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:

wherein m, 1, and n respectively represent 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

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

R ⁴ 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

R ⁴ 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 -CH ₂ -;

R ¹ represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a benzyl group, or a tri-lower alkylsilyloxy-lower alkyl group; and

R ⁴ 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

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

(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-dimethyldecahydroquinoxalin e

2-chloro-4-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-l(2H)- yl)benzonitrile

(4aS,8aR)-l-(3-chloro-4-fluorophenyl)-3,3-dimethyldecahydroq uinoxaline

(4aS,8aR)-l-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroq uinoxaline

5-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-l(2H)-yl)-l-met hyl-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-dimethyldec ahydroquinoxaline

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-napht honitrile

Q (4aS,8aS)-3,3-dimethyl-l-(lH-pyrrolo[2,3-&]pyridin-4-yl) decahydroquinoxaline _anc j

(4aS ^, ,8aS)-l-(4-(difluoromethoxy)-3-fluorophenyl)-3,3-dimet hyldecahydroquinoxaline

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:

[Table 1-2]

[Table 1-3]

[Table 1-4]

[Table 1-5]

[Table 1-6]

[Table 1-7]

Item 14. A heterocyclic compound or a salt thereof selected from the group consisting of the following compounds:

[Table 1-8]

[Table 1-9]

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, 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,

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, 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.

[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

(2)

(1)

wherein ¹ , R ² , R ³ , R ⁴ , 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 X _t 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

wherein R ² , R ³ , R ⁴ , X, 1, m, and n are defined as above; and R ^la 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

Step B (reduction)

wherein R ¹ , R ² , R ³ , 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

Step D (reduction)

wherein R ¹ , R ² , R ³ , 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

wherein 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.

[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, (η ⁴ -cyclooctadiene)(η ⁶ -cyclooctatriene)ruthenium, dichlorotricarbonylruthenium dimers, dodecacarbonyltriruthenium, ( -pentamethylcyclopentadienyl)chloro(ri ⁴ - 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, (η ⁵ - pentamethylcyclopentadienyl)dichloroiridium dimers, nickel tetrakis(triphenylphosphine), dicobaltoctacarbonyl, and (rj ⁵ -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 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.

Furthermore, substitution by heavier isotopes such as heavy hydrogen (i.e., ² H) 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

Optically active form

Absolute confi uration

[0193]

Reference Example 1

Production of cis-3,3-dimethyloctahydrocyclopentapyrazin-2-one

Relative configuration

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(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

1H- MR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

1H- MR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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 1H-NMR(CDCl ₃ )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 1H- MR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

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(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

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(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

1H- MR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

¹ H-NMR(CDCl ₃ )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

^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

1H- MR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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 1H-NMR(CDCl ₃ )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

1H- MR(CDCl ₃ )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

lH-NMR(CDCl ₃ )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

MS (M-r-l) 181

Reference Example 30 Cis-octahydro- 1 'H-spiro[cyclobutane- 1 ,2'-quinoxaline]

Relative confi uration

MS (M+1) 181 [0226]

Reference Example 31

Trans-octahydro- 1 'H-spiro[cyclopentane- 1 ,2'-quinoxaline]

Relative confi uration 1H-NMR(CDCl ₃ )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]

1H-NMR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

¹ H-N R(CDCl ₃ )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

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(CDCl ₃ )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

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(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

1H- MR(CDCl ₃ )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

1H-NMR(CDCl ₃ )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

[0238]

Reference Example 41

(4aS,8aR)-2,2-dimethyldecahydroquinoxaline

Absolute configuration

(-)-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 (CDC1 ₃ ) 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(CDCl ₃ )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

MS (MH- l) 181

Ή-NMR (CDC1 ₃ ) 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

MS (M+ 1) 181

'H-NMR (CDCI ₃ ) 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

1H-NMR(CDCl ₃ )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

1H- MR(CDCl ₃ )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

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(CDCl ₃ )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

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(CDCl ₃ )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

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(CDCl ₃ )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

1H-NMR (CDC1 ₃ ) 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

1H- MR (CDC1 ₃ ) 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

Ή-NMR (CDC1 ₃ ) 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

Ή-NMR (CDCI ₃ ) 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

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

Ή-NMR (CDC1 ₃ ) 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

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 (CDCI ₃ ) 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

[0262]

