1-(1h-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenyl propan-2-ol derivatives and related compounds as modulators of the norepinephrine (ne) and the serotonine (5-ht) activity and the monoamine reuptake for the treatment of vasomotor symptoms (vms)

[0001] This application claims priority to U.S. Application No. __ filed March 28,

2005, which reserves the benefits of U.S. Application No. 60 / 557,651 filed on March 30, 2004 and U.S. Application No. 60 / 569,863 filed on May 11, 2004.

FIELD OF THE INVENTION [0002] The present invention relates to phenylaminopropanol derivatives, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions ameliorated by monoamine reuptake, including, but not limited to, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal diseases and genitourinary diseases, chronic fatigue syndrome, fibromyalgia syndrome, nervous system diseases, and combinations thereof, and in particular disease states selected from the group consisting of recurrent depressive disorders, vasomotor symptoms, urinary incontinence and urgency urgency, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.

BACKGROUND OF THE INVENTION [0003] Vasomotor (VMS) symptoms, termed hot flushes and night sweats, are the most common symptoms associated with the period of menopause, occurring in 60% to 80% of all women after natural or surgically induced menopause. Symptoms of VMS are probably adaptive responses of the central nervous system (CNS) to decreasing sex steroid levels. To date, the most effective treatments for VMS symptoms are hormone-based treatments, including estrogens and / or certain progestins. Hormonal treatment is very effective in relieving VMS symptoms, but it is not suitable for all women. It is well known that VMS symptoms are caused by fluctuations in sex levels of steroids and can be disturbed and defective in both women and men. Hot flashes can last up to thirty minutes and vary in frequency from several times a week to repeated occurrences throughout the day. The patient experiences a hot flush as a sudden feeling of heat that quickly spreads from the face to the neck and back, and then throughout the rest of the body. He is usually accompanied by sudden heavy sweating. This can occur sometimes several times an hour, and often occurs at night. Hot flushes and sudden sweating during the night often cause sleep deprivation. Observed psychological and emotional symptoms such as nervousness, fatigue, irritation, insomnia, depression, memory loss, headaches, anxiety, nervousness or inability to concentrate are considered to be caused by sleep deficiencies resulting from hot flashes and night sweats (Kramer et al. , In: Murphy et al., 3rd Int'I Symposium on Recent Advances in Urological Cancer Diagnosis and Treatment-Proceedings, Paris, France: SCI: 3-7 (1992)).

[0004] Hot flashes can be even more dangerous in women treated for breast cancer for several reasons: 1) many survivors of breast cancer receive tamoxifen, whose most common side effect is hot flashes, 2) many women treated for breast cancer get premature menopause induced by chemotherapy, 3) women who have in theirs

History of breast cancer has generally been denied estrogen therapy because of the potential for breast cancer to recur (Loprinzi, et al., Lancet, 2000, 356 (9247): 2059-2063).

[0005] Men also experience hot flashes after withdrawal of the steroid hormone (androgen). This is the case with age-related decrease in androgen levels (Katovich, et al., Proceedings of the Society for Experimental Biology & Medicine, 1990, 193 (2): 129-35) as well as in extreme cases of hormone deprivation associated with prostate cancer treatment (Berendsen, et al., European Journal of Pharmacology, 2001, 419 (1): 47-54. As many as a third of these patients will persistently and often experience symptoms severe enough to cause significant discomfort and discomfort.

[0006] The exact mechanism of these symptoms is unknown, but they are generally thought to be disorders of normal homeostatic mechanisms controlling thermoregulation and vasomotor activity (Kronenberg et al., "Thermoregulatory Physiology of Menopausal Hot Flashes: A Review," Can. J. Physiol. Pharmacol., 1987, 65: 1312-1324).

[0007] The fact that estrogen treatment (for example, estrogen replacement therapy) relieves such symptoms is a link between these symptoms and an estrogen deficit. For example, menopausal condition in life is associated with a wide range of other acute symptoms as described above, and such symptoms are generally sensitive to estrogens.

[0008] It has been suggested that estrogens may stimulate the activity of both norepinephrine (NE) and / or serotonin (5-HT) systems (J. Pharmacology & Experimental Therapeutics, 1986, 236 (3) 646-652). It is hypothetically assumed that estrogens modulate NE and 5-HT levels by providing homeostasis at the hypothalamic thermoregulatory center. Descending pathways from the hypothalamus through the brainstem / spinal cord and adrenal glands to the skin are involved in maintaining normal skin temperature. The effects of NE and 5-HT reuptake inhibitors are known to collide in both CNS and peripheral nervous system (PNS). The pathophysiology of VMS symptoms is mediated by both central and peripheral mechanisms, and therefore interactions between CNS and PNS can count for the effectiveness of the SRI / NRI double action in the treatment of thermoregulation disorders. In fact, the physiological aspects and involvement of CNS / PNS in VMS symptoms may contribute to the lower doses proposed for the treatment of VMS (Loprinzi, et al., Lancet, 2000, 356: 2059-2063; Stearns et al., JAMA, 2003, 289: 2827-2834) compared to the doses used to treat behavioral aspects of depression. The interaction of CNS / PNS in the pathophysiology of VMS symptoms and the data presented in this document were used to support the claim that the norepinephrine system could be a target for the treatment of VMS symptoms.

[0009] Although the symptoms of VMS are most commonly treated with hormonal therapy (oral, transdermal, or via implants), some patients cannot tolerate estrogen treatment (Berendsen, Maturitas, 2000, 36 (3): 155-164, Fink et al., Nature, 1996, 383 (6598): 306). In addition, hormone replacement therapy is usually not recommended for women or men with or at risk of developing hormone sensitive cancers (e.g. breast or prostate cancer). Therefore, non-hormonal therapies (for example, fluoxetine, paroxetine [SRI] and clonidine) have been clinically evaluated. WO 99/44601 discloses a method of reducing hot flashes in women by administering fluoxetine. Other treatment options for hot flashes have been explored, including steroids, alpha-adrenergics

Agonists, and beta-blockers, with varying degrees of success (Waldinger et al., Maturitas, 2000, 36 (3): 165-168).

[0010] A receptors have been described₂Adrenergics play a role in thermoregulation impairment (Freedman et al., Fertility & Sterility, 2000, 74 (1): 20-3). Such receptors are located both pre-and post-synaptically and mediate an inhibitory role in the central and peripheral nervous system. There are four different adrenergic subtypes_α2 receptors, that is, a_2A, and_2B, and_2C and a_2D(Mackinnon et al., TIPS, 1994, 15: 119; French, Pharmacol. Ther., 1995, 68: 175). Non-selective antagonist a₂-adrenoceptor, yohimbine, causes strokes, and an α receptor agonist₂adrenergic, clonidine, soothes the effects of yohimbine (Katovich, et al., Proceedings of the Society by Experimental Biology & Medicine, 1990, 193 (2): 129-35, Freedman et al., Fertility & Sterility, 2000, 74 (1) : 20-3). Clonidine was used to treat hot flashes. However, the use of such treatment is associated with many undesirable side effects caused by the high doses needed to attenuate the hot flushes described herein and known in the art.

[0011] The presented complex multiple nature of thermoregulation and the interaction between CNS and PNS systems in maintaining thermoregulation homeostasis means that many therapies and approaches can be developed for the treatment of angioedema.

The present invention is directed to new compounds and compositions containing these compounds for these and other important applications.

BRIEF DESCRIPTION OF THE INVENTION [0012] The present invention relates to phenylaminopropanol derivatives, compositions containing such derivatives, and methods of their use for the prevention and treatment of conditions alleviated by monoamine reuptake including, but not limited to, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal diseases and genitourinary diseases, chronic fatigue syndrome, fibromyalgia syndrome, nervous system diseases, and combinations thereof, and in particular disease states selected from the group consisting of recurrent depressive disorders, vasomotor symptoms, urinary incontinence and urgency urgency, fibromyalgia, pain, diabetic neuropathy, and combinations thereof [0a0cj1i] In one embodiment, the present invention relates to compounds of formula ( AND):

<img file="PL1732887T3_D0001.tif" />

or their pharmaceutically acceptable salts;

in which formula:

a dotted line between Y and Z represents an optional double bond; the dotted line between the two R4 groups is an optional heterocyclic ring having 4 to 6 ring atoms which can be formed between the two R4 groups together with the nitrogen atom through which they are attached;

Y is N, CR6, or C = O;

Z is N, NR7, CR5, or C (R5) 2;

EP 1 732 887 B1

R1 is, independently at each occurrence, alkyl, alkoxy, halogen, CF3, OCF3, arylalkyloxy substituted with 0-3 R11, aryloxy substituted with 0-3 R11, aryl substituted with 0-3 R11, heteroaryl substituted with 0- 3 groups R11, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 groups R11, alkylsulfone, phenylsulfone substituted with 0-3 groups R11, alkylsulfonamide, phenylsulfonamide substituted with 0-3 R11, heteroaryloxy substituted with 0-3 R11, heteroarylmethyloxy substituted with 0-3 R11, alkylamido, or arylamido substituted with 0-3 R11; or two adjacent R1 groups are also methylenedioxy;

R2 is aryl substituted with 0-3 R1 or heteroaryl substituted with 0-3 R1;

R3 is H or C1-C4 alkyl;

R4 is, independently at each occurrence, H, C1-C4 alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl or cyclobutylmethyl, or two R4 groups, together with the nitrogen atom through which they are attached, form a heterocyclic ring having 4 to 6 atoms ring, where one carbon atom can optionally be replaced by N, O, S, or SO2, and wherein any ring carbon atom or additional N atom may be optionally substituted with C1-C4 alkyl, F, or CF3;

R5 is, independently at each occurrence, H, C1-C4 alkyl, aryl substituted with 0-3 R1, or cyano; or when two R5 groups are present, they form a carbocyclic ring having 3-7 carbon atoms;

R6 is H, C1-C4 alkyl or cyano;

R7 is H, C1-C6 alkyl, C3-C6 cycloalkyl, or aryl substituted with 0-3 R1;

R8 is H or C1-C4 alkyl;

R9 is H or C1-C4 alkyl;

R10 is, independently at each occurrence, H or C1-C4 alkyl; or R10 and R4 together with the nitrogen atom to which the R4 group is attached form a nitrogen containing ring having 3-6 carbon atoms;

n is an integer from 0 to 4; x is an integer from 1 to 2; and

R11 is alkyl, alkoxy, halogen, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R11 groups are also methylenedioxy;

with 1-3 carbon atoms in ring A may optionally be replaced by N.

[0014] In yet another embodiment, the present invention relates to compositions, comprising: a. At least one compound of formula (I); and b. at least one pharmaceutically acceptable carrier.

[0015] In another embodiment, the present invention relates to methods of treating or preventing ameliorated conditions by monoamine reuptake in subjects in need thereof, comprising the step of:

Administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Conditions relieved by monoamine reuptake include conditions selected from the group consisting of vasomotor symptoms, sexual dysfunctions, gastrointestinal diseases and urogenital diseases, chronic fatigue syndrome, fibromyalgia syndrome, nervous system diseases, and combinations thereof, in particular disease states selected from the group consisting of recurrent depressive disorders, angioedema symptoms, urinary incontinence and urgency urgency, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.

[0016] Methods of treating or preventing vasomotor symptoms in subjects in need thereof have been described, including the step of:

administering to the subject an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0017] Methods of treating or preventing depressive illness in subjects in need thereof have been described, comprising the step of:

administering to the subject an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0018] Methods of treating or preventing sexual dysfunction in subjects in need thereof have been described, including the step of:

administering to the subject an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0019] Methods of treating or preventing pain in subjects in need thereof have been described, comprising the step of:

administering to the subject an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0020] Methods of treating or preventing gastrointestinal or urogenital diseases, and in particular, urinary incontinence and urgency incontinence have been described in subjects in need thereof, comprising the step of: administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically useful acceptable salt.

[0021] Methods of treating or preventing chronic fatigue syndrome in individuals in need thereof have been described, comprising the step of:

administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0022] Methods of treating or preventing fibromyalgia syndrome in subjects in need thereof have been described, comprising the step of:

administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS [0023] The invention may be better understood from the following detailed description and attached

EP 1 732 887 B1 drawings, which form part of the present application.

[0024] Figure 1 shows the effect of estrogen on norepinephrine / serotonin mediated thermoregulation.

[0025] Figure 2 is a schematic representation of the interactions of norepinephrine and serotonin and their respective receptors (5-HT_2a, α₁ and a₂-adrenergiczny).

DETAILED DESCRIPTION OF THE INVENTION [0026] The present invention relates to phenylaminopropanol derivatives, compositions containing such derivatives, and methods of their use for the prevention and treatment of conditions alleviated by monoamine reuptake, including, but not limited to, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal diseases intestinal and urogenital diseases, chronic fatigue syndrome, fibromyalgia syndrome, nervous system diseases, and combinations thereof, and in particular disease states selected from the group consisting of recurrent depressive disorders, vasomotor symptoms, urinary incontinence and urgency urgency, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.

[0027] The following definitions are provided for a full understanding of the terms and abbreviations used herein.

[0028] As used herein and in the appended claims, the singular includes a reference to the plural when the context clearly does not show otherwise. Thus, for example, reference to the term "antagonist" also includes a plurality of such antagonists, and reference to the term "compound" means reference to one or more compounds and their equivalents known to those skilled in the art, and so on.

[0029] The abbreviations used in the description correspond to units of measure, techniques, properties or compounds, as follows: "min" means minute, "h" means hour (s), "μ oznacza" means micro liter (s), "ml "means milliliter (s)," mM "means millimolar," M "means molar," mmol "means millimole (s)," cm "means centimeter," SEM "means standard error of mean values ​​and" Sl "means international arrangement of units. "Δ^:Ό "and Δ" ED values₅₀ "means a dose that provides 50% relaxation of the condition or effect observed (average 50% maximum endpoint).

[0030] "Norepinephrine transporter" is abbreviated NET.

The "human norepinephrine transporter" is abbreviated as hNET.

The "serotonin transporter" is abbreviated SERT.

The "human serotonin transporter" is abbreviated as hSERT.

"Norepinephrine reuptake inhibitor" is abbreviated as NRI.

"Selective norepinephrine reuptake inhibitor" is abbreviated SNRI. "Serotonin reuptake inhibitor" is abbreviated as SRI.

"Selective serotonin reuptake inhibitor" is abbreviated SSRI. "Norepinephrine" is abbreviated as NE.

"Serotonin" is abbreviated as 5-HT.

"Subcutaneously" is abbreviated as sc.

"Intraperitoneal" is abbreviated as ip.

"Orally" is abbreviated as "after".

[0031] In the context of the present disclosure, many terms have been used. The term "treatment" as used herein includes prevention (e.g., prophylaxis), treatment or palliative treatment, and the term "treatment" as used herein also includes preventative, curative and palliative treatment.

[0032] The term "effective amount", as used herein, refers to an effective amount, at dosages, and for periods of time necessary to obtain the desired result in terms of preventing or treating vasomotor symptoms, depressive diseases, sexual dysfunction, or pain. In particular, with respect to vasomotor symptoms, an "effective amount" refers to an amount of a compound or compound composition that will increase norepinephrine levels to compensate for some or all of the lack of steroid availability in individuals affected by the vasomotor symptom. Different levels of hormones will affect the amount of compound required in the present invention. For example, a premenopausal state may require a lower level of compound due to higher hormone levels than a perimenopausal state.

[0033] It will be appreciated that the effective amount of components in the present invention will vary from patient to patient, not just for the particular compound, component or composition selected, route of administration, and component capacity (alone or in combination with one or more combination drugs). ) to elicit the desired response in individuals, but also with factors such as the disease state or severity of the disease state to be alleviated, hormone levels, age, sex, the weight of the subject, the patient's condition, and the severity of the pathological condition being treated, other treatment being used, or special diet followed by the patient, and other factors which will be recognized by one of skill in the art and ultimately the appropriate dose will depend on the attending physician. The dosage regimen can also be adjusted to provide an improved therapeutic response. Effective amount also means the amount at which any toxic or harmful effects of these components are balanced by achieving therapeutically beneficial effects.

[0034] Preferably, the compounds of the present invention are administered at a dose and for such a time that the number of hot flushes decreases compared to the number of hot flushes before starting treatment. Such treatment may also be beneficial for reducing the overall severity or intensity distribution of the hot flushes experienced, compared to the severity of the hot flushes before starting treatment. With respect to depressive diseases, sexual dysfunctions, and pains, the compounds of the present invention are administered at a dose and for such time that prevention, amelioration, or elimination of symptoms or conditions occurs.

[0035] For example, an affected patient, the compounds of formula (I), or pharmaceutically acceptable salts thereof, can be administered, preferably, at a dose of from about 0.1 mg / day to about 500 mg / day, with once or about twice a day, more preferably from about 1 mg / day to about 200 mg / day, and most preferably from about 1 mg / day to 100 mg / day, for a time sufficient to reduce and / or significantly eliminate the number and / or severity of the strokes hot, or symptoms or conditions of depressive illness, sexual dysfunction or pain.

[0036] The terms "component", "compound composition", "compound", "drug", or "agent

The pharmacologically active "or" active agent "or" medicament "are used interchangeably and refer to the compound or compounds or composition of the substance which, when administered to a subject (human or animal) produces the desired pharmacologically and / or physiologically effect by local and / or systemic action.

[0037] The terms "component", "drug" or "pharmacologically active agent" or "active agent" or "medicament" are used interchangeably and refer to a compound or compounds or compositions of substances which, when administered to the body (human or animal) ) produce the pharmacologically and / or physiologically desired effect through local and / or systemic action.

[0038] The term "modulation" refers to the ability to either increase or inhibit the functional properties of a biological activity or process, for example, receptor binding or signal activity. Such increase or inhibition may be conditioned by the occurrence of a specific event, such as activation of the transduction signal pathway, and / or may only be manifested in specific cell types. The modulator is also intended to include any compound, for example, an antibody, small molecule, peptide, oligopeptide, polypeptide or protein, preferably a small molecule or peptide.

[0039] As used herein, the term "inhibitor" refers to any agent that inhibits, suppresses, inhibits or reduces specific activity such as serotonin reuptake activity or norepinephrine reuptake activity.

[0040] The term "inhibitor" is intended to include any compound, for example an antibody, small molecule, peptide, oligopeptide, polypeptide or protein, preferably a small molecule or peptide that exhibits partial, complete, competitive and / or inhibitory effect on norepinephrine reuptake in mammals, preferably humans, either for both serotonin reuptake and norepinephrine reuptake, and thus reduce or block, preferably reduce, some or all biological effects of endogenous norepinephrine reuptake, or both serotonin reuptake and norepinephrine reuptake.

[0041] In the present invention, the compounds of formula (I) may be prepared in the form of pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic salts, and organic salts. Suitable inorganic salts include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethylene sulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, malic, maleic, mandelic, methanesulfonic, mucous, nitric 2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylic (embonic), pantothenic, phosphoric, amber, sulfuric, tartaric, p-toluenesulfonic, and the like. Hydrochloric, hydrobromic, phosphoric, and sulfuric acid are particularly preferred, and the hydrochloride salt is most preferred.

[0042] The term "administration" as used herein means both direct administration of a compound or composition of the present invention, or administration of a prodrug, derivative or analog that will form an equivalent amount of the active compound or substance in the body.

[0043] The term "subject" or "patient" refers to an animal, including a human species that is

Treated with the compositions and / or methods of the present invention. The term "subject" or "patient" is intended to refer to both males and females unless one of the sexes is specifically indicated. Accordingly, the term "patient" includes any mammal that may benefit from treating or preventing vasomotor symptoms, depressive illness, sexual dysfunction, or pain such as a human, especially when the mammal is a female, either in premenopausal, perimenopausal, or postmenopausal. In addition, the term patient includes female animals, including humans, and among humans, not only elderly women who have undergone menopause, but also women who have had surgery to remove the uterus or for some other reason have reduced estrogen production, as well as those who have undergone long-term administration of corticosteroids, suffering from Cushing's syndrome, or having gonadal dysgenesis (dysgenesis). However, the term "patient" is not intended to be limited to women.

[0044] The term "premature menopause" or "artificial menopause" refers to damage to the ovaries for an unknown cause that can occur before the age of 40 years. It may be associated with smoking, living high above sea level, or poor nutritional status. Artificial menopause may be the result of ovarian resection, chemotherapy, pelvic radiation, or any process that damages ovarian blood supply.

[0045] The term "premenopausal" means the period before menopause, the term "perimenopausal" means the period during menopause, and the term "postmenopausal" means the period after menopause. "Owarectomy" means the removal of an ovary or ovaries, and may be carried out in accordance with Merchenthaler et al., Maturitas, 1998, 30 (3): 307-316.

[0046] The term "side effect" refers to a consequence other than the one (s) for which the agent or measure was used, such as the harmful effects produced by the drug, especially in a tissue or organ other than the one that was to benefit from its administration. In this case, for example, with a high dose of NRI or NRI / SRI alone, the term "side effect" may refer to conditions such as, for example, vomiting, nausea, sweating, and headache (Janowsky, et al. ., Journal of Clinical Psychiatry, 1984, 45 (10 Pt 2): 3-9).

[0047] The term "alkyl," as used herein, refers to an optionally substituted, saturated straight chain, branched or cyclic hydrocarbon having from about 1 to about 20 carbon atoms (and in all combinations and sub-combinations of ranges and the specified number of carbon atoms), preferably from about 1 to about 8 carbon atoms, and even more preferably from about 1 to about 4 carbon atoms, hereinafter referred to as "lower alkyl". Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclopentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclohexyl, cyclooctyl , adamantyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

[0048] The term "perfluorinated alkyl," as used herein, refers to alkyl, as defined above, in which the hydrogen atoms directly attached to the carbon atoms are completely replaced by fluorine atoms.

[0049] The term "alkenyl," as used herein, refers to an alkyl group with at least two carbon atoms having one or more double bonds, in which alkyl is as defined herein

EP 1 732 887 B1 defined. Alkenyl groups may be optionally substituted.

[0050] The term "alkynyl," as used herein, refers to an alkyl group with at least two carbon atoms having one or more triple bonds, in which alkyl is as defined herein. Alkynyl groups may be optionally substituted.

[0051] The term "aryl" as used herein refers to an optionally substituted, mono-, di-, tri-, or other multicyclic aromatic ring system having from about 5 to about 50 carbon atoms (and in all combinations and sub-combinations of ranges and defined number of carbon atoms), preferably from about 6 to about 10 carbon atoms. Non-limiting examples include, for example, phenyl, naphthyl, anthracenyl, and phenantrenyl.

[0052] The term "heteroaryl," as used herein, refers to an optionally substituted, mono-, di-, tri-, or other multicyclic aromatic ring system that includes at least one, and preferably from 1 to about 4 heteroatoms as atoms ring, selected from sulfur, oxygen and nitrogen. Heteroaryl groups may have, for example, from about 3 to about 50 carbon atoms (and in all combinations and sub-combinations of ranges and a specific number of carbon atoms), preferably from about 4 to about 10 carbon atoms. Non-limiting examples of heteroaryl groups include, for example, pyril, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isilazolofuryl, , purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.

[0053] The term "heterocyclic ring," as used herein, refers to a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring that is saturated, partially unsaturated or unsaturated (aromatic), and which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, and including any bicyclic group in which any of the above defined heterocyclic rings are fused to a benzene ring.

The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring can be attached to its side group on any heteroatom or carbon atom to give a stable structure. The heterocyclic rings described herein may be substituted on a carbon atom or on a nitrogen atom if the resulting compound is stable. If specifically indicated, the nitrogen in the heterocycle may optionally be quaternized. This is advantageous if the total number of S and O atoms in the heterocycle exceeds one, then such heteroatoms are not adjacent to each other. This is advantageous when the total number of S and O atoms in the heterocycle means no more than one. Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H, 6H1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidinyl, 4aH-carbazole, 4H-quinolizinyl, 6H -1,2,5 thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzisothiazolyl, benzimazazolyl, α-carbazolyl, α-carbazolyl chromanyl, chromenyl, cininyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolurl, isobenzyl, isobenzyl isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,

EP 1 732 887 B1

1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylpyrimidinyl, phenantridinyl, phenanthrolinyl, phenoxazinyl, phenynyl, phenothiazinyl, phenoxatinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinyl pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1, 3,4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isathinyl.

Also included are fused rings and spiro compounds containing, for example, the above heterocycles.

[0054] The term "alkoxy," as used herein, refers to the group RO- where R is an alkyl group as defined herein.

[0055] The term "aryloxy," as used herein, refers to the group RO- where R is an aryl group, as defined herein.

[0056] The term "heteroaryloxy," as used herein, refers to the group RO- where R is a heteroaryl group, as defined herein.

[0057] The term "alkanoyloxy," as used herein, refers to the RC (= O) -O- moiety where R is an alkyl group having 1 to 5 carbon atoms.

[0058] The term "alkylsulfoxide," as used herein, refers to the group -S (= O) -R, where R is alkyl as defined above.

[0059] The term "alkylsulfone," as used herein, refers to the group -S (= O) 2-R, where R is alkyl as defined above.

[0060] The term "alkylsulfonamide," as used herein, refers to the -NR-S (= O) 2-R moiety, where each R is independently alkyl as defined above, or the NR part may also be NH.

[0061] The term "phenylsulfonamide," as used herein, refers to the -NR-S (= O) 2-phenyl moiety, where R is H or alkyl, as defined above.

[0062] The term "heteroarylmethyloxy," as used herein, refers to the group -OCH2-R, where R is heteroaryl, as defined above.

[0063] The term "alkylamido," as used herein, refers to the -NR-C (= O) -R moiety, where each R is independently, alkyl as defined above, or the NR part may also be NH.

[0064] The term "phenylamido," as used herein, refers to the group -NR-C (= O) -phenyl, where R is H or alkyl, as defined above.

[0065] The term "halogen," as used herein, refers to chlorine, bromine, fluorine, and iodine.

[0066] In one embodiment, the present invention relates to compounds of formula (I):

EP 1 732 887 B1

<img file="PL1732887T3_D0002.tif" />

or their pharmaceutically acceptable salts;

in which formula:

a dotted line between Y and Z represents an optional double bond; the dotted line between the two R4 groups is an optional heterocyclic ring having 4 to 6 ring atoms, which can be formed between the two R4 groups together with the nitrogen atom through which they are attached;

Y is N, CR6, or C = O;

Z is N, NR7, CR5, or C (R5) 2;

R1 is, independently at each occurrence, alkyl, alkoxy, halogen, CF3, OCF3, arylalkyloxy substituted with 0-3 R11, aryloxy substituted with 0-3 R11, aryl substituted with 0-3 R11, heteroaryl substituted with 0- 3 groups R11, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 groups R11, alkylsulfone, phenylsulfone substituted with 0-3 groups R11, alkylsulfonamide, phenylsulfonamide substituted with 0-3 R11, heteroaryloxy substituted with 0-3 R11, heteroarylmethyloxy substituted with 0-3 R11, alkylamido, or arylamido substituted with 0-3 R11; or two adjacent R1 groups are also methylenedioxy;

R2 is aryl substituted with 0-3 R1 or heteroaryl substituted with 0-3 R1;

R3 is H or C1-C4 alkyl;

R4 is, independently at each occurrence, H, C1-C4 alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl or cyclobutylmethyl, or two R4 groups, together with the nitrogen atom through which they are attached, form a heterocyclic ring having 4 to 6 atoms ring, where one carbon atom can optionally be replaced by N, O, S, or SO2, and wherein any ring carbon atom or additional N atom may be optionally substituted with C1-C4 alkyl, F, or CF3;

R5 is, independently at each occurrence, H, C1-C4 alkyl, aryl substituted with 0-3 R1, or cyano; or when two R5 groups are present, they form a carbocyclic ring having 3-7 carbon atoms;

R6 is H, C1-C4 alkyl or cyano;

R7 is H, C1-C6 alkyl, C3-C6 cycloalkyl, or aryl substituted with 0-3 R1;

R8 is H or C1-C4 alkyl;

R9 is H or C1-C4 alkyl;

R10 is, independently at each occurrence, H or C1-C4 alkyl; or R10 and R4 together with the nitrogen atom to which the R4 group is attached form a nitrogen-containing ring

Having 3-6 carbon atoms; n is an integer from 0 to 4; x is an integer from 1 to 2; and

R11 is alkyl, alkoxy, halogen, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R11 groups are also methylenedioxy;

with 1-3 carbon atoms in ring A may optionally be replaced by N.

The dotted line in the condensed ring to ring A is an optional double bond between the Y and Z substituents. The dotted line between two R4 groups is an optional heterocyclic ring having 4 to 6 ring atoms, which can be formed between two R4 groups, together with the nitrogen atom, which they are attached.

[0067] In certain preferred embodiments of the compounds of formula (I), Y is N. In certain other preferred embodiments, Y is CR6, preferably CH. In certain other preferred embodiments, Y is C = O.

[0068] In certain more preferred embodiments, Z is N. In certain preferred embodiments of compounds of formula (I), Z is NR7. In certain other more preferred embodiments, Z is CR5. In still some other more preferred embodiments, Z is C (R5) 2. In some even more preferred embodiments, Z is CH, C (CH3), or

C (CN).

[0069] In certain preferred embodiments of the compounds of formula (I), R1 is, independently at each occurrence, alkyl, preferably C1-C4 alkyl, more preferably methyl. In certain other preferred embodiments, R1 is, independently at each occurrence, alkoxy. In certain other preferred embodiments of the compounds, R1 is, independently at each occurrence, halogen, preferably F or Cl. In certain other preferred embodiments, R1 is, independently at each occurrence, CF3. In certain other preferred embodiments, R1 is, independently at each occurrence, OCF3. In some other preferred embodiments,

R1 is, independently at each occurrence, benzyloxy substituted with 0-3 of R1. In certain other preferred embodiments, R1 is, independently at each occurrence,₁ aryloxy substituted with 0-3 R groups¹. In certain other preferred embodiments, R1 is, independently at each occurrence, aryl substituted with 0-3 of the R1 group. In certain other preferred embodiments, R1 is, independently at each occurrence, heteroaryl substituted with 0-3 of the R1 group. In certain other preferred embodiments, R1 is, independently at each occurrence, hydroxy. In certain other preferred embodiments, R1 is, independently at each occurrence, alkanoyloxy. In certain other preferred embodiments, R 1 is, independently at each occurrence, a methylenedioxy moiety. In certain other preferred embodiments, R1 is, independently at each occurrence, nitro. In certain other preferred embodiments, R1 is, independently at each occurrence, nitrile. In certain other preferred embodiments, R1 is, independently at each occurrence, alkenyl. In certain other preferred embodiments, R1 is, independently at each occurrence, alkynyl. In certain other preferred embodiments, R1 is, independently at each occurrence, alkylsulfoxide. In certain other preferred embodiments, R1 is, independently at each occurrence, phenyl sulfoxide substituted with 0-3 of the R1 group. In some other preferred 13

EP 1 732 887 B1

0-3 groups R1. In certain other preferred embodiments, R1 is, independently at each occurrence, alkylsulfone. In certain other preferred embodiments, R1 is, independently at each occurrence, phenylsulfone substituted with 0-3 of the R1 group. In certain other preferred embodiments, R1 is, independently at each occurrence, alkylsulfonamide. In certain other preferred embodiments, R1 is, independently at each occurrence, phenylsulfonamide substituted with 0-3 of the R1 group. In certain other preferred embodiments, R1 is, independently at each occurrence, heteroaryloxy substituted with 0-3 of the R1 group. In certain other preferred embodiments, R1 is, independently at each occurrence, heteroarylmethyloxy substituted with 0-3 R1. In certain other preferred embodiments, R1 is, independently at each occurrence, alkylamido. In certain other preferred embodiments, R1 is, independently at each occurrence, phenylamido substituted with 0-3 of the R1 group.

[0070] In certain preferred embodiments of the compounds of formula (I), R2 is aryl substituted with 0-3 of R1, preferably unsubstituted with R1. In certain preferred embodiments, R2 is naphthyl substituted with 0-3 of R1, preferably unsubstituted with R1. In certain preferred embodiments, R2 is heteroaryl substituted with 0-3 of R1, preferably unsubstituted with R1.

[0071] In certain preferred embodiments of the compounds of formula (I), R3 is H. In certain other preferred embodiments, R3 is C1-C4 alkyl, preferably C1 alkyl.

[0072] In certain preferred embodiments of the compounds of formula (I), R4 is, independently at each occurrence, H. In some preferred embodiments, R4 is, independently at each occurrence, C1-C4 alkyl, preferably C1-C3 alkyl, more preferably methyl, ethyl, isopropyl. In certain preferred embodiments of compounds of formula (I), R4 is, independently at each occurrence, benzyl. In some preferred embodiments, R4 is, independently at each occurrence, heteroarylmethyl. In some preferred embodiments, R4 is, independently at each occurrence, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl.

[0073] In certain preferred embodiments of the compounds of formula (I), two R4 groups, together with the nitrogen atom through which they are attached, form a heterocyclic ring having from 4 to 6 ring atoms, where one carbon atom may be optionally replaced by N, O, S, or SO2, and wherein any ring carbon or additional N may be optionally substituted with C1-C4 alkyl, F, or CF3. In some more preferred embodiments, the two R4 groups, together with the nitrogen atom through which they are attached, form a pyridine, piperidine, piperazine, piperazine ring substituted with a methyl group, or a morpholine ring.

[0074] In certain preferred embodiments of the compounds of formula (I), R5 is, independently at each occurrence, H. In certain preferred embodiments, R5 is, at each occurrence, C1-C4 alkyl, preferably methyl. In some preferred embodiments of the compounds, R5 is, independently at each occurrence, aryl substituted with 0-3 of the R1 group, preferably phenyl, tolyl or xylyl. In some preferred embodiments, R5 is, independently at each occurrence, cyano.

[0075] In certain preferred embodiments of the compounds of formula (I) when two substituents are present

R5, they form a carbocyclic ring having 3-7 carbon atoms, preferably cyclopentyl or cyclohexyl.

[0076] In certain preferred embodiments of compounds of formula (I), R6 is, independently at each occurrence, H. In certain preferred embodiments of compounds, R6 is, at each occurrence, C1-C4 alkyl, preferably methyl. In some preferred embodiments, R6 is, independently at each occurrence, cyano.

[0077] In certain preferred embodiments of the compounds of formula (I), R7 is, independently at each occurrence, H. In certain preferred embodiments, R7 is, independently at each occurrence, C1-C6 alkyl, preferably C1-C4 alkyl, more preferably, methyl. In certain preferred embodiments of the compounds, R7 is, independently at each occurrence, C3-C6 cycloalkyl, preferably, cyclopentyl or cyclohexyl. In some preferred embodiments of the compounds, R5 is, independently at each occurrence, aryl substituted with 0-3 of the R1 group, preferably phenyl, tolyl or xylyl.

[0078] In certain preferred embodiments of compounds of formula (I), R8 is, independently at each occurrence, H. In certain preferred embodiments of compounds, R8 is, at each occurrence, C1-C4 alkyl, preferably methyl.

[0079] In certain preferred embodiments of the compounds of formula (I), R9 is, independently at each occurrence, H. In certain preferred embodiments, R9 is, at each occurrence, C1-C4 alkyl, preferably methyl.

[0080] In certain preferred embodiments of the compounds of formula (I), R10 is, independently at each occurrence, H. In certain preferred embodiments of compounds, R10 is, independently at each occurrence, C1-C4 alkyl, preferably methyl. In certain preferred embodiments of the compounds of formula (I), R10 and R4 together with the nitrogen atom to which the R4 group is attached form a nitrogen containing ring having 3-6 carbon atoms, especially, pyrrolidinyl, pyrrolyl, piperidinyl, pyridinyl, azepanyl, and azepinyl .

[0081] In certain preferred embodiments of the compounds of formula (I), n is an integer from 0 to 3. More preferably, n is 0 to 2. Even more preferably, n is 0 to 1. Even more preferably, n is 0.

[0082] In certain preferred embodiments of the compounds of formula (I), x is an integer from 1 to 2. More preferably, x is 1.

[0083] In certain preferred embodiments of the compounds of formula (I), 1-2 ring carbon atoms

A may optionally be replaced by N. In certain preferred embodiments of the compounds, one carbon atom in ring A may optionally be replaced by N. In certain preferred embodiments, none of the carbon atoms in ring A is replaced by N.

[0084] In certain preferred embodiments of the compounds of formula (I),

Y is N, CR6, or C = O;

Z is N, NR7, CR5, or C (R5) 2;

R1 is, independently at each occurrence, alkyl, alkoxy, halogen, CF3, OCF3, arylalkyloxy substituted with 0-3 R11, aryloxy substituted with 0-3 R11, aryl substituted with

EP 1 732 887 B1

0-3 R11 groups, heteroaryl substituted with 0-3 R11 groups, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 groups R11 'alkylsulfone, phenylsulfone substituted with 0-3 groups R11, alkylsulfonamide phenylsulfonamide substituted with 0-3 R11, heteroaryloxy substituted with 0-3 R11, heteroarylmethyloxy substituted with 0-3 R11, alkylamido, or arylamido substituted with 0-3 R11; or two adjacent R1 groups are also methylenedioxy;

R2 is aryl substituted with 0-3 R1, or heteroaryl substituted with 0-3 R1;

R3 is H;

R4 is, independently at each occurrence, H or C1-C4 alkyl;

R5 is, independently at each occurrence, H, C1-C4 alkyl, aryl substituted with 0-3 R1, or cyano; or when two R5 groups are present, they form a carbocyclic ring having 3-7 carbon atoms;

R6 is H, C1-C4 alkyl or cyano;

R7 is H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl substituted with 0-3 R1;

R8 is H;

R9 is H;

R10 is H;

n is an integer from 0 to 4;

x is 1;

R11 is alkyl, alkoxy, halogen, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R11 groups are also methylenedioxy;

wherein 1-3 carbon atoms in ring A may optionally be replaced by N.

[0085] In certain preferred embodiments of the compounds of formula (I),

Y is CR6;

Z is CR5;

R1 is, independently at each occurrence, alkyl, alkoxy, halogen, CF3, OCF3, arylalkyloxy substituted with 0-3 R11, aryloxy substituted with 0-3 R11, aryl substituted with 0-3 R11, heteroaryl substituted with 0- 3 groups R11, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 groups R11, alkylsulfone, phenylsulfone substituted with 0-3 groups R11, alkylsulfonamide, phenylsulfonamide substituted with 0-3 R11, heteroaryloxy substituted with 0-3 R11, heteroarylmethyloxy substituted with 0-3 R11, alkylamido, or arylamido substituted with 0-3 R11; or two adjacent R1 groups are also methylenedioxy;

R2 is aryl substituted with 0-3 R1 or heteroaryl substituted with 0-3 R1;

R3 is H or C1-C4 alkyl;

R4 is, independently at each occurrence, H, C1-C4 alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl;

R5 is, independently at each occurrence, H, C1-C4 alkyl, aryl substituted with 0-3 R1, or cyano; or when two R5 groups are present, they form a carbocyclic ring having 3-7

EP 1 732 887 B1 carbon atoms;

R6 is H, C1-C4 alkyl or cyano;

R7 is H, C1-C6 alkyl, C3-C6 cycloalkyl, or aryl substituted with 0-3 R1;

R8 is H or C1-C4 alkyl;

R9 is H or C1-C4 alkyl;

R10 is, independently at each occurrence, H or C1-C4 alkyl; or R10 and R4, together with the nitrogen atom to which R4 is attached, form a nitrogen containing ring having 3-6 carbon atoms;

n is an integer from 0 to 4;

x is an integer from 1 to 2; and

R11 is alkyl, alkoxy, halogen, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R11 groups are also methylenedioxy;

wherein 1-3 carbon atoms in ring A may optionally be replaced by N.

[0086] In certain preferred embodiments of the compounds of formula (I),

Y is CR6;

Z is C (R5) 2;

R1 is, independently at each occurrence, alkyl, alkoxy, halogen, CF3, OCF3, arylalkyloxy substituted with 0-3 R11, aryloxy substituted with 0-3 R11, aryl substituted with 0-3 R11, heteroaryl substituted with 0- 3 groups R11, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 groups R11, alkylsulfone, phenylsulfone substituted with 0-3 groups R11, alkylsulfonamide, phenylsulfonamide substituted with

0-3 R11 groups, heteroaryloxy substituted with 0-3 R11 groups, heteroarylmethyloxy substituted with 0-3 R11 'alkylamido groups, or arylamido substituted with 0-3 R11 groups; or two adjacent R11 groups are also methylenedioxy;

R2 is aryl substituted with 0-3 R1 or heteroaryl substituted with 0-3 R1;

R3 is H or C1-C4 alkyl;

R4 is, independently at each occurrence, H, C1-C4 alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl;

R5 is, independently at each occurrence, H, C1-C4 alkyl, aryl substituted with 0-3 R1, or cyano; or when two R5 groups are present, they form a carbocyclic ring having 3-7 carbon atoms;

R6 is H, C1-C4 alkyl or cyano;

R7 is H, C1-C6 alkyl, C3-C6 cycloalkyl, or aryl substituted with 0-3 R1;

R8 is H or C1-C4 alkyl;

R9 is H or C1-C4 alkyl;

R10 is, independently at each occurrence, H or C1-C4 alkyl; or R10 and R4, together with the nitrogen atom to which the R4 group is attached, form a nitrogen containing ring having 3-6 carbon atoms;

n is an integer from 0 to 4;

X is an integer from 1 to 2; and

R11 is alkyl, alkoxy, halogen, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R11 groups are also methylenedioxy;

wherein 1-3 carbon atoms in ring A may optionally be replaced by N.

[0087] In certain preferred embodiments of the compounds of formula (I),

Y is C = O;

Z is C (R5) 2;

R1 is, independently at each occurrence, alkyl, alkoxy, halogen, CF3, OCF3, arylalkyloxy substituted with 0-3 R11, aryloxy substituted with 0-3 R11, aryl substituted with 0-3 R11, heteroaryl substituted with 0- 3 groups R11, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 groups R11, alkylsulfone, phenylsulfone substituted with 0-3 groups R11, alkylsulfonamide, phenylsulfonamide substituted with 0-3 R11, heteroaryloxy substituted with 0-3 R11, heteroarylmethyloxy substituted with 0-3 R11, alkylamido, or arylamido substituted with 0-3 R11; or two adjacent R1 groups are also methylenedioxy;

R2 is aryl substituted with 0-3 R1 or heteroaryl substituted with 0-3 R1;

R3 is H or C1-C4 alkyl;

R4 is, independently at each occurrence, H, C1-C4 alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl;

R5 is, independently at each occurrence, H, C1-C4 alkyl, aryl substituted with 0-3 R1, or cyano; or when two R5 groups are present, they form a carbocyclic ring having 3-7 carbon atoms;

R6 is H, C1-C4 alkyl or cyano;

R7 is H, C1-C6 alkyl, C3-C6 cycloalkyl, or aryl substituted with 0-3 R1;

R8 is H or C1-C4 alkyl;

R9 is H or C1-C4 alkyl;

R10 is, independently at each occurrence, H or C1-C4 alkyl; or R10 and R4, together with the nitrogen atom to which the R4 group is attached, form a nitrogen containing ring having 3-6 carbon atoms;

n is an integer from 0 to 4;

x is an integer from 1 to 2; and

R11 is alkyl, alkoxy, halogen, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R11 groups are also methylenedioxy;

wherein 1-3 carbon atoms in ring A may optionally be replaced by N.

[0088] In certain preferred embodiments of the compounds of formula (I),

Y is C = O;

Z is NR7;

R1 is, independently at each occurrence, alkyl, alkoxy, halogen, CF3, OCF3, arylalkyloxy

EP 1 732 887 B1 substituted with 0-3 R11, aryloxy substituted with 0-3 R11, aryl substituted with 0-3 R11, heteroaryl substituted with 0-3 R11, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R11 groups, alkylsulfone, phenylsulfone substituted with 0-3 R11 groups, alkylsulfonamide, phenylsulfonamide substituted with 0-3 R11 groups, heteroaryloxy substituted with 0-3 R11 groups, heteroarylmethyloxy substituted with 0-3 R11, alkylamido, or arylamido substituted with 0-3 R11; or two adjacent R11 groups are also methylenedioxy;

R2 is aryl substituted with 0-3 R1 or heteroaryl substituted with 0-3 R1;

R3 is H or C1-C4 alkyl;

R4 is, independently at each occurrence, H, C1-C4 alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl;

R5 is, independently at each occurrence, H, C1-C4 alkyl, aryl substituted with 0-3 R1, or cyano; or in the case where two R5 substituents are present, they may form a C3-C7 carbocyclic ring;

R6 is H, C1-C4 alkyl or cyano;

R7 is H, C1-C6 alkyl, C3-C6 cycloalkyl, or aryl substituted with 0-3 R1;

R8 is H or C1-C4 alkyl;

R9 is H or C1-C4 alkyl;

R10 is, independently at each occurrence, H or C1-C4 alkyl; R10 is, independently at each occurrence, H or C1-C4 alkyl; or R10 and R4, together with the nitrogen atom to which the R4 group is attached, form a nitrogen containing ring having 3-6 carbon atoms; n is an integer from 0 to 4;

x is an integer from 1 to 2; and

R11 is alkyl, alkoxy, halogen, CF3, OCF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R11 groups are also methylenedioxy;

wherein 1-3 carbon atoms in ring A may optionally be replaced by N.

[0089] Preferred compounds of formula (I) include:

1- (1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) -1-phenylpropan-2-ol;

1- (5-fluoro-1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) -1-phenylpropan-2-ol;

1- (1H-indol-1-yl) -3-morpholin-4-yl-1-phenylpropan-2-ol;

3- (dimethylamino) -1- (1H-indol-1-yl) -1-phenylpropan-2-ol;

3- (ethylamino) -1- (1H-indol-1-yl) -1-phenylpropan-2-ol;

1- (1H-indol-1-yl) -3- (isopropylamino) -1-phenylpropan-2-ol;

3- (benzylamino) -1- (1H-indol-1-yl) -1-phenylpropan-2-ol;

3 - [(cyclohexylmethyl) amino] -1- (1H-indol-1-yl) -1-phenylpropan-2-ol;

3 - [(cyclohexylmethyl) amino] -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

3- (isopropylamino) -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

3- (ethylamino) -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

EP 1 732 887 B1

1- (1H-indol-1-yl) -1-phenyl-3-piperazin-1-yl-propan-2-ol;

1- (1H-indol-1-yl) -1-phenyl-3 - [(pyridin-4-ylmethyl) amino] propan-2-ol;

1- (5-chloro-1H-indol-1-yl) -1-phenyl-3-piperidin-1-yl-propan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

3-amino-1- (1 H-indol-1-yl) -1-phenylpropan-2-ol;

3- (ethylamino) -1- (5-fluoro-1H-indol-1-yl) -1-phenylpropan-2-ol;

3-amino-1- (5-fluoro-1H-indol-1-yl) -1-phenylpropan-2-ol;

1- (5-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

3- (methylamino) -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

3-amino-1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

3- [ethyl (methyl) amino] -1- (1H-indo) -1-yl) -1-phenylpropan-2-ol;

1- (5-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (5-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-1-ol;

1- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indole-3-carbonitrile;

1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

3- (methylamino) -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

1- (3-chlorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

1- (4-chlorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1- (3- (trifluoromethoxy) phenyl] propan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1- [2- (trifluoromethoxy) phenyl] propan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1- [2- (trifluoromethoxy) phenyl] propan-2-ol;

1- (2-chlorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1- (4- (trifluoromethoxy) phenyl] propan-2-ol;

4-amino-1- (3-chlorophenyl) -1- (1H-indol-1-yl) butan-2-ol;

1- (3-bromophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

3- [2-hydroxy-1- (1H-indol-1-yl) -3- (methylamino) propyl] benzonitrile;

1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- [3- (3-methylphenyl) -1H-indol-1-yl] propan-2-ol;

1- (4-fluorophenyl) -3- (methylamino) -1- (3-methyl-1H-indol-1-yl) propan-2-ol;

1- (2-fluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

1- (4-fluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

Of 1- (1H-indol-1-yl) -3- (methylamino) -1- (3-methylphenyl) propane-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol;

3- (ethylamino) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) propan-2-ol;

EP 1 732 887 B1

1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3-morpholin-4-yl-propan-2-ol;

1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- (propylamino) propan-2-ol;

1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) propan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1- (4-methylphenyl) propan-2-ol;

1- (2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- [3- (2-methylphenyl) -1H-indol-1-yl] propan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- (2-methyl-2,3-dihydro-1H-indol-1-yl) propan-2-ol;

1- (7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

3- (methylamino) 1- (7-methyl-2,3-dihydro-1H-indol-1-yl) -1-phenylpropan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- (7-methyl-2,3-dihydro-1H-indol-1-yl) propan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- (5-methyl-2,3-dihydro-1H-indol-1-yl) propan-2-ol;

1- (1-H-indol-1-yl) -1- (3-methoxyphenyl) -3- (methylamino) propan-2-ol;

1- (1H-indol-1-yl) -1- (4-methoxyphenyl) -3- (methylamino) propan-2-ol;

3- (methylamino) -1- (2-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

1- (1H-benzimidazol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

3- (methylamino) -1- (2-methyl-1H-benzimidazol-1-yl) -1-phenylpropan-2-ol;

1- (4-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (5-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (5-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (7-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (4-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (6-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (5-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (3-fluorophenyl) -1- (6-methoxy-1H-indol-1-yl) -3- (methylamino) propan-2-ol;

3- (methylamino) -1-phenyl-1- (1H-pyrrolo [2,3-b] pyridin-1-yl) propan-2-ol;

1- (5-chloro-2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

3- (methylamino) -1-phenyl-1- (1H-pyrrolo [2,3-c] pyridin-1-yl) propan-2-ol;

1- (5-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

3- (methylamino) -1- (3-fluorophenyl) -1- (1H-pyrrolo [2,3-c] pyridin-1-yl) propan-2-ol;

1- (5-chloro-2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

3- (methylamino) -1- (6-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

3- (methylamino) -1- (7-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- (5-methyl-1H-indol-1-yl) propan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- (7-methyl- 1H-indol-1-yl) propan-2-ol;

3- (methylamino) -1- (4-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

3- (methylamino) -1- (5-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- (4-methyl-1H-indol-1-yl) propan-2-ol;

1- (3-ethyl-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

EP 1 732 887 B1

1- (3-fluorophenyl) -3- (methylamino) -1- (3-phenyl-1H-indol-1-yl) propan-2-ol;

7-fluoro-1- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

1- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

7-fluoro-1- [1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

1- (1H-indol-1-yl) -3- (methylamino) -1- (2-thienyl) propan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1- (2-thienyl) propan-2-ol;

1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indol] -2' (1'H) -one;

2- (3-fluorophenyl) -2- (1H-indo) -1-yl) -1 - [(2S) -pyrrolidin-2-yl] ethanol;

2- (3-fluorophenyl) -2- (1H-indol-1-yl) -1- [pyrrolidin-2-yl] ethanol;

1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclobutane-1,3'-indol] -2' (1'H) -one;

1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclopentane-1,3'-indol] -2' (1'H) -one;

1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclopropane-1,3'-indol] -2' (1'H) -one;

5-fluoro-1- [2-hydroxy-3- (methylamino) -1-phenylpropyl-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

3- (cyclopropylamino) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) propan-2-ol;

7'-fluoro-1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indol] -2' (1'H) -one;

5'-bromo-1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indol] -2' (1'H) -one;

1- (3-fluorophenyl) -1- [3- (2-fluorophenyl) -1H-indol-1-yl] -3- (methylamino) propan-2-ol;

1- [3- (3,4-dichlorophenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (3-fluorophenyl) -1- [3- (3-fluorophenyl) -1H-indol-1-yl] -3- (methylamino) propan-2-ol;

1- (5-fluoro-3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

3-amino-1- (5-fluoro-3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

1- (5-chloro-3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

3-amino-1- (5-chloro-3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

[3- (5-chloro-3-methyl-1H-indol-1-yl) -2-methoxy-3-phenylpropyl] methylamine;

1- (7-chloro-3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

[3- (5-fluoro-3-methyl-1H-indol-1-yl) -2-methoxy-3-phenylpropyl] methylamine;

1- (4-bromo-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (4-bromo-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propane-2-ol;

1- (5-bromo-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (5-bromo-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indole-4-carbonitrile;

1- (6-bromo-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indole-5-carbonitrile;

1- [1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1H-indole-4-carbonitrile;

1- (6-bromo-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (6-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

3-amino-1- (3-fluorophenyl) -1- (1H-indol-1-yl) propan-2-ol;

1- (7-bromo-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (1H-indol-1-yl) -3- (methylamino) -1- [3- (trifluoromethyl) phenyl] propan-2-ol;

EP 1 732 887 B1

1- (3-fluorophenyl) -3- (methylamino) -1-spiro [cyclohexane-1,3'-indol] -1 '(2' H) -yl-propan-2-ol;

1- (2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1- [3- (trifluoromethyl) phenyl] propan-2-ol;

1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

1- (3,4-difluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- (3-methyl-1H-indol-1-yl) propan-2-ol;

1- (4-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (6-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (7-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (7-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (4-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (6-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (5-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (5-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (3-isopropyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (3-fluorophenyl) -1- (3-isopropyl-1H-indol-1-yl) -3- (methylamino) propan-2-ol;

1- (3,5-difluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

1- (3,5-difluorophenyl) -1- (2,3-dihydro-1H-indol-1-yl) -3- (methylamino) propan-2-ol;

4-amino-1- (3-fluorophenyl) -1- (1H-indol-1-yl) butan-2-ol;

1- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (3,5-difluorophenyl) -1- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3- (methylamino) propan-2-ol;

1- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- (3-methyl-2,3-dihydro-1H-indol-1-yl) propan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1-spiro [cyclopentane-1,3'-indol] -1 '(2' H) -yl-propan-2-ol;

1- (3-fluorophenyl) -1- [3- (4-methoxyphenyl) -1H-indol-1-yl] -3- (methylamino) propan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- [3- (4-methylphenyl) -1H-indol-1-yl] propan-2-ol;

1- [3- (4-tert-butylphenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (3-fluorophenyl) -1- [3- (3-methoxyphenyl) -1H-indol-1-yl] -3- (methylamino) propan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- {3- [4- (trifluoromethyl) phenyl) -1H-indol-1-yl} propan-2-ol;

1- (3,5-difluorophenyl) -1- (6-fluoro-2,3-dihydro-1H-indol-1-yl) -3- (methylamino) propan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- {3- [2- (trifluoromethyl) phenyl] -1H-indol-1-yl} propan-2-ol;

1- (3-fluorophenyl) -1- [3- (2-methoxyphenyl) -1H-indol-1-yl] -3- (methylamino) propan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- {3- [3- (trifluoromethyl) phenyl] -1H-indol-1-yl} propan-2-ol;

3-amino-1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

1- (7-fluoro-3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

3-amino-1- (7-fluoro-3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

1- (7-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (4-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1- (7-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (4-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (3-fluorophenyl) -3- (methylamino) -1- [5- (trifluoromethyl) -1H-indol-1-yl] propan-2-ol;

EP 1 732 887 B1

1- (6-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

3- (methylamino) -1-phenyl-1- [6- (trifluoromethyl) -1H-indol-1-yl] propan-2-ol;

3- (methylamino) -1-phenyl-1- [5- (trifluoromethyl) -1H-indol-1-yl] propan-2-ol;

1- (3-tert-butyl-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- (1H-indol-1-yl) -2-methyl-3- (methylamino) -1-phenylpropan-2-ol;

3- (1H-indol-1-yl) -1- (methylamino) -3-phenyl-butan-2-ol;

1-tert-butyl-3- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -3-propyl-1,3-dihydro-2H-benzimidazol-2-one;

5-bromo-1- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

6-fluoro-1- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

4-fluoro-1- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

1-cyclobutyl-3- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one;

5-fluoro-3- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1-propyl-1,3-dihydro-2H-benzimidazol-2-one;

1-ethyl-3- [1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1,3-dihydro-2H-benzimidazol-2-one;

1-ethyl-3- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one;

4-fluoro-3- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one;

1-cyclopentyl-3- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -3-isopropyl-1,3-dihydro-2H-benzimidazol-2-one;

3- [3- (ethylamino) -2-hydroxy-1-phenylpropyl] -5-fluoro-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -3-methyl-1,3-dihydro-2H-benzimidazol-2-one;

1-ethyl-5-fluoro-3- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one;

1-ethyl-4-fluoro-3- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one;

4-fluoro-3- [1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1-isopropyl-1,3-dihydro-2Hbenzymidazol-2-one;

1-ethyl-4-fluoro-3- [2-hydroxy-3- (methylamino) -1- (3-fluorophenyl) -propyl] -1,3-dihydro-2Hbenzymidazol-2-one;

1- [1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

1- [3- (2,3-difluorophenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1- [3- (2-chlorophenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; and their pharmaceutically acceptable salts, in particular the hydrochloride and dihydrochloride salts.

