MX2008004327A - 1- (1h- indol- 1-yl) -3- (methylamino) -1- phenylpropan-2-ol derivatives and related compounds as modulators of the monoamine reuptake for the treatment of vasomotor symptoms (vms) - Google Patents

Abstract

The present invention is directed to phenylaminopropanol derivatives of formulae (I), (II), and (III);or a pharmaceutically acceptable salt thereof, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions ameliorated by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disorders, and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, schizophrenia, and combinations thereof.

Description

DERIVATIVES OF FENILAMINOPROPANOL AND METHODS FOR ITS USE CROSS REFERENCE TO RELATED SOLITIONS This application claims the priority of US application No. 60/721, 676 filed on September 29, 2005, the complete disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION The present invention relates to phenylaminopropanol derivatives, compositions containing these derivatives, and methods for their use for the prevention and treatment of conditions enhanced by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders, and combinations thereof, particularly those conditions selected from the group consisting of severe depressive disorder, vasomotor symptoms, severe urinary incontinence and stress, fibromyalgia, pain , diabetic neuropathy, schizophrenia and combinations of these.

BACKGROUND OF THE INVENTION Vasomotor symptoms (VMS), referred to as hot flushes and night sweats, are the most common symptoms associated with menopause, occurring in 60% to 80% of all women after natural or surgically induced menopause. VMS are probably an adaptive response of the central nervous system (CNS) to decline sex steroids. To date, the most effective therapies for VMS are hormone-based treatments, which include estrogens and / or progestins. Hormonal treatments are very effective in relieving VMS, but they are not appropriate for all women. It is well recognized that VMS is caused by fluctuations in sexual steroid levels and can be interrupted and disabled in both males and females. A hot flash can last up to thirty minutes and vary in frequency between several times in the week to multiple occurrences per day. Patients experience a hot flash as a sudden sensation of heat that is rapidly distributed from the face to the chest and back to the face and then over the rest of the body. It is usually accompanied by eruptions of profuse sweat. It can sometimes occur several times during one hour, and frequently occurs during the night. hot flashes and suffocation that occur during the night can cause sleep deprivation, psychological and emotional symptoms observed, such as nervousness, fatigue, irritability, insomnia, depression, memory loss, headache, anxiety, nervousness or inability to concentrate is considered which are caused by lack of sleep followed by flushing and night sweats (Kramer et al, In Murphy et al, 3rd Int'l Symposium on Recent Advances in Urological Cancer Diagnosis and Treatment-Proceedmgs, Paris, France SCI 3-7 ( 1992)) The suffocation can be even more severe in women treated for breast cancer for vain reasons 1) many breast cancer survivors are given tamoxifen, the most prevalent side effect is suffocation, 2) many women treated for breast cancer suffer menopause premature due to chemotherapy; 3) women with a history of breast cancer have usually been denied estrogen therapy because of problems about potential recurrence of breast cancer (Loprinzi, et al, Lancet, 2000, 356 (9247 2059-2063) Men also experience hot flushes after the withdrawal of the steroid hormone (androgen). This is true in cases of age-related androgen decline (Katovich, et al., Proceedmgs of the Society for Experimental Biology &Medicine, 1990, 193 (2). ) 129-35) as well as in extreme cases of hormone deprivation associated with treatments for prostate cancer (Berendsen, et al., European Journal of Pharmacology, 2001, 419 (1) 47-54 As much as a third of these patients will experience persistent and frequent symptoms severe enough to cause significant discomfort and inconvenience The precise mechanism of these symptoms is unknown but is generally thought to represent disturbances in the normal homeostatic mechanisms that control thermoregulation and vasomotopic activity (Kronenberg, et al, "Thermoregulatory Physiology of Menopausal Hot Flashes A Review," Can J Physiol Pharmacol, 1987, 65 1312-1324) The fact that estrogen treatment (for example, estrogen replacement therapy) relieves symptoms, establishes the link between these symptoms and an estrogen deficiency. For example, the menopausal state of life is associated with a wide range of other acute symptoms as described above and these symptoms are usually an estrogen response It has been suggested that estrogens can stimulate the activity of the norepinephrine (NE) and / or serotonin (5-HT) systems (J Pharmacology &Experimental Therapeutics, 1986, 236 (3) 646-652). Estrogens have been hypothesized modulate the levels of NE and 5-HT that provide homeostasis in the thermoregulatory center of the hypothalamus The descendant routes of the hypothalamus via the brainstem / spinal cord and the adrenal glands of the skin are involved in maintaining the normal temperature of the skin The action of the Retoma inhibitors NE and 5-HT are known to collide with the CNS and the peripheral nervous system (SNP). The pathophysiology of VMS is mediated by both central and peripheral mechanisms and, therefore, the interaction between the CNS and SNP may have to do with the efficacy of the double performance of SRI / NRIs in the treatment of thermoregulatory dysfunction In fact, the physiological aspects and the involvement of the SNC / SNP in the VMS may be due to the two is very low provided to treat 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 SNC / SNP interaction in the pathophysiology of VMS and the data presented within this document were used to support the claims of the norepinefrma system that could be objectified to treat VMS Serotonin 2A (5-HT2A) receptors have been reported to play a role in the regulation of temperature (Berendsen, Matuptas, 2000, 36, 155). A low level of estrogen in the blood has been shown to correlate with a concentration high of the 5-HT2A receptor subtype in blood platelets (Biegon, Effects of steroid hormones on the serotonergic system In Whitaker-Azmitia, Peroutka editors The Neuropharmacology of Serotonm 1990, 427-34) and an up-regulation of 5-HT2A receptors (Fink et al, Nature, 1996, 383, 306) The 5-HT2 and 5-HT3 antagonists of mirtazapine are reported to be effective in reducing the risk of frequency and intensity of hot flushes (Waldinger, et al., Maturitas, 2000, 36, 165). The 5-HT2 receptor antagonist of mianserin is also shown to be effective in the treatment of hot flushes (Takagi, et al., Sanfujinka No Sekai (World Obstet Gynecof) 1986, 36, 853). The combination of norepinephrine reuptake inhibitor with a 5-HT2A receptor antagonist has also been reported to result in improved activity in animal models of thermoregulatory dysfunction (Deecher, et al., WO 2004/035036).

Although VMS is most commonly treated by hormone therapy (orally, transdermally, or via an implant), some patients can not tolerate estrogen treatment (Berendsen, Maturitas, 2000, 36 (3): 155-164, Fink et al. al., Nature, 1996, 383 (6598): 306). In addition, hormone replacement therapy is usually not recommended for women or men with or at risk for hormonally sensitive cancers (for example, breast or prostate cancer). Thus, non-hormonal therapies (for example fluoxetine, paroxetine [SRI] and clonidine) have been evaluated clinically. WO9944601 describes a method for decreasing the suffocation in a human female by administering fluoxetine. Other options have been studied for the treatment of hot flushes, including steroids, alpha adrenergic agonists, and beta blockers, with a degree of variability of success (Waldinger et al., Maturitas, 2000, 36 (3): 165-168).

It has been reported that a2-adrenergic receptors play a role in thermoregulatory dysfunctions (Freedman et al., Fertility &Sterility, 2000, 74 (1): 20-3). These receptors are located both pre- and post-syn- thetic and mediate an inhibitory role in the central and peripheral nervous system. There are four distinct subtypes of a2 adrenergic receptors, that is, they are a2A, a2B, a2C and a2D (Mackinnon ef al., TIPS, 1994, 15: 119, French, Pharmacol. Ther., 1995, 68: 175). It has been reported that a non-selective a2-adrenoceptor antagonist, yohimbine, induces a suffocation and an a2-adrenergic agonist, clonidine, relieves the yohimbine effect (Katovich, et al., Proceedings of the Society for Experimental Biology &Medicine, 1990 , 193 (2): 129-35, Freedman et al., Fertility &Sterility, 2000, 74 (1): 20-3). Clonidine has been used to treat hot fls. However, using such treatment is associated with a number of unwanted side effects caused by high doses necessary to abate suffocation described herein and known in the related arts.

Given the complex multifaceted nature of thermoregulation and the interaction between the CNS and SNP to maintain thermoregulatory homeostasis, multiple therapies and models can be developed to objectify vasomotor symptoms. The present invention focuses on novel compounds and compositions containing these compounds directed to these and other important uses.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to phenylaminopropanol derivatives, compositions containing these derivatives, and methods of use for the prevention and treatment of improved conditions by the monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal disorders and genitourinary, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders, and combinations of these, particularly those conditions selected from the group consisting of severe depressive disorder, vasomotor symptoms, urinary and stress urinary incontinence, fibromyalgia, pain, diabetic neuropathy , schizophrenia and combinations of these.

In one embodiment, the invention is directed to compounds of formula I: I or a pharmaceutically acceptable salt thereof; where: the dotted line between Y and Z represents an optional second link; the dotted line between the two groups R4 represents an optional heterocycle ring of 4 to 6 ring atoms that can be formed between the two R4 groups, together with the nitrogen through which they are adhered, X is - (C (R12) 2) 0-, -0 (C (R, 2) 2) 0-, - (C (R12) 2) oO-, -S (O) p (C (R, 2) ) 2) 0-, - (C (R12) 2) oS (O) p-, -N (R13) C (0) (C (R, 2) 2) 0-, - (C (R, 2) 2) oC (O) N (R13) -, -C (0) N (R, 3) (C (R12) 2) 0-, (C (R12) 2) 0N (R, 3) C (0) -, - (C (R, 2) 2) 0N (R, 3) S (O) 2-, -S (0) 2N (R , 3) (C (R, 2) 2) 0-, N (R13) S (0) 2 (C (R, 2) 2) 0-, - (C (R, 2) 2) 0S (0) 2N (R, 3) -, -NR? (C (R , 2) 2) 0-, - (C (R? 2) 2) 0NR? -, or -C = C-, And it is N, C (R6) 2, CR6, or C = 0, Z is O, S (0) p, N, NR ?, CR5, or C (R5) 2, R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido, or two R, adjacent also represent methylenedioxy, R2 is either substituted with 0-3 R, 4 or heteroanl substituted with 0-3 R? 4, R 3 is H or C, -C 4 alkyl, R 4 is, independently of each occurrence, H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both R groups, together with the nitrogen through which they are adhered, form a heterocyclic ring of 4 to 6 ring atoms, where one carbon can be optionally replaced with N, O, S, or S02, and where any atom in the ring or additional N atom can optionally be substituted with C, -C4, F, or C alkyl CF3, R5 is, independently of each occurrence, H, C, -C4 alkyl, aryl substituted with 0-3 R, 4 heteroaryl substituted with 0-3 R, 4, or cyano, or when two R5 are present, they can form a carbocyclic ring of 3-5 carbons, R6 is, independently of each occurrence, H, C, -C, or Cyan alkyl, R? is H, CrC6 alkyl, C3-C6 cycloalkyl, aryl substituted with 0-3 R, or heteroaryl substituted with 0-3 Ru R8 is H, or C? -C4 alkyl, R9 is H, or C C alkyl, R, or is, independently of each occurrence, H, or C? -C alkyl, or R, 0 and R together with the nitrogen to which R is attached form a nitrogen-containing ring containing 3-6 carbon atoms, R ,, is aryl substituted with 0-3 R, or heteroaryl substituted with 0-3 R ,, R, 2 is, independently of each occurrence, H, CrC 4 alkyl, R, 3 is H or C, -C 4 alkyl, R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, anlalkyloxy substituted with 0-3 R, anloxy substituted with 0-3 R, or substituted with 0-3 Ri, heteroanl substituted with 0- 3 R, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R ^, alkylsulfone, phenylsulfone substituted with 0-3 R, alkylsulfonamide, phenylsulfonamide substituted with 0-3 Ri, substituted heteroaploxy with 0-3 R ^ heteroanylmethyloxy substituted with 0-3 R ,, alkylamido, or arylamido substituted with 0-3 R ,, or two R, adjacent also represent methylenedioxy, m is an integer from 0 to 3, n is an integer from 1 to 2, or is an integer from 0 to 3, and p is an integer from 0 to 2, where 1-3 carbon atoms in the A ring can be replace optionally with N.

In another embodiment, the invention is directed to compounds of formula I 0 a pharmaceutically acceptable salt thereof; where: D and E, together with the carbon atom through which they are attached, form a carbocyclic ring of 6 to 8 atoms or a heterocyclic ring of 5 to 8 atoms containing 1 to 2 heteroatoms selected from O, S (0) p, and NR ?, wherein any atom in the ring can optionally be substituted with C, -C 4, F or CF 3 alkyl; the dotted line between the two groups R4 represents an optional heterocycle ring of 4 to 6 ring atoms that can be formed between the two R groups, together with the nitrogen through which they are adhered; G is NR ?, C (Rβ) 2, or C = 0; R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two R, adjacent also represent methylenedioxy; R2 is aryl substituted with 0-3 R, or heteroaryl substituted with 0-3 R,; R3 is H or C, -C alkyl; R is, independently of each occurrence, H, d-C4 alkyl, C3-C6 cycloalkyl, aplaxyl, heteroaplmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both R groups, together with the nitrogen through which they are adhered, form a heterocyclic ring of 4 to 6 ring atoms, wherein one carbon can be optionally replaced with N, O, S, or S02, and where any atom in the ring or additional N atom can optionally be substituted with C, -C, F, or CF3 alkyl, R6 is, independently of each occurrence, H, C, -C, or Cyan alkyl, R? is H, C?-C6 alkyl, C3-C6 cycloalkyl, substituted by 0-3 R, 4, or heteroaryl substituted with 0-3 R1 R8 is H, or C, -C4 alkyl, R9 is H, or C, -C alkyl, R, 0 is, independently of each occurrence, H, or C, -C, or R 10 alkyl and R 4 together with the nitrogen to which R 4 is attached form a nitrogen-containing ring containing 3-6 carbon atoms, R, 4 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, aplaxykyloxy substituted with 0-3 Ri, aploxy substituted with 0-3 R, anion substituted with 0-3 Ri, heteroaryl substituted with 0- 3 R, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R, alkylsulfone, phenylsulfone substituted with 0-3 R, alkylsulfonamide, phenylsulfonamide substituted with 0-3 R, heteroaploxy substituted with 0-3 R, heteroamptymethyloxy substituted with 0-3 R, alkylamido, or aplamido substituted with 0-3 R ,, or two R, adjacent also represent methylenedioxy, n is an integer from 1 to 2, p is an integer from 0 to 2, and q is an integer from 0 to 4, wherein 1-3 carbon atoms in ring A can optionally be replaced with N In yet another embodiment, the invention is directed to compounds of formula III or a pharmaceutically acceptable salt thereof, wherein the dotted line between Y and Z represents an optional second link, the dotted line between the two R groups represents an optional heterocycle ring of 4 to 6 ring atoms that can be formed between the two R4 groups, together with the nitrogen through which they are adhered, And it is N, C (R6) 2, CR6, or C = O, Z is O, S (0) p, N, NR ?, CR5, or C (R5) 2, R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido, or two R, adjacent also represent methylenedioxy, R2 is aplo substituted with 0-3 R, or hetero-substituted with 0-3 R,, R3 is H or C, -C4 alkyl, R4 is, independently of each occurrence, H, C, -C4 alkyl, C3-C6 cycloalkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both R4 groups, together with the nitrogen through which they are adhered, form a heterocyclic ring of 4 to 6 ring atoms, wherein one carbon can be optionally replaced with N, O, S, or S02, and wherein any atom in the ring or additional N atom can optionally be substituted with C, -C, F, or CF3 alkyl; R5 is, independently of each occurrence, H, CrC4 alkyl, aryl substituted with 0-3 R, 4-heteroaryl substituted with 0-3 R14? or cyano; or when two R5 are present, they can form a carbocyclic ring of 3-5 carbons; R6 is, independently of each occurrence, H, C, -C4 alkyl, or cyano; R? is H, C, -C6 alkyl, C3-C6 cycloalkyl, aryl substituted with 0-3 R? 4, or heteroaryl substituted with 0-3 R,; R8 is H, or C, -C4 alkyl; R9 is H, or C, -C4 alkyl; R, 0 is, independently of each occurrence, H, or C, -C 4 alkyl; or R, 0 and R4 together with the nitrogen to which R is adhered form a nitrogen-containing ring containing 3-6 carbon atoms; R 4 is, independently of each occurrence, alkyl, alkoxy, halo, CF 3, OCF 3, arylalkyloxy substituted with 0-3 Ri, aryloxy substituted with 0-3 R, aryl substituted with 0-3 Ri, heteroaryl substituted with 0- 3 R, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R1 t alkylsulfone, phenylsulfone substituted with 0-3 R, alkylsulfonamide, phenylsulfonamide substituted with 0-3 R, heteroaryloxy substituted with 0-3 R, heteroarylmethyloxy substituted with 0-3 R, alkylamido, or arylamido substituted with 0-3 R ,; or two R, adjacent also represent methylenedioxy; n is an integer from 1 to 2; and q is an integer from 0 to 4; wherein 1-3 carbon atoms in ring A can optionally be replaced with N.

In still other embodiments, the present invention is directed to compositions, comprising: to. at least one compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof; Y b. at least one pharmaceutically acceptable carrier.

In another embodiment, the present invention is directed to methods for treating or preventing an improved condition by the monoamine retake in a subject in need thereof, which comprises the step of: administering to said subject an effective amount of a compound of formula I, II, III, or pharmaceutically acceptable salt thereof.

Conditions enhanced by monoamine reuptake include those selected from the group consisting of vasomotor symptoms, sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders, and combination thereof, particularly those selected conditions of the group consisting of severe depressive disorder, vasomotor symptoms, imperious and stress urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combination of these.

In another embodiment, the present invention is directed to methods for treating or preventing vasomotor symptoms in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound of formula I, II, III, or pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention is directed to methods for treating or preventing a depression disorder in a subject in need thereof, which comprises the step of: administering to said subject an effective amount of a compound of formula I, II, III, or pharmaceutically acceptable salt thereof.

In still other embodiments, the present invention is directed to methods of treating or preventing sexual dysfunction in a subject in need thereof, which comprises the step of: administering to said subject an effective amount of a compound of formula I, II, III, or pharmaceutically acceptable salt thereof.

In additional embodiments, the present invention is directed to methods of treating or preventing pain in a subject in need thereof, which comprises the step of: administering to said subject an effective amount of a compound of formula I, II, III, or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods for treating or preventing gastrointestinal or genitourinary disorder, particularly urinary incontinence or stress, in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound of formula I, II, III, or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods for treating or preventing chronic fatigue syndrome in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound of formula I, II, III, or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods for treating or preventing fibromyalgia syndrome in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound of formula I, II, III, or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods for treating or preventing schizophrenia in a subject in need thereof, which comprises the step of: administering to said subject an effective amount of a compound of formula I or II, or pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS The invention can be understood more fully from the following detailed description and the accompanying drawings forming a part of this application.

Figure 1 is a view of the action of estrogen in thermoregulation mediated by norepinephrine / serotonin.

Figure 2 is a schematic representation of the interactions of norepinephrine and serotonin and their respective receptors (5-HT2a, a, and a2-adrenergic).

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to phenylaminopropanol derivatives, compositions containing these derivatives, and methods of use for the prevention and treatment of conditions selected from the group consisting of improved disorder by monoamine resumption including, inter alia, vasomotor symptoms (VMS). , sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders, and combinations of these, particularly those conditions selected from the group consisting of severe depressive disorder, vasomotopic symptoms, urinary and stress urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations of these The following definitions are provided for the full understanding of the terms and abbreviations used in this specification As used herein and in the appended claims, the singular forms "a", "an", and "the" include the plural reference unless the context clearly indicates otherwise. Thus, for example, a reference to "an antagonist" includes a plurality of such antagonists, and a reference to "a compound" is a reference to one or more equivalent compounds thereof known to those skilled in the art, and thus substantially The abbreviations in the specification correspond to units of measurement, techniques, properties, or compounds as follows "min" means minutes, "h" means time (s), "μL" means m? Crawl (s), "mL" means m? l? l? tro (s), "mM" means millimolar, "M" means molar, "mmole" means m? l? mole (s), "cm" means centimeters, "SEM" means standard error of the mean and "IU" mean International Units "? ° C" and? "ED50 value" means the dose that results in 50% relief of the observed condition or effect (50% of the maximum maximum endpoint) "Norepinephrna transporter" is abbreviated as NET "Human norepinephrine transporter" is abbreviated as hNET "Serotonin transporter" is abbreviated as SERT "Human serotonin transporter" is abbreviated as hSERT "Norepinephrine retake inhibitor" is abbreviated as NRI " Selective norepinephrine reuptake inhibitor "abbreviated as SNRI" Serotonin reuptake inhibitor "abbreviated as SRI" Selective serotonin reuptake inhibitor "abbreviated as SSRI" Norepinefpna "abbreviated as NE" Serotonma "abbreviated as 5-HT "Subcutaneous" is abbreviated as "Intrapentoneal" is abbreviated as ip "Oral" is abbreviated as po.

In the context of this description, a number of terms will be used. The term "treatment" as used herein includes preventive (eg, prophylactic), curative or palliative treatment and "treating" as used herein also includes preventive, curative and palliative treatment.

The term "effective amount", as used herein, refers to an effective amount, in dosage, and for periods of time necessary, to achieve the desired result with respect to the prevention or treatment of vasomotor symptoms, depression disorders. , sexual dysfunction, or pain. In particular, with respect to vasomotor symptoms, "effective amount" refers to the amount of compound or composition of compounds that would increase norepinephrine levels to partially or totally compensate for the lack of steroid availability in subjects subjected to distress. with vasomotopic symptoms. Variable hormone levels influence the amount of compound required in the present invention. For example, the pre-menopausal state may require a low level of compound due to higher hormone levels than the perimenopausal state.

It will be appreciated that the effective amount of components of the present invention will vary from patient to patient not only with the particular compound, component or composition selected, the route of administration, and the capacity of the components (alone or in combination with one or more). combination drugs) to elicit a desired response in the individual, but also with factors such as the state of disease or severity of the condition to be alleviated or hormonal levels, age, sex, weight of the individual, state of mind of the patient , and the severity of the pathological condition to be treated, the concurrent medication or special diets that must be followed by the particular patient, and other factors that those skilled in the art will be able to recognize, with the ultimately appropriate dosage at the discretion of the patient. treating doctor. Dosage regimens should be adjusted to provide the improved therapeutic response. An effective amount is also one in which any toxic or detrimental effects of the components are compensated by the beneficial effects therapeutically.

Preferably, the compounds of the present invention are administered in a dosage and for a time such that the number of hot flushes is reduced compared to the number of hot flushes before the start of treatment Such treatment may also be beneficial in reducing the severity or intensity total distribution of any of the suffocation that is still experienced, as compared to the severity of the hot flash before the start of treatment With respect to depression disorders, sexual dysfunction, and pain, the compounds of the present invention are administered in a dosage and for a time so there is the prevention, alleviation or elimination of the symptoms or condition For example, for an afflicted patient, the compounds of formula I, or a pharmaceutically acceptable salt thereof, can be administered, preferably, in a dosage from about 0 1 mg / day to about 500 mg / day, dosed one or twice daily, more preferably from about 1 mg / day to about 200 mg / day and more preferably from about 1 mg / day to 100 mg / day for a sufficient time to reduce and / or substantially eliminate the number and / or severity of hot flushes or symptoms or condition of depression disorder, sexual dysfunction, or pain The terms "component," "drug," or "pharmacologically active agent" or "active agent" or "medicament" are used interchangeably herein to refer to a compound or compounds or composition of matter that, when administered to a subject (human or animal) induces a desired pharmacological and / or physiological effect by local action and / or systemic The term "modulation" refers to the ability to improve or inhibit a functional property of a biological activity or process, for example, signaling activity or receptor binding. Such improvement or inhibition may be contingent upon the occurrence of a specific event, such as the activation of a signal transduction pathway and / or can be manifested only in particular cell types. The modulator is intended to comprise any compound, eg, antibody, small molecule, peptide, or glycopeptide, polypeptide, or protein , preferably small molecule, or peptide As used herein, the term "inhibitor" refers to any agent that inhibits suppresses, represses, or diminishes a specific activity, such as the serotonin reuptake activity or the norepinephrine retake activity, eg, antibody, molecule small, peptide, ohgopeptide, popeptide or protein, preferably small molecule or peptide, which exhibits a competitive and / or partial or complete inhibitory effect on a mammal, preferably the human norepinephrine reuptake or the serotonin reuptake and the norepinephrine reuptake, thus decreasing or blocking, preferably decreasing, some or all of the biological effects of endogenous norepinephrine reuptake or serotonin reuptake and norepinephrine reuptake Within the present invention, the compounds of formula I can 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 organic salts include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, isethionic, lactic, malic, maleic, mandelic, methanesulfonic, mucic. , nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like Hydrocarbon, hydrobromic, phosphoric and sulfuric acids are particularly preferred, and more preferably is the hydrochloric salt "Administer," as used herein, means either directly administering a compound or composition of the present invention, or administering a derivative or prodrug or analog that will form an equivalent amount of the active compound or substance within the body.

The term "subject" or "patient" refers to an animal including the human species that is treatable with the compositions, and / or method of the present invention. The term "subject" or "subjects" is intended to refer to both the male gender as feminine unless a gender is specifically indicated According to the above the term "patient" includes any mammal that may benefit from the treatment or prevention of vasomotopic symptoms, depression disorders, sexual dysfunction, or pain, such as a human, especially if the mammal is female, in the pre-menopausal, menopausal or post-menopausal period. Additionally, the term patient includes female animals that include humans and, among humans, not only older women who have gone through menopause but also women who have undergone a hysterectomy or for some other reason estrogen production has been suppressed, such as those who have undergone long-term administration of corticosteroids, who suffer from Cushing's syndrome or who have gonadal dysgenesis. However, the term "patient" is not intended to be limited to a woman.

The terms "premature menopause" or "artificial menopause" refers to ovarian failure of unknown cause that may occur before the age of 40. This may be associated with smoking, living at a high altitude, or poor nutritional status. Artificial menopause can result from oophorectomy, chemotherapy, radiation to the pelvis, or any process that deteriorates the blood supply in the ovaries.

The term "pre-menopausal" means before menopause, the term "perimenopausal" means during menopause and the term "post-menopausal" means after menopause. "Ovariectomy" means the removal of an ovary or ovaries and can be performed according to Merchenthaler et al., Maturitas, 1998, 30 (3): 307-316.

The term "collateral effect" refers to a consequence different from that for which an agent or measure is used, such as the adverse effects produced by a drug, especially on an organic tissue or system different from that for which the drug is sought. benefit through its administration. In the case, for example, of high doses of NRIs or NRI / SRI compounds only, the term "side effect" may refer to such a condition as, for example, vomiting, nausea, sweating, and hot flushes (Janowsky, et al. , Journal of Clinical Psychiatry, 1984, 45 (10 Pt 2): 3-9).

"Alkyl," as used herein, refers to a straight, branched, saturated, optionally substituted, cyclic hydrocarbon having from about 1 to about 20 carbon atoms (and all combinations or subcombinations of the ranges and specific numbers of atoms) carbon), with about 1 to about 8 carbon atoms being preferred, and with about 1 to about 4 carbon atoms, referred to herein as "lower alkyl", is most preferred. 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-d? -methylbutyl, and 2,3-d? met? lbut? lo "Heteroalkyl," as used herein, refers to a substituent of the formula (alkyl-X) n-alkyl-, wherein each "alkyl" is independently as defined above, "X" is a sulfur, oxygen , or a portion containing a heteroatom N, and n is 1-4, preferably one. Heteroalkyl groups include, but are not limited to, methoxymethyl, ethoxyethyl, methoxyethyl, methylsulfanylmethyl, ethylsulfanylethyl, methylsulfanylethyl, methylaminoethyl, ethylaminoethyl, and methylaminoethyl.

"Alkenyl," as used herein, refers to an alkyl group of at least two carbon atoms having one or more double bonds, wherein alkyl is as defined herein. Alkenyl groups may be optionally substituted "Alkynyl," as used herein, refers to an alkyl group of at least two carbon atoms having one or more triple bonds, wherein the alkyl is as defined herein. Alkynyl groups may be optionally substituted "Aplo" as used herein, refers to a mono-, di-, tp-, or otherwise optionally substituted multicyclic ring system having from about 5 to about 50 carbon atoms (and all combinations) and subcombinations of specific ranges and numbers of carbon atoms in this), with from about 6 to about 10 carbons being preferred. Non-limiting examples include, for example, phenyl, naphthyl, anthracenyl, and phenanthrenyl.

"Heteroaplo," as used herein, refers to a mono-, di-, tp-, or other multiciquid, optionally substituted aromatic ring system that includes at least one, and preferably from 1 to about 4, heteroatoms member of the ring selected from sulfur, oxygen and nitrogen. The hetero-tile groups can have, for example, from about 3 to about 50 carbon atoms. carbon (and all combinations and subcombinations of specific ranges and numbers of carbon atoms in this), with from about 4 to about 10 carbons being preferred. Nonlimiting examples of heteroaryl groups include, for example, pyrryl, furyl, pyridyl, 1, 2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl , indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.

"Heterocyclic ring," as used herein, refers to a 7- to 10-membered bicyclic heterocyclic ring or stable 5- to 7-membered monocyclic ring that is saturated, partially unsaturated or unsaturated (aromatic), and contains carbon and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and includes any bicyclic group in which any of the foregoing defined heterocyclic rings is fused to a benzene ring. The nitrogen or sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom resulting in a stable structure. The heterocyclic rings described herein can be substituted on the carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen atom in the heterocycle may optionally be quaternized. It has been preferred when the total number of S and O atoms in the heterocycle exceeds one, then these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heterocycle is not more than one. Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H.6-1-, 5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4 / - / - quinolizinyl, 6H-1, 2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4H-carbazolyl, a-, ? ß- or -carbolinilo, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2 - .6H-1, 5,2-dithiazinyl, dihydrofuro [2,3- b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,3-oxadiazolyl, 1, 2,4- oxadiazolyl, 1, 2,5-oxadiazolyl, 1,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylpyrimidinyl, fenantridinyl, phenanthrolinyl, phenoxazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 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, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1, 2,3-triazolyl, 1, 2,4-triazolyl, 1, 2,5-triazolyl, 1,4-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 isatinyl. Fused ring and eespiro compounds containing, for example, the above heterocycles have also been included.

"Alkoxy," as used herein, refers to the group R-O- wherein R is an alkyl group as defined herein.

"Aryloxy," as used herein, refers to the group R-O- wherein R is an aryl group, as defined herein.

"Heteroaryloxy," as used herein, refers to the group R-O- wherein R is a heteroaryl group, as defined herein.

"Heteroarylmethyl" as used herein, refers to the group R-CH2- wherein R is a heteroaryl group, as defined herein.

"Heteroarylmethoxy," as used herein, refers to the group R-CH2-0- wherein R is a heteroaryl group, as defined herein.

"Arylalkoxy," as used herein, refers to the group Rz-Rx-0- wherein Rz is an aryl group and Rx is an alkyl group, as defined herein.

"Alkanoyloxy," as used herein, refers to the group R-C (= 0) -0- wherein R is an alkyl group of 1 to 5 carbon atoms.

"Aplalkyl" as used herein, refers to the group Rz-Ry- where Rz is an aplo group, as defined herein, and wherein Ry is an alkyl group, as defined herein "Alkylsulfoxide," as used herein, refers as used herein, refers to -S (= 0) -R, where R is alkyl, as defined herein "Alkylsulfone," as used herein, refers to -S (= 0) 2-R, wherein R is alkyl, as defined herein "Aplsulfoxide," as used herein, refers as used herein, refers to -S (= 0) -R, where R is aplo, as defined above "Aplsulfone," as used herein, refers to -S (= 0) 2 -R, where R is aplo, as defined above "Alkylsulfonamide," as used herein, refers to -NR-S (= 0) 2-R, wherein each R is independently alkyl, as defined herein or the NR part may also be NH "Aplsulfonamide," as used herein, refers to -NR-S (= 0) 2-R, wherein each R is independently, aplo, as defined above or the part NR may also be NH (since the other R is aplo) "Heteroaplmethoxy," as used herein, refers to -OCH2-R, wherein R is hetero-transloid, as defined above "Alkylamido," as used herein, refers to -NR-C (= 0) -R, wherein each R is independently alkyl, as defined herein, or the NR part may also be NH "Aplamido," as used here, refers to -NRy-C (= 0) -Rz, where Ry and Rz are H or aplo (since at least one of Ry and Rz is aplo), as defined above "Halo," as used herein, refers to chlorine, bromine, fluorine, and iodine When any variable occurs more than once in any constituent or in any formula, its definition in each occurrence is independent of its definition in each of the other occurrences. The combinations of substituents and / or variables and / or atoms or replacement groups are permissible. only if such combinations result in a stable compound In one embodiment, the invention is directed to compounds of compound A of formula I I or a pharmaceutically acceptable salt thereof, wherein the dotted line between Y and Z represents an optional second link, the dotted line between the two groups R4 represents an optional heterocycle ring of 4 to 6 ring atoms that can be formed between the two R4 groups, together with the nitrogen through which they are adhered, X is - (C (R, 2) 2) 0-, -0 (C (R, 2) 2) 0-, - (C (R? 2) 2) 0O-, -S (O) p (C (R, 2) 2) 0-, - (C (R, 2) 2) 0S (O) p-, -N (R, 3) C (O) (C (R, 2) 2) 0-, - (C (R12) 2) 0C (0) N (R13) -, -C (O) N (R13) (C (R, 2) 2) 0-, (C (R12) 2) 0N (R, 3) C (0) -, - (C (R, 2) 2) 0N (R, 3) S (O) 2-, -S (0) 2N (R , 3) (C (R12) 2) 0-, N (R, 3) S (0) 2 (C (R, 2) 2) 0-, - (C (R? 2) 2) 0S (O) 2N (R, 3) -, -NR7 (C (R, 2) 2) 0-, - (C (R12) 2) 0NR? -, or -C = C-, And it is N, C (R6) 2, CR6, or C = 0, Z is O, S (0) p, N, NR ?, CR5, or C (R5) 2, R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two R, adjacent also represent methylenedioxy; R2 is aryl substituted with 0-3 R, or heteroaryl substituted with 0-3 R, 4; R3 is H or C, -C4 alkyl; R4 is, independently of each occurrence, H, C, -C4 alkyl, C3-C6 cycloalkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both R groups, together with the nitrogen through which they are adhered, form a heterocyclic ring of 4 to 6 ring atoms, wherein one carbon can be optionally replaced with N, O, S, or S02, and where any atom in the ring or additional N atom can optionally be substituted with C, -C4, F, or CF3 alkyl; R5 is, independently of each occurrence, H, C, -C4 alkyl, aryl substituted with 0-3 R? 4, heteroaryl substituted with 0-3 R? 4, or cyano; or when two R5 are present, they can form a carbocyclic ring of 3-5 carbons; R6 is, independently of each occurrence, H, C, -C4 alkyl, or cyano; R? is H, C, -C6 alkyl, C3-C6 cycloalkyl, aryl substituted with 0-3 R14; or heteroaryl substituted with 0-3 R, 4.

R8 is H, or C, -C4 alkyl, R9 is H, or C, -C alkyl; R, or is, independently of each occurrence, H, or C, -C alkyl; or R, 0 and R4 together with the nitrogen to which R4 is attached form a ring containing nitrogen containing 3-6 carbon atoms; R? is aryl substituted with 0-3 Ri or heteroaryl substituted with 0-3 R0 R 2 is, independently of each occurrence, H, C, -C alkyl; R, 3 is H or C, -C4 alkyl; R14 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, arylalkyloxy substituted with 0-3 R, aryloxy substituted with 0-3 R, aryl substituted with 0-3 R, heteroaryl substituted with 0- 3 Ri, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R, alkylsulfone, phenylsulfone substituted with 0-3 R alkylsulfonamide, phenylsulfonamide substituted with 0-3 R, heteroaryloxy substituted with 0 -3 R, heteroarylmethyloxy substituted with 0-3 R ,, alkylamido, or arylamido substituted with 0-3 R ,; or two R, adjacent also represent methylenedioxy; m is an integer from 0 to 3; n is an integer from 1 to 2; or is an integer from 0 to 3; and p is an integer from 0 to 2; wherein 1-3 carbon atoms in ring A can optionally be replaced with N.

In preferred embodiments of the compound of formula I, the dotted line between Y and Z represents a second bond; And it's CR6; Z is CR5.

In preferred embodiments of the compound of formula I, the bond between Y and Z is a single bond; Y is C (R6) 2; and Z is C (R5) 2.

In preferred embodiments of the compound of formula I, the bond between Y and Z is a single bond; And it is C = 0; and Z is C (R5) 2.

In preferred embodiments of the compound of formula I, the bond between Y and Z is a single bond; And it is C = 0; and Z is NR ?.

In preferred embodiments of the compound of the formula I, X is - (C (R, 2) 2) 0-, - (C (R12) 2) 00-, or -C = C-.

In preferred embodiments of the compound of the formula I, Y is C (R6) 2, CR6, or C = 0.

In preferred embodiments of the compound of the formula I, Z is CR 5 or C (R 5) 2.

In preferred embodiments of the compound of formula I, R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, or cyano.

In preferred embodiments of the compound of the formula I, R 2 is aryl substituted with 0-2 R, 4, especially, R 2 is phenyl, fluorophenyl, or difluorophenyl.

In preferred embodiments of the compound of the formula I, R3 is H.

In preferred embodiments of the compound of the formula I, R 4 is H or methyl.

In preferred embodiments of the compound of formula I, R5 is, independently of each occurrence, H, C?-C4 alkyl, aryl substituted with 0-3 R,, especially H, methyl, ethyl, n-propyl, isopropyl, substituted aryl with alkoxy, aryl substituted aryl or phenyl substituted with 1-2 halo.

In preferred embodiments of the compound of the formula I, R6 is, independently of each occurrence, H, methyl, ethyl, n-propyl, or isopropyl In preferred embodiments of the compound of the formula I, R7 is H, C, -C6 alkyl, or aplo substituted with 0-3 R14 In preferred embodiments of the compound of the formula I, R8 is H In preferred embodiments of the compound of the formula I, R9 is H In preferred embodiments of the compound of formula I, R, 0 is H In preferred embodiments of the compound of formula I, R ,? is aplo substituted with 0-3 R ,, especially R ,, is aplo substituted with 0-2 R ,, and more especially, phenyl, or aplo substituted with 1-2 halo or alkoxy In preferred embodiments of the compound of formula I, n is 1 In preferred embodiments of the compound of formula I, none of the carbon atoms in ring A are replaced with N In preferred embodiments of the compound of formula I, the dotted line between Y and Z represents a second bond, Y is CR6, Z is CR5, X is - (C (R, 2) 2) 0-, - (C (R 2) 2) 0O-, or -C = C-, R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano, R2 is aplo substituted with 0-3 R, 4 or heteropole substituted with 0-3 R,, R3 is H, R4 is, independently of each occurrence, H or methyl, R5 is, independently of each occurrence, H, methyl or aplo substituted with 0-3 R? 4, R6 is H , R8 is H, R9 is H, R ,, is aplo substituted with 0-3 Ri or heteroatlo substituted with 0-3 R ,, R? 2 is, independently of each occurrence, H or C, -C4 alkyl, R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano, m is an integer from 0 to 2, n is 1, I is an integer from 0 to 3, where none of the carbon atoms in ring A are replaced with N In preferred embodiments of the compound of formula I, the bond between Y and Z is a single bond, Y is C (R6) 2, Z is C (R5) 2, X is - (C (R, 2) 2) 0 -, - (C (R12) 2) 0O-, or -C = C-, R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano, R2 is aplo substituted with 0- 3 R, 4 or heterolalk substituted with 0-3 R? 4, R3 is H, R4 is, independently of each occurrence, H or methyl, R5 is, independently of each occurrence, H, C? -C4 alkyl or aplo substituted with 0-3 R14, R6 is independently in each occurrence, H or C, -C4 alkyl, R8 is H, R9 is H, R ,, is aplo substituted with 0-3 R, or heteroatlo substituted with 0-3 R ,, R, 2 is, independently of each occurrence, H or C, -C, R alkyl? is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano, m is an integer from 0 to 2, n is 1, and or is an integer from 0 to 3; where none of the carbon atoms in ring A are replaced with N.

In preferred embodiments of the compound of formula I, the bond between Y and Z is a single bond; And it is C = 0; Z is C (R5) 2; X is - (C (R, 2) 2) 0-, - (C (R? 2) 2) 0O-, or -C = C-; R is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; R2 is aryl substituted with 0-3 R, or heteroaryl substituted with 0-3 R1; R3 is H; R4 is, independently of each occurrence, H or methyl; R5 is, independently of each occurrence, H, or C, -C4 alkyl; R8 is H; R9 is H; R ,, is aryl substituted with 0-3 Ri or heteroaryl substituted with 0-3 R ,; R, 2 is, independently of each occurrence, H or C, -C4 alkyl; R, 4 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; m is an integer from 0 to 2; n is 1; and o is an integer from 0 to 3; where none of the carbon atoms in ring A are replaced with N.

In preferred embodiments of the compound of formula I, the bond between Y and Z is a single bond; And it is C = 0; Z is NR ?; X is - (C (R, 2) 2) 0-, - (C (R? 2) 2) 0O-, or -C = C-; R is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; R2 is aryl substituted with 0-3 R 4 or heteroaryl substituted with 0-3 R,; R3 is H; R4 is, independently of each occurrence, H or methyl; R? is C, -C6 alkyl, C3-C6 cycloalkyl, aryl substituted with 0-3 R14 or heteroaryl substituted with 0-3 R, 4; R8 is H; R9 is H; R ,, is aryl substituted with 0-3 Ri or heteroaryl substituted with 0-3 R { , R, 2 is, independently of each occurrence, H or C, -C 4 alkyl; R14 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; m is an integer from 0 to 2; n is 1; and o is an integer from 0 to 3; where none of the carbon atoms in ring A are replaced with N.

In another embodiment, the invention is directed to compounds of formula 0 a pharmaceutically acceptable salt thereof; where: D and E, together with the carbon atom through which they are attached, form a carbocyclic ring of 6 to 8 atoms or a heterocyclic ring of 5 to 8 atoms containing 1 to 2 heteroatoms selected from O, S (0) p, and NR ?, wherein any atom in the ring can optionally be substituted with C, -C 4, F or CF 3 alkyl; the dotted line between the two groups R represents an optional heterocycle ring of 4 to 6 atoms in the ring that can be formed between the two R groups, together with the nitrogen through which they are attached, G is NR ?, C (Rß) 2, or C = 0, R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido, or two adjacent Ri also represent methylenedioxy, R2 is either substituted with 0-3 R1 or hetero-substituted with 0-3 R,, R3 is H or C, -C4 alkyl, R is, independently of each occurrence, H, C, -C 4 alkyl, C 3 -C 6 cycloalkyl, aplaxyl, heteroaplmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both R groups, together with the nitrogen through which they are adhered, form a heterocyclic ring of 4 to 6 ring atoms, wherein one carbon can be optionally replaced with N, O, S, or S02, and where any atom in the ring or additional N atom can optionally be substituted with C? -C4 alkyl, F, or CF3, R6 is, independently of each occurrence, H, C, -C, or Cyan alkyl, R? is H, C? -C6 alkyl, C3-C6 cycloalkyl, substituted by 0-3 R, 4, or heteroaryl substituted with 0-3 R, R8 is H, or C, -C4 alkyl, Rg is H, or C, -C4 alkyl, R, or is, independently of each occurrence, H, or C? -C alkyl, or Rio and R4 together with the nitrogen to which R is attached form a ring containing nitrogen containing 3-6 carbon atoms, R, 4 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, aplaxykyloxy substituted with 0-3 Ri, aploxy substituted with 0-3 R ,, substituted by 0-3 R ,, heteroaryl substituted with 0 -3 R, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkyloxy, alkylsulfoxide, phenylsulfoxide substituted with 0-3 Ri, alkylsulfone, phenylsulfone substituted with 0-3 Ri, alkylsulfonamide, phenylsulfonamide substituted with 0-3 Ri, heteroaryloxy substituted with 0-3 R, heteroamptymethyloxy substituted with 0-3 R, alkylamido, or aplamido substituted with 0-3 R, or two R, adjacent also represent methylenedioxy, n is an integer from 1 to 2, p is an integer from 0 to 2, and q is an integer from 0 to 4, where 1-3 carbon atoms in ring A can be optionally replaced with N In preferred embodiments of the compound of formula II, G is C = O In preferred embodiments of the compound of formula II, G is C (R6) 2 In preferred embodiments of the compound of the formula II, R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, or cyano In preferred embodiments of the compound of formula II, R2 is aplo substituted with 0-2 R, 4 In preferred embodiments of the compound of formula II, R2 is phenyl, fluorophenyl, or difluorophenyl In preferred embodiments of the compound of formula II, R3 is H In preferred embodiments of the compound of formula II, R is H or methyl In preferred embodiments of the compound of the formula II, R6 is, independently of each occurrence, H, methyl, ethyl, n-propyl, or isopropyl.

In preferred embodiments of the compound of formula II, R? is H, C, -C6 alkyl, or aryl substituted with 0-3 R,.

In preferred embodiments of the compound of formula II, R8 is H.

In preferred embodiments of the compound of formula II, R9 is H.

In preferred embodiments of the compound of formula II, R, 0 is H.

In preferred embodiments of the compound of formula II, R14 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, or cyano.

In preferred embodiments of the compound of formula II, n is 1.

In preferred embodiments of the compound of formula II, p is 0 or 1.

In preferred embodiments of the compound of formula II, none of the carbon atoms in ring A are replaced with N.

In preferred embodiments of the compound of formula II, D and E, together with the carbon atom through which they are attached, form a carbocyclic ring of 6 to 7 atoms; G is C (R6) 2; R2 is aryl substituted with 0-3 R, 4 or heteroaryl substituted with 0-3 R,; R3 is H; R4 is, independently of each occurrence, H or methyl; R6 is, independently of each occurrence, H or C, -C alkyl; R8 is H; R9 is H; R, 4 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, 0CF3, hydroxy or cyano; n is 1; and q is an integer from 0 to 3; where none of the carbon atoms in ring A are replaced with N.

In preferred embodiments of the compound of formula II, D and E, together with the carbon atom through which they are attached, form a carbocyclic ring of 6 to 7 atoms; G is C = 0; R2 is aryl substituted with 0-3 R, or heteroaryl substituted with 0-3 R, 4; R3 is H; R4 is, independently of each occurrence, H or methyl; Rs is H; R9 is H; R? 0 is H; R1 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; n is 1; q is an integer from 0 to 3; where none of the carbon atoms in ring A are replaced with N.

In still another embodiment, the invention is directed to compounds of formula III: or a pharmaceutically acceptable salt thereof; where: the dotted line between Y and Z represents an optional second link; the dotted line between the two groups R4 represents an optional heterocycle ring of 4 to 6 ring atoms that can be formed between the two R groups, together with the nitrogen through which they are attached; Y is N, C (R6) 2, CR6, or C = 0; Z is O, S (O) p, N, NR7, CR5, or C (R5) 2; R is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two R, adjacent also represent methylenedioxy; R2 is aryl substituted with 0-3 R, 4 or heteroaryl substituted with 0-3 R,; R3 is H or C, -C alkyl; R is, independently of each occurrence, H, C, -C, C3-C6 cycloalkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both R4 groups, together with the nitrogen through which they are adhered, form a heterocyclic ring of 4 to 6 ring atoms, wherein one carbon can be optionally replaced with N, O, S, or S02, and wherein any atom in the ring or additional N atom can optionally be substituted with C, -C4, F, or C alkyl CF3; R5 is, independently of each occurrence, H, alkyl d-d, aryl substituted with 0-3 R? 4, heteroaryl substituted with 0-3 R, 4, or cyano; or when two R5 are present, they can form a carbocyclic ring of 3-5 carbons; R6 is, independently of each occurrence, H, C, -C4 alkyl, or cyano; R? is H, C, -C6 alkyl, C3-C6 cycloalkyl, aryl substituted with 0-3 R, 4, or heteroaryl substituted with 0-3 R1; R8 is H, or C, -C4 alkyl; Rg is H, or C, -C4 alkyl; R, or is, independently of each occurrence, H, or d-C4 alkyl; or R, 0 and R together with the nitrogen to which R is adhered form a ring containing nitrogen containing 3-6 carbon atoms; R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, aplalkyloxy substituted with 0-3 R1 t aploxy substituted with 0-3 R ,, substituted by 0-3 R1 t heterolalk substituted with 0-3 R, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R, alkylsulfone, phenylsulfone substituted with 0-3 R, alkylsulfonamide, phenylsulfonamide substituted with 0-3 R, hetero-substituted heterocyclic with 0-3 R, heteroamptymethyloxy substituted with 0-3 R ,, alkylamido, or aplamido substituted with 0-3 R ,, or two R, adjacent also represent methylenedioxy, n is an integer from 1 to 2, and q is an integer from 0 to 4, where 1-3 carbon atoms in the A ring can be optionally replaced with N In preferred embodiments of the compound of the formula III, the dotted line between Y and Z represents a second bond Y is CR6, and Z is CR5 In preferred embodiments of the compound of the formula III, the bond between Y and Z is a single bond, Y is C (R6) 2, and Z is C (R5) 2 In preferred embodiments of the compound of the formula III, the bond between Y and Z is a single bond, Y is C = 0, Z is C (R5) 2 In preferred embodiments of the compound of the formula III, the bond between Y and Z is a single bond, Y is C = 0, Z is NR? In preferred embodiments of the compound of the formula III, Y is C (R6) 2, CR6, or C = 0 In preferred embodiments of the compound of the formula III, Z is CR 5 or C (R 5) 2 In preferred embodiments of the compound of the formula III, R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, or cyano In preferred embodiments of the compound of the formula III, R2 is aplo substituted with O-2 R, In preferred embodiments of the compound of the formula III, R2 is phenyl, fluorophenyl, or difluorophenyl In preferred embodiments of the compound of the formula III, R3 is H In preferred embodiments of the compound of the formula III, R4 is H or methyl In preferred embodiments of the compound of the formula III, R5 is, independently of each occurrence, H, C, -C4 alkyl, substituted by 0-3 R14.

In preferred embodiments of the compound of the formula III, R5 is, independently of each occurrence, H, methyl, ethyl, n-propyl, isopropyl, substituted by alkoxy, substituted by aploxy or phenyl substituted by 1-2 halo In preferred embodiments of the compound of the formula III, R6 is, independently of each occurrence, H, methyl, ethyl, n-propyl, or isopropyl In preferred embodiments of the compound of the formula III, R7 is H, C, -C6 alkyl, or aplo substituted with 0-3 R, In preferred embodiments of the compound of the formula III, R8 is H In preferred embodiments of the compound of the formula III, R9 is H In preferred embodiments of the compound of the formula III, R, 0 is H.

In preferred embodiments of the compound of the formula III, n is 1.

In preferred embodiments of the compound of the formula III, q is an integer from 0 to In preferred embodiments of the compound of formula III, none of the carbon atoms in ring A are replaced with N.

In preferred embodiments of the compound of formula III, the dotted line between Y and Z represents a second bond; And it's CR6; Z is CR5; R is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; R2 is aryl substituted with 0-3 R, or heteroaryl substituted with 0-3 R,; R3 is H; R is, independently of each occurrence, H or methyl; R5 is, independently of each occurrence, H, methyl or aryl substituted with 0-3 R?; R6 is H; Rs is H; R9 is H; R, 4 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; n is 1; and q is an integer from 0 to 3; where none of the carbon atoms in ring A are replaced with N.

In preferred embodiments of the compound of the formula III, the bond between Y and Z is a single bond; Y is C (R6) 2; Z is C (R5) 2; R is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; R2 is aryl substituted with 0-3 R, 4 or heteroaryl substituted with 0-3 R1; R3 is H; R is, independently of each occurrence, H or methyl; R5 is, independently of each occurrence, H, C, -C4 alkyl or aryl substituted with 0-3 R,; R6 is independently in each occurrence, H or C, -C4 alkyl; R8 is H; R9 is H; R? 0 is H; R, 4 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; n is 1; and q is an integer from 0 to 3; where none of the carbon atoms in ring A are replaced with N.

In preferred embodiments of the compound of the formula III, the bond between Y and Z is a single bond; And it is C = 0; Z is C (R5) 2; R is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; R2 is aryl substituted with 0-3 R, 4 or heteroaryl substituted with 0-3 R,; R3 is H; R is, independently of each occurrence, H or methyl; R5 is, independently of each occurrence, H, or C, -C4 alkyl; R8 is H; R9 is H; R, 4 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; n is 1; and q is an integer from 0 to 3; where none of the carbon atoms in ring A are replaced with N.

In preferred embodiments of the compound of the formula III, the bond between Y and Z is a single bond; And it is C = 0; Z is NR ?; R is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; R2 is aryl substituted with 0-3 R, or heteroaryl substituted with 0-3 R,; R3 is H; R4 is, independently of each occurrence, H or methyl; R? is C, -C6 alkyl, C3-C6 cycloalkyl, aryl substituted with 0-3 R, 4 or heteroaryl substituted with 0-3 R? 4; R8 is H; R9 is H; R, 4 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy or cyano; n is 1; and q is an integer from 0 to 3; where none of the carbon atoms in ring A are replaced with N.

