8.6
Hz), 7.43-7.49 (1 H, m), 7.53 (1H, d, J = 8.6
Hz), 7.56 (1H, d, J = 8.2 Hz), 7.94 (1H, d, J =
Figure imgf000282_0001
1.8 Hz), 8.14 (1H, d, J = 7.7 Hz). (3H,
not found)
[0433]
Table 147
Absolute configuration
Figure imgf000282_0002
[0434]
Table 148 Absolute configuration
Figure imgf000283_0001
[0435]
Table 149 Absolute confi uration
Figure imgf000284_0001
1175 -H -H -H -H 317
1176 -H Ύ VCH3 -H -H -H 327
N-o
1177 -H -H -H -H 314
Figure imgf000284_0002
1180 -H -H -H -H 344
1181 -H -H -H -H 357
CH3
Figure imgf000285_0001
1191 -OCH3 -OCH3 -H -H -H 305
1192 -H -H -0(CH2)2CH3 -H -H 303
1193 -H -H — N N-CH3 -H -H 343 1 194 -F -H -OCH3 -H -H 293
1195 -CI -H -H -CF3 -H 347
1196 -CI -H -H -H -H 297
Figure imgf000286_0001
1 198 -OCH3 -H -CI -H -H 309
1 199 -F -CI -H -H -H 297
1200 -CH3 -H -OCH3 -CI -H 323
1205 -H -H -OCH(CH3)2 -H -H 303
1206 -H Y -H -H -H 312
1207 -OCH2CH3 -H -H -H -H 289
Figure imgf000287_0001
1209 -CI -CF3 -H -H -H 347
1210 -H -H -CH2CH(CH3)2 -H -H 301
121 1 -CN -H -CI -H -H 304
Figure imgf000287_0002
[0436]
Absolute configuration
Figure imgf000287_0003
Figure imgf000288_0001
1222
1223
1224
Figure imgf000288_0002
Figure imgf000289_0001
Absolute configuration
Figure imgf000289_0002
Figure imgf000290_0001
Figure imgf000291_0001
1249 286
Figure imgf000291_0002
1258 330
1259 373
1260 326
Figure imgf000292_0001
Figure imgf000292_0002
Figure imgf000293_0001
Figure imgf000294_0001
[0438]
Absolute configuration
Figure imgf000294_0002
1285 282
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
W 201
1333
Figure imgf000299_0001
1334 vi 328
Figure imgf000300_0001
Figure imgf000300_0002
[0439]
Figure imgf000300_0003
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
[0440]
Absolute configuration
Figure imgf000307_0002
Figure imgf000308_0001
Figure imgf000309_0001
1425 315
?
Figure imgf000310_0001
[0441]
Absolute configuration
Figure imgf000310_0002
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
1470 335
Figure imgf000315_0002
Figure imgf000316_0001
[0443]
Absolute configuration
Figure imgf000316_0002
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
[0444]
Figure imgf000319_0002
Figure imgf000320_0001
Figure imgf000321_0001
Figure imgf000322_0001
[0445]
Table 159
Absolute configuration
Figure imgf000323_0001
Figure imgf000324_0001
[0446]
Figure imgf000324_0002
1549
1550
1551
1552
1553
1555
Figure imgf000325_0001
Figure imgf000326_0001
[0447]
Figure imgf000326_0002
[0448]
Absolute configuration
Figure imgf000326_0003
13057923
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
[0449] Table 163 Absolute configuration
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
Absolute configuration
Figure imgf000334_0001
Figure imgf000335_0001
[0451] Table 165 Absolute configuration
Figure imgf000336_0001
Figure imgf000336_0002
Figure imgf000337_0001
Figure imgf000338_0001
Absolute confi uration
Figure imgf000339_0001
Example
NMR
No. Salt
1H-NMR (DMSO-d6) δρριτι : 0.55-0.64 (2H, m), 0.68-0.76 (2H,
m), 1.14-1.29 (2H, m), 1.35-1.47 (4H, m), 1.53 (3H, s),
1.61-1.91 (4H, m), 1.99-2.12 (1H, m), 2.94 (1H, d, J = 13.1 Hz),„ , . ,
1657 Dihydrochloricle
3.11 (1H, d, J = 13.1 Hz), 3.70-3.80 (2H, m), 3.80-3.90 (1H, m),
Figure imgf000339_0002
4.80-5.45 (1H, br), 6.83-7.00 (4H, m), 8.04-B.29 (1H, br),
9.90-10.16 (1H, br).
1 H-NMR (DMSO-d6) 5ppm : 0.61-0.76 (4H, m), 1.19-1.46 (6H,
m). 1.53 (3H, s), 1.61-1.93 (4H, m), 2.01-2.02 (1H, m), 2.92
(1H, d. J = 13.3 Hz), 3.23 (1H, d, J = 13.3 Hz), 3.68-3.78 (1H,
1658 Dihydrochloride
m), 3.82-3.88 (1H, m), 3.88-3.97 (1H, m), 4.15-4.37 (1H, br),
Figure imgf000339_0003
6.65-6.73 (1H, m), 6.87 (1H, dd, J = 2.9, 14.6 Hz), 7.21 (1H, t, J
= 9.5 Hz), 8.09-8.35 (1H, br), 9.97-10.22 (1H, br).
1 H-NMR (DMSO-d6) 5ppm : 0.61-0.80 (4H, m), 1. 8-1.33 (2H,
1659 Dihydrochloride
Λ
Figure imgf000339_0004
br). 6.91 <1H, dd, J = 2.9, 9.1 Hz), 7.02 ( H, d, J = 2.9 Hz), 7.26
( H, d, J = 9.1 Hz), 8.07-8.34 (1H, br), 9.93-10.17 (1H, br).
1 H-NMR (DMSO-d6) δρριτι : 1.28-1.47 (6H, m), 1.54 (3H, s),
Hz),
1660 , m), Hydrochloride
Figure imgf000339_0005
(1H,
d, J = 9.2 Hz), 8.18-8.43 (1H, br), 9.96-10.22 ( H, br).
Table 167 Absolute confi uration
Figure imgf000340_0001
NMR Salt
No.
1H-NMR (DMSO-d6) 5ppm : 0.56-0.64 (2H, m), 0.68-0.76 (2H,
m), 1.14-1.29 (2Hr m), 1.34-1.47 (4H, m), 1.54 (3H, s),
Figure imgf000340_0002
5.20-5.76 (1H, br), 6.84-6.99 (4H, m), 8.10-8.30 (1H, br),
9.97-10.17 (1H, br).
1H-NMR (DMSO-d6) 8ppm : 0.60-0.77 (4H, m), 1.20-1.47 (6H,
m), 1.52 (3H, s), 1.63-1.89 (4H, m), 1.97-2.10 (1H, m), 2.91
1662 (1H, d, J = 13.4 Hz), 3.24 (1H, d, J - 13.4 Hz), 3.69-3.Θ7 (4H, Dihydrochloride
Figure imgf000340_0003
m), 6.67-6.72 (1H, m), 6.87 (1H. dd, J = 2.9, 14.6 Hz), 7.21 (1H,
t, J = 9.5 Hz), 8.05-8.25 (1H, br), 9.82-10.04 (1H, br).
1H-N R (DMSO-d6) δρριτι : 0.62-0.80 (4H, m), 1.17-1.33 (2H,
1.92 (4H, m),
.20 (1H, d, J =
Dihydrochloride 4.56-5.33 (1 H,
Figure imgf000340_0004
br), 6.91 <1H, dd, J ~ 2.9, 9.1 Hz), 7.02 (1H, d, J = 2.9 Hz), 7.26
(1H, d, J = 9.1 Hz), 8.10-8.31 (1H, br), 9.98-10.19 (1H, br).
1H-NMR (DMSO-d6) 6ppm : 1.27-1.49 (6H, m), 1.53 (3H, s),
Hz).
, m), Hydrochbride
Figure imgf000340_0005
(1H,
dd, J = 1.2, 9.2 Hz), 8.15-8.44 (1H, br), 9.97-10.22 (1H, br).
Table 168 Absolute configuration
Figure imgf000341_0001
Example NMR Salt No.
1H-NMR <DMSO-d6) Bppm : 0.93-1.23(2H, m). 1.26-1.45 (5H,
Figure imgf000341_0002
9.48-9.80 (1H, br).
1H-NMR (D SO-d6) 6ppm : 1.05-1.19 (1H, m), 1.19-1.44(5H,
m), 1.52-1.80 (7H, m), 1.98-2.08 (1H, m), 2.95-3.07 (2H, m),
3.10 (1H, d, J = 12.7 Hz), 3.17-3.30 (1H, m), 4.65-5.13 (1H, br),
Figure imgf000341_0003
Hydrochloride
7.28 (2H. dd, J = 2.3, 8.8 Hz), 7.34 (1H, t, J = 74.0 Hz), 7.61
Figure imgf000341_0004
Table 169
Figure imgf000342_0001
Example R« NMR Salt
No.
(CDCI3) Sppm : 0.83-1.36 (29H, m), 1.37 (3H, s),
(4H,m), 2.23-2.30 (1H,m), 2.60 (1H,d, J =11.2 Hz),
1668 (2H, m), 4.83 (2H, s), 6.99-7.05 (2H, m), 7.50-7.56 Free
Figure imgf000342_0002
Figure imgf000342_0003
Hz), 6.91-6.97 (2H, m), 7.34-7.40 (2H, m).
Table 170 Absolute confi uration
Figure imgf000343_0001
Example R4 NMR Salt No.
1H-NMR (DMSO-d6) Bppm : 1.02-1.16 (1H, m), 1.16-1.42 (5H,
m), 1.51-1.78 (7H, m), 1.97-2.06 (1H, m), 2.90-3.01 (2H, m),
1673 3.06 (1H, d, J = 12.7 Hz), 3.15-3.28 (1H, m), 6.15-6.90 (1H, br), Dihydrochloride
Figure imgf000343_0002
7.00 (1H, t, J = 56.0 Hz), 7.22 (2H, d, J = 8.3 Hz), 7.53 {2H, d, J
= 8.3 Hz), 9.04-9.24 (1H, brm), 9.61-9.85 (1 H, bim).
1H-NMR (DMSO-d6) 6ppm : 1.10-1.23 (1H, m), 1.23-1.45 (5H,
m), 1.50 (3H, m), 1.54-1.69 (2H, m), 1.69-1.86 (2H, m),
1674 2.00-2.10 (1H, m), 3.05-3.17 (2H, m), 3.20-3.36 (2H, m), Dihydrochloride
4.69-6.42 (1H, br), 6.96-7.06 (2H, m), 7.11 (1H, t, J * 54.5 Hz),
Figure imgf000343_0003
7.53 (1H, t, J = 8.4 Hz), 8.91-9.19 (1H, m), 9.49-9.80 (1H, m).