[0090] In particular, preferred compounds of formula (I) include:

(1 RS, 2SR) -1- (1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -1- (5-fluoro-1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -1- (1H-indol-1-yl) -3-morpholin-4-yl-1-phenylpropan-2-ol;

(1 RS, 2SR) -3- (dimethylamino) -1- (1H-indol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -3- (ethylamino) -1- (1H-indol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -1- (1H-indol-1-yl) -3- (isopropylamino) -1-phenylpropan-2-ol;

(1 RS, 2SR) -3- (benzylamino) -1- (1H-indol-1-yl) -1-phenylpropan-2-ol;

(1RS, 2SR) -3 - [(cyclohexylmethyl) amino] -1- (1H-indol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -3 - [(cyclohexylmethyl) amino] -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -3- (isopropylamino) -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1 RS, 2SR) -3- (ethylamino) -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -1- (1H-indol-1-yl) -1-phenyl-3-piperazin-1-yl-propan-2-ol;

(1 RS, 2SR) -1- (1H-indol-1-yl) -1-phenyl-3 - [(pyridin-4-ylmethyl) amino] propan-2-ol;

(1 RS, 2SR) -1- (5-chloro-1H-indol-1-yl) -1-phenyl-3-piperidin-1-yl-propan-2-ol;

(1RS, 2RS) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1 RS, 2SR) -3-amino-1- (1H-indol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -3- (ethylamino) -1- (5-fluoro-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -3-amino-1- (5-fluoro-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -1- (5-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1 RS, 2SR) -3- (methylamino) -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1R, 2S) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1 RS, 2SR) -3-amino-1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -3- [ethyl (methyl) amino] -1- (1H-indol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -1- (5-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1RS, 2RS) -1- (5-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-1-ol;

1 - [(1 RS, 2SR) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indole-3-carbonitrile;

(1R, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2S) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -3- (methylamino) -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1S, 2R) -1- (3-chlorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (4-chlorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- [3- (trifluoromethoxy) phenyl] propan-2-ol;

(1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- [2- (trifluoromethoxy) phenyl] propan-2-ol;

(1R, 2S) -1- (1H-indol-1-yl) -3- (methylamino) -1- [2- (trifluoromethoxy) phenyl] propan-2-ol;

(1S, 2R) -1- (2-chlorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

(1SR, 2RS) -1- (1H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol;

(1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol;

(1R, 2S) -1- (1H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol;

(1S, 2R) -4-amino-1- (3-chlorophenyl) -1- (1H-indol-1-yl) butan-2-ol (1S, 2R) -1- (3-bromophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

3 - [(1S, 2R) -2-hydroxy-1- (1H-indol-1-yl) -3- (methylamino) propyl] benzonitrile;

(1S, 2R) -1- (3-fluorophenyl) -1- (1H-indo) -1-yl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [3- (3-methylphenyl) -1H-indol-1-yl] propan-2-ol;

(1S, 2R) -1- (4-fluorophenyl) -3- (methylamino) -1- (3-methyl-1H-indol-1-yl) propan-2-ol;

(1S, 2R) -1- (2-fluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (4-fluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (3-methylphenyl) propan-2-ol;

(1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol;

(1R, 2S) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol;

(1S, 2R) -3- (ethylamino) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3-morpholin-4-yl-propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- (propylamino) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) propan-2-ol;

(1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (4-methylphenyl) propan-2-ol;

(1S, 2R) -1- (2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [3- (2-methylphenyl) -1H-indol-1-yl] propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -l- (2-methyl-2,3-dihydro-1H-indol-1-yl) propan-2-ol;

(1S, 2R) -1- (7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol ;

(1S, 2R) -1- (7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -3- (methylamino) -1- (7-methyl-2,3-dihydro-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (7-methyl-2,3-dihydro-1H-indol-1-yl) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (5-methyl-2,3-dihydro-1H-indol-1-yl) propan-2-ol;

(1S, 2R) -1- (1H-indol-1-yl) -1- (3-methoxyphenyl) -3- (methylamino) propan-2-ol;

(1SR, 2RS) -1- (1H-indol-1-yl) -1- (4-methoxyphenyl) -3- (methylamino) propan-2-ol;

(1 RS, 2SR) -3- (methylamino) -1- (2-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -1- (1H-benzimidazol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1 RS, 2SR) -3- (methylamino) -1- (2-methyl-1H-benzimidazol-1-yl) -1-phenylpropan-2-ol;

(1 RS, 2SR) -1- (4-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (5-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (5-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (7-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (4-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (6-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1 RS, 2SR) -1- (5-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -1- (6-methoxy-1H-indol-1-yl) -3- (methylamino) propan-2-ol;

(1S, 2R) -3- (methylamino) -1-phenyl-1- (1H-pyrrolo [2,3-b] pyridin-1-yl) propan-2-ol;

(1S, 2R) -1- (5-chloro-2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -3- (methylamino) -1-phenyl-1- (1H-pyrrolo [2,3-c] pyridin-1-yl) propan-2-ol;

(1S, 2R) -1- (5-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -3- (methylamino) -1- (3-fluorophenyl) -1- (1H-pyrrolo [2,3-c] pyridin-1-yl) propan-2-ol;

(1S, 2R) -1- (5-chloro-2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -3- (methylamino) -1- (6-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1S, 2R) -3- (methylamino) -1- (7-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (5-methyl-1H-indol-1-yl) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (7-methyl-1H-indol-1-yl) propan-2-ol;

(1S, 2R) -3- (methylamino) -1- (4-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1S, 2R) -3- (methylamino) -1- (5-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (4-methyl-1H-indol-1-yl) propan-2-ol;

(1S, 2R) -1- (3-ethyl-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (3-phenyl-1H-indol-1-yl) propan-2-ol;

7-fluoro-1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

7-fluoro-1 - [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one ;

(1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2-thienyl) propan-2-ol;

(1R, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2-thienyl) propan-2-ol;

1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indol] -2' (1'H) -one;

(1S, 2R) -2- (3-fluorophenyl) -2- (1H-indol-1-y) -1 - [(2S) -pyrrolidin-2-yl] ethanol;

(1R, 2S) -2- (3-fluorophenyl) -2- (1H-indol-1-yl) -1 - [(2S) -pyrrolidin-2-yl] ethanol;

1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclobutane-1,3'-indol] -2' (1'H) -one;

1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclopentane-1,3'-indol] -2' (1'H) -one;

1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclopropane-1,3'-indol] -2' (1'H) -one;

5-fluoro-1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

(1S, 2R) -3- (cyclopropylamino) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) propan-2-ol;

7'-fluoro-1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indol] -2' (1'H) -one;

5'-bromo-1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indol] -2' (1'H) -one;

(1S, 2R) -1- (3-fluorophenyl) -1- [3- (2-fluorophenyl) -1H-indol-1-yl] -3- (methylamino) propan-2-ol;

(1S, 2R) -1- [3- (3,4-dichlorophenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -1- [3- (3-fluorophenyl) -1H-indol-1-yl] -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (5-fluoro-3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1 S *, 2 R *) - 3-amino-1- (5-fluoro-3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1S, 2R) -1- (5-chloro-3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -3-amino-1- (5-chloro-3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

[(2R, 3S) -3- (5-chloro-3-methyl-1H-indol-1-yl) -2-methoxy-3-phenylpropyl] methylamine;

(1S, 2R) -1- (7-chloro-3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

[(2R, 3S) -3- (5-fluoro-3-methyl-1H-indol-1-yl) -2-methoxy-3-phenylpropyl] methylamine;

(1S, 2R) -1- (4-bromo-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (4-bromo-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (5-bromo-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (5-bromo-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indole-4-carbonitrile;

(1S, 2R) -1- (6-bromo-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indole-5-carbonitrile;

1 - [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1H-indole-4-carbonitrile;

(1S, 2R) -1- (6-bromo-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (6-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -3-amino-1- (3-fluorophenyl) -1- (1H-indol-1-yl) propan-2-ol;

(1S, 2R) -1- (7-bromo-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- [3- (trifluoromethyl) phenyl] propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1-spiro [cyclohexane-1,3'-indol] -1 '(2' H) -yl-propan-2-ol;

(1S, 2R) -1- (2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1- [3- (trifluoromethyl) phenyl] propan-2-ol;

(1S, 2S) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3,4-difluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (3-methyl-1H-indol-1-yl) propan-2-ol;

(1S, 2R) -1- (4-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (6-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (7-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (7-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (4-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (6-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (5-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (5-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3-isopropyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -1- (3-isopropyl-1H-indol-1-yl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3,5-difluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3,5-difluorophenyl) -1- (2,3-dihydro-1H-indol-1-yl) -3- (methylamino) propan-2-ol;

(1S, 2R) -4-amino-1- (3-fluorophenyl) -1- (1H-indol-1-yl) butan-2-ol;

(1S, 2R) -1- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3,5-difluorophenyl) -1- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3- (methylamino) propan-2-ol ;

(1S, 2R) -1- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (3-methyl-2,3-dihydro-1H-indol-1-yl) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1-spiro [cyclopentane-1,3'-indol] -1 '(2' H) -yl-propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -1- [3- (4-methoxyphenyl) -1H-indol-1-yl] -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [3- (4-methylphenyl) -1H-indol-1-yl] propan-2-ol;

(1S, 2R) -1- [3- (4-tert-butylphenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -1- [3- (3-methoxyphenyl) -1H-indol-1-yl] -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- {3- [4- (trifluoromethyl) phenyl] -1H-indol-1-yl} propan-2-ol;

(1S, 2R) -1- (3,5-difluorophenyl) -1- (6-fluoro-2,3-dihydro-1H-indol-1-yl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- {3- [2- (trifluoromethyl) phenyl] -1H-indo) -1-yl} propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -1- [3- (2-methoxyphenyl) -1H-indol-1-yl] -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- {3- [3- (trifluoromethyl) phenyl] -1H-indol-1-yl} propan-2-ol;

(1S, 2R) -3-amino-1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1S, 2R) -1- (7-fluoro-3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -3-amino-1- (7-fluoro-3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol;

(1S, 2R) -1- (7-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (4-fluoro-1H-indol-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -1- (7-fluoro-1-H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (4-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [5- (trifluoromethyl) -1H-indol-1-yl] propan-2-ol;

(1S, 2R) -1- (6-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol;

(1S, 2R) -3- (methylamino) -1-phenyl-1- [6- (trifluoromethyl) -1H-indol-1-yl] propan-2-ol;

(1S, 2R) -3- (methylamino) -1-phenyl-1- [5- (trifluoromethyl) -1H-indol-1-yl] propan-2-ol;

(1S, 2R) -1- (3-tert-butyl-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- (1H-indol-1-yl) -2-methyl-3- (methylamino) -1-phenylpropan-2-ol;

(2R, 3S) -3- (1H-indol-1-yl) -1- (methylamino) -3-phenyl-butan-2-ol;

1-tert-butyl-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one;

1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3-propyl-1,3-dihydro-2H-benzimidazol-2-one;

5-bromo-1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

6-fluoro-1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

4-fluoro-1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

1-cyclobutyl-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzymidazol2-one;

5-Fluoro-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1-propyl-1,3-dihydro-2Hbenzymidazol-2-one;

1-ethyl-3 - [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1,3-dihydro-2Hbenzymidazol-2-one;

1-ethyl-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one;

4-Fluoro-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1-isopropyl-1,3-dihydro-2Hbenzymidazol-2-one;

1-Cyclopentyl-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzymidazol2-one;

1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3-isopropyl-1,3-dihydro-2H-benzimidazol-2-one;

3 - [(1S, 2R) -3- (ethylamino) -2-hydroxy-1-phenylpropyl] -5-fluoro-1-isopropyl-1,3-dihydro-2H29

Benzimidazol-2-one;

1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3-methyl-1,3-dihydro-2H-benzimidazol-2-one;

1-ethyl-5-fluoro-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2Hbenzymidazol-2-one;

1-ethyl-4-fluoro-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2Hbenzymidazol-2-one;

4-Fluoro-3 - [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one;

1-ethyl-4-fluoro-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1- (3-fluorophenyl) -propyl] -1,3-dihydro-2Hbenzymidazol-2-one;

1 - [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one;

(1S, 2R) -1- [3- (2,3-difluorophenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol;

(1S, 2R) -1- [3- (2-chlorophenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; and their pharmaceutically acceptable salts, in particular their hydrochloride and dihydrochloride salts.

[0091] Certain compounds of the present invention may contain chiral centers, and such compounds may exist as stereoisomers (e.g. enantiomers). The present invention includes all such stereoisomers and any mixtures thereof, including racemic mixtures.

Racemic mixtures of stereoisomers as well as substantially pure stereoisomers are within the scope of the invention. The term "substantially pure" as used herein means that at least about 90 mole%, more preferably at least about 95 mole%, and most preferably at least about 98 mole% of the desired stereoisomer relative to other possible stereoisomers is present. Preferred enantiomers may be separated from the racemic mixture by any method known to those skilled in the art, including high performance liquid chromatography (HPLC), and by formation and crystallization of chiral salts, or by preparation as described herein. See, for example, Jacques, et al., Enantiomers, Racematics and Resolutions (Wiley

Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron, 33: 2725 (1977); Eliel, EL

Stereochemistry of Carbon Compounds, (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving

Agents and Optical Resolutions, page. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre

Dame, in 1972).

[0092] The present invention includes prodrugs of compounds of formula (I). The term "prodrug," as used herein, means a compound that is converted in vivo by metabolic means (e.g., by hydrolysis) to a compound of formula (I). Various forms of prodrugs are known in the art, for example as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al. (Ed).

"Design and Application of Prodrugs," Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Deliver Reviews, 1992, 8: 1-38, Bundgaard, J. of Pharmaceutical Sciences, 1988, 77: 285 et seq .; and Higuchi and Stella (eds.) Prodrugs as Novel Drug

Delivery Systems, American Chemical Society (1975).

[0093] In addition, compounds of formula (I) may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, solvated forms are considered equivalent to form 30

EP 1 732 887 B1 to the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

[0094] The compounds of the present invention can be prepared by a variety of routes well known to those skilled in the art. The compounds may be synthesized, for example by the methods described below, or variations thereof that will be apparent to those skilled in the art. All processes disclosed in connection with the present invention are considered suitable for use at any scale, including milligrams, grams, multigrams, kilograms, multi-kilograms, or commercially on an industrial scale.

[0095] As is readily understood, the functional groups depicted may include protecting groups during synthesis. Protecting groups are known per se as chemical functional groups that can be selectively attached to and removed from functional groups such as hydroxyl groups and carboxyl groups. Such groups exist in a chemical compound to render a given functionality inert under the chemical reaction conditions of the compound. Any of a variety of protecting groups may be used in the present invention. Protecting groups that can be used in accordance with the present invention can be described in Greene, TW and Wuts, PGM, Protective Groups in Organic Synthesis 2nd Edition, Ed., Wiley &amp; Sons, 1991.

[0096] The compounds of the present invention are preferably prepared as described below, and specific examples. Changing substituents are as defined for formula (I), unless otherwise stated. The reagents used to prepare the compounds of this invention may be either commercially available or may be prepared by standard procedures described in the literature. In accordance with the present invention, the compounds of formula (I) are prepared by following the reaction schemes below (Schemes I-IV). [0097] The compounds of the present invention contain chiral centers, providing various stereoisomeric forms, such as enantiomeric mixtures, as well as optical isomers. Individual optical isomers can be produced directly by asymmetric and / or stereospecific syntheses, or by conventional chiral isolation of optical isomers from an enantiomeric mixture.

[0098] The compounds of the present invention are preferably prepared according to the following general description and specific examples. The substituents used herein have the meanings as defined for formula (I), unless otherwise stated. The reagents used to prepare the compounds of the present invention may be either commercially available or may be prepared by standard procedures described in the literature. In accordance with the present invention, compounds of formula (I) are prepared according to the following reaction schemes (Schemes I-IV). [0099] The compounds of the present invention contain chiral centers, providing various stereoisomeric forms, such as enantiomeric mixtures, as well as optical isomers. Individual optical isomers can be produced directly by asymmetric and / or stereospecific syntheses, or by conventional chiral isolation of optical isomers from an enantiomeric mixture.

[0100] In accordance with the present invention, compounds of formula (I) are prepared according to the following

EP 1 732 887 B1 reaction schemes (Schemes I to IV). Depending on the desired diastereomer, the compounds can be prepared by two different synthetic routes (A and B, Schemes I and II). If it is desired to synthesize compounds of formula Ia, they can be prepared from compounds of formula 4 by selectively converting the primary alcohol into a leaving group and replacing it with the desired amine. (Route A, Scheme I). Any conventional methods for selectively converting a primary alcohol into a leaving group, and any conventional methods for replacing the primary leaving group with an amine may be used for this transformation. According to a preferred embodiment of the present invention, the diol of formula 4 is treated with para-toluenesulfonyl chloride in pyridine to form the tosylate of formula 5 which is converted to the compound of formula la by treatment with an excess of an alcoholic amine solution, either at room temperature or with heating to temperature about 40 ° C to about 80 ° C in a closed pipe. Compounds of formula Ia may be converted into pharmaceutically acceptable salts by any conventional method.

<img file="PL1732887T3_D0003.tif" />

Where: A, Y, Z, R1, n, R2, R4, R8, R9, R10 have the meanings as previously defined;

R³ = C1-C4 lower alkyl;

P = protecting group; preferably trimethylsilyl, tert-butyldimethylsilyl, para-nitrobenzoyl; and OTs = para-toluenesulfonate, or any conventional leaving group.

[0101] If it is desired to prepare compounds of formula I-aa, they may be prepared from compounds of formula 4 by selective protection of the primary alcohol followed by alkylation of the secondary alcohol, and removal of the primary alcohol protecting group. Any conventional protecting groups for primary alcohol and any methods for selectively protecting primary alcohol can be used in this transformation. According to a preferred embodiment of the present invention, the reaction is carried out at low temperature in dichloromethane with trimethylsilyl chloride and triethylamine as a base to form compounds of formula 6. Alkylation of the secondary alcohol can be carried out by any conventional method of alkylating the secondary alcohols found in the literature. According to favorable

Of the secondary alcohols found in the literature. According to a preferred embodiment of the present invention, the compounds of formula 6 are reacted with an alkyl halide using sodium hydride as a base for the preparation of compounds of formula 8 from which the protecting groups can be removed for the preparation of compounds of formula 9 by any conventional methods for removing protective groups from primary alcohol. According to a preferred embodiment of the present invention, the compounds of formula 8 are treated with a dilute aqueous solution of hydrochloric acid or trifluoroacetic acid in dichloromethane to prepare compounds of formula 9. Conversion of the primary alcohol to compounds of formula 9 to complete the synthesis of compounds of formula I-aa can be carried out as previously described for the synthesis of compounds of formula Ia. Compounds of formula I-aa may be converted into pharmaceutically acceptable salts by any conventional method.

[0102] Alternatively, compounds of formula 10 may be prepared directly from compounds of formula 5. Any method of alkylating a hydroxyl group in the presence of a tosyl group may be used for this transformation. According to a preferred embodiment of the present invention, the compounds of formula 5 are treated with an alkyl triflate, e.g. methyl triflate, in the presence of a spatially expanded base, e.g. 2,6-di-tert-butyl-4-methylpyridine. The reaction can be carried out either at room temperature or with heating to a temperature of about 40 ° C to about 80 ° C. Compounds of formula 10 can be converted to compounds of formula I-aa as previously described for the synthesis of compounds of formula Ia. Compounds of formula I-aa may be converted into pharmaceutically acceptable salts using any conventional method.

[0103] If desired for the preparation of compounds Ib, they can also be prepared from compounds of formula 4 by route B (Scheme II). This route involves the selective protection of the primary alcohol followed by the conversion of the secondary alcohol into a leaving group. Any conventional methods for selectively protecting a primary alcohol, and any conventional methods for converting a secondary alcohol into a leaving group can be used for this transformation. According to a preferred embodiment of the present invention, compounds of formula 4 are treated with para-nitrobenzoyl chloride in pyridine at low temperature (preferably below about 0 ° C) to prepare compounds of formula 11. Compounds of formula 11 can be converted to a secondary mesylate of formula 12 by reaction with methanesulfonyl chloride in dichloromethane using triethylamine as a base. The reaction is preferably carried out at temperatures between about -15 ° C and about 10 ° C. Removal of the primary alcohol protecting group in compounds of Formula 12 allows for the formation of a primary epoxide in the SN2 reaction which results in inversion of the stereocenter. Any conventional methods for removing primary alcohol protecting groups, and any conventional methods for forming epoxides on an alpha leaving group may be used for this transformation. According to a preferred embodiment of the present invention, the compounds of formula 12 are treated with an aqueous solution of a suitable base in an organic solvent, preferably an aqueous solution of sodium hydroxide in dioxane. The obtained epoxide of formula 13 can be subjected to a regioselective ring-opening reaction with an amine to give the desired amino alcohol of formula

EP 1 732 887 B1

b. Any conventional regioselective ring primary epoxide ring opening method can be used for this transformation. According to a preferred embodiment of the present invention, the compounds of formula 13 are treated with an excess of an alcoholic amine solution in a closed flask, either at room temperature or with heating to a temperature of about 40 ° C to about 90 ° C. Compounds of formula Ib can be converted into pharmaceutically acceptable salts by conventional methods.

<img file="PL1732887T3_D0004.tif" />

Where: A, Y, Z, R1, n, R2, and R4, R8, R10 have the meanings as previously defined;

R9 is H;

PNB = para-nitrobenzoyl, or any conventional protecting group; and OMs = methanesulfonate, or any conventional leaving group.

[0104] If desired for the preparation of compounds of formula I-bb, they may be prepared from compounds of formula Ib by protecting the amine, alkylating the secondary alcohol and removing the amine protecting group (Scheme III). Any conventional methods for protecting the amine, alkylating the secondary alcohol, and removing the amine protecting group can be used for this transformation. According to a preferred embodiment of the present invention, compounds of formula Ib are treated with boc anhydride, where boc = tert-butoxycarbonyl, for the preparation of compounds of formula 14 that can be alkylated with an alkyl halide using sodium hydride as the base for the preparation of compounds of formula 15. The removal of the protecting group is carried out with an acid, preferably trifluoroacetic acid in dichloromethane, for the preparation of compounds of formula Ibb which can be converted into pharmaceutically acceptable salts using conventional methods.

Diagram III

EP 1 732 887 B1

<img file="PL1732887T3_D0005.tif" />

Where: A, Y, Z, R1, n, R2, and R4, R8, R10 are as previously described;

R9 is H;

R3 = C1-C3 lower alkyl, P = protecting group, preferably tert-butoxycarbonyl.

[0105] Compounds of formula 4 are prepared by a regio- and stereo-selective ring-opening reaction of an appropriately substituted epoxy of formula 17 (prepared by epoxidation of a suitably substituted allyl alcohol) with an appropriately substituted compound of formula 16 (Scheme IV). Any conventional regio- and stereo-selective epoxy ring opening methods can be used for this transformation. According to a preferred embodiment of the present invention, compounds of formula 16 are treated with a base, e.g., sodium hydride, sodium tert-butoxide, potassium hydroxide, potassium tert-butoxide, or potassium hydroxide, followed by treatment with an epoxide of formula 17. An epoxide of formula 17 it may have been previously treated with Lewis acid, for example, titanium iso-propoxide, boron trifluoride, etc. to ensure regio-selective ring opening. The reaction occurs at room temperature and lasts about 2 hours to about 72 hours. Alternatively, compounds of formula 16 that are nucleophilically suitable, e.g., indoline, can be heated with the epoxide of formula 17 at temperatures from about 50 ° C to about 170 ° C to prepare compounds of formula 4.

[0106] Epoxidation of trans-allyl alcohols can be carried out either racemically or asymmetrically using methods described in the literature. According to a preferred embodiment of the present invention, racemic epoxidation is carried out with either peracetic acid or meta-chloroperbenzoic acid. If desired to produce one enantiomer of the compounds of formula (I), the asymmetric epoxidation of allyl alcohol can be carried out with tert-butyl hydroperoxide or cumene hydroperoxide in the presence of the corresponding tartaric ester, titanium (IV) isopropoxide, and molecular sieves. This method is well known in the literature (for example, KB Sharpless, et al., J. Org. Chem. 1986, 51, 3710). Compounds of formula 16 and starting allyl alcohols are either available from commercial sources or are available by methods well known in the literature.

Diagram IV

EP 1 732 887 B1

<img file="PL1732887T3_D0006.tif" />

Where: A, Y, Z, R1, n, R8, R9, R10 and R2 have the meanings as previously given.

[0107] In other embodiments, the invention relates to pharmaceutical compositions, including:

a. at least one compound of formula (I) or a pharmaceutically acceptable salt thereof; and b. at least one pharmaceutically acceptable carrier.

In general, the compound of formula (I), or a pharmaceutically acceptable salt thereof, will be present in an amount of from about 0.1%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition. Preferably, the compound of formula (I), or a pharmaceutically acceptable salt thereof, will be present in an amount of at least about 1% by weight based on the total weight of the pharmaceutical composition. More preferably, the compound of formula (I), or a pharmaceutically acceptable salt thereof, will be present in an amount of at least about 5% by weight based on the total weight of the pharmaceutical composition. Even more preferably, the norepinephrine reuptake inhibitor or a pharmaceutically acceptable salt thereof will be present in an amount of at least about 10% by weight based on the total weight of the pharmaceutical composition. Even more preferably, the compound of formula (I), or a pharmaceutically acceptable salt thereof, will be present in an amount of at least about 25% by weight based on the total weight of the pharmaceutical composition.

[0108] Such compositions are prepared according to acceptable pharmaceutical procedures, such as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985). Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable.

[0109] The compounds of the present invention may be administered orally or parenterally, alone or in combination with conventional pharmaceutical carriers. Suitable solid carriers may include one or more substances that may also act as flavoring, lubricating, solubilizing, suspending, bulking, polishing, compaction, tabletting or disintegrating agents or encapsulating material. In powders, the carrier is a finely ground solid that mixes with the finely ground active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary properties for compression in appropriate proportions and pressed to the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable constants

Carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

[0110] Liquid carriers can be used to prepare solutions, suspensions, emulsions, syrups, and elixirs. The active ingredient of the present invention may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of the two, either in pharmaceutically acceptable oils or in fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizing agents, emulsifiers, buffers, preservatives, sweeteners, flavors, suspending agents, thickeners, dyes, viscosity regulators, stabilizers, or osmo regulators. Examples of liquid carriers suitable for oral and parenteral administration include water (in particular containing additives as defined above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (for example, fractionated coconut oil and peanut oil). For parenteral administration, the carrier may also be an oil ester such as ethyl oleate and isopropyl myristate. Sterile carriers are used in sterile liquid forms of the composition for parenteral administration.

[0111] Liquid pharmaceutical compositions that are sterile solutions or suspensions may be administered, for example by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Oral administration can be in the form of a liquid or solid composition.

[0112] Preferably the pharmaceutical composition is in unit dosage form, for example as tablets, capsules, powders, solutions, suspensions, emulsions, granules or suppositories. In such form, the composition is divided into unit doses containing appropriate quantities of the active ingredient; unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, filled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in the package.

[0113] In another embodiment of the invention, the compounds useful in the present invention may be administered to mammals with one or more other pharmaceutically active agents, such as agents used to treat any other medical condition in mammals. Examples of such pharmaceutically active agents include pain relieving agents, anti-vascular agents, anti-cancer agents, anti-diabetic agents, anti-infective agents, or gastrointestinal agents, or combinations thereof.

[0114] One or more other pharmaceutically active agents may be administered in a therapeutically effective amount simultaneously (such as singly, at the same time, or together in a pharmaceutical composition), and / or sequentially with one or more compounds of the present invention.

[0115] The term "combination therapy" refers to the administration of two or more

Therapeutic agents or compounds for the treatment of the therapeutic condition or disease described in the present disclosure, for example hot flushes, sweat, conditions or diseases associated with thermoregulation, or other. Such administration includes the use of each type of therapeutic agent in a consistent manner. In both cases, the treatment regimen will provide beneficial effects of the drug combination in the treatment of the conditions or diseases described herein.

[0116] The route of administration may be any route that effectively transports the active compound of formula (I), or a pharmaceutically acceptable salt thereof, to a suitable or desired site of action, such as orally, through the nose, into the lungs, through the skin, such as through passive delivery either by iontophoresis or parenterally, for example rectally, by depot, subcutaneous, intravenous, into the urethra, intramuscularly, intranasally, by ophthalmic solution or ointment. In addition, the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, with other active ingredients may be compatible or simultaneous.

[0117] The present invention described is believed to represent a significant breakthrough in the field of treatment, alleviation, inhibition, and / or prevention of conditions ameliorated by monoamine reuptake, including, but not limited to, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal diseases intestinal and genitourinary diseases, chronic fatigue syndrome, fibromyalgia syndrome, nervous system diseases, and combinations thereof, and in particular those selected from the group consisting of recurrent depressive disorders, vasomotor symptoms, urinary incontinence and urgency urgency, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.

[0118] Accordingly, in one embodiment, the present invention relates to methods of treating or preventing conditions ameliorated by monoamine reuptake in subjects in need thereof, comprising the step of:

administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Conditions alleviated by monoamine reuptake include those selected from the group consisting of vasomotor symptoms, sexual dysfunction, gastrointestinal diseases of genitourinary diseases, chronic fatigue syndrome, fibromyalgia syndrome, nervous system diseases, and combinations thereof, in particular conditions selected from a group consisting of recurrent depressive disorders, vasomotor symptoms, urinary incontinence and urgency, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.

[0119] The terms "vasomotor symptoms", "vasomotor syndrome" and "vasomotor disorders" include, but are not limited to, hot flashes (insomnia), insomnia, sleep disorders, mood disorders, irritation, excessive sweating, night sweats, fatigue, and the like, caused by, among others, thermoregulation disorders.

[0120] The term "hot flush" is a term known in the art and refers to an episodic disorder of body temperature, usually consisting of sudden flushing of the skin, usually accompanied by sweating of the individual.

[0121] The term "sexual dysfunction" includes, but is not limited to, disease states associated with sexual desire and / or arousal.

Related to sexual desire and / or arousal.

[0122] As used herein, the term "gastrointestinal diseases and urogenital diseases"

includes irritable bowel syndrome, symptomatic GERD, hypersensitive esophagus, functional dyspepsia, non-cardiac chest pain, biliary dyskinesia, anal sphincter with Oddi dysfunction, urinary incontinence (this is urinary incontinence, stress urinary incontinence, stress urinary incontinence and stress incontinence) mixed urinary incontinence) (including unwanted excretion of feces or urine, and dripping or leakage of either feces or urine) which can be caused by one or more than one cause, including, but not limited to, pathologies that alter the control of the anal sphincter, cognitive loss, excessive bladder stretching, increased reflexes and / or involuntary urethral relaxation, bladder weakness, or neurological deviations), interstitial cystitis (neurotic bladder), and chronic pelvic pain syndrome (including but not limited to notorious perineal pain (vulvodynia), prostate pain (prostatodynia), and anal pain (proctalgia)).

[0123] As used herein, the term "chronic fatigue syndrome" (CFS) means a condition characterized by physiological symptoms selected from weakness, muscle aches and pains, excessive sleepiness, malaise, fever, sore throat, tender lymph nodes, memory impairment and / or mental concentration, insomnia, sleep disorders, localized tenderness, soreness and fatigue, and combinations thereof.

[0124] As used herein, the term "fibromyalgia syndrome" (FMS) includes FMS and other bodily forms of the disease, including depression-related FMS, somatization disorder, conversion disorder, pain syndrome, hypochondria, body dysmorphic disorder, undifferentiated somastic disorder, and somatic NOS disorders. FMS and other bodily forms of the disease are accompanied by physiological symptoms selected from the generalized increased sensory sensation of stimulation, deviations from the norm in the sensation of pain in the form of allodynia (pain with harmless stimulation), deviation from the norm in the sensation of pain in the form of increased sensitivity to pain (hyperalgesia) (increased sensitivity to painful stimulation), and combinations thereof.

[0125] As used herein, the term "nervous system diseases" includes addiction diseases (including those caused by alcohol, nicotine, and other psychoactive substances) and withdrawal syndrome, age-related learning disorders, and mental illness (including Alzheimer's disease) , anorexia, bulimia, attention deficit disorder with or without hyperactivity, bipolar disorder, pain, cyclothymia, depressive illness (including recurrent depressive disorder, persistent depression (depression not responding to typical treatment methods), juvenile depression and minor depression), dysthymic disorder, generalized anxiety disorder (GAD), obesity (i.e. weight reduction in obese or overly obese patients), obsessive compulsive disorder and the spectrum of related diseases , oppositional defiant disorders, panic attack syndrome, post-traumatic stress disorder, premenstrual syndrome (i.e. premenstrual syndrome and premenstrual syndrome with predominant mood changes), psychotic disorders (including schizophrenia, schizoaffective and schizophrenoform disorders), depression

Chotic (including schizophrenia, schizoaffective and schizophrenoform disorders), seasonal depression, sleep disturbance (such as narcolepsy and involuntary urination), social phobias (including social anxiety disorder), selective reuptake inhibition serotonin (SSRI) (i.e., the team in which the patient stops maintaining satisfactory responses to SSRI therapy after an initial period of satisfactory responses).

[0126] As used herein, the term "pains" includes both acute and chronic pains, which may be centralized pain, generalized pain, or a combination thereof. The term includes many different types of pain including, but not limited to, neuropathic pain, visceral pain, musculoskeletal pain, bone pain, cancer pain, inflammatory pain, and combinations thereof such as lower back pain, unusual pain neck, headaches such as cluster headaches, migraine, herpes neuralgia, phantom limb pain, pelvic pain syndrome, facial muscle pain, abdominal pain, cervical pain, middle pain, dental pain, opioid-resistant pain, visceral pain, pain after surgery, pain in bone injuries, pain during childbirth and recovery, pain from burns, postpartum pain, angina pain, neuropathic pain, such as generalized neuropathy and diabetic neuropathy, postoperative pain, and pains that are morbidly associated with the nervous system diseases described herein.

[0127] As used herein, the term "acute pain" refers to centralized or generalized pain that is intense, localized, acute or pulling, and / or blunt, burning, diffuse or burning by nature and occurs for short periods of time .

[0128] As used herein, the term "chronic pain" refers to centralized or generalized pain that is intense, localized, acute or pulling, and / or blunt, burning, diffuse or burning by nature, and which occurs through prolonged periods of time (permanently and / or returns regularly), including, for the purposes of the present invention, neuropathic pain and cancer pain. Chronic pains include neuropathic pains, hypersensitivity to pain (hyperalgesia), and / or allodynia. [0129] As used herein, the term "neuropathic pain" refers to chronic pain caused by damage or pathological changes in the peripheral or central nervous system. Examples of pathological changes associated with neuropathic pain include, prolonged peripheral or central neuronal sensitization, central sensitization associated with damage to the function of inhibiting and / or stimulating the nervous system, and with abnormal interactions between the parasympathetic and sympathetic nervous systems. A wide range of clinical disease states can be associated with or form the basis for neuropathic pain including, for example, diabetes, post-traumatic amputation pain (nerve damage caused by injuries results in sensitization in the peripheral and / or central system, such as phantom limb pain) , lower back pain, cancer pain, associated with chemical wounds, toxins, and other major surgery, peripheral nerve damage caused by traumatic compression wounds, postherpetic neuralgia, trigeminal neuralgia, associated with lumbar or cervical root and nerve diseases, fibromyalgia, glossopharyngeal neuralgia, with sympathetic reflex atrophy, accidental pains, thalamic syndrome, pains at rupture of the nerve root

Atrophy of sympathetic reflexes or pain after resection of the ribs, pains in nutritional deficiencies, or viral or bacterial infections such as shingles or human immunodeficiency virus (HIV), and combinations thereof. The definition of neuropathic pain also includes secondary conditions for metastatic infiltrates, Dercum's disease, burns, conditions associated with centralized pain associated with thalamic syndrome, and combinations thereof. [0130] As used herein, the term "hypersensitivity" (hyperalgesia) refers to pains in which there is increased sensitivity to typical harmful stimulation.

[0131] As used herein, the term "allodynia" refers to increased sensitivity to typical harmless stimulation.

[0132] As used herein, the term "visceral pain" refers to pain associated with or resulting from internal organ diseases, such as, for example, ulcerative colitis, irritable bowel syndrome, neurotic bladder, Crohn's disease, rheumatological diseases (pain joints), tumors, gastritis, pancreatitis, organ infections, biliary tract diseases, and combinations thereof.

[0133] As used herein, the term "specific female pain" refers to pain that may be acute and / or chronic pain associated with female diseases. These groups of pain include those pain that are found exclusively or predominantly in females, including pain associated with menstruation, ovulation, pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, rupture of the follicular nodule or cystic corpus luteum, pelvic intestinal irritation, fibrosarcoma uterine fibroids, endometriosis, infections and inflammation, pelvic ischemia, obstruction, intra-abdominal fusion, anatomical deformation of the pelvic guts, ovarian abscess, loss of pelvic support, tumors, pelvic hyperemia, or related pains for non-gynecological reasons, and combinations thereof.

[0134] Methods of treating or preventing angioedema symptoms in subjects in need thereof are described, comprising the step of:

administering to said subject an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0135] When estrogen levels are low or estrogen is absent, normal levels between NE and 5-HT are changed, and such a change in neurotransmitter levels may result in changes in the sensitivity of the thermoregulation center. Altered chemical levels can be transformed at the center of thermoregulation as a sensation of heat, and in response, the hypothalamus can activate autonomous descending paths and, as a result, dissipate heat by vasodilation and sweating (hot flashes) (Figure 1). Accordingly, estrogen deprivation may result in altered norepinephrine activity.

[0136] Norepinephrine synthesized in the brainstem pericarion is released in the nerve endings of the hypothalamus and brainstem. In the hypothalamus, NE regulates the activity of neurons located in the center of thermoregulation. In the brainstem, NE innervates serotonergic neurons (5HT), and acts via postsynaptic adrenergic receptors_a1 and adrenergic_a2, stimulates the activity of the serotonergic system. In response, 5-HT neurons also modulate thermoregulation center activity and feedback mechanism to NE neurons. By such a connection by a mechanism

EP 1 732 887 B1 and feedback mechanism to NE neurons. By such a feedback mechanism, 5-HT, acting through 5-HT2a receptors, inhibits NE neuron activity. Norepinephrine in the synaptic cleft is also taken up by the NE transporter (NET) located in NE neurons. The transporter returns NE and makes it available for multiple neurotransmission (Figure 2). [0137] Treatment of vasomotor symptoms by means of restoring reduced norepinephrine activity has been described. Norepinephrine activities in the hypothalamus or brainstem can be increased by (i) blocking the activity of an NE transporter, (ii) blocking the activity of presynaptic adrenergic receptor_a2 by the antagonist, or (iii) blocking 5HT activity on NE neurons by the 5-HT2a antagonist.

[0138] Methods of treating or preventing depressive illness in subjects in need thereof are described, comprising the step of:

administering to the subject an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0139] Methods of treating or preventing sexual dysfunction in subjects in need thereof are described, comprising the step of:

administering to the subject an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0140] Methods of treating or preventing gastrointestinal or urogenital diseases, in particular urinary or urinary incontinence, in subjects in need thereof are described, comprising the step of:

administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0141] Methods of treating or preventing continuous fatigue syndrome in subjects in need thereof are described, comprising the step of:

administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0142] Methods of treating or preventing fibromyalgia syndrome in subjects in need thereof are described, comprising the step of:

administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0143] Methods for treating or preventing pain in subjects in need thereof are described, comprising the step of:

administering to the subject an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0144] Pain may be, for example, acute (short-term) pain or chronic (regular or permanent) pain. Pain can also be centralized or generalized.

[0145] Examples of pains that can be acute or chronic and which can be treated according to the methods of the present invention include inflammatory pains, musculoskeletal pains, bone pains, lumbosacral pains, cervical pains or upper back pains, visceral pains. , somatic pains, neuropathic pains, cancer pains, pains caused by injuries or surgical operations such as burns or dental pains or headaches such as migraines

In general, such as burn pains or dental pains, or headaches such as migraines or pressure headaches, or a combination of these pains. One skilled in the art will recognize that such pains can overlap one another. For example, pain caused by inflammation may also be visceral or musculoskeletal in nature.

[0146] In a preferred embodiment of the present invention, the compounds useful in the present invention are administered to mammals for the treatment of chronic pain such as neuropathic pain associated with, for example, damage or pathological changes in the peripheral or central nervous system; cancer pain; visceral pain associated with, for example, the area of ​​the abdomen, pelvis, and / or perineum, or pancreatitis; musculoskeletal pain associated with, for example, the lower or upper back, spine, fibromylagia, temporomandibular junction, or facial muscle pain syndrome; bone pain associated with, for example, bone disease or degenerative joint disease such as osteoarthritis, rheumatoid arthritis, or spinal stenosis; headaches such as migraine or pressure headaches; or pain associated with infections such as

HIV, sickle cell anemia, autoimmune diseases, multiple sclerosis, or inflammation such as osteoarthritis or rheumatoid arthritis.

[0147] In a more preferred embodiment, the compounds useful in the present invention are useful for the treatment of chronic pain, i.e. neuropathic pain, visceral pain, musculoskeletal pain, bone pain, cancer pain or inflammatory pain, or a combination thereof according to the methods described herein. Inflammatory pains can be associated with various medical diseases such as osteoarthritis, rheumatoid arthritis, surgery or injuries. Neuropathic pain may be associated with, for example, diabetic neuropathy, peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical nerve root and nerve disease, fibromyalgia, glossopharyngeal neuralgia, sympathetic reflex pain, accidental pain, hypothalamus, nerve root pain, or with nerve damage caused by injury resulting in sensitization in the peripheral and / or central system, such as phantom limb pain, with the disappearance of sympathetic reflexes or after removal of ribs, cancer pain, chemical wounds, toxins, nutritional deficiencies, or viral or bacterial infections, such like shingles or HIV, or combinations thereof. The methods of using the compounds of this invention further include treatments in which neuropathic pain is a secondary condition to metastatic infiltration, in Dercum's disease, burns, or disease states associated with centralized pain associated with thalamic syndrome, and combinations thereof.

[0148] As previously mentioned, the methods of the present invention can be used to treat pain that is somatic and / or visceral in nature. For example, somatic pain that can be treated in accordance with the methods of the present invention includes pain associated with structural or soft tissue wounds experienced during surgical procedures, dental procedures, burns, or traumatic injuries. Examples

Visceral pain that can be treated according to the methods of the present invention include types of pain associated with or resulting from internal organ diseases such as ulcerative colitis, irritable bowel syndrome, neurotic bladder, Crohn's disease, rheumatological diseases ( osteoarthritis), cancer, gastritis, pancreatitis, organ infections, or biliary tract diseases, or combinations thereof. One skilled in the art will also recognize that pain treated in accordance with the methods of the present invention may also be associated with a state of hypersensitivity (hyperalgesia), allodynia, or both. In addition, chronic pain can be with or without sensitization of the peripheral or central system. [0149] Compounds useful in the present invention may also be used to treat acute and / or chronic pain associated with a female condition, which may also be referred to as specific female pain. These groups of pain include those that occur exclusively or predominantly in women, including pain associated with menstruation, ovulation, severe or delivery, miscarriage, ectopic pregnancy, retrograde menstruation, rupture of the follicular nodule or corpus luteum cyst, irritation of the pelvic glands, uterine fibrosis. adenomas, endometriosis, infections and inflammation, pelvic ischemia, obstruction, intra-abdominal fusion, anatomical deformation of the pelvic guts, ovarian abscess, loss of pelvic support, tumors, pelvic hyperemia, or related pains for non-gynecological reasons.

[0150] The present invention is further defined in the following Examples, in which all parts and percentages are by weight, and degrees are degrees Celsius, unless otherwise stated. It should be understood that these examples, although indicating preferred embodiments of the invention, are given by way of illustration only. From the above discussion and these examples, a person skilled in the art can check the essential properties of this invention, and without departing from its spirit and scope, it can make various changes and modifications to the invention to suit its various applications and conditions.

EXAMPLES [0151] EXAMPLE 1: (1RS, 2SR) -1- (1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) -1-phenylpropan-2-ol dihydrochloride.

[0152] Step 1: A mixture of indole (2.34 g, 20 mmol) and ground solid potassium hydroxide (1.12 g, 20 mmol) was stirred for 30 minutes under nitrogen at room temperature. Then trans-3-phenylglycidol (3.0 g, 20 mmol) in dimethyl sulfoxide (1 mL) was added and the mixture was stirred at 70 ° C for 2 hours until there was no remaining epoxy. The mixture was then cooled and partitioned between water and dichloromethane. The organic layer was separated, washed several times with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by Biotage chromatography (FlasH40i, silica, 10%, 20%, 30% ethyl acetate / hexane) to obtain 1.92 g (36%) (2RS, 3RS) -3-indol-1-yl-3-phenylpropane -1.2-diol as oil.¹HNMR (DMSO): δ3.27 (m, 2H, CH2OH), δ4.45 (m, 1H, CHOH), δ4.80 (t, 1H, CH2OH) δ5.20 (d, 1H, CHOH), δ5. 60 (d, 1H, CHPh); MS (ESI) m / z

Δ4.80 (t, 1H, CH2OH) δ5.20 (d, 1H, CHOH), δ5.60 (d, 1H, CHPh); MS (ESI) m / z 268 ([M + H] +).

[0153] Step 2: Solution (2RS, 3RS) -3-indol-1-yl-3-phenyl-propan-1,2-diol (1.83 g, 6.8 mmol) and p-toluenesulfonyl chloride (1.31 g, 6.8 mmol ) in anhydrous pyridine (10 ml) was stirred at room temperature under nitrogen for 15 hours. The mixture was then diluted with water (10 mL), quenched with a 2N aqueous hydrochloric acid solution in an ice / water bath until a solution of pH = 3 was obtained, and extracted with dichloromethane. The organic layer was washed again with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Biotage chromatography (FlasH40i, silica, 10%, 25% EtOAc / hexane) to give 1.98 g (69%) of 2-hydroxy-3-indol-1-yl-3-phenyl-propyl acid ester (2RS, 3RS) -toluene-4-sulfonic acid as a white solid.¹HNMR (DMSO): δ3.70 and δ3.85 (dd and dd, 2H, CH2OTs), δ4.80 (m, 1H, CHOH), δ5-52 (d, 1H, CHPh), δ5.82 ( d, 1H, CHOH); MS (ESI) m / z [402125 (4 [] M + EHta] + p). 3: Mixture of 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (2RS, 3RS) toluene 4-sulfone (0.185 g, 0.4 mmol), 1-methylpiperazine (0.05 mL, 0.4 mmol) and potassium carbonate (0.07 g, 0.44 mmol) in acetonitrile (10 mL) was stirred at reflux under nitrogen for 24 hours . After cooling, the mixture was filtered, the filtrate was concentrated and purified on a Biotage chromatography system (5% methanol / dichloromethane) to give a white solid (1RS, 2SR) -1- (1H-indol-1-yl) -3- (4-methylpiperazine) -1-yl) -1fenylopropan-2-ol. The free base was dissolved in a minimum amount of ethanol and treated with a 1N ethereal solution of hydrochloric acid until a solution of pH = 3 was obtained, followed by diethyl ether. The product was then crystallized by adding the minimum amount of hexane to give the title compound (1RS, 2SR) -1- (1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) -1-phenylpropan-2-ol dihydrochloride as whitish solid. MS m / z 350 ([M + H] +); HRMS: calcd for C22H27N30 + H +, 350.22269; found (ESI, [M + H] +), 350.2228.

[0155] EXAMPLE 2: (1RS, 2SR) -1- (5-fluoro-1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) -1-phenylpropan-2-ol dihydrochloride.

[0156] In an analogous manner to EXAMPLE 1, step 1, (2RS, 3RS) -3- (5-fluoro-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 5-fluoroindole and trans -3-phenylglycidol as an oil. MS (ESI) m / z 286 ([M + H] +).

[0157] In an analogous manner to EXAMPLE 1, step 2, 3- (5-fluoro-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid (2RS, 3RS) -3- (5-fluoro-indol-1-yl) -3-phenyl-propane-1,2-diol. MS (ESI) m / z 440 ([M + H] +).

[0158] In an analogous manner to EXAMPLE 1, step 3, (1RS, 2SR) dihydrochloride -1- (5-fluoro-1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) -1-phenylpropane -2-ol was prepared from 3- (5-fluoroindol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid. MS m / z

368 ([M + H] +); HRMS: calcd for C22H26FN30 + H +, 368.21327; found (ESI, [M + H] +), 368.213.

[0159] EXAMPLE 3: (1RS, 2SR) -1- (1H-indol-1-yl) -3-morpholin-4-yl-1-phenylpropane hydrochloride45

EP 1 732 887 B1

2-ol.

<img file="PL1732887T3_D0007.tif" />

[0160] In an analogous manner to EXAMPLE 1, step 3, (1RS, 2SR) hydrochloride -1- (1Hindol-1-yl) -3- (4-methylpiperazin-1-yl) -1-phenylpropan-2-ol made from 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (2RS, 3RS) -toluene-4-sulfonic acid (EXAMPLE 1, step 3) and morpholine. MS (ESI) m / z 337 ([M + H] +); HRMS: calcd for C 21 H 24 N 2 O 2 + H +, 337.19105; found (ESI, [M + H] +), 337.1909.

[0161] EXAMPLE 4: (1RS, 2SR) -3- (dimethylamino) -1- (1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

[0162] In an analogous manner to EXAMPLE 1, step 3, (1RS, 2SR) -3 (dimethylamino) -1- (1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 2-hydroxy -3-indol-1-yl-3-phenyl-propyl ester (2RS, 3RS) -toluene-4-sulfonic acid (EXAMPLE 1, step 3) and dimethylamine hydrochloride. MS (ES) m / z 295.2 ([M + H] +); HRMS: calculated for C19H22N2O + H +,

295.18049; found (ESI, [M + H] +), 295.1829.

[0163] EXAMPLE 5: (1RS, 2SR) -3- (ethylamino) -1- (1H-indol-1-yl) -1-phenylpropan-2-hydrochloride hydrochloride.