Reference Example 58

Production process of cis tert-butyl 4-(4-chlorophenyl)decahydroquinoxaline-l -carboxylate Relative configuration

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-Bu ₃ P.HBF ₄ (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. MgS0 ₄ 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 (CDC1 ₃ ) 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

1H-NMR (CDC1 ₃ ) 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

1H-NMR (CDC1 ₃ ) 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

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

1H-NMR (CDC1 ₃ ) 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

1H-NMR (CDC1 ₃ ) 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

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)decahydroqui noxaline (0.75 g, yield: 85%). 1H-NMR(CDCl ₃ )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

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(CDCl ₃ )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

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-d ₆ )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

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-dimethyldecahydroquinoxali ne (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-trimethyldecahydroquinox aline hydrochloride (258 mg, yield: 74%) in a white powder form.

1H-NMR(CDCl ₃ )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

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(CDCl ₃ )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-dimethyldecahydroq uinoxaline

Absolute configuration

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-Bu ₃ RHBF ₄ (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. MgS0 ₄ 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 ( CDC1 ₃ ) 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-dimethyldecahydroquinoxalin e hydrochloride Absolute configuration

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-Bu ₃ P.HBF ₄ (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. MgS0 ₄ 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-dimethyldecahydroquinoxalin e hydrochloride (262 mg, yield: 55%) in a white powder form.

1H-NMR ( DMSO-d ₆ ) 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

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-Bu ₃ P.HBF ₄ (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. MgS0 ₄ 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

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-Bu ₃ P.HBF ₄ (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. MgS0 ₄ was further added thereto, and the mixture was stirred. Insoluble matter was filtered through celite, and the residue was washed with CH ₂ Cl ₂ :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 ( CDC1 ₃ ) 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-dimethyldecahydroqu inoxaline hydrochloride

Absolute configuration

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-Bu ₃ P.HBF ₄ (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 (CH ₂ Cl ₂ 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 ( CDC1 ₃ ) 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

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-Bu ₃ PHBF ₄ (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. MgS0 ₄ 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 ( CDC1 ₃ ) 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-dimethyldecahy droquinoxaline hydrochloride Absolute configuration

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-Bu ₃ P.HBF ₄ (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. MgS0 ₄ 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-dimethyldecahy droquinoxaline hydrochloride (167 mg, yield: 31%) in a white powder form.

1H-NMR ( DMSO-d ₆ ) 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

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), tBu ₃ P.HBF ₄ (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 (CDC1 ₃ ) 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

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-d ₆ ) 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

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. MgS0 ₄ 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

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), tBu ₃ P.HBF ₄ (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-d ₆ ) 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

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), tBu ₃ P.HBF ₄ (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 (CDC1 ₃ ) 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)deca hydroquinoxaline fumarate

Absolute configuration

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)decahydroq uinoxaline (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

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), tBu ₃ P.HBF ₄ (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-d ₆ ) 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)d ecahydroquinoxali ne dihydrochloride

n

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-dimethyldecahydroquinoxali ne oxalate

A on

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)deca hydroquinoxalin e dihydrochloride

A on

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

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-d imethyldecahydr oquinoxaline dihydrochloride

Absolute configuration

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-di methyldecahydroquinoxaline 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-dimethylde cahydr oquinoxaline dihydrochloride

Absolute configuration

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

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-dimethyl decahydroquinoxa line dihydrochloride

Absolute configuration

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

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

A toluene (5 mL) suspension of (2R,4aS,8aS)-2-methyldecahydroquinoxaline (300mg, 1.94mmol), 5-bromo-l-chloro-2-difluoromethoxy-3-fluorobenzene(589mg,2.1 4mmol), 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-methylde cahydroquinoxal ine oxalate

A n

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

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

-CH _r Hydrochloride 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

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,

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

(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

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),

8.45-8.69 (1H, br), 8.89-9.19 (1H, br). [0292] Table 4

Relative configuration

Example R ⁴ 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).

(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

Example R' R ⁴ 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 _j T 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

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 =

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

(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

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

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 = 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

5.4Hz ), 8.17 { 1H, br ), 9.78

[0294]

Table 6

Relative configuration

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 CH ₃ ( 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 H ₃ C^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 ).