1H-NMR (DWISO-d6) 5ppm : 1.07-1.20 (1H, tn), 1.20-1.44 (5H,
m), 1.53 (3H, m), 1.56-1.70 (2H,
1675 XL, m), 1.70-1.80 (2H, m),
2.00-2.10 (1H, m), 3.01-3.12(2H, m), 3.17 (1H, d, J = 12.9 Hz), Dihydrochloride
3.21-3.33 (1H, m), 4.21-4.79 (1H, br), 7.25 (2H, d, J = 6.4 Hz),
Figure imgf000343_0004
1H-NW1R (DMSO-d6) 5ppm : 1.00-1.16 (1H, m), 1.16-1.39 (5H,
1678 m), 1.47-1.77 (7H, m), 1.95-2.06 (1H, m), 2.82-2.98 (2H, m), Dihydrochloride
3.02 (1H, d, J = 12.4 Hz), 3.10-3.25 (3H, m), 6.10-6.74 (2H, m). 6.89-7.00 (2H, m). 7.35 (1H, t, J = 8.5 Hz), 9.00-9.23 (1 H,
br), 9.63-9.89 {1H, br).
1 H-NM (DMS0-d6) δρρπΐ : 0.99-1.41 <6H, m), 1.49-1.67 (6H,
m), 1.67-1.76 (1H, m), 1.94-2.05 (1H, m), 2.82-2.96 (2H, m),
1679 2.97-3.08 (1H, m), 3.10-3.24 (1 H, m), 3.61 (2H, q, J = 11.6 Hz), Dihydrochloride
Figure imgf000344_0001
4.28-5.69 (1H, br), 7.15 (2H, brs), 7.33 (2H. d, J = 7.8 Hz),
8.99-9.25 (1H, br), 9.59-9.84 <1 H, br).
Figure imgf000344_0002
1H-NMR (D SO-d6) 6ppm : 0.89-1.49 (10H, m), 1.51-1.80 (4H,
m), 2.43-2.60 (1 H, m), 2.64-3.05 (3H, m), 3.26 (3H, s),
Figure imgf000344_0003
3.38-4.10 (3H, br), 4.35 (2H, s), 7.05 (2H, d, J = 7.9 Hz), 7.25
(2H, d, J = 7.9 Hz).
1 H-NMR (DMSO-d6) 5ppm : 1.01-1.78 (13H, m), .83-1.96 (1H,
m), 2.74-2.86 (1 H, m), 2.89-3.04 (2H, m), 3.12-3.24 (1H, m),
1682 Oxalate
3.28 (3H, S), 4.40 (2H, S), 4.54-6.19 (3H, br), 6.90-7.00 (2H, m),
7.33-7.42 (1 H. m).
1 H-NMR (CDCI3) 6ppm : 0.62-1.41 (11H, m), 1.60-1.77 (4H,
1683 m), 2.07-2.90 (5H, m), 4.72 (2H, s), 6.96 (1H. dd, J = 1.9, 8.2 Free
Hz), 7.06 (1 H, d, J = 1.9 Hz), 7.38 (1 H, d, J = 8.2 Hz).
1 H-NMR (D SO-d6) 6ppm : 0.91-1.46 ( 0H, m), 1.53-1.82 (4H,
m), 2.50-2.63 (1H, m), 2.73-3.05 (3H, m), 3.32 (3H, s),
1684 Oxalate 3.40-4.25 (1H, br), 4.42 (2H, s), 6.98-7.15 (2H,m ), 7.31-7.44
(1H. m).
Table 171
Absolute configuration
Figure imgf000345_0001
Example
R4 NMR Salt No.
1H-NMR (DMSO-d6) 5ppm : 0.60-0.66 (2H, m), 0.73-0.81 (2H,
m), 1.03-1.23 (2H, m), 1.23-1.41 (4H, m), 1.41-1.53 (1H, m),
1685 1.53-1.67 (5H, m), 1.67-1.77 (1 H, m), 1.93-2.10 (1 H, m), Dihydrochloride
Figure imgf000345_0002
2.48-2.54 (1 H, m), 2.64-3.41 (4H, brm), 4.01-5.20 (1H, br),
6.80-7.50 (4H, brm), 8.86-9.55 (1H, br), 9.55-1.05 ( H, m).
1H-N R (DMSO-d6) 6ppm : 0.64-0.85 (4H, m), 1.00-1.40 (6H,
m), 1.47-1.65 (6H, m). 1.65-1.78 (1H, m), 1.92-2.05 (1H, m),
1686 2.65-2.90 (2H, m), 2.90-3.06 (1 H, m), 3.06-3.21 (1H, m), Dihydrochloride
Figure imgf000345_0003
3.87-3.96 (1 H, m), 6.88-7.08 (2H. m), 7.30-7.41 (1H, m),
7.55-8.85 (1H, br), 8.89-9.25 (1H, brs), 9.50-9.89 (1H, brs).
1H-NMR (DMSO-d6) δρρηΐ : 0.63-0.85 (4H, m), 0.98-1.40 (6H,
m), 1.43-1.65 (6H, m), 1.65-1.77 (1 H, m), 1.91-2.01 (1H, m),
2.70-2.86 (2H, m), 2.99 (1H, d, J = 12.4 Hz), 3.06-3.20 (1H, m),
1687 Dihydrochloride
3.88-3.96 (1H, m), 5.50-6.30 (1 H, br), 7.08-7.14 (1H, m),
Figure imgf000345_0004
7.14-7.20 (1H. m)( 7.37 (1H, d, J = 8.7 Hz), 8.90-9.15 (1 H, m),
9.51-9.70 (1 H, br).
1H-NMR (DMSO-d6) 5ppm : 0.59-0.77 (4H, m), 0.96-1.24 (2H,
m), 1.24-1.38 (4H, m), 1.41-1.63 (6H, m), 1.66-1.76 (1H, m),
1.83-1.92 (1H, m), 2.62-2.71 (1H. m), 2.80 (1 H, d, J = 12.3 Hz),
1688 Oxalate
2.95 (1H, d, J = 12.3 Hz), 3.06-3.17 (1H, m), 3.72 (3H, s),
Figure imgf000345_0005
3.74-3.81 (1H, m), 5.20-5.65 (3H, br), 6.64-6.75 (2H, m), 7.15
(1H, d, J = 8.8 Hz).
1H-NW1R (DMSO-d6) 6ppm : 0.93-1.21 (2H, m), 1.24-1.38 (4H,
1.85-1.95 (1 H. m).
Oxalate
1689 , 3.07 -3.17 (1H. m).
Figure imgf000345_0006
.6 Hz), 6.96 (1H, dd,
J = 2.5, 8.6 Hz), 7.17 (1H. d. J = 2.5 Hz), 7.61-9.77 (4H, br). 1H-NMR (D SO-d6) δρρηι : 0.82-1.01 (4H, m). 1.05-1.33 (6H,
.50 (2H, m), 1.50-1.65 (3H, m), 2.05-2.14 (1H, m),
1690 (1H, m), 2.53-2.62 (2H, m), 3.72 (3H, s), 8.49 (1H, Free
Figure imgf000346_0001
, 8.3 Hz), 6.61 (1H, d, J = 2.3 Hz), 6.66 (1H, d, J = 8.3
Hz), 8.65 (1H, s).
1H-N R (D SO-d6) 6ppm : 0.91-1.23 (2H, m), 1.23-1.42 (7H,
3CH3 3 m), 1.42-1.66 (6H, m), 1.66-1.77 (1H, m), 1.90-2.09 (1H, m),
1691 OCH2CH3 2·60"2 09 (4H,m >' 3 75 (3Η· s)' 3 98 (2Η· q- J = 6'9 Dihydrochloride
4.14-5.12 (1H, br), 6.39-7.19 (3H, brm). 8.74-9.39 (1H, br).
9.45-9.95 (1H, br).
1H-NMR (DMSO-d6) 6ppm : 0.82-1.03 (4H, m), 1.05-1.37 (6H,
m), 1.43-1.67 (5H, m), 2.07-2.18 (1H, m), 2.42-2.54 (1H, m),
2.54-2.64 (2H, m), 3.11-3.21 (1H. m), 6.76-6.89 (2H, m).
Figure imgf000346_0002
1H-NMR (DMSO-d6) 5ppm : 1.01-1.16 (1H, m), 1.16-1.39
(5H, m), 1.48-1.66 (6H, m), 1.67-1.77 (1H, m), 1.95-2.04 (1H,
1693 m), 2.78-2.94 <2H, m), 3.00 (1H, d, J = 12.5 Hz), 3.06-3.20 (1H, Dihydrochloride
m), 3.85 (3H, d, J - 0.8 Hz), 7.02-7.12 (2H, m), 9.03-9.27 (1H,
brm), 9.67-9.90 <1H, brm), 10.65-11.45 (1H, br).
1H-N R (DMSO-d6) δρρτη : 1.01-1.15 (1H, m), 1.16-1.38 (5H, , , , . ,
1694 DihydrocHonde
Figure imgf000346_0003
9.60-9.75 (1H, br).
Table 172
Absolute confi uration
Figure imgf000347_0001
Example
No.
Figure imgf000347_0002
1H-NMR (DMSO-d6) 5ppm : 1.06-1.20 (1H, m), 1.22-1.40 (5H,
.96-2.06 (1H, m).
3.14-3.26 (1H, m).
Dihydrochloride 17 (1.5H, m). 7.20
Figure imgf000347_0003
8.98-9.20 (1H, br),
9.63-9.84 (1H, br).
1 H-NMR (DMSO-d6) δρρτη : 0.97-1.40 (6H, m), 1.49-1.66 (6H,
Figure imgf000347_0004
1H-N R (DMSO-d6) δρριπ : 1.05-1.19 (1H, m). 1.19-1.40 (5H, , ,
Dihydrochloride
Figure imgf000347_0005
= 2.5. 8.9 Hz). 7.39 (1H. d, J = 2.5 Hz), 7.51 (1H, dd, J = 1.3,
8.9 Hz), 9.00-9.16 ( H, brm), 9.59-9.76 (1H, bnm).
1 H-NMR (DMSO-d6) 5ppm : 1.04- .17 (1H, m), 1.17-1.42 (5H,
m), 1.54 (3H, s), 1.57-1.78 (4H, m), 1.97-2.08 (1H, m),
1699 2.90-3.05 (2H, m), 3.05-3.15 (1H, m), 3.15-3.29 (1H, m), Dihydrochloride
Figure imgf000347_0006
7.14-7.21 (2H, m), 7.43 (1 H, t, J = 56.0 Hz), 7.51-7.57 (2H, m),
8.99-9.30 (1H, br), 9.55-9.99 (2H, br).