[0164] In an analogous manner to EXAMPLE 1, step 3, a solution of (2RS, 3RS) -toluene-4-sulfonic acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step 3, 0.42 g, 1.0 mmol) and ethylamine (2N in methanol, 5 mL) was stirred in a closed flask at room temperature for 15 hours. After dilution with a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with a solution of dichloromethane / isopropyl alcohol (3/1).

The obtained extract was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on a Biotage chromatography system (FlasH40i, silica, dichloromethane, 5% methanol / dichloromethane) to give an oil as the free base of the expected product. The free base was dissolved in a minimum amount of ethanol and treated with a 1N ethereal solution of hydrochloric acid until a solution of pH = 3 was obtained, followed by diethyl ether. The product was then crystallized by adding a minimum amount of ethyl acetate to give the title compound (1RS, 2SR) -3- (ethylamino) -1- (1Hindol-1-yl) -1-phenylpropan-2-ol hydrochloride as a beige solid. MS (ES) m / z 295.2 ([M + H] +); HRMS:

EP 1 732 887 B1 phenylpropan-2-ol as a beige solid. MS (ES) m / z 295.2 ([M + H] +); HRMS: calcd for C 19 H 22 N 2 O + H +, 295.18049; found (ESI, [M + H] +), 295.1797.

[0165] EXAMPLE 6: (1RS, 2SR) -1- (1H-indol-1-yl) -3- (isopropylamino) -1-phenylpropan-2-ol hydrochloride.

[0166] In an analogous manner to EXAMPLE 1, step 3, (1RS, 2SR) -1- (1Hindol-1-yl) -3- (isopropylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 2-hydroxy- (2RS, 3RS) -toluene-4-sulfonic acid 3-indol-1-yl-3-phenylpropyl ester (EXAMPLE 1, step 3) and isopropylamine. MS (ES) m / z 309.2 ([M + H] +); HRMS: calcd for C 20 H 24 N 2 O + H +, 309.19614; found (ESI, [M + H] +), 309.1971.

[0167] EXAMPLE 7: (1RS, 2SR) -3- (benzylamino) -1- (1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

[0168] In an analogous manner to EXAMPLE 1, step 3, (1RS, 2SR) -3 (benzylamino) -1- (1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 2-hydroxy -3-indol-1-yl-3-phenyl-propyl ester (2RS, 3RS) -toluene-4-sulfonic acid (EXAMPLE 1, step 3) and benzylamine. MS (ES) m / z 357.2 ([M + H] +); HRMS: calcd for C24H24N2O + H +, 357.19614; found (ESI, [M + H] +), 357.1962.

[0169] EXAMPLE 8: (1RS, 2SR) -3 - [(cyclohexylmethyl) amino] -1- (1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

[0170] In an analogous manner to EXAMPLE 1, step 3, (1RS, 2SR) -3 [(cyclohexylmethyl) amino] -1- (1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from (2RS, 3RS) -toluene-4-sulfonic acid 2-hydroxy-3-indol-1-yl-3-phenylpropyl ester (EXAMPLE 1, step 3) and cyclohexylmethylamine. MS (ES) m / z 363.3 ([M + H] +); HRMS: calcd for C24H30N2O + H +, 363.24309; found (ESI, [M + H] +), 363.2421.

[0171] EXAMPLE 9: (1RS, 2SR) -3 - [(cyclohexylmethyl) amino] -1- (3-methyl-1Hindol-1-yl) -1-phenylpropan-2-ol hydrochloride.

EP 1 732 887 B1

<img file="PL1732887T3_D0008.tif" />

[0172] In an analogous manner to EXAMPLE 1, step 1, (2RS, 3RS) -3- (3-methyl-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 3-methylindole and trans -3-phenylglycidol as a yellow solid. MS (ESI) m / z 282 ([M + H] +).

[0173] In an analogous manner to EXAMPLE 1, step 2, 3- (3-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid from (2RS, 3RS) -3- (3-methyl-indol-1-yl) -3-phenyl-propan-1,2-diol. MS (ESI) m / z 436 ([M + H] +).

[0174] In an analogous manner to EXAMPLE 1, step 3, (1RS, 2SR) -3 [(cyclohexylmethyl) amino] -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2 hydrochloride -ol was prepared from 3- (310-methyl-indol-1-yl-2-hydroxy-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid and cyclohexylmethylamine. MS (ES) m / z 377.3 ( [M + H] +); HRMS: calcd for C25H32N2O + H +, 377.25874; found (ESI, [M + H] +), 377.2577.

[0175] EXAMPLE 10: (1RS, 2SR) -3- (isopropylamino) -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

[0176] In an analogous manner to EXAMPLE 1, step 3, (1RS, 2SR) -3 (isopropylamino) -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 3- (3-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester (2RS, 3RS) -toluene-4-sulfonic acid (EXAMPLE

12, step 2) and isopropylamine. MS (ES) m / z 323.2 ([M + H] +); HRMS: calculated for C21H26N2O + H +,

323.21179; found (ESI, [M + H] +), 323.2135.

[0177] EXAMPLE 11: (1RS, 2SR) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

[0178] In an analogous manner to EXAMPLE 5, (1RS, 2SR) -1- (1H-indol-1-yl) 3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 2-hydroxy-3 -indol-1-yl-3-phenyl-propyl ester (2RS, 3RS) -toluene-4-sulfonic acid (EXAMPLE 1, step 3) and methylamine (2N solution in methanol). MS (ESI) m / z 281 ([M + H] +); HRMS: calcd for C18H20N2O + H +, 281.16484; found (ESI, [M + H] +), 281.166.

[0179] EXAMPLE 12: (1RS, 2SR) -3- (ethylamino) -1- (3-methyl-1H-indol-1-yl) -148 hydrochloride

Phenylpropan-2-ol.

<img file="PL1732887T3_D0009.tif" />

[0180] In an analogous manner to EXAMPLE 5, (1RS, 2SR) -3- (ethylamino) -1 (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 3- (2RS, 3RS) -toluene-4-sulfonic acid (3-methyl-indol-1-yl-2-hydroxy-3-phenyl-propyl ester) (EXAMPLE 12, step 2) and ethylamine (2N solution in methanol) MS (ESI ) m / z 309 ([M + H] +); HRMS: calcd for C20H24N2O + H +, 309.19614; found (ESI, [M + H] +), 309.198.

[0181] EXAMPLE 13: (1RS, 2SR) -1- (1H-indol-1-yl) -1-phenyl-3-piperazin-1-yl-propan-2-ol dihydrochloride.

[0182] In an analogous manner to EXAMPLE 1, step 3, (2SR, 3RS) 4- (2-hydroxy-3-indol-1-yl-3-phenyl-propyl) -piperazine-1- acid tert-butyl ester (2SR, 3RS) carboxylic acid was prepared from (2RS, 3RS) -toluene-4-sulfonic acid 2-hydroxy-3-indol-1-yl-3-phenylpropyl ester (EXAMPLE 1, step 3, 0.211 g, 0.5 mmol) and tert-butyl-1- carboxylate piperazine (0.19 g, 1.0 mmol). The product was dissolved in diethyl ether (3 mL) and treated with a 4N solution of hydrochloric acid in dioxane (0.75 mL, 3.0 mmol). Then the reaction mixture was stirred at room temperature for 15 hours, then the crude solid product was filtered off and recrystallized from ethanol with a minimum amount of diethyl ether to give the title compound (1RS, 2SR) -1- (1H-indol-1-yl) -1-phenyl dihydrochloride -3-piperazin-1-yl-propan-2-ol as a beige solid. MS (ESI) m / z 336 ([M + H] +); HRMS: calcd for C 21 H 25 N 3 O + H +, 336.20704; found (ESI, [M + H] +), 336.2085.

[0183] EXAMPLE 14: (1RS, 2SR) -1- (1H-indol-1-yl) -1-phenyl-3 - [(pyridin-4-ylmethyl) amino] propan-2-ol hydrochloride.

[0184] In an analogous manner to EXAMPLE 1, step 3, (1RS, 2SR) -1- (1Hindol-1-yl) -1-phenyl-3 - [(pyridin-4-ylmethyl) amino] propan-2 hydrochloride -ol was prepared from (2RS, 3RS) -toluene-4-sulfonic acid 2-hydroxy-3-indol-1-3-phenyl-propyl ester (EXAMPLE 1, step 3) and pyridine-4-yl-methylamine. MS (ESI) m / z 358 ([M + H] +); HRMS: calcd for C 23 H 23 N 3 O + H +, 358.19139; found (ESI, [M + H] +), 358.1928.

[0185] EXAMPLE 15: (1RS, 2SR) -1- (5-chloro-1H-indol-1-yl) -1-phenyl-3-piperidin-1-yl-propan-2-ol hydrochloride.

EP 1 732 887 B1

<img file="PL1732887T3_D0010.tif" />

[0186] In an analogous manner to EXAMPLE 1, step 1, (2RS, 3RS) -3- (5-chloro-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 5-chloroindole and trans -3-phenylglycidol as oil. MS (ESI) m / z

302 ([M + H] +).

[0187] In an analogous manner to EXAMPLE 1, step 2, 3- (5-chloro-indol-1-yl-2-hydroxy-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid was prepared from ( 2RS, 3RS) -3- (5-chloro-indol-1-yl) -3-phenyl-propan-1,2-diol MS (ESI) m / z 456 ([M + H] +).

[0188] In an analogous manner to EXAMPLE 1, step 3, (1RS, 2SR) hydrochloride -1- (5-chloro-1H-indol-1-yl) -1-phenyl-3-piperidin-1-yl-propan-2 -ol was prepared from 3- (5-chloro-indol-1-yl-2-hydroxy-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid and piperidine. MS m / z 369 ([M + H ] +); HRMS: calcd for C22H25CIN2O + H +, 369.17282; found (ESI, [M + H] +), 369.1725.

[0189] EXAMPLE 16: (1RS, 2RS) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

Step 2. To a solution of (2RS, 3RS) -3-indol-1-yl-3-phenyl-propan-1,2-diol (EXAMPLE 1, step 1, 1.83 g, 6.9 mmol) in anhydrous pyridine ( 25 ml), p-nitrobenzoyl chloride (1.3 g, 6.9 mmol) in 1 ml pyridine was added dropwise at -10 ° C. After stirring for 30 minutes, the reaction mixture was cooled in an ice bath and quenched with water and 2N aqueous hydrochloric acid until a solution of pH = 3 was obtained, followed by extraction with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to give (2RS, 3RS) -4-nitro-benzoic acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester, quantitatively, as a yellow solid. MS (ESI) m / z 417 ([M + H] +).

[0191] Step 3. To a solution of (2RS, 3RS) 4-nitro-benzoic acid and triethylamine (1.4 mL, 10.5 mmol) in dichloromethane (20-2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (2RS, 3RS) ml) methanesulfonyl chloride (0.59 ml, 7.6 mmol) was added dropwise at 0-5 ° C with stirring. After stirring for 30 minutes, the mixture was washed with 1N aqueous hydrochloric acid, 5% aqueous sodium bicarbonate, and water, then dried over anhydrous sodium sulfate, filtered, and concentrated to give a light yellow, downy solid. The crude product was recrystallized from dichloromethane with a minimum amount of diethyl ether to give 3-indol-1-yl-2-methanesulfonyloxy-3-phenyl-propyl ester (2RS, 3RS) -4-nitrobenzoic acid as a yellow solid. MS (ESI) m / z 495 ([M + H] +).

[0192] Step 4. Solution of (2RS, 3RS) -4-nitro-benzoic acid 3-indol-1-yl-2-methanesulfonyloxy-3-phenyl-propyl ester in dioxane (30 ml) and 2N aqueous sodium hydroxide solution

(15 ml) was stirred at room temperature for 4 hours. The mixture was then diluted with water and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium carbonate solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated to give (1RS, 2SR) -1- (oxiranyl-phenyl-methyl) -1H-indole as an oil. MS (ESI) m / z 250 ([M + H] +).

[0193] Step 5. (1RS, 2SR) -1- (oxiranyl-phenyl-methyl) -1H-indole was treated with 5 ml of methylamine (2N solution in methanol), with stirring, at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the crude product was recrystallized from dichloromethane. The free base of the expected product was dissolved in a minimum amount of dichloromethane, treated with a 1N ethereal solution of hydrochloric acid until a solution of pH = 3 was obtained. The solid product was then recrystallized by the addition of additional diethyl ether to obtain (1RS, 2RS) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride as a light beige solid.

MS m / z 281 ([M + H] +); HRMS: calcd for C18H20N2O + H +, 281.16484; found (ESI, [M + H] +),

281.1654.

[0194] EXAMPLE 17: (1RS, 2SR) -3-amino-1- (1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

In an analogous manner to EXAMPLE 5, (1RS, 2SR) -3-amino-1- (1H-indol-1-yl) 1-phenylpropan-2-ol hydrochloride was prepared from 2-hydroxy-3-indol-1- (2RS, 3RS) -toluene-4-sulfonic acid-3-phenyl-propyl ester (EXAMPLE 1, step 3, 0.42 g, 1.0 mmol) in a minimum amount of methanol and with an excess of 30% aqueous ammonium hydroxide solution. The crude product was dissolved in n-hexane and filtered to give a white solid as the free base. The free base of the product was dissolved in a minimal amount of ethanol and treated with a 1N hydrochloric acid ether solution until a solution of pH = 3 was obtained, followed by diethyl ether. Then the product was crystallized by adding a minimum amount of ethyl acetate to obtain the title compound as a beige solid. MS (ESI) m / z 267 ([M + H] +); HRMS: calculated for C17H18N2O + H +,

267.14919; found (ESI, [M + H] +), 267.1493.

[0195] EXAMPLE 18: (1RS, 2SR) -3- (ethylamino) -1- (5-fluoro-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

[0196] In an analogous manner to EXAMPLE 5, (1RS, 2SR) -3- (ethylamino) -1 (5-fluoro-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 3- (2RS, 3RS) -toluene-4-sulfonic acid (5-fluoro-indol-1-yl-2-hydroxy-3-phenyl-propyl ester (EXAMPLE 2, step 2) and ethylamine (2N solution in methanol) MS (ES ) m / z 313.2 ([M + H] +); HRMS: calcd for C19H21FN2O + H +, 313.17107; found (ESI, [M + H] +), 313.1706.

[0197] EXAMPLE 19: (1RS, 2SR) -3-amino-1- (5-fluoro-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

<img file="PL1732887T3_D0011.tif" />

[0198] In an analogous manner to EXAMPLE 17, (1RS, 2SR) -3-amino-1- (5-fluoro-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 3- (5- fluoro-indol-1-yl-2-hydroxy-3-phenylpropyl ester (2RS, 3RS) -toluene-4-sulfonic acid (EXAMPLE 2, step 2) and 30% aqueous ammonium hydroxide as a white solid. MS ( ES) m / z 285.2 ([M + H] +); HRMS: calcd for C17H17FN2O + H +, 285.13977; found (ESI, [M + H] +), 285.1403.

EXAMPLE 20: (1RS, 2SR) -1- (5-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

[0200] In an analogous manner to EXAMPLE 5, (1RS, 2SR) -1- (5-fluoro-1Hindol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 3- ( (2RS, 3RS) -toluene-4-sulfonic acid 5-fluoro-indol-1-yl-2-hydroxy-3-phenyl-propyl ester (EXAMPLE 2, step 2) and methylamine (2N solution in methanol) MS (ESI) m / z 299 ([M + H] +); HRMS: calcd for C18H19FN2O + H +, 299.15542; found (ESI, [M + H] +), 299.1564.

[0201] EXAMPLE 21: (1RS, 2SR) -3- (methylamino) -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

[0202] In an analogous manner to EXAMPLE 5, (1RS, 2SR) -3- (methylamino) -1 (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 3- (2RS, 3RS) -toluene-4-sulfonic acid (3-methyl-indol-1-yl-2-hydroxy-3-phenyl-propyl ester) (EXAMPLE 10, step 2) and methylamine (2N solution in methanol) MS (ESI ) m / z 295 ([M + H] +); HRMS: calcd for C19H22N2O + H +, 295.18049; found (ESI, [M + H] +), 295.1816.

[0203] EXAMPLE 22: (1R, 2S) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-L hydrochloride.

chiral [0204] In an analogous manner to EXAMPLE 1, step 1, (2R, 3R) -3-indol-1-yl-3-phenyl-propan1,2-diol was prepared from indole and [(2S, 3S) -3 -phenyloxiran-2-yl] methanol as an oil. MS (ESI) m / z 286

EP 1 732 887 B1 ([M + H] +).

[0205] In an analogous manner to EXAMPLE 1, step 2, (3-indol-1-yl) -2-hydroxy-3-phenylpropyl (2R, 3R) -toluene-4-sulfonic acid ester was prepared from (2R, 3R ) -3-indol-1-yl-3-phenylpropane-1,2-diol. MS (ESI) m / z 440 ([M + H]⁺).

[0206] In an analogous manner to EXAMPLE 5, (1R, 2S) -1- (1H-indol-1-yl) -3 (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from (3-indol-1 (2R, 3R) -toluene-4-sulfonic acid and methylamine (2N solution in methanol) as a white solid -yl) -2-hydroxy-3-phenyl-propyl ester. CD / MeOH = (+); e / e = 99.9% as determined by chiral HPLC analysis; MS (ESI) m / z 281 ([M + H] +); HRMS: calcd for C18H20N2O + H +, 281.16484; found. (ESI, [M + H] +), 281.1649. [0207] EXAMPLE 23: (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2ol hydrochloride.

<img file="PL1732887T3_D0012.tif" />

11) dissolved in methanol. The resulting solution was injected into a supercritical fluid fluid chromatography (SFC). The baseline of the separated enantiomers was drawn using the conditions described below. The enantiomeric purity for each enantiomer was determined under the same supercritical mobile phase chromatography conditions, a Chiralcel OJ-H 5u 250 mm x 4.6 mm ID column was used at a flow rate of 2.0 ml / min using a supercritical mobile phase analytical chromatography device (Berger Instruments, Inc. Newark, DE USA).

<td>SFC device:</td><td>Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE 19702.</td>

<td>Column:</td><td>Chiralcel OJ-H; 5u; 250mm lx 20mm ID (Chiral Technologies, Inc, Exton, PA, USA)</td>

<td>Temperature column:</td><td>35 ° C</td>

<td>SFC modifier:</td><td>20% MeOH with 1% diethylamine</td>

<td>Flow rate:</td><td>50 ml / min</td>

<td>Output pressure:</td><td>100 bars</td>

<td>Detector:</td><td>UV at 218 nm</td>

[0209] (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol was isolated as a peak at slower retention time with rotation (-) according to chiral detection ( CD) ie / e = 99.4% as determined by chiral HPLC analysis. The separated free base was concentrated in vacuo, dissolved in a minimum amount of ethanol and treated with a 1N ethereal solution of hydrochloric acid until a solution of pH = 3 was obtained, followed by diethyl ether. The product was then crystallized by adding a minimum amount of ethyl acetate to obtain the title compound as the hydrochloride salt as a white solid; MS (ESI) m / z 281 ([M + H] +); HRMS: calculated for C18H20N2O + H +,

White solid; MS (ESI) m / z 281 ([M + H] +); HRMS: calcd for C18H20N2O + H +, 281.16484; found (ESI, [M + H] +), 281.1646.

[0210] EXAMPLE 24: (1RS, 2SR) -3-amino-1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

<img file="PL1732887T3_D0013.tif" />

In an analogous manner to EXAMPLE 17, (1RS, 2SR) -3-amino-1- (3-methyl-1Hindol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 3- (3-methyl-indol -1-yl-2-hydroxy-3-phenylpropyl (2RS, 3RS) -toluene-4-sulfonic acid ester (EXAMPLE 9, step 2) and 30% aqueous ammonium hydroxide solution as a beige solid MS (ES) m / z 281.1 ([M + H] +); HRMS:

calcd for C18H20N2O + H +, 281.16484; found (ESI, [M + H] +), 281.1645.

[0211] EXAMPLE 25: (1RS, 2SR) -3- [ethyl (methyl) amino] -1- (1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

[0212] In an analogous manner to EXAMPLE 5, (1RS, 2SR) -315 [ethyl (methyl) amino] -1- (1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from (1RS , 2SR) -3 (methylamino) -1- (1H-indol-1-yl) -1-phenylpropan-2-ol (EXAMPLE 11) and ethylamine (2N solution in methanol) as a beige solid. MS (ES) m / z 309.0 ([M + H] +); HRMS: calcd for C 20 H 24 N 2 O + H +, 309.19614; found (ESI, [M + H] +), 309.1955.

[0213] EXAMPLE 26: (1RS, 2SR) -1- (5-chloro-1H-indol-1-yl) -3- (methylamino) -120 phenylpropan-2-ol hydrochloride.

[0214] In an analogous manner to EXAMPLE 1, step 1, (2RS, 3RS) -3- (5-chloro-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 5-chloroindole and trans -3-phenylglycidol as oil. MS (ESI) m / z 302 ([M + H] +).

[0215] In an analogous manner to EXAMPLE 1, step 2, 3- (5-chloro-indol-1-yl-2-hydroxy-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid was prepared from ( 2RS, 3RS) -3- (5-chloro-indol-1-yl) -3-phenyl-propan-1,2-diol MS (ESI) m / z 456 ([M + H] +).

[0216] In an analogous manner to EXAMPLE 5, step 3, (1RS, 2SR) -1- (5-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 3- (5-chloro-indol-1-yl-230-hydroxy-3-phenylpropyl ester (2RS, 3RS) -toluene-4-sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 315 ( [M + H] +); HRMS: calculated for C18H19ClN2O + H +,

315.12587; found (ESI, [M + H] +), 315.1258.

[0217] EXAMPLE 27: (1RS, 2RS) hydrochloride -1- (5-chloro-1H-indol-1-yl) -3- (methylamino) -154

Phenylpropan-1-ol.

<img file="PL1732887T3_D0014.tif" />

[0218] In an analogous manner to EXAMPLE 16, step 2, 3- (5-chloro-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester (2RS, 3RS) -4-nitro-benzoic acid was prepared from (2RS, 3RS) -3- (5-chloro-indol-1-yl) -3-phenyl-propane-1,2-diol (EXAMPLE 1, step 1). MS (ESI) m / z 451 ([M + H] +). [0219] In an analogous manner to EXAMPLE 16, step 3, 3- (5-chloro-indol-1-yl) -2-methanesulfonyloxy-3-phenyl-propyl ester (2RS, 3RS) -4-nitro-benzoic acid was prepared from 3- (5-Chloro-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester (2RS, 3RS) -4-nitrobenzoic acid. MS (ESI) m / z 529 ([M + H] +).

[0220] In an analogous manner to EXAMPLE 16, step 4, (1RS, 2SR) -5-chloro-1- (oxiranylphenyl-methyl) -1H-indole was prepared from 3- (5-chloro-indol-1-yl) -2-methanesulfonyloxy-3-phenylpropyl ester (2RS, 3RS) -4-nitro-benzoic acid. MS (ESI) m / z 284 ([M + H] +).

[0221] In an analogous manner to EXAMPLE 16, step 5, (1RS, 2RS) hydrochloride -1- (5-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol was prepared as beige solid. MS (ESI) m / z 315 ([M + H] +); HRMS: calcd for C18H19ClN2O + H +, 315.12587; found (ESI, [M + H] +), 315.1276.

[0222] EXAMPLE 28: 1 - [(1RS, 2SR) -2-hydroxy-3- (methylamino) -1-phenylpropyl] hydrochloride

<img file="PL1732887T3_D0015.tif" />

[0223] In an analogous manner to EXAMPLE 1, step 1, (2RS, 3RS) -3- (3-cyano-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 3-cyanoindole and trans -3-phenylglycidol as an oil. MS (ESI) m / z 293 ([M + H] +).

[0224] In an analogous manner to EXAMPLE 1, step 2, 3- (3-cyano-indol-1-yl-2-hydroxy-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid was prepared from ( 2RS, 3RS) -3- (3-cyano-indol-1-yl) -3-phenyl-propan-1,2-diol MS (ESI) m / z 447 ([M + H] +).

[0225] In an analogous manner to EXAMPLE 1, step 3, (1RS, 2SR) -1- (3-cyano-1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) -1-phenylpropane hydrochloride -2-ol was prepared from 3- (3-cyanoindol-1-yl-2-hydroxy-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid as a white solid. MS (ESI) m / z 306 ([M + H] +); HRMS: calcd for C19H19N3O + H +, 306.16009; found (ESI, [M + H] +), 306.1614.

[0226] EXAMPLE 29: (1R, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-hydrochloride hydrochloride.

EP 1 732 887 B1

<img file="PL1732887T3_D0016.tif" />

[0227] Racemic (1RS, 2RS) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol (EXAMPLE 16) was dissolved in methanol. The resulting solution was injected into a supercritical mobile phase chromatography apparatus. The baseline of the separated enantiomers was plotted, the following conditions were used. The enantiomeric purity of each enantiomer was determined under the same supercritical mobile phase chromatography conditions, a Chiralcel OJ-H 5u, 250mm x 4.6mm ID column was used at a flow rate of 2.0ml / min using a supercritical mobile phase analytical chromatography device (Berger Instruments, Inc. Newark, DE USA).

<td>SFC device:</td><td>Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE 19702.</td>

<td>Column:</td><td>Chiralcel OJ-H; 5u; 250mm L x 20mm ID (Chiral Technologies, Inc, Exton, PA, USA)</td>

<td>Temperature column:</td><td>35 ° C</td>

<td>SFC modifier:</td><td>20% MeOH with 1% ethanesulfonic acid</td>

<td>Flow rate:</td><td>50 ml / min</td>

<td>Output pressure:</td><td>100 bars</td>

<td>Detector:</td><td>UV at 220 nm</td>

[0228] (1R, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol was isolated as a peak with faster retention time with rotation (+) according to chiral detection ( CD) and e / e = 99.9%, as determined by chiral HPLC analysis.

[0229] In an analogous manner to EXAMPLE 23, the title compound was obtained as the hydrochloride salt as an off-white solid; MS (ESI) m / z 306 ([M + H] +); HRMS: calcd for C18H20N2O + H +, 281.16484; found (ESI, [M + H] +), 281.1654.

[0230] EXAMPLE 30: (1S, 2S) -1- (1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-hydrochloride hydrochloride.

What

CH, chiral [0231] In an analogous manner to EXAMPLE 29, (1S, 2S) -1- (1H-indol-1-yl) -3- (methylamino) 1-phenylpropan-2-ol was isolated as a slower peak retention with rotation (-) according to chiral detection (CD) and e / e = 99.9%, as determined by chiral HPLC.

In an analogous manner to EXAMPLE 23, the title compound was obtained as the hydrochloride salt as a white solid; MS (ESI) m / z 306 ([M + H]⁺); HRMS: calcd for C18H20N2O +

H +, 281.16484; found (ESI, [M + H] +), 281.1655.

EP 1 732 887 B1

281.16484; found (ESI, [M + H] +), 281.1655.

[0232] EXAMPLE 31: (1S, 2R) -3- (methylamino) -1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

<img file="PL1732887T3_D0017.tif" />

[0233] In an analogous manner to EXAMPLE 1, step 1, (2S, 3S) -3- (3-methyl-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 3-methylindole and [ (2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as an oil. MS (ESI) m / z 282 ([M + H] +).

[0234] In an analogous manner to EXAMPLE 1, step 2, 3- (3-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (2S, 3S) -3- (3-methyl-indol-1-yl) -3-phenyl-propane-1,2-diol. MS (ESI) m / z 436 ([M + H] +).

[0235] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (1H-indol-1-yl) -3 (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 3- (3-methyl -indol-1-yl) -2-hydroxy-3-phenylpropyl ester (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol) as a white solid. [□] D²⁵/ MeOH = +116; CD / MeOH = (-); MS (ESI) m / z 295 ([M + H] +); HRMS: calcd for C19H22N2O + H +, 295.18049; found (ESI, [M + H] +), 295.1816.

[0236] EXAMPLE 32: (1RS, 2SR) -1- (2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3 (methylamino) -1-phenylpropan-2-ol dihydrochloride.

<img file="PL1732887T3_D0018.tif" />

[0237] A mixture of 3,4-dihydro-2H-benzo [1,4] oxazine (2.027 g 15.00 mmol) and trans-ethyl-3-phenylglycinate (2.883 g, 15.00 mmol) was stirred at 135 ° C for 12 hours. After cooling, the viscous liquid was purified by FLASH Biotage Horizon high performance chromatography system (FLASH 40 M, silica, 10%, 20%, 30% EtOAc / hexane) and recrystallized (minimal amount of warm chloroform in hexane / -20 ° C) to give 4.261 g (87%) (2RS, 3RS) -3- (2,3-dihydro-4H-1,4-benzoxazin-4-yl) -2-hydroxy-3-phenylpropanoate, as a white solid. MS (ESI) m / z 328.0 ([M + H] +).

A mixture of (2RS, 3RS) -3- (2,3-dihydro-4H-1,4-benzoxazin-4-yl) -2-hydroxy-3-phenylpropanoate (283 mg, 0.864 mmol) and ethanol solution of methylamine ( 5 ml, 33% solution in ethanol) was stirred at 70 ° C in a closed tube for 5 hours. After cooling, all volatiles were removed under reduced pressure. The resulting yellow solid was purified by FLASH Biotage Horizon high performance chromatography (FLASH 12 S, silica, 20%, 35%, 50% EtOAc / hexane) to give 235 mg (87%) (2RS, 3RS) -3- (2, 3-dihydro4H-1,4-benzoxazin-4-yl) -2-hydroxy-N-methyl-3-phenylpropanamide as a white solid. MS (ESI) m / z 311.0 ([MH]^-).

[0239] Solution (2RS, 3RS) -3- (2,3-dihydro-4H-1,4-benzoxazin-4-yl) -2-hydroxy-N-methyl-3-phenylpropanamide (216 mg, 0.692 mmol) in dry tetrahydrofuran (3 mL) under a nitrogen atmosphere was treated dropwise with a boron hydride solution (1.0 M solution in tetrahydrofuran, 3.50 mL, 3.50 mmol), and the resulting solution was stirred at 70 ° C for 2 hours. After cooling in an ice bath, the reaction mixture was treated with 2N aqueous hydrochloric acid (1 mL), and the resulting mixture was heated at 50 ° C for 30 minutes. The tetrahydrofuran was removed under reduced pressure, and the aqueous residue was dissolved in water (5 mL) and washed with diethyl ether (10 mL). The aqueous layer was made into an alkaline solution with solid potassium carbonate and extracted with ethyl acetate (2x 10 mL). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under reduced pressure to obtain 202 mg (98%) (1RS, 2SR) -1- (2,3-dihydro-4H-1,4-benzoxazin-4-yl) ) -3- (methylamino) -1-phenylpropan-2-ol as a colorless oil. This oil was dissolved in ethanol (1 mL) and treated with a solution of hydrochloric acid (0.5 mL, 4M solution in 1,4-dioxane). All volatiles were again removed under reduced pressure. The resulting white solid was recrystallized (minimally warm ethanol / ethyl ether / -20 ° C) to obtain 105 mg (41%) of the dihydrochloride salt (1RS, 2SR) -1- (2,3-dihydro4H-1,4-benzoxazin-4- yl) -3- (methylamino) -1-phenylpropan-2-ol as a white solid. MS (ESI) m / z 299.0 ([M + H] +); HRMS: calcd for C18H22N2O2 + H +, 299.17540; found (ESI, [M + H] +),

299.1755.

[0240] EXAMPLE 33: (1S, 2R) -1- (3-chlorophenyl) -1- (1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0019.tif" />

[0241] Step 1: A suspension of sodium hydride (60% in mineral oil, 4.0 g, 100 mmol) in tetrahydrofuran (600 mL) was treated dropwise with diethyl ethoxycarbonylmethylphosphonate (20 mL, 100 mmol) at 23 ° C. After 1 hour, s, 3-chlorobenzaldehyde (9.3 mL, 82 mmol) was added. After an additional 1 hour, the reaction was quenched with water (20 mL) and concentrated in vacuo to remove tetrahydrofuran. The residue collected in ethyl acetate (300 mL), washed with water (5x 300 mL) and brine (1x 300 mL), dried (magnesium sulfate) and concentrated in vacuo to give (2E) -3- (3-chlorophenyl) acid ethyl ester -acrylic (18 g, quantitative) as a clear, light yellow oil. MS (ESI) m / z 210 ([M + H] +).

[0242] Step 2: (2E) -3- (3-chlorophenyl) -acrylic acid ethyl ester (17.6 g, 82 mmol) was dissolved in dry dichloromethane (300 mL), cooled to -78 ° C and treated with dihydride solution -iso-butylaluminum (1.0 M solution in hexane, 250 ml, 250 mmol) for 20 minutes. After a total of 1.5 hours, the reaction was quenched with methanol (75 mL) at -78 ° C, heated to 23 ° C and treated with saturated aqueous sodium potassium tartrate solution (300 mL). The aqueous phase was separated and extracted with dichloromethane (2x 300 mL). The combined extracts were washed with saturated aqueous sodium tartrate (450 mL), dried (sodium sulfate) and concentrated in vacuo to give a turbid yellow oil (14.6 g) which was pre-adsorbed onto silica gel (25 g). After flash column chromatography (250 g silica, 10%, 20

EP 1 732 887 B1 (25 g). Flash column chromatography (silica 250 g, 10%, 20% ethyl acetate / hexanes) gave (2E) -3- (3-chlorophenyl) prop-2-en-1-ol (12.4 g, 90%) as clear, colorless oil. MS (ESI) m / z 151 ([M + H-H2O] +).

[0243] Step 3: In an analogous manner to EXAMPLE 117, step 4, [(2R, 3R) -3- (3-chlorophenyl) oxiran-2-yl] methanol was prepared from (2E) -3- (3-chlorophenyl) prop -2-en-1-ol. MS (ESI) m / z 167 ([M + H-H2O] +).

[0244] Step 4 (Method A): In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (3-chlorophenyl) -3- (1H-indol-1-yl) propane-1,2- diol was prepared from 1H-indole and [(2R, 3R) -3- (3-chlorophenyl) oxiran-2-yl] methanol. MS (ES) m / z 302 ([M + H] +).

[0245] Step 4a (Method B): [(2R, 3R) -3- (3-chlorophenyl) oxiran-2-yl] methanol (4.8 g, 26 mmol) and indoline (d 1.063, 2.9 mL, 26 mmol) heated clean at 135 ° C in a closed flask. After 1.5 hours, the cooled mixture was pre-adsorbed onto silica gel (25 g). Flash column chromatography (silica 375 g, 20%, 40%, 80% ethyl acetate / hexanes) gave (2S, 3S) -3- (3-chlorophenyl) -3- (2,3-dihydro-1H-indol- 1-yl) propan-1,2-diol (5.8 g, 73%) as a white solid. MS (ES) m / z 304 ([M + H] +).

[0246] Step 4b (Method B): Solution (2S, 3S) -3- (3-chlorophenyl) -3- (2,3-dihydro-1H-indol-1-yl) propane-1,2-diol (5.8 g , 19 mmol) in a mixture of about 1: 1 (v / v) toluendichloromethane (200 ml) was treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.4 g, 19 mmol) in toluene (100 ml) at 0 ° C. After 30 minutes, the mixture was diluted with ethyl acetate (1 liter) and washed with 5% aqueous sodium carbonate solution (4x 1 liter, water (1 liter) and brine (1 liter), dried (magnesium sulfate) and concentrated in vacuo to give a dark oil (5.4 g) which was pre-adsorbed onto silica gel (15 g). Flash column chromatography (235 g silica, 20%, 40% ethyl acetate / hexanes) gave (2S, 3S) -3- (3-chlorophenyl) -3- (1H-indol-1-yl) propane-1,2-diol , (4.7 g, 82%), as a turbid yellow oil. MS (ES) m / z 302 ([M + H] +).

[0247] Step 5: In an analogous manner to EXAMPLE 1, step 2, 3- (3-chlorophenyl) -2-hydroxy-3-indol-1-yl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid was prepared from (2S, 3S) -3- (3-chlorophenyl) -3- (1H-indol-1-yl) propan-1,2-diol. MS (ES) m / z 456 ([M + H] +).

[0248] Step 6: 3- (3-Chloro-phenyl) -2-hydroxy-3-indol-1-yl-propyl ester (2S, 3S) -toluene-4-sulfonic acid (0.60 g, 1.2 mmol) was treated with a solution of methylamine in methanol (2.0 M solution, 3 mL, 6 mmol), the solution was stirred at 23 ° C for 18 hours. At this point, the solution was concentrated in vacuo and dissolved in diethyl ether (50 mL). The organic solution was washed

1N aqueous sodium hydroxide (50 ml), water (50 ml) and brine (50 ml), dried (sodium sulfate) and concentrated in vacuo to give an orange foam (0.30 g) which was purified by reverse phase HPLC (90 mixture: Water-acetonitrile to 50:50 water acetonitrile containing 0.1% trifluoroacetic acid (20 ml / min). The product fractions were concentrated in vacuo to remove acetonitrile and the aqueous solution was made basic with 2N aqueous ammonium hydroxide solution. The resulting milky suspension was extracted with ethyl acetate (200 mL), and the organic phase was washed with water (200 mL) and brine (100 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in absolute

Ethanol (4 mL), treated with a 4M solution of hydrochloric acid in 1,4-dioxane (1.3 equivalents) and stirred for 10 minutes. The solution was then concentrated in vacuo and then dissolved in absolute ethanol (3 mL) and allowed to stand at 23 ° C overnight. Vacuum filtration gave (1S, 2R-1- (3-chlorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan2-ol hydrochloride (62 mg, 5% for 3 steps) as white crystalline solid. HRMS calculated for C18H19ClN2O + H +, 315.12587; found (ESI) 315.1267 ([M + H] +).

[0249] EXAMPLE 34: (1S, 2R) -1- (4-chlorophenyl) -1- (1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0020.tif" />

[0250] In an analogous manner to EXAMPLE 33, step 1 (2E) -3- (4-chlorophenyl) acrylic acid ethyl ester was prepared from diethyl ethoxycarbonyl methyl phosphonate and 4-chlorobenzaldehyde. MS (ESI) m / z 210 ([M + H] +).

[0251] In an analogous manner to EXAMPLE 33, step 2 (2E) -3- (4-chlorophenyl) prop-2-en-1-ol was prepared from (2E) -3- (4-chlorophenyl) acrylic ethyl ester . MS (ESI) m / z 151 ([M + H-H2O] +). [0252] In an analogous manner to EXAMPLE 117, step 4, [(2R, 3R) -3- (4-chlorophenyl) oxiran2-yl] methanol was prepared from (2E) -3- (4-chlorophenyl) prop-2- en-1-ol. MS (ESI) m / z 167 ([M + H-H2O]⁺); [□□ D +41 (c 0.0121 g / ml, DMSO); 99.2% ee.

[0253] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (4-chlorophenyl) -3- (1Hindol-1-yl) propane-1,2-diol was prepared from 1H-indole and [(2R, 3R) -3- (4-chlorophenyl) oxiran-2-yl] methanol. MS (ES) m / z 302 ([M + H] +).

[0254] In an analogous manner to EXAMPLE 1, step 2, 3- (4-chlorophenyl) -2-hydroxy-3-indol-1-yl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid was prepared from (2S , 3S) -3- (4-chlorophenyl) -3- (1H-indol-1-yl) propane-1,2-diol. MS (ES) m / z 456 ([M + H] +).

[0255] In an analogous manner to EXAMPLE 33, step 6 (1S, 2R) -1- (4-chlorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol hydrochloride was prepared from 3- (4-Chloro-phenyl) -2-hydroxy-3-indol-1-yl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol). HRMS: calcd for C18H19CIN2O + H +, 315.12587; found (ESI) 315.124 ([M + H] +).

[0256] EXAMPLE 35: (1S, 2R1-1- (1Hindol-1-yl) -3- (methylamino) -1- (3- hydrochloride

<img file="PL1732887T3_D0021.tif" />

[0257] In an analogous manner to EXAMPLE 33, step 1, (2E) -3- (3-trifluoromethoxy-phenyl) -acrylic acid ethyl ester was prepared from diethyl and 360 ethoxycarbonylmethylphosphonate

EP 1 732 887 B1 (trifluoromethoxy) benzaldehyde. MS (ES) m / z 261 ([M + H] +).

[0258] In an analogous manner to EXAMPLE 33, step 2, (2E) -3- [3- (trifluoromethoxy) phenyl] prop-2-en-1-ol was prepared from (2E) -3- (3-trifluoromethoxy) ethyl ester phenyl) -acrylic acid. MS (ES) m / z 201 ([M + H-H2O] +).

[0259] In an analogous manner to EXAMPLE 117, step 4, {(2R, 3R) -3- [3- (trifluoromethoxy) phenyl] oxiran-2-yl) methanol was prepared from (2E) -3- [3- (trifluoromethoxy ) phenyl] prop-2-en-1-ol. MS (ES) m / z 217 ([M + H-H 2 O] +); [□] D²⁵ = + 30 ° (c = 0.0118 g / ml, DMSO); 84.4% ee.

[0260] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (1H-indol-1-yl) -3- [3- (trifluoromethoxy) phenyl] propane-1,2-diol was prepared from 1H-indole and {(2R, 3R-3- [3- (trifluoromethoxy) phenyl] oxiran-2-yl} methanol. MS (ES) m / z 352 ([M + H] +).

[0261] In an analogous manner to EXAMPLE 1, step 2 (2S, 3S) -toluene-4-sulfonic acid 2-hydroxy-3-indol-1-yl-3- (3-trifluoromethoxy-phenyl) -propyl ester was prepared from ( 2S, 3S) -3- (1H-indol-1-yl) -3- [3- (trifluoromethoxy) phenyl] propan-1,2-diol. MS (ES) m / z 506 ([M + H] +).

[0262] In an analogous manner to EXAMPLE 33, step 6, (1S, 2R) -1- (1H-indol1-yl) -3- (methylamino) -1- [3- (trifluoromethoxy) phenyl] propan-2-hydrochloride -ol was prepared from (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol) from 2-hydroxy-3-indol-1-yl-3- (3-trifluoromethoxy-phenyl) -propyl ester. MS (ES) m / z 365 ([M + H] +).

[0263] EXAMPLE 36: (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- [2-

<img file="PL1732887T3_D0022.tif" />

[0264] Step 1: In an analogous manner to EXAMPLE 33, step 1, (2E) -3 (2-trifluoromethoxy-phenyl) -acrylic acid ethyl ester was prepared from diethyl ethoxycarbonylmethylphosphonate and 2- (trifluoromethoxy) benzaldehyde. MS (ES) m / z 261 ([M + H] +).

[0265] Step 2: In an analogous manner to EXAMPLE 33, step 2, (2E) -3- [2- (trifluoromethoxy) phenyl] prop-2-en-1-ol was prepared from (2E) -3- ethyl ethyl ester (2-trifluoromethoxy-phenyl) -acrylic acid. MS (ES) m / z 201 ([M + H-H2O] +).

[0266] Step 3: A solution of (2E) -3- [2- (trifluoromethoxy) phenyl] prop-2-en-1-ol (3.9 g, 18 mmol) in dichloromethane (90 ml) was treated with meta-chloroperoxybenzoic acid (77 %, 8.0 g, 36 mmol) at 23 ° C. After 5 hours, the reaction was quenched with 1N aqueous sodium hydroxide solution (200 mL) with vigorous stirring, then the phases were separated. The aqueous phase was extracted with diethyl ether (2x 100 mL). The combined organic phases were washed with water (3x 100 mL), dried (sodium sulfate) and concentrated in vacuo to give a clear, colorless oil (3.8 g) which was pre-adsorbed onto silica gel (6 g). Flash column chromatography (silica 60 g, 10%, 20% ethyl acetate / hexanes) gave {(2RS, 3RS) 3- [2- (trifluoromethoxy) phenyl] oxiran-2-yl} methanol (2.4 g, 57%) as a white solid. MS (ES) m / z 217 ([M + H-H2O] +).

[0267] {(2RS, 3RS) -3- [2- (trifluoromethoxy) phenyl] oxiran-2-yl} methanol was dissolved in methanol.

EP 1 732 887 B1

The resulting solution was injected into a supercritical mobile phase chromatography apparatus, and a base line of separated enantiomers was drawn using the conditions described below. The enantiomeric purity of each enantiomer was determined under the same conditions as for the supercritical mobile phase chromatography using a Chiralpak AS-H 5u 250 mm x 4.6 mm ID column at a flow rate of 2.0 ml / min, a mobile phase analytical chromatography apparatus was used supercritical (Berger Instruments, Inc. Newark, DE USA).

<td>SFC device:</td><td>Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE19702.</td>

<td>Column:</td><td>Chiralpak AS-H 5u; 250mm L x 20mm ID (Chiral Technologies, Inc, Exton, PA, USA</td>

<td>Temperature column:</td><td>35 ° C</td>

<td>SFC modifier:</td><td>5% IPA / 95% CO2</td>

<td>Flow rate:</td><td>35 ml / min</td>

<td>Output pressure:</td><td>100 bars</td>

<td>Detector:</td><td>UV at 220 nm</td>

[0268] {(2R, 3R) -3- [2- (trifluoromethoxy) phenyl] oxiran-2-yl} methanol was isolated as peak 1. MS (ES) m / z 217 ([M + H-H2O] +) ; [□] D²⁵ = + 19.4 ° (c = 0.0102 g / ml, DMSO); > 99.9% ee.

[0269] {(2S, 3S) -3- [2- (trifluoromethoxy) phenyl] oxiran-2-yl} methanol was isolated as peak 2. MS (ES) m / z 217 ([M + H-H2O] +) ; [□] D²⁵ = -15.7 ° (c = 0.0125 g / ml, DMSO); 95.8% ee.

[0270] Step 4: In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (1H-indol-1-yl) 3- [2- (trifluoromethoxy) phenyl] propane-1,2- diol was prepared from 1H-indole and {(2R, 3R) -3- [2- (trifluoromethoxy) phenyl] oxiran-2-yl} methanol, substituting sodium tert-butoxide for potassium hydride. MS (ES) m / z 352 ([M + H] +).

[0271] Step 5: In an analogous manner to EXAMPLE 1, step 2, 2-hydroxy-3-indol-1-yl-3- (2-trifluoromethoxy-phenyl) -propyl ester of (2S, 3S) -toluene-4- sulfonic acid was prepared from (2S, 3S) 3- (1H-indol-1-yl) -3- [2- (trifluoromethoxy) phenyl] propan-1,2-diol. MS (ES) m / z 506 ([M + H] +).

[0272] Step 6: In an analogous manner to EXAMPLE 33, step 6, (1S, 2R) -1 (1H-indol-1-yl) -3- (methylamino) -1- [2- (trifluoromethoxy) phenyl hydrochloride ] propan-2-ol was prepared from 2-hydroxy-3-indol-1-yl-3- (2-trifluoromethoxy-phenyl) -propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N methanol solution) . MS (ES) m / z 365 ([M + H] +).

[0273] EXAMPLE 37: (1R, 2S) -1- (1H-indol-1-yl) -3- (methylamino) -1- [2-

<img file="PL1732887T3_D0023.tif" />

[0274] In an analogous manner to EXAMPLE 117, step 5, (2R, 3R) -3- (1H-indol-1-yl) -3- [2- (trifluoromethoxy) phenyl] propan-1, 2-diol was prepared from 1H-indole and {(2S, 3S) -3- [2- (trifluoromethoxy) phenyl] oxiran-2-yl} methanol (EXAMPLE 36, step 3) substituting sodium tert-butoxide in place of potassium hydride. MS (ES) m / z 352 ([M + H] +).

[0275] In an analogous manner to EXAMPLE 1, step 2, 2-hydroxy-3-indol-1-yl-3- (2-trifluoromethoxy-phenyl) -propyl ester of (2R, 3R) -toluene-4-sulfonic acid (2R, 3R) -3- (1H-indol-1-yl) -3- [2- (trifluoromethoxy) phenyl] propan-1,2-diol. MS (ES) m / z 506 ([M + H] +). [0276] In an analogous manner to EXAMPLE 33, step 6, (1R, 2S) hydrochloride -1- (1H-indol1-y) -3- (methylamino) -1- [2- (trifluoromethoxy) phenyl] propan-2 -ol was prepared from 2-hydroxy-3-indol-1-yl (3- (2-trifluoromethoxy-phenyl) -propyl ester of (2R, 3R) -toluene-4-sulfonic acid and methylamine (2N solution in methanol). MS (ES) m / z 365 ([M + H] +).

[0277] EXAMPLE 38: (1S, 2R) -1- (2-chlorophenyl) -1- (1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0024.tif" />

[0278] In an analogous manner to EXAMPLE 33, step 1, (2E) -3- (2-chlorophenyl) acrylic acid ethyl ester was prepared from diethyl ethoxycarbonylmethylphosphonate and 2-chlorobenzaldehyde. MS (ESI) m / z 210 ([M + H] +).

[0279] In an analogous manner to EXAMPLE 33, step 2, (2E) -3- (2-chlorophenyl) prop-2-en-1-ol was prepared from (2E) -3- (2-chlorophenyl) acid ethyl ester butyl ester. MS (ESI) m / z 151 ([M + HH 2 O] +).

[0280] In an analogous manner to EXAMPLE 36, step 3, [(2RS, 3RS) -3- (2-chlorophenyl) oxiran-2-yl] methanol was prepared from (2E) -3- (2-chlorophenyl) prop-2- en-1-ol.

[0281] [(2RS, 3RS) -3- (2-chlorophenyl) oxiran-2-yl] methanol was dissolved in methanol. The resulting solution was injected (50 mg / injection) into the supercritical phase mobile chromatography apparatus, and the base line of separated enantiomers was drawn using the conditions described below. The enantiomeric purity of each enantiomer was determined under the same conditions as for the supercritical mobile phase chromatography using a Chiralpak AD-H 5u column, 250 mm x 4.6 mm ID at a flow rate of 2.0 ml / minute, a mobile phase analytical chromatography apparatus was used supercritical (Berger Instruments, Inc. Newark, DE USA).

<td>SFC device:</td><td>Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE19702.</td>

<td>Column:</td><td>Chiralpak AD-H; 5u; 250mm L x 20mm ID (Chiral Technologies, Inc, Exton, PA, USA</td>

<td>Temperature column:</td><td>35 ° C</td>

<td>SFC modifier:</td><td>20% MeOH / 80% CO2</td>

EP 1 732 887 B1

<td>Flow rate:</td><td>50 ml / min</td>

<td>Output pressure:</td><td>100 bars</td>

<td>Detector:</td><td>UV at 220 nm</td>

[(2S, 3S) -3- (2-chlorophenyl) oxiran-2-yl] methanol was isolated as peak 1. MS (ES) m / z 167 ([M + H-H2O] +); [□] D²⁵ = + 2.6 ° (c = 0.0153 g / ml, DMSO); > 99.8% ee.

[0283] [(2R, 3R) -3- (2-chlorophenyl) oxiran-2-yl] methanol was isolated as peak 2. MS (ES) m / z 167 ([M + H-H2O] +); [□] D²⁵ = -2.5 ° (c = 0.0139 g / ml, DMSO); > 99.8% ee.

[0284] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (2-chlorophenyl) -3- (1Hindol-1-yl) propan-1,2-diol was prepared from 1H-indole and [(2R, 3R) -3- (2-chlorophenyl) oxiran-2-yl] methanol, sodium tert-butoxide was substituted in place of potassium hydride. MS (ES) m / z 302 ([M + H] +).

[0285] In an analogous manner to EXAMPLE 1, step 2, 3- (2-chlorophenyl) -2-hydroxy-3-indol-1-yl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid was prepared from (2S , 3S) -3- (2-chloro- phenyl) 3- (1H-indol-1-yl) -propan-1,2-diol. MS (ES) m / z 456 ([M + H] +).

[0286] In an analogous manner to EXAMPLE 33, step 6, (1S, 2R) -1- (2-chlorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol hydrochloride was prepared from 3- (2-chlorophenyl) -2-hydroxy-3-indol-1-yl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol). MS (ES) m / z 315 ([M + H] +).

[0287] EXAMPLE 39: (1RS, 2SR) -1- (1H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol hydrochloride.

<img file="PL1732887T3_D0025.tif" />

[0288] Step 1: In an analogous manner to EXAMPLE 33, step 1, (2E) -3 (4-trifluoromethoxy-phenyl) -acrylic acid ethyl ester was prepared from diethyl ethoxycarbonylmethylphosphonate and 4- (trifluoromethoxy) benzaldehyde. MS (ES) m / z 261 ([M + H] +).

[0289] Step 2: In an analogous manner to EXAMPLE 33, step 2, (2E) -3- [4- (trifluoromethoxy) phenyl] prop-2-en-1-ol was prepared from (2E) -3- acid ethyl ester (4-trifluoromethoxy-phenyl) -acrylic acid. MS (ES) m / z 201 ([M + H-H2O] +).

[0290] Step 3: In an analogous manner to EXAMPLE 36, step 3, {(2RS, 3RS) -3- [4- (trifluoromethoxy) phenyl] oxiran-2-yl) methanol was prepared from (2E) -3- [4 - (trifluoromethoxy) phenyl] prop-2-en-1-ol. MS (ES) m / z 217 ([M + H-H2O] +).

[0291] Step 4: In an analogous manner to EXAMPLE 33, step 4a (Method B), (2RS, 3RS) -3 (2,3-dihydro-1H-indol-1-yl) -3- [4- ( trifluoromethoxy) phenyl] propane-1,2-diol was prepared from indoline and {(2RS, 3RS) -3- [4- (trifluoromethoxy) phenyl] oxiran-2-yl) methanol. MS (ES) m / z 354 ([M + H] +).