[0295] Table 7

Example R ¹ R* NMR Salt

( 3H. m ), 1.21 ( 3H, s ). 1.25-1.45 ( 6H,

), 3.11 ( 1H,

37 -H dd, J = 0.9,

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 ( 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

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 ), ( 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 = 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

( 1H. br), 9.83 ( 1H, br). [0296]

Table 8

n

Example R R ⁹ 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

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

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, H ₃ ^' = 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 OC ₂ H ₅ = 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 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 ).

[0298]

[0299] Table 11

Example R ¹

( 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 = 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 ( 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

( 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

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

( 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

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,

[0301]

Table 13

Absolute configuration

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 ?H ^H -, 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 =

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

Example R* R* NMR Salt

), 1.5-1.8 , 3.6-3.75 6.95-7.05 , br).

m ), 2.93 , 8.8Hz ), Fumarate

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 ),

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 ).

[0304]

Table 16

ration

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

( 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 ), 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

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

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

CH ₃ 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 -CH ₃

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 OC ₂ H ₅ 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

( 2H, m ), 8.15-8.3 ( H, m ), 9.9-10.0

( 1H, m ).

( 1H, m ), 1.45-1.7 ( 7H, m ),

[0307] Table 19

[0308]

Table 20

Absolute configuration

Example R R* NMR Salt

Difumarate

: 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

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

( 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

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

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

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 -CH ₃ Hydrochloride

-6.75 ( 1H, m ), 7.15-7.25 (3H, m ), 7.95 ( 1H, d, J =

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

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

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,

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

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

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 ),

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

= 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

1H-NMR ( COCI3 ) Bppm . .13 ( 18H, d, J = 7.5Hz ), 1.21 ( 3H, B ), 1.28 ( 3H, β ), 1.3-1.8 { 5H, N CH ₃ 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

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,

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

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),

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 ),

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

CH ₃ ( 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

( 1 H, d, J = 3.1 Hz ), 7.36 ( 1 H, d, J = 9.2Hz ).

2.0-2.15 H, d, J = 1.8Hz ),

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

Example R' NMR Salt

), 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 .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

( 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 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

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 -CH _a -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 ( 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

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 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

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 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

Example R ¹ 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,

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 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 ^ΟΆ ν ^{ύπκΜοΜβ} (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

OCH ₃ 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

Example R ¹ 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),

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),

10.15 (2H, brs)

(3H, s), 1.84-2.21 (2H, m), 2.14 (3H, s),

m),

187 -CHj Dihydrochlorlde 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 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

Absolute configuration

NMR Salt

[0319]

Table 31

Absolute configuration

Example R* NMR Melting point (°C) Salt

-

7.39{1H, 8), e.10 (1H, Pre) Hemlfumarate

Fumarate

Fumarate

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

(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

CH ₃ (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

Dlhydrochloride

Dlhydrochloride

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

(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

Example R' R ⁴ 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

<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),

(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),

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),

(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

Example R ¹ R ⁵ 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 -CH ₃ (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),

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

Example R ¹ 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 (2H _P m), 2.85 (3H, d, J =

251 -CH, Dihydrochloride 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

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

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

280 -H Dihydrochloride .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

Example R ¹ NMR Melting point ("C) Salt

209.8 -

281 -H . CN

N Fumarate

214.2

Dihydrochloride

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

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

Example R ² ,R ^a 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 ),

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 ),

1H-NMR ( COC13 ) Bppm : 1.05-1.35 ( 3H, m ), 1.35-1.45 ( 1H, m ), 1.45-1.65

d, J = 9.1Hz).

( 10H, m ), 2.35-2.6

278 -(CH ₂ )y

8.9Hz ), 8.9-9.1 ( 1H, m ), 11-125 ( 1H, m ).

[0327]

Table 39

Absolute configuration

Dihydrochloride

Dlhydrochlorlde

XXX OCH ₃

DIhydrachlorlde

[0328]

Table 40

n

Example ' R* R ⁵ 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),

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 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

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 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

" 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 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

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,

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

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

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,

m), 7.29-7.48 (3H, m), 7.52-7.53 (1H, m), 7.73-7.80 (3H, m)

, m),

(3H,

CHpH ₃ Hz),

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£Η ₃ m), 6.97 (1H, dd, J = 6.6, 2.4 Hz), 7.22 (1H, d, J = 24 Hz), 7.34 (1H, d, J

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

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 br), 13.51-14.36 (0.55H, br)

302 , br), Dihydrochlorlde

303 Hydrochloride

[0331]

Table 43

Relative configuration

Example R ¹ * R ^¾ 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 -CH ₃ -<CH2)«- Dihydrochlorlde 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 -(CHd _f Dihydrochlorlde

(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 = 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

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

CH ₃ = 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

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

Example R ¹ 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

H ₂ C ( 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

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

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

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

[0336]

Table 48

Absolute configuration

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), 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 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), 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

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

(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

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

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

= 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

(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).