1 H-NMR (DMSO-d6) 6ppm : 1.11-1.26 (1H, m), 1.26-1.43 (5H,
m), 1.49 (3H. s), 1.54-1.70 (2H. m), 1.70-1.88 (2H. m).
2.03-2.13 (1H, m), 3.10-3.20(2H, m), 3.25-3.38 (2H. m). 6.94 , , ,
1700 Dihydrochloride
Figure imgf000347_0007
(1H, dd, J = 2.3, 8.5 Hz), 7.04 (1H, dd, J = 2.3, 11.4 Hz), 7.38
(1H, t, J = 55.7 Hz), 7.52 (1H, d, J = 8.5 Hz), 7.90-8.70 (1H, br),
9.00-9.20 (1H, brm), 9.69-9.88 (1H, brm). Table 173
Absolute confi uration
Figure imgf000348_0001
R4 NMR
No. Salt
1H-N R (D SO-CI6) Oppm : 0.94-1.22{2H, m), 1.26-1.45 (5H,
m), 1.45-1.56 (1H. m), 1.56-1.78 (5H, m), 1.97-2.09 (1H, m),
2.80 (1H, d, J = 12.5 Hz), 2.95-3.10 (2H, m), 3.32-3.55 (1H,
1701 Dihydrochloride m), 7.20 (0.25H. s). 7.33-7.46 (2.5H, m), 7.57 (0.25H, s),
Figure imgf000348_0002
7.62-7.71 (2H, m), 8.04-8.12 (1H, m), 8.45-8.54 (1H, m),
8.99-9.28 (1H, br), 9.60-9.80 (1H, br).
1H-N R <DMSO-d6) 5ppm : 1.05-1.18 (1H, m), 1.18-1.44(5H,
m), 2.92-3.13 (3H, m),
7.28 (2H, dd, J = 2.4.
1702 Hydrochloride
Figure imgf000348_0003
(1H, s), 7.66 (1H, d, J =
2.4 Hz), 7.90 (1H, d, J = 8.8 Hz), 7.94 (1H, d, J = 8.8 Hz),
8.94-9.22 (1H, br), 9.43-9.75 (1H, br).
1H-NMR (DMSO-d6) 5ppm : 0.85-1.00 (1H, m), 1.14-1.43
(5H, m). 1.50-1.79 (7H, m), 1.90-2.13 (3H, m), 2.65-2.99 (7H,
1703 Dihydrochloride m), 3.05-3.23 (1H, m), 6.96-7.05 (2H, m), 7.14 (1H, t, J = 74.4
Figure imgf000348_0004
Hz), 8.90-9.15 (1H, br), 9.42-9.75 ( H, br).
Table 174
Absolute confi uration
Figure imgf000349_0001
Example R« NMR Salt No.
Figure imgf000349_0002
1H-N R (CDCI3) 5ppm : 0.75-1.40 (32H, m), 1.54-1.76 (4H, m). 2.07-2.15 (1H, m), 2.54 (1H, d, J = 11.1 Hz), 2.67-2.76 (2H,
1707 m), 6.72 (1H, dd, J = 2.6, 12.0 Hz), 6.85-6.89 (1H, m). Free
Figure imgf000349_0003
Figure imgf000349_0004
Hz), 6.92-8.96 (2H, m), 7.35-7.40 (2H, m).
Table 175 Absolute confi uration
Figure imgf000350_0001
Example N R Salt
No.
1H-N R (D SO-d6) 5ppm : 1.01-1.15 (1H, m), 1.16-1.41 (5H,
m), 1.50-1.78 (7H, m), 1.95-2.05 (1H, m), 2.88-3.01 (2H, m),
1709 3.05 (1H, d, J = 12.7 Hz), 3.15-3.28 (1H, m), 4.75-6.40 (1H, br), Dihydrochioride
Figure imgf000350_0002
6.99 ( H, t, J = 56.0 Hz), 7.22 (2H, d, J = 8.3 Hz), 7.53 (2H, d, J
= 8.3 Hz), 8.94-9.14 (1H, brm), 9.50-9.75 (1H, brm).
1H-NMR (D SO-d6) δρρπι : 1.09-1.23 (1H. m), 1.23-1.45 (5H,
m). 1.50 (3H, m), 1.55-1.70 (2H, m), 1.70-1.85 (2H. m),
1710 2.01-2.11 (1H, m), 3.05-3.17 (2H, m), 3.20-3.36 (2H, m), Dihydrochioride
5.95-6.92 (1H, br), 6.96-7.06 (2H, m), 7.12 (1H, t, J = 54.5 Hz).
Figure imgf000350_0003
7.53 (1H, t, J = 8.4 Hz), 9.01-9.21 (1H, m), 9.64-9.85 (1H, m).
1H-NMR (DMSO-d6) 6ppm : 1.07-1.20 (1H, m), 1.20-1.44 (5H,
m), 1.53 (3H, m), 1.56-1.70 (2H, m), 1.70-1.80 (2H, m),
1711 2.00-2.10 (1H, m), 3.01-3.12(2H, m), 3.17 (1H, d, J = 12.9 Hz), Dihydrochioride
Figure imgf000350_0004
3.21-3.33 (1H, m), 4.21-4.79 (1H, br), 7.25 (2H, d, J = 8.4 Hz),
7.66 (2H, d, J = 8.4 Hz), 9.09-9.28 (1H, br), 9.65-9.82 (1H, br).
1712 Dihydrochioride
Figure imgf000350_0005
H-NMR (DMSO-d6) 5ppm : 1.15-1.29 (1H, m). 1.29-1.45 (5H,
1713 Dihydrochioride
Figure imgf000350_0006
(1H. m). 1H-NMR (D SO-de) δρριη : 1.02-1.16 (1H, m), 1.16-1.40
1714 Dihydrochloride
Figure imgf000351_0001
(1H, br), 9.60-9.80 (1H, br).
1 H-NMR (DMSO-de) 5ppm : 1.00-1.41 (6H, m), 1.48-1.78 (7H,
m), 1.94-2.05 (1H, m), 2.82-3.30 (4H, m), 3.61 (2H, q, J = 11.6
1715 Dihydrochloride
Hz), 4.50-6.30 ( H, br), 7.15 (2H, brs). 7.33 (2H, d, J = 7.8 Hz),
Figure imgf000351_0002
9.00-9.50 (1H, br), 9.60-10.10 (1H, br).
1H-NMR (DMSO-d6) 6ppm : 1.00-1.14 (1H, m), 1.15-1.56 (9H,
m), 1.56-1.79 (3H, m), 1.83-1.98 (1H. m), 2.78-2.90 (1H, m),
1716 Oxalate
2.91-3.05 (2H, m), 3.13-3.26 (1H, m), 3,6-4.10 (3H, br), 4.11
(1H, S), 7.09 (2H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.4 Hz).
1H-NMR (DMSO-d6) 6ppm : 0.90-1.48 (10H, m), 1.52-1.81 (4H,
m), 2.41-2.56 {1H, m), 2.63-3.07 (3H, m), 3.26 (3H, s),
1717 Oxalate
Figure imgf000351_0003
3.35-4.20 (3H, br), 4.35 (2H, s), 7.05 (2H, d, J = 7.8 Hz), 7.25
(2H, d, J = 7.8 Hz).
1 H-NMR (DMSO-d6) 6ppm : 1.01-1.77 (13H, m), 1.85-1.96 (1 H.
m), 2.76-2.86 (1H, m), 2.90-3.04 (2H, m), 3.13-3.23 (1H, m),
1718 Oxalate
3.28 (3H, s). 4.40 (2H, s), 5.40-6.70 (3H, br), 6.90-7.00 (2H, m),
7.33-7.42 (1H, m).
1 H-NMR (CDCI3) Bppm : 0.62-1.41 (11H, m), 1.60-1.77 (4H,
1719 m), 2.07-2.90 (5H, m), 4.72 (2H, s), 6.96 (1H, dd, J = 2.0, 8.2 Free
Hz), 7.06 (1H, d, J = 2.0 Hz), 7.38 (1H, d, J = 8.2 Hz).
1 H-NMR (DMSO-d6) 6ppm : 0.96-1.18 (4H, m), 1.19-1.44 (6H,
m), 55-1.81 (4H, m), 2.50-2.62 (1H, m), 2.74-3.04 (3H, m),
1720 Oxalate
Figure imgf000351_0004
3.32 (3H, s), 3.60-4.35 (1H, br), 4.42 (2H, s), 7.04 (1H, dd, J =
2.0, 8.2 Hz), 7.09 (1H, d, J = 2.0 Hz), 7.39 (1H, d, J = 8.2 Hz).
Table 176
Absolute confi uration
Figure imgf000352_0001
Example
NMR Salt No.
1H-NMR (D SO-d6) 6ppm : 0.60-0.67 (2H, m), 0.72-0.82 (2H,
m), 1.00-1.42 (6H, m), 1.42-1.53 (1H. m), 1.53-1.67 (5H, m),
1721 1.67-1.77 (1H, m), 1.93-2.12 (1H. m), 2.48-2.54 (1H, m), Dihydrochloride
Figure imgf000352_0002
2.60-3.45 (4H, brm), 4.12-5.45 (1H, br), 6.75-7.60 (4H, brm),
8.92-9.60 (1H, br), 9.60-1.15 (1H. m).
1H-NMR (DMSO-d6) oppm : 0.64-0.83 (4H, m), 0.99-1.40 (6H,
, m),
1722 m), Dihydrochloride
Figure imgf000352_0003
Hz),
7.40-7,95 (1H, br), 8.84-9.19 ( H, brs), 9.60-9.80 (1H, brs).
1H-NMR (DMSO-d6) 5ppm : 0.65-0.88 (4H, m), 0.99-1.41 (6H,
m), 1.41-1.66 (6H, m), 1.66-1.79 (1H, rn), 1.91-2.04 (1H, m),
1723 2.72-2.90 (2H, m), 2.95-3.06 (1H, m), 3.06-3.20 (1H, m), Dihydrochloride
Figure imgf000352_0004
3.88-3.97 (1H, m). 5.56-6.85 (1H, br), 7.05-7.22 (2H, m). 7.38
(1H, d, J = 8.7 Hz), 8.95-9.25 (1H, m), 9.55-9.80 ( H, br).