[0292] Step 5: In an analogous manner to EXAMPLE 33, step 4b (Method B), (2RS, 3RS) -3 (1H-indol-1-yl) -3- [4- (trifluoromethoxy) phenyl] propan- 1,2-diol was prepared from (2RS, 3RS) -3- (2,3-dihydro64

EP 1 732 887 B1

1H-indol-1-yl) -3- [4- (trifluoromethoxy) phenyl] propan-1,2-diol. MS (ES) m / z 352 ([M + H] +).

[0293] Step 6: In an analogous manner to EXAMPLE 1, step 2, 2-hydroxy-3-indol-1-yl-3- (4-trifluoromethoxy-phenyl) -propyl ester of (2RS, 3RS) -toluene-4- sulfone was prepared from (2RS, 3RS) -3- (1H-indol-1-yl) -3- [4- (trifluoromethoxy) phenyl] propan-1,2-diol. MS (ES) m / z 506 [(M + H] +).

[0294] Step 7: In an analogous manner to EXAMPLE 33, step 6 (Method B), (1RS, 2SR) hydrochloride -1- (1H-indol-1-yl) -3- (methylamino) -1- [4 - (trifluoromethoxy) phenyl] propan-2-ol prepared from 2-hydroxy-3-indol-1-yl-3- (4-trifluoromethoxy-phenyl) -propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid and methylamine ( 2N solution in methanol). MS (ES) m / z 365 ([M + H] +).

[0295] EXAMPLE 40: (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol hydrochloride.

<img file="PL1732887T3_D0026.tif" />

[0296] Step 1: (1RS, 2SR) -1- (1H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol hydrochloride (EXAMPLE 39, step 7), dissolved in methanol. The resulting solution was injected (35 mg / injection) into the supercritical phase mobile chromatography apparatus, and a base line of separated enantiomers was drawn using the conditions described below. The enantiomeric purity of each enantiomer was determined under the same conditions as for the supercritical mobile phase chromatography using a Chiralpak AD-H 5u column, 250 mm x 4.6 mm ID, at a flow rate of 2.0 ml / min, using a mobile phase analytical chromatography apparatus supercritical state (Berger Instruments, Inc. Newark, DE USA).

<td>SFC device:</td><td>Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE19702.</td>

<td>Column:</td><td>Chiralpak AD-H; 5u; 250mm L x 20mm ID (Chiral Technologies, Inc, Exton, PA, USA</td>

<td>Temperature column:</td><td>35 ° C</td>

<td>SFC modifier:</td><td>25% MeOH w / 1.0% DEA / 75% CO2</td>

<td>Flow rate:</td><td>50 ml / min</td>

<td>Output pressure:</td><td>100 bars</td>

<td>Detector:</td><td>UV at 220 nm</td>

[0297] (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol hydrochloride was isolated as peak 1 after neutralization and transformation the free base as the hydrochloride salt according to EXAMPLE 33, step 6. MS (ES) m / z 365 ([M + H] +); 98.4% ee.

[0298] EXAMPLE 41: (1R, 2S) -1- (1H-indol-1-yl) -3- (methylamino) -1- [4- hydrochloride

<img file="PL1732887T3_D0027.tif" />

[0299] (1 R, 2S) -1- (1H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol hydrochloride (EXAMPLE 40, step 1) was isolated as peak 2 after neutralization and conversion of the free base into the hydrochloride salt according to EXAMPLE 33, step 6. MS (ES) m / z 365 ([M + H] +); > 99.9% ee.

[0300] EXAMPLE 42: (1S, 2R) -4-amino-1- (3-chlorophenyl) -1- (1H-indol-1-yl) butan-2- hydrochloride

<img file="PL1732887T3_D0028.tif" />

(2S, 3S) -toluene-4-sulfonic acid (EXAMPLE 33, step 5, 1.9 g, 4.2 mmol) and sodium cyanide (0.23 g, 4.7 mmol) in dry dimethyl sulfoxide (20 ml) heated at 100 ° C (microwaves) . After 15 minutes, the cooled solution was collected in ethyl acetate (200 mL), washed with water (3x 200 mL), dried (sodium sulfate) and concentrated in vacuo to give a beige foam (1.3 g) which was pre-adsorbed onto silica gel (3 g) . Flash column chromatography (30 g silica, 10%, 20%, 40% ethyl acetate / hexanes) gave (3R, 4S) -4- (3-chlorophenyl) -3-hydroxy-4-indol-1-yl-butyronitrile (1.2 g, 92%) as a beige foam. MS (ES) m / z 311 ([M + H] +).

[0302] Step 2: A solution of (3R, 4S) -4- (3-chlorophenyl) -3-hydroxy-4-indol-1-yl-butyronitrile (1.2 g, 3.9 mmol) in dry tetrahydrofuran (20 mL) was treated with a solution diborane-tetrahydrofuran (1.0M solution, 20 ml, 20 mmol) at 23 ° C. After 16 hours, the reaction was quenched with methanol (7 mL) at 23 ° C and the solution concentrated in vacuo to give an off-white foam, which was partitioned between diethyl ether (200 mL) and 1N aqueous sodium hydroxide solution (200 mL). The organic phase was separated, washed with brine (200 ml), dried (sodium sulfate) and concentrated in vacuo to give a yellow foam (1.2 g), which was purified on a Biotage chromatographic system [AnaLogix silica column, 2x 40 g in series, dichloromethane to 5% ammonia saturated methanol / dichloromethane] to obtain (1S, 2R) -4-amino-1- (3-chlorophenyl) -1- (1H-indol-1-yl) butan-2-ol (0.43 g, 36%). The free base was converted into the hydrochloride salt as described in EXAMPLE 33, step 6, to give (1S, 2R) -4-amino-1- (3-chlorophenyl) -1- (1H-indol-1-yl) butan2- hydrochloride olu (0.47 g, 34%) as a foam. MS (ES) m / z 315 ([M + H] +).

[0303] EXAMPLE 43: (1S, 2R) -1- (3-bromophenyl) -1- (1H-indol-1-yl) -3 (methylamino) propan-2-ol hydrochloride.

EP 1 732 887 B1

<img file="PL1732887T3_D0029.tif" />

[0304] Step 1: In an analogous manner to EXAMPLE 33, step 1, (2E) -3 (3-bromophenyl) acrylic acid ethyl ester was prepared from diethyl ethoxycarbonylmethylphosphonate and 3-bromobenzaldehyde. MS (ES) m / z 255 ([M + H] +).

[0305] Step 2: In an analogous manner to EXAMPLE 33, step 2, (2E) -3- (3-bromophenyl) prop2-en-1-ol was prepared from (2E) -3- (3-bromophenyl) ethyl ester ) acrylic acid. MS (ES) m / z 195 ([M + H-H2O] +).

[0306] Step 3: In an analogous manner to EXAMPLE 117, step 4, [(2R, 3R) -3- (3-bromophenyl) oxiran-2-yl] methanol was prepared from (2E) -3- (3-bromophenyl) prop -2-en-1-ol. MS (ES) m / z 211 ([M + H-H2O] +); 95% ee.

[0307] Step 4: In an analogous manner to EXAMPLE 33, step 4a (Method B), (2S, 3S) -3- (3-bromophenyl) -3- (2,3-dihydro-1H-indol-1-yl) propane-1,2-diol was prepared from indoline and [(2R, 3R) -3- (3-bromophenyl) oxiran-2-yl] methanol. MS (ES) m / z 348 ([M + H] +).

[0308] Step 5: In an analogous manner to EXAMPLE 33, step 4b (Method B), (2S, 3S) -3- (3-bromophenyl) -3- (1H-indol-1-yl) propane-1,2- diol was prepared from (2S, 3S) -3- (3-bromophenyl) -3- (2,3-dihydro-1H-indol-1-yl) propan-1,2-diol. MS (ES) m / z 346 ([M + H] +).

[0309] Step 6: In an analogous manner to EXAMPLE 1, step 2, 3- (3-bromophenyl) -2-hydroxy3-indol-1-yl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid from (2S, 3S) -3- (3-bromophenyl) -3- (1H-indol-1-yl) propan-1,2-diol. MS (ES) m / z 500 ([M + H] +).

[0310] Step 7: In an analogous manner to EXAMPLE 33, step 6, (1S, 2R) -1- (3-bromophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2 hydrochloride -ol was prepared from 3- (3-bromophenyl) -2-hydroxy-3-indol-1-yl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol). MS (ES) m / z 359 ([M + H] +).

[0311] EXAMPLE 44: 3 - [(1S, 2R) -2-hydroxy-1- (1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0030.tif" />

[0312] A mixture of (2S, 3S) -3- (3-bromophenyl) - (1H-indol-1-yl) propan-1,2-diol (EXAMPLE 43, step 5, 1.4 g, 4.0 mmol), zinc cyanide (II) (4.7 g, 40 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.46 g, 0.40 mmol) in degassed 1-methyl-2-pyrrolidinone (25 ml) was heated at 150 ° C in a closed flask. After 3.5 hours, the cooled brown mixture was diluted with ethyl acetate (250 mL) and filtered through a pad of Celite. The filtrate was washed with water (5x 250 mL) and brine (1x 250 mL), dried (sodium sulfate), and concentrated in vacuo to give an amber oil (1.6 g)

EP 1 732 887 B1 which was pre-adsorbed onto silica gel (6 g). Flash column chromatography (silica 70 g, 30%, 60% ethyl acetate / hexanes) gave 3 - [(1S, 2S) -2,3-dihydroxy-1- (1H-indol1-yl) propyl] benzonitrile (1.0 g , 83%) as a light yellow foam. MS (ES) m / z 293 ([M + H] +).

[0313] In an analogous manner to EXAMPLE 1, step 2, 3- (3-cyano-phenyl) -2-hydroxy-3-indol-1-yl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid 3 - [(1S, 2S) -2,3-dihydroxy-1- (1H-indol-1-yl) propyl] benzonitrile. MS (ES) m / z 447 ([M + H] +).

[0314] In an analogous manner to EXAMPLE 33, step 6, 3 - [(1S, 2R-2-hydroxy1- (1H-indol-1-yl) -3- (methylamino) propyl] benzonitrile hydrochloride was prepared from 3- ( 3-cyano-phenyl) -2-hydroxy-3-indol-1-yl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 306 ([ M + H] +).

[0315] EXAMPLE 45: (1SR, 2RS) -3- (methylamino) -1- (4-methyl-3,4- hydrochloride salt)

<img file="PL1732887T3_D0031.tif" />

[0316] Step 1: In an analogous manner to EXAMPLE 53, step 3, 3-phenylglycidolide was prepared from cinnamon alcohol as a white solid. MS (ES) m / z 151.1 ([M + H] +).

[0317] Step 2: In an analogous manner to EXAMPLE 47, step 4, (2SR, 3SR) -3- (4-methyl-3,4-dihydroquinoxalin-1 (2H) -yl) -3-phenylpropane-1,2- diol was prepared from 1-methyl-1,2,3,4-tetrahydroquinoxaline¹ and 3-phenylglycidol as a viscous colorless oil. MS (ES) m / z 299.0 ([M + H] +); HRMS: calcd for C18H22N2O2 + H +, 299.1760; found (ESI, [M + H] +), 299.1739.

¹Cavagnol, JC; Wiselogle, FYJ Am. Chem. Soc. 1947, 69, 795-799.

[0318] Step 3: In an analogous manner to EXAMPLE 47, step 6, (1SR, 2RS) -3 (methylamino) -1- (4-methyl-3,4-dihydroquinoxalin-1 (2H) -yl) - hydrochloride 1-phenylpropan-2-ol was prepared from (2SR, 3SR) -3- (4-methyl-3,4-dihydroquinoxalin-1 (2H) -yl) -3-phenylpropane-1,2-diol as a white powder. MS (ES) m / z 312.0 ([M + H] +); HRMS: calcd for C19H25N3O + H +, 312.2076; found (ESI, [M + H] +), 312.2065.

[0319] EXAMPLE 46: (1SR, 2RS) -3- (methylamino) -1-phenyl-1- [4- (2,2,2- hydrochloride hydrochloride)

<img file="PL1732887T3_D0032.tif" />

[0320] Compound 1- (2,2,2-trifluoroethyl) -1,2,3,4-tetrahydroquinoxaline was obtained as a white powder as a byproduct of the reaction of reducing quinoxaline to 1,2,3,4-tetrahydroquinoxaline with sodium borohydride in trifluoroacetic acid.² MS (ES) m / z 217.1 ([M + H] +).

² Bugle, RC; Osteryoung, PARADISE Org. Chem. 1979, 44, 1719-1720.

[0321] In an analogous manner to EXAMPLE 47, step 4, (2SR, 3SR) -3- (4- (2,2,2-trifluoroethyl) 3,4-dihydroquinoxalin-1 (2H) -yl) -3- phenylpropane-1,2-diol prepared from 1- (2,2,2-trifluoroethyl) -1,2,3,468

Tetrahydroquinoxaline and 3-phenylglycidol (EXAMPLE 45, step 1) as a viscous colorless oil.

[0322] In an analogous manner to EXAMPLE 47, step 6, (1SR, 2RS) -3 (methylamino) -1-phenyl-1- [4- (2,2,2-trifluoroethyl) -3,4-dihydroquinoxaline hydrochloride -1 (2H) -yl] propan-2-ol was prepared from (2SR, 3SR) -3- (4- (2,2,2-trifluoroethyl) -3,4-dihydroquinoxalin-1 (2H) -yl) - 3-phenylpropane-1,2-diol as a white powder. MS (ES) m / z 380.0 ([M + H] +); HRMS: calcd for C20H24F3N3O + H +, 380.1950; found (ESI, [M + H] +), 380.1934.

[0323] EXAMPLE 47: (1S, 2R) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0033.tif" />

[0324] Step 1: To a mixture of trans-3-fluorocinnamic acid (50 g, 300 mmol) and iodomethane (300 mL) in acetone (1 liter), cesium carbonate (147 g, 450 mmol, 1.5 equivalents) was added in portions, and the mixture was heated at 65 ° C for 1.5 hours in a closed reaction vessel. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (1 L), filtered through a pad of silica gel, and concentrated to give 47.33 g (87%) of trans-3-fluoro-cinnamic acid methyl ester as a colorless oil. MS (ES) m / z 180.0 (M +). [0325] Step 2: To a solution of trans-3-fluorocinnamic acid methyl ester (69.61 g, 386 mmol) in dry dichloromethane (1 liter) at -78 ° C under a nitrogen atmosphere, diisobutylaluminum hydride (pure, 172 ml, added dropwise) 965 mmol, 2.5 equivalents) through an additional funnel. After the addition was complete, the reaction mixture was allowed to warm to -30 ° C and stirred for an additional 1 hour, followed by quenching with methanol (150 mL). After warming to room temperature, the reaction mixture was treated with saturated aqueous sodium / potassium tartrate solution (300 mL) and stirred for 30 minutes. The organic layer was washed successively with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine, and dried (anhydrous sodium sulfate). The crude oil was purified by silica gel chromatography (0-50% ethyl acetate: hexane) to give 53.07 g (90%) of trans-3-fluoro-cinnamyl alcohol as a colorless oil. MS (ES) m / z 152.1 (M +). [0326] Step 3: An oven-dried, 3-neck, 2-liter round bottom flask equipped with two oven-dried additional funnels and a rubber septum was filled with di-isopropyl D-tartrate (11.55 g, 49.3 mmol, 0.30 equivalent), 4 A powdered, activated molecular sieves (40 g) and dry dichloromethane (800 ml) under a nitrogen atmosphere. After cooling to -25 ° C, titanium isopropoxide (9.6 mL, 33 mmol, 0.20 equiv) was slowly added to the reaction mixture via a hypodermic syringe. After stirring for 10 minutes, anhydrous t-butyl hydroperoxide (5.5M solution in decane, 75.0 mL, 413 mmol, 2.5 equivalents) was added at an average speed through an additional funnel. The resulting mixture was stirred at 25 ° C for 30 minutes. Frans-3-fluorocinnamic alcohol (25.0 g, 164 mmol) in dry dichloromethane (50 mL) was added dropwise through an additional funnel, maintaining the temperature at -25 ° C. After the addition, the reaction mixture was stirred at -25 ° C for 1 hour and at 20 ° C for a further 3 hours. After the reaction was completed, the cooled aqueous solution was slowly added

EP 1 732 887 B1

After completion of the reaction, cooled aqueous sodium hydroxide solution (30%, 20 mL) saturated with sodium chloride was slowly added at -20 ° C. After addition of diethyl ether (150 mL), the cooling bath was removed and the mixture was allowed to warm to -5 ° C and stirred for 1 hour. Magnesium sulfate (anhydrous, 50 g) was added and the mixture was stirred for 20 minutes, then filtered through a pad of silica gel, and washed with ether (300 mL). The filtrate was concentrated and toluene was used to azeotropically remove excess t-butyl hydroperoxide. The residual oil was purified on silica gel (0-30% ethyl acetate: hexane) to obtain 24.80 g (90%) [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol as a viscous, colorless oil . Percentage of ee:> 96.5%. MS (ESI) m / z 169.1 ([M + H] +).

[0327] Step 4: A mixture of indoline (1.42 g, 11.89 mmol) and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (2.0 g, 11.89 mmol) was heated at 125 ° C for 5 hours in a sealed reaction vial. After cooling, the crude product was dissolved in ethyl acetate, absorbed onto Fluorocil, and purified on a Biotage chromatography system (FlasH40i, silica, 0-55% EtOAc / hexane) to give 2.55 g (75%) (2S, 3S) -3- ( 2,3-dihydro-1H-indol-1-yl) -3- (3-fluorophenyl) propane-1,2-diol as a colorless oil. MS (ESI) m / z 288.1 ([M + H] +).

[0328] Step 5: Mixture (2S, 3S) -3- (2,3-dihydro-1H-indol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol (2.00 g, 6.96 mmol) and activated manganese dioxide (20.0 g, 230 mmol) in dichloromethane (30 ml) was stirred at 20 ° C for 3 hours. The mixture was then diluted with ethyl acetate (15 mL), filtered through a silica gel pad, and concentrated. The crude product was purified by Biotage chromatography (FlasH40i, silica, 0-70% EtOAc / hexane) to give 1.40 g (71%) (2S, 3S) -3- (3-fluorophenyl) -3- (1H-indol-1 -yl) propane-1,2-diol as a colorless oil. MS (ESI) m / z 286.0 ([M + H] +). HRMS: calcd for C17H16FNO2 + H +, 286.1238; found (ESI, [M + H] +), 286.1239.

Step 6: To (2S, 3S) -3- (2,3-dihydro-1H-indol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol solution (452 ​​mg, 1.586 mmol) in dichloromethane (3 mL) under nitrogen atmosphere, triethylamine (1.1 mL, 7.93 mmol) was added. The mixture was then cooled to 0 ° C, and para-toluenesulfonyl chloride (423 mg, 2.22 mmol) was added in portions. The reaction mixture was stirred at 0 ° C for 1 hour and stored at 0 ° C overnight. Methylamine in absolute ethanol (8M solution, 5 mL, 40 mmol) was added and the reaction mixture was sealed, and stirred overnight with warming to room temperature. All volatiles were removed under reduced pressure. The oily residue was dissolved in dichloromethane (20 mL), washed with aqueous potassium carbonate solution (5 mL), dried (anhydrous sodium sulfate), and concentrated. Purified by Biotage chromatography (FlasH12i, silica, 0-15% MeOH / dichloromethane / 0.5% triethylamine) to give (1S, 2R) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3 (methylamino) propan-2-ol, which was dissolved in dichloromethane (5 mL) and treated with 1M ethereal solution of hydrochloric acid (1.9 mL, 1.9 mmol). Hexane was added to the resulting solution until a white powder formed, which was collected, washed with hexane, and dried in vacuo to give 209 mg (44%) of (1S, 2R) -1- (3-fluorophenyl) -1- (1H-indole hydrochloride) -1-yl) -3 (methylamino) propan-2-ol as a white powder. MS (ES) m / z 299.0 ([M + H] +); HRMS: calcd for C18H19FN2O + H +, 299.1554; found (ESI, [M + H] +), 299.1553.

[0330] EXAMPLE 48: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [3- (3- (hydrochloride) hydrochloride

<img file="PL1732887T3_D0034.tif" />

[0331] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3-fluorophenyl) -3- {3- [3-methylphenyl] -1H-indol-1-yl} propane-1,2 -diol prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1Hindol-1-yl) propane-1,2-diol (EXAMPLE 114, step 1) and 3-methylbenzeneboronic acid .

[0332] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- [3- (2-chlorophenyl) -indol-1-yl] -2-hydroxy-propyl acid ester (2S, 3S) -toluene-4-sulfone was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- {3- [3-methylphenyl] -1H-indol-1-yl} propan-1,2-diol.

[0333] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (3-fluorophenyl) -3 (methylamino) -1- [3- (3-methylphenyl) -1H-indol-1-yl] hydrochloride propan-2-ol was prepared from 3- (3-fluoro-phenyl) -3- [3- (3-methyl-phenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) -toluene-4 -sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 389.2; HRMS: calcd for C25H25FN2O + H +, 389.20237; found (ESI, [M + H] +), 389.2005.

[0334] EXAMPLE 49: (1S, 2R) -1- (4-fluorophenyl) -3- (methylamino) -1- (3-methyl-1H- hydrochloride

<img file="PL1732887T3_D0035.tif" />

fluorophenyl) oxiran-2-yl] methanol prepared from trans-4-fluorocinnamic alcohol³ as a white solid. Percentage of ee:> 97%. MS (ES) m / z 167.0 ([MH]^-).

³Takeuchi, R .; Ue. N .; Tanabe, K.; Yamashita, K .; Shiga, NJ Am. Chem. Soc., 2001, 123, 95259534.

[0336] Step 2: In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (4-fluorophenyl) -3 (3-methyl-1H-indol-1-yl) propane-1,2 -diol was prepared from 3-methylindole and [(2R, 3R) -3- (4-fluorophenyl) oxiran-2-yl] methanol as a viscous, colorless oil. MS (ES) m / z 300.1 ([M + H] +); HRMS: calcd for C18H18FNO2 + H +, 300.1400; found (ESI, [M + H] +), 300.1406.

[0337] Step 3: In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (4-fluorophenyl) -3- (methylamino) -1- (3-methyl-1H-indol-1-yl hydrochloride) ) propan-2-ol was prepared from (2S, 3S) -3- (4-fluorophenyl) -3- (3-methyl-1H-indol-1-yl) propan-1,2-diol as a white powder. MS (ESI) m / z 313.1 ([M + H] +); HRMS: calculated for C19H21FN2O + H⁺, 313.1711; found (ESI, [M + H] +), 313.1727.

[0338] EXAMPLE 50: (1S, 2R) -1- (2-fluorophenyl) -1- (1H-indol-1-yl) -371 hydrochloride

EP 1 732 887 B1

<img file="PL1732887T3_D0036.tif" />

[0339] In an analogous manner to EXAMPLE 47, step 1, trans-2-fluorocinnamic acid methyl ester was prepared from trans-2-fluorocinnamic acid as a white solid. MS m / z 180.9 ([M + H] +).

[0340] In an analogous manner to EXAMPLE 47, step 2, trans-2-fluorocinnamic alcohol was prepared from trans-2-fluorocinnamic acid methyl ester as a colorless oil. MS (ESI) m / z 152.0 [M] +; HRMS: calcd for C9H9FO, 152.0637; found (ESI, [M] +), 152.0640.

[0341] In an analogous manner to EXAMPLE 47, step 3, [(2R, 3R) -3- (2-fluorophenyl) oxiran-2-yl] methanol was prepared from trans-2-fluorocinnamic alcohol as a white solid. MS m / z 169.0 ([M + H] +).

[0342] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (2-fluorophenyl) -3- (1Hindol-1-yl) propane-1,2-diol was prepared from indole and [( 2R, 3R) -3- (2-fluorophenyl) oxiran-2-yl] methanol as a viscous, colorless oil. MS (ES) m / z 286.2 ([M + H] +); HRMS: calculated for C17H16FNO2 + H +,

286.1238; found (ESI, [M + H] +), 286.1231.

[0343] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (2-fluoro-phenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol hydrochloride was prepared from (2S, 3S) -3- (2-fluorophenyl) 3- (3-methyl-1H-indol-1-yl) propan-1,2-diol as a white powder. MS (ES) m / z 299.1 ([M + H] +); HRMS: calcd for C18H19FN2O + H +, 299.1554; found (ESI, [M + H] +), 299.1557.

[0344] EXAMPLE 51: (1S, 2R) -1- (4-fluorophenyl) -1- (1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0037.tif" />

[0345] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (4-fluorophenyl) -3- (1Hindol-1-yl) propane-1,2-diol was prepared from indole and [3 - (4-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 49, step 1) as a viscous, colorless oil. MS (ES) m / z 286.1 ([M + H] +); HRMS: calcd for C17H16FNO2 + H +, 286.1238; found (ESI, [M + H] +), 286.1230.

[0346] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (4-fluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol hydrochloride was prepared from (2S, 3S) -3- (4-fluorophenyl) 3- (1H-indol-1-yl) propan-1,2-diol as a white powder. MS (ES) m / z 299.1 ([M + H] +).

[0347] EXAMPLE 52: (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (3-methylphenyl) propan-2-ol hydrochloride.

EP 1 732 887 B1

<img file="PL1732887T3_D0038.tif" />

[0348] In an analogous manner to EXAMPLE 47, step 1, trans-3-methyl cinnamic acid methyl ester was prepared from trans-3-methyl cinnamic acid.

[0349] In an analogous manner to EXAMPLE 47, step 2, trans-3-methyl cinnamyl alcohol was prepared from trans-3-methyl cinnamic acid methyl ester as a colorless oil.

[0350] In an analogous manner to EXAMPLE 47, step 3, [(2R, 3R) -3- (3-methylphenyl) oxiran-2-yl] methanol was prepared from trans-3-methyl cinnamyl alcohol as a colorless oil. HRMS: calcd for C 10 H 12 O 2 + H +, 165.0916; found (ESI, [M + H] +), 165.0926.

[0351] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (1H-indol-1-yl) -3- (3-methylphenyl) propane-1,2-diol was prepared from indole and [( 2R, 3R) -3- (3-methylphenyl) oxiran-2-yl] methanol as a viscous, colorless liquid. MS (ES) m / z 282.1 ([M + H] +); HRMS: calcd for C18H19NO2 + H +, 282.1494; found (ESI, [M + H] +), 282.1488.

[0352] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (1H-indol1-yl) -3- (methylamino) -1- (3-methylphenyl) propan-2-ol hydrochloride was prepared from (2S, 3S) -3- (1H-indol-1-yl) -3- (3-methylphenyl) propan-1,2-diol as a white powder. MS (ES) m / z 295.3 ([M + H] +); HRMS: calcd for C19H20N2O + H +, 295.1805; found (ESI, [M + H] +), 295.1799.

[0353] EXAMPLE 53: (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2- hydrochloride)

<img file="PL1732887T3_D0039.tif" />

[0354] Step 1: In an analogous manner to EXAMPLE 47, step 1, trans2-methyl cinnamic acid methyl ester was prepared from trans-2-methyl cinnamic acid.

[0355] Step 2: In an analogous manner to EXAMPLE 47, step 2, trans-2-methyl cinnamyl alcohol was prepared from trans-2-methyl cinnamic acid methyl ester as a colorless oil. MS (ES) m / z 146.9 ([MH]^-).

[0356] Step 3: To a solution of trans-2-methylcinnamyl alcohol (1.50 g, 10.14 mmol) in dichloromethane (30 mL) was added sodium carbonate (1.50 g, 14.19 mmol). The mixture was cooled to 10 ° C and peracetic acid (32% by weight, 2.56 ml, 12.16 mmol) was added dropwise through an additional funnel. The reaction mixture was stirred for 3 hours with warming to room temperature, and the reaction was quenched slowly with saturated aqueous sodium sulfite solution (15 mL). More dichloromethane (30 mL) was added and the mixture was extracted. The organic layer was washed with brine, dried (anhydrous sodium sulfate), and concentrated. The oily residue was purified by silica gel chromatography (10-30% EtOAc / hexane) to give 920 mg (55%) of 3- (2-methylphenyl) glycidol as a colorless oil. HRMS: calcd for C 10 H 12 O 2 + H +, 165.0916; found (ESI, [M + H] +), 165.0936.

[0357] Step 4: In an analogous manner to EXAMPLE 117, step 5, (2SR, 3SR) -3- (1H-indol-1-yl) -3- (2-methylphenyl) propane-1,2 - diol was prepared from indole and 3- (2-methylphenyl) glycidol as a viscous, colorless liquid. MS (ES) m / z 282.2 ([M + H] +); HRMS: calcd for C18H19NO2 + H +, 282.1494;

found (ESI, [M + H] +), 282.1499.

[0358] Step 5: In an analogous manner to EXAMPLE 47, step 6, (1SR, 2RS) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2- ol was prepared from (2SR, 3SR) -3- (1H-indol-1-yl) -3- (2-methylphenyl) propan-1,2-diol as an oil.

[0359] Step 6: Racemic (1SR, 2RS) 1- (1H-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan2-ol was dissolved in ethanol (20 mg / ml). The resulting solution was injected into the supercritical phase mobile chromatography apparatus in 1 ml increments. The baseline of the separated enantiomers was drawn using the conditions described below. Enantiomeric purity for each enantiomer was determined under similar conditions to supercritical mobile phase chromatography, a Chiralcel OJ-H 5u column, 250 mm L x 4.6 mm ID was used, a flow phase analytical chromatography apparatus was used at a flow rate of 1.2 mL / min. in a supercritical state (Berger Instruments, Inc. Newark, DE USA).

<td>SFC device:</td><td>Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE 19702.</td>

<td>Column:</td><td>Chiralcel OJ-H; 5u; 250mm L x 20mm ID (Chiral Technologies, Inc., Exton, PA, USA)</td>

<td>Temperature column:</td><td>35 ° C</td>

<td>SFC modifier:</td><td>15% MeOH with 1.0% DEA / 85% CO2</td>

<td>Flow rate:</td><td>50 ml / min</td>

<td>Output pressure:</td><td>100 bars</td>

<td>Detector:</td><td>UV at 220 nm</td>

[0360] Step 7: In an analogous manner to EXAMPLE 144, step 2, (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propane- hydrochloride 2-ol was prepared as a white solid, from (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol, which was isolated as peak 1 from chiral separation (step 6). Chiral purity: 100%. MS (ESI) m / z 295.3 ([M + H] +); HRMS:

calculated for C19H22N2O + H +, 295.1805; found (ESI, [M + H] +), 295.1795.

[0361] EXAMPLE 54: (1R, 2S) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2- hydrochloride) hydrochloride

<img file="PL1732887T3_D0040.tif" />

[0362] In an analogous manner to EXAMPLE 53, step 7, (1R, 2S) -1- (1H-indol25 1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol hydrochloride prepared as a white solid, from (1R, 2S) -1 (1H-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol, which was isolated as peak 2 from a chiral separation (EXAMPLE 53, step 6). Chiral purity: 100%. MS (ESI) m / z 295.3

Separation (EXAMPLE 53, step 6). Chiral purity: 100%. MS (ESI) m / z 295.3 ([M + H] +); HRMS: calcd for C19H22N2O + H +, 295.1805; found (ESI, [M + H] +), 295.1805.

[0363] EXAMPLE 55: (1S, 2R) -3- (ethylamino) -1- (3-fluorophenyl) -1- (1H-indol-1- hydrochloride hydrochloride

<img file="PL1732887T3_D0041.tif" />

[0364] Step 1: In an analogous manner to EXAMPLE 1, step 2 (4S, 3S) -3- (3-fluorophenyl) -2-hydroxy-3- (1H-indol-1-yl) propyl 2,4-methylbenzenesulfonate made from (2S, 3S) -3- (3-fluorophenyl) -3- (1H-indol-1-yl) propan-1,2-diol (EXAMPLE 47, step 5) as an ivory solid. HRMS: calcd for C24H22FN2O4S + H +, 440.1326; found (ESI, [M + H] +), 440.1345. [0365] Step 2: (2S, 3S) -3- (3-fluorophenyl) -2-hydroxy-3- (1H-indol-1-yl) propyl 4-methylbenzenesulfonate (200 mg, 0.456 mmol) was dissolved in a solution of ethylamine in methanol (2.0M solution, 10 ml) and stirred for 12 hours in a closed reaction vessel. All volatiles were removed under reduced pressure, and the liquid residue was dissolved in dichloromethane (15 mL), washed with saturated aqueous potassium carbonate, dried (anhydrous sodium sulfate), and concentrated. Purification of the liquid residue on a Biotage chromatography system (FlasH12i, silica, 0-15% MeOH / dichloromethane / 0.5% triethylamine) gave (1S, 2R) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) - 3- (ethylamino) propan-2-ol, which was used to prepare (1S, 2R) -3- (ethylamino) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) propan-2 hydrochloride -ol, as a white powder, in an analogous manner to EXAMPLE 144, step 2. Yield: 99 mg (70%). MS (ES) m / z 313.1 ([M + H] +); HRMS: calcd for C19H21FN2O + H +, 313.1716; found (ESI, [M + H] +), 313.1716.

[0366] EXAMPLE 56: (1S, 2R) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3-morpholin-4-yl- hydrochloride

<img file="PL1732887T3_D0042.tif" />

[0367] In an analogous manner to EXAMPLE 55, step 2, (1S, 2R) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3-morpholin-4-yl-propan-2 hydrochloride -ol was prepared from morpholine and (2S, 3S) -3- (3-fluorophenyl) -2-hydroxy-3- (1H-indol-1-yl) propyl 4-methylbenzenesulfonate (EXAMPLE 55, step 1) as a white powder. MS (ES) m / z 355.1 ([M + H] +); HRMS: calcd for C 21 H 23 FN 2 O 2 + H +, 355.1816; found (ESI, [M + H] +), 355.1822.

[0368] EXAMPLE 57: (1S, 2R) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0043.tif" />

[0369] In an analogous manner to EXAMPLE 55, step 2, (1S, 2R) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- (propylamino) propane hydrochloride -2-ol was prepared from (2S, 3S) -3- (3-fluorophenyl) -2-hydroxy-3- (1H-indol-1-yl) propyl 4-methylbenzenesulfonate (EXAMPLE 55, step 1) as a white powder. MS (ES) m / z 327.1 ([M + H] +); HRMS: calcd for C 20 H 23 FN 2 O + H +, 327.1867; found (ESI, [M + H] +), 327.1873.

[0370] EXAMPLE 58: (1S, 2R) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) propan-2-ol dihydrochloride.

<img file="PL1732887T3_D0044.tif" />

[0371] In an analogous manner to EXAMPLE 55, step 2, (1S, 2R) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) dihydrochloride propan-2-ol was prepared from 1-methylpiperazine and (2S, 3S) -3- (3-fluorophenyl) -2-hydroxy-3- (1H-indol-1-yl) propyl 4-methylbenzenesulfonate (EXAMPLE 55, step 1) as a white powder . MS (ES) m / z 368.1 ([M + H] +); HRMS: calcd for C22H26FN3O + H +, 368.2133; found (ESI, [M + H] +), 368.2138.

[0372] EXAMPLE 59: (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (4-methylphenyl) propan-2-ol hydrochloride.

<img file="PL1732887T3_D0045.tif" />

[0373] In an analogous manner to EXAMPLE 47, step 3, [(2R, 3R) -3- (4-methylphenyl) oxiran-2-yl] methanol was prepared from trans-4-methyl cinnamyl alcohol³ as a colorless oil. MS (ES) m / z

165.1 ([M + H] +); HRMS: calcd for C12H12O2 + H +, 165.0916; found (ESI, [M + H] +), 165.0937. [0374] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (1H-indol-1-yl) -3- (4-methylphenyl) propane-1,2-diol was prepared from indole and [( 2R, 3R) -3- (4-methylphenyl) oxiran-2-yl] methanol as a viscous colorless liquid. MS (ES) m / z 282.1 ([M + H] +); HRMS: calcd for C18H19NO2 + H +, 282.1494; found (ESI, [M + H] +), 282.1492.

[0375] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (1H-indol1-yl) -3- (methylamino) -1- (4-methylphenyl) propan-2-ol hydrochloride was prepared from (2S, 3S) -3- (1H-indol-1-yl) -3- (4-methylphenyl) propan-1,2-diol as a white powder. MS (ES) m / z 295.1 ([M + H] +); HRMS: calcd for C19H22N2O + H +, 295.1805; found (ESI, [M + H] +), 295.1810.

[0376] EXAMPLE 60: (1S, 2R) -1- (2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) -3 (methylamino) propan-2-ol hydrochloride.

EP 1 732 887 B1

<img file="PL1732887T3_D0046.tif" />

[0377] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) hydrochloride propan-2-ol was prepared from (2S, 3S) -3- (2,3-dihydro-1H-indol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol (EXAMPLE 47, step 4) as a white solid. MS (ES) m / z 301.1 ([M + H] +); HRMS: calcd for C18H21FN2O + H +, 301.1711; found (ESI, [M + H] +), 301.1716.

[0378] EXAMPLE 61: (1S, 2R) -1- (2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0047.tif" />

[0379] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (2,3-dihydro-1H-indol-1-yl) -3-phenylpropane-1,2-diol was prepared from indoline and [ (2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a viscous, colorless oil. MS (ES) m / z 270.2 ([M + H] +); HRMS: calcd for C17H20NO2 + H +, 270.1494; found (ESI, [M + H] +), 270.1493.

[0380] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride made from (2S, 3S) -3- (2,3-dihydro-1H-indol-1-yl) -3-phenylpropane-1,2-diol as a white solid. MS (ES) m / z 283.1 ([M + H] +); HRMS: calcd for C18H21N2O + H +, 283.1805; found (ESI, [M + H] +), 283.1810.

[0381] EXAMPLE 63: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (2-methyl-2,3- hydrochloride

<img file="PL1732887T3_D0048.tif" />

[0382] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3-fluorophenyl) -3- (2-methyl-2,3-dihydro-1H-indol-1-yl) propan-1 , 2-diol was prepared from 2-methylindoline and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, colorless oil. MS (ES) m / z

302.1 ([M + H] +); HRMS: calcd for C18H20FNO2 + H +, 302.1551; found (ESI, [M + H] +), 302.1556.

[0383] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3-fluoro-phenyl) -3- (methylamino) -1- (2-methyl-2,3-dihydro-1H-indol-indol- hydrochloride) 1-yl) propan-2-ol was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (2-methyl-2,3-dihydro-1H-indol-1-yl) propan-1, 2-diol as a white solid. MS (ES) m / z 315.0 ([M + H] +); HRMS: calcd for C19H23FN2O + H +, 315.1867; found (ESI, [M + H] +), 315.1850.

[0384] EXAMPLE 64: (1S, 2R) -1- (7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) hydrochloride 77

EP 1 732 887 B1

<img file="PL1732887T3_D0049.tif" />

[0385] Step 1: A mixture of 7-fluoro-3,3-dimethyloxyindole (EXAMPLE 99, step 5, 2.24 g 12.5 mmol) in toluene (15 ml) under nitrogen was heated at 80 ° C. Vitride (strong reducing agent - sodium bis (2-methoxyethoxy) aluminum hydride) solution (65% by weight in toluene, 6 ml, 19.3 mmol) was added dropwise through an additional funnel. The resulting solution was stirred at 80 ° C for an additional 1.5 hours, and then cooled in an ice bath. Aqueous sodium hydroxide solution (1N solution, 15 ml) was slowly added to quench the reaction. Water (15 ml) was added and the reaction mixture was extracted with ethyl acetate (20 ml). The organic layer was washed with brine, dried (anhydrous sodium sulfate), filtered through a silica gel pad, and concentrated under reduced pressure to obtain 1.68 g (82%) of 7-fluoro-3,3-dimethylindoline as a colorless oil. MS (ES) m / z 166.1 ([M + H] +); HRMS: calcd for C 10 H 12 FN + H +, 166.1032; found (ESI, [M + H] +), 166.1040.

[0386] Step 2: In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3 - (3-fluorophenyl) propan-1,2-diol was prepared from 7-fluoro-3,3-dimethylindoline and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3 ) as a viscous, colorless oil. MS (ES) m / z 334.1 ([M + H] +); HRMS: calcd for C19H21F2NO2 + H +, 334.1613; found (ESI, [M + H] +), 334.1616.

[0387] Step 3: In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) - hydrochloride 1- (3-fluorophenyl) -3- (methylamino) propan-2-ol was prepared from (2S, 3S) -3- (7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1 -yl) -3- (3-fluorophenyl) propan-1,2-diol as a white solid. MS (ES) m / z 347 ([M + H] +); HRMS: calcd for C20H24F2N2O + H +, 347.1929; found (ESI, [M + H] +), 347.1935.

[0388] EXAMPLE 65: (1S, 2R) -1- (7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) 3- (methylamino) -1-phenylpropane hydrochloride 2-ol.

<img file="PL1732887T3_D0050.tif" />

[0389] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3-phenylpropan- 1,2-diol was prepared from 7-fluoro-3,3-dimethylindoline (EXAMPLE 64, step 1) and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as viscous, colorless oil. MS (ES) m / z 316.1 ([M + H] +); HRMS: calcd for C19H22FNO2 + H +, 316.1707; found (ESI, [M + H] +), 316.1690.

[0390] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (7-fluoro3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3- hydrochloride (( methylamino) -1-phenylpropan-2-ol was prepared from (2S, 3S) 78

EP 1 732 887 B1

3- (7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3-phenylpropane-1,2-diol as a white solid.

HRMS: calcd for C 20 H 25 FN 2 O + H +, 329.2029; found (ESI, [M + H] +), 329.2041.

[0391] EXAMPLE 66: (1S, 2R) -3- (methylamino) -1- (7-methyl-2,3-dihydro-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

[0392] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (7-methyl-2,3-dihydro-1Hindol-1-yl) -3-phenylpropane-1,2-diol was prepared from 7-methylindoline⁴ and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a viscous, colorless oil. MS (ES) m / z 284.2 ([M + H] +); HRMS: calcd for C18H21NO2 + H +, 284.1651; found (ESI, [M + H] +), 284.1650.

⁴ Gribble, GW; Hoffman, JH Synthesis 1977, 12.859-860.

[0393] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -3 (methylamino) -1- (7-methyl-2,3-dihydro-1H-indol-1-yl) -1- hydrochloride phenylpropan-2-ol was prepared from (2S, 3S) -3 (7-methyl-2,3-dihydro-1H-indol-1-yl) -3-phenylpropan-1,2-diol as a white solid. MS (ES) m / z 297.0 ([M + H] +); HRMS: calcd for C19H24N2O + H +, 297.1961; found (ESI, [M + H] +), 297.1957.

[0394] EXAMPLE 67: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (7-methyl-2,3-dihydro-1H-indol-1-yl) propan-2- hydrochloride ol.

[0395] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3-fluorophenyl) -3- (7-methyl-2,3-dihydro-1H-indol-1-yl) propan-1 , 2-diol was prepared from 7-methylindoline⁴ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, colorless oil. MS (ES) m / z

302.1 ([M + H] +); HRMS: calcd for C18H20FNO2 + H +, 302.1551; found (ESI, [M + H] +), 302.1551.

[0396] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3-fluoro-phenyl) -3- (methylamino) -1- (7-methyl-2,3-dihydro-1H-indol- hydrochloride) 1-yl) propan-2-ol was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (7-methyl-2,3-dihydro-1H-indol-1-yl) propan-1, 2-diol as a white solid. MS (ES) m / z 315.0 ([M + H] +); HRMS: calcd for C19H23FN2O + H +, 315.1873; found (ESI, [M + H] +), 315.1862.

[0397] EXAMPLE 68: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (5-methyl-2,3-dihydro-1H-indol-1-yl) propan-2- hydrochloride ol.

[0398] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3-fluorophenyl) -3- (5-methyl-2,3-dihydro-1H-indol-1- yl) propan-1,2-diol was prepared from 5-methylindoline and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, colorless oil. MS (ES) m / z

302.1 ([M + H] +); HRMS: calcd for C18H20FNO2, 302.1551; found (ESI, [M + H] +), 302.1551. [0399] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3-fluoro-phenyl) -3- (methylamino) -1- (5-methyl-2,3-dihydro-1H-indol- hydrochloride) 1-yl) propan-2-ol was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (5-methyl-2,3-dihydro-1H-indol-1-yl) propan-1, 2-diol as a white solid. MS (ES) m / z 315.0 ([M + H] +); HRMS: calcd for C19H23FN2O + H +, 315.1873; found (ESI, [M + H] +), 315.1896.

[0400] EXAMPLE 69: (1S, 2R) -1- (1H-indol-1-yl) -1- (3-methoxyphenyl) -3 (methylamino) propan-2-ol hydrochloride.

<img file="PL1732887T3_D0051.tif" />

[0401] In an analogous manner to EXAMPLE 33, step 1, (2E) -3- (3-methoxyphenyl) acrylate ethyl was prepared from 3-methoxybenzaldehyde and diethyl ethoxycarbonylmethylphosphonate. ¹H NMR (DMSO): □ 1.26 (t, 3H, OCH2CH3), 03.79 (s, 3H, OCH3), □ 4.19 (q, 2H, OCH2CH3), □ 6.66 (d, 1H, CH = CHC (O)), □ 6.99 (m, 1H, CH = CH (CO)), □ 7.31 (m, 3H, ArH) and □ 7.62 (d, 1H, ArH).

[0402] In an analogous manner to EXAMPLE 33, step 2, (2E) -3- (3-methoxyphenyl) prop-2-en-1ol was prepared from ethyl (2E) -3- (3-methoxyphenyl) acrylate. MS (ES) m / z 147.2 ([M + H - H2O] +).

[0403] In an analogous manner to EXAMPLE 117, step 4, [(2R, 3R) -3- (3-methoxyphenyl) oxiran-2-yl] methanol was prepared from (2E) -3- (3-methoxyphenyl) prop-2- en-1-ol. MS (ES) m / z 222 ([M + H + CH 3 CN] +); 93.2% ee.

[0404] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (1H-indol-1-yl) -3- (3-methoxyphenyl) propane-1,2-diol was prepared from 1H-indole and [(2R, 3R) -3- (3-methoxyphenyl) oxiran-2-yl] methanol. MS (ES) m / z 298.2 ([M + H] +).

[0405] In an analogous manner to EXAMPLE 1, step 2, 2-hydroxy-3- (1H-indol-1-yl) -3- (3-methoxyphenyl) propyl ester of (2S, 3S) -toluene-4- sulfonic acid was prepared from (2S, 2S) -3- (1Hindol-1-yl) -3- (3-methoxyphenyl) propane-1,2-diol. MS (ES) m / z 452.2 ([M + H] +).

[0406] In an analogous manner to EXAMPLE 33, step 6, (1S, 2R) -1- (1H-indol1-yl) -1- (3-methoxyphenyl) -3- (methylamino) propan-2-ol hydrochloride was prepared from 2-hydroxy-3- (1H-indol-1-yl) 3- (3-methoxyphenyl) propyl ester of (2S, 3S) -toluene-4-sulfonic acid. MS (ES) m / z 311.3 ([M + H] +); HRMS: calcd for C19H22N2O2 + H +, 311.17540; found (ESI, [M + H] +), 311.1758. [0407] EXAMPLE 70: (1SR, 2RS) -1- (1H-indol-1-yl) -1- (4-methoxyphenyl) -3 (methylamino) propan-2-ol hydrochloride.

EP 1 732 887 B1

<img file="PL1732887T3_D0052.tif" />

[0408] A mixture of methyl trans-3- (4-methoxyphenyl) glycidylate (2.11 g, 10.1 mmol) and indoline (1.14 mL, 10.1 mmol) was heated to 135 ° C in a closed tube for 16 hours. The cooled reaction mixture was then directly purified by flash chromatography (silica, 20%, 30% ethyl acetate / hexane) to give 2.94 g (89%) (2SR, 3SR) -3- (2,3-dihydro-1H-indol-1-yl) ) Methyl -2-hydroxy-3- (4-methoxyphenyl) propanoate, as a yellow solid. MS (ES) m / z 328.2 ([M + H] +); HRMS: calcd for C19H21NO4 + H +, 328.15434; found (ESI, [M + H] +),

328.1536.

[0409] To a solution of methyl (2SR, 3SR) -3- (2,3-dihydro-1H-indol-1-yl) -2-hydroxy-3- (4-methoxyphenyl) propanoate (2.63 g, 8.0 mmol) in anhydrous toluene (50 mL) at 0 ° C under a nitrogen atmosphere, a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.87 g, 8.2 mmol) in anhydrous toluene (50 mL) was added over 5 minutes. The reaction mixture was stirred at 0 ° C to room temperature for 1.5 hours, and then the reaction was quenched by the addition of 7% w / v aqueous sodium carbonate solution (100 ml). The resulting biphasic mixture was stirred vigorously for 5 minutes and then partitioned between ethyl acetate (300 mL) and 7% w / v aqueous sodium carbonate solution (250 mL). The organic phase was then separated, washed with 7% w / v aqueous sodium carbonate solution (3x 250 ml), water (250 ml) and saturated brine (250 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a lilac body solid. Purification by flash chromatography (silica, 20%, 30% ethyl acetate / hexane) gave 2.5 g (96%) (2SR, 3SR) -2-hydroxy-3- (1H-indol-1-yl) -3- ( Methyl 4-methoxyphenyl) propanoate as a cream solid. MS (ES) m / z 326.3 ([M + H] +); HRMS: calcd for C19H19NO4 + H +, 326.13869; found (ESI, [M + H] +), 326.1378.

[0410] A solution of methyl (2SR, 3SR) -2-hydroxy-3- (1H-indol-1-yl) -3- (4-methoxyphenyl) propanoate (2.43 g, 7.5 mmol) in a solution of methylamine (33% by weight in absolute ethanol, 40 ml) heated to 75 ° C in a sealed tube for 1 hour. The cooled reaction mixture was then concentrated under reduced pressure to obtain a yellow syrup. Purification by crystallization from an 80% chlorophom / hexane solution (50 mL) gave 1.93 g (80%) (2SR, 3SR) -2-hydroxy-3- (1H-indol-1-yl) -3- (4-methoxyphenyl) ) -N-methylpropanamide, as a white crystalline solid. MS (ES) m / z 323.2 ([MH]^-); HRMS: calcd for C19H20N2O3 + H +, 325.15467; found (ESI, [M + H] +), 325.1562.

[0411] To a solution of (2SR, 3SR) -2-hydroxy-3- (1H-indol-1-yl) -3- (4-methoxyphenyl) -N-methylpropanamide (900 mg, 2.8 mmol) in anhydrous tetrahydrofuran (50 ml) at room temperature under nitrogen, a solution of borane-tetrahydrofuran complex (1.0M solution in tetrahydrofuran, 13.9 mL, 13.9 mmol) was added dropwise and the mixture was heated at reflux for 3 hours. The reaction mixture was then cooled to

At 50 ° C, methanol (20 ml) was added, and the mixture was stirred at 50 ° C for 1 hour. The cooled reaction mixture was then concentrated under reduced pressure to obtain a white solid. Purification by flash chromatography (silica, 15% methanol / dichloromethane) gave 272 mg (32%) (1SR, 2RS) -1- (1H-indol-1-yl) -1- (4-methoxyphenyl) -3- (methylamino) ) propan-2-ol as a yellow syrup. The product was dissolved in absolute ethanol (4 mL), a hydrogen chloride solution (4M solution in 1,4-dioxane, 0.28 mL, 1.12 mmol) was added, and then the solution was stirred for 10 minutes and then concentrated under reduced pressure to obtain a white foam. After crystallization from a 1: 1: 1 volume / volume mixture, absolute ethanol: diethyl ether: hexane (12 mL) at -35 ° C, 81.3 mg (8%) of the hydrochloride (1SR, 2RS) -1- (1H-indole- 1-yl) -1- (4-methoxyphenyl) -3- (methylamino) propan-2-ol as a hygroscopic white solid. MS (ES) m / z 311.3 ([M + H] +); HRMS: calcd for C19H22N2O2 + H +, 311.17540; found (ESI, [M + H] +), 311.176.

[0412] EXAMPLE 71: (1RS, 2SR) -3- (methylamino) -1- (2-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

OH

<img file="PL1732887T3_D0053.tif" />

[0413] Step 1: A mixture of sodium hydride (60% in mineral oil, 0.40 g, 10 mmol) and tertbutanol (5 mL) was stirred for 15 minutes under nitrogen at room temperature. Then 2-methylindole (1.31 g, 10 mmol) in methylene chloride (2 mL) was added and the mixture was stirred for an additional 30 minutes at room temperature. A previously mixed solution of titanium isopropoxide (3.55 mL, 12 mmol) and trans-3-phenylglycidol (1.5 g, 10 mmol) in methylene chloride (2 mL) was added, and the reaction mixture was stirred at room temperature for 15 hours until there was no remaining epoxy as determined by tlc analysis. The mixture was filtered through a pad of Celite and then the filtrate was treated with 2N aqueous hydrochloric acid (50 ml) with stirring for 30 minutes. The organic layer was separated and the aqueous layer was extracted with methylene chloride several times. The combined extracts were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by Biotage Horizon high performance flash chromatography (Flash 40 M, silica, gradient from 10% ethyl acetate / hexane to 65% ethyl acetate / hexane) to give (2RS, 3RS) -3- (2-methyl-indole -1-yl) -3-phenyl-propane-1,2-diol as a white solid. MS (ESI) m / z 282 ([M + H] +).