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

(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

Example R* NMR Salt

(2H, m), 2.94 (1H, d, J = 13.3), 3.51

343 Dlriydrochlorlde

(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

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).

[0341]

Table 53

Relative configuration

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

Example R ⁵ R R ⁷ MS(M+1 )

351 -H -H -H -H -H 245 352 -H -H -CH ₃ -H -H 259 353 -H -CH ₃ -H -H -H 259 354 -H -F -H -H -H 263 355 -H -H -CN -H -H 270

357 -H -C _Z H ₅ -H -H -H 273 358 -H -CH ₃ -H -CH ₃ -H 273 359 -H -H -CzH. -H -H 273 360 -H -OCH ₃ -H -H -H 275 361 -H -F -H -F -H 281 362 -H -CH ₃ -CN -H -H 284 363 -H -H -(CH ₂ ) ₂ CH ₃ -H -H 287 364 -H -CH(CHj) ₂ -H -H -H 287 365 -H -H -CH(CH ₃ ) ₂ -H -H 287 366 -H -F -CN -H -H 288 -H -CN -H -F -H 288 -H -N(CH ₃ ) ₂ -H -H -H 288 -H -H . -N(CH ₃ ) ₂ -H -M 288 -H -OC ₂ H ₅ -H -H -H 289 -H -CH ₃ -OCH ₃ -H -H 289 -H -H -OCHzCHj -H -H 289

-H -H -SCH ₃ -H -H 291

-H -F -H -CI -H 297 -H -F -F -F ^■ -H 299 -H -H -C(CH ₃ ) ₃ -H -H 301 -H -CH ₃ -OCH ₃ -CH ₃ -H 303 -H •OCH(CH ₃ ) ₂ -H -H -H 303

-H -H -SCH ₂ CH ₃ -H -H 305

-OCH ₃ -H -H -CI -H 309 -H -H <r ^N -H -H 311

INK -H -CF ₃ -H -H -H 313

-H -H -CF ₃ -H -H 313

-CI -H -CI -H -H 313

-H -CI -H -CI -H 313

-H -CF ₃ -CH ₃ -H -H 327

-H -H -OCF ₃ -H -H 329

-H -CF ₃ -H -F -H 331

-F -CF ₃ -H -H -H 331

-H -CF ₃ -F -H -H 331

-H -CF ₃ -OCH ₃ -H -H 343

-H -CF ₃ -CI -H -H 347

3]

Table 55

Relative configuration

ı54

44]

Table 56

Exam le R S( +1)



]

442 -H -OCH, -H -H -H 275

443 -OCH ₃ -H -H -H -H 275

444 -CH ₃ -H -H -H 277

445 -H -CHs -H -H 277

446 -F -H -H -CH ₃ -H 277

447 -H -F -CH ₃ -H -H 277

449 -H -H -F -H 281

450 -H -H -H 281

451 -H -CH ₃ -CN -H -H 284

452 -H -C(0)CH ₃ -H -H -H 287

453 -H -H -C(0)CH ₃ -H -H 287

454 -CH ₃ -H -Ch -CH, -H 287

455 -H -H -CH(CH ₃ ) 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(CH ₃ ) ₂ -H -H 288

461 -CH ₃ -H -OCH ₃ -H -H 289

462 -H -CH ₃ -OCH ₃ -H -H 289

463 -H -CH ₃ -CH ₃ -H 291

464 -CH ₃ -CH ₃ -H -H 291

465 -H -H -SCH ₃ -H -H 291

466 -H -SCH ₃ -H -H -H 291

468 -CH ₃ -CI -H -H -H 293

469 -H -CH ₃ -CI -H -H 293

470 -H -CI -CH, -H -H 293

471 -CH ₃ -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 -(CH ₂ ) ₃ CH ₃ -H -H 301