Preferred compounds of the invention include, but are not limited to: 1- [5- (benzyloxy) -1 H -indole-1-yl] -3- (methylamino) -1-phenylpropan-2-ol 1- [4- (benzyloxy) -1 H-indol-1-yl] -3- (methylamino) -1-phenylpropan-2-ol 1- [6- (benzyloxy) -1 H -indol-1-yl] -3- (methylamino) -1-phenylpropan-2-ol 1- [7 - (benzyloxy) -1 H -indol-1-yl] -3- (methylamino) -1-phenylpropan-2-ol 1-. { 5 - [(2-methoxybenzyl) oxy] -1 H-indol-1-yl} -3- (methylamino) -1-phenylpropan-2-ol 1 -. { 5 - [(3-methoxybenzyl) oxy] -1 H -indole-1-lyl} -3- (methylamino) -1-phenylpropan-2-ol 1-. { 5 - [(4-methoxybenzyl) oxy] -1 H-indol-1-yl} -3- (methylamino) -1-phenylpropan-2-ol 1-. { 5 - [(2-chlorobenzyl) oxy] -1 H-indol-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 1-. { 5 - [(3-chlorobenzyl) ox?] - 1 H-? Ndol-1-? L} -3- (met? Lam? No) -1-phen? Lpropan-2-ol, 1-. { 5 - [(4-chlorobenzyl) ox?] - 1 H-? Ndol-1-? L} -3- (met? Lam? No) -1-phen? Lpropan-2-ol, 1 -. { 5 - [(2-fluorobenz? L) ox?] - 1 H-? Ndol-1 -? L} -3- (met? Lam? No) -1-phen? Lpropan-2-ol, 1 -. { 5 - [(3-Fluorobenz? L) ox?] - 1 H-? Ndol-1 -? L} -3- (met? Lam? No) -1-phen? Lpropan-2-ol, 1 -. { 5 - [(4-Fluorobenz? L) ox?] - 1 H-? Ndol-1 -? L} -3- (methanolamine) -1-phenolpropan-2-ol, 3- (methalamin) -1 -. { 5 - [(2-met? Lbenc? L) ox?] - 1 H-? Ndol-1 -? L} -1-phenolpropan-2-ol, 3- (met? Lam? No) -1-. { 5 - [(3-met? Lbenc? L) ox?] - 1 H-? Ndol-1-? L} -1-phen? Lpropan-2-ol, 3- (met? Lam? No) -1 -. { 5 - [(4-met? Lbenc? L) ox?] - 1 H-? Ndol-1 -? L} -1-phenyl? -propane-2-ol, 3- (meth? Lam? No) -1-phenyl? -1- [5- (1-phenoxy?) -1 H-? Ndol-1 -? l] propan-2-ol, 3- (meth? lam? no) -1-phenyl? -1- [5- (2-phen? letox?) - 1 H-? ndol-1 -? l] propan -2-ol, 3- (met? Lam? No) -1- (5-phenox? -1 H-? Ndol-1-? L) -1-phen? Lpropan-2-ol, 3- (met? lam? no) -1- (4-phenoxy? -1 H-? ndol-1-? l) -1-phen? lpropan-2-ol, 3- (met? lam? no) -1-phenyl? -1- (4-phenol-1 H-? Ndol-1 -? L) propan-2-ol, 3- (meth? Lam? No) -1-phenyl? -1- (6-phen? l-1 H-? ndol-1 -? l) propan-2-ol, 3- (meth? lam? no) -1-phenyl? -l- (7-phenol-1 H-? ndol- 1 -? L) propan-2-ol, 1- [5- (benz? Lox?) -1 H-? Ndol-1 -? L] -1 - (3-fluorophen? L) -3- (met? lam? no) propan-2-ol, 1- [5- (benz? lox?) -2,3-d? h? dro-1 H-? ndol-1-? l] -1- (3-fluorofen l) -3- (methanolamine) propan-2-ol, 1- [5- (benzylox?) -2,3-d? h? dro-1 H-? ndol-1-? l] -3- (meth? lam? no) -1-phen? lpropan-2-ol, '-chloro-1 '- [2-h? Drox? -3- (met? Lam? No) -1-phen? L? Esp] ro [c? Clohexane-1, 3' -? Ndol] - 2 '(1' H) -one, 6'-chloro-1 '- [(2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] esp? Ro [ c-Clohexane-1, 3 '-? ndol] - 2' (1 'H) -one, 6'-fluoro-1' - [2-h? drox? -3- (met? lam? no) -1 -phenyl? -propylene [c-clohexane-1, 3'-? ndol] -2 '(1' H) -one, 5'-fluoro-1 '- [2-hydrox? - 3- (methamphenoxy) -1-phenolpropyl] [c-clohexane-1, 3'-ndol] -2 '(1'H) -one, 7'-chloro- 1 '- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] esp? Ro [c? Clohexane-1, 3' -? Ndol] - 2 '(1 ?) - ona, 6'-fluoro-1 '- [1 - (3-fluorofen? l) -2-h? drox? -3- (met? lam? no) prop? l) esp? ro [c? clohexane- 1, 3 '-? ndol] -2' (1?) - one, 3- (met? lam? no) -1-phen? l-1-esp? ro [c? clohexane-1, 3 ' -? ndol] -1 '(2'H) -? lpropan-2-ol, 1- (3-fluorofen? L) -3- (met? Lam? No) -1-. { 3- [2- (tpfluoromethoxy?) Phen? L] -1H-? Ndol-1-? L} propan- 2-ol, 1- (3-fluorophenyl) -1- [3- (2-isopropoxyphenyl) -1 H -indol-1-yl] -3- (methylamino) propan-2-ol; 1- (3-fluorophenyl) -1- [3- (4-fluorophenyl) -1 H -indol-1-yl] -3- (methylamino) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1 - [3- (2-phenoxyphenyl) -1 H -indol-1-yl] propan-2-ol; 1- [3- (2,4-difluorophenyl) -1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- [3- (2,5-difluorophenyl) -1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- [3- (2,3-dimethoxyphenyl) -1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- [3- (2,4-dichlorophenyl) -1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1 - . 1 - . 1 - [3- (2-ethoxyphenyl) -1 H -indol-1 -yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (7-Chloro-5-methoxy-1 H -pyrrolo [2,3-c] pyridin-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2- ol; 1- (7-Chloro-5-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (5-methoxy-1 H -pyrrolo [2,3-c] pyridin-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (3-fluorophenyl) -1- (5-methoxy-1 H -pyrrolo [2,3-c] pyridin-1-yl) -3- (methylamino) propan-2-ol; 3- (methylamino) -1- (5-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -1-phenylpropan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- (5-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) propan-2-ol; 3- (methylamino) -1 - (7-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -1-phenylpropan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- (7-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) propan-2-ol; 1 - (3,3-diethyl-2,3-dihydro-1 H-indol-1 -yl) -1 - (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (6-fluoro-3,3-dimethyl-2,3-dihydro-1 H -indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1 - (4-benzyl-3,4-dihydroquinoxalin-1 (2H) -yl) -1 - (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1 - (5-Fluoro-3,3-dimethyl-2,3-dihydro-1 H-indol-1 -yl) -1 - (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1 - [(3 S) -3-methyl-2,3-dihydro-1 H -indol-1-yl] propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1 - [(3R) -3-methyl-2,3-dihydro-1 H -indol-1-yl] propan-2-ol; 1- (3-fluorophenyl) -1- (3-isopropyl-2,3-dihydro-1 H-indol-1-yl) -3- (methylamino) propan-2-ol; 1- (3-ethyl-2,3-dihydro-1 H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (3-ethyl-2,3-dihydro-1 H -indole-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (3-isopropyl-2,3-dihydro-1 H -indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 3-amino-1- (3,5-difluorophenyl) -1- (3,3-dimethyl-2,3-dihydro-1 H -indol-1-yl) propan-2-ol; 1- [1- (3,5-d? Fluorophen? L) -2-h? Drox? -3- (met? Lam? No) prop? L] -7-fluoro-3,3-d? Met? l-1, 3-d? h? dro-2H-? ndol-2-one, 5,7-d? fluoro-1- [1- (3-fluorofen? l) -2-h? drox? -3 - (methanolamine) prop?] -3,3-d? met? l-1, 3-d? h? dro-2H-? ndol-2-one, 1 - [1 - (3, 5-d? Fluorophen?) -2-hydroxy? -3- (meth? Lam? No) prop? L] -3,3-d? Met? L-1, 3-d? 2H-? Ndol-2-one, 1 - [2-h? Drox? -3- (met? Lam? No) -1-phenyl? -propyl] -1H-? Ndol-5-ol, 1- [1- (3-fluorophen? L) -2-h? Drox? -3- (met? Lam? No) prop?] -1 H-? Ndol-5-ol 5 '- (benz? Lox?) -1 '- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] esp? Ro [c? Clohexane-1, 3' -? Ndol] -2 '( 1?) - ona, 5- (benz? Lox?) - 1 - [2-h? Drox? -3- (met? Lam? No) -1-phenyl? -propyl] -3,3-d? meth-1, 3-d? h? dro-2H-? ndol-2-one, 1- [1- (3-chlorophen? l) -2-h? drox? -3- (met? lam? no) prop? l] -7-fluoro-3,3-d? met? l-1, 3-d? h? dro-2H-? ndol-2-one, 1- (3-chloro-5-fluorofen 1) -1- (1 H-? ndol-1-? l) -3- (methalamine) propan-2-ol, 3-chloro-N-. { 1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -1 H-? Ndol-5-? L} -4-methylbenzamide, 3-chloro-N-. { 1 - [2-h? Drox? -3- (met? Lam? No) -1-phenyl? -propyl] -2,3-d? H? Dro-1 H-? Ndol-5-? L} benzamida, 3-chloro-N-. { 1 - [2-h? Drox? -3- (met? Lam? No) -1-pfen? Lprop? L] -1H-? Ndol-5-? L} benzam? da, N-. { 1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -2,3-d? H? Dro-1 H-? Ndol-5-? L} benzam? da, N-. { 1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -1 H-? Ndol-5-? L} benzam? da, N-. { 1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -2,3-d? H? Dro-1 H-? Ndol-5-? L} c? Clohexanecarboxamide, N-. { 1 - [2-h? Drox? -3- (met? Lam? No) -1-pfen? Lprop? L] -1H-? Ndol-5-? L} c? clohexanocarboxam? da, N- (3-chlorophen? L) -1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L]? Ndol? Na-5-carboxam? Da, N - (3-chlorophen? L) -1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -1 H-? Ndol-5-carboxam? Da, 3- (met? Lam? No) -1- (6-phenox? -1 H-? Ndol-1-? L) -1-phen? Lpropan-2-ol, 3- (met? Lam? No) -1- (7-phenoxy? -1 H-? Ndol-1-? L) -1-phen? Lpropan-2-ol, 3-am? No-1- [5- (benz? Lox?) - 1 H-? Ndol-1-? L] -1-phen? Lpropan-2-ol, 1 - [5- (benz? Lox?) - 1 H-? Ndol-1 -? L] -3- (et? lam? no) -1-phenyl? -propan-2-ol, 1 - [5- (benz? lox?) - 1 H-? ndol-1 -? l] -1-phenyl? -3- (prop? lam? no) propan-2-ol, 1- [5- (benz? lox?) - 1 H-? ndol-1-? l] -3 - (? soprop? lam? no) -1-phen? lpropan -2-ol, 1- [5- (benz? Lox?) - 1 H-? Ndol-1-? L] -3- (d? Met? Lam? No) -1-phen? Lpropan-2-ol , 1- [5- (benz? Lox?) - 1 H-? Ndol-1-? L] -3- [et? L (meth? L) am? No] -1-phen? Lpropan-2-ol, 1 - [5- (benz? Lox?) - 1 H-? Ndol-1 -? L] -3- (d? Et? Lam? No) -1-phenyl? -propan-2-ol, 1 - [5 - (benz? lox?) - 1 H-? ndol-1 -? l] -1-phenyl? -3-p? rrol? d? n-1 -? lpropan-2-ol, 1- [5- (benz? lox?) - 1 H-? ndol-1-? l] -1-phen? l-3-p? pepd? n-1-? lpropan-2-ol, 1 - [5- ( benc? lox?) - 1 H-? ndol-1 -? l] -3- (4-met? lp? peraz? n-1 -? l) -1-phenylpropan-2-ol 3- (met? lam ? no) -1-phenyl-1 - [5- (p? pd? n-2-? lmethox?) - 1 H-? ndol-1 -? l] propan-2-ol, 3- (met ? lam? no) -1 -fen? l-1 - [5- (phen? let? n? l) -1 H-? ndol-1 -? l] propan-2-ol, 3- (met? lam ? no) -1-phen? l-1- [5- (2-phen? let? l) -1 H-? ndol-1-? l] propan-2-ol, 1 '- [3-am? no-2-hydroxyl-1-phenylpropyl] -6'-fluoroesp? ro [c-clohexane-1, 3 '-? ndol] -2' (1?) - one, 1 '- [3- (et? Lam? No) -2-h? Drox? -1-phen? Lprop? L] -6'-fluorosp? Ro [c? Clohexane-1, 3 '-? Ndol] -2' ( 1 'H) -one, 6'-fluoro-1' - [2-hydroxy? -3- (? Soprop? Lam? No) -1-phenyl? -propyl] c [clohexane- 1, 3 '-? Ndol] -2' (1 'H) -one, 6'-fluoro-1' - [2-h? Drox? -1-phen? L-3- (prop? Lam? No) prop? l] esp? ro [c? clohexano-1, 3 '-? nd ol] - 2 '(1' H) -one, 1 '- [3-am? no-2-hydrox? -1-phenyl? -propyl] -5'-fluorosp? ro [c-clohexane- 1, 3 '-? Ndol] -2' (1?) - ona, 1 '- [3- (et? Lam? No) -2-h? Drox? -1 -fen? Lprop? L] -5' -fluoroesp? ro [c-clohexane-1, 3 '-? ndol] - 2' (1 'H) -one, 5'-fluoro-1' - [2-h? drox? -3 - (? soprop? lam? no) -1-phen? lprop? l] esp? ro [c-clohexane-1, 3'-? ndol] -2 '(1?) - one, 5'-fluoro-1' - [2- h? drox? -1-phen? l-3- (prop? lam? no) prop? l] esp? ro [c? clohexane-1, 3 '-? ndol] -2' (1 'H) -one , 1 '- [3- (d? Met? Lam? No) -2-h? Drox? -1-fen? Lprop? L] -5'-fluorosp? Ro [c? Clohexane-1, 3'-? ndol] - 2 '(1' H) -one, 5'-fluoro-1 '- [2-h? drox? -3-morphol? n-4-? l-1-phenylpropyl]? ro [c-Clohexane-1, 3 '-? ndol] - 2' (1 'H) -one, 1' - [2-h? drox? -3- (met? lam? no) -1-phenyl? lprop? l] -5'-methox? esp? ro [c? clohexane-1, 3 '-? ndol] - 2' (1 'H) -one, 1' - [2-h? drox? -3- (methanolamine) -1-phenylpropyl] -6'-methoxyspray [c-clohexane-1, 3'-? ndol] -2 '(1' H) -one, 1 '- [2-h? Drox? -3- (met? Lam? No) -1-pfen? Lprop? L] -2'-oxo-1', 2'-d? H? Droesp? Ro [c? clohexane- 1, 3 '-? Ndol] -5'-carbon? Tplo, 1' - [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -2'-oxo -1 ', 2'-d? H? Droesp? Ro [c? Clohexane- 1, 3' -? Ndol] -6'-carbon? Tplo, 4 ', 5'-d? Fluoro-1' - [2 -h? drox? -3- (met? lam? no) -1-phen? lprop? l] esp? ro [c? clohexane-1, 3 '-? ndol] -2' (1?) - ona, 7'-fluoro-1 '- [1 - (3-fluorophen? L) -2-h? Drox? -3- (meth? Lam? No) prop? L] esp? Ro [c? Clohexane- 1, 3 '-? ndol] -2' (1?) - ona, 1 '- [1 - (3-chlorophen? l) -2-h? drox? -3- (met? lam? no) prop? l] - 6'-fluorosp? Ro [c? Clohexane-1, 3 '-? Ndol] -2' (1 'H) -one, 1- [1- (3-chloro-5-fluorofen? L) -2-h Drox? -3- (met? lam? no) prop? l] -7-fluoro-3,3-d? met? l-1, 3-d? h? dro-2H-? ndol-2-one , 1- (3-chloro-5-fluorophen? L) -1- (2,3-d? H? Dro-1 H-? Ndol-1-? L) -3- (met? Lam? No) propan -2-ol, 1- (3-chloro-5-fluorophen? L) -1- (7-fluoro-3,3-d? Met? L-2,3-d? H? Dro-1 H-? Ndol-1-? l) -3- (methanolamine) propan-2-ol, 1- (3-chloro-5-fluorophen? l) -1- (3,3-d? met? l-2,3-d) H-dro-1 -H-? ndol-1-? l) -3- (meth? lam? no) propan-2-ol, 7'-fluoro-1 '- [1 - (3-fluorofen? l) -2-h? Drox? -3- (met? Lam? No) prop? L] esp? Ro [c? Clobutane-1, 3 '-? Ndol] -2' (1?) - ona, 7'- fluoro-1 '- [1- (3-fluorophen? l) -2-h? drox? -3- (met? lam? no) prop? l] sp? ro [c? clopentane-1, 3'-? ndol] -2 '(1?) -one, 6-fluoro-1 - [1 - (3-fluorophen? l) -2-h? drox? -3- (meth? lam? no) prop? l] - 3,3-d? Met? L-1, 3-d? H? Dro-2H-? Ndol-2-one, 1 - (7-fluoro-2,3-d? H? Dro-1 H-? ndol-1 -? l) -3- (meth? lam? no) -1-phen? lpropan-2-ol, 4-fluoro-3- [1 - (3-fluorofen? l) -2-h? drox ? -3- (met? Lam? No) prop? L] -1-phenyl? -1,3-d? -hydro-2H-benz? Dazol-2-one, 4-fluoro-1 - (3-fluorophen? L) -3- [1 - (3-fluorophen? L) -2-h? Drox? -3- (met? Lam? No) prop? L] -1, 3-d? H? dro-2 H -benz? dazol-2-one, 1- [3-amino-1- (3,5-d? fluorophen? l) -2-h? drox? prop? l] -7- fluoro-3,3-d? met? l-1, 3-d? h? dro-2H-? ndol-2-one, and pharmaceutically acceptable salts thereof, especially e hydrochloride salt Especially preferred compounds of the invention include, but are not limited to 1 S, 2R) -1- [5-benzyloxy) -1H-indol-1-l] -3- (methylamino) -1-phenylpropan-2-ol 1 S, 2R) -1- [4-? benzyloxy) -1 H-indol-1 -yl] -3- (methylamino) -1-phenylpropan-2-ol 1S, 2R) -1- [6-benzyloxy) -1H-indol-1 l] -3- (methylamino ) -1-phenylpropan-2-ol 1 S, 2R) -1- [7-benzyloxy) -1H-indol-1 l] -3- (methylamino) -1-phenylpropan-2-ol 1 S, 2R) - 1-. { 5 (2-methoxybenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol 1 S, 2R) -1-. { 5- | (3-methoxybenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol 1 S, 2R) -1-. { 5- | (4-methoxybenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol 1 S, 2R) -1-. { 5 (2-chlorobenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol 1 S, 2R) -1-. { 5- | (3-chlorobenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol 1 S, 2R) -1-. { 5- (4-chlorobenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol 1 S, 2R) -1-. { 5- (2-fluorobenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 1 S, 2R) -1-. { 5- (3-fluorobenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 1 S, 2R) -1-. { 5 (4-fluorobenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 1 S, 2R) -3- (methylamino)) - 1-. { 5 - [(2-methylbenzyl) oxy] -1 H-indol-1-yl} -1-phenylpropan-2-ol 1 S, 2R) -3- (methylamino)) - 1-. { 5 - [(3-methylbenzyl) oxy] -1 H -indole-1-yl} -1-phenylpropan-2-ol 1 S, 2R) -3- (methylamino)) - 1-. { 5 - [(4-methylbenzyl) oxy] -1 H-indol-1-yl} -1-phenylpropan-2-ol 1 S, 2R) -3- (methylamino)) - 1-phenyl-1- [5- (1-phenylethoxy) -1 H -indol-1-yl] propan-2-ol; 1 S, 2R) -3- (methylamino)) - 1 -phenyl-1 - [5- (2-phenylethoxy) -1 H -indol-1-yl] propan-2-ol; 1 S, 2R) -3- (methylamino)) - 1- (5-phenoxy-1 H-indol-1-yl) -1-phenylpropan-2-ol; 1 S, 2R) -3- (methylamino)) - 1- (4-phenoxy-1 H-indol-1-yl) -1-phenylpropan-2-ol; 1 S, 2R) -3- (methylamino)) - 1-phenyl-1- (4-phenyl-1 H -indol-1-yl) propan-2-ol 1S, 2R) -3- (methylamino) )) - 1-phenyl-1 - (6-phenyl-1 H-indol-1-yl) propan-2-ol 1 S, 2 R) -3- (methi lamino)) - 1-phenyl-1 - (7 phenyl-1 H-indol-1-yl) propan-2-ol 1 S, 2 R) -1- [5- (benzyloxy) -1 H -indole-1-yl] -1 - (3-fluorophenyl) - 3- (methylamino) propan-2-ol; 1 S, 2R) -1- [5- (benzyloxy) -2,3-dihydro-1 H -indol-1 -yl] -1- (3-fluorophenyl) -3-methylamino) propan-2-ol; 1 S, 2R) -1 - [5- (benzyloxy) -2,3-dihydro-1 H -indol-1 -yl] -3- (methylamino) -1-phenylpropan-2-ol; 5'-chloro-1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' (1 'H) - ona; 6'-chloro-1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' (1 'H) - ona; 6'-fluoro-1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' (1 'H) - ona; '-fluoro-1 '- [(1S, 2R) -2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] esp? Ro [c? Clohexane-1, 3 '-? Ndol] -2' (1 'H) -one, 7'-chloro-1' - [(1 S, 2R) -2-h? Drox? -3- (met? Lam? No) - 1-phenylpropylene] [c-clohexane-1, 3'-? Ndol] -2 '(1' H) -one, 6'-fluoro-1 '- [(1 S, 2R) -1 - (3-fluorophen? L) -2-h? Drox? -3- (met? Lam? No) prop? L] sp? Ro [c? Clohexane-1, 3 '-? Ndol] -2' (1?) - ona, (1 S, 2R) -3- (met? Lam? No) -1-phen? L-1-esp? Ro [c? Clohexane-1, 3 '-? Ndol] -1 '(2?) -? Lpropan-2-ol, (1S, 2R) -1- (3-fluorophen? L) -3- (meth? Lam? No) -1-. { 3- [2- (tpfluoromethoxy?) Phen? L] -1H-? Ndol-1-? L} propan-2-ol, (1 S, 2 R) -1 - (3-fluorophen? l) -1 - [3- (2-? sopropox? phen? l) -1 H-? ndol-1 -? l] -3- (methanolamine) propan-2-ol, (1 S, 2R) -1- (3-fluorophen? L) -1- [3- (4-fluorophen? L) -1 H-? ndol-1-? l] -3- (meth? lam? no) propan-2-ol, (1 S, 2R) -1- (3-fluorophen? l) -3- (meth? lam? no) - 1- [3- (2-phenoxyphenol) -1 H-? Ndol-1-? L] propan-2-ol, (1 S, 2R) -1- [3- (2,4-d ? fluorophen?) -1 H-? ndol-1-? l] -1- (3-fluorophen? l) -3- (met? lam? no) propan-2-ol, (1 S, 2R) - 1 - [3- (2,5-d? Fluorophen? L) -1 H-? Ndol-1 -? L] -1- (3-fluorophen? L) -3- (meth? Lam? No) propan- 2-ol, (1 S, 2 R) -1- [3- (2,3-d? Methox? Phen? L) -1 H-? Ndol-1-? L] -1- (3-fluorophen? ) -3- (met? Lam? No) propan-2-ol, (1 S, 2R) -1- [3- (2,4-d? Chlorophen? L) -1 H-? Ndol-1-? l] -1- (3-fluorophen? l) -3- (meth? lam? no) propan-2-ol, (1 S, 2R) -1- [3- (2-ethoxy? phen? l) - 1 H-? Ndol-1-? L] -1- (3-fluorophen? L) -3- (meth? Lam? No) propan-2-ol, (1 S, 2R) -1 - (7-chloro -5-methox? -1 Hp? Rrolo [2,3-c] p? Pd? N-1 -? L) -1 - (3-fluorophen? L) -3- (meth? Lam? No) propan- 2-ol, (1S, 2R) -1- (7-chloro-5-met? L-1 Hp? Rrolo [2,3-c] p? Pd? N-1-? L) -3- ( met? lam? no) -1-phen? lpropan-2-ol, (1 S, 2R) -1 - (5-m etox? -1 H-pyrrolo [2,3-c] p? pd? n-1 -? l) -3- (meth? lam? no) -1-phenyl? -propan-2-ol, (1 S, 2 R) -1- (3-fluorophen? L) -1- (5-methox? -1 Hp? Rrolo [2,3-c] p? Pd? N-1-? L) -3- (methanolamine) propan-2-ol, (1S, 2R) -3- (meth? lam? no) -1- (5-met? l-1 Hp? rrolo [2,3-c] p? pd? n-1-? l) -1-phenolpropan-2-ol, (1S, 2R) -1- (3-fluorophen? L) -3- (meth? Lam? No) -1- (5-met? L-1 Hp? Rrolo [2,3-c] p? Pd ? n-1-? l) propan-2-ol, (1 S, 2R) -3- (meth? lam? no) -1- (7-met? l-1 Hp? rrolo [2,3-c ] p? pd? n-1-? l) -1-phenolpropan-2-ol, (1S, 2R) -1- (3-fluorophen? L) -3- (meth? Lam? No) -1- (7-met? L-1 Hp? Rrolo [2,3-c] p? R ? d? n-1-? l) propan-2-ol, (1 S, 2R) -1- (3,3-d? et? l-2,3-d? h? dro-1 H-? ndol-1-? l) -1- (3-fluorophen? l) -3- (meth? lam? no) propan-2-ol, (1 S, 2R) -1 - (6-fluoro-3,3) -d? met? l-2,3-d? h? dro-1 H-? ndol-1 -? l) -1 - (3-fluorofen? l) -3- (met? lam? no) propan- 2-ol, (1 S, 2 R) -1- (4-benzyl-3,4-d? -hydroquinone n-1 (2H) -? L) -1- (3-fluorophen? ) -3- (met? Lam? No) propan-2-ol, (1 S, 2R) -1- (5-fluoro-3,3-d? Met? L-2,3-d? H? Dro -1 H-? Ndol-1-? L) -1- (3-fluorophen? L) -3- (methalamine) propan-2-ol, (1 S, 2R) -1- (3- fluorofen? l) -3- (meth? lam? no) -1 - [(3S) -3-met? l-2,3-d? h? dro-1 H-? ndol-1-? l] propan -2-ol, (1 S, 2 R) -1 - (3-fluorophen? L) -3- (met? Lam? No) -1 - [(3R) -3-met? L-2,3-d H-dro-1 H-β-ndol-1 -? l] propan-2-ol, (1 S, 2R) -1- (3-fluorophen? l) -1- (3-? soprop? l-2 , 3-d? H? Dro-1 H-? Ndol-1-? L) -3- (met? Lam? No) propan-2-ol, (1 S, 2R) -1- (3-et? l-2,3-d? h? dro-1 H-? ndol-1-? l) -1- (3-fluorophen? l) -3- (met? lam? no) propan-2-ol, ( 1 S, 2R) -1- (3-et? L-2,3-d? H? Dro-1 H-? Ndol-1-? L) -3- (met? Lam? No) -1-phen ? lpropan-2-ol, (1S, 2R) -1 - (3-? Soprop? L-2,3-d? H? Dro-1 H-? Ndol-1 -? L) -3- (met? Lam? No) -1 -fen? lpropan-2-ol, (1S, 2R) -3-am? No-1- (3,5-d? Fluorophen? L) -1- (3,3-d? Met? L-2,3-d? 1 H-? Ndol-1-? L) propan-2-ol, 1 - [(1 S, 2R) -1- (3,5-d? Fluorophen? L) -2-h? Drox? -3- (methamphetamine) propylene] -7-fluoro-3,3-d? met? l- 1, 3-d? h? dro-2H-? ndol-2-one, 5,7-d ? fluoro-1 - [(1 S, 2R) -1- (3-fluorophen? l) -2-h? drox? -3- (met? lam? no) prop? l] -3,3-d? met? l- 1, 3-d? h? dro-2H-? ndol-2-one, 1 - [(1 S, 2R) -1- (3,5-d? fluorophen? l) -2-h Drox? -3- (met? lam? no) prop? l] -3,3-d? met? l-1, 3-d? h? dro-2H-? ndol-2-one, 1 - [ (1S, 2R) -2-h? Drox? -3- (met? Lam? No) -1-phenyl? -propyl] -1 H-? Ndol-5-ol, 1 - [(1 S, 2R) -1- (3-fluorophen? L) -2-h? Drox? -3- (met? Lam? No) prop? L] -1 H-? Ndol-5-ol 5 '- (benz? Lox) ?) - 1 '- [(1 S, 2R) -2-h? Drox? -3- (met? Lam? No) -1 - fen? lprop? l] esp? ro [c? clohexane-1, 3 '-? ndol] -2' (1?) - ona, 5- (benz? lox?) - 1 - [(1 S, 2R) -2-h? Drox? -3- (met? Lam? No) -1-pfen? Lprop? L] -3,3-d? Met? L-1, 3-d? H? Dro-2H-? ndol-2-one, 1 - [(1 S, 2R) -1 - (3-chlorophen? l) -2-h? drox? -3- (met? lam? no) prop? l] -7-fluoro -3,3-d? Met? L-1, 3-d? H? Dro-2 / - / -? Ndol-2-one, (1 S, 2R) -1- (3-chloro-5-fluorofen ? l) -1- (1 / - / -? ndol-1-? l) -3- (met? lam? no) propan-2-ol, 3-chloro-N-. { 1 - [(1 S, 2 R) -2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -1H-? Ndol-5-? L} -4-methylbenzamide, 3-chloro-N-. { 1 - [(1S, 2R) -2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -2,3-d? H? Dro-1H-? Ndol- 5-? L} benzamida, 3-chloro-N-. { 1 - [(1 S, 2 R) -2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -1H-? Ndol-5-? L} benzam? da, N-. { 1 - [(1 S, 2R) -2-h? Drox? -3- (met? Lam? No) -1-pfen? Lprop? L] -2,3-d? H? Dro-1 H-? ndol-5-? l} benzam? da, N-. { 1 - [(1 S, 2 R) -2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -1H-? Ndol-5-? L} benzam? da, N-. { 1 - [(1 S, 2R) -2-h? Drox? -3- (met? Lam? No) -1-pfen? Lprop? L] -2,3-d? H? Dro-1 H-? ndol-5-? l} c? Clohexanecarboxamide, N-. { 1 - [(1 S, 2 R) -2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -1H-? Ndol-5-? L} c? clohexanecarboxamide, N- (3-chlorophen? l) -1 - [(1 S, 2R) -2-h? drox? -3- (met? lam? no) -1-phen? lprop? l ]? ndol? na-5-carboxamide, N- (3-chlorophen? l) -1 - [(1 S, 2R) -2-h? drox? -3- (met? lam? no) -1-phen ? lprop? l] -1H-? ndol-5-carboxamide, 1 S, 2R) -3- (meth? lam? no) -1- (6-phenox? -1H-? ndol-1-? ) -1-phenolpropan-2-ol, 1S, 2R) -3- (meth? Lam? No) -1- (7-phenox? -1 H-? Ndol-1-? L) -1- fen? lpropan-2-ol, 1 S, 2R) -3-am? no-1- [5- (benz? lox?) - 1 H-? ndol-1-? l] -1-phen? lpropan- 2-ol, 1 S, 2R) -1- [5- (benz? Lox? -1 H-? Ndol-1 -? L] -3- (et? Lam? No) -1-phen? Lpropan-2 -ol, 1 S, 2R) -1- [5- (benc? lox? -1 H-? ndol-1 -? l] -1-phenyl? -3- (prop? lam? no) propan-2 -ol, 1 S, 2R) -1- [5- (benz? lox? -1 H-? ndol-1 -? l] -3 - (? soprop? lam? no) -1-phen? lpropan-2 -ol, 1 S, 2R) -1- [5- (benz? lox? -1 H-? ndol-1-? l] -3- (d? met? lam? no) -1-phen? lpropan- 2-ol, 1 S, 2R) -1- [5- (benz? Lox? -1 H-? Ndol-1-? L] -3- [et? L (met? L) am? No] -1 -fen? lpropan-2-ol, 1 S, 2R) -1- [5- (benz? lox? -1 H-? ndol-1-? l] -3- (d? et? lam? no) - 1-phenolpropan-2-ol, 1S, 2R) -1- [5- (benz? Lox? -1H-? Ndol-1-? L] -1-phenol-3-pyrrolidone ? d? n-1-? lpropan-2-ol, 1 S, 2R) -1- [5- (be nc? lox? -1H-? Ndol-1-? L] -1-phen? L-3-p? Pepd? N-1-? Lpropan-2-ol, (1 S, 2 R) -1 - [5- (benzyl lox?) - 1 H-? Ndol-1 -? L] -3- (4-met? Lp? Peraz? N-1 -? ) -1-phenyl-2-ol (1S, 2R) -3- (meth? Lam? No) -1-phen? L-1- [5- (p? Pd? N-2-? Lmethox? ) -1H-? Ndol-1-? L] propan-2-ol, (1S, 2R) -3- (meth? Lam? No) -1-phen? L-1- [5- (phen? Let? N? L) -1H-? Ndol-1-? L] propan-2 -ol, (1S, 2R) -3- (meth? lam? no) -1-phen? l-1- [5- (2-phen? let? l) -1H-? ndol-1-? l] propan-2-ol, 1 '- [(1S, 2R) -3-am? no-2-hydrox? -1-phen? -propyl] -6'-fluorosp? ro [c? clohexane-1 , 3 '-? Ndol] - 2' (1'H) -one, 1 '- [(1 S, 2R) -3- (et? Lam? No) -2-h? Drox? -1 -fen? lprop? l] -6'-fluorosp? ro [c-clohexane-1, 3'-? ndol] -2 '(1?) - one, 6'-fluoro-1' - [(1 S, 2R) - 2-h? Drox? -3 - (? Soprop? Lam? No) -1 -fen? Lprop? L] esp? Ro [c? Clohexane- 1,3 '-? Ndol] -2' (1?) - ona, 6'-fluoro-1 '- [(1S, 2R) -2-h? drox? -1-phen? l-3- (prop? lam? no) prop? l] sp? ro [c? clohexane -1.3 '-? Ndol] -2' (1?) - ona, 1 '- [(1S, 2R) -3-am? No-2-h? Drox? -1-phen? Lprop? L] -5'-fluoroesp? Ro [c-clohexane-1,3 '-? Ndol] -2' (1'H) -one, 1 '- [(1S, 2R) -3- (et? Lam? No) -2-h? Drox? -1-phen? Lprop? L] -5'-fluorosp? Ro [c? Clohexane-1,3 '-? Ndol] -2' (1?) - one, 5'-fluoro -1 '- [(1S, 2R) -2-h? Drox? -3 - (? Soprop? Lam? No) -1-phen? Lprop? L] esp? Ro [c? Clohexane- 1.3'- ? ndol] -2 '(1?) - ona, 5'-fluoro-1' - [(1S, 2R) -2-h? drox? -1-phen? l-3- (prop? lam? no) prop? l] esp? ro [c-clohexane-1,3 '-? ndol] -2' (1'H) -one, 1 '- [(1S, 2R) -3- (d? Met? Lam? No) -2-h? Drox? -1-phen? Lprop? L] -5'-fluorosp? Ro [c? Clohexane- 1 , 3 '-? Ndol] -2' (1?) - ona, 5'-fluoro-1 '- [(1 S, 2R) -2-h? Drox? -3-morphol? N-4-? -1-phenylpropyl] [c-clohexane-1, 3'-? Ndol] -2 '(1?) -one, 1' - [(1 S, 2R) -2-h? drox? -3- (met? lam? no) -1-phen? lprop? l] -5'-methox? esp? ro [c? clohexane-1,3 '-? ndol] -2' (1?) -one, 1 '- [(1S, 2R) -2-h? drox? -3- (met? lam? no) -1-phen? lprop? l] -6'-methox? esp? ro [c? clohexane - 1,3 '-? ndol] -2' (1?) - ona, 1 '- [(1S, 2R) -2-h? drox? -3- (met? lam? no) -1-phen ? lpropyl] -2'-oxo-1 ', 2'-d? h? d? ro? [c? clohexane-1,3' -? ndol] -5'-carbon? tr? lo, 1 '- [(1 S, 2R) -2-h? Drox? -3- (met? Lam? No) -1-phenyl? -propyl] -2'-oxo-1 ', 2'-d? H? Droesp ? ro [c-Clohexane-1,3 '-? ndol] -6'-carbon? tplo, 4', 5'-d? fluoro-1 '- [(1 S, 2R) -2-h? drox? -3- (met? Lam? No) -1-pfen? Lprop? L] esp? Ro [clohexane- 1,3'-indole] -2 '(1?) - one; 7'-fluoro-1 '- [(1 S, 2R) -1 - (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] spiro [cyclohexane-1,3'-indol] -2' ( 1?) - ona; 1 '- [(1 S, 2 R) -1- (3-chlorophenyl) -2-hydroxy-3- (methylamino) propyl] -6'-fluorospiro [cyclohexane-1,3'-indole] -2' (1 ?) - ona; 1 - [(1 S, 2R) -1 - (3-Chloro-5-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -7-fluoro-3,3-dimethyl-1,3-dihydro- 2H-indol-2-one; (1 S, 2R) -1- (3-Chloro-5-fluorophenyl) -1- (2,3-dihydro-1 H -indol-1-yl) -3- (methylamino) propan-2-ol; (1 S, 2R) -1 - (3-Chloro-5-fluorophenyl) -1 - (7-fluoro-3,3-dimethyl-2,3-dihydro-1 H -indole-1-yl) -3- (methylamino) propan-2-ol; (1 S, 2R) -1- (3-Chloro-5-fluorophenyl) -1- (3,3-dimethyl-2,3-dihydro-1 H -indol-1-yl) -3- (methylamino) propan -2-ol; 7'-fluoro-1 '- [(1 S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] spiro [cyclobutane-1,3'-indole] -2' ( 1?) - ona; 7'-fluoro-1 '- [(1 S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] spiro [cyclopentane-1,3'-indole] -2' ( 1?) - ona; 6-fluoro-1 - [(1 S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -3,3-dimethyl-1,3-dihydro-2H-indole 2-one; (1 S, 2 R) -1- (7-fluoro-2,3-dihydro-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 4-fluoro-3 - [(1 S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1-phenyl-1, 3-dihydro-2H-benzimidazole-2- ona; 4-fluoro-1 - (3-fluorophenyl) -3 - [(1 S, 2R) -1 - (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1,3-dihydro-2H -benzimidazol-2-one; 1 - [(1 S, 2R) -3-amino-1 - (3,5-difluorophenyl) -2-hydroxypropyl] -7-fluoro-3,3-dimethyl-1, 3-dihydro-2H-indole-2 -one; and pharmaceutically acceptable salts thereof, especially hydrochloride salt.

Some of the compounds of the present invention may contain chiral centers and such compounds may exist in the form of stereoisomers (ie, enantiomers). The present invention includes all such stereoisomers and any mixture 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 here, it refers to at least about 90 mol%, more preferably at least about 95 mol%, and more preferably at least about 98 mol% of the desired stereoisomer that is present relative to other possible stereoisomers. Preferred enantiomers can be Isolate from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by the methods described herein See, for example, Jacques, et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen, SH, et al, Tetrahedron, 33 2725 (1977), Ehel, The stereochemistry of Coal Compounds, (McGraw-Hill, NY, 1962), Wilen, SH Tables of Resolvmg Agents and Optical Resolutions, p 268 (EL Ehel, Ed, University of Notre Dame Press, Notre Dame, IN 1972) The present invention includes prodrugs of the compounds of formula I, II or III "Prodrug," as used herein, means a compound that is convertible by metabolic means (for example by hydrolysis) into a compound of formula I, II and lll Vanas 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 m Enzymology, vol 4, Academic Press (1985), Krogsgaard-Laren, et al, (ed) "Design and Application of Prodrugs," Textbook of Drug Design and Development, Chapter 5, 1 13-191 (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) Additionally, the compounds of formula I, II or III may exist in unsolvated forms as well as in pharmaceutically acceptable solvent solvated forms such as water, ethanol, and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purpose of the present invention In certain embodiments, the compounds of formula I, II, or III specifically exclude the following compounds 1- (1H-? Ndol-1-? L) -3- (4-met? Lp? Peraz? N-1-? L) -1-phen? Lpropan-2-ol, 1 - . 1 - (5-fluoro-1 H-? Ndol-1 -? L) -3- (4-met? Lp? Peraz? N-1 -? L) -1-phenyl? -propan-2-ol, 1- (1) -3-morpholine-4-l-1-phenolpropan-2-ol, 3-d? Methalamine) -1- (1 H-? Ndol-1-? l) -1-phen? lpropan-2-ol, 3- et? lam? no) -1- (1H-? ndol-1-? l) -1-phen? lpropan-2-ol, 1- 1 H-? Ndol-1-? L) -3 - (? Soprop? Lam? No) -1-phen? Lpropan-2-ol, 3-benzyl? -1) (1 H-? Ndol- 1 -? L) -1-phenyl? -propane-2-ol, 3- (c? Clohex? Lmet? L) am? No] -1 - (1 H-? Ndol-1 -? L) -1-phen ? lpropan-2-ol, 3- (c? clohex? lmet? l) am? no] -1- (3-met? l-1 H-? ndol-1-? l) -1-phen? lpropan- 2-ol, 3-? Soprop? Lam? No) -1- (3-met? L-1H-? Ndol-1-? L) -1-phenolpropan-2-ol, 1- 1 H-? ndol-1-? l) -3- (meth? lam? no) -1-phen? lpropan-2-ol, 3- et? lam? no) -1- (3-met? l-1 H-? ndol-1-? l) -1-phen? lpropan-2-ol, 1- 1 H-? ndol-1-? l) -1-phen? l-3-p? peraz? n-1-? lpropan -2-ol di, 1- 1 H-? Ndol-1 -? L) -1-phenyl-3 - [(p? R? D? N-4-? Lmet? L) am? No] propan -2-ol, 1- 5-chloro-1 H-? Ndol-1-? L) -1-phen? L-3-p? Pepd? N-1-? Lpropan-2-ol, 1- 1 H -? ndol-1-? l) -3- (met? lam? no) -1-phen? lpropan-2-ol, 3-am? no-1- (1 H-? ndol-1-? l) -1-phenolpropan-2-ol, 3- et? Lam? No) -1 - (5-fluoro-1 H- ? ndol-1 -? l) -1-phenyl? -propan-2-ol, 3-am? no-1 - (5-fluoro-1 H-? ndol-1 -? l) -1-phenyl-propan- 2-ol, 1- 5-fluoro-1 H-? Ndol-1 -? L) -3- (meth? Lam? No) -1-phenyl? -propan-2-ol, 3- met? Lam? No) -1- (3-met? L-1 H-? Ndol-1-? L) -1-phen? Lpropan-2-ol, 1- 1 H-? Ndol-1-? L) -3- (met ? lam?) -1-phen? lpropan-2-ol, 1- 1 H-? ndol-1-? l) -3- (meth? lam? no) -1-phen? lpropan-2-ol, 3-amin-1- (3-met? L-1 H-? Ndol-1-? L) -1-phen? Lpropan-2-ol, 3 et? L (met? L) am? No] -1- (1 H-? Ndol-1 -? L) -1-phenyl? -propan-2-ol, 1 5-chloro-1 H-? Ndol-1-? L) -3- (met? Lam? no) -1-phenolpropan-2-ol, 1-5-chloro-1 H-? ndol-1 -? l) -3- (meth? lam? no) -1-phen? lpropan-1-ol, 1-1 2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -1 H-? Ndol-3-carbon? Tplo, 1- '1 H-? Ndol-1-? L) -3- (met? Lam? No) -1-phen? Lpropan-2-ol, 1- 1 H-? Ndol-1-? L) -3 - (methanolamine) -1-phenolpropan-2-ol, 3- methalamine) -1- (3-met? l-1 H-? ndol-1-? l) -1 -fen? lpropan-2-ol, 1 -3-chlorophen? l) -1 - (1H-? ndol-1-? l) -3- (met? lam? no) propan-2-ol, 1- 4-chlorophen? L) -1 - (1H-? Ndol-1 -? L) -3- (meth? Lam? No) propan-2-ol, 1- 1 H-? Ndol-1-? L) -3- (met? Lam? No) -1- [3- (tpfluoromethoxy?) Phen? L] propan-2-ol, 1- 1 H-? Ndol-1-? L) -3- (met? Lam) ? no) -1- [2- (tr? fluorometox?) phen? l] propan-2-ol, 1- 1 H-indol-1-yl) -3- (methylamino) -1- [2- (trifluoromethoxy) phenyl] propan-2-ol; 1- 2-chlorophenyl) -1 - (1 H -indol-1 -yl) -3- (methylamino) propan-2-ol; 1- 1 H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol; 1- 1 H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol; 1- 1 H-indol-1-yl) -3- (methylamino) -1- [4- (trifluoromethoxy) phenyl] propan-2-ol; 4-amino-1- (3-chlorophenyl) -1 - (1 H -indol-1-yl) butan-2-ol 1- (3-bromophenyl) -1- (1 H -indol-1-yl) - 3- (methylamino) propan-2-ol; 3- [2-hydroxy-1- (1 H -indol-1-yl) -3- (methylamino) propyl] benzonitrile 1- (3-fluorophenyl) -1 - (1 H -indole-1-yl) -3 - (methylamino) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- [3- (3-methylphenyl) -1 H -indol-1-yl] propan-2-ol; 1- (4-fluorophenyl) -3- (methylamino) -1- (3-methyl-1 H-indol-1-yl) propan-2-ol; 1- (2-fluorophenyl) -1- (1 H -indol-1-yl) -3- (methylamino) propan-2-ol; 1- (4-fluorophenyl) -1 - (1 H -indol-1 -yl) -3- (methylamino) propan-2-ol; 1- (1 H-indol-1-yl) -3- (methylamino) -1- (3-methylphenyl) propan-2-ol; 1- (1 H-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol; 1- (1 H-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol; 3- (ethylamino) -1- (3-fluorophenyl) -1- (1 H -indol-1-yl) propan-2-ol; 1- (3-fluorophenyl) -1- (1 H -indol-1-yl) -3-morpholin-4-ylpropan-2-ol; 1- (3-fluorophenyl) -1- (1 H -indol-1-yl) -3- (propylamino) propan-2-ol; 1- (3-fluorophenyl) -1- (1 H -indol-1-yl) -3- (4-methylpiperazin-1-yl) propan-2-ol; 1 - (1 H-indol-1 -yl) -3- (methylamino) -1 - (4-methylphenyl) propan-2-ol; 1- (2,3-dihydro-1 H -indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (2,3-dihydro-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1 - [3- (2-methylphenyl) -1 H -indole-1-yl] propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- (2-methyl-2,3-dihydro-1 H-indol-1-yl) propan-2-ol; 1- (7-Fluoro-3,3-dimethyl-2,3-dihydro-1 H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1 - (7-fluoro-3,3-dimethyl-2,3-dihydro-1 H -indol-1 -yl) -3- (methylamino) -1-phenylpropan-2-ol; 3- (methylamino) -1 - (7-methyl-2,3-dihydro-1 H-indol-1-yl) -1-phenylpropan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- (7-methyl-2,3-dihydro-1 H -indol-1-yl) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- (5-methyl-2,3-dihydro-1 H-indol-1-yl) propan-2-ol; 1- (1 H-indol-1-yl) -1- (3-methoxyphenyl) -3- (methylamino) propan-2-ol; 1- (1 H-indol-1-yl) -1- (4-methoxyphenyl) -3- (methylamino) propan-2-ol; 3- (methylamino) -1 - (2-methy1-1 H-indol-1-yl) -1-phenylpropan-2-ol; 1 - . 1 - (1 H-benz? Dazol-1 -? L) -3- (meth? Lam? No) -1-phenyl? -propan-2-ol, 3- (met? Lam? No) -1 - (2-met? L-1 H-benc? M? Dazol-1 -? L) -1-phenyl? -propan-2-ol, 1- (4-methox? -1H-? Ndol-1-? L) -3- (methanolamine) -1-phenolpropan-2-ol, 1- (5-fluoro-1 H-? Ndol-1-? L) -3- (meth? Lam? No) - 1-phenolpropan-2-ol, 1- (5-methox? -1H-? Ndol-1-? L) -3- (meth? Lam? No) -1-phen? Lpropan-2-ol, 1- (7-methox? -1 H-? Ndol-1-? L) -3- (meth? Lam? No) -1-phen? Lpropan-2-ol, 1- (4-methox? -1 H -? ndol-1-? l) -3- (met? lam? no) -1-phen? lpropan-2-ol, 1 - (6-methox? -1 H-? ndol-1 -? l) - 3- (methamphenoxy) -1-phenopropan-2-ol, 1- (5-methox? -1 H-? Ndol-1-? L) -3- (meth? Lam? No) - 1-Phenolpropan-2-ol, 1- (3-fluorophen? L) -1- (6-methox? -1 H-? Ndol-1-? L) -3- (methamphenone) propan -2-ol, 3- (met? Lam? No) -1-phenyl? -1- (1 Hp? Rrolo [2,3-b] p? Pd? N-1 -? L) propan-2- ol, 1 - (5-chloro-2,3-d? h? dro-1 H-? ndol-1 -? l) -1 - (3-fluorofen? l) -3- (met? lam? no) propan-2-ol, 3- (meth? lam? no) -1-phen? l-1- (1 Hp? rrolo [2,3-c] p? pd? n-1-? l) propan-2 -ol, 1- (5-fluoro-1 H-? ndol-1-? l) -1- (3-fluorophen? l) -3- (meth? lam? no) propan-2-ol, 3- ( met? lam? no) -1- (3-fluorofen? l) -1- (1 Hp? rro [2,3-c] p? pd? n-1-? l) propan-2-ol, 1- (5-chloro-2,3-d? h? dro-1 H-? ndol-1- l) -3- (methanolamine) -1-phenolpropan-2-ol, 3- (meth? lam? no) -1- (6-met? l-1 H-? ndol-1 -? l) -1-phen? lpropan-2-ol, 3- (met? lam? no) -1- (7-met? l-1 H-? ndol-1-? l) -1-phen? lpropan-2-ol, 1- (3-fluorophen? l) -3- (meth? lam? no) -1- (5-met? l-1 H-? ndol-1-? l) propan-2- ol, 1 - (3-fluorophen?) -3- (methalamine) -1- (7-met? l-1 H-? ndol-1 -? l) propan-2-ol, 3- (met? lam? no) -1 - (4-met? l-1 H-? ndol-1 -? l) -1-phenyl? -propan-2-ol, 3- (met? lam? no) -1 - (5-met? L-1 H-? Ndol-1-? L) -1-phen? Lpropan-2-ol, 1- (3-fluorophen? L) -3- (met? Lam? No) - 1- (4-met? L-1 H-? Ndol-1-? L) propan-2-ol, 1- (3-et? L-1 H-? Ndol-1-? L) -1- ( 3-fluorophen? L) -3- (meth? Lam? No) propan-2-ol, 1- (3-fluorophen? L) -3- (met? Lam? No) -1- (3-phen? -1H-? Ndol-1-? L) propan-2-ol, 7-fluoro-1- [2h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -3 , 3-d? Met? L-1, 3- d? H? Dro-2H-? Ndol-2-one, 1- [2h? Drox? -3- (met? Lam? No) -1-fen? lprop? l] -3,3-d? met? l-1, 3-d? h? dro-2H-? ndol-2-one, 7-fluoro-1 - [1 - (3-fluorophen? L) -2-h? Drox? -3- (met? Lam? No) prop? L] -3,3-d? Met? L-1, 3-d? H? Dro-2H-? Ndol-2-one, 1- (1 H-? Ndol-1-? L) -3- (met? Lam? No) -1- (2-th? Enyl) ) propan-2-ol, 1 (1 H-? ndol-1-? l) -3- (meth? lam? no) -1- (2-th? enyl) propan-2-ol, 1 '- [ 2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] esp? Ro [c? Clohexane-1, 3 '-? Ndol] -2' (1?) - ona , 2- (3-fluorophen? L) -2- (1H-? Ndol-1 -? L) -1 - [(2S) -p? Rrol? D? N-2-? L] ethanol, 2- (3-fluorophenyl) -2- (1 H -indol-1 -yl) -1 - [pyrrolidin-2-yl] ethanol; 1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclobutane-1,3'-indole] -2' (1?) -one; 1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclopentane-1,3'-indole] -2' (1?) -one; 1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclopropane-1,3'-indo] -2' (1?) -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- (1 H -indol-1-yl) propan-2-ol; 7'-fluoro-1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' (1 'H) -one; 5'-bromo-1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' (1 'H) -one; 1- (3-fluorophenyl) -1 - [3- (2-fluorophenyl) -1 H -indol-1 -yl] -3- (methylamino) propan-2-ol; 1- [3- (3,4-dichlorophenyl) -1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (3-fluorophenyl) -1 - [3- (3-fluorophenyl) -1 H -indol-1 -yl] -3- (methylamino) propan-2-ol; 1- (5-fluoro-3-methyl-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 3-amino-1- (5-fluoro-3-methyl-1 H-indol-1-yl) -1-phenylpropan-2-ol; 1- (5-chloro-3-methyl-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 3 amino1- (5-chloro-3-methyl-1 H-indol-1-yl) -1-phenylpropan-2-ol; [3- (5-chloro-3-methyl-1 H -indol-1-yl) -2-methoxy-3-phenylpropyl] methylamine; 1- (7-chloro-3-methyl-1 H -indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; [3- (5-fluoro-3-methyl-1 H-indol-1-yl) -2-methoxy-3-phenylpropyl] methylamine; 1- (4-bromo-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (4-bromo-1 H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (5-bromo-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (5-bromo-1 H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1 - [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1 H -indole-4-carbonitrile; 1- (6-bromo-1 H-indol-1 -yl) -3- (methylamino) -1-phenylpropan-2-ol; 1 - [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1 H -indole-5-carbonitrile; 1 - [1 - (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1 H -indole-4-carbonitrile; 1- (6-bromo-1 H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (6-fluoro-1 H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 3-amino-1- (3-fluorophenyl) -1- (1 H -indol-1-yl) propan-2-ol; 1- (7-bromo-1 H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1 H-indol-1-yl) -3- (methylamino) -1 - [3- (trifluoromethyl) phenyl] propan-2-ol; 3-fluorophenyl) -3- (methylamino) -1-spiro [cyclohexane-1,3'-indole] -1 '(2?) - ilpropan-2-ol; 2,3-dihydro-1 H-indol-1-yl) -3- (methylamino) -1- [3- (trifluoromethyl) phenyl] propan-2-ol; 3-fluorophenyl) -1- (1 H -indol-1-yl) -3- (methylamino) propan-2-ol; 3,4-difluorophenyl) -1- (1 H -indol-1-yl) -3- (methylamino) propan-2-ol; 3-fluorophenyl) -3- (methylamino) -1- (3-methyl-1 H-indol-1-yl) propan-2-ol; 4-chloro-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 6-chloro-1H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 7-chloro-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 7-chloro-1 H-indol-1-yl) -1 - (3-fluorophenyl) -3- (methylamino) propan-2-ol; 4-chloro-1 H-indol-1-yl) -1 - (3-fluorophenyl) -3- (methylamino) propan-2-ol; 6-chloro-1 H-indol-1 -yl) -1 - (3-fluorophenyl) -3- (methylamino) propan-2-ol; 5-chloro-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 5-chloro-1 H-indol-1-yl) -1 - (3-fluorophenyl) -3- (methylamino) propan-2-ol; 3-isopropyl-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 3-fluorophenyl) -1 - (3-isopropyl-1 H -indol-1 -yl) -3- (methylamino) propan-2-ol; 3,5-difluorophenyl) -1- (1 H -indol-1-yl) -3- (methylamino) propan-2-ol; 3,5-difluorophenyl) -1- (2,3-dihydro-1 H -indol-1-yl) -3- (methylamino) propan-2-ol; 4-amino-1- (3-fluorophenyl) -1- (1 H-indol-1-yl) butan-2-ol; 3,3-dimethyl-2,3-dihydro-1 H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 3,5-difluorophenyl) -1- (3,3-dimethyl-2,3-dihydro-1 H -indol-1-yl) -3- (methylamino) propan-2-ol 3,3- dimethyl-2,3-dihydro-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 3-fluorophenyl) -3- (methylamino) -1- (3-methyl-2,3-dihydro-1 H-indol-1-yl) propan-2-ol; 3-fluorophenyl) -3- (methylamino) -1-spiro [cyclopentane-1,3'-indol] -1 '(2'H) -ylpropan-2-ol; 3-fluorophenyl) -1 - [3- (4-methoxyphenyl) -1 H -indol-1 -yl] -3- (methylamino) propan-2-ol; 3-fluorophenyl) -3- (methylamino) -1- [3- (4-methylphenyl) -1 H -indol-1-yl] propan-2-ol; 3- (4-tert-Butylphenyl) -1 H -indol-1 -yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 3-fluorophenyl) -1 - [3- (3-methoxyphenyl) -1 H -indol-1 -yl] -3- (methylamino) propan-2-ol; 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-1 H-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) -1 H -indol-1-yl] -3- (methylamino) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1-. { 3- [3- (trifluoromethyl) phenyl] -1 H -indole-1-yl} propan-2-ol; 3-amino-1- (3-methyl-1 H-indol-1-yl) -1-phenolpropan-2-ol; 1- (7-fluoro-3-methyl-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 3-amino-1- (7-fluoro-3-methyl-1 H-indol-1-yl) -1-phenylpropan-2-ol; 1 - (7-fluoro-1 H-indol-1 -yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (4-fluoro-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (7-fluoro-1 H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (4-fluoro-1 H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- [5- (trifluoromethyl) -1 H -indol-1-yl] propan-2-ol; 1 - (6-fluoro-1 H-indol-1 -yl) -3- (methylamino) -1-phenylpropan-2-ol; 3- (methylamino) -1-phenyl-1- [6- (trifluoromethyl) -1 H -indol-1-yl] propan-2-ol; 3- (methylamino) -1-phenyl-1 - [5- (trifluoromethyl) -1 H -indol-1-yl] propan-2-ol; 1- (3-tert-Butyl-1 H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (1 H-indol-1-yl) -2-methyl-3- (methylamino) -1-phenylpropan-2-ol; 3- (1 H-indol-1-yl) -1- (methylamino) -3-phenylbutan-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-2H-benzimidazol-2-one; 1-ethyl-4-fluoro-3- [2-hydroxy-3- (methylamino) -1- (3-fluorophenyl) -propyl] -1,3-dihydro-2H-benzimidazol-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) -1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1 - [3- (2-chlorophenyl) -1 H -indol-1 -yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1 - (2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol; 3- (methylamino) -1 - (4-methyl-3,4-dihydroquinoxalin-1 (2H) -yl) -1-phenylpropan-2-ol; 3- (methylamino) -1-phenyl-1 - [4- (2,2,2-trifluoroethyl) -3,4-dihydroquinoxalin-1 (2H) -yl] propan-2-ol; 1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -1- (3,5-difluorophenyl) -3- (methylamino) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- (2-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) propan-2-ol; 1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol; 3- (methanolamine) -1 - (6-met? L-2,3-d? H? Dro-4H-1, 4-benzoxaz? N-4-? L) -1-phen? Lpropan -2-ol, 1- (6-chloro-2,3-d? -hydro-4H-1, 4-benzoxaz? N-4-? L) -3- (met? Lam? No) -1- fen? lpropan-2-ol, 1- (6-chloro-2,3-d? h? dro-4H-1, 4-benzoxaz? n-4-? l) -3- (met? lam? no) -1-phenolpropan-2-ol, 1- (6-chloro-2,3-d? H? Dro-4H-1,4-benzoxaz? N-4-? L) -1- (3-fluorofen (l) -3- (methanolamine) propan-2-ol, 1- (2,2-d? met? l-2,3-d? h? dro-4H-1, 4-benzoxaz? n-4-? l) -1- (3-fluorophen? l) -3- (meth? lam? no) propan-2-ol, 1- (2,2-d? met? l-2,3- d? h? dro-4H-1, 4-benzoxaz? n-4-? l) -3- (meth? lam? no) -1-phen? lpropan-2-ol, 1 - (2,3-d) H-dro-4H-1, 4-benzot? az? n-4-? l) -1 - (3-fluorophen? l) -3- (methamphene) propan-2-ol, 1- (3-fluorophen? L) -3- (meth? Lam? No) -1- (2-phen? L-2,3-d? H? Dro-4H-1, 4-benzoxaz? N-4 -? l) propan-2-ol, 1- (3-fluorophen? l) -3- (meth? lam? no) -1- [2-phen? l-2,3-d? h? dro-4H -1, 4-benzoxaz? N-4-? L] propan-2-ol, 1- (3-fluorophen? L) -3- (meth? Lam? No) -1- [2-phen? L-2 , 3-d? H? Dro-4H-1, 4-benzoxaz? N-4-? L] propan-2-ol, and pharmaceutically acceptable salts of these The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized, for example, by methods described below, or variations on them as can be appreciated by those skilled in the art. TECHNICAL All processes described in association with the present invention are contemplated to be practiced at any scale, including milligrams, grams, multigrade, kilograms, multikilograms or commercial industrial scale As can be easily understood, the present functional groups may contain protecting groups during the course of the synthesis. Protective groups are per se known as chemical functional groups which can be selectively linked to, or removed from functionalities, such as hydroxyl groups and carboxyl groups These groups are present in a chemical compound to render such functionality inert to the conditions of the chemical reaction to which the compound is exposed. Any of a variety of protecting groups can be employed with the present invention. you can employed in accordance with the present invention can be described in Greene, T W and Wuts, P G M, Protective Groups in Organic Synthesis 2d Ed, Wiley & Sons, 1991 The compounds of the present invention are suitably prepared according to the following general description and specific examples. The variables used are as defined for Formula I, unless otherwise noted. The reagents used in the preparation of the compounds of this invention can be obtained commercially or can be prepared by standard procedures described in the literature The compounds of this invention contain chiral centers, which provide various stereoisomeric forms such as enantiomeric mixtures as well as optical isomers. Individual optical isomers can be prepared directly by asymmetric and / or stereospecific synthesis or by conventional chiral separation of optical isomers from the enantiomeric mixture.