1H-NMR (DMSO-d6) 5ppm : 0.59-0.77 (4H, m), 0.96-1.24 (2H,
m), 1.24-1.38 (4H, m), 1.41-1.64 (6H, m), 1.65-1.75 (1H, m),
1.84-1.93 (1H, m), 2.63-2.72 (1H, m), 2,80 (1H, d, J = 12.3 Hz),
1724 Oxalate
2.96 (1H, d, J = 12.3 Hz), 3.07-3.16 (1H, m), 3.72 (3H, s),
Figure imgf000352_0005
3.75-3.81 (1H, m), 4.40-6.10 (3H, br), 6.65-6.72 (2H, m), 7.15
(1H, d, J = 8.8 Hz).
1H-NMR (DMSO-d6) 6ppm : 0.93-1.22 (2H, m), 1.24-1.39 (4H,
(1H, m),
H, d, J =
1725 Oxalate
Figure imgf000352_0006
, s), 6.88
(1H, d, J = 8.7 Hz).6.96 (1H, dd, J = 2.5, 8.7 Hz), 7.16 (1H, d, J
= 2.5 Hz). 7.61 -9.72 (4H, br). 1H-NMR (DMSO-d6) Oppm : 0.82-1.00 (4H, m), 1.05-1.33 (6H,
m), 2.06-2.14 (1H, m),
1726 3.72 (3H, s). 6.49 (1H. Free
Figure imgf000353_0001
Hz), 6.66 (1H, d, J = 8.3
Hz), 8.64 (1H, s).
Figure imgf000353_0002
1H-NMR (D SO-d6) 5ppm : 1.02-1.16 (1H, m), 1.16-1.40
(5H, m), 1.48-1.66 (6H, m), 1.67-1.76 (1H, m). 1.94-2.03 (1H.
m), 2.77-2.86 (1H, m), 2.89 (1H, d. J = 12.5 Hz). 2.99 (1H, d, J
1729 Dihydrochloride
= 12.5 Hz), 3.07-3.20 (1H, m), 3.84 (3H, d, J = 0.8 Hz),
Figure imgf000353_0003
7.01-7.14 (2H, m), 8.96-9.20 (1H, brm). 9.59-9.84 (1H, brm),
9.87-10.47 (1H, br).
1H-N R (DMSO-d6) 5ppm : 1.02-1.16 (1H. m), 1.16-1.39 (5H,
m), 1.49-1.64 (6H. m), 1.67-1.77 (1H, m), 1.92-2.02 (1H, m),
2.71-2.81 (1H. m), 2.88 <1H, d. J = 12.4 Hz). 2.97 (1H. d, J =
1730 Dihydrochloride
12.4 Hz), 3.06-3.20 (1H, m), 3.87 (3H, s), 6.67-6.72 (1H, m),
Figure imgf000353_0004
6.75-6.82 (1H, m), 6.96-7.70 (1H, br). 8.88-9.06 (1H, br),
9.57-9.75 (1H, br).
Table 177
Absolute configuration
Figure imgf000354_0001
Example
R N R Salt No.
(7H.
12.4
1731 54.5 DihydiOchloride
( H,
Figure imgf000354_0002
1H-N R (D SO-d6) 6ppm : 1.07-1.20 (1H, m). 1.22-1.41 (5H, , . .
1732 Dihydrochlonde
Figure imgf000354_0003
9.62-9.87 (1H, br).
1 H-NMR (DMSO-d6) 6ppm : 0.99-1.42 (6H, m), 1.509-1.66 (6H,
m), 1.66-1.76 (1H. m), 1.88-2.03 (4H, m), 2.75-2.90 (2H, m),
1733 Dihydrochloride
2.93-3.05 (1H, m), 3.09-3.23 (1H, m), 7.16 (4H, s), 8.95-9.20
Figure imgf000354_0004
(1H, br), 9.55-9.80 (1H, br), 10.60-11.80 (1H, br).
1 H-NMR (DMSO-d6) 5ppm : 1.04-1.19 (1H, m), 1.19-1 ,40 (5H,
1734 Dihydrochloride
Figure imgf000354_0005
= 2.6, 8.8 Hz), 7.39 (1H, d, J = 2.6 Hz), 7.51 (1H, dd, J = 1.3,
8.8 Hz), 8.94-9.14 (1H, brm). 9.54-9.70 (1H, brm).
1 H-NMR (DMSO-d6) 5ppm : 1.04-1.15 (1H, m), 1.16-1.42 (5H,
Figure imgf000354_0006
1 H-NMR (DMSO-d6) 5ppm : 1. 0-1.25 (1H, m), 1.25-1.43 (5H,
1.55-1.70 (2H. m), 1.70-1.89 (2H, m),
.08-3.21 (2H, m), 3.21-3.38 (2H. m), 6.94
1736 Dihydrochloride
Figure imgf000354_0007
Hz), 7.04 (1H, dd, J = 2.3, 11.4 Hz), 7.38
(1H, t. J = 55.7 Hz), 7.52 (1H, d, J = 8.6 Hz), 7.80-8.80 (1H, br),
9.00-9.20 (1H, brm), 9.65-9.88 (1Ht brm). Table 178
Absolute configuration
Figure imgf000356_0001
Example
R4 NMR Salt No.
1H-NMR (DMSO-d6) 6ppm : 0.88-1.02 (1H, m), 1.06 (3H, d, J =
(3H, m), 1.52-1.63 (2H, m), 1.64-1.72 (1H,
, m), 2.53-2.62 (2H, m)t 2.65-2.76 (1H, m),
1737 Oxalate
2.7, 11.6 Hz), 3.13-3.25 (1H, m), 3.35-5.14
Figure imgf000356_0002
(3H, br), 7.15 (1H, dd, J = 2.5, 8.8 Hz), 7.21 (1H, t, J = 73.4 Hz),
7.28-7.35 (2H, m).
m), 1.07 (3H, d, J = m). 1.64-1.72 (1H,
2.67-2.79 (1H, m),
1738 Oxalate
(1H, br), 3.60-6.40
Figure imgf000356_0003
H, t, J = 73.4 Hz),
7.27-7.40 (3H, m).
1 H-IM R (DMSO-d6) 5ppm : 0.89-1.03 (1 H, m), 1.07 (3H, d, J =
Figure imgf000356_0004
1H-NMR (DMSO-d63) 5ppm : 0.86-1.03 (1H, m), 1.06 (3H, d, J
= 6.2 Hz), 1.18-1.43 (3H. m), 1.52-1.75 (3H, m), 1.76-1.90 (1H,
1740 Oxalate m), 2.54-2.66 (2H, m), 2.66-2.80 (1H, m), 3.10-3.28 (2H, m),
6.40-6.95 (3H, br), 7.15 (1H, t, J = 72.5 Hz), 7.16-7.26 (2H, m).
1H-NMR (D SO-d6) δ ppm (80 °C) : 0.88-1.17 (4H, m),
1.16-1.45 (3H, m), 1.53-1.76 (3H, m). 1.77-1.93 (1 H, m),
1741 Oxalate
2.54-2.79 (3H, m), 3.05-3.22 (2H, m), 4.75-6.50 (3H, br),
Figure imgf000356_0005
6.95-7.08 (1H, m), 7. 1-7.24 <1H, m), 7.33-7.49 (1H, m).
1H-NMR (D SO-d6) S pm (80"C) : 0.91-1.05 (1H, m), 1.08
(3H, d, J - 6.4 Hz), 1.18-1.42 (3H, m), 1.57-1.66 (2H, m),
1.66-1.74 (1H, m), 1.80-1.88 (1H, m), 2.56-2.68 (2H, m),
1742 Oxalate
GT 2.69-2.77 (1H, m), 3.12 (1H, dd, J = 3.1, 11.7 Hz), 3.16-3.27
(1H, m), 5.60-6.70 (3H, br), 7.18 (1H, dd, J = 2.6, 8.8 Hz), 7.33
(1H, d, J = 2.6 Hz), 7.40-7.46 (1H, m). Table 179
Absolute configuration
Figure imgf000357_0001
Example
NMR Salt No.
1H-N R (DMSO-d6) 5ppm : 0.88-1.01 (1H, m), 1.06 (3H, d, J =
6.3 Hz), 1.15-1.41 (3H, m), 1.52-1.64 (2H, m), 1.64-1.74 (1H, m), 1.77-1.87 (1H, m), 2.54-2.63 (2H, m), 2.66-2.77 (1H, m),
1743 Oxalate
3.08 (1H, dd, J = 2.4, 1.5 Hz), 3.143-3.26 (1H, m), 3.50-4.80
Figure imgf000357_0002
(3H, br). 7.15 (1H, dd, J = 2.3, 8.8 Hz), 7.21 (1H, t, J = 73.4 Hz),
7.28-7.35 (2H, m).
F 1H-NMR (DMSO-d6) 6ppm : 0.88-1.02 (1H, m), 1.07 (3H, d, J =
6.3 Hz), 1.13-1.41 (3H, m), 1.48-1.63 (2H, m), 1.63-1.73 (1H,
1744 X FF m), 1.77-1.87 (1H, m), 2.52-2.64 (2H, m), 2.67-2.79 (1H, m), Oxalate
3.03-3.13 (1H. m), 3.15-3.29 (1H, br), 3.60-6.00 (3H, br), 7.09
F (1 H, t, J = 54.5 Hz), 7.25 {1 H, t, J = 73.4 Hz), 7.27-7.41 (3H, m).
1H-NMR (DMSO-d6) δρριη : 0.88-1.03 (1H, m), 1.06 (3H, d, J =
6.3 Hz), 1.20-1.41 (3H, m), 1.52-1.76 (3H, m), 1.76-1.87 (1H,
1745 Oxalate m), 2.53-2.65 (2H. m), 2.65-2.78 (1H, m), 3.12-3.25 (2H, m),
5.80-6.95 (3H, br), 7.02-7.09 (2H, m), 7.19 (1H, t, J = 72.4 Hz).
1H-NMR (DMSO-d6) 6ppm : 0.86-1.03 (1H, m), 1.06 (3H, d. J =
6.2 Hz), 1.18-1.43 (3H, m), 1.52-1.75 (3H, m), 1.76-1.90 (1H,
1746 Oxalate m), 2.54-2.66 (2H, m), 2.66-2.80 (1H, m), 3.10-3.28 (2H, m),
Figure imgf000357_0003
6.40-6.95 (3H, br), 7.15 (1H, t, J = 72.5 Hz), 7.16-7.26 (2H, m).