477 -H -H -C(CH ₃ ) a -H -H 301

478 -H -H -CH ₂ N(CH ₃ ) ₂ -H -H 302

479 -H -CH ₂ N(CH ₃ ) 2 -H -H -H 302

480 -OCH{CH ₃ ) z -H -H -H -H 303

481 -H -CH ₃ -OCH ₃ -CH ₃ -H 303

482 -H -CI -CN -H -H 304

483 -H -OCH ₃ -H -OCH ₃ -H 305

484 -H -OCH, -OCHj -H -H 305

485 -OCH ₃ -H -H -OCH ₃ -H 305

486 -OCH _* -F -H -H 311

487 -H -OCH ₃ -F -H 31 1

488 -OCH ₃ -H -F -H 311

489 -H -H -OCHFz -H -H 311

491 -H -H ) -H -H 311

492 -H Y U¾ -H -H -H 311

493 -H -H -H -H 311

494 -CF ₃ -H -H -H -H 313

495 -H -CF ₃ -H -H -H 313

496 -H -H -CF ₃ -H -H 313

497 -CI -H -CI -H -H 313

498 -H -CI -H -CI -H 313

500 -H -CHj -N(CH ₃ ) ₂ -CH ₃ -H 316

501 I J -H -H -H -H 321

504 -H _. -CI -OC ₂ H _s -H -H 323

509 -H -CF ₃ -CH, -H -H 327

14 -H -OCR -H -H -H 329 15 -OCF ₃ -H -H -H -H 329 6 -H -H -OCF ₃ -H -H 329 517 -H -CF ₃ -H -H 331

518 -H -CF, -F -H -H 331

519 -H -H -0(CH _Z ) ₂ N(CH ₃ )2

520 -H -OCH ₃ -OCH ₃ -OCH ₃ -H 335

H ₂

521 -H -H -H -H 335

526 -H -CF _a -OCH ₃ -H -H 343

527 -H -H -0(CH ₂ ) ₅ CH ₃ -H -H 345

528 -H -0(CH ₂ ) ₃ N(CH ₃ ) ₂

530 -H -CI -CF ₃ -H -H 347 531 -H -CF, -CI -H -H 347

532 -CI -CI -H -CI -H 347

537 -H -H -SO _z N(CH ₃ )z -H -H 352

541 -H -H -CH ₂ N(i-Pr) ₂ -H

-H 358

542 -H -C -H -CF ₃ -H 381 

47]

[0348]

Table 63

Relative confi uration

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

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 ( 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 ( 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

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, S ), 7.21-7.28 ( 1H, m ), 7.54 ( 1H, s ), 7.60

(1H, d, J = 9.0Hz).

[0351]

Table 66

Absolute configuration

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 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,

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,

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,

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 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

[0353]

Table 68

Absolute configuration

[0354]

Table 69

Absolute configuration

( 1H, d, J = 8.5Hz), 8.22 ( 1H, br), 10.07 ( 1H, br).

[0355]

Table 70

Absolute configuration

1H-NMR (CDCI3) 5ppm : 1.11-1.19 ( 19H, m ),

H ₃ C _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 Α _Μ ³ 3.8-3.9 (1H,m), 6.41 (1H,d, J = 7.5Hz), 7.05 H ₃ C I3 _{( 1H d j} _ _85Hz j _{716 ( 1H dd j} _ ₇₆

8.3Hz ), 8.26 ( 1H, d, J = 0.8Hz ).

[0356]

Table 71

Absolute configuration

[0357]

Table 72

Absolute configuration

[0358]

Table 73

Absolute configuration

[0359]

Table 74

Absolute configuration

[0360]

Table 75

Absolute configuration

(ff _N i ^CH3

H ^4

[0361]

Table 76

Absolute configuration

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 ),

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, ^H y ^drochloride 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

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,

( 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,

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

[0363]

Table 78 Absolute configuration

[0364]

Table 79

Absolute configuration

[0365]

Table 80

Absolute configuration

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,

dd, J = 1.0, 8.3Hz ), 8.24 ( 1H, d, J = 8.1Hz ),

9.4-9.6 ( 1H, m ).

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 =

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

[0367]

Table 82

Absolute configuration

Exam

NMR Salt

[0368]

Table 83

Absolute configuration

^Ex . ^am R ⁴ 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

( 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

( 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),

[0369]

Table 84

Absolute configuration

Absolute configuration

[0371]

Table 86

Absolute configuration

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 ),

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 ).