[0414] In an analogous manner to EXAMPLE 1, step 2, 3- (2-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid (2RS, 3RS) -3- (2-methyl-indol-1-yl) -3-phenyl-propan-1,2-diol as oil. MS (ESI) m / z 436 ([M + H] +).

[0415] In an analogous manner to EXAMPLE 5, (1RS, 2SR) -3- (methylamino) -1 (2-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 3- (2-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester (2RS, 3RS) -toluene-4-sulfonic acid and methylamine (2N solution in methanol) as a beige solid. MS (ES) m / z 295.0; HRMS: calculated for C19H22N2O + H +,

295.18049; found (ESI, [M + H] +), 295.1818.

[0416] EXAMPLE 72: (1RS, 2SR) -1- (1H-benzimidazol-1-yl) -3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0054.tif" />

[0417] In an analogous manner to EXAMPLE 17, step 1, (2RS, 3RS) -3- (1H-benzimidazol-1-yl) -3-phenyl-propane-1,2-diol was prepared from benzimidazole and trans-3-phenylglycidol as an oily solid. MS (ESI) m / z 269 ([M + H] +).

[0418] In an analogous manner to EXAMPLE 1, step 2, 3-benzoimidazol-1-yl-2-hydroxy-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid prepared from (2RS, 3RS) - 1- (1H-Benzymidazol-1-yl) -3-phenyl-propan-1,2-diol as a white solid. MS (ESI) m / z 423 ([M + H] +).

[0419] In an analogous manner to EXAMPLE 5, (1RS, 2SR) -1- (1H-benzimidazo-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 3-benzimidazol-1-yl -2-hydroxy-3-phenyl-propyl ester (2RS, 3RS) -toluene-4-sulfonic acid and methylamine (2N solution in methanol) as a white solid. MS (ES) m / z 282.1; HRMS: calcd for C17H19N3O + H +, 282.16009; found (ESI, [M + H] +), 282.1617.

[0420] EXAMPLE 73: (1RS, 2SR) -3- (methylamino) -1- (2-methyl-1H-benzimidazol-1-yl) -1-phenylpropan-2-ol hydrochloride.

<img file="PL1732887T3_D0055.tif" />

[0421] In an analogous manner to EXAMPLE 17, step 1, (2RS, 3RS) -3- (2-methyl-1H-benzimidazol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 2-methylbenzymidazole and trans-3-phenylglycidol as a yellow solid. MS (ESI) m / z 283 ([M + H] +).

[0422] In an analogous manner to EXAMPLE 1, step 2, 2-hydroxy-3- (2-methylbenzoimidazol-1-yl) -3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid (2RS, 3RS) -3- (2-methyl-1H-benzimidazol-1-yl) -3-phenyl-propan-1,2-diol, as a white solid. MS (ESI) m / z 437 ([M + H] +).

[0423] In an analogous manner to EXAMPLE 5, (1RS, 2SR) -1- (2-methyl-1H-benzimidazo-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 2-hydroxy -3- (2-methylbenzoimidazol-1-yl) -3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid and methylamine as a white solid. MS (ES) m / z 296.1; SHRMS: calculated for C18H21N3O (+ H +,

296.17574; found (ESI, [M + H] +), 296.1752.

[0424] EXAMPLE 74: (1RS, 2SR) -1- (4-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenyl propan-2-ol hydrochloride.

EP 1 732 887 B1

<img file="PL1732887T3_D0056.tif" />

[0425] In an analogous manner to EXAMPLE 17, step 1, (2RS, 3RS) -3- (4-methoxy-1H-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 4-methoxyindole and trans-3-phenylglycidol as an oil. MS (ESI) m / z 298 ([M + H] +).

[0426] In an analogous manner to EXAMPLE 1, step 2, 2-hydroxy-3- (4-methoxy-indol-1-yl) 3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid from (2RS, 3RS) -3- (4-methoxy-1H-indol-1-yl) -3-phenyl-propane-1,2-diol as a white solid. MS (ESI) m / z 452 ([M + H] +). [0427] In an analogous manner to EXAMPLE 5, (1RS, 2SR) -3- (4-methoxy-1Hindol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 2-hydroxy -3- (4-methoxy-indol-1-yl) 3-phenylpropyl ester of (2RS, 3RS) -toluene-4-sulfonic acid and methylamine as a white solid. MS (ESI) m / z 311; HRMS: calcd for C19H22N2O2 + H +, 311.17540; found (ESI, [M + H] +), 311.1772 [0428] EXAMPLE 75: (1S, 2R) -1- (5-fluoro-1H-indol-1-yl) -3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0057.tif" />

[0429] In an analogous manner to EXAMPLE 17, step 1, (2S, 3S) -3- (5-fluoro-1H-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 5-fluoroindole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as an oil. MS (ESI) m / z 286 ([M + H] +).

[0430] In an analogous manner to EXAMPLE 1, step 2, 3- (5-fluoro-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (2S, 3S) -3- (5-fluoro-1H-indol-1-yl) -3-phenyl-propan-1,2-diol as an oil. MS (ESI) m / z 438 ([M + H] +).

[0431] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (5-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 3- ( 5-fluoro-indol-1-yl) -2-hydroxy-3-phenylpropyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine as a white solid. MS (ES) m / z 299.1; HRMS: calcd for C18H19FN2O + H +, 299.15542; found (ESI, [M + H] +), 299.1556.

[0432] EXAMPLE 76: (1S, 2R) -1- (5-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

<img file="PL1732887T3_D0058.tif" />

[0433] In an analogous manner to EXAMPLE 17, step 1, (2S, 3S) -3- (5-methoxy-1H-indol-184

Yl) -3-phenyl-propane-1,2-diol was prepared from 5-methoxyindole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as Oil. MS (ESI) m / z 298 ([M + H] +).

[0434] In an analogous manner to EXAMPLE 1, step 2, 3- (5-methoxy-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (2S, 3S) -3- (5-methoxy-1H-indol-1-yl) -3-phenyl-propane-1,2-diol as an oil. MS (ESI) m / z 452 ([M + H] +).

[0435] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (5-methoxy-1Hindol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 3- ( 5-methoxy-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine as a white solid. MS (ES) m / z 311.1; HRMS: calcd for C19H22N2O2 + H +, 311.17540; found (ESI, [M + H] +), 311.1745.

[0436] EXAMPLE 77: (1S, 2R) -1- (7-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

<img file="PL1732887T3_D0059.tif" />

[0437] In an analogous manner to EXAMPLE 17, step 1, (2S, 3S) -3- (7-methoxy-1H-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 7-methoxyindole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as an oil. MS (ESI) m / z 298 ([M + H] +).

[0438] In an analogous manner to EXAMPLE 1, step 2, 3- (7-methoxy-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (2S, 3S) -3- (7-methoxy-1H-indol-1-yl) -3-phenyl-propane-1,2-diol as an oil. MS (ESI) m / z 452 ([M + H] +).

[0439] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (7-methoxy-1Hindol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 3- ( 7-methoxy-indol-1-yl) -2-hydroxy3-phenyl-propyl ester (2S, 3S) -toluene-4-sulfonic acid and methylamine as a white solid. MS (ES) m / z 311.1; HRMS: calcd for C19H22N2O2 + H +, 311.17540; found (ESI, [M + H] +), 311.1753.

[0440] EXAMPLE 78: (1S, 2R) -1- (4-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

<img file="PL1732887T3_D0060.tif" />

[0441] In an analogous manner to EXAMPLE 17, step 1, (2S, 3S) -3- (4-methoxy-1H-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 4-methoxyindole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as an oil. MS (ESI) m / z 298 ([M + H] +).

[0442] In an analogous manner to EXAMPLE 1, step 2, 3- (4-methoxy-indol-1-yl) -2-hydroxy3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (2S, 3S) -3- (4-methoxy-1H-indol-1-yl) -3-phenyl-propane-1,2-diol as an oil. MS (ESI) m / z 452 ([M + H] +).

[0443] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (4-methoxy-1H85 hydrochloride)

Indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol prepared from 3- (4-methoxy-indol-1-yl) -2-hydroxy-3-phenyl-propyl acid ester (2S, 3S) - toluene-4-sulfone and methylamine as a white solid. MS (ESI) m / z 311; HRMS: calcd for C19H22N2O2 + H +, 311.17540; found (ESI, [M + H] +), 311.175.

[0444] EXAMPLE 79: (1S, 2R) -1- (6-methoxy-1H-indol-1-yl) -3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0061.tif" />

[0445] In an analogous manner to EXAMPLE 17, step 1, (2S, 3S) -3- (6-methoxy-1H-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 6-methoxyindole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as an oil. MS (ESI) m / z 298 ([M + H] +).

[0446] In an analogous manner to EXAMPLE 1, step 2, 3- (6-methoxy-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (2S, 3S) -3- (6-methoxy-1H-indol-1-yl) -3-phenyl-propane-1,2-diol as an oil. MS (ESI) m / z 452 ([M + H] +).

[0447] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (6-methoxy-1Hindol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 3- ( 6-methoxy-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine as a white solid. MS (ESI) m / z 311; HRMS: calcd for C19H22N2O2 + H +, 311.17540; found (ESI, [M + H] +), 311.1757.

[0448] EXAMPLE 80: (1RS, 2SR) -1- (5-methoxy-1H-indol-1-yl) -3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0062.tif" />

[0449] In an analogous manner to EXAMPLE 17, step 1, (2RS, 3RS) -3- (5-methoxy-1H-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 5-methoxyindole and trans-3-phenylglycidol as an oil. MS (ESI) m / z 298 ([M + H] +).

[0450] In an analogous manner to EXAMPLE 1, step 2, 3- (5-methoxy-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid (2RS, 3RS) -3- (5-methoxy-1H-indol-1-yl) -3-phenyl-propane-1,2-diol as an oil. MS (ESI) m / z 452 ([M + H] +).

[0451] In an analogous manner to EXAMPLE 5, (1RS, 2SR) -1- (5-methoxy-1Hindol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from 3- ( 5-methoxy-indol-1-yl) -2-hydroxy3-phenylpropyl ester of (2RS, 3RS) -toluene-4-sulfonic acid and methylamine as a white solid. MS (ESI) m / z 311; HRMS: calcd for C19H22N2O2 + H +, 311.17540; found (ESI, [M + H] +), 311.1756.

[0452] EXAMPLE 81: (1S, 2R) -1- (3-fluorophenyl) -1- (6-methoxy-1H-indol-1-yl) -3 (methylamino) propan-2-ol hydrochloride.

EP 1 732 887 B1

<img file="PL1732887T3_D0063.tif" />

[0453] In an analogous manner to EXAMPLE 17, step 1, (2S, 3S) -3- (6-methoxy-1H-indol-1-yl) -3- (3-fluoro-phenyl) -propane-1,2-diol was prepared from 6-methoxyindole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as an oil. MS (ESI) m / z 316 ([M + H] +). [0454] In an analogous manner to EXAMPLE 1, step 2, 3- (6-methoxy-indol-1-yl) -2-hydroxy3- (3-fluorophenyl) propyl ester of (2S, 3S) -toluene-4 acid -sulfone was prepared from (2S, 3S) -3- (6-methoxy-1H-indol-1-yl) -3- (3-fluorophenyl) -propane-1,2-diol as an oil. MS (ESI) m / z 470 ([M + H] +). [0455] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (3-fluorophenyl) -1 (6-methoxy-1H-indol-1-yl) -3- (methylamino) -1-phenylpropane hydrochloride -2-ol was prepared from 3- (6-methoxy-indol-1-yl) -2-hydroxy-3- (3-fluoro-phenyl) -propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine as a white body Constant. MS (ES) m / z 329.2; HRMS: calcd for C19H21FN2O2 + H +, 329.16598; found (ESI, [M + H] +), 329.1663.

[0456] EXAMPLE 82: (1S, 2R) -3- (methylamino) -1-phenyl-1- (1H-pyrrolo [2,3-b] pyridin-1-yl) propan-2-

<img file="PL1732887T3_D0064.tif" />

[0457] In an analogous manner to EXAMPLE 17, step 1, (2S, 3S) -3-phenyl-3- (1H-pyrrolo [2,3b] pyridin-1-yl) propane-1,2-diol was prepared from 7-azaindol and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a white solid. MS (ES) m / z 269.2; HRMS: calcd for C 16 H 16 N 2 O 2 + H +, 269.12845; found (ESI, [M + H] +), 269.13.

[0458] In an analogous manner to EXAMPLE 1, step 2, 2-hydroxy-3-phenyl-3-pyrrolo [2,3b] pyridin-1-yl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid made from (2S, 3S) -3-phenyl-3- (1H-pyrrolo [2,3-b] pyridin-1-yl) -propan-1,2-diol as an oil. MS (ESI) m / z 423 ([M + H] +).

[0459] In an analogous manner to EXAMPLE 5, (1S, 2R) -3- (methylamino) -1-phenyl-1- (1H-pyrrolo [2,3-b] pyridin-1-yl) propan-2-ol from 2-hydroxy-3-phenyl-3-pyrrolo [2,3-b] pyridin-1-ylpropyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine as a white solid. MS (ES) m / z 282.3; HRMS: calcd for C17H19N3O + H +, 282.16009; found (ESI, [M + H] +), 282.16. [0460] EXAMPLE 83: (1S, 2R) -1- (5-chloro-2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2- hydrochloride ol.

<img file="PL1732887T3_D0065.tif" />

[0461] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (5-chloro-2,3-dihydro-1H87

Indol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol was prepared from 5-chloroindoline and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, colorless oil. MS (ES) m / z 322.1 ([M + H] +); HRMS: calculated for C17H17ClFNO2 + H⁺, 322,100; found (ESI, [M + H] +), 322.1005.

[0462] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (5-chloro2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) -3 hydrochloride - (methylamino) propan-2-ol prepared from (2S, 3S) -3 (5-chloro-2,3-dihydro-1H-indol-1-yl) -3- (3-fluorophenyl) propan-1,2 -diol as a white solid. MS (ES) m / z 335.1 ([M + H] +); HRMS: calcd for C18H20ClFN2O + H +, 335.1326; found (ESI, [M + H] +), 335.1349.

[0463] EXAMPLE 84: (1S, 2R) -3-methylamino-1-phenyl-1- (1H-pyrrolo [2,3-c] pyridinium dihydrochloride dihydrochloride

<img file="PL1732887T3_D0066.tif" />

[0464] In an analogous manner to EXAMPLE 17, step 1, (2S, 3S) -3- (7-chloro-1H-pyrrolo [2,3₅

c] pyridin-1-yl) -3-phenylpropane-1,2-diol was prepared from 7-chloro-1H-pyrrolo [2,3-c] pyridine⁵ and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as an oil. MS (ES) m / z 303 ([M + H] +).

⁵ Zhang, Z., et al., J. Org. Chem. 2002, 67, 2345-2347 [0465] In an analogous manner to EXAMPLE 1, step 2, 3- (7-chloro-pyrrolo [2,3-c] pyridin-1-yl) 2-hydroxy-3-phenyl- (2S, 3S) -toluene-4-sulfonic acid propyl ester prepared from (2S, 3S) -3 (7-chloro-pyrrolo [2,3-c] pyridin-1-yl) -3-phenyl-propan-1 , 2-diol as an oil. MS (ESI) m / z 457 ([M + H] +). [0466] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (7-chloro-pyrrolo [2,3-c] pyridin-1-yl) 3-methylamino-1-phenyl-propan-2- ol was prepared from 3- (7-chloro-pyrrolo [2,3-c] pyridin-1-yl) -2-hydroxy-3-phenylpropyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine as a white solid . MS (ES) m / z 316.1 ([M + H] +).

[0467] Step 4: (1S, 2R) -1- (7-chloro-pyrrolo [2,3-c] pyridin-1-yl) -3-methylamino-1-phenyl-propan-2-ol (0.12 g , 0.38 mmol) was dissolved in ethanol (20 mL) and treated with 10% palladium on carbon. The reaction mixture was placed under 50 psi hydrogen pressure on a Parr shaker for 15 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo. The crude product was purified by Biotage Horizon high performance flash chromatography (Flash 25 S, silica, gradient from 30% to 100% 0.9% ammonium hydroxide in a 10% methanol methylene chloride / methylene chloride mixture) to give a white solid as the free base of the expected product. The free base was dissolved in a minimum amount of ethanol and treated with a 1N ethereal solution of hydrochloric acid until a solution of pH = 3 was obtained, followed by diethyl ether. Then the product was crystallized by adding a minimum amount of ethyl acetate to obtain the title compound (1S, 2R) -3-methylamino-1-phenyl-1- (1H-pyrrolo [2,3-c] pyridin-1-yl) -propan-2 dihydrochloride -olu, as a white solid. MS (ES) m / z 282.1.

[0468] EXAMPLE 85: (1S, 2R) -1- (5-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3 (methylamino) propan-2-ol hydrochloride.

EP 1 732 887 B1

<img file="PL1732887T3_D0067.tif" />

[0469] In an analogous manner to EXAMPLE 17, step 1, (2S, 3S) -3- (5-fluoro-1H-indol-1-yl) -3 (3-fluorophenyl) propane-1,2-diol prepared from 5-fluoroindole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as an oil. MS (ESI) m / z 304 ([M + H] +).

[0470] In an analogous manner to EXAMPLE 1, step 2, 3- (5-fluoro-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (2S, 3S) -3- (5-fluoro-1Hindol-1-yl) -3- (3-fluorophenyl) propane-1,2-diol as an oil. MS (ESI) m / z 458 ([M + H] +).

[0471] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (5-fluoro-1H-indol-3-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol hydrochloride made from 3- (5-fluoro-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine as a light beige solid. MS (ES) m / z 317.2; HRMS: calcd for C18H18F2N2O + H +, 317.14599; found (ESI, [M + H] +), 317.1472.

[0472] EXAMPLE 86: (1S, 2R) -3-methylamino-1- (3-fluorophenyl) -1- (1H-pyrrolo [2,3- dihydrochloride dihydrochloride

<img file="PL1732887T3_D0068.tif" />

[0473] In an analogous manner to EXAMPLE 17, step 1, (2S, 3S) -3- (7-chloro-pyrrolo [2,3-c] pyridin-1-yl) -3- (3-fluorophenyl) -propan- 1,2-diol was prepared from 7-chloro-1H-pyrrolo [2,3-c] pyridine⁵ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as an oil. MS (ESI) m / z

321 ([M + H] +).

[0474] In an analogous manner to EXAMPLE 1, step 2, 3- (7-chloro-pyrrolo [2,3-c] pyridin-1-yl) 2-hydroxy-3- (3-fluoro-phenyl) -propyl acid ester (2S, 3S) -toluene-4-sulfone prepared from (2S, 3S) -3- (7-chloro-pyrrolo [2,3-c] pyridin-1-yl) -3- (3-fluoro-phenyl) -propane -1.2-diol as oil. MS (ESI) m / z 475 ([M + H] +).

[0475] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (7-chloro-pyrrolo [2,3-c] pyridin-1-yl) 3-methylamino-1- (3-fluorophenyl) - propan-2-ol was prepared from 3- (7-chloro-pyrrolo [2,3-c] pyridin-1-yl) -2-hydroxy-3- (3-fluoro-phenyl) -propyl ester of (2S, 3S) -toluene 4-sulfone and methylamine as a white solid. MS (ESI) m / z 334 ([M + H] +).

[0476] In an analogous manner to EXAMPLE 84, step 4, (1S, 2R) -3-methylamino-1- (3-fluorophenyl) -1- (1H-pyrrolo [2,3-c] pyridin-1-yl) dihydrochloride -propan-2-ol was prepared from (1S, 2R) -1 (7-chloro-pyrrolo [2,3-c] pyridin-1-yl) -3-methylamino-1- (3-fluorophenyl) -propan-2 -olu, as a white solid. MS (ESI) m / z 282.1 ([M + H] +).

[0477] EXAMPLE 87: (1S, 2R) -1- (5-chloro-2,3-dihydro-1H-indol-1-yl) -3 (methylamino) -1-phenylpropan-2-ol hydrochloride.

EP 1 732 887 B1

<img file="PL1732887T3_D0069.tif" />

[0478] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (5-chloro-2,3-dihydro-1Hindol-1-yl) -3-phenylpropane-1,2-diol was prepared from 5-chloroindoline and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a viscous, colorless oil. MS (ES) m / z 304.1 ([M + H] +); HRMS: calcd for C17H18CINO2 + H +, 304.1099; found (ESI, [M + H] +), 304.1081.

[0479] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (5-chloro2.3-dihydro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropane hydrochloride -2-ol was prepared from 2S, 3S) -3- (5-chloro-2.3-dihydro-1H-indol-1-yl) -3-phenylpropane-1,2-diol as a white powder. MS (ES) m / z 317.1 ([M + H] +); HRMS: calcd for C18H21CIN2O + H +, 317.1421; found (ESI, [M + H] +), 317.1431.

[0480] EXAMPLE 88: (1S, 2R) -1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -1- hydrochloride

<img file="PL1732887T3_D0070.tif" />

[0481] Step 1: In an analogous manner to EXAMPLE 165, step 1, 6-chloro-3,4-dihydro-2H-1,4-benzoxazine was prepared from 6-chloro-2H-1,4-benzoxazin-3 (4H) -one as a yellow solid. MS (ES) m / z 170.0 ([M + H] +); HRMS: calcd for C 8 H 8 CINO + H +, 170.0367; found (ESI, [M + H] +), 170.0365.

[0482] Step 2: In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- ( 3,5-difluorophenyl) propane-1,2-diol was prepared from 6-chloro-3,4-dihydro-2H-1,4-benzoxazine and [(2R, 3R) -3- (3,5-difluorophenyl) oxiran-2 -yl] methanol (EXAMPLE 157, step 3) as a viscous, yellowish liquid. MS (ES) m / z 356.1 ([M + H] +); HRMS: calcd for C17H16CIF2NO3 + H +, 356.0860; found (ESI, [M + H] +), 356.0869.

Step 3: In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -1- hydrochloride (3,5-difluorophenyl) -3- (methylamino) propan-2-ol prepared from (2S, 3S) -3- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl ) -3- (3,5-difluorophenyl) propane-1,2-diol as a white powder. MS (ES) m / z 369.1 ([M + H] +); HRMS: calcd for C18H19ClF2N2O2 + H +, 369.1176; found (ESI, [M + H] +), 369.1178.

[0484] EXAMPLE 89: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (2-methyl-2,3- hydrochloride

<img file="PL1732887T3_D0071.tif" />

[0485] In an analogous manner to EXAMPLE 165, step 1, 2-methyl-3,4-dihydro-2H-1,4-benzoxazine was prepared from 2-methyl-2H-1,4-benzoxazin-3 (4H) -one⁶as a brown oil. MS (ES)

EP 1 732 887 B1 m / z 149.9 ([M + H] +).

[0486] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3-fluorophenyl) -3- (2-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl ) propan-1,2-diol was prepared from 2-methyl-3,4-dihydro-2H1,4-benzoxazine and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47 , step 3) as a viscous brown liquid. MS (ES) m / z 318.2 ([M + H] +); HRMS: calcd for C18H20FNO3 + H +, 318.1500; found (ESI, [M + H] +), 318.1513.

[0487] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3-fluoro-phenyl) -3- (methylamino) -1- (2-methyl-2,3-dihydro-4H-1 hydrochloride, 4-benzoxazin-4-yl) propan-2-ol was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (2-methyl-2,3-dihydro-4H-1,4-benzoxazin 4-yl) propan-1,2-diol as a white powder. MS (ES) m / z 331.0 ([M + H] +); HRMS: calcd for C19H23FN2O2 + H +, 331.1816; found (ESI, [M + H] +), 331.1804.

[0488] EXAMPLE 90: (1S, 2R) -3- (methylamino) -1- (6-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

<img file="PL1732887T3_D0072.tif" />

[0489] In an analogous manner to EXAMPLE 117, step 5 (2S, 3S) -3- (6-methyl-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 6-methylindole and 2R , 3R - (+) - 3-phenylglycidol, as an oil. MS (ESI) m / z 282 ([M + H] +).

[0490] In an analogous manner to EXAMPLE 1, step 2, 3- (6-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (2S, 3S) -3- (6-methyl-1Hindol-1-yl) -3-phenylpropan-1,2-diol MS (ESI) m / z 436 ([M + H] +).

[0491] In an analogous manner to EXAMPLE 5, (1S, 2R) -3- (methylamino) -1- (6-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 3- ( 6-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol); MS (ESI) m / z 295 ([M + H] +); HRMS: calcd for C19H22N2O + H +, 295.18049; found (ESI-FT / MS, [M + H] 1+), 295.1809.

[0492] EXAMPLE 91: (1S, 2R) -3- (methylamino) -1- (7-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

⁶ Wheeler, KWJ Med. Pharm. Chem. 1962, 5, 1378-1383.

<img file="PL1732887T3_D0073.tif" />

[0493] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (7-methyl-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 7-methylindole and 2R, 3R - (+) - 3-phenylglycidol, as an oil. MS (ESI) m / z 282 ([M + H] +).

[0494] In an analogous manner to EXAMPLE 1, step 2, 3- (7-methyl-indol-1-yl) -2-hydroxy-391

(2S, 3S) -toluene-4-sulfonic acid phenyl-propyl ester prepared from (2S, 3S) -3- (7-methyl-1Hindol-1-yl) -3-phenylpropane-1,2 -diol, MS (ESI) m / z 436 ([M + H] +).

[0495] In an analogous manner to EXAMPLE 5, (1S, 2R) -3- (methylamino) -1- (7-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 3- (7-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol); MS (ESI) m / z 295 ([M + H] +); HRMS: calcd for C19H22N2O + H +, 295.18049; found (ESI-FT / MS, [M + H] 1+), 295.1809.

[0496] EXAMPLE 92: ((1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (5-methyl-1H- hydrochloride

<img file="PL1732887T3_D0074.tif" />

methyl-1H-indol-1-yl) propan-1,2-diol was prepared from 5-methylindole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol, (see EXAMPLE 47, step 3 ) as oil. MS (ESI) m / z 300 ([M + H] +).

[0498] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- (5-methyl-indol-1-yl) -2-hydroxy-propyl ester of (2S, 3S) -toluene-4 acid -sulfone was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (5-methyl-1H-indol-1-yl) propan-1,2-diol; MS (ESI) m / z 454 ([M + H] +).

[0499] In an analogous manner to EXAMPLE 5, ((1S, 2R) -1- (3-fluorophenyl) -3 (methylamino) -1- (5-methyl-1H-indol-1-yl) propan-2 hydrochloride -ol was prepared from 3- (3-fluorophenyl) -3- (5-methylindol-1-yl) -2-hydroxy-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol) ; MS (ESI) m / z 313 ([M + H] +; HRMS: calcd for C19H21FN2O + H +, 313.17107; found (ESI-FTMS, [M + H] 1+), 313.17163.

[0500] EXAMPLE 93: ((1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (7-methyl-1H- hydrochloride

<img file="PL1732887T3_D0075.tif" />

[0501] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (3-fluorophenyl) -3- (7-methyl-1H-indol-1-yl) propane-1,2-diol was prepared from 7-methylindole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol, (see EXAMPLE 47, step 3) as an oil. MS (ESI) m / z 300 ([M + H] +).

[0502] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- (7-methyl-indol-1-yl) -2-hydroxy-propyl ester of (2S, 3S) -toluene-4 acid -sulfone was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (7-methyl-1H-indol-1-yl) propan-1,2-diol; MS (ESI) m / z 454 ([M + H] +).

[0503] In an analogous manner to EXAMPLE 5, ((1S, 2R) -1- (3-fluorophenyl) -3 (methylamino) -1- (7-methyl-1H-indol-1-yl) propan-2 hydrochloride -ol was prepared from 3- (3-fluorophenyl) -3- (7-methyl92

Indol-1-yl) -2-hydroxy-propyl ester (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol); MS (ESI) m / z 313 ([M + H] +); HRMS: calcd for C19H21FN2O + H +, 313.17107; found (ESI-FTMS, [M + H] 1+). 313.17141.

[0504] EXAMPLE 94: (1S, 2R) -3- (methylamino) -1- (4-methyl-1H-indo) -1-yl) -1- hydrochloride

<img file="PL1732887T3_D0076.tif" />

[0505] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (4-methyl-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 4-methylindole⁷ and 2R, 3R - (+) - 3-phenylglycidol as oil. MS (ESI) m / z 282 ([M + H] +).

⁷ Raucher, Stanley; Koolpe, Gary AJ Org. Chem. 1983, 48 (12), 2066-9 [0506] In an analogous manner to EXAMPLE 1, step 2, 3- (4-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfone was prepared from (2S, 3S) -3- (4-methyl-1Hindol-1-yl) -3-phenylpropane-1,2-diol; MS (ESI) m / z 436 ([M + H] +).

[0507] In an analogous manner to EXAMPLE 5, (1S, 2R) -3- (methylamino) -1- (4-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 3- ( 4-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol); MS (ESI) m / z 295 ([M + H] +); HRMS: calcd for C19H22N2O + H +, 295.18049; found (ESI-FT / MS, [M + H] 1+), 295.1811.

[0508] EXAMPLE 95: (1S, 2R) -3- (methylamino) -1- (5-methyl-1H-indol-1-yl) -1- hydrochloride

<img file="PL1732887T3_D0077.tif" />

[0509] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (5-methyl-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 5-methylindole and 2R, 3R - (+) - 3-phenylglycidol, as an oil. MS (ESI) m / z 282 ([M + H] +).

[0510] In an analogous manner to EXAMPLE 1, step 2, 3- (5-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (2S, 3S) -3- (5-methyl-1H-indol-1-yl) -3-phenylpropane-1,2-diol; MS (ESI) m / z 436 ([M + H] +).

[0511] In an analogous manner to EXAMPLE 5, (1S, 2R) -3- (methylamino) -1- (5-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from 3- ( 5-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol); MS (ESI) m / z 295 ([M + H] +); HRMS: calcd for C19H22N2O + H +, 295.18049; found (ESI-FT / MS, [M + H] 1+), 295.1812.

[0512] EXAMPLE 96: ((1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (4-methyl-1H93 hydrochloride

EP 1 732 887 B1

<img file="PL1732887T3_D0078.tif" />

[0513] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (3-fluorophenyl) -3- (4-methyl-1H-indol-1-yl) propane-1,2-diol was prepared from 4-methylindole⁷ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol, (see EXAMPLE 47, step 3) as an oil. MS (ESI) m / z 300 ([M + H] +).

[0514] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- (4-methyl-indol-1-yl) -2-hydroxy-propyl ester of (2S, 3S) -toluene-4 acid -sulfone was prepared from (2S, 3S) -3- (3-fluoro-phenyl) -3- (4-methyl-1H-indol-1-yl) -propan-1,2-diol; MS (ESI) m / z 454 ([M + H] +).

[0515] In an analogous manner to EXAMPLE 5, ((1S, 2R) -1- (3-fluorophenyl) -3 (methylamino) -1- (4-methyl-1H-indol-1-yl) propan-2 hydrochloride -ol was prepared from 3- (3-fluorophenyl) -3- (4-methylindol-1-yl) -2-hydroxy-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol) ; MS (ESI) m / z 313 ([M + H] +); HRMS: calcd for C19H21FN2O + H +, 313.17107; found (ESI-FT / MS, [M + H] 1+), 313.171.

[0516] EXAMPLE 97: ((1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (3-ethyl-1H- hydrochloride

<img file="PL1732887T3_D0079.tif" />

[0517] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (3-fluorophenyl) -3- (3-ethyl-1H-indol-1-yl) propane-1,2-diol was prepared from 3-etyloindolu⁸ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (see EXAMPLE 47, step 3) as an oil. MS (ESI) m / z 314 ([M + H] +).

⁸ Ainsworth, DP; Suschitzky, Hans J. Chem Soc. [Section] C: Organic 1967, (4), 315-19 [0518] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluorophenyl) -3- (3-ethyl-indol-1-yl) -2 -hydroxy-propyl ester of (2S, 3S) -toluene-4-sulfonic acid prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-ethyl-1H-indol-1-yl) propan-1, 2-diol; MS (ESI) m / z 468 ([M + H] +).

[0519] In an analogous manner to EXAMPLE 5, ((1S, 2R) -1- (3-fluorophenyl) -3 (methylamino) -1- (3-ethyl-1H-indol-1-yl) propan-2 hydrochloride -ol was prepared from 3- (3-fluoro-phenyl) -3- (3-ethyl-indol-1-yl) -2-hydroxypropyl ester (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol); MS (ESI) m / z 327 ([M + H] +); HRMS: calcd for C20H23FN2O + H +, 327.18672; found (ESI, [M + H] +), 327.1871.

[0520] EXAMPLE 98: ((1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (3-phenyl-1H-indol-1-yl) propan-2-ol hydrochloride.

EP 1 732 887 B1

<img file="PL1732887T3_D0080.tif" />

[0521] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (3-fluorophenyl) -3- (3-phenyl-1H-indol-1-yl) propane-1,2-diol was prepared from 3-phenylindole⁹ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (see EXAMPLE 47, step 3) as an oil; MS (ESI) m / z 362 ([M + H] +).

⁹ Cacchi, Sandro; Fabrizi, Giancarlo; Marinelli, Fabio; Moro, Leonardo; Pace, Paola Synlett 1997, (12), 1363-1366.

[0522] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- (3-phenyl-indol-1-yl) -2-hydroxy-propyl ester of (2S, 3S) -toluene-4 acid -sulfone made from (2S, 3S) -3- (3-fluoro-phenyl) -3- (3-phenyl-1H-indol-1-yl) -propan-1,2-diol; MS (ESI) m / z 516 ([M + H] +).

[0523] In an analogous manner to EXAMPLE 5, ((1S, 2R) -1- (3-fluorophenyl) -3 (methylamino) -1- (3-phenyl-1H-indol-1-yl) propan-2 hydrochloride -ol was prepared from 3- (3-fluorophenyl) -3- (3-phenylindol-1-yl) -2-hydroxy-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol) MS (ESI) m / z 375 ([M + H] +); HRMS: calcd for C24H23FN2O + H +, 375.18672; found (ESI, [M + H] +), 375.1886.

[0524] EXAMPLE 99: 7-fluoro-1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0081.tif" />

[0525] Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 ml) was stirred at 80 ° C. 2.6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was slowly added to the mixture. The temperature was kept between 80-90 ° C for 1 hour. The cooled reaction mixture was then poured into water and extracted twice with diethyl ether. The combined organic layers were washed with dilute sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by Biotage chromatography (FlasH90i, silica, 10% THF / hexane) and the product was washed with hexane to give 2.6-difluoronitrobenzene (7.0 g) (52%). MS (ESI) m / z 160 ([M + H] +).

[0526] Step 2: Potassium carbonate (4.41 g, 32 mmol) and dimethyl malonate (3.6 mL, 31.44 mmol) were added to a solution of 2,6-difluoro-nitrobenzene (5.0 g, 31.44 mmol) in dry N, N-dimethylformamide (50 mL). The reaction mixture was heated to 65 ° C and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with a dilute aqueous hydrochloric acid solution and extracted with diethyl ether. The ether layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. After

Dried over anhydrous magnesium sulfate, and concentrated in vacuo. After crystallization from a 5% ethyl acetate / hexane mixture, 4.6 g (54%) of 2- (6-fluoro-2-nitrophenyl) malonic acid methyl ester was obtained. MS (ESI) m / z 272 [M + H] +).

[0527] Step 3: 2- (6-Fluoro-2-nitro-phenyl) -malonic acid dimethyl ester (12 g, 44 mmol) in 6N aqueous hydrochloric acid (200 mL) was heated at reflux for 4 hours. hours. The mixture was then cooled, diluted with 250 mL water and extracted with diethyl ether. The ether layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. Crystallization from a 5% ethyl acetate / hexane mixture gave 7.6 g (6-fluoro-2-nitro-phenyl) -acetic acid (54%). MS (ESI) m / z 200 ([M + H] +).

[0528] Step 4: A mixture of (6-fluoro-2-nitro-phenyl) -acetic acid (9.6 g, 48 mmol) and 10% palladium on carbon (1.3 g) in acetic acid (100 ml) was hydrogenated at 50 psi for 24 hours. The catalyst was removed by filtration through Celite and the solvent was evaporated. The residue was then dissolved in ethanol (100 mL) and pyridinium para-toluenesulfonate (50 mg) was added and the mixture was heated at reflux for 1 hour. The mixture was then cooled, poured into water, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was filtered off and concentrated in vacuo. The solid obtained is triturated with a 5% ethyl acetate / hexane mixture to obtain 6.0 g (83%) of 7-fluoro-1,3-dihydro-indol-2-one. MS (ESI) m / z 152, [M + H] +).

[0529] Step 5: 7-fluoro-1,3-dihydro-indol-2-one (7.3 g, 48 mmol) and lithium chloride (6.67 g, 158 mmol) were dissolved in tetrahydrofuran (200 mL). The solution was then cooled to -78 ° C and n-butyllithium (40 mL, 100 mmol) was added slowly over a period of 15 minutes. After 20 minutes at -78 ° C, methyl iodide (6 mL, 96 mmol) was added and the mixture was allowed to warm to room temperature. After 24 hours, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude product was purified by Biotage chromatography (Flash40i, silica, 10% then 20% ethyl acetate / hexane) to give 4.1 g (48%) 7-fluoro-3,3-dimethyl-1,3-dihydro-2Hindol-2- one. MS (ESI) m / z 180, [M + H] +).

[0530] Step 6: A mixture of sodium hydride (244 mg, 6.1 mmol, 60% solution in mineral oil) and 7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.1 g , 6.1 mmol) in dry N, N-dimethylformamide (3.5 ml) was stirred at room temperature for 20 minutes. [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4, 460 mg, 3.0 mmol) was added and the mixture was heated to 60 ° C under nitrogen. After 20 minutes, an additional portion of [(2R, 3R) -3-phenyloxiran-2-yl] methanol (230 mg) was added, followed by a further portion of [(2R, 3R) -3-phenyloxiran-2-yl] methanol (230 mg) 30 minutes later. The course of the reaction was monitored by tlc (1: 1 hexane: ethyl acetate) determining the disappearance of the starting epoxide. The reaction mixture was then poured into a 2N aqueous hydrochloric acid solution and diluted with ethyl acetate. The layers were separated and the organic layer was washed with water and brine. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.8 g of a yellow oil as a crude product. This crude product was purified by Biotage chromatography (FlasH40i, silica, 6: 1 to 1: 1 hexane: ethyl acetate) to obtain 450 mg (23%) 1 - [(1S, 2S) -2,3-dihydroxy-1- phenylpropyl] -7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol96

EP 1 732 887 B1 (23%) 1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2 -one as a yellow oil. MS (ESI) m / z 330 [(M + H) +].

[0531] Step 7: Solution 1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -7-fluoro-3,3-dimethyl-1,3-dihydro2H-indol-2-one (870 mg, 2.6 mmol) in dry pyridine (7.5 mL) was cooled to 0 ° C. Para-toluenesulfonyl chloride (524 mg, 2.75 mmol) and 4-dimethylaminopyridine (50 mg) were added, then the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured into ice-cold 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.2 g of a viscous oil. This crude product was purified by Biotage chromatography (FlasH40i, silica, 16% then 20% ethyl acetate / hexane) to give 200 mg (22%) of 1 - [(1S, 2S) -3-chloro-2-hydroxy-1- phenylpropyl] -7-fluoro-3,3-dimethyl-1,3dihydro-2H-indol-2-one. MS (ESI) m / z 348 [(M + H) +].

[0532] Step 8: Solution 1 - [(1S, 2S) -3-chloro-2-hydroxy-1-phenylpropyl] -7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (300 mg, 0.86 mmol), sodium iodide (10 mg), and methylamine (8M solution in ethanol) was heated to 60 ° C for 1 hour. The reaction mixture was then cooled to room temperature, concentrated in vacuo and pre-adsorbed onto Celite. This crude product was purified by Biotage chromatography (FlasH40i, silica, 5%, 8% and 10% methanol with ammonia / dichloromethane) to give 187 mg of free base. This free base was dissolved in a minimal amount of dichloromethane and treated with 1M ethereal hydrochloric acid until pH = 3 followed by diethyl ether. This product was crystallized by adding a minimum amount of hexane to give the title compound 7-fluoro-1 [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3- hydrochloride dihydro-2H-indol-2-one as a white solid. MS (ESI) m / z 343 ([M + H] +); HRMS: calcd for C 20 H 23 FN 2 O 2 + H +, 343.18163; found (ESI, [M + H] +), 343.1804.

[0533] EXAMPLE 100: 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3- hydrochloride

<img file="PL1732887T3_D0082.tif" />

[0534] Step 1: In an analogous manner to EXAMPLE 99, step 6, 1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indole -2-one made from 3,3-dimethyl-1,3-dihydro-indol-2one¹⁰ and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4). MS (ESI) m / z 311 ([M + H] +). [0535] Step 2: In an analogous manner to EXAMPLE 99, step 7, 1 - [(1S, 2S) -3-chloro-2-hydroxy-1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H -indol-2-one was prepared from 1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one. MS (ESI) m / z 330 ([M + H] +). [0536] Step 3: In an analogous manner to EXAMPLE 99, step 8, 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3- hydrochloride dihydro-2H-indol-2-one was prepared from 1 [(1S, 2S) -3-chloro-2-hydroxy-1-phenylpropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2- one. MS (ESI) m / z

EP 1 732 887 B1

325 ([M + H)⁺], HRMS: calcd for C 20 H 24 N 2 O 2 + H +, 325.19105; found (ESI-FTMS, [M + H] 1+), 325.19093.

[0537] EXAMPLE 101: 7-fluoro-1 - [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -3,3-dimethyl-1,3-dihydro hydrochloride -2H-indol-2-one.

<img file="PL1732887T3_D0083.tif" />

[0538] Step 1: A mixture of 7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (EXAMPLE 99, step 5, 1.0 g; 5.58 mmol) and sodium tert-butoxide (1.0 g, 11.16 mmol) in dry dichloromethane (15 ml) was stirred at room temperature under nitrogen for 20 minutes. Titanium isopropoxide (2.0 mL, 6.70 mmol) was added, added to a solution of [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3, 844 mg, 5.02 mmol) in dry dichloromethane (6 ml) and stirred for 20 minutes at room temperature. The epoxy complex was added dropwise to the tert-butoxide mixture, and allowed to stir for 4 days. The reaction mixture was then poured into a 2N aqueous hydrochloric acid solution and diluted with ethyl acetate. The layers were separated and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2.0 g of a crude product. This crude product was purified by Isco chromatography (RediSep, silica, gradient 0% to 100% ethyl acetate in hexane) to give 600 mg (31%) (2S, 3S) -7-fluoro-1- [1- (3fluoro- phenyl) -2,3-dihydroxy-propyl] -3,3-dimethyl-1,3-dihydro-indol-2-one as an oil. MS (ESI) m / z 348 ([M + H] +).

[0539] Step 2: In an analogous manner to EXAMPLE 1, step 2, 3- (7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl) -3- (3- fluorophenyl) -2-hydroxy-propyl ester (2S, 3S) -toluene-4-sulfonic acid prepared from (2S, 3S) -7-fluoro-1- [1- (3-fluoro-phenyl) -2,3-dihydroxy-propyl] -3,3-dimethyl-1,3-dihydro-indol-2-one. MS (ESI) m / z 502 ([M + H] +).

¹⁰ A. Kende, Synth. Comm. 1: 12 (1982) [0540] Step 3: In an analogous manner to EXAMPLE 5, 7-fluoro-1 - [(1S, 2R) -1 (3-fluorophenyl) -2-hydroxy-3- (methylamino) hydrochloride propyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one made from 3- (7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1 -yl) -3- (3-fluoro-phenyl) -2-hydroxypropyl (2S, 3S) -toluene-4-sulfonic acid ester. MS (ESI) m / z 360 ([M + H] +), HRMS: calcd for C20H22F2N2O2 + H +, 361.17221; found (ESI, [M + H] +), 361.1719.

[0541] EXAMPLE 102: (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2- hydrochloride)

<img file="PL1732887T3_D0084.tif" />

[0542] Step 1: Thiophene (2.42 mL, 30.6 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to -78 ° C, and treated with n-butyllithium (9.2 mL, 18.4 mmol) and then heated to

25 ° C. The mixture was stirred for 30 minutes and then cooled to -78 ° C and a solution of 2,3-O-isopropylidene-D-glyceraldehyde was added dropwise.¹¹ (2.00 g, 15.3 mmol) in tetrahydrofuran (15.3 mL). Stirring was continued for 20 minutes then warmed to 0 ° C and quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Biotage chromatography (FlasH40i, silica, 10% acetone / hexane) to give the product 1.6 g (51%) as a 2: 1 mixture (R) - [(4R) 2,2-dimethyl-1, 3-dioxolan-4-yl] (2-thienyl) methanol and (S) - [(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] (2-thienyl) methanol as an oil. HRMS: calcd for C16H18N2OS + H +, 287.12126; found (ESI, [M + H] +), 287.1204.

¹¹Schmid, CR; Bryant, JD; Dowlatzedah, M .; Phillips, JL; Prather, DE; Schantz, RD; Sear, NL; Vianco, CSJ Org. Chem. 1991, 56, 4056.

[0543] Step 2: A mixture of (R) - [(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] (2-thienyl) methanol and (S) - [(4R) 2.2 -dimethyl-1,3-dioxolan-4-yl] (2-thienyl) methanol (1.5 g, 7.0 mmol) was dissolved in tetrahydrofuran (28 mL) and [carbide] added (2.1 g, 7.7 mmol; suspension 18% by weight in xylenes / light mineral oil), and the mixture was stirred for 2 hours. Paratoluenesulfonyl chloride (1.46 g, 7.7 mmol) was added and stirring was continued for 2 hours, followed by addition of indoline (2.5 g, 21 mmol) followed by 2.6-lutidine (0.81 mL, 7.0 mmol). After 72 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, diluted with ethyl acetate, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by Isco chromatography (Redisep, silica, 110% ethyl acetate in hexane gradient) to give 590 mg of product, which was immediately dissolved in dioxane (10 mL) and treated with dichlorodicyanobenzoquinone (552 mg, 2.4 mmol) and stirred for 30 minutes . The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Isco chromatography (Redisep, silica, gradient 120% ethyl acetate in hexane) to give 355 mg of 1 - [(S) - [(4S) -2,2-dimethyl-1,3-dioxolane-4 yl] (2-thienyl) methyl] -1H-indole. HRMS: calcd for C18H19NO2S + H +, 314.12092; found (ESI-FTMS, [M + H] 1+), 314.12111.

[0544] Step 3: 1 - [(S) - [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] (2-thienyl) methyl] -1H-indole (350 mg, 1.12 mmol) was dissolved in methanol (20 mL) and benzenesulfonic acid (17 mg, 0.11 mmol) was added. The mixture was then stirred for 6 hours and then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by flash column chromatography (silica, 5% methanol) / chloroform) to give 260 mg (82%) (2S, 3S) -3- (1H-indol-1-yl) -3-thien-2-yl- propane-1,2-diol. HRMS: calcd for C15H15NO2S + H +, 274.08963; found (ESI, [M + H] +), 274.0892.

EP 1 732 887 B1 (ESI, [M + H] +), 274.0892.

Step 4: (2S, 3S) -3- (1H-indol-1-yl) -3-thien-2-yl-propan-1,2-diol (250 mg, 0.91 mmol) was dissolved in pyridine ( 3 ml), para-toluenesulfonyl chloride (216 mg, 1.13 mmol) was added and the mixture was stirred for 2 hours. The mixture was then diluted with ethyl acetate and washed with water, and saturated aqueous copper sulfate, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Isco chromatography (Redisep, silica, gradient 0% - 100% ethyl acetate in hexane) to give 360 ​​mg of the product which was immediately dissolved in methylamine (8M solution in ethanol, 15 ml) and stirred for 16 hours. The mixture was then concentrated in vacuo and purified by flash column chromatography (silica, gradient 2% - 10% methanol saturated ammonia in chloroform) to give 180 mg (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2-thienyl) propan-2-ol as a colorless oil. The free base was dissolved in ether (5 mL) and treated with a 1N ethereal solution of hydrochloric acid (0.63 mL, 0.63 mmol, 1 equivalent). A white precipitate was collected and dried in vacuo to give 193 mg (60%) of (1S, 2R) -1- (1H-indol-1-yl) -3 (methylamino) -1- (2-thienyl) propan-2 hydrochloride ol. HRMS: calcd for C16H18N2OS + H +, 287.12126; found (ESI, [M + H] +), 287.1204 [0546] EXAMPLE 103: (1R, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2- hydrochloride)

<img file="PL1732887T3_D0085.tif" />

[0547] Step 1: Thiophene (2.42 mL, 30.6 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to -78 ° C, and treated with n-butyllithium (9.2 mL, 18.4 mmol) and then heated to 25 ° C. The mixture was then stirred for 30 minutes and then cooled to -78 ° C and a solution of 2,3-O-isopropylidene-D-glyceraldehyde was added dropwise.¹¹ (2.00 g, 15.3 mmol) in tetrahydrofuran (15.3 mL). Stirring was continued for 20 minutes then warmed to 0 ° C and quenched with saturated aqueous ammonium chloride solution. The mixture was then diluted with ethyl acetate, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Biotage chromatography (FlasH40i, silica, 10% acetone / hexane) to give the product 1.6 g (51%) as a 2: 1 mixture (R) - [(4R) -2,2-dimethyl-1, 3-dioxolan-4-yl] (2-thienyl) methanol and (S) - [(4R) 2.2-dimethyl-1,3-dioxolan-4-yl] (2-thienyl) methanol as an oil. HRMS: calculated for C16H18N2OS +

H +, 287.12126; found (ESI, [M + H] +), 287.1204.

[0548] Step 2: Mixture of (R) - [(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] (2-thienyl) methanol and (S) - [(4R) 2.2-dimethyl -1,3-dioxolan-4-yl] (2-thienyl) methanol (1.5 g, 7.0 mmol) was dissolved in tetrahydrofuran (28 mL) and [carbide] added (2.1 g, 7.7 mmol; suspension 18% by weight in the mixture xylenes / light mineral oil) and the mixture was stirred for 2 hours. Para-toluenesulfonyl chloride (1.46 g, 7.7 mmol) was added, and stirring was continued for 2 hours, followed by

100

Toluenesulfonyl (1.46 g, 7.7 mmol), and stirring was continued for 2 hours, followed by addition of indoline (2.5 g, 21 mmol) followed by 2.6-lutidine (0.81 mL, 7.0 mmol). After 72 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, diluted with ethyl acetate, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Isco chromatography (Redisep, silica, gradient 1-10% ethyl acetate in hexane) to give 590 mg of product which was immediately dissolved in dioxane (10 ml) and treated with dichlorodicyanobenzoquinone (552 mg, 2.4 mmol) and mixed for 30 minutes. The mixture was then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Isco chromatography (Redisep, silica, gradient 1-20% ethyl acetate in hexane) to give 160 mg of 1 - [(R) - [(4S) -2,2-dimethyl-1,3-dioxolane -4-yl] (2-thienyl) methyl] -1H-indole. HRMS: calcd for C18H19NO2S + H +, 314.12092; found (ESI-FTMS, [M + H] 1+), 314.12089.

[0549] Step 3: 1 - [(S) - [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] (2-thienyl) methyl] -1H-indole (160 mg, 0.51 mmol) was dissolved in methanol (10 mL) and benzenesulfonic acid (10 mg, 0.06 mmol) was added. The mixture was then stirred for 16 hours and then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by flash column chromatography (silica, 5% methanol / chloroform) to give 102 mg (74%) (2S, 3R) -3- (1H-indol-1-yl) -3-thien-2- 1,2-diol-propane, which was carried on directly to the next step.

Step 4: (2S, 3R) -3- (1H-indol-1-yl) -3-thien-2-yl-propan-1,2-diol (102 mg, 0.37 mmol) was dissolved in pyridine ( 1.5 mL), para-toluenesulfonyl chloride (88 mg, 0.46 mmol) was added and the mixture was stirred for 16 hours. The mixture was then diluted with ethyl acetate and washed with water, and saturated aqueous copper sulfate, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Isco chromatography (Redisep, silica, gradient 0% - 100% ethyl acetate in hexane) to give 140 mg of the product, which was immediately dissolved in methylamine (8M solution in ethanol, 15 ml) and stirred for 3 hours. The mixture was then concentrated in vacuo and purified by flash column chromatography (silica, gradient 2% - 10% methanol saturated ammonia in chloroform) to give 65 mg (71%) (1R, 2R) -1- (1H-indol-1- yl) -3 (methylamino) -1- (2-thienyl) propan-2-ol as a colorless oil. The free base was dissolved in diethyl ether (5 mL) and treated with a 1N ethereal solution of hydrochloric acid (0.23 mL, 0.23 mmol, 1 equivalent). The white precipitate collected was collected and dried in vacuo to give (1R, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- (2-thienyl) propan-2-ol hydrochloride. HRMS: calcd for C16H18N2OS + H +, 287.12126; found (ESI, [M + H] +), 287.1209

101

[0551] EXAMPLE 104: 1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indolo] -2' hydrochloride (1'H) -one.