1H-NMR (DMSO-d6) <5ppm (80°C) : 0.90-1.05 (1H, m), 1.07
(3H, d, J = 6.4 Hz), 1.18-1.42 (3H, m), 1.55-1.75 (3H, m),
1.79-1.89 (1H, m), 2.53-2.67 2H. m), 2.67-2.78 (1H, m), 3.13
1747 Oxalate
(1H, dd, J = 3.0, 11.7 Hz), 3.16-3.26 (1H, m), 5.05-6.60 (3H, br),
Figure imgf000357_0004
6.97-7.06 (1H, m), 7.17 (1H, dd, J = 2.4, 12.3 Hz), 7.36-7.47
(1H, m).
1H-N R (DMSO-d6) Sppm (80°C) : 0.90-1.05 (1H, m), 1.08
(3H, d, J = 6.4 Hz). 1.1 -1.42 (3H, m), 1.56-1.66 (2H, m),
1.66-1.74 (1H. m). 1.80-1.89 (1H, m), 2.55-2.68 (2H, m),
1748 Oxalate
2.68-2.78 (1H, m), 3.12 (1H, dd, J = 3.1, 11.7 Hz), 3.16-3.26
Figure imgf000357_0005
(1H, m), 5.45-6.80 (3H. br), 7.17 (1H, dd, J = 2.6, 8.8 Hz), 7.33
(1H, d. J = 2.6 Hz). 7.40-7.47 (1H, m). Table 180
Absolute configuration
Figure imgf000358_0001
Example
R NMR Salt No.
1H-NMR (CDC13) fippm : 0.94-1.07 (1H, m), 1.17-1.42 (3H, m),
1.48-1.70 (3H, m), 1.70-1.79 (2H, m), 2.34-2.41 (1H, m),
1749 2.48-2.55 (1H, m), 2.83-2.91 (1H, m), 2.98-3.06 (2H, m), Free
Figure imgf000358_0002
3.07-3.15 {1H, m), 8.49 (1H, t, J = 73.8 Hz), 7.02 (1H, dd, J =
2.5, 8.7 Hz), 7.16 (1H, d, J = 8.7 Hz), 7.22 <1H, d, J = 2.5 Hz).
Table 181
Absolute configuration
Figure imgf000358_0003
Example R4 NMR Salt No.
1H-NMR (CDCI3) 5ppm : 0.94-1.07 (1H, m), 1.16-1.42 (3H, m),
(5H, m), 2.35-2.43 (1H, m), 2.48-2.575 (1H, m),
1750 (1H, m), 2.98-3.06 (2H, m), 3.07-3.16 (1H, m). 6.49 Free
Figure imgf000358_0004
73.8 Hz), 7.02 (1H, dd, J = 2.5, 8.7 Hz), 7.16 (1H, d, J
= 8.7 Hz), 7.22 (1H, d, J = 2.5 Hz).
[0452]
Pharmacological Study 1
Measurement of serotonin (5-HT) uptake inhibitory activity of test compound using rat brain synaptosome
Male Wistar rats were decapitated, and their brains were removed and dissected to remove the frontal cortex. The separated frontal cortex was placed in a 20-fold weight of a 0.32 molarity (M) sucrose solution and homogenized with a potter homogenizer. The homogenate was centrifuged at 1000 g at 4°C for 10 minutes, and the supernatant was further centrifuged at 20000 g at 4°C for 20 minutes. The pellet was suspended in an incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride). The suspension was used as a crude synaptosome fraction.
[0453]
Uptake reaction was performed using each well of a 96-well round-bottom plate and a 200 μΐ volume in total of a solution containing pargyline (final concentration: 10 μΜ) and ascorbic acid (final concentration: 0.2 mg/ml).
[0454]
Specifically, a solvent, unlabeled 5-HT, and serially diluted test compounds were separately added to the wells, and the synaptosome fraction was added in an amount 1/10 of the final volume to each well and preincubated at 37°C for 10 minutes. Then, a tritium-labeled 5- HT solution (final concentration: 8 nM) was added thereto to initiate uptake reaction at 37°C. 10 minutes later, the uptake reaction was terminated by suction filtration through a 96-well glass fiber filter plate. Furthermore, the filter was washed with a cold saline and then sufficiently dried. MicroScint-0 (PerkinElmer Co., Ltd.) was added thereto, and the residual radioactivity on the filter was measured.
[0455]
An uptake value obtained by the addition of only the solvent was defined as 100%, and an uptake value (nonspecific uptake value) obtained by the addition of the unlabeled 5-HT (final concentration: 10 μΜ) was defined as 0%. A 50% inhibitory concentration was calculated from the test compound concentrations and inhibitory activities thereat. The results are shown in Table 60.
[0456]
[Table 60]
Test compound 50% Inhibitory concentration (nM)
Compound of Example 2 7.1
Compound of Example 7 1.0
Compound of Example 8 2.4
Compound of Example 10 6.2
Compound of Example 13 5.1
Compound of Example 15 12.5
Compound of Example 27 5.8
Compound of Example 33 2.6
Compound of Example 72 2.6
Compound of Example 77 0.8
Compound of Example 85 7.2
Compound of Example 106 9.7
Compound of Example 112 7.1
Compound of Example 118 13.7
Compound of Example 120 9.2
Compound of Example 124 8.5
Compound of Example 125 4.7
Compound of Example 130 5.3
Compound of Example 131 6.1
Compound of Example 132 8.8
Compound of Example 136 1.3
Compound of Example 150 5.4
Compound of Example 165 12.0
Compound of Example 186 5.2
Compound of Example 187 5.8
Compound of Example 188 6.0
Compound of Example 191 3.2
Compound of Example 192 2.9
Compound of Example 193 3.4
Compound of Example 196 4.4
Compound of Example 233 7.4
Compound of Example 246 6.8
Compound of Example 247 42.8
Compound of Example 273 44.0
Compound of Example 276 7.2
Compound of Example 281 5.8
Compound of Example 285 19.7
Compound of Example 288 56.1
Compound of Example 300 89.1
Compound of Example 307 19.3
Compound of Example 322 9.6
Compound of Example 344 6.8
Compound of Example 346 10.0
Compound of Example 348 6.4
Compound of Example 405 6.4
Compound of Example 409 35.6
Compound of Example 468 3.8
Compound of Example 577 5.2
Compound of Example 579 4.5
Compound of Example 580 2.5
Compound of Example 582 4.1
Compound of Example 586 5.2
Compound of Example 587 0.9
Compound of Example 593 4.9 Compound of Example 610 4.6
Compound of Example 621 7.0
Compound of Example 641 2.2
Compound of Example 654 1.5
Compound of Example 717 4.2
Compound of Example 778 87.5
Compound of Example 780 6.5
Compound of Example 781 6.2
Compound of Example 791 1.4
Compound of Example 805 42.6
Compound of Example 841 28.1
Compound of Example 850 7.3
Compound of Example 867 4.7
Compound of Example 884 7.3
Compound of Example 895 5.4
Compound of Example 918 10.0
Compound of Example 962 18.7
Compound of Example 983 6.5
Compound of Example 993 4.8
Compound of Example 1026 2.4
Compound of Example 1047 0.7
Compound of Example 1083 5.1
Compound of Example 1113 5.4
Compound of Example 1121 8.5
Compound of Example 1124 7.1
Compound of Example 1318 40.7
Compound of Example 1326 37.8
Compound of Example 1333 84.2
Compound of Example 1341 6.8
Compound of Example 1534 38.1
Compound of Example 1677 26.5
Compound of Example 1680 10
Compound of Example 1683 55.4
Compound of Example 1687 8
Compound of Example 1693 5.7
Compound of Example 1695 8.6
Compound of Example 1696 5.9
Compound of Example 1697 4
Compound of Example 1698 8.5
Compound of Example 1716 51.3
Compound of Example 1719 94.6
Compound of Example 1729 32.2
Compound of Example 1731 49
Compound of Example 1732 9.4
Compound of Example 1737 6.5
Compound of Example 1739 27
Compound of Example 1740 6.5
Compound of Example 1741 10
Compound of Example 1742 10
Compound of Example 1743 9
Compound of Example 1748 9
Compound of Example 1749 8.2
[0457]
Pharmacological Study 2
Measurement of norepinephrine (NE) uptake inhibitory activity of test compound using rat brain synaptosome Male Wistar rats were decapitated, and their brains were removed and dissected to remove the hippocampus. The separated hippocampus was placed in a 20-fold weight of a 0.32 molarity (M) sucrose solution and homogenized with a potter homogenizer. The homogenate was centrifuged at 1000 g at 4°C for 10 minutes, and the supernatant was further centrifuged at 20000 g at 4°C for 20 minutes. The pellet was suspended in an incubation buffer (20 mM
HEPES buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride). The suspension was used as a crude synaptosome fraction.
[0458]
Uptake reaction was performed using each well of a 96- well round-bottom plate and a 200 μΐ volume in total of a solution containing pargyline (final concentration: 10 μΜ) and ascorbic acid (final concentration: 0.2 mg/ml).
[0459]
Specifically, a solvent, unlabeled NE, and serially diluted test compounds were separately added to the wells, and the synaptosome fraction was added in an amount 1/10 of the final volume to each well and preincubated at 37°C for 10 minutes. Then, a tritium-labeled NE solution (final concentration: 12 nM) was added thereto to initiate uptake reaction at 37°C. Ten minutes later, the uptake reaction was terminated by suction filtration through a 96-well glass fiber filter plate. Furthermore, the filter was washed with a cold saline and then sufficiently dried. MicroScint-0 (PerkinElmer Co., Ltd.) was added thereto, and the residual radioactivity on the filter was measured.
[0460]
An uptake value obtained by the addition of only the solvent was defined as 100%, and an uptake value (nonspecific uptake value) obtained by the addition of the unlabeled NE (final concentration: 10 uM) was defined as 0%. A 50% inhibitory concentration was calculated from the test compound concentrations and inhibitory activities thereat. The results are shown in Table 61.