[0372]

Table 87

Absolute configuration

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,

dd, J = 8.6, 8.6Hz), 8.01 ( 1H, br), 9.73 ( 1H,

br).

[0373]

Table 88

Absolute configuration

[0374]

Table 89

[0375] Table 90 Absolute configuration

Exa

mple R ⁵ R ⁶ R ⁷ R ⁸ R ⁹ 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

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 )

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

Exam

R ^{4 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, ^H y ^drochlonde 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

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

(1 H, br), 8.80-11.33 (3H, brm).

[0378]

Table 93

Absolute configuration

Absolute confi uration

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

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

[0381] Table 96 Absolute confi uration

[0382]

Table 97 Absolute confi uration

[0383]

Table 98

Absolute configuration

[0384]

Table 99

Absolute confi uration

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

(1H _f 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

(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

(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

[0386]

Table 101

Ab lute configuration

[0387]

Table 102

Absolute configuration

[0388]

Table 103

Absolute configuration

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).

[0389]

Table 104

Absolute configuration

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

[0391]

Table 106

absolute confi uration 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 = 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 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

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 Hz), 7.70 (1H, d, J = 8.9 Hz), 7.92 (1H, d, J =

9.0 Hz), 8.92-11.38 (1H, br).

[0393]

Table 108

Absolute confi uration

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,

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

(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

Exam

R ⁴ 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 =

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,

brm), 9.63-9.75 (1H, brm).

Absolute onfiguration

[0396] Table 111

Absolute confi uration

[0397]

Table 112

Absolute confi uration [0398]

Table 113

Absolute confi uration

[0399]

Table 114

Absolute configuration

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,

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,

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

[0401]

Table 116

Absolute confi uration

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),

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).

[0402]

Table 117

Absolute configuration

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£ ₎ ^"ύί _θ H, ^{2 H} y ^drochloride 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

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

( 1H, d, J = 5.4Hz ), 8.75-10.3 ( 2H, m ).

[0404]

Table 119

/ Absolute configuration

[0405]

Table 120 Relative confi uration

[0406]

Table 121

Absolute configuration

Exam

R ⁴ 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 =

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- 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

( 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 ).

Absolute configuration

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

= 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

( 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

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

= 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,

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

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

[0410]

Table 125

Absolute configuration

[0411]

Table 126

Absolute configuration

[0412]

Table 127

Absolute configuration

[0413]

Table 128 Absolute configuration

[0414]

Table 129

Absolute configuration

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

= 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 =

8.8 Hz), 7.67 (1H, d, J = 8.8 Hz), 9.56 (1H,

brs).

[0415]

Table 130

Absolute configuration

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 =

2.0 Hz), 7.63-7.70 (2H, m).

7.97 (1H, d, J = 1.8 Hz). (2H not found)

[0416] Table 131

Absolute configuration

[0417]

Table 132

Absolute configuration

Exam

R ⁴ NMR Salt pie.

brs).

[0418]

Table 133

Absolute configuration

Exam

R ⁴ 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,

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

Hz), 7.47 (1H, d, J = 2.0 Hz), 7.63-7.70 (2H,

m). [0419]

Table 134

Relative confi uration

[0420]

Table 134 Absolute configuration

[0421]

Table 135

Absolute configuration

Exam

R ⁴ 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 =

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

Exam

R ⁴ 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

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 =

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),

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

[0424]

Table 138

Absolute configuration

[0425]

Table 139

Absolute configuration

8.15 (1 H, d, J = 7.7 Hz). (3H, not found)

[0426]

Table 140

Absolute configuration

^E *Jf R ⁴ NMR Salt pie

[0427]

Table 141

Absolute configuration

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, 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

(1H, d, J = 8.8 Hz), 8.29 (1H, d, J = 8.3 Hz). [0428]

Table 142

Absolute configuration

(1 H, brs).