The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized, for example, by the methods described below, or variations of them, can be appreciated by those skilled artisans. All processes described in association with the present invention are contemplated to be practiced at any scale, including milligram, gram, multigram, kilogram, multicyclone or industrial commercial scale. The compounds of the present invention are suitably prepared according to the following general description and Specific Examples The variables used are as defined for Formula I unless otherwise stated. The reagents used in the preparation of the compounds of this invention may be obtained commercially or may be prepared by standard procedures described in the literature.

The compounds of this invention contain chiral centers, provide various stereoisomeric forms such as enantiomeric mixtures as well as optical isomers. Individual optical isomers can be prepared directly by asymmetric and / or stereospecific synthesis or by conventional chiral separation of optical isomers from the mixture. enantiomépca As will be readily understood, the present functional groups may contain protecting groups during the course of the synthesis. The protection groups are known per se as chemical functional groups that can be selectively linked to and removed from functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to convert such functionality to inert in the chemical reaction conditions to which the compound is exposed. Any of a variety of protection groups can be employed with the present invention. Protection groups that can be employed in accordance with the present invention can be described in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons, 1991.

According to this invention, the compounds of formula I are produced by the following reaction schemes (Schemes I to IV). Depending on the desired diastereomer, the compounds can be prepared via two different synthetic routes (A and B, Schemes I and II). If desired to synthesize compounds of formula Na, they can be prepared from the compounds of formula 1. by selectively converting the primary alcohol to a leaving group and displacing it with a desired amine. (Route A, Scheme I) Any conventional method for the selective conversion of a primary alcohol to a leaving group, and any conventional method for displacing a primary leaving group with an amine can be used for this conversion. According to the preferred embodiment of this invention, the diol of the formula 1 is treated with para-toluenesulfonyl chloride in pyridine to form the tosylate of the formula 2, which is converted into the compound of the formula Isa by treatment with an excess of alcoholic amine solution, at room temperature or heated to about 40 ° C to about 80 ° C in a sealed tube. The compounds of the formula a can be converted to a pharmaceutically acceptable salt using any conventional method.

Scheme I the Where A, X, Y, Z, R ,, m, R2, R4, R8, R9, R, 0, R ,, are as previously described R3 = C, lower C-alkyl, P = protective group, preferably tpmethylsilyl, tert-butyldimethylsilyl, para-nitrobenzoyl, and OTs = para-toluenesulfonilate or any conventional leaving group If desired to form compounds of formula I-aa, they can be prepared from the compounds of formula 1 by selective protection of the primary alcohol, followed by alkylation of the secondary alcohol, and deprotection of the primary alcohol. Any alcohol protecting groups Conventional methods used for this conversion and any method for the selective protection of a primary alcohol can be employed. In accordance with the preferred embodiment of this invention, the reaction is carried out at low temperature in dichloromethane with tpmethylshyl chloride and tetylamine as the base for forming compounds of formula 3 The alkylation of the secondary alcohol is can be achieved by any conventional method of alkylation of a secondary alcohol found in the literature. According to the preferred embodiment of this invention, the compounds of formula 3 are reacted with an alkyl halide using sodium hydride as the base to form compounds of formula 4, which can be deprotected to form compounds of formula 5 via any conventional method for deprotection of a primary alcohol. According to the preferred embodiment of this invention, the compounds of formula 4 are treated with dilute aqueous hydrochloric acid or trifluoroacetic acid in dichloromethane to form compounds of formula 5. The conversion of the primary alcohol into compounds of formula 5 completes the synthesis of the compounds of formula I-aa which can be developed as previously described for the synthesis of the compounds of formula 1-a. The compounds of formula I-aa can be converted to a pharmaceutically acceptable salt using any conventional method.

Alternatively, the compounds of formula 6 can be prepared directly from the compounds of formula 2. Any method for alkylating a hydroxyl group in the presence of a tosyl group can be used for this conversion. According to the preferred embodiment of this invention, the compounds of formula 2 are treated with an alkyl trifluoromethanesulfonate, for example methyl trifluoromethanesulfonate, in the presence of a hidden base, for example 2,6-di-tert-butyl-4 -methylpyridine. The reaction can be run at room temperature or heated to about 40 ° C to about 80 ° C. Compounds of formula 6 can be converted to compounds of formula I-aa as previously described for the synthesis of compounds of formula Ia. The compounds of formula I-aa can be converted to a pharmaceutically acceptable salt using any conventional method.

If desired to form j ^ b compounds, they can also be prepared from compounds of formula 1 via Route B (Scheme ii). This route involves the selective protection of the primary alcohol followed by the conversion of the secondary alcohol to a leaving group. Any conventional method for the selective protection of a primary alcohol, and any conventional method for the conversion of a secondary alcohol into a leaving group can be used for this conversion. According to the preferred embodiment of this invention, the compounds of formula _ are treated with para-nitrobenzoyl chloride in pyridine at low temperature (preferably below about 0 ° C) to form compounds of formula 7. The compounds of formula 7 can be converted to a secondary mesylate of formula 8 by reaction with methanesulfonyl chloride in dichloromethane using triethylamine as the base. The reaction is preferably carried out at temperatures between about -15 ° C and about 10 ° C. Deprotection of the primary alcohol in compounds of formula 8 allows during the formation of a primary epoxide through a sn2 reaction resulting in an inversion of the stereocenter. Any conventional method for deprotection of a primary alcohol, and any conventional method for the formation of the epoxide in an alpha leaving group can be used for this conversion. According to the preferred embodiment of this invention, the compounds of formula 8 are treated with an aqueous solution of a suitable base in an organic solvent, preferably, aqueous sodium hydroxide in dioxane. The resulting epoxide of formula 9 can be a regioselectively open ring with an amine to produce the desired aminoalcohol of the formula i ^ b. Any conventional method for opening the regioselective ring of a primary epoxide can be employed for this conversion. According to the preferred embodiment of this invention, the compounds of formula 9 are treated with an excess of an alcoholic amine solution in a sealed flask, at room temperature or heated to about 40 ° C to about 90 ° C. of the formula Nb can be converted to a pharmaceutically acceptable salt using conventional methods.

SCHEME II l-b Where A, X, Y, Z, R, m, R2, and R, R8, R, 0, Rn are as previously described R9 is H PNB = para-nitrobenzoyl or any conventional protecting group, and OMs = methanesulfonate or any conventional outgoing group If desired to form compounds of formula l-bb, they can be made from compounds of formula Nb by protection of the amine, alkylation of the secondary alcohol and deprotection of the amine (Scheme III). Any conventional method for protection of an amine, alkylation of a secondary alcohol, and deprotection of an amine can be used for this conversion. In accordance with the preferred embodiment of this invention, the compounds of formula Nb are treated with boc anhydride, wherein boc = tert-butoxycarbonyl, form compounds of formula Which can be alkylated with an alkyl halide using sodium hydride as the base to form compounds of formula 11. Deprotection is achieved by using an acid, preferably tpfluoroacetic acid in dichloromethane to form compounds of formula l-bb which can be converted into a pharmaceutically acceptable salt using conventional methods SCHEME lll Nb 10 11 l-bb Where: A, X, Y, Z, R, m, R2, and R4, R8, R, 0, Rn are as previously described R9 is H R3 = lower C3 alkyl, P = protecting group, preferably tert-butoxycarbonyl The compounds of formula 1_ are formed via a regio- and stereo-selective opening of the ring of an appropriately substituted epoxide of formula 13 (formed via an epoxidation of an appropriately substituted allyl alcohol 14) with an appropriately substituted compound of formula 12 (Scheme IV). Any conventional method for the regio- and stereo-selective opening of the epoxide ring can be used for this conversion. According to the preferred embodiment of this invention, the compounds of formula 12 are treated with a base, for example sodium hydride, sodium tert-butoxide, potassium hydroxide, potassium tert-butoxide or potassium hydroxide, then treated with the epoxide of formula 13. The epoxide of formula 13 can be pre-treated with a Lewis acid, for example / titanium so-propoxide, boron trifluoride, etc. to ensure the regioselective opening of the ring. The reaction occurs at room temperature for a duration of about 2 hours to about 72 hours. Alternatively, compounds of formula 12 which are suitably nucleophilic, for example indoline, can be heated with the epoxide of formula 13 at temperatures from about 50 ° C to about 170 ° C to form compounds of formula 1.

The epoxidation of trans-allylic alcohols 14 can be developed racemically or asymmetrically using the methods described in the literature. In accordance with the preferred embodiment of this invention, the racemic epoxidation is conducted with any paracetic acid or mera-chloroperbenzoic acid. If desired to produce a single enantiomer of the compounds of formula I, the asymmetric epoxidation of an allyl alcohol can be developed with fer-t-butylhydroperoxide or eumenohydroperoxide in the presence of the appropriate tartrate ester, titanium (IV) isopropoxide, and molecular sieves. This method is well established in the literature (eg K. B. Sharpless, et al., J. Org. Chem. 1986, 51, 3710). The compounds of formula 12 and the starting allylic alcohols 14 are available from commercial sources or are accessible through well-established methods in the literature.

Scheme IV Where A, X, Y, Z, R ,, m, R2, R8, R9, R, 0 and Rn are as previously described According to this invention, the compounds of formula M are produced by the following reaction schemes (Schemes V to VIII) Depending on the desired diastereomer, the compounds can be prepared by two different synthetic routes (A and B)., Schemes V and VI) If desired to synthesize compounds of formula INa, they can be prepared from the compounds of formula 15 by selectively converting the primary alcohol to a leaving group and displacing this with a desired amine (Route A, Scheme V) Any conventional method for the selective conversion of a primary alcohol to a leaving group, and any conventional method for displacing a primary leaving group with an amine can be used for this conversion. According to the preferred embodiment of this invention, the diol of Formula 15 is treated with para-toluenesulfonyl chloride in pipdin to form the tosylate of formula 16, which is converted into the compound of the formula INa by treatment with an excess of alcoholic amine solution, at room temperature or heated to about 40 ° C to about 80 ° C in a sealed tube The compounds of the formula INa can be converted to a pharmaceutical salt. you are acceptable using any conventional method Scheme V Where: A, D, E, G, q, R2, R4, R8, Rg, Rio, and R? 4 are as previously described. R3 = C, lower C4 alkyl, P = protecting group; preferably trimethylsilyl, tert-butyldimethylsilyl, para-nitrobenzoyl; and OTs = para-toluenesulfonilate or any conventional leaving group If desired to form compounds of formula ll-aa, they can be prepared from the compounds of formula 1.5 by selective protection of the primary alcohol, followed by alkylation of the secondary alcohol, and deprotection of the primary alcohol. Any conventional alcohol protecting groups can be used for this conversion and any method for the selective protection of a primary alcohol can be employed. According to the preferred embodiment of this invention, the reaction is carried out at low temperature in dichloromethane with trimethylsilyl chloride and triethylamine as the base to form compounds of formula 17. The alkylation of the alcohol secondary can be achieved by any conventional method of alkylation of a secondary alcohol found in the literature. In accordance with the preferred embodiment of this invention, the compounds of formula 17 are reacted with an alkyl halide using sodium hydride as the base to form compounds of formula 18, which can be deprotected to form compounds of formula 19 by any conventional method for deprotection of a primary alcohol. In accordance with the preferred embodiment of this invention, the compounds of formula 18 are treated with hydrochloric acid. diluted aqueous or tpfluoroacetic acid in dichloromethane to form compounds of formula 19 The conversion of the primary alcohol to compounds of formula 19 to complete the synthesis of the compounds of formula ll-aa which can be developed as previously described for the synthesis of the compounds of Formula ll-a The compounds of the formula ll-aa are p They can be converted to a pharmaceutically acceptable salt using any conventional method Alternatively, the compounds of formula 20 can be prepared directly from the compounds of formula 16 Any method for alkylating a hydroxyl group in the presence of a tosyl group can be employed for this conversion. According to the preferred embodiment of this invention, the Compounds of formula 16 are treated with an alkyl t-fluoro-methanesulfonate, for example methyl t-fluoro-methane-sulfonate, in the presence of a hidden base, for example 2,6-d-tert-but-l-4-met? lp? pd? na The reaction can be run at room temperature or heated to about 40 ° C to about 80 ° C. Compounds of formula 20 can be converted to compounds of formula ll-aa as previously described for the synthesis of the compounds of formula II The compounds of the formula IIa can be converted to a pharmaceutically acceptable salt using any conventional method If desired to form iNb compounds, they can also be prepared from compounds of formula 15 via Route B (Scheme VI) This route involves the selective protection of the primary alcohol followed by the conversion of the secondary alcohol to a group Any conventional method for the selective protection of a primary alcohol, and any conventional method for the conversion of a secondary alcohol to a leaving group can be used for this conversion. According to the preferred embodiment of this invention, the compounds of formula 15 are treated with para-nitrobenzoyl chloride in pyridine at low temperature (preferably below about 0 ° C) to form compounds of formula 21. The compounds of formula 21 can be converted to a secondary mesylate of formula 22 by Reaction pathway with methanesulfonyl chloride in dichloromethane using triethylamine as the base. The reaction is preferably carried out at temperatures between about -15 ° C and about 10 ° C. Deprotection of the primary alcohol in compounds of formula 22 allows during the formation of a primary epoxide through a sn2 reaction resulting in an inversion of the stereocenter. Any conventional method for deprotection of a primary alcohol, and any conventional method for the formation of the epoxide in an alpha leaving group can be used for this conversion. According to the preferred embodiment of this invention, the compounds of formula 22 are treated with an aqueous solution of a suitable base in an organic solvent, preferably, aqueous sodium hydroxide in dioxane. The resulting epoxide of formula 23 can be a regioselectively open ring with an amine to produce the desired aminoalcohol of the formula iNb. Any conventional method for opening the regioselective ring of a primary epoxide can be employed for this conversion. According to the preferred embodiment of this invention, the compounds of formula 23 are treated with an excess of an alcoholic amine solution in a sealed flask, at room temperature or heated to about 40 ° C to about 90 ° C. of the formula iNb can be converted to a pharmaceutically acceptable salt using conventional methods.

SCHEME VI Where: A, D, E, G, q, R2, and R4, R8, Rio, and R are as previously described; R9 is H PNB = para-nitrobenzoyl or any conventional protecting group; and OMs = methanesulfonate or any conventional leaving group If desired to form compounds of formula IIb, they can be made from compounds of formula Nb by protection of the amine, alkylation of the secondary alcohol and deprotection of the amine (Scheme VII). Any conventional method for protection of an amine, alkylation of a secondary alcohol, and deprotection of an amine can be used for this conversion. According to the preferred embodiment of this invention, the compounds of formula INb are treated with boc anhydride, wherein boc = tert-butoxycarbonyl, to form compounds of formula 24 which can be alkylated with an alkyl halide using sodium hydride as the base to form compounds of formula 25. Deprotection is achieved by using an acid, preferably trifluoroacetic acid in dichloromethane to form compounds of formula IIb which can be converted into a pharmaceutically acceptable salt using conventional methods.

SCHEME Vil ll-bb Where: A, D, E, G, q, R2, and R, R8, R10, and R14 are as previously described; R9 is H R3 = C, lower C3 alkyl, P = protecting group, preferably tert-butoxycarbonyl The compounds of formula 15 are formed via a regio- and stereo-selective opening of the ring of an appropriately substituted epoxide of formula 13 (formed via an epoxidation of an appropriately substituted allyl alcohol 14) with an appropriately substituted compound of formula 26 (Scheme IV). Any conventional method for the regio- and stereo-selective opening of the epoxide ring can be used for this conversion. According to the preferred embodiment of this invention, the compounds of formula 26 are treated with a base, for example sodium hydride, sodium tert-butoxide, potassium hydroxide, potassium tert-butoxide or potassium hydroxide, then treated with the epoxide of formula 13. The epoxide of formula 13 can be pre-treated with a Lewis acid, for example / titanium so-propoxide, boron trifluoride, etc. to ensure the regioselective opening of the ring. The reaction occurs at room temperature for a duration of about 2 hours to about 72 hours. Alternatively, compounds of formula 26 that are suitably nucleophilic, for example indoline, can be heated with the epoxide of formula 13 at temperatures from about 50 ° C to about 170 ° C to form compounds of formula 15.

The epoxidation of trans-allylic alcohols 14 can be developed racemically or asymmetrically using the methods described in the literature. According to the preferred embodiment of this invention, the racemic epoxidation is conducted with any paracetic acid or meta-chloroperbenzoic acid. If desired to produce a single enantiomer of compounds of formula M, the asymmetric epoxidation of an allyl alcohol can be developed with urea-butylhydroperoxide or eumenohydroperoxide in the presence of the appropriate tartrate ester, titanium (IV) isopropoxide, and sieves molecular This method is well established in the literature (for example, K. B. Sharpless, e.,., J. Org. Chem. 1986, 51, 3710). The compounds of formula 26 and the starting allylic alcohols 13 are available from commercial sources or are accessible through well-established methods in the literature.

Scheme VIII 14 Where: A, D, E, G, q, R2, R8, R9, R10 and R, 4 are as previously described.

In accordance with this invention, the compounds of formula M [are produced by the following reaction schemes (Schemes IX to XII). Depending on the desired diastereomer, the compounds can be prepared via two different synthetic routes (A and B, Schemes IX and X). If desired to synthesize compounds of formula III-a, they can be prepared from the compounds of formula 27 by selectively converting the primary alcohol to a leaving group and displacing this with a desired amine. (Route A, Scheme IX) Any conventional method for the selective conversion of a primary alcohol to a leaving group, and any conventional method for displacing a leaving group of a ppmario with an amine can be used for this conversion. According to the preferred embodiment of this invention, the diol of the formula 27 is treated with para-toluenesulfonyl chloride in pyridine to form the tosylate of the formula 28, which is converted into the compound of the formula III-a by Treatment with an excess of alcoholic amine solution, at room temperature or heated to about 40 ° C to about 80 ° C in a sealed tube. The compounds of formula III-a can be converted to a pharmaceutically acceptable salt using any conventional method.

Scheme IX -aa 32 Where: Y, Z, R ,, q, R2, R, R8, R9, and R, 0, are as previously described. R3 = C, lower C-alkyl, P = protecting group; preferably trimethylsilyl, tert-butyldimethylsilyl, para-nitrobenzoyl; and OTs = para-toluenesulfonilate or any conventional leaving group If desired to form compounds of formula III-aa, they can be prepared from the compounds of formula 27 by selective protection of the primary alcohol, followed by alkylation of the secondary alcohol, and deprotection of the ppmario alcohol. any conventional alcohol protecting groups can be used for this conversion and any method for the selective protection of a ppmario alcohol can be employed. According to the preferred embodiment of this invention, the reaction is carried out at low temperature in dichloromethane with trimethylsilyl chloride and triethylamine as the base to form compounds of formula 3. The alkylation of the secondary alcohol can be achieved via any conventional method of alkylation of a secondary alcohol found in the literature. In accordance with the preferred embodiment of this invention, the compounds of formula 29 are reacted with an alkyl halide using sodium hydride as the base to form compounds of formula 30, which can be deprotected to form compounds of formula 31 by any conventional method for deprotection of a primary alcohol. In accordance with the preferred embodiment of this invention, the compounds of formula 30 are treated with acid. dilute aqueous hydrochloride or tpfluoroacetic acid in dichloromethane to form compounds of formula 31 The conversion of the primary alcohol into compounds of formula 31 completes the synthesis of the compounds of formula III-a which can be developed as previously described for the synthesis of the compounds of formula lll-a The compounds of the formula lll-aa can be converted to a pharmaceutically acceptable salt using any conventional method Alternatively, the compounds of formula 32 can be prepared directly from the compounds of formula 28. Any method for alkylating a hydroxyl group in the presence of a tosyl group can be employed for this conversion. According to the preferred embodiment of this invention, the Compounds of formula 28 are treated with an alkyl trifluoromethanesulfonate, for example methyl t-fluoro-methanesulfonate, in the presence of a hidden base, for example 2,6-d? -tert-but? l-4-met? lp? pd? na The reaction can be run at room temperature or heated to about 40 ° C to about 80 ° C. Compounds of formula 32 can be converted to compounds of formula III-aa as previously described for the synthesis of compounds of formula III. The compounds of the formula III-aa can be converted to a pharmaceutically acceptable salt using any conventional method If desired to form lll-b compounds, they can also be prepared from compounds of formula 27 via Route B (Scheme x) This route involves the selective protection of the primary alcohol followed by the conversion of the secondary alcohol to a leaving group Any conventional method for the selective protection of a primary alcohol, and any conventional method for the conversion of a secondary alcohol into a leaving group can be used for this conversion According to the preferred embodiment of this invention, the compounds of formula 27 are treated with para-nitrobenzoyl chloride in pyridine at low temperature (preferably below about 0 ° C) to form compounds of formula 33. Compounds of formula 33 can be converted to a secondary mesylate of formula 34 by Reaction pathway with methanesulfonyl chloride in dichloromethane using triethylamine as the base. The reaction is preferably carried out at temperatures between about -15 ° C and about 10 ° C. Deprotection of the primary alcohol in compounds of formula 34 allows during the formation of a primary epoxide through a sn2 reaction resulting in an inversion of the stereocenter. Any conventional method for deprotection of a primary alcohol, and any conventional method for the formation of the epoxide in an alpha leaving group can be used for this conversion. According to the preferred embodiment of this invention, the compounds of formula 34 are treated with an aqueous solution of a suitable base in an organic solvent, preferably, aqueous sodium hydroxide in dioxane. The resulting epoxide of formula 35 can be a regioselectively open ring with an amine to produce the desired aminoalcohol of formula III-b. Any conventional method for opening the regioselective ring of a primary epoxide can be employed for this conversion. In accordance with the preferred embodiment of this invention, the compounds of formula 35 are treated with an excess of an alcoholic amine solution in a sealed flask, at room temperature or heated to about 40 ° C to about 90 ° C. of formula III-B can be converted to a pharmaceutically acceptable salt using conventional methods.

SCHEME X 27 33 34 lll-b 35 Where: A, Y, Z, R ,, q, R2, and R, R8, and Rio are as previously described. R9 is H PNB = para-nitrobenzoyl or any conventional protecting group; and OMs = methanesulfonate or any conventional leaving group If desired to form compounds of the formula HNbb, they can be made from compounds of formula III-b by protection of the amine, alkylation of the secondary alcohol and deprotection of the amine (Scheme XI). Any conventional method for protection of an amine, alkylation of a secondary alcohol, and deprotection of an amine can be used for this conversion. According to the preferred embodiment of this invention, the compounds of formula III-b are treated with boc anhydride, wherein boc = tert-butoxycarbonyl, to form compounds of formula 36 which can be alkylated with an alkyl halide using sodium hydride as the base for forming compounds of formula 37. Deprotection is achieved by using an acid, preferably trifluoroacetic acid in dichloromethane to form compounds of formula III-bb which can be converted to a pharmaceutically acceptable salt using conventional methods.

SCHEME XI lll-b 36 37 Where A, Y, Z, R ,, q, R2, R4, R8, and R, 0 are as previously described R9 is H R3 = lower C-C3 alkyl, P = protective group, preferably tert-butoxycarbonyl The compounds of formula 27 are formed via a regio- and stereo-selective opening of the ring of an appropriately substituted epoxide of formula 13 (formed via an epoxidation of an appropriately substituted alcohol alcohol 14) with an appropriately substituted compound of formula 38 (Scheme Xll) Any conventional method for the regio- and stereo-selective opening of the epoxide ring can be used for this conversion According to the preferred embodiment of this invention, the compounds of formula 38 are treated with a base, for example sodium hydride, sodium tert-butoxide, potassium hydroxide, potassium tert-butoxide or potassium hydroxide, then treated with the epoxide of the formula 13 The epoxide of the formula 13 can be pre-treated with a Lewis acid, for example / so-propóx? do of titanium, boron trifluoride, etc to ensure the regioselective opening of the ring The reaction occurs at room temperature durant Alternatively, the compounds of formula 38 which are suitably nucleophilic, for example indolene, can be heated with the epoxide of formula 13 at temperatures from about 50 ° C to about 170 ° C. form compounds of formula 27 The epoxidation of trans-allylic alcohols 14 can be developed racemically or asymmetrically using the methods described in the literature. In accordance with the preferred embodiment of this invention, the racemic epoxidation is conducted with any paracetic acid or meta-chloroperbenzoic acid If desired to produce a single enantiomer of compounds of formula I, the asymmetric epoxidation of an allyl alcohol can be developed with urea-butyl hydroperoxide or eumeno hydroperoxide in the presence of the appropriate tartrate ester. titanium (IV) isopropoxide, and molecular sieves This method is established Well in the literature (eg KB Sharpless, et al, J Org Chem 1986, 51, 3710) The compounds of formula 38 and the starting alcohol alcohols 14 are available from commercial sources or are accessible through well-established methods in the literature Scheme Xll Where: A, Y, Z, Ri, q, R2, R8, R9, and R, 0 are as previously described.

In other embodiments, the invention is directed to pharmaceutical compositions, comprising: to. at least compound of formula I, II or III or pharmaceutically acceptable salt thereof; Y b.at least one pharmaceutically acceptable carrier.

Usually, the compound of Formula I, II or III or a pharmaceutically acceptable salt thereof, will be present at a level of from about 0.1%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition, based on the total weight of the pharmaceutical composition. Preferably, the compound of Formula I, II and III or a pharmaceutically acceptable salt thereof, will be present at a level of at least about 1%, by weight, based on the total weight of the pharmaceutical composition. More preferably, the compound of Formula I, II or III or a pharmaceutically acceptable salt thereof, will be present at a level of at least about 5%, by weight, based on the total weight of the pharmaceutical composition. Even more preferably, the reuptake inhibitor of norepinephrine or a pharmaceutically acceptable salt thereof will be present at a level of at least about 10%, by weight, based on the total weight of the pharmaceutical composition Still more preferably, the compound of Formula I, II or III or a The pharmaceutically acceptable salt thereof will be present at a level of at least about 25% by weight, based on the total weight of the pharmaceutical composition.

Such compositions are prepared according to acceptable pharmaceutical methods, 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 other ingredients in the formulation and biologically acceptable The compounds of this invention can be administered orally or parenterally, either pure or in combination with conventional pharmaceutical carriers.

Applicable solid carriers may include one or more substances which may also act as sabotagers, lubricants, solubilizers, suspending agents, fillers, binders, compression aids, tablet disintegrating agents or agents or an encapsulating material. In powders, the carrier is a finely divided solid that is mixed with a finely divided active ingredient In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the desired shape and size The powders and tablets preferably contain up to a 99% of the active ingredient Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextpna, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, or vinylpyrrolidine, low melting waxes and anion exchange resins Liquid carriers can be used to prepare solutions, suspensions, emulsions, syrups, and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or oils. pharmaceutically acceptable or greases The liquid carrier may contain other pharmaceutically suitable additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives such as the above, example, cellulose derivatives, preferably a solution of sodium carboxymethylcellulose), alcohols (including monohydric and aromatic alcohols, for example, ghcoles) and their derivatives, and oils (for example, fractionated coconut oil and arachis oil). parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl mipstate. Sterile liquid carriers are used in compositions of sterile liquid form for parenteral administration.

Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be administered by, for example, intramuscular, intrapeptoneal or subcutaneous injection. Sterile solutions can be administered intravenously. Oral administration can be given in a liquid or solid composition form.

Preferably the pharmaceutical composition is in a unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such forms, the composition is sub-divided into unit doses containing appropriate amounts of the active ingredient, the unit dosage forms can be packaged compositions, for example packaged powders, flasks, ampoules, prefilled syringes or bags containing liquids The unit dosage form can be, for example, a capsule or tablet, or it can be the number appropriate of any such compositions in package form In another embodiment of the present invention, the compounds useful in the present invention can be administered to a mammal with one or more pharmaceutical active agents such as those agents that are used to treat any other medical condition present in the mammal. Examples of such active agents Pharmaceuticals include pain relieving agents, anti-angiogenic agents, antineoplastic agents, anti-diabetic agents, anti-infection agents, or gastrointestinal agents, or combinations of these The one or more pharmaceutical active agents can be administered in a therapeutically effective amount simultaneously (such as individually at the same time, or together in a pharmaceutical composition), and / or successively with one or more compounds of the present invention.

The term "combination therapy" refers to the administration of two or more therapeutic agents or compounds to treat a therapeutic condition or disorder that is described in the present disclosure, for example hot flashes, sweat, condition or disorder related to thermoregulation Such administration includes the use of each type of therapeutic agent in a concurrent manner. In any case, the treatment regimen will provide beneficial effects of the combination of the drug in treating the conditions selected from the group consisting of disorder or disorders described herein.

The route of administration may be any route, which effectively transports the active compound of Formula I, II or III or a pharmaceutically acceptable salt thereof, to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal, such as passive or lontophoretic, or parenteral, eg, rectal, by deposit, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or ointment addition, administration of the compound of Formula I, II or III or a pharmaceutically salt acceptable of this, with other active ingredients can be concurrent or simultaneous It is believed that the present invention described presents substantial relief in the field of treatment, alleviation, inhibition and / or prevention of conditions selected from the group consisting of disorder enhanced by monoamine recurrence including, inter alia, vasomotopic symptoms (VMS). , sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, central nervous system disorders, and combinations of these, particularly those conditions selected from the group consisting of severe depressive disorder, vasomotopic symptoms, imperious urinary incontinence and stress, fibromyalgia, pain, diabetic neuropathy, schizophrenia and combinations of these Accordingly, in one embodiment, the present invention is directed to methods for treating or preventing an improved condition by monoamine resumption in a subject that requires it, comprising the step of administering to said subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof Conditions selected from the group consisting of disorder enhanced by the monoamine retake include those selected from the group consisting of vasomotopic symptoms, sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, central nervous system disorders, and combinations of these, particularly those conditions selected from the group consisting of severe depressive disorder, vasomotopic symptoms, urinary or stress urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations of these "Vasomotopic symptoms," "symptoms of vasomotopic instability" and "vasomotopic disturbances" include, but are not limited to, hot flushes, insomnia, sleep disturbances, mood disorders, irritability, excessive breathing, night sweats, fatigue, and the like, caused for, inter alia, thermoregulatory dysfunction The term "hot flushes" is a term recognized in the art which refers to an episodic disturbance in body temperature typically consisting of a sudden hot flash in the skin, usually accompanied by breathing in a subject.

The term "sexual dysfunction" includes, but is not limited to, the condition related to desire and / or excitement As used herein, "gastrointestinal and genitourinary disorders" include irritable bowel syndrome, symptomatic GERD, hypersensitive esophagus, non-ulcer dyspepsia, non-cardiac chest pain, biliary dyskinesia, Oddy sphincter dysfunction, incontinence (ie, urge incontinence, stress incontinence, genuine stress incontinence, and mixed incontinence) (which includes the involuntary emptying of feces or urine, and leakage of feces or urine that may be due to one or more causes that include but are not limited to pathology of impaired sphincter control, loss of cognitive function, overdistention of the bladder, hyperreflexia and / or involuntary urethral relaxation, weakness of the muscles associated with the bladder with the bladder or neurological abnormalities), interstitial cystitis (irritable bladder), and chronic pelvic pain (which includes, but is not limited to vulvodynia, prostatodynia, and proctalgia).

As used herein, "chronic fatigue syndrome" (CFS) is a condition characterized by selected physiological symptoms of weakness, muscle aches, excessive sleepiness, malaise, fever, sore throat, soft lymph nodes, impaired memory and / or mental concentration. damaged, insomnia, sleep disturbances, localized distension, diffuse pain and fatigue, and combinations of these.

As used herein, "fibromyalgia syndrome" (FMS) includes FMS and other somatoform disorders, including FMS associated with depression, somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated somatoform disorder , and NOS somatoforme. FMS and other somatoform disorders are accompanied by physiological symptoms selected from a generalized elevated perception of sensory stimulation, abnormalities in the perception of pain in the form of allodynia (pain with innocuous stimulation), abnormalities in the perception of pain in the form of hyperalgesia (increased sensitivity to painful stimulus), and combinations of these.

As used herein, "central nervous system disorders," include addictive disorders (including those due to alcohol, nicotine, and other psychoactive substances) with withdrawal syndrome, learning associated with age, and mental disorders (including Alzheimer's), anorexia nervosa, bulimia nervosa, attention deficit disorder with or without bipolar disorder and hyperactivity disorder, pain, cyclothymic disorder, depression disorder (which includes severe depressive disorder, adolescent depression, refractory depression, and minor depression), dysthymic disorder generalized anxiety disorder (GAD), obesity (that is, reducing the weight of obese or overweight patients), obsessive compulsive disorders and related spectrum disorders, oppositional defiant disorder, panic disorder, post-traumatic stress disorder , premenstrual dysphoric disorder (ie, premenstrual syndrome and lu lumer dysphoric disorder) late teal), psychotic disorders (which includes schizophrenia, schizoaffective and schizophreniform disorders), seasonal affective disorder, sleep disorders (such as narcolepsy and enuresis), social phobia (which includes social anxiety disorder), selective serotonin reuptake inhibition (SSRI) "windiness" syndrome (ie , where a patient who fails to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response) As used here, "pain" includes both acute pain and chronic pain, which can be a centralized pain, peripheral pain, or combinations of these 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 of these, such as lower back pain, atypical chest pain, headache such as cloistered headache, migraine, herpes neuralgia, phantom leg pain, pelvic pain, myofacial face pain, abdominal pain, neck pain , central pain, dental pain, opium-resistant pain, visceral pain, surgical pain, pain of bone damage, pain during work and supply, pain resulting from burns, post-partum pain, pain from angina, neuropathic pain such as peripheral neuropathy and diabetic neuropathy, post-operative pain, and pain that is co-morbid with central nervous system disorders described here As used herein, the term "acute pain" refers to a centralized or peripheral pain that is intense, localized, sharp, or prickly, and / or muffled, difficult to define, diffuse, or burning in nature and that occurs for short periods. of time As used herein, the term "chronic pain" refers to a centralized or peripheral pain that is intense, localized, sharp, or prickly, and / or muffled, difficult to define, diffuse, or inflammatory in nature and that occurs over long periods of time. of time (ie, persistent and / or recurrent regularly), which includes, for the purpose of the present invention, neuropathic pain and cancer pain Chronic pain includes neuropathic pain, hyperalgesia, and / or allodynia As used herein, the term "neuropathic pain" refers to chronic pain caused by damage to or by pathological changes in the peripheral or central nervous systems Examples of pathological changes related to neuropathic pain include prolonged central or peripheral neuronal sensitization, central sensitization related to damage to inhibitory and / or exhibiting functions of the nervous system and abnormal interactions between the parasympathetic and sympathetic nervous systems A wide range of conditions selected from the group consisting of clinical disorders may be associated with or form the basis for neuropathic pain including, for example, diabetes, post-traumatic pain by amputation (nerve damage caused by damage resulting in peripheral and / or central sensitization such as phantom leg pain), back pain, cancer , chemical damage, toxins, or other major surgeries, peripheral nervous damage due to compression due to traumatic damage, post-herpetic neuralgia, tpgeminal neuralgia, lumbar or cervical radiculopathy, fibromyalgia, glossopharyngeal neuralgia, sympathetic reflex dystrophy, casualgia, thalamic syndrome, avulsion of nerve root, dystrophy of sympathetic reflex or post-thoracotomy pain, nutptional deficiencies, or viral or bacterial infections such as zoster or human immunodeficiency virus (HIV), and combinations of these Also included in the definition of neuropathic pain a condition secondary to metastatic infiltration, adiposis painful, burns, conditions selected from the group consisting of central pain disorder related to conditions selected from the group consisting of thalamic disorders, and combinations of these As used herein, the term "hyperalgesia" refers to pain where there is an increase in sensitivity to a typical noxious stimulus As used herein, the term "allodynia" refers to an increase in sensitivity to a typical non-harmful stimulus As used herein, the term "visceral pain" refers to pain associated with or resulting from diseases of the internal organs, such as, for example, ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, (arthralgias) rheumatology, tumors, gastritis, pancreatitis, organ infections, disorders of the biliary tract, and combinations of these As used herein, the term "female-specific pain" refers to pain that may be acute and / or chronic pain associated with conditions selected from the group consisting of female disorder. Such pain groups include those that are found only or predominantly in female, including pain associated with menstruation, ovulation, pregnancy, or birth of the children, abortion, ectopic pregnancy, retrograde menstruation, rupture of a corpus luteum or follicular body, irritation of the pelvic viscera, uterine fibroids, adenomyosis, endometriosis, infection and inflammation, ischemia of the pelvic organ, obstruction, intra-abdominal adhesions, anatomical distortion of the pelvic viscera, access in ovaries, loss of pelvic support, tumors, pelvic congestion and referred pain of non-gynecological causes, and combinations of these.

In one embodiment, the present invention is directed to methods for treating or preventing vasomotor symptoms in a subject that requires it, comprising the step of: administering to said subject an effective amount of at least one compound of Formula I, II or III or a pharmaceutically acceptable salt thereof.

When estrogen levels are low or estrogen is absent, normal levels between NE and 5-HT are altered and this altered change in neurotransmitter levels may result in changes in the sensitivity of the thermoregulatory center. The altered chemical levels can be translated into the thermoregulatory center as a sensation of heat and as a response, the hypothalamus can activate the descendant autonomic pathways and result in heat dissipation via vasodilation and sweating (hot flashes) (Figure 1). Accordingly, the lack of estrogen can result in altered norepinephrine activity.

Norepinephrine synthesized in brainstem pericaria is released at the nerve endings in the hypothalamus and brainstem. In the hypothalamus, the NE regulates the activity of the neurons that reside in the thermoregulatory center. In the brainstem, the NE enervates the serotonergic neurons (5HT), and acts via post-synaptic adrenergic receptors, and adrenergic receptors2, stimulates the activity of the serotonin system. In response, 5-HT neurons also regulate the activity of the thermoregulatory center and feed NE neurons. Through this feedback connection, 5-HT, acts via the 5-HT2a receptors, inhibits the activity of NE neurons. Norepinephrine in the synaptic cleft is also taken by the NE transporter (NET) located in NE neurons. The transporter recycles the NE and makes multiple neurotransmissions available (Figure 2).

The present invention provides a treatment for vasomotor symptoms by the methods of recovering the reduced activity of norepinephrine. The activity of norepinephrine in the hypothalamus or brainstem can be elevated by (i) blocking the activity of the NE transporter, (ii) blocking the activity of the pre-synaptic adrenergic receptor2 with an antagonist, or (iii) blocking the activity of the 5-HT in NE neurons with a 5-HT2a antagonist.

In another embodiment, the present invention is directed to methods for treating or preventing a depression disorder in a subject that requires it, comprising the step of: administering to said subject an effective amount of at least one compound of Formula I, II or III or a pharmaceutically acceptable salt thereof.

In yet other embodiments, the present invention is directed to methods for treating or preventing sexual dysfunction in a subject that requires it, comprising the step of: administering to said subject an effective amount of at least one compound of Formula I, II or III or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods for treating or preventing gastrointestinal or genitourinary disorder, particularly stress incontinence or imperious urinary incontinence, in a subject that requires it, comprising the step of: administering to said subject an effective amount of a compound of the Formula I, II or III or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods for treating or preventing chronic fatigue syndrome in a subject that requires it, comprising stage of: administering to said subject an effective amount of a compound of Formula I, II or III or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods for treating or preventing fibromyalgia syndrome in a subject that requires it, comprising the step of: administering to said subject an effective amount of a compound of Formula I, II or III or a pharmaceutically acceptable salt thereof.

In additional embodiments, the present invention is directed to methods for treating or preventing pain in a subject that requires it, comprising the step of: administering to said subject an effective amount of at least one compound of Formula I, II or III or a pharmaceutically acceptable salt thereof.

The pain may be, for example, acute pain (short duration) or chronic pain (recurrent or persistent recurrent). The pain can also be centralized or peripheral.

Examples of pain that can be acute or chronic and that can be treated according to the methods of the present invention include inflammatory pain, musculoskeletal pain, bone pain, lumbosacral pain, neck or cervical pain, visceral pain, somatic pain, neuropathic pain , pain of cancer, pain caused by damage or surgery such as pain from burning or dental pain, or headaches such as migraines or tension headaches, or combinations of these pains. A person skilled in the art will recognize that these pains can overcome one another. For example, a pain caused by inflammation may also be visceral or musculoskeletal in nature.

In a preferred embodiment of the present invention the compounds useful in the present invention are administered to mammals to treat chronic pain such as pain neuropathic associated for example with damage to or pathological changes in the peripheral and central nervous systems, cancer pain, visceral pain associated with for example the abdominal, pelvic, and / or pneumonic or pancreatitis regions, musculoskeletal pain associated with eg back pain or cervical, marrow, fibromyalgia, temporomandibular joint or myofascial pain syndrome, bone pain associated with for example degenerative joint or bone disorders such as osteoartantis, rheumatoid arthritis, or spinal stenosis, headaches such as migraine or headaches stress, or pain associated with infections such as HIV, false cell anemia, autoimmune disorders, multiple sclerosis, or inflammation such as osteoartptis or rheumatoid arthritis In a preferred embodiment, the compounds useful in this invention are used to treat chronic pain which is neuropathic pain, visceral pain, musculoskeletal pain, bone pain, cancer pain or inflammatory pain or combinations thereof, according to the methods described herein. Inflammatory pain can be associated with a variety of conditions selected from the group consisting of medical disorders such as osteoartptis, rheumatoid arthritis, surgery, or damage. Neuropathic pain can be associated with for example diabetic neuropathy, peripheral neuropathy, post-herpetic neuralgia, neuralgia tpgeminal, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, sympathetic reflex dystrophy, casualgia, thalamic syndrome, avulsion of the nerve root, or nerve damage caused by resultant damage to peripheral and / or central sensitization such as extremity pain ghost, sympathetic reflex dystrophy or post-pain thoracotomy, cancer, chemical damage, toxins, nutptional deficiencies, or viral or bacterial infections such as zoster or HIV, or combinations thereof. The methods of use for the compounds of this invention additionally include treatments in which neuropathic pain is a secondary condition. to metastatic infiltration, painful adiposis, burns, or conditions selected from the group consisting of central pain disorder related to conditions selected from the group consisting of thalamic disorder 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 according to the methods of present invention include pain associated with damage in soft or soft structural tissues, experienced during surgery, dental procedures, burns, traumatic injuries of the body. Examples of visceral pain can be treated according to the methods of the present invention include those types of pain associated with or resulting from diseases of internal organs such as ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, (arthralgias) ) rheumatology, tumors, gastritis, pancreatitis, organ infections, or disorders of the biliary tract, or combinations of these. A person skilled in the art will recognize that pain treated in accordance with the methods of the present invention may also be related to conditions selected from the group consisting of hyperalgesia disorder, allodynia, or both. Additionally, chronic pain may be with or without peripheral or central sensitization.

The compounds useful in this invention can also be used to treat acute pain and / or chronic pain associated with the conditions selected from the group consisting of female disorders, which may also be referred to as female-specific pains. Such pain groups include those that are found only or predominantly in females, which includes pain associated with menstruation, ovulation, pregnancy or birth, abortions, ectopic pregnancy, retrograde menstruation, rupture of a corpus luteum or follicular cyst, irritation of the pelvic viscera , uterine fibroids, adenomyosis, endometriosis, infection and inflammation, pelvic organ ischemia, obstruction, intra-abdominal adhesions, anatomical distortion of the pelvic viscera, ovarian abscess, loss of pelvic support, tumors, pelvic congestion or so-called pelvic pain. non-gynecological causes.

The compounds of formula I, II, or a pharmaceutically acceptable salt thereof, are useful in treating and preventing schizophrenia in a subject in need thereof.

The present invention is further defined in the following Examples, in which all parts and percentages are given by weight and the degrees are Celsius, unless otherwise stated. It should be understood that these examples, while indicating the 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 determine the essential characteristics of this invention, and without departing from the spirit and scope of the same, can be various changes and modifications of the invention to adapt them to the various uses and conditions.

EXAMPLES Example 1: (1S, 2f?) - 1- [5- (benzyloxy) -1H-indol-1-ill-3- (methylamino) -1-phenylpropan-2-ol hydrochloride Step 1: A mixture of diisopropyl D-tartrate (d 1.1-19, 6.0 mL, 29 mmol), powdered molecular sieves 4 A (28 g, dried overnight at 200 ° C) and dry dichloromethane (800 mL) were added. cool to -20 ° C. Titanium (IV) isopropoxide (d 0.97, 5.9 mL, 20 mmol) is added and the mixture is stirred for 15 minutes. Anhydrous tert-butyl hydroperoxide (ca. 5.5 M in decane, 90 mL, ca. 500 mmol) is slowly added, dried further for 15 minutes on granules of 4 A molecular sieves (dried overnight at 200 ° C) , and the mixture is stirred for 45 minutes at -20 ° C. A solution of cinnamyl alcohol (27 g, 200 mmol) in dry dichloromethane (200 mL) is added for 1 hour at -20 ° C. After an additional 2 hours at -20 ° C, the reaction mixture is quenched with a cold mixture (-20 ° C) of 30% saturated aqueous sodium chloride-aqueous sodium hydroxide solution (35 mL). Diethyl ether (100 mL) is added and the mixture is stirred vigorously at 0 ° C for 1.5 hours. Magnesium sulfate (75 g) is added, the mixture is stirred for 20 minutes, then filtered through silica gel (100 g) and washed with diethyl ether (250 mL). The filtrate is concentrated under vacuum and excess tert-butyl hydroperoxide is azeotroped with several portions of toluene to give a cloudy yellow oil. Flash column chromatography (silica 500 g, 25%, 50% ethyl acetate / hexanes) gives a white crystalline solid (27 g). Recrystallization from 20% hot ethyl acetate-hexanes gives [(2R, 3R) -3-phenyloxyran-2-yl] methanol (21 g, 70%) as white needles. MS (ES) m / z 133 ([M + H- H20] +) Step 2 A suspension of 5-benzoloxidol (8 9 g, 40 mmol) in glacial acetic acid (40 mL) is treated with sodium cyanoborohydride (5.0 g, 80 mmol) as a 0 ° portion. C After 2 hours at 0 ° C, the reaction mixture is diluted with water (80 mL) and made alkaline with 40% aqueous sodium hydroxide at 0 ° C. The aqueous phase is extracted with dichloromethane (3 x 75 mL ) and the combined extracts are washed with saturated saline (100 mL), and dried (sodium sulfate). Filtration through silica gel (50 g) washed with dichloromethane gives 5- (benzyl)? ndol. Na (7 8 g, 87%) as a yellow solid, clear MS (ES) m / z 226 ([M + H] +) Step 3 A mixture of [(2R, 3R) -3-phenoloxan-2-yl] methanol (10.0 g, 66.6 mmol, from step 1) and 5- (benzyl)? Ndoliene (15.0 g, 66.6 mmol) is heated at 135 ° C for 1.5 hours The mixture is dissolved in dichloromethane (40 mL) and pre-adsorbed on silica gel (40 g) Flash column chromatography ( silica 600 g, 30%, 40%, 50%, 80% ethyl acetate / hexanes) provides (2S, 3S) -3- [5- (benzylox?) -2,3-d? -1H-? Ndol-1-? L] -3-phen? Lpropane-1,2-d? Ol (22.0 g, 88%) as an amber oil MS (ES) m / z 376 ([M + H] ] +) Step 4 A solution of (2S, 3S) -3- [5- (benz? Lox?) -2,3-d? H? Dro-1H-? Ndol-1-? L] -3-phenolpropane- 1,2-d? Ol (11.0 g, 29.3 mmol) in dry toluene (150 mL) is treated with a solution of 2,3-d? Chloro-5,6-d? C? Ano-1, 4 -benzoquinone (6 65 g, 29 3 mmol) in dry toluene (150 mL) at 0 ° C After 1 5 hours, the thick mixture is quenched with 5% aqueous sodium carbonate (370 mL) and stirred vigorously for 5-10 minutes. The mixture is partitioned between ethyl acetate (11 L) and 5% aqueous sodium carbonate (11 L). The organic phase is separated, washed with 5% aqueous sodium carbonate (4%). x 1 1 L) and saturated saline solution (1 1 L), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a crude brown solid (10 4 g) Flash column chromatography (silica 150 g, 40 %, 50%, 60%, 80%, 100% ethyl acetate / hexanes) provides (2S, 3S) -3- [5- (benzylox?) - 1 H-? Ndol-1-? L] -3-phenolpropane-1,2, d-ol (9 2 g, 84%) as a tan solid MS (ES) m / z 374 ([M + H] +) Step 5 A solution of (2S, 3S) -3- [5- (benz? Lox?) - 1 H-? Ndol-1-? L] -3-phen? Lpropane-1,2-d? Ol (7 5 g, 20 mmol) in dry pipdine (55 mL) is treated with p-toluenesulfonyl chloride (3.9 g, 20 mmol) at 23 ° C. After 21 hours, the reaction mixture it is diluted with ethyl acetate (1 L) and the organic phase is washed with 1.0 M aqueous sodium hydroxide (1 L), water (1 L), 1.0 M aqueous hydrochloric acid (1 L) and saturated saline solution (1 L). ), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a dark oil (11 g) which was dissolved in dichloromethane and pre-adsorbed on silica gel (15 g). Flash column chromatography (silica 165 g, 20%, 40%, 60% ethyl acetate / hexanes) provides 3- (5-benzyloxy-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (8.3 g, 78%) as an orange foam. MS (ES) m / z 528 ([M + H] +).