<img file="PL1732887T3_D0086.tif" />

[0552] Step 1: Spiro [cyclohexane-1,3'-indolo] -2 '(1'H) -one¹² (0.82 g, 4.1 mmol) was dissolved in N, N-dimethylformamide (1 mL), and sodium hydride (168 mg, 4.4 mmol, suspension 60% by weight in mineral oil) was added and the resulting mixture was stirred for 15 minutes. The mixture was then heated to 75 ° C and trans-3-phenylglycidyl (306 mg, 2.04 mmol) was added in four portions. Stirring was continued for 2 hours, then the reaction mixture was cooled and quenched with saturated aqueous ammonium chloride solution. Then the mixture was diluted with ethyl acetate, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Isco chromatography (Redisep, silica, gradient 20% to 100% ethyl acetate in hexane) to give 290 mg (41%) of 1 '- [(1 S, 2S) -2,3-dihydroxy-1-phenylpropyl ] spiro [cyclohexane-1,3'-indolo] -2 '(1'H) -one as an oil. Purity determined by 100% HPLC at 210-370 nm, 9.4 min .; Xterra RP18 column, 3.5u, 150 x 4.6 mm, flow 1.2 ml / minute, 85 / 15-5 / 95 (ammonium formaldehyde buffer, pH = 3.5 / ACN + MeOH) for 10 minutes, holding time 4 minutes.

¹² Fensome, A .; Miller, LL; Ullrich, JW; Bender, RHW; Zhang, P .; Wrobel, HE; Zhi, L .; Jones,

TK; Marschke, KB; Tegley, CM PCT Int. PCT Int. Appl. 2000, 127 pp. WO 2000066556 [0553] Step 2: 1 '- [(1S, 2S) -2,3-dihydroxy-1-phenyl-propyl] spiro [cyclohexane-1,3'-indolo] -2' (1'H) - he (250 mg, 0.71 mmol) was dissolved in pyridine (2.5 mL) and para-toluenesulfonyl chloride (169 mg, 0.89 mmol) was added. The reaction mixture was stirred for 5 hours, then the reaction mixture was diluted with ethyl acetate and washed with water, and a saturated aqueous solution of copper sulfate, 2N aqueous hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was immediately dissolved in methylamine (8M solution in ethanol, 15 ml) and stirred for 16 hours. The mixture was then concentrated in vacuo and purified by flash column chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 85 mg (32%) of 1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indolo] -2 '(1'H) -one as a colorless oil. The free base was dissolved in diethyl ether (5 mL) and treated with a 1N ethereal solution of hydrochloric acid (0.23 mL, 0.23 mmol, 1 equivalent). A white precipitate was collected and dried in vacuo to give 193 mg (60%) of 1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3 hydrochloride 'indol] -2' (1'H) -one. HRMS: calcd for C 23 H 28 N 2 O 2 + H +, 365.22235; found ([M + H] +), 365.2226;

[0554] EXAMPLE 105: (1S, 2R) -2- (3-fluorophenyl) -2- (1H-indol-1-yl) -1 - [(2S) pyrrolidin-2-yl] ethanol hydrochloride.

102

EP 1 732 887 B1

<img file="PL1732887T3_D0087.tif" />

[0555] Step 1: To a suspension of 3-fluorobenzyltriphenylphosphonium bromide (6.8 g, 15 mmol) in tetrahydrofuran (50 mL) at 0 ° C, sodium hydride (0.57 g, 15 mmol, suspension 60% by weight in mineral oil) was added, and the mixture was stirred for 1 hour. A solution of (S) -2-formyl-pyrrolidin-1-carboxylic acid tert-butyl ester¹³ (2.5 g, 12.5 mmol) in tetrahydrofuran (10 mL) and the mixture was stirred for 1 hour, then heated to 25 ° C and quenched with saturated aqueous ammonium chloride solution. The mixture was then diluted with ethyl acetate, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Isco chromatography (Redisep, silica, 10% ethyl acetate / hexane) to give 2.18 g (60%) (2S) -2 - [(E) -2- (3-fluorophenyl) vinyl] pyrrolidin-1- tert-butyl carboxylate as a colorless oil which was crystallized by standing. HRMS: calcd for C17H22FNO2 + H +, 292.17073; found (ESI, M + H), 292.1713.

¹³ Cook, GR; Stille, JR Tetrahedron, 1994, 50 (14), 4105.

Step 2: tert-butyl (2S) -2 - [(E) -2- (3-fluorophenyl) vinyl] pyrrolidin-1-carboxylate (400 mg, 1.37 mmol) was dissolved in dichloromethane (50 mL). Saturated aqueous sodium bicarbonate solution (50 ml) was added followed by acetone (10 ml) and tetrabutylammonium hydrogen sulfate (46 mg, 0.14 mmol). Oxone (strong oxidizing agent potassium peroxosulphate) (8.4 g, 13.7 mmol) was added with vigorous stirring for 2 hours in 8 portions (1.05 g every 15 minutes). The mixture was then stirred for an additional 16 hours and then diluted with dichloromethane. The organic layer was separated and washed with water, and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Isco chromatography (Redisep, silica, 20% ethyl acetate / hexane) to give 240 mg of product, which was immediately combined with indoline (0.14 g, 1.2 mmol) and heated to 90 ° C for 16 hours. The mixture was then cooled and the crude orange oil purified by Isco chromatography (Redisep, silica, gradient 0% to 25% ethyl acetate in hexane) to give 130 mg of the product which was immediately dissolved in dichloromethane (20 ml). Manganese dioxide (0.86 g, 10 mmol) was added and the mixture was stirred for 5 hours, then diluted with dichloromethane and filtered through a Celite pad and concentrated. This crude product was purified by Isco chromatography (Redisep, silica, gradient 0% to 50% ethyl acetate in hexane) to give 50 mg of (S) -2- [2- (R) - (3-fluoro-phenyl) tert-butyl ester ) -1-hydroxy-2-indol-1-yl-ethyl] - (S) -pyrrolidin-1-carboxylic.

[0557] Step 3: (S) -2- [2- (R) - (3-fluoro-phenyl) -1-hydroxy-2-indol-1-yl-ethyl] (S) - tert-butyl ester pyrrolidine-1-carboxylic acid (50 mg, 0.12 mmol) was dissolved in methanol (1 mL) and 1N ethereal hydrochloric acid (0.96 mL, 0.96 mmol) was added. After 6 hours, the mixture was concentrated and purified by flash column chromatography (silica, 10% methanol saturated with ammonia in chloroform) to give 6 mg¹(⁰15³%) (1 S, 2R) -2- (3-fluorophenyl) -2- (1H-indol-1-yl) in chloroform) to obtain 6 mg (15%) (1 S, 2R ) -2- (3-fluorophenyl) -2- (1H-indol-1-yl) -1 - [(2S) -pyrrolidin-2-yl] ethanol. The free base was dissolved in diethyl ether (2 mL) and treated with a 1N ethereal solution of hydrochloric acid (0.02 mL, 0.02 mmol, 1 equivalent). A white precipitate was collected and dried under vacuum to obtain 4 mg (1S, 2R) -2- (3-fluorophenyl) -2- (1H-indol-1-yl) -1 - [(2S) -pyrrolidin-2-yl] hydrochloride ethanol. HRMS: calcd for C 20 H 21 FN 2 O + H +, 325.17107;

found (ESI, [M + H] +), 325.1712 [0558] EXAMPLE 106: (1R, 2S) -2- (3-fluorophenyl) -2- (1H-indol-1-yl) -1 - [( 2S) -

<img file="PL1732887T3_D0088.tif" />

[0559] Step 1: To a suspension of 3-fluorobenzyltriphenylphosphonium bromide (6.8 g, 15 mmol) in tetrahydrofuran (50 mL) at 0 ° C, sodium hydride (0.57 g, 15 mmol, suspension 60% by weight in mineral oil) and the mixture were added stirred for 1 hour at room temperature. A solution of (S) -2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester¹³ (2.5 g, 12.5 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred for 1 hour and then heated to 25 ° C and quenched with saturated aqueous ammonium chloride solution. The mixture was then diluted with ethyl acetate, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Isco chromatography (Redisep, silica, 10% ethyl acetate / hexane) to give 2.18 g (60%) (2S) -2 - [(E) -2- (3-fluorophenyl) vinyl] pyrrolidine Tert-butyl 1-carboxylate as a colorless oil which was crystallized by standing. HRMS: calcd for C17H22FNO2 + H +, 292.17073; found (ESI, M + H), 292.1713.

[0560] Step 2: tert-butyl (2S) -2 - [(E) -2- (3-fluorophenyl) vinyl] pyrrolidine-1-carboxylate (400 mg, 1.37 mmol) was dissolved in dichloromethane (50 mL). A saturated aqueous solution of sodium bicarbonate (50 ml) was added, followed by acetone (10 ml) and tetrabutylammonium hydrogen sulfate (46 mg,

0.14 mmol). Oxone (8.4 g, 13.7 mmol) was added with vigorous stirring for 2 hours in 8 portions (1.05 g every 15 minutes). The mixture was then stirred for an additional 16 hours and then diluted with dichloromethane. The organic layer was separated and washed with water, and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Isco chromatography (Redisep, silica, 20% ethyl acetate / hexane) to give 240 mg of product, which was immediately combined with indoline (0.14 g, 1.2 mmol) and heated to 90 ° C for 16 hours. The mixture was then cooled and the crude orange oil purified by lsco chromatography (Redisep, silica, gradient 0% to 25% ethyl acetate in hexane) to give 130 mg of the product which was immediately dissolved in dichloromethane (20 ml). Manganese dioxide (0.86 g, mmol) was added and the mixture was stirred for 5 hours and then diluted with dichloromethane and filtered through a Celite pad and concentrated. This crude product was purified on the system

104

EP 1 732 887 B1 through a Celite pad and concentrated. This crude product was purified by Isco chromatography (Redisep, silica, gradient 0% to 50% ethyl acetate in hexane) to give 50 mg of (R) -2- [2- (S) - (3-fluoro-phenyl tert-butyl ester) ) -1-hydroxy-2-indol-1-yl-ethyl] - (S) -pyrrolidin-1-carboxylic.

[0561] Step 3: (R) -2- [2- (S) - (3-fluoro-phenyl) -1-hydroxy-2-indol-1-yl-ethyl] (S) - tert-butyl ester pyrrolidine-1-carboxylic acid (50 mg, 0.12 mmol) was dissolved in methanol (1 mL) and 1N ethereal solution of hydrochloric acid (1.0 mL, 1.0 mmol) was added. After 16 hours, the mixture was concentrated and purified by flash column chromatography (silica, 10% methanol saturated with ammonia in chloroform) to give 19 mg (50%) (1R, 2S) -2- (3-fluorophenyl) -2- (1H- indol-1-yl) -1 - [(2S) -pyrrolidin-2-yl] ethanol. The free base was dissolved in diethyl ether (2 mL) and treated with a 1N ethereal solution of hydrochloric acid (0.06 mL, 0.06 mmol, 1 equivalent). A white precipitate was collected and dried under vacuum to obtain 17 mg of (1R, 2S) -2- (3-fluorophenyl) -2- (1H-indol-1-yl) -1 - [(2S) -pyrrolidin-2-yl] hydrochloride ethanol. HRMS: calculated for C20H21FN2O +

H +, 325.17107; found (ESI, [M + H] +), 325.1711 [0562] EXAMPLE 107: 1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0089.tif" />

[0563] Step 1: In an analogous manner to EXAMPLE 104, step 1, 1 '- [(1S, 2S) -2,3-dihydroxy-phenylpropyl] spiro [cyclobutane-1,3'-indolo] -2' ( 1'H) -one made from spiro [cyclobutane-1,3'-Indolo] 2 '(1'H) -one¹² and trans-3-phenylglycidol. Purity from 100% HPLC analysis at 210-370 nm, 8.4 min .; Xterra RP18 column, 3.5u, 150 x 4.6 mm, flow 1.2 ml / minute, 85 / 15-5 / 95 (ammonium formaldehyde buffer, pH = 3.5 / ACN + MeOH) for 10 minutes, holding time 4 minutes.

[0564] Step 2: In an analogous manner to EXAMPLE 104, step 2, 1 '- [(1 S, 2R) 2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclo-butane-1 hydrochloride, 3'-indolo] -2 '(1'H) -one was prepared from 1' - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] spiro- [cyclobutane-1,3'-indolo] - 2 '(1'H) -one. HRMS: calcd for C 21 H 24 N 2 O 2 + H +, 337.19105; found (ESI, [M + H] +), 337.1917.

[0565] EXAMPLE 108: 1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0090.tif" />

[0566] Step 1: In an analogous manner to EXAMPLE 104, step 1, 1 '- [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] spiro [cyclopentane-1,3'-indolo] -2' ( 1'H) -one made from spiro [cyclopentane-1,3'-indolo] 2 '(1'H) -one¹² and trans-3-phenylglycidol. HRMS: calcd for C 21 H 23 NO 3 + H +, 338.17507; found (ESI, [M + H] +), 338.1769.

[0567] Step 2: In an analogous manner to EXAMPLE 104, step 2, 1 'hydrochloride - [(1S, 2R) 105

EP 1 732 887 B1

2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro- [cyclopentane-1,3'-indolo] -2 '(1'H) -one was prepared from 1' - [(1S, 2S) -2, 3-dihydroxy-1-phenylpropyl] spiro [cyclopentane-1,3'-indol] -2 '(1'H) -one. HRMS: calcd for C22H26N2O2 + H +, 351.20670; found (ESI, [M + H] +), 351.2061.

[0568] EXAMPLE 109: 1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0091.tif" />

[0569] Step 1: In an analogous manner to EXAMPLE 104, step 1, 1 '- [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] spiro [cyclopropane-1,3'-indolo] -2' ( 1'H) -one made from spiro [cyclopropane-1,3'-indolo] 2 '(1'H) -one¹⁴ and trans-3-phenylglycidol. Purity by HPLC analysis 89.1% at 210-370 nm, 7.7 min .; Xterra RP18 column, 3.5u, 150 x 4.6 mm, flow 1.2 ml / minute, 85 / 15-5 / 95 (ammonium formaldehyde buffer, pH = 3.5 / ACN + MeOH) for 10 minutes, holding time 4 minutes.

¹⁴ Roberston, DW; Krushinski, JH; Pollock, GD; Wilson, H .; Kauffman, RF; Hayes, JSJ Med. Chem. 1987, 30, 824.

[0570] Step 2: In an analogous manner to EXAMPLE 104, step 2, 1 '- [(1S, 2R) 2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro- [1,3-cyclopropane-1,3' hydrochloride -indolo] -2 '(1'H) -one prepared from 1' - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -spiro [cyclopropane-1,3'-indolo] -2 ' (1'H) -one. HRMS: calcd for C20H22N2O2 + H +, 323.17540; found (ESI, [M + H] +), 323.1744.

[0571] EXAMPLE 110: 5-fluoro-1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0092.tif" />

[0572] Step 1: 5-fluoro-1,3-dihydro-indol-2-one (2.0 g, 13.2 mmol) and lithium chloride (1.39 g, 33.0 mmol) were dissolved in tetrahydrofuran (40 mL) and cooled to 0 ° C. N-butyllithium (10.6 mL, 26.4 mmol) was added dropwise and the mixture was stirred for 20 minutes. Methyl iodide (1.63 mL, 26.4 mmol) was added slowly and stirring was continued for 2 hours at 0 ° C and then heated to 25 ° C. After 16 hours, the reaction was quenched with a saturated aqueous solution of ammonium chloride. The mixture was then diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Isco chromatography (Redisep, silica, gradient 10% to 50% ethyl acetate in hexane) to give 1.18 g (50%) 5-fluoro-3,3-dimethyl-1,3-dihydro-2H- indole-2-one as white crystals. Purity by 100% HPLC analysis at 210-370 nm, 7.1 min .; Xterra RP18 column, 3.5u, 150 x 4.6 mm, flow 1.2 ml / minute, 85 / 15-5 / 95 (ammonium formaldehyde buffer, pH = 3.5 / ACN + MeOH) for 10 minutes, holding time 4 minutes.

[0573] Step 2: In an analogous manner to EXAMPLE 104, step 1 - [(1S, 2S) -2,3-dihydroxy-1106

Phenylpropyl] -5-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one prepared from 5-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol -2-one and trans-3-phenylglycidol. HRMS: calcd for C19H20FNO3 + H +, 330.15000; found (ESI, [M + H] +), 330.1495.

[0574] Step 3: In an analogous manner to EXAMPLE 104, step 2, 5-fluoro-1 [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl hydrochloride -1,3-dihydro-2H-indol-2-one was prepared from 1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -5-fluoro-3,3-dimethyl-1,3- dihydro-2H-indol-2-one. Purity according to 100% HPLC analysis at 210-370 nm, 7.2 min .; Xterra RP18, 3.5u column,

150 x 4.6 mm, flow 1.2 ml / minute, 85 / 15-5 / 95 (ammonium formaldehyde buffer, pH = 3.5 / ACN + MeOH) for 10 minutes, holding time 4 minutes. HRMS: calcd for C 20 H 23 FN 2 O 2 + H +, 343.18163; found (ESI, [M + H] +), 343.184.

[0575] EXAMPLE 111: (1S, 2R) -3- (cyclopropylamino) -1- (3-fluorophenyl) -1- (1H- hydrochloride)

<img file="PL1732887T3_D0093.tif" />

[0576] Step 1: (2S, 3S) -3- (3-fluorophenyl) -3- (1H-indol-1-yl) propan-1,2-diol (example 47, step 5) (0.6 g, 2.1 mmol) was dissolved in pyridine (5 mL) and para-toluenesulfonyl chloride (0.44 g, 2.3 mmol) was added. The mixture was then stirred for 3 hours and then the reaction mixture was diluted with ethyl acetate and washed with water followed by a saturated aqueous solution of copper sulfate, 2N aqueous hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was immediately dissolved in methylamine (8M solution in ethanol, 25 ml) and stirred for 16 hours. The mixture was then concentrated in vacuo and purified by flash column chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give (1S, 2R) -3- (cyclopropylamino) -1- (3-fluorophenyl) -1- (1H- indol-1-yl) propan-2-ol as a colorless oil. The free base was dissolved in diethyl ether (5 mL) and treated with a 1N ethereal solution of hydrochloric acid (1 equivalent). A white precipitate was collected and dried under vacuum to obtain 80 mg (12%) of (1S, 2R) -3- (cyclopropylamino) -1- (3-fluorophenyl) -1- (1Hindol-1-yl) propan-2- hydrochloride ol. HRMS: calcd for C 20 H 21 FN 2 O + H +, 325.17107; found (ESI, [M + H] +), 325.1728.

[0577] EXAMPLE 112: 7'-fluoro-1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0094.tif" />

[0578] Step 1: 7-fluoro-1,3-dihydro-indol-2-one (EXAMPLE 99, step 4) (1.16 g, 7.68 mmol) and lithium chloride (0.81 g, 19.2 mmol) were dissolved in tetrahydrofuran (50 ml) and cooled to 0 ° C.

N-butyl lithium (6.14 mL, 15.4 mmol) was added dropwise and the mixture was stirred for 15 minutes. Slowly

107

1,5-dibromopentane (1.05 mL, 7.7 mmol) was added and stirring was continued for 2 hours at 0 ° C, followed by heating to 25 ° C. After 16 hours, the reaction was quenched with a saturated aqueous solution of ammonium chloride. The mixture was then diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This crude product was purified by lsco chromatography (Redisep, silica, gradient 5% to 40% ethyl acetate in hexane) to give 0.90 g (54%) of 7'-fluorospiro- [cyclohexane-1,3'-indolo] -2 ' (1'H) -one. Purity by HPLC analysis 95.9% at 210-370 nm, 19.2 min .; Xterra MSC18 column, 5u, 150 x 3.0 mm, flow rate 0.5 ml / minute, 95 / 5-5 / 95 (0.1% formic acid in H2O / MeOH) for 20 minutes, hold time 3 minutes.

[0579] Step 2: In an analogous manner to EXAMPLE 104, step 1, 1 '- [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -7'-fluorospiro [cyclohexane-1,3'-indolo] -2 '(1'H) -one was prepared from 7'-fluorospiro [cyclohexane-1,3'-indolo] -2' (1'H) -one and trans-3-phenylglycidol. HRMS: calcd for C22H24FNO3 + H +, 370.18130; found (ESI, [M + H] +), 370.1798.

[0580] Step 3: In an analogous manner to EXAMPLE 104, step 2, 7'-fluoro-1 '[[1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -spiro [cyclohexane hydrochloride -1,3'-indolo] -2 '(1'H) -one prepared from 1' - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -7'-fluorospiro [cyclohexan-1, 3'-indol] -2 '(1'H) -one. HRMS: calcd for C 23 H 27 FN 2 O 2 + H +, 383.21293; found (ESI, [M + H] +), 383.2109. EXAMPLE 113: 5'-bromo-1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] hydrochloride

<img file="PL1732887T3_D0095.tif" />

[0581] Step 1: In an analogous manner to EXAMPLE 104, step 1, 5'-bromo-1 '- [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] spiro [cyclohexane-1,3'-indole ] -2 '(1'H) -one prepared from 5'bromospiro [cyclohexane-1,3'-indolo] -2' (1'H) -one¹² and trans-3-phenylglycidol. HRMS: calcd for C22H24BrNO3 + H +, 430.10123; found (ESI, [M + H] +), 430.1006.

[0582] Step 2: In an analogous manner to EXAMPLE 104, step 2, 5'-bromo-1 '[[1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -spiro [cyclohexane hydrochloride -1,3'-indolo] -2 '(1'H) -one prepared from 5'-bromo-1' - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] spiro [cyclohexan-1 , 3'-indole) 2 '(1'H) -one. HRMS: calcd for C 23 H 27 BrN 2 O 2 + H +, 443.13286; found (ESI, [M + H] +), 443. 1333.

[0583] EXAMPLE 114: (1S, 2R) -1- (3-fluorophenyl) -1- [3- (2-fluorophenyl) -1H-indol-1- hydrochloride

<img file="PL1732887T3_D0096.tif" />

108

[0584] Step 1: To (2S, 3S) -3-indol-1-yl-3- (3-fluorophenyl) propane-1,2-diol solution (EXAMPLE 47, Step 5, 1.34 g, 4.56 mmol) in N, N-dimethylformamide (20 ml), ground solid potassium hydroxide (0.76 g, 13.68 mmol) was added. The mixture was then stirred for 15 minutes under a nitrogen atmosphere at room temperature, during which time iodine (1.21 g, 4.72 mmol) was added in one portion. The mixture was then stirred for 30 minutes at room temperature and then poured into 100 ml of 5% aqueous sodium thiosulfate solution. The solution was extracted 3 times with ethyl acetate and the combined extracts were washed 3 times with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Biotage chromatography (FlasH40i, silica, 40% ethyl acetate / hexane) to give 0.91 g (48%) (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1H -indol-1-yl) propane-1,2-diol as a dark brown oil. MS (ES) m / z 411.9.

[0585] Step 2: mixture of (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1H-indo) -1-yl) propan-1,2-diol (0.25 g, 0.61 mmol ), 2-fluorobenzeneboric acid (0.12 g, 0.85 mmol), and potassium phosphate (0.39 g, 1.83 mmol) in N, N-dimethylformamide (10 mL) was degassed with nitrogen for 5 minutes, followed by the addition of a catalytic amount (0.02 g) [1,4-Bis- (diphenylphosphino) butane] palladium (II) dichloride. The solution was heated to 90 ° C for 3 hours, then cooled and poured into 100 ml of water. The aqueous mixture was extracted 3 times with ethyl acetate and the combined extracts were then washed 2 times with water. The ethyl acetate was dried by filtration through a silica gel pad and then concentrated. The residue was purified by Biotage chromatography (FlasH40i, silica, 40% ethyl acetate / hexane) to give 0.14 g (2S, 3S) -3- (3-fluorophenyl) -3- {3- [2-fluorophenyl] -1H-indol-1 -yl} propane-1,2-diol as an oil which was used in the next step without further purification.

[0586] Step 3: In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluorophenyl) -3- [3- (2-fluoro-phenyl) -indol-1-yl] -2-hydroxy-propyl acid ester (2S , 3S) -toluene-4-sulfone prepared from (2S, 3S) -3- (3-fluorophenyl) -3- {3- [2-fluorophenyl] -1H-indol-1-yl} propane-1,2- diol.

[0587] Step 4: In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (3-fluoro-phenyl) -1- [3- (2-fluorophenyl) -1H-indol-1-yl] -3- hydrochloride ( methylamino) propan-2-ol was prepared from 3- (3-fluoro-phenyl) -3- [3- (2-fluoro-phenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) -toluene-4-acid sulfonic acid and methylamine (2N solution in methanol). MS (ES) m / z 393.1.

[0588] EXAMPLE 115: (1S, 2R) -1- [3- (3,4-dichlorophenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2- hydrochloride ol.

F

<img file="PL1732887T3_D0097.tif" />

[0589] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3,4-dichlorophenyl) -3- {3 [2-fluorophenyl] -1H-indol-1-yl} propane -1,2-diol prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1H-indol-1-yl) propane-1,2-diol (EXAMPLE 114, step 1) and 3,4-dichlorobenzeneboric acid.

[0590] In an analogous manner to EXAMPLE 1, step 2, 3- [3- (3,4-dichloro-phenyl) -indol-1-yl] 109

EP 1 732 887 B1

3- (3-Fluoro-phenyl) -2-hydroxy-propyl ester of (2S, 3S) -toluene-4-sulfonic acid prepared from (2S, 3S) -3- [3- (3,4-dichloro-phenyl) -indole -1-yl] -3- (3-fluoro-phenyl) -propane-1,2-diol.

[0591] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- [3- (3,4-dichlorophenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino hydrochloride) ) propan-2-ol was prepared from 3- [3- (3,4-dichloro-phenyl) -indol-1-yl] -3- (3-fluoro-phenyl) -2-hydroxy-propyl ester of (2S, 3S) acid -toluene-4-sulfonic acid and methylamine (2N solution in methanol). MS (ES) m / z 443.0.

[0592] EXAMPLE 116: (1S, 2R) -1- (3-fluorophenyl) -1- [3- (3-fluorophenyl) -1H-indol-1- hydrochloride hydrochloride

<img file="PL1732887T3_D0098.tif" />

[0593] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3-fluorophenyl) -3- {3- [3-fluorophenyl] -1H-indol-1-yl} propan-1,2 -diol prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1Hindol-1-yl) propane-1,2-diol (EXAMPLE 114, step 1) and 3-florobenzeneboric acid .

[0594] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- [3- (3-fluoro-phenyl) indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S ) -toluene-4-sulfonic acid prepared from (2S, 3S) 3- (3-fluorophenyl) -3- {3- [3-fluorophenyl] -1H-indol-1-yl} propan-1,2-diol.

[0595] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (3-fluorophenyl) -1 [3- (3-fluorophenyl) -1H-indol-1-yl] -3- (methylamino) hydrochloride propan-2-ol hydrochloride was prepared from 3- (3-fluorophenyl) -3- [3- (3-fluorophenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) -toluene o- 4-sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 393.

[0596] EXAMPLE 117: (1S, 2R) -1- (5-fluoro-3-methyl-1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0099.tif" />

[0597] Step 1: Sodium nitrite (6.3 g, 89.1 mmol) dissolved in water (7.8) was added to a mixture of 4-fluoro-phenylamine (9 g, 81 mmol), concentrated hydrochloric acid (20.4 mL), and water (35.1 mL). ml).

In a separate flask, ethyl 2-ethylacetoacetate (14.4 g, 89.1 mmol) in ethanol (63.6 mL) at 0 ° C was treated with potassium hydroxide (5.1 g, 89.1 mmol) in water (7.5 mL) and ice, and the above solution was added. The pH of the reaction mixture was adjusted to 5-6 and the reaction mixture was stirred at 0 ° C for 3 hours and then stored in the refrigerator overnight. The reaction mixture was then extracted with ethyl acetate (100 mL) and the organic layer was washed with saturated brine (100 mL), dried with anhydrous magnesium sulfate. Most of the solvent was removed in vacuo before being added dropwise to a 14.5% ethanolic hydrochloric acid solution (70 ml) at 78 ° C. Heating continued for 2 hours.

110

EP 1 732 887 B1

The solvent was removed in vacuo and the residue was treated with dichloromethane (300 ml) and water (100 ml). The organic layer was washed with saturated sodium chloride (200 mL), dried over sodium sulfate and concentrated in vacuo. Purification on a briefly washed column (silica gel, 25% ethyl acetate / hexane) gave ethyl 5-fluoro-3-methyl-1H-indole-2-carboxylate as a white solid. MS (ES) m / z 220.0.

[0598] Step 2: ethyl 5-fluoro-3-methyl-1H-indole-2-carboxylate (8.3 g, 37.5 mmol) and potassium hydroxide (6.3 g, 112.5 mmol) in a mixture of ethanol (20 mL) and water (15 ml) was heated to reflux for 1 hour. The volume was reduced to 10 ml under reduced pressure and the solution was adjusted to acidic pH with a 3N aqueous hydrochloric acid solution. The resulting precipitate was filtered, washed with water (100 ml) and dried under vacuum at 80 ° C overnight to give 5-fluoro-3-methyl-1H-indole-2-carboxylic acid as a white solid. MS (ES) m / z 192.0.

[0599] Step 3: 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (8.49 g, 43.9 mmol) and metallic copper (0.35 g, 5.5 mmol) in distilled quinoline (22 ml) was heated to reflux under reflux for 3 hours. The copper powder was filtered off and the filtrate was adjusted to pH 3 at 0 ° C with a 6N aqueous hydrochloric acid solution. The solution was extracted with ether (200 mL) and the organic layer was washed with saturated sodium chloride solution (200 mL), dried over magnesium sulfate and concentrated in vacuo to give 5-fluoro-3-methyl-1H-indole as a brown solid. MS (ES) m / z 150.0.

[0600] Step 4: To a solution of diisopropyl D-tartrate (6 mL, 28 mmol) in methylene chloride (800 mL) at -10 ° C under nitrogen atmosphere, 4A molecular sieves (15 g), titanium isopropoxide (5.9 mL, 20 mmol), and cinnamon alcohol (27 g, 200 mmol). The mixture was then allowed to age for 40 minutes at -10 ° C, after which time the mixture was cooled to -20 ° C, and treated dropwise with a solution of tert-butyl hydroperoxide (TBHP, ~ 450 mmol) in isooctane. After 18 hours at -30 to -15 ° C, the reaction mixture was treated with 30% aqueous sodium hydroxide solution (5 ml) and diethyl ether (100 ml). The cooling bath was removed and the mixture was allowed to warm to -10 ° C. Magnesium sulfate (anhydrous, 15 g) was added and then stirred for 20 minutes. After solidifying the solid components, the solution was filtered through a silica gel pad, and washed with ether (50 mL). The resulting filtrate was concentrated in vacuo and toluene was added to the azeotropically removed unreacted TBHP. The residue was then purified using a silica gel column (hexane: ethyl acetate / 3: 1) and the purified product was crystallized from a hexane / ethyl acetate mixture to obtain [(2R, 3R) -3-phenyloxiran-2-yl] methanol as white crystals (18 g, 60%, 98.2% ee). MS (ESI) m / z 151.

[0601] Step 5: A mixture of 5-fluoro-3-methyl-1H-indole (2.91 g, 19.5 mmol) and potassium hydride, 50% dispersion in mineral oil (2.8 g, 35.1 mmol), in dichloromethane (40 mL) was stirred for 10 minutes under nitrogen at room temperature. Then [(2R, 3R) -3-phenyloxiran-2-yl] methanol (2.0 g, 13.0 mmol) and a solution of titanium isopropoxide (4.3 mL, 14.3 mmol) in dichloromethane (10 mL) were added and the mixture was stirred at room temperature for 12 hours. After disappearance of the epoxide, the mixture was partitioned between 1N aqueous hydrochloric acid (50 ml) and

111

Ethyl acetate (50 ml). The organic layer was separated, washed with saturated sodium bicarbonate solution (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Biotage chromatography (FlasH40i, silica, 60% ethyl acetate / hexane) to afford (2S, 3S) -3- (5-fluoro-3-methyl-1H-indol-1-yl) -3-phenylpropane- 1,2-diol. MS (ESI) m / z 300.

[0602] Step 6: Solution (2S, 3S) -3- (5-fluoro-3-methyl-1H-indol-1-yl) -3-phenylpropan-1,2-diol (1.03 g, 3.4 mmol) and p-toluenesulfonyl chloride (0.78 g, 4.1 mmol) in anhydrous pyridine (11 mL) was stirred at room temperature under nitrogen for 12 hours. The reaction mixture was then poured into a 1N aqueous hydrochloric acid solution (50 ml) and extracted with ethyl acetate (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give 3- (5-fluoro-3-methyl-indol-1-yl) -2-hydroxy-3-phenylpropyl ester of (2S, 3S) toluene-4- sulfonic acid. This product was used in the next step without further purification. To a solution of 3- (5-fluoro-3-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl toluene-4-sulfonic acid ester (1.6 g, 3.4 mmol) in methanol (10 mL) was added a 2N solution methylamine in methanol (8.6 mL, 17 mmol), and the reaction mixture was stirred for 12 hours. Upon completion, the reaction mixture was partitioned between saturated sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Biotage chromatography (FlasH40i, silica, 20% MeOH / dichloromethane) to afford (1S, 2R) - (5-fluoro-3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol as a clear oil.

The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour. Ethanol was removed in vacuo and the clear oil was triturated with an ether / dichloromethane mixture to give (1S, 2R) -1- (5-fluoro-3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropane hydrochloride 2-ol as a white solid. MS (ESI) m / z 313.

[0603] EXAMPLE 118: (1SR, 2RS) -3-amino-1- (5-fluoro-3-methyl-1H-indol-1-yl) -1- hydrochloride

<img file="PL1732887T3_D0100.tif" />

[0604] To a solution of (2S, 3S) -toluene-4-sulfonic acid 3- (5-fluoro-3-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester (intermediate in EXAMPLE 117, step 6, 0.15 g, .33 mmol) in methanol (10 mL), concentrated ammonium hydroxide (20 mL) was added, and the reaction mixture was stirred for 12 hours. Upon completion, the reaction mixture was partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This crude product was purified by Biotage chromatography (FlasH40i, silica, 25% MeOH / dichloromethane) to afford (1SR, 21RS) -3-amino-1- (5-fluoro-3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol as a clear oil.

The free base was dissolved in a minimum amount of ethanol and treated with a 4N hydrochloric acid solution in dioxane, and stirred for 1 hour. Ethanol was removed in vacuo and the clear oil was triturated with ether / dichloromethane to give (1SR, 2RS) -3-amino-1- (5-fluoro-3112 hydrochloride)

Ether / dichloromethane to obtain (1SR, 2RS) -3-amino-1- (5-fluoro-3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride as a white body Constant. MS (ES) m / z 299.0.

EXAMPLE 119: (1S, 2R) -1- (5-chloro-3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

<img file="PL1732887T3_D0101.tif" />

[0605] In an analogous manner to EXAMPLE 117, step 1, 5-chloro-3-methyl-1H-indole-2-carboxylate was prepared from 4-chloro-phenylamine. MS (ES) m / z 235.9.

[0606] In an analogous manner to EXAMPLE 117, step 2, 5-chloro-3-methyl-1H-indole-2-carboxylic acid was prepared from ethyl 5-chloro-3-methyl-1H-indole-2-carboxylate. MS (ESI) m / z 208. [0607] In an analogous manner to EXAMPLE 117, step 3,5-chloro-3-methyl-1H-indole was prepared from 5-chloro-3-methyl-1H-indole-2 acid carboxylic acid. MS (ESI) m / z 166.

[0608] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (5-chloro-3-methyl-1Hindol-1-yl) -3-phenylpropane-1,2-diol was prepared from -chloro-3-methyl-1H-indole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4). MS (ES) m / z 316.0.

[0609] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (5-chloro-3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2 hydrochloride -ol was prepared from (2S, 3S) -3- (5-chloro-3-methyl-1H-indol-1-yl) -3-phenylpropane-1,2-diol. MS (ES) m / z 329.0.

[0610] EXAMPLE 120: (1S, 2R) -3-amino-1- (5-chloro-3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride.

<img file="PL1732887T3_D0102.tif" />

[0611] In an analogous manner to EXAMPLE 118, (1S, 2R) -3-amino-1- (5-chloro-3-methyl-1Hindol-1-yl) -1-phenylpropan-2-ol was prepared from (2S , 3S) -3- (5-chloro-3-methyl-1H-indol-1-yl) -3-phenylpropane-1,2-diol (EXAMPLE 119, step 4). MS (ES) m / z 315.1.

[0612] EXAMPLE 121: [(2R, 3S) -3- (5-chloro-3-methyl-1H-indol-1-yl) -2-methoxy-3-phenylpropyl] methylamine.

<img file="PL1732887T3_D0103.tif" />

[0613] A mixture of 3- (5-chloro-3-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (Intermediate in EXAMPLE 119 , step 6, 0.52 g, 1.1 mmol), trifluoro-methanesulfonic acid methyl ester (0.6 mL, 5.5 mmol), and 2,6-di-tert-butyl-4-methyl113

Pyridine (1.1 g, 5.5 mmol) was heated to reflux in dichloromethane (20 ml) for 2 hours. The reaction mixture was partitioned between ethyl acetate (25 ml) and 1N aqueous hydrochloric acid solution (25 ml). The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (25 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. This crude product was purified by flash column chromatography (silica, 20% ethyl acetate in hexane) to give 3- (5-chloro-3-methyl-indol-1-yl) -2-methoxy-3-phenyl-propyl acid ester ( 2S, 3S) -toluene-4-sulfonic acid. To a solution of 3- (5-chloro-3-methyl-indol-1-yl) -2-methoxy-3-phenyl-propyl toluene-4-sulfonic acid ester (0.13 g, 0.27 mmol) in methanol (10 mL) was added a 2N solution methylamine in methanol (1.4 mL, 2.7 mmol) and the reaction mixture was heated in a sealed tube for 12 hours. Upon completion, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (25 mL) and dichloromethane (25 mL). The organic layer was separated and removed in vacuo. The residue was collected in diethyl ether (25 ml) and washed with 1N aqueous hydrochloric acid (25 ml). The aqueous layer was made basic with pH 8 using saturated aqueous sodium bicarbonate (50 mL). This product was extracted with diethyl ether (25 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The free base was dissolved in a minimum amount of ethanol and treated with a 4N hydrochloric acid solution in dioxane and stirred for 1 hour. Ethanol was removed in vacuo to give [(2R, 3S) -3- (5-chloro-3-methyl-1H-indol-1-yl) -2-methoxy-3-phenylpropyl] methylamine as a yellow oil. MS (ESI) m / z 343.

[0614] EXAMPLE 122: (1S, 2R) -1- (7-chloro-3-methyl-1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0104.tif" />

[0615] In an analogous manner to EXAMPLE 117, step 1,7-chloro-3-methyl-1H-indole-2-carboxylate ethyl was prepared from 2-chloro-phenylamine. MS (ESI) m / z 238.

[0616] In an analogous manner to EXAMPLE 117, step 2, 7-chloro-3-methyl-1H-indole-2-carboxylic acid was prepared from ethyl 7-chloro-3-methyl-1H-indole-2-carboxylate. MS (ES) m / z 208.0. [0617] In an analogous manner to EXAMPLE 117, step 3,7-chloro-3-methyl-1H-indole was prepared from 7-chloro-3-methyl-1H-indole-2-carboxylic acid.

[0618] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (7-chloro-3-methyl-1Hindol-1-yl) -3-phenylpropane-1,2-diol was prepared from 7 -chloro-3-methyl-1H-indole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4). MS (ESI) m / z 316; MS (ESI) m / z 314.

[0619] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (7-chloro3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2 hydrochloride -ol was prepared from (2S, 3S) -3- (7-chloro-3-methyl-1H-indol-1-yl) -3-phenylpropane-1,2-diol. MS (ESI) m / z 329.

[0620] EXAMPLE 123: [(2R, 3S) -3- (5-fluoro-3-methyl-1H-indol-1-yl) -2-methoxy-3-phenylpropyl] methylamine hydrochloride.

114

EP 1 732 887 B1

<img file="PL1732887T3_D0105.tif" />

[0621] In an analogous manner to EXAMPLE 121, [(2R, 3S) -3- (5-fluoro-3-methyl-1H-indol-1-yl) -2-methoxy-3-phenylpropyl] methylamine hydrochloride was prepared from 3- (2S, 3S) -toluene-4-sulfonic acid (5-fluoro-3-methylindol-1-yl) -2-hydroxy-3-phenylpropyl ester (Intermediate in EXAMPLE 117, step 6). MS (ESI) m / z 327.

[0622] EXAMPLE 124: (1S, 2R) -1- (4-bromo-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

Br '[0623] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (4-bromo-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 4- bromo-1H-indole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4). MS (ESI) m / z 346.

[0624] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (4-bromo1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from (2S, 3S) -3- (4-bromo-1H-indol-1-yl) -3-phenylpropane-1,2-diol. MS (ESI) m / z 359.

[0625] EXAMPLE 125: (1S, 2R) -1- (4-bromo-1H-indol-1-yl) -1- (3-fluorophenyl) -3 (methylamino) propan-2-ol hydrochloride.

Br [0626] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (4-bromo-1H-indol-1-yl) 3- (3-fluorophenyl) propane-1,2-diol prepared from 4-bromo-1H-indole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47 step 3). MS (ESI) m / z 364.

[0627] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (4-bromo 1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan- 2-ol was prepared from (2S, 3S) -3- (4-bromo-1Hindol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol. MS (ESI) m / z 377.

[0628] EXAMPLE 126: (1S, 2R) -1- (5-bromo-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

br ·

115

[0629] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (5-bromo-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 5-bromo-1H-indole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4). MS (ESI) m / z 346.

[0630] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (5-bromo5 1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from (2S, 3S) -3- (5-bromo-1H-indol-1-yl) -3-phenylpropane-1,2-diol. MS (ESI) m / z 359.

[0631] EXAMPLE 127: (1S, 2R) -1- (5-bromo-1H-indol-1-yl) -1- (3-fluorophenyl) -3 (methylamino) propan-2-ol hydrochloride.

Br10 [0632] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (5-bromo-1H-indol-1-yl) 3- (3-fluorophenyl) propane-1,2-diol prepared from 5-bromo-1H-indoles and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47 step 3). MS (ESI) m / z 364.

[0633] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (5-bromo1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan- 2-ol was prepared from (2S, 3S) -3- (5-bromo-1H15 indol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol. MS (ESI) m / z 377.

[0634] EXAMPLE 128: 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indole-4-carbonitrile hydrochloride.

<img file="PL1732887T3_D0106.tif" />

[0635] In an analogous manner to EXAMPLE 117, step 5, 1- (2,3-dihydroxy-1-phenyl-propyl) 1H-indole-4-carbonitrile was prepared from 1H-indole-4-carbonitrile and [(2R , 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4).

[0636] In an analogous manner to EXAMPLE 117, step 6, 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indole-4-carbonitrile hydrochloride was prepared from 1- (2 3-dihydroksy1-phenyl-propyl) -1H-indole-4-carbonitrile. MS (ESI) m / z 306.

[0637] EXAMPLE 129: (1S, 2R) -1- (6-bromo-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

Br [0638] In an analogous manner to EXAMPLE 117, step 5, 3- (6-bromo-indol-1-yl) -3-phenylpropane-1,2-diol was prepared from 6-bromo-1H-indole and [( 2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4).

116

[0639] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (6-bromo1H-indol-1-yl) -3- (methylamino) -1-phenylpropan- hydrochloride 2-ol was prepared from 3- (6-bromo-indol-1-yl) -3-phenylpropan-1,2-diol. MS (ESI) m / z 359.

[0640] EXAMPLE 130: 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indole-5-carbonitrile hydrochloride.

<img file="PL1732887T3_D0107.tif" />

[0641] In an analogous manner to EXAMPLE 117, step 5, 1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -1H-indole-5-carbonitrile was prepared from 1H-indole-5-carbonitrile and [ (2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4). MS (ESI) m / z 293.

[0642] In an analogous manner to EXAMPLE 117, step 6, 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indole-5-carbonitrile hydrochloride was prepared from 1 - [( 1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -1H-indole-5-carbonitrile. MS (ES) m / z 306.1.

[0643] EXAMPLE 131: 1 - [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1H-indole-4-carbonitrile hydrochloride.

<img file="PL1732887T3_D0108.tif" />

[0644] In an analogous manner to EXAMPLE 117, step 5, 1- [1- (3-fluoro-phenyl) -2,3-dihydroxy-propyl] -1H-indole-4-carbonitrile was prepared from 1H-indole-4-carbonitrile and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47 step 3).

[0645] In an analogous manner to EXAMPLE 117, step 6, 1 - [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1H-indole-4-carbonitrile hydrochloride was prepared from 1- [1- (3-fluoro-phenyl) -2,3-dihydroxy-propyl] -1H-indole-4-carbonitrile. MS (ES) m / z 324.2.

[0646] EXAMPLE 132: (1S, 2R) -1- (6-bromo-1H-indol-1-yl) -1- (3-fluorophenyl) -3 (methylamino) propan-2-ol hydrochloride.

<img file="PL1732887T3_D0109.tif" />

[0647] In an analogous manner to EXAMPLE 117, step 5, 3- (6-bromo-indol-1-yl) -3- (3-fluorophenyl) propane-1,2-diol was prepared from 6-bromo-1H -indole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47 step 3).

[0648] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (6-bromo1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan- 2-ol was prepared from 3- (6-bromo-indol-1-yl) 117

EP 1 732 887 B1

3- (3-fluoro-phenyl) -propane-1,2-diol. MS (ES) m / z 377.1.

[0649] EXAMPLE 133: (1S, 2R) -1- (6-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- hydrochloride

<img file="PL1732887T3_D0110.tif" />

[0650] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (6-fluoro-1H-indol-1-yl) 3- (3-fluorophenyl) propane-1,2-diol was prepared from 6-fluoro-1H-indole and [(2R, 3R) -3- (3-fluorophenyl) oxiran2-yl] methanol (EXAMPLE 47 step 3). MS (ESI) m / z 304.

[0651] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (6-f) uoro1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) hydrochloride propan-2-ol was prepared from (2S, 3S) -3- (6-fluoro-1Hindol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol. MS (ES) m / z 317.1.

[0652] EXAMPLE 134: (1S, 2R) -3-amino-1- (3-fluorophenyl) -1- (1H-indol-1-yl) propan2-ol hydrochloride.

<img file="PL1732887T3_D0111.tif" />

[0653] In an analogous manner to EXAMPLE 117, step 5, 3- (3-fluoro-phenyl) -3-indol-1-yl-propane-1,2-diol was prepared from 1H-indole and [(2R, 3R) - 3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3).

[0654] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -3-amino-1- (3-fluorophenyl) -1- (1H-indol-1-yl) propan-2-ol hydrochloride was prepared from 3- (3-fluoro-phenyl) -3-indol-1-yl-propane-1,2-diol and para-toluenesulfonic acid followed by concentrated ammonium hydroxide. MS (ES) m / z

285.2.

[0655] EXAMPLE 135: (1S, 2R) -1- (7-bromo-1H-indol-1-yl) -1- (3-fluorophenyl) -3 (methylamino) propan-2-ol hydrochloride.

<img file="PL1732887T3_D0112.tif" />

[0656] In an analogous manner to EXAMPLE 117, step 5, 3- (7-bromo-indol-1-yl) -3- (3-fluorophenyl) propane-1,2-diol was prepared from 7-bromo-1H -indole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47 step 3).

[0657] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (7-bromo1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan- 2-ol was prepared from 3- (7-bromo-indol-1-yl) 3- (3-fluoro-phenyl) -propan-1,2-diol. MS (ES) m / z 377.

[0658] EXAMPLE 136: (1S, 2R) -1- (1H-indol-1-yl) -3- (methylamino) -1- hydrochloride [3118

(Trifluoromethyl) phenyl] propan-2-ol.

F

<img file="PL1732887T3_D0113.tif" />

[0659] In an analogous manner to EXAMPLE 47, step 1, m- (trifluoromethyl) -, cinnamic acid methyl ester was prepared from 3- (3-trifluoromethyl-phenyl) -acrylic acid. MS (ES) m / z

231.1.

[0660] In an analogous manner to EXAMPLE 47, step 2, (2E) -3- [3- [trifluoromethyl) phenyl] prop2-en-1-ol was prepared from m- (trifluoromethyl) -, cinnamic acid methyl ester. MS (ES) m / z 185.1.

[0661] In an analogous manner to EXAMPLE 47, step 3, {(2R, 3R-3- [3- (trifluoromethyl) phenyl] oxiran-2-yl} methanol was prepared from (2E) -3- [3- [trifluoromethyl) phenyl] prop-2-en-1-ol. MS (ES) m / z 217.3.

[0662] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (2,3-dihydro-1H-indol-1-yl) -3- [3- (trifluoromethyl) phenyl] propan-1, 2-diol was prepared from indoline and {(2R, 3R) -3- [3- (trifluoromethyl) phenyl] oxiran-2-yl} methanol. MS (ESI) m / z 338.

[0663] In an analogous manner to EXAMPLE 47, step 5, (2S, 3S) -3- (1H-indol-1-yl) -3- [3- (trifluoromethyl) phenyl] propan-1,2-diol was prepared from (2S, 3S) -3- (2,3-dihydro-1H-indol-1-yl) -3- [3- (trifluoromethyl) phenyl] propan-1,2-diol. MS (ESI) m / z 336.

[0664] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (1H-indol1-yl) -3- (methylamino) -1- [3- (trifluoromethyl) phenyl] propan-2-hydrochloride -ol was prepared from (2S, 3S) -3- (1H-indol-1-yl) -3- [3- (trifluoromethyl) phenyl] propan-1,2-diol. MS (ES) m / z 349.1.

[0665] EXAMPLE 137: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1spiro [cyclohexane-1,3'-indolo] -1 '(2'H) -yl-propane hydrochloride -2-ol.

[0666] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3-fluorophenyl) -3spiro [cyclohexane-1,3'-indolo] -1 '(2'H) -yl- 1,2-diol propane prepared from 1 ', 2'-dihydrospiro [cyclohexane1,3'-indolo]¹⁵ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a white solid. MS (ES) m / z 356.2 ([M + H] +); HRMS: calcd for C22H26FNO2 + H +, 356.2020;

found (ESI, [M + H] +), 356.2031.

¹⁵Kucerovy. AND.; Hathaway, JS; Mattner, PG; Repic, O. Synth. Commun. 1992,22,729-733.

[0667] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3-fluoro-phenyl) -3- (methylamino) -1-spiro [cyclohexane-1,3'-indolo] -1 'hydrochloride ( 2'H) -yl-propan-2-ol was prepared from

119

(2S, 3S) -3- (3-fluorophenyl) -3-spiro [cyclohexane-1,3'-indolo] -1 '(2'H) -yl-propane-1,2-diol as a white powder. MS (ES) m / z 369.2 ([M + H] +); HRMS: calcd for C 23 H 29 FN 2 O + H +, 369.2337; found (ESI, [M + H] +), 369.2332.

[0668] EXAMPLE 138: (1S, 2R-1- (2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1- [3- hydrochloride

<img file="PL1732887T3_D0114.tif" />

[0669] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1- [3- (trifluoromethyl) phenyl] propan-2-ol prepared from (2S, 3S) -3- (2,3-dihydro-1Hindol-1-yl) -3- [3- (trifluoromethyl) phenyl] propan-1,2-diol (EXAMPLE 136, step 4). MS (ES) m / z 351.1. [0670] EXAMPLE 139: (1S, 2S) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3 (methylamino) propan-2-ol hydrochloride.

<img file="PL1732887T3_D0115.tif" />

[0671] In an analogous manner to EXAMPLE 16, step 2,4-nitrobenzoate (2S, 3S) -3- (3-fluoro-phenyl) -2-hydroxy-3- (1H-indol-1-yl) propyl was prepared from 3- ( 3-fluoro-phenyl) -3-indol-1-yl-propane-1,2-diol (EXAMPLE 134, step 1). MS (ES) m / z 435.0.

[0672] In an analogous manner to EXAMPLE 16, step 3, 3- (3-fluoro-phenyl) -3-indol-1-yl-2-methanesulfonyloxy-propyl ester of 4-nitro-benzoic acid was prepared from 4-nitrobenzoate (2S, 3S) -3- (3-fluorophenyl) -2-hydroxy-3- (1H-indol-1-yl) propyl.

[0673] In an analogous manner to EXAMPLE 16, step 4, 1 - {(S) - (3-fluorophenyl) [(2R) -oxiran-2-yl] methyl) -1H-indole was prepared from 3- (3-fluoro- phenyl) -3-indol-1-yl-2-methanesulfonyloxy-propyl ester of 4-nitro-benzoic acid. MS (ESI) m / z 338.

[0674] In an analogous manner to EXAMPLE 16, step 5, (1S, 2S) -1- (3-fluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2-ol hydrochloride was prepared from 1 - {(S) - (3-fluorophenyl) [(2R) -oxiran-2-yl] methyl) -1H-indole. MS (ESI) m / z 299.

[0675] EXAMPLE 140: (1S, 2R) -1- (3,4-difluorophenyl) -1- (1H-indol-1-yl) -3 (methylamino) propan-2-ol hydrochloride.

<img file="PL1732887T3_D0116.tif" />

[0676] In an analogous manner to EXAMPLE 47, step 1, 3,4-difluoro, methyl acid ester

120

Cinnamon, (E) was prepared from 3- (3,4-difluoro-phenyl) -acrylic acid. MS (ES) m / z 199.1. [0677] In an analogous manner to EXAMPLE 47, step 2, (2E) -3- (3,4-difluorophenyl) prop-2-en1-ol was prepared from 3,4-difluoro, cinnamic acid methyl ester, (E ). MS (ES) m / z 153.1. [0678] In an analogous manner to EXAMPLE 47, step 3, [(2R, 3R) -3- (3,4-difluorophenyl) oxiran-2-yl] methanol was prepared from (2E) -3- (3,4-difluorophenyl) prop-2-en-1-ol. MS (ES) m / z 185.1.