[0429]

Table 143

Absolute configuration 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 =

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),

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

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

(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

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

[0432]

Table 146

Absolute configuration

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 =

1.8 Hz), 8.14 (1H, d, J = 7.7 Hz). (3H,

not found)

[0433]

Table 147

Absolute configuration

[0434]

Table 148 Absolute configuration

[0435]

Table 149 Absolute confi uration

1175 -H -H -H -H 317

1176 -H Ύ VCH ₃ -H -H -H 327

N-o

1177 -H -H -H -H 314

1180 -H -H -H -H 344

1181 -H -H -H -H 357

CH ₃

1191 -OCH3 -OCH3 -H -H -H 305

1192 -H -H -0(CH2)2CH3 -H -H 303

1193 -H -H — N N-CH ₃ -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

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

1209 -CI -CF3 -H -H -H 347

1210 -H -H -CH2CH(CH3)2 -H -H 301

121 1 -CN -H -CI -H -H 304

[0436]

Absolute configuration

1222

1223

1224

Absolute configuration

1249 286 1258 330

1259 373

1260 326

[0438]

Absolute configuration

1285 282

W 201

1333 1334 vi 328

[0439]

[0440]

Absolute configuration

1425 315

?

[0441]

Absolute configuration

1470 335

[0443]

Absolute configuration

[0444]

[0445]

Table 159

Absolute configuration

[0446]

1549

1550

1551

1552

1553

1555

[0447]

[0448]

Absolute configuration 13057923

[0449] Table 163 Absolute configuration

Absolute configuration

[0451] Table 165 Absolute configuration

Absolute confi uration

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),

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),

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

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 (1H,

d, J = 9.2 Hz), 8.18-8.43 (1H, br), 9.96-10.22 ( H, br).

Table 167 Absolute confi uration

NMR Salt

No.

1H-NMR (DMSO-d6) 5ppm : 0.56-0.64 (2H, m), 0.68-0.76 (2H,

m), 1.14-1.29 (2H _r m), 1.34-1.47 (4H, m), 1.54 (3H, s),

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 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,

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 (1H,

dd, J = 1.2, 9.2 Hz), 8.15-8.44 (1H, br), 9.97-10.22 (1H, br).

Table 168 Absolute configuration

Example NMR Salt No.

1H-NMR <DMSO-d6) Bppm : 0.93-1.23(2H, m). 1.26-1.45 (5H,

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),

Hydrochloride

7.28 (2H. dd, J = 2.3, 8.8 Hz), 7.34 (1H, t, J = 74.0 Hz), 7.61

Table 169

^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

Hz), 6.91-6.97 (2H, m), 7.34-7.40 (2H, m).

Table 170 Absolute confi uration

Example R ⁴ 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

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),

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),

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 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).

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),

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

Example

R ⁴ 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

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

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),

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),

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).

.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

, 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,

3CH ₃ ³ m), 1.42-1.66 (6H, m), 1.66-1.77 (1H, m), 1.90-2.09 (1H, m),

1691 OCH ₂ CH ₃ 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).

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

9.60-9.75 (1H, br).

Table 172

Absolute confi uration

Example

No.

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

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,

1H-N R (DMSO-d6) δρριπ : 1.05-1.19 (1H, m). 1.19-1.40 (5H, , ,

Dihydrochloride

= 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

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 (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

R ⁴ 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),

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 (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

Hz), 8.90-9.15 (1H, br), 9.42-9.75 ( H, br).

Table 174

Absolute confi uration

Example R« NMR Salt No.

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

Hz), 6.92-8.96 (2H, m), 7.35-7.40 (2H, m).

Table 175 Absolute confi uration

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 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).

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

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

H-NMR (DMSO-d6) 5ppm : 1.15-1.29 (1H, m). 1.29-1.45 (5H,

1713 Dihydrochioride

(1H. m). 1H-NMR (D SO-de) δρριη : 1.02-1.16 (1H, m), 1.16-1.40

1714 Dihydrochloride

(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),

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 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 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

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 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 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 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),

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 , 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

Hz), 6.66 (1H, d, J = 8.3

Hz), 8.64 (1H, s).

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),

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),

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

Example

R N R Salt No.

(7H.

12.4

1731 54.5 DihydiOchloride

( H,

1H-N R (D SO-d6) 6ppm : 1.07-1.20 (1H, m). 1.22-1.41 (5H, , . .

1732 Dihydrochlonde

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

(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

= 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,

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 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 (1H _t brm). Table 178

Absolute configuration

Example

R ⁴ 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

(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

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 =

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),

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

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

(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 ^F F 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),

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),

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

(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

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 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

Example R ⁴ 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

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