[0461]
[Table 61]
Test compound 50% Inhibitory concentration (nM)
Compound of Example 2 4.6
Compound of Example 7 9.5
Compound of Example 8 60.9
Compound of Example 10 8.8
Compound of Example 13 14.3 Compound of Example 15 Compound of Example 27 Compound of Example 33 Compound of Example 72 Compound of Example 77 Compound of Example 85 Compound of Example 106 Compound of Example 112 Compound of Example 118 Compound of Example 120 Compound of Example 124 Compound of Example 125 Compound of Example 130 Compound of Example 131 Compound of Example 132 Compound of Example 136 Compound of Example 150 Compound of Example 165 Compound of Example 186 Compound of Example 187 Compound of Example 1 8 Compound of Example 191 Compound of Example 192 Compound of Example 193 Compound of Example 196 Compound of Example 233 Compound of Example 246 Compound of Example 247 Compound of Example 273 Compound of Example 276 Compound of Example 281 Compound of Example 285 Compound of Example 288 Compound of Example 300 Compound of Example 307 Compound of Example 322 Compound of Example 344 Compound of Example 346 Compound of Example 348 Compound of Example 405 Compound of Example 409 Compound of Example 468 Compound of Example 577 Compound of Example 579 Compound of Example 580 Compound of Example 582 Compound of Example 586 Compound of Example 587 Compound of Example 593 Compound of Example 610 Compound of Example 621 Compound of Example 641 Compound of Example 654 Compound of Example 717 Compound of Example 778 Compound of Example 780 Compound of Example 781 Compound of Example 791 Compound of Example 805 Compound of Example 841 0.9
Compound of Example 850 1.0
Compound of Example 867 11.7
Compound of Example 884 4.8
Compound of Example 895 3.0
Compound of Example 918 0.8
Compound of Example 962 31.9
Compound of Example 983 47.6
Compound of Example 993 8.7
Compound of Example 1026 4.2
Compound of Example 1047 0.7
Compound of Example 1083 2.5
Compound of Example 1113 1.7
Compound of Example 1121 0.7
Compound of Example 1124 0.8
Compound of Example 1318 6.6
Compound of Example 1326 1.8
Compound of Example 1333 39.6
Compound of Example 1341 42.7
Compound of Example 1534 4.0
Compound of Example 1677 21.5
Compound of Example 1680 10
Compound of Example 1683 3.9
Compound of Example 1687 55
Compound of Example 1693 3.3
Compound of Example 1695 6.0
Compound of Example 1696 6.1
Compound of Example 1697 31
Compound of Example 1698 31.0
Compound of Example 1716 81.3
Compound of Example 1719 29.5
Compound of Example 1729 5.8
Compound of Example 1731 94
Compound of Example 1732 9.8
Compound of Example 1737 0.9
Compound of Example 1739 2
Compound of Example 1740 2.7·
Compound of Example 1741 8
Compound of Example 1742 8
Compound of Example 1743 38
Compound of Example 1748 277
Compound of Example 1749 9.5
[0462]
Pharmacological Study 3
Measurement of dopamine (DA) uptake inhibitory activity of test compound using rat brain synaptosome
Male Wistar rats were decapitated, and their brains were removed and dissected to remove the corpus striatum. The separated corpus striatum was placed in a 20-fold weight of a 0.32 molarity (M) sucrose solution and homogenized with a potter homogenizer. The homogenate was centrifuged at 1000 g at 4°C for 10 minutes, and the supernatant was further centrifuged at 20000 g at 4°C for 20 minutes. The pellet was suspended in an incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride). The suspension was used as a crude synaptosome fraction.
[0463]
Uptake reaction was performed using each well of a 96-well round-bottom plate and a 200 μΐ volume in total of a solution containing pargyline (final concentration: 10 μΜ) and ascorbic acid (final concentration: 0.2 mg/ml).
[0464]
Specifically, a solvent, unlabeled DA, and serially diluted test compounds were separately added to the wells, and the synaptosome fraction was added in an amount 1/10 of the final volume to each well and preincubated at 37°C for 10 minutes. Then, a tritium-labeled DA solution (final concentration: 2 nM) was added thereto to initiate uptake reaction at 37°C. Ten minutes later, the uptake reaction was terminated by suction filtration through a 96-well glass fiber filter plate. Furthermore, the filter was washed with a cold saline and then sufficiently dried. MicroScint-0 (PerkinElmer Co., Ltd.) was added thereto, and the residual radioactivity on the filter was measured.
[0465]
An uptake value obtained by the addition of only the solvent was defined as 100%, and an uptake value (nonspecific uptake value) obtained by the addition of the unlabeled DA (final concentration: 10 μΜ) was defined as 0%. A 50% inhibitory concentration was calculated from the test compound concentrations and inhibitory activities thereat. The results are shown in Table 62.
[0466]
[Table 62]
Test compound 50% Inhibitory concentration (nM)
Compound of Example 2 85.9
Compound of Example 7 78.9
Compound of Example 8 377.8
Compound of Example 10 64.8
Compound of Example 13 85.4
Compound of Example 15 68.4
Compound of Example 27 31.9
Compound of Example 33 15.1
Compound of Example 72 47.9
Compound of Example 77 41.2
Compound of Example 85 95.7
Compound of Example 106 336.8
Compound of Example 112 263.7
Compound of Example 118 8.3
Compound of Example 120 187.2
Compound of Example 124 9.1
Compound of Example 125 5.2
Compound of Example 130 3.9
Compound of Example 131 8.3
Compound of Example 132 3.9
Compound of Example 136 7.7
Compound of Example 150 200.5
Compound of Example 165 6.8
Compound of Example 186 29.8
Compound of Example 187 12.1
Compound of Example 188 7.9
Compound of Example 191 13.5
Compound of Example 192 8.6
Compound of Example 193 5.7
Compound of Example 196 18.3
Compound of Example 233 38.8
Compound of Example 246 8.8
Compound of Example 247 8.7
Compound of Example 273 8.7
Compound of Example 276 10.9
Compound of Example 281 6.6
Compound of Example 285 43.9
Compound of Example 288 74.7
Compound of Example 300 81.3
Compound of Example 307 68.2
Compound of Example 322 67.7
Compound of Example 344 9.8
Compound of Example 346 7.8
Compound of Example 348 27.3
Compound of Example 405 74.8
Compound of Example 409 165.3
Compound of Example 468 54.0
Compound of Example 577 47.9
Compound of Example 579 46.5
Compound of Example 580 202.0
Compound of Example 582 68.8
Compound of Example 586 93.0
Compound of Example 587 76.1
Compound of Example 593 9.7 Compound of Example 610 13.2
Compound of Example 621 128.5
Compound of Example 641 9.7
Compound of Example 654 9.0
Compound of Example 717 60.1
Compound of Example 778 4.9
Compound of Example 780 4.3
Compound of Example 781 5.2
Compound of Example 791 160.9
Compound of Example 805 83.8
Compound of Example 841 5.1
Compound of Example 850 7.0
Compound of Example 867 85.7
Compound of Example 884 52.8
Compound of Example 895 19.9
Compound of Example 918 42.0
Compound of Example 962 69.5
Compound of Example 983 172.6
Compound of Example 993 38.6
Compound of Example 1026 12.3
Compound of Example 1047 1.1
Compound of Example 1083 53.7
Compound of Example 1113 26.0
Compound of Example 1121 29.9
Compound of Example 1124 49.3
Compound of Example 1318 83.5
Compound of Example 1326 91.8
Compound of Example 1333 73.0
Compound of Example 1341 113.3
Compound of Example 1534 214.8
Compound of Example 1677 294.8
Compound of Example 1680 62.4
Compound of Example 1683 61.7
Compound of Example 1687 586
Compound of Example 1693 7.9
Compound of Example 1695 708.5
Compound of Example 1696 46.5
Compound of Example 1697 614
Compound of Example 1698 433.2
Compound of Example 1716 291.2
Compound of Example 1719 94.4
Compound of Example 1729 7.8
Compound of Example 1731 693
Compound of Example 1732 40.3
Compound of Example 1737 43.0
Compound of Example 1739 87
Compound of Example 1740 37.9
Compound of Example 1741 825
Compound of Example 1742 475
Compound of Example 1743 74
Compound of Example 1748 676
Compound of Example 1749 131.1
[0467]
Pharmacological Study 4
Forced swimming test
This test was conducted according to the method of Porsolt et al. (Porsolt, R.D., et at., Behavioural despair in mice: A primary screening test for antidepressants. Arch. int.
Pharmacodyn. Then, 229, pp 327-336 (1977)).
[0468]
A test compound was suspended in a 5% gum arabic/saline (w/v), and this suspension was orally administered to male ICR mice (CLE A Japan, Inc. (JCL), 5 to 6 week old). One hour later, the mice were placed in a water tank having a water depth of 9.5 cm and a water temperature of 21 to 25°C and immediately thereafter allowed to try to swim for 6 minutes. Then, a time during which the mouse was immobile (immobility time) was measured for the last 4 minutes. A SCANET MV-20 AQ system manufactured by Melquest Ltd. was used in the measurement and analysis of the immobility time.
[0469]
In this experiment, the animals treated with the test compounds exhibited a reduction in immobility time. This demonstrates that the test compounds are useful as antidepressants.
[0470]
Screening kinetic test 1
Test for calculating contribution rate of CYP2D6
Metabolic reaction was started by adding and mixing a qunidine solution (final concentration. 0.001 mmol/L) and a NADH/NADPH solution (final concentration: 1 mmol/L) to a human liver microsome solution containing a test compound (a potassium phosphate buffer solution (pH 7.4) at the final concentration of 100 mmol/L, 5 mmol/L of magnesium chloride, 1.5 mg/mL of human liver microsome and O.OOlmmol L of the test compound). In addition, as an internal standard solution, an acetonitrile solution of spiperone (5 ng/mL) was prepared, which solution was used as a reaction stop liquid .
More specifically, 2.5 uL of the qunidine acetonitrile solution (or acetonitrile as the control) was added and mixed with the 222.5 uL of the human liver microsome solution in ice cold water; 22.5 uL was collected therefrom and 500 uL of the reaction stop liquid was added and mixed, thereby the sample at 0 minute after the reaction being obtained. Preincubation was conducted at 37 ° C for 5 minutes thereafter, and 22.5 uL of the NADH/ ADPH solution was added and mixed to start the meatabolic reaction. Incubated at 37 C, a 25 uL of reaction solution was each fractioned at 10 minutes, 30 minutes, 60 minutes after the start of the reaction, 500 uLof the reaction stop liquid was added and mixed to stop the reaction. The mixed solution was centrifuged (6130g, 10 minutes, 4 ° C) to obtain a supernatant as a sample for LC-MS/MS measurement.
The test compound and spiperone were taken for the measurement, where the peak area ratio ([peak area of the test compound] / [peak area of the internal standard substance]) was calculated. By comparing the slope of the straight line for the control with that under the presence of qunidine obtained from each incubation time and the attenuation (logarithmic value) of the peak area ratio of the test compound to calculate the contribution ratio (%) of CYP2D6 to the test compound with ([slope of control]-[slope under the presence of quinidine]) / [slope of control] x 100.