Step 6: 3- (5-Benzyloxy-indol-1-yl) -2-hydroxy-3-phenyl-propyl (2S.3S) -toluene-4-sulfonic acid ester (4.1 g, 7.8 mmol) is treated with a solution of methylamine (2.0 M in methanol, 40 mL, 80 mmol) and the solution is stirred at 23 ° C for 24 hours. At this time, the solution is concentrated under reduced pressure and the residue is partitioned between diethyl ether (500 mL) and 1.0 M aqueous sodium hydroxide (500 mL). The organic phase is separated, washed with water (500 mL) and saturated saline (500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a tan foam (3.0 g). Flash column chromatography (silica 125 g, 2.5%, 5% dichloromethane / methanol saturated with ammonia) provides (1 S, 2f?) - 1- [5- (benzyloxy) -1 / - / - indole-1-yl ] -3- (methylamino) -1-phenylpropan-2-ol (2.3 g, 77%) as a pale yellow solid. The solid (0.28 g) is dissolved in hot methanol (2-3 mL) and treated with a solution of hydrogen chloride (4.0 M in 1,4-dioxane, 0.18 mL, 0.72 mmol). The precipitated solid is stirred vigorously with diethyl ether (25 mL) for ca. 1 minute. Vacuum filtration provides hydrochloride of (1S, 2R) -1-F5- (benzyloxy) -1H-indol-1-ill-3- (methylamino) -1-phenylpropan-2-ol (0.30 g, 97% recovery) as a white solid. MS (ES) m / z 387 ([M + H] +).

Example 2: (1S, 2R) -1- [4- (benzyloxy) -1H-indol-1-ill-3- (methylamino) -1-phenylpropan-2-ol chloride In a manner analogous to Example 1, step 2, 4- (benz? Lox?)? Ndol? Na is prepared from 4-benzoloxid MS (ES) m / z 226 ([M + Hf) In a manner analogous to Example 1, step 3, (2S, 3S) -3- [4- (benz? Lox?) -2,3-d? H? Dro- 1H-? Ndol-1-? L] - 3-phenolpropane-1,2-d-ol is prepared from 4- (benzylox?)? Ndol? Na and [(2f?, 3) -3-phen? Lox? Ran-2-? l] methanol MS (ES) m / z 376 ([M + H] +) In a manner analogous to Example 1, step 4, (2S, 3S) -3- [4- (benz? Lox?) - 1 / - / -? Ndol-1-? L] -3-phen? Lpropane-1 , 2-d? Ol is prepared from (2S, 3S) -3- [4- (benz? Lox?) - 2,3-d? H? Dro-1 H-? Ndol-1 -? L] -3-phenolpropane-1,2-d? Ol MS (ES) m / z 374 ([M + H] +) In a manner analogous to Example 1, step 5, ester of 3- (4-benzyl) -? Ndol-1-? L) -2-h? Drox? -3-phenol-propyl acid (2S, 3S) -toluene-4-sulfonyl is prepared from ((2S, 3S) -3- [4- (benzylox?) - 1 H-? Ndol-1 -? L] -3 -phen? -propane-1,2-d? ol MS (ES) m / z 528 (i [M + H] +) In a manner analogous to Example 1, step 6, (1S, 2R) -1-f4- (benz? Lox?) - 1 H-? Ndol-1-? Ll-3- (methalamine) chloride ) -1-phenylpropan-2-ol is prepared from the ester of 3- (4-benzyl) -? Ndol-1-? L) -2-h? Drox? -3-phen? L- Propriety of acid (2S, 3S) -toluene-4-sulfon? co MS (ES) m / z 387 ([M + H] +) Example 3 Chloride (1 S, 2 R) -1- [6- (benz? Lox?) - 1 H-? Ndol-1-? Ll-3- (meth? Lam? No) -1-phen? Lpropan-2 -ol WAY-318969-A-1 L31883-135-B In a manner analogous to Example 1, step 2, 6- (benz? Lox?)? Ndol? Na is prepared from 6-benzoloxid MS (ES) m / z 226 ([M + H] +) In a manner analogous to Example 1, step 3, (2S, 3S) -3- [6- (benzyloxy) -2,3-dihydro-1 H-indol-1-yl] -3-phenylpropane-1, 2- Diol is prepared from 6- (benzyloxy) indoline and [(2R, 3R) -3-phenyloxyran-2-yl] methanol. MS (ES) m / z 376 ([M + Hf).

In a manner analogous to Example 1, step 4, (2S, 3S) -3- [6- (benzyloxy) -1H-indol-1-yl] -3-phenylpropane-1,2-diol is prepared from ( 2S, 3S) -3- [6- (benzyloxy) -2,3-dihydro-1H-indol-1 -yl] -3-phenylpropane-1,2-diol. MS (ES) m / z 374 ([M + H] +).

In a manner analogous to Example 1, step 5, 3- (6-benzyloxy-indol-1-yl) -2-hydroxy-3-phenyl-propyl (2S, 3S) -toluene-4-sulfonic acid ester prepared from ((2S, 3S) -3- [6- (benzyloxy) -1H-indol-1-yl] -3-phenylpropane-1,2-diol MS (ES) m / z 528 ([M + H] + ).

In a manner analogous to Example 1, step 6, chloride (1S, 2R) -1-f6- (benzyloxy) -1H-indol-1-in-3- (methylamino) -1-phenylpropan-2-ol was prepared from 3- (6-benzyloxy-indol-1-yl) -2-hydroxy-3-phenyl-propyl (2S, 3S) -toluene-4-sulfonic acid ester. MS (ES) m / z 387 ([M + H] +).

Example 4: Hydrochloride (1 S, 2R) -1- | 7- (benzyloxy) -1 H -indole-1-p-3- (methylamino) -1-phenylpropan-2-ol In a manner analogous to Example 1, step 2, 7- (benzyloxy) indoline is prepared from 7-benzyloxyindole. MS (ES) m / z 226 ([M + H] +).

In a manner analogous to Example 1, step 3, (2S, 3S) -3- [7- (benzyloxy) -2,3-dihydro-1 / -indol-1-yl] -3-phenylpropane-1, 2 -diol is prepared from 7- (benzyloxy) indoline and [(2R, 3R) -3-phenyloxyran-2-yl] methanol. MS (ES) m / z 376 ([M + H] +).

In a manner analogous to Example 1, step 4, (2S, 3S) -3- [7- (benzyloxy) -1H-indole-1- L-3-phenolpropane-1,2-d-ol is prepared from (2S, 3S) -3- [7- (benzyllox?) -2,3-d? 1H-? Ndol-1 -? L] -3-phen? Lpropane-1,2-d? Ol MS (ES) m / z 374 ([M + H] +) In a manner analogous to Example 1, step 5, 3- (7-benzyl) -α-ddol-1- (1) -2-hydroxyl-3-phenolyl ester of acid (2S, 3S) -toluene-4-sulfon? Co is prepared from ((2S, 3S) -3- [7- (benz? Lox?) - 1 H-? Ndol-1-? L] -3 -phen? -propane-1, 2-d? ol MS (ES) m / z 528 ([M + H] +) In a manner analogous to Example 1, step 6, hydrochloride (1S, 2R) -1 -f7- (benz? Lox?) - 1 H-? Ndol-1 -? N -3 (methalamine) -1-phenylpropan-2-ol is prepared from 3- (7-benzyl) -α-ddol-1- (1) -2-h? Drox? -3-phen? L-prop ester The acid (2S, 3S) -toluene-4-sulfon? co MS (ES) m / z 387 ([M + Hf) Example 5 hydrochloride (1 S, 2R) -1-. { 5 - [(2-methox? Benc? L) ox? L-1 H-? Ndol-1-? L) -3- (meth? Lam? No) -1-phen? Lpropan-2-ol Step 1 A solution of (1 S, 2?) - 1- [5- (benz? Lox?) - 1 - / -? Ndol-1-? L] -3- (met? Lam? No) -1- phenolpropan-2-ol (1.7 g, 4.4 mmol, from Example 1, step 6) in dichloromethane (30 mL) is treated with tetylamine (d, 726, 1, 23 mL, 8, 8 mmol) and di-dicarbonate. -tert-butyl (1 2 g, 5 mmol) at 23 ° C After 16 hours, the reaction mixture is washed with 10 μM aqueous potassium hydrogen sulfate (3 × 15 mL), saturated sodium bicarbonate ( 15 mL), 10% (w / v) aqueous citric acid (15 mL) and saturated saline solution (15 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an orange foam (2 3 g) Flash column chromatography (silica 40 g, 40% ethyl acetate / hexanes) provides. { (2R, 3S) -3- [5- (benz? Lox?) - 1 H-? Ndol-1-? L] -2-h? Drox? -3-phen? Lprop? L} Ferric-butyl methylcarbamate (2 1 g, 100%) as a pale yellow foam MS (ES) m / z 487 ([M + H] +) Step 2 A solution of fer-butyl (5.3 g, 11 mmol) m 1 1 v / v ethyl acetate- Ethanol (100 mL) is hydrogenated on 10% palladium on carbon (1.7 g) at 50 psi After 16 hours, the catalyst is filtered (Cehta) and washed with hot ethanol (3 x 100 mL). The concentration of the filtrate give a tan solid (4 3 g) which is triturated overnight with ethyl acetate (30 mL) to give [(2R, 3S) -2-hydrox? -3- (5-h? drox? -1 H-β-ndol-1- (1) -3-phenolpropyl] -erbutylmethylcarbamate (3 8 g, 88%) as a white solid MS (ES) m / z 397 ([M + H] +) Step 3 A solution of [(2R, 3S) -2-h? Drox? -3- (5-h? Drox? -1H-? Ndol-1-? L) -3-phenylpropylmethylcarbamate, ferric-butyl (300 mg, 0.757 mmol) in dry acetonite (5 mL) is treated with 2-methoxylbenzyl chloride (d125, 105 uL, 0.754 mmol) followed by cesium carbonate (247 mg, 0.758 mmol). and the mixture is heated to 70 ° C. After 12 hours, the cold mixture is filtered (Celite), washed with acetonite (2 x 5 mL), and concentrated under reduced prre. Preadsorption on silica (1 g in dichloromethane) and purification via ISCO CombiFlash Companion chromatography (12 g RediSep silica, 30 mL / rnin, 0-40% ethyl acetate / hexane) provides ((2R, 3S) -2-h? drox? -3-. { 5 - [(2-methox? Benc? L) ox?] - 1 H-? Ndol-1-? L.]. 3-phenolpropyl) ferric-butyl methylcarbamate (181 mg, 46%) as a white solid MS (ES) m / z 517 ([M + H] +) Step 4 ((2R, 3S) -2-h? Drox? -3-. {5 - [(2-methox? Benc? L) ox?] -1 H-? Ndol-1-yl. -3-phenolpropyl) butyl-tert-butylcarbamate (176 mg, 0 341 mmol) is heated at 200 ° C with vigorous stirring for 8 minutes Flash column chromatography (silica 8 g, 1 25%, 2 5%, 5% dichloromethane / methanol saturated with ammonia) provides (1S, 2R) -1-. { 5 - [(2-methox? Benc? L) ox?] - 1 H-? Ndol-1-? L} -3- (methanol) -1-phenolpropan-2-ol (34 mg, 24%) as a white solid. The foam is dissolved in diethyl ether (3 mL), filtered and methanol is added. (5 gtotas) The solution is treated with a solution of hydrogen chloride (4 0 M m 1, 4-d-oxane, 0 02 mL, 0 08 mmol) and stirred vigorously for ca 1 minute. Vacuum filtration provides hydrochloride ( 1 S, 2R) -1- (5 - [(2-methox? Benc? L) ox? 1-1 H-? Ndol-1-? L.}. -3- (meth? Lam? No) -1 -phen? propan-2-ol (27 mg, 18%) as an off-white solid MS (ES) AT7 / z 417 ([M + Hf] Example 6 (1S, 2R) -1- (5 - [(3-methoxy? Benzyl) ox? L-1 H-? Ndol-1-? L) -3- (methalamine) hydrochloride ) -1-phenolpropan-2-ol In a manner analogous to Example 5, step 3, ((2R, 3S) -2-hydroxy-3. {5 - [(3-methoxybenzyl) oxy] -1H-indol-1-yl}. 3-phenylpropyl) -erc-butyl methylcarbamate is prepared from [(2R, 3S) -2-hydroxy-3- (5-hydroxy-1 H -indol-1-yl) -3-phenylpropyl] methylcarbamate. butyl, replacing 3-methoxybenzyl bromide in place of 2-methoxybenzyl chloride. MS (ES) m / z 517 ([M + Hf).

In a manner analogous to Example 5, step 4, hydrochloride of (1S, 2R) -1 - (5-1 (3-methoxybenzyloxyH-indol-1 -yl) -3- (methylamino) -1-phenylpropan-2- ol is prepared from ((2R, 3S) -2-hydroxy-3. {5 - [(3-methoxybenzyl) oxy] -1 H -indole-1-yl.} - 3-phenylpropyl) methylcarbamate of tere-butyl MS (ES) m / z 417 ([M + H] +).

Example 7: Hydrochloride of (1 S.2R) -1-. { 5 - [(4-methoxybenzyl) oxyl-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol In a manner analogous to Example 5, step 3, ((2R, 3S) -2-hydroxy-3. {5 - [(4-methoxybenzyl) oxy] -1H-indol-1-yl}. 3-phenylpropyl) tert-butyl methylcarbamate is prepared from [(2R, 3S) -2-hydroxy-3- (5-hydroxy-1H-indol-1-yl) -3-phenylpropyl] methylcarbamate ter-butyl ester. butyl, replacing 4-methoxybenzyl chloride in place of 2- methoxybenzyl MS (ES) m / z 517 ([M + H] +) In a manner analogous to Example 5, step 4, hydrochloride of (1S, 2R) -1- (5 - [(4-methox? Benc? L) ox? L-1 H-? Ndol-1 -? L) -3- (meth? Lam? No) -1-pheny? Propan-2-ol is prepared from ((2R, 3S) -2-h? Drox? -3- { 5 - [(4- methox? benc? l) ox?] -1H-? ndol-1-? l.]. 3-phenpropyl) tere-butyl methylcarbamate MS (ES) m / z 417 ([M + Hf) Example 8 hydrochloride (1S, 2R) -1-. { 5 - [(2-chlorobenzyl) ox? L-1 H-? Ndol-1-? L) -3- (meth? Lam? No) -1-phen? Lpropan-2-ol In a manner analogous to Example 5, step 3, ((2R, 3S) -3-. {5 - [(2-chlorobenzyl) ox?] -1H-? Ndol-1-? L. -2-h? Drox? -3-phen? Lprop?) Urea-butyl methylcarbamate is prepared from [(2R, 3S) -2-h? Drox? -3- (5-h? Drox H-β-ndol-1-? L) -3-phenolpropyl] -carbonic acid ester, substituting 2-chlorobenzyl bromide instead of 2-methoxyl benzyl chloride; MS (ES) m / z 521 ([M + H] +) In a manner analogous to Example 5, step 4, hydrochloride of (1S, 2R) -1-. { 5 - [(2-Chlorobenzyl) oxyl-1 H-? Ndol-1-yl) -3- (meth? Lam? No) -1-phenyl? -propan-2-ol is prepared from ((2R, 3S) -3- {5 - [(2-chlorobenzyl) ox?] - 1 H-? Ndol-1 -? L.} -2-h? Drox? -3-phen ? lpropyl) fer-butyl methylcarbamate MS (ES) m / z 421 ([M + H] +) Example 9 Hydrochloride (1 S, 2 R) -1- (5- (3-chlorobenzyl) ox? L-1 H-? Ndol-1-? L) -3- (meth? Lam? No) -1 -fen? lpropan-2-ol In a manner analogous to Example 5, step 3, ((2R, 3S) -3-. {5 - [(3-chlorobenzyl) ox?] -1H-? Ndol-1-? L. -2-hydroxy-3-phenolpropyl) tere-butyl methylcarbamate is prepared from [(2R, 3S) -2-h? Drox? -3- (5-H? Drox? -1 H-? Ndol-1 -? L) -3-phen? Lprop? L] methylcarbamate of tere- butyl, replacing 3-chlorobenzyl bromide in place of 2-methoxyl benzyl chloride MS (ES) m / z 521 ([M + Hf] In a manner analogous to Example 5, step 4, hydrochloride (1S, 2R) -1-. { 5 - [(3-chlorobenzyl) ox?] - 1 H-? Ndol-1-? L} -3- (methanolamine) -1-phenolpropan-2-ol is prepared from ((2R, 3S) -3-. {5 - [(3-chlorobenzyl) ox?] -1H-? Ndol-1 -? L.}. -2-h? Drox? -3-phen? Lprop?) Tere-butyl methylcarbamate MS (ES) m / z 421 ([M + H] ] +) Example 10 (1 S, 2 R) -1- (5-f (4-chlorobenzyl) oxyl-1 H-? Ndol-1-? L) -3- (meth? Lam? No) hydrochloride 1-phenolpropan-2-ol In a manner analogous to Example 5, step 3, ((2R, 3S) -3-. {5 - [(4-chlorobenzyl) ox?] -1H-? Ndol-1-? L. -2-hydroxy? -3-phenolpropyl) ferric-butyl methylcarbamate is prepared from [(2R, 3S) -2-h? Drox? -3- (5-hydro? -1 H-? Ndol-1-? L) -3-phenpropyl] ferric methylcarbamate butyl, replacing 4-chlorobenzyl bromide instead of 2-methoxyl benzyl chloride MS (ES) m / z 521 ([M + H] +) In a manner analogous to Example 5, step 4, hydrochloride of (1S, 2R) -1- (5 - [(4-chlorobenzyl) ox? 1-1 H-? Ndol-1-yl) -3 - (methalamine) -1-phenylpropan-2-ol is prepared from ((2R, 3S) -3-. {5 - [(4-chlorobenzyl) ox]] - 1 H-β-ndol-1 -? L.} -2-h? Drox? -3-phen? Lprop?) Ferric butylcarbamate MS (ES) m / z 421 ([M + H] + ) Example 11: (1S, 2fi) -1- hydrochloride. { 5-f (2-fluorobenzyl) oxyfl-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol In a manner analogous to Example 5, step 3, ((2R, 3S) -3-. {5 - [(2-fluorobenzyl) oxy] -1H-indol-1-yl.} -2-hydroxy- Fer-butyl 3-phenylpropyl) methylcarbamate is prepared from [(2R, 3S) -2-hydroxy-3- (5-hydroxy-1H-indol-1-yl) -3-phenylpropyl] methylcarbamate, ferric-butyl, substituting 2-fluorobenzyl bromide instead of 2-fluorobenzyl chloride; -methoxybenzyl. MS (ES) m / z 505 ([M + Hf).

In a manner analogous to Example 5, step 4, (1 S, 2f?) - 1- (5-l (2-fluorobenzyl) oxyl-1 H-indol-1-yl) -3- (methylamino) -hydrochloride 1-Phenylpropan-2-ol is prepared from ((2R, 3S) -3-. {5 - [(2-fluorobenzyl) oxy] -1 H -indole-1-yl.} -2-hydroxy -3-phenylpropyl) ferro-butyl methylcarbamate. MS (ES) m / z 405 ([M + Hf).

Example 12: (1S, 2R) -1- hydrochloride. { 5 - [(3-fluorobenzyl) oxyl-1 H-indol-1-yl > -3- (methylamino) -1-phenylpropan-2-ol In a manner analogous to Example 5, step 3, tert -butyl ((2R, 3S) -3-. {5 - [(3-fluorobenzyl) oxy] -1H-indol-1-yl.} -2 tert-butyl-hydroxy-3-phenylpropyl) methylcarbamate is prepared from ferric ((2R, 3S) -2-hydroxy-3- (5-hydroxy-1 H -indol-1-yl) -3-phenylpropylmethylcarbamate) -butyl, substituting 3-fluorobenzyl bromide in place of 2-methoxyl benzyl chloride MS (ES) m / z 505 ([M + H] +) In a manner analogous to Example 5, step 4, hydrochloride of (1S, 2R) -1- (5 - [(3-fluorobenzyl) ox? L-1 H-? Ndol-1 -? L) -3 - (methamphenoxy) -1-phenylpropan-2-ol is prepared from tert -butyl ((2R, 3S) -3-. {5 - [(3-fluorobenzyl) ox? ] -1 H-? Ndol-1 -? L.}. -2-h? Drox? -3-phen? Lprop? L) ferric-butyl methylcarbamate MS (ES) m / z 405 ([M + H] +) Example 13 (1S, 2R) -1- (5 - [(4-fluorobenzyl) ox? L-1 H-? Ndol-1-? L) -3- (meth? Lam? No) hydrochloride 1-phenolpropan-2-ol WAY-318373-A-1 L31883-71 -B In a manner analogous to Example 5, step 3, ((2R, 3S) -3-. {5 - [(4-fluorobenzyl) ox?] -1H-? Ndol-1-? L.}. -2-h? Drox? -3-phenolpropyl) ferric-butyl methylcarbamate is prepared from [(2R, 3S) -2-hydrox? -3- (5-hydro? ? -1H-? Ndol-1-? L) -3-phenolpropyl] ferric-butylcarbamate, replacing 4-fluorobenzyl bromide in place of 2-methoxyl benzyl chloride (ES) m / z 505 ([M + H] +) In a manner analogous to Example 5, step 4, hydrochloride of (1S, 2R) -1- (5-f (4-fluorobenzyl) ox? 1-1 H-? Ndol-1-? L) -3 - (methalamine) -1-phenolpropan-2-ol is prepared from ((2R, 3S) -3-. {5 - [(4-fluorobenzyl) ox]] - 1 H-β-ndol-1-α l}. -2-H? Droxx?-3-phen ?propyl) tert-butyl methylcarbamate MS (ES) m / z 405 ([M + Hf) Example 14 (1S, 2R) -3- (methalamine) -1- (5-f (2-met? Lbenc? L) ox? L-1 H-? Ndol-1-? L hydrochloride .}. -1.-Fen? Lpropan-2-ol In a manner analogous to Example 5, step 3, ((2R, 3S) -2-h? Drox? -3-. {5 - [(2-met? Lbenc? L) ox?] - 1 H-? ndol-1-? l.}. -3-phenolpropyl) tere-butyl methylcarbamate is prepared from [(2R, 3S) -2-h? drox? -3- (5-h Drox? -1H-? ndol-1-? l) -3-phen? lprop?] ferric-butyl methylcarbamate, substituting 2-methylbenzene bromide in place of 2-methoxybenzyl chloride MS (ES) m / z 501 ([M + H] +) In a manner analogous to Example 5, step 4, (1S, 2R) -3- (meth? Lam? No) -1- (5-f (2-met? Lbenc? L) ox? L-1 H hydrochloride -? ndol-1-? l) -1-phen? lpropan-2-ol is prepared from ((2R, 3S) -2-h? drox? -3- { 5 - [(2-met L-benzyl) -oxidyl-1H-β-nol-1-yl) -3-phenolpropyl) tere-butyl methylcarbamate MS (ES) m / z 401 ([M + Hf) Example 15 (1S, 2R) -3- (methalamine) -1- (5-f (3-met? Lbenc? L) ox? L-1 H-? Ndol-1-? L hydrochloride) - 1-phenolpropan-2-ol In a manner analogous to Example 5, step 3, ((2R, 3S) -2-h? Drox? -3- { 5 - [(3-met? Lbenc? L) ox?] - 1 H-? ndol-1-? l.} - 3-phenolpropyl) ferric-butylcarbamate is prepared from [(2R, 3S) -2-hydrox? -3- (5-h Drox? -1H-? ndol-1-? l) -3-phen? lprop? l] ferric-butylcarbamate, substituting 3-methylbenzene bromide instead of 2-methoxybenzyl chloride MS (ES) m / z 501 ([M + H] +) In a manner analogous to Example 5, step 4, (1S, 2R) -3- (meth? Lam? No) -1- (5-f (3-met? Lbenc? L) ox? 1-1 H hydrochloride. -? ndol-1-? l) -1-phen? lpropan-2-ol is prepared from ((2R, 3S) -2-h? drox? -3- { 5 - [(3-met L-benzyl) -oxidyl-1H-? ndol-1-yl.) -3-phenpropyl) tere-butyl methylcarbamate MS (ES) m / z 401 ([M + H] +) Example 16: (1S, 2R) -3- (methylamino) -1- hydrochloride. { 5-f (4-methylbenzyl) oxyl-1 H-indol-1-yl) -1-phenylpropan-2-ol Step 1: In a manner analogous to Example 5, step 3, ((2R, 3S) -2-hydroxy-3. {5 - [(4-methylbenzyl) oxy] -1H-indol-1-yl Ferric-butyl methylcarbamate -3-phenylpropyl) is prepared from [(2R, 3S) -2-hydroxy-3- (5-hydroxy-1 H-indol-1-yl) -3-phenylpropyl] ferric butyl methylcarbamate, replacing 4-methylbenzyl bromide in place of 2-methoxybenzyl chloride. MS (ES) m / z 501 ([M + H] +).

Step 2: A solution of ((2R, 3S) -2-hydroxy-3-. {5 - [(4-methylbenzyl) oxy] -1 H -indole-1-yl.} - 3-phenylpropyl ) tert-butyl methylcarbamate (288 mg, 0.575 mmol) in diethyl ether (3 mL) is treated with a solution of hydrogen chloride (4.0 M in 1,4-dioxane, 0.17 mL, 0.68 mmol). After 16 hours, additional hydrogen chloride solution (4.0 M in 1,4-dioxane, 0.17 mL, 0.68 mmol) is added. After 5 days, the precipitated solid is filtered under vacuum and washed with diethyl ether to give a light pink solid (216 mg) which is partitioned between dichloromethane (20 mL) and saturated sodium bicarbonate (20 mL). The organic phase is separated, washed with saturated saline (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a clear orange foam (183 mg). Flash column chromatography (silica 13 g, 1%, 2%, 4% dichloromethane / methanol saturated with ammonia) provides (1S, 2 /?) - 3- (methylamino) -1-. { 5 - [(4-methylbenzyl) oxy] -1 / - / - indol-1-yl} -1-phenylpropan-2-ol (55 mg, 24%) as a white solid. The solid is dissolved in diethyl ether (3 mL), filtered and treated with a solution of hydrogen chloride (4.0 M in 1,4-dioxane, 0.04 mL, 0.16 mmol) and stirred vigorously for ca. 1 minute. Vacuum filtration provides (1 S, 2R) -3- (methylamino) -1 - (5-f (4-methylbenzyl) oxyl-1 H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride ( 54 mg, 22%) as a light pink solid. MS (ES) m / z 401 ([M + H] +).

Example 17: Hydrochloride (1 S.2R) -3- (methylamino) -1-phenyl-1- (5-) (1 RS) - (1-phenylethoxy) -1H-indole 1-npropan-2-ol In a manner analogous to Example 5, step 3,. { (2R, 3S) -2-hydroxy-3-phenyl-3- [5- (1SR) - (1-phenylethoxy) -1H-indol-1-yl] propyl} tert-butyl methylcarbamate is prepared from [(2R, 3S) -2-hydroxy-3- (5-hydroxy-1H-indol-1-yl) -3-phenylpropyl] methylcarbamate, ferric-butyl, substituting (l-bromoethyl) -benzene instead of 2-methoxybenzyl chloride. MS (ES) m / z 501 ([M + H] +).

In a manner analogous to Example 5, step 4, hydrochloride (1 S, 2R) -3- (methylamino) -1-phenyl-1-5 5 - (1 RS) - (1-phenylethoxy) -1 H -indole-1 -illpropan-2-ol is prepared from. { (2R, 3S) -2-hydroxy-3-phenyl-3- [5- (1SR) - (1-phenylethoxy) -1H-indol-1-yl] propyl} tert-butyl methylcarbamate. MS (ES) m / z 401 ([M + Hf).

Example 18: (1S, 2R) -3- (methylamino) -1-phenyl-1-f5- (2-phenylethoxy) -1H-indol-1-illpropan-2-ol hydrochloride In a manner analogous to Example 5, step 3,. { (2R, 3S) -2-hydroxy-3-phenyl-3- [5- (2-phenylethoxy) -1H-indol-1-yl] propyl} tert-butyl methylcarbamate is prepared from [(2R, 3S) -2-hydroxy-3- (5-hydroxy-1H-indol-1-yl) -3-phenylpropyl] methylcarbamate, ferric-butyl, substituting (2-bromoethyl) -benzene for chloride of 2-methoxybenzyl. MS (ES) m / z 501 ([M + H] +).

In a manner analogous to Example 5, step 4, (1S, 2R) -3- (methylamino) -1-phenyl-1- [5- (2-phenylethoxy) -1H-indole-1-inpropan-2 hydrochloride -ol is prepared from. { (2R, 3S) -2-hydroxy-3-phenyl-3- [5- (2-phenylethoxy) -1 H -indol-1-yl] propyl} tert-butyl methylcarbamate. MS (ES) m / z 401 ([M + Hf).

Example 19: (1S, 2R) -3- (methylamino) -1- | 5- (phenoxy) -1 H -indole-1-ill-1-phenylpropan-2-ol hydrochloride Step 1: Potassium hydroxide (3.0 g, 53 mmol) is added to melt phenol (15 g, 160 mmol) at 1 10 ° C with stirring. After all the potassium hydroxide has dissolved, the solution is cooled to 23 ° C and 05-fluoro-2-nitrotoluene (7.75 g, 50.0 mmol). The mixture is heated at 130 ° C for 2 hours. At this time, an additional hot potassium phenoxide solution (5 g phenol, 1 g potassium hydroxide) is added. After 3.5 hours (total), the mixture is heated to 150 ° O. After 5 hours (total), the cold mixture is poured into 10% aqueous sodium hydroxide (200 mL) and extracted with diethyl ether (2). x 100 mL). The combined extracts are washed with 10% aqueous sodium hydroxide (2 x 100 mL) and water (2 x 100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to produce a brown oil (11.6 g) which is taken in diethyl ether and pre-adsorbed on silica gel (15 g). Purification by flash column chromatography (silica 135 g, 5% ethyl acetate / hexanes) provides 2-methyl-1-nitro-4-phenoxybenzene (11.4 g, 99%) as a clear, clear yellow oil. MS (ES) m / z 230 ([M + Hf).

Step 2: A solution of 2-methyl-1-nitro-4-phenoxybenzene (4.6 g, 20 mmol) and N, N-dimethylformamide diethyl acetal (d 0.859, 4.0 mL, 23 mmol) in? /,? / - dimethylformamide dry (12.5 mL) is heated to 150 ° C. The light yellow solution turns dark reddish-brown. After 22 hours, the cold mixture is taken up in diethyl ether (500 mL), washed with water (3 x 250 mL) and saturated saline solution (250 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give dimethyl- [2- (2-nitro-5-phenoxy-phenyl) - vinyl] -amine crude (5.5 g, 96%) as a dark red oil.

Step 3: A solution of dimethyl- [2- (2-nitro-5-phenoxy-phenyl) -vinyl] -amine (5.5 g, 19 mmol) in ethyl acetate (60 mL) is hydrogenated over 10% palladium on carbon (0.55 g) at 50 psi. After 2 hours, the catalyst is filtered (Celite) and washed with ethyl acetate (2 x 30 mL) and the filtrate is concentrated under reduced pressure to yield a brown oil (4.4 g). Purification by flash column chromatography (silica 160 g, 35% dichloromethane / hexanes) provides 5-phenoxy-1 / - / - indole (2.7 g, 68%) as white needles. MS (ES) m / z 210 ([M + H] +).

Step 4: In a manner analogous to Example 1, step 2, 5-phenoxyindoline is prepared from 5-phenoxy-1H-indole. MS (ES) m / z 212 ([M + Hf).

Step 5: In a manner analogous to Example 1, step 3, (2S, 3S) -3- [5- (phenoxy) -2,3-dihydro-1 / - / - indol-1-yl] -3- Phenylpropane-1,2-diol is prepared from 5-phenoxyindoline. MS (ES) m / z 362 ([M + H] +).

Step 6: In a manner analogous to Example 1, step 4, (2S, 3S) -3- [5- (phenoxy) -1H-indol-1 -yl] -3-phenylpropane-1,2-diol is prepared from (2S, 3S) -3- [5- (phenoxy) -2,3-dihydro-1 -ipdol-1-yl] -3-phenylpropane-1,2-diol. MS (ES) m / z 360 ([M + Hf).

Step 7: In a manner analogous to Example 1, step 5, 2-hydroxy-3- (5-phenoxy-indol-1-yl) -3-phenyl-propyl ester of (2S, 3S) -toluene-4-acid -sulfonic is prepared from (2S, 3S) -3- [5- (phenoxy) -1 H -indol-1-yl] -3-phenylpropane-1,2-diol. MS (ES) m / z 514 ([M + Hf).

Step 8: In a manner analogous to Example 1, step 6, (1S, 2R) -3- (methylamino) -1- [5- (phenoxy) -1 H -indole-1-p-1 hydrochloride -phenolpropan-2-ol is prepared from 2-hydroxy-3- (5-phenoxy-indol-1-yl) -3-phenyl-propyl ester of (2S, 3S) -toluene-4- sulphonic MS (ES) m / z 372.9 ([M + H] +).

Example 20: (1 S.2R) -3- (methylamino) -1- [4- (phenoxy) -1 H-indol-1-in-1-phenylpropan-2-ol hydrochloride Step 1 2-Met-l-3-n-trophenol (4 6 g, 30 mmol), phenylboronic acid (7 3 g, 60 mmol), copper (II) acetate (5 5 g, 30 mmol) and molecular sieves 4 A powder (30 g, dried at 200 ° C) are combined in dry dichloromethane (300 mL) at 23 ° C. Add toluene (d 0 726, 21 mL, 150 mmol) and stir the mixture vigorously at 23 ° C. ° C After 24 hours, additional phenylboronic acid (7 3 g, 60 mmol) is added. After 28 hours (total), additional copper (II) acetate (2 3 g, 13 mmol) is added after 48 hours, the mixture is filtered (Cehta) and washed with dichloromethane. The filtrate is washed with saturated aqueous EDTA solution (disodium salt) (4 x 300 mL) and saline (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to produce a brown sticky solid (6 9 g) which is dissolved in dichloromethane and pre-adsorbed on silica gel (15 g) Purification by flash column chromatography (silica 135 g, 1%, 2%, 5%, 10%, 20%, 40% of ethyl acetate / hexanes) provides 2-meth? -1-n? tro-3-phenoxybenzene (2 9 g, 91% based on 2-met? l-3-n? trophenol recovered) as a yellow oil transparent, clear MS (El) m / z 229 [M +] Step 2 In a manner analogous to Example 19, step 2, d? Met? L- [2- (2-n? Tro-6-phenox? -fen? L) -v? N? L] -am? Na prepared from 2-met? l-1-n? tro-3-phenoxybenzene Step 3 In a manner analogous to Example 19, step 3, 4-phenoxy? -1 / - / -? Ndol is prepared from d? Met? L- [2- (2-n? Tro-6-phenox? -fen? l) -v? n? l] -am? na MS (ES) m / z 210 ÜM + H? Step 4 In a manner analogous to Example 1, step 2, 4-phenoxidolone is prepared from 4-phenoxyl-1H-β-ddol MS (ES) m / z 212 ([M + H] + ) Step 5 In a manner analogous to Example 1, step 3, (2S, 3S) -3- [4- (phenoxy) -2,3-d? H? Dro-1 / - / -? Ndol-1-? l] -3-phenolpropane-1,2-d-ol is prepared from 4-phenoxydolone MS (ES) m / z 362 ([M + Hf] Step 6 In a manner analogous to Example 1, step 4, (2S, 3S) -3- [4- (phenoxy) - 1 / - / -? Ndol-1-tl] -3-phenolpropane-1, 2-d-ol is prepared from (2S, 3S) -3- [4- (phenoxy?) -2,3-d? H? Dro-1H-? Ndol-1-? L] -3-phen ? lpropane-1, 2-d? ol MS (ES) m / z 360 ([M + Hf) Step 7: In a manner analogous to Example 1, step 5, 2-h? Drox? -3- (4-phenox? -? Ndol-1-? L) -3-phenol-propyl acid ester (2S, 3S) -toluene-4-sulfon? Co is prepared from (2S, 3S) -3- [4- (phenoxy?) - 1H-? Ndol-1-? L] -3-phenolpropane -1, 2-d? Ol MS (ES) m / z 514 ([M + Hf) Step 8 In a manner analogous to Example 1, step 6, (1S, 2R) -3- (meth? Lam? No) -l- [4- (phenoxy?) - 1 H-? Ndol-1 -? Hydrochloride? ll-1-phenylpropan-2-ol is prepared from the ester of 2-hydroxyl-3- (4-phenoxy? -? ndol-1-? l) -3-phenol-prop? the (2S, 3S) -toluene-4-sulfone acid co MS (ES) m / z 372 9 ([M + H] +) Example 21 hydrochloride (1 S, 2R) -3- (meth? Lam? No) -1-phen? L-1- (4-phen? L-1 H-? Ndol-1-? L) propan-2 -ol Step 1 A mixture of 4-bromo-1 / - / -? Ndol (1 57 g, 8 0 mmol), phenylboronic acid (1 17 g, 9 6 mmol) and potassium carbonate (3 32 g, 24 mmol) in 3 1 v / v dioxane water (40 mL) is purged with a bubbling stream of nitrogen for 15 minutes Trans-d? Chlorob? S (tp-o-tol? Lfosf? Na) palad? O (ll) (0 314 g , 0.4 mmol) is then added and the reaction mixture is stirred at room temperature overnight. The mixture is then concentrated under reduced pressure and the residue is partitioned between 2 0 N sodium hydroxide solution and ethyl acetate. Separate and the aqueous layer is extracted 3 times with ethyl acetate. The combined organic layers are washed once with saline., they are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (silica gel 5% ethyl acetate in hexane) to give 45 g (94%) of 4%. phenol-1 / - / -? ndol as colored solid HRMS cream calculated for C, 4H ,, N + H +, 194 09642, found (ESI, [M + H] +), 194 0967) Step 2 In a manner analogous to Example 1, Step 2, 4-phenolindole is prepared from 4-phenol-1 / - / -? Ndol HRMS calculated for C? 4H, 3N + H + , 196 1 1207, found (ESI, [M + H] +), 196 1129 Step 3 In a manner analogous to Example 1, Step 3, (2S, 3S) -3-phen? I-3- (4-phen? L-2,3-d? H? Dro-1 H-? Ndol- 1-? L) propane-1,2-d? Ol is prepared from 4-phenol? Ndol? Na HRMS calculated for C23H23N02 + H +, 346 18016, found (ESI, [M + H] +), 346 1807 Step 4 In a manner analogous to Example 1, Step 4, (2S, 3S) -3-phenol-3- (4-phenol-1 / - / -? Ndol-1-? L) propane-1 , 2-d-ol is prepared from (2S, 3S) -3-phen? L-3- (4-phen? L-2,3-d? H? Dro-1 H-? Ndol-1- ? l) propane-1, 2-d? ol HRMS calculated for C23H2, N02 + H +, 344 16451, found (ESI, [M + H] +), 344 164 Step 5: In a manner analogous to Example 1, Step 5, 3- (4-phenol-? Ndol-1-? L) -2-h? Drox? -3-phenol-propyl ester of (2S, 3S) -toluene-4-sulfone-co-acid is prepared from (2S, 3S) -3-phenol-3- (4-phenol-1 H-? ndol-1-? ) propane-1, 2-d? ol MS (ESI) m / z 498 2 ([M + H] +) Step 6: In a manner analogous to Example 1, Step 6, (1S, 2R) -3- (meth? Lam? No) -1-phenol-1- (4-phenol-1H- hydrochloride ? dol-1-? l) propan-2-ol is prepared from the ester of 3- (4-phenol-? ndol-1-? l) -2-hydrox? -3-phen? -propyl ether (2S, 3S) -toluene-4-sulfon? co HRMS calculated for C24H24N20 + H +, 357 19614, found (ESI, [M + H] +), 357 1962 Example 22 (1S, 2R) -3- (meth? Lam? No) -1-phenol-1- (6-phenol-1 H-? Ndol-1-? L) propan-2 hydrochloride -ol In a manner analogous to Example 21, Step 1, 6-phenol-1 / - / -? Ndol is prepared from 6-bromo-1 H-? Ndol HRMS calculated for C, 4H ,, N, 193 08915 , found (El, M +), 193 0891) In a manner analogous to Example 1, Step 2, 6-phenolindole is prepared from 6-phenol-1H-β-ndol HRMS calculated for C, 4H13N, 195 10480, found (El, M + ), 195 1034 In a manner analogous to Example 1, Step 3, (2S, 3S) -3-phen? L-3- (6-phen? L-2,3-d? H? Dro-1 H-? Ndol-1- ?) propane-1,2-d? ol is prepared from 6-phenol? ndol? na HRMS calculated for C23H23N02 + H +, 346 18016, found (ESI, [M + Hf), 346 1787 In a manner analogous to Example 1, Step 4, (2S, 3S) -3-phen? I-3- (6-phen? L-1 / - / -? Ndol-1-? L) propane-1, 2 -d? ol is prepared from (2S, 3S) -3-phen? l-3- (6-phen? l-2,3-d? h? dro-1 / - / -? ndol-1- ? l) propane-1, 2-d? ol HRMS calculated for C23H21N02 + H +, 344 16451, found (ESI, [M + H] +), 344 1633 In a manner analogous to Example 1, Step 5, 3- (6-phenol-? Ndol-1-? L) -2-h? Drox? -3-phenol-propyl acid ester ( 2S, 3S) -toluene-4-sulfon? Co is prepared from (2S, 3S) -3-phenol-3- (6-phenol-1 H-? Ndol-1-? L) propane -1, 2-d? Ol MS (ESI) m / z 498 2 ([M + H] +) In a manner analogous to Example 1, Step 6, (1S, 2R) -3- (meth? Lam? No) -1-phenol-1- (6-phenol-1 H-? Ndol hydrochloride. -1-? L) propan-2-ol is prepared from the ester of 3- (6-phenol-? Ndol-1-? L) -2-h? Drox? -3-phen? L-prop The acid (2S, 3S) -toluene-4-sulfone? HRMS calculated for C24H24N2O + H +, 357 19614, found (ESI, [M + H] +), 357 1958 Example 23 (1S, 2R) -3- (meth? Lam? No) -1-phen? L-1- (7-phen? L-1 H-? Ndol-1-? L) propan-2 hydrochloride -ol In a manner analogous to Example 21, Step 1, 7-phenyl-1 H-indole is prepared from 7-bromo-1 / - / - indole. HRMS: calculated for C, 4H ,, N, 193.08915; found (El, M +), 193.0878.

In a manner analogous to Example 1, Step 2, 7-phenylindoline is prepared from 7-phenyl-1H-indole. MS (ESI) m / z 196.2 ([M + H] +).

In a manner analogous to Example 1, Step 3, (2S, 3S) -3-phenyl-3- (7-phenyl-2,3-dihydro-1H-indol-1-yl) propane-1,2-diol was prepared from 7-phenylindoline. HRMS: calculated for C23H23NO2 + H +, 346.18016; found (ESI, [M + H] +), 346.1816.

In a manner analogous to Example 1, Step 4, (2S, 3S) -3-phenyl-3- (7-phenyl-1H-indol-1-yl) propane-1,2-diol is prepared from (2S , 3S) -3-phenyl-3- (7-phenyl-2,3-dihydro-1 H-indol-1-yl) propane-1,2-diol. HRMS: calculated for C23H2, NO2 + H +, 344.16451; found (ESI, [M + H] +), 344.1626.

In a manner analogous to Example 1, Step 5, 3- (7-phenyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl (2S, 3S) -toluene-4-sulfonic acid ester prepared from (2S, 3S) -3-phenyl-3- (7-phenyl-1H-indol-1-yl) propane-1,2-diol. MS (ESI) m / z 498.2 ([M + H] +).

In a manner analogous to Example 1, Step 6, hydrochloride of (1 S, 2R) -3- (methylamino) -1-phenyl-1- (7-phenyl-1 H -indole-1-yl) propan -2-ol is prepared from 3- (7-phenyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl (2S, 3S) -toluene-4-sulfonic acid ester. HRMS: calculated for C24H24N20 + H +, 357.19614; found (ESI, [M + H] +), 357.1971.

Example 24: (1S, 2R) -1-r5- (benzyloxy) -1H-indol-1-in-1- (3-fluorophenyl) -3- (methylamino) propan-2-ol hydrochloride Step 1: A 2 L round bottom flask, three necks, oven dried with two oven-dried addition funnels and a rubber stopper loaded with D-isopropyl D-tartrate (11.55 g, 49.3 mmol, 0.30 equiv. ), activated molecular sieves, powder of 4 A (40 g) and anhydrous dichloromethane (800 mL) under nitrogen. After cooling to -25 ° C, titanium isopropoxide (9.6 mL, 33 mmol, 0.20 equiv.) Is added slowly to the reaction mixture via a hypodermic syringe. After stirring for 10 minutes, anhydrous t-butyl hydroperoxide (5.5 M in decane, 75.0 mL, 413 mmol, 2.5 equiv.) Is added in a moderate proportion via an additive funnel. The resulting mixture is stirred at -25 ° C for 30 minutes, trans-3-fluoro-cinnamyl alcohol (25.0 g, 164 mmol) in anhydrous dichloromethane (50 mL) is added dropwise via an additive funnel while maintain the temperature at -25 ° C. After the addition, the reaction mixture is stirred at -25 ° C for 1 hour and at -20 ° C for an additional 3 hours. After the reaction is complete, cold aqueous sodium hydroxide solution (30%, 20 mL) saturated with sodium chloride at -20 ° C is slowly added. After diethyl ether (150 mL) is added, the cold bath is removed and the mixture is warmed to ~ 5 ° C and stirred for 1 hour. Anhydrous magnesium sulfate (50 g) is added and the mixture is stirred for 20 minutes, then filtered through a pad of silica gel, and washed with diethyl ether (300 mL). The filtrate is concentrated and toluene is used to azeotropically remove excess t-butyl hydroperoxide. The residual oil is purified on silica gel (0-30% ethyl acetate / hexane) to give 24.80 g (90%) of [(2R, 3R) -3- (3-fluorophenyl) oxirane-2-yl] methanol as a viscous colorless oil. Percent of ee: > 96.5%. MS (ESI) m / z 169.1 ([M + H] +).

Step 2: A mixture of sodium hydride (60% in mineral oil, 0.40 g, 10 mmol) and fer-butanol (5 mL) is stirred for 15 minutes under nitrogen at room temperature. 5-Benzyloxyindole (2.23 g, 10 mmol) in methylene chloride (2 mL) is then added and the mixture is stirred for an additional 30 minutes at room temperature. A pre-mixed solution of titanium isopropoxide (3.55 mL, 12 mmol) and [(2R, 3R) -3- (3-fluorophenyl) oxirane-2-yl] methanol (68 g, 10 mmol) in methylene chloride ( 2 mL) is added, and the reaction mixture is stirred at room temperature for 15 hours until the remaining epoxide is determined by tic. The mixture is filtered through a pad of Celite, and the filtrate is then treated with a 2N aqueous solution of hydrochloric acid (50 mL) with stirring for 30 minutes. The organic layer is separated and the aqueous layer is extracted with methylene chloride several times. The combined extracts are washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by Biotage Horizon (FlasH 40 M, silica, gradient of 10% ethyl acetate / hexane at 65% ethyl acetate / hexane) to yield (2S, 3S) -3- (5-benzyloxy-1 H-indol-1-yl) -3 - (3-fluorophenyl) propane-1,2-diol as an oil. MS (ESI) m / z 392 ([M + H] +).

In a manner analogous to Example 1, step 5, 3- (5-benzyloxy-indol-1-yl) -2-hydroxy-3- (3-fluorophenyl) -propyl (2S, 3S) -toluene-4-ester -sulfonic is prepared from (2S, 3S) -3- (5-benzyloxy-1 H-indol-1-yl) -3- (3-fluorophenyl) -propane-1,2-diol as an oil. MS (ESI) m / z 546 ([M + H] +).

In a manner analogous to Example 1, step 6, (1S, 2R) -1- (5-benzyloxy-1H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) hydrochloride. propan-2-ol is prepared from 3- (5-benzyloxy-indol-1-yl) -2-hydroxy-3- (3-fluorophenyl) -propyl (2S.3S) -toluene-4-ester ester -sulfonic and methylamine solution (2.0 M in methanol) as a whitish solid. MS (ES) m / z 405.2; HRMS: calculated for C25H25FN202 + H +, 405.19728; found (ESI, [M + Hf), 405.1989.

Example 25: (1 S, 2 R) -1- [5- (benzyloxy) -2,3-dihydro-1 H-indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) hydrochloride propan-2-ol Step 1: To a mixture of trans-3-fluoro-cinnamic acid (50 g, 300 mmol) and iodomethane (300 mL) in acetone (1 L) is added cesium carbonate (147 g, 450 mmol, 1.5 equiv. .), and the mixture is heated at 65 ° C for 1.5 hours in a sealed reaction vessel, after cooling to room temperature, the reaction mixture is diluted with ethyl acetate (1 L), filtered through a silica gel pad, and concentrated under reduced pressure 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 +).

Step 2: To a solution of methyl ester of trans-3-fluoro-cinnamic acid (69.61 g, 386 mmol) in dry dichloromethane (1 L) at -78 ° C under nitrogen is added dropwise diisobutylaluminum hydride (net, 172 mL, 965 mmol, 2.5 equiv.) Via a addiction funnel. After the addition is complete, the reaction mixture is allowed to warm to -30 ° C and is stirred for an additional 1 hour, then quenched with methanol (150 mL). After warming to room temperature, the reaction mixture is treated with saturated aqueous sodium potassium tartrate solution (300 mL) and stirred for 30 minutes. The organic layer is washed sequentially with 1N aqueous hydrochloric acid solution, saturated sodium bicarbonate solution and saline, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude oil is purified by silica gel chromatography (0-50% ethyl acetate: hexane) to give 53.07 g (90%) of trans-3-Fluorocinnamyl alcohol as a colorless oil. MS (ES) m / z 152.1 (M +).

Step 3: A 2-L, 3-neck round bottom flask, oven dried with two oven-dried addition funnels and a rubber stopper is charged with diisopropyl D-tartrate (11.55 g, 49.3 mmol, 0.30 equiv.) , activated molecular sieves, in 4 A powder (40 g) and dry dichloromethane (800 mL) under nitrogen. After cooling to -25 ° C, titanium isopropoxide (9.6 mL, 33 mmol, 0.20 equiv.) Is added to the reaction mixture slowly via a hypodermic syringe. After stirring for 10 minutes, anhydrous t-butyl hydroperoxide solution (5.5 M in decane, 75.0 mL, 413 mmol, 2.5 equiv.) Is added in a moderate proportion via an additive funnel. The resulting mixture is stirred at -25 ° C for 30 min. Then trans-3-Fluorocinnamyl alcohol (25.0 g, 164 mmol) in dry dichloromethane (50 mL) is added dropwise via a funnel while keeping the temperature at -25 ° C. After the addition , the reaction mixture is stirred at -25 ° C for 1 hour and at -20 ° C for another 3 hours. After the reaction is complete, cold aqueous sodium hydroxide solution (30%, 20 mL) saturated with sodium chloride is slowly added at -20 ° C. After diethyl ether (150 mL) is added, the cold bath stir and the mixture is allowed to warm to ~ 5 ° C and stir for 1 hour. Magnesium sulfate (anhydrous, 50 g) is added and the mixture is stirred for 20 minutes, then filtered through a pad of silica gel, and washed with diethyl ether (300 mL). The filtrate is concentrated and toluene is used to azeotropically remove excess t-butyl hydroperoxide. The residual oil is purified on silica gel (0-30% ethyl acetate: hexane) to give 24.80 g (90%) of [(2R, 3R) -3- (3-fluorophenyl) oxirane-2-yl] methanol as a colorless, viscous oil. Percent of ee: > 96.5%. MS (ESI) m / z 169.1 ([M + H] +).