[0679] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3,4-difluorophenyl) -3- (2,3-dihydro-1H-indol-1-yl) propan-1,2 - diol was prepared from indoline and [(2R, 3R) -3- (3,4-difluorophenyl) oxiran-2-yl] methanol. MS (ES) m / z 306.1.

[0680] In an analogous manner to EXAMPLE 47, step 5, (2S, 3S) -3- (3,4-difluorophenyl) -3- (1Hindol-1-yl) propane-1,2-diol was prepared from (2S , 3S) -3- (3,4-difluorophenyl) -3- (2,3-dihydro-1H-indol-1-yl) propane-1,2-diol. MS (ESI) m / z 304.

[0681] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (3,4-difluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) propan-2- hydrochloride olu was prepared from (2S, 3S) -3- (3,4-difluorophenyl) -3- (1H-indol-1-yl) propan-1,2-diol. MS (ES) m / z 317.1.

[0682] EXAMPLE 141: (1RS, 2SR) -1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride .

<img file="PL1732887T3_D0117.tif" />

[0683] In an analogous manner to EXAMPLE 33, step 1, (2RS, 3RS) -3- (6-chloro-2,3-dihydro4H-1,4-benzoxazin-4-yl) -2-hydroxy-3- ethyl phenylpropanoate was prepared from 6-chloro-3,4-dihydro2H-1,4-benzoxazine (EXAMPLE 88, step 1) and trans-ethyl-3-phenylglycidate as a viscous yellow liquid. MS (ESI) m / z 362.0 ([M + H] +); HRMS: calcd for C19H20CINO4 + H +, 362.1154; found (ESI, [M + H] +), 362.1150.

[0684] In an analogous manner to EXAMPLE 33, step 2, (2RS, 3RS) -3- (6-chloro-2,3-dihydro4H-1,4-benzoxazin-4-yl) -2-hydroxy-N- methyl-3-phenylpropanamide was prepared from ethyl (2RS, 3RS) -3- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -2-hydroxy-3-phenylpropanoate as white needles. MS (ESI) m / z 34.4.9 ([MH]^-); HRMS: calcd for C18H19ClN2O3 + H +, 347.1157; found (ESI, [M + H] +), 347.1150.

[0685] In an analogous manner to EXAMPLE 33, step 3, (1RS, 2SR) -1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- (methylamino) hydrochloride -1-phenylpropan-2-ol was prepared from (2RS, 3RS) -3- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -2-hydroxy-N-methyl- Phenylpropanamide, as a white powder. MS (ESI) m / z 333.1 ([M + H] +); HRMS: calcd for C18H21ClN2O2 + H +, 333.1370; found (ESI, [M + H] +), 333.1381.

[0686] EXAMPLE 142: (1RS, 2SR) -3- (methylamino) -1- (6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -1-phenylpropan-2-ol hydrochloride .

121

EP 1 732 887 B1

<img file="PL1732887T3_D0118.tif" />

[0687] In an analogous manner to EXAMPLE 165, step 1, 6-methyl-3,4-dihydro-2H-1,4-benzoxazine was prepared from 6-methyl-2H-1,4-benzoxazin-3 (4H) -one, as yellow oil. MS (ES) m / z

150.0 ([M + H] +); HRMS: calcd for C9H11NO + H +, 150.0919; found (ESI, [M + H] +), 150.0924. [0688] In an analogous manner to EXAMPLE 33, step 1, (2RS, 3RS) -2-hydroxy-3- (6-methyl2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- Ethyl phenylpropanoate was prepared from 6-methyl-3,4-dihydro2H-1,4-benzoxazine and trans-ethyl-3-phenylglycidate as a viscous yellow liquid. MS (ESI) m / z 342.0 ([M + H] +); HRMS: calcd for C 20 H 23 NO 4 + H +, 342.1700; found (ESI, [M + H] +), 342.1683.

[0689] In an analogous manner to EXAMPLE 33, step 2, (2RS, 3RS) -2-hydroxy-N-methyl-3- (6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4- yl) -3-phenylpropanamide prepared from (2RS, 3RS) -2-hydroxy-3- (6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3-phenylpropanoate as a white powder . MS (ESI) m / z 325.0 ([MH]^-); HRMS: calcd for C19H22N2O3 + H +, 327.1703; found (ESI, [M + H] +), 327.1703.

[0690] In an analogous manner to EXAMPLE 33, step 3, (1RS, 2SR) -3 (methylamino) -1- (6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl hydrochloride ) -1-phenylpropan-2-ol was prepared from (2RS, 3RS) -2-hydroxy-N-methyl-3- (6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -Phenylpropanamide, as a white powder. MS (ESI) m / z 313.0 ([M + H] +); HRMS: calcd for C19H24N2O2 + H +, 313.1911; found (ESI, [M + H] +), 313.1908.

[0691] EXAMPLE 143: (1S, 2R) -1- (3-fluoro-phenyl) -3- (methylamino) -1- (3-methyl-1H-indol-1-yl) -propan-2-ol hydrochloride.

<img file="PL1732887T3_D0119.tif" />

[0692] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (3-fluorophenyl) -3- (3-methyl-1H-indol-1-yl) propane-1,2-diol was prepared from 3-methylindole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, yellowish oil. MS (ES) m / z

300.0 ([M + H] +); HRMS: calcd for C18H18FNO2 + H +, 300.1400; found (ESI, [M + H] +),

300.1400.

[0693] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3-fluoro-phenyl) -3- (methylamino) -1- (3-methyl-1H-indol-1-yl) -propan- hydrochloride 2-ol was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-methyl-1H-indol-1-yl) propan-1,2-diol as a white solid. MS (ES) m / z 313.0 ([M + H] +); HRMS: calcd for C19H21FN2O + H +, 313.1711; found (ESI, [M + H] +), 313.1713.

[0694] EXAMPLE 144: (1S, 2R) -1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) 3- (methylamino) -1-phenylpropan-2- hydrochloride ol.

122

EP 1 732 887 B1

<img file="PL1732887T3_D0120.tif" />

[0695] Step 1: Racemic (1RS, 2SR) -1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3 (methylamino) -1-phenylpropan-2- ol (EXAMPLE 141) was dissolved in methanol. The resulting solution was injected into a supercritical mobile phase chromatography apparatus. The baseline of the separated enantiomers was drawn using the conditions described below. The enantiomeric purity for each enantiomer was determined in the same supercritical mobile phase chromatography apparatus using a Chiralpak AD-H 5u column, 250 mm x 4.6 mm ID, at a flow rate of 2.0 ml / min, using an analytical mobile phase chromatography device in a supercritical state (Berger Instruments, Inc. Newark, DE USA).

<td>SFC device:</td><td>Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE 19702.</td>

<td>Column:</td><td>Chiralpak AD-H; 5u; 250mm L x 20mm ID (Chiral Technologies, Inc, Exton, PA, USA)</td>

<td>Temperature column:</td><td>35 ° C</td>

<td>SFC modifier:</td><td>40% MeOH with 0.5% DEA</td>

<td>Flow rate:</td><td>50 ml / min</td>

<td>Output pressure:</td><td>100 bars</td>

<td>Detector:</td><td>UV at 266 nm</td>

[0696] Step 2: Solution (1S, 2R) -1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- (methylamino) 1-phenylpropan-2- ol, isolated as a peak 1. (58 mg, 0.17 mmol) in dichloromethane (3 mL) was treated with ethereal hydrochloric acid (1M solution, 0.2 mL, 0.2 mmol). Hexane was added to the resulting solution until a white powder was formed, which was collected, washed with hexane, and dried in vacuo to give 62 mg (45%) of (1S, 2R) -1- (6-chloro-2,3-dihydro-4H- hydrochloride) 1,4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol. Chiral purity:>

99.9%. MS (ESI) m / z 333.0 ([M + H] +); HRMS: calcd for C18H21ClN2O2 + H +, 333.1370; found (ESI, [M + H] +), 333.1372.

[0697] EXAMPLE 145: (1R, 2S) -1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) 3- (methylamino) -1-phenylpropan-2- hydrochloride ol.

<img file="PL1732887T3_D0121.tif" />

[0698] In an analogous manner to EXAMPLE 144, step 2, (1R, 2S) -1- (6-chloro2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- (methylamino) hydrochloride -1-phenylpropan-2-ol was prepared from (1R, 2S) 123

EP 1 732 887 B1

1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol, which was isolated as peak 2 from chiral separation (EXAMPLE 144, step 1). Chiral purity:> 99.9%. MS (ESI) m / z 333.0 ([M + H] +); HRMS: calcd for C18H21CIN2O2 + H +, 333.1370; found (ESI, [M + H] +), 333.1374.

[0699] EXAMPLE 146: (1S, 2R) -1- (4-chloro-1H-indol-1-yl) -3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0122.tif" />

[0700] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (4-chloro-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 4-chloroindole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a viscous, yellowish oil. MS (ES) m / z 300.0 ([MH]^-).

[0701] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (4-chloro 1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from (2S, 3S) -3- (4-chloro-1H-indol-1-yl) -3-phenylpropane-1,2-diol as a white powder. MS (ES) m / z 315.0 ([M + H] +); HRMS: calcd for C18H19ClN2O + H +, 315.1259; found (ESI, [M + H] +), 315.1255.

[0702] EXAMPLE 147: (1S, 2R) -1- (6-chloro-1H-indol-1-yl) -3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0123.tif" />

[0703] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (6-chloro-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 6-chloroindole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a viscous, colorless oil. MS (ES) m / z 302.0 ([M + H] +); HRMS: calcd for C17H16CINO2 + H +, 302.0948; found (ESI, [M + H] +), 302.0946.

[0704] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (6-chloro1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from (2S, 3S) -3- (6-chloro-1H-indol-1-yl) -3-phenylpropane-1,2-diol as a white powder. MS (ES) m / z 315.0 ([M + H] +); HRMS: calcd for C18H19CIN2O + H +, 315.1259; found (ESI, [M + H] +), 315.1263.

[0705] EXAMPLE 148: (1S, 2R) -1- (7-chloro-1H-indol-1-yl) -3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0124.tif" />

[0706] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (7-chloro-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 7-chloroindole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a viscous, colorless oil. MS (ES) m / z 302.0 ([M + H] +); HRMS: calcd for C17H16ClNO2 + H +, 302.0948; found (ESI, [M + H] +), 302.0949.

124

EP 1 732 887 B1

C17H16ClNO2 + H +, 302.0948; found (ESI, [M + H] +), 302.0949.

[0707] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (7-chloro1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from (2S, 3S) -3- (7-chloro-1H-indol-1-yl) -3-phenylpropane-1,2-diol as a white powder. MS (ES) m / z 315.0 ([M + H] +); HRMS: calcd for C18H19ClN2O + H +, 315.1259; found (ESI, [M + H] +), 315.1269.

[0708] EXAMPLE 149: (1S, 2R) -1- (7-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- hydrochloride

<img file="PL1732887T3_D0125.tif" />

[0709] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (7-chloro-1H-indol-1-yl) 3- (3-fluorophenyl) propane-1,2-diol was prepared from 7-chloroindole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, colorless oil. MS (ES) m / z 320.0 ([M + H] +);

HRMS: calcd for C17H15CIFNO2 + H +, 320.0848; found (ESI, [M + H] +), 320.0858.

[0710] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (7-chloro1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan- 2-ol was prepared from (2S, 3S) -3- (7-chloro-1Hindol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol as a white powder. MS (ES) m / z 333.0 ([M + H] +);

HRMS: calcd for C18H18CIFN2O + H +, 333.1170; found (ESI, [M + H] +), 333.1189.

[0711] EXAMPLE 150: (1S, 2R) -1- (4-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- hydrochloride

<img file="PL1732887T3_D0126.tif" />

[0712] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (4-chloro-1H-indol-1-yl) 3- (3-fluorophenyl) propane-1,2-diol was prepared from 4-chloroindole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, colorless oil. MS (ES) m / z 320.0 ([M + H] +);

HRMS: calcd for C17H15ClFNO2 + H +, 320.0848; found (ESI, [M + H] +), 320.0856.

[0713] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (4-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan- 2-ol was prepared from (2S, 3S) -3- (4-chloro-1Hindol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol as a white powder. MS (ES) m / z 333.2 ([M + H] +);

HRMS: calcd for C18H18ClFN2O + H +, 333.1170; found (ESI, [M + H] +), 333.1156 ..

[0714] EXAMPLE 151: (1S, 2R) -1- (6-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- hydrochloride

<img file="PL1732887T3_D0127.tif" />

[0715] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (6-chloro-1H-indol-1-yl) 125

EP 1 732 887 B1

3- (3-fluorophenyl) propane-1,2-diol was prepared from 6-chloroindole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous colorless oil. MS (ES) m / z 320.0 ([M + H] +);

HRMS: calcd for C17H15CIFNO2 + H +, 320.0848; found (ESI, [M + H] +), 320.0855.

[0716] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (6-chloro 1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan- 2-ol was prepared from (2S, 3S) -3- (6-chloro-1Hindol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol as a white powder. MS (ES) m / z 333.2 ([M + H] +);

HRMS: calcd for C18H18CIFN2O + H +, 333.1170; found (ESI, [M + H] +), 333.1174.

[0717] EXAMPLE 152: (1S, 2R) -1- (5-chloro-1H-indol-1-yl) -3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0128.tif" />

[0718] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (5-chloro-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 5-chloroindole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a viscous, colorless oil. MS (ES) m / z 302.2 ([M + H] +); HRMS: calcd for C17H16ClNO2 + H +, 302.0948; found (ESI, [M + H] +), 302.0956.

[0719] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (5-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from (2S, 3S) -3- (5-chloro-1H-indol-1-yl) -3-phenylpropane-1,2-diol as a white powder. MS (ES) m / z 315.1 ([M + H] +); HRMS: calcd for C18H19ClN2O + H +, 315.1259; found (ESI, [M + H] +), 315.1247.

[0720] EXAMPLE 153: (1S, 2R) -1- (5-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- hydrochloride

<img file="PL1732887T3_D0129.tif" />

[0721] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (5-chloro-1H-indol-1-yl) 3- (3-fluorophenyl) propane-1,2-diol was prepared from 5-chloroindole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, colorless oil. MS (ES) m / z 320.1 ([M + H] +);

HRMS: calcd for C17H15ClFNO2 + H +, 320.0848; found (ESI, [M + H] +), 320.0854.

[0722] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (5-chloro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan- 2-ol was prepared from 2S, 3S) -3- (5-chloro-1H-indol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol as a white powder. MS (ES) m / z 333.1 ([M + H] +);

HRMS: calcd for C18H18CIFN2O + H +, 333.1170; found (ESI, [M + H] +), 333.1154.

[0723] EXAMPLE 154: (1S, 2R) -1- (3-isopropyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

126

EP 1 732 887 B1

<img file="PL1732887T3_D0130.tif" />

[0724] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (3-isopropyl-1H-indol-1yl) -3-phenylpropane-1,2-diol was prepared from 3-isopropylindole¹⁶ and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a viscous, yellowish oil. HRMS: calcd for C 20 H 23 NO 2 + H +, 310.1802; found (ESI, [M + H] +), 310.1793.

[0725] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3isopropyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from (2S, 3S) -3- (3-isopropyl-1H-indol-1-yl) -3-phenyl-propane-1,2-diol as a white powder. MS (ES) m / z 323.3 ([M + H] +);

HRMS: calcd for C 21 H 26 N 2 O + H +, 323.2118; found (ESI, [M + H] +), 323.2117.

[0726] EXAMPLE 155: (1S, 2R) -1- (3-fluorophenyl) -1- (3-isopropyl-1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0131.tif" />

[0727] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (3-fluorophenyl) -3- (3isopropyl-1H-indol-1-yl) propane-1,2-diol was prepared from 3-isopropylindole¹⁶ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, yellowish oil. MS (ES) m / z

326.2 ([MH]^-); HRMS: calcd for C 20 H 22 FNO 2 + H +, 328.1707; found (ESl, [M + H] +),

328.1709.

¹⁶ Odle, R .; Blevins, B .; Ratcliff, M .; Hegedus, LSJ Org. Chem. 1980, 45, 2709-27 10.

[0728] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3-fluorophenyl) -1- (3-isopropyl-1H-indol-1-yl) -3- (methylamino) propan- 2-ol was prepared from (2S, 3S) -3- (3-fluoro-phenyl) -3- (3-isopropyl-1H-indol-1-yl) -propan-1,2-diol as a white powder. MS (ES) m / z 341.3 ([M + H] +); HRMS: calcd for C 21 H 25 FN 2 O + H +, 341.2024; found (ESI, [M + H] +), 341.2025.

[0729] EXAMPLE 156: (1S, 2R) -1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) hydrochloride -

<img file="PL1732887T3_D0132.tif" />

[0730] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (6-chloro-2,3-dihydro-4H1,4-benzoxazin-4-yl) -3- (3-fluorophenyl) ) propane-1,2-diol was prepared from 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (EXAMPLE 88, step 1) and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2 -yl] methanol (EXAMPLE 47, step 3) as a viscous, yellowish liquid. MS (ES) m / z 335.8 ([MH]^-); HRMS: calculated for

127

EP 1 732 887 B1

C20H22FNO2 + H +, 338.0959; found (ESI, [M + H] +), 338.0959.

[0731] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (6-chloro2,3-dihydro-4H-1,4-benzoxazin-4-yl) -1- (3- fluorophenyl) -3- (methylamino) propan-2-ol prepared from (2S, 3S) -3- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- ( 3-fluorophenyl) propane-1,2-diol as a white powder. MS (ES) m / z 351.0 ([M + H] +); HRMS: calcd for C18H20CIFN2O2 + H +, 351.1276; found (ESI, [M + H] +), 351.1276.

[0732] EXAMPLE 157: (1S, 2R) -1- (3,5-difluorophenyl) -1- (1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0133.tif" />

[0733] ​​Step 1: In an analogous manner to EXAMPLE 47, step 1, trans-3,5-difluorocinnamic acid methyl ester was prepared from trans-3,5-difluorocinnamic acid as a white solid. MS (ESI) m / z 198.0; HRMS: calcd for C 10 H 8 F 2 O 2, 198.0492; found (ESI, [M] +), 198.0489.

[0734] Step 2: In an analogous manner to EXAMPLE 47, step 2, trans-3,5-difluorocinnamic alcohol was prepared from trans-3,5-difluorocinnamic acid methyl ester as a colorless oil.

[0735] Step 3: In an analogous manner to EXAMPLE 47, step 3, [(2R, 3R) -3- (3,5-difluorophenyl) oxiran-2-yl] methanol was prepared from trans-3,5-difluorocinnamic alcohol as colorless liquid. Percentage of ee: 97.9%. MS (ESI) m / z 186.0; HRMS: calcd for C9H8F2O2, 186.0492; found (ESI, [M] +), 186.0501.

[0736] Step 4: In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3,5-difluorophenyl) -3- (2,3-dihydro-1H-indol-1-yl) propan- The 1,2-diol was prepared from indoline and [(2R, 3R) -3- (3,5-difluorophenyl) oxiran-2-yl] methanol as a viscous, yellowish oil. MS (ES) m / z 306.2 ([M + H] +); HRMS: calcd for C17H17F2NO2 + H +, 306.1300; found (ESI, [M + H] +), 306.1299.

[0737] Step 5: In an analogous manner to EXAMPLE 47, step 5, (2S, 3S) -3- (3,5-difluorophenyl) 3- (1H-indol-1-yl) propan-1,2-diol prepared from (2S, 3S) -3- (3,5-difluorophenyl) -3- (2,3-dihydro-1H-indol-1-yl) propan-1,2-diol as a viscous, yellowish oil. MS (ES) m / z 304.0 ([M + H] +); HRMS: calcd for C17H15F2NO2 + H +, 304.1144; found (ESI, [M + H] +), 304.1146.

[0738] Step 6: In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1 (3,5-difluorophenyl) -1- (1H-indol-1-yl) -3- (methylamino) hydrochloride propan-2-ol was prepared from (2S, 3S) -3- (3,5-difluorophenyl) -3- (1H-indol-1-yl) propan-1,2-diol as a white powder. MS (ES) m / z 317.0 ([M + H] +); HRMS: calcd for C18H18F2N2O + H +, 317.1465; found (ESI, [M + H] +), 317.1465.

[0739] EXAMPLE 158: (1S, 2R) -1- (3,5-difluorophenyl) -1- (2,3-dihydro-1H-indol-1-yl) 3- (methylamino) propan-2-ol hydrochloride .

128

EP 1 732 887 B1

<img file="PL1732887T3_D0134.tif" />

[0740] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3,5-difluorophenyl) -1- (2,3-dihydro-1H-indol-1-yl) -3- hydrochloride (( methylamino) propan-2-ol from (2S, 3S) -3- (3,5-difluorophenyl) -3- (2,3-dihydro-1H-indol-1-yl) propan-1,2-diol as a white powder . MS (ES) m / z 319.0 ([M + H] +); HRMS: calcd for C18H20F2N2O + H +, 319.1622; found (ESI, [M + H] +), 319.1622. [0741] EXAMPLE 159: (1S, 2R) -4-amino-1- (3-fluorophenyl) -1- (1H-indol-1-yl) butan hydrochloride

<img file="PL1732887T3_D0135.tif" />

[0742] In an analogous manner to Example 1, step 2, 3- (3-fluorophenyl) -2-hydroxy-3-indol-1-ylpropyl (2S, 3S) -toluene-4-sulfonic acid ester was prepared from (2S , 3S) -3- (3-fluorophenyl) -3 (1H-indol-1-yl) propan-1,2-diol (Example 47, step 4). MS (ES) m / z 440 ([M + H] +).

[0743] EXAMPLE 160: (1S, 2R) -1- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -1- (3- hydrochloride

<img file="PL1732887T3_D0136.tif" />

[0744] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3- (3-fluorophenyl) propane -1,2-diol was prepared from 3,3-dimethylindoline¹⁵ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous brown liquid. MS (ES) m / z 316.0 ([M + H] +); HRMS: calcd for C19H22FNO2 + H +, 316.1713; found (ESI, [M + H] +),

316.1713.

[0745] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -1- (3-fluorophenyl) hydrochloride -3- (methylamino) propan-2-ol was prepared from (2S, 3S) -3- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3- (3-fluorophenyl) 1,2-diol propane as a white powder. MS (ES) m / z 329.0 ([M + H] +).

[0746] EXAMPLE 161: (1S, 2R) -1- (3,5-difluorophenyl) -1- (3,3-dimethyl-2,3-dihydro- hydrochloride

<img file="PL1732887T3_D0137.tif" />

[0747] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3,5-difluorophenyl) -3- (3,3129

Dimethyl-2,3-dihydro-1H-indol-1-yl) propan-1,2-diol was prepared from 3,3-dimethylindoline¹⁵ and [(2R, 3R) -3 (3,5-difluorophenyl) oxiran-2-yl] methanol (EXAMPLE 157, step 3) as a viscous brown liquid. MS (ES) m / z 334.0 ([M + H] +); HRMS: calcd for C19H21F2NO2 + H +, 334.1619; found (ESI, [M + H] +), 334.1619.

[0748] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3,5-difluorophenyl) -1- (3,3-dimethyl-2,3-dihydro-1H-indol-1- hydrochloride, hydrochloride yl) -3- (methylamino) propan-2-ol prepared from (2S, 3S) -3- (3,5-difluorophenyl) -3- (3,3-dimethyl-2,3-dihydro-1H-indol- 1-yl) propan-1,2-diol as a white powder. MS (ES) m / z 347.0 ([M + H] +); HRMS: calcd for C20H24F2N2O + H +, 347.1929; found (ESI, [M + H] +), 347.1929.

[0749] EXAMPLE 162: (1S, 2R) -1- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0138.tif" />

[0750] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3-phenylpropane-1,2- diol was made from 3,3-dimethylindoline¹⁵ and [(2R, 3R) -3-phenyloxirane 2-yl] methanol (EXAMPLE 117, step 4) as a viscous brown liquid. MS (ES) m / z 298.0 ([M + H] +); HRMS: calcd for C19H23NO2 + H +, 298.1807; found (ESI, [M + H] +), 298.1807.

[0751] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3- (methylamino) -1 hydrochloride -phenylpropan-2-ol was prepared from (2S, 3S) -3 (3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -3-phenylpropan-1,2-diol as a white powder . MS (ES) m / z

311.0 ([M + H] +); HRMS: calcd for C 20 H 26 N 2 O + H +, 311.2118; found (ESI, [M + H] +),

311.2107.

[0752] EXAMPLE 163: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (3-methyl-2,3-dihydro-1H-indol-1-yl) propan-2- hydrochloride ol.

<img file="PL1732887T3_D0139.tif" />

[0753] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3-fluorophenyl) -3- (3-methyl-2,3-dihydro-1H-indol-1-yl) propan-1 , 2-diol was prepared from 3-methylindoline⁴ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, yellowish liquid. MS (ES) m / z 301.8 ([M + H] +); HRMS: calcd for C18H20FNO2 + H +, 302.1551; found (ESI, [M + H] +), 302.1539.

[0754] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3-fluoro-phenyl) -3- (methylamino) -1- (3-methyl-2,3-dihydro-1H-indol- 1-yl) propan-2-ol was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-methyl-2,3-dihydro-1H-indol-1-yl) propan-1, 2-diol as a white powder. MS (ES) m / z 315.2 ([M + H] +); HRMS: calcd for C19H23FN2O + H +, 315.1873; found (ESI,

130

EP 1 732 887 B1 [M + H] +), 315.1881.

[0755] EXAMPLE 164: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0140.tif" />

[0756] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3-fluorophenyl) -3spiro [cyclopentane-1,3'-indolo] -1 '(2'H) -yl- 1,2-diol propane prepared from 1 ', 2'-dihydrospiro [cyclopentane-1,3'-indolo]¹⁵ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, yellowish liquid. MS (ES) m / z 342.2 ([M + H] +).

[0757] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3-fluoro-phenyl) -3- (methylamino) -1-spiro [cyclopentane-1,3'-indolo] -1 'hydrochloride ( 2'H) -yl-propan-2-ol was prepared from (2S, 3S) -3- (3-fluorophenyl) -3-spiro [cyclopentane-1,3'-indolo] -1 '(2'H) - 1,2-diol-propane, as a white powder. MS (ES) m / z 355.0 ([M + H] +); HRMS: calcd for C22H27FN2O + H +, 355.2180; found (ESI, [M + H] +), 355.2178.

[0758] EXAMPLE 165: (1S, 2R) -1- (2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4- hydrochloride

<img file="PL1732887T3_D0141.tif" />

[0759] Step 1: To 2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one solution¹⁷ (2.658 g, 15.0 mmol) in tetrahydrofuran (10 mL) under a nitrogen atmosphere, a borane solution (1.0M solution in tetrahydrofuran, 22.5 mL, 22.5 mmol) was slowly added using a syringe. The resulting mixture was stirred at room temperature for 10 minutes and then at 70 ° C for 1 hour. After cooling, the reaction mixture was slowly quenched with methanol (3 mL). All volatiles were removed under reduced pressure. A 1N aqueous hydrochloric acid solution (10 ml) was added to the liquid residue, and the mixture was heated to 50 ° C for 10 minutes. After cooling, the reaction mixture was converted to an alkaline solution with a saturated solution of sodium bicarbonate (15 ml), and extracted with ethyl acetate (25 ml). The organic layer was washed with water, brine, dried (anhydrous sodium sulfate), filtered through a silica gel pad, and concentrated under reduced pressure to obtain 2.310 g (94%) 2,2-dimethyl-3,4-dihydro-2H-1, 4-benzoxazine as a brown oil. MS (ES) m / z 164.0 ([M + H] +).

[0760] Step 2: In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3 - (3-fluorophenyl) propane-1,2-diol was prepared from 2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2 -yl] methanol (EXAMPLE 47, step 3) as a white solid. MS (ES) m / z 332.2 ([M + H] +); HRMS: calculated for C19H22FNO3 + H +,

332.1657; found (ESI, [M + H] +), 332.1648.

131

[0761] Step 3: In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1 (2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazine hydrochloride) -4-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol prepared from (2S, 3S) -3- (2,2-dimethyl-2,3-dihydro-4H-1 , 4-benzoxazin-4-yl) -3- (3-fluorophenyl) propan-1,2-diol as a white powder. MS (ES) m / z 345.2 ([M + H] +); HRMS: calcd for C 20 H 25 FN 2 O 2 + H +, 345.1978; found (ESI, [M + H] +), 345.1981.

[0762] EXAMPLE 166: (1S, 2R) -1- (2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4- hydrochloride

<img file="PL1732887T3_D0142.tif" />

[0763] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (2,2-dimethyl-2,3-dihydro4H-1,4-benzoxazin-4-yl) -3-phenylpropane- 1,2-diol was prepared from 2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine (EXAMPLE 165, step 1) and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a white solid. MS (ES) m / z 314.1 ([M + H] +).

[0764] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- hydrochloride (( methylamino) -1-phenylpropan-2-ol was prepared from (2S, 3S) -3- (2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3-phenylpropan- 1,2-diol as a white powder. MS (ES) m / z 327.2 ([M + H] +); HRMS: calcd for C 20 H 26 N 2 O 2 + H +, 327.2073; found (ESI, [M + H] +), 327.2082.

[0765] EXAMPLE 167: (1S, 2R) -1- (2,3-dihydro-4H-1,4-benzothiazin-4-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2- hydrochloride ol.

¹⁷Caliendo, G .; Perissutti, E .; Santagada, V .; Fiorino, F .; Severino, B .; Bianca, R.

<img file="PL1732887T3_D0143.tif" />

[0766] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (2,3-dihydro-4H-1,4-benzothiazin-4-yl) -3- (3-fluorophenyl) propan-1 , 2-diol was prepared from 3,4-dihydro-2H-1,4-benzothiazine¹⁸ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, yellowish liquid. MS (ES) m / z 320.1 ([M + H] +); HRMS: calcd for C17H18FNO2S + H +, 320.1115; found (ESI, [M + H] +), 320.1113.

¹⁸El-Subbagh, HI; Abadi, Ah; Al-Khawad, IE; Al-Rashood, KA Arch. Pharm. 1999, 332, 19-24. [0767] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (2,3-dihydro-4H-1,4-benzothiazin-4-yl) -1- (3-fluorophenyl) -3 hydrochloride - (methylamino) propan-2-ol was prepared from (2S, 3S) -3- (2,3-dihydro-4H-1,4-benzothiazin-4-yl) -3- (3-fluorophenyl) propan-1, 2-diol as a white powder. MS (ES) m / z 333.1 ([M + H] +); HRMS: calcd for C18H21FN2OS + H +, 333.1431;

found (ESI, [M + H] +), 333.1420.

[0768] EXAMPLE 168: (1S, 2R) -1- (3-fluoro-phenyl) -3- (methylamino) -1- (2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) hydrochloride propan-2-ol.

132

EP 1 732 887 B1

<img file="PL1732887T3_D0144.tif" />

[0769] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3-fluorophenyl) -3- (2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl ) propane-1,2-diol prepared from 2-phenyl-3,4-dihydro-2H1,4-benzoxazine¹⁹ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a white solid. MS (ES) m / z 380.0 ([M + H] +); HRMS: calcd for C23H22FNO3 + H +, 380.1662; found (ESI, [M + H] +), 380.1661.

¹⁹Olagbemiro, TO; Nyakutse, CA; Lajide, L .; Agho, MO; Chukwu. CE Bull. Soc. Chim. Belgian. 1987, 96, 473-480.

[0770] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3-fluoro-phenyl) -3- (methylamino) -1- (2-phenyl-2,3-dihydro-4H-1 hydrochloride, 4-benzoxazin-4-yl) propan-2-ol was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (2-phenyl-2,3-dihydro-4H-1,4-benzoxazin 4-yl) propan-1,2-diol as a white powder. MS (ES) m / z 393.2 ([M + H] +); HRMS: calcd for C24H25FN2O2 + H +, 393.1978; found (ESI, [M + H] +), 393.1986.

[0771] EXAMPLE 169: (1S, 2R) -1- (3-fluorophenyl) -1- [3- (4-methoxyphenyl) -1H-indol-1- hydrochloride

<img file="PL1732887T3_D0145.tif" />

[0772] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3-fluorophenyl) -3- {3- [4-methoxyphenyl] -1H-indol-1-yl} propan-1,2 -diol prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1H-indol-1-yl) propane-1,2-diol (EXAMPLE 114, step 1) and 4-methoxybenzeneboric acid .

[0773] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- [3- (4-methoxyphenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) acid -toluene-4-sulfone was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- {3- [4-methoxyphenyl] -1H-indol-1-yl} propane-1,2-diol.

[0774] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (3-fluorophenyl) -1 [3- (4-methoxyphenyl) -1H-indol-1-yl] -3- (methylamino) hydrochloride propan-2-ol prepared from 3- (3-fluoro-phenyl) -3 [3- (4-methoxyphenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 405.

[0775] EXAMPLE 170: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [3- (4-methylphenyl) -1H-indol-1-yl] propan-2-ol hydrochloride.

133

EP 1 732 887 B1

<img file="PL1732887T3_D0146.tif" />

[0776] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3-fluorophenyl) -3- {3- [4-methylphenyl] -1H-indol-1-yl} propane-1,2 -diol prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1Hindol-1-yl) propane-1,2-diol (EXAMPLE 114, step 1) and 4-methylbenzenic acid .

[0777] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- [3- (4-methyl-phenyl) -indol-1-yl] -2-hydroxy-propyl acid ester (2S, 3S) -toluene-4-sulfone was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- {3- [4-methylphenyl] -1H-indol-1-yl} propan-1,2-diol.

[0778] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (3-fluorophenyl) -3 (methylamino) -1- [3- (4-methylphenyl) -1H-indol-1-yl] hydrochloride propan-2-ol was prepared from 3- (3-fluoro-phenyl) -3- [3- (4-methyl-phenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 389.2.

[0779] EXAMPLE 171: (1S, 2R) -1- [3- (4-tert-butylphenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2- hydrochloride ol.

<img file="PL1732887T3_D0147.tif" />

[0780] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3-fluorophenyl) -3- {3- [4-tert-butylphenyl] -1H-indol-1-yl} propan-1 , 2-diol was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1H-indol-1-yl) propan-1,2-diol (EXAMPLE 114, step 1) and acid 4 -tert-butylofenyloborowy.

[0781] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- [3- (4-tert-butyl-phenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) -toluene-4-sulfone was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- {3- [4-tert-butylphenyl] -1H-indol-1-yl} propane-1,2 diol. [0782] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- [3- (4-tert-butylphenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino hydrochloride) ) propan-2-ol was prepared from 3- (3-fluoro-phenyl) -3- [3- (4-tert-butyl-phenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) toluene-4- sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 430.9; HRMS: calcd for C28H31FN2O + H +, 431.24932; found (ESI, [M + H] +), 431.2516.

[0783] EXAMPLE 172: (1S, 2R) -1- (3-fluorophenyl) -1- [3- (3-methoxyphenyl) -1H-indol-1-yl] -3- (methylamino) propan-2-ol hydrochloride.

134

EP 1 732 887 B1

<img file="PL1732887T3_D0148.tif" />

[0784] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3-fluorophenyl) -3- {3- [3-methoxyphenyl] -1H-indol-1-yl} propane-1,2 -diol prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1Hindol-1-yl) propane-1,2-diol (EXAMPLE 114, step 1) and 3-methoxybenzeneboric acid .

[0785] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- [3- (3-methoxyphenyl) -indol-1-yl] -2-hydroxy-propyl acid ester (2S, 3S) -toluene-4-sulfonic acid prepared from (2S, 3S) -3- (3-fluorophenyl) -3- {3- [3-methoxyphenyl] -1H-indol-1-yl} propane-1,2-diol.

[0786] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (3-fluorophenyl) -1 [3- (3-methoxyphenyl) -1H-indol-1-yl] -3- (methylamino) hydrochloride propan-2-ol prepared from 3- (3-fluoro-phenyl) -3 [3- (3-methoxyphenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 405.1; HRMS: calcd for C25H25FN2O2 + H +, 405.19728; found (ESI, [M + H] +), 405.196.

[0787] EXAMPLE 173: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- {3- [4- hydrochloride

<img file="PL1732887T3_D0149.tif" />

[0788] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3-fluorophenyl) -3- {3- [4- (trifluoromethyl) phenyl] -1H-indol-1-yl) propane -1,2-diol prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1H-indol-1-yl) propan-1,2-diol (EXAMPLE 114, step 1) and 4- (trifluoromethyl) benzeneboronic acid.

[0789] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluorophenyl) -3- [3- (4- (trifluoromethyl) phenyl) indol-1-yl] -2-hydroxypropyl acid ester ( 2S, 3S) -toluene-4-sulfonic acid was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- {3- [4- (trifluoromethyl) phenyl] -1H-indol-1-yl} propan- 1,2-diol.

[0790] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (3-fluorophenyl) -3 (methylamino) -1- {3- [4- (trifluoromethyl) phenyl] -1H-indol-1 hydrochloride -yl} propan-2-ol prepared from 3- (3-fluoro-phenyl) -3- [3- (4- (trifluoromethyl) phenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S ) toluene-4-sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 443.1.

[0791] EXAMPLE 174: (1S, 2R) -1- (3,5-difluorophenyl) -1- (6-fluoro-2,3-dihydro-1Hindol-1-yl) -3- (methylamino) propane hydrochloride 2-ol.

135

EP 1 732 887 B1

<img file="PL1732887T3_D0150.tif" />

[0792] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (3,5-difluorophenyl) -3- (6-fluoro-2,3-dihydro-1H-indol-1-yl) propane -1,2-diol was prepared from 6-fluoroindoline and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a viscous, yellowish liquid. MS (ES) m / z 324.1 ([M + H] +); HRMS: calcd for C17H16F3NO2 + H +, 324.1211; found (ESI, [M + H] +), 324.1226.

[0793] In an analogous manner to EXAMPLE 47, step 6, (1S, 2R) -1- (3,5-difluorophenyl) -1- (6-fluoro-2,3-dihydro-1H-indol-1-yl) hydrochloride -3- (methylamino) propan-2-ol was prepared from (2S, 3S) -3- (3,5-difluorophenyl) -3- (6-fluoro-2,3-dihydro-1H-indol-1-yl) 1,2-diol propane as a white powder. MS (ES) m / z 337.3 ([M + H] +); HRMS: calcd for C18H19F3N2O + H +, 337.1522; found (ESI, [M + H] +), 337.1505.

[0794] EXAMPLE 175: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (3- [2- hydrochloride

<img file="PL1732887T3_D0151.tif" />

[0795] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3-fluorophenyl) -3- {3- [2- (trifluoromethyl) phenyl] -1H-indol-1-yl} propane -1,2-diol prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1H-indol-1-yl) propan-1,2-diol (EXAMPLE 114, step 1) and 2- (trifluoromethyl) boric acid. [0796] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -2-hydroxy-3- [3- (2- (trifluoromethyl) phenyl) -indol-1-yl] -propyl ester of ( 2S, 3S) - toluene-4-sulfonic acid prepared from (2S, 3S) -3- (3-fluorophenyl) -3- {3- [2- (trifluoromethyl) phenyl] -1H-indol-1-yl} propan- 1,2-diol.

[0797] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (3-fluorophenyl) -3 (methylamino) -1- {3- [2- (trifluoromethyl) phenyl] -1H-indol-1 hydrochloride -yl} propan-2-ol was prepared from 3- (3-fluoro-phenyl) -2-hydroxy-3- [3- (2- (trifluoromethyl) -phenyl) -indol-1-yl] -propyl ester of (2S, 3S) toluene -4-sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 443.1; HRMS: calcd for C25H22F4N2O + H +, 443.17410; found (ESI, [M + H] +), 443.172.

[0798] EXAMPLE 176: (1S, 2R) -1- (3-fluorophenyl) -1- [3- (2-methoxyphenyl) -1H-indol-1- hydrochloride

<img file="PL1732887T3_D0152.tif" />

136

[0799] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3-fluorophenyl) -3- {3- [2-methoxyphenyl] -1H-indol-1-yl} propane-1,2-diol prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1Hindol-1-yl) propane-1,2-diol (EXAMPLE 114, step 1) and 2-methoxybenzeneboric acid.

[0800] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- [3- (2-methoxyphenyl) -indol-1-yl] -2-hydroxy-propyl acid ester (2S, 3S) -toluene-4-sulfone was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- {3- [2-methoxyphenyl] -1H-indol-1-yl} propane-1,2-diol.

[0801] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (3-fluorophenyl) -1 [3- (2-methoxyphenyl) -1H-indol-1-yl] -3- (methylamino) hydrochloride propan-2-ol was prepared from 3- (3-fluoro-phenyl) -3 [3- (2-methoxyphenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) -toluene-4-sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 405.1; HRMS: calcd for C25H25FN2O2 + H +, 405.19728; found (ESI, [M + H] +), 405.1984.

[0802] EXAMPLE 177: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- {3- [3- hydrochloride

<img file="PL1732887T3_D0153.tif" />

[0803] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3-fluorophenyl) -3- {3- [3- (trifluoromethyl) phenyl] -1H-indol-1-yl} propane -1,2-diol prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1H-indol-1-yl) propan-1,2-diol (EXAMPLE 114, step 1) and 3- (trifluoromethyl) benzeneboronic acid.

[0804] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- [3- (3- (trifluoromethyl) phenyl) -indol-1-yl] -2-hydroxy-propyl acid ester ( 2S, 3S) -toluene-4-sulfonic acid was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- {3- [3- (trifluoromethyl) phenyl] -1H-indol-1-yl} propan- 1,2-diol.

[0805] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- (3-fluorophenyl) -3 (methylamino) -1- {3- [3- (trifluoromethyl) phenyl] -1H-indol-1 hydrochloride -yl} propan-2-ol was prepared from 3- (3-fluoro-phenyl) -3- [3- (3- (trifluoromethyl) -phenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) toluene -4-sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 443.1; HRMS: calcd for C25H22F4N2O + H +, 443.17410; found (ESI, [M + H] +), 443.1764.

[0806] EXAMPLE 178: (1S, 2R) -3-amino-1- (3-methyl-1H-indol-1-yl) -1-phenylpropane hydrochloride

<img file="PL1732887T3_D0154.tif" />

[0807] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (3-methyl-indol-1-yl) -3-phenyl-propane-1,2-diol was prepared from 3-methylindole and [ (2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as an oil. MS (ESI) m / z 282 ([M + H] +).

137

[0808] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -3-amino-1- (3-methyl-1H-indol-1-yl) -1-phenylpropan-2 hydrochloride -ol was prepared from (2S, 3S) -3- (3-methyl-indol-1-yl) -3-phenyl-propan-1,2-diol and para-toluenesulfonic acid, followed by concentrated ammonium hydroxide as an off-white solid. MS (ESI) m / z 281.

[0809] EXAMPLE 179: (1S, 2R) -1- (7-fluoro-3-methyl-1H-indol-1-yl) -3- hydrochloride

<img file="PL1732887T3_D0155.tif" />

[0810] In an analogous manner to EXAMPLE 117, step 1, 7-fluoro-3-methyl-1H-indole-2-carboxylate ethyl was prepared from 2-fluoroaniline as a brownish solid. MS (ESI) m / z 221.

[0811] In an analogous manner to EXAMPLE 117, step 2, 7-fluoro-3-methyl-1H-indole-2-carboxylic acid was prepared from ethyl 7-fluoro-3-methyl-1H-indole-2-carboxylate as a green body Constant. MS (ESI) m / z 192.

[0812] In an analogous manner to EXAMPLE 117, step 3,7-fluoro-3-methyl-1H-indole was prepared from 7-fluoro-3-methyl-1H-indole-2-carboxylic acid as a white solid. MS (ESI) m / z 150.

[0813] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S ') - 3- (7-fluoro-3-methyl-1Hindol-1-yl) -3-phenylpropane-1,2-diol was prepared from 7-fluoro-3-methyl-1H-indole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, Step 4) as an oil. MS (ESI) m / z 300.

[0814] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (7-fluoro3-methyl-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2 hydrochloride -ol was prepared from (2S, 3S) -3- (7-fluoro-3-methyl-1H-indol-1-yl) -3-phenylpropane-1,2-diol as a white solid. MS (ES) m / z 313.1.

[0815] EXAMPLE 180: (1S, 2R) -3-amino-1- (7-fluoro-3-methyl-1H-indol-1-yl) -1- hydrochloride

<img file="PL1732887T3_D0156.tif" />

[0816] In an analogous manner to EXAMPLE 117, step 6, 3-amino-1- (7-fluoro3-methyl-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride was prepared from (2S, 3S ) -3- (7-fluoro-3-methyl-1H-indol-1-yl) -3-phenylpropane-1,2-diol (EXAMPLE 179, step 4) and para-toluenesulfonic acid followed by ammonium hydroxide as a white body Constant. MS (ES) m / z 299.0.

[0817] EXAMPLE 181: (1S, 2R) -1- (7-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

138

EP 1 732 887 B1

<img file="PL1732887T3_D0157.tif" />

[0818] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (7-fluoro-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 7-fluoro- 1H-indole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, Step 4) as an oil. MS (ES) m / z 286.1.

[0819] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (7-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from (2S, 3S) -3- (7-fluoro-1H-indol-1-yl) -3-phenylpropane-1,2-diol as a pinkish solid. MS (ESI) m / z 299.

[0820] EXAMPLE 182: (1S, 2R) -1- (4-fluoro-1H-indol-1-yl) -3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0158.tif" />

[0821] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (4-fluoro-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 4-fluoro- 1H-indole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, Step 4) as an oil. MS (ES) m / z 286.1.

[0822] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (4-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from (2S, 3S) -3- (4-fluoro-1H-indol-1-yl) -3-phenylpropane-1,2-diol as a white solid. MS (ESI) m / z 299.

[0823] EXAMPLE 183: (1S, 2R) -1- (7-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- hydrochloride

<img file="PL1732887T3_D0159.tif" />

[0824] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (7-fluoro-1H-indol-1-yl) 3- (3-fluorophenyl) propane-1,2-diol was prepared from 7-fluoro-1H-indole and [(2R, 3R) -3- (3-fluorophenyl) oxiran2-yl] methanol (EXAMPLE 47, Step 3) as a brown oil. MS (ESI) m / z 304.

[0825] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (7-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propane hydrochloride 2-ol was prepared from (2S, 3S) -3- (7-fluoro-1Hindol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol as a pinkish solid. MS (ESI) m / z 317.

[0826] EXAMPLE 184: (1S, 2R) -1- (4-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3 (methylamino) propan-2-ol hydrochloride.

139

EP 1 732 887 B1

<img file="PL1732887T3_D0160.tif" />

[0827] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (4-fluoro-1H-indol-1-yl) 3- (3-fluorophenyl) propane-1,2-diol was prepared from 4-fluoro-1H-indole and [(2R, 3R) -3- (3-fluorophenyl) oxiran2-yl] methanol (EXAMPLE 47, Step 3) as a brown oil. MS (ESI) m / z 304.

[0828] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (4-fluoro-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan- 2-ol was prepared from (2S, 3S) -3- (4-fluoro-1Hindol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol as a white solid. MS (ESI) m / z 317.

[0829] EXAMPLE 185: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [5-

<img file="PL1732887T3_D0161.tif" />

[0830] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (3-fluorophenyl) -3- (5-trifluoromethyl-1H-indol-1-yl) -propane-1,2-diol was prepared from 5-trifluoromethyl-1H-indole and [(2R, 3R) -3 (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, Step 3).

[0831] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [5- (trifluoromethyl) -1H-indol-1-yl] hydrochloride propan-2-ol was prepared from (2S, 3S) 3- (3-fluorophenyl) -3- (5-trifluoromethyl-1H-indol-1-yl) -propan-1,2-diol as an off-white solid. MS (ESI) m / z 367.

[0832] EXAMPLE 186: (1S, 2R) -1- (6-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride.

<img file="PL1732887T3_D0162.tif" />

[0833] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (6-fluoro-1H-indol-1-yl) 3-phenylpropane-1,2-diol was prepared from 6-fluoro- 1H-indole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, Step 4) as a brown oil. MS (ES) m / z 286.1.

[0834] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (6-fluoro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from (2S, 3S) -3- (6-fluoro-1H-indol-1-yl) -3-phenylpropane-1,2-diol as a white solid. MS (ESI) m / z 299.

140

[0835] EXAMPLE 187: (1S, 2R) -3- (methylamino) -1-phenyl-1- [6- (trifluoromethyl) -1H-indol-1-yl] propan-2-ol hydrochloride.

<img file="PL1732887T3_D0163.tif" />

[0836] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3-phenyl-3- [6- (trifluoromethyl) -1H-indol-1-yl] propane-1,2-diol was prepared from 6 -trifluoromethyl-1H-indole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, Step 4) as a brown oil. MS (ES) m / z 336.

[0837] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -3 (methylamino) -1-phenyl-1- [6- (trifluoromethyl) -1H-indol-1-yl] propan-2 hydrochloride -ol was prepared from (2S, 3S) -3-phenyl-3- [6- (trifluoromethyl) -1H-indol-1-yl] -propan-1,2-diol as a white solid. MS (ESI) m / z 349. [0838] EXAMPLE 188: (1S, 2R) -3- (methylamino) -1-phenyl-1- [5- (trifluoromethyl) -1H- hydrochloride

<img file="PL1732887T3_D0164.tif" />

[0839] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3-phenyl-3- [5- (trifluoromethyl) -1H-indol-1-yl] propan-1,2-diol was prepared from 5 -trifluoromethyl-1H-indole and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, Step 4) as a brown oil. MS (ES) m / z 336.

[0840] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -3 (methylamino) -1-phenyl-1- [5- (trifluoromethyl) -1H-indol-1-yl] propan-2 hydrochloride -ol was prepared from (2S, 3S) -3-phenyl-3- [5- (trifluoromethyl) -1H-indol-1-yl] -propan-1,2-diol as an off-white solid. MS (ESI) m / z

349.2.

[0841] EXAMPLE 189: (1S, 2R) -1- (3-tert-butyl-1H-indol-1-yl) -1- (3-fluorophenyl) -3-

<img file="PL1732887T3_D0165.tif" />

[0842] Step 1: To a mixture of indole (5 g, 42.7 mmol), zinc trifluoromethanesulfate (triflate) (9.3 g, 25.6 mmol), and tetrabutylammonium iodide (7.9 g, 21.4 mmol) in anhydrous toluene (120 mL), di -isopropylethylamine (8.2 mL, 47 mmol) at room temperature under a nitrogen blanket. After stirring the reaction mixture for 15 minutes at room temperature, the reaction mixture was treated with tert-butyl bromide (2.5 mL, 21.7 mmol). The reaction solution was stirred at

141

EP 1 732 887 B1 was treated with tert-butyl bromide (2.5 mL, 21.7 mmol). The reaction solution was stirred at room temperature under nitrogen for 3 hours, and then poured into a saturated aqueous solution of ammonium chloride (150 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x 50 mL). The combined organic layers were dried over magnesium sulfate, concentrated and the residue was purified by flash column chromatography (silica, 10% ethyl acetate in hexane) to give 3-tert-butyl-1H-indole as a white solid. MS (ES) m / z 174.2.

[0843] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -3- (3-tert-butyl-1H-indol-1-yl) -3- (3-fluorophenyl) propane-1,2-diol prepared from 3-tert-butyl-1H-indole and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3).

[0844] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (3-tert-butyl-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) hydrochloride propan-2-ol was prepared from (2S, 3S) -3- (3-tert-butyl-1H-indol-1-yl) -3- (3-fluorophenyl) propan-1,2-diol as a clear oil. MS (ESI) m / z 355.3. [0845] EXAMPLE 190: (1S, 2R) -1- (1H-indol-1-yl) -2-methyl-3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0166.tif" />

[0846] In an analogous manner to EXAMPLE 117, step 4, [(2R, 3R) -2-methyl-3-phenyloxiran-2-yl] methanol was prepared from 2-methyl-3-phenylprop-2-en-1-ol, as white crystals. MS (ES) m / z 147.1. [0847] In an analogous manner to EXAMPLE 117, step 5, (2S, 3S) -2-methyl-3-phenyl- [1Hindol-1-yl] propan-1,2-diol was prepared from [(2R, 3R) -2-methyl-3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) and indole.

[0848] In an analogous manner to EXAMPLE 117, step 6, (1S, 2R) -1- (1H-indol1-yl) -2-methyl-3- (methylamino) -1-phenylpropan-2-ol hydrochloride was prepared from (2S, 3S) -2-methyl-3-phenyl- [1Hindol-1-yl] propan-1,2-diol as a white solid. MS (ES) m / z 295.0.

[0849] EXAMPLE 191: (2R, 3S) -3- (1H-indol-1-yl) -1- (methylamino) -3-phenylbutan-2- hydrochloride

<img file="PL1732887T3_D0167.tif" />

[0850] In an analogous manner to EXAMPLE 117, step 4, [(2R, 3R) -3-methyl-3-phenyloxiran-2-yl] methanol was prepared from 3-methyl-3-phenylprop-2-en-1-ol, as white crystals. MS (ES) m / z 147.1. [0851] In an analogous manner to EXAMPLE 47, step 4, (2S, 3S) -3- (2,3-dihydro-1H-indol-1-yl) -3-phenylbutane-1,2-diol was prepared from [(2R , 3R) -3-methyl-3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) and indoline as a brown solid. MS (ES) m / z 284.1.