[0471]
Screening kinetic test 2
CYP inhibition test
Metabolic reaction was started by adding and mixing a test compound solution (final concentration: 0.001 mmo L) and an NADH/NADPH solution (final concentration: 1 mmol/L) to a human liver microsome solution containing a test compound (a potassium phosphate buffer solution (pH 7.4) at the final concentration of 100 mmol/L, 5 mmol/L of magnesium chloride, 0.1 mg/mL of human liver microsome, 0.005 mmol/L of diclofenac (CYP2C9), 0.01 mmol/L of bufuralol (CYP2D6) and 0.005 mmol/L of midazolam (CYP3A4)). In addition, as an internal standard solution, an acetonitrile solution of the stable isotope of the metabolite (50 ng/mL of [13C6] diclofenac hydroxide, 5 ng/mL of [2H9] bufuralol hydroxide, 5 ng/mL of [13C6] midazolam hydroxide) was prepared, which solution was used as a reaction stop liquid .
More specifically, 2 uL of the test compound acetonitrile solution (or acetonitrile as the control) was added and mixed with the 178 of the human liver microsome solution in ice cold water; 20 uL was collected therefrom and 500 uL of the reaction stop liquid was added and mixed, preincubation was conducted at 37 0 C for 5 minutes thereafter, and 20 uL of the NADH/NADPH solution was added and mixed to start the meatabolic reaction. Incubated at 37 C, a 50 uL of reaction solution was eachfractioned, and 500uLof the reaction stop liquid was added and mixed to stop the reaction. The mixed solution was centrifuged (6130g, 10 minutes, 4 ° C) to obtain a supernatant as a sample for LC-MS/MS measurement.
The metabolite and stable isotope of the metabolite were taken for the measurement, where the peak area ratio ([peak area of the metabolite] / [peak area of the corresponding stable isotope of the metabolite]) was calculated. By comparing the paeak area ratio with the addition of the test compound with that for the control to calculate the inhibition rate (%) of the test compound against each CYP molecule with (l-[peak area ratio with the addition of each test compound]) / [peak area ratio of control] x 100.
[0472]
As the result of the test on CYP2D6, the compounds of the present invention turned out to have excellent metabolic stability. Furthermore, the compounds listed in the table below showed 60% or less % inhibition against CYP2D6.
[Table 63]
Test compound
Compound of Example 1677
Compound of Example 1687
Compound of Example 1690
Compound of Example 1693
Compound of Example 1694
Compound of Example 1695
Compound of Example 1696
Compound of Example 1697
Compound of Example 1698
Compound of Example 1716
Compound of Example 1723
Compound of Example 1726
Compound of Example 1729
Compound of Example 1730
Compound of Example 1731
Compound of Example 1732
Compound of Example 1733
Compound of Example 1734
Compound of Example 1737
Compound of Example 1739
Compound of Example 1740
Compound of Example 1741
Compound of Example 1742
Compound of Example 1743
Compound of Example 1745
Compound of Example 1747
Compound of Example 1748
Compound of Example 1749

Claims

1. A medicament comprising a heterocyclic compound represented by the general formula (1) or a salt thereof:
Figure imgf000371_0001
wherein m, 1, and n respectively represent an integer of 1 or 2; X represents -O- or -C¾-;
R1 represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a protecting group, or a tri-lower alkylsilyloxy-lower alkyl group;
R2 and R3, which are the same or different, each independently represent hydrogen or a lower alkyl group; or R2 and R3 are bonded to form a cyclo-C3-C8 alkyl group; and
R4 represents an aromatic group or a heterocyclic group, wherein
the aromatic or heterocyclic group may have one or more arbitrary substituent(s).
2. The medicament according to claim 1, comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, wherein
R4 represents any of
(1) a phenyl group,
(2) an indolyl group,
(3) a benzothienyl group,
(4) a naphthyl group,
(5) a benzofuryl group,
(6) a quinolyl group,
(7) an isoquinolyl group,
(8) a pyridyl group,
(9) a thienyl group,
(10) a dihydrobenzoxazinyl group,
(11) a dihydrobenzodioxinyl group,
(12) a dihydroquinolyl group,
(13) a chromanyl group,
(14) a quinoxalinyl group,
(15) a dihydroindenyl group,
( 16) a dihydrobenzofury 1 group,
(17) a benzodioxolyl group,
(18) an indazolyl group,
(19) a benzothiazolyl group,
(20) an indolinyl group,
(21) a thienopyridyl group,
(22) a tetrahydrobenzazepinyl group,
(23) a tetrahydrobenzodiazepinyl group,
(24) a dihydrobenzodioxepinyl group,
(25) a fluorenyl group,
(26) a pyridazinyl group,
(27) a tetrahydroquinolyl group,
(28) a carbazolyl group,
(29) a phenanthryl group,
(30) a dihydroacenaphthylenyl group,
(31) a pyrrolopyridyl group,
(32) an anthryl group,
(33) a benzodioxinyl group,
(34) a pyrrolidinyl group,
(35) a pyrazolyl group,
(36) an oxadiazolyl group,
(37) a pyrimidinyl group,
(38) a tetrahydronaphthyl group,
(39) a dihydroquinazolinyl group,
(40) a benzoxazolyl group,
(41) a thiazolyl group,
(42) a quinazolinyl group,
(43) a phthalazinyl group,
(44) a pyrazinyl group, and
(45) a chromenyl group, wherein
these aromatic or heterocyclic groups may have one or more substituent(s) selected from (1-1) a halogen atom, -2) a lower alkyl group,
-3) a lower alkanoyl group,
-4) a halogen-substituted lower alkyl group,
-5) a halogen-substituted lower alkoxy group,
-6) a cyano group,
-7) a lower alkoxy group,
-8) a lower alkylthio group,
-9) an imidazolyl group,
-10) a tri-lower alkylsilyl group;
-11) an oxadiazolyl group which may have a lower alkyl group(s),-12) a pyrrolidinyl group which may have an oxo group(s),
-13) a phenyl group which may have a lower alkoxy group(s),-14) a lower alkylamino-lower alkyl group,
-15) an oxo group,
-16) a pyrazolyl group which may have a lower alkyl group(s),-17) a thienyl group,
-18) a furyl group,
-19) a thiazolyl group which may have a lower alkyl group(s),-20) a lower alkylamino group,
-21) a pyrimidyl group which may have a lower alkyl group(s),-22) a phenyl-lower alkenyl group,
-23) a phenoxy group which may have a halogen atom(s),
-24) a phenoxy-lower alkyl group,
-25) a pyrrolidinyl-lower alkoxy group,
-26) a lower alkylsulfamoyl group,
-27) a pyridazinyloxy group which may have a lower alkyl group(s),-28) a phenyl-lower alkyl group,
-29) a lower alkylamino-lower alkoxy group,
-30) an imidazolyl-lower alkyl group,
-31 ) a phenyl-lower alkoxy group,
-32) a hydroxy group,
-33) a lower alkoxy carbonyl group,
-34) a hydroxy-lower alkyl group,
-35) an oxazolyl group, ( 1 -36) a piperidy 1 group,
(1-37) a pyrrolyl group,
(1-38) a morpholinyl-lower alkyl group,
(1-39) a piperazinyl-lower alkyl group which may have a lower alkyl group(s), (1-40) a piperidy 1-lower alkyl group,
(1-41) a pyrrolidinyl-lower alkyl group,
(1-42) a morpholinyl group, and
(1-43) a piperazinyl group which may have a lower alkyl group(s).
3. The medicament according to claim 2, comprising a heterocyclic compoundrepresented by the general formula (1) or a salt thereof, wherein R4 represents any of
(1) a phenyl group,
(2) an indolyl group,
(3) a benzothienyl group,
(4) a naphthyl group,
(5) a benzofuryl group,
(6) a quinolyl group,
(7) an isoquinolyl group,
(8) a pyridyl group,
(9) a thienyl group,
(10) a dihydrobenzoxazinyl group,
(11) a dihydrobenzodioxinyl group,
(12) a dihydroquinolyl group,
(13) a chromanyl group,
(14) a quinoxalinyl group,
(15) a dihydroindenyl group,
(16) a dihydrobenzofuryl group,
(17) a benzodioxolyl group,
(18) an indazolyl group,
(19) a benzothiazolyl group,
(20) an indolinyl group,
(21) athienopyridyl group,
(22) a tetrahydrobenzazepinyl group,
(23) a tetrahydrobenzodiazepinyl group, (24) a dihydrobenzodioxepinyl group,
(25) a fluorenyl group,
(26) a pyridazinyl group,
(27) a tetrahydroquinolyl group,
(28) a carbazolyl group,
(29) a phenanthryl group,
(30) a dihydroacenaphthylenyl group,
(31) a pyrrolopyridyl group,
(32) an anthryl group,
(33) a benzodioxinyl group,
(34) a pyrrolidinyl group,
(35) a pyrazolyl group,
(36) an oxadiazolyl group,
(37) a pyrimidinyl group,
(38) a tetrahydronaphthyl group,
(39) a dihydroquinazolinyl group,
(40) a benzoxazolyl group,
(41) a thiazolyl group,
(42) a quinazolinyl group,
(43) a phthalazinyl group,
(44) a pyrazinyl group, and
(45) a chromenyl group, wherein
these aromatic or heterocyclic groups may have 1 to 4 substituent(s) selected from
( 1 - 1 ) a halogen atom,
(1-2) a lower alkyl group,
(1-3) a lower alkanoyl group,
(1-4) a halogen-substituted lower alkyl group,
(1-5) a halogen-substituted lower alkoxy group,
(1-6) a cyano group,
(1-7) a lower alkoxy group,
(1-8) a lower alkylthio group,
(1-9) an imidazolyl group,
(1-10) a tri- lower alkylsilyl group,
(1-11) an oxadiazolyl group which may have 1 lower alkyl group, (1-12) a pyrrolidinyl group which may have 1 oxo group,
(1-13) a phenyl group which may have 1 lower alkoxy group,
(1-14) a lower alkylamino-lower alkyl group,
(1-15) an oxo group,
(1-16) a pyrazolyl group which may have 1 lower alkyl group,
(1-17) a thienyl group,
(1-18) a furyl group,
(1-19) a thiazolyl group which may have 1 lower alkyl group,
(1-20) a lower alkylamino group,
(1-21) a pyrimidyl group which may have 1 lower alkyl group,
(1-22) a phenyl-lower alkenyl group,
(1-23) a phenoxy group which may have 1 halogen atom,
(1-24) a phenoxy- lower alkyl group,
(1-25) a pyrrolidinyl-lower alkoxy group,
(1-26) a lower alkylsulfamoyl group,
(1-27) a pyridazinyloxy group which may have 1 lower alkyl group,
(1-28) a phenyl-lower alkyl group,
(1-29) a lower alkylamino-lower alkoxy group,
(1-30) an imidazolyl-lower alkyl group,
(1-31) a phenyl-lower alkoxy group,
( 1 -32) a hydroxy group,
(1-33) a lower alkoxy carbonyl group,
(1-34) a hydroxy-lower alkyl group,
(1-35) an oxazolyl group,
( 1 -36) a piperidyl group,
(1-37) a pyrrolyl group,
(1-38) a morpholinyl-lower alkyl group,
(1-39) a piperazinyl-lower alkyl group which may have 1 lower alkyl group,
(1-40) a piperidyl-lower alkyl group,
(1-41) a pyrrolidinyl-lower alkyl group,
(1-42) a morpholinyl group, and
(1-43) a piperazinyl group which may have 1 lower alkyl group.