Step 4 In a manner analogous to Example 1, step 3, (2S, 3S) -3- [5- (benzylox?) -2,3-d? H? Dro-1 H-? Ndol-1-? l] -3- (3-fluorophen? l) propane-1,2-d? ol is prepared from 5- (benzylox?)? ndol? na (Example 1, step 2) and [(2R, 3R) -3- (3-fluorophen? L) ox? Ran-2? L] methanol as an amber oil MS (ESI) m / z 394 2 ([M + H] +), calculated HRMS for C24H24FNO3 + H +, 394 1813, found (ESI, [M + Hf), 394 1808 Step 5 To a solution of (2S, 3S) -3- [5- (benzylox?) -2,3-d? H? Dro-1 H-? Ndol-1-? L] -3- (3 -fluorophen? l) propane-1,2-d? ol (348 mg, 0 884 mmol) in dichloromethane (3 mL) under nitrogen is added tetylamine (0 62 mL, 43.4 mmol, 5 equiv) The mixture is cooled to 0 ° C, and para-toluenesulfonyl chloride (219 mg, 15 mmol) is added portionwise. The reaction mixture is stirred at 0 ° C for 6 hours and methylamine solution (33% in absolute ethanol, 5 mL) and the reaction mixture is sealed, and stirred overnight while remaining at room temperature. All volatiles are removed under reduced pressure. The oily residue is dissolved in dichloromethane (20 mL), washed with aqueous potassium carbonate. (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure Purification by Biotage chromatography (FlasH12 ?, silica, 0-15% MeOH / d? Chloromethane / 0 5% tpetila ina) gives 282 mg (78%) (1S, 2R) -1- [5- (benz? Lox?) -2,3-d? H? Dro-1 H-? Ndol-1-? L] -1- (3- F luorofen? l) -3- (methanolamine) propan-2-ol, which is dissolved in dichloromethane (5 mL) and treated with hydrogen chloride solution (1 0 M in diethyl ether, 0 80 mL , 80 mmol) To the resulting solution hexane is added until a white powder forms, which is collected, washed with hexane, and dried in vacuo to yield (1 S, 2R) -1- [5- (benz? lox?) - 2,3-d? h? dro-1 H-? ndol-1-? l] -1- (3-fluorofen? l) -3- (met? lam? no) propan- 2-ol as a white powder MS (ES) m / z 407 0 ([M + H] +), HRMS calculated for C25H2? FN202 + H +, 407 2129, found (ESI, [M + Hf), 407 2131 Example 26 (1S, 2R) -1- [5- (benzylx?) -2,3-d? H? Dro-1 H-? Ndol-1-? L] -3- hydrochloride (met? lam? no) -1-phen? lpropan-2-ol In a manner analogous to Example 25, step 5, hydrochloride (1 S, 2R) -1- [5- (benzyloxy) -2,3-dihydro-1 H-indol-1-yl-3- (methylamino) - 1-phenylpropan-2-ol is prepared from (2S, 3S) -3- [5- (benzyloxy) -2,3-dihydro-1H-indol-1-yl] -3-phenylpropane-1, 2- diol (Example 1, step 3) as a white powder. MS (ES) m / z 389.2 ([M + H] +); HRMS: calculated for C25H28N202 + H +, 389.2224; found (ESI, [M + H] +), 389.2220.

Example 27: 5'-chloro-1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' hydrochloride ( 1?) - ona Step 1: 5-Cloroxindole (1 g, 6.0 mmol) and lithium chloride (0.63 g, 14.8 mmol) are suspended in tetrahydrofuran (50 mL) and the mixture is cooled to 0 ° C. N-Butylithium is added slowly (6.2 mL, 12.6 mmol) and the mixture is stirred for 20 minutes, then dibromopentane (0.82 mL, 6.0 mmol) is added. The mixture is heated to 25 ° C and stirred for 16 hours. The reaction is quenched with saturated aqueous ammonium chloride and diluted with diethyl ether. The organics are washed with water and saturated saline, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography (0-20% hexane / ethyl acetate) yields 700 mg (50%) of 5'-chlorospiro [cyclohexane-1,3'-indole] -2 '(1?) -one as a solid White. MS (ESI) m / z 236 ([M + H] +).

Step 2: 5'-chlorospiro [cyclohexane-1,3'-indole] -2 '(1?) -one (700 mg, 3.0 mmol) is dissolved in N, N-dimethylformamide (10 mL) and sodium hydride ( 244 mg, 6.1 mmol, 60% by weight of suspension in mineral oil) is added in portions over 15 minutes and the mixture is stirred for an additional 30 minutes. E a separate vial, [(2R, 3R) -3-phenyloxyran-2-yl] methanol (0.8 g, 5.3 mmol, from Example 1 Step 1) is dissolved in N, N-dimethylformamide (10 mL) and isopropoxide added titanium (1.6 mL, 5.3 mmol) and the Mix is stirred 30 minutes. The isopropoxide / titanium epoxide solution is then added to the solution of sodium salt of oxindole in drop form and the mixture is stirred at room temperature for 16 hours. The mixture is then carefully quenched with 2.0N aqueous hydrochloric acid and diluted with 200 mL of 2.0 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate and then the organic layers are combined, washed with water, and saturated saline solution. , they are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified via Isco chromatography (Redisep, silica, gradient 20% to 100% ethyl acetate in hexane) to yield 0.5 g (43%) of 5'-chloro-1 '- [(1 S, 2S) -2,3-dihydroxy-1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2 '(1?) -one as a foamy solid. MS (ES) m / z 385.9 ([M + Hf).

Step 3: 5'-chloro-1 '- [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' (1 'H) -one (0.5 g, 1.3 mmol) is dissolved in pyridine (4 mL), p-toluenesufonyl chloride (310 mg, 1.6 mmol) is added and the mixture is stirred for 4 hours. The reaction mixture is then diluted with diethyl ether and washed with water, 2.0 N aqueous hydrochloric acid, saturated copper sulfate, 2.0 N hydrochloric acid, and saturated saline. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is immediately dissolved in a solution of methylamine (8.0 M in ethanol, 10 L, 80 mmol) and stirred for 16 hours. The mixture is then concentrated under reduced pressure and purified by flash chromatography (0% to 10% methanol in dichloromethane) to give 5'-chloro-1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2 '(1?) -one as a colorless oil. The free base is dissolved in diethyl ether (10 mL) and treated with a solution of hydrogen chloride (2.0 M in diethyl ether, 1.1 equivalent). The white precipitate is collected and dried under vacuum to give 180 mg (32% over three steps) of 5'-chloro-1 '- [(1 S.2R) -2-hydroxy-3- (methylamino) - hydrochloride 1-phenylpropyl-pyrrocyclohexane-1,3'-indoll-2 '(1' H) -one. HRMS: calculated for C23H27CIN202 + H +, 399.18338; found (ESI, [M + H] +), 399.1822.

Example 28: 6'-Chloro-1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' hydrochloride ( 1?) - ona In a manner analogous to Example 27, Step 1, 6'-chlorospiro [cyclohexane-1,3'-indole] -2 '(1' H) -one is prepared from 6-chloroxindole. MS (ES) m / z 236.0 ([M + H] +).

In a manner analogous to Example 27, Step 2, 6'-chloro-1 '- [(1 S, 2S) -2,3-dihydroxy-1-phenylpropyl] spiro [cyclohexane-1,3'-indole] - 2 '(1' H) -one is prepared from 6'-chlorospiro [cyclohexane-1,3'-indo] -2 '(1' H) -one. MS (ES) m / z 385.8 ([M + H] +).

In a manner analogous to Example 27, Step 3, 6'-Chloro-1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1, 3 hydrochloride] '-indole] -2' (1?) -one is prepared from 6'-chlorospiro [cyclohexane-1,3'-indole] -2 '(1?) -one. HRMS: calculated for C23H2? CIN202 + H +, 399.18338; found (ESI, [M + H] +), 399,182.

Example 29: 6'-fluoro-1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' hydrochloride ( 1?) - ona Step 1: In a manner analogous to Example 27, Step 1, 6'-fluorospiro [cyclohexane-1,3'-indole] -2 '(1' H) -one is prepared from 6-fluorooxindole. MS (ES) m / z 219.9 ([M + H] +).

Step 2: In a manner analogous to Example 27, Step 2, 1 '- [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -6'-fluorosphero [cyclohexane-1,3'- indole] -2 '(1?) -one is prepared from 6'-fluorospiro [cyclohexane-1,3'-indole] -2' (1?) -one.

Step 3: In a manner analogous to Example 27, Step 3, 6'-fluoro-1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropipespyrorcyclohexane-1,3'-hydrochloride -indoll-2 '(1?) -one is prepared from 1' - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -6'-fluorospiro [cyclohexane-1, 3'- Ndol] -2 '(1?) - ona. HRMS: calculated for C23H2? FN202 + H +, 383.21293; found (ESI, [M + H] +), 383.2139.

Example 30: 5'-fluoro-1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' hydrochloride ( 1?) - ona Step 1: In a manner analogous to Example 27, Step 1, 5'-fluorospiro [cyclohexane-1,3'-indole] -2 '(1' H) -one is prepared from 5-fluoroxyindole. MS (ES) m / z 219.9 ([M + H] +).

Step 2: In a manner analogous to Example 27, Step 2, 1 '- [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -5'-fluorospiro [cyclohexane-1,3'-indole] -2 '(1?) -one is prepared from 5'-fluorospiro [cyclohexane-1,3'-indole] -2' (1?) -one. MS (ES) m / z 369.8 ([M + H] +).

Step 3: In a manner analogous to Example 27, Step 3, 5'-fluoro-1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-] hydrochloride 1,3'-indole] -2 '(1?) -one is prepared from 1' - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -5'-fluorospir [ cyclohexane-1,3'-indole] -2 '(1?) -one. HRMS: calculated for C23H2? FN202 + H +, 383.21293; found (ESI, [M + H] +), 383.2125.

Example 31: 7'-Chloro-1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' hydrochloride ( 1?) - ona In a manner analogous to Example 27, Step 1, 7'-chlorospiro [cyclohexane-1,3'-indole] -2 '(1' H) -one is synthesized from 7-chloroxindole. MS (ES) m / z 236.0 ([M + H] +).

In a manner analogous to Example 27, Step 2, 7'-chloro-1 '- [(1 S, 2S) -2,3-dihydroxy-1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2 '(1?) -one is prepared from 7'-chlorospiro [cyclohexane-1,3'-indole] -2' (1?) - ona.MS (ES) m / z 385.8 ([M + H] +).

In a manner analogous to Example 27, Step 3, 7'-Chloro-1 '- [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1, 3'-indole] -2 '(1?) -one is prepared from 7'-chlorospiro [cyclohexane-1,3'-indole] -2' (1?) -one. HRMS: calculated for C23H27CIN202 + H +, 399.18338; found (ESI, [M + H] +), 399 1837.

Example 32: 6'-fluoro-1 '- [(1 S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] spiro [cyclohexane-1, 3'- hydrochloride] indole] -2 '(1?) - ona In a manner analogous to Example 27, Step 2, 1 '- [(1 S, 2 S) -2,3-dihydroxy-1- (3-fluorophenyl) -propyl] -6'-fluorospiro [cyclohexane-1,3' -indol] -2 '(1?) -one is prepared from 6'-fluorospiro [cyclohexane-1,3'-indole] -2' (1?) -one (from Example 29 Step 1) and [( 2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol.

In a manner analogous to Example 27, Step 3, 6'-fluoro-1 '-f (1 S, 2R) hydrochloride - 1- (3-fluorophen? L) -2-hydrox? -3- (met? Lam? No) prop? Llesp? Rofc? Clohexane-1, 3 '-? Ndoll-2' (1?) - one is prepared from 1 '- [(1 S, 2S) -2,3-d? h? drox? -1- (3-fluorophen? l) prop? l] -6'-fluorosp? ro [c? clohexane-1, 3 '-? ndol] -2' (1 'H) -one HRMS calculated for C23H26F2N202 + H +, 401 20351, found (ESI, [M + H] +), 401 2005 EXAMPLE 33 (1S, 2R) -3- (methalamino) -1-phenol-1-esp? Ro hydrochloride [c-clohexane-1, 3 '-? Ndol] -1' (2 ?) -? lpropan-2-ol In a manner analogous to Example 1, step 3, (2S, 3S) -3-phenol-3-esp? Ro [c-clohexane-1, 3 '-? Ndol] -1' (2'H) - ? -propane-1, 2-d? ol is prepared from spiro [c? clohexane-1, 3 '-? ndol? na] 1 and [(2R, 3R) -3-phen? lox? 2-? L] methanol (from Example 1, step 1) as a white solid MS (ESI) m / z 338 2 ([M + H] +), HRMS calculated for C22H2? N02 + H +, 338 2115, found ( ESI, [M + H] +), 338 2115 In a manner analogous to Example 25, step 5, hydrochloride of (1S, 2R) -3- (meth? Lam? No) -1-phen? L-1-esp? Rofc? Clohexane-1, 3'-? ndoll-1 '(2?) -? lpropan-2-ol is prepared from (2S, 3S) -3-phen? l-3-esp? ro [c? clohexane-1, 3' -? ndol] -1 '(2'H) -? Lpropane-1,2-d? Ol as a white powder MS (ES) m / z 351 2 ([M + Hf), HRMS calculated for C23H3oN20 + H +, 351 2431, found (ESI, [M + H] +), 351 2421 Example 34 (1 S.2R) -1- (3-fluorophenyl) -3- (meth? Lam? No) -1- (3- [2- (tpfluoromethoxy?) Phen? Pl H-? Ndol hydrochloride -1 -? L) propan-2-ol Kucerovy, A, Hathaway, JS, Mattner, P G, Repic, O Synth Commun 1992, 22, 729-733 Step 1: 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, from Example 25, Step 3) it is heated at 125 ° C for 5 hours in a sealed reaction flask. After cooling, the crude product is dissolved in ethyl acetate, absorbed in Fluorocil, and purified by Biotage chromatography (FlasH40i, silica, 0-55% EtOAc / hexane) to give 2.55 g (75%) of (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] +).

Step 2: A mixture of (2S, 3S) -3- (2,3-dihydro-1 / - / - indol-1-yl) -3- (3-fluorophenyl) propane-1,2-diol (2.00 g) , 6.96 mmol) and activated manganese dioxide (20.0 g, 230 mmol) in dichloromethane (30 mL) is stirred at 20 ° C for 3 hours. The mixture is diluted with ethyl acetate (15 mL), filtered through a pad of silica gel, and concentrated under reduced pressure. The crude product is purified by Biotage chromatography (FlasH40i, silica, 0-70% EtOAc / hexane) to give 1.40 g (71%) of (2S, 3S) -3- (3-fluorophenyl) -3- (1H-indole -1-yl) propane-1,2-diol as a colorless oil. MS (ESI) m / z 286.0 ([M + H] +). HRMS: calculated for C,? H? 6FN02 + H +, 286.1238; found (ESI, [M + Hf), 286.1239.

Step 3: To a solution of (2S, 3S) -3- (3-fluorophenyl) -3- (1H-indol-1-yl) propane-1,2-diol (1.34 g, 4.56 mmol) in? /, ? / - dimethylformamide (20 mL) is added powdered solid potassium hydroxide (0.76 g, 13.68 mmol). The mixture is stirred for 15 minutes under nitrogen at room temperature, then iodine (1.21 g, 4.72 mmol) is added in one portion. The mixture is stirred for 30 minutes at room temperature and then poured into 5% aqueous thiosulfate solution (100 mL). The solution is extracted 3 times with ethyl acetate and the combined extracts are washed 3 times with water. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified via Biotage chromatography (FlasH40i, silica, 40% ethyl acetate / hexane) to yield 0.91 g (48%) of (2S, 3S) -3- (3-fluorophenyl) -3- ( 3-iodo-1 / - / - indol-1-yl) propane-1,2-diol as a dark brown oil. MS (ES) m / z 411.9 ([M + Hf).

Step 4: A mixture of (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1H-indol-1-yl) propane- 1,2-diol (0.51 g, 1.24 mmol), 2- (trifluoromethoxy) phenylboronic acid (0.38 g, 1.85 mmol), and potassium phosphate (0.78 g, 3.72 mmol) in? /,? / - dimethylformamide (10 mL ) is degassed with nitrogen for 5 minutes then a catalytic amount (0.02 g) of [1,4-bis- (diphenylphosphine) butane] palladium (II) dichloride is added. The solution is heated at 90 ° C for 3 hours then cooled and poured into water (100 mL). The aqueous mixture is extracted 3 times with ethyl acetate and the combined extracts are then washed 2 times with water. The ethyl acetate phase is dried by filtration through a plug of silica gel and then concentrated under reduced pressure. The residue is purified by Biotage chromatography (FlasH40i, silica, 40% ethyl acetate / hexane) to yield 0.17 g of (2S, 3S) -3- (3-fluorophenyl) -3-. { 3- [2- (trifluoromethoxy) phenyl] -1H-indol-1-yl} propane-1,2-diol as an oil, which is used in the next step without further purification.

Step 5: In a manner analogous to Example 27, step 3, (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- hydrochloride. { 3- [2- (trifluoromethoxy) phenyl-1 H -indole-1-yl) propan-2-ol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3-. { 3- [2- (trifluoromethoxy) phenyl] -1 / - / - indol-1-yl} propane-1, 2-diol. MS (ES) m / z 459.1 ([M + Hf); HRMS: calculated for C25H22F4N202 + H +, 459.16902; found (ESI, [M + Hf), 459.1706.

Example 35: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (3- [2- (isopropoxy) phenyl-1 H-indol-1-yl) propane hydrochloride 2-ol In a manner analogous to Example 34, step 4, (2S, 3S) -3- (3-fluorophenyl) -3-. { 3- [2- (isopropoxy) phenyl] -1 / - / - indol-1-yl} propane-1,2-diol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1 / - / - indol-1-yl) propane-1, 2- diol (from Example 34, step 3) and acid 2- (isopropoxyphenyl) boronic acid.

In a manner analogous to Example 27, step 3, (1S, 2R) -1- (3-fluorophenyl) -3- (methalamine) -1- hydrochloride. { 3-f2- (isopropoxy) phenyl-1H-indol-1-yl) propan-2-ol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3-. { 3- [2- (isopropoxy) phenyl] -1 H -indole-1-yl} propane-1, 2-diol.

MS (ES) m / z 433.2 ([M + Hf); HRMS: calculated for C2? H29FN202 + H +, 433.22858; found (ESI, [M + Hf), 433.2221.

Example 36: (1 S, 2R) -1- (3-fluorophenyl) -1- [3- (4-fluorophenyl) -1 H -indole-1-ill-3- (methylamino) propan-2 hydrochloride -ol In a manner analogous to Example 34, step 4, (2S, 3S) -3- (3-fluorophenyl) -3-. { 3- [4-fluorophenyl] -1- -indol-1-yl} propane-1,2-diol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1H-indol-1-yl) propane-1,2-diol (from Example 34, step 3) and 4- (fluorophenyl) boronic acid.

In a manner analogous to Example 27, step 3, (1S, 2R) -1- (3-fluorophenyl) -1- [3- (4-fluorophenyl) -1H-indole-1-in-3 hydrochloride. - (methylamino) propan-2-ol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3-. { 3- [4-fluorophenyl] -1H-indol-1-yl} propane-1, 2-diol. MS (ES) m / z 393.2 ([M + Hf); HRMS: calculated for C24H22F2N20 + H +, 393.17729; found (ESI, [M + Hf), 393.1767.

Example 37: (1 S, 2 R) -1- (3-fluorophenyl) -3- (methylamino) -1- [3- (2-phenoxyphenyl) -1 H -indole-1-iNpropan-2-hydrochloride ol In a manner analogous to Example 34, step 4, (2S, 3S) -3- (3-fluorophenyl) -3-. { 3- [2-phenoxyphenyl] -1 H-indol-1-yl} propane-1,2-diol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1 / - / - indol-1-yl) propane-1, 2- diol (from Example 34, step 3) and 2- (phenoxyphenyl) boronic acid.

In a manner analogous to Example 27, step 3, (1 S, 2R) -1- (3-fluorophenyl) -1- [3- (2-phenoxyphenyl) -1 H -indole-1-ill-3- hydrochloride (methylamino) propan-2-ol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3-. { 3- [2-phenoxyphenyl] -1 H-indol-1-yl} propane-1, 2-diol. MS (ES) m / z 467.2 ([M + Hf); HRMS: calculated for C30H2? FN2O2 + H +, 467.21293; found (ESI, [M + Hf), 467.2131.

Example 38: (1 S, 2R) -1- [3- (2,4-difluorophenyl) -1 H -indole-1-yn-1- (3-fluorophenyl) -3- (methylamino) propan-2-ol hydrochloride In a manner analogous to Example 34, step 4, (2S, 3S) -3- (3- (2,4-difluorophenyl) -1 / - / - indol-1-yl) -3- (3-fluorophenyl) propane -1,2-diol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1 / - / - indol-1-yl) propane-1,2-diol (from Example 34, step 3) and 2,4- (difluorophenyl) boronic acid.

In a manner analogous to Example 27, step 3, hydrochloride of (1S, 2R) -1-f3- (2,4- difluorophenyl) -1 H -indole-1 -11-1 - (3-fluorophenyl) -3- (methylamino) propan-2-ol is prepared from (2S, 3S) -3- (3- (2, 4-difluorophenyl) -1 H -indol-1-yl) -3- (3-fluorophenyl) propane-1,2-diol. MS (ES) m / z 411.2 ([M + Hf); HRMS: calculated for C24H2, F3N20 + H +, 411.16787; found (ESI, [M + Hf), 411,167 Example 39: (1 S.2R) -1- [3- (2,5-difluorophenyl) -1 H -indole-1-ill-1- (3-fluorophenyl) -3- (methylamino) propan-2 hydrochloride -ol In a manner analogous to Example 34, step 4, (2S, 3S) -3- (3- (2,5-difluorophenyl) -1 H -indol-1-yl) -3- (3-fluorophenyl) propane-1 , 2-diol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1 H-indol-1-yl) propane-1,2-diol (from Example 34 , step 3) and 2,5- (difluorophenyl) boronic acid.

In a manner analogous to Example 27 step 3, (1 S, 2 R) -1- [3- (2,5-difluorophenyl) -1 H -indole-1-lime-1 - (3-fluorophenyl) hydrochloride -3- (methylamino) propan-2-ol is prepared from (2S, 3S) -3- (3- (2,5-difluorophenyl) -1H-indol-1-yl) -3- (3- fluorophenyl) propane-1,2-diol. MS (ES) m / z 411.2 ([M + Hf); HRMS: calculated for C24H2, F3N20 + H +, 41 1.16787; found (ESI, [M + Hf), 411.1663.

Example 40: (1 S.2R) -1-r3- (2,3-dimethoxyphenyl) -1 H -indole-1-ill-1- (3-fluorophenyl) -3- (methylamino) propan-2 hydrochloride ol In a manner analogous to Example 34, step 4, (2S, 3S) -3- (3- (2,3-dimethoxyphenyl) -1 / - / - indol-1 -yl) -3- (3-fluorophenyl) propane -1,2-diol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1H-indol-1-yl) propane-1,2-diol (from Example 34, step 3) and 2,3- (dimethoxyphenyl) boronic acid.

In a manner analogous to Example 27, step 3, (1 S, 2R) -1- [3- (2,3-dimethoxyphene!) - 1 H -indole-1-lime-1 - (3-fluorophenyl) hydrochloride -3- (methylamino) propan-2-ol is prepared from (2S, 3S) -3- (3- (2,3-dimethoxyphenyl) -1H-indol-1-yl) -3- (3-fluorophenyl) ) propane-1,2-diol. MS (ES) m / z 435.1 ([M + Hf); HRMS: calculated for C26H2? FN203 + H +, 435.20785; found (ESI, [M + Hf), 435.2067.

Example 41: (1 S.2R) -1-r3- (2,4-dichlorophenyl) -1 H -indole-1-ill-1- (3-fluorophenyl) -3- (methylamino) propan-2-ol hydrochloride In a manner analogous to Example 34, step 4, (2S, 3S) -3- (3- (2,4-dichlorophenyl) -1 / - / - indol-1-yl) -3- (3-fluorophenyl) propane -1,2-diol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1 / - / - indol-1-yl) propane-1,2-diol (from Example 34, step 3) and 2,4- (dichlorophenyl) boronic acid MS (ES) m / z 429.6 ([M + Hf).

In a manner analogous to Example 27, step 3, hydrochloride of (1 S, 2R) -1-f3- (2,4-dichlorophenol) -1 H -indole-1-n-1- (3 -fluorophenyl) -3- (methylamino) propan-2-ol is prepared from (2S, 3S) -3- (3- (2,4-dichlorophenyl) -1 H -indol-1-yl) -3- (3-fluorophenyl) propane-1,2-diol. MS (ES) m / z 442.7 ([M + Hf); HRMS: calculated for C24H2, CI2FN20 + H +, 443.10877; found (ESI, [M + Hf), 443.1086.

Example 42: (1 S.2R) -1-r3- (2-ethoxyphenyl) -1 H -indole-1-ill-1- (3-fluorophenyl) -3- (methylamino) propan-2-hydrochloride ol In a manner analogous to Example 34, step 4, (2S, 3S) -3- (3-fluorophenyl) -3-. { 3- [2- (ethoxy) phenyl] -1 H -indole-1-yl} propane-1,2-diol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-iodo-1 / - / - indol-1-yl) propane-1, 2- diol (from Example 34, step 3) and 2- (Ethoxyphenyl) boronic acid.

In a manner analogous to Example 27, step 3, (1 S, 2R) -1- [3- (2-ethoxyphenyl) -1 H -indole-1-lime-1 - (3-fluorophenyl) -3- hydrochloride. (methylamino) propan-2-ol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3-. { 3- [2- (ethoxy) phenyl] -1 H-indol-1-yl} propane-1, 2-diol. MS (ES) m / z 419.0 ([M + Hf); HRMS: calculated for C26H2? FN202 + H +, 419.21293; found (ESI, [M + Hf), 419.2132.

Example 43: (1 S, 2 R) -1- (7-Chloro-5-methoxy-1 H -pyrrolor-2,3-clpyridin-1-yl) -1- (3-fluorophenyl) -3- (meth) hydrochloride lamno) propan-2-ol Step 1: 2-Chloro-6-methoxy-3-nitropyridine (5 g, 0.027 mol) is dissolved in anhydrous tetrahydrofuran (200 mL) under nitrogen and the solution is cooled to -78 ° O, excess magnesium magnesium bromide is added ( 1.0 M Tetrahydrofuran, 100 mL, 100 mmol) and the reaction mixture is stirred at -20 ° C for 8 hours and then the reaction mixture is quenched with 20% aqueous ammonium chloride (150 mL). The aqueous layer is extracted with ethyl acetate and the combined extracts they are dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by Biotage Hopzon (FlasH 40 M, silica, gradient of 20% ethyl acetate / hexane at 60% ethyl acetate). ethyl / hexane) to produce 7-chloro-5-methox? -1H-pyrrolo [2,3-c] p? pd? na2 as a yellow solid MS (ESI) m / z 183 ([M + Hf) Step 2 In a manner analogous to Example 24, step 2 (2S, 3S) -3- (7-chloro-5-methox? -1 / - / - p? Rrolo [2,3-c] p? Pd? N -1-? L) -3- (3-fluorophen? L) propane-1,2-d? Ol is prepared from 7-chloro-5-methox? -1 Hp? Rrolo [2,3-c] p? pd? na and [(2R, 3R) -3- (3-fluorophen? l) ox? ran-2? l] methanol (Example 24, step 1) as an MS oil (ESI) m / z 351 ([M + Hf) In a manner analogous to Example 1, step 5, ester of 3- (7-chloro-5-methox? -1 Hp? Rrolo [2,3-c] p? Pd? N-1-? L) -2-h Drox? -3- (3-fluorophen?) -propyl (2S, 3S) -toluene-4-sulfonic acid is prepared from (2S, 3S) -3- (7-chloro-5- methox? -1 / - / - pyrrolo [2,3-c] p? pd? n-1-? l) -3- (3-fluorophen? l) -propane-1,2-d? ol as a woolly solid MS (ESI) m / z 505 ([M + Hf) In a manner analogous to Example 1, step 6 hydrochloride of (1 S, 2R) -1- (7-chloro-5-methox? -1 Hp? Rrolo [2,3-clp? Pd? N-1? ) -1- (3-fluorophen?) -3- (meth? Lam? No) propan-2-ol is prepared from the ester of 3- (7-chloro-5-methox? -1 Hp? Rrolo [ 2,3-c] p? Pd? N-1-? L) -2-h? Drox? -3- (3-fluorofen? L) -prop? Lo of (2S, 3S) -toluene-4-acid sulfonyl and methylamine solution (2.0 M in methanol) as a white solid HRMS calculated for C, 8H, 9CIFN3? 2 + H +, 364 12226, found (ESI, [M + Hf), 364 1218 Example 44 Hydrochloride of (1 S.2R) -1- (7-chloro-5-met? L-1 Hp? Rrolo [2,3-clpyr? D? N-1-? L) -3- (met? lam? no) -1-phen? lpropan-2-ol Zhang, Z, et al, J Org Chem 2002, 67, 2345-2347 Step 1: In a manner analogous to Example 43, step 1, 7-chloro-5-methyl-1 / - / - pyrrolo [2,3-c] pyridine is prepared from 2-chloro-3-nitro-6 -picoline and vinylmagnesium bromide as a yellow solid. MS (ESI) m / z 167 ([M + Hf).

In a manner analogous to Example 24, step 2, (2S, 3S) -3- (7-chloro-5-methyl-1 / - / - pyrrolo [2,3-c] pyridin-1-yl) - 3-phenyl-propane-1,2-diol is prepared from 7-chloro-5-methyl-1 H-pyrrolo [2,3-c] pyridine and [(2R, 3R) -3-phenyloxyran-2- il] methanol (from Example 1, step 1) as an oil. MS (ESI) m / z 317 ([M + Hf).

In a manner analogous to Example 1, step 5, 3- (7-chloro-5-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -2-hydroxy-3-phenyl ester (2S, 3S) -toluene-4-sulfonic acid propyl is prepared from (2S, 3S) -3- (7-chloro-5-methyl-1 / - / - pyrrolo [2,3-c] ] pyridin-1-yl) -3-phenyl-propane-1,2-diol as an oil. MS (ESI) m / z 471 ([M + Hf).

In a manner analogous to Example 1, step 6, (1S, 2R) -1- (7-chloro-5-methyl-1 H -pyrrolo [2,3-clpyridin-1-yl] -3- hydrochloride ( methylamino) -1-phenylpropan-2-ol is prepared from 3- (7-chloro-5-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -2-hydroxy- ester. 3-Phenyl-propyl (2S, 3S) -toluene-4-sulfonic acid and methylamine solution (2.0M in methanol) as an off-white solid. HRMS: calculated for C18H20CIN3O + H +, 330.13677; found (ESI, [M + Hf), 330.1355.

Example 45: (1 S, 2 R) -1- (5-methoxy-1 H -pyrrolo [2,3-clpyridin-1-yl] -3- (methylamino) -l-phenylpropan-2-ol hydrochloride Step 1: In a manner analogous to Example 24, step 2, (2S, 3S) -3- (7-chloro-5-methoxy-1 / - / - pyrrolo [2,3-c] pyridin-1-yl) -3-phenyl-propane-1,2-diol is prepared from 7-chloro-5-methoxy-1 H-pyrrolo [2,3-c] pyridine (from Example 43, step 1) and [(2R, 3R) -3-phenyloxyran-2-yl-methanol (from Example 1, step 1) as an oil. MS (ESI) m / z 333 ([M + Hf).

Step 2: In a manner analogous to Example 1, step 5, ester 3- (7-chloro-5-methoxy-1 H -pyrrolo [2,3-c] pyridin-1-yl) -2-hydroxy-3- phenyl-propyl (2S, 3S) -toluene-4-sulfonic acid is prepared from (2S, 3S) -3- (7-chloro-5-methoxy-1 / - / - pyrrolo [2,3 -c] pyridin-1-yl) -3-phenyl-propane-1,2-diol as an oil. MS (ESI) m / z 487 ([M + Hf).

Step 3: In a manner analogous to Example 1, step 6, (1S, 2R) -1- (7-chloro-5-methoxy-1H-pyrrolo [2,3-c] pyridin-1-yl hydrochloride) -3- (methylamino) -1-phenylpropan-2-ol is prepared from ester 3- (7-chloro-5-methoxy-1 H -pyrrolo [2,3-c] pyridin-1-yl) -2 -hydroxy-3-phenyl-propyl (2S, 3S) -toluene-4-sulfonic acid and methylamine solution (2.0M in methanol) as a white solid. HRMS: calculated for C, sH20CIN3O2 + H +, 346.13168; found (ESI, [M + Hf), 346.1229.

Step 4: (1S, 2R) -1- (7-chloro-5-methoxy-1 / - / - pyrrolo [2,3-c] pyridin-1-yl) -3- (methylamino) -1- phenylpropan-2-ol (0.13 g, 0.38 mmol) is dissolved in ethanol (20 mL) and treated with 10% palladium on carbon. The reaction mixture is placed under 50 psi of hydrogen in a Parr shaker for 15 hours. The reaction mixture is then filtered through a pad of Celite and the filtrate is concentrated under reduced pressure. The crude product is purified by Biotage Horizon (Flash 25 S, silica, gradient from 30% to 100% of 0.9% ammonium hydroxide in 10% methanol-methylene chloride / methylene chloride) to give a white solid as the free base of the expected product. The free base is dissolved in a minimum amount of ethanol and treated with hydrogen chloride solution (1.0 M in diethyl ether) until the solution is pH = 3 followed by diethyl ether. The product is then crystallized by adding a minimum amount of ethyl acetate to produce (1S, 2R) -1- (5-methoxy-1H-pyrrolo [2,3-clpyridin-1-yl] -3- hydrochloride ( methylamino) -l-phenylpropan-2-ol as a white solid. MS (ES) miz 311.8 ([M + Hf).

Example 46: (1S, 2R) -1- (3-fluorophenyl) -1- (5-methoxy-1 H -pyrrolof2.3-clpyridin-1-yl) -3- (methylamino) propan-2 hydrochloride -ol In a manner analogous to Example 45, step 4, (1S, 2R) -1- (5-methoxy-1H-pyrrolo [2,3-clpyridin-1-yl] -1- (3-fluorophenyl) hydrochloride) -3- (methylamino) propan-2-ol is prepared from (1 S, 2R) -1- (7-chloro-5-methoxy-1 H -pyrrolo [2,3-c] pyridin-1-yl) ) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol (Example 43) as a whitish solid. HRMS: calculated for C18H20FN3O2 + H \ 330.16123; found (ESI, [M + Hf), 330.1596.

Example 47: (1S, 2R) -3- (methylamino) -1- (5-methyl-1 H -pyrrolo [2,3-clpyridin-1-yl] -1-phenylpropan-2-ol hydrochloride In a manner analogous to Example 45, step 4, (1S, 2R) -1- (5-methyl-1 H -pyrroloyl-2,3-clpyridin-1-yl) -3- (methylamino) -1-phenylpropan- hydrochloride. 2-ol is prepared from (1 S, 2 R) -1- (7-chloro-5-methyl-1 / -pyrrolo [2,3-c] pyridin-1-yl) -3- (methylamino) -1-phenylpropan-2-ol (Example 44) as a whitish solid. MS (ESI) m / z 296 ([M + Hf).

Example 48: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (5-methyl-1 H -pyrrolof2,3-clpihdin-1-yl) propane-2-hydrochloride ol In a manner analogous to Example 24, step 2, (2S, 3S) -3- (7-chloro-5-methyl-1 / - / - pyrrolo [2,3-c] pyridin-1-yl) -3- (3-fluorophenyl) -propane-1,2-diol is prepared from 7-chloro-5-methyl-1 H-pyrrolo [2,3-c] pyridine (Example 44, step 1) and [(2 / ?, 3f?) - 3- (3-fluorophenyl) oxirane-2-ylmethanol (Example 24, step 1) as an oil. MS (ESI) m / z 335 ([M + Hf).

In a manner analogous to Example 1, step 5, ester of 3- (7-chloro-5-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -2-hydroxy-3- (3 -fluorophenyl) -propyl (2S, 3S) -toluene-4-sulfonic acid is prepared from (2S, 3S) -3- (7-chloro-5-methyl-1 H -pyrrolo [2,3-c] ] pyridin-1-1) -3- (3-fluorophen? L) -propane-1,2-d? Ol as an MS oil (ESI) m / z 489 ([M + Hf] In a manner analogous to Example 1, step 6, (1S, 2 /?) -1- (7-chloro-5-met? L-1H-p? Rrolo [2,3-c] p? R? D ? n-1-? l) -1- (3-fluorophen? l) -3- (meth? lam? no) propan-2-ol is prepared from 3- (7-chloro-5-methyl ester l-1 Hr? rrolo [2,3-c] p? pd? n-1-? l) -2-h? drox? -3- (3-fluorofen? l) -prop? lo of acid (2S , 3S) -toluene-4-sulfon? Co and methylamine solution (2.0 M in methanol) as an HRMS oil calculated for C? SH19CIFN30 + H +, 348 12734, found (ESI, [M + Hf), 348 1262 In a manner analogous to Example 45, step 4, hydrochloride of (1 S, 2R) -1- (3-fluorophen? L) -3- (meth? Lam? No) -1- (5-met? L-1) Hr? Rrolo [2,3-clp? Nd? N-1-? L) propan-2-ol is prepared from (1 S, 2f?) - 1- (7-chloro-5-met? L- 1H-pyrrolo [2,3-c] p? Pd? N-1-? L) -1- (3-fluorophen? L) -3- (meth? Lam? No) propan-2-ol as a whitish solid HRMS calculated for C? 8H20FN3O + H +, 314 16632, found (ESI, [M + Hf), 314 1599 Example 49 hydrochloride (1 S, 2R) -3- (meth? Lam? No) -1- (7-met? L-1 Hp? Rrolo [2,3-clp? Nd? N-1-? L) -1-phenolpropan-2-ol In a manner analogous to Example 43, step 1, 5-chloro-7-met? L-1 / - / - pyrrolo [2,3-c] p? Pd? Na is prepared from 2-chloro- 5-n? Tro-6-p? Col? Na and vinylmagnesium bromide as an oily solid MS (ESI) miz 167 ([M + Hf) In a manner analogous to Example 24, step 2, (2S, 3S) -3- (5-chloro-7met? L-1 / - / - p? Rrolo [2,3-c] p? Pd? N-1 -? l) -3-phen? l-propane-1,2-d? ol is prepared from 5-chloro-7-met? l-1 Hp? rrolo [2,3-c] p? pd? na and [(2R, 3) -3-phenoloxyl-2-yl] methanol (from Example 1, step 1) as an off-white solid MS (ESI) miz 317 ([M + Hf] In a manner analogous to Example 1, step 5, ester of 3- (5-chloro-7-met? L-1 Hp? Rrolo [2,3-c] p? Pd? N-1-? L) -2 -h? drox? -3-phenol-propyl of (2S, 3S) -toluene-4-sulfon? co acid is prepared from (2S, 3S) -3- (5-chloro-7-) methanol-1 / - / - pyrrolo [2,3-c] p? pd? n-1-? l) -3-phen? l-propane-1,2-d? ol as an MS oil (ESI) miz 471 ([M + Hf] In a manner analogous to Example 1, step 6, (1 S, 2f?) - 1- (5-chloro-7-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -3- (methylamino) -1-phenylpropan-2-ol is prepared from 3- (7-methyl-5-chloro-1 H -pyrrolo [2,3-c] pyridin-1-yl) -2-hydroxy ester 3-phenyl-propyl (2S.3S) -toluene-4-sulfonic acid and methylamine solution (2.0M in methanol) as an oil.

HRMS: calculated for C, sH2oCIN30 + H +, 330.13677; found (ESI, [M + Hf), 330.1354.

In a manner analogous to Example 45, step 4, hydrochloride of (1 S, 2R) -1- (7-methyl-1 H -pyrrolo [2,3-c1pihdin-1 -yl) -3- (methylamino) -1 -phenylpropan-2-ol is prepared from (1 S, 2R) -1- (5-chloro-7-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -3- ( methylamino) -1-phenylpropan-2-ol as a white solid. HRMS: calculated for C, sH2, N30 + H +, 296.17574; found (ESI, [M + Hf), 296.1758.

Example 50: (1 S, 2 R) -1- (3-fluorophenyl) -3- (methylamino) -1- (7-methyl-1 H -pyrrolo [2,3-clpyridin-1-yl] hydrochloride propan-2-ol In a manner analogous to Example 24, step 2, (2S, 3S) -3- (5-chloro-7-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -3- (3 -fluorophenyl) -propane-1,2-diol is prepared from 5-chloro-7-methyl-1 H -pyrrolo [2,3-c] pyridine (from Example 49, step 1) and [(2R, 3R ) -3- (3-fluorophenyl) oxiran-2-yl] methanol (from Example 24, step 1) as a whitish solid. MS (ESI) miz 335 ([M + Hf).

In a manner analogous to Example 1, step 5, ester of 3- (5-chloro-7-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -2-hydroxy-3- (3 -fluorophenyl) -propyl (2S, 3S) -toluene-4-sulfonic acid is prepared from (2S, 3S) -3- (5-chloro-7-methyl-1 / - / - pyrrolo [2 , 3-c] pyridin-1-yl) -3- (3-fluorophenyl) -propane-1,2-diol as an oil. MS (ESI) miz 489 ([M + Hf).

In a manner analogous to Example 1, step 6, (1S, 2ft) -1- (5-chloro-7-methyl-1 / - / - pyrrolo [2,3-c] pyridin-1-yl) -1 - (3-fluorophenyl) -3- (methylamino) propan-2-ol is prepared from 3- (5-chloro-7-methyl-1H-pyrrolo [2,3-c] pyridin-1-yl ester ) -2-hydroxy-3- (3-fluorophenyl) -propyl (2S, 3S) -toluene-4-sulfonic acid and methylamine solution (2.0M in methanol) as an oil. HRMS: calculated for C, 8Hi9CIFN30 + H +, 348.12734; found (ESI, [M + Hf), 348.1287.

In a manner analogous to Example 45, step 4, hydrochloride (1 S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1 - (7-methyl-1 H -pyrrolo [2,3-] clpiridin-1-yl) propan-2-ol is prepared from (1 S, 2 /?) - 1- (7-methyl-5-chloro-1 - / - pyrrolo [2,3-c] pyridin-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol as a white solid. HRMS: calculated for C? 8H20FN3O + H +, 314. 16632; found (ESI, [M + Hf), 314.1628.

Example 51: (1 S, 2R) -1- (3,3-Diethyl-2,3-dihydro-1 H -indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) hydrochloride propan-2-ol In a manner analogous to Example 1, step 3, (2S, 3S) -3- (3,3-diethyl-2,3-dihydro-1 H -indol-1-yl) -3- (3-fluorophenyl) propane -1,2-diol is prepared from 3,3-diethylindoline1 and [(2R, 3R) -3- (3-fluorophenyl) oxirane-2-yl] methanol (Example 25, step 3) as a colored oil amber. MS (ESI) m / z 344.2 ([M + Hf); HRMS: calculated for C2, H26FNO2 + H +, 344.2026; found (ESI, [M + Hf), 344.2048.

In a manner analogous to Example 25, step 5, hydrochloride of (1S, 2R) -1- (3,3-diethyl-2,3-dihydro-1H-indol-1-yl) -1- (3- fluorophenyl) -3- (methylamino) propan-2-ol is prepared from (2S, 3S) -3- (3,3-diethyl-2,3-dihydro-1 H-indol-1-yl) -3 - (3-fluorophenyl) propane-1,2-diol as a white powder. MS (ES) m / z 357.3 ([M + Hf); HRMS: calculated for C 22 H 29 FN 2 O + H +, 357.2337; found (ESI, [M + Hf), 357.2340.

Example 52 (1S, 2R) -1- (6-fluoro-3,3-d? Met? L-2,3-d? H? Dro-1H-? Ndol-1-? L) -1- hydrochloride (3-fluorofen? L) -3- (met? Lam? No) propan-2-ol Step 1 In a manner analogous to Example 27, step 1, 6-fluoro-3,3-d? Met? Lox? Ndol is prepared from 6-fluorooxidol and iodomethane (2 equi) as a yellowish solid MS ( El) m / z 179 1 ([Mf), HRMS calculated for C, 0H, 0FNO, 179 0746, found (El, [Mf), 179 0742 Step 2 A mixture of 6-fluoro-3,3-d? Met? Lox? Ndol (1 00 g, 580 mmol) in toluene (10 mL) under nitrogen is heated to 80 ° C. It is added as a drop. (65 wt% in toluene, 2 7 mL, 8 9 mmol) via an addiction funnel The resulting solution is stirred at 80 ° C for an additional 5 hours, then cooled in an ice bath. aqueous sodium hydroxide (1 N, 15 mL) to quench the reaction. Water (15 mL) is added and the reaction mixture is extracted with ethyl acetate (20 mL). The organic layer is washed with saline, dried over sulfate Sodium, filtered through a pad of silica gel, and concentrated under reduced pressure to yield 728 mg (79%) of 6-fluoro-3,3-d? methyleneol as a cooking oil. color amber MS (ES) m / z 166 2 ([M + Hf) Step 3 In a manner analogous to Example 1, step 3, (2S, 3S) -3- (6-fluoro-3,3-d? Met? L-2,3-d? H? Dro-1 H-? ndol-1-? l) -3- (3-fluorophen? l) propane-1,2-d? ol is prepared from 6-fluoro-3,3-dimethylindoline and [(2R, 3R) -3- (3-fluorophen? L) ox? Ran-2? L] methanol (from Example 25, step 3) as a brown solid MS (ESI) m / z 334 2 ([M + Hf), HRMS calculated for C, 9H2? F2NO2 + H +, 334-1613, found (ESI, [M + Hf), 334 1597 Step 4 In a manner analogous to Example 25, step 5, (1S, 2R) -1- (6-fluoro-3,3-d? Met? L-2,3-d? H? Dro-1 hydrochloride H-? Ndol-1-? L) -1- (3-fluorophen? L) -3- (meth? Lam? No) propan-2-ol is prepared from (2S, 3S) -3- (6 -fluoro-3,3-d? met? l-2,3-d? h? dro-1 H-? ndol-1-? l) -3- (3- fluorophen?) propane-1, 2-d? ol as a white powder HRMS calculated for C20H24F2N2O + H \ 347 1929, found (ESI, [M + Hf), 347 1914 Example 53 (1S, 2R) -1- (4-benzyl-3,4-d? -hydroquinone-1 (2H) -? L) -1- (3-fluorophenyl) hydrochloride -3- (met? Lam? No) propan-2-ol In a manner analogous to Example 1, step 3, (2S, 3S) -3- (4-benzyl-3,4-d? -hydroqual? N-1 (2H) -? L) -3 - (3-fluorophen? L) propane-1,2-d? Ol is prepared from 1-benzyl-1, 2,3,4-tetrahydroquinoxahna3 and [(2R, 3R) -3- (3- fluorophen?) ox? ran-2? l] methanol (from Example 25, step 3) as a brown, viscous oil MS (ESI) m / z 393 2 ([M + Hf), calculated HRMS for C24H25FN2O2 + H + , 393 1973, found (ESI, [M + Hf), 393 1967 In a manner analogous to Example 25, step 5, (1S, 2R) -1- (4-benzyl-3,4-d? -hydroquinone-1 (2H) -? L hydrochloride ) -1- (3-fluorophen?) -3- (meth? Lam? No) propan-2-ol is prepared from (2S, 3S) -3- (4-benzyl-3,4- d? h? droqu? noxal? n-1 (2H) -? l) -3- (3-fluorophen? l) propane-1,2-d? ol as a white powder MS (ES) m / z 406 2 ([M + Hf) EXAMPLE 54 (1S, 2R) -1- (5-Fluoro-3,3-d? Met? L-2,3-d? H? Dro-1 H-? Ndol-1-? L) hydrochloride - 1- (3-fluorofen? L) -3- (met? Lam? No) propan-2-ol In a manner analogous to Example 27, step 1, 5-fluoro-3,3-d? Met? Lox? Ndol is prepared Smith, R F, Rebel, W J, Beach, T N J Org Chem 1959, 24, 205-207 from 5-fluorooxidol and iodomethane (2 equiv) as white crystals HRMS calculated for C10H, 0FNO + H +, 180 0825, found (ESI, [M + Hf), 180 0832 In a manner analogous to Example 52, step 2, 5-fluoro-3,3-d? Met? L? Ndol? Na is prepared from 5-fluoro-3,3-d? Met? Lox? Ndol as a amber oil MS (ES) m / z 166 2 ([M + Hf), HRMS calculated for C10H, 2FN + H +, 166 1027, found (ESI, [M + Hf), 166 1024 In a manner analogous to Example 1, step 3, (2S, 3S) -3- (5-fluoro-3,3-d? Met? L-2,3-d? H? Dro-1 H-? Ndol- 1-? L) -3- (3-fluorophen? L) propane-1,2-d? Ol is prepared from 5-fluoro-3,3-dimethylindane and [(2R, 3R) -3- (3 Fluorophen? l) ox? ran-2? l] methanol (from Example 25, step 3) as a colorless, viscous oil MS (ESI) m / z 334 2 ([M + Hf), HRMS calculated for C, 9H21F2N02 + H +, 334-1613, found (ESI, [M + Hf), 334 1606 In a manner analogous to Example 25, step 5, hydrochloride of (1 S, 2R) -1- (5-fluoro-3,3-d? Met? L-2,3-d? H? Dro-1 H- β-dol-1-? l) -1- (3-fluorophen? l) -3- (meth? lam? no) propan-2-ol is prepared from (2S, 3S) -3- (5-fluoro) -3,3-d? Met? L-2,3-d? H? Dro-1 H-? Ndol-1-? L) -3- (3-fluorophen? L) propane-1,2-d? ol as a white powder MS (ESI) m / z 347 3 ([M + Hf), HRMS calculated for C20H24F2N2O + H +, 347 1929, found (ESI, [M + Hf), 347 1940 EXAMPLE 55 (1S, 2R) -1- (3-fluorophenyl) -3- (meth? Lam? No) -1 - [(3S) -3-met? L-2,3-d? Hydrochloride? h? dro-1 H-? ndol-1 -? l] propan-2-ol Step 1 In a manner analogous to Example 1, step 3, (2S, 3S) -3- (3-fluorophen? L) -3- (3-met? L-2,3-d? H? Dro-1 H -? ndol-1-? l) propane-1,2-d? ol is prepared from 3-meth? ndol? na4 and [(2R, 3R) -3- (3-fluorophen? L) ox? Ran-2? L] methanol (from Example 25, step 3) as a yellowish, viscous liquid MS (ES) m / z 301 8 ( [M + Hf), HRMS calculated for C? 8H20FNO2 + Gpbble, G W, Hoffman, J H Synthesu 1977, 12, 859-860 H +, 302.1551; found (ESI, [M + Hf), 302.1539.

Step 2: In a manner analogous to Example 25, step 5, (1 S, 2 R) -1- (3-fluorophenyl) -3- (methylamino) -1- (3-methyl-2,3-dihydro-1 H -indol-1-yl) propan-2-ol is prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (3-methyl-2,3-dihydro-1 H-indole-1 -yl) propane-1,2-diol as a colorless, viscous liquid.

Step 3: The isomeric mixture of (1 S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (3-methyl-2,3-dihydro-1H-indol-1-yl) propan -2-ol dissolves in methanol. The resulting solution is injected into the Supercritical Fluid Chromatography instrument. The baseline resolves the diastereomers, using the conditions described below, are collected.

SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.

Newark, DE 19702. Column: Chiralpak AD-H; 250mm L x 20mm ID Column temperature: 35 ° C SFC modifier: 10% MeOH, 90% C02, with 0.2% diethylamine flow rate: 50 mL / minute Exit Pressure: 100 bar Detector: UV at 254 nm Step 4: (1 S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1 - [(3S) -3-methyl-2,3-dihydro-1 H-indol-1-yl] propan-2-ol, isolated as peak 1, subjected to hydrochloride salt formation in a manner analogous to Example 25, step 5 to give (1S, 2R) -1- (3-fluorophenyl) -3- hydrochloride (methylamino) -1 - [(3S) -3-methyl-2,3-dihydro-1 H-indol-1-yl] propan-2-ol as a white powder. The stereochemistry at C3 of the indoline ring is arbitrarily assigned. MS (ES) m / z 315.2 ([M + Hf); HRMS: calculated for C, 9H23FN20 + H +, 315.1873; found (ESI, [M + Hf), 315.1885.

Example 56: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1 - [(3R) -3-methyl-2,3-dihydro-1 H-indole-1- hydrochloride il] propan-2-ol In a manner analogous to Example 55, step 4, hydrochloride of (1S, 2R) -1- (3-fluorophen-1) -3- (meth? Lam? No) -1 - [(3R) -3-met ? l-2,3-d? h? dro-1 H-? ndol-1-? l] propan-2-ol is prepared as a white powder from (1 S, 2 R) -1- (3-fluorophen? l) -3- (methalamine) -1 - [(3R) -3-met? l-2,3-d? h? dro-1 H-? ndol-1-? l] propan-2 -ol, which is isolated as peak 2 from the diastereomeric separation (Example 55, step 3) The stereochemistry at C3 of the indoline ring is arbitrarily assigned MS (ES) m / z 314 9 ([M + Hf), calculated HRMS for C, 9H23FN20 + H +, 315-1873, found (ESI, [M + Hf), 315 1880 Example 57 (1S, 2R) -1- (3-fluorophen? L) -1- (3-? Soprop? L-2,3-d? H? Dro-1 H-? Ndol-1-? Hydrochloride? l) -3- (met? lam? no) propan-2-ol Step 1 In a manner analogous to Example 1, step 2, 3-? Soprop? L? Ndol? Na is prepared from 3-? Soprop? Ldol5 as a colorless oil MS (ESI) m / z 162 2 ( [M + Hf) Step 2: In a manner analogous to Example 1, step 3, (2S, 3S) -3- (3-fluorophen? L) -3- (3-? Soprop? L-2,3-d? H? Dro-1 H-β-ndol-1- (1) propane-1,2-d-ol is prepared from 3-isopropylindole and [(2R, 3R) -3- (3-fluorophen? L) ox? Ran-2 ? l] methanol (Example 25, step 3) as a colorless oil MS (ESI) m / z 330 3 ([M + Hf), HRMS calculated for C20H24FNO2 + H +, 330-1864, found (ESI, [M + Hf] , 330 1855 Step 3 In a manner analogous to Example 25, step 5, hydrochloride (1 S, 2R) -1- (3-fluorophen? L) -1- (3? -propyl? -2,3-d? H? dro-1 -H-? ndol-1-? l) -3- (meth? lam? no) propan-2-ol is prepared from (2S, 3S) -3- (3-fluorophen? l) -3 - (3-? Soprop? L-2,3-d? H? Dro-1 H-? Ndol-1-? L) propane-1,2-diol as a white powder MS (ESI) m / z 343 0 ([M + Hf), HRMS calculated for Odie, R, Blevins, B, Ratcliff, M, Hegedus, L S J Org Chem 1980, 45, 2709-2710 C2, H27FN20 + H \ 343 2180, found (ESI, [M + Hf), 343 2191 Example 58 (1S, 2R) -1- (3-et? 1-2,3-d? H? Dro-1 H-? Ndol-1-? L) -1- (3-fluorophen? L hydrochloride -3- (met? Lam? No) propan-2-ol Step 1 In a manner analogous to Example 1, step 2, 3-et? L? Ndol? Na is prepared from 3-et? L? Ndol5 as a colorless oil MS (El) m / z 147 0 ([Mf. '), HRMS calculated for C, 0H, 3N, 147 1048, found (El, [Mf), 147 1043 Step 2: In a manner analogous to Example 1, step 3, (2S, 3S) -3- (3-et? L-2,3-d? H? Dro-1 H-? Ndol-1-? L) - 3- (3-fluorophen? L) propane-1,2-d? Ol is prepared from 3-et? L? Ndol? Na and [(2R.3R) -3- (3-fluorofen? L) ox ? -2-?] methanol (from Example 25, step 3) as a colorless oil MS (ESI) m / z 316 2 ([M + Hf), calculated HRMS for C, 9H22FN02 + H +, 316 1707, found (ESI, [M + Hf), 316 1699 Step 3 In a manner analogous to Example 25, step 5, hydrochloride of (1S, 2R) -1- (3-et? 1-2,3-d? H? Dro-1 H-? Ndol-1-? l) -1- (3-fluorophen? l) -3- (meth? lam? no) propan-2-ol is prepared from (2S, 3S) -3- (3-et? l-2,3 -d? h? dro-1 H-? ndol-1-? l) -3- (3-fluorophen? l) propane-1,2-d? ol as a white powder MS (ESI) m / z 329 0 ([M + Hf), HRMS calculated for C20H25FN2O + H +, 329 2024, found (ESI, [M + Hf), 329 2023 Example 59 (1 S, 2 R) -1- (3-et? 1-2,3-d? H? Dro-1 H-? Ndol-1-? L) -3- (methalam? No) hydrochloride ) -1-phenolpropan-2-ol In a manner analogous to Example 1, step 3, (2S, 3S) -3- (3-ethyl-2,3-dihydro-1 H-indol-1-yl) -3-phenylpropane-1,2-diol was prepared from 3-ethylindoline (from Example 58, step 1) and [(2R, 3R) -3-phenyloxyran-2-yl] methanol (Example 1, step 1) as a white solid. MS (ESI) m / z 297.8 ([M + H]); HRMS: calculated for C, 9H23N02 + H +, 298.1802; found (ESI, [M + Hf), 298.1816.