[0852] In an analogous manner to EXAMPLE 47, step 5, (2S, 3S) -3- (1H-indol-1-yl) -3142

Phenylbutane-1,2-diol was prepared from (2S, 3S) -3- (2,3-dihydro-1H-indol-1-yl) -3-phenylbutane-1,2-diol as off-white solid. MS (ESI) m / z 282.

[0853] In an analogous manner to EXAMPLE 117, step 6, (2R, 3S) -3- (1H-indol1-yl) -1- (methylamino) -3-phenylbutan-2-ol hydrochloride was prepared from (2S, 3S ) -3- (1H-indol-1-yl) -3-phenylbutane-1,2-diol as a white solid. MS (ES) m / z 295.1.

[0854] EXAMPLE 192: 1-tert-butyl-3- (2-hydroxy-3-methylamino-1-phenyl-propyl) hydrochloride -

<img file="PL1732887T3_D0168.tif" />

[0855] Step 1: To a solution of 1-fluoro-2-nitro-benzene (1 g, 7.1 mmol) in dimethylformamide (15 mL) was added tert-butylamine (0.82 mL, 7.81 mmol) at room temperature, and the reaction mixture was stirred for 12 hours at room temperature under nitrogen. Upon completion, the reaction mixture was poured into saturated aqueous sodium chloride (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue purified by flash column chromatography (silica, 1% ethyl acetate in hexane) to give tert-butyl- (2-nitrophenyl) -amine as an orange oil. MS (ES) m / z 195.2 [0856] Step 2: To a solution of tert-butyl- (2-nitrophenyl) -amine (1.27 g, 6.5 mmol), 5% palladium on carbon (0.5 g), and sodium borohydride (0.49 g, 13.1 mmol) in tetrahydrofuran (20 mL) was added dropwise with methanol (10 mL). After completion of the reaction, the mixture was filtered through a Celite pad, and the filtrate was poured into saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo to give N-tert-butyl-benzene-1,2-diamine, which was used in the next step without further purification. A solution of Nt-butylbenzene-1,2-diamine (1.1 g, 6.7 mmol) and carbonyl diimidazole (1.63 g, 10 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred at room temperature for 12 hours. Upon completion, the reaction mixture was poured into 1N aqueous hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. This crude product was purified by flash column chromatography (silica, 50% ethyl acetate in hexane) to give 1-tert-butyl-1,3-dihydro-benzimidazol-2-one as an off-white solid. MS (ES) m / z 191.1.

[0857] Step 3: A mixture of 1-tert-butyl-1,3-dihydro-benzimidazol-2-one (0.66 g, 3.5 mmol) and sodium hydride (60% dispersion in mineral oil, 0.15 g, 3.8 mmol) in anhydrous dimethylformamide (4 mL) was stirred for 10 minutes under nitrogen at room temperature.

A solution of [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4, 1.07 g, 7.1 mmol) and titanium isopropoxide (2.14 mL, 7.1 mmol) in dimethylformamide (4 mL) which was aged for 20 minutes and then added and the mixture was stirred at room temperature under nitrogen for 12 hours. After disappearance of the epoxide, the mixture was partitioned between 1N aqueous hydrochloric acid (50 ml) and ethyl acetate (50 ml). The organic layer was separated, washed with saturated

EP 1 732 887 B1 (50 ml). The organic layer was separated, washed with saturated sodium bicarbonate (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was then purified by silica gel column (60% ethyl acetate in hexane) to give 1-tert-butyl-3 - [(1S, 2S) -2,3-dihydroxy-1-phenyl-propyl] -1,3 -dihydro-2H-benzymidazol-2-one as an oil. MS (ES) m / z 341.2.

Step 4: Solution of 1-tert-butyl-3 - [(1S, 2S) -2,3-dihydroxy-1-phenyl-propyl] -1,3-dihydro-2H-benzimidazol-2-one (0.55 g, 1.6 mmol) and para-toluenesulfonyl chloride (0.37 g, 1.9 mmol) in anhydrous pyridine (5 mL) was stirred at room temperature under nitrogen for 12 hours. The reaction mixture was poured into a cold 1N aqueous hydrochloric acid solution (50 ml) and extracted with ethyl acetate (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give 3- (3-tert-butyl-2-oxo-2,3-dihydrobenzymidazol-1-yl) -2-hydroxy-3-phenyl-propyl ester ( 2S, 3S) -toluene-4-sulfonic acid.

To a solution of 3- (3-tert-butyl-2-oxo-2,3-dihydro-benzimidazol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (0.8 g, 1.6 mmol) in methanol (10 mL) a 2N solution of methylamine in methanol (4 mL, 8 mmol) was added and the reaction mixture was stirred for 12 hours at room temperature in a sealed tube. Upon completion, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 20% MeOH in dichloromethane) to give 1-tert-butyl-3 - [(1S, 2R) -2-hydroxy-3-methylamino-1-phenylpropyl] -1,3-dihydro- 2H-benzimidazol-2-one as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour. Ethanol was removed in vacuo and the clear oil was triturated with a diethyl ether / dichloromethane mixture to give 1-tert-butyl-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro hydrochloride -2H-benzimidazol-2-one, as a white solid. HRMS: calcd for C 21 H 27 N 3 O 2 + H +, 354.21760; found (ESI, [M + H] +), 354.2179.

[0859] EXAMPLE 193: 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3- hydrochloride

<img file="PL1732887T3_D0169.tif" />

[0860] In an analogous manner to EXAMPLE 192, step 1,2-nitro-N-propylaniline was prepared from 1-fluoro-2-nitro-benzene and propylamine. MS (ES) m / z 181.1.

[0861] In an analogous manner to EXAMPLE 192, step 2, 1-propyl-1,3-dihydro-2H-benzimidazol-2-one was prepared from 2-nitro-N-propylaniline. MS (ES) m / z 177.1.

[0862] In an analogous manner to EXAMPLE 192, step 3, 1-propyl-3 - [(1S, 2S) -2,3-dihydroxy-1-phenyl-propyl] -1,3-dihydro-2H-benzimidazol-2- he was prepared from 1-propyl-1,3-dihydro2H-benzimidazol-2-one and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4).

[0863] In an analogous manner to EXAMPLE 192, step 4, hydrochloride 1 - [(1S, 2R) -2144

Hydroxy-3- (methylamino) -1-phenylpropyl] -3-propyl-1,3-dihydro-2H-benzimidazol-2-one was prepared from 1-propyl-3 - [(1S, 2S) - 2,3-dihydroxy-1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2one as a white solid. HRMS: calcd for C20H25N3O2 + H +, 340.20195; found (ESI, [M + H] +), 340.2007 [0864] EXAMPLE 194: 5-bromo-1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0170.tif" />

[0865] Step 1: In an analogous manner to EXAMPLE 99, step 6, 5-bromo-1 [[2S, 3S) -2,3-dihydroxy-1-phenylpropyl] -3,3-dimethyl-1,3 hydrochloride -dihydro-2H-indol-2-one made from 5-bromo-3,3-dimethyl-1,3-dihydro-indol-2-one²⁰ and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE

117, step 4). MS (ESI) m / z 391 ([M + H] +).

²⁰WO 00/66166 [0866] Step 2: In an analogous manner to EXAMPLE 1, step 2, 3- (5-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl) -2 -hydroxy-3-phenyl-propyl (2S, 3S) -toluene-4-sulfonic acid ester prepared from (5-bromo-1 - [(2S, 3S) -2,3-dihydroxy-1-phenylpropyl] -3,3- dimethyl-1,3dihydro-2H-indol-2-one). MS (ESI) m / z 545 ([M + H] +).

[0867] Step 3: In an analogous manner to EXAMPLE 5, 5-bromo-1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl-1,3 hydrochloride -dihydro-2H-indol-2-one made from 3- (5-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl) -2-hydroxy-3-phenyl-propyl (2S, 3S) -toluene-4-sulfonic acid ester. MS m / z 404 ([M + H] +), HRMS: calcd for C20H23BrN2O2 + H +,

403.10156; found (ESI, [M + H] +), 403.0998.

[0868] EXAMPLE 195: 6-fluoro-1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0171.tif" />

[0869] Step 1: In an analogous manner to EXAMPLE 99, step 2, dimethyl (4-fluoro-2-nitrophenyl) malonate was prepared from 2,5-difluoronitrobenzene and dimethyl malonate. MS (ESI) m / z 272 ([M + H] +).

[0870] Step 2: In an analogous manner to EXAMPLE 99, step 3, (4-fluoro-2-nitrophenyl) acetic acid was prepared from dimethyl (4-fluoro-2-nitrophenyl) malonate. MS (ESI) m / z 200 ([M + H] +).

[0871] Step 3: In an analogous manner to EXAMPLE 99, step 4,6-fluoro-1,3-dihydro-2H-indol2-one was prepared from (4-fluoro-2-nitrophenyl) acetic acid. MS (ESI) m / z 152 ([M + H] +)

145

[0872] Step 4: In an analogous manner to EXAMPLE 99, step 5, 6-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one was prepared from 6-fluoro-1 , 3-dihydro-2H-indol-2-one. MS (ESI) m / z 180 ([M + H] +). [0873] Step 5: In an analogous manner to EXAMPLE 99, step 6, (2S, 3S) -1 (2,3-dihydroxy-1-phenyl-propyl) -6-fluoro-3,3-dimethyl-1 hydrochloride , 3-dihydro-indol-2-one was prepared from 6-fluoro3,3-dimethyl-1,3-dihydro-2H-indol-2-one and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4). MS (ESI) m / z 330 ([M + H] +).

[0874] Step 6: In an analogous manner to EXAMPLE 1, step 2, 3- (6-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl) -2-hydroxy-3 -phenyl-propyl (2S, 3S) -toluene-4-sulfonic acid ester prepared from (2S, 3S) -1- (2,3-dihydroxy-1-phenyl-propyl) -6-fluoro-3,3-dimethyl-1 , 3-dihydro-indol-2-one. MS (ESI) m / z 484 ([M + H] +).

[0875] Step 7: Solution of 3- (6-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl) -2-hydroxy-3-phenylpropyl acid ester (2S, 3S ) -toluene-4-sulfone (367 mg, 0.76 mmol) and methylamine (20 mL; 8M solution in ethanol) was stirred in a sealed tube for 16 hours. The solution was then concentrated in vacuo to give 250 mg of a crude product. This crude product was purified by Biotage chromatography (FlasH4Oi, silica, 5%, 8% and 10% methanol with ammonia / dichloromethane) to give 77 mg of impure desired product. After final purification by reverse phase HPLC (X-terra MS C18 19x150 mm, 60% methanol / water isocratic mixture with 0.05% amine hydroxide at 20 ml / min at 250 nm was used) 35 mg of the desired product was obtained as the free base. This free base was treated with 1M ethereal hydrochloric acid until a solution with pH = 3 was obtained, followed by diethyl ether. The product was crystallized by adding a minimum amount of hexane to give the title compound 6-fluoro-1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] 3,3-dimethyl-1,3-dihydro hydrochloride -2H-indol-2-one. MS (ESI) m / z 343 ([M + H] +); HRMS: calcd for C 20 H 23 FN 2 O 2 + H +, 343.18163; found (ESI, [M + H] +), 343.18.

[0876] EXAMPLE 196: 4-fluoro-1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0172.tif" />

[0877] Step 1: In an analogous manner to EXAMPLE 99, step 1, 1,2-difluoro-3-nitro-benzene was prepared from 2,3-difluoro-phenylamine and a mixture of sodium perborate tetrahydrate. MS (ESI) m / z 160 ([M + H] +).

[0878] Step 2: In an analogous manner to EXAMPLE 99, step 2, dimethyl (2-fluoro-6-nitrophenyl) malonate was prepared from 1,2-difluoro-3-nitro-benzene. MS (ESI) m / z 272.0576.

[0879] Step 3: In an analogous manner to EXAMPLE 99, step 3, (2-fluoro-6-nitrophenyl) acetic acid was prepared from dimethyl (2-fluoro-6-nitrophenyl) malonate. MS (ESI) m / z 200 ([M + H] +).

[0880] Step 4: In an analogous manner to EXAMPLE 99, step 4, 4-fluoro-1,3-dihydro-2H-indol146

EP 1 732 887 B1

2-one was prepared from (2-fluoro-6-nitrophenyl) acetic acid. MS (ESI) m / z 152 ([M + H] +).

[0881] Step 5: In an analogous manner to EXAMPLE 99, step 5, 4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one was prepared from 4-fluoro-1,3-dihydro- 2H-indol-2-one. MS (ESI) m / z 180 ([M + H] +). [0882] Step 6: In an analogous manner to EXAMPLE 99, step 6, 1 - [(2S, 3S) 2,3-dihydroxy-1-phenylpropyl] -4-fluoro-3,3-dimethyl-1,3 hydrochloride -dihydro-2H-indol-2-one was prepared from 4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4). MS (ESI) m / z 330 ([M + H] +).

[0883] Step 7: In an analogous manner to EXAMPLE 1, step 2, 3- (4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl) -2-hydroxy-3 -phenyl-propyl (2S, 3S) -toluene-4-sulfonic acid ester prepared from 1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -4-fluoro-3,3-dimethyl-1,3-dihydro -2H-indol-2-one. MS (ESI) m / z 484 ([M + H] +).

[0884] Step 8: In an analogous manner to EXAMPLE 195, step 7, 4-fluoro-1 [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3,3-dimethyl hydrochloride -1,3-dihydro-2H-indol-2-one was prepared from 3- (4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl) -2-hydroxy (2S, 3S) -toluene-4-sulfonic acid 3-phenylpropyl ester. HRMS: calculated for C20H23FN2O2 + H +,

343.18163; found (ESI, [M + H] +), 343.1807.

[0885] EXAMPLE 197: 1-cyclobutyl-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride.

[0886] In an analogous manner to EXAMPLE 192, step 1, N-cyclobutyl-2-nitroaniline was prepared from 1-fluoro-2-nitro-benzene and cyclobutylamine. MS (ES) m / z 193.

[0887] In an analogous manner to EXAMPLE 192, step 2, 1-cyclobutyl-1,3-dihydro-2H-benzimidazol-2-one was prepared from N-cyclobutyl-2-nitroaniline. MS (ES) m / z 189.

[0888] In an analogous manner to EXAMPLE 192, step 3, 1-cyclobutyl-3 - [(1S, 2S) -2,3-dihydroxy-1-phenyl-propyl] -1,3-dihydro-2H-benzimidazole-2- he was prepared from 1-cyclobutyl-1,3-dihydro-2H-benzimidazol-2-one and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4).

MS (ES) m / z 339.2.

[0889] In an analogous manner to EXAMPLE 192, step 4, 1-cyclobutyl-3 [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H- hydrochloride benzimidazol-2-one was prepared from 1-cyclobutyl-3 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one as a white solid. MS (ES) m / z 352.2. HRMS: calcd for C 21 H 25 N 3 O 2 + H +, 352.20195; found (ESI, [M + H] +), 352.207 [0890] EXAMPLE 198: 5-fluoro-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1-propyl- hydrochloride 1,3-dihydro-2H-benzimidazol-2-one.

147

EP 1 732 887 B1

<img file="PL1732887T3_D0173.tif" />

[0891] In an analogous manner to EXAMPLE 192, step 1. (4-fluoro-2-nitro-phenyl) -propylamine was prepared from 1,4-difluoro-2-nitro-benzene and propylamine.

[0892] In an analogous manner to EXAMPLE 192, steps 1 and 2, 5-fluoro-1-propyl-1,3-dihydrobenzymidazol-2-one was prepared from (4-fluoro-2-nitro-phenyl) -propylamine. MS (ES) m / z 195.2.

[0893] In an analogous manner to EXAMPLE 192, step 3, 5-fluoro-3 - [(1S, 2S) -2,3-dihydroxy-1-phenyl-propyl] -1-propyl-1,3-dihydro-2H- benzimidazol-2-one was prepared from 5-fluoro-1-propyl-1,3-dihydro-benzimidazol-2-one and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4). [0894] In an analogous manner to EXAMPLE 192, step 4, 5-fluoro-3 - [(1S, 2R) 2-hydroxy-3- (methylamino) -1-phenylpropyl] -1-propyl-1,3- hydrochloride dihydro-2H-benzimidazol-2-one was prepared from 5-fluoro-3 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -1-propyl-1,3-dihydro-2H-benzimidazol-2-one , as a white solid. MS (ES) m / z 358.2; HRMS: calcd for C 20 H 24 FN 3 O 2 + H +, 358.19253; found (ESI, [M + H] +), 358.1895 [0895] EXAMPLE 199: 1-ethyl-3- [1- (3-fluoro-phenyl) -2-hydroxy-3-methylaminopropyl] -1,3-dihydro- hydrochloride benzimidazol-2-one.

<img file="PL1732887T3_D0174.tif" />

[0896] Step: To a solution of ethylamine in methanol (2.0M solution, 150 mL, 300 mmol) was added 1-fluoro-2-nitrobenzene (8 mL, 75.7 mmol). The reaction mixture was placed in a closed vessel and heated to 55 ° C for 15 hours. The solvent was removed in vacuo and the residue collected in ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate (80 mL), and dried over anhydrous sodium sulfate (50 g). Removal of the solvent gave ethyl- (2-nitro-phenyl) -amine (12.5 g, 75 mmol) as a brown oil. MS (ES) m / z 167.1.

[0897] Step 2: To a solution of ethyl- (2-nitro-phenyl) -amine (12.5 g, 75 mmol) in anhydrous tetrahydrofuran (150 mL) was added sodium borohydride (5.8 g, 153 mmol), and 5% palladium on carbon (150 mg). Then methanol (25 ml) was added dropwise at room temperature under nitrogen. After the addition, the reaction mixture was stirred at room temperature for about 30 minutes until the reaction was complete. The reaction mixture was then filtered through a Celite pad. The filtrate was diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride (80 mL), dried over sodium sulfite, and concentrated in vacuo to give a crude

N-ethyl-benzene-1,2-diamine (8.4 g, 62 mmol), which was used in the next step without further purification.

148

EP 1 732 887 B1.

[0898] Step 3: To a solution of crude N-ethyl-benzene-1,2-diamine (8.4 g, 62 mmol) in anhydrous tetrahydrofuran (200 mL) was added 1,1'-carbonyldiimidazole (10g, 62 mmol). The mixture was then stirred at room temperature under nitrogen for 12 hours and ethyl acetate (250 ml) was added followed by cold 3N aqueous hydrochloric acid (200 ml). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give 1-ethyl-1,3-dihydrobenzymidazol-2-one as a white solid (8.5 g, 69% for three steps). MS (ES) m / z 163.2.

[0899] Step 4: In an analogous manner to EXAMPLE 192, step 3, 1-ethyl-3 - [(1S, 2S) -2,3-dihydroxy-1- (3-fluorophenyl) propyl] -1,3-dihydro -2H-benzimidazol-2-one prepared from 1-ethyl-1,3-dihydro-benzimidazol-2-one and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3).

[0900] Step 5: In an analogous manner to EXAMPLE 192, step 4, 1-ethyl-3 [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] hydrochloride - 1,3-dihydro-2H-benzimidazol-2-one was prepared from 1-ethyl-3 - [(1S, 2S) -2,3-dihydroxy-1- (3-fluorophenyl) propyl] -1,3-dihydro -2H-Benzymidazol-2-one, as a white solid. MS (ES) m / z 344.2 [0901] EXAMPLE 200: 1-ethyl-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0175.tif" />

[0902] In an analogous manner to EXAMPLE 192, step 3, 1-ethyl-3 - [(1S, 2S) -2,3-dihydroxy-1-phenyl-propyl] -1,3-dihydro-2H-benzimidazol-2- he was prepared from 1-ethyl-1,3-dihydro-benzimidazol-2one (EXAMPLE 199, step 2) and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4). [0903] In an analogous manner to EXAMPLE 192, steps 4 and 5, 1-ethyl-3 [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro- hydrochloride 2H-benzimidazol-2-one was prepared from 1-ethyl-3 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one as a white body Constant. MS (ES) m / z 326.2; HRMS: calcd for C19H23N3O2 + H +, 326.18630; found (ESI, [M + H] +), 326.1845.

[0904] EXAMPLE 201: 4-fluoro-3- (2-hydroxy-3-methylamino-1-phenyl-propyl) -1- hydrochloride

<img file="PL1732887T3_D0176.tif" />

[0905] In an analogous manner to EXAMPLE 192, step 1- (3-fluoro-2-nitro-phenyl) -isopropylamine was prepared from 1,3-difluoro-2-nitro-benzene and isopropylamine.

[0906] In an analogous manner to EXAMPLE 192, step 2/4-fluoro-1-isopropyl-1,3-dihydro149

Benzimidazol-2-one was prepared from (3-fluoro-2-nitro-phenyl) -isopropylamine. MS (ES) m / z 195.2.

[0907] In an analogous manner to EXAMPLE 192, step 3, 4-fluoro-3 - [(1S, 2S) -2,3-dihydroxy-1-phenyl-propyl] -1-isopropyl-1,3-dihydro-2H- benzimidazol-2-one was prepared from 4-fluoro-1-isopropyl-1,3-dihydro-benzimidazol-2-one and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4).

[0908] In an analogous manner to EXAMPLE 192, step 4, 4-fluoro-3 - [(1S, 2R) 2-hydroxy-3- (methylamino) -1-phenylpropyl] -1-isopropyl-1,3- hydrochloride dihydro-2H-benzimidazol-2-one was prepared from 4-fluoro-3 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one , as a white solid. MS (ES) m / z 358.4.

[0909] EXAMPLE 202: 1-cyclopentyl-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1- hydrochloride

<img file="PL1732887T3_D0177.tif" />

[0910] In an analogous manner to EXAMPLE 192, step 1, N-cyclopentyl-2-nitroaniline was prepared from 1-fluoro-2-nitro-benzene and cyclopentylamine. MS (ESI) m / z 207.

[0911] In an analogous manner to EXAMPLE 192, step 2, 1-cyclopentyl-1,3-dihydrobenzymidazol-2-one was prepared from N-cyclopentyl-2-nitroaniline. MS (ESI) m / z 203.

[0912] In an analogous manner to EXAMPLE 192, step 3, 1-cyclopentyl-3 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one was prepared from 1-cyclopentyl-1,3-dihydro-benzimidazol-2-one and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a white solid. MS (ES) m / z 352.9.

[0913] In an analogous manner to EXAMPLE 192, step 4, 1-cyclopentyl-3 [[1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H- hydrochloride benzimidazol-2-one was prepared from 1-cyclopentyl-3 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one as a white solid. MS (ES) m / z MS (ESI) m / z 366.

[0914] EXAMPLE 203: 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3-isopropyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride.

<img file="PL1732887T3_D0178.tif" />

[0915] In an analogous manner to EXAMPLE 192, step 1, N-isopropyl-2-nitroaniline was prepared from 1-fluoro-2-nitro-benzene and isopropylamine. MS (ES) m / z 181.2.

150

[0916] In an analogous manner to EXAMPLE 192, step 2, 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one was prepared from N-isopropyl-2-nitroaniline. MS (ES) m / z 176.9.

[0917] In an analogous manner to EXAMPLE 192, step 3, 1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -3-isopropyl-1,3-dihydro-2H-benzimidazol-2-one was prepared from 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a white solid.

[0918] In an analogous manner to EXAMPLE 192, step 4, 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3-isopropyl-1,3-dihydro-2H-benzimidazole hydrochloride -2-one was prepared from 1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -3-isopropyl-1,3-dihydro-2H-benzimidazol-2-one as a white solid. MS (ES) m / z MS (ES) m / z 340.3; HRMS: calcd for C20H25N3O2 + H +, 340.20195; found (ESI, [M + H] +), 340.2012.

[0919] EXAMPLE 204: 3 - [(1S, 2R) -3- (ethylamino) -2-hydroxy-1-phenylpropyl] -5-fluoro-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride .

<img file="PL1732887T3_D0179.tif" />

[0920] In an analogous manner to EXAMPLE 192, step 1,4-fluoro-N-isopropyl-2-nitroaniline was prepared from 1,4-difluoro-2-nitro-benzene and isopropylamine. MS (ES) m / z 199.1.

[0921] In an analogous manner to EXAMPLE 192, step 2, 5-fluoro-1-isopropyl-1,3-dihydro2H-benzymidazol-2-one was prepared from 4-fluoro-N-isopropyl-2-nitroaniline. MS (ES) m / z 195.1.

[0922] In an analogous manner to EXAMPLE 192, step 3, 5-fluoro-1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -3-isopropyl-1,3-dihydro-2H-benzimidazole- 2-one was prepared from 5-fluoro-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as white solid.

[0923] In an analogous manner to EXAMPLE 192, step 4, 3 - [(1S, 2R) -3 (ethylamino) -2-hydroxy-1-phenylpropyl] -5-fluoro-1-isopropyl-1,3- hydrochloride dihydro-2H-benzimidazol-2-one was prepared from 5-fluoro-1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -3-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and para-toluenesulfonic acid and then ethylamine as a white solid. MS (ESI) m / z 372.21; HRMS: calcd for C 21 H 26 FN 3 O 2 + H +, 372.20818; found (ESI, [M + H] +), 372.2099.

[0924] EXAMPLE 205: 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3-methyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride.

151

EP 1 732 887 B1

<img file="PL1732887T3_D0180.tif" />

[0925] In an analogous manner to EXAMPLE 192, step 3, 1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -3-methyl-1,3-dihydro-2H-benzimidazol-2-one was prepared from 1-methyl-1,3-dihydrobenzymidazol-2-one and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as a white solid.

[0926] In an analogous manner to EXAMPLE 192, step 4, 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -3-methyl-1,3-dihydro-2H-benzimidazole hydrochloride -2-one was prepared from 1 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -3-methyl-1,3-dihydro-2H-benzimidazol-2-one as a white solid. MS (ES) m / z 312.3; HRMS: calcd for C18H21N3O2 + H +, 312.17065; found (ESI, [M + H] +), 312.17.

[0927] EXAMPLE 206: 1-ethyl-5-fluoro-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride .

<img file="PL1732887T3_D0181.tif" />

[0928] In an analogous manner to EXAMPLE 199, step 1, ethyl- (4-fluoro-2-nitrophenyl) -amine was prepared from 1,4-difluoro-2-nitroaniline and ethylamine.

[0929] In an analogous manner to EXAMPLE 199, step 2, N-ethyl-4-fluorobenzene-1,2-diamine was prepared from ethyl- (4-fluoro-2-nitro-phenyl) -amine.

[0930] In an analogous manner to EXAMPLE 199, step 3, 1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one was prepared from N-ethyl-4-fluoro-benzene-1,2-diamine . MS (ES) m / z 181.2.

[0931] In an analogous manner to EXAMPLE 192, step 3, 3 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazole- 2-one was prepared from 1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as white solid. MS (ES) m / z 331.1.

[0932] In an analogous manner to EXAMPLE 192, step 4, 1-ethyl-5-fluoro-3 [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3- hydrochloride dihydro-2H-benzimidazol-2-one was prepared from 3 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one , as a white solid. MS (ES) m / z 344.2; HRMS: calcd for C19H22FN3O2 + H +, 344.17688; found (ESI, [M + H]⁺), 344.175.

[0933] EXAMPLE 207: 1-ethyl-4-fluoro-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride .

152

EP 1 732 887 B1

<img file="PL1732887T3_D0182.tif" />

made from 1,3-difluoro-2-nitroaniline and ethylamine.

[0935] In an analogous manner to EXAMPLE 199, step 2, N-ethyl-3-fluorobenzene-1,2-diamine was prepared from ethyl- (3-fluoro-2-nitro-phenyl) -amine.

[0936] In an analogous manner to EXAMPLE 199, step 3,1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazol-2-one was prepared from N-ethyl-3-fluoro-benzene-1,2-diamine . MS (ES) m / z 181.2.

[0937] In an analogous manner to EXAMPLE 192, step 3, 3 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazole- 2-one was prepared from 1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazol-2-one and [(2R, 3R) -3-phenyloxiran-2-yl] methanol (EXAMPLE 117, step 4) as white solid. MS (ES) m / z 331.1.

[0938] In an analogous manner to EXAMPLE 192, step 4, 1-ethyl-4-fluoro-3 [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1,3-dihydro hydrochloride -2H-benzimidazol-2-one was prepared from 3 - [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazol-2-one, as a white solid. MS (ES) m / z 344.2; HRMS: calculated for C19H22FN3O2 +

H +, 344.17688; found (ESI, [M + H]⁺), 344.1768.

[0939] EXAMPLE 208: 4-fluoro-3 - [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1-isopropyl-1,3-dihydro- hydrochloride 2H-benzimidazol-2-one.

<img file="PL1732887T3_D0183.tif" />

[0940] In an analogous manner to EXAMPLE 192, step 3, 4-fluoro-3 - [(1S, 2S) -1- (3-fluoro-phenyl) -2,3-dihydroxy-propyl] -1-isopropyl-1, 3-dihydro-benzimidazol-2-one was prepared from 4-fluoro-1-isopropyl-1,3-dihydro-benzimidazol-2-one (EXAMPLE 201, step 2) and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as an oil.

[0941] In an analogous manner to EXAMPLE 192, step 4, 4-fluoro-3 - [(1S, 2R) 1- (3-fluoro-phenyl) -2-hydroxy-3- (methylamino) -propyl] -1- hydrochloride isopropyl-1,3-dihydro-2H-benzimidazol-2one made from 4-fluoro-3 - [(1S, 2S) -1- (3-fluorophenyl) -2,3-dihydroxypropyl] -1-isopropyl-1 , 3dihydro-benzzymidazol-2-one, as a white solid. MS (ES) m / z 376.2 [0942] EXAMPLE 209: 1-ethyl-4-fluoro-3 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1- (3-fluoro-phenyl) -propyl] hydrochloride -1,3-dihydro-2H-benzimidazol-2-one.

153

EP 1 732 887 B1

<img file="PL1732887T3_D0184.tif" />

[0943] In an analogous manner to EXAMPLE 192, step 3, 3 - [(1S, 2S) -2,3-dihydroxy-1- (3-fluoro-phenyl) -propyl] -1-ethyl-4-fluoro-1,3- dihydro-2H-benzymidazol-2-one was prepared from 1-ethyl-4fluoro-1,3-dihydro-2H-benzimidazol-2-one (EXAMPLE 207, step 2) and [(2R, 3R) -3- (3- fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3) as a clear oil. MS (ES) m / z 349.1.

[0944] In an analogous manner to EXAMPLE 192, step 4, 1-ethyl-4-fluoro-3 [(1S, 2R) -2-hydroxy-3- (methylamino) -1- (3-fluorophenyl) propyl hydrochloride ] -1,3-dihydro-2H-benzimidazol-2-one was prepared from 3 - [(1S, 2S) -2,3-dihydroxy-1- (3-fluorophenyl) propyl] -1-ethyl-4-fluoro -1,3-dihydro-2H-benzimidazol-2-one, as a white solid. MS (ES) m / z 362.1.

[0945] EXAMPLE 210: 1 - [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -3,3-dimethyl-1,3-dihydro-2H-indole hydrochloride -2-one.

<img file="PL1732887T3_D0185.tif" />

[0946] Step 1: In an analogous manner to EXAMPLE 101, step 1, (2S, 3S) -1- [1- (3-fluoro-phenyl) -2,3-dihydroxy-propyl] -3,3-dimethyl-1 , 3-dihydro-indol-2-one made from 3,3-dimethyl-1,3-dihydro-indol-2-one¹⁰ and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 47, step 3). MS (ESI) m / z 330 ([M + H] +).

[0947] Step 2: In an analogous manner to EXAMPLE 1, step 2, 3- (3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl) -3- (3-fluoro-phenyl) -2-hydroxy-propyl (2S, 3S) -toluene-4-sulfonic acid ester prepared from (2S, 3S) -1- [1- (3-fluoro-phenyl) -2,3-dihydroxy-propyl] -3,3 -dimethyl-1,3dihydro-indol-2-one. MS (ESI) m / z 484 ([M + H] +).

[0948] Step 3: In an analogous manner to EXAMPLE 5, 1 - [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -3,3-dimethyl-1 hydrochloride, 3-dihydro-2H-indol-2-one was prepared from 3- (3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl) -3- (3-fluoro-phenyl) -2 -hydroxypropyl (2S, 3S) -toluene-4-sulfonic acid ester. MS (ESI) m / z 343 ([M + H] +).

[0949] EXAMPLE 211: (1S, 2R) -1- [3- (2,3-difluorophenyl) -1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2- hydrochloride ol.

154

EP 1 732 887 B1

<img file="PL1732887T3_D0186.tif" />

[0950] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3-fluorophenyl) - [3- (2,3-difluorophenyl) -1H-indol-1-yl] propane-1,2 -diol prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1H-indol-1-yl) propane-1,2-diol (EXAMPLE 114, step 1) and 2.3 acid -difluorobenzenoborowego.

[0951] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- (2,3-difluorophenyl) -indol-1-yl] -2-hydroxy-propyl acid ester (2S, 3S) -toluene-4-sulfonic acid prepared from (2S, 3S) -3- (3-fluorophenyl) -3- [3- (2,3-difluorophenyl) -1H-indol-1-yl] propane-1,2-diol . [0952] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- [3- (2,3-difluorophenyl) -1H-indol-1yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol was prepared from 3- (3-fluoro-phenyl) -3- (2,3-difluorophenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) -toluene-4-sulfonic acid. MS (ES) m / z 411.1; HRMS: calcd for C24H21F3N2O + H +, 411.16787; found (ESI, [M + H] +), 411.1675.

[0953] EXAMPLE 212: (1S, 2R) -1- (3-fluoro-phenyl) -3- (methylamino) -1 - [(2R) -2-phenyl-2,3-dihydro-4H-1,4-benzoxazine hydrochloride 4-yl] propan-2-ol.

<img file="PL1732887T3_D0187.tif" />

[0954] Step 1: Diastereomeric mixture (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl ) propan-2-ol (EXAMPLE 168) was dissolved in methanol. The resulting solution was injected into a supercritical mobile phase chromatography apparatus. The base line of separated diastereomers was drawn, conditions as described below were used.

<td>SFC device:</td><td>Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE 19702.</td>

<td>Column:</td><td>ethylpyridine; 250mm L x 20mm ID (Princeton Chromatography Inc.)</td>

<td>Column temperature:</td><td>35 ° C</td>

<td>SFC modifier:</td><td>15% MeOH with 85% CO2</td>

<td>Flow rate:</td><td>50 ml / min</td>

<td>Output pressure:</td><td>100 bars</td>

<td>Detector:</td><td>UV at 220 nm</td>

[0955] Step 2: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1 - [(2R) -2-phenyl-2,3-dihydro-4H-1,4155

Benzoxazin-4-yl] propan-2-ol, isolated as peak 1, was subjected to the formation of the hydrochloride salt in an analogous manner as in EXAMPLE 144, step 2, to obtain (1S, 2R) -1- ( 3-fluorophenyl) -3- (methylamino) -1 - [(2R) -2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl] propan-2-ol as a white powder. MS (ES) m / z 393.2 ([M + H] +); HRMS: calcd for C24H25FN2O2 + H +, 393.1973; found (ESI, [M + H] +), 393.1992.

[0956] EXAMPLE 213: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1 - [(2S) -2-phenyl- hydrochloride

<img file="PL1732887T3_D0188.tif" />

[0957] In an analogous manner to EXAMPLE 212, (1S, 2R) -1- (3-fluorophenyl) -3 (methylamino) -1 - [(2S) -2-phenyl-2,3-dihydro-4H- hydrochloride 1,4-benzoxazin-4-yl] propan-2-ol was prepared as a white powder from (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1 - [(2S) -2-phenyl -2,3-dihydro-4H-1,4-benzoxazin-4-yl] propan-2-ol, which was isolated as peak 2 from diastereomeric separation (EXAMPLE 212, step). MS (ES) m / z 393.2 ([M + H] +); HRMS: calculated for C24H25FN2O2 + H +,

393.1973; found (ESI, [M + H] +), 393.1982.

[0958] EXAMPLE 214: (1S, 2R) -1- [3- (2-chlorophenyl) -1H-indol-1-yl] -1- (3-

<img file="PL1732887T3_D0189.tif" />

[0959] In an analogous manner to EXAMPLE 114, step 2, (2S, 3S) -3- (3-fluorophenyl) -3- {3- [2-chlorophenyl] -1H-indol-1-yl} propane-1,2 -diol prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1Hindol-1-yl) propane-1,2-diol (EXAMPLE 114, step 1) and 2-chlorobenzenic acid .

[0960] In an analogous manner to EXAMPLE 1, step 2, 3- (3-fluoro-phenyl) -3- [3- (2-chlorophenyl) -indol-1-yl] -2-hydroxy-propyl acid ester (2S, 3S) -toluene-4-sulfone was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- {3- [2-chlorophenyl] -1H-indol-1-yl} propan-1,2-diol.

[0961] In an analogous manner to EXAMPLE 5, (1S, 2R) -1- [3- (2-chlorophenyl) 1H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) hydrochloride propan-2-ol was prepared from 3- (3-fluoro-phenyl) -3- [3- (2-chlorophenyl) -indol-1-yl] -2-hydroxy-propyl ester of (2S, 3S) -toluene-4 -sulfonic acid and methylamine (2N solution in methanol). MS (ESI) m / z 409.1; HRMS: calculated for C24H22CIFN2O + H +,

409.14774; found (ESI, [M + H] +), 409.146.

[0962] Cell lines, culture reagents, and tests

MDCK-Net6 cells, stably transfected with human hNET (Pacholczyk, T., RD ​​Blakely, and SG

Amara, Nature, 1991, 350 (6316): pages 350-4) grown in a growth medium containing

156

High glucose DMEM (Gibco, Cat. No. 11995), 10% FBS (dialyzed, heat inactivated, US Bio-Technologies, Lot FBD1129HI) and 500 □ g / ml G418 (Gibco, Cat. No. 10131). Cells were placed on 300,000 / T75 flasks and cells were split twice weekly. The JAR (human placental choriocarcinoma) cell line was obtained from ATCC (Cat. No. HTB-144). Cells were cultured in a growth medium containing RPMI 1640 (Gibco, Cat. No. 72400), 10% FBS (Irvine, Cat. No. 3000), 1% sodium pyruvate (Gibco, Cat. No. 1136) and 0.25% glucose. Cells were plated on 250,000 cells / T75 flask and separated twice a week. Throughout all tests, cells were plated in Wallac sterile 96-well plates (PerkinElmer, Cat. No. 3983498).

[0963] Assessment of norepinephrine (NE) uptake

On day 1, the cells were plated at 3,000 cells / well in a growth medium and kept in a cell incubator (37 ° C, 5% CO2). On Day 2, the growth environment was replaced by 200 μ! assay buffer (25 mM HEPES; 120 mM NaCl; 5 mM KCl; 2.5 mM CaCl2; 1.2 mM MgSO4; 2 mg / ml glucose (pH 7.4, 37 ° C)) containing 0.2 mg / ml ascorbic acid and 10 μM pargillin. Plates containing cells with 200 μl assay buffer were stabilized for 10 minutes at 37 ° C before adding the compounds. A stock solution of desipramine in DMSO (10 mM) was prepared and administered in triplicate to wells containing cells at a final test concentration of 1 μM. Data from these wells were used to define non-specific NE absorption (minimal NE absorption). Test compounds were prepared in DMSO (10 mM) and diluted in test buffer according to the range tested (1 to 10,000 nM). Twenty-five microliters of assay buffer (maximum NE uptake) or test compound was added directly to triplicate wells containing cells in 200 Pl assay buffer. Cells in the assay buffer with test compounds were incubated for 20 minutes at 37 ° C. To initiate the assimilation of NE,₃ [H] NE diluted in assay buffer (120 nM final test concentration) was delivered in 25 Pl subunits to each well and plates were incubated for 5 minutes (37 ° C). The reaction was terminated by decanting the supernatant from the plate. Cell containing plates were washed twice with 200 μl assay buffer (37 ° C) to remove free radioligand. The plates were then inverted, allowed to dry for 2 minutes, then inverted again and air dried for an additional 10 minutes. Cells were lysed in 25 Pl 0.25N NaOH (4 ° C), placed on a shaker table and vigorously shaken for 5 minutes. After lysis of the cells, 75 μl of scintillation cocktail was added to each well and the plates were sealed with tape film. Plates were returned to the shaker table and vigorously shaken for a minimum of 10 minutes to ensure proper separation of organic and aqueous solutions. Plates were counted in a Wallac Microbeta counting device (PerkinElmer) to collect raw cpm data.

[0964] serotonin uptake test (5-HT)

Methods used for functional 5-HT reuptake using a cell line

The JAR was modified by using an earlier literature report (Prasad, et al., Placenta,

1996. 17 (4): 201-7). On day 1, cells were plated at 15,000 cells / well in 96 well plates containing growth medium (RPMI 1640 with 10% FBS) and

157

EP 1 732 887 B1 was kept in a cell incubator (37 ° C, 5% CO2). On day 2, cells were stimulated with staurosporin (40 nM) to increase the secretion of the 5-HT transporter [17]. On day 3, cells were removed from the cell incubator two hours prior to testing and kept at room temperature to stabilize the growth medium to ambient oxygen concentration.

The growth medium was then replaced with 200 μΐ test buffer (25 mM HEPES; 120 mM NaCl; 5 mM KCl; 2.5 mM CaCl2; 1.2 mM MgSO4; 2 mg / ml glucose (pH 7.4, 37 ° C)) containing 0.2 mg / ml ascorbic acid and 10 μΜ pargillin. A stock solution of paroxetine (AHR4389-1) in DMSO (10 mM) was prepared and delivered in triplicate to wells containing cells for a final test concentration of 1 μΜ. Data from these wells were used to define non-specific 5-HT uptake (minimal 5-HT uptake). Test compounds were prepared in DMSO (10 mM) and diluted in assay buffer according to the range tested (1 to 1,000 nM). Twenty-five microliters of assay buffer (maximum 5-HT uptake) or test compound was added directly in triplicate to wells containing cells in 200 μΐ assay buffer. Cells were incubated with compound for 10 minutes (37 ° C). To initiate the reaction, sulfate₃ [H] hydroxytryptaminocreatinine was diluted in assay buffer delivered in 25 μ 25 subunits to each well to a final test concentration of 15 nM. Cells were incubated with the reaction mixture for 5 minutes at 37 ° C. The 5-HT uptake reaction was terminated by decanting the assay buffer. Cells were washed twice with 200 μΐ assay buffer (37 ° C) to remove free radioligand. The plates were inverted and allowed to dry for 2 minutes, then inverted again and air dried for an additional 10 minutes. Cell lysis was then carried out in 25 μΐ 0.25N NaOH (4 ° C) and then shakers were placed on the table and shaken vigorously for 5 minutes. After cell lysis, 75 μΐ scintillation cocktail was added to the wells. Plates were sealed with foil tape and placed back on the shaker table for a minimum of 10 minutes. Plates were counted in a Wallac Microbeta counting device (PerkinElmer) to collect raw cpm data.

[0965] Evaluation of results

For each experiment, the cpm value stream collected from the Wallac Microbeta counter was entered into a Microsoft Excel statistical application. Calculations of EC50 values ​​were made by transformation with a bilateral transforming logistic dose response program written by the Wyeth Biometrics Department. The statistical program uses average cpm values ​​from wells representing maximum binding or absorption (test buffer) and average cpm values ​​from wells representing minimal binding or absorption ((1 μΜ desipramine (hNET) or 1 μΜ paroxetine (hSERT)). Evaluation of EC50 values ​​completed logarithmic scale and line fit between maximum and minimum binding or assimilation values. A representation of all graphic data was created by normalizing the point for each data to a percentage average calculated for the maximum and minimum binding or assimilation values. The EC50 values ​​reported for many experiments were calculated by pooling the raw data from each experiment and analyzing the combined data as one experiment. The results are shown in Table 1.

158

EP 1 732 887 B1

Table 1

<td>Example</td><td>% braking @ 1 μΜ (hNET)</td>

<td> 1</td><td> 4.6</td>

<td> 2</td><td>66.5 (@ 10 μΜ)</td>

<td> 3</td><td> 17.6</td>

<td> 4</td><td> 24.5</td>

<td> 5</td><td> 58.1</td>

<td> 6</td><td> 13.1</td>

<td> 7</td><td> 25.6</td>

<td> 8</td><td> 53.4</td>

<td> 9</td><td>79.2 (@ 10 μΜ)</td>

<td> 10</td><td>70.5 (@ 10 μΜ)</td>

<td> 11</td><td> 94.5</td>

<td> 12</td><td> 70.6</td>

<td> 13</td><td> 34.3</td>

<td> 14</td><td> 24.4</td>

<td> 15</td><td> 8.5</td>

<td> 16</td><td> 96.8</td>

<td> 17</td><td> 71.0</td>

<td> 18</td><td> 11.3</td>

<td> 19</td><td> 31.6</td>

<td> 20</td><td> 85.0</td>

<td> 21</td><td> 97.5</td>

<td> 22</td><td> 83.8</td>

<td> 23</td><td> 89.7</td>

<td> 24</td><td> 57.2</td>

<td> 25</td><td> 37.5</td>

<td> 26</td><td> 54.0</td>

<td> 27</td><td> 75.4</td>

<td> 28</td><td> 30.1</td>

159

EP 1 732 887 B1

<td>Example</td><td>% braking @ 1 μΜ (hNET)</td>

<td> 29</td><td> 89.5</td>

<td> 30</td><td> 79.7</td>

<td> 31</td><td> 98.9</td>

<td> 33</td><td> 99.4</td>

<td> 34</td><td> 78.4</td>

<td> 35</td><td> 94.3</td>

<td> 36</td><td> 82.3</td>

<td> 37</td><td> 21.4</td>

<td> 38</td><td> 71.9</td>

<td> 39</td><td> 57.4</td>

<td> 40</td><td> 57.6</td>

<td> 41</td><td> 32.4</td>

<td> 42</td><td> 95.7</td>

<td> 43</td><td> 99</td>

<td> 44</td><td> 98.2</td>

<td> 47</td><td> 99.9</td>

<td> 48</td><td> 96.6</td>

<td> 49</td><td> 101.2</td>

<td> 50</td><td> 91.8</td>

<td> 51</td><td> 87.0</td>

<td> 52</td><td> 94.3</td>

<td> 53</td><td> 57.4</td>

<td> 54</td><td> 68.6</td>

<td> 55</td><td> 61.1</td>

<td> 56</td><td> 12.3</td>

<td> 57</td><td> 17.5</td>

<td> 58</td><td> 26.5</td>

<td> 59</td><td> 93.2</td>

<td> 60</td><td> 100</td>

160

EP 1 732 887 B1

<td>Example</td><td>% braking @ 1 μΜ (hNET)</td>

<td> 61</td><td> 99.8</td>

<td> 62</td><td> 99.7</td>

<td> 63</td><td> 91.9</td>

<td> 64</td><td> 99.9</td>

<td> 65</td><td> 100</td>

<td> 66</td><td> 86.6</td>

<td> 67</td><td> 90.9</td>

<td> 68</td><td> 99.6</td>

<td> 69</td><td> 87.5</td>

<td> 70</td><td> 77.7</td>

<td> 71</td><td> 44.9</td>

<td> 72</td><td> 24</td>

<td> 73</td><td> 21.8</td>

<td> 74</td><td> 67</td>

<td> 75</td><td> 88.4</td>

<td> 76</td><td> 75.2</td>

<td> 77</td><td> 77.3</td>

<td> 78</td><td> 70.9</td>

<td> 79</td><td> 66</td>

<td> 80</td><td> 83.5</td>

<td> 81</td><td> 58.0</td>

<td> 82</td><td> 53.9</td>

<td> 83</td><td> 99.5</td>

<td> 84</td><td> 40.9</td>

<td> 85</td><td> 97.4</td>

<td> 86</td><td> 52.7</td>

<td> 87</td><td> 99.7</td>

<td> 90</td><td> 73.1</td>

<td> 91</td><td> 90.8</td>

161

EP 1 732 887 B1

<td>Example</td><td>% braking @ 1 μΜ (hNET)</td>

<td> 92</td><td> 85.8</td>

<td> 93</td><td> 96.3</td>

<td> 94</td><td> 94.9</td>

<td> 95</td><td> 97.6</td>

<td> 96</td><td> 98.2</td>

<td> 97</td><td> 99.6</td>

<td> 98</td><td> 99.1</td>

<td> 99</td><td> 98.1</td>

<td> 100</td><td> 94.2</td>

<td> 101</td><td> 98.6</td>

<td> 102</td><td> 95.3</td>

<td> 103</td><td> 86.1</td>

<td> 104</td><td> 99.4</td>

<td> 105</td><td> 92.6</td>

<td> 106</td><td> 85.8</td>

<td> 107</td><td> 96.6</td>

<td> 108</td><td> 98.7</td>

<td> 109</td><td> 94.7</td>

<td> 110</td><td> 86.4</td>

<td> 111</td><td> 42.7</td>

<td> 112</td><td> 100.3</td>

<td> 113</td><td> 99.7</td>

<td> 114</td><td> 100</td>

<td> 115</td><td> 23.9</td>

<td> 116</td><td> 97.3</td>

<td> 117</td><td> 95.3</td>

<td> 118</td><td> 67.9</td>

<td> 119</td><td> 96.3</td>

<td> 120</td><td> 68.6</td>

162

EP 1 732 887 B1

<td>Example</td><td>% braking @ 1 μΜ (hNET)</td>

<td> 121</td><td> 21.2</td>

<td> 122</td><td> 97.4</td>

<td> 123</td><td> 65</td>

<td> 124</td><td> 91.5</td>

<td> 125</td><td> 94.3</td>

<td> 126</td><td> 92.9</td>

<td> 127</td><td> 95.7</td>

<td> 128</td><td> 45.6</td>

<td> 129</td><td> 71.8</td>

<td> 130</td><td> 76</td>

<td> 131</td><td> 63.1</td>

<td> 132</td><td> 93</td>

<td> 133</td><td> 96.4</td>

<td> 134</td><td> 68.5</td>

<td> 135</td><td> 99.5</td>

<td> 136</td><td> 97</td>

<td> 137</td><td> 99.1</td>

<td> 138</td><td> 97.9</td>

<td> 139</td><td> 94.9</td>

<td> 140</td><td> 96.7</td>

<td> 143</td><td> 96.8</td>

<td> 146</td><td> 97.1</td>

<td> 147</td><td> 91.7</td>

<td> 148</td><td> 97.8</td>

<td> 149</td><td> 100.4</td>

<td> 150</td><td> 98.3</td>

<td> 151</td><td> 94.3</td>

<td> 152</td><td> 96.2</td>

<td> 153</td><td> 97.4</td>

163

EP 1 732 887 B1

<td>Example</td><td>% braking @ 1 μΜ (hNET)</td>

<td> 154</td><td> 96.1</td>

<td> 155</td><td> 98.9</td>

<td> 157</td><td> 99.6</td>

<td> 158</td><td> 99.6</td>

<td> 159</td><td> 93.8</td>

<td> 160</td><td> 99.3</td>

<td> 161</td><td> 99.4</td>

<td> 162</td><td> 99.2</td>

<td> 163</td><td> 99.7</td>

<td> 164</td><td> 98.6</td>

<td> 169</td><td> 72</td>

<td> 170</td><td> 96.4</td>

<td> 171</td><td> 98.3</td>

<td> 172</td><td> 88</td>

<td> 173</td><td> 67.5</td>

<td> 174</td><td> 99.1</td>

<td> 175</td><td> 99.6</td>

<td> 176</td><td> 100</td>

<td> 177</td><td> 29.9</td>

<td> 178</td><td> 69.2</td>

<td> 179</td><td> 99.8</td>

<td> 180</td><td> 70.4</td>

<td> 181</td><td> 96.9</td>

<td> 182</td><td> 97.1</td>

<td> 183</td><td> 100.5</td>

<td> 184</td><td> 99.7</td>

<td> 185</td><td> 80.8</td>

<td> 186</td><td> 96.6</td>

<td> 187</td><td> 52</td>

164

EP 1 732 887 B1

<td>Example</td><td>% braking @ 1 μΜ (hNET)</td>

<td> 188</td><td> 71.6</td>

<td> 189</td><td> 99.3</td>

<td> 190</td><td> 53.7</td>

<td> 191</td><td> 63.9</td>

<td> 192</td><td> 54.6</td>

<td> 193</td><td> 98.4</td>

<td> 194</td><td> 79</td>

<td> 195</td><td> 91</td>

<td> 196</td><td> 94.6</td>

<td> 197</td><td> 97</td>

<td> 198</td><td> 97.7</td>

<td> 199</td><td> 99.1</td>

<td> 200</td><td> 97.9</td>

<td> 201</td><td> 98.8</td>

<td> 202</td><td> 92.7</td>

<td> 203</td><td> 98.9</td>

<td> 204</td><td> 47.4</td>

<td> 205</td><td> 82.9</td>

<td> 206</td><td> 96.9</td>

<td> 207</td><td> 98.3</td>

<td> 208</td><td> 99.8</td>

<td> 209</td><td> 99.3</td>

<td> 210</td><td> 96.3</td>

<td> 211</td><td> 99.8</td>

<td> 214</td><td> 99.9</td>

[0966] When ranges are given for physical properties, such as for molecular weight, or for chemical properties, such as chemical formulas, it is intended that all combinations and sub-combinations of ranges for the specific embodiments given be included.

[0967] Those skilled in the art will recognize that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention.

165

EP 1 732 887 B1 away from the spirit of the invention.