4. The medicament according to claim 3, comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, wherein m represents 2; 1 and n respectively represent an integer of 1; X represents -CH2-;
R1 represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a benzyl group, or a tri-lower alkylsilyloxy-lower alkyl group; and
R4 represents any of
(1) a phenyl group,
(2) an indolyl group,
(4) a naphthyl group,
(5) a benzofuryl group, and
(31) a pyrrolopyridyl group, wherein
these aromatic or heterocyclic groups may have 1 to 4 substituent(s) selected from
(1-1) a halogen atom,
(1-2) a lower alkyl group,
( 1 -3) a lower alkanoyl group,
(1-4) a halogen-substituted lower alkyl group,
(1-5) a halogen-substituted lower alkoxy group,
(1-6) a cyano group,
( 1 -7) a lower alkoxy group,
(1-8) a lower alkylthio group,
(1-9) an imidazolyl group,
(1-10) a tri-lower alkylsilyl group,
(1-11) an oxadiazolyl group which may have 1 lower alkyl group,
(1-12) a pyrrolidinyl group which may have 1 oxo group,
(1-13) a phenyl group which may have 1 lower alkoxy group,
(1-14) a lower alkylamino-lower alkyl group,
(1-15) an oxo group,
(1-16) a pyrazolyl group which may have 1 lower alkyl group,
(1-17) a thienyl group,
(1-18) a furyl group,
(1-19) a thiazolyl group which may have 1 lower alkyl group,
(1-20) a lower alkylamino group,
(1-21) a pyrimidyl group which may have 1 lower alkyl group,
(1-22) a phenyl-lower alkenyl group,
(1-23) a phenoxy group which may have 1 halogen atom,
(1-24) a phenoxy- lower alkyl group, (1-25) a pyrrolidinyl-lower alkoxy group,
(1-26) a lower alkylsulfamoyl group,
(1-27) a pyridazinyloxy group which may have 1 lower alkyl group,
(1-28) a phenyl-lower alkyl group,
(1-29) a lower alkylamino-lower alkoxy group,
(1-30) an imidazolyl-lower alkyl group,
(1-31) a phenyl-lower alkoxy group,
( 1 -32) a hydroxy group,
(1-34) a hydroxy-lower alkyl group,
(1-35) an oxazolyl group,
(1-36) a piperidyl group,
(1-37) a pyrrolyl group,
(1-38) a morpholinyl-lower alkyl group,
(1-39) a piperazinyl-lower alkyl group which may have a lower alkyl group(s),
(1-40) a piperidyl- lower alkyl group,
(1-41) a pyrrolidinyl-lower alkyl group,
(1-42) a morpholinyl group, and
(1-43) a piperazinyl group which may have 1 lower alkyl group.
5. The medicament according to claim 4, comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, wherein
R1 represents hydrogen;
R2 and R3, which are the same or different, each independently represent a lower alkyl group; or R2 and R3 are bonded to form a cyclo-C3-C8 alkyl group; and
R4 represents any of
(1) a phenyl group,
(2) an indolyl group,
(4) a naphthyl group,
(5) a benzofuryl group, and
(31) a pyrrolopyridyl group, wherein
these aromatic or heterocyclic groups may have 1 to 2 substituent(s) selected from
( 1 - 1 ) a halogen atom,
(1-2) a lower alkyl group,
(1-5) a halogen-substituted lower alkoxy group,
(1-6) a cyano group, and ( 1 -7) a lower alkoxy group.
6. The medicament according to claim 5, comprising a heterocyclic compound represented by the general formula (1) or a salt thereof, which is selected from
(4aS,8aR)- 1 -(4-chlorophenyl)-3 ,3-dimethyldecahydroquinoxaline
2-chloro-4-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-l(2H)-yl)benzonitrile
(4aS, 8aR)- 1 -(3 -chloro-4-fluorophenyl)-3 ,3 -dimethyldecahydroquinoxaline
(4aS,8aR)-l-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline
5-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-l(2H)-yl)-l-methyl-lH-indole-2-carbonitrile
(4a'R,8a'S)-4'-(7-methoxybenzofuran-4-yl)octahydro H-spiro[cyclobutane-l,2'-quinoxaline] (4aS,8aR)-l-(6,7-difluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline
5- ((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-l(2H)-yl)-lH-indole-2-carbonitrile
(4aS,8aR)- 1 -(7-chloro-2,3 -dihy dro- lH-inden-4-yl)-3 ,3 -dimethyldecahydroquinoxaline
6- ((4aS, 8aS)-3 ,3 -dimethyloctahy droquinoxalin- 1 (2H)-yl)-2-naphthonitrile
(4aS,8aS)-3,3-dimethyl-l-(lH-pyrrolo[2,3-i>]pyridin-4-yl)decahydroquinoxaline an(j
(4aS,8aS)-l-(4-(difluoromethoxy)-3-fluorophenyl)-3,3-dimethyldecahydroquinoxaline
7. A pharmaceutical composition comprising a heterocyclic compound represented by the general formula (1) or a salt thereof according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier.
8. A prophylactic and/or therapeutic agent for disorders caused by reduced neurotransmission of serotonin, norepinephrine or dopamine, comprising as an active ingredient a heterocyclic compound of general formula (1) or a salt thereof according to claim 1.
9. A prophylactic and/or therapeutic agent according to claim 8, wherein the disorder is selected from the group consisting of depression, depression status caused by adjustment disorder, anxiety caused by adjustment disorder, anxiety caused by various diseases, generalized anxiety disorder, phobia, obsessive-compulsive disorder, panic disorder,
posttraumatic stress disorder, acute stress disorder, hypochondria, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorder, obesity, chemical dependence, pain, fibromyalgia, Alzheimer's disease, memory deficit, Parkinson's disease, restless leg syndrome, endocrine disorder, vasospasm, cerebellar ataxia, gastrointestinal disorder, negative syndrome of schizophrenia, premenstrual syndrome, stress urinary incontinence, Tourette's disorder, attention deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, impulse control disorder, trichotillomania, kleptomania, gambling disorder, cluster headache, migraine, chronic paroxysmal hemicrania, chronic fatigue syndrome, precocious ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome and headache.
10. A prophylactic and/or therapeutic agent according to claim 9, wherein the depression is selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymic disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; hypomelancholia; recurrent brief depressive disorder; refractory depression; chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; depression caused by various physical diseases such as Cushing('s) syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea- galactorrhea syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, brain infarct^ brain hemorrhage^ subarachnoid hemorrhage, diabetes millitus, virus infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc.; presenile depression; senile depression; depression in children and adolescents; depression induced by drugs such as interferon, etc.
11. A prophylactic and/or therapeutic agent according to claim 9, wherein the anxiety caused by various diseases is selected from the group consisting of anxiety caused by head injury, brain infection, inner ear impairment, cardiac failure, arrhythmia, hyperadrenalism, hyperthyroidism, asthma and chronic obstructive pulmonary disease.
12. A prophylactic and/or therapeutic agent according to claim 9, wherein the pain is selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic cervical syndrome, spinal cord injury pain, trigeminal neuralgia, diabetic neuropathy.
13. A heterocyclic compound or a salt thereof selected from the group consisting of the following compounds:
Figure imgf000381_0001
Figure imgf000382_0001
Figure imgf000383_0001
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000386_0001
Table 7
Figure imgf000387_0002
14. A heterocyclic compound or a salt thereof selected from the group consisting of the following compounds:
[Table 8]
Figure imgf000387_0001
Figure imgf000388_0001
15. A medicament comprising the heterocyclic compound or a salt thereof according to claim 13 or 14.
16. A pharmaceutical composition comprising a heterocyclic compound or a salt thereof according to claim 13 or 14 as an active ingredient and a pharmaceutically acceptable carrier.
17. A prophylactic and/or therapeutic agent for disorders caused by reduced neurotransmission of serotonin, norepinephrine or dopamine, comprising as an active ingredient a heterocyclic compound of general formula (1) or a salt thereof according to claim 13 or 14.
18. A prophylactic and/or therapeutic agent according to claim 17, wherein the disorder is selected from the group consisting of depression, depression status caused by adjustment disorder, anxiety caused by adjustment disorder, anxiety caused by various diseases, generalized anxiety disorder, phobia, obsessive-compulsive disorder, panic disorder,
posttraumatic stress disorder, acute stress disorder, hypochondria, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorder, obesity, chemical dependence, pain, fibromyalgia, Alzheimer's disease, memory deficit, Parkinson's disease, restless leg syndrome, endocrine disorder, vasospasm, cerebellar ataxia, gastrointestinal disorder, negative syndrome of schizophrenia, premenstrual syndrome, stress urinary incontinence, Tourette's disorder, attention deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, impulse control disorder, trichotillomania, kleptomania, gambling disorder, cluster headache, migraine, chronic paroxysmal hemicrania, chronic fatigue syndrome, precocious ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome and headache.
19. A prophylactic and/or therapeutic agent according to claim 18, wherein the depression is selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymic disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; hypomelancholia; recurrent brief depressive disorder; refractory depression; chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; depression caused by various physical diseases such as Cushing('s) syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea- galactorrhea syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, brain infarct^ brain hemorrhage^ subarachnoid hemorrhage, diabetes millitus, virus infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc.; presenile depression; senile depression; depression in children and adolescents; depression induced by drugs such as interferon, etc.
20. A prophylactic and/or therapeutic agent according to claim 18, wherein the anxiety caused by various diseases is selected from the group consisting of anxiety caused by head injury, brain infection, inner ear impairment, cardiac failure, arrhythmia, hyperadrenalism, hyperthyroidism, asthma and chronic obstructive pulmonary disease.
21. A prophylactic and/or therapeutic agent according to claim 18, wherein the pain is selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic cervical syndrome, spinal cord injury pain, trigeminal neuralgia, diabetic neuropathy.
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WO2023286768A1 (en) * 2021-07-13 2023-01-19 Otsuka Pharmaceutical Co., Ltd. Hydrogenated quinoxalines

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