In a manner analogous to Example 25, step 5, (1S, 2R) -1- (3-ethyl-2,3-dihydro-1 H-indol-1-yl) -3- (methylamino) -1- hydrochloride phenylpropan-2-ol is prepared from (2S, 3S) -3- (3-ethyl-2,3-dihydro-1 H-indol-1-yl) -3-phenylpropane-1,2-diol as a toasted powder. MS (ESI) m / z 311.0 ([M + Hf).

Example 60: (1 S, 2R) -1- (3-isopropyl-2,3-dihydro-1 H-indol-1-yl) -3- (methylamino) -l-phenylpropan-2-ol hydrochloride In a manner analogous to Example 1, step 3, (2S, 3S) -3- (3-isopropyl-2,3-dihydro-1 H-indol-1-yl) -3-phenylpropane-1,2-diol was prepared from 3-isopropylindoline (from Example 57, step 1) and [(2R, 3R) -3-phenyloxyran-2-yl] methanol (from Example 1, step 1) as a colorless oil. MS (ESI) m / z 312.0 ([M + Hf); HRMS: calculated for C20H25NO2 + H +, 312.1964; found (ESI, [M + Hf), 312.1981.

In a manner analogous to Example 25, step 5, (1S, 2R) -1- (3-isopropyl-2,3-dihydro-1H-indol-1-yl) -3- (methylamino) hydrochloride -1-phenylpropan-2-ol is prepared from (2S, 3S) -3- (3-isopropyl-2,3-di idro-1 H-indol-1-yl) -3-phenylpropane-1, 2 -diol like a white powder. MS (ESI) m / z 325.0 ([M + H]).

Example 61: (1S, 2R) -3-amino-1- (3,5-difluorophenyl) -1- (3,3-dimethyl-2,3-dihydro-1 H-indol-1-yl) propane hydrochloride -2-ol Step 1: In a manner analogous to Example 25, step 1, methyl ester of trans-3,5-difluoro-cinnamic acid is prepared from trans-3,5-difluoro-cinnamic acid as a white solid. Yield: 5.387 g (99%). MS (ESI) m / z 198.0 (M +); HRMS: calculated for C, 0H8F2O2, 198.0492; found (ESI, [Mf), 198.0489.

Step 2: In a manner analogous to Example 25, step 2, trans-3,5-difluoro-cinnamyl alcohol is prepared from the methyl ester of trans-3,5-difluoro-cinnamic acid as a colorless oil. Yield: 8.64 g (95%).

Step 3: In a manner analogous to Example 25, step 3, [(2R, 3R) -3- (3,5-difluorophenyl) oxirane-2-yl] methanol is prepared from trans-3,5-difluorocyanamyl alcohol as a colorless liquid. Yield: 4.566 g (70%). Per cent of ee: 97.9%. MS (ESI) m / z 186.0 (M +); HRMS: calculated for C9H8F202, 186.0492; found (ESI, [Mf), 186.0501.

Step 4: In a manner analogous to Example 1, step 3, (2S, 3S) -3- (3,5-difluorophenyl) -3- (3,3-dimethyl-2,3-dihydro-1H-indole- 1-yl) propane-1,2-diol is prepared from 3,3-dimethylindoline6 and [(2R, 3R) -3- (3,5-difluorophenyl) oxirane-2-yl] methanol as a brown gum. MS (ESI) m / z 334.0 ([M + H]); HRMS: calculated for C, 9H2, F2N02 + H +, 334.1619; found (ESI, [M + Hf), 334.1619.

Step 5: In a manner analogous to Example 25, step 5, (1S, 2R) -3-amino-1 - (3,5-difluorophenyl) -1 - (3,3-dimethyl-2,3- hydrochloride. dihydro-1 H-indol-1-yl) propan-2-ol is prepared from (2S, 3S) -3- (3,5-difluorophenyl) -3- (3,3-dimethyl-2,3- dihydro-1H-indol-1-yl) propane-1,2-diol as a white powder substituting ammonia solution (7.0 M in methanol) with heat at 50 ° C, instead of methylamine solution (33% in absolute ethanol ). MS k Ramsay, T. .; Slater, G R.; Smith, P. Synth Commun 1995, 25, 4029-4033.

(ESI) m / z 333.0 ([M + Hf); HRMS: calculated for C, 9H22F2N20 + H +, 333.1773; found (ESI, [M + Hf), 333.1764.

Example 62: 1 - [(1 S, 2R) -1- (3,5-difluorophenyl) -2-hydroxy-3- (methylamino) propyl-7-fluoro-3,3-dimethyl-1, 3- hydrochloride dihydro-2H-indol-2-one Step 1: To a solution of 2,6-difluoronitrobenzene (5.0 g, 31.44 mmol) in dry N, N-dimethylformamide (50 mL) is added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). ). The reaction mixture is heated to 65 ° C and stirred for 24 hours. After cooling to room temperature, the mixture is neutralized with a dilute aqueous solution of hydrochloric acid and extracted with diethyl ether. The ether layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Crystallization of 5% ethyl acetate / hexane gives 4.6 g (54%) of dimethyl (3-fluoro-2-nitrophenyl) malonate. MS (ESI) miz 272 [M + Hf).

Step 2: Dimethyl (3-fluoro-2-nitrophenyl) malonate (12 g, 44 mmol) in a 6 N aqueous solution of hydrochloric acid (200 ml) is heated at reflux for 4 hours. The mixture is cooled, diluted with water (250 ml) and extracted with diethyl ether. The ether layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Crystallization of 5% ethyl acetate / hexane gives 7.6 g (54%) of (6-fluoro-2-nitro-phenyl) -acetic acid. Ms (ESI) miz 200 ([M + Hf).

Step 3: 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) is hydrogenated at 50 psi for 24 hours. The catalyst is removed by filtration through celite and the solvent is evaporated. The residue is then dissolved in ethanol (100 ml) and pyridinium para-toluenesulfonate (50 mg) is added and the mixture is refluxed for 1 hour. The mixture is cooled, poured into water, extracted with ethyl acetate and dried over Anhydrous magnesium sulfate is filtered and concentrated under reduced pressure. The resulting solid is triturated with 5% ethyl acetate / hexane to give 6.0 g (83%) of 7-fluoro-1,3-dihydro-indol-2-one. Ms (ESI) miz 152, [M + Hf).

Step 4: 7-Fluoro-1,3-dihydro-indol-2-one (7.3 g, 48 mmol) and lithium chloride (6.67 g, 158 mmol) are dissolved in tetrahydrofuran (200 mL). The solution is cooled to -78 ° C and n-butyllithium (40 mL, 100 mmol) is slowly added over a period of 15 minutes. After 20 minutes at -78 ° C, methyl iodide (6 mL, 96 mmol) is added and the mixture is allowed to warm to room temperature. After 24 hours, the mixture is poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the crude product via Biotage chromatography (Flash40i, silica, 10% then 20% ethyl acetate / hexane) gives 4.1 g (48%) of 7-fluoro-3,3-dimethyl-1,3-dihydro. -2H-indol-2-one. MS (ESI) miz 180 ([M + Hf).

Step 5: 7-Fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (2.12 g, 12 mmol) is dissolved in? /,? / - dimethylformamide (12 mL) and added in portions sodium hydride (0.92 g, 24 mmol, 60% by weight of suspension in mineral oil) for 15 minutes and the mixture is stirred for an additional 30 minutes. In a separate flask, [(2R, 3R) -3- (3,5-difluorophenyl) oxirane-2-yl] methanol (4.76 g, 25.6 mmol, from Example 61, Step 3) is dissolved in? /,? / dimethylformamide (12 mL) and titanium isopropoxide (7.0 mL, 25.6 mmol) is added and the mixture is stirred 30 minutes. The isopropoxide / titanium epoxide solution is then added to the sodium salt solution of oxindole in drop form and the mixture is stirred at room temperature for 24 hours. The mixture is then carefully quenched with 2N aqueous hydrochloric acid and diluted with 200 mL of 2N aqueous hydrochloric acid (use of hydrochloric acid is essential to prevent the precipitation of titanium salts and subsequent emulsification). The mixture is extracted with ethyl acetate and then the organic layers are combined, washed with water, and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified via Isco chromatography (Redisep, silica, gradient 20% to 100% ethyl acetate in hexane) to yield 4.0 g (91%) of 7-fluoro-1 - [(1S, 2S) -1- (3,5-difluorophenyl) -2,3-dihydroxypropyl] -3,3-dimethyl-1,3-dihydro-2 H -indole-2-one as a sticky oil.

Step 6: 7-fluoro-1 - [(1 S, 2S) -1 - (3,5-difluorophenyl) -2,3-dihydroxypropyl] -3,3-dimethyl-1,3-dihydro-2H-indole 2-one (2.3 g, 6.3 mmol) is dissolved in pyridine (15 mL) and p-toluenesufonyl chloride (1.3 g, 6.9 mmol) is added and the mixture is stirred for 4 hours. The reaction mixture is then diluted with diethyl ether and washed with water, 2 N aqueous hydrochloric acid, saturated copper sulfate, 2 N aqueous hydrochloric acid, and saturated saline. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product is immediately dissolved in methylamine solution (8.0 M in ethanol, 30 mL) and stirred for 16 hours. The mixture is concentrated under reduced pressure and purified by chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 1 - [(1 S, 2R) -1 - (3,5-difluorophenyl) -2- hydroxy-3- (methylamino) -propyl] -7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a colorless oil (0.14 g). The free base is dissolved in ether (10 mL) and treated with hydrogen chloride solution (1.0 M in diethyl ether, 0.36 mL, 1.0 equivalent). The white precipitate is collected and dried under vacuum then dissolved in 10 mL of water and lyophilized to give 110 mg (4% over three steps) of 1 - [(1 S, 2R) -1- (3, 5-difluorophenyl) -2-hydroxy-3- (methylamino) propyne-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one. HRMS: calculated for C2oH2, F3N202 + H \ 379.16279; found (ESI, [M + Hf), 379.1642.

Example 63: 5,7-difluoro-1-f (1 S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propip-3,3-dimethyl-1, 3- hydrochloride dihydro-2H-indol-2-one Step 1: 5,7-Difluorooxindol (prepared analogously to Example 62, steps 1-4 using 2,4,6-trifluoronitrobenzene in place of 2,6-difluoronitrobenzene) (0.64 g, 3.2 mmol) is dissolved in? / ,? / - dimethylformamide (3 mL) and sodium hydride (0.24 g, 6.4 mmol, 60% by weight suspension in mineral oil) is added in portions for 15 minutes and the mixture is stirred an additional 30 minutes. In a separate flask, [(2, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (1.08 g, 6.4 mmol, from Example 25 Step 3) is dissolved in? /,? / - dimethylformamide ( 3 mL) and titanium isopropoxide (1.89) is added. mL, 6.4 mmol) and the mixture is stirred 30 minutes. The isopropoxide / titanium epoxide solution is then added to the sodium salt solution of oxindole in drop form and the mixture is stirred at room temperature for 24 hours. The mixture is then carefully quenched with 2N aqueous hydrochloric acid and diluted with 200 mL of 2N aqueous hydrochloric acid (use of hydrochloric acid is essential to prevent precipitation of titanium salts and subsequent emulsification). The mixture is extracted with ethyl acetateThe combined organic layers are washed with water and saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified via Isco chromatography (Redisep, silica, gradient 20% to 100% ethyl acetate in hexane) to yield 1.02 g (87%) of 5,7-difluoro-1 - [(1 S, 2S) -1- (3-fluorophenyl) -2,3-dihydroxypropyl] -3,3-diyl-1,3-dihydro-2H-indol-2-one as a sticky oil. MS (ES) miz 365.12 (M +).

Step 2: 5,7-difluoro-1 - [(1 S, 2S) -1- (3-fluorophenyl) -2,3-dihydroxypropyl] -3,3-dimethyl-1,3-dihydro-2H-indole 2-one (1.01 g, 2.76 mmol) is dissolved in pyridine (5 mL) and p-toluenesulfonyl chloride (570 mg, 3.0 mmol) is added and the mixture is stirred for 4 hours. The reaction mixture is then diluted with diethyl ether and washed with water, 2 N aqueous hydrochloric acid, saturated copper sulfate, 2 N aqueous hydrochloric acid, and saturated saline. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product is immediately dissolved in methylamine solution (8.0 M in ethanol, 30 mL) and stirred for 16 hours. The mixture is concentrated under reduced pressure and purified by chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 5,7-difluoro-1 - [(1 S, 2f?) - 1- (3- fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a colorless oil (0.29 g). The free base is dissolved in ether (10 mL) and treated with hydrogen chloride solution (1.0 M in diethyl ether, 0.74 mL, 1.1 equivalent). The white precipitate is collected and dried under vacuum then dissolved in 10 mL of water and lyophilized to give 305 mg (26% over three stages) of 5,7-difluoro-1 - [(1 S, 2R) hydrochloride) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) -propin-3,3-dimethyl-1,3-dihydro-2H-indol-2-one. MS (ES) m / z 379 (M + H +).

Example 64: 1 - [(1 S, 2R) -1- (3,5-difluorophenyl) -2-hydroxy-3- (methylamino) propyl-3,3-dimethyl-1,3-dihydro-2H- hydrochloride indol-2-one Stage 1: Oxindol (20.0 g, 0.15 mol) and lithium chloride (21. Og, 0.49 mol) in tetrahydrofuran (400 mL) are suspended and the mixture is cooled to -78 ° C. N-Butyllithium (120.0) is slowly added. mL, 0.30 mol, 2.5M in hexanes) and the mixture is stirred for 20 minutes, then iodomethane (18.7 mL, 0.30 mol) is added. The mixture is heated to 25 ° C, stirred overnight and then quenched with saturated aqueous ammonium chloride and diluted with diethyl ether. The organic layer is washed with water and saline, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography (0-20% ethyl acetate-hexane) yields 10.0 g (41%) of 3,3-dimethyl-1,3-dihydro-indol-2-one as a yellow solid. MS (ESI) miz 162 ([M + Hf).

Step 2: In a manner analogous to Example 27, step 2, 1 - [(1 S, 2 S) -1- (3,5-difluorophenyl) -2,3-dihydroxypropyl] -3,3-dimethyl-1, 3 -dihydro-2H-indol-2-one is prepared from 3,3-dimethyl-1,3-dihydro-indol-2-one and [(2R, 3?) - 3- (3,5-difluorophenyl) oxirane-2-yl] methanol (from Example 61, Step 3). MS (ESI) miz 348 ([M + Hf).

Step 3: In a manner analogous to Example 27, step 3, 1 - [(1 S, 2R) -1- (3,5-difluorophenyl) -2-hydroxy-3- (methylamino) propyl] -3,3- dimethyl-1,3-dihydro-2H-indol-2-one is prepared from 1 - [(1 S, 2S) -1- (3,5-difluorophenyl) -2,3-dihydroxypropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a green oil. The free base is purified by reverse phase HPLC (Fenomenex Gemini, 19 x 150 mm, 60% methanol-40% water w / 0.05% ammonium hydroxide). The pure free base is concentrated under reduced pressure and dissolved in diethyl ether. A solution of hydrogen chloride (1.0 M in diethyl ether, 1.2 equivalents) is added and the resulting white precipitate is collected and dried under vacuum to give 36 mg (5% yield over two steps) of 1-hydrochloride. (1 S, 2R) -1- (3,5-d.fluorophenyl) -2-hydroxy-3- (methylamino) propyl-3,3-dimethyl-1,3-dihydro-2H- Indole-2-one. MS (ESI) miz 361 ([M + Hf). HRMS: calculated for C20H22F2N2O2 + H +, 361.17221; found (ESI, [M + Hf), 361.1721.

Example 65: 1 - [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropin-1 H-indol-5-ol hydrochloride (1 S, 2R) -1- (5-Benzyloxy-1 / - / - indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol (Example 1, 0.12 g, 0.3 mmol) was Dissolve in methanol (20 mL) and treat with 10% palladium on carbon. The reaction mixture is placed under 52 psi of hydrogen in a Parr shaker for 15 hours. The reaction mixture is filtered through a pad of Celite and the filtrate is concentrated under reduced pressure. The crude product is purified by Biotage Horizon (Flash 25 S, silica, gradient from 10% to 100% of 0.9% ammonium hydroxide in 10% methanol-methylene chloride / methylene chloride) to give a white solid as the free base of the expected product. The free base is dissolved in a minimum amount of ethanol and treated with hydrogen chloride solution (1.0 M in diethyl ether) until the solution is pH = 3 followed by diethyl ether. The product is then crystallized by adding a minimum amount of ethyl acetate to produce 1-r (1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenolpropyl-1 hydrochloride. H-indol-5-ol as a white solid. HRMS: calculated for C, 8H20N2O2 + H +, 297.15975; found (ESI, [M + H] +), 297.1599.

Example 66: 1 - [(1 S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl-I H-indol-5-ol hydrochloride In a manner analogous to Example 65, 1 - [(1 S, 2R) -1- (3-fluorophen? L) -2-h? Drox? -3- (meth? Lam? No) prop? P- hydrochloride 1 H-β-ddol-5-ol is prepared from (1 S, 2 R) -1- (5-benzyl) -1 / 7-? Ndol-1-? L) -3- (met? Lam) ? no) -1- (3-fluorophen?) propan-2-ol (Example 24) as a white solid HRMS calculated for C, 8H, 9FN202 + H +, 315 15033, found (ESI, [M + Hf), 315 1516 Example 67 5 '- (benz? Lox?) - 1' - [(1 S, 2R) -2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? Llesp hydrochloride? rofc? clohexane-1, 3 '-? ndop-2' (1?) - ona Step 1 To a solution of sporo [c-clohexane-1, 3 '- [3H]? Ndol] -2' (1 'H) -ona7 (5 g, 24 8 mmol) in tpfluoroacetic acid (19 mL) and chloroform (240 mL) is added [b? s (tpfluoroacetox?) iodo] benzene (12 8 g, 29 8 mmol) at room temperature and the reaction mixture is stirred for 12 hours. The solution is then poured into sodium bicarbonate Saturated (50 mL) and extracted with ethyl acetate (50 mL). The organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (10%). to 80% ethyl acetate gradient in hexane) to give 5'-hydroxy sp [c-clohexane-1, 3 '-? ndol] -2' (1 'H) -one MS (ES) m / z 218 ([M + Hf) Step 2: To a mixture of 5'-hydroxy? [C-clohexane-1, 3'-? Ndol] -2 '(1?) -one (062 g, 2.9 mmol) and carbonate potassium (1 2 g, 8 6 mmol) in? /,? / - d? met? lformamide (10 mL) is added benzyl chloride (1 mL, 8.6 mmol) at room temperature under nitrogen The reaction mixture The resulting mixture is stirred for 12 hours at room temperature, poured into a saturated sodium chloride solution (50 mL), and extracted with ethyl acetate (50 mL). The organic layer is separated, dried over sodium sulfate, 7 Fensome, A, Miller, L L, Ullrich, J W, Bender R H W, Zhang, P, Wrobel, J E, Zhi, L Jones, T K, Marschke, K B, Tegley, C M PCT Int Appl 2000, 127pp WO2000066556 Anhydrous magnesium is filtered and concentrated under reduced pressure. The crude product is purified by flash column chromatography (10% to 80% ethyl acetate gradient in hexane) to give 5'-benzylcox? esp? ro [c? clohexane-1, 3 '-? ndol] -2' (1?) -one as a clear oil MS (ES) m / z 308 ([M + Hf] Step 3: To a vigorously stirred mixture of 5'-benzyl lox [c-clohexane-1, 3'-ndol] -2 '(1?) -one (0 37 g, 1 2 mmol) and 60% sodium hydride (0 053 g, 1 3 mmol) in? /,? / - d? Met? Lformam? Da (4 mL) is added a solution of [(2R, 3f?) - 3-phen? loxran-2-yl-methanol (024 g, 1.69 mmol, from Example 1, Step 1) and titanium isopropoxide (0 48 mL, 1.6 mmol) in? /, / Vd? met? lformam? da (8 mL) which is prepared separately and matured for 15 minutes. The reaction mixture is stirred for 12 hours under nitrogen at room temperature, poured into a solution of 3 N aqueous hydrochloric acid (100 mL), and extracted with ethyl acetate. (2x 50 mL) The combined organic layers are concentrated under reduced pressure and the residue is purified by flash column chromatography (20% to 80% ethyl acetate gradient in hexane) to give 5'-benzyl? 1 '- [(1S, 2S) -2,3-d? H? Drox? -1-phen? Lprop? L] esp? Ro [c? Clohexane-1, 3? Ndol] 2' (1? ) -one as a clear oil MS (ES) m / z 458 ([M + Hf) Step 4 A solution of 5'-benzylx? -1 '- [(1S, 2S) -2,3-d? H? Drox? -1-phen? Lprop? L] sp? Ro [c-clohexane -1, 3 '? Ndol] 2' (1 'H) -one (0 38 g, 0 83 mmol) in dry pipdine (3 mL) is treated with p-toluenesulfonyl chloride (0 24 g, 1 3 mmol) After 12 hours, the reaction mixture is diluted with ethyl acetate (25 mL) and the organic phase is washed with 1N aqueous hydrochloric acid solution (25 mL) followed by saturated sodium bicarbonate solution (25 mL). ) The organic layer is separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a clear oil which is dissolved in methanol (10 mL) and treated with an excess of methyl amine (33% by weight). in absolute ethanol, 5 mL) The reaction solution is stirred in a sealed tube at room temperature for 12 hours, poured into saturated sodium bicarbonate solution (25 mL), extracted with ethyl acetate (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Flash column (0 to 80% methanol gradient in chloromethane) to give 5'-benzyl? -1 '- [(1 S, 2R) -2-h? drox? -3- (met? lam? no) - 1-phenylpropylene] [c-clohexane-1, 3'-nol] 2 '(1' H) -one as a light oil The oil is dissolved in ethanol (2-3 mL) and treated with hydrogen chloride solution (1 0 M in diethyl ether, 11 equivalents) Ethanol is removed to give 5'-benzyl lox? -1 '- [(1 S, 2R) -2-h? drox? -3- (met? lam? no) -1-phen? lprop? llesp hydrochloride. ? ro [C? clohexane-1, 3 '? ndoll2' (1?) -one as an amorphous solid MS (ES) m / z 471 ([M + Hf] Example 68 5-benzyl hydrochloride? -1 - [(1 S, 2R) -2-h? Drox? -3- (meth? Lam? No) -1-phen? Lprop? Ll-3.3- d? met? l-1, 3-d? h? dro-2H-? ndol-2-one In a manner analogous to Example 1, step 1, 5-h? Drox? -3,3-d? Met? L-1, 3-d? H? Dro-2H-? Ndol-2-one is prepared from of 3,3-d? met? l-1, 3-d? h? dro-2H-? ndol-2-one MS (ES) m / z 178 ([M + Hf) In a manner analogous to Example 1, step 2, 5-benzyl? -3,3-d? Met? L-1,3-d? H? Dro-2H-? Ndol-2-one is prepared from of 5-h? drox? -3,3-d? met? l-1, 3-d? h? dro-2H-? ndol-2-one MS (ES) m / z 268 ([M + Hf] In a manner analogous to Example 1, step 3, 1 - [(1 S, 2 S) -2,3-d? H? Drox? -1-phen? Lprop? L] -5-benzyl? -3, 3-d? Met? L-1, 3-d? H? Dro-2H-? Ndol-2-one is prepared from 5-benzyl? -3,3-d? Met? L-1, 3-d? H? Dro-2H-? Ndol-2-one and [(2R, 3ft) -3-phen? Lox? Ran-2? L] methanol MS (ES) m / z 418 ([M + Hf) In a manner analogous to Example 1, step 4, 5-benzyl hydrochloride? -1-1 (1 S, 2R) -2-h? Drox? -3- (met? Lam? No) -1-phen ? lprop? ll-3,3-d? met? l-1, 3-d? h? dro-2H-? ndol-2-one is prepared from 1 - [(1 S, 2S) -2, 3-d? H? Drox? -1-phen? Lprop? L] -5-benz? Lox? -3,3-d? Met? L-1, 3-d? H? Dro-2H-? Ndol- 2-one MS (ES) m / z 431 ([M + Hf) Example 69 hydrochloride of 1 - [(1 S, 2R) -1- (3-chlorophen? L) -2-h? Drox? -3- (meth? Lam? No) prop? N-7-fluoro-3, 3-d? Met? L-1, 3-d? H? Dro-2H-? Ndol-2-one Step 1: To a solution of 2,6-difluoronitrobenzene (5.0 g, 31.44 mmol) in dry N, N-dimethylformamide (50 mL) is added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). ). The reaction mixture is heated to 65 ° C and stirred for 24 hours. After cooling to room temperature, the mixture is neutralized with a dilute aqueous solution of hydrochloric acid and extracted with diethyl ether. The ether layer is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Crystallization of 5% ethyl acetate / hexane gives 4.6 g (54%) of 2- (6-fluoro-2-nitro-phenyl) -malonic acid dimethyl ester. MS (ESI) miz 272 [M + Hf).

Step 2: 2- (6-fluoro-2-nitrophenyl) -malonic acid dimethyl ester (12 g, 44 mmol) in a 6 N aqueous solution of hydrochloric acid (200 ml) is refluxed for 4 hours . The mixture is cooled, diluted with 250 ml of water and extracted with diethyl ether. The ether layer is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Crystallization of 5% ethyl acetate / hexane gives 7.6 g (54%) of (6-fluoro-2-nitro-phenyl) -acetic acid. MS (ESI) miz 200 ([M + Hf).

Step 3: 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) is hydrogenated at 50 psi for 24 hours. The catalyst is removed by filtration through celite and the solvent is evaporated. The residue is then dissolved in ethanol (100 ml) and pyridinium para-toluenesulfonate (50 mg) is added and the mixture is refluxed for 1 hour. The mixture is cooled, poured into water, extracted with ethyl acetate and the organic extract is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The solid is triturated with 5% ethyl acetate / hexane to give 6.0 g (83%) 7-fluoro-1,3-dihydro-indol-2-one. MS (ESI) miz 152, [M + Hf).

Step 4: 7-Fluoro-1,3-dihydro-indol-2-one (7.3 g, 48 mmol) and lithium chloride (6.67 g, 158 mmol) are dissolved in tetrahydrofuran (200 mL). The solution is cooled to -78 ° C and n-butyl lithium (40 mL, 100 mmol) is slowly added over a period of 15 minutes.

After 20 minutes at -78 ° C, methyl iodide (6 mL, 96 mmol) is added and the mixture is allowed to warm to room temperature. After 24 hours, the mixture is poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by Biotage chromatography (Flash40¡, silica, 10% then 20% ethyl acetate / hexane) to give 4.1 g (48%) 7-fluoro-3,3-dimethyl-1, 3- dihydro-2 / - / - indol-2-one. MS (ESI) miz 180, [M + H] *). ' Step 5: 7-Fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (0.09 g, 0.50 mmol) is dissolved in /, / V-dimethylformamide (1.0 mL) and hydride is added of sodium (0.029 g, 0.75 mmol, 60% by weight of suspension in mineral oil) and the mixture is stirred for an additional 30 minutes. In a separate flask, [(2R, 3R) -3- (3-chlorophenyl) oxiran-2-yl] methanol (0.184 g, 1.0 mmol - prepared in a manner analogous to Example 1, Step 1) is dissolved in? / ,? / - dimethylformamide (1 mL) and titanium isopropoxide (0.15 mL, 0.50 mmol) is added and the mixture is stirred for 30 minutes. The isopropoxide / titanium epoxide solution is then added to the sodium salt solution of oxindole in drop form and the mixture is stirred at room temperature for 24 hours. The mixture is then carefully quenched with 2N aqueous hydrochloric acid and diluted with 50 mL of 2N aqueous hydrochloric acid (the use of aqueous hydrochloric acid is essential to prevent precipitation of titanium salts and subsequent emulsification). The mixture is extracted with ethyl acetate the combined organic layers, washed with water, and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified via Isco chromatography (Redisep, silica, gradient 20% to 100% ethyl acetate in hexane) to yield 0.155 g (85%) of 7-fluoro-1 - [(1 S, 2S) -1- (3-chlorophenyl) -2,3-dihydroxypropyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a sticky oil.

Step 6: 7-fluoro-1 - [(1 S, 2S) -1- (3-chlorophenyl) -2,3-dihydroxypropyl] -3,3-dimethyl-1,3-dihydro-2H-indole-2- ona (145 mg, 0.4 mmol) is dissolved in pyridine (2 mL) and toluenesulfonyl chloride (76 mg, 0.4 mmol) is added. The reaction mixture is stirred for 4 hours then the mixture is diluted with diethyl ether and washed with water, 2 N aqueous hydrochloric acid, saturated aqueous copper sulfate, 2 N aqueous hydrochloric acid, and saturated saline. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product dissolves immediately in a solution of methylamine (8 M n ethanol, 10 mL) and stirred for 16 hours. The mixture is concentrated under reduced pressure and purified by chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 44 mg of 1 - [(1 S, 2R) -1 - (3-chlorophenyl) -2 -hydroxy-3- (methylamino) propyl] -7-fluoro-3,3-dimethyl-1,3-dihydro-2 / - / - indol-2-one as a colorless oil. The free base is dissolved in ether (5 mL) and treated with a solution of hydrogen chloride (1.0 M in diethyl ether, 0.12 mL, 1.0 equivalent). The white precipitate is collected and dried under vacuum to give 38 mg (24% over three steps) of 1 - [(1 S, 2R) -1- (3-chlorophenyl) -2-hydroxy-3- (methylamino ) propylN7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one. Purity HPL 100% at 210-370 nm, 7.8 min .; Xterra RP18, column 3.5u, 150 x 4.6 mm, 1.2 mL / min, 85 / 15-5 / 95 (Amount Form of Ammon Ph = 3.5 / MeCN + MeOH) for 10 minutes, kept for 4 minutes. MS (ES) miz 377.1; ([M + Hf).

Example 70: (1 S, 2R) -1- (3-chloro-5-fluorophenyl) -1- (1 H -indol-1-yl) -3- (methylamino) propan-2-ol hydrochloride Step 1: To a suspension of NaH (60% in mineral oil, 3.0 g, 75.7 mmol) in dry tetrahydrofuran (460 mL) is added triethyl phosphonoacetate (16.97 g, 75.7 mmol) at room temperature. After stirring for 1 hour, 3-chloro-5-fluorobenzaldehyde (10.0 g, 63.07 mmol) in tetrahydrofuran (20 mL) is added dropwise. The reaction is stirred for 12 hours, quenched with water (30 mL) and concentrated. The crude residue is then taken up in ethyl acetate, washed with water, and saline, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6 g (96%) of (2E) -3- ( 3-chloro-5-fluorophenyl) ethyl acrylate as a white solid. HRMS: calculated for C,? H, or CCIF02, 228.0353; found (El, [M +], 228.0340.

Step 2: To a solution of (2E) -3- (3-chloro-5-fluorophenyl) ethyl acrylate (13.76 g, 228. 65 mmol) in dry dichloromethane (200 mL) at -78 ° C under nitrogen is added dropwise diisobutylaluminium hydride (neat, 21.7 mL, 120 mmol, 2 equiv.) Via an additive funnel. The reaction mixture is stirred for an additional 30 minutes, then slowly quenched with methanol (75 mL). After warming to room temperature, the mixture is treated with saturated aqueous solution of potassium tartrate / sodium (75 mL) and stirred for 30 minutes. Ethyl acetate is added and the organic layer is washed sequentially with 1N aqueous hydrochloric acid, saturated sodium bicarbonate, and saline, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude oil is purified on silica gel (0-50% ethyl acetate: hexane) to give 7.30g (65%) of (2 £) -3- (3-chloro-5-fluorophenyl) prop-2. en-1-ol as a colorless oil. MS (ESI) m / z 168.9 ([M + H-H2Of).

Step 3: In a manner analogous to Example 25, Step 3, [(2ft, 3f?) -3- (3-chloro-5-fluorophenyl) oxirane-2-yl] methanol is prepared from (2E) -3 - (3-chloro-5-fluorophenyl) prop-2-en-1-ol. MS (ESI) m / z 244 ([M + CH3CN + Hf).

Step 4: In a manner analogous to Example 1, Step 3, (2S, 3S) -3- (3-chloro-5-fluorophenyl) -3- (2,3-dihydro-1 / - / - indole-1- il) propane-1,2-diol is prepared from indoline and [(2 /? 3) -3- (3-chloro-5-fluorophenyl) oxiran-2-yl] methanol. MS (ES) m / z 322.0 ([M + Hf).

Step 5: In a manner analogous to Example 1, Step 4, (2S, 3S) -3- (3-chloro-5-fluorophenyl) -3- (1 / - / - indol-1-yl) propane-1, 2-diol is prepared from (2S, 3S) -3- (3-chloro-5-fluorophenyl) -3- (2,3-dihydro-1H-indol-1-yl) propane-1,2-diol . MS (ES) m / z 320.0 ([M + Hf).

Step 6: In a manner analogous to Example 69, Step 6, (1 S, 2 R) -1- (3-chloro-5-fluorophenyl) -1- (1 H -indol-1-yl) -3- hydrochloride (methylamino) propan-2-ol, is prepared from (2S, 3S) -3- (3-chloro-5-fluorophenyl) -3- (1 H -indol-1-yl) propane-1, 2- diol and methylamine. MS (ES) m / z 333 ([M + Hf).

Example 71: 3-chloro-N- hydrochloride. { 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indol-5-yl} -4-methylbenzamide Step 1 A mixture of 5-amino-n-dol (1 32 g, 10 mmol), 1-hydrox-benzotpazol (1 49 g, 11 mmol), and 1- (3-d? Meth? Lam? Nopropyl) -3-et? L-carbodomide (2 11 g, 11 mmol) hydrochloride dissolve in? /,? / - d? met? lforma? da (30 mL) To this is added 3-chloro-4-methylbenzoic acid (1 71 g, 10 mmol) and the reaction mixture is stirred for 2 hours until the reaction is complete The mixture is then partitioned between water and dichloromethane solution The organic layer is separated and the aqueous layer is extracted with dichloromethane several times. The combined extracts are washed with water and saline, dried over anhydrous sodium sulfate, they are filtered, and concentrated under reduced pressure. The crude product is purified by Biotage Hopzon (FlasH 40 M, silica, gradient of 0% ethyl acetate / hexane to 70% ethyl acetate / hexane) to give 3- chloro-N- (1 H-? ndol-5-? l) -4-met? lbenzamide as a light tan solid MS (ESI) m / z 284 9 ([M + Hf) In a manner analogous to Example 1, Step 2, 3-chloro-N- (? Ndol? N-5-? L) -4-methylbenzamide is prepared from 3-chloro-N- (1 / - / -? ndol-5-? l) -4-meth? benzamide as a light tan solid MS (ESI) m / z 286 9 ([M + Hf) In a manner analogous to Example 1, Step 3, 3-chloro-N-. { 1 - [(1 S, 2S) -2,3-d? H? Drox? -1-phen? Lprop? L]? Ndol? N-5-? L} -4-methylbenzamide is prepared from 3-chloro-N- (? Ndol? N-5-? L) -4-methylbenzamide as a white fluffy sohd MS (ESI) m / z 437 ([M + Hf) In a manner analogous to Example 1, Step 4, 3-chloro-N-. { 1 - [(1S, 2S) -2,3-d? H? Drox? -1-phen? Lprop? L] -1 / - / -? Ndol-5-? L} -4-met? Lbenzam? Da is prepared from 3-chloro-N-} 1 - [(1 S, 2S) -2,3-d? H? Drox? -1-phen? Lprop? L]? Ndol? N-5-? L} -4-methylenebenzamide as an MS oil (ESI) m / z 435 1 ([M + Hf] In a manner analogous to Example 1, Step 5, (2S, 3S) -3- [5- (3-chloro-4-met? Lbenzam? Do) -1 / - / -? Ndol-1-? L] - 2-hydroxy-3-phenolpropyl 4-methoxybenzene sulfonate is prepared from 3-chloro-N-. { 1 - [(1S, 2S) -2,3-d? H? Drox? -1-phen? Lprop? L] -1H-? Ndol-5-? L} -4-methylbenzamide as an MS oil (ESI) m / z 589 ([M + Hf] In a manner analogous to Example 1, Step 6, 3-chloro-N- (1 - [(1 S, 2R) -2-h? Drox? -3- (meth? Lam? No) -1-phen hydrochloride ? lprop? ll-1 H-? dol-5-? l.} -4-met? lbenzamide is prepared from (2S, 3S) -3- [5- (3-chloro-4-met β-benzamido) -1H-β-ddol-1- l l] -2-hydroxyl-3-phenolpropyl 4-methylbenzenesulfonate and methylamine (2N solution in methanol) as a tan solid MS (ESI) ) m / z 448 ([M + Hf), Purity HPL 100% at 210-370 nm, 8 9 min, Xterra RP18, column 3 5u, 150 x 4 6 mm, 1 2 mL / min, 85 / 15-5 / 95 (Amort Form of Amon Ph = 3 5 / ACN + MeOH) for 10m? N, remains 4m? N HRMS calculated for C26H26CIN302 + H +, 448 17863, found (ESI, [M + Hf), 448 1692 Example 72: 3-Chloro-N- hydrochloride. { 1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -2,3-dihydro-1H-indol-5-yl} benzamide Step 1 In a manner analogous to Example 71, Step 1, 3-chloro-N- (1H-? Ndol-5-? L) benzamide is prepared from 5-aminophenol and 3-chlorobenzoic acid. ? co as a dark tan solid MS (ESI) m / z 270 9 ([M + Hf) Step 2: In a manner analogous to Example 1, Step 2, 3-chloro-N- (? Ndol? N-5-? L) benzamide is prepared from 3-chloro-N- (1 / - / -? Ndol -5-? L) benzamide as a light tan solid MS (ESI) m / z 272 9 ([M + Hf) Step 3 In a manner analogous to example 1, step 3, 3-chloro-n-. { 1 - [(1 s, 2s) -2,3-d? H? Drox? -1-fen? Lprop? L]? Ndol? N-5-? L} Benzamide is prepared from 3-chloro-n- (? ndol? n-5-? l) benzamide as a pale yellow solid MS (ESI) m / z 423 ([M + Hf] Step 4 In a manner analogous to Example 1, Step 5, (2S, 3S) -3- [5- (3-chlorobenz-amido)? Ndol? N-1-? L] -2-h? Drox? -3-phenolpropyl 4-methoxybenzene sulfonate is prepared from 3-chloro-N-. { 1 - [(1 S, 2S) -2,3-d? H? Drox? -1-phen? Lprop? L]? Ndol? N-5-? L} benzamide as an MS oil (ESI) m / z 578 ([M + Hf] Step 5: In a manner analogous to Example 1, Step 6, 3-Chloro-N- (1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl-2,3- hydrochloride. dihydro-1 H-indol-5-yl) benzamide is prepared from (2S, 3S) -3- [5- (3-chlorobenzamido) indolin-1-yl] -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate and methylamine (2N solution in methanol) as a pale yellow solid. MS (ES) m / z 436.1 ([M + Hf); Purity HPL 100% at 210-370 nm, 8.3 min; Xterra RP18, column 3.5u, 150 x 4.6 mm, 1.2 mL / min, 85 / 15-5 / 95 (Amount Form of Ammon Ph = 3.5 / ACN + MeOH) for 10min, remains 4min. HRMS: calculated for C25H26CIN302 + H +, 436.17863; found (ESI, [M + Hf), 434.1618.

Example 73: 3-Chloro-N- hydrochloride. { 1 - [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl1-1 H-indol-5-yl) benzamide In a manner analogous to Example 1, Step 4, 3-chloro-N-. { 1 - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -1 / - / - indol-5-yl} Benzamide is prepared from 3-chloro-N-. { 1 - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] indolin-5-yl} benzamide (from Example 72, Step 3) as an oil. MS (ES) m / z 421.1 ([M + Hf).

In a manner analogous to Example 1, Step 5, (2S, 3S) -3- [5- (3-chlorobenzamido) -1 H-indol-1-yl-2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate is prepared from 3-chloro-N-. { 1 - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -1H-indol-5-yl} benzamide as an oil. MS (ESI) m / z 576 ([M + H]).

In a manner analogous to Example 1, Step 6, 3-Chloro-N- (1 - [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl-1 H-indol-5 hydrochloride. -l) benzamide is prepared from (2S, 3S) -3- [5- (3-chlorobenzamido) -1 H -indol-1-yl] -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate and methylamine ( 2N solution in methanol) as a white solid. MS (ES) m / z 434.1 ([M + Hf); Purity HPL 100% at 210-370 nm, 8.4 min .; Xterra RP18, column 3.5u, 150 x 4.6 mm, 1.2 mL / min, 85 / 15-5 / 95 (Amount Form of Ammon Ph = 3.5 / ACN + MeOH) for 10min, remains 4min. HRMS: calculated for C25H24CIN302 + H +, 434.16298; found (ESI, [M + Hf), 434.1617.

Example 74: N- Hydrochloride. { 1 - [(1S, 2R) -2-Hydroxy-3- (methylamino) -1-phenylpropyl] -2,3-dihydro-1 H-indol-5-yl} benzamide Step 1: In a manner analogous to Example 71, Step 1, N- (1 / - / - indol-5-yl) benzamide is prepared from 5-aminoindole and benzoic acid as a light tan solid. MS (ESI) m / z 237 ([M + Hf).

Step 2: In a manner analogous to Example 1, Step 2, N- (indolin-5-yl) benzamide is prepared from N- (1 / - / - indol-5-yl) benzamide as a light tan solid. MS (ESI) m / z 239.0 ([M + Hf).

Stage 3: In a manner analogous to example 1, stage 3, n-. { 1 - [(1s, 2s) -2,3-dihydroxy-1-phenylpropyl] indolin-5-yl} Benzamide is prepared from n- (indolin-5-yl) benzamide as a pale yellow solid. MS (ESI) m / z 389.1 ([M + Hf).

Step 4: In a manner analogous to Example 1, Step 5, (2S, 3S) -3- (5-benzamidoindolin-1-yl) -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate is prepared from N-. { 1 - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] indolin-5-yl} benzamlda like an oil. MS (ESI) m / z 543 ([M + H]).

Step 5: In a manner analogous to Example 1, Step 6, N- (1-f (1S, 2R) -2-Hydroxy-3- (methylamino) -1-phenylpropyl-2,3-dihydroxyhydrochloride 1H-indol-5-yl) benzamide is prepared from (2S, 3S) -3- (5-benzamidoindolin-1-yl) -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate and methylamine (2N solution) in methanol) as a tan solid Clear. MS (ES) m / z 402.1 ([M + Hf); Purity HPL 96.8% at 210-370 nm, 7.3 min; Xterra RP18, column 3.5u, 150 x 4.6 mm, 1.2 mL / min, 85 / 15-5 / 95 (Amount Form of Ammon Ph = 3.5 / ACN + MeOH) for 10min, remains 4min. HRMS: calculated for C25H2? N302 + H +, 402.21760; found (ESI, [M + Hf), 402,212.

Example 75: N- (1 - [(1 S, 2R) -2-Hydroxy-3- (methylamino) -1-phenylpropyl-1 H -indol-5-y!) Benzamide hydrochloride In a manner analogous to Example 1, Step 4, N-. { 1 - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -1 / - / - indol-5-yl} Benzamide is prepared from N-. { 1 - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] indolin-5-yl} benzamide (from Example 74, step 3) as an oil. MS (ES) m / z 387.1 ([M + Hf).

In a manner analogous to Example 1, Step 5, (2S, 3S) -3- (5-benzamido-1 / - / - indol-1-yl) -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate is prepared from of N-. { 1 - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -1 / - / - indol-5-yl} benzamide as an oil. MS (ESI) m / z 541 ([M + Hf).

In a manner analogous to Example 1, Step 6, N- (1 - [(1S, 2R) -2-Hydroxy-3- (methylamino) -1-phenylpropyl-1 H-indol-5-yl hydrochloride) Benzamide is prepared from (2S, 3S) -3- (5- (benzamido-1H-indol-1-yl) -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate and methylamine (2N solution in methanol) as a solid whitish MS (ES) m / z 400.1 ([M + Hf); Purity HPL 100% at 210-370 nm, 7.4 min., Xterra RP18, column 3.5u, 150 x 4.6 mm, 1.2 mL / min, 85 / 15-5 / 95 (Amount Form of Ammon Ph = 3.5 / ACN + MeOH) for 10 min, maintain 4 min HRMS: calculated for C25H25N3O2 + H +, 400.20195, found (ESI, [M + Hf), 400.2034.

Example 76: N- hydrochloride. { 1 - [(1S, 2R) -2-Hydroxy-3- (methylamino) -1-phenylpropyl] -2.3- dihydro-1 H-indol-5-yl} cyclohexanecarboxamide Step 1 In a manner analogous to Example 71, Step 1, N- (1H-? Ndol-5-? L) c? Clohexanecarboxamide is prepared from 5-amino? Ndol and cyclohexanecarboxylic acid as an MS oil. (ESI) m / z 243 0 ([M + Hf) Step 2: In a manner analogous to Example 1, Step 2, N- (? Ndol? N-5-? L) c? Clohexanecarboxamide is prepared from N- (1H-? Ndol-5-? L) c ? clohexanecarboxamide as an MS oil (ESI) m / z 245 ([M + Hf] Step 3 In a manner analogous to example 1, step 3, N-. { 1 - [(1s, 2s) -2,3-d? H? Drox? -1-phen? Lprop? L]? Ndol? N-5-? L} c-Clohexanecarboxamide is prepared from N - (? ndol? n-5-? l) c? clohexanecarboxamide as a white solid MS (ESI) M / Z 395 1 ([M + Hf) Step 4: In a manner analogous to Example 1, Step 5, (2S, 3S) -3- [5- (c? Clohexanecarboxamide)? Ndol? Nl -? L] -2-h? Drox? -3-phen ? -propyl 4-methoxybenzenesulfonate is prepared from N-. { 1 - [(1 S, 2S) -2,3-d? H? Drox? -1-phen? Lprop? L]? Ndol? N-5-? L} c) Clohexanecarboxamide as an MS oil (ESI) m / z 547 ([M + Hf] Step 5: In a manner analogous to Example 1, Step 6, N- (1-f (1 S, 2 R) -2-h? Drox? -3- (meth? Lam? No) -1-phen? Lprop hydrochloride ? ll-2,3-d? h? dro-1 H-? ddol-5-? l) c-Clohexane carboxamide is prepared from (2S, 3S) -3- [5- [c? clohexanecarboxamide ) ndol? n-1-? l] -2-hydroxy? -3-phenolpropyl 4-methybenzenesulfonate and methylamine (2N solution in methanol) as an off-white solid MS (ES) m / z 408 2 ([M + Hf), Purity HPL 100% at 210-370 nm, 7 9 min, Xterra RP18, column 3 5u, 150 x 4 6 mm, 1 2 mL / mm, 85 / 15-5 / 95 ( Amon Amort Form Ph = 3 5 / CAN + MeOH) for 10m? N, remains 4m? N Example 77 N- (1 - [(1S, 2R) -2-H? Drox? -3- (meth? Lam? No) -1-phen? Lprop? Ll-1H-? Ndol-5-? ) c? clohexanocarboxam? da In a manner analogous to Example 1, Step 4, N-. { 1 - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -1 / - / - indol-5-yl} Cyclohexanecarboxamide is prepared from N-. { 1 - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] indolin-5-yl} cyclohexanecarboxamide (from Example 76, Step 3) as an oil. MS (ES) m / z 393.1 ([M + Hf).

In a manner analogous to Example 1, Step 5, (2S, 3S) -3- [5- (cyclohexane carboxamido) -1 / - / - indol-1-yl] -2-hydroxy-3-phenylpropyl 4-methylbenzene sulfonate is prepared from N-. { 1 - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -1 / - / - indol-5-yl} cyclohexanecarboxamide as an oil. MS (ESI) m / z 547 ([M + H]).

In a manner analogous to Example 1, Step 6, N- (1 - [(1 S, 2R) -2-Hydroxy-3- (methylamino) -1-phenylpropyl-1 H-indol-5-yl Hydrochloride .) Cyclohexanecarboxamide is prepared from (2S, 3S) -3- [5- (cyclohexanecarboxamido) -1 / - / - indol-1-yl] -2-hydroxy-3-phenylpropyl-4-methylbenzenesulfonate and methylamine ( 2N solution in methanol) as an off-white solid MS (ES) m / z 406.1 ([M + Hf); HPLC purity 100% at 210-370 nm, 8.0 min., Xterra RP18, column 3.5u, 150 x 4.6 mm , 1.2 mL / min, 85 / 15-5 / 95 (Amount Form of Ammon Ph = 3 5 / ACN + MeOH) for 10min, remains 4m? N HRMS: calculated for C25H3, N302 + H +, 406.24890; found (ESI, [M + Hf), 406.2492.

Example 78: N- (3-Chlorophenyl) -1 - [(1S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] indoline-5-carboxamide hydrochloride Step 1: In a manner analogous to Example 71, Step 1, N- (3-chlorophenyl) -1H-indole-5-carboxamide is prepared from 1 H-indole-5-carboxylic acid and 3-chloroaniline as a solid oily toast MS (ESI) m / z 270.9 ([M + Hf).

Step 2: In a manner analogous to Example 1, Step 2, N- (3-chlorophenyl) indoline-5-carboxamide is prepared from N- (3-chlorophenyl) -1H-indole-5-carboxamide as a solid light toasting. MS (ESI) m / z 272.9 ([M + Hf).

Step 3: in a manner analogous to example 1, step 3, n- (3-chlorophenyl) -1 - [(1s, 2s) -2,3-dihydroxy-1-phenylpropyl] indoline-5-carboxamide is prepared from of n- (3-chlorophenyl) indoline-5-carboxamide as a white solid. MS (ESI) m / z 423 ([M + H]).

Step 4: In a manner analogous to Example 1, Step 5, (2S, 3S) -3- [5- (3-chlorophenylcarbamoyl) indolin-1-yl] -2-hydroxy-3-phenylpropyl 4-methylbenzene sulfonate is prepared from N- (3-chlorophenyl) -1 - [(1 S, 2S) -2,3-dihydroxy-1-phenylpropyl] indoline-5-carboxamide as an oil. MS (ESI) miz 511 ([M + Hf).

Step 5: In a manner analogous to Example 1, Step 6, N- (3-chlorophenyl) -1 - [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] indoline- hydrochloride. 5-carboxamide is prepared from (2S, 3S) -3- [5- (3-chlorophenylcarbamoyl) indolin-1-yl] -2-hydroxy-3-phenylpropyl 4-methylbenzene sulfonate and methylamine (2N solution in methanol) as a pale yellow solid. MS (ES) m / z 436.1 ([M + Hf); Purity HPL 100% at 210-370 nm, 8.6 min .; Xterra RP18, column 3.5u, 150 x 4.6 mm, 1.2 mL / min, 85 / 15-5 / 95 (Amount Form of Ammon Ph = 3.5 / ACN + MeOH) for 10min, is maintained for 4 minutes. HRMS: calculated for C25H26CIN302 + H +, 436.17863; found (ESI, [M + Hf), 436.1802.

Example 79: N- (3-Chlorophenyl) -1 - [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1 H -indole-5-carboxamide hydrochloride In a manner analogous to example 1, step 4, N- (3-chlorophenyl) -1 - [(1s, 2s) -2,3-dihydroxy-1-phenylpropyl] -1H-indole-5-carboxamide is prepared from of n- (3-chlorophenyl) -1 - [(1s, 2s) -2,3-dihydroxy-1-phenylpropyl] indoline-5-carboxamide (from Example 78, Step 3) as an oil. MS (ESI) M / Z 421.1.

In a manner analogous to Example 1, Step 5, (2S, 3S) -3- [5- (3-chlorophenylcarbamoyl) -1H-indol-1-yl] -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate is prepared from N- (3-chlorophenyl) -1 - [(1 S, 2S) -2,3-dihydroxy-1-phenylpropi] -1H-indole-5-carboxamide as an oil. MS (ESI) miz 575 ([M + H] +).

In a manner analogous to Example 1, Step 6, N- (3-Chlorophenyl) -1 - [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indole hydrochloride -5-carboxamide is prepared from (2S, 3S) -3- [5- (3-chlorophenylcarbamoyl) -1H-indol-1-yl] -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate and methylamine (solution 2N in methanol) as a white solid. MS (ES) m / z 434.1 ([M + Hf); Purity HPL 100% at 210-370 nm, 8.7 min; Xterra RP18, column 3.5u, 150 x 4.6 mm, 1.2 mL / min, 85 / 15-5 / 95 (Amount Form of Ammon Ph = 3.5 / ACN + MeOH) for 10min, remains 4min. HRMS: calculated for C25H24CIN302 + H +, 434.16298; found (ESI, [M + Hf), 434.1634.

Example 80: (1 S, 2R) -3- (methylamino) -1- (6-phenoxy-1 H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride In a manner analogous to Example 20, Step 1, 2-methyl-1-nitro-5-phenoxybenzene is prepared from 4-methyl-3-nitrophenol. H NMR (400 MHz, (CD3) 2SO) d 2.48 (s, 3H), 7.10 (d, 2H), 7.23 (t, 1 H), 7.31 (dd, 1 H), 7.45 (t, 2H), 7.52. (d, 1 H), and 7.55 (m, 1 H).

In a manner analogous to Example 19, Step 2, dimethyl- [2- (2-nitro-4-phenoxy-phenyl) -vinylfamine is prepared from 2-methyl-1-nitro-5-phenoxybenzene. 1 H NMR (400 MHz, (CD 3) 2 SO) d 2.88 (s, 6 H), 5.66 (d, 1 H), 7.05 (d, 2 H), 7.15-7.20 (m, 2 H), 7.32 (d, 1 H) , 7.39-7.43 (m, 3H), 7.71 (d, 1 H).

In a manner analogous to Example 19, Step 3, 6-phenoxy-1 / - / - indole is prepared from dimethyl- [2- (2-nitro-4-phenoxy-phenyl) -vinyl] -amine. MS (ES) m / z 210 ([M + H] +).

In a manner analogous to Example 1, Step 2, 6-phenoxyindoline is prepared from 6-phenoxy-1 H-indole. MS (ES) m / z 212 ([M + Hf).

In a manner analogous to Example 1, Step 3, (2S, 3S) -3- (6-phenoxy-2,3-dihydro-1 H-indol-1-yl) -3-phenylpropane-1,2-diol was prepared from 6-phenoxyindoline. MS (ES) m / z 362 ([M + Hf).

In a manner analogous to Example 1, Step 4, (2S, 3S) -3- (6-phenoxy-1H-indol-1-yl) -3-phenylpropane-1,2-diol is prepared from (2S, 3S) -3- (6-phenoxy-2,3-dihydro-1 / - / - indol-1-yl) -3-phenylpropane-1,2-diol. MS (ES) m / z 360 ([M + Hf).

In a manner analogous to Example 25, Step 5, (1S, 2R) -3- (methylamino) -l- (6-phenoxy-1H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride is prepared from (2S, 3S) -3- (6-phenoxy-1 H-indol-1-yl) -3-phenylpropane-1,2-dol. MS (ES) m / z 373 ([M + Hf); HRMS: calculated for C24H24N202 + H +, 373.19105; found (ESI, [M + Hf), 373.1916.

Example 81: (1 S.2R) -3- (Methylamino) -1- (7-phenoxy-1 H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride In a manner analogous to Example 20, Step 1, 2-methyl-1-nitro-6-phenoxybenzene is prepared from 3-methyl-2-nitrophenol. 1 H NMR (400 MHz, (CD 3) 2 SO) d 2.34 (s, 3 H), 6.93 (d, 1 H), 7.07 (d, 2 H), 7.22 (t, 2 H), and 7.41-7.49 (m, 3 H) .

In a manner analogous to Example 19, Step 2, dimethyl- [2- (2-nitro-3-phenoxy-phenyl) -vinyl-amine is prepared from 2-methyl-1-nitro-6-phenoxybenzene. 1 H NMR (400 MHz, (CD 3) 2 SO) d 2.83 (s, 6 H), 4.66 (d, 1 H), 6.48 (d, 1 H), 7.04 (d, 2 H), 7.19 (t, 1 H), 7.25 (t, 1 H), and 7.32-7.43 (m, 4H).

In a manner analogous to Example 19, Step 3, 7-phenoxy-1 / - / - indole is prepared from dimethyl- [2- (2-nitro-3-phenoxy-phenyl) -vinyl] -amine. MS (ES) m / z 210 ([M + Hf).

In a manner analogous to Example 1, Step 2, 7-phenoxyindoline is prepared from 7-phenoxy-1 H-indole. MS (ES) m / z 212 ([M + Hf).

In a manner analogous to Example 1, Step 3, (2S, 3S) -3- (7-phenoxy-2,3-dihydro-1 / - / - ndot-1-yl) -3-phenylpropane-1, 2 -diol is prepared from 7-phenoxyindoline. MS (ES) m / z 362 ([M + Hf).

In a manner analogous to Example 1, Step 4, (2S, 3S) -3- (7-phenoxy-1 / - / - indol-1-yl) -3-phenylpropane-1,2-diol is prepared from (2S, 3S) -3- (7-phenoxy-2,3-dihydro-1 H-indol-1-yl) -3-phenylpropane-1,2-diol. MS (ES) m / z 360 ([M + H] +).

In a manner analogous to Example 25, Step 5, (1S, 2R) -3- (methylamino) -l- (7-phenoxy-1 H-indol-1-yl) -1-phenylpropan-2-ol hydrochloride is prepared from (2S, 3S) -3- (7-phenoxy-1 H-indol-1-yl) -3-phenylpropane-1,2-diol. MS (ES) m / z 373 ([M + Hf); HRMS: calculated for C24H24N202 + H +, 373.19105; found (ESI, [M + Hf), 373.1912.

Example 82: (1S, 2R) -3-amino-1-r5- (benzyloxy) -1H-indol-1-ill-1-phenylpropan-2-ol hydrochloride Step 1: In a manner analogous to Example 1, Step 4, (2S, 3S) -3- [5- (benzyloxy) -1H-indol-1 -yl] -3-phenylpropane-1,2-diol is prepared from (2S, 3S) -3- [5- (benzyloxy) -2,3-dihydro-1 H-indol-1-yl] -3-phenylpropane-1,2-diol. MS (ES) m / z 374 [(M + H) +].

Step 2: In a manner analogous to Example 1, Step 5, (2S, 3S) -3- (5- (benzyloxy) -1H-indol-1-yl) -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate is prepared from (2S, 3S) -3- [5- (benzyloxy) -1H-indol-1-yl] -3-phenylpropane-1,2-diol. MS (ES) m / z 528 [(M + H) + j.

Step 3: In a manner analogous to Example 1, Step 6, (1S, 2R) -3-amino-1- [5- (benzyloxy) -1H-indol-1-yl] -1-phenylpropan- hydrochloride 2-ol is prepared from (2S, 3S) -3- (5- (benzyloxy) -l H-indol-1-yl) -2-hydroxy-3-phenylpropyl-4-methylbenzenesulfonate, substituting ammonia in a solution of methanol instead of methylamine in methanol solution. MS (ES) m / z 373 [(M + H) + J.

Example 83: (1S, 2R) -1- [5- (benzyloxy) -1H-indol-1-yl] -3- (ethylamino) -1-phenylpropan-2-ol hydrochloride In a manner analogous to Example 1, Step 6, hydrochloride of (1S, 2R) -1- [5- (benz? LoxQ-1 H-? Ndol-1 -? Ll-3- (et? Lam? No) - 1-phenylpropan-2-ol is prepared from (2S, 3S) -3- (5- (benzylox?) - 1 H-? Ndol-1 -? L) -2-h? Drox? -3-phenolpropyl 4-methoxybenzenesulfonate (from Example 82, Step 2), replacing ethylamine instead of methylamine MS (ES) m / z 401 [(M + H) +] Example 84 hydrochloride (1S, 2R) -1-55- (benzylox?) - 1 H-? Ndol-1-? Ll-1-phenol-3- (prop? Lam? No) propan- 2-ol In a manner analogous to Example 1, Step 6, hydrochloride of (1S, 2R) -1- [5- (benzyloxQ-1 H-? Ndol-1 -? Ll-1-phenyl? 3- ( prop? lam? no) propan-2-ol is prepared from (2S.3S) -3- (5- (benzylox?) - 1 H-? ndol-1-? l) -2-h? drox? -3-phen? -propyl 4-methoxybenzenesulfonate (from Example 82, Step 2), replacing propylamine in place of methylamine MS (ES) m / z 415 [(M + Hf] Example 85 hydrochloride (1 S, 2) -1- [5- (benz? Lox?) - 1 H-? Ndol-1-? N-3 - (? Soprop? Lam? No) -1-phen? Lpropan -2-ol In a manner analogous to Example 1, Step 6, (1S, 2R) -1- [5- (benzylox?) -1H-? Ndol-1-? L] -3- (? Soprop? Hydrochloride. lam? no) -1-phenolpropan-2-ol is prepared from (2S, 3S) -3- (5- (benzyloxy) -l H-indol-1-yl) -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (from Example 82, Step 2), replacing isopropylamine instead of methylamine. MS (ES) m / z 415 [(M + H) +].

Example 86: (1S, 2R) -1-r5- (benzyloxy) -1H-indol-1-ill-3- (dimethylamino) -1-phenylpropan-2-ol hydrochloride In a manner analogous to Example 1, Step 6, (1S, 2R) -1- [5- (benzyloxy) -1H-indol-1-yl] -3- (dimethylamino) -1-phenylpropan-2 hydrochloride. -ol is prepared from (2S, 3S) -3- (5- (benzyloxy) -l H-tndol-1-yl) -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (from Example 82, Step 2) , substituting? /,? / - dimethylamine instead of methylamine. MS (ES) m / z 401 [(M + H) +].

Example 87: (1S, 2R) -1- [5- (benzyloxy) -1H-indol-1-yl] -3- [ethyl (methyl) amino] -1-phenylpropan-2-ol hydrochloride In a manner analogous to Example 1, step 6, (1S, 2R) -1- [5- (benzyloxy) -1H-indol-1-yl] -3- [ethyl (methyl) amino] -1 hydrochloride phenylpropan-2-ol is prepared from (2S, 3S) -3- (5- (benzyloxy) -1H-indol-1-yl) -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (from Example 82 , Step 2), replacing N-ethylmethylamine instead of methylamine. MS (ES) m / z 415 [(M + H) +].

Example 88: (1S, 2R) -1- [5- (benzyloxy) -1H-indol-1-yl] -3- (diethylamino) -1-phenylpropan-2-ol hydrochloride In a manner analogous to Example 1, Step 6, (1S, 2R) -1- [5- (benzyloxy) -1H-indol-1-yl] -3- (diethylamino) -1-phenylpropan-2 hydrochloride. -ol is prepared from (2S, 3S) -3- (5- (benzyloxy) -l H-indol-1-yl) -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (from Example 82, Step 2) , replacing dethylamine instead of methylamine. MS (ES) m / z 429 [(M + H) +].

Example 89: (1 S.2R) -1-r5- (benzyloxy) -1H-indol-1-yl-1-phenyl-3-pyrrolidin-1-ylpropan-2-ol hydrochloride In a manner analogous to Example 1, Step 6, (1S, 2R) -1- [5- (benzyloxy) -1H-indol-1-yl] -1-phenyl-3-pyrrolidin-1-ylpropan- 2-ol is prepared from (2S, 3S) -3- (5- (benzyloxy) -l H-indol-1-yl) -2-hydroxy-3-phenylpropyl 4-methylbenzene sulfonate (from Example 82, Step 2), replacing pyrrolidine instead of methylamine. MS (ES) m / z 427 [(M + H) +].

Example 90: (1S, 2R) -1- [5- (benzyloxy) -1H-indol-1-yl-1-phenyl-3-pyridin-1-ylpropan-2-ol hydrochloride In a manner analogous to Example 1, Step 6, (1S, 2R) -1- [5- (benzyloxy) -1H-indol-1-yl] -1-phenyl-3-piperidin-1-ylpropan hydrochloride. -2-ol is prepared from (2S, 3S) -3- (5- (benzyloxy) -l H-indol-1-yl) -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (from Example 82, Step 2), replacing piperidine instead of methylamine. MS (ES) m / z 441 [(M + H) +].

Example 91: (1S, 2R) -1- [5- (benzyloxy) -1H-indol-1-ill-3- (4-methylpiperazin-1-yl) -1-phenylpropan-2-ol hydrochloride In a manner analogous to Example 1, Step 6, (1S, 2R) -1- [5- (benzyloxy) -1H-indol-1-yl] -3- (4-methylpiperazin-1-yl) hydrochloride -1-phenylpropan-2-ol is prepared from (2S, 3S) -3- (5- (benzyloxy) -l H-indol-1-yl) -2-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (from Example 82, Step 2), substituting 1-methylpiperazine for methylamine. MS (ES) m / z 456 t (M + H) +], Example 92: (1S, 2R) -3- (methylamino) -1-phenyl-1- [5- (pyridin-2-ylmethoxy) -1H-indol-1-illpropan-2-ol hydrochloride In a manner analogous to Example 5, Step 3,. { (2R, 3S) -2-hydroxy-3-phenyl-3- [5- (pyridin-2-ylmethoxy) -1H-indol-1-yl] propyl} tert-butyl methylcarbamate is prepared from [(2R, 3S) -2-hydroxy-3- (5-hydroxy-1 H -indol-1-yl) -3-phenylpropyl] methylcarbamate-tert-butyl ester (Example 5, step 2), substituting 2- (bromomethyl) pyridine bromohydrate in place of 2-methoxybenzyl chloride. MS (ES) m / z 488 [(M + H) +].

In a manner analogous to Example 5, step 4, (1S, 2R) -3- (methylamino) -1-phenyl-1- [5- (pyridin-2-ylmethoxy) -1H-indole-1- hydrochloride. il] propan-2-ol is prepared from. { (2R, 3S) -2-hydroxy-3-phenyl-3- [5- (pyridin-2-ylmethoxy) -1H-indol-1-yl] propyl} tert-butyl methylcarbamate. MS (ES) m / z 388 [(M + H) +].

Example 93: (1 S, 2R) -3- (methylamino) -1-phenyl-1- [5- (phenylethyl) -1 H -indole-1-illpropan-2-ol hydrochloride In a manner analogous to Example 1, Step 2, 5-bromoindoline is prepared from 5-bromoindole. MS (ES) m / z 198 [(M + H) +].

In a manner analogous to Example 1, Step 3, (2S, 3S) -3- (5-bromo-2,3-dihydro-1 H-indol-1-yl) -3-phenylpropane-1,2-diol was prepared from [(2R, 3R) -3-phenyloxyran-2-yl] methanol (from Example 1, step 1), substituting 5-bromoindoline for 5- (benzyloxy) indoline. MS (ES) m / z 348 [(M + H) +].

In a manner analogous to Example 1, Step 4, (2S, 3S) -3- (5-bromo-1H-indol-1-yl) -3-phenylpropane-1,2-diol is prepared from (2S, 3S) -3- (5-bromo-2,3-dihydro-1H-indol-1-yl) -3-phenylpropane-1,2-diol. MS (ESI) m / z 346 [(M + H) +].

A mixture of (2S, 3S) -3- (5-bromo-1 / - / - indol-1-yl) -3-phenylpropane-1,2-diol (500 mg, 1.44 mmol), phenylacetylene (d 0.930, 0.32 mL, 2.9 mmol), copper (I) iodide (27 mg, 0.14 mmol), potassium carbonate (398 mg, 2.9 mmol) and [1,1 '-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (57 mg, 0.007 mmol) in N, N-dimethylformamide (10 mL) is purged with nitrogen for 30 minutes and then heated to 100 ° C. After 15 hours, the cold mixture is filtered through Celite and washed with acetate. of ethyl (30 mL). The filtrate is diluted with ethyl acetate (120 mL), washed with water (5 x 100 mL) and saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting dark oil is dissolved in dichloromethane and pre-adsorbed on silica gel (2.5 g). ISCO CombiFlash Companion chromatography (40 g RediSep silica, 40 mL / min, 30-50% ethyl acetate / hexane) provides (2S, 3S) -3-phenyl-3- [5- (phenylethynyl) -1 H- indole-1-yl] propane-1,2-diol (452 mg, 85%) as a tan solid. MS (ES) m / z 368 [(M + H) +].

In a manner analogous to Example 1, Step 5, (2S, 3S) -2-hydroxy-3-phenyl-3- [5- (phenylethynyl) -1H-indol-1-yl] propyl 4-methylbenzenesulfonate is prepared at starting from (2S, 3S) -3-phenyl-3- [5- (phenylethynyl) -l H-indol-1-yl] propane-1,2-diol. MS (ES) m / z 522 [(M + Hf).

In a manner analogous to Example 1, step 6, (1S, 2R) -3- (methylamino) -1-phenyl-1- [5- (phenolletinyl) -1H-indole hydrochloride. 1-illpropan-2-ol is prepared from (2S, 3S) -2-hydroxy-3-phenyl-3- [5- (phenylethynyl) -1 / - / - ndol-1-yl-propyl-4-methylbenzenesulfonate. MS (ES) m / z 381 [(M + H) +].

Example 94: (1S, 2R) -3- (methylamino) -1-phenyl-1-r5- (2-phenylethyl) -1H-indol-1-illpropan-2-ol hydrochloride A solution of (2S, 3S) -3-phenyl-3- [5- (phenylethynyl) -1H-indol-1-yl] propane-1,2-diol, Example 93, Step 4, (1.2 g, 3.3 mmol) in ethyl acetate (40 mL) is hydrogenated over 10% palladium on carbon (0.24 g) at 50 psi. After 24 hours, the reaction mixture is filtered through Celite and washed with ethyl acetate. The filtrate is concentrated under reduced pressure and the residue is dissolved in hot ethyl acetate (<; 5 mL) and pre-adsorbed on silica gel (3 g). ISCO CombiFlash Companion chromatography (80 g RediSep silica, 60 mL / min, 30-100% ethyl acetate / hexane) provides (2S, 3S) -3-phenyl-3- [5- (2-phenylethyl) -1 - indol-1 -yl] propane-1,2-diol (0.96 g, 80%) as a light yellow solid. MS (ES) m / z 372 [(M + H) +].

In a manner analogous to Example 1, Step 5, (2S, 3S) -2-hydroxy-3-phenyl-3- [5- (2-phenylethyl) -1-indol-1-yl] propyl 4-methylbenzenesulfonate was prepared from (2S, 3S) -3-phenyl-3- [5- (2-phenylethyl) -1 H -indol-1-yl] propane 1,2-diol. MS (ES) m / z 526 [(M + H) +].

In a manner analogous to Example 1, Step 6, hydrochloride of (1 S.2R1-3- (methylamino) -1-phenyl-1- [5- (2-phenylethyl) -1 H -indole-1-illpropan-2 -ol is prepared from (2S, 3S) -2-hydroxy-3-phenyl-3- [5- (2-phenylethyl) -1H-indol-1-yl-propyl-4-methylbenzenesulfonate MS (ES) m / z 385 [(M + H) + J.

Example 95: 1 '- [(1S, 2R) -3-amino-2-hydroxy-1-phenylpropin-6'-fluorospirocyclohexane-1,3'-indoll-2' (1?) -one hydrochloride In a manner analogous to Example 27, Step 3, 1 '- [(1S, 2R) -3-amino-2-hydroxy-1-phenylpropyl-6'-fluorosphero [cyclohexane-1, 3 hydrochloride] '-indoll-2' (1?) -one is prepared from 1 '- [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -6'-fluorospiro [cyclohexane-1,3' -indol] - 2 '(1' H) -one (from Example 29, Step 2), replacing ammonium hydroxide in place of methylamine in ethanol solution. MS (ES) m / z 369.1 ([M + Hf); HRMS: calculated for C22H25FN202 + H +, 369.19728; found (ESI, [M + Hf), 369.1977.

Example 96: 1 '-l (1S.2R) -3- (ethylamino) -2-hydroxy-1-phenylpropyl-6'-fluorospiro hydrochloride [cyclohexane-1,3'-indoll-2' (1?) - ona In a manner analogous to Example 27, Step 3, 1 '- [(1 S, 2R) -3- (ethylamino) -2-hydroxy-1-phenylpropin-6'-fluorospiro hydrochloride [cyclohexane-1, 3'- indoN-2 '(1?) -one is prepared from 1' - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -6'-fluorospiro [cyclohexane-1,3'-indole ] -2 '(1' / - /) - one (from Example 29, Step 2), replacing ethylamine in place of methylamine in ethanol solution. MS (ES) m / z 397.2 ([M + Hf); HRMS: calculated for C24H29FN202 + H +, 397.22858; found (ESI, [M + Hf), 397.2275.

Example 97: 6'-fluoro-1 '- [(1 S, 2R) -2-hydroxy-3- (isopropylamino) -1-phenylpropiNespirofcyclohexane-1,3'-indoll-2' (1?) -one hydrochloride In a manner analogous to Example 27, Step 3, 6'-fluoro-1 '-f (1 S, 2R) -2-hydroxy-3- (isopropylamino) -1-phenylpropylspirofcyclohexane-l, 3'-indoll hydrochloride -2 '(1?) -one is prepared from 1' - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -6'-fluorospiro [cyclohexane-1, 3'- indole] -2 '(1' H) -one (from Example 29, Step 2), substituting isopropyl amine for methylamine in ethanol solution. MS (ES) m / z 411.2 ([M + Hf); HRMS: calculated for C25H3? FN202 + H +, 411.24423; found (ESI, [M + Hf), 411.2413.

Example 98: 6l-fluoro-1 '- [(1 S.2R) -2-hydroxy-1-phenyl-3- (propylamino) propyl] spiro [1-cyclohexane-3'-indop-2' hydrochloride (1?) - ona In a manner analogous to Example 27, Step 3, 6'-fluoro-1 '- [(1 S, 2R) -2-hydroxy-1-phenyl-3- (propylamino) propyrospiro hydrochloride [cyclohexane-1, 3'-indoN-2 '(1?) -one is prepared from 1' - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -6'-fluorospiro [cyclohexane-1, 3 '-indo] -2' (1 'H) -one (from Example 29, Step 2), replacing propylamine instead of methylamine in ethanol solution. MS (ES) m / z 411.2 ([M + Hf); HRMS: calculated for C25H3? FN202 + H +, 411.24423; found (ESI, [M + Hf), 41 1.2413.

Example 99: 1 '- [(1S, 2R) -3-amino-2-hydroxy-1-phenylpropyl-5'-fluorospiro hydrochloride [cyclohexane-1,3'-indol-2' (1?) -one In a manner analogous to Example 27, Step 3, 1 '-f (1S, 2R) -3-amino-2-hydroxy-1-phenylpropyl-5'-fluorospiropyclohexane-1,3'-indon-2' hydrochloride ( 1?) -one is prepared from 1 '- [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -5'-fluorospiro [cyclohexane-1,3'-indole] -2' ( 1 'H) -one (from Example 30, Step 2), replacing ammonium hydroxide instead of methylamine in ethanol solution. MS (ES) m / z 369.1 ([M + Hf); HRMS: calculated for C22H25FN202 + H +, 369.19728; found (ESI, [M + Hf), 369.1982.

Example 100: 1 '-f (1 S, 2R) -3- (ethylamino) -2-hydroxy-1-phenylpropiM-5'-fluorospiro hydrochloride [cyclohexane-1,3'-endop-2' (1? -one In a manner analogous to Example 27, Step 3, 1 '-f (1 S, 2R) -3- (ethylamino) -2-hydroxy-1-phenylpropyl-5'-fluorospiro hydrochloride [cyclohexane-1, 3'- indol1-2 '(1?) - one is prepared from 1' - [(1 S, 2S) -2,3-dihydroxy-1-phenylpropyl] -5'-fluorospiro [cyclohexane-1,3'-indole ] -2 '(1' H) -one (from Example 30, Step 2), replacing ethylamine in place of methylamine in ethanol solution. MS (ES) m / z 397.2 ([M + Hf); HRMS: calculated for C24H29FN202 + H +, 397.22858; found (ESI, [M + Hf), 397,229.

Example 101: 5'-Fluoro-1 '- [(1 S, 2R) -2-hydroxy-3- (isopropylamino) -1-phenylpropylpyrrocyclohexane-1,3'-indoll-2' (1?) -one hydrochloride In a manner analogous to Example 27, Step 3, 5'-fluoro-1 '- [(1 S, 2R) -2-hydroxy-3- (isopropylamino) -1-phenylpropylpyrrole [cyclohexane-1, 3'- hydrochloride] indoll-2 '(1' H) -one is prepared from 1 '- [(1S, 2S) -2,3-dihydroxy-1-phenylpropyl] -5'-fluorospiro [cyclohexane-1,3'-indole] ] -2 '(1' H) -one (from Example 30, Step 2), replacing isopropylamine in place of methylamine in ethanol solution. MS (ES) m / z 411.2 ([M + Hf); HRMS: calculated for C25H3? FN202 + H +, 411.24423; found (ESI, [M + Hf), 411.2433.

Example 102: 5'-fluoro-1 '- [(1 S.2R) -2-hydroxy-1-phenyl-3- (propylamino) propyrospiro hydrochloride [cyclohexane-1,3'-indoll-2' (1? -one In a manner analogous to Example 27, Step 3, 5'-fluoro-1 '- [(1 S, 2R) -2-hydroxy-1-phenyl-3- (propylamino) propylpyrrocyclohexane-1,3'-indoll hydrochloride -2 '(1?) -one is prepared from 1' - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -5'-fluorospiro [cyclohexane-1,3'-indole] -2 '(1' / - /) - one (from Example 30, Step 2), replacing propylamine instead of methylamine in ethanol solution. MS (ES) m / z 41 1.2; HRMS: calculated for C25H3? FN202 + H +, 411.24423; found (ESI, [M + Hf), 411.2438.

Example 103: 1 '- [(1 S, 2R) -3- (dimethylamino) -2-hydroxy-1-phenylpropyl-5'-fluorospirofcyclohexane-1,3'-indoll-2' (1 'H) hydrochloride ona In a manner analogous to Example 27, Step 3, 1 '-f (1 S, 2R) -3- (dimethylamino) -2-hydroxy-1-phenylpropyl-5'-fluorospirophylcyclohexane-1,3'-indonium hydrochloride. 2 '(1?) -one is prepared from 1' - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -5'-fluorospiro [cyclohexane-1,3'-indole] - 2 '(1' / - /) - one (from Example 30, Step 2), replacing dimethylamine in place of methylamine in ethanol solution. MS (ES) m / z 397.2 ([M + Hf); HRMS: calculated for C24H29FN202 + H +, 397.22858; found (ESI, [M + Hf), 397.2283.

Example 104: 5'-fluoro-1 '-f (1 S, 2R) -2-hydroxy-3-morpholin-4-yl-1-phenylpropylpyrrocyclohexane-1,3'-indop-2' hydrochloride (1?) -one In a manner analogous to Example 27, Step 3, 5'-fluoro-1 '- [(1 S, 2R) -2-hydroxy-3-morpholin-4-yl-1-phenylpropyl-1-pyro [cyclohexane-1, 3 hydrochloride] '-indop-2' (1 'H) -one is prepared from 1' - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -5'-fluorospiro [cyclohexane-1, 3 '-indo] -2' (1 '/ - /) - ona (from Example 30, Step 2), replacing morpholine in place of methylamine in ethanol solution. MS (ES) m / z 439.1 ([M + Hf); HRMS: calculated for C26H3, FN2O3 + H +, 439.23915; found (ESI, [M + Hf), 439.2392.

Example 105: 1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -5'-methoxyspiro hydrochloride [cyclohexane-1,3'-indole] -2' (1 ?) - ona In a manner analogous to Example 27, Step 1, 5'-methoxyspiro [cyclohexane-1,3'-indole] -2 '(1' H) -one is prepared from 5-methoxyoxindole.

In a manner analogous to Example 27, Step 2, 1 '- [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -5'-methoxyspiro [cyclohexane-1,3'-indole] -2' (1?) - ona is prepared from 5'-methoxyspiro [cyclohexane-1,3'-indole] -2 '(1?) -one.

In a manner analogous to Example 27, Step 3, 1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl-5'-methoxiespiro [cyclohexane-1, 3 hydrochloride] '-indole] -2' (1?) -one is prepared from 1 '- [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -5'-methoxyspiro [cyclohexane-1, 3 '-indol] -2' (rH) -one. MS (ES) m / z 395.2 ([M + Hf); HRMS: calculated for C24H30N2O3 + H +, 395.23292; found (ESI, [M + Hf), 395.2313.

Example 106: 1 '- [(1 S, 2R) -2-Hydroxy-3- (methylamino) -1-phenylpropyl] -6'-methoxyspiro hydrochloride [cyclohexane-1,3'-indole] -2' (1?) - ona In a manner analogous to Example 27, Step 1, 6'-methoxyspiro [cyclohexane-1,3'-indole] -2 '(1' H) -one is prepared from 6-methoxyoxindole.

In a manner analogous to Example 27, Step 2, 1 '- [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -6'-methoxyspiro [cyclohexane-1,3'-indole] -2' (1?) - ona is prepared from 6'-methoxyspiro [cyclohexane-1,3'-indole] -2 '(1?) -one.

In a manner analogous to Example 27, Step 3, 1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropin-6'-methoxyspirofcyclohexane-1,3'-hydrochloride indop-2 '(1?) -one is prepared from 1' - [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -6'-methoxyspiro [cyclohexane-1,3'-indole ] -2 '(rH) -one. MS (ES) m / z 395.1 ([M + Hf); HRMS: calculated for C24H30N2O3 + H +, 395.23292; found (ESI, [M + Hf), 395.2317.

Example 107: 1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-pheny1propyl] -2'-oxo-1', 2'-dihydrospiro [cyclohexane-1, 3'-indole] -5'-carbonitrile In a manner analogous to Example 27, Step 1, 2'-oxo-1 ', 2'-dihydrospiro [cyclohexane-1,3'-indole] -5'-carbonitrile is prepared from 5-cyano-oxindole. MS (ES) m / z 225.0 ([M-H] ").

In a manner analogous to Example 27, Step 2, 1 '- [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -2'-oxo-1', 2'-dihydrospiro [cyclohexane-1, 3'-indole] -5'-carbonitrile is prepared from 2'-oxo-1 ', 2'-dihydrospiro [cyclohexane-1,3'-indole] -5'-carbonitrile. MS (ES) m / z 377.1 ([M + Hf).

In a manner analogous to Example 27, Step 3, 1 '-f (1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl1-2'-oxo-102'-dihydrospirohydrochloride [cyclohexane- 1,3'-indole-1-5'-carbonitrile is prepared from 1 '- [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -2'-oxo-1', 2'-dih Droespyrro [cyclohexane-1,3'-indole] -5'-carbonitrile. MS (ES) m / z 390.1 ([M + Hf); HRMS: calculated for C 24 H 2? N 3 O 2 + H +, 390.21760; found (ESI, [M + Hf), 390.2184.

Example 108: 1 '- [(1 S, 2R) -2-hydroxy-3- (methylamino) -1-phenylpropyl] -2'-oxo-r, 2'-dihydrospiro [cyclohexane-1,3'] hydrochloride -indol] -6'-carbonitrile In a manner analogous to Example 27, Step 1, 2'-oxo-1 ', 2'-dihydrospiro [cyclohexane-1,3'-indole] -6'-carbonitrile is prepared from 6-cyano-oxindole. MS (ES) m / z 225.0 ([M-H] ").

In a manner analogous to Example 27, Step 2, 1 '- [(1 S, 2 S) -2,3-dihydroxy-1-phenylpropyl] -2'-oxo-1', 2'-dihydrospiro [cyclohexane-1, 3'-indole] -6'-carbontrile is prepared from 2'-oxo- 1 ', 2'-d? H? Droesp? Ro [c? Clohexane-1, 3' -? Ndol] -6'-carbon? Tplo MS (ES) m / z 377 1 ([M + Hf) In a manner analogous to Example 27, Step 3, hydrochloride of 1 '- [(1 S, 2R) -2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L-2 '-oxo-1', 2'-d? h? droesp? ro [c? clohexane-1, 3 '-? ndol1-6'-carbonitrile is prepared from 1' - [(1 S, 2S) - 2,3-d? H? Drox? -1-phen? Lprop? L] -2'-oxo-1 ', 2'-d? H? Droesp? Ro [c? Clohexane-1, 3' -? Ndol ] -6'-carbon? Tr? Lo MS (ES) m / z 390 2 ([M + Hf), HRMS calculated for C24H2? N3O2 + H +, 390 21760, found (ESI, [M + Hf), 390 2186 EXAMPLE 109 4 ', 5'-d? -fluoro-1' - [(1 S, 2R) -2-h? Drox? -3- (meth? Lam? No) -1-phen? Lprop? L] hydrochloride] esp? ro [c? clohexane-1, 3 '-? ndol] -2' (1?) - ona In a manner analogous to Example 27, Step 1, 4 ', 5'-d? Fluorosp? Ro [c-clohexane-1, 3' -? Ndol] -2 '(1' H) -one is prepared from 4,5-d? Fluoro-oxidol MS (ES) m / z 238 1 ([M + Hf) In a manner analogous to Example 27, Step 2, 1 '- [(1S, 2S) -2,3-d? H? Drox? -1-phen? Lprop? L] -4', 5'-d? Fluoroesp ? ro [c-Clohexane-1, 3'-? ndol] -2 '(1' H) -one is prepared from 4 ', 5'-d? fluorosp? ro [c? clohexane-1, 3' -? ndol] -2 '(1?) - ona MS (ES) m / z 388 1 ([M + Hf) In a manner analogous to Example 27, Step 3, 4 ', 5'-d? Fluoro-1' -f (1S, 2R) -2-h? Drox? -3- (meth? Lam? No) hydrochloride 1-Phenolpropyllester [c-Clohexane-1, 3 '-? Ndon-2' (1?) - one is prepared from 1 '- [(1 S, 2S) -2.3- d? h? drox? -1-phen? lprop? l] -4 ', 5'-d? fluorosp? ro [c? clohexane-1, 3' -? ndol] -2 '(r / - /) - ona MS (ES) m / z 401 2 ([M + Hf), HRMS calculated for C23H26F2N2O2 + H +, 401 20351, found (ESI, [M + Hf), 401 204 Example 110 7'-fluoro-1 '- [(1 S, 2R) -1- (3-fluorophen? L) -2-h? Drox? -3- (met? Lam? No) prop? Llesp? Hydrochloride. ro [c? clohexane-1, 3 '-? ndoll-2' (1?) - ona In a manner analogous to Example 62, Step 4, 7'-fluorosp? Ro [c-clohexane-1, 3 '-? Ndol] -2' (1 'H) -one is prepared from 7-fluoro-1 , 3-d? H? Dro-2H-? Ndol-2-one (from Example 62, Step 3), substituting 1,5-d? Bromopentane instead of methyl iodide MS (ES) m / z 220 [( M + H) +] In a manner analogous to Example 62, Step 5, 7'-fluoro-1 '- ((1 S, 2S) -1- (3-fluorophen? L) -2,3-d? H? Drox? Prop? L ) esp? ro [c-clohexane-1, 3 '-? ndol? n] -2'-one is prepared from 7'-fluorosp? ro [c? clohexane-1, 3' -? ndol] -2 '(1' H) -one, substituting [(2R, 3R) -3- (3-fluorophen? L) ox? Ran-2? L] methanol (from Example 24, Step 1) in place of [(2f ?, 3R) -3- (3,5-d? Fluorophen? L) ox? Ran-2? L] methanol MS (ES) m / z 388 [(M + Hf) In a manner analogous to Example 62, Step 6, 7'-fluoro-1 '- [(1S, 2R) -1- (3-fluorophen? L) -2-h? Drox? -3- (met? lam? no) prop? llesp? ro [c? clohexane-1, 3 '-? ndoll-2' (1?) - one is prepared from 7'-fluoro-1 '- ((1 S, 2S) -1- (3-fluorophen? L) -2,3-d? H? Drox? Prop? L) sp? Ro [c? Clohexane-1, 3 '-? Ndol? N] -2'-ona MS ( ES) m / z 401 [(M + H) +] Example 11 1 1 '- [(1 S, 2 R) -1- (3-chlorophen? L) -2-h? Drox? -3- (meth? Lam? No) prop? L] -6'- hydrochloride fluoroesp? ro [c? clohexane-1, 3 '-? ndol] -2' (1?) - ona In a manner analogous to Example 27, Step 2, 1 '- [(1 S, 2S) -1- (3-chlorophenyl) -2,3-dihydroxypropyl] -6'-fluorospiro [cyclohexane-1,3'-indole ] -2 '(1?) -one is prepared from 6'-fluorospiro [cyclohexane-1,3'-indole] -2' (1?) -one (from Example 29, Step 1) and [(2R) , 3R) -3- (3-chlorophenyl) oxiran-2-yl] methanol (from Example 69, Step 5). MS (ES) m / z 403.9 ([M + Hf).

In a manner analogous to Example 27, Step 3, 1 '- [(1 S, 2R) -1- (3-chlorophenyl) -2-hydroxy-3- (methylamino) propyl] -6'-fluorospiro hydrochloride [cyclohexane] -1, 3'-indole] -2 '(1?) -one is prepared from 1' - [(1 S, 2 S) -1- (3-chlorophenyl) -2,3-dihydroxypropyl] -6 ' fluorospiro [cyclohexane-1,3'-indole] -2 '(1?) -one. MS (ES) m / z 417.1 ([M + Hf); HRMS: calculated for C23H26CIFN2O2 + H +, 417.17396; found (ESI, [M + Hf), 417.1739.

Example 1 12: 1-((1S, 2R) -1- (3-chloro-5-fluorophenyl) -2-hydroxy-3- (methylamino) propyl1-7-fluoro-3,3-dimethyl hydrochloride -1, 3-dihydro-2H-indol-2-one 7-Fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (0.52 g, 3.0 mmol, from Example 69, Step 4) is dissolved in? /,? / - d -methylformamide ( 3 mL) and sodium hydride (0.17 g, 4.4 mmol, 60% by weight suspension in mineral oil) is added in portions for 15 minutes and the mixture is stirred for an additional 30 minutes. In a separate flask, [(2R, 3R) -3- (3-fluoro-5-chlorophenyl) oxirane-2-yl] methanol (1.2 g, 5.9 mmol, from Example 70, Step 3) is dissolved in? /, ? / - dimethylformamide (3 mL) and titanium isopropoxide (1.76 mL, 5.9 mmol) is added and the mixture is stirred 30 minutes. The isopropoxide / titanium epoxide solution is then added to the sodium salt solution of oxindole in drop form and the mixture is stirred at room temperature for 24 hours. The mixture is then carefully quenched with 2N aqueous hydrochloric acid and diluted with 200 mL of 2N aqueous hydrochloric acid (use of hydrochloric acid is essential to prevent precipitation of titanium salts and subsequent emulsification). The mixture is extracted with ethyl acetate and then the organic layers are combined, washed with water, and saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified via Isco chromatography (Redisep, silica, gradient 20% to 100% ethyl acetate in hexane) to yield 1.01 g of 1 - [(1 S, 2S) -1- (3-chloro- 5-fluorophenyl) -2,3-dihydroxypropyl] -7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a sticky oil of 82% purity. MS (ES) miz 382.0 ([M + Hf). 1 - [(1 S, 2 S) -1- (3-chloro-5-fluorophenyl) -2,3-dihydroxypropyl] -7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indole-2 -one (1.0 g, 2.6 mmol) is dissolved in pyridine (3 mL) and p-toluenesulfonyl chloride (0.55 g, 2.9 mmol) is added and the mixture is stirred for 4 hours. The reaction mixture is then diluted with diethyl ether and washed with water, 2 N aqueous hydrochloric acid, saturated copper sulfate, 2 N aqueous hydrochloric acid, and saturated saline. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product is immediately dissolved in methylamine solution (8.0 M in ethanol, 20 mL) and stirred for 16 hours. The mixture is concentrated under reduced pressure and purified by chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 1 - [(1 S, 2 /:) -1- (3-chloro-5- fluorofenyl) -2-hydroxy-3- (methylamino) propyl] -7-fluoro-3,3-dimethyl-1,3-dihydro-2 / - / - indol-2-one (0.098 g) as an oil colorless. The free base is dissolved in methanol (10 mL) and treated with hydrogen chloride solution (1.0 M in diethyl ether, 1.0 equivalent). The mixture is concentrated under vacuum then dissolved in 10 mL of water and lyophilized to give 87 mg of 1 - [(1 S, 2R) -1- (3-chloro-5-fluorophenyl) -2-hydroxy hydrochloride. 3- (Methylamino) propyl] -7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one. MS (ES) miz 395.0 ([M + Hf). Purity HPL 100.0% at 210-370 nm, 8.3 min.; Xterra RP18, column 3.5u, 150 x 4.6 mm, 1.2 mL / min, 85 / 15-5 / 95 (Amount Form of Ammon Ph = 3.5 / ACN + MeOH) for 10min, remains 4min.

Example 113: (1 S.2R) -1- (3-Chloro-5-fluorophenyl) -1- (2,3-dihydro-1 H -indol-1-yl) -3- (methylamino) propane hydrochloride 2-ol In a manner analogous to Example 25, Step 5, (1S, 2R) -1- (3-chloro-5-fluorophenyl) -1- (2,3-dihydro-1H-indol-1-yl) hydrochloride - 3- (methylamino) propan-2-ol is prepared from (2S, 3S) -3- (3-chloro-5-fluorophenyl) -3- (2,3-dihydro-1 H-indol-1-yl ) propane-1,2-diol (from Example 70, Step 4) as a white powder. HRMS: calcd for C18H20CIFN2O + H +, 335.1321; found (ESI, [M + Hf), 335.1318.

Example 114: (1S, 2R) -1- (3-Chloro-5-fluorophenyl) -1- (7-fluoro-3,3-dimethyl-2,3-dihydro-1 H-indol-1-yl hydrochloride -3- (methylamino) propan-2-ol In a manner analogous to Example 52, Step 2, 7-fluoro-3,3-dimethylindoline is prepared from 7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (from Example 69, Step 4) as a white powder. MS (ES) m / z 166.1 ([M + Hf); HRMS: calculated for C, 0H12FN + H +, 166.1032; found (ESI, [M + Hf), 166.1040.

In a manner analogous to Example 1, Step 3, (2S, 3S) -3- (3-chloro-5-fluorophenyl) -3- (7-fluoro-3,3-dimethyl-2,3-dihydro-1H -indol-1-yl) propane-1,2-diol is prepared from 7-fluoro-3,3-dimethylindoline and [(2R, 3R) -3- (3-chloro-5-fluorophenyl) oxirane-2 -yl] methanol (from Example 70, Step 3) as an amber gum. MS (ESI) m / z 368.1 ([M + Hf); HRMS: calculated for C, 9H20CIF2NO2 + H +, 368.1223; found (ESI, [M + Hf), 368.1234.

In a manner analogous to Example 25, Step 5, (1S, 2R) -1- (3-chloro-5-fluorophenyl) -1 - (7-fluoro-3,3-dimethyl-2,3-dihydroxy) hydrochloride. 1 H-indol-1-yl) -3- (methylamino) propan-2-ol is prepared from (2S, 3S) -3- (3-chloro-5-fluorophenyl) -3- (7-fluoro- 3,3-dimethyl-2,3-dihydro-1 H-indol-1-yl) propapo-1,2-diol as an ivory solid. MS (ES) m / z 381.1 ([M + Hf); HRMS: calculated for C20H23CIF2N2O + H +, 381.1540; found (ESI, [M + Hf), 381.1533.

Example 115: (1 S, 2R) -1- (3-Chloro-5-fluorophenyl) -1- (3,3-dimethyl-2,3-dihydro-1 H-indol-1-yl) -3 hydrochloride - (methylamino) propan-2-ol In a manner analogous to Example 1, Step 3, (2S, 3S) -3- (3-chloro-5-fluorophenyl) -3- (3,3-dimethyl-2,3-dihydro-1 / - / - indole -1-yl) propane-1,2-diol is prepared from 3,3-dimethylindoline and [(2f?, 3?) -3- (3-chloro-5-fluorophenyl) oxiran-2-yl] methanol (from Example 70, step 3) as a light brown gum. MS (ESI) m / z 350.0 ([M + H]); HRMS: calculated for C, 9H2, CIFN02 + H +, 350.1318; found (ESI, [M + Hf), 350.1293.

In a manner analogous to Example 25, Step 5, (1 S, 2 R) -1- (3-chloro-5-fluorophenyl) -1- (3,3-dimethyl-2,3-dihydro-1 H- hydrochloride indol-1-yl) -3- (methylamino) propan-2-ol is prepared from (2S, 3S) -3- (3-chloro-5-fluorophenyl) -3- (3,3-dimethyl-2 , 3-dihydro-1 / - / - indol-1-yl) propane-1,2-diol as a white powder. MS (ES) m / z 363.1 ([M + Hf); HRMS: calculated for C20H24CIFN2O + H +, 363.1634; found (ESI, [M + Hf), 363.1622.

Example 116: 7'-fluoro-1 '- [(1 S.2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methalamine) propyrospiro hydrochloride [cyclobutane-1,3'-indole] -2 '(1?) - ona In a manner analogous to Example 62, Step 4, 7'-fluorospiro [cyclobutane-1, 3'-indole] -2 '(1' / - /) - one is prepared from 7-fluoro-1, 3- dihydro-2 / - / - indol-2-one (from Example 62, Step 3), replacing 1,3-dibromopropane in place of methyl iodide. MS (ES) m / z 192 [(M + H) +].

In a manner analogous to Example 62, Step 5, 7'-fluoro-1 '- ((1 S, 2S) -1- (3-fluorophenyl) -2,3-dihydroxypropyl) spiro [cyclobutane-1, 3'- indolin] -2'-one is prepared from 7'-fluorospiro [cyclobutane-1,3'-indole] -2 '(1' H) -one, substituting [(2R, 3R) -3- (3- fluorophenyl) oxirane-2-yl] methanol (from Example 24, Step 1) in place of [(2R, 3R) -3- (3,5-difluorophenyl) oxirane-2-yl] methanol. MS (ES) m / z 360 [(M + H) *].

In a manner analogous to Example 62, step 6, 7'-fluoro-1'-r (S, 2R) -1 - (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl-spiro [cyclobutane hydrochloride] -1, 3'-indol1-2 '(1?) - one is prepared from 7'-fluoro-1' - ((1 S, 2S) -1- (3-fluorophenyl) -2,3-dihydroxypropyl ) spiro [cyclobutane-1,3'-indolin] -2'-one. MS (ES) m / z 373 [(M + H) +].

Example 117: 7'-fluoro-1 '- [(1 S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propylespirofcyclopentane-1,3'-indop-2 hydrochloride '(1?) - ona In a manner analogous to Example 62, Step 4, 7'-fluorospiro [cyclopentane-1,3'-indo] -2 '(1' / - /) - one is prepared from 7-fluoro-1,3. -dihydro-2H-indol-2-one (from Example 62, Step 3), replacing 1,4-dibromobutane in place of methyl iodide. MS (ES) m / z 206 [(M + H) +].

In a manner analogous to Example 62, Step 5, 7'-fluoro-1 '- ((1 S, 2S) -1- (3-fluorophenyl) -2,3-dihydroxypropyl) spiro [cyclopentane-1,3'- indolin] -2'-one is prepared from 7'-fluorospiro [cyclopentane-1,3'-indole] -2 '(1' H) -one, substituting [(2R, 3R) -3- (3- fluorophenyl) oxirane-2-yl] methanol (from Example 24, Step 1) in place of [(2f?, 3f?) -3- (3,5-difluorophenyl) oxirane-2-yl] methanol. MS (ES) m / z 374 [(M + H) +].

In a manner analogous to Example 62, Step 6, 7'-fluoro-1 '- f (1 S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) prop hydrochloride The cyclopentane-1,3'-indoll-2 '(1?) -one is prepared from 7'-fluoro-1' - ((1 S, 2S) -1- (3-fluorophenyl) -2,3-dihydroxypropyl) spiro [cyclopentane-1,3'-indolin] -2'-one. MS (ES) m / z 387 [(M + H) +].

Example 118: 6-fluoro-1-r (1 S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyne-3,3-dimethyl-1,3-dl hydrochloride hydro-2H-indol-2-one To a suspension of sodium hydride washed with hexanes (2x) (60% in oil, 14 g, 350 mmol) in dimethyl sulfoxide (300 mL) is added dimethyl malonate (46 g, 350 mmol) as a drop at 23 ° O The reaction mixture is heated at 100 ° C for 45 minutes, then cooled to 23 ° C and 2,5-difluoronitrobenzene (25 g, 160 mmol) is added. The mixture is stirred at 23 ° C for 30 minutes, then heated at 100 ° C for 1 hour. The cold mixture is poured into a mixture of saturated aqueous ammonium chloride (1.2 L), ethyl acetate (250 mL) and hexanes (250 mL). The organic phase is separated and washed with saturated aqueous ammonium chloride (500 mL), water (3 x 500 mL) and saturated saline (500 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gives an oily yellow solid (47 g) which is recrystallized from boiling 20% ethyl acetate-hexanes (ca. 300 mL) to provide dimethyl (4-fluoro-2-nitrophenyl) malonate (35 g). g, 81%) as bright white prisms. MS (ES) m / z 270 [(M-H) "].

Dimethyl (4-fluoro-2-nitrophenyl) malonate (5.0 g, 18 mmol), lithium chloride (1.6 g, 38 mmol) and water (0.33 g, 18 mmol) are combined in dimethyl sulfoxide (100 mL) and is heated to 100 ° O After 21 hours, the cold solution is poured into a stirred mixture of saturated saline (200 mL) and ethyl acetate (200 mL). The phases are separated and the aqueous phase is extracted with ethyl acetate (200 mL). The combined organic extracts are washed with saturated saline solution (2 x 200 mL), dried over sulfate of anhydrous sodium, are filtered and concentrated under reduced pressure to give a dark oil (4.0 g) which is dissolved in dichloromethane and pre-adsorbed on silica gel (10 g) Flash column chromatography (silica 190 g, %, 10%, 20% ethyl acetate / hexanes) provides methyl (4-fluoro-2-n-trophenol) acetat (2 1 g, 54%) as a yellow oil MS (ES) m / z 212 [(MH)] (4-fluoro-2-n? Trofen? L) methyl acetate (7 1 g, 33 mmol) and iron powder (7 4 g, 130 mmol) are combined in glacial acetic acid (65 mL) and heated to 100 ° C After 2 hours, the cold mixture is concentrated under reduced pressure. The residue is dissolved in hot ethyl acetate (100 mL), filtered through Celite and washed with ethyl acetate (100 mL). Wash with 1 N aqueous hydrochloric acid (3 x 100 mL) and saturated saline solution (100 mL), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to give a solid brown Tpturation with 5% ethyl acetate. ethyl-hexanes (100 mL) afforded 6-fluoro-1,3-d? h? d-2H-? ndol-2-one (4.8 g, 96%) as a tan solid MS (ES) m / z 150 [(MH)] In a manner analogous to Example 62, Step 4, 6-fluoro-3,3-d? Met? L-1,3-d? H? Dro-2H-? Ndol-2-one is prepared from 6- fluoro-1, 3-d? h? dro-2H-? ndol-2-one MS (ES) m / z 180 [(M + H) +]

[0001] In a manner analogous to Example 62, Step 5, 6-fluoro-1 - ((1 S, 2S) -1- (3-fluorophen? L) -2,3-d? H? Drox? Prop? l) -3,3-d? met? l? ndol? n-2-one is prepared from 6-fluoro-3,3-d? met? l-1, 3-d? h? dro-2H -? ndol-2-one, substituting [(2R, 3R) -3- (3-fluorophen? l) ox? ran-2? l] methanol (from Example 24, step 1) instead of [(2R, 3R) -3- (3,5-d? Fluorophen? L) ox? Ran-2? L] methanol MS (ES) m / z 348 [(M + H) +] A solution of 6-fluoro-1 - ((1 S, 2S) -1- (3-fluorophen? L) -2,3-d? H? Drox? Prop? L) -3,3-d? Met? L-ndol? n-2-one (0 32 g, 092 mmol) in tetrahydrofuran (4 5 mL) is treated with tpphenylphosphine (0 30 g, 11 mmol) at 23 ° C When a solution had been formed, / - Chlorosuccin? m (0 15 g, 11 mmol) is added After a further 1 hour, the reaction solution is concentrated under vacuum to a small volume and pre-adsorbed on silica gel (1 g) chromatography ISCO CombiFlash Companion (12 g RediSep silica, 30 mL / mm, 0-30% ethyl acetate / hexane) provides 1 - ((1 S, 2S) -3-chloro-1- (3-fluorophen? L) - 2-hydroxypropyl) -6-fluoro-3,3-d? Met? L? Ndol? N-2-one (0 12 g, 35%) as a clear, almost colorless oyl MS (GB m / z 366 [(M + H? In a manner analogous to Example 1, Step 6, 6-fluoro-1 - [(1S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -3,3- hydrochloride dimethyl-1,3-dihydro-2H-indol-2-one is prepared from 1 - ((1 S, 2S) -3-chloro-1- (3-fluorophenyl) -2-hydroxypropyl) -6 -fluoro-3,3-dimethylindolin-2-one. MS (ES) m / z 361 [(M + H) +].

Example 1 19: (1 S, 2 R) -1- (7-Fluoro-2,3-dihydro-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride In a manner analogous to Example 1, Step 2, 7-fluoroindoline is prepared from 7-fluoroindole as a clear liquid. MS (ESI) m / z 138 ([M + Hf).

In a manner analogous to example 1, step 3, (2s, 3s) -3- (7-fluoroindolin-1-yl) -3-phenylpropane-1,2-diol is prepared from 7-fluoroindoline as a white solid . MS (ESI) M / Z 288.1 ([M + Hf).

A mixture of (2S, 3S) -3- (7-fluoroindolin-1-yl) -3-phenylpropane-1,2-diol (1.09 g, 3.8 mmol) and triphenylphosphine (1.49 g, 5.7 mmol) is dissolved in tetrahydrofuran. (30 mL). To this is added N-chlorosuccinimide (0.76 g, 5.7 mmol) and the reaction mixture is further stirred at room temperature for 30 minutes. The mixture is then concentrated under reduced pressure and the residue is purified by Biotage Horizon (FlasH 40 M, silica, gradient of 0% ethyl acetate / hexane to 40% ethyl acetate / hexane) to give (1 S) , 2S) -3-chloro-1- (7-fluoroindolin-1-yl) -1-phenylpropan-2-ol as a clear oil. MS (ESI) miz 306 ([M + Hf). (1S, 2S) -3-chloro-1- (7-fluoroindolin-1-yl) -1-phenylpropan-2-ol (0.49 g, 1.6 mmol) is treated with a solution of methylamine in ethanol (2.0 M, 8 ml, 16 mmol) and the solution was Stir in a sealed bag at room temperature for 15 hours. After dilution with a saturated aqueous solution of sodium bicarbonate, the mixture is extracted with a dichloromethane / isopropanol solution (3/1). The extract is washed with water and saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is crystallized from dichloromethane by adding a minimum amount of ethyl acetate and diethyl ether to yield the title compound hydrochloride of (1 S, 2R) -1- (7-Fluoro-2,3-dihydro-1 H- indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol as a white solid. MS (ES) m / z 300.9 ([M + Hf); HPLC purity 92.9% at 210-370 nm, 7.3 min; Xterra RP18, column 3.5u, 150 x 4.6 mm, 1.2 mL / min, 85 / 15-5 / 95 (Amount Form of Ammon Ph = 3.5 / ACN + MeOH) for 10min, remains 4min. HRMS: calculated for C18H2? FN20 + H +, 301.17107; found (ESI, [M + Hf), 301.1695.

Example 120: 4-Fluoro-3 - [(1 S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl-1-phenyl-1,3-dihydrochloride 2H-benzimidazol-2-one Step 1: To a solution of 2,6-difluoronitrobenzene (2.0 g, 6.28 mmol) and aniline (d 1022, 1.15 mL, 12.6 mmol) in dry? /, / V-dimethylformamide (10 mL) is added tert-butoxide potassium (1.40 g, 12.5 mmol) in portions. After 16 hours at room temperature, the reaction mixture is poured into saturated aqueous ammonium chloride solution and extracted with dichloromethane (2 x 50 mL). The combined organic layers are washed with water (1 x 50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to produce crude 3-fluoro-2-nitro-N-phenylaniline (1.15 g, 78%). %), which is used in the next stage without further purification.

Step 2: A mixture of 3-fluoro-2-nitro-N-phenylaniline (1.15 g, 4.9 mmol) and palladium in charcoal (10%, ca. 200 mg) in methanol (30 mL) is hydrogenated (50 psi H2 ) in a Parr shaker. After 2 hours, the catalyst is removed by filtration through a pad of celite, and the celite is washed with fresh methanol (20 mL). The combined methanol layers are concentrated under reduced pressure and the residue is purified by column chromatography (silica, 1: 0 to 9: 1 hexanes: ethyl acetate) to produce 3-fluoro-N1-phenylbenzene-1,2-diamine. (0.47 g, 47%). MS (ES) m / z 203.2 ([M + Hf).

Step 3: To a stirred solution of 3-fluoro-N1-phenylbenzene-1,2-diamine (0.247 g, 1.22 mmol) in dry tetrahydrofuran (10 mL) is added carbonyl diimidazole (0.21 g, 1.30 mmol) under nitrogen. After 30 minutes, 4-dimethylaminopyridine (catalytic amount) is added and the reaction is stirred overnight. After 16 hours an additional portion of carbonyl diimidazole is added (0.21 g, 1.3 mmol) and stirring is continued. After 48 hours, the reaction mixture is diluted with ethyl acetate (ca. 50 mL) and extracted with sodium hydroxide solution (2N, 2 x 25 mL). The combined basic extracts are washed with ethyl acetate and then acidified (hydrochloric acid, pH 1). The product is collected by filtration and then washed with water, hexanes and air dried to yield 4-fluoro-1-phenyl-1H-benzo [d] imidazole-2 (3H) -one (0.117 g, 42% ) as a white solid. MS (ES) m / z 228.9 ([M + Hf).

Step 4: Sodium hydride (60% in oil, 33 mg, 0.89 mmol) is added to 4-fluoro-1-phenyl-1 H -benzo [d] imidazole-2 (3H) -one (0.102 g, 0.447 mmol ) in dry N, N-dimethylformamide (3 mL) under nitrogen, and the mixture is stirred for 20 minutes. In a separate flask, [(2f?, 3f?) -3- (3-fluorophenyl) oxirane-2-yl] methanol (from Example 24, Step 1, 0.15 g, 0.89 mmol) in dry dimethylformamide (3 mL) was treated with titanium tetra isopropoxide (0.26 mL, 0.89 mmol). After 20 minutes this mixture is added to that prepared first. After 16 hours the reaction mixture is quenched by the addition of 2N aqueous hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is then purified by column chromatography (silica, 1: 0 to 0: 1 hexanes: ethyl acetate) to yield 4-fluoro-3 - ((1 S, 2S) -1- (3-fluorophenyl) -2 , 3-dihydroxypropyl) -1-phenyl-1 H -benzo [d] imidazole-2 (3H) -one (0.146 g, 82%), which is used without further evaluation.

Step 5: To a solution of 4-fluoro-3 - ((1 S, 2S) -1- (3-fluorophenyl) -2,3-dihydroxypropyl) -1-phenyl-1 H -benzo [d] imidazole-2 (3 H) -one (0.146 g, 0.37 mmol) in dry pyridine (3 mL) was add p-toluenesulfonyl chloride (0 076 g, 0 39 mmol) After 3 hours, add an additional portion of p-toluenesulfonyl chloride (050 g, 0 27 mmol) and the reaction is stirred overnight. 16 hours the mixture is diluted with ethyl acetate and washed with saturated aqueous copper II sulfate solution (x2) and water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is then dissolved in methylamine solution (8M ethanol, 10 mL) and stirred overnight After 16 hours, the mixture is evaporated under reduced pressure and the residue is dissolved in ethyl acetate, washed with 2 N sodium hydroxide solution aqueous (10 mL), and water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, 100 to 95 dichloromethane methanol saturated with ammonia) to produce 4-fluoro-3 - [(1 S, 2R) -1- (3-fluorophen? L) -2-h? Dro x? -3- (met? lam? no) prop? l] -1-phen? l-1,3-d? h? dro-2 / - / - benz? m? dazol-2-one (0 027 g, 16%) The solid is then dissolved in ethanol and treated with 2N hydrochloric acid solution (0 1 mL), concentrated under reduced pressure and triturated with diethyl ether to produce 4-fluoro-3- [hydrochloride]. (1S, 2R) -1- (3-fluorophen? L) -2-h? Drox? -3- (met? Lam? No) prop? L] -1-phen? -1,3-d? H-dro-2 H -benz? dazol-2-one (6 mg) as a white solid HRMS calculated for C23H2? F2N302 + H +, 410 16746, found (ESI, [M + Hf), 410 1662 Example 121 4-fluoro-1- (3-fluorophenyl) -3 - [(1S, 2R) -1- (3-fluorophenyl) -2-h? Drox? 3- (methalam) hydrochloride ? no) prop? p-1, 3-d? h? dro-2H-benz? dazol-2-one 2,6-d? Fluoron? Trobenzene (5 g, 31 4 mmol), potassium fer-butoxide (3 5 g, 31 3 mmol), and 3-fluoroanaline (3 47 g, 31 3 mmol) in anhydrous dimethyl sulfoxide (20 mL) is stirred at room temperature. After completion, the reaction is partitioned between saturated ammonium chloride solution (50 mL) and ethyl acetate (50 mL). The organic phase is separated, dried over sodium sulfate, Anhydrous magnesium is filtered and concentrated under reduced pressure. The product is purified on silica gel to give (3-fluoro-2-n? tro-phen?) - (3-fluoro- phenyl) -amine that is carried directly in the next stage.

A solution of (3-Fluoro-2-nitro-phenyl) - (3-fluoro-phenyl) -amine (3.27 g, 13 mmol) in methanol (50 mL) is hydrogenated over 10% palladium on carbon (ca. mg) at 50 psi. After completing the reduction, the reaction is filtered through a pad of celite and concentrated on silica gel. The product is purified on silica gel to give 3-fluoro-N 1 - (3-fluorophenyl) benzene-1,2-diamine (1.26 g, 44%). MS (ES) m / z 221 ([M + Hf); HRMS: calculated for C? 2H10F2N2 + H +, 221.08848; found (ESI, [M + Hf), 221.0858. 3-Fluoro-N1- (3-fluorophenyl) benzene-1,2-diamine (1.15 g, 5.22 mmol) and carbonyl diimidazole (1.46 g, 9 mmol) in dioxane (20 mL) is stirred at room temperature for 16 hours. After completion, the reaction is partitioned between 1N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The organics are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-fluoro-1- (3-fluorophenyl) -1,3-dihydro-2H-benzimidazol-2-one (0.75 g, 59 %). MS (ES) m / z 247.0 ([M + Hf).

In a manner analogous to Example 120, Step 4, 4-fluoro-1- (3-fluorophenyl) -3 - [(1 S, 2S) -1- (3-fluorophenyl) -2,3-dihydroxypropyl] -1, 3-dihydro-2H-benzimidazol-2-one is prepared from 4-fluoro-1- (3-fluorophenyl) -1,3-dihydro-2H-benzimidazol-2-one and [(2R, 3R) -3 - (3-fluorophenyl) oxiran-2-yl] methanol. MS (ES) m / z 415.0 ([M + Hf); HRMS: calculated for C22H,? F3N203 + H +, 415.12640; found (ESI, [M + Hf), 415.1263.

In a manner analogous to Example 25, Step 5, 4-fluoro-1- (3-fluorophenyl) -3 - [(1 S, 2R) -1- (3-fluorophenyl) -2-hydroxy-3- ( methylamino) propyl] -1,3-dihydro-2H-benzimidazol-2-one is prepared from 4-fluoro-1- (3-fluorophenyl) -3 - [(1 S, 2S) -1- ( 3-fluorophenyl) -2,3-dihydroxypropyl] -1,3-dihydro-2H-benzimidazol-2-one. HRMS: calculated for C23H2oF3N3? 2 + H +, 428.15804; found (ESI, [M + H] +), 428.1581.

Example 122: 1-f (1 S, 2ffl-3-amino-1 - (3,5-difluorophenyl) -2-hydroxypropyl-7-fluoro-3,3-dimethyl-1,3-dihydro-2H- indol-2-one To a solution of 7-fluoro-1 - [(1S, 2S) -1- (3,5-difluorophenyl) -2,3-dihydroxypropyl] -3,3-dimethyl-1,3-dihydro-2H-indole 2-one (2.21g, 6.05 mmol, from Example 62, Step 5) in tetrahydrofuran (30 mL) is added triphenylphosphine (1.98g, 7.56 mmol). The mixture is stirred at room temperature until all the triphenylphosphine is dissolved. To this solution is then added N-chlorosuccinimide (1.01g, 7.56 mmol) and the resulting mixture is allowed to stir at room temperature for 50 minutes. The mixture is concentrated under reduced pressure and the residue is purified using a silica gel column (eluted with a gradient from 0% to 40% ethyl acetate in hexane) to yield the chloride intermediate (1.85g, 80%). .

To a solution of chloride over (0.35 g, 0.9 mmol) in dry? /,? / - dimethylformamide (5 mL) is added sodium iodide (0.15 g, 1 mmol) and sodium azide (0.16 g, 2.3 mmol). The mixture is heated at 70 ° C for 18 hours, then poured into a saturated solution of ammonium chloride (80 mL). The aqueous mixture is extracted with ethyl acetate (3x20 mL), the combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is then taken up in methanol (20 mL) and 5% palladium on carbon is added. The mixture is subjected to hydrogenation (40 psi H2) for 2 hours and then filtered through a pad of celite to remove palladium on carbon. The filtrate is concentrated and purified on a column of silica gel (9% methanol in methylene chloride) to give 1 - [(1 - (3,5-difluorophenyl) -2-hydroxypropyl] -7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as an oil. The free base is dissolved in ether (10 mL) and treated with hydrogen chloride solution (1.0 M in diethyl ether, 1.0 equivalent). The precipitate White is collected and dried under vacuum then dissolved in 10 mL of water and lyophilized in 1 - [(1 S, 2R) -3-amino-1- (3,5-difluorophenyl) -2-hydroxy] hydrochloride. propyl] -7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one. MS (ES) m / z 364.9 ([M + Hf).

CELLULAR LINES. CULTURE REAGENTS. AND TESTS MDCK-Net6 cells, stably transfected with human hNET (Pacholczyk, T., RD Blakely, and SG Amara, Nature, 1991, 350 (6316): p.350-4) are cultured in a growth medium containing DMEM of high glucose (Gibco, Cat. No. 11995), 10% FBS (dialysed, heat inactivated, US Bio-Technologies, Lot FBD1129HI) and 500 Dg / ml G418 (Gibco, Cat. No. 10131). The cells are plated in a 300,000 T75 bottle and then the cells are divided twice a week. The JAR (human placental choriocarcinoma) cell line is purchased from ATCC (Cat. No. HTB-144). Cells are grown 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. The cells are plated in flasks at 250,000 cells / T75 and divided twice a week. For all assays, the cells are plated in sterile 96-well Wallac plates (PerkinElmer, Cat. No. 3983498) Norepinephrine Assay (NE) On day 1, the cells are plated at 3,000 cells / well in the growth medium and maintained in a cell incubator (37 ° C, 5% CO2). On day 2, the growth medium is replaced with 200 μl of 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 pargyline. Plates containing cells with 200 μl of assay buffer are equilibrated for 10 minutes at 37 ° C before the addition of the compounds. A stock solution of desipramine is prepared in DMSO (10 mM) and supplied to the wells in triplicate containing cells for a final concentration assay of 1 μM. The data from these wells are used to define the return of non-specific NE (minimum return of NE). The test compounds are prepared in DMSO (10 mM) and diluted in test buffer according to the test range (1 to 10,000 nM). Twenty-five microliters of assay buffer (maximum NE reuptake) or test compound are added directly to triplicate wells containing the cells in 200 μl of assay buffer. Cells in the assay buffer with the test compounds are incubated for 20 minutes at 37 ° C. To initiate NE reuptake, [3 H] NE is diluted in assay buffer (120 nM final assay concentration) is supplied in aliquots of 25 μl to each well and plates are incubated for 5 minutes (37 ° C). The reaction is terminated by decanting the supernatant from the plate. The plates containing the cells are washed twice with 200 μl of assay buffer (37 ° C) to remove the free radioligand. The plates are then inverted, allowed to dry for 2 minutes, then re-inverted and air-dried for an additional 10 minutes. The cells are lysed in 25 μl of 0.25 NaOH solution (4 ° C), placed on a shaking table and shaken vigorously for 5 minutes. After lysis of the cells, 75 μl of the scintillation cocktail are added to each well and the plates are sealed with film tape. The plates are returned to the stirring board and stirred vigorously for a minimum of 10 minutes to ensure an adequate partition of the organic and aqueous solutions. Plates are counted in a Wallac Microbeta counter (PerkinElmer) to collect the raw cpm data.

TEST OF SEROTONINE TAKE (5-HT) The methods for functional 5-HT reuptake using the JAR cell are modified using a previous literature report (Prasad, et al, Placenta, 1996. 17 (4): 201-7). On day 1, the cells are plated at 15,000 cells / well in 96-well plates containing the growth medium (RPMI 1640 with 10% FBS) and kept in a cell incubator (37 ° C, 5% CO2 ). On day 2, the cells are stimulated with staurosporine (40 nM) to increase the expression of the 5-HT transporter [17]. On day 3, the cells are removed from the cell incubator for two hours before the assay and kept at room temperature to balance the growth medium to the ambient oxygen concentration. Posteporously, the growth medium is replaced with 200 μl of assay buffer (25 mM HEPES, 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl2, 1.2 mM MgSO, 2 mg / ml glucose (pH 7.4 , 37 ° C)) containing 0.2 mg / ml ascorbic acid and 10 μM pargylline. A mother solution of Paroxetine (AHR-4389-1) is prepared in DMSO (10 mM) and is supplied to triplicate wells containing the cells for a final assay of concentration of 1 μM. The data from these wells are used to define a non-specific 5-HT reuptake (minimum 5-HT intake). The test compounds are prepared in DMSO (10 mM) and diluted in assay buffer according to the assay range (1 to 1 000 nM). 25 microliters of assay buffer (maximum 5-HT reuptake) or test compound are added directly to the triplicate wells containing the cells in 200 μl of assay buffer. The cells are incubated with the compound for 10 minutes (37 ° C). To initiate the reaction, [3H] sulfate hydroxytryptamine creatinine is diluted in assay buffer in 25 μl aliquots to each well for a final concentration test of 15 nM. The cells are incubated with the reaction mixture for 5 minutes at 37 ° C. The reaction of taking 5-HT is terminated by decanting the assay buffer. The cells are washed twice with 200 μl of assay buffer (37 ° C) to remove the free radioligand. The plates are reinvested and left to dry for 2 minutes, then reinvested and air-dried for an additional 10 minutes. Posteporously, the cells are lysed in 25 μl of 0.25 N NaOH (4 ° C) then placed on a shaker and shaken vigorously for 5 minutes. After cell lysis, 75 μl of scintillation cocktail is added to the wells, the plates are sealed with film tape and repositioned on the shaker table for a minimum of 10 minutes. The plates are counted in a Wallac Microbeta counter (PerkinElmer) to collect raw cpm data.

EVALUATION OF RESULTS For each experiment, a data stream of cpm values collected from the Wallac Microbeta counter is downloaded to a Microsoft Excel statistical application program. Calculations of the EC 0 values are made using the logistic dose response program of both transformed sides described by Wyeth Biometrics Department. The statistical program uses mean cpm values of the wells representing the maximum bound or intake (assay buffer) and the mean cpm values of the wells represent the minimum bound or retake ((1 μM desipramine (hNET) or 1 μM of paroxetine (hSERT)) The estimation of the EC50 value is completed on a logarithmic scale and the line is adjusted between the maximum and minimum bound values.

All the representation of graphic data is generated by normalizing each data point to an average percentage based on the values of link or maximum and minimum take. The EC50 values reported from multiple experiments are calculated by grouping the raw data from each experiment and analyzing the data grouped as an experiment.

FLIPR 5-HT ESSAY? A Cellular Conditions: CHO cells are transfected with cDNA expressing the human 5-HT2A receptor cultured in Dulbecco modified Eagle medium (Gibco # 11995-065) supplemented with 10% fetal bovine serum, non-essential amino acids and selection markers. The cells are washed with PBS without Ca2 + and 3 mL of Trypsin is added to dissociated cells. After 3 minutes of incubation, 7 mL of Trypsin Neutralizing Solution is added. The cells are aspirated then aspirated from the bottle and mixed in a 50 mL conical tube. 10 μL of sample is used to count the cells in a hemacytometer. Cells are then plated at 40,000 cells per well in 96-well sterile black well plates with clear backgrounds (VWR # 29443-152) for 24 hours.

Preparation of the Drug Plate: Two 96-well drug plates are prepared for each cell plate. Plate 1 will contain compounds to be tested and plate 2 will contain the DOI agonist (3 nM) to activate a calcium response. Specific details of the preparation of the compounds are listed below. All compounds are made in 1X HBSS (Gibco # 14175-095) supplemented with 20 mM HEPES (Gibco # 15630-080). Outside wells are not used due to an edge effect seen in these cells.

The reference agonist compounds DOI and 5-HT are used as agonists 5HT standard. MDL and Mianserin are used as selective dHT ^ receptor antagonists.

Preparation of Plate 1: Test Compound Plate For the Selection Test Compounds in 1 μM, 1 mM of the stock solution is diluted in 19 μM (FLIPR will be the final solution) and 50 μL per well is added to 4 wells in the assay plate. The standards for a plate are Vehicle, 1 μM DOI, and 3 nM MDL For the determination of the IC50 value, concentrations are generated by serial dilution of a 1 mM stock solution. On the day of the test, the test compound solutions of appropriate concentrations are diluted in a test buffer as described for the single concentration test. This procedure is followed to ensure that the concentration of the solvent is consistent through the dilutions. The typical concentration test range of the compounds is 10"10 - 10'5 M in increments of half log or complete log.

Preparation of Plate 2: Plate (DOI) Agonist. 10 μM of DOI stock solution is diluted to 60 nM and added to the respective wells. The FLIPR pipetting station will be made in additional dilutions 20 times for a final concentration of 3 nM. The standards for this plate include Vehicle and 3 nM DOI.

Preparation of Calcium Dye: The contents of the dye vial (Molecular Devices # R8090) are dissolved in 100 mL of 1X HBSS supplemented with 20 mM of HEPES. Aliquots can be frozen at -20 ° C for one week for future use. On the day of the test, the dye is thawed and diluted to medium concentration. Probenecid (Sigma # P-8761), a calcium anion exchange inhibitor, is made fresh from powder on the day of the experiment and added to the Calcium Buffer at 2.5 mM of the final concentration before addition to the cells.

FLIPR Machine Loading: The cells are allowed to adhere for 24 hours in 96-well plates. At this test time, the cultured medium is removed from the cells and replaced with 180 μL by weight of Calcium Assay Buffer 3 and incubated for 1 hour at 37 ° C with 5% C02.

The cell, the compound and the DOI plates are loaded in the FLIPR machine. The fluorescence level of the free base is read once every second the fluorescent level of the baseline every second for 1 minute. The compound (10 μL) is transfected from the compound plate for the cells and the fluorescence level recorded 2 minutes to determine any agonist activity. The fluorescence of the baseline is recorded again every second for 10 seconds. For antagonist determination, 10 μL of 3 nM DOI is transferred from the DOI plate to the cells and the fluorescence level is recorded every 6 seconds for 5 minutes. The pipetting unit of the FLIPR machine completes all transfers.

Analysis of Results: Single Concentration The stimulation of the agonist is expressed as a percentage of the response observed with 1 uM of DOI.

The antagonist inhibition of 3 nM of DOI stimulation is expressed as a percentage of the response observed with 3 nM of DOI alone.

Concentration curve A logistic function of parameter 4 is used to generate EC50 values. The data is transformed log before the analysis.

The results of the standard experimental test procedures described in the preceding paragraphs are shown in Table 1: Table 1 fifteen fifteen fifteen fifteen fifteen fifteen fifteen fifteen fifteen fifteen * Percentage of inhibition at 1 DM ND = Not determined When ranges are used for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and sub-combinations of ranges of specific modalities here are intended to be included.

The descriptions of each Patent, Patent Application, and Publication cited or described in this document are incorporated herein by reference, in their entirety.

Those skilled in the art will appreciate 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. Therefore, it is intended that the appended claims cover all those equivalent variations so that they fall within the true spirit and scope of the invention.

Claims (88)

1. A compound of the formula I: or a pharmaceutically acceptable salt thereof; where: the dotted line between Y and Z represents an optional second link; the dotted line between the two R groups represents an optional heterocycle ring of 4 to 6 ring atoms that can be formed between the two R groups, together with the nitrogen through which they are adhered; X is - (C (R12) 2) o-, -O (C (R, 2) 2) 0-, - (C (R, 2) 2) 0O-, -S (0) p (C (R , 2) 2) 0-, - (C (R12) 2) oS (O) p-, -N (R, 3) C (O) (C (R12) 2) 0-, - (C (R12) 2) 0C (O) N (R, 3) -, C (O) N (R, 3) (C (R, 2) 2) or-, - (C (R12) 2) 0N (R, 3) C (O) -, - (C (R, 2) 2) 0N (R13) S (O) 2-, -S (O) 2N (R13) (C (R12) 2) o-, -N (R13) S (O) 2 (C (R12) 2) 0 -, - (C (R12) 2) 0S (O) 2N (R13) -, -NR? (C (R12) 2) 0-, - (C (R, 2) 2) 0NR? -, or -C = d; Y is N, C (R6) 2, CR6, or C = 0; Z is O, S (0) p, N, NR ?, CR5, or C (R5) 2; R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, year, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two R, adjacent also represent methylenedioxy; R2 is aryl substituted with 0-3 R, or heteroaryl substituted with 0-3 R,; R 3 is H or C 1 -C 4 alkyl; R4 is, independently of each occurrence, H, C, -C, C3-C6 cycloalkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both R groups, together with the nitrogen through which they are adhered, form a heterocyclic ring of 4 to 6 ring atoms, wherein one carbon can be optionally replaced with N, O, S, or S02, and where any atom in the ring or additional N atom can optionally be substituted with d-C4 alkyl, F, or CF3; R5 is, independently of each occurrence, H, C, -C4 alkyl, aryl substituted with 0-3 R? 4, heteroaryl substituted with 0-3 R,, or cyano; or when two R5 are present, they can form a carbocyclic ring of 3-5 carbons; R6 is, independently of each occurrence, H, C, -C4 alkyl, or cyano; R? is H, C? -C6 alkyl, C3-C6 cycloalkyl, aryl substituted with 0-3 R, 4; or heteroaryl substituted with 0-3 R, 4; R8 is H, or C, -C alkyl; R9 is H, or C, -C4 alkyl; R-io is, independently of each occurrence, H, or C, -C alkyl; or R, 0 and R4 together with the nitrogen to which R is adhered form a nitrogen-containing ring containing 3-6 carbon atoms; Rn is aryl substituted with 0-3 R, or heteroaryl substituted with 0-3 Rx, R, 2 is, independently of each occurrence, H, C 4 C 4 alkyl; R, 3 is H or C, -C4 alkyl; R, 4 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, arylalkyloxy substituted with 0-3 R, aryloxy substituted with 0-3 Ri, aryl substituted with 0-3 Ri, heteroaryl substituted with 0- 3 R, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R, alkylsulfone, phenylsulfone substituted with 0-3 R1: alkylsulfonamide, phenylsulfonamide substituted with 0-3 R, heteroaryloxy substituted with 0-3 R, heteroarylmethyloxy substituted with 0-3 R ^ alkylamido, or arylamido substituted with 0-3 R? Or two R, adjacent also represent methylenedioxy; m is an integer from 0 to 3; n is an integer from 1 to 2; or is an integer from 0 to 3; and p is an integer from 0 to 2; wherein 1-3 carbon atoms in ring A can optionally be replaced with N.
2. 2. A compound according to claim 1, wherein: the dotted line between Y and Z represents a second link.
3. 3. A compound according to claim 1, wherein: X is - (C (R, 2) 2) 0, -O (C (R, 2) 2) 0-, -C = C-.
4. 4. A compound according to any one of claims 1 to 3, wherein: Y is C (R6) 2, CR6, or C = 0.
5. 5. A compound according to any one of claims 1 to 4, wherein: Z is CR 5 or C (R 5) 2.
6. 6. A compound according to any one of claims 1 to 5, in where: R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, or cyano.
7. 7. A compound according to any one of claims 1 to 6, wherein: R 2 is aryl substituted with 0-2 R,.
8. 8. A compound according to any one of claims 1 to 6, wherein: R 2 is phenyl, fluorophenyl, or difluorophenyl.
9. 9. A compound according to any one of claims 1 to 8, wherein: R3 is H.
10. 10. A compound according to any one of claims 1 to 9, wherein: R 4 is H or methyl.
11. 11. A compound according to any one of claims 1 to 10, wherein: R5 is, independently of each occurrence, H, C, -C4 alkyl, aryl substituted with 0-3 R -
12. 12. A compound according to any one of claims 1 to 10, wherein: R5 is, independently of each occurrence, H, methyl, ethyl, n-propyl, isopropyl, aryl substituted with alkoxy, aryl substituted by aryloxy or phenyl substituted by 1-2 halo.
13. 13. A compound according to any one of claims 1 to 12, wherein: R6 is, independently of each occurrence, H, methyl, ethyl, n-propyl, or isopropyl
14. A compound according to any one of claims 1 to 13, wherein R? is H, C, -C6 alkyl, or aplo substituted with 0-3 R,
15. A compound according to any one of claims 1 to 14, wherein R8 is H
16. A compound according to any one of claims 1 to 15, wherein R9 is H
17. A compound according to any one of claims 1 to 16, wherein R, or is H
18. A compound according to any one of claims 1 to 17, wherein R ,, is aplo substituted with 0-3 R,
19. A compound according to any one of claims 1 to 17, wherein R ,, is phenyl, or aplo substituted with 1-2 halo or alkoxy
20. A compound according to any one of claims 1 to 17, wherein R ,, is aplo substituted with 0-2 R,
21. A compound according to any one of claims 1 to 20, wherein n is 1
22. A compound of formula II or a pharmaceutically acceptable salt thereof, wherein D and E, together with the carbon atom through which they are attached, form a carbocyclic ring of 6 to 8 atoms or a heterocyclic ring of 5 to 8 atoms containing 1 to 2 heteroatoms selected from O, S (0) p, and NR ?, where any atom in the ring can optionally be substituted with C, -C4, F, or CF3 alkyl, the dotted line between the two R groups represents an optional heterocycle ring of 4 to 6 ring atoms that can be formed between the two R4 groups, together with the nitrogen through which they are adhered, G is NR ?, C (R6) 2, or C = 0, R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido, or two R, adjacent also represent methylenedioxy, R2 is either substituted with 0-3 R? 4 or hetero-substituted with 0-3 R, 4, R3 is H or C, -C4 alkyl, R4 is, independently of each occurrence, H, CrC alkyl, C3-C6 cycloalkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both R4 groups, together with the nitrogen through which they are adhered, form a heterocyclic ring of 4 to 6 ring atoms, wherein one carbon can be optionally replaced with N, O, S, or SO2, and where any atom in the ring or additional N atom can optionally be substituted with C, -C4, F, or CF3 alkyl; R6 is, independently of each occurrence, H, alkyl d-C, or cyano; R? is H, C? -C6 alkyl, C3-C6 cycloalkyl, aryl substituted with 0-3 R,; or heteropole substituted with 0-3 R,. R8 is H, or d-C4 alkyl; R9 is H, or C4 alkyl; River is, independently of each occurrence, H, or C C alkyl; or Rio and R4 together with the nitrogen to which R is adhered form a ring containing nitrogen containing 3-6 carbon atoms; R 4 is, independently of each occurrence, alkyl, alkoxy, halo, CF 3, OCF 3, arylalkyloxy substituted with 0-3 R, aryloxy substituted with 0-3 R, aryl substituted with 0-3 Ri, heteroaryl substituted with 0 -3 R, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R, alkylsulfone, phenylsulfone substituted with 0-3 R, alkylsulfonamide, phenylsulfonamide substituted with 0-3 R ,, heteroaryloxy substituted with 0-3 R ,, heteroarylmethyloxy substituted with 0-3 R ,, alkylamido, or arylamido substituted with 0-3 R-i; or two R, adjacent also represent methylenedioxy; n is an integer from 1 to 2; p is an integer from 0 to 2; Y q is an integer from 0 to 4; wherein 1-3 carbon atoms in ring A can optionally be replaced with N.
23. 23. A compound according to claim 22, wherein: R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, or cyano.
24. 24. A compound according to claim 22 or 23, wherein: R2 is aryl substituted with 0-2 R, 4.
25. 25. A compound according to claim 22 or 23, wherein: R 2 is phenyl, fluorophenyl, or difluorophenyl.
26. 26. A compound according to any one of claims 22 to 25, wherein: R3 is H.
27. 27. A compound according to any one of claims 22 to 26, wherein: R is H or methyl.
28. 28. A compound according to any one of claims 22 to 27, wherein: R6 is, independently of each occurrence, H, methyl, ethyl, n-propyl, or isopropyl.
29. 29. A compound according to any one of claims 22 to 28, wherein: R? is H, C, -C6 alkyl, or aryl substituted with 0-3 R,.
30. 30. A compound according to any one of claims 22 to 29, wherein: R8 is H.
31. 31. A compound according to any one of claims 22 to 30, wherein: R9 is H.
32. 32. A compound according to any one of claims 22 to 31, wherein: R, or is H.
33. 33. A compound according to any one of claims 22 to 32, wherein R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, or cyano.
34. 34. A compound according to any one of claims 22 to 33, wherein n is 1.
35. 35. A compound according to any one of claims 22 to 34, wherein p is 0 or 1.
36. 36. A compound of formula III: lll or a pharmaceutically acceptable salt thereof; where: the dotted line between Y and Z represents an optional second link; the dotted line between the two groups R4 represents an optional heterocycle ring of 4 to 6 ring atoms that can be formed between the two groups R, together with the nitrogen through which they are attached; Y is N, C (R6) 2, CR6, or C = 0; Z is O, S (O) p, N, NR ?, CR5, or C (R5) 2; R, is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two R, adjacent also represent methylenedioxy; R2 is aryl substituted with 0-3 R, 4 or heteroaryl substituted with 0-3 R, 4; R3 is H or C, -C4 alkyl; R4 is, independently of each occurrence, H, d-C alkyl, C3-C6 cycloalkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both groups R, together with the nitrogen through which they are adhered, form a heterocyclic ring of 4 to 6 atoms in the ring, where a carbon can be optionally replaced with N, O, S, or SO2, and where any atom in the ring or additional N atom can optionally be substituted with C, -C, F, or CF3 alkyl; R5 is, independently of each occurrence, H, C? -C alkyl, aryl substituted with 0-3 Ru, heteroaryl substituted with 0-3 R,? or cyano; or when two R5 are present, they can form a carbocyclic ring of 3-5 carbons; R6 is, independently of each occurrence, H, alkyl d-C, or cyano; R? is H, C6 alkyl, C3-C6 cycloalkyl, aryl substituted with 0-3 R1? or heteroaryl substituted with 0-3 R, 4; R8 is H, or C, -C4 alkyl; R9 is H, or C, -C alkyl; R10 is, independently of each occurrence, H, or C, -C alkyl; or R, 0 and R4 together with the nitrogen to which R4 is adhered form a nitrogen-containing ring containing 3-6 carbon atoms; R, 4 is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, arylalkyloxy substituted with 0-3 R, aryloxy substituted with 0-3 Ri, aryl substituted with 0-3 R, heteroaryl substituted with 0 -3 R, hydroxy, alkanoyloxy, nitro, cyano, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 Ri, alkylsulfone, phenylsulfone substituted with 0-3 Ri, alkylsulfonamide, phenylsulfonamide substituted with 0-3 Ri, heteroaryloxy substituted with 0-3 R, heteroarylmethyloxy substituted with 0-3 R ^ alkylamido, or arylamido substituted with 0-3 R ,; or two R, adjacent also represent methylenedioxy; n is an integer from 1 to 2; and q is an integer from 0 to 4; wherein 1-3 carbon atoms in ring A can optionally be replaced with N.
37. A compound according to claim 36, wherein: the dotted line between Y and Z represents a second link.
38. A compound according to claim 36, wherein: Y is C (R6) 2, CR6, or C = 0.
39. A compound according to claim 36 or 37, wherein: Z is CR5 or C (R5) 2.
40. 40. A compound according to any one of claims 36 to 39, wherein: Ri is, independently of each occurrence, alkyl, alkoxy, halo, CF3, OCF3, hydroxy, alkanoyloxy, nitro, or cyano.
41. 41. A compound according to any one of claims 36 to 40, wherein: R2 is aryl substituted with 0-2 R, 4.
42. 42. A compound according to any one of claims 36 to 40, wherein: R 2 is phenyl, fluorophenyl, or difluorophenyl.
43. 43. A compound according to any one of claims 36 to 42, wherein: R3 is H.
44. 44. A compound according to any one of claims 36 to 43, wherein: R 4 is H or methyl.
45. 45. A compound according to any one of claims 36 to 44, wherein: R5 is, independently of each occurrence, H, C?-C4 alkyl, aryl substituted with 0-3 R, 4.
46. 46. A compound according to any one of claims 36 to 45, wherein: R5 is, independently of each occurrence, H, methyl, ethyl, n-propyl, isopropyl, aryl substituted with alkoxy, aryl substituted by aryloxy or phenyl substituted by 1-2 halo.
47. 47. A compound according to any one of claims 36 to 46, wherein: R6 is, independently of each occurrence, H, methyl, ethyl, n-propyl, or isopropyl.
48. 48. A compound according to any one of claims 36 to 47, wherein: R? is H, C? -C6 alkyl, or aryl substituted with 0-3 R,.
49. 49. A compound according to any one of claims 36 to 48, wherein: R8 is H.
50. 50. A compound according to any one of claims 36 to 49, wherein: R9 is H.
51. 51. A compound according to any one of claims 36 to 50, wherein: R10 is H.
52. 52. A compound according to any one of claims 36 to 51, wherein: n is 1.
53. 53. A compound according to any one of claims 36 to 52, wherein: q is an integer from 0 to 2.
54. 54. A compound selected from the group consisting of: 1 - [5- (benzyloxy) -1 H -indole-1-l] -3- (methylamino) -1-phenylpropan-2-ol; 1- [4- (benzyloxy) -1 H -indole-1-l] -3- (methylamino) -1-phenylpropan-2-ol; 1 - [6- (benzyloxy) -1 H -indole-1-l] -3- (methylamino) -1-phenylpropan-2-ol; 1- [7- (benzyloxy) -1 H -indole-1 l] -3- (methylamino) -1-phenylpropan-2-ol; 1-. { 5 - [(2-methoxybenzyl) oxy] -1 H-indol-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 1 -. { 5 - [(3-methoxybenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 1 -. { 5 - [(4-methoxybenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 1 -. { 5 - [(2-Chlorobenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 1-. { 5 - [(3-chlorobenzyl) oxy] -1 H-indol-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 1 -. { 5 - [(4-chlorobenzyl) oxy] -1 H -indole-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 1-. { 5 - [(2-Fluorobenzyl) oxy] -1 H-indol-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 1-. { 5 - [(3-Fluorobenzyl) oxy] -1 H-indol-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 1-. { 5 - [(4-Fluorobenzyl) oxy] -1H-indol-1-yl} -3- (methylamino) -1-phenylpropan-2-ol; 3- (methylamino) -1 -. { 5 - [(2-methylbenzyl) oxy] -1 H -indole-1-yl} -1-phenylpropan-2-ol; 3- (methylamino) -1-. { 5 - [(3-methylbenzyl) oxy] -1 H-indol-1-yl} -1-phenylpropan-2-ol; 3- (methylamino) -1-. { 5 - [(4-methylbenzyl) oxy] -1 H-indol-1-yl} -1-phenylpropan-2-ol; 3- (methylamino) -1-phenyl-1 - [5- (1-phenylethoxy) -1 H -indole-1-yl] propan-2-ol; 3- (methylamino) -1-phenyl-1 - [5- (2-phenylethoxy) -1 H -indol-1-yl] propan-2-ol; 3- (methylamino) -1 - (5-phenoxy-1 H-indol-1-yl) -1-phenylpropan-2-ol; 3- (methylamino) -1 - (4-phenoxy-1 H-indol-1-yl) -1-phenylpropan-2-ol; 3- (methylamino) -1-phenyl-1- (4-phenyl-1 H -indol-1-yl) propan-2-ol; 3- (methylamino) -1-phenyl-1- (6-phenyl-1 H -indol-1-yl) propan-2-ol; 3- (methylamino) -1-phenyl-1 - (7-phenyl-1 H-indol-1-yl) propan-2-ol; 1- [5- (benzyloxy) -1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- [5- (benzyloxy) -2,3-dihydro-1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- [5- (benzyloxy) -2,3-dihydro-1 H -indol-1-yl] -3- (methylamino) -1-phenylpropan-2-ol; 5'-chloro-1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indo] -2' (1 'H) -one; 6'-chloro-1 '- [(2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' (1'H) -one; 6'-fluoro -1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' (1 'H) -one; 5'-fluoro-1' - [ 2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2 '(1?) -one; 7'-chloro-1' - [2-hydroxy-3-] (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2 '(1' H) -one; 6'-fluoro-1 '- [1- (3-fluorophenyl) -2-hydroxy -3- (methylamino) propyl] spiro [cyclohexane- 1,3'-indole] -2 '(1?) - one; 3- (methylamino) -1-phenyl-1-spiro [cyclohexane-1,3'-indole] -1 '(2?) - ilpropan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1-. { 3- [2- (trifluoromethoxy) phenyl] -1 H -indole-1-yl-propane-2-ol; 1- (3-fluorophenyl) -1 - [3- (2-isopropoxyphenyl) -1 H -indol-1 -yl] -3- (methylamino) propan-2-ol; 1- (3-fluorophenyl) -1- [3- (4-fluorophenyl) -1 H -indol-1-yl] -3- (methylamino) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1 - [3- (2-phenoxyphenyl) -1 H -indol-1-yl] propan-2-ol; 1- [3- (2,4-difluorophenyl) -1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- [3- (2,5-difluorophenyl) -1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- [3- (2,3-dimethoxyphenyl) -1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- [3- (2,4-dichlorophenyl) -1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- [3- (2-ethoxyphenyl) -1 H -indol-1-yl] -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (7-chloro-5-methoxy-1 H -pyrrolo [2,3-c] pyridin-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (7-chloro-5-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (5-methoxy-1 H -pyrrolo [2,3-c] pyridin-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (3-fluorophenyl) -1- (5-methoxy-1 H -pyrrolo [2,3-c] pyridin-1-yl) -3- (methylamino) propan-2-ol; 3- (methylamino) -1- (5-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -1-phenylpropan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- (5-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) propan-2-ol; 3- (methylamino) -1- (7-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) -1-phenylpropan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- (7-methyl-1 H -pyrrolo [2,3-c] pyridin-1-yl) propan-2-ol; 1- (3,3-diethyl-2,3-dihydro-1 H-indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (6-fluoro-3,3-dimethyl-2,3-dihydro-1 H -indol-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (4-benzyl-3,4-dihydroquinoxalin-1 (2H) -yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (5-fluoro-3,3-dimethyl-2,3-dihydro-1 H -indole-1-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2- ol; 1- (3-fluorophenyl) -3- (methylamino) -1 - [(3 S) -3-methyl-2,3-dihydro-1 H-indol-1-yl] propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1 - [(3R) -3-methyl-2,3-dihydro-1 H -indol-1-yl] propan-2-ol; 1- (3-fluorophenyl) -1- (3-isopropyl-2,3-dihydro-1 H-indol-1-yl) -3- (methylamino) propan-2-ol; 1 - . 1 - (3-et? L-2,3-d? H? Dro-1 H-? Ndol-1 -? L) -1 - (3-fluorofen? L) -3- (met? Lam? No) propan-2-ol, 1 - (3-et? l-2,3-d? h? dro-1 H-? ndol-1 -? l) -3- (met? lam? no) -1-phen ? lpropan-2-ol, 1 - (3-? soprop? l-2,3-d? h? dro-1 H-? ndol-1 -? l) -3- (met? lam? no) -1 -fen? lpropan-2-ol, 3-am? no-1- (3,5-d? fluorophen? l) -1- (3,3-d? met? l-2,3-d? h? dro-1 H-? ndol-1-? l) propan-2-ol, 1- [1- (3,5-d? fluorophen? l) -2-h? drox? -3- (met? lam? no) propyl] -7-fluoro-3,3-d? met? l-1,3-d? h? dro-2H-? ndol-2-one, 5,7-d? fluoro-1- [1- (3-fluorophen? L) -2-h? Drox? -3- (met? Lam? No) prop? L] -3,3-d? Met? L-1, 3-d? H? dro-2H-? ndol-2-one, 1- [1- (3,5-d? fluorophen? l) -2-h? drox? -3- (met? lam? no) prop? l] -3 , 3-d? Met? L-1, 3-d? H? Dro-2H-? Ndol-2-one, 1 - [2-h? Drox? -3- (met? Lam? No) -1 - fen? lprop? l] -1 H-? ndol-5-ol, 1 - [1 - (3-fluorofen? l) -2-h? drox? -3- (met? lam? no) prop? l] -1 H-? Ndol-5-ol 5 '- (benz? Lox?) - 1' - [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] esp ? ro [c-Clohexane-1, 3 '-? ndol] -2' (1?) - one, 5- (benz? lox?) - 1 - [2-h? drox? -3- (met? lam ? no) -1-phenylpropyl] -3,3-d? met? l-1, 3-d? h? dro-2H-? ndol-2-one, and pharmaceutical salts acceptable to these
55. A compound selected from the group consisting of 1- [1- (3-chlorophen? L) -2-h? Drox? -3- (met? Lam? No) prop? L] -7-fluoro-3,3-d? Met? L-1, 3-d? H? Dro- 2 / - / -? Ndol-2-one, 1- (3-chloro-5-fluorophen? L) -1- (1H-? Ndol-1-? L) -3- (met? lam? no) propan-2-ol, 3-chloro-N-. { 1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -1 H-? Ndol-5-? L} -4-methylbenzamide, 3-chloro-N-. { 1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -2,3-d? H? Dro-1H-? Ndol-5-? L} benzamida, 3-chloro-N-. { 1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -1 H-? Ndol-5-? L} benzam? da, N-. { 1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -2,3-d? H? Dro-1 H-? Ndol-5-? L} benzam? da, N-. { 1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -1 H-? Ndol-5-? L} benzam? da, N-. { 1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -2,3-d? H? Dro-1 H-? Ndol-5-? L} c? Clohexanecarboxamide, N-. { 1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L] -1 H-? Ndol-5-? L} c? clohexanocarboxam? da, N- (3-chlorophen? L) -1- [2-h? Drox? -3- (met? Lam? No) -1-phen? Lprop? L]? Ndol? Na-5-carboxam? Da, N- (3-chlorophenyl) -1- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -1H-indole-5-carboxamide; 3- (methylamino) -1- (6-phenoxy-1 H-indol-1-yl) -1-phenylpropan-2-ol; 3- (methylamino) -1- (7-phenoxy-1H-indol-1-yl) -1-phenylpropan-2-ol; 3-amino-1 - [5- (benzyloxy) -1 H -indol-1 -yl] -1-phenylpropan-2-ol; 1- [5- (benzyloxy-1 H-ndol-1-yl] -3- (ethylamino) -1-phenylpropan-2-ol; 1- [5- (benzyloxy 1 H-ndol-1 l] -1- phenyl-3- (propylamino) propan-2-ol; 1- [5- (benzyloxy • 1H ndol-1 l] -3- (isopropylamino) -1-phenylpropan-2-ol; 1- [5- (benzyloxy 1 H ndol-1 l] -3- (dimethylamino) -1-phenylpropan-2-ol; 1- [5- (benzyloxy-1 H ndol-1 l] -3- [ethyl (methyl) amino] -1- phenylpropan-2-ol; 1- [5- (benzyloxy-1 H ndol-1 l] -3- (diethylamino) -1-phenylpropan-2-ol; 1- [5- (benzyloxy-1 H ndol-1 l ] -1-phenyl-3-pyrrolidin-1-ylpropan-2-ol; 1- [5- (benzyloxy-1 H ndol-1 l] -1-phenyl-3-piperidin-1-ylpropan-2-ol; 1- [5- (benzyloxy) -1H-indol-1-yl] -3- (4-methylpiperazin-1-yl) -1-phenylpropan-2-ol 3- (methylamino) -1-phenyl- hydrochloride 1- [5- (pyridin-2-ylmethoxy) -1H-indol-1-yl] propan-2-ol; 3- (methylamino) -1-phenyl-1- [5- (phenylethyl) -1 H- indol-1-yl] propan-2-ol; 3- (methylamino) -1-phenyl-1- [5- (2-phenylethyl) -1 H -indol-1-yl] propan-2-ol; 1 ' - [3-amino-2-hydroxy-1-phenylpropyl] -6'-fluorospiro [cyclohexane-1,3'-indole] -2 '(1?) - one; 1' - [3- (ethylamino) -2 -hydroxy-1-phenylpr opyl] -6'-fluorospiro [cyclohexane-1,3'-indole] -2 '(1' H) -one; 6'-fluoro-1 '- [2-hydroxy-3- (isopropylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' (1?) -one; 6'-fluoro-1 '- [2-hydroxy-1-phenyl-3- (propylamino) propyl] spiro [cyclohexane-1,3'-indole] -2' (1 'H) -one; 1 '- [3-amino-2-hydroxy-1-phenylpropyl] -5'-fluorospiro [cyclohexane-1,3'-indole] -2' (1?) -one; 1 '- [3- (ethylamino) -2-hydroxy-1-phenylpropyl] -5'-fluorospiro [cyclohexane-1,3'-indole] -2' (1 'H) -one; 5'-fluoro-1 '- [2-hydroxy-3- (isopropylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' (1 'H) -one; 5'-fluoro-1 '- [2-hydroxy-1-phenyl-3- (propylamino) propyl] spiro [cyclohexane-1,3'-indole] -2' (1 'H) -one; 1 '- [3- (dimethylamino) -2-hydroxy-1-phenylpropyl] -5'-fluorospiro [cyclohexane-1,3'-indole] - 2 '(1' H) -one; 5'-fluoro-1 '- [2-hydroxy-3-morpholin-4-yl-1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2' (1'H) -one; 1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -5'-methoxyspiro [cyclohexane-1,3'-indole] -2' (1 'H) -one; 1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -6'-methoxyspiro [cyclohexane-1,3'-indole] -2' (1 'H) -one; 1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -2'-oxo-1', 2'-dihydrospiro [cyclohexane-1,3'-indole] -5'-carbonitrile; 1 '- [2-hydroxy-3- (methylamino) -1-phenylpropyl] -2'-oxo-1', 2'-dihydrospiro [cyclohexane-1,3'-indole] -6'-carbonitrile; 4 ', 5'-difluoro-1' - [2-hydroxy-3- (methylamino) -1-phenylpropyl] spiro [cyclohexane-1,3'-indole] -2 '(1' H) -one; 7'-fluoro-1 '- [1 - (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] spiro [cyclohexane-1,3'-indo] -2' (1?) -one; 1 '- [1 - (3-chlorophenyl) -2-hydroxy-3- (methylamino) propyl] -6'-fluorospiro [cyclohexane-1,3'-ndol] -2' (1 'H) -one; 1 - [1 - (3-chloro-5-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one; 1- (3-chloro-5-fluorophenyl) -1- (2,3-dihydro-1 H -indol-1-yl) -3- (methylamino) propan-2-ol; 1- (3-Chloro-5-fluorophenyl) -1- (7-fluoro-3,3-dimethyl-2,3-dihydro-1 H -indol-1-yl) -3- (methylamino) propan-2- ol; 1- (3-chloro-5-fluorophenyl) -1- (3,3-dimethyl-2,3-dihydro-1 H -indol-1-yl) -3- (methylamino) propan-2-ol; 7'-fluoro-1 '- [1 - (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] spiro [cyclobutane-1,3'-ndol] -2' (1'H) -one; 7'-fluoro-1 '- [1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] spiro [cyclopentane-1,3'-indole] -2' (1?) -one; 6-fluoro-1 - [1 - (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -3,3-dimethyl-1,3-dihydro-2H-indol-2-one; 1- (7-fluoro-2,3-dihydro-1 H-indol-1-yl) -3- (methylamino) -1-phenylpropan-2-ol; 4-fluoro-3- [1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1-phenyl-1,3-dihydro-2H-benzimidazol-2-one; 4-fluoro-1- (3-fluorophenyl) -3- [1- (3-fluorophenyl) -2-hydroxy-3- (methylamino) propyl] -1, 3- d? h? dro-2 H -benz? dazol-2-one, 1 - [3-am? no-1 - (3,5-d? fluorophen? l) -2-h? drox? prop? ] -7-fluoro-3,3-d? Met? L-1, 3-d? H? Dro-2H-? Ndol-2-one, and pharmaceutically acceptable salts of these
56. A compound according to claim 54 or 55, wherein said pharmaceutically acceptable salt is hydrochloride
57. A pharmaceutical composition, comprising to at least one compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, and b at least one pharmaceutically acceptable carrier
58. A method for treating or preventing an improved condition by the monoamine retake in a subject in need thereof, comprising the step of administering to said subject an effective amount of a compound according to any one of claims 1 to 56, or pharmaceutically acceptable salt thereof
59. A method according to claim 58, wherein said condition improved by the monoamine retake is selected from the group consisting of vasomotopic symptoms, sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders, and combination of these
60. A method according to claim 59, wherein said condition improved by the monoamine retake was selects from the group consisting of severe depressive disorder, vasomotor symptoms, imperious and stress urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combination of these.
61. 61. A method for treating or preventing at least one vasomotor symptom in a subject in need thereof, comprising the stage of: administering to said subject an effective amount of a compound according to any one of claims 1 to 56, or pharmaceutically acceptable salt thereof.
62. 62. A method according to claim 61, wherein said vasomotor symptom is suffocating.
63. 63. A method according to claim 62, wherein said subject is a human.
64. 64. A method according to claim 63, wherein said human is a female.
65. 65. A method according to claim 64, wherein said female is pre-menopausal.
66. 66. A method according to claim 64, wherein said female is peri-menopausal.
67. 67. A method according to claim 64, wherein said female is post-menopausal.
68. 68. A method according to claim 63, wherein said human is a man.
69. 69. A method according to claim 68, wherein said man is naturally, chemically or surgically andropáusico.
70. 70. A method for treating or preventing at least one depression disorder in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound according to any one of claims 1 to 56, or pharmaceutically acceptable salt thereof.
71. 71. A method according to claim 70, wherein said depression disorder is severe depressive disorder, anxiety, sleep disturbance, or social phobia.
72. 72. A method according to claim 71, wherein said subject is a human.
73. 73. A method for treating or preventing at least one sexual dysfunction in a subject in need of these, comprising the stage of: administering to said subject an effective amount of a compound according to any one of claims 1 to 56, or pharmaceutically acceptable salt thereof.
74. 74. A method according to claim 73, wherein said sexual dysfunction is related to the desire or is related to the excitement.
75. 75. A method according to claim 73, wherein said subject is a human.
76. 76. A method for treating or preventing pain in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound according to any one of claims 1 to 56, or pharmaceutically acceptable salt thereof.
77. 77. A method according to claim 76, wherein said pain is acute centralized pain, is acute peripheral pain, or a combination of these.
78. 78. A method according to claim 76, wherein said pain is chronic centralized pain, chronic peripheral pain, or a combination of these.
79. 79. A method according to claim 76, wherein said pain is neuropathic pain, visceral pain, musculoskeletal pain, bone pain, pain from cancer, pain from inflammation, or a combination of these.
80. 80. A method according to claim 79, wherein said neuropathic pain is associated with diabetes, post-traumatic pain by amputation, lumbar pain, cancer, chemical damage, toxins, major surgery, peripheral nerve damage due to compression due to traumatic injury, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, sympathetic reflex dystrophy, casualgia, thalamic syndrome, avulsion of the nerve root, sympathetic reflex dystrophy or post-thoracotomy pain, nutritional deficiencies, viral infection , bacterial infection, metastatic infiltration, painful adiposis, burns, conditions selected from the group consisting of central pain disorder related to conditions selected from the group consisting of thalamic disorders, and combinations of these.
81. 81. A method according to claim 79, wherein said visceral pain is associated with ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, (arthralgias) rheumatology, tumors, gastritis, pancreatitis, organ infections, disorders of the biliary tract, and combinations of these.
82. 82. A method according to claim 76, wherein said pain is specific pain to the females.
83. 83. A method according to claim 82, wherein said subject is human.
84. 84. A method for treating or preventing gastrointestinal or genitourinary disorder in a subject in need thereof comprises the step of: administering to said subject an effective amount of a compound according to any one of claims 1 to 56, or pharmaceutically acceptable salt thereof.
85. 85. A method according to claim 84, wherein said disorder is stress incontinence or imperious urinary incontinence.
86. 86. A method according to claim 84, wherein said subject is human.
87. 87. A method for treating or preventing chronic fatigue syndrome in a subject in need thereof comprises the stage of: administering to said subject an effective amount of a compound according to any one of claims 1 to 56, or pharmaceutically acceptable salt thereof.
88. 88. A method according to claim 87, wherein said subject is human. A method to treat or prevent fibromyalgia syndrome in a subject in need of this, comprises the stage of: administering to said subject an effective amount of a compound according to any one of claims 1 to 56, or pharmaceutically acceptable salt thereof. A method according to claim 89, wherein said subject is human. A method to treat or prevent schizophrenia in a subject in need thereof, comprises the stage of: administering to said subject an effective amount of a compound according to any one of claims 1 to 56, or pharmaceutically acceptable salt thereof. A method according to claim 91, wherein said subject is human. Use of a compound according to any one of claims 1 to 56 in the manufacture of a medicament for administration in a method according to any one of claims 58 to 92.